Textbook of Natural Medicine, Third Edition, Two Volumen Set

Contributors Kathy Abascal, BS, JD, RH(AHG) Vashon, Washington Steve Austin, ND Nutrition Editor Emerson Ecologics Update Portland, Oregon JeffreyGlen Baker, ND Health Science Liaison Health Science Education Great Smokies Diagnostic Lab Asheville, North Carolina Stephen Barrie, ND Malibu, California Robert Barry, ND Seattle, Washington Peter W. Bennett, ND,LAC Private Practice Victoria, British Columbia Jeffrey S. Bland, PhD, FACN, CNS President and Chief Science Officer Chairman Institute for Functional Medicine Metagenics, Inc. Gig Harbor, Washington Peter B. Bongiomo, ND, Dip1 Ac InnerSourceHealth.com New York, New York JenniferL. Booker, ND Private Practice Olympia, Washington Dennis Bourdette, MD Chairman and Roy and Eulalia Swank Research Professor Neurology Oregon Health and Science University Portland, Oregon

J. Alexander Bralley, PhD Chief Executive Officer Metametrix Clinical Laboratory Norcross, Georgia

Donald J. Brown, ND Director of Natural Products Research Consultants Seattle, Washington Car10 Calabrese, ND, MPH Research Professor National College of Naturopathic Medicine; Senior Investigator Helfgott Research Institute Portland, Oregon

Qiang Cao, LAC,OMD, ND Professor School of Acupuncture and Oriental Medicine Bastyr University; Wedgwood Acupuncture & Botanical Medicine Seattle, Washington Leon Chaitow, ND, DO Register of Osteopaths British Osteopathic Asssociation; Honorary Fellow School of Integrated Health University of Westminister, London London, United Kingdom Anthony J. Cichoke, DC,PhD, DACBN Author; Fellow of the International Association for the Study of Pain; American ChiropracticAssociation; Medical Enzyme Research Society; Nationally Syndicated Radio Show, "The Dr. Enzyme Self-HELP Show" Portland, Oregon George Wm. Cody, JD, MA InterdisciplinaryArts and Sciences University of Washington Bothell, Washington

Randall S. Bradley, ND Private Practice Omaha, Nebraska vii

Kevin L. Conroy, ND Faculty, Assistant Professor, Supervisor Immune Wellness Center Naturopathic Medicine Bastyr University Kenmore, Washington Walter J. Crinnion, ND Chair Department of Environmental Medicine and Public Health National College of Naturopathic Medicine Tempe, Arizona

Heidi B. Hascall, MA Doctoral Candidate Political Science University of Oregon Eugene, Oregon Jason A. Hawrelak, BNat (Hons), PhDc School of Natural and Complementary Medicine Southern Cross University; Australian Centre for Complementary Medicine Education and Research (a joint venture of the University of Queensland and Southern Cross University) Lismore, Australia

T.Michael Culp, MA, ND Integrative Health Solutions, Ltd. London, United Kingdom Peter J. D’Adamo, ND The DAdamo Clinic Wilton, Connecticut Rhonda Dorren, BSc Pharm Private Practice Calgary, Alberta Cathryn M. Flanagan, ND Private Practice Old Saybrook, Connecticut

Alan R. Gaby, MD Author, lecturer Carlisle, Pennsylvania Leo Galland, MD Director Foundation for Integrated Medicine New York, New York

Alan Goldhamer, DC Director TrueNorth Health Rohnert Park, California Mark D. Groven, ND Private Practice Seattle, Washington Patrick Hanaway, MD Medical Director Great Smokies Diagnostic Lab Asheville, North Carolina

Kathleen A. Head, ND Editor-in-Chief Alternative Medicine Review; Technical Advisor Thorne Research Sandpoint, Idaho Gina Honeyman-Lowe, DC Advisory Board for Fibromyalgia Research Foundation Specialty, Metabolic Rehabilitation Boulder, Colorado

Ton Hudson, ND Professor National College of Naturopathic Medicine; Clinical Professor Southwest College of Naturopathic Medicine Portland, Oregon Corene Humphreys, BHSc, ND, DipMedHerb, DipHom South Pacific Association of Natural Therapists; New Zealand Charter of Health Practitioners; Medical Education Great Smokies Diagnostic Lab Asheville, North Carolina Mary James, ND, AANP Senior Staff Physician Health Science Liason; Editorial Review Board Alternative Medicine Review; Medical Education Great Smokies Diagnostic Lab Asheville, North Carolina Herb Joiner-Bey, ND Adjunct Professor Naturopathic Medicine Bastyr University Seattle, Washington

Contributors Julie S.Jurenka, BS, MT(ASCP) Technical Research Assistant Contributor for Alternative Medicine Review Sagle, Idaho Gregory S. Kelly, ND Medical Director Signature Health Partners VP Healthcoach Systems Santa Barbara, California Parris M. Kidd, PhD Director PMK Biomedical El Cerrito, California Lori Kimata, ND, HS NP,AANP, ACNO Midwife Sacred Healing Arts Honolulu and Haleiwa, Hawaii Richard Kitaeff, MA, MD, Dip1 Ac, LAC Naturopathic Physician and Acupuncturist Director New Health Medical Center; Staff Acupuncturist Northwest Hospital (Seattle); Edmonds, Washington

Private Practice Seattle, Washington Pina LoGiudice, ND, LAC Medical Director InnerSourceHealth.com Syosset, New York Richard S. Lord, PhD Director Metametrix Clinical Laboratory Science & Education Norcross, Georgia John C. Lowe, MA, DC Director of Research Fibromyalgia Research Foundation Boulder, Colorado Bobbi Lutack, MS, ND Private Practice Evergreen Center for Integrative Medicine Seattle, Washington Michael R. Lyon, BSc, MD Medical & Research Director Canadian Center for Functional Medicine Coquitlum, British Columbia

Thomas A. Kruzel, MT, ND Scottsdale Natural Medicine & Healing Clinic, LLC Scottsdale, Arizona

Stephen P. Markus, MD Creekside Center for Integrative Medicine Bellevue, Washington

Elizabeth Kutter, PhD Head Laboratory of Phage Biology Member of the Faculty in Biophysics Scientific Inquiry The Evergreen State College Olympia, Washington

Morgan Martin, ND, LM Chair Naturopathic Midwifery Department Bastyr University Kenmore, Washington

Andrew Lange, BSc, ND Private Practice Boulder, Colorado

Buck Levin, PhD, RD Adjunct Associate Professor of Nutrition Bastyr University Kenmore, Washington Douglas C.Lewis, ND Former Chair Department of Physical Medicine School of Naturopathic Medicine Bastyr University

Robert M. Martinez, DC,ND Private Practice Kirkland, Washington Steven C. Milkis, ND Clinical Faculty Bastyr University Seattle, Washington Alan L. Miller, ND Technical Advisor Thorne Research, Inc.; Senior Editor Alternative Medicine Review Sandpoint, Idaho

Laurie K. Mischley, ND Private Practioner University Health Clinic Specialty Care & Research Center; Adjunct Faculty Bastyr University Seattle, Washington Stephen €! Myers, PhD, BMed, ND Professor, Director Australian Centre for Complementary Medicine Education and Research (a joint venture of the University of Queensland and Southern Cross University) Lismore, Australia Mark Harrison Nolting, ND, LAC Naturopathic Physician; Acupuncturist; Associate Medical Director American WholeHealth Inc. Edmonds, Washington Lara Pizzomo, MA (Divinity), MA (Literature),LMT Senior Medical Editor Salugenecists, Inc. Seattle, Washington Dirk Wm. Powell, ND Faculty Bastyr University; Private Practioner Kent, Washington Peter T.Pugliese, MD President Peter T. Pugliese and Associates Reading, Pennsylvania David W.Quig, PhD Vice President Scientific Support Doctor’s Data Inc. St. Charles, Illinois Paul Reilly, ND, LAC Adjunct Faculty Bastyr University Kenmore, Washington Corey Resnick, ND Integrative Therapeutics Inc. Lake Oswego, Oregon

Nancy Roberts, ND Sequoia Naturopathic Seattle, Washington

Sally J. Rockwell, PhD, CCN Owner Diet Designs; Private Practice Seattle, Washington Robert A. Ronzio, PhD Director of Research and Development Q Health Resorts, Inc. McMinnville, Oregon Sam RUSSO,ND, MSAc President Vermont Association of Naturopathic Physicians; Private Practice Winooski, Vermont Trevor K. Salloum, ND Private Practice Kelowna, British Columbia Alexander G. Schauss, PhD, FACN Director National and Medicinal Products; Research AIBMR Life Sciences, Inc. Puyallup, Washington Michael A. Schmidt, PhD Ames Associate NASA Ames Research Center Moffett Field, California Lynne Shinto, ND Assistant Professor Department of Neurology; Assistant Professor Ob/G yn-Integrative Medicine Division Center for Women’s Health Oregon Health & Science University Portland, Oregon Pamela Snider, ND Consortium Director Academic Consortium for Complementary and Alternative Healthcare; Vice President, Board of Directors Integrated Health Care Policy Consortium; Faculty, Former Associate Dean College of Naturopathic Medicine Bastyr University Seattle, Washington

Contributors

Virender Sodhi, MD(Ayurveda),ND Ayurvedic and Naturopathic Clinic Bellevue, Washington Nick Soloway, LMT, DC,LAC Private Practice; Faculty Big Sky Somatic Institute Helena, Montana Leanna J. Standish, ND, PhD, LAC Research Professor Bastyr University Kenmore, Washington

R.W. Watkins, MD, MPH, FAAFP Associate Clinical Professor Department of Family Medicine UNC Chapel Hill School of Medicine Chapel Hill, North Carolina The Wanek Medical Center, Institute for Functional Medicine Greensboro, North Carolina

Terry Willard, CIH, PhD President, Clinical Herbalist Herbology Wild Rose College Calgary, Alberta

Nancy Sudak, MD Clinic Physician Northland Health and Wellness; Clinical Instructor and Medical Director UMD Quickcare Clinic, University of Minnesota; Member Board of Directors American Board of Holistic Medicine; Member Textbook Faculty Institute for Functional Medicine Duluth, Minnesota

Michelle Won& BS Executive Director Hawaii State Consortium for Integrative Healthcare Honolulu, Hawaii

Sherry Torkos, RPh Pharmacist Health Author Ontario, Canada

Jared Zeff, ND, LAC Professor of Naturopathic Medicine Adjunct Professory Naturopathic Medicine Bastyr University Bathel, Washington

Alex Vasquez, DC, ND Private Practice Houston, Texas Carl P.Verdon, PhD Research Chemist Centers for Disease Control and Prevention Inorganic Toxicology and Nutrition Branch National Center for Environmental Health Centers for Disease Control and Prevention Atlanta, Georgia Aristo Vojdani, PhD, MT Director Immunosciences Lab, Inc. Beverly Hills, California

Eric L. Yarnell, ND, RH(AHG) President Botanical Medicine Academy; Adjunct Professor Department of Botanical Medicine Bastyr University Seattle, Washington

Ira D. Zunin, MD, MPH, MBA Medical Director Manakai 0 Malama Integrative Healthcare Group and Rehabilitation Center; President Hawaii State Consortium for Integrative Healthcare Honolulu, Hawaii

Preface The scientific support for the philosophical and therapeutic foundation of natural medicine has evolved remarkably over the past 35 years. Concepts that were once considered ”quaint” at best are now recognized as fundamental to good health and the prevention and treatment of disease. This textbook, with its roughly 10,000 citations to peer-reviewed research literature, provides well-documented standards of practice for natural medicine. Based on a sound combination of philosophy and clinical studies, this work provides the astute practitioner with a reliable informational resource to provide health care that identifies and controls the underlying causes of disease, is supportive of the body’s own healing processes, and is considerate of each patient’s unique biochemistry. This textbook is composed of six sections, each focused on a fundamental aspect of the practice of natural medicine. ”Philosophy of Natural Medicine” covers the history and conceptual basis of natural medicine. “Supplementary Diagnostic Procedures” provides a primer on diagnostic procedures not commonly taught

in conventional medical schools. Diet analysis, food allergy testing, immune function assessment, fatty acid profiling, and hair mineral analysis are examples of these analytical procedures. The next section, ”Therapeutic Modalities,” provides a descriptive, practical, scientific, and historical review of the common modalities of natural medicine, including botanical medicine, nutritional therapy, therapeutic fasting, exercise therapy, hydrotherapy, counseling, acupuncture, homeopathy, and soft tissue manipulation. “Syndromes and Special Topics” considers underlying issues relevant to many diseases. “Pharmacology of Natural Medicines” covers the pharmacognosy, pharmacology, and clinical indications for the most commonly prescribed botanical medicines, special nutrients, and other natural agents. Finally, ”Specific Health Problems” provides an in-depth natural medicine approach to more than 70 specific diseases and conditions. The comprehensive therapeutic rationales are well documented and based on the pathophysiology and causes of each condition.

Joe Pizzorno Michael Murray Seattle 2005

xiii

Acknowledgments We would like to thank Inta Ozols, the original commissioning editor; and the staff at Elsevier (Kellie White, Kim Fons, Trish Tannian, Kristine Feeherty, Paula Ruckenbrod, and JulieBurchett).

Philosophy of Natural Medicine Nature is doing her best each monienf to nuke us well. She existsfor no other end. Do not resist. With the least inclination to be well, we -Henry David Thoreau should not be sick.

1 Eastem Origins of Integrative Medicine and Modem Applications 3 2 Functional Medicine in Natural Medicine 13 3 A Hierarchy of Healing: The Therapeutic Order 27 4 The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing 41 5 The History of Naturopathic Medicine, Part 11: Decline 6 7 8 9 10

and Rejuvenation-Politics and Professionalization 67 Philosophy of Naturopathic Medicine 79 Placebo and the Power to Heal 89 Positive Mental Attitude 111 Research in Natural Medicine 117 Women in the History of Medicine 127

One of the features of the various schools of natural medicine that differentiate them from conventional (allopathic) medicine is their strong philosophical foundation. The basic philosophical premise of naturopathic medicine, for example, is that there is an inherent healing power in nature and in every human being. We believe that a primary role of the physician is to bring out or enhance this innate healing power within his or her patients. In many ways, thiswas the most difficult section of the textbook to write, as no comprehensive history of the social, political, and philosophical development of naturopathic medicine had ever been written, and even in the halcyon years of the 1920s and 1930s, the profession was never able to agree upon a concise philosophy. This situation has now changed. We provide here a well-documented chapter detailing the roots of American naturopathy. After a century of maturation, the profession has now widely agreed to a comprehensive definition, set of principles, and system of case analysis that

provide a systematic guide for the application of these concepts in a clinical setting. The seven fundamental principles of naturopathic medicine are as follows: 1. The healing power of nature (uis rnedicutrix nntrirue) 2. First do no harm (priniuni non nocere) 3. Find the cause (tolle causarn) 4. Treat the whole person 5. Preventive medicine 6. Wellness 7. Doctor as teacher

These principles translate into the following questions the practitioner applies when analyzing a case: What is the first cause; what is contributing now? How is the body trying to heal itself? What is the minimum level of intervention needed to facilitate the self-healing process? What are the patient’s underlying functional weaknesses? What education does the patient need to understand why he or she is sick and how to become healthier? How does the patient’s physical disease relate to his or her psychological and spiritual health? We have further expanded on the philosophical basis of naturopathic medicine by having these concepts addressed by several authors whose backgrounds allow each of them a unique and, we believe, complementary insight into some of the fundamental questions of the goals of health care. Although the dominant school of medicine has essentially ignored these issues, we believe that the true physician cannot function without a sound philosophical basis to guide his or her actions. Without a more than superficial understanding of health and disease, the physician is more likely to function as a technician, temporarily alleviating symptoms while allowing the real disease to progress past the point of recovery.

1

Eastern Origins of Integrative Medicine and Modern Applications Ira D. Zunin,MD, MPH Michelle Wong, BS CHAPTER CONTENTS Introduction 3 Terminology 3 Comparison of Eastern and Western Medicine: Origins and Philosophies 4 Historical Origins 4 Philosophies in Contrast 5 Overview and Comparison of Eastern Traditions 5

INTRODUCTION Emaho, the Tibetan word for ”wondrous,” aptly describes the history of healing. The healing art of medicine is neither fixed in one theory of disease nor has its origins in a single body of perceptions. Its roots reveal rich and fascinating strands to its heritage. Each strand has developed potent theories and recommendations that inform prevention, illness, and treatment. These differences profoundly influence the vision and values among the members of a given culture-how to live well and how to address illness and health. Specifically, the contrast in Eastern and Western approaches have been like strangers from afar, now newly becoming aware of each other and saying hello in an emerging field called ”integrative medicine.” Each has its advantages and limitations. Recognizing and skillfully combining the best of both approaches is an ongoing challenge and a noteworthy, positive advance for humanity. Only in the past 10 years has medicine in the West begun to diligently examine and include indigenous traditions in medical practice. The term integrative medicine emerged in the early 1990s to describe an evolving paradigm shift in modern medicine. Integrative medicine holds that rather than using only one medical system, Reader’s note: An essentially identical version of this chapter appeared in integrative Medicine: A Clinician’s Journal (VZ.2) and is reprinted with approval from InnoVision Communications.

Modern Applications:The Age of Integration 8 The Birth and Evolution of a Medical Profession in the United States: Complementary and Alternative Medicine Professions 9 Tools for Integration 10

drawing from multiple traditions clearly better serves the public. Integrative medicine in the West is the first movement this century to examine indigenous healing modalities with scientific rigor, while retaining respect for their history and culture. Given the current dominance of modern medicine rooted in science and replicable evidence, this movement, with its emphasis on quality research evidence for safety and efficacy of indigenous modalities, has furthered acceptance in the West and spawned a resurgence of interest in their countries of origin. To date, Eastem healing traditions have made some of the greatest advances in integration with modern medicine. This chapter seeks to find the balance between respect for long-standing healing traditions and submitting these traditional methods to critical examination in order to procure the most appropriate and effective practice of indigenous traditions in modem medicine. To understand the issues implicit to integration and why this transition in medicine is occurring now, the reader should review the historical origins of Eastern and Western traditions, understand the contrast in philosophies, and examine in greater detail the landscape of the Eastern healing traditions.

Terminology First, a disclaimer to the reader on terminology is necessary. Because of its newness and rapid growth, terminology used to define this emerging field has evolved 3

quickly and consensus on this terminology has not yet been reached. Consequently, semantic confusion is rampant. Definitions and meanings change with the times and with shifts in paradigm; as another shift in paradigm approaches with the "age of integration," meanings are expected to adjust accordingly once again. Current terms often connote power hierarchies or ethnocentric judgment. For the sake of discussion, this chapter uses terms appropriate to this specific period in history. For example, "modern medicine" is used to describe the most conventional medicine practiced and determined by the evolving scientific method, and "complementary and alternative medicine" (CAM) is used to describe less conventional practices that are not yet understood through the scientific method. Similarly, theories on medicine or health generally fall into two frameworks named by convention: Western, originating from Greco-Roman philosophy, and Eastern, encompassing Asian-Pacific philosophy. The very definition of "modern" medicine implies fluidity, and it is fitting to use such terminology during this period of expanding medical boundaries.

COMPARISON OF EASTERN AND WESTERN MEDICINE: ORIGINS AND PHILOSOPHIES Historical Origins The world's major healing traditions are commonly categorized as Eastem, influenced by Asian-Pacific philosophy, or Western, molded by Greco-Roman philosophy, and later, the scientific revolution of the sixteenth and seventeenth centuries. The foundation of Eastern healing traditions inextricably embraces the philosophies of early Eastern thought, those of Buddhism, Taoism, and Hinduism, and of their founders. These philosophies still provide the underpinnings for contemporary Eastern cultures, allowing Eastern indigenous healing traditions to maintain widespread acceptance and practice. Several unique but related traditions developed in the East before the Christian era and are still heavily practiced today as discrete systems. These include Chinese Medicine, Ayurveda (traditional Indian medicine), and Tbetan Medicine. Other Eastem traditions enjoy moderate practice in their indigenous areas, including Persian Medicine, medicine as set forth in the Dead Sea Scrolls, and folk shamanism and animism. The origins, philosophies, and practice of Chinese Medicine, Ayurveda, and Tibetan Medicine are closely examined and compared later in this chapter, along with their current transformations in the West. In contrast, modem medicine in the West has developed quite independently from religion. It was, and continues to be, shaped by science. Modem scientific

thought evolved from the Greek philosophers beginning with Euclid around 300 BC and later Plato, Socrates, and Aristotle. These men used reasoning and deduction to develop theories to espouse what they deemed absolute truth. The mathematic theories of these Greek philosophers set the foundation for Renaissance scientists more than 1500 years later, who developed the "scientific method. " During the sixteenth and seventeenth centuries, Copernicus, Galileo, Bacon, Descartes, and Newton continued to reform modem scientific thought in the West. Early in the seventeenth century, Descartes crystallized the objective notion that "knowledge is seeing." Furthermore, Descartes proposed that the mind clearly views ideas or objects to discern knowledge. Through the mind's processes of reason and deduction, both ideas and knowledge are objectified and this forms reality..' The philosophy of reductionism is important because it was based on the notion of separation of mind and body. Modern thought, stemming from the Cartesian theory of dualism, states: "Nothing about the body, neither imagination nor emotion nor perception nor any detail of the biological nature of the body, need be known in order to understand the nature of the mind."2 Descartes' philosophy went further to embrace reductionism, which conceived that all aspects of life could be reduced to smaller basic features or "simple natures" of reality. He contended that mathematics (rational thought) or direct observation (empiricism) expresses the basic fundamental structure of all other knowledge? These principles of Descartes and his contemporaries, along with the foundation of Greek philosophy, set forth the scientific method, which describes a system of thought rather than a set of formal procedures. This constant process of empirical observation, logical reasoning, and skepticism to discern knowledge, which differs from the Greeks as it does not claim to find ultimate truths, is stiU the thought process used to validate modem medicine. The scientific method was not a mainstay of modem medicine until the turn of the twentieth century. The Flexner Report (1910) standardized medical education through the basic sciences, and with World War I, shifted the focsus of medical care toward cures for acute conditions that were defined with the precision of the scientific method. Yet the definition of "modern" medicine experienced further radical shifts in the nineteenth and twentieth centuries. It changed in dynamic ways from heroic medicine, which "cured," for example, by bloodletting and purging, to quackery movements spurred by the Romantic era, and finally to scientific "biomedicine" in the midtwentieth century. In the early nineteenth century, modem medicine was pluralistic in nature as "professional care was mostly provided by botanical healers and midwives, supplemented by surgeons,

barber-surgeons, apothecaries, and ’uncounted cancer doctors, bonesetters, inoculators, abortionists, and sellers of nostrums.’ ”4 During much of this same period, the profession of naturopathy flourished to the benefit of many. At this time, the medical profession was still in its early stages in the United States. By the early to midtwentieth century, medicine became much more narrowly defined through the scientific method. In the past 10 years, however, the United States has experienced another shift, arguably a shift again to the medical pluralism from more than 100 years ago. This raises an important question: Is this merely historical pattern or the birth of a unique era? If one defines science as an ongoing methodical study of the world in order to discern knowledge, then it must inherently evolve and expand over time. Therefore the definition of science should continue to expand, beyond objectivity, toward phenomena that have not yet been explicitly defined or successfully examined by scientific inquiry. The application of theses ideas in modem medicine is thus evolutionary. If the culture of medicine is experiencing yet another paradigm shift, that culture will necessarily move beyond the older ethos of the scientific method that defined its previous paradigm. Master Hong succinctly comments on this point, ”What gong] master possesses isn’t magic. It is just this [Qi In the twentyscience that has not yet been e~amined.”~ first century, the culture of medicine is once again embracing its diverse options for health care, shifting yet again toward pluralism, and reflecting the social landscape of a new generation. What is happening invites all healers to enlarge their ideas of disease and health and to welcome an expanded and deeper perspective.

Philosophies in Contrast ”Viva la difference.” The differences in Eastern and Western medical traditions stem directly from their foundational differences in world views. Judith Farqhuar describes these essential differences in world views as ”the differencebetween a world of fixed objects and a world of transforming effects. . . . Like the solid inertial world of modern natural science traditions, the . . . transformative world of Chinese medicine seems to exist prior to all argument, observation, and intervention. Perhaps with a certain discomfort, Western readers must acknowledge that ’their’ abstractions about such things make as much sense as ’ours.’ “6 One of the most obvious and far reaching differences between Eastern and Western medical traditions is the concept of inter- and intrapersonal relationships. Stemming from the Socratic model and Cartesian dualism, Western medicine heavily delineates between mind and body, between doctor and patient, and between healthy and diseased. On the other hand, medicine originating in the East finds little distinction in these areas. Instead,

it views continuity and balance as vital to health. Illness is defined by imbalances of patterns that should naturally be in harmony. Multiple aspects of the being including the mind, body, and spirit are integral to this harmony. In contrast, illness in modern Western medicine is described by a specific pathology, caused by discrete foreign pollutants and often cured by another foreign element. In its extreme, the patient is an accident attached to the disease under treatment. Unlike Eastern healing traditions, in which the religions and philosophies of Buddhism, Taoism, and Hinduism hold such a foundational role, modern Western medicine, developed from reductionism, always separates religion and science. Instead, Western medicine is mainly guided by science in which truth is derived from the empirically correct interpretation. The intuitive experiences of others are often discounted rather than being incorporated into one’s knowledge base, because “that is not science, that is faith.”7In the Western philosophical framework, faith (that which cannot be proven through the scientific method) is seen as of lesser value than knowledge gained by direct experience. The fundamental concepts of Eastern healing traditions are deeply embedded in the philosophies of their cultures. Consequently, they are perceptions, ideas, and values shared by most society members. Although health is integral to one’s everyday life in Eastern societies, it is only one part of Western society. Likewise, health is defined in the East as a unity of individual, environmental, and societal factors. Although the Western definition of health has moved toward encompassing physical, mental, social, and spiritual arenas, each is still defined as a separate entity, and theories of pathology still drive mechanism perceptions of health disorders. These distinct differences in vision and approach shape the patient-doctor relationship. In Eastern traditions, the unique balance of the factors cited earlier is critical to diagnosis and treatment of a patient’s disharmony rather than disease. Physicians in Western medicine look beyond the patient-doctor relationship to an external body of knowledge to diagnose and treat, guided by categories of symptoms. A general comparison of Eastern and Western concepts in regard to health is shown in Table 1-1.

Overview and Comparison of Eastern Traditions As mentioned, while several indigenous healing traditions in the East have been preserved, Chinese, Ayurvedic, and Tibetan Medicine remain among the most heavily practiced traditions in their respective regions. All three traditions stem largely from similar philosophical foundations; thus in all, health and disease

Comparison of Western and Eastern concepts Western

Eastern

World views

Reductionist

Holistic

Mechanism of disorder

Pathologic mechanism

Imbalance of harmonies

Foundational structure

Logic, mathematics

Eastern religions and philosophies

Patientdoctor relationship

Access external body of knowledge for diagnosis and treatment

Unique balance critical to diagnosis and treatment

~~

Comparison of Tibetan, Ayurvedic, and Chinese medicine Tibetan

Ayurveda

Chinese

Defined by balance or imbalance of states

Health and disease

3 humors: wind, bile, phlegm

3 humors (doshas): air, fire, water principles

Qi, blood, Shen

Principle of opposites

Hot/cold

Hot/cold

Yinlyang

5 Elements

Air, water, fire, ether, earth

Ether, water, fire, earth, air

Air, water, fire, metal, earth

Fundamental textures

Diagnostics Treatment modalities

Origin Religious Text Recent history (post-Newtonian, within past century)

Pulse (most important), urine, tongue, morphology Behavioral (lifestyle, meditation), diet, herbals, external treatment (acupuncture, massage)

Dietary alterations, yoga, exercise, herbal formulas, surgical techniques

Acupuncture, herbals, Qi gong

Intimately related to Buddhist philosophy but stands on its own

Intimately related to Hindu philosophy but stands on its own

No formal tie to Taoism or Buddhism

Gyu-zhib.il(

Rig Veda (second millennium BC) 800 BC

2598 BC Nei Jing

Enjoyed the greatest continuity

Transformation by Cultural Revolution

ffiyud-bzhi)

Transformation by Chinese invasion

are seen as inextricably interrelated. They play integral parts in the delicate balance of harmony and disharmony. What creates and influences these patterns of harmony are the intricate details that define them as unique systems of healing. Table 1-2 provides a comparison of these three traditions. Several other healing traditions have developed in the East, which have encountered more moderate levels of practice in their indigenous regions and abroad. These include Persian Medicine, traditions from the Dead Sea Scrolls, shamanism, and animism. Although there are numerous detailed differences,they, too, share basic philosophical similarities with the other Eastern traditions.

Origins Tibetan Medicine and Ayurvedic Medicine have similar historical origins, as Ayurveda is the root of Tibetan Medicine. Ayurvedic origins are found as early as the second millennium BC in the Rig Veda, with its second classical stage in the Brahmanical period in 800 BC, where it continued as an unbroken lineage until the

Moslem conquest of India in the thirteenth century. During that time in the sixth century BC, the historical Buddha, Shakyamuni, was born in India, and after achieving Enlightenmentunder a Bodhi tree in Bodhgaya and delivering the teachings of the Four Noble Truths, Buddhism was born.* The Tibetan medical tradition offers that the Buddha, often called the “Great Physician,” taught the medical texts himself, including the Gyu-zhi, the most important Tibetan medical text. The Sanskrit version of the Gyu-zhi, however, was probably not written until around 400 AD.* While some scholars may debate whether the historical Buddha’s teachings are the precise origin of Tibetan and thus Ayurvedic medicine, Buddhism’s influence on these two healing traditions is unquestionable. Like Ayurveda, the origins of Chinese medicine date back to the second millennium BC, to the era of the great Yellow Emperor, Huangdi (-2698-2598 BC). The classic ‘Lineage refers to the descendants of a common ancestor considered to be the founder of the line.

Eastern Origins of Integrative Medicine and Modern Applications

medical text written during his reign is Huangdi Nei Jing (The Yellow Emperor‘s Inner Cannon). Yet perhaps of more influence to the systematic and well-structured Chinese medicine known today is the Nun Jing (The Classic of D~ficultIssues), written around the first or second century AD. As Harrison notes in the chapter on Acupuncture in this edition, the Nei Jing deals more with ”demonological medicine and religious healing,” while the Nan ling develops Chinese medicine as an original system, with well-defined and organized principles, diagnostics, and therapeutics? Chinese medicine has also witnessed various transformations, most notably its recent evolution into Traditional Chinese Medicine (TCM), the modem form of Chinese medicine practiced in China and worldwide. Influenced by the advent of modem science, Chinese medicine was required during the 1950s to establish increased legitimacy in the face of the new Marxist ideology, which emphasized “natural science” and delegitimized Confucian influences. Its decline began as early as 1914, when the minister of education announced discontinued use of traditional medicine. Several changes to traditional Chinese medicine followed, which stifled its growth. The previous pluralism of classic medical readings merged into Chung-I, which described a general practice and theory of Chinese medicine. Initially, the People’s Republic of China (PRC) denounced folk, demonic, and Buddhist temple medicine.1° However, in 1951, Mao-Tse-Tong revived and then canonized portions of the tradition with his ”Chinese medicine is a great treasure-house” speech.’* In Mao’s Cultural Revolution, Chinese medicine was transformed to TCM and embraced as a means to preserve the ”spirit of a nation.” The “new medicine” movement highlighted traditional medicine’s ability to arouse one’s own bodily defenses against illness while excluding metaphysical ideologies. TCM thus embodied one general theory of Chinese medicine and discouraged diverse readings and interpretations by practitioners and students. Of the three traditions, Tibetan medicine enjoyed the most continuity in lineage until the Chinese invasion consummated in 1959. With the Moslem invasion of India in the thirteenth century, much of the Ayurvedic medical system was destroyed, along with many Buddhist texts. Fortunately, by the seventh century AD, Ayurvedic medicine had traveled to Tibet and was safely preserved in the Himalayan Mountains. Once in Tibet, Buddhism and its medicine first adapted to the indigenous shamanic religious culture, Bon, whose greatest contribution to the Tibetan medical system was its knowledge of the indigenous medical herbs of the sub-Himalayan plateaus. With King Strongtsan Gampo’s formal introduction of Buddhism to Tibet in the early seventh century, the influence of Buddhism on its medicine flourished. This continued up until the Chinese invasion in 1959.

Despite its isolation in practice, Tibetan medicine shares several principles with other Eastern healing traditions. Its strongest ties are with Chinese medicine to the north and Ayurvedic medicine to the south. Eastern traditions of healing are undoubtedly intertwined in a rich tapestry, stemming partly from an extraordinary meeting of healers. During the seventh century, the Tibetan King Gampo held the world’s first recorded international medical conference. Noted physicians from India, China, Greece, Nepal, Persia, and Mongolia dialogued in a cross-cultural exchange, and texts from each medical tradition were translated.

Fundamental Philosophies: Tools to Assess Balance The notion that ill health stems from the imbalance of certain fundamental forces or “textures” stands at the core of many Eastern healing traditions. While the traditions may vary as to which fundamental forces, textures, or elements are involved in diagnosis and treatment, certain philosophies are shared. In these, the five elements, fundamental textures, and principles of opposites govern the universe. The five-element theory is the most common approach used to diagnose and restore health. The five elements are commonly understood to define, control, and at the same time be governed by a constellation of internal and external phenomena. These phenomena include human emotions, human senses, body organs, and climate. Humoral pathology, central to Ayurvedic, Tibetan, Persian, and Greek systems, is the core principle that unifies the mind with the body and the individual with his environment. It defines the balance or imbalance of the textures that influence one’s state of health. These humors define an array of biologic, physiopathologic, and psychologic phenomena related to the body, the mind, and the environment. In both Tibetan and Ayurvedic medicine, three humors, or primary qualities, maintain aspects of health. In Tibetan medicine they are Vuyu (Tib. Rlung), P i t h (Tib. Khrid), and Kapha (Tib. Bad-hn), translated as ”wind,” “bile,” and ”phlegm,” respectively. Yet the English translation is imprecise and limits the meanings of wind, bile, and phlegm principles, which further describe the mind, energy, and inert matter. Analogies can be drawn using conventional physics. Wind can be compared with kinetic energy, bile with caloric energy, and phlegm with mass energy. With reference to personality, those governed by air tend to be wiry and impulsive; bile types are muscular and quick to anger; and those ruled by phlegm are normally heavy set and tend to avoid conflict. Additionally, the humors are the products of the three delusions, which are the root cause of all suffering in the Buddhist tradition: phlegm, a product of ignorance, bile from anger, and wind from attachment. Understanding the humors as

products of the three delusions underlines the interrelationship between Buddhism as a spiritual practice and the healing professions. In Ayurvedic medicine, these humors are the three Doshas, known as Vat; Pit, or fire principle; and Kaph, or water prinaple, and carry specific actions. Vat is the bodily air prinaple and governs movement; Pit is the bodily fire prinaple that controls metabolism; Kaph is the biologic water prinaple that provides physical structure. These principles are also associated with the metabolic activities of anabolism, catabolism, and metabolism. In addition, they are associated with certain personalities and certain physical characteristics of dry or oily, light or heavy, and hot or cold. For a more complete discussion of the Doshas and their related properties and functions, see Chapter 34. Chinese medicine, on the other hand, lacks this system of detailed humoral pathology yet encompasses a similar principle that certain fundamental qualities must be in balance to achieve a healthy state. These fundamental textures are the universal Qi, Blood h e ) , Essence (jing), and Spirit (shed. Like the humors of Tibetan and Ayurvedic medicine, Q is universal and encompasses and connects all animate phenomena internally (body, mind, organ, senses) and externally (organism to environment). Q1 generates change both on a small scale and in the larger picture of Yin and Yang, those opposite forces of light and dark, female and male, that embody all organisms. Qi has five major functions: movement, protection, harmonious transformation, stability and retention, and warming of the body. The definition of blood in Chinese medicine goes beyond the physical concept of blood in Western medicine, as it is the Yin complement to the clinical Yang Q, functioning to nourish, circulate, and moisten the body. Essence is specific to organic life and slowly perpetuates life forward. Whereas Qi is the fluid movement of ordinary time, Essence spans a lifetime and embodies all characteristics involved with birth, maturation, and death. Lastly Spirit is unique to human life but is beyond mindconsciousness.It is what prompts humanity and relationships with one's self and other humans, and it examines all facets of humanity-moral, social, mental, physical, and emotional. While the concept of Yin and Yang is at the core of Chinese medicine, principles of opposites to achieve balance and optimal health are central to a l l three traditions. The Tibetan and Ayurvedic systems employ "hot" and "cold" to depict opposites. These fundamental opposites, fundamental textures, and five elements are intricately related to one another, providing a holistic framework in which to consider health and illness.

Diagnostics and Treatments In accordance with its foundational philosophies, diagnostics in Eastem traditions take into account the person

as a whole. The patient's physiologic characteristics, mental dispositions, and other personal, social, economic, and environmental details are assessed. In addition, diagnosis includes the following examinations: general physical, pulse, urine, tongue and eyes, skin and ears. The core principle in treatment is to restore the person's health to equilibrium, through severalbehavioral, lifestyle, diet, manual, and medicinal treatment approaches. Treatment methods in the Tibetan tradition are arranged in a hierarchy of usage: (1) behavioral practices (lifestyle, meditation), (2) diet, (3) herbal medicines, and (4)external treatments (acupuncture, massage, moxa, and surgery). Treatment therapies in Ayurveda include dietary alterations, yoga, exercise, herbal formulas, and surgical techniques. Ayunreda places special emphasis on diet as a modality, as it considers the human body a mental and physical product of the food consumed. Main treatment methods in Chinese medicine include acupuncture, herbal medicine, and sometimes Qi Gong.

MODERN APPLICATIONS: THE AGE OF INTEGRATION [The interpreter's] task is rather to seize the vital conception of the art-work, to blend it with his own ego and the views of his period, and thus to imbue it with life and efectiveness. His artistry is a product of its mental culture. It develops and changes with the evolution of artistic requirements. His formative and emotional powers are derived from the spirit of the epoch to which he belongs. Much that charmed former generations has no effect in ours; so much is part and parcel of its passing. Only what is exalted over time and place remains as eternal gain; and here, again, another generation finds new treasures that earlier ones passed by unheeding. This is the unfailing criterion of true greatness, that its creations continually beget ever-new, everchanging values, that they bring to each successive generation new revelations. -Max Spicker, 1912 As the social landscape changes, the culture of medicine continually redefines what is considered "conventional." Numerous recent studies have shown that since the early 1990s, consumers have been demanding alternatives to modem care.12Only since then has integrated medicine, including naturopathy, penetrated the Ivory Tower and research institutions in the United States. Driven by scientific advancement and a need for increased knowledge, this movement toward a more pluralistic medicine has now brought us beyond the age of information and into the "age of integration." With the current plethora of health information, it is becoming more apparent that optimal healing is not the property of any one tradition or system. As a result, previously marginalized traditions have experienced

Eastern Origins of Integrative Medicine and Modern Appli a resurgence in interest and usage. They are now finally finding inclusion. Integrative clinics that incorporate multiple healing systems thrive throughout the country and at major academic medical institutions. Employers and managed care agencies are beginning to offer limited coverage for acupuncture, chiropractic, naturopathy, and massage services. The Academic Consortium for Integrative Medicine has been formed among top-ranked medical schools to integrate CAM into their curriculums. The NIH has devoted an institute just for CAM and allots a budget of $113.2 million for research and educational initiative^.'^ Despite the recent explosion of integrative medicine entering research, education, and clinical arenas, several barriers still limit the growth of integrative medicine in the United States. The most pressing and present barrier to clinical integration is reimbursement. To persuade insurers to cover the costs of CAM therapies, research evidence built on rigorous clinical trials and data that demonstrate cost-efficacy of these modalities are necessary. Perhaps an even greater barrier to integration is the challenge of how to establish safe and effective practices for these modalities, while carefully preserving the lineage of indigenous traditions. To examine this issue, the authors outline the birth and evolution of indigenous traditions as medical professions in the United States and later provide units on clinical practice, risk management, professional communications, practice management, and research that serve as essential tools for integration. The current dilemma in the development of these CAM professions is how to perpetuate lineages during this integration with other health care professions, while not lowering standards for CAM practitioners. This present boom in alternative health care has resulted in the current state of integrative medicine: a confusing situation with too many practitioners offering a wide range of skills but leaving consumers without tools to decipher which are the most effective or true to tradition. Now the middle path must be taken by raising the bar for practice standards. If the bar is too low, traditions will no longer be protected and they will not be as efficacious in practice. Consequently, practitioners may not be appreciated by either patients or traditional providers. If the bar is too high, few will find access and few will be able to practice. Either way, invaluable traditions may be lost.

The Birth and Evolution of a Medical Profession in the United States: Complementary and Alternative Medicine Professions In the last years of the twentieth century, the United States witnessed the beginning transformations of indigenous healing traditions into CAM professions. After the counter-culture years of the 1960s and 1970s

that challenged institutionalized medicine, interest in “natural healing” practices surged. As a result, chiropractic care and naturopathy were the first traditions to become formalized in modem medicine. Since then, Chinese medicine-namely acupuncture-has made the largest entrance into health care in the United States, with more than 50 TCM and acupuncture schools in the United States and Canada accredited by the Accreditation Commission for Acupuncture and Oriental Medicine (ACAOM), adoption of licensure laws in the majority of states, and an increasing number of insurers offering coverage for TCM treatments. A far second to Chinese medicine has been the development of Ayurvedic and Tibetan medicine, which are still in the early phases of their evolution as professions in the United States. Every medical tradition, even the current scientificbased modem medicine, began at the margin and progressed through a similar cycle to become an established practice or profession. Currently, CAM modalities are finding similar challenges as they endure this evolution toward becoming established professions. Typically, in stage 1, lone practitioners of the tradition arrive in the United States and provide informal workshops to the public and interested health care providers. These CAM practitioners practice their traditions informally. Stage 2 develops only after public and provider acceptance of safety and efficacy. Stage 2 marks the development of professional education and associations; providing standards for school accreditation; credentialing; and, ultimately, licensure by state boards. With regulation through professional associations, third-party payers become amenable to insurance reimbursement for CAM treatments. Finally, stage 3 results in set state and national standards for the profession, including education, practice, and methods to evaluate safety and efficacy, as well as widespread acceptance and practice. Achieving a code for Medicare reimbursement is one measure of success of the integration of CAM with modern health care. In this current era, the accomplishment of stage 3 is inherently dependent on the respectful and appropriate blending of these CAM traditions with the dominant medical paradigm based in science. At this time in the United States, the professions of naturopathy, chiropractic, acupuncture, and massage are in stage 2 or early stage 3 of their professional and legislative developments, where accredited schools in all these fields have been undoubtedly established and licensure is being governed by state boards. For instance, acupuncture currently has two established organizations that help to set standards for training and practice: the ACAOM and the National Certification Commission for Acupuncture and Oriental Medicine (NCCAOM). ACAOM is recognized by the U.S. Department of Education to accredit first professional master’s degree and master’s level programs in acupuncture and

Oriental medicine and is currently petitioning to begin accrediting postgraduate, clinical doctoral programs. Acupuncturists are currently licensed according to state boards, but licensure laws vary from state to state. Many states recognize NCCAOM certification as a national standard, and thus practitioners can earn licensure with NCCAOM certification in these states. However, licensure laws still vary widely by state. Acupuncture as practiced by approximately 5000 medical doctors in the United States is currently the fastest growing medical specialty. The American Academy for Medical Acupuncture now offers specialty board certification in the field. Nevertheless, while several thirdparty payers are beginning to offer insurance coverage for acupuncture, barriers such as standardization in education, practice, and research still exist.

Clinical

Prevention and identification of medical emergencies in the CAM clinic Prevention and appropriate medical responses to adverse reactions of CAM therapies Recommendations for interdisciplinarycare of common complaints Guidelines for selected scope of practice issues Herbs as neutraceutical Risk Management

Malpractice Informed consent Expert testimony Charting Regulatory issues Insurance

TOOLS FOR INTEGRATION

Professional Communications

As providers of CAM services join professional networks and become increasingly integrated into conventional health delivery, the CAM professions gain both credibility and exposure. Integration brings with it a new set of responsibilities. Utilization is growing and evolving so quickly that the educational institutions preparing C A M providers for licensure are hard-pressed to keep up with the trend. As a result, CAM provider education often does not fully prepare its graduates to meet the growing expectations of the public, the medical community, or the legal system. Providers must gain competency in "tools for integration" that lead to a new set of skills for clinical practice, risk management, professional communications, practice management, and research. These tools include, but are not limited to, those listed in Box 1-1. The emerging field of integrative medicine has arrived at the end of the beginning. It is no longer simply a vision of what could be. Billions of dollars are now spent out of pocket for several hundred million visits to integrative providers and for herbs and neutraceutical each year. The majority of medical schools now offer some form of CAM education for physicians in training. Yet until now the consumer has carried the day. As physicians move forward into the twenty-first century, they are ready to enter the beginning of the middle. The transition is rapidly under way and is best facilitated by successful clinical models for integration and quality studies that demonstrate clinical outcomes of integrative services and the extent to which these services provide cost offsets compared to conventional care. As the more developed CAM professions continue to evolve and new traditions like Tibetan or Ayurveda move into a new phase, it will be increasingly important to respect the lineage of indigenous traditions as they enter U.S. culture. In credentialing practitioners, it must

Patient presentations Referral protocols Operations Human resources Patient relations Using information technology Research

A survey of conventional research tools Customizing conventional research tools to study CAM Evaluating research publications Using research findings Performing original research CAM, Complementary and alternative medicine.

be acknowledged that training is traditionally based on lineage passed on by oral tradition. This makes an argument for dual pathways for credentialing that allow for both apprenticeship and degree programs with standardized testing. Researchers must also recognize the unique set of challenges when studying the health benefits of these traditions, as traditions become more subject to the gold standard of randomized controlled trials (RCTs) to gain acceptance. The work of medical anthropologists will become crucial to preserving cultural sensitivity as research in CAM progresses. Several compromises need to occur for smooth integration in research. For instance, outcome studies must seek to capture quality of life. Addressing the different taxonomy of illness when studying indigenous traditions is also essential. In practice, it is also increasingly necessary to build bridges between the indigenous community, evolving CAM professions, and established medical institutions.

Eastern Origins of Integrative Medicine and Modern Applications

Researchers, academicians, and health care professionals from multiple backgrounds need to understand these issues in integration in order to provide optimal health with wisdom for this generation and the next. Only through partnership can the best medicine be offered

and this evolution in the culture of health care be assisted. In the words of Albert Einstein, “Whoever undertakes to set himself up as judge in the field of Truth and Knowledge is shipwrecked by the laughter of the gods.”

1.Lakoff G, Johnson M. Philosophy in the flesh: the embodied mind and its challenge to Western thought. New York Basic Books, 1999~395-398. 2. Lakoff G, JohnsonM. Philosophy in the flesh the embodied mind and its challenge to Western thought. New York Basic Books, 1999:408. 3. Robinson G. Introducing Descartes. Cambridge, UK: Icon Books, 1999:20. 4. Kaptchuk T, Eisenberg D. Varieties of healing. 1: Medical pluralism in the United States. Ann Intern Med 2001;135:189. 5. Liu H, Perry P (Contributor).The healing art of Q1 Gong: ancient wisdom from a modem master. New York Warner Books, 19996. 6. Farquhar J. Knowing practice: the clinical encounter of Chinese medicine. In Kaptchuk T, ed. The web that has no weaver: understanding Chinese medicine, ed 2. Chicago: Contemporary Books, 2000:67. 7. Binion T. In The Urantia book. Evolution of the scientific method. Chicago: Uversa Press. 1998:2.

8. Rechung R, Kunzang J. libetan medicine. Berkeley: University of California Press, 19733. 9. Nolting M. Acupuncture. In Pizzorno J, Murray M, eds. Textbook of natural medicine, ed 2. New York: Churchill Livingstone, 1999:254. 10. Unschuld P. Medicine in China: a history of ideas. Berkley: University of California Press, 1985:250. 11. Farquhar J. Rewriting traditional medicine in post-Maoist China. In Bates D, ed. Knowledge and the scholarly medical traditions. New York: Cambridge University Press, 1995251. 12. EisenbergD, Davis R, Ettner S, et al. Trends in alternativemedicine use in the United States, 1990-1997 results of a follow-up national survey. JAMA 1998;2801569-1575. 13. Figure from National Center for Complementary and Alternative Medicine, for fiscal year 2003.

Functional Medicine in Natural Medicine Buck Levin, PhD, RD Jeffrey S. Bland, PhD Michael A. Schmidt, PhD CHAPTER C O N T E N T S PART I:THE PHILOSOPHY OF FUNCTIONAL MEDICINE 13 Introduction 13 Theoretical Aspects 14 The Philosophy of Function in a Medical Context 14 Function as a Mediator for Opposition Thinking in the Sciences 15 EnergyJMatter 10 Body Systems from a Functional Medicine Perspective 19 PART 11: THE CLINICAL APPLICATION OF FUNCTIONAL MEDICINE 21 Basic Concepts in Functional Practice 21 Biochemical Individuality 21

INTRODUCTION This textbook bears witness to the remarkable evolution of naturopathic medicine in the United States since Benedict Lust first opened his American School of Naturopathy on 59th Street in New York City in 1902. During the intervening century, naturopathic physicians have become recognized as primary health care providers in about one fourth of all states. Naturopathic practice has become part of publicly funded clinics. Accredited training has become available in all regions of the country. In addition, naturopathic philosophy has influenced medical philosophy as a whole, including the functional approach that we have espoused in our own work. Naturopathic recognition of key medical principles, including tolle cuusurn (idenhfy and treat the causes), prirnum non nocere (first do no harm), and docere (doctor as teacher) has helped the authors clarify their vision of a functional approach to health that

Health as a Positive Vitality 21 Life Processes as Homeodynamic 21 Assessment and Treatment from a Functional Perspective 21 Illness as Information 22 Treatment Decisions 22 Concept of Total Load 23 Depth of Action 23 Mechanism and Outcome 23 Prevention, Early Detection, and Functional Medicine 24 Approach to the Patient 24 Laboratory and Instrumental Diagnosis from a Functional Perspective 24 Pattern Recognition 25 Summary 25

worked develop an approach to health care that can be incorporated into the everyday practice of all health care practitioners regardless of training or specialty. Moreover, the authors have tried to carve out an approach that capitalizes not only on the foremost accomplishments of basic and applied science but on the strengths of specialty fields and specialized approaches to clinical practice. The authors hope that naturopaths, osteopaths, chiropractors, medical doctors, nutritionists, dietitians, herbalists, homeopaths, acupuncturists, Ayurvedic physicians, and other diversely trained practitioners can find in functional medicine an approach that naturally extends and enhances their current practice. Functional medicine is not a "new" or "alternative" approach that requires a change in basic clinical orientation or political allegiance. It only requires a willingness to take seriously one's basic medical philosophy and engage the science of our time with the spirit of true discovery, open-mindedness, and due diligence. This chapter specifically addresses 13

Philosophy of Natural Medicine

the consequences of such an approach for naturopathy and its clinical practice.

THEORETICAL ASPECTS The Philosophy of Function in a Medical Context Most dictionary definitions of “function” indicate the word derived from the Greek term ergonr which means “the kind of action or activity proper to a person or thing; the purpose for which something is designed or exists.”’ This definition indicates that the concept of function must be viewed in the same category as the concepts of “purpose” and “design.” In addition, understanding the function of a person or thing is not possible without also understanding the purpose for which that person or thing is designed. In early Greek philosophy the term ergon was frequently contrasted with the term pathemfa-things that happened to a person or thing? This comparison focused on the difference between things with the capacity to act (poiein) and things that were, in contrast, “passive activations” (patheJ3En-ergia-being in activity or functioning-was considered to be the telos (end purpose) of being alive. Today, when people refer to disease as ”pathology based,” they are actually linking disease, etymologically,to this realm of pathemafa and pathe. They define disease as something that ”happens to” a person, something that is not a part of that person’s purposeful activity. Etymologically, the term “functional medicine” moves people away from this pathologic model and aligns them with a medicine that views disease as part of something that is purposeful and is proceeding actively in accordance with some design. The history of philosophy-at least as far back as the writing of Aristotle in the third century ~c-has witnessed an ongoing debate between “vitalistic” and “mechanistic” approaches to life and health. Naturopathic medicine has consistently aligned itself with the vitalistic side of this argument. Naturopathy recognizes a vital force-vis rnedicatrix naturue or healing power of nature-that is present in all living things, including the human body For naturopaths, this vital force is ultimately responsible for healing. The functional medicine emphasis on purpose and design is closely related to this recognition of vital force in naturopathy. When functional practitioners recognize purpose and design in physiologic events (including “disease of unknown origin”), they are acknowledging that body function is guided by a universal, supraindividual set of principles. They are acknowledging that physiologic function originates from an infinite, complex, patterned matrix of occurrences that both precede and transcend individual human experience. The purpose

and design of functional medicine therefore echo the spirit of vitalism. This spirit of vitalism does not mean, however, that the healing force is totally mysterious or unapproachable. While the universal, patterned matrix of events is infinite and cannot be fully understood, it is nevertheless a complex pattern that can be observed and analyzed within the limits of a human perspective. Pursuit of this possibility is essential to a functional approach. The more that can be learned about the patterned matrix of universal events, the better the practitioner can support healing. The termsfom andfunctionare probably most familiar to us from the field of architecture. At the turn of the twentieth century, U.S. architect Louis Sullivan coined the phrase “form follows function,” recognizing that purpose precedes the blueprint. But in our philosophy of the body’s architecture, how do these terms apply? In the case of several body systems-the musculoskeletal system or the circulatory system, for example-shape and form give an initial hint about function, design, and purpose. Observing the body’s skeleton is difficult without concluding that it has been designed for structural support. With other physiologic systems, these connections are not nearly so obvious. Phrenology, described by English historian J.C. Flugel a century after its origin as ”psychology’s greatest faux pas,” argued that the quality of a person’s mental faculties was determined by the size of the brain area on which those faculties depended, and this quality could be judged by the contours of the skull adjacent to the area! This literal equating of brain function with brain form, launched in 1810 in Pans by FrancoisJoseph Gall and his student J.C. Spurzheim, met with some immediate difficulty in application. After discovering that the skull of French philosopher Rene Descartes was particularly small in the anterior and superior regions of the forehead, understood to be the seat of a person’s rational faculties, Spurzheim reportedly commented, ”Descartes was not so great a thinker as he was held to be.”5 The inability of phrenologists to make sense of function by reference to form alone is one example of a difficulty that continues to permeate twentieth-century medicine. Naturopathy has made great strides in linking form with function, by accommodating into its practice long-standing medical traditions that treat function by working with form. Naturopathy’s embrace of physical medicine-from craniosacral therapy and osseous manipulation to hydrotherapy and physiotherapy-has made the connection between form and function more accessible. A final common ground between functional and naturopathic medicine involves the idea of a ”medical philosophy.” The need for practical solutions in everyday

Functional Medicine in Natural Medicine

medical practice is great-so great that most practitioners do not see themselves as having the time or inclination to “philosophize.”Yet from a functional and naturopathic perspective, it is impossible to approach health without paying continual attention to one’s philosophy of medicine. The remainder of this section provides several examples of philosophic thinking that the authors believe continue to represent stumbling blocks for an integrated, twentyfirst-century medicine. Each example thinks ”dualistically” about medical concepts and, in so doing, loses sight of function.

Function as a Mediator for Opposition Thinking in the Sciences Padwhole The traditional philosophical dualism of “part/whole” has been directly addressed in the field of holistic health. Two national organizations, the American Holistic Health Association (AHHA),headquartered in Anaheim, CA, and the American Holistic Medical Association (AHMA), located in Raleigh, NC, have each referred to this dualism in defining their field of study According to the AHHA, Rather than focusing on illness or specific parts of the body, holistic health considers the whole person and how it interacts with its environment. It emphasizes the connection of body, mind, and spirit. Holistic Health is based on the law of nature that a whole is made up of interdependent parts. The earth is made up of systems, such as air, land, water, plants, and animals. If life is to be sustained, they cannot be separated, for what is happening to one is also felt by all of the other systems. In the same way, an individual is a whole made up of interdependent parts, which are the physical, mental, emotional, and spiritual. When one part is not working at its best, it will impact all the other parts of that person. Further, this whole person, including all of the parts, is constantly interacting with everything in the surrounding environment!

And according to the AHMA, Wellness is defined as a state of well-being in which an individual’s body, mind, emotions, and spirit are in harmony with and guided by an awareness of society, nature, and the universe. . . . (It) encompasses all safe modalities of diagnosis and treatment, including the use of medications and surgery, emphasizing the necessity of looking at the whole person?

On its Internet website, the AHMA states, ”Optimal health is much more than the absence of sickness. It is the conscious pursuit of the highest qualities of the spiritual, mental, emotional, physical, environmental, and social aspects of the human experience.”8 With respect to their characterization of ”part” and ”whole,” these definitions of holistic medicine are largely compatible with a functional approach. Because the

concept of function asks us to consider why a thing is here, what it is “doing” in the universe, it asks us to be holistic and take into account the holon-which in early Greek philosophy meant both ”universe” and “organism.” Wholeness becomes a necessary concept for understanding function, and holistic medicine has done medical philosophy an important service by renewing its focus on the whole. At the same time, the authors invite supporters of holistic medicine to consider an extension of their philosophy in two ways. First, they invite consideration of a multilevel understanding of wholeness that does not predetermine a frame of reference or specific context in which wholeness is to be evaluated. For example, if it is unknown whether planetary indices of geomagnetic disturbance-like sunspot relative number, area, and geomagnetic activity-are as valuable a “whole” or ”universe” against which to evaluate and treat cardiovascular disease as homocysteine imbalances (the ”whole” or “universe” of the cell) or ”heartlessness”and ”disheartenment” (a psychologic or sociocultural “whole” or “context”), benefits might be expected by keeping a radical open-mindedness about frames of reference, levels of wholeness, and their ultimate interrelationship in a holistic model. Instead of trying to simplify with three or four frames of reference based on early twentieth-century psychology (i.e., wholeness as the sum of physical, emotional, mental, and spiritual frames of reference) or a few contexts based on specialty (physical body, immediate external environment, global environment), such conclusions could simply be postponed until more is learned about levels of wholeness and their relationship. From a functional perspective, the authors suspect this relationship closely resembles the one described by U.S.engineer, designer, and architect Buckminster Fuller in his discussion of “functions” in his 1975 opus, Synergetics: “Functions occur only as inherently cooperative and accommodatively varying subaspects of synergistically transforming whole^."^ The relationship of part to whole is a second area in which a holistic perspective could be logically extended. We believe the concept of function necessitates a view of “part” and “whole” that is quite different from the image of a disassembled jigsaw puzzle or a shattered china teacup, which can be reassembled or glued back together to reestablish the ”whole” from which it came. In both examples, the parts have a visible connection to the whole, but in and of themselves they are a diverse array of pieces in all shapes and sizes, bearing no individual resemblance to the whole from which they came. From a functional perspective, the authors believe this image of part and whole should be changed. Instead of a shattered teacup or a disassembled puzzle, the authors propose a shattered hologram. When a hologram breaks,

it does not shatter into discrete pieces with different sizes and shapes that individually bear no resemblance to the original hologram. It splits into separate pieces, each of which visibly contains the complete and original hologram. From a medical perspective, this change means that health care practitioners would stop assigning partial functions to anatomically distinct body parts or systems and begin treating all parts as visibly containing the original hologram (i.e., whole body capability). For example, physicians have traditionally viewed the gastrointestinal (GI) tract, brain, and immune system as separate, identifiable parts unable to carry out each other’s basic functions. In the case of the GI tract, these functions have traditionally been limited to digestion, absorption, secretion, and motility. Researchers have discovered that the GI tract has its own immune system (GALT) and its own brain (memory T cells disseminated to the intestinal epithelium and lamina propria providing the functional basis for oral tolerance)1° and can carry on functions traditionally reserved for other systems of the body. Similarly, it is recognized that the eye does not simply ”see.”It helps set the body’s circadian rhythms through the production of melatonin’l and may therefore coordinate reproductive signaling as w e l l 2These findings encourage recognition of the whole inside each part. Equally encouraging have been the many “reflexologies” that have dotted the landscape of alternative medicine and have been given openminded consideration in naturopathy-foot reflexology, iridology, intestinal reflexology in colonics, contact reflex analysk-each pointing toward a ”shattered hologram” model in which the unbroken whole is visible in its seemingly separate parts.

Inside/Outside The classic debate over nature versus nurture, heredity/ environment, geneticdexperience has had troublesome consequences for a patient-centered approach to wellbeing. The authors have seen what can happen when the ”insides,” in their purist form, are equated with the chromosomal material inside the nucleus of the cell. What can happen is a philosophy of development that treats the three billion base pairs in the human genome as a largely unalterable blueprint working from the inside to define a person’s potential with respect to the ”great taskmaster outside” (i.e., the environment). This extremist view of inside/outside, equating insidethe true ”inner sanctum”-with the gene, has led to a national eugenics movement based on misinterpretation of ethnic differences in intelligence quotient (IQ), a national backlash against elementary school “mainstreaming” based on misinterpretation of learning disorders, and a popular anthropology of racial difference based on misinterpretation of the anthropologic facts.

Two examples from the history of biology can help place the dualism of “inside/outside” in a more functional context. The first example involves a chapter of a book written by Swiss zoologist Adolph Portmann in 1967. In his chapter, titled ”The Outside and the Inside,” Portmann writes: Biologists . . . have worked from the outside inwards, from what is visible and tangible to what is more and more deeply hidden. . . . But such probing makes us strangers to the appearance of the living creatures around us. . . . With a knowledge of the developmental conditions under which, for instance, a feather primordium develops and its pigment is formed, it is only the problem of shape that has been solved. But it still remains to be shown what brings about that special distribution of color in the pattern on the feather germ which is specifically directed towards the whole form in its final ~0ndition.I~

In his book Portmann argues that outsides of animals are expressions of their inwardness (i.e., their developmentally unfolding uniqueness and individuality). He also concludes that the ultimate purpose of this “insidesbecoming-outsides” is to help living creatures find each other and ”break the ban of i~olation.”’~ Portmann’s writing expresses a desire to blur (or even erase) the line between inside and outside. What is innermost “feels a desire” to become outermost, for the purpose of connecting up with the innermost sanctum of another. Health care practitioners are familiar with the notion of a milieu inttrieur-an interior, homeostatic, calm harbor maintained in the wake of outside, stormy seas. Pasteur ’s contemporary Claude Bernard first wrote about this concept in 1865 in his classic text, An Zntroduction to the Study of Experimentd Medicine,15 and it still serves as a cornerstone of understanding cellular events. But what health care practitioners are not familiar with, in this second example, is the extent to which Bernard was forced to dismiss the relevance of purpose and design in positing the milieu inttrieur: Neither physiologists nor physicians need imagine it their task to seek the cause of life or the essence of disease. That would be entirely wasting one’s time in pursuing a phantom. The words life, death, health, disease have no objective reality.16 Sickness and death are merely a dislocation or disturbance of the mechanism which regulates the contact of vital stimulants

with organic units.*7 Of course, the interior milieu regulates this contact. But by making such an absolute division between inside and outside, Bernard ends up placing all responsibility and focus on this “mechanism” that connects ”in” with ”out” and turning his back on the purpose and essence of life/death and health/disease. Both examples caution health care practitioners against drawing absolute lines between inside and outside. So does the concept of function itself. When it is recognized

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that function requires purpos,ome goal or endpoint toward which activity is directed-it is also recognized that function requires potential, a goal or endpoint that is capable of being reached but has not yet been attained in actuality. Without potentiality, there is no function. In functional medicine, no question is more critical than the question of this potentiality and its "location." To what extent is potential "inside" people, inside their cells, thoughts, and genes? How are "outside" events related to this potential? In immunology, at least since the end of World War 11, a self/nonself model has developed that is forcing health care practitioners to relabel long lists of diseases as diseases of autoimmunity, diseases in which the distinction between self and nonself has become confused. But from a functional perspective, an absolute division between self and nonself is a too-literal separation of inside from out. Autoimmune diseases cannot be a set of inside, interior dynamics in which "self" mistakes "self" for "nonself" and self-destructs. If this were the case, health care practitioners would not discover all the risk factors for autoimmune disorder on the outside, removed from the self. Yet that is exactly where they are being found. The 17-aminoacid sequence in bovine serum albumin that travels from cow's milk formulas to pancreatic beta cell surface proteins (p69) and increases risk for the autoimmune disease called juvenile-onset diabetes,'8 the links between xenobiotic exposure and systemic lupus erythematosus,19and the newly designated "autoimmune polyendocrine syndromes" and their responsiveness to dietary modification are all examples that point to dangers outside the self and their key role in the development of autoimmune disease. But it is not only negative potential that gets locked outside the self when a line is drawn too absolutely between inside and out; it is positive potential as well. Function requires purpose. Purpose requires potential. "Plurifunctioning" organisms must also be "pluripotential" organisms. And because the unbroken whole is visible in the parts, this pluripotential must reside in the parts as well, even in that innermost part called the human genome, locked away inside the nucleus of the cell.

Genomics One of the greatest dangers health care practitioners face over the next 50 years in health care is letting the genetics revolution further seduce us into an absolutist view of inside/out. Announcement of the completed DNA reference sequence for Homo sapiens by the Human Genome Project (HGP) in April 2003 catapulted us into a new age of bioinformatics and called for the generation of an entirely new vocabulary including terms like "genomics," "phenomics" (metabolomics), and "proteomics." The basic goals of the HGP were mind-boggling: (1)to identdy the 20,000-25,000 genes in human DNA and (2) to determine the sequences of three billion base pairs in human

DNA. The speedy transfer and creative application of this knowledge in the private sector has been equally astonishing. Changes in law enforcement, industrial manufacture, environmental biotechnology, agribusiness, anthropology research, and clinical medicine exemplify the far-reaching impact of the HGP. The potential for development of a personalized functional medicine has been increased dramaticallyby these advances in genomics, phenomics, and proteomics. For the first time in medical history, general contracting of body structures can be evaluated against architectural blueprints, and the outermost manifestations of disease can be examined against the innermost predilections. Remarkable insights into body function have already begun to flourish as a result of this newfound perspective. But a great temptation in the wake of this bioinformatic paradigm shift is to treat inside and outside as even more separate than before, further apart and further removed from mutual influence. On one side of this inside/outside dichotomy, health care practitioners in this field might be tempted to think of themselves as "insiders" who have now for the first time in human history penetrated the deepest recesses of self and stand poised to unlock its greatest potential. From this perspective, the genome might mistakenly be viewed as hard-wired cirmitry that explains every aspect of self, including individual development of disease. On the opposite side of the dichotomy, it might be tempting to dismiss the relevance of the outside and establish the phenome as an immovable object toward which the genome inexorably heads. Both types of temptation would miss a fundamental, underlying truth of genomics and phenomics. The bioinformatic paradigm shift is making clear that not only is there no absolute division between inside and outside, but the two dimensions are absolutely inseparable. Gene regulatory networks (GRNs)involved with the up- and down-regulation of gene expression can involve multitiered cascades that take researchers far outside the cell nucleus or even immediate intracellular context. While immediate events that coregulate rate of gene transcription may OCCUT in nearby upstream DNA segments (promoter regions) in the nucleus of the cell, promoters are themselves polymorphic and subject to whole body and whole life impacts. When viewed phenomically the genome can only be described as pluripotent. When viewed genomically, the phenome can only be described as interactively and unpredictably expressed. To account in full for a single genetic event, researchers must step far outside the genome into a constantly changing environment and the organism's purposeful interaction with it. For example, in 2002, a team of researchers at the Hokkaido University School of Medicine in Sapporo, Japan, discovered a polymorphism in the RANTES (Regulated upon Activation Normal T-cell Expressed

and Secreted) chemo-attractant cytokine gene promoter that is associated with late-onset (Polymorphism in the RANTES promoter gene have been associated with other disease conditions in which cytokine signaling plays a key role, including stomach ulcer and HN infection). Exact causes of RANTES polymorphism have yet to be identified, and underlying mutations involving insertion-deletion length, simple sequence repeat length, or single nucleotides could be involved. Whatever the classification, however, the full implications of the RANTES research cannot be understood unless researchers are willing to leap far outside the genome. Asthma is a condition increasingly associated with poor environmental quality, and any environment can become a repository for genotoxic substances known to cause singlestrand deletions and base pair substitutions in human DNA. In the case of asthma exposure to diisocyanates, aldehydes, anhydrides, chlorofluorocarbons, chloramines, or persulfates could conceivably be associated with mutations underlying the RANTES polymorphism. The more attention paid to this inseparability of inside and out, the better the chances for a truly personalized functional medicine. Molecular medicine is teaching us there is no untouchable inside. Our outside experience, including our dietary intake, continually modifies the expression of our genes. Control of gene expression is highly encrypted; that is, genes have inducer binding sites and promoter sequences that modify their expression. Numerous nutritional components have been shown to m o w that expression, including linoleic and alphalinoleic acid, isoflavones, quercetin, ellagic acid, vitamin A, and vitamin B6?* The potentiality is ever present, even when IQ suggests otherwise. At their innermost, genetic selves, humans are always also outside of themselves, linked to wholes through their potential.

CauseKffect In the fourth century K, in a treatise titled Physicu, the

Greek philosopher Aristotle described a doctrine of four causes: formal cause (eidos), producing in a thing its constitutive essence; material cause (hyle), providing a thing with its ”matter” and embodiment; efficient cause (kinoun), initiating change in a thing; and final cause (telos), providing an ultimate purpose for the change. Since the word cause has several meanings, Aristotle wrote, ”It follows that there are several causes of the same thing (not merely in virtue of a concomitant attribute), for example, both the art of the sculptor and the bronze are causes of the statue.”= What appears treatable or preventable to practitioners depends entirely on their philosophy of medicine. Whether dysfunction is treatable or preventable depends on what caused the dysfunction in the first place (i.e., on one’s concept of causality). Keith Block, MD, medical

director of the Cancer Institute at Edgewater Medical Center in Chicago, recently argued that the labeling of any cancer as “terminal” is both scientifically and spiritually unju~tifiable.~~ His argument is based on a view of cancer causality that includes an active role for the self in deciphering and acting on the cosmic event that cancer represents. But the views of Aristotle and Block, welcoming a complex view of causality into our understanding of health, are far from our classic heritage in the sciences. As French Nobel Prize winner Jacques Monod wrote, in his classic 1970 work, Chance and Necessity: The cornerstone of the scientific method is . . . systematic denial that “true”knowledge can be got at by interpretingphenomena in terms of final causes-that is to say, of “ p ~ r p o ~ e . ” ~ ~ Against this notion, this powerful feeling of destiny, we must be constantly on guard.z Monod’s philosophy is the authors’ reigning medical philosophy-me steeped in the Darwinian legacy of a universe with minimal original essence, minimal momentary stability, and an indefinite horizon of It is a philosophy that tells health care practitioners they must be careful when reading purpose into dysfunction, and that they should accept whole categories of disability and death as purposeless, chance events that are essentially not preventable. Naturopathy, with its focus on prevention, has helped to transform this perspective. Most naturopaths would readily subscribe to the mission statement of the Foundation for Preventive Medicine, based in New York City, when it describes its mission as ”enhancing the public’s awareness of recent information indicating that most causes of death in our society. . . are now regarded as potentially preventable. Preventive, functional, and naturopathic medicine all seem to agree that lack of wellbeing, lack of vitality, depression, and deficiency in energy are also associated with largely preventable conditionstV and that each time we transfer a health condition from the category of ”not preventable” to “preventable,” we are honoring our medical philosophy.”

Energymatter Most scientists subscribe to an energy-based view of human function. They believe that healthy function rests on the shouldersof gated ion channels, electrolytebalance, membrane potential, redox, electrochemical gradients, and high-energy phosphate bonds. In these scientists’ view, the release of heat energy from cells is what makes biologic order actually possible in the first place.28Yet in spite of its acceptance at a biologic and biochemical level, this energy-based paradigm has yet to become fully integrated into medicine. While electrocardiographic, magnetic resonance, and single photon emission imaging have become standard parts of the diagnostic repertoire,

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electroacupuncture biofeedback devices, despite their research record and use in many ~ountries,2~ remain unapproved for clinical use in the United States. Once again, naturopathic medicine has provided leadership in this area. Energy-based medicine has been given open-minded consideration in naturopathy, and whole traditions based on energeticprinciples-including acupuncture and Oriental medicinehave been treated as essential areas for understanding and research. Similarly, acceptance of homeopathy-an energy-based medicine used by a quarter of a million practitioners worldwidem-has been nurtured in the United States by the supportive position adopted by naturopaths and naturopathic institutions. From a functional perspective, the rightful place of ”energy medicine” in health care approaches is woven into the term “function” itself, which derives from the Greek en-ergiu, literally, ”functioning” or ”being in activity.” But clearly, practitioners are just starting to explore this energy-matter relationship in their medical philosophy. In nutrition, for example, they are just beginning to shed the nineteenth-century steam engine model, which perceived the body as a large furnace combusting matter (food) for the sake of extracting caloric energy. In this model, energy is not useful unless extracted out of matter, and matter, once depleted of its energy, is of little use as well. This food-as-fuel model has left us with an underappreciation of food’s matter and its energy. As raw material for caloric extraction, food becomes most important for its gross, undifferentiated macronutrient content-its 20 g of fat or 100 g of carbohydrate. Subtler distinctions involving omega-3-tmmega-6 or oligosaccharide-to-polysaccharide ratios have been slow to evolve. Likewise, food energetics, including the issues of raw food, live food, food enzymes, and active cultures, have been negligibly addressed. Interestingly, practitioners are finding that the role of light, in the form of food pigments, including the heme, chlorophylls, carotenoids, and flavonoids, is slowly revolutionizing the approach to food in the same way that light (and the frame of reference it represented) revolutionized the approach to mass and energy in physics.

Body Systems from a Functional Medicine Perspective Historical and Philosophical Perspective Students of science and medicine in the United States and other Western countries learn anatomy and physiology from a systems approach. They learn to view organ systems, individual organs, tissues, cells, and subcellular spaces as separate entities that interact with one another to create form and function. The better one understands any one system or entity, by this model, the more skilled he or she will be at treating dysfunction of that entity. This model served well in developing a rational method

of inquiry into the etiology of many diseases. Indeed, the advancement of medical science has long been measured by progress made in understanding the mechanisms of disease related to dysfunction in the body’s distinct compartments. Fundamental to the systems model has been the assumption that the more that is known about individual organs or systems, the better the medicine will be. Until recently, this assumption had been widely validated throughout medical history by remarkable progress in diagnosis and treatment of disease, surgical practice, and the development of medications for symptom reduction related to specific diseases. The progress that resulted from this compartmentalizing approach can be compared to advances in biology that followed Linnaeus’s development of a system of taxonomic classification of living organisms in the eighteenth century. The formalized system of learning allowed for sigruficantadvancement in the field of biology. By the 1970s, however, many biologists had become aware of the limitations of description and classification as an epistemology. Their science had outgrown the model. Through advancements in the disciplines of ecology and environmental science, they knew they could class@ all the plants and animals in an ecosystem and yet understand nothing about the functioning of the ecosystem as an integrated whole. The need had arisen to address the larger issues of how compartments within the ecosystem interact to give rise to its function and survival. From the perspective of these advancements in biology, one could view medicine as a specialized discipline within the broader field of human ecology. To understand health and disease, one would be required to examine the functional interadion of organ systems with the human environment. Furthermore, one would have to observe the functional interaction between the total human environment and the energy processing and control systems within it. Examining any discipline from a new point of view makes it possible to ask new questions and gain new insights. Looking at human health and medicine from the point of view of interactive function raises questions about the homeodynamic interplay between the external and internal environments of the individual. The functional viewpoint is the longer, larger view; it moves away from the narrow focus on pathology of various parts of the body. It removes the principal focus from diagnosis of pathology and places it on evaluation of genetic pluripotential and its translation into homeodynamic function. It views disease not as an enemy with which to grapple but as a manifestation of the breakdown of mechanisms that establish control and resilience. To restore these processes, functional medicine uses a broader range of methods than the cut-and-paste tools

of compartmentalized medicine. Among others, it employs nutrition, environmental adaptation, lifestyle changes, activity or stress pattern adjustment, or molecular pharmacology, and its selection of tools is based on the unique needs of the individual. The traditional anatomy/physiology model of Western medicine still has great value in diagnosis and treatment, and it has wide application in responding to many specific disease states. This traditional model breaks down, however, when it is applied to chronic conditions that transcend individual organs or organ systems. Among these chronic health problems are inflammation, fatigue, pain, immune dysfunction, and digestive problems. All of these conditions are characterized, not by endstage pathologies, but by altered physiologic function, and they require a more integrative model to design a therapeutic approach that can improve long-term outcome. This more integrative model is built on the understanding that dysfunction is not compartment or organ specific but is an alteration in integrated homeodynamic processes. The functional medicine approach incorporates evaluation of antecedents to a health problem, its triggering factors, mediators of altered physiologic function, and the relationship to signs and symptoms to develop an integrated view of the patient’s health status. It focuses less on defining the disease and more on understanding the functions that give rise to the expression of symptoms. A woman m ay approach her physician complaining of chronic intestinal pain and symptoms of irritable bowel syndrome, for example. A medical history and initial evaluation might uncover other symptoms, including joint pain, headache, low energy, sleep disturbances, and eczema. Rather than come up with a primary and secondary diagnosis and prescribe symptom-relieving medications, a functional medicine practitioner would delve further in evaluating the source of the inflammation. The practitioner might assess gastrointestinal function, hepatic detoxification ability, and immunologic status and then assess their relationship to oxidative stress mediators. Based on this ”second tier” of assessments, he or she would develop an integrated approach to mod* triggers and mediators using specific biologic response modifiers and lifestyle alterations of the individual.

Systems Integration and Functional Medicine The emerging science of today has blurred distinctions among organs, and separation of function into distinct compartments is less useful as a concept. Now it is known, for example, that identical signaling molecules are released and received by all organ systems, and each influencesthe function of the others. The view of the body as a collection of separate, interconnected parts is being replaced by an image of the body as a hologram. The endocrine system synthesizes a neurotransmitter that is

released by the nervous system and has a receptor site on the white blood cell. A blood cell synthesizes cytokines that are released by the immune system and have receptor cites on the glial cell in the brain. The liver synthesizes steroid hormones that are released by the endocrine system and have immune and nervous system receptors, and vice versa. In other words, all the organs and organ systems of the body are constantly engaging in “cross communication” that makes distinctions among them a matter of definition rather than function. In the past 10 years medicine has witnessed a revolution in molecular biology. For example, modifiers of gene expression are known to be not only produced by different organs but also by exposure to various agents in the diet and environment, including chemicals and electromagnetic radiation. Practitioners have learned that the processes that give rise to an individual’s health or disease are not controlled by genes alone. Instead, modification of function comes about through alteration in gene expression, transmitting new physiologic messages about individual regulation and control. This new view of health focuses on maintaining metabolic and homeodynamic freedom based on interconnectedness, pluripotential, diversity, and redundancy of function. Loss or decline in any of these parameters can be seen as an altered state of health. Altered physiologic diversity, for example, translates to a loss of metabolic freedom and a subsequent state of lower health reserve. Assessing health, therefore, depends on measuring this reserve rather than evaluating pathology. Functional challenge tests, an integral part of the practice of functional medicine, make it possible to measure specific reserves under conditions of stress. Examples of functional tests include the exercise treadmill test for cardiac function, oral glucose tolerance testing for blood sugar management, and food provocation challenges for food sensitivity. Functional medicine practitioners use the patient as his or her own ”universe,” or point of reference in which his or her unique set of interconnections, potentials, diversities, and redundancies is realized. Whether changing conditions involving time, temperature, electromagnetic energy gradients, infective organisms, or trauma lower degrees of metabolic freedom is a question that can be answered only in the context of the individual and his or her ability to maintain reserve and avoid reduced stability that comes from lost potential. Functional medicine focuses on maintenance of stability and pluripotential across organ domains. From this perspective, all organ-specific symptoms the patient possesses at any one moment reflect homeodynamic alterations at a broad, ”weblike” level and result in new meta-stable physiologic states characterized by lowered stability and reduced degrees of metabolic freedom and efficiency.The more freedom lost at this weblike level, the

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more symptoms become manifest, and the more closely they resemble classical pathology. It is the integrative, homeodynamic, regulatory role of the web that is being altered, however, not a circumscribed set of functions within a specific organ domain. As a diagnostician,a practitioner might look through a focused lens like a radiograph, blood chemistry, or computed tomography scan at an isolated, compartmentalized organ system. As a functional medicine practitioner, however, he or she views alteration in this seemingly distinct compartment as a reflection of change in the web, the whole of which is the individual and his or her unique life experience in the world.

model, is the state of positive vitality unique to each individual within his or her life context. Functional medicine employs new assessment tools to help quantify individual well-being and evaluate his or her physiologic, cognitive/emotional, and physical function. Functional medicine practitioners cannot narrowly focus on a patient’s symptoms, complaints, or history of illness. They must also evaluate the patient’s history of wellness by asking when in life the individual has felt best and what circumstances would be necessary to make that patient feel truly well again. Although relief of symptoms might be one goal of the application of functional medicine, the broader goal would be to support vitality in the patient’s life experience.

Life Processes as Homeodynamic

BASIC CONCEPTS IN FUNCTIONAL PRACTlCE The practice of functional medicine is guided by the three basic concepts of biochemical individuality, health as positive vitality, and life processes as homeodynamic.

Biochemical Individuality Each individual is unique. This uniqueness encompasses voluntary activities, such as decision making, personality development, and emotional response, and involuntary activities like metabolism of nutrients, cellular processing of information, and communications among the body’s organ systems. The concept of biochemical individuality is central to every aspect of the practice of functional medicine, from clinical assessment and diagnosis to the broad spectrum of treatment modalities. As traditionally practiced, medicine and nutrition have given only token consideration to the concept of individuality. In conditions such as phenylketonuria (PKU) or maple sugar urine disease (MSUD), for example, although medicine has long recognized that specific metabolic aberrations alter the afflicted individual’s nutrition and health needs, it has taken the view that these defects are so rare as to be inconsequential. A functional medicine practitioner, on the other hand, considers that all individuals have unique metabolic patterns that affect their nutrition and health needs. In comparing two individuals whose blood levels of B vitamins are nearly identical, for example, one might have five times as high a level of B vitamins in his or her cells as the other. Individuals also respond uniquely to environmental toxins, food additives, and prescription medications.

Health as a Positive Vitality Functional medicine views health as more than the absence of disease. Health, in the functional medicine

Homeodynamics as a principle of functional medicine contrasts to the concept of “homeostasis” in conventional medicine. Homeostasis describes the balance of interconnected components that keep a physical or chemical parameter of the body relatively constant. Homeodynamics posits a similar control system functioning to maintain biochemical individuality. Applied to the body, the term horneodynamic describes a range of continuously occurring metabolic and physiologic activities that enable an individual to adapt to changing circumstances, stresses, and experiences. The homeodynamics of one’s health are constantly at work to enable him or her to function as a unique individual. Supporting health at a homeodynamic level may require one to focus attention on cellular processes or organ function at sites that seem to be far removed from the patient’s area of discomfort and at levels that may be unusual from a conventional point of view.

ASSESSMENT AND TREATMENT FROM A FUNCTIONAL PERSPECTIVE Healing practices in any society evolve within a cultural context and draw on the belief systems and resources of the healers within that culture. In traditional societies, the background and support of healing derived from the natural world. In industrialized societies, evolving in a framework erected by Newton and Descartes, medicine formed a different understanding of the body and its function. The term diagnosis derives from the Greek word dia-gnosis, which means, literally, “through gnosis, through the knowledge gained through a perspective.” In conventional Western medicine, diagnosis is defined as ”the art of distinguishing one disease from another” or ”the determination of the nature of a case of a disease.’’ Clinical diagnosis is ”diagnosis based on symptoms, irrespective of the morbid changes producing them.” Differential diagnosis is “determining which of two or

Philosophy of Natural Medicine more diseases or conditions a patient suffers from, by systematically comparing and contrasting their symptoms.” Key concepts in these definitions are ”disease,” “symptoms,” and “suffers from,” and analysis of these concepts yields clues to the philosophic perspective underlying the Western medical approach to managing health. This underlying perspective is the key factor that differentiatesone healing system from another. It is the basis by which the authors examine patients and develop a plan of action or treatment. A physician whose perspective is oriented toward pharmacology views patients in terms of what drugs are needed. A nutritionist might look for specific nutrients or dietary changes that would benefit patients. A psychotherapist might ask which form of counseling or behavioral intervention is warranted. In each case, the course of action is dictated by the practitioner’s underlying perspective. The underlying perspective of functional medicine is based on process, dynamics, and purpose. Functional medicine focuses on dynamic processes that underlie and precede the pathologic state. Acknowledging the existence and necessity to understand pathology, functional medicine focuses on underlying processes and seeks solutions that address these processes. The practice of functional medicine does not focus on diagnosis that compartmentalizes diseases into known entities. Such a system, although it might be useful, is apt to presume that if a disorder can be named, it can be understood how it came about. Functional medicine practitioners recognize diagnosis categories, but they also investigate underlying dietary, nutritional, lifestyle, environmental, and psychosocial factors that might alter the patient’s state of health and investigatethe “purpose” behind the expression of illness.

Illness as Information From the traditional medical viewpoint, illness ”happens” to a human being; an outside force upsets a system of the body. The clinician, then, seeks to discover precisely what it was that caused the illness. Although this method is a useful view in diagnosis (since many factors including food, chemicals, and microorganisms affect our homeodynamics), it places constraints on both patient and clinician. On the other hand, if the human body is viewed as an energy-driven, energy-sensitive system that interacts constantly with its surroundings, illness can be viewed as a form of communication from one level to a level of conscious awareness. Conscious awareness enables the individual to begin to understand the factors that collectively led to the illness. Because it has a purpose, illness can be seen as a functional condition. It may function as an agent for change. It may itself be an epiphenomenon that requires treatment, but paying heed to the “message” that is

being communicated by the illness may be what finally enables healing to occur. Both scientific and popular literature often describe cases of recovery from serious illness that occurred as a result of the individual’s paying attention to the message contained in the symptoms. In clinical practice, illness communicates its messages in many ways, including symptoms arising from exposure to chemicals,rashes or breathing difficultiesfrom consming food allergens, neck pain from repetitive workplace activity, and stress-induced chest pains. Patients who present with these complaints are all getting messages about their bodies’ interactions with their surroundings. In neurology, occurrences of hysterical blindness or hemiplegia are examples of illness as information. In both conditions, physical symptoms arising from deep psychologic problems mimic severe organic disease.3l In making a diagnosis, the functional medicine practitioner must be aware of the message being sent and approach the patient’s illness not as an adversary to be overcome but as information that must be understood and acted on.

Treatment Decisions The experienced practitioner of functional medicine knows that illness typically arises from multiple influences, and his or her assessment and treatment takes this array of influences into account. In dealing with a problem like migraine headaches, for example, this approach contrasts with the traditional Western medicine approach. The latter would identify the symptom pattern, rule out vascular and intracranial pathology, and test for the presence of hypertension or renal disease. Treatment would be with drugs like sumatriptan, propranolol, or ergotamine. Biofeedback might be employed as an adjunctive therapy. The functional medicine practitioner, in contrast, would ask the migraine sufferer about dietary, nutritional, genetic, environmental, lifestyle, psychosocial, or spiritual factors that might be interacting in his or her life. The practitioner would inquire into functional changes that might underlie the expression of migraine symptoms. The goal would be to develop a range of potential patient-centered solutions to migraine headache.Remediation of migraine, for example, has been reported with oral magnesium therapy (M.A. Schmidt, unpublished data);essential fatty acid supplementation (S. Baker, personal communication, 1996); removal of food, chemical, and inhalant triggers32;sublingual neutralization therapy; spinal manipulation (P. Bolin, personal communication, 1996); acupuncture; homeopathy; and the botanical feverfew (Tanaceturn partheniurn).M The functional medicine practitioner might employ any one or a combination of these therapies, realizing that no single approach is effective with all migraine sufferers. Rea found the headache

Functional Medicine in Natural Medicine symptoms of 100% of a group of 30 migraine sufferers were triggered by chemicals under controlled challenge, but these were patients who reported chemical sensitivity.35A patient-centered approach that recognizes statistical tendencies and diagnostic categories, but is not constrained by them, is desirable. Another example of the value of the functional medicine approach is in assessing microbe-associated illness. The traditional approach to infectious disease regards the organism as an external threat that must be eradicated by intervention specifically targeting that organism. The microbe is the enemy, and drug therapy is the typical weapon. A broader, functional medicine approach would view the microbe as just one (albeit important) of the factors contributing to poor health. The functional medicine practitioner would consider the state of the host’s defenses and evaluate factors that influence host defenses by examining nutritional, metabolic, environmental, lifestyle, and psychosocial factors that influence immune vigdance. The philosophic basis of functional medicine leads to treatment decisions quite different from those typically encountered in an infectious disease model. For example, a patient with Down syndromewho suffers from recurrent infection with Streptococcus pneurnoniue or Hmophilus influenme may experience an increase in IgG2 and IgG4 production and a reduction in infection susceptibility with selenium supplementation.36A child with otitis media with effu-sion might be treated not with antimicrobials, but with elimination of allergenic f0ods.3~An endurance runner who suffers from upper respiratory tract infection associated with heavy training might be given antioxidant^.^^

Concept of Total Load Total load refers to the sum of influences affecting an individual’s life. Initially advanced by environmental medicine practitioners, the concept is now widely adopted. Included in the total load are chemicals, food, microbes, psychologic stressors, and other factors, each of which alone might not give rise to the symptoms of illness. Together, however, the factors that comprise the total load may overwhelm the patient’s metabolic management system. According to Rea, more than 20,000 patients at his Environmental Health Center in Dallas experienced relief of symptoms of a range of clinical disorders through reduction of total l0ad.3~ A person’s biochemical individuality affects his or her susceptibility to toxins, and intervention aimed at improving function can help reduce susceptibility or sensitivity. A defective sulfur metabolism pathway, for example, might cause an individual who reacts to sulfurrich foods to react to other substances in ways that lead to metabolic disturbance. Nutrient modulation might lessen his or her sensitivity to these environmental

substances. Efforts to reduce total load should be balanced by efforts to restore function, with the long-range goal being reduced susceptibility.

Depth of Action The functional perspective requires the practitioner to examine the processes that give rise to symptoms. Arriving at a diagnosis does not guarantee that practitioners understand what is happening or what the patient needs. For example, a practitioner might amve at a diagnosis of “mood disorder” in a depressed patient and assume he or she would benefit from a drug like fluoxetine. If the depression arose from a spiritual or relationship crisis, however, the drug therapy might actually interfere with the problem-solving processes that would lead to true healing. Mood and quality of life might appear to improve with drugs, but the patient’s long-term healing would not have been facilitated. A group of epileptic children who were videotaped as they interacted with their families illustrates the point. Emotionally fraught family encounters were, in many cases, followed by seizures. When the epileptic patients were later shown films of these episodes, and they saw the relationship between emotional events and seizures, they were able, in many instances, to become almost seizure free.40Granted, drug therapy might have helped these patients control seizures, but if drugs were the only means of intervention employed, the epileptic children would not have had the opportunity to experience healing at a deeper level.

Mechanism and Outcome Understanding biochemical mechanisms enables functional medicine practitioners to apply them in diagnosis and treatment. Understanding the mechanism of homocysteine accumulation, for example, allows them to recommend nutritional strategies like folic acid and vitamin BI2therapy. By understanding fatty acid synthesis and the arachidonic acid cascade, they can develop nutritional therapies that mod+ inflammation. Knowing that copper accumulation leads to Wilson’s disease allows them to use zinc therapy. Some treatment modalities bring positive outcomes for which the mechanism is not yet well understood. Spinal manipulation in asthmatics admitted to the emergency department, for example, can lessen anxiety and ease breathing. This treatment typically brings about a 25% to 70%improvement in measurement of peak blood fl0w.4~Using premanipulation and postmanipulation tympanographs, Fallon showed that spinal manipulation in children with otitis media led to normalization of abnormal tympanograms (J. Fallon, personal communication of prepublication findings, 1995). Similarly, in personal communication (1996), V. Fryman has shown

Philosophy of Natural Medicine

that cranial manipulation normalizes tympanographic measurements in some children. Knowledge that viscerosomatic and somatovisceral reflexes influence the flow of information within the human body suggests the possible mechanism by which manipulation affects visceral function, although the mechanism is not yet clearly understood. Improved function, patient outcome, and quality of life are central to the success of any healing system, however, whether or not we understand the mechanisms of action. Homeopathic medicine is a discipline that is not bound by mechanism but is rooted in careful analysis and pattern recognition. Reilly demonstrated that asthmatic patients who took homeopathic preparations showed signhcant improvement in only 1 week compared with those taking placebo. These dramatic results led him to conclude that either homeopathic medicine worked beyond a shadow of a doubt, or the double-blind, placebocontrolled trial, the gold standard of proof on which modem pharmacology is built, is essentially invalid.42 Throughout the range of healing arts and sciences, numerous examples of positive treatment outcomes occur,even though the mechanism cannot be explained. In functional medicine, the value of understanding mechanisms is in improving human function and patient outcome.

Prevention, Early Detection, and Functional Medicine ”Prevention” has become a welcome and popular concept in recent years in the practice of medicine. A distinction must be made, however, between true prevention and “early detection.” Although periodic mammography has been heralded as a form of preventive medicine, for example, it is clearly in the realm of early detection. Prevention assumes an understanding of factors that give rise to breast cancer and recommendatiodadoption of habits or patterns that prevent disease occurrence. Both prevention and early detection are included in the practice of functional medicine, but the patient’s individuality remains paramount. Functional medicine practitioners work to prevent a specific disorder by managing risk factors, but they also strive to raise the individual’s functional capacity within his or her unique life circumstances.

Approach to the Patient Functional medicine is always patient centered, but it is not the only discipline that fits this description. Naturopathic medicine has helped pioneer a patientcentered medical approach, not only by making the whole person the center of its practice, but also by incorporating highly patient-centered traditions into its repertoire, including traditional Chinese medicine, Ayurvedic

medicine, homeopathy, chiropractic, and physical therapy, including manipulation and massage. The focus on the patient is important, however, because as methods of data management become more sophisticated, the tendency is to think in terms of probability instead of thinking in terms of the individual patient. Probability is useful in understanding the broad context of health and disease, but clinical practice is filled with so many exceptions that relying on statistics is difficult.

Laboratory and Instrumental Diagnosis from a Functional Perspective In assessing a patient’s health, the functional medicine practitioner uses tools that help him or her understand how the patient functioned before he or she developed the pathology. These tools also help the practitioner understand function in the existence of pathology and assist in predicting preventive measures. Serum glucose measurement is a traditional assessment of a fixed analyte at a fixed point in time. Although this measurement yields useful information, it does not reveal how serum glucose responds under varying dietary conditions. The glucose challenge test, on the other hand, is a functional test that assesses glucose status over time. Similarly,although a resting electrocardiogram (ECG) provides useful information, it does not indicate how the heart would respond to a physical challenge. The stress ECG shows how the heart responds to exertion. Assessment of magnesium is a third example. Magnesium is an intracellular element, which means that most of the body’s magnesium stores are contained within cells, and only a small amount circulates in blood. A measurement of serum magnesium levels, therefore, does not reflect total body magnesium or the functional status of magnesium. Red cell magnesium is a better indicator of status, although it is a measurement of a fixed analyte at a fixed point in time and has limitations as well. Magnesium loading and subsequently assessing retention by measuring urinary excretion provides a means to assess the functional magnesium status and the unique needs of a particular patient. For functional medicine practitioners, tools that view the body under challenge conditions give a more accurate assessment of body function. This is especially true when one wishes to examine the body’s response to exogenous substances. Some individuals experience an adverse reaction to any given drug, and these reactions are regarded as atypical and unavoidable. From a different perspective, however, the reactions are not atypical and unavoidable; they are typical and avoidable for that person, and he or she would typically be expected to have an adverse reaction on ingestion of this drug. This understanding comes from developments in understanding the body’s detoxification mechanisms. When a drug or medication is ingested, it is metabolized

Functional Medicine in Natural Medicine

by the body and prepared for excretion. The process of detoxification and preparation for excretion takes place in two distinct biochemical phases, known as phases 1 and 2. In the biotransformation of a drug or chemical, the agent is progressively converted to a more watersoluble, excretable substance. In phase 1,which generally occurs first, a family of isozymes known as cytochrome P450 (cP450) converts the drug or substance into a reactive intermediate, which, although it may be excreted in its present form, is typically further acted on by phase 2 processes. In phase 2, conjugating substances are attached to the phase 1product to facilitate its excretion.Phase 2 reactions typically take place through glucuronidation, amino acid conjugation, glutathione conjugation, acetylation, and methylation.” The phase 2 process, which depends strongly on adequacy of specific nutrients, must be capable of transforming all of the phase 1-generated reactive molecules into excretable compounds. If this process is incomplete, toxic intermediates can build up. Acetaminophen is a typical drug that undergoes conversion for excretion through these two pathways. A common over-the-counter and prescription pain-relieving drug, acetaminophen is a useful model because more than 70,000 incidents of acetaminophen overdose were reported to U.S. poison control centers in 1994.44 Acetaminophen normally undergoes phase 2 transformation through the sulfation and glucuronidation pathways, with a small amount being metabolized through glutathione conjugation after conversion in phase 1.45 When the drug is not efficiently converted for excretion, the metabolites that build up can have negative metabolic consequences. Accumulations of one extremely toxic metabolite, NAPQI, may cause liver and nervous system damage. An individual with an adequately functioning detoxification ability that facilitates efficient phase 2 conversion of acetaminophen is less likely to have a negative experience than one whose ineffective conversion pathways allow toxic intermediates to accumulate. If an individual ingests acetaminophen on a regular basis, the sulfur-bearing nutrients glutathione, methionine, and cysteine can be depleted rapidly, with accompanying liver cell damage.& Therefore adverse acetaminophen reactions may result from alterations in detoxification pathways. The acetaminophen challenge test effectively assesses function of these pathways. After the individual has consumed a challenge substance, measurements of acetaminophen metabolites in urine

can determine the efficiency of the various conversion processes and provide information about the individual’s unique susceptibility. It may be that alterations in the detoxification pathways of many individuals who have ”atypical” drug reactions are making them predictably susceptible to certain kinds of substances. If practitioners can gather this information about them, they may be able to predict their response to drugs, as well as chemicals, foods, and plants. Practitioners may be able to understand the functional derangement that underlies the pathology that can result from interaction with the environment. And they may be able to use diet and nutrition to help individuals restore function in these pathways.

Pattern Recognition The next step in the evolution of functional assessment is to consider human physiology as a dynamic process involving the interrelationship of multiple systems. Functional assessment of only one pathway or one series of pathways may yield useful information, but it still provides a limited view. Functional testing will no doubt evolve to assess multiple analytes and use sophisticated pattern recognition methods. Pattern recognition is not new. For centuries, traditional Chinese medicine has dealt with ”patterns of disharmony.” The clinician trained in this discipline learns to recognize the pattern and assign it to a specific diagnostic category. In homeopathic medicine, it was pattern recognition that led to the extensive muferiu medicu. In psychotherapy, an evaluation of the patient’s life events and stories is conducted in an effort to understand the patterns that produce disharmony. In all these examples, the mechanisms are unimportant; the pattern leads to treatment decisions.

SUMMARY Pattern recognition, depth of action, total load, energetics, information, and patient-centered decisions all describe the early stages of development of the evolving functional approach to assessment and treatment. They also characterize a functional approach with a strong focus on the integrative use of treatment modalities based on recognition of underlying purpose in the transformations practitioners view as they work with individual patients. This is also the integrative paradigm that unites naturopathy with functional medicine.

1. Urdang L, Flexner SB. Random House dictionary of the English language. New York Random House, 1968:535. 2.Peters FE. Greek philosophical terms. New York New York University Press, 196761-62. 3.Peters FE. Greek philosophical terms. New York: New York University Press,1967152-155. 4. Young R. Mind, brain and adaptation in the nineteenth century. Oxford, UK:Clarendon Press,19709-53. 5. Young R. Mind, brain and adaptation in the nineteenth century. Oxford, UK:Clarendon Press,197043. 6. Allison N, ed. Illustrated encyclopedia of body-mind disciplines. New Yorum, NY Rosen Publishing Group, 1998. 7. Anderson R. Wehess medicine. Lynnwood, WA: American Health Press, 19876. 8. American Holistic Medical Association. Raleigh, NC: Available online at http:/7www.doubleclickd/com/about-ahma.htm1. 9. Fuller RB. Synergetics: explorations in the geometry of thinking. New York Macmillan Publishing, 1975:58. 10. Weiner LH, Mayer LF, eds. Oral tolerance: mechanisms and applications. Ann N Y Acad Sci 1996;778:xiii-xvii:6-7. 11. Raloff J. Eyes possess their own biological clocks. Sci News 1996;149245. 12. Tamarkin L, Bond CJ, Baird J, et al. Melatonin: a coordinating signal for mammalian reproduction? Science 1985;227714-720. 13. Portrnann A. Animal forms and patterns: a study of the appearance of animals. New York schocken Books, 1967;17:34. 14. Portmann A. Animal forms and patterns: a study of the appearance of animals. New York Schocken Books, 1967;17196. 15. Bernard C. An introduction to the study of experimental medicine (1865).Gmne HC, transl. New York Dover Publications, 1957. 16. Bemard C. An introduction to the study of experimental medicine (1865).Greene HC, transl.New York Dover Publications, 195767. 17. Bemard C. An introduction to the study of experimental medicine (1865).Greene HC, transl. New York Dover Publications, 195776. 18. Karjalainen J, Martin JM, Knip M, et al. A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med 1992;327(5):302-307. 19. National Academy of Sciences. Biologic markers in immunotoxicology. Washington, DC:National Academy Press, 199255. 20. Nobuyuki H, E t s w Y, Satoshi K, et al. A functionalpolymorphism in the RANTES gene promoter is associated with the development of late-onset asthma. Am J Respir Crit Care Med 2002; 166:686-690. 21. Berdanier CD, Hargrove JL. Nutrition and gene expression. Boca Raton, n:CRC Press, 1993. 22. McKeon R. Introduction to Aristotle. New York: Modem Library, 1947123. 23. Block KI. The role of self in healthy cancer survivorship: a view from the frontlines of treating cancer. Adv Mind Body J 1997. 24. Monod J. Chance and necessity. New York Vintage, 1971:21. 25. Monod J. Chance and necessity. New York Vintage, 1971:145.

26. Jonas H. The phenomenon of life: toward a philosophical biology. New York: Delta, 1971:46-47. 27. Foundation for Preventive Medicine. New York Available online at

http://wuw. prpuentiwemed.org. 28. Alberts B, Bray D, Lewis J, et al. Molecular biology of the cell. New York: Garland Publishing, 198362. 29.Zong-xiang Z. Recent advances in the electrical specificity of meridians and acupuncture points. Am J Acupunct 1981;9(3):203-215. 30.Cook TM. Homeopathic medicine today. New Canaan, CT: Keats Publishing, 1989~21-30. 31. DeMeyer WE. Technique of the neurological examination, ed 4. New York McGraw-Hill, 1994512-513. 32. Rea WJ. Chemical sensitivity, vol 4. Boca Raton, FL: CRC Press, 19961177-1178. 33. Hoover S. Meniere’s migraine and allergy. In Claussen CF, Kirtan MV, W i t t e r K, eds. Vertigo, nausea, tinnitus, and hypoacusia in metabolic disorders. New York: Elsevier Science Publishers, Biomedical Dvision, 1988:293-300. 34. Awang DVC. Feverfew. Can Pharm J 1989;122:266-270. 35. Rea WJ. Chemical sensitivity, vol 4. Boca Raton, FL: CRC Press, 1996:1177. 36. Anneren G, Magnusson CGM, Nordvall SL. Increase in serum concentrationsof IgG2 and IgG4 have been observed with selenium supplementation in children with Down syndrome. Arch Dis Child 1990;65:1353-1355. 37. Nsouli TM. Role of food allergy in serous otitis media. Ann Allergy 1994;73(3):215-219. 38. Peters EM. Vitamin C supplementation reduces the incidence of post-race symptoms of upper respiratory tract infection. Am J Clin Nutr 1993;57. 39. Rea WJ. Chemical sensitivity, vol 4. Boca Raton, n:CRC Press, 1996 preface. 40. Brown B. Supermind: the ultimate energy. New York Harper & Row, 1980:275. 41. Paul FA, Buser BR. Manipulative treatment applications for the emergency department patient. J Am Osteopath Assoc 1996;96(7):

403-409. 42. Reilly DT. Is evidence for homeopathy reproducible? Lancet 1994;344:1601-06. 43. Murray R, Granner D, Mayes P, Rodwell V. Harper’s biochemistry. Norwalk, CT: Appleton & Lange, 1990. 44.Anil D, Sorrell MD. Acetaminophen overdose: need to consider intravenous preparation of N-acetylcysteine in the United States. Am J Gastroenterol1996;91(7):1476. 45. Pate1M, Tang B, Kalow W. Variability of acetaminophen metabolism in Caucasians and Orientals. Pharmacogenetics 1992;238-45. 46.Willson RA, Hall T. The concentration and temporal relationships of acetaminophen-inducedchanges in intracellular and extracellular total glutathione freshly isolated hepatocytes from untreated and 3-methylcholanthrene pretreated Sprague-Dawley and Fischer rats. Pharmacol Toxic01 1991;69:205-212.

A Hierarchy of Healing: The Therapeutic Order The Unifying Theory of Naturopathic Medicine Jared Zeff, ND, LAC

Pamela Snider, ND Stephen P.Myers, ND, BMed, PhD CHAPTER CONTENTS A Brief History of Naturopathic Medicine 27

Original Philosophy and Theory 28 Modern Naturopathic Clinical Theory: The Process of Development 29

A Theory of Naturopathic Medicine 31

2. Stimulate the Self-Healing Mechanisms 36

3. Support Weakened or Damaged Systems ororgans 36 4. Address Structural Integrity 37 5. Address Pathology: Use Specific Natural Substances, Modalities, or Interventions 37 6. Address Pathology: Use Specific Pharmacologic or Synthetic Substances 38 7. Suppress Pathology 38

Illness as Process 32 Theory in Naturopathic Medicine 38 The Determinants of Health 34 Therapeutic Order 34 1. Establish the Conditions for Health 34

A BRIEF HISTORY OF NATUROPATHIC MEDICINE Benedict Lust "invented" naturopathy in 1902. Naturopathic medicine has deep roots, some of its therapies emerging from the mists of prehistory, but the modern naturopathic profession originated with Lust, and it grew under his tireless efforts. He crisscrossed the United States lecturing and lobbying for legislation to license naturopathy, testifying for naturopaths indicted for practicing medicine without a license and traveling to many events and conferences to help build the profession. He also wrote extensively to foster and popularize the profession, and through his efforts the naturopathic profession grew By the 1940s naturopathic medicine had developed a number of 4year medical schools and had achieved licensure in about one third of the United States, the District of Columbia, four Canadian provinces, and a number of other countries?** By 1957, however, there was only one naturopathic college left. By 1965 only eight states still licensed naturopathic physicians, and by 1979 there were only six. A survey conducted in 1980 demonstrated only about 175 naturopathic practitioners still licensed and practicing in the

United States and Canada.5 In 1951 the number was approximately 3000.6 The decline of naturopathic medicine after a rapid rise was due to several factors. By the 1930s a significant tension was developing within the profession regarding naturopathic practice; the development of unified standards; and the role of experimental, reductionist science as an element of professional d e v e l ~ p m e n t . This ~,~ tension split the profession of naturopathic physicians from within after the death of Lust in the late 1940s, at a time when the profession was subject to both s i m c a n t external forces and internal leadership challenges. Many naturopathic doctors questioned the capacity for the reductionist scientific paradigm to research naturopathic medicine objectively in its full scope. This perception created mistrust of science and of research. Science was also frequently used as a bludgeon against naturopathic medicine, and the biases inherent in what had become the dominant paradigm of scientific reductionism made a culture of scientific progress in the profession challenging. The discovery of effective antibiotics elevated the standard medical profession to dominant and unquestioned stature by a culture that had turned to mechanistic 27

science as an ultimate authority. The dawning of the atomic age reinforced a fundamental place for science in a society increasingly dominated by scientific discovery. In this culture, standard medicine, with its growing political and economic strength, was able to force the near elimination of naturopathic medicine through the repeal or sunsetting of licensure acts.’Jr9 In 1956, as the last doctor of naturopathy (ND)program ended (at the Western States College of Chiropractic), several doctors in the Northwest created the National College of Naturopathic Medicine in Portland, OR, to keep the profession alive. But that school was nearly invisible, the last vestige of a dying profession, and attracted rarely as many as 10 new students a year. The profession was considered dead by its historic adversaries. The culture of America, dominated by standard medicine since the 1940s, began to change by the late 1960s. The promise of science and antibiotics was beginning to seem less perfect. Chronic disease was increasing in prevalence as acute infection was less predominant, and standard medicine had no ”penicillin” for chronic diseases. In the late 1970s, family medicine proposing a biopsychosocial model of care emerged within conventional medicine in response to the perception then of a growing crisis in standard medicine. The publication of Engel’s “The Need for a New Medical Model”loin April 1977 signaled this trend. Elements of the culture were rebelling against plastics and cheap synthetics, seeking more natural solutions. The publication of Rachael Carson’s Silent Spring, an indictment of chemical pesticides and environmental damage, marked a turning point in cultural thinking. In Silent Spring (1962) Carson challenged the practices of agricultural scientists and the government and called for a change in the way humankind viewed the natural world.” New evidence of the dangers of radiation, synthetic pesticides, and herbicides, as well as environmental degradation from industrial pollution, were creating a new ethic. Organic farming, natural fibers, and other similar possibilities were starting to capture attention. A few began seeking natural alternatives in medicine. By the late 1960s and early 1970s, enrollments at National College of Naturopathic Medicine began to reach into the 20s. In 1975 National College enrolled a class of 63 students. The 1974 class had numbered 23.12 The profession was experiencing a resurgence. In 1978, with increasing enrollment interest at National College, Joseph E. Pizzorno, ND, LM, and his colleagues (Les Griffith, ND, LM; Bill Mitchell, ND; and Sheila Quinn) created the John Bastyr College of Naturopathic Medicine in Seattle,WA. With the creation of Bastyr, named after the eminent naturopathic physician Dr.JohnBartholomew Bastyr (1912-1995),the profession entered a new phase. Not only did this new college

double the profession’s capacity to produce new doctors, it also firmly placed the profession upon the ground of scientific research and validation. ”Science-based natural medicine” was a major driving force behind the creation and mission of Bastyr. Both Drs. Bastyr and Pizzorno had significant influence and leadership in achieving this focus. One of Bastyr’s important legacies was to establish a foundation and a model for reconciling the perceived conflict between science and the deeply established healing practices of naturopathic medicine. Kirchfeld and Boyle described his landmark contribution as follows: Although naturopathic colleges in the early 1900s did include basic sciences training, it was not until Dr.John Bastyr (1912-1995) and his firm,efficient and professional leadership that science and research-based training in natural medicine was inspired to reach its fullest potential. Dr. Bastyr, whose vision was one of “naturopathy’s empirical successes documented and proven by scientific methods,” was himself “the prototype of the modem naturopathic doctor, who culls the latest findings from the scientific literature, applies them in ways consistent with naturopathic principles and verifies the resultswith appropriatestudies.“Bastyr also saw a tremendous expansion in both allopathic and naturopathic medical knowledge, and he played a major role in making sure the best of both were integrated into naturopathic medical ed~cation.3,’~ Bastyr met Lust on two occasions and was closely tied to the nature cure tradition of Kneipp through his mother and Dr. Elizabeth Peters. He effortlessly reconciled the empirical tradition of naturopathy with the latest scientific studies, and helped create a new and truly original form of clinical care naturopathic medicine. He spent the twentieth century preparing the nature cure of the nineteenth century for entry into the twenty-first century.’J3 “Today’s debates concerning the philosophical range in the profession are no longer about science. They tend to center on challenges to “green allopathy’’ vs the importance of implementing the full range of healing practices derived from nature cure, along with natural substances. Professional consensus appears strong that the fullrange of naturopathic healing practices must be retained, strengthened and engaged in the process of education and scientific research and discovery in the twenty-first century.14-16

ORIGINAL PHILOSOPHY AND THEORY Through the initial 50-year period of professional growth and development (1896-1945), naturopathic medicine had no clear and concise statement of identity. The profession was whatever Lust said it was. He defined “naturopathy” or ”nature cure“ as both a way of life and a concept of healing that used various

A Hierarchy of Healing: The Therapeutic Order natural means of treating human infirmities and disease states. The “natural means” were integrated into naturopathic medicine by Lust and others based on the emerging naturopathic theory of healing and disease etiology. The earliest therapies associated with the term involved a combination of American hygienics and AustroGermanic nature cure and hydrotherapy. Leaders in this field included Lindlahr, Trall, Kellogg, Holbrook, Tilden, Graham, Kuhne, McFadden, Rikli, and others who wrote foundationalnaturopathic medicine treatises or developed naturopathic clinical theory, philosophy, and texts, enhancing, agreeing with, and diverging from Lust’s original Naturopathic medicine was defined most formally by the various licensure statutes, but these definitions were legal and scope-of-practice definitions, often in conflict with each other, reflecting different standards of practice in different jurisdictions. In 1965 the U.S. Department of Labor’s Dictionary of Occupational Titlesz6 presented the most formal and widespread definition, perhaps, but it reflected one of the internally competing views of the profession, primarily the nature cure perspective: Diagnoses, treats and cares for patients using a system of practice that bases treatment of physiological function and abnormal conditions on natural laws governing the human body. Utilizes physiological, psychological and mechanical. methods such as air, water, light, heat, earth, phytotherapy, food and herbs therapy, psychotherapy, electrotherapy,physiotherapy, minor and orificial therapy, mechanotherapy,naturopathic corrections and manipulations, and natural methods or modalities together with natural medicines, natural processed food and herbs and natural remedies. Excludes major surgery, therapeutic use of x-ray and radium, and the use of drugs, except those assimilable substances containing elements or compounds which are components of body tissues and physiologically compatible to body processes for the maintenance of life.26

This definition did not list drugs or surgery within the scope of modalities available to the profession. It defined the profession by therapeutic modality and was more limited than most of the statutes under which naturopathic physicians practiced, even in 1975 when there were only eight licensing authorities still a~tive.2~ The bulk of professional theory was found in Lust’s magazines: Herald of Health and The Naturopath. These publications displayed the prodigious writings of Lust but did not contain a comprehensive and definitive statement of either philosophy or clinical theory. Lust often stated that all natural therapies fell under the purview of naturopathy. Several other texts were also used as somewhat definitive by various aspects of the

profession at different times. These texts included Henry Lindlahr, MD’s seven-volume Natural Therapeutics, published in the early 1900s.Lindlahr’s Nature Cure (1913) is considered a seminal work in naturopathic theory, laying the groundwork for a systematicapproach to naturopathic treatment and diagnosis. Lindlahr ultimately presented the most coherent naturopathic theory extant, summarized in his Catechism of Naturopathy, which presented a five-part therapeutic progression: 1.“Return to Nature,” which meant attend to the basics of diet, dress, exercise, rest, etc. 2. Elementary remedies-water, air, light, electricity 3. Chemical remedies-botanicals, homeopathy, etc. 4.Mechanical remedies-manipulations, massage, etc. 5. Mental/spiritual remedies-prayer, positive thinking, doing good works, etc.= In the 1950s Spitler wrote Basic Naturopathy, a and Wendel, Standardized N ~ t u r o p a t h yThese .~~ texts presented the somewhat opposing perspectives of the more science-based, or “green allopathic,” and the nature cure camps. Kuts-Cheraux’s Naturopathic Materia Medica, written in the 1950s, was produced to satisfy a statutory demand by the Arizona legislaturebut persisted as one of the few extant guides. Practitioners have relied on a number of earlier texts, many of which arose from the German hydrotherapy pra~titioners~l-~ or the Eclectic school of medicine (a refinement and expansion of the earlier ‘Thomsonian” system of medicine)3741and predated the formal American naturopathic profession (1896). But by the late 1950s, publications diminished. The profession was generally considered on its last gasp, an anachronism of the preantibiotic era.

MODERN NATUROPATHIC CLINICAL THEORY THE PROCESS OF DEVELOPMENT ”Medical philosophy comprises the underlying premises on which a health care system is based. Once a system is acknowledged, it is subject to debate. In Naturopathic medicine, the philosophical debates are a valuable, ongoing process which helps the understanding of health and disease evolve in an orderly and truth revealingfashion.” -Randall Bradley, ND.42

After the profession’s decline in the 1950s and 1960s, a rebirth was experienced, more grounded in medical sciences and fueled by a young generation with few teachers. The profession’s roots were neglected out of ignorance, for the most part, along with a youthful arrogance. By the early-1980s it was apparent that attempts

to regenerate the progress made by Lust would require the creation of a unified professional organization and all which that entailed: accreditation for schools, national standards in education and licensure, clinical research, and the articulation of a coherent definition of the profession for legislative purposes, as well as for its own internal development. These accomplishments would be necessary to be able to demonstrate the uniqueness and validity of the profession, guide its educational process, and jusbfy its status as a separate and distinct medical profession. In 1987the newly formed (1985)American Association of Naturopathic Physicians (AANP) began this task under the leadership of James Sensenig, ND, (president) and Cathy Rogers, ND, (vice president) appointing a committee to head the creation of a new definition of naturopathic medicine. The ”Select Committee on the Definition of Naturopathic Medicine” succeeded in a %year project that culminated in the unanimous adoption by A A ” s House of Delegates of a comprehensive, consensus definition of naturopathic medicine in 1989 at the a n n d convention held at Rippling River, OR.M5The unique aspect of this definition was its basis in definitive principles, rather than therapeutic modalities, as the defining characteristicsof the profession. In passing this resolution, the House of Delegates (HOD) also asserted that the principles would continue to evolve with the progress of knowledge and should be formally reexamined by the profession as needed, perhaps every 5 years.In September 1996 the AANP HOD passed a resolution to review three proposed principles of practice that had been recommended as additions to the AANP definition of naturopathic medicine originally passed by the HOD in 1989. These three new proposed principles were rejected, and the AANP HOD reconfirmed the 1989 AANP definition unanimously in 1999. The results of a profession-wide survey conducted from 1996-1998 on these three new proposed principles demonstrated that while there was lively input, the profession agreed strongly that the original definition was accurate and should remain intact. The HOD recommended that the discussion be moved to the academic community involved in clinical theory, research, and practice for pursuit through scholarly dial0gue.4~-~~ This formed the basis for further efforts to articulate a clinical theory. AANP members had stated in 1987-1989 during the definition process: “These principles are the skeleton, the cure of naturopathic theory. There will be more growth from this f~undation.”~~ By 1997 this growth in modern clinical theory was evident. The first statement of such a theory was published in the AANP’s Iournal of Naturopathic Medicine in 1997 in an article titled “The Process of Healing, a Unifying Theory of Naturopathic Medicine.” This article contained three fundamental concepts that were presented as an

organizing theory for the many therapeutic systems and modalities used within the profession and was based on the principles articulated in the consensus AANP definition of naturopathic medicine. The first of these is the characterization of disease as a process rather than a pathologic entity. The second is the focus on the determinants of health rather than on pathology. The third is the concept of a therapeutic hierarchy? The article, ”The Process of Healing: A Urufylng Theory of Naturopathic Medicine” signaled the emergence of a growing dialogue amongst physicians, faculty, leaders and scholars of naturopathic philosophy concerning theory in naturopathic medicine. The hope and dialogue sparked by this article was the natural next step of a profession redefining itself both in the light of today’s advances in health care, and with respect to the foundations of philosophy at the traditional heart of naturopathic medicine. This dialogue naturally followed the discussionsof the definition process and created a vehicle for emerging models and concepts to be built on the bones of the principles. The genome of traditional naturopathic philosophy had been carried in the hearts and minds of a new generation of naturopathic physicians into the twenty-first century-these modern naturopathic physicians began to gather to redefine and reurufy the soul of the medicine and articulate the code of the naturopathic genome. This new dialogue was formally launched in 1996, when the AANP Convention opened with the plenary session: “Towards a Ururylng Theory of Naturopathic Medicine” with four naturopathic physicians presenting facets of emerging modem naturopathic theory. The session closed with an open microphone. The impassioned and powerful comments of the naturopathic profession throughout the United States and Canada engaged in the vital process of deepening and clarifymg its urufying theory. Dr. Zeff presented “The Process of Healing: The Hierarchy of Therapeutics”; Dr.Mitchell presented “The Physics of Adjacency, Intention Naturopathic Medicine and Gaia”; Dr.Sensenig presented “Back to the Future: Reintroducing Vitalism as a New Paradigm”; and Dr. Snider announced the Integration Project, inviting the profession to engage in it by ”sharing a beautiful and inspiring anguish-the labor pains of naturopathic theory in the twenty-first century. We know what we have done, and we know there is much more. . . . The foundation is laid. We are ready now [for integrati~n].”~~ Days later, in September 1996, the Co&ortium of Naturopathic Medical Colleges (now American Association of Naturopathic Medical Colleges [AANMC]) formally adopted and launched the Integration Project: an initiative to integrate naturopathic theory and philosophy throughout all divisions of all naturopathic college curricula, from basic sciences to clinical training. A key element of the project engaged the further development

A Hierarchy of Healing: The Therapeutic Order

and refinement of naturopathic theory. The project has been cochaired by Drs. Snider and Zeff since 1996. Steering members from all colleges have participated and ~ o n t r i b u t e d .Methods ~~ include professional and scholarly research, expert teams, symposiums, and training. The proposed result is the fostering of systematic inquiry among academicians, clinicians, and researchers concerning the underlying theory of naturopathic medicine and to bring the fruits of this work and inquiry into the classroom and into scientific research.% The Integration Project has sustained both formal and informal dialogue since its inception in 1996, which continues today. The work has engaged faculty and scholars of naturopathic philosophy in the United States, Canada, and Australia. It also engaged institutional leaders and practicing doctors and faculty in all areas of the profession. Why? Naturopathic philosophy is deeply felt as the "commons" of naturopathic medicine: a place where the profession meets; one that is owned by all naturopathic physicians; and reflects, holds, and deepens the heart of naturopathic medicine. Naturopathic philosophy is the foundationand heart of naturopathic medicine. It remains valid by evolving with the progress of knowledge, the progress of science, and the progress of the human spirit. Because naturopathicphilosophy engages the felt mission of nature doctors, it is vital that the profession periodically gathers to renew and revitalize progress regarding its u"lfymg foundations. The Integration Project sparked a wide range of activities in all six ND colleges, resulting in all-college retreats to share tools, retreats for training of non-ND faculty in naturopathic philosophy, integration of basic sciences curriculum, expert teams revision of core competencies across departments ranging from nutrition to case management and counseling, development of clinical tools and seminars for clinic faculty, creation of new courses, and the integration of important research questions derived from naturopathic philosophy into research studies and initiatives?' North American core competencies for naturopathic philosophy and clinical theory were developed by faculty representing all accredited ND colleges in a landmark AANMC retreat in 2000. The AANMC's Dean's Council formally adopted these competencies in 2000 and recommended that they be integrated throughout curricula in all ND colleges. These national core competencies included the hierarchy of therapeutics, or the therapeutic 0rder.%3~ Finally, many meetings with scholars and teachers of naturopathic theory and other faculty and leadersformal and informal-have resulted in the further development and refinement of the hierarchy of therapeutics developed by Dr. Zeff in 1997. Drs. Snider and Zeff and naturopathic theory faculty have worked closely with other naturopathic faculty from AANMC colleges in a series of revisions. Drs. Snider and Zeff collaborated in

1999 to develop the hierarchy of therapeutics into the therapeutic order. The therapeutic order has been subsequently explored and refined also through a series of faculty retreats and meetings, as well as experience with students. A key fkding of the clinic faculty at Bastyr University was the emphasis on the principle "holism: treat the whole person" and respect for the patient's own unique healing order and his or her values as a context for applying the therapeutic order to clinical decision maknig@ . -' The therapeutic order, or hierarchy of healing, is now incorporated into ND college curricula throughout the United States, Canada, Australia, and New Zealand. For example, an important international outgrowth of the profession's development of theory is the adoption of the unified "Working Definition of Naturopathic Nutrition" in June 2003 by the Australian naturopathic profession (Box 3-1). The 3-year project under the coordination of Professor Stephen Myers, ND, BMed, PhD, brought together nutrition faculty from naturopathic medicine colleges throughout Australia. The project was cohosted by the Naturopathy and Nutrition panel, an independent group of naturopaths and nutrition educators whose mission is to foster and support the development of the science, teaching, and practice of naturopathic nutrition, and the School of Natural and Complementary Medicine at Southern Cross University. The definition evolved over two retreats attended by more than 40 faculty members involved in teaching nutrition as part of naturopathic medicine education. It commenced as a general agreement within the group that there was a real and distinct difference between conventional nutrition and naturopathic nutrition. General agreement was that the distinction between the two had to date been poorly defined and had been the source of dissonance between the naturopathic and science faculty within the colleges. The obvious next step was to define that difference to ensure that nutrition curriculum within naturopathic medicine colleges reflected the core elements of naturopathic nutrition. At the second retreat held in June 2003, the working definition was adopted with a recommendation that it be widely circulated within the naturopathic medicine profession to commence a dialog aimed at both appropriate revision and broad adoption. This process created a much-needed consensus definition on naturopathic nutrition. This definition is based on the AANP defining principles and incorporates the therapeutic order theory.

A THEORY OF NATUROPATHIC MEDICINE Standard medicine, or biomedicine, has a simple and elegant paradigm. Simply stated, it would be "the diagnosis and treatment of disease." In practice, this statement

Philosophy of Natural Medicine

Preamble Naturopathic medicine is a distinct system of primary health carart, science, philosophy and practice of diagnosis, and treatment and prevention of illness. Naturopathic medicine is distinguished by the principles that underlie and determine its practice. These principles include the healing power of nature (vis medicatfix naturae), identification and treatment of the causes (tole causam), the promise to first do no harm (primum non nocere), doctor as teacher (docere), treatment of the whole person, and emphasis on prevention.These principles give rise to a practice that emphasizes the individual and empowers him or her to greater responsibility in personal health care and maintenance. Definition

Naturopathicnutrition is the practice of nutrition in the context of naturopathic medicine. Naturopathic nutrition integrates both scientific nutrition and the principles of naturopathic medicine into a distinct approach to nutritional practice. Core components of naturopathicnutrition are: A respect for the traditional and empirical naturopathic approach to nutritional knowledge The value of food as medicine An understanding that whole foods are greater than the sum of their parts and recognition that they have vitality (properties beyond physiochemical constituents) Individuals have unique interactions with their nutritional environments Practice In the context of the definition, and with respect to the therapeutic order, the practice of nafuropathic nutrition may include the appropriate use of the following: Behavioral and lifestyle counseling Diet therapy (including health maintenance, therapeutic diets, and dietary modification) Food selection, preparation, and medicinal cooking Therapeutic application of foods with specific functions Traditional approaches to detoxification Therapeutic fasting strategies Nutritional supplementation Data from Snider P, Payne S. Making naturopathic curriculum more naturopathic: agendas, minutes, 1999-2001. Clinic faculty task force on integration. Faculty development retreat, Bastyr University, 1999.

contains several assumptions. One assumption is that illness can be understood in terms of discrete diseases (i.e., human suffering can be divided into identifiable entities, such as measles or cancer [in its specific types], or all the other catalog of illnesses to which we are subject). Next is that “cure” is the elimination of the disease entity. Third, this is accomplished by the evidencebased application of pharmaceuticals, surgeries, or similar treatments to eliminate, palliate, or suppress the entity and its symptomatic expressions. These are so obvious that they are not commonly considered. They form the background thinking in medical decision making: idenhfy and treat the disease.

The elegance of this model, and the science behind it, has taken medicine to its highest point in history as a reliable vehicle to ease human suffering, and its application has saved countless lives. The understanding of the physician, at least about the nahm of pathology, has never been as complete. But illness has a near infinite capacity to baffle the physician. New diseases arise, such as human immunodeficiency virus/acquired immune deficiency syndrome, and shifts occur in disease focus, such as the shift between 1900 and 2000 from acute infection to chronic illness as the predominant cause of death. Beyond these obvious changes, even with the current depth of understanding, standard medicine physicians continue to experience a depth of ignorance. So, even representing a n apex of human achievement as it does, modem medicine is not without its weaknesses. Its greatest weakness is probably its inability to cure chronic illness as easily as it once dealt with thingslike infectious pneumonia with penicillin, or even tuberculosis with streptomycin. To compound that problem is the growing prevalence of antibiotic-resistant infections. Part of the reason for the failures within modem medical science is the mechanistic basis of it, with its fundamental ignorance of and disrespect for the wholeness of the individual, the natural laws of physiology governing health and healing, and especially for all things spiritual. Inherent in the dictum-diugnoseand treat the diseuse-is the general neglect of the larger understanding that disease is a process conducted by and within an intelligent organism “whose genome(s) is (are) developed and expressed in the natural world.”’ The uniqueness of naturopathic medicine is not in its therapeutic modalities, ”natural” alternativesto the drugs and surgeries of standard medicine. It is in the clinical theory that govern the selection and application of these modalities, captured in the unifying definition adopted in 1989and expressed more specifically in the continuing articulation of clinical theory. That is, it is the way the naturopath thinks about illness and healing. The first element of this theory is based upon the first defining principle: vis rnedicutrix naturae. It is based on the understanding that disease can be seen as a process, as well as an entity. One can analyze the process of illness and derive some understanding. But to do this,one needs to examine the assumptions underlying this concept. The governing assumptions of standard medicine are principally that diseases are entities and that drugs and surgery can eliminate these entities from the suffering person. These are not the governing assumptions of naturopathic medicine.

ILLNESS AS PROCESS Naturopathic medicine can be characterized by a different model than “idenhfy and treat the disease.”

A Hierarchy of Healing:The Therapeutic Order

“The restoration of health’’ would be a better characterization. In fact, naturopathic physicians adopted the following ultrashort definition of naturopathic medicine in 1989 in an AANP position paper: ”Naturopathic physicians treat disease by restoring health.” Immediately one can see a difference: Standard medicine is disease based; naturopathic medicine is health based. Although naturopathic medical students study pathology with the same intensity and depth as standard medical students, as well as its concomitant (diagnosis), the naturopathic physician applies that information in a different context. In standard medicine, pathology and diagnosis are the basis for the discernment of the disease ”entity” that afflicts the patient, the first of the two steps of idenwing and destroying the entity of affliction. In naturopathic medicine, however, disease is seen much more as a process than as an entity. Rather than viewing the ill patient as suffering from a ”disease,” the naturopath views the ill person as functioning within a process of disturbance and recovery, in the context of nature and natural systems. Various factors disturb normal health. If the physician can idenidy these disturbances and moderate them (or at least some of them), the illness and its effects abate, at least to some extent, if not totally. As disturbances are removed, the body can improve in function, and in doing so the health naturally improves. The natural tendency of the body is to maintain itself in as normal a state of health as is possible. The role of the physician is to facilitate this self-healing process. The obvious first task of the naturopathic physician, therefore, is to determine what is disturbing the health so that these causative elements may be ameliorated. Disease is the process whereby the intelligent body reacts to disturbing elements. It employs such processes as inflammation and fever to help restore its health. In general, one can graph this process simply: healthy state + disturbing factors + disturbance of function + reaction + discharge of the products of reaction + resolution

One can see this most easily in the common cold. Within standard medical understanding, the common cold is caused by a virus, from among a family of pathologic viruses, which infects the person. The immune system responds, developing appropriate antibodies, which eventually neutralize the virus. There is no ”cure” yet discovered, except time. Medications are used to ameliorate the symptomatic experience: aspirin or acetaminophen for fever, antihistamines to dry the mucus discharge, etc. These measures are not cures: They reduce the symptomatic expression of the ”cold” but often lengthen the process. In naturopathic medicine, the cold is seen not as a disease entity but as a fundamental process whereby the body restores itself.

If colds were caused solely by a virus, then everyone who came in contact with the virus would get the cold. Obviously, this does not happen. Susceptibility factors include immune competence, fatigue, vitality, and other resistance factors. The virus enters a milieu in which all these factors affect the process. Once the virus enters the system, if it overcomes some resistance factors, one begins to see disturbance of function. One does not feel quite right. One may begin to get a sore throat, the first inflammatory reaction, occurring at the point of entry of the virus into the body. The immune factors may overcome the virus at this point or may be insufficient or suppressed. All of this is mutable to some extent and is affected by nutrition, fatigue, an increase in immune tonics, vitamin C, etc. But the ”cold” may proceed into a general state of fatigue and inflammation, possibly fever, etc., followed by mucus discharge, cough, and so forth, as the body processes the virus and its effects, eventually overcoming it and eliminating the results. This model is not understood so much to be a separate disease entity but a general andfundamental process of disturbance and recovery within the living body. It is a method whereby the body restores itself after a sufficient amount of disturbance accumulates within the system. This is why the cold has no ”cure.” It is the cure for what is ailing the body. Chronic illness arises, in general, when any or all of three factors occur: (1) The disturbing factors persist, such as a chronically improper diet, which continues to burden the body cumulatively, as the digestive processes slowly weaken under the stress of that improper diet; (2) The reactive potential is blocked or suppressed, usually by drugs, which interferes with the capacity of the body to process and remove its disturbances; or (3) The vitality of the system is insufficient to mount a significant and sufficient reaction. As these three factors prevent a sufficient reactive purge of disturbances, the body slides into a chronic, weaker reactive state or episodes of intermittent reaction, perceived as persistent and chronic illness. Ultimately, as function is sufficiently disturbed, structures or functions are damaged and chronic inflammation becomes ulceration or scar tissue formation. Atrophy, paralysis, or even tumor formation may occur. All of this is the body manifestly doing the best it can for itself in the presence of persistent disturbing factors and with respect to the limitations and range of vitality influenced by the constitution, psycho-emotional/spiritual state, and genotype of the person and his or her surrounding environment. The reversal of this condition is rarely accomplished by ”drugging” the pathologic state, which usually results in the control of symptoms and persistence of the illness, hopefully controlled in its more dangerous

aspects by the presence of the drug or performance of the surgery. Reversal is more likely accomplished by identifymg and ameliorating the disturbance, and as necessary, strengthening or supporting the reactive potential. The first step in this process is to identdy and reduce disturbing factors.

THE DETERMINANTS OF HEALTH In order to reduce the disturbance, one must identdy the disturbance. In standard medicine, the first step is to identdy the pathology, which is then treated. In naturopathic medicine, one must come to understand what is disturbing the health. To do this, the physician needs to understand what determines health in the first place. The physician can then evaluate the patient in these terms and come to understand what is disturbing the natural state of health. Such a list could be created by any doctor, certainly any naturopathic physician. The authors propose the list in Box 3-2. The naturopathic physician evaluates the patient with these areas in mind, looking for aspects of disturbance, first in the spirit, and most generally in diet, digestion, and stress in its various aspects. In this evaluation the naturopathic physician brings to bear a body of knowledge somewhat unique to naturopathic medicine, to evaluate not solely in terms of pathologic entity but in terms of normal function and prepathologic functional disturbance. Locating areas of abnormal function or

In order to understand what disturbs health, one must understand what determines health. Therefore doctors of naturopathy study the determinants of health. A determinant of health becomes a disturbance when it is absent or present but distorted. 1. Inborn

Genetic makeup (genotype) Intrauterine/congenital Maternal exposures Drugs Toxins Viruses Psychoemotional Maternal nutrition Maternal lifestyle Constitution: determines susceptibility 2. Hygienic FactorsRistyle Factors: How We Live

Environment, Lifestyle, Psychoemotional, and Spiritual Health Spiritual life Self-assessment Relationship to larger universe Exposure to Nature Fresh air

disturbance, the physician acts or recommends ways to ameliorate the disturbance. As disturbing factors are reduced in the system, the natural tendency of the system to improve and optimize its function directs the system back toward normalcy. This is the removal of the obstacles to cure, which allows the action of the vis rnedicutrix nuturue, the vital force, the healing power of .nature. This is the first step in the hierarchy of healing and what naturopathic physicians may call the overarching clinical theory of naturopathic medicine: the therapeutic order.

THERAPEUTIC ORDER The therapeutic order is a natural hierarchy of therapeutic intervention, based on or dictated by observations of the nature of the healing process, from ancient times through the present.61 It is a natural ordering of the modalities of naturopathic medicine and their application. The concept is somewhat plastic in that one must evaluate the unique needs, and even the unique healing requirebut in general ments, of the specificpatient or the nature of healing dictates a general approach to treatment. In general, this order is listed in Box 3-3.

1. Establish the Conditions for Health Identify and Remove Disturbing Factors If one understands health to be the natural state and “disturbance” the original culprit, then identifymg and

Clean water Light Diet, Nutrition, and Digestion Unadulterated food Toxemia Rest and Exercise Rest Exercise Socio-economicFactors Culture Loving and being loved Meaningful work Community Stress (Physical, Emotional) Trauma (physicaVemotiona1) Illnesses: pathobiography Medical interventions (or lack of) Surgeries Suppressions Physical and emotional exposures, stresses, and trauma Toxic and harmful substances Addictions

From Zeff J, Snyder I?Course syllabus: NM51 71, Naturopathic clinical theory. Seattle: Bastyr University, 1997-2005.

A Hierarchy of Healing: The Therapeutic Order

1. Establish the conditions for health Identify and remove disturbing factors Institute a more healthful regimen 2. Stimulate the healing power of nature (vis medicatfix nafufae):the self-healing processes 3. Address weakened or damaged systems or organs Strengthen the immune system Decrease toxicity Normalize inflammatory function Optimize metabolic function Balance regulatory systems Enhance regeneration Harmonize with your life forces5 4. Correct structural integrity 5. Address pathology: Use specific natural substances, modalities, or interventions 6. Address pathology: Use specific pharmacologicor synthetic substances 7.Suppress or surgically remove pathology ~~

From Zeff J. Snyder P.Course syllabus: NM51 71. Naturopathic clinical theory. Seattle: Bastyr University, 1997-2005. The actual therapeutic order may change, depending on the individual patient's needs for safe and effective care. The needs of the patient are primary in determining the appropriate approach to therapy.

reducing disturbance is the obvious first step, unless there is immediate danger to life or limb, in which case acting to preserve life or limb is paramount. In most chronic disease, neither life nor limb is immediately threatened. This understanding dictates the first thing the physician must attend to: the identificationand amelioration of those factors disturbing health, especially factors that most disturb health (inappropriate diet, excessive stress, and spiritual disharmony). To understand what disturbs health, one must understand what determines health. The naturopathic physician evaluates a patient with reference to the determinants of health to discover wherein the patient's health is disturbed. In this step, the physician is essentially "removing the obstacles to cure, and allowing the vis rnedicutrix naturue to do its work." Among these many possibilities, in general, the most significant are diet, digestion, stress, and what might be called "spiritual integrity." Humans are spiritual beings. They are spirits that reside within bodies. Though the general purview of the physician is the body, that instrument cannot be separated from the spirit, which animates it. If the spirit is disturbed, the body cannot be fundamentally healthy. Hahnemann, the brilliant founder of homeopathy, instructs physicians thus. Disturbance in the spirit permeates the body and eventuates in physical manifestation. Physicians are responsible for perceiving such disturbances and addressing them. At colleges of naturopathic medicine in Australia and North America, faculty work with naturopathic medicine students to develop their ability to perceive the spiritual nature of an individual as those factors that give rise to an individual's

"will to live," their "joie de vivre," and their core beliefs and values. This is a foundational skill in addressing spirituality and health. Using this definition, both atheists and agnostics can be seen to have a spiritual aspect. This definition also removes spirituality from religiosity in a way that does not denigrate any individual religious belief a patient may hold, allowing the naturopathic clinician to explore this aspect of the individual. Perceived in this way, it is also easier to understand that many individuals within society are experiencing a "spiritual crisis." One of the oldest concepts in naturopathic medicine is the concept of toxemia. Toxemia is the generation and accumulation of metabolic wastes and exogenous toxins within the body. These toxins may be the results of maldigestive processes, non-end product metabolites, environmental xenobiotics, colon bacteria metabolites, etc. These toxins become irritants within the body, resulting in inflammation of tissues and interference with biochemical processes. The maldigestive and dysbiotic origin of these toxins is the product of inappropriate diet, broad spectrum antibiotics, and the effects of excessive stress on digestion. Eating a diet that cannot be easily digested or is out of appropriate nutrient balance for the individual results in the creation of metabolic toxins in the intestines. Stress, resulting in the excessive secretion of cortisol and adrenalin, results in the decrease of blood flow to the digestive process, which decreases the efficient functioning of digestion and increases the tendency toward maldigestion, dysbiosis, and toxemia. Physicians can now easily measure the degree of toxemia in various ways (e.g., urinary indican or phenol). Spiritual disharmony, inappropriate diet, digestive disturbance, stress, and toxemia are primary causes of chronic illness and must be addressed if healing is to occur. Beyond these, other disturbing factors must be discerned and addressed, whichever pertain to the individual patient.

Institute a Healthier Regimen As a corollary of the first, once physicians have determined major contributingfactors to illness, they construct a healthier regimen for the patient. Some disturbing factors can be eliminated, like inappropriate dietary elements. Others are a matter of different choices or living differently. The basics to consider are: appropriate diet, appropriate rest and exercise, stress moderation, a healthy environment, and a good spiritual connection. If this model is correct, these measures alone should result in enhanced health. The problem arises in knowing how to do these things. What is an appropriate diet? This is an area of considerable controversy. Physicians think about diet in many different ways. The goal of dietary improvement is to reduce the symptomatic consequences of the patient's diet and provide optimal nutrition to the patient. The point here, regardless of

how this is done, is that it is central and essential for fundamental health improvement. If the diet is not correct, if digestion is not appropriate, if nutrition is not adequate, the patient cannot maximally improve. If the diet and digestion are appropriate, the basis for improvement in other areas is enhanced. The same is true with these other fundamental elements, to which Lindlahr referred in the first element of his catechism, ”return to nature”: exercise, rest, dress, etc.28These have been expanded in the ”determinants of health.” They create the basis for improvement. What thisreally means is to change the ”terrain,” the conditions in which the disease has formed-not only to change but to improve the conditions so that there is less basis for the disease. Hahnemann addresses this on the first page of his Orgunon ofMedicine. He identified four tasks for the physician: to understand the true nature of illness, “what is to be cured”; to understand the healing potential of medicines; to understand obstacles to recovery and how to remove them; and to understand the elements that derange health and how to correct them so that recovery may be permanent.@ Changing and improving the terrain in which the disease developed is the obvious first step in bringing about improvement. This sets up the basis for the following elements to have the most beneficial effects.

Many naturopathic modalities can be used to stimulate the overall vital force. More specific approaches to stimulation, though general in effect, are applied differently to each patient and have a less general effect than those previously mentioned. Homeopathy and acupuncture are primary methods of such stimulation. They add little to the system: They are not gross chemical treatments. They work with what is there, stimulating a reaction, stimulating function, correcting disturbed patterns. Each method helps move the system out of its disturbed state and, with the reduction of encumbrance, helps move it toward health. Finally, exposure to the patterns, rhythms, and forces of nature is a traditional part of naturopathic medicine and the tradition of nature doctors throughout the world. As Pizzorno and Snider wrote: “We are natural organisms, our genomes developed and expressed in the natural world. The patterns and processes inherent in nature are inherent in us. We exist as part of complex patterns of matter, energy, and spirit.”’ The natural processes of these patterns and the drive toward health inherent in them is a natural ally for the physician. Exposure to appropriate rhythms, patterns, and forces of nature strengthens vitality and stimulates the healing power of nature.

2. Stimulate the Self-Healing Mechanisms

3. Support Weakened or Damaged Systems or Organs

A certain percentage of patients improve sufficiently simply by removing disturbing factors and establishing a healthier regimen. Most require more work. Once the patient is prepared, once the terrain is beginning to clear of disturbing factors, then one begins to apply stimulation to the self-healing mechanisms. The basis of this approach is the underlying recognition of the vis rnedicufrix nufurue, the tendency of the body to be self-healing, the wisdom and intelligence within the system that constantly tends toward the healthiest expression of function, and the healing “forces” in the natural environment (air, water, light, etc.). The body heals itself. The physician can help create the circumstances to promote this. Then, as necessary, the physician stimulates the system. One of the best ways to do this is through constitutional hydrotherapy, as developed by Otis G. Carroll, ND, early in the past century. This procedure is simple, involving the placement of hot and then cold towels on the trunk and back, in specific sequence (depending on the patient), usually accompanied by a sine wave stimulation of the digestive tract. This is a dynamic treatment, simple, inexpensive, and universally applicable. It helps recover digestive function, stimulates toxin elimination, ”cleans the blood,” enhances immune function, and has several other effects. It moves the system along toward a healthier state.” Exercise often achieves similar results.

Some systems or functions require more than stimulation to improve. Some organs are weakened or damaged (e.g., adrenal fatigue after prolonged stress), and some systems are blocked or congested (e.g., the hepatic detoxification pathways) and require extra help. This is where naturopathic physicians use their vast natural medicinary. Botanical medicines can affect any system or organ, enhancing its function, improving its circulation, providing specific nutrition, stimulating repair. Glandular substances can be applied to a similar purpose. And then there are the growing number of evidence-based “nutraceuticals,” biological compounds that enhance metabolic pathways and provide substance for metabolic function. Naturopathic physicians can also apply specific homeopathic medications, usually in the lower potencies, which act nutritively and can stimulate specific organs or functions. This method can be used to stimulate detoxificationof specific substancesfrom the body in general or of specific organ systems or tissues. Dr.Pizzorno’s work in Total Wellness and the work of “functional medicine” leader Jeffrey Bland, PhD, exemplify the clinical strategies applied at this level of the therapeutic order. These strategies are used to restore optimal function to an entire physiologic system (immune, cardiovascular, detoxification, life force, endocrine, etc.).65

A Hierarchy of Healing: The Therapeutic Order One can use specific exercises to stimulate or enhance organ health. Some systems of Yoga and Qi Gong are organ specific.And specific applications of hydrotherapy and other physiotherapy systems can be applied to enhance the function of organs or tissues. These methods, combined with an appropriate diet and a healthier regimen, along with constitutional hydrotherapy, appropriate homeopathy, and acupuncture, usually bring most health problems back to normal, without negative consequence, rapidly, efficiently, and permanently.

4. Address Structural Integrity Many structural problems result from stress of some kind on internal systems. For example, midback misalignment or discomfort is often found associated with a history of underlying stress on the digestive organs, the ennervation of which originates at those spinal segments. One can manipulate that vertebra back into proper alignment or massage contracted musculature, but until one corrects the underlying functional disturbance, there will be a tendency to repeated structural misalignment. In some circumstances the singular problem may be simply structural disintegrity. One may have fallen or been hit in some fashion and simply need the neck manipulated back into proper alignment and the surrounding soft tissue relaxed. There may be no diet error or other disturbance aside from the original injury, and correction requires only simple manipulation or therapeutic massage. This is an example of the flexibility of the “therapeutic order” concept. In this case, first-order therapeutics is to manipulate the cervical spine or to relax chronically contracted muscles. Usually, however, the problem of structure is part of the larger problem, and such intervention becomes a fourth-order therapeutic. Reintegrating structure can occur in many ways, one of which is the method of ”bone cracking” known to the ancient Greeks and Chinese and probably all other ancient healing cultures. But there are nonforce manipulative systems that include many modalities of therapeutic massage. Some systems of exercise are designed to reintegrate and maintain normal structural relationships. Any of these might be appropriate to a specific patient. By approaching the problem in the context of the therapeutic order, one can expect structural corrections to be required only occasionally and for the results to be more or less permanent.

5. Address Pathology: Use Specific Natural Substances, Modalities, or Interventions Having gone through the first four steps of this therapeutic hierarchy, most patients improve. The improvement is based on the sound footing of the underlying correction

or removal of fundamental causative elements. It is also based on the intrinsic nature of the body to heal itself by using the least possibleforce. Most pathology improves or disappears under these circumstances. Sometimes it is necessary to address pathology. This may be the case because the particular pathology may be threatening to life or limb. Acting on this threat is imperative. It can be done often with naturopathic means, directed specifically against the pathology. Biochemical or genetic individuality also can demand an emphasis at this level of intervention. One of the major conflicts in naturopathic medicine is that some practitioners find it expedient to diagnose and treat pathology (the standard medical model) rather than pursue a naturopathic model of practice. This approach tends to be less satisfymg and less productive of the most elegant outcomes and the long-term continued health of the patient. It also reduces the capacity of the physician to treat, such as in cases where there is no evidencebased treatment for the pathology in question, or where there is no clear diagnosis (i.e., no distinct pathology to treat). This approach is increasingly referred to as ”green allopathy.” But the vast body of knowledge that naturopathic education presents in this arena makes such an approach seductive, especially in a culture that more or less expects, supports, reinforces, and pays for an “allopathic” approach to diagnosis and treatment. It is easy to do this. The culture is accustomed to this model and often expects to encounter this in the naturopathic physician’s office. In some states, such as Oregon, where the naturopathic formulary includes most antibiotics and many pharmaceutic drugs, one can practice almost without distinction from a medical doctor. The typical naturopathic formulary is often sufficient to prescribe on a strictly pathologic basis. The problem with this is that it is generally not as effective, especially in the treatment of chronic disease. The value of naturopathic medicine in our culture is not that naturopathic physicians can function almost like medical doctors, with a ”natural” formulary instead of drugs. It is that they offer a fundamentally different approach, one based on the restoration of health rather than the treatment of pathology. Given all of this, it still may be useful to directly address the pathologic entity or its etiology. When treating an antibiotic-resistant infection, for example, it may be useful to apply botanical medicines with specific antibiotic properties along with immune tonics, and the more fundamental steps of this therapeutic hierarchy. In difficult cases, such as many cancers, using agents that have specific, pathology-based therapeutics may be an essential element of comprehensive treatment. The naturopathic formulary provides a vast and increasing number of such options. One advantage of such treatment is that, in general, when applied by a knowledgeable

Philosophy of Natural Medicine

practitioner, it rarely adds more burden or toxicity to the system. Naturopathic pathology-based treatments still follow the dictum ”do no harm.”

6. Address Pathology: Use Specific Pharmacologic or Synthetic Substances About 800,000 medical doctors and osteopathic physicians in the United States are well trained in the science of pathologic-based treatment, using pharmaceuticals, surgery, etc. There are times when such an approach is necessary to preserve life, limb, or function. Although some naturopathic physicians, by training and by statute, may prescribe pharmaceutics or even perform surgeries, naturopathic physicians may also refer patients in need of such services to appropriate medical doctors or osteopaths, depending on licensed formulary. In a growing number of states, NDs can legally provide an expanding range of prescription drugs. Although this is an important tool for the naturopathic primary care giver, this privilege requires enhanced responsibility for the ND to prescribe those substances only as needed-and to thoroughly rely on applying the least force appropriate to effect recovery and protect patient safety. Naturopathic physicians are well trained in this regard and respect the necessity and utility of standard medical practice in appropriate situations.Some disagreement exists regarding which situationsmay be appropriate. The AANP has developed position papers to resolve some of these questions. In general, while recognizing the necessity of such treatment, most naturopathic physicians also recognize that such treatment often carries consequences that must also be addressed.

7. Suppress Pathology Sometimes it is necessary, for the preservation of life or limb, to suppress pathology. Medical doctors are especially trained in this art and have powerful and effective tools with which to do this. Unfortunately, suppression, because it does not fundamentally remove or address essential causative factors (such as dietary error) often results in the development of other, often-deeper disturbance or pathology. Since much pathologic expression is the result of the actual self-healing mechanisms, such as inflammation, suppressive measures are, in general, anti-vis rnedicutrix nuturue. The result of suppression is that the fundamental disturbing factors are still at play within the person, still disrupting function to some extent, while the suppression reduces the symptomatic expression and resolution of disturbance. One simple example of this is the use of steroidal antiinflammatory and antihistaminic drugs in the treatment of acute asthma. This usually effectively opens the airways. But prolonged use weakens the patient. If the

treatment persists, the patient becomes immune compromised and osteoporotic and can develop psychologic disorders. These symptoms are part of the long-term effects of prednisone. It may necessarily maintain breathing, but the long-term cost to the organism is expensive. Suppression, although it may be life saving, often has serious consequences. With standard medical methods of care, cure of chronic illness is often elusive. This is the benefit of the naturopathicapproach: by taking a nonsuppressive course of action, based on sound physiologic principles, one can often restore health without recourse to the potential damage of suppression. Naturopathic physicians, while recognizing the occasionalnecessity of suppressive approaches, in general avoid suppression, which is a primary way in which physicians can inflict harm, even with the best of intentions.

THEORY IN NATU ROPATHIC MEDICINE This therapeutic hierarchy is based on the observation of the nature of healing and the inherent order of the healing process. It is part of a unifying theory of naturopathic medicine, an outgrowth of the principles which underlie naturopathic thinking. It provides the physician with instructions that order the many therapeutic modalities used by the practice. The consensus definition of naturopathic medicine, adopted by the AANP in 1989, is a statement of identity, distinguishingnaturopathic medicine from other systems of medical thought. Contained within it is a set of instructions regarding the practice of the medicine. The three concepts discussed here-”disease as process,” “the determinants of health,” and “the therapeutic order”-are an articulation of these instructions. They are presented as a clinical theory of naturopathic medicine. They are abstracted, as is the definition, from the observationby nature doctors throughout time and across many traditions of the nature of health and of disease and of the nature of healing. They provide the physician with instructions. These instructions include a procedure for thinking about human illness in such a way that one can approach its cure in an ordered and elegant fashion by understanding its process as an expression of the vis rnedicutrix naturue. It provides the framework for truly evaluating the patient as a whole being: spiritual, mental/emotional, and physical, rather than as a category of pathology. And it provides the physician a system for organizing and efficiently integrating the vast therapeutic array provided in naturopathic medicine. Ultimately, it satisfies Hahnemann’s observation of’the ideal role of medicine, that ”the highest ideal of cure is rapid, gentle and permanent restoration of the health . . . in the shortest, most reliable and most harmless way, upon easily understood principles.”63As in any system

A Hierarchy of Healing: The Therapeutic Order of medicine, it is understood that medicine evolves with understanding. The roots of the observations that form this theory are traceable through the mid- and earlytwentieth century, to the traditional theory of nineteenth-century European nature cure, and to the roots and theories of traditional world medicines. Hippocrates' writings on the vis medicutrix nuturue form a foundation that historically underpin the development of this t h e ~ t - y . ~ , ~ ~ Finally, it is observable across many traditional world medicines that various healing orders are described.

Such structures hold implications for public and community health priorities and suggest the reprioritization of health care priorities and financing. Implications for public policy and the growing national disease debt invite exploration. Although this presentation is not comprehensive, the attempt has been made to demonstrate these roots, at least in some of their major articulations. The work presented here is a continuation of this historical process, which ultimately is driven by the true mission of the physician: to ease suffering and to preserve life.

1. Pizzomo J, Snider P. Naturopathic medicine. In Micozzi MS, ed. The fundamentals of complementary and alternative medicine. New York Churchill Livingstone, 2001. 2.Cody G. The history of naturopathic medicine. In Pizzorno J, Murray M, eds. Textbook of natural medicine. New York Churchill Livingstone, 1999. 3. Kirchfeld F, Boyle W. The nature doctors: pioneers in naturopathic medicine. Portland, OR Medicina Biologica, 1994. 4.Schramm A, ed. Yearbook of the International Society of Naturopathic Physicians and Emerson University Research Council. April 1945. 5. Tribe W. Personal communication, 1980. National College Professional survey. 6. Wendel P. Standardized naturopathy. Brooklyn, Ny: Paul Wendel, 1951. 7. Kirchfeld F, Boyle W. Nature doctors. East Palestine, O H Buckeye Naturopathic Press, 1994:202-208,258-260. 8. Freibott G. Report submitted to Lanso Cavasos, secretary of education, U.S. Department of Education, 1990. 9. Coulter H. Divided legacy: a history of the schism in medical thought. Washington DC:Wehawken Book Company, 1973. 10.Engel GL. The need for a new medical model a challenge for biomedicine. Science 1977;196129-136. 11. Lear L. Rachel Carson biography. Available online at h t t p : / / m . ruchelcarson.org/index.cfm?fuseuction=bio[accessed 20 June 20041. 12. Enrollment records. National College of Naturopathic Medicine. [accessed June 20,20041 13. Kirchfeld F, Boyle W. The nature doctors: pioneers in naturopathic medicine. Portland, OR Medicina Biologica 1994;310-312. 14.The future of naturopathic medical education-primary care integrative natural medicine: the healing power of nature. In Cronin M, ed. Best of naturopathic medicine: anthology 1996 celebrating 100 years of naturopathic medicine. Tempe, Az: Southwest College of Naturopathic Medicine Publications, 1996. 15. Snider P. Integration project survey results: report to the AANMC dean's council: 1999. Database: Snider l', Monwai M. 16. Standish L, Calabrese C, Snider l', et al. Naturopathic medical research agenda: report to NCCAM: Draft 5,2004. 17. Tilden JH. Toxemia explained: an antidote to fear, frenzy, and the popular mad chasing after so-called cures: the true interpretation of the cause of disease, how to cure is an obvious sequence. Rev. ed. Denver: FJ Wolf, 1926. 18. Trall R. The true healing art. New York Fowler & Wells, 1880. 19. Graham S. Greatest health discovery: natural hygiene & its evolution past, present & future.Chicago: Natural Hygiene Press, 1860. 20. Kellogg J. Rational hydrotherapy, ed 2. Philadelphia: FA Davis Co, 1903.

21. Kuhne L. Neo-naturopathy: the new science of healing or the doctrine of the unity of diseases. Butler, NJ: Benedict Lust, 1917. 22. Kuhne L. The science of facial expression: the new system of diagnosis, based on original researches and discoveries. Butler, NJ: Lust, 1917. 23. McFadden B. MacFadden's encyclopedia of physical culture, 5 volumes. New York Physical Culture Publishing, 1920. 24. Rikli A. Die Grunderhren der Naturheilkunde einschliesslich "Dia atmospharische Kure," "Es werde Licht" und "Abschiedsworte" (The Fundamental Doctrines of Nature Cure including "the Atmospheric Cure," "Let There Be Light" and "Words of Farewell"), ed 9. Wolfsberg: G. Rikli, 1911. 25. Tilden JH. Impaired health: its cause and cure-a repudiation of the conventional treatment of disease, ed 2. Denver: Tilden, 1921. 26. Dictionary of Occupational Titles, vol 1, ed 3. The United States Department of Labor, 1965. 27. Schram A. Acts and laws. Yearbook of the International Society of Naturopathic Physicians & Emerson University Research Council, 1948. 28.Lindlahr H. Nature cure: philosophy and practice based on the unity of disease and cure. Chicago: Nature Cure Publishing, 1913. 29. Spitler HR. Basic naturopathy, a textbook. New York American Naturopathic Association, 1948. 30. Wendel P. Standardized naturopathy. Brooklyn: Published by the author, 1951. 31. Kneipp S. Thus shalt thou live. Kempten, Bavaria: Koesel, 1889. 32.Kneipp S. My water cure. UK: Thorsons, 1979. Reprint of 1891 edition. 33. Kneipp S. My will. Kempten, Bavaria: Koesel, 1894. 34. Trall RT. Hydropathic encyclopedia: a system of hydropathy and hygiene. New York Fowlers & Wells, 1851. 35. Rausse JH. Der Geist der Graffenberger Wasserkur. Zeitz: Schieferdecker, 1838. 36. Rikli A. Die Thermodiatetik oder das tagliche thermoelectrische Licht und Luftbad in Verbindung mit naturfemasser Diat als zukunftige Heilmethode. Vienna: Braumueller, 1869. 37. Thomson S. A brief sketch of the causes and treatment of disease. Boston: EG House, 1821. 38. Beach W. A treatise on anatomy, physiology and health. New York Author, 1847. 39. Ellingwood F. American materia medica, therapeutics, and pharmacognosy. Evanston: Ellingwood's Therapeutist, 1919. 40. Felter H. The eclectic materia medica, pharmacology, and therapeutics. Cincinnati: John K Sadder, 1922. 41. Boyle W. The herb doctors. East Palestine, OH: Buckeye Naturopathic Press, 1988.

Philosophy of Natural Medicine 42. Bradley R. philosophy of naturopathic medicine. In Pizzorno J,

Murray M, eds.Textbook of natural medicine. New York Churchill Livingstone, 1985. 43. AANP House of Delegates Resolution. Rippling River, OR: 1989. 44.Select Committee on the Definition of Naturopathic Medicine, Snider F‘, Zeff J, cochairs. Definition of naturopathic medicine: AANP position paper. Rippling River, OR 1989. 45.Select Committee on the Definition of Naturopathic Medicine, AANP 1987-1989. Report submitted to AANP in 1988, final recommendation submitted to AANP house of delegates, September, 1989. 46.Snider P, Zeff J. Personal letters and communications, 1987-1989. 47.Zeff J. Convention theme: “what is a naturopathic physician?” AANP Q News 19883:1,11. 48. Snider F’, Zeff J. Definition of naturopathic medicine: first draft. AANP Q News 19889:6. 49. North American Association of Naturopathic Medical Colleges Integration Project Survey 1997-1999.P r e w report.October 26, 1999. Snider P, Zeff J, co-chairs. Mitchell M, Bastyr University Integration Project Student Task Force Chair. Monwai M, database and research assistant. 50. Snider F’, Zeff J. Integration project report on survey data and proposed principles of naturopathic medicine to the AANMC dean’s council, 1999. 51.The integration project update 2ooO: AANP house of delegates principles survey, presented by Mitchell M, IP student task force chair 1997-2000.Comments presented by Snider S, Zeff J, cochairs integration project 1996-2OOO. Monwai M, database manager. Saunders F, data analyst. 52. OKeefe M, Milliman B, Zeff J. Proposed new principles of naturopathic medicine: wehess, least force, relieve suffering. Submitted to the AANP house of delegates, 1996. 53. Resolution introduced in HOD regarding new principles: passed 2000 AANP convention, Seattle. The HOD recommended that the

discussion be moved to the academic community involved in clinical theory and practice for development. 54. Zeff J. The process of healing: a unifying theory of naturopathic medicine. J Naturopath Med 1997;l:lZ-126. 55. Snider P, Zeff J, Sensenig J, et al. Towards a unifying theory of naturopathic medicine. AANP plenary session. Portland, OR, 1996. 56. Snider P. Integration project: timeline, scope of work, goals, methods. Proposal adopted by CNMC 1996, readopted by AANMC 1997-1998. 57. CNME report from Bastyr University, 1999. Standard XI and appendices: curriculum. 58. AANMC dean’s council minutes and correspondence, 2OOO. 59. Snider P, Downey C, co-chairs. Invitation letter, supporting information, agenda, minutes, tools and materials. AANMC integration project retreat for naturopathic philosophy and clinical theory faculty, basic sciences chairs and clinic directors. August 20-21,2001. 60.Snider P, Payne S. Making naturopathic curriculum more naturopathic: agendas, minutes, 1999-2001. Clinic faculty task force on integration. Faculty development retreat, Bastyr University, 1999. 61. Hippocrates. The genuine works of Hippocrates. Adam F, trans. Baltimore: Williams & Wilkins, 1939. 62. Zeff J, Snyder P.Course syllabus: NM51 71, Naturopathic clinical theory. Seattle: Bastyr University, 1997-2005. 63. Hahnemann S. Organon of medicine. Philadelphia: Boericke & Tafel, 1922. 64. Boyle W, Saine A. Naturopathic hydrotherapy. East Palestine, O H Buckeye Naturopathic Press, 1988. 65. Pizzomo J. Total wellness. Rocklin, CA: Prima Publishing, 1996. 66. Snider P, Weeks J. Design principles for healthcare renewal 2002. Available online at wurw.thecoZZnboration.org [accessed June 4,20041. 67. Weeks J. Integrative medicine industry leadership summit 2001. Altem Ther Health Med 2002;8:S3-11.

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing George Wm. Cody, JD, MA CHAPTER CONTENTS Introduction 41 A Brief History of Early American Medicine with an Emphasis on Natural Healing 42 Medicine in America: 1800-1875 42 The American Influence 45 The Beginnings of “Scientific Medicine” 47 The New “Sects” 48

The Convergence with American Influences 55

Early Twentieth-Century Medicine 57 The Metamorphosis of Orthodox Medicine 57 The Halcyon Years of Naturopathy 58 The Emerging Dominance of American Medical Association Medicine 60 The Modern Rejuvenation 61

The Founding of Naturopathic Medicine 48 Benedict Lust 48 The Germanic Influence 53

INTRODUCTION Naturopathy, as a generally used term, began with the teachings and concepts of Benedict Lust. Naturopathy, or ”nature cure,” is both a way of life and a concept of healing that employs various natural means of treating human infirmities and disease states. The earliest mechanisms of healing associated with the term, as used by Lust, involved a combination of hygienics and hydropathy (hydrotherapy). The term itself was coined in 1895 by Dr. John Scheel of New York City to describe his method of health care. But earlier forerunners of these concepts had already existed in the history of natural healing, both in America and in the Austro-Germanic European core. Lust came to this country from Germany in 1892 as a disciple of Father Sebastian Kneipp, a Domenican priest, and as a missionary dispatched by Kneipp to bring hydrotherapy to America. Lust purchased the term ”naturopathy” from Scheel in 1902 to describe the eclectic compilation of doctrines of natural healing that he envisioned to be the future of natural medicine. In January 1902, Lust, who had been publishing the Kneipp Water Cure Monthly and its German language counterpart in New York since 1896, changed the name of the journal

to The Nuturopathic and Herald of Health and evoked the dawn of a new health care era with the following editorial: Naturopathy is a hybrid word. It is purposely so. No single tongue could distinguish a system whose origin, scope and purpose is universal-broad as the world, deep as love, high as heaven. Naturopathy was not born of a sudden or a happen-so. Its progenitors have for eons been projecting thoughts and ideas and ideals whose culminations are crystallized in the new Therapy. Connaro, doling out his few fixed ounces of food and drink each day in his determined exemplification of Dietotherapy; Priessnitz, agonizing, despised and dejected through the long years of Hydropathy’s travail; the Woerishofen priest, laboring lovingly in his little parish home for the thousands who journeyed Germany over for the Kneipp cure; Kuhne, living vicariously and dying a martyr for the sake of Serotherapy;A.T. Still, studying and struggling and enduring for his faith in Osteopathy; Bemarr Macfadden, fired by the will to make Physical Culture popular; Helen Willmans, threading the mazes of Mental science, and finally emerging triumphant; Orrison Sweet Maraden, throbbing in sympathy with human faults and failures, and longins to realize Success to all mankind-these and hosts of others have brought into being single systems whose focal features are perpetuated in Naturopathy.

41

Philosophy of Natural Medicine Jesus Christ-I say it reverently-knew the possibility of physical immortality. He believed in bodily beauty; He founded Mental Healing; He perfected Spirit-power. And Naturopathy will include ultimately the supreme forces that made the Man of Galilee omnipotent. The scope of Naturopathy is from the first kiss of the newfound lovers to the burying of the centenarian whose birth was the symbol of their perfected one-ness. It includes ideally every life-phase of the id, the embryo, the foetus, the birth, the babe, the child, the youth, the man, the lover, the husband, the father, the patriarch, the soul. We believe in strong, pure, beautiful bodies thrilling perpetually with the glorious power of radiating health. We want every man, woman and child in this great land to know and embody and feel the truths of right living that mean conscious mastery. We plead for the renouncing of poisons from the coffee, white flour,glucose, lad,and like venom of the American table to patent medicines, tobacco, liquor and the other inevitable recourse of perverted appetite. We long for the time when an eight-hour day may enable every worker to stop existing long enough to live; when the spirit of universal brotherhood shall animate business and society and the church; when every American may have a little cottage of his own, and a bit of ground where he may combine Aerotherapy, Heliotherapy, Geotherapy, Aristophagy and nature’s other forces with home and peace and happiness and things forbidden to flat-dwellers; when people may stop doing and thinking and being for others and be for themselves; when true love and divine marriage and prenatal culture and controlled parenthood may fill thisworld with germ-gods instead of humanized animals. In a word, Naturopathy stands for the reconciling, harmonizing and urufylng of nature, humanity and God. Fundamentally therapeutic because men need healing; elementally educational because men need teaching; ultimately inspirational because men need empowering, it encompasses the realm of human progress and destiny. Perhaps a word of appreciation is due Mr. John H. Scheel, who first used the term ”Naturopathic” in connection with his Sanitarium ”Badekur,” and who has courteously allowed us to share the name. It was chosen out of some 150 submitted, as most comprehensive and enduring. All our present plans are looking forward some five or ten or f&y years when Naturopathy shall be the greatest system in the world. Actually the present development of Naturopathy is pitifully inadequate, and we shall from time to time present plans and ask suggestions for the surpassing achievement of our worldwide purpose. Dietetics, Physical Culture and Hydropathy are the measures upon which Naturopathy is to build; mental culture is the means, and soul-selfhood is the motive. If the infinite immensity of plan, plea and purpose of this particular magazine and movement were told you, you would simply smile in your condescendingly superior way and straightway forget. Not having learned as yet what a brain and imagination and a will can do, you consider Naturopathy an ordinarily innocuous affair, with a lukewarm purpose back of it, and an ebbing future ahead of it. Such is the character of the average wishy-washy health movement and tumultuous wave of reform. Your incredulous smile would not discomfit us-we do not importune your belief, or your help, or your money. Wherein we

differ from the orthodox self-labeled reformer, who cries for sympathy and cringes for shekels. We need money most persistently-a million dollars could be used to advantage in a single branch of the work already definitely planned and awaiting materialization; and we need co-operation in a hundred different ways. But these are not the things we expect or deem best. Criticism, fair, full and unsparing is the one thing of value you can give this paper. Let me explain. Change is the keynote of this January issue-in form, title, make-up. If it please you, your subscription and a word to your still-benighted friends is ample appreciation. But if you don’t like it, say so. Tell us wherein the paper is inefficient or redundant or ill-advised, how it will more nearly fit into your personal needs, what we can do to make it the broadest, deepest, truest, most inspiring of the mighty host of printed powers. The most salient letter of less than 300 words will be printed in full, and we shall ask to present the writer with a subscription-receipt for life. By to-morrow you will probably have forgotten this request; by the day after you will have dropped back into your old ways of criminal eating and foolish drinking and sagged standing and congested sitting and narrow thinking and deadly fearing-until the next progress paper of New Thought or Mental Science or Dietetics or Physical Culture prods you into momentary activity. Between now and December we shall tell you just how to preserve the right attitude, physical and mental, without a single external aid; and how, every moment of every day, to tingle and pulsate and leap with the boundless ecstasy of manhood consciously nearing perfection.

A BRIEF HISTORY OF EARLY AMERICAN MEDICINE WITH AN EMPHASIS ON NATURAL HEALING To understand the evolutionary history of naturopathic medicine in this country, it is necessary to view the internal development of the profession against the historical, social, and cultural backdrop of American social history.

Medicine in America: 1800-1875 In the America of 1800, although a professional medical class existed, medicine was primarily domestically oriented. An individual who fell ill was commonly nursed by a friend or family member who relied upon William Buchan’s Domestic Medicine (1769), John Wesley‘s Primitive Physic (1747, or John G m ’ s DomesficMedicine (1830).’

Professional Medicine Professional medicine transferred from England and Scotland to America in prerevolutionary days. However, eighteenth- and early nineteenth-century America considered the concept of creating a small, elite, learned profession to run counter to the political and institutional concepts of early American dem0cracy.l The first medical school in the American colonies was opened in 1765 a t what was then the College of

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing

Philadelphia (later the University of Pennsylvania), and the school came to be dominated by revolutionary leader and physician Benjamin Rush, a signatory to the Declaration of Independence. The proliferation of medical schools to train the new professional medical class began seriously after the war of 1812. Between 1810 and 1820, new schools were established in Baltimore, Lexington, Cincinnati, and even rural communities in Vermont and Western New York. Between 1820 and 1850 a substantial number of schools were established in the western rural states. By 1850 there were 42 medical schools recognized in the United States, although there were only three in all of France. Generally, these schools were started by a group of five to seven local physicians approaching a local college with the idea of establishing a medical school in conjunction with the college’s educational facilities. The schools were largely apprenticeship based, and the professors received their remuneration directly from fees paid by the students. The requirements for a Doctor of Medicine (MD) degree in late eighteenth- and early nineteenth-century America were roughly as follows: Knowledge of Latin, natural and experimental philosophy 3 years of serving an apprenticeship under practicing physicians Attending of two terms of lectures and passing of attendant examinations A thesis Graduating students had to be at least 21 years of age.’ The rise of any professional class is gradual and marked by difficulties, and varying concepts existed as to the demarcation of a “professional” physician. Contrasts included: graduates of medical school versus nongraduates, medical society members versus nonmembers, and licensed physicians versus unlicensed “doctors.” Licensing statutes came into existence between 1830 and 1850 but were soon repealed, as they were considered ”undemocratic” during the apex of Jacksonian democracy.’

Thomsonianism In 1822 the rise in popularity of Samuel Thomson and his publication of New Guide to Health helped to frustrate the creation of a professional medical class. Thomson’s work was a compilation of his personal view of medical theory and American Indian herbal and medical botanical lore. Thomson espoused the belief that disease had one general cause-“cold” influences on the human body-and that disease had therefore one general remedy-”heat.” Unlike the followers of Benjamin Rush and the American ”heroic” medical tradition who advocated blood-letting, leeching, and the substantial use of

mineral-based purgatives such as antimony and mercury, Thomson believed that minerals were sources of “cold” because they come from the ground and that vegetation, which grew toward the sun, represented “heat.”’ As noted in Griggs’ Green Pharmacy (the best history of herbal medicine to date), Thomson’s theory developed as follows? Instead, he elaborated a theory of his own, of the utmost simplicity: ”Alldiseases. . . are brought about by a decrease or derangement of the vital fluids by taking cold or the loss of animal warmth. . . the name of the complaint depends upon what part of the body has become so weak as to be affected. If the lungs, it is consumption, or the pleura, pleurisy; if the limbs, it is rheumatism, or the bowels, colic or cholera morbus . . . all these different diseases may be removed by a restoration of the vital energy, and removing the obstructions which the disease has generated . . .” Thus the great object of his treatment was always to raise and restore the body’s vital heat: “All . . . that medicine can do in the expulsion of disorder, is to kindle up the decaying spark, and restore its energy till it glows in all its wonted vigor.”

Thomson’s view was that individuals could be selftreating if they had a sincere understanding of his ”new guide to health philosophy and a copy of his book, New Guide to Health. The right to sell “family franchises” for use of the Thomsonian method of healing was the basis of a profound lay movement between 1822 and Thomson’s death in 1843. Thomson adamantly believed that no professional medical class should exist and that democratic medicine was best practiced by laypersons within a Thomsonian ”family” unit. By 1839 Thomson claimed to have sold some 100,000 of these family franchises called ”friendly botanic societies.” Although he professed to have solely the interests of the individual at heart, his system was sold at a profit under the protection of a patent he had obtained in 1813.

The Eclectic School of Medicine Some of the ”botanics” (professionalThomsonian doctors) wanted to separate themselves from the lay movement by creating requirements and standards for the practice of Thomsonian medicine. Thomson, however, was adamantly against a medical school founded on his views. Thus it was not until the decade after Thomson’s death that independent Thomsonians founded a medical college (in Cincinnati) and began to dominate the Thomsonian movement. These Thomsonian botanics were later absorbed into the medical sectarian movement known as the ”eclectic school,” which originated with the New Yorker Wooster Beach. Beach was another of medical history’s fascinating characters. From a well-established New England family, he started his medical studies at an early age, apprenticing under an old German herbal doctor, Jacob Xdd.

After Tidd died, Beach enrolled in the Barclay Street Medical University in New York. Griggs2 wrote the following: Beach’s burning ambition was to reform medical practice generally-not to alienate the entire profession by savage attacks from without-and he was convinced that he would be in a stronger position to do so if he were himself a diplomatized doctor. The faculty occasionally listened to criticism from within their own number: against onslaughts of “illiterate quacks” like Samuel Thornson, they simply closed ranks in complacent hostility.

After opening his own practice in New York, Beach set out to win over fellow members of the New York Medical Society (into which he had been wannly introduced by the screening committee) to his point of view that heroic medicine was inherently dangerous to mankind and should be reduced to the gentler theories of herbal medicine. He was summarily ostracized from the medical society. To Beach this was a bitter blow, but he soon founded his own school in New York, calling the clinic and educational facility “The United States Infirmary.” However, due to continued pressure from the medical society, he was unable to obtain charter authority to issue legitimate diplomas. He then located a financially ailing but legally chartered school, Worthington College, in Ohio. He opened a full-scale medical college; out of its classrooms he launched what became known as the eclectic school of medical theory. Griggs related the following? Beach had a new name for his practice: While explaining to a friend his notions of combining what was useful in the old practice with what was best in the new, the friend exclaimed, “You are an eclectic!” to which, according to legend, Beach replied, “You have given me the term which I have wanted: I am an eclectic!”

Cincinnati subsequently became the focal point of the eclectic movement, and the medical school remained until 1938 (the last eclectic school to exist in America).’ The philosophies of the sect helped to form the theoretical underpinnings of Lust’s naturopathic school of medicine. Despite his criticism of the early allopathic medical movement (although the followers of Rush were not as yet known by this term, reputed to have been coined by Samuel Hahnemann) for their “heroic” tendencies, Thomson’s medical theories were “heroic” in their own fashion. Although he did not advocate blood-letting, heavy metal poisoning, and leeching, botanic purgatives-particularly Lobelia inflllta (Indian tobacco)-were a substantial part of the therapy.

The Hygienic School of Thought One other forerunner of American naturopathy, also originating as a lay movement, grew into existence at

this time. This was the ”hygienic” school, which had its genesis in the popular teachings of Sylvester Graham and William Alcott. Graham began preaching the doctrines of temperance and hygiene in 1830. In 1839he published Lectures on the Science of Human Lqe, two hefty volumes that prescribed healthy dietary habits. He emphasized a moderate lifestyle, recommending an antiflesh diet and bran bread as an alternative to bolted or white bread. Alcott dominated the scene in Boston during this same period and, together with Graham, saw that the American hygienic movement-at least as a lay doctrine-was well e~tablished.~

Homeopathy By 1840 the profession of homeopathy had also been transplanted to America from Germany. Homeopathy, the creation of an early German physician, Samuel Hahnemann (1755-1843))had three central doctrines:

..

The “law of similars” (that like cures like) That the effect of a medication could be heightened by its administration in minute doses (the more diluted the dose, the greater the “dynamic” effect) That nearly all diseases were the result of a suppressed itch, or ”psora”

The view was that a patient’s natural symptomproducing disease would be displaced after homeopathic medication by a similar, but much weaker, artificial disease that the body’s immune system could easily overcome. Originally, most homeopaths in this country were converted orthodox medical men, or “allopaths.” The high rate of conversion made this particular medical sect the arch-enemy of the rising orthodox medical profession. (For a more detailed discussion of homeopathy, see Chapter 39.) The first homeopathic medical school was founded in 1850 in Cleveland; the last purely homeopathic medical school, based in Philadelphia, survived into the early 1930s.’

The Rise and Fall of the Sects Although these two nonallopathic sects were popular, they never comprised more than one fifth of the professional medical class in America. Homeopathy at its highest point reached roughly 15%, and the eclectic school roughly 5%. However, their very existence for many years kept the exclusive recognition desired by the orthodox profession from coming within its grasp. Homeopathy was distasteful to the more conventional medical men not only because it resulted in the conversion of a substantial number of their peers, but also because homeopaths generally also made a better income. The rejection of the eclectic school was more

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing

fundamental: It had its roots in a lay movement that challenged the validity of a privileged professional medical class. The existence of three professional medical groupsthe orthodox school, the homeopaths, and the eclecticscombined with the Jacksonian view of democracy that prevailed in mid-nineteenth century America, resulted in the repeal of virtually all medical licensing statutes existing before 1850.But by the 1870s and 1880s, all three medical groups had begun to voice support for the restoration of medical licensing. Views differ as to what caused the homeopathic and eclectic schools to disappear from the medical scene in the 50 years following 1875. One view defines a sect as follows4: A sect consists of a number of physicians, together with their professional institutions, who utilize a distinctive set of medically invalid therapies which are rejected by other sects. . .

By this definition, the orthodox or allopathic school was just as sectarian as the homeopathic and eclectic schools. Rothstein’s view is that these two nineteenthcentury sects disappeared because, beginning in the 1870s, the orthodox school grasped the European idea of ”scientific medicine.” Based on the research of such men as Pasteur and Koch and the ”germ theory,” this approach supposedly proved to be the medically proper view of valid therapy and gained public recognition because of its truth. Another view is that the convergence of the needs of the three sects for professional medical recognition (which began in the 1870s and continued into the early 1900s)and the ”progressive era’’ led to a political alliance in which the majority orthodox school ultimately came to be dominant by sheer weight of numbers and internal political authority. Starr’ noted the following: Both the homeopaths and eclectics wanted to share in the legal privileges of the profession. Only afterward did they lose their popularity. When homeopathic and eclectic doctors were shunned and denounced by the regular profession, they thrived, but the more they gained an access to the privileges of regular physicians, the more their numbers declined. The turn of the century was both the point of acceptance and the moment of incipient disintegration. . .

In any event, this development was an integral part of the drive toward professional authority and autonomy established during the progressive era (1900-1917). It was acceptable to the homeopaths and the eclectics because they controlled medical schools that continued to teach and maintain their own professional authority and autonomy. However, it was after these professional goals were attained that the lesser schools of medical thought went into rapid decline.’

The American Influence From 1850 through 1900, the medical counterculture continued to establish itself in America. From its lay roots in the teachings of the hygienic movement grew professional medical recognition, albeit a small minority and “irregular” view, that hygiene and hydropathy were the basis of sound medical thought (much like the Thomsonian transition to botanic and eclectic medicine).

Trall The earliest physician who came to have a significant impact on the later growth of naturopathy as a philosophical movement was Russell Trall, MD. As noted in Whorton’s Crusaders for Fitness? he “passed like a meteor through the American hydropathic and hygienic movement”: The exemplar of the physical educator-hydropath was Russell Thatcher Trall. Still another physician who had lost his faith in regular therapy, Trall opened the second water cure establishment in America, in New York City in 1844. Immediately he combined the full Preissnitzian armamentarium of baths with regulation of diet, air, exercise and sleep. He would eventually open and or direct any number of other hydropathic institutions around the country, as well as edit the Water-Cure Journal, the Hydropathic R&, and a temperance journal. He authored several books, including popular sex manuals which perpetuated Graham-like concepts into the 1890’s, sold Graham crackers and physiology texts at his New York office, was a charter member (and officer) of the American Vegetarian Society, presided over a short-livedWorld Health Association, and so on. His crowning accomplishment was the Hygeian Home, a “model Health Institution [which] is beautifully situated on the Delaware River between Trenton and Philadelphia.”A drawing presents it as a palatial establishment with expansive grounds for walking and riding, facilities for rowing, sailing, and swimming, and even a grove for open-air ”dancing gymnastics.” It was the grandest of water cures, and lived beyond the Civil War period, which saw the demise of most hydropathic hospitals. True, Trall had to struggle to keep his head above water during the 1860’~~ but by the 1870’s he had a firm financial footing (being stabilized by tuition fees from the attached Hygeiotherapeutic College). With Trall’s death in 1877, however, the hydropathic phase of health reform passed.

As evident later in this chapter, this plethora of activity is similar to that engaged in by Benedict Lust between 1896 and his death in 1945, when he worked to establish naturopathic medicine. The Hygeian Home and later “Yungbom”establishmentsat Butler, NJ,and Tangerine, FL, were similar to European nature cure sanitariums, such as the ori@ Yungbom founded by Adolph just and the spa/sanitarium facilities of Preissnitz, Kneipp, and Just. Trall gave a famous address to the Smithsonian Institution in Washington, D.C., in 1862, under the sponsorship of the Washington Lecture Association. ”The true healing art: or hygienic vs drug medication,” a 2.5-hour

lecture purported to have received rapt attention, was devoted to Trall’s belief in the hygienic system and in hydropathy as the true healing art. The address was reprinted by Fowler and Wells (New York, 1880) with an introduction written by Trall, before his death in 1877. Trall also founded the first school of natural healing arts in this country to have a Cyear curriculum and the authorization to confer the degree of MD. It was founded in 1852 as a “hydropathic and physiological school” and was chartered by the New York State Legislature in 1857 under the name “New York HygioTherapeutic College,” with the legislature’s authorization to confer the MD degree. In 1862 Trall went to Europe to attend the International Temperance Convention. At this meeting of reformers, he took prominent part, specifically relating to the use of alcohol as a beverage and as a medicine. He eventually published more than 25 books on the subjects of physiology, hydropathy, hygiene, vegetarianism, and temperance, among many others. The most valuable and enduring of these was his Hydrqathic Encyclopedia, a volume of nearly 1000 pages that covered the theory and practice of hydropathy and the philosophy and treatment of diseases advanced by older schools of medicine. At the time of his death, according to the December 1877 Phrenological Journal cover article featuring a lengthy obituary of Trall, this encyclopedia had sold more than 40,000 copies since its original publication in 1851. For more than 15 years, Trall was editor of the WaterCure Journal (also published by Fowler and Wells). During this period, the journal went through several name changes including the Hygienic Teacher and The Herald of Health. When Lust originally opened the American School of Naturopathy, an English-language version of Kneipp’s Water-cure (or in German Meine Wasser-kurr)being unavailable, he used only the works and writings of Trall as his texts. By 1871 Trall had moved from New York to the Hygeian Home on the Delaware River. His water-cure establishment in New York became The New Hygienic Institute. One of its coproprietors was Martin Luther Holbrook, who later replaced Trall as the editor of The Herald ofHealth. Professor Whorton noted the following? But Holbrook‘s greatest service to the cause was as an editor. In 1866 he replaced Trall at the head of The Herald of Health, which had descended from the Water-Cure Journal and Herald ofR.$orms (1845-1861)by the way of the Hygienic Teacher and Water-Cure Journal (1862). Under Holbrook’s direction the periodical would pass through two more name changes (Journal ofHygiene Herald ofHealth, 1893-1897, and Omega, 18981900)before merging with Physical Culture.

Trall and Holbrook both advanced the idea that physicians should teach the maintenance of health

rather than simply provide a last resort in times of health crisis. Besides providing a strong editorial voice espousing vegetarianism, the evils of tobacco and drugs, and the value of bathing and exercise, dietetics and nutrition along with personal hygiene were strongly advanced by Holbrook and others of the hygienic movement during this era. Whorton described the idea as follows3: The orthodox hygenists of the progressive years were equally enthused by the recent progress of nutrition, of course, and exploited it for their own ends, but their utilization of science hardly stopped with dietetics. Medical bacteriology was another area of remarkable discovery, bacteriologists having provided, in the short space of the last quarter of the 19th century, an understanding, at long last, of the nature of infection. This new science’s implications for hygienic ideology were profound-when Holbrook locked horns with female fashion, for example, he did not attack the bulky, ground-length skirts stiU in style with the crude Grahamite objection that the skirt was too heavy. Rather he forced a gasp from his readers with an account of watching a smartly dressed lady unwittingly drag her skirt ”over some virulent, revolting looking sputum, which some unfortunate consumptive had expectorated.”

Holbrook expanded on the work of Graham, Alcott, and Trall and, working with an awareness of the European concepts developed by Preissnitz and Kneipp, laid further groundwork for the concepts later advanced by Lust, Lindlahr, and others3: For disease to result, the latter had to provide a suitable culture medium, had to be susceptible. As yet, most physicians were still so excited at having discovered the causative agents of infection that they were paying less than adequate notice to the host. Radical hygienists, however, were bent just as far in the other direction. They were inclined to see bacteria as merely impotent organisms that throve only in individuals whose hygienic carelessness had made their body compost heaps. Tuberculosis is contagious, Holbrook acknowledged, but “the degree of vital resistance is the real element of protection. When there is no preparation of the soil by heredity, predisposition or lowered health standard, the individual is amply guarded against the attack.” A theory favored by many others was that germs were the effect of disease rather than its cause; tissues corrupted by poor hygiene offered microbes, all harmless, an environment in which they could thrive.

In addition to introducing the works of Kneipp and his teachings to the American hygienic health care movement, Holbrook was a leader of the fight against vivisection and vaccination3: Vivisection and vaccination were but two of the practices of medicine criticized in the late 19th century. Therapy also continued to be an object of protest. Although the heroism of standard treatment had declined markedly since mid-century, a prescription was still the reward of any visit to the doctor, and drugless alternatives to healing were appearing in protest. Holbrook published frequent favorable commentaries on the revised water cure system of Germany‘s Kneipp. A combination

The History of Naturopathic Medicine, Part I:The Emergence of an American School of Healing of baths, herbal teas, and hardening exercises, the system had some vogue in the 1890’s before flowering into naturopathy. Holbrook’s journal also gave positive notices to osteopathy and “chiropathy” [chiropractic],commending them for not going to the “drugstore or ransack[ing] creation for remedies nor load[ing]the blood with poison.” But though bathing and musculoskeletal manipulation were natural and nonpoisonous, Holbrook preferred to give the body complete responsibility for healing itself. Rest and proper diet were the medicines of this doctor who billed himself as a “hygienic physician” and censured ordinary physicians for being engrossed with disease rather than health.

The Beginnings of “Scientific Medicine” While the hygienic movement was making its impact, the orthodox medical profession, in alliance with the homeopaths and eclectics, was making sigruficant advances. The orthodox profession, through the political efforts of the American Medical Association (AMA), had first tried to remove sectarian and irregular practitioners by segregating them from the medical profession altogether. It did so by formulating and publishing its first national medical code of ethics in 1847. (In 1846 the orthodox profession formed the AMA to represent their professional views.) The code condemned proprietary patents (even carrying over into a physician’s development of surgical or other medical implements, which led to its greatest criticism); encouraged the adoption of uniform rules for payment in geographic areas; condemned the practice of contract work; prohibited advertising and fee-sharing even among specialists and general practitioners; eliminated blacks and women; and, most significantly,prohibited any consultation or contact with irregulars or sectarian practitioners. The code stated the following? No one can be considered as a regular practitioner, or a fit associate in consultation, whose practice is based on an exclusive dogma, to the rejection of the accumulated experience of the profession, and of the aids actually furnished by anatomy, physiology,pathology, and organic chemistry. In the late 1870s and into the 1880s, the major sectsthe orthodox or allopathic school, the homeopaths, and the eclectics-began to find more reason to cooperate to obtain common professional goals. These included the enactment of new licensing laws and the creation of a “respectable” medical educational system. Also at this time, the concept of “scientificmedicine” was brought to America. (Although Starr differs from Rothstein about the cause of the death of the homeopathic and eclectic sectarian schools, he notes that Rothstein clearly documents the transition, during the nineteenth century, of medicine to a recognized professional class composed of both the minority sects and the orthodox school.) This transition from conflict between the major sects resulted in the erosion of the implementation of the code of ethics, the cooperation among the sects to revive

medical licensing standards, the admission of sectarian physicians to regular medical societies, and, ultimately, a structural reorganization of the AMA, which occurred between 1875 and 1903.l” Once the cooperation among the three medical views had begun, the medical class as dominated by the regular school came fully into power. And the homeopathic and eclectic schools of thought met their demise, which was finally brought about by two significant events: (1)the rapid creation of new medical educational standards between 1900 and 1910, culminating in the publication of the famous “Flexner Report” (1910), and (2) the effective infusion of millions of dollars into selected allopathic medical schools by the newly created capitalistic philanthropic foundations, principally the Carnegie and Rockefeller foundations.

The Foundations The impact of the monies from the Carnegie and Rockefeller foundations has been clearly documented6 and is described in detail, albeit for the advancement of a particular political point of view, in Brown’s Rockefeller Medicine Men. The impact of the monies from these foundations, as contributed to medical schools that met the AMA‘s view of medical education and philosophy, cannot be underestimated. As disThis process has been well cussed by Burrows,(rthis educational reform allowed the AMA to form a new alliance with legislators and push quickly for medical licensing designed to reward the educational and medical expertise of the new orthodox “scientific medicine” and the exclusion of all others.s

Medical Education in Transition Based on the rising example of scientific medicine and its necessary connection to research, the educational laboratory, and a more thorough scientific education as a preamble to medical practice, Harvard University (under the presidency of Charles Elliott) created a 4-year medical educational program in 1871. The primal modern medical educational curriculum was devised and set in motion more than 20 years later at Johns Hopkins University under the leadership of William Osler and William Welch, using the resources from the original endowment of the hospital and university from the estate of Johns H0pkins.l Other schools followed suit. By the time the AMA set up its Council on Medical Education in 1904, it was made up of five members from the faculties of schools modeled on the Johns Hopkins prototype. This committee set out to visit and rate each of the 160 medical schools then in operation in the country. The ratings used were class “ A (acceptable), class “B” (doubtful), and class ”C” (unacceptable).

Eighty-two schools received a class " A rating, led by Harvard, Rush (Chicago), Western Reserve, the University of California and, notably, Johns Hopkins. Forty-six schools received a class "B" rating, and tlurtytwo a class "C"rating. The class "C" schools were mostly in rural areas, and many of them proprietary in nature.

Flexner Report Subsequent to the AMA ratings, the Council on Medical Education applied to the Carnegie Foundation to commission an independent report to verify its work. Abraham Flexner, a young, energetic, and noted educator, was chosen for this task by the Carnegie Foundation and accompanied by the secretary (Nathan Colwell, MD) of the Council on Medical Education, who had participated in all of the committee site visits. Flexner visited each of the 162 US. medical schools then operating. The widely publicized Flexner Report put the nails in the coffins of all schools with class "C" ratings and many with class " B ratings. SigIuiicantly, the educational programs of all but one eclectic school (in Cincinnati)and one homeopathic school (in Philadelphia) were eliminated by 1918. The eclectic medical schools, in particular, were severely affected by the report. Griggs explained this effect as follows2: Of the eight Eclectic schools, the Report declared that none had "anythmg remotely resembling the laboratory equipment which is claimed in their catalogs."Three of them were underequipped; the rest "are without exception filthy and almost bare. They have at best grimy little laboratories. . . a few microscopes, some bottles containing discolored and unlabeled pathological material, in an incubator out of commission, and a horrid disseding room.''The Report found them more culpable than a regular school for these inadequacies: ". . . the Eclectics are drug-mad; yet, with the exception of the Cincinnati and New York schools, they are not equipped to teach the drugs or drug therapy which constitutestheir sole reason for existence."

The other regular schools that had conducted homeopathic or eclectic programs had by that time phased them out in the name of "scientific medicine."

Pharmaceutical Industry During this same time period, the AMA, through several of its efforts, began a significant alliance with the organized pharmaceutic industry of the United States, shaping it in a manner acceptable to the allopathic profe~sion.',',~

The New "Sects" The period from 1890-1905 saw the rise of three new medical sects and several other smaller "irregular" schools, which replaced those soon to pass away. In Missouri, Andrew Taylor Still, originally trained as an orthodox practitioner, founded the school of medical

thought known as "osteopathy" and in 1892 opened the American School of Osteopathy in Kirksville, MO. In 1895 Daniel David Palmer, originally a magnetic healer from Davenport, IA, performed the first spinal manipulation, which gave rise to the school he termed "chiropractic." He formally published his findings in 1910, after having founded a chiropractic school in Davenport, IA. And in 1902 Lust founded the American School of Naturopathy in New York. Although some of the following discussion are devoted to the schools of healing called osteopathy and chiropractic, only that portion of their histories related to the history of naturopathy is mentioned.1° (A full study of osteopathic medicine in America may be found in The D.0.sby Gevitz," and a reasonable sketch of chiropractic medicine may be found in Kapling's chapter in Al temative Medicine. lo) As noted by Starr,' these new sects, including Christian Science, formulated by Mary Baker Eddy (see SilbergerI2for further discussion), either rose or fell on their own without ever completely allying with orthodox medicine. Starr theorized that these sects arose late enough that the orthodox profession and its political action arm, the AMA, had no need to ally with them and would rather battle with them publicly. This made these sectarian views separate and distinct from the homeopathic and eclectic schools.

THE FOUNDING OF NATUROPATHIC MEDICINE Benedict Lust Lust came to the United States in 1892 at the age of 23. He had suffered from a debilitating condition in his late teens while growing up in Michelbach, Baden, Germany, and had been sent by his father to undergo the Kneipp cure at Woerishofen. He stayed there from mid-1890 to early 1892; not only was he "cured" of his condition, but he also became a protbgk of Kneipp. Dispatched by Kneipp to bring the principles of the Kneipp water cure to America, he emigrated to New York City. By making contact in New York with other German Americans who were also becoming aware of the Kneipp principles, Lust participated in the founding of the first "Kneipp Society," which was organized in Jersey City, NJ, in October 1896. Lust also attended the first organizational meeting (in mid-October 1896) of the Kneipp Society of Brooklyn. Subsequently, through Lust's organization and contacts, Kneipp Societies were founded in Boston; Chicago; Cleveland; Denver; Cincinnati; Philadelphia; Columbus; Buffalo and Rochester, NY; New Haven, CT; San Francisco; New Mexico; and Mineola on Long Island, NY. The members of these organizations were provided with copies of the Kneipp Blatter and a companion

English publication Lust began to put out called The Kneipp Water Cure Monthly. The first “sanatorium” using Kneipp’s principles was organized in this country shortly before Lust’s arrival. Charles Lautenvasser, an earlier student of Kneipp‘s who called himself a hydrophic physician and natural scientist, opened the Kneipp and Nature Cure Sanatorium in Newark, NJ, in 1891. In 1895 the Brooklyn Light and Water-Cure Institute was established in Brooklyn, NY,by L. Staden and his wife Carola, both graduates of Lindlahr’s Hygienic College in Dresden, Germany. According to their advertising, they specialized in natural healing, Kneipp water treatment, Kuhne’s and Preissnitz’s principles (including diet cure, electric light baths [both white and blue], electric vibration massage, Swedish massage and movements, and Thure-brandt massage). In 1895 Lust opened the Kneipp Water-Cure Institute in New York City, listing himself as the owner and Dr.William Steffens as the residing physician. At the same address (on 59th Street) in October of that year, Lust opened the first “Kneipp store.” In the originating November 1896 edition of The Kneipp Water Cure Monthly and Kneipp Blutter, he advertised his store and sanitarium as personally authorized by Kneipp. In the first part of 1896, just before his organizing of various Kneipp Societies around the New York area, Lust returned to Woerishofen to study further with Kneipp. Kneipp died in Germany, at Woerishofen, in June 1897. With his passing, Lust was no longer bound strictly to the principles of the Kneipp water cure. He had begun to associate earlier with other GermanAmerican physicians, principally Dr. Hugo R. Wendel (a German-trained Nutururzt), who began, in 1897, to practice in New York and New Jersey as a licensed osteopathic physician. In 1896 Lust entered the Universal Osteopathic College of New York, graduated in 1898, and became licensed as an osteopathic physician. In 1897 Lust became an American citizen. Once he was licensed to practice as a health care physician in his own right, Lust began the transition toward the concept of “naturopathy.” Between 1898 and 1902, when he adopted the term ”naturopath,” Lust acquired a chiropractic education and changed the name of his Kneipp store to Health Food Store (the original facility to use that name and concept in this country), specializing in providing organic foods and the materials necessary for drugless cures. He also began the New York School of Massage (listed as established in 1896) and the American School of Chiropractic, all within the same facility-Lust’s Kneipp Institute. Photographs of this facility taken between 1902 and 1907, when the facility moved to another location, show a five-story building listing “Benedict Lust-Naturopath, Publisher, Importer.”

He returned to Germany in 1907 to visit with Dr. Baumgarten, Kneipp’s medical successor at the Woerishofen facility, which was then run,in cooperation with Baumgarten, by the Reverend Prior Reily, the former secretary to Kneipp and his lay successor at Woerishofen. As directed by Kneipp, Reily had completed, after Kneipp’s death, Kneipp’s master work Dus grosse Kneipp-Buch. Lust maintained contact with the partnership of Reily and Baumgarten throughout the early part of the twentieth century. In 1902, when he purchased and began using the term naturopathy and calling himself a “naturopath,” Lust, in addition to his New York School of Massage and American School of Chiropractic, his various publications, and his operation of the Health Food Store, began to operate the American School of Naturopathy, all at the same 59th Street address. By 1907, Lust’s enterprises had grown sufficiently large that he moved them to a 55-room building. It housed the Naturopathic Institute, Clinic and Hospital; the American Schools of Naturopathy and Chiropractic; the now entitled Original Health Food Store; Lust’s publishing enterprises; and New York School of Massage. The operation remained in this four-story building, roughly twice the size of the original facility, from 1907 to 1915. From 1912 through 1914, Lust took a “sabbatical” from his operations to further his education. By this time he had founded his large estatelike sanitarium in Butler, NJ, known as “Yungborn” after the German sanitarium operation of Adolph Just. In 1912 he attended the Homeopathic Medical College in New York, which, in 1913, granted him a degree in homeopathic medicine and, in 1914, a degree in eclectic medicine. In early 1914, Lust traveled to Florida and obtained an MD’s license on the basis of his graduation from the Homeopathic Medical College. Thereafter he founded another “Yungborn” sanitarium facility in Tangerine, FL, and for the rest of his life, while continuing his publications, engaged in active lecturing. He also continued to maintain a practice in New York City and operated the sanitariums in Florida and New Jersey. His schools were operated by Hugo R. Wendel. From 1902, when he began to use the term naturopathy, until 1918, Lust replaced the Kneipp Societies with the Naturopathic Society of America. Then, in December 1919, the Naturopathic Society of America was formally dissolved due to its insolvency and Lust founded the American Naturopathic Association. Thereafter 18 states incorporated the association. In 1918, as part of his effort to replace the Naturopathic Society of America (an operation into which he invested a great deal of his funds and resources in an attempt to organize a naturopathic profession) and replace it with

the American Naturopathic Association, Lust published the first Universal Naturopathic Directory and Buyer’s Guide (a ”yearbook of drugless therapy”). Although a completely new version was never actually published, in spite of Lust’s announced intention to make this volume an annual publication, annual supplements were published in either The Naturopath and Heruld of Health or its companion publication, with which The Naturopath at one time merged, Nature’s Path (which commenced publication in 1925). The Naturopath and Herald ofHeulth, sometimes printed with the two phrases reversed, was published from 1902 through 1927, and from 1934 until after Lust’s death in 1945. This volume documents the merging of the German and American influences that influenced Lust in his development of the practice of naturopathy,The voluminous tome, which ran to 1416 pages, is dedicated to: The memory of all those noble pioneers and discoverers who have died in the faith of Naturopathy, and to their courageous successors in the art of drugless healing, all of whom have suffered persecution for saving human lives that medical autocracy could not save, this work is respectfully dedicated by its editor Benedict Lust, N.D., M.D., “The Yungbom,” Butler, New Jersey, U.S.A., April 1, 1918.

Lust’s introduction is reprinted here in its entirety to show the purpose of the directory and the status of the profession in the early 1900s: Introduction To the Naturopathic Profession, the Professors of Natural Healing in all its branches, the Professors of Scientific Diet, Hydrotherapy, Heliotherapy, Electrotherapy, Neuropathy, Osteopathy, Chiropractic, Naprapathy, Magnetopathy, Phytotherapy, Exercise, Swedish Movements, Curative Gymnastics,Physical and Mental Culture, Balneopathy, and all forms of Drugless Healing, the Faculties of all Drugless Colleges, Institutions, Schools, and all Professors of Hygiene and Sanitation; Manufacturers of Naturopathic Supplies; Publishers of Health Literature, and Natural Healing Societies, GREETINGS: I have the honor to present to your consideration and goodwill, this Volume, No. 1, Year 1918-1919, of the Universal Naturopathic Directory, Year Book of Drugless Healing, and Buyers’ Guide. For twenty-two years past, the need of a directory for Drugless Therapy has been felt. The medical world is in a condition of intense evolution at the present time. It is evolving from the Drugging School of Therapy to the Drugless School. People by the million have lost confidence in the virtues of Allopathy and are turning with joyful confidence to the Professions of Natural Healing until it has been estimated that there are at least forty thousand practitioners of Naturopathic healing in the United States. The motto that IN UNITY THERE IS STRENGTH is the foundation of the present enterprise. Hitherto, the drugless profession has lacked that prestige in the eyes of the public, which comes from the continuous

existence of a big institution, duly organized and wielding the immense authority which is derived no less from organization and history than from the virtues of the principles that are held and practiced by such institutions. The public at large instantaneously respects an institution that is thoroughly organized and has its root earthed in history. The time has fully arrived when the drugless profession should no longer exist in the form of isolated units, not knowing one another and caring but little for such knowledge. Our profession has been, as it were, as sheep without a shepherd, but the various individuals that constitute this movement so pregnant with benefits to humanity, are now collected for the first time into a Directory and Year-Book of Drugless Healing, which alone will give immense weight and dignity to the standing of the individuals mentioned therein. Not only will the book add to the prestige of the practitioner in the eyes of his patients, but when the scattered members of our profession in every State desire to obtain legislative action on behalf of their profession and themselves, the appeal of such a work as our directory will, in the eyes of legislators, gain for them a much more respectful hearing than could otherwise be obtained. Now, for the first time, the drugless practitioner finds himself one of a vast army of professional men and women who are employing the most healthful forces of nature to rejuvenate and regenerate the world. But the book itself throws a powerful light upon every phase of drugless healing and annihilates time and distance in investigating WHO IS WHO in the realm of Drugless Therapy. A most sincere effort has been made to obtain the name and address of every adherent of the Rational School of Medicine who practices his profession within the United States, Canada and the British Isles. It is impossible at this stage of Naturopathic history, which is still largely in the making, to obtain the name and address of every such practitioner. There were some who, even when appealed to, refused to respond to our invitation, not understanding the object of our work. Many of even the most intelligent members have refused to advertise their professional cards in our pages. But we can only attribute these drawbacks to the fact that every new institution that has suddenly dawned upon human intelligencewill find that a certain proportion of people who do not understand the nature of the enterprise because the brain cells that would appreciate the benefits that are sought to be conferred upon them, are undeveloped, but a goodly proportion of our Naturopaths have gladly responded to the invitation to advertise their specialty in our columns. These, of course, constitute the brightest and most successful of our practitioners and their examples in this respect should be followed by every practitioner whose card does not appear in this book. We take it for granted that every one of the forty thousand practitioners of Naturopathy is in favor of the enterprise represented by this Directory. This work is a tool of his trade and not to possess this book is a serious handicap in the race for success. Here will be found an Index of by far the larger number of Naturopaths in the country arranged in Alphabetic, Geographic and Naturopathic sections. Besides this, there is a classified Buyers’ Guide that gives immediate information regarding where you can find special supplies, or a certain

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing apparatus, or a certain book or magazine, its name, and where it is published. The list of Institutions with the curriculum of each will be found exceedingly useful. Natural healing, that has drifted so long, and, by reason of a lack of organization, has been made for so many years the football of official medicine, to be kicked by any one who thought fit to do so, has now arrived at such a pitch of power that it has shaken the old system of bureaucratic medicine to its foundations. The professors of the irrational theories of life, health and disease, that are looking for victims to be inoculated with dangerous drugs and animalized vaccines and serums, have begun to fear the growth of this young giant of medical healing that demands medical freedom, social justice and equal rights for the new healing system that exists alone for the betterment and uplifting of humanity. I want every Professor of Drugless Therapy to become my friend and co-worker in the great cause to which we are committed, and those whose names are not recorded in this book should send them to me without delay. It will be of far greater interest and value to themselves to have their professional card included amongst those who advertise with us than the few dollars that such advertisement costs. It will be noted that there are quite a number of Drugless Healers belonging to foreign countries (particularly those of the Western Hemisphere) represented in this Directory. The profession of medicine is not confined to any race, country, clime or religion. It is a universal profession and demands universal recognition. It will be a great honor to the Directory, as well as to the Naturopathic profession at large to have every Naturopathic practitioner, from the Arctic Circle to the furthest limits of Patagonia, represented in the pages of this immense and most helpful work. I expect that the Directory for the year 1920 will be larger and even more important than the present Directory and that it will contain the names of thousands of practitioners that are not included in the present work. The publication of this Directory will aid in abolishing whatever evils of sectarianism, narrow-mindednessand lack of loyalty to the cause to which we are devoted, that may exist. That it will promote a fraternal spirit among all exponents of natural healing, and create an increase of their prestige and power to resist the encroachments of official medicine on their constitutional rights of liberty and the pursuit of happiness, by favorably influencing Legislators, Law courts, City Councils and Boards of Health everywhere, is the sincere belief of the editor and publisher. Having introduced the volume, Lust leads off with his article entitled ”The principles, aim and program of the nature cure system.”Again, thisrelatively brief article is reproduced here in its entirety, so that one can see the merging of influences: The principles, aim and program of the nature cure system Since the earliest ages, Medical Science has been of all sciences the most unscientific. Its professors, with few exceptions, have sought to cure disease by the magic of pills and potions and poisons that attacked the ailment with the idea of suppressing the symptoms instead of attacking the real cause of the ailment. Medical science has always believed in the superstition that the use of chemical substances which are harmful and

destructive to human life will prove an efficient substitute for the violation of laws, and in this way encourages the belief that a man may go the limit in self indulgences that weaken and destroy his physical system, and then hope to be absolved from his physical ailmentsby swallowinga few pills, or submitting to an injection of a serum or vaccine, that are supposed to act as vicarious redeemers of the physical organism and counteract life-long practices that are poisonous and wholly destructive to the patient’s well-being. From the earliest ages to the present time, the priests of medicine have discovered that it is ten times easier to obtain ten dollars from a man by acting upon his superstition, than it is to extract one dollar from him,by appealing to reason and common sense. Having this key to a gold mine within their grasp, we find official medicine i n d u l p g at all times in the most blatant, outrageous, freakish and unscientific methods of curing disease, because the methods were in harmony with the medical prestige of the physician. Away back in pre-historic times, disease was regarded as a demon to be exorcized from its victim, and the medicine man of his tribe belabored the body of his patient with a bag in which rattled bones and feathers, and no doubt in extreme cases the tremendous faith in this process of cure that was engendered in the mind of the patient really cured some ailments for which mental science and not the bag of bones and feathers should be given credit. Coming down to the middle ages, the Witches’ Broth-one ingredient of which was the blood of a child murderer drawn in the dark of the moon-was sworn to, by official medicine, as a remedy for every disease. In a later period, the “docteur a la mode,” between his taking pinches of snuff from a gold snuff box, would order the patient bled as a remedy for what he denominated spirits, vapors, megrims, or miasms. Following this pseudo-scientific diagnosis and method of cure, came the drugging phase in which symptoms of disease were unmercifully attacked by all kinds of drugs, alkalis, acids and poisons which were supposed, that by suffocating the symptoms of disease, by smothering their destructive energy, to thus enhance the vitality of the individual. All these cures have had their inception, their period of extensive application, and their certain desuetude. The contemporary fashion of healing disease is that of serums, inoculations and vaccines, which, instead of being an improvement on the fake medicines of former ages are of no value in the cure of disease, but on the contrary introduce lesions into the human body of the most distressing and deadly import. The policy of expediency is at the basis of medical drug healing. It is along the lines of self-indulgence, indifference, ignorance and lack of self-control that drug medicine lives, moves and has its being. The sleeping swineries of mankind are wholly exploited by a system of medical treatment, founded on poisonous and revolting products, whose chemical composition and whose mode of attacking disease, are equally unknown to their originators, and this is called “Scientific medicine.“ Like the alchemist of old who circulated the false belief that he could transmute the baser metals into gold, in like manner the vivisector claims that he can coin the agony of animals into

Philosophy of Natural Medicine cures for human disease. He insists on cursing animals that he may bless mankind with such curses. TOunderstand how revolting these products are, let us just refer to the vaccine matter which is supposed to be an efficient preventive of smallpox. Who would be fool enough to swallow the putrid pus and corruption scraped from the foulest sores of smallpox that has been implanted in the body of a calf? Even if any one would be fool enough to drink so atrocious a substance, its danger might be neutralized by the digestive juices of the intestinal tract. But it is a far greater danger to the organism when inoculated into the blood and tissues direct, where no digestive substances can possibly neutralize its poison. The natural system for curing disease is based on a return to nature in regulating the diet, breathing, exercising, bathing and the employment of various forces to eliminate the poisonous products in the system, and so raise the vitality of the patient to a proper standard of health. official medicine has in all ages simply attacked the symptoms of disease without paying any attention to the causes thereof, but natural healing is concerned far more with removing the causes of disease, than merely curing its symptoms. This is the glory of this new school of medicine that it cures by removing the causes of the ailment, and is the only rational method of practicing medicine. It begins its cures by avoiding the uses of drugs and hence is styled the system of drugless healing. It came first into vogue in Germany and its most famous exponents in that country were Priessnitz, Schroth, Kuhne, Kneipp, Rickli, Lahmann, Just, Ehret, Engelhardt, and others. In Sweden, Ling and others developed various systems of mechano-therapy and curative gymnastics. In America, Palmer invented Chiropractic; McCormick, Ophthalmology.Still originated Osteopathy; Weltmer, suggestive Therapeutics. Lindlahr combined the essentials of various natural methods, while Kellogg, Tiden, Schultz, Trall, Lust, Lahn, Arnold, Struch, Havard, Davis, Jackson, Walters, Deininger, Tyrell, Collins and others, have each of them spent a lifetime in studying and putting into practice the best ideas of drugless healing and have greatly enlarged and enriched the new school of medicine. Life Maltreated by Allopathy The prime object of natural healing is to give the principle of life the line of least resistance, that it may enable man to possess the most abundant health. What is life? The finite mind of man fails to comprehend the nature of this mysterious principle. The philosopher says "Life is the sum of the forces that resist death," but that definition only increases its obscurity. Life is a most precious endowment of protoplasm, of the various combinations of oxygen, hydrogen, carbon and nitrogen, and other purely mineral substances in forming organic tissues. As Othello says, referring to Desdemona's life, which he compares to the light of a candle"If I quench thee thou flaming minister, I can thy former light restore Should I repent me; but once put out THY light, I know not whence is that Promethean heat That can thy light relume."

The spark of life flickers in the sockets of millions and is about to go out. What system of medicine will most surely restore that flickering spark to a steady, burning flame? Will [it be] the system that employs poisonous vaccines, serums and inoculations, whose medical value has to be supported by the most mendacious statements, and whose practitioners are far more intent on their emoluments and fame, than they are in the practice of humanity? The Allopathic system, which includes nine tenths of all medical practitioners, is known by its fruits, but it is an appalling fact that infant mortality, insanity, heart disease, arteriosclerosis, cancer, debility, impoverished constitutions, degeneracy, idiocy and inefficiencyhave enormously increased, particularly during the last twenty-five years, that is, during the regime of inoculations, serums and vaccines. Naturopathy, on the other hand, so far as it has been developed, and so far as official medicine will allow it to act, leaves no such trail of disease, disaster and death behind it. Natural healing is emancipation from medical superstition, ignorance and tyranny. It is the true Elixir of Life. The Allopaths have endeavored to cure sick humanity on the basis of the highly erroneous idea that man can change the laws of nature that govern our being, and cure the cause of disease by simply ignoring it. To cure disease by poisoning its symptoms is medical manslaughter. Dr. Schwenninger of Germany says: "We are suffering under the curse of the past mistakes of our profession. For thousands of years medical doctors have been educating the public into the false belief that poisonous drugs can give health. This belief has become in the public mind such a deepseated superstition, that those of us who know better and who would like to adopt more sensible, natural methods of cure, can do so only at the peril of losing practice and reputation. "The average medical man is at his best but a devoted bigot to this vain school-craft, which we call the Medical Art and which alone in this age of science has made no perceptible progress since the days of its earliest teachers. They call it recognized science! Recognized ignorance! The science of to-day is the ignorance of to-morrow. Every year some bold guess lights up as truth to which but the year before the schoolmen of science were as blind as moles." And Dr.O.W. Holmes, Professor of Anatomy in Harvard University, states: "The disgrace of medicine has been that colossal system of self-deception, in obedience to which mines have been emptied of their cankering minerals, entrails of animals taxed for their impurities, the poison bags of reptiles drained of their venom, and all the inconceivable abominations thus obtained thrust down the throats of human beings, suffering from some fault of organization, nourishment, or vital stimulation." And these misguided drug doctors are not only not ashamed of their work, but they have induced subservient legislators to pass laws that perpetuate the age-long scandal of allopathic importance, and the degenerative influence of the poisons, and to actually make it a crime on the part of nature doctors to cure a man of his ailment. The brazen effrontery of these medical despots has no limits. They boast of making the State legislators their catspaw in arresting, fining and imprisoning the professors of natural healing for saving human life.

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing Legislators have no right to sit in judgment over the claims of rival schools of healing. They see tens of thousands of sick people go down to their graves by being denied the cures that the employers of nature’s forces alone can give them. It is their business to provide for the various schools of medicine a fair field and no favor. A citizen has an inalienable right to liberty in the pursuit of happiness. Yet the real saviors of mankind are persecuted by the medical oligarchy which is responsible for compulsory vaccination, compulsory medical inspection of public school children, and the demands for State and Federal departments of health, all for the ostensible good of the people, but in reality for the gain of the Medical Trust.

The Naturopaths The Naturopaths are desirous of freedom for all schools of medicine. They are responsible practitioners who are willing to be examined by an impartial council, appointed by and acting for the State, who will testify to the life and character of every drugless physician before he is entitled to practice medicine. Not one invidious discriminationshould be made between the different schools of medicine. The state should see to it that each school should have a full opportunity to do its best for the up-lifting of its citizens.

The Program of Naturopathic Cure 1.ELIMINATION OF EVIL HABITS, or the weeds of life, such as overeating, alcoholic drinks, drugs, the use of tea, coffee and cocoa that contain poisons, meat eating, improper hours of living, waste of vital forces, lowered vitality, sexual and social aberrations, worry, etc. 2. CORRECTIVE HABITS. Correct breathing, correct exercise, right mental attitude. Moderation in the pursuit of health and wealth. 3. NEW PRINCIPLES OF LIVING. Proper fasting, selection of food, hydropathy, light and air baths, mud baths, osteopathy, chiropractic and other forms of mechano-therapy, mineral salts obtained in organic form, electropathy, heliopathy, steam or Turkish baths, sitz baths, etc. Natural healing is the most desirable factor in the regeneration of the race. It is a return to nature in methods of living and treatment. It makes use of the elementary forces of nature, of chemical selection of foods that will constitute a correct medical dietary. The diet of civilized man is devitalized, is poor in essential organic salts. The fact that foods are cooked in so many ways and are salted, spiced, sweetened and otherwise made attractive to the palate, induces people to over-eat, and over eating does more harm than under feeding. High protein food and lazy habits are the cause of cancer, Bright’s disease, rheumatism and the poisons of auto-intoxication. There is really but one healing force in existence and that is Nature herself, which means the inherent restorative power of the organism to overcome disease. Now the question is, can this power be appropriated and guided more readily by extrinsic or intrinsic methods? That is to say, is it more amenable to combat disease by irritating drugs, vaccines and serums employed by superstitious modems, or by the bland intrinsic congenial forces of Natural Therapeutics, that are employed by this new school of medicine, that is Naturopathy, which is the only orthodox school of medicine?

Are not these natural forces much more orthodox than the artificial resources of the druggist? The practical application of these natural agencies, duly suited to the individual case, are true signs that the art of healing has been elaborated by the aid of absolutely harmless, congenial treatments, under whose ministration the death rate is but five per cent of persons treated as compared with fifty per cent under the present allopathic methods.

The Germanic Influence The philosophical origins of naturopathy were clearly Germanic. The most significant influences, except those of Russell Trall and the Osteopathic concepts of A.T. Still (at this time strictly the correction of spinal lesions by adjustment), and the chiropractic principles of D.D. Palmer, were all Germanic. (This is well documented in the January 1902 editorial of Water Cure Monthly.) The specific influences on which Lust drew for his work, in order of their chronological contributions to the system of naturopathy, are the following: 1. Vincent Preissnitz (1799-1851) 2. J o h m Schroth (1798-1856) 3. Father Sebastian Kneipp (1821-1897) 4. Amold Rickli (1823-1926) 5. Louis Kuhne (c. 1823-1907) 6. Henry Lahman (no dates known) 7. F.E. Bilz (1823-1903) 8. Adolph Just (?-1939).

Also of note were Theodor Hahn and T. Meltzer, who, in the 1860s, were well known for their work in the movement called, in German, Nuturutz or ”naturism.” In photographs accompanyinghis article “The principles, aim and program of the nature cure system,” Lust described each of these thinkers as follows: 1. VINCENT PREISSNITZ, of Graefenberg, Silesia. Founder of Hydropathy. Born October 4,1799. A pioneer Naturopath, prosecuted by the medical authorities of his day, and convicted of using witchcraft, because he cured his patients by the use of water, air, diet and exercise. He took his patients back to Nature-to the woods, the streams, the open fieldstreated them with Nature’s own forces and fed them on natural foods. His fame spread over the whole of Europe, and even to America. His cured patients were numbered by the thousands. The Preissnitz compress or bandage is in the medical literature. Preissnitz is no more, but his spirit lives in every true Naturopath. 2. J O H A ” SCHROTH, a layperson, not described in Lust’s directory but often talked of in later works and prominently mentioned for his curative theories in Bilz’s master work, The Natural Method of Healing. Schroth smashed his right knee in an accident with a horse and it remained stiff in spite of repeated medical treatment. At last, a priest told schroth that

Preissnitz’s methods might help, and Schroth decided to give them a try. In order to avoid frequent changing of the packs that were directed by Preissnitz, he placed several packs on top of one another, wrapping the whole portion with a woolen cloth. He left this pack on the injured knee for several hours and produced a moist heat which he theorized to cause the poisonous toxins to dissolve and be swept away. These packs are still used as part of the ”Schroth cure” and have reportedly become famous for their blood-cleansing effect. (From an article in the March 1937 Naturopath and Herald of Health by Dr.T.M. Schippel.) As noted by Bilz, the Schroth cure, called by Bilz “the regenerative treatment,” was developed for treatment of chronic diseases through the use of an extreme diet following total fasting by withdrawing of all food and drink and then the use of totally dry grain products and the eventual reintroduction of fluids. 3.FATHER SEBASTIAN KNEIPP, of course, is much described and the photos include one of Kneipp lecturing to the multitudes at Wandelhale at Woerishofen, attending Pope Leo XIII in 1893, noting this is the only consultation on health care matters that Kneipp ever consented to outside of Woerishofen, though many famous and aristocratic individuals desired his counsel, and a picture of Kneipp with the Archdukes Joseph and Francis Ferdinand of Austria walking barefoot in new-fallen snow for purposes of hardening the constitution. It was noted that the older Archduke was cured by Kneipp of Bright’s disease in 1892, and it noted that the Archduke Joseph, in appreciation of this cure, donated a public park in the town of Woerishofen at a cost of $150,000 florens. The Archduke Francis Ferdinand, the son of Archduke Joseph, was the individual whose murder precipitated World War I. There is a further picture of Kneipp surrounded by “Doctors” from different parts of the world while he gave consultation to numerous patients. 4.ARNOLD RICKLI, founder of the light and light and air cures (atmospheric cure). Dr. Rickli was one of the foremost exponents of natural living and healing. In 1848, he established at Veldes, Krain, Austria, the first institution of light and air cure or as it was called in Europe the ”atmospheric cure.” In a limited way (rather very late) his ideas have been adopted by the medical profession in America for the cure of consumption. He was an ardent disciple of the vegetarian diet and exemplified the principles of natural living in his own life. The enclosed photo shows him at the age of 97, when he was still active and healthy. He has since passed on, but his work still lives as a testimonial of his untiring efforts. He was the founder and for over 50 years the President of the National Austrian Vegetarian Association.

5. LOUIS KUHNE wrote, in 1891, The New Science of Healing, the greatest work of basic principles in natural healing. In the tradition of Natural Healing and prevention, Kuhne has been described as one who ”. . . advocated sun, steam baths, a vegetarian diet, and whole-wheat bread . . . in these relatively early days.” His renowned work constitutes the only true scientific philosophy for the application of all Drugless Methods. He was the first to give to the world the comprehensible idea of pathology and the first to proclaim the doctrine of the ”unity of cure.’’ His book Facial Expression gives the means of diagnosing a patient’s pathological condition and determining the amount and location of the systemic encumbrance. He is the founder and first Master of Naturopathy. 6. DR. H. LAHMAN. When the University of Leipzig expelled H. Lahman for his spreading medical sedition among the students, it added a staunch advocate to natural healing. Dr.Lahman finished his medical education in Switzerland and returned to Germany to refute in practice the false ideas of medical science. He later founded the largest Nature Cure institution in the world at Weisser Hirsch, near Dresden, Saxony.He was a strong believer in the “Light and Air” cure and constructed the first appliances for the administration of electric light treatment and baths. He was the author of several books on Diet, Nature Cure and Heliotherapy. As noted in Other Healers, Other Cures: “Heinrich Lahmann came along to stress no salt on foods and no water with meals . . . ”* His works on diet are authoritative and his “nutritive salts theory” forms the basis of rational dietetic treatment. This work has but recently come to light in America, and progressive dietitians are forsaking their old, worn-out, high protein, chemical and caloric theories for the “organic salts theory.” Carque, Lindlahr, McCann, and other wide awake food scientists have adopted it as a basis for their work. Dr. Lahman was a medical nihilist. He denounced medicine as unscientific and entirely experimental in its practice and lived to prove the saneness of his ideas as evidenced by his thousands of cured patients. 7. PROFESSOR F.E. BILZ. That real physicians are born, not made, is well illustrated in the case of Dr. Bilz, who achieved his first success in healing as a lay practitioner. As a mark of gratitude, a wealthy patient presented him with land and a castle in which to found a Nature Cure sanitarium. . . . The Bilz institution at Dresden-Rdebeul, Germany, became world renowned and was long considered the center of the Nature Cure movement. Professor Bilz is the author of the first Naturopathic encyclopedia, The Natural Method of Healing, which has been translated into a dozen

‘See Kruger.16

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing languages, and in German alone has run into 150 editions. He has written many works on Nature Cure and Natural Life, among them being The Future State, in which he predicted the present World War, and advocated a federation of nations as the only logical solution of international problems. 8. ADOLPH JUST, famous author of Return to Nature and founder of original ”Yungborn” in Germany. Both Adolph Just’s Return to Nature and Louis Kuhne’s The Natural Science ofHealing were translated into English by Lust and released through his publication house.

The Convergence with American Influences The Universal Naturopathic Directory was truly eclectic in its compilation and composition. Besides the Lust article noted previously, the volume included: ”How I became acquainted with nature cure” by Henry Lindlahr, MD, ND (which has been reproduced in large part in the introduction to volume 1 of Lindlahr13); “The nature cure” by Carl Strueh, MD, ND; ”Naturopathy” by Harry E. Brook, ND; “The present position of naturopathy and allied therapeutic measures in the British Isles” by J. Allen Pattreiouex, ND; “Why all drugless methods?” by Per Nelson; and “Efficiency in drugless healing” by Edward Earle Purinton (a reprint of the 1917 publication, referred to earlier, which was composed of a series of articles published in The Herald of Health and Naturopath between August 1914 and February 1916). The volume also contained Louis Kuhne’s ”Neonaturopathy (the new science of healing)” in the first publication of the translation by Lust, and articles on electrotherapy, neuropathy, dietology, chiropractic, mechanotherapy, osteopathy, phytotherapy, apyrtropher, physical culture, optometry, hydrotherapy, orthopedics, pathology, natural healing and living, astroscopy, phrenology, and physiology-all of which were specially commissioned for the directory from practitioners and authors considered expert in these subjects. The volume also included the directory of drugless physicians in alphabetical order, geographically arranged and itemized by profession; biographical notes on American contributors of note; the naturopathic book catalog; a guide to natural healing and natural life books and periodicals; a classified list of medical works; a series of book reviews; a buyer’s guide for naturopathic supplies; and, in addition to extensive indexes, a “parting word“ by Lust. In addition, the volume contained numerous advertisements for naturopathic schools, sanitariums, and individual practices, and it closed with the following note: This, then, completes Volume 1 of the Naturopathic Directory, Drugless Yearbook and Buyer’s Guide for the years 1918 and 1919.

Into it, has been placed the conscientious labor of many willing hearts, hands and minds. It is their contribution to the noble cause of natural healing. It will stand as a monument to their endeavors, as well as a memorial to the great souls, the fathers of natural healing, who have passed on. Let this, then, herald a new era-the era wherein man shall recognize the omniscience of Nature, and shall profit through conforming to her laws.

In the biographical section, it becomes apparent that Lust owed a great deal of the feeling of camaraderie in the nature cure movement to some varied American practitioners. The most prominent of these have had their biographical sections as contained in the 1918 directory. Two of them deserve specific note and attention: Palmer and Still. Lust met A.T. Still in 1915 in Kirksville, MO, shortly before Still‘s death. From their meetings, Lust noted later in the Naturopath and Herald of Health (June 1937) that Still believed that osteopathy by “compromising with medicine . . . is doomed as the school that could have incorporated all the natural and biological healing arts . . .” Lust wanted naturopathy to fill this void. Lust also had lengthy acquaintance with B.J. Palmer (the son of D.D. Palmer, the founder of chiropractic), who, following in his father’s footsteps, put Davenport, IA, and the Palmer Chiropractic College on the map. Lust also became connected with Henry Lindlahr, MD, ND, of Chicago (as noted in the autobiographical sketch contained in the directory14and reprinted in volume 1 of Lindlahr13). Lindlahr was a rising businessman in Chicago with all the bad habits of the “gay nineties” era. In his 30s he became chronically ill. He had gone to the orthodox practitioners of his day and received no relief. Then he was exposed to Schroth’s works, and in following them began to feel somewhat better. Subsequently, he liquidated all his assets and went to a German sanitarium to be cured and to learn nature cure. He returned to Chicago and enrolled in the Homeopathic/Eclectic College of Illinois. In 1903 he opened a sanitarium, which included a residential sanitarium, located in Elmhurst, IL, a “transient” clinic (office)on State Street in Chicago, and ”Lindlahr’s Health Food Store.” Shortly thereafter he founded the Lindlahr College of Natural Therapeutics, which included hospital internships at the sanitarium. The institution became one of the leading naturopathic colleges of the day. In 1908 he began to publish Nature Cure Magazine and began publishing his series of Philosophy of Natural Therapeutics, with volume 1 (“Philosophy”) in 1918. This was followed by volume 2 (“Practice”) in 1919, volume 3 (“Dietetics”; republished with revisions as it had originally been published in 1914), and, in 1923, volume 6 (“Iridiagnosis”).The intended volumes 4 and 5 were in

Philosophy of Natural Medicine

production at the time of Lindlahr’s death in 1927. As described in Other Healers, Other Cures: Henry Lindlahr, another American, is remembered for his conviction that disease did not represent an invasion of molecules, but the body’s way of healing something. In other words, he viewed symptoms as a positive physiological response-proof that the body is fighting whatever’s wrong. Accordingly, a fever is a ”healthy” sign and one should be let alone, unless it is dangerously high, of course.

The impact of all these gentlemen on the development of naturopathy in America, under Lust‘s guidance, was profound. From these beginnings, the naturopathic movement gathered strength and continued to grow through the 1920s and 1930s, having a major impact on natural healing and natural lifestyle in the United States. Along the way, Lust was greatly influenced by the writings of John H. Tilden, MD (largely published between 1915 and 1925). Tiden was originally a practicing physician in Denver who became disenchanted with orthodox medicine and began to rely heavily on dietetics and nutrition, formulating his theories of ”auto-intoxication” (the effect of fecal matter remaining too long in the digestive process) and ”toxemia.” Lust was also greatly influenced by Elmer Lee, MD, who became a practicing naturopath in about 1910 and whose movement was called the “hygienic system,” following the earlier works of Russell Trall. Lee published Health Culture for many years. In addition to John Tiden, MD, and Elmer Lee, MD, another medical doctor, John Harvey Kellogg, MD, who turned to more nutritionally based natural healing concepts, was greatly respected by Lust. Kellogg was renowned through his connection with the Battle Creek Sanitarium. The sanitarium itself was originally founded in the 1860s as a Seventh Day Adventist institution designed to perpetuate the Grahamite philosophies of Sylvester Graham and William Alcott. The sanitarium was on the verge of being closed, however, due to economic failure, when in 1876 Kellogg, a new and more dynamic physician-in-chief, was appointed. Kellogg, born in 1852, was a ”sickly child” who, at the age of 14, ran across the works of Graham and converted to vegetarianism. At the age of 20 he studied for a term at Trall’s Hygio-Therapeutic College and then earned a medical degree at New York’s Bellevue Medical School. He maintained an affiliation with the regular schools of medicine during his lifetime, due more to his practice of surgery than his beliefs in the area of health care.3 Kellogg designated his concepts, which were basically the hygienic system of healthful living, ”biologic living.” Principally, Kellogg defended vegetarianism, attacked sexual misconduct and the evils of alcohol, and was a prolific writer through the late nineteenth century

and early twentieth century. He produced a popular periodical, Good Health, which continued in existence until 1955. When Kellogg died in 1943 at the age of 91, he had had more than 300,000 patients through the Battle Creek Sanitarium (which he had had renamed from Western Health Reform Institute shortly after his appointment in 1876), including many celebrities, and the “Sad’ became nationally well known. Kellogg, along with Tilden and Elie Metchnikoff (director of the prestigious Pasteur Institute and winner of the 1908 Nobel Prize for a contribution to immunology), wrote prolifically on the theory of “auto-intoxication.” Kellogg, in particular, felt that humans, in the process of digesting meat, produced various intestinal self-poisons that contributed to “auto-intoxication.” As a result, Kellogg became a near fanatic on the subject of helping humans return to a more healthy, natural state by returning to the naturally designed usage of the colon. He felt that the average modem colon was devitalized by the combination of sedentary living, the custom of sitting rather than squatting to defecate, and the modem civilized habit of ignoring ”nature’s call” out of an undue concern for politeness. Further, Kellogg concentrated on the fact that the modem diet had insufficient bulk and roughage to stimulate the bowels to proper action. Kellogg was also extremely interested in hydrotherapy. In the 1890s, he established a laboratory at the San to study the clinical applications of hydrotherapy. This led, in 1902, to his writing Rational Hydrotherapy. The preface espoused a philosophy of dmgless healing that came to be one of the bases of the hydrotherapy school of medical thought in America. Tiden, as mentioned, was of a similar mind. Indeed, he must have been to have provided natural health care literature with his 200-plus page dissertation entitled “constipation,” with a whole chapter devoted to the evils of not responding when nature called. This belief in the “evils“ drawing away from the natural condition of the colon was extremely important to Kellogg’s work? Because of Lust’s interest, Kellogg’s The Nau Dietetics (1921) became one of the bibles of naturopathic literature.15 Lust was also influenced by the works of Sidney Weltrner, the father of “suggestive therapeutics.” The theory behind Professor Weltmer’s work was that whether it was the mind or the body that first lost its grip on health, the two were inseparably related. When the problem originated in the body, the mind nonetheless lost its ability and desire to overcome the disease because the patient “felt sick” and consequently slid further into the diseased state. Alternatively, if the mind first lost its ability and desire to ”be healthy” and some physical infirmity followed, the patient was susceptible to being overcome by disease.

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing

Weltmer’s work dealt specifically with the psychologic process of desiring to be healthy. Lust enthusiastically backed Weltmer’s work and had him appear on the programs at various annual conventions of the American Naturopathic Association (which commenced after its founding in 1919). Lust was also personal friends with and a deep admirer of Bernarr MacFadden. MacFadden was the founder of the ”physical culture” school of health and healing, also known as ”physcultopathy.” This school of healing gave birth across the country to gymnasiums at which exercise programs, designed to allow the individual man or woman to maintain the most perfect state of health and human condition possible, were developed and taught? Other Healers, Other Cures described it as followd6: The next Naturopathic star, after Kellogg, was Bernarr MacFadden, the physical culturist who built a magazine-publishing empire (hisfirst magazine was Physical Culture founded in 1898).MacFadden proselytizesfor exerciseand fresh vegetables, hardly eccentric notions. But his flamboyant efforts to publicize them and his occasionalcrack-pot ideas (likefreezing the unemployed, then thawing them out when the Depression was over) alienated many people. Still, he was his own best advertisement. He fathered nine children by four wives and was parachuting from planes in his 80s. One of MacFadden‘s admirers was that arch-foe of the medical profession, George Bernard Shaw, the longevous eccentric in his own right. . . Lust was also interested in, and helped to publicize, “zone therapy,” originated by Joe Shelby Riley DC,a chiropractor based in Washington, D.C., and one of the early practitioners of “broad chiropractic.” Zone therapy was an early forerunner of acupressure as it related ”. . . pressures and manipulations of the fingers and tongue, and percussion on the spinal column, according to the relation of the fingers to certain zones of the body. . . .”I4 Several other American drugless healers contributed to a broad range of “-opathies” that Lust merged into his growing view of naturopathy as the eclectic compilation of methods of natural healing. The Universal Directory also contained a complete list of osteopaths and chiropractors as drugless healers within the realm of Lust’s view of naturopathic theory. His other sigruficant compatriots at the time of the publication of the directory were Carl Stueh, described by Lust as “one of the first medical men in this country who gave up medicine and operation for natural healing”; F.W. Cohgs, MD, DO, DC, an early graduate of the American school of Naturopathy (1907) who went on to graduate from the New Jersey College of Osteopathy (1909) and the Palmer School of Chiropractic (1912); another “broad chiropractor,” Anthony Matijaca, MD, ND, DO, the naturopathic resident expert in electrotherapy and an associate editor of the Herald and Health Naturopath (the inverted name of the Lust journal at the time of the directory); and Carl Schultz, ND, DO, MD, president and general manager of the

Naturopathic Institute and Sanatorium of California, essentially the second school in the country to pursue the education of physicians under the name of ”naturopathy.”

EARLY TWENTIETH-CENTURY MEDICINE The Metamorphosis of Orthodox Medicine In many ways, naturopathy’s formative years, as well as its halcyon days, were from 1900-1917.In many jurisdictions, modern licensing laws, crafted during this time, were not yet in effect, so varied views of health care could be openly practiced. By 1920, however, the American world of medicine had undergone a sharp transition, culminating 4 decades of change. A look at the structure of early medical care in the United States, even as practiced and dominated by the orthodox school, is instructive, when one notes the changes occurring between 1875 and 1920. In 1875 the following was generally true of American medical practice: The practice, even in urban areas, sent the doctor to the patient; the “house call” was the norm. There was little modem licensing regulation. Hospitals were charitable institutions where persons too poor to otherwise receive health care were usually sent when ill. The AMA, although formed in 1846, and generally representative of the professional goals of the regular or orthodox school of medicine, had scarcely begun to make any political inroads at all. Medical schools required little or no college education for entrance and were largely apprenticeship based and proprietary in nature, having changed little throughout the century. *Although some doctors had begun to specialize, to do so was far from the norm. The major recognized specialties were surgery, obstetrics, and gynecology. Many different types of doctors existed, and society’s recognition of the profession neither recognized specific expertise nor necessarily rewarded professionals in medical practice well. Although the orthodox school made up roughly 80% of the professional medical practitioners, the homeopaths and the eclectics were visible and respected in their own communities for their abilities and expertise, and much of the public relied on other “irregular” practitioners. By comparison, in 1920, total metamorphosis of medicine as a profession had occurred:

By 1920, practices had become office oriented and clinic oriented. Modern licensing principles had become fully developed, and physicians and surgeons were licensed in

all jurisdictions. Most other health care providers had some licensing restrictions placed on them if they were recognized at all. 0 Due largely to the introduction into surgery of the practice of antiseptic techniques and aseptic procedures, and a correspondent decline in operative mortality, institutional care in the hospital became increasingly accepted. Also, clinical pathology and diagnostic laboratory procedures had become well developed, and the hospital had become a major training and clinical research facility that was generally more acceptable to the patient. The AMA was approaching the peak of its political power, having exercised, through its Council on Medical Education and its Council of Pharmacy and Chemistry, major effects on medical schools and the pharmaceutic industry. The transition to research- and education-based medical schools, instead of practitioner apprenticeships and proprietary education, had become complete. AU recognized medical schools had a Pyear curriculum, with an undergraduated e w or substantial undergraduate study required as a prerequisite. In addition, most schools, in conjunction with most licensing statutes, required a year’s internship. Specialization was becoming well developed, and the number of specialty groups had increased considerably. This would continue through the 1930s and into the early 1940s. Professional authority and autonomy had undergone a substantial transition; and the allopathic physician was now recognized as the medical expert. By 1922, the last eclectic school was on the verge of closure, and in the early 1930s the last of the homeopathic schools in the United States was also on the verge of closure. The influence of these sects on orthodox medicine had dwindled to almost nothing. Natwopaths and other alternative health care practitioners had adopted the areas of expertise previously considered the temtory of homeopaths and eclectics.

The Halcyon Years of Naturopathy In 1924 Morris Fishbein succeeded George Simmons as editor of the journal of the American Medical Association (JAMA).Fishbein had joined the editorial staff of j A M A under Simmons immediately following his graduation from Chicago’s Rush Medical School in 1913. Campion pointed out the following7: Over the years Fishbein not only established himself as the &ted editor of the most widely read medical journal in the United States; he also learned how to extend his editorial position, how to project his opinions nationwide. He became, as the saying went in those years, a “personality.“ TIME referred to him as “the nation’s most ubiquitous, the most widely maligned, and perhaps most influential medico.”

In addition to his development of JAMA as an editorial and personal voice, Fishbein also continually railed against ”quackery.” Lust, among others, including MacFadden, became Fishbein’s epitome of quackery. When MacFadden became a wealthy man, after his publishing company included popular magazines like True Confessions and True Detective, he began campaigning for the 1936 Republican presidential nomination. In response, a physician submitted, under the initials“K.G.,” a tonguein-cheek listing of the cabinet that would exist under MacFadden, including the newly created ”Secretary of Aviation” for Lust. Lust was a popular figure by thistime who conducted such a busy lecture scheduleand practice, alternating between the “Yungborns” in Butler, NJ, and Tangerine, FL, that he had become almost as well known as an airline traveler. Lust devoted a complete editorial in Nature’s Path to a response. While Fishbein had j A M A as a personal editorial outlet, Lust had his own publications. Commencing with the Naturopath and Herald of Health in 1902 (which changed its name to Herald of Health and Naturopath in 1918), Lust continually published this and other monthly journals. In 1919 it became the official journal of the American Naturopathic Association, mailed to all members. Each edition contained the editorial column ”Dr.Lust Speaking.” In the early 1920s the “health fad” movement was reaching its peak in terms of public awareness and interest. As described, somewhat wistfully, in his June 1937 column, Lust announced the approach of the 41st Congress of Natural Healing under his guidance: The progress of our movement could be observed in our wonderful congresses, in 1914 Butler, N.J., 1915 Atlantic City, 1916 in Chicago, 1917 Cleveland, 1918 New York, 1919 Philadelphia, 1920 and 1921 again New York, and 1922 in Washington, D.C., where we had the full support and backing of the Congress of the United States. President Harding received the president and the delegates of our convention and we were the guests of the City of Washington. Through the strenuous efforts of Dr. T.M. Schippel, Hon. Congresswoman Catherine Langley of Kentucky, and eight years of hard work financed and sustained by Dr. Schippel and her powerful friends in Congress, Naturopathy was fully legalized as a healing art in the District of Columbia and the definition was placed on record and the law affirmed and amended by another act which has been fully published over and over again in the official journal of the A.N.A., Nuturoputh. In 1923 in Chicago, with the help and financing of the great and never-to-be forgotten Dr.Henry Lindlahr, we had a great convention. Not only were all the Naturopaths there but even to an extent our congress was recognized and acknowledged as official and of great importance by the medical people, particularly by the Health Commissioner of Chicago. We held a banquet, and there were discussions covering all platforms of the healing art. It was the first congress in the United States where medicine and Naturopathy in all its branches such as

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing

the general old-time Nature Cure, Hydrotherapy and Diet, Osteopathy, Naprapathy, Chiropractic, Neuropathy and Physiotherapy were represented on the same platform. The speakers represented every modem school of healing and the movement at that time was in the direction of an entirely recognized and independent school of healing. There were two camps, official medicine and official Naturopathy, the medical camp having all that is good and bad in medicine and surgery and all the other schools of healing that had sold their birthright and trusted to the allurement of organized medicine, such as Homeopaths, Eclectics, Physio-medics, and the Osteopaths to a large extent. The Osteopaths were always in the wrong camp when they went on mixed boards and Dr.Andrew Taylor Still, the father of Osteopathy, told me in 1915 that by compromising with medicine Osteopathy is doomed as the school that could have incorporated all of the natural and biological healing arts. The year following we had the great congress in Los Angeles which has never been duplicated. We had to meet in two hotels because the crowds ran over 10,000. The glorious banquet will never be forgotten and the congress celebrated and demonstrated that the initial and first intent of the A.N.A. to teach the public Natural Living and Nature Cure was realized. We will never forget the glorious week in Los Angeles where the authoritiesand the whole city joined us. The success of that congress was largely due to the talent of Dr. Fred Hirsch, the successor to Prof. Arnold Ehret and the noble and generous Naturopaths of the A.N.A. of Cal. There was never a second congress like that. Then we had the great congresses of New York in 1925, Indianapolis 1926, Philadelphia 1927, Minneapolis 1928, Portland, Oregon 1929, New York 1930, Milwaukee 1931, Washington, D.C., 1932, Chicago 1933, Denver 1934, San Diego 1935, and Omaha 1936.

In 1925 Lust began to try to reach more of the general populace through the lay publication Nature’s Path. The Naturopath and Nature‘s Path were later merged because the self-supportingadvertising and subscription monies were more available by publication to the general populace than to the members of the association (The Naturopath, 1902-1927; Nature’s Path, 1925-1927; merged 1927-1933; separated 1934-1938; Nature‘s Path, 1939-?). In January 1934 Lust commenced republication under the title Naturopath and Heruld of Health in addition to Nature’s Path. Each volume opened with his column, which was different for each publication. Both publications were issued continuing through 1938, when the Nature‘s Path again became the sole publication until Lust‘s death in 1945. After the Universal Directory, Lust continued to write volumes on naturopathic principles, although he was more of a synthesizer, organizer, lecturer, and essayist than a lasting scientific author of naturopathic articles. His most enduring contributions remain his early translations of Kuhne’s and Just’s works. During the 1920s and up until 1937, Lust’s brand of “quackery“ as labeled by Fishbein, was in its most

popular phase. Although the institutional markings of the orthodox school had gained ascendancy, before 1937 it had no real solutions to the problems of human disease. Instructive in this regard is Louis Thomas’s interesting work The Youngest Science. Thomas compares his education and internship as a physician to his father’s life as a physician. His father believed that bedside manner was more important than any actual medication offered by the physician. Indeed, his father went into general surgery so that he could offer some service to his patients that actually made some change in their condition. Thomas points out that the major growth of “scientific medicine” until 1937 advanced diagnosis rather than offering any hope of cure. During this time, Lust’s naturopathic medicine, as well as both chiropractic and osteopathic medicine, continued to be on the outside looking in. Practitioners of all three groups were continually prosecuted for practicing medicine without a license, although they often won their cases by establishing before juries that their practices were, even according to the testimony of medical men, not the same at all. Additionally, because the orthodox practitioners could offer little or no actual hope of cure for many diseases, the “health food and natural health” movement was generally popular. During the 1920s, Gaylord Hauser, later to become the health food guru of the Hollywood set, came to Lust as a seriously ill young man. Lust, through application of the nature cure, removed Hauser’s afflictions and was rewarded by Hauser’s lifelong devotion. His regular columns in Nature’s Path became widely read among the Hollywood set. As noted in Other Healers, Other Cures? The last big name in Naturopathy was Gaylord Hauser, a Viennese-Born food scientist (as one of his early books identified him) turned to Naturopathy in his later years. He is best remembered for advising the eating of living foods, not dead foods, and for escorting Greta Garbo around. In addition to fresh fruits and vegetables, Hauser’s ”Wonder Foods” were skinned milk, brewers yeast, wheat germ, yogurt, and black strap molasses. In 1937, however, all thisbegan to change. The change came, as both Thomas and Campion note in their works, with the era of “miracle medicine.” Lust recognized this and his editorializing became, if anythmg, even more strident. From the introduction of sulfa drugs in 1937 to the Salk vaccine‘s release in 1955, the American public became used to annual developments of miracle vaccines and antibiotics. Lust died in September 1945 at the Yungbom facility in Butler, NJ, preparing to attend the 49th Annual Congress of his American Naturopathic Association. In August 1945, for the official program of that congress

held in October 1945 just after his death, he dictated the following remarks What is the present condition of Naturopathy? What is its future? I can give my opinion in a very few words. For fifty years I have been in the thick of the fight to bring to the American people the Nature Cure. During that period I have had an opportunity to judge what Naturopathy has done, and can accomplish and the type of men and women, past and present, who make up the Naturopathic ranks. Let us take the present situation first. What is Naturopathy accomplishing? The answer to that is: “Everything.” Naturopathy holds the key for the prevention, alleviation and cure of every ailment, to man and beast alike. It has never failed in the hands of a competent Naturopath. Whatever the body can “catch”-that same body, with proper handling, can eliminate. And that takes in cancer, tumors, arthritis, cataract and the whole gamut of “incurable medical” disease and ailments. During my years of practice I, personally, have seen every type of human ailment and so-called serious ”disease” give way to the simple, proven Naturopathic methods. I make no exception to that statement. Now let us see the type of men and women who are the Naturopaths of today. Many of them are fine, upstanding individuals, believing fully in the effectiveness of their chosen profession-willing to give their all for the sake of alleviating human suffering and ready to fight for their rights to the last ditch. More power to them! But there are others who claim to be Naturopaths who are woeful misfits. Yes, and there are outright fakers and cheats masking as Naturopaths. That is the fate of any scienceany profession-which the unjust laws have placed beyond the pale. Where there is no official recognition and regulation, you will find the plotters, the thieves, the charlatans operating on the same basis as the conscientious practitioners. And these riff-raff opportunists bring the whole art into disrepute. Frankly such conditions cannot be remedied until suitable safeguards are erected by law, or by the profession itself, around the practice of Naturopathy. That will come in time. Now let us look at the future. What do we see? The gradual recognition of this true healing art-not only because of the efforts of the present conscientious practitioners but because of the bungling, asinine mistakes of orthodox m e d i c i n e Naturopathy’s greatest enemy. The fiasco of the sulpha drugs as emphasized disastrously in our armed forces is just one straw in the wind. The murderous Schick test-that deadly “prevention” of diphtheria-is another. All these medical crimes are steadily piling up. They are slowly, but inevitably, creating a public distrust in all things medical. This increasing lack of confidence in the infallibility of Modem Medicine will eventually make itself felt to such an extent that the man on the street will turn upon these self-constituted oppressors and not only demand but force a change. I may not be here to witness this revolution but I believe with all my soul that it is coming. Yes, the future of Naturopathy is indeed bright. It merely requires that each and every true Naturopath carry o n - c a n y on-to the best of his and her abilities. May God bless you all.

The naturopathic journals of the 1920s and 1930s are instructive. Much of the dietary advice focused on poor

eating habits, including the lack of fiber in the diet and an overrelianceupon red meat as a protein source. More than half a century later in the 1980s, the pronouncements of the orthodox profession, the National Institute of Health and the National Cancer Institute finally became aware of the validity of the early assertions of the naturopaths that such dietary habits would lead to degenerative diseases, including cancers associated with the digestive tract and the colon. The December 1928 volume of Nature’s Path was the first American publication of the works of Herman J. DeWolff,a Dutch epidemiologistwho was one of the first individuals to assert, based on studies of the incidence of cancer in the Netherlands, that there was a correlation between exposure to petrochemicals and various types of cancerous conditions. He saw a connection between chemical fertilizers and their usage in some soils (principally clay) that led to their remaining in vegetables after they had arrived at the market and were purchased for consumption. Again, it was 50 years later before orthodox medicine began to see the wisdom of such assertions.

The Emerging Dominance of American Medical Association Medicine The introduction of ”miracle medicine,” the impact of World War I1 on health care, and the death of Lust in 1945 all combined to cause the decline of naturopathic medicine and natural healing in the United States. (During the war, the necessity for crisis surgical intervention techniques for battlefront wounds encouraged use of morphine and sulfa drugs and penicillin for diseases not previously encountered by American citizens. This resulted in rapid development of high-technology approaches to medicine and highly visible successes.) The effects of these events on osteopathy and chiropractic, however, were completely different. In the early days of osteopathy, there was a sigruficant split between the strict drugless systems advocated by A.T. Still and the beliefs of many MDs who converted to osteopathy because of its therapeutic value. The latter group did not want to abandon all of the techniques they had previously learned and all of the drugs they had previously used when those therapy techniques were sometimes effective. Ultimately, most schools of Osteopathy, commencing with the school based in Los Angeles, converted to more of an imitation of modern orthodox medicine. These developments led to more of an accommodation between the California osteopaths and the members of the California Medical Association. (This developing cooperation between the California Osteopathic and Medical Association was one of the major issues leading to the downfall, in 1949, of Fishbein’s editorial voice in ]M.) Thus osteopathy found a place in professional medicine, at the cost of its drugless healing roots and therapies?

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing

The effect on chiropractic of the postwar years was somewhat different. Because of educational recognition under the G.I. Bill, the number of chiropractors in the country grew substantially, and their impact on the populace grew accordingly. The sect eventually grew powerful enough in terms of numbers and economic clout that it could pose a legal challenge to the orthodox monopoly of the AMA. However, in the immediate postwar years, the AMA gained tremendous political clout. Combined with the American Legion and the National Board of Realtors,” these three groups posed a powerful political triumvirate before the U.S.Congress. These years, called the years of the ”great fear” in Caute’s book by that name,18 were the years during which to be unorthodox was to be “un-American.” Across the country, courts began to take the view that naturopaths were not truly doctors, as they espoused doctrines from ”the dark ages of medicine” (something American medicine had apparently come out of in 1937) and that drugless healers were intended by law to operate without “drugs” (which became defined as anythmga person would ingest or apply externally for any remedial medical purpose). In this regard, the Washington State Supreme Court case of Kelly v. CuwoZl* and the Arizona State Supreme Court case of Kuts-Chuux v. Wilson document how sigruficant limitations were placed on naturopaths under the guise of calling them ”druglesshealers.” In the state of Tennessee, as a reaction to the 1939 publication of the book Buck to Eden by herbalist Jethro Kloss, court action initiated by the Tennessee State Medical Association led first to the publishers being forbidden to advertise the book for any therapeutic purpose. They were allowed only to acknowledge that it was in stock. The Tennessee State Legislature then declared that the practice of naturopathy in the state of Tennessee would be considered a gross misdemeanor, punishable by up to 1 year in jail. Although it was under considerable public pressure in those years, the American Naturopathic Association undertook some of its most scholarly work, coordinating all the systems of naturopathy under commission. This resulted in the publication of a basic textbook on naturopathy (BasicNuturuputky published in 1948 by the ANA19) and a sigruficant work compiling all the known theories of botanical medicine (as commissioned by the ANA’s successor after its 1950 name change to the American Naturopathic Physicians and Surgeons Association), the Nuturue Medicinu published in 19533O Naturopathic medicine began splintering when Lust‘s ANA was succeeded by six different organizations in the mid-1950s. T h e defendant was Otis G. Canoll of Spokane,WA. He and his brother, Robert V. Carroll, Sr., of Seaffle were longtime associates of Benedict Lust. As members of Lust‘s Ameikan NaturopathiiAssociation, they had advanced naturopathy‘s presence in Washington state through the Washington State Naturopathic Association.

The primary organizations among these were the successor to the ANA, which underwent a name change in 1950 to the American Naturopathic Physician and Surgeon’s Association, and subsequently changed to the American Association of Naturopa thic Physicians (AANP) in 1956, and the International Society of Naturopathic Physicians formed under the leadership of M.T. Campenella of Florida shortly after Lust’s death, with its American offshoot, the National Association of Naturopathic Physicians. By 1955, the AANF, as it ultimately became known, had recogruzed only two schools of naturopathic medicine, the Central States College of Physiatrics in Eaton, OH, under the leadership of H. Riley Spitler, and Western States College of Chiropractic and Naturopathy located outside Portland, OR, under the leadership of R.A. Budden. Budden was a kdlahr graduate and among the group that took over control of the Lindlahr College after Lindlahr’s death in the 1920s. He moved west after World War 11when the northwestern states, including Oregon, became the last bastion of naturopathic medicine in thiscountry.

THE MODERN REJUVENATION After the counterculture years of the late 1960s and America’s disenchantment with organized institutional medicine, which began after the miracle era faded and it became apparent that orthodox medicine had its limitations,alternativemedicine began to gain new respect. Naturopathic medicine underwent an era of rejuvenation. As succinctly described in Cassedy’s Medicine in America: A Short this phenomenon, which is not limited to naturopathic medicine, is consistent with the modern, and continuing, ”search for health beyond orthodox medicine”: It should not have been surprising to anyone that certain organized therapeutic sects continue to exist in mid-twentieth century America as successful and conspicuous alternatives to regular medicine. This is not to say that they offer the same threats to the medical establishment or play the same roles as their nineteenth-century counterparts had, as complete therapeutic systems. But they do continue to hold a strong collective appeal for individuals who mistrust or are somehow disenchanted with mainline medicine. They have appealed also to antiauthoritarian sentiments that flourish throughout society. Moreover, as earlier, they satisfy various needs that regular medicine continues to neglect or ignore.

The same author, in describing the post-World War II decades and the changing fortunes of such healing theories as naturopathic medicine, observed as follows: The period also brought about the renewal or updating of certain previously widely used therapies and considerable experimentationwith others, some of them exotic. To an extent this trend represented the rediscovery by trained physicians, nurses, and other regular health professionals of certain values

Philosophy of Natural Medicine and older styles of therapy. The participation of such professionals proved to be an essential ingredient in the rebirth of several such therapies. However, the major reason for the new successes was the widespread active interest and involvement of America’s literate lay people in the search for more personal or humane forms of treatment. As another author, John Duffy,has observed in From Humors to Medical Scienct?: Since health is too closely related to cultural, social, and economic factors to be left exclusively to doctors, American lay people have always engaged in do-it-yourself medicine, resorted to ”irregulars and quacks,” and supported health movements. As a result of the current fad for physical fitness, our streets are beset by sweat-suited individuals of all ages doggedly jogging their way to health and long life. In addition, stores selling “natural” foods are flourishing, physical fitness salons have become a major business, and anti-smoking and weight-loss clinics and workshops are attracting thousands of individuals bent on leading cleaner and leaner lives. And those for whom physical activity in itself is not enough are seeking physical and mental well-being through faith healing, yoga, and a host of major and minor gurus. When neither mental effort nor physical exercise can solve medical problems, the sceptics of modem medicine can always turn to the irregulars. A recent estimate places a number of Americans who have relied on an irregular practitioner at some time in their lives at 60 million, and, aided by the high cost of orthodox medicine, irregular medical practice appears tobeontherise.. .

At the beginning of this period of rejuvenation, the profession’s educational institutions had dwindled to one, the National College of Naturopathic Medicine (which had branches in Seattle, WA, and Portland, OR), which was created after the death of R.A. Budden and the conversion of Western States College to a straight school of chiropractic. Kruger’s book Other Healers, Other CuresI6described it a s follows in 1974: Today, Naturopaths in seventeen states are licensed to diagnose, treat, and prescribe for any human disease through the use of air, light, heat, herbs, nutrition, electrotherapy, physiotherapy, manipulations, and minor surgery. At present, one can eam an D.N. [a misnomer, actually-N.D.] degree at the National College of Naturopathic Medicine in Seattle and Emporia, Kansas, [where, by contract, the first two years of the four year medical education were then taught], or the new North American Naturopathic Institute in North Arlington, New Jersey [there is also a school in Montreal]. The four-year curriculum covers many standard medical courses-anatomy, bacteriology, urology, pathology, physiology, X-ray reading etc.-but also includes botanical medicine, hydrotherapy, electrotherapy, and manipulative technique. . .

The public, by the late 1970s, was particularly ripe for another rejuvenation of naturopathy’s brand of “alternative” health care. As described in Murphy’s

Enter the Physician: The Transformation of Domestic

Medicine, 1760-1860, when discussing this cyclical rejuvenation in the mid-twentieth century23: Contemporary crusaders still stress prevention as the layperson’s primary duty, but a growing chorus is calling for every person to assume the newly proactive role in his or her own health care. This is essential, say the analysts, because both lay people and doctors have placed far too much faith in the power of medicine and technology to work miracles. For a host of different reasons and from a variety of different perspectives, health advocates are calling on each person to “accept a certain measure of responsibility for his or her own recovery from disease or disability.” What would this entail? There are probably as many answers to this question as there are respondents, but it is striking to note how many of the solutions would have been familiar to our ancestors who lived between 1760 and 1860.One reaming idea, for instance, is that each person knows his or her own constitution history the best, and therefore has a duty to communicate that knowledge to medical personnel. Another is a refurbished concept of vis medicatrix naturae, the belief that many diseases are self-limiting and therefore do not require much medical intervention-and certainly not the amount or the sort to which contemporary Americans are accustomed. Most significantly, today’s analysts are calling on professionals and non professionals to build and nurture a health-care partnership very much like that envisioned by nineteenth-century health publicists: a partnership based on mutual respect, clear understanding and faithful execution. In that scenario, both as it originally evolved and in its updated version, it is the doctor who directs treatment, but crucial to a successful outcome are the informed and responsible actions of the patients, other care givers, and the patient’s family and friends.

In 1978 the John Bastyr College of Naturopathic Medicine was formed in Seattle by Joseph E. Pizzorno, Jr, ND (founding president), Lester E. Griffith, ND, and William Mitchell, ND (all graduates of the National College of Naturopathic Medicine), who felt that it was necessary to have more institutions devoted to naturopathic care and the teaching of naturopathic therapeutics. During the late 1970s, other naturopathic doctors also recognized this need and naturopathic colleges were established in Arizona (the Arizona College of Naturopathic Medicine), Oregon (the American College of Naturopathic Medicine), and California (the Pacific College of Naturopathic Medicine). Unfortunately, none of these three survived. However, the current status of naturopathic medicine, a s represented by Bastyr University a n d National College of Naturopathic Medicine, and now joined by the Southwest College of Naturopathic Medicine and Health Sciences in Arizona and a program in naturopathic medicine at the University of Bridgeport in Connecticut, is that of growth and presumably a solid future. There are currently favorable commentaries on the state of naturopathic medicine and its continuing efforts to reinvest various diverse theories of ”natural healing” with modem vigor.

The History of Naturopathic M By 1902, he had founded the American School of Naturopathy In Other Healers, Unorthodox Medicine in America (edited by Norman Gevitz, the author of The D . O . ’ S )a~ ~ ~in New York City. The practice quickly spread across the United States volume written to provide “a scholarly perspective on (California was the first State to pass a law regulating natural unorthodox movements and practices that have arisen medicine, in 1919). in the United States” (from the editor’s preface), part Numerous schools offeringa variety of training cropped up of this effort is described by Author Martin Kauffman and disappeared. The movement peaked in America around (from the Department of History at Westfield State 1950 and nearly died out by the early 1960’s. The legal climate College), a modern expert on homeopathy: for naturopathy turned cold in many States, in the face of the powerful modern medical establishment. While naturopathy In addition to the revival of classical homeopathy, a major medicine is now legal (in several states), many naturopaths development in recent times has been the teaching of homeoppracticing in other states are old-timers, practicing under athy at naturopathic colleges on the West coast. In Seattle, John their original ”drugless therapy” licenses, issued before laws Bastyr, a Naturopath and Homeopath who had been practicing prohibiting new naturopathic practices went into effect. Today, for fifty years, readied the move in 1956 to establish the there are only two schools in naturopathic medicine in the national college of Naturopathic Medicine, which was later United States: the National College in Portland, Oregon, and moved to Portland, Oregon. The College’s four-year curricuJohn Bastyr College in Seattle, Washington. The American lum includes a required third-year course in homeopathy, with Association of Naturopathic Physicians is beginning to organhomeopathic electives being available to third and fourth year ize and unify the profession, with its own definition and students. philosophy of modem naturopathic medicine. In 1978, three naturopathic practitioners in Seattle founded Alaska, Arizona, Connecticut, Oregon, Washington, and the John Bastyr College of Naturopathic Medicine. During the Hawaii recognize naturopathy as a primary medicine with sixth quarter all students at that school are required to take specific licensing laws, as do the Canadian provinces of British 44 hours of course work in homeopathy, after which they may Columbia, Manitoba, Ontario, and Saskatchewan. In other elect another 66 hours and up to 238 hours of clinical homeostates, efforts are under way to gain licensure for naturopaths pathic instruction. The significance of the naturopathic schools (this description was circa 1989). to the resurgence of homeopathy is demonstrated by the fact The movement continues to grow, and so, the impact that “about one third of the graduating class specialized in homeopathic practice, a total of about 50 each year in all” of natural healing has come full circle. In a n era where (citing The American Homeopath). the statistical number of persons born who are expected to contract cancer, now recognized as a degenerative disease, has increased rather than declined, and the And, as described in the Encyclopedia of Alternative incidence of other degenerative diseases (arthritis, arteHealth Care by O l ~ e n ~ ~ : riosclerosis, atherosclerosis, etc.) has increased in direct Today in Germany, the nature care movement in herbal relation to the lengthening of life expectancies produced remedies tradition has matured into a well-established health by improved sanitation and nutrition (although specare practice, with about 5,000 professionals throughout the ciously claimed by AMA medicine to be the result of country.. . . their therapies), the early teachings of Lust, Lindlahr, One Kneipp practitioner, Benedict Lust, emigrated to a n d others appear to have more validity than ever. America to begin teaching and practicing naturopathy here.

1. Starr I? Social transformation of American medicine. New York Basic Books, 1983107. 2.Griggs 8. Green pharmacy. London: Jill, Norman, & Hobhouse, 1981:180-183, 251. 3. Whorton J. Crusaders for fitness. Princeton, NJ: Princeton Press, 1982138-147. 4. Rothstein W. American physicians in the 19th century. Baltimore: Johns Hopkins Press, 1972. 5. Haller J. American medicine in transition, 1850-1910. Urbana, E University of Illinois Press. 1981:234-279. 6. Rosen G. The structure of American medical practice. Philadelphia: University of Pennsylvania, 1983. 7. Campion F. AMA & US health policy since 1940. Chicago: AMA Publishers, 1984. 8. Burrows J. Organized medicine in the progressive era. Baltimore: Johns Hopkins Press, 1977~31-51. 9.Coulter H. Divided legacy, vol II. Washington, DC: Wehawken Books, 1973:402-423.

10. Salmon JW. Alternative medicines. New York Tavistock, 1984: 80-113. 11. Gevitz N. The D.O.’s.Baltimore: JohnsHopkins Press, 1982. 12. Silberger J. Mary Baker Eddy. Boston: Little Brown, 1980. 13. Lindlahr H. Philosophy of natural therapeutics, vol. I. Maidstone, England: Maidstone Osteopathic, 1918 (vol 2-Practice: 1919; vol &Dietetics: 1914; Reprints: CW Daniel Co, Essex, England, 1975,1981,1983). 14. Lust B. Universal directory of naturopathy. Butler, NJ: Lust, 1918. 15.Kellogg JH. New dietetics. Battle Creek, MI: Modem Medical Publications, 1923. 16. Kruger H. Other healers, other cures. A guide to alternative medicine. New York Bobbs-Merrill, 1974182-183. 17. Goulden J. The best years. New York Athenium, 1976. 18. Caute D. The great fear. New York Simon & Schuster, 1978. 19. Spitler HR. Basic naturopathy. Des Moines: ANA, 1948. 20. Kuts-Cheraux AW. Naturae medicina. Des Moines: ANPSA, 1953.

Philosophy of Natural Medicine 21. Cassedy JH. Medicine in America: a short history. Baltimore: Johns Hopkins University Press,1991:147-148. 22. Duy. J. From humors to medical science: a history of American medicine, ed 2. Urbana, E University of Illinois Press, 1993350. 23. Murphy LR. Enter the physician: the transformation of domestic medicine, 1760-1860. University of Alabama Press,1991:226-227.

24. Gevitz N. Other healers: unorthodox medicine in America. Baltimore: Johns Hopkins University Press, 1988:116-117. 25. Olsen KG. The encyclopedia of alternative health care. New York Pocket Books, 1989:209-210.

General

Thomas L. The youngest science. Boston: Viking, 1983. Whorton J. Crusaders for fitness.Princeton, NJ: Princeton Press, 1982. Wirt A. Health & healing. New York Houghton W i n , 1983. Wohl S. Medical industrial complex. New York Harmony, 1983.

B m t t S, Herbert V. The vitamin pushers: how the health food industry is selling America a bill of goods. New York Prometheus Books, 1994. Barrett S, Jarvis W. The health robbers: a close look at quackery in America. New York Prometheus Books, 1993. Berlinger H. A system of medicine: philanthropic foundations in the Flexner era. New York Tavistock Publishers, 1985. Breiger G. Medical America in the 19th century. Baltimore: Johns Hopkins Press, 1972. Brown ER. Rockefeller medicine men. Berkeley, CA: University of California Press,1978. Burrows J. Organized medicine in the progressiveera. Baltimore: Johns Hopkins Press, 1977. Campion F. AMA & U.S. health policy since 1940. Chicago: AMA Publishers, 1984. Cassedy JH. Medicine in America: a short history. Baltimore: Johns Hopkins University Press, 1991. Coulter H. Divided legacy, vol3. Washington, DC:Wehawken Books, 1973. Coward R. The whole truth:the myth of alternative health. London: Faber & Faber, 1989. Duy. J. The healers. Urbana, E University of Illinois Press, 1976. Duyr J. From humors to medical science: a history of American medicine, ed 2. Urbana, I L University of Illinois Press, 1993. Gevitz N. The D.O.’s.Baltimore: JohnsHopkins University Press, 1982. Gevitz, N. Other healers: unorthodox medicine in America. Baltimore: Johns Hopkins University Press, 1988. Dr Goodenough’s Home Cures & Herbal Remedies. New York Crown, 1982. Green H. Fit for America: health, fitness, sport & American society. New York Pantheon Books, 1986. Griggs B. Green pharmacy. London: Jill, Norman & Hobhouse, 1981. Haller J. American medicine in transition, 1850-1910. Urbana, E University of Illinois Press, 1981. Inglis B, West R. Alternativehealth guide. New York Knopf, 1983. Kruger H. Other healers, other cures: a guide to alternative medicine. New York Bobbs-Merrill, 1974. Ludmerer K. Learning to heal. New York: Basic Books, 1985. Manger LN. A history of medicine. New York Marcel Dekker, 1992. McKeown T. The role of medicine: dream, mirage, or nemesis? London: Nuffield Provinaal Hospitals Trust, 1976. Murphy LR. Enter the physician: the transformation of domestic medicine, 1760-1860. Tuscaloosa, AL University of Alabama Press,1991. Rosen G. The structure of American medical practice: 1875-1941. Philadelphia: University of Pennsylvania, 1983. Rosenberg C. The care of strangers: the rise of America‘s hospital system. New York: Basic Books, 1987. Rothstein W. American physicians in the 19th century. Baltimore: Johns Hopkins Press, 1972. Salmon JW. Alternative medicines. New York Tavistock, 1984. Serrentino J. How natural remedies work. Vancouver, B C Hartley & Marks, 1991. Silberger J. Mary Baker Eddy. Boston: Little Brown, 1980. Starr P. Social transformation of American medicine. New York Basic Books, 1983.

A Naturopathic Bibliography Abbot JK. Essentials of medical electricity. Philadelphia:WB Saunders, 1915. Altman N. The chiropractic alternative: how the chiropractic health care system can help keep you well. Los Angeles: JP Tarcher, 1948. Barber ED. Osteopathy complete. Kansas City: Private, 1896. Baruch S. An epitome of hydro-therapy. Philadelphia: WB Saunders, 1920. Benjamin H. Everybody’s guide to nature cure, ed 7. London: Thorsons, 1981. Bennet HC. The electro-therapeuticguide. Lima, O H National College of Electro-therapeutics, 1912. Bilz FE. The natural method of healing, vols 1 and 2. (English trans.) New York Bilz, International News, 1898. Dejarnette MB. Technic & practice of bloodless surgery. Nebraska City, NE: Private, 1939. Downing CH. Principles & practice of osteopathy. Kansas City: Williams, 1923. Filden JH. Impaired health (its cause & cure), ed 2. Denver: Private, 1921. Finkel H. Health via nature. New York: Barness Printing & Society for Public Health Education, 1925. Foster AL. Foster’s system of non-medicinal therapy. Chicago: National Publishing Association, 1919. Fuller RC. Alternative medicine and American religious life. New York Oxford University Press, 1989. Goetz EW. Manual of osteopathy. Cincinnati: Nature’s Cure, 1909. Gottsschalk FB. Practical electro-therapeutics.Hammond, IN: Frank Betz, 1904. Olsen KG. The encyclopedia of alternative health care. New York Pocket Books, 1989. Graham RL. Hydro-hygiene. New York: Thompson-Barlow, 1923. Inglis B. Natural medicine. London: William Collins, 1979. JohnsonAC. Principles & practice of drugless therapeutics. Los Angeles: Chiropractic Education Extension Bureau, 1946. Just A. Retum to MW. Lust B, trans. Butler, NJ. Lust Publications, 1922. Kellogg JH. New dietetics. Battle Creek, M I Modern Medical Publications, 1923. Kellogg JF. Rational hydrotherapy. Battle Creek, MI: Modem Medical Publications, 1901,1902. King FX. Rudolf Steiner and holistic medicine. York Beach, MA: Nicolas-Hays, 1987. Kuhne L. Neo-naturopathy (new science of healing). Lust B, trans. Butler, NJ: Lust Publications, 1918. Kuts-Cheraux AW. Naturae medicina. Des Moines: M A , 1953. Lust B. Universal directory of naturopathy. Butler, NJ: Lust Publications, 1918. Lindlahr H. Philosophy of natural therapeutics, vol 1. Maidstone, England: Maidstone Osteopathic, 1918. (vol 2-Practice: 1919;vol3Dietetics: 1914;Reprints: CW Daniel, Essex, England, 1975,1981,1983)

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing MacFadden 8. Building of vital power. NJ: Physical Culture Publications, 1904. MacFadden 8.Power & beauty of superb womanhood. NJ: Physical Culture Publications, 1901. Murray CH. Practice of osteopathy. Elgin, E Private, 1909. Murray MT, Pizzorno JE. Encyclopedia of natural medicine. Rocklin, CA: Prima, 1998. Pizzomo JE.Total wellness. Rocklin, CA. Prima, 1996.

Richter JT. Nature-the healer. Los Angeles: Private, 1949. Spitler HR.Basic naturopathy. Lks Moines: ANA, 1948. Trall RT.Hydropathic encyclopedia (vols 1-3).New York SR Wells, 1880. Turner RN. Naturopathic medicine: treating the whole person. London: Thorsons, 1984. Weltmer E. Practice of suggestive therapeutics. Nevada, M O Weltmer Institute, 1913.

The History of Naturopathic Medicine, Part 11: Decline and Rejuvenation-Politics and Professionalization George Wm. Cody, JD Heidi B. Hascall, MA CHAPTER CONTENTS The Emergence 67 Naturopathy’s Period of Emergence-Education and Professional Presence 69

Developments Outside the United States 75 Canada 75 Elsewhere 75 Other Relevant Scholarship 75

The Long Decline 71 Conclusion 76 The Period of Rejuvenation 73 The Twenty-First Century Awaits

74

Since the earlier chapter, “The History of Naturopathic Medicine,” first appeared in 1985, naturopathic medicine has continued its rejuvenation, accompanied by a growing scholarly interest. This philosophy of health and healing was reported in the mid- to late-1970s to have reached extinction. Renewed interest has been inspired by, and within, diverse academic disciplines: medical history (Professor James Whorton, University of Washington), medical sociology (Walter I. Wardwell, University of Connecticut), and medical anthropology (Professor Hans A. Baer, University of Arkansas, Little Rock). Baer provided a useful analysis of the changing state of naturopathic medicine in a trilogy of writings on the subject.” He described naturopathy as passing through “three stages of development: (1)its emergence around the turn of the twentieth century; (2) its period of decline beginning in the late 1930s; and (3) its recent potential rej~venation.”~ Each stage of development can be examined in turn; new scholarship and historical information covering each stage has become available.

THE EMERGENCE Naturopathic medicine has evolved from a health philosophy first publicly labeled naturopathy in 1902 by German-born Benedict Lust.* Naturopathy as described

and advanced by Lust was an eclectic collection of “natural” treatment philosophies and modalities (see previous chapter) that from the 1920s to the 1950s rose and fell with chiropractic.32,48In The Great American Water-Cure Craze: A History of Hydropathy in the United States (1967),Weiss and Kemble described the life’s work of Benedict Lust in ”Chapter IX-The Father Kneipp Treatment.” At the time of Weiss and Kemble’s writing, little attention had been paid to Lust’s work in the 20 years since his death, which was described by the authors: Lust was the author of many books and magazine articles.

In his battle against the drug trust, he was arrested sixteen times. He died in Butler, New Jersey,September 5,1945.

Since the reemergence and rejuvenation of naturopathy as naturopathic medicine in the 1970s (discussed later),

‘See Chapter 4. In Nature Doctors (Pioneersin Natura/ Medicine), Kirchfeld and BoyleZ7noted “A conflicting and probably inaccurate vemion of the term’s evolution given by George Cody states that it was coined in 1895 by Dr. Scheel and purchased by Lust in 1902.”This was taken directly from the lead editorial of the first edition of Lust‘s Naturopatb and Herald of HeaM (January 1902). Lust’s great-niece, Anita Lust Boyd, privately published Lust‘s memoirs in 1997 as Yungborn: The Life and Times of Dr. Benedict Lust, Founder and Father of Nitturnpathy. The same explanation for the coining of the term ‘naturopathy” appears in the memoirs on pp. 77-78.

67

Whorton51conducted the first scholarly examination of the work and writings of Lust in Nature Cures: The History of Alternative Medicine in America. The first outside examinations of naturopathy were hostile ones, labeling it a "healing cult" tied to chiropractiS2and a type of "medical Discussion of Lust and naturopathy from the 1920s through the 1970s had been placed against the backdrop of these related, negative assessments in Louis Reed's32 work The Healing Cults (published under the often-praised and presumably objective sponsorship of the Committee on the Costs of Medical Care [CCMC]) and Morris Fishbein's unabashedly "quackery"-oriented writings.* New scholarship by Professor Jonathan Engel (Seton Hall University) has shown the clear imprint of the American Medical Association (AMA)-in the person of its theninfluential Journal of the American Medical Association Editor Fishbein-n this aspect of the work of the CCMC, which calls into question Reed's objectivity in assessing naturopathy and chir~practic.'~~ Whorton, instead of relying on these 1930s sources, undertakes a fresh examination of the actual writings and life's work of Lust in Nature Cures. His interest in naturopathy goes back to the mid-1980s. In Drugless Healing in the 1920s: the Therapeutic Cult of Sanipractic, W h o r t ~ described n~~ the history of a philosophy of drugless healing that Reed32had described as distinguished from naturopathy in name only. He also described the history of Washington's Drugless Healing Act of 1919 with all of its own peculiarities.$ This piece of history is more than just tangentially related to the ultimate rejuvenation of naturopathy as naturopathic medicine.As Whorton additionallydescribes, well-intentioned drugless healers in Washington state, among them John Bastyr, doctor of chiropractic (DC), 'As an example see Gardner and Martin's In the Name of Science, Chapter 16 "Medical Cults," (GP Putnam. 1952), later appearing as fads and Fallacies (in the Name of Science), (Dover Publications, 1957). +Engel, as part of his research, examined Fishbein's papers archived at the University of Chicago: 'In 1931, Louis Reed, a staff researcher for the CCMC, wrote to Fishbein to ask him to chedc the manuscript the committee was preparing on sectarian healers. 'If it is possible,' wrote Reed, 'I should like very much to have you read the section of this devoted to healing cults. so that I may have the benefit of your criticisms and suggestions.' Fishbein obliged the request (as he almost always did) and wrote back detailed comments on the section."13 T h e story of sanipractic is the story of John Lydon and his regional rivalry with naturopathy during naturopathy's period of emergence (1902-1930s) and naturopathy's period of decline from the late 1930s until the late 1960s. As described by Whorton, sanipractic did not survive long enough to see the rejuvenation and revival of naturopathy as naturopathic medicine and the adoption of Washington's Naturopathic Practice Act in 1988. Whorton viewed Lydon as a leader of the legislative drive to open the state to the 'irregular" practices that had been emerging in the Pacific Northwest under the banner of "drugless healing." These various philosophies opposed the use of 'pharmaceutic drugs and poisons," in the language of the 1919 Act. But the world of American drugless healing, which joined together a variety of irregulars that opposed the rising strength and burgeoning monopoly of the American Medical Association and conventional biomedicine, included some well-intentioned healers, some true visionaries, and healers of dubious credentials and intentions. Whorton clearly views Lydon as one of the latter.

doctor of naturopathy (ND), sought to escape the dubious legacy of being linked to Lydon's sanipracticby petitioning to be recognized as naturopaths in the late 1950s. This effort kept naturopathy alive in Washington just long enough for this school of healing to rejuvenate and reemerge as naturopathic medicine in the 1970s (as discussed later). In Inner Hygiene: Constipation and the Pursuit of Health in Modern Society, WhortonWoffered his first assessments of the work of Lust as it related to the emergence of naturopathy in the early twentieth century: Most of the drugless clan also identified themselves as practitioners of naturopathy, a system of practice that grew out of hydropathy, as well as German water-cure and nature-cure traditions. Organized in the late 1890s under the leadership of German immigrant Benedict Lust, naturopathy sought to cure the full scope of human ills with natural agents (herbs, water, air, sunlight, electricity, massage, and others), agents that supported and stimulated the body's own healing mechanisms.

In his extensive assessments of Lust's work and writings in Nature Cures: the History of Alternative Medicine in America, Morton51has attempted to put the philosophical development of naturopathy in a reasonable historical context: However much a dreamer Lust was in some respects, he was an insightful realist in others. He was correct in believing that simply giving nature support as it ran its course was the best one could do with many diseases in his day. He was correct in seeing self-abuse as the source of much physical, and emotional, suffering and attacked it with an ardor that MDs could not bring to the task until nearly a century later. Recent medical lamentations over the evils of smoking, sexual promiscuity, and other risky behaviors adopted in the thoughtless chase after pleasure have nothing on Lust's jeremiads. . . Lust was right in reprimanding allopaths for focusing so strongly on disease as to lose sight of the importance of promoting health. He was right in appreciating the need to "individualize" the treatment of each patient-and in seeing patient self-responsibility as part of that individualization.

How large a professional movement Lust inspired during this period of naturopathy's emergence was difficult to gauge at any point until a government survey was undertaken in 1965. But, as Morton described, naturopathy had an impact: Those were messages that had enough appeal, evidently, to allow naturopathy to expand steadily though the first decades of the century until by 1923Lust could estimate that there were nine thousand.naturopaths, a "vast army of professional men and women" working on all continents to "rejuvenate and regenerate the world." His figures undoubtedly inflated. An independent study [the work of the CCMC discussed later] put the number of naturopaths at "possibly 1500," allowing that if the "allied groups" that advocated drugless healing under other names [physiotherapy, sanipractic] were added on the total may reach 2500. Yet whatever their numbers, naturopaths had grown into a force not to be ignored.

The History of Naturopathic Medicine, Part II: Decline and Rejuvenation-Politics and Professionalization

While Lust’s claim of 9000 naturopaths worldwide is difficult to assess, 5000 practitioners may be a reasonable estimate of the reach of his naturopathy in the United States by the late 1920s and into the 1930s. As Whorton51 reported, ”without making the connection-the mixer orientation within Chiropractic was also becoming a growing presence. And, as will be discussed later in relation to Professor Wardwell’s work, this orientation was a philosophy that tended to merge Chiropractic and Naturopathy in education and practice.”* Whorton noted a ”1930 survey in which some 1,800 chiropractors participated, found, for example, that 1,124 employed hydrotherapy, 1,173 used light therapy, 1,257 provided electrotherapy,and a full 1,352 trusted vibration therapy.’’ In other words, they practiced naturopathy. Naturopaths were less successful in the 1940s and 1950s than osteopathy and chiropractic in accomplishing professionalization by raising professional standards, as Whorto~Pnotes, including in education. This occurred despite the formation of a National Board of Nature pathic Examiners of the American Naturopathic Association (ANA) in 1940. There was constant internal bickering, which “by the 1940s had taken on a more ominous tone.” While ”standards at naturopathic schools were steadily raised from the 1940s on, thanks to both professional idealism and the requirements of state licensing laws,” based on ”a perusal of the statutes of the dozen states in which naturopaths were licensed in the late 1940s,” the divisive trends within naturopathy ”would not begin to be reversed until the 1970s.” Whorton51observed that there was no misunderstanding where Lust himself stood on the need for professional standards: Obtaining their own licensing statutes was perceived by alternative practitioners as a critical measure for purging incompetence and quackery from their own rank. ”Where there is no official recognition and regulation,’’ the founder of naturopathy, Benedict Lust maintained, “youwill find the plotters, the thieves, the charlatans . . . (The) riff-raff opportunists bring the whole art into disrepute.” By the time Lust said this, shortly before his death in 1945, frustrating experience had demonstrated that “that is the fate of any science-any profession-which the unjust laws have placed beyond the pale.” In following the evolution of alternative medicine over the first third of the twentieth century, it is essential to keep in mind that constant battle of each system to bring itself within the pale. “Although homeopathy has undergone a small revival in recent years, very few MDs now practice it. It is currently mainly of interest to naturopaths, who earn doctor of naturopathy (ND) degrees, and to a few chiropractors. Naturopaths closely resemble chiropractors in that they use spinal manipulative therapy (henceforth SMT) and because so-called mixer chiropractors also use such naturopathic methods as heat, cold, hydrotherapy, physiotherapy, dietary supplements, and even some herbal and homeopathic remedies. That is why the traditional, or ‘straight,’ chiropractors disparagingly call them ‘medipractors.’ Until the middle of the twentieth century a few mixer schools both DC and ND degrees, either as alternatives or together after an additional semester of study.“48

NATUROPATHY’S PERIOD OF EMERGENCE-EDUCATION AND PROFESSIONAL PRESENCE Naturopathy became an element of chiropractic education and practice at least as early as 1910 with the founding of the Peerless College of Chiropractic and Naturopathy in Portland, OR.48 From this point on, naturopathic education developed in two tracks: schools of naturopathy owned and operated by naturopaths and chiropractic schools that had naturopathy curricula in addition to the core chiropractic programs. These latter schools were a central part of the mixer orientation within chiropractic.3zt48 Initial assessments of schools of naturopathy occurred in the 1920s and 1930s. These assessments came from those within, or allied with, allopathy and are therefore hardly unbiased, but much of the information in these assessments seems credible. The progression of education in naturopathy would be expected to have been similar to that of chiropractic, if somewhat smaller in scale. In this regard Walter I. Wardwell noted4? Wiese and F e r g u s ~ nidentified ~~ 392 different chiropractic schools as having existed in the United States. When those for which there is no evidence of more than a year of operation are eliminated, the number is reduced to 188. Most of them probably produced few graduates-the number of schools increased rapidly to their largest between 1910 and 1926, and then contracted, particularly during the depression of the 1930s and World War II.

The history of schools of naturopathy followed much the same pattern. Whorton51notes that this was the case. The operators of these schools seemed, at least on the surface, aware of the kind of criticisms to which proprietary trade and professional schools are subjected: limited facilities, limited resources, and an emphasis on collecting revenue versus providing a full professional education.3z*48 The leading operators of schools of naturopathy sought, at least on paper, to respond to these criticisms. By letter agreement dated October 7, 1922, four of the most identifiable leaders of naturopathyBenedict Lust, Joe Shelby Riley, F.W. Collins, and Henry Lindlahr**ommitted to the formation of the Associated Naturopathic Schools and Colleges of America and committed themselves as “the Presidents of Naturopathic Schools in the United States of America” to specific educational m i n i m u m s ”on and after January 2, 1923”: “all matriculants must have a primary school educationt and

‘Lust signed on behalf of the American School of Naturopathy, Riley on behalf of the Universal Spinal Therapy and Naturopathii College, Collins on behalf of the United States School of Naturopathy (the letter appears on this school‘s stationary), and Lindlahr on behalf of the Lindlahr College of Natumpathy. The letter‘s Mth sip natory is Dr. M.E.Yergin on behalf of the National Natumpathic and Health School. +‘Primary education”-circa 1922-was an eighth-grade education, and this educational base would have been the same as required by chiropractic.

all naturopath courses must be composed of four years of six months each." Additionally, the letter provided that "time allowance or credits may be given to practitioners in the field who desire to take up the naturopathic courses, and to licensed physicians of other methods of healing,'' the amount of such credit being left to each school's discretion. In the summer and fall of 1927, representatives of the AMA's Council on Medical Education and Hospitals conducted inspections-unannounced and incognitof schools of "chiropody, chiropractic, naturopathy, optometry, osteopathy, physical therapy, as well as a large number of institutions." From these inspections several reports were generated, including the Council's report on "Schools of Chiropractic and Naturopathy in the United States," which appeared first as part of the Council's Annual Report, 1928, and later as reprinted in The Journal of the American Medical Association.* The report identified 40 schools of chiropractic and 10 schools of naturopathy and detailed the inspections of "some schools of Chiropractic and of Naturopathy": Palmer School of Chiropractic (a straight school), National College of Chiropractic (a mixer school that was reported as having recently purchased and assimilated Lindlahr College of Natural Therapeutics), Los Angeles College of Chiropractic (another leading mixer school), the combined American School of Naturopathy, Inc. and American School of Chiropractic, Inc. (Lust's own New York City schools, though Lust was observed to have been "in Florida" at the time of the inspections), and the Naturopathic College and Hospital of Philadelphia. The reports were predictably negative with regard to facilities, resources, and the clearly proprietary nature of the establishments. The CCMC's Reed, in discussing "Naturopathic relied heavily on this report from the AMA's Council and observed that "in 1927, according to the American Medical Association, there existed twelve naturopathic colleges with not over 200 students. These figures would probably hold good for the present time." Reed also concluded that there were "a considerable number of miscellaneous drugless healers of a type similar to chiropractors practice in this country" as of 1932 and that "the naturopaths form the largest group of these practitioners. . . . Of these various cults, only the naturopaths and the sanipractors have any considerable membership. Many of the (other) cults are really part of the naturopathic As to numbers of drugless practitioners, Reed observed that ''only the roughest estimate can be made-probably there are about 2500,'' of which naturopaths "number possibly 1500," and sanipractors--"only the name distinguishes sanipractors from the naturopaths"-numbered 'VOl 9611733-1738, 1928.

some 500 in their Washington state "stronghold." Reed also observed that as of 1932:"A few states-Connecticut, Florida, Oregon, South Carolina, Utah, Washington and the District of Columbia-provide for licensing of naturopaths as limited practitioners. . . . In addition to those mentioned, certain states (Alabama, Colorado, Illinois, Indiana, Michigan, Ohio, Pennsylvania, New Jersey, and Wyoming) make (other) provision for the licensing of drugless or limited practitioner^."^^ Reed's work for the CCMC, though clearly biased against all of the healing philosophies he identifies as "medical cults" (ala Fishbein), principally osteopathy, chiropractic, and naturopathy, is the only work that attempts to survey the presence and impact of these schools of healing in the United States in the 1920s and 1930s.*A decade later, in April 1945, another work of this kind appeared in the Rhode Island Medical Journal? The article, "Naturopathic Legislation and Education," was written by the Rhode Island Medical Society's Executive Secretary, John E. Farrell, to set out some of the society's reasons for opposing legislation that would license naturopathy in Rhode Island. The article noted that according to the 1942-1943 Report of the Committee on Education of the ANA, 13 schools of naturopathy in the United States met criterion of the ANA; the article goes on to make a lengthy "Report on Schools" through visits to most of the identified schools.$The predictable criticisms of these schools as underfinanced, underresourced, and proprietary in nature appear once again, though by actual detail of description, National College (Chicago) and Western States (Portland) seem to be wellestablished, functioning mixer schools of chiropractic and naturopathy. Another source of information about the state of naturopathy, its licensure, and its schools comes from within the profession, covering the mid-1940s to the mid-1950s. The International Society of Naturopathic Physicians (ISNP)was founded in California in 1938; the ISNP's original moving spirit, and first president, was Arthur Shramm of Los A n g e l e ~ Under . ~ ~ Shramm the ISNP published a yearbook for its membership in 1945,1946, and 1948. Shramm was followed in the presidency by Mario T. Campanella, based in Graham, FL.

'The results of Reed's work are also summarized in the CCMC's Publication No. 27, The Costs of Medical Care, Falk, Rorem and Ring (1933), p. 292, as 'Naturopaths and Other Drugless Healers." Wolume 28:248-253, 262-263. With lengthy discussion of Central States College of Physiatrics (Eaton, OH), The Colorado Mineral Health School (Denver), Columbia College of Naturopathy (Kansas City), First National University of Naturopathy (Newark, NJ, earlier the United States School), The Metropolitan College (Cleveland), The Nashville College of Drugless Therapy (Tennessee), The National College of Drugless Physicians(part of the NationalCollegeof Chiropractic,Chicago),The Polytechnic College and Clinic of Natural Therapeutics (Fort Wayne, IN), The Southern Universityof Naturopathyand Physio-Medicine (Miami), The University of Natural Healing Arts (Denver), and The Western States College (Portland, OR).

The History of Naturopathic Medicine, Part II: Decline and Rejuvenation-Politics and Professionalization

Under Campanella the ISNP published a membership directory in 1952 and again in 1955. Each membership publication contained current information regarding existing schools, state associations, and licensing laws, as well as other demographic information about the state of the profession. The 1948 yearbook details the high-water mark for the emergence period, which extended past Lust's death in 1945 into the late 1940s: licensure in 13 states, the territory of Hawaii, and three Canadian provinces.* State associations were identified for 32 states, and associations were also identified for five Canadian provinces and Great Britain, Australia, New Zealand, India, Germany, the Netherlands, Luxemburg, and Spain.

THE LONG DECLINE In the face of the AMA's determination to eliminate chiropractic, and with it naturopathp7-healing philosophies that were linked through the mixer orientation within chiropractic (during the 1930s and through the 1960s the majority camp within a divided chiropractic)naturopathy went through a period of decline described by Baer.45 Wardwell is a sociology professor emeritus who became an early leader in what developed as a subspecialty in the 1950s: medical sociology. His earliest work, starting with his doctoral dissertation (1951) at Harvard, focused on chiropractic as an example of a marginalized health profession: As early as his doctoral dissertation, Wardwell discussed naturopathy as an adjunct discipline to chiropractic in the context of the continuing division of chiropracticinto mixers and straights. As he later noted43: Comparison of the survival of chiropractic with that of osteopathy and naturopathy is a quite different matter which does not involve metaphysical or epistemological differences between them. Furthermore, the overlap in theory between chiropractic, osteopathy and naturopathy is very great. Differences between osteopathic and chiropractic manipulative treatment appear to be more a matter of who applies the technique rather than differences in technique itself. The distinction between chiropractors and naturopaths is even more blurred because they often trained at the same schools and sometimesthey studied both fields simultaneously.As recently as 1948, three of the currently accredited chiropractic colleges *The laws for 12 states and Hawaii, as well as three provinces, were reprinted in the yeabook together with contact names and addresses for the respective examining boards for all but California and Pennsylvania, where licensing was done through a pluralistic medical board. The states licensed in 1948 were: Arizona, California, Connecticut, Florida, Oregon, Pennsylvania, South Carolina, Utah, Washington (which had a drugless healing law), and Virginia. Tennessee had originally been included, but note was made that the Tennessee licensure had been repealed in 1947. Licensure in these states plus Hawaii was the highwater mark for licensure before the period of decline. The three Canadian provinces were Ontario, Manitoba, and British Columbia. *Over the course of his academic career, Wardwell wrote a series of articles about the emerging concepts of medical sociology and chiropractic's evolution as a marginalized profession.

offered N.D. (Doctor of Naturopathy) and D.C. (Doctor of Chiropractic) degrees.

In this context he described naturopathy as a school of healing that became extinct as two historical factors converged: the death of Lust in 1945, leaving naturopathy without its "founder," and the mandate in the early 1950s by the major mixers' professional group, the National Chiropractic Association (NCA), that it would no longer accredit chiropractic schools that granted degrees in naturopathf3: In the case of naturopathy, chiropractic's victory is nearly complete. Although there may still be up to 2000 naturopaths in practice* with naturopaths licensed in a few states, and one small school in Portland, Oregon, still offers naturopathic degrees, none of the schools that formerly offered both chiropractic and naturopathic degrees currently does so. With practically no new recruits entering the profession, naturopathy must disappear.

By the late 1970s, Wardwell had learned of efforts in the Pacific Northwest to keep naturopathy alive. In his chapter in the handbook of Medical Sociology, Wardwell@ noted this presence in the Northwest (which had received no mention in the first two editions in 1963 and 1972): The accrediting of chiropractic colleges is encouraging uniformity, not only in curricula but in scope of practice. Those colleges that formerly offered the Doctor of Naturopathy (N.D.) as well as the D.C. degree have ceased doing so, leaving naturopathy with only one remaining small college in Portland, Oregon."

By publication of his masterwork, Chiropractic: History and Evolution of a New Profession (1992); Wardwell devoted substantial attention to the impact of naturopathy on the mixer orientation within chiropractic and traced naturopathy's final educational decline to the untimely death in 1954 of William A. Budden, DC,ND, the president of Western States Chiropractic College (WSCC, Portland, OR). Following Budden's death, WSCC continued to teach naturopathy until 1958 but dropped its Doctor of Naturopathy (ND) degree program in 1956. This was the last resistance to the position of the accrediting committee of the NCA, and no chiropractic ND programs remained. Wardwell observed, though, that the seeds of a naturopathic reemergence had been planted in the Northwest after Budden's death and that naturopathy may indeed survive. The last ND diplomas had been granted at WSCC in 1958 to students who were enrolled in the ND program at the time of Budden's death. Brinkergwrote the following: Political pressure from the chiropractic profession had begun in the late 1940s to force chiropractic schools to relinquish 'As to those calling themselves naturopaths, this number was considerably too high, as will become apparent. Whorton calls this Wardwell's "excellent survey of Chiropractic's history-'

Philosophy of Natural Medicine programs granting naturopathic degrees. After threatening loss of accreditation, the National Chiropractic Association finally forced Western States College to drop its School of Naturopathy in 1956, and it became exclusively Western States Chiropractic College? Efforts to keep naturopathy alive through education and licensure were examined by two reports prepared in 1958, a time when the Utah legislature was reexamining naturopathy’s licensure in the aftermath of a case from the Utah Supreme Court that had dealt its practicing NDs a crippling blow.* The first was A Study of the Healing Arts with a Particular Emphasis Upon Naturopathy (November 1958), prepared as “A Report to the Utah Legislative Council” by legislative council staff. As part of its work, the staff conducted inquiries of, and site visits to, seven schools accredited by the Utah Naturopathy Examining Board as of August 1957. Separately, the Bureau of Economic and Business Researcht of the University of Utah (BEBR) undertook a study focusing on schools that had granted naturopathy degrees and produced Survey of Naturopathic Schools (“Prepared for the Utah State Medical Society,” December 1958).Preparation of the study was, as noted in the title, undertaken by the university research program at the request of the state medical society, but the preparation of the study was independent, and “no attempt was made by that group to influence the results of the study.” (Foreword and Acknowledgements). The BEBR study, done with the requested cooperation of investigators from five other universities located in various sections of the United States, surveyed all of the schools listed by Utah licensees as schools of graduation or schools attended, using records maintained by the Utah Department of Business Registration.lo Since the state of naturopathic education in the 1950s is relevant, some observations from this study are worth noting: One of the most important results to emerge from this study is that there are virtually no schools now teaching naturopathy. Of the twenty-six schools investigated during this study, only nine were still in existence in the fall of 1958. Of these nine, only three are now granting naturopathic degrees and two others are teaching naturopathy.’O Of the three schools granting ND degrees, the study found that one school, Sierra States University in California, began offering a ”postgraduate” ND degree after the most highly respected chiropractic program in the country, Los Angeles College of Chiropractic, had discontinued its ND degree program in 1948. National College of Naturopathic Medicine (NCNM), the Oregon

‘The Utah Attorney General in 1955 had reversed opinions by several of his successors in office and issued an opinion that declared naturopathy in Utah to be a completely ‘drugless“ practice. The profession, represented by the examining board, challenged this opinion in court and lost. tNow the National Bureau of Economic Research.

school, had-in 1957, its first year of operation-four ND students who were starting at NCNM and 60 enrolled ”postgraduate” DCs pursuing ND degrees. The school had been recognized by the Utah examining board but had not yet granted degrees. The third school granting ND degrees as of 1957-1958 was the Central States College of Physiatrics in Eaton, OH, essentially the one-man operation of H. Riley Spitler, author of Basic Naturopathy (published by the ANA in 1948).This school granted a Doctor of Mechanotherapy (DM) degree, recognized in only Ohio and Alabama by law, or an ND degree to anyone who sought licensure in a state where an ND degree would quallfy a graduate for licensure. The course of study for both degrees was the same, and the school had graduated 10 students in the previous 2 years. Its ND degrees were recognized in Utah. This state of affairs was accurately described by Homola” in his book on the history and evolution of chiropractic: As of 1958, only five states (Arizona,Connecticut,Oregon, Virginia and Utah) separately classified and provided licensing provisions for the naturopath. A few states, however, did permit licensing of drugless healers following examination by (a) board. (A good number of states have repealed their laws licensing naturopaths in recent years.) Chiropractic schools that employ the use of physiotherapy teach a course that is very similar to the practice of naturopathy. Likewise, the three or four naturopathic schools still operating today have a curriculum similar to that of many chiropractic colleges. In fact, at least four chiropractic colleges awarded naturopathic degrees along with the chiropractic degree before they came under the jurisdiction of the national Chiropractic Association. With the approval of this organization, the schools were prohibited from issuing naturopathic degrees. This practically amounted to a death-dealingblow to the profession of naturopathy?* In 1967 the U.S. Department of Health Education and Welfare, Public Health Service, National Center for Health Statistics (NCHS) published Public Health Service Publication number 1758, State Licensing ofHeulth Occupations. With the assistance of The Council of State Governments, the NCHS collected data regarding licensure of health professionals at the state level. ”Chapter 8, Naturopaths” recorded the available data for the ‘Various sources document how dismal this status became in the 1950s and 1960s. Brinker noted that in 1955, “the Western States College School of Naturopathy was one of only two programs (together with Central States) that was recognized by the remaining professional association as the “renamed American Association of Naturopathic Physicians (AANP)” and that Western States enrollment was “49% naturopaths and 5196 chiropractors.“8 Wardwelr noted that Western States never was a large school, and that in the years following its discontinuance of its School of Naturopathy (1956-1970), it never had a total enrollment greater than 38 students. But NCNM, the successor to the WSCC naturopathy program, graduated only 29 NDs from 1956-1973.9 According to documentation provided to the federal Department of Health Education and Welfare in 1968 by the again-renamed professional associatioMy now the National Association of Naturopathic PhysiciansACNM granted only 17 degrees were granted from 1960-1968. By 1968 this association had only 168 members.

The History of Naturopathic Medicine, Part 11: Decline and Rejuvenation-Politics

naturopathic profession as of the mid-1960s. In summary, the NCHS identified five states and the District of Columbia as licensing naturopaths as of 1967 Arizona, Connecticut, Hawaii, Oregon, and Utah. California and Florida were identified as renewing existing licenses but granting no new licenses. The publication reported that by 1965, California had renewed 66 licenses and Florida, 136. Licenses in effect by state were: Arizona (loo), Connecticut (47), Hawaii (14),Oregon (la), and Utah (42). No numbers were provided for the District of Columbia. The report stated the following: In addition to Doctors of Naturopathy (N.D.) there are other limited branches of medicine; these have not been included in the study. In the State of Washington the Drugless Therapeutics Examining Committee functions (for such licensure). The Ohio law states which branches are to be specified on certificates issued by the State Medical Board to limited practitioners. No attempt has been made to collect information on these drugless healers who are few in number.12

Active state practitioners were also numbered (though the reason for the differentiationis not clear) as: Arizona (53), Connecticut (29), Hawaii (13), and Oregon (121). Given the existence of approximately 50 practitioners at the time in Washington, and some practicing in Idaho under a decision of the Idaho Supreme Court, there appear to have been perhaps as many as 600 to 700 remaining naturopaths practicing at the end of the 1960s.* According to documentation provided to the federal Department of Health Education and Welfare in 1968 by the again-remaining professional association-the National Association of Naturopathic Physicians-only 17 degrees were granted from 1960-1968. By 1968 this association had 168 members and estimated that there were perhaps 500 "active" naturopaths in the United States. Congress had adopted Medicare in 1965. The legislation covered payment for the services of physicians (essentially MDs and Dos), hospital services, and "other therapeutic services" that would commonly be provided through these conventional means. As Wardwell reported:* in 1967 Congress directed the Secretary of the Department of Health, Education, and Welfare (HEW),Wilbur Cohen, to study the inclusion services of "additional types of licensed practitioners." The surgeon general and other HEW staff prepared the resulting Independent Practitioners under Medicare using advisory committees only (Wardwellserved on the Expert Review The State Licensing of Health Occupations, U.S. Department of Health, Education and Welfare, National Center for Health Statistics, Public Health Service Publication No. 1758 (1967) reported: "Naturopaths are specifically licensed in at least five States and the District of Columbia. The absence of a State from this list does not imply that there are no licensed naturopaths. Illinois, for example, could be covered by the medical practice act. Texas and Virginia provide for naturopaths on examining boards but no information is available on licensing practices. Elsewhere licensing powers have been abolished and no new licenses have been issued for example, in 1965 naturopathic licenses renewed in California numbered 66 and in Florida, 136."

and Professionalization

Committee for Chiropractic and Naturopathy), which actually had little input.@ This report documents the ebb tide of naturopathy's "period of decline" as Baer later labeled it.4The section of the report Naturoputhy concludes that as of 1968: Naturopathic theory and practice are not based on the body of basic knowledge related to health, disease, and health care which has been widely accepted by the scientific community. Moreover, irrespective of its theory, the scope and quality of naturopathic education do not prepare the practitioner to make an adequate diagnosis and provide adequate treatment.

Considering the state of the profession in 1968, these negative assessments were hardly unexpected.

THE PERIOD OF REJUVENATION Baer is a professor of cultural anthropology at the University of Arkansas, Little Rock. Like Wardwell, Baer's scholarship in the 1980s focused on two areas: (1)the scholarship of medical anthropology and (2) the once-marginalized health philosophies-osteopathy, chiropractic, and, secondarily, naturopa thy. Baer's interest in the evolution of chiropractic as a philosophy of healing led him to Wardwell's work,+ and to Wardwell's earlier scholarship that had been tied to the mixer orientation within chiropractic.+Baer took note of his descriptions of naturopathy as a near-extinct philosophy. Predictions of extinction were consistent among the assessments of social scientists in the 1970s and continuing into the mid-1980s. R ~ t h ?Twaddle ~ and Hessler,36Rosengren,34 Whorton," and most notably Wardwel14>46sall discussed naturopathy as a onceobservable but marginalized philosophy of health and healing at odds with the conventional medical claims of a scientific medicine. These social scientists placed naturopathy's demise sometime in the 1950swhen chiropractic severed its open naturopathic link by terminating ND programs. But Baer, perhaps before Wardwell, took note of two related developments: (1) the founding in 1978 by

'In a relevant article,' he discussed the three stages undertaken toward competition by a dominant professional system in a pluralistic medical system: (1) deviance, (2) legitimization, and (3)cooptation, through an examination of organized, 'regular" medicine versus osteopathy; he referenced Wardwell as having documented these three stages of action by organized medicine toward chiropractic with no mention of naturopathy. +"The development of American chiropractic was particularly shaped by the internecine battles between "straights" and "mixers"Y-those who wished to focus on spinal adjustment as a central modality and those who wished to incorporate many other modalities from what is loosely termed naturopathy. Because of its extreme eclecficism, naturopathy provided mixers with a ready source from which to add a wide variety of techniques to their own treatment program. For many years, many mixer schools offered their students the ND (doctor of naturopathy) diploma in addition to the DC (doctor of chiropractic) diploma. Registration as naturopaths allowed chiropractors in some states to engage in a wide scope of treatment practice without danger of legal repercussions." During the 1950%however, many states repealed their laws licensing naturopaths."

naturopaths Joseph Pizzorno, William Mitchell, Lester Griffith, and Sheila Quinn of John Bastyr College of Naturopathic Medicine (JBCNM) in Seattle and (2) the professionalization represented by JBCNM’s scientific medicinebased curriculum and the publication of a JBCNMproject, The Textbook of Natural Medicine.+ In his 1992 Medical Anthropology article “The Potential Rejuvenationof American Naturopathy as a Consequence of the Holistic Health Movement,” Baer detailed his own view of Naturopathy’s ”three stages of development” noted at the outset of this chapter. Besides relying on material covered in the original chapter of “The History of Naturopathic Medicine,” which first appeared in 1985, Baer covered much of the new material regarding the emerging (1900-1930s) and declining (1940-1970s) stages of naturopathy. Baer particularly broke new ground with his recognition of a “potential rejuvenation” of naturopathy as naturopathic medicine and his recognition that the profession had knowingly or unknowingly adopted a recognized survival strategy as a matter of organizational policy: professionalization.Baer also broke new ground in advancinga theory regarding the “potential rejuvenation’’ as tied to the emergencein the 1970s of holistic medicine. Holistic medicine, as a philosophy of healing, had a cultural affinity with the eclecticism inherent in naturopathic philosophy. In his 2001 book Biomedicine and Alternative Healing Systems in America, Baer updated this view of the status of naturopathic medicine in a chapter entitled “Naturopathy and Acupuncture as Secondary Professionalized Heterodox Medical system^."^ With the passage of the additional 10 years, Baer observes: Unlike chiropractic, which no longer poses a serious threat to biomedicine because of its status as a specialty emphasizing spinal manipulation, a rejuvenated naturopathy finds itself in direct competition with biomedicine because both systems claim to provide a comprehensive approach to health care. As osteopathy and chiropractic did earlier, naturopathy . . . (is)increasingly incorporating the theory and social organization of biomedicine. (N)aturopathy . . . with (its) reductionist philosophy and (its) focus on individual responsibility for healthy living may well undergo further growth in an era of growing health

THE TWENTY-FIRST CENTURY AWAITS Baer carried his examination of the sociopoliticalaspects forward in his 2001 article, The Sociopolitical Status 0fU.S. ‘Twaddle and Hessler (professors of sociology, Universityof Missouri) were actually the first to take notice of an ‘expansion and professionalization of naturopathy“ in the second edition of A Sociology of Health.37They summarized the situation in the late 1980s in this way: Clearly, naturopaths are making a considerable effort to increase the standard of training and to define a professionalalternative to allopathic medicinethat preserves much of the natural healing traditions of the nineteenth century. They seem to be making progress, while remaining a small group with little impact on medicine as a whole at the present time. They have not yet received the attention of sociological research.

Naturopathy at the Dawn of the 21st C m t uy.6He updated the “three stages of development” explored in his earlier writings* and then examined the state of naturopathic medicine as it prepared to enter the twenty-first century. Baer saw three main twenty-first century issues confronting naturopathic medicine as critical to the future of the profession: While “professionalizednaturopathy has undergone tremendous growth and legitimization since the late 1970s, nevertheless, it finds itself in a tenuous situation at the dawn of the twenty-first century in that its strength is confined primarily to the Far West and New England; it faces increasing competition from the partially professionalized and lay naturopaths; and it faces the danger of being overshadowed by a powerful biomedical system that is increasingly incorporating aspects of holistic health into its own practice.”6 Although he offered no definitive answers to these issues concerning naturopathic medicine’s future, he also highlighted additional areas needing further attention by social scientists: continued exploration of the reasons for naturopathy’s decline and rejuvenation and continued study of the naturopathic profession in recognition of its state of professionalization. In closing, Baer observed: ”In sum, while changes in the popular ideas about health and healing unleashed the social forces that enabled professional naturopathy to get back on its feet, those same social forces may overwhelm its core claim to being a unique, natural approach to healing. Whorton expresses the view that in many respects the transition from the marginalized naturopathy to the professionalized naturopathic medicine has now been accomplished.He traces his view of this transformation as part of the larger transformation “from alternative medicine to complementary medicine” on the part of osteopathy, chiropractic, and naturopathy? Whorton describes the factors that allowed this transformation even after the death of Lust in 1945: The issue of the “field’s lack of a scientific basis” was determined internally when the ”diedin-the-wool believers in ‘nature cure’ ” were outlasted by the “liberal practitioners belonging to the so-called westem group, naturopaths concentrated in the western states who recognized the validity of mainstream medicine’s scientific foundation and sought to incorporate biomedical science into their own system and apply it under the guidelines of naturopathic philo~ophy.’’~~ As Whorton noted, “a key figure among the pseudomedicals was John Bastyr-a practitioner in Seattle since the 1930s, and particularly well-known for his advocacy of natural childbirth.” Bastyr, Whorton noted, “recognized the necessity of naturopathy staying abreast of ‘Three stages of development:(1) its emergence around the turn of the lwentieth century; (2) its period of decline beginningin the late 1930s;and (3) its recent potential rejuvenation.“‘ +Baercoauthored one publication with a professor from a West German university, Eduard Seidler.

advances in biomedical science and applying those advances ‘in ways consistent with naturopathic principles.’ ”51 Bastyr was directly involved with the formation and maintenance of the NCNM during the years of naturopathy’s decline and lived to see much of “the short history of John Bastyr College (of Naturopathic Medicine) (which) is the most compelling illustration of the triumphant rebirth of naturopathy as naturopathic medicine.”51 Bastyr has been called “The Father of Modern Naturopathic Medicine” by Pizzomo, ND,3l the moving spirit behind the professionalization of naturopathic medicine and the founding president of Bastyr University. No individual has carried the practice of NDs in the United States in the way that Lust did, but Bastyr and the others profiled by Kirchfeld and Boyle in Nature Doctors kept naturopathy alive during its decline in the 1950s and 1960s so that it could, in time, reemerge.

DEVELOPMENTS OUTSIDE THE UNITED STATES Canada Two sources of information that describe the development of naturopathy in Canada deserve mention. In 1966 the Royal Commission on Health Services published its Study of Chiropractors, Osteopaths and Naturopaths in Canada, otherwise known as the Mills Report after the chief author of the report, Donald L. Mills, professor of sociology, University of Alberta. The Mills Report observed the followinf-‘: Chiropractic,naturopathy and osteopathy have beginnings which lie outside Canada. Osteopathy and chiropractic had their start in the United States in the last 19”’ century, with osteopathy beginning about a generation earlier than chiropractic. Naturopathy,on the other hand, has antecedentsgoingback earlier in the 19* century, and its development was largely in Central Europe, but it was considerably later that it came to the North American continent. Chiropractic and osteopathy began to develop in Canada shortly after emerging in the United States-that is around the beginning of the 20* century. Naturopathy, on the other hand, appears to have developed rather later on the Canadian scene that (sic) was true in the United States. To some extent each of these health serviceswas developed as a reaction to the practice of medicine as it existed in an earlier time, and in the instances of osteopathyand naturopathy, people who had been trained in medicine of the day played important parts in this development. The Mills Report in due course covered “The Origins and Definition of Naturopathy” ”The General Development of Naturopathy in Canada,” ”The Development of Naturopathy in Ontario,” “The Development of Naturopathy in Eastern Canada,’’ and ”The Development of Naturopathy in Western Canada.”30 A later article, Naturopathy in Canada: Changing Relationships to Medicine, Chiropractic and the State, by Gort

and Cobumzoupdated the development of naturopathy in Canada. The article examined the development of naturopathy in Ontario, Canada: As well, the relationships between naturopathy, medicine, and the state will be analyzed through examination of three health commissions in Ontario (including the Mills Report). Then the changing connections between naturopathy and chiropractic will be described. We conclude by commenting on the relevance of the social history of naturopathy for issues of occupational formation, for professionalization, and for medical dominance. The authors trace an emergence of naturopathy in Canada (1930s-1950s)that mirrors that of its history in the United States, which may not be surprising considering that many naturopaths and chiropractors were trained in the United States through the mid-twentieth century. They describe a decline and rejuvenation similar to that in the United States as well: From 1964 until at least 1975 there has been little if any official contact between the chiropractorsand the naturopaths. Beginning about 1975 a number of young chiropractors took a renewed interest in naturopathy, to the point where these new recruits now form the bulwark of naturopathy. They have assumed leadership roles in both the association and on the licensing board. They upgraded their qualificationsto become full-fledged naturopaths and now identdy themselves not as chiropractorsbut as naturopaths. Thus, the history of relations between the two occupations shows chiropractic first supporting naturopathy for purposes of increased scope of practice, then narrowing its focus and trying to put as much distancebetween chiropractic and naturopathy as possible. Naturopaths were forced to cooperatewith chiropractic. More recently, however, naturopathy has begun to attract those not satisfied with spinal manipulation and related therapies even though the two occupations are now completely separate.20

Elsewhere English freelance writer Robert Bloomfield traced a short but more international history of naturopathy in Traditional Medicine and Health Care Coverage.* His historical approach confirms that the development of naturopathy in the United Kingdom-with the exception of Canada-owes more to the health philosophies of Henry Lindlahr (see previous chapter) than to the father of U.S. naturopathy, Lust. Two English-language articles published in the mid1980s by Cultural Anthropology Professor Thomas Maretzki of the University of Hawaii-based on many German-language sources-trace the modem German development of naturopathy and classic German Nature Cure (The “Kur”).

OTHER RELEVANT SCHOLARSHIP As M o r t o n noted, ”Naturopathic medical practice nevertheless is still composed of distinctive therapies

backed by faith in nature. Among the most common treatment categories are clinical nutrition, botanicals, homeopathy, acupuncture, hydrotherapy, physical medicine (massage, heat, cold, electricity), spirituality, and lifestyle ~ ~ u n ~ e l i n g . ” ~ ~ Some of these therapies originated in the German nature cure tradition, and some are more American homegrown; all of them fit within the eclecticism that was part of the naturalism and vitalism that made up Lust’s vision of naturopathy. Several of these threads, as they otherwise were woven into the American medical tradition, have been the subject of recent scholarly attention that deserves mention: 1.Nature Doctors: Pioneers in Naturopathic MedicinS7 is, as Whorton put it, “the best English-language survey of the German nature cure tradition.” 2 . A n Alternative Path: The Making and Remaking of Hahnemann Medical College and Hospital of Philadelphia,33 the modern history of America’s ’‘only institution in the world to offer an M.D. degree in Homeopathy,’’ a degree program that lasted from 1848 (its founding) until 1947 when homeopathy became an elective. It was still taught until Garth Boericke, Hahnemann’s last teacher of the therapy, retired in 1958. 3. ( A profile in) Alternative Medicine: The Eclectic Medical College of Cincinnati, 1845-1942,u the history of the flagship educational institution of America’s eclectic medical philosophy and a history of the philosophy as well. 4. Kindly Medicine: Physio-Medicalism in America, 18361 9 1 P is a history of the medical philosophy that naturopathy adopted as physiatrics. 5. Medical Protestants: Eclectics in American Medicine, 1825-193921is the definitive history of the eclectic medical philosophy in which Lust was educated and trained by the American professional botanical movement’s foremost historian, John S. Haller. 6. John Uri Lloyd: The Great American EclecticI9 is the definitive biography of the last great defender of the botanical medical tradition in the United States; a pharmacist, not a physician, Flannery is the other recognized scholar of the history of botanical medicine in the United States. 7. Vox Populi: America‘s Botanical Movements7 is “the first comprehensive study of the American botanical (medical) movement.” The authors noted that the botanic legacy survived the death of the eclectic medical philosophy because, through Lust, ”naturopathy would eventually adopt much of eclectic pharmacy as its therapeutic mainstay.” They noted that Lust received an MD degree from the Eclectic Medical College of New York in 1914, the ANA’s Naturae Medicina (1953) compiled over 5 years between 1947

and 1952 was ”a compendium of 310 botanicals covering their composition, preparation, actions and therapeutic uses, and toxicology,” and that “even postmortem, eclecticism lives on in modified forms in American naturopathy” as ”best exemplified by Bastyr University.” 8. Homeopathy in America by Martin Kaufmann appears in Other Healers: Unorthodox Medicine in America, edited by Norman Gevitz. The book also has contributions by James Whorton (on popular health reform) and Walter Wardwell (on Chiropractic). Kaufmann’s contribution is notable for these observations: In addition to the revival of classical homeopathy, a major developmentin recent times has been the teaching of homeopathy in naturopathic colleges on the West Coast. In Seattle, John Bastyr, a naturopath and homeopath who had been practicing for fifty years, led the move in 1956 to establish the National College of Naturopathic Medicine, which later moved to Portland, Oregon. The college’sfour-year curriculum includes a required third-year course in homeopathy, with homeopathic electives being available to third- and fourthyears students. In 1978, three naturopathic practitioners in Seattle founded the John Bastyr College of Naturopathic Medicine. During the sixth quarter all students at that school are required to take 44 hours of course work in homeopathy, after which they may elect to take another 66 hours and up to 238 hours of clinical homeopathic instruction. The sigruficance of the naturopathic schools to the resurgence of homeopathy is demonstrated by the fact that ”about one third of the graduating class specializesin homeopathic practice, a total of about 50 each year in all.”(citations omitted)

CONCLUSION As Baer proposed, naturopathy has developed in the United States (and in Canada as well) through stages aptly described as emergence, decline, and rejuvenation. The emergence occurred during Lust’s lifetime, between 1902 when he introduced the healing philosophy that he named naturopathy and the late 1940s. Then clearly it declined, for reasons discussed in the earlier chapter and also because of its loss of professional momentum when Lust died and because chiropractic, for its own political reasons and to reshape its political profile, separated from naturopathy. Now its rejuvenation, which began in the mid-1980s when the earlier chapter first appeared, has continued bringing naturopathic medicine to an almost identical political profile to where it was when Lust died: licensed in a similar number of states and composed of a similar number of practitioners. Naturopathic medicine is a more professionalized health system than the earlier naturopathy however, and it seems that more of an impact from the naturopathic profession lies ahead.

The History of Naturopathic Medicine, Part 11: Decline and Rejuvenation-Politics and Professionalization

1.Baer HA. Organizational rejuvenation of osteopathy Soc Sci Med 1981;15A:701-711. 2. Baer HA. A comparative view of a heterodox system: chiropractic in America and Britain. Med Anthropol1984;8:151-168. 3. Baer HA. The American dominative medical system as a reflection of social values in the larger society. Soc Sci Med 1989;28:1103-1112. 4. Baer HA. The potential rejuvenation of American naturopathy as a consequence of the holistic health movement. Med Anthropol Q 1992;13369-383. 5. Baer HA. Biomedicine and alternative healing systems in America. Madison: University of Wisconsin Press, 2001a:101-102. 6. Baer HA. The sociopolitical status of U.S. naturopathy at the dawn of the 21st century. Med Anthropol2001b;15(3):329-346. 7. Berman A, Flannery MA. America’s botanico-medical movements: vox populi. Oxford, Ms: PharmaceuticalProducts Press, 2001:157-159. 8. Bloomfield RJ. Naturopathy in traditional medicine and health care coverage. Bannerman RH, Burton J, Wen-Chieh C, eds. Geneva: World Health Organization, 1983. 9. Brinker F. The role of botanical medicine in 100 years of American naturopathy. HerbalGram 1998;42:49-59. 10. Bureau of Economic and Business Research. Survey of naturopathic schools. Salt Lake City: University of Utah, 1958:3. 11. Cody G. History of naturopathic medicine. In Pizzorno J, Murray M, eds. Textbook of natural medicine, ed 4. Orlando FL, Churchill Livingstone, 19991740. 12. Cohen W. Naturopathy. In Independent practitioners under Medicare: a report to Congress. Washington, Dc:US Department of Health, Education, and Welfare, 1968;61:126-145. 13. Engel J. Doctors and reformers. Columbia: University of South Carolina Press, 2001:63. 14. Farrell JB. Naturopathic legislation and education. Rhode Island Med J 1945;28248-263. 15. Fishbein M. The medical follies. New York Boni & Liveright, 1925. 16. Fishbein M. Quacks and quackeries of the healing cults. Girard, Ks: Haldeman-Julius Publications, 1927. 17.Fishbein M. The new medical follies. New York: Boni & Liveright, 1928. 18.Fishbein M. Fads and quackery in healing. New York Covici, FriedePublishers, 1932. 19. Flannery MA. John Uri Lloyd: the great American eclectic. Carbondale: Southern Illinois University Press, 1998. 20. Gort EH, Cobum D. Naturopathy in Canada: changing relationships to medicine, chiropractic and the state, social science and medicine. 1988;261061-1072. 21. Haller JS Jr. Medical Protestants: the eclectics in American medicine, 1825-1939.Carbondale: Southern Illinois University Press, 1994. 22. Haller JS Jr. Kindly medicine: physio-medicalism in America, 1836-1911. Kent, O H Kent State University Press, 1997. 23. Haller JS Jr.A profile in alternative medicine: the Eclectic Medical College of Cincinnati, 1845-1942. Kent, O H Kent State University Press, 1999. 24. Homola S. Bonesetting, chiropractic and cultism. Panama City, FL: Critique Books, 1963:75. 25. International Society of Naturopathic Physicians Yearbook. Los Angeles: lSNP, 1948. 26. Kaufmann M. Homeopathy in America. In Gevitz N, ed. Other healers: unorthodox medicine in America. Baltimore: Johns Hopkins University Press, 1988. 27. Kirchfeld F, Boyle W. Nature doctors: pioneers in naturopathic medicine. Buckeye, O H Buckeye Naturopathic Press, 1994. 28. Maretzki TW,Seidler E. Biomedicine and naturopathic healing in West Germany: a historical and ethnomedical view of a stormy relationship. Cult Med Soc 1985;9:383-421.

29. Maretzki TW. The “Kur” in West Germany, Soc Sci Med 1987;2412. 30. Mills D. Study of chiropractors, osteopaths and naturopaths in Canada. Ottawa, Canada: Royal Commission on Health Services, 1966:2,212-215. 31. P i i o m o JF’Jr., Bastyr J. The father of modem naturopathic medicine. Integr Med 2004;3:28-29. 32. Reed L. The healing cults. Committee on the Costs of Medical Care 19324148,61-62,66-69. 33. Rogers N. An alternative path: the making and remaking of Hahnemann Medical College and Hospital of Philadelphia. New Brunswick, NJ: Rutgers University Press, 1998. 34. Rosengren WR. Sociology of medicine: diversity, conflict and change. New York Harper & Row, 1980. 35. Roth J. Health purifiers and their enemies: a study of the natural health movement in the United States. New York Prodist, 1976. 36. Twaddle AC, Hessler RM. A sociology of health. New York Macmillan, 1977. 37. Twaddle AC, Hessler RM. A sociology of health, rev ed. New York: Macmillan, 1987. 38. Utah Legislative Council Staff. A study of the healing arts with particular emphasis upon naturopathy (a report to the legislature, 1958). 39. Vollmer HM, Mills DL, eds. Professionalization. Upper Saddle River, NJ: Prentice-Hall, 1966. 40. Wardwell WI. Social strain and social adjustment in the marginal role of the chiropractor (PhD dissertation). Boston: Harvard University, 1951:137. 41. Wardwell WI. A marginal professional role: the chiropractor. Social Forces. 1952;30339-348. 42. Wardwell WI. The reduction of strain in a marginal social role. Am J Sociol1955;61:16-25. 43. Wardwell WI. Comparative factors in the survival of chiropractic: a comparative view. Sociol Symp 1978;22:6-17. 44.Wardwell WI. Limited and marginal practitioners. In Freeman H, Levine S, Reeder LG. Handbook of medical sociology, ed 3. Upper Saddle River, NJ: Prentice-Hall1979:242. 45. Wardwell WI. The present and future role of the chiropractor. In Haldemann S, ed. Modern developments in chiropractic. New York Appleton, 19802541. 46. Wardwell WI. Chiropractors: challengers of medical domination. In Roth J, ed. Research in the sociology of health care. Greenwich, CT: JAI Press, 1982207-250. 47. Wardwell WI. Chiropractors. In Gevitz N, ed. Other healers: unorthodox medicine in America. Baltimore: Johns Hopkins University Pkss, 1988. 48. Wardwell WI. Chiropractic;history and evolution of a new practice. St Louis: Mosby, 19923,131-136,164-168. 49. Whorton JC. Drugless healing in the 1920s: the therapeutic cult of sanipractic. Pharm Hist 1985;28:14-25. 50. Whorton JC. Inner hygiene: constipation and the pursuit of health in modem society. Oxford, England Oxford University Press, 2000:157. 51. Whorton JC. Nature cures: the history of alternative medicine in America. Oxford, England: Oxford University Press, 2001:139,184, 203-204,234-235,288-292. 52. Wiese G, Ferguson A. How many chiropractic schools? An analysis of institutions that offered the D.C. degree. Chiropract Hist 1988;8(1):27-36. 53. Wardwell WI. Orthodox and unorthodox practitioners: changing relationships and the future status of chiropractors. In Wallis R, Morley P, eds. Marginal medicine. London: Peter Cohen, 1976. 54.Baer HA. Divergence and convergence in two systems of manual medicine: osteopathy and chiropractic in the United States. Med Anthropol Q 1989;1:176-193.

Philosophy of Naturopathic Medicine Randall S. Bradley, ND CHAPTER CONTENTS Introduction 79 Medical Philosophy 79 Vitalism versus Mechanism 80 Meaning of Disease 82 Changing Society 83 Scientific Medicine 84

Natural Medicines and Therapies 85 Family and Specialty Practice 86 The Philosophical Continuum Conclusion

86

87

Naturopathic Philosophy 84 Vis Medicatrix Naturae 85

INTRODUCTION This chapter examines the philosophical foundation of naturopathic medicine and its modem applications. Unlike most other health care systems, naturopathy is not identified by any particular therapy or modalities. In fact, a wide variety of therapeutic styles and modalities is found within the naturopathic community (Box 6-1). For example, there are still practitioners who adhere to the strict “nature cure” tradition and focus only on diet, ”detoxification,” lifestyle modification, and hydrotherapy. There are also those who specialize in homeopathy, acupuncture, or natural childbirth. At the other end of the spectrum are naturopathic physicians who use natural medicinal substances extensively to manipulate the body’s biochemistry and physiology. Finally, there is the majority, who practice an eclectic naturopathic practice that includes a little of everything. From its inception more than 100 years ago, naturopathic medicine has been an eclectic system of health care. This characteristic has allowed it to adopt many of this century’s more effective elements of natural and alternative medicine as well as to adopt conventional medicine’s basic and clinical sciences and diagnostics (see Chapter 4 for further discussion).Through all of this eclecticism, naturopathic medicine has always identified the Latin expression vis medicatrix naturae (the healing power of nature) as its philosophical linchpin. However, the expression vis medicatrix naturae, by itself, does not provide a clear picture of naturopathic medical philosophy or an understanding of the practice

of naturopathic medicine in all of its varied forms. With the profession’s history of eclecticism, no two practitioners treat any individual patient exactly alike. This situation has its advantages (e.g., individualization of each patient’s care, more therapeutic options) but also makes it difficult to perceive the profession’s philosophic cohesiveness. Another major disadvantage of this eclecticism is the difficulty in developing consistent practice staiidards. To attempt to solve this problem, the modem profession has articulated a general statement of naturopathic principles that expand on vis rnedicatrix naturae (Box 6-2). However, this statement of principles is probably still not adequate to address the issues that concern modern students of naturopathic medicine or other professionals. Therefore, in order to gain a more in-depth understanding of naturopathic medicine, one must discuss medical philosophy in general.

MEDICAL PHILOSOPHY The issues fundamental to medical philosophy have changed little since naturopathy first appeared as a distinct profession at the end of the 19th century. What has changed is the level of understanding of the biologic process and the language of science. Most people who study the early writers on naturopathic medical philosophy quickly get lost in the archaic language and arguments used to justify the theories. This chapter translates these concepts and issues into modem terms. 79

Naturopathic physicians are trained to use a number of diagnostic and treatment techniques. These modalities include the following: Diagnosis. All of the conventional clinical laboratory, physical diagnosis, and imaging (e.g., radiography) techniques, as well as holistic evaluation techniques Counseling. Lifestyle, nutritional and psychological Naroral medicines. Nutritional supplements (i.e., all food constituents, constituents of biochemical pathways, etc.), botanical medicine, and homeopathy Physical medicine. Hydrotherapy, naturopathic manipulative therapy, physiotherapy modalities, exercise therapy, and acupuncture Family practice. Natural childbirth, minor surgery, natural hormones, biologicals, and natural antibiotics

The Healing Power of Nature: V/s Medlcatrix Naturae

Nature acts powerfully through healing mechanisms in the body and mind to maintain and restore health. Naturopathic physicians work to restore and support these inherent healing systems when they have broken down by using methods, medicines, and techniques that are in harmony with natural processes. First Do No Harm: Primum Non Nocem

Naturopathic physicians prefer noninvasive treatments that minimize the risks of harmful side effects. They are trained to know which patients they can treat safely and which ones they must refer to other health care practitioners. Find the Cause: Toile Causam

Vitalism versus Mechanism Historically, there have been two main medical philosophies, those of vitalism and mechanism. Their origins can be traced to the Hippocratic writings of ancient Greece. Throughout history, the line separating these two schools of thought has not always been clear, but their philosophical perspectives have generally been in opposition. The conflicting goals and philosophical foundations of these two concepts remain relevant as the modem practices of conventional and altema tive physicians come into conflict. As will be seen, the foundations of naturopathic medical philosophy are found in vitalism. However, naturopathy also recognizes the practical value of the mechanistic approach to health care.

Mechanism Up to the early part of the twentieth century, there was considerable debate over the issue of vitalism v&us mechanism in the field of biology. The mechanists, or materialists, maintained that the phenomenon of life could be explained exclusively as the product of a complex series of chemical and physical reactions. They denied the possibility that the animate had any special quality that distinguished it from the inanimate. It was their contention that the only difference between life and non-life is the degree of complexity of the system. Mechanism has several other distinctive characteristics. Its most obvious is that it is reductionistic. In fact, reductionism is often used as a synonym for mechanism. Mechanistic science is also characterized by an emphasis on linear causality. Without this emphasis on reductionism and linear causality, Western science and medicine would probably have not been so successful. As the twentieth century advanced, each new discovery in biologic and medical science reinforced the arguments for mechanism, until by the middle of the century, the biology community had almost exclusively embraced the philosophy of mechanism.

Every illness has an underlying cause, often in aspects of the lifestyle, diet, or habits of the individual.A naturopathic physician is trained to find and remove the underlying cause of a disease.

Doctor as Teacher: Docere A principal objective of naturopathic medicine is to educate the patient and emphasize self-responsibilityfor health. Naturopathic physicians also recognize and employ the therapeutic potential of the doctor-patient relationship. Treat the Whole Person

Health or disease comes from a complex interaction of physical, emotional, dietary, genetic, environmental, lifestyle, and other factors. Naturopathic physicians treat the whole person, taking all of these factors into account. Preventive Medicine

The naturopathic approach to health care can prevent minor illnesses from developing into more serious or chronic degenerative diseases. Patients are taught the principles with which to live a healthy life; by following these principles they can prevent major illnesses.

Mechanism is the philosophical foundation of biomedical science and conventional medicine. Mechanistic medicine identifies disease and its accompanying signs and symptoms as simply the result of a disruption of normal chemical reactions and physical activities. Such disruptions are caused by the direct interference in these reactions and activities of a “pathogenic agent.” (For the purposes of this discussion, the general expression pathogenic agent refers to any known or unknown etiologic agent or condition; examples are microbial agents, autotoxins, genetic defects, environmental toxins, non-endproduct metabolites, and physical and emotional stress and trauma.) A living organism, then, is simply a very complex machine that, owing to external agents and ”wear and tear,” breaks down. Because the signs and symptoms of disease are thought to be due only to these mechanical disruptions and interference with reactions,

Philosophy of Naturopathic Medicine

they are considered to be completely destructive phenomena and are therefore to be eliminated. Disappearance of the signs and symptoms indicates that the pathogenic agent and its resulting disease have been eradicated, or at least controlled. The goals of mechanistic medicine tend to be the quick removal of the signs, symptoms, and pathogenic agent. Mechanistic medicine is being practiced in cases in which the intention of the therapy is to intervene in the perceived mechanism of the disease and/or to relieve the symptoms. Examples would be the use of antihistamines to relieve rhinitis, vitamin B6 to help premenstrual syndrome, surgery and emergency care for traumatic injuries, coronary bypass surgery, antiinflammatory agents in systemic lupus erythematosus (SLE), and insulin in juvenileonset diabetes. Mechanism is also being used when an identified pathogenic agent is directly attacked or eliminated, for example, the use of antibiotics or the isolation of a patient from a particular allergen. Clearly, mechanistic medicine can be very effective in achieving its goals. In the presence of modem medical technology, it is easy to see how this philosophy came to dominate biology, medicine, and the attention of the public. However, the unsolved problems of mechanistic medicine-particularly those of chronic degenerative disease; authoritarianism, which alienates patients from responsibility for their own health, and the rising cost of health care-suggest that there are limits to the mechanistic perspective and explain why vitalism has not disappeared and is, in fact, in resurgence.

Vitalism The philosophy of vitalism is based on the concept that life is too well organized to be explained simply as a complex assemblage of chemical and physical reactions (i.e., a living system is more than just the sum of its parts). This is in contrast to the mechanist’s contention that ”the only difference between life and non-life is the degree of complexity.’’ Throughout the nineteenth century, the debate between vitalism and mechanism was carried on mostly by biologists, whose interests were mainly in the study of the organism’s specific cellular activities, such as morphologic development. These activities were argued to be “vital” and, therefore, not explainable by mechanistic science. The tendency was to infer a metaphysical quality to this concept. As can be imagined, these earlier debates lurched from one specific argument to the next as modem biology unraveled the secrets of cellular metabolism. Fortunately, the debate has now shifted back to the relevant and holistic general concepts. Although modem vitalism is inherently holistic in its view and has an emphasis on circularity as its causality (i.e., feedback loops), there is no conflict with the findings of biomedical science. Eventually, all of the individual

chemical and physical reactions that are found in the processes of life will probably be identified. What is significant is not the individual reaction, but the fact that they are all coordinated to such a degree as to produce the special activities of a living organism. An organism’s unique complexity-as demonstrated by its ability to grow and develop, respond to stimuli, reproduce, and repair itself-requires a level of organization and coordination that suggests a distinct quality that is not readily explained by mechanism. This organization and coordination have been identified as ”homeostasis” by physiology. All organisms, up to the point of death, are attempting to return to this ideal state whenever injured or ill. Because there is no inanimate counterpart to this level of complexity and organization, ”homeostasis” is the most dramatic general argument in favor of vitalism. A less dramatic argument used to support the vitalistic perspective is the ”problem of entropy.” Entropy is the tendency of any closed system to find equilibrium, that is, the state of least organization. In other words, systems tend to run down and become less complex over time. In defiance of this universal rule, life, up until the point of death, consistently creates more complex systems out of simple ones. To do this, life actively pursues external matter and energy to incorporate into itself while also selectively eliminating by-products from its utilization of this matter and energy. When the problem of entropy is examined on the molecular level, the same individual chemical processes and elements may be found in both animate and inanimate systems. In the inanimate system, however, there is a constant move toward a state of chemical equilibrium. This type of system cannot maintain an unstable chemical state and always seeks stabilization. Even after the addition of external exciting energy, the system returns to the simplest, least reactive state possible. The animate system is virtually the opposite. It is continuously in a state of dynamic chemical instability, actively seeking energy to maintain this instability and consistently moving to more complex and more organized states (and back again). It is only at the onset of death that an animate system begins to move toward equilibrium. The third general argument in favor of a vitalistic view of life is evolution. For evolution to exist as a force in nature, generations of living organisms have to survive long enough to grow, reproduce and then evolve. In order for this survival to take place, the organisms’ homeostatic and repair processes must be consistently directed toward maintaining a state of balance with the external environment (i.e., health). Any organisms that did not behave biochemically and physiologically in this manner would have died and would not have evolved. Thus the phenomenon of evolution, as the action of countless living organisms over eons, multiplies life’s

Philosophy of Natural Medicine antientropic quality and is incompatible with a mechanistic view of living systems. These easily observable examples of life’s ”special quality” suggest an “organizing force” that goes beyond what is possible from mere chemistry. This quality that makes life unique should not be mistaken as a metaphysical concept, although an argument for or against such concepts is not intended here. The point is only that vitalism is a medical philosophy based on observable scientific phenomena. Unfortunately, a definitive definition of this quality (in the old literature called the “vital force,” defense mechanism, or simply “Nature”) will have to wait for more research. At this point in the discussion, not many mechanistic practitioners would have reason to be uncomfortable, because the ideas proposed are relatively noncontroversial and just follow generally accepted physiologic principles. Interestingly, many of these practitioners probably have personal belief systems that are quite compatible with this stage of the vitalistic argument. However, the conflict becomes evident with examination of the premises upon which the practice of vitalistic medicine is based. What truly separates vitalism from mechanism, and makes it useful as a medical philosophy, is its perspective on disease and the associated symptoms.

Meaning of Disease Vitalism maintains that the pathogenic agent does not directly cause the symptoms accompanying disease; rather, they are the result of the organism’s intrinsic response or reaction to the agent and the organism’s attempt to defend and heal itself. Symptoms, then, are part of a constructive phenomenon that is the best “choice” the organism can make, given the circumstances at any particular time. These symptoms can be further described as arising from two situations. The first and most common situation is when they are from a ”healing reaction,” which is the organism’s concerted and organized attempt to defend and heal itself. These healing reactions produce what can be called “benign symptoms.” Examples are fever and inflammation in infections, almost any reaction of the immune system, and many of the symptoms of chronic disease. This interpretation of symptoms is generally ignored by mechanism. Instead, it views a symptom as the result of a destructive process and focuses on intervening by relieving the symptom or manipulating the pathologic mechanism. Mechanistic medicine is therefore most often working contrary to homeostasis and the organism’s attempt at healing (in fact, this is usually its intent). When this therapeutic approach is effective, vitalists call the result a ”suppression” (Box 6-3). This approach to health care is so pervasive that most people, lay and

When symptoms improve following treatment (regardless of the therapeutic system), it is for one of three reasons: Cure. The symptoms go away and the patient’s overall health improves. In this case the treatment can be discontinued and the patient continues to do well. Suppression. The symptoms go away but overall the patient becomes less healthy. The treatment can be discontinued and the symptoms will stay away, but either the patient feels worse generally (i.e., deceased sense of well-being, less energy, or experiencing moods) or new, often more limiting, symptoms eventually develop (e.g., suppressed eczema leading to asthma). Palliation.The symptoms are improved but only as long as the treatment is continued. At best, palliation is something that is given while a curative treatment is given time to work. In and of itself, palliation will never lead to a cure, but unfortunately, continued palliation may eventually lead to suppression.

The four types of healing reactions Reaction

Description

Acute, asymptomatic

Organism easily defends itself Relative strengths of pathogenic agent and organism similar; symptoms of body defending itself apparent

“Healing crisis”

Vigorous but unsuccessful Chronic, mildly symptomatic

Pathogenic agent stronger than organism; death if no intervention Healing reaction feeble but adequate to maintain life; progressive degeneration

professional alike, today routinely suppress mild fevers with antipyretics. In contrast, vitalism considers these symptoms to be the product of a constructive phenomenon and therapeutically stimulates and encourages this directed healing process. Rather than simply trying to eliminate a pathogenic agent, as mechanistic therapy might, vitalism focuses more on augmenting the organism’s resistance to that agent. That is not to say that vitalists object to removing the agent, only that it should be done in the context of simultaneouslyincreasing resistance (in other words, decreasing susceptibility).The importance of this approach becomes evident when one recognizes that disease is only possible when both a pathogenic agent and a susceptibility to that agent are present. Healing reactions can take several forms, as shown in Table 6-1. In the first type, an organism’s response to a pathogenic agent does not produce symptoms. When the organism is capable of easily defending itself from the agent, no symptoms are perceivable. This is a common homeostatic process and is demonstrated when a potential pathogen, such as beta-hemolytic streptococcus, is

Philosophy of Naturopathic Medicine

cultured from a healthy person’s throat. However, when the organism is more susceptible or the relative strength of the pathogenic agent is greater, a threshold is reached and symptoms become perceivable. Successful healing reactions of this type include vigorous acute diseases that quickly resolve. The early naturopaths would have called these acute reactions “healing crises.” As the susceptibility of the organism increases relative to the strength of the pathogenic agent, there is a greater likelihood that the healing attempt will not be successful. When such a reaction is unsuccessful but vigorous, death may result, unless there is timely application of vitalistic or mechanistic therapy. Examples of this situation are acute bacterial meningitis and cholera. When the healing attempt is feeble and therefore ineffective, the reaction usually goes into the “chronic disease” stage. Vitalists observe that suppression seems to increase the likelihood that the reaction will be forced to go into such a chronic stage. In this situation the reaction is “smoldering,” and most often the organism cannot overcome the pathogenic agent unassisted. It just “holds its own,” and if the organism’s general health decreases over the years, the reaction gradually degenerates, producing symptoms that become less benign as it moves to an end-stage pathology. If the organism can be therapeutically stimulated to produce a more vigorous healing reaction, it can often successfully complete the original healing attempt. This augmented reaction is another example of a naturopathic healing crisis and would also be called an “aggravation” by the vitalists who practice homeopathic medicine. Intervening in the mechanism of disease by relieving symptoms does little to stimulate or encourage the healing response; in fact it usually actually inhibits the healing response. In contrast, vitalistic therapies can be very effective in helping these healing reactions, because the goals of such therapies are precisely the same as those of the organism. Thus, it is thought that vitalistic medicine works because, by honoring this process and thereby strengthening the whole organism, it encourages a more effective healing effort. Ideally, the organism is then able to accelerate and complete its reaction against the pathogenic agent, leading to the permanent disappearance of the symptoms as it returns to a state of health. It would be naive to say that every stage of the healing reaction is positive and in the best interest of the organism or that no symptoms should be palliated. The modern vitalist acknowledges that intervention is sometimes necessary. On the other hand, it is important to note that routine intervention can encourage its own worstcase scenarios. When mechanistic therapies successfully suppress an organism’s chosen healing reaction, a less effectiveand less desirable response is often produced. Therefore, when suppression occurs, it can lead to a more complicated medical situation. Consequently, the

very practice of mechanistic medicine tends to reinforce its practitioner’s conviction that intervention is usually necessary. It should be noted, however, that not all intervention leads to suppression. It happens less often when the pathogenic agent can be readily eliminated, such as in nonrecurring acute bacterial infections, or when relatively noninvasive therapies are used, such as natural medicines. The second type of symptom-producing situation occurs when the organism produces symptoms in response to an organic lesion that arises from the direct pathologic influence of a pathogenic agent. These can be called ”morbid symptoms,” examples of which are symptoms from the mass of an invasive tumor, shortness of breath from emphysema, and pain of an injury or myocardial infarction. It should be mentioned that even these symptoms are the result of the organism’s overall effort to maintain homeostasis; benign symptoms are also often present. In addition, a morbid symptom is not necessarily produced for a negative reason. For instance, pain is valuable as an indication of tissue damage. As can be seen, many, if not most, of these situations involve ”end-stage” disease. Here mechanistic therapies can be very positive when the goals of the therapy do not conflict with those of the organism. There are instances when invasive intervention will probably be required to save “life and limb.” These include such conditions as birth and genetic defects, serious traumatic injuries, crisis situations, overwhelming infections, and many malignancies. Unfortunately, conventional intervention does not guarantee a successful outcome either. Even in these situations, however, the effectiveness of vitalistic and natural therapy should not be underestimated, and their concurrent use will certainly augment any mechanistic intervention. The concept of benign and morbid symptoms can be a useful tool to help the understanding of the healing and disease process, but in many situations, it may not be possible to categorize the type of symptoms produced. A rough rule of thumb, however, would be that virtually all symptoms accompanying “reversible” or functional diseases are benign. On the other hand, many of the symptoms associated with traumatic injury and end-stage pathology would be morbid symptoms.

Changing Society After this discussion of vitalism’s perspective on disease, the question that comes to mind is “If most health problems are likely to respond to vitalistic medicine, then why is mechanism dominant?” The best answer is probably found in examination of the general attitudes held by society during the Industrial Age just ending. Mechanism came into dominance during this period because it fit neatly into the Industrial Age‘s worldview. This is the ”man conquers nature” view that regards

Philosophy of Natural Medicine

humanity as above and separate from the world in which it lives. It follows that nature is simply a resource that technology will eventually subdue or subjugate and put into order. Although this perspective is still very strong in Western society, there has been a dramatic change within the last 40 years. Attitudes are now shifting in favor of the ecologic integration of humanity into the environment. This "new" worldview holds that humanity is part of an orderly nature and that to ignore this fact creates situations that eventually become problems. Most ecologic disasters are excellent examples of the results of the old view. In addition, the new view contends that if an effort is made to understand how nature functions and an attempt is made to work within that understanding, humanity's needs can be more efficiently met. Mechanistic medicine, as part of the "old" worldview, generally sees disease as something to conquer and put into order. Vitalistic medicine, on the other hand, looks at the order that is already present and attempts to integrate its therapy into that orderly process. As a result, vitalism is becoming increasingly popular as society shifts from the old to the new worldview. The belief systems of many mechanistic practitioners recognize this order. However, because of education and peer pressure, these personal beliefs are rarely translated into clinical practice. The mechanistic view is still relatively pervasive in society, and because mechanism is convenient (e.g., taking aspirin for a headache), vitalistic practitioners can generally shift their perspective and successfully use mechanistic therapy (although their therapeutic goals may be different). On the other hand, because mechanists dispute the premises upon which vitalistic medicine is based, they generally have great difficulty when attempting to practice or research a vitalistic therapy and frequently cannot demonstrate its efficacy.

Scientific Medicine Although mechanism and vitalism represent opposing perspectives, the systems of medicine that represent these philosophies can be successfully tested and examined with the scientific method.+ That is not to say that the philosophy of vitalism has been unquestionably proven-only that the validity of vitalistic interventions can be scientifically demonstrated. If a therapy can be proven effective, the effectiveness implies the accuracy 'A thorough review of all health care modalities in use today reveals a category that could be called 'esotericia." Although the category is not historically relevant to this discussion of medical philosophy, and its brief mention is not intended as an argument for or against "legitimacy," esotericia would include such things as prayer, faith healing, psychic healing, Healing Touch, Touch for Health, and medical dowsing. Generally speaking, the actual operator of the therapy must call on God or have some special endogenous skill or 'power" that goes beyond intellectual knowledge. These modalities are all 'operatordependent" and cannot be examined separate from the practitioner-thus greatly increasing the dmuity of their scientific verification.

of the philosophy upon which it is based. Unfortunately, very few of the vast resources of the twentieth century biomedical community have been directed toward investigating vitalistic medicine. Conventional medicine, as the dominant health care system and a representative of mechanism, has claimed for itself the title "scientific medicine." However, it is inherently no more or less scientific than vitalistic medicine. A system is scientific only when it has met the criteria of the scientific method. This method requires the collection of data through observation and experimentation, and the formulation and testing of hypotheses. Nonprejudicial science can effectively study any system, but the researcher must understand the system's particular paradigm. Experiments on a vitalistic therapy based on a reductionistic and mechanistic model would be less than satisfactory. The criteria of the scientific method can be met by vitalistic medicine, but only when the researchers recognize that it cannot be studied as though it is reductionistic or based on a simplistic model of linear causality. When the experimental model acknowledges the complexity of a living system in a social context (i.e., holism and circularity), vitalistic medicine proves to be both verifiable and reproducible and, thus, scientific. Unfortunately, because of its current political and economic dominance, conventional medicine is in the position to dictate (through economic and publication control) that research, and therefore the scientific method, will be applied primarily to itself. The result is that most conventional practitioners dismiss vitalistic medicine, along with all alternatives, as unscientific. This is unfortunate because most vitalistic physicians also have extensive training in mechanistic and/or conventional medicine. Generally, they are capable of practicing mechanistically, and do so to greater or lesser degrees. The conflict between the practitioners of these different systems is very often due to a lack of constructive dialogue. This can be attributed to two general causes: The first is simply that each system defines the world of "correct" medicine in terms of its own principles; the second is the issue of who controls the economic and political power.

NATUROPATHIC PHILOSOPHY Historically, naturopathy is a vitalistic system of medicine. However, over the last 100 years it has also incorporated a number of therapies that can function mechanistically. What makes them acceptable, given naturopathic medicine's vitalistic foundation, is that they are natural therapies. Natural medicines and therapies, when properly used, generally have low invasiveness, and there is little evidence that they cause suppression or side effects. When used mechanistically, they entail

some intervention while still allowing the organism’s healing abilities the opportunity to continue unopposed, especially when they are used to support the body’s own healing processes.

Vis Medicatrix Naturae Naturopathic physicians assert that all true healing is a result of vis medicatrix nafurae (the healing power of nature). Unfortunately, some people in the field of alternative medicine (including some naturopathic physicians and students)have mistakenly translocated this concept to the therapy. These practitioners tend to operate as though this ”healing power” is an intrinsic property of the natural therapy or medicinal substance itself. In contrast, proponents of vitalism and naturopathic medicine have always understood that the “healing power of nature” is an inherent property of the living organism. Vis medicafrix nafurae is the living organism’s ”desire” and ability to heal itself. The application of this principle in practice depends, of course, on the patient’s needs. Ideally, it involves only the use of therapies that support the organism and encourage its intrinsic healing process to work more effectively.It also avoids the use of medicines and procedures that interferewith natural functions or have harmful side effects. Natural medicines and therapies are therefore preferred, because when they are used properly and in appropriate circumstances, they are the least harmful, least invasive, and best able to work in harmony with the natural healing process. The total organism is involved in the healing attempt, so the most effective approach to diagnosis and treatment is to consider the whole person. In addition to physical and laboratory findings, important consideration is given to the patient’s attitude, psychological and spiritual state, social circumstances,lifestyle, diet, heredity, and environment. Careful attention to each person’s unique individuality and susceptibility to disease is critical to the proper evaluation and treatment of any health problem. Naturopathic physicians contend that most disease is the direct result of the ignorance and violation of what would be traditionally called “natural living laws.” These general lifestyle rules (includingdiet) are based on the concept that there is an environment (both internal and external) that optimizes the health of an organism. Analysis of the lifestyles of Paleolithic and healthy primitive and modern cultures gave naturopathic physicians and their progenitors many clues as to what a healthy lifestyle should involve. Throughout most of modern history, biomedical science has focused primarily on researching the sick. Recently it has finally begun to evaluate what makes for a healthy lifestyle. To no one’s surprise, this lifestyle looks like the same one advocated by naturopaths for

the last 100 years. A healthy lifestyle could be generalized to include the following: Consuming natural unrefined foods Getting adequate amounts of exercise and rest Living a moderately paced lifestyle Having constructive and creative attitudes Connecting to other people socially Being present to the spiritual aspects of life Avoiding toxins and polluted environments Maintaining proper elimination It is also important to control these areas during illness, in order to remove as many unnecessary stresses as possible and to optimize the chances that the organism’s healing attempt will be successful. Therefore patient education and responsibility, lifestyle modification, and preventive medicine are fundamentalto naturopathic practice. Although the practice of naturopathic medicine is grounded in vis medicatrix naturae, it also recognizes that intervention in the disease process is sometimes efficacious and, at times, absolutely necessary. Naturopathic physicians treat patients with a wide variety of therapeutic modalities. Some of these are vitalistic and some mechanistic. It is the goal of the therapy that ultimately determines which approach is utilized. Naturopathic physicians have a long-standing tradition of integrating the best aspects of traditional, alternative, and conventional medicine in the interest of the patient. As appropriate, patients are referred to other health care practitioners. Whenever possible, every effort is made to use all treatment techniques in a manner that is harmonious with the naturopathic philosophy.

Natural Medicines and Therapies The medicines administered and prescribed by naturopathic physicians are primarily natural and relatively unprocessed. Although it is recognized that some situations may require the use of synthesized medicines, their use is considered less desirable. Some of the argumentsin favor of natural medicinal substances have already been discussed. In addition to the reasons noted previously, natural agents are preferred because their constituents have been encountered in nature for millions of years. This long period of exposure has enabled the body to develop metabolic pathways capable of effectivelyutilizing, processing, and detoxifying these medicines. Four categories of natural medicines can be defined. The first consists of substancesfound in nature that have been only minimally processed. Examples include, but are not limited to, foods, clean air and water, and whole herbs. The early ”nature cure” practitioners used this category primarily. The second category involves agents extracted or made from naturally occurring products. Although these medicines have undergone pharmacologic processing, their constituents are still in the form

Philosophy of Natural Medicine

found in the original natural substance. These first two types of natural medicinal substances have synergistic constituents that allow their use at lower doses with a resultant broader and safer therapeutic index. Examples of this category are tinctures and other botanical extracts, homeopathic medicines, glandular extracts, and other substances of animal origin. The third category of natural medicines comprises those highly processed medicinal substances that are derived from a natural source. Often everything has been removed from such substances but the identified active in@ent, and they no longer have any synergistic constituents. Examples are many new phytotherapeutic agents, constituents of biochemical pathways, enzymes, amino acids, minerals, vitamins, and other food extracts. The fourth category that may be considered "natural" are those manufactured medicines that are presumed to be identical to naturally occurring substances.They have the advantage of being less expensive and are typically available in higher concentrations. However, their use is less desirable for the following reasons: The difficulty of determining whether they are indeed the equivalent of the natural product. Their lack of natural synergistic components. The inclusion of contaminates from the manufacturing process; these contaminates are often chemically and structurally similar to the desired medicine but generally interfere with the normal pathways rather than enhance them. Examples of these manufactured "natural" medicines include hormones, synthetic vitamins, and analogues of plant and animal constituents. Increasingly, medicines of the types identified in the third and fourth categories are being grown "synthetically" by microorganisms specially engineered to produce the desired medicinal substance.It is difficult to say which of these categories best describes this situation. There are also potential problems with this kind of manufacturing process, as evidenced by the tryptophan disaster of 1989. Naturopathic physicians also use many natural therapies. What makes a therapy "natural" is that it is derived from a phenomenon of nature and is used to stimulate the body to heal itself. Examples of these phenomena are air, light, heat, electricity, sound, and mechanical force. Some of these natural therapies are mechanical and manual manipulation of the bony and soft tissues (naturopathic manipulative therapy), physiotherapy modalities (e.g., electrotherapy and ultrasound), hydrotherapy, and exercise therapy. Naturopathic physicians also use lifestyle modification, counseling, and suggestive therapeutics. These therapies are all discussed in more detail in other chapters.

Family and Specialty Practice Naturopathic physicians, like other types of primary care providers, develop practices that meet their personal interests and skills. Although most are engaged in general and family practice, many have also specialized in particular therapeutic modalities and/or types of health problems. In all situations, however, the emphasis is still on treating the whole person. The practice of family medicine requires the use of some techniques and devices that are not, in the strict sense of the word, natural therapies but belong among the comprehensive family practice services offered by the naturopathic profession. Included in family practice are such services as the prescription and fitting of birth control devices, first aid, and minor surgery. Minor surgery includes the repair of minor wounds and lesions and the removal of growths and foreign bodies from superficialtissues. When necessary, it involves the use of local anesthetics and appropriate first aid procedures. First aid comprises the treatment of ambulatory acute injuries and conditions that are routinely seen and handled in general practice. Many naturopaths have also developed advanced expertise in different natural therapeutic modalities. These practitioners have usually invested in postgraduate training, such as that available through residencies. Three therapeutic specialties that merit mention are natural childbirth, acupuncture, and homeopathy.

THE PHILOSOPHICAL CONTINUUM When the various healing systems are examined and placed on a philosophical continuum, mechanism and vitalism are on different ends of the same health care spectrum. Both ends of this health care continuum have their strengths and weaknesses. Mechanistic medicine is effective for trauma, crisis care, end-stage disease, and many acute disorders. It is essentially a failure for chronic disease. In fact, conventional medicine considers most chronic diseases incurable. Vitalistic medicine, on the other hand, has its most dramatic successes with chronic disease and is effective with many kinds of acute disease. It is not very effective with trauma and crisis care or with end-stage disease, although it can be a very useful complement to conventional medicine. As can be seen, both ends of the health care spectrum are necessary if every patient's health care needs are to be met: Although aspects of naturopathic medicine (e.g., constitutional hydrotherapy) and conventional medicine (e.g., chemotherapy)represent the archetypes of vitalism and mechanism, the space between the ends of this spectrum is a gray area within which both naturopathic and conventional physicians operate on a continual basis. Naturopathic physicians integrate vitalistic therapies

Philosophy of Naturopathic Medicine

With a thorough grounding in vis medicatrix naturae, modern naturopathic medicine will flourish and achieve a leadership position as the dominant health care paradigm shifts to the integrated medicine of the future.

with some mechanistic therapies, but it is not possible for everyone to be experts in everything. The vast majority of naturopathic or conventional physicians cannot learn and competently practice all types of health care. Consequently, to effectively meet society’s health care needs, it is necessary to create an integrated health care system. Such an integrated system would have both vitalistic and mechanistic practitioners working together in the same clinical settings. The trends of popular culture and a biomedical science that is finally beginning to study alternative medicine suggest that the creation of an integrated health care system is now under way. However, it takes no great skill for a mechanistic medical doctor to switch from giving a synthetic drug for a disease to giving a natural medicinal substance. If naturopathic medicine becomes just another mechanistic system using natural medical substances to treat disease (instead of a system identified with treating the whole person vitalistically), it will lose its unique niche in an integrated health care system. To survive and thrive in this new environment, naturopathic medicine must keep its vitalistic roots.

The practice of naturopathic medicine can be summarized most simply as helping the body/mind heal itself in the least invasive, most fundamentally curative manner possible. This approach is not tied to any particular therapy or modality, but rather is oriented to a rational blend of vitalistic and mechanistic principles working with the whole person and educating the patient in the ways of health. As naturopathic knowledge of health and disease grows, new therapies and approaches to health care will be added as they satisfy the principle of vis rnedicatrix naturae. With integration of the larger health care system, naturopathic medicine’s place is assured as the profession that truly understands each unique human being’s power to heal.

Baer HA. The potential rejuvenation of American naturopathy as a consequence of the holistic health movement. Med Anthropol 1992;13:369-383. Coulter HL. Divided legacy. Richmond, CA. North Atlantic Books, 1975 (vol. I), 1977 (vol. 2), 1982 (vol. 3), 1994 (vol. 4). Coulter HL. Homeopathic science and modern medicine. Richmond, CA North Atlantic Books, 1980. Dubos R. Mirage of health utopias, progress, and biological change. New York Harper, 1959, p. 131. Kirchfeld F, Boyle W. Nature doctors: pioneers in naturopathic medicine. Portland, OR: Medicina Biologica, 1994. Lindlahr H. Philosophy of natural therapeutics. Maidstone, Kent, U K Maidstone Osteopathic Clinic, 1975. McKee J. Holistic health and the critique of western medicine. Soc Sci Med 1988;26775-784.

McKeown T. The role of medicine: dream, mirage or nemesis? Oxford: Basil Blackwell, 1979. Payer L. Medicine and culture: varieties of treatment in the United States, England, West Germany, and France. New York: Henry Holt and Company, 1988. Schubert-Soldern R. Mechanism and vitalism: philosophical aspects of biology. Notre Dame, IN: University of Notre Dame Press, 1962. Selys H. The stress of life. New York McGraw-Hill, 1956. Sinnott E. The bridge of life: from matter to spirit. New York Simon and Schuster, 1966. Spitler HR. Basic naturopathy: a textbook. New York American Naturopathic Association, 1948. Zeff JL.The process of healing: a unifying theory of naturopathic medicine. J Nat Med 1997;7122-125.

CONCLUSION

Placebo and the Power to Heal Peter Bennett, ND CHAPTER CONTENTS Introduction 89

The Vis Medicatrix Naturae 95 Conscious Control over Homeostasis 95

Placebo Response 90 Why Study the Placebo Effect? 90 History of Placebo 91

Physiologic Mechanisms 95 Brain Region Activity 96 Placebo and Stress Physiology 96 Physiologic and Psychologic Stress 97 Endorphins, Hormones, and Neuropeptides 97

Origin of theTerm Placebo 91 Clinical Observations of “Known” Placebo Therapy 92 Other Clinical Observations 92 Placebo Myths 93 Myth1 93 Myth2 93 Myth3 94 Myth4 94 Pharmacodynamics 94 Packaging and Delivery 94 Placebo Interactions 94

Clinical Application 98 Prima Non Nocerum: Prioritize a Treatment Program and Establish a Hierarchy of Care Tollem Causum: Remove the Cause of Disease 99 Support the Therapeutic Relationship 99 Enhance Positive Emotional States 100 Implement Therapeutic Conditioning or Learning 102 Use Altered States of Consciousness 104

98

Ethics 105 Conclusion 106

Placebo Healing Mechanisms 94 The Role of Emotions 95

INTRODUCTION As living organisms, we have evolved with an innate capacity for self-healing. This most remarkable fact is one of the most interesting discoveries in medicine. In November 2000’17 health centers and agencies gathered together for 3 days to explore the science of self-healing hidden in the power of placebo. This conference focused on the powerful mind-brain physiology of placebo and its potential for affecting the course of human disease.’ One of the conclusions of the conference was that the “placebo response’’ has potential use for medical application and needs further exploration. Research has shown that the impressions and thoughts in a patient’s mind and the attending physician’s intention have such a profound effect on the

health of the patient. The ability of the patient’s mind to affect the process of virtually every disease has been well documented,23 and the internal mechanisms and pathways by which the mind can positively or negatively affect the immune and healing processes has been investigated in the scientific literature of psychoneuroimmunology.45 As the body of knowledge documenting the critical role of the patient’s psyche in the therapeutic environment has grown, it has become increasingly important for all schools of medicine to teach the healing potential of the human mind. Conventional medical thinking has tumed its opinion of placebo from that of a nineteenth century pejorative to a concept that sums up the complex mind-body interactions affecting the power of people to heal.’ 89

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Unfortunately, the most modern abuse of the concept of placebo comes from biased critics of alternative medicine who have chosen to label the beneficial effects of these therapies as merely from placebo. These critics dismiss the science of natural healing as an imaginary phenomenon and the last resort for quack doctors who had no real medical treatments to offer their patients? The most interesting aspect of placebo literature is exploration of extent of the potential of the mind to influence human health. The “power of placebo” draws upon the innate ability of the body to spontaneously heal itself, a fundamental principle of naturopathic medicine. This point separates the care delivered by naturopathic physicians from the pharmaceutical and surgical approaches of current medical “standard of care” procedures. If common medical texts on internal medicine or ambulatory care are examined, the word ”healing”is not found in the index. Except for the diagnostic evaluation of “self-limitingdiseases’’and “spontaneousregression,” the ability of the human organism to self-right and repair from a state of acute or chronic disease is explored in modem medicine except under the designation “placebo response.” The placebo response therefore, represents all the “unknown” variables that conspire to heal a patient in spite of pharmaceutical and surgical intervention.

PLACEBO RESPONSE Placebo response represents the power of the mind, through intention, to effect (1)a change in oneself, (2) a change in those around one, and (3) a change in the environment one lives in. Intention has been observed to affect machines7and remote biologic systems? Distantly influenced systems include another person’s electrodermal activity, blood pressure, and muscular activity; the spatial orientation of fish; the locomotor activity of small mammals and the rate of hemolysis of human red blood cells. Prayer, an example of intention, has been extensively studied as a therapeutic healing modality? One study showed a dramatic result in cardiac intensive unit recovery when patients were prayed for by someone at a distant location.’O Patients in this study were 5 times less likely to require antibiotics, 3 times less likely to experience pulmonary edema, 12 times less likely to require endotracheal intubation, and significantly less likely to suffer cardiac mortality. Our biologic systems must conform to the laws of physics. Modem physics has investigated the effect of an observer on the system observed. It has been shown that an electron will acquire a definite axis of measurement in the process of measurement. Bell’s theorem supports the idea that our universe consists of particles unified instantly as an indivisible whole; our biologic homeostatic systems cannot be analyzed in terms of independent parts. The interconnected nature of our biologic systems

has been known for thousands of years; the ancient Buddhist concept of “interdependent phenomena” accurately describes this paradigm. Our current medical system has not shifted with the developments in modem physics. These modem ideas of biologic systems are diametrically opposed to Cartesian paradigms that our internal and external environment consists of separate parts joined by local connections. Medicine must take a ”quantum leap” to catch up with the knowledge we possess about our environment through quantum physics. We can see clearly that it is impossible for a doctor to observe a patient without the observation’s affecting the health of the patient. Pierre Teilhard de Chardin postulated, and Rupert Sheldrake proved, the possibility of a ”morphogenetic field” for the subliminal communication to all members of our species.” The effect of human thought on other members of society has been described in human society since the beginning of our earliest cultures. Naturopathic physicians believe that the body has a powerful ability to maintain health and repair to a healthy state after disease by virtue of its inherent power of vitality. This homeostatic healing mechanism has been selected by Nature in the same way that the organs that we consider to be vital to our survival have been selected. Healing happens unaided by simply maintaining an environment that does not obstruct the path of cure. Because placebo literature documents the philosophical foundations of naturopathic health care model, it is important to review the full scope of this subject. Integrating known placebo initiators in clinical practice is essential for good patient care.

WHY STUDY THE PLACEBO EFFECT? For hundreds of years, physicians have watched their patients respond to therapies with a wide range of results. Some patients recover fully, whereas others, with apparently identical diseases and therapies, wither and die. Today, a skilled physician can correctly diagnose the condition of a patient by applying the sophisticated techniques of modern medicine. Then an appropriate therapy, the efficacy of which has been thoroughly proven in research and clinical trials, can be prescribed. Through this process the patient will have received the best care available through current medical technology. But if the diagnosis, therapy, and therapeutic interaction do not stimulate the hope, faith, and belief of the patient, the chances of success are measurably diminished. It has been repeatedly demonstrated in the literature on the placebo effect,’2 psychoneuroimmunology~and psychosomatic,I3beha~iora1,’~J~ and psychiatric16medicine that the beliefs of the both the patient and the doctor, and their trust in each other and the process, generate a sigruficant portion of the therapeutic re~u1ts.l~

Placebo and the Power to Heal

The placebo and its effect are not separate from any aspect of the therapeutic interaction, nor are they ”nuisance variables” muddying a clear clinical picture. Rather, they send the physician a strong message: It is a patient’s own belief system that mobilizes the inherent healing powers of the mind. By studying the placebo effect, a physician is better able to fully harness this power to trigger internal healing mechanisms. Yet, despite the quantity of documentation, the placebo effect remains one of the most misunderstood areas in modern medicine. The physician should always strive to stimulate selfhealing, or the placebo effect, as fully as possible to maximize its potential for healing. Someday physicians will be able to explore the deepest recesses of the unconscious to directly access therapies that assist the body in restoration of internal homeostasis. The optimal model for health care is the marriage of appropriate medical technology with the factors that have been shown to generate the placebo effect. This exciting scenario shines on the horizon as the health care of the future. Because the doctor-patient relationship is such fertile ground for stimulating the healing response,1E2o it serves a physician well to comprehend the nature of the placebo phenomena in order to fully realize this potential for healing.

HISTORY OF PLACEBO Both the modern physician and primitive medicine men and shamans of the past have used ineffective therapies to stimulate healing in their patients. As Shapiro observes, ”the true importance of placebo emerges with a review of the history of medical treatment.”21It has been noted that the historic therapies of the medical profession and traditional healers, ”purging, puking, poisoning, puncturing, cutting, cupping, blistering, bleeding, leeching, heating, freezing, sweating, and shocking,”22 worked because of the placebo effect. Although in retrospect, these practices might seem ludicrous, all of these therapies were once considered effective. As an embarrassing epilogue, placebo literature has shown that ineffective procedures are just as pervasive in modern medicine as in the jungle hut of the shaman. We must therefore ask ourselves how unfounded medical therapies can survive peer review literature and centuries of cultural acceptance. The power of the patient’s belief in the potential for cure has been consistently observed throughout history. Both Galen and Hippocrates recognized the strong effect of the mind on disease and recommended that faith, treatment ritual, and a sound doctor-patient relationship could provide important therapeutic results.= Recognition of the power of positive expectation was recorded frequently in the medical literature of the seventeenth and

eighteenth centuries. It was in the eighteenth century that placebo was first defined as a ”commonplacemethod of medicine.”24As the importance of drug therapy grew in the nineteenth century, the term placebo became identified with medicines involving substances that resembled drugs. But in the 1940s, because of the increase in double-blind research, it became associated with inert substances that were used to replace active medication.

ORIGIN OF THE TERM PLACEBO The original Latin meaning of placebo is ”I shall please.”25 Although the term had a purely medical application in the first half of the twentieth century, its meaning has been subject to various interpretations throughout the last several hundred years. Before the 1940s, placebos were pharmacologically inactive substances, such as saline and lactose pills, used to satisfy patients that something was being done for them-in other words, the doctor was ”pleasing” the patient. The 1940s and 1950s saw an explosion of the use of double-blind experimental procedures to evaluate the growing number of new drugs and medical procedures. Suspicion arose that all medical therapies contained an element of placebo phenomena.26This new understanding pressed the scientific community to offer new, far broader definitions. ShapiroZ offered the classic definition of a placebo: Any therapeutic procedure (or that component of any therapeutic procedure) which is given deliberately to have an effect, or unknowingly has an effect on a patient, symptom, syndrome, or disease, but which is objectively without specific activity for the condition being treated. The therapeutic procedure may be given with or without the conscious knowledge that the procedure is a placebo, may be an active (non-inert) or inactive (inert) procedure, and includes, therefore, all medical procedures no matter how specific-oral and parenteral medications, topical preparations, inhalants, and mechanical, surgical, and psychotherapeutic procedures. The placebo must be differentiated from the placebo effect which may or may not occw and which may be favorable or unfavorable. The placebo effect is defined as the changes produced by placebos. The placebo is also used to describe an adequate control in research.

A more accurate definition would be as follows: “Placebo effect is the process of a physician working with the self-healing processes of a patient. Placebo response means healing that results from the patient’s own natural survival and homeostatic defense mechanisms.” Modern placebo definitionsextend to its nature, properties, and effects. Placebo can be known or unknown, active or inactive, positive or negative in results (placebo effect vs. nocebo effect), and can extend to all forms of diagnostic or therapeutic m~dalities?~ further defined in BOX7-1.

Philosophy of Natural Medicine now gone, his last hope vanished, and he succumbed in less than two days.B Known placebo: Placebo used in a single-blindexperiment. The doctor knows it is placebo but the patient does not. Unknown placebo: Double-blind use of placebo. Neither the doctor nor the patient knows that the medication is a placebo. Active placebo: Any substance that has an intrinsic physiologic effect that is irrelevant to the ensuing placebo effect. The vasodilating effect of niacin would make it a good active placebo. Inactive placebo: Any substance that is used with medicinal intent but that has no inherent physiologic effect. Aside from the glucose effect in a sugar pill (or, to complicate things, an allergic reaction to some component of the supposedly inert substance), it has no physiologic effect. Placebo edfect Any changes that occur in a patient as the result of placebo therapy. Nocebo effect: Any changes that occur as a result of placebo therapy that are perceived as negative or counterproductive to the path of cure.

CLINICAL OBSERVATIONS OF “KNOWN” PLACEBOTHERAPY One of the more dramatic examples of the placebo effect reported in the medical literature involved a patient with advanced lymphosarcoma, which KlopferZ8 reported was highly susceptible to the patient’s faith in a n experimental drug called Krebozion. When the patient was started on the drug injections, his enthusiasm was so intense that ”The tumor masses had melted like snowballs on a hot stove, and in only a few days, they were half their original size!”28The injections were continued until the patient was discharged from the hospital and had regained a full and normal life, a complete reversal of his disease and its grim prognosis. Within 2 months of this recovery, reports that the drug Krebozion was ineffectual were leaked to the press. Learning of this report, the patient quickly began to revert to his former condition. Suspicious of the patient’s relapse, his doctors decided to take advantage of the opportunity to test the dramatic regenerative capabilities of the mind; a single-blind study was performed on the patient using pure placebo. He was told that a new version of Krebozion had been developed that overcame the difficulties described in the press, and some of the drug was promised to him as soon as it could be procured. With much pomp and ceremony saline water placebo was injected, increasing the patient’s expectations to a fevered pitch. Recovery from his second near terminal state was even more dramatic than the first. Tumor masses melted, chest fluid vanished, he became ambulatory, and even went back to flying again. At this time he was certainly the picture of health. The water injections were continued, since they worked such wonders. He then remained symptom-free for over two months. At this time the final AMA announcement appeared in the press“nationwide tests show Krebiozen to be a worthless drug in the treatment of cancer.” Within a few days of this report, h4r.Wright was readmitted to the hospital in extremis. His faith

Other famous placebo case studies are one reported by on “voodoo death” caused by belief, and one reported by Kirkpatrick,30who documented the spontaneous regression of lupus erythematosus resulting, in part, from the patient’s belief in the removal of a curse.

Other Clinical Observations Belief sickens, belief kills, belief heals.31 Evans3* and B e e ~ h e rreviewed, ~~ between them, 26 double-blind studies on the efficacy of active analgesic drugs in the treatment of pain. Independently, they concluded that 35% of patients suffering from pain experienced a 50% reduction in their symptoms after placebo medication. These are particularly remarkable results when viewed in the context of Evans’s observation that with a standard dose of morphine, only 75% of the patients experience a 50% reduction in pain. In calculating the efficiency index of placebo analgesia, a method often used to determine the relative efficiency of drugs, placebo was 0.56 as effective as a standard dose of morphine. This prompted Evans to remark, ”Thus, on average, placebo is not a third as effective as a standard injection of morphine in reducing severe clinical pain of various kinds but is in fact 56%as effecti~e.”~~ As discussed previously, placebo has been evaluated in a wide variety of clinical settings in addition to pain management (Box 7-2). When a phenomenon such as placebo has been observed to be active in diverse clinical situations, such as surgery, drug therapy, psychotherapy, and biofeedback, and over a range of physical and mental symptoms, the conclusion that it must be a factor in all aspects of medicine is inescapable. In addition to the variety of positive effects that placebo produces are the nocebo effects, perceived as counterproductive to the therapeutic goals. These side effects are frequently consistent with those of the medication that patients believe they are getting. For example, the studies that measure the effects of a supposed aspirin usually show nocebo effects of ulcerlike p a h a

AngeP Anorexia% Behavioral changess Depression37 Dermatitis medicamentosa35 Diarrhea= Drowsiness37 Epigastric pain%

Hallucinations3 He a d a ~ h e ~ ~ Lightheadedness% Pal~itation~~ Pupillary dilations Rash% Weakness35

Placebo and the Power to Heal

In homeopathy, aggravations and ameliorations are commonly seen when a placebo is given to fend off a patient’s need to take a medication while the homeopathic physician is waiting to see whether a high-potency remedy will effect a cure. Homeopathic doctors report that placebos can cause anxiety and loneliness as well as calmness and immediate relief from insomnia.4l

PLACEBO MYTHS ~

~~

Investigation of the understanding of placebo found in the current medical literature reveals the misconceptions that prevail about the nature of placebo therapy and its eff&tiveness.q A study undertaken to examine doctors’ and nurses’ attitudes about the efficacy and use of placebos showed that both groups underestimated the number of patients who could be helped by placebo.q Physicians showed a consistent pattern of placebo use, as follows: Placebos were used to prove the patient wrong through diagnosis of psychogenic symptoms in patients who were thought to be exaggerating, imagining, or faking their symptoms. Placebos were used in the treatment of alcoholic, psychotic, and demanding patients who were disliked by the staff of the hospital. In situations in which standard treatments had failed or the patient was getting worse, placebos were used as treatment. These misconceptions regarding the nature of the placebo have accounted for its widespread misuse for patients who are perceived as uncooperative or who are suspected of malingering. Myths about placebos continue to hinder full understanding about the power inherent in thisaspect of health care. The most common myths are discussed here.O

Heart

Improved exercise toleranceu*& Decreased serum lipoprotein^^^ ImprovedT waves47 Decreased pulse rate and arterial pressure“

Sympathetic stimulation

Decreased tremulousness, sweating, and tachycardia%

Claudication

Increased walking distance49 Addictive drug withdrawal=

Postsurgical trauma

Decreased facial swelling51

Diabetic blood sugar dyscrasias (NIDDM)

Lowered fasting blood sugaFB

Gastrointestinal secretion and motility

Decreased gastric acid secretion% Changes in gastric motility55.56 Healing of duodenal

Hypertension

Lowered blood p r e s ~ u r e ~ ~ - ~ Reduced urinary catecholaminessl

Motor dysfunction

Improved tremor magnitudeB2

Anginau.eama Anxiety35.66.67 Arthritis40-68*69 Asthma7073 Behavioral problems74 Claudication, intermittenPg Common Cough7g DepressionrnfB1 Diabetes (non-insulin-dependent diabetes mellitus)s.53 Drug dependence= DysmenorrheaB2 Dyspepsias3

Gastric ulcersw Hayfe~eP~,~ Temporal and vascular headachesB74s H y pert ens i ~ n~ - ~ l Labor and postpartum painw Premenstrual syndromeg3 MBniere’s diseaseM Nausea of pregnancy35 Paing5.= Psychoneur~ses~~~~~ Rhinitis= Sleep disturbanceslW TremoP

Myth 1 ”Since placebos tend to be physiologically inert, it is not possible for them to have an effect on physiologic homeostasis.”

Fact. Research shows that placebos have a wide range of effects (Table 7-1) that are found throughout all aspects of human physiology.

Myth 2 “Placebos are useful only with symptoms that are associated with psychologic or psychosomatic complaints. Patients who need a placebo are hypochondriacs with vivid imaginations and need to be palliated with something ’to please them.’”

Fact. Placebos have been shown to be effective in the care of all types of patients, with a consistent level of positive results for a wide variety of accuratelydiagnosed diseases.

Beecher17was one of the first to compile a listing of the therapeutic effectiveness of placebo, thereby uncovering the wide range of therapeutic applications, which were previously thought to be limited to only pain control. He concluded, ”there is too little scientific as well as clinical appreciation of how important unawareness of these placebo effects can be and how devastating to experimental studies as well as to sound clinical judgement lack of attention to them can be.”*’ The large and ever-growing number of studies on placebo and double-blind research (Box 7-3)supports the following assertion made by Beecher1730 years ago: Many “effective” drugs have power only a little greater than that of placebo. To separate out even fairly great true effects above those of placebo is manifestly difficult to impossible o n the basis of clinical impression. Many a drug has been extolled o n the basis of clinical impression when the only power it had was that of a placebo.

Philosophy of Natural Medicine

Myth 3 "The placebo effect is found only in substances that are inert."

Fact. Placebo phenomena have been observed across a wide spectrum of medical disciplines, including surgery;O1 drug therapy,lmand biofeedback.'03

Myth 4 "The patient who responds to placebo can be characterized as someonewho is of a typical neurotic disposition.""

Fact. Although many studies have tried to impute a personality type, d i s p o ~ i t i o n , ' ~or~ Jcertain ~ epidemiologic class105 to the patient who responds to placebo, this has yet to be well-demonstrated, because given the right circumstances, any person can become a placebo rea~tor.'~J~' After reviewing the bulk of the research on this subject, Bush'O* and Wolf and Pinsky35 concluded that the attempts to pigeonhole personalities into a clinical profile ignored the complexity of the human mind. Gliedman et alv similarly reported that age, sex, marital status, social class, and intelligence are unimportant factors in determining a patient's response to placebo. Wolf summarized that attempts to idenhfy placebo reactors need to "idenhfy the nature of the symptom being treated, the motivation of the patient and physician, the nature of the test agent, its mode of administration and the life situation of the subject at the time he is tested. The sigrulicant point here is not the apparently conflicting findings of investigators with respect to placebo reactors, but rather that in any given situation,responses to a placebo may vary as compared to any other situation and the significanceof situations to human subjects cannot be precisely d~plicated."~~

PHARMACODYNAMICS The physiologic response of the "inert and inactive'' placebo extends into the realm of drug pharmacodynamics. Dose-response time curves, cumulative effects (increasing therapeutic efficacy with repeated doses),lW variable strengths of analgesia based on a patient's drug e~pectation,6~ drug i n t e r a c t i ~ n s , ~ ~ and J l ~ carryover have all been demonstrated. The effects of placebo are so pronounced that some observers have suggested that they can exceed the effects attributable to potent pharmacologic agents.35

Packaging and Delivery Several studies have found that the effectiveness of a placebo therapy depends on the mode of deli~ery.4~ For example, one study found that green tablets improved anxiety and yellow tablets improved depression,"'

whereas another study found that blue capsules were more sedative and pink capsules were more stimulatinga Placebo injections appear to be more effective than oral administration after oral placebo has failed to relieve the symptoms.40

Placebo Interactions Benson112writes that the patient's belief is also a powerful force in determining the level of relief afforded by the placebo. An increase in patient expectation enhances the physician's ability to elicit a placebo response. Even if patients know that they are receiving placebos, the expectation and relief brought about by the therapeutic interaction provides positive re~ults."~ The importance of expectation is further demonstrated by the observation that the greater the stress level of the patient and the greater his or her need for assistance, the greater the effectiveness of placebo.37This is seen even in patient responses to psychotropic drugs: LSD-25 (Dlysergicacid diethylamide tartrate 25) can have no effect if the patient is told that the drug is a p l a ~ e b o . ' ~ ~ J ~ Patients, such as war heroes, who have severe injuries but do not have great mental suffering attached to their pain need less pain medication than persons with similar injuries who have pain that engenders anxiety and connotes di~aster."~

PLACEBO HEALING MECHANISMS When animals or humans can react to their own deviations from homeostasis and when these deviations set off restorative processes, therapeutic intervention, including placebo, has an already existing substrate of recovery for exp10itation.l~ A human being has an intrinsic ability to "selfright"-vis medicufrix naturue (the healing power of nature). This is the keystone of a philosophy that has been held for thousands of years by naturally oriented physicians (see Chapter 6). The concept of a homeostatic, self-regulatingmechanism is central to the understanding of basic concepts of physiology: Negative feedback loops control virtually all systems of the body. According to Guyton,116"the body is actually a social order of about 75 trillion cells organized into different functional structures. . . . [Elach cell benefits from homeostasis and in turn each cell contributes its share towards the maintenance of homeostasis." The body can maintain health and reestablish a healthy state after disease by virtue of its inherent vitality. This is part of the definition of a homeostatic mechanism; it has been selected by nature in the same way that organs vital to our survival have been selected. The surviving species are those most fitted and best able to cope with dysfunction. Those organisms that can tolerate the greatest stresses and still maintain a normal physiology

Placebo and the Power to Heal

are the hardiest survivors and ensure the species' ability to increase the limits of its adaptation. Therefore, given that an organism is self-maintaining when in an environment that it has been selected for, healing happens unaided through simply maintaining an environment that does not obstruct the path of cure. As Norman Cousins117observed, "without any help, the human body is able to prescribe for itself. It does so because of a healing system that is no less real than the circulatory system, the digestive system, the nervous system, or any of the other systems that define human beings and enable them to function."

The Role of Emotions Reviews of studies that explore how specific emotions can increase cancer sus~eptibility,l'~J~~ examine the effect of emotions and recovery from cancer,'z0 investigate the increased incidence of sudden and rapid death during psychological stress,lZ1 and monitor the changes in immune function during emotional all confirm that emotions play a powerful role in the prognosis of a patient. Cannonz9and Tregearl" document dramatic case histories of pioneering anthropologists who witnessed the power of taboos and curses to kill strong healthy men and women in third world cultures throughout Africa, South America, and the South Pacific. TregearlZ4wrote, "I have seen a strong young man die the same day he was tauped [tabooed]; the victims die under it as though their strength ran out as water."

The Vis Medicatrix Naturae The healing process described as vis medicatrix naturae demonstrates the sigruficant power and potential of the self-generated healing capacity. For a physician, there is no more powerful stimulator of this healing mechanism, the placebo effect, than a strong the doctor-patient interaction. Just walking through the door of the physician's office nudges a patient's internal homeostatic mechanisms into seeking higher levels of health, healing, and adaptation. The placebo effect is a result or effect of the patient's seeking the assistance of the doctor's ability to heal and cure. As Benson1lZnoted: When we dissected the placebo effect a number of years ago, we found three basic components: One, the belief and expectation of the patient; two, the belief and expectation of the physician; and three, the interaction between the physicianand the patient. When these are in concert, the placebo effect is operative. . . . Perhaps nothing is being transmitted from the healer to the patient, but rather it's the belief the patient has in the healer that's helpful.

Conscious Control over Homeostasis The body has two internal forces to maintain homeostasis: a lower drive and a higher drive. The lower drive is the inherent internal healing mechanism, the vital force,

or the primitive life support and repair mechanism that can operate even in a person who is asleep, unconscious, or comatose. The higher drive is the power of the mind and emotions to intervene and affect the course of health and disease by depressing or stimulating the internal healing capacities. The effect of this drive can be seen in the clinical observation of patients who move toward spontaneous remission of a life-threatening disease through positive emotional supportlzJzOand in patients who fail to express emotions compatible with the body's attempts to survive.120 In any disease process, the consciousnessof the patient decides the effectiveness of any therapy. Experiments in remote intention-generated healing and prayer show that the intention of others is a factor in the homeostatic capabilities of the mind and body. The fact that the homeostatic mechanism can sense and respond to these remote intentions is a reflection of the power of the human mind. Some authors believe that there is a physiologic basis for the unlimited possibility of human voluntary control.125 The ultimate control of psyche over soma demonstrates the priority of the conscious mind over physiologic processes such as immunity and pain control.126This Puts an enormous responsibility on the physician. He or she must take fullaccount of a patient's mental and emotional states when treating chronic or lifethreatening disease.

PHYSIOLOGIC MECHANISMS Identification of a biochemical mechanism for placebo analgesia has done more to change the image of placebo than any amount of arguing about the importance of beliefs and the mind.lZ7 The mechanisms of placebo response have been suggested to be a mixture of psychological interactions mediating physiologic responses.16 Psychological components of the patient's placebo effect have been shown to include the decreased anxiety and the increased relaxati0n,6~~onditioning,'~expectation,2O and well-being generated by the establishment of a sound doctorpatient r e l a t i ~ n s h i p . ~ ~ ~ J ~ ~ The physiologic mechanisms of the placebo effect have been suggested to include chemicals, catalysts, and enzymes. It is believed that steroids, catecholamines,lz the autonomic nervous ~ y s t e m , ~neuropeptides, ~J~~ and endorphins131are also involved. These physiologic mechanisms interrelate synergistically and are rapidly being researched within the rapidly developing field of psychoneuroimmunology? through which the links between depression, affective disorders, emotions, and the immune system and central nervous system (CNS) are being explored. Susceptibility to depression and sensitivity to pain have now been found to be mediated through neurotransmitters such as catecholamines, serotonin, and dopamine.

technology. This functional MRI (fMRI) can measure The current model for explaining the mechanism by blood flow into specific areas of the brain. One study has which emotions, mood, and psychologicalstress suppress shown that expectation or hope is able to stimulate a cerimmune function involves cerebral-hypothalamic and tain part of the brain that is activated by pain medicapituitary interaction, which translates stress and anxiety tions and is associated with pain relief. Placebo analgesia into an autonomic-endocrine response. This response has been found to be related to decreased brain activity adversely affects the immune function, particularly after in pain-sensitive brain regions, including the thalamus, chronic stimulation. Stressful stimulation is received in h u l a , and anterior cingulate cortex. It was also associthe sensory cortex of the brain and is then referred to the ated with increased activity during anticipation of pain limbic system and the hypothalamus. This interface of the in the prefrontal cortex, providing evidence that placehigher brain functions and homeostatic regulating centers bos alter the experience of pain.134 provides the communication linkbetween the psyche and In another study, researchers found that empathy soma. According to Rossi,’6 “The hypothalamus is thus could activate a portion of the brain. They showed that the major output pathway of the limbic system. It intesome of the brain regions involved in feeling physical grates the sensory-perceptual, emotional, and cognitive pain become activated when someone empathizes with function of the mind with the biology of the body.” another’s pain. Using fMRI, study subjects were In the hypothalamus are the nerve centers that control observed when they experienced a painful stimulus, and both branches of the autonomic nervous system, both the results were compared to those elicited when the parasympathetic and sympathetic, nerve cells that subjects observed their spouses receiving a similar pain secreteendocrine-releasingfactors, and neural pathways stimulus. The bilateral anterior insula, rostra1 anterior that release hormones directly into the posterior cingulate cortex, brainstem, and cerebellum were actipituitary. The corticosteroids and catecholamines from vated when subjects received pain and also by a signal sympathetic stimulation are key factors in the alterthat a loved one experienced pain.135 A group of ation of disease susceptibility in response to stress. researchers at University of California at Los Angeles Corticosteroidsinhibit the function of both macrophages and lymphocytes, as well as lymphocyte ~roliferation.’~~(UCLA), using a new technology called quantitative electroencephalography (QEEG)showed that “effective” Corticosteroids also cause the thymic and lymphoid placebo treatment induces changes in brain function that atrophy noted by Hans Selye in his experiments on are different from those associated with antidepressant stress-induced immune dysfunction. The autonomic release of catecholamines stimulates medication. Placebo responders (those who showed a response to placebo) showed a sigruficant increase in receptors on the surface of lymphocytes, thereby increasprefrontal activity starting early in treatment that was ing their maturation rate. When in a mature state, the not seen in medication responders or in subjects who lymphocytes’ ability to kill bacteria and cancer cells and showed no response to medication or placebo. Because a produce interferon seems to become paralyzed.I3 Thus high percentage of antidepressant medication represents a population of mature lymphocytes develops, ready the placebo effect, it is important to be able to predict to defend the body from infection and inflammation who will be placebo responders.136 yet remaining paralyzed until the ”red alert” signal of sympathetic fight or flight is turned off, signaling the Placebo and Stress Physiology appropriate time to rest and repair. Stress “letdown” of a patient in the therapeutic environA number of other peptides, E-type prostaglandins, ment is one of the mechanisms producing the placebo somatotropin, histamine, insulin, endorphins, antidieffect. It results from the patient’s perception that a tranuretic hormone (ADH),and parathyroid hormone (F’TH) all have receptor sites on lymphocytes and can stimulate sition from a stressful situation to a nonstressful situation has occurred. M ~ w r e r observed ’~~ that with a decrease the same cyclic --mediated response resulting in in anxiety there is a concomitant increase in hope, sigrufylymphocyte maturation and inhibition.132A study of the ing that the period of suffering is over. Certain familiar effect of catecholamines on the human immune system images and signals, such as white coats, syringes,behavshowed that when a physiologic dose of epinephrine is ioral procedures, and clinical protocol, create a condiinjected into a healthy volunteer, there is an increase in tioned response-relief now that help has arrived. Evans the number of circulating suppressor T lymphocytes and and Hoylea similarly observed that ”the reduction of a decrease in the number of circulating helper T lymphofear through the shared expectations that the doctor’s cytes (changes similar to those found in acquired medicine will work-even if unknown to the patient immunodeficiency syndrome [AIDS]).132 it is placebemediates powerful therapeutic effects.” Brain Region Activity The placebo effect in the clinical environment transforms the emotional and mental stress of the Some of the most interesting research on placebo has patient. These effects, also observed and described by evolved out of the new magnetic resonance imaging

Placebo and the Power to Heal Franz Ale~ander,'~ Hans George Solomon,138 and Walter allow the patient to escape the "fight or flight" response that can cause, and maintain, the state of illness.

Physiologic and Psychologic Stress S e l ~ edemonstrated '~~ that physiologic stress can have a dramatic effect on the immune and endocrine systems of the body. Laudenslager" went on to show that it is not just stress that creates these physiologic changes, but also the perception that stress is "inescapable" that is critical to the response. More recently, studies on the effects of psychological stress have demonstrated significant changes in immune capability. Maladjustment to "life-change stress" correlates with reduced activity of natural killer cells,138decreased T- and B-cell responsivity,'" and diminished lymphocyte cytotoxicity.142For example, Riley143observed increased tumor activity in a controlled stress environment and concluded: Emotional, psychosocial, or anxiety-stimulated stress produces increased plasma concentrations of adrenaline, corticosteroids and other hormones through well-known neuroendocrine pathways. A direct consequence of these increased corticoid concentrations is the injury to elements of the immunologic apparatus, which may leave the subject vulnerable to the action of the latent oncogenic viruses, newly transformed cancer cells, or other incipient pathologic processes that are normally held in check by an intact immune system.

The damage to the immune system by stress, mediated though the hypothalamic-pituitary axis, has been shown to be due to the increase in serum levels of cortisol. In one study, elderly caregivers were shown to have higher cortisol levels and poor antibody response to influenza vaccine.lMThe impact of cortisol on immune and other regulatory functions like blood sugar, dehydroepiandrosterone (DHEA), insulin,testosterone, bone resorption flag it as having highly destructive potential. Anxiety, depression, heart disease, AIDS and osteoporosis have all been linked with elevated cortisol levels. DHEA, another adrenal hormone is also modulated by stress physiology though it seems to have the opposite effect to cortisol. High levels of DHEA seem to protect the body from the damaging effects of elevated cortisol. In fact, ratios of DHEA to cortisol are highly predictive of the individual's ability to tolerate stress.145 Current reviews of the literature relating psychological stress and immune dysfunction support the hypothesis that the homeostatic immune mechanisms, both humoral and cellular, are sigruficantly impaired by both natural and experimental s t r e ~ s . h " ~ J ~ ~ , ~ ~ common colds,148coronary artery and myocardial ischemia" have been linked to adverse stress physiology. Stress even has the ability to increase

permeability of the blood-brain barrier.151The implications of stress-relatedalterations in the blood-brain barrier exposes important insights into enigmatic diseases like chronic fatigue syndrome and stress-induced neurologic disorders.

Endorphins, Hormones, and Neuropeptides . . . one rapidly activated psychoneuroendocrine mechanism through which a placebo stimulus may reduce both depression and pain is produced by stimulating the endorphin system.15 Research on endorphins is a relatively new area of study in the field of psychoneuroimmunology. Original research by Levine et a195suggested that the pain relief noted in placebo studies could be explained by the simple mechanism of endorphin-mediated actions. The original emphasis on endorphins and enkephalins was plausible, considering their known modulation of pain and mood functions. This position was further supported by later observations that depression increases chronic clinical pain152and that decreased activity in endogenous opioids may be part of the pathophysiology of depression.13 With the information that placebo can stimulate endorphins, Levine et aP5 believed that an explanation for the action of placebos had finally been found. However, this hypothesis failed to account for the broad spectrum of placebo effects as well as for the fact that the analgesia associated with hypnosis is not affected by an opioid a n t a g ~ n i s t . ' ~ItJ is ~ ~important to note that later literature suggests that Levine et a195were not entirely wrong in implicating the role of endorphins in the placebo mechanism; rather, these researchers were right for the wrong reason. Endorphins are mainly derived from three precursor proteins (by separate biochemical processes).lMThese opioid peptides are released from central and peripheral areas in response to pain, stress, and emotions and perform many physiologic functions, of which analgesia is but However, it is becoming evident that the boundaries between the CNS and the immune system are not as clear as once thought. The several known effects of endorphins on immune system function are listed in Table 7-2.lS When the functions of neurotransmitters such as endorphins are found to have such an intimate relationship with immune integrity, the paradigm of a body with functions performed independently by its parts-a newtonian type of thinking-begins to lose credibility. To further blur the already hazy distinction between the CNS and the immune system, research has demonstrated that endorphins and peptide hormones, such as adrenocorticotropic hormone (ACTH), thyroid-stimulating

Immune system function

Endorphin effect@)

Lymphocyte production

Increased and decreased

Chemotaxis

Increased

T-cell sensitivity to prostaglandin E2

Increased

Antibody production

Increased and decreased

Complement

Binding of fractions C5B-C9

T-cell proliferation Natural killer cell function

Modulation of Modulation of

B a l l differentiation

Modulationof

hormone (TSH), human chorionic gonadotropin (hCG), and luteinizing hormone (LH), are produced by lymphocytes.lB It is clear that the demarcation between the CNS and the immune system is impossible to distinguish. The brain and the immune system are the only tissues in the body that have a memory, and the level of communication between the two argues a taxonomy that identifies them as one. Evidence of the innervation of the thymus gland, bone marrow, spleen, and lymph nodes supports the finding that the immune system is subject to efferent CNS information.’B In addition, studies demonstrating the atrophy of the thymus and lymphatic tissues in the absence of growth hormone,’59corticotropin (ACTH), and increased steroid production by adrenal cells after interferon stimulation, indicate that “in the future it will be difficult to distinguish the receptors and signals that are used within and between the neuroendocrine and immune system.’’158

CLINICAL APPLICATION A physician with an interest in the psychopharmacologic treatment, which can be expensive, elaborate, detailed, time consuming, esoteric, and dangerous, usually has considerableknowledge about such treatment. He or she is interested in the symptoms of the patient and the differential response to various drugs and is careful to observe side effects, which may be dangerous. The physician may encourage the patient to call at any time if side effects develop.= The application of placebo phenomena in clinical practice should not be a vague attempt to replace the skill of the medically trained physician with obscure ”hand waving,“ incantations, and inert lactose pills. In primary care and specialty clinical practice, the physician’s intent should be to optimize patient care by engaging restorative defense mechanisms. To effectively apply current placebo research, the physician must

Prima non nocerum: Prioritize a hierarchy of therapeutic intervention. Tolem causum: Remove the obstacles. Support the therapeutic relationship. Enhance positive emotional states. Implement therapeutic conditioning or learning. Use altered states of consciousness.

understand several principles (listed in Box 7-4 and discussed here).

Prima Non Nocerum: Prioritize a Treatment Program and Establish a Hierarchy of Care Prima non noceium is the Hippocratic injunction dictating that a physician care for the patient so that self-healing mechanisms can engage. This ancient phrase means “Do not disturb the organism’s ability to heal itself.” The body must be given the full range of possibilities in allowing the power of homeostasis, vis medicatrix naturue, to have its optimum capability. ”Doing no harm” means that a patient is supplied with the level of medical intervention that is appropriate to his or her ability to maintain life support. The job of the physician is to determine when homeostasis or defense mechanism has lost the ability to respond to disease. Acute traumatic swelling and inflammation and shock are examples of the human defense mechanism responding in a way that threatens the health of the organism. It is most interesting that the organism would make choices, as in shock and inflammation, that could kill it. To practice the principle of prima non nocuum, a physician must learn when to act and when to let the body heal itself. This is the highest art of medicine; each case and situation is different and it is up to the physician to interpret the needs of the moment. By implication, the physician who seeks to apply this principle understands the principles of physiology upon which human life depends for homeostasis. Prima non nocerum does not necessarily mean that a physician withholds invasive therapy: it is the physician’s responsibility to determine when the body is unable to reestablish homeostasis and therapy is indicated. If an arm must be severed to save the patient’s life, there is no violation of prima nun nocerum. However, to enhance the principle of prima non nocerum, a physician sometimes must withhold therapies and must be content to leave the patient to self-heal. Hippocrates understood the wisdom of letting the body heal on its own that is implicit in the “do no harm”

Placebo and the Power to Heal

injunction. The following account of the treatment of Charles I1 of England is a case in point: A pint of blood was extracted from his right arm and a half pint from his left shoulder, followed by an emetic, two physics, and an enema comprisedof fifteen substances;themyal head was shaved and a blister raised; then sneezing powder, more emetics, and bleeding, soothing potions, a plaster of pitch and pigeon dung on his feet, poisons containing ten different substances, chiefly herbs, finally forty drops of extract of human skull and an application of bezoar stone; after which his majesty died.’60 When this treatment is compared with modem procedures such as mammary artery ligation for the relief of angina-a procedure that has no more benefit than sham artery ligation-it appears that physicians have continued throughout the centuries to rely on the placebo effect for the care and cure of their patients. Because this effect plays such an important role in health care, simple, noninvasive, and effective treatments should be the goal of all therapeutic approaches. Robert Burton161wrote in 1628, “an empiric oftentimes, and a silly chirurgeon, doth more strange cures than a rational physician . . . because the patient puts confidence in him.” The rational physician will also recognize that healing and curing are not necessarily the same. If a patient is helped in any way by the doctor, with or without the use of placebo, the path of cure has been assisted, although the specific disease may not have responded. Not all patients can be cured, but most patients can be helped.

Tollem Causum: Remove the Cause of Disease Tollern cuusum is the principle that seeks to remove the obstacles to cure. The forces “inhibiting the floodgates of health from opening” must be removed for the full force of the patient’s beliefs to effect the path of cure. This concept is fundamental to the philosophy of naturopathic medicine with its strong emphasis on diet, detoxification, and a pattern of living that is consistent and compatible with the context in which humans evolved. Obstacles to cure block the self-healing capacity of the organism. Contamination with heavy metals and xenobiotics (see Chapter 36), focal infections, electromagnetic pollution, scar tissue, genetic metabolic abnormalities, and parenchymal organ damage defeat the best therapeutic intentions and must be addressed. The patient’s habitat is an important aspect of the therapeutic protocol, not only in the diagnosis and care of internal mental and physiologic dysfunction but also in determining which environmental factors may be contributing to dysfunction and disease. These factors might include diet, lifestyle, and living environment. It is of the utmost importance to remove a patient from surroundings that are associated with illness or to assist the patient in creating an environment more conducive to health.

Factors that provide conditioning that reinforces the disease process can be associated directly or indirectly with one’s environment. For example, if animals are returned to situationswhere their experimental neuroses were induced, their pathologic behavior reactivates.162 When a patient leaves the offending environment to receive treatment from a physician, the prognosis is correspondingly more fav0rab1e.I~ The physician has the added advantage of a patient’s heightened expectation during an office visit-a patient’s positive associations with the ”healing” environment increases his or her receptivity to treatment.la If the home or work environment is a source of “dis-ease” and an obstacle to cure, providing an alternative environment may be a most helpful way to remove the obstacles to cure.

Support the Therapeutic Relationship Confidence should surround all aspects of the therapeutic interaction. The patient must have confidence in the doctor’s ability to assist a cure, the doctor must have confidence in the efficacy of his or her therapy,’” and there must be an understanding or relationship between the doctor and patient that is mutually conducive to respect, trust, and compassion. The quality of the doctor-patient relationship is paramount. The therapeutic approach to a patient that optimizes the confidence of the patient in the skill of the doctor stimulates the inherent self-regulating healing mechanisms by relaxing the anxiety the patient has about the illness. Anxiety is a well-known immunosuppressant and aggravates the body’s defense mechanism. An optimum therapeutic relationship, when combined with the clinical skill to remove the cause of homeostatic dysfunction, is the height of therapeutic acumen. As Lewith’G so accurately states, “The general practitioner may therefore wish to employ all his knowledge, enthusiasm, consultation technique and sympathy, to create the best possible atmosphere in which to elicit a placebo response from the patient.” Current research on factors contributing to the genesis of the placebo effect consistently documents the importance of the doctor-patient relationship.16168 The healing power of the therapeutic interactionhas been demonstrated by the commencement of the placebo effect even before the actual administration of the pill.169 The physician facilitates the cultivation of a sound relationship by developing good communication skills. The art of the bedside manner has been recognized throughout history as the primary skill a successful physician needs.l’O Indeed, the history of medicine is as much a history of the relationship between doctor and patient as the evolution of medical technology and techniques. Through centuries in which doctors were doing more harm than good, little more than the esteem of their

Philosophy of Natural Medicine aspects of the situation producing this effect include not only clientele sustained the medical profession. But however presentation of a symbol of the physician’s healing powers little real help the doctor had to offer, it was to him that (a pill), but any attention and interest shown by professional people turned when illness struck.171 personnel. Bedside manner has been found in clinical studies to This phenomenon was also observed in industry and entirely alter the course of double-blind studies, and the termed the ”Hawthorne effect.” As a direct result of the quality of a therapeutic encounter has been found to facilgreater attention factory workers received during invesitate or disrupt the efficacy of a treatment.lR Listening to tigation, the quality of their work improved.lmIn concluthe patient,’n verbal and nonverbal communication of the physician, amount of time spent with the patient,’73 sion, the importance of a doctor-patient relationship and the confidence that it engenders shows that all human patient education,”* demeanor of the ph~sician,’~~ and beings need to share their feelings and experience the interview skills173have been suggested as factors and therapeutic benefits of touch: The doctor-patient relacomponents of effective physician communication skills. tionship provides an ideal way to meet these fundamenTouch is an important form of communication and is sometimes forgotten as a key aspect of the doctor-patient tal needs. relationship. Highly skilled clinicians with many years Enhance Positive Emotional States of experience, such as now deceased Dr.John Bastyr (whose remarkable healing abilities inspired the foundLove in all its subtleties is nothing more, and nothing less, ing of Bastyr University by those privileged to have been than . . . the psychical convergence of the universe upon itself. his students), frequently impressed upon clinicians the -Pierre Teilhard de Chardin, The Phenomenon of Man importance of always using diagnostic and therapeutic touch during a patient visit. The doctor’s touch can be diagnostic, therapeutic, and, perhaps most important, a For optimum enhancement of the psychoneuroimmune system, the physician must assist the patient in developmeans of communicating that he or she is deeply attuned to the problems, needs, and fears of the patient.176Touch ing practices that amplify positive emotional states and can heal by increasing tissue mobility and fluid exchange, reduce negative emotional state. A negative mental as in massage, or by relieving pain, as demonstrated by state (anxiety, stress, panic, anger, depression, neurotic research on healers who use their hands.174Touch has behavior, self-deprecation, self-destructive feelings and also been documented in well-designed double-blind tendencies, and a weak will to live) hinders the ideal research to extend an unusual healing power that can be functioning of the psycho-neuro-immune-endocrine transmitted through the hands to plants and animals.178 axis, disrupting homeostasis. Englelsl has termed this Among other methods of enhancing confidence the giving-uplgiven-up complex: between the doctor and patient, the setting in which a Study of the life settings in which patients fall ill reveals that doctor provides therapy to a patient also determines its iUness is commonly preceded by a period of psychological effectiveness. The doctor’s office setting is very impordisturbance, during which the individual feels unable to cope. tant for optimum and effective treatment: Tools and This has been designated the giving-up/given-up complex support systems are more accessible, and a heightened and has the following five characteristics: a feeling of giving patient response results from seeking out the “healing” up, experienced as helplessness or hopelessness; a depreciated environment. In a clinical trial with hypertensive image of the self; a sense of loss of gratification from relationpatients, placebo alone was not as effective as when it ships or roles in life; a feeling of disruption of the sense of was administered in conjunction with hospitalization. continuity between past, present, and future; and a reactivation The visit to the physician represents a search for changes of earlier periods of giving-up. It is proposed that this state that cannot be found through “self-care” or overreflects the temporary failure of the mental coping mechanisms the-counter medicines. According to Frank’? with a consequent activation of neurally regulated biologic

In short, it appeared that the placebo situation relieved chiefly anxiety and depression, that the degree of relief was unrelated to personality and autonomic measures, and that the patients who responded strongly to a placebo at one time might not at another. In conjunction, these results suggest that the extent of responsiveness to a placebo depends on the interaction of the patient’s state at a particular time with certain properties of the situation. The finding that administration of tests and questionnaires seemed to have at least as beneficial an effect as had the pill implies that any interaction between patient and situation that heightens expectations of help may lead to symptom reduction and improvement in mood. The

emergency patterns. Changes in body economy so evoked may alter the organism‘s capability to deal with concurrent pathogenic processesl permitting disease to develop.

The importance of reducing negative mental states in acute and chronic conditions has been discussed extensively.lZ1Acute psychologic stress is documented to cause various forms of cardiopulmonary dysfunction, even death.l13 Chronic mental and emotional strain causes breakdown of the immune system and disease. The homeostatic processes become overwhelmed by autoimmune,

Placebo and the Power to Heal

microbial, or neoplastic invasion. Major writers on the subject of acute and chronic stress emphasize the high priority of managing the physiologically and immunologically destructive effects of the human body's response to stress. Pelletier182lists hypertension, arteriosclerosis, migraine headache, cancer, chronic bronchitis, emphysema, asthma, and arthritis as disease processes that are caused or exacerbated by stress physiology. A study researching the relationship between resistance to streptococcal infections in families and stress load in the family found a positive correlation.ls3 Another study on the psychosomatic susceptibility to infectious mononucleosis found that two psychosocial factors, high motivation and poor academic performance, significantly increased the risk of "dis-ease" infection.184 In still another, anticipation of mood and menstrual discomfort were positively correlated and manipulated, thereby supporting the suspicion that expectations act as a determinant of mood.185 The conclusion that there is no acute, chronic, or degenerative disease that is not affected by a patient's mental and emotional state must be drawn from the pervasive immunoendocrine effects generated by the mind and emotions. WolFS6and Cousins18' write of the power of panic as a factor in myocardial infarction, Marbach et describe depression as a component in myofascial pain dysfunction, and Shekelle et allmnote, in a 17-year follow-up study, a twofold increase in the incidence of cancer in depressed patients. The clinical scenarios these observers describe imply that the placebo effect can control the onset and advance of a disease by shutting down the destructive thoughts, images, and feelings that mediate stress. Enhancing positive emotions is the corollary to controlling the damaging effects of negative mental and emotional states. Laughter?O hope,lS9acceptance,'15 and the reduction of suffering'% have been shown to speed the course of healing and reduce the level of pain and distress reported by patients. Although pain is sometimes the only language nature can use to adequately communicate to the patient that something is in need of healing, "the relief of suffering and the cure of disease must be seen as twin obligations of a medical profession that is truly dedicated to the sick."'% Acceptance has been observed to be a key factor that assists patients in better understanding their pain.l15 Acceptance does not mean complacency in the face of disease, but a rational understanding of the situation and the limitations that can sometimes accompany a disease process. The importance of cultivating hope in a patient also cannot be ~nderestirnated.'~~ The fact that a patient seeks the help of a physician or "caregiver" already implies a substrate of hope and is a signal that the patient can visualize the potential for recovery. The treatment needs

to merely stimulate this willingness to envision a future of health. Hope is an embodiment of the patient's and the doctor's ability to visualize an image of healing and recovery. This process is a recurrent theme in imagery therapy,192visualization therapy,'93 therapeutic and psychic healing.lg5Hope is both an active and a passive placebo. Passive hope placebo is that brought with the patient as the act of seeking help generates a level of unspoken faith in an image or potential for cure. Active hope placebo is generated by the physician, who consciously instills a vision or image of cure in the patient as an adjunct to therapy. Frank'79 performed a double-blind study in which patients were divided into control and induction groups. The induction group was led through a process whereby their hope was strengthened to conform with the expectations of the therapist: It introduces some perceptual clarity into the process of treatment; and to the extent that all our therapists adhered roughly to the insight model of therapy, it helped to bring the patient's expectations in line with what actually occurred in treatment, and also helped him behave in accordance with the therapist's expectations of a good patient.ln

The induction group were actually being consciously strengthened to a level of optimal response but not being led into false expectation^.'^^ This type of patient education or active placebo is a necessary and useful tool for framing and directing a positive outlook and prognosis. If a patient can conceive of a state of wellness, then that state of wellness can be achieved. It is the job and domain of the physician to discover those images, emotions, and perceptions that reside in the conscious and subconscious mind of the patient that block the image of a positive state of health. He or she must actively work to control these with the same level of intent as with any presenting gross complaint or physiologic dysfunction. Finding these dysfunctional mental substrates and working with the patient to try to change them is fundamental to treating the true cause of disease (see earlier discussion of tollum causum). Research has demonstrated the importance of positive and negative thinking in heart disease and cancer, the two areas of disease that cause the highest death rate: Doctors' health care management protocols should reflect this research in the same way that attention to proper diet is a part of a management approach to high serum cholesterol. It is now clearly established, for instance, that even low levels of stress trigger the onset of myocardial ischemia.lg7We also know from the work of Steven and David SpiegeP that the attitude and emotional exploration are critical to breast cancer survival. Knowing these scientific facts, all doctors must have strategies for helping their patients explore the

Philosophy of Natural Medicine areas of stress management, group therapy, and support groups and skills in building positive attitudes.

Implement Therapeutic Conditioning or Learning Those who remain at least dimly aware that everything they say or do to a patient conveys a major or minor, positive or negative, helpful or harmful psychologic impact are likefy to be more flective physicians.200 Conditioning of the mind has been suggested as a mechanism by which the placebo effect becomes a learned r e s p ~ n s e . ’ ~ , The ’ ~ J ~future of therapeutic application of placebo will probably hinge primarily on the use of conditioning. A doctor who can understand this will pay close attention to the stimuli of his or her patients and mod@ these stimuli in a scientific way to help treat immune-related and neurologically related diseases. Modem psychology acknowledges two models of conditioning or reinforcement of learning behavior, operant and classical. Operant conditioning is a behavior response that theoretically occurs in the presence of some stimulus that is a positive reinforcement; for example, a rat will leam to press a conditioning bar if a food pellet is dispensed as a result. Classical conditioning is a behavior response created by the simultaneous pairing of unconditioned and conditioned stimuli prior to an evoked response. This is best illustrated by the experiments of Pavlov and his “salivating dog.” In Pavlov’s experiment with the conditioning of a dog’s salivary response to the ringing of a bell, the bell ring is the conditioned stimuli, the food the unconditioned stimuli. The salivation is the unconditioned response to the food that becomes the conditioned response. When the dog finally associates the bell ring with the food, the ringing alone causes salivation, the conditioned response. The principle of classical conditioning has far-reaching implications for the diagnosis and treatment of disease because of the pervasive and permeating implications that conditioning has in all the sensory stimuli of daily existence, in sickness and in health: “Pavlov’s teachings, concepts and basic notions afford the real and ultimately scientific basis for the recognition of the potentialities of medical science attacking diseases from both the psychic and somatic sides.”201 For the purposes of this discussion, one must recognize that classical conditioning happens randomly in our environment and is closely linked to health and healing phenomena. Subconsciously, we note random events and associate them with previous events and observations, independent of an intended learning behavior. Operant conditioning happens in the context of reward, and classical conditioning happens in the context of

associated stimuli. There is a much greater predominance and range of associated stimuli (classical conditioning) than operant conditioning for the genesis of the placebo effect. This is because the operant depends on reward, although operant conditioning can happen in the medical mode: “Pain-killing drugs that I have taken in the past kills pain; therefore this capsule, which is a painkiller, will kill my pain.” Gliedman et all4 note that drugs that affect the CNS are readily conditioned, whereas drugs that affect the peripheral nervous system and are secretory stimulators (e.g., atropine and pilocarpine) do not result in the establishment of a conditioned response. The primary importance of psychological states to CNS excitation demonstrates that the pivotal loci of command for conditioning reside within the hypothalamus and the limbic system. Therefore, a doctor who can induce a state of central excitation in the patient can encourage and condition the patient to make those changes that are deemed necessary for the recovery of health. The conditioning of a patient to a placebo response is modified by learning stimuli associated with the illness, the stimuli of the doctor and the therapeutic setting, the stimuli of the therapy, previous health, medical therapy, and authority-related experiences.202The way that all of these factors interact in the psyche of the patient determines the nature of the placebo response that is achieved. Satiation obscures the conditioned response, whereas situations of increased stress seem to potentiate the responsiveness of the placebo effect.lI5 Placebo, conditioning, and learning may therefore be subject to the nature of central excitatory states as well as levels of stress and distress. The physiologic breadth of the placebo response in humans can now be understood in terms of the variety of interactions and effects that drugs, therapeutic procedures, and sensory phenomena of the medical environment have on the psychosomatic matrix of a patient’s consciousness. Rossi16notes that this complicated web of sensory processing reveals how any facet of therapy “that alters any aspect of the body’s sensory, perceptual or physiologic responsiveness on any level can disrupt the more or less fragile state-dependant encoding of symptoms and thereby evoke a ’nonspecific’ but real healing effect that we call the placebo response.” In fact, the scientific basis of therapeutic applications of psychoneuroimmunology is based on classical conditioning. Ader and CohenZo3 performed research to show that the immune system could be conditioned for therapeutic purposes. They conditioned immunosuppression in rats by injecting them with a conditioned stimulus of cyclophosphamide (a potent immunosuppressing agent) while feeding them a saccharine solution as an unconditioned stimulus.203The idea of conditioning for

Placebo and the Power to Heal

immunomodulation in human patients is therefore a realize that the patients are taking in all the information promising therapeutic modality. Applying conditioning about the surroundings, interactions, and therapy and techniques for the treatment of systemic lupus erytheare making associations that can potentially affect the matosus involving a dosage that normally had minimal course of their responsiveness to therapy. results resulted in a delay in the development of the M ~ w r e r ’observed ~~ that the “safety signals” of disease.204 syringes, lab coats, and behavioral procedures are all To fully account for the extent of previous and future retained in the patient’s psyche for future association. A conditioning in a patient, the physician must take a physician can skillfully take advantage of these signals by complete and exhaustive history in order to explore the encouraging and cultivating response generalization or influences of family, work, accidents, emotional predisby associating previous therapeutic situations with subsepositions, past medical history, and neutral stimuli as quent treatments by means of unconditioned stimuli such contributing factors during the onset of an illness. as office music, odors, and images. Giving patients some Lifestyle and emotional, behavioral, or physiologic factors sort of unconditioned stimulus that can be taken home might contribute to maintaining the state-dependent allows them to associate with the conditioned response, learning pattern of disease and dysfunction or give clues eliciting the memory of the therapeutic interaction while to a successful therapeutic intervention. A good example patients are away from the doctor‘s office. These uncondiof this is the demonstration by Batterman and L0wel.2~~ tioned stimuli or placebos can be given in multiples at one and delivof increased analgesics effectiveness based on similar time,’29 changed for more powerful ~timuli,~ previous therapy. A physician who knows which theraered at the end of an induction, suggestion, or imagery pies succeeded and which failed can take advantage of procedure. They should not be limited to pills or other the patient’s conditioning and encourage biochemical apparent medicaments, but should extend to sounds, smells, visualizations, and feelings. pathways that the body has learned. Drug or therapeutic interventions are not procedures that can be predicted It should be remembered that therapeutic conditionin the same way that in vivo experimental results can. ing depends on a perceived physiologic shift or change in the patient as described in the theory and research of The variables involved in human responses to therapy are clearly underestimated in the current rush of researchbiofeedback.*@This shift can be experienced as a sense oriented therapeutic e v a l ~ a t i o nTherefore, .~~ a patient of relaxation, increased warmth or circulation, altered who has been treated by a number of physicians or pracautonomic tone, or change in some sensory perception. Patients know immediately when there is no change in titioners for a complaint and has received no results or relief has been conditioned to believe that consultation their disease or dysfunction after they have been given and treatment by a physician will provide no positive placebo.209Therefore some patients need a more active form of therapeutic management that allows for some changes. When the patient visits the next practitioner, even if this practitioner can offer a diagnosis and treatlevel of perceived change. Ideally this perception would ment that are correct answers to the long-sought cure, be a sense of being free from pain or alteration from a state of abnormal physiologic function to a state of improved there are very real patient conditioning factors that must physiologic function. Acupuncture, spinal manipulation, still be considered. Consider the case of a young woman who was underdrug therapy, physiotherapy, hydrotherapy, and surgery going treatment for breast cancer and the clinical course are all therapies that can create an immediate biochemiof the ensuing metastases. Each time she had a positive cal impact perceived by the patient. response to therapy, she experienced a subsequent The optimum model to apply to the concept of condiremanifestation of the cancer. The result of this conditioning therapy and the selection of an appropriate thertioning was that she came to equate each new course of apy or modality was proposed by Greene and Laskin210 chemotherapy as a herald of some new manifestation: in their evaluation of myofascial pain dysfunction (MPD). She ”was torn between a desire to live and the fear that During an 11-year follow-up study of patients with MPD, allowing hope to emerge again would merely expose her these researchers concluded that, when comparing the effectiveness of a wide variety of reversible and nonreto misery if the treatment failed.”206 The parameters of conditioning in a clinical setting versible (surgical)therapies, conservative and reversible extend to all aspects of the patient’s sensory perceptions. therapies were the most important and appropriate Consciously, or unconsciously, the physician is providtreatment factors for the patient’s health and well-being. ing an environment for patient learning. LipkinZo7 points Focusing on patient communication, educating patients out that every drug, every apparatus, every injection, about reversibility of the condition and the nature of and every piece of information or advice carries a sugmuscle dysfunction as it relates to stress-pain-spasm, gestion of help and hope, regardless of the physiologic developing a therapeutic strategy based on increasing effects that may accompany it. The physician must patient awareness and self-management skills, and

Philosophy of Natural Medicine

selecting a flexible treatment strategy were all found to be essential for achieving a good initial response that could lead to long-term wellness. Greene and Laskin210 believed that the specifics as to which therapy was most indicated were not as important as the need to focus on the nature of presenting musculoskeletal problems and the factors and complexity of the treatment environment. Routine use of active pharmacologic substances reinforces the relationship between conditioned and unconditioned stimuli. However, routine use of unconditioned stimuli in the absence of a conditioned response weakens the therapeutic efficacy of the practitioner and has been described as ”placebo sag.”15Therefore the learning of a conditioned response from unconditioned stimuli could diminish if the conditioned stimuli fail to produce an adequate or reliable conditioned response. Without the intermittent demonstration of active strength, the placebo effect will get weaker and weaker. The implications of placebo sag for practitioners of alternative medicine, who try to work with the body’s own defense mechanisms without overwhelming medical intervention, are that periodic use of perceptually active therapy is needed to support a patient who is not able to respond to, or responds too slowly to, a gentler therapeutic nudge. In this case, the physician must recondition the vital force to open a path to homeostasis. In a sense, this may be a paradigm of the therapeutic situation, in which changes towards health are induced in the patient by a doctor who is able to cultivate a basic state of arousal, presumably central in nature. This state of arousal causes the patient to become accessible to the doctor’s expectations of the patient.I4 The typical placebo burst, in which a therapy is initially effective after a short period but then wanes, is now understood in terms of the placebo sag from lack of effective unconditioned stimuli to maintain the conditioned framework.68Physicians who lack the ability to extract themselves from a series of unsuccessful therapies risk eventual placebo sag: [Tlherapists who primarily use their active strengths (or unconditionedstimuli) paradoxically will get stronger placebo effects than quacks, will enjoy escalating credibility, and will seem as miracle men-when in fact perhaps only half their miracles can be traced to their active ingredients while the other half is a function of the anticipatory (or conditioned) response elicited by their conditioned features.15

Because the visit to a physician is often initiated by the physical pain of the patient, it stands to reason that skillfulpain management is a high priority in establishing a therapeutic conditioned response. Pain management by hypnosis, transcutaneous electrical nerve stimulation (TENS),therapeutic touch, direct or indirect manipulation, imagery, acupuncture, rneditation,2l1and an understanding that aims to elicit the nature of suffering206can

all be valuable therapeutic adjuncts to establishing a therapeutic environment that conditions the patient for full potentiation of his or her healing capabilities. (See Chapter 42 for a full discussion of these techniques.) With the recent development of standardization of, research into, and concentrationof the active components of plant medicines, vitamins, and biochemical precursors, naturopathic medicine as well as other forms of alternative medicine stands on a stronger therapeutic base because of an ever-growing verification of its pharmaceutical and therapeutic armamentarium. These therapeutic modalities are characterized by safe, yet physiologically active, substances and procedures; therefore they provide some defense against placebo sag.

Use Altered States of Consciousness Since ancient times, aboriginal humans have recognized the tremendous therapeutic power that lies dormant in the subconscious mind. For thousands of years, shamans and medicine men have used trance states to engage the most subtle aspects of the patient’s subconscious to affect factors in disease pathogenesis and In modern medicine, it has been documented that shamanistic healing involving altered states can offer dramatic “spontaneous remissions”30; the mechanisms of this process have been explored in the theory and application of hypnosis.2J26 Most currently accepted techniques employed to trigger the subconscious to effect positive changes in somatic or psychic health involve hypnosis. Placebo effect has been linked with hypnosis, or “low arousal states,” which are therefore believed to be critical factors in the evaluation of the mechanisms and perimeters of placebo.201A review of the literature documenting the potency of hypnosis and the observed results of placebo clearly demonstrates that these two areas yield remarkably similar clinical results. The inquiry into hypnosis grew out of the simple intent to validate the effectiveness of the mind in healing processes, whereas most placebo literature grew out of the intent to demonstrate a certain percentage of chance, fluke, spontaneous remission, or psychosomatic illness as a factor to be ruled out in the delivery of intelligent, scientific health care. Using these antiquated definitions of placebo and hypnosis, one is led to believe that hypnosis describes a process of healing based on the skillful guidance of a qualified practitioner, and that placebo describes a process based on chance, regardless of the professional circumstances. On closer inspection, the distinction between the two blurs: They appear to be much the same process. Illness, healing, and health states shift constantly in the homeostatic system, a system that is affected by stimuli received through the different levels of awareness and can be accessed, investigated, and modified by a variety of techniques. These include placebo, hypnosis,

Placebo and the Power to Heal

and induced altered states of consciousness. Ros@ notes that because memory depends on and is limited to the level of awareness in which the memory was acquired, it is “state bound information”: State dependent memory, learning, and behavior phenomena are the missing link in all previous theories of mind body relationships. . . . The major thrust of these hypotheses is that mind-body information and state-dependent memory, learning and behavior mediated by the limbic-hypothalamic system, are the two fundamental processes of mind-body communication and healing. . . . The new approach to mind-body healing and therapeutic hypnosis may be conceptualized as processes of accessing and utilizing state-dependent memory, learning and behavior systems that encode symptoms and problems and then reframing them for more integrated levels of adaptation and development.

Some psychosomatic phenomena are coded into the behavior of an individual through state-induced patterning. Until the patient can access the state in which somatic complaints are induced, possibly through hypnosis or other methods that break the sympathetic dominance of “encoded” shock,21° the psyche cannot clear them from the soma: A person in a traumatic car accident experiences an intense rush of the alarm reaction hormones. His detailed memories of the accident are intertwined with the complex psychophysiological state associated with these hormones. When he returns to his usual or “normal” psychophysiological states of awareness a few hours or days later, the memories of the accident become fuzzy or, in really severe cases . . . the victim may be completely amnesic. The memories of the accident have become ”state-bound”-that is, they are bound to the precise psychophysiological state evoked by the alarm reaction, together with its associated sensory-perceptual impressions.I6

In accessing these psychosomatic state-dependent areas of homeostatic dysfunction, the physician must use techniques that relax the conscious mind and allow access to subconscious content for reframing. The nature of the visit to a physician encourages a patient into more accessible unconscious states as demonstrated by higher placebo effects when patients present in a hospital setting.’@These labile states of consciousness are quite natural; humans constantly cycle in and out of different consciousness states.l@ These cycles, or ultradian rhythms, are described as alternating cycles of hemispherical dominance that change every one-and-a-half hours. When these cycles are interrupted by behavioral stress, psychosomatic behavioral responses such as ulcers, gastritis, asthma attacks, and rashes develop.214 A change in these rhythms manifests as a period of psychic repose. If an individual is in the midst of performing a task, daydreaming or the perceived need for a rest or coffee break may be the external manifestation of an

internally sensed signal of a change in rhythm. This is also a period when one is highly susceptible to hypnotic suggestion. Because these rhythms are very flexible and labile, they can be invoked through hypnosis, or if the physician senses a natural lull indicating a hemispherical switch, a “natural” trance can be induced. Centuries ago in India, practitioners of hatha yoga observed the effect of mental states on the breathing patterns of an individual. With anger, frustration, and mental instability, the breath reflects a short, arrhythmic pattern that mirrors the disturbed psyche of the person. Conversely, when a person is in a peaceful, relaxed, deep meditative state, the breath is long, rhythmic, and barely perceptible. Their discovery formed the basis for the development of breathing exercises called prunayurnu (literally, regulation or restraint of the vital energy),which aimed to calm the breath so that deep states of meditation and focused concentration could be attained. Current research has affirmed the powerful effect these exercises have on asthma, diabetes, chronic gastrointestinal disorders, and psychosomatic and psychiatric dysfunction.215 Therapeutic exercises that use somatic stimuli to effect changes in the psyche create fertile environments for stimulating the placebo response. A breathing technique used to decrease sympathetic tone or alter nostril predominance for causing shifts in hemispherical activity,216 an exercise to release fascia1 muscle tension and thereby effect mood enhancing blood flow in the brain,217,218 and a biofeedback treatment that aids in slowing the heart rate and decreasing negative emotional states208are all examples of how the psyche can be accessed by the soma. The whole process of eliciting the placebo response involves an attempt to marshal all the reserves and potential for healing through a doctor-patient interaction, engaging both the patient’s mind and body to reestablish homeostatic equilibrium. Health care professionals can use the wisdom of psychosomatic therapies as a central part of their therapeutic protocol. In addition to the specific therapeutic regimen, treatment of the whole patient can be achieved through these harmonious techniques. If physicians could persuade patients to care daily for their emotions, minds, and spirits the way they care for their hair or teeth, the effectiveness of any prescribed treatment would be greatly enhanced. As a primary therapeutic adjunct and important basis for preventive medicine, this line of treatment is all too often ignored.

ETHICS It is important to remember that there are two forms of “conscious” placebo use by the physician. The use of placebo as a gentle therapeutic agent by a practitioner is very different from the use of placebo in a controlled trial in which the possibility of a known therapy is withheld

in a treatment group. Some researchers believe that use of placebo in clinical trial breeches the Declaration of Helsinki, which states that every patient should be assured of the best proven diagnostic and therapeutic method.219The ethical problems of delivering health care in a research design, in which there is a possibility of favorableoutcome and half of the group is denied access to this possible favorable outcome, make it a troubling issue. The ethical use of placebo has also been questioned in an attempt to determine whether a physician should be deceiving patients during the process of healingz0 Although some writers advocate a restricted use of pure and impure placebo because of its ”deceptive”natureFm it becomes clear in a brief review of the current literature* that any argument for or against the use of placebo assumes the existence of medical procedures that are free of potential placebo effect. BrodyZ6concludes that placebo can be called the ”lie that heals.” However, closer examination shows that it is not the lie that does the healing, but rather the relationship between the patient and doctor that stimulates a natural self-healing mechanism via psychologic, symbolic, and biologic intervention: For some time, medical science has looked almost exclusively at technical means of diagnosis and treatment; the doctor/ patient relationship that forms the setting for their application has been naively viewed as a noncontributory background factor, relegated to the amorphous realm of the “art of medicine,’’ or simply ignored. In this setting, the placebo effect has inevitably been viewed as a nuisance variable, interfering with ow ability to elicit ”clean data” from clinical trials; and deception in medicine has been seen either as an unimportant side issue or as a tolerated means toward an end. But as the doctor/patient is rediscovered as a worthy focus for medical research and medical education, the placebo effect assumes center stage as one approach to a more sophisticated understanding of this relationshipF6

indications even more carefully than when prescribing specific therapy and (2) to avoid missing a disease process that can be easily treated with an empirically proven protocol (e.g., vitamin BI2-deficientperipheral neuropathy), the physician should not relax a diagnostic protocol because a patient seems to be responding to placebo.u0 The final ethical hurdle of placebo use, or for that matter any medical treatment, is the abuse of hope in the patient’s path of healing. It is one thing to make a harmless recommendation that provides no therapeutic value, but another to subject a patient to known consequences of a dangerous procedure in the pursuit of a dubious outcome. Hope can be abused, leading the patient to experience unreasonable suff ering.221

CONCLUSION Health practitioners must be equipped with a better understanding of placebo therapeutics.6m For many years now, the study of placebo has been recommended to doctors and other health care professionals. The ideal environment for the dissemination of the therapeutic implications of the doctor-patientrelationship is in medical schools as a required part of the curriculum. After finding a pattern of misuse and misunderstanding about the nature and efficacy of placebo, Goodwin et al“ recommended that better education might result in more effective placebo use. In 1938, Hou~ton’’~ wrote of the need to reaffirm the art of medicine because he perceived a trend in medicine that invested in a concept of the therapeutic dodorpatient interaction as “undisciplined thought.” Houston’s remedy for the intellectual bias that viewed medicine as a ”tight, fast-set science” was to emphasize the importance of psychobiology in medical schools:

A physician’s correct understanding of the nature of placebo therapy has been observed as able to coexist with its inaccurate use and abuse.“ It has been recommended, however, that: (1)pure placebo should not be prescribed unless the physician has examined the exact

One of the most hopeful moves in medical education is teaching to first-year students the elements of psychobiology. A system of belief is implanted best in the young. It would be my suggestion that psychobiology be taught in the premedical years, that the doctor/patient relationship be the beginning of medical studies.A deep insight into this fundamental philosophy is a chief concern of the

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200. Cornell Conference on Therapy. The use of placebos in therapy. NY State Med J 1946;46:1718-1726. 201. Volgyesi FA. “School for patients,” hypnosis therapy and psychoprophylaxis. Br J Med Hypn 1954;5:8-17. 202. Epstein JEi. Understanding placebos in dentistry. J Am Dent Assoc 1984;109:71-74. 203. Ader R, Cohen N. Behaviorallyconditioned immunosuppression. Psychosom Med 1975;37333-340. 204. Ader R. Behaviorally conditioned modulation of immunity. In Guillemin R, Cohn M, Melnechuk T, eds. Neural modulation of immunity: proceedings of an internationalsymposium held under the auspices of the Princess Liliane Cardiology Foundation in Brussels, Belgium, October 27 and 28, 1983. New York Raven Press, 1985. 205. Batterman RC, Lower WR. Placebo responsiveness-influence of previous therapy. Curr Ther Res Clin Exp 1968;10136-143. 206. Cassel EJ. The nature of suffering and the goals of medicine. N Engl J Med 1982;306:639-645. 207. Lipkin M. Suggestion and healing. Perspect Biol Med 1984;28: 121-126. 208. Schwartz GE. Biofeedback, self-regulation, and patterning of physiological processes. Am Sci 1975;63314-324. 209. Modell W, Houde RW. Factors influencing clinical evaluation of drugs. J Am Med Assoc 1958;1672190-2199. 210.Greene CS, Laskin DM. Long-term evaluation of treatment of myofascial pain-dysfunction syndrome: a comparative analysis. J Am Dent Assoc 1983;107235-238. 211. Kabat-Zinn J. An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: theoretical considerations and preliminary results. Gen Hosp Psychiatry 1982;433-47. 212.Halifax J. Shamanic voices: a survey of visionary narratives. New York: Dutton, 1979. 213.Klinghardt DK. Neural therapy. J Neurol Orthop Med Surg 1993;14:109-114. 214. Orr WC, Hoffman HJ, Hegge FW.Ultradian rhythms in extended performance. Aerosp Med 1974;45:995-1OOO. 215. Goyeche J. Yoga as therapy in psychosomatic medicine. Psychother Psychosom 1979;31:373-381. 216. Wemtz D. Cerebral hemispheric activity and autonomic nervous function, doctoral dissertation, San Diego, University of California, 1981. 217.Zajonc RB. Emotion and facial efference: a theory reclaimed. Science 1985;22815-21. 218.Critchley EM. The human face. Br Med J (Clin Res Ed) 1985; 291:1222-1223. 219.Rothman KJ, Michaels KB. The continuing unethical use of placebo controls. N Engl J Med 1994;331:394-398. 220. Bok S. The ethics of giving placebos. Sci Am 1974;231:17-23. 221. Mukejee S. The anatomy of hope: care of the vital organ. New York T i e s February 22,2004. 222. Leslie A. Ethics and practice of placebo therapy. Am J Med 1954;16854-862.

Positive Mental Attitude Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 111

Attitude and Self-Actualization 112

Attitude, Personality, Emotions, and Immune Function 111

Clinical Aspects of Learned Optimism 114

Attitude and Cardiovascular Health 112

INTRODUCTION A positive mental attitude is one of the important foundational elements of good health. This axiom has been contemplated by philosophers and physicians since the time of Plato and Hippocrates. In addition to simple conventional wisdom, modern research also has verified the importance that attitude-the collection of habitual thoughts and emotions--plays in determining the length and quality of life. Specifically,studies using various scales to assess attitude, including the Optimism-Pessimism (PSM) scale of the Minnesota Multiphasic Personality Inventory (MMPI), have shown that individuals with a pessimistic explanatory style have poorer health, are prone to depression, are more frequent users of medical and mental health care delivery systems, exhibit more cognitive decline and impaired immune function with aging, and have a shorter survival rate compared with optimists.14This research highlights the fact that although life is full of events that are beyond one’s control, people can control their responses to such events. Attitude goes a long way toward determining how people view and respond to the stresses and challenges of life. Attitude is reflected by explanatory style, a term developed by noted psychologist Martin Seligman to describe a cognitive personality variable that reflects how people habitually explain the causes of life events.8 Explanatory style was used to explain individual differences in response to negative events during the attributional reformulation of the learned helplessness model of depression developed by Seligman (described in Chapter 144). To determine a patient’s level of optimism, have him or her take the Attributional Style Questionnaire developed by Seligman (see Appendix 11) or use the PSM

scale of the MMPI. Techniques to help patients learn to be optimistic are given in the following discussion.

AlTITUDE, PERSONALITY, EMOTIONS, AND IMMUNE FUNCTION The importance of attitude to human health has been examined in the link among the brain, emotions, and the immune system. Research in the field of psychoneuroimmunology indicates that every part of the immune system is connected to the brain in some way, either via a direct nervous tissue connection or through the complex language of chemical messengers and hormones. What scientists are discovering is that every thought, emotion, and experience sends a message to the immune system that either enhances or impairs its ability to function. A simplistic view is that positive emotions, such as joy, happiness, and optimism, tend to boost immune system function whereas negative emotions, such as depression, sadness, and pessimism, tend to suppress it. Studies examining immune function in optimists versus pessimists have demonstrated sigruficantlybetter immune function in the optimists. Specifically, studies have shown that optimists have increased secretory immunoglobulin A (IgA) function, natural killer cell activity, and cell-mediated immunity, which is demonstrated by better ratios of helper to suppressor T-cells, than p e s s i r n i ~ t s . ~ , ~ - ~ ~ The immune system is so critical to preventing cancer that, if emotions and attitude were risk factors for cancer, one would expect to see an increased risk of cancer in people who have long-standing depression or a pessimistic attitude. Research supports this association; for example, smokers who are depressed have a much greater risk of lung cancer than smokers who are not depressed.13 111

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Depression and the harboring of other negative emotions contribute to an increased risk of cancer in several ways. Most of the research has focused on the impact of depression and other negative emotions on natural killer cells. Considerable scientific evidence has now documented the linkbetween a higher risk of cancer and negative emotions, stress, and a low level or activity l cells.14 Negative emotions and stress of ~ t u r akiller paralyze many aspects of immune function and literally can cause natural killer cells to b ~ r s t . ’ ~Furthermore, *’~ the prototypical cancer personality-an individual who suppresses anger, avoids conflicts, and has a tendency to have feelings of helplessness-has lower natural killer cell activity than other personality types.I1J2These studies also indicate that individuals with a personality type that is prone to cancer have an exaggerated response to stress, which compounds the detrimental effects stress has on natural killer cells and the entire immune system. Depression and stress not only affect the immune system but also appear to hinder the cell’s ability to repair damage to DNA. Most carcinogens cause cancer by directly damaging DNA in cells, thereby producing abnormal cells. One of the most important protective mechanisms against cancer in the cell’s nucleus is the enzymes responsible for the repair or destruction of damaged DNA. Several studies have shown that depression and stress alter these DNA repair mechanisms; for example, in one study, lymphocytes (a type of white blood cell) from depressed patients demonstrated impairment in the ability to repair cellular DNA damaged by exposure to x-rays.16J7 Just as research has identified personality, emotional, and attitude traits that are associated with impaired immune function, likewise the field of psychoneuroimmunology has identified a collection of ”immune power” traits that include a positive mental attitude, an effective strategy for dealing with stress, and a capacity to confide traumas, challenges, and feelings to oneself and others.14J8

AlTlTUDE AND CARDIOVASCULAR HEALTH In addition to the brain and immune system, the cardiovascular system is another body structure intricately tied to emotions and attitude. The relationship of an optimistic or pessimistic explanatory style with incidence of coronary heart disease was examined as part of the Veterans Affairs Normative Aging Study, an ongoing cohort study of older men.7 These men were assessed by the MMPI PSM scale. During an average 10-year follow-up, 162 cases of incident coronary heart disease occurred: 71 cases of incident nonfatal myocardial infarction, 31 cases of fatal coronary heart disease, and 60 cases of angina pectoris. Men reporting high levels of optimism

had a 45% lower risk for angina pectoris, nonfatal myocardial infarction, and coronary heart disease death than men reporting high levels of pessimism. Interestingly, a clear dose-response relationship was found between levels of optimism and each outcome. To illustrate how closely the cardiovascular system is linked to attitude, one study showed that measures of optimism and pessimism affected something as simple as ambulatory blood pressure.19 Pessimistic adults had higher blood pressure levels and felt more negative and less positive than optimistic adults. These results suggest that pessimism has broad physiologic consequences. Excessive anger, worrying, and other negative emotions have also been shown to be associated with an increased risk for cardiovascular disease; however, these emotions may simply reflect a pessimistic explanatory style.

AlTITUDE AND SELF-ACTUALIZATION A physician’s role should include not only facilitating the health of the patient but also helping the patient achieve self-actualization, which is a concept developed by Abraham Maslow, the founding father of humanistic psychology. His work and theories were the result of intense research on psychologically healthy people over more than 30 years. Essentially Maslow was the first psychologist to study healthy people. He strongly believed that the study of healthy people would create a firm foundation for the theories and values of a new psychotherapy. Maslow discovered that healthy individuals are motivated toward self-actualization, a process of “ongoing actualization of potentials, capacities, talents, as fulfillment of a mission (or call, fate, destiny, or vocation), as a fuller knowledge of, and acceptance of, the person’s own intrinsic nature, as an increasing trend toward unity, integration, or synergy within the person.”2o Maslow developed a five-step pyramid of human needs in which personality development progresses from one step to the next. The needs of the lower levels must be satisfied before the next level can be achieved.When needs are met, the individual moves toward well-being and health. Figure 8-1 displays Maslow’s hierarchy of needs. The primary needs that form the base of the pyramid are basic survival or physiologic requirements: the satisfaction of hunger, thirst, sexuality, and shelter. The second step consists of the needs for safety, which are essential for dealing with the world: security, order, and stability. The individual then progresses to the third step, which involves the ability to love and be loved: belonging. The fourth step involves self-esteem and selfrespect: approval, recognition, and acceptance. The final step is self-actualization: the use of one’s creative potential for self-fulfillment. In modern life, a person’s occupation often correlates with the ability to achieve these needs. Table 8-1 provides

Positive Mental Attitude

Deficit Needs Figure 8-1

Maslow’s Hierarchy of Needs.

an application of Maslow’s Hierarchy of Needs in an occupational environment. Maslow studied and noted that self-actualized people had strikingly similar characteristics. Here are some of Maslow’s key findings in an abbreviated form: Self-actualized people perceive reality more effectively than others and are more comfortable with it. They have an unusual ability to detect the spurious, the fake, and the dishonest in personality. They judge experiences, people, and things correctly and efficiently. They possess an ability to be objective about their own strengths, possibilities, and limitations. This self-awareness enables them to clearly define values, goals, desires, and feelings. They are not frightened by uncertainty.

I

Practical application of Maslow’s Hierarchy of Needs

Level of need

General rewards

Occupationalfactors

Self-actualization

Growth Achievement Advancement Creativity

Challengingjob Opportunities for creativity Achievement in work Promotion

Self-esteem

Self-respect Status Prestige

Social recognition Job title High status of job Feedback from the job itself

Belonging

Love Friendship Belongingness

Work groups or teams Supervision Professionalassociations

Safety

Security Stability Protection

Health and safety Job security Contract of employment

Physiologic

Food Water Sleep Sex

Pay Working conditions

Self-actualized people have an acceptance of self, others, and nature. They can accept their own human shortcomings without condemnation. They do not have an absolute lack of @t, shame, sadness, anxiety, and defensiveness, but they do not experience these feelings to unnecessary or unrealistic degrees. When they do feel guilty or regretful, they do something about it. Generally they do not feel bad about discrepancies between what is and what ought to be. Self-actualized people are relatively spontaneous in their behavior and even more spontaneous in their inner life, thoughts, and impulses. They are unconventional in their impulses, thoughts, and consciousness. They are rarely nonconformists, but they seldom allow convention to keep them from doing anything they consider important or basic. Self-actualizedpeople have a problem-solving orientation toward life instead of a self orientation. They commonly have a mission in life, some problem outside themselves that enlists much of their energies. In general, this mission is unselfish and is involved with the philosophical and ethical. Self-actualized people have a quality of detachment and a need for privacy. Often it is possible for them to remain above the battle, to be undisturbed by what upsets others. They are self-governing people who find meaning in being active, responsible, self-disciplined, and decisive rather than being pawns or helplessly ruled by others. Self-actualized people have a wonderful capacity to appreciate the basic pleasures of life, such as nature, children, music, and sex, again and again. They approach these basic experiences with awe, pleasure, wonder, and even ecstasy. Self-actualized people commonly have mystical or “peak” experiences, times of intense emotions in which they transcend the self. During a peak experience, they have feelings of limitless horizons and unlimited power while simultaneously feeling more helpless than ever before. There is a loss of place and time, and feelings of great ecstasy, wonder, and awe. The peak experience ends with the conviction that something extremely important and valuable has happened, so that the person is transformed and strengthened by the experience to some extent. Self-actualized people have deep feelings of identification with, sympathy for, and affection for other people in spite of occasional anger, impatience, or disgust. Self-actualized people have deeper and more profound interpersonal relationships than most other adults, but not necessarily deeper than children’s. They are capable of more closeness, greater love, more perfect identification, and more erasing of ego boundaries than other people would consider possible. One consequence is that self-actualized people have

Philosophy of Natural Medicine

especially deep ties with relatively few individuals, and their circle of friends is small. They tend to be kind or at least patient with almost everyone, yet they speak realisticallyand harshly of those who they feel deserve it, especially hypocritical, pretentious, pompous, or self-inflated individuals. Self-actualized people are democratic in the deepest possible sense. They are friendly toward everyone, regardless of class, education, political beliefs, race, and color. They believe it is possible to learn something from everyone. They are humble, in the sense of being aware of how little they know in comparison with what could be known and what is known by others. Self-actualized people are strongly ethical and moral. However, their notions of right and wrong and good and evil are often unconventional. For example, a selfactualized person would never consider segregation, apartheid, or racism to be morally right even though it may be legal. Self-actualized people have a keen, unhostile sense of humor. They do not laugh at jokes that hurt other people or are aimed at others’ inferiority. They can make fun of others in general, or of themselves, when they are foolish or try to be big when they are small. They are inclined toward thoughtful humor that elicits a smile, is intrinsic to the situation, and is spontaneous. Self-actualizedpeople are highly imaginative and creative. The creativeness of a self-actualized individual is not of the special-talent type, such as Mozart’s, but rather is similar to the naive and universal creativeness of unspoiled children.

CLINICAL ASPECTS OF LEARNED OPTIMISM Fortunately, humans are optimists by nature, according to Martin Seligman, the world’s leading authority on attitude and explanatory style.21Optimism not only is a necessary step toward achieving optimal health, as emphasized in the preceding, but also is critical to happiness and a higher quality of life. In many instances, it is not what happens in one’s life that determines one’s direction; to a large degree, it is the response to those challenges that shapes the quality of life and determines one’s level of health. Surprisingly, it is often true that hardship, heartbreak, disappointment,and failure serve as the sparks for joy, ecstasy, compassion, and success. The determining factor is whether these challenges are viewed as stepping stones or stumblingblocks. A person’s attitude is like his or her physical body: It must be conditioned to be strong and positive. Conditioning an attitude to be positive and optimistic

requires adopting specific healthy habits. Here are three key areas of focus for helping patients develop a positive mental attitude: Help them become aware of self-talk.Tell them that all people conduct a constant runningdialog in their heads. In time the things people say to themselves and others percolate down into their subconscious minds. Those inner thoughts, in turn, affect the way people think and feel. Naturally a steady stream of negative thoughts will have a negative effect on a person’s mood, immune system, and quality of life. The cure is to become aware of self-talk and then to consciously work to feed positive self-talk messages to the subconsciousmind. Help them ask better questions. The quality of a person’s life is equal to the quality of the questions habitually asked. For example, if a person experiences a setback, does he or she think “Why am I so stupid? Why do bad things always happen to me?” or “Okay, what can be learned from this situation so that it never happens again? What can I do to make the situation better?” Clearly, the latter response is healthier. Regardless of the situation, asking better questions is bound to improve one’s attitude. Some examples of questions that can improve attitude and self-esteem when asked regularly follow: “What am I most happy about in my life right now?” “What am I most excited about in my life right now?” ”What a m I most grateful about in my life right now?” “What am I enjoying most in my life right now?” “What am I committed to in my life right now?” “Who do I love? Who loves me?” ”What must I do today to achieve my long-term goal?” Help them set positive goals. Learning to set achievable goals is a powerful method for building a positive attitude and raising self-esteem. Achieving goals creates a success cycle: A person feels better about himself or herself, and the better he or she feels, the more likely he or she is to succeed. Some guidelines for helping patients set health goals follow: State the goal in positive terms and in the present tense; avoid negative words. It’s better to say, ”I enjoy eating healthy, low-calorie, nutritious foods” than to say “I will not eat sugar, candy, ice cream, and other fattening foods.” Make the goal attainable and realistic. Start out with goals that are easily attainable, like drinking six glasses of water a day or switching from white to whole-grain bread. Initially choosing easily attainable goals creates a success cycle that helps build a positive self-image. Little things add up to make a major difference in the way a person feels about himself or herself.

Positive Mental Attitude

Be specific. The more clearly the goal is defined, the more likely it will be achieved. For example, if a person wants to lose weight, he or she should define the desired weight and the body fat percentage or measurements to be achieved. Counseling is necessary for the severely pessimistic individual. Forms of cognitive therapy appear to be the most useful therapy at this time. Cognitions comprise the whole system of thoughts, beliefs, mental images, and feelings. Cognitive therapy can be as effective as the use of antidepressant drugs in the treatment of moderate depression, and there tends to be a lower risk of relapsethe return of depression-with cognitive therapy? One reason for this is that cognitive therapy teaches people practical skills they can use to combat depression any time, anywhere, every day for the rest of their lives. Cognitive therapy avoids the long-drawnout (and expensive) process of psychoanalysis. It is a practical, solution-oriented psychotherapy that teaches skills a person can apply to improve the quality of life.

1.Maruta T, Colligan RC, Malinchoc M, Offord Kl? Optimismpessimism assessed in the 1960s and self-reported health status 30 years later. Mayo Clin Proc 2002;77:748-753. 2. Taylor SE, Kemeny ME, Reed GM, et al. Psychological resources, positive illusions, and health. Am Psychol 2000;55:99-109. R. Cognitive bias of 3. Schweizer K, Beck-Seyffer A, %eider optimism and its influence on psychological well-being. Psychol Rep 1999;&1.627-636. 4.Chang EC, Sanna LJ. Optimism, pessimism, and positive and negative affectivity in middle-aged adults: a test of a cognitiveaffective model of psychological adjustment. Psychol Aging 2001;16:524531. 5. Segerstrom SC. Optimism, goal conflict, and stressor-related immune change. J Behav Med 2001;24441-467. 6. Maruta T, Colligan RC, Malinchoc M, Offord Kp. Optimists vs pessimists: survival rate among medical patients over a 30-year period. Mayo Clin Proc 2000;75:140-143. 7. Kubzansky LD, Sparrow D, Vokonas P, Kawachi I. Is the glass half empty or half full? A prospective study of optimism and coronary heart disease in the normative aging study. Psychosom Med 2001;63910-916. 8. Peterson C, Seligman M, Valliant G. Pessimistic explanatory style as a risk factor for physical illness: a *-five year longitudinal study. J Pers Soc Psychol 1988;55:23-27. 9. Brennan FX,CharnetskiCJ. Explanatory style and immunoglobulin A (IgA). Integr Physiol Behav Sci 200035251-255. 10. Kamen-Siege1L, Rodin J, SeligmanME, Dwyer J. Explanatory style and cell-mediated immunity in elderly men and women. Health Psych01 1991;10229-235. 11. Imai K, Nakachi K. Personality types, lifestyle, and sensitivity to mental stress in association with NK activity. Int J Hyg Environ Health 2001;204:67-73.

Mental health specialists trained in cognitive therapy seek to change the way the depressed person consciously thinks about failure, defeat, loss, and helplessness. To do so, they employ five basic tactics that help patients to do the following: Recognize the negative automatic thoughts that flit through consciousness at the times when they feel the worst. Dispute the negative thoughts by focusing on contrary evidence. Learn a different explanation to dispute the negative automatic thoughts. Avoid rumination (the constant churning of a thought in one’s mind) by helping the patient better control his or her thoughts. Question depression-causing negative thoughts and beliefs, and replace them with empowering positive thoughts and beliefs.

12.Segerstrom SC. Personality and the immune system: models, methods, and mechanisms.Ann Behav Med 2000;22:180-190. 13. Jung W, Irwin M. Reduction of natural killer cytotoxic activity in major depression: interaction between depression and cigarette smoking. Psychosom Med 1999;61:263-270. 14. Kiecolt-Glaser JK, McGuire L, Robles TF, Glaser R. Emotions, morbidity, and mortality: new perspectives from psychoneuroimmunology. Annu Rev Psychol 2002;5383-107. 15. Maddock C, Pariante CM. How does stress affect you? An overview of stress, immunity, depression and disease. Epidemiol Psichiatr Soc 2001;10153-162. 16. Kiecolt-Glaser JK, Stephens R, Lipitz P, et al. Distress and DNA repair in human lymphocytes. J Behav Med 1985;8:311-320. 17. Glaser R, Thorn BE, Tam KL, et al. Effects of stress on methyltransferase synthesis: an important DNA repair enzyme. Health Psychol 1985;4403-412. 18. Kiecolt-Glaser JK, Glaser R. Psychoneuroimmunology and cancer: fact or fiction? Eur J Cancer 199935:1603-1607. et al. Effects of optimism, 19. Raikkonen K, Matthews KA, Flory JD, pessimism, and trait anxiety on ambulatory blood pressure and mood during everyday life. J Pers Soc Psychol 1999;76:104-113. 20. Maslow A. The farther reaches of human nature. New York Viking, 1971. 21. Seligman M. Learned optimism. New York Knopf, 1991. 22. Casacalenda N, Perry JC, Looper K. Remission in major depressive disorder: a comparison of pharmacotherapy, psychotherapy, and control conditions. Am J Psychiatry 2002;1591354-1360.

Research in Natural Medicine CadaCalabrese, ND, MPH CHAPTER CONTENTS What Is Natural Medicine? 117 Purpose of Research

Observational Studies 123 Basic Science Studies 124

117 Criteria for a Prioritized Research Program 125

Methodologic Problems and Strategies 118 Clinical Trials 118

The improvement of understanding is for two ends:first, our own increase of knowledge; secondly, to enable us to deliver that knowledge to others. -John Locke

WHAT IS NATURAL MEDICINE? For the purposes of this chapter, natura2 medicine is defined as a paradigm of healing found throughout the world and guided by several distinguishing principles. Care is patient-centered rather than practitioner-centered. Emphasizing self-responsibility and self-care, it supports the body's own healing processes and treats causes rather than simply alleviating symptoms. Especially in the modem era, natural medicine distinguishes itself in a preference for medicines and health aids from the natural environment (e.g., those with which human beings have coevolved). Despite the preference for remedies from nature, natural medicine is a practice; it is not defined only by the substances it uses. Under the proper social cultivation, such practices have evolved to be internally coherent and efficient, although the theories governing them may not be well articulated. The skills are distributed over numerous professional groups (e.g., naturopathic doctors, traditional east and south Asian medical systems, mixer chiropractors, practitioners of many indigenous medicines), and also are practiced widely among conventional medical doctors and other eclectic healers. In some cases they represent the vestigial core, the first principles, of what modem medicine has become. It may be perilous to ignore the precepts of natural medicine, but they can be obscured in the fascination with modem civilization's abilities to manipulate the molecular fine points. As such, natural medicine may be a wellspring of aids to ameliorate the diseases of civilization. In other cases,

however, the practices may be harmful sociocultural delusions. How does one tell the difference? Multifarious separate practices, procedures, and substances can be included under the term natural medicine. Many of the practices considered to be complementary or alternative medicine (CAM), holistic medicine, or integrated medicine may be subsumed in the natural medicine rubric. There have been a great many published reviews of its practices and especially of its substances and approach to diseases, including the present volume.'" Nevertheless most of the practices have not borne the level of scrutiny of modem conventional medicine, in part because their practitioners are healers who may not have the facility or interest in modem scientific methods and in part because the practices may be difficult to study scientifically. Some within CAM ranks have resisted the usual scientific evaluation as necessarily reductionistic and an inappropriate means to the understanding of healing. This chapter addresses needs in the development of relevant original data in natural medicine.

PURPOSEOFRESEARCH What is the role of research in natural medicine? The improvement of healing practices is the purpose of health research. The purpose is not defense of a theory, guild, or faith nor the amusement of wandering through the arcana of methodology. An improvement could be clinical (with which individual patients may be helped) or economic (in which society's abilities to reduce total suffering and maximize health enhancement are enhanced). Various parts of the community (e.g., consumers, practitioners, government, industry) hope for research to respond to the questions "Does it work?" "Does it work better?" and "What works best?" To 117

Philosophy of Natural Medicine respond, one should know what “it” is (learned through observation and qualitative research) and what “works” means (the measures of the reduction of suffering and improvement of performance). Research tools such as descriptive statistics and hypothesis testing are epidemiologic techniques: They lead to generalizations about populations. They have limitations in clinical practice, in which the focus is on one patient at a time. Current biomedical research inmasingly focuses on strategy developed from molecular (lately genetics and proteomics) and physical (surgical and prosthetic) models. In research practice, hypothesis testing is usually more sensitive to a selected outcome and more internally valid (able to answer the precise question it set for itself) when it is redudionistic. The more discrete variables of chemistry and mechanics lend themselves to more reductionistic hypothesis testing. In turn,the validity of the reductionistic approach depends on the precision (narrowness) of the question. Natural medicine is ecologic and holistic in its orientation, with numerous broad inputs and outputs with more analog data and what might appear to be intuitive discriminations. The common models in research that emphasize transferability, internal validity, replicability, and generalizability in molecular and physical systems may conflict with model validity when one is studying natural medicine system^.^ Model validity ensures that the study design reflects the structure and logic of the practices of interest. Thus one might ask whether alternative medicine calls for alternative science. It may be so; in fact some philosophers of science and mathematicians are working toward methods that may be better suited to the evaluation of natural medicine While the development of accepted research methods that incorporate more complex and subtle biomedical quanta are awaited, much can be done with the biomedical research tools currently available.

METHODOLOGIC PROBLEMS AND STRATEGIES Medical research rightly results in a generalizable approach to human degeneration and injury. Thus one can expect to do research only with medical practices that are defined and transferable to other practitioners and patients. Successful research determines whether it is true that interventions produce benefit and how reliable they are in their effects. Research needs to be replicable if it is to evaluate a therapy for potential promulgation and thus qualifies for social support. The obvious is stated here because studies of natural medicine may have difficulty achieving these well-accepted research ideals. What does replicability mean for a medicine that may offer individualized treatment to every patient?

How does individualized treatment map onto an evaluative system in which outcomes typically refer to populations? Some have argued that a new research paradigm needs to be shaped for what has been described as an alternative paradigm of practice. Is alternative science needed for alternative medicine? There is no doubt that better tools are needed to understand and evaluate these practices, particularly informational tools that go beyond current physiologic, psychological, pharmaceutical, and epidemiologic method^.^,^ In the meantime, many accommodations within clinical study methodology can be made that will reduce the apparent contradictions of the different medical value systems. For example, the fact that conditions and treatments should be replicable does not mean that every patient needs to be denominated with a disease and that the treatment of every patient with that denomination needs to be the same. It is a corollary of individualized holistic medicine that such categorization should be done cautiously if the optimal outcome is to be reached. When performing research studies in natural medicine that might lead to improved practice and relief of suffering, one must address issues that are different from or need more emphasis than those in conventional biomedicine. All of the conventional biomedical research domains (e.g., clinical, physiologic, epidemiologic,in vitro, animal) may have an appropriate part in better defining and measuring the effects of natural medicine practices. This chapter touches on some of the methodologic issues for clinical trials, observational studies, and basic science studies.

Clinical Trials Properly performed clinical research in conventional medicine is a demanding discipline that encompasses study design, determination of sample size and population characteristics, ethics, clinical care, definition and sensitive measurement of diseases and outcomes, project management, recruitment, participant adherence and retention, data management and statistics, analysis, and interpretation. For any type of natural medicine clinical trial, the following issues bear additional attention beyond those required for pharmaceutical trials: 1.Standardization 2. Individualizationof treatment: nosology and indication 3. Combination therapies: effect size and safety 4. Nonspecific healing effects 5. Outcomes and measures 6. Controls and blinding 7. Whole practice models

It is necessary to consider these issues in the variety of types of clinical trials that may be useful in the

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investigation of natural medicine. Different approaches to clinical trials include: (a) efficacy trials, which are randomized and placebo-controlled; @) comparative trials, which test treatments against each other; and (c) pragmatic trials, in which model everyday practice conditions to the extent possible.

Standardization Replicability is a hallmark of the scientific method. Specifically what is tested (e.g., a substance, treatment procedure, or system of practice) must be defined, described, and stabilized so that it can be delivered reliably from patient to patient and study to study. Although standardization is a great strength of modern medicine’s pharmacotherapeutics, natural medicine does not have as a definitive a codex. Rather, its practices evolve year by year, with some areas highly dependent on current scientific discovery, and in others they rely empirically, rather than rationally, on procedures that are hundreds or thousands of years old. The concepts of natural medicine are often implicit in the practices rather than academically and replicably explicit. The organized natural medical professions are just beginning to evolve more definitive articulations of philosophy and clinical strategies. What constitutes a competent practitioner often remains uncertain, and many natural medicine approaches, like those of indigenous practices, are unlikely ever to be codified.’ Even with the better-regulated practices (e.g., naturopathic medicine, acupuncture, and chiropractic),health insurance coverage for those licensed practices that have practitioner-review panels (are impaneled by third-party payers) is only recent. It is only in the last few years that coding systems for alternative practices have begun to describe the array of interventionsavailable in the United States? The current emphasis on research in CAM practices calls for speeding up the process of standardization toward replicability. Communication about natural medicine research issues can be problematic when using standard clinical practice and biomedical research metaphors. One way to understand the problem is to say that natural medicine’s critical practices lack articulation and operationalization of accepted and, within the respective practitioner groups, widely understood memes. Memes are collective concepts: ideas, behaviors, or skills that are transferred from one person to another by imitation and replicable on a population basis. The term was coined by Richard Dawkins in his best-selling 1976 book, The Selfish Gene. When a meme is expressed in a phrase, it invokes meaning beyond those of the words themselves, such as in the principle vis medicutrix nuturue (the healing power of nature). Dictionaries of memes may be needed: one for the collective concepts of natural medicine practice, and another for the departures from standard research methodologies that may be necessary as the practices are

investigated. The development of memes through which to express the syncretic concepts of natural medicine is one of the benefits of researching the practices. The dearth of thisarticulation of its conepts accounts in part for natural medicine’s remarkable variation among practitioners. Its transfer from mentor to student may be imprecise or misinterpreted even before practitioner preferences and personalities are brought into play. This is not to say that the concepts of natural medicine practice are not reliably transmitted from mentor to student; only that they are not yet always articulated in ways that can be operationalized into clinical trials. The simpler problems in standardization of natural remedies are increasingly well understood; for example, those of botanical medicine. It is possible to perform a single-agent controlled trial of herbs in a specific disease; however, numerous choices should be made about the intervention. Studies should begin with verification of plant species used, growth and harvesting conditions, and the stability of purported active compounds. Selections should be made of plant parts, various crude extracts, or specific chemical constituents that may be concentrated in various ways and to varying degrees of purity. Crude fresh extracts, to which many clinical herbalists are partial, are susceptible to deterioration. In more sophisticated systems of botanical medicine preparation, a product is standardized to guarantee the minimum or maximum concentration of a number of ingredients. For example, this is true of Egb 761 (Schwabe GmbH, Karlsruhe, Germany), the Ginkgo bilobu that has been the most researched. Standardizing on particular constituents has its challenges. Active ingredients in plants often are classes of molecules (e.g., polysaccharides, saponins, terpenes) that are difficult to distinguish in biological activity among its members. Different compounds in a single species may have similar, possibly complementary effects, such as the polysaccharides and isobutyramides in Echinuceu spp. During in vitro assays, which guide fractionation of the crude extract toward a single active molecule, it is not uncommon for activity to increase but then diminish as greater purity of an identified molecular species is reached, as was the case of the terpenes of Androguphis puniculufa (AndroVir,Paracelsian, Inc., Ithaca, NY), which have an influence in cell signaling. Some manufacturers add cellular activity assays in the effort to standardize for a biologic effect rather than the quantity of a chemical constituent. When such problems are addressed successfully, these levels of standardization lead to testing the industrialization of plant medicine rather than its origins and do not answer the questions of whether the more commonly used crude plants produce the hoped-for clinical benefits. Nevertheless, most manufacturers are moving rapidly toward chemical standardizationand certified Good Manufacturing Practices (GMP). The Policy Announcement on

Philosophy of Natural Medicine

the Quality of Natural Products of the National Institutes of Health (NIH) National Center for Complementary and Alternative Medicine (NCCAM) has brought some light to the botanical standards for NlH-sponsored trials (http:/ /www.nccam.nih.gov/research /policies/naturalproducts.htm). Nutrition can be divided into dietary practices and nutritional supplements. Studies in dietary interventions are demanding. The gold standard for dietary intervention is a residential facility to maintain adherence to the therapeutic regimen, but this solution is expensive and difficult to recruit for. Frequently a long observation time is needed in dietary studies because diets are often intended as preventives or restoratives for which clinical outcomes would take a long time to observe. There are special foods and nutritional supplements, such as probiotics (live bacteria and taken to normalize commensal bacterial populations) and algae. Studies in these types of interventions have some of the same complications as botanical medicine studies. In addition, the interactions of live probiotics with commensal bacteria and the gut are incompletely understood. Homeopathy is a special case in standardization, in that chemical standards are largely irrelevant for remedies that rely on ultradilutional ”potentization” and that may contain no molecules of the material originally potentized. Biologic testing of homeopathics is in its infancy, and reliability is not ensured. Thus only the manufacturing process can be standardized at this time. ”Body, mind, spirit” is a leitmotif of natural medicine. The interplay of psychodynamic phenomena and physical health are only partially encompassed by the behaviorist approach of most recent health psychology research. Otherwise there has been relatively little progress in specific methods since the publication of George Engel’s seminal 1977 Science article that popularized the term biopsychosocial medicine, though the interplay of mindbody techniques and C A M has been explored?JOOne exception to the lack of methodologic advance has been in growing attention to the placebo effect, at times in an inclusive way as well as mechanistically.”J2Conversely the realm of meaning has been relegated most often by modem medicine to spiritual caretakers. Yet intentional spiritual interventions (e.g., personal prayer, meditation, religious practice or belief) are frequently arenas of critical importance to many natural medicine practitioners. Patients may turn to them because they afford greater attention to a spiritual dimension and their world view is consonant with the patient’s own. Although they are a small proportion of all health studies, questions about spirituality remain of persistent investigative interest. However, there are few authoritative and widely used research methods in the study of spiritual medical practices. Operationalizationof spiritual experience is likely to be idiosyncratic or culture specific.

It was only in the fourth edition of the Diagnostic and Statistical Manual (DSM-IV), published in 1995, that the possibility of a religious or spiritual problem was even recognized. Definitions of spirituality in the medical literature may refer to hope and meaning, a personal relationship with God, serenity, or connectedness, all perhaps related to states of the patient’s consciousness.13~14 A number of thinkers bemoan the lack of definition in the area.15 Although efforts to present a cogent, broadly acceptable definition have been made, they have not been widely successful.16J7Thus a better approach to speclfying spiritual interventions may be needed before they will be accessible to replicable research. In a March 2005 PubMed search, in which the denominator “spiritual” was crossed with “clinical trial,” only 12 of the 48 citations were controlled trials of spiritual interventions. There have been no replications despite the fact that most of the studies reported positive results.

Individualization of Treatment Natural medicine’s disease taxonomies (classificationsof human illness) are not always congruent with those of Western molecular biomedicine. Primary variance (differences in outcome) of efficacy is more likely to vary with the conditions of a practice’s native taxonomy than with a foreign one. For example, “strengthening the immune system,” “decreasing toxicity,” and “fortdying the will to health” are common goals in natural health therapeutics but rare in conventional practice. Treatment response would be expected to have a different profile because different diseases are being treated. Thus the speed to healing as well as the disease being treated may be confounded in the evaluation of one system by the other’s definitions and rules. These concepts are themes to be described more explicitly in natural medicine diagnosis. Some natural medicine concepts may no longer have or may never have had a biomedical equivalent, and although they are not diseases, they are diagnoses that help guide treatment. An example is the concept of ”constitution” used in naturopathy, homeopathy, and Asian medical systems. This is a patient’s given biologic potential, tendencies, and patterns of long-standing psychophysical strengths and weakness that are genetically and embryologically determined. Others are the ”biologic terrain” (the background physical health and individual context for the immediate medical problem) and the “vital force” (the motive plan or spirit animating mind and body expressed as physiologic and psychological functionality and adaptability). Biomedical equivalents exist in some parameters for system control concepts; however, they are therapeutically exploited more thoroughly by holistic practitioners. Such concepts are “balance” (as in the immune system, among microbial symbionts, hormones, and neurotransmitters), deficiency

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(not just nutritional but organ deficiencies, such as hypochlorhydria and hypothyroidism), functional reserves, endogenous and exogenous toxicities, and dysmetabolisms (e.g., syndrome X). An important concept is that a disease syndrome may be an attempt by the body to adapt to ecologic stress and so should not be unnecessarily suppressed. This is of interest not only because it is an independent variable (baseline factor) but also because it influences the measurement of the dependent variable (outcome). A skilled natural medicine practitioner necessarily expects success through individualization of treatment regimens. Individualization means that remedies are prescribed not solely on the basis of disease entities but also according to other characteristics of the specific patient. Such characteristics may be transient, constitutional, or representative of the entire constellation of the patient’s health problems and strengths and his or her capacity for self-care. The lack of fit of a person’s health syndrome with a conventional disease model, expressed perhaps in the inability or reluctance of a conventional practitioner to diagnose a particular health problem, may be the very reason a patient turns to natural medicine. A medical system that does not recognize an entity is unlikely to have an effective therapy for it. The complaint will be managed as something else, resulting in ineffective treatment while exposing the patient to the side effects of the ”remedy.” Conversely a medical system that provides an adequate explanatory model for a patient’s symptoms-their origin, aggravators, and ameliorators-has a better chance of effective treatment or management of the condition. Thus individualization of treatment is a strength of natural medicine rather than merely a research problem. Compromises may be made in practice to make a trial of specified therapy possible, but they may diminish therapeutic effect. If the need for individualization is neglected in natural medicine research design, the design will fail to apply the medicine as practiced and thus to evaluate its potential benefit.

Combination Thera eutics: Effect, Size, and Sa ety

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Combination treatment is almost a rule among natural medicine practitioners, who use multiple remedies individualized for each case on the understanding that a disease is not a single entity but a complex expression of broad inputs. This practice complicates the design of clinical trials, yet the evaluation of combination interventions is critical to assessing an examined practice. Single natural agents may have a true effect small enough that a very large patient sample size is necessary to detect a treatment difference. However, the size of the effect of several agents acting together, especially if they act by different mechanisms, may be determined by cumulative or synergetic interactions. Larger effects are more readily

detectible in a clinical trial. Combination treatment also may afford the practitioner latitude in choosing the correct remedies for a patient’s condition, thereby increasing the treatment responder rate. Another strategy in choosing elements of combinations is tailoring them to a case to efficiently address multiple conditions simultaneously, and thereby achieving better global outcomes. Yet another is to use some agents as governors to ameliorate potential side effects of primary remedies. The possibility of adverse events could theoretically rise with combinations. Although the problems of additive and synergetic actions, inhibition, and toxicity associated with multiple synthetic and novel pharmaceuticals in combination are both formidable and ubiquitous, the history of use of natural remedy candidates and the experience of clinicians in using combinations of natural products in various clinical populations mitigate these problems in everyday practice. For example, when whole botanicals are used at a traditional-use dose, early toxicity is most likely to result in nausea and vomiting or diuretic action. More serious adverse events (e.g., anaphylactoid reactions) are rarer with nutrients and botanicals of traditional medicinal use than with novel drugs of a single molecular species. Modem practitioners of natural medicine also combine modalities (e.g., homeopathy and counseling, or manipulation and herbs) that are extremely unlikely to lead to a deleterious interaction but that, if successful, could each stimulate improvement by a completely different route. Because of the breadth of options in affecting a condition, a skilled practitioner can avoid remedies that pose a risk in a particular case while still attaining the targeted pharmacologic action. There is no systematic study of the safety of combinations, but data from licensing authorities and professional liability companies for practices covered show modest levels of adverse experience.

Nonspecific Healing Effects A confounder in a clinical trial is an apparent therapeutic effect that can be attributed not to the test treatment but to a factor associated with the treatment, disease, or population studied. This is a risk inherent to all research and is the reason why randomization, blinding, and “hard” objective measures are valuable in distinguishing true differences in effect among medications. The most honest scientists may have conscious or unconscious behaviors that could bias study results if differentially applied to study groups. Yet similar behaviors are at work in everyday clinical practice to induce affiliation, confidence, commitment, and satisfaction in patients and are, in fact, the responsibility and sine qua non of skilled healers. An important confounder that may be integral to treatment is intentionality. The potential therapeutic action of pure intention, which is not mediated by language or any well-known material force, might be

espoused explicitly by only a minority of holistic practitioners, although actually it may be widely practiced among them. This may be called "psychic healing" or simply "healing." If the intent is to determine whether these techniques have effect on disease, surprisingly, there may be no particular difficulties in conducting studies than are already addressed here. Trials of intercessory prayer may provide a model.I8Design differencesmay be versus ordicalled for if the therapists are special (Ged) nary people, or if the healing energy is directed or willed versus invoked (as from God or spirits). Little has been written on the capacity of intention to influence physical outcomes; in fact, there is implicit rejection of the idea based on Cartesian mind-body duality. Nevertheless a number of studies indicate its existence.l9J0Studies of the effect of prayer or other spiritual practices also may be relevant here and raise the possibility that specific kinds of intentionality may make a difference.2I Intuition is a similarly nebulous practitioner-associated quality that may have an influence on outcome. It might be thought to bear on diagnosis as a source of data or on therapeutics as a guide among possible alternative strategies. Although intentionality and intuition are not typically listed in the educational catalogs of natural medicine academic institutions as requisite health care skills to be acquired, they may be common concepts in the culture of the institutions. Generally they are not considered antiscientific concepts that should be expunged from the awareness of students. Indeed they might be acknowledged and even honored as possible sources of data and therapeutic direction as long as their "discoveries" are not contradicted by harder evidence. The informality of the inclusion of intention and intuition in practice compounds the difficulty of including these concepts in some reproducible way in research protocols. Health care is practiced within a culture whereby practitioners and patients have roles and expectations that reinforce belief in expected outcomes. Some studies have indicated that good practitioner-patient communication results in better health outcomes. Thus some of the magnitude of effect may depend on the setting in which care is offered. Differences in outcome between medical practices may also hinge on the difference between research and nonresearch settings. For example, it is possible that subjects who refuse random assignment have a psychological orientation that may work synergistically with the physical effects of the practices of a medical culture that they prefer or to which they are native. If this is true, the evaluation of systems of practice relative to each other would preclude simple randomization. Trials that should be of real interest to policy-makers are those that determine not simply whether a practice works for anyone to whom it is applied but whether it works (and is cost effective) among those who choose it. A study design that could determine the added value of

the availability of some form of natural health care in those who choose would be one that randomly assigns patients to either a group that undergoes further randomization to strict assignment of alternative or conventional care or a group offering them a choice of alternative or conventional care.= Such a four-group trial including randomization with choice would compare the effect of the different practices among those patients who discriminatively select among them versus those who are simply assigned to them. Natural medicine has little language for placebo and other nonspecific healing effects despite the fact that many conventional scientific authorities think this is an area in which there is much to offer. Both unintentional nonspecific healing effects and intentional psychospiritual medicine are areas in which the discovery and definition of important memes, especially those that may serve research, are poorly evolved not only for natural medicine but also for Western biomedicine.

Outcomes and Measures Because natural medicine is holistic, it is expected by practitioners to have broad benefit (e.g.' correcting deficiencies, strengthening and balancing metabolic processes, and "removing the obstacles to cure"). If a natural medicine intervention for a particular disease is shaped and delivered, a benefit is likely to affect more than one disease condition at a time. The RCT, as it is usually but not necessarily performed, tends to overlook effects on diseases other than the target disease and neglects effects on the entire constitution of the patient. Clients expect to see positive results not only in objective disease parameters but also in general body functions (e.g., fatigue and energy, pain, inflammation, digestion, mental and emotional function) at a perceptible level. Thus methods to assess the efficacy of the medicine should use holistic measures accounting for effects throughout the body systems and over the life cycle, if possible. Beyond the effectiveness of medicine for the individual patient, measures of an entire holistic practice may reasonably be expected to address public health as well as environmental, social, and economic outcomes. Of course, this is ideally the way conventional medicine also should be assessed. When consistentlyapplied to both, a comparison of the practices' comparative virtues might be performed. In the past 25 years, substantial strides have been made in the development of measures that assess individual health globally. There has been progress with the development and wide adoption of instruments such as the Medical Outcomes Study 36-item Short Form questionnaire (SF-36) and of measures such as "qualityadjusted years of life saved." However, there continues to be a lack of sensitivity to changes in disease at the upper levels of function in which the burden of human suffering is great, given the number of "walking

Research in Natural Medicine

wounded,” and which has enormous societal costs, both medical and nonmedical, in life quality, functional impairment, and missed opportunity. The lack of sensitivity in the upper levels of function relates to the general absence of health measures in clinical trials as opposed to disease measures. Gentle natural treatments may show smaller more gradual improvements than may be expected from carefully engineered pharmaceutical and surgical interventions, and instruments sensitive to change are needed if trials are to be relatively short. Ultimately the possibility of the superiority of natural health care in a few areas, such as longevity, the incidence of chronic disease in aging, and the incidence and prevalence of disease in progeny, ideally will require multidecade evaluation.

Controls and Blinding The choice of appropriate comparison controls is an important issue because every alteration of control answers different questions. The different questions in the comparison of a test intervention with placebo, a specific standard of care, usual care (the patient’s baseline care), or time-attention-behavior controls are all of interest. Sometimes ethical constraints may prevent a natural medicine therapy from being evaluated without a concomitant conventional therapy. Some cases of special interest are whether natural health care leads to lower overall morbidity and mortality (1)in patients who are randomly assigned to it compared with those who are not, (2) in patients to whom it is equally available on the basis of cost and access compared with those to whom is not, and (3) in patients who would actively pursue it in the presence of health system structural resistance (e.g., devoted consumers) compared with those who would choose it only if it were equally available or with those who would explore it only under special circumstances. The answers to these questions involve belief, motivation, cost, the restraint of use because of cost (from the consumer’s side), the restraint of access because of cost (from the provider’s side), and compliance. These answers may be fundamental to determining both the efficacy and efficiency of the inclusion of various forms of natural medicine in a rationally structured health care delivery system. Treatments can be categorized simply into substances (drugs, remedies), procedures, and interactions (verbal and behavioral medicine). The double-blind RCT test system is mostly easily applied with the evaluation of substances. Nonmaterial process interventions, such as manipulation, exercise, acupuncture, other forms of point work, and psychological and spiritual treatment, are more methodologically problematic in the RCT desideratum of blinding. Blinding is likely to prove difficult for most dietary manipulations, psychospiritual practices, and any whole practice intervention. In these

cases, blinding often may be at least partially maintained by separating evaluation from treatment and blinding the evaluator. In considering the value of blinding one should remember that studies that blind the practitioner and patient decrease or eliminate the possibility that intentionality will contribute to a positive outcome. Yet, CAM theories explicitly accommodate bonding and expectation as contributors to outcome.23

Whole Practice Models Given that individualized combinationsof modalities and remedies generally are the rule in natural medicine and that their selection is guided by a health system’s own principles and guidelines, evaluation of models of whole practices is most likely to reveal their potential health benefit. The main difficulty that arises is in attaining replicability of the intervention. Although they remain both innovative and challenging, a number of intervention models are possible in approaching the ideal. The simplest is a fixed combination of remedies, although this approach abandons individualization. If it is applied in trials with specific inclusion and exclusion criteria, however, the loss of individualization may be tolerable. A slightly more ambitious approach to whole practice is a menu of choices applied, say, to several possible etiologies in a symptom manifestation (disease) under study. As alternative medicines have been studied in recent years, ”pragmatic” trials have been increasingly explored to treat the practitioner at some specified level of qualification as the unit of intervention. This may be understood as treating the practitioner as a ”black box.” A further step in sophistication is the intervention driven by an algorithm. Such algorithms may be derived through expert practitioner panels. The design and replicability of best practice protocols are just beginning to be studied in naturopathic and Chinese medicine. The complexity of the models that have resulted may well require a manual for the guidance of practitioners, who must be well trained to assess patients and deliver a standardized intervention flexibly.“ A manualized practice would also provide the documentation necessary for ethical and regulatory reviews. A new question that would arise in such studies of manualized practice is the degree of adherence by the provider to the protocol.

Observational Studies There are essentially two components to scientific research observation and experimentation. Observation describes existing reality and the natural history of clinical concepts within medicine. It is where ideas of association are formed and hypotheses are generated. Observation requires focus; therefore the context for observation is the choice of focus. Operating questions that are preliminary to experimentation include: Does

Philosophy of Natural Medicine the phenomenon (or a relationship) exist? and What are its characteristics (description)?Experimentation in medicine is more about influencing future reality. Experimentation tests hypotheses, presumes a focus, and goes on to the context problem of how to model the experimental conditions to reflect a current or potential reality. In medicine, the operating question often concerns causing a desired outcome by manipulating the independent input variables. The input variables are discovered ultimately through observation, as are the models in which to study them. Both observation and experimentation are needed to validly evaluate medical practices. The challenge to results observed in evaluation of clinical practice is determining whether the observed association reflects a causative relationship. Observational studies (quantitative or qualitative) have been considered low on the hierarchy of validity in evaluation of medical practices. Effect sizes found in observational studies are often considered inflated. Yet recent work has shown effect sizes from clinical trials and observational studies to be ~ i m i l a r . ~ , ~ ~ Observational studies, in particular outcomes research, have some unique advantages in the study of natural medical practice. Outcomes research involves cohort studies wherein repeated health status evaluations in ordinary care settings compare outcomes of spontaneously arising variations of care, such as standard care and alternatives to it. Variations may be specific remedies, treatment approaches, or even whole professional practices. Advantages include the lack of ethical conflicts about withholding conventional treatment because the patients choose their practitioner. The effect of intention on the part of patient and practitioner is not abrogated. The medicine is implemented fully individualized with no constraint on the combinations considered best for a patient. The cost of research per case is a lesser constraint than in randomized trials if patients (or third parties) cover the cost of care. Cost-effectivenesscan be incorporated in design as an outcome. More early observational studies will help to guide future trials. Even best-case series, a very simple approach to observational study in CAM, are having a n effect on research directi~ns.~’ The slowly growing coverage of CAM practitioners by third-party payers in health delivery systems over the past 20 years has generated a surfeit of data on use and cost for currently licensed natural medicine practitioners that can be used for comparison with outcomes of standard therapy, although these data remain largely unexplored. Other observational studies have been undertaken, although most have been preliminary and unpublished. Daniel Cherkin’s study of the model of the National Ambulatory Care survey is remarkable in ascertaining the content of practice of state-licensed naturopaths, acupuncturists, chiropractors, and massage therapists.28The care of patients currently using natural

medicine is a valuable source of data for evaluating and monitoring health outcomes over time or against different forms of practice. Observationalstudies in general and in such studies in natural medicine in particular suggest that large amounts of data are generated in the course of well-designed studies. The complexities of natural medicine, with its multiple inputs (patient characteristics and combination individualized treatments), broad measures, standardization data, complex control conditions (e.g., ”usual” care), and early descriptive work, all imply data for specification and exploration. To plan studies, including single-agent trials, and to understand results, natural medicine research would benefit greatly from dedicated infrastructure for data management and quantitative analysis. The NIHNCCAM has recognized the need and value of developing such infrastructure at CAM institutions that have clinical expertise in the practices.29

Basic Science Studies Data from the basic sciences ensure the causal chain linking a happy clinical observation and an intervention. They help the community understand and use the natural medicine professions’ knowledge. All of the natural medicine practices would benefit from greater exposure to the entire array of laboratory pharmacology and might, in turn,inform pharmacology of their own useful strategies. In the exploration of natural medical theory and in refining remedies, it would be useful to have access to a range of basic science techniques from analytic chemistry to classical microbiology to advanced molecular biology. Thousands of natural products have been screened for numerous laboratory outcomes. However, new understandings of human biology and advances in technology have made many more types of studies possible in areas such as combinatory pharmacodynamics, gene expression, proteomics, glycobiology, and immunology. Practitioners could guide the refinement of study questions from their best clinical judgment for future investigation. One continuing need is in standardization of materia rnedicu, not only on chemical constituents but also on biologic activity. Other needed in vitro work includes combination effects and safety, and high dilutional effects. Mechanistic studies of natural treatments with substantial clinical evidence may provide knowledge useful across medical cultures. Recently, NCCAM explicitly turned toward the basic sciences in future CAM research centers to be funded. Animal studies present their own complexities for the practices of interest. On one hand, acupuncture and homeopathic veterinary are common, and demonstration of the concepts of the animal study practices seems a reasonable route to improving practice. On the other, some CAM institutions have policies prohibiting animal

Research in Natural Medicine research on the basis of cruelty. Many vitalists and holistic practitioners hold that neither animal studies nor in vitro work appropriately reflects the human being. Their arguments may bear legitimate scrutiny. However, when animal work is the most fruitful way to pursue an important clinical goal, some natural medicine academic centers are willing to collaborate with animal laboratories. Considering the salugenic rather than disease-oriented goals of most natural medicine practices, it may prove a valuable direction for natural medicine institutions to improve collective understanding through the basic science of normal and optimal physiology and the effects and mechanisms in which they are most likely to be expert. Alternative practitioners may in fact be well suited to contribute knowledge in the measurement of overall health.

CRITERIA FOR A PRIORITIZED RESEARCH PROGRAM The entire array of research designs has a place in natural medicine research. There is a wide range of discussions in the literature and many currently ongoing studies spurred by substantial funding from the NIH. Methodologists have covered many problems in evaluation of different expressions of natural medicine, and the approaches and methods have been well s u m m a r i ~ e d . However, ~~,~ resources are always limited; thus research should be prioritized. Some major criteria to consider in developing programs of research to be considered are the following: 1. Focus on diseases with the highest burden of human suffering and the greatest public health significance as well as those in which standard therapy falls short of cure and effective management.

1. Jonas W, Levin J, eds. Essentials of complementary and alternative medicine. Philadelphia: Williams & W h , 1999. 2. Emst EM, Pittler MH, Stevinson C, et al, eds. Complementary and alternative medicine: a desktop reference. St Louis: Mosby, 2001. 3. Jellii JM, ed. Natural medicines: comprehensive database, ed 3. Stockton, CA: Therapeutic Research Faculty, 2000. 4. Jonas WB, Linde K. Conducting and evaluating clinical research on complementary and alternative medicine. In Gallin I, ed. Principles and practice of clinical research. San Diego: Academic Press, 2002. 5.Bell IR, Caspi 0, Schwartz GE, et al. Integrative medicine and systemic outcomes research issues in the emergence of a new model for primary health care. Arch Intern Med 2002;162:133-140. 6. Goldberger AL. Non-linear dynamics for clinicians: chaos theory, fractals, and complexity at the bedside. Lancet 1996;3471312-1314. 7. Eisenberg DM, Cohen MH, Hrbek A, et al. Credentialing complementary and alternative medical providers. Ann Intern Med 2002; 137965-973. 8. Dumoff A. New codes for CAM: HHS review could make them a reality. Altern Ther Health Med 2002;832-33,35-36. 9.Engel GL. The need for a new medical model a challenge for biomedicine. Science 1977;196129-136.

2. Evaluate first the treatments that have the greatest likelihood of reducing the burden of suffering-the low-hanging fruit among natural medicine therapeutics and preventives. There are two sources for targeting decisions in this regard: the evidence already present in the scientific literature, particularly systematic reviews, and the opinions and data of experienced natural medicine practitioners. 3. Attend to methodologic evolution and the necessary sequencing of studies to achieve long-range goals and to explore for and validate positive clinical experiences. Some research questions require methodologic innovation because we do not yet know exactly how to answer them (e.g., in evaluating the whole-systemsapproach to disease, long-term safety, ultradilution and combinatorial effects, and spiritual practices). Important questions may call for complex designs that combine observational and experimental research. Clinical research often requires preclinical preparation. The confidence of investigators and funders and the clarity of their direction improve with preliminary data from pilot studies and observational outcomes studies. 4.Attend to questions that are fundable and for which infrastructure exists or can be quickly built. This requires attending to the issues that four funding sources-the NIH, foundations, commercial interests, and philanthropy-are prepared to act on.

Finally, we must prepare and build for the long run when husbanding and developing research resources. There is no ultimate proof in medicine, only evidence that inclines us in the right direction for a time but that can be superseded at any moment.

10. Freeman LW, Lawlis GF, eds. Mosby’s complementary and alternative medicine: a research-based approach. St Louis: Mosby, 2000. 11. Kaptchuk TJ.The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann Intern Med 2002;136:817-825. 12. Russo E. The biological basis of the placebo effect: imaging technologies bring empirical rigor to the study of a mysterious medical phenomenon. Scientist 2002;1630-33. 13. Swanson CS. A spirit-focused conceptual model of nursing for the advanced practice nurse. Issues Compr Pediatr Nurs 1995;18: 267-275. 14. Roberts KT, M a l l A. Serenity as a goal for nursing practice. Image J Nurs Sch 1996;28:359-364. 15. Goddard NC. Spirituality as integrative energy: a philosophical analysis as requisite precursor to holistic nursing practice. J Adv NUS 1995;22:808-815. 16. Dyson J, Cobb M, Forman D. The meaning of spirituality: a literature review. J Adv Nurs 1997;261183-1188. 17. Pehler SR. Children’s spiritual response: validation of the nursing diagnosis spiritual distress. Nurs Diagn 1997;8:55-66.

18. Harris WS, Gowda M, Kolb JW, et al. A randomized, controlled trial of the effects of remote, intercessory prayer on outcomes in patients admitted to the coronary care unit. Arch Intern Med 1999;1592273-2278. 19. h o r DJ. Healing research: holistic energy medicine and spirituality. Munich: Helix Verlag, 1993. 20. schlitz M, Braud W. Distant intentionality and healing: assessing the evidence. Altern Ther Health Med 1997;3:62-73. 21. Targ E. Research methodologies for studies of prayer and distant healing. In Lewith G, Jonas WB,Walach H, eds. Clinical research in complementary therapies: principles, problems and solutions. New York Churchill Livingstone, 2002. 22. Institute of Medicine, National Academy of Sciences, Committee on the Use of Complementary and Alternative Medicine Use by the American Public. Complementary and alternative medicine in the United States. Washington, Dc: National Academies Press, January 12,2005. 23. Wirth DP. The signhcance of belief and expectancy within the spiritual healing encounter. Soc Sci Med 1995;41:249-260. 24. Schnyer R, Allen JJ. Bridging the gap in complementary and alternative medicine research manualization as a means of promoting

standardization and flexibility of treatment in clinical trials of acupuncture. J Altern Complement Med 2002;8:623-634. 25. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000;342: 1878-1886. 26.Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2OOO;3421887-1892. 27. Nahin RL, Straw SE. Research into complementary and alternative medicine: problems and potential. BMJ 2001;322:161-164. 28. Cherkin DC,Deyo RA, Sherman KJ, et al. Characteristics of visits to licensed acupuncturists, chiropractors, massage therapists, and naturopathic physicians. J Am Board Fam Pract 2002;15: 463-472. 29. Lewith G, Jonas WB, Walach H. Clinical research in complementary therapies: principles, problems and solutions. New York Churchill Livingstone, 2002. 30. Nahin RL. Use of the best case series to evaluate complementary and alternative therapies for cancer: a systematic review. Semin 0nc0l 200229:552-562.

Women in the History of Medicine Jennifer L. Booker, ND CHAPTER CONTENTS Introduction 127 From Ancient Greece to Thirteenth-Century Rome 127 The Fourteenth through Seventeenth Centuries 128 The Witch Hunts 129 Discrediting the Midwives 130 Conclusion 130 The Battle of the Sects in Nineteenth-Century America 130

INTRODUCTION Traditionally women have been the healers, caring for their families and neighbors and helping one another through childbirth. Over centuries women developed and used herbal remedies, poultices, diet therapies, water treatments, and techniques for bone setting and the suturing of wounds. Their methods were passed down to form not only the basis of naturopathic medicine but also much of what is allopathic medicine. Women always have been at the forefront in providing humane health care, from the venerated women healers of ancient Greece, to the persecuted medieval women lay healers, to the pioneering women of North America. The witch burnings of medieval Europe; the persecution of midwives in the eighteenth, nineteenth, and twentieth centuries; and the discrimination experienced by women in medicine today are all part of the history and development of medicine. To be unaware of women’s role in medical history is to be ignorant of half the story of medicine. Today health care is primarily in the hands of men, with women playing helpmate roles. The history of women as primary health care givers has been almost completely obliterated. Information about women healers is not part of mainstream knowledge; the interested reader must seek out books specifically about women healers that, until recently, have been generally unavailable. Indeed, women are excluded from history books

Rise of the Medical Establishment 130 Upheaval of the Feminist and Popular Health Movements 132 The Threat of Women Doctors 134 Hydrotherapy:A Haven for Women 135 Victory for a Male Profession 136 Midwives:The Last of the Women Healers to Fall 137

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138

Conclusion 140

generally, not only those concerned with medicine (see Spender for further discussion).’ This dearth of information is a reflection of the pervasive sexism of civilization. It is the author’s intent to reclaim here part of the history of women in medicine. At the original writing of this chapter in 1988,93% of medical doctors (MDs) or allopathic physicians were men. Throughout the industrialized world there were still only few women physicians: England with 24%* and Canada with Statistics from 1997 indicated that 40%of allopathic medical school graduates were women, making up 21.3% of MDs.4 This underrepresentation of women in medicine is the culmination of events that date back to early Greece. This chapter investigates the chronologic events that have resulted in a medical system dominated by white, middle-class and upper-class men.

FROM ANCIENT GREECE TO THIRTEENTH-CENTURY ROME Trotula lived in the eleventh century and studied and taught in Salerno, Italy. Her gynecologic work, De Mulerium Passionibus (On the Sufming of Women), the earliest known compendium of women’s health care, includes the treatments used by Greek, Roman, and Arab physicians. This text was used across most of Europe during the ensuing 300 years. First typeset in 1544, it was reprinted many times in several languages?

127

Unfortunately, Italy was an exception in allowing women into medical schools and careers. The faculty of medicine at the University of Paris absolutely opposed female physicians. In 1220, the law strictly prohibited anyone who was not a faculty member from the practice of medicine, and women were effectively eliminated. There was little need to enforce the law until 1322 when Jacoba Felicie, along with several other women, was charged with examining sick persons, prescribing remedies, curing patients, and receiving fees without a license. Although many of Jacoba’s patients testified in her favor, and she demonstrated that her procedures were the same as those used by licensed physicians, she was stiU charged and fined. This discrimination continued in France, without remittance, until 1868 (600 years later), when the first woman was allowed entry into the Paris Medical School. Generally the tradition of women healers, which had begun in the ancient world, continued until approximately the thirteenth century. Surgery was commonly undertaken by nuns at the local convents or by the ”lady of the manor” in wealthy homes as a charitable duty. Some women healers received payment for their skills. Queen Phillippa, wife of Edward I11 (1327-1377), employed Cecelia of Oxford, who was the designated wise woman of the village, as court surgeon. In the thirteenth century, contact with Arabian scholars stimulated a revival of interest in learning that resulted in two major developments that led directly to the exclusion of women from the healing professions: the appearance of medical schools in universities and the formation of barber-surgeon guild^.^ With the incorporation of medicine into universities, only licensed doctors were given the legal right to practice with the title of physician. With the exception of Italy, all European universities were closed to women. Official recognition of their medical skills was no longer available. The development of universities and medicine was strictly controlled by church doctrine, and innovation was suppressed. Medical students studied Plato, Aristotle, and Christian theology. Medical theory was restricted to Galen and the study of the “complexions” and “temperaments” of men. Students rarely, if ever, saw patients, and the church outlawed human dissection. Surgery was considered degrading and menial. Treatment consisted of bleeding, leeches, and quasireligious rituals. For example, the physician to Edward 11, an Oxford graduate, prescribed writing ”in the name of the Father, the Son and the Holy Ghost, Amen,” on the patient’s jaw for a toothache.6 In contrast, the women healers of this era, practicing illegally, followed the healing methods of Trotula and St. Hildegarde of Bingen, Germany. Hildegarde (10981179) wrote a compendium of natural healing methods

entitled Libw Simplicis Medicine. In it, at a time when male physicians had no use for such advice, she lists the healing properties of 213 plants and 55 trees and asserts the importance of cleanliness for proper treat~nent.~ Although the natural healing methods of these women resulted in their being persecuted and burned at the stake as witches in the Middle Ages, many of these methods continue to be used in naturopathic medicine today. Viewed from the perspective of the late twentieth century, church doctrine was disturbingly misogynistic. Pain in labor was perceived as the Lord‘s just punishment for Eve’s original sin. In the thirteenth century, St. Thomas Aquinas2wrote:

As regards the individual nature, woman is defective and misbegotten, for the active power in the male seed tends to the production of a perfect likeness according to the male sex; while the production of women comes from defect in the active power, or some material indisposition. . . . (Summa Teleologicn) This attitude toward women climaxed in the fifteenth century with the burning of witches or lay healers (discussed later). The second development of the thirteenth century that served to exclude women from the healing professions was the formation of barber-surgeon guilds. These guilds laid down regulations for apprenticeship and membership. In return for guaranteeing standards of practice, members were given exclusive rights to their home town’s needs for surgical care and could prosecute non-gculd members who dared to perform surgery. Those most affected were the midwives. Forceps, a surgeon’s invention, could be used legally only by guild members; therefore a midwife was required to call in a barbersurgeon during a difficult delivery. The surgeon would either remove the infant piecemeal by hooks and perforators or perform cesarean section once the mother was dead.6 Occasionally women were allowed admittance into barber-surgeon guilds through patrimony or apprenticeship, but their numbers were small. By the end of the fourteenth century, organized medicine had effectively excluded women. The church joined the witch hunts in the fifteenth century, and the long tradition of women healers was almost completely eradicated.

THE FOURTEENTH THROUGH SEVENTEENTH CENTURIES By the fourteenth century, professional, universitytrained physicians were in demand by the wealthy. Middle- and upper-class educated women healers were eliminated through being excluded from universities and licensing. This left only the women lay healers of the peasant class as competition. The medical profession appealed to the church for help, and the church

Women in the History of Medicine ~~

~

responded by persecuting women in one of the most vicious rampages in history. There were two reasons for this victimization: The witch healer was an empiricist in direct opposition to church doctrine, and women represented sexuality, a betrayal of faith through sensory awareness and alignment with the devil. The church believed women to be the conduit of all evil. All pleasure was condemned because the devil was considered its source. Women were associated with sex, and lust in either husband or wife was blamed on the woman. A male priest immediately baptized a newborn to ensure salvation of its soul, which had been exposed to the wickedness of the woman for 9 months while in the womb. It was believed that upon resurrection, all humans would be reborn as men? Women healers had sins to atone for other than their sex. The so-called witches relied on their senses and observation in treating their patients. The church believed that to trust one's senses was wrong: The senses were the devil's playground and were used by the devil to lure men into the conceits of the intellect and delusions of carnality, and away from the faith.9 The methods of the witch healer were based on years of experience. She maintained an attitude of active inquiry, learning through trial and error, and cause and effect. Her repertoire included herbal remedies such as clary, hyssop, lily, ergot, belladonna, and digitalis, many of which are still used by naturopathic physicians today. Codified in the written works of Hildegarde of Bingen and Trotula of Italy, her approach was scientific according to today's standards. Even established medicine referred to these works for ~enturies.~ The approach of MDs, deeply antiempirical, with no concern for the material world and empirical observation, was more consistent with church doctrine. They did not search for the natural laws governing physical phenomena but instead abided by the belief that the Lord created the world anew each moment, and hence there was no point in questioning one's surroundings.

The Witch Hunts During the fourteenth through seventeenth centuries, witch hunts spread across Europe. Thousands of executions, usually live bumings at the stake, were carried out, first in Germany and Italy and later in France and England. In 1484, a witch-hunting manual, the Malleus, was written by reverends Kramer and Sprenger, sons of Pope Innocent VIII. It contained specific instructions for conducting witch hunts and methods of torture for extracting confessions and names of other witches. Witchcraft was defined as political subversion, religious heresy lewdness, and blasphemy. Women were accused of every conceivable sex crime against men. They were accused of being organized, of having magical healing powers, and of harming with magic. According to the Malleus, "All

witchcraft comes from carnal lust which in women is insatiable. . . . And blessed be the highest who so far has preserved the male sex from so great a rime."^ Women often were charged and burned at the stake simply for possessing medical knowledge and obstetric skills. "If a woman dare to cure without having studied, she is a witch and must die" Of course, women could not officially study because they were not allowed into medical schools. English physicians complained to Parliament about the "worthless and presumptuous women who usurped the profession" and requested that fines and long imprisonment be the punishment for any woman "who dared to use the practice of Fisyk."lo King Henry VIII heard their plea and secured nationwide regulation of medicine and surgery with the Act of 1512,which installed a system of licensing that approved practitioners and punished and suppressed all others.8 In Europe, the church was given the responsibility of implementing the program to eliminate women healers and "witchcraft." In several German cities, approximately 600 burnings occurred each year, two each day except Sundays. More than 900 "witches" were executed in 1 year in the Wiirzburg area, and more than 1000 in the area of Como, Italy. In Toulouse, France, 400 women were put to death in 1 day. In the Bishopric of Trier in 1585, so many women were killed that two villages were left with only one woman each. It has been estimated that the total number of executed "witches" (85% of whom were women) was in the million^.^ The persecution of women healers greatly strengthened the relationship between the church and the medical profession. The doctor was considered the medical expert, giving an aura of authority to the witch hunt as he decided whether the accused was a witch and what afflictionswere the results of witchcraft. The dogma was that if a woman effected a cure, it was with the help of the devil, whereas if a male priest or doctor effected a cure, it was with the help of God. The Lord worked through male priests and doctors, not through women.2 The majority of witches were the general practitioners of the peasant population, and for 1000 years they were the only source of health care for the general population. The poor did not have access to hospitals or universitytrained physicians and were bitterly afflicted with poverty and disease. The church upheld a double standard in terms of who should receive health care. It was a given for the upper classes and nobility. For the poor, life experience in the world was considered fleeting and unimportant and so was their suffering. The peasants were offered little in the form of relief or even words of comfort from the church: "You have sinned and God is afflicting you. Thank him and you will suffer so much less the torment in the life to come. Endure, suffer, die. Has not the church its prayer for the dead?'r9

Philosophy of Natural Medicine The witch hunts deprived the peasantry of the only health care that was available to them and helped establish the dominance of a technologic and rather violent male-dominated medical profession by eliminating the last of their competition. Not only during the medieval period in Europe but also until about 1875, universitytrained doctors depended on blood-letting and purgatives. Calomel, a mercury salt and the most popular purgative and cure-all medical remedy, was used in large doses for acute problems.” Through the seventeenth century, doctors derived their prognoses from astrology and the theory of ”complexions and temperaments,’’ partially treating their patients with incantations and quasireligious rituals. A common treatment for leprosy, for example, was a soup made of black snake caught on dry land among stones? In contrast, the approach of the medieval woman healer emphasized the role played by the patient’s innate power of healing, a view still held in naturopathic medicine today. She regarded illness as part of the life process and an attempt on the part of the organism to regain homeostasis. Her methods included herbs, diet therapy, massage, water cures, poultices, and other gentle health-promoting approaches.12 Women healers used their extensive knowledge of physiology, anatomy, and herbs gained through experience and observation. Their superior healing abilities were acknowledged by Paracelsus, who in 1527burned his texts on pharmaceuticals, confessing he “had learned from the Sorceress all he knew.”5 However, the witch hunts branded women healers as superstitious and potentially malevolent and so thoroughly discredited women healers among the emerging middle class that, in the seventeenth and eighteenth centuries, devastating inroads were made into their last preserve, midwifery.

Discrediting the Midwives The English Act of 1512, which ultimately controlled the licensing of physicians, made no mention of midwives, probably on the basis that midwifery was considered part of surgery? The system of licensing that did develop for midwives was concerned mainly with social and religious functions, for there was no way for a woman to become educated and therefore no possibility that she could achieve legitimate status through government licensing. As already mentioned, medical schools and universities were closed to women everywhere in Europe except Italy. The majority of midwives were peasants who could not afford to travel abroad to study. As a result, midwives lacked the knowledge of Latin and Greek necessary to read texts or communicate their knowledge of female anatomy and physiology. The few midwives who did manage to educate themselves, by

witnessing dissections and reading medical works, still remained legally unqualified because they could not attain a university degree.E Midwives in England organized in the mideighteenth century to protest the Act of 1512 and the intrusion of male doctors into their realm. They charged doctors with commercialism,damaging infants’ skulls with dangerous overuse of forceps, and causing undue harm to mothers. But because midwives did not know proper medical terminology and many of their members were being burned as witches even as they spoke, their protests were easily dismissed as “old wives’ tales” based on ignorance and superstition. Their skill and tradition were so discredited that they lost claim to their own techniques. For example, when Ambroise Pare (1510-1590), surgeon to the King of France, developed an interest in childbirth, he laid claim to discovery of the podalic version, the method used and described by the woman physician Aspasia in secondcentury Rome.5The male medical profession could now boast of their superior obstetric methods. By the early 1600s, male “midwives” began to establish themselves in earnest. They were called in for difficult cases, often with disastrous results. Nevertheless, childbirth had become the province of male physicians throughout Europe by the end of the eighteenth century.*

Conclusion The persecution of witches was a major exercise in medical and social control, eliminating women healers and removing the peasants’ only source of health care. World views that conflicted with church doctrinefor example, that recognized the nature principle and the holistic quality of human life-were exorcised from the healing arts, not to be revived until the women’s movement in North America in the 1700s and 1800s. Perhaps most significant was the effect the witch hunts had on society’s perception of women, firmly establishmg the suspicion of evil, black magic, and the immoral sexuality of women in general, and women healers specifically.

THE BAlTLE OFTHE SECTS IN NINETEENTH-CENTURY AMERICA Rise of the Medical Establishment In early colonial America, the responsibility for healing was in the hands of women, as was general family care. University-trained physicians (allopaths) did not immigrate from Europe and Great Britain to the colonies until the late 1700s, and then only a few came. In the New World, formal education, including medicine, was not available at the university level. In New Jersey, for

Women in the History of Medicine

example, medical practice, except in extraordinary cases, was mainly in the hands of women as late as 1818.13 Colonial women brought centuries of healing lore with them, handed down from the ”witch” healers of medieval Europe. Knowledge of indigenous herbs learned from the Native Americans was combined with the European traditions of massage, hydrotherapy, botanicals, and midwifery. Medical practice was open to anyone who could demonstrate healing skills, regardless of formal training, race, or sex. Then, in the early lBOOs, American university-trained doctors, modeled after the established European allopaths, began to become available. The four medical schools established by the turn of the century were far below European standards, and programs were only a few months in length. Most schools lacked clinical facilities and did not require even high school diplomas for entry. As the number of formally trained doctors grew, it became clear that much needed to be done before they could achieve the prestige and economic status of European MDs. One of their first tasks was to distinguish themselves from lay healers. Allopaths already were easily identified: They were male, middle- and upper-class, and almost always more costly Their clientele consisted of middle- and upper-class citizens who could afford the prestige of being under their care. It was fashionableamong upper-class women, for example, to employ male doctors for obstetric care, much to the horror of the general populace, who considered it immoral for a woman to expose herself in such a manner to a man.I3 However, the allopaths had little to offer in terms of theory or practice that was superior to what was available through folk medicine. Women healers used gentle botanical medications, offered dietary advice based on generations of experience, and, perhaps most importantly, did little or no harm. Allopathic doctors distinguished themselves by doing a great deal of harm in the form of ”heroic medicine.” Benjamin Rush has been credited with playing a central role in establishing heroic medicine. Along with a small group of elite American MDs, he completed his medical education with a few years of study in Great Britain. Here the group developed the style of the genteel, highly paid European physician, and aspired to establish a similar medical model in the New World. To accomplish this, they had to persuade the general public that the allopaths were able to offer medical care superior to the inexpensive and efficacious care provided by women lay healers and midwives. An all-encompassingtheory and system of therapeutics was developed that had immediate, although extremely dangerous, results. The purpose was to produce the strongest possible visible response in the patient. The

stronger a drug or procedure, the greater its therapeutic value was purported to be. Bloodletting, purgatives, laxatives, enemas, and blistering were among the most common treatments. A patient was bled until either he fainted or his pulse was no longer palpable. In 1847, one physician, after observing that extensive blistering of children often led to convulsions, gangrene, or even death, concluded that blistering ”ought to be held in high rank” in the treatment of childhood diseases.” Not all physicians agreed with these methods, however. Douglas observed, “Frequently there is more danger from the physician than from the Distemper . . . but sometimes not withstanding the Male Practice, Nature gets the better of the Doctor and the patient recovers.”’l Aside from the lack of effective therapeutic techniques, there was a total void where medical theory should have been. Air was considered the carrier of disease, and getting wet was thought to enhance susceptibility to disease. Those who listened lived in fear of bathing, sunlight, and breezes. Drinking water was kept from the ill, and windows were kept shut and covered with heavy drapes. Women were advised to keep themselves covered from the sun at all times with parasols and veils. Heroic medicine gave regular doctors the appearance of being able to keep back disease, winning the ”battle” against disease even if it killed the patient. Some of these doctors became wealthy and gained much influence with statesmen and other powerful members of the upper classes. Politically this influence was essential to subsequent events in the development of allopathic medical dominance in North America. Professions are the creation of the ruling class. To become sole providers of health care and succeed with the sham of heroic medicine, allopaths needed patronage from the ruling class. According to sociologist Elliot Friedson, “A profession attains and maintains its position by virtue of the protection and patronage of some elite segment of society which has been persuaded that there is some special value in its work.”l Between 1800 and 1820, allopaths used their newly acquired influence to pressure 17 states into passing licensing laws restricting the practice of medicine to their own kind. In 10 states, practicing without a license meant imprisonment.l4 However, two major unforeseen political problems appeared to disrupt the allopaths‘ plans. First, the general populace and lower classes did not accept the hazards and pretensions of heroic medicine, preferring the more effective and much less painful and expensive health care provided by lay healers. The second problem was enforcement of licensing laws. The general populace was not prepared to persecute their own trusted healers, who often were the women of their own families or wellknown neighbors. The new laws incited public outrage.

Philosophy of Natural Medicine The popular health movement emerged, fanned by the labor rebellion against upperclass elitism and exploitation of burgeoning industrialization.

Upheaval of the Feminist and Popular Health Movements In the early 1800s, the industrial revolution created a deep economic division between the upper and lower classes. Factory employees and unskilled laborers lived in abject poverty on the edge of starvation while working long hours for ridiculously low wages. Single-family farmers and owners of small businesses were exploited by banks whose financial manipulations often pushed them into ruin. Upper-class industrialists flaunted wealth gained at the expense of the lower classes. The labor movement arose from this setting, with its membership of farmers, artisans, and factory workers. At the same time, the women’s movement began to take greater hold among working-class women. In early industrialized society, many women were thrown together, free of the company of men. Women were either confined to home and church or worked in all-female factories such as those in the New England mill towns. Discovering their common aversion to heroic male medicine, women began to develop alternative^.'^ Among the hundreds of benevolent associations, charitable institutions, and mutual support groups was the “Ladies Physiological Society,” a feminist health care group. At society meetings, women learned about female anatomy, physiology, and personal hygiene; oldtime home remedies were recultivated and exchanged; and the lore of botanical healing and other techniques used by the pioneer women healers were recovered. In opposition to the dangerous therapies of allopathic doctors, they emphasized preventive care-frequent bathing, loose-fitting clothing, whole grains, and fresh air-all in direct opposition to the medical dogma of the day. University-trained regular doctors were considered members of the parasitic, nonproducing classes. The women’s health movement was at the forefront of general social upheaval, a radical assault on medical elitism, and an affirmation of traditional ”people’s” medicine. Women’s outrage against allopathic medicine, shared by working-class men, resulted in a mass movement against medical professionalism and ”expertism” of all forms. It was a class war, and the allopathic doctors were on the side of the aristocraticupper class. Regular doctors, with their claim to educational superiority, were denounced, along with the universities that trained them. It was popularly believed that students learned in the universities to look on labor as “servile and demeaning.”’2 By the 1830s, the labor and feminist movements had converged into the popular health movement. According to historian Richard Shryock, “This crusade for women‘s health was related both in cause and effect to the demand for women’s rights in general and the

health and feminist movement became indistinguishable at this point.”” The health movement was concerned with women’s rights, and the women‘s movement was concerned with health care and access to medical training for women. However, it took a male voice to repeat what women had already said and done before any change took place. Samuel Thomson is credited with laying the foundation of a theory (see Chapter 35) and practice of folk medicine for the working class and feminists. A poor New Hampshire farmer, he had watched his wife and mother die at the hands of allopathic doctors. Outraged by their violent methods, he began to reconstruct the folk medicine he had learned from a woman healer and midwife named Mrs. Benton. According to Thomson: The whole of her practice was with roots and herbs applied to the patient, or given in hot drinks, to produce sweating which always answered the purpose. . . . By her attention to the family, and the benefits they received from her skill, we became very much attached to her; and when she used to go out and collect roots and herbs, she would take me with her, and learn me their names, with what they were good

Thomson’s methodology systematized Mrs. Benton’s methods, which she in turn had learned from Native American Indians and the tradition of women healers before her. In 1822, he published A New Guide to Health, which basically described her entire healing system. His intention was to provide the public with self-sufficient health care and remove healing as a commodity from the marketplace. Although less toxic and more natural than the medical therapies of the day, Thomson’s treatments were not always particularly gentle. For example, lobelia was given as an emetic to cleanse the stomach and followed with capsicum to induce fever. He also used steam baths (his followers were often called ”steamers”) and sought to restore equilibrium through the use of Myrica cerifera (bayberry), Nympheu odoruta (pond lily), Pinus canadensis (spruce), and Rhus glabrurn (sumac).16 The Thomsonian Movement was in full swing by 1835, claiming just less than one fourth of the entire U.S. population. Five Thomsonian journals included articles concerned with health, women’s rights, and affronts to female health inflicted by “heroic” obstetric practices. Thomson held that women were natural healers and believed strongly that doctors, who graduated without ever having witnessed a delivery, should leave obstetrics to midwives. His son, John Thomson, wrote: We cannot deny that women possess superior capacities for the scienceof medicine, and although men should reserve for themselves the exclusive right to mend broken limbs and fractured skulls, and to prescribe in all cares for their own sex, they should give up to women the office of attending upon women.15

These ideas were in direct opposition to those of regular doctors, who believed that women had no place in

Women in the History of Medicine medicine and continued to put much effort into keeping them out. Women were still not allowed into regular medical schools, and the new licensing laws forbade anyone who was not licensed and university educated from practicing the healing arts. Perhaps an extreme example of discrimination against women is that of Henrietta Faber, who studied and practiced medicine in Havana, Cuba, disguised as a man. When she revealed her true sex in 1820 so that she could marry, she was sentenced to 10 years in prison.17It was not until 1849that the first woman, Elizabeth Blackwell, entered a U.S. medical school. (When she was applying to the 42 all-male medical schools, a well-meaning professor at Jefferson Medical College recommended she attend classes disguised as a man.) Healing systems similar to Thomson's grew in the radical climate of the 1830s. Sylvester Graham founded a movement of physiologically based healing called the Hygienic Movement. The Grahamites were so antimedicine that they rejected the use of botanicals as well as drugs. Instead the system encouraged a vegetarian diet of raw fruits and vegetables and whole grains, whereas allopaths held that uncooked produce was injurious to health and white bread was a status symbol. Both the Thomsonians and hygienists upheld the belief that health care and healing skills belonged to the people and should not be a marketable commodity. Followers of Thomson and Graham fought the new licensing laws for physicians alongside the feminists and working-class activists: Any system that teaches the sick that they can get well only through the exercise of the skill of someone else, and that they remain alive only through the tender mercies of the privileged class, has no place in nature's scheme of things, and the sooner it is abolished, the better off mankind will be.18

(It should be noted, however, that although the Thomsonians and hygienists actively recruited women and strongly believed in the importance of women's improving their health and that of their families, they were not particularly supportive of feminism.) By the mid-l830s, every state with restrictive licensing laws had either softened or repealed them. Some states, like Alabama and Delaware, exempted Thomsonians and Grahamites from any re~tricti0ns.l~ Regular doctors now became recognized as just another sect and were revealed as the sect that had attempted to monopolize health care at the expense of the working class. Unfortunately, however, the popular health movement began to decline shortly after its greatest victory. By the late 1830s, some of the Thomsonian and Grahamian practitioners wanted professionalism and the establishment of schools and licensing for their graduates, seeking what they had fought so hard against and reversing some of the original tenets of the movement. Infighting began over the loss of basic principles.

Much competition developed between their schools for students, creating a larger rift. Along with these events occurred a loss of public support. Feminists turned away from health issues and refocused their efforts on women's rights in a world controlled by men. The radicalism of the working class trailed off toward Andrew Jackson's Democratic Party and away from socialist revolution. During the lull, allopaths began adopting enough of the principles of natural healing to appear credible. The reputation of MDs was in a terrible state. Their professionalism had been significantly undermined, and uncontrollable growth of their ranks, from a few thousand in 1800 to more than 40,000 in 1850, resulted in decreased medical fees and lowered economic status.I4 Many of the graduates, unable to make a living from their practice, chose to open schools of their own. Allopaths were also experiencing stiff competition from herbalists, hydropaths, midwives, homeopaths, and the eclectics who mixed natural healing with allopathy. Each healing art had its own schools, journals, and dedicated following. Homeopaths were particularly threatening because they appealed to the upper class, the patient population most coveted by allopathic physicians. In 1847, a small group of allopathic doctors formed the American Medical Association (AMA). On surveying their affairs, they concluded, "NOwonder the profession of medicine has measurably ceased to occupy the elevated position which once it did; one wonders that the merest pittance in the way of remuneration is scantily doled out even to the most industrious of our ranks."14 One of the first acts of the newly formed AMA was to extend the length of required study from 4 to 6 months and to require 2 years of approved preceptorship. However, practically all hospitals barred women from internship programs. In 1857, Elizabeth Blackwell, after being barred from all New York hospitals (despite her degree), opened the first woman-dominated hospital in the world, the New York Infirmary for Women. Internships for women continued to be limited (in the early 1940s, 607 of 712 hospitals would not accept women) until World War 11, when the shortage of male doctors opened the doors for women. The problems for women were further aggravated by the AMA's Consultation Clause, which barred women from membership in the AMA and prohibited members from providing consultations for irregular doctors. Although the Consultation Clause was effective, it was not until the early 1900s that allopathic medicine was able to establish supremacy and essentiallyeliminate women allopaths and natural healers of both sexes from the field. This was accomplished through the adoption of the new religion of "science" and the infusion by the chemical and drug industry (primarily through the Rockefeller and Carnegie foundations) of millions of dollars into their drug-oriented schools.

Philosophy of Natural Medicine

The Threat of Women Doctors From the 1850s through the turn of the century, allopathic doctors relentlessly attacked their competition: the sectarian or irregular and women practitioners. The natural healing-riented groups were attacked for allowing women among their ranks, and women doctors were attacked for their sectarian methods. But the worst was yet to come. By midcentury, middle- and upper-class women were aspiring to become regular doctors. They too were motivated by reform, as were the women of the popular health movement, but their spirit of reform was moral rather than social. Middle- and upper-class women were outraged by the implicit indecency of a male doctor’s treating a female patient. Catherine Beecher, a wellknown doctor and journalist of her time, publicly raised charges of seduction and sexual abuse by male doctors.I9 A women’s society in Philadelphia made it quite clear that “the Bible recognizes and approves only women in the sacred office of midwife.”2”A popular women’s magazine, Godey‘s Lady’s Book, argued strongly in favor of women physicians: “We would, in all deference, suggest that, first of all, there will be candor in the patient to the female physician, which would not be expected when a sense of native delicacy and modesty existed to the extent of preferring to suffer rather than divulge the symptoms.“2o Women began to force their way into allopathic medical schools. Elizabeth Blackwell gained admission into Geneva Medical College in upstate New York in 1849 after having been tumed down by 16 other schools. After her graduation, the college quickly passed a resolution barring entry of women.20In the same year, Harriet Hunt was admitted to Harvard Medical College, but the decision was reversed when the all-male student body threatened to riot. Instead, she attended and graduated from an irregular Emily Howard Jennings returned to Canada from the New York Medical College for Women in 1867 to become the first recognized Canadian woman doctor.21Ironically the first woman doctor to practice in Canada was actually James Barry, who posed as a man right up to her death. Even in death her sex went unreported by the embalmer; only when her grave was exhumed did her sex become known. The truth had been too embarrassing for the male embalmer to reveal, because women were not believed to have the intellect necessary to study, let alone become physicians,” yet Barry had become the chief military doctor for the country. Through the efforts of the sisters Augusta Jennings Kimball and Ella Jennings, the second and third Canadian women doctors, and those who followed, there were approximately 5000 women doctors in the United States and Canada by 1900. More than 1500 women were enrolled in medical colleges exclusively for women, seven in the United States20and

two in Canada2I(Toronto Women’s Medical College and Queens Women’s Medical College). One of the strongest women physicians at the turn of the century, both as a feminist and as a leader of the natural health movement, was Aloysia Stroebele. In the early 1890s, Stroebele, originally from Sigmaringen, Germany, opened the Bellevue Sanitarium in Butler, New Jersey, a nature cure retreat. As the personal aide to Lady Cooke, the famed suffragist leader, she became a strong advocate of “feminine independence and the emancipation of women.’’22During the several years she spent with Lady Cooke, she made three trips around the world, and in the process met with several natural healers, one of whom, Rickli, influenced her greatly. Her accomplishments were many: cofounding the first naturopathic college, cofounding the famed Yungborn sanitarium, funding the journal Nut uropufh, and writing several articles and books. She married Benedict Lust, the founder of naturopathic medicine, in 1901and changed her name to Louisa Lust. Her most telling contribution, besides her famous cures at “the Bellevue” through her integration of diet therapy, hydrotherapy, and the Rickli air cure, were the funds she contributed to fight 17 legal actions taken against practitioners of naturopathy.23 The male medical profession understood all too well the economic threat of these women physicians. Any middle- or upper-class woman who found the idea of revealing herself to a male doctor too repulsive could turn to a woman who was a regular, allopathic physician, still the preferred healer of the upper classes. She no longer had to quibble over going to see ”irregular”women physicians. Male physicians fought back with all the misogynous slander they could muster. They argued that women were too frail to practice medicine, incapable of operating while menstruating, and unable to survive the vulgarities of anatomy class or the shocking truths of reproduction.2°The idea that women were too delicate and modest to survive medical training, let alone desire it, meant that women who insisted on their rights were not really women at all. Alfred Stille, president of the AMA in 1871, explained the phenomenon of women in medicine in his presidential address: Certain women seek to rival men in manly sports . . . and the strange-minded ape them in all things, even in dress. In doing so they may command a sort of admiration such as all monstrous production inspires, especially when they tend towards a higher type of their own.ll

The editor of the Bufulo Medical Journal was more explicit: If I were to plan with malicious hate the greatest curse I could conceive for women, if I could estrange them from the protection of men, and make them as far as possible loathsome and disgusting to man, I would favor the so-called reform which proposes to make doctors of them.18

Women in the History of Medicine In other words, women who became physicians, or even desired to become physicians, were not only less than women, they were less than human. In addition to public slander, male MDs and students did all they could to make the lives of women aspiring to medical careers as miserable as possible. In class they were harassed with insolent and offensive language, and missiles of tobacco quid and garbage were thrown at them. Anatomy teachers often refused to lecture if women were present.20An 1848 obstetrics textbook explained how: “She (woman) has a head almost too small for intellect but just big enough for love.”” Once graduated, women doctors were allowed into few hospitals, and internships were almost nonexistent. Nor were women doctors allowed to join medical societies or publish in medical journals. The AMA did not admit its first female physician until 1915. The entry of women into medicine was fiercely resisted by male doctors, not only because of their deeply rooted misogyny, dating from the beginnings of Christianity and the economic threat they posed, but also because of their association with the popular health movement. The integrity of allopaths had been assaulted by the general public and by the popular health movement in which women and feminism had played a central role. The irregular schools of nature cure continued to welcome women students, and many of the irregular doctors were women providing a gentle and viable alternative to the dangers of regular health care. During the late eighteenth and early nineteenth centuries, women applying to medical school were considered guilty by association of being in opposition to regular medicine and of being feminists.2

Hydrotherapy: A Haven for Women In terms of women’s liberation and medical thought, the most revolutionary alternative system of healing was the hydrotherapy movement, or “hydropathy” as it was known in nineteenth century America. The original system consisted of using hot and cold water for bathing, wrapping, douching, and spritzing (spraying all or parts of the body). Allopathic medicines were excluded. Instead, a vegetarian diet, fresh air, exercise, regular bathing with cold water, and drinking numerous glasses of pure water were considered the pathways to health. Later the principles of hydrotherapy were combined with those of the hygienic, Grahamian, and eclectic systems to form naturopathic medicine. The formal practice of hydrotherapy began with Vincent Priessnitz, who opened a water cure clinic in Graefenburg, Germany, in 1829.24An MD, Joel Shew, and his wife, Mary Louise Shew, introduced hydrotherapy to the United States in 1843, where the cause was most visibly carried forward by Mary Gove Nichols and Russell Thatcher Tra11.24

Women played a major role in hydrotherapy as practitioners, educators, and leaders in health reform and women’s rights. Many women worked alongside husbands or male professionals, specializing in the care of obstetric and gynecologic patients. Most prominent was Mary Gove Nichols, who in 1846 opened her own water cure establishment in New York.” In 1851, she and her physician husband Thomas Nichols opened a medical school in New York based on water cure principles. Other prominent water cure partners were Racheal Brooks Gleason and her physician husband Silas Gleason, James Jackson, Thodoria Gilbert (who opened the Glen Haven Water Cure), and Harriet Austin, who later worked with Jackson.24 The concept of women as protectors of the family’s health and morality was one of the major tenets guiding the hydrotherapist’s insistence that women take control of their own health and personal power. They believed that by developing a healthy lifestyle and independence, women could work alongside men to improve society. These ideas were in direct opposition to the dominant social ethics and medical thought of the day. Allopaths viewed puberty, menses, pregnancy, childbirth, and menopause as a series of potentially dangerous pathologic events. Women were relegated to the domestic sphere because of their supposed weak physical and intellectual nature. In the home, they could be protected by men.25 In contrast, the hydropaths viewed women’s physiology and reproductive functions as normal, healthy processes. Water cure establishments provided a haven where women could receive sympathetic care, find relief from constant pregnancies, and receive psychological and emotional support.25 Women were inspired to achieve beyond the domestic realm, and many went on to become hydropaths themselves. Taking the cure at the hydrotherapy establishments became fashionable among the wealthy during the late nineteenth century. Between 1843 and 1900, 213 water cure sanitariums opened.” Numerous journals, books, and magazines devoted to the tenets of water cure and a natural lifestyle were published during this time. They became forums for disseminating hydropathic ideals of the perfect society in which women no longer wore tight corsets or long dresses, or suffered the ill effects of the allopaths’ overmedication with mercury (for postpartum hemorrhage), lead (for dyspepsia), opium, leeches, and bloodletting. Women were encouraged to avoid the meat-, salt- and stimulant-rich diet of the day. In the vision of the hydropaths, women were free to pursue any career they chose, with hydrotherapy and medicine being the most Thomas Nichols’s statement in the Water Cure Ioumal clearly describes their intent: “Never has woman had such an opening for usefulness and influence as this.No water

Philosophy of Natural Medicine

cure establishment is complete without a qualified woman phy~ician.”~’ Mary Gove Nichols, in her inaugural address at the opening of the American Hydropathic Institute, professed, ”Women are peculiarly fitted to the art of healing because of their tenderer love, the sublime devotion, the never to be wearied patience and kindness of woman.”28 Women composed 30% to 50% of the graduates from the hydrotherapy schools. They worked diligently as the heads of the ladies’ departments of the water cure establishments, attending to all facets of women’s and children’s health care. They provided prenatal care, for which allopaths had little to offer, recommending a diet of fruit, vegetables, whole grains, and milk. Loose clothing, daily exercise, and cold baths were recommended to tone the body in preparation for ~hildbirth.2~ After the birth, women were encouraged to get out of bed within days, if not the same day, thus decreasing the risk of postpartum blood clots and pulmonary embolism. Women were taught to experience childbirth as an empowering, natural, and holy function, rather than as an event to be dreaded because it risked imminent death. Hydrotherapy, more than any other nineteenth century medical sect, had the strongest connection with the women’s movement.

Victory for a Male Profession Until the early twentieth century, allopaths had little to offer that was superior to the other types of health care practices. They had neither economic dominance nor elevated social status over the irregular or natural health care practitioners. In spite of the AMA’s valiant attempts to establish allopathy as the only legitimate form of healing, only 8000 out of 125,000 doctors in the United States were members of the AMA at the turn of the century.29 European allopaths had better success in establishing themselves among the upper class. With the introduction of the germ theory by French and German scientists came the first scientifically demonstrablebasis for disease prevention and treatment. European medical men were the first to adopt scientific methodology into medical practice and education. This served to further enhance their already elevated status. Science had become the new religion of the general public and was held up as the answer to all social, economic, and health problems. The new religion was received in North America with tremendous enthusiasm. Science became a national moral value in North America; any discipline that wanted to justify its existence had to adopt scientific doctrine. Social work, philanthropy, housekeeping, childrearing, business management, public administration, law, and medicine all began to search for a scientific basis. The adoption of scientific principles was synonymous with reform?

In the late nineteenth century, a small group of American doctors traveled to German and French medical universities for further training and retumed determined to install a n elite medical educational system that would elevate their professional status. In 1893, they founded Johns Hopkins University, the first medical school in North America with laboratories and full-time professors. Eight years later, the Rockefeller Institute for Medical Research was opened. The institute was, and is still today, solely concerned with pure research and helped to exalt the mystery of European scientism. One of the founders of the institute and a close friend of the Rockefellers described the place as “a theological seminary, presided over by the Reverend Simon Flexner, M.D.”30 Having finally created a credible academic and research model for medical education, the AMA began to effectively use economic and political pressure to ensure that all schools providing a medical education either ascribed to the model provided by the Rockefeller Institute and Johns Hopkins University or were closed. This was accomplished through a cooperative effort between the AMA’s Council on Medical Education (made up of faculty from the medical schools modeled on the Johns Hopkins prototype) and the Camegie and Rockefeller foundations. The Carnegie Foundation ostensibly agreed to conduct a study of the educational institutions found in the various healing professions. The results were then used to determine which schools and sects were to receive a portion of $150 million in endowments. The study was conducted by Abraham Flexner, brother of the director of the Rockefeller Institute, Simon Flexner, a graduate of Johns Hopkins University. In the survey, schools such as Harvard were seen to be conforming to the new scientific model quite well. They had the money (granted by the foundations) to employ fulltime professors and install expensive laboratories. These schools were given large endowments. The smaller, poorer schools, which provided medical education for women, nonwhites, and people interested in natural healing, did poorly in meeting allopathic requirements and hence received no funds from the Rockefeller and Camegie foundations. According to Flexner ’s report, these schools were not worth saving and their closure would be no loss. Even though 10 medical colleges at the time that provided medical education solely for women, Flexner also decided that few women doctors were needed. He perceived a lack of “any strong demand for women physicians or any strong ungratified desire on the part of women to enter the profe~sion”!~~ Flexner did deduce that some nonwhite doctors were needed, but only enough to check the spread of disease from nonwhite to white neighborhoods, because ”ten millions of them live in close contact with sixty million whites.”31For both

Women in the History of Medicine

economic and philosophical reasons, the irregular schools, which had been havens for women, and women’s medical colleges did not conform to the new allopathic model and were discredited by the Flexner report. From 1904 to 1915, of the 92 schools closed or merged: Five out of seven nonwhite medical schools closed, seven out of 10 medical schools for women shut their doors, and the majority of the alternative medical schools were eliminated. As a direct result, the number of women graduates from allopathic medical schools dropped from 4.3%to 3.2%.In the meantime, from 1910 to 1930, more than $300 million was poured into the medical schools that ascribed to the Johns Hopkins Not only women and nonwhites were affected by these events; scientism became the domain of the upper classes. The reforms that ruled the existence of medical schools included an entrance requirement of 2 years of university training. This effectively made a medical career impossible for all but the middle and upper classes because of the expense. Medical schools that had been economically accessible to the working class ceased to exist, and the entrance of blacks into medical schools was limited by racial discrimination. Women suffered sex discrimination in their attempts to enter the remaining medical colleges,2 with percentages of women students steadily shrinking until the 1970s and the resurgence of feminism.33The medical profession had become an institution composed almost entirely of white, middle- and upper-class men confirmed in their opposition to women and natural healing methods. It is true that turn-of-the-twentieth-century medicine needed some form of standardization of education and health care. However, in the fervor of scientism, sexism, racism, and the allopaths’ rush for economic control, the alternatives to allopathic medicine were effectively eliminated. Despite the new reforms, the quality of medical care was not necessarily improved. The new system of lengthy scientific training did not guarantee that physicians were any more effective or humanely empathic than the irregular healers they replaced. In fact quite the opposite appears to have been the case (see Ivan Illich, Limits to Medicine and elsewhere in thisbook).34Although the scientific method has much to offer, it is arguable that, in the context of the stifling, one-dimensional philosophy and male elitism of the medical profession, the use of the banner of scientism to establish political and economic protection from competing ideas actually inhibited the development of health care in this country.

Midwives: The Last of the Women Healers to Fall In 1900, approximately 50% of all births in North America were attended by midwives? The babies of

middle- and upper-class women were delivered by licensed MDs. Lower-class blacks and European immigrants could not afford MDs, nor did they want them. Midwifery was a respected tradition held in high esteem, particularly by Africans and Europeans. This meant fewer obstetric cases for teaching medical students, because upper-class women certainly did not want a room full of men, medical students or not, witnessing their birthing efforts. Therefore it was said that midwives, by providing affordable and readily available obstetric care to the lower class, were depriving medical students of valuable learning experiences. To remedy the situation, medical schools began to associate themselves with local charity hospitals, offering medical trainees as staff in return for patients they could learn on. In the meantime, the medical profession put considerable energy into making midwifery illegal. An editorial in the Journal of the American Medica2 Association by Charles Ziegler stated the situation as follows: “It is at present impossible to secure cases sufficient for the proper training in obstetrics, since 75%of the material otherwise available for clinical purposes is utilized in providing a livelihood for midwives.”12The “material,” of course, was the bodies of pregnant women. A campaign was launched to rally support among members of the profession to outlaw midwifery by appealing to their sense of what was best for medical education and by portraying midwives as ”hopelessly dirty, ignorant and incompetent relics of a barbaric past” who could do only harm to mother and child: They may wash their hands, but oh what myriads of dirt lurk under their fingernails. Numerous instances could be cited and we might well add to other causes of pyosalpinx “dirty midwives.“ She is the most virulent bacteria of them all and she is truly a micrococcus of the most poisonous kind.26,35 An obvious solution to the problem of the “dirty and ignorant midwives” would have been to educate them in hygiene, the use of an eyedropper to prevent gonococcal eye infections in the newborn, and the use of forceps in difficult births. However, the medical profession wanted obstetrical ”material,” not to train midwives to further improve their effectiveness and legitimacy. Through cooperation with midwives, the MDs could have learned much about childbirth and improved their own reputations. The MDs version of childbirth was dangerous. If the labor was going too slowly for his schedule, he used forceps and cesarean section with considerable risk to mother and child.6 In teaching hospitals, there was a definite bias in favor of surgery to provide experience for students in abnormal deliveries.12 In fact, a 1912 study by Johns Hopkins University found the majority of American doctors less competent than the midwives they had replaced. According to the study, they were

Philosophy of Natural Medicine

less experienced, less observant, and less likely to be present at the critical moment.% It appears that the MDs realized they could not fill the void of service left if midwives were eliminated. One obstetrician in 1915 admitted that of all births in New York State, 25% would be entirely deprived of assistance once midwifery was eliminated.%Yet between 1900 and 1930, midwives were almost totally eliminated from North America. With the demise of the midwife, American women lost their last independent role as healers. More than one historian has referred to the years from 1900 to 1965 as the Dark Ages in terms of the progress of women in the healing arts.37 Although there were women allopathic physicians, their numbers were small. In 1900, women composed 5% of all physicians of all sects, but by 1926 they made up only 2%. Not until the 1970s, with the resurgence of feminism, did the number of women in allopathic medical schools approach even 6%.32 The remaining irregular schools had continued accepting women students without discrimination, although the numbers were not as high as they are now. In the early 1970s, the naturopathic student body was approximately33%female.

WOMEN IN MEDICINE TODAY Today’s dominant form of medicine is a refined form of the heroic techniques of tum-of-the-twentieth-century allopaths, and women have only recently begun to make real progress in entering the ranks of male-dominated technologic medicine. From 1968 to 1978, the number of women enrolled in regular medical schools rose dramatically, from 7% to 25%. Because of federal legislation instituted between 1964 and 1974 that rendered racial and gender discrimination illegal in education and employment, as well as the pressures of threatened lawsuits, the numbers of women enrolled in medical schools increased sigruficantly. At McMaster Medical School in Hamilton, Ontario, more than 50%of the 1978 graduating class were women. This represented the first time in North America that the number of women in an allopathic medical school was greater than that of men.%Data from the year 2000 indicate that women made up 43% of all allopathic medical students, 37%of all residents, and 23%of MD practitioners. In comparison, women composed more than 50%of naturopathic medical school students and 50% of practitioners of naturopathic medicine.* Discussion of the disparity between the numbers of women allopathic students and the number of women who go into practice has included barriers to mentoring and internship positions,

‘Schools surveyed include Bastyr University, Southwest College of Naturopathic Medicine, and University of Bridgeport College of Natumpathic Medicine.

lack of parental leave of absence, lack of on-site child care, and financial and family responsibilities to children and s p ~ u s eHowever, .~ discrimination against women in medicine persists. According to a 1985-1986 survey conducted by the AMA, women eamed 62% of the salary of their male c0lleagues.3~As of 1987, women filled less than 3% of administrative positions in medical schools and only two American allopathic medical colleges had a female dean. Data from 1998 indicated that only 6%of all medical schools’ department chairs were women, an average of one per medical school.4oAs of September 1999, six of the 125 U.S. allopathic medical schools’ deans were women. A survey of three U.S.naturopathic medical schools (see earlier footnote),’ however, showed that 30% to 50% of academic deans were women. Academic ranking for 1987 also shows discrimination, because women compose 23.6% of assistant professors but only 6% of full professor^.^^,^^ Data for the year 2000 indicated that fewer than 11% of full professors at allopathic schools were women, 19%were associate professors, 50%were assistant professors, and 17% were instructors. For men, the numbers were 31% full professors, 25% associate professors, 35% assistant professors, and 8% instructors.40Men are more equally distributed among the rankings of teaching positions. Factors affecting the upward mobility of women are similar for all professions, including medicine. US. culture allows a narrower band of acceptable behaviors required for competition for jobs and positions of authority. What is seen as appropriately goal oriented and competitive in men is perceived as “harsh and “confrontational”in women. Competency and femininity are still perceived as conflicting q u a l i t i e ~This .~~ discrimination among rankings of women is evident in naturopathic medical schools, although to a lesser degree. Barriers to admitting women into medical schools have been lowered considerably for several reasons: The adoption of civil rights and affirmative action legislation, and resolutions on equal opportunity in the United States and Canada. The women’s movement has encouraged women to seek nontraditional careers and assert their rights to pursue them.O Although the number of women in medicine is growing, sexist attitudes seem to have changed little since the tum of the twentieth century. Ramey, referring to the scarcity of women in administrative positions, commented in 1980 that “women are prone to emotions, verbosity, pettiness and pregnancy.”pq In this author’s opinion, the final proof of the continued existence of discrimination against women in allopathic medicine is this statistic: Women account for only 10%of practicing allopathic physicians; in contrast, 40% of practicing naturopathic physicians are women.

Women in the History of Medicine

Continuing discrimination against women in medicine has manifested itself in many There is no school-supported recruitment of women such as there is for minority students. There is a reluctance to admit married women because they may become pregnant and, if they have families, may not use their education. There is overt discrimination in the classroom, including baiting, hostility, and derogatory comments. It has been documented that lecturers, in dealing with problems in medical practice, direct all of their questions and comments to male student^!^,^^ The prevalence of stereotyping women as sex objects within the profession is exhibited by the number of female students who have been sexually embarrassed, harassed, or abused by their male instructors. Reports of such incidents at a conference on women in medicine in Toronto in 1985 were too frequent to be considered extraordinary.& A 1988 study of the gender climate in medical school found that 80% of women students reported discrimination by faculty and other physicians, with faculty displaying subtle to blatant sexism.4’A later study at a Midwest medical school found that gender discrimination increased in intensity as women moved closer to graduation and li~ensing.4~ The types of discrimination reported included sexual remarks, jokes, and innuendoes relegating women into stereotyped roles, sexual advances by married mentors, and blatant sexual manipulation.48The same study also found that two thirds of practicing male physicians admitted that they did not accept women as professional peers. A prevalent argument used to justify reluctance in allowing women into allopathic medical school is that women MDs are less p r o d ~ c t i v eHowever, .~~ evidence suggests that the opposite is true. The January 1976 Bulletin of the Professional Corporation of Physicians of Quebec indicated that although women doctors work only 66% of the hours that male doctors do, they provide 92% of the patient care that male doctors provide. Although it is true that not all women physicians continue to practice throughout the entire span of their potential working years, it is also true that women doctors are still expected to carry on with traditional family roles, a continuing societal problem. A study of women doctors in Detroit indicated that only 59% had worked without interruption since graduation and that 76% of women physicians are still doing all of the cooking, shopping, housekeeping, and child care.40,48Women’s advancement within the profession is inversely related to marital status and family size.37As a direct result of carrying the lion’s share of family responsibility, and the discrimination they experience in obtaining an education and competing for career opportunities, women allopathic physicians are severely underrepresented in private practice, surgical

specialties, and administrative and policymaking positions. Still, the future of women in allopathic medicine looks brighter because their numbers are increasing. It was predicted in 1985 that women will make up 35% of the medical profession within the next decade or two.& Data from the year 2000 indicate that 43% of allopathic medical students are women. As to the types of medicine women will be practicing, it seems that women are returning to their traditional role of providing preventive health care. According to Spiro, ”The long-standing interest of women in preventive medicine, and the current public dissatisfaction with crisis-oriented care have led still others to predict that one contribution of women may be a more ’health-oriented’ medical practice.”MHis statement is irrefutable when one considers the percentage of women in naturopathic medicine. The return of women to their role as primary providers of humane, holistic health care can be attributed to the following events: The resurgence of irregular and naturopathic medicine in North America and Europe as indicated by the increasing number of colleges and institutions providing training in massage, herbal medicine, midwifery, acupuncture, homeopathy, and naturopathy The revival of the feminist movement since the late 1960s Women‘s growing interest in self-health care, as reflected by the rising number of women’s organized health information groups The growing dissatisfaction of the general public with allopathic medicine, who recognize it as expensive and potentially dangerous to one’s health. (For further discussion, see Illich,34Mendelsohn,51and M c K e o ~ n . ~ ~ ) These events and social conditions have created an atmosphere similar to the one in which the popular health movement became successful in the early 1800s. Feminism of the 1960s and 1970s resulted in the growth of women’s self-help groups that taught female anatomy and principles of health and self-care, the publication of Our Bodies Ourselves by the Boston’s women’s movement, and the springing up of clinics devoted solely to women’s health and run by women practitioners. Now, as during the early 1800s, there is considerable public discontent with a “heroic” medicine emphasizing laboratory results and procedures with little attention to wellinformed patient relationships. A recultivation of “folk” medicine with emphasis on the whole person, including emotional, physical, and spiritual well-being, has become a public revolution in thinking. Today’s health care consumer feels empowered to question any health care he or she is receiving. Also similar to the 1800s is the increasing use of “alternative” or ”unconventional” approaches to health care considered nonallopathic

Philosophy of Natural Medicine ~~

because they are not mainstream for MDs. These methods include herbal medicines, treatment diets, nutritional supplements, massage, emotional counseling, acupuncture, and hydrotherapy. Eisenberg and published a landmark study in 1993 indicating that the use of such medicines was common to 34% of the U.S. population. Subsequent studies have put this figure at more than 65%.History is indeed repeating itself with women at the forefront of the revolution in health care. Today, women make up close to or more than 50% of the student bodies at Bastyr University, Canadian College, Southwest College, University of Bridgeport, and National Colleges of Naturopathic Medicine. Much of the philosophy and therapeutic approach of naturopathic medicine has been derived from the work of women healers dating back to ancient Greece and the Roman Empire. In allopathic medicine women physicians are highly valued by women and men patients alike, because they are perceived as less intimidating and more caring, empathic, and willing to listen.

CONCLUSION The history of women in medicine is not well known outside their traditional roles as helpmates and nurses

1. Spender D. Man made language. London: Routledge and Kegan Paul, 1985. 2. Ehrenreich B, English D. Witches, midwifes and nurses: a history of women healers. Old Westbury, NY: The Feminist Press, 1973. 3. Avery ME. Women in medicine, 1979: what are the issues? J Am Med Womens Assoc 1981;36:79-81. 4. More ES, Greer MJ. American women physicians in 2000 a history in progress. J Am Med Womens Assoc 2OOO;55:6-9. 5. Hurd-Mead KC. A history of women in medicine from the earliest times to the beginning of the nineteenth century. Haddam, CT: Haddam Press, 1938. 6. Szasz TS.The manufacture of madness: a comparative study of the Inquisition and the mental health movement. New York Harper & Row, 1970. 7. Thorndike L. A history of magic and experimental science, vol II. New York Macmillan, 1923. 8. Donnison J. Midwifes and medical men: a history of interprofessional rivalries and women‘s rights. New York Schocken Books, 1977. 9. Michelet J. Satanism and witchcraft, a study in medieval superstition. Secaucus, NJ: Citadel Press, 1939. 10. Hughes MJ. Women healers in medieval life and literature. Freeport, Ny: Books for Libraries Press, 1943. 11. Shryock RH. Medicine and society in America: 1660-1860. Ithaca, NY Great Seal Books, 1960. 12. Ehrenreich B, English D. For her own good: 150 years of the expert’s advice to women. Garden City, Ny: Anchor Press, 1978. 13. Kett J. The formation of the American medical profession: the role of institutions. New Haven, C T Yale University Press, 1968. 14. Rothstein WG. American physicians in the nineteenth century: from sects to science. Baltimore: Johns Hopkins University Press, 1972.

to male physicians. It is not generally known that women have been primary health care providers from ancient Greece through the beginning of the nineteenth century. Many factors have created the low percentage of women in the medical profession today. Throughout the ages, women have been intensively persecuted for practicing medicine: Aspasia by Roman law, women folk healers of medieval times who were burned as witches, English midwives who were legislated out of practice in 1512, and women healers of all kinds in early America who were virtually barred from entering allopathic medical schools in North America until the end of the nineteenth century, and then allowed in only very limited numbers. Today, women have made substantial progress in breaking into the allopathic medical profession despite continuing discrimination. The real changes for women in medicine may come with recent trends toward natural therapies and preventive health care, and the resurgence of midwifery and naturopathic medicine. Along with increasing public interest in irregular medicine and the resurgence of colleges providing credible training in alternative health care, a growing number of primary health care givers once again are women.

15. Ryan MP. Womanhood in America: from colonial times to the present. New York New Viewpoint, 1975. 16. Kaufman M. Homeopathy in America: the rise and fall of a medical heresy. Baltimore: Johns Hopkins Press, 1971. 17. Miscellany. Women in medicine. JAMA 1901;371403. 18. Bums D, ed. The greatest health discovery: natural hygiene and its evolution past present and future. Chicago: Natural Hygiene Press, 1972. 19. Beecher C. On female health in America. In: Cott N, ed. Roots of bitterness: documents of the social history of American women. New York EP Dutton, 1972. 20. Woody T. A history of women’s education in the United States, vol II. New York Octagon Books, 1974. 21. Hacker C. The indomitable lady doctors. Toronto, Ontario: Irwin, 1974. 22. Lust-Boyd A. Yungbom: the life and times of Dr. Benedict Lust, founder and father of naturopathy. Self published, 1997. 23. Kirchfield F, Boyle W. Nature doctors: pioneers in naturopathic medicine. Portland, OR Medicina Biologica, 1994. 24. Donegan JB. Hydropathic highway to health: women and watercure in antebellum America. New York Greenwood Press, 1986. 25. Cayleff S. Wash and be healed: the water-cure movement and women’s health. Philadelphia: Temple University Press, 1987. 26. Weiss HB, Kemble HR. The great American water cure craze, a history of hydropathy in the United States. Trenton, NJ: The Past Times Press, 1967. 27. Nichols TL. Medical education. The American hydropathic institute. Water-Cure J 1851;1266. 28. Gove Nichols MS. Woman the physician. Water-Cure J 1851;1274. 29. Berliner HS. A larger perspective on the Flexner Report. Int J Health Sew 1975;5:573-592.

Women in the History of Medicine 30. Brown RE. Rockefeller medicine men: medicine and capitalism in America. Berkeley, CA. University of California Press, 1979. 31. Flexner A. Medical education in the United States and Canada: a report to the Camegie Foundation for the advancement of teaching. New York Amo Press, 1972 (c. 1910). 32. Markowitz G, Rosner DK. Doctors in crisis, a study of the use of medical education reform to establish modem professional elitism in medicine. Am Q 1973;25:83. 33. Walsh MR. Doctors wanted no woman need apply. New Haven, CT Yale University Press, 1977. 34. Illich I. Limits to medicine, medical nemesis, the expropriation of health. New York Penguin, 1977. 35. Barker-Benfield GJ. The horrors of the half-known life: male attitudes toward women and sexuality in nineteenth-century America. New York: Harper & Row, 1976. 36. Kobrin FE. The American midwife controversy: a crisis of professionalization. Bull Hist Med 1966;40:350-363. 37. Morantz RM, Pomerleau CS, Fenichel CH, eds. In her own words: oral histories of women physicians. Westport, C T Greenwood Press, 1982. 38. Carver C, Berlin S. Proposal for study on productivity of women doctors. Toronto, Ontario: Women's Research and Resource Center, The Ontario Institute for Studies in Education, 1978. 39.Donaghue GD. Eliminating salary inequities of women and minorities in medical academia. J Am Med Womens Assoc 1988; 43:28-29. 40. Bickel J. Women in academic medicine. J Am Med Womens Assoc 2000;5510-12,19.

41. Bartlik BD, Smith CA. Women doctors meet to map working strategies. J Am Med Womens Assoc 1981;3623&238. 42. Valian V. Why so slow? The advancement of women. Cambridge, MA: MIT Press, 1998. 43. More ES, Greer MJ. American women physicians in 2000 a history in progress. J Am Med Womens Assoc 2000;556-9. 44. Braslow JB, Heins M. Women in medical education: a decade of change. N Engl J Med 1981;304:1129-1135. 45. Lain BM. Women in medicine. Metuchen, NJ: ScarecrowPress, 1980. 46. Proceedings of symposium on murmurs of the heart: issues for women in medical training, Toronto, Ontario, 1985. 47. Grant L. The gender climate of medical school perspectives of women and men students. J Am Med Womens Assoc 1988;43: 109-110,115-119. 48. Coombs RH, Hovanessian HC. Stress in the role constellation of women resident physicians.J Am Med Womens Assoc 1988;43:21-27. 49. Campbell MA. Why would a girl go into medicine? Medical education in the United States. A guide for women. Old Westbury, Ny: Feminist Press, 1973. 50. Spiro HM. Myths and mirths: women in medicine. N Engl J Med 1975;292:354-356. 51. Mendelsohn RS.Confessions of a medical heretic. Lincolnwood, IL: Contemporary Publications, 1987. 52. McKeown T. The role of medicine: dream, mirage, or nemesis? London: Nuffield Provincial Hospital Trust, 1976. 53. Eisenberg DM, Kessler RC, Foster C, et al. Unconventional medicine in the United States: Prevalence, costs, and pattems of use. N Engl J Med 1993;328:246-252.

Supplementary Diagnostic Procedures 11 Apoptosis Assessment 145 12 Bacterial Overgrowth of the Small Intestine Breath Test 153 13 Cell Signaling Analysis 161 14 Comprehensive Digestive Stool Analysis 2.0 165 15 Erythrocyte Sedimentation Rate 179 16 Fantus Test 185 17 Fatty Acid Profiling 189 18 Folic Acid Status Assessment 199 19 Food Allergy Testing 203 20 Hair Mineral Analysis 209 21 Heidelberg pH Capsule Gastric Analysis 21 7 22 Immune Function Assessment 221 23 Intestinal Permeability Assessment 241 24 Laboratory Tests for the Determination of Vitamin Status 251 25 Lactose Intolerance Testing 255 26 Metal Toxicity: Assessment of Exposure and Retention 263 27 Mineral Status Evaluation 275 28 Oral Manifestations of Nutritional Status 281 29 Rapid Dark Adaptation Test 283 30 Urinary Organic Acids Profiling for Assessment of Functional Nutrient Deficiencies, Gut Dysbiosis, and Toxicity 285 31 Urinary Porphyrins for the Detection of Heavy Metal and Toxic Chemical Exposure 299 32 Urine Indican Test (Obermeyer Test) 305

Over the past 50 years, tremendous progress has been made in the development of laboratory procedures for the diagnosis of

disease. However, this work has focused primarily on pathologic processes-little has been done to help the physician recognize physiologic abnormalities before they progress to the pathologic stage. The problem is further aggravated for doctors of preventive and natural medicine, who need to evaluate in an objective manner the nutritional status, lifestyle, physiology, and health of their patients. The few widely available tests that exist tend to be oriented to measuring absolute values rather than functional indices and generally indicate abnormal values only after serious dysfunction develops. We have compiled a number of useful procedures that we believe will greatly aid physicians who would like to utilize more objective tests in their evaluation of the pathophysiologic status of their patients. These are not meant to replace the standard, pathologically oriented, diagnostic procedures but rather to supplement them and aid in the early diagnosis of disease susceptibility and the quantification of the processes that usually precede clinical disease. Where possible, preference is given to tests that measure function rather than abstract absolute values. In keeping with the metabolic and scientific orientation of this textbook, emphasis has been placed on those procedures that have good support in the scientific literature for the evaluation of nutritional status. Most of these laboratory procedures are on the cutting edge of our understanding of the assessment of the physiologic function of metabolically unique individuals. Because it is an emerging field, few experts exist and most are employed by the commercial laboratories performing and providing the procedures. A list is given on the copyright page (p. iv) of chapter authors for whom such a potential conflict of interest exists.

143

Apoptosis Assessment AristoVojdani, PhD, MT CHAPTER CONTENTS Introduction 145 Measurable Features of Apoptosis 145 Different Stages of Apoptosis 146 Apoptosis Is Induced by Chemicals to Control Malignancy 146 Clinical Applications 147

INTRODUCTlON Apoptosis is a distinct form of cell death controlled by an internally encoded suicide program. It is believed to occur in the majority of animal cells. It is a distinct event that triggers characteristic morphologic and biologic changes in the cellular life cycle. It is common during embryogenesis, normal tissue and organ involution, and cytotoxic immunologic reactions and occurs naturally at the end of the life span of differentiated cells. Apoptosis can also be induced in cells by the application of a number of different agents, including physiologic activators, heat shock, bacterial toxins, oncogenes, chemotherapeutic drugs, various toxic chemicals, and,ultraviolet and gamma radiation. When apoptosis occurs, the nucleus and cytoplasm of the cell often fragment into membranebound apoptotic bodies, which are then phagocytized by neighboring cells. Alternatively, during necrosis, cell death occurs by direct injury to cells, resulting in cellular lysing and release of cytoplasmic components into the surrounding environment, often inducing an inflammatory response in the tissue. A landmark of cellular selfdestruction by apoptosis is the activation of nucleases and proteases that degrade the higher-order chromatin structure of the DNA into fragments of 50 to 300 kilobases and subsequently into smaller DNA pieces of about 200 base-pairs in length. Using fluorescent-labeled reagents, it is possible to tag the DNA break and identify the percentage of apoptotic cells with a high degree of accuracy.’4

Measurable Features of Apoptosis One of the most easily measured features of apoptotic cells is the breakup of the genomic DNA by

Apoptosis in Autoimmune Diseases 147 Apoptosis during Viral Infection 148 Apoptosis in Acquired Immunodeficiency Syndrome 149 Apoptosis in the Heart and Brain 149

Conclusions

150

cellular nucleases. These DNA fragments can be extracted from apoptotic cells and result in the appearance of DNA laddering when the DNA is analyzed by agarose gel electrophoresis. The DNA of nonapoptotic cells, which remains largely intact, does not display this laddering on agarose gels during electrophoresis. The large number of DNA fragments appearing in apoptotic cells results in a multitude of 3’-hydroxyl termini of DNA ends. This property can also be used to identify apoptotic cells by labeling the DNA breaks with fluorescent-tagged deoxyuridine triphosphate nucleotides (F-dUTP). The enzyme terminal deoxynucleotidyl transferase (TdT) catalyzes a template-independent addition of deoxyribonucleotide triphosphates to the 3’-hydroxyl ends of double- or single-stranded DNA. A substantial number of these sites are available in apoptotic cells, providing the basis for the single-step fluorescent labeling and flow cytometric method. Nonapoptotic cells do not incorporate significant amounts of the F-dUTP owing to the lack of exposed 3’-hydroxyl DNA ends. Apoptosis can also be characterized by changes in cell membrane structure. During apoptosis, the cell membrane’s phospholipid asymmetry changes-phosphatidylserine (PS) is exposed on the outer membrane, while membrane integrity is maintained. Annexin V specifically binds phosphatidylserine (PS), whereas propidium iodide (PI) is a DNA-binding fluorochrome. When a cell population is exposed to both reagents, apoptotic cells stain positive for annexin V and negative for PI; necrotic cells stain positive for both, and live cells stain negative for both.3 This process of apoptosis and its analysis by flow cytometry are shown in Figures 11-1and 11-2. 145

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THE EXECUTIONER IL,+ converting enzyme Granzymes

Figure 11-1 Detection of apoptosis using damaged membrane or DNA single-strand break and flow cyiometry.

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Figure 11-3 Various stages of "inside out" cell death or apoptosis.

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ANNEXIN V Figure 11-2 Separation of cells by flow cytometry and detection of apoptotic population.

Different Stages of Apoptosis The process of apoptosis is divided into three different stages: Induction Sensing or triggering Execution These stages of apoptosis are depicted in Figure 11-3. Induction represents the initial events that signal a cell so that apoptosis may begin. This induction phase may be induced by various physical agents such as toxic chemicals, radiation, chemotherapy agents, hormones, and CD95 or Fas ligation. However, in a series of experiments, I and my colleagues demonstrated that this induction stage of apoptosis is prevented by many antioxidants (vitamin C, beta-carotene, and vitamin E)

and also by various biologic response modifiers, including lentinan, thymic hormones, viral antigens, and cytokines. The induction stage is followed by a decision on whether or not the cell will undergo apoptosis. The decision to die is under the control of a number of different pathways or cellular sensors that induce the apoptosis signal, which then triggers the central mechanisms. During this stage, enzymes such as ILI-p converting enzymes, serine protease, cysteine protease, granzymes, and cyclin-dependent kinases become activated. Once activated, these enzymes dismantle the cell and trigger the cell surface changes that cause direct cell recognition and engulfment of the dying cells by phagocytes. These central events are prevented by various antioxidants and biologic response modifiers.

Apoptosis Is Induced by Chemicals to Control Malignancy Many chemicals have the capacity to bind to DNA, form DNA adducts, or cause DNA single-strand breaks, possibly leading to cancer. However, the body is equipped with many factors, enzymes, suppressor genes, and cellular sensors, all with the capacity to prevent this action of chemicals on DNA by activating apoptosis-inducing signals. The role of apoptosis in regulating tissue growth is readily apparent in the simple equation in which the rate

Apoptosis Assessment

of growth is equal to the difference between the rates of cell proliferation and cell death. Thus tissues expand if the rate of proliferation exceeds the rate of cell death. This is one of the reasons for suggesting that defects in apoptosis may contribute to the transformed state. An important prediction of the relevance of apoptosis to malignancy is that the rate of apoptosis versus mitosis should influence the behavior of a tumor. Recently, the relationship between the apoptotic and mitotic indices in a tumor was demonstrated predictive of outcome: Higher ratios correlate with positive prognosis. Further, it was found that this is not simply a function of cell death per se. Tumors with a high incidence of necrosis rather than apoptosis were correlated with poor prognosis. It therefore follows that treatments or conditions that favor apoptosis should have desirable effects, and that defects in the pathways leading to apoptosis are likely to play important roles in the process of oncogenesis.45 Many reactive chemicals and drugs such as acetaminophen, diquat, carbon tetrachloride, quinones, cyanide, polyhydroxyl polyether, methyl mercury, and organotin have been implicated in apoptosis (programmed cell death) and necrosis (toxic cell death).7-14 Most research on chemical induction of apoptosis is carried out with primary cultures of cell lines (e.g., neurons, thymocytes, carcinoma cells, leukemia cells, neuroblastoma, breast cancer cells, lymphoma); little has been published on the in vivo effects of chemicals on apoptotic cells in animal models and none in humans. Therefore it was of interest to examine the effects of exposure to low levels of benzene, as well as through drinking water concentrations of up to 14 ppb on the apoptotic cell population, as well as to examine possible changes in the cell-cycle progression.' Evidence is suffiaent for the carcinogenicity of benzene in humans; therefore there is no safe level of exposure to this chemical or its metabolites. Published case reports, a case series, epidemiologicstudies, and both cohort and case-control studies have shown statistically sigruficant associations between leukemia and occupational exposure to benzene and benzene-containing s~lvents.*~J~ It is indicated that possibly 800,000 persons are exposed to benzene from coke oven emissions at levels greater than 0.1 ppm, and 5 million may be exposed to benzene from petroleum refinery emissions at levels of 0.1 to 1ppm. Since then, numerous chemicals have been implicated in apoptosis (or programmed cell death), which arises from damage to DNA. We hypothesized that in individuals with a certain genetic makeup, benzene or its metabolites act as haptens, which may induce programmed cell death. The study involved a group of 60 male and female subjects who were exposed to benzene-contaminated water (at concentrations up to 14 ppm for a period of 3 to 5 years). For comparison, we recruited a control group consisting of 30 healthy males

and females with a similar age distribution and without a history of exposure to benzene. Peripheral blood lymphocytes of both groups were tested for percentage of apoptotic cell population, using flow cytometry. When exposed individuals were compared with the control group, statistically sigruficant differences between each mean group were detected (27.5 f 2.4 and 10 f 2.6, respectively),indicating an increased rate of apoptosis in 86.6% of exposed individuals (p c 0.0001, Mann-Whitney U-test). Flow cytometry analysis of apoptosis in a healthy control and a patient with chronic fatigue syndrome is shown in Figure 11-4. We have already shown that benzene induction of apoptosis is caused by a discrete block of the cell cycle progression. Because it was shown that the ratio of apoptosis to mitosis is predictive of tumor growth, with increased apoptosis favoring positive prognosis. We analyzed their data and expressed them in terms of this ratio? As shown in Table 11-1, about 10%of the chemically exposed individuals demonstrated a rate of mitosis greater than that of apoptosis, which is predictive of cancer development. Therefore the tendency of normal cells to commit suicide when deprived of their usual growth factors, or of physical contact with their neighbors due to chemical exposure, is probably a built-in defense against metastasis. Prompt activation of apoptosis in tumor cells that leave their native tissue presumably eradicates many metastatic cells before they have a chance to proliferate. In cancer, it is tumor cells that neglect to sacrifice themselves or forget to die. Indeed, researchers increasingly describe cancer as a disease involving both excessive proliferation of cells and abandonment of their ability to die. Cancer develops after a cell accumulates mutations in several genes that control cell growth and survival. When a mutation seems irreparable, the affected cell usually kills itself rather than risk becoming deranged and potentially dangerous. But if the cell does not die, it or its progeny may live long enough to accumulate mutations that enable it to divide uncontrollably and metastasize, to break away from the original tumor and establish masses at distant sites. In many tumors, genetic damage apparently fails to induce apoptosisbecause the constituent cells have inactivated the gene that codes for the P53 protein. This protein, it will be recalled, can lead to activation of the cell's apoptotic machinery when DNA is injured by environmental agents such as benzene or its metabolites. Thewfore it is important to study cell suicide in health and diseases.

CLINICAL APPLICATIONS Apoptosis in Autoimmune Diseases In cancer, it is the tumor cells that forget to die-in autoimmunity, immune cells fail to die when they are

Supplementary Diagnostic Procedures Negative control

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Figure 11-4 Enhanced apoptotic cell population in benzene-exposed chronic fatigue syndrome individuals. Flow cytometry analysis of apoptotic cell population in negative mntrol cells (HL-60 leukemic cell line), positive control cells (HL-60 leukemic cells treated with the m e n camptothecin), control subjects, and benzene-exposed individuals. Peripheral blood leukocytes were isolated. cultured for 12 hours paraformaldehyde-fixed, F-dUTP-labeled, and analyzed for apoptosis by flow cytornetry.

supposed to. Virtually all tissues harbor apoptotic cells at one time or another. Damaged cells usually commit suicide for the greater good of the body; when this does not occur, disease may develop. Autoimmunity occurs when the antigen receptors on immune cells recognize specific antigens on healthy cells and cause the cells bearing those particular substances to die. But true autoimmune diseases that involve apoptosis do exist. Under normal conditions, the body allows a certain number of self-reactive lymphocytes to circulate. These cells normally do little harm, but they can become overactive through several processes. For instance, if these reactive lymphocytes recognize some foreign antigen such as microbes on food and haptenic chemicals, then exposure to that antigen causes them to become excited. If, due to molecular mimicry, these antigens are similar to normal tissues, the activated cells may expand their numbers and attack the healthy tissue, thus causing an autoimmune disease.'J7Js Autoimmune reactions usually are self-limited-they disappear when the antigens that originally set them off are cleared away. In some instances, however, the autoreactive lymphocytes survive longer than they should and continue to induce apoptosis in normal cells. Some evidence in animals and humans indicates that extended survival of autoreactive cells is implicated in at least two chronic autoimmune syndromes-systemic

lupus erythematosus and rheumatoid arthritis. In other words, the lymphocytes undergo too little apoptosis, with the result that normal cells undergo too

Apoptosis during Viral Infection Disturbance in the regulation of apoptosis participates in various diseases. Viral illnesses are among the diseases caused by apoptosis dysregulation. After entering a cell, viruses attempt to shut down the cell's ability to make any proteins except those needed to produce more virus. This act of stalling host protein synthesis is enough to induce many kinds of cells to commit suicide. If the host cell dies, the virus is also eliminated. Therefore certain viruses have evolved ways to inhibit apoptosis in the cells they infect. Epstein-Barr virus, which causes mononucleosis and has been linked to lymphomas in humans, uses a mechanism that has been seen in other viruses. It produces substances that inhibit apoptosis. Other viruses, such as P53, inactivate or degrade the induced apoptosis. Papillomavirus, a major cause of cervical cancer, is one example. Cowpox virus, a relative of which is used as the smallpox vaccine, is another. Both elaborate a protein that prevents proteases from carrying out the apoptotic program. Investigators interested in antiviral therapy are now exploring ways to block the activity of the antiapoptotic molecules manufactured by viruses.19

Apoptosis Assessment -

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(benzene). In patients 11 and 14, the rate of mitosis is twice that of apoptosis, yielding a ratio of apoptosis to mitosis close to 0.5. Others present ratios

Sample no.

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34 29 48 47 20 42 23 26 35 44 18 19 32 19 27 29 28 24 7 10

18.3 25 46 52 18 17 17 19 13 19 33 15 12 35 16 19 27 19 6 11

Apoptosis in Acquired Immunodeficiency Syndrome Induction of apoptosis by viruses in healthy cells is believed to contribute to the immune deficiency found in patients with acquired immunodeficiency syndrome (AIDS). In these patients, infection with human immunodeficiency virus (HIV) causes T-helper cells to die. As T-helper cells gradually disappear, cytotoxic cells, such as natural killer (NK) cells, perish as well through apoptosis, since they cannot survive without the growth signals produced by T-helper cells. When the number of T-cells dwindles, so does the body’s ability to fight infections, especially viral and parasitic. Researchers have shown that many more helper cells succumb than are infected with HA? It is also highly probable that a large number of the cells probably die through apoptosis. Apparently, Fas plays a crucial role in this process. Normally, T cells make functional Fas only after they have been active for a few days and are ready to die. But helper cells from AIDS patients may display high amounts of functional Fas even before the cells have encountered an antigen. This display of Fas would be expected to cause the cells to undergo apoptosis prematurely whenever they encounter Fas ligand on other cells (such as on T cells already activated against HIV or other microbes).

Ratio of apoptosidmitosis

1.9 1.2 1.05 0.9 1.1 2.5 1.35 1.37 2.7 2.3 0.54 1.26 2.66 0.54 1.68 1.52 1.03 1.26 1.16 0.9

In addition, if the primed cells encounter the antigen recognized by their receptors, they may trigger their own death. It is also possible that oxygen-free radicals trigger the suicide of virus-free T cells. These highly reactive substances are produced by inflammatory cells drawn to infected lymph nodes in HIV patients. Free radicals can damage DNA and membranes in cells. They will cause necrosis if they do extensive damage, but they can induce apoptosis if the damage is more subtle. In support of the free-radical theory, researchers have found that molecules capable of neutralizing free radicals prevent apoptosis in T-cells obtained from AIDS patient~.l~,*~ Therapies with antiapoptotic medication, such as Trolox, a water-soluble analog of vitamin E that prevents oxidative stress, and pyrrolidine dithiocarbamate, a potent inhibitor of nuclear factor kB (NF-KB),are now the focus of AIDS and autoimmune disease studies.21”

Apoptosis in the Heart and Brain In contrast to cancer, where cells forget to die and insufficient apoptosis occurs, excessive apoptosis accounts for much of the cell death that follows heart attacks and strokes. In the heart, vessel blockage decimates cells that were fully dependent on the vessel. Those cells die by

Supplementary Diagnostic Procedures necrosis, partly because they are catastrophically starved of the oxygen and glucose they need to maintain themselves and partly because calcium ions, which are normally pumped out of the cell, rise to toxic levels. Over the course of a few days, cells surrounding the dead zone-which initially survive because they continue to receive nourishment from other blood vessels-can die as well. Later, however, many cells die by necrosis after being overwhelmed by the destructive free radicals that are released when inflammatory cells swarm into the dead zone to remove necrotic tissue. The less injured cells commit suicide by apoptosis. If the patient is treated by restoring blood flow, still more cells may die by necrosis or apoptosis because reperfusion leads to a transient increase in the production of free radicals. Similarly, in strokes due to inflammation, release of such neurotransmitters as glutamate lead to necrosis and apoptosis. Understanding of the factors that lead to the tissue death accompanying heart attack, stroke, and reperfusion has led to new ideas for treatment. Notably, cell death might be limited by drugs and other agents that block free-radical production or inhibit proteases. Apoptosis also accounts for much of the pathology seen in such diseases as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis (Lou Gehrig disease), which are marked by the loss of brain neurons. Elevated apoptosis in these neurologic diseases seems to be related to lack of production of the nerve growth factor and to free radical damage. It seems likely that a combination of such factors could cause many cells to destroy themselves. Manipulation of this process of cell killing may help in treating these neurologic diseases. In fact, studies in animal models imply that long-term delivery of nerve growth factors could protect against programmed cell death in these conditions. Therefore a greater understanding of the mechanisms involved in cell death should greatly enhance those important step^."*^',^

Figure 11-5 Balance or imbalance between the rate of apoptosis and mitosis determines tissue homeostasis,atrophy, cell proliferation, and development of cancer.

Apoptosis and cell proliferation play an important role in development, differentiation, homeostasis, and aging2” The balance established between these two processes depends on various growth and death signals that are influenced by diet, nutrition, lifestyle, and other environmental factors.

When the equilibrium between life and death is disrupted by aberrant signals (e.g., low levels of antioxidants in the blood or tissue cells), either tissue growth or atrophy occurs. Under normal conditions with optimal nutritional factors, tissue homeostasis is sustained by balancing the effects of mitosis and apoptosis. The importance of this balance can clearly be seen when one of these processes becomes predominant (Figure 11-5). During viral or chemical exposure and in preneoplastic tissue, the number of cells undergoing apoptosis increases, possibly to compensate for an increase in proliferation. As the cell loses functional tumor-suppressor genes (the P53), the propensity to undergo apoptosis decreases and the population of tumor cells grows. Inefficient immune function such as low NK activity due to stress or antioxidant deficiencies may contribute further to this mitosis and apoptosis imbalance, which results in additional tumor cell growth.

1. Wyllie AH,Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol 1980;68:251. 2. White E. Life, death and the pursuitof apoptosis.Genes Dev 1996;lOl. 3. Jarvis WD, Kolesnick RN, Fomari FA, et al. Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. Proc Natl Acad Sci U S A 1994;91:73.

4. Green DR,Martin SJ.The killer and the executioner:how apoptosis controls malignancy.Curr Opin Immunol 1995;7694. 5.Arends MJ,McGregor AH, Wyllie AH. Apoptosis is inversely related to necrosis and determines net growth in tumors bearing constitutively expressed myc, ras and HPV oncogenes. J Pathol 1994;144:1045.

CONCLUSIONS

Apoptosis Assessment 6. Marchetti P, Hirsch T, Zamzami M, et al. Mitochondrial permeability triggers lymphocyte apoptosis. J Immunol1996;1574830. 7.Vojdani A, Mordechai E, Brautbar N. Abnormal apoptosis and cell cycle progression in humans exposed to methyl tertiary-butyl ether and benzene contaminating water. Human Exp Toxic01 1997;16485-494. 8. Walker PR, Smith C, Youdale T, et al. Topoisomerase 11-reactive chemotherapeutic drugs induce apoptosis in thymocytes. Cancer Res 1991;51:1078-1085. 9. Brown DB, Sun Xh4, Cohen GM. Dexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation. J Biol Chem 1993;268:3037. 10. Reynolds ES, Kanz MF, Chicco P, Moslen MT. 1.1-Dichloroethylene: an apoptotic hepatotoxin? Environ Health Perspect 1984;57313. 11. Aw TY, Nicotera P, Manzo L, Orrenius S. Tributyltin stimulates apoptosis in rat thymocytes. Arch Biochem Biophys 1990; 28346. 12. Rossi AD, Larsson 0,Manzo L, et al. Modification of Ca2+signaling by inorganic mercury in PC12 cells. FASEB 1993;71507. 13. Kunimoto M. Methyl mercury induces apoptosis of rat cerebellar neurons in primary culture. Biochem Biophys Res Commun 1994; 204:310. 14.Vivian 8, Rossi AD, Chow SC, Nicotera P. Organotin compounds induce calcium overload and apoptosis in PC12 cells. Neurotoxicology 1995;1619.

15. Ledda-Columbano GM, Coni P, Curto M, et al. Induction of two different modes of cell death, apoptosis and necrosis in rat liver after a single dose of thioacetamide. Am J Pathol1991;139:1099. 16. ATSDR (Agency for Toxic Substances and Disease Registry). Toxicologicalprofile for benzene, draft report. Atlanta: Department of Health and Human Services, Agency, 1987. 17. National Institute of Environmental Health Sciences. Sixth annual report on carcinogens. Benzene Case No. 71-43-2: 35. Research, 1991. Triangle Park, NC: National Institute of Environmental Health Sciences, 1991, 18. Golstein P, O~ciusDM, Ding-E Young J. Cell death mechanisms and the immune system. Immunol Rev 1991;121:29. 19.Cohen JJ, Duke RC, Fadok VA, Sellins KS. Apoptosis and programmed cell death in immunity. Ann Rev Immunol 1992; 10:267. 20. Duke RC, q c i u s DM, Ding-E Young J. Cell suicide in health and disease. Sci Am 1996;275:80. 21. Martin SJ, Green DR. Protease activation during apoptosis: death by a thousand cuts. Cell 1995;82:349. 22.Forrest VJ, Kang Y, McClain DE, et al. Oxidative stress-induced apoptosis prevented by Trolox. Free Radic Biol Med 1994;16: 675-684. 23. Schreck R, Meier B, Mannel DN, et al. Dithiocarbamates as potent inhibitors of nuclear factor kB activation in intact cells. J Exp Med 1992;175:1181.

Bacterial Overgrowth of the Small Intestine Breath Test Mary James, ND CHAPTER CONTENTS Introduction 153 Frequency of Small Intestinal Bacterial Overgrowth 153 Pathophysiology 153 Diagnosis 154 Laboratory Assessment Endoscopy 155 Breath Testing 155

155

INTRODUCTION Small intestinal bacterial overgrowth (SIBO)is an abnormal colonization within the small bowel by bacteria normally found in the colon, mouth, or pharynx.’ Also called BOSI (bacterial overgrowth of the small intestine), “bhd-loop,” or ”stagnant loop,”2 SIBO is a potentially serious disorder that leads to problems such as malabsorption, anemia and weight loss, malnutrition? increased intestinal permeability (”leaky gut”),“ and bone loss? Breath testing for hydrogen and methane provides a simple noninvasive means of detecting SIBO. Once SIBO has been identified, antimicrobials are typically administered to eradicate the bacteria. Further treatment then can be commenced to address the underlying causes of SIBO to prevent a recurrence.

Frequency of Small Intestinal Bacterial Overgrowth Bacterial overgrowth of the small intestine is a frequently overlooked contributing factor in several common disorders.6For example, irritable bowel syndrome (IBS), responsible for up to 40% of referrals to gastroenterologists? is frequently associated with SIBO. One study of more than 200 patients with IBS found that 78% tested positive for SIBO. Of those successfully treated for SIBO, 48% no longer met the Rome criteria for IBS.8 Patients with fibromyalgia9 and chronic fatigue syndromeS also have been observed to have a high rate of SIBO (78% and 77% of subjects, respectively).

Treatment of Bacaial Overgrowth 157 Bacterial Eradication 157 Antibiotics 157 Antibiotic Alternatives 157 Addressing the Underlying Cause 158 Restoration of Gastric Acidity 158 Normalization of Intestinal Motility 158 Supportive Measures 158

About half of such patients who tested positive for SIBO in one study experienced marked subjective improvement after antibiotic administration. Interestingly both of these disorders have been observed to overlap with IBS.’O Other groups of patients particularly prone to bacterial overgrowth of the small intestine include those with intestinal dysmotility syndromes associated with systemic disease (e.g., diabetes, scleroderma, and intestinal pseudoobstruction), prior intestinal surgery, and strictures of the small bowel. Both jejunal diverticulosis6and Crohn’s disease” have been associated with SIBO, particularly in patients with Crohn’s disease who have undergone previous intestinal surgery. Interestingly most patients with celiac disease whose gastrointestinal symptoms persist with a gluten-free diet have been shown to have SIBO, with amelioration of symptoms after bacterial eradication.I2 The incidence of bacterial overgrowth increases with age, particularly in people 80 years and 01der.I~It has been found that 64% of individuals older than 75 years with chronic diarrhea have colonic-type flora in their small bowels6and that SIBO is the most common cause of clinically sigruhcant malabsorption in elderly persons?

Pathophysiology Although the concentration of bacteria increases exponentially toward the distal end of the small intestine, particularly the ileum: far fewer bacteria normally 153

Supplementary Diagnostic Procedures inhabit the small intestine than the Two major factors control the numbers and kinds of bacteria found within the small bowel: intestinal peristalsis and gastric acid ~ecretion."'~Consequently SIBO has been associated Other with both intestinal stasis and hyp~chlorhydria.'~ factors that discourage small intestinal flora overgrowth are pancreatic enzyme secretion,'6 disaccharidase production by intestinal mi~rovilli,'~ the ileocecal valve,18 bile salts, luminal pH, and oxidation-reduction p~tential.'~ Intestinal immunoglobulinsecretion and a m u m bamer that prevents bacterial adherence are unproven mechanisms for limiting bacterial growth in humans.15 Alterations in any of these normal functions (whether endogenous or drug-induced) favor uncontrolled bacterial proliferation in the small inte~tine.'~ A variety of anatomic and motor disorders of the small bowel may also lead to SIBO, such as surgical loops, diverticula, strictures, adhesions, tumors, fistulas? s~leroderma,'~ intestinal pseudoobstruction,2°and diabetic enteropathy2' All have as a common feahm the stasis of small bowel contents, which allows bacterial concentrations increasingly to resemble those of the large intestine (Box 12-l).14*15 The composition of small bowel flora varies among individuals with SIBO; however, the concentration of organismsis always higher than normal. The predominant flora is composed of coliform organisms and strict anaerobes (both rare in the small bowel), such as Bacteroides, Clostridium, and Bifid~bacterium.'~ To have clinical consequences, SIBO appears to require an adequate concentration of organisms with particular metabolic properties within specific locations of the small intestine. For example a heavy concentration of strict anaerobes and coliforms in the proximal small intestine is more likely to be associated with malabsorption than a flora consisting of fewer strict anaerobes or coliforms or when strict anaerobes or coliforms are located in the distal small inte~tine.'~ For this reason SIBO may be asymptomatic in some individuals, whereas in others

Gas, bloating, or diarrhea, usually after eating Unexplained weight loss Evidence of malabsorption Chronic hypochlorhydria or achlorhydria Use of acid-blocking medications Prior intestinal surgery, chronic constipation, or other causes of intestinal stasis Intolerance of disaccharides (lactose) Unexplained vitamin BI2 deficiency, weight loss, or bone loss Unexplained nutrient insufficiencies(e.g., calcium, magnesium, fat-soluble vitamins) Elevations of fecal short chain fatty acids Unexplained "leaky gut"

Achlorhydria, hypochlorhydria, drug-induced hypoacidity Chronic constipation Stasis resulting from structural changes (e.g., diverticulosis, blind loops, radiation damage, stricture, fistulas, intestinal pseudoobstruction,adhesions resulting from prior surgery) Chronic pancreatic insufficiency Disaccharidase deficiencies (lactase) Damaged ileocecal valve Immunodeficiency (especially of secretory immunoglobulin A) Diabetes mellitus Scleroderma Crohn's disease

Gas, bloating, and flatulence Diarrhea Abdominal cramping Steatorrhea Lactose intolerance Megaloblastic anemia

it may produce a variety of signs and symptoms. Box 12-2 outlines clinical signs and symptoms that alert the practitioner to consider testing for SIBO.

Diagnosis Signs and Symptoms Although many of the bacteria found in SIBO play beneficial roles within the colon, these same microorganisms may have deleterious effects within the delicate environment of the small intestine. The classic SIBO syndrome is characterized by megaloblastic anemia resulting from vitamin BI2 deficiency, and weight loss and diarrhea secondary to fat malab~orption.'~ However, many patients present with nonspecific symptoms such as bloating, flatulence, and abdominal pain resulting from bacterial fermentation of intraluminal sugars and associated gas production

(BOX12-3).'J2 Via secretory and osmotic processes, diarrhea may o c m even in the absence of sigruficant steatorrhea. Unabsorbed fats and bile salts are modified by bacteria in the colon to hydroxylated fats and free bile acids, respectively, which stimulate colonic secretion of water and electr01ytes.l~ Bile salts, which are essential to emulsification and assimilation, must be conjugated with either taurine or glycine to function properly. In SIBO, bacteria in the proximal small intestine (predominantly anaerobes such as Bacteroides, B$dobacteriurn, VeilloneZla, enterococci, and CZ~stridiurn)'~ are capable of deconjugating bile salts

Bacterial Overgrowth of the Small Intestine Breath Test

l e v e l ~ . ~Although J~ intrinsic factor is not altered by to form free bile acids.14 This deconjugation can have anaerobic bacteria, these microbes are capable of detachtwo major clinical repercussions: (a) the free bile acids ing vitamin B12 from intrinsic factor as well as directly may become concentrated enough to cause mucosal using Bl2.l8Either mechanism has the effect of rendering damage (Figure 12-l),resulting in reduced brush-border the vitamin unavailable to the host. Vitamin B12bound to enzyme activities (especially lactase)?’ defects in bacteria also may be partially metabolized to inactive mucosal uptake of sugars and amino acids, enteric blood analogues that compete with normal vitamin B12binding loss, and protein-losing enteropathy, or (b) the conjuand absorption.” Paradoxically, serum folate values gated bile salt concentration may fall below the concenusually are normal or even elevated in SIBO, a result of tration necessary for effective micelle formation, leading the ability of bacteria to synthesize the vitamin.= to fat malabsorption and steatorrhea (fecal fat).I4J5This Hypoproteinemiaalso may occur in SIBO, secondary to fat malabsorption may lead to insufficiencies of fatprotein-losing enteropathy and protein malab~orption.~,’~ soluble vitamins (e.g., E, A, K, and D).3 In addition bacteria may metabolize proteins to ammonia Electron microscopy research also has revealed the and fatty acids, thereby rendering them unavailable to presence of a pseudomembrane that mechanically the host.= interferes with the absorption of fats in many cases of SIBO. This pseudomembrane is thought to represent a maladaptive defense mechanism against the bacterial LABORATORY ASSESSMENT Thus, two possible mechanisms appear to o~ergrowth.’~ The composition of the bacterial populations contamibe involved in fat malabsorption in patients with SIBO, nating the small bowel is complex and variable.’ In deconjugationof bile acids and maladaptive pseudomemone study, the main bacteria recovered from patients branes that block the absorption of fats. with SIBO consisted of the microaerophilic bacteria Intraluminal fatty acids from fat malabsorption may Strqtococcus, Escherichia coli, Staphylococcus, Micrococciis, form insoluble soaps with calcium and magnesium, thus rendering them unavailable for a~similation.~ KkbsieIla, and Proteus and the anaerobic bacteria Lactobacillus, Bacteroides, Clostridium, Veillonella, Osteomalacia, night blindness, hypocalcemic tetany,’ Fusobacteriurn, and Peptostreptococcus.’ However, the and metabolic bone disease5 have been known to diagnosis of SIBO tends to be oriented less to the identidevelop as a consequence of lipid malabsorption in fication of specific microorganisms and more to overall patients with SIBO. Although rare, iron deficiency bacterial concentrations? anemia may result from blood SIBO may lead to vitamin B12 deficiency, with associEndoscopy ated megaloblastic anemia and low serum cobalamin Culture of a small bowel aspirate via endoscopy is considered the most direct method for diagnosing SIBO. High bacterial counts (exceeding 104organisms/ml from the jejunum or lo7 organismslml from the ileum) confirm the diagn0~is.l~ This method offers good sensitivity, although fairly low specificity. Because the aspirate is typically taken from only one location, overgrowth located in the more distal end of the small bowel or concentrated in a large diverticulum or blind loop may be missedF6 Intubation methods are also time consuming, uncomfortable, and expensive.

Breath Testing

Ffgure 12-1 In small intestinal bacterial overgrowth, free bile acids can damage the brush border, resulting in reduced enzyme activity and maldigestion. (Courtesy Great Smokies Diagnostic Lab, Asheville, “2.)

Breath tests were devised as less invasive alternatives to endoscopy and intubation. Breath tests have good sensitivity:’ are simple to administer, and offer greater patient comfort and convenience compared with intubation and culture. Most breath tests are based on the ability of intestinal microbes to ferment carbohydrates,producing hydrogen or methane in the process. A fraction of these gases naturally diffuses from the bowel to the circulation and is excreted with expired air. Because there is no other metabolic production of hydrogen and methane, the

hydrogen or methane. One study found that individuals pulmonary excretion may be used as a measure of bactewho produce higher amounts of H2 relative to CHI rial fermentation during the passage through the gasreported significantly increased bloating and cramping trointestinal tractF8 after carbohydrate ingestion, whereas individuals who The lactulose breath test is commonly used for the produce high CH4reported no significant increase in diagnosis of SIBO. Typically the patient ingests a chalthese symptoms.35Patients with IBS have been found to lenge dose of lactulose (a synthetic, nonabsorbed disaccharide) after 2 days of a fiber-restricted diet and a excrete significantly more H2 than healthy controls, although the total volumes of hydrogen and methane 12-hour fast.29Glucose has also been used as a challenge produced by the two groups did not differ.% Still other agent, although the sensitivity is reduced for distal ileum researchers observed associations between breath gas bacterial overgrowth because of rapid absorption of the values and specific IBS symptoms; methane production and the agent clearly is not suitable for patients with diabetes, hypoglycemia, or other blood sugar disorwas associated 100% with constipation-predominant ders. Other compounds that have been used in breath IBS, whereas hydrogen production was associated with testing are '4C-glycocholic acid and D-xylose (fermented diarrhea.37 to C02),2both of which have some l i m i t a t i ~ n s .No ~ ~ , ~ ~ Correlations between breath CHI values and colon cancer have been reported in the but subsematter which agent is used, intestinal bacteria modify the quent studies failed to substantiate the correlation?y challenge substance in such a way that an early peak in Interestingly, in vitro research suggests a possible role breath gas value is produced in patients with SIBO. In the for bile acids in the accumulation of hydrogen gas in the case of lactulose, which offers the advantage of traveling intestine; bile acids were found to inhibit methanogenesis the full length of the small intestine, the early hydroin a dose-response fashion.4O gen/methane peak is typically followed by a prolonged peak representing colonic bacterial a~tivity.2~3 Interpretation In the lactulose breath test, breath specimens are collected by having the subject exhale into a special mouthLactulose is not fermented in a healthy subject until it piece that is connected to a vacuum-sealed collection tube. reaches the colon. As a result the typical fasting breath sample contains less than 20 ppm of hydrogen or A fasting (prechallenge)breath sample is collected, 10 g of lactulose is ingested (lesser amounts for small children), methane. An increase in breath gas levels in the fifth or and then five more breath specimensare collected at timed sixth breath specimen (90 and 120 minutes, respectively) intervals over a 2-hour period. Breath levels of hydrogen usually reflects colonic bacterial fermentation and is and methane are plotted over time; early rises in breath considered normal. Lack of the expected colonic peak gas values are thought to correlate with more proximal may result from antibiotics or an acidic colonic pH.33,41 However, this should not affect results for the small portions of the small intestine. Hydrogen appears in the breath about 8 minutes after lactulose comes into contact intestine.29 with gut bacteria.3l This speed of response allows one to In patients with SIBO, the lactulose is fermented in the small intestine. This process leads to an earlier peak distinguish between small bowel bacterial overgrowth in breath gas values followed by a larger, more prolonged and the normally dense colonic flora, the latter of which peak reflecting colonic f e r m e n t a t i ~ n . ~ ~ typically gives a later, more prolonged yield of breath gas levels (roughly 90 minutes into the collection process). A positive test result (indicating SIBO) is defined by either (a) the presence of a total hydrogen/methane gas Hydrogen versus Methane peak more than 15 ppm above baseline levels, occurring within 90 minutes of lactulose ingestion or (b) an elevated Many studies using carbohydrate challenges have measured only breath hydrogen (H2).However, 30% to 50% baseline (fasting)breath gas concentration, even if there is of H2 producers also produce methane (CHJ,32 most not a large rise from baseline over the next few samples." likely because "methanogenic" bacteria consume H2and Elevated fasting values occur in up to one third of cases33 and are thought to relate to the fermentation of endogeproduce CH, in the process.2yIndividuals who harbor methanogenic bacteria (primarily Methnnobrevibncter nous brush-border glycoproteins in patients with SIBO.@ ~ r n i f h i iin ) ~ their ~ intestines typically produce greater In some cases of slow transit, high levels of gases in amounts of breath CH4during the breath test; thus those the fifth or sixth breath specimens may indicate SIBO in the distal ileum rather than the usual colonic peak, thus with SIBO may be missed by a test that examines only HPMConsequently the addition of methane to the analy- complicating the interpretation. sis provides a more thorough assessment of bacterial False-Positive and False-Negative Results overgro~th.~~,~~ Various researchers have noted clinical correlations Various factors may interfere with the lactulose breath between various disorders and the production of test, resulting in false-negative or false-positive results.

Bacterial Overgrowth of the Small Intestine Breath Test

Detailed instructions for breath collection are aimed at minimizing this interference and must be followed carefully.

False-Positive Results The following factors may account for a false-positive result on a breath test: Failure to fast for at least 12 hours before the test or to avoid dietary fiber the day before collection may result in a high "background noise" that contributes significantly to the overall concentration of breath gases.28 Sleeping, smoking, or eating shortly before or during sample collection can increase concentrationsof breath gases4 Fermentation by mouth and oropharyngeal flora may lead to early, transient elevations in breath gases after carbohydrate ingestion.45As a result, thorough teeth and tongue brushing before specimen collection is recommended.

False-Negative Results False-positive results on a breath test can be caused by the following factors: Diarrhea or the recent administration of antimicrobials can temporarily reduce the concentration of gut bacteria,& leading to a false-negative result. Laxatives and enemas may have a similar effect." It is recommended that the patient wait at least 1 week after antibiotic therapy before performing the test. SIBO that is confined to the distal ileum may go undetected if the breath gas peak produced in the ileum merges with the breath gases produced by the colonic Rapid intestinal transit time may cause delayed increases in breath gases, leading to a rise only after the lactulose has already reached the cecum.&This is particularly relevant for patients with SIBO who have undergone small bowel resection.

TREATMENT OF BACTERIAL OVERGROWTH Bacterial Eradication More often than not, addressing only the contributing factors to SIBO fails to adequately resolve the bacterial overgrowth; therefore the primary treatment of SIBO is directed at altering the intestinal flora with antibiotics.l5 Most patients with clinically significant SIBO host an intestinal flora consisting largely of anaerobes; however, some patients harbor a predominance of gram-negative

aerobes, such as Escherichiu coli, Klebsiella, and Pseudomon~s.4~ Therefore it is generally agreed that the most effective antimicrobial agent is one that targets both aerobic and anaerobic microorganisms.2

Antibiotics The first-line antibiotic for SIBO has traditionally been tetracycline (250 mg QID)? However, the high prevalence of bacterial resistance to the drug (up to 60% of patients with SIB0)2 has led to the use of alternative antibiotics. The most effective alternative agents, shown either empirically or by clinical trials, are the quinolones (e.g., ciprofloxacin or norfloxacin), amoxicillin with clavulanic acid (Augmentin), clindamycin, and metroni d a ~ o l e .Other ~ ~ , ~antibiotics ~ that have been reported to be effective in SIBO are ampicillin, erythromycin, lincomycin, oral aminoglycosides, cephalosporins (Keflex), and chloramphenicol. Antibiotics that show poor activity against anaerobes probably should be avoided in the treatment of SIBO (e.g., penicillin, ampicillin, and the oral aminoglycosides kanamycin and neomycin).2 The use of more poorly absorbed antibiotics may help minimize the risk of side effects. Rifaximin, a nonabsorbable rifamycin derivative, compared favorably with tetracycline in one study; a 7-day course of rifaximin at 400 mg TID normalized breath hydrogen excretion in 70% of patients with SIBO, whereas tetracycline normalized breath hydrogen excretion in only 27% of patients.52 In most patients, a single course of antibiotic therapy (7 to 10 days) is adequate; in others, cyclic therapy (1 week out of every 4) or continuous therapy (1 to 2 months) may be needed? Prolonged antibiotic therapy significantly raises the risk of diarrhea, Clostridium dificile infection, and bacterial resistance? The administration of probiotics usually helps to minimize such side effects.17 A poor response to antibiotics may indicate slowly reversible or irreversible mucosal disease, antibiotic resistance, antibiotic-associated diarrhea, or an incorrect diagno~is.'~,~~

Antibiotic Alternatives Aromatic oils have been shown to be effective antimicrobials. Peppermint oil, which has been used successfully in patients with IBS, has demonstrated antimicrobial properties in vitro.%In a case study, enteric-coated peppermint oil (dose of 0.2 ml tid) was seen to dramatically reduce gastrointestinal symptoms in a patient with SIBO?5 Follow-up breath testing indicated some persistent bacterial overgrowth; the addition of an established antimicrobial agent such as berberine may help to improve the results.% Research on the effectiveness of other botanical agents in SIBO is clearly needed.

A small double-blind study examined the effect of oral probiotics (combined Lactobacillus acidophilus and L. cusei strains) on SIBO. A significant decrease in breath hydrogen concentration was noted as early as 1 week into treatment, providing evidence that LactobacilIus strains may be effective in the treatment of bacterial o~ergrowth.~~

addressed. When not resulting from anatomic or organic causes, reduced motility may be improved with measures such as increased dietary fiber, water, probiotics, stress management, and exercise. Surgical correction of anatomic causes of intestinal stasis, such as small bowel diverticula, may be ~ a r r a n t e d . 5 ~

Addressing the Underlying Cause

Patients may become lactose intolerant secondary to an acquired disaccharidase deficiency caused by SIBO.*l Avoiding lactose as well as other disaccharides such as sucrose, maltose, and isomaltose (concentrated in grains) may help to “starve” the excess bacteria and allow healing of the intestinal lining.6o Substituting more easily absorbed medium-chain triglycerides for most dietary fat may be helpful in patients with diarrhea and steatorrhea.z Probiotics and prebiotics are recommended to help restore normal balance of intestinal flora, especially in patients with a history of antibiotic use. Various strains of Lactobacillus and Bifidobacterum have been used successfully to treat SIB0.17,57

Bacterial overgrowth of the small intestine may recur easily if the root causes are not addressed.

Restoration of Gastric Acidity Because gastric acidity is an important deterrent to SIBO, the restoration of normal stomach pH in the patient with hypochlorhydria or achlorhydria is essential. This may include the use of betaine hydrochloride with meals or the discontinuation of antacid medications. SIBO has been found in both patients with ulcer and healthy subjects after even short-term (5-week) administration of omeprazole (a proton pump inhibitor). The bacterial overgrowth was associated with greater deconjugation of bile acids and fat malabsorption and was thought to be induced by a shift to neutral pH in the gastric juice.58

Supportive Measures

Acknowledgment Special thanks to Sharon Rock for her research assistance.

Normalization of Intestinal Motility Intestinal stasis, whether functional or anatomic, is another major contributing factor to SIBO that should be

1. Bouhnik Y, et al. Bacterial populations contaminating the upper gut in patients with small intestinal bacterial overgrowth syndrome. Am J Gastroenterol1997;94:1327-1331. 2. Toskes PP. Bacterial overgrowth of the gastrointestinal tract. Adv Intern Med 1993;38387-407. 3. Keusch GT, Solomons NW. Microorganisms, malabsorption, diarrhea and dysnutrition. J Environ Pathol Toxic01 Oncol 1985;5: 165-209. 4. Riordan SM, et al. Luminal bacteria and small-intestinalpermeability. Sand J Gastroenterol 1997;32:556-563. 5. Di Stefan0 M, et al. Small intestine bacterial overgrowth and metabolic bone disease. Dig Dis Sci 2001;46:1077-1082. 6. Thomas PD, et al. Guidelines for the investigation of chronic diarrhoea. Gut 2003;52(Suppl 5):vl-15. 7. Zaman A. Irritable bowel syndrome. Clin Cornerstone 2002;4:22-33. 8. Pimentel M, Chow EJ, Lm HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol2000;95:3503-3506. 9. Pimentel M, et al. Small intestinal bacterial overgrowth a possible association with fibromyalgia. J Musculoskelet Pain 2001;9:107-113. 10. Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med 2000;160:221-227. 11. Castiglione F, et al. Orocecal transit time and bacterial overgrowth in patients with Crohn’s disease. J Clin Gastroenterol2000;31:63-66.

12. Tursi A, Brandimarte G, Giorgetti G. High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal. Am J Gastroenterol2003;98:839-843. 13. Riordan SM, et al. Small intestinal bacterial overgrowth in the symptomatic elderly. Am J Gastroenterol 1997;92:47-51. 14. Anonymous. Small intestinal bacterial overgrowth syndrome. Gastroenterology 1981;80834-845. 15. Kirsch M. Bacterial overgrowth. Am J Gastroenterol 1990;85: 231-237. 16. Hill M. Normal and pathological microbial flora of the upper gastrointestinal tract. Scand J Gastroenterol1985;111(Suppl):1-6. 17. Rolfe RD. The role of probiotic cultures in the control of gastrointestinal health. J Nutr 2000;130(Suppl):396SO2S. 18. King CE, Toskes PP. Small intestine bacterial overgrowth. Gastroenterology 1979;76:1035-1055. 19. Rose S, Young MA, Reynolds JC. Gastrointestinal manifestations of scleroderma. Gastroenterol Clin North Am 1998;27563-594. 20. Camilleri M. Small bowel motility disorders. Rev Gastroenterol Mex 1994;59:120-126. 21. Virally-Monod M, et al. Chronic diarrhoea and diabetes mellitus: prevalence of small intestinal bacterial overgrowth. Diabetes Metab 1998;24:530-536. 22. Sherman P,Lichtman S. Small bowel bacterial overgrowth syndrome. Dig Dis Sci 1987;5:157-171.

Bacterial Overgrowth of the Small Intestine Breath Test 23. Fagundes-Net0 U, et al. Studies of the small bowel surface by scanning electron microscopy in infants with persistent diarrhea. Braz J Med Biol Res 2000;331437-1442. 24. Murphy MF, et al. Megaloblastic anaemia due to vitamin BIZdeficiency caused by small intestinal bacterial overgrowth possible role of vitamin BI2 analogues. Br J Haematol 1986;62:7-12. 25. Camilo E, et al. Folate synthesized by bacteria in the human upper small intestine is assimilated by the host. Gastroenterology 1996;110991-998. 26. OLeary C, Quigley EM. Small bowel bacterial overgrowth, celiac disease, and IBS: what are the real associations?Am J Gastroenterol 2003;98:720-722. 27. Rhodes JM, Middleton P, Jewel1 DP. The lactulose hydrogen breath test as a diagnostic test for small-bowel bacterial overgrowth. Scand J Gastroenterol1979;14:333-336. 28. Brummer RJ, et al. The hydrogen (H2)breath test: sampling methods and the influence of dietary fibre on fasting level. Scand J Gastroenterol1985;201007-1013. 29. Hamilton LH. Breath tests and gastroenterology, 2nd ed. Milwaukee: QuinTron Instrument Company, 1998. 30. Cloarec D, et al. Breath hydrogen response to lactulose in healthy subjects: relationship to methane producing status. Gut 1990;31: 300-304. 31. Bond JH Jr, Levitt MD. Use of pulmonary hydrogen (H2) measurements to quantitate carbohydrate absorption: study of partially gastrectomized patients. J Clin Invest 1992;51:1219-1225. 32. Rumessen JJ, Nordgaard-Andersen I, Gudmand-Hoyer E. Carbohydrate malabsorption: quantification by methane and hydrogen breath tests. Scand J Gastroenterol1994;29:826-832. 33. Romagnuolo J, Schiller D, Bailey RJ. Using breath tests wisely in a gastroenterology practice: an evidence-based review of indications and pitfalls in interpretation. Am J Gastroenterol2002;971113-1126. 34. Corazza G, et al. Prevalence and consistency of low breath H2excretion following lactulose ingestion: possible implications for the clinical use of the H2breath test. Dig Dis Sci 1993;382010-2016. 35. Kajs TM, et al. Influence of a methanogenic flora on the breath H2 and symptom response to ingestion of sorbitol or oat fiber. Am J Gastroenterol1997;9289-94. 36. King TS, Elia M, Hunter JO. Abnormal colonic fermentation in irritable bowel syndrome. Lancet 1998;352:1187-1189. 37. Pimentel M, et al. Methane production during lactulose breath test is associated with gastrointestinal disease presentation. Dig Dis Sci 2003;48:86-92. 38. Haines A, et al. Breath-methane in patients with cancer of the large bowel. Lancet 1977;2(8036):481-483. 39. Pique JM, et al. Methane production and colon cancer. Gastroenterology 1984;87601-605. 40. Florin TH, Jabbar IA.A possible role for bile acid in the control of methanogenesis and the accumulation of hydrogen gas in the human colon. J Gastroenterol Hepatol 1994;9:112-117.

41. Vogelsang H,et al. Acidic colonic microclimate-possible reason for false negative hydrogen breath tests. Gut 1988;29:21-26. 42. Kerlin P, Wong L. Breath hydrogen testing in bacterial overgrowth of the small intestine. Gastroenterology 1988;95:982-988. 43. Perman JA, Modler S. Glycoproteins as substrates for production of hydrogen and methane by colonic bacterial flora. Gastroenterology 1982;83388-393. 44. Solomons N. Evaluation of carbohydrate absorption: the hydrogen breath test in clinical practice. Clin Nutr J 1984;3:71-78. 45. Thompson DG,OBrien JD, Hardie JM. Influence of the oropharyngeal microflora on the measurement of exhaled breath hydrogen. Gastroenterology 1986;91:853-860. 46. Gilat T,et al. Alterations of the colonic flora and their effect on the hydrogen breath test. Gut 1978;19:602-605. 47. Solomons NW, et al. H2breath tests during diarrhea. Acta Paediatr %and 1979;68:171-172. 48. Caride VJ, et al. Scintigraphic determination of small intestinal transit time: comparison with the hydrogen breath technique. Gastroenterology 1984;86714-720. 49. Kocoshis SA, et al. Duodenal bile acids among children: keto derivatives and aerobic small bowel bacterial overgrowth. J Pediatr Gastroenterol Nutr 1987;6:686-696. 50. Meyers JS, Ehrenpreis ED, Craig RM. Small intestinal bacterial overgrowth syndrome. Curr Treat Options Gastroenterol2001;4:7-14. 51. Attar A, et al. Antibiotic efficacy in small intestinal bacterial overgrowth-related chronic diarrhea: a crossover, randomized trial. Gastroenterology 1999;117794-797. 52. Di Stefan0 M, et al. Rifaximin versus chlortetracycline in the shortterm treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther 2000;14551-556. 53. Bjomeklett A, Hoverstad T, Hovig T. Bacterial overgrowth. Scand J Gastroenterol1985;109(Supp1):123-132. 54. Shapiro S, Meier A, Guggenheim B. The antimicrobial activity of essential oils and essential oil components towards oral bacteria. Oral Microbiol Immunol 1994;9:202-208. 55. Logan AC, Beaulne TM. The treatment of small intestinal bacterial overgrowth with enteric-coated peppermint oil: a case report. Alt Med Rev 2002;7410-417. 56. Birdsall T,Kelly G. Berberine: therapeutic potential of an alkaloid found in several medicinal plants. Alt Med Rev 1997;294-103. 57. Gaon D, et al. Effect of Lactobacillus strains (L. casei and L. acidophilrts strains cereal) on bacterial overgrowth-related chronic diarrhea. Medicina (Brazil) 2002;62:159-163. 58. Shindo K, et al. Omeprazole induces altered bile acid metabolism. Gut 1998;42266-271. 59. Drude RB Jr, et al. Malabsorption in jejunal diverticulosis treated with resection of the diverticula. Dig Dis Sci 1980;25:802-806. 60. Gottschall E. Breaking the vicious cycle. Baltimore: Kirkton Press, 1994.

Cell Signaling Analysis Aristo Vojdani, PhD, MT CHAPTER CONTENTS Introduction 161 The Cell Cycle 161

Clinical Application 162 Patients Exposed to Carcinogenic Chemicals and Patients with Chronic Fatigue Syndrome 162

Flow Cytometry to Assess Cell Cycle Status 162

INTRODUCTION Signaling pathways in normal cells consist of growth and controlling messages from the outer surface deep into the nucleus. In the nucleus, the cell cycle clock collects different messages, which are used to determine when the cell should divide. Cancer cells often proliferate excessively because genetic mutations cause induction of stimulatory pathways and issue too many "go ahead" signals, or the inhibitory pathways can no longer control the stimulatory pathways.' Over the past 5 years, impressive evidence has been gathered with regard to the destination of stimulatory and inhibitory pathways in the cell. These pathways converge on a molecular apparatus in the cell nucleus that is often referred to as the cell cycle clock. The clock is the executive decision maker of the cell; apparently, it runs amok in virtually all types of human cancer. In a normal cell, the clock integrates the mixture of growth-regulating signals received by the cell and decides whether the cell should pass through its life cycle. If the answer is positive, the clock leads the process.

THE CELL CYCLE A scheme of the classical cell cycle is shown in Figure 13-1. The cell cycle compartments are drawn such that their horizontal position reflects their respective DNA content. Cells that contain only one complement of DNA from each parent (2C) are referred to as diploid cells. Cells that have duplicated their genome, and thus have 4C amounts of DNA, are called tetraploid cells.

The cell cycle is classically divided into the following phases: Go

G1 *S G2

*M The cell cycle phase of G1 was historically considered to be a time when diploid (2C) cells had little observable activity. Since this time precedes DNA synthesis, the term Gap 1 ( G I )was coined. Now it is known that there is quite a bit of transcription and protein synthesis during this phase. At a certain point in the cell's life, the DNA synthetic machinery turns on. This phase of the cell's life is labeled "S" for synthesis. As the cell proceeds through this phase, its DNA content increases from 2C to 4C. At the end of S, the cell has duplicated its genome and now is in the tetraploid state. After the S phase, the cell again enters a phase that was historically thought to be quiescent. Since this phase is the second gap region, it is referred to as G2. In the G2phase, the cell is producing the necessary proteins that play a major role in cytokinesis. After a highly variable amount of time, the cell enters mitosis (M). DNA content remains constant at 4C until the cell actually divides at the end of telophase. The enlarged parent cell finally reaches the point where it divides in half to produce its two daughters, each of which is endowed with a complete set of chromosomes. The new daughter cells immediately enter GI and may go through the full cycle again. Alternatively, they may stop cycling temporarily or permanently? 161

Supplementary Diagnostic Procedures

CLINICAL APPLICATION Patients Exposed to Carcinogenic Chemicals and Patients with Chronic Fatigue Syndrome To determine whether peripheral blood lymphocytes (PBLs) isolated from chronic fatigue syndrome (CFS) individuals and chemically exposed patients represent a discrete block in cell cycle progression, PBLs isolated from CFS and control individuals were cultured, harvested, fixed, PI-stained, and analyzed by flow cytometry. The nonapoptotic cell population in PBL isolated from CFS individuals consisted of cells arrested in the late S and G2/M boundaries, as compared with healthy controls. The arrest was characterized by increased S and G2/M phases of the cell cycle (from 9% to 33% and from 4% to 21%, respectively) (Table 13-1, Figure 13-2) at the expense of Go/GI. Such an abnormality in cell cycle

Phase

Healthy controls

Chemically exposed

GdGi

88.6f 1.4 8.6f 1.2 3.6f 0.82

51.7k 2.4 33.2k 4.3 21 .O k 2.6

S GdM

,

Figure 13-1 Stages of cell cycle (Go, G,, S.GZ,and M phases) (A) and DNA histogram (6)generated by flow cytometry.

FLOW CYTOMETRY TO ASSESS CELL CYCLE STATUS Flow cytometry is a method of measuring cell properties as they “flow” through a detector while being illuminated with intense light. Tissues are generally disaggregated into single-cell suspensions and stained with one or more fluorescent dyes. The cells are forced to flow within a sheath of fluid, eventually being intersected and interrogated by an intense light source such as a laser beam. As the cell enters the laser beam, it scatters light in all directions. The measurement of light scattered in the forward direction yields information on the particle’s size. Scattered light at right angles to the incident light beam provides information on the internal granularity of the cell. If the cell has been stained with one Or more fluorescent a ‘Orrelated measurement Of more than one cellular parameter can be achieved.

Figure 13-2 Cell cycle analysis of peripheral blood lymphocytes from healthy controls (A) and patients exposed to benzene (B). Note that in patients’ samples, the majority of cells switched from GJG, to S and GJM phases.

Cell Signaling Analysis

progression is an indication of abnormal mitotic cell division in patients who have been exposed to chemicals and who suffer from CFS. From these results, we concluded that PBLs of patients with chemical exposure and CFS grow inappropriately, not only because the signaling pathways in cells are perturbed, but also because the cell cycle clock becomes deranged and stimulatory messages become greater than the inhibitory pathway^.^,^

However, in order to limit cell proliferation and avoid cancer, the human body equips cells with certain back-up systems that guard against runaway division. One such back-up system present in lymphocytes of CFS patients provokes the cell to undergo apoptosis. This programmed cell death occurs if some of the cell's essential components are deregulated or damaged. For example, injury to chromosomal DNA can trigger a p o p t o s i ~ . ~ , ~ , ~

1. Weinberg RA. How cancer arises. Sci Am 1996;275:62. 2. Wheeless LL, Coon JS, Cox C, et al. Precision of DNA flow cytometry in inter-institutional analyses. Cytometry 1991;12405. 3. Wersto RE', Liblit RL, Koss LG. Flow cytometric DNA analysis of human solid tumors: a review of the interpretation of DNA histograms. Hum Pathol1991;22:1085. 4. Shankey TV, Rabinovitch PS, Bagwell 8, et al. Guidelines for implementation of clinical DNA cytometry. Cytometry 1993;14472.

5. Vojdani A, Ghoneum M, Choppa PC, et al. Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. J Intern Med 1997;242:465-478. 6. Vojdani A, Mordechai E, Brautbar N. Abnormal apoptosis and cell cycle progression in humans exposed to methyl tertiary-butyl ether and benzene contaminating water. Human Exp Toxic01 1997;16: 485494.

Comprehensive Digestive Stool Analysis 2.0 R.W. Watkins, MD, MPH, FAAFP CHAPTER CONTENTS Introduction 165 The GastrointestinalTract The Digestive Process Mouth 166 Esophagus 166 Stomach 167 Small Intestine 167 Large Intestine 167

165

166

Absorption of Nutrients 168 Carbohydrate Digestion 168 Lipid Digestion 168

Microbiology 169 Intestinal Microflora 169 Pathogens 169 Yeast 170 Dysbiosis 170 Using Comprehensive Digestive Stool Analysis 2.0 170 Digestive Function 170 Interpretation at a Glance 174 Conclusion

174

Digestive Abnormalities 168 Maldigestion 168 Pancreatic Exocrine Insufficiency 168 Malabsorption 168

INTRODUCTION Within the philosophy of natural medicine, sound nutrition and digestion are seen as fundamental to long-term health. Without proper digestive function to ensure adequate breakdown and assimilation of nutrients, even the most nutritious diet may be ineffective for optimizing health. Moreover, incomplete or faulty digestive processes, left undiagnosed and untreated, are believed to raise the risk of many diseases and may lead to a variety of chronic disorders. Problems related to the gastrointestinal (GI) tract are among the most common symptoms experienced by patients.' One study reported that during a 3-month period, nearly 70% of American households had at least one person who experienced GI symptoms.2 Problems with digestion, absorption, and inflammatory processes--even imbalances in gut flora and ecologyoften underlie the most common GI complaints. Furthermore, these common symptoms may herald much more complex and serious clinical signs and illnesses.

The Comprehensive Digestive Stool Analysis (CDSA) 2.0 provides the physician with a critical noninvasive tool for evaluating the functional and clinical status of the GI tract (Figure 14-1). By measuring key markers of digestion/absorption, gut immunology, metabolism, and intestinal microflora, this in-depth analysis can help uncover the underlying causes of GI symptoms or disease states that may have originated in the intestine. This is accomplished by identifymg critical, previously unsuspected imbalances and important physiologic connections among diet, digestive function, mucosal integrity, and the etiology of diseases, such as colon cancer, inflammatory bowel disease (IBD), and type 2 diabetes.

THE GASTROINTESTINAL TRACT Most food molecules are complex polymers that cannot be absorbed or used by the body in their native state. The primary function of the GI system is to break down these complex lipids, proteins, and carbohydrates into 165

Figure 14-2 The healthy ecology and functioning of the gastrointestinal tract depend on a host of interdependent nutritional, biochemical, and microbial interactions.

Figure 14-1 The functional status of the gastrointestinal tract can be evaluated noninvasively with the Comprehensive Digestive Stool Analysis 2.0. (Courtesy Great Smokies Diagnostic Lab, Asheville, NC.)

simple absorbable nutrients (monomers), such as monosaccharides, monocyglycerols, fatty acids, amino acids, vitamins, minerals, and water. Once broken down into these monomeric building blocks, nutrients can be transported into interstitial fluids as they move across the inner layer, or mucosa, of the GI tract, to be distributed to cells throughout the body.3 Digestion is a chemical breakdown of food accomplished chiefly by enzymes secreted into the lumen of the GI tract by glandular cells in the mouth and stomach, by exocrine cells of the pancreas, and by enzymes in the brush-border membrane and cytoplasm of mucosal cells (enterocytes) of the small i n t e ~ t i n e .Its ~ ,proper ~ function relies on a series of interdependent nutritional, biochemical, and microbial interactions (Figure 14-2). While allowing the diffusion of life-sustaining nutrients, the mucosa must also act as a barrier to prevent the passage of potentially life-threatening bacteria and toxins into the systemic circulation. In this way the GI mucosa constitutes the body’s frontline defense against immune system attack and the arena in which the battle for healthy GI function, to absorb nutrients while excluding toxins, is fought.

THE DIGESTIVE PROCESS Mouth Homogenization of ingested food first occurs in the mouth via the grinding and mixing action of the teeth. Salivary glands provide hydration to form a bolus and protect the pharyngeal and esophageal mucosa, primarily with secretory IgA antibodies. The process of starch and fat hydrolysis is initiated with the release of lingual lipase, salivary amylase, and p t ~ a l i n . ~ , ~

Esophagus As the food bolus is swallowed, the epiglottis closes, providing a one-way valve that allows the food to pass into the GI tract and not the respiratory tract. Food is then transported down the esophagus in peristaltic waves past the lower esophageal sphincter into the stomach. Gastroesophageal reflux disease (GERD) can occur when there are transient lower esophageal sphincter relaxations, decreased lower esophageal sphincter resting tone, delayed stomach emptying, ineffective esophageal clearance, and diminished salivation. Factors that may exacerbate the symptoms of GERD in some patients include smoking, caffeine, chocolate, fatty foods, overeating with gastric distention, tight clothing, the presence of a hiatal hernia, and certain medications.

Comprehensive Digestive Stool Analysis 2.0

Small Intestine

of approximately 200 to 250 square meters, about the surface area of a tennis co~rt.3,~,8 Even after prolonged contact with pancreatic enzymes, a substantial portion of ingested carbohydrates and amino acids remains as dimers and oligomers. For final digestion, these compounds depend on hydrolytic enzymes (disaccharidases such as maltase, sucrase, lactase, enterokinase, and peptidases) produced by the brush-border membrane? For this reason, damage to the intestinal brush borderresulting from inflammation, trauma, disease, parasite infection, bacterial overgrowth, chronic nonsteroidal antiinflammatory drug use, and other factors-may interfere sigruficantly with the proper absorption of nutrients. Such damage also can disrupt the intracellular tight junctions that are vital to the protective barrier function of the gut mucosal layer, increasing the intestinal permeability of potentially harmful macromolecules, such as bacteria and toxins, into the systemic circulation. This syndrome, sometimes called "leaky gut," has been cited as an important contributory or causative factor in gluten enteropathy, Crohn's disease, food allergy, various arthritides and autoimmune diseases, chemotherapy complications, and many other conditions?-13

Most digestion and assimilation occur in the small intestine. Digestion is mediated chiefly by pancreatic enzymes, including proteolytic enzymes, nucleolytic enzymes, lipases, alpha-amylase, and phospholipase A2, which hydrolyze macromolecules to oligomers, dimers, or monomer^.^ Pancreatic enzymes are most active in the neutral pH rangePr4and bicarbonate begins the process of neutralizing stomach acid. Pancreatic proteases are secreted into the duodenum as inactive precursors, trypsinogen, chymotrypsinogen, and proelastase, and are activated by brush-border enzymes such as enterokinase to form trypsin, chymotrypsin, and elastase, respective1Y . ~ Bile secreted by the liver (about 700 ml/day) also plays a role in the solubilization and emulsification of lipids, enabling enzymatic hydrolysis. Bile is also critical for elimination of both endogenous byproducts, such as cholesterol, and exogenous xenobiotics, such as drugs and heavy metals. Bile acids (also called bile salts) are the major organic component of bile and compose about half of its solid content. From the small intestine, bile acids are absorbed into the portal blood and are taken up by hepatocytes, conjugated with taurine and glycine, and resecreted in bile, a process known as enterohepatic circulation." The digestive and absorption capacities of the small intestine are greatly enhanced by circular folds and fingerlike projections of the intestinal mucosa called microvilli. This region, dubbed the "brush border," increases the luminal surface area of the intestinal wall by about 600 times, creating a total absorptive surface

A primary role of the large intestine is to absorb water, about 1 liter daily. The large intestine also provides an environment for microbial fermentation of soluble fiber, starch, and undigested carbohydrates. Soluble fibers are more readily fermented than insoluble fibers.I4 Nondigestible carbohydrates (e.g., fiber), polysaccharides, and oligosaccharides contain chemical bonds that make them incapable of complete digestion by pancreatic or brush-border enzymes. As they move through the digestive tract, these undigested compounds play an important role in intestinal transport mechanisms. Once in the colon, they are cleaved and modified by enzymes produced by resident colonic bacteria to form shortchain fatty acids (SCFAs) and various gases, such as methane, hydrogen, and carbon dioxide.' The SCFAs, in combination with amines derived from protein degradation, provide fuel for colonocytes, act as buffering agents, and cause the pH of luminal contents to decrease. This pH decline is important because the bacterial enzyme 7-alpha-dehydroxylase, which triggers the formation of potentially carcinogenic secondary bile acids from primary bile acids, is active only above pH of 6.5.14 The epithelial layer of the colon is only one cell deep and, unlike the small intestine, has no villi. To form this layer, crypt cells located below it must differentiate. Although adequate differentiation of crypt cells is vital, excessive cell division (cell proliferation) of the epithelial layer is linked to tumorigenesis. Thus dietary agents that

Complications of GERD include esophageal erosion, esophageal ulcer, and esophageal stricture; replacement of normal esophageal epithelium with abnormal (Barrett's) epithelium; and pulmonary aspiration.

Stomach The stomach produces churning action and initiates protein and lipid hydrolysis. Peptides, amino acids, and fatty acids released in this process synchronize the release of pancreatic juice and bile into the small intestine? About 2 liters of gastric juice are produced each day, containing several important component^.^ Hydrochloric acid (secreted by the parietal cells) activates pepsinogen to convert to pepsin, which renders some minerals (e.g., calcium and iron) more absorbable. It also creates an essentially sterile environment to prevent bacterial overgrowth. Mucus forms an acid- and pepsin-resistant coating for the stomach lining. Gastric lipase secreted by gastric mucosa begins to hydrolyze triglycerols, producing 1,2-diacylglycerols and fatty acids. The optimal pH of gastric lipase is about 4, but the enzyme is active up to pH 6 or 6.5.7

Large Intestine

Supplementary Diagnostic Procedures

promote differentiation and apoptosis are believed to reduce colon cancer risk, whereas those that stimulate cell division are considered car~inogenic.'~

ABSORPTION OF NUTRIENTS Carbohydrate Digestion Digestible carbohydrates, such as sucrose, starch, and lactose, are the body's principal sources of energy? and their proper digestion is vital for adequately sustaining its energy needs. Dietary carbohydrates consist of monosaccharides, disaccharides, and polysaccharides. Monosaccharides are absorbed directly by sodium-dependent transport carrier mechanisms. Disaccharides require small intestinal surface enzymes for hydrolysis to monosaccharides; polysaccharides depend on pancreatic amylase and surface enzymes for this process. Final hydrolysis of disaccharides and oligosaccharides to monosaccharides is carried out by surface enzymes (e.g., sucrase, maltase, lactase) of the small intestinal epithelial cells.5

Lipid Digestion Lipid digestion is the most complex of the digestive and absorptive processes. The primary function of this process is to convert water-insoluble lipids, primarily triacylglycerols, phospholipids, and cholesterol esters, into soluble, absorbable forms. The absorption of lipophilic compounds, such as fat-soluble vitamins and certain drugs, depends on proper lipid digestion and ab~orption.~ Although a small amount of lipid digestion occurs in the mouth with the secretion of lingual lipase, the primary process of lipid digestion begins in the stomach. Gastric lipase is secreted by gastric mucosa to hydrolyze triacylglycerols, producing 1,2-diacylglycerolsand fatty acids. Optimal pH is about 4,but the enzyme is active at pH 6 to 6.5. After partial digestion in the stomach, the lipid emulsion moves to the small intestine, where further digestion of triacylglycerol is performed, primarily by pancreatic lipase. However, triacylglycerol lipid droplets covered in bile salts are not accessible to pancreatic lipase and require the action of colipase, which allows binding of lipase molecules to the lipid droplets to hydrolyze tria~ylglycerol.~ The digestion of lipids produces mainly monoacylglycerols, fatty acids, lysophosphatidylcholine, and cholesterol. Because these products have limited ability to dissolve in water, they have difficulty reaching the epithelial surface of the small intestine, which is covered by the unstirred water layer. To be more effectively absorbed, they must form aggregates (micelles)with bile acids (which act as biologic detergents) that can penetrate the unstirred water layer. Without bile acids, only a small number of lipid molecules permeate through the water layer to be taken up by the brush-border membrane

of the enterocytes. Mixed micelles increase the concentrations of fatty acids, cholesterol, and other lipids near the epithelial absorptive surface of the small intestine by a factor of 100 to iOO0.7

DIGESTIVE ABNORMALITIES Maldigestion Gastric acid secretion is a fundamental step in digestion and assimilation. Many clinical conditions may originate with decreased gastric acidity. It has been argued that chronic hypochlorhydria can lead to reduced mineral absorption, bacterial overgrowth, amino acid deficiency, GI symptoms, depression, and other s y n d r ~ m e s . ' ~ J ~ Maldigestion of carbohydrates can also cause chronic GI symptoms. Disaccharides, oligosaccharides, and polysaccharides not hydrolyzed by alpha-amylase or intestinal surface enzymes cannot be absorbed. Bacterial fermentation of these undigested carbohydrates in the lower intestine and colon increases the osmotic retention of water. This can lead to cramping, abdominaldistention, and diarrhea.45

Pancreatic Exocrine lnsufficiency Inadequate delivery of enzymes to the small intestine can lead to inadequate breakdown of fats, carbohydrates, or protein. The net effect is poor nutrition and an unhealthy environment for the flora of the large colon. It has been argued that even small decreases in exocrine pancreatic output can contribute substantially to maldigestion and may have far-reaching effects in chronically ill patients. Significant decreases in exocrine pancreatic secretion have been associated with the aging process and are theorized to play an important role in intestinal trophicity and pr01iferation.l~In addition, decreased exocrine pancreatic function has been associated with osteoporosis,'s diabete~,'~,*~ and numerous other chronic disease states! Excessive consumption of carbohydrates and lipids is increasingly becoming a common characteristic of the average Western dieP; this trend may promote cyclical, self-perpetuating imbalances that lead to maldigestion and chronic ill health (Figure 14-3).

Malabsorption Malabsorption can be characterized by abnormal fecal excretion of fat (steatorrhea);abdominal pain; and variable malabsorption of fats, fat-soluble vitamins, other vitamins, proteins, carbohydrates, minerals, and water. Common causes include the following: Bile salt deficiency, resulting in inadequate solubility of fatty acids7 Rapid transit, which does not allow adequate time for absorption

Comprehensive Digestive Stool Analysis 2.0 depends on substrate availability rather than neuronal or hormonal pathways.25 Because the oxygen content of the colon is low, roughly 99% of the colonic flora is composed of anaerobes, predominantly Bacteroides, Eubacterium, Bfidobacterium, and Peptostreptococcus.26 Bifidobacterium, Lactobacillus, and nonpathogenic Escherichia coli are the main strains of beneficial with bifid bacteria constituting about one fourth of the microbial flora found in adults.26These strains play pivotal roles in gut health, including: (a) control of potentially pathogenic organisms, (b) production and absorption of nutrients, (c) removal of toxins from the gut, and (d) stimulation of the intestinal immune system.25For this reason, they are employed as key indicators of eubiosis, or healthy overall gut flora. Stress can profoundly alter the microbial milieu, increasing gut permeability, enhancing bacterial adherence of gut pathogens, and reducing the luminal level of beneficial bacteria such as L a c t o b a ~ i l Z u s . ~ ~ ~ ~ ~

Figure 14-3 Chronic maldigestion can set off a cascade of gastrointestinal imbalances that synergistically trigger malnutrition, toxic overload, and poor health. (Courtesy Great Smokies Diagnostic Lab, Asheville, NC.)

Mucosal cell abnormality and inadequate surface area Pancreatic insuffi~iency~,~ Intestinal infection and bacterial overgrowth syndromes Malabsorption can arise from any condition that results in decreased gastric acidity and pancreatic insufficiency. Malabsorption often increases with agG3; atrophic gastritis is estimated to affect 10% to 30% of individuals more than 50 years old and often leads to inadequate absorption of key nutrients such as vitamin BI2.= General malabsorption syndromes are associated with many disorders of the intestinal tract, including celiac sprue, bacterial overgrowth, gluten enteropathy, IBD, giardiasis, cryptosporidiosis, lactose intolerance, and eosinophilic gastroenteritis.Because amino acids, carbohydrates, vitamins, and mineral are absorbed through different processes, individuals with malabsorption are at risk for development of a wide range of nutrient deficiencies.

MICROBIOLOGY Intestinal Microflora The human colon is host to more than 2 billion organisms per gram of stool, with 17 different bacterial families, 50 different genera, and almost 500 different species.” Therefore the bacteria in the gut exceed the total number of eukaryotic cells in the entire human body. Therefore the microflora can be perceived as an organ of the body in its own right. The key difference is that their metabolism

Pathogens In addition, bacterial cultures identify pathogens and potential pathogens. Pathogens are defined according to Koch’s postulates: The organism must be present in every case of the disease. It must be possible to isolate the organism from the disease host and grow it in pure culture. The pure culture of the organism, when inoculated into a new susceptible host, must produce the same symptoms of disease. The term potential pathogen can be used to indicate microbes that do not strictly meet Koch’s postulates for the definition of pathogen yet have the potential to be etiologic agents of disease in certain susceptible hosts (Box 14-1). These agents may be involved in the etiology of GI disorders; moreover, by triggering bacterial translocation and molecular mimicry, they may also be involved in various chronic or systemic diseases seemingly unrelated to GI function, such as arthritis and autoimmune disorders. For example, Klebsiella and Proteus are not routinely reported in conventional laboratories, but both have

Citrobacter Klebsiella Proteus Pseudomonas Morganella Enterobacter Enterotoxin-producingBacillus cereus (4+) Enterotoxin-producingStaphylococcus aureus (4)

demonstrated antigenic cross-reactivity to human leukocyte antigens (HLA antigens). KZebsieZlu has been associated with ankylosing spondylitis (AS) when crossreactivity occurs with the HLA-B27 antigen. Similarly, Proteus mirabilis has been associated with reactive arthritis and is known to cross-read with the HLA-DR4 antigen.3031 Other potential pathogens may cause clinical and subclinical malabsorption and increase bowel permeability to large molecules. Abnormalities of the immune or mechanical barriers can lead to enhanced uptake of inflammatory luminal macromolecules and pathogenic bacteria. Bacterial antigens are capable of inducing antibodies, which cross-react with host antibodies, forming systemic immune c o m p l e x e ~ This . ~ ~ ~process ~~ been linked with the etiology of chronic gut inflammation, systemic lupus erythematosus, and a r t h r i t i ~ . ~ 3 ~

Yeast Colonic yeast infections have attracted attention and controversy as a possible cause of chronic complex illnesses.36Investigators have suggested that an intestinal overgrowth of yeast such as Cundidu ulbicuns may be involved in the etiology of allergic disorders such as scleroderma and a ~ t h m a , 3 ~chronic 3 chemical sensitivity,%and other hypersensitivity conditions. The presence of large amounts of dead C. ulbicuns and other yeast in stool has also been reported in patients with irritable bowel syndrome (IBS); it is theorized that this overgrowth could underlie some of the sympt o m in IBS, such as recurrent diarrhea and abdominal cramping.40 Although these associations have been highly disputed, there is strong evidence that yeast overgrowth may have pathogenic potential in susceptible individuals, particularly in those with weakened immune systems. One large-scale review concluded that nearly all comparative studies have found significantly higher yeast counts in patients than in healthy controls.41Other studies have linked Candidu overgrowth to higher rates of death and neoplastic complications in patients with leukemia and of GI hemorrhage in renal transplant recipients.*,43 The GI tract in healthy individuals normally harbors small amounts of yeast. However, many conditions are known to promote the overgrowth of Cundidu sp. in the bowel, including diabetes, alcoholism, mucosal damage, neoplasms, and treatment with antibiotics, steroids, or antacids.%S4For this reason researchers have suggested that the interpretation of yeast levels in stool may be most valuable when carefully correlated with clinical conditions in the i n d i v i d ~ a l . ~ ~

Dysbiosis Dysbiosis is a state of disordered microbial ecology that may cause illness or disease. It can exist in the oral cavity,

Poor diethutritional status Stress Antibiotidother drug therapy Decreased immune status Decreased gut motility Maldigestion Intestinal infection Xenobiotics Increased intestinal pH Diabetes, scleroderma Gastrointestinaltract surgery

GI tract, or vaginal cavity. In dysbiosis, organisms of low intrinsic virulence, including bacteria, yeasts, and protozoa, may grow or migrate beyond their normal limitations. In the GI tract, this can result in intensified microbial competition for nutrients and damage to the mucosal layer, which alters the nutritional status and immune function of the host.& Major causes of dysbiosis are listed in Box 14--2.29,47-51 Published research has implicated intestinal dysbiosis as contributing to vitamin and amino acid deficiencies, malabsorption of carbohydrates, IBD, autoimmune arthropathies, and colon and breast cancer.37,38,49~50~2-54 One controversial theory posits that food allergy is not strictly an immunologic disease but instead is a chronic disorder of excessive bacterial fermentation in the colon. In this model, the combined mechanisms of reduced gut enzyme concentrations, imbalanced bacterial flora, and increased intestinal permeability act synergistically to trigger symptoms of food int~lerance.~~

USING COMPREHENSIVE DIGESTIVE STOOL ANALYSIS 2.0 The CDSA 2.0 provides an indepth noninvasive analysis of digestion/absorption, gut immunology and metabolism, microbial flora, and colon cancer risk.

Digestive Function DigestiodAbsorption Pancreatic Elastase 1 An enzyme produced exclusively by the human pancreas, pancreatic elastase 1 (PE1) is an extremely reliable and specific marker of exocrine pancreatic function.56 PE1 is concentrated fivefold to sixfold higher in feces than when it enters the duodenum. This reflects the stability of PE1 in the GI tract.57PE1 is not degraded during intestinal transit, nor is it significantly affected by increases or decreases in intestinal transit Unlike other pancreatic markers, such as chymotrypsin, PE1 results are not affected by pancreatic enzyme replacement

Comprehensive Digestive Stool Analysis 2.0 therapy.56 This feature makes it a valuable marker for monitoring and adjusting enzyme replacement.% Pancreatic function diminishes with Exocrine pancreatic insufficiency may result in inadequate nutrient metabolism, leading to nutrient deficiency states. Malabsorption of fats and proteins may be accompanied by a deficiency of vitamins, particularly lipid-soluble vitamins. Mineral deficiencies, including calcium depletion, may also occur. Problems with glucose control may be exacerbated in diabetics because of inadequate nutrient metabolism.20Nearly one third of patients with osteoporosis have reduced concentrations of PE1.I8 Vitamin D levels may also be significantly lower in these patients?" Pathologic conditions such as alcoholism, cholelithiasis, diabetes, IBD, autoimmune or connective tissues diseases, and pancreatic cancer are other well-known causes of pancreatic insufficiency.

ValeratelIsobutyrate Valerate and isobutyrate are produced exclusively by bacterial fermentation of polypeptides and amino acids. These SCFAs are putrefactive, and their presence suggests underlying maldigestion, malabsorption, or bacterial overgrowth in the small intestine. Other causes are GI disease (resulting from the fermentation of blood or mucosal cells delivered to the colon)61and rapid transit time (resulting from inadequate time for digestion and absorption of peptides and amino Short-Chain Fatty Acids SCFAs are produced by the anaerobic bacterial fermentation of primarily nonabsorbed dietary fiber.63SCFAs: Provide energy for the colonocytes and exert a trophic effect on the intestinal lining." Act as antidiarrheal agents by removing sodium and water from the ~0lon.6~ Improve colonic blood flow.& Deter the colonization of pathogens in the bowel." Provide 5% to 30% of systemic daily energy req~irements.6~ Reduce ammonia uptake from the intestine."

In general, the more slowly fermented forms of fiber tend to maintain low pH and raise SCFAs along the entire length of the bowel.

N-Butyra te Butyrate, the major fuel for colonocytes, assists in the maintenance of colonic integrity.@Because of its trophic effect on the colonic epithelium, butyrate protects against ulcerative colitis and colon ~ancer.6~ In Crohn's disease, butyrate decreases production of tumor necrosis factoralpha production and the activity of lipopolysaccharideinduced nuclear factor kappaB (NFKB)in intestinal cells,

both of which are key factors in its path~genesis.~" Low levels of N-butyrate are associated with slow transit time, antibiotic therapy, insufficient dietary fiber, and increased risk of adenomas and colorectal Levels of N-butyrate may be increased by dietary fiber, Larch arabinogalactan (Larix sp.), normalization of pH and transit time, probiotics/prebiotics, and butyric acid (oral or r e ~ t a l ) ? ~ , ~ ~ - ~

Gut Immunology Eosinophil Protein X Eosinophil protein X (EPX)is a glycosylated protein that serves a marker of eosinophil activation and degranulation. It has potent cytotoxic and neurotoxic properties and is released from the eosinophils after being activated and stimulated by cytokines. EPX can attack cell membranes, making the membranes porous, which in turn causes osmotic lysis.85 Accumulation of EPX in the GI tract is associated with chronic intestinal inflammation and tissue Elevations can occur in response to food allergy, proteinsensitive enteropathy, helminthic infection, IBD, cancer, allergic colitis, and gastroesophageal reflux.86100 Ca1proteetin Calprotectin belongs to a group of calcium-binding neutrophil-derived proteins. Calprotectin makes up about 5% of the total protein content of the neutrophil and about 60% of the cytosolic proteins. Fecal calprotectin is a direct and sensitive marker of gut inflammation and correlates closely with IBD activity.'"' Calprotectin enters the bowel lumen as part of an inflammatory process rather than through bleeding. Increased calprotectin levels in colorectal cancer are believed to be caused by the infiltration of white blood cells into the tumor, with subsequent shedding into the lumen. This explains why Tibble et a1.lo2reported that the sensitivity of calprotectin for identifying adenomas was 55%,compared with only 10% for fecal occult blood testing; they also estimated the sensitivity of calprotectin for detecting colorectal cancer at 90%, compared with 58% for fecal occult blood.lo2 The conundrum of trying to distinguish functional abdominal pain from serious or life-threatening conditions faces the clinician frequently. IBS accounts for up to 12%of primary care consultations and 28% of referrals to gastroenterologists.103,104 Because symptoms often overlap, early IBD is often misdiagnosed as IBS. In fact, more than 25% of patients with IBD (particularly those with Crohn's disease) are given the diagnosis of IBS in the prodromal stages of their disease.lo5 This misdiagnosis often leads to extensive and invasive radiographic and endoscopic testing to make a "diagnosis of exclusion" in patients with IBS.

Supplementary Diagnostic Procedures Laboratory markers used to assess disease activity in IBD, such as C-reactive protein, erythrocyte sedimentation rate, white blood cell count, and cytokines (e.g., interleukin-6, tumor necrosis factor-alpha, and interleukin-1), have achieved only limited This is because these markers may be affected by malabsorption, mechanical obstruction, poor nutrition, and drug therapy as well as other infective or inflammatory conditions. Calprotectin provides a much more convenient and sensitive noninvasive alternative for assessing inflammatory activity in IBD. Fecal calprotectin levels have been shown to correlate significantly with histologic and endoscopic assessment of disease activity in ulcerative colitis"' and with indium-111-labeled white blood cells (the gold standard for assessing gut inflammation) in patients with Crohn's disease.Il2Indeed, increased levels of fecal calprotectin have been found in more than 95% of patients with IBD and appear to correlate well with disease activity in IBD.Il3 A 2000 study has confirmed the usefulness of fecal calprotectin in predicting IBD relapse.l14This predictive ability is important for timing interventions to reduce gut inflammation before patients experience a recurrence of debilitating symptoms. In patients with clinically quiescent IBD, fecal calprotectin levels higher than 50 mg/L (pg/g) predicted the relapse of the disease within 3 months with more than 80% sensitivity. Another study showed that at a cutoff level of 50 mg/L (pg/g), the sensitivity of calprotectin for predicting IBD relapse was 90%, and the specificity was 83%.l15This evidence suggests that symptomatic relapse in IBD occurs when inflammation in the gut reaches a critical level of intensity. Calprotectin also can be used to evaluate treatment efficacy in IBD, allowing the patients to avoid prolonged, ineffective, and potentially harmful courses of corticosteroids and other medication fraught with side effects.l16 Other inflammatory conditions are also associated with elevated calprotectin levels (Box 14-3).

Metabolism PH Fecal pH is an indicator of the health or status of the colonic digestive process. Intestinal pH is affected by

Parasite, viral, or bacterial infection Nonsteroidal antiinflammatory drug enteropathy Inflammatory bowel disease activity Bowel polyps or neoplasia

fiber and food constituent intake,l17-l19fermentative processes, bacterial populations, antibiotics,n and transit time.62The pH serves as a useful biomarker for assessing colonic neoplasm risk,lz0malabsorptive syndromes, and the cause of diarrhea.lZ1Fiber (especially cellulose and resistant starch) decreases pH, whereas high-protein intake causes higher (more alkaline) pH.

Beta-Glucuronidase Beta-glucuronidase is an inducible enzyme elaborated by anaerobic E . coli, Peptostreptococcus, Bacteroides, and Clostridi~rn.'~~J~~ By uncoupling glucuronides (xenobiotics and endogenous compounds detoxified via the glucuronidation pathway), this enzyme can deconjugate potential toxins, enhancing the formation of local carcinogens in the boweP4 and promoting the enterohepatic recirculation of toxins, hormones,125and various drUgslZ6 in the body. For this reason, excess amounts of the enzyme may promote higher risk of colon cancer. Both the incidence of colon cancer and levels of betaglucuronidase tend to be higher in individuals consuming Western diets (high in saturated fat, low in fiber) than in individuals consuming diets high in fiber and low in saturated fat.127 However, an adequate amount of beta-glucuronidase activity is probably important to maintain normal enterohepatic recirculation of endogenous compounds such as vitamin D,128thyroid hormone,lZ9and estrogen.53 In addition, the bioavailability of the cancer-protective isoflavone glycosides genistein and daidzein depends on initial hydrolysis by intestinal beta-glucuronidase and sulfatase enzymes. Abnormally low levels of beta-glucuronidase may reduce the efficacy of these

compound^.'^^ Bile Acids The relationship between dietary fat and increased risk of colon cancer is believed to hinge on the excess production of bile acids and the bacterial conversion of conjugated primary bile acids to potentially dangerous unconjugated secondary bile acids.l3I Studies have found that a higher ratio of secondary bile acids, specifically, an elevated ratio of lithocholic acid to deoxycholic acid (LCA/DCA ratio), is associated with higher susceptibility to polyps and colorectal c a n ~ e r . ~ Increased ~~J~ secondary bile acid excretion and a rise in the LCA/ DCA ratio have also been observed in patients with gallstones.lM Bacterial overgrowth markedly increases the concentration of unconjugated bile acids, and this mechanism may play an important role in the pathophysiology of gut mucosal injury.135 Probiotic treatment with Lactobacillus reiiteri has been demonstrated to lower the bioavailable concentration of toxic bile acids.131

Comprehensive Digestive Stool Analysis 2.0

Microbiology Beneficial Bacteria Analysis of stool samples provides a window for viewing the distal colonic flora population. Levels of growth reflect the density of colony formation on the primary culture performed at the laboratory and can indicate the need for supplementation. Adequate amounts of lactobacilli, bifidobacteria, and E. coli are essential for the maintenance of a healthy digestive system. These beneficial flora help protect against overpopulation of potentially pathogenic organisms, enhance nutrient production, and stimulate the immune system. For example, the lactic acid and acetic acid produced by lactobacilli and bifidobacteria reduce intestinal pH, which in turn can restrict the growth of bacterial toxins.26 Many factors are thought to affect the composition of the colonic flora, including diet, transit time, stool pH, age, microbial interactions, colonic availability of nutrients, bile acids, sulfate, and the ability of the microbes to metabolize these s ~ b s t r a t e s . ~ ~ Additional Bacteria Bacteriology also cultures for additional bacteria that are nonpathogens, potential pathogens, and pathogens. These include alpha-hemolytic Streptococcus, beta-hemolytic Streptococcus,Citrobucterfreundii, and Klebsiellu pneumoniae. Serotyping for E. coli and Cumpylobucter cultures is performed on diarrheal specimens. Because the microflora is influenced by environmental factors and the competitive ecosystem of the organisms in the GI tract, the clinical interpretation of these bacterial findings should be based on patient symptoms and reproducibility of bacterial recovery.

Mycology The CDSA 2.0 includes a mycology culture that identifies and quantitates fecal yeast. Some of the more commonly identified species are Cundida albicans, Cundida tropiculis, Rhodotorula, and Geotrichum. Broth dilution sensitivity analyses are performed on all yeast cultures yielding scores of 2+ or greater for natural and pharmaceutical substances. Quantitative minimum inhibitory concentration (MIC) sensitivity analysis determines the relative potency of various antimycotic agents. This procedure provides information on the effective agents and doses that may be used to treat yeast growth. MIC analysis is available by request for cultures with yeast scores below 2+.

Additional Tests The additional tests included in the CDSA 2.0, described here, can be helpful in diagnosing and monitoring diseasespecific infections or conditions.

Helicobacter pylori Stool Antigen Helicobacter pylori remains a highly prevalent infection, with infection rates in middle-aged adults reaching more than 80% in areas of low socioeconomicstatus and 20% to 50% in most industrialized countries.'36 H. pylori is the major cause of peptic ulcer disease. For those infected, the lifetime risk for development of H. pylori-associated peptic ulcer is estimated to be 10% to 20%.137 H. pylori infection also increases the risk of gastric adenocarcinoma, with clinical sequelae of gastric atrophy, intestinal metaplasia, and, ultimately, gastric carcinoma.'38 H. pylori stool antigen (HpSA) testing provides a simpler alternative to urea breath testing. This U.S. Food and Drug Administration-approved marker is a measure of H . pylori antigens shed directly into the stool. Sensitivity is 89% to 98% and specificity exceeds 90%. HpSA testing is appropriate for diagnosis and follow-up of infection, and can be used 7 days after eradication (versus 4 weeks for breath te~ting).'~~-l~l Because HpSA testing performs well in children of all ages, it may be the noninvasive procedure of choice for this group.'37 Shiga Toxin-Producing E. coli Shiga toxin-producing Escherichiu coli (STEC)is a group of bacterial strains that have been identified as a worldwide cause of severe GI disease and life-threateningillnesses.lq STEC may produce Shiga-like toxin I or Shiga-like toxin 11, both of which are similar to the toxins expressed by Shigellu d y s e n t e r i ~ e . ' ~These ~ - ~ ~ ~toxins destroy the colonic epithelium and may cause small blood vessel damage in various tissues, including the kidney. Red blood cells passing through the damaged vessels can fragment as result, causing anemia and thrombocytopenia.'" STEC is believed to reside primarily in the intestinal tract of animals, most commonly dairy and beef cattle. Foods associated with infection include ground beef, sausage, salami, roast beef, raw milk, mayonnaise, apple cider, and raw vegetables. Because the organism has a low infective dose, food outbreaks may affect a large number of people.144J46 Campylobacter jejuni Cumpylobucter jejuni is a gram-negative, microaerophilic, thermophilic rod first identified as an important human pathogen in the late 1970s. Both C. jejuni and Cumpylobucter coli have been recognized as primary agents of GI infe~tion.'~'J~ Clinical and epidemiologic studies have identified C. jejuni as the most common cause of bacteria-induced diarrhea. The isolation rate exceeds the rates of both Salmonella and Shigellu combined. In the United States, the infection rate has been reported as high as 1000 per 100,000 population. The prevalence is even greater in developing c ~ u n t r i e s . ' ~ ~ - ' ~ ~

Supplementary Diagnostic Procedures The highest incidence of C. jejuni infection occurs in infants and young children younger than 5 years; daycare centers frequently harbor the organism. Adults 20 to 40 years old are the next most commonly affected segment of the population.*B3 Possible sources of infection include fecal-oral transmission, ingestion of contaminated animal-based foods (e.g., poultry, red meat, milk), and consumption of untreated surface water.

Clostridium diflicile Clostridium dificile is an anaerobic, spore-forming, grampositive bacterium that can be part of the normal intestinal flora. After a disturbance of the gut flora (usually caused by antibiotics) colonization with C. dificile can o c m . Toxigenic C. dificik produces two toxins, A and B, which are the main virulence factors. Human infection with C. di’cile can take many forms. Some infected individuals may be ”carriers” and appear clinically healthy. Some may have recurrent, mild to moderate diarrhea and other symptoms resembling those of IBS.Others may have recurrent severe cramps and diarrhea, with or without flatulence, and may be misdiagnosed as having IBD.152 C. di’cile also may manifest as a condition indistinguishable from colitis, with cramps, diarrhea, urgency, mucus, and blood. However, severe, fulminant pseudomembranous colitis accounts for less than 3%of cases.153 Unless it is clearly diagnosed by testing for both toxins A and 8, infection with C. dificile may be misdiagnosed as IBS or IBD.

the stool sample because of blood loss somewhere in the GI system. This could be caused by conditions such as ulcers, polyps, diverticulosis, IBD, and colorectal cancer.154 Vitamin C should be avoided before stool sample collection and, ideally, a high-roughage diet (e.g., bran cereal, nuts, popcorn, raw fruits or vegetables) should be started 2 days before the test and maintained for the duration of the testing period. These preparations help to uncover “silent” lesions, which may bleed only intermittently.

Interpretation at a Glance For ease of interpretation, the CDSA 2.0 report consists of an aggregate of abnormal indicators arranged by clinical significance. This allows the practitioner to quickly assess how the composite test results may be interpreted in relation to digestive deficiency, inflammation/IBD, dysbiosis, and neoplastic risk.

CONCLUSION

Fecal Occult Blood A monoclonal antibody technology is used to detect fecal occult blood. Fecal occult blood can be present in

Abundant evidence underscores the importance of maintaining optimal functioning and ecology of the GI tract as a fundamental strategy for improving human health and wellness. The CDSA 2.0 is a comprehensive noninvasive analysis that provides advanced clinical insight into digestion/absorption, gut immunology, metabolism, and microflora balance. Test results allow practitioners to optimize nutritional and lifestyle interventions; diagnose, treat, and monitor prevalent GI disorders; and prevent the potential ”ripple effect” whereby gut dysfunction spirals into chronic poor health and systemic disease states.

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Erythrocyte Sedimentation Rate Michael T.Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 179 Erythrocyte Aggregation

179

Procedures 180 Westegren Method 180 Wintrobe Method 180 Results 180

INTRODUCTION The erythrocyte sedimentation rate (ESR), the rate at which erythrocytes settle out of nonclotted blood in 1 hour, has been one of the most widely performed laboratory tests in the past 55 years. Used primarily to detect occult processes and monitor inflammatory conditions, the ESR test has undergone little change since 1918 when Fahraeus discovered that erythrocytes of pregnant women sedimented in plasma more rapidly than they did in nonpregnant women. Since its incorporation into standard laboratory diagnosis, the ESR has been shrouded with medical myths and is often misinterpreted or misused. This chapter provides a rational guideline for its use as a nonspecific measure of inflammatory, infectious, neoplastic, and cardiovascular diseases.14

ERYTHROCYTE AGGREGATION Normally, erythrocytes settle quite slowly, as the gravitational force of the erythrocyte's mass is counteracted by the buoyant force of the erythrocyte's volume. However, when erythrocytes aggregate, they sediment relatively rapidly because the proportional increase in their total mass exceeds the proportional increase in their volume.14 Therefore the major determinant in the sedimentation rate of erythrocytes is erythrocyte aggregation, which usually occurs along a single axis (rouleaux formation). The aggregation of erythrocytes is largely determined by electrostatic forces. Under normal circumstances, the erythrocytes have a negative charge and therefore repel

Interpretation 180 Elevated Erythrocyte Sedimentation Rate 180 Decreased Erythrocyte Sedimentation Rate 182 Monitoring of Disease Activity 182 Summary 182

each other. However, many plasma proteins are positively charged and neutralize the surface charge of erythrocytes, thereby reducing repulsive forces and promoting aggregation The relative contribution of the various "acute-phase" reactant proteins to aggregation is shown in Table 15-1. One protein that has no direct effect on the ESR in physiologic concentrations, but which is associated with certain inflammatory, degenerative, and neoplastic diseases, is the C-reactive protein. Its major function is facilitation of the complement system. Like the ESR, measurement of the C-reactive protein is used in the monitoring of patients with chronic inflammatory conditions.' An elevated C-reactive protein provides evidence of an inflammatory process despite a normal ESR. Therefore when used in conjunction with the ESR, it greatly increases the sensitivity in detecting inflammatory/infectious processes, especially when variables such as anemia confound the ESR. The ESR is also elevated in patients with proteinemias (myeloma, macroglobulinemia, cryoglobulinemia, and cold agglutinin disease).l-" Disorders of erythrocytes such as anemias alter the ESR and may interfere with accurate interpretation.I4 Since the ESR is directly proportional to the mass of the erythrocyte and inversely proportional to its surface area, large erythrocytes sediment more rapidly than smaller cells. Therefore in macrocytic anemia there is an increased ESR, and in microcytic anemia there is a decreased ESR. Although the usefulness of ESR determination has decreased as new methods of evaluating disease have been developed, it remains quite helpful in the diagnosis 179

Relative contribution of acute-phase reactant proteins to erythrocyte aggregation Blood constituent

Relative contribution

Fibrinogen

10

Beta-globulin

5

Alpha-globulin

2

Albumin

1

of some diseases, such as temporal arteritis and polymyalgia rheumatica. Perhaps more useful is its use in monitoring these conditions and others including chronic inflammatory diseases such as rheumatoid arthritis and Hodgkin's disease and other cancers. Although the use of the ESR as a screening test to idenhfy patients who have serious disease is not supported by the literature, it does provide a general gauge of inflammatory process in the body. It is well accepted that an extreme elevation of the ESR is strongly associated with serious underlying disease, most often infection, collagen vascular disease, or metastatic malignancy. Recently, there has been a growing appreciation of the value of the ESR as a marker for atherosclerosis and coronary artery

PROCEDURES Various methods for determination of the ESR have been developed. Currently the Westegren method is recommended by the International Committee for Standardization in Hematology.

Westegren Method In the standard Westegren method, the following procedure is used: 1. Dilute venous blood 4:l with anticoagulant sodium citrate. 2. Put in a 200-nun long, 2.5-mm internal diameter, glass tube (Westegren tube). 3. Allow to stand in a vertical position for 1 hour. 4.At the end of 1hour, the distance from the meniscus to the top of the column of erythrocytes is recorded as the ESR.

The modified Westegren method uses edetic acid (EDTA) rather than sodium citrate as an anticoagulant and is more convenient, since the same tube of blood can be used for other hematologic studies. The standard and modified methods give identical results.'"

Wintrobe Method The second most commonly used method is the Wintrobe method. This method is performed with a

Westegren (normal results) Men: 0-10 mm/hr Women: 0-15 mm/hr Children: 0-10 m d h r Wintrobe (normal results) Men: <6.5m d h r Women: 4 6 m d h r

100-mm tube (Wintrobe tube) containing oxalate as the anticoagulant. It is more sensitive than the Westegren method in the "normal" to "mildly elevated range; however, in the more highly elevated ESR, the short tube leads to relatively insensitive readings due to packing of cells.*

Results The results of both the Westegren and Wintrobe methods are listed in Box 15-1.

INTERPRETATION Several factors may result in false ESR values; the more significant of these are listed in Box 15-2. In addition, it is important to recognize that in acute disease, the change in rate may lag behind the temperature elevation and leukocytosis for 6 to 24 hours, and in unruptured acute appendicitis the rate may be normal. In convalescence, the increased rate tends to persist longer than the fever or leukocytosis. Box 15-3 lists the most common clinical implications of changes in the ESR. An ESR value exceeding 100 mm/hr has a 90% predictive value for serious underlying disease, most often infection, collagen vascular disease, or metastatic tumor.'

Elevated Erythrocyte Sedimentation Rate Asymptomatic Patients The presence of an elevated ESR as the only manifestation of a disease process is quite rare. However, when present, it can be highly significant. For example, in one study of 17 patients whose increased ESR was the sole initial clue to disease, two had tuberculosis and one had colon cancer (outcomes of which are improved by early detection), one had systemic lupus erythematosus and three had ankylosing spondylitis (diagnoses that typically become apparent only after several years of observation), and four men had a persistently elevated ESR several years before a myocardial infarction. The remaining patients developed myeloma, prostate cancer, psoriasis, benign monoclonal gammopathy, and pancreatic cancer.2 Although the ESR generally makes a small contribution to disease detection in asymptomatic persons, the presence of an elevated ESR as the only clue to illness in an asymptomatic person indicates the need for a careful

False Increase Elevated levels of fibrinogen, globulins, and cholesterol High room temperature Macrocytic anemia Menstruation Pregnancy Running a refrigerated blood sample before it has returned to room temperature Tilted erythrocyte sedimentation rate tube Certain drugs: dextran, methyldopa, methysergide, oral contraceptive agents (OCAs), penicillamine, procainamide, theophylline, trifluperidol, vitamin A False Decrease Cachexia Clotting of blood sample Elevated bile salts Elevated phospholipids >2-hr delay in running the test High doses of adrenal steroids Hypofibrinogenemia Hyperglycemia Hyperalbuminemia Leukocytosis Microcytic anemia Newborn Certain drugs: adrenocorticotropichormone, cortisone, ethambutol, quinine, salicylates Data from references 1 and 4.

Increased Rate Acute heavy metal poisoning All collagen diseases Carcinoma Cell or tissue destruction Gouty arthritis Infections Inflammatory diseases Leukemia Multiple myeloma Myocardial infarction Nephritis Pneumonia Rheumatoid arthritis Syphilis Toxemia Decreased Rate Congestive heart failure Polycythemia Sickle cell disease

heart disease in the National Health and Nutrition Examination Survey I.5 The risk was highest when the ESR was greater than 22 mm/hr. Subsequent studies and the growing awareness that atherosclerosis is associated with chronic inflammation has given support to the use of the ESR as a prognostic indicator on the risk of coronary artery disease?,’ It was hypothesized and later shown that an elevated ESR reflected an elevated blood fibrinogen level (see Chapter 15 for further discussion of fibrinogen).

diagnostic work-up; it may be the first sign of an occult malignancy or a chronic inflammatory disease. Laboratory evaluation for an asymptomatic patient with an elevated sedimentation rate should include complete blood cell count with differential, blood urea nitrogen and creatinine, alkaline phosphatase measurement, serum protein electrophoresis, urinalysis, guaiac tests of stool, and chest radiograph.2 An ESR that exceeds 100 mm/hr is definitely associated (predictive value of >95%)with infection, malignancy, or connective tissue disease. Rarely does disease remain undiagnosed when the ESR is greatly e1evated.l4 If, after further clinical evaluation, an elevated ESR cannot be explained, the ESR should be repeated in 1month. In one study where 43 patients with an elevated ESR remained undiagnosed, the elevation was transitory in 32. The remaining 11 were followed for a period of 10 years: 2 developed cancer, 1had a benign dysproteinemia, and no diagnosis was ever made for the remaining 9.2

The ESR is sometimes used to provide confirmation of a disease process when the history and physical findings point toward a specific diagnosis. Although the ESR itself does not diagnose a specific disease, when combined with information gathered in a history and physical, as well as in conjunction with other laboratory tests, it can be a great help in the formation of a specific diagnosis. In patients with vague, unsubstantiated illness, the ESR offers limited benefit due to the lack of specificity and the presence of a normal ESR in a wide variety of illnesses. However, the ESR offers great diagnostic benefit when other signs, symptoms, and laboratory findings are present. This is particularly true in malignancies, temporal arteritis and polymyalgia rheumatica, inflammatory arthritis, and suspected infection.

As a Predictor of Coronary Artery Disease

Erythrocyte Sedimentation Rate in Cancer

An elevated ESR in white men aged 45 to 64 years was

Malignancy is quite common in symptomatic patients with an elevated ESR. In one study, 70 (8.8%)of 790 clinic

found to be an independent risk factor for coronary

Symptomatic Patients

Supplementary Diagnostic Procedures

patients with an elevated ESR had cancer.' However, of the 70 patients with malignancy and an increased ESR, 68 had local signs that led directly to the diagnosis. Thus occult malignancy was present in only 2 of the 790 subjects. In addition, the ESR is often normal in patients with cancer, indicating that the ESR should not be relied on as a test to exclude occult malignancy in patients with vague symptoms. In a prospective follow-up of 300 patients with prostate cancer, an ESR greater than 37 mm/hr was associated with a higher incidence of disease progression and death. These findings paralleled other prognostic indicators such as M and T categories, grade, performance status, and age, but nonetheless indicate that ESR does provide additional value in the monitoring of these patients and presumably others with invasive cancet3

Temporal Arteritis and Polymyalgia Rheumatica Temporal arteritis and polymyalgia rheuma tica are related syndromes that can occur together or alone. Both occur in older individuals and are associated with an increased ESR. Symptoms of temporal arteritis include unilateral throbbing headache, scalp sensitivity, visual symptoms, jaw claudication, and localized thickening or loss of pulsation of the temporal artery. Polymyalgia rheumatica is a fast-developing condition characterized by pain and stiffness of the pelvis and shoulder girdle, in association with fever, anemia, malaise, and weight loss. It is typically self-limited to 1 to 2 years. Determination of the ESR is of critical importance in the diagnosis and management of patients with temporal arteritis, a condition that can result in blindness due to obstruction of the ophthalmic arteries. When the clinical evidence for temporal arteritis is limited, a normal ESR reduces the probability of the disease to less than 1%. When the clinical evidence is strong, it is extremely rare to have a normal ESR. Achievement of a normal ESR by the use of antiinflammatory agents, such as cortisone or the natural medicines discussed in Section 5, greatly reduces the risk of developing blindness.'T2

Inflammatory Arthritis The ESR is sometimes used to distinguish inflammatory arthritis from other causes of joint symptoms. This is particularly true in the differentiation of rheumatoid arthritis, which has an elevated ESR, and osteoarthritis, which typically has a normal ESR. It is not appropriate to place much value on the ESR as an independent diagnostic predictor of rheumatoid arthritis. An elevated ESR in patients with joint symptoms simply indicates an active inflammatory process.'P2

Suspected Infection Leukocytosis and fever are better indicators than the ESR of an acute infectious process, as the ESR is typically

normal during the first stages of infection. However, the ESR is of some value in the differentiation of an intact versus ruptured appendix. Researchers demonstrated that only 2 of 25 patients with nonruptured appendicitis had an ESR of greater than 20 mm/hr. In contrast, 67%of patients with ruptured appendixes had an elevated ESR.'

Decreased Erythrocyte Sedimentation Rate The causes of a low ESR (0 to 1 mm/hr) are listed in Boxes 15-2 and 15-3. In one study of patients with a low ESR, 38% had no evidence of disease and only 6% had one of the diseases commonly associated with a low ESR. The remaining patients had a wide variety of diagnoses. A low ESR is generally of little significance and may actually indicate a healthy state.I4

Monitoring of Disease Activity The ESR is well recognized as an aid in monitoring the activity of such inflammatory diseases as temporal arteritis, polymyalgia rheumatica, and rheumatoid arthritis.'" In general, improvements in ESR levels generally reflect clinical improvement and vice versa.

Temporal Arteritis and Polymyalgia Rheumatica The ESR is the most widely used test for assessing disease activity in patients with temporal arteritis and polymyalgia rheumatica because these conditions have few specific clinical indicators of disease activity. However, both the ESR and clinical status need to be monitored in these patients and appropriate therapy instituted if the ESR increases or if there is a worsening in the clinical picture.',2,8

Rheumatoid Arthritis Although 5% to 10% of patients with rheumatoid arthritis have a normal ESR, the ESR generally parallels disease activity. Therefore monitoring the patient's ESR provides invaluable feedback on therapeutic effect. An isolated elevated ESR is not useful for prognosis, but sustained extreme elevation of the ESR is associated with a poor prognosis.'-3

Other Inflammatory Diseases Other inflammatory diseases, particularly collagen diseases such as systemic lupus erythematosus, can be monitored by the ESR in a fashion similar to that for rheumatoid arthritis.'"

SUMMARY The ESR is a simple, valuable, and useful laboratory procedure. Although it is a nonspecific indicator, an elevated ESR (i.e., greater than 80 mm/hr) indicates the presence of significant disease in more than 95% of individuals. The ESR should never be used as the sole diagnostic test.

Erythrocyte Sedimentation Rate

Clinical presentation, comprehensive history, laboratory investigation, and other diagnostic procedures should always be considered when interpreting ESR results. The ESR may be used as a nonspecific gauge of therapeutic

efficacy and as a monitoring tool in several inflammatory conditions, including temporal arteritis, polymyalgia rheumatica, rheumatoid arthritis, certain malignancies, and atherosclerosis.

1. Brigden ML. Clinical utility of the erythrocyte sedimentation rate. Am Fam Physician 1999;601443-1450. 2. Sox HC Jr, Liang MH. The erythrocyte sedimentation rate. Guidelines for rational use. Ann Intern Med 1986;104515-523. 3. Bedell SE, Bush BT. Erythrocyte sedimentation rate, from folklore to facts. Am J Med 1985;781001-1009. 4. Saadeh C. The erythrocyte sedimentation rate: old and new clinical applications. South Med J 1998;91:220-225. 5. Gillum RF, Mussolino ME, Makuc DM. Erythrocyte sedimentation rate and coronary heart disease: the NHANES I Epidemiologic Follow-up Study. J Clin Epidemiol 1995;48:353-361.

6. Erikssen G, Liestol K, Bjomholt JV,et al. Erythrocyte sedimentation rate: a possible marker of atherosclerosis and a strong predictor of coronary heart disease mortality. Eur Heart J 2000;21:1614-1620. 7. Danesh J, Collins R, Peto R, Lowe GD. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur Heart J 2000;21:515-520. 8. Cantini F, Salvarani C, Olivieri I, et al. Erythrocyte sedimentation rate and C-reactive protein in the evaluation of disease activity and severity in polymyalgia rheumatica: a prospective follow-up study. Semin Arthritis Rheum 2000;30:17-24.

Fantus Test Dirk W m .Powell, ND CHAPTER C O N T E N T S Introduction 185

Reagents 186 Results 186

Clinical Application 185 Interpretation 186 Procedure 186 Method 186

INTRODUCTION The Fantus test is a simple test for measuring urinary output of chlorides. It is generally used to estimate dietary sodium chloride intake. For this purpose, it has been shown to give accurate results if two factors are taken into consideration’”: Concentration of urinary chloride is generally proportional to urinary sodium except with increased ingestion of non-sodium chloride salts (e.g., NH4C1 or KCl). Urinary output of sodium chloride may not be indicative of sodium intake when an individual is affected by a salt-wasting disorder (Box 16-1).

CLINICAL APPLICATION The Fantus test was first described by J.B. Fantus in 1936.4It was originally used for the diagnosis of salt and water depletion and for the differential diagnosis of edema.5However, this test has been found to be particularly useful for the monitoring of sodium intake in individuals with blood pressure disorders, including both hypotension and hypertension. Since 1904 when Ambard and Beaujard6 first implicated salt as a major factor in the pathogenesis of hypertension, conflicting opinions and data have confused this issue. In 1944 Kempner7published a classic article describing the effective treatment of essential hypertension using a salt-restricted ”rice diet.” Many studies have subsequently demonstrated the effectiveness of salt-restricted diets in treating hypertension.8-12Substantial evidence now exists that sodium alone does

not raise blood pressure as had been previously thought, but rather that chloride also plays an important role in the elevation of blood pressure when consumed as sodium chloride, or common table salt.13J4For example, sodium bicarbonate has not been found to have the same hypertensive effect as sodium chloride. The Fantus test, an indirect test for sodium, actually measures chloride ion concentration. Considering that sodium chloride intake, rather than sodium ion alone, is a significant factor in blood volume expansion and blood pressure elevation, the Fantus test may be preferable to direct tests for urinary sodium when managing hypertension or fluid retention.13J4 When attempting to clinically manage hypertension by restricting salt ingestion, two difficulties arise15: Effective salt restriction is difficult to maintain because of the prevalence of large amounts of salt in the daily diet, particularly convenience and prepared foods. Salt must be restricted to quite low levels to be effective in the treatment of hypertension. Sodium chloride, measured in terms of sodium, must be restricted to approximately 3 g per day, as compared to the 12 to 27 g of sodium per day commonly consumed in the typical Western diet. Because the Fantus test is an inexpensive, simple in-office test, it can be effectively used to monitor salt intake where frequent sampling is useful in the management of salt-restricted diets. The Fantus test can be useful in monitoring salt intake in various clinical disorders. Salt restriction may be therapeutic in various disorders including hypertension, congestive heart failure, 185

Supplementary Diagnostic Procedures recorded as grams of Na per liter of urine (g Na/L urine). Adrenocortical insufficiency Addison's syndrome Salt-wasting renal disease Large sweat loss of electrolytes Strenuous physical exercise Unusual fluid losses from the gastrointestinal tract Chronic fatigue syndrome

premenstrual syndrome, edema, and chronic kidney disorders. The Fantus test is also useful in monitoring salt intake in clinical conditions where salt depletion can be an aggravating factor, such as in postural hypotension and chronic fatigue syndrome. The Fantus test is also useful in monitoring sodium chloride levels in clinical conditions where restricted salt ingestion is not desirable, such as with the conditions listed in Box 16-1. Another use of the Fantus test is in the identification of people who are ingesting excessive amounts of salt, but who are without symptoms or overt signs of disease. It has been observed that a high intake of sodium chloride decreases longevity in animals,16 and salt-induced angiotensin elevation may adversely affect the myocardium in humans, even when the blood pressure remains within normal limits.17 It is found that these adverse effects of excess salt may persist for an extended time after excess salt ingestion is d i s c o n t i n ~ e d . ~ ~ J ~ Identifying those people at risk of the harmful effects of excessive salt consumption is a significant aspect of preventive medicine. People with risk factors for hypertension should restrict salt intake. Included in this group of people at risk are individuals with chronic renal disease, those with a hypertensive parent, and individuals older than age 50.20The potential benefits of identdymg those people at risk due to excess salt intake suggest the usefulness of the Fantus test.

Method 1. Collect a 24-hour urine sample. 2. Measure and record the 24-hour volume. 3. In a test tube add one drop of 20% K2Cr04solution to 10 drops of the sample of the 24-hour urine specimen. 4. Xtrate (add one drop at a time) with the 2.9%AgN03 solution. 5. Record the number of drops needed to turn color from yellow to brown as g Na/L.

(If sodium chloride is present in too low a concentration to accurately measure, use 20 drops of urine. Each drop of AgN03 is then equal to 0.5 g Na/L.)

Reagents AgN03: 2.9% aqueous solution K2Cr04:20% aqueous solution

Results Typical Western diet: 12 to 27 g Na/24 hr Salt-restricted diet: 0.6 to 3.5 g Na/24 hr

INTERPRETATION

The Fantus reagent is prepared so that the number of drops of silver nitrate used in the titration step can be

Normally, urinary sodium varies with the sodium chloride intake, reflecting the salt content of the diet. The typical Western diet contains 12 to 27 g of sodium in a 24hour period (80 to 180 mEq/24 hr)?l On a saltrestricted diet, the goal is usually to reduce 24-hour urine Na to close to the minimum considered safe (i.e., 0.6 to 3.5 g Na/24 Water consumption is generally closely related to salt intake. A salt intake of 3 g Na/day corresponds to an intake of 2750 ml of water from both solids and fluids, which is the average water turnover for a 70-kg adult. After evaporation from the lungs and other losses, the amount of water excreted by the kidneys would be approximately 1500 ml in 24 hours.5This would produce a urinary excretion of sodium of 3 g in 24 hours and a urinary sodium concentration of 2 g/L.

1 . Luft FC, Fineberg NS, Sloan RS. Overnight urine collections to estimate sodium intake. Hypertension 1982;4494-498. 2. DeGowin E, DeGowin R. Bedside diagnostic examination.New York M a d a n , 1969:37-38. 3. Krupp M, Sweet N, JawetzE, et al. Physician's handbook. Los Altos, CA: Lange Medical, 1973213. 4. Fantus J. Fluids postoperatively.JAMA1936;10717. 5. Mamott H. Water and salt depletion. Springfield, IL:CC Thomas, 195055-56.

6. Ambard L, Beaujard E. Causes de I'hypertensionarteriole.Arch Gen Med 1904;1:520-533. 7. Kempner W. Treatment of kidney diseases and hypertensive diseases with rice diet. N C Med J 1944;5:125-133. 8. Chapman CB, Gibbons T, Henschel A. The effect of the ricefruit diet on the composition of the body. N Engl J Med 1950;243: 899-905. 9. Grohman A, Harrison T, Masom M, et al. Sodium restriction in the diet for hypertension. JAMA1945;129:533.

PROCEDURE

Fantus Test 10. Dustan HP, Bravo EL, Tarazi RC. Volume-dependent essential and steroid hypertension. Am J Cardiol1973;31:606-615. 11. Dustan HR, Tarazi RC, Bravo EL. Diuretic and diet treatment of hypertension. Arch Intern Med 1974;133:1007-1013. 12. Parijs J, Joossens JV,Van der Linden L, et al. Moderate sodium restriction and diuretics in the treatment of hypertension. Am Heart J 1973;85:22-34. 13. Kotchen TA, Luke RG, Ott CE, et al. Effect of chloride on renin and blood pressure responses to sodium chloride. Ann Intern Med 1983;98:817-822. 14. Kurtz T, Morris R Jr. Dietary chloride as a determinant of sodiumdependent hypertension. Science 1983;222:1139-1141. 15. Hunt J, Margie J. The influence of diet on hypertension management. In Hunt J, ed. Hypertension update. Bloomfield, NJ: Health Learning Systems, 1981:197-207.

16. Meneely GR, Batterbee HD. High sodium-low potassium environment and hypertension. Am J Cardiol1976;38:768-785. 17. Khairallah,’l Sen S, Tarazi R. Angiotensin, protein biosynthesis and cardiovascular hypertrophy (abstr). Am J Cardiol1976;37148. 18. Tobian L, Ishii M, Duke M. Relationship of cytoplasmic granules in renal papillary interstitial cells to “postsalt” hypertension. J Lab Clin Med 1969;73:309-319. 19. Dahl LK. Effects of chronic excess salt feeding. Induction of selfsustaining hypertension in rats. J Exp Med 1961;114231-236. 20. Scribner BH. Salt and hypertension. JAMA 1983;250388-389. 21. Davidson I, Henry J, Todd-Sanford. Clinical diagnosis by laboratory methods. Philadelphia: WE3 Saunders, 19741386.

Fatty Acid Profiling Richard S. Lord, PhD f. Alexander Brdley, PhD C H A P T E R CONTENTS Introduction 189 Methodologic Issues 189 Plasma versus Erythrocyte Fatty Acid Profiles Concentration versus Percentage 190

189

Interpretation of Abnormal Fatty Acid Results 190 Omega-3 (n-3) Fatty Acids 191

INTRODUCTION The analysis of fatty acids in blood provides useful information about fatty acid deficiencies and imbalances and can also reveal a functional need for certain vitamins and minerals. Clinical interventions involve changes in food selection or supplementation with selected nut or seed extract oils and required micronutrients. Laboratory reports of fatty acid profiles typically list the fatty acids by structural type in the following order: omega3-polyunsaturates, omega-Gpolyunsaturates, monounsaturates, even-numbered saturates, odd-numbered saturates, and, finally, trans-monounsaturates. Several ratios may be calculated, and for plasma, the total fatty acid concentration may be calculated by summing the individual components and expressing the total in milligrams per deciliter, consistent with the units for serum triglycerides that are directly related to total fatty acid content.

METHODOLOGIC ISSUES Plasma versus Erythrocyte Fatty Acid Profiles A plasma fatty acid profile is an amplification of the standard serum triglyceride analysis. In both cases, the fatty acids are present in lipoprotein particles. Instead of measuring only the total of all fatty acids present, the profile test reports the individual concentrations of each fatty acid. An individual with high serum triglycerides has higher levels of many individual fatty acids in plasma. Of course, any condition associated with

Omega-6 (n-6) Fatty Acids 192 Monounsaturated Fatty Acids 193 Saturated Fatty Acids 194 Odd-Numbered Fatty Acids 195 Trans-Fatty Acids 195 Fatty Acid Ratios 195 Summary 196

elevated serum triglycerides is likewise revealed as elevated plasma fatty acids. Patterns of the high and low concentrationsin plasma depend on recent dietary intake, rates of metabolic conversion from precursor to product fatty acids, and the type of stored fatty acids. Plasma is the preferred specimen for routine evaluation of the balance of fatty acid being delivered to the tissues for energy and maintenance. Interpretation of plasma profile data is less complicated by metabolic issues and is useful for determining dietary changes needed to restore balance. Erythrocyte membrane fatty acid profiling is the most commonly used test to determine the presence of metabolic conversion problems and effects of genetic diseases. The erythrocyte membrane is 45% fatty acids in the form of various phosphatides and glycolipids. The procedure used for profiling measures total concentrations of individual fatty acids per milliliter of packed cells. Erythrocyte data are generally preferred for assessing intracellular metabolism of fatty acids, and the levels reflect those present in most tissues. Both erythrocyte and plasma have been used to maintain brain fatty acid balance in Zellweger syndrome.' Both specimens have also revealed the need to supplement infant formulas with omega3 fatty acids2 The triglyceride-lowering drug gemfibrozil causes a profound suppression of erythrocyte unsaturated fatty acids, even in the presence of high concentrations of the same compounds in plasma. The effect is apparently due to stimulation of the peroxisomal beta-oxidation ~ y s t e m .Because ~ of the metabolic effect of the drug, a patient consuming a diet high in olive oil (largely oleic 189

acid) may show low levels of oleic acid in erythrocyte membranes while maintaining high oleic acid in plasma. Thus plasma profiles show the dietary changes, and erythrocyte fatty acids show the metabolic impact of the drug.

Concentration versus Percentage Before 1996, virtually all clinical laboratories reporting fatty acid fractionations had little choice but to express each fatty acid as a percentage of the total fatty acids present. Actual concentrationscould not be reported due to the lack of pure standards necessary to build calibration curves. The reporting of “relative area” data has some utility but leaves important points obscured. The most abundant fatty acids are present at concentrations 50 times higher than those of the lesser components.4 In percent area calculations, variations in the most abundant components have disproportionate impact on the minor components. If linoleic acid is the same in two cases, for example, while palmitic acid is low in the first and high in the second, the percent linolenic can appear high in the first and normal in the second. This is because palmitic acid makes up so much of the total, and

Name Omega-3 polyunsaturated Alpha linolenic Eicosapentaenoic Docosapentaenoic Docosahexaenoic Omega-6 polyunsaturated Linoleic Gamma linolenic Eicosadienoic DGIA Arachidonic Docosadienoic Docosatetraenoic Omega-6 polyunsaturated Mead Mono-unsaturated Vaccenic Myristoleic Palmitoleic Oleic 11-Eicosenoic Nervonic Erucic Saturated Capric acid Lauric Myristic Palmitic Stearic

Abnormality

the ratios of the minor components such as linolenic acid are calculated by dividing by the total. With the availability of pure standards, it is now possible to measure the actual concentrations of each fatty acid. Since the molecular weights span a range of more than 70-fold for these homologous compounds, molar units allow more meaningful comparisons. This unit also simplifies interpretation of plasma fatty acids, where the total of all fatty acids is directly proportional (and closely equivalent) to the values for total triglycerides from a standard serum chemistry assay. For erythrocytes, concentration is based on packed cell volume or on total lipid extract volume.

INTERPRETATION OF ABNORMAL FATTY ACID RESULTS Table 17-1 summarizes common fatty acid abnormalities and interventions for correction using specific dietary oils. Table 93-4 in Chapter 93 lists the typical symptoms and diseases associated with various fatty acid abnormalities. The significance of abnormal levels and ratios of fatty acids is discussed as follows.

Metabolic association

Potential responses*

L L L L

Essential fatty acid Eicosanoid substrate Nerve membrane function Neurologic development

Add flax or fish oils, or both

L

Essential fatty acid Eicosanoid precursor Desaturase inhibition Eicosanoid substrate Eicosanoid substrate

Add corn or borage oil Add evening primrose oil Zn Add borage oil Reduce red meats

H

Increase in adipose tissue

EFA and glycemic control

H

EFA deficiency

Add balanced EFA

H H H

Membrane fluidity

See discussion

L

H L

Add fish oils

H,

I:

MAD Riboflavin

H

H L

Cholesterogenic

Reduce sat. fats; add niacin

Elevated triglycerides Cancer marker

Reduce sat. fats; add niacin

Fatty Acid Profiling

Name

Abnormalitv

Metabolic association ~______

Potential resoonses'

A6 desaturase inhibition

Check eicosanoid ratios

Nerve membrane function

Consider canola or mustard oils

Propionate accumulation

Vitamin BI2 or biotin suppress intestinal bacterial overgrowth

Trans fatty acids Palmitelaidic Elaidic or total C18 trans

Metabolic interference

Eliminate hydrogenated oils

Ratios and indexes WDGLA DGW E P A

A 6 desaturase enzyme

Add zinc Add fish oils Add borage oil Add fish oils Add balanced EFA Add dietary unsaturates See discussion

~~

Arachidic Behenic Lignoceric Hexacosanoic Odd-numbered Pentadecanoic Heptadecanoic Nonadecanoic Heneicosanoic Tricosanoic

H

~

~

H

Eicosanoid imbalance WEPA Trienenetraene

PIS ratio Stearidoleic (RBC)

EFA deficiency Overall fatty acid status Cancer marker

*Adult supplement doses usually range from 1-3 g/day in the form of extracted nut and seed oils that may contain 30%-60%of the fatty acid by weight. See appropriate chapters for supplementation levels for vitamins and minerals indicated. AA, Arachidonic; €PA, eicosapentaenoic acid; €FA, essential fatty acid; DGLA, dihomogamma-linolenic acid; LA, linoleic acid; MAD, multiple Acyl-CoA disorder; P/S, polyunsaturatedkaturated[fatty acid ratio]; RBC, red b l d cell.

Omega-3 (n-3) Fatty Acids Alpha-linolenic Acid (18:303) Many edible plants produce this 18-carbon polyunsaturated fatty acid, but because of the small amounts of fresh vegetables consumed by many people, it is one of the least abundant of the essential fatty acids in most diets. It is found in relatively high amounts in flax, hemp, canola seed, soybean, and walnut oils and in dark green leaves. It must be supplied by such foods, since human tissues lack the necessary enzymes for its formation. Dietary insufficiencies and imbalances of alpha-linolenic acid (ALA) and its counterpart, gammalinolenic acid (GLA), play a central role in many disease processes (see Tables 93-4 and 93-5 in Chapter 93). The wide range of symptoms and disease associations is due to the function of this fatty acid in critical cell processes of membrane integrity and eicosanoid local hormone production. The hormone function uses the 20-carbon fatty acid eicosapentaenoic acid (EPA, see later), which can be produced from ALA by elongation and desaturation. This conversion depends strongly on zinc status. Inadequate conversion of ALA into EPA is a sensitive biochemical marker of zinc in sufficiency and is indicated by low EPA and docosahexaenoic acid (DHA) in the presence of normal ALA.5

Correction of low body pools of ALA requires dietary changes or the use of dietary supplements containing ALA. Table 17-2 lists food sources of ALA. The origin of ALA deficiency disorders can be seen by inspecting the ALA content of corn, safflower, and peanut oils that are so predominant in modern diets.

Eicosapentaenoic Acid (20:503) Insufficiencies of EPA are likely the most prevalent fatty acid abnormality affecting the health of individuals in Western societies. Low levels in plasma or erythrocytes are indicative of insufficiency. Arthritis, heart disease, and accelerated aging result from direct or indirect effects of inflammatory responses that may be modulated by raising EPA levels. Supplementation with EPA-rich fish oils aids in the prevention of cardiac arrhythmias.6 Significant reduction in total cholesterol and triglyceride has been achieved with a combination of garlic concentrate (900 mg/day) and fish oil ~upplementation.~ EPA is the parent of the 3-series prostanoids and leukotrienes, which moderate the proinflammatory effects of the 2-series derived from arachidonic acid (AA). Although EPA can be produced from the essential fatty acid (EFA) ALA, dietary intake of this fatty acid is generally poor. The conversion also requires the action of the delta-6

Supplementary Diagnostic Procedures

I

~~

~

~

~~

Distribution of ALA and LA in foods with predominantly €PA

DHA

20511-3 0.62

22:6n-3 1.29

~

Food

EPAlDHA Total n-3 2.01 0.48

AM

LA

Food

18:3n-3

18:2n-6

n-an-6

Salmon, Atlantic, farmed

Flaxseed oil

59.1

14

4.22

Salmon, Atlantic, wild

0.32

1.12

0.29

1.73

Flax seed

18.1

4.19

Herring, Pacific

0.97

0.69

1.41

1.72

Walnuts

39

1.02

Anchovy, European

0.54

0.91

0.59

1.45

4.32 38.1

Butter

1.18

0.64

Salmon, Chinook

0.79

0.57

1.39

1.44

Canola oil

9.3

20.3

0.46

Bluefish

0.25

0.52

0.48

0.77

Salad dressing

3.3

24.6

0.13

Shrimp, mixed species

0.26

0.22

1.18

0.49

Soybean oil

6.8

51

0.13

Halibut

0.07

0.29

0.24

0.43

Margarine, soybean

1.5

19.4

0.08

Tuna, yellow fin

0.04

0.18

0.22

0.23

Palm oil

0.2

9.1

0.02

Cod, Atlantic

0.06

0.12

0.53

0.19

Corn oil

0.7

58

0.01

Sesame oil

0.3

41.3

0.01

1.83

Peanuts

0

15.6

0

Safflower margarine

0

44.5

0

Sunflower oil

0

65.7

0

ALA, Alpha-linolenic acid; LA, linoleic acid.

desaturase enzyme, which may be low due to inadequate zinc, magnesium, or vitamins B3, Bb, and C.B Such enzyme impairment would be indicated if EPA is low and ALA is normal or high. High levels of saturated, monounsaturated, and trans-fatty acids and cholesterol also slow the conversion of ALA to EPA (as well as GLA to dihomogammalinolenic acid [DGLA]). Fish oils are rich sources of EPA, as shown in Table 17-3. Dietary supplementation of EPA is an important part of nutritional support in patients with compromised immune responses, including postoperative and trauma cases? Fish oil supplementation lowers triglycerides without effect on glycemic control in type 2 diabetes.'O All such clinical presentations should be monitored by evaluation of fatty acid profiles to ensure that balance is restored and maintained.

Docosa entaenoic Acid (22:503), Docosa exaenoic Acid (22:6co3)

R

Growth and development of the central nervous system in particular depend on the presence of an adequate amount of the long-chain, highly unsaturated fatty acids docosapentaenoic acid (DPA) and DHA."J2 Attention deficit hyperactivity disorder and failures in development of the visual system in EFA deficiencies are two examples of this dependen~y.'~ DHA is an important member of the long-chain fatty acids (C22-C26), which characteristically occur in glycosphingolipids, particularly those in the brain. Since thisfatty acid is so important in early development, it is worth noting that the levels in

DHA, Docosahexaenoic acid; €PA, eicosapentaenoic acid.

breast milk are correlated with the mother's intake of fish oils, which are rich sources of DHA and DPA.I4 Plasma DHA levels should be checked as early as possible in pregnancy. The finding of low DHA in plasma or erythrocytes also justifies the use of supplemental DHA for depre~sion.'~

Omega-6 (n-6) Fatty Acids Linoleic Acid (18:206) Linoleic acid (LA) is by far the most abundant polyunsaturated fatty acid (PUFA) in most human tissues. It is one of the essential fatty acids because it contains a double bond at the omega-6 position that is beyond the reach of the human desaturase enzyme. Low levels indicate dietary insufficiency, which leads to various symptoms (see Table 93-4 in Chapter 93). Some of these symptoms result from a lack of LA in membranes, where it has a role in structural integrity. Most, however, are from failure to produce the 1-series and 3-series local hormones known as prostunoids. LA is the starting point for this pathway. Normal neonatal status of this fatty acid can be marginal, if not insufficient.I6Fetal linoleic and cervonic acids (DHA) are correlated with maternal red blood count 1e~els.I~ However, since dietary sources (especially com oil) are abundant, LA may be found to be above normal in some adults. Excessive LA can contribute to an overproduction of the proinflammatory 2-series local hormones derived from AA. Dietary fatty acids can strongly inhibit intestinal microbial growth. Compared with other fatty acids, LA caused growth inhibition of Helicobacter pylori, the bacterium thought to cause gastric ulcer.'* Although the n-6 fatty acids, especially LA, are widely imputed as dietary offenders because of their relative overabundance in modem diets, it is important to recognize that the clinical imperative is to identify PUFA

Fatty Acid Profiling imbalance. The only sure way to know whether a patient is in n-6 fatty acid deficit or excess is to perform a laboratory evaluation of fatty acid status. The data then can guide interventions that sometimes call for adding, rather than restricting, dietary LA sources.

Gamma-Linolenic Acid (18:3co6) GLA is the precursor of DGLA, the parent of the 1-series prostanoids, that can go on to form AA, the parent of the 2-series prostanoids. GLA is found in hemp, borage, blackcurrant, and evening primrose oils. It can be produced in human tissues by the action of desaturase enzymes on LA. Use of 1.4 g/day in the form of borage seed oil resulted in a clinically important reduction in the signs and symptoms of rheumatoid artluitis19(see Table 93-4in Chapter 93 for other clinical associations).In cases of cancer, it is especially important that low levels of GLA should not be supplemented without added omega-3 fatty acids because omega-6 fatty acids can enhance tumor formation and growth, while omega-3 fatty acids inhibit GLA corrects most of the biologic effects of zinc deficiency, indicating that the requirement of the delta-5 desaturase enzyme for zinc is a first-order essential function of zinc.21

Dihomogammalinolenic Acid (18306) Diets low in the EFA LA are almost universally also low in DGLA. The 1-series prostanoids and leukotrienes are derived from DGLA, so an insufficiency of this fatty acid impairs a wide range of cellular functions and tissue responses. The 1-series compounds act like the 3-series derived from ALA to moderate the proinflammatory 2-series. In tumor response, however, they are unique in being promoters of growth where the 3-series are inhibitors. When testing reveals low levels of DGLA, supplementation with borage or evening primrose oils should be considered, but if a history of tumor formation is known, ALA sources (blackcurrant)should always be considered as well. See the earlier EPA discussion for other factors affecting the desaturase enzyme required for conversion of GLA into DGLA.

Arachidonic Acid (18:406) Because of the prevalence of corn and corn oil products in feed for cattle and hogs, diets high in these red meats are rich in AA. AA is a 20-carbon or eicosanoate fatty acid that serves as a substrate for the cyclooxygenaseand lipoxygenase enzymes, leading to the production of the 2-series prostanoids and leukotrienes. Several of these products have potent proinflammatory and thrombogenic activity. High AA also promotes gallstone formation by stimulating mucin production in the gallbladder mucosa.22 Elevated AA is a frequent finding in profiles of fatty acids in plasma or erythrocytes. Such findings should trigger counseling regarding dietary AA reduction and appropriate supplementation to restore n-3/n-6 balance.

Docosadienoic Acid (22:2&), Docosatetraenoic Acid (22:406) When omega-6 dietary fatty acids are constantly supplied in overabundance, the intermediate products of further desaturation and elongation are not used as fast as they are produced. Under these conditions, the process of modification can continue through docosadienoic acid to the 22-carbon, four double-bonded docosatetraenoic acid (DTA).These fatty acids can then accumulate in adipose tissue. Data from our own studies indicate a positive association of DTA in plasma with obesity. Apparently this fatty acid accumulates in adipose tissue, from which it is mobilized in the fasting state. No such association has been seen in erythrocyte fatty acid profiles, indicating rapid utilization of these fatty acids once they are mobilized. The level of DTA in plasma may be useful in monitoring the metabolic aspects of weight control and especially in avoiding the risk of EFA deficiencies while maintaining a low-fat diet. A low level of DTA in an individual who is on a fat-restricted weight loss program may indicate a state of EFA deprivation. The same factors that govern the rate of formation of Mead acid (see later) also act to control DTA formation.

Mead Acid (20:309) Individuals with good fatty acid status contain low levels of the n-9 PUFA called Mead acid in plasma. Mead acid can be produced in human tissues by repeated desaturation of stearic acid. Under conditions of EFA sufficiency, the desaturase enzymes stay largely occupied by the much more strongly binding n-3 and n-6 members. As EFA intake falls, Mead acid production rises, making this n-9 PUFA a marker of EFA deficiency.16 Although Mead acid cannot participate in eicosanoids formation, it does serve to mimic the membrane fluidity contributions of PUFAs derived from essential precursors. We have observed a stimulatory effect of both EPA and AA on Mead acid formation. Under the special conditions of sustained high intake of EFAs, false elevations of Mead acid may be seen. The discussion of the Triene/Tetraene ratio at the end of this chapter provides a method for further investigating the cause of Mead acid elevation using the data from a plasma fatty acid profile.

Monounsaturated Fatty Acids Vaccenic Acid (14:109), Palmitoleic Acid (16:109), and Myristoleic Acid (18:107) The ratio of vaccenic acid to palmitoleic acid has been reported to be a valuable indicator of biotin deficien~y.~~ Vaccenic acid also seem to have large effects on membrane fluidity, possibly due to the fact that the omega-7 double bond does not align with the much more abundant

Supplementary Diagnostic Procedures

omega-9 positions of the majority of fatty acids present in the membrane. Inhibition of tumor growth in cell culture has been reported for vaccenic acid.24 Myristoleic and palmitoleic acids are normally found in small amounts because the desaturase enzymes have weak affinity for their saturated fatty acid precursors, myristic and palmitic acids. In long-term EFA deficiency, the low concentrations of PUFAs allow higher rates of formation of myristoleic and palmitoleic acids.

Oleic Acid (18109) Oleic acid is present in virtually all whole foods and is easily produced by the fatty acid synthetic pathways present in normal human hepatic cells. It constitutes 15% of the fatty acids in erythrocyte membranes. Because of the presence of the double bond in the center of the molecule, it helps to govern the critical nature of fluidity of the membrane matrix. The pathogenesis of atherosclerosis involves accumulation of foam cells along the arterial wall. Lipids that transform macrophages into these foam cells are provided by oxidized low-density lipoproteins (LDLs). Oleic acid is the principal lipid of a class that makes LDLs resistant to oxidation, and thus a diet rich in this fatty acid reduces foam cell accumulation rates and thereby lowers the chances of atherosclerosisE (see Chapter 150 for a more complete discussion). In tumors, the net result of modification in fatty acid enzymes is low stearic acid and high oleic acid, causing a profound shift in the ratio of stearic to oleic acids.26 One likely outcome of this shift is an increased fluidity of the tumor cell membrane, resulting in more rapid movement of nutrients and waste products and allowing for faster metabolic rate. The stearic/oleic ratio is used as a monitor of the effectiveness of cancer therapy.27 High oleic acid intake (usually as olive oil) can raise total oleic acid content of plasma above the reference range. This finding alone is not highly significant, since oleic acid is a cholesterol neutral fatty acid and is produced in humans from stearic, so it is not an EFA.

Erucic Acid (22109) This fatty acid is apparently one of the components responsible for the favorable response of individuals with adrenal leukodystrophy (ALD) to preparations containing canola and mustard seed oils.28Other studies using Lorenzo oil containing glycerol tierucate revealed no appreciable changes in brain lipid content.29 In Zellweger syndrome, where peroxisomes are absent, erucic and adrenic acids (DTAs) accumulate. It is speculated that either the anabolic enzymes are inhibited from producing sphingolipids or the catabolic enzymes are stimulated to faster clearance of the offending products.30

Nervonic Acid (24:1n9) Nervonic acid contains the longest chain of carbon atoms of all monoenoic fatty acids present at appreciable levels in plasma and erythrocytes. The unique structure of nervonic acid confers special properties to nerve membranes, where it is found in highest concentrations. The myelin sheath is especially rich in nervonic acid. Nervonic acid accumulation in red blood cells yields information on cerebrum maturation in premature infants.31Demyelination in ALD is associated with an accumulation of long-chain saturated fatty acids, such as 26:0, stemming from a genetic defect in the peroxisomal beta oxidation system responsible for the chain shortening of these fatty acids. Long chain monoenoic acids, such as erucic acid, 22:1(n9), can normalize elevated serum levels of 26:O in ALD by depressing their biosynthesis from shorter chain saturated fatty acids.32Impairment in the provision of nervonic acid in demyelinating diseases is indicated, suggesting that dietary therapy with oils rich in very long chain, monoenoic fatty acids may be beneficial in such conditions.

Saturated Fatty Acids Capric Acid (10:0), Lauric Acid (120), Myristic Acid (14:O) These medium-chain saturated fatty acids correspond to the dicarboxylic acids that accumulate in the fatty acid catabolic disorders known as multiple acyl-coenzyme A dehydrogenation disorders (MADs).~~ One type of this enzyme defect is responsive to riboflavin at levels far above normal intakes.%A pattern of low levels of the shorter-chain fatty acids and high levels of longer-chain fatty acids may indicate a fatty acid-restricted diet, in which case there is a stimulation of hepatic synthesis and elongation enzymes.

Palmitic Acid (160) The liver can convert fatty acids into cholesterol. Although any fatty acid can enter this pathway, palmitic acid is the most stimulatory one known and high levels lead to increased serum cholesterol levels and thus to increased risk of atherosclerosis, cardiovascular disease, and stroke. Most other fatty acids are either cholesterol neutral or have reverse effects, as in the case of EPA. Palm kernel and coconut oils are rich sources of palmitic acid. Palmitic is also the principal fatty acid product of human fatty acid synthesis, which is stimulated by hyperinsulinemia and by diets high in simple carbohydrates.

Stearic Acid (18:O) Stearic acid is a saturated fatty acid that is two carbon atoms longer than palmitic and is similarly cholesterogenic. High levels in plasma are therefore a risk

factor in atherosclerotic vascular disease (see earlier discussion on palmitic acid). Abnormal levels in erythrocyte membranes cause alteration in membrane fluidity with numerous consequences. Low levels give increased fluidity, which is associated with active tumor proliferation.

Arachidic Acid (20:O) Arachidic acid (20:O) can be used as an energy source or 1-position phospholipid, but it serves no other special function. Its accumulation is most likely to exacerbate EFA metabolism as it binds to the delta-6 desaturase enzyme and inhibits the insertion of double bonds needed to produce DGLA, EPA, and AA.

Behenic Acid (22:0), Lignoceric Acid (24:0), Hexacosanoic Acid (26:O) Accumulation of certain long-chain fatty acids is associated with degenerative diseases of the central nervous system such as ALD. A large number of known genetic disorders involve accumulation of sphingolipids, usually due to the lack of enzymes necessary to maintain the turnover of membrane components. Behenic, lignoceric, and hexacosanoic acids, as well as the unsaturated members of the C22-24 classes, especially nervonic, are found elevated in such cases.

Odd-Numbered Fatty Acids Pentadecanoic Acid (15:0), Heptadecanoic Acid (1201, Nonadecanoic Acid (1901, Heneicosanoic Acid (21:0), and Tricosanoic Acid (23:O) Because the normal synthetic pathway for fatty acids leads to only even numbers of carbon atoms in the products, it may seem curious to find any odd-numbered chains present in human tissues. Fatty acids with odd numbers of carbon atoms are produced primarily by initiating the synthetic pathway with the three carbon compound, propionic acid. Vitamin BI2 is required for the conversion of propionate into succinate for oxidation in the central energy path~ays.3~ Deficiency of vitamin B12 results in accumulation of propionate and subsequent buildup of the odd-numbered fatty acids. Normal fatty acid biosynthesis also depends on biotin cofactor availability. The initiation of fatty acid synthesis through methylmalonylCoA is a biotin-dependent step. In biotin deficiency, the rate of this step in which acetyl-CoA is converted into malonyl-CoAis reduced, allowing propionate to enter in greater amounts. Elevated levels of odd-numbered chain fatty acids have been shown to occur in human plasma phospholipids and in the plasma, heart, and liver of experimental animalswith biotin defi~iency.~J~ Bacteria in the gut of ruminants produce large amounts of propionate, which is absorbed and enters

the metabolism. Consequently, the intake of animal and dairy products favors higher levels of odd-numbered fatty acids. Alternatively, it is possible that the bacteria in the human gut could produce sufficient amounts of propionate to lead to an elevation in the odd-carbon fatty acids.38 This would only occur under conditions of significant gut dysbiosis. The association between vitamin B12 and abnormal fatty acid synthesisprovides a rationale for the neuropathy of cobalamin deficiency. Odd-chain fatty acids would build up in membrane lipids of nervous tissue, resulting in altered myelin integrity and demyelination, leading to impaired nervous system fun~tioning.~~

Trans- Fatty Acids Palmitelaidic Acid (16:lo9t), Elaidic Acid (18:lo9t), and Other Trans-Fatty Acids The trans-fatty acids, elaidic and palmitelaidic acid, are prevalent in most diets because of the widespread use of hydrogenated oils by manufacturers of margarine, bakery products, and peanut butters. These fatty acids contain one double bond and thus are included in the unsaturated category. Because of the geometry of the trans bond, however, they behave like saturated fats on the one hand, leading to higher cholesterol On the other hand, they mimic unsaturated fats in binding to desaturase enzymes and interfering with the normal production of critical products. The net effect is to raise plasma LDL and lower high-density lipoprotein. The growing consensus among experts in lipid nutrition is that foods containing hydrogenated oils are to be avoided. The bacteria in the gut of ruminant animals also produce these fatty acids, which is the reason that beef and milk contain small amounts (1% to 3%) of elaidic acid. Dietary trans-fatty acid contributed by milk products is of little concern. If plasma or erythrocyte levels of trans-fatty acids are elevated, foods containing hydrogenated oils need to be avoided. Foods that generally contribute the greatest amounts of trans-fatty acids include stick margarine; peanut butters; and bakery products such as breads, rolls, cookies, crackers, pies, and cakes. Products with labels that say simply "vegetable oil" should be substituted in place of those containing hydrogenated oils. Two other 18-carbon positional isomers of elaidic acid are called petroselenic and trunsvaccenic acids. Because the clinical impact of trans-fatty acids is governed by the total body status of the three isomers, it is expedient for laboratories to report the total C18 trans-fatty acid concentration rather than attempting to isolate each isomer.

Fatty Acid Ratios As with all ratios of reported laboratory values, the calculated value allows a comparison of the relative

magnitudes of the two individual measurements. The added value lies in the use of the ratio as a quick guide to the balance between two parameters. Sometimesvaluable insights into imbalances are found in ratio values, even though the individual components are normal.

The Linoleic AcidDihomogammalinolenic Acid Ratio The ratio of LA to DGLA increases when zinc deficiency or excesses of saturated, monoenoic, or trans-fatty acids inhibit the A-6 desaturase enzyme. Under these conditions, the enzyme cannot convert the substrate (LA) to the product (DGLA) fast enough. The production of all desaturation products is affected, including EPA and AA. These longer chain polyunsaturated fatty acids then must be supplied from the diet or supplemented forms.

The Dihomogammalinolenic A c i d Eicosapentaenoic Acid Ratio The balance of 20-carbon or eicosanoic fatty acids is critical for proper supply of the prostanoid and leukotriene 1-, 2-, and 3-series local hormones that control a host of cellular functions and responses. The DGLA/EPA ratio is typically high due to DGLA being elevated relative to EPA, indicating a need for EPA sources such as fish oils. When the ratio is low, sources of DGLA (borage or evening primrose oil) are indicated.

The Arachidonic AcidEicosapentaenoic Acid Ratio This ratio allows a quick comparison of the relative amounts of these two eicosanoid precursors. An abundance of AA is quite common in Western diets high in meat and corn oil and can result in the elevation of the AA/EPA ratio. This is one of the indicators that extra omega-3 fatty acids, including EPA of fish oils, would be beneficial.

The Trienemetraene Ratio The ratio of the triene Mead acid to the tetraene AA has been used as a further marker of EFA deficiency. This ratio is commonly used in studies of EFA deficiency.41 In cases where long-term EFA supplementation has stimulated the production of Mead acid with concurrent elevation of AA, the ratio of the two is not above the normal reference limit. Only when the Mead elevation is found without high levels of PUFAs is the triene/tetraene ratio high, indicating true EFA deficiency.

Red Cell StearidOleic Index The ratio of stearic to oleic acids in red cell membranes has been found to be a strong indicator of the presence of malignant tissue, as it reflects the lowered ratio found in malignant tissue cell membranes.42Values below 1.1 are associated with the presence of malignancy. The ratio was

found to respond to hormonal therapy for prostatic cancer and, in studies following surgical cures, individuals who maintained this ratio above 1.1 had no tumor recurrences.

The Polyunsaturated-to-Saturated Fatty Acid Ratio Originating primarily as a measure of the quality of dietary fats, this ratio is sometimes used also as a general measure of physiologic fatty acid balance. This ratio increases markedly during exercise, as the saturated fatty acids are preferentially used as energy sources, causing plasma levels to fall relative to the unsaturated fatty a ~ i d s . The 4 ~ availability of individual fatty acid data allows the inclusion of trans-fatty acids in the saturated group, since their physiologic behavior is the same. This has not normally been done in the food industry to date, giving misleadingly favorable ratios on labels. The overall effect of higher levels of the polyenoic fatty acids is suppression of hepatic lipogenesis.44

Total Fatty Acid Concentration (Calculated) When the concentrations of total fatty acids present in plasma are summed and expressed in units of mg/100 dl, the result is closely equivalent to that of the routine serum triglyceride assay. In both cases, fatty acids are normally present in the form of LDL particles. The treatment of elevated levels by various actions involving dietary restriction of fats and the use of pharmacologic doses of niacin and lipid-lowering drugs is in common practice, depending on the class of hyperlipidemia found by studies of lipoprotein subclasses and cholesterol levels. When total fatty acids are low, there is the possibility of stimulation of peroxisomal oxidation of fatty acids. A number of structurally diverse chemicals have been found to cause proliferation of peroxisomes in liver and other tissues.45Paradoxically, high-fat diets also cause such proliferation. The increased oxidative activity leads to higher levels of hydrogen peroxide and development of liver tumors in laboratory animals.& In humans, the related disorder, hypobetalipoproteinemia, is associated with increased risk for various cancers, pulmonary, and gastrointestinal di~eases.4~

SUMMARY Recent advances in laboratory methodologies now allow measurement of absolute, as well as relative, levels of essential, nonessential, and potentially damaging types of fatty acids in the blood. The research literature now provides guidance for interpretation of the clinical significance of various fatty acid patterns. Fatty acid manipulation through diet and supplementation is a powerful therapeutic resource (see Chapter 93).

Fatty Acid Profiling

1.Martinez M. Polyunsaturated fatty acids in the developing human brain, erythrocytes and plasma in peroxisomal disease: therapeutic implications. J Inherit Metab Dis 1995;18:61-75. 2. Hoffman DR, Uauy R. Essentiality of dietary w-3 fatty acids for premature infants: plasma and red blood cell fatty acid composition. Lipids 1992;27886-895. 3. Hashimoto F, Ishikawa T, Hamada S, Hayashi H. Effect of gemfibrozil on lipid biosynthesis from acetyl-CoA derived from peroxisoma1 beta-oxidation. Biochem Pharmacol1995;49:1213-1221. 4.Manku MS, Horrobin DF, Huang YS, Morse N. Fatty acids in plasma and red cell membranes in normal humans. Lipids 1983; 18:906. 5. Cunnane SC,Yang J, Chen ZY. Low zinc intake increases apparent oxidation of linoleic and alpha-linolenic acids in the pregnant rat. Can J Physiol Pharmacol1993;71:205-210. 6. Nair SS, Leitch JW, Falconer J, Garg ML. Prevention of cardiac arrhythmia by dietary (n-3) polyunsaturated fatty acids and their mechanism of action. J Nutr 1997;127383-393. 7. Adler AJ, Holub BJ. Effect of garlic and fish-oil supplementation on serum lipid and lipoprotein concentrations in hypercholesterolemic men. Am J Clin Nutr 1997;65445-450. 8. Tsuge H, Hotta N, Hayakawa T. Effects of vitamin B-6 on (n-3) polyunsaturated fatty acid metabolism. J Nutr 2000; 130: 3335334s. 9. Grimm H, Kraus A. Immunonutrition-supplementary amino acids and fatty acids ameliorate immune deficiency in critically ill patients. Langenbecks Arch Surg 2001;386369-376. 10. Montori VM, Farmer A, Wollan PC, Dinneen SF. Fish oil supplementation in type 2 diabetes: a quantitative systematic review. Diabetes Care 2000;231407-1415. 11. Mischoulon D, Fava M. Docosahexanoic acid and omega-3 fatty acids in depression. Psychiatr Clin North Am 2000;23:785-794. 12. Innis SM. n-3 Fatty acid requirements of the newborn. Lipids 1992; 27879-885. 13. Stevens LJ, Zentall SS, Deck JL, et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr 1995;62761-768. 14. Henderson RA, Jensen RG, Lammi-Keefe CJ, et al. Effect of fish oil on the fatty acid composition of human milk and maternal and infant erythrocytes. Lipids 1992;27863-869. 15. Hibbeln JR, Salem N Jr. Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy. Am J Clin Nutr 1995; 621-9. 16. Lee EJ, Simmer K, Gibson RA. Essential fatty acid deficiency in parenterally fed preterm infants. J Paediatr Child Health 1993;29:51-55. 17. van Houwelingen AC, Puls J, Homstra G. Essential fatty acid status during early human development. Early Human Dev 1992;31:97-111. 18. Khulusi S, Ahmed HA, Pate1 P, et al. The effects of unsaturated fatty acids on Helicobacterpylon in vim. J Med Microbiol1995;42276-282. 19. Leventhal LJ, Boyce EG, Zurier RB. Treatment of rheumatoid arthritis with gammalinolenic acid. Ann Intern Med 1993;119867-873. 20. Noguchi M, Rose DP, Earashi M, Miyazaki I. The role of fatty acids and eicosanoid synthesis inhibitors in breast carcinoma. Oncology 1995;52265-271. 21. Huang YS, Cunnane SC,Horrobin DF, Davignon J. Most biological effects of zinc deficiency corrected by gamma-linolenic acid (18:306) but not by linoleic acid (18:2w6). Atherosclerosis 1982; 41:193-207. 22. Hayes KC, Livingston A, Trautwein EA. Dietary impact on biliary lipids and gallstones. Ann Rev Nutr 1992;12:299-326. 23. Liu W, Shigematsu Y, Bykov I, et al. Abnormal fatty acid composition of lymphocytes of biotin-deficient rats. J Nutr Sci Vitaminol 1994;40:283-288.

24. Awad AB, Herrmann T, Fink CS, Horvath PJ. 18:l n7 fatty acids inhibit growth and decrease inositol phosphate release in HT-29 cells compared to n9 fatty acids. Cancer Lett 1995;9:55-61. 25. Anonymous: How monounsaturates may save arteries. Science News 1990;367, June 9. 26. Wood CB, Habib NA, Thompson A, et al. Increase of oleic acid in erythrocytes associated with malignancies. Br Med J 1985;291: 163-165. 27. Apostolov K, Barker W, Catovsky D, et al. Reduction in the stearic to oleic acid ratio in leukaemic cells-a possible chemical marker of malignancy. Blut 1985;50349-354. 28. Rizzo WB, Leshner RT, Odone A, et al. Dietary erucic acid therapy for X-linked adrenoleukodystrophy. Neurology 1989;39: 1415-1422. 29. Poulos A, Gibson R, Sharp P, et al. Very long chain fatty acids in Xlinked adrenoleukodystrophy brain after treatment with Lorenzo’s oil. Ann Neurol1994;36741-746. 30. Christensen E, Hagve TA, Christophersen 80. The Zellweger syndrome: deficient chain-shortening of erucic acid (221 (n-9)) and adrenic acid (224 (n-6)) in cultured skin fibroblasts. Biochim Biophys Acta 1988;959:134-142. 31. Babin F, Sarda P, Limasset B, et al. Nervonic acid in red blood cell sphingomyelin in premature infants: an index of myelin maturation? Lipids 1993;28:627-630. 32. Sargent JR, Coupland K, Wilson R. Nervonic acid and demyelinating disease. Med Hypotheses 1994;42237-242. 33. Saudubray JM, Mitchell G , Bonnefont JP, et al. Approach to the patient with a fatty acid oxidation disorder. In Coates PM, Tanaka K, eds. New developments in fatty acid oxidation. New York Wiley-Liss, 1992, pp 271-288. 34.Roettger V, Marshall T, Amendt R. Multiple acyl-coenzyme A dehydrogenation disorders (MAD) responsive to riboflavin: biochemical studies in fibroblasts. In Coates PM, Tanaka K, eds. New developments in fatty acid oxidation. New York Wiley-Liss, 1992, pp 319-326. 35.Metz J. Cobalamin deficiency and the pathogenesis of nervous system disease. Annu Rev Nutr 1992;12:59-79. 36. Mock DM, Johnson SB, Holman RT. Effects of biotin deficiency on serum fatty acid composition: evidence for abnormalities in humans. J Nutr 1988;118:342-348. 37. Mock DM, Mock NI,Johnson SB, Holman RT. Effects of biotin deficiency on plasma and tissue fatty acid composition: evidence for abnormalitiesin rats. Pediatr Res 1988;24396-403. 38. Thompson GN, Walter JH,Bresson JL, et al. Sources of propionate in inborn errors of propionate metabolism. Metabolism 1990;39: 1133-1137. 39. Frenkel EP, Kitchens RL, Johnston JM. The effect of vitamin BI2 deprivation on the enzymes of fatty acid synthesis. J Biol Chem 1973;248:7450-7456. 40. Abbey M, Nestel PJ. Plasma cholesterol ester transfer protein activity is increased when trans-elaidic acid is substituted for cis-oleic acid in the diet. Atherosclerosis 1994;106:99-107. 41. Mascioli EA, Lopes SM, Champagne C, Driscoll DF. Essential fatty acid deficiency and home total parenteral nutrition patients. Nutrition 1996;12245-249. 42. Persad RA, Gillatt DA, Heinemam D, et al. Erythrocyte stearic to oleic acid ratio in prostatic carcinoma. Br J Urol1990;65268-270. 43. Mougios V, Kotzamanidis C, Koutsari C, Atsopardis S. Exerciseinduced changes in the concentration of individual fatty acids and triacylglycerolsof human plasma. Metabolism 1995;44:681-688. 44. Blake WL, Clarke SD. Suppression of hepatic fatty acid synthase and 514 gene transcription by dietary polyunsaturated fat. J Nutr 1990;1201727-1729.

Supplementary Diagnostic Procedures 45.Reddy JK, Lalwai ND. Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. Crit Rev Toxicol1983;121-58. 46. Reddy JK, Lalwani ND. Peroxisome proliferation and hepatocarcinogenesis.In Vainio H, Magee I",McCregor DB, McMichael AJ, eds.

Mechanism of carcinogenesis in risk identification. Lyon: International Agency for Research on Cancer. New York Oxford University Press, 1992, pp 225-235. 47. Schonfeld G. The hypobetalipoproteinemias. Annu Rev Nutr 1995;15:23-34.

Folic Acid Status Assessment Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 199

Procedure 200 Method 200 Results 200

Clinical Application 199

Interpretation 200

INTRODUCTION Folate, one of the water-soluble B vitamins, is an essential carrier of methyl groups. Folic acid is a pteridine derivative linked through a methylene bridge to a molecule of para-amino-benzoyl-glutamicacid. Folate coenzymes are widely distributed in the body and are involved in a diverse variety of metabolic processes: single carbon transfer reactions; biosynthesis of purines, the pyrimidine, thymidine (which is necessary for the formation of DNA), methionine, and choline; histidine degradation; methylation of biogenic amines such as serotonin; the hydroxylation of proline for collagen formation; and the maturation of erythrocytes and leukocytes (Figure 18-1).1 Although widely distributed in nature, folic acid is thought to be the most common hypovitaminosis of humans with African Americans having lower intakes DNA synthesis

dUMP

v

defect^.^

CLINICAL APPLICATION Clinical conditions that can be caused by a folate deficiency include megaloblastic anemia, glossitis, diarrhea, affective disorders such as depression, certain kinds of cancer, elevation of homocysteine, heart disease, neural tube defects, increased incidence of spontaneous abortion, and weight loss. Signs and symptoms may include

Folic acid

t dTMP-

than other races.2Deficiency is common during pregn a n ~ y ,lactation, ~ early infancy, and adolescence4; and in those taking a wide range of antitumor, antimalarial, antibacterial, anticonvulsive, and contraceptive drugs. Recent public health measures encouraging women to take folic acid supplements have been successful in decreasing the incidence of neural tube

1 1

Dihydrofolate(DHF)

1

Tetrahydrofolate (THF)

DNA methylation A

Methionine

+ SAM

5-Methyl THF

1 J” )

5,lO-MetiIene THF

Homocysteine t SAH

-CH3

Figure 18-1 Role of folate coenzymes in DNA synthesis and modification.Arrows indicate natural biosynthetic pathways. dTMe Deoxythymidine rnonophosphate; dUMe deoxyuridine rnonophosphate; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; THE tetrahydrofolate. Enzymes: [ f ] , thymidylate synthase; [Z], 510-methylene-THF reductase; [3], methionine synthase. (From Li GM, Presnell SR, Gu L. Folate deficiency, mismatch repair-dependent apoptosis. and human disease. J Nutr Biochem 2003;10:568-575.)

199

ulcerative stomatitis; hyperpigmentation of the skin; cervical dysplasia; hepatomegaly; splenomegaly; ankle edema; and the typical nonspecific signs of anemia such as palpitations, angina, light-headedness, and faintness? Folate deficiency has also been shown to impair the phagocytosis and bactericidal activity of neutrophils.6 A prolonged dietary folic acid deficiency, or the presence of folate antagonists, results in the progressive development of biochemical and hematologic abnormalities, as shown in Table 18-1.7fiAs indicated, although an abnormal folate status is traditionally suspected by the presence of a megaloblastic anemia, this is a late-stage development. Serum folate only reflects recent dietary intake, and elevated homocysteine level measurement is nonspecific. The measurement of neutrophil hypersegmentation is a far better indicator of incipient folate deficiency9and is an inexpensive test that can be added to the repertoire of the nutritionally oriented doctor. Serum folate is somewhat unreliable since a vitamin BI2 deficiency results in invalidly high levels, and although RBC folate is more accurate, it is not widely available, is expensive to run,is assay dependent, and gives abnormally low values in patients with a vitamin BI2 deficiency.’O Table 18-2 lists the typical causes of folic acid deficiency by mechanism.”

Causes of folic acid deficiency Mechanism

Cause

Inadequate intake

Alcoholism Dietary insufficiency

Increased requirements

Pregnancy Severe hemolysis Chronic hemodialysis

Inadequate absorption

Tropical sprue Gluten-sensitive enteropathy Crohn’s disease Lymphoma of small bowel Arnyloidosis of small bowel Diabetic enteropathy Intestinal resection or diversion Drugs that block absorption -cholestyrarnine -phenobarbital 4iguanides

Impaired metabolism

Drugs blocking action of dihydrofolate reductase -methotrexate 4rimethoprim -pyrimethamine -anticonvulsants Drugs interfering by other means -phenytoin -ethanol -antituberculous drugs - o r a l contraceptives -aspirin

PROCEDURE The measurement of neutrophil hypersegmentation is a useful test that correlates well with serum folate levels (R = -0.772) and is easily performed by a clinician or clinical lab~ratory.~

Method 1. Take a standard peripheral blood smear on a 1- by 3-inch glass slide.

Modified from Schrier GM: SL: Anemia: Production defects. In Dale DC, Federman DD, eds. Scientific American medicine. New York: 1997;5:111:1-19.

2. Stain with Leishman or other convenient stain. 3.Count the lobes on 100 neutrophils using an oil immersion objective. 4. Calculate the segmentation index (SI):

SI = neutroDhils with 5+ lobes x 100 neutrophils with 4 lobes Progressive manifestationsof folate deficiency Duration (wk)

Abnormality

2-6

Decreased serum folate levels

6-11

Neutrophil hypersegmentation

13

High urinary formiminoglutamate

17

Low red blood count folate

18

Macro-ovalocytosis

19

Megaloblastic marrow

20

Megaloblastic anemia

Data from references 7 and 8.

Results Normal: SI = 2% to 30% Folate deficient: SI = 31.5% to 116%

INTERPRETATION Although abnormal folate levels are responsible for 90% of patients with neutrophil hypersegmentation in the absence of macrocytic anemia, other causes must be considered. It is seen in uremia, and 7% have a vitamin BI2 deficiency.12It is also a congenital condition in as much as 1%of the p0pu1ation.l~

Folic Acid Status Assessment

1. Roe DA. Drug-induced nutritional deficiencies. Westport, CT AVI Publications, 1976:7-11. 2. Ford ES, Ballew C. Dietary folate intake in US adults: findings from

the third National Health and Nutrition Examination Survey. Ethn Dis 1998;8:299-305. 3.Green NS. Folic acid supplementation and prevention of birth defects. J Nutr 2002;132:2356S2360S. 4. Daniel WA, Gaines EG, Bennet DL. Dietary intakes and plasma folate in healthy adolescents. Am J Clin Nutr 1975;28:363-370. 5. Shorvon SD, Carney MWP, Chanarin I, et al. The neuropsychiatry of megaloblastic anemia. Br Med J 1980;281:1036. 6. Youinou PY, Garre MA, Menez JF, et al. Folic acid deficiency and neutrophil dysfunction. Am J Med 1982;73:652. 7. Shamberger RJ. Implications of chronic vitamin undemutrition. In Bland J, ed. Medical applications of clinical nutrition. New Canaan, CT: Keats, 1983:262-263.

8. Herbert V. Biochemical and hematological lesions in folic acid deficiency. Am J Clin Nutr 1967;20:562-569. 9. Bills T, Spatz L. Neutrophilic hypersegmentation as an indicator of incipient folic acid deficiency.Am J Clin Pathol 1977;68:263-267. 10. Clifford AJ, Noceti EM, Block-Joy A, et al. Erythrocyte folate and its response to folic acid supplementation is assay dependent in women. J Nutr 2005;135:137-143. 11. Schrier GM: SL: Anemia: Production defects. In Dale DC, Federman DD, eds. Scientific American medicine. New York 1997; 5:III:l-19. 12. Hattersley PG, Engels JL. Neutrophilic hypersegmentation without macrocytic anemia. West J Med 1974;121:179-184. 13. Herbert V. Studies of folate deficiency in man. Proc R SOCMed 1964;57377-384.

Food Allergy Testing Stephen Barrie, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 203 Laboratory Methods 203 Enzyme-LinkedlmmunosorbentAssay 203 RadioallergosorbentTest 204 RadioallergosorbentProcedure 204 Provocation-Neutralizationand Serial-Dilution Titration Tests 204

Electroacupuncture,According to Voll, Technique 205 Kinesiologic 205 Experiential Challenge Methods 205 Challenge/Oligoantigenic Diet Method 205 Dietary Fast with Food Challenge 206 Summary 207

INTRODUCTION The purpose of food allergy testing is to determine, in a reliable and reproducible manner, a patient’s food sensitivities. When used in conjunction with a comprehensive history and food diary, the tests discussed here can help to determine to which foods or chemicals an individual might be sensitive. Often, patients are unaware that they are sensitive to one or more foods because their reactions are masked, delayed, or lost in the crowd of other symptoms. Several well-known immunologic mediators of food sensitivity are IgA, IgE, IgM, IgG, and various immune complexes, as well as one or more unknown mechanisms of food allergy or food intolerance (see Chapter 5 3 ) . ’ p 2 Two broad categories of applicable tests are commonly used: Laboratory methods that attempt to measure immune complex formation in various ways (both in vitro and in vivo) Experiential clinical tests that challenge the patient with suspected allergens while carefully monitoring for reactions.

LABORATORY METHODS When this chapter was first published in the late 1980s, many of the following tests were just becoming clinically available. Their primary value is in detecting nonimmediate hypersensitivity reactions (i.e., ”hidden” allergic reactions to foods). At that time, our main critique was

the lack of good quality, controlled studies assessing validity. Unfortunately, the research support for most of these procedures continues to be limited. A recent review by Niggemann and Grubel3 that critically evaluated most of the following methodologies found none of them as accurate as the oral food challenge. Interestingly, the article in their reference list included few of the studies supporting accuracy of these methodologies.Clearly, considerable validity research is necessary.

Enzyme-Linked lmmunosorbent Assay The enzyme-linked immunosorbent assay (ELISA) is an in vitro test that requires serum from the patient. This immunologic procedure uses an enzyme-bonding process to detect antibody levels and has been hailed as a ”safe, economical, and highly sensitive test.” It is currently the most popular method in use. The ELISA can measure IgE, I&, I&,, and IgA antibodies, therefore idenhfymg both immediate and delayed hypersensitivity reactions. In general, the ELISA method has replaced radioactive testing methods because it is less expensive and avoids the use of and exposure to radioactive material, as used in the RAST and RASP tests (discussed later). In addition to the procedural advantages, one of the key advantages of the ELISA over other laboratory methods is its ability to measure IgG4 antibodies. This subclass of antibody was initially thought to act as a blocking antibody, thereby exerting protective effects against allergy. However, it now appears that I&, antibodies are actually involved in producing allergic symptoms.4For example, in a study in asthmatics it was demonstrated that asthma in these patients could be 203

produced in response to inhaled antigens that did not bind to IgE antibodies but did bind to These results suggested that IgG4 antibodies play a major role in atopic disease. In short, I&, has been shown to act as an anaphylactic antibody, especially to food antigens? With regard to food allergy testing, it has been shown that the “combination of specific IgE and specific IgG4 is a better correlate to positive food challenge than is skin testing a l ~ n e . ” However, ~,~ a small study found test/retest reliability low?

RadioallergosorbentTest The radioallergosorbent test (RAST)is an in vitro test that requires serum from the patient. Suspected allergens are coupled to a solid matrix, followed by application of a sample of the patient’s serum. If the patient’s serum or plasma contains an antibody specific to the antigen, it couples with the antigen, thus becoming attached to the solid matrix. A minute amount of radioactive-polyclonal antireaginic-antibody is then added. After incubation and subsequent washing, the residual radiation is measured to determine what percentage of the radioactive antibody became bound to the allergen-antibody solid matrix. The higher the radioactive bond, the greater the amount of reaginic antibody specific to the allergen tested is present in the patient’s senun.l0 The underlying assumption in this test is that a person without food sensitivity has little or no food antigen-specific antibodies in his or her blood. The RAST primarily measures immediate IgE-mediated sensitivities (i.e., type 1 reactions that occur in <1 hour). While traditional allergistsbelieve that most food allergy is IgE mediated, growing evidence suggests that other immunologic factors, especially I&, may be considerably more imp~rtant.ll-’~ RAST seems to have better specificity and sensitivity for inhalants than for foods. Some studies have shown a poor correlation of RAST results with individual food ~hallenge,’~ while others have demonstrated a positive ~orrelation.’~ RAST results are not influenced by B-receptor stimulants, ephedrine, antihistamines, or steroids, which can sometimes influence other tests (e.g., the skin scratch test). Results can be available within several days or up to several weeks, depending on where the laboratory is located (serum can be mailed without affecting the results). Many commercial laboratories offer the test, and it is available in kit form for in-office laboratories. Pharmacia was the first to market test kits for specific IgE (called Phadebas RAST). RAST results contain more false-negatives than false-positives. A variant of this radioimmune assay (RIA)procedure is the enzyme immunoassay (EIA). In EIA, the same principles as in RIA are used. Using colorimetry or spectroscopy, EIA measures the enzyme broken off at the

disulfide bridge on the anti-IgE to which the enzyme was tagged. Pharmacia offers EL4 as Phadezym IgE (PRIST).

Radioallergosorbent Procedure The radioallergosorbent procedure (RASP) is a variant of the RAST, although it follows a slightly different protocol. It has been shown to have a higher degree of sensitivity and specificity for food allergens than the RAST.12J4J5 In clinical practice, it appears to uncover a much higher degree of food allergy. Recent information suggests that the RASP may be measuring some IgG complexes in addition to IgE, which helps to explain the increased sensitivity.

Provocation-Neutralization and Serial-Dilution Titration Tests These controversial techniques are employed primarily by clinical ecologists. Provocation-neutralization (P-N) testing is an in vivo technique that diagnoses a sensitivity by assessing the ability of a test dose to evoke symptoms and induce wheal growth. In the P-N method, 0.5-ml serial dilutions (in a 1:5 ratio) of each whole extract antigen dissolved in glycerin, phenol, or distilled water are administered intradermally.I6 The goals of this method are (1) to idenhfy substances that provoke symptoms and (2) to discover which dilutions of those substances are appropriate for treatment. Some research has shown clinical efficacy, such as in dysphonia, when the identified delayed food allergens were eliminated,17 while other research has indicated it is no more effective in detecting food allergies than skin testing.18 Empirically, it has been found that certain dilutions of an offending substance provoke, while other dilutions relieve, various of the patient’s characteristic symptoms during a 10-minute test period after each dilution.19The P-N method is applicable for a wide range of allergensfoods, pollens, dusts, molds, and chemicals.20In the P-N method, the neutralizing dose is a symptom-relieving dilution. Both stronger and weaker dilutions can provoke symptoms. Thus the doseresponse curve is often nonmonotonic (i.e., biphasic). The P-N method may be used with wheal response alone or in combination with symptom response. A variant (especially useful in children) involves provocation through sublingual drops. With this approach, symptom provocation and neutralization are the only criteria for diagnosing sensitivities. Sublingual P-N is frequently used for testing food colorings and certain food chemicals and is frequently effective for diagnosing sensitivities in hyperkinetic children.21 Although there have been both positive and negative studies, the P-N technique enjoys wide clinical Due to its expense, patient time requirements (3 hours for four foods), and potential patient discomfort,

Food Allergy Testing

the P-N is not a practical broad-screening technique for foods, except in special circumstances. The serial dilution (SD) technique is similar to the P-N technique. This titration method uses wheal changes alone to identify, and then neutralize, natural inhalants such as pollens, dusts, and molds.25

Electroacupuncture, According to Voll, Technique The electroacupuncture diagnostic method uses a galvanometer designed to measure the skin‘s electrical activity at designated acupuncture points. Electroacupuncture, according to Voll (EAV), has been used in Europe for many years to determine the abnormalities or energy imbalances of the body. Proponents claim that allergy is a pathogenic and measurable entity. This controversial technique purports to measure both general allergic pathology and specific food sensitivity? The patient holds a negative electrode in one hand, and the positive electrode probe is used to press selected acupuncture points. When a suspected food is placed on an a h minum tray that is connected into the circuit, certain galvanometer reading changes indicate sensitivity. If the appropriately diluted form of the extract is then placed on the tray, equilibrium of the reading should occur. One study found good discrimination between allergic and nonallergic substances,2’ while double-blind studies did not find any clinical benefit.2s,29 In order for this technique to gain acceptance, research and clinical trials must be conducted and a scientifically satisfactory explanation of its mode of operation must be developed.

Kinesiologic Practitioners of applied kinesiology (AK) claim that kinesiologic muscle testing can diagnose food allergies. After either the patient has ingested a small amount of the antigen, or the antigen has been placed on the surface of the patient’s body, certain of the muscles are tested kinesiologically for strength and weakness. This technique is widely used by AK practitioners (particularly chiropractors) and, if it is effective, does have the advantage of being inexpensive and fast. Only a limited amount of research on small samples exists. Some studies report correlation with immunoglobulins,3O while others show no test/retest reliabilityY More research, especially with larger sample sizes, must be done to confirm the limited clinical claims, and, as with the EVA technique, a satisfactory explanation of its mode of action must be developed.

EXPERIENTIAL CHALLENGE METHODS Many physicians believe that oral food challenge is the definitive method (”gold standard”) for diagnosing food

sensitivities. Orthodox practitioners, clinical ecologists, and naturopathic physicians agree that food challenge is an accurate and useful procedure when used with an appropriate patient. The advantage of challenge testing is supported by research reports of food intolerance that is not detected by current immunologic assessments. For example, a study carefully evaluated antibody levels in four infants who had rice intolerance with symptoms including shock, vomiting, diarrhea, and positive occult blood tests.32None of the immunologic tests was positive. All the symptoms disappeared during 6 weeks of a diet free of rice and flour. Histologic changes in the intestinal mucosa were noted after rice was reintroduced. This information is especially important, since rice is commonly suggested as a component of an elimination diet in patients with food allergy. When the relationship between ingestion of certain foods and resulting symptoms is unclear, the use of food challenge methods is warranted. A wide variety of protocols and indications among the physicians using these methods exist. Two broad categories of food provocation challenge testing are the following: Elimination or oligoantigenic diet, followed by food reintroduction Pure water fast, followed by food challenge Food challenge may be performed in an open, singleblind, or double-blind manner. Note: Food challenge testing should not be used in patients with symptoms that are potentially life threatening (such as airway constriction or other severe anaphylaxis).

Challenge/Oligoantigenic Diet Method The patient is placed on a limited diet; common foods are eliminated and replaced with either hypoallergenic and rarely eaten foods or special hypoallergenic f o r m ~ l a s .The ~-~ fewer ~ the allergic foods, the greater the ease of establishing a diagnosis with an elimination diet. The patient stays on the limited diet for at least 1 week (up to 1 month). The first 4 days are considered the ”cleansing period,” with the gastrointestinal tract being cleared of previously ingested foods, thus decreasing food sensitivity reactions. On the fifth or sixth day, symptoms due to food allergy usually disappear (if the food was eliminated) and the patient generally feels better. Care must be taken to ensure that suspected foods are not hidden in other foods and thus unknowingly consumed. Beginning on day 7, individual foods are reintroduced according to some type of plan. Methods range from having the patient reintroduce only a single food every 2 days to one every one or two meals. A careful record is made of any symptoms that may reappear.36

It can be useful to have patients track their wrist pulse during the trial, as it has been shown that pulse changes can occur in some people when a sensitive food is ingested?’ During the cleansing period, the patient typically develops an increased intolerance, or ”hyperreactivity,” to sensitive foods. This explains why the reintroduction of foods may produce a more severe or recognizable symptom than before. The challenge/elimination diet has proven clinically useful in several studies. For example, one group of researchers studied 322 children younger than 1year of age, 99% of whom had allergic rhinitis symptoms, while 85% had bronchial asthmatic symptoms.38The children, who were negative for inhalant skin tests, were placed on a 6-week hypoallergenic diet consisting of a meatbased formula: beef, carrots, broccoli, and apricots. Twohundred ninety-two, or 91%, experienced improvement of respiratory symptom scores during the trial. Oral food challenge produced symptoms in 51% of the children. Milk, eggs, chocolate, soy, legumes, and cereals, in that order, were the most commonly offending foods. Only 6%of the children showed any evidence of food hypersensitivity 5 years later. For patients with limited financial resources, as well as those with less severe health problems, elimination

diets offer a viable means of detection. Because the patient can sometimes dramatically experience the effects of food reactions, motivation for therapy can be improved. The procedure is time consuming and requires patient discipline and motivation.

Dietary Fast with Food Challenge A refinement that yields more results than the simple elimination diet is the 5-day water fast with subsequent challenge. Proponents of this approach believe that it is necessary for the patient to fast for at least 5 days in order to “clear” the body of all allergic re~ponses.3~ This procedure can be performed on an outpatient basis, or in a hospital clinical ecology unit. During the fast, patients are likely to experience “withdrawal” symptoms, which usually subside by the fourth day. As in the elimination diet, symptoms caused by food allergy diminish or are eliminated after the fourth day. After the 5-day fast, individual foods are singly reintroduced, with the patient monitoring symptoms and pulse. Due to the hyperreactive state, symptoms tend to be more acute and pronounced than before the fast. This method can produce dramatic results, greatly motivating the patient to follow whatever therapeutic procedures are appropriate.

Procedure

Advantaaes

Disadvantaaes

ELSA

Patient convenience Detects both IgE and IgG, Good sensitivity

Limited research substantiation

RAST

Patient convenience Good for inhalants Office kits available

Low sensitivity Expensive Detects IgE only

RASP

Patient convenience Good sensitivity

Expensive Not widely available Detects IgE and only some IgG

Skin prick

Widely available Good for inhalants

Poor sensitivity Inconvenient

Provocation

Good for chemicals Office procedure Aids therapy

Expensive Time consuming Limited research support

EAV acupuncture

Inexpensive Easily applied

No scientific basis Few clinical studies

Kinesiologic

Inexpensive Easily applied

No scientific basis Few clinical studies

Oligoantigenic

Sensitive to all types of food intolerance Inexpensive Improved patient motivation

Requires highly compliant patient Can be dangerous if severe reaction Susceptible to irrelevant events

FasVchallenge

Sensitive to all types of food intolerance Inexpensive Improved patient motivation

Requires highly compliant patient Can be dangerous if severe reaction Susceptible to irrelevant events

EAV. Electro-acupuncture. according to Voll: €LISA, enzyme-linked immunosorbent assay: RASE radioallergosorbent procedure; RAST; radioallergosorbenttest.

Food Allergy Testing

A wide variety of diagnostic food allergy test methods are available. These procedures encompass a broad range of accuracy, sensitivity, specificity, patient

economics, risk factors, suitability, and comfort, not to mention “medicophilosophic” paradigms. Table 19-1 summarizes the advantages and disadvantages of each methodology. Each practitioner must develop his or her own operating plan, bearing in mind that different procedures are suitable in certain conditions and that new procedures are constantly being developed. No matter which methods are used, there is a wonderful cross-check for results: If the offending food is eliminated, the patient feels better; if it is not, he or she feels the same!

1.Galant SP, Bullock J, Frick OL. An immunological approach to the diagnosis of food sensitivity. Clin Allergy 1973;3:363-372. 2. Todd S, Mackamess R. Allergy to food and chemicals. Investigation and treatment. Nurs Times 1978;74506-510. 3.Niggemann B, Gruber C. Unproven diagnostic procedures in IgE-mediated allergic diseases. Allergy 2004;59806-808. 4. AAAI Board of Directors. Measurement of specific and nonspecific IgG, levels as diagnostic and prognostic tests for clinical allergy. J Allergy Clin Immunol1995;95:652-654. 5. Gwynn CM, Ingram J, Almousawi T, et al. Bronchial provocation tests in atopic patients with allergen specific I&, antibodies. Lancet 1982;1:254-256. 6. Shakib F, Brown HM, Phelps A, et al. Study of IgG sub-class antibodies in patients with milk intolerance. Clin Allergy 1986;16451458. 7. Rafei AE. Diagnostic value of IgG4 measurements in patients with food allergy. Ann Allergy 1989;6294-99. 8. Husby S, Jensenius JC, Svehag SE. ELISA quantitation of IgG subclass antibodies to dietary antigens. J Immunol Methods. 1985; 82:321-31. 9. Jenkins M, Vickers A. Unreliability of IgE/IgG4 antibody testing as a diagnostic tool in food intolerance. Clin Exp Allergy 1998;28: 1526-1529. 10. Wide L. Clinical significance of measurement of reaginic (IgE) antibody by RAST. Clin Allergy 1973;3:583-595. 11. Perelmutter L. Non-IgE mediated atopic disease. Ann Allergy 1984;52:640-688. 12. Hamburger R. Proceedings of the First International Symposium on Food Allergy, Vancouver, BC, 1982. 13. Egger J, Carter CM, Wilson J, et al. Are migraines food allergies? Lancet 1983;ii:8355-8363. 14. Wright JV,Moore R. Unpublished data. 15. Foucard T, Johansson D. Indications and interpretations of RIST and RAST. Pediatrician 1976;5:228-236. 16. Rinkel HJ. The diagnosis of food allergy. Arch Otolaryn 1964;7971-79. 17. Dixon HS. Dysphonia and delayed food allergy: a provocation/ neutralization study with strobovideolaryngoscopy.Otolaryngol Head Neck Surg 1999;121:418-429. 18. Fox RA, Sabo BM, Williams ’I”,Jofies MR. Intradermal testing for food and chemical sensitivities: a double-blind controlled study. J Allergy Clin Immunol 1999;103:907-911. 19. Miller JB. Food allergy: provocative testing and injection therapy. Springfield, IL: CC Thomas, 1972. 20. Dickey LD, ed. Clinical ecology. Springfield, E CC Thomas, 1976. 21. Rapp DJ. Food allergy treatment for hyperkinesis. J Learning Dis 1979;1260&616. 22. Rapp DJ. Sublingual provocative food testing. Ann Allergy 1981; 46176.

23. King WP, Rubin WA, Fadal RG, et al. Provocation-neutralization: a two-part study. Part I. The intracutaneous provocative food test: a multi-center comparison study. Otolaryngol Head Neck Surg 1988;99:263-271. 24. Breneman JC, Crook WC, Deamer W. Committee on provocative food testing. Ann Allergy 1973;31:375-383. 25. Rinkel HJ. Inhalant allergy: the whealing response of the skin to serial dilution testing. Ann Allergy 1949;7625-630. 26. Tsuei JJ, Lehman CW, Lam FMK Jr, Zhu DAH. A food allergy study utilizing the EAV acupuncture technique. Am J Acupunc 1984; 12105-116. 27. Krop J, Lewith GT, Gziut W, Radulescu C. A double-blind, randomized, controlled investigation of electrodermal testing in the diagnosis of allergies. J Altem Complement Med. 1997;3:241-248. 28. Lewith GT, Kenyon JN, Broomfield J, et al. Is electrodermal testing as effective as skin prick tests for diagnosing allergies? A double blind, randomized block design study. BMJ 2001;322131-134. 29. Semizzi M, Senna G, Crivellaro M, et al. A double-blind, placebocontrolled study on the diagnostic accuracy of an electrodermal test in allergic subjects. Clin Exp Allergy 2002;32:929-932. 30. Schmitt WH Jr, Leisman G . Correlation of applied kinesiology muscle testing findings with serum immunoglobulin levels for food allergies. Int J Neurosci 1998;96237-244. 31. Ludtke R, Kunz B, Seeber N, Ring J. Test-retest-reliability and validity of the kinesiology muscle test. Complement Ther Med 2001;9:141-145. 32. Cavataio F, Carroccio A, Montalto G, Iacono G. Isolated rice intolerance: clinical and immunologic characteristics in four infants. J Pediatr 1996;128558-560. 33. Dockhom RJ, Smith TC. Use of a chemically defined hypoallergenic diet in the management of patients with suspected food allergy. AM Allergy 1981;47264-266. 34. Rowe AH, Rowe A. Food allergy. Its manifestations and control and the elimination diets. Springfield, E CC Thomas, 1972. 35. Vlieg-Boerstra BJ, Bijleveld CM, van der Heide S, et al. Development and validation of challenge materials for double-blind, placebo-controlled food challenges in children. J Allergy Clin Imm~n0l2004;113:341-346. 36. Metcalfe D. Food hypersensitivity. J Allergy Clin Immunol 1984;73:749-761. 37.Coca AF. Art of investigating pulse diet record in familial nonreaginic food allergy. Ann Allergy 1944;2:1. 38.Ogle KA, Bullock JD. Children with allergic rhinitis and/or bronchial asthma treated with elimination diet: a five-year follow-up. Ann Allergy 1980;44:273-278. 39. Rinkel HJ, Randolph T, Zeller M. Food allergy. Springfield, I L CC Thomas, 1951.

This method is only advisable for people who are physically and mentally capable of a 5-day water fast. Close patient monitoring during the fast is a necessity. At times, careful interpretation of results is necessary due to the occurrence of delayed reactions.

SUMMARY

Hair Mineral Analysis Steve Austin, ND Nick Soloway, LMT, DC, LAC CHAPTER CONTENTS Introduction 209 Specific Minerals 210 Calcium and Magnesium 210 Chromium 210 Copper 210 Manganese 210 Selenium 211 Sodium and Potassium 21 1

INTRODUCTION Despite many research studies since the original publication of this chapter in 1985, there has been little change in the diagnostic value of hair analysis (HA). Outside its accepted use for diagnosis of heavy metal toxicity (see Chapter 26), at this time HA still has only limited clinical application. In recent years, several attempts have been made to standardize hair analysis testing techniques,1 but laboratories still did not have an agreement on procedures for handling a hair sample.z4 Many conditions and diseases have been tested for abnormal HA patterns, and a number have been shown to have patterns differing significantly from the norm, including the following: Learning disabilitiess7 Birth Hyperactivitylo-l2 Down syndrome13J4 Neurosis and psychosis15 Senile dernentiaI6 Autism17 Alopecia areatals Insulin-dependent diabetes m e l l i t u . ~ ~ ~ , ~ ~ Cystic fibrosis21 Beta-thalassemia= Spasticity in childrenz3 Repeated exposure to Nasopharyngeal Aplastic anemiaz9

Zinc 21 1 Other Minerals 21 1 Drug Abuse

211

Ratios 211 Discussion 212

HA has been used successfully to test for drug abu~e,3O-~~ although the indices measured (drug metabolites) are not found on most commercial hair analyses. HA appears to offer real potential as a diagnostic tool in a few of the listed conditions. For example, the high hair sodium values in infants with cystic fibrosis shows very little overlap with those in controls, and one study demonstrated that children with learning disabilities can be diagnosed with 98% accuracy because of a consistent pattern of high hair values of cadmium, manganese, and chromium in conjunction with low values of lithium and ~ o b a l t .As ~ a result of this progress, the noninvasive nature of the procedure, its low cost, and the philosophic relevance of mineral balance, HA has remained popular with nutritionally oriented practitioners. The usefulness of HA as a research tool hardly can be questioned. However, significant controversy exists about the use of the method for the clinical diagnosis of diseases other than heavy metal toxicity and as an indicator of nutritional status. Moreover, several studies question the interlaboratory accuracy of hair analysis.37,38 The difference between research and clinical use is significant. Whereas it may be of interest in a research setting that patients with various skin conditions have lower mean levels of hair magnesium than controls, the two groups overlap so much that the procedure is diagnostically useless.18Moreover, even when an altered HA pattern has been associated with a disease, generally there are few investigations as to whether mineral supplementation would affect the clinical condition or even revert the hair mineral pattern to normal. 209

Supplementary Diagnostic Procedures Wide overlap of values in disease and control groups is frequently the case with HA, resulting in excessive false-positives and false-negative results. For example, mentally retarded patients have been found to have hair lead, sodium, and potassium hair values approximately twice those of controls,13but the standard deviations are extremely large for some minerals (for sodium, 1644.71 f 1814.93 versus 744.43 k 198718; and for potassium, 870.15 f 1009.19 versus 408.35 f 689.99), and the large overlap greatly reduces the clinical use of HA. In addition, many of the altered HA patterns associated with the diseases previously listed are as yet unconfirmed.

SPECIFIC MINERALS Calcium and Magnesium

Chromium levels decrease with age,V but the meaning of this change remains unknown. Hair and tissue chromium levels vary greatly during pregnancy, being very high during the first few months of normal pregnancy and subsequently decreasingms1 Late in pregnancy, hair chromium content typically becomes suggesting deficiency.30However, high hair chromium value in pregnancy is associated with low-birth-weight infants.53 In patients with gestational diabetes, hair chromium content is high early in pregnancy but decreases in late pregnancy.%Increasing dietary intake of chromium has been linked to increasing hair chromium val~es,5~ but supplemental chromium does not seem to alter hair Although normal and deficiency ranges should be more clearly defined, hair chromium content appears to have potential future use in clinical settings. However, current knowledge remains inadequate to help clinicians treat patients on the basis of abnormal hair chromium levels.

Hair calcium and magnesium values were found to be elevated in patients with fibr~myalgia.~~ High hair calcium content has been associated with a reduced risk of coronary heart disease.40Low hair calcium content has Copper been found in the last trimester of pregnancy:' and hair calcium content inmased in response to supplementation Oral contraceptive use is associated with decreased hair during pregnancy." Low hair magnesium levels have copper and increased serum c0pper.5~High hair copper been reported in autistic children, children with attention levels are associated with being female, lactation, deficit hyperactivity disorder, patients with various skin idiopathic scoliosis, and pregnancy in some but not all disorders, and patients with several types of leukemia, studies.5B61Surprisingly, conditions that affect systemic whereas high levels have been reported in conjunction copper status have been shown not to affect hair levels. with dyslexia and Prader-Willi ~ y n d r o m e . ' ~ JThe ~ J ~ , ~Copper ~ Wilson disease,@PMand cirrhosis65 meaning of these associations remains unknown for the do not significantly alter hair copper content. Hair most part. copper levels also vary with geographic location.% A 2001 study concluded that analysis of hair calcium However, fur and liver copper values have been found and phosphorus content was of value as a complemento correlate in rats,& and one study reported that suppletary detection tool in abnormalities of bone metabomental copper raises hair copper levels?' Hair color lism.46 Elevations in both calcium and magnesium also has been found to influence the levels of copper in were correlated with a low dietary calcium-magnesium the ratio in one study, suggesting that this finding may be At this time, hair copper measurement appears unreindicative of an induced hyperparathyroidi~m,4~ but liable for clinical a p p l i c a t i ~ n . ~ ~ that hypothesis remains unproven. Hair calcium and Manganese magnesium also vary in response to the hardness and pH of the water in which the hair is usually washed.40 Levels of hair manganese in mothers of infants with conSupplementation of dietary magnesium has been genital malformations and their offspring were sigrufireported to increase hair magnesium levels in deficient cantly lower in one studys which may allow maternal children.'@Nonetheless in one study of congenital hypohair manganese levels to be used as an indicator of the magnesemia, researchers concluded that hair magnesium risk for malformations. Both nonsignificantly altered69 level was not a useful tool in monitoring mineral status and normal levels of manganese7"have been reported in patients with epilepsy.69Hair manganese values have because the values were higher in affected subjects than in subjects who were not deficient.49 been reported to be elevated in people with violent behavior, with varying levels of sigrufi~ance.~~,~~ Evidence There is limited evidence to support the use of hair that manganese supplementation affects behavior does calcium and magnesium measurements in clinical diagnosis at this time. not appear to exist at present. Hair manganese may serve as a useful research tool in Chromium the study of altered behavior, but the most promising Hair chromium content is low in insulin-dependent diabetvalue of hair manganese may lie in the prediction of ics,2O although there is much overlap with normal persons. congenital malformations.

Hair Mineral Analysis

Selenium Levels of selenium in well water and hair show good correlation." High hair selenium levels are seen in toxicity,'3,74 and low levels are seen in defi~iency.~~ Low hair selenium values have been reported in babies with neural tube defects and their mothers9 as well as in patients with phenylket~nuria.~~ Tissue selenium values reflect short-term variations in intake,%and hair levels of the element rise significantly after ~upplementation.",~~ As with chromium, insufficient data are now available to establish reliable norms for measurement of hair selenium values, and the incidence of false-positive and false-negative results remains unknown. Hair selenium measurement shows promise for clinical use when these problems are resolved.

Sodium and Potassium It is generally accepted, even by proponents of HA, that hair sodium and potassium do not reflect dietary status. High elevations of hair sodium may be diagnostic in cystic fibrosis?l but require confirmation. A relatively low Na/K ratio has been reported in celiac disease.79 Although many HA advocates site low hair sodium and potassium as indicative of "adrenal exhaustion," the only (preliminary) study exploring this subject reported that hair sodium and potassium do not correlate with adrenal function.80Except for cystic fibrosis, hair sodium and potassium appear to hold little promise for clinical use.

Zinc Hair zinc levels have received more research attention than any other mineral. Low hair zinc has been associated with zinc deficiency, anorexia nervosa, hyperactivity, gender, age, atherosclerosis, beta-thalassemia, vegetarianism, lung cancer, leukemia, celiac disease, epilepsy in males, epilepsy in general, short stature in childhood, poverty, insulin-dependent diabetes mellitus, neural tube defects, and during It also has been reported in neonates if the time between pregnancies is short.99 Because a few of these conditions have been associated with potential zinc deficiencies and supplemental zinc has been shown to increase hair zinc levels, practitioners who use HA often rely on hair zinc as an indicator of zinc status. However, one trial reported that hair zinc levels declined after supplementation.* Other factors that affect hair zinc levels also interfere with the clinical use of this tool. Shampooing and dying affect hair zinc levels;02 as does the sex of the subject,1°2-106 and hair growth rate. Malnourished children have shown both 10w96J07J08 and highloghair zinc. ~~~

~~

*References 42, 81,82, 93, 100, 101.

Poor correlations between hair zinc and height,"O weight, and zinc consumption also have been rep0rted,6~J~ although one study reported a correlation among hair zinc, weight, and zinc consumption.'1° Another study found that obese people of both sexes had higher hair zinc than those of normal weight and that there was a correlation between the degree of obesity and higher hair zinc 1evels.l'l Although low hair zinc levels have been reported in patients with insulin-dependent diabetes mellitus,*OO generally there is considerable overlap between cases and controls. To further complicate the picture, in a study of female descendants of non-insulin-dependent (NIDDM) parents, hair zinc was found to be significantly higher compared with women with no family history of NIDDM.l12 At this time there is no definitive understanding of the meaning of abnormal hair zinc levels. The hypothesis that high hair zinc levels reflect acute deficiency, whereas low levels indicate chronic deficiency remains unproved.

Other Minerals Hair iron was found to correlate positively with serum ferritin,'13 although the clinical relevance of this finding is un~1ear.l~~ Hair lithium has been reported to show a linear response to extra-dietary s o ~ r c e sLow . ~ hair levels of lithium also have been reported in conjunction with heart disease, learning disability, and violent beha~ior.~ However, research findings are far from the point at which hair lithium could be used to help clinicians diagnose or treat these conditions.

DRUG ABUSE HA has been used to detect drugs of abuse and their metabolites when urine tests were negative.mJ2Hair analysis has been used as evidence in a court of law concerning past drug abuse.3l Although there are concerns about the role of HA in testing for drug abuse,l15HA does seem to be a valuable tool in drug screening.3s36As mentioned, drug metabolites and not mineral levels are measured in these trials, and drug metabolites typically are not reported on most commercially available hair analyses.

RATIOS The experimental documentation for most of the "ideal" ratios that have been published by several HA companies has not been found. The Zn/Cu ratio has been reported to be altered in violent patients." This ratio was also elevated in survivors of myocardial infarcts>16 Strong correlations between several mineral ratios and atherosclerosis also have been reported117;however, the clinical significance of these ratios is not known.

Supplementary Diagnostic Procedures

The Mg/Zn ratios helped to separate healthy (cl/l) from epileptic (>l/l)subjects in one study.g0

DISCUSSION Hair mineral analysis is conceptually enticing and potentially a valuable clinical tool. However, problems abound with standardization of sampling, handling, and analysis of hair ~ a r n p l e s . Additionally, ~~,~~ reference values can differ ~ i d e l y , ” and ~ J ~many ~ variables affect the results (see Austin for a review)I2? GendeP Age68,121,122 Environment12q1E Hair c0lol.6~~~ Cold waving Bleaching Exogenous contaminationM Variations in mineral content within a given sample

This is further aggravated by the reporting of different results on the same sample from different laboratories.38J26 The distribution of elements within the lipid and nonlipid portions of hair and the treatment of the sample As noted, before testing may explain these dietary intakes do not consistently correlate with hair levels; and hair color, sex, age, and other variables appear to sigruficantly affect levels of some minerals. Separate norms for age, gender, and hair color are now being established.61J22J28 However, reviews of the literature attempting to establish reference values continue to show a large variance in mean values, standard deviations, and

1. Passwater RA, Cranton EM. Trace elements, hair analysis and nutrition. New Canaan, CT: Keats Publishing, 1983. 2. Blaurock-Bus& E. Attacking and defending hair mineral analysis. Townsend Letter for Doctors & Patients 2001;251:86-89. 3. Sen J, Das Chaudhuri AB. Brief communication: choice of washing method of hair samples for trace element analysis in environmental studies. Am J Phys Anthropol2001;115:289-291. 4. Bass DA, et al. Trace element analysis in hair: factors determining accuracy, precision and reliability. Altern Med Rev 2001; 6472-481. 5. Pihl RO, Parkes M. Hair element content in learning disabled children. Science 1977;198:204. 6. Marlowe M, Moon C. Hair aluminum concentration and nonadaptive classroom behavior. J Adv Med 1988;1:135-142. 7. Schrauzer GN, Shrestha KP, Flores-Arce ME Lithium in scalp hair of adults, students, and violent criminals. Effects of supplementation and evidence for interactions of lithium with vitamin 812 and with other trace minerals. Biol Trace Elem Res 1992;34.161-176. 8. Saner G, Dagoglu T, Ozden T. Hair manganese concentrations in newborns and their mothers. Am J Clin Nutr 1985;41:1042-1044.

range^.^,'^^ Additionally, there is no basis for the nutritional advice suggested by some laboratories. As a result of the gulf between available information on the one hand, and the clinical interest by some practitioners on the other, several articles have appeared decrying the misuses of HA.37,38J3@132 Hambidgel3I has said that, “There is a wide gulf between the limited and mainly tentative justification for their use on an individual basis and the current exploitation of multielement chemical analysis of human hair.” Klevay and as~ociates’~~ acknowledge the experimental usefulness of HA but go on to say that, ”. . . its use in clinical medicine for diagnosis, prognosis, and therapy will remain limited until validation by the standard methods of clinical investigation is achieved.” Steindel and H ~ w a n i t zconclude: l~~ Physicians a n d other health care professionals who are considering ordering hair analysis to assess nutritional status or who are basing nutritional counseling or therapy on hair analysis should reconsider this approach unless and until the reliability of hair analysis value is established a n d evidence becomes available that clinical recommendations based on hair analysis improve patient outcomes.

Widespread use of speculative diagnostic procedures invites condemnation, especially when the burden of these speculations falls on the pocketbook and psyche of the patient. HA is a valid and useful screening tool for toxic metal exposure (lead, mercury, cadmium, arsenic, and selenium). It has the potential of becoming a clinical tool of considerable use in other areas. Current abuse and nonstandardization of laboratory procedures are more likely to hinder this development than to help it.

9. Guvenc H, et al. Low levels of selenium in mothers and their newborns in pregnancies with a neural tube defect. Pediatrics 1995;95:879-882. 10. Barlow PJ. A pilot study on the metal levels in the hair of hyperactive children. Med Hypotheses 1983;11:309. 11. Barlow PJ, et al. Trace metal abnormalities in long-stay hyperactive mentally handicapped children and agitated senile dements. J R Soc Med 1986;79:581-583. 12. Kozielec T, Starobrat-Hermelin B. Assessment of magnesium levels in children with attention deficit hyperactivity disorder (ADHD). M a p Res 1997;10:143-148. 13. Marlowe M, et al. Hair mineral content as a predictor of mental retardation. J Orthomol Psychiatry 1983;12:26. 14. Shrestha KP, Carrera AE. Hair trace elements and mental retardation among children. Arch Environ Health 1988;43:396-398. 15. Kracke K. Biochemical bases for behaviour disorders in children. J Orthomol Psychiatry 1982;11:289. 16. Vobecky J, et al. Hair and urine chromium content in 20 hospitalized female psychogeriatric patients and mentally healthy controls. Nutr Rep Int 1980;22:49-55.

Hair Mineral Analysis 17. Marlowe M, et al. Decreased magnesium in the hair of autistic children. J Orthomol Psychiaby 1984;13117. 18. Cotton DW, Porters JE,Spruit D. Magnesium content of the hair in alopecia areata atypica. Dermatologica 1976;15260-62. 19. Amador M, et al. Hair-zinc concentrations in diabetic children. Lancet 1975;2:1146. 20.Hambidge KM, Rodgerson DO, OBrien D. Concentration of chromium in the hair of normal children and children with juvenile diabetes mellitus. Diabetes 1968;17517-519. 21. Kopito L, Elian E, Shwachman H. Sodium, potassium, calcium, and magnesium in hair from neonates with cystic fibrosis and in amniotic fluid from mothers of such children. Pediatrics 1972;49:620-624. 22. Dogru U,Arcasoy A, Cavdar AO. Zinc levels of plasma, erythrocyte, hair and urine in homozygote beta-thalassemia. Acta Haematol 1979;62:41. 23. Man CK, Zheng YH, Mak PK. Hair analysis of spastic children in Hong Kong. Sci Total Environ 1996;191:291-295. 24. Majumdar S, Chatterjee J, Chaudhuri K. Ultrastructural and trace metal studies on radiographers’ hair and nails. Biol Trace Elem Res 1999;67127-136. 25. Chatterjee J, et al. Trace metal levels of X-ray technicians’blood and hair. Biol Trace Elem Res 1994;46211-227. 26. Man AC, Zheng YH, Mak PK. Structural and trace element changes in scalp hair of radiographers. Biol Trace Elem Res 1998;6311-18. 27. Leung PL, Huang HM. Following the recovery of nasc-pharyngeal cancer patients by trace elements in hair using statistical pattern recognition methods. Biol Trace Elem Res 1998;62235-253. 28. h u n g PL, Huang HM. Analysis of trace elements in the hair of volunteers suffering from nasopharyngeal cancer. Biol Trace Elem Res 1997;5719-25. 29. Wang J, et al. Contents of trace elements in the hair of aplastic anemia patients and their treatment based on an overall analysis of symptoms and signs. J Trad Chin Med 1994;1498-100. 30. Graham K, et al. Determination of gestational cocaine exposure by hair analysis. JAMA 1989;2623328-3330. 31. Strang J, Marsh A, DeSouza N. Hair analysis for drugs of abuse. Lancet 1990;335:740. 32. Gaillard Y, Vayssette F, Pepin G. Compared interest between hair analysis and urinalysis in doping controls. Results for amphetamines, corticosteroids and anabolic steroids in racing cyclists. Forensic Sci Int 2000;107361-379. 33.Nakahara Y. Hair analysis for abused and therapeutic drugs. J Chromatogr B Biomed Sci Appl1999;733161-180. 34. Gaillard Y, Pepin G. Testing hair for pharmaceuticals. J Chromatogr B Biomed Sci Appl1999;733231-246. 35. Rivier L. Is there a place for hair analysis in doping controls? Forensic Sci Int 2000;107309-323. 36. Klien J, Karaskov T, Koren G. Clinical applications of hair testing for drugs of abuse: the Canadian experience. Forensic Sci Int 2000;107281-288. 37. Barrett S. Commercial hair analysis. Science or scam? JAMA 1985;254:141-145. 38. Seidel S, et al. Assessment of commercial laboratories performing hair mineral analysis. JAMA 2001;285:67-72. 39.Ng SY. Hair calcium and magnesium levels in patients with fibromyalgia: a case center study. J Manipulative Physiol Ther 1999;22586-593. 40. Noble RE. Uptake of calcium and magnesium by human scalp hair from waters of different geographic locations. Sci Total Environ 3999;239:189-193. 41. Huang HM, et al. Hair and serum calcium, iron, copper, and zinc levels during normal pregnancy at three trimesters. Biol Trace Elem Res 1999;69111-120. 42. Leung PL, et al. Hair concentrations of calcium, iron and zinc in pregnant women and effects of supplementation. Biol Trace Elem Res 1999;69:269-282.

43. Sahin G, et al. High prevalence of chroNc magnesium deficiency in T cell lymphoblastic leukemia and chronic zinc deficiency in children with acute lymphoblastic leukemia and malignant lymphoma. Leuk Lymphoma 2000;39:555-562. 44.Capel ID, et al. Comparisons of concentrations of some trace, bulk, and toxic metals in the hair of normal and dyslexic children. Clin Chem 1981;27879-881. 45. Marlowe M, et al. Hair minerals and diet of Prader-Willi syndrome youth. J Autism Dev Disord 1987;17365-374. 46. Miekeley N, et al. Elemental anomalies in hair as indicators of endocrinologic pathologies and deficiencies in calcium and bone metabolism. J Trace Elem Med Biol2001;15:46-55. 47. Bland J. Dietary calcium, phosphorus and their relationships to bone formation and parathyroid activity. J John Bastyr Col Nat Med 1979;1:3. 48. Kozielec T, et al. The influence of magnesium supplementation on magnesium and calcium concentrations in hair of children with magnesium shortage. M a p Res 2001;1433-38. 49. Guillard 0, et al. Congenital hypomagnesemia: alternatives to tissue biopsies for monitoring body magnesium status. Clin Biochem 1992;25:463465. 50. Hambidge Kh4, Franklin ML, Jacobs MA. Changes in hair chromium concentrations with increasing distances from hair roots. Am J Clin Nutr 1972;25:380-383. 51. Aharoni A, et al. Hair chromium content of women with gestational diabetes compared with nondiabetic pregnant women. Am J Clin Nutr 199255104-107. 52. Jeejeebhoy KN, et al. Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition. Am J Clin Nutr 1977;30:531-538. 53. Rowland A. Trace metals leave more than trace effects. Sci News 1984;125373. 54. Aharoni A, et al. Hair chromium content of women with gestational diabetes compared with nondiabetic pregnant women. Am J Clin Nutr 1992;55104-107. 55. Hunt AE, Allen KGD, Smith BA. Effect of chromium supplementation on hair chromium concentration and diabetic status. Fed Proc 1983;24925. 56. Hambidge KM, Franklin ML, Jacobs MA. Hair chromium concentration. Effects of sample washing and external environment. Am J Clin Nutr 1972;25:384-389. 57. Deeming SB, Weber CW. Hair analysis of trace minerals in human subjects as influenced by age, sex, and contraceptive drugs. Am J Clin Nutr 1978;31:1175. 58. Klevay LM. Hair as a biopsy material. II. Assessment of copper nutriture. Am J Clin Nutr 1970;23:1194-1202. 59. Pratt WB, Phippen WG. Elevated hair copper levels in idiopathic scoliosis. Preliminary observations. Spine 1980;5:230-233. 60. Vir SC,Love AH, Thompson W. Serum and hair concentrations of copper during pregnancy. Am J Clin Nutr 1981;34:2382-2388. 61. Bertazzo A, et al. Determination of copper and zinc levels in human hair influence of sex, age, and hair pigmentation. Biol Trace Elem Res 1996;5237-53. 62. Bradfield RB, et al. Hair copper in copper deficiency. Lancet 1980;2:343-344. 63. Mediros D, et al. Trace elements in human hair. Lancet 1982; 2:608. 64.Watt F, et al. Analysis of copper and lead in hair using the nuclear microscope; results from normal subjects, and patients with Wilson’s disease and lead poisoning. Analyst 1995;120789-791. 65. Epstein 0,et al. Hair copper in primary biliary cirrhosis. Am J Clin Nutr 1980;33967. 66. Iyengar V, Woittiez J. Trace elements in human clinical specimens: evaluation of literature data to identify reference values. Clin Chem 1988;34:474-481.

67. Jacob RA, Klevay LM, Logan GM Jr. Hair as a biopsy material. V. Hair metal as an index of hepatic metal in rats: copper and zinc. Am J Clin Nutr 197831:477480. 68. Sturaro A, et al. The influence of color, age, and sex on the content of zinc, copper, nickel, manganese, and lead in human hair. Biol Trace Elem Res 1994;Ml-8. 69. Papavasilious PS, et al. Seizure disorders and trace metals: manganese tissue levels in treated epileptics. Neurology 1979;29: 1466-1473. 70. Gottschalk LA, et al. Abnormalities in the hair trace elements as indicators of aberrant behavior. Comp Psychiatry 1991;32229-237. 71. Cromwell PF, et al. Hair mineral analysis: biochemical imbalances and violent criminal behavior. Psycho1 Rep 1989;64:259-266. 72.Valentine JL, Kang HK, Spivey GH. Selenium levels in human blood, urine, and hair in response to exposure via drinking water. Environ Res 1978;17347-355. 73. Yang GQ, et al. Endemic selenium intoxication of humans in China. Am J Clin N u b 198337872-881. 74. Srivastava AK, et al. Hair selenium as a monitoring tool for occupational exposures in relation to clinical profile. J Toxic01 Environ Health 1997;51:43745. 75. Keshan Disease R e s e d Group of the ChineseAcademy of Medical Sciences, Beijing. Epidemiological studies on the etiologic relationships of selenium and Keshan disease. Chin Med J 1979,92477. 76. Jochum F, et al. Effects of a low selenium state in patients with phenylketonuria. Acta Paediatr 1997;86:775-777. 77. Gallagher ML, et al. Selenium levels in new growth hair and in whole blood during injection of a selenium supplement for six w ~ k sNutr . Res 1984;4577-582. 78. Terada A, et al. Selenium administration to a ten-year-old patient receiving long-term total parenteral nutrition (TI"):changes in selenium concentration in the blood and hair. J Trace Elem Med Biol 1998;lOl-5. 79. Maugh TH II. Hair a diagnostic tool to complement blood serum and urine. Science 1978;2021271-1273. 80.Wright JV,Severtson RB. Observations on the interpretations of hair mineral analysis in human medicine. J Intl Acad Prev Med 1982;April:13-16. 81. Pekamk RS, et al. Abnormal cellular immune responses during acquired zinc deficiency.Am J Clin Nutr 1979;321466-1471. 82. Ward NI.Assessment of zinc status and oral supplementation in anorexia nervosa. J Nutr Med 1990;1:171-177. 83. Gibson Rs, et al. Growth in children from the Wosera subdistrict, Papua New Guinea, in relation to energy and protein intakes and zinc status. Am J Clin Nutr 1991;53:782-789. 84. Zachwieja Z, et al. Evaluation of zinc status in children's hair. Biol Trace Elem Res 1995;47141-145. 85. Bales CW, et al. Zinc, magnesium, copper and protein concentrations in human saliva: age- and sex-related differences. Am J Clin Nutr 1990;51:%2-469. 86. Strain WH, Pones WJ. Zinc levels of hair as tools in zinc metabclism. In Prasad A, ed. Zinc metabolism. Springfield, I L Charles C Thomas, 1966363. 87.Fmland-Graves JH, Bodzy PW, Eppright MA. Zinc status of vegetarians. J Am Diet Assoc 1980;77:655-661. 88. Piccinini L, et al. A case-control study on selenium, zinc, and copper in plasma and hair of subjects affected by breast cancer and lung cancer. Biol Trace Elem Res 1996;51:23-30. 89. Varkonyi A, et al. Coeliac disease: always something to discover. Scand J Gastroenterol Suppl1998;228:122-129. 90. Ashraf W, et al. Utilization of scalp hair for evaluating epilepsy in male and female groups of the Pakistan population. Sci Total Environ 1995;164:69-73. 91. Ilhan A, et al. Serum and hair trace element levels in patients with epilepsy and healthy subjects: does antiepileptic therapy affect the element concentration of hair? Eur J Neurol 1999;6705-709.

92. Bradfield RB, Hambidge Kh4. Problems with hair zinc status as an indicator of body zinc status. Lancet 1980;1:363. 93. Anonymous. Zinc supplementation in healthy short children. Int Clin Nutr Rev 1984;4:28. 94. Perrone L, et al. Long-term zinc and iron supplementation in children of short stature: effect of growth and on trace element content in tissues. J Trace Elem Med Biol1999;1351-56. 95. Hambidge KM, et al. Zinc nutrition of preschool children in the Denver Head Start program. Am J Clin Nutr 1976;29734-738. 96. Weber CW, et al. Trace elements in the hair of healthy and malnourished children. J Trop Pediatr 1990;36:230-234. 97. Gibson RS, et al. A growth-limiting, mild zinc-deficiency syndrome in some southern Ontario boys with low height percentiles. Am J Clin Nutr 1989;491266-1273. 98. Srinivas M, et al. Association between lower hair zinc levels and neural tube defects. Indian J Pediatr 2001;68:519-522. 99. Rathi SS, et al. Zinc levels in women and newborn. Indian J Pediatr 1999;66:681-684. 100. Greger JL, Geissler AH. Effects of zinc supplementation on taste acuity of the aged. Am J Clin Nutr 1978;31:633-637. 101. Sandstead HH, et al. Effects of repletion with zinc and other micronutrients on neuropsychologic performance and growth of Chinese cluldren. Am J Clin Nutr 1998;68:4705475S. 102. Clanet P, et al. Effects of some cosmetics on copper and zinc concentrations in human scalp hair. Clin Chem 1982;282450-2451. 103. McKenzie JM. Content of zinc in serum,urine, hair, and toenails of New Zealand adults. Am J Clin Nutr 1979;32570-579. 104. Heinersdorff N, Taylor TG. Concentration of zinc in the hair of schoolchildren. Arch Dis Child 1979;54:958-960. 105. Smit Vanderkooy PD, Gibson RS. Food consumption patterns of Canadian preschool children in relation to zinc and growth status. Am J Clin NU&1987;45:609-616. 106. Meng Z. Age- and sex-related differences in zinc and lead levels in human hair. Biol Trace Elem Res 1998;61:79-87. 107. Weber CW, Pearson PB, Nelson GW. Mineral levels in hair of malnourished children. Fed Proc 1980;39:551. 108. Saner G. Hair trace element concentrations in patients with protein-energy malnutrition. Nutr Rep Int 198532:263-268. 109. Erten J, et al. Hair zinc levels in healthy and malnourished children. Am J Clin Nutr 1978;31:1172. 110. Hogan SE. Dietary intake and hair zinc status of persons with severe physical and developmental disabilities. Nutr Res 1996;16 401412. 111. Taneja SK, Mahajan M, Arya P. Excess bioavailability of zinc may cause obesity in humans. Experientia 1996;52:31-33. 112. Taneja SK, et al. Assessment of copper and zinc status in hair and urine of young women descendants of NIDDM parents. Biol Trace Elem Res 1998;62:255-264. 113. Bisse E, et al. Hair iron content: possible marker to complement monitoring therapy of iron deficiency in patients with chronic inflammatory bowel disease? Clin Chem 1996;42:1270-1274. 114. Beutler E. Hair iron content possible marker to complement monitoring therapy of iron deficiency in patients with chronic inflammatory bowel disease? Clin Chem 1997;43:1099-1100. 115. Bailey DN. Drug screening in an unconventional matrix: hair analysis. JAMA 1989;262:3331. 116. Bialkowska M, et al. Hair zinc and copper concentration in survivors of myocardial infarction. Ann Nutr Metab 1987;31: 327-332. 117. Femandez-Britto JE, et al. Coronary atherosclerosis and chemical trace elements in the hair. A canonical correlation study of autopsy subjects, using an arthrometric system and the X-ray fluorescence analysis. Zentralbl Pathol 1993;139:61-65. 118. Miekeley N, Dias Cameiro MT, da Silveira CL. How reliable are human hair reference intervals for trace elements? Sci Total Environ 1998;218:9-17.

Hair Mineral Analysis 119. Druyan ME, et al. Determination of reference ranges for elements in human scalp hair. Biol Trace Elem Res 1998;62:183-197. 120. Austin 5. Hair analysis: a reappraisal. NCNM Rev 1982;3:21. 121. Sakai T, Wariishi M, Nishiyama K. Changes in trace element concentrations in hair of growing children. Biol Trace Elem Res 2000;7743-51. 122. Perrone L, et al. Trace elements in hair of healthy children sampled by age and sex. Biol Trace Elem Res 1996;51:71-76. 123. Nowak B, Kozlowski H. Heavy metals in human hair and teeth the correlation with metal concentration in the environment. Biol Trace Elem Res 1998;62213-228. 124. Tommaseo Ponzetta M, et al. Trace elements in the human scalp hair and soil in Irian Jaya. Biol Trace Elem Res 1998;62:199-212. 125. Batzevich VA. Hair trace element analysis in human ecology studies. Sci Total Environ 1995;164:89-98. 126. Spilker BA, Maugh TH 11. How useful is hair analysis? J Energy Med 1980;1:15-19.

127. Attar KM, Abdel-Aal MA, Debayle P. Distribution of trace elements in the lipid and non lipid matter of hair. Clin Chem 1990;36:477-480. 128. Senofonte, Violante N, Caroli 5. Assessment of reference values for elements in human hair of urban schoolboys. J Trace Elem Med Biol2000;146-13. 129. Taylor A. Usefulness of measurements of trace elements in hair. Ann Clin Biochem 1986;23:364-378. 130. Rivlin RS.Misuse of hair analysis for nutritional assessment. Am J Med 1983;75:489-493. 131. Hambidge KM. Hair analyses: worthless for vitamins, limited for minerals. Am J Clin Nutr 1982;36943-949. 132. Steindel SJ, Howanitz PJ. The uncertainty of hair analysis for trace metals. JAMA2001;285:83-85. 133.Klevay LM, et al. Hair analysis in clinical and experimental medicine. Am J Clin Nutr 1987;46:233-236.

Heidelberg pH Capsule Gastric Analysis Stephen Barrie, ND CHAPTER CONTENTS Introduction

217

Physiology of Digestion in the Stomach

Interpretation 218 217

Procedure 218 Equipment 218 Methods 218

Clinical Application Indications 219 Aging 219 Conclusion

INTRODUCTION Proper digestion is a prerequisite for optimum health, and incomplete or disordered digestion can be a major contributor in the development of many diseases. The problem is not only that ingestion of the best nutritional substances may be of little benefit when breakdown and assimilation are inadequate, but also that incompletely digested macromolecules can be inappropriately absorbed into the systemic circulation. This process can lead to various immune complex deposition diseases and is now theorized to be an integral part of the etiology of food allergies. Adequate gastric hydrogen chloride (HC1) is also necessary for protection of the gastrointestinal tract from ingested pathogens and for the maintenance of proper bowel flora. A healthy flora is known to be important for proper immune function, vitamin absorption, and the prevention of opportunistic infections such as Cundidu ulbicuns in the gut. The Heidelberg gastric analysis technique was developed to measure the hydrogen ion concentration (pH) of the digestive tract and determine the acid secretory ability of the parietal cells. Its use of radiotelemetry allows the gathering of this important information in a convenient and accurate manner. The Heidelberg pH capsule system had its origin about 50 years ago at Heidelberg University in Germany. In research sponsored by Telefunken, a West German electronics firm, the inventor H.G. Noeller studied gastric acidity in 10,000 people. Since then, about 140 studies, according to a PubMed inquiry, have used the Heidelberg system to investigate various aspects

219

220

of Physicians and researchers now use this technique for measuring the pH of the digestive system.

PHYSIOLOGY OF DIGESTION IN THE STOMACH The epithelium of the stomach contains many gastric glands. These tubular glands consist of parietal, chief, and mucous cells. The antral portion of the stomach produces the digestive hormone gastrin, the release of which is stimulated by the following: Vagal nerve stimulation The physical bulk of the ingested food distending the stomach Partially digested proteins After gastrin is absorbed into the bloodstream, it is carried to the gastric glands, where it stimulates the parietal cells to produce hydrochloric acid and, to a lesser extent, the chief cells to produce digestive enzymes (such as pepsin and intrinsic factor). With adequate stimulation, the parietal cells increase their production of HC1 by as much as eightfold. When the pH of the stomach reaches about 2, the gastrin mechanism becomes blocked and feedback causes the parietal cells to decrease production of HC1. This concentration of hydrogen ions (by a factor of 100,000) is an energy-dependent process. Dietary protein is composed of amino acids held together by peptide linkages. Pepsin A, the major gastric protease, cleaves these in the stomach and is most active at pH values of between 2 and 3. It is inactive at a

217

Supplementary Diagnostic Procedures

pH of 5 and above. Consequently, in order to have any significant digestive effect in the stomach, the gastric juices must be acidic. Trypsin (a protein-splitting enzyme secreted by the pancreas) completes the process, yielding amino acids and dipeptides. The biochemical messenger that stimulates this pancreatic secretion is the acidic bolus of food moving from the stomach into the duodenum.

PROCEDURE Equipment The Heidelberg system consists of the following equipment: Radiotelemetry capsule-a hard plastic capsule (about 2 c m long x 0.8 cm in diameter) that contains a miniature radio transmitter, a pH sensing device, and a saline-activated battery. Waistband antenna-receives the signal from the capsule and relays it to the receiver. Receiver/recorder-receives and translates the signal. The pH reading is displayed on a meter and recorded by a continuous printer for a permanent record. The receiver also contains a calibration probe used to calibrate each capsule with known pH 1and 7 solutions. Heater block-maintains the calibrating solutions at 37" C.

Methods The test can be conducted in two ways: the tethered capsule repeat challenge and the flow-through method. Each gives different information and has its advantages and disadvantages. For both procedures, the test begins after the patient has fasted (food and liquid) for 8 hours.

The Tethered Capsule Repeat Challenge In this procedure, the capsule is tethered so that it remains in the stomach while the stomach is challenged by the ingestion of a saturated sodium bicarbonate solution (NaHC03,i.e., baking soda).8The challenge solution triggers a rise in stomach pH and a subsequent attempt by the parietal cells to reestablish appropriate acidity. The majority of people have a normal initial pH of between 1 and 2.3. Abnormalities of stomach secretions are usually found only after the stomach is challenged. (A more involved protocol can be found in Wright.*) The procedure is as follows: 1. The waistband antenna is fastened around the patient's waist and the receiver/recorder is turned on and calibrated. 2. The patient swallows the capsule, which is attached to a 1-m-long, thin cotton thread (a small amount of distilled water is allowed). The pH reading typically

starts at 7 and falls toward 1. After about 5 minutes, the capsule reaches the bottom of the stomach (which normally displays a pH of between 1 and 2) and the remaining thread is taped to the cheek in order to prevent movement of the capsule out of the stomach and into the intestine. 3. If the fasting pH is normal, the patient swallows the first challenge of 5 ml of the alkaline solution. Within 30 seconds, the pH normally rises to 7 and the patient is asked to lie down on his or her left side (to keep the stomach contents in as long as possible). 4. If stomach function is normal and acid is secreted sufficiently in response to the alkali challenge, the pH retums to normal (between 1and 2) within 20 minutes. 5. The challenge is repeated up to four times, as long as the response time is within 20 minutes.

Flow-Through Capsule In this procedure, the capsule is not tethered to a thread and is allowed to move freely from the stomach into the duodenum and the rest of the small intestine. The proponents of this method claim that this allows measurement of the gastric emptying time and intestinal pH, both of which are important parameters.

INTERPRETATION Results may be classified as normal, hypochlorhydria, achlorhydria, and hyperchlorhydria.

Normal. The patient successfully reacidifies after four challenges (Figure 21-1). Number 1 shows the capsule entering digestive tract; number 2 shows the capsule reaching bottom of stomach and alkaline challenge occurring; and number 3 shows a pH rise after swallow and subsequent reacidification within 20 minutes. Hypochlorhydriu. The patient requires more than 20 minutes to reaciddy (Figure 21-2). Number 4 shows a pH of 1

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I

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Normal Heidelberg gastrogram.

Heidelberg pH Capsule Gastric Analysis

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-1

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3 2 1 I

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Figure 21-2

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Hypochlorhydric gastrogram.

The Heidelberg pH capsule system offers a convenient and accurate outpatient testing system to clinicians interested in evaluating gastric function. Hydrochloric acid, pepsin, and intrinsic factor are involved directly in digestion and contribute to the chemical changes in the intestines that assist in the absorption of many nutritional factors. For example, vitamin B12 absorption requires intrinsic factor, while zinc, calcium, and iron are poorly assimilated when gastric acidity is OW.^-^^

INDICATlONS Many symptoms and signs suggest impaired acid secretory ability, and a number of specific diseases have been found to be associated with achlorhydria and hypochlorhydria (particularly HLA-B8-related autoimmune diseases). These are listed in Boxes 21-1, 21-2, and 21-3.12-2327

Aging

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Achlorhydric gastrogram.

Numerous studies have shown that acid secretory ability decreases with age. Low stomach acidity has been found in more than half of those older than age 60.24,25 One study of the elderly found that their tissue nutrient levels could be saturated only through the use of intramuscular supplementation; oral supplementation was ineffective. The authors speculated that this was due to atrophy of various digestive organs.26

being reached after 30 minutes. Note that on the third challenge, the pH comes back only to about 5.

Achlorhydriu. The patient's stomach shows little acid secretion and is not able to secrete enough acid to bring the pH below 4, even on the first challenge (Figure 21-3). The pH remains at about 4.2 for almost 2 hours. Hyperchlorhydria. The gastrogram would show extremely rapid reacidification (within 5 minutes) after each challenge. Depending on specific curve components, some investigators believe that mucous quantity, fresh or chronic ulcers, and acute gastritis conditions can at times be identified.

CLINICAL APPLICATION Although much is said about hyperacidity conditions, probably more sigruficanthealth problems are caused by hypochlorhydria and achlorhydria. Direct measurement of gastric acid secretion through intubation and aspiration is uncomfortable and unacceptable to many patients.

Bloating, belching, burning, and flatulence immediately after meals A sense of "fullness" after eating Indigestion,diarrhea, or constipation Multiple food allergies Nausea after taking supplements Itching around the rectum Modified from Wright JV. Healing with nutrition. Emmaus, PA: Rodale Press, 1985.

Weak, peeling, and cracked fingernails Dilated capillaries in the cheeks and nose (in nonalcoholics) Postadolescent acne Iron deficiency Chronic intestinal parasites or abnormal flora Undigested food in stool Chronic candidal infections Upper digestive tract gassiness Modified from Wright JV. Healing with nutrition. Emmaus. PA: Rodale Press, 1985.

1. Addison's disease 2. Asthma 3. Celiac disease 4. Dermatitis herpetiformis 5. Diabetes mellitus 6. Eczema 7 . Gallbladder disease 8. Graves disease 9. Chronic autoimmune disorders 10. Hepatitis 11. Human immunodeficiency virudacquired immunodeficiency syndrome 12. Chronic hives

13. Helicobacter pylori infection 14. Lupus erythematosus 15. Myasthenia gravis 16. Osteoporosis 17. Pernicious anemia 18. Psoriasis 19. Rheumatoid arthritis 20. Rosacea 21. Sjogren syndrome 22. Thyrotoxicosis 23. Hyperthyroidismand hypothyroidism 24. Vitiligo

Data from references 13-23 and 27.

The Heidelberg pH capsule system is an effective and convenient method to determine gastric acid secretory ability under conditions simulating ingestion of food.

Results are extremely valuable in identifying the large number of people who have impaired secretion function. Ramificationsof impaired acid secretion are widespread. This technology has become an accepted method of assessing gastric pH in several research settings.

1.Noeller HG. The use of a radiotransmitter capsule for the measurement of gastric pH. German Medical Monthly 1961;63. 2. Noeller HG. Results of examinations of stomach functions with the endo-radio capsule-a new appliance for assisting stomach diagnosis. Fortschritte der Medizin 1962;80:351-363. 3. Steinberg WJ, Mina FA, Pick PG. Heidelberg capsule. In vitro evaluation of a new instrument for measuring intragastric pH. J Pharm Sci 1965;54:772-778. 4. Stavney LS,Hamilton T, S i n s W. Evaluation of the pH-sensitive telemetry capsule in the estimation of gastric secretory capacity. Am J Dig Dis 1966;ll:lO. 5. Dabney R, Yarbrough I, McAlhany JC. Evaluation of the Heidelberg capsule method of tubeless gastric analysis. Am J Surgery 1969;117:185. 6. Andres MR, Bingham JR. Tubeless gastric analysis with a radiotelemetry pill. CMA 1970;1021087-1089. 7. Mojaverian P, Ferguson RK, Vlasses PH, et al. Estimation of gastric residence time of the Heidelberg capsule in humans. Gastroenterology 1985;89:392-397. 8. Wright J. A proposal for standardized challenge testing of gastric acid secretory capacity using the Heidelberg capsule radiotelemetry system. J John Bastyr Coll Nat Med 1979;l:S-11. 9. Brewer GJ. Effect of intragastric pH on the absorption of oral zinc acetate and zinc oxide in young health volunteers. J Parent Ent N u b 1995;19:393-397. 10.Mahoney AW, Hendricks DG. Role of gastric acid in the utilization of dietary calcium by the rat. Nutr Metab 1974;16: 375-382. 11. Jacobs A, Rhodes J. Gastric factors influencing iron absorption in anaemic patients. Scan J Hematol1967;4:105-110. 12. Wright JV.Healing with nutrition. Emmaus, PA Rodale Press, 1985. 13.Howitz J, Schwartz M. Vitiligo, achlorhydria, and pernicious anemia. Lancet 1971;i:1331-1334.

14. Bray GW. The hypochlorhydria of asthma in childhood. Br Med J 1930;i:181-197. 15. Hosking DJ, Moody F, Stewart IM, et al. Vagal impairment of gastric secretion in diabetic autonomic neuropathy. Br Med J 1975;1588-590. 16. Rabinowitch IM.Achlorhydria and its clinical significance in diabetes mellitus. Am J Dig Dis 1949;18:322-333. 17. Carper WM, Butler TJ,Kilby JO, et al. Gallstones, gastric secretion and flatulent dyspepsia. Lancet 1967;1413-415. 18. Rawls WB, Ancona VC. Chronic urticaria associated with hypochlorhydria or achlorhydria. Rev Gastroent 1950;0ct:267-271. 19.Gianella RA, Broitman SA, Zamcheck N. Influence of gastric acidity on bacterial and parasitic enteric infections. Ann Intern Med 1973;78:271-276. 20. De Witte TJ, Geerdink PJ, Lamers CB. Hypochlorhydria and hypergastrinemia in rheumatoid arthritis. Ann Rheum Dis 1979;38:14-17. 21.Ryle JA, Barber HW. Gastric analysis in acne rosacea. Lancet 1920;ik1195-1196. 22.Ayres S. Gastric secretion in psoriasis, eczema and dermatitis lierpetiformis. Arch Derm 1929;July:854-859. 23. Dotevall G, Walan A. Gastric secretion of acid and intrinsic factor in patients with hyper and hypothyroidism. Acta Med Scand 1969i186529-533. 24. Rafsky HA, Weingarten M. A study of the gastric secretory response in the aged. Gastroenterology 1946;May:348-352. 25. Davies D, James TG. An investigation into the gastric secretion of a hundred normal persons over the age of sixty. Brit J Med 1930;i:1-14. 26. Baker H, Frank 0, Jaslow SP. Oral versus intramuscular vitamin supplementation for hypovitaminosis in the elderly. J Am Geriat Soc 1980;48:42-45. 27. Shelton MJ, Adams JM, Hewitt RG, Morse GD. Previous infection with Helicobacter pylori is the primary determinant of spontaneous gastric hypoacidity in human immunodeficiency virus-infected outpatients. Clin Infect Dis 1998;27:739-745.

CONCLUSION

Immune Function Assessment Aristo Vojdani, PhD, MT CHAPTER C O N T E N T S Introduction 221 Recent Advances in Immune Function Assessment 222 Disorders of the Immune System Underlie Many Diseases and Disorders 223 Monocyte and Lymphocyte Enumeration 223 Flow Cytometry in Clinical Medicine 223 Monoclonal Antibodies for Routine Clinical Enumeration of Lymphocyte Subpopulation 224 Measurement of Activation Molecules and Lymphocytes 226 Summary of Lymphocyte Enumeration 227 Assessment of Monocyte and Macrophage Function 228 Production of Interleukin-1 by Monocytes 228 Bacterial Phagocytosis and Killing by Monocytes 228

INTRODUCTlON The human immune response depends on a diverse army of cells and molecules working in concert to protect the body against invaders. The ultimate target of all immune responses is an antigen, which is usually a foreign molecule from an invading microorganism or cancer cell. The immune system is composed of essentially two aspects: nonspecific defenses, called cell-mediated immunity, and specific defenses, called humoral immunity. Cell-mediated immunity, the first strike force, involves special white cells (typicallyT lymphocytes and neutrophils) that immediately attack the invader and either prevent its entry into the body or, if the invader manages to gain a foothold, quickly destroy it. Cellmediated immunity is especially important in the body's ability to resist infection by yeasts (such as Candida albicans), fungi (such as those that cause athlete's foot), parasites (worms), and viruses (such as herpes simplex and Epstein-Barr).Cell-mediated immunity is also critical in protecting against the development of cancer and is commonly involved in allergic reactions.

Measurement of Bacterial Phagocytes by Flow Cytometry 229 Measurement of Oxidative Burst in Monocytes 229

Assessment of T- and B-Cell Function 230 Lymphocyte Proliferation Assay Procedure 230 Clinical Application 232 Function of Helper TType 1 and 2 Cells 232 Clinical Application 233 Natural Killer Cell Cytotoxicity 233 Killer T Cell on the Warpath 233 Characteristics of Natural Killer Cells 233 Determination of Natural Killer Activity 234 Calculation of Results in Natural Killer Activity Assay 234 Natural Killer Cell Activity in Human Diseases 234 Conclusion 236

Humoral immunity involves sensitized white cells and antibodies. Formed to uniquely match the surface of invaders, the humoral immunity team either damages them directly (sometimes by making them clump together) or alerts and activates other white cells to attack the pathogen. Although powerful, these sensitized white cells and antibodies are tailored to suit a specific invader, so they take several days to develop. Specialized antigen-presenting cells (APCs), such as macrophages, roam the body, ingesting the antigens they find and fragmenting them into antigenic peptides. This activates circulating T cells that recognize the specific antigen. For a cell-mediated immune response to occur, antigen-specific T cells must be stimulated. Interleukin-1 (IL-l), a product of activated macrophages, enhances this T-cell response. T-cell stimulation results in the clonal proliferation of helper T cells, cytotoxic (killer) T cells, suppressor T cells, and memory T cells. When activated, T cells produce and secrete a wide variety of immune chemicals, including IL-2, interferon-gamma (IFN-y), and B-cell growth factors. These chemicals, known as cytokines, recruit and activate nonspecific 221

Supplementary Diagnostic Procedures

destructor cells such as natural killer (NK)cells, polymorphonuclear phagocytes (PMNs), and macrophages. Cytokines also stimulate the further growth and differentiation of T and B cells. In the presence of antigen and activated T cells, B cells rapidly proliferate and differentiate into plasma cells. Plasma cells secrete antibody into the blood and lymph. The antibody bind5 to the antigen that stimulated its production. This response, also antigenspecific and known as humoral immunity, is shown in Figure 22-1.

Recent Advances in Immune Function Assessment Unraveling the immune system's intricacies and finding better methods for diagnosing and treating its disorders are two of the most formidable challenges facing contemporary medicine. The best way to meet these challenges is through painstaking research that draws upon and combines the expertise of diverse disciplines. Only through leadership in research can a brighter future be anticipated by the estimated 65 million Americans with dysfunctional immune systems. Research into the immune system, how it functions, and its relationship to health and disease is therefore vital to identdymg the cause and potential cure of the immunologically mediated diseases.

Figure 22-1

In the last several years, immunology as a section of the diagnostic clinical laboratory has increased tremendously in scope. New knowledge about cellular immunity, including lymphocyte subsets and advances in protein chemistry, bacteriology, and cell biology, has improved our understanding of human immunopathology and has made available clinically useful antigens and antibodies with great specificity and sensitivity. The developing technologies of monoclonal antibody production and genetic engineering have had tremendous impact on the quality of reagents available to research and clinical laboratories. Recognizing the need for research as well as the importance of education, the National Coalition on Immune System Disorders (NCISDs)was established in 1987 to represent the millions of adults and children afflicted with immune system-related disorders and diseases. Since 1987, significant achievements made in the field of immunology have contributed to the advancement of biomedical science. On the basis of these achievements, "our science is maturing, and the power of using the immune system for diagnosis and treatment of diseases is in place."'-'* Some of these developments of most interest are the ability to monitor the involvement of helper T cells TH1 and TH2 and suppressor T cells Tsl and TG in immune dysregulation, the lymphokines and

Humoral immunity. Ig, Immunoglobulin; IL-2, interleukin-2.

Immune Function Assessment

cytokines produced by these lymphocyte subsets, and the capability of measuring these lymphocytes at the message level as well as at the protein level. All of these developments are now possible, thanks to two major discoveries of the 1970s and 1980s in the field of molecular immunology: the monoclonal antibody and the polymerase chain reaction. Polymerase chain reaction (PCR) technology enables laboratories to detect genomes of many infectious agents at the level of femtograms. This makes PCR the most sensitive method of detection for viral and bacterial genomes in a clinical setting. Because many infectious agents have been implicated in immune dysregulation and immune dysfunction, early detection by PCR helps in the treatment of many immune disorders.

Disorders of the Immune System Underlie Many Diseases and Disorders Disorders and diseases of the immune system affect the health and quality of life of approximately one in four Americans.The data in Box 22-1 exempldy the magnitude of this problem. Listing the incidence of these immune dysfunction diseases, however, does not begin to estimate their costs in terms of number of work and school days lost, cost of medication, hospitalization, diminished quality of life, and involvement of family and friends during illness. Although these diseases differ in terms of their severity, most have their roots in an immune system that has either failed to develop or gone awry. The integrity of the immune system can be assessed in two different ways: by evaluation of cell number and by testing cell function.

MONOCYTE AND LYMPHOCYTE ENUMERATION The number and functional capacity of circulating peripheral blood leukocytes reflect the overall state of immune competence of an individual. In a variety of

73 million have chronic respiratory problems

60 million have asthma or allergic disease 43 million, of which 250,000are children, have arthritis 20 million have diabetes 2 million have ileitis and colitis

About 1 million are infected with the HIV virus 1.4million have systemic lupus erythematosus(9:l are women) 419,000have multiple sclerosis More than 200,000have acquired immunodeficiency syndrome (AIDS) (the U.S. Center for Disease Control has counted more than 900,000AIDS cases since 1981 and 924,060deaths; as of 1999,between 850,000and 950,000Americans were alive with human immunodeficiency virus infection) 250,000have a primary immune deficiency disorder

clinical situations, tests for granulocyte, lymphocyte, and monocyte number and function have become routine in the diagnosis of disease and the monitoring of immunosuppressive and immunorestorative treatments. In the early 1980s, flow-cytometric tests for lymphocyte subsets began to take their place as useful diagnostic and prognostic indicators in several clinical situations, including bone marrow and organ transplantation, diagnosis of leukemias and lymphomas, and evaluation of immune deficiency disorders. Flow-cytometric measurements allow the enumeration of different types of lymphocytes that are known to have distinctive functional activities.1-3 The techniques available to enumerate lymphocytes of various types have improved as a result of the development of monoclonal antibodies against cell surface differentiation antigens. These reagents are especially valuable when used in conjunction with flow cytometry to define lymphocyte cell surface phenotypes. T lymphocytes, B lymphocytes, and NK cells, as well as subsets of these populations, can be discriminated. The close correlation of lymphocyte phenotype with function results in part from the fact that some of the molecules in the cell membranes of lymphocytes play a role in the specific functions that these cells perform. Such functions are recognition of antigen or other cells in the immune system, regulation of the immune response, cytotoxicity, and a variety of other cellular interactions. Many of the monoclonal antibodies against lymphocytes react with molecules that participate in one or more of these lymphocyte functions. Other monoclonal antibodies that are valuable in characterizing lymphocyte subpopulations react with receptors for soluble molecules that regulate the immune system. Overall, the cell surface phenotype of lymphocytes may reflect their lineage, differentiation state, and immunologic Enumeration of lymphocytes is done by the most reliable technique-flow cytometry.

Flow Cytometry in Clinical Medicine Flow cytometry, in conjunction with monoclonal antibody staining, has a number of advantages over alternative methods of lymphocyte enumeration. The technique is quick, precise, reproducible, and quantitative. Furthermore, it can be subjected to stringent quality control and standardization. The lymphocyte population of human peripheral blood is composed of three cell types: T (thymusderived), B (bone marrow-derived), and null cells. These cells are morphologically indistinguishableon microscopy but can be identified from characteristic antigenic differences in their cell membrane^.^,^ Flow cytometry is a technique that enables rapid, multiparameter, correlated analysis of a large number of single cells. This method has been of particular importance

in clinical immunology when used for the identification of human lymphocyte subsets based on the expression of cell surface antigens. This application has expanded over the past decade as a result of the development of specific monoclonal antibodies with specificity for lymphocyte surface antigens. For preparation of flow cytometry samples, whole blood lysis is the most common technique used in clinical laboratories. This method consists of mixing a fixed volume of whole blood with one or more directly conjugated monoclonal antibodies, then incubating the mixture at a designated temperature and time. Next, the red blood cells are lysed with the use of tris ammonium chloride or a hypotonic buffer. The sample is washed and then run into the flow cytometer, usually after being fixed in para formaldehyde to reduce the infectious risk of the sample and improves its ~tability.~ The LeucoGATE reagent is used to stain the first aliquot of whole blood from each subject with CD45 and CD14 monoclonal antibodies. The four parameters measured on this t u b e t w o light scatter and two fluorescence-allow the SimulSET software to determine an optimal light scatter "gate," which identifies the lymphccyte cluster in all subsequent tubes from the same sample. This LeucoGATE analysis identifies lymphocytes, monocytes, and granulocytes from a combination of antigen expression and light scatter characteristics (Figure 22-2). The use of this automated multiparameter procedure for setting the lymphocyte acquisition gate provides a sigruficant advantage over operator-defined light scatter gating, because there is some overlap between the different cell lineages when light scatter is used as the sole criterion to identify lymphocytes. Furthermore, with

LeucoGATE analysis, uniform and reproducible acquisition gating is possible, and consistently more than 95% of the total lymphocytes can be located and evaluated with less than 10%contamination by debris, granulocytes, or monocytes. Macrophages play a central role in cell-mediated immunity because they are involved both in the initiation of responses as APCs and in the effector phase as inflammatory, tumoricidal, and microbicidal cells. Through the use of CD14 monoclonal antibodies, it is possible to define the percentage of monocytes in the blood.

Monoclonal Antibodies for Routine Clinical Enumeration of Lymphocyte Subpopulation The nomenclature adopted by the International Leukocyte Differentiation Antigen Workshop is used in this chapter to designate the antigens with which various monoclonal antibodies r e a ~ t . ~Monoclonal -l~ antibodies with the following cluster designations (CDs) are used to determine the lymphocyte subpopulation.

CDll for Identification of T Lymphocytes The CD4 antigen is associated with the E-rosette receptor and has a molecular weight of 50 kilodaltons (kDa). The T11 antigen is normally present on more than 9%of thymocytes and 100% of E-rosetting-positive lymphocytes, including T lymphocytes and a fraction of null cells. It is also found on more than 90% of tumor cells from patients with T-cell acute lymphoblastic leukemia (ALL) and Sezary syndrome, and in a rare leukemic population of myeloid lineage. The CD4 antigen is not present on non-T-cell ALL cells.

Figure 22-2 Lymphocyte gates set using LeucoGATE. Lymphocyte gates for data acquisition were established using SimulSET software. Acquisition gates are defined by combining the fluorescence parameters from the LeucoGATE tube (A) with the forward- and right-angle light-scattering parameters (B). The light scatter gate (region 5 , panel B) was set to include at least 95% of the lymphocytes. The cells of other lineages that also were included in this gate can be identified and enumerated from their characteristic immunofluorescence(C). Lymphocytes are confined to region 1, monocytes are found in region 2, and granulocyte and debris fall in regions 3 and 4, respectively. The analysis of subsequent tubes can be corrected by using the numbers of cells with each of the regions defined in C, to obtain more precise values for enumeration of lymphocyte subsets.

Immune Function Assessment

Clinical relevance. The CD4 monoclonal antibody is used to quantitate total T lymphocytes in circulating blood (both mature and immature) and to determine T-cell lineage of lymphoid tumor cells. Decreased numbers of T lymphocytes are found in patients with autoimmune disorders, including multiple sclerosis (MS), systemic lupus erythematosus (SLE), and eczema. Thymic aplasia (DiGeorge syndrome) is associated with a decreased number of T lymphocytes. Increased numbers of T lymphocytes are noted in patients with acute infectious mononucleosis and some forms of acquired agammaglobulinemia because of the presence of activated suppressor cells.14

CD19 for Identification of B Lymphocytes The CD19 antigen defines a bimolecular structure of 40 and 80 kDa. The specificity of the CD19 monoclonal antibody for surface immunoglobulin of the B lymphocyte was determined through removal of the CD19-positive population (CD19+) from peripheral blood by sorting the cell population that is induced to differentiate into immunoglobulin-secreting plasma cells in a pokeweed mitogen-driven system. The CD19 monoclonal antibody recognizes the CD19 antigen on human B lymphocytes. The CD19 antigen is expressed on all normal B lymphocytes, follows the Ia antigen in B-cell ontogeny, and is only lost prior to the plasma cell. The CD19 antigen is present on all B cells isolated from lymphoid organs and on approximately 5% of normal adult bone marrow cells. In addition, CD19 is expressed on greater than 95% of non-T-cell ALL cells, and on 90% of B-cell lymphomas and B-cell chronic lymphocytic leukemia (CLL)cells, but is not expressed on T-cell or myeloid tumors. The CD19 antigen appears to be the earliest B cell-associated antigen demonstrated in fetal tissues.

Clinical relevance. The CD19 monoclonal antibody appears to be useful in defining the cellular lineage of non-T cells. ALL cells, chronic myelogenous leukemia (CML) blast crisis cells, non-T ALL cells, and CML blast crisis cells are reactive with this antibody, suggesting a B-cell origin for these tumor cells. The CD19 monoclonal antibody may also be useful in defining early B cells and in the study of immunodeficiency diseases.15

CD4 for Identification of Helper T Cells Two main types of T lymphocytes can be distinguished according to their function and surface proteins. These are the inducer/helper (CD4-t) and suppressor/cytotoxic (CD8+) T lymphocytes. The CD4 antigen has a molecular weight of 62 kDa. It is normally present on a majority of thymocytes (approximately 80%) and approximately 60% of peripheral blood T lymphocytes. The CD4+ lymphocytes play a central role in regulating the immune response. In peripheral blood, the CD4+ lymphocytes provide an

inducer function for T cell-T cell, T cell-B cell, and T cellmacrophage interaction. The CD4+ antigen reacts with the class I1 major histocompatibility complex (MHC) antigen on target cells.

Clinical relmance. Identification of abnormal levels of CD4+ lymphocytes may aid in the diagnosis and/or prognosis of immunodeficiencydiseases such as agammaglobuIinemia, thymic aplasia (DiGeorge syndrome), severe combined immunodeficiency, and acquired immunodeficiency syndrome (AIDS). Measurement of CD4+ lymphocytes may also aid in phenotyping certain T-cell leukemias. Examples of these diseases are adult T-cell leukemia/ lymphoma, T-cell ALL, and T-cell chronic leukemia. Infection with human immunodeficiency virus (HIV), the etiologic agent of AIDS,results in profound immunosuppression due predominantly to a selective depletion of the CD4+ lymphocytes that express the receptor for the virus (the T4 cell surface antigen). Progressive clinical and immunologic deterioration generally correlates with a falling CD4+ lymphocyte count.16

CD8 for Identification of Suppressor T Cells The CD8 antigen has a molecular weight of 76 kDa. It is normally present on a majority of thymocytes (approximately 80%) and approximately 30% to 35% of peripheral blood T lymphocytes. The CD8+ lymphocytes play a central role in regulating the immune response through suppressor and cytotoxic actions. The CD8 antigen reacts with the class I MHC antigen on target cells.

Clinical relevance. Identification of abnormal levels of CD8+ lymphocytes may aid in the diagnosis and/or prognosis of immunodeficiency diseases such as agammaglobulinemia, thymic aplasia (DiGeorge syndrome) and severe combined immunodeficiency. Measurement of CD8+ lymphocytes may also aid in phenotyping certain T-cell leukemias. Examples of these diseases are adult T-cell ALL and T-cell chronic leukemia. The finding that increased levels of CD8+ cells are associated with viral infections such as hepatitis B, Epstein-Barr virus, and cytomegalovirus infection may also be of diagnostic and/or prognostic significance.”

CDWCDS Ratio for Determination of Helper T Cell/Suppressor T Cell Ratio Disease-related changes in CD4+ and/or CD8+ lymphocyte levels may alter the CD4/CD8 ratio, or the ratio of inducer to suppressor/cytotoxic cells. As a result, CD4/CD8 ratios may also be useful as diagnostic and/or prognostic indicators of immune competence.

Clinical relevance. CD4/CD8 ratios in conjunction with CD4+ lymphocyte cell numbers have been the most widely used laboratory parameters for the evaluation of

Supplementary Diagnostic Procedures

AlDSrelated complex and AIDS. CD4/CD8 ratios fall toward zero in patients with advanced AIDS and no detectable levels of CD4+ lymphocytes. In such cases, CD8+ lymphocyte levels may be normal, increased, or decreased. Modulations in CD4/CD8 ratios and CD4+ and T8+ lymphocyte levels may occur in autoimmune diseases such as MS and SLE. Increased CD4/CD8 ratios and decreased numbers of CD4-t and CD8+ lymphocytes have been observed in patients with progressive (active) MS. The lymphocyte response pattern in SLE, however, appears to reflect clinical disease activity and the level of organ involvement in the SLE disease process. For example, high T4/T8 ratios and elevated CD4+ lymphocyte percentages have been found in patients with active/ inactive SLE who have multisystem disease, including lymphadenopathy, but little or no renal disease. High T4/T8 ratios but decreased percentages of CD&t lymphocytes have also been documented in similar patients with active SLE. Further, high CD4+ and low CD8+ lymphocyte percentages have been measured in patients with active SLE who have central nervous system disease but no renal disease. In contrast, low CD4/CD8 ratios and decreased CD4+ lymphocyte percentages have been noted in patients with active/inactive SLE, manifested as severe renal disease and/or thrombocytopenia. In other patients with active/inactive SLE, both low CD4+ and high CDW lymphocyte percentages have been recorded. Finally, normal CD4/CD8 ratios have been obtained in patients with widespread multisystem SLE, which often includes the renal and central nervous systems. Increased CD4/CD8 ratios with high CD4+ and low CD8+ lymphocyte percentages have been reported in patients with head and neck cancer who have elevated circulating immunoglobulin (lg)A and generalized hypergammaglobulinemia. Decreased CD4+ and increased CD8+ lymphocyte percentages without significant changes in CD4/CD8 ratios have been observed in patients with stable renal allograft function after transplantation. Similar findings have been reported in patients with B-cell CLL, except that CD4/CD8 ratios were decrea~ed.’”’~

CD4 and CD29 for Determination

of Helperhnducer Subpopulations of Lymphocytes The CD29 cell surface antigen has a molecular weight of 134 kDa and defines a common B1 subunit of the heterodimeric glycoprotein family called very late activation antigen (VLA). It appears on approximately 41% of unfractionated human T lymphocytes, 41% of CD4+ inducer lymphocytes, 43% of CD8+ suppressor / cytotoxic lymphocytes, 5% to 30% of B lymphocytes, and more than 30% of null cells, macrophages, and thymic lymphocytes. The CD29 antigen is not present

on granulocytes. The monoclonal antibody identifies the helper /inducer (CD4+CD29+)subpopulation of CD4 1ymphocytes. Research relevance. Disease-related changes in CD4+ lymphocyte levels may alter levels of the CD4+CD29+ helper/inducer and suppressor/inducer subpopulations. The presence of CD4+CD29+cells has been reported in the joints of patients with rheumatoid arthritis and may account for the inflammatory process. Decreased numbers of these cells have also been observed in HTV-positive patients in the early phases of infection. Accumulation of C W D 2 9 + cells in tissues has also been reported in patients with tuberculoid leprosy and MS.I9

CD16 and CD56 for Determination of Natural Killer Cells NKH-1 (CD56 and CD16) defines a human natural killer cell antigen with a molecular weight of 200 to 220 kDa. It is expressed on a subpopulation of peripheral blood large granular lymphocytes (LGLs) that demonstrate natural killer activity. More than 95% of cells capable of mediating spontaneous non-MHC-restricted cytotoxicity in peripheral blood are contained within the 10% to 12%of peripheral blood mononuclear cells (PBMCs) that express NKH-1. Seventy-five percent to 80% of NKH-1 cells coexpress CD3 and T-cell receptor gene products. This latter population, which represents approximately 2% of PBMCs in normal individuals, also mediates non-MHC-restricted cytotoxic activity. NKH-1 is not expressed on other T- or B-lymphocyte, monocyte, granulocyte, or erythrocyte populations. Research relevance. The NKH-1 antibody can aid in the detection and enumeration of NK cells in normal and disease states. For example, low numbers of NKH-l+T3cells have been found in patients with chronic fatigue syndrome. When used with T3 antibodies, NKH-1 can be used to define distinct subsets of non-MHC-restricted cytolytic cells within the NKH-1 population, namely, NKHlCD3- and NKH-1KD3-e. Also, this antibody can be used in the identification and enumeration of lymphoproliferative diseases involving NK cells and may be used in the purification of human NK cells and lymphokine-activated killer (LAK) cells.*O

MEASUREMENT OF ACTIVATION MOLECULES AND LYMPHOCYTES Many lymphocytes can be differentiated by measuring the level of activation markers on their surfaces, as discussed here.

CD25 antigen (Tuc). A single-chain glycoprotein with a molecular weight of 55 kDa, Tac is the low-affinity

Immune Function Assessment

receptor for IL-2. It is found on activated T and B cells, on activated macrophages, and on T-cell clones. It is not found on thymocytes, resting T cells, B cells, and null cells.

CD26 (TAI). TAl antigen has a molecular weight of 105 kDa and is a lymphocyte surface antigen. It is strongly expressed on activated human T cells and IL-2-dependent human T-cell lines and clones. It is also weakly expressed on a small fraction of peripheral blood T cells. This activation marker was found to be elevated in 80% of patients with chronic fatigue syndrome as well as a high percentage of patients with a history of exposure to toxic chemicals. CD69 antigen. CD69 antigen is a 60-kDa homodimer phosphorylated glycoprotein known as an activation inducer molecule (AIM). This structure contains two polypeptide chains of molecular weights 32 and 28 kDa. This activation antigen appears very early (before other activation antigens such as IL2-R) after T- or B-cell activation. It is also expressed by activated macrophages and by NK cells but is absent in resting lymphocytes. CD45RA epitope. The CD45RA epitope is present on all the CD45-restricted molecules in which the A axon is expressed. CDll recognizes some peripheral T cells, CD4+ T lymphocytes, and CD8-t T lymphocytes, but specifically nonnaive lymphocytes. The coexpression of CD4 and CD45RA antigens allows the identification of the suppressor/inducer subpopulation of CD4 lymphocytes. It also reacts with B cells, monocytes, and granulocytes. This marker was found to be elevated in patients with rheumatoid arthritis. CD45RO molecule. The CD45RO molecule is the 180-kDa isoform of the leukocyte common antigen. This isoform is the CD45-restricted form of the lowest molecular weight. CD45RO is a single-chain glycoprotein that is expressed by thymocytes, the CD4+ memory T-cell subset, and activated T cells. The CD45ROtcM T cells that provide the helper/inducer function have been found to be elevated in synovial tissue of patients with arthritis. CDlla antigen. CDlla antigen (leukocyte functionassociated molecule-1, or LFA-I) is the 180/95-kDa integrin aL-chain that is noncovalently associated with the 95-kDa CD19 (integrin p2). It promotes adhesion between lymphoid cells and the adhesion of lymphoid cells to the vascular endothelium. LFA-1 can interact with various ligands, including the intercellular adhesion molecules ICAM-1 (CD54), ICAM-2 (CD102), and ICAM-3 (CD50). CDlla antibodies have a strong reactivity with all leukocytes but do not recognize platelets. These antibodies react with most peripheral blood T and B cells and with a portion of monocytes and granulocytes.

CDllb antigen (Mud). Macl is the 165/95-kDa integrin aM chain that is noncovalently associated with CD18 (integrin p2). It has been identified as the C3bi complement receptor (CR3). As a member of the p2 integrin family of adhesion molecules, Macl mediates adherences of PMNs and monocytes to the endothelium. Additional CDllb ligands are ICAM-1 (CD54), factor X, fibrinogen, and endotoxin. CDllb antibodies react mainly with myeloid and NK cells. The Bear1 (Macl) antibody recognizes some peripheral blood lymphocytes and a subset of T cells (a portion of CDllb+ cells is also positive for CD8). It also reacts with granulocytes and monocytes. This population of CD8+CDllb+ lymphocytes is reported to be lower than normal in patients with chronic f a t i g ~ e ? l - ~ ~ 13 W A - D R antigen). The MHC class I1 HLA-DR antigen

I3 is expressed by human monocytes, macrophages, B lymphocytes, and activated T lymphocytes. Anti-I3 is used for classification and enumeration of Ia-positive B-cell lymphoproliferative malignancies (acute and chronic lymphocytic leukemias, non-Hodgkin lymphomas, etc.) and acute myelogenous leukemias as well as for identification of states of T-lymphocyte activation due to viral illnesses. Therefore, the number of HLADR+ cells is sigruficantly increased in patients with chronic fatigue syndrome.

CD38. A protein with a molecular weight of 45 kDa, CD38 is expressed on thymocytes, activated T cells, and plasma cells. Because of an increase in activated T cells in chronic fatigue syndrome, the population of CD8 lymphocytes that carry the CD38 receptor is significantly elevated."

Summary of Lymphocyte Enumeration Immunophenotyping by flow cytometry is common in most larger clinical laboratories. The application of this technology has moved forward in response to significant improvements in instrumentation and an increase in the availability of reagents. Properly performed, flow cytometry can identify lymphocyte subpopulations rapidly and accurately. The primary clinical uses of immunophenotyping are to quantitate CD4 T-cell counts in HIV infection and to assign lineage and/or monoclonality in leukemias and lymphomas. Additional uses are characterizing immune deficiency disorders, evaluating immune-mediated inflammatory diseases, and assessing patients before and after organ transplantation. Although certain surface antigens are associated with functional status, such as the isoforms of CD45 that appear to identdy naive (CD45RA) or memory (CD45RO) T cells, these classifications are not absolute and must not be considered determinants of cell function.

Supplementary Diagnostic Procedures Immunophenotyping is a means of identifying cells but it is not the equivalent of a functional evaluation. Therefore, for determination of functional leukocyte capacity, macrophage function, NK cytotoxic activity, and T- and B-cell function should be measured.21-26 In many patients, lymphocyte subpopulation numbers are normal, but their functional capacity for killing bacteria or tumor cells and reaction to antigens are completely abnormal. Hence, the major emphasis of this chapter is on the functional capacity of lymphocytes.

ASSESSMENT OF MONOCYTE AND MACROPHAGE FUNCTION The major function of monocytes and macrophages is host defense against the microorganisms, removal of necrotic and cellular debris, and interaction with lymphoid components in the generation and effector phases of immune responses. Patients in whom a deficiency of cell-mediated immunity is suspected are candidates for evaluation of monocyte functions, even if the numbers and functionsof T and B cells are normal. Various assays of monocyte competence are performed in the immunology laboratory, including mediating tumor cell-dependent cellular cytotoxicity, microbial killing, production of prostaglandins, generation of respiratory burst, and the ability of monocytes’ antigen-induced activation of T cells and production of IL-1. The test for IL-1 production, representing accessory function and antigen presentation, is the most useful in evaluating immunodeficiency. Other tests, such as microbial killing, cytotoxicity, prostaglandin, and generation of peroxide, are more useful in the evaluation of patients suffering repeated infections by fungi, protozoans, saprophytic microorganisms, and atypical mycobacteria.27-30

Production of Interleukin-l by Monocytes Measuring IL-1 production represents an important assay of monocyte function as it directly relates to accessory function and interaction with helper T cells. IL-1 is produced by monocyte-macrophages, endothelial cells, and other nonleukocytic cell types. Monocytes can also release IL-1 in response to stimulation with the neuropeptide substance P, providing a potential link between the nervous system and immune system. The IL-1 family consists of three peptides: IL-la, IL-lp, and IL-1 receptor antagonist (IL-lra). IL-1 has numerous diverse effects, including induction of fever, hypotension, sleep, and stimulation of T and B cells; IL-lra binds the IL-1 receptor but does not activate it; and IL-lra may diminish the disease-mediating effects of IL-1 .29,30 IL-1 production can be measured by enzyme immunoassay and the use of IL-1 messenger. RNA can also be measured by PCR with much higher sensitivity.

In many clinical conditions, the message of cytokines may be abnormal, but the protein level is within the normal range. Therefore, a combination of both measurements (protein and message) is the logical step.

Procedure Monocytes are isolated from peripheral blood mononuclear leukocytes by sequential buoyant-density centrifugation over Ficoll-Hypaque, Percoll, or similar gradient media and adherence to glass or plastic surfaces. The buoyant density of monocytes is similar to that of other peripheral blood mononuclear leukocytesbut is considerably less than that of Ph4Ns and erythrocytes. Separation of monocytes from lymphocytes with similar density takes advantage of the greater adherent properties of the mononuclear phagocyte. Heparinized venous blood is diluted with an equal volume of phosphate butter saline (PBS) or Hanks’s balanced salt solution (HBSS) and carefully layered over 2 ml of Ficoll-Hypaque medium in sterile culture tubes. The diluted blood is added carefully so as to avoid turbulence, which would disturb the interface. The tubes are centrifuged at approximately 500 x g at room temperature for 30 minutes. When the tubes are removed from the centrifuge, a distinct band can be seen between the plasma layer and the Ficoll-Hypaque layer. The top layer containing plasma is pipetted and discarded, and the bottom layer above the Ficoll-Hypaque layer is harvested with a sterile Pasteur pipette; the top one-third of the Ficoll-Hypaque layer is taken up in addition to the cells. The bands from several tubes are then combined in another tube, and the cells are washed with either HBSS or PBS two or more times by centrifuging at 103 x g for 8 minutes. This cell pellet should be relatively free of platelets and erythrocytes and should contain about 60% to 80% lymphocytes and 20% to 40% monocytes. The mixture of lymphocytes and monocytes is suspended in a Roswell Park Memorial Institute (RPMI) culture medium with 10% human AB serum or fetal calf serum (FCS) at a concentration of 2 x 106/ml in the presence or absence of endogenous activators such as bacterial lipopolysaccharide (LPS) with a concentration of 10 to 20 pg/ml. The cultures are kept in a C 0 2 incubator for a period of 72 hours, and supernatant-containing cytokines are removed and measured for IL-1 concentration using enzyme-linked immunosorbent assay (ELISA) methodology. Results are expressed as picograms of IL-1 per million lymphocytes and used in a culture in the presence or absence of an endogenous activator (LPS).

Bacterial Phagocytosis and Killing by Monocytes The capacity of monocytes to ingest and digest bacteria is generally determined with a method in which the monocytes are allowed to ingest and subsequently kill a measured number of microorganisms. Once inside the

Immune Function Assessment

monocyte, the microorganism is exposed to the microbicidal components of the cell. After an appropriate time, the monocytes are lysed, and the intracellular organisms are released and assayed by a colony-counting method to determine the number of viable organisms remaining within the cell. Microbial killing is enhanced when resting monocytes undergo activation.

Procedure The procedure for the microbial killing assay involves preparation of a suspension of adherent monocytes in a glass Petri dish. Bacterial suspensions are prepared with either Staphylococcus aureus or Streptomyces albus and are cultured for 16 to 24 hours at 37°C in trypticase soy broth. The bacterial culture is centrifuged, washed twice in PBS, and adjusted to a concentration of approximately lo8 bacteria/ml through measurement of turbidity. The bacterial suspension is eventually diluted with HBSS to obtain a final working concentration of lo7 bacteria/ml. Autologous or normal pooled AB serum can be used as a source of opsonin for the bacteria. In plastic culture tubes, 0.1 ml of medium, 0.2 ml of bacterial suspension at lo7 bacteria/ml, and 0.5 ml of monocyte suspension (lo6 monocytes/ml) are mixed. This mixture, along with proper controls, is then incubated for 1 to 2 hours at 37°C. Before culturing, a sample of the suspension is taken out for bacterial counts. After the 2-hour incubation, the cells are resuspended and colony counts are performed once more to determine the total amount of bacteria remaining. The tubes are then centrifuged, and colony counts are performed on the supernatant by means of classic microbiology techniques. The colonyforming units (CFUs) are counted to quantitate the remaining viable b a ~ t e r i a . ~The l - ~percentage ~ of bacteria ingested and killed by the monocytes is calculated with the following formula: (CFU at zero time - CFU in 15 min supernatant [sup]) (CFU at 1hour total - CFU in 1hour sup) CFU at zero time - CFU in 15 minsup

Measurement of Bacterial Phagocytes by Flow Cytometry Similar measurements of bacterial engulfment and killing are possible with the use of flow cytometry. For the assessment of phagocytosis by flow cytometry, 100 p1 yeast cells labeled with fluorescein isothiocyanate (FITC) (5 x 106/ml) are mixed with 100 pl autologous plasma, 200 ml PBS, and 100 ml granulocytes (1x 106/ml).After incubation at 37" C with continuous agitation for 1hour, 1 ml of ice-cold PBS is added. After incubation at 20" C for 10 minutes, the cells are washed twice in ice-cold PBS. The cells are then taken up by the flow cytometer in 0.5 ml of PBS. The number of granulocytes showing green fluorescence (i.e., phagocytosing cells) is evaluated

using the FACScan flow cytometer (Becton-Dickinson, USA). The gates are set around the granulocyte cluster in a cytogram, for simultaneous evaluation of forwardangle and right-angle light-scattering properties of the cell passing through the focused laser beam. The percentage of granulocytes with green fluorescence containing engulfed yeast cells in the histogram is determined on the FL1 channel (FITC filter transmission, 530 f 30 nm) of the FACScan. Using this methodology, we found that the percentages of phagocytosing cells in healthy subjects were between 45% and 55%. Significant reduction in the percentage of phagocytosing cells was found in patients with chronic illnesses, including chronic fatigue immune dysfunction ~ y n d r o r n e . ~ ~ - ~ For assessment of the percentage of yeast cells killed after phagocytosis, 100 pl of the yeast cell suspension (1x 106/ml) are mixed with autologous plasma (100 pl), PBS (100 pl), and 100 pl of granulocyte (1 x 106/ml). A control consists of 100 ml of yeast cells mixed with 100 ml of autologous plasma and 200 p1 of PBS in the absence of cells. After incubation at 37" C with continuous agitation for 2 hours, 100 pl cold 0.5% Triton X-100 is added to lyse leukocytes. To remove DNA released from the lysed granulocytes, 1 ml of a warm (37°C) DNAase solution (40 pg deoxyribonuclease 1 from bovine = 2000 pancreas units dissolved in PBS) is added, and the mixture is incubated for 5 minutes with periodic agitation. The tubes are centrifuged (500 x g for 5 minutes) and the cell pellet is resuspended in 1 ml of PBS; 20 p1 of propidium iodide (red fluorescence), 0.05 mg/ml, is then added, and the tubes are incubated for 5 minutes at 4" C. The gate is set around the yeast cell cluster on the FL1 channel of the FACScan. The percentage of yeast cells showing red fluorescence (i.e., killed cells) is evaluated on the FL3 channel (red pass filter, transmission 650 30 nm) within the gated region. The percentage of yeast cells killed is expressed as the percentage of cells killed in the test sample minus the percentage of cells killed in the control test tube.35-37In healthy controls examined in our laboratory, between 25% and 30% of yeasts were killed by this method, but in patients with chronic illnesses, these numbers may drop to less than 10%.

*

Measurement of Oxidative Burst in Monocytes Phagocytosis and its associated oxidative burst are essential for certain monocyte functions. During the respiratory burst of hydrogen peroxide, hydroxyl radicals, nitric oxide, and superoxide anion are produced as toxic oxygen metabolites. Hydrogen peroxide released from monocytes can be measured as a function of oxidative burst activity in response to stimulation. Hydrogen peroxide can be evaluated with a fluorescent scopoletin assay or with a photometer-based microassay requiring the horseradish

Supplementary Diagnostic Procedures peroxidadependent oxidation of phenol red. Hydrogen peroxide release is measured after in vitro stimulation by an inducer of the oxidative burst, such as phorbol myristate acetate (PMA) or serum-opsonized zymosan, which contains cell walls of Saccharomyces cereuisiue. Different studies have demonstrated that the production of nitric oxide (NO) by macrophages is important in the killing of intracellular parasites.w38Several different pathogens, including Mycobacteriu m bovis, bacille Calmette-Guerin vaccine (BCG), and M . tuberculosis, are reported to be susceptible to NO. Furthermore, it is reported that activated macrophages contribute to the suppression of antigen-specific T-cell proliferation through their NO production during primary listerial infection. The suppressive effect of NO is also observed in concanavalin A ( C o d ) responsiveness and in IFN-yand IL-2-induced production of T cells. These findings suggest that NO not only is the molecule responsible for the tumoricidal and microbicidal effects but also is one of the crucial factors controlling immunologic responses. In macrophages, NO is generated from oxidation of the terminal guanidino nitrogen atom of L-arginine by inducible NO synthase (iNOS),an enzyme known to be induced by cytokines such as IFN-y, tumor necrosis factor-a, IL-1, and LPS. Expression of N O S is also inducible by infection with Listeria rnonocytogenes, M . tuberculosis, and BCG in mice and by M. uvium in humans. Therefore measurement of NO is a measure not only of phagocytosis but also of normal or abnormal immunologic responses. For measurement of NO generation, Ficoll-Hypaque-separated mononuclear cells (2 x 106/ml)are cultured in complete-RPMI medium for 24 hours at 37" C. The nonadherent cells are removed by gentle washing with HBSS, and adherent cells are used as macrophages. Macrophages are stimulated with 10 pg/ml of LPS or 1 x lo6 CFU/ml of BCG for 2 days at 37" C. After removal of the supernatant, the level of NO is measured through determination of the amount of nitrite with Griess reagent. Briefly, a 300-ml aliquot of each sample is mixed with an equal volume of Griess reagent (0.5% sulfanilamide, 0.05% naphthylethylenediamine, and 2.5%H,PO,), and absorbance at 550 nm is determined after 10 to 15 minutes of incubation at room temperature. Sodium nitrite is used as a standard. Results are expressed as nanograms of NO produced by 1million m o n ~ c y t e s . ~ ~ Defects in monocyte phagocytosis are reported in a variety of clinical conditions, including SLE, monocytic leukemia, and congenital deficiency of membrane-adherence glycoproteins (CDl1-CD18 complex). Impaired oxidative burst activity and defects in microbicidal activity characteristically involve the neutrophil and monocyte in chronic granulomatous disease (CGD). Generation of toxic oxygen intermediates may also be impaired by some malignancies and infectious diseases.

For the preceding reasons and for the general assessment of the immune function, monocyte phagocytosis should be recommended. Performance of this test is also instrumental in evaluation of augmentative therapy using different biologic response modifiers, including antioxidants.

ASSESSMENT OFT- AND B-CELL FUNCTlON T- and B-cell function is assessed with the standard lymphocyte proliferation assay or with the newly developed fast immune assay system manufactured by BectonDickinson that uses flow cytometry. Lymphocyte proliferation or transformation is the process whereby new DNA synthesis and cell division take place in lymphocytes after a stimulus of some type, resulting in a series of changes. The lymphocytes increase in size, the cytoplasm becomes more extensive, the nucleoli are visible in the nucleus, and the lymphocytes resemble blast cells. The term "blast transformation" is also sometimes applied to this process. Lymphocytes from humans proliferate in response to antigens to which they are sensitized. This in vitro response correlates with the existence of delayed-type hypersensitivity in the host. Lymphocyte proliferation also occurs in response to different histocompatibility antigens when leukocytes from two donors are mixed in a mixed leukocyte culture. Mitogens, including pokeweed mitogen, phytohemagglutinin (PHA), LPS, and C o d , induce proliferation of normal cells in culture. Evaluation of lymphocyte proliferation can be quantitated through determination of either the percentage of lymphoblasts or increased DNA synthesis.This evaluation may be achieved by the addition of a radiolabeled precursor of DNA (usually tritiated thymidine) to the culture medium and the subsequent detection of the amount of radioactivity incorporated into the cells. The assay involves the in vitro culture of a lymphocyte population in the presence or absence of a selected stimulus for various periods. The changes induced in the stimulated groups are compared with changes in the unstimulated cell populations. Radiolabeled amino acids are used most commonly for these comparisons, as they offer a means of quantitating the changes in a simple, reproducible manner. The use of automated harvesting procedures allows for greater reproducibility and ease of performanceof the assay.3941

Lymphocyte Proliferation Assay Procedure After separation through the use of Ficoll-Hypaque gradient medium, peripheral blood mononuclear cells are counted and adjusted to the concentration of 1x 106/ml. Cells are cultured in quadruplicate in flat-bottomed microtiter plate wells with 10 pg/ml of T-cell mitogens (PHA, C o d ) or 5 pg/ml of B-cell mitogens (LPS or

Immune Function Assessment

pokeweed). After 48 hours of incubation at 37' C in a water-saturated atmosphere of 95% air and 5% C02, cells are pulsed with 2 pCi/well of tritiated thymidine for 16 to 18 hours. Incorporation of 3H-thymidine into cellular DNA is determined through harvest of the cultures in a harvester. Radioactivity is measured with liquid scintillation counting. The percentage of induction of 3H-thymidine uptake is determined by the following formula: counts/minute in the presence of mitogen counts/minute in the absence of mitogen

Optimal DNA synthesis in response to mitogens is usually detected in 2 to 4 days, whereas 5 to 7 days is needed for detection of optimal responses to antigens and mixed allogenic leukocytes. Under suboptimal conditions (either low cell numbers or low concentrations of mitogen), the response to mitogens also peaks after 4 days, suggesting a relationship between the number of responding cells and the rate of DNA synthesis. This method not only is lengthy and labor-intensive and involves radioactive material; it also does not provide information about individual lymphocyte subsets responding to particular stimuli. In contrast, multiparameter flow cytometry offers the potential to analyze selected lymphocyte subset responses to a variety of stimuli (e.g., pathogens and bioresponse modifiers). The graph in Figure 22-3 compares CD69 expression and 3H-thymidineincorporation and suggests that T-cell

Po

2001

-

0

activation, as measured by the expression of CD69 on CD3-positive cells, parallels the proliferative response determined by 3H-thymidineincorporation. In most cases, activation of T cells requires the presence of accessory cells or APCs. Under appropriate conditions, in vitro, antigenic, or mitogenic stimuli activate T cells via the T-cell receptor complex. This results in a number of biochemical and morphologic changes that culminate in T-cell differentiation and proliferation and expansion of memory cells. One of the earliest changes noted is the expression of the activation antigen CD69, which reaches a peak within 8 hours of stimulation. Other activation markers, including CD25 (IL-2 receptor), CD71 (transferrin receptor) and HLA-DR, which are expressed later during this process, are shown in Figure 22-4.

2

5 10 20 40 CDZCD2R kg/mL

60

h

X

70

Figure 22-3 CD69 expression versus tritiated thymidine incorporation. Incorporation of 3H-thymidine was compared with CD69 expression as a measure of T-cell response to varying concentrations of a comitogenic pair of antibodies, CD2 and CDSR. Tritiated thymidine incorporation was measured after 3 days of stimulation of peripheral blood mononuclear cells in media plus autologous plasma: the percentage of CD69 expression was measured by flow cytometry after 4 hours of stimulation under identical conditions.

Figure 22-4 Expression of different activation markers on T lymphocytes after polyclonal mitogenic stimulation.

Supplementary Diagnostic Procedures Because expressionof CD69 does not reflect some of the downstream events involved in signals for proliferation, such as IL-2 receptor expression, we use a combination of CD69KD25 to cover the early and late signals involved in lymphocyte proliferation. These properties suggest that the CD69tCD25 markers presented in Figure 22-3 are generic markers for lymphocyte activation and are well suited to rapid analysis of functioning lymphocytes. The assay utilizes fluorescence triggering on CD3positive lymphocytes in the FL3 channel of the FACScan and subsequent two-color analysis of the activation marker (CD69 PE) versus the subpopulation marker (such as CD4 FITC or CD8 FITC). T-cell activation is measured as a function of the percentage of T cell subsets (FL1 channel) that express CD69 (FL2channel). The FASTIMMUNE system includes a two-color reagent, CD69 PE/CD3 PerCP, that allows customized subset analyses. The functions of specific T-lymphocyte subpopulations may be studied by adding FITC-labeled T-cell subset markers to the two-color reagent. The open system utilizes isotype and activation controls. Isotype control, yl, FITC/yl, PE/CD3 PerCP, is used to set the boundaries between positive and negative results for the FL1 and FL2 channels. The activation control, CD2/CD2R, is a combination of comitogenic monoclonal antibodies that ensure that the activation system is working properly.4l."

Basic Procedure Sample Preparation and Mitogenic Stimuli 1. Whole blood is collected with the use of a sodium heparin anticoagulant. 2.Mitogenic or antigenic ligands and the FASTIMMUNE activation control are added to separate 200- to 500-pl aliquots of heparinized whole blood. 3. Stimulated samples and unstirnulated control samples are incubated for 4 hours at 37" C in a water bath or an incubator. Three-Color lmmunofluorescent Staining 1. FASTIMMUNE three-color antibody conjugate combinations, including fluorochrome-labeled isotypematched staining controls, are added to 5Oyl aliquots of stimulated and control samples. 2. Cells are stained for 15 minutes at room temperature. 3. Samples are lysed and fixed with 450 pl of FACS lysing solution for 15 to 60 minutes at room temperature to analyze the percentage of activated lymphocytes by flow cytometry.

Clinical Application The lymphocyte transformation test has a broad range of applications, including the following: *Assessment and monitoring of congenital immunologic defects

Assessment of either immunosuppressive or immunoenhancing therapies Determination of histocompatibility matching in transplantation Identification of serum or plasma factors that may suppress or enhance reactivity Diagnostic testing for detection of previous exposure to a variety of antigens, allergens, or pathogens Determination of a variety of cytokines A wide variety of acquired conditions have been shown to include impaired lymphocyte transformation. Such conditions are a variety of bacterial and viral infections as well as chemotherapy and autoimmune diseases such as Sjogren syndrome and SLE. A variety of other clinical conditions have also been shown to affect lymphocyte transformation, including surgery and anesthesia, stress, aging, malnutrition, a variety of malignancies, uremia, and major burns. In patients with congenital immunologic defects, lymphocyte transformation ranges from complete lack of function, as in severe combined immunodeficiency disease and DiGeorge syndrome; to a partial deficit, as in ataxia telangiectasia, Wiskott-Aldrich syndrome, and chronic mucocutaneous candidiasis; to normal reactivity, as in X-linked hypogammaglobulinemia. Lymphocyte transformation has also been used to monitor sequential samples from patients undergoing a variety of immunoenhancing or immunosuppressive therapies in the treatment of diseases states. This approach is especially sensitive when patients show nearly complete deficits before initiation of therapy, such as immunodeficient subjects who are to undergo bone marrow transplantation. Patients undergoing immunoenhancing therapy with lymphokines, such as recombinant interferon or the interleukins for cancer, can be monitored for increased reactivity after therapy.3943 Therefore enhancement of T- and B-cell function is the best screening method for selection of biologic response modifiers, including botanicals.

FUNCTION OF HELPER T TYPE 1 AND 2 CELLS ~

Helper T lymphocytes can be divided into at least two functionally distinct subpopulations, defined on the basis of clonal analysis as helper T 1 (TH1)and helper T 2 (TH2).However, at present, no phenotypic markers exist to distinguish between the TH1 and TH2 cells or between those that generate type 1and type 2 responses. Thus, type 1 and type 2 responses depend on functional parameters that are more complex than the phenotypic markers based on cell surface a n a l y s i ~ . ~ ' TH1 lymphocyte clones are characterized by the production of type 1 cytokines or IL-2 and IFN-8. The TH2

Immune Function Assessment

lymphocyte clones produce type 2 cytokines, which are IL-4, IL-5, IL-6, IL-10 and IL-13. Therefore, measurements of these cytokines are an indirect way to assess helper T 1 and 2 cell function. The TH1-TH2concept has been broadened to include the type 1 and type 2 responses, which reflect the functional profiles of interacting cell populations of the immune system and summarize the two modalities by which the immune system responds to antigenic stimuli. A type 1response can be defined as a cytokine profile in which there is appreciable production of TH1 cytokines and/or expression of cytokine messenger RNA. This response is characterized by the activation of cellmediated immunity and by certain isotypes of antibody. Type 2 responses can be defined as a cytokine profile characterized by a polarized production of TH2cytokines, which induce strong humoral immunity and antibody production, including immunoglobulin, and switch from IgG to IgE production. Type 1responses are negatively regulated by IL-4 and IL-10, and type 2 responses are down-modulated by IFN-6 and IL-12. Increase in production of type 2 cytokines and decreasein production of type 1 cytokines have been described in a variety of immunologic conditions, including immunodeficiencies and immune activations.

Clinical Application Evidence is accumulating that the pathogenesis of some human diseases may be conceptualized in terms of T helper type 1 and type 2 cell cytokine profiles. Many of these diseases are due to infectious agents, including: Viruses such as HIV-1 and the measles paramyxovirus Mycobacteria such as M. leprae (leprosy) and M. tuberculosis Spirochetes such as Treponernu pullidurn (syphilis) and Borrelia burgdorferi (Lyme disease) Parasitic diseases such as leishmaniasis and filariasis Mycoplasma, such as Mycoplasrna ferrnentuns, which have been described as a cofactor in AIDS and as one possible cause of chronic fatigue syndrome

In these patients, a switch in the pattern of T H 1 to TH2 cell populations has been observed. Stimulationof lymphocytes to produce IFN-6 or other type 1 cytokines, but not IL-4, is the best method of screening biologic response modifiers and botanical immunomodulators for treatment of immune disease^.^'

NATURAL KILLER CELL CYTOTOXICITY Natural killer cells are large granular lymphocytes that play an important role in a variety of human diseases. Compromise or absence of natural immunity, as measured in vitro by decreased NK activity and/or depressed absolute numbers of circulating NK cells,

has been linked to the development and progression of cancer; chronic and acute viral infections, including AIDS; chronic fatigue syndrome; psychologic dysfunction; various immunodeficiencies; and certain autoimmune diseases.I4 Recent evidence indicates that NK cells are involved in multiple effector, regulatory, and developmental activities of the immune system and that deficiencies or abnormalities in NK cell function may contribute to, or may be a biologic marker for, disease. For the preceding reasons, it is important to reliably detect abnormalities in NK cell function and monitor prognosis of chronic illnesses after therapy with biologic response modifiers or other agents.&53

Killer T Cell on the Warpath Although the main task of the immune system is to protect against the multitude of external microorganisms and other foreign perils, some of its weapons are reserved for combating abnormal cells. Their task is strongly reminiscent of the secret police in a dictatorship. Killer cells move constantly through the body’s tissues, combing the tissues for deviant cells. T lymphocytes originate in the bone marrow, enter the blood stream, and settle in the thymus for awhile. Here, they become immune-competent.Some of them are classed as T helper cells, others as suppressor T cells, and a third, exceedingly aggressive category as killer cells. The killer cells are equipped with special weapons that can kill the deviant cells. Although most white cells of the immune system react to foreign antigens on the surfaces of invading microorganisms, the killer cell reacts to both foreign antigens and the body’s own antigens. Very often, for example, a virus conceals itself inside body cells, safe from antibodies, complement factors, and scavenging cells. It is protected by the antigens of the infected cell, to which the body’s defenses do not respond. The killer cell, however, detects the virus because the infected cell bears both the body’s own antigens and foreign virus antigens on its surface.

Characteristics of Natural Killer Cells Morphologically, NK cells belong to a subset of large granular lymphocytes (LGLs). With the use of monoclonal antibodies, NK cells can be distinguished from other lymphocytes because they express a characteristic set of surface markers; they are CD3-, CD2+, CD16+, and CD56(NKHl)+. They do not productively rearrange T-cell receptor genes and do not express the CD3 complex, NK cells are cytotoxic effectors that are capable of spontaneously killing tumor or virus-infected ~ e l l s . ~ * J ~ Their cytolytic activity is not restricted by or dependent on expression of the major histocompatibility complex (MHC) on target cells. Although the basis for target cell recognition by NK cells is not clear at this time, they are

Supplementary Diagnostic Procedures

capable of distinguishing and sparing most normal tissue ~ e l l s . ~ 5 ~

Determination of Natural Killer Activity The number of NK cells in the blood or cellular suspensions is determined through staining of mononuclear cell populations with monoclonal antibodies against surface antigens on NK cells such as CD56 and CD16. NK activity is measured in a 4hour cytotoxicity assay using cultured tumor cells as targets and mononuclear cells isolated from the blood or tissues as effectors. Tumor cells used as targets are sensitive to human NK cells and K562, a cell line derived from a patient with CML who is in blast crisis. The targets are first labeled with radioactive chromium (51Cr) and extensively washed to remove any unbound radioisotope. The K562 line is maintained in culture in the presence of 10% (v/v) FCS and is provided regularly with fresh medium to ensure that cells used as targets are in the log phase of growth; this is important to ensure high viability and good uniform uptake of the radioisotope. NK activity in the blood is measured through the use of unfractionated mononuclear cells. These are prepared fresh and maintained in medium supplemented with 5% (v/v) FCS prior to the assay. A constant number (usually 5 x 103) of 51Cr-labeledK562 target cells is mixed with graded numbers of effector cells in triplicate wells of U-shaped microtiter plates. These plates are centrifuged briefly to bring effectors and targets into contact with each other, and then they are placed in a 37" C incubator for 4 hours. Killed targets are quantitated through measurement of the amount of 51Cr released into the supernatant after the 4-hour incubation of effectors and targets. Each plate contains wells for determination of the spontaneous chromium release from target cells (i.e., target cells in medium only) and of the maximal chromium release from lysed tumor cells through the addition of acid or detergents. The harvested supernatants from control and experimental wells are counted in a gamma counter. The amount of 51Crreleased into the supernatant is directly related to the proportion of target cells killed by effector cells.%%

Calculation of Results in Natural Killer Activity Assay Results of the NK cell assay for each effector/target (E:T) ratio can be expressed as a percentage of specific lysis, but more commonly NK activity is expressed in terms of "lytic-units" (LUS). To calculate LUs of NK activity, we combine the percentage of specific lysis at all the measured E:T ratios. First, the E:T ratio yielding 20% lysis (E:T2,,) is estimated from these measurements. The standard number of effectors (Estd)is typically chosen to be lo7, and the standard

number of target cells (Tstd)is typically 5 x lo3. Then the lyhc activity is reported as follows: number of LUs x

lTstd

E:T20

-

T:E20

Tstd/Estd

The size of a lytic batch, which is (E:T2,,)(Tstd)effector cells, represents 1 LU. Therefore, because lytic units (LUs) are a convenient way to quantitatively compare the relative cytotoxic activities of effector cell populations from different individuals or from the same individual over time, we use LUs to express NK activity of their clinical specimens. For this type of reproducibility, it is necessary to compare the percentage of specific lysis at all the measured E:T ratios. First, the E:T ratio yielding 20% lysis (E:TZ0)is estimated from these measurements. The choice of 20% as a reference level of lysis is arbitrary; however, it is quite common and seems to be a good choice, because experimental E:T ratios can be chosen so that the calibration will rarely require extrapolation beyond the range of the experiment. The estimation of E:T2,, is usually accomplished by fitting a curve to the measured points on the graph of percentage of lysis versus E:T ratio and then calibrating. One feature of the LU, in contrast to using the percentage of lysis at a single E:T ratio, is that four values at four distinct ratios are used, implying greater amounts of information and, therefore, greater precision. For example, the mean of four measurements has half the standard deviation of a single measurement. Also, LUs provide a measure of potency and dosage, when effector cells are infused in a clinical trial or experiment. The total activity of a bolus of cells might be well represented as the size of the bolus divided by the size of an LU.57 These optimal conditions for NK cell cytotoxic assay and criteria for a reproducible assay were first established in Dr. Herberman's laboratory at the Pittsburgh Cancer Institute in 1990.57On the basis of these criteria, we established conditions for obtaining a reproducible assay using 24-hour-old blood drawn in a yellow-top (ACD) tube and a computer program; lytic units are calculated from 12 tubes used for each patient. Examples of lyhc units calculations for healthy subjects and patients are shown in Figures 22-5 through 22-7.

Natural Killer Cell Activity in Human Diseases The biologic roles of natural killer cells are listed in Box 22-2. As indicated, N K cells are involved not only in defense against pathogens and elimination of metastases but also in a variety of other biologic interactions. It has been well established that patients with a variety of solid malignancies and large tumor burdens have decreased NK activity in the circulation and that this low

Immune Function Assessment

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there appears to be a correlation between NK activity and the status of disease; the more advanced the disease, the lower the NK activity. Decreased NK activity may also be an important risk factor for the development of malignancy in humans. The prognostic significance of low NK activity in patients with cancer has been established; thus low NK activity may have prognostic value in predicting relapses, poor responses to treatment and, especially, shorter survival time without meta~tases.~’”~ NK cells are sensitive indicators of activation by biologic response modifiers, and their monitoring has been used to document alterations in the activity of circulating immune cells during therapy with these agents. In patients with cancer who are treated with radiation or chemotherapy, NK activity becomes depressed as a result of the therapy. Given a role for natural immunity in tumor control, it may be clinically important to monitor the extent and duration of suppression of NK activity in order to minimize it through adjustments to the extent and/or duration of cytoreductive therapy. In human bone marrow transplantation, NK cells may influence the outcome by helping in engraftment and controlling viral infections and may mediate antileukemic effects important for the elimination of residual tumor cells. On the other hand, there is also evidence for the ability of NK cells to suppress hematopoietic devel0prnent.5~ Furthermore, evidence indicates that there is a relationship between an individual’s reaction to emotional stress and NK activity. Attempts are being made to define the mechanism responsible for low NK activity in individuals who have difficulties handling stress and in those suffering from behavioral disordersm The role of NK cells in viral disease has been known for a long time. The correlationbetween low NK activity and serious viral infections in immunocompromised hosts, such as patients with AIDS, those who have undergone transplantation, and those with certain congenital immunodeficiencies, has been well documented. Abnormalities in NK function have been described in a variety of autoimmune diseases, and because these diseases are commonly associated with serious viral infections and malignancy, low levels of NK activity may be

Lymphocyte to target ratio Figure 22-7 Low natural killer cell activity of a patient with chronic fatigue syndrome. Lymphocyte-to-target ratio giving 20% killing = 109.55. Results: lytic units = lo00 + 109.55= 9.13.

NK activity may be sigruficantly associated with the development of distant metastases. Furthermore, in patients treated for metastatic disease, the survival time without metastases correlates directly with levels of NK a~tivity.5~ In patients with hematologic malignancies,

Antitumor effects and elimination of cancer Antiviral and antibacterial activity Regulation of immune system Regulation of hematopoiesis Interaction with the neuroendocrine system Effects on reproduction

Supplementary Diagnostic Procedures biologically important in individuals with autoimmune disorders.%Finally, CFIDS is characterized by a number of immunologic abnormalities, the most consistent being a significant depression of NK activity.61,62*66,68 A similar phenomenon (low NK cytotoxic activity) has been reported by our laboratory in patients who have a history of toxic chemical exposure or silicone breast

Enhancement of Natural Killer Cell Activity by Buffered Vitamin C (Ultrapotent C) in Patients with Chronic Fatigue Syndrome Who Are Exposed to Toxic Chemicals After exposure to numerous toxic chemicals, NK function can be decreased sigruficantly.Weeks or months later, NK function can rebound to normal levels in some persons and but remain suppressed for prolonged periods in others. In view of these results, we decided to study the effect of buffered vitamin C on function of NK, T, and B cells in patients who had been exposed to toxic chemicals. Immediately after the first blood sample was collected, 55 patients ingested granulated buffered vitamin C in water at a dose of 60 mg per kg of body weight. Exactly 24 hours later, blood was again collected for a follow-up study of NK,T, and B cell function. In 78% of patients, vitamin C in a high oral dose enhanced NK activity up to 10-fold. Lymphocyte blastogenic responses to T- and B-cell mitogens were restored to the normal level after vitamin C usage. Signal transduction enzyme protein kinase C (PKC) appeared to be involved in the mechanism of induction of NK activity by vitamin C. These researchers concluded that immune functional abnormalities after toxic chemical exposure can be restored by oral use of vitamin C. The enhancement of NK activity in patients exposed to chemicals is shown in Figure 22-8. We used a buffered preparation of vitamin C or ultrapotent C concentration of 60 mg/kg. This preparation

100

90

was found to be very well tolerated at high doses. A large number of patients have been monitored by means of physical examination and hematology and blood chemistry evaluations, including liver enzyme measurements and complete urinalysis, for a period of 3 years of after ultrapotent C use; no signs of tissue toxicity (liver or kidney) or other abnormalities were detected. Although vitamin C was capable of enhancing functions of NK,T, and B cells, nonsigruficant improvement in the described symptoms was observed. However, enhancement in functions of NK, T, and B cells by vitamin C may prevent or delay infections or other health problems in patients who are at increased risk because of exposure to toxic chemicals. In our study, we proposed that immune function testing should become routine, not only in patients after toxic chemical exposure but also in patients who suffer from malignant diseases and are undergoing chemotherapy and radiation therapy. These treatment modalities may further impair immune function; thus, the body’s capacity to fight malignant cells is reduced. In these patients, immune modulation or stimulation should be attempted. These researchers successfully accomplished modulation or stimulation with ultrapotent C in a majority (78%)of the patients studied. Other biologic response modifiers, such as lentinan IL-2 and other cytokines, should be examined and then may be recommended for the 22% of patients in this study whose immune function did not respond to vitamin C.7l

CONCLUSION A collection of these tests not only reflects the function of the immune system but also represents the most important markers for detection of oxidative stress. Under normal conditions, T, B, and NK cells maintain a suitable redox equilibrium by balancing cytoplasmic levels of oxidants and antioxidants. After activation by infectious

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Immune Function Assessment

agents, especially their superantigens and haptenic chemicals through different receptors, mitochondria1 respiration increases, resulting in higher levels of reactive oxygen intermediates. When cellular antioxidant levels are insufficient or cellular exposure to reactive oxygen intermediates occurs, oxidative stress may be invoked. This leads to activation of PKR and NF-KB and, finally, to DNA damage. Oxidative damage to DNA and activation of RNA-dependent protein kinase (PKR) and nuclear factor kappa B (NF-KB) first lead to malfunction of NK, T, and B cells and then to the activation of death genes, which causes a change in cell signaling (see Chapter 13) and programmed cell death (or apoptosis; see Chapter 11). Therefore the measurement of NK cell activity along with cell cycle and apoptosis, as shown in Figure 22-9, in patients with chronic illnesses will enable clinicians to simultaneously assess the function of the immune system and evaluate the cellular level of oxidative stress. Moreover, these tests are extremely important for the follow-up treatment and prognosis of diseases by means of biologic response modifiers, antioxidants, growth hormone, cytokines, plant extracts, and other modalities. In many ChroIIic illnesses, the final goal of many cians is to reverse tissue abnormalities and sustain tissue homeostasis,and this goal could be documented only with the laboratory examinations described in this chapter.

1. Weiss A, Imboden J. Cell surface molecules and early events involved in human T lymphocyte activation. Adv Immunol 1987;41:1. 2. Reinherz EL, Schlossman SF. Strategies for regulating the human immune response by selective T cell subset manipulation. In Feifer A, ed. The potential role of T-cell populations in cancer therapy. New York Raven Press, 1982253. 3. Reinherz EL, Cooper MD, Schlossman SF. Abnormalities of T cell maturation and regulation in human beings with immunodeficiency disorders. J Clin Invest 1981;68:699. 4. Reinherz EL, Morimoto C, Fitzgerald KA, et al. Heterogeneity of human T4+ inducer T cells defined by a monoclonal antibody that delineates two functional subpopulations.J Immunol1982;128:463. 5. Reinherz EL, Meuer SC,Schlossman SF. The delineation of antigen receptors on human T-lymphocytes. Immunol Today 1983;45. 6. Bass DA, Parse JW, DeChatelet LR, et al. Flow cytometry studies of oxidative product formation by neutrophils: a graded response to membrane stimulation.J Immunol1983;1301910. 7. Kammer GM. T-lymphocyte activation. In Rose NR,DeMacario EC, Fahey JL et al, eds. Manual of clinical laboratory immunology. Washington, Dc:American Society for Microbiology, 1992. 8. Waggoner A, Emst LA. Fluorescence reagents for flow cytometry. In Bauer KD, Duque RE, Shankey TV, eds. Clinical flow cytometry, principles and application. Baltimore: Williams & Wilkins, 1993. 9. Vowells SJ, Sekhsaria S, Malech HL, et al. Flow cytometric analysis of the granulocyte respiratory burst: a comparison study of fluorescent probes. J Immunol Methods 1995;17889.

Figun, 22-9 Natural killer (NK) cell activity,apoptosis, and cell cycle in health and disease.

10. National Committee for Clinical Laboratory Standards. Clinical applications of flow cytometry: quality assurance and immunophenotyping of peripheralblood lymphocytes. NCCLS Document H42. Villanova, PA NCCLS, 1992. 11. Lewis DE, Rickman WJ. Methodology and quality control for flow cytometry. In Rose NR,DeMacario EC, Fahey JL et al, eds. Manual of clinical laboratory immunology, 4th ed. Washington, DC: American Society of Microbiology, 1992. 12. Renzi P, Ginns LC. Analysis of T cell subsets in normal adults: comparison of whole blood lysis technique to Ficoll-Hypaque separation by flow cytometry. J Immunol Methods 1987;98:53. 13. Yamada M, Tamura N, Shirai T, et al. Flow cytometric analysis of lymphocyte subsets in the bronchoalveolarlavage fluid and peripheral blood of healthy volunteers. %and J Immunol1986;24559. 14. Campana D, Thompson JS, Amiot P, et al. The cytoplasmic expression of CD3 antigens in normal and malignant cells of the T lymphoid lineage. J Immunol1987;138:6481. 15.Anker R, Conley ME, Pollock BA. Clonal diversity in the B-cell repertoire of patients with X-linked agammaglobulinemia. J Exp Med 1989;1692109. 16. Phillips AN, Lee CA, Elford J, et al. Serial CD4 lymphocyte counts and development of AIDS. Lancet 1991;337389. 17.Morimoto C, W i n NL, Distaso JA, et al. The isolation and characterization of the human suppressor inducer T-cell subset. J Immunol1985;134:1508. 18.Ramos EL, Turka LA, Leggat JE, et al. Decrease in phenotypically defined T-helper inducer cells (THEW) and increase in

T-suppressor effector cells (T8tW4-t) in stable renal allograft recipients. Transplantation 1989;47%5. 19. Raziuddin S, Nur MA, Alwabel AA. Selective loss of the CD4-t inducers of suppressor T-cell subsets (W4+)in active systemic lupus erythematosus. J F&eumatol1989;16:1315. Bensussan 5, et al. Generation of monoclonal 20. Hercend T, Griffin JD, antibodies to a human natural killer clone: characterization of two natural killer-associated antigens (NKH-1A and NKH-2), expressed on subsets of large granular lymphocytes. J Clin Invest 1985;75932. 21. Jackson AL, Matsumoto H, Janszen M, et al. Restricted expression of p55 interleukin 2 receptor (CD25) on normal T cells. Clin Immunol Immunopathol1990;54:126. 22.Westermann J, Pabst R. Lymphocyte subsets in the blood: a diagnostic window on the lymphoid system? Immunol Today 1990;11:406. 23. Sanders ME, Makgoba MW,Shaw 5. Human naive and memory: reinterpretation of helper-inducer and suppressor-inducer subsets. Immunol Today 1988;9:195. 24. Landay A, Jessop C, Lennette ET, Levy JA. Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet 1991338:707. 25. Vojdani A, Ghoneum M, Brautbar N. Immune alteration associated with exposure to toxic chemicals. Toxicol Ind Health 1992;8231. 26. Vojdani A, Ghoneum M, Brautbar N. Immune functional abnormalities in patients with clinical abnormalities and silicone breast implants. Toxicol Ind Health 1993;8:415. 27. Johnston RB. Monocytes and macrophages. N Engl J Med 1988; 318:747. 28.Smith PD, Ohura K, Masur H, et al. Monocyte function in the acquired immune deficiency syndrome. J Clin Invest 1984;742121. 29. Lotz M, Vaughan JH, Carson DA. Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science 1988;241:1218. 30.Dinmllo CA, Wolff SM. Mechanisms of diseases: the role of interleukin-1 in disease. N Engl J Med 1993;328:106. 31. Gartner 5, Markovits P, Markovits DM. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 1986;233215. 32. Lucey DR, Hensley RE, Ward WW, et al. CD4+ monocyte counts in persons with HIV-1 infection:an early increase is followed by a pmgressive decline. J Acquir Immune Defic Syndr 1990;424. 33. Weinberg JB, Hobbs MM, Misukonis MA. Phenotypic characterization of gamma-interferon-induced human monocyte polykaryons. Blood 1985;66:1241. 34.Bandres JC, Trial J, Musher D. Increased phagocytosis and generation of reactive oxygen products by neutrophils and monocytes by men with stage 1human immunodeficiency virus infection. J Med Dis 1993;168:75. 35. Gabrilovich D, Serebrovskaya L. Assessment of phagocytic activity in whole blood using laser flow cytometry.J Immunol Methods 1991; 140:289. 36. Malech HL, Gallin JI. Neutrophils in human diseases. N Engl J Med 1987217587. 37. Buschman H, Winter M. Assessment of phagocytic activity of granulocytes using laser flow cytometry. J Immunol Methods 1989; 124231. 38. Yang J, Kawamura I, Zhuh H, Mitsuyama M. Involvement of natural killer cells in nitric oxide production by spleen cells after stimulation with mycobacterium bovis BCG. J Immunol1995;155:5728. 39. Ling NR, Kay JE. Lymphocyte stimulation. Oxford: North Holland, 1975. 40.Dean JH, Connor R, Herberman RB, et al. The relative proliferation index as a more sensitive parameter for evaluating lymphoproliferative r~sponsesof cancer patients to mitogens and doantigens. Int J Cancer 1977;20:359. 41. Farrant J, Clark JC, Lee H, et al. Conditions for measuring DNA synthesis in PHA stimulated human lymphocytes in 20pl hanging

drops with various cell concentrations and periods of culture. J Immunol Methods 1980;33301. 42. D'Ambrosio D, Trotta R, Vacca A, et al. Transcriptional regulation of interleukin-2 gene expression by CD69-generated signals. Eur J Immunol 1993;232993. 43. Oppenheim JJ, Dougherty S, Chen SC,Baker J. Utilization of lymphocyte transformation to assess clinical disorders. In Vyas GN, ed. Laboratory diagnosis of immunological disorders. New York Grune & Stratton, 1975:87-109. 44. Mossman TR, Coffman RL. THl and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Ann Rev Immunol1989;7145. 45.Romagnani S. Human THl and TH2 subsets: doubt no more. Immunol Today 1991;12256. &.Shearer GM, Clerici M. Is HIV infection associated with a TH18TH2 switch? Immunol Today 1993;14107. 47. Field EH, Noelle RJ, Rouse T, et al. Evidence for excessive TH2 CD4+ subset activity in vivo. J Immunol1993;151:48. 48. Herberman RB, Ortaldo JR.Natural killer cells: their role in defense against disease. Science 1981;241:24. 49. Trunchieri G, Perussia B. Human natural killer cells: biologic and pathologic aspects. Lab Invest 1984504489, 50.Takayama H, Trenn G, Humphrey W, et al. Antigen receptortriggered secretion of a trypsin-type esterase from cytotoxic T lymphocyte. J Immunol 1987;138:566. 51.Whiteside TL, Herberman RB. The role of natural killer cells in human disease. Clin Immunol Immunopathol198853:l. 52. Gorelik E, Wdtrout RH,Okumura K, et al. Role of NK cells in the control of metastatic spread of tumor cells in mice. Int J Cancer 1982;30:107. 53. Herberman RB, Holden HT. Natural cell-mediated immunity. Adv Cancer Res 1978;27305. 54. Abo T, Miller CA, Balch CM. Characterization of human granular lymphocyte subpopulations expressing NHK-1 (Leu-7 and Leu-11) antigens in the blood and lymphoid tissues from fetuses, neonates and adults. Eur J Immunol1984;1:616. 55. limonen T, Ortaldo JR, Herberman RB. Characteristics of human large granular lymphocytes and their relationship to natural killer (NK) cells. J Exp Med 1981;153:569. 56.Whiteside TL, Herberman RB. Role of human natural killer cells in health and disease. Clin Diag Lab Immunol1994;1:125. 57. Whiteside TL, Bryant J, Day R, Herberman RB. Natural killer cytotoxicity in the diagnosis of immune dysfunction: criteria for a reproducible assay. J Clin Lab Anal 1990;2102. 58. Whiteside TL, Herberman RB. The role of natural killer cells in immune surveillance of cancer. Curr Opinion Immunol1995;7704. 59. Pross HR, Lotzova E. Role of natural killer cells in cancer. Nat Immunol 1993;12:279. 60.Levy SM, Herberman RB, Simons A, et al. Persistently low natural killer cell activity in normal adults: immunological, hormonal and mood correlates. Nat Immun Cell Growth Regul1989;8173. 61. Aoki R, Usuda T, Miyakoshi H, et al. Low NK syndrome (LNKS): clinical and immunologic features. Nat Immun Cell Growth Regul 1987;6116. 62. Eby N, Grufferman S, Huang M, et al. Natural killer cell activity in the h n i c fatigueimmune dysfunction syndrome. In Ades EW, Lopez C, 4 s . Natural killer cells and host defense. Karger: Basel, 1988141. 63. Marshall GD Jr, Agarwal SK. Stress, immune regulation, and immunity: applications for asthma. Allergy Asthma Proc 2000;241:6. 64.Saeij JP, Verburg-van Kemenade LB, van Muiswinkel WB, Wiegertp GF. Daily handling stress reduces resistance of carp to Trypanoplasma borreli: in vitro modulatory effects of cortisol on leukocyte function and apoptosis. Dev Comp Immunol2003;27233. 65. Skwarlo-Sonta K, Majewski P, Markowska M, et al. Bidirectional communication between the pineal gland and the immune system. Can J Physiol Pharmacol2003;81:342.

Immune Function Assessment 66. Biron C, Byron KS, Sullivan J. Severe herpes virus infections in an adolescent without natural killer cells. N Engl J Med 1989;3201731. 67.Purtilo DT, Strobach FS, Okano M, et al. Epstein-Barr virusassociated lymphoproliferative disorders. Lab Invest 1992;675. 68. Plaeger-Marshall S, Spina CA, Giorgi JV,et al. Alterations in cytotoxic and phenotypic subsets of natural killer cells in acquired immunodeficiency syndrome (AIDS). J Clin Immunol1987;716. 69. Vojdani A, Campbell A, Brautbar N. Immune functional impairment in patients with clinical abnormalities and silicone breast implant. Toxicol Ind Health 1992;8:415.

70. Campbell A, Brautbar N, Vojdani A. Suppressed NK cell activity in patients with silicone breast implant reversal upon explanation. Toxicol Ind Health 1994;10:149. 71. Heuser G, Vojdani A. Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: the role of protein kinase-C. Immunopharmacol Immunotoxicol 1997;19:291.

Intestinal Permeability Assessment Corene Humphreys, BHSc, ND, DipMedHerb, DipHom CHAPTER C O N T E N T S Introduction 241 Gut Mucosal Integrity: Mechanisms of Disruption 241 Clinical Applications 242 Inflammatory Bowel Disease 242 Celiac Disease 243 Food Allergies 243 Diabetes 244 Inflammatory Joint Diseases 244 Alcoholism 244 Factors Affecting Intestinal Permeability 244 Nonsteroidal Antiinflammatory Drugs 244 Intestinal Infection/Dysbiosis 245 Nutritional Depletion 245 Trauma 245 Chemotherapy 245

Measuring Intestinal Permeability 245 Challenge Substance 245 Test Procedure 246 Interpretation 246 Factors That Affect the Excretion of Lactulose and Mannitol 246 Therapeutic Considerations 246 L-Glutamine 246 Beneficial Bacteria (Lactobacillus, Bifidobacterium) 246 Essential Fatty Acids 247 Bovine Colostrum 247 N-acetyl-D-glucosamine 247 Sodium Cromoglycate 247 Bombesin 247 Conclusion 247

INTRODUCTION If the size of an organ were related to its importance, the small intestine would be a perfect example of this relationship, because of its vast surface area and the critical physiologic functions it performs in the body. If one were to unravel the mucosal folds, villi, and microvilli of the small intestine, its luminal absorptive surface area would span roughly 250 square meters! The small intestine is a multifaceted organ, playing a major role in digestive and absorptive processes as well as acting as a barrier against harmful macromolecules. However, when this absorptive capacity or barrier function is compromised, the health of the individual may be adversely affected. Pathologic changes in the permeability of the intestinal mucosa have been identified in a number of local and systemic disease conditions. The chapter focuses on clinical consequences that may result from a breech of gut mucosal integrity and on how they relate to specific disease states. It also outlines the use of noninvasive testing to idenbfy intestinal permeability and explore therapeutic options to restore mucosal integrity.

GUT MUCOSAL INTEGRITY MECHANISMS OF DISRUPTION A key function of healthy gut mucosa is to prevent bacteria and their endotoxins from reaching portal circulation. For this purpose a natural physiologic barrier is formed by the mucous layer, the epithelial cells and tight junctions, and the gut-associated lymphoid tissue. When one or more of these components is impaired, damage to the intestinal barrier may result, allowing bacteria to translocate from the gut into the systemic circulation (Figure 23-1)' The small intestine consists of specific intrinsic factors that help protect the host from environmental pathogens. These are enterocytes as well as paracellular spaces composed of structures called tight junctions, intermediate junctions, and desmosomes. The tight junctions surround the upper portion of the lateral surfaces of the adjacent epithelial cells to create fusion points. This creates distinct fluid compartments that maintain cellular polarity and regulate the passive transepithelial movement of molecules. A number of signaling molecules, such as Ca2+,phospholipases A2 and C , protein kinase C, and G proteins, 241

Figure 23-1

Damaged intestinal microvilli (arrowheads).

serve to regulate the function of tight junctions. Resistance to the passive flow of potentially toxic macromolecules across the paracellular pathway is normally very high; however, bacterial toxins, cytokines, hormones, and drugs can affect these signaling molecules and alter tight junction permeability.* The immune system of the gastrointestinal (GI) tract also helps prevent the translocation of harmful molecules across the gut mucosa. Gut-associated lymphoid tissue composes approximately 25% of the mucosal mass of the intestine. It is considered the body’s largest immune organ, containing 40% of its immune effector cells. Gut immunityconsists of two distinct mucosal defense mechanisms: the specific system and the nonspecific system. The specific system is composed of secretory immunoglobulin A (sIgA). The nonspecific system comprises gastric acidity, motility, mucus, digestive enzymes, normal bacterial flora, and bacterial antagonism. Disruptions in gut barrier function may result from impaired host immunity, alterations in gut flora, or direct mucosal injury.3 Ordinarily, normal gut microflora provides ”resistance to colonization,” preventing the adherence of pathogenic organisms to the intestinal wall and their subsequent translocation? Changes in the gut ecology, however, can reduce this natural resistance and encourage the colonization of potentially harmful bacterial species. Bacteria and the toxins they produce can alter membrane integrity through various mechanisms. Bacteria can secrete enzymes, such as elastase and protease, which hydrolyze the epithelial membrane and cause cells to detach from the epithelial sheet. Bacterial toxins may act on or within membranes and compromise tight

junction integrity by binding to membrane receptors. Some toxins can transverse the cell membrane and inhibit cellular growth by altering protein synthesis. They also may alter membrane lipid composition, act as a detergents, or form transmembrane pores. The net effect is cellular swelling, lysis, loss of intracellular constituents, and uncontrolled influx of toxic substances? Bacterial endotoxins and cytokines have been shown to impair gut barrier function by activating inducible nitric oxide synthase. Upregulation of this enzyme increases the amount of nitric oxide. Prolonged exposure of the cells to nitric oxide is thought to inhibit cellular respiration, decrease mesenteric blood flow, and alter A second proposed mechanism by which ~ermeability.~ endotoxin-induced nitric oxide production affects gut barrier function is through the formation of the oxidant peroxynitrite. Nitrosyl-derived products such as this have been found to injure the intestine directly.

Clinical Applications Because the intestinal mucosa plays a pivotal role in immune defense and nutrient absorption, a wide variety of diseases and conditions are associated with abnormal bowel permeability (Box 23-1).Abnormal permeability is often identified through assessment of the relative rate at which two nondigestible sugars, lactulose and mannitol, permeate the intestinal mucosa. A higher lactuloseto-mannitol (L:M) ratio indicates increased gut permeability (see “Measuring Intestinal Permeability”).

Inflammatory Bowel Disease Both Crohn’s disease and ulcerative colitis are characterized by an exaggerated immune response by gut-associated lymphoid tissue to luminal or enteric

Intestinal Permeability Assessment

Inflammatory bowel disease Celiac disease Food allergy Diabetes mellitus Inflammatory joint disease Rheumatoid arthritis Ankylosing spondylitis Reiter syndrome Alcoholism

bacterial antigens: The initiating pathogenic event is believed to be a disrupted intestinal barrier, which increases the antigenic load of the lamina propria7 (the connective tissue layer beneath the mucosa). Studies have demonstrated the superiority of measuring intestinal permeability over other noninvasive biochemical indices to assess disease activity in patients with Crohn's disease. Routine laboratory tests such as white blood cell count and measurements of erythrocyte sedimentation rate, C-reactive protein, serum iron, interleukin-2, and alphal-glycoprotein have all been used to evaluate disease activity in patients with Crohn's disease, but none of these markers can predict disease relapse. Intestinal permeability testing is able to identify patients with Crohn's disease who are currently in remission but have a high risk of clinical relapse. For example, DInca et a18demonstrated a significant association of relapse within 4 months in patients in whom the L:M ratio was greater than 0.035. Restoring normal permeability function in patients with Crohn's disease may reduce the risk of clinical relapse. Studies have demonstrated a longer remission period (>6 months) in patients with Crohn's disease who were treated for "leaky g ~ t . ' ' ~ , ' ~

Celiac Disease Celiac disease has an extremely varied clinical presentation, ranging from no symptoms to overt chronic symptoms such as diarrhea, weight loss, and folate or iron deficiencies." Regardless of their symptoms one must treat all patients with celiac disease with a gluten-free diet to prevent long-term complications such as infertility and malignancy.'2 Intestinal permeability is increased in nearly all patients with untreated celiac disease. Intestinal permeability testing is therefore an ideal noninvasive screening test, offering a sensitivity of 96%in identifymg those with the disea~e.'~,'~ Although jejunal biopsy is considered the gold standard for detecting celiac disease, this test is time consuming, unpleasant, and costly, making it unsuitable as a screening tool for the general population."

An elevated L:M ratio helps identify which patients should undergo jejunal biopsy when clinical features are compatible with celiac disease. It also can help determine the timing of follow-up biopsy and monitor the recovery of the mucosa. Impaired permeability tends to normalize within 5 months when a gluten-free diet is followed. Serial intestinal permeability testing is a noninvasive and economical way to monitor dietary compliance in these patients.I3Increased intestinal permeability also has been found in first-degree relatives of patients with celiac disease in the absence of villus atrophy on jejunal biopsy. It is thought that this finding may reflect a latent form of the disease in this subset of individual^.'^ Johnston et all5 found the L:M ratio to be a better screening test than measurement of serology markers as for celiac disease, such as antigliadin antibodies, antiendomysial antibodies, and antireticulin antibodies. When used solely in the clinical setting, the intestinal permeability test had a sensitivity of 81%and a negative predictive value of 90%. When it was used as a screening test for the general population, the test's sensitivity and negative predictive value rose to 87%and 96%, respectively.

Food Allergies A number of natural host factors function interdependently as a barrier to antigens, allergens, and toxins. Gastric and intestinal secretions help to hydrolyze large molecules, and glycoprotein secretions coating the external surface of the epithelial cell help prevent these molecules from adhering to the cell surface and moving into the enterocytes. Macrophages in the lamina propria also are able to hydrolyze large molecules, and sIgA helps protect the epithelium from absorbing antigenic substances. Any condition that results in an increased concentration of macromolecules available for contact with the enterocytes increases the risk of antigen absorption.I6 Both animal and human studies have shown that hypersensitivity reactions are associated with specific functional and morphologic changes within the GI tract. Immediate hypersensitivity reactions (IgE-mediated) cause edema, shedding of the enterocytes, and disruption of the basement membrane. Delayed, cell-mediated immune reactions (IgG-mediated), on the other hand, cause villus atrophy and crypt hyperplasia. In both reaction types, in vitro studies have demonstrated enhanced transport of macromolecules, reflecting disruption of the mucosal barrier.17 These mechanisms help explain why increased intestinal permeability has been associated with the development of multiple food allergies. Paganelli et all8 demonstrated that in patients with chronic urticaria and arthralgias, alterations in gut permeability may be caused by increased circulating IgGs from absorbed food proteins. Measuring intestinal permeability after challenging the body with food proteins such as cow's milk

Supplementary Diagnostic Procedures can help determine whether a patient may benefit from dietary restriction. Research on hypersensitive subjects also has shown that the ingestion of allergenic foods increases the amount of lactulose crossing the intestinal mucosa, increasing urinary excretion of lactulose and elevating the L:M

etiologic factor in the disease or an adverse effect of antiinflammatory medications.33.34Measuring intestinal permeability before and after NSAID therapy in patients with inflammatory joint disease helps establish whether mucosal disruption is solely an iatrogenic response.

Diabetes

Alcohol consumption can lead to pronounced changes in the ultrastructure of enterocytes in the small intestine. A number of studies using different methodologies have found an increase in intestinal permeability in patients who have liver disease. These changes to gut barrier function could allow bacterial endotoxins to enter the systemic circulationand contribute to the greater liver inflammation often associated with alcohol conswnption.35a Bjarnason et aP7 demonstrated that elevated intestinal permeability was evident for up to 2 weeks after the cessation of alcohol consumption.

Although limited research has explored the relationship between diabetes and intestinal function, studies suggest that the gut immune system may have a key role in controlling insulin-specific immunity induced by dietary insulin. Aberrant function of the gut immune system has been reported in type 1 diabetes, with intestinal immune activation and increased intestinal permeability?O Changes to gut permeability in patients with type 1 diabetes also have been shown to alter postprandial blood glucose levels and adversely affect metabolic controlF1 Maldigestion can occur in diabetic patients when endocrine pancreatic insufficiency accompanies exocrine insufficiency. Some studies suggest that small intestinal bacterial overgrowth, originating from exocrine pancreatic insufficiency, may be the initiating factor in malabsorption and altered gut permeability. In addition, gluten-sensitive enteropathy appears to be far more common in diabetic patients than previously suspected. However, unlike patients with overt celiac disease, who exhibit a reduced mannitol recovery, patients with diabetes show increased urinary recovery of mannitol. Whether this finding is a primary feature resulting from diabetes itself or is a result of altered microvilli function that precedes mucosal atrophy and that eventually may progress to celiac disease has yet to be determined.22,23

Inflammatory Joint Diseases Numerous studies have shown a correlation between different types of arthritides and increased intestinal ~ermeability.~~ However, it has not been fully determined whether this correlation results from the disease process itself or is due to mucosal damage caused by treatment with nonsteroidal antiinflammatory drugs (NSAIDs).E*26 Another possibility is that this correlation may be related to gut microbial infections. Specific pathogenic organisms (Salmonella, Campylobacter, Proteus, and Yersinia) have been found in patients with various arthritides who have altered intestinal ~ermeability.~’-~ It has been postulated that these organisms, when absorbed by the intestinal mucosa, elicit an immune response, with tissue damage occurring from molecular mimicry.31 Patients with ankylosing spondylitis have shown a marked increase in intestinal ~ermeability.~~ It is also uncertain whether this increased permeability is an active

Alcoholism

Factors Affecting lntestinal Permeability A variety of treatments and conditions may impair mucosal integrity and trigger changes in intestinal permeability (Box 23-2).

Nonsteroidal Antiinflammatory Drugs NSAIDs are the most commonly prescribed antirheumatic drugs; NSAID enteropathy is estimated to occur in 65% of patients undergoing treatment with the agents. Even short-term NSAID therapy has been shown to cause changes in intestinal permeability that are similar to those in patients with active inflammatory bowel Somasundaram et aP9have hypothesized a sequence of events in the pathogenesis of NSAID enteropathy. The initiating event proposed is the uncoupling of mitochondrial oxidative phosphorylation, which increases production of free radicals and damages the intracellular junctions. The damaged mucosa then is exposed to endogenous substances such as bile, bacterial products, and hydrolytic and proteolytic enzymes, which generate a chemotactic neutrophilic response. Secondary damage with the subsequent loss of blood and protein that is associated with NSAID enteropathy o c m s only when a neutrophil chemoattractant gains access to the mucosa.los NSAID therapy can also cause intestinal damage by inhibiting the activity cyclooxygenase-1. In fact, an increase in permeability has been detected 12 hours after

Nonsteroidalantiinflammatorydrugs Intestinal infectioddysbiosis Nutritional depletion Trauma and endotoxemia Chemotherapy

Intestinal Permeability Assessment

the administration of a single dose of cyclooxgenase-1 inhibitors. However, for most patients inflammation develops after 1 year of NSAID use.13 In patients with increased intestinal permeability caused by NSAID therapy, switching to cyclooxygenase-2 inhibitors may result in greater drug tolerability even with long-term use. BjamasonMhas demonstrated a significant decrease in GI damage with the use of specific NSAIDs that selectively reduce cyclooxygenase-2.

Intestinal Infection/Dysbiosis A number of factors can trigger a change in gut ecology and potentially harm the mucosal barrier. They include contaminated food and water, stress, and antibiotic therapy. For example, an overgrowth of Clostridium dificile can occur after treatment with broad-spectrum antibiotics. C. dificile is an anaerobic spore-fonning bacillus that has been shown to adversely affect the integrity of the intestinal epithelial cells. C. dificile produces two toxins, A and B, as well as tissue-degrading enzymes such as collagenases, proteases, hyaluronidase, heparinase, and chondroitin-4 sulfatase. Toxins A and B disrupt the enterocyte brush-border membranes, resulting in mucosal damage, an influx of white blood cells into the lamina propria, and toxic megacolon and intestinal perforation. C. difficile's ability to alter the intestinal barrier has been hypothesized to facilitate microbial penetration and the translocation of intestinal bacteria. This is theorized to be the initiating event in the pathogenesis of systemic infection, particularly in high-risk patients!' Changes in intestinal permeability have been observed in patients with protozoan infections, specifically those caused by Giardia lamblia and Blastocystis h ~ m i n i s . QGut ~ ~ permeability appears to retum to normal 3 to 4 weeks after acute infection. It is thought that changes in gut permeability could be of importance in relation to chronic infection and malnutrition associated with G. lamblia.@ Protozoa conventionally classified as nonpathogens (e.g., Entamoeba coli) do not appear to alter intestinal permeability." A shift in the L:M ratio has also been observed in patients with small intestinal bacterial overgrowth. Riordan et a145found an increase in intestinalpermeability associated with an overgrowth of colonic-type bacteria, specifically Enterobacteriaceae, within the small intestine.

Nutritional Depletion In animal studies, malnutrition has been associated with intestinal weight loss, reduction of protein and RNA content, villus atrophy, macromolecule absorption, and abnormal mucin and sIgA levels.&Parenteral nutrition and enteral starvation in humans have been shown to raise intestinal permeability and reduce villus height. These effects may be associated with reduced concentrations of the amino acid L-glutamine in the intestinal mucosa.'

Trauma In patients who sustain severe trauma are more likely to experience an intense systemic inflammatory response that may be followed by organ dysfunction and multiple organ failure. However, patients with systemic inflammatory response syndrome and multiple organ failure often show no evidence of uncontrolled sepsis. For this reason, it has been postulated that altered intestinal permeability secondary to mucosal damage in the gut may be an etiologic factor!'In this theory, greater permeability results in bacterial translocation and penetration of the gut wall by intraluminal toxins, thereby initiating the secondary systemic inflammatory response. In the past, studies performed intestinal permeability testing in patients with trauma upon their arrival at the hospital or 1 week after. Later research has found that testing for altered permeability on the fourth day of the hospital stay leads to closer correlation of results with the severity of the traumatic insult.@

Chemotherapy Like hemopoietic cells, enterocytes are rapidly dividing cells that are sensitive to the effects of chemotherapeutic agents. Pledger et a149demonstrated a significant reduction in the absorption of mannitol and an increased L:M ratio in children treated for solid tumors. A study by Fazeny-Dorner et a1%found an acute, transient elevation in intestinal permeability after initiation of drug therapy, with permeability returning to normal in all patients 2 weeks after the commencement of therapy. This toxicity to the GI tract is an important factor that greatly limits the dose of antineoplastic medication a patient can receive. For this reason, monitoring intestinal permeability in patients with cancer can be a valuable means of determining the optimal timing and dosage of their medications?'

MEASURING INTESTINAL PERMEABILITY Challenge Substance Altered intestinal permeability, or "leaky gut," can be assessed with a challenge test that measures the recovery of two nonmetabolizable sugars: lactulose and mannitol. The different molecular weights of these sugars enable assessment of both transcellular and paracellular absorption. Mannitol is a small molecule (molecular weight [MW] 182) that is thought to traverse the epithelium via waterfilled pores in the lipid membrane of the enterocyte. Lactulose is a larger molecule ( M W 342) that passes through the intestinal epithelium via the paracellular route. Diseases and treatments that alter the membrane composition and affect the tight junctions between the cells increase transport via the paracellular route (Figure 23-2).13

Supplementary Diagnostic Procedures L:M ratio, which reflects disturbances in the functional integrity of the small

FactorsThat Affect the Excretion of Lactulose and Mannitol The excretion of lactulose and mannitol depends on many factors, which can be categorized as follows:

Premucosal factors. Proper digestion, gastric dilution and emptying, intestinal dilution, transit time, and bacterial degradation. Mucosal factors. Brush-border hydrolysis, permeation pathways, and blood flow. Postmucosal factors. Endogenous sugar production, metabolism, tissue distribution, renal excretion, and proper urine test collection.

Figure 23-2 Permeation of water-soluble molecules. (Courtesy Great Smokies Diagnostic Lab, Asheville, NC.)

The sensitivity and specificity of the test are markedly increased it two challenge substances are used and a pretest sample is collected.1°When both challenge substances are administered simultaneously and their ratio determined, extraneous factors such as gastric and bladder emptying, renal and hepatic disease, and intestinal motility are eliminated." A pretest urine sample identifies a small percentage of patients who produce mannitol endogenously.'l

Although a number of challenge substances have been used to assess intestinal permeability, all have certain limitations. Ideally a challenge substance should be nontoxic, completely absorbable via passive diffusion, THERAPEUTIC CONSIDERATIONS and easily measured in urine. It should not be a substance L-Glutamine produced endogenously, degraded enzymatically, or consumed in the diet.13 The amino acid L-glutamine, a preferential fuel for the Other commonly used markers to assess transcellular small intestine, is considered vital for the maintenance and paracellular pathways are cellobiose/mannitol, of mucosal growth, structure, and functi0n.'~5~ Dietary lactulose/rhamnose, and cellobiose/rhamnose.52 The deficiency of L-glutamine is associated with atrophy and drawback of using cellobiose (an alternative for lactulose) degenerative changes to the small bowel after injury, is that it can be hydrolyzed by the brush-border enzyme surgery, irradiation, infection, and stress. Parenteral or enteral feedings of L-glutamine are able to restore normal lactase." Rhamnose (an alternative for mannitol) is incompletely excreted after an oral 10ad.I~Hence, lactulose and cellularity and function to the small i n t e ~ t i n e . ~ 5 ~ mannitol are the best-documented substances for assessSecretory IgA is considered central to the function of the intestinal immune system. It is the most abundant ing intestinal permeability and most closely meet the preceding criteria for an ideal challenge s ~ b s t a n c e . ' ~ ~ immunoglobulin in external secretions and appears to require L-glutamine for expression and synthesis. Test Procedure Animal studies have demonstrated improved gut immune function and protection of IgA-producing cells The patient collects a first-morning prechallenge urine after administration of L-glutamine.60 By preventing sample after an overnight (%hour) fast. A premeasured bacterial translocation, sIgA may guard against the lactulose/mannitol drink then is ingested, and urine is secondary cascade of events that results in inflammation collected for the following 6 hours. The total urine and disruption of the intestinal barrier.6l volume is recorded, and both samples are returned to the laboratory for assessment of the individual recovery Beneficial Bacteria (Lactobacillus, of the two sugars and their ratio (L:M).

Bifidobacterium)

Interpretation Under pathologic conditions, the amount of lactulose permeating the intestinal barrier increases, and the amount of mannitol permeating the intestinal barrier does not change or decreases. This results in a rise in the

Probiotics (live microbial foods beneficial to health) have been found to protect the intestinal mucosa by several proposed mechanisms. Beneficial bacteria may stabilize the immunologic barrier of the intestinal mucosa by modulating

Intestinal Permeability Assessment proinflammatory and antiinflammatory cytokines and stimulating sIgA.62Lactobacillus rhamnosus has been shown to reduce fecal concentrations of tumor necrosis factor-alpha and increase the production of interferongamma, eliciting protective effects on the mucosa.62 Bifidobacteria downregulate inflammatory mediators such as interleukin-1, interleukin-6, and tumor necrosis factor-alpha, thereby preventing damage to the epithelial tight junctions. Both lactobacilli and bifidobacteria have been found to enhance intestinal sIgA activity, reducing the intestinal inflammatory response. Probiotics also may exert beneficial effects by stimulating nonspecific host resistance to microbial pathogens. For example, beneficial microbes can reduce luminal pH and normalize fecal urease concentrations, helping to stabilize gut ecology and reduce inflammation.62,63

Essential Fatty Acids In vitro studies have shown that omega-3 and omega-6 polyunsaturated acids reduce transcellular non-receptormediated permeation of proteins without altering paracellular permeability." Animal studies have demonstrated that docosahexaenoic acid reduces small intestinal permeability caused by oral administration of methotrexate.65 Administering fish oils to patients with Crohn's disease may prolong diet-induced clinical remission by reducing the synthesis of proinflammatory eicosanoids.66 Oral ingestion of gamma-linolenic acid from borage seed oil can help prevent and treat GI mucosal inflammation. This omega-6 fatty acid acts as a direct precursor for the synthesis of antiinflammatory prostaglandins, specifically prostaglandin El. In fact, oral administration of gamma-linolenicacid has been found to be as effective as direct administration of prostaglandin El for reducing mucosal inflammati~n.~~

Bovine Colostrum Bovine colostrum is rich in nutrients, antibodies, and growth factors and appears to reduce NSAID-induced GI damage in humans. The multiple growth factors contained in colostrum are thought to protect against the proteolytic digestion of immunoglobulins.Preliminary studies suggest that this supplement could be a novel therapy for both the prevention and treatment of NSAID enteropathy.@

MacetyI-D-g lucosamine N-acetyl-D-glucosaminehas been found to support glycoprotein synthesis in patients with inflammatorybowel

disease and colon cancer.67The intestinal glycocalyx is the most superficial, viscous layer of the gut mucosa and serves to protect the underlying tissues from enzyme exposure, acid activity, and bacterial assault. Abnormalities in glycoprotein synthesis that inhibit the N-acetylation of glucosamine-6-phosphate have been found in patients with inflammatory bowel disease. This inhibition diminishes the protective properties of the glycocalyx, making the intestinal mucosa more vulnerable to insult and inflammation. N-acetyl-D-glucosamine is readily absorbed via passive diffusion through the gut lumen and is incorporated into the glycocalyx. Therefore when exogenously administered it is able to bypass the defective acetylation step, allowing normal glycoprotein formation to occur. Studies have shown N-aCetyl-D-glUCOSamine to be an effective promoter of Bifidobacterium;it also can inhibit the adherence of Candidu albicans to the gut wall. In addition, N-aCetyl-D-glUCOS~mine binds to dietary lectins, thereby reducing their harmful effects in the i n t e ~ t i n e . ~ ~

Sodium Cromoglycate Beneficial changes in intestinal permeability have been observed in children with food allergy after the administration of sodium cr~moglycate.~~ Sodium cromoglycate has been found to stabilize mast cells and IgE-producing cells in the lamina propria of the gut and to reduce local inflammation that can contribute to increased intestinal permeability.

Bombesin Research has now identified bombesin, a tetradecapeptide, as an important immunopotentiating substance in the intestine. Bombesin has been found to promote sIgA production and increase intestinal mucosal height, providing protection against bum-induced bacterial translocation in the animal model.70

CONCLUSION Intestinal barrier function has important implications for the etiology and pathogenesis of numerous intestinal and systemic diseases. Using lactulose and mannitol as markers to measure intestinal permeability is a safe, welltolerated, and noninvasive way to assess the integrity of the small bowel. Intestinal permeability testing can be used as a screening tool to identdy patients who require further, more invasive investigation, or to assess clinical progress and response to therapy7Izn

Supplementary Diagnostic Procedures

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24. Picco P, Gattomo M, Marchese N, et al. Increased gut permeability in juvenile chronic arthritides: a multivariate analysis of the diagnostic parameters. Clin Exp Rheumatol2OOO;18:773-778. 25. Jenkins RT, Rooney PJ, Jones DB, et al. Increased intestinal permeability in patients with rheumatoid arthritis: a side-effect of oral nonsteroidal anti-inflammatory drug therapy? Br J Rheumatol 1987;26:103-107. 26. Bjamason I, Williams P, So A, et al. Intestinal permeability and inflammation in rheumatoid arthritis effects of non-steroidal antiinflammatory drugs. Lancet 1984;24;2(8413):171-1174. 27. Wamn CP. Arthritis associated with Salmonella infections. Ann Rheum Dis 1970;29:483487. 28.Berden JH, Muytjens HL, van de Putte LB. Reactive arthritis associated with Campylobacter jejuni enteritis. Br Med J 1979;1(6160): 380-381. 29. Ebringer A, Cox NL, Abuljadayel I, et al. Klebsiella antibodies in ankylosing spondylitis and Proteus antibodies in rheumatoid arthritis. Br J Rheumatol 1988;27(Suppl2):72-85. 30.Ah0 K: Yersinia arthritis. In Miclants H, Veys EM, eds. Spondoarthrpathies: involvement of the gut. Amsterdam: Excerpta Medica, 198793-95. 31. Bjamason I, Peters TJ: Intestinal permeability, non-steroidal antiinflammatory drug enteropathy and inflammatory bowel disease: an overview. Gut 1989;30:22-28. 32. Smith MD, Gibson RA, Brooks PM: Abnormal bowel permeability in ankylosing spondylitis and rheumatoid arthritis. J Rheumatol 1985;12299-305. 33. Morris AJ, Howden CW, Robertson C, et al. Increased intestinal permeability in ankylosing spondylitis-primary lesion or drug effect? Gut 1991;32:1470-1472. 34. Martinez-Gonzalez 0, Cantero-Hinojosa J, Paule-Sastre P, et al. Intestinal permeability in patients with ankylosing spondylitis and their healthy relatives. Br J Rheumatol1994;33:644-647. 35. Aldersley MA, Howdle PD. Intestinal permeability and liver disease. Eur J Gastroenterol Hepatol1999;11:401-403. 36. Parlesak A, Schafer C, Schutz T, et al. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol2OOO;32742-747. 37. Bjamason I, Peters TJ, Wise RJ. The leaky gut of alcoholism: possible route of entry for toxic compounds. Lancet 1984;1(8370):79-182. 38. Aabakken L. Small-bowel side-effects of non-steroidal antiinflammatory drugs. Eur J Gastroenterol Hepatol 1999;11:383-388. 39. Somasundaram S, Hayllar H, Rafi S, et at. The biochemical basis of non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract: a review and a hypothesis. Scand J Gastroenterol 1995;30289-299. 40.Bjamason I. Forthcoming non-steroidal anti-inflammatory drugs: are they really devoid of side effects? Ital J Gastroenterol Hepatol 1999;31(S~ppl1):S27-S36. 41. Feltis BA, Kim AS, Kinneberg KM, et al. Clostridium dificile toxins may augment bacterial penetration of intestinal epithelium. Arch Surg 1999;134(11):1235-1241. 42. Buret AG, Mitchell K, Muench DG, et al. Giardia lamblia disrupts tight junctional Z(T1 and increases permeability in non-transformed human small intestinal epithelial monolayers: effects of epidermal growth factor. Parasitology 2002;125(Pt 1):ll-19. 43. Dagci H, Ustun S, Taner MS, et al. Protozoon infections and intestinal permeability. Acta Trop 2002;81:1-5. 44.Serrander R, Magnusson KE, Sundqvist T. Acute infections with Giardia lamblia and rotavirus decrease intestinal permeability to low-molecular weight polyethylene glycols (PEG 400). %and J Infect Dis 1984;16:339-344.

Intestinal Permeability Assessment 45. Riordan SM, McIver CJ, Thomas DH, et al. Luminal bacteria and small-intestinal permeability. Scand J Gastrwnterol1997;32:556-563. 46. Welsh FK, Farmery SM, MacLennan K, et al. Gut barrier function in malnourished patients. Gut 1998;42:396-401. 47. Anup R, Aparna V, Pulimood A, et al. Surgical stress and the small intestine: role of oxygen free radicals. Surgery 1999;125:560-569. 48. Faries PL, Simon RJ, Martella AT, et al. Intestinal permeability correlates with severity of injury in trauma patients. J Trauma 1998;44:1031-1035. 49. Pledger JV, Pearson AD, Craft AW, et al. Intestinal permeability during chemotherapy for childhood tumours. E u r J Pediatr 1988; 147123-127. 50. Fazeny-Dorner B, Veitl M, Wenzel C, et al. Alterations in intestinal permeability following the intensified polydrug-chemotherapy IFADIC (ifosfamide,Adriamycin, dacarbazine). Cancer Chemother Pharmacol2002;49:294-298. 51. Inutsuka S, Takesue F, Yasuda M, et al. Assessment of the intestinal permeability following postoperative chemotherapy for human malignant disease. Eur Surg Res 2003;35:22-25. 52. Bland JS, Costarella L, Levin B, et al. Clinical nutrition: a functional approach. Gig Harbor, WA: Institute for Functional Medicine, 1999. 53. van Elburg RM, Uil JJ, Kokke ET, et al. Repeatability of the sugarabsorption test, using lactulose and mannitol, for measuring intestinal permeability for sugars. J Pediatr Gastroenterol Nutr 1995;20184-188. 54. Souba WW, Smith RJ, Wilmore DW. Glutamine metabolism by the intestinal tract. J Parenter Enteral Nutr 1985;9:608-617. 55. Klimberg VS, Salloum RM, Kasper M, et al. Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation. Arch Surg 1990;125:1040-1045. 56. Wilmore DW, Smith RJ, O'Dwyer ST, et al. The gut: a central organ after surgical stress. Surgery 1988;104917-923. 57. Klimberg VS, Souba WW, Dolson DJ, et al. Prophylactic glutamine protects the intestinal mucosa from radiation injury. Cancer 1990;6662-68. 58. Klein S. Glutamine: an essential nonessential amino acid for the gut. Gastroenterology 1990;99:279-281. 59. Souba WW, Klimberg VS, Plumley DA, et al. The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J Surg Res 1990;48:383-391.

60. Alverdy JC. Effects of glutamine-supplemented diets on immunology of the gut. J Parenter Enteral Nutr 1990;14(4Suppl):109S113S. 61. Johansson JE, Ekman T. Gut mucosa barrier preservation by orally administered IgA-IgG to patients undergoing bone marrow transplantation: a randomized pilot study. Bone Marrow Transplant 1999;24:35-39. 62. Isolauri E, Sutas Y, Kankaanpaa P, et al. Probiotics: effects on immunity. Am J Clin NU~I2001;73(2 S~ppl):444S-45OS. 63. Caplan MS, Miller-Catchpole R, Kaup S, et al. Bifidobacterial supplementation reduces the incidence of necrotizing enterocolitis in a neonatal rat model. Gastroenterology 1999;117577-583. 64.Rosella 0, Sinclair A, Gibson PR. Polyunsaturated fatty acids reduce non-receptor-mediated transcellular permeation of protein across a model of intestinal epithelium in vitro. J Gastroenterol Hepatol2000;15:626-631. 65. Horie T, Nakamaru M, Masubuchi Y. Docosahexaenoic acid exhibits a potent protection of small intestine from methotrexateinduced damage in mice. Life Sci 1998;62(15):333-1138. 66. OSullivan MA, OMorain CA. Nutritional therapy in Crohn's disease. Inflamm Bowel Dis 1998;4:55-53. 67. Ackerson A, Resnick C. The effects of L-glutamine, N-acetylD-glucosamine,gamma-linolenic acid and gamma-oryzanolon intestinal permeability. Townsend Letter for Doctors January 1993, p 20. 68. Playford RJ, MacDonald CE, Calnan DP, et al. Co-administration of the health food supplement, bovine colostrum, reduces the acute non-steroidal anti-inflammatory drug-induced increase in intestinal permeability. Clin Sci (Lond) 2001;100(6):627-633. 69. Falth-Magnusson K, Kjellman NI, Magnusson KE, et al. Intestinal permeability in healthy and allergic children before and after sodium-cromoglycate treatment assessed with different-size polyethyleneglycols (PEG 400 and PEG 1000).Clin Allergy 1984;14: 277-286. 70. Chen LW, Hsu CM, Huang JK, et al. Effects of bombesin on gut mucosal immunity in rats after thermal injury. J Formos Med Assoc 2000;99:491-498. 71. Travis S, Menzies I. Intestinal permeability: functional assessment and significance. Clin Sci (Lond) 1992;82:471-488. 72. Pearson AD, Eastham EJ, Laker MF, et al. Intestinal permeability in children with Crohn's disease and coeliac disease. Br Med J (Clin Res Ed) 1982;285(6334):20-21.

Laboratory Tests for the Determination of Vitamin Status Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 251

Conclusion 253

Assessment of Vitamin Status 251 Water-Soluble Vitamins 251 Fat-SolubleVitamins 253

INTRODUCTION Laboratory assessment of vitamin status is a significant challenge for the clinician. Although measurement of blood and serum levels is easily available, their clinical value is limited to the detection of severe deficiencies. Detection of functional deficiencies requires far more sophistication.

ASSESSMENT OF VITAMIN STATUS See Table 24-1 for laboratory tests and optimal ranges for common

Water-Soluble Vitamins Ascorbic Acid (Vitamin C) Assessment of vitamin C is particularly difficult because ascorbate readily oxidizes in assay samples. In addition, serum levels reflect recent dietary uptake rather than actual tissue levels. Leukocyte levels are not as susceptible to dietary levels but are also readily affected by infection, hypoglycemia, and many common prescription and over-the-counter drugs. The popular lingual ascorbate test does not appear to be reliable because it does not correlate very well with leukocyte or serum levels. The loading test, if carefully controlled, is probably most accurate, although good standard ranges have yet to be determined.

Biotin Biotin is a vitamin B complex especially affected by oral antibiotics. Food is a poor source of this vitamin, making humans more dependent on gut flora sources.

Elevation of beta-hydroxyisovalarate due to deficiency of the biotin-dependent enzyme appears a useful measure.

Folate Serum folate is too greatly affected by recent consumption to be clinically useful. Homocysteine levels may be elevated because of deficiency of vitamins B6 and/or BI2. RBC folate is more accurate, but it is not widely available, it is expensive, and results vary depending on assay methods. The neutrophil hypersegmentation test is a useful functional test. A deficiency of folate (as well as vitamin BI2) causes an overaging of white cells, which results in increased lobulation of their nuclei. The test result may not be reliable during pregnancy. See also Chapter 18 for a more complete discussion.

Niacin Although measurement of nicotinic acid in the blood is not very reliable, measurement of its metabolites provides a clinically useful function assessment. Several metabolites tests are now available.

Pantothenic Acid Blood pantothenic acid does not correspond well with dietary intake. Measurement of urinary excretion of pantothenic acid appears reliable.

Pyridoxine Several procedures are available for assessing vitamin B6 status. Unfortunately, substantial agreement on the best methodology has not been established,because variations in phenotypes sigruficantly alter the results of functional and loading tests. The active form of pyridoxine (P5P) is 251

Supplementary Diagnostic Procedures

Nutrient

Test

Acceptable level

Serum Leukocyte Load test

>0.3 mg/dl 30 pg/l O8 WBCs 0.3-2.0 mg/hr in control 24-49 mg/hr after 500 mg

Biotin

Beta-hydroxyisovalerate

QO pg/mg creatinine (overnight urine)

Folate

RBC folacin Neutrophil hypersegmentation Serum homocysteine CBC

>160-650 ng/ml ~30% with five or more lobes c10 pmol/L Macrocytic anemia

Niacin

Urinary Kmethylnicotinamide RBC NADlNADP

>1.6 mag creatinine >1.o

Pantothenic acid

Urinary pantothenic acid

>1 mg/day

Pyridoxine

Serum level Tryptophan load EGOT EGPT Plasma pyridoxal Serum homocysteine

>50ngml <35 mg/24 hr xanthurenic acid

Water-soluble Ascorbic acid

Riboflavin

4 . 5 (ratio) 4.25 >8 ng/ml 4 0 pmoWL

RBC glutathione reductase FAD effect

4 0 % increase

Thiamine

RBC transketolase

4 5 % increase

Vitamin B12

Serum B12 Urinary methylmalonic acid Serum homocysteine

<5 pg/rng creatinine 4 0 prnol/L

Plasma retinol: 0-5months 6 months-17 years Adult

15-60 pg/dl: >20 >30 >20

Plasma carotene: 0-5months 6-11 months 1-17 years Adult Pregnancy

80-400 pg/dl: >10

Fat-soluble Vitamin A

>150 pg/ml

>30 9 0 >40 >80 10-80 ng/ml 21-45 paml

Vitamin D

Cholecalciferol (D3) 1,25-dihydroxycholecalciferol

Vitamin E

Serum tocopherol RBC hemolysis in H202 Serum tocopherol/triglyceride

>0.7mg/lOO dl

Abnormal prothrombin antigen assay

4 0 ng/ml

Vitamin K

40% 35-120

Data from references 1-5. 'EGOS; Erythrocyte glutamic oxaloacetic transaminase; EGPS; erythrocyte glutamic pyruvic transaminase; FAD, flavin adenine dinucliotide; NAD, nicotinamide adenine dinucleotide; NADF: nicotinamide adenine dinucleotide phosphate; RBC, red blood cell; WBC. white blood cell.

involved in some 60 enzymes, so deficient activity of these enzymes can be measured as a functional assessment of pyridoxine.

Riboflavin The most common measure of riboflavin is red blood cell (RBC) glutathione reductase activity. The enzyme is stimulated in vitro by the addition of flavin adenine

dinucleotide. Elevation of activity greater than 20% is suggestive of a functional deficiency. Blood riboflavin levels are not reliable because of technical difficulties in measurement.

Thiamine The most common measure of thiamin is RBC transketolase activity. The enzyme is stimulated in vitro by the

Laboratory Tests for the Determination of Vitamin Status

addition of thiamine pyrophosphate. Elevation in activity greater than 15% indicates a functional deficiency. The test is not reliable in patients with diabetes mellitus, pernicious anemia, or a significant negative nitrogen balance. More recently, measurement of amino acids and their ketoacid analogues that are excreted in thiamine deficiency is being used. (See Brally and Lord4for a more complete discussion.)

Vitamin BI2 Serum levels of vitamin BI2 are of value, though they do not track cerebrospinal fluid levels very well. Erythrocyte cell size is also not reliable, as neurologic signs and symptoms can precede macrocytosis by 6 to 12 months. Measurement of urinary methylmalonic acid is sensitive and accurate, especially when expressed as a ratio with the urinary creatinine measurement. Elevated homocysteine concentrations can be of same value as well.

Fat-Sohble Vitamins Vitamin A Although liver biopsy is the most accurate method of vitamin A assessment, other less invasive and less expensive methodologies are more appropriate. As with most other nutrients, serum levels of vitamin A fall significantly only after tissue reserves have been depleted. Fortunately, the dark adaptation test detects early deficiency of this nutrient (see Chapter 29).

1. Tiemey LM, McPhee SJ, Papdakis MA. Current medical diagnosis and treatment. Stamford, CT Appleton & Lange, 2001:1239-1244. 2. Rubenstein E, Federman DD. Scientific american medicine. New York

Scientific American, 2004:1-15. 3. Werbach MR Textbook of nutritional medicine. Tarzana, C A Third Line Press, 1999.

Vitamin D Serum levels of vitamin D, especially its activated dihydroxy form, are clinically accurate and useful.

Vitamin E Platelet vitamin E levels seem to be the most accurate measure of intake. However, a more clinically relevant measure appears to be the ratio of this important antioxidant with one of the key molecule it protects, triglycerides. Adipose and platelet levels of vitamin E are perhaps most accurate.

Vitamin K The various prothrombin and clotting time assays appear to be useful ways to assess vitamin K status.

CONCLUSION As described here, many procedures are now available for the assessment of functional vitamin status. Although research continues in this important area, the reader is advised to study carefully the discussion of urinary organic acids profiling (see Chapter 30). Utilizing metabolic products excreted in the urine now allows the clinician far greater specificity in recognizing dysfunctional enzyme systems, whether they are due to genetic deviations or nutritional deficiencies.

4. Brally J, Lord RS. Laboratory evaluations in molecular medicine. Norcross, GA: Institute for Advances in Molecular Medicine, 2001. 5. Homocysteine Lowering Trialists Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 1998;316:894-898.

Lactose Intolerance Testing Jeffrey Glen Baker, ND CHAPTER CONTENTS Introduction 255

Diagnosis of Lactose Intolerance 258 Nutritional History 258 Empirical Testing (Trial Elimination of Milk Products from the Diet) 258 Breath Testing 259 Genomic Testing 260 Histology 260 Blood and Urine Tests 260

Prevalence of Lactose Intolerance 255 Pathophysiology 256 Lactose Intolerance versus Lactase Deficiency 256 Lactose Intolerance versus Dairy Allergy

256

Adult-Type (Primary) Lactase Deficiency 257 Acquired-Type (Secondary) Lactase Deficiency 257

Other Types of Sugar Intolerances 260 Fructose 260 Sucrose 260 Maltose 260 Summary 261

Congenital Lactase Deficiency 257

INTRODUCTION Lactose intolerance is the inability to properly digest lactose, the disaccharide found in mammalian milk. Affecting

testing for adult-type lactase defi~iency.~ In addition to diagnostic testing, the patient’s nutritional history and the relationship between lactose consumption and GI symptoms are important for accurately diagnosing lactose intolerance.6

more than 50 million Americans, this condition is one of the most common gastrointestinal (GI) disorders seen by primary care physicians. Lactose intolerance is commonly overlooked because its symptomsAiarrhea, bloating, PREVALENCE OF LACTOSE and abdominal pain-are similar to those of many other INTOLERANCE conditions.’ However, when properly diagnosed, lactose intoleranceis easily treated with patient education, lactase Lactose intolerance affects an estimated 25% of supplementation, and dietary modifications2 Americans and 75%of adults ~ o r l d w i d eAs . ~ shown in Self-diagnosis and empirical testing for lactose intolTable 25-1, the condition occurs in people of all ethnic erance often produce erroneous results. When this backgrounds, with the highest prevalence observed in happens, nutrient-rich dairy foods may be removed Asians and blacks. from the diet unnecessarily; without appropriate subThe symptoms of lactose intolerance can range from stitutions, such an elimination diet may increase the minor dyspepsia, bloating, and flatulence to severe risk of osteoporosis, heart disease, and colon ~ a n c e r . ~ diarrhea and abdominal cramps (Box 25-1). Studies This common clinical mistake can be avoided if the suggest that lactose intolerance may contribute to, or proper diagnostic procedure is followed. Measuring cause, many other conditions with similar symptoms. For example, lactose intolerance and irritable bowel synbreath levels of hydrogen and methane is the method of choice for diagnosing lactose maldigestion.4 The disdrome (IBS) have nearly identical clinical presentations, covery of the gene responsible for ”lactase nonpersisand it is thought that the two conditions may overlap or tence” also has led to the development of genomic coexist. For this reason, lactose intolerance should 255

Supplementary Diagnostic Procedures

Prevalence of lactose intolerance by ethnic group GrouD

For susceptible children with lactose maldigestion, only 12 g of lactose (-1 cup of milk) daily has been shown to be associated with increased abdominal pain.19

Prevalence (%)

African blacks

97-100

PATHOPHYSIOLOGY

Asians

90-100

North American blacks

70-75

Mexicans

70-80

Persons of Mediterraneandescent

60-90

Persons of Jewish descent

60-80

Lactose is a disaccharide normally hydrolyzed by the lactase enzyme lactase-phlorizin hydrolase (LPH) into glucose and galactose, which are actively absorbed in the small intestine (Figure 25-1). Lactase deficiency, also known as lactase nonpersistence or hypolactasia, is a physiologic decline in activity of LPH. It occurs when LPH activity is decreased in the brush-border membrane of the distal duodenum and proximal jejunum, leading to lactose maldigestion.20 When amounts of lactose ingested exceed digestion capacity, lactose persists in the lumen, ultimately reaching the colon, where it may lead to osmotic retention of fluid and bacterial fermentation and thus cause the symptoms characteristic of lactose intolerance (see Figure 25-1).12 The development of lactose intolerance depends on a number of factors: (a) lactase deficiency, (b) relatively high lactose load, (c) rapid rate of gastric emptying, (d) rapid small bowel transit, and (e) inadequate beneficial bowel flora.*O

~~~~

North American whites

7-15

Northern Europeans

1-5

Indigestion Bloating Flatulence Nausea Diarrhea Failure to thrive Abdominal cramps

always be investigated in cases of IBS, a condition that affects up to 20%of Americans? LACTOSE INTOLERANCE VERSUS In fact, many cases of IBS may be caused by lactose LACTASE DEFICIENCY intolerance? In a study of 146 children with a diagnosis of IBS, 24.3%had evidence of lactose malabsorption on Lactose intolerance and lactase deficiency are not synonyhydrogen breath testing. Symptoms improved signifimous. Several studies document the absence of lactose cantly after these patients were started on a lactose-free intolerance in verified cases of lactase deficiency.21-23 diet. Five years later, 87.5%of the patients still reported In these cases, beneficial bacteria may hydrolyze lactose benefit from the diet. They also reported 75% fewer even in the absence of sufficient lactase activity." visits to outpatient clinics compared with the same time One should connect the patient's symptoms with the preceding the lactose-free diet (reduction from 192 to consumption of lactose before reaching a final diagnosis, 45 visit^).^ In another study, lactose malabsorption was because several tests (e.g., genomic testing) idenbfy lactase diagnosed in 68% of patients with IBS who denied a deficiency only. One benefit of breath testing is that history of lactose intolerance. Symptoms improved after it measures hydrogen production, which is associated a lactose-free diet was introduced.10 with both lactase deficiency and the symptoms of lactose Lactose intolerance may occur more frequently in intolerance. certain types of IBS. Rana et all1found that patients with Some researchers have proposed that lactose maldigesdiarrhea-predominant IBS have a higher incidence of tion resulting from lactase deficiency may be beneficial lactose intolerance (82%)than patients who have either in the absence of lactose intolerance; this theory is based spastic-type IBS or features of both IBS types. on the idea that lactose acts as a prebiotic in the colon.25,26 Other conditions causing intestinal mucosal damage and villus atrophy may reduce the activity of the LACTOSE INTOLERANCE VERSUS enzyme lactase, which is needed to digest lactose. For DAIRY ALLERGY this reason, lactose intolerance has been observed as a secondary feature in celiac disease, tropical sprue, acute Lactose intolerance and dairy allergy are quite different. intestinal infections, neomycin toxicity, cystic fibrosis,12 Lactose intolerance results from the maldigestion of alc~holism,'~ pelvic radiation the rap^,'^ and Crohn's dairy carbohydrate (lactose), whereas dairy allergy is an disease.15Treating the underlying condition has resulted immune response to dairy proteins (e.g., casein, lactalbuin restored lactase activity.16 min, whey). Dairy allergy may involve reactions that A number of studies suggest that transient lactose affect the GI tract, skin, respiratory tract, or multiple intolerance also is associated with infantile ~ o l i c . ' ~ , ' ~systems, as in systemic anaphylaxis. These immediate

Lactose IntoleranceTesting

Figure 25-1

reactions often are mediated by immunoglobulin E (IgE) and can cause severe morbidity and even death; however, in such cases, dietary elimination of dairy products is associated with good prognosis.27The prevalence of IgE-mediated allergic reaction to dairy protein in the general population is estimated at a 1%to 3%,being highest in infants and lowest in adults. However, the prevalence of IgG-mediated allergic reactions may be higher.

ADULT-TYPE (PRIMARY) LACTASE DEFICIENCY It is theorized that the ability to digest lactose in adulthood (lactase persistence) is the result of a relatively new evolutionary genetic mutation that occurred after the domesticationof farm animals5This theory could explain why increased lactase persistence is found primarily in northern Europeans, where dairy farming began. In other populations, adult-type lactase deficiency is a common autosomal-recessive condition resulting from the physiologic decline in the activity of LPH that occurs after weaning. The single nucleotide polymorphisms C/T-13910 and G/A-22018 contribute to the lactase non-persistence phenotype. C/T-13910 occurs in distantly

Lactose digestion.

related populations, indicating that it is the original form of the gene.

ACQUIRED-TYPE (SECONDARY) LACTASE DEFICIENCY Because LPH is located in the brush border of gut mucosal cells, its deficiency may be secondary to diseases that damage the jejunal mucosa. If mucosal integrity is restored, lactase activity should normalize. One study showed that 48% (21/44) of patients with celiac disease tested positive for lactose maldigestion. All patients tested negative for lactose maldigestion after 8 weeks of a gluten-free diet, indicating that mucosal integrity and lactase activity had been re~t0red.l~

CONGENITAL LACTASE DEFICIENCY Congenital lactase deficiency (alactasia) is a very rare inborn error of metabolism characterized by the absence of lactase. At birth, lactase is not detectable in affected infants. Clinical symptoms, which include severe diarrhea, dehydration, and malnutrition, appear during the first week with the consumption of lactose. Because

Supplementary Diagnostic Procedures

congenital lactase deficiency persists throughout life, persons with this condition must always avoid lactosecontaining foods?

DIAGNOSIS OF LACTOSE INTOLERANCE Controversy surrounds the subject of lactose intolerance, stemming from the dramatic decrease in dairy consumption that can result from its diagnosis. Numerous studies show a correlationbetween decreased dairy consumption and a rise in calcium-dependent conditions, such as osteoporosis, heart disease, and colon cancer.2835Studies also indicate that food-based calcium is a better source of this nutrient than supplements. In a metaanalysis of 42 randomized, controlled calcium-intervention trials, Griffith et a131 concluded that dietary sources of calcium more effectively lowered blood pressure. Because dairy foods are the richest and best-absorbed dietary sources of calcium, careful diagnosis should be made before these foods are eliminated from the patient’s diet. This diagnosis should be based on nutritional history, the relationship between diet and GI symptoms, and diagnostic testing: Dairy consumption may have health consequences unrelated to lactose intolerance (e.g., dairy allergy) that may require further investigation.

Obvious Sources Milk (whole, skim, dry powdered, evaporated) Cheeses Butter, many margarines Goat‘s milk Half-and-half cream Ice cream and many sherbets Yogurt Hidden Sources Artificial sweeteners containing lactose Breads, biscuits and crackers, doughnuts made with milk Breading on fried foods Breakfast and baby cereals containing milk solids Buttered or creamed foods (soups and vegetables) Cake and pudding mixes, many frostings Candies with milk chocolate Cookies made with milk Hot dogs, luncheon meats, sausage, hash, processed and canned meats Mayonnaise and salad dressings made with milk Nondairy creamers (except for Coffee Rich)

Nutritional History A detailed history of the patient’s average consumption of ladose-containing food should be obtained. Often, patients do not consider yogurt, ice cream, chocolate milk, and milk ingested with cereal as important sources of lactose. They also may not be aware that lactose is added to many nondairy products to provide texture, flavor, and browning and to absorb flavors, aromas, and food colors (Box 25-2). In addition, because of its excellent binding ability, lactose is contained in many drugs and overthecounter products (Box 25-3).Idenhfymg all sources of lactose is necessary to (a) identrfy the potential relationship between GI symptoms and lactose consumption and (b)develop an effective lactose-free diet, if necessary.

EmpiricalTesting (Trial Elimination of Milk Products from the Diet) If the patient experiences symptoms after consuming food products containing lactose, lactose intolerance should be considered. A temporary exclusion of all lactose-containing products from the diet as a preliminary diagnostic procedure may be helpful. However, diagnosis of lactose intolerance should not be based solely on this empirical testing for the following reasons: All sources of lactose may not be eliminated. Many sources of lactose are hidden (see Box 25-3) and may produce symptoms during the testing period, resulting in falsenegative results.

Prescription Drugs Ativan Burnex Calan Coumadin tablets ERYC Glucotrol Lasix Lotronex Mevacor Premarin Prilosec Propecia Reglan Synthroid Vasotec Xanax Over-thecounter Drugs Actifed tablets Allbee C-800 Plus iron tablets Benadryl tablets Chlor-Trimeton Allergy tablets Ferro-Sequels lrnodium A-D caplets Marezine tablets Pepcid AC chewable Slow FE iron tablets Sudafed Plus tablets Unifed Chewable tablets

Lactose IntoleranceTesting

Unrelated symptoms may abate during testing period. Unrelated conditions with intermittent symptoms may lead to a false-positive results if the symptoms abate during the testing period.36

carbohydrate reaching the colon produce a detectable increase in breath hydrogen.51

Hydrogen and Methane Responses

The normal breath hydrogen level in a healthy, fasting patient is less than 10 ~ p m . ~ * Patients with lactose malabsorption show an increase Breath testing is the method of choice for diagnosing in breath hydrogen concentration of 20 pprn or more lactose maldigestion? It is sensitive and specific,J7simple to perform, noninvasive, and inexpensive.36Breath testing during the test peri0d.25~5~ Those who can absorb lactose may show a small variation in breath hydrogen (2 to is based on the ability of intestinal microbes to ferment 3 ppm) during the test period. carbohydrates, in this case lactose, producing hydrogen The normal breath methane level in a fasting or methane in the process. A fraction of these gases patient is 0 to 7 ppm. An increase of at least 12 ppm naturally diffuses from the bowel to the circulation and is of methane alone during the test is considered positive eliminated via the lungs. Because there is no other metafor lactose malabsorption, regardless of the hydrogen bolic production of hydrogen and methane, pulmonary r e s pon~e.4~,~5~ excretion of these gases may be used as an indirect measure of lactose maldigestion, indicating lactase defi~iency.~~ If both breath hydrogen and methane rise after a lactose challenge, the two responses are added to The benefits of breath testing are as follows: estimate the degree of malabsorption. The rises in Its results correlate strongly with the symptoms of breath hydrogen and methane levels together must be lactose i n t ~ l e r a n c e . ~ ~ 20 pprn or more to suggest lactose rnalab~orption.~~ It can be done at home by the patient or in the physiThe extent of elevation relates to the degree of cian’s o f f i ~ e . ~ ~ , ~ malabsorption: The lower challenge dose of lactose causes signifiRise of 20 to 40 ppm: mild absorption cantly fewer side effects than the large doses used in Rise of 40 to 80 ppm: moderate absorption blood- and urine-galactose tests.4I Rise of 280 ppm: severe malabsorption Breath testing is completely noninvasive. The breath hydrogen/methane test is the standard in pediatric cases in which other tests would be difficult False-Positive Results to perform.4245 False-positive results occur rarely and are usually a consequence of the following interfering factors: Historically, breath testing has measured hydrogen only. However, Tormo et a14 showed that methane is Fiber intake. Fiber should be avoided 24 hours produced instead of hydrogen in some patients with before the test. Ingesting fiber in food or in lactose malabsorption. They concluded that measuring supplements increases fermentation and hydrogen both gases is necessary for accurate diagnosis of lactose production.56-58 maldigestion. Other researchers suggest that although Exposure to tobacco smoke. Tobacco smoke increases methane is produced predominantly in some cases, hydrogen levels and should be avoided immediately hydrogen production correlates more strongly with before and during testing.59 symptoms; therefore hydrogen testing alone may be Sleeping. Sleeping between breath sample collections sufficient for the diagnosis of lactose i n t ~ l e r a n c e . ~ , ~ ~ may increase both hydrogen and methane levels.60 Breath testing using a radiolabeled lactose (C-13-lactose) challenge dose that produces 1302shows poor correlaFalse-Negative Results tion with lactose i n t ~ l e r a n c e . ~ ~ Breath hydrogedmethane testing has a false-negative Procedure rate of approximately 5%;the false-negative rate is 10% if only hydrogen is measured. False-negative results can After an overnight fast, a baseline breath sample is occur because of the following factors: collected 30 minutes after rising. The patient then ingests a challenge dose of lactose (up to a maximum of 25 g), Use of lactase supplements.61 and breath samples are collected 1,2, and 3 hours after Use of antibiotics prior to the test. Antibiotics decrease ingestion of the challenge dose.4g50 the bacteria that ferment Interpretation Use of laxatives or enemas prior to the test. These decrease hydrogen and methane responses in patients If lactose maldigestion is present, breath levels of with lactose malabsorption and reduce fermentation in hydrogen or methane will rise within 1 to 2 hours the colon.63 after ingesting the lactose challenge. As little as 2 g of

Breath Testing

Supplementary Diagnostic Procedures

Severe diarrhea or hyperacidic colon contents. Hyperacidity inhibits the production of hydrogen and promotes the production of methane by colonic bacteria.@*& One can reduce false-negative results as follows: Wait at least 1 week after antibiotic treatment and reestablish colonic flora. Avoid testing during severe diarrhea. Have the patient avoid lactase enzyme supplements 24 hours prior to the test.

of hydrogen and methane gases, which are thought to cause the symptoms of lactose intolerance. Bacteria may adequately metabolize lactose in the patient with hypolactasia; therefore a patient with the CC-recessive DNA code may not be lactose intolerant.

Histology An endoscopic biopsy of the small intestine can be tested

in vitro for its ability to metabolize lactose into glucose and galactose. This test is rarely used for disaccharide intolerance because of the expense and discomfort for patients.

High Baseline Levels

Blood and Urine Tests

An elevated baseline level of breath hydrogen indicates

Plasma testing for 13-glucose, using a challenge dose of 13C-lactose,has been shown to have increased ability to differentiate between those who can digest lactose digesters and those with maldige~tion.~~ However, this method has not been evaluated for its ability to identify symptoms directly related to lactose intolerance. Serum and urine testing for galactose change require large amounts of lactose (-2 g/kg of body weight), which commonly produce adverse reactions in lactasedeficient patients. Also these tests require oral ingestion of alcohol to suppress rapid hepatic metabolism of galactose. These added risks appear unnecessary because there is no evidence that these methodologies are superior to breath testing?]

that one or more interfering factors are present. Testing must be repeated to obtain reliable results. The degree of elevation can help to idenhfy interfering factors. A baseline breath hydrogen level >10 ppm can be due to: Improper fasting. Consumption of high-fiber foods the day before testing. Performance of test immediately after awakening.45 A baseline breath hydrogen level >20 ppm can be due to:

Possible small intestine bacterial overgrowth.66 Elevated fasting levels of hydrogen occur in up to one third of patients with small intestinal bacterial overgrowth6’ and may be caused by the fermentation of endogenous brush-border glycoproteins.bs Small intestine bacterial overgrowth may elevate baseline methane readings as we11.45,69,70

Genomic Testing Adult-type lactase deficiency is a common autosomalrecessive condition. No DNA variations have been found in the gene that encodes for LPH. However, haplotype analysis, disequilibrium mapping, and association analyses have linked adult-type lactase deficiency with an adjacent DNA variant, C/T-13910. In a study showing the distribution of genotypes in individuals with verified lactase persistence or nonpersistence, C/T-l3910 markers identified lactase nonpersistence in 100% of patients (n = 144) with homozygous recessive traits (CC) and lactase persistence in 100% of patients (11 = 187) with heterozygous- and homozygous-dominant traits (CT and TT,re~pectively).~ Genomic testing requires a single blood sample and avoids the diet restrictions, lengthy collection regimen, and potential for abdominal symptoms that are associated with breath testing. However, genomic testing identifies hypolactasia only. It does not identify the presence

OTHER TYPES OF SUGAR INTOLERANCES Inability to properly digest other types of saccharides can produce symptoms similar to those caused by lactose intolerance. For this reason, it may be necessary to investigate other types of sugar intolerances, especially in patients whose clinical test results do not support a diagnosis of lactose intolerance.

Fructose Fructose is a monosaccharide used as a sweetener in many soft drinks and is present in a number of fruits. Individuals with fructose malabsorption may suffer symptoms similar to lactose intolerance.

Sucrose Sucrose is common table sugar. Sucrase is needed to hydrolyze sucrose into glucose and fructose. If carbohydrate malabsorption symptoms exist but lactose testing results are negative, sucrose intolerance should be considered.

Maltose Maltose is contained in some foods, particularly grains. Maltase is necessary to hydrolyze maltose into two

Lactose Intolerance Testing

Although lactose intolerance is one of the most common GI disorders seen by primary care physicians, it remains underdiagnosed, especially when it overlaps or coexists with other conditions that have a similar clinical presentation. On the other hand, lactose intolerance may be erroneously diagnosed because of

improper diagnostic procedure. In this case, calciumrich dairy foods may be unnecessarily eliminated from the diet, raising the risk of osteoporosis, heart disease, and colon cancer. The majority of the world’s population is lactase deficient. However, lactose intolerance may not develop in all of these individuals. A comprehensive evaluation that incorporates diagnostic testing, the patient’s nutritional history, and the relationship between diet and GI symptoms is necessary for an accurate diagnosis. Breath testing for a change in hydrogen/methane production after a lactose challenge is the diagnostic method of choice.

1. Vemia P, Di Camillo M, Marinaro V. Lactose malabsorption, irritable bowel syndrome and self-reported milk intolerance. Dig Liver Dis 2001;33234-239. 2. Rusynyk RA, Still CD. Lactose intolerance. J Am Osteopath Assoc 2001;101:s10-12. 3.Moore BJ. Dairy foods: are they politically correct? Nutr Today 2003;3882-90. 4. Vemia P, Camillo MD, Marinaro V, Caprilli R. Effect of predominant methanogenic flora on the outcome of lactose breath test in irritable bowel syndrome patients. Eur J Clin Nutr 2003;57: 1116-1119. 5. Enattah NS, Sahi T, Savilahti E, et al. Identification of a variant associated with adult-type hypolactasia. Nat Genet 2002;30: 233-237. 6. Aurisicchio LN, Pitchumoni CS. Lactose intolerance: recognizing the link between diet and discomfort. Postgrad Med 1994;95:113116, 119-120. 7.Srinivasan R, Minocha A. When to suspect lactose intolerance: symptomatic, ethnic, and laboratory clues. Postgrad Med 1998;104 109-111,115-116,122-123. 8.Zaman A. Imtable bowel syndrome. Clin Cornerstone 2002;4 22-33. 9. Gremse DA, Nguyenduc GH et al. Irritable bowel syndrome and lactose maldigestion in recurrent abdominal pain in childhood. South Med J 1999;92:778-781. 10. Vemia P, Ricciardi MR, Frandina C, et al. Lactose malabsorption and irritable bowel syndrome: effect of a long-term lactose-free diet. Ital J Gastroenterol 1995;27117-121. 11. Rana SV, Mandal AK, Kochhar R, et al. Lactose intolerance in different types of irritable bowel syndrome in north Indians. Trop Gastroenterol2001;22:202-204. 12. Berkow R, Fletcher AJ, eds. The Merck manual, ed 16. Rahway, J: Merck, 19922322-830. 13. Keshavarzian A, Iber FL, Dangleis MD, Comish R. Intestinal-transit and lactose intolerance in chronic alcoholics. Am J Clin Nutr 1986;44:70-76. 14. Henriksson R, Franzen L, Sandstrom K, et al. Effects of active addition of bacterial cultures in fermented milk to patients with chronic bowel discomfort following irradiation. Support Care Cancer 1995;3:81-83. 15. von Tirpitz C, Kohn C, Steinkamp M, et al. Lactose intolerance in active Crohn’s disease: clinical value of duodenal lactase analysis. J Clin Gastroenterol2002;34:49-53. 16. Kanabar D, Randhawa M, Clayton P. Improvement of symptoms in infant colic following reduction of lactose load with lactase. J Hum Nutr Diet 2001;14359-363.

17. Moore DJ, Robb TA, Davidson GP. Breath hydrogen response to milk containing lactose in colicky and noncolicky infants. J Pediatr 1988;113:979-984. 18. Gremse DA, Greer AS, Vacik J, DiPalma JA. Abdominal pain associated with lactose ingestion in children with lactose intolerance. Clin Pediatr 2003;42:341-345. 19. Murphy MS, Sood M, Johnson T. Use of the lactose H2breath test to monitor mucosal healing in coeliac disease. Acta Paediatr 2002;91:141-144. 20. Saavedra JM, Perman JA. Lactose malabsorption and intolerance. In Dulbecco R, ed. Encyclopedia of human biology. New York Academic Press, 1991. 21. Peuhkuri K, Vapaatalo H, Korpela R, Teuri U. Lactose intolerance: a confusing clinical diagnosis. Am J Clin Nutr 2000;71:600-602. 22. Suarez FL, Adshead J, Fume JK, Levitt MD. Lactose maldigestion is not an impediment to the intake of 1500 mg calcium daily as dairy products. Am J Clin Nutr 1998;68:1118-1122. 23. Yang Y, He M, Cui H, et al. The prevalence of lactase deficiency and lactose intolerance in Chinese children of different ages. Chin Med J (Engl) 2OOO;1131129-1132. 24.Rizkalla SW, Luo J, Kabir M, et al. Chronic consumption of fresh but not heated yogurt improves breath-hydrogen status and short-chain fatty acid profiles: a controlled study in healthy men with or without lactose maldigestion. Am J Clin Nutr 2000;7214741479. 25. Szilagyi A. Review article: lactose: a potential prebiotic. Aliment Pharmacol Ther 2000;161591-1602. 26. Segal I. Physiological small bowel malabsorption of carbohydrates protects against large bowel diseases in Africans. J Gastroenterol Hepatol2002;17249-252. 27. Bahna SL. Cow’s milk allergy versus cow milk intolerance. Ann Allergy Asthma Immunol2002;8956-60. 28.Park YK, Yetley EA, Calvo MS. Calcium intake levels in the United States: issues and considerations. Available online at http://mjao.org/ docrep/W7336T/w7336t06.htm 29.Lipkin M, Newmark H. Calcium and the prevention of colon cancer. J Cell Biochem Suppl1995;22:65-73. 30. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 1997;3361117-1124. 31. Griffith LE, Guyatt GH, Cook RJ, et al. The influence of dietary and nondietary calcium supplementation on blood pressure: an updated metaanalysis of randomized controlled trials. Am J Hypertens 1999;1284-92. 32. Lupton JR. Dairy products and colon cancer: mechanisms of the protective effect. Am J Clin Nutr 1997;66:1065-1066.

molecules of glucose. If carbohydrate malabsorption symptoms exist but lactose testing results are negative, maltose intolerance should be considered.

SUMMARY

Supplementary Diagnostic Procedures 33. Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. N Engl J Med 1999;340:101-107. 34. Holt PR, Atillasoy EO, Gilman J, et al. Modulation of abnormal colonic epithelial cell proliferation and differentiation by low-fat dairy foods: a randomized controlled trial. JAMA 1998;280: 10741079. 35. Lipkin M, Newmark H. Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. N Engl J Med 1985;313:1381-1384. 36. Montes RG, Perman JA. Lactose intolerance. Pinpointing the source of nonspecific gastrointestinal symptoms. Postgrad Med 1991;89 175-178,181-184. 37. Newcomer AD, McGill DB, Thomas PJ, Hofman AF. Prospective comparison of indirect methods for detecting lactase deficiency. N Engl J Med 1975;2931232-1236. 38. Brummer RJ, Armbrecht U, Bosaeus I, et al. The hydrogen (HJ breath test. Sampling methods and the influence of dietary fibre on fasting level. Scand J Gastroenterol 1985;201007-1013. 39. Zhong Y, Yin W, Huang C, Vonk RJ. [Study on the expired gas of subjects with lactose intolerance by using H,/13C02 breath test]. Wei Sheng Yan Jiu 200231:180-183. 40.Metz G, Jenkins DJ, Peters TJ,et al. Breath hydrogen as a diagnostic method for hypolactasia. Lancet 1975;1(7917):155-157. 41.Lerch MM, Rieband HC, Feldberg W, Matem S. Concordance of indirect methods for the detection of lactose malabsorption in diabetic and nondiabetic subjects. Digestion 1991;48:81-88. 42. Barillas-Mury C, Solomons NW. Test-retest reproducibility of hydrogen breath test for lactose maldigestion in preschool children. J Pediatr Gastroenterol Nutr 1987;6281-285. 43. Barillas-Mury C, Solomons NW. Variance in fasting breath hydrogen concentrations in Guatemalan preschool children. J Pediatr Gastroenterol Nutr 1987;6:109-113. 44. Solomons NW, Barillas C. The cut-off criterion for a positive hydrogen breath test in children: a reappraisal. J Pediatr Gastroenterol Nutr 1986;5:920-925. 45. Hamilton LH. Breath tests and gastroenterology. Milwaukee: QuinTron Instruments Company, 1998. 46.Tormo R, Bertaccini A, Conde M, et al. Methane and hydrogen exhalation in normal children and in lactose malabsorption. Early Hum Dev 2001;65(Suppl):S165-172. 47. Montes RG, Saavedra JM, Perman JA. Relationship between methane production and breath hydrogen excretion in lactose-malabsorbing individuals. Dig Dis Sci 1993;38445-448. 48. Bond JH, Levitt MD. Quantitative measurement of lactose absorption. Gastroenterology 1976;70:1058-1062. 49. Kolars JC, Levitt MD, Aouji M, Savaiano DA. Yogurt: an autodigesting source of lactose. N Engl J Med 1984;3101-3. 50. Robb TA, Davidson GP. Two-hour lactose breath hydrogen test. J Pediatr Gastroenterol Nutr 1987;6481-482. 51.Levitt MD. Production and excretion of hydrogen gas in man. N Engl J Med 1969;281:122-127. 52. Newcomer AD. Screening tests for carbohydrate malabsorption. J Pediatr Gastroenterol Nutr 19843:6-8.

53. Jain NK, Patel VP, Pitchumoni CS. Efficacy of activated charcoal (AC) in reducing intestinal gas: a double blind clinical trial. Am J Gastroenterol 1986;81:532-535. 54. Cloarec D, Bomet F, Gouilloud S, et al. Breath hydrogen response to lactulose in healthy subjects: relationship to methane producing status. Gut 1990;31:300-304. 55. Fritz M, Siebert G, Kasper H. Dose dependence of breath hydrogen and methane in healthy volunteers after ingestion of a commercial disaccharide mixture, Palatini. Br J Nutr 1985;54389-400 56. Behall KM, Scholfield DJ, van der Sluijs AM, Hallfrisch J. Breath hydrogen and methane expiration in men and women after oat extract consumption. J Nutr 1998;128:79-84. 57. Behall KM, Howe JC. Breath-hydrogen production and amylose content of the diet. Am J Clin Nutr 1997;65:1783-1789. 58.Kondo T, Nakae Y. Breath hydrogen and methane excretion produced by commercial beverages containing dietary fiber. J Gastroenterol 1996;31:654658. 59. Rosenthal A, Solomons NW. Time-course of cigarette smoke contamination of clinical hydrogen breath-analysis tests. Clin Chem 1983;29:1980-1981. 60.Solomons N. Evaluation of carbohydrate absorption: The hydrogen breath test in clinical practice. Clin Nutr J 1984;371-78. 61.Lerch MM, Rieband HC, Feldberg W, Matem S. Concordance of indirect methods for the detection of lactose malabsorption in diabetic and nondiabetic subjects. Digestion 1991;48:81-88. 62. Gilat T, Ben Hur H, Gelman-Malachi E, et al. Alterations of the colonic flora and their effect on the hydrogen breath test. Gut 1978;19602-605. 63. Solomons NW, Garcia R, Schneider R, et al. H2 breath tests during diarrhea. Acta Paediatr Scand 1979;68:171-172. 64. Vogelsang H, Ferenci P,Frotz S, et al. Acidic colonic microclimate possible reason for false negative hydrogen breath tests. Gut 1988;29:21-26. 65.Perman JA, Modler S, Olson AC. Role of pH in production of hydrogen from carbohydrates by colonic bacterial flora: studies in vivo and in vitro. J Clin Invest 1981;67643-650. 66. Kerlin P, Wong L. Breath hydrogen testing in bacterial overgrowth of the small intestine. Gastroenterology 1988;95982-988. 67. Romagnuolo J, Schiller D, Bailey RJ. Using breath tests wisely in a gastroenterology practice: an evidence-based review of indications and pitfalls in interpretation. Am J Gastroenterol 2002;97 1113-1126. 68. Perman JA, Modler S. Glycoproteins as substrates for production of hydrogen and methane by colonic bacterial flora. Gastroenterology 1982;83:388-393. 69. Perman ]A, Modler S, B a n RG, Rosenthal P. Fasting breath hydrogen concentration: normal values and clinical application. Gastroenterology 1984;87:1358-1363. 70. Kerlin P, Wong L, Harris B. Lactose tolerance despite hypolactasia in adult celiac disease. Gastroenterology 1986;901491. 71. Vonk RJ, Lin Y, Koetse HA, et al. Lactose (ma1)digestionevaluated by the '.T-lactose digestion test. Eur J Clin Invest 2000;30140-146.

Metal Toxicity: Assessment of Exposure and Retention David W. Quig, PhD CHAPTER C O N T E N T S Introduction 263 Assessment of Toxic Metal Exposure 264 Hair Elemental Analysis 264 Blood Analysis: Toxic Metal Exposure 265 Blood Analysis: Biomarkers of Toxic Effects 266 Urinalysis of Toxic Metals: Unprovoked 266 Urinalysis: Biomarkers of Renal Toxicity 267

DMPS 267 DMSA 269 Nonpharmaceutical Agents

270

Fecal Metals Analysis 270 Conclusion 271

Assessment of Retention: Urinalysis, Provocation Tests 267 EDTA 267

INTRODUCTION The incidence of high-level exposure to toxic metals and resultant acute "poisoning" is relatively rare, most commonly associated with occupational exposure, and the associated symptoms are well defined and accepted in the conventional medical and toxicology arenas. A plethora of published research has clearly defined many of the precise biochemical mechanisms by which specific metals elicit a vast array of adverse physiologic effects that can culminate in neurotoxicity, nephrotoxicity, cardiovascular and pulmonary disease, cancer, teratogenicity, and dysregulation of immune function. Despite knowledge of the effects of metals on the most basic biochemical processes that affect human health, the concept that "subthreshold" levels of metals in the body can negatively affect health and daily functioning is not generally accepted by the dominant medical community. However, with respect to lead, mercury, and cadmium, a consultant to the National Institute of Environmental Health Sciences stated that the margin between the levels of exposure for people in industrialized nations and the levels of exposure that are currently recognized as producing the lowest adverse effect levels is The methods for assessing metal toxicity established as standards for medical practice are best suited for

detection of acute metal poisoning or recent or ongoing exposure but do not provide an accurate determination of the actual levels of metals that have accumulated in the body over extended periods. The purpose of this chapter is to provide an overview of the various traditionally accepted and other laboratory tests for the assessment of (a) exposure to toxic metals and (b) the net retention and physiologic impact of toxic metals. It is beyond the scope of this chapter to discuss the sources and symptoms associated with long-term exposure to the most commonly encountered metals. Thorough reviews of these topics have been published el~ewhere.~~ The most commonly encountered toxic metals (mercury, lead, cadmium, and arsenic) are natural constituents of the earth's crust, but their increasing abundance in air, water, and surface soil results primarily from industrial demand and energy production (pollution).Consequently the environment today has become contaminated to the point that we are all, regardless of occupation, at higher risk for at least long-term, low-level exposure to toxic metals. However, consistent with the basic principles of toxicology, confirmation of exposure is by no means valid documentation of clinically significant retention and toxicity. For a given individual, toxicity is exhibited only when the level of retention exceeds physiologic 263

Supplementary Diagnostic Procedures tolerance, and net retention (body burden) is determined by the relative rates of toxic metal assimilation and excretion. Two important concepts that have been largely overlooked with respect to metal toxicity may explain the discrepancies of opinion expressed by practitioners of traditional medicine and preventive medicine. The first is the potential for the combined effects of multiple toxic metals, which can have not only additive but also synergistic adverse physiologic effects! This concept should be further extended to include consideration of the potential combined effects of toxic chemicals and toxic metals, the total toxic load. The broad heading of toxic chemical entities includes not only naturally occurring and synthetic exogenous compounds but also noxious endogenous compounds derived from a severely dysbiotic or poorly functioning gastrointestinal (GI) system. The second is the remarkable individual variability in susceptibility or tolerance to toxic metals. Established precedence for the phenomena has been provided by such observations as the rapid contact allergic response that is elicited by mercury in a small percentage of a population? Individual variability in susceptibility is likely determined in part by genetic polymorphisms, nutritional status, and the total toxic l ~ a d . ~The , ' ~factors of multiple toxins and individual variability impede simple interpretation of any test result for an individual patient. No single perfect test is available for the diagnosis of chronic metal toxicity; any test result must be interpreted in conjunction with a thorough review of a patient's physical findings, exposure history, and symptoms. However, the symptoms associated with a chronic, low rate of toxic metal retention appear to be diverse and rather nondescript, and they may not be fully expressed until later in life. Clear examples of such latency of symptom expression have been provided for lead and hypertension" and cardiovascular mortality.I2 Therefore, to address the needs of clinicians who focus on preventive medicine as opposed to crisis management, the following review of laboratory tests emphasizes testing that has greater sensitivity with respect to detection of chronic "low-level" accumulation of the most commonly encountered toxic metals. In addition, an attempt has been made to distinguish between testing that is most appropriate for assessment of exposure and that for net retention and physiologic impact.

ASSESSMENT OF TOXIC METAL EXPOSURE Hair Elemental Analysis When performed properly, hair elemental analysis can serve as a qualitative screening test for exposure to toxic metals, but because of limitations, it cannot alone be considered a reliable method for the diagnosis of metal

toxicity. Hair is an excretory tissue that can provide a chronologic record of bioavailable trace elements in the body, and the hair content of mercury, arsenic, lead, and thallium has been used as evidence for the cause of death.I3Once metals are incorporated into growing hair there is no back-exchange into the body; therefore the concentration of metals in hair is usually far greater than that in blood or urine. The length of the hair specimen analyzed dictates the duration of time during which exposure occurred, and segmental analysis of hair can be used forensically to estimate the chronologic course of exposure. In situations in which exposure to toxic metals is more or less constant, the relationship between the concentrations in blood and tissues also should remain steady. A study of the lead and mercury content of hair from a long-deceased president of the United States was performed at the Armed Forces Institute of Pathology in Washington, DC,exemphfymg the potential utility of hair analysis for exposure to toxic rnetals.I4Detection of toxic metals in hair actually predates that in blood and urine.15 A growing number of peer-reviewed publications support the value of elemental analysis of hair specimens for the detection of exposure to toxic metals. For example, elevations of arsenic in both hair and urine confirmed arsenic exposure from a pesticide in an individual with peripheral neuropathy and macrocytosis.16Hair levels of lead, manganese, cadmium, and other toxic metals have been correlated with psychological conditions and deviant or violent beha~i0rs.I~ Lead, cadmium, and mercury levels in children's hair has been correlated with childhood intelligence. Hair analysis has been used to identify historical as opposed to current exposure to lead.'* School children with relatively high levels of lead in their hair had slower reaction times and less flexibility in changing their focus of attention than children with relatively low concentrations of lead in hair.19 The Agency for Toxic Substances and Disease Registry (ATSDR), the United States Environmental Protection Agency, and the National Academy of Sciences recognize the scientific validity of hair mercury levels as an indicator of maternal and fetal exposure to methylmercury. In a cognitive performance study of children in the Faroe Islands, there were detectable effects on brain function in the children whose mothers had elevated levels of hair mercury.20History of fish consumption and mercury in hair samples are considered the best indicators of human exposure to methylmercury?] Fish consumption among Scandinavianz and Tyrrhenian men,= Amazonian children," and people from the h4inamata Bay areaz4was positively correlated with hair and blood mercury levels. Note that hair elemental analysis definitely provides useful information about exposure to methylmercury (fish consumption); however, it is not nearly as useful for disclosing information about exposure to inorganic mercury as

Metal Toxicity: Assessment of Exposure and Retention

derived from dental amalgams.” The concentration of methylmercury in hair is about 300 times higher than that in In sharp contrast, about 75%of total hair arsenic is present in the inorganic form.26 Although an increasing number of peer-reviewed reports support the clinical utility of elemental analysis of hair for the assessment of exposure to specific toxic metals, some considerations prevent its acceptance by governmental agencies in the United States. In June 2001, the ATSDR convened a panel of scientists with some expertise in hair analysis or risk assessment to explore ”the state of the science of hair analysis.”27 Overall the discussion was objective and focused on the existing scientific data. A summary statement from the meeting concluded, ”In general, hair analysis results can provide limited qualitative insights into environmental exposures and rarely can answer questions about potential health effects.”28Primary concerns raised by the group pertained to uncertainties about the quantitative relationship among the actual ”internal dose,” the rate of incorporation into hair, and the current lack of wellestablished data to enable one to predict potential health effects for a given concentration of a specific metal in hair. Overinterpretation of the results of elemental analysis of hair is a serious concern shared by science-based laboratories and astute clinicians as well as the ATSDR. It should be kept in mind that the ATSDR has been interested in the use of hair analysis as an initial screening tool for inexpensive exposure biomonitoring of groups of people who are exposed to toxins at suspected sites of contamination. The goal of the ATSDR to be able to use hair elemental analysis as confirmation of toxicity is quite different from the use of the procedure in preventive or comprehensive medicine simply to provide an initial indication of exposure. The consensus report by the ATSDR is consistent with the aforementioned statement that hair analysis can provide some qualitative information about exposure to toxic metals but does not provide a basis for diagnosis of metal toxicity. As such, hair analysis may be helpful to clinicians as a first step toward idenhfying potential health problems that may be associated with toxic metal exposures before significant symptoms are expressed. Further testing should be performed before treatment options are considered. The clinician should be wary of laboratories that perform hair analysis as a vehicle to sell nutritional supplements and should be aware of interlaboratory variation.29Clinicians are recommended to use only laboratories that can validate their certification or accreditation and incorporate state-of-the-art methodologies for washing, digesting, and analyzing hair specAppropriate quality control characteristics and the validation of the establishment of reference ranges, accuracy, precision, and reliability of state of the art hair analysis have been d e s ~ r i b e d . ~ l - ~ ~

Blood Analysis: Toxic Metal Exposure For the most commonly encountered toxic metals, the current standard for diagnosis of metal toxicity is abnormally high concentrations in whole blood or urine. However, blood analysis for toxic metals is a better indicator of exposure than toxiaty in most cases. Distribution of metals such as lead in the body has been long recognized as initially dependent of the rate of delivery via the blood to various tissues and organs.34Subsequent redistribution then depends on the relative affinities of tissues for the metals and toxicodynamics, which can vary markedly among individuals. Tissue affinities for metals is determined in large part by the high relative intracellular concentrations of reduced glutathione and metall~thionein.~~ Further, blood levels can fluctuate considerably with intermittent exposure and assimilation. Thus determination of a single blood metal level does not accurately reflect total body retention, being more useful for assessment of recent or ongoing exposure.36 Examining kinetic models of metal metabolism shows that the blood metal compartment has the shortest biologic half-life. Metals leave the blood by means of excretion (urine, bile, and sweat) and transfer to tissues. The retention by tissues such as bone, kidneys, and brain accounts for the much longer biologic half-lives of most toxic metals in the body. This simple concept has been obviated in studies presented in the Physician’s Desk Reference.37 Adult and pediatric patients who had been diagnosed with lead toxicity on the basis of elevated blood lead values exhibited marked reductions in blood lead levels after chelation therapy with succimer. However, 2 weeks after cessation of chelation, blood lead levels rebounded to 60% to 85% of pretreatment levels (the rebound effect is associated to some degree with all pharmacologic chelators). The relationship between blood lead levels and the quantity of lead excreted after EDTA chelation is nonlinear, in that arithmetic increases in blood lead are associated with exponential increases in lead excretion. The correlation between blood lead and chelatable lead is poor in adults with past exposure.’ Under extreme conditions of massive accumulation of metals (long-term occupational exposure), the equilibrium between the tissue stores and blood can result in blood metal levels that are at or above the established threshold values for the diagnosis of metal toxicity but still do not indicate the extent of total body retention. The current gold standard of blood lead measurement for assessment of lead toxicity in children is disturbing: No minimum response levels have been established for lead because a threshold has yet to be defined for the most sensitive effect of lead, neurot~xicity.~~ Interestingly, fractionization of blood into the plasma versus red blood cell compartments can provide valuable information to the clinician about the primary sources of

exposure to mercury. Approximately 95% of methylmercury, most commonly derived from contaminated fish, is associated with red blood ce11~13~,~ whereas about 90% of inorganic mercury (amalgams, occupational exposure) is found in the plasma compartment bound to albumin, cysteine and nonspecific proteins.40Because the first step in successful detoxification is to remove the source of exposure, documentation of the primary source of exposure to mercury can be instrumental for efficient detoxification. Blood arsenic levels, albeit with a very short half-life (approximately 6 hours), reflect exposure to inorganic arsenic and methylated metabolites of arsenic, but not dietary arsenic (shellfish) that is rapidly excreted in the urine.41,* The analysis of whole blood, plasma, and red blood cells can provide valuable information about exposure to specific forms of some metals without the need for expensive determination of subspeciation.

Blood Analysis: Biomarkers of Toxic Effects Given the dynamic nature of blood lead levels that fluctuate with intermittent exposure, standard medical practice is to further analyze blood for abnormal levels of metabolites of heme biosynthesis to accurately diagnosis lead toxicity. Currently accepted markers of exposure and physiologic impact of lead are elevated blood levels of erythrocyte zinc protoporphyrin (ZPP) and deltaamino-levulinic acid, which is the product of the enzyme aminolevulinic acid dehydrogenase (ALAD). As with any biomarker, signhcant limitations are associated with ZPP and ALAD. For example, as is well known, heme biosynthesis also can be affected by iron deficiency3and by chronic diseases such as alcoholism, cirrhosis, and porphyria.44Further, ZPP has been shown to be insensitive for detection of increased blood lead at the critical threshold (5 to 12 pg/dl) in children and adult women.45 ZPP also may be affected by zinc deficiency. T i i g of sampling also can confound interpretation of ZPP levels. With chronic lead exposure, blood lead appears to peak at 3 to 6 months, whereas peak ZPP levels lag sigruficantlybehind (6 to 9 m0nths).4~Findings of concomitant elevations of blood lead and ZPP are very likely to be good indicators of significant lead exposure associated with adverse effects on heme biosynthesis. However, confounding variables may cause discordance between the levels of the two parameters, and markers for aberrant heme biosynthesis may not be sensitive enough to permit early detection of lead exposure or retention that significantly affects the highly vulnerable central nervous system in children.

Urinalysis of Toxic Metals: Unprovoked In general, and despite the current standards for medical care, urinalysis for toxic metals does not provide a

scientifically valid basis for diagnosis of metal toxicity. However, in some cases it provides an indication of recent or ongoing exposure to certain metals. A 1993 study concluded: Urinary lead is generally not a useful biomarker to estimate low-level exposure to lead. However, elevated urinary lead-chelate complexes resulting from the EDTA mobilization test provide a good means to assess increased lead body burden.46

A different scenario exists for organic arsenic as well as inorganic and organic mercury. The most commonly accepted biomarker for exposure to inorganic mercury is the urinary level of inorganic mercury." However, the World Health Organization (WHO) standard for occupational exposure is very high (50 pg/g creatinine).48 This high standard has been challenged because neurologic impairment has been reported for occupationally exposed s u b j e ~ t swhose ~ ~ s urinary mercury levels were well below the WHO standard. Evidence that urinary mercury levels are indicative of exposure to implanted mercury amalgams has also been p u b l i ~ h e dIn . ~a~study of 1127 Vietnam-era veterans reported by the National Institute of Dental Research, a highly statistically significant correlation was detected between the level of amalgam exposure and urinary mercury levels, albeit mean urinary mercury levels were only about 2 pg/g creatinine. Several other studies have reported an association between amalgam exposure and urinary mercury level^.^^-^^ Elevations of urinary arsenic have been detected in workers during periods of occupational exposure, including copper smelting, spraying of insecticides or herbicides, and application of wood treatments .56 Arsenic can be markedly and transiently elevated in individuals within 48 hours after consumption of shellfish that contain high levels of relatively nontoxic species of organic ar~enic.~' Urinary mercury is frequently elevated in people who consume high levels of fish.2z,58 Therefore, analysis of an unprovoked urine specimen is highly recommended to avoid alarmism and confounding the interpretation of the results of a urinary metals provocation test, and patients should be instructed to abstain from the consumption of fish and shellfish for about a week before a chelation challenge is performed. The elevated urinary values of arsenic and mercury associated with the specific dietary and occupational conditions reflect recent or ongoing high-level exposure but are not necessarily reflective of the body burden of the specific metals. Although blood metal levels reflect transient transport in the body, urinary levels qualitatively reflect excretion of an unknown fraction of the total body pools of assimilated metals.

Metal Toxicity: Assessment of Exposure and Retention

Urinalysis: Biomarkers of Renal Toxicity Toxic metals such as cadmium, mercury, and lead are known to be nephrotoxic at high levels of assimilation. Cadmium is of particular concern because of its exceedingly long residence time in the kidneys.59Therefore, in addition to urine levels of cadmium, urinary biomarkers of renal damage should be assessed for documentation of cadmium toxicity. Early markers of cadmiuminduced renal damage include proteinuria, glucosuria, aminoaciduria, hypercakiuria, and polyuria.60Sensitive urinary biomarkers for more advanced cadmiuminduced tubular damage include elevated levels of the low-molecular-weight protein beta2-microglobulin,retinalbinding protein, and N-acetyl-beta-D-glucosaminidasee (NAG).61Abnormal urinary levels of NAG have also been reported in association with markedly high urinary mercury levels (35 pg/g creatinine) in chlor-alkali workers with long-term exposure to inorganic mercury?* It is noteworthy that the urinary NAG levels were correlated with urinary mercury and integrated dose of exposure but not with concurrently measured blood mercury levels?1 Thus it appears that assessment of urinary biomarkers of renal damage may be useful in the diagnosis of toxicity in cases of very high exposure to cadmium and perhaps mercury. However, negative findings for the renal biomarkers do not exclude the possibility of chronic low-level metal toxicity that is most commonly encountered in general clinical practice.

ASSESSMENT OF RETENTION: URINALYSIS, PROVOCATIONTESTS The best currently available method to estimate the level of retention of toxic metals in the body is urinalysis for toxic metals lifter the administration of a chelating agent. In the 1970s the value of a standardized Ca-Na,-EDTA (Ca-disodiumethylenediaminetetraaceticacid) provocative test was recognized as sensitive to determine the mobile and potentially toxic body lead stores, and to assess response to chelation therapy in pediatric patients with high blood lead levels.- Subsequently, Markowitz and Rosen& described the results of a comparable, yet more convenient test that would permit use in a greater number of qualifymg patients (single versus two intramuscular injections and 8-hour versus 24-hour urine collection). The concept and value of using metal complexing agents to estimate the body burden of readily available tissue depots of other toxic metals have gained increasing acceptance in the United States, and currently, several other chelators are widely used for this purpose. The most commonly used pharmaceutical agents are Ca-Na2-EDTA, DMPS (Dimaval, -(R,S)-2,3-dimercapto-propropane-l sulfonate), and DMSA (meso-2,3-dimercaptosuccinic acid). Nonpharmaceutical compounds that have also

been utilized as potentially useful provocation agents include N-acetyl-cysteine (WAC), potassium citrate, and reduced glutathione. The latter compounds are not chelators by definition and have not been studied extensively?'

EDTA Ca-Na2-EDTA (EDTA) has been approved by the U.S. Food and Drug Administration (FDA) and used intravenously for many years as the provocation agent and therapeutic agent of choice for patients exposed to lead. The compound is also well known to be effective for increasing the urinary excretion of iron, copper, nickel, cadmium, and manganese.68EDTA also has a high affinity for free zinc and, if not used properly, can cause zinc deficiency. The maximum recommended EDTA (50 mg/ kg, 13 g) infusion rate is 1g per hour, and clinicians are strongly encouraged to assess glomerular function before use (EDTA-mobilized metals are excreted in the urine). Before attempting to embark on the safe and effective use of EDTA, clinicians should attend specific training courses offered by the American Board of Clinical Metal Toxicology (formerly the American Board of Chelation Therapy). Although the "fast-push" Ca-Na2-EDTAprotocol that has been recently introduced in the United States appears to be effective for increasing the urinary excretion of it has not been thoroughly evaluated for safety. EDTA is not nearly as effective a chelator of mercury as are the dithiol chelators. Therefore this chapter focuses on the metal complexing agents that are newer to the United States, the dithiol agents DMPS and DMSA. A thorough review of the history and appropriate use of EDTA has been published.68

DMPS DMPS appears to be the most productive agent for the mobilization of mercury, as determined in vitro70and in a comparative study during the Iraqi mercury crisis, in which people were acutely poisoned after consumption of grains contaminated with a methylmercury-containing fungicide.'* More relevant to the typically encountered clinical situation, a DMPS provocation study was conducted with volunteer college students.72Subjects with and without amalgam fillings were given 300 mg DMPS (orally), and all urine was collected over the subsequent 9 hours. DMPS raised mean urinary mercury for the nonamalgam group from 0.27 to 5.1 pg and that of the amalgam group from 0.7 to 17.2 pg over the 9-hour period. A highly significant positive correlation was detected between the amount of mercury excreted after the DMPS challenge and amalgam surface area. An additional study supports the value of provocation testing for people occupationally exposed to mercury vapors. A comparison of urinary mercury levels was

Supplementary Diagnostic Procedures

only from compounding pharmacies for oral and made before and after oral administration of a 300-mg intravenous (IV) or intramuscular injection. Slow infudose of DMPS to dental technicians, dentists, and nonoccupationally exposed controls.53 Unprovoked urine sion (5 to 10 minutes) is recommended when giving mercury levels were comparable for dental technicians DMPS IV (3 to 5 mg/kg, not to exceed 250 mg) to avoid and dentists and were about five times higher than in hypotension. Because DMPS is not an FDA-approved drug but is permitted to be compounded for use by controls. Compared with prechallenge values, DMPS physicians, the clinician is advised to obtain a signed induced urinary mercury (c(g/6 h) increased by a factor of 87,49, and 34 for the technicians, dentists, and controls, informed consent form from each patient before administering DMPS. DMPS is associated with a very low incirespectively. Post-DMPS urinary mercury levels were 16 dence of serious side and its safety in general is and 6 times higher than in controls for the technicians evident from the observations made during the course of and dentists, respectively. The group mean urinary merextensive IV administration (250 mg every 4 hours for cury for the technicians after DMPS was 424 k 85 pg/6 h (to put thisvalue in perspective see Figure 26-1). Baseline 12 consecutive days) in a young woman who had severe arsenic The most commonly reported side urinary coproporphyrin levels, which are biomarkers of effects associated with DMPS are nausea, weakness, veraberrant heme biosynthesis, were significantly correlated tigo, chills, fever, cutaneous reactions/itching, erythema with urinary mercury levels after DMPS but were not multiforme, and elevations of tran~aminases.~~,~~," An correlated with baseline urinary mercury levels. The researchers concluded that post-DMPS urinary mercury extensive review of the German literature about the pharmacokinetics, affinities for various metals, and side levels are better indicators of exposure and retention than effects of DMPS is available.= unprovoked urinary mercury levels. A detailed description of an extensively used oral The pharmacokinetics of DMPS have been well DMPS provocation protocol has been presented," as d e f i ~ ~ e d , 'and ~ , ~the ~ efficacy of DMPS for detoxification well as an intravenous DMPS provocation protocol? of rnerc~ry,'~arsenic,'6 and lead (pediatric)= have been To establish the basal urinary rate of metal excretion, documented. Although DMPS is not approved by the the patient is instructed to fast overnight and to collect a Food and Drug Administration (FDA),it is registered in urine specimen. In the morning, with an empty stomach Germany with the German Drug Regulatory Authorities and is available in the oral form without pre~cription.~~and after the bladder is emptied, the patient is given 300 mg (or 10 mg/kg) DMPS PO, and all urine is collected In the United States, DMPS is available by prescription

H g in 2 Hour Urine (5 m g DMPSlkg BW)

68th Percentile

95th Percentile

70 60

c

0

20 10

0 <3

3-20

21-40

41-60

61-80

81-100

101-120

121-140

141-160

161-180

181-200

201-220

>220

p g Hg per g creatinine

Figure 26-1 Post-DMPS urinary mercury levels. Urinary mercury levels (pug creatine) were determined for patients ( n = 259) who had received 250 mg DMPS (Dirnaval) intravenously.All urine was collected for 2 hours. (From Bass DA. Urek K. Quig D. Clin Chem 1999:45:A164. Poster presented at American Association of Clinical Chemistry Conference, New Orleans, July 1999.)

Metal Toxicity: Assessment of Exposure and Retention

for the subsequent 6 hours.73A light meal (no seafood or fish) may be consumed after about 4 hours, and fluid consumption is encouraged. The specific laboratory instructions should be followed for preserving and shipping the specimen. Equilibrium and stability constants (in vitro) for various DMPSmetal complexes have been presentedn and can be used for guidance. In the clinical setting, DMPS is effective for the mobilization and excretion of bismuth, mercury (organic and inorganic), copper, lead, arsenic, antimony, cadmium, nickel, tin,tungsten, thallium, and gold but does not affect aluminum or uranium excretion. In the vast majority of adult patients, mercury is the predominant metal excreted after DMPS, and elevation of copper is normal. As mercury levels decline during detoxification therapy, it is common to see increased urinary levels of other metals, such as lead, cadmium, and tin,with subsequent challenges. The shifting pattern of metal species excreted is based on a combination of affinities of DMPS for the different metals as well as on mass competition for metal binding sites. There are no well-established guidelines for the interpretation of the results of the DMPS challenge test. Figure 26-1 presents a summary of the distribution of the post-DMPS (5 mg/kg, IV) urinary mercury concentrations (pg/g creatinine) for 259 patients who were tested at a clinic in Nevada that specializes in nutritional therapy, homeopathy, and antiaging medicine. Some of the patients presented with fatigue, whereas others were asymptomatic and merely interested in antiaging medicine.78 Most of the patients had dental amalgams. Statistical analysis revealed that in 68% of the patients, urinary mercury concentrations were less than 66 pg/g creatinine, whereas in 5% of this population, values exceeded 145 pg/g creatinine. These data are presented simply to give an indication of the range of values that one might expect to see in clinical practice. Urinary mercury values expressed per gram creatinine are higher in specimens collected from 90 minutes to 2 hours after DMPS infusion than with longer collection times, because the peak rate of mercury excretion occurs about 90 minutes after infusion of DMPS." Conclusions about toxicity cannot be made from the DMPS test results alone. Consideration has to be given to the overall medical examination, medical and exposure history, and presenting symptoms. If a decision is made to proceed with some form of detoxification therapy, the initial challenge result can serve as a reference point against which subsequent challenge results can be compared to evaluate the efficacy of treatment. Some individuals may be significantly affected at a much lower level of retention than others, and some individuals may be completely asymptomatic at relatively high levels of retention. The levels of other toxic metals also should be considered, and one should note that DMPS does not provide direct information

as to the level of mercury present in the central nervous system. It is beyond the scope of this chapter to discuss protocols for metal detoxification; but it is emphasized that if a pharmaceutical metal complexing agent is to be used, glomerular filtration must be assessed before initiation of chelation therapy. Metals mobilized by DMPS are excreted primarily by the kidney and to a much lesser extent by the liver (biliary/fe~al).~~ A thorough discussion of mercury detoxification protocols based on clinical experience has been pre~ented.~

DMSA Another dithiol metal complexing agent, DMSA, is also widely used for provocation testing, as well as detoxification therapy for lead, mercury species, and other sulfhydryl reactive metals (e.g., arsenic, antimony). Several studies demonstrate the effectiveness of DMSA to increase the urinary excretion of lead and mercury and decrease the blood levels of these metals.79-81 DMSA was approved by the FDA for lead detoxification and is the method of choice for lead detoxification in children and adults. DMSA is available only for oral administration, and only about 20% of orally administered DMSA is systemically available after a single DMSA, when used in conjunction with Ca-Na,-EDTA, increases cumulative urinary lead excretion and ameliorates redistribution of lead and mercury to soft DMSA is restricted to the extracellular ~ o m p a r t m e n tand ~~ does not appear to cross the blood-brain barrier. In rodent models, however, DMSA has been demonstrated to be effective in decreasing the levels of lead and mercury in the brainw Animal studies also indicate greater efficacy of DMSA for lead detoxification when the compound is concomitantly administered with antioxidant^.^^,^ This is probably the case for all metal complexing agents. However, the antioxidants lipoic acid and N-acetylcysteine alone had no effect on lead excretion. To date, no reliable studies have been published to indicate that lipoic acid is an effective metal-binding agent that has a net effect on metal excretion in humans, and the potential for lipoic acid-induced mercury redistribution, particularly to the brain, is a sigruficant con~ideration.~~ DMSA is generally well tolerated with common but mild side effects, including GI bloating/gas, occasional loose stools, and skin rash. Periodic assessment of liver enzyme levels is recommended during the course of extended administration. Compared with DMPS and EDTA, DMSA has minimal effect on essential elements such as copper and zinc, but DMSA is excreted primarily as a mixed disulfide with two molecules of c y ~ t e i n e . ~ ~ Thorough reviews of the pharmacokinetics and clinical use of DMSA have been p r e ~ e n t e d . ~It, ~should ~ , ~ ~be ,~~ noted that there is a tremendous difference between the DMSA protocol described for acute lead poisoning82and that commonly used for chronic low-level lead retention.

Supplementary Diagnostic Procedures

Various protocols for DMSA provocation testing have been suggested?,%The most commonly used protocol in recent years has entailed a daily dosage of 10 mg/kg, PO tid for 3 consecutive days, with a 24-hour urine collection on day 3 (total daily dose of 30 mg/kg). However, a much more convenient and productive provocation protocol has been described that entails giving a single dose of DMSA PO (30 mg/kg) on an empty stomach and collection of all urine for the subsequent 6 hours.67The peak rate of excretion of mercury occurred after about 3 hours. The protocol is well tolerated, enhances compliance, and significantly reduces exposure to the compound. However, the potential for a single large dose of DMSA to leave behind some metals that have been mobilized but not excreted should be considered. It may be wise to continue to give DMSA at the standard treatment dose of 10 mg/kg tid for the next day or two to "clean up" metals that may have been left behind. Patients should be advised in advance that their urine will transiently have a foul, sulfurous odor.

Nonpharmaceutical Agents Nonpharmaceutical compounds, such as N-acetyl-L-cysteine (N-AC) and potassium citrate (K-citrate)have been tested for efficacy as provocation agents for mercury in one published study.67 Urinary mercury levels, expressed as pg/l, were compared before and after a single oral dose of N-AC (30 mg/kg), K-citrate (5 g in 200 ml water), DMSA (30 mg/kg), or DMPS (Unithiol, 250 mg in 5 ml water). Basal urinary mercury levels (about 5 pg/l) were comparable for all of the treatment groups, each of which contained 16 to 65 polysymptomatic subjects. All subjects either had dental amalgams or had recently undergone removal of amalgams. Urine was collected for 3 hours after the challenge compounds were given, except that urine was collected for only 2 hours after the DMPS. The different collection time for the DMPS prohibits valid comparisons of the effects of the other agents with that of DMPS. The high bolus doses of N-AC and K-citrate significantly increased urinary mercury, by 131%and 83%,respectively, compared with basal values. Under these conditions of different collection times, DMSA and DMPS increased mercury excretion by 163% and 135%, respectively. No mention was made of the urine volumes associated with the different test groups, and clearly, the data would have been easier to interpret had the results been standardized per gram urinary creatinine. Grossly misleading values for urinary metals can be associated with expression of excreted metals because concentration per unit volume of urinary output can vary considerably. No other data are currently available to permit further evaluation of the value of the nonpharmaceutical compounds as provocation agents. These two compounds also should be tested in animal models to determine

whether they are associated with sigruficant redistribution of metals among various tissues, because neither is a true chelator and their stability constants are likely to be low. Currently, no definitive studies are available to assess the utility of either orally or parentally administered reduced glutathione as a metal complexing agent, although the compound is being used for that purpose. A final note about other routes of administration of various authentic and potential metal detoxification agents, particularly with respect to provocation testing: The author is not able to find any published research addressing the systemic bioavailability or efficacy of any agent that is given as a rectal suppository or via a transdermal delivery system. Such methods of administration are currently being used, and they may or may not be effective. Clearly, additional clinical studies should be performed before sound conclusions can be made.

FECAL METALS ANALYSIS Several toxic metals, including mercury, lead, and cadmium, are naturally excreted primarily or partially in the bile. Therefore under certain conditions analysis of fecal metals, without provocation, may provide at least qualitative information about the rate of biliary excretion of assimilated metals. However, contaminated foods present a significant source of exposure to metals, and metals that have not been assimilated by the GI tract can contribute to a significant percentage of the total amount of metals measured in a fecal specimen. In addition to dietary contamination, fecal mercury is very much influenced by the amount of mercury that is present in the mouth in the form of mercury amalga1ns.9~ Fecal mercury concentrations,expressed per gram of dry weight, are roughly an order of magnitude higher in people who have an average of six to eight mediumsized amalgams than in individuals who are amalgam free.95Day-to-day variability in fecal mercury levels in amalgam bearers who do not consume fish are remarkably reproducible. Fecal mercury levels are highly correlated with the number of amalgams (Figure 26-2). Further it has been demonstrated that fecal mercury levels decline significantly after extraction of amalgams.96 Therefore levels of fecal metals generally are more a representation of exposure to metals than an indication of total body retention or toxicity. Current research efforts are focusing on the identification of metal complexing agents that increase the biliary or fecal excretion of metals. To date no such agent or phytonutrient has been identified. Preliminary evidence suggests that high-dose vitamin C (50 g) given intravenously may markedly enhance the biliary excretion of lead and mercury97; however, additional studies are needed. Fecal metals have been analyzed for autistic children ( 1 1 = 54), and on average they are higher compared

Metal Toxicity: Assessment of Exposure and Retention

Conc. (PPW

Number of amalgams Figure 26-2 Fecal mercury levels versus the number of dental amalgams. Fecal mercury (pglkg dry weight) was plotted against number of amalgams for 200 subjects. (From Bass DA. Urek K. Quig D. Clin Chem 1999;45:A164. Poster presented at American Association of Clinical Chemistry Conference, New Orleans, July 1999.)

Summary of the potential value of hair analysis Urine (retention) Metallmetalloid

Hair (exposure)

No provocation

DMSA

DMPS

Ca-Na,-EDTA

Aluminum

Fair

Poor

Poor

Poor

Fair, best with deferoxamine

Antimony Arsenic

Good Good

Poor Poor

Good Good

Good Excellent

Good Poor

Cadmium

Fair

Poor

Fair

Fair

Good

Lead

Good

Poor

Good

Good

Excellent

Inorganic mercury

Poor to fair

Poor

Excellent

Excellent

Poor

Organic mercury

Excellent

Poor

Excellent

Excellent

Poor Good

Nickel

Poor

Poor

Fair

Fair

Tin

Poor

Good

Good

Good

Iron

Poor

Poor Poor

Poor

Poor

Good, best with deferoxamine

Tungsten

?

Poor

Fair

Fair

Poor

Uranium

Excellent

Poor

Poor

Poor

?, Poor

~~~~~~~~~

Summary of the potential value of hair analysis (exposure), and the most commonly used provocation agents used in conjunction with urinalysis for the detection of retention of specific metals. It is emphasized that retention is not necessarily associated with overt toxicity. The qualitative guidelines are based on the authors' perception of affinities, in vivo, derived from examination of thousands of test results, and stability constants as determined under highly defined conditions in vitro. The information provided does not include the potential use of adjunctive agents/protocols and does not cover all known metal complexing agents.

with age-matched, nonautistic controls (n = 83).98The reason for the higher levels in association with autism is not known, and pica is a possible issue that may contribute to higher levels of exposure in autistic patients.

CONCLUSION Chronic, low-level exposure to environmental toxins is a growing global problem, and evidence is accumulating to link the bioaccumulation of toxic metals in humans to subtle and overt health effects. Increasing numbers of patients dissatisfied with the care provided by clinicians who rely only on methods for the assessment of acute

metal poisoning are seeking out progressive clinicians who are more aware of the value of tools that are yet to be accepted for the assessment of subacute metal toxicity. Analyses of metals in hair, blood, and urine all have advantages and disadvantages, and no single test is likely to enable unequivocal diagnosis of low-level metal toxicity. However, consideration of the results of the various tests discussed in this chapter as well as a complete medical examination and exposure history can be used to design a comprehensive therapeutic detoxification program that is likely to provide signtficant relief for the patient. Table 26-1 provides an overview of value of the various tests for assessing a patient's problem with metals.

Supplementary Diagnostic Procedures

1. Goyer R. Chelation of toxic metals: current interests. Env Health Persp 1995;103:98&989. 2. Goyer RA, Cherian MG, Jones MM, et al. Role of chelating agents for prevention, intervention, and treatment of exposures to toxic metals. Env Health Persp 1995;11:1048-1341. 3. Patrick L. Mercury toxicity and antioxidants. Part I. Role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity. Altern Med Rev 2002;7456-471. 4. Patrick L. Toxic metals and antioxidants. Part II. Arsenic and cadmium toxicity. Altern Med Rev 2003;8:106-128. 5. Crinnion WJ. Environmental medicine. Part III. Long-term effects of chronic mercury exposure. Altern Med Rev 2000;5:209-223. 6. Q u g D. Cysteine metabolism and metal toxicity. Altern Med Rev 1998;3262-270. 7. Grandjean P. International perspectives of lead exposure and lead toxicity. Neurol Toxicol 1993;14:9-14. 8. Schubert J, Riley EJ, Tyler SA. Combined toxic effects in toxicology, rapid systematic testing procedure: cadmium, mercury and lead. J Toxicol Environ Med 1978;4763-776. 9. Finne K, Goransson K, Winkler L. Oral lichen planus and contact allergy to mercury. Int J Oral Surg 1982;11:236-239. 10. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for lead. Atlanta: U.S. Department of Health and Human Services, Public Health Service, 1993:134. 11. Nash D, Magder L, Lustberg M, et al. Blood lead, blood pressure, and hypertension in perimenopausal women. JAMA 2003;289:1523-1532. 12. Lustberg M, Silbergeld E. Blood lead levels and mortality. Arch Intern Med 2002;1622443-2449. 13. Bencze K. Determination of metals in human hair. In Seiler HG, Sigel A, Sigel H, eds. Handbook on metals in clinical and analytical chemistry. New York Dekker, 1994:214. 14. Deppisch LM, Centeno JA, Gemmel DJ, et al. Andrew Jackson’s exposure to mercury and lead: poisoned president? JAMA 1999;282:569-571. 15. Bencze K. Determination of metals in human hair. In Seiler HG, Sigel A, Sigel H, eds. Handbook on metals in clinical and analytical chemistry. New York Dekker, 1994:202. 16. Heaven R, Duncan M, Vukelja S. Arsenic intoxication presenting with macrocytosis and peripheral neuropathy, without anemia. Acta Haematol1994;92:142-143. 17.Rose J, ed. Environmental toxicology. New York Gordon and Breach, 1997. 18. Marlow M, Vukelja S. Correlations of metal-metal interactions as measured in hair on childhood intelligence. J Advancement Med 1988;1:195-203. 19. Minder B, Das-Smaal EA, Brand EF, et al. Exposure to lead and specific attentional problems in school children. J Learn Disabil 1994;27393-399. 20. Grandjean P, Weihe P, White RF, et al. Cognitive performance of children prenatally exposed to “safe” levels of methylmercury. Environ Res 1998;77:165-172. 21. Malm 0, Branches FJ, Akagi H, et al. Mercury and methylmercury in fish and human hair from the Tapajos river basin, Brazil. Sci Total Environ 1995;175141-150. 22. Salonen JT, Seppanen K, Nyssonen K, et al. Intake of mercury from fish, lipid peroxidation, and the risk of myocardial infarction and coronary, cardiovascular, and any death in eastern Finnish men. Circulation 1995;91:646-655. 23. HoLsbeek L, Das HK, JoirisCR Mercury in human hair and relation to fish consumption in Bangladesh. Sci Total Environ 1996;186: 181-188. 24. Harada M, Nakanishi J, Kunuma S. The present mercury contents of scalp hair and clinical symptoms in inhabitants of the Minamata area. Environ Res 1998;77:160-164.

25. Phelps RW, Clarkson TW, Kershaw TG, et al. Interrelationships of blood and hair mercury concentrations in a North American population exposed to methylmercury. Arch Environ health 1980;35:161-168. 26. Yamato N. Concentration and chemical species of arsenic in human urine and hair. Bull Environ Contam Toxicol 1988;40: 633-640. 27. Eastern Research Group. Hair Analysis Panel discussion: exploring the state of the science. Lexington, MA: Agency for Toxic Substances and Disease Registry, 2001. 28. Agency for Toxic Substances and Disease Registry (ATSDR). Document 03-0330: Hair Sampling Testing-Scientific. PM65. Available online at: http://www.atsdr.cdc.gov/hir-analysis. 29. Seidel S, Kreutzer R, Smith D, et al. Assessment of commercial laboratories performing hair mineral analysis. JAMA 2001;285: 67-72. 30.Steindel SJ, Howanitz PJ. The uncertainty of hair analysis for trace metals. JAMA 2001;28583-85. 31. F’uchyr RF, Bass DA, Gajewski R. Preparation of hair for measurement of elements by inductively coupled mass spectrometry (ICP-MS).Biol Trace Elem Res 1998;62167-182. 32. Bass DA, Hickok D, Quig D, et al. Trace element analysis in hair factors determining accuracy, precision, and reliability. Altem Med Rev 2001;6:472481. 33. Druyan ME, Bass DA, Puchyr R, et al. Determination of reference ranges for elements in human scalp hair. Biol Trace Elem Res 1998;62183-197. 34. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for lead. Atlanta: U.S. Department of Health and Human Services, Public Health Service, 1993100. 35. Sanders BM, Goering PL, Jenkins KJ. The role of general and metal-specific cellular responses in protection and repair of metal-induced damage: stress proteins and metallothioneins. In Chang LW, ed. Toxicology of metals. New York CRC Press, 1996165-187. 36. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for lead. Atlanta: U.S. Department of Health and Human Services, Public Health Service, 1993:ll. 37. Physicians desk reference, ed 54. Montvale, NJ:Medical Economics, 2000. 38. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for lead. Atlanta: U.S. Department of Health and Human Services, Public Health Service, 1993:108. 39. Gehardsson L, Skerfving F. Concepts on biological markers and biomonitoring for metal toxicity. In Chang L, ed. Toxicology of metals. New York CRC Press, 199681-110. 40.Ishihari N. Inorganic and organic mercury in blood, urine and hair in low level mercury vapor exposure. Int Arch Occup Environ Health 1978;40249-253. 41. Foa V, Colombi A, Maroni M, et al. The speciation and chemical forms of arsenic in the biological monitoring of exposure to inorganic arsenic. Sci Total Environ 1984;34:241-259. 42. Iffland R. Arsenic. In Seiler HG, Sigel A, Sigel H, eds. Handbook on metals in clinical and analytical chemistry. New York Dekker, 1994243. 43. Hastka J, Lasserre JJ, Schwarzbeck A. Zinc protoporphyrin in anemia of chronic disorders. Blood 1993;81:1200-1204. 44. Somashekaraiah BV, Venkaiaha B, Prasad AR. Biochemical diagnosis of occupational exposure to lead toxicity. Bull Environ Contam Toxic01 1990;44:268-275. 45. Lueng FY, Bradley C, Pellar TG. Reference intervals for blood lead and evaluation of zinc protoporphyrin as a screening test for lead toxicity. Clin Biochem 1993;26491496.

Metal Toxicity: Assessment of Exposure and Retention 46. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for lead. Atlanta: US.Department of Health and Human Services, Public Health Service, 1993131. 47. Clarkson TW. Principles of risk assessment. Adv Dent Res 1992;6:22-27. 48. World Health Organization (WHO). Inorganic mercury. Environmental Health Criteria 118. Geneva: World Health Organization, International Program on Chemical Safety, 1991. 49. Echeverria D, Heyer NJ, Martin MD, et al. Behavioral effects of lowlevel exposure to HgO among dentists. Neurotoxicol Teratol 1995;17161-168. 50. Langworth S, Almkvist 0, Soderman E, et al. Effects of occupational exposure to mercury vapour on the central nervous system. Br J Indust Med 1992;49:545-555. 51. Kingman A, Albertini T, Brown LJ. Mercury concentrations in urine and whole blood associated with amalgam exposure in a US military population. J Dent Res 1998;77:461-471. 52. Skare J, Engqvist A. Human exposure to mercury and silver released from dental amalgam restorations. Arch Environ Health 1994;49:384-394. 53. Gonzalez-Ramirez D, Maiorino RM, Zuniga-Charles M. Sodium 2,3-dimercaptopropane-l-sulfonatechallenge test for mercury in humans. 11. Urinary mercury, porphryns and neurobehavioral changes of dental workers in Monterey, Mexico. J Pharmacol Exper Ther 1995;272264-274. 54. Schweinsberg F. Risk estimation of mercury intake from different sources. Toxicol Lett 1994;72:345-351. 55. Begerow J, Zander D, Freier I, et al. Long-term mercury excretion in urine after removal of amalgam fillings. Int Arch Occup Environ Health 1994:66209-212. 56. Apostoli P, Bartoli D, Alessio L, et al. Biologicalmonitoring of occupational exposure to inorganic arsenic. Occup Environ Med 1999;56:825-832. 57. Buchet JP, Pauwels J, Lauwerys R. Assessment of exposure to inorganic arsenic following ingestion of marine organisms. Environ Res 1994;66:44-51. 58. National Research Council. Toxicologicaleffects of methylmercury. Washington, DC:National Academy Press, 2000:31-70. 59. Lauwerys R, Bernard A, Roels HA, et al. Cadmium exposure markers as predictors of nephrotoxic effects. Clin Chem 1994;40: 1391-1394. 60. Herber RFM. Cadmium. In Seiler HG, Sigel A, Sigel H, eds. Handbook on metals in clinical and analytical chemistry. New York Dekker, 1994202,289-290. 61. Verschoor M, Herber R, Van Hemmen J, et al. Renal function of workers with low-level cadmium exposure. Scand J Work Environ Health 1987;13:232-238. 62. Barregard L, Hultberg B, Schutz A, et al. Enzymuria in workers exposed to inorganic mercury. Int Occup Environ Health 1988;61:65-69. 63. Centers for Disease Control. Preventing lead poisoning in young children. J Pediatr 1978;93:709-714. 64. Chisolm JJ Jr. Chelation therapy in children with subclinical plumbism. J Pediatr 1974;53:441-449. 65. Chisolm JJ Jr. The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood. J Pediatr 1968; 73~1-15. 66. Markowitz ME, Rosen JF. Assessment of lead stores in children: validation of an 8-hour CaNa2EDTA provocative test. J Pediatr 1984;1O4:337-341. 67. Hibberd AR, Howard MA, Hunnisett AG. Mercury from dental amalgam fillings: studies on oral chelating agents for assessing and reducing mercury burdens in humans. J Nutr Environ Med 1998;8:219-231. 68. Rozema TC. Protocols for chelation therapy. J Adv Med 1997;lO 3-100.

69. Quig DW. Systematic and functional assessment of nutritional status and exposure to toxins. Paper presented at Orthomolecular Health and Medicine Conference, San Francisco, March 2003. 70. Keith RL, Setiarahardojo I, Fernando Q, et al. Utilization of renal slices to evaluate the efficiency of chelating agents for removing mercury from the kidney. Toxicology 1997;11667-75. 71. Clarkson TW, Magos L, Cox C, et al. Tests of efficacy of antidotes for removal of methylmercury in human poisoning during the Iraq outbreak. J Pharmacol Exp Therap 1981;218:74-83. 72. Aposhian HV,Bruce DC,Alter W, et al. Urinary mercury after administration of 2,3-dimercaptopropane-l-sulfonicacid: correlation with dental amalgams. FASEB J 1992;62472-2476. 73. Aposhian HV, Maiorino RM, Gonzalez-Ramirez D, et al. Mobilization of heavy metals by newer, therapeutically useful chelating agents. Toxicology 1995;9723-38. 74. Aposhian HV.DMSA and DMPS: water soluble antidotes for heavy metal poisoning. Ann Rev Toxicol 1983;23:193-215. 75. Campbell JR, Clarkson TW, Omar MD. The therapeutic use of 2,3-dimercaptopropane-l-sulfonate in two cases of inorganic mercury poisoning. JAMA 1986;256:3127-3130. 76. Wax PM, Thorton CA. Recovery from severe arsenic-induced peripheral neuropathy with 2,3-dimercapto-l-propanesulfonic acid. Clin Toxicol 2000;38:777-780. 77. Dimival (DMPS): summary of scientific literature. Houston: Heyltex Corp, 1991:6237-6793. 78. Quig DW, Gerber M. Effects of toxic metals on nutritional status and immune function. Paper presented at American College for Advancement in Medicine Conference, Salt Lake City, UT, October 2000. 79. Graziano JH, Siris ES, LoIacono NJ, et al. 2,3-dimercaptosuccinic acid as an antidote for lead intoxication. Clin Pharmacol Ther 1985;37431-438. 80. Grandjean P, Jacobsen LA, Jorgensen PJ. Chronic lead poisoning treated with dimercaptosuccinic acid. Pharmacol Toxicol 1991;68:266-269. 81. Roels HA, Boeckx M, Ceulemans E. Urinary excretion of mercury after occupational exposure to mercury vapour and influence of the chelating agent meso-2,3-dimercaptosuccinic acid (DMSA). Br J Ind Med 1991;48:247-253. 82. Physicians desk reference, ed 54. Montvale, NJ: Medical Economics, 2000. 83. Lee B, Schwartz BS, Stewart W, et al. Provocation chelation with DMSA and EDTA evidence for differential access to lead storage sites. Occup Environ Med 1995;5213-19. 84. Besunder JB, Super DM, Anderson RL. Comparison of dimercaptosuccinic acid and calcium disodium ethylenediaminetetraacetic acid versus dimercaptopropanol and ethylenediaminetetraacetic acid in children with lead poisoning. J Pediatr 1997;130966-971. 85. Aaseth J. Treatment of mercury and lead poisonings with dimercaptosuccinic acid and sodium dimercaptopropane sulfate. Analyst 1995;120853-854. 86. Jones MM, Singh PK, Kostial K, et al. Comparative in vivo lead mobilization with meso- and rac-2,3-dimercapto-succinicacids in Albino Wistar rats. Pharmacol Toxicol 1997;186:182-186. 87. Gong Z, Evans HL. Effects of chelation with meso-dimercaptosuccinic acid (DMSA) before and after the appearance of lead-induced neurotoxicity in the rat. Toxicol Appl Pharmacol1997;144.205-214. 88. Smith D, Bayer L, Strupp 8. Efficiency of succimer chelation for reducing brain lead levels in a rodent model. Environ Res 1998;78:168-176. 89. Pande M, Mehta A, Pant BP, et al. Combined administration of a chelating agent and an antioxidant in the prevention and treatment of acute lead intoxication.Environ Toxicol Pharmacol2001;9:173-184. 90. Pande M, Flora SJS. Lead induced oxidative damage and its response to combined administration of a-lipoic acid and succimer in rats. Toxicology 2002;177:187-196.

Supplementary Diagnostic Procedures 91. Gregus Z, Stein AF, Varga F, et al. Effect of lipoic acid on biliary exmtion of glutathione and metals. Toxicol Appl Pharmacol 1992;11486-96. 92. Maiorino RM, Aposhian MM, Xu ZF, et al. Determination and metabolism of thiol &elating agents. XV. The meso-2,3-dimercaptosuccinic acid-cysteine (1:2) mixed disulfide, a major urinary metabolite of DMSA in the human, increases the urinary excretion of lead in the rat. J Pharmacol Exp Therap 1993;2671221-1226. 93. Miller A. Dimercaptosuccinic acid (DMSA), a non-toxic, watersoluble treatment for heavy metal toxicity. Altem Med Rev 19983:199-207. 94. Frumkin H, Manning CC, Williams PL, et al. Diagnostic chelation challenge with DMSA: a biomarker of long-term mercury exposure? Environ Health Persp 2001;109:167-171.

95. Bass DA, Urek K, Q u g D. Measurement of mercury in feces. Clin Chem 1999;45:A164.Poster presented at American Association of Clinical Chemistry Conference, New Orleans, July 1999. 96. Bjorkman L, Sandborg-Englund G, Ekstrand J. Mercury in saliva and feces after removal of amalgam fillings. Toxicol Appl Pharmacol1997;144:156-162. 97. Quig D. Metal detoxification: a research based update. Paper presented at the International Oxidative Medicine Association Conference, Westminster, CO, March 2000. 98. Quig D. Mineral status, toxic metal exposure and childrens’ behavior. Paper presented at American Academy of Environmental Medicine Conference, Hot Springs, VA, November 2002.

Mineral Status Evaluation Stephen P. Markus, MD Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Introduction 275 Minerals and Disease 275 Essential Minerals 276 Calcium 276 Chromium 276 Copper 277

INTRODUCTION The importance of trace mineral metabolism has become appreciated only in the past 35 years. Minerals play as important a role as vitamins in the subtle biochemistry of the body. Virtually all reactions in the body require minerals as cofactors. Infinitesimally small amounts of some trace elements may be necessary, but others, such as calcium, make up a quarter of our body weight. Assessment of body status for a particular trace element is extremely difficult (Table27-1 lists recommended methods for the different elements).l For years there has been considerable controversy about hair mineral analysis. Although hair is the most convenient tissue for analyzing minerals, only a limited number of elements in the hair accurately reflect the true body content (see Chapter 20). Others are better measured intracellularly or extracellularly, depending on their state of equilibrium, or in specific cells, such as leukocytes. Many factors, such as specific protein carriers, the ionic charge of the element, and its capacity to be in equilibrium in the blood, affect the usefulness and reproducibility of a specific assay method and the appropriateness of a chosen tissue. Over the last century, with increasing industrialization of our society, our exposure to toxic metals has grown enormously. Hair serves as an excellent source for measurement of continuous cumulative exposure more typical of environmental sources. Hair is biologically stable and can be stored for analysis over a long period without degradation. Hair also concentrates toxic minerals several hundred times higher than blood, allowing for analytical determinationsof ultra-trace quantities. The fact that toxic

Iron 277 Magnesium 277 Manganese 278 Potassium 278 Selenium 278 Zinc 278

Conclusion 279

minerals can have deleterious effects on multiple enzyme systems, neuronal structures, and organs, including the brain, heart, thyroid, liver, kidneys, and skin, at extraordinarily low levels suggests that hair mineral analysis should be an important screening test for many patient^."^

MINERALS AND DISEASE Serum levels of selenium, as well as zinc, copper, magnesium, calcium, and manganese, have been investigated as possible clinical markers and prognostic indicators of various disease states. Patients with cirrhosis have demonstrated low serum selenium, calcium, magnesium, and zinc levels. Those with emphysema and cancer have shown elevated serum copper concentration, and copper and manganese levels are often elevated in congestive heart failure, infection, and pschoses.6Other associations have been observed between trace minerals and cases of breast cancer: gastrointestinalmalignancy,8and malignant ascites? although in other studies, selenium, copper, zinc, and magnesium seem to have no diagnostic value for distinguishing malignant from nonmalignant effusions'O or cervical cancer." Differences in arterial and serum concentrations of calcium, magnesium, zinc, and copper among different types of arterial pathologies have also been documented. Heart tissue levels of selenium, iron, copper, zinc and phosphorus are associated with ejection fraction and cardiac index.12 In men infected with human immunodeficiency virus (HIV), helper T type 4 cells seem closely correlated with serum magnesium c~ncentration.'~ Zinc, magnesium, and 275

Supplementary Diagnostic Procedures Recommended methods for assessing essential mineral status Mineral

Method

Normal range

Calcium

Hair analysis

340-850 pg/g

Chromium

Hair analysis

0.5-1.5 ppm

Copper

Serum copper

0.8-1.5 ppm

Hair analysis

8-22 ppm

Serum iron

0.65-1.75 ppm

Serum ferritin

Male, 27-329 ng/rnl Female, 12-120 ng/ml

Magnesium

Mg retention test Leukocyte Mg

<25%, normal 0.98-2.82 pg/L

Manganese

Whole M o d Mn

0.005-0.02 ppm 3741-4045 ppm

Iron

Potassium

Whole blood K

Selenium

Hair analysis

1.O-3.0 ppm

Zinc

Leukocyte zinc

0.082-0.57 pg/L

copper in hair may play an indicator role in the diagnosis of epilepsy.l4 The ratios of trace elements may also serve as prognostic indicators for various diseases. The concentrations of copper, zinc, and selenium and their relative levels in whole blood and thyroid tissue of patients follow specific patterns for various thyroid disorders, including thyroid cancer.15 In one study, serum copper/zinc ratios were shown be of diagnostic and prognostic value in head, face, and neck cancer, with alterations in copper, zinc, and copper/zinc ratio related to the stage of the disease.16 Although the mechanisms are unclear, the copper/zinc ratio has been found to be sigruficantly increased in patients with breast cancer but not in patients with benign breast diseases.I3 Other studies have identified distinct differences in copper/zinc ratios among various levels of skin disease severity." Unfortunately, there is much controversy about how to measure mineral status. It is clear that developing more consistent methodologies of mineral testing will have positive clinical ramifications regarding how many diseases are diagnosed, monitored, and treated in the future.

ESSENTIAL MINERALS Calcium Despite detailed calcium balance studies measuring both intake and excretion with radiolabeled isotopes, determining calcium balance in an outpatient setting is extremely difficult.18 Assessment of dietary intake of calcium is confounded by multiple factors that affect absorption, such as the following: The quantity of fiber and other natural chelators in the diet

Gastric acidity The ratio of dietary calcium to phosphorus (and dietary magnesium) Gut transit time, and so on When all of these are considered, multivariate analysis is currently very difficult with so many uncontrolled and difficult to measure variables. Serum calcium, like other electrolytes, is so closely regulated (by the parathyroid gland) that its use as a measurement of calcium balance is rarely of value. Ionized calcium is currently being examined in more detail and may play a partial role in evaluation of calcium status in the future. Urinary calcium is of value in a patient with a known low total calcium intake and persistent calciuria. At present, perhaps the most useful screening test for calcium balance is hair analysis. However, hair calcium levels are subject to considerable variability and should not be taken as quantitative determinations of calcium status. A few studies evaluating calcium content in hair have shown promising correlations. Two studies in particular were able to find a relationship between hair calcium level and coronary d i s e a ~ e . ' ~ Future , ~ ~ studies must be conducted for further verification. One team of researchers conducted careful studies of a group of patients and showed that calcium intake, and the ratio of calcium intake to phosphorus intake, significantly altered hair calcium. In patients with high phosphorus and low calcium intakes, hair calcium level was consistently as much as three times higher than normal. Hair calcium returned to normal with proper supplementation and dietary changes.2* Some researchers are beginning to find value in studying levels of erythrocyte membrane content of minerals like calcium and magnesium. One study evaluated intracellular, plasma, and membranous levels of calcium and magnesium in hypertensive patients. Although there were no differences between controls and patients with regard to plasma and intracellular calcium and magnesium levels, the absolute levels of calcium and magnesium were lower, and the calcium/magnesium ratio in membranes was signhcantly higher, in patients with essential hypertension than in healthy subjects." Although more studies are needed, erythrocyte membrane studies may prove clinically valuable as a method of evaluating mineral levels in humans.

Chromium Establishment of reliable laboratory assays for the assessment of chromium status has been a subject of considerable research. Only recently has analytical instrumentation of sufficient sensitivity been developed to allow accurate quantitative analysis of this ultra-trace mineral. Plasma chromium is probably not a valid indicator of body status because it is not in equilibrium with

Mineral Status Evaluation

tissue chromium, and plasma levels may be less than 1 ng/ml, making measurement very difficult. Because 80% of chromium is excreted in the urine, urinary chromium concentration may be the most valid indicator of chromium status. Glucose consumption has been shown to increase plasma and, subsequently, urinary chromium. Urinary chromium concentrationshave been measured before and after glucose loading, but results have shown unacceptable variability. Substantial glucose tolerance factor (GTF) activity has been found in hair follicles, suggesting that hair chromium level may be a useful indicator of body status.B25 This mineral is found in the hair at concentrations more than 100 times that found in the blood, making measurement more technically feasible.

Copper Under normal conditions, far more copper is absorbed than is needed by the body. Nearly all dietary copper is initially stored in the liver, leaving only a small percentage in the blood. Because 95%of plasma copper is bound to the protein ceruloplasmin, with almost no ionic copper, urinary output is nil. The principal homeostatic mechanism for controlling copper is excretion through the biliary system. As one might expect with such a large turnover of absorbed copper, assessing copper status is not easy. At present, serum copper level may be the best indicator, if the clinical conditions that are known to cause abnormalities in copper metabolism (e.g., Wilson disease, cirrhosis of the liver) are first ruled out.26 Measurement of superoxide dismutase function has been used in the assessment of copper status, but because this enzyme also requires zinc and manganese, its measurement is not adequately specific. Additionally, there is no evidence of a relationship between serum copper and superoxide dismutase a~tivity.2~ The usefulness of hair analysis as an indicator of chronic copper toxicity is well documented, although external contamination must be considered and it is not reliable in Wilson disease. Some studies have shown hair

copper measurement to be an acceptable method of assessment of copper s t a t u ~ . ~More *,~~ studies are needed in this area.

Iron Serum iron concentration has a long history of use as an indicator of iron deficiency. It is not of much value by itself, however, because there is considerable variation in serum iron concentration, even when samples are taken from the same person at the same time each day, and there is also a large diurnal variation. The measurement is much more reliable when combined with measurement of serum transferrin or ferritin. Ferritin is an iron storage protein accounting for 20% of the total body iron in normal adults. It is found principally in the cytoplasm of reticuloendothelial cells and liver cells, and, to some degree, in developing red cell precursors in bone marrow. It is involved in both absorption and recycling of iron. During the early stages of iron deficiency, a decreased serum ferritin level is the first sign that body stores are low. As iron deficiency progresses, anemia, decreased serum iron concentration. and elevated iron-binding capacity become apparent.3031The patient is done a disservice if the physician waits for hypochromia and microcytosis to appear before making a diagnosis of iron deficien~y.~~ Table 27-2 compares the various methods of determining iron deficiency. Serum ferritin concentrationsare, however, not totally reliable because they are inappropriately elevated in several common medical conditions, including cancer, infections, inflammation, and acute and chronic liver diseases. When iron overload is associated with hemochromatosis, hemosiderosis, or thalassemia, serum ferritin is also elevated. Overall, serum ferritin measurement is a convenient and usually reliable indicator of total body iron storage.

Magnesium Measurement of magnesium status, like other minerals, has many problems. The magnesium retention test is

Iron Deflciencv Method Plasma iron level (@lo0

ml)

Iron-bindingcapacity (pg/lOOml) Hemoglobin level (g/lOOml)

Normal

With anemia

Without anemia

75-150 300-400 13-15

Normal or reduced

Normal or reduced

<40

Normal or elevated

Normal or elevated

A00

13-15

9-12

6-7

Severe iron deficiency

Hypochromia and microcytosis

Not present

Not present

SI or not present

Profound

Ferritin level (ng/ml)

12-300 30-70

<12

42

<6

Normal or elevated

>loo

>loo

Free erythrocyte protoporphyrin ( ~ g00 h ml) S/, Slight.

probably the most accurate method of assessment currently available.%The test procedure is as follows: 1.The patient is injected with 2 ml of a 50% MgSO, solution. 2.24-hour preinjection and postinjection urine samples are collected and analyzed for magnesium and creatinine levels. 3. Retention of more than 25% indicates magnesium deficiency. Needless to say, this is a cumbersome procedure. Serum magnesium concentration is of little value because it is influenced by many factors. Plasma magnesium concentrations reflect disorders in magnesium handling poorly because plasma magnesium content constitutesonly about 1%to 3%of total body magnesium stores and does not reflect the levels in other tissues.” The level of binding, complexing, or chelating of magnesium to serum proteins and other fractions is subject to many uncontrollable variables. Values of serum magnesium levels as low as 1.2 mEq/L have been measured in patients with normal total body magnesium.” Although there has been interest in red blood cell magnesium content, it has been shown to vary by a factor of five depending on the age of the RBC, making the measurement somewhat ~nreliab1e.l~ Early research is indicating that white blood cell (WBC) magnesium content is far easier to measure and may be nearly as accurate as the magnesium retention test; the clinical usefulness of the technique awaits further studies.35 Erythrocyte membrane tests are also proving useful to test the status of minerals like magnesium and calcium (see earlier discussion of calcium) and have been shown to be more clinically relevant than either plasma or intracellular studies.= Although the calcium/magnesium ratio in erythrocyte membranes was shown to be high in essential hypertension patients, it is unclear whether this finding is a cause or an effect of hypertension. However, it has been well suggested in the literature that magnesium levels are indeed low in hypertension patients.%

Manganese Assessment of body status for manganese is difficult owing to the mineral’s normally low levels (1%of the level of copper or zinc in blood). Whole blood manganese concentration is a valid indicator of body manganese and soft tissue levels.37Proper technique is essential in the collection procedure as well as the actual analysis. Hair manganese level may be a rough indicator, especially in chronic toxicity, but is not as reliable as whole blood measurement.

Potassium Because potassium is primarily an intracellular ion, serum measurements do not accuratelyreflect body stores. A low

serum potassium level usually indicates an advanced intracellular deficit. However, an intracellular deficit may also occur with normal or high serum potassium concentration. Several researchers have been studying RBC potassium content, which has been shown to reflect the potassium content of other tissue ~ e l l s . Although ~J~ RBCs do not have nuclei, the sodium-potassium membrane pump is intact, maintaining the proper influx and efflux of these ions. Whole blood potassium concentration is almost as accurate as RBC potassium level, since 98% of the potassium is intracellular. An example of the validity of measuring intracellular potassium was demonstrated in a study that measured the repolarization phase electrocardiographically in the elderly. Alterations of repolarization correlated well with intracellular potassium levels but showed no correlation with serum

Selenium After absorption, selenium is distributed throughout the tissues but does not seem to equilibriate with blood selenium levels. Research currently indicates that blood selenium levels do not correlate with selenium intake, except at extremes.41Furthermore, serum levels of selenium does not seem to be associated with mortality and morbidity in relationship to infectious although one study did find low serum levels of selenium and zinc to be associated with advanced gastrointestinal cancer.8 Conversely, hair selenium level does seem to correlate ~ e l l . As 4 ~with ~ chromium and manganese, special analytical techniques must be used to ensure accuracy of measurements of this element.

Zinc Zinc is an intracellular ion, and some research shows that plasma and serum zinc concentrations are not sensitive indicators of depletion.& Erythrocyte membrane zinc content may be an even less sensitive indicator of zinc status than plasma concentration. Urinary zinc level is also not a good indicator. Low hair zinc levels indicate depletion, but normal values do not rule out low body Leukocyte zinc level has been investigated and found to be an accurate index of body stores.51 In one investigation, 16 young women were given high and then low zinc dietary intake for specified periods. It was observed that low zinc intake status was not correlated with plasma zinc levels. In this study, isotope techniques were used to study fractional zinc absorption and endogenous fecal zinc excretion. Plasma zinc concentration was not sigruficantly lower during the low dietary intake period than during the high dietary intake period. However endogenous fecal zinc excretion was found to be significantly lower during the low intake period than during the high intake period, and there was

Mineral Status Evaluation no significant change in fractional zinc absorption or urinary zinc excretion.52

CONCLUSION Given the plethora of research correlating mineral levels with multiple disease conditions, developing more reliable methods of study will undoubtedly help clinicians evaluate disease status, progression, and prognosis as well as give information to make better treatment choices. However, no analytical test is better than the laboratory performing it. Proper analytical procedures must be used, and each step in the collection and preparation of a sample must be carefully monitored.

1. Savory J, Wills M. Trace minerals: essential nutrients or toxins? Clin Chem 1992;38:1565-1573. 2. Katz S, Chatt A. Hair analysis applications in the biochemical and environmental sciences. New York VCH Publishers, 1988. 3. Vienna A, Capucci E, Wolfsperger M, et al. Heavy metal concentration of hair of students in Rome. Anthropol Anz 1995;53:27-32. 4. Foo S, Khoo N, Heng Y, et al. Metals in hair as biological indices for exposure. Int Arch Occup Environ Health 1993;65:%3-%6. 5. Jenkins D. Toxic metals in mammalian hair and nails. EPA report 600/4-79-049. August 1979. (Available through National Technical Information Service.) 6. Sullivan JF, Blotcky AJ, Jetton MM, et al. Serum levels of selenium, calcium, copper, magnesium, manganese and zinc in various human diseases. J Nutr 1979;109:1432-1437. 7. Kuo HW, Chen SF, Wu CC, et al. Serum and tissue trace elements in patients with breast cancer in Taiwan. Biol Trace Elem Res 2002; 89:1-11. 8. Jia ZG. Analysis of serum levels of selenium, zinc, and copper in 132 patients with malignant tumors. Zhonghua Yu Fang Yi Xue Za Zhi 1991;25:205-207. 9. Celik HA, Aydin HH, Ozsaran A, et al. Trace elements analysis of ascitic fluid in benign and malignant diseases. Clin Biochem 2002; 35:477-481. 1O.Teksen F, Mungan D, Sayal A, et al. Serum and pleural fluid selenium, copper, zinc, and magnesium levels in malignant and nonmalignant pleural diseases. Respiration 1996;63:25-27. 11. Altintas A, Vardar MA, Gonlusen F, et al. Copper, zinc, and magnesium tissue and serum levels in patients with cervical carcinoma. Eur J Gynaecol Oncol1995;16278-281. 12. Oster 0, Dahm M, Oelert H. Element concentrations (selenium, copper, zinc, iron, magnesium, potassium, phosphorous) in heart tissue of patients with coronary heart disease correlated with physiological parameters of the heart. Eur Heart J 1993;14: 770-774. 13. Beck KW, Schramel P, Hedl A, et al. Serum trace element levels in HIV-infected subjects. Biol Trace Elem Res 1990;25:89-96. 14. Ilhan A, Uz E, Kali S, et al. Serum and hair trace element levels in patients with epilepsy and healthy subjects: does the antiepileptic therapy affect the element concentrations of hair? Eur J Neurol 1999;6705-709. 15. Kucharzewski M, Braziewicz J, Majewska U, et al. Copper, zinc, and selenium in whole blood and thyroid tissue of people with various thyroid diseases. Biol Trace Elem Res 2003;93:9-18.

For example, in hair analysis, proper washing of hair and use of ultrahigh pure digesting acid and distilled water are important. In blood analysis, collection tubes specially designed for the specific mineral being collected must be used. Ultimately, it is the physician’s responsibility to verify the validity of an analytical procedure. When in doubt, one should obtain a copy of the actual procedure for review and compare it with the limits of detection for the particular instrument being used. Many of the reference articles listed in the References are reviews, and thus can serve as sources of additional information.

16. Iskra M, Patelski J, Majewski W. Relationship of calcium, magnesium, zinc and copper concentrations in the arterial wall and serum in atherosclerosis obliterans and aneurysm. J Trace Elem Med Biol 1997;11:248-252. 17. Gupta SK, Shukla VK,Vaidya ME’, et al. Serum trace elements and Cu/Zn ratio in breast cancer patients. J Surg Oncol1991;46:178-81. 18. Albanese A. Bone loss: causes, detection, and therapy. New York Alan R Liss, 1977. 19. Basco J. On determination of calcium in hair and its use for investigation of coronary heart disease and calcium metabolic rate. Atomki Kozl1985;262324-2325. 20. MacPherson A, B a h t J, Basco J. Beard calcium concentration as a marker for coronary heart disease affected by supplementation with micronutrients including selenium. Analyst 1995;120871-875. 21. Bland J. Dietary calcium, phosphorus and their relationships to bone formation and parathyroid activity. J John Bastyr Col Naturopathic Med 1979;l:l. 22. Kosch M, Hausberg M, Westermann G, et al. Alterations in calcium and magnesium content of red cell membranes in patients with primary hypertension. A m J Hypertens 2001;14:254-258. 23. Wallach S. Clinical and biochemical aspects of chromium deficiency. J Am Coll Nutr 1985;4:107-120. 24. Hambidge K. Chromium nutrition in man. Am J Clin Nutr 1974; 27505-514. 25.Aharoni A, Tesler B, Paltieli Y, et al. Hair chromium content of women with gestational diabetes compared with nondiabetic pregnant women. Am J Clin Nutr 1992;55:104-107. 26. Solomons N. Biochemical, metabolic and clinical role of copper in human nutrition. J Am Coll Nutr 1985;4:83-105. 27. Magalova T, Beno I, Brtkova A, et al. Levels of Cu, Zn, Se and their relation to levels of ceruloplasmin and the activity of antioxidative enzymes. Bratisl Lek Listy 1997,98:8-11. 28. Piccinhi L, Borella P, Bargellini A, et al. A case control study on selenium, zinc, and copper in plasma and hair of subjects affected by breast and lung cancer. Biol Trace Element Res 1996;51:23-30. 29. Donma M, Donma 0,Tas MA. Hair zinc and copper concentrations and zinc:copper ratios in pedmtric malignancies and healthy children from SoutheasternTurkey. Biol Trace Element Res 1993;36:51-63. 30. Cook J, Lipschitz DA, Miles LE, et al. Serum ferritin as a measure of iron in normal subjects. Am J Clin Nutr 1974;27:681-687. 31.Peter F, Wang S . Serum iron and total iron binding capacity compared with serum ferritin in assessment of iron deficiency. Clin Chem 1981;27:276-279.

Supplementary Diagnostic Procedures 32. Rubenstein E, Federman DD. Scientific American medicine, vol II. New York Scientific American, 19855. 33. Seelig M. Magnesium deficiency in the pathogenesis of disease. New York: Plenum Medical Books, 1980. 34.Ryschon TW,RosenStein DL, Rubinow DR, et al. Relationship between skeletal muscle intracellular ionized magnesium and measurements of blood magnesium. J Lab Clin Med 1996;127207-213. 35. Hosseini JM, Johnson E, Elin RJ. Comparison of two separation techniques for the determination of blood mononuclear cell magnesium content. J Am Coll Nutr 1983;2361-368. 36. Kisters K, Tepel M, Spieker C, et al. Decreased membrane Mg2+ concentrations in a subgroup of hypertensives: membrane model for the pathogenesis of primary hypertension. Am J Hypertens 1998; 11:1390-1393. 37. Keen C. Whole blood manganese as an indicator of body manganese. N Engl J Med 1983;308:1230. 38. Bahemuka M, Hodkinson H. Red blood cell potassium as a practical index of potassium status in elderly patients. Age Ageing 1976; 524-30. 39. Lans K, Stein F,Meyer KA. The relationship of serum potassium to erythrocyte potassium in normal subjects and patients with potassium deficiency. Am J Med Sci 1952;223:65-74. 40.Barbagallo Sangiorgi G, Costanza G, Di Sciacca A, et al. Serum potassium levels, red-blood-cell potassium and alternations of the repolarization phase of electrocardiography in old subjects. Age Ageing 1984;13309-312. 41. Lane HW,Warren DC,Taylor BJ, et al. Blood selenium and glutathione peroxidase levels and dietary selenium of free-living and institutionalized elderly subjects. Proc Soc Exp Biol Med 1983;173: 87-95.

42. Olmez A, Yalcin S, Yurdakok K, et al. Serum selenium levels in acute gastroenteritis of possible viral origin. J Trop Pediatr 2004; 5078-81. 43. Peng X, Lingxia Z, Schrauzer GN, Xiong G. Selenium, boron, and germanium deficiency in the etiology of Kashin-Beck disease. Biol Trace Elem Res 2000;77:14. 44.Shamberger RJ. Validity of hair mineral testing. Biol Trace Elem Res 2OO2;871-28. 45. [No authors listed.] Observations on effect of sodium selenite in prevention of Keshan disease. Chinese Med J 1979;92:471-476. 46.Spallholz JE, Martin JL, Gerlach ML, et al. Immunologic responses of mice feed diets supplemented with selenite selenium. Proc Society Exp Biol Med 1973;143:685-689. 47.Valentine JL, Kang HK, Spivey GH. Selenium levels in human blood, urine and hair in response to exposure via drinking water. Environ Res 1978;17:347-355. 48.Davies S. Assessment of zinc status. Intl Clin Nutr Rev 1984;4 122-129. 49. Hambidge KM, Hambidge C, Jacobs M, et al. Low levels of zinc in hair, anorexia, poor growth and hypogeusia in children. Pediatr Res 1972;6868-874. 50.Pekarek R, Sandstead HH, Jacob RH, et al. Abnormal cellular immune response during acquired zinc deficiency. Am J Clin Nutr 1979;321466-1471. 51. Jones R, Keeling PW, Hilton P, et al. The relationship between leukocyte and muscle zinc in health and disease. Clin Sci 1981; 60~237-239. 52.Griffin IJ, Hicks PD, Liang KL, et al. Metabolic adaptations to low zinc intakes in premenarcheal girls. Am J Clin Nutr 20@4;80 385390.

Oral Manifestations of Nutritional Status Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER C O N T E N T S Introduction 281

Abnormalities of the Oral Membranes

281

The Healthy Mouth 281

INTRODUCTION The structures and lining of the oral cavity offer valuable, and easily accessible, information on the nutritional status of an individual. The lesions may indicate a nutrient deficiency or may be manifestations of gastrointestinal or other disease.' Because of the very rapid cell turnover of the oral mucosa, these lesions often may precede other manifestations of nutrient deficiency or systemic disease. Some typical lesions are mucosal ulceration, cheilosis, gingivitis, and glossitis. Between 5%and 10% of the people in the United States are deficient in one or more nutrients, so signs of nutritional deficiency are common.

regular dental checkups. Here are some key nutritional considerations for examination of the teeth2: Having fewer than 20 teeth as an adult is associated with a significantly reduced capacity to eat nutritious foods, such as salads, raw fruit and vegetables, nuts, and whole grain products. The same applies even to denture wearers. Bulimia may manifest as erosive tooth wear. Osteoporosis may manifest initially as changes in jaw structure and/or loose teeth. Presence of mercury amalgams may be associated with systemic disease, especially neurologic conditions.

THE HEALTHY MOUTH

ABNORMALITIES OF THE ORAL MEMBRANES

The ventral surface of the healthy tongue is covered with smooth, pink mucous membrane and lymphoid follicles. On the dorsal surface, the filiform, fungiform, and circumvallate papillae (which contain the organs of taste) produce a rough, grayish red appearance. The thick epithelial tufts of the filiform papillae give the tongue its characteristic grayish white coating, whereas the globular, pale red fungiform papillae give it a speckled pink appearance. Furrows are not a characteristic of the healthy tongue. The buccal mucosa has a grayish red color and may be crossed by fine grayish ridges where it touches the closed teeth. The healthy gums have a light reddish appearance and cover the roots of the teeth completely. The assessment of oral health, obviously, must assess the health and status of the teeth. Patients should be asked about their dental history and encouraged to have

Table 28-1 summarizes the typical oral manifestations associated with a particular nutrient deficiency, and Table 28-2 summarizes common disorders associated with oral In general, ulceration should be considered a nonspecific expression of a disease state. A search for the etiology will usually result in a specific therapy. Aphthous stomatitis is a common example of a mucosal ulceration and is discussed in detail in Chapter 148. Similarly, cheilosis is a common expression for acquired nutrient deficiency. Gingivitis is associated with the classic signs of scurvy, but other nutrients have now been shown to play a role in gingival health; this subject is discussed in Chapter 201. Glossitis is associated with numerous vitamin deficiency states, each with a characteristic appearance. Like glossitis, intruoral burning represents a nonspecific expression of a possible nutrient deficiency or 281

Supplementary Diagnostic Procedures Oral signs of nutrient deficiency Nutrient

Sians of oral deficiencv

Vitamins Biotin

Geographic tongue, atrophy of lingual papillae

Folic acid

Gingivitis, glossitis with atrophy or hypertrophy of filiorm papillae, cheilosis

Niacin

lntraoral burning, canker sores, halitosis, glossitis, tongue swollen with red tip and sides, swollen red fungiform papillae, filiform papillae becoming inflamed and losing their epithelial tufts (giving the characteristic slick red appearance)

Common disorders associated with oral manifestations Oral manifestation

Disorder(@

Cheilosis

Crohn’s disease, acrodermatitis enteropathica, alcoholism, celiac disease, malabsorption syndrome

Gingivitis

Crohn’s disease, anorexia nervosa, celiac disease, scurvy

Erythroplakia

Dysplasia or carcinoma

Glossitis

Crohn’s disease, diabetes, alcoholism, celiac disease, malabsorption syndrome, pernicious anemia, iron-deficiencyanemia, amyloidosis, carcinoid syndrome, cigarette smoking, anemia

Pyridoxine

lntraoral burning, glossitis. mucosal ulcerations and erosions, cheilosis

Vitamin B,2

lntraoral burning, mucosal ulcerations and erosions, painful glossitis with a beefy red or fiery appearance eventually resulting in an atrophic (smooth and shiny) tongue

lntraoral burning

Menopause, diabetes mellitus, esophageal reflux, Sj6gren syndrome

Leukoplakia

Chronic irritation, dysplasia, early invasive squamous cell carcinoma

Riboflavin

Soreness and intraoral burning, cheilosis, angular stomatitis, glossitis with a magenta tongue

Ulcerations, erosions

Vitamin C

Sore and bleeding gums, deep blue-red color to gums, loose teeth, follicular hyperkeratosis

Crohn’s disease, ulcerative colitis, celiac disease, corticosteroid use, acrodermatitis enteropathica, anorexia nervosa, pernicious anemia, iron-deficientanemia, mercury poisoning, nicotine withdrawal

Vitamin D

lntraoral burning

Vitamin E

Glossitis

Minerals Calcium

Periodontal disease, tooth decay

Iron

Cheilosis, atrophic glossitis, gingivitis, candidiasis, intraoral burning or pain, mumsal ulcerations and erosions, pallor

Zinc

Marked halitosis, cheilosis, stomatitis, discrete red, scaly plaques from short-lived vesicles, white coating on tongue and mucosa, intraoral burning

Data from references 1-12.

systemic Possible causes in addition to those listed in Table 28-2 are as follows: Xerostomia Dentures Deficiencies of iron, vitamin BI2 folic acid, vitamin B6, and protein

1. Beitman R, Frost S, Roth J. Oral manifestations of gastrointestinal disease. Dig Dis Sci 1981;26741-747. 2. Budtz-Jorgensen E, Chung JP, Rapin CH. Nutition and oral health. Best Pract Res Clin Gastroenterol 2001;15885-896. 3.Basker RM, Sturdee DW, Davenport JC. Patients with burning mouths. Brit Dent J 1978;145:9-16. 4. Maragou P, Ivanyi L. Serum zinc levels in patients with burning mouth syndrome. Oral Surg Oral Med Oral Pathol 1991;71:447-450. 5. Ship JA, Grushka M, Lipton JA, et al. Burning mouth syndrome: an update. J Am Dental Assoc 1995;126843-853. 6. Werbach MR. Nutritional influences on disease. Tarzana, CA: Third Line Press, 1993.

Data from references 2-12.

Steatorrhea Antibiotic use Changes in mucosal innervation Anxiety states

In people who do not wear dentures, nutritional disorders are the most common causative factors? Leukoplakiu is any white lesion of the oral cavity that cannot be removed by rubbing the mucosal surface. Although the lesions are usually only a sign of chronic irritation, 2% to 6% represent either dysplasia or early invasive squamous cell carcinoma: Erythroplakia is similar to leukoplakia, except that it has a definite erythematous component. This is a far more serious sign, with 90%of such lesions representing dysplasia or carcinoma.

7. Shepherd A. The impact of oral health on nutritional status. Nurs Stand 2002;16:37-38. 8. Homick B. Diet and nutrition: implications for oral health. J Dent Hyg 2002;7667-78. 9. Enwonwu CO, Sanders C. Nutrition: impact on oral and systemic health. Compend Contin Educ Dent 2001;22 (3 Spec No):12-18. 10. Rugg-Gunn AJ. Nutrition, diet and oral health. J R Coll Surg Edinb 2001;46:320-328. 11. Mojon P, Budtz-Jorgensen E, Rapin CH. Relationship between oral health and nutition in very old people. Age Ageing 1999;28: 463-468. 12. Walls AW. Oral health and nutrition. Age Ageing 1999;28:419-420.

Rapid Dark Adaptation Test Dirk Wm. Powell, ND CHAPTER CONTENTS Introduction 283

Method 283 Results 284

Clinical Application 283 Interpretation 284 Procedure 283 Equipment and Supplies 283

INTRODUCTlON The earliest sign of vitamin A deficiency is a decrease in dark adaptation, or poor night vision. Serum retinol levels are not predictive of mild deficiency states. However, classic dark adaptation testing is a cumbersome and timeconsuming process (usually taking 45 minutes or longer). A rapid test (6 minutes) was described by Thornton' and evaluated by Vinton and Russell.* This rapid dark adaptation test (RDAT) has significant clinical utility. The basis for the test is the measurement of the time of the so-called Purkinje shift. This term refers to the shifting of peak retinal wavelength sensitivity from the red toward the blue end of the visual spectrum during the transition from day (cone-mediated)vision to night (rodmediated) vision. When color vision is nonfunctional, this shift causes the intensity, not the color, of blue to appear brighter than red under dim lighting.

CLINICAL APPLICATION Although the various dark adaptation tests have the advantage of being in vivo tests, and therefore directly related to function, they are also somewhat less specific. Box 29-1 lists conditions that may give abnormal dark adaptation results despite normal serum levels of vitamin A.

PROCEDURE Equipment and Supplies Lightproof room A standard darkroom light fixture fitted with a 7.5 W bulb and a neutral-density filter (allowing 1%

transmittance).Alternately, an exposed x-ray film may serve as the filter. The bottom of the fixture is suspended 1.2 m above the work surface, so that the target brightness on the work area is approximately 0.0068 candela/m2. Munsell color disks with matte finish: five white disks (N9.5/-), six blue disks (5PB5/10), and seven red disks (5R5/10) (available from Munsell Color and Macbeth Division, Baltimore, MD) A nonreflective work surface A stopwatch A standard x-ray viewbox

Method 1. The procedure is explained to the subject. 2. The subject's vision is light-adapted by fixation on a standard x-ray viewbox for 1 minute at a distance of 0.5 m. The x-ray viewbox is then turned off (the darkroom light remains on). 3. The subject is given a pile containing all 18 disks mixed in random order, and the stopwatch is started. 4. The subject separates the white and then the blue disks as fast as possible. Under these controlled lighting conditions, the subject will not be able to recognize the colors, because the cones cannot distinguish color with the limited light available. The ability to separate the disks by brightness therefore depends on the rods. Any disk mistakenly separated by the subject is returned to the original pile until 100% accuracy of sorting is achieved, at which point the stopwatch is stopped and the time is recorded as the result.

283

Supplementary Diagnostic Procedures

In subjects with normal vision, results are given according to age group:

Zinc deficiency Cataract Retinitis pigmentosa Diabetic retinopathy Severe errors of refraction Miosis caused by pharmaceutical agents Tinted corrective lenses

20 to 39 years old: 3.03 f 1.00 minutes 40 to 60 years old: 4.41 f 0.83 minutes

Results in subjects who are vitamin A deficient average 7.63 & 1.79 minutes.

INTERPRETATION ~~

Viiton and Russellz reported the following results.

The RDAT time depends largely on the individual setting. However, the difference in the RDAT time between normal and vitamin A-deficient individuals is sigruficant, and therefore standardization is easily achieved. The normal values depend on the age of the subject, with older subjects having an increased RDAT time. An increased RDAT time may also indicate a zinc deficiency.

1. Thornton SP. A rapid test for dark adaptation. Ann Ophthalmol 1977;9:731-734.

2. Viton NE, Russell RM. Evaluation of a rapid test of dark adaptation. Am J Clin Nutr 1981;341961-1966.

5. The first test performed by a subject should be redone to allow for learning and standardization.

Results

Urinary Organic Acids Profiling for Assessment of Functional Nutrient Deficiencies, Gut Dysbiosis, and Toxicity J. Alexander Bralley, PhD Richard S. Lord, PhD CHAPTER C O N T E N T S Introduction 285 Organic Acids

Fatty Acid Oxidation 292 Adipate, Suberate, and Ethylmalonate 292

286

Urinary Organics Profiling 287 Central Energy Pathway Intermediates 287 Citrate, Isocitrate, alpha-Ketoglutarate, cis-Aconitate, Succinate, and Fumarate 287 Lactate and Pyruvate 290 Carbohydrate Metabolism 291 beta-Hydroxybutyrate 291 alpha-Hydroxybutyrate 291 Indicators of a Specific Vitamin Deficiency 291 beta-Hydroxyisovalerate 291 Hydroxymethylglutarate 291 B-Complex Insufficiency Markers 291 alpha-Ketoisovalerate, alpha-Ketoisocaproate, and alpha-Keto-beta-methylvalerate 291 Methylmalonate 292 Formiminoglutamate 292 Kynurenate and Xanthurenate 292

INTRODUCTION Urinary organic acid analysis for metabolic profiling has traditionally been used only to assess and define inborn errors of metabolism that cause death within the first year of life or severe mental retardation. The identification of isovaleric acidemia in 1966 was followed quickly by numerous additional acidurias because the severe enzyme impairments of genetic diseases were found to result in urinary excretion of greatly elevated amounts of organic compounds.' Profiling of organics in urine as a routine laboratory evaluation of chronic diseases is a relatively recent addition to clinical assessment procedures.

Neurotransmitter Metabolism 293 Vanilmandelate and Homovanillate 293 5-Hydroxyindolacetate 293 Products of Gut Microflora 293 Phenylacetate, Phenylpropionate, pHydroxybenzoate, pHydroxyphenylacetate, pHydroxyphenylpropionate, and Tricarballylate 293 Arabinose and Arabinitol 294 D-Lactate 294 Indicators of Detoxification Function 294 Glucarate 294 Orotate 294 p-Hydroxyphenyllactate 295 2-Methylhippurate 295 Pyroglutamate 295 Sulfate 295 Summary 295

The availability of instrumentation with improved reliability, sensitivity, and reduced cost now is allowing greatly expanded clinical application of this testing. The test profile data can be used to detect subtle functional nutritional deficiencies, to identify genetic variants, and to establish the source of toxicants from the environment and gut.24 For example, elevated methylmalonic acid in urine is a well-established and sensitive indicator of functional vitamin BI2 defi~iency.~ This method of assessing nutritional status is of greater clinical applicability than serum levels of specific nutrients because it allows a functional evaluation of 285

nutritional status, thus identifying biochemical individuality in a population with normal serum levels of nutrient-derived cofactors.6 In addition to early detection of impending anemia and other clinical consequences of vitamin BI2deficiency, organic acid profiling of urine has been found useful in numerous clinical evaluations, as shown in Table 30-1.

ORGANIC ACIDS The term organic acids refers to a broad class of compounds formed in fundamental metabolic processes of the body. Metabolic oxidation reactions produce carboxylic acid groups in the compounds derived from digestion of dietary protein, fat, and carbohydrate.

Clinical applications of organic acids in urine testing Condition

Compound(s)

Acidosis with metformin Acute appendicitis

Lactate 5-Hydroxyindoleacetate

Reference(s) 73 9

Adult neurologic complaints and breathing problems

Pyroglutamate

10

Alcoholic delirium tremens

Vanillylrnandelate

11

Anemia

Methylmalonate

12

Antibiotic-induced metabolic acidosis

Pyroglutamate

13

Arginine-responsive hyperammonemia

Orotate

14

Attention deficit-hyperactivitydisorder

Homovanillate

15

Autism

Tartrate, citramalate

16

Bacterial overgrowth syndromes in acutely ill infants and children

pHydroxyphenylacetate

17

Biotin-responsive orificial skin lesions, lethargy, hypotonia, and alopecia

3-Hydroxyisovalerate

18

Birth asphyxia

Lactate, pyruvate. 3-hydroxybutyrate, 4-hydroxyphenyllactate, 2-hydroxybutyrate, 2-oxo-isocaproate, 2-0x0-3-methylvaleric

19

Calcium urolithiasis

Citrate

20-22

Carnitine-responsive familial Reye-like syndrome

Pyruvate, alpha-ketoglutarate, alpha-ketoadipate

23

Cerebral palsy

Fumarate

24

Chronic fatigue syndrome

Succinate

25

Chronic lactic acidosis (weakness, shortness of breath)

Alpha-ketoglutarate, alpha-hydroxybutyrate

26

Encephalomyelopathy

Alpha-ketoglutarate, succinate, adipate, suberate

27

Encephalopathy

o-Lactate

28

Folate deficiency developmental disorders

5-Hydroxyindoleacetate

29

Glycine-responsive malnutrition

Pyroglutamate

30

Glycogen storage disease

Citrate

22

Gut flora and Klebsiellaspecific metabolites

Benzoate, phenylacetate, phydroxyphenylpropionic, dihydroxyphenylacetate

31,32 33

Hemoblastoses and nephroblastorna

pHydroxyphenyllactic

Hepatic detoxification

Pyroglutamate

34

Homocystinuria resulting from a cystathionine synthetase defect

Pyroglutamate

35

Hyperammonemic encephalopathy

Orotate

36

Liver function in hepatobiliary disease

Glycyl-PABA

41

Neuroblastorna, pheochromocytoma

Hornovanillate, vanillylrnandelate

37-40

Obesity (murine)

Malate, aconitate, hydroxyrnethylglutarate, ethylmalonate, phydroxyphenylacetate

42

Phenol exposure

eCresol

43

Urinary Organic Acids Profiling Clinical applications of organic acids in urine testing4ont’d Condition

Comooundfs~ ~

Referencels)

~~

Pregnancy decrease of biotin status

3-Hydroxyisovalerate

44

Recent alcohol use

5-Hydroxyindoleacetate

45,46

Riboflavin-responsive inspiratory stridor

Ethylmalonate

47

Sleep-waking rhythm

Tartrate

48

Small-bowel disease

pHydroxyphenylacetate

17

Thiamin-responsive maple syrup urine disease

Alpha-ketoisovalerate

49

Toluene exposure

Hippurate

50

Vitamin deficiency in the elderly

Homocysteine, 2-methylcitrate

51

Xylene exposure

2-Methylhippurate

52,53

The resulting organic acids are used by the body to generate cellular energy and provide the building blocks necessary for cell function. Chemically they share the common features water solubility, acidity, and triketohydrindene hydrate (Ninhydrin) negativity; therefore amino acids are usually excluded from this group. Organic acids are generally considered to include all carboxylic acids, with or without keto, hydroxyl, or other nonamino functional groups. Some nitrogen-containing compounds are included; for example, pyroglutamate and amino conjugates such as hippurate (benzoylglycine). Short-chain fatty acids are also included. With the inclusion of neutral compounds of fungal origin such as arabinose and arabinitol in the metabolic profile, the name organic acid analysis is more correctly termed organics profiling because the compounds have no carboxylic acid group.

URINARY ORGANICS PROFILING The quantitative measurement of specific organic acids and neutrals in urine allows the simultaneous assessment of mitochondrial energy production efficiency, functional vitamin, mineral, and certain amino acid deficiencies, neurotransmitter metabolism, clinically significant microflora imbalances in the gut, and metabolic toxicity problems. The test is performed on an overnight urine sample, from which the organic compounds are extracted and analyzed by gas chromatography with mass spectrometric detection. The basic methodologies are well known but improvements are reported Methods using liquid chromatography with tandem mass spectrographic detection promise to revolutionize the field because of greater sensitivity and accuracy. Sample preparation procedures can be simplified greatly with these technologies.

The information content of the profile is high, but the interpretation is simplified if one keeps in mind that the data supply answers to four basic questions of clinical relevance: 1. Is mitochondrial energy production adversely affected? 2. Are functional nutrient deficiencies present? 3. Are symptoms related to excessive growth of bacteria and fungi in the gut? 4. Is there an undue toxic load, and if so, is it adversely affecting detoxification capacity? Each of several compounds reported in the typical profiling of organics in urine is discussed briefly, to indicate how they are related to these clinical questions. Figure 30-1 provides a graphic overview of the nutrient requirements for the citric acid cycle, whereas Table 30-2 shows various nutrient-related abnormalities that might appear on a typical quantitative report of organics in urine. The supplementary nutrient amounts are given as guides to starting points that might improve clinical outcomes for adults. For more information on how well the associations are established, see the discussions that follow.

CENTRAL ENERGY PATHWAY INTERMEDIATES Citrate, Isocitrate, alpha-Ketoglutarate, cis-Aconitate, Succinate, and Fumarate The components citrate, isocitrate, alpha-ketoglutarate (aKG), cis-aconitate, succinate, and fumarate are intermediates in the core metabolic pathway that generates cellular energy. The Krebs or citric acid cycle (CAC) is not only the final common pathway of food components but also the source of basic structural or anabolic molecules that feed and support organ maintenance and neurologic function. Therefore the CAC serves both anabolic

FATS

PROTEINS

CARBOHYDRATES

assimilation

r Glucose 8

Fatty acids. glycerol

-

(G)

other sugars

Amino acids

Y

omioacetate

Citrate %s-Aconitate

Malate CiMc acid cycle

($

a-ketoglutarate

- - 3 ADP + 2 Pi

NADH

Electron transport

1

oxidative

NADH dehydrogenase

phosphorylation

1 Cytochromes

m 2H+

- - 3ATP

n

+ 1/2 0

2

HZO

Figure 30-1 Vitamin and mineral cofactor requirements for the extraction of energy from food.

and catabolic functions of the body, representing the "crossroads" of food conversion and use. Conversions of the CAC intermediates are under the control of enzymes that often require vitamin-derived cofactors and minerals for their function. Abnormal spilling of CAC intermediates can indicate mitochondrial inefficiencies at specific steps in energy production.

This fundamental pathway of energy flow is critical for all organ systems. The measurement of the intermediates listed in the preceding provides a unique perspective to energy metabolism, along with clues to how to improve energy production by supplying B complex vitamins to assure adequate coenzyme concentrations. For example, in cytochrome C oxidase deficiency there

Urinary Organic Acids Profiling

Quick reference to clinical significance of abnormal levels of organics in urine Name

Abnormality

Potential intervention'

Energy Production Citrate

L

Aspartic acid, 500 mg

Cis-aconitate

H

Iron, 18 mg; Nacetylcysteine, 1000 mg bid

lsocitrate

H

aKG, 300 mg tid; B3, 100 mg Magnesium, 400 mg; manganese, 20 mg

Alpha-ketoglutarate

L H

aKG, 300 mg; arginine, 1000 mg; glutamine, 1-5 g B complex, 1 tid; lipoic acid, 100 mg

Succinate

L H

Isoleucine, 1000 mg tid; valine, 1000 mg tid Magnesium, 500 mg Tyrosine, 1000 mg bid; phenylalanine, 500 mg bid

Metabolic pathway

Citric acid cycle intermediates

Fumarate

L

Malate

H

B3, 100 mg tid

Lactate

H

COOlo, 50 mg tid

Pyruvate

H

B complex, 1 capsule tid; B1, 100 mg tid; lipoic acid, 100 mg tid

Aerobidanaerobic energy production

H

B complex, 1 capsule tid; B,, 100 mg tid; lipoic acid, 100 mg tid

Amino acid catabolism using B-complex vitamins Tryptophan metabolism

Specific Vitamin Indicators Alpha-ketoisovalerate, Alpha-ketoisocaproate, Alpha-keto-beta-methylvalerate Kynurenate

H

Be, 100 mg

Xanthurenate

H

Be, 100 mg

Methylmalonate

H

B12,1000 pg tid

BCAA input to Krebs cycle

FIGLU

H

Folic acid

Histidine metabolism

Beta-hydroxyisovalerate

H

Biotin, 5 mg bid; magnesium, 100 mg bid

Dicarboxylicacid metabolism requiring biotin

Hydroxymethylglutarate Carbohydrate Metabolism Beta-hydroxybutyrate

H/L

CoQlo, 50 mg tid

CoQIo synthesis

H

Chromium picolinate, 200 pg bid

Balance of fat and CHO metabolism

DetoxificationIndicators Glucarate

H

Glycine, GSH, NAC, 500-5000 mglday

Detoxifying liver enzyme induction

Orotate

H

aKG, 300 mg tid; arginine, 1-3 glday; aspartic acid, 500 mg bid; magnesium, 300 mg

Ammonia clearance, pyrimidine synthesis

p Hydroxyphenyllactate

H

Vitamin C up to 100 mglkg

Prooxidant and carcinogen

2-Methylhippurate

H

Avoidance of xylene

Hepatic conjugation

Alpha-hydroxybutyrate

H

NAC, 1000 mg; glutathione, 300 mg; lipoic acid, 600 mg Taurine, 500 mg bid; glutathione, 300 mg

Hepatic glutathione synthesis

Pyroglutamate

H

Glutathione wasting in amino acid recovery

Sulfate

L

Detoxifying and antioxidant functions

Fatty Acid Oxidation Adipate, suberate, ethylmalonate

H

L-Carnitine, 250 mg tid; B2, 100 mg bid; B5, 500 mg bid; choline, 100 mg tid; vitamin C, 1000 mg tid; CoQ,, 150 mg

Fatty acid oxidation

NeurotransmitterMetabolism Vanilmandelate, homovanillate

L/H

Tyrosine may stimulate rates of catecholamine production; contraindicatedfor patients taking MA0 inhibitors

Catecholamine catabolism, neurotransmitter metabolites

5-H ydroxyindolacetate

L

5-Hydroxytryptophancan stimulate rates of serotonin production;contraindicatedfor patients taking SSRl

Quinolinate

H

Magnesium, 300 mg

Serotonin catabolism Continued

Quick reference to clinical significance of abnormal levels of organics in urin-ont'd Name

Abnormality

Potential intervention*

Dysbiosis Markers (Products of Abnormal Gut Microflora) H If any of these compounds is high, Products of bacterial growth: the possibility of dysbiosis is reinforced. benzoate, hippurate, Glutamine, 10-30 g daily, and free-form phenylacetate, phenylpropionate, amino acids normalize gut permeability. p hydroxybenzoate, phydroxyphenylacetate, Take appropriate steps to ensure tricarballylate, favorable gut microflora population. phydroxyphenylpropionate D-Lactate Products of yeast growth o-Arabinital BCAA. Branchedchain amino acids; CHO, carbohydrate: CooIlhcoenzyme NAC, N-acetyl-L-cysteine. 'Supplemental dosages are in the upper range of agressive repletion

Qlo;

is inefficient removal of the primary product of the CAC (nicotinamide adenine dinucleotide, reduced form [NADH]), and citrate, malate, fumarate, and aKG are all increased.52Coenzyme Qlo(CoQlo)deficiency also can result in elevations of CAC intermediates (see "Hydroxymethylglutarate"). The use of several other nutrients at high levels to bring about normalization of mitochondria1 oxidative phosphorylation function has been discussed in connection with diagnosis of specific genetic dis0rders.5~ Mild inborn errors of energy metabolism that may be compatible with survival at least into young adulthood, but not with normal development of mental and neurologic functions, have been associated with the excretion of elevated CCKG.% The clinical heterogeneity of neurometabolic disorders and the importance of organic acid analysis in the diagnosis of static encephalopathy were underscored by the finding of excretion of excess fumaric acid in a 5-year-old girl with a previous diagnosis of cerebral palsy.55 Urinary levels of citrate, a marker of acid-base status, normally decrease with age.%Metabolic compensation in type la glycogen storage disease leads to low urinary citrate concentration and higher incidence of nephrolithiasis. Citrate supplementation may help avoid urinary calculi in patients with low urinary citrate levels.57 Drinking bicarbonate-rich mineral water also has been shown to help raise urinary citrate concentration, and this dietary change has been suggested to prevent the recurrence of calcium oxalate and uric acid stones.% Intermediates of the cycle also can be derived from amino acids. This explains the energy-boosting effect people often report when they take free-form amino acid supplements. The effect resultsfrom the conversion of specific amino acids directly into CAC intermediates needed

Metabolic pathway Numerous interferences in pathways and cellular energy control mechanisms

GSH, glutathione; H, high: KG. ketoglutarate; L, low; MAO, monoamine oxidase;

for the energy-producing cycle. The fatiguereducing effect of supplementation of aspartate salts and a-ketoglutaric acid has been attributed to such a m e c h a n i ~ m . ~ ~ , ~ Supplementation of the precursors serves to drive the cycle and generate reducing equivalents used in the electron transport chain in which ATP is produced via oxidative phosphorylation. Low levels of a specific metabolite may indicate suboptimal amino acid availability and the need for supplemental amounts of these specific amino acids for improved function.

Lactate and Pyruvate Lactate and pyruvate provide useful insight into basic metabolic factors because of their position in the energy production process. Pyruvate is the anaerobic breakdown product of glucose. Its further conversion to acetyl-coenzyme A (acetyl-CoA) requires the pyruvate dehydrogenase enzyme complex. For optimal function, this single enzymatic step requires the simultaneous binding of cofactors derived from thiamin, riboflavin, niacin, lipoic acid, and pantothenic acid. Elevations of pyruvate may reflect failure of the enzyme because of a functional need for increased B vitamins, particularly thamin and pantothenic acid. Levels of pyruvate in the tissues are further controlled by the biotin-containing protein pyruvate carboxylase, which controls the first step in the reformation of glucose from pyruvate. Multiple forms of pyruvate carboxylase deficiency, some of which are biotin responsive, have been reported.6l Lactate accumulates when there is a block in the final oxidative phosphorylation (ox/phos) stage of energy production. Such a block results in inactivation of the CAC. CoQlo has been used in cases of lactic acidosis associated with ox/phos i m p a i r r n e n t ~ . ~ Increased ~,~~

Urinary Organic Acids Profiling

lactate is a common acidotic condition that can be caused by a variety of metabolic problems. Decreased lactate is seen in people who have very little physical activity.Highly trained athletes have such efficient conversion of lactate to glucose that they also demonstrate lower lactate levels.

CARBOHYDRATE METABOLISM Beta-Hydroxybutyrate Students of health science encounter beta-hydroxybutyrate as one of the classic ketone bodies. Ketone body production occurs in conditions in which glucose oxidation is impaired and free fatty acids are used as the predominant energy source. Ketone bodies can be thought of as a transportable form of acetate resulting from oxidation of fatty acids. Beta-Hydroxybutyrate is normally produced in much larger amounts than the alpha-isomer, but both compounds can serve the energy needs of most tissues. Elevations seen in an overnight-collection urine specimen may indicate inefficient use or mobilization of carbohydrate stores. Excessive fatigue on exertion is the most common symptom associated with ketosis. Chromium and vanadium supplementation may support carbohydrate use by improving the action of insulin.

Alpha-Hydroxybutyrate Alpha-hydroxybutyrate is a by product of the conversion of cystathionine to cysteine. This reaction in intermediate to the conversion of methionine via homocysteine to supply cysteine for hepatic glutathione synthesis. When demand for glutathione increases due to oxidative stress or detoxification requirements, the flow through this pathway increases with concomitant increases in the excretion of alpha-hydroxybutyrate. The enzyme alphahydroxybutyrate dehydrogenase (AHBD) occurs at high concentrationsin cardiac muscle tissue, and its elevation in serum is widely used to estimate infarct size and reperfusion effectiveness.H Recent studies of organic acids during a xylene exposure incident for an autistic child in our laboratory indicate that a-hydroxybutyrate is excreted at higher levels when epinephrine is stimulated.65These findings are consistent with observations of AHBD changes in mice caused by acute stressM

INDICATORS OF A SPECIFIC VITAMIN DEFICIENCY Beta-Hydroxyisovalerate Beta-Hydroxyisovalerate is an ideal marker compound for evaluating biotin status because it is produced in the highflux pathway for degradation of the most abundant dietary amino acid, isoleucjne. The carboxylase enzyme that is necessary for the step that clears beta-hydroxyimvalerate requires the active form of biotin; human biotin deficiency has been shown to quickly produce elevation of urinary

beta-hydroxyi~ovalerate.~~ Beta-Hydroxyisovalerate is elevated in inherited disorders of multiple carboxylase insufficiency (biotin is the cofactor for three mitochondrial carboxylase enzymes).@ Symptoms of multiple carboxylase deficiencies include alopecia, rash, Cundidu dermatitis, unusual odor to the urine, immune deficiencies, and muscle weakness. Biotin deficiencies of various degrees develop in a substantial minority of normal pregnancies and in patients undergoing long-term therapy with a n t i c o n v u l ~ a n t sOther . ~ ~ ~ possible ~~ indications of biotin deficiency are elevations of lactate and alanine in urine, and accumulations of odd-chain fatty acids in plasma or red cell membranes.’l Supplementation of biotin may improve these conditions.

Hydroxymethylglutarate Hydroxymethylglutarate (HMG) is the metabolic precursor of cholesterol and CoQlo. Low levels may reflect inadequate synthesis and possible deficiency of the CoQlo. The statins are cholesterol-lowering drugs that block use of HMG for cholesterol synthesis. They cause greatly elevated urinary HMG and lower serum CoQlo levels.” CoQlo is used in the mitochondrial oxidative phosphorylation pathway for ATP synthesis and is a potent antioxidant. It has been employed extensively as a cardiovascular protective agent.” CoQlo has also been used successfully to improve mitochondrial function in clinical situations of cardiac and skeletal muscle weakness and cramping and, in the extreme, mitochondrial e n ~ e p h a l o m y o p a t h y .The ~~,~~ coenzyme has been found helpful in the treatment of fatigue, particularly when both lactate and pyruvate are elevated. Such responses reflect the inability of mitochondrial oxidative phosphorylation to proceed efficiently, possibly because of CoQlodeficiency.

B-COMPLEX INSUFFICIENCY MARKERS Alpha-Ketoisovalerate, alphaKetoisocaproate, and alpha-Keto-betamethylvalerate The ketoacids of the branched-chain amino acids isoleucine, leucine, and valine are alpha-ketoisovalerate, alpha-ketoisocaproate, and alpha-keto-beta-methylvalerate, respectively. They are formed by the removal of the amine group in branched-chain amino acid catabolism and are excreted in large amounts along with their amino acid precursors in the inherited disorder known as maple syrup urine disease. There are several known metabolic disorders in the pathways of catabolism of the ketoacids. The reactions require enzymes similar to pyruvate dehydrogenase that use the B-complex cofactors B1, B2 B5 B5, and lipoic acid. Elevations of the branched-chain ketoacids provide a functional assessment of the sufficiency of these vitamins, especially

Supplementary Diagnostic Procedures

Figure 30-2 Methionine is recovered from homocysteine by methylation in which vitamin BIZ is the cofactor and methyl tetrahydrofolate is the methyl donor. Methylmalonate is converted into succinic acid using a vitamin B,,-dependent enzyme, methylmalonyl CoA mutase. Both homocysteine and methylmalonate serve as metabolic markers of vitamin B,2 deficiency.

Methylmalonate

Kynurenate and Xanthurenate

Methylmalonate is converted into succinic acid by means of a vitamin B12-dependentenzyme, methylmalonyl CoA mutase (Figure 30-2). The lack of vitamin B12 impairs this conversion, as well as the one in which methionine is recovered from homocysteine, leading to accumulation of homocysteine. As discussed previously, high levels indicate a functional deficiency of vitamin B12." A differential diagnosis can be made when both methylmalonate and the amino acid homocysteine are measured. If both homocysteine and methylmalonate are elevated, both B12 and folate functional deficiencies are indicated. Folate supplementation is suggested if homocysteine alone is high. B12 supplementation is needed if methylmalonate alone is elevated.

Metabolites of tryptophan, kynurenic and xanthurenic acids are produced in increasing amounts with the development of vitamin B6 insufficiency. As xanthurenate excretion increases, niacin production from tryptophan decreases if vitamin B6is insufficient to maintain the niacin-conversion pathway.8l These two markers of vitamin B6deficiency are much higher in the kidney than in blood. Both kynurenine and 3-hydroxykynurenine are formed in liver, but they appear in urine as total kynurenine.82 Pregnancy may have independent effects on kynurenine excretion, and studies in rats seem to show that the effects of pregnancy and diet are additive.=

Formiminoglutamate

FAlTY ACID OXIDATION Adipate, Suberate, and Ethylmalonate

Formiminoglutamate (FIGLU) is a biochemical marker of folic acid insufficiency. Histidine metabolism is interrupted in the absence of adequate levels of folic acid and vitamin B12 such that the intermediate compound formiminoglutamic acid accumulates and spills into urine.78 FIGLU may be a more sensitive marker for vitamin B12deficiency than methylmalonate. In a cohort of 15 leukemia cases, three patients showed elevated FTGLU, whereas the entire group had normal methylmalonate levels.79An instance of genetic variance in the vitamin BI2-dependent FIGLU transferase enzyme has been reported in which normal serum folate and vitamin B12values were present, whereas gross excretion of FIGLU was found in a child with failure to thrive and vomiting.s0

Adipate and suberate are short-chain dicarboxylic fatty acids produced by an alternate oxidation pathway called omega-oxidation. Their production normally is low because the predominant pathway is beta-oxidation in the mitochondria. However, transport of fatty acids into the mitochondria requires carnitine as a carrier. Suboptimal levels of carnitine result in inadequate transfer of fatty acids into the mitochondria and subsequent compensation via omega-oxidation, producing excess amounts of adipate and suberate. Similar carnitine transport impairment leads to elevation of urinary ethylmalonate. Urinary concentrations of all three of these compounds are elevated in overt enzyme failure, but the patterns of elevations in milder carnitine deficiencies vary.

Urinary Organic Acids Profiling Symptoms include periodic mild weakness, nausea, fatigue, hypoglycemia, ”sweaty feet” odor, recurrent infections, and increased free fatty acids. Patients may also exhibit a Reye-like syndrome with dicarboxylic aciduria, which has been associated with various metabolic toxins generated from viral infections that affect mitochondria1 function. Mild heterozygotic forms of dicarboxylic aciduria may be commonly seen clinically and may go unrecognized. The enzymes involved also respond to environmental toxin exposure with altered lipid metabolism, which can lead to impaired immune responsivene~s.~,~~ Supplementation of carnitine and riboflavin is indicated when urinary adipate, suberate, or ethylmalonate is elevated. (See Chapter 76 for a full discussion of this useful nutrient.)

NEUROTRANSMITTER METABOLISM Vanilmandelate and Homovanillate Vanilmandelate (VMA) (also called vanillylmandelate) is the principal metabolite of the catecholamine epinephrine. Low urinary levels have been associated with low central nervous system (CNS) levels of the neurotransmitter. Symptoms associated with this condition are depression, sleep disturbances, inability to deal with stress, and fatigue. Treatments aimed at improving protein digestion and supplementation of the amino acid precursors can normalize neurotransmitter levels in the CNS.& The much more commonly encountered conditions of elevated adrenal gland output resulting from chronic stress produce high urinary levels of VMA. Because of the rapid clearance rate for this hormone, high VMA does indicate an elevated rate of turnover of the catecholamines, but does not necessarily indicate elevated concentration of the hormones in a blood specimen that has not been gathered during the stressful event. HVA is the principal product of dopamine catabolism. Elevated urinary values indicate increased production and turnover of dopamine. VMA is greatly elevated by pheochromocytomas, and both VMA and homovanillate (HVA) are measured in screening and prognosis for hemoblastoses and n e u r o b l a ~ t o m a . ~ ~ , ~

5-Hydroxyindolacetate Catabolic breakdown of serotonin leads to excretion of 5-hydroxyindoleacetate (5-HIA).Abnormally high levels of this metabolite result from increased release of serotonin from any of three primary sites: CNS, argentaffin cells in the gut, and platelets. Carcinoid tumors composed of chromaffin tissue also can release large amounts of serotonin. Serotonin is necessary for control of gut motility because it activates smooth muscle activity. Inadequate production of serotonin leads to constipation. Low levels

also have been associated with depression, fatigue, insomnia, suicide, attention deficit disorder, and behavioral disorders. When 5-HIA levels are low, dietary therapy should focus on improving protein digestion and increasing consumption of foods high in tryptophan, including turkey, bananas, low-fat milk, lentils, and eggs. (See elsewhere in this volume for discussions of hypochlorhydria and pancreatic insufficiency.) These actions minimize the need for oral tryptophan or 5-hydroxytryptophan use.

PRODUCTS OF GUT MICROFLORA Several studies have used the appearance of unique products of microbial metabolism in urine as an indicator of the abnormal overgrowth of unfavorable intestinal microflora, a condition sometimes called “gut dysbiosis.” Such a condition has been related to a wide variety of symptoms caused by pathogenic toxins produced by these populations of microflora. No false-negative results and only 2% of false-positive results for small bowel disease and bacterial overgrowth syndrome were found in a study of p-hydroxy-phenylacetate in 360 acutely ill babies and children.89Some compounds are absorbed and enter the detoxification pathways of the liver, to be excreted as products that can serve as sensitive indicators of changes in gastrointestinal (GI) flora?O One product of anaerobic bacteria, 3-phenylpropionic acid, is normally converted to common hippuric acid but is excreted as 3-phenylpropionylglycinein individuals with a relatively common inborn error of fatty acid oxidation?l The incidence of this disorder may be 1in 10,000 in people of northwestern European origin.

Phenylacetate, Phenylpropionate, p Hydroxybenzoate, pHydroxyphenylacetate, p Hydroxypheny lpropionate, and Tricarballylate For individuals with normal, healthy intestinal function, the compounds phenylacetate, phenylpropionate, p-hydroxybenzoate,p-hydroxyphenylacetate,p-hydroxyphenylpropionate, and tricarballylate should not appear at more than background concentrations in urine because of the efficient metabolic conservation or recycling of phenyl-group compounds of which they are composed. They are produced by microbial action on tyrosine and phenylalanine and are markers of bacterial growth in the gut. p-Hydroxyphenylacetic aciduria has been found useful in detecting small bowel disease associated with Giurdiu lumblia infestation, ileal resection with blind loop, and other diseases of the small intestine associated with anaerobic bacterial o v e r g r o ~ t h Use .~~ of antibiotics such as neomycin, which act primarily against aerobic bacteria, can encourage the growth of

Supplementary Diagnostic Procedures

Giurdia and anaerobic bacteria, which then produce greater amounts of these c0mpounds.9~ Other GI disorders, including cystic fibrosis of the pancreas, celiac disease, and unclassified enteritis, have been associated with increased excretion of p-hydroxybenzoate, phenylacetate, and p-hydroxyphenylacetate. The patients with cystic fibrosis had elevations of p-hydroxyphenylacetate even while undergoing pancreatin therapy. Variations in the relative amounts of these compounds observed with this type of GI disturbance are an indication that the patterns of excretion are apparently determined by the microbial flora present in the patient's intestinal lumen.94Tricarballylate is produced by aerobic bacteria that quickly repopulate in the gut of germ-free animal~4.9~ Tricarballylate build-up due to overgrowth of Acidaminococcus fmentans or Selenomonas ruminan tium in the rumen of sheep produces magnesium deficiency that can be fatal.%Tricarballylate lowers magnesium because of tight binding in the gut and in blood. Magnesium absorption is reduced and excretion is increased.

Arabinose and Arabinitol

phase I1 detoxification reactions involving glucuronic acid conjugation. A great variety of drugs, environmental toxins, food components, and products of gut microbial metabolism are prepared for excretion by glucuronidation. Decreased glucarate is an indicator of reduced overall hepatic function, whereas elevation of this compound is an indication of enzyme induction caused by such potentially toxic e x p o s ~ r e s . ~ ~ ~ ~ ~ ~ ~ The excretion of Dglucaric acid is considered a marker of the viability of hepatocytes and is a useful clinical prognostic predictor in biliary atresia.'" Most exposures that result in stimulation of hepatic cytochrome P450 activity result in increased excretion of glucarate. For example, urinary Dglucaric acid is elevated in pesticide-exposed groups.1o5Patients with clinically quiescent chronic pancreatitis also show elevations of urinary glucarate, indicating a relationship of toxic metabolite stress to heightened free radical activity and hence to the genesis of chronic pancreatitis.'% The evidence of increased use of phase II conjugation pathways of xenobiotic disposal is in keeping with ongoing toxic metabolite stress from heightened phase I oxidative metabolism. Glucarate measurements have been advanced as useful biomarkers to xenobiotic exposure, being particularly useful as a screening tool in reproductive epidemi~logy.'~~

Arabinose is a carbohydrate and arabinitol is the related sugar-alcohol that is a product specifically of anaerobic fungal growth in the gut. The Disomer of arabinitol is produced by fungal metabolism, and urinary excretion is elevated in patients with invasive ~ a n d i d i a s i s . 9 ~ ~ ~ ~Orotate Orotic acid accumulation is a sensitive marker of ammoD-Lactate nia buildup. Ammonia (via glutamine) is normally disposed of by forming carbamoyl phosphate, which enters Intestinal Lactobacillus ucidophilus produces the D-isomer the urea cycle. When there is insufficient capacity for of lactic acid from the fermentation of undigested detoxifying the load of ammonia, carbamoyl phosphate dietary carbohydrate. L. ucidophilus usually is regarded leaves the mitochondria and stimulates the synthesis as a favorable organism because moderate amounts of of orotic acid.Io8Increased orotic acid production is a D-lactate can be oxidized to C 0 2by intestinal and hepatic sensitive indicator of arginine availability. Most of the enzymes. The organism produces other desired products symptoms that develop after arginine deprivation can and helps discourage colonization by pathogens. Under be accounted for largely by a diminished efficiency of conditions of carbohydrate malabsorption, however, ammonia detoxification. Greater orotic biosynthesis is Dlactate output can exceed metabolic conversion capacobserved with rising ammonia concentrations in rat, ity and accumulate, causing systemic acidosis and mouse, and human liver and is reduced by in vitro encephalopathy.99J" Elevated urinary Dlactate is characarginine supplementation.Im teristic of this condition.Other bacteria, such as Bacteroides Medium-chain acyl CoA dehydrogenase deficiency fragilis and Klebsiellu, also can produce Dlactate, but they and other disorders of fatty acid oxidation may appear lack the ability to proliferate in the highly acidic environlong after infancy in some patients, such as those with ment created by high accumulations of lactic acid. a clinical diagnosis of Reye syndrome. These disorders DLactic encephalopathy is found in a high percentage of may mimic defects in the urea cycle such as that reported patients with short bowel syndrome after intestinal resection, and high Dlactate excretion has been found in for a 13-year-old girl with hyperammonemic encephaloantibiotic-associated diarrhea.'O' pathy and orotic aciduria caused by ornithine transcarbamylase deficiency."O Responses should include steps to stimulate ureogenesis, including alpha-ketoglutarate, INDICATORS OF DETOXIFICATION magnesium, and aspartic and glutamic acids. FUNCTION In addition, orotate requires magnesium for its metabGlucarate olism. Although a normal level in a urinary organic acid panel may not necessarily indicate magnesium Glucaric acid (glucarate) is the oxidation product of glusufficiency, high levels should alert one to a significant curonic acid. It is a by-product of the predominant liver

Urinary Organic Acids Profiling possibility of intracellular magnesium insufficiency. Red blood cell magnesium levels can confirm a deficiency condition. Symptoms of magnesium insufficiency include irritability, muscle cramping and twitching, irregular heart rhythm, and fatigue.

p-liydroxyphenyllactate

of glutathione is split and then reformed by an ATPrequiring enzymatic step. When the energy-requiring step is impaired, the glutamic acid portion of glutathione is converted to pyroglutamate. This pathway conserves amino acids at the expense of glutathione. Pyroglutamaturia in an adult receiving antibiotic therapy is evidence for a renal-associated mechanism.12' Other cases of pyroglutamaturia accompanying homocystinuria indicate a glutathione-wasting mechanism leading to elevated urinary pyroglutamate.122Glutamic acid, aKG, methionine, and glutathione can replenish the intermediates in the amino acid recovery cycle and help rebuild total body glutathione.

p-Hydroxyphenyllactate (HPLA) is a carcinogenic metabolite of tyrosine that increases lipid peroxidation in the liver."' Methyl p-hydroxyphenyllactate (MeHPLA) is an important cell growth-regulating agent, and tumor cells contain esterase enzymes that hydrolyze the compound to the free acid, HPLA.'12 HPLA is an important regulator of normal and malignant cell growth and it Sulfate appears to mediate the cancer-promoting effects of estroUrinary sulfate is the only inorganic compound somegen. MeHPLA blocks uterine growth in vivo and inhibits growth of MCF-7 human breast cancer cells in ~ i t r o . " ~ times reported with the profiling of organics. It is meaHigh doses of ascorbic acid (100 mg/kg body weight sured in a separate assay and is included because of its added value in assessing the functioning of the detoxifidaily) were shown to arrest or sigrulicantly inhibit the cation pathways. Sulfation pathways are used in phase I1 excretion of HPLA in patients with hemoblastoses and liver detoxification for the important biotransformation nephrobla~toma.~~ HPLA also may be produced by some of many drugs, steroid hormones, and phenolic commicrobes that could inhabit the gut, but the cell proliferpounds, among others. The ratio of sulfate to creatinine ative and prooxidant functions are of greater clinical has been used to assess the body's reserve of sulfurrele~ance."~ containing compounds (especially glutathione) used in 2-Methylhippurate phase I1 pathways. These stores need replenishment 2-Methylhippurate is a metabolite of the detoxification when the sulfate/creatinine ratio is low. Administration of the common solvent xylene. Elevations indicate an of glutathione, in combination with oral cysteine and exposure to this potentially toxic c o m p o ~ n d . ' ~ ~ Jtaurine ~ and salts of sulfate, is used to replenish sulfur Urinary levels of methylhippurate, the product of hepatic pathways and restore the hepatic supply of inorganic s ~ l f a t e . ' ~Glutathione ~J~~ levels in the liver can be oxidation and conjugation of xylene, are used to monitor xylene e~posure."~ increased 35% in normal individuals by supplementation A wide range of compounds that may of Silyburn rnuriunurn (see Chapter 111). be abused by inhalation can be detected by measurement of the excretion of this compound or one of its metabolic products."* A study of spray-painters showed elevated SUMMARY methylhippurate, indicating recent exposure to ~ylene."~ Patient counseling in avoidance of these compounds is Measurement of organics in the urine has become an indicated. indispensable tool for clinicians interested in deeply understanding the metabolic status of their patients. Pyroglutamate With appropriate interpretation of results, energy production, carbohydrate metabolism, functional nutriPyroglutamate (sometimes called 5-oxoproline) is a cyclic form of glutamic acid. Small amounts are always tional status, fatty acid metabolism, detoxification, gut biosis, and neurotransmitter metabolism can all be present in overnight urine because the substance is proassessed. Many of the detected abnormalities can then duced as an intermediate in a cycle thought to be used in be corrected through the appropriate use of dietary a renal recovery pathway involving active transport of changes, lifestyle improvements, and nutritional and amino acids.120This process uses glutathione as a carrier. With each molecule of amino acid resorbed, one molecule botanical supplements.

Supplementary Diagnostic Procedures

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Urinary Porphyrins for the Detection of Heavy Metal and Toxic Chemical Exposure Carl P. Verdon, PhD J. Alexander Bralley, PhD Richard S. Lord, PhD CHAPTER CONTENTS Introduction 299 Definitions 299 Porphyrias

300

INTRODUCTION Toxic chemicals affect human biochemistry at any level of long-term exposure. Fortunately the body has mechanisms for transforming, eliminating, or compartmentalizing the many toxic chemicals encountered over a lifetime. Nonetheless these "safety" mechanisms may be inadequate or even inappropriate in the modem industrialized society, especially for susceptible people such as the elderly, individuals with poor nutritional habits, and others who are physiologically stressed.'J2 Recognizing and identifying offending chemical@) can present a difficult challenge for the clinician. Many chemicals exert their effect at such low concentrations that they escape detection except by very sophisticated laboratory methods. Although measuring effects of toxicity by observing symptoms is a time-honored procedure, determination of the actual toxicant often requires the use of laboratory methods that measure biornurkers, which are specific indicators of the toxicant's action. Porphyrins measured in urine serve as such a biomarker. Porphyrins are particularly well suited as biomarkers for two reasons. First, they are produced in the highly active heme pathway, so any disturbance tends to cause rapid and relatively large accumulations of intermediates. Second, some of the enzymes of the porphyrinproducing pathway are highly sensitive to the presence of various toxins and they are rapidly turned over. Their short half-lives, of minutes or hours, cause a demand for rapid synthesis in response to changing environmental signals. The enzymes normally associate with nutrient metal ions to produce heme and cobalamin (and, in

Porphyrinopathies 300 Procedure 300 Clinical Applications 302 Conclusion

303

plants, chlorophyll), sometimes called the pigments of life.3 The presence or elevation of various urinary porphyrin species can flag a potentially toxic condition. Metals and other toxic chemicals with prooxidant reactivity can inactivate porphyrinogenicenzymes, deplete glutathione and other antioxidants, and increase oxidant stress, all of which lead to damage to membranes, enzymes, and other proteins in cells?j5 In addition, porphyrinogens (precursors to porphyrins in the reduced state) themselves are easily nonenzymaticallyoxidized to porphyrins by toxic metals such as mercury (Figure 31-1). Thus the distribution pattern of porphyrins in the urine serves as a functional fingerprint of toxicity? The utility of urinary porphyrin measurement as a diagnostic tool is not new: Its use has been documented in the literature since 1934. Specific diseases collectively known as the porphyrius, which can be inherited or acquired (e.g., acute intermittent porphyria, porphyria cutanea tarda, variegate porphyria), are often diagnosed with the aid of information about the distribution profile of individual porphyrin species in human urine.

DEFINIT10NS Porphyrins are oxidized by-products that have escaped from the heme biosynthetic pathway, an essential pathway occurring in all nucleated mammalian cells. Heme is the all-important iron-binding molecule essential for the proper function of many proteins, including hemoglobin (oxygen transport), cytochrome c (energy production) and cytochrome P-450 (detoxification). Biosynthesis of 299

Supplementary Diagnostic Procedures

Organelle perturbation

-

Increased reactive oxidant production Redox cycling Porphyrinogen

n Porphyria

4

W

W

Accumulation Excretion

U Cell injury

Porphyrin

J\l

Functional SH enzymedproteins

iloss of

: GSH

enzymedproteins

Oxidation of cellular constituents

Figure 31-1 Toxic metal induction of porphyria and cell injury occurs as follows: ( 1 ) metals promote an increase in reactive prooxidants; (2) metals complex with glutathione, compromising antioxidant and thiol status; (3) metals impair enzymes and other proteins via complexation with sulfhydryl groups of cysteine residues: and (4) oxidant stress induced by metals causes cell injury and oxidation of porphyrinogens to porphyrins that are excreted in the urine (porphyrinuria). (Modified from Rocchi E, Casalgrandi G, Masini A, et al. ltal J Gastroenterol Hepatol 1999; 31361-867.)

heme involves eight enzymes (Figure 31-2), five of which produce intermediate molecules that are collectively called porphyrinogens. Some porphyrinogens escape the intracellular pathway to become oxidized by other cellular processes to porphyrins. In turn,some porphyrins are excreted in urine and feces. The different molecular species of porphyrins that occur in the urine of healthy individuals form a predictable, characteristic pattern. An elevation of one or more porphyrins is designated porphyrinuria. The term porphyria is reserved for primary conditions exhibiting specific clinical symptoms caused by an inherited defect in one or more of the heme biosynthetic enzymes. Porphyrinoputhy is an umbrella term for any disorder in porphyrin metabolism.

PORPHYRlAS The porphyrias have been classified in the literature in several different ways. Most commonly porphyrias are presented in textbooks with specificbiochemical reference to the principal enzyme deficiency (e.g., delta-aminolevulinate [ALA] dehydratase deficiency) and the site of the deficiency (e.g., hepatic, erythropoietic, or both). Furthermore the temporal pattern of appearance of overt clinical signs (acute versus chronic) and the primary presentation of symptoms (neuropathic, dermatopathic, or mixed) are valid classificationsthat arrange porphyrias according to symptomatology. It is useful also to organize porphyrias according to etiology (hereditary versus acquired or toxicant-induced).

PORPHYRINOPATHIES Inhibition of an enzyme for heme biosynthesis can result in the inappropriate accumulation of that enzyme’s substrate. The more severe the enzyme‘s inhibition becomes, the greater the tissue accumulation of porphyrins, sometimes becoming severe enough to cause clinical porphyria. One class of toxic chemicals capable of subtle yet insidious health effects that may mimic other disorders, especially in children, is the heavy metals. Lead, mercury, arsenic, aluminum, and cadmium are well-documented examples. Long-term exposure to these metals often results in organ-specific accumulation that compromises target organ physiology. Heavy metals damage many aspects of metabolism, as shown in Figure 31-1. Similarly, long-term exposure to organic chemicals such as herbicides, pesticides, and industrial and manufacturing by-products can have a deleterious effect on the body’s biochemistry that results in the decline of cellular function (Table 31-1).4 Whatever the cause, porphyrins induce oxidative cellular damage when they accumulate. The mechanism involves increases in free iron, even though the total iron pool is not elevated?

Procedure The clinical utility of urinary porphyrins is maximized if urine samples are taken when the patient is experiencing symptoms (see Table 31-1). Urine is best collected over a 24-hour period with 7 g of sodium carbonate added as a preservative. It may be useful in some patients to provoke

Urinary Porphyrins for the Detection of Heavy Metal and Toxic Chemical Exposure

Figure 31-2 Biosynthesis of heme. The enzymes that drive the heme pathway are: ( f ) delta-aminolevulinate( A M ) synthetase; (2) ALA dehydratase; (3) uroporphyrinogen I synthetase (porphobilinogen deaminase) and uroporphyrinogen 111 cosynthetase, two enzymes that work in concert; (4) uroporphyrinogendecarboxylase; (5) coproporphyrinogen oxidase; (6) protoporphyrinogen oxidase; and (7) fermchelatase (heme synthetase). Spilled porphyrins derived from porphyrinogens with 8-, 7-, 6-, 5,and 4-carboxyl groups are largely excreted in the urine, whereas the less polar 2-carboxyporphyrin (protoporphyrin) is excreted exclusively in the feces. The physiologically relevant pathway leading to heme is via uroporphyrinogen111, in which the propionyl and acetyl groups are "reversed" compared with the type I pathway, which "dead-ends" with coproporphyrinogen I.The physiologic significance of the type Ipathway remains unclear; however, coproporphyrin I is elevated in hepatobiliary diseases.

Symptomatologyof the porphyrinopathies Primary complaints

Neurologic Presentations Abdominal pain; nausea; vomiting; constipation; seizures

Cutaneous Presentations Changes in skin pigmentation; changes in facial hair; fragile skin; rashes; blistering may be present

Associated symptoms

Condition exacerbated by

Headaches; difficulty in concentration; personality changes; weakness; muscle and joint aches; unsteady gait, poor coordination; numbness, tingling of arms and legs; fluid retention; rapid heart rate; high blood pressure; increased sweating; intermittentfever

Low carbohydrate diets (skipped meals); intake of alcoholic beverages; medications, including sulfa-drug antibiotics, barbiturates, estrogen, birth control pills; exposure to toxic chemicals

Darkcolored urine (especially after exposure to sunlight), and above symptoms

Above factors, and skin symptoms made worse by exposure to sunlight. Copper or brass jewelry exacerbates reaction

their porphyria (a low-carbohydrate diet for 2 days can be effective).

Clinical Applications Changes in the urinary porphyrins (e.g., porphyrinuria) coincident with provocation (e.g., fasting) or therapeutic intervention (e.g., medications, chelation therapy) are suggestive of some type of porphyrinopathy. If the patient's response on provocation can be duplicated, porphyria should be investigated. If 24-hour output of any urinary porphyrin is three or more times the upper limit of the reference range, organ accumulation of porphyrins may be reaching pathologic levels. In such cases, a comprehensive porphyria evaluation is warranted. For out-of-range results that are lower than three times the upper limit, the rationale for further porphyria testing is predicated on the availability of corroborating clinical or biochemical data, such as complaints, and family and patient medical history. Elevations of the individual porphyrin species values above the normal range have a number of causes, both inherited and environmental (Table 31-2 and Box 31-1).* The effect of chemicals on the porphyrin pathway has been the subject of many scientific reports. Lead, mercury, or arsenic toxicity induces porphyrinuria? as do polychlorinated phenyls (e.g., dioxin, polychlorinated biphenyls)1°and many drugs (Box 31-2)." In long-term cultures of adult rat hepatocytes, exposure to submicromolar concentrations of lead increases porphyrin excretion after a delay of 15 to 22 days.12A study of practicing dentists reported correlations between elevations of urinary 5-carboxyporphyrin, precoproporphyrin, and coproporphyrin, and behavioral changes that were related to urinary excretion of m e r c ~ r y . ' ~Together, ,'~ elevations of these porphyrins served as biomarkers of mercury toxicity. Upregulation of the heme biosynthetic pathway, with the concomitant increase in ALA, is another mechanism

izymatic defects of the common porphyrias Enzymatic defect

Porphyria

Delta-aminolevulinic acid (AM) synthetase A I A dehydratase

Plumboporphyria

Porphobilinogen deaminase

Acute intermittent porphyria

Uroporphyrinogen cosynthetase

Congenital erythropoietic porphyria

Uroporphyrinogen decarboxylase

Porphyria cutanea tarda and hepatoerythropoietic porphyria

Coproporphyrinogen

Hereditary coproporphyria

Protoporphyrinogen

Variegate porphyria

Ferrochelatase

Protoporphyria

by which porphyria can be precipitated. Increased ALA production is usually a normal physiologic response to provide enough of this preporphyrin precursor to meet the body's demand for heme. However, overproduction of ALA can overwhelm even a normally functioning heme biosynthetic pathway, resulting in the inappropriate accumulation of ALA or the porphyrins.6 Commonly, active porphyria occurs when overproduction of ALA coincides with inhibition of one or more of the porphyrinogenic enzymes. Often porphyria is the result of a chemical insult to a porphyrinogenic enzyme combined with an external stressor that provokes dysregulation of the heme biosynthetic pathway. It is estimated that among patients with a porphyrinogenic enzyme deficiency, as many as 90% are healthy throughout adulthood, until their porphyria is triggered midlife by toxic chemicals or drugs, an acute illness or worsening chronic condition, or a major dietary change (Table 31-3).15

Urinary Porphyrins for the Detection of Heavy Metal and Toxic Chemical Exposure

Intoxications: Alcoholism Foreign and environmental chemicals (e.g., hexachlorobenzene, polyhalogenated biphenyls, dioxins, vinyl chloride, carbon tetrachloride, benzene, chloroform) Heavy metals such as lead, arsenic, mercury Drugs Liver diseases: Cirrhosis Active chronic hepatitis Toxic and infectious hepatitis Fatty liver Alcoholic liver syndromes Drug injury Cholestasis Cholangitis Biliary cirrhosis Adverse effect of drugs: Analgesics Sedatives Hypnotics Anesthetics Sex hormones Sulfa-drug antibiotics Infectious diseases: Mononucleosis Acute poliomyelitis

Diabetes mellitus Myocardial infarction Hematologic diseases: Hemolytic, sideroachrestic, sideroblastic, aplastic anemias Ineffective erythropoiesis (intramedullary hemolysis) Pernicious anemia Thalassemia Leukemia Erythroblastosis Iron deficiency anemia Malignancies: Hepatocellular tumors Hepatic metastases Pancreatic carcinoma Lymphomatosis Other systemic diseases Disturbance of iron metabolism: Hemosiderosis Idiopathic and secondary hemochromatosis Hereditary hyperbilirubinemias: Dubin-Johnson syndrome Rotor syndrome Pregnancy Carbohydrate fasting Bronze baby syndrome Erythrohepatic protoporphyria Hereditary tyrosinemia

CONCLUSION

Aminopyrine Aminoglutethimide Antipyrine Barbiturates NButylscopolammonium bromide Carbamazepine Carbromal Chlorpropamide Chloral hydrate Danazol Dapsone Diclofenac Diphenylhydantoin Ergot preparations Ethanol (acute) Ethchlorvynol Ethinamate Glutethimide

Griseofulvin lsopropyl meprobamate Mephenytoin Meprobamate Methyprylon Nitrous oxide Novobiocin Phenylbutazone Primidone Pyrazolone preparations Succinimide Sulfonamide antibiotics Sulfonethylmethane Sulfomethate Synthetic estrogens, progestins Tolazamide Tolbutamide Trimethadione Valproic acid

Although this list includes many of the better known drugs that can exacerbate porphyria, it should not be considered complete.

Use of porphyrin measurements as biomarkers of chemical toxicity is reasonable in combination with other laboratory tests (e.g., hair analysis in cases of suspected metal toxicity). The clinician should realize that many conditions unrelated to primary or toxicantinduced porphyria can cause porphyrin~ria.'~When considering a urinary porphyrin result, the clinician should be mindful that the distribution of normal urinary porphyrin values, representing healthy individuals, overlaps significantly with values representing those who have suffered from porphyria at one time or another. Any patients in whom a urinary porphyrins test result is positive should receive more specific testing for a differential diagnosis. Tests that assay toxic metals directly in biologic samples (e.g., blood, urine, and hair) are essential for confirming whether the toxicity symptoms are caused by a metal. Identification of toxic organic chemicals by laboratory methods is also possible. Ruling out porphyria as the primary cause of porphyrialike symptoms requires tests for porphyrinogenic enzyme activities (e.g., uroporphyrinogen decarboxylase), as well as tests for blood, fecal, and urine porphobilinogen (PBG) and A M .

Interpretation of abnormal urinary porphyrin test results: relationship to heme pathway defects and possible causes (with emphasis on toxic metals) Abnormal test result'

Heme pathway defect'

Possible environmental cause*

Uroporphyrin and 7-carboxyporphyrin (sometimes)

Uroporphyrinogen decarboxylase

Arseni$ Certain organic chemicals

5-Carboxyporphyrin and coproporphyrin

Uroporphyrinogen decarboxylase

Mercug

6-Carboxyporphyrin (sometimes)

Coproporphyrinogen oxidase

Certain organic chemicals

Precoproporphyrinl(almost always accompanied by elevated coproporphyrin 111)

Uroporphyrinogen decarboxylase (possibly)

Mercug

Coproporphyrin 111, coproporphyrin I (sometimes)

Coproporphyrinogen oxidase

Lead or mercury* Certain organic chemicals

Coproporphyrin 1/1H ratio >1

Hepatobiliarydysfunction4 Porphobilinogen deaminase

Arsenic

'Reference ranges vary depending on the laboratory doing the analysis. The following reference range (in units of nanomoles/24 hr) was set to accentuate sensitivity (e.g., more patients with true porphyrinuria being detected at the risk of an increased false-positiverate). +Multiplication factors to convert ValUeS to ~ 9 / 2 4hr are shown in parentheses: uroporphyrin. 41 (0.830); 7-carboxyporphyrin, 14 (0.787); 6carboxyporphyrir1, 6 (0.743);bcarboxyporphyrin. 5 (0.699);coproporphyrin I. 40 (0.654);coproporphyrin 111, 79 (0.654).The reference range for the particular laboratory conducting the analysis should be used. Inherited disorders in the enzymes of heme biosynthesis are relatively rare, but such a possibility should be considered if urinary porphyrins are greatly elevated. A specialist in inherited disorders should be consulted if such a disorder is suspected. When urinary porphyrin results are being evaluated to arrive at a diagnosis of metal or chemical toxicity, the following should be ruled out: use of ethanol, estrogens, oral contraceptives, antibiotics, sedatives. analgesics, dietary brewer's yeast; also pregnancy, liver disease, malignancies, and hematologic diseases such as pernicious or iron deficiency anemias. §Thedetection of precoproporphyrin is specifically diagnostic for mercury toxicity6

1. Rowland I, ed. Nutrition, toxicity, and cancer. Boca Raton, n:CRC Press, 1991. 2. Baker S. Detoxification and healing. New Canaan, CT: Keats Publishing, 1997. 3.Thunell S. Porphyrins, porphyrin metabolism and porphyrias. I. Update. Scand J Clin Lab Invest 2000;60:509-540. 4. Chang L, Magos L, Suzuki T, eds. Toxicology of metals. Boca Raton, n:CRC Press, 1996. 5. Fowler BA, Oskarsson A, Woods JS. Metal- and metalloid-induced porphyrinurias: relationships to cell injury. Ann N Y Acad Sci 1987;514:172-182. 6. Woods JS, Bowers MA, Davis HA. Urinary porphyrin profiles as biomarkers of trace metal exposure and toxicity: studies on urinary porphyrin excretion patterns in rats during prolonged exposure to methyl mercury. Toxicol Appl Pharmacol1991;110464-476. 7. Rocchi E, Casalgrandi G, Masini A, et al.Circulating pro- and antioxidant factors in iron and porphyrin metabolism disorders. Ital J Gastroenterol Hepatoll999; 31:861-867. 8. Kappas A, Sassa S, Galbraith RA, Nordmann Y. The porphyrias. In Scriver CR, et al, eds. The metabolic and molecular bases of inherited disease, ed 7. New York McGraw-Hill, 1995:2103-2159.

9. Woods JS. Porphyrin metabolism as indicator of metal exposure and toxicity. In Goyer RA, Cherian MG, eds. Handbook of experimental pharmacology. Berlin: Springer-Verlag, 199519-52. 10. Doss MO. Porphyrinurias and occupational disease. In Silbergeld E, Fowler B, eds. Mechanisms of chemical-induced porphyrinopathies. New York: New York Academy of Sciences, 1987204-218. 11. Moore MR, Disler PB. Drug-induction of the acute porphyrias [review]. Adverse Drug React Acute Poisoning Rev 1983;2: 149-189. 12.Quintanilla-Vega B, et al. Porphyrin production and excretion by long-term cultures of adult rat hepatocytes and effect of lead exposure. Toxicology 1995;102275-283. 13. Woods JS, et al. Urinary porphyrin profiles as a biomarker of mercury exposure: studies on dentists with occupational exposure to mercury vapor. J Toxicol Environ Health 1993;40:235-246. 14. Woods JS. Altered porphyrin metabolism as a biomarker of mera r y exposure and toxicity. Can J Physiol Pharmacol 1996;74: 210-215. 15. Donnay A, Ziem G. Porphyria protocol packet (on evaluating disorders of porphyrin metabolism in chemically sensitive patients). Baltimore: MCS Referral and Resources, 1995.

Urine Indican Test (Obermeyer Test) Dirk Wm. Powell, ND CHAPTER C O N T E N T S Introduction 305

Reagents 305 Results 305

Clinical Application 305 Interpretation 306 Procedure 305 Method 305

INTRODUCTlON The essential amino acid tryptophan is converted to indole by intestinal bacterial cleavage of the tryptophan side chain. After absorption, indole is converted to 3-hydroxy indole (indoxyl or indican) in the liver, where it is then conjugated with potassium sulfate or glucuronic acid. It is then transported through the blood to the kidneys for excretion.

CLINICAL APPLICATION Because most of the endogenous indoles have a side chain that prevents cleavage and are instead metabolized to skatole, the production of indicans (indoxyl potassium sulfate and indoxyl glucuronate) reflects bacterial activity in the small and large intestines. Box 32-1 lists conditions in which increased levels are found.14 Elevations of indicans are an indicator of intestinal toxemia and overgrowth of anaerobic bacteria (dysbiosis). The indican test is also used to monitor the efficacy of treatment of gastrointestinal dysbiosis.

PROCEDURE Detection of indican depends on its decomposition to indoxyl and subsequent oxidation to indigo blue. It is then concentrated in a layer of chloroform for easier measurement.

Method 1.Place 5 ml of fresh urine in a test tube. 2.Add 5 ml of Obermeyer reagent (under a hood to exhaust vapors), and cork securely. 3. Invert several times to mix.

4.Add 2 ml of chloroform, cork securely, and invert several times. 5. Allow the chloroform to settle, and observe. 6. The results are then graded according to the color present in the chloroform layer.

Reagents Obermeyer reagent is prepared by dissolving 0.8 gm ferric chloride in 100 ml concentrated HC1 (caution: caustic). Chloroform (caution: volatile and toxic, keep tightly capped).

Results Urine color: 0 (normal) Light blue: +1 Blue: +2 Violet: +3 Jet-black +4

Inflammatory bowel disease Celiac disease Hypochlorhydria Gastric ulcer Biliary and intestinal obstruction Jejunal diverticulosis Scleroderma Postgastrectomy Hartnup disease Pancreatic insufficiency Diminished peristalsis Blue diaper syndrome Data from references 1-4.

305

Supplementary Diagnostic Procedures

INTERPRETATION A positive result may indicate one of several disorders, including hypochlorhydria, bacterial overgrowth within the digestive tract, presence of unfriendly bacterial flora, malabsorption of protein, and excessive dietary protein intake (see Box 32-1). The effect of excessive dietary protein intake can be eliminated by the institution of a moderate-protein diet for 2 days prior to testing.

1. Todd J. Clinical diagnosis and management by laboratory methods.

Philadelphia:WB Sunders, 1979592-593. 2. Greenberger N, Saegh S, Ruppert RD. Urine indican excretion in malabsorptivedisorders. Gastroenterology1968;55204-211.

False-negative results occur when formalin, methenamine, or sulfasalazine (Azulfidine) is present? Indigo red may occasionally form from slow oxidation. The presence of iodine, salicyluric acid, methylene blue, or thymol causes a violet color, which can be removed with the addition of a crystal of sodium thiosulfate. Bile pigments can interfere with the reaction but can be removed by shaking the urine with barium chloride and filtering.

3. Curzon G, Walsh J. Value of measuring urinary indican excretion. Gut 1966;7711. 4. Asatoor AM, Craske J, London DR, et al. Indole production in Hartnup disease. Lancet 1963;1:126-128.

Th e r a p e u t i c h/lo d a 1i t i e s 33 Acupuncture 309 34 Ayurveda: The Science of Life and Mother of the Healing Arts 317 35 Botanical Medicine-A Modem Perspective 327 36 Environmental Medicine 339 37 The Exercise Prescription 355 38 Glandular Therapy 377 39 Homeopathy 387 40 Hydrotherapy 401 41 Manipulation 417 42 Nonpharmacological Control of Pain 431 43 Nontransfusion Significance of ABO and ABO-Associated Polymorphism 441 44 Nutritional Medicine 461 45 Peat Therapeutics and Balneotherapy 475 46 Preventive Genomics, Nutrigenomics, and the Promise of Personalized Medicine 487 47 Rotation Diet: A Diagnostic and Therapeutic Tool 497 48 Soft Tisue Manipulation: Diagnostic and Therapeutic Potential 501

49 Spirituality and Healing 519 50 Therapeutic Fasting 533

This section presents an historic, scientific, and practical review of the schools of thought and modalities of natural medicine. We have compiled the work of experts in their fields into what we hope the reader will find a concise, yet useful, description of these practices and modalities. Because of the clinically oriented and alternative nature of these disciplines, the scientific evaluation of their theories and efficacy has been limited. However, published research in natural medicine has increased dramatically since A Textbook of Natural Medicine was first published in 1985. Although this textbook is strongly oriented to the scientific method and the use of the peer-review literature for documentation of the efficacy of a therapy, these modalities’ widespread clinical use and long history of patient satisfaction demand that they be given a place here even though the mechanism of action of several have yet to be elicited.

307

Acupuncture Mark Harrison Nolting, ND, LAC CHAPTER C O N T E N T S Introduction 309

The Five Elements 312 Points and Meridians 312

Acupuncture Defined 310 Evidence-BasedAcupuncture

312

History 310 Fundamentalsof Acupuncture 312 Qi 312 Zang Fu 312

INTRODUCTION Thirty years ago acupuncture was virtually unknown in America despite its existence since the first wave of Chinese people immigrated in the 1800s searching for the “Golden Mountain.” Traditional Chinese medicine (TCM)was surprisingly, at least for a short time, the treatment of choice in some areas of the Western frontier. For several epidemic illnesses of the day such as influenza, TCM was the only type of medicine that offered effective treatment.’ This became a forgotten relic of the past as Western medicine rapidly gained ground. By the time antibiotics became available, any evidence of TCM practice was relegated to inner-city Chinatowns, foreign to the society as a whole. Even in countries such as France, Germany, and Russia, where acupuncture has a much longer history of use, compared with the American experience, there has been a general lack of sophistication of practice and little institutional acceptance. And in China, Western medicine has surged forward over the years, threatening to drive traditional Chinese medicine into obscurity. If not for the efforts of people like Cui Yue Li, former Minister of Health in China during the 1980s, TCM would have nearly vanished from the mainstream due to lack of funding and inclusion in the statecontrolled health care system. Reuben Amber, writing in Mary Austin’s book The Textbook of Acupuncture Therapy, captured this emerging American profession in 1972: This unusual interest in the traditional medicine of China comes at a time when, unfortunately, there are few qualified spokesman and practicing physicians of this healing art in the United States. The American public is being inundated with

Additional Online Resources for Acupuncture 314

sensational articles, but these are often misleading. The ”experts” in 1972 are allopathic physicians who up until a few months ago never even heard the word acupuncture or were dimly aware of the contribution that China has made in the philosophy, theory, and practice of medicine. At present there are no medical schools of acupuncture and no hospitals practicing this effective type of healing in the United States. There is no licensure of this proved therapy in any of the states. The professional literature in English is practically non-existent, and the few books dealing with the subject are written for those physicians who are at home with its philosophy and familiar with acupuncture techniques?

Fast forward 34 years: It is now estimated that as many as 1in 10Americans have now tried some form of acupuncture, it is regulated in most states, there are many schools and established programs, literature in English is plentiful, serious research is being funded, and acupuncture as a major part of Complementary and Alternative Medicine (CAM) has found its way into managed care? Note the following as of August 2004: Forty-three states and the District of Columbia license or cerhfy the practice of acupuncture, and more than 30 states allow practice without referral from a phy~ician.~ National board certification for acupuncture is available through the National Certification Commission of Acupuncture and Oriental Medicine. Thousands of people have been nationally certified! Fifty-four member colleges and branches are in the Council of Colleges of Acupuncture and Oriental Medicine (CCAOM)? 309

Twenty-one percent of employers provide some form of acupuncture or acupuncture coverage.6 0 One of the biggest winners of the National Center of Complementary and Alternative Medicine’s (NCCAM’s) latest round of funding is the acupuncture and Oriental medicine profession. Of the 14 grants awarded by NCCAM, eight relate directly to the study of acupuncture, herbal remedies, or traditional Chinese medicine, or a combination. Together, the grants total more than $9.5 million and will be used to conduct much-needed research into the mechanisms of acupuncture and other components of Asian healing? More than 15,000 licensed acupuncturists and more than 4200 students of acupuncture are in the United States.8 Hundreds of certified Doctor of Medicine and Doctor of Osteopathy acupuncturists have taken the Helms course? This ”professionalizing of American acupuncture” since the 1970s has many acupuncturists, as well as mainstream doctors, wondering how best to respond to, control, and guide all of this “progress.”1oFor the typical acupuncturist, academically ”born and raised” in a system of practice altogether alien to the basic tenets and culture of Western medicine, this often amounts to the medical equivalent of David and Goliath. But increasingly there is an integration of the systems, as well as a rapid increase in the numbers of Westem-trained professionals seeking acupuncture training. This cultural mixing is constantly affecting the evolution of the terrain of American acupuncture. What all of this growth and ”acceptance” of the practice eventually means for the future of acupuncture is unclear. Acupuncturists tend to be a strongly independent type of professional and are heavily influenced by Asian cultures. Many acupuncturists in the field fight any form of diversity of the practice, while others embrace the evolving field.

ACUPUNCTURE DEFINED The definition of acupuncture is not as firmly agreed upon as one would imagine. Acupuncture as simply “a Chinese medical practice or procedure that treats illness or provides local anesthesia by the insertion of needles at specified sites of the body” is an oversimplification of a practice that has evolved over many generations with many variations and can describe an entire field of medical practice rooted in ancient classics.” A more comprehensive definitionagreed upon by the greater acupuncture community helps in the transmission of acupuncture principles to the world at large, aiding in the support of new research and advances in the field.

As for historical perspective on the actual term, according to George Lewith’s writings, ”acupuncture, or needle puncture, is a European term invented by Willem Ten Rhyne, a Dutch physician who visited Nagasaki in Japan in the early part of the seventeenth century. The Chinese describe acupuncture by the character ’Chen,’ which literally means ‘to prick with a needle,’ a graphic description of this therapeutic technique.”12 The California Acupuncture Board, which licenses more than 5000 acupuncturists, stated the following: Acupuncture means the stimulation of a certain point or points on or near the surface of the body by the insertion of needles to prevent or m o d e the perception of pain or to normalize physiological functions, including pain control, for the treatment of certain diseases or dysfunctions of the body and includes the techniques of electroacupuncture, cupping, and moxibustion.13

The practice of acupuncture, according to Business and Professions Code section 4937 (b)of California, is as follows: to perform or prescribe the use of oriental massage,acupressure, breathing techniques, exercise, or nutrition, including the incorporation of drugless substancesand herbs as dietary supplements to promote health.13

In November 1997 the National Institutes of Health (NIH) convened a consensus development conference on the subject of acupuncture. After discussion among a board of experts, the following working definition was included in the N M Consensus Statement: Acupuncture describes a family of procedures involving stimulation of anatomical locations on the skin by a variety of techniques.There are a variety of approaches to diagnosis and treatment in American acupuncture, which incorporates medical traditions from China, Japan, Korea, and other countries. The most studied mechanism of stimulation of acupuncture points employs penetration of the skin by thin,solid, metallic needles, which are manipulated manually or by electrical stimulation.14

The NIH conference has had a lasting positive impact on the growth of acupuncture in America and probably in the world. The definitions and recommendations for further research have sparked wider acceptance within the medical profession. No longer is acupuncture merely a novelty practice from the East.

HISTORY The historical timeline of Chinese medicine spills over thousands of years to the present. This vast expanse of history can only be captured in mere snapshots of traditional practice, some of it legend, some of it practiced to

Acupuncture

this day. Indeed, a rich folk medicine survives in the dozens of minority cultures making up the whole of China. Some attempt exists today to revive an element of these practices. Chinese medicine begins with a legend about the infamous Yellow Emperor, Huangdi (-26982598 8c).l5,I6The so-called ”Father of Chinese Medicine,” Huangdi reigned over a vast Chinese empire. The core of Chinese medicine, acupuncture, and pharmaceutics is traced to the greatest and oldest medical text on earth, the Yellow Emperor’s Canon ofMedicine. Unknown medical scholars of the Warring States period (221 BC and 220 AD) wrote the text that is fixed to Huangdi’s name.I7 Nevertheless, this book is attributed to the reign of Huangdi and is said to highlight questions and answers among the emperor and his ministers, particularly a physician named Qi Bo. Huangdi discoursed on medicine, health, lifestyle, nutrition, and religious tenets of the times. He is ascribed such a high place in Chinese history that many Chinese people consider themselves descendants. Huangdi is viewed as the “symbol of vital spirit of Chinese civilization.”18 Probably the most important text in the history of Chinese medicine, often overshadowed by the “reputation and authority of the original classic,” the Huangdi Nei ling, was the Nan ling (The Classic of Difficult Issues), thought to have been compiled around the first or second century AD. According to Uns~huld,’~ the Nun ling was “a sigruficant and innovative work that was the apex and conclusion of the developmental phase of the conceptual system unknown as the medicine of systematic correspondence.” He goes on to describe the importance of the Nan Jing, saying “the Nan-ching (jing in pinyin romanization) is comprehensive . . . discusses the origins and the nature of illness; outlines a system of therapeutic needling; and developin great detail-an innovative approach to diagnosis.” The Nei ling predates the historically available writings of ancient China and delves strongly into “demonological medicine and religious healing,” while the Nan ling is homogeneous and highly systemized, basically intact and well focused.20 In terms of acupuncture, Unshuld21cites no “reliable” references before 90 BC appearing in Chinese literature. Ancient works as a whole were written on bamboo strips and silk. These went through countless hands and copies, creating a body of written work that contained numerous errors and omissions. It was not until 26 BC that the Chinese government organized medical officials to collate and revise the royal collection of medical works preserved at the Mifu Natnal Royal Library.” The earliest recorded physician reputed to be versed in pulse-taking and acupuncture was Bian Que (-500 BC). Several medical works ascribed to him have all been lost.23Su Ma Qian, historian of the Han dynasty (206 BC220 AD), wrote a chapter on the biography of Bian Que

in the Historical Note about 100 BC.This was the first reliable reference documenting acupuncture and moxibustion in Chinese. He told many stories of Que’s ability to treat with acupuncture.B a n g Ji (AD 150-219),referred to as the sage of Chinese medicine, authored the classic work Shanghnlun. Statues of the legendary Zhong Ji are common on many of the TCM college campuses in mainland China today. Another of the famous ancient masters of Chinese medicine was Hua Tuo (?-208 AD), a surgeon and practitioner of an eclectic range of therapies including acupuncture and hydrotherapy and an originator of the therapeutic exercises called the ”five animals.”24 Huangfu Mi (214282 AD), a famous acupuncturist, compiled Zhen Jiu lia Yi ling (A Classic of Acupuncture and Moxibustion), the first monograph on acupuncture in history, around 282 AD. These 12 volumes covered all aspects of acupuncture practice and theory and are considered a monumental work.= The first usage of the English term acupuncture, meaning needle puncture, is attributed to a Dutch physician, Rhyne, who visited Japan sometime in early seventeenth century.26Dr.Berlioz of the Paris Medical School was attributed with the first recorded use of acupuncture in the West. John Churchill, in 1821, was the first British acupuncturist publishing works highlighting treatment of tympany and rheumatism. Acupuncture is also mentioned in Lancet’s first edition in 1823. Dr. Elliotson published results of 42 cases of acupuncture treatment of rheumatism, concluding that acupuncture was effective as a treatment?’ As noted earlier, in 1849 the Gold Rush in California help to spark a large immigration of mostly male Chinese people into Western America. Heading for “Gold Mountain,” they brought all elements of their culture including their traditional medicine with its acupuncture and Chinese herbs. Writing in his book Chinese Medicine on the Golden Mountain, Paul Buell stated the following: [There] was an acute shortage of any form of medical care in Western America where most Chinese settled. . . . Well practiced Chinese medicine was often superior to contemporary Westem practice. . . . Western medicine did not gain any real advantage over well practiced Chinese medicine until the coming of any ”wonder drugs” in the 1930s, and in some respects, as in many chronic ailments, (traditional) Chinese medicine is still superior.’

In an interesting mention of acupuncture in 1892, William Osler wrote, in his Principles and Practice of Medicine, about the use of acupuncture in the treatment of sciaticaF8There would be few other mentions of the subject in American medical literature for many years to come.

Therapeutic Modalities

FUNDAMENTALS OF ACUPUNCTURE Acupuncture is a technique involving the insertion of fine needles into the skin at select points or points of tenderness. As discussed earlier, the theory, or acuology, that surrounds the practice dates back as many as 4000 to 5000 years. Possible historical links to India and even other areas have been suggested.. For many contemporary practitioners, their practices of acupuncture are defined by the theory of the fundamental principles: five elements (e.g., phases, movements), Yin, Yang, Qi, and Zang Fu. For still others these ancient theories remain just that-ancient and removed from modem s c i e n c e and they practice acupuncture solely on the basis of recent theories of mechanism and anecdotal evidence.29 Yin and Yang, on which all diagnosis and treatment in TCM is based, is the central theory in the practice of acupuncture. In perfect balance, in optimal health, Yin and Yang are harmonious, the ebb and flow of the tides, day and night, male and female. The theory when translated can be set in quite poetic terms. A deficiency of liver and kidney Yin, for example, might result in clinical symptoms such as dizziness, vertigo, insomnia, dry throat, and lumbago, whereas a deficiency of spleen and kidney Yang may manifest clinically as cold limbs, lumbago, diarrhea, and scanty urine. Excess is usually seen as a relative state due to the deficiency of the other, as in deficient Ym resulting in an apparent excess of Yang.

secretes bile and metabolizes blood-borne compounds. The Chinese gan stores blood, and Q and is responsible for the smooth transmission of Qi and blood throughout the body. Moreover, it has a chief role in emotions; an unbalanced gan (liver) results in anger, high blood pressure, and a general state of agitation. The liver in the Chinese sense is much more a functional system with many body-wide interactions.The hollow organs are the gallbladder, large and small intestines, ”triple burner,” urinary bladder, and stomach. The triple burner is a good example of how different the Western and Chinese views are, since this has no meaning in the West. In the Zang Fu system, the triple burner corresponds to the thoracic and abdominal regions including all of the organs within. It has a specific function that distinguishes it as a fu organ, namely to transport water.

The Five Elements The five elements (also called the five phases or in Chinese, wu Xing) are fire, metal, wood, earth, and water. The correspondences among these elements have led to a method of diagnosing and treating patients. In the West, a school of thought following the teachings of Dr.Worsley in England has evolved and grown into a worldwide system of schools and practitioners associated with the so-called law of five elements. There is a stark contrast between this system of acupuncture practice and the TCM systems.

Qi

Points and Meridians

Qiis the energy and potential energy that courses

The other key aspect of the fundamentals of acupuncture is, of course, the theory of the channels. There are the basic 365 mapped acupuncture points along the 12 major and 8 extra channels, as well as more than 1000 extra points and special use points, including the microsystems such as the hand, ear, and scalp, all with specialized functions. The so-called ashi points, or pain points, can literally be located anywhere on the body where there is a pain locus. Qi and blood flow throughout the channels, and this is where the proper manipulation of the needle is critical in properly moving this flow.

throughout the organism and defines what we call life. The lack of proper Q flow in the system results in numerous maladies. Q stagnation often manifests as pain. Rebellious Q manifests as belching, burping, and vomiting, a reversal of the normal downward movement digestively. Potential QI is that energy that is bond of Qi up in inanimate objects, such as rocks and furniture, that can become more active if expressed or liberated. And then there is the Q1 that waves through space connecting us to the web of the universe-a concept that begins to sound like theories in quantum physics.

Zang Fu

EVIDENCE-BASED ACUPUNCTURE

The Zang Fu are the Chinese organs, five solid Yin and six hollow Yang. In the West, English names are used for the organs-liver, heart, spleen, kidneys, and lungs-but depending solely on the Western name without a thorough understanding of the traditional Chinese meaning leads to much confusion clinically. A complete and clinically sound synthesis of the Western biomedical understanding with the traditional Chinese understanding has not occurred to date. For example, the liver as known in the West is defined according to its anatomical structure and function (i.e., it is a large glandular organ that

The defining moment for acupuncture research came with the conclusion of the NIH Consensus Conference in 1997. For the first time, a Western panel of medical experts gathered to review, critique, and set guidelines for the use of acupuncture in the medical field in America. Before this conference, research in acupuncture was acknowledged by some Western doctors but largely dismissed. The view of Asian studies and indeed of studies from other countries in general was not making an impact on the American radar. The conference helped focus the attention, collect what research has been

Acupuncture

completed to date, and concluded that there was merit in the use of acupuncture for certain conditions and, most importantly, that there was a real need and demand that acupuncture be better studied and used. Acupuncture was finally “on the map” in the West.30 Since the conference, there has been much progress and, most importantly, the NCCAM was created. Following is an overview from the website regarding the status of research in the field: NCCAM and the Office of Alternative Medicine have supported scientific research to find out more about acupuncture. Examples of recent NCCAM-supported projects include: Studying the safety and effectiveness of acupuncture treatment for osteoarthritis of the knee. Investigating whether electro acupuncture works for chronic pain and inflammation (and, if so, how). Finding out how acupuncture affects the nervous system by using magnetic resonance imaging technology. Bringing together leaders from the Oriental medicine and conventional medicine communities to collaboratively study the safety and effectiveness of acupuncture and further develop the standards for clinical trials. Studying whether acupuncture can decrease the release of adrenaline in heart patients and improve their survival and quality of life. Adrenaline can make the heart beat faster and can thereby contribute to heart failure. Looking at the effectiveness of acupuncture for treating high blood pressure. Studying the effects of acupuncture on the symptoms of advanced colorectal cancer. Testing the safety and effectiveness of acupuncture for a type of depression called major depression.14 Western medical practice has grown within a system of great scrutiny and self-analysis. A massive research culture spins off studies by the thousands. The doubleblinded, placebo-controlled trial has become the hallmark of the ”appropriately conducted research trial.” Acupuncture evolved in a completely different culture, that of China, where, ironically, as we were ”discovering” the Chinese traditional system of acupuncture, not so many years previously the Chinese began a wholesale discovery of traditional Western medicine. Acupuncture, and indeed all that is traditional Chinese medicine, has been extensively researched in China. Large research academies, the largest being the China Academy of Traditional Chinese Medicine in Beijing, and various universities and schools of TCM, have created a huge research culture in China since the 1970s. Although there is considerable emphasis on herbal research, there is still quite a lot of research examining the other areas of TCM including acupuncture. But what does this Chinese

research culture mean for Western medicine? This is a big question that is being sorted out in numerous ways today. The issues still at hand regarding Chinese research are the following: Too many poor translations Lack of studies using “approved” Western research standards Terminology issues Major design issues Inflated outcome assumptions Lack of Western acceptance of Chinese studies To date, few cross-cultural studies have been undertaken and researchers are just making headway into reproducing studies from a Western perspective. An important step along the way in the documentation of the body of clinical outcomes-based research that exists in English can be found in the book Acupuncture E f i ~ a c y . ~ ~ For more information regarding acupuncture research, readers can refer to the following: NCCAM Clearinghouse Toll free in the United States: 1-888-644-6226 International: 301-519-3153 TTY (for deaf or hard-of-hearing callers): 1-866-4643615 E-mail: [email protected] Website: nccam.nih.gov Address: NCCAM Clearinghouse, P.O. Box 7923, Gaithersburg, MD 20898-7923 Fax: 1-866-464-3616 Fax-on-demand service: 1-888-644-6226 The NCCAM Clearinghouse provides information on CAM, including acupuncture, and on NCCAM. Services include fact sheets, other publications, and searches of federal databases of scientific and medical literature. The clearinghouse does not provide medical advice, treatment recommendations, or referrals to practitioners. CAM on PubMed website: www.nlrn.nih.gov/nccam/ camonpubmed.htm1 CAM on PubMed, a database on the Internet developed jointly by NCCAM and the National Library of Medicine, offers citations to (and in most cases, brief summaries 00 articles on CAM in scientifically based, peer-reviewed journals. CAM on PubMed also links to many publishers’ websites, which may offer the full text of articles. National Institutes of Health (NIH) website: www.nih.gov Address: Building 1, 1 Center Drive, Bethesda, MD 20892

” s mission is to uncover new knowledge that leads to better health for everyone. Composed of 27 separate

Therapeutic Modalities

components, mainly Institutes and Centers, NIH works toward that mission by conducting and supporting research, training researchers, and fostering communication of medical information. Descriptions of each of the Institutes and Centers, along with their research priorities and links to their websites, can be accessed from the main NIH website at www.nih.gov. Combined Health Information Database (CHID) website: chid.nih.gov E-mail: [email protected] CHID Online is a searchable and user-friendly database produced by more than a dozen health-related agencies of the federal government, including NCCAM. This database provides titles, abstracts, health information, and education resources for fields including acupuncture and TCM. ClinicalTrials.gov website: www.clinicaltrials.gov ClinicalTrials.gov is a database of information on clinical trials, primarily in the United States and Canada, for a wide range of diseases and conditions. It is sponsored by NIH and the FDA. Computer Retrieval of Information on Scientific Projects (CRISP)website: crisp.cit.nih.gov CRISP is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other research institutions. The database, maintained by the Office of Extramural Research at NIH, includes projects funded by NIH and other health-related federal agencies. NIH Consensus Program Information Center Toll-free in the United States: 1-888-644-2667 E-mail: consensus-statement.gov Fax: 301-593-9485 Address: P.O. Box 2577,Kensington, MD 20891

This center issues the NIH Consensus Statement on Acupuncture (1997). To access this statement, go to odp. od.nih.g0v/consensus/cons/l07/l07~staternent.htrn.~

ADDITIONAL ONLINE RESOURCES FOR ACUPUNCTURE China Academy of Traditional Chinese Medicine (CATCM) http://www.cintcrn.ac.cn/garn/garny/e-zyyjy.html American Academy of Medical Acupuncture (AAMA) http://www.medicalacupuncture.org Medical Acupuncture Research Foundation (MAW) http://www.medicalacupunct ure.org/aarna_rnarf_marf. html Acupuncture and Oriental Medicine Alliance (AOMA) http://m.acuall.org/

American Academy of Veterinary Acupuncture http://www.auriculothera py.com Council of Colleges of Acupuncture and Oriental Medicine (CCAOM) http://www.ccaorn.org National A c u p u n m Detoxification Association (NADA) http://m.acudetox.org National Certification Commission for Acupuncture and Oriental Medicine (NCCAOM) http://m.nccaorn.org NIH CAM on PubMed h t t p : / / m .nlm.nih.gov/nccam/camonpubmed.html Society for Acupuncture Research (SAR) http://m.acupuntureresearch.org British Acupuncture Council h t t p : / / m . a c upunCture.0rg.uk/ Auricular Acupuncture Bibliography http://www.auriculo.ifrance.com/auriculo Online Study Material on Acupuncture and TCM in Humans and Animals http:/,ornepage. tinet.ieP/07Eprogers/study.htm Beijing College of Acupuncture and Orthopedics (China) ht t p : / / m .cscse.ed u.cn/laihua/gaoxiao/zjxy.html Continuing Medical Pain Education (Australia) http://www.pain-education.com Guang An Men Hospital Affiliated to China Academy of TCM (China) http://china-window.com/zhongy/gamy/esgk. html Osaka Medical College (OMC) The Department of Anesthesiology-Acupuncture Group (Japan) ht tp://www.osaka-med .ac.jpPh7Eane005/ACUINDEX.ht ml Shanghai Medical University Web Page (China) http://m.shmu.edu.cn/ The International Academy of Medical Acupuncture Inc. WMA) (USA) http://www.iama.edu/ Acupuncture References from the National Institutes of Health (USA) http://m.nlrn.nih.gov/pubs/cbm/acupuncture.html Acupuncture Events around the World ht tp://users.rned .au th.gr/%o7Ekaranik/english/articles/sinedr. html Acupuncture Foundation of Canada Institute (Canada) http://m.afcinstitute.com/afci.htrnI Australian Medical Acupuncture Society (Australia) http://www.ozacupuncture.com Canadian Medical Acupuncture Society (Canada) ht t p : / / m . a c upu ncture.corn/Referrals/Can.h t rn Danish Medical Association of Acupuncture (Denmark)

http://www.acumed.dk/index.htm German Academy of Acupuncture and Auricular Medicine (Germany) h t t p : / / m . a k upun ktu r-arzt .de German Medical Acupuncture Society (Germany) h ttp://www.daegfa .de/

Acupuncture

Accreditation Commission for Acupuncture and Oriental Medicine (ACAOM) http://www.acaorn.org/ National Acupuncture Detoxification Association (NADA) http://www.acudetox.corn/index.htm

Society for Acupuncture Research http://www.acupunctureresearch.org Federation of Acupuncture and Oriental Medicine Regulatory Agencies (FAOMRA) ht tp://wwwJaornra.com

1. Buell P. Chinese medicine on the Golden Mountain an interpretive guide. Boise ID:Idaho State Historical Society, 1984. 2. Austin M. The textbook of acupuncture therapy. New York AS1 Publishers, 1972W. 3. NCCAOM. Survey finds one in ten adults has received acupuncture; high satisfaction reported. Diplomate 2003;75. 4. National Certification Commission for Acupuncture and Oriental Medicine. Available online at wzv.nccaom.org [accessed March 30, 20051. 5. Council of Colleges of Acupuncture and Oriental Medicine. Available online at www.ccuom.org [accessed March 30,20051. 6. NCCAOM. One in four employers providing coverage. Diplomate 2003;73. 7. Devitt M. NCCAM awards 9.5 million for acupuncture, TCM research. Acupuncture Today Online. Available online at

17. Veith I. The Yellow Emperor’s Classic of Internal Medicine. Baltimore: Williams & Wilkins, 1949. 18.Maoshing N. The Yellow Emperor’s classic of medicine: a new translation of the Neijing Suwen with commentary, ed 1. Boston: Shambhala, 1995. 19. Unschuld PU. Nan-ching: the classic of difficult issues. Berkeley: University of California Press, 19863-4. 20.Unschuld PU. Medicine in China: a history of ideas. Berkeley: University of California Press, 1985. 21. Unschuld PU, ed. Approaches to traditional Chinese medical literature. Proceedings of an International Symposium on Translation Methodologies and Terminologies. Dordrecht, Netherlands: Kluwer, 1989. 22. Porkert M, Hempen CH. Chinese Academy of TCM, classical acupuncturethe standard textbook. Dinkelscherben, Germany: Phainon Edititrus & Media GmbH, 1995. 23. Wei-kang F. The story of Chinese acupuncture and moxibustion, ed 1. Peking: Foreign Languages Press, 1975. 24. Hoizey D, Hoizey M. A history of Chinese medicine. Vancouver, Bc: UBC Press, 199342-3. 25. State Administration of Traditional Chinese Medicine. Advanced textbook on traditional Chinese medicine and pharmacology, vol 1, ed 1. Ekijing: New World Press,1995. 26.Zhang R, Wu X, Wang N. Illustrated dictionary of Chinese acupuncture. Hong Kong: Sheep’s Publication, 1985403. 27. Lewith GT. The history of acupuncture in China. In Acupuncture: its place in Western medical science. Suffolk, England: Green Press, 1998. 28. Osler W. Prinaples and practice of medicine, designed for the use of practitioners and students of medicine. New York Appleton & Company, 1892. 29. Ross J. Zang Fu. The organ systems of traditional Chinese medicine. Edinburgh: C h m Livingstone, 1985. 30. National Center for Complementary and Alternative Medicine. Acupuncture. Publication No. DOO3, March 2002. 31. Birch S, H a r m n e d a g R. Acupuncture efficacy: a summary of controlled clinical hi&. Tarrytown, Ny: American Association of Acupuncture and Oriental Medicine, 1996.

http://www.ucupuncturetoday.com/archives2004/jan/01nccam. html [accessed August 24,2004J. 8. Acupuncture Today. Circulationcounts by drculation staff. Available

online at zuww.acupuncturetoday.com[accessed March 30,20051. 9. American Academy of Medical Acupuncture. -.medicalacupuncture.org [accessed March 30,20051. 10.Barnes LL. The acupuncture wars: the professionalizing of American acupuncture-a view from Massachusetts. Med Anthr0~012003;22:261-301.

11. Webster’s Encyclopedic Unabridged Dictionary of The English Language. New York Gramercy Books, 199621. 12. Lewith GT. The history of acupuncture in China. In Acupuncture: its place in Western medical science. Suffolk, England Green Press, 1998. 13. California Acupuncture Board. Available online at www.acupuncture. c u g m [accessed August 2,20051. 14. Acupuncture. Consensus Development Conference Statement. National Institutes of Health. November $5,1997. Available online at http://consensus.nih.gov/cons~07/107~statement.htm[accessed August 25,20041. 15. I-Yen Yang. Personal communication. 1997. 16.Zhufan X, Xiaokai H, eds. Dictionary of traditional Chinese medicine. Hong Kong: The Commercial Press, 198432.

Ayurveda: The Science of Life and Mother of the Healing Arts Virender Sodhi, MD (Ayurveda), N D CHAPTER C O N T E N T S Introduction 317 History 317 The Development of Ayurvedic Medicine 317 The Major Schools and Specialties 318 School of Physicians (Atreya Sampradaya) School of Surgeons (Dhanvantri Sampradaya) 318 Branches of Ayurveda 318

Functions of 7iidosha 320 Individual Psychosomatic Constitutions-Prakriti 320 Mental Constitutions 321 Health and Disease 322

318

Philosophy 318 Five Basic Elements and the Universe (Panchbhuta Philosophy) 319 Five Elements and the Senses 319 Physiology 320 Properties of Dosha 320

INTRODUCTION Ayurveda is one of the most ancient systems of medicine known today. The origins of this science of life (Ayulife, and Veda-knowledge), though difficult to pinpoint, have been placed by scholars of ancient Indian Ayurvedic literature somewhere around 6000 BC.’ Ayurveda is a holistic science of health and a balance in lifestyle. Disease is seen as an imbalance, and its treatment involves diverse strategies to restore optimal function and balance. Using dietary alterations, yoga, and exercise, along with elaborate surgical techniques and complex, integrated herbal formulas, the Ayurvedic physician treats the whole person, removing disease completely by ending the imbalance that created it.

HISTORY In ancient India, it was custom for a teacher’s instruction to be recorded by his students, who would eventually repeat the same information orally to their own disciples.

Modes of Therapy 323 Diet 323 Individualization of Medicinal Therapy Pharmacy in Ayurveda 324

324

Research 324 Ayurvedic and Modern Medicine 325 Summary 325

Thus according to the different interpretations given by various disciples of Ayurveda, a number of treatises were written. Although specific instructions differed, the basic principles remained the same. Ayurvedic teachings were orally transmitted for thousands of years and then written down in melodious Sanskrit poetry. The contents of a number of Sanskrit verses, or shlokas, though written many centuries ago, still sound a note of familiarity in today’s scientific environment. Ayurveda, in its first recorded form (vedus: the world’s oldest literature), is specifically called Athurvedu.

The Development of Ayurvedic Medicine Hindu legend holds that, after seeing the suffering of human beings, Lord Brahma, the god of creation, elaborated ways to ease that suffering to Daksha, who, in turn, taught them to the Ashwin twins.Figure 34-1 presents the chronology of Ayurveda’s development. Dhanvantari and Bhardwaj separately developed the surgical and medical aspects of Ayurveda around the 317

Therapeutic Modalities Brahrna

I I

described the Tridosh physiology (Vat, Pit, and Kaph), seven Dhatus (tissues), and three Malas (excretions). His text covered the pathophysiology and treatment of diseases, human constitution (Prakriti),classificationsand preparations of drugs, diet, ”right conduct,’’ medical ethics, and many other aspects of medicine.

1

School of Surgeons (Dhanvantari Sampradaya)

Daksha

Ashwins

lndra

Sushruta wrote the first comprehensive works on surgery. These were later revised by Nagajuna in the second century AD. The major subjects in his texts were the following:

Dhanvantari (developed school of Surgeons)

Bhardwaj

I

V

8-6th century BC

Atreya (developed school of

Physicians)

1

Agnivesha, Harita, Bhela (all wrote compendia on Ayurveda)

Sushruta (wrote

1st century AD

suturing Asepsis Sterilization Operation theaters Hospitals Sushruta described 141 types of instruments and listed 40 types of surgeries and surgical techniques for treating cataracts, hemorrhoids, hernias, and bone problems, for cosmetic and plastic purposes, and for the removal of renal and gallstones.

(revised

Agnivesha Samhita)

Sushruta Sarnhita)

Nagariuna (revised Sushha Samhita)

1

Charak

Injections Preoperative care Postoperative care

Ayurveda encompasses eight specialties or branches. They comprise a system developed to prevent and cure disease, as well as achieve and maintain excellent health. Table 34-1 lists the branches.

2nd century AD

7th century

AD

Vagbhatta (wrote commentary on Charak’s work)

Figure 34-1

Branches of Ayurveda

The chronology of Ayurveda.

ninth century BC. Their students recorded these principles in great detail in compendia that are called Sumhitas. The Sushruta Samhita, one of the most widely accepted Ayurvedic texts, emphasizes the surgical aspects of therapy. Its author, Sushruta, is considered the father of surgery (particularly of plastic and reconstructive surgery). The medical teachings of Charak were a synthesis of earlier work. His material has become a classic text of the nonsurgical medical wisdom of Ayurveda. Successive generations have modified his work, the Samhita.

THE MAJOR SCHOOLS AND SPECIALTIES School of Physicians (Afreya Sampradaya) Charak wrote a complete text on Ayurvedic medicine in which he revised the work of Agnivesh. Charak’s text

PHILOSOPHY Ayurvedic philosophy is based on the Samkhya philosophy of creation. It has influenced major strains of philosophy in both Eastern and Western civilization. The word Samkhya is derived from the Sanskrit words Sat (truth) and Khya (to know). The Rishi Kapila (Rishimeans realized

Specialties in Ayurveda Avurvedic name Shalya Tantra Shalkya Kaya Chikitsa Bhutvidya

Kumar-Bhritya Agada Tantra

Rasayana Vajikaran

Enolish name General surgery

Ophthalmology and otorhinolaryngology Medicine Psychiatry Pediatrics, obstetrics, gynecology Toxicology and jurisprudence Geriatrics

Fertility and sterility

Ayurveda: The Science of Life and Mother of the Healing Arts

beings or seers of truth) realized the Samkhya philosophy of creation. They perceived the following: The close relationship between humans and the universe (that humans are a microcosm, a universe within themselves, while the external environment is the macrocosm) Cosmic energy is manifest in all living and nonliving things The 24 elements of the universe The source of all existence is cosmic consciousness, manifest as male (Shivu, Purusha) and female (Shukti, Prakriti) energy

Purush is formless, colorless, and beyond attribute. It is choiceless, does not take an active part in the manifestation of the universe, and has a passive awareness. Prakriti has form, color, awareness, and choice. Prukriti creates all the forms of the universe and has three attributes (Gunas): Sutvu (essence), Rajas (movement), and Tamus (inertia).It is also represented by Brahma (the god of creation), Vishnu (god of protection), and Mahesh (god of destruction),which together comprise a cycle active in this universe. In Prakriti, the three attributes are in balance. Whenever this balance is disturbed, they interact to bring about the evolution of the universe, yielding the cosmic vibration of Aum. The cosmic intellect (the M a h d ) manifests itself as ego 1Ahmkur), which, through the help of Sutvu, manifests the five senses and five motor organs, which together constitute the "organic universe." Ego further manifests into the five basic elements (space, air, fire, water, and earth), which, under the influence of Turnas, create the "inorganic universe." Rajus is the active vital force that moves both the organic and inorganic universes to Satvu and Tamas, respectively. Satvu and Tarnas are inactive, potential energies that need the active kinetic protective force of Rajas. Sutvu is a creative potential (Bruhmu), Rajas is a kinetic protective force (Vishnu), and Tams is a potentially destructive force (Mahesh). These three-Brahmu, Vishnu, and Muhesh-are constantly operating in the universe.

to form molecules of earth. Thus all matter was born from the five elements. These five elements exist in subatomic forms. Humans are a microcosm of nature and, as such, themselves comprise the five basic elements: Ether is represented in the hollow spaces of the mouth, nose, gastrointestinal tract, abdomen, thorax, respiratory apparatus, capillaries, lymphatics, tissues, and cells. Air exists as movement-as pulsation, expansion, or contraction of the various organs. Bodily movement is controlled by the central nervous system, itself governed by air. Fire is the source of heat and light somatically present as metabolism, gray matter, vision, temperature, digestion, and intelligence. Water exists as secretions of the salivary and digestive glands and the mucous membranes, and within plasma and cytoplasm. Earth is the solid structures (i.e., the bones, cartilage, nails, muscles, tendons, skin, and hair).

Five Elements and the Senses The five elements also connect with the five senses: ether-hearing, air-touch, fire-vision, water-taste, and earth-smell, and they are present in certain physiologic functions. Expressing the functions of the sensory organs are five actions (Table 34-2).In this manner, the elements are directly related to humans' abilities both to perceive the external environment in which they live and to respond to it: Ether is the medium through which sound travels. The ear is the organ of hearing, expressing its action through the organ of speech, which creates meaningful sound. Air is related to skin and the sense of touch. Its organ of action is the hand, which is e s p e d y sensitive.The hand performs the actions of holding, giving, and receiving. Fire produces light, heat, and color and is thus related to vision and direction. Its organ is the eye. Water relates to the organ of taste. The tongue is also related to the action of the genitals, the penis, and

Five Basic Elements and the Universe (Panchbhuta Philosophy) Ayurvedic knowledge is based on the concept of the five basic elements: ether (space), air, fire, water, and earth. The &his perceived that consciousness consists of these five basic elements or principles. At the beginning of the world, consciousness was without form, existing as the subtle vibration of the cosmic "soundless" sound Aum. Within these vibrations appeared the element ether, Ether started to move, creating air. The movement of ether also produced friction and, through friction, generated heat, then fire.From the heat of the fire,ethereal elements dissolved and liquefied into water. Water then solidified

The five elements and the senses Vehicle of action

Element

Sense

Organ

Action

Ether

Hearing

Ear

Speech

Mouth

Air

Touch

Skin

Holding, giving, receiving

Hand

Fire

Vision Taste

Eye

Walking

Feet

Water

Tongue

Procreation

Genitals

Earth

Smell

Nose

Excretion

Anus

Therapeutic Modalities

clitoris. In Ayurveda, the penis and clitoris are called the lower tongues. By controlling the upper tongue, one naturally controls the lower tongue. The earth element relates to the sense of smell, and the nose is its organ.

PHYSIOLOGY The five elements manifest within the body as the Tridosh ( D o s h means protective or, when out of balance, disease producing). The Tridosh are the three humors, or basic principles, described earlier-Vat, Pit, and Kuph. From the bodily combination of ether and air comes the bodily air principle, Vat Dosha. Likewise, fire and water combine as Pit D o s h , or fire principle, and earth and water produce the Kaph Dosh, or water principle. These three control all biologic, psychologic, and physiopathologic functions of the body, mind, and consciousness. They produce natural urges and individual tastes in food, flavor, and temperature. They govern the maintenance and destruction of bodily tissue and the elimination of waste products. They also are responsible for psychologic phenomena, including the emotions of fear, anger, and greed, as well as the highest order of emotions: understanding, compassion, and love.

Properties of Dosha Vat, Pit, and Kaph control all human biologic, psychologic, and physiopathologic functions and have subtle properties, as shown in Box 34-1. The Doshas increase by similar properties and are diminished by opposite properties. For example, Vat is dry, light, and cold, so any food, medicine, lifestyle, or behavior that increases these qualities increases Vat within the body. Conversely, oily, heavy, or hot factors decrease Vat.

Functions of Tridosha Each humor has a specific action. Vat is the principle of movement and may be called the bodily air principle, as opposed to the environmental air principle. Vat is a subtle

Vat

Pit

Kaph

Dry Light Cold Rough Subtle Mobile Clear Dispersing Smells sour

Oily Light Hot Liquid Penetrating Mobile

Oily Heavy Cold Slimy Soft Static Dense Slow

energy governing all biologic movement-breathing, blinking, muscle and joint movement, heartbeat, and all nerve and membrane contractions and expansions. In addition, it controls the psychologic functions governing the emotions of fear and anxiety. Vat also controls pain, tremors, and spasms. Broadly speaking, the whole nervous system can be labeled as Vat function. The large intestine, pelvic cavity, bones, skin, ears, and thighs are the places of Vat.Any excess of Vat accumulates in these areas. Pit, or bodily fire, governs digestion, absorption, assimilation, nutrition, temperature, skin color, luster of the eye, intelligence,and understanding. It arouses anger, hate, and jealousy. The small intestine, stomach, blood, sweat glands, fat, eyes, and skin are the places of Pit;in fact, all metabolism is governed by Pit. Kaph, biologic water, is the cement of the body, providing for physical structure. It is responsible for body resistance and biologic strength. It lubricates the joints; provides moisture to skin; and promotes wound healing, strength, vigor, and stability. It supports memory, gives energy to the heart and lungs, and maintains immunity. Kuph is present within the throat, chest, head, sinuses, nose, mouth, stomach, joints, the cytoplasm, plasma, and liquid secretions. Psychologically, Kuph governs attachment, greed, long-standing envy, calmness, forgiveness, and love. A balance of the Dosh is necessary for optimal health. Together, they govern all metabolic activities: anabolism (Kuph), catabolism (Vat), and metabolism (Pit).An excess of Vat results in an excess of catabolism, creating emaciation. When anabolism outstrips catabolism, there is an increase of growth and repair in the organs and tissues. Excessive Pit disturbs metabolism. In childhood, Kaph elements, associated with growth, predominate. In adulthood, Pit is more apparent. As the body deteriorates in old age, Vat is most prominent.

Individual Psychosomatic Constitutions-Prakriti Prakriti, a Sanskrit word composed of pra (before) and akriti (creativity), denotes the constitution of each individual as determined at conception. At the time of fertilization permutations of Vat, Pit, and Kaph determine the constitution of the new individual, with maleness or femaleness dominating other traits. These basic traits are also shaped by other important factors such as diet, lifestyle, behavior, emotions, and seasons. As illustrated in Box 34-2, up to seven different constitutions can exist depending on the permutation and combination of Vat, Pit, and Kuph. Prakriti is genetically determined; the basic constitution, the combination of the three humors, remains unchanged throughout an individual's lifetime. The combination can, however, respond to environmental changes.

Ayurveda: The Science of Life and Mother of the Healing Arts

lifestyle, and behavior. The characteristicsof the corresponding psychosomatic constitutionsare listed in Table 34-3. Vat

Pit-Kaph Kaph-Vat Vat-fit-Kaph

Pit

Kaph Vat-Pit

Mental Constitutions

Life is considered a sacred path in Ayurveda, a ceaseless interaction between the internal (Tridosha) environment and the external environment, or the sum of cosmic forces. To counteract external change, an individual may create a balance in the internal forces by altering diet,

On the mental and astral planes, three Gunas (attributes of female energy or Prakriti) correspond to the three humors that make up the physical constitution. In the Ayurvedic system, the Gunas are Satva, Rajas, and Tamas. They provide the basis for the distinctions in human temperament and individual differences in psychologic and moral dispositions. These attributes are further subdivided, but that is beyond the scope of this chapter.

Characteristic

Vat

Pit

KaDh

Body frame

Tall or small, thin, ill-nourished, hard, dry, cold

Medium, many moles, well nourished, pimples, patches of freckles, pigment, tender appearance

Stout, well-nourished, big, oily, greasy, cold, beautiful

Skin

Dry, cracked, tough, broken, brownish, black

Soft, thin, yellow, red, pink

Greasy, soft, yellow, white

Body hair

Scanty, coarse, dry, brown

Moderate, soft, pink

Plentiful, smooth, greasy, black

Hair on head

Brown, scanty, coarse, curved, wavy, wrinkled

Pinkish, yellow, moderate, soft, baldness, premature graying

Black, plentiful, firm, wavy, curved

Head

Small size

Moderate in size

Big and steady

Forehead

Small

Moderate with many folds

Big, broad

Eyebrows

Small, thin, unsteady

Moderate

Thick, plentiful

Eyelashes

Small, dry, firm

Small, thin

Big, greasy, firm

Eyes

Small, dry, thin, muddy brown, unsteady gaze, not pleasant looking

Thin, yellow, pink coppery, quickly become inflamed, pleasant looking

Big, white, pink, pleasant looking, thick, fixed, greasy

Nose

Small, dry, firm

Medium

Thick, big, greasy

Mustaches

Small, coarse, dry, blackish

Soft, pink, moderate

Heavy, thick, shining, black

Lips

Thin, small, blackish, brownish, dry, unsteady

Moderate, red, pink

Thick, big, smooth, firm, greasy

Teeth and gums

Dry, small, rough

Moderate

Thick, greasy, moist, soft, pink

Tongue

Thin, dry, fissured, unsteady

Moderate, pink, reddish

Thick, big, smooth, moist

Palate

Dry, blue, black

Pink

Moist, white

Lower jaw

Thin, small, dry

Moderate

Thick, big

Shoulders

Thin, small, unsteady, dry

Moderate

Thick, big, firm

Chest

Thin, small, not well built

Moderate

Thick, big, well developed

Arm

Thin, small, poorly built

Moderate

Thick, big, well built

Hands

Thin, dry, small rough, fissured, unsteady

Moderate, pink

Thick, oily, big, hard

Calves

Small, hard

Loose, soft

Shaped firmly, hard

Feet

Thin, small, coarse, dry, cracked, fissured, unsteady

Medium, soft, pink

Big, hard, steady

Joints

Thin, small, dry, unsteady, produce sound

Medium, soft, loose

Thick, big, well built

Nails

Thin, small, dry, rough, black

Medium, soft, pink

Thick, big, greasy, smooth, white, firm

Body weight

Less

Moderate

Heavy Continued

Therapeutic Modalities Psychosomatic constitutions (Pra&r&/)-cont’d Characteristic

Vat

Pit

KaDh

Action of body

Quick unsteady walk, quick actions and movements

Moderate, intelligent actions

Steady walk slow and dignified

Eliminations

Less, constipated

Copious, watery

Moderate, solid

Strength

Less, tires quickly

Moderate

Strong, hard worker, can withstand strains

Body odor Voice

No smell, less sweating

Heavy sweating, bad smell

Less sweating, pleasant smell

Feeble, broken, hidden, hoarse, unpleasant Quick, very talkative

High pitch

Pleasant, deep bass voice, good tone

Moderate

Slow, definite

Poorqualii things, irregular eating habits, likes roaming, journeys, dance, hunting, quarrels, stories, music, painting, artistic pursuits

Moderate, eats more, drinks more, likes sweet, bitter, and astringent tastes, cold food, hates hot, eats often, likes flowers, scents, music

Poor appetite, thirstless, likes sweet, pungent, hot, bitter, astringent, and fat tastes, likes flowers and cosmetics

Mental and temperament

Poor memory, quick forgetting, quick mind; unsteady courage, quick passion and attachment, cowardice, sorrowful, steals, jealous, ungrateful; no control over senses, Atheist, impoverished. less resourceful, few friends

Loves opposite sex, intelligent, scholar, genius, quick to anger and cool off, brave, adventurous, active, alert, secretive, politician, cruel in punishing disobedience, speaks well of obedient subordinates, invincible in assemblies, moderate wealth, resourceful

Good insight and forethought; slow to grasp, scholar, courageous; firm belief in religion, science, faithful, intelligent, little anger or desire, calm, civilized, grateful, truthful, shy, obedient, wealthy, does not waste money, resourceful, many friends

Sleep

Less sleep, wakeful at night Moving in sky, action

Speech Likes and dislikes

Dreams

Moderate

Sleeps a good deal

Cold, flowers, sun, fire, lightning, red, frightful dreams

Ponds, lakes, flowers, swans, beautiful sights Great sex capacity

Sex

Less sex capacity, less semedmenses, few children

Less sex capacity, few children

Life expectancy

Short

Moderate

Long-lived

Reaction to disease

Quick to get diseases, usually nemus disorders Minimum dosages required

Moderate, usually inflammations

Good resistance, usually cold and phlegm type

Intoleranceto drugs

Slow, tolerates at high dose

Reaction to drugs

Satva This type of mind expresses essence, understanding, purity, clarity, compassion, and love. People of Satvic psyche (Satou temperament) have healthy bodies and pure behavior and consciousness.They believe in the existence of God and are religious, often holy persons.

while those of Rajasic or Tamasic mind have difficulty. These three subtle mental energies are responsible for behavior patterns that may be altered and improved through practice and spiritual discipline, such as yoga and meditation.

Rajas

HEALTH AND DISEASE

This type of mind operates on the sensual level. Such persons are intemted in business, prosperity, power, prestige, and position. They enjoy wealth, are generally extroverted, and are politically minded.

Health is defined in Ayurveda as the soundness of body (Shriru), mind (Mums), and soul (Atma).Each part of this tripod of life should receive equal attention to ensure that the individual achieves sound health. Ayurvedic medicine stresses that psychic influences strongly affect the body in health as well as disease, a fact that must also be taken into account in modem therapeutics. Modem science takes pride in its understanding of physiology but, in doing so, has emphasized fragmentation, isolation, and disunity Instead of wholeness and interaction, thismodem view accepts only physical objects

Tamas This type is distinguished by its ignorance, inertia, heaviness, and dullness. Tamasic people are lazy, selfish, and destructive by nature. They show little respect to others. All their activities are egocentric. The Satvic person attains self-realization without much effort,

Ayurveda: The Science of Life and Mother of the Healing Arts

as causes of disease, whereas these objects are merely the agents of disease, able to cause specific symptoms, but

only in a susceptible host. Disease is the result of a disruption of the spontaneous flow of nature’s intelligence within physiology. When people violate nature’s law and cannot adequately rid themselves of the results of this action, then they acquire diseases. Ayurveda is based on certain fundamental doctrines (Box 34-3) known as the Darshnus. It conceives of the body as being composed of three principal divisions: three Doshu (humors), seven Dhutus (tissues), and three Malas (excretions). The three Doshas regulate cell functions. Pit gives energy and is responsible for cellular, enzymatic, and metabolic functions; Kuph helps in synthesizingblocks of cells; and Vat controls the other two.A balance of these Doshus, good-quality tissues (the seven Dhutus), and a certain character of excretions are essential for maintaining health. However, all are subject to qualitative and quantitative alterations. As explained earlier, an individual is born with a particular Dosha predominating in his or her constitution (Prakriti). This predominant Doshu, quite apart from genetic, age, environment, and dietary factors, may make an individual susceptible to a certain disease. For example, Pit Prakriti individuals are more prone to develop a disease syndrome with symptoms similar to a peptic ulcer. This is due to hyperactivity of the Pit Doshu,which regulates enzymatic activity. Hyperpepsinogenemic individuals are more susceptible to duodenal ulcer formation? Ayurveda teaches that the origin of most diseases is found either in an exogenous or endogenous Doshu imbalance, or in an inherent or acquired weakness of the tissues. Therefore a successful treatment or prevention of disease consists of normalizing cellular functions through correcting any Doshu imbalance or improving inherent tissue vitality. For example, in the treatment of cancer, the use of agents cytotoxic to the cancer cells is important. However, equally important is potentiation of the immune system and stimulation of the body’s own healing mechanisms.

Doshas (humors) Vat Pit Kaph Dharus (tissues) Ras (secretion) Rakata (blood) Mamsa (muscles) Meda (fat)

Dharus (tissues)-cont’d Asthi (bone and cartilage) Majja (bone marrow) Shaukra (sex hormones and immunity) Malas (excretions) Svet (sweat) Poorish (feces) Mutra (urine)

MODES OF THERAPY Once a diagnosis is made, Ayurveda offers various modes of therapy. The treatment is chosen according to patient constitution, as well as disease process. Modalities include dietary alterations, botanical medicines, minerals, animal products, exercise, yoga, meditation, counseling, and surgery. Ayurveda places great emphasis on diet, for both its direct effect on the individual’s physiologic state and its influence on the action of medicines. Proper assimilation of dietary constituents is essential for the maintenance of good health. Improper assimilation results in the formation of intermediary products of digestion that have toxic properties and are therefore treated as foreign by the body. Such toxic products are called Ama (this leads to the concepts of immune and autoimmune disorders). Arthritic diseases such as rheumatoid arthritis are attributed to an accumulation of Amu. Could these toxic intermediates-macromolecules absorbed transmucosally from the intestine (in nutritionally insignificant amounts)-provoke strong immune reactions? The human gut has a complex system to control the continuous onslaught of antigenic substances derived from food, microorganisms, and toxins? It has been suggested that absorption of such compounds could underlie the pathogenesis of disease in the gut, as well as in distant sites such as the liver and spleen: Ayurveda stresses prevention of the formation and accumulation of Ama through appropriate diet and the use of therapies to improve digestion. It also considers various dietary factors that trigger or eliminate certain diseases? That is why Ayurveda places emphasis on diet according to the patient’s psychosomatic constitution (Prakriti), time of day (Dincharya),and season ~Rituchuyu). For example, a person with the Pit psychosomatic constitution should not eat foods that are hot, pungent, or spicy at noon in the summer, as this tends to increase diseases of inflammation. Ayurveda prescribes specific diets for several psychiatric disorders. Recent research supports this approach. Brain levels of the neurotransmitters 5HT, catecholamine, and acetylcholine have been found to be influenced by dietary constituents. Consequently, it has been suggested that normal brain functions and mental disease can be altered by diet.6 Recent exciting developments include the successful treatment of mental depression with neurotransmitter prec~rsors.’,~ Ayurveda also prescribes certain diets (Pathyu)during drug therapies, as dietary constituents are believed to influence drug action.

Therapeutic Modalities

Individualization of Medicinal Therapy

Pharmacy in Ayurveda

Medicinal therapy is highly individualized in Ayurveda? The choice and dose of medicine are influenced not only by disease but by the individual's constitution and the environmental conditions likely to affect that individual's Doshs. For example, Piper rotudum (black pepper) and Zingiber oficinale (ginger), which increase Pit (increasing stomach acid and pepsin secretion), are used cautiously in individuals with a Pit constitution. Another example is in the treatment of the patient with hypertension. Ayurveda prescribes Terminah chebuli for the treatment of hypertensive patients who have Vat Prakriti, while for the patient with Pit Prakriti, one uses Terminalia arjunu. A parallel to this approach can be found in modem medicine. For example, it is well known that hypertensive patients with normal renal status respond better to betablockers or angiotensin-converting enzyme inhibitors than do those with a poor renal status.'O In the Virnanastrana, Charak presents an interesting discussion of host- and drug-related factors that help in the determination of the drug and dosage (Box 34-4). Ayurveda also emphasizesproper timing for the administration of medicines. Considering that chronopharmacology (the study of the timing of drug administration in relation to physiologic function) has only recently been developed as a branch of modem therapeutics, it seems remarkable that such astute observations about the timing of medicaments were made so many centuries ago.

In Ayurveda, pharmacy is highly developed. Almost 70 books contain more than 8000 recipes for the preparation of different medicines, most of which are derived from minerals and plants. Many formulations including simple distillates (Arka), decoctions (Kwutha), tinctures (Avleha), powders (Churna), pills (Vati, Goti, and Modak), fermented products (Asua), and medicated oils (Tailaand Ghritu) are available. The oil preparations are particularly useful as they help to target the sites of actions. Detailed descriptions of the methods are recommended to ensure a medicine is suitable for human use.ll One pharmaceutic technique, Surnskara (refinement), is known as Shudhi (purification), a process that eliminates the toxicity of some minerals and plants. Another practice is the administration of drugs in combination (Samyogu) in order to reduce toxicity and increase efficacy. At the beginning of the twentieth century, Paul Ehrlich introduced the Western world to the concept of targeting drugs to the site of action. This concept was used in the East since the teachings of Charak, who wrote, among other texts, the Adhisthana in the first century AD, in which he described using drugs that have an affinity for specific tissues.

Drug Factors Prakriti Guna Prabhava Desh RitU Grahan Nihit Sanskar Matra Sanyog Adhishthan

Constitution of the drug Properties Activity (potency) Place Season Storage Transport Refinement Dose Combination Ability to reach site of action

Host Factors Prakriti Vayam Vikriti Sar Satamya Satva Ahar ShaMi Vyayarn ShaMi Balam

Constitution of host Age Pathologic condition System strength Tolerability Psychologic state Digestive capacity Exercise tolerance Strength of host

Considerable modem research has proven the efficacy of Ayurvedic herbal preparations, and research has now moved to elucidating their mechanisms and sites of action.12 Reserpine, an antihypertensive drug, was isolated from Rauwolfia serpentina (Sarpgandha, used for hypertension). Curcumin, the active principle of Curcuma longa, has been found to exert an anti-inflammatory effect by inhibiting prostaglandin synthesis. Further, it has been shown to selectively inhibit platelet prostaglandin production, while sparing vascular endothelial prostaglandin synthesis. Many plant preparations have been used to strengthen general host resistance. Rusayna, Jeevaniya, and Balya increase tissue resistance to disease, a concept similar to "prohost therapy" as put forward by Hadden.13 Prohost therapy claims to augment cellular responses and, consequently, ameliorate disease states.14 Perhaps most exciting, however, is the current research demonstrating efficacy of Ayurvedic herbal preparations in conditions for which modem medicine has limited or no success. For example, animal studies have shown that Winthaniu somniferu (Ashwagandna) can reverse the immunosuppression cyclophosphamide, azathioprin, and prednisolone, and a 50% alcoholic extract of Phyllanthus emblica protects the liver from p a r a ~ e t a m o l . ' ~Recent J~ human studies found that patients with acne vulgaris demonstrated substantial improvement, with no significant side effects, after using Sunder Vuti when compared with placebo. Interestingly,

Ayurveda: The Science of Life and Mother of the Healing Arts

the study found three other Ayurvedic formulas ineffective. Patients with osteoarthritis experienced substantial, highly significant improvement in pain and disability with no significant side effects (however, the radiologic findings did not improve).”

AYURVEDIC AND MODERN MEDICINE In evaluating Ayurvedic medicine by modem standards, one encounters a number of difficulties. First, there is in nature a wide variation in the quantity of pharmacologically active substances in plants. In addition, many findings are more subjective than objective. The modern scientist has difficulty recognizing subjective experiences because no reliable methodology has been developed to measure and reproduce such experiences. Yet totally objective experience, which completely disregards the subjective, may be wrong and even dangerous. In fact, there is no such thing as complete objectivity. What people claim as such is merely agreement among many minds. Subjective experience is limited. Senses vary in ability, and reality for one is unreality for another. When using the tools of quantitative, technical science to describe biologic and living systems phenomena, one soon encounters limits. Artificial distinctions must be imposed to reduce variables and interpret nonlinear events intelligibly. Science has often confused the map for the actual reality. Take the example of color vision in bees. The eye of a bee is more sensitive to blue, violet, and ultraviolet light, while receptors in the human eye more readily detect red, green, and blue wavelengths. Thus bees are nearly blind to red light, and humans are quite blind to ultraviolet light. These differing characteristics result in members

1. Gordon BL. Medicine throughout antiquity. Philadelphia: FA Davis, 1949313-354. 2. Rotter JI, Sones JQ, Samloff IM, et al. Duodenal-ulcer disease associated with elevated serum pepsinogen I an inherited autosomal dominant disorder. N Engl J Med 1979;300:63-66. 3. Walker WA. Antigen handling by the gut. Arch Dis Child 1978; 53527-531. 4. Tagesson C, Sjodahl R, Thoren 8. Passage of molecules through the wall of the gastrointestinaltract. %and J Gastroent 1978;13:519-524. 5. Gulabkunverba S. Charak sutra 26, Charak samhita. Jamnagar, India: Ayurvedic Society, 1949:124141. 6. Ferstorm JD. Dietary pl.ecursors and brain neurotransmitter formation. Annu Rev Med 198132413425. 7. Copen A, Shaw DM, Farrell MB. Potentiation of the antidepressive effect of a monoamine oxidase inhibitor by tryptophan. Lancet 1963; 79-81. 8. Gelenberg AJ, Wojcik JD,Growden JH, et al. Tyrosine for the treatment of depression. Am J Psychiat 1980;137622-623. 9.Sasdri RD, Gulabkunverba S. Charak sutra 8. Jarnnagar, India: Ayurvedic Society, 1949105.

of each species forming a completely different perception of the same object. Color, rather than being a part of the “reality” of a perceived object, is an expression of sensory apparatus, determined by each species’ or individual’s unique pattern of interneural connections. Even more interesting is the fact that, within the same species, perception may vary considerably. Ayurvedic philosophy may strike the contemporary reader as unnecessarily complex for the conceptual territory it addresses. However, it is actually quite succinct and relevant to modern life. Its precepts have influenced many systems of healing, including naturopathic medicine, through the several paths of its root traditions. It emerged alongside systems known to early Persians and Greeks, as well as the Chinese. Modern medicine is itself a distillation of these same rich traditions. When one compares Ayurvedic concepts with those of preindustrial Europe, much similarity becomes apparent.

SUMMARY Only some glimpses of Ayurveda are presented here. This ancient system of medicine, developed over centuries, has a consistent and logical framework and gives detailed instructions for the preservation of health and the treatment of disease. Ayurveda faced a setback when modem medicine subjected all knowledge to experimental and statistical verification which, although useful, is limited by the tools available and the perceptions underlying the questions asked. Now that considerableknowledge of cellular physiology has accumulated and more sensitive modem biomedical research tools exist, we may be able to evaluate the concepts of Ayurveda more effectively.

Buhler FR, Seldin, eds. Frontiers in hyper10. Laragh JH. In Laragh JH, tension research. New York Springer-Verlag, 1981:183-194. 11. Budar Peth YJEL Sharangdhar samhita, Part II. Pune, India: YJ Dixit, 1908. 12. Satyavati GV, Raina MK, Sharma M. Medicinal plants of India, vols 1and 2. New Blhk Indian Council of Medical Research, 1976. 13. Hadden JW. Immunomodulators in the immunotherapy of cancer and other diseases. Trends Pharm Sci 1982;3:191-194. 14. Srivastva R, Puri V, Srimal RC, et al. Drug Res 1986;30. 15. Ziauddin M, Phansalkar N, Patki P, et al. Studies on the immunomodulatory effects of Ashwagandha. J Ethnopharmacol 1996; 5069-76. 16. Gulati RK, Agarwal S, Agrawal SS. Hepatoprotective studies on Phyllanthus emblica Linn. and quercetin. Indian J Exp Biol 1995; 33261-268. 17. Paranjpe P, Kulkarni PH. Comparative efficacy of four Ayurvedic formulations in the treatment of acne vulgaris: a double-blind randomised placebo-controlled clinical evaluation. J Ethnopharmacol 1995~49~127-132.

Therapeutic Modalities

Budwar Peth YJB. Sharangdhai samhita, part 1. Pune, India: Dixit, 1908. Dahanukar SA, Date SG, Karainchikar SM. Cytoprotective effect of Terminalia chebula and Asparagus racemosa on gastric mucosa. Indian Drugs 1983;20442-495. Dahanukar SA, Karandikar SM. Evaluation of antiallergic activity of Piper longum. Indian Drugs 1984;21:377-383. Gulabkunverba S. Charak Samhita and Sushruta Shamita. Chaunkamba orientale, Varanasi. Jamnagar,India: Ayurvedic Society, 1980. Kerup PVN. In Bannerman RH, Burton J, WmChieh C, eds.Traditional medicine and health care coverage. Geneva: WHO, 1983:50-58. Kulkami RR, Patki PS,JogVP, et al. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cmss-over study. J Ethnopharmacol199133:91-95. Lad V. Ayurveda, the science of self healing. Sante Fe, NM: Lotus Press, 1984.

Lad V. Ayurveda. A holistic medical approach. Probe 1987;26293-297. McIntosh RP. The importance of timing in hormone and drug delivery. Trends Pharm Sci 1984;5:492-501. Meerson FA. Adaptation, stress and prophylaxis. New York SpringerVerlag, 1984936-93. Rege NN, Dahanukar SA, Karandikar SM. Hepatoprotective effect of Tiospora cordifolia against carbon tetrachloride induced liver damage. Indian Drugs 1984;21:!544-580. Singhal GD, Tripathi SN, Chaturvedi GN. Fundamental and plastic surgery considerations in ancient Indian surgery, vol 1. Varanasi, India: Singhal Publications, 1981:15-16. Srikantamurthy KR. Clinical methods in Ayurveda. Varanasi, India: Chaukhambha Orientalia, 1983. Thakkar C. Ayurveda, the Indian art and science of medicine. New York Noble Offset Printers, 1974.

Botanical Medicine-A

Modern Perspective Michael T. Murray, ND Joseph E. Pizzorno Jr, ND

CHAPTER CONTENTS Introduction 327 The Role of Herbs in Modern Pharmacy 328 Science Has Fueled the “Herbal Renaissance” 329 The Advantages of Herbal Medicines 329 The Study of Herbal Medicine 330 The History of Herbal Medicine 330 In the Beginning 330 Materia Medicas 330 Galen’s Influence 330 The Black Plague and Syphilis 331 Challenges to Galenical Medicine 331 The Thomsonian and Eclectic Movements 332 The Growth of the Pharmaceutical Industry 332

Determining Quality 333 Collection/Harvesting 334 Analytic Methods 335 Organoleptic 335 Microscopic Evaluation 335 PhysicaVChemicalAnalysis 335 Chromatography 336 Biologic Analysis 336 Quality Control in Herbal Products 336 The Issue of “Phytoequivalence” 336 Standardized Extracts versus Tinctures 337 Final Comments 337

Herbal Preparations 332 Extracts 333

INTRODUCTION The term herb refers to a plant used for medicinal purposes. Are herbs effective medicinal agents or is their use merely a reflection of folklore, outdated theories, and myth? To the uninformed, herbs are generally thought of as ineffective medicines used before the advent of more effective synthetic drugs. To others, herbs are simply sources of compounds to isolate and then market as drugs. But to some, herbs and crude plant extracts are effective medicines to be respected and appreciated. For many people of the world, herbal medicines are the only therapeutic agents available. The World Health Organization has estimated that about 80%of the world’s population relies on herbs for primary health care needs.’ This widespread use of herbal medicines is not restricted to developing countries, as it has been estimated that 70%of all medical doctors in France and Germany regularly prescribe herbal preparations. Although herbal medicine has existed since the dawn of time, knowledge of how plants actually affect human physiology remains largely unexplored. Many individuals

formulate their view of herbal medicine based on opinion, philosophy, and ideology. This chapter seeks to facilitate an informed view of herbal medicine. The past and future of herbal medicines are discussed. We believe that the continued evolution of the tradition of herbal medicine can only be accomplished within the context of continued scientific investigation. Throughout the world but especially in Europe, the United States, Canada, Australia, and Japan, a tremendous renaissance in the use and appreciation of herbal medicine occurred in the latter part of the twentieth century. For example, in the United States, the sale of herbal products skyrocketed from $200 million in 1988 to more than $3.3 billion in 1997. Within the European Community annual sales exceeded $7 billion in 1997.2 The rebirth of herbal medicine, especially in developed countries, is largely based on a renewed interest by the public and scientific researchers. During the past 20 to 30 years, there has been a virtual explosion of scientific information concerning plants, crude plant extracts, and various substances from plants as medicinal agents. 327

Therapeutic Modalities

THE ROLE OF HERBS IN MODERN PHARMACY Plants still play a major role in modem pharmacy. For the past 50 years, about 25% of all prescription drugs in the United States and other developed countries have contained active constituents obtained from plants. Digoxin, codeine, colchicine, morphine, vincristine, and yohimbine are some popular examples. Many overthe-counter (OTC) preparations are also composed of plant compounds. Pharmacognosy, the study of natural drugs and their constituents, plays a major role in current drug development. Unfortunately, the standard path of the approval of a drug is a process that typically takes 10 to 18 years at a total cost of roughly $250 million (Table 35-1). Because a plant cannot be patented, plants are screened for biologic activity and then the so-called “active” constituents (compounds) are isolated and, typically, chemically modified to produce unique substances. If the compound is powerful enough, the drug company begins the process to procure Food and Drug Administration (FDA) approval. Of 520 new drugs approved by the FDA or comparable entities in developed countries, 30 came directly from natural product sources and another 173 were either semisynthetic h m a natural source or modeled after a naturally occurring compound.’ Because of the expense and lack of patent protection, few clinical evaluations were done before 1980 on whole plants or crude plant extracts as medicinal agents per se. A key factor in contributing to more research into herbal medicines after thistime was the development in Europe of regulatory policies and practices that made it economically feasible for companies to do research. For example, in Germany regulations allowed herbal products to be marketed with drug claimsif they have been proven to be safe and effective? Whether the herbal product is available by presrription or OTC is based on its application and safety of use. Herbal products sold in pharmacies are reimbursed by insurance if they are prescribed by a physician. The proof required by a manufacturer in Germany to illustrate safety and effectiveness for an herbal product is less (and more appropriate)than the proof required by the FDA for drugs in the United States. In Germany a special commission (Commission E) developed a series of 400 monographs on herbal products similar to the OTC monographs in the United States. An herbal product is viewed as safe and effective if a manufacturer meets the quality requirements of the monograph or produces additional evidence of safety and effectiveness that can include data from existing literature, anecdotal information from practicing physicians, and limited clinical studies. In contrast, in the United States, extracts that are identical to those approved in Germany as drugs are

Clinical use

Botanical source

Atropine

Anticholinergic

Atropa belladonna

Caffeine

Central nervous system stimulant

Cola nitida

Camphor

Rubefacient

Cinnamomum camphora

Cocaine

Local anesthetic

Erythroxylon coca

Codeine Colchicine

Analgesidantitussive Antigout

Papaver somniferum Colchicum autumnale

Digitoxin

Cardiotonic

Digitalis purpurea

Digoxin

Cardiotonic

Digitalis lanata

Emetine

Amebicide/emetic

Cephaelis ipecacuanha

Ephedrine

Sympathomimetic

Ephedra sinica

Gossypol

Male contraceptive

Gossypium spp.

Hyoscyamine

Anticholinergic

Hyoscyamus niger

Kawain

Tranquilizer

Piper methysticum

Methoxsalen

Psoriasidvitiligo

Ammi majus

Morphine

Papaver somniferum

Noscapine

Analgesic Antitussive

Physostigmine

Cholinesterase inhibitor

Physostigma venenosum

Pilocarpine

Parasympathomimetic

Pilocarpus jaborandi

Podophyllotoxin

Topical wart remedy

Podophyllum peltatum

Quabain

Cardiotonic

Strophanthus gratus

Quinine

Antimalarial

Cinchona ledgeriana

Reserpine

Antihypertensive

Rauwolfia serpentine

Scopolamine

Sedative

Datura mete1

Sennosides Theophylline

Laxative

Cassia spp. Camellia sinensis

Tubocurarine

Muscle relaxant

Chondodendron tomentosum

Yohimbine

Male erectile dysfunction

Pausinystalia yohimbe

Papaver somniferum

Bronchodilator

Modified from De Smet PA. Drugs 1997;54:801-840.

available as “dietary supplements,” yet manufacturers are prohibited from making any therapeutic claims for their products. No medicinal claims are allowed for most herbal products in the United States because the FDA requires the same standard of absolute proof as required for new synthetic drugs. Thus far, the FDA has rejected the idea of establishingan independent ”expert advisory panel” for the development of monographs similar to Germany’s Commission E monographs, as well as other ideas to create a suitable framework for the marketing of herbal products in the United States. The monograph system in Germany allowed companies to market their products according to the guidelines

of Commission E. With the ability to make appropriate claims, many companies achieved success with their products and were enabled to fund the necessary research to gain greater acceptance within mainstream, conventionalmedicine. The use of St. John’s wort extract in the treatment of depression is a perfect case in point to illustrate how Commission E monographs have led to significant documentation of the efficacy of plants with a long history of folk use for depression. When the CommissionE monograph for St. John’s wort came out in 1984, it identified the constituent hypericin as the active constituent and permitted the medicinal use of the herb (in average doses of 2 to 4 g of herb, or 0.2 to 1 mg total hypericin) for depression, anxiety, or nervous excitement. Originally it was thought that hypericin acted as an inhibitor of the enzyme monoamine oxidase, thereby resulting in the increase of central nervous system monoamines such as serotonin and dopamine. However, it was later shown that St. John’s wort does not inhibit monoamine oxidase in vivo.4 The antidepressant activities appear to be related more to serotonin reuptake inhibition as occws with the drugs Prozac, Paxil, and Zoloft; modulation of neuroendocrinefunction; as well as downregulation of beta-adrenergic receptors and up-regulation of serotonin receptors in the brain areas that are implicated in depression.42 In addition, it appears that although hypericin is an important marker, other compounds such as flavonoids are also thought to play a major role in the pharmacology of St. John’s wort. The key point here is that the further understanding and documentation of clinical effectiveness of St. John’s wort extract was largely the direct result of a commercial incentive created by the existence of Commission E.

Science Has Fueled the “Herbal Renaissance” Improvements in analytic techniques and modern pharmacology have given researchers the tools and understanding necessary to evaluate herbal medicines properly. Improvements in plant cultivation techniques and the quality of herbal extracts (quality control and standardization) have also led to the development of some effectiveplant medicines. These advances have created a renaissance in the appreciation and use of herbal medicine. It seems that science and medicine have finally advanced to a level where nature can be appreciated rather than discounted. The scientific investigation of plant medicines is replacing some of the mystery and romance of herbalism with a greater understanding of the ways in which herbs work. llurty years ago it was impossible to determine exactly how herbs promote their healing effects because analytic science had not advanced to a sufficient level of sophistication. This point is well illustrated by the fact that the main mechanism of action

responsible for aspirin’s anti-inflammatory effect was not understood until the early 1970s, and its mechanism of action for pain relief has yet to be fully understood. Since the mechanism of therapeutic action of a particular herb could not be fully elicited, many effective plant medicines were erroneously labeled as possessing no pharmacologic activity. Now, researchers equipped with greater understanding and more sophisticated technology are rediscovering the wonder of plants as medicinal agents. Much of the increased understanding is, interestingly, a result of synthetic drug research. For example, one of the modem classes of drugs is the calcium channel blockers. These agents block the entry of calcium into smooth muscle cells, thereby inhibiting contraction and promoting muscular relaxation. Calcium channel blocking drugs are currently being used in the treatment of high blood pressure, angina, asthma, and other conditions associated with smooth muscle contraction. They represent a highly evolved stage of modem drug pharmacy. After calcium channel drugs became better understood, it was discovered that many herbs contain components that possess calcium channel blocking activity. In most cases, the historical use of these herbs corresponded to their calcium channel blocking activity. In addition to possessing currently understood pharmacologic activity, many herbs possess pharmacologic actions that are not consistent with modem pharmacologic understanding. For example, often an herb appears to affect homeostatic control mechanisms to aid normalization of many bodily processes. When there is a hyperstate, the herb has a lowering effect, and when there is a hypo-state, it has a heightening effect. This action is totally baffling to orthodox pharmacologists, but not to experienced herbalists who have used terms such as alterative, amphoteric, aduptogen, or tonic to describe this effect.

The Advantages of Herbal Medicines In general, herbal preparations are thought to have three major advantages: lower cost, fewer side effects, and medicinal effects that tend to normalize physiologic function. When used most effectively, the mechanism of action of an herb often corrects the underlying cause of a disorder. In contrast, a synthetic drug is often designed to alleviate the symptom or effect without addressing the underlying cause. Interestingly, research has often shown for many plants that the whole plant or crude extract is much more effective than isolated constituents. In many instances, multiple components produce multiple pharmacologic actions. Herbal medicine will certainly play a major role in future medicine. As modern medicine gains more knowledge and understanding about health and disease, it is adopting therapies that are more natural and less toxic. Lifestyle modification, stress reduction, exercise,

meditation, dietary changes and many other traditional naturopathic therapies are becoming much more popular in standard medical circles. This illustrates the paradigm shift that is occurring in medicine. With the continuing advancement in science and technology, there has been a great improvement in the quality of herbal medicines available and in the understanding of their optimal clinical use. Improvements in cultivation techniques coupled with improvements in quality control and standardization of potency will continue to increase the effectiveness of herbal medicines.

THE STUDY OF HERBAL MEDICINE The study of herbal medicine spans the breadth of pharmacology, the study of the history, source, physical and chemical properties, mechanisms of action, absorption, distribution,biotransformation,excretion, and therapeutic uses of ”drugs.” In many respects, the pharmacologic investigation of herbal medicine is just beginning. This textbook is replete with examples of herbs whose historical use is being justified by new investigations into its pharmacology.

The History of Herbal Medicine The history of the use of plants as medicines is full of interesting stories and fascinating facts. The evolution that has occurred in herbal medicine over the centuries is only beginning to be recognized as more natural medicines gain acceptance. Interestingly, this acceptance is largely a result of increased scientific investigation. A trend exists toward using natural substances including compounds found in the human body such as interferon, interleukin, insulin,and human growth hormone, as well as foods, food components, herbs, and herbal compounds. More and more researchers are discovering the tremendous healing properties of these natural compounds and their advantages over synthetic medicines and surgery in the treatment of many health conditions. Through these scientific investigations, a trend toward natural medicine is emerging. To better appreciate this evolutionary trend, this section presents some of the historical aspects of herbal medicine. Much of the following is derived from Barbara Griggs’ Green P h u m c y : A Histo y of Herbal Medicine.’

In the Beginning Plants have been used as medicines since the dawn of animal life. The initial use of plants as medicines by humans is thought to have been a result of ”instinctive” dowsing. Animals in the wild still provide evidence that this phenomena occurs. Animals, with a few notable exceptions, eat plants that heal them and avoid plants that do them harm. Presumably humans also possessed this instinct at one time.

As civilizations developed, medicine men and women were responsible for transmitting the information on herbs to their successors. Before the advent of written language, this information was handed down by verbal and experiential means. Besides instinctive dowsing, it was commonly believed that plants had been signed by the “creator” with some visible or other clue that would indicate its therapeutic use. This concept is commonly referred to as “the doctrine of signatures.” Common examples of this doctrine are the following:

Panax ginseng (ginseng): Its root bears strong resemblance to a human figure, and its general use is as a tonic. Cuulophyllurn thlictroides (blue cohosh): Its branches are arranged like limbs in spasm, indicating its usefulness in the treatment of muscular spasm. Sanguimria canadensis (bloodroot): Its roots and sap are a beautiful blood color, corresponding to its traditional use as a “blood purifier.” Lobeliu influfa (lobelia): Its flowers are shaped like a stomach, corresponding to its emetic qualities. Hydrastis canadensis (goldenseal): Its yellow-green root sigrufies its use in jaundice as well as infectious processes. All of these uses have been confirmed by recent research.

Materia Medicas With the development of written language, materia medicas (books containing prescribing information on herbs) became the vehicle of passing information about the medicinal use of herbs to future herbalists. Materia medicas were recorded in ancient China, Babylon, Egypt, India, Greece, and other parts of the world. From these materia medicas, it is quite obvious that herbal medicines were highly respected therapies in ancient times.

Galen’s Influence No system, rules, or classification to Western herbal materia medicas existed until the first century AD when Galen, the Greek physician who founded experimental physiology, established his system of rules and classification. Galen’s classification was based on Hippocratic medicine (i.e., balance of the four humors: blood, bile, phlegm, and choler) and a profound belief in a beneficent nature. Although his system is considered seriously flawed in the light of modern medical knowledge, Galen is historically considered to be the founder of scientific herbalism. Galen evaluated and classified each plant according to its relation to Hippocraticmedical theory. Although based initially in Hippocratic principles, Galen constructed his

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own elaborate, and rigid, system of medicine. Galen’s work also s i g h e d the beginning of a clear division between the professional physician and the traditional healer. As only the well educated could understand Galen’s system, and even with the best schooling it remained a mystery to many, all challengesto the professional physician were effectively squelched by dogma. Galen’s system dominated European medical thinking for 1500 years. Perhaps if the Roman Empire had continued to flourish, others would have surfaced to develop alternative theories. Instead, Galenical medicine reigned unchallenged throughout the Middle Ages. By the nineteenth century, the ”professional”physician, confident in his supposedly superior knowledge, took Galenical philosophy to an extreme probably never imagined by Galen by the adoption of bloodletting, purging, and administering exotic medicines. This was in direct contrast to the traditional healer’s patient use of traditional herbs and tremendous faith in the healing power of nature.

The Black Plague and Syphilis Although Galenical medicine dominated the Middle Ages, herbal medicine was still deeply entrenched in European culture. The Black Plague of 1348 may have been the beginning of change in medical thought, as conventional medicine was totally useless. As nearly one third of Europe died during thisplague, the public began to lose faith in Galenical medicine. Nearly 150 years later another blow was dealt to Galenical medicine, when syphilis became the major medical problem. Unlike the Black Death, patients with syphilis tended to survive longer, giving physicians more time to experiment with treatments. At this time, perhaps the greatest hoax in the history of medicine began. Mercury became the standard medical treatment for syphilis despite the fact that even Galen thought mercury too poisonous to use. Syphilis did, however, open the door for the use of some new herbs from the Americas. A French physician, Nicholas Monardes, published a comprehensive account of sarsaparilla and several other ”new” drugs in the treatment of syphilis in 1574. Many Europeans at the time believed that syphilis had come to Europe from the West Indies with Columbus’s sailors, and because there was a general belief that whatever disease was native to a country might be cured by the medicinal herbs growing in that region, it was only natural for sarsaparilla to become a popular remedy. Because the standard treatment of syphilis was the use of mercury, which often resulted in greater morbidity than did syphilis, sarsaparilla was a welcome alternative. Despite initial excitement, Monardes’ sarsaparilla cure eventually lost favor, probably due to other components in the cure; specifically, patients were confined to a warm room for 30 days and for the following 40 days were required to abstain from both wine and sexual intercourse.

Modern Perspective

Although the public popularity of sarsaparilla waned, it continued to be used in the treatment of syphilis. During military operations in Portugal in 1812, a British Inspector General of Hospitals noted that the Portuguese soldiers suffering from syphilis who used sarsaparilla recovered much faster and more completely than their British counterparts who were treated with mercury. Sarsaparilla was also used by the Chinese in the treatment of syphilis. Later clinical observations in China would demonstrate, through the use of blood tests, that sarsaparilla is effective in about 90% of cases of acute syphilis and 50%of cases of chronic syphilis. Although sarsaparilla was clearly more beneficial than mercury in the treatment of syphilis, mercury was the standard medical treatment of choice for more than four and a half centuries. Some historians have stated that ”the use of mercury in the treatment of syphilis may have been the most colossal hoax ever perpetrated” in the history of medicine. Mercury represented a new kind of medicine, one formulated and prepared in a laboratory using the new techniques of chemistry. It helped to prepare the way for future synthetic and mineral drugs at the expense of herbal medicines.

Challenges to Galenical Medicine The 1500s also saw a strong challenge to Galenical medicine from within the traditional circles. Specifically, Paracelsus, an alchemist who believed strongly in the doctrine of signatures, was responsible for founding modem pharmaceutic medicine. Paracelsus is probably most remembered for the development of laudanum (tincture of opium). After Paracelsus, Galenical preparations and treatments fell greatly out of favor. In public circles, herbal medicine was regaining some respect as well. In the early 1600s, Culpepper, an English pharmacist, published his book The English Physician. Instead of requiring patients to purchase expensive exotic or imported drugs, Culpepper recommended the herbs his clients and readers had growing in their own backyards. Although Culpepper’s herbal philosophy is based on astrologic rationalizations, it reinforced a strong English tradition of domestic herbal medicine. This came at a time when professional physicians were beginning to become contemptuous of herbal medicine. Meanwhile, in the Americas during the 1600 and 1700s, herbs used traditionally by Native Americans were becoming quite popular, especially in the treatment of malaria and scurvy. Herbal medicine continued to gain even greater respect in the late 1700s, as exemplified by English physician Withering’s classic description of digitalis. However, mercury, bleeding, and purging were still the ”standard” medical treatments, epitomized by George Washington’s death from complicationsincurred during treatment of a sore throat (i.e., he was bled to death).

The Thomsonian and Eclectic Movements During the early 1800~~ standard medicine may have been ready to reconsider traditional herbal remedies, but then came the Thomsonian movement. Samuel Thomson (1769-1843) patented a system of herbal medicine that, in 1839, claimed more than 3 million faithful followers. Although Thomson brought back to medicine the vitalistic Hippocratic idea of vis medicutrix nuturue and gained widespread public support for the use of herbal medicine, the Thomsonian movement was probably detrimental to medical reform. Thomsonians became locked in prejudice and dogma and insisted that all medical knowledge was complete and could be found in Thomson’s works. These and other claims roused scom, indignation, rage, and resentment in the average North American doctor. Frequently based on purging through the use of herbal emetics, Thomson’s treatments often were as harsh as the standard treatments of the times (for further discussion, see Chapter 4). During the 1800s, the Eclectic movement attempted to bridge the gaps between standard medical thought, Thomsonianism, and traditional herbal medicines. Rather than attack the existing medical system, the Eclectic movement sought to bring about reform by educating physicians about the use of herbal medicines. Several Eclectic medical collegeswere established and, for a while, it appeared that the Eclectic movement was making headway in its attempt to reform the medical system from within. The movement eventually failed, however. Several factors were probably responsible for this: a split in the ranks, which diluted the movement; harsh measures like mercury, calomel, and bloodletting were finally discarded by the conventional professional physician due to a decrease in infectious disease as a result of improved sanitation and hygiene; and, perhaps most important, the failure to establish and sustain quality medical schools. The Flexner report on medical education in 1910 spelled doom for the eclectics: By 1920, seven of the eight schools that existed before the report had closed, with the last school closing in 1938. Meanwhile, the standard medical schools, aided by the Rockefeller Foundation, flourished, promoting the growth of the modem pharmaceutic industry and the current near-monopoly of the medical profession.

The Growth of the Pharmaceutic Industry Because a plant cannot be patented, little research was done before the latter part of the twentieth century. Instead, pharmaceutic firms and researchers screened plants for biologic activity and then the so-called active constituents were isolated and chemically modified to produce unique, patentable compounds. Much to the

dismay of the researchers was the discovery that in many instances the isolated constituents were less biologically active than the crude herb. Because the crude herb provided no economic reward to the American pharmaceutic firm,the crude herb or extract never reached the marketplace. In contrast, European policies on herbal medicines made it economically feasible for companies to research and develop phytopharmaceutics. The policies in the United States contributed to the tremendous growth of the pharmaceutic industry and loss of appreciation and respect for herbal medicine. The herbal industry further compounded the problem by failing to provide quality herbal products or take advantage of technologic advances that allowed for standardization of chemical constituents. The herb that best exemplifies the failure to adopt standardization techniques is digitalis. One batch of crude digitalis might have a low level of active constituents, making the crude herb ineffective, while the next batch might be unusually high in active constituents, resulting in toxicity or even death, when standard amounts are used. The lack of standardization made it easier for US. pharmaceutic firms to rationalize their economic need to isolate, punfy, and chemically modify the active constituents of digitalis so they could market these compounds as drugs. The problem with using the pure active constituent is that the safe dosage range is smaller: Digitalis toxicity and death have increased dramatically as a result of purification. Toxicity was less of a factor when using the crude herb because overconsumption of potentially toxic doses resulted in vomiting or diarrhea, thus avoiding the severe heart disturbance and death that now occur with pure digitalis cardiac glycoside drugs. Fortunately, several European and Asian pharmaceutic firms began specializing in phytopharmaceutics in the latter half of the twentieth century. These companies have played a prominent role in researching, developing, and promoting herbal medicines. Research is demonstrating that crude extracts often have greater therapeutic benefit than the isolated ”active” constituent. This has been long known in other parts of the world, but in this country isolated plant drugs are still thought of as having the greatest therapeutic effect. This myth is gradually being eroded as our knowledge of herbal medicines increases. If current standardization techniques had been available earlier in this century, it is possible that the majority of our current prescription drugs would be herbal extracts instead of isolated and modified active constituents or synthetic chemicals.

HERBAL PREPARATIONS The clinical application of botanical medicine involves the use of various herbal preparations. That being the

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case, it is imperative that practitioners and physicians using herbal medicines understand the differences among the various forms. Commercial herbal preparations are as whole fresh and dried herbs, teas, tinctures, fluid extracts, and tablets or capsules. In addition, juices, purified compounds, and specific fractions of plants (e.g., volatile oil preparations) can also be considered herbal medicines. Each form has advantages and disadvantages and varying ways of expressing its medicinal strength. Any form may be an effective medicine as long as it can deliver an effective dosage of active compounds. The following section reviews the major extraction forms, discusses the benefits of standardized botanical extracts, and emphasizes the importance of delivering a clinically effective level of active compounds regardless of the form of the herbal preparation.

Extracts Extracts Defined An extract is a concentrated form of an herb obtained by mixing the crude herb with an appropriate solvent (such as alcohol or water, or both). A major advance in the herb industry has been the improvement in extraction and concentration processes. When an herbal tea bag is steeped in hot water, it is ~ actually a type of herbal extract known as a i infusion. The water is serving as a solvent in removing some of the medicinal properties from the herb. Teas are often better sources of bioavailable compounds than powdered herbs but are relatively weak in action compared with tinctures, fluid extracts, and solid extracts. These forms are commonly used by the lay public and herbal practitioners for medicinal effects. Tinctures are typically made using an alcohol and water mixture as the solvent. The herb is soaked in the solvent for a specified amount of time, depending on the herb. This soaking is usually from several hours to days; however, some herbs may be soaked for much longer periods of time. The solution is then pressed out, yielding the tincture. Fluid extracts are similar to, but more concentrated than, tinctures. Although they are most often made from hydroalcoholic mixtures, other solvents may be used (e.g., vinegar, glycerin, propylene glycol). Commercial fluid extracts are usually made by distilling off some of the alcohol, typically by using methods that do not require elevated temperatures, such as vacuum distillation and counter-current filtration. However, some small manufacturers produce fluid extracts in a similar manner to tinctures via percolation at room temperature. A solid extract is produced by further concentrationof the extract by the mechanisms described earlier for fluid extracts, as well as by other techniques such as thin-layer evaporation. The solvent is completely removed, leaving a viscous extract (soft solid extract) or a dry solid extract

Modern Perspective

depending on the plant, portion of the plant, solvent and drying process (if any) used. The dry solid extract, if not already in powdered form, can be ground into coarse granules or a fine powder. A solid extract also can be diluted with alcohol and water to form a fluid extract or tincture.

Strengths of Extracts The potencies or strengths of herbal extracts are generally expressed in two ways. If they contain known active principles, their strengths are commonly expressed in terms of the content of these active principles. Otherwise, the strength is expressed in terms of their concentration. For example, tinctures are typically made at a 1:5 to 1:lO concentration. This means one part of the herb (in grams) is soaked in five parts solvent (in milliliters of volume), meaning there is five times the amount of solvent (alcohol/water) in a tincture as there is herbal material. Fluid extracts are typically 1:l. A 4:l concentration means that one part of the extract is equivalent to, or derived from, four parts of the crude herb. This is the typical concentration of a solid extract. A quantity of 1g of a 41 extract is concentrated from 4 g of crude herb. Typically, 1g of a 41 solid extract is equivalent to 4 ml of a fluid extract and 20 to 40 ml of a tincture. Some solid extracts are concentrated as high as 100:1, meaning it would take nearly 100 g of crude herb, or 100 ml of a fluid extract, or 1 L of a tincture, to provide an equal amount of herbal material in 1 g of a 1OO:l extract.

Determining Quality Before the 198Os, the quality of the extract produced often was difficult to determine because many of the active principles of the herbs were unknown. However, advances in extraction processes, coupled with improved analytic methods, have reduced this problem of quality control.89The concentration method of expressing the strength of an extract does not accurately measure potency because there may be great variation among manufacturing techniques and raw materials. By using a high-quality herb (i.e., rich in active compounds), it is possible to have a more potent dried herb, tincture, or fluid extract compared with the solid extract that was made from a lowerquality herb. Standardization of herbal extracts for key active constituents has been suggested to be the solution to thisproblem.l0

Standardized Extracts: the Best Solution Standardized extracts (also referred to as guaranteed potency extracts) refer to an extract guaranteed to contain a "standardized" level of active compounds or key chemical marker. Stating the content of active compounds or key chemical marker rather than the concentration ratio allows for more accurate dosages to be made.

Therapeutic Modalities However, the complex composition of an herbal medicine makes it unwise to ignore the other constituents. The best scenario for determining the quality of an herb is the level of active components or key biologic markers, along with taking into consideration the complete chemical profile. Regardless of the herb's form, it should be analyzed to ensure that it contains these components at an acceptable standardized level. More accurate dosages can then be given. This form of standardization has emerged as the preferred method, but it is not without its shortcoming. Chief among them is that assigning too much importance to individual components rather than the entire chemical profile has led to the assumption that controlling for the level of marker compounds is equivalent to controlling the entire pharmacologic effect of the herbal medicine. However, stating the content of active constituents versus drug concentration ratio does allow for more accurate dosages to be based on active constituents and provides the greatest degree of consistency and assurance of quality, especially if attention is also given to the other constituents. Although referred to in terms of active constituents, it must be kept in mind that these are still whole extracts and not isolated constituents. For example, an Uvu ursi extract standardized for its arbutin content, say lo%, still contains all of the synergistic factors that enhance the active ingredient's function.

Techniques Used in the Production of Herbal Products A tremendous range of sophistication exists in processing herbs, from crude herb to highly concentrated standardized extracts. Nonetheless, there are some common stages. Following are some of the processes in the production of herbal products and the machines that perform the fUnctions.'O

Collectioflarvesting When plants are collected from their natural habitat, they are said to be "wild-crafted." When they are grown using commercial farming techniques, they are said to be "cultivated." Collection of plants from cultivated sources ensures that the plant collected is the one that is desired. When an herb is wild-crafted, there is a greater chance of picking the wrong herb and of variation in potency. However, some herbal practitioners believe that wildcrafted herbs are inherently superior because growth in their natural habitat produces an herb with constituents and properties more consistent with traditional use. The use of analytic techniques can be employed to guarantee that the plant collected is the one desired and that its concentrations of medicinal constituents are within an acceptable range. In the U.S. marketplace, herbs from all over the world are marketed. Herb collectors vary from uneducated

natives to self-proclaimed "herbalists" to trained botanists. The mode of harvesting varies from hand labor to sophisticated equipment. The mode is not as important as the time of year. A plant should be harvested when the part of the plant being used contains the highest possible level of active compounds. Again, this is ensured by the use of analytic techniques.

Drying After harvesting, most herbs have a moisture content of 60% to 80% and cannot be stored without drying. Otherwise, important compounds would break down or microorganisms would contaminate the material, or both. As many of the desired compounds are heat labile, the majority of herbs require relatively mild conditions for drying. Commercially, most plants are dried within a temperature range of 100" F to 140" F. During drying, the plant constituents must not be damaged or suffer losses that would prevent them from conforming to accepted standards. With proper drying, the herb's moisture content is reduced to less than 14%.

Garbling Garbling refers to separation of the portion of the plant to be used from other parts of the plant, dirt, and other extraneous matter. This step is often done during collection. Although there are machines that perform garbling, garbling is usually performed by hand.

Grinding Grinding or mincing an herb means mechanically breaking down either leaves, roots, seeds, or other parts of a plant into small pieces ranging from larger course fragments to fine powder. Grinding is employed in the production of crude herbal products, as well as in the initial phases of extracts. Often the material must be prechopped or minced before feeding it into a grinder. In the process of grinding, a number of machines can be used, but the most widely used is the hammer mill. These machines are simple in design. The hammers, arranged radially, follow the rotation of the shaft to which they are attached, breaking up the material that is fed into the machine from above. On the walls of the chamber is a grid, which determines the size of the material that is passed through it. Other types of grinders include knife mills and teeth mills.

Extraction The process of extraction is used in making tinctures, fluid extracts, and solid extracts. Extraction in the context of this textbook refers to separating by physical or chemical means the desired material from a plant with the aid of a solvent. In the U.S. health food industry, most extracts use alcohol and water mixtures as solvents

Botanical Medicine-A

to remove soluble compounds from the herb. The exceptions are liposterolic extracts, which are produced either through the use of lipophilic solvents or with the aid of hypercritical carbon dioxide (C02 gas compressed to a liquid by high pressures). Most extracts that are produced by small manufacturers use maceration procedures. The simplest process consists of soaking the herb in the alcohol/water solution for a period of time and then filtering it. For many botanicals this process yields a lower quantity of active constituents at a higher price because of the cost of the solvent. Because tinctures are 1:5 concentrates, 80% of the bottle is alcohol and water and only 20% is herbal material. In essence, the cost of the alcohol is a major portion of the retail price of tinctures. Larger manufacturers use more elaborate techniques to ensure that the herb is fully extracted and the solvent is reused. For example, counter-current extraction is often used. In this process, the herb enters the column of a large percolator composed of several columns. The material to be extracted is pumped through the different columns at a specific temperature and flow speed, where it continuously mixes with solvent. The extract-rich solvent then passes into another column, while fresh solvent once again comes into contact with herbal material as it is passed into a new chamber. In this process, complete extraction of health-promoting compounds can be performed. The extract-rich solvent is then concentrated by the following techniques.

Concentration After extraction of the herb, the resulting solutions can be concentrated into fluid extracts or solid extracts. In large manufacturing operations, techniques and machines such as thin-layer evaporators are used to ensure that the extracted plant components are not damaged. These machines work by evaporating the solvent and leaving the plant compounds. The solvent vapors pass into a condenser whereby they return to a liquid and for reuse. The result is separation of the extracted materials from the solvent so that the final product is a pure extract and the solvent can be used again and again.

Drying of Extracts Many practitioners prefer the extract dried to a solid form because it is more chemically stable and lower in cost (alcohol is often more expensive than the herb). In addition, tinctures and fluid and soft extracts can more easily be contaminated by bacteria and other microorganisms. Liquid forms of extracts also promote reactions that eventually break down some active constituents. A number of drying techniques are employed, including freeze-drying and spray-drying (atomization).The result is a dried powdered extract that can then be put into capsules or tablets.

Modern Perspective

Excipients The same excipients used in the manufacture of drug preparations and vitamin and mineral supplements are often used in the production of tablets and capsules containing herbs or herbal extracts. Many manufacturers provide a list of excipients contained in their products.

ANALYTIC METHODS Improvements in analytic methods have definitely led to improvements in harvesting schedules, cultivation techniques, storage, stability and concentration of active compounds, and product purity. All of these gains have resulted in tremendous improvements in the quality of herbal preparations now available. Methods currently used in evaluating herbs and their extracts include the following: Organoleptic Microscopic Physical Chemical/physical Biological

Organoleptic Orgunoleptic means the ”impression of the organs.” Organoleptic analysis involves the application of sight, smell, taste, touch, and occasionally even sound to identdy the plant. Typically, the initial sight of the plant or extract is so specific it is easily recognized. If this is not enough, perhaps the plant or extract has a characteristic odor or taste. Organoleptic analysis represents the simplest, yet the most human, form of analysis.

Microscopic Evaluation Microscopic evaluation is indispensable in the initial identification of herbs, as well as in identifying small fragments of crude or powdered herbs. It is also important in the detection of contaminants and adulterants (e.g., insects, animal feces, mold, fungi). Every plant possesses a characteristic tissue structure, which can be demonstrated through study of tissue arrangement, cell walls, and configuration when properly mounted in stain reagents and media.

PhysicaVChemical Analysis In crude plant evaluation, physical methods often are used to determine the solubility, specific gravity, melting point, water content, degree of fiber elasticity, and other physical characteristics. Various chemical/physical methods also are used to determine the percentage of active principles, alkaloids, flavonoids, enzymes, vitamins, essential oils, fats, carbohydrates, protein, ash, acid-insoluble ash, or crude fiber present.

Chromatography The most sophisticated analytic processes involve more highly technologic assays to determine quality. Advanced techniques such as thin-layer chromatography, highpressure liquid chromatography (HPLC), capillary electrophoresis, and nuclear magnetic resonance (NMR) are used to precisely separate, idenhfy, and quanbfy molecules. The readings from these machines provide a chemical “fingerprint” as to the nature of chemicals contained in the plant or extract.” These techniques are invaluable in the effort to idenhfy herbs, as well as standardize extracts.

Biologic Analysis The plant or extract can also be evaluated by various biologic methods, mostly in vitro or animal tests, to determine pharmacologic activity, potency, and toxicity.

1. Selection of suitable plant material 2. Botanical investigationusing organoleptic and microscopic techniques 3. Chemical analysis using appropriate laboratory equipment 4. Screening for biologic activity 5. Analysis of active fractions of crude extracts 6. Isolation of active principles 7. Determinationof chemical structure of active principles 8. Comparison with compounds of similar structure 9. Analytic method developed for formulation 10. Detailed pharmacologic evaluation 11. Studies performed to determine activity and toxicity of formulation 12. Studies on absorption, distribution, and elimination of herbal compounds 13. Clinical trials performed to determine activity in humans

QUALITY CONTROL IN HERBAL PRODUCTS Quality control refers to processes involved in maintaining the quality or validity of a product. Regardless of the form of herbal preparation, some degree of quality control should exist. Without quality control, there is no assurance that the herb contained in the bottle is the same as what is stated on the outside. One of the key solutions to the quality control problem that exists in the United States is for manufacturers and suppliers of herbal products to adhere to quality control standards and good manufacturing practices. With improvements in the identification of plants by laboratory analysis, consumers should at least be guaranteed that the right plant is being used. Consumers, health food stores, pharmacists, herbalists, and physicians who use or sell herbal products should ask for information from the suppliers of herbal products on their quality control process. What do they do to guarantee the validity of their product? As more consumers, retailers, and professionals begin demanding quality control from the suppliers, manufacturers will use more quality control processes. Currently, only a few manufacturers adhere to complete quality control and good manufacturing practices. Companies supplying standardized extracts currently offer the greatest degree of quality control; hence these products typically offer the highest quality. The production of standardized extracts seeking registration in Europe may serve as a model for quality control processes for all forms of herbal preparations (Box 35-1). In general, it is believed that if the active components of a particular herb are known, whatever the form of the herb product, the herb should be analyzed to ensure that it contains these components at a medicinally appropriate

level. More accurate dosages can then be given. Products should also be subjected to bacteriologic counts and be free of contaminants.

The Issue of “Phytoequivalence” It is often difficult to translate the effectiveness of a particular form of an herbal product to another form. For example, how many milk thistle (SiZyburn marianurn) seeds are required to produce the same effects as those demonstrated in clinical studies conducted on milk thistle extracts standardized to contain 70% silymarin? Or does an extract of St. John’s wort that is standardized to contain 0.3% hypericin and 3% to 5% hyperforin, but whose remaining chemical profile is substantially different from the clinically proven St. John’swort, produce the same benefits? The real answers to these questions require investigations into phytoequivalence and pharmacokinetics. The concept of phytoequivalence dictates that if a particular extract has demonstrated certain clinical results, a second extract can only be considered as being equivalent if it possesses the same chemical profile as the first extract. This definition of phytoequivalence requires that not just the level of marker compounds or key active constituents, or both, be the same, but that the extracts be identical in the complete spectrum and quantity of all constituents. However, assuring identical chemical equivalence may not assure true therapeutic equivalence if pharmacokinetic factors are not taken into consideration regarding how the herbal medicine is delivered. In fact, true phytoequivalence may not be related to having identical extracts but rather to being able to produce the same pharmacokinetic pattern.

Botanical Medicine-A

Standardized Extracts versus Tinctures Several misconceptions regarding standardized extracts need to be addressed. One is that standardizing an extract results in the loss of important compounds. This is simply not true for the vast majority of standardized extracts. Chemical analysis of standardized extracts and tinctures, whether it be thin-layer chromatography or HPLC, has clearly demonstrated that standardized extracts are not only higher in active compounds but also have a broader range of chemical constituents due to more effective extraction. Another common misconception is that they are more expensive than alcohol-based tinctures and fluid extracts. Calculations based on the cost of delivery of an effective dosage show that the standardized extract is sigruficantly more cost effective.This is because, as noted earlier, there is less of the herb in tinctures and fluid extracts, resulting in consumers paying extra for alcohol, bottle, and the cost of shipping.

FINAL COMMENTS The effectiveness of any herb or herbal product from a pharmacologic perspective is dependent on providing an effective dosage of active compounds. Regardless of the form of the herbal preparation, clinical effectiveness requires delivery of an active dosage. At this time, standardization or accurate analysis of the content of active constituents or key biologic markers is the only real assurance of the delivery of an effective dosage. This view should not be controversial. Unfortunately, controversy arises from the fact that from a pharmacologic perspective it is unlikely that the dosage schedules historically recommended for most herbal tinctures are sufficient to produce significant pharmacologic effects. Although tinctures of such potentially toxic herbs as Gelsemium, aconite, belladonna, and digitalis often produce a pharmacologic effect when given at low dosages, for most common medicinal herbs it is difficult to produce an adequate and cost-effective response when the herb is administered in tincture form. The administration of small dosages of herbs in tincture form is an offshoot of the homeopathic and eclectic use of ”mother tinctures” and “specific medicines.” The effectiveness of these preparations and their ability to exert pharmacologic effects has not been proved for all but a few botanicals.

Modern Perspective

The questioning of the clinical effectiveness of herbal tinctures by science-based or evidence-based naturopathic physicians is often viewed as heretical and sacrilegious by many professing to be ”master herbalists.” The opinion of the editors of this textbook is that if a natural medicine, whether it is a tincture, standardized extract, or nutrient, is truly clinically effective, it should be able to stand up to scientific scrutiny and rationale. The systems of herbal medicine that have been proved to a large extent are based on delivering much higher levels of herbal compounds than those easily obtained via the use of tinctures. Specifically, we are referring to the use of highly concentrated standardized extracts from Europe and the use of herbal preparations in traditional Chinese Medicine and Ayurveda. In traditional Chinese Medicine, the typical daily dosage of prescribed crude herbal material is approximately 20 g. This high level of dosage is in stark contrast to a much smaller average amount of the herbal material recommended in the British Hmbul Pharmacopoeia of 2 to 4 ml of a 1:5 tincture, which provides less than 1 g of herbal material. This difference in dosage may explain the differences in popularity of herbal medicine in China, Japan, India, and Germany compared with its relative obscurity in England, as well as in the United States before the previous decade. The key point is that herbal medicine is not going to be popular if it is not effective. It can be argued that the greater the effectiveness, the greater the popularity. The tremendous growth noted in the United States since the mid-1980s is, in our opinion, the result of the influx of high-quality standardized extracts into the marketplace. Developments in cultivation, extraction, and concentration processes led to the successful commercial development of these herbal products. Better clinical results were achieved with these herbal medicines because they were able to deliver an effective dosage of active constituents. Although the future looks extremely promising for herbal medicine, ultimately its growth and continued success will be determined by the following: Continued scientific investigation and clinical research Adoption by manufacturers of recognized standards of quality Governmental regulations that allow meaningful therapeutic claims

Therapeutic Modalities

1.De Smet PA. The role of plant-derived drugs and herbal medicines in healthcare. Drugs 1997;54:801-840. 2. Mahady GB. Global harmonization of herbal health claims. J Nutr 2001;131(suppl3):112OS1123S. 3. Keller K. Legal requkments for the use of phytopharmaceutical drugs in the Federal Republic of Germany. J Ethnopharmacol 199132225-229. 4. Thiede HM, Walper A. Inhibition of M A 0 and C O W by H y p e r i m extracts and hypericin. J Geriatr Psychiatry N e w 1 1994;7554-56. 5.Perovic S, Muller WEG. Pharmacological profile of H y p e r i m extract. Effect of serotonin uptake by postsynaptic receptors. Arzneim Forsch 1995;451145-1148. 6. Butterweck V. Mechanism of action of St. John's wort in depression: what is h o r n ?CNS Drugs 2003;17539-562.

7. Griggs B. Green pharmacy. A history of herbal medicine. London: Robert Hale, 1981. 8.Bonati A. Formulation of plant extracts into dosage forms. In Wijeskera ROB, ed. The medicinal plant industry. Ekxa Raton, FL: CRC P-s, 1991:107-114. 9.Karlsen J. Quality control and instrumental analysis of plant extracts. In Wijeskera ROB, ed. The medicinal plant industry. Boca Raton, n:CRC Press, 19919-106. 10. B o ~ t A. i How and why should we standardize phytopharmical drugs for clinical validation? J Ethnopharmacol1991;32:195-197. 11. Gong F, Liang YZ, Xie FS, Chau l T.Information theory applied to chromatographicfingerprint of herbal medicine for quality control. J Chromatogr A 2003;10022540.

Environmental Medicine Walter J. Crinnion, ND CHAPTER CONTENTS Introduction 339 Environmental Toxic Load 339 Prevalence of Environmental Toxins in Humans 339 Sources of EnvironmentalToxins 340 Health Effects of Environmental Toxins 341 lmmunotoxicity 341 Autoimmune Disease 342 Toxin-Associated Cancers 342 Neurotoxicity 344 Endocrinotoxicity 345

INTRODUCTION The twentieth century, with its promise of "better living through chemistry," has also brought a host of chemical toxin-related illnesses (referred to here as "environmental illnesses"). Recent articles in medical literature have shown that the rate of cancers not associated with smoking is higher for those born after 1940 than before and that this increase of cancer is due to environmental factors not related to smoking.' People are also experiencing the new medical diagnoses of sick (closed) building and multiple chemical sensitivity (MCS),& both of which are known to be related to overexposure to environmental contaminants. The environmental toxins that cause the most problems are pesticides, solvents, and heavy metals. The primary damage caused by the solvents and major pesticide classes is to disrupt neurologic functi~n."~ In addition to being neurotoxic, these compounds are profoundly immunotoxic and are often toxic to the endocrine system as well?-'* The adverse health effects are not limited to those systems only, as these compounds can also cause various dermatologic, gastrointestinal, genitourinary, respiratory, musculoskeletal, and cardiological problems. Heavy metals poison a diverse range of enzyme functions, affecting virtually every system of the body?

Diagnosis 346 History 346 Laboratory 346 Treatment 347 Avoidance 347 Nutritional Support 347 Botanical Medicines 349 Depuration (Cleansing) 349 Summary 351 Treatment Overview 351

ENVIRONMENTALTOXIC LOAD Prevalence of Environmental Toxins in Humans The environment is currently flooded with chemicals that contaminate the air, water, food, and humans. Since 1976 the Environmental Protection Agency (EPA) has been engaged in the National Human Adipose Tissue Survey (NHATS).'3In this study, adipose samples are taken from cadavers and elective surgeries from all regions of the country and the levels of toxins are measured. In 1982 the EPA expanded beyond its original list to look for the presence of 54 different environmental chemical toxins. The results are a cause for great concern. Five of the chemicals-octachlorodibenzop-dioxin (OCDD); styrene; 1,4dichlorobenzene; xylene; and ethylphenol-were found in 100% of all samples. Another nine chemicals-benzene, toluene, chlorobenzene, ethylbenzene, dichlorodiphenyldicholoroethylene (DDE),+ three dioxins, and one furan-were found in 91% to 98% of all samples. In addition, polychlorinated biphenyl (PCB) was found in 83% of all samples and beta-benzene hexachloride (BHC) in 87%. A total of 20 toxic compounds were found in 76% or more of all

'Proper use of half life is tlR.

339

Therapeutic Modalities

Sources of EnvironmentalToxins samples! These ongoing assessments have shown quite This multiple chemical load is due to several decades of clearly that it is not a question of if humans are carrying chemical exposure from contaminated air, food, and a burden of toxic xenobiotic compounds, but one of how water. Both outdoor and indoor air is contaminated with much and how it affects public health. chemicals. The EPA’s TEAM (total exposure assessment Additional studies have shown the same alarming methodology) study has documented the following facts. A Centers for Disease Control and Prevention (CDC) chemicals as ’ubiquitous’ in the air study of 5994 persons aged 12 to 74 found that 99.5%had p,p-DDE at levels in the range of 1to 379 ppb.14A study p-Xylene of adipose levels of chemicals in persons from Texas Tetrachloroethylene showed the presence of p,p-DDE, dieldrin, oxychlorEthylbenzene dane, heptachlor epoxide, and para-BHC in 100%of all Benzene sample^.'^ That study was done on adipose samples 1,1,1-Trichloroethane taken from autopsies and was from older subjects. A o-Xylene study of 4year-olds in Michigan showed the presence of Listed as ”often present” were the following2*: DDT in more than 70%, PCB in 50%, and polybrominated biphenyl (PBB) in 13% to 21%.16Nursing was the Chloroform primary source of exposure for these children. Carbon tetrachloride Interestingly, four different phthalate compounds Styrene were found in adipose samples from the NHAE study: p-Dichlorobenzene diethyl phthalate (42%), di-n-butyl phthalate (a%), This study found that air samples taken with a perbutylbenzyl phthalate (69%), and di-n-octyl phthalate sonal monitor attached to the study individuals showed (31%).More recently these plasticizers have been found higher levels of Chemicals in the ”personal” air space to be ubiquitous in the urine of U.S. residents. Samples taken from 289 participants of the NHANES 111 over a 24hour period than in outdoor air samples. These elevated personal levels and elevated breath levels were study revealed two phthalates in all samples tested (monobenzyl [MBzP] and monobutyl phthalates [MBP]). more directly attributable to indoor air pollution. However, they did note that persons who visited a service Monoethyl phthalate (MEP) and monoethylhexyl phthalate (MEHP) were both found in more than 75% of the station or a dry cleaner had elevated personal breath levels samples as well.” The levels of MEP in particular were of the solvents, as well as those who smoked and drove quite elevated in the study, having the highest mean a vehicle during the day. They also found that certain average of all phthalates at 176.0 pg/L. Elevated serum occupations, such as chemical manufacturing, painting, levels of several phthalates and the metabolite MEHP and plastic manufacturing, caused higher levels of have been found elevated in the serum of young girls exposure. Testing for chemical residues on food has been (aged 6 months to 8 years of age) who have premature breast development.l routinely employed throughout the world. None of the studies has found food sources free of contamination.On In the recent CDC report on environmental chemicals the contrary, multiple contaminants are usually found. in humans, the metals cadmium, cesium, cobalt, lead, The most comprehensivefor the United States is the ongomercury, and thallium were present in virtually all ing Food and Drug Administration’s Total Diet Survey.” sample^.'^ These samples were taken from people who Although the Total Diet Survey looked for the presence were ”generally healthy” and who had no known expoof many different chemicals, the findings for chlorinated sure to the chemicals beyond the general environment. pesticides, listed in Table 36-1, are alarming. For example, One piece of good news in this report was that the mean blood lead level for children (1 to 5 years old) dropped DDE was found in 63% or more of the 42 foods sampled. Foods with the highest concentrations of DDE were as from 2.7 pg/dl from 1991-1994 to 2. They also showed a follows: decrease in cotinine levels of approximately 75% for the same time frame. Fresh or frozen spinach (mean concentration, 0.0234 The load of xenobiotics in the typical U.S. resident PPm) expanded sigruficantly with the release of a nine-person Butter (mean concentration, 0.0195 ppm) study in February 2003.2O The serum of this small group Collards (0.0126 ppm) was tested for the presence of 210 xenobiotic comPork sausage (0.0124 ppm) pounds, of which 167 were found. The average number Lamb chops (0.0113ppm) of compounds found in each person was 91. This study Canned spinach (0.0109 ppm) tested for more compounds in each individual than any Because DDT and DDE were banned in the United previous study and in so doing showed the possibility that States in 1972, it is likely that some of this contamination humans carry a greater burden than previously thought.

Environmental Medicine

Presence of DDT in U.S. food samples

Food Raisins, spinach (fresh and frozen), chili con came (beef and bean), beef American processed cheese, hamburger, hot dogs, bologna, collards, chicken, turkey, ice cream

Percentage of samples contaminated 100

93

Lamb chops, salami, canned spinach, meatloaf, butter

87

Cheddar cheese, pork sausage, pounders, white sauce, creamed spinach

81

DDE is formed by a partial dechlorination of DDT. This can m u r in the human body within 6 mo of exposure to DDT. It also occurs in nature, but studies vary as to the half-life (tm) of DDT in nature. Previously, the half-life of DDT was thought to be 2 years, but recent findings in Yakima, WA, indicate that it may be decades in certain circumstances. On degradation the DDT becomes DDE or DDD.

is from produce imported from other countries where it is still used. Unfortunately, since toxic chemicals are ubiquitously used throughout the world, they move easily around the globe on the winds. Unless these pesticides are trapped in the soil, tree bark, or other stable materials, persistent volatile pesticides including DDT and toxaphene begin a wind-driven leapfrogging around the globe. The more volatile the chemical, the faster it hops and the less readily it enters the fat of any plant or animal it contacts. Volatile chemicals applied in tropical regions evaporate into the atmosphere and then condense in cooler climates. As the ambient temperature falls, the compound becomes less volatile, so the periods between hopping of a compound from one place to another tend to lengthen. For example, if two forests were exposed to identical amounts of a volatile pesticide, trees in the colder climate would become more heavily contaminated. DDT and DDE are less volatile than solvents and do not leapfrog as well, so they tend to stay where they land and may be there for a year before jumping again. This global leapfrogging can account for one alarming study of the diet of Arctic indigenous women. The diet of two groups of women (from the Eastern and Western Canadian Arctic) were found to be high in organochlorine compounds (OCC). The primary sources of these compounds were the meat and blubber of ringed seal, walrus, mattak, and narwhal, as well as caribou, whitefish, inconnu, trout, and duck.= Because these OCCs were transported in the air, they landed in the Arctic, but due to the low temperature were unable to volatilize again and leapfrog away.

HEALTH EFFECTS OF ENVIRONMENTALTOXINS Although there is virtually no debate left about whether our world is polluted or not, there is a considerable amount of debate as to whether these environmental toxins are at high enough levels to cause adverse health effects in humans. This chapter provides information that supports the concept that accumulation of recurrent low-level exposures to environmental toxins is damaging to health. Enough evidence of a positive association between chemical exposureand disease exists to document that a serious problem exists and that caution is urged. An article published in the Journal of the American Medical Asociafion in 1994 by Devra Lee Davis and c0lleagues,2~ entitled "Decreasing Cardiovascular Disease and Increasing Cancer among Whites in the United States from 1973 through 1987, Good News and Bad News," showed that although heart disease was declining, cancer mortality for men and women born after 1940 was much higher than for previous generations. These cancers were not linked to smoking but were relegated to other environmental factors. For men the rate of cancer was 200% of that of previous generations, and for women the rate was 50% higher. Not only are cancer rates rising, but there is currently an alarming rise in the incidence of asthma, especially among children throughout the world. These incidents appear to be associated with ambient pollution levels. Much has also been said about the estrogenic effect of certain environmental chemicals and the devastating effect upon wildlife, and possibly humans as well. Therefore much evidence indicates that several chronic health problems appear to be related to environmental chemicals.For the purpose of this chapter, the discussion is confined to the known immunotoxic, neurotoxic, and endocrinotoxic effects of these environmental chemicals.

lmmunotoxicity Environmental chemicals have a wide range of damaging effects on the function of the immune system. These range from decreased cell-mediated immunity (with a decrease in infection and tumor fighting) to increased sensitivity (allergy) and increased autoimmunity.&*'

Organochlorine Compounds Among the OCCs, DDT has been found to have many damaging effects on the immune system: Reduced killing capacity of polymorphonuclear leukocytes Reduced number of plasma responder cells Increased degranulation of mast cells Leukopenia Decreased phagocytic ability Changes in the spleen, thymus, and lymph glands

Therapeutic Modalities

Similar effects have also been found after exposure to hexachlorobenzene (HCB) and the chlordanes (also OCCS).~HCBis a chlorinated pesticide used as a fungicide. It is also present in chlorinated solvents such as perchloroethylene, which is used in dry cleaning and is elevated in individuals from Western Europe. Chlordanes were primarily used as termiticides in the United States and Canada until 1978, when they were banned from use in the home. They are still used on certain crops and in some seed treatments. Studies of thousands of patients at the Environmental Health Center (EHC) in Dallas have shown that persons with two or more OCCs present in their serum have some form of immunotoxicity.28

massive PBB spill occurred from 1973-1974. During that time, a PBB-containingflame retardant called "Firemaster" was inadvertently sold as an animal feed called "Nutrimaster." This mistake was devastating to both the livestock and those who raised them and consumed their products. Exposed individuals were found to have lower levels of circulating T lymphocytes and reduced lymphoproliferation response, resulting in reduced cellmediated immunity (CMI). They also had a high prevalence of persistent skin, neurologic, and musculoskeletal These changes have persisted in all subsequent studies. This seems to indicate that when these toxins are concentrated in the food chain before reaching humans, their effect is longer lasting. (For a good review of numerous studies on the immunotoxicity of pesticides, I recommend reading Repetto and B a l i g a ' ~publication.) ~~

Polycyclic Aromatic Hydrocarbons

Autoimmune Disease

The chemicals produced by combustion, the polycyclic aromatic hydrocarbons (PAHs), have been shown to have similar inhibiting effects on the immune system, including the following29:

The development of autoimmunity has been linked with chemical exposure as well. The notion of chemically induced autoimmune states is, of course, not new because many chemicals are known to induce the onset of SLE. Some chemicals, like formaldehyde and other volatile organic compounds, are thought to induce tissue-specific autoimmune reactions by acting as haptens. These low-molecular-weight molecules bind to various tissues in the body, making a new antigenic combination. The immune system then makes an antibody to this new combination, which can attack the parent tissue with or without the chemicalsbeing present. Chemically exposed individuals often present with elevated antibodies to certain body tissues, including antimyelin, antiparietal, anti-brush border, and anti-smooth muscle.33 The abnormalities found in a study of 298 patients exposed to industrial chemicals are shown in Box 36-1.34

Variation in complement Disturbances in fetal and perinatal immune regulation

Decreased T cell-dependent antibody response Decreased splenic activity Diminished T-cell effector functions Suppression of T-cytotoxic induction Lower natural killer cell activity They are also highly carcinogenic.

Organophosphate Pesticides The organophosphate pesticides (OPs),which are not as biologically persistent as the OCCs, are also toxic to the immune system. They have been found to cause decreased percentages of CD4and CD5cells, increased number and percentages of CD26cells, increased incidence of atopy and antibiotic sensitivity, and high rates of autoimmunity. This elevation in autoimmunity is reflected by high levels of antibodies to smooth muscle, parietal cells, brush border, thyroid, myelin, and elevated antinuclear antibodies.30Similar immunosuppression is also found for the organotins and heavy metalsw The mode of exposure to the pesticide appears to have an effect on the persistence of immunotoxicity, as demonstrated by two PBB spills. One exposure took place in Taiwan when rice bran cooking oil was contaminated with PBBs. Those who used this oil for cooking were found to have immune abnormalities. One year after exposure, they were found to have decreased concentrations of IgM and IgA (with normal I@), low Tsuppresser cells, low B cells, and suppression of delayed hypersensitivity to recall antigens. When rechecked 2 years after exposure, the above indices had returned to normal. This was not the case in Michigan, where a

Toxin-Associated Cancers As mentioned earlier, the Davis and colleagues" study showed that men born in the 1940s had twice as many

Either very low activity or very high enzyme activity when compared with controls Lymphocyte blastogenic responses to T-cell mitogens (PHA, CONA) and B-cell mitogens were between 30% and 45% lower than controls Elevated IgG and IgM levels against formaldehyde, trimellitic anhydride, phthalic anhydride, and benzene ring (these rates were usually higher in persons with elevated T4n8 ratio, which was found in almost 15%of the exposed patients) Autoantibodies against their own tissue Modified from Vojdani A, Ghoneum M, Brautbar N. Toxicol Ind Health 1992; 81239-254.

Environmental Medicine cancers as those born in 1888-1897and more than twice as many cancers not linked to smoking. Women born in the 1940s had 50% more cancers and 30% more cancers not linked to smoking (whites). The following sections present a condensed version of the voluminous amount of information available in the literature associating cancers with environmental toxins.

Breast Cancer Multiple studies have examined the association of breast cancer with OCCs. Three studies have shown elevated levels of different OCCs in the adipose tissue of breast cancer patients as compared with controls. The chemicals found to be higher in the women with malignancies were DDT, DDE, PCBs, and HCH (hexachlorocyclohexane; also known as Lindune or BHC, this is a chlorinated pesticide that is still commonly used to treat lice infestations [Kwell Not only were they higher in the adipose tissue of breast cancer patients, but they were actually found in higher concentrations in the malignant tissue than in adjacent healthy ti~sue.3~ Studies looking at serum levels of OCCs in relation to breast cancer have given mixed results. Elevated levels of DDE and PCB in the serum were associated with a fourfold increased risk of breast cancer compared with normal risk in one well-known study.38Subsequent studies have mostly failed to confirm those data, with the most recent studies failing to find any association. I have found that individuals with breast cancer often have both higher serum levels and greater numbers of individual OCCs than other patients in my private practice.

Childhood Cancers Childhood cancers have also been evaluated for epidemiologic association with chemical exposure. In one study, 45 childhood brain cancer patients were compared with 85 friend controls. A significant positive association was found between brain cancer and exposure to no-pest strips, termite treatment, Kwell shampoo (Lindane), flea collars on pets, diazinon use in the garden or orchard, and the use of herbicides in yard (odds ratio [OR], 6.2). When compared with 108 controls, a signhcant positive association was found with pesticide bombs in the home; termite treatment; flea collars on pets; and the use of insecticide, carbaryl, and herbicide in the garden.39 Several other studies of childhood chemical exposures found the following associations: Chlorophenoxy acid herbicide (2,4-D, a common weed killer) use around the home associated with soft tissue sarcomas (OR, 4)40 No-pest strips in the home associated with leukemia (OR, 3) Insecticide use in the home associated with brain tumors for those younger than 20 years of age (OR, 2.3)

Household pesticide use associated with leukemia (OR 4) Garden pesticide use associated with leukemia (OR, 5.6) Household insecticide use associated with nonlymphocytic leukemia (OR, 3.5) 2,4-D gained notoriety from its combination with 2,4,5-T to form a mixture known as ”Agent Orange.” It is commonly used by municipalities and states to spray roadways and rights-of-way to keep weeds down. It can be purchased at home stores for home lawn care and is often applied by chemical lawn care companies. It contains several dioxin contaminates and, in my opinion, is quite toxic to animals, children, and adults. For adults, the use of 2,4-D has been strongly associated with an increased incidence of lung cancer, stomach cancer, leukemia, Hodgkin’s lymphoma (two studies found a fivefold increased risk), non-Hodgkin’s lymphomas (NHL, fivefold to sixfold increased risk), and soft tissue sarcomas (many studies have shown a fivefold to sevenfold increased risk, with one review study finding a fortyfold increased risk).41One study showed Kansas farmers having a sixfold increased risk of lymphomas and soft tissue sarcomas after using 2,4-D more than 20 days/ year compared with nonexposed individuals. Those who mixed and applied herbicides and were exposed more than 20 days/year were eight times as likely to contract NHL. Factors associated with increased risk of NHL from 2,4-D exposure are the following: Increased time period of exposure Not using protective equipment Using a backpack or hand sprayers Employing tractor-mounted or mist blower sprayer Applying herbicides aerially

Hematologic Malignancies Several studies have associated exposure to solvents with acute myelogenous leukemia (AML), multiple myeloma, and other forms of leukemia. A retrospective cohort study of 14,457 workers exposed to trichloroethylene between 1952 and 1953 showed that mortality was increased for multiple myeloma and NHL in white women.@In a Finnish study, workers exposed to l,l,ltrichloroethylene showed excess cancers of the cervix uteri and lymphohematopoietic tissues. After 10 years (from the first measurement), excess pancreatic cancer and NHL were seen. At a 20-year follow-up, excess multiple myeloma and cancer of the nervous system were found. Workers exposed to trichloroethylene showed (after a 20-year follow-up) an excess of cancers of the stomach, liver, prostate, and lymphohematopoietic tissues.43

Therapeutic Modalities A review article revealed 280 cases of aplastic anemia associated with pesticide exposure reported in the literature. The majority of these cases were in young people (average age 34)with a short latency (mean, 5 months) and who had a history of occupational exposure to pesticides.44Another study on the cancer risk for painters showed increased cancer rates for multiple myeloma (OR, 1.95), bladder tumors (OR, 1.52), and kidney and other mthelial tumors (OR, 1.45).45A study in Sweden of 275 confirmed diagnoses of multiple myeloma showed a clear association between farming and multiple myeloma. This study revealed that exposures to chlorophenoxy acid herbicides (2,4-D) and DDT were prime risk factors.%

Neurotoxicity The nervous system is a particularly sensitive target for toxic agents for several reasons, as listed in Box 36-2. Besides the nervous system being such a good target, powerful neurotoxic agents are available to attack it. Most of the major classes of pesticides kill pests by attacking their nervous system. They are neurotoxinsby design. The OCCs affect the nerve by disrupting the ion flow along the axon. The OPs, which came out of nerve gas research, and carbamates affect acetylcholinesterase, resulting in excessive acetylcholine levels in the synapses. Solvents, some of which were originally used as anesthetics, dampen the propagation and transmission of electrical impulses along the nerve axons. All of these agents produce various forms of toxic encephalopathy (either acute or chronic, selective or diffuse toxic encephalopathies), as neuronopathies, axonopathies, myelinopathies, or vasculopathies.

The adult neuron does not divide, and therefore replacement of lost neurons is not possible. Nerve cells killed by toxins cannot regenerate. The Mood-brain barrier does not block nonpolar substances or items that are actively transported. Since the normal function of the nervous system requires the action of a complex integrated network, damage to even a small portion of the nervous system can sometimes result in marked effects on function. Neurons depend on glucose and oxygen, and some cell bodies exist at borderline levels of 02.If highenergy demands are placed on the system and delivery of O2 is reduced, then cell death may occur. Because of high lipid content (myelin), there is an accumulation and storage of lipophilic xenobiotics. Neurons have high surface areas and therefore increased exposure to toxins.

Neuronopathies Neuronopathies can be diffuse or selective, depending on whether specificneurons are affected or if the damage is more broadly spread throughout the nervous system. The target site of toxic agents producing neuronopathies is the nerve cell body, with the consequence of either axonal or dendritic breakdown. An example of a neurotoxin causing diffuse neuronopathy is methylmercury, which preferentially damages the granule cells of layer 4 in the visual cortex, granule cells in the granular layer of the cerebellum, and the sensory neurons of the dorsal root ganglia.3l This brings about neuronal degeneration, progressing to necrosis with axonal dystrophy and demyelination. Another is aluminum, which causes fatal dialysis encephalopathy following 3 to 7 years of intermittent dialysis.Although brain aluminum levels were elevated, there was no evidence of neurofibrillary tangles in these patients, indicating that the presence of aluminum alone is insufficient to lead to the senile dementia of the Alzheimer’s type. The neuronopathies can also be selective, affecting only certain neurons. Examples of agents causing selective neuronopathies would include Adriamycin, which affects the dorsal root ganglia; cisplatin, which affects sensory neurons; and manganese (metal fume fever), which produces a Parkinson-like syndrome. Manganese-induced damage is found in the substantia nigra, globus pallidus, and caudate nucleus, with depletion of dopamine and serotonin levels. Symptoms begin with psychiatric changes followed by impaired motor activity with muscle rigidity and tremors. Parkinsonism is also caused by l-methyl4phenyl-l,2,3,6-tetrahydropyridine (MI”),a contaminant found in synthetic heroin.” Both of these compounds appear to damage the mitochondrial DNA throughout the central nervous system, specifically the substantia nigra pars compacta. MPTP has brought on sudden Parkinson-like symptoms rapidly after exposure to heroin. MI’” is metabolized in tissues containing the enzyme monoamine-oxidase (MAO) to WP+, “the ultimate neurotoxin to MAO-containing tissues,’’ which appears to be selectively toxic to substantia nigra cells effectively blocking dopamine

Axonopathies Axonopathies are differentiated by the area of the axon that is affected. The proximal axon is different in its ability to initiate action potentials and to synthesize protein. Damage to thispart of the axon is referred to as proximal uxonoputhy. This is the type of damage seen in amyotrophic lateral sclerosis (ALS). Proximal axonopathies are often caused by volatile organic compounds (e.g., halomethane, methylene chloride, carbon tetrachloride, butane), all of which decrease the excitability of the neuron by stabilizing membranes and decreasing ion flux.

Environmental Medicine Distal axonopathies are caused by various compounds including Acrylamide (a polymerking agent to strengthen paper), which primarily affects sensory fibers, and carbon disulfide (a solvent for fats and lacquers and for extraction of oil from olives, palmstones, and other oilbearing fruits), which produces distal axonopathy to both sensory and motor fibers. It also decreases norepinephrine levels. Hexacarbon solvents lead to multifocal distal progressive sensorimotor axonopathy with giant axonal swelling. Paranodal demyelination of swollen axons occurs frequently with exposure to these solvents. The group of compounds that causes distal axonopathies also includes the OPs (e.g., Parathion, malathion, diazinon) and the carbamates. OPs cause acetylcholinesterase enzymes to be phosphorylated. Exposures may be additive and the effects may last until more acetylcholineesterase is synthesized. Carbamates (carbaryl, aldicarb) cause the acetylcholinesterase to be carbamylated. This is not a stable bond and is hydrolyzed fairly easily.

Myelinopathies Myelinopathies are caused by the organotins, which are used as stabilizers in plastic polymers and catalysts in silicone and epoxy curing. They are also used in wood and textile preservation as fungicides, bactericides, and insecticides. Examples of the organotins are tetracycline (TET) and trimethyltin chloride (TMT).Hexachlorophene (HCP) added to soaps for antimicrobial action also causes damage to the myelin. It is readily absorbed through intact skin and mucous membranes. Like TET and TMT, it causes blurred vision and muscular weakness progressing to paralysis. The optic nerve is particularly susceptible to HCP. The optic nerve is also sensitive to solvents such as ingested methanol and ethanol, inhaled trichloroethylene, toluene, CS2 and benzene. Other solvents can lead to s p e a f ~myelinopathies, as the trigeminal nerve is especially sensitiveto trichloroethylene (found in dry cleaning fluid). Hearing loss is commonly caused by toluene, styrene, xylene, and trichloroethylene, which causes myelin damage to the vestibulocochlear nerve. Other toxins, such as carbon monoxide and cuprisone (a copper chelating agent used in the treatment of Wilson’s disease), affect the maintenance of myelin. Lead, a well-known neurotoxin, brings about encephalopathy by causing vascular changes leading to neuronal degeneration and necrosis, as well as by causing neuronal degeneration itself. Early stages of plumbism include headache and nausea. Demyelination of motor nerves is also seen with lead.

Endocrinotoxicity With the exception of the rodenticide Vacor, agents that affect endocrine function, other than reproduction, tend to be compounds with extensive effects on other organs

Sleep disturbances or changes in energy level or mood Alterations in weight, appetite, and bowel function Sexual interest and function change; in females any menstrual change Changes in temperature perception, sweating, or flushing Alteration of hair growth and skin texture

as well (heavy metals, pesticides, solvents). It would be unusual to find an endocrine disorder as the sole or primary manifestation of an environmental toxicity. The most common symptoms of toxic damage to the endocrine system are listed in Box 36-3.

Adrenal Gland In addition to the well-documented estrogenic effect of the OCCs, actual damage to the endocrine organs is also noticeable. Aliphatic compounds (3-6 carbons in length with electronegative groups on both ends) cause necrosis of zona fasciculata and zona reticularis of the adrenals, where the glucocorticoids are produced. OCCs and carbamates have caused histologic changes to these areas in animal model^.^',^^ Cadmium and CCl, have both been shown to cause nonspecific inhibition of steroidogenesis. Occupational lead workers showed decreased secretions of corticosteroids,both glucocorticoids (17-hydroxy)and androgenic steroids (17-keto). In these persons, the lesion was apparently at the hypothalamus/pituitary level because normal ACTH response was found with stimulation. Dioxins and mirex (used to treat fire ants) cause direct suppression of glucocorticoid synthesis, resulting in hypoglycemia.

Thyroid The thyroid is not immune to environmental toxins, as many chemicals can cause a reduction of both T4 and T3. Thiocyanates, perchlorates, and pertechnetates are all competitive inhibitors of iodine transport in the thyroid, causing decreases in T4 and T3 and an increase in thyroid-stimulating hormone (TSH). Compounds that inhibit the thyroid peroxidase needed in the second step of thyroid hormone synthesis include the following: Thiourea Thiouracil Propylthiouracil Carbimazole Aniline derivatives Para-aminobenzoicacid Substituted phenols like resorcinol Phloroglucinol Iodide and lithium block thyroid hormone release from the gland itself. Depressed levels of thyroid function have

Therapeutic Modalities

been correlated with exposures to lead, carbon disulfide, and PBBs. Lead workers, a heavily studied population, appear to suffer from a decrease in thyroid secondary to problems with the hypothalamus (TRF). In Michigan, PBB-exposed persons showed nongoitrogenic thyroid dysfunction. Less well documented, but suggested to adversely affect the thyroid, are: Organophosphates Carbarnates

occs

Fungicides Food coloring PCBs Mercury (animal studies) Inducers of hepatic cytochrome P450 such as phenobarbital, benzodiazepines, calcium channel blockers, steroids, retinoids, chlorinated hydrocarbons, and polyhalogenated biphenyls (in addition to inducing P450)cause alteration in thyroid structure, leading to reduction in T4.30 Besides causing reduced functioning,some compounds also cause thyroid cancer. Polycyclic hydrocarbons, nitrosamines, and other compounds are initiators of thyroid carcinogenesis. A common component of permanent hair dye preparations, 2,Pdiaminoanisole sulfate (2,4 DAAS), when fed at high doses, caused a 58%incidence of thyroid neoplasms in male rats and 42% in females, compared with 7%to 8%in controls.30

DBCP or it may serve as a model of other OCC-induced spermatogenesis problems.

DIAGNOSIS History A comprehensive history is the cornerstone of detecting chemically induced health problems. When taking a history, special attention should be paid to both occupational and nonoccupational chemical exposures. Occupational exposures are usually the easiest to document and should always be followed up with a request for the material safety data sheet on each chemical from the employer. Nonoccupational exposures are harder to document but in a family practice are often found to be the main culprit. Specific questions that should be asked about the history of residences include the following: Where does the patient live? How old is the structure? How old is the carpet? When was the place remodeled? What type of heating is used? Are indoor or outdoor pesticides used? Is there an attached garage? Once the history of residential exposure is garnered and compared with the chronologic symptom history, the answer may become quite clear.

Reproductive

Laboratory

The estrogenic effect of environmental chemicals, espe cially the OCCs, are well documented. While many are estrogenic by themselves, when combined their estrogenicity can increase by a factor of 1600. Some combinations can also cause previously nonestrogenic compounds to become estrogenic.50The facts about environmental estrogens have been cogently set forth in The0 Colborn and colleague’s Our Stolen Future, and the reader is directed to that excellent resource for a comprehensive di~cussion.~~ However, there are also nonestrogenic toxic effects of the OCCs on both male and female reproduction. High levels of OCCs in the serum have been strongly linked to infertility, stillbirths, and Urban air pollution has been associated with reduced male fertility.53Although there appears to be a worldwide decline in the sperm levels of males,% males who are organic farmers have high sperm density.55This gives rise to the supposition that exposure to environmental chemicals lowers sperm levels and that avoidance of such chemicals may help to bring the levels back up. Multiple studies have been done on one OCC that is used agriculturally,dibromochloropropane(DBCP),looking at its effect on sperm levels. These studies have demonstrated that exposure to DBCP leads to azoospermia and severe oligospennia.56This may be only associated with

Given the ubiquitous nature of the chemicals in question, a history may not always provide a clear picture of exposure. Laboratory tests may be helpful in these cases. The standard complete blood cell count and general blood chemistry tests are usually unremarkable in cases of chronic low-level exposures (although I have often found leukopenia in my population of toxic patients). In addition, liver enzymes, even when solvents and pesticides are present in the serum, are rarely ele~ated.5~ Serum tests for the presence of OCCs and solvents are invaluable in detecting such problems. When interpreting these tests, the clinician must keep in mind that the laboratory “normals” generally reflect the average level found in the blood of the most toxic population in the country (the population tested by the laboratory), not the average American. There is no “RDA” for pesticides or solvents, and the presence of any of these compounds should be cause for concern. It should also be kept in mind that serum levels of these compounds are generally lower than tissue levels. This has been demonstrated with DDE in which 1ppb in the serum indicates that 5 to 10 ppb would be found in the brain, 47 ppb in the liver, and 100 to 300 ppb in the adipose tissue. If the patient has been exposed to OPs or carbamates, then plasma or red blood cell cholinesterase levels can be

Environmental Medicine

measured. Unfortunately, it is often difficult to assess an OP or carbamate pesticide exposure with this method unless a pre-exposure cholinesterase was obtained for use as a baseline. If that was not done, then a follow-up cholinesterase test may be done after 3 months, provided that the patient does not return to more exposures. Carbon monoxide exposure can be easily checked with a carboxyhemoglobin level. If the patient is poisoned by a chemical that cannot be tested for in the serum or urine, then other tests can be considered. Immune panels including T and B subsets, autoantibody panels, chemical antibodies, and natural killer cell activity all indicate that toxin-induced damage to the immune system has occurred.28 Neurotoxicity can be diagnosed by single photon emission computed tomography scans,58 evoked response audi0metry,5~balance testing, and measurement with an iris corder. It can also be indicated when a positive rombergism is present.w

TREATMENT The basics of effective treatment for chemically induced illnesses are as follows: Avoidance of further exposures Supplementation to support chemical elimination and antioxidant protection mechanisms Reduction of the body burden of xenobiotics

Avoidance Avoidance of further chemical exposure cannot be overlooked, although compliance is often difficult to obtain. In cases of multiple chemical sensitivity, avoidance is indispensable. Compounds to be avoided include the following: Solvents Paints Exhaust fumes Perfumes Hair sprays New furniture Carpeting and cabinetry Plastics Gas or oil heat Because the home is the environment that is most in the patient’s control, it must be made a “safe oasis.” If building materials are off-gassing chemicals and these materials cannot be removed, they should be sealed. A number of good books are available to help with this process.60-62 If the living space contains mold, an ozone generator can be used to clear it out. No one can be present in the home when an ozone generator is being used, as ozone is a potent respiratory sensitizer.

In addition to avoiding environmental chemicals, any foods that cause adverse reactions should be avoided (see Chapter 53). Organically grown foods should be consumed whenever possible, and purified water should be drunk. Air purifiers can be used to help reduce the level of chemicals in the indoor air. Charcoal or high-efficiency particulate air filters do the best job of clearing toxins out of the air, but some plants do an admirable job as well. In a study from NASA, five plants were found to be the most effectivein cleaning the a s : Mass cane (Dracaena massangeana) Pot mum (Chrysanthemum morifolium) Gerbera daisy (Gerberajumesonii) Wamecki (Dracaenaderemensis ”Wamecki”) Ficus (Ficus benjamina)

If plants are chosen as the preferred method for cleaning the air, then the specific room to be cleaned must have many plants put in it. A single plant in a normal-sized room has no effect. I generally tell my patients to “make your home a jungle.” Those who have complied with these instructions have invariably reported decreased symptoms.

Nutritional Support Nutritional support is aimed at two main areas: critical cofactors for enzymatic biotransformation of xenobiotic compounds and antioxidants. Additional supplementation is undoubtedly necessary to address the organ systems and tissues that have been damaged by the xenobiotic compounds. However, that is not the focus of this chapter.

Protein Metabolism of toxic chemicals and drugs has been shown to be impaired by protein deprivation (Box 36-4). Increased toxicity of chemical compounds and drugs has been reported with protein deficiency. Protein deficiency decreases the activity of liver mixed function oxidase (MFO) systems, which results in an increase in the halflife of numerous toxic chemicals and drugs and potentiates drug action and toxicity. The quantity and quality of protein in the diet alter both phases 1 and 2 liver drug

Decreased cytochrome P450 content of liver, secondary to decreased quantity of rnicrosornal protein Decreased NADPH-cytochrorne P-450 (c) reductase Decreased cytochrome b5 Decrease in hepatic GSH Increased liver UDP-glucuronlytransferase(phase 2)

GSH, Glutathione; NADPH, reduced nicotinamide adenine dinucleotide phosphate; UDe uridine diphosphate.

Therapeutic Modalities

metabolism processes (a gelatin diet induces low h4FO activity). The toxicity of OCCs, acetylcholinesterase inhibitors, herbicides, and fungicides have all been shown to be increased severalfold by protein deficiency. Reduced clearance and increased half-life of antipyrine are found in Asian vegetarians eating a low-protein diet. This was not found in Caucasian vegetarians with adequate protein intake. Although protein defiaency clearly reduces the ability of the body to adequately metabolize chemicals, the opposite also appears to be true.@Isocalorically increasing the ratio of dietary protein to carbohydrate in well-nourished volunteers has been shown to enhance clearance of antipyrine and theophylline. Although it is not clear if the effect of the protein is due to the amino acid content alone, it is known that methionine and cysteine defiaency leads to reduction of intestinal and hepatic MFO enzyme activity. Hepatic MFO activity can also be suppressed by folic and choline deficiency. Low methionine intake also affects selenium metabolism by making less selenium available for glutathione (GSH)-peroxidase biosynthesis. High sugar intake is also known to reduce the clearance rate of certain chemicals from the liver.

Other items that lower vitamin A levels are the following: Alcohol coffee Cold weather Cortisone Diabetes Excessive iron Infections Laxatives Liver disease Mineral oil Nitrates

sugar Tobacco Vitamin D deficiency Zinc deficiency

Thiamin Thiamin depletion occurs from excess formaldehyde

Vitamin E is a well-known stabilizer of membranes and therefore facilitates a suitable environment for the synthesis and activity of membraneassociatedenzymes that p m ted against toxin damage. In addition, it has antioxidant properties. Although CCl, does not cause liver damage via lipid peroxidation, vitamin E partially prevents CCl, hepatotoxicity. Pretreatment of animals and humans with vitamin E before ozone and nitrous oxide exposure has been shown to provide partial protection against the toxicity of these agents.

exposure or any other items that increase aldehydes (e.g., alcohol, Cundida) because the coenzyme of thiamin pyrophosphate (TPP)is used to metabolize the aldehyde group. Magnesium is also used in this process. Thiamin also serves as a coenzyme (TPP) for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. Besides being used in the phase 2 pathways, thiamin is necessary to restore oxidized GSH. Thiamin deficiency increases the toxicity of PCBs, dieldrin, heptachlor, and the aniline dyes. These compounds can also lead to thiamin deficiency, which enhances their toxicity. Treatment of cattle with 100 mg/day of thiamin prevents clinical signs of lead poisoning and death.

Vitamin A and Beta-carotene

Riboflavin

Beta-carotene is required for epithelial cell differentiation and regulates the stability of biologic membranes. It quenches singlet oxygen species nonchemically and is essential for a normal estrogen cycle. Beta-carotene also protects against singlet oxygen-induced damage. Deficiency of vitamin A is associated with increased binding of benzo(u)pyrene to tracheal epithelia. OPs, DDT, and PCBs decrease the vitamin A content in the liver, which increases their toxic effect on the body. In another example of how veterinarian nutritional care is more advanced than human care, an intramuscular injection of 1,500,000 units of vitamin A is given yearly to cattle to treat organophosphate poisoning. OPs are applied directly to the animals once yearly to take care of insects that would otherwise cause problems with the cattle. I have not yet heard of farmers who apply these pesticides by hand to their cattle ever getting the vitamin A injection!

Riboflavin is a component of the coenzymes in various flavoprotein enzymes required for oxidation/reduction reactions. Liver microsomal flavoprotein reduced nicotinamide adenine dinucleotide phosphate (NADPH)cytochrome reductase supplies reducing equivalents to cytochmme P450.These are essential for proper functioning of the phase 1biotransformation pathways. Riboflavin facilitates the destruction of azo dyes in the liver by MFO, thereby protecting against azo dye-induced cancer. Riboflavin is also used in the GSH reductase pathways, which work with superoxide dysmutase to block free radical damage.

Vitamin E

Niacin Nicotinamide is a component of two related coenzymes, NAD and NADP, which are oxidized to NAD+ and NADP+ and are reduced to NADH and NADPH. These are necessary for the proper functioning of

Environmental Medicine

phase 1detoxification. This vitamin is used in the deamination of amino acids, fatty acid synthesis, and betaoxidation of fatty acids. It also participates in steroid formation and drug metabolism.

Pyridoxine Exposure to carbon disulfide (CS& PCBs, and penicillamine has been shown to disrupt the normal function of vitamin B,. Chronic exposure to these compounds can cause B6 deficiency. William Rea, MD? has stated that 60% of the chemically sensitive patients at the EHC in Dallas are deficient in this nutrient, whether or not they are taking oral supplements. Low B6can lead to low taurine levels. When taurine is low, extreme sensitivities to chlorine, chlorite (bleach), aldehydes, alcohols, solvents, and ammonia can develop. Vitamin B, deficiency also results in poor ability to conjugate epinephrine and serotonin.

Vitamin C A cellular antioxidant, ascorbic acid scavenges free radical superoxides and hydroxyl radicals. It protects against phenol, phenylqumolin, carboxylic acid, and barbiturate toxicity. It protects against ozone-induced pulmonary edema, O2 toxicity, and CCl, toxicity. It reduces the toxicity of pesticides, heavy metals, hydrocarbons, PCB, and acetaminophen. It enhances MFO activity (there is decreased cytochrome P450 activity in vitamin C deficiency) and enhances the incorporation of iron into heme. Vitamin C prevents nitrosamine formation from nitrites in the gastrointestinal tract and protects against lead and cadmium toxicity. Elevated levels of dietary vitaminC may facilitatemetabolic degradation of xenobiotics by liver MFO. Conversely, xenobiotics increase vitamin C excretion in the urine.

Selenium Selenium is a required component of GSH peroxidase (GSH-PX), which maintains integrity of cellular and subcellular membranes, as well as being one of the main molecules for phase 2 xenobiotic conjugation.Fortunately, selenium supplementation increases GSH-PX levels, something that reduced GSH supplementation does not appear to do. This feat is also accomplished by supplementation with N-acetyl cysteine and L-cysteine. This provides a low-cost, reliable method to increase GSH levels. Selenium reduces the toxicity of lead and increases biliary excretion of cadmium and mercury. It also prevents the typical cadmium-induced decrease of Cyto-P450. Selenium deficiency increases the toxicity of numerous xenobiotic compounds.

Zinc Both deficient and excess zinc can influence the metabolism and detoxification of xenobiotics. Zinc deficiency decreases enzyme function, but excess zinc decreases cytochrome P450 levels! Zinc deficiency also reduces GSH levels.

Glutathione

Iron plays a central role in the heme-containing molecules of cytochrome P450 and hemoglobin. However, there is no apparent increase in phase 1 detoxification levels with supplementation of iron. Aniline metabolism is most sensitive to iron deficiency and increases susceptibility to lead toxicity, yet there is a decrease in MFO activity in iron-overloading states.

Not only is GSH crucial to the GSH conjugation pathway, one of the phase 2 pathways, but it is also one of the main molecules that quenches the lipid peroxide molecules in the body, especially in the liver. Although many naturally minded physicians give reduced GSH to their patients in hopes of increasing their levels, there is insufficient evidence to support this practice at present. One human study on oral GSH absorption subjects showed no increase in subjects’ GSH levels with oral supplementation.% All of the other studies reported the use of injectable or food source GSH rather than oral doses. On the other hand, there have been many studies showing that supplementation with selenium, N-acetyl cysteine, cysteine, vitamin A, and vitamin E can increase GSH levels.66Other compounds such as the botanical medicine Silybum marianum have also been shown to increase the GSH level. Vitamins E and C, as well as cysteine, have all been shown to inhibit GSH depletion and lipid peroxidation after endrin exposure.

Magnesium

Botanical Medicines

A deficiency of magnesium was found in 40% of the chemically sensitive patients at EHC in Dallas? Defiaency of magnesium leads to decreased amounts of cytochrome P450 and NADPH cytochrome reductase, both of which are essential to the proper functioning of phase 1. Decreased hydroxylation of aniline and demethylation of aminopyrine are seen in cases of magnesium deficiency. Fortunately, magnesium supplementation reverses both effects.

The two major botanical medicines useful in treating chemical toxicity are Silybum marianum (milk thistle) and Curcuma longa (turmeric). The reader is referred to Chapters 125 and 87 for further information.

Iron

Depuration (Cleansing) Removal of impurities from the body is known as depurution. This is the preferred term for cleansing xenobiotics from the body. The commonly used term detoxification

means to remove or alter the toxic quality of a compound. Because healing for the toxic person involves removal of the actual xenobiotic from the body, rather than mere alteration of the compound, the word depuration is used. Only two methods of xenobiotic depuration are discussed in the scientific literature. Most of the published literature is from one of the Health Med clinics, associated with the Church of Scientology, which is doing the ”Hubbard purification rundown.” This protocol uses exercise, high-temperature saunas, increasing doses of niacin, and electrolytereplacement.They have published several studies showing the benefit of this protocol for reducing levels of PCBs, PBBs, and H C B S .Their ~ ~ ~stud~ ies, along with unpublished data from Rea at the EHC in Dallas, have shown that sauna therapy brings about a reduction of the xenobiotic levels in treated individuals. The only published treatment besides sauna therapy that has shown benefit in treating poisoned individuals is fasting (see Chapter 50). This has been documented in a study that looked at individuals poisoned by PBBcontaminated rice bran cooking oil in Taiwan?O Although fasting reduced their symptoms, it increased the level of circulating xenobiotics in their serum. Presumably the elevation of circulating toxins is due to the increased rate of lipolysis in fasting individuals. Thus the fat-soluble PBBs were released from storage into the bloodstream at higher than normal rates. At that point, it would be up to the liver to clear these out of the serum or they would be redeposited into the adipose tissue. More research is obviously necessary on the role of fasting in the treatment of environmental overload. I developed a comprehensive naturopathic protocol for treating environmentally poisoned individuals and have been using it for more than 20 years. An outcome study on patients who underwent this protocol for various chemically induced ills showed it to be surprisingly effective. Of the subjects (with various problems) treated with the depuration protocol, 83% rated their results as good or great. The two conditions in which 100% of the participants reported great results were asthma (n = 3) and addiction recovery (n = 1). Unfortunately these numbers are too small to make any estimate of the benefit of the program with larger populations. The problem (chief complaint) categories in which 100%of the participants rated their results as moderate, good, or great were autoimmune, dermatological, and gastrointestinal/liver. Those with autoimmune diagnoses have not only enjoyed symptomatic relief but typically find a reduction of autoantibodies in serum testing. The categories with the next highest ratings of moderate, good, or great were fatigue, with 92% improvement; allergies, with 85% improvement; and chemical sensitivities, with 84% impr~vernent.’~ Before and after serum testing for chlorinated pesticides, PCBs and solvents has been done on some of the individuals undergoing this

depuration protocol. Each who has had this testing has seen a clear reduction of the body burden of these compounds with cleansing. Most have had a complete clearance of PCBs from their serum.n

The Crinnion Depuration Protocol The Crinnion depuration protocol consists of the following components:

Exercise Daily exercise usually consists of using an exercycle, rebounder, or brisk walking to begin lipolysis and diaphoresis. Thermal chambers-Up to three 60-minute ”sauna” sessions are held with temperatures ranging from 120”F to 135” F with cool-down periods in between. Glass bottled spring water is given along with electrolyte replacement. Although the Hubbard clinics use higher temperatures, we find that individuals put out more toxins (as evidenced by stronger chemical odors) and experience fewer adverse symptoms when the lower temperatures are used. The thermal chambers increase the rate of lipolysis in the adipose tissue throughout the body. When this occurs, the lipophilic xenobiotics are released into the bloodstream. The compounds in the subcutaneous fat pads are mobilized through sweat, as well as into the blood. Constitutional hydrotherapy-The use of alternating hot and cold towels with sine wave stimulation as done by pioneering naturopath doctors O.G. Carrol and Harold Dick. This therapy has been used for decades to stimulate the body’s own self-healing activity. We have found that it also increased the amount of toxin-laden bile dumped from the liver into the intestines. Also assisting the choleretic and cholagogue action on the liver is an herbal capsule taken daily consisting of Chelidoniurn, Chionanthus, Taraxacurn,Arctiurn lappa, Silyburn rnarianurn, and Urtica dioca. Colonic irrigation-Gravity-fed machines are used to gently introduce triple-filtered water into the large intestines, providing an avenue for the toxic bile to rapidly leave the body. Individuals routinely have “liver dumps” of bile that range in color from yellow to red, with occasional gray or brown. The color of bile normally ranges from green to yellow to orange to red depending on the amount of time of exposure to bacterial action in the bowel. However, in this situation we believe that it is dumped from the liver and rapidly passed through the small intestines, similar to what is seen in ”gastric dumping” syndrome. We are therefore unable to account for the differencesin color of this effluent. In some patients with heavy agricultural exposure, we have seen higher amounts of fluorescent yellow bile. Hence the bile color may be more attributable to the

Environmental Medicine chemical compounds in the bile than the bacterial action on the bile. We have documented that chlorinated pesticides are present in this effluent that we refer to as "bile dumps." Constitutional homeopathy--This has been used primarily as a stand-alone treatment with the use of any other supplements or treatments prohibited. However, we have found it to be a valuable component of this protocol and completely compatible with all the other treatment methods involved. It appears most beneficial in individuals who need a boost for their vital force to facilitate moving toward healing, as well as for those who are stuck in emotional issues that they have not been willing to address. Body therapies (massage, shiatsu, craniosacral, visceral, spinal, and joint adjustmentkThese are done as necessary for the individual to treat specific musculoskeletal problems and to assist in mobilizing toxins that were stored in the tissues. Counseling-Mental and emotional toxins are as big a problem as physical/chemical toxins. When people are exposed to powerful emotional toxins (e.g., abuse) for which they have no outlet for handling, they end up "stuffing" the emotional toxins. When this "emotional stuffing" occurs, any physical toxins that they were exposed to at that time are also "stuffed" (stored) rather than being eliminated. Because of this, when they start to mobilize the physical toxins, the old emotional issues come back into consciousness. When this occurs and individuals choose once again to suppress the emotional issues (rather than facing them), their physical cleansing also stops. This is evidenced by the observation that they stop sweating in the thermal chambers, stop heating the cold towels in the hydrotherapy, and stop having good liver releases during the colonic therapy. When the emotional "toxins" are faced and released, these cleansing parameters are returned to former levels. Assisting all of the individuals going through this depuration protocol with their emotional issues helps them to cleanse physically. (See Chapter 7, especially the section on using altered states of consciousness, for a more complete discussion of the role of past emotional states and associations in the development and maintenance of disease.)

This protocol is used on a daily basis that usually lasts between 4 and 8 weeks (five sessions weekly). The protocol begins the depuration process, which must then continue once the individual returns home. Most individuals need to continue regular cleansing (use of home

saunas, hydrotherapy, and colon therapy) for at least 12 months after completing their intensive in-office cleansing. When testing for serum levels of OCCs and solvents is repeated, along with immune parameters after 12 months, improvements are routinely seen. In addition to symptomatic relief, improvements in the laboratory reports (e.g./ decrease in serum xenobiotics and reduction in autoantibodies) are clearly evident.

SUMMARY Environmental chemicals are ubiquitous in our environment. Once they enter the body, they bioaccumulate and are stored in adipose tissue throughout the body. They alter the functioning of the immune system, nervous system, and endocrine system, leading to a host of chronic problems. The diagnosis of xenobiotic-induced damage can be elucidated by a comprehensive history, along with evidence of serum toxin levels and toxin-induced immune system damage.

Treatment Overview Avoidance of further chemical exposure through air, food, and water Nutrient support for transformation, elimination, and antioxidant pathways Vitamin C: 6000 to 12,000 mg/day Vitamin E: 400 to 1200 units of D-alpha-tocopherol/ day 8-complex: once daily Vitamin A 25,000 to 50,000 units/day (unless the person is a menstruating female who is at risk for PregnmCY) N-acetyl cysteine: up to 500 mg/day Selenium: 300 to 600 mcg/day SiZybum rnariunurn (standardized): 100 mg two to three times/day Adequate protein in diet with each meal Magnesium: 300 to 600 mg/day Psyllium husks powder: begin with 0.5 tsp in water nightly (to bind bile in the intestines) Depuration protocol Daily exercise Thermal chambers (low-temperature saunas) Constitutional hydrotherapy Colonic irrigations Constitutional homeopathy Body work Counseling

1. Davis DL, Dinse GE, Hoe1 DG. Decreasing cardiovascular disease and inmasing cancer among whites in the United States from 1973 through 1987. Good news and bad news. JAMA 1994;271:431-437. 2.Rogers SA. Diagnosing the tight building syndrome. Environ Health Persped 1987;76195-198. 3. Godish T. Sick buildings, definition, diagnosis, and mitigation. Boca Raton, n:Lewis Publications, 1995. 4. Cullen MR, ed. Workers with multiple chemical sensitivities.Occup Med 1987;2:655-661. 5. Hileman B. Multiple chemical sensitivity. Chem Eng News 1991;69:29. 6.Rea WJ.Chemical sensitivity, vols 1-3. Boca Raton, n: Lewis Publications, 1992,1994,1996. 7. Chambers JE,Levi PE, eds. Organophosphates,chemistry, fate, and effects. San Diego, CA: Academic Press,1992. 8. Arlien-Soborg P.Solvent neurotoxicity. Boca Raton, n. CRC Press, 1992. 9.Luster MI, Rosenthal GJ. The immunosuppressive influence of industrial and environmentalxenobiotics. TIPS 1986;40&412. 10. Vial T, Nicolas B, Descotes J. Clinical immunotoxicity of pesticides. J Toxicol Environ Health 1996;4&215-219. 11. Heuser G. Diagnostic markers in clinical immunotoxicology and neurotoxicology. Int J Occup Med Tox 1992;l:v-ix. 12.Rea WJ. Chemical sensitivity, vol 3. Boca Raton, F L CRC Press, 1996. 13. Environmental Protection Agency, Office of Toxic Substances. EPA560/5-86-035, Broad scan analysis of the FY82 National Human Adipose T i u e Survey specimens. Washington, DC:EPA, 1986. 14. Stehr-Green PA. Demographic and W~SOMI influences on human serum pesticide residue levels. J Toxicol Environ Health 1989;27 405421. 15.Adeshina F, Todd EL. Organochlorine compounds in human adipose tissue from north Texas. J Toxicol Environ Health 199029: 147-156. 16.Jacobson JL,Humphrey HE, Jacobson SW, et al. Determinants of polychlorinated biphenyls (PCBs). Polybrominated biphenyls (PBBs) and dichlorodiphenyl trichloroethane (DDT) levels in the sera of young children. Am J Public Health 1989;791401-1404. 17.Blount BC, Silva MJ, Caudill SP, et al. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Persped 2O00;108:979-982. 18. Colon I, Cam D, Bourdony CJ, Rosario 0. Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development.Environ Health Persped 2000;108:895-900. 19. National report on human exposure to environmental chemicals. Department of Health and Human Services, Centers for Disease Control. March 2001. 20. Houlihan J, Wiles R, Thayer F, Gray S. Body burden, the pollution in people. Available online at h t t p : / ~ . ~ g . o r g / r e p o r t s / b o d y b u r den/index.php [accessed August 2,20051. 21. Wallace LA, Pellizzari E, Harthwell T, et al. Personal exposures, indoor/outdoor relationship and breath levels of toxic air pollutants measured for 355 persons in New Jersey. Atmos Environ 1984;19: 1651-1661. 22.Gunderson EL. FDA total diet survey, April 1982-April 1986, dietary intakes of pesticides, selected elements and other chemicals. Washington, DC: Food and Drug Administration, Division of ContaminantsChemistry. 23.Kuhnlein HV, Receveur 0, Muir DC, et al. Arctic indigenous women consume greater than acceptable levels of organochlorines. J NU&1995;125:2501-2510. 24. Davis DL, Dinse GE, Hoel, DG. Decreasing cardiovascular disease and increasing cancer among whites in the United States from 1973 through 1987, good news and bad news. JAMA 1994;271:431-437.

25.Luster M, Rosenthal GJ. The immunosuppressive influence of industrial and environmental xenobiotics. TIPS 1986;Oct:40&412. 26. Vial T, Nicolas B, Descotes J. Clinical immunotoxicity of pesticides. J Toxicol Environ Health 1996;4&215-229. 27. Hueser G. Diagnostic markers in clinical immunotoxicology and neurotoxicology. Int J Occup Med Tox 1992;l:v-ix. 28.Rea WJ. Presentation at 13th International Symposium on Man and His Environment in Health and Disease. Dallas, 1995. 29. Haschek WM, Rousseaux CG. Handbook of toxicologic pathology. San Diego, CA: Academic Press, 1991:442-448. 30. Thrasher JD, Madison R, Broughton A. Immunologic abnormalities in humans exposed to chlorpyrifos: preliminary observations.Arch Environ Health 1993;4&89-93. 31. Anderson HA, Lilis R, Selikoff IJ, et al. Unanticipated prevalence of symptoms among dairy farmers in Michigan and Wisconsin. Environ Health Perspect 1978;23:217-226. 32. Repetto R, Baliga SS. Pesticides and the immune system; the public health risks. Washington, DC:World Resources Institute, 1996. 33. Broughton A, Thrasher JD.Chronic health effects and immunological alterationsassociated with exposure to pesticides. C o r n Toxicol 199O;4:59-71. 34.Vojdani A, Ghoneum M, Brautbar N. Immune alteration associated with exposure to toxic chemicals. Toxicol Ind Health 1992;8:239-254. 35. Wassermann M, Nogueira DP, Tomatis L, et al. Organochlorine compounds in neoplastic and adjacent apparently normal breast tissue. Bull Environ Contam Toxicol 1976;15:47&484. 36. Mussalo-Rauhamaa H, Hasanen E, Pyysalo H, et al. Occurrence of beta-hexachlorocyclohexane in breast cancer patients. Cancer 1990;66:21242128. 37. Falck F Jr, Ricci A Jr, Wolff MS, et al. Pesticides and polychlorinated biphenyl residues in human breast lipids and their relation to breast cancer. Arch Environ Health 1992;47143-146. 38. Wolff MS, Toni010 PG, Lee EW, et al. Blood levels of organochlorine residues and risk of breast cancer. J Natl Cancer Inst 1993;8564&652. 39. Davis JR, Brownson RC, Garcia R, et al. Family pesticide use and childhood brain cancer. Arch Environ Contam Toxicol 1993;24: 87-92. 40. Leks JK, Savitz DA. Home pesticide use and childhood cancer: a case-control study. Am J Public Health 1995;85249-252. 41.Claggett S. 2,4-D Information packet. Northwest Coalition for Alternatives to Pesticides. 1990. 42. Spirtas R, Stewart PA, Lee JS, et al. Retrospective cohort mortality study of workers at an aircraft maintenance facility. I. Epidemiological results. Br J Ind Med 1991;48:515-530. 43. Anttila A, Pukkala E, Sallmen M, et al. Cancer incidence among Finnish workers exposed to halogenated hydrocarbons. J Occup Envirvn Med 1995;37797-806. 44.Fleming L, T i e n y W. Aplastic anemia and pesticides, an etiologic association?J &cup Environ Med 1993;351106-1116. 45. Bethwaite PB, Pearce N, Fraser J. Cancer risks in painters: study based on the New Zealand Cancer Registry. Br J Ind Med 1990;47 742-746. 46. Eriksson M, Karlsson M. Occupational and other environmental factors and multiple myeloma: a population based case-control study. Br J Ind Med 1992;4995-103. 47. Synder SH, DAmato RJ. Predicting Parkinson's disease. Nature 1985;31719&199. 48. Calne DB, Langston JW, Martin WR, et al. Positron emission tomography after h4PTl? observations relating to the cause of Parkinson's disease. Nature 1985;317246-248. 49. Lund BO,Bergman A, Brandt I. Metabolic activation and toxicity of a DDT-metabolite, 3-methylsulphonyl-DDE, in the adrenal zona fasciculatain mice. Chem Biol Interact 1988;65:25-40.

Environmental Medicine 50. McLachlan JA. Estrogen pairings can increase potenq. Sci News 1996;149:356. 51.Colbom T, Myers JP, Dumanoski D. Our stolen future: are we threatening our fertility, intelligence and survival? A scientific detective story. New York Penguin Group, 1997. 52. Leoni V, Fabiani L, Marinelli G, et al. PCB and other organochlorine compounds in blood of women with or without miscamage: a hypothesis of correlation. Ecotoxicol Environ Saf 1989;171-11. 53.Laino C. City air pollution linked to male infertility. Med Trib 1995;9:14. 54. Carlsen E, Giwercman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of semen during past 50 years. BMJ 1992;305: 609-613. 55. Abell A, Emst E, Bonde JP. High sperm density among members of Organic Farmers Association. Lancet 1994;343:1498. 56. Sever LE, Hessol NA. Toxic effects of occupational and environmental chemicals on the testes. Endocrine toxicity. Berkeley, C A Raven Press, 1985211-248. 57.Lundberg I, Hakansson M. Normal serum activities of liver enzymes in Swedish paint industry workers with heavy exposure to organic solvents. Br J Ind Med 1985;42:596-600. 58. Simon TR. Brain SPECT and neurotoxicity. Presentation at the 14th International Symposium on Man and His Environment in Health and Disease. Dallas, 1996. 59. Jauman M. Use of evoked response audiometry to assess neurotoxicity. Presentation at the 14th international symposium on man and his environment in health and disease. Dallas, 1996. 60.Gorman C. Less toxic living.Environmental Health Center-Dallas, 1993.

61. Golos N. Success in the clean bedroom: a path to optimal health. Rochester, NY: Pinnacle, 1992. 62. Rousseau D. Your home, your health, your well-being. Vancouver, BC: Hartley & Marks, 1988. 63. Wolverton BC, Johnson A, Bounds K. Interior landscape plants for indoor air pollution abatement. Stennis Space Center, MS: National Aeronautics and Space Administration, 1989. 64.Meydani M. Dietary effects on detoxification processes. In Hathcock J, ed. Nutritional toxicology, vol2. New York Academic Press, 1987. 65. Witschi A, Reddy S, Stofer 8, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol1992;43667-669. 66. Numan IT, Hassan MQ, Stohs SJ. Protective effects of antioxidants against Fndrin-induced lipid peroxidation, glutathione depletion, and lethality in rats. Arch Environ Contam Toxic01 1990;19:302-306. 67. Schnare DW, Denk G, Shields M, Brunton S. Evaluation of a detoxification regimen for fat stored xenobiotics. Med Hypotheses 1982;9:265-282. 68. Schnare DW, Ben M, Shields MG. Body burden reductions of PCBs, PBBs, and chlorinated pesticides in human subjects. Ambio 1984;13 378-380. 69.Tretjak Z, Shields M, Beckmann SL. PCB reduction and clinical improvement by detoxification: an unexploited approach? Hum Exp Toxic01 1990;9235-244. 70. Imamura M, Tung TC. A trial of fasting cure for PCB-poisoned patients in Taiwan. Am J Ind Med 1984;5147-153. 71.Crinnion WJ. Results of a decade of naturopathic treatment for environmental illness. J Nat Med, 1977;721-28. 72. Crinnion WJ. Unpublished data.

The Exercise Prescription Bobbi Lutack, h4S, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER C O N T E N T S Introduction 355 Exercise Physiology 356 Muscle Physiology 356 The Components of Physical Fitness 357 Cardiovascular Endurance 357 Muscular Strength 358 Muscular Endurance 358 Flexibility 358 Body Composition 358 Body Mass Index 358 The Exercise Prescription: Basic Guidelines 358 Cardiorespiratory Conditioning 359 The Three Phases of Cardiorespiratory Exercise 359 Muscular Conditioning 360 Flexibility Conditioning 360 Exercise and Specific Diseases 361 Coronary Heart Disease 361 Hypertension 362 Cancer 362 Obesity 362 Diabetes 363 Pulmonary Disease 364 End-stage Renal Disease 364 Chronic Pain 364 Low Back Pain 365 Arthritis 365 Peripheral Vascular Disease 365

INTRODUCTION The publication of Dr.Kenneth Cooper’s book Aerobics in 1968 had a profound influence on the exercise habits of Americans. Sedentary men and women all across the country were prompted by the book’s message to take up aerobic training programs. Aerobics became the exercise catchword, and the fitness boom had begun. Running was the primary aerobic exercise, and beginning in the

Neuromuscular Disease 365 Chronic Fatigue/Fibromyalgia 366 Mental Health 366 Exercise in Special Conditions 366 Pregnancy 366 Children 367 PostmenopausalWomen 367 The Elderly 368 Exercise and the Immune System 368 Environmental Considerations 368 Heat and Humidity 368 Cold 369 Air Pollution 369 Altitude 369 Side Effects and Contraindications of Exercise 370 Athlete’s Heart 370 Sports Anemia 370 Athlete’s Hematuria and Albuminuria 370 Exercise-InducedAsthma 370 Exercise-InducedUrticaria and Anaphylaxis 370 Menstrual Dysfunction and Changes in Sex Hormones 371 Osteoporosis 371 Incontinence 371 Acute Muscle Injury 371 Heat Stroke 372 Sudden Death 372 Steroid Use 372 Conclusion 372

mid-l970s, marathon running became popular. More than 20,000 runners now annually participate in the New York, London, and Glasgow marathons. In 1984, however, running took a giant step backward with the death of JimFixx, an internationally known runner and author who died of a massive myocardial infarction (MI) while running in Vermont. With him died an exercise myth: marathoner immunity to heart disease. 355

Although a complete description of the physiologic changes induced by exercise is beyond the scope of this chapter, the following review helps to provide a basis for understanding the exercise prescription. The basics of exercise physiology are reviewed, considering the benefits and adverse effects of exercise with regard to the primary and secondary prevention of chronic lifestyle diseases, and the potential contraindications to exercise are discussed. Special topics are also discussed.

EXERCISE PHYSIOLOGY Exercise places sigruficant metabolic and cardiorespiratory stress on the body. At maximal exertion, skeletal muscle increases its metabolic rate fdtyfold, the overall metabolic rate tenfold, and cardiac output from fourfold to as much as sixfold in the physically fit (due primarily to a threefold increase in heart rate).'Z In healthy individuals at submaximal workloads, the relationship between heart rate and oxygen uptake is essentially linear. The physiologic effects of exercise depend on the intensity, duration, and frequency, as well as the type of exercise. Isometric exercise (increase in muscle tension without a shortening in muscle length) increases peripheral vascular resistance without a sigruficant change in cardiac output. Isotonic exercise (shortening of muscle with little increase in tension) increases cardiac output and decreases peripheral vascular resistance. Isometric exercise increases muscle strength and bulk but has little effect on cardiorespiratory conditioning, while isotonic exercise increases endurance and cardiorespiratory conditioning, the goal of most exercise programs. Well-conditioned individuals typically have lower heart rates than those who are sedentary. This is thought to be due to increased vagal tone, decreased sympathetic activity (probably due to the drop in beta-adrenergic receptor density), and increased stroke volume.2 The best overall measurement of physical fitness is V 0 2max, which decreases with age; for example, a 60-year-old has only two thirds the V02 of a 20-year-old. However, this trend is much less apparent in those who exercise regularly. Three weeks of bed rest cause a 20% to 25% decline in V 0 2 -, while sedentary individuals can increase their V02,, by 30% to 40% by engaging in a program of moderate exercise?

-

glycolytic enzymes and myosin ATPase activity; and fast in reaction time? Sprinters have high proportions of white fibers for high-intensity exercise, while long-distancerunners have a preponderance of red fibers. It is unclear, however, if training can alter the phenotype of muscle

fiber^.^ As skeletal muscle contains only limited amounts of high-energy phosphate compounds-for example, preformed adenosine triphosphate (ATP)and creatine phosphate (CP) muscle stores are inadequate for a 100-yard dash-energy must be generated during exercise. Three sources of fuel are available to skeletal muscle:

Endogenous muscle glycogen Blood glucose Free fatty acids (WAS)derived from muscle triglyceride stores or adipose tissue Table 37-1 lists the body's relative proportions of each of these energy stores. The intensity of exercise determines the substrate used. Low-intensity exercise and exercise well within the aerobic limits preferentially use free fatty acids (FFAs) first and muscle glycogen second. Catecholamines, released early in exercise, stimulate adipose lipase, which cleaves triglyceride into glycerol and three FFAs. Serum FFA levels of six times the normal level are rapidly induced during exercise. In muscle, FFAs are metabolized to acetyl CoA, which undergoes oxidative metabolism in the citric acid cycle to produce ATP production during exercise (see Figure 37-1 and Figure 50-1 in Chapter 50).r4 As the exercise intensity increases, glycogen becomes more important than FFAs, contributing twice the energy at 80%maximal work capacity and virtually all at 100%. While within the aerobic limit, glycogen is metabolized in the cytoplasm to pyruvate, which then enters the citric acid cycle. When sufficient oxygen is not available in anaerobic metabolism, energy is produced by glycolysis (only 5% as efficient) and pyruvate is reduced to lactate instead of entering the citric acid cycle. The resulting acidosis limits muscular performance, and buffering by bicarbonate generates CO, causing ta~hypnea.~,~

MUSCLE PHYSIOLOGY Skeletal muscle is composed of two types of fiber: red fibers (type 1) and white fibers (type 2). The red fibers are high in myoglobin content, mitochondria, and oxidative capacity but are low in glycolytic enzymes and slow in contraction time. White fibers are lower in myoglobin content, mitochondria, and oxidative capacity; high in

Body store

Size of store (kcal)

Running distance (miles)

Blood glucose

40

Liver glycogen

220

0.5 2.2

Muscle glycogen

380

3.8

Adipose tissue

100,000

1000

The Exercise Prescription

. co,

Figure37-1 Muscle energy metabolism.

THE COMPONENTS OF PHYSICAL FITNESS Physical fitness includes five components: Cardiovascular endurance Muscular strength Muscular endurance Flexibility Body composition

Cardiovascular Endurance Cardiovascular endurance refers to the ability of the heart, lungs, and blood vessels to function optimally both at rest and during exercise. From the exercise specialist’s point of view, it is the most important component. This variable is addressed through the aerobic portion of an exercise program. Aerobic is defined as the ability to process and deliver enough oxygen to meet tissue energy needs. At workloads above 80% of maximum, skeletal muscle demands more oxygen than can be delivered, thus exceeding the aerobic limit.2As muscle metabolism becomes anaerobic, energy is produced by glycolysis rather than glucose oxidation. This results in the build-up of lactic acid, requiring the buffering of bicarbonate. The subsequent C02release results in increased

respiratory rate, a sensation of dyspnea, and progressively decreased work capacity. (Althoughsome athletes inhale 100°/~of oxygen after intense activity to hasten recovery and improve subsequent performance, this has proven to be ineffe~tive.~) To quahfy as an aerobic activity, the exercise must be continuous, rhythmical, use large muscle groups, and be performed at an intensity that sigruhcantly increases cardiovascular output. Examples of aerobic exercise include running, cross-country skiing, cycling, swimming, skating, and hiking. The aerobic concept, applied to physical fitness, requires following specific training guidelines. If pursued regularly and with proper intensity and duration, this training accomplishes the following? Strengthens the respiratory muscles Increases breathing efficiency Stabilizes or lowers blood pressure Improves tissue capacity to use oxygen and dispose of waste products Increases muscular endurance Increases heart function and circulation Controls body weight Provides increased energy Promotes psychologic well-being

Cardiovascular endurance can be measured in the physician’s office with a graded exercise test on a treadmill or bike or in the field with, for example, the popular 12-minute walk-run (seeCooper7for a detailed description) on a measured course. The distance covered correlates well with maximum oxygen consumption.’

Muscular Strength Muscular strength refers to the ability of a muscle to exert force against resistance. Typically, strength is defined relative to maximum force-producing capabilities. A simple but accurate estimate of strength, referred to as the one repetition maximum,is to have an individual lift as much as he or she can lift just one time. Upper and lower body strength can be assessed using exercises like the bench press and the leg press.* As a rule of thumb, the ability to bench press one’s own body weight indicates good upper body strength.

Muscular Endurance Muscular endurance is the ability of a muscle or muscle group to sustain repeated contractions of a given force over time. This ability is highly correlated with strength. Push-up and sit-up tests have traditionally been used to determine muscular endurance, although abdominal “crunches” or half sit-ups are actually a better measure of abdominal endurance/strength. An example of good muscular endurance for a 30-year-old male is the ability to perform 35 to 39 timed (60-second) sit-ups. For a 30-year-old female, 25 to 39 modified push-ups and 31 to 35 timed (60-second) sit-ups would indicate good muscular endurance?

Flexibility Flexibility is the ability to move a muscle through its full range of motion, which involves the interrelationships among muscles, ligaments, tendons, and joints. Range of motion is restricted by a lack of flexibility, and the performance of routine movement is hindered. It is difficult to test flexibility as it is joint specific, but one test that is frequently used to test low back, hamstring, and hip flexibility is the “sit and reach test.” This test is described in detail in Appendix 12. A good score is 19 to 21 inches.s An exercise program that incorporates stretching and yoga exercises can increase flexibility.

Body Composition Body composition is the interrelationship between lean body mass (muscle, bones, and connective tissues) and body fat. For optimal fitness, high levels of lean tissue and relatively low levels of body fat (about 20% for women and 15%for men) are desirable. The percentage of body fat can be measured quickly, accurately, and relatively inexpensively in a physician’s office through the use of skinfold calipers (we recommend high-quality calipers such as Lange or Harpenden). Several skinfold

sites must be measured to maximize accuracy. One set of recommended measurement sites for women comprises the thigh, triceps, and suprailium, and for men the thigh, chest, and abdomen. These measurements are then used in a regression equation or a table (such as the one found in Pollack and colleagues: p. 220) to estimate body fat. The body fat percentages are based on Siri’s underwater equation, where percentage fat = [(4.95/Db) - 4.51 x 100, where Db is the body density. (See Chapter 194 for a discussion of one- and four-site skinfold measurement techniques and interpretive tables.)

Body Mass Index In the past decade, the U.S. government’s Dietary Guidelines for Americans has moved toward the use of criteria for overweight and obesity that is more consistent with international standards? Central to this criteria is the construct of the body mass index (BMI). Figuring BMI involves a simple calculation: BMI = weight (kg)/height (m)*

This calculation takes into account the subject’s weight and height to produce a quantitative sense of obesity. In general, a value between 25 and 29.9 is considered ”overweight.’’ See Table 37-21° for specific age ranges in regard to BMI. At any age, ”obesity” is generally considered a BMI value greater than or equal to 30. One criticism of these given age-specific ranges may be the underlying message that some weight gain is considered “normal” as one gets older, a phenomenon that does not necessarily occur with many individuals who keep an active healthy lifestyle and exercise regularly. At any rate, clinicians may use BMI as a means to set goals and monitor the effects of exercise prescription and diet.

THE EXERCISE PRESCRIPTION: BASIC GUIDELINES Many people are confused about the type and amount of exercise necessary to become fit. Knowledgeable and

Years of aae

Bodv mass index considered overweiaht Ika/m21

19-24

>24

25-34

>25

35-44

>26

45-54

>27

55-65

>28

6%

>29

Modified from National Research Council (U.S.). Committee on Diet and Health. Diet and health: implications for reducing chronic disease risk. Washington, DC: National Academy Press, 1989.

The Exercise Prescription

accurate instructions are important to help prepare an exercise program that meets an individual‘s specific needs. The American College of Sports Medicine (ACSM), an internationally recognized expert organization in the field of exercise science, has published a position paper on the proper exercise prescription for healthy adults. This paper, based on existing documentation from throughout the world, summarizes the most widely accepted guidelines for developing and maintaining cardiovascular fitness and optimal body composition. The following is a summary of its content.

Cardiorespiratory Conditioning The Essential Components of Cardiorespiratory Exercise A sound cardiorespiratory exercise program has four essential components:

Type of Activity The activity should be aerobic, as defined previously Zntensity The exercise must be strenuous enough to place an “overload” on the cardiorespiratory system. This corresponds to 60%to 90% of maximum heart rate. To calculate maximum heart rate (MHR), subtract the individual’s age from 220. Multiplying this figure by 0.60 and 0.9 yields the target heart rate (THR), or the range of sufficient intensity to overload the cardiorespiratory system. The following example is for a 40-year-old: MHR = 220 - 40 = 180 beats per minute (bprn) 180 bpm” 60% = 108 bpm 180 bpm” 90% = 162 bpm THR = 108 - 162 bpm Although the MHR covers a wide range, it is useful as a ballpark measure of how to determine the intensity of exercise. To further increase the accuracy of intensity evaluation, a rating scale of perceived exertion ( W E )can be used. The Borg scale of perceived exertion is a good example.” The Borg scale is numerical, ranging from 6 to 20, with corresponding verbal descriptions provided at odd numbers of how hard the exercise feels. For example, a rating of 6 to 7 corresponds to “very, very easy,” while a rating of 19 to 20 corresponds to “very, very hard.” The W E response to graded exercise correlates closely with cardiorespiratory and metabolic variables such as heart rate. As a valid and reliable indicator of the level of exertion of a given exercise, it can be used to prescribe intensity. A rating of 12 to 13 (described as “comfortable” to “somewhat hard”) corresponds to about 60%of MHR, and a rating of 15 to 16 (expressed as ”hard”) corresponds to about 90% of MHR.12When prescribing an exercise program, a perceived exertion range of ”comfortable”to ”hard” is the recommended intensity

level. When used in conjunction with the THR at the beginning of an exercise program, it helps participants to develop a physical and cognitive ”feel” for how hard exercise should be. Once this knowledge is obtained, WE can be used as the primary indicator of intensity.

Duration This is inversely related to intensity. Duration of aerobic exercise, exclusive of warm-up and cool-down, typically varies in length from 15to 60 minutes. A common conditioning phase is 30 minutes. High-intensity exercise requires a shorter duration for the same cardiovascular effect, and vice versa. High-intensity, short-duration exercise is not recommended until good cardiovascular conditioning has been achieved. A good rule of thumb to gauge a proper intensity/duration ratio is the degree of fatigue experienced 1hour after exercising.

Frequency Three to five exercise sessions per week are recommended, with no more than 48 hours between workouts. Depending on the level of fitness, intensity, duration, and motivation, sessions can be daily. With fewer than three sessions per week, improvement in cardiorespiratory endurance is minimal and there is no loss in body fat.13 When instructing previously sedentary individuals on how to exercise properly and become conditioned, emphasis should be placed on making progression slowly. People who have been sedentary for years require time to rebuild their bodies. It is better to do too little than too much. All too often, people who are motivated to ”get back in shape” overexert themselves their first time out (e.g.,by jogging 2 miles instead of combining walking and jogging).When they wake up the next day with sore muscles and unaccustomed pain, they give up on the exercise program. The adage ”no pain, no gain” is an exercise myth (exceptin strength building, as noted later).The aerobic exercise component of a physical fitness program should feel fairly comfortable. Being able to talk with an exercise partner while working out suggests an appropriate level of exercise, while breathlessness and inability to carry on a conversation indicates excessive intensity. Being able to sing suggests too little intensity.

The Three Phases of Cardiorespiratory Exercise In addition to the components of mode, frequency, intensity, and duration, the effective exercise session is divided into three phases: Warm-up Cardiorespiratory conditioning Cool-down The warm-up phase should be of 5 to 10 minutes’ duration and should prepare the body for the conditioning activity. Light calisthenics, stretching, or the conditioning

activity, or a combination, performed at a light intensity (approximately 50% of the intensity of the conditioning phase) are suitable warm-up activities. Breaking into "a light sweat" is a sign that the body is warming up. Proper warm-up may also help to prevent exerciseinduced muscle pulls, strains, and ~0reness.I~ The conditioning phase is the 15 to 60 minutes of aerobic activity described earlier. Vigorous participation in sports is recommended as an enjoyable alternative but only after an adequate level of fitness is achieved. The adage "don't play sports to get in shape, get in shape to play sports" is sound advice. The recommended cool-down is 5 to 10 minutes of tapering-off activity, such as slowing the intensity of the exercise performed in the conditioningphase, stretching, and then relaxing for a short period. For most people, the heart rate should be under 100 bpm at the end of the cool-down period.14The major purpose of this phase is to keep the primary muscle groups involved in the conditioning phase moving, to prevent peripheral pooling of blood, which can cause a vaso-vagal response. Cooling down can also help to prevent muscle soreness!

Muscular Conditioning Most attention for exercise program prescriptions has focused on the cardiovascular component, probably due to the belief of exercise authorities that cardiovascular fitness is the most important component. However, flexibility, strength, and muscular endurance also form an important part of any physical fitness program. Sound musculoskeletal function is necessary throughout life to make daily living activities easier to perform, to help prevent low back problems, and to help prevent the inevitable loss of lean body tissue as one ages. As lean body mass is lost, a concomitant decrease in basal metabolic rate and strength occurs. Individual exercise prescriptions for developing muscular endurance and strength should be tailored to the sport being played or to the individual's goals. Weight loss (fat loss), for example, would necessitate a different prescription from power lifting. For a general overall strength/endurance-building program, the following guidelines may be used: Mode-free weights, universal, Nautilus, Cybex, calisthenics, etc. Duration--one to three sets of 5 to 15 repetitions (optimal strength gains appear to be achieved with five to seven repetitions if the muscle is maximally fatigued). Allow about 1minute's rest between sets. ZntmsiQ-the intensity (weight lifted) should be such that only 5 to 15 repetitions can be performed. The adage "no bum, no gain" has much validity. Frequency--3 to 5 days per week (5 days only after preconditioning). Allow at least a 24-hour rest period

between workouts of the same muscle group (i.e., a complete day of rest between workouts)! Example: Monday: upper body workout Tuesday: lower body workout Thursday: upper body workout Friday: lower body workout Proper and safe strength training requires emphasis on form, technique, and execution. The following guidelines can help to maximize the effects and minimize the risks of exercise programd2: Warn-up. To prepare the muscles for the intense effort that lies ahead, stretch and perform a few repetitions with about 50% of the weight to be used during the training sets. Controlled movement. Control all movements to achieve steadiness. Do not "throw" the weight. For maximum strengthening benefits, at the height of the lift or at its fullest extension or flexion, pause briefly before lowering the weight. A good routine is to lift for 2 seconds, pause, and then lower for 4 seconds. Muscle group isolation. Concentrate on isolating the muscle(s) being exercised and moving them through their full range of motion. Fatigue avoidance. Proceed from major muscle groups to minor muscle groups to minimize fatigue. Proper breathing. Do not hold the breath or perform the Valsalva maneuver. Exhale as the weight is lifted and inhale as it is lowered. For additionalinformation,please refer to Appendix 12.

Flexibility Conditioning Flexibility is necessary to ensure maintenance of adequate range of motion of all joints. Decreased flexibility can lead to the common complaint of low back pain (discussed further later).*Stretching should be done at least three times per week (ideallybefore and after each workout) and can be part of the warm-up and cool-down phases of the cardiovascular portion of the fitness program. Stretchingshould be preceded by a mild warm-up (e.g., light calisthenics), and the exercises tailored to the muscles being worked. Stretches should be performed slowly and progressively, using a dynamic movement followed by a static stretch held for 30 to 60 seconds. The stretch should cause a feeling of tightness but no pain.I5 Although stretching is a well-established principle of physical care, some research suggests it may not be useful and could even decrease physical ability. In one study, stretching has been shown to be ineffective at reducing muscle soreness.An analysis of five randomized or quasi-randomized studies of moderate quality that reported data from 77 healthy young adults demonstrated

The Exercise Prescription

that stretching produced small and statistically insignificant reductions in muscle soreness 24 hours after exercising.16Even more surprising, stretching appeared to actually impair balance and worsen reaction and movement times. In a second study, 16 subjects were tested before and after both a static stretching of the quadriceps, hamstrings, and plantar flexors or a similar duration control condition. The stretching exercise comprised a 5-minute cycling warm-up followed by three stretches to the point of discomfort of 45 seconds each with 15-second rest periods for each muscle group. It was found that those who stretched experienced a 9.2% decrease in balance versus the control group, which enjoyed a 17.3% increase in balance ability. The stretch condition also resulted in prolonged reaction time and movement time of 4% and 1.9%, respectively, for the stretching group versus decreases of 5.8%and 5.7y0for the nonstretched subjects." These changes may prove to be detrimental for elite athletes, where winning and losing depends on minute differences in performance, as well as in the elderly, who may already be at a disadvantage regarding these parameters. At this point, a note of caution is also necessary regarding exercise programs and conditioning work. The previously mentioned recommendations and guidelines are designed for apparently healthy, asymptomatic adults. According to the ACSM, apparently healthy individuals younger than the age of 45 can begin and participate in exercise programs without prior stress testing; however, some screening before participation is recommended.12 The age, health status, and type of exercise program the participant engages in determinesthe degree of evaluation required. Individuals with known cardiac, pulmonary, or metabolic disease or who have symptoms suggesting coronary artery disease or at least one major coronary risk factor, or both, should undergo a maximal exercise tolerance test before beginning a vigorous exercise program. The ACSM also recommends such a test for anyone who is 45 or older before participation in an exercise program.

EXERCISE AND SPECIFIC DISEASES (Additional discussion of the current research into the benefit of exercise can be found in the chapters covering most of the following conditions.)

Coronary Heart Disease Running was the popular aerobic exercisein the 1970sand was touted to have many beneficial side effects. During its heyday, Dr.Tom Bassler even proposed that marathoners were immune from heart disea~e.'~J~ The death of JimFixx in 1984 laid that theory permanently to rest. The concept that regular aerobic exercise provides some protection against the clinical manifestation of

coronary heart disease (CHD) is generally accepted today by both the public and health professionals. Regular exercise, in conjunction with other risk-reducing behaviors, is believed to help protect against an initial cardiac event (primary prevention), aid in the recovery following a cardiac event (e.g., MI, coronary artery bypass graft surgery), and help to reduce the risk of recurrent cardiac events (secondary prevention).The exercise conditioning effects that help to prevent CHD are listed in Box 37-1.20,21 Although the etiology and pathogenesis of CHD and atherosclerosis are still not completely understood, multiple research approaches have identified several factors that play causative roles. Endothelial injury and vessel denudation results in dysfunction that appears to be the initiating event in the development of atherosclerosis. Aerobic exercise training has been shown to improve endothelial dysfunction. This improvement is currently hypothesized to enhance coronary blood flow in patients with or at risk for cardiovascular disease, and thus to reduce the risk for atherosclerosis progression and recurrent events.22Although a cause-and-effect relationship has yet to be definitively demonstrated, there are strong indications that regular exercise leads to reduced risk for CHD and its clinical manifestations of myocardial ischemia, MI, and cardiac arrest. Pioneering observational studies by Morris and colleagues,= Paffenbarger and colleagues,U and Taylor and colleaguesE of London bus drivers and postal workers,

Serum Lipid Effects Reduction of serum cholesterol and triglycerides Increase of serum highdensity lipoproteins (HDL,) Metabolic Elfects Lowering of circulating catecholamines-lowering of circulating by exercise Reduction of blood clotting-reduction by exercise; tendencies Increased fibrinolysis Increase of insulin sensitivity-increased by exercise Cardiac Effects Augmentation of coronary arterial bed Decrease of myocardial work and oxygen demand Increase of myocardial function (increased stroke volume) Reduction of systolic and diastolic blood pressure-reduction by exercise Miscellaneous Effects Improvement of psychologic outlook-improvement Reduction of adiposity Data from references 20 and 21.

by exercise

Hypertension longshoremen, and U.S. railroad workers, respectively, were among the first to report an inverse correlation Exercise training clearly decreases the risk of hyperbetween CHD risk and physical activity. Another land- tension, most likely by weight-reduction mechanisms." mark investigation,the Framingham study, also indicated One study of 6000 healthy adults found a 52%increased that moderate exercise was associated with decreased risk for hypertension in sedentary individuals compared with those who were fit, while another found a 35% CHD More recently, an observational study by Leon found increa~e.~ Regular , ~ ~ exercise produces a sustained physical inactivity to increase risk of heart attack, and decrease in systolic and diastolic blood pressure and catthe 7-year Multiple Risk Factor Interventiontrial echolamine levels in hypertensive patients." One study study showed that moderate exercise reduced both fatal of patients with mild hypertension found that half could and nonfatal CHD events.27B discontinue their antihypertensive drugs after engaging in a regular aerobic program." A note of caution: As Research has shown that higher levels of leisure-time physical activity are associated with increased longevity isometric exercisescause an acute increase in blood presin college alumni, while Paffenbarger and c ~ l l e a g u e s ~ ~sure, a static exercise by patients with significant hyperhave shown that it was physical activity as an adult, not tension should be supervised. college athleticism, that is associated with a decreased Cancer risk of death. In a study conducted at the Cooper Clinic in Dallas, Lack of regular physical activity has been linked to colon the physical fitness and risk of all-cause and cause- cancer, breast cancer, and lung cancer, with most of the specific mortality were followed in 10,OOO men and 3000 research focusing on the link between fitness and colon c a n ~ e r . Physical ~' activity may reduce the incidence of women for an average of 8+ years.31The study concluded that poor physical fitness was an important risk factor in colon cancer because it reduces intestinal transit time.& both men and women. Higher levels of physical fitness In the Cooper clinic study, higher levels of physical fitness were associated with delayed mortality partly due appeared to delay all-cause mortality, primarily due to lowered rates of CHD and cancer. This study is particuto lowered rates of cancer.31 larly important, as it is the first large-scale study to Exercise may also be useful for active cancer include extensive follow-up, maximal exercise tests, treatment and rehabilitation. About 70% of people with a wide range of physical fitness evaluations, an objective cancer report feelings of fatigue during radiotherapy end-point (mortality), and a large enough sample of or chemotherapy, or after surgery. Traditionally, cliniwomen to permit meaningful comparative gender cians have told their oncology patients to rest extenanalyses. The results of the study are useful from both a sively due to cancer related-fatigue, a consideration clinical and a public health standpoint. similar to that past advice erroneously given to heart In addition to lowering risk for developing CHD, aerdisease patients. Exercise programs of low to moderate obic exercise training has been shown to help in recovery intensity have been shown to substantially reduce from cardiac events (cardiac rehabilitati~n).~~-~ cancer-related fatigue and improve the quality of life of Research also shows that weight-resistance training these ~atients.4~ also has a beneficial effect on CHD risk by favorably Obesity affecting lipoprotein-lipid profiles, insulin response to glucose ingestion, and blood pressure.538 A study of Physical inactivity may be a major cause of obesity in the 23 men who were 6 weeks post-acute MI and without United States. Indeed, childhood obesity seems to be associated more with inactivity than overeating. Strong exercise-induced ischemia were randomly assigned to combine weight and cycle training versus cycle training evidence suggests that 80% to 86% of adult obesity only for 10 weeks. Although arm and leg strength sigbegins in childhood. In the adult population, Brownell and Stunkard found that obese adults were less active nificantly increased in each group, the change was greater for the combined training group (31%versus 16% than their normal-weighted counterparts? However, it is for leg strength and 20% versus 10% for arm strength, still unclear whether inactivity is a cause of obesity or a respectively). There were no changes in either group result of it. Despite the lack of definitive evidence, regular with regards to resting hemodynamics, body weight and exercise should be prescribed for the obese due to the composition, left ventricle wall segment motion, left following factors: ventricular fractional shortening, and early diastolic function. No adverse clinical or exercise-related compliWhen weight loss is achieved by dieting without cations were observed.% Given that the time period exercise, a substantial portion of the total weight loss was only 10 weeks, it seems probable that other paramecomes from the lean tissue, primarily as water loss.5o ters such as left ventricle function and body weight comWhen exercise is included in a weight-loss program, position would favorably change over a longer period there is usually an improvement in body composition of time. due to a gain in lean body weight because of an

The Exercise Prescription

increase in muscle mass and a concomitant decrease in body fat.31S1 Exercise helps to counter the reduction in basal metabolic rate (BMR) that usually accompanies calorie restriction Exercise increases the BMR for an extended period of time following the exercise session.12 Moderate to intense exercise may have an appetite suppressant eff ect.I2 Those subjects who exercise during and after weight reduction are better able to maintain the weight loss than those who do not exercise.53 The concept of "spot reduction" is a myth.%Exercise draws from all of the fat stores of the body, not just from local deposits. Although aerobic exercise generally enhances weight-loss programs, weight-training programs can also substantially alter body composition, by increasing lean body weight and decreasing body Research into the use of resistance training during energy restriction is limited, but preliminary evidence suggests that calorie restriction does not affect the strengtheningor hypertrophic response of muscle.57Thus weight training may be just as, or more, effective than aerobic exercise in maintaining or increasing lean body weight and, therefore, the metabolic rate of individuals undergoing weight reduction. Generally, aerobic exercise prescriptions for weight loss should emphasize long duration, low intensity, and a frequency of at least 3 to 4 days/week since, as the earlier discussion of muscle metabolism indicates, this type of exercise preferentially uses fatty acids from adipose stores. Swimming appears less effective than walking or cycling for reducing body It takes 35 miles of walking or jogging to metabolize the calories contained Metabolic costs* of various activities

Occupational

Recreational

Energy used (kcaVrnin) 2-2.5

Desk work, driving

Standing, walking

Janitor, typing

Level bicycling

Cleaning windows

Cycling, 6 mph; walking, 3 rnph

4-5

Painting, paperhanging

Dancing, table tennis

5-6

Digging in garden

Walking, 4 rnph; skating

6-7

Shoveling, 10 Ib 1Odmin

Cycling, 11 rnph; tennis

7-8

Sawing hardwood

Jogging, 5 mph; basketball

8-10

Shoveling, 14 Ib 10drnin

Running, 5.5 rnph; handball

10-11

Shoveling, 16 Ib 10xftnin

Running, >6 rnph

2.5-4

> I0

Modified from Rubenstein E, Federman DD. Scientific American medicine. NewYork: Sci Am 1991:CTM 1:l-32.

'Includes resting metabolic needs.

in 1pound of fat. Table 37-3 lists the metabolic costs of various activities. Weight loss (combined diet and exercise) should not exceed 2 to 3 pounds/week.12

Diabetes The current treatment for type 2 diabetes is exercise, oral hypoglycemics, and dietary modification.'* Exercise is beneficial to diabetics as it increases insulin sensitivity and enhances the biologic effects of endogenous attenuation of liver glucose production, and increased muscle glucose use.A regimen of mild to moderate intensity exercise favorably affects blood glucose in type 2 diabetics, and effect is found to continue into the postexercise period." As mentioned previously, exercise can also help by combating obesity and improving lipoprotein profiles. Special precautions need to be taken when prescribing exercise for those with insulin-dependent diabetes, as exercise may induce hypoglycemia through its insulinlike effect. An exercising insulin-dependent diabetic needs to reduce insulin intake or increase carbohydrate intake. The following regimen is recommended for insulindependent diabetics who exercise to maintain blood glucose control:

1.Monitor blood glucose more frequently. 2. Decrease insulin dose (I to 2 units or as needed) or increase carbohydrate intake (10 to 15 g/0.5 hr of exercise) before an exercise session. 3. Inject insulin into a site that will not be active during exercise (e.g., runners might inject into the abdomen). 4. Avoid exercise during peak insulin periods. 5. Eat carbohydrate snacks before and during prolonged exercise sessions. 6.Exercise with a partner (in case of a hypoglycemic reaction). 7. Avoid late evening exercise* .',@' 8. Wear a medical-alert bracelet. The exercise prescription needs to be individualized, and in some cases exercise is not advisable due to proliferative retinopathyZ poor metabolic control, or frequent hypoglycemic reactions.60 For type 1 diabetics, exercise consistency is most important.6l Daily exercise helps to maintain a regular pattern of diet and insulin dosage. Intensity can be prescribed in the normal range (i.e., 60% to 90% of MHR), and duration need only be 20 to 30 minutes per session due to the high frequency. Prescribing exercise for type 2 diabetics is not as complicated. As obesity is a key contributing factor to this type of diabetes, emphasis should be placed on high frequency (5 to 7 days/wk), long duration (45 to 60 minutes per session), and low intensity (about 60% of MHR) for maximizing caloric expenditure from fat s t o r e ~ . l ~ , ~ ~ Diabetic patients with advanced retinopathy should not participate in activities that jar or those that cause

marked fluctuations in blood pressure. A nonjarring exercise like swimming is recommended.12

Pulmonary Disease In patients with advanced chronic obstructive pulmonary disease (COPD),dyspnea at progressively lower levels of exertion often results in deconditioning, which can lead to further disability. Although aerobic exercise does not improve indices of pulmonary function,62fl it may improve endurance and exercise Furthermore, research has suggested that patients with chronic respiratory diseases can acquire and maintain substantial improvements in skeletal muscle function, physical function, and quality of life through participation in a well-structured program of resistance exercise training?' For example, in patients with mild to moderate asthma, 3 months of controlled, submaximal exercise can produce sigmticant improvements in fitness and cardiorespiratory performance.@ The effects of exercise are tempered by the severity of airway obstruction, which may vary from mild to severe. Individuals with mild COPD respond to exercise in a similar way to patients with CHD, so the intensity can also be prescribed by the heart rate method. The recommended duration, frequency, and mode are also the same as for CHD patients.12 Individuals suffering from more severe COPD who experience dyspnea with mild exercise are limited by their dysfunctional respiratory systems. Supplemental oxygen may be used during exercise if a tial shows objective improvement in exercise capacity as a result of oxygen use; however, modifications to the exercise prescription are required.'2 Duration should be "as tolerated," with perhaps two 10-minute or four 5-minute sessions/ day to build up tolerance. As tolerance increases,sessions can gradually be reduced to 3 to 5 days/wk for 20 to 30 minutes. Intensity should be determined by signs of breathlessness. Lower body aerobic exercise, such as walking or cycling, is preferable to upper body exercise due to the higher ventilation requirement of upper body exercise. Additional benefits of exercise therapy for pulmonary patients include improved mechanical skills in the trained muscles, particularly in the respiratory muscles, and improved psychologic ~ t a t e . 6 ~ ~ ~ ~

End-stage Renal Disease Many patients with end-stage renal disease (ESRD)suffer from muscle weakness, fatigue, bone disease, CHD, and multiple psychosocial problems. Attention has recently been directed at rehabilitation of this patient group. Exercise training has been found to be especially beneficial for selected patients undergoing hemodialysis. The incidence of ESRD in the United States is approximately 1 in 10,OOO per m u m , and the average age of

patients on dialysis is 4€L71The most common treatment for ESRD patients is hemodialysis. A major study conducted at the WashingtonUniversity school of Medicine and the ChromalloyAmerican Kidney Center using an aerobic exercise program on nondialysis days found the following71: A 19%increase in the duration of exercise tolerance A 21% increase in V 0 2 , Improvements in blood pressure and lipoprotein profiles Lowered fasting plasma insulin A 27% increase in hematocrit A reduction of depression No changes in these parameters occurred in the control group. Positive results were also reported by Squires and colleaguesR with exercise training following renal transplantation. Exercise training (specifically cycling) has also been performed during hemodialysis.n The benefits are similar to those found with training on nondialysis days. Because typical hernodialysis patients use an artificial kidney machine three times a week for 4 to 5 hours/session, exercise training could help to alleviate the tediousness of the sessions and provide a supervised setting for exercise in this high-risk group of patients. The exercise prescription for ESRD patients has to be a low-intensity (use the RPE method to designate intensity), non-weight-bearing (e.g., stationary cycling), interval (i.e., exercise period followed by a rest period) activity. Frequency should be at least 3 days/wk, and duration should be about 30 to 45 minutes. Exercise sessions should be monitored and adjustments made to accommodate any complications (e.g., an increase in serum p ~ t a s s i u m ) . ~ ~ , ~ ~

Chronic Pain Pain is the leading symptom that prompts patients to see physicians. Today, virtually all pain management programs include some type of aerobic or weight-training exercise program, or b0th.7~Pain specialists attribute the positive effects of decreased sensitivity to pain and significant psychologic benefit to exercise-induced elevation of endorphins.76*nA recent study proposed that prolonged rhythmic exercise activates central opioid systems by triggering increased discharge from mechano-sensitive afferent nerve fibers in contracting skeletal muscle and that many of the cardiovascular, analgesic, and behavioral effects of exercise are mediated by this mechanism. The authors also proposed that the same or similar mechanisms are responsible for the central and peripheral effects of acupuncture." Aerobic exercise may also help to reduce pain through promotion of delta sleep, the deepest stage of sleep, during which musculoskeletal renewal takes place." The two most common pain

complaints are low back pain (LBP),affecting about 15% of Americans, and headaches.75

Low Back Pain Although 90% of patients with back injuries return to work within 2 months, the remaining 10% account for billions of dollars in medical expenses, lost income and productivity, workers’ compensation benefits, and litigation It has been postulated that postinjury deconditioning, not the original injury, is the primary cause of the chronic pain condition and is frequently the major impediment to functional Reversal of postinjury deconditioningthrough a progressive, active physical exercise program can restore function and decrease pain. While healing may restore structural integrity, it does not restore flexibility, strength, endurance, or coordination. Unrecognized or untreated deconditioning can lead to the recurrence of pain on return to work or resumption of normal activities. It is theorized that high-resistance exercise training helps minimize pain by breaking down existing muscle fiber and stimulating its replacement with stronger and more flexible replacement fiber.”

Arthritis With arthritis, slight pain may have to be tolerated during exercise sessions in order to achieve the painalleviating effects of conditioning. Exercise producing excessive stress on osteoarthriticjoints should be avoided, but a program designed to improve range of motion and muscle strength should be performed daily to combat the effects of disuse and decrease pain. Exercises of short duration and high frequency help to limit stress on the joints. Weight-bearing activities may have to be limited due to inflammation, but cycling, rowing, swimming, In a controlled etc. are all acceptable modes of exercise.12,79 study, both aquatic and on-land exercise programs have demonstrated a beneficial effect over lack of exercise with regard to functional fitness, activities of daily living, and isometric strength tests when evaluated in 22 osteoarthritic and 8 rheumatoid patients using an %week program.E0 Regarding elderly adults with arthritis, The American Geriatrics Society (AGS) has proposed the following: Mild- to moderate-level exercise does not exacerbate arthritis pain. Exercise programs should be individualized to address the specific needs of the patient. The exercise program should focus on controlling arthritic pain, improving ability to perform activities of daily living, increasing flexibility, and improving muscular strength and endurance. The AGS panel also concluded that, to help people with arthritis, an effective exercise program should go beyond improving overall fitness levels for exercise participants.

These protocols should include education about joint protection, weight counseling for obese individuals, development of pain-coping skills, and enhancement of social s u p p ~ r t . ~ , ~ ~ Despite common perception, there is no evidence to support the assertion that running exercise causes degenerative joint d i ~ e a s e .Since ~ ~ , synovial ~~ fluid enters cartilage to provide nutrition through exercise-induced compression, it is possible that long-term repetitive exercise is actually beneficial for joints, as well as bones.2 Excessive trauma is, however, associated with joint degeneration (see Chapter 195). From a naturopathic perspective, it is best to assure proper musculoskeletal dynamics using orthotics to adjust foot arch support and by using massage, physical, and manual therapies as appropriate to decrease muscle hypertonicity and poor skeletal alignment, for these may encourage uneven movement of joints, contributing to pathologic joint wear.

Peripheral Vascular Disease Individuals with peripheral vascular disease (PVD) suffer claudication discomfort ranging from excruciating and unbearable pain to definite discomfort. Exercise can help to alleviate the pain. Frequency should be 7 days/wk, preferably with two periods of exercise per day. The duration should be at least 20 minutes (exercise might have to be intermittent), and the type of exercise should be aerobic (walking, stationary cycling, warm water exercise, etc.). The intensity is determined by the level of pain (moderate discomfort or pain from which the patient can be distracted by conversation or other stimuli may have to be tolerated).I2

Neuromuscular Disease Patients with neuromuscular disease may well benefit from carefully prescribed resistance-training programs, which may positively modulate neural factors, as well as change muscle size to increase strength.84Eight-week courses of resistance trainingin patients with mild to moderate Parkinson’s disease have demonstrated increases in performance or strength similar to that of normal adults of the same age in a resistance-training program, with functional improvements in gait.s5 Charcot-Marie-Tooth disease (CMTD) is one of the most common inherited neurologic disorders, affecting approximately 1in 2500 people in the United States. Also known as hereditary motor and sensory neuropathy, demyelination and remyelination of peripheral nerves, weakness and muscle atrophy, disuse atrophy, and deconditioning are hallmarks of this condition. There are no treatments for CMTD and as of now, exercise therapy is not routinely prescribed. In one study, 20 volunteers with CMTD performed a 3-day-per-week, at-home, progressive strength training regimen using adjustable wrist and ankle weights. These subjects found improvements

Therapeutic Modalities

in strength and activities of daily living (such as rising from a chair without using the arms, rising from a supine position on an examination table, and stair climbing. The authors of this study noted that, like many other treatments and natural remedies, patient compliance was a key. In this study, the researchers achieved 87% compliance. To attain the best compliance possible, we suggest that physicians (1)urge patients to progress slowly in order to minimize muscle soreness, fatigue, and injury; (2) suggest a home treatment for convenience; (3) provide a visual aid such as a video to assist the patient; and (4) require patients to keep self-recorded logs and report results for feedback.@j For neuromuscular conditions such as those mentioned earlier, as well as various muscular dystrophies, individualized regimens are crucial to achieve gains without adding to discomfort and possible injury. It has also been established that fatigue and metabolite accumulation do not appear to be critical stimuli for strength gain~.~'Thereforeresistance training should and can be effectively employed without the severe discomfort and acute physical effort associated with exhaustive exercise.

Chronic FatigueFibromyalgia Exercise alone has been demonstrated to have a tremendous impact on improving mood and the ability to handle stressful life situations.88Graded exercise therapies, by which the patient begins with gradual walking and weight exercises and increases time and intensity as is comfortable over time, may be the best approach and can be effective to increase muscle mass and functional ability in chronic Fatigue/fibromyalgia s ~ f f e r e r s .One ~ ~ ,published ~ work by Jones and Clarkg1 has specific examples of exercises for fibromyalgia and is a good reference for designing a regimen. Although there is a concern over overtraining, it has been shown that graded therapies are superior to relaxation and flexibility exercises (see Chapter 159 for more information).

Mental Health A considerable body of knowledge attests to the mental health benefits associated with long-term aerobic exercise.92-95Improved mood has been observed in both nonhospitalized outpatientsand normal individuals, as well as those suffering from psychopathology.%Exercise may also help normal individuals, as it decreases stress and emotions, such as anxiety, and decreases the sympathoadrenal response to stress found in men with a type A p e r s o ~ d i t y ? ~An - ' ~"improved sense of well-being" has been reported by many people following exercise. In general, thishas been attributed to a decrease in anxiety and depression.%Exercise is almost as effective as antidepressant drug therapy in selected types of anxiety and depression."JO'

Although studies are controversial, the endorphin hypothesis has become widely accepted as a mechanism by which exercise improves mood.lo2The controversy is largely due to the inability of some investigators to block exercise-inducedmood elevationwith naloxone." Perhaps the dosages were insufficient or other mechanisms are in action. Evidence also indicates that aerobic exercise produces an effect in depressed persons that is similar to the effect caused by tricyclic antidepressants (i.e., it increases the production of the neurotransmitter norepinephrine). This exercise effect is not found in those who are not depressed.lo3 Whatever the relationship, cause and effect, or association, there is sufficient evidence to support regular, vigorous exercise to promote psychologic well-being. In general, the principles of exercise prescription described for healthy adults are also appropriate for those who suffer from mental illness.

EXERCISE IN SPECIAL CONDITIONS Pregnancy Many physically active women want to continue exercising during pregnancy. The currently accepted view is that this is satisfactory if they take some precautions. In addition to benefits cited earlier, exercising during pregnancy can104-106: Enhance self-esteem Increase energy Improve sleep Decrease backache Decrease problems with varicose veins Decrease water retention Improve posture and appearance Possibly decrease labor complications Shorten labor and postpartum recovery For trained women, exercise therapists typically recommend continuing the prepregnancy exercise program at the same "perceived level of exertion" (use WE) during pregnancy. Women who previously have been sedentary and want to exercise while pregnant should begin at a low intensity and increase gradually.lo7 General and relative contraindications include: hemodynamically sigruficant CHD, toxemia, eclampsia, uncontrolled diabetes mellitus, uncontrolled hypertension, and obesity.l2JwPregnant women should avoid participating in sporting activities that involve physical contact or that might induce a fall (e.g., downhill skiing for the inexperienced). As body weight increases, a non-weightbearing activity might be more suitable (e.g., swimming instead of jogging), and intensity should be decreased to minimize oxygen debt and lactate production. Intensity and duration should also be modified to limit core temperature increases.1w

The Exercise Prescription

Some concerns regarding fetal heart rate during maternal exertion have been raised. Signs of fetal distress include prolonged fetal bradycardia and tachycardia. Several studies have shown no effect on fetal heart rate with maternal exertion at 70% to 80%of the MHR.'09-11' With some modifications, continuing a regular exercise program during pregnancy can be both a safe and enjoyable experience for the expectant mother.

Children The leading causes of mortality in the United States are lifestyle-induced diseases, typically originating in childhood. Risk factors such as smoking, hypertension,obesity, diabetes mellitus, hyperlipidemia, and stress are seen in children and youth aged 7 to 17 years. Studies have also reported high-risk profiles in preschool-age children.l12 Approximately 15% of 6- to ll-year-olds and 12- to 19-year-oldsare overweight, and 11.2% of the 12- to 19year-olds have a BMI greater than 30, which is considered obese.113Furthermore, an American child has a one in five chance of developing clinical symptoms of CHD before the age of 16.112 Although studies in adults have linked regular exercise to decreased overall risk for mortality, the few studies of children have been equivocal, except those conducted on obesity, which confirm that increased daily activity and exercise help to control weight in obese children.ll*As mentioned earlier in the section on obesity, studies suggest that childhood obesity is associated more with inactivity than with overeating. Encouraging exercise habits at an early age is especially important in light of research indicating that advancing age and elapsed time after initial adaptation of an activity routine are among the most consistent predictors of inactivity.l12The ACSM currently recommends 20 to 30 minutes of vigorous exercise every day.l14 As indicated in Table 37-4,115-117 strength training with weights shows differing results in prepubescent (Tanner stage 2) and postpubescent boys and girls.

and girls Group

Strength

Muscle mass

Boys

SI increase in only abdomen and back

No change

Girls

No data

No data

Prepubescent

Postpubescent BOYS

Increases

Increases

Girls

Increases

No change, unless anabolic steroids are used

Data from references 115-1 17. SI, Slight.

A special concern that needs to be addressed in exercising children is the still common practice of "making weight" by wrestlers (i.e., losing weight to be certified for a weight class lower than their preseason weight). Wrestlers typically make weight by a combination of food restriction, fluid deprivation, and sweating induced by thermal or exercise procedures.l18 Dehydration through sweating appears to be the most commonly used method.Il8Misuse of rubber suits, saunas, laxatives, steam rooms, and diuretics, singly or in combination, have all been employed in the practice of making weight.l18 Not only are these practices dangerous, but a recent study on repeated weight loss and gain, or weight cycling, in adolescent wrestlers also indicated decreased resting metabolic rate, which may result in an increase in body fat.l19 The possibility of future problems with obesity is suggested. Physicians can help to prevent such problems by educating coaches, wrestlers, and others in the same manner suggested in the section on steroids.

PostmenopausalWomen Women have a number of risk factors for morbidity and mortality that modulate following the onset of menopause. Sigruficant decreases in strength often are subsequent to menopausal onset.lZ0Lowered levels of estrogen may in part explain the increased risk of osteopenia, osteoporosis and cardiovascular illness. It likely that sedentary status also plays a major role. Exercise training has been shown to increase lean body tissue and decrease fat tissue, with body composition effects independent of exogenous hormonal intake.lZ1 One pilot study examined a specific exercise program designed for skeletal muscle strengthening in postmenopausal women. In this work, 18healthy female volunteers aged 50 to 64 years completed 8 weekly hour-long group exercise sessions supplementedwith twice-weekly sessions at home. Partiapants achieved a 21% increase in quadriceps, 9%increase in hamstrings, and a 14%increase in grip strength. As expected, a positive dose-response relationship was observed between strength gains and compliance with the program. The program consisted of patterns of movement using diagonal and spiral patterns, superimposed on a progressive weight-bearing sequence from prone lying to standing.lZ Although more work is necessary, finding a program that is enjoyable and effective is an important goal, and evaluations like those mentioned earlier are useful to help us understand which programs will work for which women. In a 6-month study,21 osteopenic or osteoporotic women with an average age of 62 were given brief but progressively resisted isometric exercises for 10 minutes daily. The researchers observed that these exercises were able to stimulate muscle strengthening of the neck, back, upper and lower extremities and enhance bone formation.'= Bone mineral density has exhibited sigruficant

increases using a 24week program of aerobic high-impact loading exercise in one postmenopausal osteopenic study.'" A second 24week study showed increases in strength but no bone mineral density benefit in the lumbar area.lZ

The Elderly From peak function at the age of 30, the functional capacity of most organ systems decreases at a rate of about 0.75% to 1%per year. Physical work capacity, muscle strength and mass, flexibility, cardiac output, maximum heart rate, vital capacity, and renal and liver function all decline approximately 30% between the ages of 30 and 70.'26Moreover, by the age of 70, women lose 30%, and men about 15%, of their bone mass. Approximately 50% of this decrease in function can be attributed to decreased physical activity.126 The following comment is according to one investigator: Because of their low functional status and high incidence of the population that can benefit more from exercise than the elderly.'" chronic disease, there is no segment of

humans indicated that frequent tai chi quan induced increases in T-lymphocyte count; exercise increased T lymphocytes in the body.132The research thus far suggests that moderate exercise stimulates the immune system,'33 while intense exercise (e.g., training for the Olympics) can have the opposite effect.'% The combination of increased stress and intense training that competitive athletics require may explain this phenomenon. The mechanism responsible for exercise-induced suppression or enhancement of immune function may be increased cortisol, catecholamines, or endorphins, singly or in combination.

ENVIRONMENTAL CONSIDERATIONS For outdoor exercisers, uncontrolled factors such as heat, cold, air pollution, and altitude affect the exercise prescription.

Heat and Humidity

During exercise, 75% of the metabolic energy of muscle action is converted to heat. Elite marathoners generate It has been shown that a program of even once- or heat at 15to 18 times the basal rate, which, if no heat were dissipated externally, would result in a 1"C increase in twice-weekly resistance training can confer muscle strength gains similar to training 3 days per week in core temperature every 5 minutes." older adults. Moreover, 1 to 2 days a week is associIt is not surprising, then, that a number of deaths have ated with improved neuromuscular performance. Such been attributed to exercising in heat coupled with high improvement could potentially reduce the risk of falls relative h ~ m i d i t y . ' ~When ~ , ' ~ exercising in hot weather, and fracture in older adults.'28 the body relies on the sweating mechanism for cooling, Exercise training can help to offset the decline in but in high humidity, evaporation cooling is limited. The physiologic function associated with aging and i1lne~s.l~~amount of sun exposure is also critical as direct radiation Elderly males and females can help to maintain bone is a major source of heat gain. Evaporation is also reduced mass and increase their physical work capacity through when air movement is low. improving their cardiorespiratory endurance, strength, An exercising individual can decrease his or her risk flexibility, and body composition.130 These positive of suffering heat-caused illness (heat cramps, heat changes are demonstrated regardless of previous exercise exhaustion, heat stroke, or heat syncope) or death while exercising in hot weather. Adequate hydration is a pripatterns and current fitness status. The degree of improvement (expressed in relative terms) is comparable mary concern, particularly as strenuous exercise in a to that demonstrated by younger individuals, although warm environment can result in water loss of up to the mechanism for the improvement may differ (i.e., 2 L/hr. The thirst mechanism is not a reliable indicator of strength may increase through improved recruitment of the need to drink, as dehydration will have already motor units rather than muscle hypertrophy).lm begun.'37 Water should be consumed before (6 to 8 oz), The older individual may need to begin exercising at a regularly during, and after strenuous exercise. Water lower intensity and progress more slowly than a younger and a diluted electrolyte solution appear to be the best subject, but with time the benefits will be the same. fluids for quick rehydration.6Fluids high in glucose conPlease see the earlier section on arthritis for specific tent slow gastric emptying and are not re~ommended.'~' recommendations regarding arthritis. Salt tablets are also not recommended, as they draw water from the cells back into the gastrointestinalsystem. If necExercise and the Immune System essary, extra salt added to food is more Recently, attention has been focused on the possible effects Exercising during the cooler part of the day (i.e., early of exercise on immune function. Early research with expermorning or early evening) and avoiding the sun's direct imental animals found that it may enhance resistance to radiation is recommended. Wearing light-colored and minthe growth of experimentally induced tumors,suggesting imal clothing (to expose the skin to air) is also recomthat exercise may stimulate the immunosurveillance mended, as well as decreasing the intensity and duration of function of natural immunity.131 A recent study in exercise during high-temperature or high-humidity days.

The Exercise Pre

Exercisers should be able to recognize the early symptoms of heat injury, which include excessive sweating, headache, nausea, dizziness, and any impairment of consciousness.136They should also be aware that some populations are more susceptible than others (the very young and very old, the obese, the unconditioned, the unacclimatized) and that heat injury can occur under varied conditions: high temperature and low humidity; high humidity and low temperature; high solar radiation; little wind; on a relatively warm day following a bout of cooler weather; and, of course, the lethal combination of high temperature and high humidity.'% Individuals respond differently to heat, and for those who cannot or do not want to change their routines, acclimatization helps the body to tolerate heat much more effectively. Fourteen days of training in the heat is necessary to become 90% acclimatized? The ACSM recommends against distance races when the wet bulb temperature exceeds 28" C.

Cold Cold weather exercising presents far fewer problems than exercising in the heat. Temperatures (including wind chill factor) as low as -20" F can be tolerated if an individual is dressed appropriately? Clothing should be worn in layers to allow flexibility in achieving the desired level of heat retention. The inner layer-cotton or silk-should absorb sweat to keep the outermost layer dry. A middle layer of wool absorbs excess sweat and allows evaporation, and an outermost layer of Goretex or polypropylene protects against wind, rain, and snow yet lets the body "breathe." A hat that covers the ears is important, as 50% of body heat is lost or gained via the head. (On extremely cold days, goggles, a mask, and petroleum jelly on the face might be necessary.) Gloves or mittens are particularly critical as circulation to the extremities is decreased due to their distance from the heart and limited musculature. Socks should be a wool/cotton mix or a ribbed, woven synthetic material! Overdressing should be avoided; when appropriately dressed, the exerciser should feel slightly chilly at the start of exercise and begin to warm shortly after. The clinical manifestations of cold injury include chilblains, muscle cramps, frostbite, and whole-body hypothermia (i.e., a rectal temperature of c35" C).138 Conditions that increase the risk of cold stress include wet clothing, wind chill, remaining outside while sweating after cessation of the exercise session, and becoming lost while exercising in the cold. The wind chill factor, or combined effects of absolute temperature and wind velocity, should be a matter of great concern to the outdoor exerciser. Wind c h i l l can dramatically affect absolute temperature (e.g., a 15-mph wind at 0" F would reduce effective temperature to -32" F)! Severe cold such as this can freeze exposed

skin within minutes. As the exerciser tires, the metabolic heat production from exercise may decrease (if energy substrates are no longer available) to a point where heat loss to the environment exceeds heat production. After 1to 2 hours of exposure, there are potentially fatal consequences? Some people are uncomfortable breathing cold air (especially cardiac patients susceptible to angina). A scarf draped around the face or a knitted ski mask worn to warm the inhaled air can help prevent discomfort.8 The aforementioned guidelines are for outdoor exercise in cold air.Rapid heat loss is also a serious situation when swimming in a nonheated water environment. Extreme caution is advised.138

Air PoII ut ion Air pollution has become another factor to be concerned about when exercising outdoors, particularly in large metropolitan areas. Carbon monoxide, due to its great affinity for binding with hemoglobin, impedes oxygen transport. High concentrations of carbon monoxide greatly decrease physical work capacity. Ozone has also been shown to have a negative effect on exercise performance.8Although only one pollutant in a given area may be identified as having reached an "alert" level, typically other pollutants are also present, with cumulative detrimental effects on exercising individuals. Exercisers can decrease air pollution exposure by exercising during the early morning hours before pollution accumulates, during periods of increased air movement (i.e., windy days), in less traveled areas, or indoors when pollution levels are high. We have found value in wearing a surgical mask while exercising in major metropolitan areas but have been unable to find any studies that have evaluated the efficacy of this or other more extreme precautionary measures, such as gas masks.

Altitude As altitude increases, the partial pressure of oxygen is proportionately lower than at sea level. This makes it more difficult to deliver oxygen to the exercising muscles, and so performance is decreased in direct proportion to altitude? As elevation increases, ambient temperature decreases, adding the stressor of cold to the equation. As a result of this additional stress, exercise intensity should be decreased. If the WE method for determining exercise intensity is used regularly, exercisers can adjust to maintain a level of exertion at high altitudes comparable to that they experience at sea level. After several weeks at a particular altitude, the body partially acclimatizes, but performance is still compromised. Caution must be exercised by individuals with CHD or abnormal lung function (i.e., emphysema and chronic bronchitis).8

SIDE EFFECTS AND CONTRAINDICATIONS OF EXERCISE Athlete's Heart Although originally a pathologic diagnosis, athlete's heart, or increased heart size, is now known as a normal physiologic response to training. Increased heart size may manifest as the following? Bradycardia A more prominent sinus arrhythmia A forceful apical impulse Third and fourth heart sounds Systolic flow murmurs Electrocardiogram changes consistent with increased vagal tone (sinusbradycardia and arrhythmia, PR prolongation, and Wenckebach second-degreeheart block) and ventricular hypertrophy may also be present.

Sports Anemia A mild decreasein hemoglobin or hematocrit, the so-called sports anemia, is commonly seen in endurance athletes. This, however, is not a true anemia, as red cell mass is normal. Rather, plasma volume is disproportionately increased? Although only a small amount of iron is lost through perspiration, menstruating women who consume a low-iron diet may be at risk. Exercise-induced hemolysis or gastrointestinal bleeding (occurring in 8% to 22% of marathon runners) may, however, exist and should be considered. While footstrike can produce intravascular hemolysis in runners, intravascular hemolysis has also been reported in swimmers, suggesting that trauma alone does not explain the phenomenon? Contact activities such as karate, marching, and football may produce enough trauma to capillaries to damage normal red blood cells. The effects are typically short term, and chronic anemia is rare. Sickle cell trait may increase risk, but the research is mixed.2

Athlete's Hematuria and Albuminuria Exercise-inducedhematuria and albuminuria are benign, self-limiting conditions occurring in many athletes. Mcroscopic or gross hematuria and mild albuminuria are most likely in the first urine voided after exercise and should resolve within 48 hours2Severe or slowly resolving hematuria or albuminuria indicate the need for careful urinary tract evaluation.

Exercise4nduced Asthma The association between vigorous exercise and asthma has long been recognized. Exercise-induced asthma (EIA) is not a variant form of asthma but rather a nonspecific response occurring in approximately 12% of the population. During or immediately after exercise, symptoms and signs of EIA or bronchospasm are recognizable as

dyspnea, choking, increased mucous production, fatigue, chest pain, or wheezing. The mechanism by which EIA is triggered is still unknown. It has been suggested that the increased loss of heat or water, or both, from the respiratory tract that results from exercise-induced hyperpnea may be a trigger.139It has also been suggested that exercise intensity is the triggering factor and that climatic conditions modify the severity of the EIA. In the study by Noriski and colleagues,14 it was found that the higher the intensity, the more severe the EM. Exercise therapy for asthma was not generally accepted as a treatment 10 to 15 years ago, due to the 40% to 95% rate of exercise-induced bronchospasm in asthmatic children exercising at school or on a playground.141Today it is recognized that although exercise does not change the basic asthmatic condition as objectively measured by spirometry, it does improve physical fitness, develop skills, and help affected individuals to cope with the disease and its emotional component.'" EIA is frequently defined as 5 to 15 minutes of respiratory difficulty following 5 to 8 minutes of sustained exercise.'" Running appears to be the most attack-provoking exercise and swimming the lea~t.'"J~~ Swimming the backstroke may help to alleviate breathing problems encountered in the water.141 The exercise prescription should initially be limited to 5-minute intervals to avoid triggering an attack. Short bursts of activity are tolerated well. The mode of exercise tolerated best appears to be that performed indoors in a controlled environment such as swimming, wrestling, or stationary bicycling. Intensity can be high if intervals are short, 2 to 3 minutes. However, moderate exercises build endurance more effectively.'@Frequency is the same as recommended for those without EIA. After training regularly for a year, other modes of exercise, even running, may be sub~tituted.'~~

Exercise-Induced Urticaria and Anaphylaxis Exercise, fever, or a warm bath may induce a hypersensitivity reaction characterized by tiny urticaria1 lesions surrounded by large areas of erythema. Serum histamine levels are elevated and wheezing may occut (see Chapter 213 for further discussion and therapeutic approach). Occasionally, exercise may produce a syndrome virtually identical to allergen-induced anaphylaxis. The syndrome begins with a prodrome fatigue, warmth, and pruritus, progressing to generalized urticaria and possibly to angioedema. Full-blown attacks result in choking, respiratory distress, abdominal colic, nausea, and syncope.2Although the cause is unknown, the mechanism includes mast cell activation and elevated levels of histamine. There is a possible link to specific foods,'44 and familial cases have been reported.

The Exercise Prescription

Menstrual Dysfunction and Changes in Sex Hormones Delayed menarche has been reported in girls who train heavily before puberty and amenorrhea or oligomenorrhea in highly trained adult female athletes. Nineteen percent of Olympic marathon runners are amenorrheic. The pathogenesis is unknown but is most likely multifactonal. Many factors have been associated with athletic menstrual dysfunction (AMD): Weight loss Intensity of exercise Energy drain Quantity and quality of diet Aberrant nutritional patterns Chronologic age Gynecologic age Competition stress-induced hypothalamic dysfunction (elevated serum cortisol and catecholamines appear to suppress LH release and possibly FSH, prolactin, and estradiol). No long-term effects on reproductive function have been noted? A frequently cited cause of low body fat is based on the work of Frisch and McArthur. They suggested that 22% body fat is necessary for onset and maintenance of menstrual function and hypothesized that this amount of body fat is necessary as adipose tissue converts androgens to estrogen. The major criticism of their research is that they used an indirect method (i.e., equations and heightlweight tables) to estimate body fat. Other researchers using more direct body fat measurement (i.e., hydrostatic weighing) found no signhcant association between the percentage of body fat and AMD.'" The body fat connection to athletic amenorrhea is controversial. Although some studies have found a correlation,'46 several others have not,'45J47-149 suggesting that other factors are involved. Endurance athletes, especially those who are amenorrheic, may be taking in too few calories to compensate for their energy output. Yet these athletes appear to maintain a stable weight, suggesting that there may be conservation of energy in other areas. As a lower resting metabolic rate has been associated with calorie restriction, it has been proposed that amenorrhea may be an energyconserving response to a hypocaloric diet. Eating disorders have been found to be prevalent among endurance athletes,ballet dancers, and recreational and competitive body b ~ i l d e r s . Research ~~~,~~ attention is now being focused on the association between diet and athletic activity as the cause of AMD. One recent study found that amenorrheic high-mileage runners seem to have a less adequate diet than eumenorrheic runners, although they appear to maintain an adequate energy balance

and stable weight through a reduction in resting metabolic rate.'" In men, acute exercise increases, while chronic exercise and weight loss decrease, testosterone. A small number of highly trained marathon runners are also found to have oligospennia.2

Osteoporosis Amenorrheic athletes may be at risk for osteoporosis. Vertebral (but not radius) bone density is reduced in these women, and an increased incidence of fractures has been found? Young ballet dancers with delayed menarche and secondary amenorrhea have an increased risk of scoliosisand stress fractures.151Slightly decreasing exercise or increasing body weight usually reestablishes their menstrual cycle. Both menstruating and menopausal physically fit women have higher bone density than sedentary women.

Incontinence A common, although little known, problem for women is incontinence during exercise. Although considerable research has studied the effects of exercise on most of the body's organs and structures, little attention has been paid to the lower urogenital tract until recently. A 1990 study by Nygaard and colleagues152found that 47% of participants had some degree of incontinence. This figure correlated with the number of vaginal deliveries. Of these, 30% noted incontinence during at least one type of exercise. Exercises involving repetitive bouncing (i.e., running, high-impact aerobics, tennis, low-impact aerobics, and walking) were associated with the highest incidence of incontinence. Incontinence caused 20% of exercisers to stop an exercise, 18% to change the way a specific exercise was performed, and 55% to wear a pad during exercise. With one in three women experiencing the problem, this study clearly demonstrated that incontinence during exercise is not unusual. Exercise per se is not the cause of incontinence (only one woman was incontinent solely during exercise)but could prove to be a possible obstacle for some women. In this study, women appeared to be adaptive. Some nonsurgical options to ameliorateincontinence include Kegel exercises, weighted vaginal cones, and interferential therapy.153

Acute Muscle Injury Elevated levels of muscle enzymes usually accompany exercise. Creatine kinase (CK) is the most sensitive, rising within minutes of even mild exercise and lasting for days after strenuous exercise. Delayed-onset muscle sorenessafter exercise correlateswith CK levels. Strenuous exercise produces mild elevations in serum aspartate aminotransferase (AST, formerly SGOT) and myoglobin, while high levels of the latter may indicate potentially serious rhabdomyolysis.

Heat Stroke Heat stroke, representing a serious failure of thermoregulation, is a medical emergency. A diminution of sweating is commonly observed before the onset of symptoms, which are typically the following: The abrupt onset of altered consciousness Prostration Flushed, dry skin Tachycardia Dehydration Body temperatures in excess of 41.1" C are common, although some victims have lower temperatures. The primary treatment is intravenous fluids and active cooling, involving the application of ice packs or ice-water baths until core temperature reaches 39" C. Adjunct therapy includes fluids, electrolytes as needed, correction of acidosis, treatment of arrhythmias, and circulatory and respiratory s ~ p p o r t . ~

Sudden Death The 1984 death of author and marathon runner Jim Fixx raised questions about the safety of vigorous exercise. As exercising increased in popularity in the 1970s and 1980s, several studies were published reporting cardiovascular complications and sudden deaths during or following vigorous exercise.1s159 However, a report by Koplanlm estimated that, statistically, 100 deaths per year would occur during jogging, simply by chance. The risk of a major cardiovascular event during exercise increases tenfold for those with underlying cardiovascular disease." The cause of death in both the young (younger than 30 years of age) and old (older than 30 years of age) conditioned subjects who die suddenly during or immediately following vigorous exercise is congenital or acquired CHD in 90% of cases.161In those older than age 30, atherosclerotic heart disease is the primary killer, while in those younger than age 30, congenital coronary artery anomalies and hypertrophic cardiomyopathyare the primary causes.161-163 Sudden death in young men is often predated by such symptoms as syncope and chest pain. Data suggest that exercise contributes to sudden death in susceptible persons. This implies that those older than age 30 who participate in vigorous exercise without also modlfylng other high-risk factors for CHD (e.g., hypercholesterolemia, smoking) increase their risk of sudden death during vigorous exercise.lMJ6This is, however, offset by the decreased risk of cardiac mortality induced by fitness.

Steroid Use Anabolic-androgenic steroid use is currently viewed as a serious health problem. At one time, weightlifters were

the primary consumers of these drugs, but recently both male and female power athletes, endurance athletes, and even nonathletes are consuming steroids. Although the use of steroids may be accompanied by gains in lean body mass, body weight, and strength, it has also been associated with adverse effects. These include liver, cardiovascular, reproductive, and psychologic abnormalities,as well as lowered HDL l e ~ e l s . 2 , ' ~ J ~ ~ Other risks include diseases associated with shared needles, such as hepatitis and AIDS.168 Despite the growing awareness of the potential side effects of steroid use, its popularity is increasing and the consumers are getting younger. A recent study by Windsor and D u m i t r ~ found ' ~ ~ a sigruficant percentage of male and female high school students (particularly male athletes from upper socioeconomic levels) using anabolic steroids obtained illicitly (group 1male athletes reported a 10.2%prevalence). Athletes use steroids in an attempt to improve performance in various sports, most commonly those requiring considerable strength such as football, wrestling, weight lifting, sprinting, and shot put. They are also used by swimmers, cyclists, and male and female bodybuilders. One recent study found users among high school students who did not even participate in organized sports.170 The use of androgenic steroids began in the 1950s and has increased in the decades since, despite warnings of potential harmful side effects and their banning by the International Olympic Committee.166 Education is of vital importance to curb the abuse of steroids. Physicians can contribute to the education effort by providing athletes and other users with timely and accurate information on the health risks and performance enhancement effects of steroid use.

CONCLUSION Although many unanswered questions remain, sufficient data are available to conclude that regular physical activity promotes good health. This may seem an obvious statement to those who believe in the value of exercise, but due to the multifactorial nature of disease, it is a difficult hypothesis to prove. The probable benefits of exercise are many, including prevention of the leading causes of morbidity and mortality in the United States. Exercise therapy plays a major role in naturopathic medicine, which advances the concept that a healthy and fit body promotes a healthy and fit mind.

The Exercise Prescription

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Glandular Therapy Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 377 Methods of Manufacture of Glandular Preparations 377 The Azeotrophic Method 378 The Salt Precipitation Method 378 Freeze-drying 378 Predigestion 378

Clinical Applications 379 Adrenal Extracts 379 Aortic Glycosaminoglycans 379 Liver Extracts 380 Pancreatic Extracts 380 Spleen Extracts 380 Polyerga 381 Thymus Extracts 383 Thyroid Extracts 384

Spongiform Encephalopathy 378 Summary 384 Evidence for Intact Protein Absorption 378

INTRODUCTION For almost as long as historic records have been kept, glandular therapy has been an important form of medicine. The basic concept underlying the medicinal use of glandular substances from animals is that ”like heals like.” For example, if the liver needs support or a patient is suffering from liver disease, then he or she may benefit from eating beef liver. Modern glandular therapy, however, primarily involves the use of concentrated glandular extracts. A gland is defined as a secretory organ. The internal secretory organs of the body are called endocrine glands. These ductless glands secrete hormones directly into the bloodstream. The glands known to have endocrine function include the pineal, pituitary, thyroid, parathyroid, thymus, adrenal, pancreas, and gonads (testes or ovaries). Although not technically glands, it is common to refer to other organs of the body as glandulars when they are used in glandular therapy. For example, tissue extracts of heart, spleen, prostate, uterus, brain, and other tissues are often used in glandular or organotherapy. Research has shown that certain glandular preparations and hormones are quite effective when taken orally. A number of glandular preparations are effective orally because of active hormone or enzyme content (e.g., thyroid, adrenal cortex, and pancreatin preparations).A good deal of literature supports pharmaceutic grade liver, aorta, and thymus extracts, and some support exists for

pituitary, spleen, orchic (testes), and ovarian extracts as well. However, despite this scientific support, many still question the effectiveness of glandular products on human health. A key challenge to the use of glandulars is the lack of widely accepted standards for extraction and quantification. Each manufacturer of a glandular product claims its method of extraction is the most ideal. However, the majority of these contentions are based on theoretic or philosophic grounds, not on research or clinical results. No quality control procedures or standards are enforced in the glandular industry. It is left up to the individual company to adopt quality control and good manufacturing procedures. Nonetheless, many glandular preparations available in the U.S.marketplace appear to be effective.

METHODS OF MANUFACTURE OF GLANDULAR PREPARATIONS It is critical that properly processed glandular material be used, as the biologically active material such as enzymes, soluble proteins, natural lipid factors, vitamins, minerals, and hormone precursors are destroyed or eliminated if the product is not prepared properly. Most glandular products are derived from beef (bovine) sources, the exception being pancreatic extracts that are most often derived from pork (porcine). The four most widely known methods of processing are the 377

azeotrophicmethod, salt precipitation, freeze-drying, and predigestion.

The Azeotrophic Method The azeotrophic method begins by quick freezing the material at well below 0" F, and then washing the material with a solvent (such as ethylene dichloride) to remove the fatty tissue. The solvent is then distilled off, and the material is dried and ground into a powder so that it can be placed in tablets or capsules. Although the azeotrophic method eliminates the problem of fat-stored toxins like pestiades and healthy metals, unfortunately it also removes fat-soluble hormones, enzymes, essential fatty acids, and other potentially beneficial materials, and traces of the solvent still remain.

The Salt Precipitation Method This method involves the maceration of fresh glandular material in salt and water. Because the salt increases the density of the water-soluble material, when the mixture is centrifuged the lighter fat-soluble material can be separated out. The material is then dried and powdered. The benefit with the salt precipitation method is that no toxic solvents are used to separate the fatty material. The downside is the increased salt content of the product.

Freeze-drying The freeze-drying process involves quickly freezing the glandular material at temperatures of -40" F to -60" F and then placing the material into a vacuum chamber, which removes the water by direct vaporization from its frozen state (hence the term freeze-drying). The benefit of freeze-drying is that it contains a higher concentration of unaltered protein and enzymes, as well as all of the fat-soluble components. Since the fat is not removed, it is critical that the glands are derived from livestock that have grazed on open ranges not sprayed with pesticides or herbicides. The animals must also be free from antibiotics, synthetic hormones, and infection.

Predigestion The predigestion method employs plant and animal enzymes or some other method to partially digest or hydrolyze the glandular material. The partially digested material is then passed through a series of filtrations to separate out fat-soluble and large molecules. The purified material is then freeze-dried. This method of extraction is best for glandulars (such as the liver and thymus) where the polypeptide and other water-soluble fractions are desired.

SPONGIFORM ENCEPHALOPATHY Bovine spongiform encephalopathy (BSE), also known as mad cow disease, is a transmissible, slowly progressive,

degenerative, fatal disease affecting the central nervous system of adult cattle. The transmissible agent in BSE is a modified form of a normal cell surface component known as a prion protein. Unlike infectious organisms, prions are resistant to common treatments, such as heat and digestive secretions. Eating the meat of an animal with BSE may lead to a disease similar to BSE in humans called variant Creutzfeldt-Jakob Disease (CJD),or vCJD. Approximately 100 cases have been verified since 1986. BSE was first reported among cattle in the United Kingdom in 1986 and has been a major concern since. The outbreak in the United Kingdom may have started from the feeding of scrapie-contaminated sheep meatand-bone meal to cattle. Scrapie is a disease of sheep that is related to BSE in cattle. Evidence is strong that the outbreak in cattle was amplified in the United Kingdom by feeding rendered bovine meat-and-bone meal to young calves. BSE has been reported in cattle throughout Europe. There has been a single case in Canada and, most recently, in the United States from a cow imported from Canada. Wild game in the United States such as deer and elk have been affected with a similar disease known as chronic wasting disease (CWD). The reason American cattle have been spared may be due to the active surveillance and import measures taken by the U.S. Food and Drug Administration (FDA) and the U.S. Department of Agriculture (USDA). The USDA has restricted the importation of live ruminants, such as cows and sheep, and food products from these animalsfrom BSE countries since 1989, and from all European countries since 1997. In addition, the FDA prohibits the use of most mammalian protein in the manufacture of animal feeds given to ruminants because this kind of feeding practice is believed to have initiated and amplified the outbreak of BSE in the United Kingdom. To reduce the risk of ingesting beef with BSE, it is critical to use products manufactured under the following guidelines: The June 2000 European CommissionDecision regulating the use of material presenting risks for BSE A "Certification of Suitability" by the European Directorate of Quality of Medicines to ensure the highest quality, pharmaceutic grade material is being used The FDA's guidelines for sourcing and processing of bovine material

EVIDENCE FOR INTACT PROTEIN ABSORPTION Contrary to long-held theories that the healthy intestinal mucosa is an essentially impermeable barrier to proteins and large polypeptides, there is now considerable evidence that large macromolecules pass intact from the

normal human gut into the bloodstream. In some instances, the body appears to recognize which molecules it needs to absorb intact and which molecules it needs to break down into smaller units.This phenomenon may help to explain the effectivenessof glandular therapy. Numerous whole proteins have been shown in human and animal studies to be absorbed intact into the bloodstream following oral administrati~n.'-~ These include human albumin and lactalbwnin, bovine albumin, ovalbumin, lactoglobulin,ferritin (molecular weight 500,000), chymotrypsinogen,elastase, and other large molecules. Furthermore, proteins and polypeptides, as well as various hormones that are absorbed intact from the gut, have been shown to exert effects in target tissues. For example, in addition to thyroxine or thyroid hormone and cortisone, several peptide hormones are known to be biologically active when administered orally, including luteinizing hormone-releasing factor and thyrotropinreleasing h ~ r m o n e .Even ~ , ~ insulin has been shown to be absorbed orally under certain circumstances (e.g., in the presence of protease inhibitors or hypertonic solutions in the intestines).lOJ These data indicate that at least some of the larger molecules in glandular products are absorbed intact to induce physiologic effects, particularly polypeptides, which exert hormone or hormonelike action.

Therapeutic uses of glandular extracts Extract

Clinical amlications

Adrenal extracts

Chronic fatigue Asthma Eczema Psoriasis Rheumatoid arthritis

Aortic Cerebral and peripheral arterial insufficiency glycosaminoglycans Venous insufficiency and varicose veins Hemorrhoids Vascular retinopathies, including macular degeneration Postsurgical edema Liver extracts Chronic hepatitis Chronic liver disease Pancreatic extracts

Spleen extracts

CLINICAL APPLICATIONS An adequate body of research now exists to support the

use of orally administered glandular extracts. The following is a brief discussion of several glandular preparations and their use. Table 38-1 lists the primary conditions responding to glandular therapy.

Adrenal Extracts Oral adrenal extracts have been used in medicine since at least 1931.12Adrenal extracts may be made from the whole adrenal or just from the adrenal cortex. Whole adrenal extracts (usually in combination with essential nutrients for the adrenal gland) are most often used in cases of low adrenal function, presenting as fatigue, inability to cope with stress, and reduced resistance. Because extracts made from the adrenal cortex contain small amounts of corticosteroids, they are typically used as a "natural" cortisone in severe cases of allergy and inflammation (e.g., asthma, eczema, psoriasis, rheumatoid arthritis).

Dosage The dosage of adrenal extract depends on the quality and potency of the product. The best measure of an effective dose for a preparation may be the level of stimulation (irritability,restlessness, and insomnia) the patient experiences. When prescribing adrenal extracts, start at one third of the recommended dosage on the label and slowly

Pancreatic insufficiency Cystic fibrosis Inflammatory and autoimmune diseases such as rheumatoid arthritis, scleroderma, athletic injuries, and tendinitis Cancer Infections After splenectomy Immune potentiation Infection Cancer Hyposplenia Celiac disease Dermatitis herpetiformis Ulcerative colitis Rheumatoid arthritis Glomerulonephritis Systemic lupus erythematosus Vasculitis Low white cell counts Thrombocytopenia

Thymus extracts

Recurrent and chronic viral infections, such as chronic fatigue syndrome, respiratory infections, AIDS, acute hepatitis 6 infection Cancer patients with immune depression from chemotherapy or radiation Asthma, hay fever, eczema, and food allergies Autoimmune disorders, such as rheumatoid arthritis, lupus erythematosus, and scleroderma

Thyroid extracts

Hypothyroidism

increase the dosage every 2 days until a stimulatoryeffect is noted. Once this effect is noticed, reduce the dosage to a level just below the level that will produce stimulation.

Aortic Glycosaminoglycans A mixture of highly purified bovine-derived glycosaminoglycans (GAGS) naturally present in the aorta including dermatan sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, and related hexosaminoglycans has been shown to protect and promote normal artery

and vein function. More than 50 clinical studies have shown an orally administered complex of aortic GAGs to be effectivein a number of vascular disorders, including the following: Cerebral and peripheral arterial insufficiency Venous insufficiency and varicose veins Hemorrhoids Vascular retinopathies, including macular degeneration postsurgical Significant improvements in both symptoms and blood flow have been noted. In addition, aortic GAGs have many important effects that interfere with the progression of atherosclerosis, including preventing damage to the surface of the artery, formation of damaging blood clots, migration of smooth muscle cells into the intima, and formation of fat and cholesterol deposits, as well as lowering total cholesterol levels while raising high-density lipoprotein cholester01.~~~

Dosage The dosage of the mixture of highly purified bovine derived GAGs naturally present in the aorta is 100 mg daily. Similar, but not nearly as impressive, results in the treatment of atherosclerosis have been noted with chondroitin sulfate at a daily dose of 3 g (1 g, threetimes daily).%

Liver Extracts Beef (bovine)liver extracts and concentrates are a rich natural source of many vitamins and minerals, including iron. Liver extracts can confain as much as 3 to 4 mg of heme iron per gram. In addition to its use as a source of iron and other nutrients, hydrolyzed liver extracts have been used to treat chronic liver diseases since 1896. Numerous Scientific investigations into the therapeutic efficacy of liver extracts have demonstrated that these extracts improve fat utilization, promote tissue regeneration, and prevent damage to the liver.B32In short, clinical studies have demonstrated that oral administration of hydrolyzed liver extracts can be quite effective in improving liver function. For example, in one doubleblind study, 556 patients with chronic hepatitis were given either 70 mg of liver hydrolysate or a placebo three times daily.32 After 3 months of treatment, the group receiving the liver extract was shown to have far lower serum liver enzyme levels. Since the level of liver enzymes in the blood reflects damage to the liver, it can be concluded that the liver extract is effective in chronic hepatitis via an ability to improve the function of damaged liver cells, as well as prevent further damage to the liver.

Dosage The dosage is entirely dependent on the concentration, method of preparation, and quality of the liver extract.

The highest-quality products are aqueous hydrolyzed extracts because they have had the fat-soluble components removed and typically contain more than 20 times the nutritional content of raw liver, including 3 to 4 mg of heme-iron per gram.

Contraindication Liver extracts should not be used in patients suffering from an iron-storage disorder such as hemochromatosis.

Pancreatic Extracts Pancreatic enzymes are most often employed in the treatment of pancreatic insufficiency. Pancreatic insufficiency is characterized by impaired digestion, malabsorption, nutrient deficiencies, and abdominal discomfort. Pancreatic enzymes are also used by physicians in the treatment of the following: Cystic fibrosis Inflammatory and autoimmune diseases like rheumatoid arthritis, scleroderma, athletic injuries, and tendinitis Cancer Infections For a full discussion of pancreatic enzymes, see Chapter 112.

Dosage Full-strength products are preferred to lower potency pancreatin products because lower potency products are often diluted with salt, lactose, or galactose to achieve desired strength (e.g., 4x or lx). The dosage recommendation for a lox U.S. Pharmacopoeia (USP) pancreatic enzyme product is 500 to 1000 mg three tirnes a day immediately before meals when used as a digestive aid and at least 20 minutes before meals or on an empty stomach when antiinflammatory effects are desired. Pancreatic extracts are generally well tolerated and are not associated with any sigTuficant side effects.

Spleen Extracts As early as the 1930s, orally administered bovine spleen extracts were shown to possess some physiologic action in increasing white blood cell counts in patients with extreme deficiencies of white blood cells, as well as being of some benefit in patients with malaria and typhoid Like thymus extracts, pharmaceutic-grade bovine spleen extracts are currently quite popular in Germany for the treatment of infectiousconditions and as immuneenhancing agents in cancer. Spleen tissue extracts may be of benefit in enhancing general immune function, as many potent immune system-enhanchg compounds secreted by the spleen are low molecular weight peptides.

Glandular Therapy

For example, the potent immunostimulants tuftsin and splenopentin are composed of only four and five amino acids, respectively. Both tuftsin and splenopentin have been shown to exert profound immune-enhancingactivity. Tuftsin stimulates macrophages that have taken up residence in specific tissues like the liver, spleen, and lymph nodes. These large cells engulf and destroy foreign particles, including bacteria, cancer cells, and cellular debris. Macrophages are essential in protecting against invasion by microorganisms, as well as cancer. Tuftsin also helps to mobilize other white blood cells to fight against infection and cancer. A deficiency of tuftsin is associated with signs and symptoms of frequent infections.36 Splenopentin, like tuftsin, has also demonstrated sigruficant immune-enhancing effects. Its effects are primarily directed toward enhancing the immune system’s response to regulating compounds such as colony-stimulating factors?’ Colony-stimulatingfactors, such as interleukin-3, and granulocyte/macrophage colony-stimulating factors stimulate the production of white blood cells. Splenopentin is probably the factor responsible for the resultsnoted in those clinical studiesduring the 1930swith spleen extracts in the treatment of depressed white blood cell counts. Splenopentinhas also been shown to enhance natural killer cell activity?’ Natural killer cells destroy cells that have become cancerous or infected with viruses and are the body’s first line of defense against cancer. In addition to tuftsin and splenopentin, hydrolyzed (predigested) spleen extracts concentrated for peptides have demonstrated impressive immune restorative properties in mice.39In one study, mice were exposed to radiation to sigruficantly damage the immune system. Mice treated with the spleen extract recovered within 6 to 8 weeks. In contrast, those treated with a placebo recovered after 10 weeks at the earliest. The primary clinical uses of spleen extracts are after removal of the spleen and the following conditions associated with low spleen function (hyposplenia): Celiac disease Dermatitis herpetiformis Ulcerative colitis Rheumatoid arthritis Glomerulonephritis Systemic lupus erythematosus Vasculitis Thrombocytopenia Spleen extracts may also be useful in the treatment of low white blood cell counts, bacterial infections, and as an adjunct in cancer therapy. Individuals who have had splenectomies or who have low tuftsin levels or autoimmune conditions linked to low activity of the retidoendothelial system (RES) should use spleen extracts.

Since the spleen is difficult to repair, severe spleen trauma usually requires splenectomy to stop the severe hemorrhage. The spleen is also removed in the medical treatment of certain diseases such as idiopathic thrombocytic purpura (ITP) and to determine the extent of Hodgkin disease. Removal of the spleen is associated with an increased risk for infection. In children and adults this increased risk of infection makes them particularly susceptible to pneumococcal pneumonia. About 2.5% of patients who have their spleen removed die from pneumococcalpneumonia within 5 years of splenectomy. It is often recommended that a child who has undergone a splenedomy receive a pneumococcal vaccine and receive long-term antibiotic treatment. Use of spleen extracts, especially those rich in tuftsin, may be a natural alternative. Spleen extracts should probably be viewed as a necessary medicine for people who have had their spleen removed. If the thyroid, adrenals, or ovaries are removed, most patients would be prescribed the corresponding hormone. It only makes sense that if the spleen is removed, the body should be supplied with necessary spleen substances like tuftsin and splenopentin. The increased risk of infection is attributed primarily to a deficiency of t u f t ~ i n .T~ uf,ts ~in ~ is produced only in the spleen; without the spleen there simply is no tuftsin in the circulation. Without tuftsin, the body is without one of its key stimulators of the immune system. Individuals without spleens need an outside source of tuftsin like spleen extracts.

Dosage Clinically, hydrolyzed (predigested) products concentrated for tuftsin and splenopentincontent are preferable to crude preparations. The daily dose should provide 50 mg tuftsin and splenopentin or roughly 1.5 g of total spleen peptides. No side effects or adverse effects have been reported with the use of oral spleen preparations.

Polyerga Before the development of manufacturing techniques for human insulin to be used in the treatment of diabetes, the source was insulin isolated from pig pancreas. In Germany, after World War 11, there was a shortage of pigs and subsequently a shortage of insulin. A German researcher, Walter Kuhlmey, MD, PhD, subsequently sought to produce insulin for other animal organs, most notably the spleen. In the process, it led to the serendipitous discovery of Polyerga. Kuhlmey found that the pig spleen extract not only had some insulin-like activity, but that it also increased the general sense of well-being and gave people more energy. He named his new product Polyerga (in Latin poly means ”multiple” and ergu means ”power”).

Therapeutic Modalities

Initially, Polyerga had a general use.In 1951 an event changed Polyerga’s clinical use.Julia Meir was a patient of oncologist Heinrich Pophanken, MD, who had an advanced cancer of the pancreas. She was considered incurable, and her death was expected shortly. In an effort to ease her pain, lift her fatigue, and stimulate a sense of well-being in Julia, Pophanken gave her Polyerga (via injection). Surprisingly, the dying patient began to recover. Pophanken gave Julia three to six intramuscular injections of Polyerga per week during the first 2 months and then just two injections a week thereafter. In 1954 Julia died of causes unrelated to her cancer. When the autopsy was conducted, the egg-sized tumor in her pancreas had disappeared entirely. This single case history led to the focus of research on Polyerga as a cancer therapy.

Cancer Therapy Polyerga has been evaluated in several clinical studies in cancer patients. In one of the largest trials, 158 breast cancer patients were divided into two groups. The women in the Polyerga group received injections of Polyerga three times per week, while the women in the control group received a placebo injection. In the Polyerga group, the percentage of white blood cells, various parameters of immune function, body weight, and general sense of wellbeing all improved sigruficantly compared with the control group.q In a double-blind, placebo-controlled study in patients with head and neck cancers, Polyerga was shown to support patients who were receiving the chemotherapy drugs 5FU and ~isplatin.4~ Polyerga was shown to stabilize the levels of lymphocytes. Typically,patients receiving 5-FU, cisplatin, and other chemotherapy drugs experience a reduction in lymphocytes. This effect was noted in the placebo group but not in the patients receiving Polyerga. In addition, the Polyerga group reported less fatigue and higher energy levels than the placebo group, and there was no weight loss. Prevention of weight loss is a major goal in the support of the cancer patient, as significant weight loss reduces the tolerance to anticancer drugs,reduces the functioningof the immune system, and is considered to be a major cause of death in the cancer patient. In another study of 248 cancer patients, giving them Polyerga orally for 4 months improved appetite, reduced pain, increased energy and activity levels, and improved their general sense of well-beingu Furthermore, a reduction of the extent of the illness, along with a clear improvementof health, was recorded by observing physicians. Best results were obtained in breast cancer patients and patients suffering from colon and other carcinomas, while lung cancer patients and patients with metastases did not seem to respond as well to Polyerga. Other studies have shown Polyerga to produce similar benefits, as well as enhance survival time and reduce

metastasis (spreading) in patients with cancers of the colon, stomach, and lungs.&From the totality of existing clinical studies, animal studies, and test tube (in vitro) studies, it can be concluded that Polyerga does the following: Exerts significant immune-enhancing effects Prevents some side effects of chemotherapy, especially the detrimental effects on the immune system Enhances the effectivenessof conventional chemotherapy and radiation treatment Prevents metastasis Enhances the general sense of well-being, improves energy levels, and prevents detrimental weight loss in cancer patients Enhances both the quality of life and survival time in cancer patients

The Mechanism of Action Many effects of Polyerga may be the result of boosting the output of gamma-interferon.%This important chemical acts as the communication linkbetween the macrophages and lymphocytes. Reduction in the level of gammainterferon results in sigruficantly impaired immune function. Low gamma-interferon levels are common in cancer patients. By increasing gamma-interferon levels, Polyerga creates a cascading of effects that lead to enhanced immune function in cancer patients. Polyerga increases activation of natural killer ~ells.4’-~

Other Uses Polyerga may be helpful any time immune support is required, such as in chronic viral infections including hepatitis C, human immunodeficiency virus (HIV), and Epstein-Barr. In a study of 10 patients with chronic hepatitis B, Polyerga administration (intramuscularly twice weekly and orally 3 tablets daily for 24 weeks) led to complete resolution in 3 of the 10 and lowering of liver enzymes in individuals with lower viral loads?* Polyerga may also be quite helpful to people who have had their spleens removed.

Dosage Most studies with Polyerga used injectable preparations. Based on dose-effect studies in animals, as well as human clinical data, an effective oral dosage was determined. Each Polyerga tablet contains 100 mg of polypeptides. The optimum dosage recommendation is one to two tablets three times per day. For patients up to 140 lb body weight, the dosage is one tablet three times per day. For each additional 40 lb body weight, add a tablet (e.g., a 220-lb person would take five tablets daily in divided dosages). There is no toxicity with Polyerga, so there is no concern about o ~ e r d o s a g e Taking .~~ more than recommended does not necessarily result in better

Glandular Therapy

results, however. For best results, Polyerga should be ingested on an empty stomach before meals.

Thymus Extracts A substantial amount of clinical research supports the effectivenessof orally administered thymus extracts. Specifically, numerous clinical trials have shown that oral administration of predigested calf thymus extract rich in thymus-derived polypeptides is effective in doing the following: Preventing recurrent respiratory infections in children Correcting the T-cell defects in HIV infections (acquired immunodeficiency syndrome [AIDS]) Treating acute hepatitis B infections Restoring the number of peripheral leukocytes in cancer patients with chemotherapy-induced depression of WBC counts Treating asthma, hay fever, and food allergies in children53” The effectiveness of the thymus extract in these conditions is reflective of broad-spectrum immune system enhancement presumably mediated by improved thymus gland activity. This effect fits in nicely with one of the basic concepts of glandular therapy (i.e., that the oral ingestion of glandular material of a certain animal gland strengthens the corresponding human gland). The result is a broad general effect indicative of improved glandular function. Interestingly, thymus extracts have been shown to normalize the ratio of T-helper cells to suppressor cells whether the ratio is low, as in AIDS, chronic infections, and cancer, or high, as in allergies, migraine headaches, and autoimmune diseases like rheumatoid arthritis.

Chronic Viral Infections Recurrent or chronic infections, including the so-called chonic fatigue syndrome and chronic postviral syndrome, are characterized by a depressed immune system. This is a difficult condition to treat due to the repetitive cycle of a compromised immune system leading to infection, which leads to damage to the immune system, further weakening resistance to viral infection. Thymus extracts may provide the answer to chronic infections by restoring healthy immune function. The ability of thymus extracts to treat and then reduce the number of recurrent infections has been studied in groups of children with a history of recurrent respiratory tract infections. Controlled clinical studies revealed not only that orally administered thymus extracts were able to effectively eliminate infection, but also that treatment over the course of a year sigruficantlyreduced the number of respiratory infections and significantly improved numerous immune ~arameters.5~ One of the most difficult viral infections for the body to eliminate is type B viral hepatitis. Thymus extracts

have been shown to be effective in several clinical studies in both acute and chronic cases. In these studies, thera-

peutic effect was noted by accelerated decreases of liver enzymes (transaminases), elimination of the virus, and a higher rate of seroconversion to anti-HBe, signifying clinical r e m i ~ s i o n . ~ > ~ The most extreme example of a chronic viral infection is AIDS. Although thymus extracts have not been shown to reverse this difficult disease, studies have shown an ability to improve several immune parameters, including an ability to raise the T-helper cells, a critical goal in AIDS treatment.%

Cancer The primary application of thymus extracts in cancer has been to counteract the immune-suppressing effects of radiation and chemotherapy. The net effect of thymus extract administration is to prevent the tremendous depression of white blood cell levels and activity that result from chemotherapy or

Allergies In patients with allergies, levels of the allergic IgE antibody and eosinophils are typically elevated, while levels of suppressor T-cells are typically depressed. These abnormalities are clear indications of altered immune function. The oral administration of thymus extracts has been shown in double-blind clinical studies to improve the symptoms and course of hay fever, allergic rhinitis, Presumably this asthma, eczema, and food allergies.54*6062 clinical improvement is the result of restoration of proper immune function, as levels of IgE and eosinophils have been shown to be reduced while the ratio of helper to suppressor T-cells has improved. Interestingly, in several clinical studies, children receiving thymus extracts during food allergy elimination diets are often able to tolerate foods that had previously been allergenic and symptom producing.61,62

Autoimmune Disorders Autoimmune disorders, such as rheumatoid arthritis, are characterized by autoimmunity. Central to this immune dysfunction is a high T-helper-to-suppressor cell ratio. A high T-helper-to-suppressor cell ratio results in increased antibody formation. The higher the ratio, the higher the number of antibodies being produced to damage body structures. In one clinical study, rheumatoid arthritis patients with a T-helper-to-suppressor cell ratio of 3.3 achieved normal ratios (1.02 to 2.46) after 3 months of therapy with a thymus extract.54 Although use of a thymus extract may not result in substantial clinical improvement, it appears to be useful in restoring proper immune function in autoimmunediseases including rheumatoid arthritis, lupus, and scleroderma.

Dosage From a practical view, products concentrated and standardized for polypeptide content are preferable to crude preparations. The daily dose should be equivalent to 120mg pure polypeptides with molecular weights less than lO,OOO, or roughly 750 mg of the crude polypeptide fraction. No side effects or adverse effects have been reported with the use of thymus preparations.

Thyroid Extracts

it is nearly impossible to remove all the hormone from the gland. These nutritional thyroid preparations can be considered milder forms of desiccated natural thyroid. The primary use of thyroid preparations is in the medical treatment of hypothyroidism. In all but its mildest forms, treatment involves the use of desiccated thyroid or synthetic thyroid hormone. For more discussion, see Chapter 179.

Dosage Dosage is determined by basal body temperature (see Chapter 179 for directions).

Desiccated natural thyroid is available by prescription according to USP guidelines. Preparations are derived from porcine thyroid glands. Many naturopathic physicians prefer natural thyroid to isolated synthetic T4, as it contains both thyroxine (T4) and tri-iodothyronine (T3). Typical levels of thyroid hormone contained per grain in USP thyroid are 38 pg of T4and 9 pg of T3. The thyroid extracts sold as "nutritional supplements" are required by the FDA to be thyroxine free. However,

From the scientific data that currently exists, there is enough evidence to support the use of orally administered glandular extracts. For best results, physicians should choose glandular products made by reputable companies that employ established methods of manufacture to produce extracts of known concentration.

1.Gardner ML. Gastrointestinal absorption of intact proteins. Annu Rev Nutr 1988;8.329-350. 2. Gardner ML. Intestid assimilation of intact peptides and proteins from the dkt-a neglected field? Biol Rev 198459289-331. 3. Udall JN, Walker WA. The physiologic and pathologic basis for the transport of macromolecules across the intestinal tract. J Pediatr Gastroenterol Nuk 1982;1:295-301. 4. Kleine MW,Stauder GM, Beese EW. The intestinal absorption of orally administered hydrolytic enzymes and their effects in the treatment of acute herpes zoster as compared with those of oral acyclovir therapy. Phytomedicine 1995;27-15. 5. Hemmings WA, Williams EW. Transport of large breakdown products of dietary protein through the gut wall. Gut 1978;19715-723. 6. Ambrus JL, Lassman HB, De Marchi JJ.Absorption of exogenous and endogenous proteolytic enzymes. Clin Pharmacol Ther 1967;8362-368. 7. Kabacoff BB. Absorption of chymotrypsin from the intestinal tract. Nature 1963;199:815. 8.Ormiston BJ. Clinical effects of TRH and TSH after IV and oral administration in normal volunteers and patients with thyroid disease. In Hal R, Werner I, Holgate H, eds. Frontiers of hormone mearch, vol 1.Basel, Switzerland Karger, 1972:45-52. 9. Amos MS, Rivier J, Guillemin R. Release of gonadotrophins by oral administration of synthetic LRF or tripeptide fragment of LRF. J Clin Endocrinol Metab 19729375-177. 1 O . S e i f e r t J. Mucosal permeation of macromolecules and particles. An@ology1966;17505-513. 11. Laskowski M Jr, Haessler HA, Miech RP, et al. Effect of trypsin inhibitor on pasage of insulin across the intestinal barrier. Science 1958;1271115-1116. 12.Britton SW, Silvette H. Further experiments on cortico-adrenal extract. Its efficacy by mouth. Science 1931;74:440-441. 13. Abate G, Berenga A, Caione F, et al. Controlled multicenter study on the therapeutic effectiveness of mesoglycan in patients with cerebrovascular disease. Minerva Med 1991;82101-105.

14. Mansi D, Sinsi L, De Michele G, et al. Open trial of mesoglycan in the treatment of cerebrovascular ischemic disease. Acta N e w 1 (Napoli) 1988;10:10&112. 15. Laurora G, Cesarone SR, De Sanctis MT, et al. Delayed arteriosclerosis progression in high risk subjects treated with mesoglycan. Evaluation of intima-media thickness. J Cardiovasc Surg 19939: 313-318. 16. Vecchio F, Zanchin G, Maggioni F, et al. Mesoglycan in treatment of patients with cerebral ischemia. Effects on hemorheologic and hematochemical parameters. Acta Neurol (Napoli) 1993;15:449-456. 17. De Donato G, Sangiuolo P. [Instrumental evaluation of the effects of mesoglycan in venous disease patients. Prospective randomized double-blind study]. Minerva Med 1986;77:1927-1931. 18. Oddone G, Fiscella GF, De Franceschi T. Assessment of the effects of oral mesoglycan sulphate in patients with chronic venous pathology of the lower extremities. Gazz Med Ital1987;146:111-114. 19. Prandoni P, Cattelan AM, Carta M. [Long-term sequelae of deep venous thrombosis of the legs. Experience with mesoglycan]. Ann Ital Med Int 1989;4:378-385. 20. Sangrigoli V, Carra G, Lazzara N, et al. [Mesoglycan in acute and chronic venous insufficiency of the legs]. Clin Ter 1989;129207-209. 21. Petruzzellis V, Velon A. [Therapeuticaction of oral mesoglycan in the pharmacologic treatment of the varicose syndrome and its complications]. Mherva Med 1985;76543-548. 22. Saggioro A, ChiozziniG, Pallini P, et al. [Treatment of hemorrhoidal crisis with mesoglycan sulfate]. Minerva Dietol Gastroenterol 1985;31:311-315. 23. Stevens RL, Colombo M, GonzalesJJ, et al. The glycosaminoglycans of the human artery and their changes in atherosclerosis. J Clin Invest 1976;58:470-481. 24.Tammi M, Seppala PO, Lehtonen A, et al. Connective tissue components in normal and atherosclerotic human coronary arteries. Atherosclerosis 1978;29:191-194. 25. Day CE, Powell JR, Levy RS.Sulfated polysaccharide inhibition of aortic uptake of low density lipoproteins. Artery 1975;1:126-137.

SUMMARY

Glandular Therapy 26. Postiglione A, De Simone B, Rubba P, et al. Effect of oral mesoglycansulphate on plasma lipoprotein concentration and on lipoprotein concentrationin primary hyperlipidemia.Pharmacol Res Commun 1984;16:1-8. 27. Saba P, Galeone F, Giuntoli F, et al. Hypolipidemic effect of mesoglycan in hyperlipidemic patients. Curr Ther Res 1986;40:761-768. 28. Nakazawa K, Murata K. The therapeutic effect of chondroitinpolysulphate in elderly atherosclerotic patients. J Int Med Res 1978;6 217-225. 29. Nagai K. A study of the excretory mechanism of the liver-effect of liver hydrolysate on BSP excretion. Jpn J Gastroenterol 1970;67 633-638. 30.Ohbayashi A, Akioka T, Tasaki H. A study of effects of liver hydrolysate on hepatic circulation. J Therapy 1972;54:1582-1585. 31. Sanbe K, Murata T, Fujisawa K, et al. Treatment of liver d i s e a s e with particular reference to liver hydrolysates. Jpn J Clin Exp Med 1973;502665-2676. 32. Fujisawa K, Suzuki H, Yamamoto S, et al. Therapeutic effects of liver hydrolysate preparation on chronic hepatitis-a double blind, controlled study. Asian Med J 1984;26497-526. 33. Minter MM. Agranulocytic angina: treatment of a case with fetal calf spleen. Texas State J Med 1933;2338-343. 34.Gray GA. The treatment of apanulocytic angina with fetal calf spleen. Texas State J Med 1933;29366-369. 35. Greer AE. Use of fetal spleen in agranulocytosis.Preliminaryreport. Texas State J Med 1932;28:338-343. 36. Fridkin M, Najjar VA. Tuftsin: its chemistry, biology, and clinical potential. Crit Rev Biochem Mol Biol1989;241-40. 37.Diezel W, Weber HA, Maciejewski J, Volk HD. The effect of splenopentin (DA SP-5) on in vitro myelopoiesis and on AZTinduced bone marrow toxicity. Int J Immunopharmacol 1993;15: 269-273. 38. Rastogi A, Singh VK,Biswas S, et al. Augmentation of human natural killer cells by splenopentin analogs. FEBS Lett 1993;31793-95. 39.Volk HD, Eckert R, Diamantstein T, et al. [Immunorestitutive action of hydrolysates and ultrafiltrates of bovine spleen]. Armeimittelforschung1991;41:1281-1285. 40. He SW. [Effect of splenectomy on phagocyhc function of leukocytes]. Zhonghua Wai Ke Za Zhi 1989;27354-356,381. 41. Spirer Z, Zakuth V, Diamant S, et al. Decreased tuftsin concentrations in patients who have undergone splenectomy.Br Med J 1977; 215741576. 42. Berressem P, Frech S, Hartleb M. Additional therapy with Polyerga improve immune reactivity and quality of life in breast cancer patients during rehabilitation. Tumor Diagnos Ther 1995;16:45-48. 43. Borghardt J, Rosien B, Gortelmeyer R, et al. Effects of a spleen peptide preparation as supportive therapy in inoperable head and neck cancer patients. Armeimittelforschung2000;50:178-184. 44.Maar K. Improvement of the general condition of tumor patients. Erfahrungsheilkunde1998;4760-64. 45. Klose G, Mertens J. Long term results of post-operative treatment of carcinoma of the stomach with Polyerga. Therapiewoche 1977;27 5359-5361. 46.Baier JE,Neumann HA, Taufighi-Chirazi T, et al. Thymopentin, Factor AF2, and Polyerga improve impaired mitogen induced

interferon-g release of peripheral blood mononuclear cells derived from tumor patients. Tumor Diagnos Ther 1994;15:21-26. 47. Zarkovic N, Hartleb M, Zarkovic K, et al. Spleen peptides (Polyerga) inhibit development of artificial lung metastases of murine mammary carcinoma and increase efficiency of chemotherapy in mice. Cancer Biother Radiopharm 1998;13:25-32. 48. Jurin M, Zarkovic N, ILic Z, et al. Porcine splenic peptides (Polyerga) decrease the number of experimentallung metastases in mice. Clin Exp Metastasis 1996;1455-60. R, Portoles P, et al. Polyerga, a biological 49. de Ojeda G, Diez-jas response modifier enhancing T-lymphocyte-dependent responses. Res Exp Med (Berl) 1994;194:261-267. 50. Klingmuller M. Spleen peptides activate natural killer cells. Erfahrungsheilkunde 1999;12:756-759. 51.Vassilev M, Antonov K, Theocharov P, Krastev Z. Effects of low molecular weight glycoproteins in chronic hepatitis B. Hepatogastroenterology1996;43882-886. 52. Hartleb M, Leuschner J. Toxicological profile of a low molecular weight spleen peptide formulation used in supportive cancer therapy. Arzneimittelforschung 1997;471047-1051. 53. Cazzola P, Mazzanti P, Bossi G. In vivo modulating effect of a calf thymus acid lysate on human T lymphocyte subsets and CD4+/ CD8+ ratio in the course of different diseases. Curr Ther Res 1987; 421011-1017. 54. Kouttab NM, Prada M, Cazzola P. Thymomodulin:biological properties and clinical applications. Med Oncol Tumor Pharmacother 1989;65-9. 55. Fiocchi A, Borella E, Riva E, et al. A double-blind clinical trial for the evaluationof the therapeutic effectivenessof a calf thymus derivative (Thymomodulin) in children with recurrent respiratory infections. Thymus 1986;8:331-339. 56. Galli M, Crocchiolo P,Negri C, et al. Attempt to treat acute type B hepatitis with an orally administered thymic extract (Thymomodulin).Preliminary results. Drugs Exp Clin Res 1985;ll: 665-669. 57.Bortolotti F, Cadrobbi P, Criverllaro C, et al. Effect of an orally administered thymic derivative, Thymodulin, in chronic type B hepatitis in children. Curr Ther Res 1988;43:67-72. 58. Valesini G, Bamaba V, Benvenuto R, et al. A calf thymus lysate improves clinical symptoms and T-cell defects in the early stages of HIV infection. Second report. Eur J Cancer Clin Oncol 198723: 1915-1919. 59.Kang SD, Lee BH, Yang JH, Lee CY. The effects of calf-thymus extract on recovery of bone marrow function in anticancer chemotherapy.N Med J (Korea) 1985;2811-15. 60.Marzari R, Mazzanti P, Cazzola P, Piodda E. [Perennial allergic rhinitis. Prophylaxis of acute episodes using thymomodulin]. Minerva Med 1987;78:1675-1681. 61.Genova R, Guerra A. Thymomodulin in management of food allergy in children. Int J Tisue React 1986;8:239-242. 62. Cavagni G, Piscopo C, Rigoli E, et al. Food allergy in children: an attempt to improve the effects of the elimination diet with an immunomodulating agent (thymomodulin).A double-blind clinical trial. Immunopharmacol Immunotoxicol1989;11:131-142.

Homeopathy Andrew Lange, BSc, ND CHAPTER CONTENTS Introduction 387 History 387 Philosophy 388 Provings 388 Like Treating Like 388 The Organon of Medicine 389 Vitalism 389 The Clinical Application of Homeopathic Principles 390 The Homeopathic Interview 390 Follow-up and Case Evaluation 391

INTRODUCTION Homeopathy is a highly systematized method of medical therapeutics and clinical evaluation. The term homeopathy is derived from the Greek words homeos, meaning “similar,“ and pathos, meaning “suffering.” The medicines used in this system of therapeutics are chosen according to the Law of Similars (the concept of like curing like), a fundamental homeopathic principle based on the observed relationship between a medicine’s ability to produce a specific constellation of signs and symptoms in a healthy individual and the same medicine’s ability to c m a sick patient with similar signs and symptoms. This principle was first recognized by Hippocrates, who noticed that herbs given in low doses tended to cure the same symptoms they produced when given in toxic doses. Homeopathic medicines are derived from a wide variety of plant, mineral, and chemical substances. They are prepared according to standards of the US. Homeopathic Pharmacopoeia, a revised version of which has been approved by the U.S.Food and Drug Administration and US.Congress.

HISTORY The homeopathic school of medicine was founded by a German physician, Samuel Hahnemann. He had already

Prescription 391 Homeopathic Pharmacy and Potency Selection 392 Mechanism of Action 392 Determination of Potency 393 The Study of the Materia Medica 393

Research in Homeopathy 394 Meta-analyses 394 Human Trials 394 Animal Studies 395 Basic Research 395 Conclusion 396

gained a reputation in chemistry and medicine, having formulated a soluble form of mercury and developed a safer method for its use, and having written a number of works on pharmacology, hygiene and public health, industrial toxicology, and psychiatry. His treatise on arsenic poisoning (1786) is still considered authoritative. A prolific writer, Hahnemann collected, compiled, revised, and edited the existing pharmacologic knowledge. The work was well received by the medical profession of the time. In fact, Hahnemann was one of the most learned men of his generation in medicine, chemistry, and pharmacology, making his later criticisms of medicine all the more sigruficant.l Disillusioned with the theories and practice of eighteenth century medicine, Hahnemann retired from practice in 1782 and spent the next 14years earning a meager living doing chemical research; writing; and translating English, French, Italian, and Latin works. He wrote of his time of practice: It was painful for me to grope in the dark, guided only by books in the treatment of the sick. To prescribe according to this or that (fanciful)view of the nature of diseases, substances that only owed to mere opinion their place in the materia rnedica; I had conscientious scruples about treating unknown morbid states in my suffering fellow creatures with these unknown medicines which, being powerful substances, may, 387

if they were not exactly suitable (and how could the physician know whether they were suitable or not, seeing that their peculiar special actions were not yet elucidated) easily change life into death, or produce new affections and chronic ailments, which are often more difficult to remove than the on@ disease.

In his struggle to determine a reliable basis for therapeutics, he was distressed by his inability to provide medical care for the acute illnesses of even his own growing family. In 1790, during his translation of William Cullen’s (a Scottish physician) Muteriu Medicu, he added a footnote disagreeing with Cullen’s conclusions that the basis of cinchona bark‘s effectiveness was its bitter and astringent qualities. Cinchona officinalis (Peruvianbark), from which the drug quinine is derived, was known to be clinically effective in malaria and intermittent fevers (then called ague). He argued that there were several drugs in common usage that, in smaller doses, had greater bitter and astringent qualities yet had no specific action on fevers. As an experiment, Hahnemann took four drachms of cinchona twice daily and soon developed the paroxysmal symptoms characteristic of intermittent fevers. This duplication of symptoms was a revelation to him and ultimately resulted in his formulation of the concept of determining the properties of a medicine by studying its effects on healthy humans. Although homeopathy offers a profoundly deep and unified evaluation in the treatment of chronic diseases (see the section on evaluating the case later), it had gained most of its early reputation in the treatment of acute and epidemic diseases. An uproar was caused in Cincinnati in 1849 when two immigrant German homeopaths, treating cholera with camphor and other homeopathically prescribed remedies, published in the newspapers statistics indicating that only 35 of their 1116 treated cases had died. During the nineteenth century, 33% to 50% of patients with cholera who were given standard medical care died. In the 1879 epidemic of yellow fever, New Orleans homeopaths treated 1945 cases with a mortality rate of 5.6%, while the standard medical doctors were losing 16%. These and similar statistics had a profound effect on Congress and public opinion? Over time, homeopathsestablished their own network of treatment facilities. By 1892 in the United States, they controlled 110 hospitals, 145 dispensaries, 62 orphan asylums and retirement homes, more than 30 nursing homes and sanatoria, and 16 insane asylums. Constantine Hering established the first homeopathic medical school in the United States in 1835.It later moved from its original site in Allentown, PA, to Philadelphia, where it remains today as an orthodox medical school: the Hahnemann Medical College and Hospital. Hering’s promotion of homeopathy and development of the

mferiu rnedica was equaled only by Hahnemann himself. His 10-volumework, The Guiding Symptoms ofour Muteria Medica, remains a definitive work on the clinical verifications of the homeopathic approach. Unfortunately, of the many medicines introduced by Hering, only nitroglycerin orthodox medical practice as a tribute to his ine re& medical genius. Throughout the world, homeopathy has maintained a consistent tradition. Frederick Harvey Foster Quinn introduced it to England in the 1840s. It has since become a postgraduate medical specialty, recognized by the Department of Health by virtue of an Act of Parliament. Homeopathic hospitals and outpatient clinics are part of England’s national health system. Homeopaths have been engaged as personal physicians to the Royal family for the past four generations. Homeopathy is widely practiced in Europe, India, Argentina, and Mexico, and is experiencing a renaissance in the United States.

PHILOSOPHY Provings Hahnemann defined his method of testing medicines on healthy people as ”provings.” He expanded his investigations to include a wide range of substances, using his family, friends, and associates as experimental subjects. Historically, Hahnemann was not the first to use this methodology. In 1760 Anton Stoerck reported testing strumonium (datura) by rubbing it on the skin, inhaling the vapors of the freshly crushed leaves, and, finally, ingesting the fresh extract. He theorized that if strurnoniurn disturbs the senses and produces mental derangements in healthy people, it might be administered to maniacs for the purpose of restoring the senses by effecting a change of ideas. Recent medical literature has contained examples of inadvertent provings: In 1983a study in the New England Journal of Medicine reported that pyridoxine (vitamin B6), which is used in the treatment of some types of peripheral neuropathy, was also capable of producing neuropathies when given in large doses.3In 1796 Hahnemann published, in Hufelund‘s Journal, the fruit of his investigations in an article, “Essay on a New Principle for Ascertaining the Curative Power of Drugs, with a Few Glances at Those Hitherto Employed.”

LikeTreating Like Hahnemann also recognized the tendency of a natural disease to have a ”homeopathic effect” (i.e., a preventive or therapeutic effect) on other diseases with similar symptomatology. Although he ascribed this to the stimulation of the organism to eradicate the disease, he felt the deliberate induction of a disease to be difficult, uncertain, and dangerous? This concept has many parallels in modern

medical science. Descriptions of viral interference under natural conditions were described in 1937 by G. Findlely and F. MacCallum, who found that monkeys infected with the Raft Valley fever virus were protected from the more fatal yellow fever virus. They adopted the term “virus interference” and believed that when one virus infects a group of cells, a second virus is somehow excl~ded.~ This eventually led to the discovery of interferon in 1957 by Alick Isaacs and Jean Lindenmann. These methods of inducing self-regulation are critical in enhancing the ability for the body to recognize and resolve illness. In 1799 Hahnemann gained increased professional acceptance of his ideas by the successful application of atropa belladonna (deadly nightshade) in the prevention and treatment of scarlet fever (which had at that time reached epidemic proportions). In 1860 it was recommended as the treatment of choice in the National Dispensatory, which stated: “As long as persons are under the influence of belladonna . . . the liability to contract scarlatina is very much diminished.”6

The Organon of Medicine In 1810 Hahnemann published his Organon ofMedicine, a book that, through six editions, formed the foundation and definition of the homeopathic practice of medicine. It contains the philosophy, observations, and clinical applications of homeopathy, as well as citations from the historical and current literature of the time. Hahnemann challenged the reductionistic and mechanistic practices of his time, stating that the nature of disease is dynamic and could not be defined by isolating processes, grasping for an explanation. He further asserted that the cause of disease could not be known and that the categorization of disease states and attempts to manipulate physiology were insufficient, since they did not address the integrity and complexity of organization of the organism as a whole. He described this organization as dynamic, meaning in accordance with the animating principle of life, which is the underlying energetic pattern to which matter conforms. Disease is therefore addressed descriptively in the context of the whole patient, with the patient’s unique symptoms being indicative of that individual’s vital response to the condition. For any given disease there may be a long list of remedies that have been clinically effective, but it is the individualization and differentiation among medicines, based on the patient’s unique indications, that leads to a successful homeopathic prescription.

Vitalism Disease, in the homeopathic model, is thought to arise from inherent or developed weaknesses in the patient’s

defense mechanisms, creating a susceptibility to ”morbific influences” (e.g., toxic factors in the environment, bacteria, psychologic stresses). This viewpoint is considered ”vitalistic” (see Chapter 6 for a more detailed discussion) and, while not denying a corporeal reality, considers pathology to be but a singular focus in a complex net of interactions. William Boyd, in A Textbook of Pathology, discusses the limitations of the causal approach to disease, currently in vogue in medicine, when he states’: We must admit, however unwillingly, that we seldom or never really know the cause of anyhng. Many a beautiful idea has been slain by ugly fact. We merely note a constant association with one thing always following another. We say that the tubercle bacillus is the cause of tuberculosis. That is merely another way of saying that the bacillus is associated with a constant type of lesion; it is no explanation of how the lesions are produced by the bacillus. Nor does it explain why some persons and animals are susceptible to the infection while others are immune.

Vitalism can be better understood in the context of Hahnemann’s time, when theories of the causation of disease and its treatment abounded, such as: Galen’s doctrine that the secondary quality of a medicine (i.e., its action on the disease) can be determined from its primary qualities, such as its taste or smell; the evaluation of medicines by the study of their interactions when mixed with human blood in a jar; iatrochemistry, which had been reduced from the Paracelsian application of spagyric tinctures or oils of metals to dangerous toxic doses; the classification of drugs according to the Dioscoridian approach, which was based on the physiologic action (e.g., diuresis, diaphoresis) and chemical composition; and the “doctrine of signatures,” which held that the outer form and color of a plant revealed its inner archetypal a c t i ~ n . ~ , ~ Although some studies of the effects of medicinal agents were done with animals, Hahnemann observed that they had different effects on humans: Pigs could safely eat nux vornica in quantities that would immediately kill humans. Dogs could eat aconitum napellus, a deadly poison to humans, without injury. He also rejected the method of testing drugs by studying their effects on the sick as haphazard and unreliable, particularly since the results being sought were often only symptomaticrelief rather than eradication of the disease state. Hahnemann defined the application of medicines whose purpose was to alter physiology or act as an antagonist to disease as the practice of “allopathy” ( d o meaning ”contrary” in Greek). The current dominant medical system is heavily influenced by the causalistic and allopathic paradigms. This results in the diagnosis being the focal point of practice, without which appropriate therapy cannot be instituted. The pharmacologic

approach is limited to the end results of disease rather than the origins of pathogenesis. Subsequent problems are classified as unwanted side effects, since only the primary action of the pharmaceutic agent is used for treating a specific disease state. By focusing on only the primary effects of a drug, a diverse remaining range of physiologic, as well as psychologic effects, are ignored. In the homeopathic model, the side effects are an important part of the agent’s action and the body’s response to them, and by ignoring them, a drug’s range of usefulness is greatly limited, while its toxicity is increased. Hahnemann’s empirical investigations not only led to new applications of medicines but provided a method for integrating the physical, mental, and emotional effects of a drug. This allowed the treatment of the totality of a patient’s symptoms as a dynamic pattern of interaction. Vitalists stress the teleologic behavior of organisms (i.e., the goal directedness and design in biologic phenomena). Disease is therefore regarded as a positive expression of the organism’s self-regulatory process in response to environmental or other stresses. Disease is not accidental but is rather the effort of the organism to ward off deeper or more internal disorganization. It is the natural wisdom of the body, the vis rnedicutrix nuturue, or, using current scientific terminology, the tendency of the body to maintain homeostasis. Medical intervention often acts in conflict with these vital intracellular and extracellular regulatory functions. Karl Menninger, in 1948, commented on this medical dilemmalo: I believe that clinicians have come to think more and more in terms of a disturbance in the total economics of the personality, a temporary overwhelming of the efforts of the organism to maintain a continuous internal and external adaptation to continuously changing relationships, threats, pressures, instinctive needs and reality demands . . . It is the imbalance, the organismic disequilibrium, which is the real pathology, and when that imbalance reaches a degree or duration that threatens the comfort or survival of the individual, it may correctly be denoted disease.

Homeopathy is a method of specific induction of nonspecific resistance, which stimulates the body’s lnherent defense and self-regulatory mechanisms, rather than by taking over a function of the body, initiating dependency on the medicine itself.

THE CLINICAL APPLICATION OF HOMEOPATHIC PRINCIPLES The homeopathic clinical and therapeutic process consists of three interrelated processes: case taking, evaluation, and prescribing. The process is comprehensive and engages the observations of the patient, as well as those

of the doctor. Hahnemann describes the process in paragraphs 84 to 103 of the Orgunon and stresses the importance of distinguishing between chronic and acute, or self-limiting, disease.

The Homeopathic Interview The initial history of complaints is elicited from the patient with as little interruption as possible (as long as the patient does not digress unduly) so that the patient’s train of thought is not disrupted or directed along lines imposed by the physician’s biases. According to Hahnemann: The physician elicits further particulars about each of the patient’s statements without ever putting words in his mouth, or asking a question that can be answered only by yes or no, which induces the patient to affirm something untrue or half true or else deny something really there to avoid discomfort or out of desire to please, thereby giving a wrong picture of the disease, which would lead to the wrong treatment.

An entire review of symptoms is recorded in descriptive detail, taking into consideration all modalities that affect a symptom. Hahnemann emphasized the general symptoms (i.e., those affecting the entire organism, as the leading indications for the remedy). These key symptoms include mental and emotional affects, the metabolism and its reactions to environmental stimuli, sleep positions, food cravings and aversions, thirst, body type, and all manifestations of unconscious and autonomic regulation. Unique characteristic symptoms, particularly those regarded as ”strange, rare, and peculiar,” are important considerations in the selection of the remedy. These might be the expression of a paradoxical or unusual relationship, such as pain ameliorated by pressure or the sensation of the legs being made of wood or glass. The association of the start of a disease or symptom complex with an environmental or emotional event can be important and emphasizes the importance of an accurate and extensive interview. Hahnemann emphasizes the importance of taking a comprehensive case, particularly in chronic disease”: In chronic diseases in women one should pay particular attention to such things as pregnancy, infertility, sexual desire, confinement, miscarriages, nursing, vaginal discharges, and the condition of the monthly flow, especially noting whether it recurs at intervals that are too short or too long, how many days it lasts, whether or not it is interrupted, the quantity, how dark with color, any leukorrhea before or after the flow. If there is leukorrhea, what it is like, what symptoms accompany it, what is its quantity, under what conditions does it appear, what brings it on?

Since the patient’s symptoms are the expressions of the body’s attempts to heal itself, symptomatictreatment (i.e.,many allopathic therapies) can impair the physician’s

Homeopathy ability to obtain vital information and complicate the taking of the case. This problem has also been recognized by some medical authors, such as Boyd, who stated: “We recognize that the pattern of disease has changed out of recognition during the last 30 to 40 years owing to modern drugs, particularly the antibiotic^."^

Follow-up and Case Evaluation Considering the vitalistic and holistic perspective of the homeopathic approach, a clear definition of cure is necessary in order to establish the treatment goal. Mere palliation or suppression of symptoms at the cost of the overall vitality and function of the individual is considered negligent by the homeopathic practitioner. For example, if a patient’s skin disease is treated and appears to resolve but is followed by asthma, fatigue, and confusion, the treatment is evaluated as having been suppressive. If, upon proper treatment, the more serious lung and systemic disruptions are alleviated and the prior skin lesions return, the patient is considered as progressing toward a cure. When further appropriate therapy results in final alleviation of the skin disease, without any undue stress to the patient, it is then considered a true cure. This evaluative procedure is part of Hering’s Law of Cure, an observation of the principles of curative responses that can be applied to any healing process, regardless of the school of thought. In true healing, according to this set of observations, symptoms follow these patterns: From above, down the body to the extremities From within to without (often in the form of discharges and other eliminative processes) From the most important organs (e.g., the CNS) to the least important organs (typically the skin) In reverse order of their appearance (i.e., the chronologically most recent being replaced by those of the earlier stages of the disease, and, in some instances, earlier in the patient’s life) Homeopathy holds that the disease first affects the vital force and is manifested first by a change in the patient’s well-being, long before any objective changes can be observed. Illness is usually first recognized when the patient becomes aware of the early manifestations of the disease. Disease and cure must also be considered in the context of the belief system and culture of the patient. Much of what we call disease arises from the individual’s inability to find meaning and purpose. Many forms of healing are capable of enabling the person to integrate into the fabric of daily life and of providing ways to help the person address personal needs for fulfillment. In his study of disease, Hahnemann noted that there were inherited predispositionsto disease,which he related

to the improper treatment, and therefore suppression, of skin eruptions and venereal disease. He called these predispositions miasmas and, in 1828, published his findings in Chronic Diseases: Their Nature and Homeopathic Cure. He observed that many people, despite apparently healthy lifestyles, develop degenerative diseases. These often become established in childhood and continue to plague the person throughout life, despite medical treatment. He described three miasmas: psora, which represents a fundamental flaw in human ability to eradicate disease related to the suppression of skin disease; syphilis and sycosis, which is caused by the suppression of the figwort, or what is now known as human papilloma virus. Hahnemann describes the chronic effects of bacterial and viral diseases in his explanation of miasmas. In his discussion of viral diseases such as smallpox and other epidemic diseases, Hahnemann’s descriptions of the nature of viruses and their treatment predate their discovery by 50 years. He was a contemporary of Edward Tenner and supported his use of smallpox vaccination. More recently, George Vithoulkas, a contemporary homeopathic author and teacher, has defined health on three levels: mental, emotional, and physical. The mind should be capable of functioning with clarity, rationality, coherence, and logical sequence. It should be capable of engaging in creative service for the good of others, as well as for the good of oneself, demonstrating a freedom from selfishness and possessiveness. On the emotional level, there should be a state of serenity free from excessive passion, a state that should not be confused with lack of emotional response generated as a protection against emotional vulnerability. Finally, on the physical level, there should be freedom from pain. The healing person should experience a subjective sense of wellbeing and a progressive increase in vitality.I2

Prescription Since homeopathy is oriented toward the administration of a single medicine at a time, careful prescribing is important. It is through the application of single medicines that physicians have been able to record clinical verification of the provings and amass an impressive body of literature. Combination homeopathic medicines have been introduced as specific remedies for diseases and therefore have not represented homeopathic methods, though many studies support their efficacy. The process of selecting the correct remedy involves both careful study of the patient’s symptomatology and medical history and matching these with the appropriate remedy. This requires a sound understanding of the homeopathic materia medica (see later). The symptoms of the homeopathic materia medica are indexed in repertories that have evolved both in reference books and computer analysis programs.

Homeopathic Pharmacy and Potency Selection This leads to a discussion of what has remained the greatest mystery of homeopathic medicine (and the source of considerable ridicule and misunderstanding): the use of "potentized" substances. As Hahnemann began his research, he found that when treating patients according to the Law of Similars there was an initial aggravation of the symptoms, the "healing crisis," when using the high dosages typical of that era. He empirically tried using progressive dilutions of the medicines, beginning with tinctures from plants and titurations with milk sugar for metals and salts. He made the dilutions serially by mixing 1 drop of the tincture to 100 drops of alcohol, which were then "succussed" (shaken by pounding against a resilient surface) vigorously. He found that, with increasing dilution, the severity of the aggravation lessened while the patient continued to improve, often with deeper and more enduring results. He called these diluted remedies "potentized." As an analytic chemist, he was aware of Avogadro's theories (they were contemporaries), but he persisted in evaluating dilutions beyond the point where chemical activity could be detected. This problem has been addressed by recent workers, who have suggested that the therapeutic properties of the remedy lie in the energetic impression they make on the diluting vehicle (typically alcohol and water or lactose). Various techniques have been used to determine if there is a physical difference between the potentized dilution and the unmodified vehicle. These studies have used ultraviolet spectroscopy, conductivity measurements, infrared spectroscopy, surface tension measurements, Ranian-Laser spectroscopy, nuclear magnetic resonance, and other methods. Much of this work has shown regular peaks and troughs in activity with progressive dilutions, and Heintz has claimed that the peaks correspond to the maximum effects found in the biologic studies he has reported (see later section on basic re~earch).'~

Mechanism of Action To date there is no conclusive understanding of the mechanism of action of the potentizing process. However, this has not inhibited the use of potencies, which have been diluted by a factor of 100 up to 100,000 times (102°0~ooo). At this time, most explanations for the mechanism of homeopathic high potencies are provisional (such as the postulate that the remedies act in resonance with the magnetic fields of the body, or that the physiochemical properties of water can be modified by a solute and remain so even in the absence of the solute).14 This has not affected the clinical practice or demonstration of efficacy in clinical trials any more than the use

of aspirin did, despite the fact that the discovery of its mechanism of action through modulation prostaglandins did not occur until the 1980s. There are many forces whose nature can only be recognize by their results (e.g., gravity). These observations of relationships, confirmations of experience, are the basis of an empirical system. Medicine remains an art in the field of science. Oddly, a group operating in the Hematology Department of the School of Pharmacy in Bordeaux, France tested both the effect of common aspirin and homeopathic preparations on the vascular walls of rats. Aspirin at high concentrations (100 mg/kg) induced a decrease in platelet aggregation (amplitude and speed), as well as a decrease in the area of the thrombi (arterial and venous) and the number of emboli (arterials and venous). Aspirin at ultra-low doses (9, 15, 30 CH) induced an increase in platelet aggregation (amplitude and speed), as well as an increase in the area of thrombi (arterial and venous) and the number of emboli (arterial and venous). The anti-aggregation and antithrombotic action of aspirin at high concentrations (100 mg/kg) was inhibited by the concomitant injection of aspirin 15 CH.15 This confirmed Hahnemann's observations of the primary and secondary effects of medicines mentioned in the Organon.Ib Bellavite describes these effects as "biologically active compounds (which) may cause inverse or paradoxical effects on a complex homeostatic system when either the doses of the compound, or the methods of preparation and of administering, or the sensitivity of the target system are changed."l7Js Research into both the pharmacologic effects of homeopathic preparations and the paradoxical effects of orthodox drugs that confirm the Law of Similars underlying homeopathic prescribing are a growing body of literature. Certain pharmacologic substances when tested in high dilutions act on the same biologic ~ y s t e m s . ' ~ - ~ The reaction to the high dilutions can also be the opposite to a drug at low dilutions (e.g., proinflammatory agents can be antiinflammatory at high dil~tions).2~*~ Paradoxical effects of medicines are the basis of the Amdt-Schulz Law in pharmacology and hormesis. The Amdt-Schulz law states that weak stimuli slightly accelerate vital activity, medium strong stimuli raise it, strong ones suppress it, and strong ones arrest it?O Southam and Erlich3' reported the stimulatory effect of an antifungal agent when used at low doses and proposed the term homesis. Hormesis is defined as "the stimulatory effect of subinhibitory concentrations of any toxic substance on any organism."32Hormesis is considered a nonspecific phenomenon increasing the resistance and growth of the treated organism. It exists in all living organisms. This "action-reaction" model shows the efficacy of the "vital activity" in fighting the poison in a nonspecific way,

regular arguments between low- and high-potency even though specific defense molecules are also synprescribers as to the most effective method. t h e t i ~ e dA. ~modem ~ ~ and important pathologic model has shown that a single dose of an antitumoral immunoThe Study of the Materia Medica suppressive substance (cisplatin) induced increased lymphokine-activated killer a~tivity.3~ Wagner and colConstantine Hering once stated the following: leagues demonstrated that low doses of cytostatic agents stimulate human granulocyte and lymphocyte g r o ~ t h . ~ A mere acquaintance with the principal symptoms cannot be called studying the materia medica, although we make it the The goals and methods of homeopathic pharmacy basis of our study. The study of materia niedica must be have their roots in earlier Paracelsian and spagyric regarded and dealt with in exactly the same manner as that of medical systems. The challenge remains to define homeother natural sciences. opathic empirical science in the context of a modern science. It may be that homeopathy presents a challenge To give a perspective on the way in which homeoto science itself that will bring forth new models for pathic physicians organize the proving symptoms into pharmacology. The more central challenge is for homeclinical pictures, we draw from an essay on Sepia by E.B. Nash4? opathy to discover how it can apply its own critical methods to develop a more effective health care service. This is another of our wonderful remedies of which the domThe assumption that we can find substances in nature inant school knows nothing, except what they have learned that can alter disease underlies the history of medicine from us. Its chief sphere of action seems to be in the abdomen and pharmacology, yet healing remains a mystery. and pelvis, especially in women. No remedy produces stronger Further studies are necessary to confirm and develop symptoms here. We quote from different but equally good the understanding of the mechanisms and validity of observers. Sensation of bearing down in the pelvic region, with draghomeopathic medicines. ging pains from the sacrum; or feeling of bearing down of all

Determination of Potency

In terms of clinical practice, general guidelines have evolved for the determination of potency. In the sixth edition of the Orgunon, Hahnemann recommends ascending the scale of potencies gradually. In paragraph 248, he suggests that the medicinal solution be ”succussed anew with use.” In chronic cases, the patient is directed to take one teaspoonful daily or every otherday, and in acute diseases, as frequently as needed. If the solution is used up before the problem alleviates, the next higher dilution is used (if still indicated by the symptom pattern)?* The higher potencies, whose use largely developed in the United States, are repeated much less frequently and are generally reserved for the experienced practitioner. The more potentized the remedy, the closer it must meet the Law of Similars (i.e., the accuracy of the prescription must be high for a curative effect). Lower potencies are often repeated daily depending on the condition being treated. Several ranges of potencies include the decimal scale, which uses a 1:lO dilution; the centesimal scale, which is diluted 1:lOO; and the LM potencies introduced in the sixth edition of the Organon, using daily doses of 1:50,000 dilutions. Important to note is that the sixth edition was unavailable until 1924, 76 years after Hahnemann’s death. The predominant clinical application of homeopathic potencies had developed using an ascending scale. A single dose was used until its action had ceased, when the same potency would be repeated. When that potency seemed to no longer demonstrate an enduring effect, a higher potency was used. There have been

pelvic organs. (Hahnemann) Labor-like pains accompanied with the feeling as though she must cross her legs and “sit close” to keep something from coming out through the vagina. (Guernsey) Pain in uterus, bearing down, comes from back to abdomen, causing oppression of breathing; crosses limbs to prevent protrusion of parts. (Hering) Prolapse of the uterus, of the vagina, with pressure as if everything would protrude. (Lippe) Experience has shown its value in cases of ulceration and congestion of the 0s and cervix uteri. Its use supersedes all local applications. (Dunham) No higher authority than the united testimony of these five of our best observer could be brought to show the action of Sepia upon the pelvic organs. Now when we come to examine the provings in Allen’s Encyclopedia, we find that these symptoms were mainly produced by Hahnemann and his provers, and Hahnemann advocated proving remedies in the 30th, and some of them were produced by the 200th, especially those most strongly verified by black-faced type. We confess that we cannot understand how so many question the value of potencies for proving or curing. . . Sepia, like Sulphur, affects the general circulation in a very marked manner. Flashes of heat with perspiration and faintness is almost as characteristic of this remedy as of Sulphur. But there are, with Sepia, more apt to be associated with them the pelvic symptoms already given, and they are also more apt to occur in conjunctionwith the climacteric. Indeed, these flashes often seem with Sepia to start in the pelvic organs and from thence to spread over the body. But this irregularity of circulation extends as far as that of Sulphur. The hands and feet are hot alternately, that is, if the feet are hot, the hands are cold, and vice versa. There is not so much sensation of burning with Sepia as with Sulphur, but there is

Therapeutic Modalities actual heat, and the venous congestion, which seems to be the real state of the organs where the pressive bearingdown et cetera is felt, is also accompanied with much throbbing and beating. This local congestion to the pelvic organs is not simply sensational. There are actual displacements in consequence of it, and the long continued congestion results in inflammations, ulcerations, leukorrheas and even malignanaes or cancerous organizations. Induration with a painful sense of stiffness in the uterine region is characteristic. This pelvic congestion also affects the rectum in a marked degree. The rectum prolapses, there is a sensation of fullness, or of a foreign substance as of a ball or weight, and oozing of moisture from the rectum.Indeed, the rectal and anal symptoms are almost as strong as the uterine and va@. It is impossible to enumerate all the symptoms connected with the circulatory disturbances of Sepia in such a work as this,only a general study of the Materia Medica can do it. The urinary organs come in for their share of symptoms. The same pressure and fullnessconsequent upon the portal congestion reaches here. We will now proceed to give what we have found to be particularly valuable symptoms under the various organs in this region. “Pressure on bladder and frequent miduration with tension in lower abdomen.” “Sediment in the urine likeclay; as if clay burnt on the bottom of the vessel; urine very offensive (Indium),can’t endure to have it in the room, it is reddish or may be bloody.” This is found mostly in women. With c h i l h n there is one pecuhar symptom which has often been verified. “The child always wets the bed during its first sleep.” Upon the male organs I have found it particularly useful in chronic infection. There is not much discharge, but a few drops, perhaps, which glue up the orifice of the urethra in the morning; but it is so persistent and the usual remedies will not “dry it up.” In my early practice I used to use a weak injection of Sulphte ofzinc, but it used to annoy me that I could not use it without resorting to local measures. Sepia does it in the majority of cases and Kali wdatum will do it in the rest. I have, where there was a thick discharge of long standing and the smarting and burning on urination continued, several times finished the case with Capsicum. As a rule, thislong continued slight, passive sleety discharge is a result of weakness of the male genitals, us is shown by u j u c -

cidity of the organs and frequent seminal emissions. The emissions are thin and watery. Sepia covers all of this and often sets all to rights in a short time. The mind symptoms of Sepia are like Pulsutillu, in that she is sad and cries fresuently without knowing the reason why. So if in a tearful mind with uterine disturbances Pulsutillu should fail you, the next remedy to be studied is Sepia.But there is another condition of mind not found under Pulsutillu or any other remedy in the same degree, and that is, that, notwithstanding there is no sign of dementia from actual brain lesion, the patient, contrary to her usual habit, becomes indifferent to her occupation, her house work, her family or their comfort, even to those whom she loves the best. This is a very peculiar symptom and a genuine keynote for the exhibition of Sepia . . . I once cured a very obstinate case of entero-colitis (so-called cholera infantum), after the complete failure of two eminent allopaths, with Sepia, the leading symptom being, always worse after taking milk. Oozing of moisture from the anus finds its remedy here sometimes, but oftener in Antimonium crudum. The Sepia patient is very weak. A short walk fatigues

her very much. She faints easily from extremes of cold and eat, after getting wet, from riding in a carriage, while kneeling at church, and on other trifling occasions. This fainting, or sense of sinking faintness, may be found in pregnancy, child bed, or during lactation; or, again, it may come on after hard work, such as “laundry work;” so it has come to be called the “washer woman’s” remedy.

As can be seen by this excerpt, the indications for a remedy are complex,requiring study and understanding.

RESEARCH IN HOMEOPATHY Since homeopathy arose from empiric observations and operates from empiric clinical evidence and phenomenologically descriptive fields rather than causal relationships, its evaluation by the scientificmethod, as described by Karl Popper, poses unique problems. The most promising evidence for the efficacy of homeopathy has always come from its efficacy in clinical trials. Its mechanism of action has remained a central dilemma for its detractors.

Meta-analyses The following briefly discusses some of the studies that have been done.

A critical review appeared in the British Homeopathic Journal describing the methods used in various attempts to verify this school of medicine. The study evaluated 107 controlled trials and found there was a positive trend regardless of the quality of the trial or variety of homeopathic medications used.& A meta-analysis published in the British Medical Journal of a total of 105 controlled trials showed positive results for homeopathic treatment in 81 trials, leading its authors to state, “The evidence in this review would probably be sufficient for establishing homeopathy as a regular treatment for certain indications.”44 In another meta-analysis of 119 trials that met the inclusion criteria, 89 had adequate data for meta-analysis, and 2 sets of trials were used to assess reproducibility. The combined odds ratio for the 89 studies were in favor of h0meopathy.4~ In a third meta-analysis of the effect of homeopathy versus placebo, 32 trials with a total of 1778 patients met the criteria of randomization/partial randomization comparing individual homeopathy with placebo or no treatment. Homeopathy was sigruficantly more effective than placebo in 19 trials.&

Human Trials During World War I1 isopathic preparations were given prophylactically, and homeopathic therapies were used in mustard gas burns. A recent statistical analysis shows that these treatments yielded significant results when compared with placebos. The remedies used were mustard gas, Rhus toxicodendron, and kali bi~hrornium.’~

Homeopathy

Gibson and colleagues47published a double-blind clinical trial of homeopathic treatment in rheumatoid arthritis. The 3-month study was elegantly designed in that the prescribing was individualized to the patient's symptoms and was controlled, on a double-blind basis, by giving half the patients the correct remedy and the rest a placebo. All patients continued to use conventional, nonsteroidal, antiinflammatory drugs, and the treated group showed significant improvement in subjective pain, articular index, stiffness, and grip strength. In 1980 a Scottish group published a study on rheumatoid arthritis in the British ]ournu1of Pharmacology showing improvement in 82% of patients treated, compared with only 21% in the placebo group." A 2004 triple-blind study of homeopathic treatment of chronic fatigue syndrome, published in the Journal for Psychosomatic Research, was conducted showing significant improvement clinically and as measured using the Multidimensional Fatigue Inventory scale.@ Other published studies demonstrating the efficacy of homeopathic treatment include treatment of headache, attention deficit-hyperactivity disorder in children, asthma, upper respiratory tract infections, otitis media, arthritis, allergies, male infertility, influenza, cardiac insufficiency, herpes, osteoarthritis, and acquired immunodeficiency ~ y n d r o m e . ~ ~ - ~ ~

The use of homeopathic dilutions of hormones and immunomodulators have shown potential. Immunostimulatory effects of high dilutions of thymic hormones and interferons were demonstrated in mice by Bastide's g r o ~ p . ~Other ~ , ~ studies ~ - ~ ~ have demonstrated that extremely small amounts of antigens are specific for i m m u n o m o d ~ l a t i o nThese .~~~~ have tremendous implications in pharmacy, immunology, and clinical health care that demand continued research.

Basic Research

Clinical and experimental data obtained in studies about the effect of homeopathic preparations in inflammatory conditions present a considerable degree of reprodu~ibility.~"'~~ The inability for the Benveniste group to replicate their nature study using the Human Basophil Degradation Test (HBDT) to establish the ability for high dilutions to trigger the degranulation of anti-IgE has caused considerable distraction from other more credible r e s e a r ~ h . ' ~ ~ J ~ Another group (Brown and Ennis) using different methods demonstrated the efficacy of high dilutions of histamine to inhibit the activation of basophils using HBDT.lo5Instead of measuring degranulation provoked by ultramolecular dilutions of anti-IgE, as Benveniste did, they examined the inhibition of activation of basophils by ultramolecular dilutions of histamine. Animal Studies The experiments used ultramolecular dilutions of histamine (15 to 19 c), prepared with vortexing (instead of Cuulophyllum (in the thirtieth centesimal potency) was succussion). The main experiment, performed by all the given to 10 sows to test its efficacy in the control of stilllaboratories, was based on inhibition of basophil activabirths. The results showed a statistically sigruficant drop in the number of stillbirths and led to a larger, uncontion as measured by degranulation. Flow cytometry experiments at three laboratories showed compatible trolled study in a whole herd. After 4 months of therapy, results, with inhibition of activation as high as 43%. piglet mortality dropped from 20% to 2.6%.82 Nearly all experiments showed statistically significant Cloudhury obtained dramatic results from injecting inhibition of basophil mice intraperitoneally with kali phosphoricum, calcarea Experimental study of homoeopathy in allergology1I0 phosphorica, or ferrum phosphorica (in the thirtieth dec~ - Iwell I ~ as in imal potency) 12 days after implantation of fibrosarcoma. effects have been reported in V ~ V O , ~ ~ as ,itro.ll4-1l8 Of the 77 treated mice, 52% were cured and survived The physical properties of homeopathic preparations more than 1 year, whereas all of the 77 controls died are gaining considerable understanding in research. within 10 to 15 days.83 Studies demonstrating that the physico-chemical properScofield, in his review article, discusses numerous experiments with humans, animals, and plants using ties of extremely diluted solutions (EDS)are different from those of pure untreated water, notwithstanding the identiisopathic treatment for poisoning and experimental liver cal chemicalcomposition of the two liquid^.^^^-'^^ The same damage, and various in vitro studies.13 A number of studies have been conducted to invesconclusions are inferred by LO.'^,^^ Rey'" has shown that tigate the ability for homeopathic preparations to the structure of hydrogen bonds in pure water is different from that of an extremely diluted solution obtained by an effect either the elimination or consequences of toxic iterative procedure of successive dilutions and succussubstances. sions, not identical as expected. Recent studies on the Homeopathy may be effective in assisting in the physico-chemical properties of water provide evidence elimination and treatment of heavy metals and other that the most studied liquid by far, water, still exhibits toxins. Studies of arsenic,@ b i s m ~ t h , ' ~ ~ ~ ~ , ~ ~ unexpected properties.125131Lobyshev and coworkers132 merc~ry,8~B carbon tetrachloride,21,26a-amanitine (from have shown that low concentrations and electromagnetic the mushroom Amanita phalloides)F7 and carcinogens fields can produce largescale realignmentsof its structure, such as 2-acetylaminoflourene and phen~barbitol~~ have which can be either reversible or irreversible. One can been published.

deduce from these studies that water and aqueous solutions are complex systems, capable of auto-organization as a consequence of small perturbations of various kinds. The question of whether water can maintain “memory” of solutes in EDS is best understood by understanding the physical characteristics of water and its ability to form stable clusters and crystals. This aspect of physics is not widely studied but is well documented.”9-123,1~1~,1~

CONCLUSION Homeopathy represents an integrated holistic system of natural therapeutics. Its capacity for addressing psychosomatic disease and acute pathology as a dynamic process is unique. It has remained a coherent system, with extensive clinical verification, for more than two centuries. Homeopathy is an economical and effective method that has been established as an integral part of the medical system in many countries. With the resurgence of interest in natural medicine, this discipline will undoubtedly be more widely used. Homeopathy plays an important role in the context of modern naturopathic medicine. Hahnemann emphasized the importance of lifestyle in the treatment of the

The research section of this chapter is deeply indebted to the works of Peter Fisher, editor of the British Homeopathic Journal, Madeleine Bastide, Paolo Bellavite, and Andrea Signorini. The clinical training I received from Alan Sutherland and Marion Belle Rood has continued to be the foundation of sound practice and the inspiration to sustain study in the philosophy of nature. Books

Boerke W. Pocket Manual of materia medica with repertory, 1936. Reprint, New Dehi, India: Jain, 1982. Clark 1. Dictionary of practical materia medica, vols 1-3,1900.Reprint, Essex, England Health Sciences, 1962. Kent JT. Materia medica. Philadelphia: P Blakiston, 1900. Nash EB. Leaders in homeopathic therapeutics, 1898. Reprint, New Delhi,India: lain, 1983. Hahnemann S.Organon of medicine. Los Angeles: JP Tharcher, 1982. Hahnemann S. Chronic Diseases: Their specific nature and homeopathic treatment. New York Wm Radde, 1845. Lange A. Getting at the root: treating the deepest source of disease. Berkeley: North Atlantic Books, 2002. Roberts HA. The principles and art of cure by homeopathy. Essex, England Health Sciences, 1942. Edzard E, Hahn EG. Homeopathy, a critical appraisal. Oxford, England Butterworth Heinemann, 1998. Bastide M. Signals and images. Dordrecht, Netherlands: Kluwer Academic Publishers, 1997. Bellavite P, Signorini A. Homeopathy, a frontier in medical science. Berkeley, CA: North Atlantic Books, 1995.

patient. One of his primary dictums was to first remove the obstacles to cure, as he said While taking a case of chronic disease one should examine and weigh the particular conditions of the patient’s day to day activities, living habits, diet, domestic situation,and so on. One should ascertain whether there is anything in them which may cause or sustain the disease and remove it to help the cure. Unfortunately, homeopathy is also an extremely difficult system to master, requiring both considerable understanding of case taking and materia rnedica, as well as extensive consultation time with the patient. It has therefore often been discarded, even by those aware of its efficacy. Although attempts have been made to reduce it to simpler systems (e.g., allergy desensitizations, vaccinations, Schuessler’s cell salts, and isopathic preparations from diseased tissues and heavy metals), they are not considered strictly homeopathic unless prescribed according to their effects upon healthy people or the confirmed observations of cured symptoms. Homeopathy is representative of a principle found throughout nature and its role in bringing forth concepts of resonance, constitution, and holism are shared throughout fields of science and healing.

Journals

Simillimum, journal of the Homeopathic Academy of Naturopathic Physicians The Homeopath, journal of the Society of Homeopaths (UK) Homeopathy, formerly the British Homeopathic ]ournal; the official journal of the faculty of homeopathy, London The American Homeopath, journal of the North American society of Homeopaths Homeopathic Links, international journal for classical homeopathy Web Resources

British Homeopathic Library is a library and information service dedicated to the research and practice of homeopathy. Website: http://dspace.dial.pipex.com/hom-inform/index.shtml Ad Hom, the Academic Departments of Homeopathy at Glasgow Homeopathic Hospital. Website: www.adhom.com HOMINT Documentation Information System VSM, Alkmaar (Netherlands)/DHU, Karlsruhe (Germany) containing 35,000 references, major articles, homeopathicjournals, literature-search on request. Ajo Bol, information specialistVSM/Susanne Rehm, DHU. E-mail: [email protected] Homoepathic Educational Resources Database, compiled by Dr.Russell Malcolm of the Glasgow Homoeopathic Hospital. E-mail: gh/@gn.apc.org

Homeopathy

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Hydrotherapy Robert Barry, ND Revised and Edited by Douglas C. Lewis, ND CHAPTER C O N T E N T S Introduction 401 History 402 Properties of Water 402 Physiologic Effects 403 Hydrotherapy Research 403 Local and Systemic Effects of Cold Applications 404 Local and Systemic Effects of Hot Applications 405 Local Hot Applications 405 General Hot Applications 406 Principles of Blood Movement with Hydrotherapy 406 Revulsive Effect 406 Derivative Effect 407 Spinal Reflex Effect 407

INTRODUCTlON Hydrotherapy may be defined as the use of water, in any of its forms, for the maintenance of health or the treatment of disease. In his original article, Dr.Barry wrote: ”Although one of the oldest known therapies, it [hydrotherapyJ has received little attention from the research community, particularly recently. Much of the informationpresented here is compiled from older works which, although they lack the quantification available with current technology, show a remarkable attention to clinical effects and patient response.” When the original article was published, in 1985, reviews of the available literature were at best slow and laborious. Citations were discovered while looking through large tomes that were often heavy enough to produce low back pain. Once an interesting citation was discovered, the researcher had to search through stacks of journals, only to discover that the one desired had been lost, stolen, or was in the hands of another researcher. Today, the power of the computer has been directed toward removal of some of the former limitations to

Collateral Circulation Effect Arterial Trunk Reflex 408

407

General Rules of Hydrotherapy 408 Possible Side Effects of Hydrotherapy 409 Safety Aspects of Hydrotherapy 409 Pregnancy 409 Hypertension and Cardiovascular Disease 409 Hydrotherapy Techniques 410 Compresses 410 Baths 411 Cold Friction Rubs and Ablutions 413 Constitutional Hydrotherapy 41 3 Wet Sheet Pack 414 Sauna 415 Conclusion 415

research of the available literature. Large databases with fast search engines have made it possible to perform massive literature searches that were effectively impossible only a few years ago. Now, instead of low back pain from carrying those large tomes, we have upper back and neck pain from long hours spent in front of our computers. We now have the ability to search subject headings we might never have thought of or bothered with before. The bigger problem today is sorting out the useful from the worthless. For example, while preparing this revision, sitting at an office computer with high-speed Internet access, a search of PubMed was performed. The limits for the search were established as follows: all publication types, all ages, dates ranging only from January 1,1990, to the present, human studies only, published in English. A search using the term “sauna” yielded 126 citations, 11 of which were classified as randomized controlled studies and included abstracts. A search using the term ”balneology” yielded 845 citations, 71 of which were classified as randomized controlled studies and included abstracts. 401

Therapeutic Modalities A search using the term “hyperthermia” yielded 10,531 citations, 679 of which were classified as randomized controlled studies and included abstracts. Many of these newer studies are cited here, while little of what was written previously has been changed. Additions have been made where appropriate to clarify the existing material or to add new information.

HISTORY As one of the ancient methods of treatment, hydrotherapy has been used to treat disease and injury by many different peoples, including the Egyptians, Assyrians, Persians, Greeks, Hebrews, Hindus, and Chinese. In the Rig Veda, written about 1500 BC, we read that “water cures the fever’s glow.” Hippocrates used hydrotherapy extensively around 400 BC. In his writings concerning baths are some of the earliest dictum on the therapeutic uses of water’: Much will depend on whether the patient, when in good health, was very fond of the bath, and in the custom of taking it: for such persons, especially feel the want of it, and are benefited if they are bathed, and injured if they are not. In general it suits better with cases of pneumonia than in ardent fevers; for the bath soothes the pain in the side, chest and back; cuts the sputum, promotes expectoration, improves the respiration, and allays lassitude; for it soothes the joints and outer skin, and is diuretic, removes heaviness of the head, and moistens the nose. Such are the benefits to be derived from the bath, if all the proper requisites be present; but if one or more be wanting, the bath, instead of doing good, may rather prove injurious; for every one of them may do harm if not prepared by the attendants in the proper manner.

He writes further to explain the specific contraindications to the use of the bath. As these early writings show, the uses of water had been explored extensively at very early times, with many of the principal effects having been observed and used. The modem history of hydrotherapy begins with the publication, in 1697, of The History of Cold Bathing by Sir John Floyer. Following Floyer were several works that attempted to provide a scientific foundation for the uses of water in medicine. Probably the strongest impetus for its use came from central Europe, where it was advocated by such well-known hydropaths as Priessnitz, Rausse, and Father Kneipp. They were able to popularize specific water treatments, which quickly became the vogue in Europe during the nineteenth century. By the end of the nineteenth century, many individuals in the United States and Europe were actively engaged in practicing hydrotherapy. Probably the best known American was J.H. Kellogg, a medical doctor who approached hydrotherapy scientifically, performing many and varied experiments on its

use and effects. In 1900 he published what may still be considered a definitive treatise on hydrotherapy, entitled Ratioiial Hydrotherapy? in which he considered the physiologic and therapeutic effects of water, along with an extensive discussion of hydrotherapeutic techniques. The scientific and lay literature of this period shows a wide disparity of thought as to the validity and efficacy of hydrotherapeutic treatments. In Germany the uses of hydrotherapy were openly embraced, whereas in nearby France hydrotherapy was seriously questioned, never becoming as popular or widely used. During the twentieth century, the popularity of hydrotherapy treatments declined, along with the n u n bers of practitioners and institutions providing treatments. One of the few physicians to maintain an active practice in hydrotherapy was Dr. O.G. Carroll, a naturopath practicing for many years in Spokane, WA. He developed a specific constitutional hydrotherapy treatment, which is currently receiving an increased amount of interest from the naturopathic profession. Although hydrotherapy declined in use for many years, it is rightfully being revived at the present time. It is a highly effective, noninvasive means of treating the sick, which may be used both in the office and in the home. It is also economical and involves patients directly in their care. As such, hydrotherapy is an ideal naturopathic treatment modality.

PROPERTIES OF WATER Water has several unique properties that contribute to its effectiveness as a therapeutic agent. It has an ability to store and transmit heat, which renders it most appropriate for treatment purposes. Water absorbs more heat for a given weight that any other substance-almost twice as much as alcohol or paraffin, 10 times more than copper or iron, and 30 times more than lead or gold. Water is also a good conductor of heat. The solvent properties of water account for its usefulness in the most common of all hydrotherapy procedures, baths and showers. Water is commonly considered the universal solvent. Water’s nontoxicity allows for its use both internally and externally, even in individuals who are extremely sensitive to their surroundings. Water also has the ability to change states within a narrow, easily obtainable temperature range. As ice, it is an effective cooling agent. In the liquid state, water may be applied as packs, baths, sprays, compresses, and douches at any desired pressure and temperature. As a vapor, it may be employed in vapor or steam baths or by inhalation. Because the density of water is near that of the human body, it can be used as an exercise medium for patients with paralysis, inflammations, or a t r ~ p h y . ~

Upon immersion of the body in water, hydrostatic pressure is exerted on the body surface, which has the effect of increasing venous and lymph flow from the periphery and increasing urine output. Water is also unique in that it is universally available, readily accessible, and applied with relatively simple and inexpensive equipment.

Physiologic Effects The physiologic effects of hydrotherapy may be classified as thermal, mechanical, and chemical. Thermal effects are produced by the application of water at temperatures above or below that of the body The greater the variation from body temperature, the greater the effect produced, other factors being equal. The mechanical effects are produced by the impact or force of water acting on the surface of the body in the form of sprays, douches, frictions, immersions, whirlpools, etc. The chemical effects are produced when it is taken by mouth or used to irrigate a body cavity, such as the large colon. The most commonly used effect, therapeutically, is the thermal one. It is the only one that will be dealt with in this section. Heat may be transferred from one object to another in several different ways, including conduction, convection, or conversion. In hydrotherapy the heating and cooling effects are produced by conduction of heat from the water to the body. The contact of water with the body is accomplished by means of baths, showers, sprays, packs, compresses, etc. The primary variable of concern is temperature, both of the water and of the patient. The temperature of the human body in a state of health is considered to be normal at 98.6" F orally, although it varies throughout the day from a low of near 97" F between 3 and 6 AM to a high of more than 99" F around 6 PM. These variations are important to consider when evaluating an individual before a hydrotherapy application. There is also a wide range of temperature variation within the healthy human body, as can be seen in Table 40-1.2 Body temperature is also a reflection of other factors, such as exercise, fasting, and ovulation. In an infant, the temperature may be elevated by 1" F to 3" F during a prolonged crying spell. Temperature of various tissues Tissue

Temperature (" F)

Skin

Average 93

Blood

Average 102

Brain Liver

104 106

Left ventricle of the heart

107

is immersed in water of various

Temperature (" F)

Description

Sensation

>lo4

Very hot

Can tolerate for only a short period

98-104 95-98 92-95 80-92 65-80 55-65 32-55

Hot

Skin redness if prolonged

Warm

Comfortably warm

Neutral

No sensation

Tepid

Slightly cooling

Cool

Cool

Cold

Sensation of coldness

Very cold

Pain and numbness

During a fever, the temperature is elevated due to any of several factors including the following: Infection Tissue destruction Malignancy Foreign proteins in the blood Dehydration Hormonal imbalances Muscular or chemical activity Proper evaluation of the degree and cause of a fever is necessary before hydrotherapy treatments. When we consider water temperature, the terms "hot" and "cold are related to body temperature. The range of temperatures useful in hydrotherapy applications varies from very cold to very hot. Table 40-2 provides general terminology. Deep well water is near 53" F. Cold tap water in Seattle varies in temperature throughout the year depending on the depth of the pipes and other exposures to the environment. During the winter it may be as low as 40" F, and in the summer as high as 60" F. This temperature variation may be a significant factor in hydrotherapy treatments; therefore it is advisable to be aware of the water temperature when using hydrotherapy techniques.

HYDROTHERAPYRESEARCH In a 1996 article Doering, Brix, Schneider, and Rimplefl discuss their study of the effect of hot and cold applications on cerebral hemodynamics and cerebral metabolism. Their purpose was to determine if local thermal applications would affect central nervous system reactions. Hot packs and cold packs were applied to the thighs of volunteers. Before, during, and after treatment the researchers measured cerebral blood flow velocity (CBFV),cerebral respiratory chain enzyme cytochrome aa3 (cCytaaS),and cerebral oxygen saturation (cHb02).

Therapeutic Modalities

When cold packs were applied, CBFV increased, whereas cCytaa3 and cHb02 both decreased. Upon removal of the cold packs, there was a sigruficantincrease above baseline of both cCytaa3 and cHb02. When hot packs were applied, cCytaa3 increased significantly and then decreased with removal of the hot stimulus. Likewise, with hot applications there was an increase in cHbOz during the treatment phase and a decrease following removal of the hot application. These results are in agreement with the principles of hydrotherapy as discussed elsewhere in this article: the spinal reflex response, the contrary response to hot and cold applications, and the reaction to cold.

Local and Systemic Effects of Cold Applications Cold applications may be made by means of ice, cold water, cold air, or the evaporation of water or other liquids from the surface of the body. Although the applications may vary, the principles and effects remain consistent. The primary or direct effect of cold applications is depressant in nature, leading to a decrease in function, either locally or systemically, depending on the application. The longer and colder the application, the longer and more intense the depressant effect. Local cold applications produce vasoconstriction in the local tissues that leads to a slowing of the local circulation. If the cold application is long, intense, and covering a large enough area, a slowing of the general circulation may occur. The migration of leukocytes and inflammatory agents from the vascular system into the local tissues is impeded and local metabolic activity is decreased. Nerve conduction velocities are diminished, resulting in decreased sensation and slowed motor response. Muscle tissue tends to contract, and connective tissues become less plastic. As a result of the decrease in local circulation, intense cold applications may result in a great depth of penetration. As we know from frostbite, it is possible to literally freeze tissues solid. Hence, care should be taken when applying ice packs. The greatest benefits of local cold derive from the vasoconstriction response, decrease in nerve conduction velocity, and the tendency of muscles to contract in response to cold applications. Inflammatory responses may be controlled by cold applications, leading to a better healing response to sprains and strains. Pain may be diminished through the mechanism of reduced nerve conduction velocity. Cold applications may assist in the tonification of muscle tissue, leading to benefits such as increased urinary sphincter tone. General applications of cold are hypothermic and produce a peripheral vasoconstriction with shunting of the blood to the core. There is a general decrease in the metabolism, heart rate, and respiratory rate. Muscles

become sluggish, the digestion is retarded, and eventually stupor sets in before death finally occurs. Few therapeutic applications are available for general applications of cold. Probably the best use is in lowering body temperature caused by fever due to illness or increased core temperature from exposure or exercise. As the body responds to the cold application, there is a return to normal function, which may lead to a state of increased activity. This is known as the secondary, or indirect, effect of cold, also termed the ”reaction.” If the cold application is a short one, the reaction follows quickly, its intensity reflecting the intensity (i.e., coldness) of the application. The secondary effect, or reaction, occurs only when the body has the vitality to respond to the cold, either following its removal from the body, in such applications as showers, sprays, and baths or after the body has warmed the application, in such cases as cold compresses or packs. Generally, the colder the application the greater the reaction. The reaction to a brief, vigorous cold application produces a slowing of the heart rate with a mild increase in blood pressure. Muscle tone is increased, and an increase in heat production is triggered. There is an increased sense of vigor and well-being. Many hydrotherapy techniques are directed at producing the reaction to the cold application. Cold applications are often prescribed for the relief of pain. Saeki5 found cold, but not hot, applications to be useful in the relief of prickly pain sensations experimentally induced in study subjects. Pain sensations were measured on the visual analog scale. Skin blood flow (BF) and the skin conductance level (SCL) were measured as well. Cold applications decreased pain, BF, and SCL, whereas hot applications increased pain, BF, and SCL. In 2002 a small (19 patients) study titled “To Evaluate the Effect of Local Application of Ice on Duration and Severity of Acute Gouty Arthritis” was published.6 The researchers divided the group in half. Both groups received oral prednisone 30 mg tapered to 0 mg over 6 days and colchicine 0.6 mg daily. Group A was treated daily with ice, Group B was not. At the end of a 7-day trial, Group A participants had a sigruficant reduction in pain over the control group. Schlesinger and colleagues6 concluded: “Joint circumference and synovial fluid volume tended to be more effectively reduced after 1 week of therapy in the ice group compared with controls, but these did not achieve statistical significance.” In 1993 Finan and colleagues’ tested the effects of cold applied to the abdomen of women who had undergone exploratory laparotomy. The cold was applied to 13 patients and not to 12 controls using a Hot/Ice Thermal Blanket. Self-administered morphine use was measured in both groups, with the cold group using more morphine on the first day postoperatively than the control group.

Hydrotherapy

Cold sponging has often been recommended for the reduction of fevers in children. Two articles published in 19978,9compared the use of sponging to oral antipyretics. Both studies concluded that sponging is more effective than medication in the first 30 minutes, but after that, the antipyretic medications are more effective. In 2002 Knoll, Wimmer, Gumpinger, and Haberl'O published the results of a study performed to evaluate the safety of mild hypothermia for stroke victims. Slight hypothermia has been shown to be neuroprotective in animal models. The question these researchers asked was if hypothermia would be safe for human use. The researchers concluded: "Continuous body core temperature reduction of 1"C to 2" C may safely be attained by a cooling mattress in nonventilated stroke unit patients."

Local and Systemic Effects of Hot Applications Heat may be applied to the body in various ways, including hot packs, fomentations, steam, hot air, baths, and showers.All hot applications produce definite physiologic responses, which are attempts to eliminate heat in order to prevent a rise in local and systemic temperatures. The effects produced by hot applications depend on the mode, temperature, and duration of the application and the condition of the patient. Intense moist heat applied for a long period of time (several minutes) has a depth of penetration not exceeding about 3.4 cm. A local vasodilation occurs, increasing local BF. The increased BF through the area carries away heat conducted into the tissues from a hot application and limits the depth of penetration. (This "radiator-like" effect can be overcome by intense applications of heat that are destructive to the tissues, and deep tissue destruction can occur.) Local hot applications result in increased arterial and venous capillary pressure, arterial and venous capillary oxygen carrying capacity, local metabolic activity, and migration of lymphocytes through vessel walls and into the local tissues. Local sweating is increased, and muscle relaxation occurs. General hot applications can have dramatic effects on the cardiovascular system. Peripheral dilation occurs with a marked increase in BF of as much as 400%, the pulse rate increases (6 to 10 beats per minute per 1"F rise in body temperature), cardiac stroke volume decreases, systole increases initially followed by a decrease in both systole and diastole resulting in an increased pulse pressure. The respiratory rate increases some five to six breaths per minute per 1"F rise in body temperature. Hyperventilation may occur and result in respiratory alkalosis. The blood volume increases as a result of the uptake of fluids from the tissues, leading to a decrease in the hematocrit.

A transient leucopenia occurs in the first few minutes following a hyperthermia treatment, followed thereafter by a leukocytosis. Sweating is increased, leading to a loss of water, salt, urea, uric acid, creatinine, sulfates, lactic acid, and other metabolites. Water at 98" F or above is generally perceived as hot, and water higher than 104" F is considered very hot. At 120" F, an immersion bath becomes unendurable, although small areas of the body, such as the hand, may be conditioned to endure a temperature of 10" to 15" higher for short periods. The mucous membranes, unlike the skin, may endure temperatures as high as 135" F, which accounts for our ability to drink very hot liquids, such as tea or coffee. Hot air may be tolerated by many individuals for fairly long periods, such as in a sauna, in which the temperature may reach as high as 200" F. Although exposure to the high temperatures of hot tubs and saunas has become quite popular in recent years, Kellogg believed that repeated and prolonged use may act to weaken the individual, unless counteracted by frequent cold applications, such as showers or ablutions2 In general we should consider that hot relaxes and sedates while cold stimulates, invigorates, and tonifies. However, very hot can stimulate and also be destructive while prolonged cold can be depressive and destructive. A comparison of the effects of hot and cold on several body systems is given in Table 40-3.

Local Hot Applications Inhalation of steam for the treatment of the common cold has often been prescribed. Four studies"-14 published between 1987 and 1994 demonstrated the benefit of steam inhalation regarding symptoms and nasal airflow. One of these studied3 demonstrated a decrease in inflammatory mediators in the local tissues. Another" also measured viral shed in volunteers with experimental cold. In that study, no decrease in the shedding of rhinovirus was detected. These findings were confirmed in a review performed by The Cochrane Library.15 Other local hot applications have also been used clinically. A Cochrune Reviezd6 of interventions for chronic abacterial prostatitis concluded: "The routine use of antibiotic and alpha blockers for chronic abacterial prostatitis is not supported by the existing evidence. The small studies examining thermal therapy appear to demonstrate benefit of clinical significance and merit further evaluation." Two recent studies17J8of the treatment of benign prostatic hypertrophy using thermotherapy both demonstrated a sigruficantdecrease in bladder outlet obstruction. One of these studies used heated water in a closed loop catheter system.17The other used high-energy microwave radiation to heat the tissues.18

Cold Systedorgan

Primary

Secondary

Hot

Skin Blood vessels Respiration Heat loss Blood vessels

Constriction Decreased Decreased Constriction

Dilation Increased Increased

Dilation Increased Increased

Dilation

Dilation (constriction if intense)

Heart

Rate increased

Rate decreased

First decreased, then increased

Nerves

Numbed

Excited

Muscles

Volume decreased

Volume increased

Respiration

Slowed and deepened

Rate increased

Stomach

Motility and HCI increased

Motility and HCI decreased

_ _ _ _ _ ~ ~ _ _ _

Modified from Kellogg JH Rational hydrotherapy, ed 4 Battle Creek, MI. Modern Medicine, 1923 721-722

Physicians do not normally think of hot applications in the treatment of acute sports injuries. However, one recent study19 compared the use of hyperthermia to therapeutic ultrasound. In comparing 21 randomized patients with acute muscular injuries of different sites and severity to 19 controls, researchers discovered that after 2 weeks of treatment, the hyperthermia group had signhcantly less pain and faster hematoma resolution.

General Hot Applications The presence of fever has long been associated with better survival and shorter duration of disease in cases of infection. Many studies have demonstrated the causes of that beneficial response. Four studies reviewed for this chaptePB demonstrated the activation and mobilization of blood mononuclear cells with hyperthermia treatments. One of these studies*"demonstrated signhcantly increased serum cortisol, plasma norepinephrine, and plasma epinephrine and hypothesized that these elevated stress hormones were responsible for the rise in mononuclear cells. One study" concluded that "fever-induced Hsp70 expression may protect monocytes when confronted with cytotoxic inflammatory mediators, thereby improving the course of the disease." Two recently published studies of sauna bathing24,E demonstrated improved vascular endothelial function in patients with coronary risk factors and patients with chronic heart failure. In both studies patients were treated in saunas at 60" C for 15 minutes daily for 2 weeks.

PRINCIPLES OF BLOOD MOVEMENT WITH HYDROTHERAPY In order to promote healing, either locally or systemically, it is important to maximize circulation of well-oxygenated, nutrient-rich, toxin-low blood. Hydrotherapy techniques

are one of the most effective means of accomplishing this, if used in conjunction with proper levels of activity, optimal nutritional intake, and adequate detoxification. Four basic modifications of blood movement exist within the body: Increased rate of BF through an organ or area of the body Decreased rate of BF through an organ or area of the body Increased volume of blood in an anemic area Decreased volume of blood in a congested area In order to accomplish these modifications, five relevant physiologic principles can be applied: Revulsive effect Derivative effect Spinal cord reflex Collateral circulation Arterial trunk reflex

Revulsive Effect The revulsive effect provides a means of increasing the rate of BF through an organ or other body part, such as an extremity. The most effective means of accomplishing this is by using alternating hot/cold either as compresses, baths, showers, sprays, etc. This is commonly referred to as contrast hydrotherapy. Local, alternating, hot and cold applications produce marked stimulation of local circulation. It has been shown that a 30-minute contrast bath produces a 95% increase in local BF when the lower extremities alone are immersed. When all four extremities are immersed at the same time, there is a 100% increase in BF in the upper extremities and a 70% increase in the lower extremities.26

Hydrotherapy

Contrast applications to the area of skin that is in reflex relationship to an organ increase the functional activity of that organ. Hence, liver function is increased by contrast application applied over the right upper quadrant of the abdomen. Several studies have researched the optimal treatment times for revulsive effects. Woodmansey and coll e a g u e ~found ~ ~ 6 minutes of hot application and 4 of cold to be optimal for the British subjects he studied. Krussen28found 4 minutes hot and 1 minute cold to be the best treatment protocol. Moorz9states that 3 minutes hot, followed by 30 to 60 seconds of cold, provides satisfactory clinical results. From these variations, it can be inferred that, due to the variations in procedures and locales, it is best for practitioners to determine their own ideals, based on their observations of clinical results. Basically, the cold application need only be long enough to produce vasoconstriction, and this can be shown to occur in as short a period as 20 seconds. Repetition of applications is another important variable to be considered when applying revulsive treatments. A series of three hot/cold applications seems to be practical. Most individuals show a decreasing secondary reaction to repeated applications of cold. Due to the increased BF within an area, the revulsive effect is ideal for treating situations presenting primarily as congestion. An example of this effect is the use of alternating hot/cold compresses over the face for sinus congestion. As a powerful decongestant, the revulsive effect also acts as an analgesic for pain resulting from congestion. Because of its marked stimulation of local circulation, the revulsive treatment is an exceptionally effective hydrotherapeutic procedure and one of the most generally useful considering its simplicity.

Derivative Effect The derivative effect may be considered the opposite of the revulsive effect. Its primary intent is to alter the volume of blood in an organ or area of the body. This effect is best obtained by the prolonged use of either cold or heat depending on whether one wants to draw blood into an area (hot application) or to drive blood out of an area (cold application). An example of the derivative effect would be the prolonged application of heat to the feet, as with a hot foot bath, in order to decrease congestion in the head. This form of treatment may be quite successful for certain forms of congestive headaches. In general, the greater the area of the body exposed to the application, the more extreme the temperature, and the longer the application, the greater the effect.

Spinal Reflex Effect The spinal reflex effect (see Moo$9) provides a means of affecting a distant area of the body through a local application. A sufficiently intense local application of hot or

cold not only affects the immediate skin area but also causes remote physiologic changes, mediated through spinal reflex arcs. These effects have been carefully observed over many years and have led to a mapping that correlates each surface area with its corresponding internal area or organ, or both. Most texts on hydrotherapy contain such a diagram.2,29 Some examples of studies dealing with specific reflex effects follow. Hewlett,30 Stewart?l and B r i ~ c o eall ~~ noted changes in BF in the opposite arm and hand when one arm and hand were placed in hot or cold water. R ~ h r n a n nobserved ~~ that when cold was applied to the epigastrium, there was a decrease in tone of the stomach, with a quieting of the pyloms. Heat at 50" C applied to the epigastrium produced increased tone in a relaxed stomach and decreased tone in a contracted stomach. PoultonMdemonstrated that esophageal function could be influenced by irritation of the skin over the sternum. Bing and T ~ b i a s s e nshowed ~~ reflex relationships between the skin of the abdominal wall and the colon. They also demonstrated a reflex relationship between the lungs and the skin of the chest wall. Kuntz"6stated the following: In view of the facility with which cutaneous stimulation elicits reflex visceral reactions, particularly vasomotor changes and changes in the tonic state of the visceral musculature, it must be apparent that many visceral disorders, particularly disorders of the gastrointestinal canal, may be influenced beneficially by appropriate stimulation of the corresponding cutaneous area.

Fisher and Solomon37stated: "externally applied heat not only decreased intestinal blood flow, but also diminishes intestinal motility and decreases acid secretion in the stomach, while cold has the opposite effect." This is an example of a contrary effect in which the reflex effect is not the same as that observed in the local reflex skin area (i.e., local heat decreases, rather than increases, intestinal BF as one might expect). Prolonged cold has the opposite effect. Tables 40-4 through 40-6 show some of the observed reflex effects of hydrotherapeutic p r o c e d ~ r e s . ~ ~

Collateral Circulation Effect The collateral circulation effect may be considered as a special case of the derivative effect.2In general use, the derivative effect involves blood volume changes from one area of the body to another, as previously discussed. The collateral circulation effect, on the other hand, more specifically considers the local circulatory effects on deep (rather than superficial) collateral branches of the same artery. Considering the circulatory patterns of a large body part, such as the thigh, it is clear that both superficial and deep areas are supplied by the same artery. A hot

I

Reflex effects of short cold

Reflex effects of prolonged heat

Application location

Effect

Application location

Effect

One extremity

Vasodilation in contralateral extremity

General peripheral vasoconstriction

Abdominal wall

Decreased intestinal blood flow, intestinal motility and acid secretion

Local application of intense cold as brief as30seconds

Pelvis

Relaxes pelvic muscles, dilates blood vessels, increases menstrual flow

Face, hands, and head

Increase in mental alertness and activity

Precordial area

Increase in heart rate and stroke volume

Precordium

Increases heart rate, decreases its force, and lowers blood pressure

Chest, with friction or percussion

Initial increase in respiratory rate, then slower, deeper respiration

Chest

Promotes ease of respiration and expectoration

Trunk

Relaxes ureters or bile ducts, relieves renal or gallbladder colic

Over kidney

Increases production of urine

in order to increase circulation and speed healing of the injured part.

GENERAL RULES OF HYDROTHERAPY

ADDlication location

Effect

Trunk of an artery

Contraction of the artery and its branches

Nose, back of neck and hands

Contraction of the blood vessels of the nasal mucosa

Precordium (ice bag)

Slows the heart rate and increases its stroke volume

Abdomen

Increases intestinal blood flow, intestinal motility, and acid secretion

~~

Pelvic area

Stimulates muscles of the pelvic organs

Thyroid gland

Contracts its blood vessels and decreases its function

Hands and scalp

Contraction of brain blood vessels

Acutely inflamed joints or bursae

Vasoconstriction and relief of pain

application to this area dilates the surface vessels, drawing blood to the superficial areas and concurrently decreasing the BF to the deep areas. A cold application causes the opposite effect. Local compresses and fomentations are the most commonly used techniques to affect collateral circulatory changes.

Arterial Trunk Reflex The arterial trunk reflex effect is a special case of general reflex effects2 It has been observed that prolonged cold applied over the trunk of an artery produces contraction of the artery and its branches distal to the application. Prolonged hot applications have the opposite effect of producing dilatation in the distal arterial bed. An example of this effect is the application of prolonged cold to the area of the femoral artery in the groin in order to decrease BF in a foot or ankle that had sustained an acute injury that resulted in either internal or external hemorrhage. Following the acute phase, prolonged hot applications might be used in like manner

1.The first rule of hydrotherapy is the same as for any therapy: Treat the whole person. This involves considering all aspects, including medical history, current condition, current medications, and any other relevant information. 2. Use hydrotherapy treatments in a coordinated and integrated manner with any treatments or medications the individual is receiving. 3. Always measure the person’s temperature before beginning a treatment. If the temperature is below normal, apply more heat or leave the hot applications on for a longer time. If body temperature is above normal, use less heat and more intense cold during the treatment. 4.Explain the treatment procedure before beginning, including the technique to be used, the duration, frequency, and any other relevant factors. Try to ensure that the patient feels comfortable with the procedure before beginning. 5. In order to provide as precise a treatment as possible, grade the patient in terms of age, severity of problems, vitality, emotional state, circulatory condition, etc. Be especially careful with young or elderly persons, individuals who are chilly, have cardiac problems, are weak or debilitated, are obese, or have other severe physical compromises. For individuals with insulin-dependent diabetes, the application of heat to the extremities may be contraindicated. The body dissipates heat conducted into the tissues in much the same way a radiator works. The heat is transferred to the circulating blood. Cooler blood is brought into the area and hence the heat is “moved elsewhere.’’ With poor circulation, less heat is dissipated and the local tissue temperature rises, perhaps to unsafe levels. Diabetics frequently have arterial disease, which may reduce BF to an extremity. The application of heat increases the metabolism of the tissues. Due to impaired circulation, the metabolic needs can quickly overuse

the nutrients and oxygen available from the blood and cells may die from oxygen depletion simply as the result of hot application^.^^ Therefore hot foot baths are contraindicated in diabetics. For diabetics with conditions in which a hot application to the feet would normally be the treatment of choice, a large hot compress can be used instead to the lower abdomen, groin, and thighs in order to get a reflex reaction in the lower extremities. Diabetics may also display peripheral neuropathies that decrease their ability to sense heat, thereby increasing the possibility of causing a bum with hot applications. Other individuals with neurologic injury or disease should also be treated with extreme caution during hot applications. 6. The environment in which the treatments are given should enhance and stimulate the healing forces as much as possible. This may include such considerations as color of the room, light intensity, music, and plants. 7 If a patient becomes chilled during a treatment, it may be necessary to stop the treatment and warm the person. Sometimes it may suffice to warm the person (by such means as hot drinks, friction rubs, additional blankets, or a hot water bottle to the feet) while continuing the treatment. If the person fails to warm following these attempts, then stop the treatments and warm him or her. Never allow a patient to become chilled to the point of shivering. 8. Follbwing a hydrothirapy treatment, avoid excessive heat in the form of overly warm clothing, overly warm rooms, sun exposure, or exercise. Excessive heat may slow or prevent the body reaction to the treatment and negate the benefit of the treatment. 9. It is best to do the treatment at an optimal time of day for that patient. It is best to do treatments before meals, or at least 1hour after a meal.

As with any therapy, it is important to practice hydrotherapy with a research orientation, noting unusual reactions and physiologic effects. Many physiologic parameters, such as urine chemistries and microscopic components, specific gravity, body temperature, and blood sugar levels, may be easily monitored and recorded during treatment. This information helps to optimize the treatment protocols, stimulates further research, and validates hydrotherapy as an effective and useful therapeutic modality.

cases, result simply from the individual's reaction to the treatment. They may, in the long term, be beneficial. Any time an individual experiences an undesired effect following a treatment, the therapist should review the treatment's length, intensity, and appropriateness for the individual at this time. If more treatments are considered, they may need to be modified in order to lessen the undesired effects. Some of the possible side effects of hydrotherapy treatments are as follows: Headache (resulting from too long or intense a treatment, or from the release of toxic products in the body) Vertigo Nervousness Aches and pains Insomnia Hyperventilation Nausea Palpitations Faintness Chilliness A synergistic effect has been demonstrated with hyperthermia and radiation treatments given in cancer care. Any patient receiving radiation therapy should not be indiscriminately treated concurrently with hyperthermia. Following an unpleasant reaction to a hydrotherapy treatment, discontinue the treatment and wait at least 2 to 3 hours before attempting another treatment. In cases of chilliness, always act quickly to warm the person. Coaching the person in deep, slow-breathing exercises for several minutes often relaxes the person and decreases the reaction.%If the treatment occurs in the practitioner's office, the practitioner should reassure himself or herself that the patient has fully regained balance before allowing him or her to leave. Although these effects may occur during or immediately following treatments, they may also occur as long as 24 hours later. Therefore it is important for practitioners to be available to patients during off-duty hours.

SAFETYASPECTSOFHYDROTHERAPY Pregnancy

POSSIBLE SIDE EFFECTS OF HYDROTHERAPY

What to do or take in pregnancy is always a concern. Bathing in hot water is no exception. Ridge and B ~ d d , 3 ~ in a letter to the editor of the New England Journal of Medicine, summarized these concerns and concluded "that for pregnant (or potentially pregnant) women using a spa pool at a water temperature of 40" C (104"F), any immersion longer than 10 minutes may be too long."

Although hydrotherapeutic procedures are generally mild, they may in some situations produce unexpected or undesired effects. These effects may be the result of improperly applied treatments, but they may, in some

Two studies published in 199840,41 demonstrated no adverse cardiovascular effects from bathing in water

Hypertension and Cardiovascular Disease

Therapeutic Modalities above 40" C and a response to heat stress no different form normotensive subjects. In a 1999 study of patients with coronary artery disease treated with sauna,42it was shown that "there were no arrhythmias of ECG changes," but there was evidence of "scintigraphically demonstrated myocardial ischemia."

HYDROTHERAPYTECHNIQUES The various ways in which water may be applied to the human body therapeutically is only limited by the imagination of the practitioner. J.H. Kellogg, in his seemingly exhaustive treatise on hydrotherapy, devotes 541 pages to describing the techniques of hydrotherapy. Several other books describe in detail specific procedures and t e c h n i q ~ e sThose . ~ ~ desiring to use these techniques in practice are encouraged to obtain one or more of these reference works. To successfully use hydrotherapy, one must be familiar enough with the procedure to use it in an efficient and competent manner. Although the equipment required for these techniques is quite simple, it is important that it be clean, easily available, and maintained properly. Care for the comfort and confidence of the patient greatly increases the effectiveness of the treatments.

Compresses Compresses are of three basic types: hot, cold, and alternating hot and cold. They are each applied using cloth, or other compress material, which is wrung out to the desired amount of moisture and then applied to any surface of the body. A single compress consists only of layers of the wet material, whereas a double compress is one in which the wet cloth is completely covered by dry material, usually wool, which acts to prevent cooling by evaporation or heat loss. This allows the body, in the case of a cold double compress, to warm the area, thereby producing a secondary reaction to the cold. Compresses are commonly referred to by the area of the body they are applied to, such as the throat, head, joint, trunk,or limb.

Cold Compresses and Packs A cold compress consists of a cloth wrung from cold or ice water and then applied to the body. Some practitioners may add solutes to the water such as sodium chloride, baking soda, Epsom salts, boric acid, or cider vinegar. Herbs may also be used to create a more specific effect from the compress. Some commonly used herbs are hayflower, oatstraw, and fenugreek, made as teas into which the compress cloths are dipped. Packs are also used if the goal is to cool the tissues more aggressively. Packs

may be made from crushed ice or purchased as commercially available gel packs that may be kept in the freezer. The cold puck or compress has primarily a vasoconstrictive effect, both locally and distally. Due to this effect, it may be used to prevent or relieve congestion, reduce BF to an area, prevent edema following injury, inhibit inflammation, and relieve pain due to congestion. It may also be used to reduce body temperature when applied over a large area of the body. Compresses are renewed frequently (every 1to 5 minutes) in order to maintain the primary cold effect, whereas packs remain cold longer. The temperature of a cold compress depends on the specific problem being treated, as well as the state of health of the patient. In general, the colder the application, the briefer the period of application. Cold compresses should not be used locally in a person who is chilly or who has pleurisy, sinusitis, or acute asthma, as these conditions may be seriously aggravated.

Hot Compress The hot compress is a prolonged application of moist heat, generally to a local area of the body. The fomentation is a special case of a hot compress, which provides prolonged exposure at a higher temperature. Hot compresses and fomentations have several therapeutic effects. In many situations they may create an analgesic effect, thereby decreasing pain. They are generally more effective locally for pain resulting from spasm than for pain due to congestion. They also create a derivative effect, which may be used to increase BF to the periphery, thereby decreasing internal congestion. By applying short, intensely hot compresses, a stimulation effect may be obtained. This may be used to increase BF to a part, to stimulate certain organ functions, to decrease others, and to produce tissue warming and relaxation. Mildly hot compresses may be beneficial for their sedative effects in treating insomnia, nervous tension, and mild muscular spasms. Fairly hot compresses may be applied directly to the skin surface, with care taken to not bum or startle the patient. As stated previously, hot applications are contraindicated on the extremities of diabetic individuals. When treating the elderly or those with impaired neurologic function, edema, or decreased circulation, special caution must also be taken. Fomentations are commonly applied at temperatures that are not tolerated directly on the skin, and therefore must be applied over a bath towel placed on the area.

Heating Compresses The heating compress, also known as the cold double compress, consists of a cold compress covered completely by several layers of dry material such as flannel or wool.

Hydrotherapy

It is allowed to remain on until warmed by the body. The layers of dry material prevent heat loss by evaporation, thereby permitting accumulation of heat and cresting a general heating effect. Heating compresses are used most commonly in upper respiratory infections, such as sore throats, bronchitis, influenza, pneumonia, and swollen lymph glands in the neck. They may also be applied over the trunk or abdomen, genital area, joints, limbs, or feet. A classic example of the heating compress is the wet sock treatment. This treatment is used for congestive headaches, sinusitis, and otitis media in young children. Socks are wrung from cold water and pulled on the feet. These are then covered with another pair of socks (preferably wool) and left overnight to be warmed by the patient. Frequently, the wet socks are dry by morning. The primary effect of the heating compress is to increase the local circulation, thereby providing for increased nutrition and oxygenation of the tissues, as well as increased elimination of metabolic waste from the area. In the previous example of wet socks, it is the derivative effect of the wet socks treatment that is the desired effect. As with cold compresses, the temperature of the initial application depends on the state of the patient and the condition being treated. In general, the colder the application, the stronger the secondary reaction to the cold. As weak and debilitated patients are unable to generate a strong secondary reaction, cool rather than cold application may be indicated. The same general precautions as for a cold single compress should be followed.

Baths Baths are full or partial immersions of the body into water of various temperatures: cold, hot, or contrasting. Bath waters may contain additional substances such as salts, minerals, herbs, or medications and may be in an agitated state, as with a whirlpool.

Hot Full-Immersion Baths These baths are given within a temperature range of 100" F to 106" F for 20 to 60 minutes or longer. They are indicated for rheumatoid arthritis, to aid in relief of muscular spasms, for cleansing the body, to stimulate the immune system, to induce sweating, and many other purposes. They are probably most useful in applying heat to produce a hyperthermic response in the tissues or to raise core temperatures. As stated previously, hyperthermia treatments have been found useful in the treatment of infections and malignancies. Water immersions for hyperthennia have the benefit of low cost and more consistent heating of tissues. When performing local immersions, the water temperature may be as high as is tolerable. The duration of treatment is typically 15 to 20 minutes. Treatments should be given daily.

Whole body immersion at home should be limited to a water temperature of approximately 104" F and not longer than for about 30 minutes. Treatments may be given daily for several treatments, but it may be better to limit daily use to three to four treatments. Treatments should be given every other day if many treatments are to be undertaken. Individual tolerance varies from these suggestions. Patients should have assistance when performing hyperthennia treatments at home. When hyperthermia treatments are given in the office, close supervision may allow more aggressive treatment. The water temperature may be increased to 106" F, and the duration of treatment may exceed 60 minutes. Patient tolerance is the key to performing safe and effective hyperthermia. When performing hyperthermia treatments, the following precautions should be observed regardless of whether the treatment is performed at home or in the office: Hypotension may result from hot immersions. When arising from the tub, patients may become lightheaded and lose their footing. Patients should not take hyperthermia treatments on either an empty or full stomach. Too little food may result in a hypoglycemic episode, and too much food may result in nausea and vomiting. Hyperventilation sometimes occurs. On rare occasions patients may go into early tetany from respiratory alkalosis. Being present with the patient and coaching his or her breathing can prevent this. Headaches can and often do occur. These can be prevented by the early and frequent use of cold compresses to the head, face, and ears. The sauna or steam bath can often be used interchangeably with the immersion bath. Immersion, sauna, and steam are most similar with respect to their immune stimulant and detoxification benefits. In most instances they are best followed by a brief cool bath, shower, or spray. Prolonged hot tub baths are never appropriate in the very old or very young, weak or anemic persons, individuals with severe organic disease, or in anyone with a tendency to hemorrhage. Given for brief periods, they may help to reduce fevers by creating peripheral vasodilation, thereby promoting an increased heat loss.

Neutral Bath The neutral bath is a full immersion bath given at the average temperature of the skin, 92" F to 95" F, in which the recipient has neither the sensation of being warmed nor that of being cooled. A minor variation in temperature of as little as 2" F may create a totally different therapeutic effect. As the ideal temperature depends on

Therapeutic Modalities the patient's condition and reaction to the water, it is often better to use his or her sensation, rather than a thermometer, as a guide to adjusting the temperature. The duration of a neutral bath may vary from 15 minutes to 4 hours. If the bath lasts longer than 20 minutes, it is necessary to add warm water to maintain the temperature. The primary effect of a neutral bath is to create a state of decreased excitation. This sedative effect, similar to that produced in deprivation tanks, calms the nervous system. A second effect is activation of the kidneys, creating increased urinary output due to the absorption of water into the body during periods of prolonged immersion.48 It is aided by the neutral temperature, which provides no stimulus for water loss through sweating. Nephrotic patients display increased phosphate excretion following prolonged immersion; therefore they warrant special care when given prolonged immersion Lastly, the neutral bath causes a decrease in the surface temperature of the body due to the lack of the normal heat-producing stimulus of cool air on the skin. As a result, the surface may be cooled as much as 6" F, creating a tendency to chill following the bath. This effect necessitates special care in keeping the patient warm. When prescribed for home treatment, a neutral bath is best taken just before getting into bed, in order to avoid chilling. Therapeutically, neutral baths are most commonly used for their calming effects in cases of insomnia, anxiety, nervous irritability, exhaustion, or chronic pain. By increasing kidney output, they may be appropriate in detoxification programs for substances such as alcohol, tobacco, or coffee, or as an adjunct treatment for peripheral edema. They also serve a valuable role in the control of fevers in individuals who would not be able to react to stronger measures, such as the Brand bath. These patients would include the very young, very old, feeble, or exhausted. Start the baths at about 98" F and lower the temperature slowly over a period of 5 to 10 minutes to 92" F to 93" F, until the desired body temperature is rea~hed.4~

Sitz Bath The sitz bath is a partial immersion bath of the pelvic region. It is more easily given in a specially constructed tub but may also be effectively done in a regular bath tub. Often it is taken with the feet immersed in a separate tub of hot water before or during the bath. A sitz bath may be taken hot, neutral, cold, or contrast hot and cold. The sitz bath may be undertaken at home with a bathtub and basin of cold (ice) water. The patient should sit in the hot half bath (hot water above the navel) for the prescribed time. The cold application can then be

performed with a towel wrung from cold water. The patient wrings the cold towel, stands in the bath, and pulls the cold towel into the groin, holding it like a diaper for the time prescribed for the cold application. Care should obviously be taken when standing in a tub of water, especially when standing up from a hot bath. The hot sitz bath is generally taken for 3 to 10 minutes at 105" F to 115" F. The primary effect is analgesic. It may be helpful in cramps of the uterus or ureters, pain from hemorrhoids, ovaries or testicles, sciatica, urinary retention, and after cystoscopy or hemorrhoidectomy. It is followed by cool sponging or effusion of the area. Hot sitz baths are not indicated in cases of acute inflammation but may be appropriate for chronic pelvic inflammatory disease (PID). Hot applications to the pelvis are also contraindicated during menses in most instances. The hot sitz bath is best taken with a hot foot bath at 110" F to 115" F. Neutral sitz baths are more appropriate for situations of acute inflammation, such as cystitis and acute PID. They are given at 92" F to 95" F for between 15 minutes and 2 hours. It is necessary to provide adequate coverings during this period to avoid chilling. Neutral sitz baths may also be effective for pruritus of the anus or vulva. Appropriate herbs, salts, or other medications may be added to the water to optimize the treatment. The cold sitz bath is given immediately following a warm-to-hot sitz bath of 1 to 3 minutes and lasts (at a temperature of 55" F to 75" F) from 30 seconds to 8 minutes. It is important to ensure that the water level of the hot bath on the body is at least 1 inch above the level of the cold water. This ensures adequate warming of the area, thereby preventing chilling. Friction rubs to the hips during the cold sitz bath promote an increased reaction. The cold sitz bath is used mainly for its tonifying effects. It may be used for subinvolution of the uterus, metrorrhagia, atonic constipation, enuresis, atony of the bladder, and chronic prostatic congestion. Since it increases the tone of the smooth muscles of the uterus, bladder, and colon, it lessens the tendency to bleed from the uterus, the lower bowel, and rectum. Contrast sitz baths are given in groups of three (i-e., three alterations of hot to cold). Two separate tubs are necessary to facilitate this process. The hot is at 105" F to 115" F, the cold at 55" F to 85" F, with the temperatures again dependent on the condition being treated and the strength of the patient. A standard treatment would be 3 minutes hot and 30 seconds cold. The water level in the hot tub is set 1 inch higher than in the cold. Adequate draping is necessary to prevent chilling. As with all hydrotherapy treatments, one always finishes with the cold. The contrast sitz bath increases pelvic circulation and tone of the smooth muscles of the region. It is indicated

Hydrotherapy

in chronic PID, chronic prostatitis, atonic constipation, and other atonic conditions of the pelvis. The strong revulsive effect created increases the BF in the pelvic region dramatically.

Cold Friction Rubs and Ablutions Cold friction rubs, or ablutions, consist of frictioning the body in a predetermined sequence with cold water. They differ from sponging in that they are more tonifying and are done more vigorously with rougher materials. A woolen bath mitt works well, but if this is not available, a coarse washcloth or loofa may also be used. A whole body ablution is carried out with the patient lying supine, covered completely and not chilly. Using cool to cold water, the therapist dips the mitt into the water and vigorously causes friction on a portion of the body. Depending on the cooling effect desired, the mitt may either be saturated or wrung dry before the friction occurs. The body part is treated until reddening occurs. If the patient is weak, it is best to dry the areas as one proceeds using a coarse dry towel. If the patient is strong and vigorous, one can wait and dry the areas at the end of the treatment. One sequence for an ablution treatment would be, with the patient supine, to proceed from the chest to the arms, and then the legs, then, turning the patient over, to do the back of the legs and feet, the buttocks, and finally the back. Only that part being treated is exposed at any time. The primary effect of a cold ablution is tonic. Therefore it may be used for any condition in which you desire a tonifying treatment, such as fatigue following illness or surgery or after hot applications, such as saunas, whirlpools, or hot baths. It is an excellent prophylactic hydrotherapy technique when used regularly along with saunas, hot tubs, and massage.

Constitutional Hydrotherapy The constitutional approach to hydrotherapy was, as stated earlier, developed by Carroll and was developed as an application of first hot, then cold to the trunk, front, and back. Apart from contrast hydrotherapy applications, it is the most generally useful of the various hydrotherapy treatments. It is commonly used to balance body functions, strengthen the immune system, and promote healing. It is a useful adjunct to detoxification. Constitutional hydrotherapy may be used as an adjunct to the treatment of any condition. It may be used to treat acute conditions such as upper respiratory infections, bronchitis, asthma, stomach flu, and in chronic conditions such as irritable bowel, ulcerative colitis, PMS, and arthritis. (As a general rule of thumb “when in doubt, try constitutional hydrotherapy.”)

Materials The practitioner should have the following materials available: Bed or treatment table One double sheet folded end to end (or two twin sheets) Two wool blankets (or acrylic) Three bath towels (a small bath towel is best, one that when folded in half reaches side to side across the patient and from shoulders to hips) One hand towel Source of hot and cold water Low-volt electrical muscle stimulation (EMS) unit (electrical stimulation with constitutional hydrotherapy may be optional)

Procedure The practitioner should follow these steps:

1.While preparing two hot towels, have the patient undress to the waist and lie down face up between the sheets, under one blanket. 2. Place an oral thermometer in the patient’s mouth. 3. Place EMS pads on the back at the T6 level. 4.Auscultate the patient’s heart. 5. Place two hot folded bath towels (four layers) on the patient’s trunk,shoulders to hips, side to side. 6. Cover with sheet and one blanket. 7. Check patient’s temperature, leave on for 5 minutes. 8. Return with one hot bath towel and one cold hand towel. 9. Place the new hot towel on top of two old towels and flip all three towels. Remove two old hot towels, leaving the new hot towel in place. Place the cold towel on top of the new hot towel and flip again. Remove the hot towel, leaving the cold one in place. 10. Cover the patient and add an extra layer of blanket. 11.Turn on EMS to “strong” stimulation, AT PATIENT COMFORT LEVEL. Leave on for 10 minutes or until the cold towel is well warmed. 12. Return and remove the warmed towel. Move the EMS pads transabdominally to T12 and the supraumbilical position. Turn on the device for 10 minutes with intensity at “strong” stimulation, AT PATIENT COMFORT LEVEL. 13. Return with two hot towels and have the patient roll prone. 14. Place two hot folded bath towels (four layers) on the patient’s trunk,shoulders to hips, side to side. 15. Cover with sheet and one blanket, leave on for 5 minutes. 16. Return with one hot bath towel and one cold hand towel.

Therapeutic Modalities

17. Place the new hot towel on top of two old towels and flip all three towels. Remove two old hot towels, leaving the new hot towel in place. Place the cold towel on top of the new hot towel and flip again. Remove the hot towel, leaving the cold one in place. Leave on for 10 minutes or until the cold towel is well warmed. 18. Return and remove the warmed towel. Recheck oral temperature. If the patient is warm, he or she may leave at this time. If the patient is chilled, provide hot packs or dry friction rubs to warm him or her and alter your treatment approach next visit to prevent chilling. As a variation, the contrast may be narrowed (not as hot or cold) for the very ill or weak patient or may be pushed to the hot for sedation or to cold to tonify and strengthen.

Precautions/Special Considerations If using the patient’s bed, take care not to get it wet. Hot water from the tap is usually hot enough. The hot towel should be hot enough that it’s just possible to wring it out. The cold towel should be quite cold (use ice water), but wring it out thoroughly and use only one layer. If the patient has trouble warming the cold towel, massage the back (through the blankets and towel) and feet. Patients with asthma often react negatively to cold applications on the chest. For these persons, begin with a smaller cold towel applied to the abdomen only. With later treatments, gradually increase the size of the cold towel until the entire chest and abdomen can be covered without any negative reaction.

Wet Sheet Pack The wet sheet pack is one of the most useful of all hydrotherapy procedures. It may be done either in the office or as a home treatment, if adequate direction is provided. It requires from 1 to 3 hours, depending on the patient’s condition. The technique is common to most schools of hydrotherapy. Understanding the process completely before using this treatment is important:

1. Using either a bed or treatment table, place two wool blankets lengthwise on the table with a small pillow at the head. The blankets must be large enough to cover the person being treated. If wool is not available, acrylic is the next best choice. 2. The patient must be warm before the pack is applied. If not, the patient may be warmed by a hot bath or shower, dry blanket pack, diathermy over the back, or any other appropriate technique. 3. Once the patient is ready, a clean white cotton sheet (equal in length to the height of the patient) is wrung as dry as possible after being soaked in cold water. It is much easier if two people are available to wring out the sheet. The sheet is opened and placed lengthwise

along the table with equal amounts draped over each side of the table. The sheet should be 1 to 2 inches below the height of the blankets. 4. The patient now removes all clothing and lies on the wet sheet with shoulders 4 inches below the top of the sheet. Both arms are raised while the attendants quickly wrap one side of the sheet around the body, tucking it in on the opposite side, and carefully molding it to the body. Below the hips, the sheet is wrapped around the leg on the same side. 5. The arms are now lowered, and the opposite side of the sheet is drawn over the body, covering both arms. It also wraps the opposite leg. The wet sheet is quickly smoothed over the body to ensure complete contact and is tucked in around the feet. As this is a shocking experience, it should be performed quickly and efficiently. 6 . At this point, the blankets are quickly pulled over the body and tucked in firmly, ensuring there are no drafts around the neck or the feet. Additional blankets may be laid over the patient and tucked in as appropriate. A stocking cap may be pulled over the head to increase the heating effect. While the patient is in the pack, it is necessary to have someone nearby at all times. Sudden attacks of claustrophobia in some individuals can create extreme anxiety. Allowing the patient to have one arm free during the procedure does not adversely affect the outcome of the procedure itself and often prevents the claustrophobic reaction. However, should it occur, first remove the sheet from the feet, as this may allow enough movement to allay the attack. If this is unsuccessful, it may be necessary to stop the treatment. Providing hot teas is helpful throughout the treatment. If the patient complains of chilliness, add blankets, place a hot water bottle to the feet, or provide warm drinks. The wet sheet pack proceeds through four stages: tonic or cooling, neutral, heating, and eliminative. Depending on the desired effect, the therapist may wish to prolong any one specific stage:

Tonic stage. This stage may last from 2 to 15minutes and is finished when the patient no longer perceives the sheet as being cold. This phase is intensely alterative to the body, due to the intense thermic reaction induced. The length of this stage is directly dependent on the amount of water left in the sheet. For weak or exhausted patients, the sheet should be wrung out as completely as possible. For young, strong individuals for whom a more tonifying treatment is desired, more water may be left in the sheet.

Neutral stage. Once the sheet reaches body temperature, the person no longer feels cold. At this time,

the neutral phase begins. It may last from 15 minutes to an hour or longer, depending on the vitality of the patient. During this phase, there is a sense of calm that is similar to that experienced during a neutral bath. Often the patient falls asleep during this phase. This stage is indicated in cases of insomnia, anxiety, and delirium. In order to prolong the neutral phase, provide only adequate covering to prevent the patient feeling cool. Greater amounts of blankets trap more heat, and the neutral phase finishes sooner. Heating stage. As heat accumulates beneath the blankets, the patient gradually senses the warming and eventually begins to show light perspiration on the forehead. The time between the patient feeling warm and the beginning of perspiration is known as the heating phase. This may last from 15 minutes to 1hour. Elimination stage. The final stage begins when the body begins to perspire. In a febrile patient this stage is reached sooner. This stage is especially beneficial for those patients in a detoxification process such as from alcohol, tobacco, coffee, or other toxins. It may also be used with acute infections, such as colds, flu, or bronchitis. Certain skin conditions, such as jaundice, may also benefit from this stage, as well as acute inflammatory conditions, such as arthritis. During the elimination phase, it is important to provide adequate fluid to the patient. Herbal teas, used for either their diaphoretic or therapeutic effects, are most appropriate. This phase may last up to 1 hour. The treatment should be ended quickly if the patient begins to feel chilled or becomes uncomfortable. The treatment is ended by quickly removing the patient from the pack, frictioning the skin briskly with a dry towel, and having the patient dress. As this is often an intensive treatment, it should be followed with rest or appropriate activity. Lying in a warm room for an hour is an ideal follow-up to this treatment. If done at home, it is best done in the evening just before retiring.

1. Hippocrates. Hippocratic writings. In The Great Books. Chicago: William Benton, 1952. 2. Kellogg JH. Rational hydrotherapy, ed 4. Battle Creek, MI: Modem Medicine, 1923:721-722. 3. Golland A. Basic hydrotherapy. Physiotherapy 1981;67258. 4. Doering TJ,Brix J, Schneider B, Rimpler M. Cerebral hemodynamics and cerebral metabolism during cold and warm stress. Am J Phys Med Rehabil1996;75408-415. 5. Saeki Y.Effect of local application of cold or heat for relief of pricking pain. Nurs Health Sci 2002;497-105. 6.Schlesinger N, Detry MA, Holland BK, et al. Local ice therapy during bouts of acute gouty arthritis. J Rheumatol 2002;29: 331-334.

Sauna A recent review of the benefits and risks of sauna bathing50concluded the following: It is well tolerated by most healthy adults and children. It does not influence fertility. It is safe during uncomplicated pregnancy. It may help lower blood pressure and increase left ventricular ejection in patients with congestive heart failure. It produces transient improvement in pulmonary function, which may be helpful for patients with asthma and chronic bronchitis. It decreases pain and increases mobility in patients with rheumatic diseases. It may be contraindicated in patients with unstable angina pectoris, recent myocardial infarction, and severe aortic stenosis. It is safe for patients with stable angina pectoris and old myocardial infarction. Krop5I published a case study in 1998 demonstrating the usefulness of sauna in the detoxification of a patient with 20 years’ duration chemical sensitivity resulting from low-level exposure to solvents. Ernst, Wirz, and P e c h ~performed ~~ a long-term prospective study called “Prevention of Common Colds by Hydrotherapy.” The researchers compared 25 volunteers to 25 controls. Volunteers were asked to work up to a 5-minute hot shower followed by a 2-minute cold rinse. The study demonstrated a decrease in both the frequency and intensity of common colds as seen in the treatment group as compared with the control group.

CONCLUSION Hydrotherapy provides the naturopathic physician with an effective form of treatment for many conditions. This chapter has touched on only a few of the many techniques developed over the years. References 2, 11, 20, and 21 provide those who are interested in further study in this area with appropriate information.

7. Finan MA, Roberts WS, Hoffman MS, et al. The effects of cold therapy on postoperative pain in gynecologic patients: a prospective, randomized study. Am J Obstet Gynecol 1993;168:542-544. 8. Aksoylar S, Aksit S, Caglayan S, et al. Evaluation of sponging and antipyretic medication to reduce body temperature in febrile children.Acta Paediatr Jpn 1997;39:215-217. 9. Agbolosu NB, Cuevas LE, Milligan P,et al. Efficacy of tepid sponging versus paracetamol in reducing temperature in febrile children. Ann Trop Paediatr 1997;17283-288. 10. Knoll T, Wimmer ML, Gumpinger F, Haberl RL. The low normothermia concept-maintaining a core body temperature between 36 and 37 degrees C in acute stroke unit patients. J Neurosurg Anesthesiol2002;14304-308.

Therapeutic Modalities 11. Hendley JO, Abbott RD, Beasley PP, Gwaltney JM Jr. Effect of inhalation of hot humidified air on experimental rhinovirus infection. JAMA 1994;271:1112-1113. 12. Georgitis JW. Nasal hyperthermia and simple irrigation for perennial rhinitis. Changes in inflammatory mediators. Chest 1994; 106:1487-1492. 13. Georgitis JW. Local hyperthermia and nasal irrigation for perennial allergic rhinitis. effect on symptoms and nasal airflow. Ann Allergy 1993;71:385-389. 14.Ophir D, Elad Y. Effects of steam inhalation on nasal patency and nasal symptoms in patients with the common cold. Am J

Otolaryngol1987;8:149-153. 15. Singh M. Heated, humidified air for the common cold (Cochrane Review). In The Cochrane Library, Issue 1. Oxford, England Update Software,2003. 16. McNaughton Collins M, MacDonald R, Wilt T. Interventions for chronic abacterial prostatitis (Cochrane Review). In The Cochrane Library, Issue 1. Oxford, England: Update Software, 2003. 17. Cioanta I, Muschter R. Water-induced thermotherapy for benign prostatic hyperplasia. Tech Urol2OOO;6294299. 18. de la Rosette JJ, de Wildt MJ, Hofner K, et al. Pressure-flow study analyses in patients treated with high energy thermotherapy. J Urol 1996;156:1428-1433. 19. Giombini A, Casciello G, Di Cesare MC, et al. A controlled study on the effects of hyperthermia at 434 MHz and conventional ultrasound upon muscle injuries in sport. J Sports Med Phys Fitness 2001;41:521-527. 20. Kappel M, Stadeager C, Tvede N, et al. Effects of in vivo hyperthermia on natural killer cell activity, in vitro proliferative responses and blood mononuclear cell subpopulations. Clin Exp Immunol 1991;&1:175-180. 21. Kappel M, Barington T, Gyhrs A, Pedersen BK. Influence of elevated body temperature on circulating immunoglobulin-secreting cells. Int J Hyperthermia 1994;10653-658. 22. Oehler R, Pusch E, Zellner M, et al. Cell type-specific variations in the induction of hsp70 in human leukocytes by feverlike whole body hyperthermia. Cell Stress Chaperones 2001;6:306-315. 23. Zellner M, Hergovics N, Roth E, et al. Human monocyte stimulation by experimental whole body hyperthermia. Wien Klin Wochenschr 2002;114102-107. 24. Imamura M, Biro S, Kihara T, et al. Repeated thermal therapy improves impaired vascular endothelial function in patients with coronary risk factors. J Am Coll Cardiol2001;381083-1088. 25.Kihara T, Biro S, Imamura M, et al. Repeated sauna treatment improves vascular endothelial and cardiac function in patients with chronic heart failure. J Am Coll Cardiol2002;39:754-759. 26. Engel JP,Watkin G, Erickson DJ, Krussen FH. The effect of contrast baths on the peripheral circulation of patients with R.A. Arch Phys Med 195031:135. 27. Woodmansey A, Collins DH, Ernst MM. Vascular reactions to the contrast bath in health and in rheumatoid arthritis. Lancet 1938;ii:1350. 28. Krusen FH. Physical medicine; the employment of physical agents for diagnosis and therapy. Philadelphia: WE3 Saunders, 1941.

29. Moor FB, Peterson S, Manwell E, et al. Manual of hydrotherapy and massage. Mountain View, C A Pacific Press, 1964:9-15,964. 30.Hewlett AW. The effect of some hydrotherapeutic procedures on the blood flow in the arm. Arch Intern Med 1911;8:591. 31. Stewart GN. The effect of reflex vasomotor excitation on the blood flow in the hand. Heart 1912;3:76. 32. Briscoe G. Observations on venous and capillary pressures with special reference to the Raynaud Phenomena. Heart 1918;735. 33. Ruhmann W. Reflex irritability of abdominal organs by local application of heat and cold. Munchn Med Wochensdu 1926;73:401. 34.Poulton El? An experimental study of certain visceral sensations. Lancet 1928;ii:1223,1277. 35. Bing HJ, Tobiassen ES. Viscerocutaneous and cutovisceral abdominal reflexes. Acta Med S a n d Supp 1936;78:824. 36. Kuntz A. Autonomic nervous system. Philadelphia: Lea & Febiger, 1945. 37.Fisher E, Soloman S. Physiological responses to heat and cold. In Licht S, ed. Therapeutic heat and cold, ed 2. New Haven, C T Elizabeth Licht, 1965. 38. Thrash AM, Thrash CL. Home remedies. Seale, A L Thrash, 1981. 39. Ridge BR, Budd GM. How long is too long in a spa pool? N Engl J Med 1990;323:835-836. 40.Allison TG, Reger WE. Comparison of responses of men to immersion in circulating water at -40.0 and 41.5 degrees C. Aviat Space Environ Med 1998;69:845-850. 41. Kellogg DL Jr, Morris SR, Rodriguez SB, et al. Thermoregulatory reflexes and cutaneous active vasodilation during heat stress in hypertensive humans. J Appl Physiol 1998;85:175-180. 42. Giannetti N, Juneau M, Arsenault A, et al. Sauna-induced myocardial ischemia in patients with coronary artery disease. Am J Med 1999;107228-233. 43. Buchman D. The complete book of water therapy. New York: EP Dutton, 1979. 44.Ring J, Teichmann W. Immunologische Veranderungen bei hydrotherpeutischer Kurbehandlung. Dtsch Med Wochenschr 1977;1021625-1630. 45.Bierman W, Licht S. Physical medicine in general practice. New York: Hoeber, 1957. 46.Finnerty GB, Corbitt T. Hydrotherapy. New York Frederick Ungar, 1960. 47. Jones WB. Mineral springs and medicine in North Carolina. N C Med J 1983;44:593. 48. Epstein M, Saruta T. Effect of water immersion on renin, aldosterone, and renal sodium handling in normal man. J Appl Physiol 1971;31:368-374. 49. Brown C, Sutton JV,Adler A, et al. Renal calcium and magnesium handling in water immersion in nephrotic patients. Nephron 1983;33:17-20. 50. Hannuksela ML, Ellahham S. Benefits and risks of sauna bathing. Am J Med 2001;110:118-126. 51. Krop J. Chemical sensitivity after intoxication at work with solvents: response to sauna therapy. J Altem Complement Med 1998;477-86. 52.Ernst E, Wirz P, Pecho L. Prevention of common colds by hydrotherapy. Physiotherapy 1990;76;207-210.

Manipulation Robert M. Martinez, DC, ND CHAPTER C O N T E N T S Therapeutic Keys

Methods of Accentuating the Signs and Symptoms of Space-Occupying Lesions of the Spine 423 Cervical Spine 424

417

Historical Perspective 418 Schools of Thought in Manipulation 418 Early History (Oriental, Egyptian, Greek, Indian) 418 Bone Setters of England 418 Differential Diagnosis 420 Five Basic Categories of Spinal Disorders 420 Pretreatment Assessment 423 Lumbar Spine and Sacroiliac Joint

423

THERAPEUTIC KEYS Manipulation is a passive manual maneuver that is performed in such a way that the patient cannot prevent it and that introduces movement beyond the passive range of motion's elastic barrier but does not exceed the anatomic barrier.l Mobilizations are passive stretches with or without oscillations over which the patient can exert control? Spinal adjustments are chiropractic techniques that range in force from a near imperceptible force to high-velocity thrust with joint cavitation (popping noise). Initial evaluation to determine if manipulation of the patient is appropriate seeks for contraindications and "red flags" of fracture, infection, neoplasm, progressive neurologic deficit, cord pressure, or cauda equina syndrome as a prudent starting p~int.~A A correct differential diagnosis is key to the selection of patients, and the functional assessment is key to the selection of appropriate manual medicine techniques? If gross signs of inflammation are present in a joint (heat, swelling, redness, and pain), manipulation of that joint would most likely aggravate the condition. When bringing the joint complex to tension, if the pain peripheralizes, it is a contraindication to manipulation.

The Differential Diagnosis of Soft Tissue Injuries by Means of Active and Passive Movements 424 Active Movements 424 Passive Movements 425 Barrier Concepts 425 Treatment Concepts 425 General Guidelines for Manipulative Technique 426 Motion Palpation 427 Psychology 429

Following a progression of force, the manipulator can reduce the risk of adverse events. Relaxation techniques (heat, muscle work, calming environment) before a manipulation are helpful in achieving best results. They are especially indicated in patients complaining of aching and stiffness before manipulation.6 If pain is the chief complaint, icing the area for 5 minutes causes surface anesthesia, and 20 minutes causes sedation of the actions of the muscle spindle cells. Sedation of a muscle reflex arc before manipulation of a fixated painful joint facilitates the treatment.* If the patient reports an increase in pain or stiffness after a manipulation, ice the area of treatment for 10 to 30 minutes after manipulation to reduce spasm and ~ a i n . ~ , ~ "The goal of manipulation is to restore maximal pain-free movement of the musculoskeletal system in postural balan~e."~ Don't treat muscle spasm as a primary condition. Muscle spasm is almost always a response of the body to a noxious stimulus. Find the cause and treat it.1o Trigger points (TPs) are myofascial irritations that are frequently caused by underlying joint fixations. If one 417

Therapeutic Modalities

manipulates over a ’I”, it frequently precipitates a muscle spasm later that day or the next morning.”

HISTORICAL PERSPECTIVE The popularity of manipulation could be likened to the course of a roller coaster-diving up and down and taking many unexpected turns. The literature is replete with references to the use of manipulation. Manipulations are depicted in prehistoric cave drawings and Chinese statues, circa 2700 w.12 The early history of manipulation has been researched by Lomax and PIPsented in two papers. She credits Hippocrates with the earliest recorded written physician’s prescription of manipulative treatment methods. Worthington notes that Hippocrates in On Joints clearly states method and motive for the application of manipulative therapy.13 Hippocrates advocated many of the premises in use today: judicious use of force, direction of thrust, and proper levering of the joints. Even at this early date, mention is made of the abuse of manipulative therapy.l3 Until the sixth century, manipulative treatment saw little change. At that time, treatment with open wounds was used by Arab physicians, based on the humoral theory of disease.I3During the Dark Ages, priests provided medical treatment at their monasteries. Kessler states: “Friar Moultan, of the order of St. Augustine, wrote The Complete Bonesetter. The text, which was revised by John Turner in 1656, suggests that manipulation was practiced in medical settings throughout the Middle Ages and Renai~sance.”’~ The course of the history of manipulation in the late 1700s and afterward is colorful and flamboyant. Three main concepts developed during this time still have a major influence on our thoughts regarding manipulation. The first held that vertebral luxation was responsible for spinal deformity. The second was held by the largest group that followed the writings of Percival Pott and maintained that caries of the spine were more common than previously thought. This idea caught hold and was taken to an extreme. This faction of physicians treated spinal deformity by blood-letting and rest, while condemning extension and manipulation as both useless and dangerous. A third group held that muscles were the main cause of problems, and treatment should be complete rest or active exercise, as the case ~ a r r a n t e d . ’ ~ Central to the early issues, aside from the political and economic waves the irregulars were creating for the allopaths, were concerns about the potentially disastrous effects of manipulating tuberculous, neoplastic, rheumatic, or fractured joints. More recently, questions of vertebral disk herniation, precipitation of CVAs (cerebral vascular accidents),and the lack of a differential diagnosis by many nonallopathic manipulators has caused concern. To this add the controversial issues of cost-effectiveness

and efficacy of treatment, and one can begin to understand the apprehension with which allopathic practitioners approach manipulative therapy. It is interesting to note the following: Hippocrates railed against the abuse of manipulative therapy by physicians and others of his time. Physicians of the late 1700s assailed one another’s methods of treatment (e.g., in The Lancet, December 16, 1826, the banner on page 347 appropriately read ”THE YELLOW JOURNAL”). Surgeons held “bonesetters” in great contempt “when they condescend[ed] to speak at all of bonesetters and their works.”I2 Bonesetters held their secrets and passed them from father to son. Financial competition was noted early in the literature. “It is known to most practitioners of surgery, and has been made known to many to their great cost and loss, that a large portion of the cases of impaired mobility or usefulness of limbs after injury fall into the hands of a class of men called bone setter^'."'^ Although there is a great deal of animosity, and claims of superiority are made by the various practitioners of manipulative treatment even today, “specific conclusions cannot be derived from the scientific literature for or against either the efficacy of spinal manipulative therapy or the pathophysiologic foundations from which it is derived.”16 Nothing appears to be new in the controversies except the names of the groups and the coined terms they use. The allopathic group claims the right to control over all the healing arts, and the sole privilege of using the generic terms “physician,” “medicine,” and ”medical treatment.”” The “unorthodox” groups buck this authority. They seek a physician’s position, while not always being willing to accept the accompanying responsibilityof adequate differential diagnosis and critical assessment and validation (other than empirical and anecdotal reporting) of their therapeutic regimens. Each group maneuvers politically, judicially, and economically to gain advantage over the other.18

SCHOOLS OF THOUGHT IN MANIPULATION Early History (Oriental, Egyptian, Greek, Indian) Knowledge of exactly which techniques were used, and with what success, is limited or speculative. It is known that many cultures have used manipulativetechniques.12

Bone Setters of England Bonesetters of England generally held that a bone was out of place and had a “feel” for what was wrong. Hutton described the information gained from a bonesetter as

Manipulation

”bring[ing] some spoils out of the camp of the philistine^."'^

Chiropractic D.D. Palmer, “the founder,” and his son B.J. Palmer, ”the developer,” of chiropractic added one of the most colorful pages to the history of manipulative treatment. D.D., who “rediscovered” the principle of ”lost nerve tone” in a revelation from a deceased friend, Dr.Atkinson, reestablished this method of healing. The first chiropractic manipulation was given to a deaf janitor. D.D. learned that the janitor’s hearing had been lost when he stooped over and felt something give in his back. D.D. reasoned that if the deafness occurred from something slipping out, restoring the vertebra to its correct position should cure the condition: “With this new objective in view, a half-hour’s talk persuaded Mr. Lillard to allow me to replace it.”19 The stormy history of chiropractic was led by a son who hated his father (and was actually accused of running him down in a parade, causing injuries that led to his death), who drove chiropractic to a zenith, and who later nearly destroyed the profession. The evolution of chiropractic is well documented by Gibbons. Interestingly, many early developments in chiropractic were years ahead of their time. B.J. developed the prototype of today’s electroencephalogram, he started a radiology laboratory only 13 years after Roentgen discovered x-radiation, and he had one of the finest diagnostic centers in the Midwest at his school (completewith MDs and PhDs)?O A new focus in chiropractic is rehabilitation and incorporation of manual medicine techniques. Rehabilitation of the Spine, A Practitioner’s Manual, edited by Craig Liebenson; is considered by many in the field a landmark publication. It emphasizes the need for rehabilitation and includes manipulation as a component of the process.

Naturopathic All naturopathic techniques result from the blending of the thoughts of the other schools of medicine. This is appropriate when one realizes there is little new in manipulation, only refining and relabeling. It is also appropriate that naturopathy does not lay claim to originating a school of thought on manipulation but uses this method of treatment, when indicated, not exclusively but as part of a therapeutic regimen. Several naturopathic schools in the past were associated with chiropractic and eclectic schools of medicine. The genesis of the naturopathic profession is well documented in Chapter 4.

Osteopathic Andrew Still, three of whose children died from meningitis, in the tradition of Hanneman left the practice of medicine and started the school of osteopathy in Kirksville, MO. It is highly probable that D.D. Palmer

went to this school and learned some of the techniques, but it is not well documented. The famed ”equal but separate” movement of the osteopaths led to a 1921 resolution, submitted at the American Osteopathic Association convention, that allowed entrance of chiropractors with advanced standing into their schools. Still, before his death, saw the defection of his osteopathic profession into the ranks of medical orthodoxy.20-22 Interestingly, manipulation is now only an elective segment in some American osteopathic schools, while in England it is still the mainstay of osteopathic practice. The resurgence of interest in manual medicine has been brought to the forefront by the Osteopathic College at Michigan State University. Greenman’s’ Principles of Manual Medicine adds a useful text to the field of manual medicine. This school has been teaching manual medicine to physical therapists, Doctors of Medicine, and Doctors of Osteopathy.

Allopathic In the twenty-first century, the numbers of allopathic practitioners who promote manipulative treatment are growing daily. The individuals mainly responsible for major contributions are James Cyriax, James Mennell, and John Mennell. These brilliant physicians have written valuable texts on manipulative therapy, although they do not agree totally on the effects they achieve with manipulation. Mennell holds to the correction of lost joint play and denies effect on the intervertebral disk,= while Cyriax claims reduction of a protruding disk.1° Bourdillion, Calliet, McNabb, Maigne, Maitland, Kaltenbom, and Williams are popularizing the treatment modality. Their works are too exhaustive to mention in this brief chapter. “Controversy and contention” best describe the higher levels of the respective schools of medical thought. The impression one gets in reading through the literature is intolerance of others’ ideas expressed in ad hominem attacks. The mistake “lay” manipulators and ”nonphysicians” make is not ineffectiveness but their willingness to seek training outside the fraternal order of the “medical” brotherhood; to address the public directly rather than communicating exclusively within the order; and, worst of all, to openly compete, economically and politically, against the fraternal ~ r d e r . ~ ~ J ~ , * ~ Donald B. Tower, in the chairman’s summary at the National Institute of Neurological and Communicative Diseases and Stroke conference in 1975, noted a physician who has received little credit for his early contribution to the field: J. Evans Riadore, a London physician who wrote a treatise on the irritation of spinal nerves in 1843. He attributed many diseases to this condition, stating: “If any organ is deficiently supplied with nervous energy of blood, its functions immediately, and sooner or later its structure, become deranged.” This was a

Therapeutic Modalities viewpoint subsequently echoed by osteopaths and chiropractors.” Spinal Manipulation (edition 5) by Bourdillion and colleagues,25the first author of whom was a medical manipulator, has been largely reworked from previous editions and heavily influenced by osteopathic methods. Over the past 15 years, American awareness of contributions in manual medicine from other countries has been growing. Jirout, Lewit, Janda, Bogduk, and many others have been teaching and publishing in the United States.

Physical Therapy The field of physical therapy is diverse, and only one major group, influenced by James Cyriax, MD, is discussed. Dr.Cryiax had a major influence on physical therapy by training physical therapists (PTs) in assessment, deep tissue cross fiber massage, and manipulation. Cryiax influenced Robin McKenzie, a New Zealand I T who subsequently developed a systematic approach to mechanical diagnosis and treatment of musculoskeletal conditions. McKenzie’s approach is often prejudicially dismissed as ”extension exercises for the low back.” He proposed a new tack in the approach to back pain that has been found to be highly effective in acute and chronic back pain populations and low in cost.26 McKenzie Mechanical Diagnosis and Therapy (MDT) approach is evaluation and treatment of musculoskeletal disorders based on a mechanical history and the patient’s symptomatic and mechanical response to movement, positions, and 10ading.2~His observations that most conditions are self-resolving and the focus should be on prevention by teaching patients proper posture and self management are astute. After years of studying manipulation, he feels that only 20% of patients need manipulative therapy, and 80% can self-treat using end-range loading strategies from books or practitioners.28

DIFFERENTIAL DIAGNOSIS The methodology for performing the differential diagnosis of musculoskeletal pain can follow many diverse patterns depending on the approach taken, but the multiple branching pathway3.29 for patient selection is a good start. Five basic categories of spinal disorders are proposed to begin the sorting process: neoplasm, infection, neurologic, psychosocial, and mechanical disorder. The following presents a brief overview in differentiating among these and is organized to aid the generalist in selecting a starting point for making the final diagnosis. Refer to the texts and articles noted for detailed information.

Five Basic Categories of Spinal Disorders 1. Neoplasm When the patient history includes prior episode of cancer, a red flag goes up as the spine is a common site

for metastasis. A family history of neoplasm is less of a concern, but risk factors should be double-checked. The character of the pain is often described as deep, boring, and usually worse at night. The pain is progressivesometimes better, sometimes worse-but is usually always present to some degree. Laboratory tests may reveal an elevated sedimentation rate, C-reactive protein (CRP), or anemia. Although there may be no signs in the early stages of cancer, the American Cancer Society has identified seven major warning signs: A change in bowel or bladder habits A sore that does not heal Unusual bleeding or discharge from any place A lump in the breast or other parts of the body Chronic indigestion or difficulty in swallowing Obvious changes in a wart or mole or Persistent coughing or hoarseness Most mechanical conditions show a 50% improvement in 2 to 4 weeks with appropriate care, or the patient should be carefully reevaluated or referred for a second opinion.

2. Infection There may be signs of acute or chronic illness.30 Laboratory tests may reveal a shift to the left in the white blood cell count (WBC) and possibly an elevated sedimentation rate or CRP. There may be local joint inflammation.

3. Neurologic A routine office neurologic screening examination may reveal the presence of a lesion. A screening examination will help to determine if additional testing or referral to a specialist is indicated. The search pattern for neurologic lesions breaks the system into the following: Cerebrum. Lesions are discovered during the consultation by the patient’s affected cognition; interaction; mannerisms; or loss of orientation in time, space, or body part awareness. Nausea, vomiting, seizure, loss of consciousness, visual disturbances, and headache are warning signs. Cerebellar versus posterior column lesions. Test coordination of movements, with basic differentiation done by repeating acts with the eyes open and eyes closed. Cerebellar. Actions are jerky with the eyes open or closed; dysarthria, ataxic (drunken) gait, and dysdiadochocinesia may be present. Posterior columns. The actions are smooth with the eyes open but cannot be repeated as well with the eyes closed, due to the loss of proprioception. A broadbased, stomping gait may be present.

Manipulation Brainstem. This area is evaluated by testing the cranial nerves. Differentiation between upper and lower motor neuron lesions. Think of the abnormal reactions by focusing on the words “spastic” and “flaccid.” If the superficial reflexes are absent, continue with tests to rule out upper motor neuron lesions (UMNs) and lower motor neuron lesions (LMNs). Table 41-1 lists the key differential considerations. Muscle stretch reflexes (MSRs). These are often incorrectly called deep tendon reflexes.31Communication of results can be confusing, since various practitioners use different notations (e.g., a grade 3 may be listed 3, +3, 3+, H+, or just 3) and do not have a consistent definition. Table 41-2 lists a grading scale that is commonly used. The main objective is to compare the reflexes side to side and in comparison with Table 41-2. If the reactions are not equal, note according to the scale. Pathologic reflexes. Toe sign (Babinski),Hoffman’s, and glabellar signs are only present in UMN lesions. Newborn babies may display these signs, and this is an opportunity for one to elicit and observe these abnormal signs. Painless loss of strength. This is usually neurologic. Use numbers 0 to 5 to rate muscle strength according to the scale shown in Table 41-3. Loss of sensation. If it follows a dermatome, the problem is usually a nerve root; if it follows a named nerve pattern, a peripheral mixed nerve is involved. If it affects the entire extremity, consider circulatory, metabolic, and pathologic processes. Nerve root tension signs. Patients may be bracing themselves when they present (in an effort to decompress Comparison of neurologic signs of upper versus lower motor neuron disease Sign/symptom

Upper motor neuron (spastic)

LMN (flaccid)

Paralysis

Spastic

Flaccid

Deep tendon reflexes

Clonic

Diminished absent

Muscle tone

Hypotonia, then in 2-3 wk hypertonia

Decreased

Pathologic reflexes

Present

Absent

Superficial reflexes

Absent

Decreased-absent

Fasciculations

Absent

Present while LMN degenerates

Reaction of degeneration

Not characteristic

May occur

Modified from Haerer A, ed. DeJong’s the neurologic examination, ed 5. Philadelphia: Lippincott, 1992339, 433, 445. LMN,Lower motor neuron lesions.

Grading of reflexes Grade

Reflex

0 1 2

Absent with reinforcement Hypoactive-less than the expected response Normal-you may note brisk or sluggish

3

Hyperactive--more than the expected response

4

Hyperactive with transient clonus

5

Hyperactive with sustained clonus

Clonus

More than one muscle jerk when the tendon is tapped

the nerve root) and may complain of pain radiating into an extremity.Movement may cause pains shooting into the extremity. Loss of sensation follows the dermatome distribution, MSRs are diminished or lost, and muscle strength in muscles innervated by the affected nerve is lost or diminished.

If neurologic findings are present, other than minor changes in sensation, keep the patient under close observation. Direct nerve root pressure can cause permanent muscle weakness with resultant permanent impairment. Appropriate conservative care is Progressive neurologic deficit is an indication for referral to a neurosurgeon or physiatrist.

4. Psychosocial If the presenting complaints do not seem to follow a mechanical pattern and the pain diagram is nonanatomic, consider the possibility of psychosocial factors. Psychosocial workplace factors associated with risk of spinal injury include high job dissatisfaction, high psychologic job demands, employer practices, coping abilities, lack of recognition at work, low supervisor support, a high frequency of job problems, and negative beliefs of or attitudes toward the consequences of having “low back trouble.’f33,34A major factor in identifying the incidence of future pain is the patient’s perception of being disabled.35

1 Grading of muscle strength Grade

Muscle strength

0 (zero)

No trace of muscle contraction

1 (trace)

Evidence of slight contractility, no joint motion

2 (poor) 3 (fair)

Complete range of motion with gravity eliminated

4 (good)

Complete range of motion against gravity with some resistance

5 (normal)

Complete range of motion against full resistance

Complete range of motion against gravity

Therapeutic Modalities

5. Mechanical

The test by definition has a positive response, which correlates to a specific condition, that must be produced when the test is performed for the test to be positive (e.g., Lindner's test and Soto Hall test are performed in the same way, but the findings to report a positive test are different). The test must reproduce the pain of the primary complaint and be positive by the test's definition. The tests are centered in allopathic medicine to diagnose pathology, fracture, moderate to severe sprain/ strain and dislocation and are often negative in the ambulatory, chronic patient.

Mechanical factors include fractures, dislocations, sprain/ strain, derangement, dysfunction, and mechanical overload of normal tissue. Mechanical overload of normal tissue is a common cause of pain. To illustrate this point, bend your finger backward until you feel strain and hold it. At first you may only feel discomfort, but after an extended period of time it will become painful. Next, try bending the finger backward beyond strain until it hurts. The pain you feel is due to abnormal stresses on a normal tissue; there is nothing wrong with your finger! You do not When used without an understanding of the mechaneed drugs, modalities, or manual therapy. Simply stop nism of action of the stress and the tissues the stress overstraining the soft tissues. Robin McKenzie uses this act on, the plethora of tests and maneuvers available seemingly simple experiment to teach the consequences of sustained end-range loading as a cause of ~ a i n . ~ usually , ~ ~ serve to confuse the practitioner and aggravate the patient's condition. A detailed text that covers this This is profound when you think of the workers hanging and bouncing. area in detail, such as Magee38or is helpful and should be referred to for additional information. A fracture is usually traumatic when presenting in young and middle-aged patients. In older patients, pathoMcKenzie Concepts logic fractures are a concern. Presentation may be delayed The MDT is an invaluable system for practitioners in motor vehicle accidents or athletic injuries or nontraumatic fractures in the elderly. The cardinal signs of fracture who perform manual therapy. Rather than technique, it is a method that, once mastered, allows rapid assessare the following: ment and selection of patients for treatment and identiPinpoint pain over the site fies those not likely to respond to conservative care Deformity of the part so they can quickly receive and appropriate referral. Crepitus Two weeks of instruction by the McKenzie Institute Loss of function of the part, usually proportional to the on Mechanical Diagnosis and Therapy, McKenzie's severity of the injury textbook^,^,^^ and a chapter in Liebenson's text cover Abnormal mobility at the site of pain this material in detail. Only a few of the helpful concepts Always check for nerve lesions and soft tissue injuries from the McKenzie method are discussed as follows. Keep in mind that McKenzie asserts only 20% of patients that would complicate the injury before beginning treatment. need manipulative therapy, and prevention is key to success in his model. Also check for multiple injuries (ring fracture in two places). In particular, look above and below the site of Centralization and Peripheralization injury, as the force of trauma may be transmitted and cause a fracture some distance from the site of impact.29 A cervical spine problem can refer pain to the shoulder blade, arm, forearm, and hand. A low back problem can Note: Do not be deceived by the absence of obvious signs of fracture. refer pain to the sacroiliac joint (SIJ),buttock, thigh, leg, and foot. When the referred pain from the spine is Orthopedic Tests brought closer to the midline in response to movements, position, or load and remains reduced, it is called "cenOrthopedic tests are designed to stress the damaged tissue tralization."" When the pain moves out from the spine and reproduce the pain of the primary complaint. The in response to movements, position, or load, it is examiner is not looking merely for pain to be reported as a called "peripheralization." When a movement produces result of the maneuver, but rather pain that is specific for centralization, it is a motion to pursue for treatment. the test and reproduces the pain of the primary complaint. When a movement causes peripheralization, it is a motion Therefore the following should be remembered: to avoid, as it will likely worsen the condition. If no movement or position centralizes the pain, it is a poorer progThe examiner can make the patient worse by forcing tests or performing them incorrectly. nosis for response to the treatment method being used. Although this phenomenon is typically associated with The least stressful tests should be done first. If the first vertebral disk problems, it can be observed in many mustest causes severe pain, most of the other motions will be painful afterward and confuse the findings. culoskeletal problems.

Manipulation

End-Range Pain and Pain during Motion End-range pain (ERP) is felt only when the joint is moved to end range (ER). It is a sign of shortened soft tissues around the joint complex. The importance is that this is an indication that stretching and mobilizing techniques should be used before manipulation. If the joint is not mobilized to ER repeatedly the manipulation may cause aggravation of the complaint. When the joint is fully stretched, following a progression of forces described later, the practitioner can determine when and if manipulation is indicated. Pain during motion (PDM) is pain that is felt during joint movement, as well as at the end range. The joint range of motion may be restricted as well. PDM is a sign of soft tissue inflammation or a vertebral disk problem. Movements or positions that increase the PDM and restriction should be avoided. When a mobilization or manipulation increases PDM or restriction, it is important to find a motion or position that will reduce the PDM and restore the motion as soon as possible to reduce the irritation of the tissues. Progression of Forces This is a logical stepwise progression of the force generated first by the patient, then by the practitioner. The advantages are increased patient comfort, ability to “test the waters,” and decreased risk of harm from the procedure. The steps are as follows: 1. Patient-generated force-the patient does all the motion actively. 2. Patient generated overpressure-the patient uses a strap, fulcrum, etc. to increase the movement to ER. 3. Practitioner-generated force-the practitioner mobilizes the joint to ER repeatedly. 4. Practitioner uses manipulative thrust. Positive responses would include centralization, reduction of antalgic postures, increased range of motion, and decreased PDM. It is a relative contraindication to continuing to step 4 if there is no positive response in steps 1 to 3.

PRETREATMENT ASSESSMENT Observe the posture of the patient. If he or she becomes antalgic to the side and forward, or both, due to this episode, it indicates a large space-occupying mass, which is most often the disk but could be other soft tissue or pathology. Proceed slowly and carefully, avoiding any movements that cause peripheralization, increase PDM, or increase the obstruction of motion. Establish the baseline of the location of the complaint and its response to motion and then repeat motions to ER. In the cervical spine test flexion, extension, rotation, and lateral bending. In the lumbar spine test flexion,

extension, and lateral translation. The testing procedures are described in detail with photos in Liebenson’s text.43 Note the ranges of motion. If there are complaints at or below the shoulder blade or buttock, it is important to test reflexes, muscle strength, sensation, and nerve root tension signs to assess if the nerve root is affected. Additional tests can be added as indicated.

Lumbar Spine and Sacroiliac Joint During supine straight leg raise (SLR) the lumbar nerve roots begin to develop tension at about 35 degrees. If SLR is causing leg pain below 30 degrees, it is likely due to stretch of the lumbar nerve root in the presence of a space-occupying lesion or significant hip pathology. SLR above 30 degrees causes increasing ipsilateral nerve root tension, causes ipsilateral hamstring tightness, and may expose lumbar dysfunction or derangement as the straight leg moves toward end range (ER). Once the painful ER is found, one lowers the limb to the pain-free range and then performs internal rotation and dorsiflexion of the foot and great toe. If this maneuver causes return of the leg pain, there is likely tension on the lumbar nerve roots. Because the SLR maneuver stresses multiple tissues, the test can be misleading and somewhat difficult to determine what a positive finding is until the practitioner’s skills are developed, but the positive result should be described to help clarify the findings.

Methods of Accentuating the Signs and Symptoms of Space-Occupying Lesions of the Spine Following the principle of ”Do no harm,” one should test reflexes and sensation first, then proceed to active tests such as the Valsalva maneuver to test for increased intrathecal pressure. If radiating pain results, it is a sign of a space-occupying lesion. Next the practitioner should do light stretch/distraction tests (SLR and dorsiflexion of the foot with extension of the great toe) and finally compression tests (Milgram’s bilateral leg raising and Lindner’s test [forcefully flexing the trunk while the patient is supine]): This forces the disk posteriorly (if herniated) and causes increased intraabdominal pressure, resulting in increased intrathecal pressure (Valsalva effect). ButleP described in detail the identification of cervical root tension signs, by upper limb tension tests developed by Elvy in 1979. The tests are used primarily by physical therapists but may be useful to help guide treatment. Some additional ideas to finding the area of lesion in the lumbar spine are as follows: Support Adams (the belt test)-With the patient standing, the doctor has him or her bend forward and notes the level of pain. The doctor then secures the patient’s pelvis by hugging the anterior superior iliac spines with

the arms, pressing the patient’s sacrum into the doctor’s hip. If the patient’s pain is decreased, it indicates the lesion is in the pelvis (probably the SIJ or hip); if pain increases, it is in the lumbar spine (probably the lumbar disks). Patrick’s test-Flexion, abduction, and external rotation of the hip are blocked; this causes pain over the inguinal fossa and into the thigh when a hip lesion is present.

This is only an introduction to one common problem that may present with many variations. Careful study of the mechanism of action of the tests used can confirm, rather than confuse, a diagnostic impression.

Cervical Spine The cervical spine presents another diagnostic challenge. Although the mechanism of the tests in the lumbar spine are similar, the area is much more delicate and thus requires more careful application. There is considerable discussion of the topic of vertebrobasilar stroke (VBS) following manipulation of the cervical spine. Tests done in the office have not proved effective, but the history should alert the practitioner to the possibility of VBS insult from manipulation. The presence of the “five Ds” (dizziness, drop attacks, diplopia, dysarthria, dysphagia) and “three N’s” (nausea, numbness, nystagmus) are important to note. The most important risk factors identified by Terrett were dizziness, unsteadiness, giddiness, vertigo, and sudden severe pain in the side of the head or neck, which is different from any pain the patient has had bef0re.4~If the practitioner elects to follow the pattern of the progression of force, the occurrence of these sympt o m in the early mobilizations would contraindicate manipulation. However, VBS has occurred with testing and with a patient simply turning his or her head. The incidence is small, but clinical presentation should not be missed. If there is compression of the nerve root or cervical instability, the patient may present holding the head, lifting it cephalically to decompress the spine and root, an indication to stabilize and transport. Any such presentation is best handled by emergency department staff because even passive range-of-motion assessment may cause permanent injury. If there is irritation of the brachial plexus or a nerve root, the patient may support the arm in abduction and flexion, often resting the hand on the top of his or her head. This is a sign to proceed cautiously. Any movements that cause peripheralization must be avoided, and movements that produce centralization should be pursued. If overt signs of nerve root compression are present, mobilization and manipulation must be performed with skill and caution.

Cervical Distraction If distraction of the head from the shoulders causes aggravation of the patient’s complaints at 12 lb of traction (the average weight of the head), stabilization and relaxation techniques are indicated. If distraction of the head from the shoulders causes relief of the radiating pain at 12 lb of traction, slowly increase the traction to 25 lb. If this relieves the complaint of neck pain, it is an indication that mobilization and traction are indicated therapies. If it aggravates the complaint, it is an indication of inflammation or instability and suggests caution in using mobilization or traction. Cervical compression that causes radiating pain to the arms is a sign that indicates nerve root irritation from the disk and is treated by symptom response that centralizes the arm complaint.

Maximum Cervical Rotation, Lateral Bending, and Compression If maximum cervical rotation, lateral bending, and compression (MCRC) causes radiating arm pain, it is a sign of nerve root compression and manipulation in that direction should be avoided.

Spurling‘s Maneuver When combined cervical rotation, lateral bending, and extension with overpressure (Spurling’s maneuver) aggravates or reproduces the complaint or radiating pain to the midback or arm, it indicates nerve root irritation, and manipulation in that direction places the patient at risk for aggravation of this condition. If the pain is local, it is a sign of facet irritation that often responds well to manipulation. The practitioner can test the response with repeat mobilization to the ER and if only ERP increased force can be used. After determining that the lesion is not a “hard” orthopedic or neurologic lesion, differential tissue tension tests are used to determine the involved tissue.

THE DIFFERENTIAL DIAGNOSIS OF SOFT TISSUE INJURIES BY MEANS OF ACTIVE AND PASSIVE MOVEMENTS This is based on the work of James Cryiax,’O but recent texts give a much improved presentation of the materia1.143 This brief overview is only intended to give an introduction to the material.

Active Movements First, active ranges of motion (ROM) are performed to determine voluntary ROM and patient status. Measuring active ROMs cannot differentiate whether the loss of function is due to pain, weakness, or stiffness/lesion but is helpful to determine patient tolerance to motion and how guarded the patient is when moving.

Manipulation

Resisted Isometric Tests Next, isometric muscle tests are performed to test the contractile tissue (muscle and tendons) with the joint in neutral to avoid involving the noncontractile tissues. The following results may be noted: Normal-painless and full strength Minor tear-pain with full strength Moderate tear-pain with little strength Neurologic deficit-no pain and little strength

Passive Movements When the joint is put through passive motion, it reaches an end point, which has an “end-feel” that helps to determine the status of the soft tissue around the joint. The end-feel of a joint may be one of the following: Normal-the amount of motion and feel of the tissues are appropriate for age Abnormal-normal end-feels that are not normal for the joint and ROM that are being tested (e.g., the feeling of bone on bone is the normal end-feel at the elbow when extended but is abnormal when it occurs at the ER of knee extension) Pathologic-these end-feels are only present in joints that have undergone pathologic changes

Normal End-Feels Capsular end-feel. This is a firm, “leathery” feeling, felt, for example, when the normal shoulder is at full external rotation. When felt in conjunction with a capsular pattern of restriction, and in the absence of significant inflammation or effusion, it indicates capsular fibrosis.

Bony end-feel. This feels abrupt, as when moving the normal elbow into full extension. When accompanying a restriction of movement, it may suggest hypertrophic bony changes, such as those that occur with degenerative joint disease, or possible malunion of bony segments following healing of a fracture. Soft tissue approximation end-feel. This is a soft end-feel, as when fully flexing the normal elbow or knee. It may accompany joint restriction in the presence of significant muscular hypertrophy.

Muscular end-feel. This more rubbery feel resembles what is felt at the extremes of straight-leg raising from tension on the hamstrings. It is less abrupt than a capsular end-feel. Pathologic joint end-feels indicate disease; they are limited and are never normal: Empty-bursitis, space-occupying lesion, neoplasm Boggy-joint effusion Spasm-guarding from inflammation Internal derangement-loose body/ torn meniscus

The tissue involved is determined by the response to the passive ROMs and by moving the joint into closed pack position.

Muscle or tendon. Active and passive movements are limited or painful, or both, when the muscle is contracting and the muscle is being stretched at the same time. Ligaments. Both active and passive movements are limited or painful, or both, in the same direction. Capsular pattern. Only joints that are controlled by muscles have a capsular pattern. Pain is caused on both active and passive motions, and the limitation of motion is in a specific proportion that is listed in tables in the texts referenced.

Barrier Concepts’ Joint motion is described from neutral to an ER that is ultimately limited by the anatomic barrier of the surrounding tissues, which, if exceeded, causes tissue trauma. The extent of the active ROM can be increased by passive motion to a point at which all of the tissues around the joint have been brought to tension, called the elastic barrier. Beyond the elastic barrier is a small ROM referred to as the paraphysiologic It is within the paraphysiologic space that joint cavitation, the “popping’’ sound, occurs. When joints and soft tissues are dysfunctional, alterations of ROMs may occur both within the ROM and at the end of it. If one focuses only on working in the paraphysiologic space, one severely limits the effects that can be made on dysfunction.

TREATMENT CONCEPTS In the case of injury, treatment with passive therapies is indicated to control pain and inflammation until the tissues heal. Use of passive therapies in chronic conditions is falling into disfavor due to the issues of cost-effectiveness and managed care protocols. Determining the stage of inflammation can be accomplished by comparing the cardinal signs of inflammation (heat, swelling, pain, redness, and loss of function) with the suspected stage of the acute inflammatory process. In reality, the stages overlap and a continuum exists4’: 1. Vasoconstriction-inconsistent, lasting only 3 to 5 seconds in minor injuries 2. Active congestion-caused by vasodilation and increased vessel permeability (minutes to hours) 3. Passive congestion-the venous return is partially dammed by clotting (minutes up to 48 hours) 4.Consolidation-fibrinous coagulation at the site of the injury (3 to 5 days) 5. Fibrosis-resulting from the formation of scar tissue (5 to 20 days)

Therapeutic Modalities

6. Remodeling-21 days generally and completed at 6 to 8 weeks, but major injuries may continue up to 12 months By knowing time frame and pathophysiology of the affected tissues, one can select an appropriate therapy. Manipulation is generally contraindicated until the tissue has sufficiently healed. Often the presenting problem does not have tissue damage, just pain from mechanical causes. Treatment of the tissues should be directed according to the level of inflammation. Observe the posttreatment results to see if the signs of inflammation worsen, indicating incorrect application or inappropriate therapy. During treatment, the patient should be in a position that relieves symptoms. If the patient cannot get into such a position, it is probable that the severity of the lesion is such that it will not respond to conservative therapy alone or that the patient's condition is misdiagnosed or misunderstood. The practitioner can use the differential tissue tension tests and joint function tests to determine joint lesions and functional assessment to determine the therapeutic regimen. Before using manipulation, think about the joint endfeel (the way the joint feels at the end of its ROM) and determine which pattern is present: Edematous and boggy end-feel-indicates joint effusion and possibly inflammation. Muscle spasms should not be treated as a primary condition, as they are almost always the body's response to a noxious stimulus or pathophysiologic fault. Cryotherapy; positive galvanism; pulsed ultrasound; and gentle, frequently repeated movements within the active ROM are indicated. Springy and taut end-feel-ligamentous fixations (as felt in the normal knee in lateral bending stress tests and drawer tests). Manipulation works well on these types of fixations. Surging sinusoidal and interferential current, ultrasound, and moist hot packs facilitate the treatment. One can use follow with cryotherapy in the subacute stages. Bone on bone end-feel-usually indicative of degenerative joint disease (as felt in the normal elbow in extension). If there is fine crepitus, mild degenerative joint disease (DJD) may be present; coarse crepitus indicates moderate DJD; and joint creaking may be advanced DJD. Diathermy, contrast baths, and other naturopathic therapies indicated in osteoarthritis are helpful. The practitioner should develop the habit of examin-

ing the sedimentation rate, CRP, and WBC differential count to avoid missing a concurrent condition or a difficult diagnosis.

By always starting high on the differential list, one misses few diagnoses. Exhaustive work-ups are infrequently warranted, but if treatment is directed to mechanical relief and the patient cannot find a comfortable position that relieves the pain, it is doubtful that satisfactory results can be achieved using a mechanical approach.

General Guides for Manipulative Technique Texts on manipulative techniques by Liebenson, Lewit, Greenman, McKenzie, Bourdillion, and Maitland are good sources for learning the basics of the art (refer to the reading list later). Personal instruction is invaluable, but unless the rationales of joint mechanics, pathomechanics, and pathophysiology are the basis of the teacher's approach, it can be confusing and lead to cookbook approaches.

Functional Assessment Often the focus is on injury, pathology, and disease, but the majority of musculoskeletal pain is from pathomechanics due to postural and repetitive strain, disuse, deconditioning, fatigue, and nutritional factors that must be addressed if treatment is to be successful. Once the portion of the patient's condition that is a musculoskeletal problem has been established, the mechanical fault should be determined. Manipulative treatment without correction of the mechanical fault results in prolonged treatment and recurrence. Detecting this is sometimes easy, while at other times it is a mystery that takes careful investigation, as discussed in M c K e n ~ i e , 3Greenman,' ~,~~ Lewit? and Liebenson.4

Preparation for the Manipulation The patient should be comfortable and relaxed on a firm but well-padded table. The room should be at a comfortable ambient temperature, and the physician should wear no watches or jewelry that might catch the patient's hair or skin. The physician must be comfortable and relaxed. Manipulation is an individual art, but in general sideposture manipulation of the pelvis and lumbar spine is easiest on a table that is at knee height; prone and supine thoracic manipulation is easiest at midthigh height; and cervical manipulation is easiest when seated, kneeling, or on a table at waist height. One may either change the height of the table or simply bend at the knees. Manipulation of the joints of the extremities can be performed in any position that allows the physician control over the joint and body parts.

Notes on the Art Manipulation is an art. Assuming a proper differential diagnosis, one acquires a "feel" that allows recognition

Manipulation

of the differences among the three basic types of fixations and knowledge of when to manipulate. If a movement causes pain, it should not be performed unless the diagnosis of the patient’s condition is sure and the motion will cause no harm. Frequently, motion in the direction that is free and painless will free other ROMS.~

Joint Motion Joint motion descriptions can become elaborate, or one may simply say that there are six degrees of freedom of motion (plus long-axis extension): flexion, extension, left and right rotation, and left and right lateral bending. Not all joints have all six degrees of motion. The normal degrees and ROMs of joints are listed in anatomy and kinesiology texts. If a degree of motion is lost or blocked, the type of fixation and which form of manual medicine is indicated should be determined.

The Fixation Manipulation of a joint is performed to correct joint fixation. Therefore one must do the following: 1. Determine if mobilization or manipulation is the appropriate technique. 2. Identify the location and direction of the fixation. 3. Bring the joint to tension removing the periarticular tissue slack. Mobilization with tissue slack not taken up is safe, but manipulation when tissue slack is present invites injury. 4.Test the direction of manipulative thrust with repeat mobilization to ER to ascertain that the pain does not peripheralize, the movement does not increase PDM, and the movement does not result in increased obstruction to motion from mobilization. 5. Thrust only when the patient is relaxed and the fixation is felt. 6. After the elastic barrier has been stretched, repeated manipulation in the same direction is complicated because the end-feel tension normally felt before a manipulation is reduced or absent for at least 20 minutes. The same phenomenon occurs when one “pops” knuckles. The risk of injury is much greater, and changing to mobilization or active muscular relaxation techniques is recommended rather than repeated manipulation.

Stabilization A point of stabilization is created by one hand and the physician’s body weight, while the other hand performs the manipulation. Minor corrections of the position of the stabilized part or hand, or both, are frequently interpreted by an observer as twisting or wrenching motions. Twisting and wrenching are difficult to control and may injure the patient.

Thrust The manipulative thrust can be described according to the following: Direction of line of thrust-through the joint space, parallel to joint surfaces, or tangential to the point of fixation Velocity-slow for mobilizations. High velocity can correct joint fixations, and the speed must be faster than the patient’s reaction time or a strain injury will result if the patient’s muscular resistance occurs at the time of the manipulative thrust Amplitude--governed by the quality of the health of the tissue, the quality of the fixation, and the location of the condition on the spedrum of the inflammation response

Reassess The condition of the joint fixation should be reassessed after each treatment to determine if the therapy has been successful. A single manipulation rarely corrects a problem completely. Learning a joint-scanning technique shows one where the problems are that need further evaluation. The goal is to alleviate acute conditions or, if unsuccessful, to turn them into subacute conditions and resolve subacute and chronic conditions before they cause a chronic fatigue response, joint fixation, degeneration, or chronic myositis.

Troubleshooting Technique Common problems blocking successful manipulation can be overcome by the following: Learning joint play analysis on the peripheral joints and practicing manipulations of those joints before attempting to manipulate the spinal joints Practicing the manipulative procedure with repeated light oscillatory movements while modifying the direction to feel the changes in joint tension, thus gaining experience, confidence, and knowledge without inflicting injury Being sure of the procedure; otherwise, the patient may sense the physician’s hesitation and guard, preventing the manipulation and increasing the risk of a poor outcome Feeling the fixation of the joint as it is brought to tension; otherwise, the manipulation traumatizes the tissues unnecessarily or does not gain the desired result Learning the arthrology of the joint to be manipulated so as not to put the joint in a ”locked” or jammed position that will cause the force of the manipulation to be dispersed to the surrounding tissues and joints

Motion Palpation The following is a short lesson in motion palpation to determine the presence of SIJ fixation.

Therapeutic Modalities

Review of Anatomy and Motion Mechanism Anatomy of the sacroiliac joint. The joint is L- or ear-shaped, with the apex of the L facing anteriorly. There can be fixation of the upper fibrous or lower synovial SIJ, thus altering the normal axis of rotation of the pelvis and causing excess wear on the lumbar spine, hip, knee, and ankle joints.

SacroiZiac gait mechanism. The sacrum and both ileums must be free to move in relation to each other. The sacrum flexes, extends, and ”nutates” (nods) in a gyrating figure-of-eight motion.

Effect of position on sacroiliac angles. As one sits, there is usually a decreased sacral base angle (slight flexion of the pelvis), and as one stands, the sacral base slightly increases (the pelvis slightly extends). Mechanism of gait. Analysis of the normal right forward step is as follows:

1. The left leg is weight bearing. 2. The right leg is in swing phase just before heel strike. 3. The left gluteus medius contracts to tilt the pelvis right superior, and the right sacrospinalis contracts and is counteracted by contraction of the left psoas muscle. 4.The right knee bends, allowing for foot-drop. 5. The hip rotates internally on the weight-bearing side (left)and rotates externally on the non-weight-bearing side (right). This motion results in right ilium flexion, left ilium extension, and a relative flexion of the sacrum in relation to the ilium on the left. In normal gait, the lumbar spine does not deviate to either side. The sacrospinalis exerts a pull on the weightbearing side, and the psoas group counters the movement by contracting on the non-weight-bearing side, so the lumbar spine remains in the midline. In the past, many practitioners have used the Gillette‘s test, described later, to identify fixation of the SIJ. It is helpful to remember that the SIJ is the ”dumping ground” for pain from the lumbar spine, just as the shoulder blade is the “dumping ground” for pain from the cervical spine. The key to determining if the problem is in the SIJ is to rule out all lumbar problems first. Second, Laslete9has determined that when two or more of the following SIJ tests produce concordant pain, it is highly likely the SIJ is the pain generator. 1. Gapping test-patient is supine. The examiner crosses his or her arms, placing hands on the anterior superior iliac spine, forcefully pressing laterally and down into the table to ”gap” the SIT, attempting to stretch the anterior SIJ ligaments.

2. Compression test-The patient is side lying with the painful SI up. The pressure is directed to the opposite iliac crest, attempting to compress the anterior SI and stretch the posterior SIJ ligaments. 3. Posterior shear or “thigh thrust”-The patient is supine with a small block or sand bag under the sacrum, the hip and knee are flexed to 90 degrees, and overpressure is applied down the shaft of the femur. One should avoid adduction of the hip, as this will cause pain in normals. 4. Pelvic torsion (Gaenslen’s test)-The patient is supine at the edge of the table with one thigh extended over the edge of the table. On the other side, the hip and knee are flexed to the chest. Overpressure is applied to the extended thigh to accentuate the posterior rotation of the opposite side. This should be performed on both sides. 5. Sacral thrust-With the patient lying prone, the examiner thrusts down on the sacrum. 6 . Cranial shear-With the patient prone, cranial pressure is applied to the apex of the sacrum with the examiner‘s hands, while the painful side ankle is placed between the examiner’s knees and is tractioned caudally.

Method of Motion Palpation of the Sacroiliac Joints Practitioners should follow these steps to palpate the SIJs: Contact the posterior sacroiliac spine (PSIS) on the right with the right thumb. Contact the second sacral tubercle with your left thumb. Ask the patient to flex his or her right thigh slowly three times up and down to below 90 degrees. This causes flexion of the right innominate, while the sacral prominence remains relatively stationary. The motion of the PSIS is normally posterior, toward the floor, and slightly toward the midline. If no motion occurs between the PSIS and second sacral tubercle, there is a fixation of the right upper joint in flexion. Remember, it is the motion between the PSIS and second sacral tubercle, not the motion of the joint relative to the floor, that is important. 4. Ask the patient-to flex his or her left thigh slowly three times above 90 degrees. The right leg is now weight bearing and fixed, and this motion causes the sacrum to flex, which causes a relative extension of the right ilium. If the sacral prominence does not swing medially away from the PSIS as the left thigh flexes above 90 degrees, theh the right upper joint is fixed in extension.

Manipulation

Maigne (pp. 390-395), Bourdillion (pp. 146-173), and Maitland (pp. 314-317).

5. Shift your right thumb to the posterior inferior iliac spine (PIIS) and have the patient slowly flex their right thigh three times to below 90 degrees again. The PIIS should move laterally away from the sacral prominence, or there is a flexion fixation of the right lower SIJ. 6. Again, the left thigh is flexed slowly three times above 90 degrees and the sacral prominence should swing medially away from the PIIS, unless there is an extension fixation of the right ilium in the lower joint (after Gillette and Gittleman).

Psychology Management of chronic pain and assistance for the patient in dealing with stress are of major importance in the treatment of all conditions, especially neuromuscular spindle injuries. The psychosomaticcomponent of myofascial pain syndromes and the unique combination of therapies the naturopathic physician can offer necessitate a thorough understanding of the relaxation response, hypnosis, biofeedback, guided imagery, and personal motivation. If this area is not developed, some patients seeking help do not find their treatment results satisfactory.

Techniques for correction of these fixations are described in many manipulative texts. I recommend

~

1. Greenman P. Principles of manual medicine. Baltimore: Williams & Wilkins, 1996:39. 2. Maitland GD. Peripheral manipulation, ed 3. London: ButterworthHeinemann, 1991. 3. Bigos S, Bowyer 0,Braen G, et al. Acute low back problems in adults. Rockville, MD: US Department of Health and Human Services,Public Health Service, Agency for Health Care Policy and Research, 1994. 4. Liebenson C, ed. Rehabilitation of the spine: a practitioner’s manual. Baltimore: Williams & Wilkins, 1996:355. 5. Lewit K. Manipulative therapy in rehabilitation of the locomotor system. London; Boston: Butterworth-Heinema, 1985:5. 6. Amell P, Beattie S. Heat and cold in the treatment of hypertonicity. J Can Phys Assoc 1972;24:61-67. 7. Stamford B. Giving injuries the cold treatment. Available online at

http://www.physsportsmed.com/issues/l996/03_96/cold.htm#avoid [accessed December 29,20031. 8. Rizzo TD. Using RICE for injury relief. Available online at http://www.physsportsmed.com/issues~996/10_96/rizzo.htm [accessed December 29,20031. 9. Dvorak J, Dvorak V, Schneider W, eds. Manual medicine. Heidelberg, Germany: Springer Verlag, 1985. 10. Cryiax J. Textbook of orthopaedic medicine, vol 1, ed 8. London: Bailliere Tindall, 198210. 11. Travel1 JG, Simons DG. Myofascial pain and dysfunction: the trigger point manual. Baltimore: Williams & Wilkins, 198355. 12. Schafer R. Chiropractic health care: a conservative approach to health restoration, maintenance, and disease resistance. Des Moines: Foundation of Chiropractic Education and Research, 1976. 13.Lomax E. Manipulative therapy. In Buerger AA, Tobis JS, eds. Approaches to the validation of manipulation therapy. Springfield, I L CC Thomas, 1977. 14. Kessler RM. Management of common musculoskeletal disorders: physical therapy principles and methods. Philadelphia: Harper & Row, 1983:129. 15. Hood W. On the so-called ”bone-setting,” its nature and results. Lancet 1871:1:304-10,344-349. 16. Goldstein M. The research status of spinal manipulative therapy: a workshop held at the National Institutes of Health, February 2-4, 1975. Bethesda, MD: US Department of Health, Education, Welfare, Public Health Service, National Institutes of Health, National Institute of Neurological and Communicative Disorders and Stroke, 19756. 17. Webster’s New Collegiate Dictionary. Springfield, MA: GC Merriam, 1975.

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18. Starr P. The social transformation of American medicine, the rise of a sovereign profession and the making of a vast industry. New York Basic Books, 1982. 19. Palmer DD. The science, art and philosophy of chiropractic. Portland, OR Portland Printing House, 1910:18. 20. Gibbons R. The evolution of chiropractic: medical and social protest in America. Notes on the survival years and after. In Haldeman S, ed. Modem developments in the principles and practice of chiropractic. New York Appleton-Century-Crofts. 19803-24. 21. Northup G. History and development of osteopathic concepts: osteopathic terminology. In Goldstein M. The research status of spinal manipulative therapy: a workshop held at the National Institutes of Health, February 2-4, 1975. Bethesda, MD: US Department of Health, Education, Welfare, Public Health Service, National Institutes of Health, National Institute of Neurological and Communicative Disorders and Stroke, 1975, p. 43-51. 22. Wardwell WI. Discussion: the impact of spinal manipulative therapy on the health care system. In Goldstein M. The research status of spinal manipulative therapy: a workshop held at the National Institutes of Health, February 2-4, 1975. Bethesda, MD: US Department of Health, Education, Welfare, Public Health Service, National Institutes of Health, National Institute of Neurological and Communicative Disorders and Stroke, 1975:20-21. 23. Zhon DA, Mennell JM. Musculoskeletal pain: diagnosis and physical treatment. Boston: Little, Brown and Company, 1976:147.

24.Tower DB. Chairman summary: evolution and development of the concepts of manipulative therapy. In Goldstein M, ed. The research status of spinal manipulative therapy: a workshop held at the National Institutes of Health, February 2-4, 1975. Bethesda, MD: US Department of Health, Education, Welfare, Public Health Service, National Institutes of Health, National Institute of Neurological and Communicative Disorders and Stroke, 1975:59. 25. Bourdillion JF, Day EA, Bookhout MR. Spinal manipulation, ed 5. Oxford, England; Boston: Butterworth-Heinema, 1992ix-x. 26. McKenzie R. The lumbar spine. Waikanae, New Zealand: Spinal Publications, 1981. 27. Liebenson C, ed. Rehabilitation of the spine: a practitioner’s manual. Baltimore: Williams & Wilkins, 1996251. 28. McKenzie R, Kubey C. Seven steps to a pain-free life: how to

rapidly relieve back and neck pain using the McKenzie method. New York: Plume, 2000:121.

Therapeutic Modalities 29. Waddell G. An approach to backache. Br J Hosp Med 1982;28:187, 190-1,1934. 30.Wasson J, et al. The common symptom guide: a guide to the evaluation of 100 common adult and pediakic symptoms, ed 2. New York McGraw-Hill, 1984. 31. Haerer A, ed. DeJong’s the neurologic examination, ed 5. Philadelphia: Lippincott, 1992339,433,445. 32. Beneliyahu DJ. Chiropractic management and manipulative therapy for MRI documented cervical disk herniation. J Manipulative Physiol Ther 1994;17177-185. 33. Krause N. Psychosocial job factors, physical workload, and incidence of work-related spinal injury: a 5-year prospective study of urban transit operators. Spine 1998;23:2507-2516. 34. Feuerstein M, Berkowitz SM, Huang GD. Predictors of occupational low back disability: implications for secondary prevention. J &cup Environ Med 1999;41:1024-1031. 35.Estlander AM, Takala EP, Viikari-Juntura E. Do psychological factors predict changes in musculoskeletal pain? A prospective, two-year follow-up study of a working population. J Occup Environ Med 1998;40:445-453. 36. McKenzie R, Kubey K. Seven steps to a pain-free life: how to rapidly relieve back and neck pain using the McKenzie method. New York:Plume, 2000:21. 37. McKenzie R. Treat your own back, ed 7. Waikanae, New Zealand: Spinal Publications, 19978.

38. Magee DJ. Orthopedic physical assessment, ed 2. Philadelphia: WB Saunders, 1992. 39. Evans RC. Illustrated essential in orthopedic physical assessment. St. Louis: Mosby, 1994. 40.McKenzie R. The lumbar spine. Waikanae, New Zealand Spinal Publications, 1997. 41. McKenzie R. The cervical and thoracic spine. Waikanae, New Zealand: Spinal Publications, 1990. 42. McKenzie R. The lumbar spine. Waikanae, New Zealand: Spinal Publications, 198122. 43. Liebenson C, ed. Rehabilitation of the spine: a practitioner’s manual. Baltimore: Williams & Wilkins, 1996:251. 44. Butler D. Mobilization of the nervous system. New York Churchill Livingstone, 1991:147. 45. Terrett AGJ. Vertebrobasilar stroke following manipulation. West Des Moines, Iowa: National Chiropractic Mutual Insurance Company, 1996:24. 46.Sandoz R. Some physical mechanisms and effects of spinal adjustments. Ann Swiss Chirop Assoc 1976;691. 47.Robbins SL, Cotran RS. Pathologic basis of disease, ed 2. Philadelphia: WB Saunders, 1979:55-106. 48.Maigne R. Orthopedic medicine, a new approach to vertebral manipulation. Springfield, IL: CC Thomas, 1972:137. 49. Laslett M, Williams M. The reliability of selected pain provocation tests for sacroiliac joint pathology. Spine 1994;19:1243-1249.

BourdilLion JF, Day EA, Bookhout h4R. Spinal manipulation, ed 5. Oxford, England; Boston: Butterworth-Heineman, 1992. A good text that covers the bases. It is exceeded in ninny areas by Greennian’s text. Boyling JD, Palastanga N. Grieve’s modem manual therapy, ed 2. New York Churchill Livingstone, 1994. A heavily rqferenced tome. Cox JM. Low back pain: mechanism, diagnosis and treatment, ed 5. Baltimore: Williams & W W , 1990. Addresses aspects of consmative care of low back, especially lumbar disk herniation history, research, diagnosis,and consmativc treatment with statisfics and research that supports the methods described. Cryiax J. Textbook of orthopaedic medicine, vol 1, ed 8. London: Bailliere Tidall, 1982. A dificult text to read that has been translated to a readable format by the other authors listed, but a classic. He was strongly anfi-nltmiatiiie medicine in his approach to certain aspects of physical medicine fespecially those who should and should not practice it), and his z~iewpointsare narrow arid limited compared with the more recent publications and jo~inials. Greenman P. Principles of manual medicine, ed 2. Baltimore: Williams & Wilkins, 1996. One of the best texts that covers the material in a clear, undcrstniidable, and usableformat. Haldeman S, ed. Principles and practice of chiropractic, ed 2. New York Appleton-Cenhuy-Crof, 1992. The second edition has major changes and new contributors and is an excellent source of information on history, research, diagnosis. and treatment of all phases of manipulation, with special attention to the spine. Kessler RM. Management of common musculoskeletal disorders, physical therapy prinaples and methods, ed 3. Philadelphia: Harper & Row, 1996.

A good text for the therapist’s approach to treatment, with recap of much of Cyiax’s work. Basic concepts of embryology, arthrology, pain, and assessment. Techniques of case management, use of hot and cold, manipulative, and relaxation techniques. Ends with detailed discussion of all of the joints of the body. Well worth rending. Liebenson C, ed. Rehabilitation of the spine: a practitioner’s manual. Baltimore: Williams & Wilkins, 1996. Liebenson has brought together many fine contributors who address the cutting edge methods of nianual medicine. It covers much of what is needed in clinical practice. Very useful and readable. A gold mine of information. Magee DJ. Orthopedic physical assessment, ed 2. Philadelphia: WB Saunders, 1992. One of the best texts for learning the orthopedic assessment techniques and many of thefunctional tests. Maitland GD. Vertebral manipulation, ed 4. London; Boston: Butterworth-Heineman, 1977. A physical therapist’s approach with emphasis on patienf selection, pretreatment assessment, assessment during treatment, assessment after treatment, and therapeutic approach for each area of the spine. Maitland GD. Peripheral manipulation, ed 3. London; Boston: Butterworth-Heineman, 1991. The Snme approach as previous book, but for the extremities. The author suggests learning on the extremities bt$orc attempting to learn spinal manipulation. After all, a joint is a joint. Walther DS.Applied kinesiology, vols 1 and 2. Pueblo, C O Systems DC, 1983. A chiropractic approach thnt is in a different realm froin physical medicine texts. Treatment approaches that arc dificult to find and that are empirically based+teti gives a iiscful solution that defies scient+c fact.

Nonpharmacological Control of Pain Richard Kitaeff, MA, MD, Dip1 Ac, LAC CHAPTER CONTENTS Introduction 431 The Experience of Pain 431 A Psychological Model 431 Neuropsychological Mechanisms of Pain 432 Pain in Childbirth 432

Counterstimulus Methods: Massage, Acupuncture, Transcutaneous Electrical Nerve Stimulation 434 Other Methods 438 Conclusion 438

Pain Control 433 Moderating Variables and Psychological Techniques 433

INTRODUCTION Pain in its myriad forms is one of the most common symptoms for which patients seek relief. Acute pain is an unpleasant experience primarily associated with tissue injury, and the protective response patients have to pain provides the clinician with valuable diagnostic information. The reaction to pain is highly subjective and, as a function of higher centers, is extremely variable. It is influenced by many factors, depending on the individual patient and his or her situation. When pain becomes chronic, the multifactorial influences (e.g., anxiety, depression, social, cultural, and economic factors, secondary gain) play an even larger role. When treating a patient for pain, the clinician must first determine the primary cause, the pathogenesis, and the secondary or contributing factors. The relief of pain may then be achieved by removal of the primary cause (e.g., cure of an infection), neutralization of the effect of the stimulus (e.g., emollients for an ulcer), relief of discomfort (e.g., biofeedback), suppression of the disease process (e.g., antiinflammatory agents), and dulling or obliteration of the sense of pain (e.g., analgesics or acupuncture).' Although the medical profession has chosen to emphasize the pharmacologic methods of pain control, many nonpharmacological options are available. Their applicability and efficacy are documented here. (Although this chapter liberally utilizes pain control in

childbirth, the examples and concepts can be generalized to any situation involving acute and/or chronic pain.)

THE EXPERIENCE OF PAIN A Psychological Model Pain is generally acknowledged to be a complex physiologic/ psychological phenomenon. It involves motivational and emotional components and conceptual interpretation, which may or may not have their basis in actual nociception. Verbal reports of pain and associated behavioral responses are controlled, at least in part, by psychological, cultural, and situational factors. For acute pain, such as that of childbirth, in which the painful experience can be directly related to nociceptive input, a multiprocess feedback model can be considered. However, one must keep in mind the complexity of the psychological processes intervening between sensory event and observable response, ranging from the physiologic to the social aspects of personality. These include elements of the following: Information processing Performance ability Attention Memory Expectancy Attitudes and beliefs Secondary gain 431

Therapeutic Modalities Self-concept Designated sick roles

In the psychological model, the brain infers information from bodily signs and integrates it with existing personal and situational variables to direct behavior. When consideration must also be given to the interactions with interested observers, such as physicians, family members, and birth attendants, who influence the interpretation with their own experiences and attitudes about pain, the complexity becomes even greater. According to this model, which does not differ in essence from a general model of stress, a primary appraisal of the personal danger or threat posed by the painful stressor is followed by a secondary appraisal of one's ability to cope, based on emotional feedback, and contributions of situational and sociocultural response factors. On this basis, a woman in labor could choose to regard pain as "positive," "functional," or "creative"; "pain with a purpose"; or, alternatively, "part of a process involving injury."2 In the course of a pain management program carried out with 84 patients with low back pain, those who more strongly endorsed "organic" concepts about the nature and treatment of pain reported higher levels of disability, whereas reductions in reported "organic" pain beliefs improved reported disability, and endorsement of "psychological" concepts about the nature and treatment of pain was not associated with di~ability.~ Several studies indicate that "catastrophizing" predicts pain or is associated with lower pain tolerance.4$This conceptualization of painful stress suggests that intervention could be successful at several levels: cognitive patterning, physiologic arousal associated with emotional stress, and control of environmental stimuli. Examples of appropriate strategies are cognitive coping skills such as restructuring and utilization of preparatory information and attention shifts; muscular relaxation, physical or electrical stimulation, and biofeedback techniques; and structuring of the environment in a way conducive to effective coping (such as by making it nonthreatening and comfortable).6

Neuropsychological Mechanisms of Pain According to research on the mechanisms of pain, pain can be treated not only by anesthetic blocks, surgical intervention, and the like but also by influencing the motivational-affective and cognitive factor^.^ The traditional specificity theory of pain, first enunciated by Descartes in the seventeenth century, holds that pain messages are conducted from specific pain receptors at the periphery through discrete pathways to pain centers in the brain. However, there are individual differences in pain responses, pain is not consistently stopped by cutting or blocking of the "pain pathway," and it is now known that nonpainful types of stimulation activate the

A-delta and C fibers (see next paragraph) that are associated with pain. Therefore, later modifications of pain theory took into account patterning of nerve impulses over time to reflect differences in degree and intensity of stimuli and summation of signals from an extended area.8 The currently accepted view of pain is the gate control theory, which Melzack and Wall9formulated in 1965. Based on neurologic data and a categorization of the words used to describe pain, this theory conceptualizes the pain experience as having sensory-discriminative, motivational-affective, and cognitive-evaluative components or modalities, corresponding to different patterns of nervous impulses. Neurologically, a specialized cluster of nerve cells in the substantia gelatinosa of the spinal column is thought to operate like a valve or gate, controlling nerve signals before they evoke the perception of, and response to, pain. Besides this monitoring of sensory data in the central nervous system, gating is also influenced by the relative amount of activity in large-diameter (A-beta) and small-diameter (Adelta and C ) nerve fibers. The large fibers tend to inhibit transmission, or close the gate, preventing pain, and the small fibers tend to facilitate transmission, or open the gate, resulting in pain. The fact that large fibers are activated by pressure, touch, massage, and vibration suggests a mechanism for such pain control techniques as acupressure, acupuncture, and transcutaneous electrical nerve stimulation (TENS). Such stimulation apparently closes the spinal gate via the large-fiber system. Melzack and Casey' expanded this theory by proposing the possibility of a higher-level gate, in the reticular or limbic structures of the brain, that probably mediates the drive to escape from unpleasant stimuli. At central nervous system levels, the biochemical mechanisms of gate control may involve the endorphins, natural morphinelike substances that have been implicated in the pain-controlling effects produced by acupuncture.'"

Pain in Childbirth A psychological/social learning approach to pain emphasizes control of motivation, expectation, focus of attention, stress, and feelings of anxiety, depression, and helplessness. Factors specifically operative in labor pain involve these as well as social support and the physiologic factors of hunger, rest, and muscular tension." All of these factors can contribute to the interpretation of pain being placed on the nociceptive message provided by uterine contractions. The influence of motivation on labor pain was effectively demonstrated in a prospective study of maternal attitudes toward pregnancy in 8000 American women. One of the factors found to be strongly related to maternal attitude toward having a baby was the need for analgesics in labor.I2

NonpharmacologicalControl of Pain

Cultural conditioning may also be fundamental to the labeling of childbirth as painful. Throughout most of the world, analgesics are not required for labor; in fact, a Japanese anesthesiologistsuggests that the idea of "painless delivery" is a strange one to his culture.13 American women, on the other hand, "live through a largely self-fulfilling prophecy of birth as a painful, terrifying ordeal, and/or as a medical, drugged process over which they have no control."" This idea relates to body fantasies of injury, brought about in a hospital environment where distress is an expected response to the expulsive reflex.2

PAIN CONTROL Moderating Variables and Psychological Techniques Psychological Strategies The psychological strategies recommended for control of labor pain, many of them part of prepared childbirth programs, generally aim to provide control, communication, relaxation, attention focus, and support as well as physical counterstimuli. Considerable psychological research supports the use of these strategies in the development of pain tolerance. The significance of various characteristics of an individual's psychological profile has been studied by evaluating the effects on pain perception of such parameters as the following:

Introversion-extr~version~~-~~ Augmenters-reducersl7 9 Field dependen~e'~.'~ Repression-sensitizationz@z 9

For example, on the repression-sensitizationaxis, repressors may be characterized as people who avoid having to cope with pain. Sensitizers, however, have an obsessive need to cope; they like to be informed in advance about the situation and to have control over it. The superior initial tolerance exhibited by repressors in response to heat and pressure stimuli disappears in repeated trials, showing that the sensitizers' predilection for challenge enables them to endure long-term pain better. The importance of individual difference variables is also illustrated by the observation that one third of patients undergoing surgical operations do not request pain-killing medi~ation.2~ This common ability to suppress pain indicates that not all surgical patients consider themselves passive victims. In fact, during the postoperative period, pain persists longer for those who accept medication.

Cognitive Strategies The impetus for devising cognitive strategies to promote tolerance of pain has been particularly supported by

investigations showing that pain tolerance increases with greater predictability and perception of ~ o n t r o l . ~ ~ - ~ ~ Similarly, preparatory communications and information received before the onset of experimental or surgical pain consistently decreases the subjects' perception of ~ain.*~ Animal - ~ l studies have demonstrated higher rates of instrumental responses when painful shocks are signaled than when they are u n ~ i g n a l e d Kanfer . ~ ~ and S e i d r ~ e found r ~ ~ that subjects who could advance slides of travel pictures at their own rate tolerated iced-water immersion of the hand longer than yoked subjects whose slides were changed by the experimenter. When surgical patients were given a sense of control by being provided with preparatory information about postoperative discomforts and operative care, in combination with training in rehearsal of realistic, positive aspects of the surgical experience, they showed a significant reduction in postoperative anxiety (as indicated by nurses' observations),requests for sedatives, and length of hospital stayMFurthermore, preparation for second periodontal procedures by auditory and visual messages classified as "control enhancement" was associated with reduction of pain after a second operation.35Subjects who could cognitively redefine a threat of electric shocks as interesting new physiologic sensations also reduced stress to a greater extent than subjects not provided with this coping strategy.36 A typical cognitive behavioral procedure utilizes "stress inoculation," beginning with an educational phase (in which the client is given a conceptual framework for understanding the nature of his or her stressful reactions), followed by rehearsal of behavioral and cognitive coping skills, based on a set of coping self-statements generated by the client in collaboration with the therapist. Such cognitive-behavioral techniques, sometimes in combination with electromyography (EMG) biofeedback control, have been found successful in treatment of chronic low back pain.37-39 Also, cognitive-behavioral strategies have been effective in alleviating the pain of irritable bowel syndrome,4O temporomandibular joint syndr0rne,4~,~~ cancer,43migraine headaches,44rheumatic conditions,"537 fibromyalgia,mand complex regional pain syndr0me.4~ This emphasis on conceptualization, preparatory information, and cognitive transformation seems to have been incorporated into the Read method of natural childbirth, which replaces fear with knowledge about birth.lz Sheila Kitzinger: in her method of prepared childbirth, similarly emphasizes the necessity of "acquiring knowledge and understanding of what labor involves, the terminology used by obstetricians and midwives, and information about what happens in hospitals." A study by Stevens and Heide50 conducted at the University of Wisconsin used iced water to test perception and endurance of pain in subjects who had been taught methods used in childbirth education classes.

The control subjects for this training and an additional control group were offered only distraction during the tests. Those who had been taught the techniques reported only about half the pain of that reported by control subjects and endured it 2.5 times longer. The prepared childbirth strategies improved with practice, were effective for pain lasting longer than most contractions in labor, and were more effective than distraction techniques.” However, this last finding introduces some confusion, because some prepared childbirth methods include either distraction techniques or some other deliberate disposition of one’s attention.

Attention-Focusing Distraction or focused attention, mostly utilizing the rhythms of the breath, is essential to the Lamaze method, the most popular prepared childbirth program in America, and is important in the Bradley and other methods. Sheila Kitzinger2 describes the controlled attention focusing as:

. . . concentrationon what is happening, one‘s response to it as a task, and visualization of what is being achieved by the work of the uterus during contractions. The focus may be on the fantasy of the contractions as a shape provided by actual objects (furniture, architectural details, flowers, a painting) in the room, or a combination of these factors. Stevens and HeideWfound that attention-focusing functions effectively as an analgesia for labor pain. Such strategies are strongly supported by much psychological research. Hospitalized children with chronic illnesses who were taught distraction techniques were able to reduce measures of distress before and during medical procedures such as intramuscular and intravenous inject i o n ~In . ~a~study of patients with bum pain, sensory focusing techniques were more successful than distraction techniques in controlling pain, and both were more successful than standard care.52The focus may be on a competing response, as in a study by Kanfer and GoldfooP3showing that when attention was directed to self-presented external slides, individuals were able to increase their tolerance of the pain of cold water. Focus on a competing response is also shown in the use of hypnosis as an analgesic and in the meditative states of Raj yogis, who pinpoint attention on the tip of the nose or a point on the back of the skull, and then do not react physiologically to cold water, bright lights, or sudden s 0 u n d s . ~ 5Other ~ adepts in unusual feats of pain tolerance, such as having spikes stuck through the skin, either maintain an unfocused attitude, without evaluation, or pinpoint attention totally on the pain, but without e ~ a l u a t i o nIn . ~ ~such cases, the attitude of detachment from the pain can be reflected by an undisturbed electroencephalography (EEG) pattern of alpha or beta waves throughout performance of the feat.

Relaxation Training Relaxation training, another essential element of pain control, is found in all childbirth training programs. A considerable body of literature supports its importance in pain control, because a state of lowered autonomic arousal is incompatible with anxiety. Although progressive muscular relaxation, systematic desensitization, and autogenic training are all well-established physiologic approaches to muscular relaxation, meditation traditions provide quicker methods to achieve what B e n ~ o has n~~ called, the “relaxation response.” One of the simplest meditation practices-maintaining a focal awareness of the flow of the breath-is taught by Rahima Baldwin” in Special Delivery and is identical to the ancient Buddhist practice of vipassarza, or insight meditation.

Hypnosis Hypnosis or autohypnosis is another method utilized to induce deep relaxation for pain control. It incorporates many of the therapeutic elements already referred tofocused attention, positive expectation, and a supportive or permissive attitude-in making suggestions that alleviate anxiety. Thus, its success in pain management may be viewed from a cognitive-behavioral perspective.%In one technique, “glove anesthesia” is induced in one hand and the “numb, heavy wooden feeling” so produced is transferred to the other hand, the face, and eventually to the abdomen in order to “relieve the discomfort” of uterine contractions (the word ”pain” is never used, because its use would be countersuggestive).59 Pain modulation in “high hypnotizable” subjects has been confirmed through brain measurement of somatosensory event-related potentials (SEWS)to noxious stimuli, with highest amplitudes for these subjects recorded at frontal and temporal scalp sites.60

Control of Environmental Stress KitzingerZ cites animal research to show how environmental stress can interfere with the physiologic processes of labor and delivery. Education for childbirth therefore promotes verbal and nonverbal support from husband, obstetrician, midwife, or anyone else who is part of the birthing environment. Touch relaxation and coaching techniques combine the essential elements of relaxation, massage counterstimulus, and the direct supportive communication of a partner.” Several studies agree that comfort in labor is also enhanced by a more vertical position, such as the squatting posture that is adopted in many other

Counterstimulus Methods: Massage, Acupuncture, Transcutaneous Electrical Nerve Stimulation The hand reflexology method of grasping combs during labor to activate points on the fingertips and balls of the

Nonpharmacological Control of Pain ~~

hand that relate to uterine functioning is one example of counterstimulus strategy.” Foot reflexology, acupressure, acupuncture, and TENS might also share a common autonomic nervous mode of operation.

Transcutaneous Electrical Nerve Stimulation The use of TENS to control pain during delivery has been evaluated by several studies. The method used in a Swedish study,64which was subsequently replicated in Germany and Britain, was originally developed in the United States by Shealy and MaureP for the control of acute and chronic pain. In a controlled study of experimentally induced cold-pressor pain, the effect of electrical stimulation with TENS electrodes at two traditional acupoints in 20 subjects had an analgesic effect with statistical significance comparable to that of morphine, and the combined effect of TENS with morphine was stronger than TENS alone.66A series of controlled randomized double-blind studies on carpal tunnel syndrome pain found that the combination of low-level laser and microcurrent TENS on distant and local points significantly decreased McGill Pain Questionnaire Score, sensory and motor latencies, and Phalen and Tine1 signs, compared with sham treatment.67A British study, investigating the relative hypoalgesic effects of different TENS parameters upon experimentally induced mechanical pain, found that low-frequency, high-intensity, extrasegmental stimulation (i.e., over an acupuncture point rather than over a nerve distribution) produced a rapid-onset hypoalgesic effect, which increased during the stimulation period and was sustained for 30 minutes after stimulation.68 Generally in TENS, the electrodes are placed over the painful area in order to stimulate the cutaneous nerves in that area. For use in labor, four electrodes are placed on either side of the midline of the spine to stimulate the posterior primary rami of the spinal segments (T11-Ll and S2-s4) receiving the painful stimuli during labor. It is interesting to note that these are the loci of acupuncture points (BL-20, BL-27, and BL-28) that are traditionally thought to reflect female reproductive function. The selection of this area for stimulation is based on Bonica’s account of the neurologic mechanism of delivery pain.69 During the first stage, pain receptors are assumed to be activated by contractions of the uterus and dilation of the cervix. The evoked impulses are mediated in afferents that run in the hypogastric nerves and reach the spinal cord via the dorsal roots T10-L1. The pain is referred to large areas of the abdomen and back. During the second stage, pain is also caused by distention and stretching of the delivery canal, the pelvic floor, the vulva, and the perineum. The pain is localized, and the impulses reach the spinal cord mainly via the pudendal nerves and the dorsal roots S2-s4. The pain during the first stage is characterized as an ache considered to

be mediated in small-diameter C fibers. During the second stage, the pain has the more localized intensive nature usually identified with the delta afferent fiber~.6~*~O In the typical application of this technique for control of pain during labor, low-intensity stimulation is given continuously and a high-intensity stimulation can be initiated by the parturient herself whenever pain increases. Stimulation via the thoracic electrodes is maintained throughout the delivery at an amplitude that is maximal for a pleasant sensation, whereas sacral stimulation is added from the later part of the first stage. Table 42-1 summarizes the uniformly good results that have been reported. Those patients who complained of backache have especially appreciated it. An Austrian study compared the analgesic effects of TENS, pethidine, and placebos on labor pain in 30 parturient women during the first stage of labor. No sigruficant difference was found between the placebo, unspecific TENS, and control groups in the increase in pain during the test period. Patients who had received pethidine and those who had been given TENS experienced considerable relief of pain.” It is curious that apart from a passing reference by Shealy and M a ~ r e to r ~its ~ use in labor, no research on the obstetric application of TENS appeared for many years in any of the U.S. literature. A 1996 review of 30 studies on TENS stimulation of acupuncture points in labor substantiated the conclusions of earlier research.76 In view of the relatively good results and lack of complications, the consensus of all the preceding studies is that the TENS method is recommended as a primary pain-relieving measure, to which conventional methods can be added as needed. Robson7 comments that TENS is noninvasive and is believed to be safe for both mother and baby. It is easy to apply and can be operated throughout labor by the doctor, midwife, father, or mother. Augustinsson et al.a were most impressed by the lack of complications, because the conventional methods, including analgesic and sedative drugs, nitrous oxide

Results (%)

Study

No. of patients

Good

Moderate

Augustinsson et aIw

147

44

44

12

Andersson et aI7’

27

48

37

15

~ Kanfer & G ~ l d f o o t ~ 35

20

62

18

Stewart72

31

56

13

67

None

Kubista et a173

102

55

24

21

Bundsen et a174

347

47

42

11

inhalation, epidural anesthesia, and local blockades, all possess a varying level of potential risk.6.’ Another advantage is that TENS, because it does not give complete analgesia, does not eliminate pain as a diagnostic tool; it can be interrupted whenever needed for clinical evaluation. More important, perhaps, from the point of view of the woman in labor is the fact that her consciousness is not altered to the point of excluding her own active participation in, and experience of, the delivery. Both Stewartn and Augustinsson et al.65 reported TENS alone to be inadequate for analgesia in the second stage of labor. The second group of researchers regards this difference as possible support for the assumption that C fiber-mediated pain is more amenable to blocking by electrical stimulation than A fiber-mediated pain. Stewart72mentions simply that many women did not wish to use the stimulator at that stage because it proved a distraction from their efforts to bear down. In this connection, it is interesting to note that “those who were well prepared and keen on natural childbirth were not always the most enthusiastic and, in fact, two of the early failures were patients who had been to relaxation cla~ses.’”~ Robsonn explains that TENS could distract some patients from their breathing or other focus of attention learned in childbirth preparation classes. A related issue in the TENS literature is introduced by the comment of Anderson et al.71that there was a correlation between the level of hypnotizability and that of pain relief in their subjects. Such a correlation may, of course, imply only a susceptibility to any type of therapeutic effect. Neumark et al.” tested this effect by including a placebo group that was given no current through the electrodes; these researchers found that the result for the placebo group was not different from that of TENS applied nonspecifically (i.e., incorrectly) but was sigruficantly different from the effect of TENS placed over the relevant nerve distribution and from that of pethidine. Robson,= although making no attempt to assess a patient’s level of susceptibility to hypnosis, switched off the TENS machine for at least two contractions. All patients asked for it to be switched on again, indicating that the technique was providing pain relief. Augustinsson et a1.@consider the suggestive effect, if it occurs, to be of minor sigruficance,because several investigators have found the pain-reducing effect of TENS to be achieved through demonstrable neurophysiologic mechanisms.Stewartn points out that the greater personal contact between patient and attendant essential to the use of this method may introduce an element of suggestibility or distraction that affects the pain experience.

Acupuncture Hundreds of studies have investigated the efficacy and mechanisms of acupuncture analgesia for acute and chronic pain, in surgical operations, and in childbirth.

In a review article of 24 studies, Lewith and found that the typical clinical trial showed a 70%efficacy of acupuncture compared with placebo treatment. Reichmanis and B e ~ k e found r ~ ~ similar results in a review of 17 studies of acupuncture analgesia in experimentally induced pain. On the basis of a thorough review of the clinical and experimental research on acupuncture pain control, Stux and PomerantzsO concluded that acupuncture analgesia helps from 55% to 85% of patients with chronic pain, comparing favorably with the effects of potent pain medication (such as morphine, which is 70% effective), and clearly distinct from the placebo effect, which helps 30%to 35%.80Atthe same time, somatosensory EEG-evoked potential studies have provided objective evidence of the analgesic effect of ac~puncture.~~-~~ Recent randomized and double-blinded controlled studies have demonstrated clinical effectiveness of acupuncture in treating chronic lateral epcondylitiss4 and chronic neck pain.85In the neck pain study, stimulation at distant points of the neck-related meridians were more effective than sham acupuncture points and “dry needle” injections of local myofascial trigger points, reducing motion-related pain by one third after a single treatment. A single-blind randomized controlled trial showed that electroacupuncture ( E N is superior to manual acupuncture in treating patients with tennis elbow.%A review article on treatment of fibromyalgia pain for patients at a hospital in Brazil showed improvement with traditional acupuncture, measured on subjective scales and number of tender points.87Preoperative EA has led to reduction in intraoperative and postoperative requirement of analgesic medications (alfentanil and morphine) in patients receiving gynecologic lower abdomen surgery.88In fact, surgery that requires general anesthesia in Western countries is routinely performed in Chinese hospitals with the combination of acupuncture and local anesthesia for pain control, providing a considerable decrease in risk for surgical patients. Hyodo and Gega13 of the Osaka Medical College have reviewed the literature (summarized in Table 42-2) on acupuncture anesthesia and analgesia in normal delivery and found mixed results. For example, Wallis et a1.90reported that although 19 of their 21 volunteer parturients considered acupuncture unsuccessful in providing analgesia for labor, one third indicated that they would choose acupuncture analgesia in labor again. Some researchers criticize the technique as being inconsistent, unpredictable, incomplete, timeconsuming, and interfering with movement and electronic monitoring. In their own study, Hyodo and Gega13tested 32 patients, equally divided between primaparas and multiparas. Low-frequency electrical current was introduced through

Nonpharmacological Control of Pain EA seems to operate along this pathway.94A study carried out on dogs seems to ver* the traditional theory of points of tonification and sedation, through differential production of sympathomimetic and parasympathResults I%) omimetic effects on the cardiovascular system upon Study No.of patients Good Poor or none stimulation of different points. Carlsson,96 a Swedish Hyodo & Gega13 researcher, concludes that a mechanism for therapeutic 16 62.5 37.5 Primiparas acupuncture must include peripheral events that release Multiparas 16 93.7 7.3 neuropeptides, spinal mechanisms such as gate control, it0*9 80 85 15 and supraspinal mechanisms through the descending pain inhibitory system, the sympathetic nervous system, Wallis et atw 9-33 67-91 and the hypothalamic-pituitary-adrenal (HPA) axis. He Abouleish & Deppgl 80.5 19.5 cautions that much of animal and human experimental acupuncture research shows only short-term hypoalgesia; that almost all such experimental research has been performed with EA rather than the more gentle manual needles at LI-4, ST-36, and SP-6, a standard therapeutic style of therapeutic acupuncture; and that pain threshold repertory for sedation of the reproductive organs. The elevation in human experimental research does not results were assessed from relief noted by the patient necessarily predict the clinical outcome. (subjective scale) as well as from the obstetrician's obserIn a study of labor induction and inhibition by EA, vation (objective scale); among the primiparas, 62.5% Tsuei et al.97utilized SP-6 and SP-4 points, which are found good or excellent effect on the subjective scale, and located in the territory of the L4 dermatome. The spleen 62.6%good or excellent on the objective scale; and among meridian, to which these loci belong, runs across the derthe multiparas, 93.8% subjective relief and 93.7% objecmatomes of LA, W, L2, and L1, and then upward from tive relief. Overall, 90% of the patients experienced relief T12 to T5. Because the sympathetic nerve controlling the of pain within 20 minutes of initiation of acupuncture uterus through the pelvic plexus receives preganglionic anesthesia. These researchers noted the considerable fibers from T5 to L4, Tsuei et al?' concluded that it is disparity in reports of effectiveness of acupuncture from highly possible that stimulation of the electropermeable Japan and America, explaining it as a novelty effect. It is loci within this area may alter the physiologic function natural that in Japan, where no analgesic methods are of the uterus. The LI-4 points of the upper extremities, normally used, the scoring in favor of acupuncture often added to the spleen meridian points in the would be high compared with that in America. acupunctural control of labor pain, perhaps represent Hyodo and Gega13concluded that acupuncture analgethe central approach to the autonomic nervous system, sia is useful for delivery, especially because of its safety, because these loci control pain to the head and neck. even though its results are more erratic and less potent than It should be noted, however, that Motoyama,ss who has those of conventional anesthetic techniques.More recently, attempted to verify the traditional subtle anatomy of a randomized controlled trial investigating acupuncture meridian pathways through tests of electrocutaneous treatment as a complement or an alternative to convenresistance at meridian points, claims that these effects tional analgesia for labor in a Swedish hospital found that cannot be adequately explained in terms of the convenacupuncture sigruficantly reduced the need for epidural tional sympathetic dermatomes but instead imply an analgesia, and parturients receiving acupuncture achieved alternative bioelectric transmission system. a better extent of relaxation than the control g r o ~ p . ~ The discovery of the Head McKenzie sensory A considerable amount of research has focused on zones has shown the possible mediation of the invisible determining a mechanism for acupuncture analgesia. meridians and points of traditional Eastern medicine A 1995 review of studies on acupuncture effects in pain between internal organs and corresponding skin areas. and disease pointed out that, like exercise, acupuncture N a k a t a r ~ was i ~ ~ able to detect the electropermeable produces rhythmic discharges in nerve fibers and causes line as an apparent viscerocutaneous autonomic nerve the release of endogenous opioids and oxytocin. Furtherreflex when organic diseases were involved. Hyodolmhas more, "experimental and clinical evidence suggests that explained acupuncture stimulation as the transmission acupuncture may affect the sympathetic system via of impulses centrally from the reactive electropermeable mechanisms of the hypothalamic and brain-stem loci, via a sympathetic afferent fiber, and that the autolevels."91 Animal studies continue to demonstrate that nomic nerve in the viscera is stimulated to response by acupuncture analgesia is mediated in the central and peripheral nervous systems by opioid ~ e p t i d e s . The 9 ~ ~ ~ the reverse of the McKenzie theory. An exciting recent development in acupuncture research has been the findcortex and hippocampus appear to participate in the ing by functional neuroimagery of neuronal correlates of modulation of chronic pain, and the analgesic action of Results of acupuncture analgesia in the control of labor pain

Therapeutic Modalities

This chapter has presented many of the current nonpharmacological strategies for control of pain. Because

the mechanism of pain perception has been shown to involve both physiologic and psychological components, the optimal treatment might combine psychological factors, such as preparatory information, attention focus, relaxation, and supportive communication, with the physical stimuli of TENS or acupuncture. In fact, such a multidisciplinary approach to patients with chronic back pain was evaluated after a 4-week program that included back schooling, psychological intervention, and treatment by acupuncture, chiropractic, the Alexander technique, and a pain specialist. Significant improvement was maintained for a period of 6 months.lffi Dental researchers of the Pediatric Pain Program of the University of California at Los Angeles School of Medicine searched several databases for reports of randomized, controlled clinical trials of complementary and alternative medical modalities used to treat chronic facial pain. Three acupuncture trials, eight biofeedback trials, and three relaxation trials met the researchers’ inclusion criteria, suggesting that these modalities were comparable to conventional treatment such as an intraoral appliance.lo7 Increasingly, the multidisciplinary pain management team, incorporating a variety of nonpharmacological treatment modalities, is being considered “the optimal method for delivery of comprehensive treatment to patients in pain.”losThe incorporation of ”alternative” forms of pain management, including acupuncture, relaxation techniques, hypnosis, biofeedback, and guided imagery, is acknowledged by the Children’s Hospital of the Medical College of Wisconsin to complement pharmacologic management of children’s pain.Im The selection, balance, and application of these treatment components should be based on consideration of an individual’s coping styles. Such a treatment program could be developed to provide a more consistently effective analgesia than the individual components can provide separately. Relieving the pain of childbirth, for example, without diminishing or distorting the full consciousness of the experience for the mother, would be consistent with the goals of the contemporary physician of natural medicine.

1. Krupp MA, Chatton MJ. Current medical diagnosis and treatment. Los Altos, CA: Lange Medical, 1984:l-5. 2. Kitzinger S. Pain in childbirth.J Med Ethics 1978;4119-121. 3. Walsh DA, Radcliffe JC. Pain beliefs and perceived physical disability of patients with chronic low back pain. Pain 2002;97: 23-31. 4. Haythronthwaite JA, Lawrence JW, Fauerbach JA. Brief cognitive interventions for bum pain. Ann Behav Med 2001;U:42-49. 5. P i a T, Taplin JE, Goodenough B, von Baeyer CL. Cognitive-behavioural predictors of children’s tolerance of laboratory-induced

pain: implications for clinical assessment and future direction. Behav Res Ther 2002;40571-584. 6. Kitaeff R. Cognitive strategies for control of painful stress. Unpublished manuscript, 1979. 7. Melzack R, Casey KC. Sensory, motivational and central control of pain. In Kenshalo DR, ed. The skin senses: proceedings. Springfield, n: Charles C Thomas, 1968:423-443. 8. Feumrstein M, Skjei E. Mastering pain. New York Bantam, 1979:17-21. 9.Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150971-979.

acupuncture stimulation in the human brain. In a controlled study of electroacupuncture (EA) stimulation of GB-34 on the left leg, real EA elicited significantly higher activation over the hypothalamus and primary somatosensory motor cortex than mock and minimal EA, showing that the hypothalamic-limbic system was sigruficantly modulated by EA at acupoints.’”’

Other Methods The scope of this chapter does not permit detailed discussion of other promising methods of pain control, but mention can be made of massage, biofeedback, and nutritional and botanical agents for treatment of pain. A literature search led to the conclusion that massage, particularly acupressure, is effective for low back pain, especially when it is combined with exercises and education, with beneficial effects lasting at least 1 year after the end of treatment.’”*A vast literature is available on biofeedback training for pain. An article suggesting a future direction in pain medicine describes the use of “off-the shelf,” low-cost, and low-bandwidth telemedicine equipment to deliver clinical biofeedback treatment when the patient and provider are in two different locat i o n ~ . In ’ ~a~randomized double-blind trial of 30 patients with chronic maxillofacial pain, significant reduction in pain scores and improvement in tolerance of experimentally induced dental pain were achieved with administration of 3 g daily of the amino acid tryptophan and a high-carbohydrate, low-fat, low-protein diet in comparison with placebo.’04Among botanical agents for pain, corydalis rhizome or tuber (yanhusuo) is well known in the Chinese materia medica for its analgesic effect, containing combined alkaloids found to be 40% as effective as morphine. Acting probably through inhibition of the reticular activating system, corydaline was shown in one clinical study to decrease or relieve pain in 32 of 44 patients with dysrnen~rrhea.’~~

CONCLUSION

NonpharmacologicalControl of Pain 10. Cheng RS, Pomeranz B. Electroacupuncture analgesia could be mediated by at least two pain-relieving mechanisms: endorphin and non-endorphin systems. Life Sci 1979;25:1957-1962. 11. Baldwin R. Special delivery: the complete guide to informed birth. Millbrae, CA: Les Femmes, 1979. 12. Laukaran VH,van den Berg BJ. The relationship of maternal attitude of pregnancy outcomes and obstetric complications: a cohort study of unwanted pregnancy. Am J Obstet Gynecol1980;136374-379. 13. Hyodo M, Gega 0.Use of acupuncture anesthesia for normal delivery. Am J Chin Med 1977;5:63-69. 14. Davidson PO, McDougall CE. The generality of pain tolerance. J Psychosom Res 1969;13:83-89. 15. Eysenck S. Personality and pain assessment in childbirth of married and unmarried mothers. J Mental Sci 1961;107:417429. 16. Levine F, Tursky B, Nichols D. Tolerance for pain, extroversion and neuroticism: failure to replicate results. Percept Mot Skills 1966;23:847-850. 17. Morgan AH, Lezard F, Prytulak S, Hilgard ER. Augmenters, reducers, and their reaction to cold-pressor pain in waking and suggested hypnotic analgesia. J Pers Soc Psychol 1970;16:5-11. 18. Mumford JM, Newton AV, Ley P. Personality, pain perception and pain tolerance. Br J Psychol 1973;64:105-107. 19. Sweeney DR, Fine BJ. Pain reactivity and field dependence. Percept Mot Skills 1965;21:757-758. 20. Andrew J. Coping style, stress-relevant learning and recovery from surgery. Diss Abstr 1968;28:1182-1183. 21. Davidson PO, Bobey MJ. Repressor-sensitizer differences on repeated exposure to pain. Percept Mot Skills 1970;31:711-714. 22. Cohen F, Lazarus R. Active coping processes, coping dispositions, and recovery from surgery. Psychosom Med 1973;35:375-389. 23. Chapman CR. Lecture, University of Washington, October 1979. 24. Bowers K. The effects of UCS temporal uncertainty on heart rate and pain. Psychophysiology 1971;8:382-389. 25. Bandler RJ Jr, Madaras GR, Bem DJ. Self-observation as a source of pain perception. J Pers Soc Psychol 1968;9205-209. 26. Geer JH, Davison GC, Gatchel RI. Reduction of stress in humans through non-veridical perceived control of aversive stimulation. J Pers Soc Psychol 1970;16:731-738. 27.Pervin L. The need to predict and control under conditions of threat. J Pers Soc Psychol 1963;31:570-585. 28. Staub E, Tursky 8 , Schwartz GE. Self-control and predictability: their effects on reactions to aversive stimulation. J Pers Soc Psychol 1971;18:157-162. 29. Johnson JE. Effects of accurate expectations about sensations on the sensory and distress components of pain. J Pers Soc Psychol 1973;27261-275. 30.Neufeld RW, Davidson PO. The effects of vicarious and cognitive rehearsal on pain tolerance. J Psychosom Res 1971;15 329-335. 31. Staub E, Kellett DS.Increasing pain tolerance by information about aversive stimuli. J Pers Soc Psychol 1972;21:198-203. 32. Seligman M, Maier S, Solomon R. Unpredictable and uncontrollable aversive events. In Brush F, ed. Aversive conditioning and learning. New York: Academic Press, 1969. 33. Kanfer FH, Seidner ML. Self-control: factors enhancing and tolerance of noxious stimulation. J Pers Soc Psychol 1973;25: 381-389. 34. Langer E, Janis I, Wolfer J. Effects of cognitive device and preparatory information on psychological stress in surgical patients. Unpublished manuscript, 1973. 35. Croog SH, Baume RM, Nalbandian J. Pain response after psychological preparation for repeated periodontal surgery. J Am Dent ASSW1994;1251353-1360. 36. Holmes DS,Houston BK. Effectiveness of situation redefinition and affective isolation in coping with stress. J Pers SOCPsychol 1974;29:212-218.

37. Newton-John TR, Spence SH, Schotte D. Cognitive-behavioural therapy versus EMG biofeedback in the treatment of chronic low back pain. Ekhav Res Ther 1995;33691-697. 38. Vlaeyen JW, Haazen IW, Schuerman JA, et al. Behavioural rehabilitation of chronic low back pain: comparison of an operant treatment, an operant-cognitive treatment and an operant-respondent treatment. Br J Clin Psychol 1995;34:95-118. 39. Turner JA, Jensen MP. Efficacy of cognitive therapy for chronic low back pain. Pain 1993;52169-177. 40. van Dulmen AM, Fennis JF, Bleijenberg G. Cognitive-behavioral group therapy for irritable bowel syndrome, effects and long-term follow-up. Psychosom Med 1996;58:508-514. 41. Dworkin SF. Behavioral and educational modalities. Oral Surg Oral Med Pathol Oral Radio1 Endod 1997;83:128-133. 42. Gardea MA, Gatchel RJ, Mishra KD. Long-term efficacy of biobehavioral treatment of temporomandibular disorders. J Behav Med 2001;24341-359. 43. Arathuzik D. Effects of cognitive-behavioral strategies on pain in cancer patients. Cancer Nurs 1994;17207-214. 44.Osterhaus So, Passchier J, van der Helm-Hylkema H, et al. Effects of behavioral psychophysiological treatment on school children with migraine in a nonclinical setting: predictors and process variables. J Pediatr Psychol 1993;18:697-715. 45. Basler HD. Group treatment for pain and discomfort. Patient Educ COLUW 1993;20167-175. 46. Sinclair VG, Wallston KA. Predictors of improvement in a cognitive-behavioral intervention for women with rheumatoid arthritis. AM Behav Med 2001;23:291-297. 47. Astin JA, Beckner W, Soekin K, et al. Psychological interventions for rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheum 2002,47291-302. 48. Williams DA, Cary MA, Groner KH, et al. Improving physical functional status in patients with fibromyalgia: a brief cognitive behavioral intervention. J Rheumatol2002;29:1280-1286. 49. Lee BH, Scharff L, Sethna NF, et al. Physical therapy and cognitivebehavioral treatment for complex regional pain syndromes. J Pediatr 2002;141:135-140. 50. Stevens RJ, Heide F. Analgesic characteristics of prepared childbirth techniques:attention focusing and systematic relaxation. J Psychosom Res 1977;21:429-438. 51. Dahlquist LM, Busby SM, Slifer KJ, et al. Distraction for children of different ages who undergo repeated needle sticks. J Pediatr Oncol NUIS 2002;19:22-34. 52. Haythronthwaite JA, Lawrence JW, Fauerbach JA. Brief cognitive interventions for bum pain. Ann Behav Med 2001;23:42-49. 53. Kanfer FH, Goldfoot DA. Self-control and tolerance of noxious stimulation. Psychol Rep 1966;18:79-85. 54. Evans MB, Paul GL. Effects of hypnotically suggested analgesia on physiological and subjective responses to cold stress. J Consult Clin Psycho1 1970;35:362-371. 55. Anand BK, Chhina ES, Singh B. Some aspects of electroencephalographic studies in yogis. EEG Clin Neurophysiol 1961; 13~452-456. 56. Pelletier K, Peper E. The chutzpah factor in altered states of consciousness. J Humanis Psych 1977;1763-73. 57. Benson H. The relaxation response. New York: Avon, 1976. 58. Chaves JF. Recent advances in the application of hypnosis to pain management. Am J Clin Hypn 1994;37117-129. 59. Kroger WS. Clinical and experimental hypnosis in medicine, dentistry, and psychology. Philadelphia: Lippincott, 1963:197-198. 60. De Pascalis V, Magurano MR, Bellusci A, Chen AC. Somatosensory event-related potential and autonomic activity to varying pain reduction cognitive strategies in hypnosis. Clin Neurophysiol 2001;112:1475-1485. 61. Dunn PM. Obstetric delivery today: for better or for worse? Lancet 1976;1:790-793.

Therapeutic Modalities 62.Flynn A, Kelly J. Continuous fetal monitoring in the ambulant patient in labour. Br Med J 1976;2:842-843. 63. Liu YC. Effects of an upright position during labor. Am J Nurs 1974j742202-2205. 64.Augustinsson LE, Bohlin P, Bundsen P, et al. Pain relief during delivery by transcutaneous electrical nerve stimulation. Pain 1977;459-65. 65.Shealy CN, Maurer D. Transcutaneous nerve stimulation for control of pain: a preliminary technical note. Surg Neurol 1974;2:45-57. 66. Yuan CS, Attele AS, Dey L, et al. Transcutaneous electrical acupoint stimulation potentiates analgesic effect of morphine. J Clin Pharmacol2002;42:899-903. 67. Naeser MA, Hahn KA, Liebennan BE, Branco KF. Carpal tunnel syndrome pain treated with low-level laser and microamperes transcutaneous electric nerve stimulation: a controlled study. Arch Phys Med Rehabil2002;83:978-988. 68.Chesterton LS, Barlas P, Foster NE, et al. Sensory stimulation (TENS): effect of parameter manipulation on mechanical pain thresholds in healthy human subjects. Pain 2002;99:253-262. 69. Bonica JJ. Fundamental considerations. Vol I, Principles and practice of obstetric analgesia and anesthesia. Philadelphia: FA Davis, 1967. 70. Bonica JJ. The nature of pain in parturition. Clin Obstet Gynecol 1975;2499-516. 71. Andersson SA, Block E, Holmgren E. Lagfrekvent transkutan elektrisk stimulering for smartlindring vid forlassning, Lakartidningen 1976;73:2421-2423. 72. Stewart P.Transcutaneous nerve stimulation as a method of analgesia in labour. Anaesthesia 1979;34:361-364. 73. Kubista E, Kucera H, Riss P. The effect of transcutaneous nerve stimulation on labor pain. Geburtshilfe Frauenheilkd 1978%: 1079-1084. 74.Bundsen P, Carlsson CA, Forssman L, Tyreman NO. Pain relief during delivery by transcutaneous electrical nerve stimulation. Prakt Anaesth 1978;13:20-28. 75.Neumark J, Pauser G, Scherzer W. Pain relief in childbirth: an analysis of the analgesic effects of transcutaneous nerve stimulation (TNS),pethidine and placebos. Prakt Anaesth 1978;13:13-20. 76. Kemp T. The use of transcutaneous electrical nerve stimulation on acupuncture points in labour. Midwives 1996;109:318-320. 77.Robson JE. Transcutaneous nerve stimulation for pain relief in labour. Anaesthesia 1979;34:357-360. 78. Lewith GT, Machin D. On the evaluation of the clinical effects of acupuncture. Pain 1983;16111-127. 79. Reichmanis M, Becker RO. Relief of experimentally-induced pain by stimulation at acupuncture loci: a review. Comp Med East West 1977;5:281-288. 80. Stux G, Pomeranz B. Basics of acupuncture. New York: SpringerVerlag, 1988. 81. Chapman CR, Colpitts YM, Benedetti C, et al. Evoked potential assessment of acupunctural analgesia: attempted reversal with naloxone. Pain 1980;9:183-197. 82.Kumar A, Tandon OP, Bhattarcharya A, et al. Somatosensory evoked potential changes following electreacupuncture therapy in chronic pain patients. Anaesthesia 1995;50:411-414. 83. X u X, Shibasaki H, Shindo K. Effects of acupuncture on somatosensory evoked potentials: a review. J Clin Neurophysiol 1993;10370377. 84. Fink M, Wolkenstein E, Luennemann M, et al. Chronic epicondylitis: effects of real and sham acupuncture treatment: a randomized controlled patient- and examiner-blinded long-term trial. Forsch Komplementarmed Klass Naturheilkd 2002;9:210-215. 85. Imich D, Behrens N, Gleditsch JM, et al. Immediate effects of dry needling and acupuncture at distant points in chronic neck pain: results of a randomized, double-blind, sham-controlled crossover trial. Pain 2002;99:83-89.

86.Tsui P, h u n g MC. Comparison of the effectiveness between manual acupuncture and electreacupuncture on patients with tennis elbow. Acupunct Electrother Res 2002;27107-117. 87. Targino RA, Imamura M, Kaziyama HH, et al. Pain treatment with acupuncture for patients with fibromyalgia. Cum Pain Headache Rep 2002;6379-383. 88. Sim CK, Xu I T , Pua HL, et al. Effects of electroacupuncture on intraoperative and postoperative analgesic requirement. Acupunct Med 2002;20:56-65. 89. It0 T. Painless labor with acupuncture anesthesia. Japan J Anesth 1974;2310-16. 90. Wallis L, Shnider SM, Palahniuk RJ, Spivey HT. An evaluation of acupuncture analgesia in obstetrics. Anesthesiology 1974;41:596-601. 91. Abouleish E, Depp R. Acupuncture in obstetrics. Anesth Analg 1975;54:82-88. 92. Ramnero A, Hanson U, Kihlgren M. Acupuncture treatment during labour: a randomized, controlled trial. Br J Obstet Gynecol 2002;109:637-644. 93. Wu GC, Zhu J, Cao X. Involvement of opioid peptides of the preoptic area during electroacupuncture analgesia. Acupunct Electrother Res 1995;201-6. 94. Zhu L, Li C, Ji C, Li W. The role of OLS in peripheral acupuncture analgesia in arthritic rats. Zhen Ci Yan Jiu [Acupunct Res] 1993;18214-218. 95. Zhou L, Jiang JW, Wu GC, Cao XD. Changes of endogenous opioid peptides content in RFGL during acupuncture analgesia. Sheng Li Xue Bao 1993;45:36-43. 96. Carlsson C. Acupuncture mechanisms for clinically relevant longterm effects: reconsideration and a hypothesis. Acupunct Med 2002;2082-99. 97. Tsuei JJ, Lai Y, Sharma SD. The influence of acupuncture stimulation during pregnancy. Obstet Gynecol1977;50479-448. 98. Motoyama H. How to measure and diagnose the functions of meridians and corresponding internal organs. Tokyo: Institute for Religious Psychology, 1976. 99. Nakatani Y. A guide for application of Ryodoraku autonomous nerve regulatory therapy. Tokyo: Japanese Society of Ryodoraku Autonomic Nervous System, 1972. 100.Hyodo M. New management of pain. Tokyo: Chiyugai Igakushiya, 1970. 101. Wu MT, Sheen JM, Chuang KH, et al. Neuronal specificity of acupuncture response: a fMRI study with electroacupuncture. Neuroimage 2002;161028-1037. 102. Furlan AD, Brosseau L, Imamura M, Irvin E. Massage for low back pain: a systematic review within the framework of the Cochrane Collaboration Back Review Group. Spine 2002271896-1910. 103. Earles J, Folen RA, James LC. Biofeedback using telemedicine: clinical applications and case illustrations. Behav Med 2001;27 77-82. 104. Seltzer S, Dewart D, Pollack RL, Jackson E. The effect of dietary tryptophan on chronic maxillofacial pain and experimental pain tolerance. J Psychiatr Res 1982-83;17181-186. 105. Bensky D, Gamble A. Chinese herbal medicine materia medica. Seattle: Eastland Press, 1986:389. 106. Elkayam 0, Ben Itzhak S, et al. Multidisciplinary approach to chronic back pain: prognostic elements of the outcome. Clin Exp Rheumatol1996;14281-288. 107. Myers CD, White BA, Heft MW. A review of complementary and alternative medicine use for treating chronic facial pain. J Am Dental Assoc 2002;133:1189-1196. 108. Golden BA. A multidisciplinary approach to nonpharmacologic pain management. J Am Osteopath Assoc 2002;102:Sl-S5. 109. Rusy LM, Weisman SJ. Complementary therapies for acute pediatric pain management. Pediatr Clin North Am 2000;47589-599.

Nontransfusion Significance of ABO and ABO -Associated Polymorphisms Peter J. D’Adamo, ND CHAPTER CONTENTS Introduction

441

Background 441 ABH Antigens 441 ABH Secretors and Nonsecretors 442 Blood Group as Self-Declaration and Adhesion Molecules 443 Blood Group Antibodies 444 ABO and Secretor Blood Group Genetics 445 Additional Physiologic Correlations 446 Major Diseases and ABO 447 Cardiovascular Disease 447

INTRODUCTION Concepts without percepts are empty; percepts without concepts -1mmanuel Kant (1724-1804) are blind. Since Landsteiner first described the ABO typing system in 1900, the preeminent clinical role of thisred cell antigenserum antibody system has been the prediction of reactions involving transfused blood and, to a lesser degree, transplanted organs. Despite this exceedingly important role, however, no rational individual should conclude that the proper exchange of blood or other tissues constitutes their primary biologic role. It can be argued that the overwhelming and revolutionizing influence of the ABO system on the history and practice of transfusion medicine and the general reluctance of allopathic medicine to find a workable niche for the nonreducible have had the effect of precluding interest in the nontransfusion sigruficance of ABO polymorphism and, attendant to that, of a lack of any meaningful medical applications. This chapter examines the biologic sigruficance of the ABO blood grouping and the ABH secretor system, with special attention to the effects of ABO expression as a “tipping point” for a variety of physiologic and

Cancer 448 Infection 450

Blood Groups and Dietary Lectins 451 Historical Perspective 451 Actions 453 Role of ABO Blood Groups 455 Clinical Applications of ABO Polymorphism 455 The Blood Type Diet 455 Materia Medica 456 Conclusion 456

pathologic manifestations that may be of interest to the practitioner of natural medicine.

BACKGROUND Although a comprehensive review of the glycobiology of the ABO system is beyond the scope of this work, the brief overview given here should allow the reader to understand the basic mechanics and nomenclature of the system. All humans can be typed for ABO blood group. There are four basic blood types: A, B, AB, and 0.The system is composed of two antigens and two antibodies. The specific combination of these four components determines that individual‘s type. Table 43-1 shows the possible permutations of antigens and antibodies with the corresponding ABO types.

ABH Antigens The ABO blood group antigens are not primary gene products but instead the enzymatic reaction products catalyzed by the enzymes called glycosyltransferases. As depicted in Figure 43-1, they are synthesized from an oligosaccharide intermediate, H substance, which is

441

Possible combinations of antibodies and antigens in the ABO blood grouping system ABO blood tvDe

A antiaen

B antigen

Anti-A antibody

Anti-B antibody

A

Yes

No

No

Yes (IgM)

B

No

Yes

Yes (IgM)

No

0 AB

No

No

Yes (IgM. IgG)

Yes (IgM, IgG)

Yes

Yes

No

No

/g, Immunoglobulin.

produced by the presence of the monosaccharide fucose. Group A or B activity is produced by the addition of a single sugar on the nonreducing end of the H chain. Adding the glycoprotein N-acetyl galactosamine to the end of the chain results in blood group A antigenicity; with blood group B, the terminal carbohydrate and B group antigen is the monosaccharide galactose. There is no true 0 antigen: However, group 0 cells still contain H antigen, so the terminal carbohydrate of 0 (H) antigen is the monosaccharide fucose. Therefore, we identdy the blood types as "ABO but typically refer to the actual antigen system as "ABH." ABH substances manifest quite early in the life process,' appearing in the cell membranes and secretions of human embryos at about 5 weeks' gestational age. The membrane substances are found first in the epithelium and virtually all vascular endothelium.

In endothelial cells the expression of ABH antigen is ubiquitously upregulated in fetal organs and is considered suggestive evidence that blood group antigens serve as early immunomorphologic markers of the endothelial differentiation of mesenchymal cells, specifymg the location of future blood vessels.2 All embryonic epithelia contain the ABH antigen except those of the nervous system, adrenal glands, and liver. The antigens subsequently disappear from epithelia in an orderly and predictable manner as evidence of morphologic differentiation appears, and by about the end of the third intrauterine month, the adult pattern of distribution is achieved. The embryonic expression of ABH antigens may be an important aspect in the pathogenesis of certain diseases: A scrutiny of 2557 medical records for children with type 1 diabetes and controls showed ABO blood group incompatibility in close to 90% of children with diabetes: indicating that maternal-fetal ABO incompatibility may have acted to inhibit normal pancreatic islet formation in the fetus. The expression of ABH antigens in the adult is tightly regulated, and their reappearance in adult tissue normally devoid of them is virtually always a sign of disease. Inappropriate ABH expression is one of the prime manifestations of the aberrant glycosylation state that is a hallmark of malignancy. Instances have been observed indicating that aberrant ABH expression may be paralleled in entirely different organ systems: A link has been demonstrated between ABH antigen expression in normal and neoplastic colonic epithelia and consequent alterations of ABH expression in the thyroid?

ABH Secretors and Nonsecretors

Figure 43-1 Structures of the nonreducing end of the ABH and Lewis blood group antigen determinants.

By 1930 it had been shown that some people do and others do not secrete into their saliva antigens corresponding to their ABO blood group. Persons with these substances in saliva (secretors) have more ABH substances in their tissues than those lacking the substance in their saliva (nonsecretors). The ability to secrete behaved as a simple Mendelian function dominant to nonsecretion. Persons with blood groups A, B, and AB who are secretors secrete the antigens corresponding to

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms

their blood groups. Group H persons secrete the H substance, as do all other secretors to a somewhat less extent. ABH secretor status is a major conditioner of the gut mucosa and ecosystem. ABH secretors have greater quantities of free ABH antigens in the makeup of their intestinal secretions, which has sigruficant effects on bacterial and lectin adherence to the gut microvilli. ABH substances are secreted by mucous glands in many organs, including the upper respiratory tract, the gastrointestinal tract from the esophagus through the colon, and the uterine cervix. The secretor gene regulates the synthesis of blood group substances in superficial glands of the gastric and small intestine mucosa. Large amounts of ABH material are found in all secretors.% In the gastric mucosa of healthy individuals the normal mucosa of secretors is characterized by a uniform distribution of blood type antigens in the pits. Healthy mucosa of nonsecretors shows little staining for these blood type antigens? Some ABH expression is independent of secretor status: Glands situated deep in the mucosa of the pylorus and small intestine (Brunner glands) and gastric parietal glands both produce A and B substances without regard to secretor status. ABO type and ABH secretor status together can exert significant effects on several digestive parameters. The most significant are presented here. For a more detailed discussion of the metabolic consequences of ABH secretor status, the reader should refer to my review article specifically on the subject.1°

Brush-Border Hydrolases ABO blood group determines much of the enzyme activity in the tissue (brush border) of the intestine. At least six intestinal hydrolases have ABO blood group antigenic determinants directly related to ABO blood group. Intestinal glycoproteins of blood group A and B individuals express A or B antigens, whereas blood group 0 subjects express the H determinant. The expression of these ABH antigens is under the control of the secretor gene, so these ABH antigens are not detected in the hydrolases of nonsecretor subjects.’l

Intestinal Alkaline Phosphatase Activity The intestinal component of alkaline phosphatase is involved with both the breakdown of dietary cholesterol and the absorption of calcium. The activity of intestinal alkaline phosphatase (IAP) and serum alkaline phosphatase is strongly correlated with ABH secretor phenotypes. Independent of ABO blood group, ABH nonsecretors have lower alkaline phosphatase activity than ABH secretors. It has been estimated that the serum alkaline phosphatase activity of nonsecretors is only about 20% of the activity in the secretor In addition to ABH secretor status, ABO polymorphism is linked to the levels and persistence of IAl?16

Numerous studies have associated group 0 individuals with the highest alkaline phosphatase activity, and group A with the 10west.l~In addition, one study has implied that the group A antigen itself may inactivate IAP.lX

Bacterial Flora The role of the ABO blood group in determining the bacteria making up a healthy gastrointestinal ecosystem is particularly strong in ABH secretors. Because ABH secretor status and ABO blood group dictate the presence and specificity of A, B, and H blood group antigens in human gut mucin glycoproteins, their status can influence the populations of bacteria capable of taking up local residence. This occurs because some of the bacteria in the digestive tract are actually capable of producing enzymes that allow them to degrade the terminal sugar of the ABH blood type antigens for a constant food supply.19 For example, bacteria capable of degrading blood group B antigen produce enzymes that allow them to detach the terminal alpha-D-galactose and use this sugar for food. Blood group A-degrading bacteria would have similar capabilities with respect to N-acetyl galactosamine (GaNAc). Because of this capability, the bacteria that use ABH antigens for food have a competitive advantage and can thrive in the environment created by the preconditioning of ABH secretions. Although comparatively small populations of bacteria produce blood group-degrading enzymes (estimated populations are 108 bacteria per g), the quantity of these bacteria are several orders of magnitude greater in different blood types, and they are much more stable residents. For example, B-degrading bacteria have a population density about 50,000-fold greater in blood group B secretors than in other subjects. Similar bacterial specificity and enzyme activity are found in other blood types.20

Immunity Evidence suggests that ABH nonsecretors have lower levels of immunoglobulin (Ig) G2Ipz and secretory IgA concentrations than s e ~ r e t o r s . ABH ~ ~ , ~nonsecretors ~ appear to have a higher prevalence of a variety of autoimmune diseases, including ankylosing spondylitis, reactive arthritis,psoriatic arthropathy, Sjogren syndrome, multiple sclerosis, and Grave d i s e a ~ e . ~ , ~ ~ - ~ ’

Blood Group as Self-Declaration and Adhesion Molecules In the larger world of glycoproteins, ABH antigens are characterized as 0-linked glycans (glycosylation at serine or threonine residues by GalNAc). All cells and many proteins in nature carry these dense and complex arrays of covalently attached sugar chains. Their biologic roles are particularly important in construction of

Therapeutic Modalities complex multicellular organs and organisms, a process that requires interactions of cells with one another and with the surrounding extracellular matrix. The glycans are typically on the outer surfaces of cellular and secreted macromolecules and are therefore in optimal positions to mediate interactions between organisms and a variety of cell-to-cell and cell-to-matrix interactions crucial to the development and function of a complex multicellular organism. Glycans can have a sigruficant effect on fungal, viral, and bacterial pathogenicity. H substance, a fucosylated glycan, can serve as a ligand in cell adhesion and is a receptor for several microorganisms, most notably Cundida albicans, which produces an adhesin with high H specificity.28 ABH antigens are ubiquitous in nature, found abundantly in foodstuffs (where they are thought to play a role in the induction of opposing blood group antibodies early in life) and in a host of microorganisms. A 1995 study showed that of 833 fungi harvested from 1977 to 1994,422 extracts (47.8%)produced agglutination of human red blood cells (RBCs), equally distributed against type 0, A, and B cells. Obviously, these fungi are not producing agglutinins with the direct intent of clumping human red cells but, rather, are desirous of attaching and infecting seeds or other microbes that possess some "ABO blood type" activity of their ABH antigens appear in secretions by 8 to 9 weeks of age, first in the salivary glands and stomach, then throughout the gastrointestinal and vaginal tracts. The ABH variation of blood group antigen expression on vaginal epithelial cells and mucus has a sigruficant role in susceptibility to urinary tract infections in women.30

Blood Group Antibodies The antibodies in the ABO system (isoagglutinins) are naturally occurring in the sense that they are non-RBCstimulated. Anti-A and anti-B are not normally present at birth because with their underdeveloped immune system and lack of provocation, newborns cannot synthesize immunoglobulins. The antibodies develop between 3 and 6 months of age as a result of unknown antigenic stimuli, presumably bacteria and foodstuffs. In a type 0 child, for example, antibodies begin forming to type A and B RBC antigens as soon as the child starts eating food, because the A and B antigens are actually found in quite a number of plants. So,as soon as the child starts eating plant food, he or she will be exposed to those antigens and start making antibodies against them. Isoagglutinins are typically IgM class antibodies, although group 0 individuals can and do produce IgG class anti-A and anti-B in addition to an IgG antibody to both A and B epitopes (anti-AB).

It has been shown that levels of the anti-blood type isoagglutinins are rising: A French study showed that they are about 50%higher in children in 1979 than was found in 1929.31The researcher suggested that the increased immune reactivity of children observed currently may be due to the greater use of prophylactic vaccinations, although dietary changes may have also played a role. GrundbacheP2 found that isoagglutinins were typically higher in black than in white persons, white persons having higher anti-A than anti-B levels, with the levels being higher in females than in males. In black persons the anti-B levels were almost as high as the levels of anti-A, and little sex difference was found. In another study, one fifth of sera from young, black, group 0 Zimbabwean blood donors were strongly hemolytic for either A or B cells or both.3 ABO blood type incompatibility may be a critical factor in infertility. ABO-incompatible mating couples (a type A male fertilizing a type 0 female) are a common Occurrence in miscarriages, especially very early in the gestational term. One study of 288 miscarriages showed that there was an excess of blood type A and type B in otherwise normal fetuses. The researchers concluded that the ABO incompatibility between mother and fetus is likely to be a cause of early miscarriages, but almost exclusively in chromosomally normal fetuses.%

Infertility In a study of 102 infertile couples, S ~ l i s hfound ~ ~ that 87%were blood type incompatible. The same study also found that in 7 couples with markedly delayed fertility, the 9 children who did result were all blood type 0, and hence would have been compatible with the mother. This researcher suggested that the infertility was due to the presence of antibodies in the secretions of the mother's genital tract or incompatible sperm from the father. In another study, a total of 589 compatible mating couples were compared with 432 incompatible mating couples. The mean number of living children presented a significant difference. There was a 21% deficiency of type A children in the two groups. Similarly, there was a 16% deficiency of type B children in the two groups. It appears that a 31.9%rate of miscarriage is associated with incompatible matings, compared with 17.15% in compatible matings. This finding has led some researchers to theorize that ABO incompatibility results in "cervical hostility" between the man's blood type antigens, which are present in his sperm, and the woman's opposing antibodies, present in her cervical mucus.36

Other Immune Correlates In 1991, DAdamo and Z a m p i e r ~ nreported ~~ that individuals of group 0 blood reporting a previous urticaria

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms or anaphylaxis showed high residual titers of anti-A isoagglutinins. When a score value was assigned to each agglutination reaction to allow for characterization, individualswith these disorders showed remarkably high titration scores compared with controls of the same blood group. In several cases, the subjects’ scores were almost threefold higher. A mild increase was noted for group 0 subjects with severe eczema or asthma, but total scores in these subjects were only marginally greater than those of controls. However, a striking association was shown for group 0 women suffering from end0metriosis.3~

ABO and Secretor Blood Group Genetics ABO System Epstein and Ottenberg suggested that the ABO blood group system could be inherited in 1910.38The determination of ABO status is the result of two codominant alleles and one recessive allele found on chromosome 9q band 34. A and B blood groups are dominant over the 0 blood group, and the A and B group genes are themselves codominant. The ABH antigens are not primary gene products but, instead, the enzymatic reaction products catalyzed by the enzymes called glycosyltransferases. ABO genes consist of at least seven exons, and the coding sequence in the seven coding exons spans more than 18 kb of the genomic DNA. The single nucleotide deletion found in most (but not all) of the 0 alleles and responsible for the loss of the activity of the enzyme is located in exon 6.39

ABH Secretor System The secretor gene (FLIT2 at 19q13.3)codes for the activity of glycosyltransferases needed to assemble (“secrete”) free ABH antigen in places like saliva, semen, vaginal fluid, and goblet and mucous gland cells, resulting in their presence in these bodily fluids and cells. This is accomplished in concert with the gene for group 0, or H (FUTZ). Secretor status is determined by two alleles on FUT2, Se (dominant) and se (recessive),with approximately 80% of the population typing as secretors (SeSe or Sese).

Lewis Blood Groups and Their Association with the ABH Secretor System The ABH secretor system is a major determinant of the Lewis (Le) blood grouping system. This is due to the fact that, in addition to ABH, FUTZ and FUT2 provide the glycans necessary for conversion of Lewis antigens as well. Two broad categories of Lewis blood type exist. These are the “Lewis positive” (either Lea+b or Lea*) and “Lewis negative” (Lea*) phenotypes. Depending on race, between 1%and 8%of the population are Lewis negative. In Lewis-positive phenotypes, Lea is formed initially, and in the case of nonsecretors (lacking the Se gene, FUT2), Lea substance is adsorbed onto the red cell, and they type as Lea. In the case of secretors, the Se gene activates the H gene, which causes an additional sugar to be added to Lea, converting it to Leb(see Figure 43-1). Among Lewis-positiveindividuals, ABH secretors are always Lea* because they convert all their Lea antigen into Leb.Conversely, among Lewis-positive people, ABH nonsecretors are always Lea+b because they lack the FUT2-dependent glycosyltransferase to accomplish this conversion. Thus it is often possible (and quite handy) to use the Lewis groups to infer ABH secretor status, because Lewis typing is fairly quick to perform and easy to master compared with the salivary inhibition test traditionally used. However, using Lewis typing to infer ABH secretor status works only in those individuals who are Lewispositive (about 9 of every 10 patients). Lewis-negative individuals can either be secretors or nonsecretors. However the Lewis-negative patient carries important metabolic consequences of their own, worthy of much attention.’O Table 43-2 shows Lewis blood types and their relationship to ABH secretor/nonsecretor status. Sialylated forms of several Lewis variations (sialyl Lewis A, sialyl Lewis X) are oligosaccharide ligands now considered crucial to the initial adhesion of white blood cells to a site of injury mediated by E-selectins. Large quantities of sialyl Lewis X have also been found on the surfaces of certain tumor and cancer cells and one of its variants (sialyl fj-sulfo Lewis X) appears to be involved in routine homing processes involving a variety of chemokines.

Lewis blood types and their relationship to ABH secretorhonsecretor status Lewis type

Category

ABH secretor status

Leave Lewis a antigen but not Lewis b

Lewis positive

ABH nonsecretor

Lea. Lewis b antigen but not Lewis a

Lewis positive

ABH secretor

Lea-b Neither Lewis a nor Lewis b

Lewis negative

Lewis outcome cannot determine ABH secretor status

Therapeutic Modalities Individuals of blood group 0 phenotype run an approximate 1.5- to 2-fold higher risk for development of acid peptic disease,40although there is no direct correlation between ABO blood group phenotypes and the prevalence of Helicobucter pylori infection. However in addition to H type 1, the Lebantigen is also a binding receptor for H. pyZori, and in this capacity it can best be described as a ”virulence promoting factor.” For virulent strains, Lebantigen binding activity targets the microbes to the epithelial cell surfaces and potentiates the effect of secretion of virulence factors such as the vacuolating cytotoxin and/or neutrophil activating/recruiting factors.41

Linkage When genes occur on the same chromosome, they are inherited as a single unit. Genes inherited in this way are said to be linked. Gene linkage analysis has demonstrated several associations between the ABO locus and several coadjacent genes. For example, there are strong indications that a gene regulating dopamine beta hydroxylase (DBH) activity is linked to the ABO blood group locus.42DBH is a key enzyme in the conversion of dopamine to norepinephrine. This linkage may help explain the continued sigruficance of ABO group as a discreet and sigruficant genetic marker for a variety of affective disorders, including type A behavior in men subsequent to myocardial infarct i ~ and n ~bipolar ~ d e p r e s s i ~ n ,each ~ . ~ of ~ which is associated with blood group 0.The ABO locus shows putative linkage with platelet monoamine oxidase activity,& reduced levels of which have been noted in group 0 healthy men?7 Additional evidence implies that there is a linkage between the ABO gene and the gene that regulates the activity of the enzyme argininosuccinate synthetase, which recycles arginine from citrulline in the production of nitric oxide.&A letter to the editor in the journal Lancet reported differences between ABO groups in their responsiveness to inhaled nitric oxide (NO) therapy, types with a B antigen (B and AB) having less success with this thera~y.4~ Elevated factor VIII (FVIII) levels contribute to venous thrombotic risk. FVIII levels are determined to a large extent by levels of von Willebrand factor (VWF), its carrier protein that protects FWII against proteolysis.m ABO polymorphism is one of the best-characterized genetic modifiers of plasma FVIII; it accounts for approximately 30% of the total genetic effe~t.~’ Subjects with blood group non-0 have higher VWF and FVIII levels than individuals with blood group 0.52

Additional Physiologic Correlations In addition to the previously described variations in IAP and brush border hydrolase activity, several additional circumstances where ABO polymorphism exerts a significant influence on physiology have been reported.

Gastric Acidity Because the prevalence of both pernicious anemia and gastric cancer is higher in individuals of blood group A and that of duodenal ulcer higher in those of group 0, a hypothesis relating blood group effects on acid secretion was i n e ~ i t a b l e Early . ~ ~ work confirmed that acid output tended to be greater in group 0 than in group A subje~ts.~,~~

Gastrin and Pepsinogen In one study, serum pepsinogen A (pepsinogen I) levels were studied in relation to ABO blood group, age, and sex in 700 healthy blood donors. Serum pepsinogen A levels were higher in males than in females and rose with increasing age. Blood group 0 individuals showed higher serum pepsinogen A levels than blood group A individuals.” There is also evidence that the type A antigen in gastric juice binds to pepsin and possibly inactivates it.57A recent study using serum pepsinogen levels as a marker for gastric atrophy showed a high association with blood groups A and B.58 However, possibly owing to the polygenic nature of pepsinogen activity, one study failed to find any sigruficant difference in pepsinogen levels between ABO gr0ups.5~ Another study looking at ABO polymorphism and serum gastrin concentration after stimulation by a glycine drink could find no correlation with ABO blood group.@’ However the study had a simple preprandial and postprandial methodology. In a separate study, the concentrations of gastrin were measured in the blood of 121 fasting healthy Greek volunteers of both sexes and of different ABO blood types, aged between 20 and 70 years. The testing took place after a test meal while the subjects were fasting, and again at 10 minutes and 40 minutes. The researchers found that gastrin levels took 40 minutes to increase after the meal in the blood types A and B subjects but that a sipficant increase had appeared already 10 minutes after the meal in the blood type 0 subjects.61

Cholesterol Although several studies on highly select populations have yielded conflicting results,62,63the general consensus is that blood group A individuals have a significantly higher basal cholesterol level than those in other blood groups. The relationship between ABO blood phenotype and total serum cholesterol level was examined in a Japanese population to determine whether elevated cholesterol values are associated with blood type A. Their results showed that cholesterol levels were very significantly elevated in the blood type A group compared with the non-A group (p < 0.00001).64 In a nationwide sample of more than 6000 black and white adolescents aged 12 to 17 years, ABO blood group and coronary risk factor levels were measured. Blood group A was associated with significantly higher serum

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms total cholesterol levels in white females independent of all other risk factors, in white males independent of age and weight, and in southern black females independent of age and weight.65 A separate study (the Bogalusa Heart Study) looked at 656 white and 371 black adolescents and found the same results with regard to cholesterol (A higher than others) and also showed higher levels of LDLcholesterol in type A adolescents than in the other blood types.% Whether the association between group A and elevated cholesterol values is through linkage or environmental factors, such as diet, remains to be determined. The aforementioned ABO variations in IAP levels have been posited as a potential causative factor.

Stress In addition to the previously mentioned associations between ABO group and affective disorders, several studies have identified difference between ABO group and possible chemical responses to stress. Interestingly, individuals of blood group A appear to have a lower incidence of ”type A per~onality.”~~ A study that evaluated the influence of blood type (A versus 0) coupled with a mirror drawing stressor on very-low-densitylipoprotein (VLDL) toxicity-preventing activity (TxPA) and plasma cortisol levels showed significant ABO variation. Exposure to the stressor significantly decreased TxPA and increased cortisol for the total group of 25 older men. However, the stress response patterns of the 15 blood type A men were different from those of the 10 type 0 subjects. The blood type A group had higher initial levels of TxPA and cortisol as well as quicker stress recovery rates than the type 0 g r o ~ p . ~ Using the act of venipuncture as an inherently stressful event, researchers then proceeded to measure the cortisol and catecholamine response to venisection by humans with different blood groups. Blood group A individuals responded to the stressful situation with higher levels of cortisol and, possibly, of adrenah1e.6~

Rheology Rheology is the science of deformation and flow. One common factor of solids, liquids, and all materials whose behavior is intermediate between solids and liquid is that if a stress or load is applied on any of them, they will deform or strain. For purposes of this discussion, rheology is used to describe the dynamics between blood clotting (moving toward a solid state) and blood thinning (moving toward a liquid state). It might be tempting to substitute the word viscosity for rheology when talking about blood types and clotting. Viscosity, however, does not cover the ”dynamics” of how, when, and why blood can change texture; it only distinguishes one texture state from another.

There is evidence that the rheology of blood may play a role in a variety of chronic anxiety states. When compared to normal subjects, chronic depressive and schizoid patients had very significant differences in their blood rheology and in the ability of their RBCs to aggregate. When patients having schizoid anxiety were compared to those having depressive anxiety, their ratio of albumin to globulin was increased. When patients were divided according to their ABO blood groups, significant differences were found in their albumin/fibrinogen ratio and their blood viscosity. This was particularly true for women who had blood type A and who suffered from depressive anxiety: their blood tended to be substantially ”thicker” and to have higher amounts of serum proteins in it than women with similar depression who had blood type 0.70 Associations between the ABO phenotype and variations in blood rheology have been also reported in high blood pressure?* stress,” diabetes,” heart attack, cancer and thyroid kidney and malignant melanoma.76

Soluble Endothelial Cell Markers Selectins are cell-cell adhesion molecules that are involved in leukocyte+ndothelial cell adhesive interaction, which is required for extravasation at target tissue sites. Three types of selectins have been discovered so far: L-selectins are generally expressed on almost all leukocytes; E-selectins are inducible on vascular endothelium upon stimulation with cytokines; and P-selectins were originally found on activated platelets. Less known is the role of thrombomodulin as a c-type lectin with a domain that interferes with neutrophil adhesion to endothelial cells. Elevated levels of E-selectin (p < 0.001) and thrombomodulin (p < 0.001) are linked with blood type A individuals.n

MAJOR DISEASES AND ABO Cardiovascular Disease Stroke A European study comparing 50 patients with stroke and the standard expected frequency of ABO blood types in the surrounding population showed that the frequency of the blood group A in the patients with stroke was 120% greater than would normally be expected. The percentage of blood type B was even higher (159% of expected rate of occurrence).Patients with blood type 0 were only 85% as likely to experience stroke as those with blood type 0 in the surrounding p ~ p u l a t i o n . ~ ~ A 1979 study of 220 patients with stroke looked at the viscosity of their blood a few hours after the stroke event. About 80% of the patients had blood cells that easily aggregated. What was especially interesting was the discovery by the researchers that the clotting of blood in patients with A and B blood types was due to

Therapeutic Modalities

fibrinogen, whereas in blood types 0 and AB it was caused by other clotting factors.79 Individuals with blood types A and AB have a generalized tendency toward problems associated with blood clotting, whereas problems in those with blood types B and 0 appear to be linked to excessive bleeding and poor clotting. This observation was verified in several studies, the largest being performed in 1460 patients with “stroke” and reported in the journal Lancet. In 329 cases, the cause of death was certified as cerebral thrombosis (brain clot). In the thrombosis cases there was an excess of patients of blood types A and AB and a deficiency of those with blood types 0 and B. In the 482 ”strokes” that were due to cranial bleeding, the reverse was true: There was a significantly higher proportion of patients with blood types 0 and B than of those with blood types A and AB.so

Peripheral Artery Disease and Venous Thromboembolism It is estimated that peripheral artery disease (PAD) occurs in approximately 12%of the adult population, or approximately 22 million Americans. The prevalence of PAD rises with advancing age such that almost 20% of people older than 70 years have the disease. E-selectin and thrombomodulin levels are always elevated in intermittent claudication, a disorder almost always found with PAD and carrying a distinct association with blood type A.81 The ABO blood groups were determined in 125 patients suffering from venous thrombosis in a Brazilian population. A higher than expected proportion of blood group A and a lower than expected proportion of blood group 0 were observed among the patients.s2This is consistent with the previously discussed influence of ABO on a third soluble endothelial product, VWF, and its role in thromboembolism.

Heart Disease There is a clear-cut association with having A and AB phenotypes and an increased risk for heart disease. This association has been reported continuously in the scientific literature over the last 50 years. Individuals who have blood type A have higher rates of heart attack in all age groups, both genders, and all ethnic and national groups. In 1962, the Framingham Heart Study typed the blood of the surviving 4125 members of the original study group of 5209 people first examined in 1948 to 1951. The most striking observance was the lower rates of nonfatal heart disease in men aged 39 to 72 years with blood type 0 than in those with blood type A.mA 1994 Polish study on patients undergoing coronary bypass surgery who had highly advanced arteriosclerosis of the coronary arteries found a sigruficantly higher number of cases with group AB and a lower number of those with group O.@A 1981

German study of 13,175 patients showed a prevalence of blood type A in all types of heart disease examined.85 In a study of 191 coronary artery bypass candidates, investigators paradoxically found an excess of type 0 over type A subjects. After examining the data more closely, they concluded that the tendency of type A subjects for more ready development of blood clots (”thrombotic proneness”) led to a poorer prognosis. In essence, the blood type A subjects were missing from the study because they had already died in greater numbers, leaving a disproportionate number of type 0 subjects among the long-term survivors.86In a study of male survivors of heart disease, researchers found that there were fewer patients who were type A and younger than 55 years than would have been otherwise expe~ted.~’ A 1975 Italian study of 746 patients with high blood pressure, 3258 with congenital heart disease, and 4503 with a history of heart attack found a significant lack of patients with type 0 blood, and a significant excess of blood type A patients in the group with myocardial infarction. The study also showed an excess of blood type A patients with high blood pressure, and a lack of patients who were blood type B.8s A 1983 study of 255 women originally investigating the effects of smoking on the rates of heart attack in women also found several other factors significantly associated with heart attacks in this group, including hypertension, angina pectoris, family history, diabetes mellitus, and blood type A.89 Platt et alWexamined blood type and heart attacks in two different age groups. The patients were divided into two groups: 65 years or older and younger than 65 years. The predominance of blood type A in patients with cardiac infarction was “highly significant” in both age groups (p < 0.005). This study was unique in that it excluded other risk factors, such as smoking, high blood pressure, diabetes, and high cholesterol levels. When the researchers looked specifically at the older group, the predominance of blood group A in those with cardiac infarction was even higher ( p < 0.001). The researchers concluded, ”Our investigation strongly suggests the existence of a genetic factor associated with blood group A and independent of the other risk factors, which is also responsible for a greater incidence of cardiac infarction.”%An 8-year study of 7662 men found that blood type A is linked to the incidence of ischemic heart disease as well as higher total serum cholesterol concentrations?l

Cancer Cancer and Altered Glycosylation Some cancers contain an A-like substance men when they occur in persons who are not A or AB. These observations suggest that in the tissues, both normal and neoplastic, of all persons, there are blood group A-like antigens present at a biochemical level, which are usually inaccessible to the immune system. -AE Mourant (Blood Groups and Disease, 1977)

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms

Variation in blood group antigen (BGA) expression in normal and neoplastic tissues of BGAs

Expression of BGAs in malignancy

Colon’

Present

Absent

94

Bladder+

Present

Prostate

Absent Present

Absent

95 96

Liver’

Absent

Present

97

Squamous

Present

Absent

98

Endometrium5

Absent

Present

99 1 00

Normal expression Tissue. oraan

References

Stomach

Present

Absent

Thyroid”

Absent

Present

101

Esophagus

Present

Absent

102

‘Inversely correlated. tBGAs better than all other tumor markers. *BGAs effective at predicting hepatitis transformation to malignancy. §Vast majority of BGAs secreted are H antigen.

Tumor development is usually associated with changes in cell surface carbohydrates. The changes are often divided into those related to terminal carbohydrate structures, which include incomplete synthesis and modification of normally existing carbohydrates, and those in the carbohydrate core structure. Cell glycosylation depends on the expression and function of various glycosyltransferases and glycosidases. Numerous data demonstrate that malignant transformation is associated with various and complex alterations in the glycosylation process. These changes provide a selective advantage for tumor cells during their progression to more invasive and metastatic forms. The blood group-related carbohydrate structures Le(x), sialyl-Le(x), ABH, and Le(y) are examples of terminal carbohydrate structures that are related to tumor prognosis. These structures are of increasing interest because they may function as adhesion molecules or motility Deletion, reduction, or inappropriate expression of blood group A or B antigen in tumors of blood type A or B individuals is clearly correlated with the level of malignancy and metastatic p0tential.9~The most significant variations are summarized in Table 43-3. A and B blood group antigens are present on carcinoma cells at the early stages of carcinogenesis and tend to disappear at later stages. The blood group A antigen may render malignant cells resistant to apoptosis; in animal studies, the faster tumor growth of the A antigenpositive cells in immunocompetent animals was due to their higher ability to escape immune control, which was associated with their higher degree of resistance to apoptosis.lo3 Lewis blood groups can modulate the expression of several tumor-associated antigens, including DU-PAN9

and CA19-9, and some researchers have suggested that taking into account Lewis secretor status in order to establish reference ranges for the tumor antigen measurements might actually be a way to improve their clinical utility. This relationship is shown in Table 43-4.

Thomsen-Friedenreich Antigen Many malignant cells (such as those found in breast and stomach cancers) develop a tumor marker called the Friedenreich-Friedenreich(T) antigen (also called TFA). This antigen is encrypted in normal healthy cells, much like a rock is covered over by water at high tide. T antigen becomes “unsuppressed” only as a cell moves toward malignancy, much like the covered rock example is uncovered as the tide moves out. It has been estimated that T antigen (or its precursor, Tn antigen) is expressed and uncovered in about 90% of all cancers, earning it the appellation “pancarcinoma associated antigen.”lD4As a general rule, an orderly expression of T antigens on a cancer cell usually indicates

Correlation of CA19-9 and DU-PAN-9 expression in colorectal cancer with Lewis type Lewis phenotype

CA19-9 expression’

DU-PAN-9 expression

Le (a+b-)

Highest levels

Lower levels

Le (a-b-t)

High levels

Lower levels

Le (a-b-)

Zero to very low levels

Highest levels

‘Individuals having homozygous inactive Se alleles (sese) and homozygous active Le alleles (LeLe), exhibited the highest mean CA19-9 value. All of the Lewis-negative individuals (/e/e genotype) had complete absence of CA19-9, irrespective of the Se genotype.1°

a cancer with a relatively favorable outlook. However, a prevalence of Tn antigens (a less well-developed T antigen) on a cancer cell usually denotes a highly aggressive, metastatic cancer, irrespective of the organ involved and the form of cancer. It is so rare to find the Tn antigen in healthy tissue that most people produce antibodies (TFA agglutinins) to itprobably in response to cross-induction by the gut flora. ABO blood group appears to influence the amount and activity of these antibodies against T and Tn antigens. Although derived from the M blood type antigen, Tn antigen shows structural homology to the A antigen. Antibodies against Tn antigen cross-react with A glycolipids. Because Tn antigen and A glycolipids share terminal GalNAc, Tn antigen was concluded to be an A-like antigen in a broad sense. "A-like" is actually considered an antigenic entity, a substance not A and not Tn but capable of sharing antigenic sensibility with them.Io5 That blood group A patients with gastric cancer have the greatest and most uniform suppression of the level of TFA agglutinins, irmpective of age, cancer stage, or tumor morphology, and lower levels of anti-B isohemagglutinins'06 strongly supports the notion. The association of group A with gastric carcinoma is quite old, having first been demonstrated by Aird et allw in 1953. One hypothetical mechanism behind the association between blood group A and gastric carcinoma is that the carcinoma cells produce an antigen immunologically related to blood group A, which may have a protective effect, particularly in blood group 0 individuals, by prevention of the growth and spread of the tumor.'08 It appears that the progression of stomach cells to stomach cancer involves a necessary mutation at the ABO gene, the result of which is the production of A antigen, even if this is not the person's blood type. This "A-like" antigen may not be the true A antigen but rather, what one researcher has called "tumorassociated, A cross-reacting antigens occurring in a wide variety of human adenocarcinomasof hosts belonging to all ABO blood groups."'Og Breast cancer researchers have given this aberrant glycosylation moiety the moniker "ligand-like complex" (LLC), which by virtue of altered antigenicity both allows for metastatic egress from the regional lymph nodes and detachment from the extracellular matrix and thus is associated with cancers with poor prognosis.110I believe that LLC may well be the "A-like," pan-carcinoma crossreacting antigen, because of observations that the GalNac binding lectin from the Roman snail, Helix pomatia agglutinin (HPA), appears to identify this oligosaccharide"' and because of separate reports that "Springer's vaccine" (human group 0 RBC membrane-derived T/Tn antigen containing traces of phosphoglycolipid A hyperantigen) has had significant effect as an immune modulator in breast carcinoma of even advanced stage.'I2

Epidermal Growth Factor The epidermal growth factor receptor (EGF-R) bears an antigenic determinant that is closely related to the human blood group A carbohydrate structure. A higher number of high-affinity EGF binding sites was observed in donors with blood group A1 erythrocytes than in donors with blood groups 0 and B.'I3 That the blood group A antigen can also bind to EGFRs is now well documented. So it is not unlikely that free A antigen in individuals with blood groups A and AB (especially if they are secretors) can find their way onto these excess EGF-Rs and act to simulate cell growth. As with VWF and factor VIII, excessive activation of the EGF-R results in cancer cells that become more mobile and better able to develop new and additional blood supplies (angiogenesis).'I4 One reason that low stomach acid is linked to type A blood may have to do with the role of EGF discussed in the previous section on saliva. As described, the EGF-R has a high affinity for the type A antigen, and although the major action of EGF is to stimulate repair of the digestive lining, it has also been shown to decrease acid production in the stomach.

Infection The previous section appears to imply a selection disadvantage for group A individuals, and it has been argued that under present-day civilized living conditions, blood type 0 carriers have a preservation advantage over blood group A carries.l15 This may be the result of the deletion of the selection factor "infectious disease," which may nevertheless regain importance if environmental changes occur.116 To a great extent, infectious diseases, especially the worldwide epidemic diseases, have selective effects. This is demonstrated inter alia in the different "selection values" in the ABO blood group system. During the eons before antimicrobial intervention, selection variability via ABO polymorphism was the preeminent natural survival mechanism. Historically, some of the most catastrophic epidemic and endemic diseases are ABO selective and in many instances demonstrate ABO variation in morbidity, mortality, or microcharacteristics such as substrain preferentiality and level of inflammatory response. They include cholera (0),smallpox (A), malaria (A), and influenza (variable subsets depending on strain). The influence of ABO polymorphism on infectious disease appears to stem from a multitude of unique factors. These are encapsulated in Table 43-5. A morbidity and mortality variation among the ABO and secretor groups is presented in Table 43-6. A special examination of polymorphic differences in uropathic infectious disease is presented in Table 43-7.

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms

Mechanisms of ABO influence on infectious disease Class

Mechanism

Description

Example

Selectivity

Adhesion kinetics

Adhesin or lectin specificities of the infectious agent based on particular ABH glycosylation Inadequate production or activity of isoagglutinin Infectious agent is antigenically similar to host's ABO group

Candida albicans (group 0 )

Humoral dynamics Molecular mimicry Response variability

Neisseria gonorrhoeae (group B) Giardia lamblia (group A)

Host response

Variation in severity of disease through unique biologic response (examples: inappropriate inflammatory response, rosette formation)

Cholera (group 0) Dengue fever (group B) Malaria (group A)

Substrain susceptibility

Different ABO groups often show variations in susceptibilityto individual bacterial, fungal, or parasitic species or viral strains

Influenza (all groups) Malaria (group 0 versus group A)

For a more detailed examination of particular infectious scenarios, the reader is referred to my comprehensive survey."'

BLOOD GROUPS AND DIETARY LECTINS ABO polymorphism is one of the prime determinants of the glycosylation variability of gut mucin. As such, it affords insight into the actions of a class of carbohydrate-binding dietary proteins called lectins, which are increasingly the subject of interest for nutritional researchers.

Historical Perspective Stillmark at the University of Dorpat in Estonia first identified lectins in 1888. While investigating the toxic effects on blood of castor bean extract (Ricinus cornrnunis), he noticed that the RBCs were being agglutinated. He isolated the material responsible for the agglutination and called it ricin. In 1945, William Boyd of the Boston University School of Medicine discovered that lectins can be blood group specific, being able to agglutinate the RBCs of one type but not those of another. He discovered that h a bean lectin would agglutinate RBCs of human blood type A

Influence of ABO polymorphismon susceptibilityto various infectious agents Strain

Susceptible phenotype(s1

Amoebic dysentery

0,A

Blood type B and AB persons have a degree of resistance against development of severe or acute dysentery, especially the amoebic forms.

Candida carriage

0, nonsecretor

Candida carriage was associated with blood group 0 (p < 0.001) and, independently, with nonsecretion of blood group antigens (p < 0.01). Candida albicans extracellular polymeric material (EP)contains a mannoprotein adhesin with a lectin-like affinity for H (type 2) blood group antigen. There were a significantly higher number of nonsecretors (48.9%) among 174 patients with either oral or vaginal Candida infections than in the local population (26.6%). Nonsecretorsaliva actually seemed to enhance Candida attachment.

Cholera

0, AB

Blood type 0 individuals have a greater risk of infection with cholera and have the most severe and life-threateningforms of this illness, as documented in several studies. Patients with type 0 had more diarrhea-likestools per day than persons of other blood groups, were more likely to report vomiting and muscle cramps, and were almost eight times more likely to require hospital treatment. Type AB persons, on the other hand, appear to have the highest degree of protection from cholera infections.

Coccidioidomycosis

B

Blood type B individuals are more prone to disseminated disease after exposure.

Dengue fever

B

According to researchers, blood type B is strongly associated with the severe form of dengue fever known as dengue hemorrhagic fever.

Comments

Continued

Influence of ABO polymorphismon susceptibility to various infectious agent-ont'd Strain

Susceptible phenotype(s)

Dermatophytosis

A

The fungus Trichophyton rubrum, isolated from 54.5% of the patients tested, was more common in individuals in blood group A.

Escherichia coli

Variable subsets

Giadia

A

It appears that many forms of E. coli capable of causing diarrhea are immunologically "B-like."This results in a substantially higher number of cases of diarrhea among individuals of Mood types B and AB. However, when it comes to the overall severity of infection with E. coli, individuals with type B, AB and 0 also are most likely to have a severe form of diarrhea. Persons with blood group A are more susceptible to giardiasis, especially the asymptomatic form, whereas those with blood group B are less susceptible.

Helicobacter pylori

0, nonsecretor

Comments

H. pylorivariants produce a variety of blood group antigens, including A, Lewis (a), and a variety of type 1 H-like antigens (0). Blood group 0 would be a moderate risk factor for infection by H. pylori, with more severe cases in men. Persons with blood group 0 have a more pronounced inflammatory reaction to H. py/ori. Group 0 cells release significantly more interleukin-6and tumor necrosis factor in response to H. pylori infection. The Le (a*) nonsecretor phenotype and blood group 0 are relevant genetic markers of peptic ulcer. The Lewis (a*) nonsecretor phenotype and blood group A are also positively associated with esophageal adenocarcinoma. with concurrent H. pylori infection.

Hookworm

0

A 1972 Egyptian study correlated type 0 with higher incidence of hookworm and strongyloidiasis.

Influenza

Variable subsets

Blood group A individuals generate a quick and substantial antibody response against influenza type A(H1 N1) and especially A(H3N2). The antibody response against influenza B is not quite as dramatic. Blood group AB types have a relatively poor ability to generate high antibody levels against any of the influenza viruses. Blood group B persons show a reasonable, but not great ability to generate an antibody response against influenza A (H1N1) and the slowest (3-5 months) and weakest ability to generate antibodies against influenza A (H3N2 'Hong Kong") of any Mood type.Against influenza B virus, Mood group B has a significant advantage, respondingdifferently from blood groups A and 0; the blood type B immune response happens much earlier and persists longer. Blood group 0 shows a moderate ability to generate antibody response against influenza A(H1N1) and A(H3N2) viruses. Antibody response against influenza B is not as dramatic as that of blood type B.

Malaria

A, AB

Evidence suggests that blood types A and 0 individuals might have a higher predispositionto infection with the Plasmodium viva species and that blood type B individuals tend toward higher infection rates with Plasmodium falciparum. Malaria-infectedred blood cells sometimes bind to uninfected red blood cells (RBCs) to form dumps called rosettes. The rosettes can obstruct flow in small blood vessels, leading to tissue damage and severe malarial disease. The tendency for malaria to be worse among individuals with blood types A and AB is due primarily to a greater degree of rosette formation by RBCs with these antigens. von Willebrand factor, always elevated in type A, also enhances rosette formation.

Neisseria gononhoeae

B

The relation of infection with N. gonorhoeae to the blood groups A, B, AB, and 0 was examined in 584 women attending a prenatal clinic. The occurrence of gonorrhea was significantly higher in black patients with blood group B than in those with blood groups A, AB, or 0. Depending on the ABO blood group, gonorrhea may affect the titers of isohemagglutininscompared with those of uninfected controls. The isohemagglutinin titers in group 0 patients were significantly increased (p < 0.001) against erythrocytes A, B, and AB. In group A patients, only the titer against AB erythrocytes was significantly increased. In group B patients, the titer against AB erythrocytes was significantly lower (p < 0.001) than that in sera of healthy persons.

Norwalk virus (norovirus)

0

It appears that group 0 RBCs are most easily bound by noroviruses, whereas group B RBCs are apparently little bound at all. Individuals with an 0 phenotype are more likely to be infected with Norwalk virus. The preferred binding site is apparently the H type 2 antigen, which functions as the viral receptor on human type 0 RBCs.The Lewis B antigen (found in secretors) is also a binding site.

Nontransfusion Significance of ABO and ABO-Associated Polyrnorphisms Influence of ABO polymorphism on susceptibility to various infectious agents-ont’d Strain

Susceptible phenotype(s)

Schistosomiasis

A

Group A individuals tend to be more susceptible to infection, tend to have more intense symptoms after infection, and are much more likely to have damage to organs (such as the liver) after infection.

Shigellosis

B, AB

There is a strong association between blood type B (and AB to a slightly lesser degree) and shigellosis.

Smallpox

A

Group A persons have higher mortality from smallpox infection; also have more reactions to smallpox vaccination. The leukocytesof peripheral blood in group A individuals show a poorer binding capacity with respect to the smallpox vaccine virus. Blood group A also shows a high rate of chromosomal aberration after vaccination, resulting to some extent from increased proliferative ability of the cells.

Staphylococcus aureus

A

Persons with blood type A are much more likely to be chronic carriers of S.aureus, partly because they have a lower ability to mount an aggressive antibody (or immune) response against this organism.

Streptococcus (group B)

B

A blood type connection with neonatal group B streptococci infection exists for blood type B. Mothers with blood group B have double the risk for infection among their infants.

Strongyloidiasis

0

A 1972 Egyptian study correlated type 0 with higher incidence of hookworm and strongyloidiasis.

Tuberculosis

0

Group 0 blood has a much higher rate of infection with tuberculosis (particularly true in individuals of European descent). Tuberculosis runs a much more aggressive and detrimental course in patients with blood type 0, whereas those with type A are afforded the highest degree of protection. Typically, during the first 2 years of infection with bacillary tuberculosis, individuals with blood types 0 and AB have a significantly higher rate of infection.

Comments

but not those of 0 or B. The seeds of Lotus tetragonolobus can agglutinate group 0 specifically, and Bundeirueu sirnplicifoliu is specific to group 8.The specificity of lectins is so sharply defined that they can differentiate among blood subgroups. Dolichos bifZorens lectin reacts more vigorously with blood group Al than with A2. Influence of ABO polymorphism on susceptibility to various uropathic infectious agents Blood type

Uropathogenic strains

A

Staphylococcussaprophyticus

B

Klebsiella pneumoniae Proteus spp. Pseudomonas sp. K. pneumoniae Proteus spp. Pseudomonas spp. S.saprophyticus Uropathogenic Escherichia coli

AB

Nonsecretor

As a general rule: Blood type B is most plagued by chronic or recurrent urinary tract infections

(UTls). Type AB is next on the susceptibility list, followed by type A. Type 0 is the most protected. Nonsecretorsare much more prone to repeated and severe UTls.

The word lectin was proposed by William Boyd in 1954 to describe a class of blood type-specific agglutinins that had been found in certain plants. The word is allegorical to a degree, because it derives from a Latin word meaning ”to choose.”

Actions The surface epithelium of the gut is extensively glycosylated,l18 mainly because most membrane proteins, including hormone and growth factor receptors, transport proteins, and brush-border enzymes, are glycosylated before being embedded in the brush-border membrane. Membrane lipids and gangliosides are also glycosylated, and all secreted mucins are carbohydraterich glycoproteins. Thus the scope of potential lectincarbohydrate interactions is quite wide. However, not all lectins react with the epithelium, and even those that do react vary in their ability to recognize and bind to specific types of carbohydrate receptors. Because lectin reactions are quite specific, it is imperative that the correct carbohydrate structures be present on the surface of the gut mucosa. Factors that are known to influence lectin activity are summarized in Box 43-1. Lectins can have a variety of biologic effects, including: induction of mitosis in lymphocytes, cellular agglutination via cross-linking of membrane sugars, preferential agglutination of malignant cells, precipitation

Therapeutic Modalities

Animal species Blood group specificity Age Particular area of the small intestine Position along the villi State of cell maturation Diet Bacterial status Sickness or pathology Modified from PusztaiA, BardouS.Trends GlycoxiGlycotechnol1996;8:149-165.

of polysaccharides and glycoproteins, and activation of complement. The variety of reported effects resulting from the ingestion of dietary lectins is summarized in Table 43-8. Most lectins in the U.S. diet are resistant to breakdown during gut passage and are bound and endocytosed

by epithelial cells. These lectins are powerful exogenous growth factors for the small intestine, and they can induce dramatic shifts in its bacterial flora and interfere with its hormone secretion. In addition, lectins that are transported across the gut wall into the systemic circulation can modulate the body’s hormone balance, metabolism, and health. In contrast to dietary proteins, lectins resist degradation in the small intestine and are also resistant to breakdown by most gut bacteria. Thus, most lectins survive, at least in part, the passage through the digestive tract in an immunologically and functionally intact form.12’ Although lectin binding is most commonly studied in the small intestine, similar binding can OCCUT throughout the entire digestive tract, from the stomach to the distal colon. However, surface glycosylation varies in the different functional parts of the gut, so lectin binding is not uniform in the digestive tract. Binding of lectins and their endocytosis by enterocytes occur throughout the gut, although endocytosis in the small intestine

Reported effects of dietary lectins Action

Description

Induction of interleukins (ILs)

Dietary lectins are known to induce interleukins IL-4 and IL-13. Because lectins can enter the circulation after oral uptake, they might play a role in inducing the so-called early IL-4 required to switch the immune response toward a helper T cell type 2 response and type I allergy.llg

Induction of autoimmunity

The interaction of dietary lectins with enterocytes and lymphocytes may facilitate the translocation of both dietary and gut-derived pathogenic antigens to peripheral tissues, which in turn causes persistent peripheral antigenic stimulation. In genetically susceptible individuals, this antigenic stimulation may ultimately result in the expression of autoimmune disease.lm

Interference with protein digestion

Aminopeptidase activity (the enzyme that breaks down polypeptides into amino acids) is inhibited by several dietary lectins.121

Interaction with the brush-border membrane

Lectins, which bind avidly to the brush-border membrane, are potent hyperplastic growth factors for the gut.lZ Binding of lectins to the epithelium is obligatory for growth stimulation, and their growth factor activity is determined mainly by the strength and intensity of their binding.lZ3

Antinutrient effects

Rats fed a diet composed principally of raw navy bean flour were smaller and had 50% less ability to absorb glucose and utilize dietary protein than a control group that was fed navy beans in which the lectin had been inactivated.lZ4

Enhancement of gut permeability

In one study, rats fed on diets containing kidney beans showed greater intestinal permeabilityto serum proteins that had been injected into the blood stream. After challenge with kidney bean proteins, the protein injected into the blood stream was detected in both the lumen (open space) and the walls of the small intestine. The researchers suggested that dietary lectins may, at least in part, be responsible for loss of serum proteins and may contribute to other food intolerance secondary to the loss of gut integrity.lZ5

Activation of gut hormones

Cholecystokininis induced by several dietary lectins.lZ6

Hormone and growth factor mimicry

Because surface membrane receptors of cells are glycosylated, lectins are good mimics of the effects of endogenous growth factors, hormones, and cytokines in all types of cells.127Lectins can mimic the effect of the natural ligands and induce similar physiologic reactions. It is also possible that bound lectin induces conformationalchanges in the receptor and/or physically blocks the active site of the receptor, thereby attenuating or completely abolishing the physiologic effect of the natural ligand.

Mucotractive effects

Many lectins stimulate the production of mucus. This is possibly a protective function or an allergic response and was for a time thought to be an action of lectins that promised some therapeutic benefit that could be applied in patients with cystic fibrosis.lZ8

Mitogenic effects

Several foodstuffs and herbal medicines are known to contain lectins that are capable of inducing T- or 6-cell blastogenesis.

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms

I

Primary and secondary much glycosides known to be associated with ABO polymorphism

CLINICAL APPLICATIONS OF ABO POLYMORPHISM The BloodType Diet

The advantage of a low-lectin diet can be exemplified by the best known application of the ABO polymorA phisms, The Blood Type Diet, popularized by publication Glycophorin AI3* Galactosyl-A glyc01ipid.s~~~ in 1997 of my New York Times bestseller Eat Right 4 Your "Band 3"lM Type. Eat Right 4 Your Type was the first "diet b o o k that B Galactose KNeuraminic Glycophorin B1= both looked at foods as medicine tailored to the individKAcetyl g1ucosamine136138 ual rather than simply as part of a generic single-purpose 0 Fucose mechanism (i.e., weight loss, cholesterol control). Like the very antigens that it uses for its determination, The Blood Type Diet is "nonreducing," meaning that the food value system is essentially stateless: A food that becomes appreciable only in the presence of large nummight cause difficulties in one ABO phenotype may well bers of commensal bacteria. As expected, endocytosis of possess therapeutic value in another, a concept that lectins is more extensive in the colon, where bacterial harkens back to the observation of the Roman philosocounts are high.Iz8 pher Lucretius, "What is food to one man may be fierce How prevalent are lectins in the diet? A superficial poison to others." survey done in the early 1980s implied that they are The Blood Type Diet inventories a variety of paramequite extensively distributed in our food supply.1z9 ters, including the physiologic and pathologic distincIn this study, the edible parts of 29 of 88 foods tested, tions between the blood groups as reported in the including common salad ingredients, fresh fruits, roasted literature, lectin, and agglutinin characterizations (both nuts, and processed cereals, were found to possess sigrufmine and others'), and variations in isoagglutinin titer icant lectin-like activity as assessed with blood agglutiand reactivity with regard to food challenge (both nation and bacterial agglutination assays. in vitro and in vivo). It also provides specific recommenLectin content is a prime area of manipulation for the dations regarding foods that should be considered beneproduction of transgenic foods,130so they will probably ficial and should be emphasized and others that may be continue to occupy the attention of nutritionally oriented problematic and might better be avoided. physicians well into the future. One advantage conferred by the theory is the notion Role of ABO Blood Groups that certain individuals may be better suited to Paleolithic or vegetarian diets. Despite certain locutions Because ABO blood group is a prime determinant of glyand circumlocutionsoffered by proponents of one system cosylation, it is not surprising that a substantial number or the other, most clinicians have ample experience with of food lectins show ABO specificity. However, equally the simple fact that certain patients make better vegetariimportant, but not typically recognized, is my observaans or carnivores than others. Conversely, the ability to tion that ABO status appears to influence variability in identify particular individuals at risk of an adverse reacsecondary glycosides, which are not integral to the ABO tion to high-protein/low-carbohydratediets can lead to type of the hosts. These secondary glycosides appear actions aimed at the prevention of such consequences. to provide additional conditioning of the much manuFor example, high-protein diets are known to upregufactured by the particular ABO type, perhaps offering late soluble endothelial adhesion factors,140whereas a some explanation for the apparent effects of panhemagsoy-based, lipid-lowering diet is known to decrease glutinins and other non-ABO specific lectins on one endothelial adhesion factors, including VWF, E-selectin, particular ABO type over another. These effects are listed in Table 43-9. and intercellular adhesion molecule (ICAM).141-143 Because individuals with blood group A have been The ability to use the ABO groups as a predictive reported to have increased levels of all three endothelial device in narrowing down potential food reactions in adhesion factors and, perhaps consequently, a higher sensitive subjects lies in its low cost to the patient and incidence of cardiovascular disease, a modified Asian/ the clinician's ability to discern interactions that are Mediterranean, plant-based diet would appear ideal for not easily testable via standard food allergy isolation this phenotype. methods. A useful resource for clinicians seeking more Conversely, in 1998, I examined serum cholesterol information on lectins is Lectser, the world's most complete lectin characterization database, available at my levels in small number of group 0 subjects after a minimum of one month of the blood type diet recommended ~ebsite.~~~ Blood arouD

Primarv qlvcoside Secondarv alvcosidels) NAcetyl galactosamine MannoseI3l

for that phenotype.'@Group 0 individuals following the "Type 0 Diet" (higher protein, lower carbohydrate) showed a consistent drop in serum cholesterol (n = 14; average 237.3 mg/dl before diet, 200.2 mg/dl withdiet); in subjects with elevated serum triglyceride values, the results were more pronounced (n = 6; average 387.1 mg/dl before diet, 168.8 mg/dl with diet). The Blood Type Diet has produced an extensive library of works, at a various levels of information density. Eat Right 4 Your Type has been translated into more than 60 languages, and well over 3 million individuals follow the system.145

Materia Medica ABO polymorphism and its clinical expression have led to new or rediscovered applications and contraindications for several traditional naturopathic treatment modalities. The most significant are summarized in Table 43-10.

CONCLUSIONS It is my sincere hope that this abbreviated survey proves sufficient to persuade the reader that ABO and ABOrelated polymorphisms, in both genotypic and phenotypic

Modalities known to exert effects at least partially preferentialto ABO group Agenffspecies

Common names

Actions

Notes

References

Fucus vesiculosus

Bladderwrack kelp

Anti-adhesive Candicidal

Best suited for 0, nonsecretors

146-148

Bapfisia tinctoralis

Wild indigo

Induces anti-Tn or cross-reacting antibodies

Best suited for A, AB

149, 150

Urfica dioica rhizome

Stinging nettle root

'Superantigen" lectin T-cell mitogen (CD& and CD8+) Candicidal

Not useful in B or AB

151,152

Helix pornafia agglutinin

Roman or escargot snail

Contains Tn-, LLC-, and "A-like"specific lectins

Best suited for A, AB

110,111

Agaricus bisporus

Domestic mushroom

Lectin stimulates insulin release by pancreatic islets Lectin binds Tn antigen; stimulates differentiation of undifferentiated colon cancer cells; inhibits proliferation of epithelial cell lines

Best suited for A

153,154

Marrubium spp.

Horehound

Contains Tn-specific lectins

Best suited for A, AB

155

Salvia spp.

Sage

Contains Tn-specific lectins Attenuates soluble endothelial adhesion factors

Best suited for A. AB

155,156

Vicia faba

Fava bean

VFA stimulated an undifferentiated colon cancer cell line to differentiate into glandlike structures. The adhesion molecule epCAM is involved in this process. Dietary or therapeutic VFA may slow progression of colon cancer

Best suited for A; can be used by 0,B

157

Griffonia (Bandeiraea) simplicifolia

African legume from which 5-HTP is extracted

Griffonia contains 5 isolectins, at least 3 of which are blood group agglutinating GSA &Q is a serologically Lewis b (Lebkactive binding lectin claimed to be blood group B specific as well The "&-rich lectin preferentially agglutinates blood group A, and the "B"-rich lectin preferentially agglutinates blood group B cells and is specific for alpha-galactose residues

Not useful in A, AB, B or secretors

158-160

Artocarpus integrifolia

Jackfruit seeds

Contains T- and Tn-specific lectin (jacalin)

Best suited for A, AB; can be used by 0, B

161

~~

epCAM, Epithelial cell adhesion molecule; GSA. Grihbnia simplicifolia agglutinin; LLC. ligand-like complex; VFA. Vicia faba agglutinin.

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms

expression, exert biologic sigruficance far beyond the surface of an erythrocyte, and that this expression is worth factoring into the everyday algorithms of a nutritional practice. Perhaps the advent and acceptance of the newly emerging science of "nutrigenomics" might provide the conceptual framework needed to allow

the nontransfusion significance of ABO and secretor polymorphism to parse into meaningful scientific dialogue. At that point, natural medicine could be considered to have the rational beginnings to delivering its long-awaited promise, "Treating the patient, not the disease."

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the fecal population density of certain enteric bacteria. J Clin Invest 1976;577482. 20. Hoskins LC, Boulding ET. Degradation of blood group antigens in human colon ecosystems. I. In vitro production of ABH blood group-degrading enzymes by enteric bacteria. J Clin Invest 1976;5763-73. 21. Al-Agidi SK, Shukri SM. Association between immunoglobulin levels and known genetic markers in an Iraqi population. Ann Hum Biol1982;9:565-569. 22. Shinebaum R. ABO blood group and secretor status in the spondyloarthropathies. FEMS Microbiol Immunol1989;1:389-395. 23. Grundbacher FJ. Immunoglobulins, secretor status, and the incidence of rheumatic fever and rheumatic heart disease. Hum Hered 1972;22:399-404. 24. Grundbacher FJ. Genetic aspects of selective immunoglobulin A deficiency.J Med Genet 1972;9:344-347. 25. Pal A, Hill M, Wordsworth P, Brown M. Secretor status and ankylosing spondylitis. J Rheumatol 1998;25:318-319. 26. Manthorpe R, Staub Nielsen L, et al. Lewis blood type frequency in patients with primary Sjogren's syndrome. A prospective study including analyses for AlA2B0, secretor, MNSs, P, Duffy, Kell, Lutheran and rhesus blood groups. Scand J Rheumatol 1985;14: 159-162. 27. Toft AD, Blackwell CC, Saadi AT, et al. Secretor status and infection in patients with Graves' disease. Autoimmunity 1990;7279-289. 28. Tosh FD, Douglas LJ. Characterization of a fucoside-binding adhesin of Candida albicuns. Infect Immun 1992;60:4734-4739. 29. Furukawa K, Ying R, Nakajima T, Matsuki T. Hemagglutinins in fungus extracts and their blood group specificity. Exp Clin Immunogenet 1995;12223-231. 30.Navas EL, Venegas MF, Duncan JL, et al. Blood group antigen expression on vaginal and buccal epithelial cells and mucus in secretor and nonsecretor women. J Urol1993;1491492-1498. 31. Godzisz J. [Synthesis of natural allohemagglutinins of the ABO system in healthy children aged 3 months to 3 years]. Rev Fr Transfus Immunohematol1979;22:399-412. 32. Grundbacher FJ. Genetics of anti-A and anti-B levels. Transfusion 1976;16:48-55. 33. Adewuyi JO, Gwanzura C, Mvere D. Characteristics of anti-A and anti-B in black Zimbabweans. Vox Sang 1994;67307-309. 34. Lauritsen JG, Grunnet N, Jensen OM. Matemo-fetal ABO incompatibility as a cause of spontaneous abortion. Clin Genet 1975;7308-316. 35. Solish GI. Distribution of ABO isohaemagglutinins among fertile and infertile women. J Reprod Fertil1969;18:459-474. 36. Cantuaria AA. Blood group incompatibility and cervical hostility in relation to sterility. Obstet Gynecol1978;51:193-197. 37. DAdamo PJ, Zampieron ER. Does ABO "bias" in natural immunity imply an innate difference in T-cell response? J Naturopath Med 1991;2:11-17. 38. Greenwalt TJ. A short history of transfusion medicine. Transfusion 1997;37550-563. 39. Yamamoto F. Blood group antigen gene mutation database. The Bumham Institute. Available online at www.bioc.aecorn.yu.edu/bgmut/ abo.htm (accessed 27 March 2004).

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63. Tarjan Z, Tonelli M, Duba J, Zorandi A. Correlation between ABO and Rh blood groups, serum cholesterol and ischemic heart disease in patients undergoing coronarography. Orv Hetil1995;136767-769. 64.Wong FL, Kodama K, Sasaki H, et al. Longitudinal study of the association between ABO phenotype and total serum cholesterol level in a Japanese cohort. Genet Epidemiol1992;9405-418. 65. Gillum RF. Blood groups, serum cholesterol, serum uric acid, blood pressure, and obesity in adolescents. J Natl Med Assoc 1991;83 682-688. 66. Fox MH, Webber LS,Thurmon m,Berenson GS. ABO blood p u p associations with cardiovascular risk factor variables. II. Blood pressure, obesity, and their anthropometric covariables. The Bogalusa Heart Study. Hum Biol1986;58549-584. 67. Mao X, Xu M, Mu S, et al. [Study on relationship between human ABO blood groups and type A behavior pattern]. Hua Xi Yi e Da Xue Xue Bao 1991;22:93-96. 68.Neumann JK, Arbogast BW, Chi DS,Arbogast LY. Effects of stress and blood type on cortisol and VLDL toxicity preventing activity. Psychosom Med 1992;54:612-619. 69. Locong AH, Roberge AG. Cortisol and catecholamines response to V enisection by humans with M e r e n t blood groups. Clin Biochem 1985;1867-69. 70. Dintenfass L, Zador I. Blood rheology in patients with depressive and schizoid anxiety. Biorheology 1976;13:33-36. 71. Dintenfass L, Bauer GE. Dynamic blood coagulation and viscosity and degradation of artificial thrombi in patients with hypertension. Cardiovasc Res 1970;4:50-60. 72.Dintenfass L, Zador I. Effect of stress and anxiety on thrombus formation and blood viscosity factors. Bib1 Haematol1975;41:133-139. 73. Dintenfass L, Davis E. Genetic and ethnic influences on blood viscosity and capillaries in diabetes mellitus. Microvasc Res 1977; 14161-172. 74. Dintenfass L, Forbes CD. Effect of fibrinogen on aggregation of red cells and on apparent viscosity of artificial thrombi in haemophilia, myocardial infarction, thyroid disease, cancer and control systems: effect of ABO blood groups. Microvasc Res 1975;9107-118. 75. Dintenfass L, Steward JH. Formation, consistency and degradation of artificial thrombi in severe renal failure: effect of ABO blood groups. Thromb Diath Haemorrh 1968;20:267-284. 76.Dintenfass L. Some aspects of haemorrheology of metastasis in malignant melanoma. Haematologia (Budap) 1977;11:301-307. 77. Blann AD, Daly RJ, Amiral J. The influence of age, gender and ABO blood group on soluble endothelial cell markers and adhesion molecules.Br J Haematol1996;92498-500. 78. Sostaric V, Bozicevic D, Brinar V, Grbavac Z. Hereditary antigen characteristics of blood in ischemic cerebrovascular accident. Neurol Croat 1991;40:3-11. 79. Ionescu DA, Ghitescu M, Marcu I, Xenakis A. Erythrocyte rheology in acute cerebral thrombosis: effects of ABO blood groups. Blut 1979;39:351-357. 80.Ionescu DA, Marcu I, Bicescu E. Cerebral thrombosis, cerebral haemorrhage, and ABO blood-groups. Lancet 1976;1:278-280. 81. Horby J, Gyrtrup HJ, Grande P, Vestergaard A. Relation of serum lipoproteins and lipids to the ABO blood groups in patients with intermittent claudication.J Cardiovasc Surg (Torino) 19893: 533-537. 82. Robinson WM, Roisenberg I. Venous thromboembolism and ABO blood groups in a Brazilian population. Hum Genet 1980;55:129-131. 83. Havlik RJ, Feinleib M, Garrison RJ, Kannel WB. Blood-groups and coronary heart-disease. Lancet 1969;2:269-270. 84.Slipko Z, Latuchowska B, Wojtkowska E. [Body structure and ABO and Rh blood groups in patients with advanced coronary heart disease after aorto-coronary by-pass surgery]. Pol Arch Med Wewn 1994;91:55-60. 85.Meshalkin EN, Okuneva GN, Vlasov IuA, Vel'tmander NN. [ABO and Rh blood groups in cardiovascular pathology]. Kardiologiia 1981;21:46-50.

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms 86. Erikssen J, Thaulow E, Stormorken H, et al. ABO blood groups and coronary heart disease (CHD): a study in subjects with severe and latent CHD. Thromb Haemost 1980;43137-140. 87. Allan TM. ABO blood groups, age and work in ischaemic heart disease. Atherosclerosis 1975;21:459461. 88. Galeazzi L, Gualandri V. [ABO blood-group phenotypes and pathogenesis of cardiovascular diseases. Congenital, rheumatic and coronaric heart disease and arterial hypertension (author’s transl)]. G Ital Cardiol 1975;5744751. 89. Rosenberg L, Miller DR, Kaufinan DW, et al. Myocardial infarction in women under 50 years of age. JAMA 1983;250:2801-2806. 90. Platt D, Muhlberg W, Kiehl L, Schmitt-Ruth R. ABO blood group system, age, sex, risk factors and cardiac infarction. Arch Gerontol Geriatr 1985;4241-249. 91. Whincup PH, Cook DG, Phillips AN, Shaper AG. ABO blood group and ischaemic heart disease in British men. BMJ 1990;300:1679-1682. 92. Dabelsteen E. Cell surface carbohydrates as prognostic markers in human carcinomas. J Pathol 1996;179358-369. 93. Ichikawa D, Handa K, Hakomori S. Histo-blood group A/B antigen deletion/reduction vs. continuous expression in human tumor cells as correlated with their malignancy. Int J Cancer 1998;76284249. 94. Cooper HS, Marshall C, Ruggiero F, Steplewski Z. Hyperplastic polyps of the colon and rectum. An immunohistochemical study with monoclonal antibodies against blood groups antigens (sialosyl-Lea, Leb, Lex, Ley, A, B, H). Lab Invest 1987;57:421-428. 95. Saegusa M. [Isoantigens ABH in bladder tumors as an indicator of malignant potential a combined study with CEA, BMG, Leu-M1 and H-Ag]. Hinyokika Kiyo 1989;351311-1321. 96. Abel PD, Marsh C, Henderson D, et al. Detection of blood group antigens in frozen sections of prostatic epithelium. Br J Urol 1987;59:430435. 97. Lin XS. [The expression and siguficance of blood group antigens (BGA) A, B, H, Le(a) and Le(b) in hepatocellular carcinoma and chronic hepatitis] Zhonghua Sing Li Xue Za Zhi 1992;21:2426. 98. Robey-Cafferty S, El Naggar AK, Sahin AA, et al. Prognostic factors in esophageal squamous carcinoma. A study of histologic features, blood group expression, and DNA ploidy. Am J Clin Pathol 1991;95:844849. 99. Inoue M, Sasagawa T, Saito J, et al. Expression of blood group antigens A, B, H, Lewis-a, and Lewis-b in fetal, normal, and malignant tissues of the uterine endometrium. Cancer 1987;60:2985-2993. 100. Matias-Guiu X, Giux M. ABO (H) blood group antigen expression in gastric mucosa. Pathol Res Pract 1988;183:476-480. 101. Larena A, Vierbuchen M, Fischer R. Blood p u p antigen expression in malignant tumors of the thyroid a parallel between medullary and nonmedullary carcinomas. Langenbecks Arch Chir 1995;380: 269-272. 102. Tauchi K, Kakudo K, Machimura T, et al. Immunohistochemical studies of blood group-related antigens in human superficial esophageal carcinomas. Cancer 1991;673042-3050. 103. Marionneau S, Le Moullac-Vaidye 8, Le Pendu J. Expression of histo-blood group A antigen increases resistance to apoptosis and facilitates escape from immune control of rat colon carcinoma cells. Glycobiology 2002;12851-856. 104. Springer GF. T and Tn pancarcinoma markers: autoantigenic adhesion molecules in pathogenesis, prebiopsy carcinoma-detection, and long-term breast carcinoma immunotherapy. Crit Rev Oncog 1995;657-85. 105. Garratty G. Blood group antigens as tumor markers, parasitic/ acterial/viral receptors, and their association with immunologically important proteins? Immunol Invest 1995;24213-232. 106. Kurtenkov 0,Klaamas K, Miljukhina L. The lower level of natural anti-Thomsen-Friedenreichantigen (TFA) agglutinins in sera of patients with gastric cancer related to ABO(H) blood-group phenotype. Int J Cancer 1995;60:781-785.

107. Aird I, Bentall HH, Roberts JA. A relationship between cancer of stomach and the ABO blood groups. Br Med J 1953;1:799-801. 108. Beckman L, Angqvist KA. On the mechanism behind the association between ABO blood groups and gastric carcinoma. Hum Hered 1987;37140-143. 109. Hirohashi S, Clausen H, Yamada T, et al. Blood group A crossreacting epitope defined by monoclonal antibodies NCC-LU-35 and -81 expressed in cancer of blood group 0 or B individuals: its identification as Tn antigen. Proc Natl Acad Sci U S A 1985; 82:7039-7043. 110. Brooks SA, Leathem AJ. Prediction of lymph node involvement in breast cancer by detection of altered glycosylation in the primary tumour. Lancet 1991;338:71-74. 111. Brooks SA, Hall DM, Buley I. GalNAc glycoprotein expression by breast cell lines, primary breast cancer and normal breast epithelial membrane. Br J Cancer 2001;851014-1022. 112. Springer GF. Immunoreactive T and Tn epitopes in cancer diagnosis, prognosis, and immunotherapy. J Mol Med 1997;75: 594602. 113. Defize LH, Amdt-Jovin DJ, Jovin TM, et al. A431 cell variants lacking the blood group A antigen display increased high affinity epidermal growth factor-receptor number, protein-tyrosine b a s e activity, and receptor turnover. J Cell Biol1988;107939-949. 114. Engelmann 8, Schumacher U, Haen E. Epidermal growth factor binding sites on human erythrocytes in donors with different ABO blood groups. Am J Hematol1992;39239-241. 115. Jorgensen G. [ABO blood groups in physicians more than 75 years old: on the hypothesis concerning “little more fitness of blood group 0 1 . MMW Munch Med Wochenschr 1974;116649-652. 116. Jorgensen G. [Human genetics and infectious diseases (author’s transl)] . M M W Munch Med Wochenschr 1981;1231447-1452. 117. D’Adamo P. The complete blood type encyclopedia: the A-Z reference guide for the blood type connection to symptoms, disease, conditions, vitamins, supplements, herbs, and food. New York Riverhead Books, 2002. 118. Pusztai A, Bardou S. Biological effects of plant lectins on the gastrointestinal tract: metabolic consequences and applications. Trends Glycosci Glycotechnol 1996;8:149-165. 119. Haas H, Falcone FH, Schramm G, et al. Dietary lectins can induce in vitro release of IL-4 and IL-13 from human basophils. Eur J Immunol1999;2991&927. 120. Cordain L, Toohey L, Smith MJ, Hickey MS. Modulation of immune function by dietary lectins in rheumatoid arthritis. Br J Nutr 2000;83207-217. 121. Erickson RH, Kim J, Sleisenger MH, Kim YS. Effect of lectins on the activity of brush border membrane-bound enzymes of rat small intestine. J Pediatr Gastroenterol Nutr 1985;4984-991. 122. Pusztai, A. Plant lectins. Cambridge: Cambridge University Press, 1991. 123. Pusztai A, Ewen SWB, Grant G, et al. Relationshipbetween survival and binding of plant lectins during small intestinal passage and their effectiveness as growth factors. Digestion 1990;46:30&316. 124. Weinman MD, Allan CH, Trier JS, Hagen SJ. Repair of microvilli in the rat small intestine after damage with lectins contained in the red kidney bean. Gastroenterology 1989;971193-1204. 125. Greer F, Pusztai A. Toxicity of kidney bean (Phaseolus vulgaris) in rats: changes in intestinal permeability. Digestion 1985;32:42-46. 126. Jordinson M, Playford RJ, C a l m J. Effects of a panel of dietary lectins on cholecystokinin release in rats. Am J Physiol 1997;273:G946-G950. 127. Pusztai A. Dietary lectins are metabolic signals for the gut and modulate immune and hormone functions. Eur J Clin Nutr 1993;47691-699. 128. Freed DJ. Dietary lectins. In Brostoff J, Challacombe S, eds. Food allergy and intolerance. Philadelphia: Bailliere Tmdall Publishers, 1987.

129. Bardocz S, Grant G, Ewen SW, et al. Reversible effect of phytohaemagglutinin on the growth and metabolism of rat gastrointestinal tract. Gut 1995;37353-360. 130. Nachbar MS, Oppenheim JD.Lectins in the United States diet: a survey of lectins in commonly consumed foods and a review of the literature. Am J Clin Nutr 1980;332338-2345. 131. Ewen SW, Pusztai A. Health risks of genetically modified foods. Lancet 1999;354:684. 132. Czirok E, Marton A, Csik M, Solt M. Virulence factors of Escherichia coli. I. Mannose resistant haemagglutinating capacity is associated with serogroup but not with site of infection. Acta Microbiol Hung 1984;31:187-195. 133. Podbielska M, Krotkiewski H. Identification of blood group Aand B antigens in human glycophorin. Arch Immunol Ther Exp (Warsz) 2ooO;48:211-221. 134.Clausen H, Stroud M, Parker J, et al. Monoclonal antibodies directed to the blood group A associated structure, galactosyl-A: specificity and relation to the Thomsen-Friedenreich antigen. Mol h~n011988;25:199-204. 135. Slomiany BL, Murty VL,Slomiany A. Structural features of carbohydrate chains in human salivary mucins. Int J Biochem 1993; 25:259-265. 136. Kochetkov NK,Derevitskaya VA, Arbatsky NP. The structure of pentasaccharides and hexasaccharides from blood group substance H. Eur J Biochem 1976;67:129-136. 137. Johansson I, Bratt P, Hay DI, et al. Adhesion of Candida albicans, but not Candida krusei, to salivary statherin and mimicking host molecules. Oral Microbiol Immunol2000;15:112-118. 138. Schulte BA, Poon KC, Rao KF,' Spicer SS. Lectin histochemistry of complex carbohydrates in human cervix. Histochem J 1985;17 627-654. 139. DAdamo P. LECster 2.3. Eat right 4 your type. Available online at wwu.dadamo.com/7ecster2/lecster.cgi[accessed 27 March 20041. 140. Fleming RM. The effect of high-protein diets on coronary blood flow. Angi010g~2000;51:817-826. 141. Blann AD, Jackson P, Bath PM, Watts GF. von Willebrand factor, a possible indicator of endothelial cell damage, decreases during long-term compliance with a lipid-lowering diet. J Intern Med 1995;237:557-561. 142. Yildirir A, Tokgozoglu SL, Oduncu T, et al. Soy protein diet significantly improves endothelial function and lipid parameters. Clin Cardiol2001;24:711-716. 143. Fuentes F, Lopez-Miranda J, Sanchez E, et al. Mediterranean and low-fat diets improve endothelial function in hypercholesterolemic men. Ann Intern Med 2001;132.1115-1119.

144. DAdamo P. Unpublished results. Some data available online a t uuw.dadamo.com/outcome-l998.htm/ 145. More information, including an extensive knowledge base, is available at the author's primary internet portal: uuw.dadamo.com/ 146. Ferreiros CM, Criado MT. Purification and partial characterization of a Fucus vesiculosus agglutinin. Rev Esp Fisiol 1983;39:51-59. 147. Roberts DD, Ginsburg V. Sulfated glycolipids and cell adhesion. Arch Biochem Biophys 1988;267405-415. 148.Criado MT, Ferreiros CM. Selective interaction of a Fwcus vesiculosus lectin-like mucopolysaccharide with several Candida species. Ann Microbiol (Pans) 1983;134A:149-154. 149. Boericke W. Pocket materia medica. San Francisco, 1927. 150. Jenkin CR, Jackson GD. Artificial antigens and immunity to infectious disease. Prog Immunobiol Stand 1970;4493-504. 151. Galelli A, Truffa-BachiP. Urtica dioica agglutinin: a superantigenic lectin from stinging nettle rhizome. J hunol1993;151:1821-1831. 152. DAdamo P. Unpublished observations, 1987-1994. 153. Gray AM, Flatt PR. Insulin-releasing and insulin-like activity of Agaricus carnpestris (mushroom). J Endocrinol 1998;157 259-266. 154. Yu LG, Femig DG, White MR, et al. Edible mushroom (Agaricus bisporus) lectin, which reversibly inhibits epithelial cell proliferation, blocks nuclear localization sequence-dependent nuclear protein import. J Biol Chem 1999;2744890-4899. 155. Bird GW, Wingham J. More Tn-specific lectins from seeds of the genus Labiatae: Hyptis sp. Chan, Salvia lyrata and Marrubium velutinum. Clin Lab Haematol 1982;4403-404. 156. Ren de C, Du GH, Zhang JT. Inhibitory effect of the water-soluble extract of Salvia miltiorrhiza on neutrophil-endothelial adhesion. Jpn J Pharmacol2002;90:276-280. 157. Jordinson M, El-Hariry I, CaInan D, et al. Vicia faba agglutinin, the lectin present in broad beans, stimulates differentiation of undifferentiated colon cancer cells. Gut 1999;44:709-714. 158. Khan F, Khan RH, Shenvani A, et al. Lectins as markers for blood grouping. Med Sci Monit 2002;8:RA293-RA300. 159. Ito N, Nishi K, Kawahara S, et al. Difference in the ability of blood group-specific lectins and monoclonal antibodies to recognize the ABH antigens in human tissues. Histochem J 1990; 22~604-614. 160. Vandonselaar M, Delbaere LT, Spohr U, Lemieux RU. Crystallization of the lectin IV of Griflonia simplicifolia and its complexes with the Lewis b and Y human blood group determinants. J Biol Chem 1987;26210848-10849. 161. Wu AM, Wu JH, Lin LH, et al. Binding profile of Artocarpus integrifolia agglutinin (Jacalin). Life Sci 2003;72:2285-2302.

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Nutritional Medicine Michael T. Murray, ND Joseph E. Pizzorno Jr, ND C HA PTE K C 0N TE NT S Introduction

461

Evolutionary Aspects in Human Nutrition 461 A Look at Our Closest Wild Relatives 461 Hunter-Gatherer Diets 462 The Importance of a Plant-Based Diet 462 The Pioneering Work of Burkitt and Trowell

462

Trends in U.S. Food Consumption 463

2. Reduce Exposure to Pesticides and Food Additives 466 3. Eat to Support Blood Sugar Control 467 4. Reduce Intake of Meat and Other Animal Foods 468 5. Eat the Right Type of Fats 468 6. Keep Salt Intake Low, Potassium Intake High 469 7. Avoid Food Additives 470 8. Take Measures to Reduce Foodborne Illness 470 9. Drink Sufficient Amounts of Water Each Day 471

The Government and Nutrition Education 463 Nutritional Supplementation 471 The Optimal Health Food Pyramid 465 1. Eat a “Rainbow” Assortment of Fruits and Vegetables 465

Let your food be your medicine and let your medicine be your food. -Hippocrates

INTRODUCTION Nutritional medicine, as described in this textbook, consists of the use of diet and nutritional supplementation as therapeutic modalities. The foundation of nutritional medicine is a health-promoting diet that focuses on the consumption of whole, natural foods. Nutritional supplements are used in the overall context of nutritional medicine as complementary agents, not as sole primary medicines. Diet is always primary, and supplementation secondary.

EVOLUTIONARY ASPECTS IN HUMAN NUTRITION Although the human gastrointestinal tract is capable of digesting both animal and plant foods, a number of physical characteristics indicate that Homo sapiens evolved to digest primarily plant foods. Specifically,our teeth are composed of 20 molars, which are perfect for crushing and grinding plant foods, along with eight

Final Comments 472

front incisors, which are well suited for biting into fruits and vegetables. Only our front four canine teeth are designed for meat eating. Our jaws swing both vertically to tear and laterally to crush, but carnivores’ jaws swing only vertically. Additional evidence that support the body’s preference for plant foods is the long length of the human intestinal tract. Carnivores typically have a short bowel, and herbivores have a bowel length proportionally comparable to that of humans. Thus the human bowel length favors plant f0ods.l

A Look at Our Closest Wild Relatives To answer the question “What should humans eat?“ many researchers look to other primates, such as chimpanzees, monkeys, and gorillas. Nonhuman wild primates are also omnivores or, as often described, herbivores and opportunistic carnivores. They eat mainly fruits and vegetables but may also eat small animals, lizards, and eggs if given the opportunity. Only 1%and 2%, respectively, of the total calories consumed by gorillas and orangutans are animal foods. The remainder of their diet is from plant foods. Because humans are between the weights of the gorilla and orangutan, it has been suggested that humans are designed to eat 461

Therapeutic Modalities

around 1.5% of their diet as animal foods.2 Most Americans derive well over 50% of their calories from animal foods. Although most primates eat a considerable amount of fruit, it is critical to point out that the cultivated fruit in American supermarkets is far different from the highly nutritious wild fruits these animals rely on. Wild fruits have slightly higher protein contents and a higher content of certain essential vitamins and minerals, but cultivated fruits tend to be higher in sugars. Cultivated fruits are therefore very tasty to humans, but because they have a higher sugar composition and also lack the fibrous pulp and multiple seeds found in wild fruit that slow down the digestion and absorption of sugars, cultivated fruits raise blood sugar levels much more quickly than their wild counterparts. Wild primates fill up not only on fruit but also on other highly nutritious plant foods. As a result, wild primates weighing Ho as much as a typical human ingest nearly 10 times the level of vitamin C and much higher amounts of many other vitamins and minerals. Other differences in the wild primate diet are also important to point out, such as a higher ratio of alpha-linolenic acid, the essential omega3 faty acid, to linoleic acid, the essential omega4 fatty acid2(Table 44-1).

Hunter-Gatherer Diets Determining what foods humans are best suited for may not be as simple as looking at the diet of wild primates. There are some structural and physiologic differences between humans and apes. The key difference may be a larger, more metabolically active brain. In fact, it has been theorized that a shift in dietary intake to more animal foods may have produced the stimulus for brain growth. The shift itself was probably the result of limited food availability that forced early humans to hunt grazing mammals such as antelope and gazelle. Archeologic data supports this association: The brains of humans started to grow and become more developed at about the

Mineral Calcium Phosphorus Potassium Sodium Magnesium

Total daily intake of 7-kg adult monkey (ma) 4571 728 6419

Recommended daily allowance for 70-kg man (ma) 800 800

The Importance of a Plant-Based Diet The evidence supporting diet‘s role in chronic degenerative diseases is substantial and overwhelming. There are two basic facts linking the diet-disease connection: (1)a diet rich in plant foods (i.e., whole grains, legumes, fruits, and vegetables) is protective against many diseases that are extremely common in so-called Western society, and (2) a diet providing a low intake of plant foods is a causative factor in the development of these diseases and provides conditions under which other causative factors are more active.

1600-2000

182

500

1323

350 10

Iron

38.5

Manganese

18.2

2.0-5.0

2.8

1.5-3.0

Copper

same time as evidence shows an increase in bones of animals butchered with stone tools at sites of early villages. Improved dietary quality alone cannot M y explain why human brains grew, but it definitely appears to have played a critical role. With a bigger brain, early humans were able to engage in more complex social behavior, which led to improved foraging and hunting tactics, which in turn led to even higher quality food intake, fostering additional brain evolution. Data from anthropologists looking at hunter-gatherer cultures are providing much insight as to what humans are designed to eat; however, it is very important to point out that these groups were not entirely free to determine their diets. Instead, their diets were molded by what was available to them. For example, the diet of the Inuit Eskimos is far different from that of the Australian aborigines. It may not be appropriate to answer the question “What should humans eat?” simply by looking at these studies. Nonetheless, it is important to point out that regardless of whether hunter-gatherer communities relied on animal or plant foods, the rate of diseases of civilization, such as heart disease and cancer, is extremely low in such communities? It should also be pointed out that the meat that our ancestors consumed was much different from the meat found in supermarkets today. Domesticated animals have always had higher fat levels than their wild counterparts, but the desire for tender meat has led to the breeding of cattle that produce meat with a fat content of 25% to 30% or more, compared with less than 4% for free-living animals and wild game. In addition, the type of fat is considerably different. Domestic beef contains primarily saturated fats and virtually undetectable amounts of omega3 fatty acids. In contrast, the fat of wild animals contains more than five times more polyunsaturated fat per gram and has good amounts of beneficial omega3 fatty acids (approximately 4%).4

The Pioneering Work of Burkitt and Trowell Much of the link between diet and chronic disease originated from the work of two medical pioneers Denis Burkitt, MD, and Hugh Trowell, MD, authors of Western Diseases: Their Emergence and Prevention, first published in 1981.5Although now extremely well-recognized,

Nutritional Medicine

their work is actually a continuation of the landmark work of Weston A. Price, a dentist and author of Nutrition and Physical Degeneration. In the early 1900s, Dr. Price traveled the world observing changes in teeth and palate (orthodontic) structure as various cultures discarded traditional dietary practices in favor of a more “civilized” diet. Price was able to follow individuals as well as cultures over periods of 20 to 40 years and carefully documented the onset of degenerative diseases as their diets changed. On the basis of extensive studies examining the rate of diseases in various populations (epidemiologic data) and his own observations of primitive cultures, Burkitt formulated the following sequence of events:

First stage. In cultures consuming a traditional diet consisting of whole, unprocessed foods, the rate of chronic diseases like heart disease, diabetes, and cancer is quite low. Second stage. Commencing with eating a more “Western” diet, there is a sharp rise in the number of individuals with obesity and diabetes. Third stage. As more and more people abandon their traditional diet, conditions that were once quite rare become extremely common. Examples are constipation, hemorrhoids, varicose veins, and appendicitis. Fourth stage. Finally, with full westernization of the diet, other chronic degenerative or potentially lethal diseases, such as heart disease, cancer, osteoarthritis, rheumatoid arthritis, and gout, become extremely common. Since Burkitt and Trowell’s pioneering research, a virtual landslide of data has continually verified the role of the Western diet as the key factor in virtually every chronic disease, especially obesity and diabetes. Box 44-1 lists diseases with convincinglinksto a diet low

-

Metabolic Obesity, gout, diabetes, kidney stones, gallstones Cardiovascular High blood pressure, strokes, heart disease, varicose veins, deep vein thrombosis, pulmonary embolism Colonic Constipation, appendicitis, diverticulitis, diverticulosis, hemorrhoids, colon cancer, irritable bowel syndrome, ulcerative colitis, Crohn’s disease Other Dental caries, autoimmune disorders, pernicious anemia, multiple sclerosis, thyrotoxicosis, psoriasis, acne

in plant foods. Many of these now common diseases were extremely rare before the twentieth century.

TRENDS IN U.S. FOOD CONSUMPTION During the twentieth century, food consumption patterns changed dramatically (Table 44-2). Total dietary fat intake has risen from 32%of the calories in 1909 to 43% by the end of the century. Overall carbohydrate intake dropped from 57% to 46%; and protein intake has remained fairly stable at about 11%. Compounding these detrimental changes are the individual food choices accounting for the changes. The biggest changes were in sigruficant rises in the consumption of meat, fats and oils, and sugars and sweeteners in conjunction with the decreased consumption of noncitrus fruits, vegetables, and whole-grain products. The absolutely largest change in the last 100 years of human nutrition is the switch from a diet with a high level of complex carbohydrates, as found naturally occurring in grains and vegetables, to a tremendous and dramatic increase in the number of calories consumed from simple sugars. Currently, more than half of the carbohydrates being consumed are in the form of sugars (sucrose, corn syrup, etc.) being added to foods as sweetening agents. High consumption of refined sugars is linked to many chronic diseases, including obesity, diabetes, heart disease, and cancer.

THE GOVERNMENT AND NUTRITION EDUCATION Throughout the years, various governmental organizations have published dietary guidelines, but the recommendations of the United States Department of Agriculture (USDA) have become the most widely known. In 1956, the USDA published Foodfor Fitness-A Daily Food Guide. This became popularly known as the Basic Four Food Groups. The Basic Four were composed of the following: 1. The Milk Group: milk, cheese, ice cream, and other milk-based foods 2. The Meat Group: meat, fish, poultry, eggs, with dried legumes and nuts as alternatives 3. The Fruit and Vegetable Group 4.The Breads and Cereals Group

One of the major problems with the Basic Four Food Groups model was that it graphically suggested that the food groups are equal in health value. The result was overconsumption of animal products, dietary fat, and refined carbohydrates, and insufficient consumption of fiber-rich foods like fruits, vegetables, and legumes. This in turn has resulted in diet’s being responsible for many premature deaths, chronic diseases, and increased health care costs.

Therapeutic Modalities

Foods Meat, poultry, and fish: Beef Pork Poultry Fish

1909

1967

1985

1999

54 62 18 12 -

81 61 46 15

73 62 70 19

66 50 68 15 -

~

~

146

203

224

199

37

40

32

32

223

47 -

232 44 15 159 -

122 112 26 190 -

112 101 30 210 -

339

450

450

453

18 1 8 12 2

6 10 16 5 16

5 11 23 46 25

5 8 22 29 -

41

53

68

70

17

60

72

79

154 8

73 35

87

115

34

37 -

179

168

193

231

46 34

36 25

38 31

55 39

136 8

87 35

96 34

126 39 -

TOTAL

224

183

199

259

Potatoes, white Fresh Processed

182 0

67 19

55 28

TOTAL

Eggs Dairy products: Whole milk Low-fat milk Cheese Other TOTAL

Fats and oils: Butter Margarine Shortening Lard and tallow Salad and cooking oil TOTAL

Fruits: Citrus Noncitrus Fresh Processed TOTAL

Vegetables: Tomatoes Dark green and yellow Other Fresh Processed

64 5

49 91

As the Basic Four Food Groups became outdated, various other governmental as well as medical organizations developed guidelines of their own designed to reduce the risk of either a specific chronic degenerative disease, such as cancer or heart disease, or of all chronic diseases. In an attempt to create a new model in nutrition education, the USDA first published the “Eating Right Pyramid” in 1992. Since that time it has received harsh criticisms from numerous experts and other organizations. One big question that should be asked is ”Is it appropriate to have the USDA making these recommendations?” After all, the USDA serves two somewhat conflicting roles: (1)it represents the food industry and (2) it is in charge of educating consumers about nutrition. Many people believe that the pyramid was weighted more toward dairy products, red meat, and grains because of influence from the dairy, beef, and grain farming and processing industries. In other words, the pyramid was designed not to improve the health of Americans but rather to promote the USDA agenda of supporting multinational agrifoods giants (Figure 44-1). One of the main criticisms of the Eating Right Pyramid is that is does not stress strongly enough the importance of quality food choices. For example, the bottom of the pyramid represents the foods that the USDA thinks should make up the bulk of a healthy diet: the Bread, Cereal, Rice, and Pasta Group. Eating 6 to 11 servings a day from this group is supposedly the path to a healthier life. In thisway, the pyramid sets a person up for insulin resistance, obesity, and adult-onset diabetes if he or she consistently chooses refined rather than whole-grain products in this important category. This is one example of how the Eating Right Pyramid does not take into consideration how quickly blood glucose levels rise after eating a certain type of food-an effect referred to as the food’sglycmic index (GI). The GI is a numerical scale used to indicate how fast and how high a particular food raises blood glucose (blood

~

TOTAL

Dry beans, peas, nuts, and soybeans Grain products: Wheat products Corn Other grains TOTAL

Sugar and sweeteners: Refined sugar Syrups and other sweeteners TOTAL

182

86

83

140

16

16

18

22

216 56 19

116 15 13

122 17 26

150 28 24 -

291

144

165

202

77 14

100 22

63 90

68 91

91

122

153

159

Modified from United States Department of AgricuRure. Food Review 2000; 2318-1 5.

Figure 44-1

U.S. Department of Agriculture Food Pyramid.

Nutritional Medicine

sugar) levels. There are two versions of the GI, one based on a standard of comparison with glucose as 100, and the other based on white bread. Foods are tested against the results of the selected standard. Foods with a lower GI create a slower rise in blood sugar, whereas foods with a higher GI create a faster rise in blood sugar. One of the major problems with the Eating Right Pyramid is that the glycemic indices of some of the foods that the pyramid is directing Americans to eat more of, such as breads, cereals, rice, and pasta, can greatly stress blood sugar control, especially if derived from refined grains, and are now being linked to an increased risk for obesity, diabetes, and cancer. As a result, the goal of the Eating Right Pyramid was to improve the health of Americans and, hopefully, slow down the growing trend toward obesity and diet-related disease, but because of poor individual food choices within the categories, the pyramid has only worsened the problem.

THE OPTIMAL HEALTH FOOD PYRAMID On the basis of existing evidence we have created The Optimal Health Food Pyramid (Figure 44-2). The major difference from the USDA pyramid is that the Optimal Health Food Pyramid incorporates the best of two of the most healthful diets ever studied-the traditional Mediterranean diet (see later) and the traditional Asian diet. In addition, the Optimal Health Food Pyramid more clearly defines what the healthy components within the categories are and stresses the importance of vegetable oils and regular fish consumption as part of a healthful diet. Appendix 8 provides a patient handout

that clearly defines the components of the Optimal Health Food Pyramid. We based the Optimal Health Food Diet on the following nine principles: 1. Eat a ”rainbow” assortment of fruits and vegetables. 2. Reduce exposure to pesticides. 3. Eat to support blood sugar control. 4.Do not overconsume animal foods. 5. Eat the right types of fats. 6 . Keep salt intake low, potassium intake high. 7. Avoid food additives. 8. Take measures to reduce foodborne illness. 9. Drink sufficient amounts of water each day.

1. Eat a “Rainbow” Assortment of Fruits and Vegetables A diet rich in fruits and vegetables is the best bet for preventing virtually every chronic disease. That fact has been established time and again in scientific studies on large numbers of people. The evidence in support of this recommendation is so strong that it has been endorsed by U.S. government health agencies and by virtually every major medical organization, including the American Cancer Society. “Rainbow” simply means that selecting colorful foods-red, orange, yellow, green, blue, and purple-provides the body the full spectrum of pigments with powerful antioxidant effects as well as the nutrients it needs for optimal function and protection against disease (Box 44-2). Fruits and vegetables are so important in the battle against cancer that some experts have said, and we believe, that cancer is a result of a ”maladaptation” over

Red

Dark Green-cont’d

Apples (red) Bell peppers (red) Cherries Cranberries Grapefruit Grapes (red) Plums (red) Radishes Raspberries Strawberries Tomatoes Watermelon

Bell peppers (green) Broccoli Brussels sprouts Chard Collard greens Cucumber Grapes (green) Green beans Honeydew melons Kale Leeks Lettuce (dark green types) Mustard greens Peas Spinach Turnip greens

Dark Green Exercise Daily

TEAM:; watching

Pure Water 8-12 glasses

Flgure 44-2 The Optimal Health Food Pyramid.

Artichoke Asparagus

Continued

Therapeutic Modalities

Yellow and Light Green

Orange-cont’d

Apples (green or yellow) Avocado Banana Bell peppers (yellow) Bok choy Cabbage Cauliflower Celery Fennel Kiwi fruit Lemons Lettuce (light green types) Limes Onions Pears (green or yellow) Pineapple Squash (yellow) Zucchini (yellow)

Cantaloupe Carrots Mangoes Oranges Papaya Pumpkin Sweet potatoes Yams

Orange Apricots Bell peppers (orange) Butternut squash

Purple Beets Blackberries Blueberries Cabbage (purple) Cherries Currants Eggplant Grapes (purple) Onions (red) Pears (red) Plums (purple) Radishes

time to a reduced level of intake of fruits and vegetables. As a study published in the medical journal Cancer Causes and Control put it, ”Vegetablesand fruit contain the anticarcinogenic cocktail to which we are adapted. We abandon it at our peril.”6 A vast number of substances found in fruits and vegetables are known to protect against Some experts refer to these as “chemopreventers,” but they are better known to many as phytochemicals (Table 44-3). Phytochemicals include pigments such as carotenes, chlorophyll, and flavonoids; dietary fiber; enzymes; vitamin-like compounds; and other minor dietary constituents. Although they work in harmony with antioxidants like vitamin C, vitamin E, and selenium, phytochemicals exert considerably greater protection against cancer than these simple nutrients. Among the most important groups of phytochemicals are pigments such as chlorophyll, carotenes, and flavonoids.

2. Reduce Exposure to Pesticides and Food Additives In the United States, more than 1.2 billion pounds of pesticides and herbicides are sprayed on or added to food crops each year. That is roughly 5 lb of pesticides for each man, woman, and child. There is a growing concern that in addition to the sigruficant number of cancers caused by the pesticides directly, exposure to these chemicals damages the body’s detoxification mechanisms, thereby raising the risk of cancer and other diseases. To illustrate

Examples of anticancer phytochemicals Phytochemical

Action(s)

Sources

Carotenes

Antioxidants Enhance immune functions

Dark-colored vegetables such as carrots, squash, spinach, kale, tomatoes, yams, sweet potatoes; fruits such as cantaloupe, apricots, citrus fruits

Coumarin

Antitumor properties Enhances immune functions Stimulates antioxidant mechanisms

Carrots, celery, fennel, beets, citrus fruits

Dithiolthiones, glucosinolates. and thiocyanates

Block cancer-causing compounds from damaging cells Enhance detoxification

Cabbage-familyvegetables-broccoli, Brussels sprouts, kale, etc.

Flavonoids

Antioxidants Direct antitumor effects Immune-enhancingproperties

Fruits, particularly darker fruits such as berries, cherries, citrus fruits; also tomatoes, peppers, greens

lsoflavonoids

Block estrogen receptors

Soy and other legumes

Lignans

Antioxidants Modulate hormone receptors

Flax seed and flax seed oil; whole grains, nuts, seeds

Limonoids

Enhance detoxification Block carcinogens

Citrus fruits, celery

Polyphenols

Antioxidants Block carcinogen formation Modulate hormone receptors

Green tea, chocolate, red wine

Sterols

Block production of carcinogens Modulate hormone receptors

Soy, nuts, seeds

Modified from Steinmetz KA, Potter JD. J Am Diet Assoc 1996;96:1027-1039

Nutritional Medicine

just how problematic pesticides can be, one can take a quick look at the health problems of the farmer. The lifestyle of farmers is generally healthy: Compared with city dwellers, farmers have access to lots of fresh food; they breathe clean air, work hard, and have a lower rate of cigarette smoking and alcohol use. Yet studies show that farmers have a higher risk of lymphomas, leukemias, and cancers of the stomach, prostate, brain, and Exposure to pesticides may explain this occurrance. Perhaps the most problematic pesticides are the family of halogenated hydrocarbons, such as 1,l-dichloro-2,2bis(4-chloropheny1)ethylene (DDE), polychlorinated biphenyl (PCB), pentachlorophenol (PCP), dieldrin, and chlordane. These chemicals persist almost indefinitely in the environment. A similar pesticide, dichlorodiphenyltrichlorethane (DDT),has been banned for nearly 30 years yet it can still be found in the soil and root vegetables such as carrots and potatoes. The human body also has a tough time detoxlfylng and eliminating these compounds. Instead, they end up being stored in fat cells. Moreover, inside the body these chemicals can act like the hormone estrogen. They are thus suspected as a major cause of the growing epidemic of estrogen-related health problems, including breast cancer. Some evidence also suggests that these chemicals raise the risk of lymphomas, leukemia, and pancreatic cancer as well as play a role in low sperm counts and reduced fertility in men.I4 Avoiding pesticides is especially important in children of preschool age. Children are at greater risk for two reasons: they eat more food relative to body mass, and they consume more foods higher in pesticide residue-uch as juices, fresh fruits, and vegetables. A recent University of Washington study15that analyzed levels of breakdown products of organophosphoruspesticides (a class of insecticides that disrupt the nervous system) in the urine of 39 urban and suburban children aged 2 to 4 years found that concentrationsof pesticide metaboliteswere six times lower in the children who ate organic fruits and vegetables than in those who ate conventional produce. After conducting an analysis of USDA pesticide residue data for all pesticides for 1999 and 2000, Consumers Union16warned parents of small children to limit or avoid conventionally grown foods known to have high pesticide residues, such as cantaloupes, green beans (canned or frozen), pears, strawberries, tomatoes (Mexican grown), and winter squash. The University of Washington study added apples to this list.

Recommendations for Patients to Avoid Pesticides in the Diet Patients can avoid consuming pesticides in their foods by following these recommended practices: 1.Do not overconsume foods that have a tendency to

concentrate pesticides, such as animal fat, meat, eggs, cheese, and milk.

2. Buy organic produce, which is grown without the aid of synthetic pesticides and fertilizers. Although less than 3% of the total produce in the United States is grown without pesticides, organic produce is widely available. 3. Develop a good relationship with your local grocery store produce manager. Explain your desire to reduce your exposure to pesticides and waxes. Ask what measures the store takes to ensure that pesticide residues are within approved limits. Ask where the store obtains its produce; make sure the store is aware that foreign produce is much more likely to contain excessive levels of pesticides as well as pesticides that have been banned in the United States. 4.Try to buy local produce, in season. 5. Peeling off the skin or removing the outer layer of leaves of some produce may be all you need to do reduce pesticide levels. The downside is that many of the nutritional benefits of fruits and vegetables are concentrated in the skin and outer layers. An alternative measure is to remove surface pesticide residues, waxes, fungicides, and fertilizers by soaking the item in a mild solution of additive-free soap such as Ivory or pure Castile soap. All-natural, biodegradable cleansers are also available at most health food stores. To use, spray the food with the cleanser, gently scrub, and rinse.

3. Eat to Support Blood Sugar Control Refined sugars, white flour products, and other sources of simple sugars are quickly absorbed into the blood stream, causing a rapid rise in blood sugar. In response, the body boosts secretion of insulin by the pancreas. High-sugar, "junk food" diets definitely lead to poor blood sugar regulation, obesity, and ultimately type 2 diabetes and heart di~ease.''-*~The stress on the body that they cause, however, including secretion of too much insulin,can promote the growth of cancer and increases the risk of heart disease as well. As already discussed, the GI of a food refers to how quickly blood sugar levels will rise after it is eaten. However, the GI does not tell how much.of that carbohydrate is in a typical serving of a particular food, so another tool is needed. The glycerrzic loud (GL) is a relatively new way to assess the effect of carbohydrate consumption that takes the GI into account but gives a fuller picture of the effect that a food has on blood sugar levels than GI alone. A GL of 20 or more is high, a GL of 11 to 19 inclusive is medium, and a GL of 10 or less is low. For example, beets have a high GI, but a low GL. Although the carbohydrate in beet root has a high GI, the amount of carbohydrate is low, so a typical serving of cooked beet root has a relatively low GI (about 5). Thus as long one eats a reasonable portion of a low-GL food, the impact on blood sugar is acceptable, even if the food has

Therapeutic Modalities a high GI. For example, a diabetic can enjoy some watermelon (GI 72) as long as he or she keeps the serving size reasonable; the GL for 120 g watermelon is only 4. In essence, foods that are mostly water (e.g., apple, watermelon), fiber ( e g , beet root, carrot) or air (e.g., popcorn) will not cause a steep rise in blood sugar even if their GIs are high as long as portion sizes are moderate. To help design a healthy diet, we provide a list of the GI, fiber content, and GL of common foods in Appendix 6.

4. Reduce Intake of Meat and Other Animal Foods Study after study seems to indicate that the higher the intake of meat and other animal products, the higher the risk of heart disease and cancer, especially the major cancers like those of the colon, breast, prostate, and lung, whereas a diet focusing on plant foods exerts the opposite effect."*21 There are many reasons for this association. Meat lacks the antioxidants and phytochemicals that protect from cancer. At the same time, it contains lots of saturated fat and other potentially carcinogenic compounds-including pesticide residues, heterocyclic amines, and polycyclic aromatic hydrocarbons, which form when meat is grilled, fried, or broiled. The more well done the meat, the higher level of amines.' Some proponents of a diet high in meats claim that people should eat the way their "caveman" ancestors did. That argument does not really hold up. As already discussed, the meat of wild animals that early humans consumed had a fat content of less than 4%. The demand for tender meat has led to the breeding of cattle whose meat contains 25% to 30% or more fat. Domestic beef contains primarily saturated fats and virtually no beneficial omega-3 fatty acids (discussed later), whereas the fat of wild animals contains more than five times the polyunsaturated fat per gram and has substantial amounts (about 4%) of omega-3 fatty acids. Range-fed animals also contain ten times as much conjugated linoleic acid (CLA) as grain-fed animals. CLA is a slightly altered form of the essential fatty acid linoleic acid. It occurs naturally in meat and d a q products. CLA was discovered in 1978, when researchers at the University of Wisconsin were looking for cancer-causing compounds that result from cooking. Instead, they found CLA, which appears to be an anticancer compound. Preliminary studies show that CLA might reduce the risk of heart disease and cancer.u Particularly harmful to human health are cured or smoked meats, such as ham, hot dogs, bacon, and jerky, that contain sodium nitrate and/or sodium nitritescompounds that keep the food from spoiling but that dramatically raise the risk of cancer. These chemicals react with amino acids in foods in the stomach to form highly carcinogenic compounds known as nitrusarnines.

Research in adults makes a convincing argument to avoid these foods. Even more compelling is the evidence linking consumption of nitrates to a sigruficantlyincreased risk of the major childhood cancers (leukemias, lymphomas, and brain cancers), as follows: '

Children who eat 12 hot dogs per month have nearly ten times the risk of leukemia in children who do not eat hot dogs.24 Children who eat hot dogs once a week double their chances of brain tumors; eating hot dogs twice a week triples the risk.24 Pregnant women who eat two servings per day of any cured meat have more than double the risk of bearing children who have brain cancer.25 Kids who eat the most ham, bacon, and sausage have three times the risk of lymphoma." In addition, kids who eat ground meat once a week have twice the risk of acute lymphocytic leukemia compared with those who ate none; eating two or more hamburgers weekly triples the risk.24 Fortunately, vegetarian alternatives to these standard components of the American diet are now widely available, and many of them actually taste quite good. Consumers can find soy hot dogs, soy sausage, soy bacon, and even soy pastrami at their local health food stores as well as in many mainstream grocery stores.

5. Eat the RightType of Fats There is no room for debate: A diet high in fat, particularly saturated fat and cholesterol, has been linked to numerous cancers. Both the American Cancer Society and the National Cancer Institute recommend a diet that supplies less than 30%of calories as fat. However, just as important as the amount of fat is the type of fat consumed. The goal is to decrease total fat intake (especially intake of saturated fats, trans fatty acids, and omega-6 fats) while increasing intake of omega-3 fatty acids and monounsaturated fatty acids. What makes a fat "bad" or "good" has a lot to do with the function of fats in the body's cellular membranes. Membranes are made mostly of fatty acids. What determines the type of fatty acid present in the cell membrane is the type of fat consumed. A diet composed mostly of saturated fat, animal fatty acids, and trans fatty acids (from margarine, shortening, and other sources of hydrogenated vegetable oils) and high in cholesterol results in membranes that are much less fluid in nature than a diet with optimal levels of unsaturated fatty acids. Modem pathology clearly indicates that an alteration in cell membrane function is the central factor in the development of virtually every disease. As it relates to diabetes, abnormal cell membrane structure due to eating the wrong types of fats leads to impaired action of insulin.

Nutritional Medicine Without a healthy membrane, cells lose their ability to hold water, vital nutrients, and electrolytes. They also lose their ability to communicate with other cells and to be controlled by regulating hormones, including insulin. Without the right type of fats in cell membranes, cells simply do not function properly. Considerable evidence indicates that cell membrane dysfunction is a critical factor in the development of many diseases. The type of dietary fat profile that is linked to many diseases is an abundance of saturated fat and trans fatty acids (hydrogenated vegetable oils) along with a relative insufficiency of monounsaturated and omega-3 fatty acids. One of the key reasons appears to be that because dietary fat determines cell membrane composition, such a dietary pattern leads to reduced membrane fluidity, which in turn causes reduced insulin binding to receptors on cellular membranes and/or reduced insulin action. Particularly harmful to cell membrane function are margarine, vegetable oil shortening, and other foods containing trans fatty acids and partially hydrogenated oils. These "unnatural" forms of fatty acids interfere with the body's ability to utilize important essential fatty acids and are now linked to an increased risk for heart disease, diabetes, and cancer. Just the opposite effect has been shown for diets high in monounsaturated fats and omega-3 fatty One diet that appears to be representative of a way of eating that that provides an optimal intake of the right types of fat is the traditional Mediterranean dieta term with a specific meaning. It reflects food patterns typical of some Mediterranean regions in the early 1960s, such as Crete, parts of the rest of Greece, and southern Italy. The traditional Mediterranean diet has shown tremendous benefit in fighting heart disease and cancer as well as diabetes.30 It has the following characteristics:

agents that may also account for some of its health benefits. Olive oil is particularly valued for its protection against heart disease. It lowers the harmful low-density lipoprotein (LDL) cholesterol and increases the level of protective high-density lipoprotein (HDL) cholesterol. It also helps circulating LDL cholesterol from becoming damaged by free radicals and has been proved to contribute to a better control of the elevated blood triglycerides that is so common in diabetes.30

6. Keep Salt Intake Low, Potassium Intake High The electrolytes-potassium, sodium, chloride, and magnesium-are mineral salts that can conduct electricity when dissolved in water. For optimal health, it is important to consume these nutrients in the proper balance. Too much sodium in the diet from salt (sodium chloride) can disrupt this balance. Many people know that a high-sodium, low-potassium diet can cause high blood pressure and that doing the opposite can lower blood pressure13132but not as many are aware that the former diet also raises the risk of ~ancer.3~ In modem Western society, only 5% of sodium intake comes from the natural ingredients in food. Prepared foods contribute 45% of our sodium intake; 45%is added in cooking, and another 5%is added as a condiment. Patients can reduce their salt intake by following these tips:

Olive oil is the principal source of fat. It centers on an abundance of plant food (fruit, vegetables, breads, pasta, potatoes, beans, nuts, and seeds). Foods are minimally processed, and there is a focus on seasonally fresh and locally grown foods. Fresh fruit is the typical daily dessert, sweets containing concentrated sugars or honey being consumed a few times per week at the most. Dairy products (principally cheese and yogurt) are consumed daily in low to moderate amounts. Fish is consumed on a regular basis. Poultry and eggs are consumed in moderate amounts (1-4 times weekly) or not at all. Red meat is consumed in low amounts. Wine is consumed in low to moderate amounts, normally with meals.

1.Take the salt shaker off the table. 2. Omit added salt from recipes and food preparation. 3. If you absolutely must have the taste of salt, try the salt substitutes such as NoSalt and Nu-Salt. These products are made with potassium chloride and taste very similar to sodium chloride. 4. Learn to enjoy the flavors of unsalted foods. 5. Try flavoring foods with herbs, spices, and lemon juice. 6 . Read food labels carefully to determine the amounts of sodium. Learn to recognize ingredients that contain sodium. Salt, soy sauce, salt brine, and any ingredient with "sodium" (such as monosodium glutamate) or "baking soda" (sodium bicarbonate) as part of its name contains sodium. 7. In reading labels and menus, look for words that signal high sodium content, such as smoked, barbecued, pickled, broth, soy sauce, teriyaki, Creole sauce, marinated, cocktail sauce, tomato base, Parmesan, and mustard sauce. 8. Do not eat canned vegetables or soups, which are often extremely high in sodium. 9. Choose low-salt (reduced-sodium) products when available.

Olive oil consists not only of the monounsaturated fatty acid oleic acid; it also contains several antioxidant

Most Americans have a potassium/sodium (K:Na) ratio of less than 1:2.In other words, they ingest twice as

much sodium as potassium. But experts believe that the optimal dietary potassium/sodium ratio is greater than 5:l-ten times higher than the average intake. However, even this may not be optimal. A natural diet rich in fruits and vegetables can easily produce much higher KNa ratios, because most fruits and vegetables have a K:Na ratio of at least 50:l. The average K:Na ratios for several common fresh fruits and vegetables are as follows: Carrots: 75:l Potatoes: 11O:l Apples: 90:l Bananas: 44O:l Oranges: 260:l

7. Avoid Food Additives Food additives are used to prevent spoiling or to enhance flavor; they include such substances as preservatives, artificial colors, artificial flavorings, and acidifiers. Although the government has banned many synthetic food additives, it should not be assumed that all the additives currently used in the U.S. food supply are safe. A great number of synthetic food additives remain in use that are being linked to such diseases as depression, asthma or other allergy, hyperactivity or learning disabilities in children, and migraine headaches.g37 The U.S. Food and Drug Administration (FDA) has approved the use of more than 2800 different food additives. It is estimated that the per capita daily consumption of these food additives is approximately 13 to 15 g. This amount is astounding and leads to many questions. Which food additives are safe? Which should be avoided? An extremist might argue that no food additive is safe. However, many food additives fulfill important functions in the modem food supply. Many compounds approved as additives are natural in origin and possess healthpromoting properties, whereas others are synthetic compounds with known cancer-causing effects. Obviously, the most sensible approach is to focus on whole, natural foods and avoid foods that are highly processed. An illustration of the problem with food additives, is one of the most widely used synthetic food colors, FD&C (Food, Drug and Cosmetic Act) yellow dye no. 5, or tartrazine. Tartrazine is added to almost every packaged food as well as to many drugs, including some antihistamines, antibiotics, steroids, and sedatives. In the United States, the average daily per capita consumption of certified dyes is 15 mg, of which 85% is tartrazine; among children, consumption is usually much higher. Although the overall rate of allergic reactions to tartrazine is quite low in the general population, allergic reactions to tartrazine are extremely common (20% to 50%) in individuals sensitive to aspirin as well as other allergic individuals. Like aspirin, tartrazine is a known inducer of asthma, hives, and other allergic conditions,

particularly in children. In addition, tartrazine, as well as benzoate and aspirin, increases the production of a compound that raises the number of mast cells in the body. Mast cells are involved in producing histamine and other allergic compounds. A person with more mast cells in the body is typically more prone to allergies. For example, examination of patients with hives shows that more than 95% have a higher than normal number of mast cells. In studies using provocation tests to determine sensitivity to tartrazine and other food additives in patients with hives, results have ranged from 5% to 46%. Diets eliminating tartrazine as well as other food additives in sensitive individuals have, in many cases, been shown to be of great benefit in patients with hives and other allergic conditions, such as asthma and eczema.

8.Take Measures to Reduce Foodborne Illness Foodborne illness is caused by consumption of contaminated foods or beverages. Although the food supply in the United States is one of the safest in the world, the Centers for Disease Control and Prevention estimates that 76 million people get sick, more than 300,000 are hospitalized, and 5000 Americans die each year from foodborne illness.38The microbe or toxin enters the body through the gastrointestinal tract and often causes the first symptoms there, so nausea, vomiting, abdominal cramps, and diarrhea are common symptoms in many foodbome diseases. Most cases of foodbome illness are mild, but serious diarrheal disease or other complications may occur. More than 250 different organisms have been documented as being capable of causing foodborne illne~s.3~ Most of these cases are infections by a variety of bacteria, viruses, and parasites, but poisonings can also occur as a result of ingestion of harmful toxins or chemicals from organisms that have contaminated the food; for example, botulism occurs when the bacterium Clostridiurn botuliizurn grows and produces a powerful paralytic toxin in foods. The botulism toxin can produce illness even if the bacteria are no longer present. Most of the common causes of foodbome infections are microorganisms frequently present in the intestinal tracts of healthy animals. Meat and poultry can become contaminated during slaughter by contact with small amounts of intestinal contents, and fresh fruits and vegetables can be contaminated if they are washed or imgated with water that is contaminated with animal manure or human sewage. The most common causes of foodbome infections are the bacteria Carnpylobacter, Salmonella, and Escherichia coli 0157:H7 and a group of viruses called caliciviruses, also known as the Norwalk and Norwalk-like viruses. Undercooked meat and poultry, raw eggs, unpasteurized

Nutritional Medicine milk, and raw shellfish are the most common sources of these organisms. Curnpylobacter is a bacterial pathogen that causes fever, diarrhea, and abdominal cramps. It is the most commonly identified bacterial cause of diarrheal illness in the world. These bacteria live in the intestines of healthy birds, and most raw poultry meat has Cumpylobacter on it. Eating undercooked chicken or other food that has been contaminated with juices dripping from raw chicken is the most common source of this infection. Salmonella is widespread in the intestines of birds, reptiles, and mammals. It can spread to humans via a variety of different foods of animal origin. The illness it causes, salmonellosis, typically involves fever, diarrhea, and abdominal cramps. In persons with poor underlying health or weakened immune systems, the organism can invade the bloodstream and cause life-threatening illness. E. coli 0157H7 is a bacterial pathogen with a reservoir in cattle and other similar animals. Human illness typically follows consumption of food or water that has been contaminated with microscopic amounts of cow feces. The illness it causes is often a severe and typically provokes bloody diarrhea and painful abdominal cramps, without much fever. In 3%to 5%of cases, a complication called hemolytic-uremic syndrome (HUS) can occur several weeks after the initial symptoms. This severe complication consists of temporary anemia, profuse bleeding, and kidney failure. Calicivirus, or Norwalk-like virus, is an extremely common cause of foodborne illness, though it is rarely diagnosed because the laboratory test for its detection is not widely available. The v h s causes an acute gastrointestinal illness, usually with more vomiting than diarrhea, that usually resolves within 2 days. It is believed that unlike many foodborne pathogens that have animal reservoirs, Norwalk-like viruses spread primarily from one infected person to another. Infected kitchen workers can contaminate a salad or sandwich as they prepare it, if they have the virus on their hands. Infected fishermen have contaminated oysters as they harvested them. The foremost measure to reduce the risk of foodborne illness is to cook meat, poultry, and eggs thoroughly. Using a thermometer to measure the internal temperature of meat is a good way to be sure that it is cooked sufficiently to kill bacteria. For example, ground beef should be cooked to an internal temperature of 160" F, poultry should reach a temperature of 185" F, and an egg should be cooked until the yolk is firm. One must also take care to avoid contaminating foods by making sure to wash hands, utensils, and cutting boards after they have been in contact with raw meat or poultry and before they touch another food. Cooked meat should be served on a clean platter, rather than back on one that held the raw meat. To prepare produce,

one should wash fresh fruits and vegetables in running tap water. A soft-bristle brush with a little a mild soap can be used. Greens can be soaked in cold water as many times as needed to get them clean.

9. Drink Sufficient Amounts of Water Each Day Water is essential for life. The average amount of water in the human body is about 10 gallons. The recommendation to drink at least 48 ounces of water per day to replace the water that is lost through urination, sweat, and breathing is valid. Even mild dehydration impairs physiologic and performance Many nutrients dissolve in water so they can be absorbed more easily in the digestive tract. Similarly, many metabolic processes need to occur in water. Water is a component of blood and thus is important for transporting chemicals and nutrients to cells and tissues. Each cell is constantly bathed in a watery fluid. Water also carries waste materials from cells to the kidneys for filtering and elimination.Water absorbs and transports heat. For example, heat produced by muscle cells during exercise is carried by water in the blood to the surface, helping to maintain the right temperature balance. The skin cells also release water as perspiration, which helps maintain body temperature. Several factors are thought to increase the likelihood of chronic mild dehydration: a faulty thirst "alarm" in the brain; dissatisfaction with the taste of water; regular exercise that increases the amount of water lost through sweat; living in a hot, dry climate; and consumption of the natural diuretics caffeine and alcohol. There is currently a great concern over the U.S. water supply. It is becoming increasingly difficult to find pure water. Most of the water supply is full of chemicals, including not only chlorine and fluoride, which are routinely added, but also a wide range of toxic organic compounds and chemicals, such as PCBs, pesticide residues, and nitrates, and heavy metals such as lead, mercury, and cadmium. It is estimated that lead alone may contaminate the water of more than 40 million Americans. Patients should be encouraged to determine the safety of their tap or well water by contacting their local water companies; most cities have quality assurance programs that perform routine analyses. Patients can simply ask for the most recent analysis.

NUTRITIONAL SUPPLEMENTATION Nutritional supplementation-the use of vitamins, minerals, and other food factors to support good health as well as preventing or treating illness-is an important component of nutritional medicine. The key functions of nutrients like vitamins and minerals in the human body revolve around their role as essential components in

Therapeutic Modalities

enzymes and coenzymes. One of the key concepts in nutritional medicine is to supply the necessary support or nutrients to allow the enzymes of a particular tissue to work at their optimum levels. The concept of “biochemical individuality” was coined by nutritional biochemist Roger Williams in the 1970s to recognize the wide range in enzymatic activity and nutritional needs of humans. These observations also provided the basis for ”orthomolecular medicine” as envisioned by two-time Nobel laureate Linus Pauling. In addition to serving as necessary components in enzymes and coenzymes, many nutrients appear to exert pharmacologic effects. Most of these effects appear to be the result of enzyme induction. In other words, when used at supraphysiologic levels, nutrients can induce the manufacture of enzymes, induce enzymes to become more active, or even inhibit enzyme action. For example, the B vitamin niacin (nicotinic acid) is well known as a lipid-lowering agent when given at high dosages (2-6 g/day in divided doses). Its mechanism of action is quite diverse but appears to occur via inhibition of enzymes that manufacture of very-low-density

lipoprotein (VLDL) while stimulating the production or activity of enzymes that take up LDL in the liver. The advantage of using nutrients at pharmacologic dosages is that they are more recognizable and better metabolized by the body, as evidenced by a broader therapeutic index. Even so, the use of nutrients as pharmacologic agents is closely akin to drug therapy. That being the case, it is imperative that they be used and monitored appropriately.

1. Ryde D. What should humans eat? Practitioner 1985;232:415-418. 2. Milton K. Nutritional characteristics of wild primate food: d o the diets of our closest living relatives have lessons for us? Nutrition 1999;1548&498. 3.Cordain L, Eaton SB, Miller JB, et al. The paradoxical nature of hunter-gatherer diets: meat-based, yet non-atherogenic. Eur J Clin Nutr 2002;56(S~ppll):S42-S52. 4. Eaton SB, Eaton SB 3rd. Paleolithic vs. modem diets-seleded pathophysiological implications. Eur J Nutr 2OOO;39:67-70. 5. Trowell H, Burkitt D. Westem diseases: their emergence and prevention. Cambridge, MA: Harvard University Press, 1981. 6. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. 11. Mechanisms. Cancer Causes Control 1991;2:427-442. 7. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc 1996;96:1027-1039. 8. La Vecchia C, Tavani A. Fruit and vegetables, and human cancer. Eur J Cancer Prev 1998;73-8. 9. Van Duyn MA, Pivonka E. Overview of the health benefits of fruit and vegetable consumption for the dietetics professional: selected literature. J Am Diet Assoc 2OOO;100:1511-1521. 10. Aronson KJ, Miller AB, Woolcott CG, et al. Breast adipose tissue concentrations of polychlorinated biphenyls and other organochlorines and breast cancer risk. Cancer Epidemiol Biomarkers Prev 2000;955-63. 11. Baris D, Zahm SH. Epidemiology of lymphomas. Curr Opin Oncol 2OOO;12:383-394. 12. Blair A, Zahm SH. Agricultural exposures and cancer. Environ Health Perspect. 1995;103(Suppl8):205-208. 13. Mao Y, Hu J, Ugnat AM, White K. Non-Hodgkin’s lymphoma and occupational exposure to chemicals in Canada. Canadian Cancer Registries Epidemiology Research Group. Ann Oncol 2000;ll (SUPPI1):69-73. 14. Jaga K, Brosius D. Pesticide exposure: human cancers on the horizon.Rev Environ Health 1999;1439-50.

15.Lu C, Knutson DE, Fisker-Andersen J, Fenske RA. Biological monitoring survey of organophosphorus pesticide exposure among preschool children in the Seattle metropolitan area. Environ Health Perspect 2001;109(3):299-303. 16. Consumers Union of United States, Inc. Do you know what you’re eating? An analysis of U.S. government of data of pesticide residues in foods. Washington, DC:Consumers Union, February 1999. 17. Jenkins DJ, Kendall CW, Augustin LS, et al. Glycemic index: overview of implications in health and disease. Am J Clin Nutr 2002;76:266S2673S. 18. Willett W, Manson J, Liu S. Glycemic index, glycemic load, and risk of type 2 diabetes. Am J Clin Nutr 2002;76274S2805. 19. Liu S, Willett WC, Stampfer MJ, et al. A prospective study of dietary glycemic load, carbohydrate intake, and risk of coronary heart disease in US women. Am J Clin Nutr 2000;71:1455-1461. 20. Bingham SA. High-meat diets and cancer risk. Proc Nutr Soc 1999;58:243-248. 21. Segasothy M, Phillips PA. Vegetarian diet: panacea for modem lifestyle diseases? QTM 1999;92:531-544. 22. Zheng W, Gustafson DR, S i a R, et al. Well-done meat intake and the risk of breast cancer. J Natl Cancer Inst 1998;901724-1729. 23. Whigham LD, Cook ME, Atkinson RL. Conjugated linoleic acid: implications for human health. Pharmacol Res 2000;42.503-510. 24. Blot WJ, Henderson BE, Boice JD Jr. Childhood cancer in relation to cured meat intake: review of the epidemiological evidence. Nutr Cancer 1999;34:111- 118. 25. Preston-Martin S, Pogoda JM, Mueller BA, et al. Maternal consumption of cured meats and vitamins in relation to pediatric brain tumors. Cancer Epidemiol Biomarkers Prev 1996;5599-605. 26. Bougnoux P. n-3 polyunsaturated fatty acids and cancer. Curr Opin Clin Nutr Metab Care 1999;2:121-126. 27. Bucher HC, Hengstler P, Schindler C, Meier G. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med 2002;112:298-304.

FINAL COMMENTS The dietary guidelines and principles that are detailed in this chapter represent our answer to the hotly debated question “What is the best diet?“ After a review of every popular diet in detail as well as thousands of scientific articles on the role of diet in human health, our offering here is based on the evolutionary understanding of what constitutes the optimal diet. The bottom line for a healthpromoting diet is to reduce the intake of potentially harmful substances-foods laden with empty calories, additives, and artificial sweeteners-and replace them with natural foods, preferably organically grown.

Nutritional Medicine 28. Fraser GE. Nut consumption, lipids, and risk of a coronary event. Clin Cardiol1999;22(Suppl):ll-15. 29. Jiang R, Manson JE,Stampfer MJ, et al. Nut and peanut butter consumption and risk of type 2 diabetes in women. JAMA 2002;288: 2554-2560. 30.Alarcon de la Lastra C, Barranco MD, Motilva V, Herrerias JM. Mediterranean diet and health: biological importance of olive oil. Cum Phan-n Des 2001;7933-950. 31. Whelton PK, He J. Potassium in preventing and treating high blood pressure. Semin Nephrol1999;19494-499. 32. Sacks FM,Svetkey LP, Vollmer Wh4, et al.Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001;344:3-10. 33. Jansson B. Potassium, sodium, and cancer: A review. J Env Pathol TOX~COI On~011996;15:65-73.

34. Boris M, Mandel FS.Foods and additives are common causes of the attention deficit hyperactive disorder in children. Ann Allergy 1994;72462-468. 35.Lessof MH. Reactions to food additives. Clin Exp Allergy 1995;25(S~ppl1):27-28. 36. Groten JP, Butler W, Feron VJ,et al. An analysis of the possibility for health implications of joint actions and interactions between food additives. Re@ Toxic01 Pharmacol2000;31:77-91. 37. Simon RA. Adverse reactions to food additives. Curr Allergy Asthma Rep 2003;3:62-66. 38. Lasky T. Foodborne illness-old problem, new relevance. Epidemiology 2002;13:593-598. 39. Tauxe RV. Emerging foodbome pathogens. Int J Food Microbiol 2002;78:3141. 40. Kleiner SM. Water: an essential but overlooked nutrient. J Am Diet ASSW1999;99:200-206.

Peat Therapeutics and Balneotherapy Mark D. Groven, ND CHAPTER CONTENTS Introduction 475 Balneology 476 History 476 Balneotherapy in Combination with Other Therapies 476 Physiologic Effects 476 Circadian Rhythms 477 Peat Therapeutics 477 History 477 Skin Response 477 Physiologic Effects 478 Hyperthermia 478 Clinical Applications 479 Discopathy 479 Myopathy 479 Scoliosis 479 Arthritis 479 Headache 479

INTRODUCTION Nature has provided many gifts of healing. One of the most outstanding and exciting is peat. The use of organic peat and its constituents is ancient, yet people with pain, injury, and dermatologic, rheumatic, and other conditions are benefiting from modern peat therapy today. This pleasant and safe healing discovery has brought relief and cure for many.'-'* BaZneoZogy is the study of the art and science of bathing. Balneotherapy is the use of natural thermal mineral waters, additive baths, peloids, and other natural substances as well as various atmospheric or environmental elements singly or in combination for the prevention and treatment of disease. The aim of balneotherapy is to change regulation and reactive functions, leading to improvement of capacity, adaptation, and ~elf-healing.'~ Peloid refers to the pulp of a substance that is applied to the body. It may be in pack form or bath, either local or whole body. The concentration of peloidal solutions

Hamstring Strain 479 Ankle Sprain 479 Molluscum Contagiosum 479 Hypertension 480 Dermatologic Problems 480 Scleroderma 480 Human Papillomavirus 480 Herpes Virus 480 Infertility 480 Ankylosing Spondylitis 480 Hematoma 480 Immune Stimulation 480 Clinical Procedures 481 Hyperthermic Medicinal Peat Bath 481 Medicinal Peat Peloid 483 Partial-Immersion Medicinal Peat Bath 484 Combination Full Bath and Peat Pack 484 Conclusion 484

can vary and should be applied to the skin in a specific manner for a specific condition to optimize results. Common peloids are peat pulp, lake or sea muds, and plant substances. For many conditions balneotherapy works synergistically with peloid therapy, and the percutaneous absorption of their constituents along with the physiological and psychologic effects provides an excellent therapy for people who can no longer tolerate oral or injectable pharmaceuticals and are suffering from chronic degenerative diseases. Life is stressful, and our society is aging. We would be wise to utilize the positive benefits of balneotherapy in the conventional treatment of pain and illness as well as in health maintenance and prevention of disease. The purpose of this chapter is to describe the general concept of balneotherapy with emphasis on the therapeutic application of peat. There certainly is a distinction between the application of peat and the application of other muds such as lake mud or clay. 475

Vitally important are the characteristics of the specific peat mud constituents being used as well as the manner of their application.*

BALNEOLOGY History Therapeutic bathing is an ancient art and probably the oldest of medical procedures. Hippocrates wrote on the application of therapeutic bath in 400 BC and how it soothed pain in the side, improved respiration, soothed the joints and skin, was diuretic, and removed heaviness of the head. It was suited for those who benefited but could be unsuitable if applied in the wrong way. It enjoyed tremendous popularity until about 75 years ago when, along with other natural techniques, it fell out of favor as conventional medicine produced its modem successes. Since then, the large corpus of empirical wisdom has been expanded on and much scientific evidence has contributed to the advancement of balneology as a science. Regular research continues in this field. Every 4 years a conference of the International Society of Medical Hydrology and Climatology (ISMH)presents new scientific research and validates its findings. World Peat Congresses meet to discuss the medical use of peat, and symposiums are held on peat therapeutics and its application in health care?6 Many institutions are teaching hydrotherapy and balneologic techniques, and many spas have wonderful programs for people to utilize. It is not hard to imagine that the reason this art has survived and improved is because it can better people’s health. Balneotherapy’s modem-day roots lie predominantly in European spas, which have some of the longest continuously running histories of any medical institution. Millions of patients flock to clinics throughout Europe and the world each year for treatment in hydrology departments under the supervision of physicians and their staffs. Such clinics provide a variety of balneotherapeutic techniques. Spa therapy is a term used for the combination of balneotherapy and other techniques usually delivered at a resort setting. The effects of spa therapy are influenced positively by the pleasure of being in a beautiful setting with the stresses of home and work removed. Medical spas are often in an area where earth’s elements enter in. The pristine air, the ambient temperature, the humidity or amount of light, nourishing food, and exercise can affect a change in the spirit, mind, and body.”

Balneotherapy in Combination with Other Therapies Many therapies work well together, such as phototherapy and mud therapy in the treatment of psoriasis. ‘References7. 10. 11. 13. 16.18-25.

Mud pack therapy, peloidotherapy, massage, soft and osseous tissue manipulation, iontophoresis, phonophoresis, and exercise work t0gether.2~The combination of buoyancy and heat in the water make sense,for example, in underwater traction bath and massage, which have been shown to reduce the levels of analgesic consumption in patients.ls In my own experiences with patients, hydrotherapy with and without mud in combinationwith other treatments such as naturopathic manipulation can work like nothing else to help people heal and stay healthy. A multitude of conditions can be treated with balneotherapeutic methods--pain, injury, and dermatologic and rheumatic conditions rank high?JyBBUnder the right conditions and with the right application, balneotherapy stimulates healing and speeds recovery. Contrast bath in the treatment of obesity may function to promote homeostasis when used in combination with exercise. Promotion of thermogenesis mechanisms may help obese patients begin to lose weight, enhance lipid metabolism, and improve some aspects of hypertension. Contrast bath enhances the positive effects of dietary changes; when these methods are given in combination patients have the best results.3o

Physiologic Effects Balneotherapeuticsinduce direct and indirect actions on the body. The direct actions of balneotherapy take into consideration the physical actions of water on the body, such as hydrostatic pressure, buoyancy, viscosity, and frictional resistance, as well as thermal effects and the chemical and pharmacologic effects of the percutaneous absorption of the substance being used. Such substances are hot spring waters of various types, such as carbon dioxide, hydrogen sulfide, chloride, sulfate, iron, acid, and radon. Mineral waters contain cations such as Na+, K+, Ca+,and Mg+ and anions SO4-, C1-, and HC03-. The concentrations of these ions are usually significantly high (1 g/L). In spring water, levels of nitrogen compounds such as NO3, NO2,and NO are very low and the water is free of or low in bacteria.17 Peat muds, plant preparations, and mineral-containing muds are also used. In Europe, peat bath and peloids are traditional. These applications are used in combination with exercise, aquatics, steam bath, sauna therapy, climatotherapy, physical therapy, and pharmacotherapy, among others, with important consideration being given during treatment to the chronobiologic and circadian rhythmic phases of the body.1J4,U,25-28 The indirect actions of balneotherapy arise from the repeated application of therapeutic stimulation, such as climatic exposure to the elements, training effects of exercises, and social and psychological effects arising from changes in environment. These elements act as a complex stimulation in a nonspecific manner of the

Peat Therapeutics and Balneotherapy

physiologic function of the organism's central nervous system, autonomic nervous system, endocrine system, immune system, and so on. The result of these stimulations is a reactive response by the body, leading to activation and improvement of capacity, adaptation, and self-healing potential. In other words balneotherapy has a normalizing effect on the body's systems and rhythms.*

Circadian Rhythms Biorhythms are important in the expression of many cond i t i ~ n s . Sunlight, ~ , ~ ~ mealtimes, and seasonal changes are external cues that, together with internal cues such as blood pressure and respiration, affect the hypothalamus or master clock. This part of the brain then signals hormones, enzymes, and other substances to facilitate healing, produce cells, or cause pain and symptoms. It has been shown that different times of day affect the amount of muscle torque potential, body temperature, and clockgene messenger RNA (mRNA)expression.42A cold or hot foot bath can induce rise in temperature of oral mucosa up to 1"C, but the extent of the oral temperature increase depends on the body's reaction to this stimulus, which is influenced by the body's own internal clock.' Conditions such as arthritis have pain with varying cycles.43It is thought that some of these cycles are in synchrony with the moon and the sun. Heart attacks, asthma, and rheumatoid arthritis joint pain are early morning diseases, so medication and treatment can be tailored for different times of day when it is sigruficantly more helpful and less wasteful when not needed. Serum adrenocorticotropic hormone (ACTH), prolactin, luteinizing hormones, and immune parameters such as plasma levels of soluble p75 tumor necrosis factor (sTNF-R75)and tumor necrosis factor-alpha (TNF-a)vary in 24hour rhythms in the body? These may be affected through balneotherapy, as may melatonin production and expression. Melatonin affects the organization and expression of biorhythms and is easily susceptible to oxidative stress. Symptom remission in some conditions coincides with a normalization of circadian rhythms promoted by balneotherapeutic treatment.4447In a European study, the combination of carbon dioxide bath and mud bath was shown to downregulate the systolic pressure in hypertension while having a balancing effect on biologic clocks.48A study on patients fibromyalgia in whom altered reactivity of the hypothalamic-pituitaryadrenal (HPA) axis was observed supports the theory that mud pack therapy works in synergy with antidepressant treatment to decrease pain and improve depression. Balneotherapy can promote the body's

*References 2, 4, 7, 10, 11, 15, 31-39.

response systems, such as the stress response system, to achieve homeo~tasis.4~

PEAT THERAPEUTICS History The ancients used peat extract baths, and the antiseptic properties of peat mud were recognized in World War I when it was applied directly to wounds to prevent infe~tion.4~ Native used mud externally and internally. Peat has been used as a medicinal preparation in baths and peloid packs extensively in Europe for the past 200 years. This unique substance contains many chemical constituents that can interact with organic and inorganic compounds.20The scientific basis for the physical, chemical, and pharmacologic effects of peat baths has been long known, and such baths have been used extensively in balneotherapeutic applications in Europe and other parts of the world to treat rheumatic diseases, gynecologic disorders, osteoarthritis, lumbago, sciatica, skin diseases, trauma and its sequelae, and many other aliments and afflictions. The many substances in peat offer a vast possibility of medicinal cure a p p l i ~ a t i o n s . 5 ~ ~ ~ It is important to consider the region and origin of the peat being used for medicinal purposes. Low moor peat has been shown to contain higher concentrations of nitrous substances, which are thought to contain a higher content of biologically active substances than the high moor peats or peats taken from a shallower depth. It is not just high nitrous content that makes a certain peat more medically useful, but the quality, type, and amount of the biologically active substances it contains that are the determining factors in medicinal effect. In Germany these types of peats are now a national resource.

Skin Response The skin is a reflex, metabolic, immune, and excretory organ. It affects the autonomic, immune, and circulatory systems and participates in the biosynthesis of not only vitamin D but also acetylcholine, histamine, and serot ~ n i n . ~ ,Sigruficantly ~ J ~ J ~ higher concentrationsof minerals and medicaments can be attained in the epidermis with baths than with systemic flooding via the vascular system. There is percutaneous uptake of many substances by the skin but not in large amounts for most natural substances. Permeation into the dermis does occur especially for humic acids, and uptake beyond the stratum corneum is exemplified by measurable urinary excretion rates.60,61 The primary effects of bath components take place within the skin. For instance, hydrogen sulfide acts as a trap for oxygen radicals, functioning to reduce inflammation. It is thought that the action comes from the effect

of sulfur on the Langerhans cells, which play a role in immune presentation and inflammation modulation. In this way, skin responses can act as transmitter-activating helper functions. Sulfur-containing peat baths demonstrate a pain-reducing and healing effect on rheumatic and degenerative diseases. One reason may be the reduction in Langerhans cell activity in producing cytokines that results from the combination of the components within peat and thermal radiation.*

Physiologic Effects Peat has a structure containing micropores, which accounts for its spongelike watercarrying capacity and its ability to maintain either hot or cold temperatures. When applied, peat produces a gradient rise or fall in temperature, which is especially desirable in a therapeutic bath. A peat formulation bath influences and neuromuscular, endocrine, and pulmonary functions,kidney hemodynamics, depending on the consistency and volume of the partial or full bath?JOPeat has well-documented effects such as tissue dilatation and increases in strokevolume, metabolism, and immunologic stimulation. Peat bath may be preferable to water bath if one considers the gradient rise and fall of temperature, increased buoyancy, and prevention of heat loss during a bath and the possible positive chemical and pharmacologic effects of the constituents of peat.59a Those who have experienced a therapeutic bath can appreciate the feelings of exhilaration and deep relaxation induced by a bath that contains an additive such as peat. The response is affected by the constituents in the water, the temperature of the bath, and the time of day the stimulus is given.63 The patient’s genetics and physical capacity are also important. Peat bath enhances circulation significantly longer than water bath.21 Microcirculatory vasodilatation in the skin has been shown to increase even without hyperthermia. The peripheral and deeper arteries such as the intrauterine vessels have shown prolonged increased flow after peat bath. The effects of peat constituents can occur without heat, but heat increases the effect on the body. The antirheumatic activity of thermal muds has a precise pharmacologic character. Therapy can be prescribed according to the characteristics of the mud for specific For example, specific muds work better with phototherapy for psoriasis and atopic dermatitis. The length of time that the peat mud has undergone humificaton and maturation lends unique characteristics. Maturation of peat muds increases their thermoinsulating, hydration, and, importantly, biochemical characteristics. The sulfoglycolipid content of mature mud differentiates a natural remedy from a specific

‘References 2, 7, 15. 19. 22. 49, 62.

application with a precise pharmacologic character. These sulfoglycolipids are absorbed through the skin and stimulate an antirheumatic effect.65 Several peat substances are able to permeate the skin.61Their absorption and action have been documented by the comparisons of placebo, water bath, and peat bath using Doppler ultrasound measurement. One study that measured circulation in the uterine artery after bath therapy showed that only the peat bath achieved the physiologic effect of prolonged vasodilatation and circulation. This effect lasts for several hours after the treatment. It is thought that absorption of peat substances takes place through the hair follicles and apocrine glands via diffusion and partial pinocytosis.21”8The fractions of peat components that penetrate the skin include the humic acid fractions, fulvic, ulmic, and volvic. The excitatory effect of humic acid fractions such as fulvic acid impact the reactivity of a2 and D2 receptors of smooth muscle cells.62 The functions of peat in medicinal applications are antimicrobial, antiviral, antiinflammatory, and antineoplastic, to name a few.63Many biochemical effects have been demonstrated in humans and animals. The antiinflammatory effect of peat mud has been attributed to a sulfoglycolipid associated with a decrease in serum interleukin-1 (IL-1) in patients with arthritis.” The effects of mud applications include elevation of protein synthesis, reduction of arachidonic acid, and inhibition of inflammatory mediators such as leukotrienes, prostaglandins, and thromboxane. Biologic activity is ascribed to peat ingredients such as sulfur compounds, magnesium, manganese, iron, and humic acids.* Mud pack therapy decreases the proinflammation factors IL-1 and TNF-a and also increases serum levels of insulin-like growth factor 1(IGF-l), which is cartilage protective. Humic substances spread widely in nature and found mainly in highly degraded peat have been shown to have a proliferative effect on certain leukocytes. Water-soluble oxihumate, given orally or dermally, increases the proliferative response in mononuclear leukocytes as well as production and expression of IL-2.2,49

Hyperthermia The thermal properties of peat mud applications have been shown to be much greater than those of waterbath because of the former’s dynamic viscosity, decreased convective cooling, and a protective effect on the skin with hot applications? Whole-body, extracorporal, and local infrared applications of hyperthermia have uses in cancer therapy. Hyperthermic effects include changes in heat shock proteins (HSP) and upregulation of heart antioxidant defense proteins such as manganese superoxide d i ~ m u t a s eAlso . ~ ~ plasma B-endorphins rise

’References 6, 7, 10, 11, 16. 19, 24

Peat Therapeutics and Balneotherapy

in response to hot water bathing and may be responsible for the euphoric feeling the bath may bring.& In a study of patients with cancer, hyperthermia was shown to create the same endorphin rise both after sauna bath and in whole-body infrared hyperthermia. Whole-body hyperthermia (WBH) stimulates an increase in T cells such as monocytes and absolute numbers of white blood cells.& There is an increase in homing response to different tissues of lymphocytes, which contributes to antitumor activity. Hyperthermia may increase lymphocyte migration into inflamed tissue or lymphoid tissues such as lymph nodes and Peyer’s patches; this effect may help generate the cellular immune response. TNF-a and IL-6 are regulated by the stimulus of h y p e r t h e ~ - r n i aHSPs . ~ ~ ~produced ~ by hyperthermia can provide protection against the muscle damage that occurs through a pathologic increase in intracellular calcium or uncoupling of the mitochondria1 respiratory chain. Hyperthermia provides protection to typical damage from reperfusion after ischemia or with excessive exercise damage. Calcium homeostasis, energy loss, increased free radical-mediated reactions, and activation of apoptosis pathways are affected. I use a thermal application of the partial or full peat-additive bath for the treatment of back pain, musculoskeletal disorders, skin problems, viral illnesses, and more. The use of heat in the right amount is crucial to treatment e f f i c a ~ y . ~ , ~ ~ , ’ ~

muscles and can be valuable in assisting with osseous manipulation once the muscles are more relaxed.

Scoliosis Peat bath followed by traction of the spine can be very helpful in patients with scoliosis who have back pain. Also applying a peat pack over the area of spinal pain can be useful.

Arthritis Peat treatments have shown efficacy for both osteoarthritis and rheumatoid arthritis. One needs to be careful with acute rheumatoid arthritis because treatment may initially stir up symptoms. Generally in osteoarthritis these treatments have been shown in both the literature and my experience to be very beneficial. I have observed significant decreases in swelling and pain with one treatment multiple times in osteoarthritis of the knee and other areas. Generally a series of either combination bath and pack or single bath or packs is given. Treatments are done every day or two.

Headache Chronic headaches can respond to peat bath or to peat packs especially on the neck or over the cervical spine. One must be careful not to overheat the medulla with the cervical pack treatment; thus, mud applications are usually applied below the second cervical vertebra.

CLINICAL APPLICATIONS

Hamstring Strain

Care must be exercised in the selection of patients for any type of thermal therapy. It is important to allow each patient time to adapt by starting with lower-temperature and shorter-duration treatments first. Patients with neurodegenerative diseases like multiple sclerosis (MS) and conditions such as diabetes are not good candidates for WBH. In MS, the excitatory effect on nerves from heat leads to muscle cramping and in diabetes, heat may lead to an ultimate drop in blood sugar and lightheadedness or loss of consciousness. Peat has many beneficial applications, however, as described here.

One of the best applications of bath followed by mud pack is in a hamstring muscle strain. In my experience, athletes even of professional stature have been able to ”get back into the game” faster and with more function than they would have with any other type of treatment.

Discopathy A series of treatments using first peat bath followed by manual traction and then a peat pack over the affected area of the spine has worked marvelously for many of my patients with discopathy. The first thing that is helped is the pain; then there is an improvement in structural integrity and function over time. It is necessary to perform these combination treatments three times a week for 3 to 12 weeks if there is sigruficant discopathy.

Myopathy Muscle pain is easily treated with a thermal peat bath or peat pack. The increase in circulation is very helpful to

Ankle Sprain Partial peat bath immersion of the foot and leg for ankle sprain is very effective. One can see in older sprains the immediate reduction of ecchymosis after the treatment. Patients can perform home treatments in a plastic wastepaper basket on a daily basis for three to six treatments. This approach is inexpensive and wonderfully effective.

Molluscum Contagiosum A small amount of peat material applied to the molluscum twice a day can produce a reaction in about 2 weeks, when treated lesions flare and then fall off. This is a very inexpensive treatment and does not have the same danger of drug reaction as the new pharmaceuticals for this application. In one patient who had a full-body, itchy drug rash from a topical application for molluscum, I used a neutral-temperature peat bath that took the itch away and turned the full-blown red, raised,

rash to slightly raised, nonred, and nonitchy rash within 30 minutes. Within 12 hours the symptoms were almost entirely resolved.

Hypertension Ambulatory blood pressure has been shown to be affected positively by balneotherapy. After a series of treatments blood pressure at rest and during standardized levels of ergonomic exercise tend to decrease as does nocturnal blood pressure. The effect is sustained sometimes permanently.48I do not necessarily recommend this treatment for people with hypertension, except that the bath can have a major homeostatic effect on biorhythms, which can often affect hypertension positively with or without other treatments. People with hypertension have more cardiovascular problems that must be considered before they undergo thermal therapy. Generally people with mild hypertension tolerate the bath better than people with mild hypotension.

Dermatologic Problems Psoriasis and atopic dermatitis are the dermatologic conditions more commonly treated with peat bath. I, however, have had very good success in eczema and dermatitis with both peat bath and cream application. There are multiple possibilities with dermal applications.

Scleroderma Peat bath weekly for 6 to 12 treatments is often a good method of treating scleroderma. Treatment should start with a tolerable temperature and increase slowly over the series of baths so that the patient can adapt.

Human Papillomavirus Antiviral effects of topical peat application have been demonstrated on several viruses, including the human papillomavirus. Remission and prevention of implantation of the virus has been described. This is a measure that prevents cancer. The antiviral and antineoplastic effects are thought to be associated with the ability of peat constituents such as humate to bind on lectinbinding junctions, thereby blocking viral entry into ceUs.2'5'

Herpes Virus Topical treatment of herpes virus skin disease with humic and fulvic fractions of peat has been effective. I have had significant success with zoster outbreaks. Most important, the topical application of specific peat formulation creams that include humic acids has been very helpful to some of my patients.

therapy in comparison with pharmacotherapy. In the peat therapy group, the rate of pregnancy was very good, along with a practically nonexistent spontaneous abortion rate, whereas in the pharmacotherapy group the rate of spontaneous abortions was very high.&

Ankylosing Spondylitis In the treatment of ankylosing spondylitis, peat therapy has shown a decrease in the level of C-reactive protein and an elevation of hemoglobin with a series of treatments. This coincided with a significant reduction in pain and an improvement in f u n ~ t i o n .Peat ~ ~ ,bath ~ ~ and pack and just the bath are options. If a patient is not a candidate for thermal bath, the packs over the spine can be very useful.

Hematoma Organic peat with its intense vasodilating, antiinflammatory effects, interactions of ions and mineral properties, enhances reduction of hematomas. Hematomas treated with thermal peat application have been reported to resolve 50% faster, with no hemosiderin residue, than those treated with only heat applications, which often left residues.71 One can see bruising decrease with pack application immediately after the treatment and an enhancement in the absorption of the hematoma in significantly less time with bath and pack.

Immune Stimulation Peat bath in combination with hyperthermia demonstrates leukocyte elevation. The immune-stimulating effects of peat bath seen clinically correspond to hematologic changes after baths.70 Some effects on immune function are due to heat and others are due to the constituents in peat. A favorable effect is seen on peripheral blood lymphocytes in atherosclerotic disease after hydrogen-sulfide bath independent of heat.70Oxihumate has shown antiviral activity plus immuno-stimulatory effect on mononuclear lymphocytes while also having very low or no toxicity, showing promise for treatment of immunocompromised patients.35Immune stimulation or regulation may also be due to increases or changes in immunocyte numbers and function and the balancing of chronobiologic rhythms. Oral oxihumate, a potassium salt of oxihumic acid, may show some activity in blocking human immunodeficiency virus type 1 infection of MT-2 cells and may be helpful in the topical treatment of herpes virus-induced skin diseases.35 There are also internal uses for constituents of peat. Interestingly electrophoresis of peat mud showed benefits

Infertility A study on infertility due to immature follicle maturation syndrome demonstrated good results with peat

'References 44,49.67,69,70,72,73,76,79.

Peat Therapeutics and Balneotherapy in patients with duodenal ulcer, secondary to hormone shifts and normalization of collagen metabolism in the duodenal m ~ c o s aAlso, . ~ ~the internal use of peat fractions such as humic acid increase the proliferation of some T cells.49

CLINICAL PROCEDURES The following procedures should be applied with care and forethought as to diagnosis and the skillful administration of the treatment. These procedures are stimulations to the body, and the thermal effects should not be taken lightly. Patients must be thoroughly screened for contraindications to treatment before undergoing fullbody immersion hyperthermia. The very young and very old should, in general, have very gentle hot or cold stimulation if any at all. Generally, up to three thermal baths are given per week if they are hot. Thermal therapy can be depleting for some patients so consideration to the patient's vitality is primary.

Hyperthermic Medicinal Peat Bath The indications for and contraindications to hyperthermic medicinal peat bath are given in Box 45-1.

Muscle tension Neurological disorders Obesity Orthopedic disorders Osteoarthritis Postoperative rehabilitation Premenstrual syndrome Prostatitis Psoriasis Rashes Rheumatoid arthritis Sciatica Scleroderrna Skin care Sprains Strains Stress relief Trauma Viral infections

Contraindications Acute hypertension Breastfeeding Cardiac deficiency Diabetes Multiple sclerosis Neurodegenerative disease

Peat bath material-I use Healing Botanical's professional use peat bath formula containing peat extract, sulfur, wintergreen, and pine oil. Tub with water thermometer and safety features like handrails and nonslip floor mats Room with table for perspiration time Gown or loose-fitting bathing suit Two sheets Two wool blankets Two large towels (one for patient to dry off after treatment and one for head wrap) Basin with iced water and a hand towel for cooling patient's face Digital thermometer or otothermometer for patient monitoring (no glass mercury thermometers).A microcomputer-based data acquisition device that records electrocardiogram (ECG) and body and ambient temperatures during bathing can be used; this is preferred over individual readings of pulse and oral temperature during the bath because the ECG shows heart function and the clinician is freed from the task of doing the monitoring. This device can be a real-time recorder for the bath.75 Exhaust fan or room air filter Footstool for entering and leaving tub The design of the bath area should take into consideration getting patients in and out of the tub and then as directly as possible to a treatment table.

Indications Acne Arthritis pain Back pain Benign prostatic hypertrophy Bursitis Carpal tunnel syndrome Dermatitis Eczema Fibromyalgia Flu Fractures Acute gouty toe Chronic gout Gynecologic disorders Headaches Hematomas Hives Insomnia Lumbalgia Metabolic disorders

Materials

Open wounds Preexisting high fever Pregnancy Pulmonary deficiency Respiratory insufficiency Systemic lupus erythematosus

Procedure 1. Before a patient begins treatment, cardiovascular risk and any other conditions that do not respond to or are aggravated by thermal therapy should be ruled out. Once the patient has been classified as to risk factors for thermal therapy, the clinician should ask about previous experience with heat in sauna or steam baths or other types of infrared heating of the tissues. Much depends on the patient's positive health perspective of the self and of the pain or disease process, and the patient's expectations of the therapeutic bath or application. 2. Make sure the tub is clean without a ring. Check log book on last treatment and cleaning. If any evidence of an unclean tank is seen, it must be cleaned and disinfected before use: Wearing rubber gloves, use a soft scouring sponge to scrub the tank with disinfectant soap, followed by a rinse of hot water. Then spray the surface with 10%bleach solution, and wait 10 minutes before rinsing with very hot water. Alternatively, a nonbleach product that is antimicrobial can be used; there are many choices for practitioners to choose from on the market. 3. Fill the tub to 10 inches from the top with water at a temperature of 105" to 113" F (41"to 45" C).

Therapeutic Modalities 4. The starting temperature and possible duration of treatment are determined by the condition. 5. Straight water bath should not exceed 110" F. With peat additive, the temperature should not exceed 113" F. 6. Add peat to the bath. 7. Close monitoring during treatment, by means of periodic recording of the patient's pulse, oral temperature, duration of treatment, and tank temperature, is necessary. A quick spike in pulse above initial pulse within the first minute or minutes is a contraindication to treatment. Any adverse reaction, such as tingling of fingers and toes, nausea, headache, lightheadedness, or vertigo, should be evaluated closely, and treatment terminated. Some patients may be able to tolerate only a low temperature and short duration for the first treatment. For a patient having a series of treatments, the first treatment is of shorter duration and lower temperature to see how the patient responds. The ability to tolerate treatments should improve as patients acclimate through their series of treatments. 8. The patient should enter extremely still water slowly. It will not feel as hot if the water is still. 9. Have the patient remain still as he or she becomes fully immersed, to help decrease the sensation of intense heat. 10. To treat the pelvis, utilize a sitz bath rather than a full bath to concentrate the effects of the treatment. A full bath after the sitz bath may be useful. 11. The water will cool as time passes, although the peat material will help maintain the temperature. If the starting temperature was 105" F, hot water may have to be added. 12. Bath duration is 8 to 20 minutes and should not exceed 20 minutes owing to the additive pharmacologic effects and the tendency for hyperthermia to produce increased metabolism and mobilization of chemicals within the body. 13.If the patient becomes fatigued or distressed, he should exit the bath to be wrapped in the waiting sheet and wool blankets; do not wait longer to have the patient leave the bath. 14. The patient must have help exiting the tub, from two people who provide lifting support from under the arms on either side. This is a time to be very careful. The clinician should assist the patient by placing an arm under the patient's arm but having the patient use his or her own ability to walk and get out of the tub. If the clinician tries to lift the patient rather than provide necessary support, the patient's tendency is to put all his or her weight on the clinician, which is not the goal. After thermal therapy, patients are usually fine to walk, but there is a chance of

lightheadedness and, in rare cases, vertigo. Patients may need assistance. 15. Encourage the patient to concentrate on walking on his or her own. 16. Have the patient lie down on a fresh sheet and wrap the patient in both sheets and two or three wool blankets. Cover the head with a towel. 17. Continue to monitor pulse and oral temperature for the duration of the 20-minute perspiration time. 18. Rinse a face cloth in cold water and apply for 10 seconds or long to the patient's face every 1or 2 minutes during both bath and perspiration times. This is extremely important during the bath. 19. Encourage the patient to relax and help the patient to focus on pleasant matters during the bath. The psychological component of the bath is huge. Having patients think and talk about whatever excites and pleases them about their lives or their future during the difficult part of the bath and the treatment will help them tolerate the heat and reframe their disease processes. 20. After the patient has been wrapped from head to foot in sheet and wool blankets (it is not necessary to have blankets under the patient, as the table is a good insulator that prevents the blankets from getting wet), allow the patient to go through the hydrotherapy reaction of rise and fall in temperature, pulse, and diaphoresis three times. Then remove the patient from the sheets and allow him or her to return to normal activities. This cyclic reaction is seen with peat bath. With water bath, the patient may or may not sweat after the bath. With peat bath, perspiration is helpful, as there is increased absorption or skin effect if perspiration is allowed to continue after the bath. 21. Have the patient rest and replace electrolytes after treatment. The patient should not do a lot of exercise for 12 to 24 hours after a full bath especially the patient with back problems. The patient should promote good posture in the treated area during this time. 22. During the perspiration time, manual traction can be applied to the spine. This is done by grasping the ankles of the 'supine patient and pulling for 30 to 45 seconds with enough traction that the patient almost slides on the table. Indications for manual traction are disc problems, scoliosis, and impingement; it is a nice addition to any peat bath for any condition because it feels good to the patient. 23. Advise the patient not to shower with soap for up to 12 hours after the peat bath, as absorption rates continue after the bath if peat additives have been used. 24. Patients should dry thoroughly and remain covered, warm, and out of draft for 3 hours after treatment. This precaution can easily be overlooked and cause

Peat Therapeutics and Balneotherapy aggravation if cold stimulation is allowed to happen. More than one reminder to the patient is necessary, as after thermal bath people naturally are ready to cool down. 25. Clean the tank and room thoroughly after use. Log out times of bath and tank cleaning.

Medicinal Peat Peloid The indications for and contraindications to this procedure are given in Box 45-2. Care should be taken when performing this application to avoid bums. It is important for the patient to have a strong feeling of warmth without a hot burning sensation. For a typical application, this heat sensation should last for 20 to 30 minutes and may take a few minutes to start once the mud has been applied. Start timing from the point that the patient first feels warmth. The practitioner should use his or her own touch and sense of heat during the application.

Materials Peat poultice material-I use Healing Botanical’s professional use poultice formula containing peat pulp, peat extract, sulfur, wintergreen, and pine oil. Hot water should be added to this dry material 3 minutes before application, and the solution should be mixed so it becomes very slightly supersaturated. The point at which it just becomes shiny and has the consistency of mixed cake batter is perfect. In 1 to 3 minutes it will be time to apply it to the area being treated.

Indications Acne Arthritis pain Back pain Bursitis Carpal tunnel syndrome Eczema Fibromyalgia Fractures Acute gouty toe Chronic gout Headaches Hematomas Hives Lumbalgia Muscle tension

Molluscum contagiosum Orthopedic disorders Osteoarthritis Postoperative rehabilitation Premenstrual syndrome Prostatitis Psoriasis Rashes Rheumatoid arthritis Sciatica Skin care Sprains Strains Stress relief Trauma

Contraindications Open wounds Pregnancy Very thin, fragile skin

Heat-insensitive skin Allergies to any of the peloid materials

It will still be warm for application because hot water was used. Three large towels Small towel Face cloth Small blanket to cover hydrocollator Two small stainless steel basins One small paper cup Hydrocollator (alternativelyhot water bottle can be used)

Procedure This is a thermal peat pack meant to be applied for 30 minutes. The procedure is as follows: 1. Make a square layer of peat material about 0.25 inches thick, 2 inches bilaterally over the spine and 6 to 8 inches long over the spine. If the spinal area is not being treated, area to be treated is covered. The area of application should be as flat and level as possible. 2. Cover the peat directly with a single-layer warm wet facecloth. So as to remember the borders of peloid exactly, ridge the facecloth around the margins of the peat. 3. Border the wet face cloth-covered peloid with a rolled bath towel, making a quarter turn at the comers while folding the towel to match the margin of the peat. 4.Apply one layer of towel over the facecloth and peat material. Depending on the size and mass of the hydrocollator and its temperature, this layer may not be necessary. 5.Put a fresh hydrocollator pack directly over the towel. The hydrocollator should be heated at a gentle boil for 1hour before use. Do not allow any exposed skin to come in contact with the hydrocollator. 6. Cover the hydrocollator pack with a towel or small blanket to insulate it and prevent heat loss. 7. Have a cup of cold water ready to pour on the wet face cloth-covered peloid if it gets too hot. In a good treatment, the peloid pack should get hot enough to require two to three dousings of water or more. 8. As soon as the patient says that the pack is getting too hot, lift up the hydrocollator pack and towel and pour the water directly over the face cloth-covered peloid until cool. Then replace the hydrocollator and coverings. 9. Never leave the patient unattended with the hydrocollator on the mud! 10. Treatment time is approximately 25 to 30 minutes. 11. To remove the peat from the skin after treatment, slide a small basin along the skin under the peat, scraping the peat into the bowl. Wipe the area with a full facecloth wetted with warm water in a gentle twisting motion back and forth to remove peat residue from the skin.

Therapeutic Modalities

12.Cover the treated area after treatment to maintain warmth for 3 hours. The patient's clothing is fine but a wool blanket would do a better job.

Combination Full Bath and Peat Pack Materials

Partial-Immersion Medicinal Peat Bath

The same materials as described for the two preceding applications.

The indications for and contraindications to this procedure are given in Box 45-3.

Procedure

Materials Deep-well basin-the tall plastic wastebasket size works well for the leg Medicinal peat bath Water thermometer Small towel

Procedure 1. Fill basin to three-quarters fullwith 108"to 114" F water. 2. Add peat to the bath. 3. Have the patient immerse the wrist, ankle, or elbow slowly into the water. Try to immerse the forearm and leg if treating the hand or foot. 4. Keep the body part immersed for 25 minutes. 5. After the treatment, cover the area with a wool sock or clothing, and keep covered for 3 hours after treatment. 6. Often peat material is sent home with the patient to do home treatments. 7.Clean up the basin by washing with antimicrobial soap. Then disinfect with 10% bleach solution, and rinse after 10 minutes.

Indications Arthritis pain Bursitis Carpal tunnel syndrome Eczema Fibromyalgia Fractures Acute gouty toe Chronic gout Hematomas Orthopedic disorders Osteoarthritis

Plantar fascitis Postoperative rehabilitation Psoriasis Rashes Rheumatoid arthritis Skin care Sprains Strains Tendinitis Tenosynovitis Trauma

Contraindications Open wounds Pregnancy

Heat-insensitive area

This treatment is used for many conditions. I particularly like it for treatment of vertebral disc injury or degenerative joint conditions. This procedure is also very good for injuries such as hamstring strain. It focuses the balneologic effects in the area to which the peloid pack is applied. Performing the peat bath first and then applying the peat pack is the ultimate treatment for those who can tolerate the bath. After the patient steps out of the bath, he or she walks to the table and lies face up for the regular traction sequence. After three tractions, it is appropriate to turn the patient face down and apply the peat pack over the spine or area being treated.

CONCLUSION As a physician using balneotherapy for 10 years, I have achieved excellent results in a large percentage of patients who undergo peat therapy. This therapy often helps other therapies to work better. Balneotherapy can be primary or adjunctive. The potential effect on the body should not be taken lightly. I have observed excellent results for the following conditions: Arthritis Tenosynovitis Strains and sprains Discopathy Plantar fascitis Low back pain, including sciatica Scoliosis Fractures Gout Muscle pain Dermatologic conditions such as eczema The combination of medical sophistication in diagnosis and application of various balneologic methods provides an excellent tool for physicians to treat in a natural way to the great benefit of their patients.

Peat Therapeutics and Balneotherapy

1. Sukenik S, Flusser D, Abu-Shakra M. The role of spa therapy in various rheumatic diseases. Rheum Dis Clin North Am 1999;25:883-897. 2. Matz H, Orion E, Wolf R. Balneotherapy in dermatology. Dermatol Ther 2003;16:132-140. 3. Braverman DL, Ericksen JJ, Shah RV, et al. Interventions in chronic pain management. 3. New frontiers in pain management: complementary techniques. Arch Phys Med Rehabil2003;84:1. 4. Dietrich J. Endocrinological changes after peat therapy. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 5. Tishler M, Yaron M, Brostovski Y.Effect of spa therapy in Tiberias on patients with ankylosing spondylitis. Clin Rheumatol 1995;1421-25. 6. Guillemin F, Constant F, Collin JF, Boulange M. Short and long-term effect of spa therapy in chronic low back pain. Br J Rheumatol 1994;3:2. 7. Ponikowska I, Przemyslaw A, Nowobilski KV, Nowobilski R. The clinical principals of balneology and physical medicine. Massage Ther J 2003;Winter:90-103. 8.Storojenko N, Tupikova V, Kibzun V, Tsopikov V. Treatment of patients affected by bums with hydrosulphur mineral water irrigation at health resorts of Sochi (Russia). Presented at 2nd Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1994. 9. Faizullin ZZ. Rehabilitation of patient with chronic persistent hepatitis by means of sulphide-chloride-sodium-bathsat the sanatorium stage. Presented at 2nd Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1994. 10. Sukenik S, Buskila D, Neumann L, et al. Sulphur bath and mud pack treatment for rheumatoid arthritis at the Dead Sea area. BeerSheva, Israel: Ben-Gurion University of the Negev, 1989. 11. Agishi Y, Ohtsuka Y. Recent progress in medical balneology. Hokkaido University Medical Library Series 1995;34. 12. Callies R, Kaiser G. Leukocyte evaluation of RA for efficacy of a peat cure. Physiotherapy 1978;30:19-26. 13.Bellometti S, Cecchettin M, Galzigna L. Mud pack therapy in osteoarthrosis: changes in serum levels of chondrocyte markers. Clin Chim Acta 1997;268101-106. 14. Agishi Y, Ohtsuka Y, Watanabe I, et al. Effects of therapeutic elements on physiological functions in man and balneotherapy recent progress in medical balneology and climatology. Hokkaido University Medical Library Series 1995;34. 15. Korepanov AM, Zhukova MA, Chernysheva NG, et al. [SMC-electrophoresis of peat mud in the treatment of patients with duodenal ulcer in outpatient care unit]. Vopr Kurotol Fizioter Lech Fiz Kult 2003;5:22-25. 16. Konrad K, Tatrai T Hunka A, et al. Controlled trial of balneotherapy in treatment of low back pain. Ann Rheum Dis 1992;51:820-822. 17. Praetzel HG, Aigner UM, Wemert D, et al. Therapeutic effects of sulfur-peat baths on patients with rheumatic muscle pain. Phys Rehab Kur Med 1992;2:92-97. 18.Scheffel KZ, Praetzel HG. Analgesic effects of humic acid bath. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 19. Bender T, Karagulle Z, B a h t P, et al. Hydrotherapy, balneotherapy, and spa treatment in pain management. Rheumatology International Clinical and Experimental Investigations July 15, 2004. Available online at http:~springerlink.metupress.com/mediu/ H82CAPLNZKWW4UP J4P1Contributionsf7/3. 20. Given PH, Spackman W, Imbalzano JR, et al. Physiochemical characteristics and levels of microbial activity in some Florida peat swamps. Int J Coal Geol 1983;3:77-99.

21.Goecke C. Efficacy of peat therapy: health resort medicine. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 22. Elkayam 0, Wigler I, Tishler M, et al. Effect of spa therapy in Tiberias on patients with rheumatoid arthritis and osteoarthritis. J Rheumatol1991;18:1799-1803. 23. Bellometti S, Cecchettin M, Lalli L, Galzigna L. Mud pack treatment increases serum antioxidant defenses in osteoarthrosic patients. Biomed Pharmacother 1996;50:37. 24. Weislaw 0, Turowski G, Tmwski ZM. The influence of balneotherapy on T-cell populations and direct lymphocytotoxicity in patients with vascular disorders of lower limbs. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 25.Praetzel HG, Aigner UM, Weinert D, Limbach B. The analgesic effects of sulfur peat baths for non-articular rheumatic afflictions. Presented at 2nd Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1994. 26. Magyarosy KL, Resch KH, Krause W, et al. Electromyographic research for the efficacy of function of peat packs on musculature of the back. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology),Bad Worishofen, Germany, April 1994. 27. Falch 8. Balneophototherapy for atopic dermatitis new scientific findings in dermatology. Schweiz Z Ganzheits Medizin 2002;146@63. 28. Pizzoferrato A, Garzia I, Cenni E, et al. Beta-endorphin and stress hormones in patients affected by osteoarthritis undergoing thermal mud therapy. h4inerva Med 2000;91:239-245. 29.Praetzel HG. Preface. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 30. Kasianova IM.Hydrotherapy in the treatment of obesity. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Munich: April 1994131-133. 31. Praetzel HG. Forty years of medical balneology and climatology: Director Medical Institute of Balneology and Climatology. Munich: Ludwig Maxmillions University, 1990. 32. Gyarmati. Heviz Hungary heilbad (curebath). Presented at Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1990. 33.Dafinova I, Boncheva DV. The effect of mud applications and helium-neon laser irradiation on osteoarthrosis patients with changes in knee joints. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 34. Grigor’eva VD, Mamiliaeva DR. The use of low-temperature peloids in treating patients with rheumatoid arthritis (I). Vopr Kurortol Fizioter Lech Fiz Kult 1994;Sept/Oct:17-21. 35. Grigor’eva VD, Mamiliaeva DR. The use of low-temperature peloids in treating patients with rheumatoid arthritis (11). Vopr Kurortol Fizioter Lech Fiz Kult 1995;Jan/Feb:20-23. 36. Praetzel HG, Schnizer W. Handbook of medical bath. Heidelberg, Karl F Haug, 1992. 37. Schmidt KL. Sulfur water. In Compendium of balneology and cure medicine. Darmstadt: Steinkopff, 1989. 38. Solovieva VP, Sotnikova EP, Naumova GV, Kosobokova RV. Biologicallyactive peat preparations and their possible applications in medicine. In International Peat Society: Proceedings of the 6th International Peat Congress, Duluth, Minnesota, Aug 17-23, 1980.

39. Artmann C, Pratzel HG. Influence on the immune system by sulfur water bath. Presented at Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1990. 40.Cutolo M, Seriolo B, Craviotto C, et al. Circadian rhythms in RA. Ann Rheum Dis 2003;62:593-596. 41.Pollmann L, Hildebrandt G. Temperature changes of the oral mucosa induced by footbaths: preventive effect against common cold infections.Marburg, Germany, Institute fur Arbeitsphysiologie und Rehabilitationsforschung der Universitat Marburg, 1993. 42. Gauthier A, Davenne D, Martin A, et al. lime of day effects on isometric and isokinetic torque developed during elbow flexion in humans. Eur J Appl Physiol2001;84:249-252. 43. When taking medications, timing is everything. Tufts University Health and Nutrition Letter 2003;21:2. 44.Peter A, Flach R. Changes in immunoglobulin G and acute phase proteins in bath cures. Physiotherapy 1974;26357-364. 45. Agishi Y, Ohtsuka Y. Chronobiological aspects of cure treatment. In New frontiers in health resort medicine, No. 059-04. Hokkaido, Japan: Noboribetsu Branch Hospital, Hokkaido University School of Medicine, 1996. 46.Bellometti S, Galzigna L. Function of the hypothalamic adrenal axis in patients with fibromyalgia syndrome undergoing mud-pack treatment. Int J Clin Pharm Res 1999;24:27-33. 47. Hamilos DL, Nutter D, Gershtenson J, et al. Circadian rhythm of core body temperain subjects with chronic fatigue syndrome. Clin Physiol2001;21:184-195. 48. Ekmekcioglu C, Strauss-Blasche G, Feyertag J, et al. The effect of balneotherapy on ambulatory blood pressure. Altem Ther Health Med 2000;6:46. 49. Joone GK, Dekker J, Jansen van Rensburg CE. Investigation of the immunostimulatory properties of oxihumate. Z Naturforsch [C] 2003;58:263-267. 50. Beer AM, Luttig G, Lukanov J. Moortherapie 2000: Vortrage des Internationalen Moortherapie-Symposions, Bad Kissingen, Oktober 1999. 51. Beer M. Indications for gynecological balneotherapy. In Health resort medicine: 32nd World Congress of the International society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 52.Kuhn G, Rohwer J, Buhring M. Balneotherapy for progressive systemic sclerosis Presented at 2nd Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1994. 53. Sukenik S, Neumann L, Buskila D, et al. Dead Sea bath salts for the treatment of rheumatoid arthritis. Clin Exp Rheumatol 1990;8 353-357. 54. Kotwica S, Split W, et al. Spa treatment of sciatic pains at Swieradow. Neurol Neurochir Pol 1976;10715-722. 55. Levitskii EF, Abdoulkina NG, Zaitsev AA, et al. The optimization of the duration of the sanitarium-health resort treatment of patients with neurological manifestations of spinal osteochondrosis (I). Vopr Kurortol Fizioter Lech Fiz Kult 1996;Sep/Oct:26-28. 56. Siderov W,Mamiliaeva DR. The current aspects of pelotherapy of patientswith rheumatoid arthritis.ArthritisRheum 199437 1132-1137. 57. Konrad K, Tatrai T, Hunka A, et al. Controlled trial of balneotherapy in treatment of low back pain. Now and Then Nov 1991. 58.Bellometti S, Galzigna L. Serum levels of a prostaglandin and leukotriene after thermal mud pack therapy. J Invest Med 1998; 46:140-145. 59.Beer AM, Grozeva A, Sagorchev P, Lukanov J. Comparative study of the thermal properties of mud and peat solutions applied in clinical practice. Biomed Tech (Berl) 2003;48:301-305.

60.Praetzel HG. Balneologically activated skin functions and their clinical evidence. J Jpn Assoc Phys Med Balneol Climatol1993;5711-13. 61. A l l Beer A, Junginger HE, Lukanov J, et al. Evaluation of the permeation of peat substances through human skin in vitro. Int J Pharm 2003;253169-175. 62. Beer AM, Sagorchev P, Lukanov J. Isolation of biologically active fractions from the water soluble components of fulvic and ulmic acids from peat. Phytomedicine 2002;9:659-666. 63.Kubota K, Kurabayashi H, Tamura K, et al. A transient rise in plasma &endorphin after a traditional 47°C hot-spring bath in Kusatsu-Spa, Japan. Life Sci 1992;51:1877-1880. 64.Tolomio C, Ceschi-Berrini C, Moschin E, Galzigna L. Colonization by diatoms and antirheumatic activity of thermal mud. Cell Biochem Funct 1999;17:29-33. 65. Maglara AA, Vasilaki A, Jackson MJ, McArdle A. Damage to developing mouse skeletal muscle myotubes in culture: protective effect of heat shock proteins. J Physiol2003;253:837-846. 66. Zellner M, Hergovics N, Roth E, et al. Human monocyte stimulation by experimental whole body hyperthermia. Wien Klin Wochenschr 2002;114:102-107. 67. Rhind SG,Gannon GA, Shek PN, et al. Contribution of exertional hyperthermia to sympathoadrenal-mediated lymphocyte subset redistribution. J Appl Physiol 1999;87:1178-1185. 68.Atanackovic D, Pollock K, Corovic A, et al. Effects of 41.8"C whole body hyperthermia (WBH) on T cell homing molecules in patients with advanced malignancies (abstract 3475). Proc Am SOCClin Oncol2003;22:864. 69. Carroll NM, Elaraj DM, Puhlmann M, et al. Alterations in tumor necrosis factor-induced endothelial cell procoagulant activity by hyperthermia. Int J Cancer 2004;111:457-462. 70. Haveman J, Van Der Zee J, Wondergem J, et al. Effects of hyperthermia on the peripheral nervous system: a review. Int J Hyperthennia Jun 2004;20:371-391. 71. Olivera AP, Schirmer MH, Olivera VM. Treatment of hematomas with peat used in balneotherapy. J Med Esthetics 1997;31-3. 72. Peter A. CR Proteins of rheumatic afflictions. Physiotherapy 1987;39: 331-335. 73. Ohtsuka Y, Yabunaka N, Watanabe I, et al. Platelet antioxidative defense system is modified by balneotherapy and bathing temperature. In:New frontiers in health resort medicine, No. 059-04. Hokkaido, Japan: Noboribetsu Branch Hospital, Hokkaido University School of Medicine, 1996. 74. Bellometti S, Poletto M, Gregotti C, et al. Mud bath therapy influences nitric oxide, myeloperoxidase and glutathione peroxidase serum levels in arthritic patients. Int J Clin Pharmacol Res 2000;20:69-80. 75. Yoshhiro U, Yoshiharu Y, Caldwell WM, Hahn AW. A microcomputer-based data acquisition system for ECG, body and ambient temperatures measurement during bathing. International ISA Biomedical Sciences Instrumentation Symposium 36,2000373-eoa. 76. Ortyl W, Turowski G, Zubel M. The influence of balneotherapy on T-cell populations and direct lymphocytotoxicity in patient with vascular disorders of lower limbs. Mater Med Pol 1991;3:79. 77.Poensin D, Carpenter PH, Fechoz C, Gasparini S. Effects of mud pack treatment on skin microcirculation. Joint Bone Spine 2003; 70:367-370. 78. Basili S, Martini F, Ferroni P, et al. Effects of mud-pack treatment on plasma cytokine and soluble adhesion molecule levels in healthy volunteers. C l i Chim Acta 2001;314:209-214.

Preventive Genomics, Nutrigenomics, and the Promise of Personalized Medicine T. Michael Culp, MA, ND Patrick Hanaway, MD CHAPTER CONTENTS Introduction 487

The Clinical Application of Nutrigenomics-the Example of Cardiovascular Disease 491 Electrolytes and Hypertension 493 Homocysteine and Micronutrients 493 Summary 494

Genes and Environment-Nature and Nurture 488 The Clinical Utility of Genomics

489

From Early Detection to Preventive Genomic Testing 489 Why Do Polymorphisms Exist?

490

Nutritional Genomics (Nutrigenomics) 490

INTRODUCTION Medicine is the practice of restoring sick individuals to health. Since the days of Hippocrates, medical practice has struggled to achieve two elusive ideals. The first is to treat sick individuals truly as individuals, with the understanding that the patient at hand is unique in potential, experience, environmental influences, and disease processes and, as such, forms a n integrated being who can genuinely be understood only as a unique whole, a gestalt. The second ideal of medicine strives for its own annihilation: It is always better to prevent disease than to cure it. The reality of medical practice, however, often falls short of its ideals. All too often medical practice adopts assembly line tactics whereby ”one size fits all,” and prevention is largely confined to pronouncements based on epidemiologic studies about what appears to be healthy for the population as a whole, with little information available to assist the individual in his or her particular struggle to attain optimal health. In truth, although medicine has long had the desire for personalization and prevention, it has not had the tools to make these values a reality. The genomic revolution is beginning to offer practitioners and patients new and exciting tools that may extend the promise of personalized medicine as well as personalized prevention to every individual.

Clinical Challenges for Preventive and Nutritional Genomic Testing 494 Bioethical Considerations: Opportunities and Potential for Discrimination 494 Summary

495

Until recently, the use of genetic information in medicine was limited to identifying single-gene disorders with high penetrance, often called Mendelian disorders, f i e cystic fibrosis, Tay-Sachsdisease, Huntington’s disease, hemophilia, and sickle cell anemia, or to screen for metabolic disorders in newborns, like phenylketonuria. With the mapping of the human genome, our paradigm for understanding medical genetics is shifting away from the idea of single-gene defects causing specific diseases and toward the concept that genetic variability plays a significant role in the pathophysiology of nearly all diseases.’ Indeed, genomics as an emerging field of study is based on the premise that health and disease depend on the totality of all our genes as a dynamic system, influencing and being influenced by our biochemistry, our physiology, and our environment. Within the human genome are literally millions of subtle variations of the genetic code, known as polymorp h i s m ~(literally, ”many shapes”). It is these polymorphisms that are largely responsible for our biochemical individuality. In other words, our polymorphisms make us unique individuals. There are many types of polymorphisms, but by far the most common is singlenucleotide polymorphisms (SNPs, pronounced “snips”), in which a single nucleotide of the DNA is altered and may in turn alter the amino acid sequence coded for by 487

Therapeutic Modalities

that section of the DNA or may affect transcription in some other way, or, what is most often the case, may have no specific physiologic effect at all. Still, the sum total of all of an individual’s polymorphisms significantly affects physiologic function, rendering that individual biologically unique. The Centers for DiseaseControl and Prevention (CDC)* published a Gene-Environment Interaction Fact Sheet in August 2000 that outlines the basic principles of a broad understanding of the causal interaction of genes and environment in human disease. In it the CDC makes the following four main points: 1. Virtually all human diseases result from the interaction of genetic susceptibility and modifiable environmental factors. 2. Variations in genetic makeup are associated with almost all disease. 3. Genetic variations do not cause disease but rather influence a person’s susceptibility to environmental factors. 4. Genetic information can be used to target interventions.

In this brief paper, the CDC has essentially outlined the chief tenets of preventive genomics (or predictive genomics) as a new field of medical inquiry and practice. These ideas are not exactly new. Indeed, in 1909, Archibald Garrod3published lnborn Errors of Metabolism, in which, after idenhfymg the first human disease that behaved as a Mendelian recessive trait (alkaptonuria), he went further to make the sweeping hypothesis that altered heredity was in fact ”the seat of chemical individuality.” ”Inborn errors of metabolism,” he wrote, “are due to a failure of a step in the metabolic sequence due to loss or malfunction of an enzyme.” By examining the subtle end products of metabolism, he continued, we should be able to identify the differences that altered heredity produces in each individual. This is a remarkable insight, given that the words gene and genetic did not exist in 1909, and it would be roughly 50 years before the structure and true function of DNA were confirmed. Garrod’s book was published 3 years before the first vitamin was discovered. He concludes his nearly prophetic work by envisioning the complex interaction between our unique genetic constitution and environmental factors in the simple statement “These idiosyncrasies may be summed up in the proverbial saying that one man’s meat is another man’s poison.”3 It is only by virtue of understanding these idiosyncrasies, or polymorphisms, that medicine can advance to the point at which it may be able to treat patients as unique, whole, and particular individuals. This is the promise and the potential of preventive genomics. In this chapter, we discuss the current state of preventive

genomics in terms of both theoretical understanding and clinical practice. As a concrete clinical example, we focus on cardiovascular disease and the gene-environment interactions that affect its prevention, treatment, and clinical outcomes.

GENES AND ENVIRONMENT-NATURE AND NURTURE Environrnent is broadly understood in genomics to involve everything that is not the genome, including physical agents, exogenous chemicals, and infectious agents and also diet, lifestyle, and behavioral factors. The complex interactions between genes and environment are only beginning to be fully understood. Scientists once believed that genes were immutable archives of information digitally coding for proteins, but it is now clear that gene expression is substantially affected by and sensitive to environmental changes. Genes literally respond to the environment, and by extension, it is possible to alter gene expression by proactively modlfylng our environment, broadly under~tood.~ Herein lies the rationale for individual prevention and treatment strategies: The expression of our genes is modified by the environment we subject them to. The cures for complex diseases and syndromes are not to be found exclusively in nature or in nurture but in the interactive symphony between the two. Nature (our genes) provides a plastic template that is largely adaptable to a wide range of environments (“survival of the most adaptable”). By contrast, nurture (our environment) switches genes on and off, largely controlling genetic expression (the molecular process by which adaptation occurs). When this concept is seen in light of polymorphic differences between individuals, the environment we choose can multiply the physiologic effects of our subtle genetic differences. To illustrate this idea of gene-environment interaction, we consider the research of Caspi et a1.5 They studied variations in the promoter sequence for the gene coding for monoamine oxidase-A (MAO-A) and found that a promoter polymorphism caused some people to have high-activity MAO-A genes and others to have lowactivity genes. They then examined whether these genes played a role in antisocial and violent behavior in men who had been abused as children. Remarkably, they found that men with the high-activity MAO-A gene were virtually immune to the effects of maltreatment as children, seldom if ever becoming violent offenders, whereas men with the low-activity MAO-A gene were much more antisocial and violent, but only if they were themselves abused as chldren. In other words, for violent behavior to manifest in adulthood, both the low-activity gene (nature) and childhood maltreatment

Preventive Genomics, Nutrigenomics, and the Promise of Personalized Medicine

(nurture) needed to be present. If either was missing from the equation, the adult was very likely to be well socialized and nonviolent.

THE CLINICAL UTILITY OF GENOMICS The ability of environmental changes to affect gene expression is the cornerstone for developing a strategy of clinical intervention through understanding and manipulating the molecular pathophysiology of complex diseases. Preventive genomics is that branch of medicine that identifies polymorphisms in the individual in order to predict the likelihood of development of a particular disease or functional imbalance in that individual when he or she is exposed to a particular "environment." From this understanding we are able not only to give an increasingly precise estimate of disease risk but also, in susceptible individuals, to develop comprehensive preventive strategies and, in already affected individuals, to determine a more optimal treatment regimen. Unfortunately for this process, there are literally millions of polymorphisms in the human genome, most of which have little or no effect on physiology, health, or disease. In order for preventive genomics to be clinically useful, polymorphisms must meet four criteria. Clinically useful polymorphisms must be relevant, prevalent, modifiable, and measurable. First, the only polymorphisms in the genome of medical interest are those that exert a significant effect on specific aspects of our biochemistry and physiology (relevant). Second, given our current knowledge of the human genome, only polymorphisms that exist in a substantial portion of a population are likely to be able to be demonstrated in epidemiologic and case-controlled studies to be clinically relevant-in essence, we compare polymorphisms that occur in substantial numbers in both groups (prevalent). Third, only polymorphisms whose genetic expression is modz@bZe via reasonable clinical intervention are clinically useful. Such an intervention may be any modification of environment, including diet, lifestyle, and targeted nutriceuticals or pharmaceuticals. Although genes themselves are not modifiable, the phenotype they generate is modifiable via these environmental changes. Finally, because our genes do not themselves change, we must be able to measure changes in our functional physiology in order to determine that the environmental changes have in fact been effective in modifymg the phenotypic expression of our unique genes. For this purpose, functional laboratory testing must be available: The effects of our therapeutic interventions must be measurable. To illustrate this model of clinical utility, let us consider the example of the antioxidant protection afforded by the hepatic enzyme glutathione-Stransferase (GSTM1).

High levels of oxidative stress are associated with numerous degenerative diseases and with the aging process itself. So an enzyme like GSTMl that protects against such oxidative damage is clearly relevant. Indeed, the GSTMl null genotype has been associated with numerous cancers in epidemiologic and casecontrol studies.6 Although there a several isoforms of GST, the p isoform (GSTM1) is the most common in the liver. Up to 50%of the population does not have the gene for GSTM1, so the mutation is highly prevalent. Because other forms of GST and other antioxidant pathways exist, it is possible to improve antioxidant protection by maintaining a high reduction potential through exogenous avenues, including supplemental dietary antioxidants. Thus the increased oxidative stress is modifiable. Finally, we can validate the clinical efficacy of our intervention strategy by measuring functional levels of oxidative stress through any number of simple laboratory tests, such as urinary lipid peroxide and serum glutathione measurements.

FROM EARLY DETECTION TO PREVENTIVE GENOMIC TESTING A susceptibility gene is one that may render us more susceptible to development of a chronic disease when we are exposed to an adverse environment. Most susceptibility genes have a low positive predictive value (the probability that a disease will develop in a person with a positive test result) and a low attributable risk (the proportion of cases of a disease that can be attributed to a susceptibility gene).7 Therefore, some researchers have questioned the clinical utility of susceptibility genetic testing? but such arguments, by applying a single-gene/single-disease model to susceptibility genes, miss the potential clinical relevance. Susceptibilitygenes, much like taking a family history, must be seen as important but incomplete contributors in what is invariably a multifactorial risk assessment. In terms of health outcomes, preventive genomic polymorphisms raise disease risk modestly and are additive in their effects (genegene interactions), and their actual phenotypic expression is strongly affected by diet, lifestyle, and environment (gene-environment interactions). Rather than negate their clinical utility because of a low positive predictive value and a low attributable risk, these polymorphisms begin to offer a molecular basis for understanding the pathophysiology of complex multifactorial diseases; an understanding of the environmental factors that affect gene expression begins to evoke effective preventive therapeutic strategies. Because environment is broadly understood to refer to anything outside the genome itself, therapeutic regimens may be constructed to include any portion of the

Therapeutic Modalities environment that has been shown to affect gene expression and phenotype. This is tmly a holistic approach because effective therapeutic strategies may involve diet, nutritional, and targeted pharmaceutical supplementation, lifestyle and behavioral modification, and avoidance or elimination of toxins, xenobiotics, and microbes. Intervention at any level of our "environment" may prove clinically beneficial. Functional medicine is the clinical discipline designed to promote health, to anticipate and prevent disease, or to correct an existing disease by improving physiologic function. The underlying assumption is that health and disease lie on the same continuum and the connecting thread of the continuum is physiologic function. Prior to the manifestation of any frank disease, a progressive loss of homeostasis and increasing dysfunction occur. Clinical intervention in this strategy may begin at the earliest signs of imbalan~e.~ The promise of preventive genomics is that the point of effective intervention may begin even earlier, before the beginnings of physiologic dysfunction.

WHY DO POLYMORPHISMS EXIST? The theory of natural selection has two central tenets, as follows (1) all organisms compete for limited resources and (2) organisms with some advantage in acquiring those resources are more likely to survive, to thrive, and to pass on that advantage to their offspring. Polymorphic variations are the ultimate source of these advantages. Indeed, all polymorphisms that are prevalent in a species likely afford some adaptive advantage in some particular environment. Genetic polymorphisms have been preserved in populations when they endow a better chance of survival or of reproduction. The cumulative weight of slight genetic variations over time is the means by which variability within a species arises and by which new species also emerge. However, what may be good for a species and its evolution may not be good for a specific individual, because the environmental pressures exerted on a species over millions of years may be very different from the environment encountered in the present. In individuals, altered polymorphic genes (the legacy of evolution) produce altered proteins, and altered proteins exhibit altered functions. For the individual, altered protein function may be beneficial, neutral, or harmful. More precisely, given the pressures of natural selection, polymorphisms and the proteins they code for are likely to be beneficial in some environments but harmful in others. Because we cannot change our genes, the goal of preventive genomics is to alter an individual's environment in order to maximize his or her genetic potential. Genes cannot be modified, but gene expression can be. One of the common misconceptions of polymorphisms

is that they reveal only limitations, but in reality, they reveal an individual's potential.

NUTRITIONAL GENOMICS JNUTRIGENOMICS) The links between diet and health and between poor diet and chronic disease were well established over the previous century, but the advent of genomic testing has generated renewed interest in the molecular links between genes and diet and how those links affect both health and disease. Using our molecular understanding of the effects of polymorphisms on nutritional biochemistry, nutritional genomics (or nutrigenomics) promises to promote a new understanding of optimal nutrition for individuals, including macronutrient balance as well as unique vitamin and mineral requirements based on their genotypes.'O Nutrigenomics promises to be clinically applicable both reactively, in the treatment of physiologic dysfunction and disease, and proactively, in the promotion of optimal health. Both macronutrients and micronutrients function as dietary signals that influence gene and protein expression and hence alter the metabolic activity and homeostatic balance of cells." With high-throughput genomic tools that can measure subtle alterations in messenger RNA and cellular protein production, nutritional researchers are able to elucidate the molecular actions of specific nutrients, including the variations in effects of nutrients in the presence of various genetic polymorphisms.'* The ultimate goal of such investigations would be the ability to personalize dietary, nutrient, and supplement recommendations. However, the thorough investigation of the genetic and metabolic effects of hundreds of foods and nutrients on people of varying genotypes will take years or decades to complete. Currently, most of the clinically relevant nutrigenomic information available relates to the relationship between polymorphisms with increased chronic disease risk and the dietary therapies and supplements that have been demonstrated to treat the physiologic imbalance effectively. This is particularly true of SNPs; in as many as one third of gene mutations, the corresponding enzyme has a decreased binding affinity for a vitamin or mineral coenzyme, resulting in a lower rate of reaction and altered enzyme function. In a review article, Ames et all3provide evidence of more than 50 human diseases involving defective enzymes that can be remedied or ameliorated by the administration of high doses of vitamins, which at least partially restore enzymatic activity. Thus the clinical validity of high-dose nutrient therapy is established, but only in genetically susceptible individuals. From the novel perspective of nutrigenomics, nutrients may be viewed as dietary signals that are detected by the cellular sensor systems that influence gene and protein

Preventive Genomics, Nutrigenomics, and the Promise of Personalized Medicine

expression and, consequently, metabolite production and cellular Such alterations may affect any functional biochemical pathway, including cell-cell signaling, oxidative stress, inflammation, hormone response, nutrient absorption, energy homeostasis, and waste product detoxification and excretion. Theoretically,this approach allows two complementary strategies for molecular nutrigenomics research and eventually for clinical intervention. First, the nutrients that affect specific gene expression must be identified, along with the alterations in gene-nutrient interactions caused by the presence of specific polymorphisms. Second, by using high-throughput computer chip assays, researchers may be able to idenhfy protein and metabolite “signatures” associated with nutrient changes. Monitoring these molecular signatures may provide ”early warnings” of nutrient-induced changes to homeostasis, effectively screening for impending disease. Although a complete review of all known nutrient interventions to correct for the metabolic imbalances associated with polymorphisms is well beyond the scope of this chapter, we propose to illustrate the potential effect of genomic testing on the nutritional amelioration of physiologic imbalances, morbidity, and mortality associated with cardiovascular disease.

THE CLINICAL APPLICATION OF NUTRIGENOMICS-THE EXAMPLE OF CARDIOVASCULAR DISEASE Cardiovascular disease accounts for approximately 40% of all deaths in most industrialized countries and is also responsible for signhcant morbidity and diminished quality of life. Furthermore, using data from more than 84,000 women who were monitored for 14 years, epidemiology researchers at Harvard University estimated that about 83% of cardiovascular disease could be prevented if everyone ate a reasonably healthy diet, exercised daily, did not smoke, maintained a normal weight, and drank 1 to 2 alcoholic beverages per day.14 Even though these five diet and lifestyle changes seem simple, only about 3% of the women in the study actually performed them. Not only is compliance an issue, but epidemiologic studies raise deeper philosophical questions, because such studies assume that all participants are essentially similar to one another. Are the same therapies equally effective for all individuals? Do all individuals need the same quantities of these diet and lifestyle modifications? Can preventive genomic testing help us individualize our therapeutic protocols? Let us begin by asking what proportions of carbohydrate, protein, and fat in the diet are the most effective in maintaining normal serum cholesterol levels? Is it a low-fat, low-cholesterol diet as touted by Nathan Pritikin and Dean Ornish? Or perhaps a 40-30-30

(40% carbohydrate, 30% protein, 30% fat), low-calorie ”Zone” diet as proposed by Barry Sears? Or a low-carbohydrate, high-protein, high-fat diet such as that made popular by Robert Atkins? Logically they cannot all be the best diet for everyone, yet some people swear by each of them as THE answer for optimal diet. There is mounting evidence that optimal macronutrient proportions in the diet may be a function of certain polymorphisms. Apolipoprotein E (APOE)is a molecule that mediates the interaction of chylomicron remnants and intermediate-density lipoprotein particles with lipoprotein receptors, including the low-density lipoprotein (LDL) receptor and the chylomicron remnant or APOE receptor. There are three variations of the APOE gene, known as APO ~ 2 ~ , 3 and , ~ 4 and , these polymorphic variants are important genetic modifiers of serum lipid responses and consequently may significantly affect an individual’s risk for development of coronary artery disease. The ~ 3 / &genotype is the most common in all populations and serves as the benchmark genotype for comparison with any other possible genotype. The ~4 allele is associated with a moderately increased risk of atherosclerosis and coronary artery disease (odds ra ti0 [OR] = 1.53 for men and 1.99 for women in one study).15 The ~2 allele is associated with lower LDL cholesterol levels. LDL cholesterol levels declined with each A P O E ~ allele by 8.8 mg/dL in Hispanics, by 25.6 in nonHispanic white persons, and by 18.1 mg/dL in AfricanAmericans.l6 Given that each person inherits two alleles, there are six possible genotypes: ~ 2 / ~~22, / ~~33, / ~&2/&4, 3 , &3/~4, and &4/~4. In patients with elevated serum total and LDL cholesterol, the cholesterol-lowering response to a low-fat, low-cholesterol diet increased as the sum of the allele numbers increased (in other words, response improved in the order that the genotypes are listed in the first sentence in this paragraph).”J8 Conversely, individuals carrying an ~4 allele who ate a high-fat diet were much more likely to have elevated serum ch~lesterol.’~ By contrast, serum triglyceride levels were found to be significantly higher in men who carried an ~2 allele. ~ 3 / individuals ~ 3 were found to have the lowest triglyceride levels, and ~4carriers to have intermediate 1e~els.l~ In another multiethnic study, plasma triglyceride levels were inversely correlated with the number of A P O E ~ alleles (175,159, and 143 mg/dL with 0, 1, and 2 alleles, respectively).16Still another study found ~4 carriers to have elevations in triglycerides, but only those who consumed alcohol regularlyz0A study of Turkish men who did not consume alcohol found no elevated triglyceride values in ~4carriers2*The most effective dietary therapy to lower triglycerides is restricting carbohydrate, especially sugar, consumption. Because A P O E ~men are prone to significant triglyceride elevations and their cholesterol levels are less sensitive to dietary fat intake,

Therapeutic Modalities a lower-carbohydrate, higher-protein, higher-fat diet may be therapeutically desirable for them. Individuals with the &/& genotype are moderately affected by dietary fat intake but tend to have lower triglyceride levels than the other genotypes. In one study, individuals with high cholesterol and triglyceride values were treated with a short-term (7-day) very-low-calorie juice fast ( ~ 2 0 8calories/day), and their responses were stratified by APOE genotype.= Only E3/& individuals experienced significant improvement in all parameters, experiencing reductions in LDL cholesterol by =lo% and in triglyceride values by ~ 1 8 %In. these individuals, it is tempting to speculate, the low-calorie, moderate 40-30-30 carbohydrate-pmtein-fat ratio diet (”TheZone” diet) might be more effective in treating both hypercholesterolemia and hypertriglyceridemia, although no clinical trials to validate this hypothesis have yet been published. Also in this trial, E2 carriers experienced a -31% drop in LDL levels but a ~ 1 5 %increase in triglyceride levels, lending some additional support for the carbohydrate-sensitive triglyceride hypothesis. ~4 carriers had an opposite response, consisting of a reduction of triglyceride levels by 4 9 % but a rise in LDL levels by ~ 1 3 % . Other dietary interventions that affected cholesterol levels were fiber and alcohol. High intake of soluble fiber (>5.7 g/MJ) reduced LDL cholesterol by 6.6% and 5.6%, respectively in ~3 and ~4 allele carriers but had little effect on 122carriers.” Similarly, a study of Korean patients with coronary artery disease found that replacing white rice with whole grains produced the greatest benefit in E 3 / ~ 3individuals (12% reduction in triglyceride, 8% reduction in LDL cholesterol, and 8% increase in high-density lipoprotein [HDL] cholesterol levels), moderate benefit in ~4 carriers (including a 15% increase in HDL cholesterol values), and no effect in ~2 carriers.24 Thus, a high-fiber diet may be clinically most useful for E 3 / ~ 3individuals, modestly useful for 124carriers, but not particularly useful for ~2carriers. The modest consumption (1-2 drinks) of alcohol daily has been shown epidemiologically to be very protective against coronary artery disease in the general population. However, APOE genotyping reveals that the benefits are not the same for everyone. In a comparison of nondrinkers with drinkers of alcohol, women who were drinkers had lower cholesterol (total and LDL) than nondrinkers, regardless of APOE genotype. In men, however, A P O E carriers ~ who were drinkers had lower cholesterol but APO ~4 carriers had higher cholesterol, and alcohol consumption had no significant effect for APOE3/E3 individuakE It is worth noting that moderate exercise, although not dietary therapy, was found to be effective in improving serum lipids in ~2 and ~3 genotypes but not in ~4 carriers.26In another study, however, high-intensity

physical exercise was most effective in ~4 carriers?’ Thus, ~2 and ~3 carriers may benefit from modest daily exercise, but for an individual with an 124 allele to benefit from exercise, it must be high-intensity. Similarly, knowledge of APOE genotype may allow for a more discriminating and more effective use of targeted pharmaceuticals for patients with lipid abnormalities. Statin drugs exhibited a greater cholesterol-lowering effect in A P O E ~carriers, followed by APOE3/&3,with less effectiveness for AP0124carriers. A P O Ecarriers ~ also showed better response to gemfibrozil and cholestyramine than the other genotypes. The greatest cholesterol~ came from probucol, lowering effects for A P O Ecarriers a potent antioxidant.26However, even though statins had a weaker cholesterol-lowering effect in A P O Ecarri~ ers, statins were most protective in preventing a second heart attack in men with an ~4 allele. Statin use reduced the risk of a second heart attack in ~4 carriers by 64%, compared with only 33%for other genotypes.28 To be sure, more prospective clinical trials are needed to fully elucidate the optimal therapeutic dietary interventions to protect against coronary artery disease in individuals based on their APOE genotype status. However, distinct patterns are beginning to emerge in terms of dietary and lifestyle management for the prevention and treatment of coronary artery disease; they are summarized in Table 46-1. Apolipoprotein E polymorphisms are the best studied in terms of their association with atherosclerosis and coronary artery disease, but other polymorphisms exert similar effects. Cholesteryl ester transfer protein (CETP) is responsible for the transfer of insoluble cholesteryl esters from HDL to other lipoprotein^.^^ The TaqlB polymorphisms of the CETP gene result in increased CETP levels, with impaired ability to remove cholesterol from the cells and the blood stream. The TaqlB polymorphism is associated with lower HDL cholesterol levels and with an increased risk of development of atherosclerosis and coronary artery disea~e.3~,~* In one study, individuals who were homozygous for the TaqlB polymorphism had larger reductions in LDL and VLDL levels through eating a low-fat diet with a high ratio of polyunsaturated to saturated dietary fat.32Furthermore, daily moderate alcohol consumption raised HDL levels substantially, but only in individuals with the CETP p ~ l y r n o r p h i s r n . ~ ~ , ~ E-selectin (SELE) is a glycoprotein molecule that modulates the adhesion of circulating neutrophils to the endothelial lining of blood vessels. E-selectin is expressed on the surface of endothelial cells after stimulation by dammatory mediators (mediated by nuclear factorkappaB [NFKB]). Several polymorphisms in the SELE gene increase adhesion activity of E-selectin, dramatically increasing the risk of atherosclerosisand premature coronary artery d i ~ e a s e . ~ ~ , ~ ~

Preventive Genornics, Nutrigenornics, and the Promise of Personalized Medicine

Genotype* TheraDv

~2Jdor E2/~3

€31~3

€41~3or €41~4

Diet

Lower-carbohydrate

Low-calorie, moderate-fat Soluble fiber

Low-fat, no-cholesterol Soluble fiber

Alcohol intake

Daily (women and men)

Daily (women) (little effect for men)

Daily (women) None (men)

Exercise

Moderate

Moderate

High-intensity

Pharmaceutical/nutriceutical

Bile sequestrants Statins

Statins

Probucol Statins

*The EUE~ genotype is extremely rare and therefore lacks statistical power in both association studies and prospective trials.

The primary therapeutic aim for carriers of an SELE polymorphism is to decrease NFKBstimulation, in turn reducing SELE expression. Maintaining high antioxidant potential has been shown to decrease NFkB activation.37,38 Thus higher levels of dietary antioxidants and possibly supplemental antioxidants may be beneficial. The proinflammatory cytokines tumor necrosis factoralpha (TNF-a) and interleukin-1 (IL-1) also increase and milk thistle NFKBactivation. Antioxidants, fish (silymarin) supplementation have each been shown to suppress IL-1 and TNF-a production directly and would therefore lower NFKBactivation.

Electrolytes and Hypertension Hypertension is an independent risk factor for coronary artery disease and for stroke. Therapeutic response to sodium restriction in hypertensive individuals is highly variable. A SNP in the angiotensinogen gene (AGT) allows an amino acid substitution in which threonine (T) replaces methionine (M) at amino acid 235. The T allele is associated with increased production of angiotensin, with a tendency for higher blood pressure. There is a stepwise increase of serum AGT from MM to MT to TT genotypes among pesons with hypertension40and those with normal blood pressure.4l Although there have been some discrepancies between studies, a metaanalysis of all studies published between 1992 and 1996 showed the 235T allele to have consistent, mild associations with hypertension (OR = 1.20), a positive family history of hypertension (OR = 1.42),and more severe hypertension (OR = 1.34).42 The 235T allele of the angiotensinogen gene is associated with greater blood pressure decreases than the 235M allele after an intervention to reduce sodium intake (<5 m g / d a ~ ) . 4Persons ~ with the TT and MT genotypes showed significant systolic blood pressure reductions when consuming mineral salt compared with control subjects ( p = 0.02 and p = 0.001, respectively), but persons

with the MM genotype did not (p = 0.10). The net adjusted systolic and diastolic blood pressure reduction was -8.6 mmHg systolic/-3.9 mmHg diastolic for persons with the TT genotype, -9.O/-5.2 for those with the MT genotype, and -5.3/-1.0 for the MM genotype. Aerobic exercise was effective in reducing blood pressure but only in the MM (-3.7 mmHg) and MT (-3.4 mmHg) genotypes, and not in the TT (-0.4 mmHg) individuals, among 477 previously sedentary white Americans.44And finally, the use of angiotensin-converting enzyme inhibitors produced more dramatic reductions in blood pressure in 235T allele carriers (TT and MT) than in the MM gen0type,4~,~ illustrating the notion that diverse modifications in “environment” (diet, exercise, targeted pharmaceuticals) may produce similar alterations in phenotype (in this case blood pressure) among genetically susceptible individuals.

Homocysteine and Micronutrients As mentioned previously, one common physiologic effect of SNPs is a decreased binding affinity of a vitamin or mineral coenzyme for the structurally altered enzyme. There is mounting evidence that in most cases, the diminished rate of reaction of that polymorphic enzyme can increase with high-dose cofactor micronutrient ~upp1ementation.l~ Perhaps the best studied example of this model is the enzyme 5,lO-methylenetetrahydrofolate reductase (mercifully known by the acronym MTHFR), which is responsible for remethylating homocysteine into methionine, allowing methylation reactions to occur efficiently in the body. When methylation reactions are impaired, plasma homocysteine levels rise, and elevated homocysteine values have been associated with increased risk of atheros~lerosis,4~ risk of early coronary increased risk of hemostasis and artery venous thrombosis,5031decreased bone preeclampsia, neural tube defects and spina bifida,53,54and acute leukemia in a d ~ l t s . 5The ~ risk of heart disease

Therapeutic Modalities

is increased for heterozygotes as well as 677T/T homozygotes.56Folic acid, B2 (as FAD), B6, and B12 are all cofactors in the methylation cycle, and a dietary deficiency of any of these vitamins can result in elevated homocysteine levels. But elevated homocysteine levels can also result from two common polymorphisms in MTHFR a 677C-T nucleotide substitution and a 1298 A-C nucleotide substitution. Someone with a 677TlT genotype has a 50% reduction in MTHFR enzyme activity, while a 1298C/C genotype has a 32% reduction. In one study, -28% of patients with elevated homocysteine did not respond to supplementation with folic acid, B12, and B6 because they had the 677T/T genotype, and severely impaired MTHFR activity.57It is worth noting that the 677C-T polymorphism occurs in the FAD binding site of MTHFR, suggesting that B2 supplementation may be a critical component of supplement interventi~n.'~ Three rational therapeutic strategies may help to resolve the elevated homocysteine levels. First, highdose supplementation of the vitamin cofactors of MTHFR which relies on the simple logic of the law of mass action in chemical reaction: higher concentrations of substrates drive the chemical reaction forward. Second, the metabolic products of the MTHFR enzyme, namely 5-methyltetrahydrofolate, may be supplemented. Third, alternate re-methylation pathways may be stimulated, namely supplementing trimethylglycine or betaine as alternate methyl group donors. In practice, because of the low-cost and high degree of safety associated with each of these options, all three strategies may be employed simultaneously. Regardless, serial plasma homocysteine measurements allow the practitioner to determine that the therapy employed has been successful.

Summary While the science of nutrigenomics is still in its infancy, several principles have become clear with enormous potential impact for clinical medicine. Nutrients act as dietary signals that may alter gene expression, especially in genetically susceptible individuals. Genomic information and nutritional therapy can therefore be used proactively to alter gene expression and to mitigate risk for developing various forms of cardiovascular disease. This principle holds true for macronutrient balance in the diet, as well as for micronutrients, which includes vitamins, minerals, and electrolytes. While our primary focus here has been on nutrient-gene interactions, the same principles hold true for lifestyle changes and targeted pharmaceuticals. In fact, nutritional intervention is merely a more specific application of environmental modification to alter gene expression. What should be clear is that as our knowledge of gene-gene and

gene-environment interactions increases, so too will our capacity for delivery of increasingly personalized medicine and primary prevention.

CLINICAL CHALLENGES FOR PREVENTIVE AND NUTRITIONAL GENOMIC TESTING Preventive and nutritional genomic testing in clinical practice has its critics, who argue predominantly that there are insufficient numbers of clinical trials to demonstrate the diagnostic and therapeutic efficacy of genomic profiles.5s But rather than demonstrating that all preventive genomic testing is "premature and scientifically unsound," as suggested recently by Dr. Muin Khoury of the CDC,* such objections merely underscore the perspective we have shared here. Namely, it is precisely because chronic disease is multifactorial with complex gene-gene and gene-environment interactions that the diagnostic and therapeutic utility of preventive genomic testing must meet the four criteria of being relevant, prevalent, modifiable, and measurable. The last criterion, measurable, is key at this early stage of preventive genomic testing. We must be able to measure beneficial phenotypic, physiologic changes in individuals that result from the therapeutic strategy employed. There will always remain a possibility that other genetic polymorphisms or other environmental influences that we have not yet identified may also affect an individual's disease risk. A similar cautionary argument should be made in cases in which current genomic knowledge offers conflicting therapeutic advice. A man with an A P O Eallele ~ presumably should not drink alcohol, but what if he also has a CETP TaqlB polymorphism for which alcohol has been shown to boost HDL cholesterol levels dramatically? At present, we do not know the answer to this clinical conundrum. Fortunately, because subfractionated lipid levels are easily measurable, the effects of moderate, daily alcohol intake on such a specific individual's lipid profile may be easily ascertained. Thus medicine must be empirical, relying on trial and error until the desired result (e.g., lower serum cholesterol) is achieved.

BIOETHICAL CONSIDERATIONS: OPPORTUNITIES AND POTENTIAL FOR DISCRIMINATION Genetic information, because it represents an unchangeable state, has the potential at least to be used in a discriminative manner by insurers, employers, and society at large. However, it should be noted that the primary paradigm for such discrimination views genetic

Preventive Genomics, Nutrigenomics, and the Promise of Personalized Medicine information as representing an individual's immutable limitations, as typified by single-gene diseases (e.g., TaySachs disease, Huntington disease, sickle cell anemia). A central tenet of preventive or nutritional genomics is the idea that the phenotypic outcome of any unique genotype is modifiable through environmental changes. Preventive genomic testing, rather than revealing an individual's genetic limitations, more accurately reflects an individual's genetic potential, given the right environment. Genetic polymorphisms have the potential to guide an individual to adopt appropriate dietary, lifestyle, and environmental changes that can optimize health and longevity. Now that we know there are definite connections between genes and environment, and we are learning their myriad effects on health and disease, ignorance is no longer ethically neutral. Choosing not to use genomic information in treating patients, now that its health implicationsare being effectivelydocumented, is ethically untenable. For the first time in the history of medicine, preventive genomic testing allows us to assess individual risk for development of chronic diseases, to develop comprehensive risk reduction strategies before imbalances in homeostasis occur, and to institute optimal therapeutic interventions for patients who are already sick. This new personalized medicine, made possible by the advent of preventive genomics and nutrigenomics, offers

1. Khoury MJ. Genetics and genomics in practice: the continuum from genetic disease to genetic information in health and disease. Genet Med 2003;5:261-268. 2. Centers for Disease Control. Geneenvironment interaction fact sheet. Available online at wwu.cdc.gov/genetics [accessed August 2,20051. 3. Garrod A. Inborn errors of metabolism. London: H Frowde and Hodder & Stoughton, 1909. 4.Ridley M. Nature via nurture: genes, experience, and what makes us human. New York Harper Collins, 2003. 5. Caspi A, McClay J, Moffitt TE, et al. Role of genotype in the cycle of violence in maltreated children. Science 2002;297851-854. 6. Hayes JD, Strange RC. Glutathione Stransferase polymorphisms and their biological consequences. Pharmacology 2000;61:154-166. 7. Khoury MJ, Newill CA, Chase GA. Epidemiologic evaluation of screening for risk factors: application to genetic screening. Am J Public Health 1985;75:1204-1208. 8. Holtzman NA, Marteau TM. Will genetics revolutionize medicine? N Engl J Med 2000;343:141-144. 9. Bland JS.The use of complementary medicine for healthy aging. Altem Ther Health Med 1998;442-48. 10. Elliott R, Ong TJ. Nutritional genomics. BMJ 2002;3241438-1342. 11. Francis GA, Fayard E, Picard F, Auwerx J. Nuclear receptors and the control of metabolism. Annu Rev Physiol2003;65:261-311. 12. Muller M, Kersten S. Nutrigenomics: goals and strategies. Nat Rev Genet 2003;4:315-322. 13. Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding

practitioners and patients new opportunities for the prevention and treatment of disease and for the promotion of optimal health.

SUMMARY Preventive and nutritional genomics testing is new and exciting. Though what we know is dwarfed by what we do not know, this imbalance does not negate the current therapeutic power that the last 10 years of genomic research have revealed. We agree the following assertions made by L o k t i ~ n o v ~ ~ : There are examples of effective research on geneenvironmental interactions. There is sufficient evidence to make clinical recommendations on the basis of individualized genomic predisposition. There is a need for research on traits that protect from, as well as predispose to, disease. Environmental modification, including dietary change, may be the easiest and most efficient way to influence the risks of many diseases common today. This new form of personalized medicine in understanding our genetic potential offers new opportunities to focus on prevention of disease and promotion of optimal health.

affinity (increased K(m)):relevance to genetic disease and polymorphisms. Am J Clin Nutr 2002;75:616-658. 14. Stampfer MJ, Hu FB, Manson JE,et al. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med 2000;34316-22. 15. Wilson PW, Myers RH, Larson MG, et al. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham Offspring Study. JAMA 1994;272:1666-1671. 16. Pablos-Mendez A, Mayeux R, Ngai C, et al. Association of apo E polymorphism with plasma lipid levels in a multiethnic elderly population. Arterioscler Thromb Vasc Biol1997;173534-3541. 17.Ordovas JM, Lopez-Miranda J, et al. Gene-diet interaction in determiningplasma lipid response to dietary intervention.Atherosclerosis

1995;118(S~ppl):Sll-S27. 18. Gylling H, Miettinen TA. Cholesterol absorption and synthesis related to low density lipoprotein metabolism during varying cholesterol intake in men with different apoE phenotypes. J Lipid Res 1992;33:1361-1371. 19. T i a n e n MJ, Huttunen JK, Ehnholm C, Pietinen P. Apolipoprotein E4 homozygosity predisposes to serum cholesterol elevation during high fat diet. Arteriosclerosis 1990;10285-288. 20. Frikke-Schmidt R, Nordestgaard BG, Agerholm-Larsen B, et al. Context-dependent and invariant associations between lipids, lipoproteins, and apolipoproteins and apolipoprotein E genotype. J Lipid Res 2OOO;41:1812-1822. 21. Mahley RW, Palaoglu KE, Atak Z , et al. Turkish Heart Study: lipids, lipoproteins, and apolipoproteins. J Lipid Res 1995;36:839-859.

22. Lehtimaki T, Frankberg-Lakkala H, Solakivi T, et al.The effect of short-term fasting, apolipoprotein E gene polymorphism, and sex on plasma lipids. Am J Clin Nutr 1997;66599-605. 23. Wolever TM, Hegele RA, Connelly PW, et al. Long-term effect of soluble-fiber foods on postprandial fat metabolism in dyslipidemic subjects with apo E3 and apo E4 genotypes. Am J Clin Nutr 1997; 66:584-590. 24. Jang Y, Kim OY, Park HY, et al. Effect of apolipoprotein E polymorphism on the serum lipid and insulin response to whole grain consumption in coronary artery disease patients. Nutr Res 2001;21:1463-1473. 25. Corella D, Tucker K, Lahoz C, et al. Alcohol drinking determines the effect of the APOE locus on LDL-cholesterolconcentrations in men: the Framingham Offspring Study. Am J Clin Nutr 2001;73:736-745. 26. Hagberg JM, Wilund KR, Ferrell RE. APO E gene and gene-environment effects on plasma lipoprotein-lipid levels. Physiol Genomics 2000;4101-108. 27. Bemstein MS, Costanza MC, James RW, et al. Physical activity may modulate effects of ApoE genotype on lipid profile. Arterioscler Thromb Vasc Biol2002;22:133-140. 28.Gerdes LU, Gerdes C, Kervinen K, et al. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: a substudy of the Scandinavian Simvastatin Survival Study. Circulation 2000; 101:1366-1371. 29. Oliveira HC, Ma L, Milne R, et al. Cholesteryl ester transfer protein activity enhances plasma cholesteryl ester formation: studies in CETP transgenic mice and human genetic CETP deficiency. Arterioscler Thromb Vasc Biol 1997;171045-1052. 30. Kuivenhoven ]A, Jukema JW, Zwinderman AH, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis: the Regression Growth Evaluation Statin Study Group. N Engl J Med 1998;338:86-93. 31. Zhong S, Sharp DS,Grove JS,et al.Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest 1996;972917-2923. 32. Dullaart RF', Hoogenberg K, hemens SC, et al. Cholesteryl ester transfer protein gene polymorphism is a determinant of HDL cholesterol and of the lipoprotein response to a lipid-lowering diet in type 1 diabetes. Diabetes 1997;46:2082-2087. 33. Fumeron F, Betoulle D, Luc G, et al. Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction. J Clin Invest 1995;96:1664-1671. 34.Hannuksela ML, Liinamaa MJ, Kesaniemi YA, Savolainen MJ. Relation of polymorphisms in the cholesteryl ester transfer protein gene to transfer protein activity and plasma lipoprotein levels in alcohol drinkers. Atherosclerosis 1994;110:35-44. 35. Wenzel K, Felix S, Kleber FX,et al. E-selectin polymorphism and atherosclerosis:an association study. Hum Mol Genet 19943:1935-1937. 36. Zheng F, Chevalier JA, Zhang LQ, et al. An HphI polymorphism in the E-selectin gene is associated with premature coronary artery disease. Clin Genet 2001;5958-64. 37. Bowie AG, ONeill LA. Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase. J Immunol2oOo;165:7180-7188. 38. Bowie A, ONeill LA. Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem Phannacol2000;5913-23. 39. Meydani SN, Endres S, Woods MM, et al. Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between young and older women. J Nutr 1991;121:547-555. 40. Jeunemaitre X, Soubrier F, Kotelevtsev YV, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell 1992;71:169-180.

41. Winkelmann BR, Russ AP, Nauck M, et al. Angiotensinogen M235T polymorphism is associated with plasma angiotensinogen and cardiovascular disease. Am Heart J 1999;137698-705. 42. Kunz R, Kreutz R, Beige J, et al. Association between the angiotensinogen 235T-variant and essential hypertension in whites: a systematic review and methodological appraisal. Hypertension 1997;30:1331-1337. 43. Hunt SC, Geleijnse JM, Wu LL, et al. Enhanced blood pressure response to mild sodium reduction in subjects with the 235T variant of the angiotensinogen gene. Am J Hypertens 1999;12: 460466. 44.Rankinen T, Gagnon J, Perusse L, et al. AGT M235T and ACE ID polymorphisms and exercise blood pressure in the HERITAGE Family Study. Am J Physiol Heart Circ PhysioI2000;279:H368-H374. 45. Hingorani AD, Jia H, Stevens PA, et al. Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition. J Hypertens 1995;13 1602-16W. 46.Tumer ST, Schwartz GL, Chapman AB, et al. Antihypertensive pharmacogenetics: getting the right drug into the right patient. J Hypertens 2001;19:1-11. 47. Bova I, Chapman J, Sylantiev C, et al. The A677V methylenetetrahydrofolate reductase gene polymorphism and carotid atherosclerosis. Stroke 1999;30:2180-2182. 48. Gallagher I'M, Meleady R, Shields DC,et al. Homocysteine and risk of premature coronary heart disease: evidence for a common gene mutation. Circulation 1996;942154-2158. 49. Kluijtmans LA, Kastelein JJ, Lindemans J, et al. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation 1997;96:2573-2577. 50. Kluijtmans LA, Boers GH, Verbruggen B, et al. Homozygous cystathionine beta-synthase deficiency, combined with factor V Leiden or thermolabile methylenetetrahydrofolate reductase in the risk of venous thrombosis. Blood 1998;91:2015-2018. 51.Gemmati D, Previati M, SeMo ML, et al. Low folate levels and thermolabile methylenetetrahydrofolate reductase as primary determinant of mild hyperhomocystinemia in normal and thromboembolic subjects. Arterioscler Thromb Vasc Biol1999;191761-1767. 52. Miyao M, Morita H, Hosoi T, et al. Association of methylenetebahydrofolate reductase (MTHFR) polymorphism with bone mineral density in postmenopausal Japanese women. Calcif Tissue Int 2000; 66:190-194. 53. Martinez de Villarreal LE, Delgado-Enciso I, et al. Folate levels and N(5),N(10)-methylenetetrahydrofolatereductase genotype (MTHFR) in mothers of offspring with neural tube defects: a case-control study. Arch Med Res 2001;32:277-282. 54. Ou CY, Stevenson RE, Brown VK, et al. 5,lO-Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects. Am J Med Genet 1996;63:610-614. 55. Skibola CF, Smith MT, Kane E, et al. Polymorphism in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci U S A 1999;96 12810-12815. 56. Kluijtmans LA, Whitehead AS. Methylenetetrahydrofolate reductase genotypes and predisposition to atherothrombotic disease; evidence that all three MTHFR C677T genotypes confer different levels of risk. Eur Heart J 2001;22:294-299. 57. Engbersen AM, Franken DG, Boers GH, et al. Thermolabile 5,lO-methylenetetrahydrofolatereductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet 1995;56:142-150. 58.Haga SB, Khoury MJ, Burke W. Genomic profiling to promote a healthy lifestyle: not ready for prime time. Nat Genet 2003;34 347-350. 59. Loktionov A. Common gene polymorphisms and nutrition: emerging links with pathogenesis of multifactorial chronic diseases (review). J Nutr Biochem 2003;14426-451.

Rotation Diet: A Diagnostic and Therapeutic Tool Sally J. Rockwell, CNN, PhD CHAPTER CONTENTS Introduction 497 The Elimination Diet 497 Variations of the Elimination Diet Procedure 498

497

INTRODUCTION Food allergy/intolerance is a common component of many chronic diseases (see Chapter 53). However, it is often not recognized as problematicbecause conventional laboratory diagnosis is not very sensitive for food allergies and most allergists dismiss the concept of delayed hypersensitivity reactions to foods (see Chapter 19). A time-honored, effective approach to both diagnosis and treatment of food sensitivities is an eliminationrotation diet. This approach has the advantage of being low cost, but the techniques must be followed assiduously to ensure clinical efficacy. Box 47-1 lists the typical indications for an elimination diet.

THE ELIMINATION DIET The first step in the elimination diet is to remove from the diet (1) all of the most common allergenic foods-i.e., wheat and other glutinous grains, dairy products, eggs, corn, soy and tofu, peanuts, citrus fruits, yeast, and refined sugars-and (2) other often problematic substances, such as highly processed foods, chemicals, additives, preservatives, artificial colorings, flavorings, caffeine (coffee, tea, cola drinks, chocolate), and alcohol. The object is to avoid intake of all suspect foods and substances for at least 5 days, or long enough to clear all traces of those foods from the digestive tract. The omitted foods are then reintroduced into the diet one at a time. Keeping an accurate food and symptom diary enables the offending foods to be identified and eliminated; then, depending on the severity of the initial test response, the foods can be retested and added back into the diet within 3 to 6 months. Although some authorities recommend eliminating only one food at a time, clinicians in this area have found

The Diversified Rotation Diet 499 Using the Master Charts 499 Modifications for Vegans 499 Food Preparation 499 Helpful Hints and Suggestions 500

that multiple allergies are the rule, not the exception. Eliminating only one allergen may not improve sympt o m enough to allow the improvement to be recognized. The advantages of eliminating all major allergens in the beginning are rapid clearing, minimal adverse reactions, and accurate test results. Also, when symptoms clear rapidly, the patient is inspired and eager to continue with the testing. As Dr. Doris Rapp' explains: If there are several tacks in the bottom of a shoe, the whole foot hurts; removing only one tack will make little or no difference. But remove all the tacks, let the foot heal, then add back one tack at a time and the source of pain is isolated and easily identified. If only one tack (or food) is removed, no significant difference will be noted.

Variations of the elimination diet range from the most stringent plan, involving elimination of all the major allergens, refined foods, and toxic substances, to a more lenient approach, which eliminates only wheat, dairy, and refined sugars. Consideration of the patient's lifestyle, age, weight, general health, food preferences, attitude, and family system determines the approach. For children and pregnant or lactating women, the amount of calories or carbohydrates should not be restricted; one should simply omit the major allergens.

Variations of the Elimination Diet As can be seen in Table 47-1, all elimination/challenge diets are simply variations on the same following procedure: 1. Eliminate suspect foods for at least 5 days. 2. Introduce/test by challenge ingestion. 3. Carefully record reactions.

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Therapeutic Modalities

4.Rotate foods, avoiding those shown to cause disagreeable reactions.

Water Fast Water fast should be done only under the close guidance of a health professional experienced in supervising fasts. A lifetime of accumulated toxins can be released in a short time, creating unwarranted discomfort and complications that overwhelm the patient and interfere with testing (see Chapter 50 for a complete description of fasting methodologies).

The Dilute Juice Fast

the third day. In addition, liberal amounts of pure water should be consumed throughout the day in order to dilute and flush out toxic substances. Note: This approach works for most patients with Candida yeast infections, because the juice is so dilute that it rarely creates a problem. However, commercially prepared juices (especially tomato and citrus juice) often contain molds, which can be problematic.

Fruit and/or Vegetable Plan In the fruit and/or vegetable plan, the patient consumes unlimited amounts of clean fresh fruit and melons and raw, steamed, or baked vegetables throughout the day. If Cundidu overgrowth is severe, or if weight loss is desired, vegetables should be emphasized and fruits limited.

Less severe than water fasting, and more acceptable to patients, is the dilute juice fast. The diluted juices provide a modest amount of calories, stabilize blood glucose levels, and decrease the adverse detoxificationwithdrawal reactions that may occur during elimination of all common allergens. The basic procedure is to use three parts of distilled or mineral water to one part of fresh, sugar-free juice. The diluted juices are sipped throughout the day. Ideally, a different juice is used each day: celery, carrot, papaya, cranberry, berry, apple, pineapple, and other fruits or vegetables that have not been consumed on a daily basis. Citrus fruits should be avoided. Low-allergen protein supplements, such as Ultra Clear, MEDIPRO Protein Powder, pure free-form amino acids, N Foods, and Vivonex, may be added after

The caveperson plan consists of the following basic foods that the caveperson consumed, after the major allergenic foods have been eliminated: vegetables, fruits, berries, honey, nuts, seeds, beans, peas, sprouts, roots, gourds, poultry, fish, seafood, and wild game.

Documented or suspected food allergiedintolerances Chronic complaints that have not subsided with treatment Patients who have symptoms and whose tests results are all “normal” Patients in whom mental health problems are suspected because of lack of significant progress Children and teens who are labeled as having attention deficit disorder (ADD) or as being hyperactive or autistic or who have behavior problems

Any one, or any combination, of the previously described elimination plans will clear the patient of allergenic substances. If after 5 days the patient’s symptoms have not diminished (or disappeared), continue the diet for another 5 days. If symptoms are not clear in 10 days, begin to rotate foods, because the patient may be reacting to a food or substance he or she is consuming every day. (Unsuspected environmental allergens may be contributing to the symptoms also; see “Helpful Hints and Suggestions” later in chapter.)

The Caveman (Caveperson)Plan

Procedure Beginning the Elimination Diet An ideal elimination diet begins as follows:

1 . 2 days of diluted juices 2. Fruits and vegetables for the next 2 days 3. The caveperson diet for 2 days or until symptoms clear

Testing by Challenge Ingestion ination diet variants Type

Protocol

Water fast

Water-only fast for 5 days; reintroduction of foods

Dilute juice fast

Diluted fruit juice fast for 5 days; reintroduction of omitted foods

Fruit, melon, and vegetable plan

Only fruits, melons, and vegetables for 5 days; reintroductionof omitted foods

Caveman (caveperson) plan

Proteins, nuts, seeds, legumes, fruits, and vegetables for 5 days; reintroduction of omitted foods Only natural, unprocessedfoods are eaten

One suspect food is introduced every other day. The object is to give the patient sufficient calories, build a reliable list of safe foods, and delay unpleasant reactions for as long as possible. Challenge should begin with rarely ingested foods because they are least likely to cause adverse reactions. Foods that are known to cause severe reactions should not be tested with challenge.

Suggested Testing Sequence Foods should be introduced back into the diet in the following order whenever possible: vegetables, fruits, melons, beans, nuts and seeds, yeasts, dairy products,

Rotation Diet: A Diagnostic and Therapeutic Tool

and, finally, grains. When dairy is added, goat products should be tested first: plain yogurt, cheeses, and then milk. The same process is performed with cow's milk. Grains are tested in the following order: quinoa, amaranth, buckwheat, wild rice, brown rice, millet, barley, speZt, lcamut, tef, oats, rye, corn, and, lastly, wheat (glutencontaining grains are in italics). Dietary supplements should also be tested one at a time. Food and Symptom Diay The patient records, chronologically in a notebook, all foods, liquids, supplements, moods, symptoms, and reactions. The foods eaten throughout the day should be noted in either pencil or blue or black ink.Symptoms are highlighted or circled in colored ink so that those adverse reactions stand out clearly. In 2 to 3 weeks, a repetitive pattern of symptoms will be clearly visible, allowing for identification and elimination of the problematic foods or food combinations that cause symptoms. In the beginning, a patient may not be able to describe in exact words how he or she feels, so a numbering system may be useful for noting general moods throughout the day. Numbers go from 1 (poor) to 10 (excellent); feeling sort of medium, neither poor nor excellent, would be recorded as a 5. In general, depending on the patient's health and motivation, foods causing a mild reaction should be avoided for 3 months, and those causing a severe reaction are best avoided for at least 6 months before being reintroduced. Testing Children The clinician can play a game with children to make testing fun.For instance, they can be asked to draw a picture of how they feel or write their names before and after testing a substance. The clinician should note the differences in the two drawings or writings.

THE DIVERSIFIED ROTATION DIET The basic concept of the diversified rotation diet is to achieve the following: Eliminate all major allergenic substances. Eat the remaining foods once every 4 days. Allow 2 to 4 days between food families. Rotation can be simplified by using a templatethe "master chart"-with foods correctly arranged according to their botanical family classifications. The spacing of the foods, and food families, are preorganized into four columns, one for each day, so the patient simply chooses foods from the appropriate column each day. A colorcoding system further simplifies the process of choosing the correct foods. Appendix 10 contains the charts and plans used. The master chart for plan I is the more liberal of the

two plans. It provides 4 days between specific foods and only 2 days between food families. The master chart for plan I1 is used for severely sensitive individuals. It calls for 4 days between specific foods and 4 days between food families. If necessary, it can be easily adapted to a 7-day rotation.

Using the Master Charts The clinician uses a pencil to cross out the major allergens, plus any known or suspected problem foods, in each of the four columns. The patient may eat the remaining foods from the appropriate column throughout the day. The foods that are not crossed out are what the patients is allowed to eat. Each arrow on the chart (H) indicates a food that is essentially the only food of a family and that is not crossreactive with other foods. Therefore it is not restricted to any one particular day and can be moved to another column if additional food choices are needed. Patients who will be rotating foods for any length of time will welcome the benefits of using the color-coding system. A color is assigned to each day. Each column represents a day: Day 1, green, is column 1; day 2, yellow, column 2; day 3, blue, column 3; and day 4, red, column 4. After day 4, the patient returns to day 1 and repeats the process. Food containers are labeled and color-coded to coordinate with the color of the day; for example, green labels, twist-ties, or rubber bands are placed on all containers of foods for day 1. The colorcoding system enables the entire family to see at a glance which foods the patient is permitted to eat on each day.

Modifications for Vegans The master charts can be used for vegans if all foods of animal origin are crossed out. After the initial elimination phase, the patient proceeds with the food challenges. Legumes (beans and peas) are generally an important part of the vegan diet, so all legumes should be tested, one at a time, beginning with the least allergenic, rarely eaten beans and proceeding to soy and tofu, with peanuts tested last. Depending on the allergic response to legumes, the patient may be able to tolerate legumes daily, as long as he or she eats a different legume each day. In other words, although the 4-days-between-foods rule continues to be honored, the l-day-between-foodfamilies rule may be safely ignored for some patients.

Food Preparation For testing purposes, fresh, organic foods should be used whenever possible. Otherwise, frozen or dehydrated foods are a better choice than canned goods. Most vegetables are best eaten raw, steamed, or baked. Fish, poultry, and meat are best poached, steamed, sautked, baked, or simmered in a slow cooker (e.g., Crock-Pot). Soups and stews are fine. Only sea salt should be used

Therapeutic Modalities

for seasoning; all spices and flavorings must be avoided until they are individually tested. Blood glucose levels can be stabilized if the patient eats small, frequent meals throughout the day. Using hypoallergenic foods, the patient may prepare four mixtures of "trail mix"-nuts and dried fruits-one for each day (refer to the master chart for specific food choices).A supply of healthy snacks should be maintained everywhere: home, school, office, and automobile.

Helpful Hints and Suggestions Control of Withdrawal Symptoms and Allergenic Reactions Ascorbates buffered with calcium, potassium, and/or magnesium are suggested as a daily source of vitamin C for allergenic individuals. These substances help to balance an acidic body pH and are valuable for neutralizing unpleasant allergic reactions. Stabilization of pH eases the symptoms of withdrawal from allergenic foods and the cravings that occur when the patient is breaking an addiction, whether it is to sugar, wheat, coffee, cigarettes, alcohol, or a drug. For daily use,the clinician determines an individual's requirement for vitamin C. The patient begins with '/s tsp of buffered ascorbate in V 2 cup of water 3 times a day (between meals and at bedtime). The amount is gradually increases by an additional '/s tsp per dose every 2 days until the patient reaches bowel tolerance-loose stool, gas, or diarrhea-at which point the dosage is reduced. As the patient improves, the vitamin C requirement will likely diminish, and the dosage may need to be reduced again. Note: Buffered vitamin C should not be taken with meals because it would neutralize stomach acid, which is often deficient in patients with food allergy/intolerance (see Chapter 53). For temporary relief of symptoms or to neutralize an adverse reaction, the patient should mix and drink V 2 teaspoon of buffered vitamin C in '/z cup of water or dilute juice. Available commercial products include Klaire Labs Bi-carbs, Cardiovascular's Tri-salts, and Alka Seltzer

1. Rapp D.The impossible child in school, at home, ed 2. Buffalo, NY Practical Allergy Research Foundation, 1989.

Gold label (not the blue label): If none of these products is available, V 2 teaspoon of baking soda in 7 2 cup of water can be useful.

Environmental Allergies If the patient does not respond in a timely fashion and all other possibilities have been ruled out, the clinician should suspect environmental and/or chemical sensitivities. The first step in this instance is to eliminate use of all scented toiletries, room sprays, and cleaning solutions in the home and workplace.*

Ensuring Adequate Protein Intake As the most allergenic foods also tend to be those highest in protein, care must be taken to ensure that the patient is consuming enough protein. Patients with large numbers of food allergies should be referred to a competent nutritionist to help them develop an adequately balanced diet.

Patience The clinician must be especially patient with and supportive of individuals who have experienced long-term conventional treatment only. He or she may be the first physician to remind them that symptoms are the body's way of communicating and that learning to pay attention to what they eat and drink, and the possible adverse symptoms, is a vital part of getting well again.

Allergy-Free Cookbooks Recipes plus dozens of helpful hints and suggestions can be found in specialty cookbooks. I have published several self-help books and tapes, including The Rotation Game, complete with instructions, colored visual aids, recipes, and so on. It is available in hard-copy book form and as a software program for Microsoft Windows (see contact information in footnote; a free copy of Allergy Alert newsletter is available on request). 'Contact me for a patient "how-to" checklist: PO Box 31065, Seattle, WA. 98103; telephone: 206-547-1814 (or toll free 1-888-DIET4U2 1343-84821); fax: 206-5477696; e-mail: SR @ DrSallyRockwell.corn;website: www.DrSa//yRockwe//..Com.

Soft Tissue Manipulation: Diagnostic and Therapeutic Potential Leon Chaitow, ND, DO CHAPTER CONTENTS Introduction 501 Soft Tissue Points 502 Methods of Identification 502

General Soft Tissue Manipulation Techniques 503 Discrete Palpable Points Related to Trauma of Strain 503 Point Classification System 505 Different Muscle Types 510

INTRODUCTION Acupuncture, osteopathy, chiropractic, naturopathic medicine, orthopedic medicine, and physiotherapy all pay attention to the diagnostic and therapeutic potential of the soft tissues of the body. These and other similar therapeutic systems have developed methods of identifying those aspects of soft tissue dysfunction that indicate disease, injury, or reflex activity of some type. Regardless of the terms used or the theories propounded, all the systems seem to refer to the same phenomenon: distinct, palpable, usually sensitive areas of soft tissue aberration that are either directly or reflexively related to local or organ The sustained or intermittent adaptive results to the influences listed in Box 48-1 can result in progressive changes, summarized in Box 48-23-8and shown in Figures 48-1 and 48-2. Soft tissue manipulation may be used to accomplish the following: Normalize dysfunction preparatory to manipulation of osseous structures9 Restore postural or functional integrity-achieving what osseous adjustments can seldom achieve: actual alterations in structural position of musculoskeletal segments1°

Emotional Influence on Soft Tissues 51 1 Summary 512 Reflexes Related to Organ or System Dysfunction 512 Therapy as a Stress Factor 515 The Potential of Soft Tissue Manipulation 515 Summary 515

Function as part of a comprehensive approach to health care in which the reflex activity, as manifested in surface structures, is used diagnostically and therapeutically" The distinguished Western acupuncture pioneer Dr. Felix Mann has stated that with the vast number of acupuncture and other reflexively active points now charted, little, if any, of the body surface is left that has not been ascribed therapeutic potential.I2 Thus he

Congenital factors, such as short leg, small hemipelvis Birth trauma, such as cranial trauma from forceps delivery, which distorts the internal cranial fascia-tentorium cerebelli and falx cerebri-which, because of body-wide fascia1 continuity, can cause distortions elsewhere Overuse, misuse, or abuse of the musculoskeletal system in work or recreational settings Habitual postural stress Habitual upper chest breathing pattern Trauma-ither repetitive minor forms or major incidents Reflexive factors, including myofascial trigger points and viscerosomatic influences Chronic somatization influences generated by negative psychosomatic factors and emotional coping traits, including fear, anger, anxiety, depression, etc. Biochemical changes resulting from nutritional, toxic, endocrine, infectious, and other influences

501

Therapeutic Modalities

1. An initial "alarm" response occurs in which tissues become hypertonic. 2. If not short term, localized oxygen deficit is probable, together with retention of metabolic waste products, both of which result in discomfort or pain and the likelihood of an increased hypertonic response. 3.The constant activity of the neural reporting stations of these tissues leads to increased sensitization and the development of a tendency to hyperreactivity (known in osteopathic medicine as "facilitation"). 4. Macrophages become activated-along with increased vascularity, fibroblast action, and connective tissue production-leading to cross-linkage and shortening of tissues. 5. Changes in the muscles as a result of hypertonicity which, if sustained, results in progressive fibrotic modification. 6.Sustained hypertonicity leads to drag on tendinous attachment to the periosteum and the likelihood of pain and dysfunction in these tissues. 7. If such stressed tendons or muscles cross joints, they become crowded and their function is modified. 8. The antagonists of chronically hypertonic muscles are reciprocally inhibited; as a result, normal firing sequences of muscles may alter-e.g., excessive activity of synergist muscles occurs in order to take on the tasks of weakened (inhibited) prime movers, or synergists. 9. Chronically shortened hypertonic structures have a sustained inhibitory effect on their antagonists. One example is the short, tight, erector spinae muscles and weakened (inhibited) abdominal muscles seen in the typical "slouching," pot-bellied,sway-back posture; another example is the inhibition of deep neck flexors associated with short tight neck extensor muscles, seen in the typical "chin-poke" head position (Figures 48-1 and 48-2).

Upper and Lower Crossed Syndromes 1. Chain reactions of such dysfunction can occur, resulting from the

shortening over time of postural muscles (type 1 fibers) and the inhibition and weakening (without shortening) of phasic muscles (type 2 fibers). 2. Localized areas of hyperreactivity (facilitation) may evolve paraspinally, or in particular stress-prone regions of any myofascial structures-trigger points and other reflexively related changes. 3.These triggers themselves commonly become sources of pain and of further dysfunction. 4. Postural and functional changes will become apparent throughout the body, e.g., in relation to breathing pattern dysfunction ("upper chest breathing"), which can result from (for example) poor, slumped posture and which cannot be easily normalized until the structural changes that encourage it are corrected. 5. Therapeutic input in response to such changes must address the multiple changes that have occurre6to reduce hypertonicity, resolve fibrotic changes, lengthen shortened structures, tone weakenedhnhibited structures, mobilize joints, deactivate trigger points-as well as to remove habitual patterns of use that have added to or caused the dysfunctional patterns, including postural and respiratory reeducation. 6.The musculoskeletal changes described previously may have biomechanical, biochemical, and psychological components, all of which must be understood and, if possible, modified or removed. Data from references 3-8.

Figure 48-1 Lower crossed syndrome. An example of a common postural imbalance pattern. involving a chain reaction of hypertonia and hypotonia in which excessively tight and short muscles are inhibiting their antagonists. (From Chaitow L. Advanced soft tissue techniques. In Chaitow L, ed. Muscle energy techniques, ed 2. London: Churchill Livingstone, 2001.)

maintains that the traditional concept of points and meridians is no longer a valid hypothesis. He concludes that the whole body is, in fact, an acupuncture point. If other systems of identifying discrete areas of reflex potential in the soft tissue, such as Chapman's neurolymphatic reflexes13 and Bennett's neurovascular reflexes14 (see later), are examined alongside both traditional and more recently described acupuncture points, Mann's statement becomes readily acceptable.

SOFT TISSUE POINTS A degree of reductionistic thinking is necessary to understand the nature and value of the reflex areas, points, and zones that have been described by the many systems of soft tissue manipulation. In general, these points can be divided into sensitive soft tissue alterations that result from physical strain or trauma (including the soft tissue effects of emotional stress) and alterations that are the result of reflex activity (e.g., viscerosomatic reflexes). These changes can be regarded as adaptive responses to patterns of stress as outlined previously.

Methods of Identification There are a variety of methods by which soft tissue changes may be located through palpation. They include the following: Traditional massage methods Specific palpation techniques, such as those developed by osteopathic and other school^'^

Soft Tissue Manipulation: Diagnostic and Therapeutic Potential

Figure 48-2 The upper crossed syndrome, as described by Janda. (From Chaitow L. Patterns of function and dysfunction. In Chaitow L, ed. Muscle energy techniques, ed 2. London: Churchill Livingstone, 2001.)

Neuromuscular technique (a method of combined assessment and therapy developed in the 1930s by Stanley Lief, an American-trained naturopathic and chiropractic physician working in Europe)” Skin distraction techniques evolved by the practitioners of German connective tissue massage (Bindesgewebsmassage) (see Hyperalgesic Skin Zones)16 All of these as well as other methods of palpation may be utilized to idenhfy areas of local soft tissue dysfunction that may be either sources or results of reflex activity or other local adaptive response^.'^ The analysis of the available information present in localized areas of the soft tissues requires consideration of a variety of classificationsand systems. It is necessary to examine some of the systems that have described the same tissue changes in different ways, in order to compare the similarities and differences in the descriptions of points (discrete, usually sensitive areas of altered structure and function in the soft tissue) and the diagnostic and therapeutic significance ascribed to them.

GENERAL SOFT TISSUE MANIPULATIONTECHNIQUES18 Therapeutic effort may be directed toward the diagnosis and correction of the mechanical aspects of dysfunction (trauma, strain, etc.) or toward the use of the available informationfrom such reflex areas in a more wide-ranging, holistic approach to the health of the patient.

General, rhythmic techniques are often employed on the soft tissues to relieve local dysfunction and/or to prepare for subsequent adjustment of osseous structure. They may include all or some of the methods listed in Table 48-1.9 In all of these variations, the objectives are improvement of circulation and drainage, release of contracture, and greater range of movement. “Inhibition” implies a degree of pressure sufficient to achieve reduction in hypertonia or neurologic activity. All of these methods may be applied in a stimulatory as well as a relaxing manner, but care should be taken to prevent stimulation from becoming irritation.

DISCRETE PALPABLE POINTS RELATED TO TRAUMA OR STRAIN Researchers and clinicians have used differing terminology to describe similar phenomena, resulting in confusion of what is essentially an uncomplicated pattern. In the musculature and connective tissues of the body, often in the regions of the origins and insertions of the muscles, there are palpable, sensitive areas of altered structure resulting from injury, irritation, stress, and so on. These areas have been described as “tender points,”18 “trigger points,”19 ”Ah Shi points” in traditional acupuncture (literally translated as ”spontaneously tender points”),19 and “indurated points,”20 among other descriptions. Common to these points are their size, which ranges from 0.5 to 1.0 cm across, and their feel, which is described either as harder or firmer

of structure and function are found to lie in shortened muscle tissue or f a s ~ i a . ~ ~ , ~ , ~ ~ The morphology of acupuncture points has been analyzed and described by various workers. BossyB has Technique Description noted that all of the maxima points described by Repetitive passive movements employing Articulation the motor points of medical electrotherapy,26and fully leverage through variable ranges of the arc 70% of Travell’s trigger are all acupuncture Superficial drainage technique derived from Effleurage points described in traditional Chinese medicine. As massage therapy noted in the following discussion, there is also a large Describes an objective rather than a method; Inhibition/ischemic overlap between these and points described in reflex consists of pressure applied for lengthy compression systems, such as Chapman’s neurolymphatic reflexes13 periods, slowly applied and slowly released, using thumb contact as a rule (which include all the traditional acupuncture alarm points) and Bennett’s neurovascular reflexes14 (which Deep or superficial rhythmical pressure, Kneading usually applied by thenar or hypothenar include all traditional acupuncture-”associated” points). eminence Bossy23 notes that the common structures found Approaches that, instead of acting directly on Positional release under all acupuncture points are neurovascular strucrestricted or shortened structures, aim to methods tures, connective tissues, and subcutaneous fatty tissues. position them in a state of ”ease”by moving The connective tissues are thought to be vital in producaway from restriction barriers, allowing a ing the acupuncture sensation noted as being essential to spontaneous normalization to occur, involving neural (muscle spindle) resetting effective therapy.28These structures impart the ”gripand circulatory enhancement ping” of the needle, and the manipulation of the needle These methods include what is known as affects, through localized tissue traction, minute neural straidcounterstrain as well as much reporting stations, such as Meissner corpuscles, muscle craniosacral work spindles, and Golgi tendon organs. Because many of Rhythmic traction Repetitive attempts to separate articulations the systems of reflex soft tissue manipulation (strain/ in order to stretch interarticular and counterstrain, etc.) maintain that it is just such neural periarticular structures structures that produce the reflex effects in their methodSpringing Repetitive, usually slowly applied, pressure ology,8 there appears to be common ground between of a gradual nature, often used diagnostically (see viscerosomatic reflex in Table 48-3) acupuncture and these other systems. This similarity is found in both the identification of the reflex structure Stretching Short and long amplitude attempts at separation of muscular attachments, and (acupuncture point, trigger point, tender point, etc., stretch of ligaments, fascia, and membranes being the same phenomena in different systems of clasRapid oscillatory pressure or movement Vibration sification) and, at least in part, the element that acts to convey reflex benefits (e.g., Golgi tendon organs). Other features of connective tissue are capable of than surrounding normal tissue or as having an edemaresulting either in excessively increased general tone or in localized areas of soft tissue distress and dysfunction. tous or stringy Staubesand and Li29.30 studied the fascia cruris in It is often noted that these localized areas of altered structure and function occur in bands of stressed fibers, humans with electron photomicroscopy and found large both fascial and muscular. In all cases, such localized numbers of smooth muscle cells embedded within the areas are, to a greater or lesser degree, sensitive or tender collagen fibers. Describing a rich intrafascial supply of out of proportion to the amount of pressure exerted.22 capillaries, autonomic nerves, and sensory nerve endAll these points are potential ”trigger points,” but only ings, these researchers concluded that these intrafascial those that, upon pressure, are noted to refer pain or other smooth muscle cells enable the autonomic nervous system to regulate a fascial pre-tension independently of symptoms to a distant (target)area, and that are recognizable as “familiar” to the individual, are so clas~ified.~J~ the muscular tonus. They suggest that this understanding of fascia as an actively adapting organ may have farIdentification of these points as areas of localized dysreaching clinical implications.30One such implication is function depends on palpatory literacy-the ability of the spelled out in the influence of blood pH on smooth examiner to readily distinguish the textures and other muscle status or tone. Alkalosis increases smooth muscle characteristics of normal tissues from those of abnormal contraction/spasm (for example, worsening symptoms tissues. Development of such a level of sensitivity is a of asthma).31Breathing pattern disorders, such as commatter of practice and is readily acquired by any practitioner willing to spend but a little time touching, feeling, monly occur with anxiety and hyperventilation, lead to assessing, comparing, and judging what it is that is excess carbon dioxide exhalation, increased alkalinity, and automatic smooth muscle contraction, so affecting being felt.15In most, but not all, cases, these altered areas

Soft Tissue Manipulation: Diagnostic and Therapeutic Potential

the overall tone of connective tissue, particularly involving the smooth muscle cell tissues embedded in the fascia.32It is therefore unsurprising that pain and trigger point activity often emerge from a background of anxiety and breathing pattern imbalance.

value of these safe methods in bedridden, hospitalized patients (Figure 48-3).% The points described in this method are similar to those known as Ah Shi points in traditional acupuncture.I9Almost identical criteria are used to identify spontaneously sensitive Ah Shi points, which are then Point Classification Systems utilized for acupuncture or acupressure therapy (see later). It is reasonable, therefore, to suppose that the In an attempt to make sense of the vast amount of informaintenance of inhibitory pressure on the tender point is mation available from soft tissue changes, a number of itself of some therapeutic value, inducing a degree of systems have been developed that classlfy variations in significance, role, potential for therapy, and so on. Some local and reflex inhibition. JonesI8denies that this is the of these systems are described here. intention, stating that he considers the pressure used in his system to be purely diagnostic, but it must remain a All such points are sensitive to pressure, but some strong probability that reflex inhibition of neural activity also refer symptoms to a distant site when stimulated. in the point is occurring as a result of this pressure, The points that refer symptoms to distant sites are because of evidence supporting the efficacy of pressure described as active trigger points if the pain is familiar to techniques in inducing pain relief in such condition^.^^,^^ the individual, and the points that do not are potential or Indeed, findings of animal studies suggest that preslatent trigger points.24They may be classified in a variety of ways, depending on the system in q ~ e s t i o n . ~ ~ , ~ ~ sure techniques have a greater efficacy in promoting endorphin release and ultimate pain relief than does Tender Points needling.35Because Chinese texts describe pressure and needling of points as having the same pain-relieving In the system of soft tissue manipulation named strain/counterstrain, described by Lawrence Jones)8,34 effect, it is reasonable to assume that endorphin and/or enkephalin release is an important mediating element the tender point lies in a particular area in relation to any in such relief.37In these studies, artificial cerebrospinal strain of a given joint or area. It is often found not in the fluid was perfused through the lateral ventricle of a donor area complained of by the patient but in shortened tisrabbit while it was receiving finger-pressureacupuncture. sues associated with the strain. Thus in flexion strains of the low back (strains that occur in a forward-bending position), the appropriate tender points are almost always found on the anterior surface of the body-that is, around the lateral abdominal region or anterior pelvis, even though the patient reports back pain. On palpation, these anteriorly located points are reported to be extremely sensitive, although the patient is seldom aware of them prior to their being palpated. Jones’s method is to maintain palpatory contact with the tender point while repositioning the patient’s body in such a manner as to reduce the reported sensitivity from the point. This position of relative ease is then maintained for some 90 seconds while the neurologic reporting stations in the injured tissues reestablish a balanced feedback to the central nervous system (CNS), with resulting release of spasm or contraction. No further therapy is required, because the repositioning usually achieves release of soft tissue dysfunction resulting from strain and a return to normality. In many cases the position of ease mimics or exaggerates either the position in which the original injury occurred or the position into which the patient is distorted by the contraction or spasm. Thus, an individual -unable to stand erect (because of low back strain, for example), may be placed in a position of increased flexFigure 48-3 Position of ease for flexion strain of T9 to lower lumbar regions involves flexion, side-bending, and rotation until ease is achieved in monitored ion while the palpation of the tender point is used to tender point on the lower abdominal wall or the anterior superior iliac spine (ASS) ”fine tune” the exact position of maximum ease of pain area. (From Chaitow L. Modified straidcounterstraintechnique. In Chaitow L, ed. Positional release techniques, ed 2. London: Churchill Livingstone. 2001.) at that point. There is recent evidence confirming the

removed by therapy. Without therapy they are usually self-perpetuating, unless the factors that caused them (e.g., overuse) are removed.17 Once a trigger point is appropriately treated, the muscle in which it lies should be examined for other trigger points, and target tissues should be searched for "satellite" trigger point^.'^,^' Travell and Bigelodl have reported a wide range of symptoms in target tissues associated with trigger point activity, including pain, local vasomotor disturbances (abnormality in pallor, coldness, cyanosis, flushing, etc.), increased or decreased sweat production, and pilomotor activity (all via autonomic nervous system involvement). GutsteinQ reports trigger point involvement in production of a wide range of symptoms, such as menopausal Trigger P0ints~~3* hot flushes and other premenopausal and postmenopausal symptoms (trigger points noted in occipital, A trigger point is a localized palpable spot of deep hypercervical, interscapular, sternal, and abdominal strucsensitivity from which noxious impulses bombard the tures) as well as gastrointestinal symptoms, including CNS to give rise to referred pain and other symptoms. pylorospasm, halitosis, regurgitation, heartburn, nausea, Trigger points, as described by Simons et a1,24are respondistention, constipation, and diarrhea (trigger points sive to pressure techniques, to spray and stretch methods noted in the lower sternum, epigastrium, and paraster(see later), to injection with procaine and other anesnal regions). thetics, and to acupuncture (dry Whichever The ramifications of trigger point activity are now method is used to obliterate the local trigger point known to extend beyond musculoskeletal pain synmanifestation, several important additional measures are dromes; for example, the study by Weis& showed that called for. One of these is identification of the cause, because if it is not resolved, relief is often short-lived. after treatment of myofascial trigger points by means of manual physical therapy to the pelvic floor, 35 (83%)of the Thus, factors such as posture, use of the body (ergonomics applied to sport or occupational habits, etc.), emo42 patients with the urgency-frequency syndrome (with or tional stress, breathing pattern anatomic without pain) showed moderate to marked improvement or complete resolution, and 7 of the 10 (70%)patients with abnormalities (e.g., short leg), nutritional status, and inherited elements all require analysis, in this as in all interstitial cystitis had moderate to marked improvement. areas of somatic dysfunction (Figure 48-4).33 It is worth noting that the mean durations of symptoms before treatment, in patients with interstitial cystitis and It is also necessary to normalize the ability of the musthe urgency-frequency syndrome, were 14 (median 12), cles in which the trigger points are located so that the muscles can subsequently reach normal resting length.21Js*M and 6 years (median 2.5), respectively. Trigger points are not found in muscles able to achieve Treating Trigger Points their normal resting lengths. Trigger points are localized foci of neurologic disorder that continue to bomDirect local pressure starts the process of removing trigger bard the CNS and, reflexively, their target tissues until points. It should involve enough pressure to produce the referred symptoms and then should be maintained in a make-and-break pattern (5 seconds "on" and 2-3 seconds reduced by about a third) until symptoms noticeably lessen or tissue changes are palpated.34,44 This is followed by chilling of both the trigger and target areas with fluoromethane spray (or ice) together with simultaneous and subsequent stretching of the involved muscle in order to achieve a normal resting length.17,21,40,45 Mennell" advocates the spray and stretch methods, as do Simons, Travell, and Sim0ns,2~as part of the method used for obliteration of active trigger points. Many practitioners, such as Gutstein,Q advocate injection into trigger points of anesthetic substances (procaine, etc.) and some, Figure 48-4 The local changes in the muscle of an area being stressed in such as Dittrich,%recommend surgical excision. Another this way include the evolution of fibrotic changes and myofascial trigger points. alternative, after identificationand ischemic compression (From Chaitow L. Patterns of function and dysfunction. In Chaitow L, ed. Muscle energy techniques, ed 2. London: Churchill Livingstone, 2001.) (inhibition) of the point described, would be to place it

When this perfusate was injected into a recipient rabbit, a pain threshold increase of 82% was noted. When CSF from an untreated rabbit was similarly injected, no change was noted in the pain threshold. Highly sigruficant changes were thus noted involving what is assumed to be met-enkephalin. The rabbit research group at the Peking Medical College stated, "From the historical viewpoint, finger pressure was probably the most ancient methods of acupuncture. In our own experience the feeling of soreness and swelling stirred by finger-acupuncture was sometimes even keener than that experienced in traditional needling, whereas the local tissue damage was much less with finger-acupuncture."

Soft Tissue Manipulation: Diagnostic and Therapeutic Potential

into a position of ease (as in the strain/counterstrain methodology discussed earlier) prior to stretching the muscle housing the trigger p0ints.4~,~ Whichever method is used, stretching of the muscles involved to induce a return to normal resting length is usually necessary to ensure complete removal of the trigger point. To achieve this, a number of methods, apart from standard active and passive stretching techniques, have been developed. Among these is the muscle energy technique. An alternative approach to deactivating a trigger point might be to attempt to remove or mod* the stress patterns that have caused or that perpetuate trigger point activity. New Zealand physiotherapist Dinah Bradley, an expert in breathing rehabilitation, identifies key trigger points in her patients at the outset of their course of breathing rehabilitati0n.4~She asks them to ascribe a value, out of 10, to the trigger point when under 4 kg of digital pressure. This is done before the patient commences the exercise and treatment program (i.e., no direct treatment is given to the trigger points themselves), with periodic retesting during the course as well as at the time of discharge. She states, "I use trigger point testing as an objective measurement. Part of [the patient's] recovery is a reduction in musculoskeletal pain in these overused muscles. I use a numeric scale to quantify this. Patients themselves feel the reduction in tension and pain, a useful subjective marker for them, and an excellent m ~ t i v a t o r . " ~ ~

Muscle Energy Techniques A potentially stressful physical therapy modality, known as proprioceptive neuromuscular facilitation (PNF)

and involving full-strength muscular contractions, has evolved into a gentler (very light contractions) method in osteopathic methodology, now called muscle energy technique (MET) or hold reflex technique.5051It is aimed at restoring shortened, tight structures to a normal resting length, although variations aim at toning inhibited musculature. A vast amount of research and clinical investigation into the value of this method has been conducted in Europe, mainly in Scandinavia and Czechoslovakia.'5l The muscles requiring muscle energy attention are identified by standard orthopedic tests for length and by palpation. Additionally, dysfunctional muscles can be identified through reading of the firing sequence of muscles in particular movement patterns. For example, with the patient in the prone position, if the leg is elevated (hip extension), the firing sequence when normal is gluteus maximus, hamstrings, and contralateral and ipsilateral erector spinae. If this sequence is palpated as anything else, commonly hamstring and erector contraction and subsequent gluteal firing, the implication is presence of overactivity in the erectors and hamstrings, and inhibition of the gluteals, with a requirement for normalization of the overactive muscles using muscle energy technique or other appro ache^.^^ Another common imbalance is evaluated with the patient in the lateral recumbent position (side-lying; Figure 48-5). The practitioner stands facing the patient's back or front, at hip level, palpating the gluteus medius, tensor fascia lata (TFL), and quadratus lumborum (QL) simultaneously. The patient abducts the upper leg. In balanced abduction, the gluteus medius fires first, with the TFL operating later in the pure abduction of the leg.

Figure 48-5 Palpation assessment for quadratus lumborum overactivity. The muscle is palpated, as is gluteus medius, during abduction ofthe leg. The correct firing sequence should be gluteus, followed at around 25 degrees of elevation by the quadratus. An immediate "grabbing"action by the quadratus indicates overactivity, and therefore stress, so shortness can be assumed. (From Chaitow L, ed. Muscle energy techniques, ed 2. London: Churchill Livingstone, 2001.)

The QL should not become active until the leg has reached 25 to 30 degrees of abduction. When it is overactive, the QL often fires first along with the TFL. This evidence suggests shortness in the QL (which therefore affects breathing, because the QL merges with the diaphragm as well as acting to stabilize the 12th rib on exhalation) and probable inhibition of the gluteus medius. This type of functional evidence of imbalance directs the practitioner toward those tissues in most need of rehabilitation.Once overtight or shortened muscles have been relaxed and released, there is automatic toning of their previously inhibited antagonists. It is at this stage that rehabilitation can achieve results, as the individual learns better patterns of use and posture.

MET. Muscle energy technique involves the use of two physiologic phenomena, postisometric relaxation and reciprocal inhibition. When a muscle is held in isometric contraction, its release is followed by a degree of relaxation not present prior to the c ~ n t r a c t i o nThus, . ~ ~ when muscle fibers contract, but approximation of the origin and insertion is prevented by an exactly equal counterforce, usually provided by the operator (i.e., an isometric contraction), and this contraction is maintained for a specific time (typically 7-10 seconds), after which relaxation is allowed, a marked release of hypertonicity in the tissues occurs. This allows a greater degree of pain-free A new, stretch to take place in the shortened fiber~.’5~ but probably as yet still limited, resting length is then achieved, which is used as the starting position for the next isometric contraction. This phenomenon of postisometric relaxation (PIR) is used to sequentially stretch tight musculature in which trigger points are found.’$’ If the tight or shortened tissues are too sensitive to allow active isometric contraction, their antagonists are contracted isometrically, producing the phenomenon of reciprocal inhibition, which is similarly used to gradually increase normal resting length in the shortened structures.’ A

There are a number of variations in muscle energy technique. It is extremely gentle, utilizing only a small percentage of available strength (unlike PNF), making it applicable to almost any condition of soft tissue dysfunction, either alone or in combination with pressure and other techniques.33

Variations. Whereas isometric contractions can lead to postisometric relaxation, or reciprocal inhibition, of involved musculature, isotonic exercises have other potentials. For example, a method known as slow eccentric isotonic stretch (SEIS) involves the patient’s engaging a restriction bamer and then attempting to maintain that barrier position (using between 40% and 80% of available strength) while the practitioner s2owIy overcomes this resistance, returning the area to neutral by eccentrically stretching the contracted antagonist.54 The purpose of this technique is to facilitate (tone) the muscles being slowly isotonically stretched (antagonist to shortened muscles) and at the same time to reciprocally inhibit the shortened muscles, so that they can subsequently be more easily stretched. The indication for the technique arises when there is a need to release tension in individual or multiple muscles (ideally, hypertonic postural muscles) and simultaneously tone their weakened/inhibited antagonists (Figure 48-6). MET and joints. Hartman9 describes the use of muscle energy techniques in the preparation of a joint for manipulation. The joint is placed in the appropriate position for adjustment, and the patient is then asked to push against the hands of the operator, so that an isometric contraction develops in the tissues surrounding the joint or area being adjusted. After this contraction is released, the degree of “slack” available to the operator is greater, and the joint is more easily and effectively adjusted. Indeed, adjustment often occurs during the isometric contraction described (Table 48-2).

B

Figure 486 A and 6, Eccentric resistance of wrist and finger extension and thumb abduction. (From Chaitow L, ed. Muscle energy techniques, ed 2. London: Churchill Livingstone. 2001 .)

Soft Tissue Manipulation: Diagnostic and Therapeutic Potential Muscle energy technique: summary of variations Type of contraction

Indications

Modus operandi

Forces

Duration

Repetitions

Isometric, patient direct

Relaxing muscular spasm or contraction Mobilizing restricted joints Preparingjoint for manipulationto increase tolerance to stretching, allowing increased range of motion

Affected muscle not employed Antagonists used; therefore shortened muscles relax via reciprocal inhibition Patient is attempting to push through the barrier of restriction After the isometric contraction, the tissues are taken to the new restriction barrier (in acute settings) or are stretched through the barrier (in fibrotic settings)

Operator's and patient's forces are matched Initial effort involves approximately 20% of patient's strength; slow increase to no more than 50% on subsequent contractions Increase in duration often more effective than increase in force

4-10 seconds initially, increasing to up to 30 seconds in subsequent contractions, in order to recruit additional fibers during the contraction effort

2-3

Isometric, operatordirect

Relaxing muscular spasm or contraction Mobilizing restricted joints Preparingjoint for manipulation

Affected muscles used; therefore shortened muscles relax via postisometric relaxation Operator is attempting to go through barrier of restriction After the isometric contraction, the tissues are taken to the new restriction barrier (in acute settings) or are stretched through the barrier (in fibrotic settings)

Operator's and patient's forces are matched Initial effort involves approximately 20% of patient's strength; slow increase to no more than 50% on subsequent contractions Increase in duration often more effective than increase in force

4-10 seconds initially, increasing to up to 30 seconds in subsequent contractions, if greater effort required

3-5

Isotonic concentric

Toning weakened musculature

Contracting muscle is allowed to do so, with some resistancefrom operator

Patient's force is greater than operator resistance Patient uses maximal effort available but force is built slowly, not via sudden effort

3-4 seconds

5-7

Isotonic eccentric (isolytic)

Stretchingtight fibrotic musculature

Contracted muscle is preventedfrom doing so via superior operator effort Origin and insertion do not approximate Muscle is taken to, or as close as possible to, full physiologic resting length

Operator's force is greater than patient's Less than maximal patient's force employed at first Subsequent contractions build toward this, if pain not excessive

2-4 seconds

3-5, if pain not excessive

lsokinetic (isotonic and isometric contractions)

Toning weakened musculature Building strength in all muscles involved in particular joint function Training effect on muscle fibers

Patient resists with moderate effort at first, progressingto maximal effort subsequently, as operator puts joint through its full range of movements

Operator's force overcomes patient's effort to prevent movement First mobilization involves moderate force, progressingto full force subsequently

Therapeutic Modalities

Zones of Irritation Dvorak and Dvorak17have described a system that identifies localized areas of spinal sensitivity. In this system, zones of irritation (ZI)55are identified by palpation in the paraspinal tissues. These appear in most respects to correspond both with the paraspinal acupuncture points described in the second century AD by Hua T U O ’and ~~ with Jones’s tender points.ls In acupuncture, they are needled or pressed to produce appropriate local and distant effects. In the Dvorak method, the ZI are used to identify the ideal manipulative direction for adjustment. They are contacted by a palpating thumb or finger (as in Jones’s method) and pressure is exerted against the spinous process adjacent to the ZI in such a manner as to reduce their sensitivity. This is considered to be the direction of desirable adjustment. A marked similarity to the method described by Morrison (discussed later) and with strain/ counterstrain techniques is recognizable. DvorakI7 elaborates on the ZI phenomenon by describing what are termed spondylogenic reflex syndromes, in which ZI in specific paraspinal sites are noted to produce particular patterns of dysfunction in other spinal structures, including muscle groups and vertebral regions. Induration Technique The induration technique, almost precisely the same technique as that advocated by the Dvoraks, was developed by Morrison” in the 1940s.The sensitive paraspinal point is identified and a push (not an adjustment) is made on the adjacent spinous process until a direction is found in which sensitivity reduces or tissue release is noted. The pressure is then held for a not less than 20 seconds, and no other therapy is used. Release of the contracted tissues and lessening of pain on palpation are noted. This is very similar to the Jones’s method and is ideal for use by therapists not qualified or licensed to manipulate the osseous structures (Figure 48-7).33 Nimrno’s Receptor Tonus Technique Other workers, such as Raymond N i m m ~who , ~ ~developed the receptor tonus technique, have described similar variations on the theme of identification and normalization of local areas of soft tissue dysfunction using pressure and stretching methods. Nimmo maintained that pressure on such points should last no more than 5 to 7 seconds and that further pressure was likely to injure tissue. Trigger points thus treated would, he maintained, subsequently resolve. He also advocated stretching of the structures. His pressure was delivered by the use of a rubber-tipped wooden instrument, a T-bar, held in the palm of the hand in the interest of reducing stress on the operator’s digits.

Figure 48-7 Hand positions for induration technique. Pressure used on the spinous processes is measured in ounces (grams) at most. (From Chaitow L. Spontaneous positional release variations. In Chaitow L, ed. Positional release techniques, ed 2. London: Churchill Livingstone, 2001.)

Different Muscle Types In all of these systems, the tissues in which points are found are described as having a characteristic shortened or tight feel, and the work of Lewit’ and Janda%helps explain why they are found mostly in particular muscles. Janda58states that there are two basic muscle activities and types, those that are predominantly postural and those that are mainly phasic in action. Postural muscles are as follows: Tibialis posterior Gastrocnemius-soleus Rectus femoris Iliopsoas Tensor fascia lata Hamstrings Short thigh adductors Quadratus lumborum Piriformis Some paravertebral muscles Pectoralis major (and perhaps minor) Sternocleidomastoid Upper trapezius Levator scapula Flexors of the upper extremity These are all prone to shortening and hypertonia when stressed, abused, underused, or overused. Figure 48-8 illustrates the major postural muscles. A number of conditions exist in which specific patterns of dysfunction are associated with shortening of such muscles (e.g., iliopsoas, piriformis, tensor fascia lata, and iliotibial band), treatment of which is possible by means of variations of the techniques discussed here (neuromuscular technique, muscle energy technique, e t ~ . ) . ~ ~ , ~ ~

Soft Tissue Manipulation: Diagnostic and Therapeutic Potential A

B

Figure 48-8 A, The major postural muscles of the anterior aspect of the body. B,The major postural muscles of the posterior aspect of the body. (From Chaitow L. Patterns of function and dysfunction. In Chaitow L, ed. Muscle energy techniques, ed 2. London: Churchill Livingstone, 2001 .)

The phasic muscles include the following: Tibialis anterior The vasti The glutei Abdominal muscles (mainly the recti) Lower stabilizers of the scapula Some deep neck flexors Extensors of the upper extremity These muscles all tend to hypotonia, weakening, and atrophy under conditions of underuse, overuse, or abuse. Janda% asserts that before any attempt is made, via exercise and so on, to strengthen weakened musculature, it is critical for the shortened antagonists to be stretched and relaxed. Commencing with exercise of the weakened structures is likely to further increase tone in the already tight musculature. Tight muscles act in an inhibitory way on their antagonists, creating hypotonia. This situation can be altered by normalization of the tight structures. Whether the stretching is achieved with muscle energy techniques or active or passive stretching is a matter of the operator’s choice.

Emotional Influence on Soft Tissues Selective Motor Unit Inv~lvernent~~ The effect of psychogenic influences on muscles may be more complex than a simplistic ”whole” muscle or region involvement. Waersted, Eken, and W e ~ t g a a r dat ~ ~the National Institute of Occupational Health in Oslo have demonstrated that a small number of motor units in particular muscles may display almost constant, or repeated, activity when influenced psychogenically (for example, a normal individual performing a reaction time task). Using the trapezius muscle as the focus of attention, these researchers were able to demonstrate low-amplitude levels of activity (using surface electromyography [EMG]) when individuals were inactive but mentally ”stressed.” They explain this phenomenon as follows: In spite of low total activity level of the muscle, a small pool of low-threshold motor units may be under considerable load for prolonged periods of time. . . . If tension provoking factors are frequently present and the subject, as a result, repeatedly recruits the same motor units, overload may follow, possibly resulting in a metabolic crisis and the appearance of Type 1 fibres with abnormally large diameters, or “ragged-red” fibres, which are interpreted as a sign of mitochondria1overload.”

Therapeutic Modalities The implications of this information are profound because it suggests that emotional stress can selectively involve postural fibers of muscles, which shorten over time when stressed.

Summary The shortened fibers of the soft tissues usually house the palpable and sensitive points, discussed earlier. These points may be the result of a combination of structural anomalies, trauma, and/or physical or emotional stress and are always influenced by underlying nutritional and behavioral elements. Some of them may be the source of reflex symptoms and pain (active trigger points). All such soft tissue dysfunctions respond to manual pressure, needling, local anesthesia, chilling, and so on, as well as to release via positional alteration and/or resolution of identifiable underlying or causative factors.

REFLEXES RELATED TO ORGAN OR SYSTEM DYSFUNCTION Connective Tissue Massage The German system of connective tissue massage (CTM) has identified a number of regions or zones that are associated with specific organ or functional problems (e.g., liver zone, constipation zone, arterial disturbance of the legs z 0 n e ) . ” J ~ 3Identification ~,~ of such zones in a patient depends on a method of skin stretching by lifting that indicates the degree of adherence between overlying structures and underlying connective tissue. There is decreased elasticity in areas of dysfunction. Therapy involves a dry contact that lifts and stretches these tissues, producing powerful viscerocutaneous reflex effects. Clinical evidence shows this therapy to be of use in a wide range of problems, because it improves organ, circulatory, and neural dysfunction. A hospital study in Scotland found CTM to be effective in producing marked reduction in anxiety levels, with resolution of symptoms such as insomnia in patients resistant to drug therapyY

Chapman‘s Neurolymphatic Reflexes Chapman’s neurolymphatic reflexes, described in osteopathic literature, involve the use of pairs of reflex points located anteriorly and posteriorly on the body surface.11J333,62,63 The feel of such a reflex point is described as similar to that of a nodule, an edematous structure, or a fibrous shotty plaque, depending on the location. These reflexes are stated to be the somatic component of lymphatic stasis in associated structures, and their treatment is believed to assist in resolution of such stasis. A reflex is said to be active if both points of a pair are found to be palpable and sensitive. Treatment is initiated with direct firm rotary pressure, via the tip of a finger or thumb, on the anterior point for 20 seconds to 2 minutes

or until decongestion (tissue change) is noted. The posterior point is then similarly treated. Subsequent reexamination of the anterior point of the pair is conducted to ascertain whether sensitivity is still present. If sensitivity is not present, successful resolution of the associated lymphatic stasis is anticipated. If sensitivity is still noted, however, the pathology is considered to be too great for this method to be effective, and other therapeutic input is required. This approach makes the method a useful prognostic indicator, whether or not the reflexes are used therapeutically in the manner described. When methods such as hydrotherapy, botanical medicine, acupuncture, massage, and nutritional adjustment or supplementation are utilized to treat a particular condition, the activity and sensitivity of Chapman’s neurolymphatic reflex points may be monitored in order to assess progress. Also, because these points become active long before symptoms are obvious in associated structures or organs, the method is of significant early diagnostic and prognostic value. These reflex pairs have been studied in hospitals by the osteopathic profession and were found to be powerful reflex areas. Whether or not the influence is directly on the lymphatic structures is a matter of debate.@ Points are utilized therapeutically in groups associated with systems, such as the respiratory and gastrointestinal systems, rather than as individual pairs of points. There are some 50 pairs of points, many of which are identical to acupuncture points in location if not in ascribed areas of influence. The location of such points and the corresponding organs, tissues, systems, or symptoms have been clearly outlined and diagrammed elsewhere.33

Bennett’s Neurovascular Reflexes A system developed by chiropractic practitioner Terence Bennett utilizes reflex areas, mainly on the abdomen and Bennett’s neurovascular reflexes involve identification of localized areas of dysfunction (points) that are contracted or indurated and that display increased sensitivity. These areas are said to be related to vascular dysfunction. Therapy is accomplished via gentle skin distraction over the point until a pulsation is noted under the palpating digit.65Contact is maintained for a few seconds to several minutes in order to achieve this reflex effect. Many of the points are used only for diagnostic purposes, and others are used both diagnostically and therapeutically.

Cross-Fertilization of Systems Systems such as applied kinesiology,66touch for and sacro-occipital technique (SOT)67have incorporated into their therapeutic and diagnostic methodology the use of many of the reflex points described by Chapman and Bennett.

Soft Tissue Manipulation: Diagnostic and Therapeutic Potential

Alarm and Associated Points In acupuncture, there exists a series of specialized points (known as alarm and associated points) in the meridian system that are found to become sensitive to pressure when the meridian or organ to which they are reflexively connected is distressed.@The points that are sensitive to deep pressure are thought to be involved in excessive energy problems, and those noted on light pressure are related to deficiency problems. Many of the neurolymphatic and neurovascular reflexes described previously are found to correlate with these two sets of points in location, and sometimes in ascribed effect (alarm points are found ventrally, and associated points dorsally). They are treated by needling as appropriate, or by pressure and by attention to the needs of the system correlated to the dysfunction noted.

Tsubo, G-Jo, Judo Revival, and Other Point Systems Related to Oriental Medicine A number of systems with common roots in acupunG-Jo,7O and judo revival7I for examplwmploy Tsub0,6~ reflex points in a variety of ways. Some utilize strong stimulation imparted via the thumbnail to produce rapid reflex effects, whereas others use more gentle pressures. One method indicates a point on the upper lip (Du26) as an ideal locality for strong stimulation in attempting revival of unconscious children suffering grand ma1 or petit ma1 seizures.72It was noted in some hundreds of cases thus treated that termination of the convulsion and full revival of consciousness were achieved in an average of less than 20 seconds. The only failures were in children who were not fully unconscious, for whom the vigorous stimulation was too painful.

Viscerosomatic Reflexes The osteopathic literature describes viscerosomatic reflexes as being localized, sensitive, palpable areas, often found in paraspinal tissues and associated with visceral dy~function.~~ Bea174notes that rigidity is the most common soft tissue manifestation of such a reflex. Initial changes include vasomotor alterations, such as increased skin temperature, and subtle changes, such as increases in thickness of the skin, subcutaneous fluid, and muscular contraction. In chronic conditions, all of these changes become more evident (Figure 48-9). Usually two or more adjacent spinal segments are involved in any viscerosomatic reflex, encompassing, as a rule, the costotransversejunction. Areas that are most frequently involved are T1 to T5 (associated with viscerosomatic reflexes from the cardiac structures), T5 to T10 (esophagus, stomach, small intestine, liver, gallbladder, spleen, and pancreas), and T10 to L2 (large bowel, appendix, kidney, ureter, testes, ovaries, adrenal medulla, urinary bladder, and prostate). There is usually

Flgure 48-9 Schematic representation of the neurologic influences involved in the process of facilitation resulting from visceral dysfunction (cardiac disease in this example). Hyperirritable neural feedback to the central nervous system will result, which influences muscle, skin (both palpable), and venous structure in associated areas as well as the neural supply to the organ itself. (From Chaitow L. Patterns of function and dysfunction. In Chaitow L, ed. Muscle energy techniques, ed 2. London: Churchill Livingstone, 2001.)

some lateralization; for example, the liver reflex is found on the right. For assessment, a springing technique is used in which the palpating hand is slid under the supine patient in order to push upwards on the paraspinal regions. Neuromuscular technique is also an excellent method of assessing such Bea174suggests that digital pressure may be used to effect local changes and to reflexively influence the involved organs (somaticovisceral reflex). This approach would have only a moderate effect on advanced organic disease, so these reflexes are of more diagnostic than therapeutic value. Also, because they are manifested long before other evidence of organ distress is available, they are useful early warnings of developing dy~function.’~ Regular assessment of the paraspinal tissues, therefore, acts as a monitor of the internal function. This concept is well documented medically and is of potential value in monitoring the efficacy of any type of therapy, because the reflex condition shows improvement in tandem with the organ ~ t a t e .The ~ ~overlap , ~ ~ between these reflexes and the points and zones described previously should be borne in mind (Table 48-3).

Hyperalgesic Skin Zones Skin changes are noted overlying all points and zones involved in reflex activity, characterized by what may be termed hyperulgesiu. A reduced degree of elasticity is observed, and this is diagnostic. Lewit’ maintains that the introduction of a mild stretch into these hyperalgesic

Therapeutic Modalities

System

Pointdreflexes

Location

Relationship

Paravertebral

Diseases of the abdomen and local and lumbar dysfunction

Posterior reflexes Reflex No. 12

8tW9tW10th interspaces

Reflex No. 33 Reflex No. 42

10th costotransverse junction 9th-10th or 10th-11th intertransverse

Small intestine dysfunction (anterior in 8th/9th/lOth intercostal spaces) Pyloric stenosis (anterior reflex is on the sternum intercostal space) Ovaries (anterior point is on the round ligaments from the superior border of the pubic bone inferiorly)

Bilaterally bladder point 18 Bilaterally bladder point 19

ah-10th interspace 10th-11th interspace

Liver meridian Gall bladder meridian

Connective tissue zone

Left side Right side Central area

Stomach zone Liver zone Kidney and part of the head zone

Trigger points

Lower trapezius, multifidus, iliocostalis, and longissimus muscles

Wide distribution of target areas

Zone of irritation

Costotransverse junction

Spondylogenic reflex syndromes involving tissues connected to C2 C7, T l T6, L1 L5,S1, S3,and S4

Viscerosomatic reflexes

T5-TlO

Esophagus, stomach, small intestine, liver, gallbladder, spleen, pancreas

Hua Tuo Neurolymphatic reflexes

Associated points

Extension strain at this level

Tender points

skin areas has a powerful reflex effect on underlying dysfunction (i.e., the trigger or tender point, or zone). Assessment is made by gentle distraction of the skin in order to compare it with the surrounding skin and with the skin in the same region on the contralateral side of the body. The underlying reflex areas may be mapped and confirmed through the use of pressure to ascertain sensitivity and possible referred symptoms. Treatment consists of maintaining the degree of distraction in the skin zone (fingers pulling gently apart or, for larger areas, lateral aspects of the hands doing the same) until a degree of release is noted, as the skin relaxes and is stretched to its normal range. This is all the treatment required to normalize the tissues and to introduce reflex changes into the underlying structures. The maintenance of the restored elasticity depends on whether the causative factors have also been dealt with and on the level of activity in associated reflexes. A number of other methods of normalization can be utilized, including skin rolling, as described in Western and Oriental massage te~ts.”,~~J’ Chinese massage methods include pinch-pull techniques that can be used to torufy or sedate the patient and that have marked similarities to German CTM methods. CTM, as described previously, involves far more powerful skin stretching

methods than either the pinch-pull techniques or Lewit’s distraction and stretch techniques.16

Neuromuscular Technique The methods of the neuromuscular technique involve the systematic combing of the tissues for the soft tissue changes already described.11,33,78,79 Its economy of effort and combining of diagnostic and therapeutic procedures have made the neuromuscular technique popular among practitioners in Europe, where it evolved as a combination of methods derived from Ayurvedic massage,80traditional massage, and an American “bloodless surgery” (not to be confused with the Philippine faithhealers’ “bloodless surgery”) method.8l Typically, the operator’s thumb tip is used to exert variable pressure on all the accessible origins and insertions and muscle masses in order to identify changes, and, with variations in that pressure, to simultaneously treat the recognized abnormalities. This approach is regarded as part of an overall assessment rather than as an end in itself. Other methods of traditional massage from both East and West are combined with NMT to normalize those aspects of soft tissue dysfunction that are manifestations of stress, strain, and trauma and to address reflex changes when applicable.

Soft Tissue Manipulation: Diagnostic and Therapeutic Potential

THERAPYASASTRESSFACTOR Stress is any added load imposed by forces brought to bear on an individual, organ, or tissue. It may be chemical, toxic, psychic, emotional, or Adaptation denotes the ways in which the organism adjusts itself to intrinsic disturbances or challenges. These responses may be shortterm or long-term, representing the body’s homeostatic mechanisms at work. Sel~e,8~ in his classic experiments, noted specific and general responses in disease, observing that ”stress can either cure or aggravate a disease, depending upon whether the inflammatory response to a local irritant is necessary or superfluous.” In landmark research in the 1 9 4 0 ~ Speransky84 ~ stated, ”It is obvious from this research that the initation of any point of the complex network of the nervous system can evoke changes not only in adjacent parts but also in remote regions of the organism.” He continues, “There is a rule that only weak degrees of irritation can have useful SigIuficance,strong ones inevitably do damage.”% Many therapeutic measures involve a degree of stress, whether this be an acupuncture needle, surgery, or intake of toxic substances, even in homeopathic dilutions; applications of heat or cold, or electrotherapy; or, indeed in this consideration, manual pressures and efforts. Attaining the desired response, therefore, depends on the therapeutic effort’s not overwhelming the homeostatic potential of the organism.20Therapy may be considered to consist largely of the application of graduated degrees of stress, to which the organism responds according to its unique attributes and potentials. Whether it causes benefit or harm depends on the degree of that stimulus and, most important, on the vitality of the patient. The implications for manual therapists are obvious and call for thoughtful application of the varieties of techniques available.

THE POTENTIAL OF SOFT TISSUE MANIPULATlON The professions within medicine that utilize manual therapy, such as physiotherapy, have tended to discard the tradition of ”hands-on” treatment in favor of a more technologic approach, leaving the soft tissues to massage therapists and sports therapists. Osteopathy (as practiced in Europe, where it is not a part of a general medical practice as in the United States but, rather, a system that addresses structural and functional dysfunction via

manipulative methods9fi) and chiropractic, which are conceived as being largely concerned with the joints and osseous component of the musculoskeletal system, have come to recognize the vast importance, both diagnostic and therapeutic, of the soft tissues. The musculoskeletal system is both the greatest energy consumer of the body and its largest organ of sensory input. Although this primary machinery of life has long been unappreciated, in therapeutic terms, the development of methods such as strain/counterstrain, muscle energy technique, and neuromuscular technique and the huge amount of information derived from acupuncture tradition and research as well as other reflex systems ensure that the diagnostic and therapeutic potential of the soft tissues are now being recognized and utilized. Korr,% the premier osteopathic researcher of the second half of the twentieth century, summarizes another vital implication of soft tissue dysfunction-interfemce with axonal transport mechanisms-thus: Any factor that causes derangement of transport mechanism in the axon or that chronically alters the quality or quantity of the axonally transported substances could cause the trophic influences to become detrimental. This alteration in turn would produce aberrations of structure, function and metabolism, thereby contributing to dysfunctionand disease. Almost certainly to be included among these harmful factors are the deformation of nerves and roots, such as compression, stretching, angulation and torsion that are known to occur all too commonly in the human being and that are likely to disturb the interaxonal transport mechanisms, intraneural microcirculation and the blood-nerve barrier. Neural structures are especiallyvulnerable in their passage over highly mobile joints, through bony canals, intervertebral foramina, fascia1 layers and tonically contracted muscles. Many of these biomechanically induced deformationsare of course subject to manipulative amelioration and correction.

SUMMARY This survey has touched on some of the many ways in which soft tissue dysfunction may impinge upon the economy of the body as a whole. Soft tissue manipulation is an important diagnostic and treatment modality and should be considered an integral part of the practice of any physician or practitioner whose intent is to care for the whole person. (Those interested in studying this topic in more depth will find references 33 and 38 very helpful. These works thoroughly cover the topics surveyed here and provide useful tables, charts, and diagrams as well as pictures of the various techniques as they are applied to a patient.)

1.Lewit K. Manipulative therapy in rehabilitation of the motor system. Boston, MA: Butterworths, 1985. 2. Baldry P. Acupuncture, trigger points and musculoskeletal pain. London: Churchill Livingstone. 1993. 3. Janda V. Introduction to functional pathology of the motor system. Proceedings of W commonwealth and international conference on sport. Physiother Sport 19823:39. 4. Liebenson C. Rehabilitation of the spine. Baltimore: Williams & Wilkins, 1995. 5. DiGiovanna E, ed. An osteopathic approach to diagnosis and treatment. Philadelphia: Lippincott, 1991. 6. Greenman P. Principles of manual medicine. Baltimore: Williams & Wilkins, 1996. 7. Chaitow L. Palpation skills. London: Churchill Livingstone, 1996. 8. Korr I. Neurological mechanisms in manipulative therapy. New York Plenum Press, 1978. 9. Hartman L. Handbook of osteopathic technique. London: Hutchinson. 1985. 10.Rolf I. Rolfing: the integration of human structures. New York Perennial Library, Harper and Row, 1977. 11. Chaitow L. Neuromuscular technique. Rochester, VT: Thorsons, 1980. 12. Mann F. International Conference on Acupuncture and Chronic Pain, New York, September 1983. 13.Owens C. An endocrine interpretation of Chapman's reflexes. Carmel, CA: Academy of Applied Osteopathy, 1963. 14.Bennett T. Dynamics of correction of abnormal function. Sierra Madre, C A Ralph Martin, 1977. 15. Mitchell FL Jr. The training and measurement of sensory literacy in relation to osteopathic structural and palpatory diagnosis. J Am Osteopath Assoc 1976;75874-884. 16. Ebner M. Connective tissue massage: theory and therapeutic application. Edinburgh: E&S Livingstone, 1962. 17. Dvorak J, Dvorak V. Manual medicine: diagnostics. New York: Thieme-Stratton, 1984. 18.Jones L. Strain and counterstrain. Colorado Springs, CO: American Academy of Osteopathy, 1981. 19. Academy of Traditional Chinese Medicine. An outline of Chinese acupuncture. Peking: Foreign Languages Press, 1975. 20. Momson M. Lecture notes. London: British College of Naturopathy and Osteopathy, 1970. 21. Travell J, Simons D. Myofascial pain and dysfunction: the trigger point manual. Baltimore: Williams & Wilkins, 1983. 22. Menneu JM. The therapeutic use of cold. J Am Osteopath Assoc 1975;74:1146-1158. 23. Bossy J. Morphological data concerning acupuncture points and channel networks. Acupunct Electrother Res 1984;9:79-106. 24. Simons D, Travell J, Simons L. Myofascial pain and dysfunction: the trigger point manual, vol 1 , h d ed. Baltimore: Williams & Wilkins, 1999. 25.Head H. On disturbances of sensation with especial reference to pain of visceral disease. Brain 1893;161-133; 1894;17339-480; 1896;19:153-276. 26.Shestack R. Handbook of physical therapy. New York: Springer Publications, 1956. 27. Melzack R, Stillwell DM, Fox EJ. Trigger points and acupuncture points for pain. correlations and implications. Pain 1977;3:3-23. 28. National Symposia of Acupuncture. Moxibustion and acupuncture anaesthesia, Peking, June 1-9,1979. 29. Staubesand J, Li Y. Zum Feinbau der Fascia cruris mit besonderer Beriicksichtigung epi- und intrafaszialer Nerven. Manuelle Medizin 1996;34:196-200.

30.Staubesand J, Li Y. Begriff und Substrat der Faziensklerose bei chronisch-venoser Insuffizienz. Phlebologie 1997;26:72-79. 31. Clarke PS,Gibson JR. Asthma, hyperventilation and emotion. Aust Fam Physician 1980;9:715-719. 32. Chaitow L, Bradley D, Gilbert C. Interdisciplinary approaches to breathing pattern disorders. Edinburgh Churchill Livingstone, 2002. 33. Chaitow L. Soft tissue manipulation. Rochester, VT.Thorsons, 1987. 34. Schwartz HR. The use of counterstrain in an acutely ill in-hospital population. J Am Osteopath Assoc 1986;86:433-442. 35. Scientia Sinica, XW. Peking: Science Press, 1974;112. 36.Chaitow L. Acupuncture treatment of pain. Rochester, VT: Thorsons, 1976. 37. Kiser RS, Khatami MJ, Gatchel RJ, et al. Acupuncture relief of chronic pain syndrome correlates with increased plasma metenkephalin concentrations. Lancet 1983;21394-1396. 38. Chaitow L, DeLany J. Clinical applications of neuromuscular techniques, vols 1,2. Edinburgh: Churchill Livingstone, 2000,2002. 39. Melzack R. Myofascial trigger points: relation to acupuncture and mechanisms of pain. Arch Phys Med Rehabil 1981;62:114-117. 40.Lewit K, Sions DG. Myofascial pain. relief by post-isometric relaxation. Arch Phys Med Rehabil1984;65:452-456. 41. Travell J, Bigelow N. Role of somatic trigger areas in the patterns of hysteria. Psychosom Med 1947;9:358. 42. Gutstein R. A review of myodysneuria (fibrositis). Am Pract Digest Treat 1955;6570-757. 43. Weiss JM. Pelvic floor myofascial trigger points: manual therapy for interstitial cystitis and the urgency-frequency syndrome. J Urol 2001;166:2226-2231. 44.Chaitow L. Instant pain control. New York: Wallaby Books/Simon & Schuster, 1981. 45.Gelb H. Clinical management of head, neck and TMJ pain and dysfunction. Philadelphia: WB Saunders, 1977. 46.Dittrich RJ. Somatic pain and autonomic concomitants. Am J Surg 1954;876673. 47. Chaitow L. Integrated neuromuscular inhibition technique in treatment of trigger points. Br J Osteopathy 1994;13:17-21. 48. Chaitow L. Modern neuromuscular techniques. Edinburgh Churchill Livingstone, 1996. 49.Gilbert C, Seals C, Wyka K, Bradley D. Breathing retraining: advice from three therapists. J Bodywork Movement Ther 1999;3 158-167. 50.Mitchell F, Moran P, Pruzzo N. An evaluation and treatment manual of osteopathic muscle energy procedures. Valley Park, M O published by authors, 1979, 51. Evjenth 0, Hamberg J. Muscle stretching in manual therapy: a clinical manual, vols 1, 2. Alfta, Sweden: Alefta Rehab Vorlag, 1984. 52. Jull G, Janda V. Muscle and motor control in low back pain. In Twomey L, Taylor J, eds. Physical therapy of the low back. New York Churchill Livingstone, 1987. 53.Grieve G. Mobilization of the spine. New York: Churchill Livingstone, 1984. 54. Liebenson C. Rehabilitation of the spine: a practitioner's manual. Baltimore: Williams & Wilkins, 1996. 55. Caviezel H. Beitrag zur Kenntnis der Rippenlaisonen. Mannuele Medizin 1974;5110. 56. Ji XP. Teaching round: sciatica. J Tradit Chin Med 1986;6131-134. 57. Nimmo R. Receptor tonus: a neural therapy. London, England Seminar Notes, 1966 58. Janda V. Muscles, central nervous motor regulation and back problems. In Korr I, ed. Neurobiologic mechanisms in manipulative therapy. New York: Plenum Press, 1978.

Soft Tissue Manipulation: Diagnostic and Therapeutic Potential 59. Waersted M, Eken T, Westgaard RH. Psychogenic motor unit activity: a possible muscle injury mechanism studied in a healthy subject. J Musculoskeletal Pain 1993;1:185-190. 60. Bischof I, Elmiger G. Connective tissue massage. In Licht S, ed. Massage, manipulation and traction. New Haven, CT: Licht, 1960. 61.McKechnie AA, Wilson F, Watson N, Scott D. Anxiety states: a preliminary report on the value of connective tissue massage. J Psychosom Res 1983;27125-129. 62. Arbuckle B. The selected writings of Berly Arbuckle. Camp Hill, PA: The National Osteopathic Institute and Cerebral Palsy Foundation, 1977. 63. Chaitow L. An introduction to Chapman’s reflexes. Br Naturopathic J 1965; Spring:lll-113. 64.Mannino JR. The application of neurological reflexes to the treatment of hypertension. J Am Osteopath Assoc 1979;79225-231. 65. Thie J. Touch for health. Santa Monica, C A De Vorss, 1973. 66. Goodheart G. Applied kinesiology research manuals. Detroit: published by author, 1964-1971. 67. De Jamette 8. Sacro occipital seminar notes. Nebraska City, N B De Jamette, 1975. 68. Pennell R, Heuser G. The ”how to” seminar of acupuncture for physicians. Independence, M O IPCI, 1973. 69. Serizawa K. Tsubo: vital points for Oriental therapy. Tokyo: Japan Publications, 1976. 70. Blate M. The G-Jo handbook finger-pressure techniques for paramedical use. Davie, FL Falkynor Books, 1983. 71. Lawson-Wood DJ. Judo revival points, athletes points and posture. Santa Barbara, C A Health Science Press, 1960. 72. Pothmann R, Schmitz G. Acupressure in the acute treatment of cerebral convulsions in children. Alt Med Holland 1985;1:63-67.

73. Postgraduate Institute of Osteopathic Medicine and Surgery, New York. The physiological basis of osteopathic medicine. New York Insight Publishing, 1970. 74. Beal MC. Palpatory testing for somatic dysfunction in patients with cardiovascular disease. J Am Osteopath Assoc 1983;82822-831. 75. Ward A. Somatic component to myocardial Infarction. Br Med J (Clin Res Ed) 1985;291:603. 76. Ashby EC. Abdominal pain of spinal origin. Ann R Coll Surg Engl 1977;59:242-246. 77. Scott J. The treatment of children’s diseases. J Chin Med 1980; 3~13-22. 78. Lief l? Neuromuscular technique. Br Naturopathic J Osteopath Rev 1963;5304-324. 79. Youngs B. The physiological background of neuromuscular technique. Br Nat J Osteopath Rev 1963;5176-178. 8O.Varma D. The human machine and its forces, pranotherapy. London: Health for All Publishers, 1937. 81.Fielder S, Pyott W. The science and art of manipulative surgery. Salt Lake City: American Institute of Manipulative Surgery, 1955. 82. Wright H, MacAdam D. Clinical thinking and practice: diagnosis and decision in patient care. New York Churchill Livingstone, 1979. 83. Hoag J. Osteopathic medicine. New York McGraw-Hill, 1969. M.Speransky A. A basis for the theory of medicine. New York International Publishers, 1943. 85. Chaitow L. Osteopathy: a complete health-care system. Rochester, VT: Thorsom, 1982. 86. Korr IM.The spinal cord as organizer of disease processes. IV. Axonal transport and neurotrophic function in relation to somatic dysfunction. J Am Osteopath Assoc 1981;80451-459.

Spirituality and Healing Lara Pkzorn~,MA (Divinity), MA (Literature), Lh4T CHAPTER CONTENTS Introduction 519 The Conceptual Ground for the Efficacy of Spirit in Healing 520

Surgical Outcome 526 Length and Quality of Life 526 Delinquency 526

Spirituality:The Province of Physicians? 527 The Healing Effects of Prayer: Evidence of the Nonlocal Activity of Consciousness 522 Specific Areas in Which Prayer and Religious Activity Have Been Shown Effective in Humans 522 Cardiovascular Disease 522 Hypertension 523 Cancer 524 Acquired Immunodeficiency Syndrome 525 Alcohol and Drug Abuse 525 Suicide 525

INTRODUCTION Faith and medical science are not mutually exclusive. In fact, faith's efficacy as a powerful healing force has been scientifically validated by numerous studies, many of which exhibit all the criteria of the best science.' A substantial and growing body of research on the healing power of participation in religious activities such as prayer has demonstrated that faith in a Spiritual Reality, an Almighty Spirit, a Beneficent Presence-whether the label given is God, Allah, Atman, Brahman, the Tao, Qi, the Christ, the Absolute, the Universal Mind-has significant, beneficial effects on health. Some of these effects are as follows: Lowering blood pressure Protecting against heart disease Improving surgical outcomes and lessening recovery time Increasing feelings of well-being Ameliorating depression Improving the ability to cope with stress while lessening its adverse physiologic effects

The Practical Application: Integrating Spirituality into Medical Practice 527 The Most Effective Prayer 527 Side Effects and Contraindications 528 Illness, the Gift of Spiritual Healing 528 The Experience of Spirit 528 Summary

530

Well-designed studies provide documentation that: Religious commitment can help protect children from drug abuse, alcohol abuse, and suicide. Individuals for whom a spiritual dimension of life is integral embrace healthier lifestyle practices. Among the elderly, those who live in faith tend to live longer.2 In the current medical model, most physicians are led to believe that any consideration of religious commitment is beyond the legitimate interest and scope of medical care. The dogma is that faith is not amenable to serious scientific scrutiny, but is merely a relic from earlier, less enlightened ages, a crutch for the scientifically disinclined. Medical students and residents all too often get the subliminal message that to personally pursue an active religious faith is to court schizophrenia, traveling simultaneouslydown the right-brain path of faith, religion, and prayer (read irrationality and superstition) and the left-brain road of logic, analytical dialectic, and rational thought (read: Science). In modern medical education, devotions are to be paid only to "Science" with a capital "S," which leaves 519

Therapeutic Modalities

the whole realm of the numinous outside the Venn diagram locus of serious medicine. So members of the health care professions tend to disassociate their spirituality from their science, both in their training and later in their clinical practice and academic endeavors. Not only does such an approach desiccate human life, shutting us off from the true and unbounded Source of our strength, insight, and joy but also recent scientific research has, itself, made such an uncritical stance not only irrational but medically irresponsible.

THE CONCEPTUAL GROUND FOR THE EFFICACY OF SPIRIT IN HEALING Sigruficant evidence exists that, to use descriptive terminology coined by Dossey, we live in a nonlocal universe and are, at our deepest level, nonlocal beings ourselves. In the rarefied air of quantum physics as well as in a raft of common experiences that will not neatly fit within the confines of reductionistic rationalism-such as dkja vu, synchronicities, premonitions, and near-death experiences-the evidence clearly suggests that a Creative Intelligent Force manifests throughout the universe, including us, and that this Force, which I refer to as Mind or Spirit, is not wholly localized to points in space (such as brains or bodies) or even to single moments in time. Advances in genomics notwithstanding, we have barely begun to scratch the surface of the issue who and what we really are. In his books Healing Beyond the Body3 and Reinventing Medicine: Beyond Mind-Body fo a New Era of Healing? Dossey provides a conceptual framework that integrates modem medicine’s past while providing insight into its future. He divides the history of scientific medicine into three epochs, which he calls Era I, Era 11, and Era In. Era I, the first scientific medical era, which began around 1860, was engendered by the classic laws of matter and energy, the mechanistic model of the universe laid out by Sir Isaac Newton that grounds newtonian physics. According to this view, the entire universe is a vast clockwork that functions according to deterministic, causal principles. In Era I, reality is composed of energy and matter, and mind is considered an artifact, a delusion produced by chemical reactions occurring in the brain. Era I, or materialistic and mechanistic, medicine encompasses virtually all forms of modem medicine today-drugs (green or allopathic), surgery, irradiation, cardiopulmonary resuscitation, chiropractic, nutrition, vitamins, gene therapy, DNA manipulation, organ transplants, cloning, and so on-any form of therapy that focuses solely on the effects of things in the body. Obviously, Era I medicine is local in nature, that is, restricted in time and space, and cannot account for a wide range of phenomena such as the placebo effect,

psychosomatic illness such as posttraumatic stress disorder, or the influence of religious belief on the body. After World War II, Era I1 medicine, or what we now call mind-body medicine (although a more accurate term would be brain-body medicine because this view remains localized and materialistic), began to take shape. Jean-Martin Charcot, the great nineteenth century neurologist, studied hysterical reactions and the effect of suggestion on bodily function. Freud, a student of Charcot, extended these ideas and emphasized the influence of the unconscious on health and behavior. Although by the mid-twentieth century most authorities had decided that ”mind” and “consciousness”were unnecessary, and the terms were simply redundant symbols for the brain, it became obvious via psychosomatic disease that the brain did affect the body. Hans Selye demonstrated that rats and mice confined in close quarters and subjected to environmental stressors they could not predict or control, such as intermittent loud noises and electrical shocks, experienced gastrointestinal ulcerations, hypertension, and heart disease and often died. It became clear that humans could react similarly when subjected to stress perceived as uncontrollable. Then, research on the placebo effect demonstrated that through suggestion, expectation, and positive thinking, the mind could have beneficial as well as negative effects on the body. Placebo is considered the bane of researchers, who devised the double-blind study to try to eliminate its effects. Not only will placebo not go away, its widespread nature and effectiveness have been blazingly demonstrated in two recent studies, one published in April 2002 that compared St. John’s wort with sertraline (Zoloft) and a placebo? and the other a 2002 metaanalysis of the results of antidepressant trials published between 1979 and 1996. The first study showed that St. John’s wort cured 24% of the depressed people who received it, Zoloft cured 25%, and the placebo cured 32%.The metaanalysis was conducted by Seattle psychatrist Arif Khan and associates> who studied the placebo effect in 96 trials submitted to the U.S. Food and Drug Administration (FDA).These researchers found that in 52% of the trials, the effect of the antidepressant, whether botanical or pharmaceutical, could not be distinguished from that of the placebo. Several other reviews published in the Journal of the American Medical Association have noted that, in the treatment of depression, the placebo effect seems to be growing. Greater percentages of people tended to get better with placebos during trials of antidepressants in 2000 than in 1981.&13 These studies strongly suggest that Era I1 or mindbody medicine is here to stay, but although it recognizes the mind as an important factor in healing, Era 11 medicine limits the mind’s causal powers to within the individual person. In Era 11, medicine has moved beyond the

Spirituality and Healing

materialistic boundaries of newtonian physics to include any therapy emphasizing the effects of the individual’s consciousness but still restricts the activity of consciousness to within the individual’s body. Examples of Era I1 therapies are psychoneuroimmunology, counseling, hypnosis, biofeedback, and relaxation therapies. Today, modem medicine is a combination of Era I and 11. For example, patients with cancer receive psychological counseling along with chemotherapy, surgery, vitamins, and nutritional counseling. In heart disease, stress management is used along with dietary manipulations, beta-blockers or statin drugs, and coronary bypass surgery. The key here is that both Era I and Era I1 are descriptive of a universe in which mind or consciousness is localized and equated with the individual brain. Consciousness is assumed to be a byproduct of the brain’s chemistry and physiology, in spite of the fact that no one knows how the brain ”makes” the mind or even that it does. As a number of modem philosophers and physicists have observed, no one has the slightest idea how mind or consciousness can arise from anything material. No one even knows what it would be like to have the slightest idea how anything material could be conscious. To quote physicist Niels Bohr, “We can admittedly find nothing in physics or chemistry that has even a remote bearing on consciousness.~’4~14 When Descartes spoke his famous dictum “I think, therefore I am,” he saw the brain as a signal transducer, a piece of equipment through which the input of Mind was received, specificallyin the pineal gland, and thence transmitted to the material plane. Although descartesian dualism has been used not only to bifurcate reality but also to dismiss anything not perceivable through the senses, this is the exact opposite of what Descartes actually claimed was the truth about reality. For Descartes, the material world and our senses are unreliable; and Mind (not the brain) is the only bona fide assurance of the fact of our existence. To sum up, Era I medicine emphasized a completely physical, body-based approach to health and illness, which Era I1 medicine expanded by recognizing the effects of mind-although the mind is typically (and without scientific foundation) equated with the brain, and mind-body effects remain restricted to within each individual-ne’s own mind affecting only one’s own body. This restriction is the target of the opening and expansion that is occurring in Era I11 medicine, in which, Dossey believes, the evidence in current physics and our own experience is firmly pushing us, kicking and screaming all the way, to paradigm transformation. Era In, nonlocal medicine, is based on current quantum physics, which describes a world in and through which One Energy, which I will refer to as Mind, God, or Spirit, moves unbounded by time or space. Within the last 50 years, physicists have firmly established that

atoms and electrons behave nonlocally, suggesting that nonlocality is the truth underlying the visible world we inhabit, and our truth as well. The scientific birth of the nonlocal universe began in 1935, with the now-famous paper “Can Quantum Mechanical Description of Physical Reality Be Considered Complete?” in which Albert Einstein, Boris Podolosky, and Nathen Rosen pointed out that under certain conditions, photons set off in opposite directions at the speed of light might still have a connection with each other, a connection that Einstein described as a ”ghostly action at a distance” and that bothered him a great deal because it would allow the possibility of messages to be sent faster than the speed of light. Because, according to the theory of relativity, it is impossible for an informational connection to be maintained between two points that are receding from each other at the speed of light, Einsteinmistakenly as we now know-concluded that something was fundamentally wrong with quantum theory. In 1964, physicist John Bell at the European Organization for Nuclear Research (CERN)proved the far-reaching inequality theorem now known as Bell’s theorem, in which he rigorously described the consequences of Einstein’s action at a distance hypothesis. Bell’s theorem implied that if an experiment involving protons going off in opposite directions were actually carried out, then, according to another Nobel Prize winning physicist, Brian Josephson, ”there must be a mechanism whereby the setting on one measuring device can influence the reading of another instrument, however rernote.”I5 The appropriate physics experiments testing this conjecture have now been carried out in several laboratories worldwide: by Freeman and Clauser in Berkeley in 1972, by Aspect et a1 in Paris in 1982, and by Gisin at the University of Geneva in 1997.15What these experiments all show is that when one measures the polarization of a pair of photons born in the same interaction but traveling in different directions, the polarization of one photon appears to be altered by the mere act of observing the other, even when the photons are widely separated over distances of several kilometers. In sum, laboratory experiments have confirmed that a nonlocal correlation between photons does exist, a correlation that physicists Bohm and Hiley, in their physics textbook The Undivided Universe, call “quantum interconnectedness.”16 Although our naive realist picture of our reality is one in which separate individuals occupy their own wellcircumscribed points in space-time, modem physics, for the past 30 years, has been asserting that this concept is incorrect. The quantum physicist’s view is that we live in a nonlocal reality in which we can be affected by events distant in space and time from our ordinary awareness. An avalanche of data supports thisview. This research includes recently declassified experiments, run by the

Therapeutic Modalities

U.S.Central Intelligence Agency during the Cold War, that involved remote viewing and were conducted at the Stanford Research Institute, as well as literally millions of experiments at the Princeton Engineering Anomalies Research facility (PEAR) that demonstrate that individuals can mentally affect the function of sensitive electronic devices not only regardless of distance but also in the future or even the past. When applied to the individual, these data clearly suggest that we are fundamentally nonlocal beings for whom the accepted boundaries imposed by space and time are not the ineluctable limitations we have defined them to be. The evidence in quantum physics points to One Creative Energy, Intelligence, or Mind as fundamental, as transcending the physical mind or ego, and as present everywhere in both space and time. In a very real sense, the universe physicists now describe is the map upon which a new worldview is emerging. They are the exploratory cartographers of a new view of consciousness, a view that is forcing a sigruficant change in our assumptions about the nature of the human mind and its relationship to the physical human body. The truth is that no localized, mechanistic description of what goes on in the brain can shed any light whatsoever on why consciousness exists. According to physicist and astronomer David Darling? there is a very simple reason for this: ”The brain does not produce consciousness at all, any more than a television set creates the programs that appear on its screen. On the contrary, the brain filters and restricts consciousness, just as our senses limit the totality of experience to which we might otherwise have access.” This view is seconded by philosopher Michael G ~ o s s o ,who ~ ~ describes the relationship between consciousness or the mind and the brain as somewhat analogous to that between a radio and radio waves. The radio does not produce the radio waves; it simply detects, transmits, and filters them. If your radio breaks down, it does not follow that the sounds you were listening to have ceased to exist; they just cease to be detectable. In Era 111, the mind is recognized to be more than the brain because an overwhelming amount of scientific data demonstrates that the mind can do things the brain cannot, such as acting remotely from the body and outside the present time. Era 111 medicine recognizes that an aspect of the mind is not restricted to the body, the brain, or a particular moment in time, but is linked with Mind-the infinite, eternal aspect of Consciousness that is a natural part of who we essentially are. In addition to the research carried out at Stanford and Princeton, this aspect of our being has been demonstrated in literally hundreds of studies showing that healing can be achieved at a distance by direct, loving, compassionate thoughts, intentions, and prayers for others, even those who are unaware of these efforts for their well-being.

THE HEALING EFFECTS OF PRAYER: EVIDENCE OF THE NONLOCAL ACTIVITY OF CONSCIOUSNESS A large body of credible scientific evidence shows that mind directed in prayer can function at a distance to change physical processes in a variety of organisms. In addition to humans, study subjects have included water, enzymes, bacteria, fungi, yeast, red blood cells, cancer cells, pacemaker cells, seeds, plants, algae, moth larvae, mice, and chicks-a wide range of entities whose responses are unlikely to be due to placebo effect. Processes influenced include the activity of enzymes, growth rates of leukemic white blood cells, mutation rates of bacteria, germination and growth rates of various seeds, firing rates of pacemaker cells, healing rates of wounds, the sizes of goiters and tumors, the time required to awaken from anesthesia, autonomic effects such as electrodermal activity of the skin, rates of hemolysis of red blood cells, and hemoglobin levels.ls

SPECIFIC AREAS IN WHICH PRAYER AND RELIGIOUS ACTIVITY HAVE BEEN SHOWN EFFECTIVE IN HUMANS Cardiovascular Disease Social epidemiologist Jeff Levin, a Senior Research Fellow of the National Institutes of Health (NIH), is recognized as one of the leading researchers in the field of spirituality and health. In his book God, Faith and Health, Levin provides an overview of the published studies that offer compelling evidence for the connection between health and a wide spectrum of spiritual beliefs and practices, including prayer, attendance at religious services, meditation, and faith in a Spiritual Reality (i.e., God by whatever name)? As a first-year graduate student in the School of Public Health at the University of North Carolina in Chapel Hill, Levin became intrigued by two articles that found a surprising and significant connection between spirituality and heart disease, a connection that remains one of the best-researched areas of the positive effects of religious behavior on health. In God, Faith and Health, Levin notes that the medical literature now contains more than 50 studies in which religious practices were found to be protective of a wide range of heart diseaserelated conditions: death due to circulatory system diseases; atherosclerotic heart disease incidence and death; myocardial infarction incidence and death; coronary heart disease incidence, prevalence, and death; rheumatic, nonrheumatic, and hypertensive heart disease and death; angina pectoris incidence; aortic calcification prevalence; death due to chronic endocarditis; and incidence of numerous risk factors, including cholesterol, lipid, and triglyceride levels and caloric and fat intakes.

Spirituality and Healing The protective effects offered by religious belief and/or practice that Levin cites from a number of studies are far from insignificant, as the following examples show: Scientists at the Missouri Center for Health Statistics found that the death rate due to ischemic heart disease in members of the Reorganized Church of Jesus Christ of Latter Day Saints was 20% lower than that of other Missourians. Investigators at the University of Colorado, Case Western Reserve University, and Johns Hopkins University studied death rate patterns in the Old Order Amish people of Indiana, Ohio, and Pennsylvania. Men aged 41 to 69 years had a 35% lower death rate due to circulatory system diseases than non-Amish men of the same ages. A team from the University of Utah found that among Mormons, the death rate due to ischemic heart disease was 35% lower than among non-Mormons and that Mormons also had a lower risk of death from hypertensive and rheumatic heart diseases. Researchers from the Institute for Social Medicine in Utrecht found that Seventh Day Adventists had a 57% lower risk of death due to ischemic heart disease than non-Adventists. In addition to studies focusing on communities with well-known health-promotinglifestyle practices, another study not limited to a specific religious group found an inverse association between frequency of religious attendance and rates of atherosclerotic disease in both men and women.I9Even after allowing for the effects of smoking, socioeconomic status, and water hardness, the risk for atherosclerosis among men who attended church frequently was 40% less than that for men who attended church infrequently. For women, the risk of dying from heart disease was approximately twice as high among those attending church infrequently as among those who attended church weekly or more often.

Prayer and Coronary Heart Disease Perhaps the research that has most decisively forced the issue of acknowledging and incorporating our nonlocal nature into the practice of medicine appeared in 1988 in the Coronary Care Unit at San Francisco General Hospital, when cardiologist Randolph Byrd conducted a study on the effects of distant prayer on healingz0Byrd and his research assistant, Janet Greene, asked each patient in the coronary care unit whose condition was stable whether he or she would agree to help study the effect of prayer on treatment. Over a 10-month period, a computer assigned the 393 patients who agreed to participate to either a group that was prayed for by home prayer groups (192 patients) or a control group that did not receive this prayer support (201 patients).

The study was randomized and double-blinded, so that patients, nurses, doctors did not know which patients were in which group. Byrd recruited members of several Protestant and Roman Catholic groups from around the country to pray. The pray-ers were given their patients’ first names and a brief description of their diagnoses and conditions and were asked to pray each day, but were given no instructions as to how to do so. Each pray-er prayed for many different patients, so each patient had between five and seven people praying for him or her. Ten months later, when the results were evaluated, Byrd presented a significant challenge to the medical status quo. The patients receiving prayer support were five times less likely to have required antibiotics (3patients vs. 16) and three times less likely to have experienced pulmonary edema (6 vs. 18). None of the prayed-for group required endotracheal intubation, compared with 12 in the nonprayer group, and fewer patients in the prayed-for group died (13 vs. 17), a difference that was not considered statistically significant. Overall, the prayed-for patients achieved a 5% to 7% advantage over the controls, a very respectable level of improvement compared with other areas of medicine, as Dossey4 makes clear in his comparison of the Byrd study results with those found in a meta-analysis of whether aspirin helps prevent heart attacks published in Science in 1990. Although aspirin has long been touted as effective in the prevention of heart attack, this metaanalysis found that only 5 of 25 studies showed aspirin to be of any value, whereas 80% found that it provided no clinical advantage whatsoever. A later study was designed to investigate whether the scores from a questionnaire measuring spiritual wellbeing correlated with progression or regression of coronary heart disease as measured with computerized cardiac catheterization data. Participants in Omish’s Lifestyle Heart Trial were given the “Spiritual Orientation Inventory.” A sigruficant difference was found in the spirituality scores between a control group and a research group that practiced daily meditation. The spirituality scores were highly correlated with the degree of progression or regression of an individual’s coronary artery obstruction over a 4-year period. Those with the lowest scores of spiritual well-being experienced the most progression of coronary obstruction, and those with the highest scores showed the most regression. The researchers concluded that lack of spiritual well-being may be an important factor in the development of coronary artery disease.2I

Hypertension So many studies have been conducted in the area of hypertension and spirituality that Levin and Vanderpool felt the need to summarize them and did so in a detailed

Therapeutic Modalities

review that was published in the British journal Social Science and Medicine.22 Their review noted a significant inverse correlation between strong religious commitment and blood pressure that was evident no matter what religion an individual chose to practice or his or her geographical location or ancestry. Some of the studies discussed in the review are described here. A California study of adults of Chinese, Filipino, and Japanese ancestry found that those with religious affiliation had a 15% rate of hypertension, approximately half the 29.3% rate seen in subjects with no religious affiliation. An examination of the incidence of hypertension in South African Zulus by the Harvard School of Public Health showed that among urban women, membership in a Christian church was associated with normal blood pressure, whereas nonmembership was linked to hypertension, particularly among women who reported being “bewitched,” who were twice as likely to have high blood pressure as their churchgoing peers. A study of Jewish families in Jerusalem reported that the advantage of religious affiliation extended even to the families of religiously active subjects, regardless of the family members’ own levels of religious activity. Female children whose fathers had attended yeshiva for at least 5 years had a mean diastolic blood pressure of 65.2 mmHg, compared with 74.5 mmHg for those whose fathers had less than 5 years of religious training, and 71.5 mmHg for those whose fathers had no formal Jewish education. Levin and Vanderpool’s comment about these statistics is “A little religion may be worse than none.”22 I suggest, however, that the disparity between the daughters of men with no formal religious education and those of men with less than 5 years of religious education may be explained by the fact that merely having no formal religious training does not mean one has no spiritual life, but that choosing to discontinue religious education may indicate a disaffection with all things spiritual due to an unsatisfactory encounter with religion. How many of us have not only thrown away a form of organized religon we found intolerable, but mistakenly limited God to the concept of It taught in the religion we disavowed? A matched study performed at Duke University found that people who attended religious services at least weekly and prayed or studied the Bible at least daily had consistently lower blood pressure than those who did so less frequently or not at all. A study conducted by the National Cancer Institute and Georgetown University, comparing death rates in clergymen and in the general white population, found American Baptist ministers were almost 40% less likely to die of hypertension-related heart disease, Presbyterian ministers 29% less likely, and Episcopalian and Lutheran ministers 41% less likely. Also, Japanese researchers study concluded that Zen Buddhist priests were half as likely to die from hypertension as other Japanese men.

Another study that Levin does not include in his metaanalysis focused on women, examining the association between blood pressure, selected health behaviors, and religious activity. Data were obtained on 112 women who were at least 35 years old and of Judeo-Christian faiths. Resting blood pressure measurements were taken with an automated sphygmomanometer; height and weight were measured to determine body mass index (BMI); and intermediate health variables (e.g., physical activity, smoking, diet, and alcohol consumption) were measured with a questionnaire. A multifactorial questionnaire was used to assess various dimensions of religious activity. Multiple-regression analysis found a direct inverse effect between both systolic and diastolic blood pressure values and the level of religious activity, not mediated by changes in health behavi0rs.2~ Two other studies included in Levin’s metaanalysis contradict the theory that religion is clinically beneficial only because it helps people avoid risk-producing behaviors. In one, people who both were frequent church attendees and rated their religion as very important were found to have lower diastolic blood pressure values, and this association that held true even for smokers. Smokers who rated religion as very important were 7.1 times less likely to have an abnormal diastolic blood pressure value than those smokers who gave a low rating for the personal importance of religion. Another study found that smokers who attended church weekly or more often were 4 times less likely to have abnormal diastolic pressure values than those with low or no church attendance. Even when the analysis was adjusted for other blood pressure risk factors, such as age, socioeconomic status, and weight, the mean diastolic blood pressure value in subjects who rated religion as highly important to them and who attended church weekly or more often was almost 5 mmHg lower than that in subjects who rated religion as unimportant and attended church infrequently or never.22

Cancer Dozens of epidemiologic studies report that some religious groups have significantly lower risks of cancer, both overall and for many specific types. This research, which Levin’ summarizes in God, Faith and Health, includes the following studies: Studies at University of California at Los Angeles, University of Utah, and University of Alberta found a lower overall death rate in Mormons of both sexes from the 1950s to 1970s, in Utah, California, and Canada, respectively. Mormons were shown to be protected not just from dying of cancer but also from development of cancer. Studies at Lorna Linda University School of Public Health identified lower cancer incidences and death rates in Seventh-Day Adventists overall and for

Spirituality and Healing several cancer sites, including the colon, rectum, lung, and mouth. A study from the Danish Cancer Registry showed that Adventist men had significantly lower risk than men in the general Danish population for cancers of the colon, respiratory system, and bladder. An Indiana University study summarizing 30 years of data from California found that Adventist women had higher 1-, 3- and 5-year survival rates than women in the general U.S. population after diagnosis with breast cancer. Levin7 cites data from studies dating back to the first half of the twentieth century documenting that some religious groups have a much lower incidence of reproductive cancers. He reviews data from more than 50 studies published into the 1990s, all of which consistently show that Mormons, Seventh Day Adventists, Hutterites, Amish, Muslims, Parsis, and Jews, especially Jewish women, have lower incidence (new cases), prevalence (total cases), and mortality from reproductive cancers than the general U.S. population. Among Jews, the lower rates of uterine and cervical cancers and the virtual nonexistence of penile cancer have been ascribed to the hygienic benefit of circumcision, yet a number of studies have found Jews to have considerably lower rates of other unrelated cancer sites, as follows7: A Dutch study from more than 50 years ago reported fewer than expected deaths among Jews from cancers of the stomach and bile passages. A University of Texas Medical Branch study conducted over 15 years found an average annual rate of death due to lung cancer in non-Jewish men of 148.6 per 100,000, compared with 95.5 per 100,000 in Jewish men-more than 60% lower. A National Cancer Institute review of data from studies conducted in New York City demonstrated lower rates of death in Jews than in non-Jews for cancers of the buccal cavity, pharynx, prostate, and bladder.

Acquired Immunodeficiency Syndrome Both acknowledgement of a spiritual dimension in an individual's life and intercessory prayer have been found to benefit patients with acquired immunodeficiency syndrome (AIDS). One study of 100 patients with AIDS found a sigruficant positive correlation between a sense of spiritual well-being and hardiness." A double-blind, randomized, controlled trial conducted by researchers at the California Pacific Medical Center and published in the Western lournu2 of Medicine examined the effects of distant healing and prayer on 40 patients with advanced AIDS,finding that those who were prayed for did sigruficantly better than controls. In this study, patients were randomly assigned to

treatment and control groups; treatment was 1 hour a day, 6 days a week for 10 weeks. Investigators recruited 40 healers from seven traditions-christians, Jews, Buddhists, Native Americans, students of shamanism, and graduates of training programs in bioenergetic and meditative healing-living distant from the patients. The healers, who were scattered across North America and averaged 17 years in experience, were assigned on a rotating basis, with each patient receiving treatment from a different healer each week. The healers were given only the first name and a photograph of each patient, whom they never met. At the conclusion of this 6-month study, a medical chart review-also conducted in blinded fashion-found that patients who had been prayed for had fewer new AIDS-defining illnesses (0.1 vs. 0.6 average per patient) and less severe illness (severity scale score of 0.8 vs. 2.65); required fewer doctors visits (9.2 vs. 13.0), fewer hospitalizations (0.15 vs. 0.6), and fewer days of hospitalization (0.4 vs. 3.4); and experienced improved mood according to scores on the Profile of Mood States scale (-26 vs. 14).=

Alcohol and Drug Abuse A PubMed review I conducted in 2002 found 688 studies noting a relationship between spirituality and prevention of substance abuse; 95 new studies had been published in this area since 1998. Studies2743consistently find that drug abuse is correlated with the absence of religious commitment in a person's life and that religious commitment is protective against alcohol and drug abuse, is of significant benefit in recovery from addiction and substance abuse, and makes a crucial difference in the prevention of drug and alcohol use among youth. A lournu1 of Psychology and Theology review of the empirical data in the field published in 1991 summarized findings that have been corroborated in well over a hundred studies since, as followsz6:"Whenever religion is used in an analysis, it predicts those who have not used an illicit drug, regardless of whether the religious variable is defined in terms of membership, active participation, religious upbringing, or the meaningfulness of religion as viewed by the person himself ."

Suicide A number of studies indicate that an individual's spiritual convictions sigruficantly affect the likelihood of his or her choosing to commit suicide; consider the following examples: One community study found that persons who did not attend church were four times more likely to commit suicide than were frequent church attendees. A review of studies on suicide revealed 12 out of 12 studies showing that persons with a strong religious commitment were substantially less likely to commit

Therapeutic Modalities suicide. The religiously committed had fewer suicidal thoughts and more negative attitudes towards taking their lives.44 A study that evaluated a possible link between religious activity and suicidal ideation in a sample of adult Latin American immigrants (145 women, 56 men) found that self-perception of religiosity, influence of religion, and church attendance were significantly negatively associated with suicidal ideation. No relationship was found between religious affiliation and suicidal ideation; all religiosity was protective against suicide.%

Surgical Outcome Both an individual’s spiritual beliefs and intercessory prayer have been shown to improve surgical outcome in a number of studies. A study of elderly women recovering from hip surgery found that those who regarded God as a source of strength and comfort and who attended religious services frequently were less depressed and could walk a greater distance at discharge. The researchers suggested that the ability to walk farther was possibly explained by the fact that the more religious patients were less depressed and thus responded better to physical thera~y.4~ Results of a study that assessed the effects of prayer on postoperative psychological recovery in a group of 151 older patients after coronary bypass surgery showed that 1 year after coronary artery bypass grafting, those patients who prayed about their postoperative problems experienced significantly less depression and general distress than those who did not.@ As previously noted, cardiologist Byrd20ran a doubleblind intervention study that measured the effect of prayer on cardiac surgery outcome. In a coronary care unit in a large general hospital, 393 patients who consented to participate were randomly assigned either to receive or not to receive regular intercessory prayers by an interdenominational group of committed Christians who were unknown to the patients. The patients themselves, staff, and doctors were unaware which patients were assigned to which group. Each intercessor was asked to pray on a daily basis for each of the following clinical issues: rapid recovery, prevention of complications and death, and any other areas the intercessor believed would be beneficial to the patient. Patients who received daily intercessory prayer were found to have a 5% to 7% outcome advantage over those who did not, consisting of fewer life-threatening events and complications (congestive heart failure, cardiopulmonary arrests, intubations, and pneumonia) during their stays in the hospital coronary care unit, than the control group, who were five times more likely to need antibiotics and three times more likely to experience complications.

Length and Quality of Life Numerous studies involving large numbers of older persons find that living with an awareness of Spirit translates to living longer and more joyfully. Five community-based studies have shown that religiously committed people, particularly those who attend church, have a greater likelihood of living longer than people lacking a religious ~ommitment.4~3 Not only do the religiously committed have a greater chance of living longer, they are also more satisfied with their lives, as the data suggest in these five studies and a sixth study that also showed that those who frequently pray and who have a close relationship with God have h g h levels of life satisfaction, existential well-being, and overall happiness.45 One of the largest of the community-based studies, which was conducted by scientists at Harvard and Yale and funded by the NIH, investigated the protective effects of spirituality on death rates in a population of nearly 400 older adults living in Connecticut. Among those healthy at the onset of the study, the death rate was so low it was thought unlikely that any additional factors would lower it further. Among those ill at the study’s outset, however, very different findings emerged. Over the course of the study, the death rate in sick men who did not have a spiritual life was 42%, compared with 19%in sick men whose lives had a spiritual dimension. Similar results were found for women, those with no spiritual practice having a death rate of 20%, compared with 11% for women whose lives included spiritual awareness and activity. Actual attendance at religious institutions had the smallest effect, which led the researchers to conclude that it is “unlikely that the benefits of religiousness are predominantly due to the social contacts associated with church attendan~e.’’~~ A clinical study at Dartmouth involving more than 200 patients who had undergone cardiac surgery yielded similar results. During a 6-month follow-up period after open-heart surgery, the mortality rate was 11% in patients who considered themselves “not at all,” ”slightly,” or ”fairly” religious. In those who saw themselves as “deeply” religious, the death rate was zero.51

Delinquency Studies indicate that Spirituality protects not only the elderly but also the young. In two reviews summarizing 13 studies, 12 of the studies found that religious commitment-particularly church attendance-played a protective role against d e l i n q ~ e n c y .An ~ ~additional ,~ study by Freeman%showed that the black young men who were able to leave the ghetto and avoid falling prey to delinquency or drug abuse were those who attended church on a regular basis. The protective effects of religion against delinquency are also corroborated in a 2001 review published in the International lournal of Psychiatry and Medicine.

Spirituality and Healing This review evaluated 630 separate data-based reports on the protective effects of religion on not only delinquency but also on depression, suicide, anxiety, psychosis, alcohol and drug abuse, cigarette smoking, and extramarital sexual behaviors, as well as its beneficial effects on well-being, hope and optimism, meaning and purpose, and marital ~tability.5~

finding can be explained by the fact that their physicians have seen merely the disease rather than the spiritual truth of the people who have come to them for ~ a r e . 5 ~

THE PRACTICAL APPLICATION: INTEGRATING SPIRITUALITY INTO MEDICAL PRACTICE

Given the cumulative scientific evidence of prayer‘s potential beneficial effects, not praying for the best insight into or understanding of how to treat your patients as well as for their best possible outcome is In an excellent editorial on spirituality and clinical care in equivalent to deliberately withholding an effective therthe British Medical Journal in December 2002, psychiatrist apeutic intervention. Yet given the time constraints of Larry Culliford appealed to physicians to “recall, reinterpret, and reclaim our profession’s sacred d i m e n s i ~ n . ” ~ ~the typical practice, along with the reticence to approach the subject of spirituality bred into Western medicine One particularly impressive source that Culliford cites, along with the “scientific method,” availing oneself of which documents the need for physicians to treat the the power of prayer is indeed a formidable challenge. whole person, is a critical, systematic, and comprehenPotential rewards, however, both personal and professive analysis of empirical research on the relationship sional, make a trial run of the following simple practices between spirituality and many health conditions that the only rational choice: covers more than 1200 studies and 400 review^.^' In this work, a 60% to 80% positive relationship between better Pray. Before going in to see your first patient, take just health and spirituality is found in both correlational and a few seconds to focus your healing, benevolent intenlongitudinal studies of heart disease, hypertension, ceretion. Ask that your heart and mind become instrubrovascular disease, immunologic dysfunction, cancer, ments of God’s will. Ask for the strength, compassion, mortality, pain and disability, psychosis, depression, anxand insight to be of help to all you will see today. iety, suicide, and personality problems. The high correlaInvite dialogue on the subject of Spirituality.Ask about tion between health and spirituality is also evidenced your patient’s spirituality as part of the medical in health behaviors such as taking exercise, smoking, history by asking questions such as “Do you feel substance abuse, burnout, family relationships, and marclose to a higher power?” ”Are your beliefs a source ital breakdown. The benefits of recognizing the spiritual of strength?” ”Can you see any goodness, anything of dimension of one’s patients’ lives are threefold: aiding value, any life lessons that you are gaining from this prevention, speeding recovery, and fostering equanimity experience?” ”What has become clear to you since last in the face of ill health. we met?” Even for those patients who do not believe in God, Be compassionate and validating. Support your physicians who ignore spirituality are dismissing that patients’ belief in Spirit as a healing force that reveals central core that strives for meaning, purpose, and healmeaning and value in their lives-in sickness as well ing, and that is our source of reverence and awe in our as in health. recognition of the simple, miraculous fact that Life is, Empower patients with information about research on and is manifest in and as each one of us. The growing the positive effects of spirituality on health. Provide a recognition that spirituality powerfully affects human handout of possible resources, such as those recomhealth is also reflected in recent polls, according to which mended at the end of the chapter. Add some of these the majority of patients want physicians to include faith books to your waiting room reading materials. as part of a comprehensivedoctor-patient interview: In a Draw strength and solace from your own faith. When poll conducted in 1996 of 1000 U.S. adults, 79% of the concern for a patient overwhelms you, pray for guidrespondents expressed belief that spiritual faith can help ance, pray for faith, pray ”Thy will be done.“ When people recover from disease, and 63% that physicians you have done all you can, know that you are not should talk to patients about spiritual faith.% alone in your healing efforts, that Spirit in the form of A telephone survey conducted in 2002 showed that the vis medicutrix nuturue is at work in and through you 80% of respondents believe God acts through physicians and your patient. Let go and trust in God. to cure illness, 40% believe God’s will is the most important factor in recovery, and 69%say they would want to The Most Effective Prayer speak to someone about spiritual concerns if seriously After spending more than a decade performing simple ill, although only 3%would initiate a conversation about laboratory experiments demonstrating that prayer spiritual factors with a physician. Perhaps this last

SPIRITUALITY: THE PROVINCE OF PHYSICIANS?

Therapeutic Modalities works, the Spindrift organization in Salem, Oregon, investigated which type of prayer strategy works best. Distinguishing essentially two types of prayer, directed prayer, in which pray-ers have a specific goal, image, or outcome in mind, and undirected prayer, in which no specific outcome is requested, researchers found that although both types of prayer produced results, the undirected approach was quantitatively more effective, frequently yielding results twice as great, or more, compared with the directed approach.” “Thy will be done” confers its own immediate blessing, regardless of physiologic outcome. Such undirected prayer, a letting go and affirmation of trust in the Absolute, is at once a source of release, peace, and hope.

Side Effects and Contraindications As with any intervention, misuse or inappropriate use of our nonlocal nature can cause problems. As the research described here collectively and conclusively demonstrates, our thoughts and intentions, our prayers do exert effects, and negative intention, negative prayer can be harmful. In Be Carefil What You Pray for . . . You lust Might Get It, Dossey6l reviews a surprising amount of research on negative prayer and makes a cogent argument that each of us must assume responsibility for our negative thoughts and wishes. His insightful discussion of the unfortunate effects of nocebo underscores the physician’s difficult responsibility-to convey truth with compassion and without eradicating hope. The significant positive effect on clinical outcomes of the explicit inclusion of faith and prayer in health care does not mean, however, that these approaches can take the place of effective treatment. Unfortunately, some religious beliefs can be interpreted to prohibit many types of conventional medical interventions. One disconcerting study evaluated the deaths of children from families whose beliefs prohibited certain types of medical interventions. The researchers evaluated the records of 172 such children who died in the United States between 1975 and 1995 and for whom there was sufficient documentation to determine the cause of death. Medical intervention would have resulted in a typical survival rate of 90% in 140 of these cases and of more than 50% in 18; in all but 3 of the remaining 14, intervention would likely have had some benefit.62Although the research was flawed by the design bias-i.e., researchers did not look for positive results, only negative results-the study gives cause for grave concern. It is easy for the clinician and social worker to condemn the belief systems of these children’s families, but one must wonder how much the well-documented unwillingness of most practitioners to regard faith and religious practice as factors in the therapeutic process contributes to these families’ extreme position? It is clearly time for physicians to acknowledge and utilize

both science and spirituality as effective factors in health and healing.

ILLNESS. THE GIFT OF SPIRITUAL HEALING We assume illness is the enemy when, in fact, it is our teacher. Illness always offers a door to spiritual awakening, to an expansion of understanding that is healing. In the words of Paramahansa Yogananda, “Your trials did not come to punish you, but to awaken you-to make you realize that you are a part of Spirit and that just behind the spark of your life is the Flame of Infinity.”63 Or as Germany’s great poet, Ranier Maria Rilke,64 explained, illness can teach us to be patient and can help us learn to trust in the vis medicutrix naturue, the healing power that naturopathic philosophy recognizes is life’s fundamental impulse toward health: So you must not be frightened. . . .You must think that. . . life has not forgotten you, that it holds you in its hand; it will not let you fall. Why do you want to shut out of your life any agitation, any pain, any melancholy, since you really do not know what these states are working upon you? Why do you want to persecute yourself with the question when all this may be coming and whither it is bound? . . . [Tlust remember that sickness is the means by which an organism frees itself of foreign matter; so one must just help it to be sick, to have its whole sickness and break out with it, for that is its progress . . . [Ylou must be patient as a sick man . . . [Tlhere are in every illness many days when the doctor can do nothing but wait. And this it is that you, insofar as you are your own doctor, must now above all do.

Although physicians are taught to banish pain at all costs, and allopathic doctors are trained to eliminate symptoms as quickly as possible with drugs and surgery, failure to effect an immediate physiologic cure does not necessarily mean failure to assist in a patient’s healing process. Particularly during times of serious illness, we are forced to be quiet, to tune in to our true center. When our stillness is grounded in faith, what we recognize when we search within is God. Prayer at this intersection of quiet and acceptance, where we become truly aware that we are not our disease but essentially something inviolate, is the type of prayer most commonly associated with miracle cures, radical spontaneous remissions, and healings. On a spiritual level, simply to recognize this dimension of ourselves, to know the numinous, is to be healed. As Jung put it, “The approach to the numinous is the real therapy and inasmuch as you attain to the numinous experiences you are released from the curse of pathology. Even the very disease takes on a numinous character.’’65

THE EXPERIENCE OF SPIRIT The practice of Era 111 medicine involves a personal choice, a commitment to openness, to an awareness of

Spirituality and Healing ~

and an alignment with Spirit that is both the most intimate and the most universal aspect of our being. How do we tune in to and draw from this inner Source of our Life, this Source in which we are all joined as One, this Source that manifests as the drive to an ever fuller unfolding of Life, this Source that is the Creator of Health, this Intelligence, this Pervasive Loving Intelligence that is the vis medicafrix naturae, the Dynamic Pattern that encompasses both the widest spans of rational thought and the intuitive nonrational aspects of our being? How do we open up our awareness to and align with this Power, which is called Spirit, Mother/Father God or Abba, Atman, Brahman, Qi, the Tao, the Christ-so many names for One Reality, of which the Life Force is one demonstration, this reality that is the Core of Healing, of Health? How do we tune in? Many traditions have tried to cod* and develop the Way, and essentially, all have the common concept "Be still, and know that I AM." In silence, you, who have been chosen by life as Its healers, who have through long and diligent study learned to discriminate the facts of Science, will be given the gift of another knowing, that of the perfection of Life that is within you and within each of your patients. Just be quiet, open your heart and mind, and listen to the heartbeat of the ground of your being, for It will speak, and you will know. All you need do is to set the intention to hear, and the recognition that the Power driving the Universe is Love expressed as Intelligence in an infinity of ways will flow through you. This Reality is always available to us; It is always expressing through us, we are breathing It, immersed in It, but we must choose to know this, we must choose to be quiet and receptive and to listen, deep in our souls where this Truth expresses. In the Bible, Jesus tells us that God stands at the door and knocks. God does not arrive in a bulldozer and force an entry (although if it is ignored, I have found, the knocking can become quite insistent). Spirit waits upon us. We have ears to hear the inner wisdom of Spirit only when we choose to listen. Tools for becoming aware of the Almighty yet still small voice within each of us take many different forms. For we are each unique and need to try and to use different methods of access, not only among ourselves but at different times within our individual lives. Try all that call to you. Seek out those that work for you now, and gain an acquaintance with others that may prove useful later. Reverend Kathianne Lewis, Senior Minister at the Center for Spiritual Living in Seattle, suggests three ways in which we can develop our spiritual practice: prayer, meditation and availing ourselves of the thoughts and words given to us in the sacred works of the many spiritual traditions of our world.

Prayer is active, directive, generative. In our prayers, we talk of and to God, manifesting our realization of the nature of Spirit and therefore of Life and ourselves. Remembering, recognizing Who God is and that we are Its beloved creations enable us to find the faith, the knowing that Good that is present in every situation. Meditation is passive, open, receptive. In meditation, focusing on our breath, we can experience the understanding that we are literally inspired by the Creative Intelligence that is the Source of Life. We can rest in the knowing that we are cradled, held, and supported, our very being renewed in every second by Life Itself, a gift given freely and the understanding of which is limited only by our ability to receive it. The record writ by Spirit upon human history offers insights recorded in every culture and in every age. The selection is voluminous and includes the Bible, the Koran, the Tao de Ching, and the writings of Native American healers, of Buddhism, of the Sufi mystics Hafiz and Rumi, of the Transcendentalists such as Wordsworth, Shelly, Thoreau, and Emerson and their descendants, of the founders of New Thought such as Emma Curtis Hopkins, Thomas Troward, and Ernest Holmes, the Course in Miracles, and recent works like Neale Donald Walsh's Conversations with God, Ram Dass's Journey of Awakening, and Naiomi Remen's Kitchen Table Wisdom. Seek out what nourishes you, and spend the last moments before falling asleep or the first minutes of your day replenishing your spiritual stores. Consider it an investment in yourself and your practice that will pay immense untold dividends. Take the time to tune in to the recognition that your life, your awareness is a gift, the most incredible, outrageous, wonderful gift. That you are Spirit using a body, not simply a physical being but a unique manifestation of the joyful creativity of Spirit. And that you and your patients are alike, are One in this most essential fact of your life. This is where the true doctor-patient interaction takes place, the level that generates placebo effects-the deepest level where we experience that the essence of Life itself is Good, is driving towards an ever fuller expression of Itself, ever more complete Health, and that It lives within each of us as the very core. Your patients come to you not merely for analysis of dysfunction to be corrected through the dosing of some supplement or green drug; they come to you to be known as Who They Really Are. They come to you for your faith in their true Health. They come to you for the recognition that Health is their Truth, their natural state, their God-given inheritance. And when you see themwhen you really see them-you will be seeing yourself, as the Sufi mystic, Hafiz,66 clearly understood and

described as follows: There Is a Wonderful Game There is a game we should play And it goes like this:

.... We hold hands and look into each other’s eyes And scan each other’s face. Then I say, “Now tell me a difference you see between us.“ And you might respond, ”Hafiz, your nose is ten times bigger than mine!” Then I would say, ”Yes, my dear, almost ten times!” But, let’s keep playing. Let’s go deeper, Go deeper. For, if we do, Our spirits will embrace And interweave. Our union will be so glorious That even God Will not be able to tell us apart. There is a wonderful game We should play with everyone And it goes like this . . .

Really seeing the Truth, the Essence of Health, the Goodness in another human being is the core of all healing interactions. When you greet your patient, take a moment to see the unique, beautiful manifestation of Spirit that he or she is. Bask in the recognition of the Life Force that informs this person’s life, your life, the Life that you share. When you walk into the examination room and see your patient, see yourself. See a unique expression of the

1. Dossey L. Healing words. New York: HarperSanFrancisco/ H a r p e r C o h , 1993. 2. Oman D, Reed D. Religion and mortality among the communitydwelling elderly. Am J Pub Health 1998;88:1469-1475. 3. Dossey L. Healing beyond the body. Boston: Shambhala Publications, 2001. 4. Dossey L. Reinventing medicine: beyond mind-body to a new era of healing. San Francisco: Harper, 1999. 5.Vedantam S. Placebos improve mood, change brain chemistry in majority of trials of antidepressants. Washington Post, May 7, 2002, p A01. 6. Khan A, Leventhal RM, Khan SR, Brown WA. Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J Clin Psychopharmacol 2002;22:40-45. 7. Levin J . God,faith and health. New York John Wiley & Sons,2001. 8. Kirsch I. Antidepressants proven to work only slightly better than placebo. Available online at rvrvrc~.m~rcoln.~oiiiR002/juIy/31.

abundant and perfect realization of Life and Health that is God. See Love expressing through Wisdom as Joy. Pray for guidance, insight, support, and peace. Be bold in your confidence, in your trust, in your delight, for your path is truly grounded in Spirit, and is blessed and is a blessing to all you will serve. In the path of the healer, it is so easy to see that we are in the service of God, that all that we do is for the fullest, most joyful expression of Spirit. Do what you do for the joy of it, for the love of one another, and you will never lose heart or hope or strength. Everything we do is sacred service; it is just a question of becoming aware of this and taking this awareness with us as the ground upon which we live and walk and breathe, into every situation, every exchange. Remember that a desired outcome for yourself or your patient is just one tiny potential static point in time, but our lives are hundreds of thousands of moments, an unfolding that is happening now, in this instant, in every exchange. Your life as a physician is the essence of every exchange you have. May all your exchanges be healing.

SUMMARY Religious faith, as measured primarily by regular attendance at religious services and a personal belief in God, is remarkably effective in the promotion of health. A substantial body of research published in diverse journals documents the efficacy of faith and prayer, both for the pray-ers and those prayed for, in longevity, recovery from surgery, prevention of disease, and improvement in lifestyle and behaviors. All practitioners committed to providing the best possible care need to be aware of, and to use, this powerful healing factor, not only for our patients but for ourselves.

9. Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M. Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 2002 Jan;159:122-129. 10.Mayberg HS, Silva JA, Brannan SK, et al. The functional neuroanatomy of the placebo effect. Am J Psychiatry 2002;159: 728-737. 11. Schneider LS,Small GW. The increasing power of placebos in trials of antidepressants. JAh4A2002;288:450. 12. Sapir M. The increasing power of placebos in trials of antidepressants. JAMA 2002;288:450. 13. Brandon TH, Irvin JE, Hendricks PS.The increasing power of placebos in trials of antidepressants. JAMA 2002;288:449-50. 14. Bohr; quoted in Heisenberg W. Physics and Beyond, translated by AJ Pomerans. New York: Harper & Row, 1971. 15. Targ R, Katra J. Miracles of mind. Novato, CA: New World Library, 1999.

16. B o b D, Hiley BJ. The undivided universe. New York Routledge, 1993 (as discussed in reference 15).

Spirituality and Healing 17. Grosso M. Soulmaking. Charlottesville, VA Hampton Roads, 1997 (as discussed in reference 4). 18.Benor DJ. Survey of spiritual healing research. Comp Med Res 1990;4:9-33. 19. Craigie FC, Larson DB ,Liu IY.References to religion in The Journal of Family Practice: dimensions and valence of spirituality. J Fam Pract 1990;30477-480. 20. Byrd RC. Positive therapeutic effects of intercessory prayer in a coronary care unit population. South Med J 1988;8:826-829. 21. Morris EL. The relationship of spirituality to coronary heart disease. Altem Ther Health Med 2001;796-98. 22. Levin JS, Vanderpool HY. Is religion therapeutically sigruficant for hypertension? Soc Sci Med 1989;29:69-78. 23. Hixson KA, Gruchow HW,Morgan DW. The relation between religiosity, selected health behaviors, and blood pressure among adult females. Prev Med 1998;27545-552. 24. Carson VB, Green H. Spiritual well-being: a predictor of hardiness in patients with acquired immunodeficiency syndrome. J Prof Nurs 1992;8:209-220. 25. SicherF, Targ E, Moore D 2nd, Smith HS.A randomized double-blind study of the effect of distant healing in a population with advanced AIDS: report of a small scale study. West J Med 1998; 169356-363. 26.Gartner J, Larson DB, Allen G. Religious commitment and mental health: a review of the empiricalliterature. J Psychol The01 1991;196-25. 27. Argyle M, Beit-Hallahmi B. The social psychology of religion. London: Routledge & Kegan Paul, 1975. 28. Walters 0s. The religious background of 50 alcoholics. Q J Studies Alcohol 1957;18:405413. 29. Larson DB, Wilson Wl? Religious life of alcoholics. South Med J 1980;73723-727. 30. Pullen L, Modrcin-Talbott MA, West WR, Muenchen R. Spiritual high vs high on spirits: is religiosity related to adolescent alcohol and drug abuse? J Psychiatr Ment Health Nurs 1999;63-8. 31. Oetting ER. Primary socialization theory: developmental stages, spirituality, government institutions, sensation seeking, and theoretical implications. V. Subst Use Misuse 1999;34:947-982. 32. Karlsen S, Rogers A, McCarthy M. Social environment and substance misuse: a study of ethnic variations among inner London adolescents. Ethn Health 1998;3:265-273. 33. DOnofrio BM, Murrelle L, Eaves LJ, et al. Adolescent religiousness and its influence on substance use: preliminary findings from the Mid-Atlantic School Age Twin Study. Twin Res 1999;2:156-168. 34.Margolis R, Kilpatrick A, Mooney 8. A retrospective look at long-term adolescent recovery: clinicians talk to researchers. J Psychoactive Drugs 2000;32:117-125. 35.Brush BL, McGee EM. Evaluating the spiritual perspectives of homeless men in recovery. Appl Nurs Res 2OOO;13181-186. 36. Pardini DA, Plante TG, Sherman A, Stump JE.Religious faith and spirituality in substance abuse recovery: determining the mental health benefits. J Subst Abuse Treat 2000;19:347-354. 37. Yamold BM. Cocaine use among Miami‘s public school students, 1992: religion versus peers and availability. J Health Soc Policy 1999;11:69-&1. 38. Hillman SB, Haskin JM. Personality and drug abstention in adolescents. Psychol Rep 2000;871023-1026. 39. Miller L, Davies M, Greenwald S. Religiosity and substance use and abuse among adolescents in the National Comorbidity Survey. J Am Acad Child Adolesc Psychiatry 2000;39:1190-1197. 40.Sutherland I, Shepherd JP. Social dimensions of adolescent substance use. Addiction 2001;96445458. 41. Avants SK, Warburton LA, Margolin A. Spiritual and religious support in recovery from addidion among W-positive injection drug users.J Psychoactive Drugs 2001;333945.

42. Miller L, Weissman M, Gur M, Adams P. Religiousnessand substance use in childrenof opiate addicts. J Subst Abuse 2001;13323-336. 43. Stewart C. The influence of spirituality on substance use of college students. J Drug Educ 2001;31:343-51. 44. Comstock GW, Partridge KB. Church attendance and health. J Chronic Disease 1972;25:665-672. 45. Poloma Mh4, Pendleton BF. The effects of prayer and prayer experiences on measures of general well-being. J Psychol Theology 1991;1971-83. 46.Hovey JD. Religion and suicidal ideation in a sample of Latin American immigrants.Psychol Rep 1999;85:171-177. 47. Pressman P, Lyons JS, Larson DB, Strain JJ. Religious belief, depression, and ambulation status in elderly women with broken hips. Am J Psychiatry 1990;147:758-760. 48. Ai AL, Dunkle RE, Peerson C, Bolling SF. The role of private prayer in psychological recovery among midlife and aged patients following cardiac surgery. Gerontologist 1998;38:591-601. 49.Larson DB, S h e d KA, Lyons JS, et al. Associations between dimensions of religious commitment and mental health reported in the American Journal of Psychiatry and Archives of General Psychiat y: 1978-1989. Am J Psychiatry 1992;149557-559. 50. Larson D, Swyers J, McCullough M. Scientific review on spirituality and health. Rockville, MD: National Institute of Health Care Research, 1998. 51.Zuckerman DM, Kasl SV, Ostfeld AM. Psychosocial predictors of mortality among the elderly poor. Am J Epidemiol 1984:119 4104-4123. 52. O m a n TE, Freeman DH, Mannheimer ED. Lack of social participation or religious strength and comfort as risk factors for death after cardiac surgery in the elderly. Psychosom Med 1995575-15. 53. Comstock GW, Partridge KB. Church attendance and health. J Chronic Dis 1972;25:665-672. 54. Freeman RB. Who escapes? The relation of church-going and other background factors to the socio-economic performance of black male youths from inner-city poverty tracts. Working Paper No. 1656. Cambridge, MA: National Bureau of Economic Research (1050 Massachusetts Ave), 1985. 55. Koenig HG. Religion and medicine II: religion, mental health, and related behaviors. Int J Psychiatry Med 2001;31:97-109. 56. Culliford L. Spirituality and clinical care. BMJ 2002;325:1434-1435. 57. Koenig HK, MCCullough ME, Larson DB. Handbook of religion and health. Oxford: Oxford University Press, 2001. 58. McNichol T. The new faith in medicine. USA Today, April 7,1996, p 4. 59. Mansfield CJ, Mitchell J, King DE. The doctor as God‘s mechanic? Beliefs in the Southeastem United States. Soc Sci Med 2002;54: 399-409. 60. Owen R. Qualitative research: the early years. Salem, OR: Grayhaven Books, 1988. 61. Dossey L. Be careful what you pray for . . . you just might get it. New York HarperSanFrancisco/HarperCollins, 1998. 62. Asser SM, Swan R. Child fatalities from religion-motivated medical neglect. Pediatrics 1998;101:625-629. 63. Yogananda P. Autobiography of a yogi, ed 13. Los Angeles: Selfrealization fellowship, 1998. 64. Rilke RM. Letters to a young poet, translated by M.D. Herter. New York Norton Press, 1934. 65. Adler G, Aniela Jaffb A, eds. Jung’s letters, vol. 1. Princeton, NJ: Princeton University Press, 1973, p 377. 66. Ladinsky D. I heard God laughing: renderings of Hafiz. Oakland, C A Mobius Press, 1996.

Benor DJ. Spiritual healing, healing research, vol 1. Southfield, I L Vision Publications, 2001. Dossey L. Be careful what you pray for ... you just might get it. New York HarperSanFrancisco/Harper Collins, 1998. Dossey L. Healing beyond the body. Boston: Shambhala Publications, 2001. Dossey L. Healing words. New York: HarperSanFrancisco/Harper Collins, 1993. Dossey L. Prayer is good medicine. New York: HarperSanFrancisco/ Harper Collins, 1996. Dossey L. Reinventing medicine: beyond mind-body to a new era of healing. New York Harper Collins, 1999. Hitchcock J. Healing our worldview. West Chester, PA: Chrysalis Books, 1999. Justice B. Who gets sick? New York: G.P. Putnam’s Sons, 1987.

Laskow L. Healing with love. New York HarperSanFrancisco/Harper Collins, 1992. Levin J. God, faith and health. New York John Wiley & Sons,2001. Katra J, Targ R. The heart of the mind. Novato, CA: New World Library, 1999. Katra J, Targ R. Miracles of mind. Novato, C A New World Library, 1999. Moyers 8.Healing and the mind. New York Doubleday, 1993. Remen RN. Kitchen table wisdom. New York Riverhead Books, 1996. Shealy CN, Myss CM. The creation of health. Walpole, NH: Stillpoint Publishing, 1993. Walsh ND. Conversations with God. Charlottesville, PA: Hampton Roads Publishing, 1998.

Therapeutic Fasting Trevor K. Salloum, ND

Alan Goldhamer, DC CHAPTER CONTENTS Introduction 533 History 534 Herbert M. Shelton 534 Clinical Research 534 Diabetes 535 Epilepsy 535 Obesity 535 Heart Disease 535 Pancreatitis 535 PCB and DDT Contamination 535 Autoimmune Disease 535 Arthritis 535 Food Allergy 536 High Blood Pressure 536 Other Diseases 536 Physiology 536 Energy Production and Utilization 537 Early Fasting 538 Fasting 539 Starvation 539 Mechanism of Ketosis 539 Mechanism of Acidosis 540 Amino Acid Metabolism 540 Electrolyte Balance 540

INTRODUCTION Fasting is defined as abstinence from all food and drink except water for a specific time, usually for a therapeutic or religious purpose.' This process spares essential tissue (i.e., vital organs) while utilizing nonessential tissue (i.e., adipose tissue, digestive enzymes, muscle contractile fibers, and glycolytic enzymes) for fuel. Some medical references use the terms fasting and stamation interchangeably.Unlike fasting, however, starvation is a process in which the body uses essential tissue for fuel. During starvation, the body relies on protein as a major fuel source, because most fat stores have been depleted. If an organism does not receive food at the end of the maximum fasting period (several weeks to

Physical Changes during Fasting 540 Laboratory Changes during Fasting 540 Hormonal Changes during Fasting 540 Effects of Fasting on Immune Function 541 Clinical Protocol 541 Consultation Standards 541 Clinical Standards 541 Water versus Juice 541 Quantity of Water 541 Supplements 541 Exercise 541 Sunlight 542 Rest 542 Laboratory Tests 542 Enemas 542 Length of Fast 542 Patient Attitude 542 Side Effects 542 Contraindications 542 Conclusion

543

months depending on fat stores, metabolism, stress, and activity), starvation follows and death will ensue.2 Although the termfasting is used loosely in medical literature, the strictest definition (comsumption of water only) is the focus of this chapter. Some medical studies recommend supplementation with vitamins, fruit and vegetable juices, acaloric fluids (coffee, tea, etc.), and drugs while the patient is "fasting." These practices have not been shown to produce any advantage, and serious problems have sometimes occurred, especially when nonessential medication was permitted. (In special cases it may be necessary to keep the patient on essential medication*.g., thyroid, prednisone, and insulin-during fasting.) 533

Therapeutic Modalities Therapeutic fasting is probably one of the oldest known therapies, but it has been the subject of limited study by the scientific community. A professional organization involved in the study and promotion of fasting is the International Association of Hygienic Physicians (IAHP)? It is composed of doctors specializing in therapeutic fasting as an integral part of total health care. The section on clinical protocol given here reflects the format practiced by the IAHP.Any doctor contemplating the use of therapeutic fasting should receive adequate training. The IAHP provides guidelines for doctor interested in this training3 Another group of doctors known as clinical ecologists use short-term fasting as part of their diagnosis and treatment of food intolerance!”

HISTORY Throughout history, people of various cultures and religions have recognized the value of fasting. Numerous references appear in the Bible, Koran, pagan writings, and writings of the ancient Greeks.6-s One of the earliest doctors to use therapeutic fasting in the United States was Isaac Jennings (1788-1874). In 1822, Jennings discarded the use of drugs and, through the influence of Presbyterian preacher Sylvester Graham (1794-1851),began advocating fasting and other aspects of hygienic treatment (vegetarian diet, pure water, sunshine, clean air, exercise, emotional poise, and rest). This treatment later came to be known as natural hygiene or the hygienic system?-” Other doctors who followed in the hygienic tradition were James C. Jackson (1811-1895), Russell T. Trall (1812-1877), William A. Alcott (1798-1859), Mary Grove Nichols (1810-1884), Thomas L. Nichols (1815-1901), Edward H. Dewey (1837-1904), George H. Taylor (1821-1896),Harriet Austin (1826-1891),Charles E. Page (1840-1925), Emmett Densmore (1837-1911), Helen Densmore (?-1904),Susanna W. Dodds (1830-1915),Felix Oswald (1845-1906), Robert Walter (1841-1921),John H. Tilden (1851-1940),and George S. Weger (1874-1935).Most of these physicians graduated as MDs from eclectic medical schools and published various works on hygiene?-16

Herbert M. Shelton The hygienic lineage continued into the mid-1900s owing mainly to Herbert M. Shelton (1895-1985), who developed a stricter protocol for fasting (water only; no enemas, exercise, or treatments; and complete rest) and other aspects of hygiene. Shelton began his study of fasting in 1911 by reading the popular writers of his day: Sinclair, Carrington, Hazzard, Haskell, Purinton, Tilden, and MacFadden. He studied under the fasting authorities of his time at MacFadden’s College (Chicago), Crane’s Sanatorium (Elmhurst, IL), and Crandall‘s Health School (York, PA).yJo(Among the earliest fasting

institutions of this time were MacFadden’s Healthatorim, Tilden’s Health School, Lindlahr’s Nature Cure Sanatoriums, and Lust’s Jungborn-the last operated by Benedict Lust, the founder of naturopathy in the United States.’O) In 1924, Shelton completed doctorates from the American School of Chiropractic and the American School of Naturopathy in New York. Shelton was a dynamic lecturer, prolific writer, and publisher. In 1928, he founded a fasting institution and health school that provided services for more than 40 yearsy In 1949, along with William Esser, ND, DC, Christopher Gian-Cursio, ND, DC, and Gerald Benesh, ND, DC,Shelton formed the American Natural Hygiene Society, now called the National Health Association:J6 a lay organization dedicated to preserving the tenets of hygiene. In 1978, a professional branch was formed, the aforementioned IAHR3Today, the IAHP organizes training and certification for doctors specializingin therapeutic fasting.

CLINICAL RESEARCH Research into fasting has been reported since 1880, and medical journals have carried articles on the use of fasting in the treatment of the following conditions: High blood pressure (BP) Diabetes Mental disease Skin disease Obesity Cardiovascular disease Gastrointestinal disease Chemical poisoning Arthritis Allergies The earliest research was primarily observational; physiologic and metabolic changes were recorded while an individual fasted. These individuals were Tanner, 40 days (1880),17Jacques, 30 days (1887) and 40 days (1888),18Penny, 30 days (1905),” and Levanzin, 31 days (1912).20The earliest record of therapeutic fasting in the medical literature appeared in 1910. Further investigation into the physiologic changes that accompany fasting was conducted in 1923 at the University of Nebraska by Morgulis.21This classic study, Fastirig and Undernutrition,provides an in-depth analysis of animal and human reactions during fasting. In 1950, Ancel Keys et alZ at the University of Minnesota compiled two volumes entitled The Biology of Human Starvation. Thrty-two volunteers fasted for up to 8 months while detailed observations were made. These findings were compared with food deprivation observations made during the Second World War. Through their studies, these researchers found that fasting did not cause vitamin

Therapeutic Fasting

or mineral deficiencies and that diabetes and skin diseases improved.

Diabetes G ~ e l p recorded a~~ the benefits of fasting in diabetes and gout as well as in inflammation and after surgery. The treatment of diabetes with fasting was further explored by Allenz4in 1915. He noted that rest and fasting usually stopped glycosuria, and he also observed improvements in gangrene and carbuncles.

Epilepsy The treatment of seizures through fasting was begun in the early 1900s in France by Guelpa and Marie (cited by K e ~ m t ~In ~ )1924, . Hoeffel and Moriarty26described fasting’s beneficial effects in epilepsy. In 1928, concurring with other researchers, LennoxZ7found that the induction of ketosis via fasting decreased the duration, severity, and number of seizures.

Obesity Fasting for obesity has probably received more attention in the scientific literature than any other aspect. The earliest studies were conducted by Folin and Denis,28who in 1915 advocated short fasts as a safe and effective way to lose weight. Duncan et a1,3031Drenick et al?2D and Thompson et alMhave published numerous works on the use of short and long fasts in obesity. Perhaps the most famous study on obesity appeared in the Postgraduate Medical Journal of 1973,which reported the experience of a 27-year-old man who fasted without complications for 382 days and lost 276 pounds.35 In general, initial weight loss during fasting is approximately 0.30% of body weight per day, with a gradual decrease to 0.10% per day after 30 days. The initial weight lost is primarily that of water and salt. For every pound lost, the body loses approximately 140g of protein and 250 g of fat.% Although fasting is very effective for weight reduction, fasting alone, without counseling and other lifestyle modifications, does not ensure long-term maintenance of the lower body weight. This fact is well documented in a study of 121 obese patients who were monitored for 7.3 years after fasts that had averaged 2 months. After 2 to 3 years, 50% of patients had returned to their prefast weights, and by the end of the study, 90% weighed the same as before their fa~ts.3~

Heart Disease Studies of the effects of fasting on patients with heart disease began in the early 1960s. Duncan et alm noted improvements in hypertension and chronic cardiac disease. Others have also found fasting to be benefiaal in heart disease:Gresham,%L a ~ l o r ?S~u ~ u k iand , ~ Vessby4’ Improvements noted include reductions in serum

triglyceride values, BP, atheromas, and total cholesterol levels; increased ratio of HDL cholesterol to total cholesterol; and alleviation of congestive heart failure.2833-36,38

Pancreatitis In a 1984 randomized clinical trial (n = 88), fasting was determined to be the treatment of choice for patients with acute pancreatitis. The researchers suggested that ”fasting alone be initially used as the simpler and more economical therapy.” They found that “neither nasogastric suction nor cimetidine offer any advantage over fasting alone in the treatment of mild to moderate acute pancreatitis of any etiology.”42

PCB and DDT Contamination Another encouraging finding for the use of fasting was published in the American Journal of Industrial Medicine in 1984.This study involved patients who had ingested rice oil contaminated with polychlorinated biphenyls (PCBs). All patients reported improvement in symptoms, and some experienced “dramatic” relief, after undergoing 7- to 10-day fasts.40This research supports past studies conducted by Inamura with PCB-poisoned patients and suggests a detoxification effect of fasting. Caution must be used, however, in the treatment of patients known to suffer significant contamination with fat-soluble toxins. Dichlorodiphenyltrichloroethane (DDT) is mobilized during a fast and may reach blood levels toxic to the nervous system.

Autoimmune Disease The beneficial effect of fasting on certain autoimmune diseases was reported in Lancet in 1958. The researchers found that fasting shortened the early stages of acute glomerulonephritis (reduced glomerular filtration rate, high BP, and edema), thus improving the prognosis. They concluded that “all patients with acute glomerulonephritis should fast.”43Other autoimmune diseases that have responded to fasting are rosacea, systemic lupus erythematosus, chronic urticaria, and colitis.-

Arthritis The subject of arthritis and fasting has received substantial attention in the scientific literature, with most of the research coming from Scandinavia. Scientists have documented the antiinflammatory effects of fasting with observations of decreases in erythrocyte sedimentation rate (ESR), arthralgia, pain, stiffness, and need for medi~ation.4~-~ Consistent with those findings, a 1984 U.S. study of 43 patients with definite or classic rheumatoid arthritis found sigrulicant improvements in grip strength, pain, swelling of proximal interphalangeal joints, ESR, and functional activity after a fast of 7 days.5l A strong link between arthritis and food intolerance has been revealed through fasting (see also Chapter 207).

The diminution in symptoms of rheumatoid arthritis during fasting may be due to the decrease in gut permeability that accompanies fastingm which would reduce the absorption of antigenic molecules into the blood from the gastrointestinal tract. In a 1984 study in Bulletin ~~ the following on Rheumatic Diseases, P a n ~ s hproposed two theories: Nutritional modification might alter immune responsiveness and thereby affect manifestationsof rheumatic diseases. Rheumatic disease may be a manifestation of a food allergy or hypersensitivity.

Food Allergy Fasting, in conjunction with food challenging, is now being used as a diagnostic test to determine food intolerances. Patients are fasted for a minimum of 4 days, and then individual foods are given to determine whether a reaction occurs. This method correlates well with skin-prick and radioallergosorbent testing. A letter in a 1984 Lancet issue states, "When food avoidances prevent headaches, [irritable bowel syndrome], arthralgia and depression, it is more effective and less costly than traditional treatment and the observation also throws light on the etiology of the disorder. '%

High Blood Pressure In the June 2001 issue of the Journal of Manipulative and Physiological Therapeutics, Goldhamer et a157reported on a study involving medically supervised water-only fasting in the treatment of hypertension. In this evaluation of 174 consecutive patients with high BP, all patients were able to achieve BP sufficient to eliminate the need for medication, and more than 90% became normotensive. In patients with stage Ill hypertension (systolic BP greater than 180 mmHg) the average reduction in systolic BP exceeded 60 points. This is the largest effect ever published in the scientific literature. Nine months later, Goldhamer et al% reported on a study involving 68 consecutive patients with borderline high BP. The average ending BP in these subjects was 99 mmHg systolic/67 mmHg diastolic. In a letter to the editor published in Journal of Alternative and Complementary Medicine in December 2002, GoldhameS9described initial results in 30 patients with high BP participating in a residential health education program that included the supervision of water-only fasting for an average of 14 days. The BP, weight, and cost of treatment and medications were compared for the year prior to and the year after fasting. Preliminary data demonstrated sustained clinical improvement in terms of BP reduction and weight reduction and an average reduction in combined medical and drug costs of almost $2700 per year per subject.

Other Diseases Other diseases in which the scientific literature indicates that fasting has led to improvement are as follows: Psychosomatic diseases@ Neurogenic bladderm Psoriasis'*MJ1 Ec~ema~,~~ Thromb~phlebitis~~ Varicose ulcers61 Neurocirculatory disease@ Irritable bowel syndrome@ Dysorexia nervosa (impaired or deranged appetite)60 Bronchial asthmaM) Lumbago@ Depressionm Neurosis and schizophrenia62 Parasites63 Duodenal ulcers"' Uterine fibroid4 High BP5'58 Autoimmune disese& These diseases are not a complete list of indications for fasting but, rather, are those that have been studied in the scientific literature. There has been considerable empirical study of fasting in the treatment of a wide variety of diseases. Records of the results can be found in lay, hygienic, and medical literature published since the early 1 9 0 0 ~ .The ~ - vast ~ ~ potential of therapeutic fasting is only beginning to be realized. Extensiveresearch reveals such pervasive and important effects, including the enhancement of immune system f u n ~ t i o n . 5 ~ ~ ~ ~ ~ 8

PHYSIOLOGY The study of the physiology of fasting reveals a highly ordered series of events (Figure 50-1) that conserve body energy reserves while maintaining the basal metabolic rate (BMR); the BMR decreases by about 1%per day during fasting until it stabilizes at about 75%of normal.36 It has been suggested that humans, like other species, have evolved special biochemical pathways to subsist for long periods without During periods of food scarcity due to climate, injury, illness, and so on, animals require adaptive mechanisms to survive. It is now apparent that, in addition to maintaining the BMR, fasting also enhances the healing process. Research in the early 1990s using magnetic resonance spectroscopy indicated that glucogenesis may be responsible for 64%, and hepatic glycogenolysis for 36%, of fuel requirements in the first 22 hours of fasting. This is a radical departure from biochemistry of the past, which suggested that hepatic glycogenolysis represented 65% of fuel requirements in the first 22 hours of fasting. scientists agree that this preliminary research necessitates

Therapeutic Fasting Early fasting

Fasting

Starvation

100%

80% 60%

40%

20% /

Digestion

1

1

2

3

Glycogenolysis

4

5

6

7

2

Days Figure 50-1

3

4

5

6

7

8

Weeks

? + l +2

+3

Months

Energy reserve utilization during fasting.

their use for energy production can be simplified as follows:

further studies before any strong conclusions can be

The body’s response to the lack of energy input can 1. Fatty acid catabolism occurs in the mitochondria of be divided into three stages: early fasting, fasting, and starvation. Maintaining adequate energy resources for virtually all tissues except the brain and red blood metabolism during fasting involves several adaptations, cells (RBCs). In the energy-producing process of betaoxidation, two-carbon fragments are successively which change as the body moves from one stage to the removed from the fatty acid to form acetyl coenzymeA next. The following discussion, Tables 50-1 to 50-4,36,83-s6 (CoA) and adenosine triphosphate (AT). The acetyl and Figures 50-1 and 50-2 describe these stages and their CoA enters the Krebs cycle for conversion to more ATI? metabolic significance. First, however, a summary of 2. Energy is produced by glucose metabolism primarily energy production and utilization is useful. through the formation of pyruvate (glycolysis),which is Energy Production and Utilization converted to acetyl CoA for entry into the Krebs cycle. 3. When used for energy production, the L-amino acids Glucose, fatty acids, and a amino acids are the major are, in general, converted to pyruvate, alpha-ketoglufuels of the body. Although a complete description of tarate, and oxaloacetate, again for entry into the Krebs their metabolism is beyond the scope of this chapter cycle. (a good resource is Biochemistry: A Case-Oriented

Mobilizabiefuel reserves in a 70-kg man Glucoselglycogen

Protein

Triglyceride

9

kcal

9

15

60

100

400

5

45

100

400

100

400

450

Intestines (1)

0

0

100

400

Brain (1.4)

2

8

40

160

50 0 0

300 20

1200 80

4000 300

16,000

Adipose (15) Skin, lung, spleen (4)

13

52

450

1800

240 4880

960 -

TOTAL

Tissue (weight in kg)

Blood (10) Liver (1)

Muscle (30)

kcal

1200 19,520

9

0

0

600 12,000

108,000

40 12,695

114,255

~~

Modified from Elkeles RS. Tavill AS. Biochemical aspects of human disease. Boston: Blackwell Scientific, 1983.

kcal

5400 360

Therapeutic Modalities

The major form of utilizable energy in all cells is Am, which is produced by oxidative catabolism of D-glucose, alpha-ketones, fatty acids, and/or L-amino acids. The energy for resting heart and skeletal muscle is met primarily by oxidation of acetoacetate (produced by the liver from acetyl CoA) and fatty acids and secondarily by glucose oxidation. Muscle contraction

~

I Enerav source ~~~~~~

~~~~~

Utilization of energy reserves Reserve'

~~~~~

Glucose

1 hour

Digestion

4-8 hours

Glycogen

12 hours

Amino acids

48 hours

Protein

3 weeks (if protein were the only fuel used for gluconeogenesis) 24 weeks (obligatory loss only)

Triglycerides

8 weeks

Early Fasting

Data from references 36 and 84-86. 'These estimates are based on 100% utilization of each fuel

Daily resource utilization of an average 70-kg man during fasting Late (a)

Resource Protein

requires a continuous supply of ATP, large amounts of which may be almost instantaneously produced by massive conversion of glycogen to lactate (the primary purpose of muscle glycogen). During extreme muscle activity, other short-term energy sources, such as phosphocreatine, are also used. Neither of these is utilized, however, to maintain energy levels during fasting. Exercise also greatly increases glucose utilization by heart and skeletal muscle, which, as discussed later, is probably why resting is important in fasting, because the major source of glucose during fasting is protein catabolism. Under normal feeding conditions, the energy requirement of the mature brain is met almost entirely by glucose. Because the glycogen content of the brain is very low (0.1%), there is essentially no brain glucose reserve. After a few days of fasting, the brain switches to oxidation of beta-hydroxybutyrate (produced by the liver from acetyl CoA) as its primary energy source.

60-84

18-24

Fat

100-140"

160-200*

Glucose

100-180

80

Sodium

3.5-5.8

0.02-0.35

Potassium

1.6-1.8

0.4-0.6

Modified from Shils ME Modern nutrition in health and disease, 9th ed Philadelphia Lea 8 Febiger, 1998 'These values are much higher in obese individuals

The initial physiologic response to the lack of food is the increased synthesis of the glucose by the liver for release into the blood stream. Glucose is especially needed by the brain, which consumes about 65% of the total circulating glucose (400-600 kcal/day), and the R B C S . ~ ~ , ~ ~ Together they consume 100 to 180 g of glucose per day. Early on in fasting, the liver is the sole source of glucose for the blood stream. The liver initially synthesizes glucose from glycogen through glycogenolysis. However, liver glycogen stores can supply enough glucose for only a few hours (see Tables 50-1 and 50-2), and glucose production from gluconeogenesis soon becomes necessary. Although muscle actually contains more glycogen than liver, it lacks the enzyme ~-glucose-6-phosphataseand therefore cannot convert glycogen to glucose for release into the blood stream.88Later in fasting, the glycogen reserves are restored.89

Summary of metabolic events in early versus late stages of fasting Earlv

Late

Brain

Uses glucose for fuel

Adapts to using ketones and some glucose

Liver glycogen

Breaks down to supply glucose

Slowly regenerates

Amino acids

In high demand for making glucose

In significantly reduced demand for making glucose

GIyce rol

In high demand for making glucose

In significantly reduced demand for making glucose

Fatty acids

Supply energy directly for most tissues

Major source of energy for most tissues, including ketones for brain

Metabolic rate Net effect

Slight reduction

Significant reduction

High use of protein to supply glucose to the brain

Less need for glucose, conservation of protein, utilization of fat reserved

Therapeutic Fasting

Liver Glycogen+

Glucose 6-P+

Glucose

I I

Muscle

Blood

1

>Glucose+

Glycerol Lactate

Alanine

<

Flgure 50-2

Glucose 6-P+

+Pyruvate

I

Alanine

Glycogen catabolism Protein

Keto acids

Mechanisms of glucose production during fasting.

Gluconeogenesis utilizes primarily L-amino acids for glucose synthesis, although glycerol from triglyceride catabolism is also used. Because liver glycogenic amino acid stores are quickly depleted, substrate from other tissues, primarily the muscles, is required. As the fast proceeds, the kidneys become progressively more important in the maintenance of blood glucose levels, and eventually the renal cortex synthesizes more glucose from amino acids than does the liver.79If the body were to continue to require its normal 100 to 180 g/day of glucose, gluconeogenesis during fasting would quickly use up much body protein, and death would ensue within 3 to 4 weeks.84Early on in fasting, the body catabolizes 60 to 84 g/day of protein. Initially, sodium, potassium, and water diuresis occurs, and hypovolemia develops. Calcium and magnesium are also lost. Plasma ketone levels rise, and ketones appear in the urine by the third day.%

Fasting Research using respiratory quotient and urinary nitrogen studies has repeatedly shown that triglycerides are the major fuel during f a ~ t i n g . ~ To ,~~ , ~ ,the ~ ~ adi~ leave pocyte, triglycerides must first be hydrolyzed (lipolysis) to fatty acids and glycerol. The fatty acids are transported in the blood, in a physical complex with albumin, to the liver, muscle, and other tissues. Although the brain converts to oxidation of betahydroxybutyrate after 4 to 7 days, there is still an obligatory need for approximately 80 g/day of glucose for the brain, red cells, muscles, and other tissues.88 This requirement rises sigruficantly during exercise. Although much of the lactate produced by anaerobic metabolism of glucose and glycogen is resynthesized to glucose by the liver via the Cori cycle, the need for glucose is increased, because there is a net loss due to urinary excretion of lactic acid and metabolic inefficiency. Approximately 16 g of glucose is synthesized from triglyceride glycerol, with the rest of the glucose

requirement (and the other metabolic processes requiring amino acids, such as enzyme turnover) being met by the catabolism of 18 to 24 g/day of protein. In experimental animals, as much as 14% of the energy needed by muscle may come from the oxidation of branched-chain amino acids. Glucose is also recycled by the breakdown of blood cells in the l i ~ e r . ~The , ~ mechanisms ,~~ of glucose production during fasting are summarized in Figure 50-2. Research has determined that an average 70-kg man has the fat stores to maintain basic caloric requirements for 2 to 3 months of

Starvation Starvation occurs when the body’s fat reserves are depleted and sigruficant protein catabolism again becomes necessary for energy production? As previously noted, unless fat reserves are being utilized for energy production and glucose sparing, the body protein stores are adequate for only a few weeks of gluconeogenesis, after which essential proteins are utilized and death occurs.

Mechanism of Ketosis During fasting, when excessive amounts of fatty acids are being oxidized and inadequate glucose is available, large quantities of ketones are secreted into the blood stream. Ketone bodies are made in the liver from acetyl CoA. During adequate energy input, the conversion of fatty acids to acetyl CoA is regulated by the availability of L-glycerol3-phosphate (derived from glucose through the glycolytic pathway). As the concentration of acetyl CoA rises, it is resynthesized into triglycerides, with L-glycerol 3-phosphate serving as the accepter to which three acyl CoA groups are attached (through esterification).During fasting, there is inadequate glucose to provide the needed glycerol for triglyceride synthesis, resulting in acetyl CoA levels in excess of the oxidative capacity of the Krebs cycle. The excess is then shunted into the synthesis of ketone bodies.= These ketone bodies

Therapeutic Modalities

(acetoaceticacid, acetone, and beta-hydroxybutyric acid) are utilized by the heart and, later in fasting, by the brain for energy production.

Mechanism of Acidosis Because the ketone bodies are acids, their entry into the plasma results in a rise in hydrogen ions. This change is buffered by the conversion of bicarbonate into carbonic acid and then to CO, which is exhaled. Eventually the buffering capacity is exceeded, and the plasma pH decreases, leading to mild metabolic acidosis. The body compensates by raising the respiratory rate to promote further elimination of C 0 2 and by excreting ketone bodies in the urine. These adaptations may result in some electrolyte imbalance.=

Changes on an electrocardiogram include sinus bradycardia, decreased QRS complex and T-wave amplitude, elongation of the QT interval, and shifts to the right of the QRS and T-wave axes. These changes return to normal after f a ~ t i n g . ~ , ~ ~ - ~

Laboratory Changes during Fasting

Most laboratory values for the body fluids during fasting do not follow specific patterns but are unique to the individual and the disease process.34,W Assessment of a fasting patient's progress is based not on a sign or symptom but on the total clinical picture. Although specific predictions of laboratory values during fasting are not possible, some general observations have been made. Some authorities indicate that triglyceride levels decline with fasting but report elevations if liver damage is present. The serum Amino Acid Metabolism protein value usually declines with fasting. Pancreatic lipase and amylase values also usually drop with fasting." With the exception of leucine, which appears to be a regulator of protein turnover in muscleP3 all amino acids Liver enzyme values may increase considerably if are glucogenic. However, alanine plays a prominent liver disease is present and may rise even if liver disease role in a cycle analogous to the Cori cycle for l a ~ t a t e ? ~ , ~ is~not present. Triglyceride, cholesterol, and uric acid The alanine cycle provides the mechanism for the recylevels usually rise during fasting,'"-102 indicating mobicling of a fixed supply of glucose and the effective translization of tissue stores. Postfast values often show a portation to the liver of amino acid nitrogen derived decrease from prefast va1ues.26*41J01 A rise in blood urea from muscle breakdown. Because muscle, unlike liver, is nitrogen (BUN) value may occur, but some authorities incapable of synthesizing urea, most of the amino nitrohave observed a d e c r e a ~ e . ~ The , ~ ~serum , ~ ~ Jcreatinine ~~ gen from protein breakdown is transferred to pyruvate value may be elevated4','@'or may remain stable.'"" Blood to form alanine. The alanine enters the blood and is glucose values drop in most patients,"~~~,~~,~' possibly taken up by the liver. The amino groups are removed below 30 mg/dl.'@' If the blood glucose value is low to form urea, and the resulting pyruvate is converted to before fasting, it may rise after fasting. glucose. The newly synthesized glucose is secreted into Complete blood counts usually show no sigruficant the blood, taken up by the muscle, and catabolized to but decreases in hemoglobin and hematocrit pyruvate to reseed the alanine ~ycle.8~ values have been o b ~ e r v e d ? ~When ~ ~ @they ' ~ ~occur, ~ hemolysis or hemorrhage must be ruled Hematocrit and Electrolyte Balance hemoglobin values as well as RBC count may be increased, but such findings usually indicate reduced h y d r a t i ~ n ? ~ ~ ~ ~ J @ ' Although serum electrolyte levels usually do not change significantly during fasting and are not good indicators ESR usually drops after fasting, although it may rise of tissue stores, they are considered the most important during the fast.5052,'" White blood cell (WBC) counts are blood values during During early fasting the usually unchanged or decrease slightly with fasting; howbody loses 150 to 250 mEq (3.5-5.8 g) of sodium and 40 ever, infection may cause an increase.An increase may also to 45 mEq (1.6-1.8 g) of potassium a day; later, these be observed if levels are low prior to values drop to 1to 15mEq (0.02-0.35 g) and 10 to 15 mEq Urinalyses may be difficult to interpret during fasting, because the body discards considerable waste via (0.4-0.6 g), respectively. The total body store of sodium is the kidneys.37It is not uncommon to see various types of 83 to 97 g (of which 65% is exchangeable), and that of potassium is 115 to 131g (of which 98%is exchangeable). casts, RBCs, WBCs, bilirubin (+1to +2), protein (trace, The typical daily dietary intake of sodium is 3 to 7 g, +2), and ketones (+4), and, if liver disease is present, and of potassium, 3 to 5 g.% Serum potassium usually urobilinogen elevation. Specific gravity is commonly decreases but may be elevated. Values below 3 mEq/L or elevated (possibly to 1.035), a finding that may reflect above 6 mEq/L may necessitate breaking of the fast. The inadequate hydration.'" total calcium value is usually stable, but ionic calcium levels often diminish, especially if vomiting is present.96 Hormonal Changes during Fasting Hormonal changes during fasting typically consist of Physical Changes during Fasting decreases in insulin79~90~92~99J06 and thyroid hormone Physical changes during the fast generally consist of l e ~ e l s . ' ~ ,Increased ~J~~ levels of growth decreases in body weight, pulse12°*22,97 and BP.20,21,22,98cortisol,78glucag0n,7~~~~ plasma norepinephrine,'08 serum

Therapeutic Fasting

melatonin,lO*and certain prostaglandins (in animals) usually occur.1o9By contrast, a decrease in growth hormone is usually found in obese individuakW In one study conducted in 10 postmenopausal women who underwent short-term fasts, no signhcant changes in adrenal hormones, androgens, serum and urinary estrogens, plasma epinephrine, or dopamine were recorded.lo8

Effects of Fasting on Immune Function The immune system undergoes very important changes during the fast, and an increase in various aspects of immune function has been observed. The first evidence of this change came from the study in 1923 that found greater resistance to infection during the postfast period.2I Changes in the immune system during fasting include the f o l l o ~ i n $ ~ , ~ ~ ~ ~ : Greater macrophage activity Increased cell-mediated immunity (T lymphocytes and 1ymphokines) Decreases in complement factors Reductions in antigen-antibody complexes Higher immunoglobulin levels Greater neutrophil bactericidal activity Depressed lymphocyte blastogenesis Heightened monocyte killing and bactericidal function Enhanced natural killer cell activity in animals and humans

CLINICAL PROTOCOL Therapeutic fasting is best conducted under supervision at an inpatient facility. Several facilities now exist in the United States, Canada, England, and Australia, and these centers follow the standards of care and principles of ethics established by the IAHP.3

ConsuItation Standards Consultation standards for any patient in whom fasting is considered as treatment are as follows: Appropriate case history Physical examination Evaluation or assessment of the chief complaints Explanation and recommendations

Clinical Standards Clinicians should adhere to the following standards for any patient undergoing fasting as treatment: Provide an environment conducive to rest and comfort. Maintain a daily record of progress, including appropriate vital signs. Supply adequate amounts of water. Ensure the availability of attendants.

Exercise care in terminating a fast and supervising postfast recuperation, consistent with professional hygienic principles.

Water versus Juice Only pure water (distilled, filtered or reverse osmosis) is recommended during fasting.68*RSome authorities have recommendedjuice, but thisis considered a restricted diet, not a fast, because juice is a food and the continued consumption of carbohydrates inhibits the body’s conversion to ketotic metabolism. In most cases, the fast is superior to the restricted diet because (1) hunger almost totally disappears,22a(2) ketosis occurs more quickly and efficientlyZa (3) famine edema does not occur,= (4)sodium diuresis is more pronounced,29(5)weight loss is more dramatic and is from fat rather than protein stores, (6) healing time is shorter, and (7) patient strength may be greater.* It is interesting to note that people in developing world countries who have protein-deficient diets die sooner than those who fast completely? Restricted diets, however, are often useful before and after fasting and for patients in whom a crisis develops or a fast is contraindicated.71

Quantity of Water The optimal quantity of water to ingest during fasting is generally best determined by thirst, but patients should drink at least a few glasses (40 0 2 ) a day. During fasting the need for water decreases, because obligatory water excretion is reduced (owing to lower excretion of urea, the major osmotic solute) and water is released from catabolized fat.79One cup of water each day may be sufficient to maintain adequate hydration for most peopleY9 although researchers fasting obese individuals often recommend 3 L/day.%

Supplements Loss of minerals or vitamins is usually not a concern, and deficiencies during fasting are rare.* In fact, problems such as nausea and indigestion have been reported when mineral and vitamin supplements were taken during f a ~ t i n g . For ~ ~ Jexample, ~ it is well known that nicotinic acid supplementation inhibits the release of free fatty acids from adipose tissue.% In one patient in whom vitamin deficiency was reported in the medical literature, the actual fasting protocol was not described; in addition, the patient’s physical activity was not restricted and oral medication for intercurrent illness was maintained during Vitamin and mineral excretion becomes very low after 10 days.

Exercise Exercise while fasting is discouraged. Fuel conservation is necessary to allow maximal healing and the avoidance ‘References 22,29, 6 4 7 2 , 110, 111.

Therapeutic Modalities

of unnecessary g l u c o n e ~ g e n e s i s The . ~ ~ ~body ~ utilizes certain muscle proteins early in a fast, thus initiating the natural restriction of activity. Short walks or light stretching is permissible, but intense exercise inhibits repair and elimination. In serious chronic disease, an excess of activity has been suspected as cause of death during fasting.l12 Even moderate activity can double caloric ~tilization."~

Sunlight Sunlight is important for general health during fasting, and patients should try to obtain 10 to 20 minutes per day. An increase in heart rate of 10 to 15 beats/minute may indicate excessive sun exposure.

Rest Rest is a most important aspect of the fast, and patients may nap throughout the day. Less sleep is common at night, possibly owing to the decreased daily activity and the increase in daytime rest.

Laboratory Tests Laboratory tests such as a complete blood count and serum chemistry screen are usually performed weekly, and others are performed as necessary. Regular urine tests are performed, and vital signs are checked daily.37J00

Enemas Enemas are not usually necessary and do not generally offer any added benefit during fasting.& Some authorities have found that enemas also cause discomfort.n To help prevent constipation, prefast meals of only fresh fruit and vegetables for at least 2 days will assist in establishing proper elimination before the fast is initiated.

Length of Fast The length of a fast is difficult to predict. Factors to consider include size of reserves (see Tables 50-3 and 50-4)) individual metabolism, financial limitations, work schedules, severity of disease, age, and sex. This decision is based on all factors, especially the patient's mental state. "The doctor will look for good practical recovery where patient is symptom free and signs of regeneration are pre~ent.""~ Although many old texts refer to "fasting to completion" (i.e., exhaustion of nutrient reserves), this practice is now uncommon and not usually ne~essary."~

Patient Attitude A positive mental outlook is important for any patient undergoing a fast. It should be emphasized that the benefits are broad and affect multiple body systems. Perhaps the greatest value for patients is the satisfaction of playing a major role in improvement of their own health.

SIDE EFFECTS Side effects of fasting are rarely serious, but fasting may uncover disease and reveal weaknesses that were previously sub~linical.~~ Discomfort during fasting may be due to withdrawal from stimulants, hypoglycemia, acidosis, elimination of wastes, and enhancement of repair. Patients may experience headaches, insomnia, skin irritations, dizziness, nausea, coated tongue, body odor, aching limbs, palpitations, mucous discharge, and visual and hearing disturbances. Hair growth is usually arrested, and skin may become dry and scaly. Most signs and symptoms are usually brief as the body works to remove the disease.'15 In certain cases, complications occur that may necessitate breaking the fast early. Examples of such conditions are as follows: A sudden drop in BP (possibly due to peripheral circulatory collapse) Delirium Prolonged hypothermia Rapid, slow, feeble, or irregular pulse Extreme weakness Dyspnea Vomiting and diarrhea leading to dehydration Gastrointestinal bleeding Hepatic decompensation Renal insufficiency Severe gout Cardiac arrhythmias Emotional distress Fasting elevates serum uric acid values and uric acid excretion, and if fluid intake is insufficient, gout or renal stones may be precipitated.36J6 A few studies have discussed the development of Wemicke encephalopathy during prolonged fasting, but because it rarely occurs during hygienic fasting, it is difficult to determine whether the condition is related to methodology. It is important, however, to acknowledge the importance of utilizing B vitamins, especially thiamine, when any fast is broken with intravenous glu~ose."~J~* The decision to terminate the fast should be based on the complete clinical picture and not on an isolated sign or symptom.

CONTRAINDICATIONS Contraindications to fasting are few, and each case must be judged individually, because no two cases are alike. For example, an inexperienced practitioner may assume that emaciated patients should not fast, but about this issue Sheltonn had the following to say: "Extreme emaciation: In such cases a long fast is impossible. A short fast of 1-3 days may be found beneficial, or a series of

Therapeutic Fasting evident, the only genuine contraindicationis fear. . . .As for the such short fasts with longer periods of proper feeding other conditions often mentioned, e.g. kidney disease, heart intervening may be found advisable.” impairment, [tuberculosis], etc., they merely require extreme Contraindications to fasting include severe anemia, caution, because of the limits imposed by pathology, but they porphyria, and serious malnutrition. Individuals with a are not inexorable contraindications. rare fatty acid deficiency of the enzyme medium-chain acyl-CoA dehydrogenase (MCAD) should also avoid fasting4 Supervised fasting as a therapeutic procedure is genThe fasting of children and pregnant women is conerally safe and effective. The incidence of death at fasttroversial. Although a short fast is appropriate for the ing institutions is low, a fact that is promising because sick child who does not want to eat, fasting in a pregnant many of the patients have serious chronic diseases woman may be strongly contraindicated;ketosis in pregand have exhausted other therapeutic options. Of the nant diabetic women is known to be associated with hundreds of cases of fasting described in the scientific literature, only seven cases of death had been reported fetal damage. Although this association is commonly before 1985.60,”2,’20-123 In all cases, the patients had serirecognized, the fact that this information has come only from research of diabetic pregnant women is not ous chronic disease before fasting, and in five of the seven cases, drugs were given to the patients while fastas widely k n o ~ n . ”There ~ appear to be no studies of the effects of nondiabetic ketosis on fetal developing; in the other two, no description of protocol was provided. ment. Doctors (e.g., Shelton, Benesh, Sidwha, and Burton) with considerable experience of fasting pregThere is no evidence in the scientific literature to sugnant women during all three trimesters have found no gest that fasting itself can be considered a cause of death. Death during fasting indicates that the remedial efforts adverse effects with fasts of a few days to 2 to 3 weeks. of the body have been overpowered by the pathologic Although the fasting of pregnant women appears from process. This situation occurs in serious disease, whether clinical observation to be safe, definitive pronouncement the patient is eating or fasting. In examining the fallacy cannot be made until careful research is performed (such of attributing the cause of death to fasting, Stewart and as a controlled retrospective analysis of existing cases). Fleming’” wrote, ”Fasting short of emaciation is not hazFasts for children and pregnant women should be shorter and should be meticulously supervised by an ardous; if death results, reasons other than those of the fast should be considered before concluding that all experienced doctor. In The Science and Fine Art of supervised fasts should be discouraged.” Fasting, S h e l t ~ writes, n ~ ~ “Few infants require more than 2-3 days of fasting. . . . I have never hesitated to permit a sick infant to fast and I have yet to see one harmed by it.” CONCLUSION Regarding pregnancy he says, ”The author would object to a long fast in chronic ’disease’ during this period. Therapeutic fasting is a useful protocol for any physician interested in studying and promoting the inherent abilThere can, however, be no objection to a short fast.”” ity of the body to heal itself. This fine art and science is It is well recognized that fasting during lactation is not generally advised, because milk flow is halted generally a safe, economical, and effective therapy for most patients with disease. Those interested in further by fasting and is difficult to resume.72Although fasting is considered inappropriate in renal ins~fficiency,~~study should initially direct their attention to the main historical texts and then to the later hygienic and scienwe have seen patients with 65% renal function return tific literature. The references provide a greater depth of to normal as a result of fasting and dietary management. information for the topics discussed in this chapter. With regard to fasting contraindications in general, Burton114stated: Internship with a clinician skilled in therapeutic fasting is strongly advised for anyone interested in providing I have found few health problems which are absolute safe and effective patient care. contraindications to fasting. In my experience, if the need is

1. Mosby’s medical &nursingdictionary. St Louis, MO CV Mosby, 1983. 2. Lehninger A. Biochemistry: the molecular basis of cell structure and function. New York Worth Publishing, 1961:841-845. 3. Personal communication, IAHF Secretary/Treasurer Atty. Mark A. Huberman, 2005. 4. Randolph TG. Human ecology and susceptibility to the chemical environment.Springfield,I L Charles C Thomas, 1962.

5. Dickey LD, ed. Clinical ecology. Springfield, k Charles C Thomas, 1976. 6. Arbesmann R. Fasting and prophecy in pagan and Christian antiquity. Traditio 1951;71-71. 7. MacDermot V. The cult of the seer in the Ancient Middle East: a contribution to current research on hallucinationsdrawn from Coptic and other texts. Berkeley, C A University of California Press, 1971.

Therapeutic Modalities 8. Muhammad A. The religion of Islam: a comprehensive discussion of the sources,pMciples and practices of Islam. Lahore, India: The Ahmadiyya Anjuman Isha’at Islam, 1936. 9. Burns D. The greatest health discovery. Chicago: Natural Hygiene Press, 1972. 10.Shelton HM. Some fasting history. Shelton‘s Hygienic Review 1964;XXV:291-293. 11. Shelton HM. Rubies in the sand. San Antonio, TX:Shelton’s Health School, 1961. 12. Numbers RL. Prophetess of health: a study of Ellen G White. New York Harper & Row, 1976. 13. Weiss HB, Kemble HR.The great American water-cure craze: a history of hydropathy in the United States. NJ: The Past Ties Press, 1967. 14.Shelton HM. Natural hygiene: Man’s pristine way of life. San Antonio, Tx: Shelton’s Health School, 1968. 1 5 . S h y r d RH. Medicine in America: historical essays. Baltimore: Johns Hopkins Press, 1966. 16. American National Hygiene Society, 12816 Race Track Road, Tampa, FL, 33625. 17. Dr Tanner’s fast. Br Med J 1880;2171. 18. Paton DN, Stockman R. Observations of the metabolism of man during starvation. Proc R Soc Edinb 1888-89;16:121-131. 19. Penny F. Notes on a thvty day’s fast. Br Med J 1909;1:1414416. 20.Benedict FG. A study of prolonged fasting. Publication K03. Waslungton, DC:Camegie Institute, 1915. 21.Morgulis S. Fasting and undemutrition; a biological and sociological study of inanition. New York EP Dutton & company, 1923. 22.Keys A, Brozek J, Herschel A, et al. The biology of human starvation, vols 1and 2. Minneapolis:University of Minnesota Press, 1950. 23. Guelpa G. Starvation and purgation in the relief of diabetes. Br Med J 1910;21050-1051. 24.Allen FM. Prolonged fasting in diabetes. Am J Med Sci 1915;150480-485. 25.Guelpa M, 1910; cited in Kemdt PR, Naughton JL, Driscoll CE, Loxterkamp DA. Fasting: the history, pathophysiology and complications. West J Med 1982;137379-399. 26. Hoeffel G, Moriarty M. The effects of fasting on the metabolism. Am J Dis Child 1924;28:16-24. 27.Lennox WG, Cobb S. Studies in epilepsy. Arch Neurol Psych 1928;20711-779. 28. Folin 0, Denis W. On starvation and obesity with special reference to acidosis. J Biol Chem 1915;21:183-192. 29. Bloom WL. Fasting as an introduction to the treatment of obesity. Metabolism 1959;8:214220. 30.Duncan GG, Jenson WK, Cristofori FC, Schless GL. Intermittent fasts in the correction and control of intractable obesity. Am J Med Sci 1963;245:515-520. 31. Duncan GG, Duncan TG, Schless GL, CristoforiFC. Contraindications and therapeutic results of fasting in obese patients. Ann N Y Acad Sci 1965;131:632-636. 32. Drenick EJ, Swenseid ME, Blahd WH, Tuttle S. Prolonged starvation as a treatment for severe obesity. JAMA 1964;187100-105. 33. Drenick EJ. Contraindications to long term fasting. JAMA 1964;188:88. 34.Thompson TJ, Runcie J, Miller V. Treatment of obesity by total fast for up to 249 days. Lancet 1966;2992-996. 35. Stewart WK, Fleming LW. Features of a successful therapeutic fast of 382 days’ duration. Postgrad Med J 1973;49:203-209. 36.Shils ME. Modem nutrition in health and disease, 9th ed. Philadelphia: Lea & Febiger, 1998. 37. Scott DJ. Personal communication, 1986. 38. Gresham GA. Is atheroma a reversible lesion? Atherosclerosis 1976;23:379-391.

39. Lawlor T, Wells DG. Metabolic hazards of fasting. Am J Clin Nutr 1969;22:1142-1149. 40.Imamura M, Tung T. A trial of fasting cure for PCB poisoned patients in Taiwan. Am J Ind Med 1984;137147-153. 41. Vessby 8, Boberg M, Karlstrom B, et al. Improved metabolic control after supplemented fasting in overweight type 2 diabetic patients. Acta Med Scand 1984;21667-74. 42. Navarro S, Ros E, Aused R, et al. Comparison of fasting, nasogastric suction and cimetidine in the treatment of acute pancreatitis. Digestion 1984;30224230. 43.Brod J, Pavkova L, Fencl V, et al. Influence of fasting on the immunological reactions and course of acute glomerulonephritis. Lancet 1958;1:760-763. 44.Fuhrman J. Fasting and eating for health. New York: St. Martin’s Press, 1995. 45. Okamoto 0,Murakami I, Itami S, Takayasu S. Fasting diet therapy for chronic urticaria: report of a case. J Dermatol1992;19:428-431. 46.Fuhrman J, Sarter B, Calabro DJ. Brief case reports of medically supervised, water-only fasting associated with remission of autoimmune disease. Altem Ther Health Med 2002;8112,110-111. 47. Lithell H, Bruce A, Gustafsson IB, et al. A fasting and vegetarian diet treatment trial on chronic inflammatory disorders. Acta Derm Venereol1983;63397-403. 48. Skoldstam L, Larsson L, Lindstrom FD. Effect of fasting and lactovegetarian diet on rheumatoid arthritis. Scand J Rheumatoll979; 8249-255. 49. Skoldstam L, Lindstrom FD, Lindblom B. Impaired conA suppressor cell activity in patients with rheumatoid arthritis shows normalization during fasting. Scand J Rheumatol 1983;12:369-373. 50. Sundqvist T, Lindstrom F, Magnusson KE, et al. Influence of fasting on intestinal permeability and disease activity in patients with rheumatoid arthritis. Scand J Rheumatol 1982;11:33-38. 51. Kroker GF, Stroud RM, Marshall R, et al. Fasting and rheumatoid arthritis: a multicenter study. Clin Ecol1984;2:137-144. 52. Uden AM, Trang L, Venizelos N, Palmblad J. Neutrophil function and clinical performances after total fasting in patients with rheumatoid arthritis. Ann Rheum Dis 1983;42:45-51. 53. Palmblad J, Hafstrom I, Ringertz B. Antirheumatic effects of fasting. Rheum Dis Clin North Am 1991;17351-362. 54. Kjeldsen-Kragh J, Mellbye OJ, Haugen M, et al. Changes in laboratory variables in rheumatoid arthritis patients during a trial of fasting and one-year vegetarian diet. Scand J Rheum 1995; 24235-93. 55. Panush RS. Controversial arthritis remedies. Bull Rheum Dis 1984;34:1-10. 56. Gerrard JW. Food intolerance. Lancet 1984;2:413. 57.Goldhamer AC, Lisle DJ, Parpia B, et al. Medically supervised water-only fasting in the treatment of hypertension. J Manipulative Physiol Ther 2001;24335-339. 58. Goldhamer A, Lisle D, Sultana P,et al. Medically supervised wateronly fasting in the treatment of borderline hypertension. J Altem Complement Med 2002;8:643-650. 59. Goldhamer A. Initial cost of care results in medically supervised water-only fasting for treating high blood pressure and diabetes. J Altem Complement Med 2002;8:696-697. 60.Suzuki J, Yamauchi Y, Horikawa M, Yamagata S. Fasting therapy for psychosomatic disease with special reference to its indications and therapeutic mechanism. Tohoku J Exp Med 1976;118: 245-259. 61. Spencer 10. Death during therapeutic starvation for obesity. Lancet 1968;l:1288-1290. 62. Boehme DH. Preplanned fasting in the treatment of mental disease: survey of the m n t Soviet literature. Schizophr Bull 1977;328&296. 63. Milet V, Spencer MJ, Chapin M, et al. Dientamoeba fragilis, a protozoan parasite in adult members of a semicommunal group. Dig Dis Sci 1983;28:335-339.

Therapeutic Fasting 64.Johnston DA, Wormsley KG. The effects of fasting on 24-h gastric secretions of patients with duodenal ulcers resistant to ranitidine. Aliment Pharmacol Ther 1989;3:471-479. 65. Dewey EH. The no-breakfast plan and the fasting-cure. New York The Health Culture Co, 1900. 66. MacFadden 8. Fasting for health: a complete guide on how, when and why to use the fasting cure. New York MacFadden, 1923. 67. Hazzard LB. Scientific fasting. New York Grant Publications, 1927. 68. Carrington H. Fasting for health and long life. Mokelumne Hill, CA: Health Research, 1963. 69. De Vries A. Therapeuticfasting.Los Angeles: Chandler Book Co, 1963. 70. Shelton Hh4. Fasting can save your life. Chicago: Natural Hygiene Press, 1964. 71. Shelton Hh4. Fasting for renewal of life. Chicago: Natural Hygiene Press, 1978. 72. Shelton HM. The science and fine art of fasting. Chicago: Natural Hygiene Press, 1978. 73. Oswald ]A, Shelton HM. Fasting for the health of it. Pueblo, CO: Nationwide Press, 1983. 74. Wing EJ, Boehme SM, Barczynski LK. Effects of acute nutritional deprivation on immune function in mice I. Macrophages. lmmun010g~1983;48:543-550. 75. Wing EJ, Stank0 RT, Winnkelstein A, Adibi SA. Fasting-enhanced immune effector mechanisms in obese subjects. Am J Med 1983; 75~91-96. 76. Friend PS, Femandes G, Good RA, et al. Dietary restrictions early and late: effects on the nephropathy of NZB X NZW mouse. Lab Invest 1978;38:629-632. 77. Miller JD. Life extension. N Eng J Med 1985;313:760-761. 78. Palmblad J, Cantell K, Holm G, et al. Acute energy deprivation in man. Effect on serum immunoglobulins, antibody response, complement factors 3 & 4, acute phase reactants and interferon producing capacity of blood lymphocytes. Clin Exp Immunol 1977; 3 0 50-55. 79. Young VR, Scrimshaw NS. The physiology of starvation. Sci Am 1971;225:14-21. 80. Rothman DL, Magnusson I, Katz LD, et al. Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science 1991;254573-576. 81. Insights into fasting. Lancet 1992;339152-153. 82. Koff RS. Rapid induction of gluconeogenesis during fasting. Gastroenterology 1992;1022174-2175. 83. Elkeles RS, Tavill AS. Biochemical aspects of human disease. Boston, MA: Blackwell Scientific Publications, 1983. 84. White A, Handler P, Smith EL. Principles of biochemistry, 6th ed. New York McGraw-Hill, 1978. 85. Montgomery R, Dryer RL, Conway TW, Spector AA. Biochemistry: a case-oriented approach, 6th ed. St Louis: CV Mosby, 1996. 86. Nutrition reviews’ present knowledge in nutrition, 5th ed. Washington, DC:Nutrition Foundation, 1984, p. 439-453. 87. Reinmuth OM, Scheinberg P, Bourne B. Total cerebral blood flow and metabolism. Arch Neurol 1965;1249-66. 88. Saudek CD, Felig P. The metabolic events of Starvation. Am J Med 1976;60:117-126. 89. Haro EN, Blum SF, Faloon WW. The glucagon response of fasting obese subjects. Metabolism 1965;14976-984. 90.Cahill GF Jr, Owen OE, Morgan AP. The consumption of fuels during prolonged starvation. Adv Enzyme Regul1968;6:143-150. 91. Cahill GF Jr, Owen OE. Starvation and survival. Trans Am Clin Climatol Assoc 1968;79:13-20. 92. Felig P, Owen OE, Morgan AP, Cahill GF Jr. Utilization of metabolic fuels in obese subjects. Am J Clin Nutr 1968;21:1129-1133. 93. Buse MG, Reid SS.Leucine, a possible regulator of protein turnover in muscle. J Clin Invest 1975;561250-1261. 94. Felig P, Pozefsky T, Marliss E, Cahill GF Jr. Alanine: key role in gluconeogenesis. Science 1970;1671003-1004.

95. Mallette LE, Exton JH, Park CR. Control of gluconeogenesis from amino acids in the perfused rat liver. J Biol Chem 1969;244: 5713-5723. 96. Cinque R. Hematological changes during fasting. IAHP Newsletter 1993;76-8. 97. Theorell T, Kjellberg J, Palmblad J. Electrocardiographic changes during total energy deprivation (fasting). Acta Med Scand 1978;203:13-19. 98. Consolazio CF, Nelson RA, Johnson HL, et al. Metabolic aspects of acute starvation in normal humans: performance and cardiovascular evaluation. Am J Clin Nutr 1967;20:684-693. 99. Kemdt PR, Naughton JL, Driscoll CE, Loxterkamp DA. Fasting: the history, pathophysiology and complications. West J Med 1982;137379-399. 100. Goldhamer A. Personal communication, 1986. 101. Valenta LJ, Elias AN. Modified fasting in the treatment of obesity. Postgrad Med 1986;79:263-267. 102. Ende N. Starvation studies with special reference to cholesterol. Am J Clin Nutr 1962;11:270-280. 103. Immerman AM. Fasting and diet restriction in the treatment of cardiovascular disease. ACA J Chiropractic 1980;140:S42-S54. 104. Rapoport GL, From A, Hudson H. Metabolic studies in prolonged fasting: inorganic metabolism and kidney function. Metabolism 1965;14:30-47. 105. Rooth G, Carlstrom S. Therapeutic fasting. Acta Med Scand 1970;187455-463. 106. Spark RF, Arky RA, Boulter PR, et al. Renin aldosterone and glucagon in the natriuresis of fasting. N Eng J Med 1975;292: 1335-1340. 107. Harrison MT, Harden RM. The long-term value of fasting in the treatment of obesity. Lancet 1966;2:1340-1342. 108. Beitins IZ,Barkan A, Kiblanski A, et al. Hormonal responses to short term fasting in postmenopausal women. J Clin Endocrinol Metab 1985;60:1120-1126. 109. Kim YC, Brodows RG. Starvation stimulates pancreatic PGE content. Prostaglandins 1983;25:365-371. 110. Cinque R. Personal communication, 1986. 111. Benesh G. Personal communication, 1986. 112. Kahan A. Death during therapeutic starvation. Lancet 1968;l: 1378-1379. 113. Cahill GF. Famine symposium: physiology of acute starvation in man. Ecol Food Nutr 1978;6221. 114. Burton A. Fasting too long. J Health Science 1979;2:144-146. 115. Salloum TK. Fasting signs and symptoms. East Palestine, OH: Buckeye Naturopathic Press, 1992. 116. Drenick EJ. Hyperuricemia, acute gout, renal insufficiency and urate nephlithiasis due to starvation. Arth Rheum 1965;8: 988-997. 117. Devathansen G. Wernicke’s encephalopathy in prolonged fasting. Lancet 1982;2:1108-1109. 118. Falzi G, Ronchi E. Wernicke’s lethal encephalopathy in voluntary, total prolonged fasting. Forensic Sci Int 1990;4717-20. 119. Churchill JA, Berendes HW, Nemore J. Neuropsychological deficits in children of diabetic mothers. Am J Obset Gynecol 1969;105257-268. 120. Cubberley PT, Polster SA, Schulman CL. Lactic acidosis and death after treatment of obesity by fasting. N Eng J Med 1965;272 628-630. 121. Gamett ES, Bamard DL, Ford J, et al. Gross fragmentation of cardiac myofibrils after therapeutic starvation. Lancet 1969;1:914-916. 122. Norbury FB. Contraindication to long term fasting. JAMA 1964;18888. 123. Runcie J, Thompson TJ. Prolonged starvation-a dangerous procedure. Br Med J 1970;3:432-435. 124. Stewart WK, Fleming LW. Fragmentation of cardiac myofibrils after therapeutic starvation. Lancet 1969;1:1154.

Syndromes and Special Topics 51 52 53 54 55 56 57 58 59 60 61 62

Cancer-Integrated Naturopathic Support 549 Chronic Candidiasis 573 Food Reactions 583 Functional Toxicology 593 Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease 609 Hyperventilation Syndrome/ Breathing Pattern Disorders 629 Immune Support 645 Intestinal Protozoan Infestation and Systemic Illness 655 Maldigestion 661 Role of Dietary Fiber in Health and Disease 665 Sports Nutrition 677 Stress Management 701

Careful study of the various diseases to which humans are heir indicates that a limited number of underlying problems either cause or significantly contribute to most diseases. The reductionist philosophy underlying most of modem medical research and practice results in better diagnosis and progressively more specific therapies for a given disease, but makes recognition of broad patterns of disease causation extremely difficult.

We believe the reader will find the syndromes discussed in this chapter interesting, relevant, and a compelling inducement for developing a more holistic approach to patients. Oldfashioned ideas such as “bowel toxemia” and ”liver toxicity” not only are intuitively reasonable but now have solid scientific evidence to support their validity. As one reads the chapters in this section, a compelling concept of medicine emerges: Poor diet + unhealthy lifestyle + toxin exposure

.1 Nutritional deficiencies + food allergies + toxicity 5 Metabolic dysfunction + subacute disease 5 Clinically recognizable diseases that are apparently unrelated to the underlying causes

547

Cancer-Integrated

Naturopathic Support Paul Reilly, ND, LAC

CHAPTER C O N T E N T S Diagnostic Summary

549

General Considerations 549 Defining the Problem 549 Cancer Overview 550 Therapeutic Considerations 553 Goals of Naturopathic Oncology Support 554 Stages of Clinical Care 554 Surgery 554 Natural Medicine Support for Surgery 555 Chemotherapy and Biologic Response Modifiers 556 Chemotherapy Agents 556 Clinical Uses of Chemotherapy 557 Actions of Chemotherapeutic Drugs 557 Families of Chemotherapy Drugs 557 Biologic Response Modifiers 557 New-Breed Chemotherapy Agents 558

DIAGNOSTIC SUMMARY Cancer is not a single disease. It is a group of more than 200 individual diseases all characterized by uncontrolled growth, proliferation, and spread of abnormal cells. Diagnosis and treatment vary depending on the type of cancer cells and their location, the extent of total tumor burden, the health and performance status of the patient and prior treatments administered, as well as consideration of which conventional treatment regimens are currently considered the "standard of care."

GENERAL CONSIDERATIONS Defining the Problem More than 1.25 million new cases of cancer will have been diagnosed in the United States in 2004, not including basal and squamous cell type skin cancers. The most common cancers are colorectal (152,000 cases), breast (205,000 cases), prostate (189,000 cases), and lung (169,000 cases). More than 555,000 cancer patients will die of their disease this year.'

Modes of Administration 558 Side Effects of Chemotherapy 559 Chemotherapy Resistance Testing 559 General Recommendations for Chemotherapy 559 Specific Recommendations for Chemotherapv 560 Recommendations for Specific Individual Chemotherapy Agents 563 . <

Radiation 565 Types of Radiation Therapy 565 Side Effects of Radiation Therapy 566 Naturopathic Support During Radiotherapy Summary 567

566

Antioxidants, Chemotherapy, and Radiation 567 Clinical Trials

568

Diet for Cancer Patients 569 Conclusions

569

The extent of the problem is reflected in the following sobering statistics: Cancer will affect one in three persons alive today. Cancer causes one in five deaths in the United States. Half of those diagnosed with cancer will eventually die of their disease, even with the best treatment available today. Prevention should obviously take precedence over treatment. The occurrence of disease is generally thought to involve two compounding factors, genetic susceptibility and environmental exposure to carcinogens. Research studies following 90,000 twins in Scandinavia suggest that environmental factors contribute more than half of the risk to the 11 most common cancers? Naturopathic medicine can help patients to reduce most lifestylebased risk factors and even counteract some genetic risk factors. Adequate screening and sensitive diagnostic testing are necessary in order to detect cancer in its early stages when it is more curable. Once cancer has been diagnosed, 549

Syndromes and Special Topics

the need for the support of naturopathic medicine both during and after treatment should be recognized. The roles that naturopathic medicine can play include, but are not limited to, the following:

0

Provide good primary care for prevention and screening Aggressively test and evaluate suspicious lesions for early detection and treatment Reduce the side effects of conventional therapies Improve tumor kill from conventional therapies Change the environment that allowed the growth of the tumor Support the patient metabolically while starving the tumor Slow or arrest abnormal cell division Promote normal cell differentiation and apoptosis Reduce metastasis, angiogenesis Enhance cell-to-cell communication Use natural antitumor agents Block hormonal stimulation of tumors though normalizing hepatic clearance of hormones Support a healthy immune response Support secondary prevention for the patient after treatment Deal with death and dying for those who eventually succumb to their disease Encourage primary prevention and aggressive screening for family members of the patient

This chapter addresses all of these roles. As in any specialty of medicine, there are terms and language specific to the practice of oncology. A brief review is included to help the reader understand discussions in clinical reports and textbooks and research on oncology literature.

Cancer Overview What Is Cancer? Cancer is a general term applied to cells that have undergone a number of mutations altering them from their normal phenotype. The normal healthy, mature, fully differentiated cell is responsive to a series of inhibitory signals that limit cell division and invasiveness. Transformation of a healthy cell into a cancerous one is a multistep process involving multiple mutations over time. The alteration of a healthy cell into a malignant one begins when mutations lead to more rapid cell division, sometimes described as hyperplasia. The next stage is development of changes in cellular architecture, known as dysplasia. As the cell further mutates, it becomes a premalignant cell or carcinoma in situ. When sufficient mutations have accumulated, the cell crosses a border into the realm defined as cancer. These mutations generally include development of self-sufficiency in growth signals, insensitivity to normal antigrowth signals, evasion of normal apoptotic processes, limitless replicative

potential, sustained angiogenesis, and loss of the need for basement membrane contact. The combination of these mutations produces cancerous cells able to perpetrate tissue invasion and metastasis? These processes are sometimes divided into three stages: initiation, promotion, and progression. Initiation is the stage of damage to cellular DNA, leading to mutations that eventually result in the original development of a cancerous cell. The promotion stage is the stage where factors in the cellular environment such as free radicals, xenobiotic chemicals, and hormones "feed" the cancerous cell, allowing it to grow into a tumor. The progression stage is when a tumor begins to metastasize and spread to other parts of the body.

The Cell Cycle Normal cell division proceeds in an orderly manner through a series of phases. Each phase is characterized by certain chemical and genetic processes, and each must proceed properly for cell division to occur. The orderly succession in the cell cycle is controlled by a group of molecules known as cyclins and cyclin-dependent kinases, which regulate the entrance into each phase of the cycle. The cell cycle is usually divided into four or five phases as follows:

GO phase: This is the resting state, also known as the gap phase. Many cells spend most of their time in this phase and are either at rest or performing their assigned duties in the body. Cells in this phase are generally resistant to most types of chemotherapy. G1 phase: This is also known as the gap 2 phase or the interphase. In this stage cells begin to synthesize RNA and to prepare for cell division. S phase: This is also called the synthesis phase because the cell begins to duplicate the DNA in preparation for creating a daughter cell. G2 phase: This is also called the gap 2 phase. In this phase DNA synthesis has been completed, and the microtubule members of the mitotic spindles are produced. M phase: This phase, also known as mitosis, is the stage at which all the previously produced DNA and cellular proteins are divided into two daughter cells. After completing this phase, most cells return to the GO or resting phase (Figure 51-1). Certain chemotherapeutic agents work best in particular phases of the cell cycle. A rough breakdown is as follows:

G1: Asparaginase S phase: antimetabolites, Procarbazine, Topotecan, topoisomerase I inhibitors G2 phase: Etoposide, Bleomycin, Taxol, and topoisomerase I1 inhibitors M phase: vinca alkaloids

Cancer-Integrated

Figure 51-1 The cell cycle.

Types of Cancer Carcinomas are cancers deriving from cells of epithelial origin. Most common cancers including breast cancer, prostate cancer, lung cancer, colon cancer, and melanoma are carcinomas. Sarcomas are cancers derived from cells of mesenchymal origin such as bone, muscle, or fibrous tissue. Sarcomas can be further divided into those of bone origin and those derived from soft tissues. Examples include osteosarcoma and leiomyosarcoma. Leukemias are cancers derived from white blood cell-producing tissues such as the bone marrow. Leukemia types include chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), and acute myelogenous leukemia (AML). Other less common subtypes are not discussed due to space constraints. Lymphomas are malignancies that develop in the lymphatic system. Most arise in lymph nodes. Lymphomas are generally divided into Hodgkin disease and nonHodgkin lymphomas (NHL). NHL can be further subdivided by types of cells involved (e.g., T cell or B cell), physical form (e.g., follicular, diffuse), and their degree of indolence or aggressiveness.

Staging Staging is a process of determining the spread of disease. The purpose of staging is to provide information that can be used in making treatment decisions, evaluating responses, and making survival prognoses. Most staging is based on the anatomic spread of disease, but certain cancers have other characteristics

Naturopathic Support

that affect staging. For example, any breast cancer of the inflammatory subtype is automatically considered stage 4, no matter the extent of spread of the disease. In another example, colon cancer, the depth of penetration through the wall of the colon is important in the staging of the disease. A complete staging description should include information about the tumor and the host. Information necessary for staging includes origin of the tumor, as well as histologic type and grade. The extent of the spread of tumor and locations of metastatic lesions should be described, as well as the functional status of the ~ a t i e n t . ~ The first step in staging is determination of the tumor node metastasis (TNM) rating. The TNM score gives a relatively precise description of the size of the tumor (T), the number of involved lymph nodes (N), and the presence or absence of distant metastatic disease (M). Each type of cancer has slightly different criteria for each characteristic, but in general one can expect a T1 lesion to be smaller, usually less than 1 or 2 cm, while a T4 lesion is larger and often extending into local tissues. Lymph node staging generallybegins with NO, which signifies no nodal involvement detected, to N1, which signhes limited nodal involvement, on up to N3, which sigrufies involvement of distant nodes. The metastatic rating is limited to MO for no detectable metastases or M1, which indicates positive findings for any metastatic disease. For example, the description of a breast cancer that has a primary tumor 2.5 cm in size, with positive lymph nodes in the ipsilateral axilla and no detectable metastatic lesions, would be T2,Nl,MO. After establishing a TNM score, the information can be simplified into a “stage,” the term with which most patients are familiar. Once again staging varies with cancer type but generally follows a pattern. Stage 0 is in situ or noninvasive disease. Stage 1is small localized disease. Stage 2 generally is somewhat larger disease but still localized, perhaps involving a small number of local lymph nodes. Stage 3 disease is regionally advanced, and stage 4 is advanced metastatic disease. Doctors use TNM and staging information to help make decisions regarding the aggressivenessof treatment to suggest for the patient, as well as to answer general questions about prognosis. The two types of staging are (1)clinical staging, which is based on physical examination, radiographs, ultrasounds, and computed tomography (CT) scans, and (2) surgical staging (also known as pathologic staging), which can determine the ultimate accuracy of the clinical staging. Oftentimes the staging is upgraded to the next level during surgery when it is found that the disease has extended farther or more lymph nodes are involved than were detectable on the clinical staging scans. In some cancers surgical staging allows the final determination. In the example of colon cancer, this is because determination of the depth of

Syndromes and Special Topics penetration through the wall of the colon is critical to analysis. Full details on the staging of all cancer types are available in reference manuals published by the American Joint Commission on Cancer and by the International Union Against Cancer. Simplified details are available in most textbooks on oncology.

Tumor Markers Tumor markers are a group of proteins that can be measured in the blood to indirectly evaluate progression of cancer. These proteins are normally expressed in healthy tissue in small amounts, but the amount secreted is frequently increased in malignant tissue. Common examples of these would be markers like the prostate specific antigen (PSA) for prostate cancer, carcinoembryonic antigen (CEA) for colon cancer, and CA 125 for ovarian cancer. Although these markers can be useful in disease management, there are several caveats in their use. First, most are not considered useful as screening tests for cancer. This is because not all cancerous tissue expresses large amounts of the proteins and because the line between normal levels and cancerous levels is still under debate. Noncancerous tissue can also secrete higher amounts of these markers in conditions such as inflammation and infection. This is even true with the PSA test, which is perhaps best accepted for screening. In fact, many men with an elevated PSA have prostatitis or benign prostatic hypertrophy rather than prostate cancer. At the same time, up to 30% of men with prostate cancer show normal levels of FSA at the current normal range. The second caveat is that although tumors have ”classical” markers, they may express a different marker than that which is typically found in a tumor type. For example, a breast tumor may express PSA rather than the typical CA 27-29. This reflects the fact that tumor cells have become less differentiated and therefore less typical of their original cell type, and during this process they may begin to develop characteristics of other cells. Tumor markers are most useful in monitoring response to a treatment or progression of disease. The direction and rate of change enable the provider to assess efficacy of treatment. It is often helpful to measure tumor markers before a patient has a tumor removed in order to determine if there is a viable marker to follow for later evaluation. If the patient has a large tumor but all tumor markers are negative, there is less reason to follow those markers as a sign of recurrence after treatment. Table 51-1 lists common tumor markers and diagnoses. The raw number of a tumor marker is generally less important than the direction of change. One person with a low tumor marker may have a larger disease burden than another patient with a higher tumor marker due to differences in the biology of their cancer. However, if the

Common tumor markers Tumor marker

Tvpical tumor twes

CEA

Colorectal, breast, small cell lung

PSA

Prostate, some breast

CA 15-3

Breast

CA 19-9

Pancreas, hepatic, biliary, gastric, colon

CA 27-29

Breast

CA 125

Ovarian

Beta-HCG

Testis, trophoblastic neoplasia

Beta 2 microglobulin

Multiple myeloma, lymphoma

Thyroglobulin

Thyroid

tumor marker is dropping, the assumption can be made that treatment is working. Conversely, if the marker is rising, the assumption is that the current treatment plan needs modification.

Performance Indexes Oncologists use a series of performance indexes to indicate the level of a patient’s health. The most commonly used indexes are the Karnofsky and ECOG (for Eastern Cooperative Oncology Group) scores. These indexes are based on the patient’s ability to perform daily activities, need for assistance, and need for medical treatment. Such tools are useful because they reflect the level of vitality remaining in a patient and suggest a potential ability to withstand and respond to further treatment. Two patients with similar stages of disease but radically different performance indexes (based on variables such as previous treatments, organs involved, and pain levels) may have very different outcomes. Examples of the Kamofsky and ECOG systems are compared in Table 51-2.

Tumor Response Criteria and Terminology Tumor response criteria are often quoted in research studies and journal articles. Although they do give some understanding of the therapeutic potential of a treatment, it is important to understand that a tumor response does not always equate with a cure or even an improvement in survival. When a tumor responds initially to a treatment, it often reflects a susceptible clone of tumor cells being killed by the treatment. However, just as antibiotic treatments eventually select for resistant strains of bacteria, cytotoxic therapy selects for resistant clones of tumor cells, which over time no longer respond to a treatment. When reading about complete response, partial response, etc., it is important to know exactly what those terms imply. A cure is defined as a treatment that allows the patient to live as long as an age-matched cohort or to allow the patient to die of other causes, even if some disease was still present. For example, if a prostate cancer patient had a radical prostatectomy and later developed

Cancer-Integrated Comparison of Karnofsky and ECOG scoring Karnofsky score

Description

100

Asymptomatic

90

Normal activity, minor disease signs

80

Some disease signs with exertion

70 60

Cares for self, unable to do active work

ECOG score

Requires occasional assistance, in bed

4 0 % of day 50

Requires considerable assistance and medical care

3

40

Disabled; requires special assistance; in bed S O % of day

3

Severely disabled; hospital indicated

4

Very ill; requires active supportive traction, bedridden

4

10

Moribund

4

0

Deceased

5

30 20

Modified from Murray M, BirdsallT, Pizzorno JE, Reilly P. How to prevent and treat cancer with natural medicine. New York: Riverhead Books, 2002. €COG,Eastern Cooperative Oncology Group.

metastases to the bone, but died of a stroke, that could be considered a cure. Remission is complete disappearance of all detectable tumors. In fact, even in a remission with no detectable disease, it is possible to have millions of tumor cells present, and thus remission is probably a better term than cure, until there is a better way of identifymg residual tumor cells that may be lying dormant. A complete response is the term used to reflect the complete disappearance of all evidence of disease for at least two measurement periods at least 4 weeks apart. A partial response is a decrease of 50% or more in the diameter of all measurable lesions with no appearance of new lesions for at least 4 weeks. Stable disease is a decrease of less than 50%up to an increase of 25% in measurable lesions. Progression is an increase of more than 25% or the appearance of new lesions. PaZliation is treatment not aimed at curing a patient but just at the reduction of symptoms, such as obstruction or pain by reducing the size of the tumor, or a transient extension of life for a brief period without real hope of achieving a cure.

THERAPEUTIC CONSIDERATIONS The majority of patients diagnosed with cancer in this country use one or more forms of conventional therapy. This chapter assumes that the patient is receiving conventional therapy for their disease along with naturopathic support. The treatment of cancer with natural

Naturopathic Support

therapies alone is too complex to cover adequately in this chapter. Furthermore, the treatment of patients with natural therapies alone is controversial and evaluation of its efficacy is limited by the absence of quality research with documented results. When making therapeutic decisions, it is my contention that it is necessary to be able to show results at least as good as those of conventional therapies in order to jushfy declining those therapies. In most cases those statistics are just not available. Cancer is not a self-limiting disease and it must be remembered that our advice may determine whether a patient lives or dies. In such a situation it is incumbent on the naturopathic physician (as well as all other providers) to make recommendations on the basis of hard data, not theory, anecdote, or opinion. Abundant evidence indicates that individual nutrients and botanicals can affect tumor growth both in vitro and in vivo. Many conventional chemotherapy agents are, in fact, derived from natural compounds. However, in order to be reliably cytotoxic, most natural compounds must be strong enough to also be toxic to healthy cells. A better way to use the natural therapies is to support the normal healthy processes of cellular communication, differentiation, and apoptosis, thereby changing the environment that allowed cancer cells to develop and survive in the first place, rather than focusing on killing cancer cells directly. This theory was eloquently discussed in a paper entitled “Shifting the paradigm: must we kill to cure?’‘ in the Journal of Clinical Oncology. Schipper and colleagues5 argued that the killing hypothesis has had some success, such as the treatment of testicular cancer, but in general has not led to dramatic changes in survival rates of more common cancers.The authors argue instead for a concerted effort to affect the regulatory imbalance rather than attempting to kill all cancer cells.5 This is exactly where the use of natural therapies can be most beneficial. Nutrients and herbs can affect the cell cycle and cell division, angiogenesis, cell-to-cell communication, metastatic processes, growth signaling (e.g., tyrosine kinases), and many other aberrant processes in cancer. However, in most cases this is not enough in itself to guarantee a cure. Combining this approach with rationally selected conventional care can improve outcomes while reducing side effects, and this is the approach advocated here for most patients as giving the best opportunity for remission and increased survival, along with good quality of life. In cases where it is known that conventional therapies have no further meaningful benefit or if the patient chooses to adamantly refuse all conventional treatment, then the use of natural therapies alone may be justified. However, it is incumbent on the practitioner to discuss the lack of solid research supporting ”natural cures for cancer” and to continue conventional monitoring in order to evaluate treatment success and make changes as indicated.

Syndromes and Special Topics

Several large peer reviewed reports have reported that two thirds to three fourths of all cancer patients make use of one or more alternative or complementary therapies while undergoing treatment for Many of these patients make decisions on the basis of information on the Internet or from well-meaning but uninformed relatives or health food store employees. An important part of our role as naturopathic physicians is to help patients sort through the overwhelming amounts of promotional literature in order to identify treatments that are not cost or clinically effective from those with well-established benefit.

Goals of Naturopathic Oncology Support The goals of treatment vary sigruficantly depending on the wishes of the patient and the stage of treatment. Some patients only want help with controlling the symptoms of treatment, while others seek a comprehensive management approach. Equally important is to help the patient select the best goals in his or her case. Late-stage patients may primarily need support for pain relief or appetite stimulus. Putting late-stage patients on a severely restricted diet is more likely to hasten their demise than improve their health. Early-stage patients are most likely to benefit from dramatic changes in lifestyle and aggressive supplemental and botanical support. In brief, the goals of treatment include the following: Improve nutrition Selectively starve the tumor Inhibit metastasis Reduce side effects of treatment Maximize tumor kill from conventional therapies Support normal cell division Remove tumor promoters Use antitumor herbdnutrients (and help patient not waste money on worthless products) Support immune function Support positive attitude and healthy lifestyle Encourage regular secondary cancer screening after completion of treatment

Stages of Clinical Care A typical clinical pattern occurs in most cases of cancer:

1. The first step is detection of an abnormality suggestive of a possible cancer. Symptoms vary with the type of tumor but include a mass, lymphadenopathy, pain, bleeding, or some other abnormal finding on physical examination or in laboratory results. 2. The next step is evaluation of the suspicious finding with imaging studies such as CT scans, ultrasounds, etc. to determine if cancer is a likely diagnosis. In any questionable case, some type of biopsy is taken to make the final determination of malignancy versus

benign tissue and to establish the type of tumor and degree of abnormality. 3. Once the diagnosis is made and the staging process completed as described earlier, most patients with solid malignancies have surgery to remove the tumor or debulk its mass. In some cases, the tumor is inoperable and this step is bypassed. In other cases neoadjuvant chemotherapy is administered before surgery to shrink the tumor and make the surgery less invasive. 4.The next stage may include one or more types of chemotherapy,radiation, hormones, or biologic response modifiers. 5. After completion of these therapies, most patients are monitored for recurrence. They may also receive additional therapy in the form of biologic response modifiers based on the type of cancer. The specifics of each individual cancer are too complex to be covered adequately in the limited space available here. This chapter covers some of the issues related to each of the previously mentioned conventional therapies and how best to improve the response to those therapies.

SURGERY Surgery is the first treatment in approximately 75% of cancers. In some cases the surgery is done diagnostically in the form of a biopsy, but most often it is done with a curative intent. In later stages of disease, the surgery may be intended only to debulk a tumor or to remove an obstruction or painful lesion. Of all the conventional treatments available, surgery has the greatest potential for true cure. If it is possible to remove all cancerous tissue with adequate tumor-free margins before the tumor has had time to metastasize, then a patient can truly be considered “cured.” The biggest difficulty is determining if all malignant cells have been fully removed. A 1-cm tumor has more than 1 billion cells. Clusters of cells or micrometastases are so small that they are impossible to detect by current methods. It is therefore impossible to say with certainty that “we got it all,” and all that can be said with certainty is that “we removed all visible signs of diseased tissue.” The benefits of surgical tumor removal come at the risk of complications.The most common potential problems encountered in the surgical and postoperative period include: bleeding, anesthesia reactions, infections, blood clots, dissemination of cancer cells during the procedure, and damage to nearby nerves or tissues during surgery. Postsurgical adhesions can cause various complications as late sequelae and may lead to the necessity for further surgical interventions to release the adhesions. Other potential complications vary depending on the tumor location, tissues involved, and skill of the surgeon.

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The goals of natural therapies include reduction of all the previously mentioned complications, improved rates of healing and recovery, and support for formation of healthy scar and connective tissue. All licensed naturopathic physicians have been well trained in the support of surgical patients, and many have their favorite nutritional, botanical and homeopathic regimens. In addition to the usual treatments, several specific things are important to keep in mind when dealing with cancer patients. Most important is that these patients may already be quite weakened or debilitated by their disease or their previous treatments and may therefore need more aggressive support than one usually provides. A second concern when dealing with surgery in cancer patients is the potential for spread of tumor cells during the perioperative period. Several studies have shown that patients with no tumor cells detectable in circulation before surgery frequently have detectable levels of micrometastases in the general circulation after surgiThis means that one or more cal removal of the of those circulating cells can attach to a new site, penetrate the basement membrane, and begin to grow into a new tumor. This is one of the reasons that adjuvant chemotherapy is given, since it is impossible to predict with 100%certainty that every single tumor cell has been removed by surgery alone. To reduce the potential for the spread of micrometastases, one can use several natural agents including fractionated citrus pectin, larch arabinogaledins, fish oils, and proteolytic enzymes.

Natural Medicine Support for Surgery Fractionated Citrus Pectin Fractionated citrus pectin (FCP), also known as modified citrus pectin (MCP), is a complex of polysaccharides derived from seeds and skins of citrus fruits.The pectin fractions are rich in galactose residues with the ability to bind to receptors on tumor cells known as galactan 3 receptors. These receptors normally enable tumor cells to attach to each other and to healthy tissues, assisting the metastatic process. By binding to the galactan 3 receptors, MCP has been shown to significantlyreduce the aggregation of cancer cells and the adhesion of prostate, breast, and melanoma cells to healthy epithelium. Fractionation of the pectin molecules breaks them down into the correct size to specifically bind to galactan 3 receptors. Whole pectins from fruits and vegetables are less efficient at this process due to their large molecular sue. All cancer patients are strongly advised to use FCP preoperatively and postoperatively in order to minimize the possibility of tumor cell adhesion. One situation where this is most advisable is during biopsy procedures. Disturbance of the tumor bed during the biopsy may allow dissemination of a previously localized tumor, and it is desirable to do everythmg possible to avoid this.

Naturopathic Support

General Preo erative Guidelines (Begin 2 Wee s Presurgery)

E

Patients should be advised to avoid the following: Alcohol Recreational drugs Tobacco Sugar Fried foods Anything capable of causing increased bleeding such as aspirin, Ginkgo biloba, high doses of garlic, and high doses of fish oil Use caution with any drugs or herbs that might react with anesthesia including kava, Hypericurn, and valerian. These should be discontinued at least 5 days before surgery unless there is a pressing need for their continuation. Caffeine should be tapered slowly to avoid severe withdrawal headaches while in the hospital. Patients should be advised to increase the following: Fiber Protein (1to 2 g/kg body weight) Vegetables Fresh fruit Fluids Essential fatty acids (EFAs) Probiotic agents Vitamin C with bioflavonoids Some specific suggested doses for several nutrients that I regularly use are included as examples (Box 51-1). This is not to suggest that other nutrients may not be equally helpful.

Postoperative Nutrition Nutritional support may be resumed as soon as the patient can consume foods. The patient should not be started on vitamins or herbs if he or she can receive nothing by mouth (non per os, NPO). This means the patient should not be consuming any foods. Once patients can consume liquids, herbal teas and homeopathic remedies can be added, and once patients are allowed foods without restriction, they may also resume all indicated medications. The naturopathic physician must be aware of all prescription medications the patient is taking and verify that there are no adverse interactions between the natural medications and the prescription items. Multiple sources of information on drug-nutrient interactions are available, such as The A-Z Guide to Drug-Nutrient Interactions by Steve Austin and colleagues. Several websites now have extensive lists of the specific cytochrome p450 enzyme families and drugs metabolized via those pathways. One excellent site is http://medicine.iupui.edu/flockhart/ By comparing clearance pathways for current medications,

Syndromes and Special Topics

Fractionated citrus pectin 6 g bid (to inhibit micrometastases). Gotu kola to reduce adhesions, three cups tea daily. High-potency multivitamin. Vitamin A (25,000-50,000 IU/day) (5000 in pregnancy) to support healing. Vitamin C 2000-5000 mg daily. Vitamin C promotes healing, supports immunity, and helps to build strong collagen. Milk thistle is a hepatoprotective agent included in the protocol to support hepatic clearance of anesthetic agents, as well as the multiple other medications often prescribed during perioperative hospitalizations. Typical dosage is 200 mg of standardized extract bid. Zinc (60 mg/day) speeds healing, localizes to healing tissues, and is most active in the second phase of healing.'lg A study of 10 random healthy young men receiving surgical excision of pilonidal cysts showed zinc supplementation sped up healing time almost 300% in the zinc group over the control group.llg B vitamins (50-100 mg) are generally included in the multivitamin formula. Immune support as desired to reduce probability of infection, including hospital-acquired respiratory infections. Protein powder or free-form glutamine and arginine supplementation have been shown to speed postoperative recovery and promote protein synthesis necessary for collagen formation. Glutamine supplementation also reduced total hospital costs, rates of infection, and nitrogen balance in bone marrow transplant patients.llg Arnica and Traumeel are two homeopathic remedies that have been traditionally used to speed recovery from injury or trauma. Although no studies have evaluated the effectiveness of these remedies, their long history of use, low cost, and apparent clinical benefit justify their addition to a postsurgicalsupport protocol.

one can predict the likelihood of negative interactions and avoid those combinations. Continue all presurgical support medications for at least 2 weeks postoperatively or until the patient has fully recovered. Particularly important at this time is the continued use of the modified/fractionated citrus pectin in order to inhibit aggregation and attachment of any tumor cells that might have been released into circulation during the surgical procedure. This product should be continued for 3 to 6 months afterward whenever possible. Additional nutrients that may be added postoperatively include the following: Vitamin E to reduce the risks of thromboses and adhesions Bromelain to reduce inflammation, pain, and the risk of thrombophlebitis Protein drinks or smoothies to provide easily assimilated amino acids necessary for tissue repair and collagen formation The patient should be encouraged to ambulate as soon as possible in order to reduce the risk of blood clots, constipation, and muscle atrophy. Patients should also

be encouraged to return home as soon as possible in order to reduce the risks of hospital-acquired infections, sleep disruptions, and medication errors that can occur in busy hospitals. Conversely, if patients feel something is not right, they should not leave the hospital just because they have reached some statistical average-stay length. It is better to remain an extra 1or 2 days until all infections or problems are resolved than to go home early, have a complication, and then spend additional days or weeks in intensive care dealing with that problem. Patients should report any unusual symptoms such as fever, swelling, and excessive pain. Although hospital stays are generally limited according to diagnostic codes, attending doctors can override these guidelines for medical reasons or complications.

CHEMOTHERAPY AND BIOLOGIC RESPONSE MODIFIERS Chemotherapy is the use of chemical agents that affect rapidly dividing cells. Technically, this category includes both cytotoxic therapies and biologic response modifiers such as hormones and vaccines. For clarity this group is divided into two sections: chemotherapy agents and biologic response modifiers.

Chemotherapy Agents Chemotherapy agents are developed for their toxicity to rapidly dividing cells. This damage ultimately leads to cell death through apoptosis. Unfortunately, most chemotherapy drugs cannot distinguish between cancer cells and normal cells and thus attack any rapidly dividing cell, including healthy cells in the bone marrow, hair follicles, and lining of the gastrointestinal (GI) tract. This inability to distinguish between cancer and healthy cells produces most of the side effects associated with chemotherapy. Chemotherapy as it is currently practiced began in the late 1940s, after World War 11. Someone made the observation that mustard gas caused bone marrow suppression and that this effect might be used therapeutically in a disease marked by hyperactive bone marrow, such as leukemias. Over time, newer agents known as antimetabolites and akylating agents were added and the role of chemotherapy gradually evolved from that of an experimental procedure to a standard of care. Today about 50 chemotherapy agents are commonly used, and new agents are approved on a regular basis. Chemotherapy has enabled the high likelihood of cure for several cancers including testicular cancer, some forms of childhood leukemia, Hodgkin's disease, some non-Hodgkin lymphomas, and some cases of ovarian cancer. Unfortunately, for many of the more common cancers such as breast, prostate, colon, and lung cancers, chemotherapy has had a more limited success. This is

Cancer-Integrated Naturopathic Support due to the high frequency of side effects limiting dosage and the fact that many cancer cell types begin to develop drug resistance after multiple courses of treatment, eventually no longer responding to available agents.

Clinical Uses of Chemotherapy Chemotherapy is used clinically in a number of situations with different objectives. These include the following: 1.Neoudjuvunt treatment is the use of chemotherapy before other treatments such as surgery or radiation. The goal in this situation is to shrink a tumor, making it more easily treatable with less extensive surgery or radiation, thus reducing the surgical mutilation or long-term postradiation complications. Examples of disease that receive this type of treatment are breast cancers, some rectal cancers, bladder cancer, and esophageal cancer. 2. Adjuvant treatment is chemotherapy used after control of visible tumor with treatments such as surgery or radiation. The goal in adjuvant treatment is to destroy any undetectable cancer cells and reduce the likelihood of recurrence of the disease. Conditions where this type of chemotherapy is commonly used include breast cancer and colon cancer. 3. Second-line chemotherapy is treatment given on evidence of a tumor recurrence. Treatment at this time is still generally attempting to put the patient into remission, but generally uses agents different from the first time the tumor was treated, on the presumption that frequently the remaining cells have developed resistance to the first agents. 4.Pulliu tive treatment is chemotherapy given with the intention to reduce symptoms such as pain by temporarily shrinking a tumor that is pressing on a vital organ or nerve. Palliative treatment is not intended to cure a patient. In some cases it may extend life for a short period, but the primary goal is improving quality of life by reducing pain or obstruction. 5. High-dose chemotherapy is given with the intention of delivering enough chemotherapy to kill all cancer cells. Unfortunately, the side effect is loss or complete destruction of bone marrow capacity as well, and the patient needs some form of "rescue" therapy, either a bone marrow transplant or a stem cell transplant. High-dose chemotherapy is generally used in hematologic malignancies such as leukemia and multiple myeloma or in aggressive cancers such as advanced breast cancer. The study of bone marrow transplant and stem cell transplant is beyond the scope of this chapter.

Actions of Chemotherapeutic Drugs Chemotherapeutic agents can be divided into various subcategories, but all tend to work in one of two general manners. They are either cytotoxic, meaning they are intended to kill all rapidly dividing cells, or cytostatic,

meaning they slow cell division but do not necessarily cause cell death. Some agents have other secondary effects such as being antiangiogenic in lower dosages. Chemotherapy is usually given in combinations of two or more agents in order to take advantage of differences in metabolism or actions for particular tumor types. In general, chemotherapy is also given in cycles that consist of a specific number of infusions followed by a rest period. The number and timing of the infusions vary widely with the type of agent being used, as well as the type of tumor and health of the patient. The specifics are determined by the oncologist in each case.

Families of Chemotherapy Drugs Alkylating Agents and Platinum Compounds Alkylating agents substitute an alkyl group for hydrogen to produce defects in DNA. The effects are similar in many ways to the DNA damage caused by radiation. Common members of this group include Cisplatin, Carboplatin, and Cyclophosphamide.

Antitumor Antibiotics Antitumor antibiotics bind between DNA base pairs interfering with normal mitosis. Many also generate free radicals. Common examples of this group include Adriamycin, Mitomycin, and Bleomycin.

Antimetabolites Antimetabolites substitute structural analogs of normal metabolites, thus interfering with replication of DNA. Common examples include Methotrexate (MTX), Fluorouracil, and Hydroxyurea.

Microtubule and Chromatin Inhibitors Microtubule inhibitors and topoisomerase inhibitors work by interfering with the normal intracellular mechanisms necessary for mitosis. They work by blocking either topoisomerase enzymes used in DNA replication or binding to tubulin and blocking assembly or disassembly of microtubules necessary for mitosis. Examples of microtubule inhibitors include Vinblastine, Vinorelbine, Taxol, and Taxotere. Examples of topoisomerase inhibitors include CPT-11 and Etoposide.

Biologic Response Modifiers Biologic response modifiers comprise a large, diverse group of medications with many actions. In general, the group can be divided into several subgroups including antiangiogenic agents, immune modulators, hormones and hormone blockers, and "new breed" agents.

Antiangiogenic Antiangiogenic agents inhibit the growth of new blood vessels. Since tumors require increased vasculature to

support their high metabolic rate, agents that prevent the development of blood vessels theoretically inhibit the ability of tumors to grow. Examples of this include Thalidomide, Angiostatin, Endostatin, Erbitux, Avastin, and matrix metalloproteinase inhibitors. Many other agents, including taxaine-based chemotherapy at low doses, can also have a weak antiangiogenic action.

Alkylating Agents Nitrogen mustard

Chlorambucil, Cyclophosphamide, estramustine, Ifosphamide, Melphalan Carboplatin, Cisplatin Carmustine, Lomustine

Metal salts Nitrosurea

Immune Response Modulators Immune modulators, vaccines, and monoclonal antibodies all work by increasing the immune response directly or indirectly. This category includes commonly used agents like interferon and interleukins, as well as newer agents such as Herceptin. Included in this group for simplicity are various bone marrow-stimulating agents such as Neupogen, Epogen, and Leukine, although these could also be included in the group of hormones and hormone inhibitors.

Antibiotics

Adriamycin, Doxil, Epirubicin, Mitomycin, Bleomycin

Antimetabolites Antifolates Pyrimidine analogs

Methotrexate, Trimetrexate Fluorouracil, Fluorodeoxyuridine, Xeloda Thioguanine, Mercaptopurine, fludarabine

Purine analogs

Microtubule and Chromatin Inhibitors

Hormones and Hormone Inhibitors Hormones and hormone inhibitors are used to manipulate the signals that regulate cell growth. A well-known example of a hormone inhibitor is Tamoxifen, which blocks estrogen receptors to slow growth of estrogen receptor-positive breast cancer. Lupron is commonly used in prostate cancer to inhibit the production of testosterone. An example of a hormone used therapeutically is prednisone in the chemotherapy combination of Cyclophosphamide, Doxoeubicin HCL, Oncovin, and Prednisone, used for hematologic malignancies, or the use of Megace to stimulate the appetites of advanced cancer patients.

New-Breed Chemotherapy Agents These newer agents (e.g., Gleevec, Thalidomine, and photosensitizing agentsI2)work by various methods. For some, like Gleevec, their strength is the specificity of their action, which limits the majority of their effects to the target tumor cells. Others, such as photosensitizing agents, have less toxicity than most systemic chemotherapy agents and allow for specific activation in the areas desired with a laser light source (Box 51-2).

Modes of Administration Most chemotherapy agents are given intravenously, although a few are oral agents (e.g., Xeloda, Tamoxifen) or intramuscular agents (e.g., Lupron). The intravenously administered agents can be given in various schedules. Typically drugs are given in "cycles"; the chemotherapy is given for several sessions, and then the patient takes a drug holiday to recover. The most common protocol is an intravenous (IV)bolus of chemotherapy once every 3 weeks, but some agents can also be administered daily for up to a week or given in a 24-hour continuous infusion pump. Some more progressive oncologistsare using "fractionated chemotherapy," in which the total dose is

Mitotic inhibitors Microtubule stabilizer Topoisomerase I inhibitors Topoisomerase II inhibitors

Vinblastine, Vincristine, Vinorelbine Pactitaxel, Docetaxel Irinotecan,Topotecan Etoposide, Teniposide

Biologic Response Modifiers Hormones

Dexamethasone, Prednisone, Diethylstilbestrol, Megestrol acetate Lupron, Tamoxifen, Raloxifene, Flutamide, Bicalutamide Anastrazole, Letrozole, Aminoglutethimide Interferon, Interleukin-2, Neupogen, Epogen, Neulasta, Leukovorin, Leukine Herceptin, Rituxan, Bexar, Melacine

Hormone antagonists Aromatase inhibitors Immune modulators

Monoclonal antibodies and vaccines ~

_

_

~

"fractionated" or broken into multiple smaller doses given more frequently, such as once weekly. Using this method, patients generally have fewer side effects and equal or better tumor responses.13 The length of treatment depends on many variables including the subtype of tumor, its stage and grade at the time of diagnosis (more aggressive tumors are generally treated longer and with more agents), and the type of chemotherapy being used. Another important variable is how well the patient tolerates treatment without excessive side effects such as bone marrow depression. An interesting variable currently being explored is chronotherapy, the study of how timing the dose of chemotherapy during the 24-hour circadian rhythm affects response and side effects. For example, chemotherapy given early in the day seems to cause a smaller drop in white blood cells. Since breast cancer cells tend to be more active in the evening, chemotherapy given at that time might prove to be more effective with fewer side effects than the same treatment given at another time.I4 One problem with chronotherapy is the logistical

Cancer-Integrated difficulty of administering different agents at different times of day. This would necessitate having treatment centers open round the clock, with all the staffing issues attendant on such a schedule. For this reason, and the fact that the field of chronotherapy is still young with much additional research necessary, it is likely to be a long time before conventional oncologists incorporate this information into standard treatment protocols.

Side Effects of Chemotherapy These vary depending on the chemotherapy agent used, the timing and dosage administered, and what protective measures are available and used to reduce side effects. Individual factors including the general health of the patient, efficiency of liver enzymes, and the amount of prior treatment (which can cause bone marrow suppression) also affect the degree of side effects. Each chemotherapy agent has specific side effects that occur more commonly. For example, Taxol often causes significant myalgia and arthralgia, whereas a similar drug, Taxotere, causes fewer of those symptoms but more bone marrow depression. Common short-term side effects caused by chemotherapy agents are listed in Box 51-3. Long-term side effects are those that persist after completion of chemotherapy. Late side effects are those that may occur months to years after treatment as a result of the chemotherapy. Some potential long-term problems are listed in Box 51-4.

Chemotherapy ResistanceTesting A new and promising option, which is still in early developmental stages, is the testing of tumor tissue for resistance to common chemotherapeutic agents. Currently, chemotherapy is given to patients on the basis of results of treatment to large groups of patients with the same type of tumor, assuming that all similar tumors are likely to respond to the same chemotherapy agents. Whether an individual patient's tumor is responsive to a particular agent is determined by measuring shrinkage of visible tumors, or, if there is no measurable tumor after surgery, is assumed based on prior studies. Unfortunately, a large percentage of tumors are resistant to one or more common

Nausedvomiting Mucositis Diarrhea Fatigue Hair loss Anemia Leucopenia Thrombocytopenia Bruising Cardiac damage

Neuropathy Pneumonitis Nephropathy Tinnitus Infections "Chemo brain" Hand-foot syndrome Alterations of taste and smell Anorexia

Naturopathic Support

Development of tumor resistance to chemotherapy Increased risk of secondary cancers Increased risk of leukernidlymphoma Infertility and premature menopause Persistent unexplained fatigue Persistent bone marrow suppression or myelodysplasia Persistent "chemo brain" or short-term memory dysfunction

chemotherapy agents, leading to needless side effects and delay of treatment with an appropriately effective agent. In resistance testing a small amount of the fresh, unpreserved tumor tissue taken from the patient during biopsy or surgery is sent to a research laboratory that grows cell cultures from the sample and then tests the patient's cell lines for resistance to chemotherapeutic agents typically used for that tumor type. The underlying assumption is that if concentrations of chemotherapy much higher than those achievable in the body do not slow tumor growth in vitro, then they are unlikely to do so in the patient and there is little reason to expose the patient to the risks, expense, and side effects of treatment with that particular chemotherapy agent. This allows oncologists to make decisions about therapies most likely to benefit the patient. The technique of chemotherapy resistance testing is still controversial but makes sense and can help avoid the cost and potential medical complicationsof treatment with a toxic agent that is unlikely to provide any benefit. Chemotherapy resistance testing is not yet widely available, but at least three laboratories are currently doing some variation of the procedure. In order to do the test, the laboratory must receive fresh living tumor tissue collected at the time of biopsy and shipped via overnight express on dry ice. The test, which costs approximately $2500, is not generally covered by insurance companies at this time, but the potential benefit of knowing that one's treatment is appropriate for one's specific cancer seems to justdy the expense if it all possible. An emerging technique is the use of genetic testing of the tumor tissue to determine specific characteristics that may indicate the best therapeutic agents, as well as predict the risk of recurrence more accurately to help in determining who might not need any chemotherapy at all.

General Recommendations for Chemotherapy To Improve Effectiveness Although chemotherapy can be life saving at times, it has many limitations. Tumors sometimes do not respond completely or respond at first but later become resistant to chemotherapy. Some researchers question whether medicine has really made any significant progress against the most common cancers that affect Ameri~ans.'~ Other "breakthroughs" may add only a few months to

actual survival. For example, when the chemotherapy drug Gemzar was introduced, it was hailed as a breakthrough in the treatment of pancreatic cancer. In reality, the increases in survival were modest, generally adding 3 months or less to overall survival compared with current therapies.16 A metaanalysis of studies of breast cancer treatment has found that for most earlystage patients with minimally aggressive cancers, chemotherapy adds 10.3months of relapse-free survival and 5.4 months of overall survival for premenopausal women and 6.8 months relapse-free survival with 2.9 months overall survival for postmenopausal women." Obviously there is a need to improve the effectiveness of chemotherapy, leading to more sigruficant changes in survival times. Fortunately, there are ways to improve the potential benefits from standard treatment. In addition to appropriate timing and dosage schedules, one can select specific nutrients to enhance specific chemotherapy agents. These nutrients are best taken for at least 2 weeks before beginning chemotherapy until completion of treatment. They may have various actions including normalizing cell division, increasing apoptosis, increasing uptake of chemotherapy into cells, reducing development of drug resistance, and stimulating normal cell differentiation. The broad range of chemotherapy agents and the even broader range of potential natural support makes an exhaustive review of this topic impossible in a summary chapter. However, a few examples can illustrate the potential benefits of using this approach.

Melatonin A study of 250 stage 4 cancer patients with various tumor types who were treated with conventional therapies or with the same therapies adding 20 mg of melatonin nightly found that the response rates to chemotherapy were doubled and the survival at 1year was doubled in those taking the melatonin. Moreover, the addition of melatonin to the chemotherapy regimen reduced the incidence of toxicity symptoms such as thrombocytopenia, neurotoxicity, and cardiotoxicity.'8 Green Tea In a similar fashion, the simple addition of green tea enhanced 2.5-fold the inhibitory effects of Adriamycin against Ehrlich ascites tumors in mice. Interestingly, this effect was seen only in tumor cells and not the healthy cells.19 These studies illustrate that although chemotherapy alone has some benefit, the addition of appropriate nutrients to the protocol can significantly increase therapeutic efficacy.

To Reduce Side Effects Due to variations in their mode of action and path of elimination, each chemotherapy agent can cause damage to certain organs. For example, Adriamycin has been

implicated in causing severe cardiac damage at high doses, and even lower doses appear to affect heart function negatively.20Taxol can cause neuropathy and myalgias. Taxotere causes less neuropathy but greater marrow suppression. Cisplatin can cause neuropathy and cystitis. Each of these side effects can be avoided or minimized with nutritional support. Using the appropriate support throughout the patient's treatment is particularly important because, in some cases, once the damage has occurred, it is irreversible. Certain general measures should be emphasized in all cases in order to reduce side effects from chemotherapy. Some, such as encouraging the patient to stay adequately hydrated and eating a healthy diet, are basic and obvious. Even a simple, broad-based, high-potency multiple vitamin, along with good diet, goes a long way toward reducing complications.Finding open-minded oncologists who support the patient in making wise dietary and supplement choices makes the job of supporting patients easier.

Specific Recommendations for Chemotherapy Entire books are written on the actions, effects, and side effects of chemotherapy agents. It is not the intention here to replace a thorough understanding and knowledge of that information. Rather, the following highlights a few of the more commonly used agents and demonstrates the type of information that must be understood about any agent before treating a patient receiving that drug. The fact that some drugs used in combination may have contradictory requirements is noteworthy. In these cases, contraindications are the trump card and nutrients contraindicated by any of the agents in a chemotherapy protocol should be avoided. For example, in the commonly used combination CMF (Cytoxan, MTX, and fluorouracil [5-FU]) for breast cancer, the use of additional folate could support the actions of Cytoxan but might potentially interfere with the benefits of MTX. Therefore high doses of folate are not recommended at this time. The selection of appropriate nutrients and botanicals for support during chemotherapy is a complex discussion. Each case must be evaluated on the basis of many factors, and the full complexity cannot be covered here. Instead, presented here is a basic support protocol appropriate for virtually all outpatient chemotherapy treatments, as well as a discussion of specific nutrients to consider adding for the most common chemotherapy agents used today. General recommendations safe for all chemotherapy regimens include a high-potency multivitamin (Box 51-5), fish oil capsules, melatonin, green tea, and some form of immune support. See later for further details on basic support.

Melatonin Melatonin is a pineal hormone that is secreted in response to darkness. It is thought to serve as a synchronizer of

Cancer-Integrated

Multivitamin Vitamin A: 5000 IU Mixed natural carotenoids: 10,000-25,000 IU B complex: 25-50 mg Folic acid: 400-800 pg Vitamin BIZ:200-1000 pg Vitamin E succinate: 400 IU Vitamin C: 500-1000 mg Vitamin D: 400-800IU Trace minerals:full complement Calcium: 500 mg Magnesium:250 mg Melatonin 20 mg at bedtime

Vitamin C 3000-10,000 mg daily in divided doses according to bowel tolerance Fish Oils To provide 2 g total combined eicosapentaenoic acid (EPA) and

docosohexaenoic acid (DHA) daily Mushroom Extractdlmmune Support Use various immune modulators and switch them regularly to avoid downregulation of receptors. Standard doses for polysaccharide krestin mushrooms are 3 g of the extract daily. Suggested dosage for Maitake D or MD fractions is 0.5-1 mg of extract per kg body weight. Other botanical immune modulators may be used as desired. Enzymes Use pancreatic enzymes with meals and mixed enteric-coated enzymes between meals. Green l e a Capsules and beverages should total the equivalent of 5-10 cups green tea daily. Caffeinated form is preferred if caffeine is tolerated, as there is some possibility of removing the desirable EGCG in the decaffeinating process. Whey Protein Shake with Fruit Daily This is a source of easily assimilated protein and amino acids, particularly glutamine.

biologic rhythms. Melatonin has been shown to slow the development of a wide variety of tumor types including breast, endometrial, non-small cell lung, hepatocellular, renal, colon, and prostate cancers. For a full discussion of the topic see Melatonin after Four Low levels of melatonin have been associated with increased risks of cancers including breast cancer.22Multiple studies have confirmed the antiproliferative action of melatonin when given alone and when combined with chemotherapy or radiation. The actions have been attributed to the fact that melatonin is a potent antioxidant; may inhibit the action of hormones such as prolactin, estrogen, and

Naturopathic Support

testosterone; and may inhibit the transformation of linoleic acid into tumor growth-promoting metabol i t e ~ ? ~ Melatonin ,*~ used alone in late-stage patients refractory to other treatments has led to increased survival and improved well-being in more than one third of subjects.= Addition of melatonin to hormonal therapy protocols has improved responses, even in some cases that were no longer responsive to the hormonal treatments aloneF6 Melatonin added to conventional treatment with doxorubicin reduced the drug’s known cardiotoxic effects and at the same time produced better responses as measured by long-term ~urvival.~’ A study mentioned earlier in this chapter evaluated the efficacy of chemotherapy in 250 advanced cancer patients with various tumor types. Half of the group received appropriate conventional chemotherapy, and half received appropriate chemotherapy with the addition of 20 mg of melatonin. Tumor response rates were observed in 42 of 124patients receiving melatonin versus in 19 of 126 receiving chemotherapy without melatonin. Survival responses were equally impressive:63 of 124patients receiving melatonin plus chemotherapy were alive at 1 year versus 29 of 126 in the chemotherapy group. Melatonin was not a cure-all, but it essentially doubled responses to conventional treatment and doubled survival.28 Melatonin is appropriate in almost all solid tumor types, but there are a few safety considerations to keep in mind. Research on the safety or efficacy in hematologic malignancies is scant, and some of what is available suggests negative outcomes when using melatonin in malignancies like leukemia, lymphoma, and myeloma.29 At this time melatonin is not recommended for these tumor types. The majority of melatonin research has used 20 mg at bedtime, and this is the suggested dosing schedule mtil further research is done on the question of melatonin given at other times of day. Finally, if a patient is taking a selective serotonin reuptake inhibitor-type medication (e.g., Zoloft, P a d , Celexa), lower doses of melatonin should be used to avoid any potential interactions or development of serotonin syndrome, although this is unlikely.

Green Tea Green tea, particularly the polyphenol components, inhibits the initiation, promotion, and progression stages of carcinogenesis. The cancer preventive aspects of green tea are well documented and are not reviewed here.30,31 Of more interest in this situation are the effects of green tea in promoting cell cycle arrest and even a p o p t ~ s i s . ~ ~ Recall that apoptosis is critical to adequate antitumor response to chemotherapeutic agents. When given with chemotherapy, green tea extracts have shown the ability to reduce drug resistance and increase the concentration of chemotherapy agents within tumor ~ e l l s . 3 ~ , ~ Green tea catechins have also been shown to inhibit angiogenesis, the process of blood vessel growth that

Syndromes and Special Topics

is crucial for tumor growth and m e t a ~ t a s i sGreen . ~ ~ tea polyphenols have a profound growth inhibitory effect on cancer cells without inhibiting the growth of healthy cells. This differential effect is thought to be due to the fact that differential modulation of genes regulating cell signaling may be involved, leading to death in cancer cells.%

Multiple Vitamin A high-potency multiple vitamin is essential to provide additional nutritional support during cancer therapy. Patients have multiple physiologic stresses including the demands of surgery, chemotherapy and radiation, difficulty eating due to nausea or fatigue, and increased susceptibility to infection caused by leukopenia. Maintaining adequate levels of nutrients not only improves overall patient health but can improve responses to chemotherapy. For example, simply increasing levels of folic acid in rats improved response to cyclophosphamide from 53% to 97%, with 5-FU from 46% to 66%, and from doxorubicin from 25% to 61%.37 The approximate parameters suggested for the multiple vitamin are listed in BOX51-5.

Eicosapentaenoic Acid/Fish Oils Fish oils are a concentrated source of omega3 fatty acids such as eicosapentaenoicacid (EPA) and docosa-hexaenoic acid (DHA). These fatty acids are important precursors to protective prostaglandins and are associated with reduced risks of numerous cancers including breast prostate and colon EPA and DHA have been demonstrated to improve levels of regulatory molecules such as bcl-2 leading to apoptosis of tumor cells in various in vitro models.41EPA and DHA improve response rates to some chemotherapy agents including Irinotecan and Doxorubicin." Fish oils in most studies have demonstrated the ability to slow, or even reverse, the wasting syndrome of advanced cancer known as cachexia. In one study, 6 g daily of EPA halted weight loss in pancreatic cancer patients who had previously been losing an average of 2 kg monthly, leading to stabilization of weight for the duration of the 12-week study period.43 Another advantage to fish oils is their well-documented ability to reduce platelet aggregation. Cancer patients are more prone to thromboses than the average person, and it has also been postulated that reduction of thromboses can inchctly reduce metastases since many micrometastases are encased in platelet aggregates, effectively masking the tumor cells from the immune system.& Flax oil is sometimes considered a vegetarian alternative to fish oils since it also contains omega3 fats. Although flax oil is beneficial in cancer, the majority of studies have used the pre-formed EPA/DHA of fish oils, the currently recommended form.

Vitamin C Vitamin C has been well documented to reduce the incidence of most cancers in h~rnans.4~ What has been hotly debated is whether vitamin C has any therapeutic effect in the treatment of cancer. Linus Pauling and Ewan Cameron reported in 1976 that high-dose ascorbic acid (typically 10 g/day via IV infusion) increased average survival of advanced cancer patients by a factor greater than 4, and for a small group of responders, survival was increased up to 20 times longer than that of controls.46 Similar results were reported by Murata and colleagues with ascorbate-treated terminal patients surviving six times longer than matched controls, with 3 of 55 terminal patients still alive after more than 4 ~ears.4~Two follow-up studies did not find similar result^,^,^^ but various methodologic differences called their results into question. Most significant was the fact that the positive studies looked at survival in terminal patients, whereas the 1985 negative study compared time to progression before starting chemotherapy rather than overall survival. Tumor cells take up vitamin C and, due to lower catalase activity, produce high levels of intracellularhydrogen peroxide. Some studies suggest that high dose ascorbic acid may have active antitumor activity,s52 but it should be noted that oral dosing is unlikely to achieve the millimolar concentrations needed to produce cytotoxic activity. Daily IV infusions of 10 to 30 g may show some benefit. This discussion is directed more to the reduction of toxicity and improvement of tumor kill when combining vitamin C with conventional therapy. Vitamin C has been shown to reduce the general toxicity and cardiotoxicity of Adriamycin with no reduction in the antitumor activity, in Vitamin C has been fact, producing a prolongation of shown to increase the tumoricidal action of Cisplatin, DTIC, Adriamycin, and Pa~litaxe1.~5~ Combined administration of vitamins C and K simultaneously potentiated the therapeutic effect of six different chemotherapy agents.% The combined use of vitamin C with chemotherapy is even more desirable when one considers all the beneficial actions of vitamin C on immune function, tissue repair, detoxification, and the fact that cancer patients are diagnosed with frank scurvy at a rate more than 10 times greater than non-cancer patients.57

Mushroom Extracts Many various botanical and nutritional agents may be useful for immune support during chemotherapy treatment. Some of the best studied are mushroom extracts include Maitake and Coriolus. Both mushrooms are high in beta-glucan rich molecules shown to support healthy immune function. Polysaccharide krestin (PSK) is an extract of the Coriolus versicolor mushroom, which has been studied in Japan since the early 1970s. When PSK was combined

Cancer-Integrated

with conventional surgery and radiation for lung cancer patients, those receiving the PSK extract had a 5-year survival of 39% for stages 1 and 2 and 22% for stage 3 versus survival of 16% for stages 1 and 2 and 5% for stage 3 without the PSK.58PSK also improved 5-year survival in gastric cancer when combined with surgery and chemotherapy, producing a 73% survival versus 60% in the control g r o ~ p . Improvements 5~ were also seen in studies looking at breast cancer, leukemia, and colorectal cancer.60In total, more than 400 studies have evaluated PSK extracts for cancer. Most studies have indicated that the primary benefit of PSK is due to immunomodulating activity, but there is also evidence that the extract may act to suppress metastases.61PSK has also been shown to reduce the development of cancer in vulnerable cell lines by protecting against oxidative stress.62 Maitake mushrooms (Grifola frondosa) have also been shown to be rich in beta-glucan molecules and to have immunostimulating activity.63Maitake extracts have the benefit of being more easily found in the United States than PSK, but overall there have been fewer studies of these products combined with conventional therapy than there have been with PSK. The two products will likely be found to be more or less equivalent in activity as further studies are completed. Maitake extracts have been shown to potentiate the activity of Carmustine against prostate cancer cells in vitro.@

Enzymes Pancreatic enzymes have been used as cancer support since the works of John Beard were published in the early 1900s. The best-known modem advocate of pancreatic enzymes for cancer therapy is Nicholas Gonzalez, MD. In an unblinded study of 10 patients with stage 2 to 4 pancreatic cancer, 81% survived for 1 year, 45% survived for 2 years, one patient survived for more than 3 years, and one was alive and well at 4 years. This is compared with a 10% typical 2-year survival with conventional chemotherapy.65 Clinical studies have compared the survival of patients when enzymes have been added to conventional chemotherapy with improved results in lung cancer, gastric cancer, ovarian cancer, colon cancer, and multiple myeloma. The results indicated fewer side effects of treatment, and most studies also demonstrated increased survival in the patients receiving the enzyme preparations.% Some studies have indicated that enzyme preparations may produce beneficial effects by their impact on production and release of cytokines such as tumor necrosis factor.67Enzymes also have antiinflammatory activity, and it is being discovered that antiinflammatory drugs inhibit the progression of cancer via multiple pathways including blockade of COX-2 and inhibition of metastases. Cancer patients often have difficulty with digestion, due to side effects of treatment, as well as the disease

Naturopathic Support

process, and in order to assure adequate assimilation of foods and supplements, some form of digestive support is desirable. When using enzymes for digestive support, they should be taken with meals; however, when using enzymes for their antiinflammatory activity, antimetastatic activity, or synergy with chemotherapy, they should be taken between meals on an empty stomach (see Box 51-5).

Recommendationsfor Specific Individual Chemotherapy Agents Each chemotherapeutic agent has a typical side effect profile, as well as certain nutrients that can enhance effectiveness while reducing undesirable side effects. Individual agents are discussed as follows with notes regarding nutrients to be considered in addition to the basic protocol mentioned earlier. Unless there is reason to give larger doses of a nutrient already mentioned, under General Recommendations, it is not repeated or discussed in this section. For a more complete resource on individual chemotherapy agents, their actions and side effects, the reader is referred to Physician’s Cancer Chemotherapy Drug Manual 2001 by Edward Chu, MD, and Vincent DeVita, Jr., MD.

Adriamycin Adriamycin (doxorubicin) is an antitumor antibiotic agent isolated from the Streptornyces spp. It inhibits DNA synthesis and RNA polymerases, as well as having a secondary action of inhibiting topoisomerase ILa Side effects include hair loss, leukopenia, nausea and vomiting, and cardiotoxicity. Evidence indicates that doxorubicin may increase the risk of secondary leukemia. The biggest concern is the potential for irreversible cardiotoxicity. When patients receive this agent, they should drink additional green tea, which has been shown to enhance 2.5-fold the inhibitory effects of doxorubicin on tumor growth by increasing the concentration of the chemotherapy agent in tumor cells, but not in healthy cells.69 Genestein also increased the antitumor effects of doxorubicin and was noted to be effective in both ER-positive cells and in ER-negative cells, which tend to be more difficult to treat.70 The most worrisome side effect of doxorubicin is cardiotoxicity.Several studies suggest this damage to be due to free radical injury. By the time symptoms manifest clinically, the damage may be irreversible.7l Fortunately, several antioxidants can protect against this damage including vitamin C, vitamin E, and Coenzyme Qlo (COQ~~).”~~ Fortuitously, several of these agents were also found to increase the beneficial effects of doxorubicin.

Cytoxan Cytoxan (cyclophosphamide)is an alkylating agent that is inactive until transformed by the p450 enzyme system into cytotoxic metabolites, which are active in all phases

Syndromes and Special Topics

of the cell cycle.75It is notable for being orally active and not requiring IV administration. Cytoxan is used in several common chemotherapy combinations for the treatment of breast and ovarian cancers, leukemias and lymphomas, and several types of sarcoma. The major side effects of cytoxan include myelosuppression, nausea and vomiting, bladder toxicity, and alopecia. There is also an increased risk of bladder cancer and acute leukemia as long-term side effects. Cytoxan also has some cardiac toxicity that can be synergistic when combined with Adriamycin, as it often is for breast cancer. Natural products of benefit with this agent include fish oils, folic acid, vitamin E, Withania sornnifera (ashwaganda), and mushroom extracts. Fish oils have been shown to enhance the antitumor efficacy of cytoxan while simultaneously exerting a protective effect against side effects, possibly due to changes in liver p450 enzyme a~tivity.’~ The benefits of folic acid with cytoxan were mentioned previously and included decreased side effects, as well as an increase of antitumor response from 53% in folate-deficient animals to 97% in folate replete rats. Vitamin E combined with cyclophosphamide produced a stronger antitumor response than the chemotherapy alone in rats with fibrosarcoma and in rats with prostate cancer.77Mushroom extracts from Coriolus versicolor have been shown to be helpful in partially reversing the immunosuppression induced by Cytoxan.78 Because of the tendency to cause cystitis, it is important to keep the patient well hydrated when taking cytoxan. Patients should consume at least 2 quarts of fluids daily while on this drug.

Cisplatin and Carboplatin Both of these platinum-based agents cause cross-linking of DNA leading to inhibition of DNA synthesis and cell replication. Cisplatin is used primarily for ovarian cancer and testicular cancer. Its use is limited by the side effect profile and higher degree of toxicity, particularly nephrotoxicity, neurotoxicity, and myelosuppression. Carboplatin is used for similar treatments but is generally better tolerated, especially when given in lower weekly doses. One of the best studied natural supports during treatment with platinum agents is the concurrent use of glutathione. Combining IV glutathione immediately before administration of cisplatin was shown to reduce side effects including nephrotoxicity, neurotoxicity, and myelosuppression without reducing the effectiveness of the chemotherapy against tumors. In fact, most studies showed slight trends toward increased response to chemotherapy. In some cases this was attributed to the fact that dose reductions due to side effects were not required, and therefore patients received a larger total cumulative dose.7941Similar results have recently been

published demonstrating similar benefits with a newer platinum compound, Oxiliplatin, which was recently approved for use in the United States. Simultaneous coadministration of selenium with cisplatin allowed for higher doses with less toxicity and a higher therapeutic i n d e ~ .Milk ~ ~ ,thistle ~ ~ extracts can also reduce the toxicity of cisplatin but should probably be avoided on the day of treatment to prevent too rapid clearance of the chemotherapy. Vitamin A has shown a synergistic effect when combined with cisplatin for head and neck cancers. Vitamin C also improves the antineoplastic activity of cisplatin, as does vitamin E.&l Spleen extracts used in combination with cisplatin have demonstrated a stabilizing effect on white blood cells, body weight, and fatigue.85PSK enhanced cytotoxicity of cisplatin against human ovarian cancer cells, but not normal cells.%

Fluorouracil 5-FU and related drugs, capecitabine (Xeloda), and fluorodeoxyuridine (FUDR) are pyrimidine analog antimetabolites. 5-FU is primarily used for colorectal cancers and as part of the combination of cytoxan, MTX, and 5-FU used for breast cancers. It is also used to treat pancreatic cancer, ovarian cancer, head and neck cancers, and basal cell cancers of the skin. Toxicity and side effects include mucositis (mouth sores), diarrhea, and bone marrow depression.An unusual symptom is hand-foot syndrome, which is characterized by redness, swelling, and numbness in the hands and feet. Neurologic symptoms may include confusion and seizures. 5-FU can also cause inflammation and blockage of the tear ducts and chronic conjunctivitis. It can cause cardiac changes, although not as frequently or severely as those from Adriamycin. Vitamin E has been demonstrated to increase the antitumor activity of 5FU against colorectal cancer both in vitro and in vivo by causing an upregulation of the proapoptotic enzyme ~ 2 1 . Other 8 ~ studies have suggested an augmentation of the proapoptotic protein ”bax” in response to vitamin E combined with 5-FU.88Vitamin B6 at 100 mg daily has shown some benefit in reducing the incidence and severity of hand-foot syndrome.89Other studies have used upto 100 mg B6 three times daily with benefit.

Methotrexate MTX is an antifolate analog that works via inhibition of the enzyme dihydrofolate reductase, blocking the conversion of folic acid into its active metabolite folinic acid. Without adequate folinic acid, cells cannot duplicate their DNA. Folic acid in the levels of a multivitamin do not interfere with the action of this drug but higher doses should be avoided. The primary toxicity of MTX is myelosuppression. Other toxic symptoms include mucositis, which can be

Cancer-Integrated

severe enough to limit dosage. Nausea and vomiting are dose dependent. MTX can lead to acute renal failure, and both liver enzymes and kidney functions must be monitored regularly during treatment. Less common side effects include lung inflammation or pneumonitis and severe headaches. Patients can also develop skin rashes, itching, photosensitivity, and hyperpigmentation. An unusual condition known as "radiation recall" can occur where areas previously irradiated again develop redness and pain. Both men and women can experience gonadal failure after treatment with MTX. Several interactions with common medications should be avoided while receiving treatment with MTX. The first is to avoid aspirin and other antiinflammatory medications. These medications can reduce the renal elimination of MTX leading to higher blood levels and higher toxicity. Penicillin can also produce a similar effect and should be avoided during treatment. The amino acid glutamine has been shown to increase the intratumoral levels of MTX in rats. This may be due to the effect of glutamine in decreasing the intratumor levels of glutathione, making tumors more susceptible to the MlX90Glutamine is a primary nutrient for enterocytes lining the GI tract, and using glutamine during chemotherapy appears to reduce incidence of mucositis and diarrhea caused by the MTX. VitaminA has also been demonstrated in animal studies to limit the GI damage from MTX without reducing the antitumor benefit of the drug?*

Taxol/Taxotere The taxanes are semisynthetic isolates from Yew species (Pacificyew for paclitaxel [Taxol] and European yew for docetaxel [Taxotere]). Both drugs bind microtubules, resulting in inhibition of mitosis and cell division. First approved for ovarian cancer, taxanes are now used for a wide variety of tumor types including breast, lung, gastric, bladder, prostate, esophageal, and head and neck cancers. Both agents can also be used as radiosensitizers, making tumors more sensitive to radiotherapies. Side effects include hypersensitivity reactions, neuropathy, arthralgia and myalgias, mucositis, onycholysis, and myelosuppression. Taxol tends to cause greater arthralgia and myalgia, whereas Taxotere causes greater myelosuppression. Nutrients helpful with these agents include vitamin C, glutamine, and EFAs. Vitamin C has been demonstrated in vitro to improve the response to Taxol in a partially synergistic manner.84Glutamine 10 g three times a day is helpful in reducing the myalgias and neuropathy associated with the taxanes?2 EFAs including gamma linolenic acid, alpha linolenic acid, EPA, and DHA all enhanced the cytotoxic activity of Taxol against human breast cancer cells in an in vitro model. Of these EFAs, GLA was the most active and linoleic acid was found to have no benefit?3

Naturopathic Support

Many other nutrients are potentially beneficial with the agents mentioned, as well as many other chemotherapy agents, but space limitations prohibit more extensive discussion of this topic.

RADIATION Along with surgery and chemotherapy, radiation completes the triumvirate of standard therapies for most cancers. Radiation works by causing damage to the DNA of cells. In most cases this does not cause immediate cell death but leads to apoptosis the next time the cell tries to divide. The effects of radiation are more localized than that of chemotherapy. This can be either an advantage or a disadvantage depending on the situation. It does limit side effects to the region being radiated but misses any malignant cells outside the field of treatment. Radiation can be used as primary therapy to shrink tumors or postoperatively to limit survival of any malignant cells potentially missed by the surgical procedure. Radiation can also be used for management of metastatic lesions and for palliative reduction of tumors that are causing symptoms.

Types of Radiation Therapy Radiation therapy generally refers to the use of ionizing radiation from a machine source or a radioactive isotope, but in the broadest sense, the term could also be used to refer to other forms of radiant energy such as photodynamic therapy and hyperthermia treatments. This section deals only with forms of ionizing radiation. Ionizing radiation generated from machine sources can be divided into several types including photon radiation, which has no mass and no charge, and particle radiation including neutron therapy and proton therapy. Neutrons have mass but no charge, while protons have mass and a positive charge. Particle radiation has some advantages including the ability to be effective even in low-oxygen environments.

Machine-Generated Beams Machine-generated beams come in several forms including two-dimensional (2-D) external beam therapy, threedimensional (3-D)conformal therapy, intensity-modulated radiation therapy (IMRT), and tomotherapy. The degree of sophistication and control of field shape increases with each of the listed types. The 2-D external beam is the oldest form and causes the most collateral damage to healthy tissues. The 3-D conformal therapy and IMRT use more angles of treatment and field-shaping collimators to reduce radiation exposure of healthy tissues. The newest and most sophisticated form of treatment is tomotherapy, in which the field and dose are administered according to resultsof a simultaneous CT scan, thus permitting a degree of targeting accuracy impossible to achieve until recently.

Another precise form of radiation therapy is gamma knife surgery, used primarily for intracranial neurologic lesions.

Brachytherapy Brachytherapy is the use of localized radiation sources placed within the tumor. This may include permanent placement of seeds such as is now common in prostate cancer or temporary placement of a high-intensity source within a tumor or operative site. Examples include highdose brachytherapy for the prostate, in which the radioactive seeds are placed within the prostate for short periods, or the newer procedure of brachytherapy within a lumpectomy site immediately after surgery. In both cases the advantage is that a precise dose can be administered to the areas of greatest concern, while less radiation reaches healthy tissue.

Radioimmunotherapy Radioimmunotherapy, the final form of radioactive treatment, includes the use of radioactive moieties linked to a monoclonal antibody, which are then injected into the bloodstream. The monoclonal antibody targets the appropriate abnormal tissue marker and delivers the bulk of the dose to specific tumor tissues while sparing most other tissues. An example of this therapy is Bexar, which uses radioactively linked monoclonal antibodies to treat lymphoma. A similar treatment, without the monoclonal antibodies, is the use of radioactive iodine11, which is used to treat thyroid cancer. Since most of the iodine is taken up by the thyroid, the majority of the radioactivity is also delivered to the tumor.

Side Effects of Radiation Therapy In general, most patients find radiation therapy more tolerable than chemotherapy, but the type and extent of side effects is quite variable. Factors affecting this include the location of the tumor, the size of the treatment field (and the organs or tissues within the field), prior or concurrent chemotherapy (which may act as a radiosensitizer), and the presence or absence of radioprotective agents. Radiation side effects can be divided into early and late effects. Typical early side effects include localized superficial burning, discoloration and desquamation, fatigue, reduced blood counts, and collateral damage to localized nerves, organs, and tissues within the field of treatment. Late or long-term side effects can include increased risk of secondary cancers, permanent scarring or fibrosis of tissues, and impaired organ function.94 All side effects are variable according to the location of treatment and which adjacent tissues may suffer direct or collateral damage. This is why it is important to use the newest and most sophisticated machinery available, because of its ability to limit radiation exposure to uninvolved tissues.

When designing a treatment program for a patient undergoing radiation therapy, it is important to ascertain the type of radiation being planned, the areas in the treatment field, and the adjacent organs. For example, only radiation to the abdomen is likely to cause nausea, whereas radiation to the prostate can lead to either proctitis or cystitis if either tissue is within the field. Early effects of head and neck radiation include severe mucositis and pain, often resulting in dehydration and inability to eat, but late effects are more likely to include dry mouth due to damage to salivary glands. Radiation to the outer portions of the breast are unlikely to damage the heart, lungs, or esophagus, but treatment to the medial breast may.

Naturopathic Support During Radiotherapy Naturopathic support during radiation treatment has four goals:

1.Help the patient to decide if radiation is appropriate by reviewing all the relevant survival data with the patient. An example is reviewing data for radiation versus surgery versus hormonal therapy for a prostate cancer patient. Each choice has advantages and disadvantages, and patients appreciate help in understanding the pros and cons of each. 2. If a patient will undergo radiotherapy, help him or her idenhfy the most advanced equipment available in order to maximize tumor kill while reducing collateral damage to healthy tissues. 3. Consider radiosensitizing support to increase the degree of tumor kill. 4.Consider whether radioprotective agents are appropriate and which ones to use. The first two steps require some prior understanding by the provider of treatment options for common tumor types and which local or regional centers may offer those options. For example, as of thiswriting, only seven centers in the entire United States offer tomotherapy.

Radiopotentiation Various conventional and natural therapies can improve the tumoricidal benefits of radiation therapies. Certain pharmaceutic agents including 5-W,Taxol, and cisplatin are sometimes administered concurrently with radiation to increase the damage to tumor DNA. Radiation is also known to be less effective in hypoxic tissues, so radiation oncologists use various methods to increase oxygenation including hyperthennia (increases local circulation via vasodilation), carbogen gas inhalation, and hemoglobininducing therapies including either erythropoietin or transfusions. Natural therapies to potentiate radiation benefits can act by two methods: a direct enhancement of tumoricidal action or by preventing the need for dose reduction due to excessive side effects. Because the second action is

Cancer-Integrated Naturopathic Support actually a radioprotective one, it is discussed later in the radioprotection section. Research on natural radiopotentiators is limited. One agent shown to have benefit is melatonin. In a study of 30 patients with glioblastoma multiforme randomized to receive either radiation therapy (RT) alone or RT plus melatonin, those receiving melatonin along with RT had significantly higher survival at 1 year. In addition, the melatonin group had fewer side effects than those treated by RT al0ne.9~ Flavonoids including Genestein and quercetin were also shown to increase tumor cell death in combination with RT, with Genestein being most active. Whereas RT alone reduced surviving hepatoma cell population by a factor of 20, RT plus continuous Genestein during radiation led to a reduction by a factor of 10,000.96 Ashwaganda, mentioned earlier, is a well-known Ayurvedic medicinal herb that has also shown radiosensitizing properties. A small in vivo study in hamsters indicated that withafarin A, isolated from Withaniu, increased sensitivity to radiation by approximately 50% with no untoward PSK has also been shown to improve survival in a number of cancers, most likely due to enhancement of immune function. In a study of 185 non-small cell lung cancer patients treated with combined RT and PSK versus RT alone, patients receiving the combined treatment had significantly improved survival. Patients with stages 1and 2 disease had a 5-year survival of 39% with combined RT and PSK versus only 22% in the RT-only group. For patients with stage 3 disease, the 5-year survival was 16%with combined RT and PSK versus 5% in the RT-only Combined vitamin K3 plus vitamin C when used as pretreatment for RT has been found in animal studies to increase the reduction in tumor volume produced by RT alone. The authors have postulated that the combination of vitamin K3 and vitamin C produces additional oxyradicals, which have an additive effect to that of RT alone.%

Radioprotection Many nutrients have shown radioprotective activity, and not all can be discussed here due to space constraints. In most cases all antioxidants seem to have some degree of radioprotective activity. At massive doses (i.e., 1400 to 2800 mg CoQlo daily), modest reductions of RTinduced tumor kills have been seen. However, at normal or mildly elevated doses (i.e., 700 mg CoQlo),no reduction of tumor kill is seen.loO Similar results have been noted with vitamins E and C. Typical doses given during or immediately before RT lead to normal or enhanced tumor responses to RT.101J02 Similar conclusions have been reached about other antioxidants, including N-acetylcysteine (NAC), in that "clinically relevant concentrations of NAC are incapable

of protecting tumor cells against clonogenic killing by x-rays . . .''Io3 The safest conclusion to be made is that standard doses of antioxidants such as those in a high-potency multiple vitamin mineral do not reduce the efficacy of radiation therapy but do appear to have protective activity for normal cells. Furthermore, because antioxidants are a crucial factor in the apoptotic cascade, they probably enhance the secondary response to RT by triggering greater rates of apoptosis following treatment.lM Glutamine has shown benefit in protecting mucus membranes during RT and in healing radiation-induced enteritis and proctitis after RT. When given in combination with RT, glutamine protects the patient and increases the selectivity of therapy for the t ~ m ~ r . ~ ~ ~ J ~ ~ Alkylglycerols and squalene have also demonstrated radioprotection, in particular helping to maintain bone marrow function and white blood cell counts during RT. Squalene has also demonstrated the ability to prolong survival after lethal doses of whole body radiation.lo7 Various topical agents can be applied to reduce buming of the skin surface during radiation therapy. These include aloe Vera gel (the fresh leaf is most effective), vitamin E, MSM creams, glutathione gels, and calendula creams. These may be applied nightly throughout the treatment but must be completely washed off each morning before treatment so as to not alter the penetration or scattering of the radiation beams. A degree of redness and peeling is common, particularly in fair skinned individuals, but the agents mentioned here do seem to help with healing and discomfort.

Summary RT is a critical part of the treatment plan for many cancer patients at some time during the course of their disease. Even when not curative, RT can improve quality of life by spot treatment to metastatic lesions in bone and brain. If patients will be undergoing RT, they can safely take typical doses of vitamins and minerals without concerns about interference but should probably avoid megadoses. Radioprotective agents such as glutamine and radiopotentiators such as quercetin, ashwaganda, and PSK can be used to maximize therapeutic benefit of RT. Topical bum creams may be used but must be removed before receiving each dose of RT.

ANTIOXIDANTS, CHEMOTHERAPY, AND RADIATION The use of antioxidants with chemotherapy is one of the most controversial aspects of natural support during cancer treatments. The thinking of conventional oncologists is that most chemotherapeutic agents work via oxidative damage to the DNA of cancer cells. Therefore anything that protects the cells from oxidative damage

might interfere with the action of the chemotherapy.lm However, looking at the published research on this topic, the results consistently show that most antioxidants not only reduce the side effects of chemotherapy but actually improve the tumoricidal action. This finding appears to be consistent across a wide range of chemotherapy agents and types of antioxidants. Extensive reviews of this topic are available.lOg-lll How is it possible to have a theoretic problem but no apparent negative actions in reality? A review article in Scient@cAmericun explained the seeming contradiction in the followingway: “[Flor many years it was assumed that radiation therapy and many chemotherapeutic drugs killed malignant cells directly by wreaking widespread havoc in their DNA. We now know that the treatments often harm DNA to a relatively minor extent. Never-theless the affected cells perceive that the inflicted damage cannot be easily repaired and they actively kill themse1~e.s.”~~~ This process of active cell death is also known as upuptosis. An article in the journal Cell stated that cancer cells often fail to undergo apoptosis in response to treatment, and those agents that stimulate apoptosis would be This is exactly the action of the antioxidants. benefi~ial.”~ This ability of antioxidants to promote apoptosis in cancer cells probably explains the apparent contradiction. Another possible explanation for the apparent contradiction is that the original theory is wrong and that oxidative damage is not the primary mediator of the actions of chemotherapy. In experimental studies, coadministration of free radical scavengers did not reduce the antitumor effect of doxorubicin and cisplatin and survival of animals was increased in the group receiving the antioxidants with treatment compared with those receiving chemotherapy a10ne.l~~ Another recent experiment demonstrated that the commonly used chemotherapy agents cisplatin and VP-16 induced tumor cell death in the absence of any detectable lipid or protein oxidation. Furthermore, it appeared that oxidative stress actually reduced the effectiveness of the chemotherapy agents, and that addition of antioxidants enhanced the tumor killing a ~ t i o n . ” ~ , ” ~ In addition to damaging organs and increasing the risk of secondary cancers, oxidative byproducts of chemotherapy may be counterproductive because free radicals and reactive oxygen species increase processes such as production of vascular endothelial growth factor, which has been implicated as crucial for growth and invasiveness of On the basis of all these data it is my opinion that the benefits of appropriately chosen and dosed antioxidants outweigh any theoretic concerns. This conclusion is based on the following logic: 1.Many patients are forced to discontinue or delay chemotherapy due to side effects that can be sigruficantly reduced with nutrition.

2. Many other patients refuse to even consider starting chemotherapy because of fear of side effects. 3. Chemotherapy and radiation have been implicated in causing increased rates of secondary cancers, many of which are theoretically preventable with nutrition. 4. Approximately 50%of tumors have been found to have abnormal p53 enzymes, making them less responsive to chemotherapy. This abnormality is partially reversible with antioxidants. Increasing p53 activity improves apoptotic response to chemotherapeutic agents. 5. Chemotherapy for common cancers has a limited ability to produce meaningfully sigruficant improvements in survival when used alone. Combination with antioxidants allows the use of higher, and potentially more effective, doses without the dose-limiting results of toxic side effects. Antioxidants, when combined with chemotherapy and radiation, have been shown to reduce negative side effects, increase tumor responses, and increase survival times in numerous studies. Therefore with a few specific exceptions, there is no reason to advise our patients against the use of antioxidants when undergoing conventional cancer treatment; in fact, they should be considered an important part of any naturopathic treatment regimen. The bottom line is that medicine is an evidence-based science. When the theory does not fit the facts, science will eventually modlfy the theory rather than deny the facts, although this can often take up to 50 years. The use of antioxidants becomes even more appealing when one considers the risks of not using them. Chemotherapy agents can damage vital tissues such as the heart, nerves, and kidneys. The vast majority of this damage is completely avoidable with appropriately selected nutritional support. One of the unfortunate long-term side effects of chemotherapy is a n increased risk of secondary cancers due to the actions of the drugs. By using complementary treatment at the time of therapy and in the posttherapy period, one can reduce the risk of developing secondary cancers.

CLINICAL TRIALS A natural question asked by many cancer patients is: “If conventional chemotherapy will only make a 10% to 20% change in my outcome, should I enter clinical trials to get a better drug?” Unfortunately, in most cases the answer is no. Clinical trials are important and provide valuable information to cancer researchers but often have little benefit to patients enrolled in the trial. Understanding thisrequires knowledge of how clinical trials are run.They are divided into three phases. Phase 1 trials test drugs primarily for toxicity and tolerable doses. Phase 2 trials examine promising drugs to see if they cause responses or shrinkage of tumors. Phase 3 trials are conducted on large groups of patients with

Cancer-Integrated

Naturopathic Support

similar diagnoses and prognoses to compare response to a new drug versus the response to standard drugs. In phase 1 and 2 trials, there is little gain for the patient and high risk of being injured by toxicity. By the time a drug reaches phase 3 trials, it may have some benefit. However, patients are usually randomized, so there is a 50-50 chance that they will not receive the new drug but will instead receive the protocol to which they were seeking an alternative. This means that unless there is an extremely promising drug that appears to be dramatically superior to current treatment, one will gain little from participating in a trial unless there are other benefits such as free testing or medical care for the duration of the trial. This does not mean that patients should not participate, only that they should be aware that in most cases there is more risk than gain for participants in most of these trials. Many patients agree to participate in clinical trials for altruistic reasons, hoping to benefit others in the future.

CONCLUSIONS

1. Jemal A, Thomas A, Murray T, et al. Cancer statistics, 2002. CA Cancer J Clin 2002;52:23-47. 2. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer-analysis of cohorts of twins from Sweden, Denmark and Finland. N Engl J Med 2OOO;343 78-85. 3. Hanahan D, Weinberg R. The hallmarks of cancer. Cell 2OOO;100 57-70. 4. Casciato D, Lowitz B. Manual of clinical oncology, -. ed 3. Boston: Little Brown, 199510. 5. Schipper H, Goh CR, Wang TL. Shifting the cancer paradigm: must we kill to cure? J Clin Oncol1995;13801-807. 6 . Richardson MA, Sanders T, Palmer JL, et al. Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology. J Clin Oncol2000;18:2505-2514.

7. Sollner W, Maislinger S, DeVreis A, et al. Use of complementary and alternative medicine by cancer patients is not associated with perceived distress or poor compliance with standard treatment but with active coping behavior. Cancer 2000;89:873-880. 8. Patterson RE, Neuhouser ML, Hedderson MM, et al. Types of alternative medicine used by breast, colon, and prostate cancer patients: predictors, motives and costs. J Altem Complement Med 2002;8: 477-485. 9. Weitz J, Kienle P, Lacroix J, et al. Dissemination of tumor cells in patients undergoing surgery for colorectal cancer. Clin Cancer Res 1998;4343-348. 10.Naik H, Pilat MJ, Donat T, et al. Inhibition of in-vitro tumor cell-endothelial adhesion by modified citrus pectin: a pH modified natural complex carbohydrate. Proc Am Assoc Cancer Res 1995;36a377.

When I first began to learn more about the actions of natural agents and cancer cells, I became extremely optimistic that with the proper combination of agents, most patients would need little or no conventional therapy. Unfortunately, despite a few remarkable successes, for the majority of patients, natural therapies alone were unable to completely control the disease process. Judiciously combining naturopathic therapies with conventional treatments did lead to greater success and significantly improved quality of life. It is not unusual for patients to report actually feeling better than they had in many years, even in the midst of integrated cancer therapy. This also reduces the need for patients to make the difficult choice of either doing natural therapy and declining any potential benefit of conventional treatments or vice versa. Treating cancer is more complex than many other conditions because the clinical situation changes rapidly, treatments change frequently, and the volumes of inforDIET FOR CANCER PATIENTS mation to digest continue to grow exponentially.The key to success in this endeavor is not to have the "cookbook The central role of diet in increasing the risk and preventing the occurrence of cancer is well d~cumented."~ answer" of what nutrient to match with what disease or chemotherapy agent. Rather, it is to understand the disResearch indicates that 30% to 40% of all cancers can be ease process, the treatments, and the patient enough to prevented by lifestyle and dietary measures. Although no manage every eventuality as successfully as possible. diet has been demonstrated to cure cancer, eating a diet Once again, it is comforting for the patient to work with known to prevent cancer and avoiding foods and dietary oncologists who have the therapies and experience to behaviors known to increase the risk of cancer is an deal with the occasional crisis, while using the naturoextremely important component of comprehensivecare. pathic treatments to reduce the likelihood of crisis occurIn general, the diet should be high-fiber, whole food ring at all. In the integrated cancer center where I work, (the foods organically grown), rich in fruits, vegetables, it is unusual for patients to need hospitalization due to beans, seeds, and cold-water fish. It should be low in side effects of their treatments. high-calorie, low-nutrient foods such as junk foods, Naturopathic medicine can play a large role in candy, and soft drinks. Allium and cruciferous vegetaimproving the quality of life and success of cancer bles, especially broccoli sprouts, are beneficial. For a patients and should be a critical part of any oncology complete discussion and a useful resource for patients, treatment protocol. see How to Prevent and Treat Cancer with Natural Medicine by myself and others.l19

11. Pienta KJ, Naik H, Akhtar A, et al. Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst 1995;87348-353. 12. [No authors listed]. Oncology prescribing guide, ed 2. Montvale, NJ: Medical Economics Company, 1998. 13.Loesch D, Robert N, Asmar M, et al. Phase II multicenter trial of a weekly paclitaxel and carboplatin regimen in patients with advanced breast cancer. J Clin Oncol2002;203857-3864. 14. Hrushesky W. liming is everything. Sciences 1994;July/Aug:32-37. 15.Bailar JC III, Gomick HL. Cancer undefeated. N Engl J Med 1 9 7 3 6 :1569-1574. 16.Burris H A III, Moore MJ, Anderson J, et al. Improvements in survival and clinical benefit with gemcitabine as first line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol1997;152403-2413. 17. Cole BF, Gelber RD, Gelber S, et al. Polychemotherapy for early breast cancer: an overview of the randomised clinical trials with quality adjusted survival analysis. Lancet 2001;358:277-286. 18. Lissoni P, B a d S, Mandala M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer 199935:1688-1692. 19. Sadzuka Y, Sugiyama z Hirota S. Modulation of cancer chemotherapy by green tea. Clin Cancer Res 1998;4153-156. 20. Okuma K, Furuta I, Ota K. [Protective effect of coenzyme QlO in cardiotoxicity induced by adriamycin.] Gan To Kagaku Ryoho 1984;11:502-508. 21. Olcese J, ed. Melatonin after four decades: an assessment of its potential. New York Kluwer Academic/Plenum, 1999. 22. Davis S, Mirick D, Stevens R. Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 2001;93:1557-1562. 23. Lemus-Whn A, Kelly PA, Blask DE. Melatonin blocks the stimulatory effects of proladin on human breast cancer cell growth in culture. Br J Cancer 1995;72:1435-1440. 24. Blask DE, Sauer LA, Dauchy RT, et al. Melatonin inhibition of cancer growth in-vivo involves suppression of tumor fatty acid metabolism via melatonin receptor-mediated signal transduction events. Cancer Res 19995946934701. 25. Neri B, De Leonardis V, Gemelli M, et al. Melatonin as biological response modifier in cancer patients. Anticancer Res 1998;18: 1329-1332. 26. Lissoni P, Cazzaniga M, Tancini G, et al. Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin. efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone. Eur Urol 1997; 31~178-181. 27. Wahab MH, Akoul ES, Abdel-Aziz AA. Modulatory effects of melatonin and vitamin E on doxorubicin-induced cardiotoxicity in Ehrlich ascites carcinoma-bearing mice. Tumori 2OOO;86.157-162. 28.Lissoni P, Bami S, Mandala M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumor patients with poor clinical status. Eur J Cancer 1999351688-1692. 29. Persengiev SP, Kyurkchiev S. Selective effect of melatonin on the proliferation of lymphoid cells. Int J Biochem 1993;25:441-444. 30.Kohlmeier L, Weterings KG, Steck S, et al. Tea and cancer prevention: an evaluation of the epidemiologic literature. Nutr Cancer 1997;27:1-13. 31. Fujiki H, Suganuma M, Okabe S, et al. Japanese green tea as a cancer preventive in humans. Nutr Rev 1996;54:S67-70. 32. Ahmad N, Feyes D, Nieminen A, et al. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 1997;891881-1886. 33. Sadzuka Y, Sugiyama T, Sonobe T. Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance. Toxic01Lett 2OOO;114155-162.

34.Jodoin J, Demeule M, Beliveau R. Inhibition of the multidrug resistance p-glycoprotein activity by green tea polyphenols. Biochim Biophys Acta 2002;1542:149-159. 35. Sartippour MR, Heber D, Zhang L, et al. Inhibition of fibroblast growth factors by green tea. Int J Oncol2002;21:487491. 36.Chen ZP, Schell JB, Ho CT, et al. Green tea epigallocatechin gallate shows a pronounced growth inhibitory effect on cancerous cells but not on their normal counterparts. Cancer Lett 1998;129 173-179. 37. Branda RF, Nigels E, Lafayette AR, et al. Nutritional folate status influences the efficacy and toxicity of chemotherapy in rats. Blood 1998;92:2471-2476. 38. Noguchi M, Rose D F ' , Earashi M, et al. The role of fatty acids and eicosanoid synthesis inhibitors in breast carcinoma. Oncology 1995;52:265-271. 39. Bartram HF', Gostner A, Scheppach W, et al. Effects of fish oil on rectal cell proliferation, mucosal fatty acids, and prostaglandin E2 release in healthy subjects. Gastroenterology 1993;105:1317-1322. 40.Rose DP, Connolly JM. Omega-3 fatty acids as cancer chemopreventive agents. Pharmacol Ther 1999;83:217-244. 41. Chiu LC, Wan JM. Induction of apoptosis in HL-60 cells by eicosapentaenoic acid (EPA) is associated with downregulation of bcl-2 expression. Cancer Lett 1999;14517-27. 42. Hardman WE, Moyer MP, Cameron I. Fish oil supplementation enhanced CPT-11 (irinotecan) efficacy against MCF7 breast carcinoma xenografts and ameliorated intestinal side-effects. Br J Cancer 1999;81:440-448. 43. Wigmore SJ, Barber MD, Ross JA, et al. Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer 2OOO;36177-184. 44.Rose DP, Connolly JM. Effects of dietary omega-3 fatty acids on human breast cancer growth and metastases in nude mice. J Natl Cancer Inst 1993;85:1743-1747. 45. Block G. Epidemiologic evidence regarding vitamin C and cancer. Am J Clin Nutr 1991;54:13105-1314S. 46.Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A 1976;73:3685-3689. 47. Murata A, Morishige F, Yamaguchi H. Prolongation of survival times of terminal cancer patients by administration of large doses of ascorbate. Int J Vitam Nutr Res Suppl1982;23:103-113. 48. Creagan ET, Moertel CG, OFallon JR, et al. Failure of high dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. N Engl J Med 1979;301:687-690. 49. Moertel CG, Fleming TR, Creagan ET, et al. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N Engl J Med 1985;312:137-141. 50. Campbell A, Jack T, Cameron E. Reticulum cell sarcoma: two complete "spontaneous" regressions, in response to high-dose ascorbic acid therapy. A report on subsequent progress. Oncology 1991;48: 495-497. 51. Padayatty SJ, Levine M. Reevaluation of ascorbate in cancer treatment: emerging evidence, open minds and serendipity. J Am Coll Nutr 2000;19:423-425. 52. Maramag C, Menon M, Balaji KC, et al. Effect of vitamin C on prostate cancer cells in vitro: effect of cell number, viability, and DNA synthesis. Prostate 1997;32188-195. 53.Shimpo K, Nagatsu T, Yamada K, et al. Ascorbic acid and Adriamycin toxicity. Am J Clin Nutr 1991;54:1298S1301S. 54. Prasad KN, Hernandez C, Edwards-Prasad J, et al. Modification of the effect of tamoxifen, cis-platin, DTIC, and interferon-alpha 2b on human melanoma cells in culture by a mixture of vitamins. Nutr Cancer 1994;22:233-245. 55. Kurbacher CM, Wagner U, Kolster B, et al. Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and

Cancer-Integrated paclitaxel in human breast carcinoma cells in vitro. Cancer Lett 1996;103:183-189. 56. Taper HS, de Gerlache J, Lans M, et al. Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pretreatment. Int J Cancer 1987;40:575-579. 57. Fain 0,Mathieu E, Thomas M. Scurvy in patients with cancer. BMJ 1998;316:1661-1662. 58. Hayakawa K, Mitsuhashi N, Saito Y, et al. Effect of krestin (PSK) as adjuvant treatment after radical radiotherapy in patients with nonsmall cell lung cancer. Anticancer Res 1993;13:18151820. 59. Nakazato H, Koike A, Saji S, et al. Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Lancet 1994;343:1122-1126. 60. Torisu M, Hayashi Y, Ishimitsu T, et al. Sigruficant prolongation of disease-free period gained by oral polysaccharide K (PSK) administration after curative surgical operation of colorectal cancer. Cancer Immunol Immunother 1990;31:261-268. 61. Kobayashi H, Matsanuga K, Oguchi Y. Antimetastatic effects of PSK (Krestin), a protein bound polysaccharide obtained from basidiomycetes: an overview. Cancer Epidemiol Biomarkers Prev 1995;4275-281. 62. Fisher M, Yang LX. Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy. Anticancer Res 2002;221737-1754. 63.Adachi K, Nanba H, Kuroda H. Potentiation of host-mediated antitumor activity in mice by beta-glucan obtained from Grifola frondosa (maitake). Chem Pharm Bull (Tokyo) 1987;35262-270. 64.Fullerton SA, Samadi AA, Torterelis DG, et al. Induction of apoptosis in human prostatic cancer cells with beta-glucan (maitake mushroom polysaccharide). Mol Urol2OOO;47-13. 65. Gonzalez NJ, Isaacs LL. Evaluation of pancreatic proteolytic enzymes treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer 1999;33117-124. 66. Leipner J, Saller R. Systemic enzyme therapy in oncology. Drugs 2000;59:769-780. 67. Desser L, Rehberger A. Induction of tumor necrosis factor in human peripheral blood mononuclear cells by proteolytic enzymes. Oncology 1990;47475-477. 68.Chu E, DeVita V, eds. Physicians cancer chemotherapy drug manual. Boston: Jones & Bartlett, 2001:184. 69. Sadzuka Y, Sugiyama T, Hirota S. Modulation of cancer chemotherapy by green tea. Clin Cancer Res 1998;4153-156. 70.Monti E, Sinha BK. Antiproliferative effect of genestein and Adriamycin against estrogen-dependent and -independent human breast carcinoma cell lines. Anticancer Res 1994;141221-1226. 71. Okada K, Yamada S, Kawashima Y, et al. Cell injury by antineoplastic agents and influence of coenzyme QlO on cellular potassium activity and potential difference across the membrane in rat liver cells. Cancer Res 1980;40:1663-1667. 72.Shimpo K, Nagatsu T, Yamada K, et al. Ascorbic acid and Adriamycin toxicity. Am J Clin Nutr 1991;54(6 suppl):1298S1301S. 73. Geetha A. Effect of alpha-tocopherol on doxorubicin-induced changes in rat heart lysosomal enzymes. Indian J Exp Biol1993;31: 288-290. 74. Folkers K, Wolaniuk A. Research on coenzyme Q l O in clinical medicine and in immunomodulation. Drugs Exp Clin Res 1985;11:539-545. 75.Chu E, DeVita V, eds. Physicians cancer chemotherapy drug manual. Boston: Jones & Bartlett, 2001:136-137. 76. Shao Y, Pardini L, Pardini RS.Effects of dietary menhaden oil on cyclophosphamide toxicity and antitumor activity. Proc Am Assoc Cancer Res 1996;37283. 77. Drago JR, Nestbitt JA, Badalament RA, et al. Chemotherapy and vitamin E in treatment of rat prostate tumors. In Vivo 1988;2399-401. 78. Qian ZM, Xu MF, Tang PL. Polysaccharide peptide (PSP) restores immunosuppression induced by cyclophosphamide in rats. Am J Clin Med 1997;25:27-35.

Naturopathic Support

79. DiRe F, Bohm S, Oriana S, et al. High-dose cisplatin and cyclophosphamide with glutathione in the treatment of advanced ovarian cancer. Ann Oncol1993;455-61. 80. B o b S, Oriana S, Spatti G, et al. Dose intensification of platinum compounds with glutathione protection as induction chemotherapy for advanced ovarian carcinoma. Oncology 1999;57115-120. 81. Smyth J, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improved quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double blind, randomised trial. Ann Oncol 1997;8569-573. 82. Hu Y, Chen Y, B a n g Y, et al. The protective role of selenium on the toxicity of cisplatin-containing chemotherapy regimen in cancer patients. Biol Trace Elem Res 199736331-341. 83. Bokemeyer C, Fels LM, Dunn T, et al. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer 1996;742036-2041. 84. Kurbacher CM, Wagner U, Kolster B, et al. Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in-vitro. Cancer Lett 1996;103183-189. 85.Borghardt J, Rosien 8, Gortelmeyer R, et a]. Effects of a spleen peptide preparation as supportive therapy in inoperable head and neck cancer patients. Arzneimittelforschung 2000;50178-184. 86. Kobayashi Y, Kariya K, Saigenji K, et al..Enhancement of anti-cancer activity of cisdiaminedichloroplatinumby the protein-bound polysaccharide of Coriolus versicolor QUEL (PSK) in vitro. Cancer Biother 1994;9351-358. 87.Chinery R, Bmkman J, Peeler M, et al. Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAFl/CIPl via C/EBPbeta. Nat Med 1997;3:1233-1241. 88. Adeyamo D, Imtiaz F, Toffa S, et al. Antioxidants enhance the susceptibility of colon carcinoma cells to 5-fluorouricilby augmenting the induction of the bax protein. Cancer Lett 2001;164:77-84. 89. Molina R, Fabian C, Slavik M, et al. Reversal of palmar-plantar erythrodysesthesia (PPE) by 86 without loss of response in colon cancer patients receiving 200 mg/m2/day continuous 5-FU. Proc Am Soc Clin Oncol1987;690 (abstract). 90. Rouse K, Nwokedi E, Woodliff JE,et a1 Glutamine enhances selectivity of chemotherapy through changes in glutathione metabolism. AM Surg 1995;221:420-426. 91. Nagai Y, Hone T, Awazu S. Vitamin A, a useful biochemical modulator capable of preventing intestinal damage during methotrexate treatment. Pharmacol Toxic01 1993;73:69-74. 92. Savarese D, Boucher J, Corey B. Glutamine treatment of paclitaxelinduced myalgias and arthralgias. J Clin Oncol1998;16:3918-3919. 93. Menendez JA, del Mar Barbacid M, Montero S, et al. Effects of gamma-linolenic acid on paclitaxel cytotoxicity in human breast cancer cells. Eur J Cancer 2001;37402-413. 94. Kony SJ, de Vathaire F, Chompret A, et al. Radiation and genetic factors in the risk of second malignant neoplasms after a first cancer in childhood. Lancet 1997;35091-95. 95. Lissoni P, Meregalli S, Nosetto L, et al. Increased survival time in brain glioblastomas by a radioendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 1996;53:43-46. 96. van Rijn J, van den Berg J. Flavonoids as enhancers of x-rayinduced cell damage in hepatoma cells. Clin Cancer Res 1997;3: 1775-1779. 97. Devi PU. Withania somnifera Dunal (Ashwagandha): potential plant source of a promising drug for cancer chemotherapy and radiosensitization. Indian J Exp Biol1996;34:927-932. 98. Hayakawa K, Mitsuhashi N, Saito Y, et al. Effect of krestin (PSK) as adjuvant treatment on the prognosis after radical radiotherapy in patients with non-small cell lung cancer. Anticancer Res 1993; 13:1815-1820.

Syndromes and Special Topics 99.Taper HS,Keyeux A, Roberfroid M. Potentiation of radiotherapy by nontoxic pretreatment with combined vitamins C and K3 in mice bearing solid transplantable tumor. Anticancer Res 1996; 16499-503. 100.Lund EL,Quistorff B, Spang-Thornsen M, et al. Effect of radiation therapy on small-cell lung cancer is reduced by ubiquinone intake. Folia Microbial (Praha) 1998;43505-506. 101.Kagerud A, Peterson HI. Tocpherol in irradiation of experimental neoplasms. Acta Radio1 Oncol1981;2097-100. 102.Okunieff P, Suit H. Toxicity radiation sensitivity modification, and combined drug effects of ascorbic acid with misonidazole in vivo on FSaIImurine fibrosarcomas. J Natl Cancer Inst 1987;79377-381. 103.Wanamarta AH, van Rijn J, Blank LE, et al. Effect of N-acetylcysteine on the antiproliferative action of x-rays or bleomycin in cultured human lung tumor cells. J Cancer Res Clin Oncol 1989;115340-344. 104.Rupnow BA, Murtha AD, Alarcon RM, et al. Direct evidence that apoptosis enhances tumor responses to fractionated radiotherapy. Cancer Res 1998581779-1784. 105.Kliberg V, McClellan J, Claude H Organ, Jr. Honorary lectureship. Glutamine, cancer, and its therapy. Am J Surg 1996;172: 418-424. 106.Klimberg VS, Souba WW, Dolson DJ, et al. Prophykactic glutamine protects the intestinal mucosa from radiation injury. Cancer 1990;66:62-68. 107.Storm HM, Oh SY, Kimnler BF, et al. Radioprotection of mice by dietary squalene. Lipids 1993;28555-559. 108.Labriola D, Livingston R. Possible interactions between dietary antioxidants and chemotherapy. Oncology (Huntingt) 1999;13: 1003-1008.

109.Lamson DW,Brignall MS. Antioxidants in cancer therapy; their actions and interactions with oncologic therapies. Altern Med Rev 1999;4:304-329. 110.Lamson DW, Brignall MS. Antioxidants and cancer therapy II: quick reference guide. Altern Med Rev 2000;5:152-163. 111. Prasad KN, Kumar A, Kochupillai V, et al. High doses of antioxidant vitamins: essential ingredients in improving the efficacy of standard chemotherapy. J Am Coll Nut 1999;1813-25. 112.Weinberg R4.How cancer arises. Sci Am 1996;27562-70. 113.Lowe SW, Ruley HE, Jacks T, et al. Dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993;74957-967. 114. Weijl NI, Cleton FJ, Osanto S. Free radicals and antioxidants in chemotherapy induced toxicity. Cancer Treat Rev 1997;23: 209-240. 115.Senturker S,Tschirret-Guth R, Morrow J, et al. Induction of apoptosis by chemotherapeutic drugs without generation of reactive oxygen species. Arch Biochem Biophys 2002;397:262-272. 116.Shacter E, Williams J, Hinson R, et al. Oxidative stress interferes with cancer chemotherapy:inhibition of lymphoma cell apoptosis and phagocytosis. Blood 2O00;96:307-313. 117.Beinert T, Binder D, Oehm C, et al. Further evidence for oxidantinduced vascular endothelial growth factor up-regulation in the bronchoalveolar lavage fluid of lung cancer patients undergoing radiochemotherapy J Cancer Res Clin Oncol2000;6352-356. 118.Donaldson MS. Nutrition and cancer: a review of the evidence for an anti-cancer diet. Nutr J 2004;319. 119.Murray M, Birdsall T, Pizzorno JE, Reilly P. How to prevent and treat cancer with natural medicine. New York Riverhead Books, 2002.

Chronic Candidiasis Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER C O N T E N T S introduction 573 General Considerations 573 Causal Factors 573 Syndromes Related to the Yeast Syndrome 575 Diagnosis 575 Questionnaire 575 The Comprehensive Stool and Digestive Analysis 575

INTRODUCTION In the past 20 years overgrowth in the gastrointestinal(GI) tract of the usually benign yeast Cundida albicuns has become increasinglyrecognized as a complex medical syndrome known as chronic cundidiusis, or the yeast syndrome.’S2 Specifically, the overgrowth of C. ulbicans is believed to cause a wide variety of symptoms in virtually every system of the body, with the GI, genitourinary, endocrine, nervous, and immune systems being most s~sceptible.~ Although chronic candidiasis has been clinically defined for a long time, it was not until Orion Truss published The Missing Diugnosis and William Crook published The Yeast Connection that the public and many physicians became aware of the magnitude of the

Therapeutic Considerations 575 Diet 575 Enhancing Immunity 576 Promoting Detoxification 577 Natural Antiyeast Agents 578 Therapeutic Approach

580

the symptoms patients with the yeast syndrome may e~perience.~ The typical patient with the yeast is female, as women are eight times more likely to experience the yeast syndrome compared with men due to the effects of estrogen, birth control pills, and the higher number of prescriptions for antibiotics (Box 52-1).4

Causal Factors Chronic candidiasis is a classic example of a ”multifactorial” condition, as shown in Box 52-2. Therefore the most effective treatment involves addressing and correcting the factors that predispose to C. ulbicans overgrowth. It involves much more than killing the yeast with antifungal agents, whether synthetic or natural.

GENERAL CONSIDERATIONS

Antibiotics

Normally, C. ulbicans lives harmoniously in the inner warm creases and crevices of the digestive tract (and vaginal tract in women). However, when this yeast overgrows, immune system mechanisms are depleted, or the normal lining of the intestinal tract is damaged, the body can absorb yeast cells, particles of yeast cells, and various toxins3 As a result, there may be significant disruption of body processes, resulting in the development of the “yeast syndrome.” This syndrome is generally characterized by patients saying they “feel sick all over.” Fatigue, allergies, immune system malfunction, depression, chemical sensitivities, and digestive disturbances are just some of

Prolonged antibiotic use is believed to be the most important factor in the development of chronic candidiasis in most cases. Antibiotics, through suppressing normal intestinal bacteria that prevent yeast overgrowth and suppression of the immune system, strongly promote the overgrowth of Candida. There is little argument that, when used appropriately, antibiotics save lives. However, there is also little argument that antibiotics are seriously overused. Although the appropriate use of antibiotics makes good medical sense, what does not make sense is reliance on them for such conditions as acne, recurrent bladder infections, chronic ear infections,chronic sinusitis, chronic bronchitis, 573

Syndromes and Special Topics

Sex: female Age: 15-50 yr General Symptoms Chronic fatigue Loss of energy General malaise Decreased libido

Gastrointestinal Symptoms Thrush Bloating, gas Intestinal cramps Rectal itching Altered bowel function

Genitourinary System Complaints Vaginal yeast infection Frequent bladder infections

Endocrine System Complaints Primarily menstrual complaints

Nervous System Complaints Depression Irritability Inability to concentrate

Immune System Complaints Allergies Chemical sensitivities Low immune function

Past History Chronic vaginal yeast infections Chronic antibiotic use for infections or acne Oral birth control usage Oral steroid hormone usage

Associated Conditions Premenstrual syndrome Sensitivity to foods, chemicals, and other allergens Endocrine disturbances Eczema Psoriasis Irritable bowel syndrome

Other Craving for foods rich in carbohydratesor yeast

and nonbacterial sore throats. Relying on antibiotics in the treatment of these conditions does not make sense,as either the antibiotics rarely provide benefit or these conditions are effectively treated with natural measures.

Decreased digestive secretions Dietary factors Impaired immunity Nutrient deficiency Drugs (particularly antibiotics) Impaired liver function Underlying disease states Altered bowel flora Prolonged antibiotic use

The problem of antibiotic resistance is growing. Widespread use and abuse of antibiotics is becoming increasingly alarming for many reasons besides the epidemic of chronic candidiasis, including the development of ”superbugs” that are resistant to currently available antibiotics. According to many experts, as well as the World Health Organization (WHO), we are coming dangerously close to arriving at a ”postantibiotic era” in which many infectious diseases will again become almost impossible to i ~ e a t . ~ - ~ Inappropriate use greatly increases the risk of developing complications such as overgrowth of C. albicans and other organisms, as well as increasing the risk of developing a bacterial infection that is resistant to antibiotics. Antibiotic resistance is probably an inevitable process, as bacteria transfer genetic material both within species and among species to help ensure survival of the organism. It has been well demonstrated that antibiotic resistance is much more common where antibiotics are used more often.6 This is particularly a problem in hospitals, where infections caused by resistant strains of organisms such as Staphylococcus aureus and Pseudomonas aeruginosa often lead to fatal complications. Because of evidence that resistance to antibiotics is less of a problem when antibiotics are used sparingly, reduction in antibiotic prescriptions may be the only significant way to address the problem. According to several authorities, as well as the WHO, antibiotic use must be restricted and the inappropriate use halted if the growing trend toward bacterial resistance to antibiotics is to be stopped or r e ~ e r s e d .However, ~-~ prescriptions for antibiotics are not the only source of concern. Antibiotics have also been added to animal nutrition since the 1950s. In addition to creating antibiotic-resistant microorganisms, it may be several more decades before it is truly known what effects the widespread use of antibiotics is having on many health conditions. For example, antibiotic exposure is now being linked to Crohn’s disease! Before the 1950s, Crohn’s disease was found in selected groups with a strong genetic component. Since the 1950s, there has been a rapid increase in developed countries, particularly in the United States, and in countries that

Chronic Candidiasis

had previously not reported cases. In fact, since 1950, Crohn’s disease has spread like an epidemic. The annual increase in antibiotic prescriptions and the parallel increase in the annual incidence of Crohn‘s disease are causing great concern. Comparative statistics have shown that wherever antibiotics are used early and in large quantities, the incidence of Crohn’s disease is high.

Syndromes Related to the Yeast Syndrome Eventually the “yeast syndrome” will likely be replaced by a more comprehensive term to include small intestinal bacterial overgrowth and the leaky gut syndrome. Both conditions are often associated with C. albicans overgrowth and may produce identical symptoms to the yeast syndrome. For further discussion of small intestinal bacterial overgrowth and leaky gut syndrome, see Chapters 12 and 23.

DIAGNOSIS Questionnaire One of the most useful screening methods for determining the likelihood of yeast-related illness is a comprehensive questionnaire (see Appendix 1). Although the Candida questionnaire can help, the best method for diagnosing chronic candidiasis is clinical evaluation by a physician knowledgeable about yeastrelated illness. More than likely, the manner in which the doctor will diagnose the yeast syndrome will be based on clinical judgment from a detailed medical history and patient questionnaire. He or she may also employ laboratory techniques such as stool cultures for C. albicans and measurement of antibody levels to C. albicans or C. albicans antigens in the blood. Although these laboratory examinationsare useful diagnostic aids, they should be used to confirm the diagnosis. In other words, the diagnosis is best made by evaluation of a patient’s history and clinical picture.

The Comprehensive Stool and Digestive Analysis Rather than simply culture a stool sample for the presence of C. ulbicans, the comprehensive digestive stool analysis (CDSA) is more clinically useful (discussed in detail in Chapter 14). This battery of integrated diagnostic laboratory tests evaluates digestion, intestinal function, intestinal environment, and absorption by carefully examining the stool. It is a useful tool in determining the digestive disturbance that is likely to be the underlying factor responsible for C. albicans overgrowth. In addition, the CDSA may determine that the symptoms are not related to C. albicans overgrowth but rather to conditions such as small intestinal bacterial overgrowth and the leaky gut syndrome.

Antibody and Antigen Levels Another laboratory method to confirm the presence of C. albicans overgrowth is measuring the level of antibodies to Candida or the level of antigens in the b l o ~ d . ~ , ~ However, these tests are rarely necessary, as the results typically only confirm what the patient history, physical examination, and CDSA reveal. Hence the test does not change the course of action. Nonetheless, some patients and physicians may desire confirmation that C. albicaizs is a responsible factor in the patient’s health equation. In this situation, blood studies can be helpful and can also be used as a way of monitoring therapy.

THERAPEUTIC CONSIDERATIONS A comprehensive approach is more effective in treating chronic candidiasis than simply trying to kill the C. albicans with a drug or natural anti<. albicans agent. Drugs like nystatin, ketoconazole, and Diflucan, as well as various natural anti<. albicans agents, rarely produce significant long-term results because they fail to address the underlying factors that promote C. albicans overgrowth. The pharmaceutical approach is a bit like trying to weed a garden by simply cutting the weeds, instead of pulling them out by the roots. Nonetheless, in many cases it is useful to try to eradicate C. albicans from the system, preferably with the help of natural anti-C. albicuns therapies such as timed-release caprylic acid preparations, enteric-coated volatile oil preparations, or fresh garlic preparations. A follow-up stool culture and C. albicans antigen determination will confirm if the C. albicans has been eliminated. If it has and symptoms are still apparent, it is likely that the symptoms they are experiencing are unrelated to an overgrowth of C. albicuns. Similar symptoms to those attributed to chronic candidiasis can be caused by small intestinal bacterial overgrowth. In this scenario, pancreatic enzymes and berberinecontaining plants like goldenseal can be helpful. In addition to using natural agents to eradicate C. albicans, it is important to address predisposing factors, recommend a C. albicans control diet, and support various body systems according to the individual patient’s need.

Diet A number of dietary factors appear to promote the overgrowth of C. albicans. The most important factors are a high intake of sugar, milk, and other dairy products; foods containing a high content of yeast or mold; and food allergies.

Sugar Sugar is the chief nutrient of C. albicans. It is well accepted that restriction of sugar intake is an absolute necessity in the treatment of chronic candidiasis. Most patients

do well by simply avoiding refined sugar and large amounts of honey, maple syrup, and fruit juice.'"

Milk and Other Dairy Products Several reasons to restrict or eliminate the intake of r n i k in patients with chronic candidiasis are the following: High lactose content promotes the overgrowth of Candida. Mill< is one of the most frequent food allergens. Milk may contain trace levels of antibiotics, which can further disrupt the GI bacterial flora and promote Candida overgrowth.14.

Mold and Yeast-Containing Foods Many experts generally recommend that individuals with chronic candidiasis avoid foods with a high content of yeast or mold including alcoholic beverages, cheeses, dried fruits, and peanuts. Even though many patients with chronic candidiasis may be able to tolerate these foods, we think it is still a good idea to eliminate them from the diet. At the least, they should be avoided until the situation is under contro1.l4

Food Allergies Food allergies are another common finding in patients with the yeast syndrome? ELISA tests, which determine both IgE- and IgG-mediated food allergies, are often helpful in identifymg food allergies.

Hypochlorhydria An important step in treating chronic candidiasis in many cases is improving digestive secretions. Gastric hydrochloric acid, pancreatic enzymes, and bile all inhibit the overgrowth of C. albicans and prevent its penetration into the absorptive surfaces of the small intestine. Decreased secretion of any of these important digestive components can lead to overgrowth of C. afbicans in the GI tract. Therefore restoration of normal digestive secretions through the use of supplemental hydrochloric acid, pancreatic enzymes, and substances that promote bile flow is critical in the treatment of chronic candidiasis. The comprehensive stool and digestive analysis can provide valuable information in identifying which factor is most important. People on antiulcer drugs like Tagamet (cimetidine) and Zantac (ranitidine) actually develop C. albicans overgrowth in the stomach.'0 This occurrence highlights the importance of hydrochloric acid in the prevention of C. albicans overgrowth. Restoring proper levels of gastric acid by supplemental hydrochloric acid is often quite useful in chronic candidiasis. Pancreatic enzymes can also be useful in the treatment of chronic candidiasis. As well as being necessary

for protein digestion, the proteases serve several other important functions. The proteases are largely responsible for keeping the small intestine free from parasites (including bacteria, yeast, protozoa, and intestinal ~ o r m s ) . 'A~ lack , ~ ~of proteases or other digestive secretions greatly increases an individual's risk of having an intestinal infection, including chronic C. albicans infections of the GI tract.

Enhancing Immunity Recurrent or chronic infections, including chronic candidiasis, are characterized by a depressed immune system. What makes it difficult for these people to overcome chronic candidiasis is a repetitive cycle-a compromised immune system leads to infection, and infection leads to damage to the immune system, further weakening resistance. The importance of a healthy immune function protecting against C. aZbicans overgrowth is well known by any physician who has seen a patient suffering from AIDS or taking drugs that suppress the immune system. In either case, severe overgrowth of C. albicans is a hallmark feature. The occurrence of C. albicans overgrowth in these conditions provides considerable evidence that attaining better immune function is absolutely essential in the patient with chronic candidiasis. In addition, patients with chronic candidiasis often suffer from other chronic infections, presumably due to a depressed immune system. Typically, this depression of immune function is related to decreased thymus function demonstrating primarily as depressed cellmediated immunity. Although expensive laboratory tests can document this depression, it is better to rely on the history of repeated viral infections (including the common cold), outbreaks of cold sores or genital herpes, and prostatic (men) or vaginal (women) infections.

Causes of Depressed Immune Function in Candidiasis The patient with chronic candidiasis is typically stuck in a vicious cycle (Figure 52-1). With regard to the immune system, a triggering event such as antibiotic use or nutrient deficiency (Box 52-3) can lead to immune suppression, allowing C. albicans to overgrow and become more firmly entrenched in the lining of the GI tract. Once the organism attaches itself to the intestinal cells, it competes with the cell and ultimately the entire body for nutrition-potentially robbing the body of vital nutrition. In addition, C. albicans secretes a large number mycotoxins and antigens.13J4 C. aZbicans is referred to as a "polyantigenic" organism because more than 79 distinct antigens have been identified. Because of this tremendous number of antigens, an overgrowth of C. albicans greatly taxes the immune system.

-

0 .1

<- - Candida

Overgrowth

{Digestive insufficiency\ High-sugar diet Impaired immunity Nutrientdeficiencies

Drugs Impaired liver function Underlyingdiseases

Absorption of yeast products

\

A

I

immune svstem

Positive feedback

Nutrient deficiencies lmoaired liver function

J ltisystem involvementwith multiple food allergies, chemical sensitivities, low immune function and endocrine imbalance Figure 52-1 The vicious cycle of chronic candidiasis.

Antibiotic use Corticosteroid use Other drugs that suppress the immune system Nutrient deficiency Food allergies High-sugar diet Stress

nutrients such as carotenes, vitamin C, vitamin E, zinc, and selenium Use of nutrients that are required in the manufacture or action of thymic hormones

Promoting Detoxification

Restoring proper immune function is one of the key goals in the treatment of chronic candidiasis. No single magic bullet exists to immediately restore immune function in patients with chronic candidiasis. Instead, a comprehensive approach involving lifestyle, stress management, exercise, diet, nutritional supplementation, glandular therapy, and the use of plant-based medicines is used. Perhaps the most effective intervention in reestablishing a healthy immune system is employing measures designed to improve thymus function. The clinical remission of oral candidiasis has been shown to be critically dependent on T-cell fun~tion.’~,’~ Not surprisingly, oral candidiasis occurs in roughly 90% of HIV-positive individuals. Presumably, improving thymus-mediated immunity is critical in the remission of chronic candidiasis as well. Promoting optimal thymus gland activity involves the following:

Patients with chronic candidiasis usually exhibit multiple chemical sensitivities and allergies, an indicator that detoxification reactions are stressed. Therefore their liver function must be supported. In fact, improving the health of the liver and promoting detoxification may be one of the most critical factors in the successful treatment of candidiasis. Damage to the liver is often an underlying factor in chronic candidiasis, as well as chronic fatigue. When the liver is even slightly damaged by chemical toxins, immune function is severely compromised. The immune system suppressing effect of nonviral liver damage has been repeatedly demonstrated in experimental animal studies and human studies. For example, when the liver of a rat is damaged by a chemical toxin, immune function is severely hindered.” Liver injury is also linked to C. ulbicuns overgrowth, as evident in studies with mice demonstrating that when the liver is even slightly damaged, C. ulbicuns runs rampant through the body.18 A rational approach to aiding the body’s detoxification involves the following:

*Prevention of thymic involution or shrinkage by ensuring adequate dietary intake of antioxidant

A diet focused on fresh fruits and vegetables, whole grains, legumes, nuts, and seeds

Restoring Proper Immune Function

A healthy lifestyle including avoiding alcohol and exercising regularly A high-potency multiple vitamin and mineral supplement Lipotropic formulas and silymarin to protect the liver and enhance liver function A 3-day fast at the change of each season

If any of the factors in Box 52-4 apply to the patient, enhancing detoxification is a major therapeutic goal.

Lipotropic Factors The nutrients choline, betaine, and methionine are often beneficial in enhancing liver function and detoxification reactions. These compounds, referred to as Zipotropic agents, promote the flow of fat and bile to and from the liver. In essence, they produce a “decongesting” effect on the liver and promote improved liver function and fat metabolism. Formulas containing lipotropic agents are useful in enhancing detoxification reactions and other liver functions. Lipotropic formulas have been used for a wide variety of conditions by nutrition-oriented physicians, including a number of liver disorders such as hepatitis, cirrhosis, and chemical-induced liver disease. The daily dosage should be 1000 mg of choline and 1000 mg of methionine or cysteine, or both. Lipotropic formulas appear to increase the levels of two important liver substances: SAMe (Sadenosylmethionine), the major lipotropic compound in the liver, and glutathione, one of the major detoxifymg compounds in the liver.l9z0

Silymarin A long list of plants exert beneficial effects on liver function. However, the most impressive research has been done on a special extract of milk thistle (SiZyburn marianurn) known as sizymarin. Silymarin refers to a group of

More than 20 Ib overweight Diabetes Presence of gallstones History of heavy alcohol use Psoriasis Natural and synthetic steroid hormone use Anabolic steroids Estrogens Oral contraceptives High exposure to certain chemicals or drugs Cleaning solvents Pesticides Antibiotics Diuretics Nonsteroidal antiinflammatorydrugs Thyroid hormone History of viral hepatitis

flavonoid compounds. These compounds exert tremendous effect on protecting the liver from damage, as well as enhancing detoxification processes. Silymarin has shown impressive results in double-blind studies?l-B The standard dosage for silymarin is 70 to 210 mg three times daily.

Promoting Elimination In addition to directly supporting liver function, proper detoxification also involves promoting proper elimination. A diet that focuses on high-fiber plant foods should be sufficient to promote proper elimination by supplying an ample amount of dietary fiber. If additional support is needed, fiber formulas can be prescribed. These formulas are composed of natural plant fibers derived from psyllium seed, kelp, agar, pectin, and plant gums like karaya and guar. Alternatively, they can be purified semisynthetic polysaccharides like methyl-cellulose and carboxymethyl cellulose sodium. Psyllium-containing laxatives are the most popular and usually the most effective. Fiber formulas approximate most closely the natural mechanism that promotes a bowel movement. In the treatment of candidiasis, 3 to 5 g of soluble fiber at bedtime should be recommended, especially if antiyeast therapies are employed, to ensure that dead yeast cells are excreted and not absorbed.

Probiotics Intestinal flora plays a major role in the health of the host, especially in the battle against GI tract infe~tion.2~3 Intestinal flora is intimately involved in the host’s nutritional status and affects immune system function, cholesterol metabolism, carcinogenesis, and aging. Due to the importance of L. acidophilus and B. bifidum to human health, probiotic supplements can be used to promote overall good health. However, probiotics have several specific uses. The four primary uses related to chronic candidiasis are promotion of proper intestinal environment, postantibiotic therapy, vaginal yeast infections, and urinary tract infections. The dosage of a commercial probiotic supplement is based on the number of live organisms. The ingestion of 5 to 10billion viable L. acidophilus or B. bifidum cells daily is a sufficient dosage for most people. Amounts exceeding these may induce mild GI disturbances, while smaller amounts may not be able to colonize the GI tract. See Chapters 117 and 118 for a more comprehensive discussion of these useful agents.

Natural Antiyeast Agents A number of natural agents have proven activity against C. albicuns. Rather than relying on these agents as a primary therapy, however, it is important to address the factors that predispose one to chronic candidiasis, especially lack of either hydrochloric acid or pancreatic enzymes. The five approaches we feel most comfortable

Chronic Candidiasis

in recommending as natural agents against C. albicans are as follows: Caprylic acid Berberine-containingplants Garlic Enteric-coated volatile oil preparations Propolis Most, but not all, patients can achieve benefits from the natural agents described here rather than the drug approach. Use of any effective antiyeast therapy alone likely results in the Hemheimer ("die-off") reaction due to the rapid killing of the organism and subsequent absorption of large quantities of yeast toxins, cell particles, and antigens. The Herxheimer reaction refers to a worsening of symptoms as a result of thisdying off. The Herxheimer reaction can be minimized by the following measures: Following the dietary recommendations for a minimum of 2 weeks before taking an antiyeast agent Supporting the liver by following the recommendations made earlier Starting any of the previously described antiyeast medications in low doses and gradually increasing dosages over 1month to achieve full therapeutic dosage

Caprylic Acid Caprylic acid is a naturally occurring fatty acid that has been reported to be an effective antifungal compound in the treatment of ~andidiasis.2~2' Since caprylic acid is readily absorbed in the intestines, it is necessary to take timed-release or enteric-coated caprylic acid formulas to allow for gradual release throughout the entire intestinal tractF8 The standard dosage for these delayed-release preparations is 1000 to 2000 mg with meals.

Berberine-Containing Plants Berberine-containingplants include goldenseal (Hydrastis canadensis), barberry (Berberis vulgaris), Oregon grape (Berberis aquifolium), and goldthread (Coptis chinensis). Berberine, an alkaloid, has been extensively studied in both experimental and clinical settings for its antibiotic activity. Berberine exhibits a broad spectrum of antibiotic activity, having shown antibiotic activity against bacteria, protozoa, and fungi,including C. ~ l b i c a n s . ~ - ~ ~ Berberine's antibiotic action against some of these pathogens is actually stronger than that of antibiotics commonly used for the disease these pathogens cause. Berberine-containing plants should be considered in infectious processes involving the previously mentioned organisms. Berberine's action in inhibiting C. albicans, as well as pathogenic bacteria, prevents the overgrowth of yeast, which is a common side effect of antibiotic use. Diarrhea is a common symptom in patients with chronic candidiasis. Berberine has shown remarkable

antidiarrheal activity in even the most severe cases. Positive clinical results have been shown with berberine in relieving diarrhea in cases of cholera, amebiasis, giardiasis, and other causes of acute GI infection (e.g., Escherichiu coli, Shigellu, Salmonella, and Klebsiellu)and may also relieve the diarrhea seen in patients with chronic candidiasis.The dosage of any berberine-containing plant should be based on berberine content. As there is a wide range of quality in goldenseal preparations, standardized extracts are preferred. Three times a day dosages are as follows: Dried root or as infusion (tea), 2 to 4 g Tincture (1:5), 6 to 12 ml(1.5 to 3 tsp) Fluid extract (l:l),2 to 4 ml(0.5 to 1tsp) Solid (powdered dry) extract (4:lor 8%to 12%alkaloid content), 250 to 500 mg Note that the dosage recommendations for berberine would be 25 to 50 mg three times daily or a daily dosage of up to 150 mg. This dosage is consistent with the dosage range in the positive clinical studies in patients with GI infections. For children, a dosage based on body weight is appropriate. The daily dosage would be the equivalent of 5 to 10 mg of berberine/kg (2.2 lb) body weight. Berberine and berberine-containing plants are generally nontoxic at the recommended dosages; however, berberine-containing plants are not recommended for use during pregnancy and higher dosages may interfere with B vitamin m e t a b ~ l i s m . ~ ~

Alliurn sativum Garlic has demonstrated sigruficant antifungal activity. In fact, its inhibition of C. albicuns in both animal and test tube (in vitro) studies have shown it to be more potent than nystatin, gentian violet, and six other reputed antifungal agents.The active component is allicin-the pungent and odorous principle of garlic. The modern clinical use of garlic features the use of commercial preparations designed to offer the benefits of garlic without the odor. These preparations are prepared in such a manner that the allicin is not formed until the enteric-coated tablet is delivered to the small and large intestine. The treatment of chronic candidiasis requires a daily dose of at least 10 mg allicin or a total allicin potential of 4000 pg. This amount is equal to approximately one clove (4 g) of fresh garlic. Going beyond this dosage with these preparations usually results in the odor of garlic being detectable.

Enteric-Coated Volatile Oils The most recent "new wave" of natural anti<. albicans formulas are enteric-coated volatile oil preparations. Volatile oils from oregano, thyme, peppermint, and

Syndromes and Special Topics rosemary are all effective antifungal agents. One study compared the anti<. albicuns effect of oregano oil with that of caprylic a ~ i d . Although 4~ the minimum inhibitory concentration of oregano oil was less than 0.1 pg/ml and the 0.1% survival of C. albicuns occurred at a concentration of 45 pg/ml, the minimum inhibitory concentration of caprylic acid was less than 500 pg/ml and 0.1% survival occurred at a concentration of 5000 pg/ml. These results indicate that the anti<. dbicuns activity of oregano oil is greater than 100 times more potent than caprylic acid. Because volatile oils are quickly absorbed and associated with inducing heartburn, an enteric coating is recommended to ensure delivery to the small and large intestine. An effective dosage for an enteric-coated volatile oil preparation is 0.2 to 0.4 ml twice daily between meals.

Melaleuca alternafolia Tea tree oil is another option, especially in the topical treatment of candida infections such as thrush or vaginal yeast infection. In one open study, 27 patients with AIDS and oral candidiasis clinically refractory to fluconazole were randomized to receive either an alcohol-based or alcohol-freeMeZaZeuca altemufoliu oral solution four times daily for 2 to 4 weeks. Overall, 60% of patients demonstrated a clinical response to this oral solution (seven patients cured and eight patients clinically improved) at the 4-week evaluation.&

Propolis Propolis has shown considerable in vitro antimicrobial activity against C. aZbicans, as well as an ability to enhance the effectiveness of conventional antifungal d r u g ~ . 4Its ~ -cytotoxic ~~ activity against C. albicans, along with its immune-enhancing effects, make propolis a strong candidate for treatment of chronic candidiasis.

THERAPEUTIC APPROACH The following is a comprehensive step-by-step approach to the successful elimination of chronic candidiasis. Step 1. Identify and address predisposing factors: Eliminate the use of antibiotics, steroids, immunesuppressing drugs, and birth control pills (unless there is an absolute medical necessity) Perform a CDSA Follow the specific recommendations if the identifiable predisposing factor is dietary factors, impaired immunity, impaired liver function, or an underlying disease state

Step 2. Recommend the C. albicuns control diet: Eliminate refined and simple sugars Eliminate milk and other dairy products Eliminate foods with a high content of yeast or mold including alcoholic beverages, cheeses, dried fruits, melons, and peanuts Eliminate all known or suspected food allergies Step 3. Provide nutritional support: A high-potency multiple vitamin and mineral formula Additional antioxidants 1T of flaxseed oil daily Step 4.Support immune function: Promote a positive mental attitude Help patients deal with stress by teaching positive stress-coping techniques Recommend avoiding alcohol, sugar, smoking, and elevated cholesterol levels, which can impair immune function Recommend plenty of rest and good sleep Support thymus gland function; prescribe 750 mg of crude polypeptide fractions daily Step 5. Promote detoxification and elimination: Recommend 3 to 5 g of a water-soluble fiber source such as guar gum, psyllium seed, or pectin at night If necessary, recommend lipotropic factors and silymarin to enhance liver function Step 6. Recommend probiotics: Dosage: 5 to 10billion viable L. ucidophilus and B. bifidurn cells daily Step 7. Use appropriate antiyeast therapy: Ideally, use the recommended nutritional or herbal supplements, or both, to help control against yeast overgrowth and promote a healthy bacterial flora If necessary, use prescription antiyeast drugs appropriately These simple steps should take care of chronic candidiasis in most cases. If a patient follows these guidelines and fails to achieve significant improvement or complete resolution, further evaluation is necessary to determine if chronic candidiasis is the underlying factor. Repeat stool cultures and antigen levels are often helpful in this goal. If the organism has not been eradicated, stronger prescription antibiotics can be used, along with the other general recommendations.

Chronic Candidiasis

1. Truss 0.The missing diagnosis. Birmingham, A L POB 26508,1983. 2. Crook WG. The yeast connection, ed 2. Jackson, TN: Professional Books, 1984. 3.Kroker GF. Chronic candidiasis and allergy. In Brostoff J, Challacombe SJ, eds. Food allergy and intolerance. Philadelphia: WB Saunders, 1987850-872. 4. Crook WG. The yeast connection and the woman. Jackson, TN: Professional Books, 1995. 5. Woodhead M. Antibiotic resistance. Br J Hosp Med 1996;56314315. 6. Cohen ML. Epidemiology of drug resistance. Implications for a post-antimicrobial era. Science 1992;2571050-1055. 7. World Health Organization. Fighting disease, fostering development. Report of the Director General. London: HMSO, 1996. 8.Demling L. Is Crohn’s disease caused by antibiotics? Hepatogastroenterology 1994;41:549-551. 9. Bauman DS,Hagglund HE. Correlation between certain polysystem chronic complaints and an enzyme immunoassay with antigens of Candida ulbicans. J Advancement Med 1991;45-19. 10. Boer0 M, Pera A, Andriulli A, et al. Candida overgrowth in gastric juice of peptic ulcer subjects on short- and long-term treatment with H2-receptorantagonists. Digestion 1983;28:158-163. 11. Rubinstein E, Mark Z, Haspel J, et al. Antibacterial activity of the pancreatic fluid. Gastroenterology 1985;88:927-932. 12. Sarker SA, Gyr K. Non-immunological defence mechanisms of the gut. Gut 1992;33987-993. 13. Iwata K. Toxins produced by Candiah albicans. Contrib Microbiol I m m ~ n o1977;4:77-85. l 14. Axelsen NH. Analysis of human Candida precipitins by quantitative immunoelectrophoresis: a model for analysis of complex microbial antigen-antibody systems. Scand J Immunol1976;5177-190. 15. Farah CS, Elahi S, Drysdale K, et al. Primary role for CD4(+) T lymphocytes in recovery from oropharyngeal candidiasis. Infect Immm 2002;70724-731. 16. Fidel PL Jr. Immunity to Candidu. Oral Dis 2002;8(suppl2):69-75. 17. Klein A, Pappas SC,Gordon P, et al. The effect of nonviral liver damage on the T-lymphocyte helper/suppressor ratio. Clin Immunol Immunopathol 1988;46:214220. 18. Abe F, Nagata S, Hotchi M. Experimental candidiasis in liver injury. Mycopathologia 1987;100:37-42. 19. Barak AJ, Beckenhauer HC, Junnila M, et al. Dietary betaine promotes generation of hepatic Sadenosylmethionine and protects the liver from ethanol-induced fatty infiltration. Alcohol Clin Exp Res 1993;17552-555. 20. Zeisel SH, Da Costa KA, Franklin PD, et al. Choline, an essential nutrient for humans. FASEB J 1991;5:2093-2098. 21. Salmi HA, Sama S. Effect of silymarin on chemical, functional, and morphological alteration of the liver. A double-blind controlled study. Scand J Gastroenterol1982;17517-521. 22. Boari C, Montanari FM, Galletti GF’, et al. [Toxic occupational liver diseases. Therapeutic effects of silymarin.] Minerva Med 1981; 722679-2688. 23. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989;9:105-113. 24. Isolauri E. Probiotics in human disease. Am J Clin Nutr 2001; 731142S116S. 25. Sullivan A, Nord CE. The place of probiotics in human intestinal infections. Int J Antimicrob Agents 2002;20313-319. 26. Keeney EL. Sodium caprylate. A new and effective treatment of moniliasis of the skin and mucous membrane. Bull Johns Hopkins Hosp 1946;78333-339. 27. Neuhauser I, Gustus EL. Successful treatment of intestinal moniliasis with fatty acid resin complex. Arch Intem Med 1954;93:53-60.

28. Schwabe AD, Bennett LR, Bowman LP. Octanoic acid absorption and oxidation in humans. J Appl Physiol 1964;19:335-337. 29. Hahn FE,Ciak J. Berberine. Antibiotics 1976;3:577-588. 30. Amin AH, Subbaiah TV, Abbasi KM. Berberine sulfate. Antimicrobial activity, bioassay, and mode of action. Cun 1 Microbiol 1969; 15~1067-1076. 31. Johnson CC, Johnson G, Poe CF. Toxicity of alkaloids to certain bacteria. II. Berberine, physostigmine, and sanguinarine. Acta Pharmacol Toxic01 1952;871-78. 32. Kaneda Y, Toni M, Tanaka T, et al. In vitro effects of berberine sulphate on the growth of Entamoeba histolyticu, Giurdiu lumbliu and Trichomonas vaginalis. Ann Trop Med Parasitol 1991;85:417-425. 33. Subbaiah TV, Amin AH. Effect of berberine sulphate on Entumoebu histolyticu. Nature 1967;215:527-528. 34. Ghosh AK, W h i t MM, Ghosh DK. Effect of berberine chloride on Leishmania donovani. Indian J Med Res 1983;78:407-416. 35. Mahajan VM,Sharma A, Rattan A. Antimycotic activity of berberine sulphate. An alkaloid from an Indian medicinal herb. Sabouraudia 1982;2079-81. 36. Gupte S. Use of berberine in treatment of giardiasis. Am J Dis Child 1975;129866. 37. Bhakat MP, Nandi N, Pal HK, et al. Therapeutic trial of Berberine sulphate in non-specific gastroenteritis. Indian Med J 1974;6&19-23. 38.Kamat SA. Clinical trial with berberine hydrochloride for the control of diarrhoea in acute gastroenteritis. J Assoc Physicians India 1967;15525-529. 39. Desai AB, Shah KM, Shah DM. Berberine in the treatment of diarrhoea. Indian Pediatr 1971;8462-465. 40. Sharma R, Josh CK, Goyal RK. Berberine tannate in acute diarrhoea. Indian Pediatr 1970;7496-501. 41. Choudhry VP, Sabir M, Bhide VN. Berberine in giardiasis. Indian Pediatr 1972;9:143-146. 42. Rabbani GH, Butler T, Knight J, et al. Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerue. J Infect Dis 1987;155:979-984. 43. Kowalewski Z, Mrozikiewicz A, Bobkiewicz T, et al. [Toxicity of berberine sulfate.] Acta Pol Pharm 1975;32:113-120. 44. Moore GS, Atkins RD. The fungicidal and fungistatic effects of an aqueous garlic extract on medically important yeast-like fungi. Mycologia 1977;69341-348. 45. Sandhu DK, Warraich MK, Singh S. Sensitivity of yeasts isolated from cases of vaginitis to aqueous extracts of garlic. Mykosen 1980;23:691-698. 46. Prasad G, Sharma VD.Efficacy of garlic (Allium sativum) treatment against experimental candidiasis in chicks. Br Vet J 1980;136:448-451. 47. Stiles JC, Sparks W, Ronzio RA. The inhibition of Candida albicans by oregano. J Appl Nutr 1995;4796-102. 48. Vazquez JA, Zawawi AA. Efficacy of alcohol-based and alcohol-free melaleuca oral solution for the treatment of fluconazole-refractory oropharyngeal candidiasis in patients with AIDS.HIV Clin Trials 2002;3:379-385. 49. Stepanovic S, Antic N, Dakic I, et al. In vitro antimicrobial activity of propolis and synergism between propolis and antimicrobial drugs. Microbiol Res 2003;158:353-357. 50.Ota C, Unterkircher C, Fantinato V, et al. Antifungal activity of propolis on different species of Candida. Mycoses 2001;44:375-378. 51. DAuria FD, Tecca M, Scazzocchio F, et al. Effect of propolis on virulence factors of Candida albicans. J Chemother 2003;15: 454-460. 52. Martins Rs, Pereira ES Jr, Lima SM, et al. Effect of commercial ethanol propolis extract on the in vitro growth of Candida albicans collected from HIV-seropositive and HIV-seronegative Brazilian patients with oral candidiasis. J Oral Sci 2002;44:41-48.

Food Reactions Stephen Barrie, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Introduction 583 History of Food Allergy 583 Allergies Today 584 Causes and Development 584 Signs and Symptoms 584

Food Allergy Testing 586 Radioallergosorbent, Skin, and Oral Challenge Testing 586 Follow-upTesting 587 Related Tests to Consider 587

The Role of the Immune System in the Allergic Response 585 Innate Immunity 585 Acquired Immunity 585 Types of Immune Reactions 585 Role of IgE and IgG 586 IgUlgG and Physiologic Function 586

Therapeutic Considerations 588 Diet 588 Reestablishing a Healthy Bowel Microflora 588 Reestablishing Normal Digestion 589

INTRODUCTION Food and environmental allergies and sensitivities, collectively called “adverse food reactions” for the purposes of this chapter, have been implicated in a wide range of medical conditions affecting virtually every part of the body-from mildly uncomfortable symptoms such as indigestion and gastritis to severe illnesses such as celiac disease, arthritis, and chronic infection. Allergies and sensitivities have also been directly linked to serious disorders of the central nervous system including depression, anxiety, and chronic fatigue. Adverse food reactions cause the immune system to synthesize and release reactive chemical agents such as histamines, cytokines, lymphokines, and interferons. These hormonelike substances can dramatically influence cellular physiology, producing far-reaching effects on the immune, endocrine, and nervous systems. Because toxins can initiate a similar set of reactions, food allergy and toxicity are considered intimately connected in a clinical sense. Although the terms are often loosely interchanged, food reactions may be classed into two categories. First, there are true food allergies, which can cause atopic hypersensitivity reactions, including airway closure, throat and tongue edema, urticaria, and other severe symptoms leading up to anaphylaxis. Second, there are “allergies” that do not cause overt symptoms and these are loosely classified

Summary

589

as ”sensitivities” or ”intolerances”by many practitioners. An example of a sensitivity may be an allergic response to a food or environmental inhalants, which may be the culprit lurking behind a “mysterious” set of symptoms that are not readily diagnosableusing conventionalmethods of testing. Not being able to effectively pinpoint the cause of these vague or mysterious symptoms can create profound frustration for the physician and the patient alike. Testing for specific allergies (covered in Chapter 19) is one way to uncover foundational causes of illness. Armed with the knowledge provided by approach, the physician can design a specific treatment program to reduce or eliminate exposure to antigenic substances and thus effectively help to alleviate the patient’s symptoms. Allergy testing is also valuable as a preventive measure for patients who are not currently experiencing overt symptoms related to allergic reactions. It can reveal unsuspected food sensitivities that, if ignored, could result in cumulative stress on the immune and other systems over time-a condition that may eventually lead to severe illnesses.

History of Food Allergy Hippocrates recorded the first recognition of food sensitivity, observing that milk could cause gastric upset and urticaria. In 200 AD Galen described a case of allergy to goat’s milk, and in 1679 Willis observed that the ingestion of wine could precipitate asthma. 583

Soon after the turn of the twentieth century, Shloss described several cases that established a strong correlation between food allergy and the pathogenesis of atopic dermatitis.’ W. W. Duke was one of the first to make extensive observations of foods causing allergic responses. In the early 1920s, Duke published several papers linking food ingestion to bladder pain, Meniere syndrome, colitis, gastrointestinal (GI) upset, and diarrhea.2J Not long afterward, Walzer and his colleagues45 performed experiments clearly demonstrating how ingested food antigens penetrate the GI barrier and are transported through the bloodstream to mast cells in the skin. In the 1930s Rinkel first described food sensitivities that differed from the classic immediate anaphylactic reactions. The symptoms he described occurred hours or days subsequent to ingestion and could be masked or unmasked by the offending food.6 Rinkel’s discovery has been borne out by recent research confirming that delayed-type food allergies play a primary role in the immune system’s response to ingestants?

Allergies Today The incidence of food and environmental allergies and the number of atopic individuals have increased dramatically in recent times. Hypersensitivities involving bronchial symptoms and asthma, for example, nearly doubled in the 1 9 8 0 ~It. ~is estimated that atopic dermatitis alone now affects between 10% and 15%of the population at some time during their lives, and that this condition is often directly provoked by food antigens?Jo Adverse reactions to food have been reported in about 25% of younger children.” As an often well-known example of food allergy in kids, the peanut is the most common childhood allergenI2and occurs in about 1%of children, 1.4% of the population overall, and is responsible for half of the food reaction-related death^.'^,'^ Some physicians even claim that food allergies are a leading cause of most undiagnosed symptoms. As one investigator noted, ”The management of allergic diseases involves considerable financial and other costs. In industrialized countries, atopic disease is the commonest cause of morbidity and a significant factor in mortality.”a Why has the incidence of allergy risen so dramatically? Food products most frequently incriminated in allergic reactions are often hidden as ingredients in commercial foods.15 Many modem foods, as well as medicinal drugs such as penicillin, also contain preservatives, stabilizers, artificial colorings, and flavorings. Some scientistsbelieve that increased chemical pollution in our air, water, and food is to blame. Foods can easily become contaminated by the use of insecticides in farming. Other possible reasons for increased food hypersensitivity include: earlier weaning and earlier introduction of solid foods to infants; genetic manipulation of plants, resulting in food components that cross-react with

normal tissues; and less diversity in the average dietleading to repeated exposure to foodsubstances and the subsequent development of hypersensitivities. Probably all of these and more have contributed to the increased frequency and severity of allergic symptoms.

Causes and Development Food allergy is well documented as an expression of an inherited genetic predisposition.16 Hence allergic histories can often be found in both parents and siblings. One study discovered that when both parents are allergic, 67% of the children are also allergic. When only one parent is allergic, 33% are allergic.” Inadequate digestion of food products due to hypochlorhydria or pancreatic enzyme deficiency, or both, is also thought to be a significant cause of food allergies. When proteins are not digested to amino acids, dipeptides, or short chain polypeptides, they retain their antigenic properties. These antigenic molecules may then be absorbed through a “leaky gut” and exposed to the immune system, creating a state of chronic immune hypersensitivity.

Signs and Symptoms Food and environmental allergies have been linked to a wide range of medical conditions affecting virtually every part of the body. They have been shown to cause migraines,’a ec~erna,’~ thrombophlebitis?oarthritis,colitis:1 enuresis, ear infections, gallbladder disease,22childhood hyperactivity,= hypotension,” ~ r t i c a r i a , ~ ~ ~ , ~ glaucoma,30and many other pathologic conditions. Any of the symptoms shown in Table 53-1 may be a result of possible food allergies.

1 Symptoms and diseases commonly System

Symptoms and diseases

Gastrointestinal

Canker sores, celiac disease, chronic diarrhea, duodenal ulcer, gastritis, irritable colon, malabsorption, ulcerative colitis, vomiting

Genitourinary

Bed-wetting, chronic bladder infections, nephrosis

Immune

Chronic infections, frequent ear infections

MentaUemotional

Anxiety, depression, hyperactivity, inability to concentrate, insomnia, irritability, mental confusion, personality change, seizures

Musculoskeletal

Bursitis, joint pain, low back pain

Respiratory

Asthma, chronic bronchitis, wheezing

Skin

Acne, eczema, hives, itching, rash

Miscellaneous

Arrhythmia, edema, fainting, fatigue, headache, hypoglycemia, itchy nose or throat, migraines, sinusitis

Food Reactions GI dysfunctions such as peptic ulcer, dyspepsia, gastroduodenitis, and hiatal hernia may promote some of these adverse reactions to Substantial information in the medical literature has emerged regarding the role of systemic inflammation in cardiovascular disease, diabetes, and obesity. These works demonstrate that there are immune and inflammatory mechanisms that underlie insulin resistance and atherosclerosis?z-x Because food allergies can trigger mild, chronic, and systemic inflammation, there are direct reasons to think that food allergy also encourages the progression of cardiovascular aliments.

THE ROLE OFTHE IMMUNE SYSTEM IN THE ALLERGIC RESPONSE The immune system is a complex molecular network with specific functions that defend the human host against invading organisms. The body develops two types of immunity to protect itself innate immunity and acquired immunity.

Innate Immunity When functioning properly, the immune system can resist organisms and toxins that damage human tissue. Resistance includes the following: 1. Phagocytosis of bacteria and other invaders by white blood cells and cells of the macrophage system 2. Destruction of organisms by the acid secretion of the stomach 3. Integumentary defense 4.Destruction of foreign organisms or toxins by chemical compounds in the bloodstream (lysozyme, complement complex, polypeptides, natural killer cells)

Acquired Immunity Acquired immunity is the human body’s ability to develop extremely powerful specific immunity against individual invading antigens such as lethal bacteria, viruses, and toxins. The following are two basic types of acquired immunity: 1. Humoral, or B-cell, immunity, which involves the production of circulating antibodies 2. Cell-mediated, or T-cell, immunity, which involves the formation of large numbers of activated lymphocytes specifically designed to destroy the foreign agent

Acquired immunity is extensively involved in allergic reactions. Substances that initiate immune response are known as antigens. Generally, antigens are proteins or large polysaccharides having a high molecular weight (28000 Da). Food represents the largest antigenic challenge confronting the human immune system.35As Sid Baker, MD, has pointed out, the surface area of the GI tract is greater

than the area of a tennis court, making it the largest, most active immune-reacting surface in the body. Immunologically mediated food hypersensitivity is the result of interactions among ingested food antigens, the digestive tract, tissue mast cells, circulating basophils, and food antigen-specific immunoglobulins. The five major classes of immunoglobulins are IgA, IgD, IgE, IgG, and IgM. (“Ig” stands for immunoglobulin, and the other letter simply designates the class of the antibody.) IgE defends against parasitic infection and is known as the reaginic antibody for its major role in instigating immediate allergic responses to foods and other environmental antigens. The other immunoglobulins appear to be more involved in less immediate reactions. Of these, IgG is the most abundant, comprising about 80% of all circulating a n t i b ~ d i e s . ~ ~

Types of lmmune Reactions Although the function of the immune system is to protect the host from foreign antigens, abnormal immune responses can lead to tissue injury and disease. Food allergy reactions are just one expression of this type of immune-mediated damage. Gell and C ~ o m b have s~~ classified the mechanisms of immune tissue injury into four distinct types:

Type 1: lmmediate hypersensitivity reactions These reactions occur within 2 hours of contact with allergens. Antigens bind to preformed IgE antibodies already attached to the surface of the mast cell or the basophil and cause the release of chemical mediators such as histamine and eosinophilic chemotactic factor. Various allergic symptoms may result, depending on the location of the mast cell: In the nasal passages there may be sinus congestion; in the bronchioles, constriction (asthma); in the skin, hives and eczema; in the synovial cells, arthritis; in the intestinal mucosa, inflammation with resulting intestinal spasm or malabsorption; and in the brain, headaches, loss of memory, and inability to concentrate.

Type 2: Cytoxic reactions These reactions involve the binding of either IgG or IgM antibodies to cell-bound antigen. The antigen-antibody binding activates the complement cascade, resulting in damage to the cell to which the antigen is bound. Type 3: lmmune complex-mediated reactions Immune complexes are formed when antigens bind to antibodies. If not excessive, and assuming a healthy immune response, these complexes are usually cleared from the circulation by the phagocytic system. However, deposition of these complexes in tissues or in vascular endothelium can produce immune complex-mediated tissue injury. This tissue damage is further enhanced

Syndromes and Special Topics

by the presence of vasoactive amines, which increase vascular permeability and promote the deposition of more immune complexes. Type 3 responses are usually delayed, occurring hours or even days after exposure. They have been shown to involve both IgG and IgG immune c0mplexes.3~~

Type 4: T-cell dependent reactions This delayed-type reaction is mediated primarily by T lymphocytes, after an allergen makes contact with a mucosal surface. By stimulating sensitized T cells, inflammation may result within 36 to 72 hours of contact. A type 4 reaction does not involve antibodies.

Role of IgE and IgG IgE antibodies are believed to trigger allergic reactions when they crosslink on the surface of GI mast cells, stimulating the release and production of chemical mediators such as histamine, proteoglycans, and leukotrienes. These potent reactors instigate a barrage of effects on surrounding intestinal tissue and, by inducing intestinal permeability, may also allow passage of food antigens into the bloodstream. When this happens, other organs in the body then become targets for the allergic reaction; further involvement with other cell types in the body may result in the creation of a chronic, perpetual immune response. Because most severe, immediate allergy symptoms are IgE mediated, many doctors have limited their testing to this class of immunoglobulins. Certainly, an abundance of medical literature supports using the IgE assay as a means of diagnosing type 1 allergic react i o n ~There . ~ ~is~also considerable evidence, however, underscoring the sigruficance of IgG as a marker in allergy testing as well. In fact, it is estimated that IgG and IgG complex mediators are involved in 80% of all food allergy reactions.44 Repeated exposure to an antigen can eventually produce allergy-like responses or hypersensitivities. These reactions are usually delayed, with symptoms that may not surface until hours, or even days, after the initial exposure. One study found that nearly 60% of patients with food intolerance exhibited late (delayed) rather than early or immediate reactions to provoking f0ods.4~ Although IgE may be involved, it is theorized that these delayed reactions are primarily mediated by IgG. Specific IgE has a half-life in circulation of 1 to 2 days, and a half-life on the mast cell of about 14 days. IgG, on the other hand, appears to have a circulating half-life of 21 days, with a residual time on the mast cells that can last as long as 2 to 3 months4 Thus an I& assay is an essential tool for diagnosing the possible causes of delayed, nonanaphylactic responses, the so-called hidden allergies, which cannot be detected with conventional IgE

tests such as radioallergosorbent test (RAST) or skin testing. Numerous studies indicate a role for IgG in non-IgE, mast-cell mediated diseases, as well as various food a l l e r g i e ~ . ~IgG ~ - ~ lcan induce basophil degranulation, triggering the release of histamine and other potent chemical mediators on exposure to specific antigens-a common mechanism of allergic reactions. In one study, individuals with hypersensitivity to shrimp were determined by double-blind, placebocontrolled challenges. Shrimp-specific IgE and IgG, but not IgM and IgA, were sigruficantly higher in the group with shrimp hypersensitivity as compared with controls.52 Another group of researchers verified that children with atopic eczema showed much higher levels of IgG antibodies to casein and ovalbumin subclasses than did controls.

IgEAgG and Physiologic Function Besides providing a means for diagnosing suspected antigens, IgE and IgG can have crucial implications for GI and immune function. In experimental models, IgG antibodies have been shown to increase intestinal perm e a b i l i t ~ .Thus ~ ~ high levels of IgG to food antigens have been found in other disease conditions associated with increased intestinal permeability, such as IgA deficiency and inflammatory bowel disease.%This increased permeability is believed to be caused by a selective transport mediated by Fc receptors on epithelial surfaces. By increasing intestinal permeability, undetected elevated levels of IgG could result in increased exposure to antigens. Production of IgG and IgE is controlled by at least two cytokines, interleukin-4 (IL-4) and interferon-y (IFN-y). Because there is evidence that increased synthesis of IgG and IgE is a result of decreased inhibitory effect of IFN-y,”56 it is postulated that defective immunoregulation involving IL-4 and IFN-y both sustains and increases the synthesis of IgG and IgE a n t i b ~ d i e s . ~ ~

FOOD ALLERGY TESTING Radioallergosorbent, Skin, and Oral Challenge Testing Although many food allergy experts regard oral challenge testing for immediate food hypersensitivities as accurate and reliable, it can be time consuming and potentially dangerous if the reaction is severe?* Nevertheless, food challenges represent the state-of-the-art meth~d.~~fjO To summarize briefly, once the patient is placed on an oligo-allergenic diet, suspected foods are given in a titrated manner until there is a clear clinical reaction, or the highest dose of that particular item is achieved. Double-blind, placebo-controlled food challenges are also possible to study this method by using placebo

Food Reactions instead of a challengingfood. The effort involved in such a procedure is justified because it can elucidate relevant food allergens in some cases and in others can prevent individuals from being exposed unnecessarily to diets that may be harmful to them.59 Conventional skin testing, atopic patch tests, and RAST tests measuring IgE-mediated reactions cannot guide physicians as to the potential for delayed, nonIgE-mediated reaction^.^^ In one study, researchers surmised that because an IgG subclass was involved in late-onset reactions, patients exhibiting delayed bronchial allergic reactions failed to show positive skin test reactions or RAST results to a specific allergen.6I In addition, there are clinical situations where skin-testing is unfeasible and may inadvertently trigger life-threatening symptoms.62

Follow-up Testing The immune system is a highly sensitive, reactive molecular network that is constantly changing and adapting in response to myriad stimuli. Because of this ongoing state of flux, food sensitivities in the same individual may vary over the course of time. In one study, 580 patients with pathologic reactions to foods were examined after a period of 9 years. Researchers found a dramatic shift in the patients’ antigenic responses to different food groups, with many individuals exhibiting sensitivities to foods they had not reacted to 9 years earlier, perhaps due to changes in food consumption patterns and preparation methods.15 Approximately 20% of children also outgrow peanut allergies.13As allergic relationships change, there is a need for ongoing, consistent follow-up testing as time progresses, to carefully monitor the patient’s immune response and to modify therapeutic interventions as needed.

Related Tests to Consider Intestinal Permeability A healthy intestinal tract provides an effective barrier against excessive absorption of food antigens. With increased gut permeability, greater quantities of antigens are allowed to penetrate the GI barrier, resulting in an overly sensitized, reactive immune system in some individuals. Increased permeability has been implicated in type 1, type 2, and type 4 allergies.63It has also been suggested that high fat intake may destabilize GI tight junctions and cell membranes, thus compromising the epithelial function as a barrier for passage of toxic substances and allergenic agents to the circulatory system.@ Contact between an allergen and the digestive tract significantly increases intestinal absorption of macromolecules, leading researchers to conclude: “Evaluation of intestinal permeability . . . provides an objective means of diagnosing food allergy and assessing the effectiveness of anti-allergic Intestinal permeability

testing evaluates the small intestine’s effectiveness as a macromolecule barrier, monitors changes in mucosal permeability, and determines underlying causes of systemic problems linked to GI function (see Chapter 23 for a complete discussion of this important topic).

Comprehensive Digestive Stool Analysis Maldigestion of food products is considered a significant cause of food allergy. When proteins are not digested properly to amino acids, dipeptides, or short-chain polypeptides, they retain their antigenic properties. This can trigger repeated allergic responses by the immune system, possibly leading to a state of chronic hypersensitivity. The comprehensive digestive stool analysis (CDSA) can provide clues about the possible cause of food allergies by closely examining the digestion and absorption status of the GI tract. Some researchers have suggested that food allergy is not an immunologic disease but a disorder of bacterial fermentation in the colon. According to this theory, food intolerance is caused by a combination of factors, including reduced gut enzyme concentrations, imbalanced bacterial flora, and increased intestinal permeability (also known as “leaky gut syndrome”67;see Chapter 23 for a more complete discussion on intestinal permeability and Chapter 14 for a more complete discussion of CDSA).

Fecal sIgA Secretory IgA (sIgA) is the predominant immunoglobulin in intestinal secretions, the first-line defender against GI pathogens68 including bacteria, parasites, fungi, toxins, and viruses. Found abundantly in saliva and other mucosal fluids, sIgA works by forming immune complexes with pathogenic microorganisms, allergenic food proteins, and carcinogens, preventing them from binding to the surface of absorptive cells. If sIgA response is impaired, mucosal tissue repair may be compromised, leading to reduced mucosal integrity, decreased tolerance mechanisms to foods,@and reduced immunity against foreign invaders. Fecal sIgA testing uses sIgA as a clinical marker to evaluate the status of mucosal immunity. Low sIgA levels can signal the presence of a previously unsuspected allergy or other autoimmune disorder.

Adrenocortex Stress and Melatonin Profiles Because the etiology of food and environmental allergy involves interaction among numerous chemical mediators in the immune system, including serotonin, many sensitized individuals commonly exhibit various endocrine dysfunctions. By producing various cytokines, the hypothalamus modulates neuroendocrine function during systemic i n f l a ~ ~ ~ ~ ~ Animal ~ t i o studies n . ~ ~ have demonstrated that lowered hypothalamic-pituitary

Syndromes and Special Topics adrenal axis function may contribute to inadequate immunoregulation under stressful conditions, thus leading to chronic inflammation and susceptibility to allergic di~ease.~O*~~ Animal experiments have also shown that intracerebroventridar transplantation of hypothalamic tissue from inflammation-resistant rats into susceptible rats can reduce peripheral inflammation by more than 85%.69Moreover, the severity of allergy symptoms often follow a chronobiotic pattern, highly influenced by circadian hormone rhythms.

THERAPEUTIC CONSIDERATIONS Allergy testing reveals whether certain food and environmental substances may be antigenic, providing the clinician with clear, specific results to use in designing an effective therapeutic program. Treatment involves five essential components: Avoidance of identified allergens Rotation diet until sensitivity is decreased Reestablishment of proper microbial milieu Healing of the damaged intestinal mucosa Correction of underlying causative factors, such as maldigestion Because the body’s immunologic response involves a complex series of molecular relationships that are still not fully understood, it is important that each patient’s case be carefully evaluated using various criteria. Antibody test results, a detailed medical history, and a thorough physical examination are all important factors to consider when diagnosing a suspected adverse reaction to food or inhalants. Additional challenge tests may also be necessary, once certain antigen candidates have been ruled out as unlikely by preliminary diagnostic tests. In any case where allergic reaction may potentially cause a life-threatening anaphylaxis, it is important for the patient to have an autoinjectable epinephrine preparation available (commonly known as an EpiPen) to avoid a fatal reaction.

Diet Oligoantigenic Diet An oligoantigenic diet has been proven, in a large

number of studies, to be highly effective in treating many types of food allergies. Children with attention deficit disorder show a marked improvement in their hyperactive behavior following the removal of provoking foods from their diets.73In another study, 93% of 88 children with severe frequent migraine recovered on an oligoantigenic diet, even in instances when the migraines were provoked by additional factors such as blows to the head, exercise, or flashing lights.74A lowallergen diet also significantly reduced symptoms of

colic in infants and chronic urticaria with arthralgia in adult

Rotation Diet Diversified rotation diets are often used to prevent new allergies from developing and to give the immune system a rest and the intestines a chance to heal (see Chapter 47). These diets are also shown to sigruficantly improve GI symptoms in patients with concomitant environmental illness.76Once the intestines are damaged and a food allergy susceptibility established, virtually any food eaten regularly will eventually establish an antibody response. This diet consists of eating tolerated foods at regularly spaced intervals of 4 to 7 days.” This approach is based on the principle that infrequent consumption of tolerated foods is not likely to induce new sensitivities or increase any mild sensitivities, even in highly sensitized and immune-compromised individuals. As tolerance for eliminated foods retums, they may be added back into the rotation schedule without reactivation of the allergy. Because patients commonly experience difficulties in adhering to the diet, profe~sional’~ nutritional counseling should be provided to a person attempting to design a rotation diet, in order to assist what may be a confusing process, as well to ensure proper nutritional intake and classification of foods by related taxonomical groupings. An excellent aid (The Rotation Game by Sally Rockwell, available at PO Box 31065, Seattle, WA, 98103) is available to assist patients.

Reestablishing a Healthy Bowel Microflora Fundamental to correction of GI dysfunction is reestablishment of the appropriate microbial flora of the intestine. The health-inducing bacteria are especially important because they suppress the growth of toxic bacteria. Reseeding the intestines is done through the use of probiotics and prebiotics. Probiotics are the normal bacteria found in the healthy intestines. Prebiotics are indigestible substances that help the healthful bacteria grow. Both prebiotics and probiotics also help by increasing the production of secretory IgA in the intestines, which also helps protect against bacteria and food allergens.27*78 Probiotic therapy has been shown to mitigate allergic inflammation, as demonstrated by the control of clinical symptoms and the reduction of local and systemic inflammatory markers.79As such, probiotics can be used as tools to alleviate intestinal inflammation, normalize gut mucosal dysfunction, and downregulate hypersensitivity reactions, probably by increasing intestinal permeability and by improvement of the intestine’s immunologic bar1ier.2~ The primary beneficial organisms used to reseed the intestines are Lactobacilli and Bifidobucteriu. They play

many important roles, a crucial one of which is inhibiting the growth of toxic bacteria, viruses, fungi, yeasts, and parasites.80 An important part of reseeding the intestines is to ensure that the food the health-promoting bacteria need to live on is easily available. One of the best ways to do this is with oligosaccharides, especially fructooligosaccharides.Fructooligosaccharidesare shortchain carbohydrates composed of 3 to 10 molecules of sugars, at least 2 of which are fructose. This molecule is essentially indigestible by humans. However, Bijidobucteria and Lactobacilli preferentially use fructooligosaccharides to grow and multiply. In contrast, toxic bacteria are unable to use these short-chain carbohydrates.81Foods rich in fructooligosaccharides include onions, asparagus, bananas, and maple syrup. See Chapters 117 and 118 and for a comprehensive discussion of methods for reestablishing a healthy GI microbial milieu.

Healing the Damaged Gut Reestablishing a healthy intestine is critical for the elimination of food allergies because a leaky gut will continue to expose food antigens to the immune system. Healing the damaged intestinal mucosa requires a comprehensive approach that includes eliminating all factors that injure the intestine (such as toxic bacteria), reestablishing the normal bowel flora, removing toxins from the intestines, improving digestion, decreasing inflammation, and promoting the metabolism and repair of the intestinal-liningcells.

Decreasing the Gut Inflammato y Reaction Several nutrients help decrease the local inflammatory reaction. Quercetin is a natural bioflavonoid that inhibits the release of inflammatory chemicals from sensitized mast cells, an especially useful effect for the sensitized gut. Quercetin and other bioflavonoids have been shown to decrease the release of intestinal prostaglandins and nitric inhibit the release of inflammatorychemicalsfrom mast cells, scavenge free radicals, and inhibit irritability of the muscles of the intestines. It has been used in animal studies to reduce the intestinal damage caused by ingestion of food allergems A typical dosage of Quercetin is 250 mg three times a day along with vitamin C. Also of value are fish oils, which have now been used for a wide variety of inflammatory and allergic diseases.@Fish oil is rich in the polyunsaturated N-3 fatty acids, eicosapentaenoic acid (EPA),and docosahexaenoic acid (DHA). EPA competes with arachidonic acid (AA) for metabolism by the cyclooxygenase and lipoxygenase pathways. Metabolites derived from EPA have reduced inflammatory activities as compared with their

AA-derived counterparts. Dietary supplementation with EPA leads to incorporation of EPA into membrane phospholipids, inhibition of 5-lipoxygenase pathway activity, and a reduction of the elaboration of platelet-activating factor. Neutrophil chemotaxis and the capacity of these cells to adhere to endothelial cells are also substantially attenuated. Clinical trials in rheumatoid arthritis, psoriasis, atopic dermatitis, and bronchial asthma have shown beneficial effects.= The typical EPA dosage is 1 to 3 g/day. Although no research has been done to document its efficacy, an old naturopathic remedy, Robert’s formula, has a long history of use in decreasing gut inflammation (see Chapter 181 for a full description).

Stimulating Regeneration of the Gut Mucosa Several nutrients help heal the intestines. Of particular value is glutamine, the most abundant amino acid in the blood. As one of the principal fuels used by the intestinal lining cells, it accounts for 35% of their energy production. Although readily available in the diet and synthesized in the body, supplementation improves the energy metabolism of the GI mucosa, thus stimulating regeneration.86Glutamine prevents intestinal mucosal damage by protecting epithelial tight junctions and by precluding paracellular permeabilities through an epidermal growth factor receptor-dependent mechanism.87Glutamine has been shown to decrease bacterial leakage across the intestines after they are damaged, presumably by stimulating repair.%A typical dosage of glutamine is 100 mg three times a day, although glutamine may be used at much higher doses (see Chapter 98).

Reestablishing Normal Digestion The Heidelberg gastric analysis test should be performed if achlorhydria or hypochlorhydria is suspected (see Chapter 21). Hypochlorhydria can be treated with oral betaine hydrogen chloride supplementation (see Appendix 7). Pancreatic insufficiency can be treated with exogenous pork or beef pancreatin (see Chapter 112) or microbial-derived digestive enzymes such as those extracted from Aspergillus oryzae.

SUMMARY Adverse food reactions are a widespread, often unrecognized cause of chronic ill health and disease. Substantial experience has shown remarkable clinical response when the offending foods are recognized and eliminated from the diet. The primary challenge is the difficulty in making an accurate diagnosis.

1.Shloss OM. Allergy to common foods. Trans Am Pediatr Soc 1918;2762-68. 2. Duke WW. Food allergy as a cause of abdominal pain. Arch Intern Med 1921;28151. 3. Duke WW. Meniere’s syndrome caused by allergies. JAMA 1923;81:2179. 4. Brunner M, Walzer M. Absorption of undigested proteins in human beings: the absorption of unaltered egg protein in infants. Arch Intern Med 1928;42:173-179. 5. Wilson SJ, Walzer M. Absorption of undigested proteins in human beings. IV.Absorption of unaltered egg protein in infants. Am J Dis Child 19359~49-54. 6. Rinkel HJ. Food allergy. J Kans Med Soc 1936;37177. 7. Breneman JC. Immunology of delayed food allergy. Otolaryngol Head Neck Surg 1995;113702-704. 8.Chandra RK. Food allergy and food intolerance: lessons from the past and hopes for the 21st century. Bib1 Nutr Dieta 1991;48: 149-156. 9. Sampson HA. Eczema and food hypersensitivity. In Metcalfe DD, Sampson HA, Simon RA, eds. Food allergy: adverse reactions to foods and food additives. Boston: Blackwell Scientific Publications, 1991:113-128. 10. Sampson HA. Food hypersensitivity and dietary management in atopic dermatitis. Pediatr Dermatol 1992;9:376379. 11. Kjellman NI. Natural history and prevention of food sensitivity. In Metcalfe DD, Sampson HA, Simon RA, eds. Food allergy: adverse reactions to foods and food additives. Boston: Blackwell Scientific Publications, 1991:319-331. 12. Roberts G, Lack G. Diagnosing peanut allergy with skin prick and specific IgE testing. J Allergy Clin Immunol2005;115(6):1291-1296. 13. Fleischer DM, Conover-WalkerMK, Christie L, et al. Peanut allergy: recurrence and its management. J Allergy Clin Immunol 2004; 114(5):1195-1201. 14. Berg S. Tackling the peanut allergy. Asthma Magazine 2004:9(4)13-15. 15. Andre F, Andre C, Colin L, et al. Role of new allergens and of allergens consumption in the increased incidence of food sensitizations in France. Toxicology 1994;93:77-83. 16. Gerrard JW, Vickers P, Gerrard CD. The familial incidence of allergic disease. Ann Allergy 1976;36:10-15. 17. Taube EL. Food allergy and the allergic patient; a simple review of problems encountered by the recently diagnosed patient. Springfield, IL:Thomas, 1978. 18. MONOJ, Brostoff J, Carini C, et al. Food allergy in migraine. Study of dietary exclusion and RAST. Lancet 1980;21-4. 19. Atherton DJ, Sewell M, Soothill IF, et al. A double-blind controlled crossover trial of an antigen-avoidance diet in atopic eczema. Lancet 1978;1:401-403. 20. Rea WJ, Peters DW, Smiley RE, et al. Recurrent environmentally triggered thrombophlebitis: a five year follow-up. Ann Allergy 1981;47:338-344. 21. Andresen AFR. Ulcerative colitis-an allergic phenomenon. Am J Dig Dis 1942;9:91. 22. Ader R, ed. Psychoneuroinununology. New York: Academic Press, 1981. 23. Egger J, Carter CM, Graham PJ, et al. Controlled trial of oligoantigenic treatment in the hyperkinetic syndrome. Lancet 1985;l: 540-545. 24. Edwards AM. Food-allergic disease. Clin Exp Allergy 1995;25 1619. 25. Michaelsson G, Juhlin L. Urticaria induced by preservatives and dye additives in food and drugs. Br J Dermatol1973;88:525-532. 26. Warin RF’, Smith RJ. Challenge test battery in chronic urticaria. Br J Dermatol 1976;94:401-406.

27. Isolauri E, Sutas Y,Kankaanpaa P, et al. Probiotics: effects on immunity. Am J Clin Nutr 2001;73(suppl2):444S45OS. 28. Werfel T. Skin manifestations in food allergy. Allergy 2001; 56(~~~~1)6798-101. 29. Rowe AH, Young EJ. Bronchial asthma due to food allergy alone in 95 patients. JAMA 1959;169:1158. 30.Raymond LF. Allergy and chronic simple glaucoma. Ann Allergy 1964;22:146. 31. Ciprandi G, Canonica GW. Incidence of digestive diseases in patients with adverse reactions to foods. Ann Allergy 1988;61:334-336. 32.Schmidt MI, Duncan BB. Diabesity: an inflammatory metabolic condition. Clin Chem Lab Med 2003;41:1120-1130. 33. Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord 2003;27(supp13):S53-555. 34. Sanchez-RecaldeA, Carlos Kaski J. Diabetes mellitus, inflammation and coronary atherosclerosis: current and future perspectives. Rev Esp Cardiol2001;54:751-763. 35. Spencer MJ. Immunologic methods useful in the diagnosis of infectious disease. In Lawlor GJ Jr, Fischer TJ, eds. Manual of allergy and immunology: diagnosis and therapy. Boston: Little Brown 1981: 365-92. 36. Buckley RH, Metcalfe D. Food allergy. JAMA 1982;248:2627-2631. 37. Perelmutter L. 1 6 4 : non-IgE mediated atopic disease. Ann Allergy 1984;52:64-69. 38. Paganelli R, Levinsky RJ, Atherton DJ. Detection of specific antigen within circulating immune complexes: validation of the assay and its application to food antigen-antibody complexes formed in healthy and food-allergic subjects. Clin Exp Immunol 1981;46 44-53. 39. Kaczmarski M, Malinowska I, Stasiak A, et al. IgE in children with adverse reactions to food. Pneumonol Alergol Pol 1992;608-15. 40. Edwards AM. Food allergic disease. Clin Exp Allergy 1995;25:1619. 41. Businco L, Falconieri P, Giampietro P, et al. Food allergy and asthma. Pediatr Pulmonol 1995;11:59-60. 42. Moneret-Vautrin DA, Kanny G, Halpem G. Detection of antifood IgE by in vitro tests and diagnosis of food allergy. Allerg Immunol (Paris) 1993;25:198-204. 43. Shakib F, McLaughlan P, Stanworth DR, et al. Elevated serum IgE and IgG4 in patients with atopic dermatitis. Br J Dermatol1977;9759-63. 44.Hamburger R. Proceedings of the First International Symposium on Food Allergy. Vancouver, BC, 1982. 45. Vatn MH, Grimstad IA,Thorsen L, et al. Adverse reaction to food: assessment by double-blind placebo-controlled food challenge and clinical, psychosomatic and immunologic analysis. Digestion 1995;56:421-428. 46. El Rafei A, Peters SM, Hams N, et al. Diagnostic value of IgG4 measurement in patients with food allergy. Ann Allergy 1989;629499. 47. Vijay HM, Perelmutter L. Inhibition of reagin-mediated PCA reactions in monkeys and histamine release from human leukocytes by human IgG4 subclass. Int Arch Allergy Appl Immunol1977;5378-87. 48. Vijay HM, Perelmutter L, krstein IL. Possible role of IgG4 in discordant correlations between intracutaneous skin tests and RAST. Int Arch Allergy Appl Immunol 1978;56:517-522. 49. Fagan DL, Slaughter CA, Capra JD, et al. Monoclonal antibodies to immunoglobulin G4 induce histamine release from human basophils in vitro. J Allergy Clin Immunol1982;70399-404. 50. Nakagawa T, Stadler BM, Heiner DC,et al. Flow-cytometric analysis of human basophil degranulation. 11. Degranulation induced by anti-IgE, anti-IgG4, and the calcium ionophore A23187. Clin Allergy 1981;11:21-30. 51. Parish WE. The clinical relevance of heat stable, short term sensitizing anaphylactic IgG antibodies (IgG STS) and of related activities of IgG4 and IgG2. Br J Dermatol1981;105223-231.

Food Reactions 52. Daul CB, Morgan JE, Lehrer SB. The natural history of shrimp hypersensitivity. J Allergy Clin Immunol1990;8688-93. 53. To10 K, Brandtzaeg P, Jonsen J. Mucosal penetration of antigen in the presence or absence of serum-derived antibody. Immunology 1977;33:733-743. 54. Paganelli R, Fagiolo U, Cancian M, Scala E. Intestinal permeability in patients with chronic urticaria-angioedema with and without arthralgia. Ann Allergy 1991;66181-184. 55. Romagnani S. Regulation and deregulation of human IgE synthesis. Immunol Today 1990;11:316-321. 56. Schultz CL, Coffman RL. Control of isotype switching by T cells and cytokines. Curr Opin Immunol1991;3350-354. 57. Barnes RM, Lewis-Jones MS, Allan S, et al. Development and isotype diversity of antibodies to inhalant and dietary antigens in childhood atopic eczema. Clin Exp Dermatol1993:18211-216. 58.Van Arsdel PP Jr, Larson EB. Diagnostic tests for patients with suspected allergic disease. Utility and limitations. Ann Intem Med 1989;110304-312. 59. Niggemann B. Role of oral food challenges in the diagnostic workup of food allergy in atopic eczema dermatitis syndrome. Allergy 2004;59(~~~~1)78:32-34. 60. Eigenmann PA. Do we have suitable in-vitro diagnostic tests for the diagnosis of food allergy? Curr Opin Allergy Clin Immunol2004; 4211-213. 61. Gwynn CM, Ingram J, Almousawi T, et al. Bronchial provocation tests in atopic patients with allergen-specific IgG4 antibodies. Lancet 1982;1:254-256. 62. Sampson HA, Metcalfe DD. Food allergies. JAMA 1992;268: 2840-2844. 63. Butkus SN, Mahan LK. Food allergies: immunological reactions to food. J Am Diet Assoc 1986;86:601-608. 64.nback NG, Nyblom M, Carlfors J, et al. Do surface-active lipids in food increase the intestinal permeability to toxic substances and allergenic agents? Med Hypotheses 2004;63:724-730. 65. Andre F, Andre C, Feknous M, et al. Digestive permeability to different-sized molecules and to sodium cromoglycate in food allergy. Allergy Proc 1991;12293-298. 66. Andre C, Andre F, Colin L, et al. Measurement of intestinal permeability to mannitol and lactulose as a means of diagnosing food allergy and evaluating therapeutic effectiveness of disodium cromoglycate.AM Allergy 1987;59:127-130. enterometabolic disorder? Lancet 67. Hunter JO. Food allergy-r 1991;338:495-496. 68. Russel GW, Kilian M, Lamm ME. Biological activities of IgA. In Ogra PL, Mestecky J, Lamm ME, et al, eds. Mucosal immunology. San Diego, C A Academic Press, 2004:225-240. 69. Wong ML, Bongiorno PB, Rettori V, et al. Interleukin (IL) lbeta, IL-1 receptor antagonist, IL-lo, and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: pathophysiological implications. Proc Natl Acad Sci U S A 1997;94227-232. 70. Buske-Kirschbaum A, Hellhammer DH. Endocrine and immune responses to stress in chronic inflammatory skin disorders. Ann N Y Acad Sci 2003;992231-240.

71. Buske-Kirschbaum A, Geiben A, Hollig H, et al. Altered responsiveness of the hypothalamus-pituitary-adrenal axis and the sympathetic adrenomedullary system to stress in patients with atopic dermatitis. J Clin Endocrinol Metab 2002;874245-4251. 72. Stemberg EM. Neuroendocrine factors in susceptibility to inflammatory disease: focus on the hypothalamic-pituitary-adrenal axis. Horm Res 1995;43:159-161. 73. Carter CM, Urbanowicz M, Hemsley R, et al. Effects of a few food diet in attention deficit disorder. Arch Dis Child 1993;69:564-568. 74. Egger J, Carter CM, Wilson J, et al. Is migraine food allergy? A double-blind controlled trial of oligoantigenic diet treatment. Lancet 1983;2865-869. 75. Hill DJ, Hudson IL, Sheffield LJ, et al. A low allergen diet is a significant intervention in infantile colic: results of a communitybased study. J Allergy Clin Immunol1995;96886-892. 76. Taylor JP, Krondl MM, Csima AC. Symptom relief and adherence in the rotary diversified diet, a treatment for environmental illness. Altern Ther Health Med 2004;1058-64. 77. Rinkel RJ. Food allergy IV.The function and clinical application of the rotary diversified diet. J Pediatr 1948;32266. 78.Gibson GR, Roberfroid MG. Dietary modulation of the human colonic microbiota. Introducing the concept of prebiotics. J Nutr 1995;125:1401-1412. 79. Miraglia del Giudice M, De Luca MG. The role of probiotics in the clinical management of food allergy and atopic dermatitis. J Clin Gastroenterol2004;38(suppl6):s84-85. 80. Lee Y-K, Salminen S. The coming of age of probiotics. Trends Food Sci Techno1 1995;6:241-245. 81. Hidaka H, Hirayama M, Tokunaga T, Eida T. The effects of undigestible fructo-oligosaccharides on intestinal microflora and various physiological new functions in human health. I. In Furda I, Brine CJ, eds. New developments in dietary fiber. New York: Plenum Press, 1990105-117. 82. Raso GM, Meli R, Di Carlo G, et al. Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1. Life Sci 2001;68921-931. 83. Di Carlo G, Mascolo N, Izzo AA, et al. Effects of quercetin on the gastrointestinal tract in rats and mice. Phytother Res 1994;8: 42-45. 84. Cleland LG, James MJ, Proudman SM. Food inflammation and the anti-inflammatory aspects of food. Asia Pac J Clin Nutr 2004; 13(suppl):S26. 85. Lee TH, Arm JP, Horton CE, et al. Effects of dietary fish oil lipids on allergic and inflammatory diseases. Allergy Proc 1991;12: 299-303. 86. Souba WW. Glutamine. A key substrate for the splanchnic bed. Annu Rev Nutr 1991;11:285-308. 87. Seth A, Basuroy S, Sheth P, et al. L-Glutamine ameliorates acetaldehyde-induced increase in paracellular permeability in Caco-2 cell monolayer. Am J Physiol Gastrointest Liver Physiol 2004;287: G510-517. 88. Klimberg VS, Salloum RM, Kasper M, et al. Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation. Arch Surg 1990;125:1040-1045.

Functional Toxicology Michael R. Lyon, BSc, MD CHAPTER CONTENTS Introduction 593 Common Toxins That Affect Human Health 594 Organohalogens 594 Organophosphates 594 Organic Solvents 594 Heavy Metals 594 Mechanisms of Toxic Injury 596 Targets of Toxicity 596 Biotransformation 596 Hormone Disruption 597 Toxicity of Heavy Metals 597 Biochemical Individuality and Toxic Response 598 Detoxifying Enzymes and Genetic Polymorphism 598 Metallothioneins and Genetic Polymorphism 598

Monofunctional and Multifunctional Effects 599 Fasting 599 Phase2 599 Other Nutritional Factors 600 Exercise 600 Nutritional and Environmental Regulation of Toxic Metals 600

Assessing the Toxicologically Impaired Patient 601 Organic Toxicants 601 Metal Toxicants 602 Detoxification 602 The Detoxification Lifestyle 602 Nutritionally Controlled Fasting 603 Gastrointestinal Rehabilitation 604

Nutritional and Environmental Factors That Modify Susceptibilityto Environmental Toxicants 599

INTRODUCTION The wide array of persistent toxicants in our environment has undoubtedly caused or contributed to a great diversity of health threats. Prominent biologists Colbom and Myers’ document the precarious state of the human as a species in the best-selling book Our Stolen Future. Although the environment-cancer connection has been acknowledged for many years, this book documents the increasing evidence that chemical pollutants pose a significant threat to our fertility, our intelligence, and many other aspects of health as well. Furthermore, the scientific literature is beginning to reflect an increasing awareness that polysymptomatic disorders such as multiple chemical sensitivity syndrome, sick building syndrome, chronic fatigue syndrome, and the Gulf War syndrome are all strongly associated with toxic chemical exposures.23 Humans reside on the top of the food chain and are subject to the phenomenon of bioconcentration or

biomagnhcation, as are other species near or at the top of the food chain. Additionally, long lives, occupational exposures, household chemicals, prescription drugs, and dental amalgams are some of the many reasons why humans are in a class of their own for magnitude and diversity of chemical exposure. Chemical threats to human health exist in both organic and inorganic forms. The actual number of xenobiotic chemicals that are encountered on a daily basis is vast. It is becoming clear that few, if any, of these toxicants act alone but, instead, generally act in synergy with other chemicals! Chemical synergy can increase a chemical’s toxicity by several hundredfold, resulting in ”superinteractions’’ far exceeding even those of an additive nature? In fact, synergistic chemical reactions may occur even before the toxicants enter the human body, changing the chemical’s nature and complicating their toxicologic evaluation even further.6 In addition, many toxins are now known to exert toxic effects at levels vastly lower 593

Syndromes and Special Topics than originally assumed. For example, cadmium has been shown to have estrogen-mimicking effects in tissue at a level of 100,OOOth of a part per billion.'

COMMON TOXINS THAT AFFECT HUMAN HEALTH Organohalogens Organohalogens are chemicals that are generally highly persistent in the natural environment, as well as the human body. The major categories of organohalogens are the organochlorine pesticides, polychlorinated biphenyls (PCBs),polybrominated diphenyl ethers (PBDEs), plastic residues, dioxins, and organic byproducts of water chlorination. All of these agents are subject to bioaccumulation in the food chain and are highly persistent within the human b0dy.8,~ One of the first manmade chemicals to be recognized as a persistent contaminant of the food chain with a distinct presence in human tissues was the organochlorine dichlorodiphenyltrichloroethane (DDT). Several other organochlorine pesticides, as well as the family of PCBs and fire retardants (PBDEs) are now established to be highly persistent and widely distributed as human contaminants. These agents were introduced and strongly promoted, in part, because they have minimal shortterm toxicity. However, they now are established to be highly disruptive to the endocrine system and have been linked to problems such as breast cancer, infertility, and premature onset of puberty.l0J1 More subtle effects of endocrine-disrupting organohalogens, particularly effects on behavior and neuropsychologic function have now been well described.12J3The ubiquitous and highly persistent nature of this group of chemicals makes them of grave concern to human health.

Organophosphates In the 1930s, Nazi scientists synthesized the organophosphate nerve agents Tabun and Sarin while looking for more effective pesticides. Although Sarin and Tabun are now classified as weapons of mass destruction and are officially banned from most nations, they formed the prototypes for the currently used organophosphate pesticides. Pesticides in use today are acutely less toxic than the parent chemical warfare agents. However, they use the same basic mechanism for exerting toxicity and they have no known safe dose at which no neurologic effects occur. Even though their half-lives are short in the environment, because they are so ubiquitous in our diets and used so frequently in homes, on pets, and in the environment, they pose a sigruficant risk to humans.14 Symptoms of chronic organophosphate pesticide toxicity can be subtle and cumulative. Mental and emotional dysfunction may develop so gradually that it can go unnoticed for years, or it may be attributed to aging.I5

Organic Solvents Numerous solvents are used occupationally and in the home for a multitude of purposes. Benzene, toluene, and various petrochemical solvents such as gasoline are all significantlyneurotoxic in long-term, low-level exposure and are of particular concern for pregnant women and ~ h i l d r e n . ' ~Solvents J~ have also been shown to carry signhcant carcinogenic potential.'*

Heavy Metals Numerous hazardous metals are part of daily life. The potential effects of toxic metals on human function are so vast that toxicity may manifest as almost any symptom humans are capable of experiencing. Although acute heavy metal poisoning is relatively rare, chronic low-grade heavy metal toxicity may actually be one of the most pervasive antecedents contributing to chronic disease. Except for the past 100 years, toxic metals were virtually absent from the general population. Adaptive physiologic mechanisms are phylogenetically unprepared for more than small trace quantities of toxic metals. Metals are not biodegradable and thus accumulate in the environment and enter the food chain. The recognition of heavy metal toxicity as a primary cause of chronic illness may be impaired by the vast economic importance of metals to the economy of all nations. The 30 years of intense fighting between scientists and industrial lobbyists over lead in gasoline illustrates the effort required to bring about changes in public health policy when it comes to metals.I9The hot debate over mercury in dental amalgams is becoming an even more intense war of vested intereskZ0The reclassification of sewage sludge from a toxic waste to an acceptable source of nitrogen for fertilizers is an example of how money drives unsustainable environmental practices that are leading to a rapid accumulation of toxic metals in the environment." Because of their ubiquitous distribution and their welldocumented toxicity, lead, mercury, arsenic, aluminum, and cadmium are of particular importance to the general population. The discussion of toxic metals in this chapter is limited to lead and mercury.

Lead Lead has been known to affect workers for at least 1000 years, and its hazards to the reproductive process have been known for at least a century. Childhood lead poisoning was first described in Australia 100 years ago, and for 50 years it was believed that if lead did not kill the child, he or she would be not affected by any residual problems.22However, careful follow-up of children who had recovered from lead poisoning showed that most suffered from school failure and behavioral problems. More recent evidence confirmed that subclinical levels of lead cause measurable deficits in neuropsychologic function.

FunctionalToxicology

Despite reduced use of lead-based paints and gasoline, lead continues to be a worldwide public health hazard. The marked effects of lead toxicity on the central nervous system (CNS)-lowering IQ and impairing memory, reaction time, the ability to concentrate-are well Lead is also a sigruficant health threat to adults. Several studies have found that the bones of modem humans contain lead on the order of 1000 times greater than bones of preindustrial humans." Apart from its effect on the brain, lead affects the function of the kidneys and the cardiovascular system.= Lead, at low levels, may act in synergy with other common toxicants to subtly suppress the immune system and impair health.z6

Mercury Mercury is the one of the most toxic of all elements, far Mercury is the deadliest and most more toxic than pervasive pollutant in the aquatic ecosystems, and its presence is steadily rising in most regions throughout North America, primarily due to coal burning power plants, and mining activities. Humans are exposed to mercury through consumption of fish (methylmercury), occupation (ionic mercury and mercury vapor), vaccinations (ethyhercury), and dental amalgams (mercury vapor). Except for populations that consume large amounts of seafood or workers in industries where mercury exists as an occupational hazard, the majority of the population is exposed to mercury through dental The basic premise for regarding the amalgam filling as safe was the assumption that the amalgamation process resulted in a stabilization of the normally volatile mercury. This premise has since been proven entirely false. Since the 1980s, it has been well established that mercury vapor is continuously released from amalgam fillings. The release of this vapor into the mouth increases immediately after chewingz9or tooth brushing30 and can result in a daily absorbed dose of mercury that exceeds the excretory capacity via the urine and stool. It has now been well established and published by several authorities, including the World Health Organization (WHO), that amalgam tooth fillings are, by far, the major source of mercury exposure for the general population.28 According to the WHOs expert committee, the daily human exposure to mercury vapor from amalgam fillings ranges from 3 yg to 17yg, compared with a maximum of 2.6 pg from all other sources. Mercury vapor released from dental amalgams is efficiently absorbed through the alveoli. Following absorption through the lungs, elemental mercury vapor (HgO) is only found transiently in the blood. Due to its high lipid solubility, elemental mercury is rapidly transported through cell membranes (includingmembranes of the cells comprising the blood-brain barrier). Once inside

metabolically active cells, HgO is then oxidized by catalase to form ionic mercury (Hg2+).Hg2+is not lipid soluble and therefore results in a high degree of retention of absorbed mercury and a tissue half-life ranging from days to decades depending on the particular ~ r g a n . ~ ~ , ~ ~ This phenomenon clarifies why studies have repeatedly demonstrated that after placement of amalgam fillings, blood, hair,and urinary mercury levels remain relatively low even though many organs develop concentrations of mercury many times greater than that of the b l ~ o d ? ~ , ~ Thus blood, hair,or nonchdenged urinary mercury levels bear little relationship to the total body burden of mercury gradually acquired from amalgam fillings. Once mercury enters the cell, it ultimately becomes bound covalently to the sulfhydryl groups found in glutathione and, to a lesser degree, to cysteine, biotin, lipoic acid, and coenzyme A, as well as to other protein sulfhydryl groups. The major intracellular sulfhydryl compound in mammals is the tripeptide glutathione. Glutathione and the enzyme glutathione peroxidase are probably the most important antioxidant defenses in h ~ m a n s . 3Mercury ~ has been shown to cause a marked reduction in glutathione production and glutathione peroxidase activity, and thus it may result in a marked rise in oxidative stress within the brain and other organs. Apart from the loss of antioxidant protection from mercury-induced inhibition of glutathione and glutathione peroxidase, mercury results in a marked increase in free radical generation through Fenton reactions and other mechanisms.36 In addition to its key role in antioxidant defenses, glutathione is also a critical component in the liver's detoxification mechanisms. Enzymes within the liver must form conjugates between glutathione and certain toxic metabolites, organic xenobiotics, and heavy metals to enable these toxins to be eliminated from the body. This process of glutathione conjugation makes toxic molecules more water soluble and enables their excretion via the bile or through the kidney. If liver glutathione production is markedly inhibited, as occurs when mercury accumulateswithin hepatocytes, mercury and numerous other toxic substances may more readily accumulate throughout the body because the excretion of such substances is sigruficantly irn~aired.3~ Furthermore, because most mercury is excreted through the stool and urine as a glutathione conjugate, individuals with longstanding body burdens of mercury (and thus depleted glutathione production) may not demonstrate elevated levels of mercury in the urine, blood, or stool when specimens are gathered in the absence of a challenge with an appropriate metal chelating agent. Thus tissue biopsy of target organs or a provocation test measuring urinary mercury after the administration of a chelating agent may currently be the only valid means to assess chronic mercury body burden.38

Numerous studies have demonstrated the body tissue uptake and distribution of mercury from dental amalgams. Studies using whole body imaging in primates with dental amalgams have clearly demonstrated that the amalgams result in high levels of mercury in the kidney, intestinal tract, brain, liver, and other organs.39 The impact of chronic, low-level mercury exposure is now known to adversely affect numerous other cellular and organ system processes. Ionic mercury may contribute siphcantly to autoimmune processes.mOf particular concern to the natural medicine practitioner is the impact that low levels of inorganic mercury have on gut flora. Research has demonstrated that multiple strains of antibiotic-resistant bacteria develop rapidly in the gut and oral cavity of both humans as well as nonhuman primates following the placement of amalgam fillings.*l Furthermore, subclinical levels of inorganic mercury have been shown to markedly impair the immune system's ability to suppress the growth of

Candida albicans." Amalgam fillings have been shown to contribute to mercury accumulation in human and animal kidneys, and this has been associated with a significant decrease in renal Human fertility has also been shown to be sigruficantly affected by low-level exposure to mercury vapor. A recent study examining 7000 dental assistants demonstrated that this group experiences a fertility rate approximately 40% less than that of women who have no occupational exposure to mercury.& Of perhaps greatest concern is the potential role of low-level, chronic mercury exposure on CNS function. It is now well established that amalgam-derived mercury accumulates in human brain tissue^."^ Mercury has been shown to concentrate selectively in human brain regions involved with memory function, and it may play a significant role in the etiology of Alzheimer's disease.&

Other reports have shown subclinical motor and neuropsychologic deficits among dentists and dental workers compared with control ~ubjects.4~ In fact, mounting evidence has led some researchers to suggest that mercury from amalgams may play a highly sigrulicant role in the etiology of numerous mental illnesses and neuropsychologic disorders (Table 54-1).4&50

MECHANISMS OF TOXIC INJURY Targets of Toxicity Xenobiotic-initiated injury may be largely described as affecting three possible targets5? 1.Toxicant agents may alter, remove, or impair the synthesis of specific molecules (e.g., phospholipids, fatty acids, proteins, nucleotides or glutathione). 2. Toxicants may alter structural entities (e.g./ mitochondria, cytoskeleton, plasma membrane or nucleus). 3. Toxicants may create disturbances in cell signaling (e.g., cytokines, eicosanoids, hormones, calcium channels, or neurotransmitters).

Biotransformation Most drugs, metals, and xenobiotics undergo biotransformation before being excreted through the stool, urine, or sweat. Although not every molecule is processed in this way biotransformation typically involve phase 1 and phase 2 modificationsin the liver. Most phase 1 modifications involve oxidation but can involve demethylation, hydroxylation, or dehalogenation. Phase 2 modifications result in conjugation of xenobiotic or metal ion with a carrier molecule such as glutathione, cysteine, sulfate, or glycine. The cytochrome P-450 enzymes are essential molecules involved in the metabolism of drugs, foreign chemicals, arachidonicacid, cholesterol,steroids, and other important lipids. However, xenobiotic biotransformation

Examples of toxic metal contaminants in humans Toxic metal

Some common sources

Effects of low-level chronic accumulation

Aluminum

Drinking water, antiperspirants, antiperspirant crystals, antacids, baking powder, bentonite

Immune suppression, cognitive dysfunction, dementia

Arsenic

Preserved wood (playgrounds and garden borders), drinking water, pesticides, fish

Gastrointestinalirritation, fatigue, cardiovascular damage, peripheral nerve damage, skin changes, cancer

Cadmium

Cigarette smoke, welding or grinding, air pollution, food from contaminated soils, chocolate

Kidney damage, cardiovascular damage, cognitive impairment

Lead

Old paint, lead solder water pipes, Contaminated soil, car batteries, sewage sludge, chocolate, popular calcium supplements

Brain and nervous system damage, decreased intelligence, high blood pressure, cardiovascular disease

Mercury

Dental amalgam fillings, freshwater fish and larger predatory ocean fish, vaccines (thimerosal preservative), broken thermometers, spilled liquid mercury

Depression, anxiety, intellectual impairment, severe fatigue, chronic pain, immune suppression, autoimmune disorders, dementia, peripheral neuropathies

Functional Toxicology

by cytochrome P-450 mixed function oxidases is a twoedged sword.52On one hand, many xenobiotics are highly toxic when entering the body and phase 1oxidation can change the ”molecular identity” of the molecule, Also, rendering it less toxic (phase 1 det~xification)?~ P-450 oxidation can render a xenobiotic more water soluble (more readily excreted and less prone to penetrate cell membranes). Because a sigruficant proportion of xenobiotics are lipid soluble, they readily pass through cell membranes (and the blood-brain barrier) and may accumulate in fatty tissues, causing prolonged toxic effects. Thus adequate activity of phase-1 liver detoxification is critical in protecting humans from toxic stress. However, biotransformation by cytochrome P-450 enzymes may play a significant role in establishing or increasing the toxic nature of a xenobiotic. Cytochrome P450 enzymes oxidize the xenobiotic entity and transform it into a reactive electrophile. This reactive intermediate, if not immediately transformed further by one of several conjugating enzymes (phase 2 detoxification), may exert toxic effects within the liver or systemically if it escapes from the hepatocyte. These effects may include one or more of the following reactions5’:

.

1. Covalent binding of the reactive metabolite to: Proteins (e.g., cross-linking of structural proteins; change in conformation of receptors, membrane pumps, enzyme carrier proteins, or peptide hormones) Lipids (e.g., cell membrane phospholipid binds to reactive, intermediate-forming,lipid-soluble xenobiotic, initiating lipid peroxidation) Nucleic acids (e.g., irreversible binding to DNA, initiating carcinogenesis)

.

2. Creating oxidative stress by one of three mechanisms: Cytochrome P-450 enzymes are oxidases that, in the process of xenobiotic biotransformation, generate reactive oxygen species (superoxide,peroxide, or hydroxyl radicals) exceeding the normal flu of reactive oxygen species generated by mitochondria1 respiratory activity. Xenobiotics, once biotransformed, are reactive electrophiles that are quenched by cellular antioxidant defenses (superoxide dismutase, catalase, glutathione peroxidase). This oxidative stress can lead to depletion of cellular antioxidant defenses.

.

Hormone Disruption The homeodynamic balance of virtually any of the body’s hormonal systems may be disrupted through toxic stress. Such disruptions may occur through effects upon the hypothalamic, pituitary, endocrine gland axis or peripherally on hormone production or hormone receptors. The estrogenic effect of environmental agents

has been a major focus in toxicology research.54It has been recognized for some time that a number of chemicals in the environment possess estrogenic activity in various biologic systems. These compounds include plant and fungal products, pesticides, plasticizers, estrogenic agents administered to livestock, and various other chemicals. It was originally postulated that estrogenic agents interacted with the estrogen receptor in an “on-off switch” fashion. This is now considered to be overly simplistic or even i n ~ o r r e c t . ~ ~ Different estrogenic agents bind to a wide variety of estrogen receptors and create hormone-receptor complexes with variable life spans and molecular conformation. The hormone-receptor complex then binds to one of several dozen nucleotide estrogen response elements. This trimolecular complex binds to various target genes in the nucleus and either activates or suppresses transcription. Depending on the ”flavor” of the hormone-receptorestrogen response element complex, a wide variety of specific hormonally mediated effects may occur. This phenomenon helps to explain how certain estrogenic agents can be carcinogenic (organochlorine pesticides) while others can be anticarcinogenic (phytoestrogens).The wide variety of responses of different tissues to estrogenic influences also helps to understand how some agents, for example, affect the risk of cancer while others affect behavior or sexual responsiveness.56

Toxicity of Heavy Metals Toxic metals share many of the deleterious effects of organic xenobiotics, particularly organically bound metals (e.g., methylmercury, tetraethyl lead, methylcyclopentadienyl manganese tricarbonyl [MM]). However, toxic metals have some peculiarities not exhibited by organic xenobiotics. For example, toxic metals act as ”chemical competitors” with chemically and physically similar nutritional trace metals (e.g., cadmium competes with zinc, lead competes with calcium, mercury competes This phenomenon may result in high with ~elenium)?~ rates of loss of the competitive nutrient metal or, alternatively, inhibition (or overactivation) of metal-dependent physiologic systems such as enzymes.

Metal-Catalyzed Oxidative Injury In addition, nonnutrient metals may bind to molecular regions where they carry out inappropriate catalytic activities including the generation of free radical^.^^,^^ The resulting oxidative damage to high-energy membrane pumps and other transport mechanisms required for the homeodynamic regulation of trace mineral and electrolyte balance may then exacerbatenutrient mineral loss even further. If membrane pumps are damaged, sharp concentration gradients of minerals and electrolytes can become blunted, leading to marked changes in the regulatory activity of the cell?’ For example, cytosolic levels

Syndromes and Special Topics of calcium are normally 1/ 10,OOOth the concentration found outside the cell or inside the endoplasmic reticulum or mitochondria. Oxidative injury to membrane pumps or calcium channels can result in a loss of this steep gradient. This rise in cytosolic calcium can result in overactivation of calcium-dependent systems such as the calmodulin family of enzymes. This may, in turn, result in various events such as hypertonia of skeletal muscle or activation of membrane phospholipases with subsequent degradation of membrane phospholipids and increased inflammation.

Mitochondria1 Disruption Toxic metals and a wide variety of xenobiotics also target the membranes of the mitochondria and result in marked alterations of energy m e t a b ~ l i s mToxic . ~ ~ mitochondrial damage may lead to rapid cellular aging, cell death, or intracellular acidosis. Paradoxically, intracellular acidosis may then place the cell into a partially "hibernative" state in which it is protected from lethal injury." This may help to explain the high degree of functional impairment and the minimal risk of lethality in patients with conditions such as chronic fatigue syndrome or fibromyalgia. In this model, toxic mitochondrial injury results in energy depletion, clinical exhaustion, and evidence of intracellular acidosis.

BIOCHEMICAL INDIVIDUALITY AND TOXIC RESPONSE Detoxifying Enzymes and Genetic Polymorphism A signhcant amount of cumulative data demonstrates that widespread genetic polymorphism for the expression of cytochrome P-450 enzymes exists within the human species.61The sigruficance of this phenomenon has not been completely described, but several studies suggest a strong correlation between genetic deficiency of certain cytochrome P-450 enzymes and susceptibility to environmentally mediated disorders such as Parkinson's diseasea and lung cancer.63In addition, individual variation in drug or xenobiotic metabolism due to genetic variation has been extensively investigated. Population studies have shown a wide range in metabolizing ability for all detoxification pathways including both cytochrome P-450 systems and conjugating pathways.@ The most well-described polymorphism in this category is due to the absence of cytochrome P-4502m. Such individuals, comprising 5% to 10% of Caucasian populations, are referred to as poor metabolizers (PMs). These individuals have a severely impaired capacity to metabolize more than 25 therapeutic drugs and a wide range of xenobiotics.@On the other end of the spectrum are individuals described as extensive metabolizers (EMS). Such individuals require a higher dose of several drugs to achieve

therapeutic effects and may have a more robust capability to handle certain environmental toxins. Heritable polymorphisms are also known for several conjugating enzymes (phase 2 detoxification) that are extensively involved in the metabolism of exogenous chemicals." For example, genetic polymorphism of the glutathioneStransferase (phase 2, glutathione conjugation) enzyme family is known to This is well regarded as a significant factor conferring susceptibility to environmental toxins. The significance of these genotypic variants to the incidence of functional illnesses such as chronic fatigue syndrome or fibromyalgia is likely but has not been studied.

Metallothioneins and Genetic Polymorphism One of the most important detoxification systems in all species from bacteria to humans depends on the production of a family of four different proteins known as metallothioneins (MTs). MTs are highly unusual proteins composed of about 30% cysteine and are responsible for storage, transfer, and detoxification of intracellular metal ions.68The primary role of MTs in the absence of toxic metals is the transport and short-term storage of zinc and copper. However, the importance of MT in protection against and elimination of toxic metals is also well described. MT is known to efficiently bind several toxic metals (particularly cadmium and mercury) and act as a transporter of the toxic metal to the liver or kidneys, where glutathione conjugation and subsequent excretion of the toxic metal may then occur. Because MT forms high affinity complexes with several metals, it may prevent toxic metals from reacting with other biomolecules or acting as free radical catalysts, thus attenuating their There is a wide variation in the concentration of MTs among species. Humans, for example, have about 10 times the concentration of MT in their organs as do rats or mice. Additionally, genotypic polymorphism for expression of certain MTs within a species has been demonstrated. Mutant mice and rat models have been identified with complete absence of the genes for one of four MT isoforms. In these MT-deficient animals, susceptibility to the toxic effects of heavy metals is increased by 60- to 100-fold. In contrast, it has been shown in animal models that resistance to heavy metal toxicity may be conferred in mutants that possess multiple copies of MT genes in their chromosomes. These animals may be capable of more prolific upregulation of MT p r o d u ~ t i o nGenetic .~~ polymorphism for MT expression also exists in Human cancer cell lines are known to be highly polymorphic in their ability to express MT genes. This is the primary reason why cancer patients vary in their resistance to metal cancer chemotherapeutic drugs." Some laboratories have begun to offer test panels that assess

FunctionalToxicology

MT function. These assays may provide clinically significant means to screen an individual’s susceptibility to metal intoxication. Importantly, gene expression for MT production is highly inducible (e.g., through zinc supplementation and exercise).7s75Because of this, working with the factors that induce optimal production of MT may be important during a heavy metal detoxification regimen.

shown to have highly beneficial effects on detoxification systems.Onions and garlic; cruciferous vegetables; chlorophyll; terpenoids (e.g., citrus, @go biloba, menthol, camphor); bioflavonoids (e.g., citrus, pine bark, grape seed, green tea); and others all act in a complex yet highly beneficial manner in bringing about improvements in detoxification ~apability.~~

NUTRITIONAL AND ENVIRONMENTAL FACTORS THAT MODIFY SUSCEPTIBILITY TO ENVIRONMENTAL TOXICANTS

One significant consideration for the natural medicine clinician is the impact of fasting on detoxifying enzyme function. For the most part, P-450 enzymes are relatively resistant to depletion during fasting and may even be significantly induced by products of starvation such as ketones and xenobiotics released from stored fat.76On the other hand, the conjugating enzymes are highly dependent on dietary provision of adequate amounts of substrate and are consumed rapidly under states of high xenobiotic load or oxidative stress.79 Because they do not provide adequate substrate for phase 2 detoxification, complete fasting, juice fasts, or other nutritionally marginal fasting regimens may therefore result in a marked rise in highly toxic bioactive intermediates and free radicals with a concomitant decrease in phase 2 detoxification activity. This state of unbalanced detoxification can result in marked oxidative stress and may be particularly deleterious to chronically ill patients whose antioxidant reserves are already exhausted or signtficantlyweakened. Perhaps in the past, when tissue burdens of xenobiotics and heavy metals were low, fasting regimens were of significant benefit. However, the modern human is probably ill advised to follow such traditional detoxification methods, especially for lengthy periods of time.

Although genetic predisposition may confer certain absolute risks in an individual’s response to toxic stress, most aspects of detoxification and resistance to toxic agents involve highly modifiable nutritional, environmental, and lifestyle factors. The cytwhrome P-450 enzymes (P-450)are located primarily in the liver. However, several other organs including the small intestine, lungs, brain, and kidneys contribute in a lesser way to the P-450 mediated oxidation of xenobiotics, as well as endobiotics such as hormones and neurotransmitters. Numerous factors can markedly influence phenotypic expression of these critical enzymes. Although there have been more than 30 P-450s characterized in detail in humans, it appears that the majority of P-450 activity is carried out by about 6 i s ~ f o r r n sThe . ~ ~ impact of various physical, chemical, and microbiologic agents on P-450 activity is highly complex and may invoke either upregulation, downregulation, inhibition or stimulation of enzyme activity.

Monofunctional and Multifunctional Effects Some agents act in a monofunctional manner, upregulating only one P-450, whereas others are multifunctional, with a wide pattern of induction or inhibition, or both, of several phase 1and phase 2 enzyme systems. The impact of any factor on detoxification status results from the sum of all effects on phase 1 and phase 2 enzyme systems. For example, moderately high-protein diets bring about upregulation of P-450s in a pattern that decreases susceptibility to pesticides and other xenobiotics, while low-protein diets increase pesticide toxicity because of P-450 downregulation. On the other hand, cigarette smoking effects a monofunctional induction of P-450, bringing about biotransformation of certain xenobiotics into potent carcinogens while simultaneously increasing oxidative stress.n Numerous phytochemicals are known to exert potent effects on both phase 1 and phase 2 enzyme activities. With few exceptions (such as grapefruit slowing drug metabolism or St. John’s wort accelerating drug metabolism), plant foods common to the human diet have been

Fasting

Phase 2 Phase 2 detoxification systems are particularly dependent on and responsive to adequacy of substrates necessary to carry out the conjugation of oxidized intermediates. Adequate amounts of protein with special attention to the adequacy of glycine, L-glutamine, methionine, L-cysteine, and N-acetylcysteine, along with inorganic sulfate, selenium, and additional taurine are all examples of nutrients that are highly important in the support of phase 2 Lipoic acid supplementation markedly enhances the level of intracellular glutathione in states of adequate sulfur amino acid intake.84Undenatured whey protein, rich in glutathione precursors, has been shown in several studies to increase cellular and plasma glutathione.85Cruciferous vegetables significantly upregulate phase 2 enzyme activity.86Antioxidants also provide a highly supportive role in liver detoxification by reducing oxidative stress resulting from phase 1 activity and by preventing glutathione consumption by reactive oxygen species. Milk thistle, curcumin, and green

loss of mineral from the body.104Therefore the requirement for several nutrient minerals may rise significantly above the recommended daily allowance in the metal Other Nutritional Factors toxic patient. The clinician must also be aware that certain nutritionally necessary metals (e.g., iron, copper) Other nutritional factors affect detoxification. High carbohydrate diets bring about downregulation of P-450~ can become conditionally toxic and perhaps should only be supplemented if a deficiency is determined. The best in a pattern that results in an undesirable reduction in the metabolism of several drugs and hormones.52 example of this is excessive iron stores in patients who are homozygous or heterozygous for a hemochromatosis Intestinal dysbiosis inhibits P-450 activity through an mutation, the most common genetic disorder. Although increase in nitric oxide production.g0On the other hand, homozygotes are relatively uncommon, heterozygotes supplementation with probiotic bacteria can markedly for this disorder may be as high as one in five in certain reduce the adverse effects of bacterial endotoxin on the populations and these individuals may be at risk for liver, as well as decreasing gut perrneability?l Certain manifestations of iron toxicity, particularly if iron suptypes of dietary fiber markedly enhance the activity of plementation is admini~tered.'~~ Other nutrient metals both phase 1 and phase 2 detoxification systems in the (e.g., manganese) may be nontoxic unless control of Fiber also decreases stool transit time, acts to absorption is bypassed through inhalation or injection.la sequester conjugated xenobiotics and endobiotics located in the bile, and reduces the level of bacterial The excretion of toxic metals is governed by a complex chain of interwoven activities. If any link in this deconjugating enzymes in the stool. All of these effects reduce the recycling of xenobiotics and endobiotics chain is broken, proper elimination of the toxic metal through the enterohepatic c i r ~ u l a t i o n . ~ ~ , ~ ~ may not occur. Toxic metals must be released from the cell; moved from the extracellular fluid into the blood; Exercise transported from the blood to the liver or kidneys; and then transported from the kidneys to the urine or the Exercise, if accompanied by adequate calories and proliver into the bile. Once the metal is in the bile, it must tein, has been shown to result in liver hypertrophy and then be transported out of the body in the stool before a multifunctional induction of detoxification enzyme being reabsorbed back into the circulation. systems, as well as a marked increase in antioxidant enzymes and reduced glutathione in several 0 r g a n s . 9 ~ ~ ~ For example, the first step in mercury excretion Additionally, exercise results in a mobilization of extrainvolves binding of the mercury to metallothionein (MT) cellular fluid and lymph where xenobiotics often temor glutathione within the cell. Metallothionein producporarily reside after being released from cells by exocytosis tion in tum, is highly inducible through exercise and supplementation with zinc, while zinc deficiency results or other mechanisms. In addition, sweating augments the liver's detoxification mechanisms; it has been shown in MT depletion. Metallothionein production is also to be a highly important route of elimination for both induced by supplementary L-cysteine or by brief periods o r g a n i ~ ~and * * metalliclOOJO1 ~ toxicants. of oxidative stress (as occurs from aerobic exercise).lo7 MT works in cooperation with glutathione in the initial Nutritional and Environmental Regulation mobilization of mercury from cells, and it also shares of Toxic Metals intracellular antioxidant activity with glutathione (MT is Nutritional adequacy has a marked influence on the 50 times as potent as an antioxidant as glutathione).'08 Selenium may also play a role in binding to mercury absorption, retention, toxicity, and excretion of toxic within the cell and forming a transportable complex. The absorption of lead, as well as cadmium, is Therefore selenium supplementation has been recomincreased in states of iron or calcium deficiency. In addimended in the treatment of mercury toxicity.'@' tion, iron deficiency is one of many factors that lead to Once mercury is mobilized by MT or glutathione, it is increased intestinal permeability. This in turn markedly enhances the uptake of aluminum, an abundant dietary transported through the cell membrane (probably by constituent that is not well absorbed through intact exocytosis). Mercury must then be carried away from the cell to limit toxicity on the cell membrane and to enteric mucosa.lo3The absorption of several other toxic transport mercury to the liver. Exercise is probably helpmetals may be enhanced by increased intestinal permeability. Inadequacy of certain minerals also leads to ful in accelerating the movement of mercury from the enhanced retention of toxic metals. For example, calcium extracellular fluid, through the lymph and into the blood. deficiency increases both lead and cadmium body burden As well as exercise, hyperthermic therapy such as with a and selenium deficiency increases mercury retention. sauna may be helpful in mobilizing mercury directly from the extracellular fluid.'oo Once the mercury reaches the As described previously, toxic metals compete with liver, it usually undergoes conjugation with glutathione nutritional minerals and lead to displacement of nutrient minerals from protein binding sites, as well as excessive and is transformed into a mercapturate. The mercury tea extracts are particularly useful antioxidants for the li~er.8~~~

FunctionalToxicology

mercapturate is then released into bile.”O Both the liver and the kidneys are highly sensitive to glutathione depletion by mercury. Hepatic and renal glutathione production can be enhanced by supplementing the diet with L-cysteine, N-acetylcysteine, glutathione, cruciferous vegetables, dietary fiber, undenatured whey protein, lipoic acid, onions, and garlic. Lipoic acid may also assist in this process by directly binding inorganic mercury in the liver and accelerating its excretion into the bile while simultaneously inducing the formation of glutathione.”’ Once mercury has entered the intestine through the release of bile, it must leave the body via the stool. Optimal gastrointestinal function is important to prevent recycling of mercury through the enterohepatic circulation. Fiber has been shown to have a sigruficant effect in lowering total body burden of mercury through sequestration of intestinal mercury and reduction in stool transit time.l12 Other factors, including increased gut permeability, or intestinal dysbiosis resulting in deconjugating bacterial enzymes, are all key factors that determine how efficiently mercury can leave the body once it has passed from the liver into the small intestine. Since about 90% of excreted mercury leaves the body through the enteric route, colonic elimination is a vital component in maintaining an unbroken and efficient chain of excretion from the cell to the outside of the body for mercury, as well as a host of other toxicants.

Community City and neighborhood air quality, noise, electromagnetic fields Home Home heating and ventilation, cleaning chemicals, pesticides, paints, carpets, building materials, molds, allergens, water Hobbies Toxic chemicals, paints, solvents, metal fumes Occupation Workplace air quality, toxic chemicals Personal habits Smoking, drinking, drug use, sun exposure, exercise, stress management Diet Overall quality of diet, overeating or undereating, meat eater or vegetarian, fast foods, snack foods, deep-fried foods, fish and seafood, organic or nonorganic foods, food allergies or intolerances, leaky gut syndrome, abnormal microbial ecology of the digestive tract Drugs Prescription and nonprescription Dental Amalgams placed and removed, extractions, root canals Development Mother’s pregnancy history (e.g., smoking, drugs, drinking, toxic exposures, dental work), childhood exposures (e.g., leaded paints, pesticides, secondhand smoke)

ASSESSING THE TOXICOLOGICALLY IMPAIRED PATIENT

reduced glutathione, whole blood metallothioneins, copper/zinc ratio, reduced glutathione/metallothionein ratio, and zinc/metallothionein ratio. Other examples include the functional liver detoxification profiles offered through several commeraal laboratories. In these tests, patients are given drugs (often acetaminophen, aspirin, and caffeine) as a single oral dose. Urine is gathered following the ingestion of the test, and levels of metabolites processed through phase 1and phase 2 detoxification are measured. Although no profile that assays the function of more than a few out of the several dozen possible detoxification enzymes currently exists, these tests often do provide useful information for the clinician.

A carefully gathered toxic exposure history is a vital part of the clinical evaluation. The mnemonic C(H2) OP(D4) aids in remembering important elements of the toxic exposure history, as shown in Box 54-1. Of course, patients may not be aware of important sources of toxic exposure. They may also have genetic, nutritional, or lifestyle factors that leave them at elevated risk for toxicologically mediated health problems. The field of toxignomics is in its infancy, but several laboratories have begun to offer toxignomic assays to help in evaluating a patient’s genetic risk of toxin-mediated illness. Evaluations of single nucleotide polymorphisms (SNPs) to assess cytochrome P-450 variability, DNA, or RNA amplification techniques (primarily polymerase chain reaction, PCR) to assess adequacy of metallothionein or glutathione Stransferase activity are examples of toxignomic tests that are or are becoming commercially available to the clinician. Some laboratories have developed panels that include evaluation of several factors relative to a particular toxicologic system. For example, an available metallothioneine profile consists of measurements of seruin zinc, serum copper, serum ceruloplasmin, serum ceruloplasmin copper, nonceruloplasmin (“free”) copper, whole blood

In some cases an occupational history provides clues for which specific toxicants should be searched. Some toxicology laboratories offer extensive panels to quanhfy the level of organic toxins in blood, urine, or adipose tissue. Available panels include PCBs, organochlorine pesticides, PBDE fire retardants, furans, and dioxins. Body burdens for these agents are accurately assessed by providing a small sample of adipose tissue (often taken through a small incision under the umbilicus).For example, an electric utility worker with chronic fatigue syndrome may have a high body burden of PCBs as measured in a provided fat biopsy. In this case PCB tissue levels can be followed in a serial fashion following detoxification efforts. Such assessment may also help a patient to support a disability or worker’s compensation claim. However, unless a specific chemical or family of chemicals can be suggested by an exposure history, the range of possible organic toxicants is far too vast to be determined practically and financially in most cases. It is generally more realistic to assume that all functionally impaired patients carry a wide range of synergistically active organic toxicants at various levels and focus

Organic Toxicants

instead on engaging the patient in a comprehensive detoxification program using outcome-based measures and functional testing to gauge success.

Metal Toxicants On the other hand, the definitive assessment of a patient's

heavy metal burden is relatively simple and probably should be performed early on in the assessment of most patients with polysymptomatic, chronic illness. Metal toxic patients p m n t a unique clinical challenge and, if a sigruficant toxic metal burden is present, the outcome of clinical intervention may be disappointing unless the metal burden is effectively diminished. Once metal burdens are diminished, patients often respond far more effectively to other clinical interventions. OnIy a limited number of toxic metals are commonly found in humans, and most laboratories provide panels that include most of these metals. Hair analysis is simple and inexpensive to perform, and it may provide a reasonable means to screen patients for levels of certain metals such as lead or methylmercury (from seafood). However, the precision of this methodology in determining long-standing body burdens of most other metals is probably too low to base confident clinical decisions on and some toxicology authorities suggest that hair analysis be limited to population ~creening."~ Conventional toxicologists generally rely on other methodologies of assessing metal burden to gauge clinical decision making. "Acceptable" blood levels of lead in children and adults, as well as blood and urine levels of several other metals in industrial settings, have been widely suggested in published literature. However, the limitation of blood or urine tests is that they largely reflect only the level of ongoing exposure to the metal and may bear little relationship to tissue levels. Since tissue biopsy for heavy metal levels is impractical, postprovocative urine testing is probably the most reliable means to assess body burden of metals acquired through long-standing, low-level exposure, especially in the assessment of low-level inorganic mer~urialisrn."~ Although many variations on the challenge test have been performed with various metal chelating agents, a methodology used by the German toxicologist Daunderer is simple, relatively inexpensive, and correlates to clinical response to further t~vatment."~J~~ This methodology utilizes the chelating agent Dimercapto-propane sulfonate (DMPS) (Box 54-2). The use of the oral chelator dimercaptosuccinic acid (DMSA or succimer) for diagnostic postprovocative challenge testing has not been established, and some data suggest that it does not reflect mercury body burden."' Although no challenge test for mercury has been accepted using the chelators DMSA or EDTA, both agents may be useful for the assessment of lead burden (seeBox 54-2)."*

Not every clinician has the training or legal ability to safely use drug chelating agents to assess metal burdens or provide metal detoxification therapies. In the United States, DMSA is currently classified as a nutritional supplement. In several regions of the United States and Canada, naturopathic physicians can administer both oral and IV chelating drugs.

DETOXlFlCAT10N The Detoxification Lifestyle When working with chronically ill patients whose health is affected by toxicologic stresses, clinicians need to provide education to help these individuals develop habits of living that will reduce their exposure to toxicologic factors and improve the efficiency of their detoxification mechanisms. The mnemonic A NERD can help the clinician remember the important elements of a detoxification lifestyle. Patients who learn to follow these habits of living create a foundation for better long-term health, and their response to more extensive clinical interventions will be more successful. Avoid exposure to all known sources of toxicity. Chemical dependencies; smoking; excessive alcohol; unnecessary prescription drugs; toxic work environments;

The patient empties his or her bladder completely, drinks a large glass of water, and then has an IV inserted.The patient is placed supine, and DMPS is administered undiluted at a dose of 3-4 mg/kg (5250mg) over 20 minutes. Following the DMPS injection, the patient is instructed to walk around for approximately 11/2 hours and then a random urine sample is gathered. The volume of urine does not need to be measured in this case. The urine metal values are reported in micrograms of metal per gram of urinary creatinine. This method of reporting normalizes the sample for level of urinary concentration. A postprovocative urinary level of mercury A 0 pg mercury per gram of urinary creatinine is indicative of significantly elevated mercury body burden. Because a 24-hr collection is not used, the test is much easier for patients to perform and results in a much higher compliance than 24-hr sampling methods. Patients are not required to collect multiple samples and record urine volumes, so the accuracy may be improved over 24-hr methods as well. The half-life of DMPS is short, and the short sampling interval is a good reflection of quantities of toxic metals excreted with one injection. The lack of a baseline or preinjection urine sample is a departure from usual methodologies. However, the purpose of urine collection beforehand and afterward is to compare the level of current metal exposure (presample) to the body burden (postsample). Because most patients are not industrially exposed and probably have little ongoing exposure, the level of metals found on the preinjection sample is usually extremely low and these data do not add information to guide clinical decisions. Modified from references 115 and 116.

homes with lead paint; severe air pollution; polluted drinking water; standard North American dietsparticularly sugary drinks, junk foods, processed meats, fast foods, and deep-fried foods-and dental amalgam fillings are all examples of toxic sources that must be removed or avoided. Nutrition must be optimized for efficient detoxification. The diet must be based on whole foods (plenty of vegetables, fruits, and fiber) and should emphasize foods with a net alkalinizing impact with lower amounts of acid-forming foods. Generous portions of cruciferous vegetables should be eaten daily with modest amounts of olive oil, as well as onions, garlic, and modest amounts of lean, unprocessed protein. Supplements can include alkalinizing minerals (Ca, Mg, K, Zn)along with multivitamin/ trace elements, essentialfatty acids (DHA/EPA), N-acetylcysteine, lipoic acid, and antioxidant support (vitamin C, vitamin E, grape seed extract, green tea extract). Undenatured whey protein supports synthesis of glutathione. Detoxification medical food products are available with a base of undenatured whey, rice or pea protein, along with a range of nutrients to support detoxification.These can be used as a supplement to or in replacement of one meal per day to simphfy the daily detoxification supplement program. Exercise accelerates lymphatic flow, induces sweating, and increases metabolism and detoxification efficiency. Exercise should be a daily part of the detoxification lifestyle. Rest including proper sleep, relaxation, and stress management is an essential element in the detoxification lifestyle. Detoxification as a specific therapeutic activity should be considered as a periodic means to improve vitality and reduce toxic body burdens. Traditions of fasting and purification have been incorporated into the way of life, and health care systems of most traditional cultures and variations of fasting are central to the practices of ~tural, integrative,and functional medicine. Taking a few days to rest and rejuvenate the gastrointestinal tract and bolster the excretion of xenobiotics is a lifestyle habit that can improve a patient's vitality. Nutritionally controlled fasting for 5 to 7 days with every change of seasons is a reasonable recommendation for cliniaans to make to their patients. Another alternative is to have patients undergo a nutritionally controlled fast 1day per week on an ongoing basis. In addition, natural health care providers may use more intensive or lengtluer detoxification pmgrams for specific conditions responsive to these interventions.

Nutritionally Controlled Fasting The traditional practices of fasting or purification are usually religious in nature and usually involve an abstinence from food or certain kinds of food and a

focus on spiritual disciplines of prayer or meditation. Practitionersof natural medicine have also used various forms of fasting in order treat various chronic maladies and to decrease toxic stress. In some countries the use of water fasting as part of an inpatient sanitarium treatment remains a popular and accepted means of treatment for pain and fatigue syndromes, as well as certain autoimmune disorders.119Extreme low-calorie or zerocalorie forms of fasting result in loss of adipose tissue, with glucose being liberated from hepatic and muscle glycogen stores. Within 2 days of starvation or near starvation, necessary glucose is provided from cellular apoptosis and autophagy (programmed degradation of cellular organelles and muscle protein),'2o and the brain increasingly adapts to the use of the ketone body, betahydroxybutyrate.121(See Chapter 50 for a more complete discussion of fasting metabolism.) During fasting, stored xenobiotics and heavy metals are released and may largely be redistributed to and accumulate in the liver, kidneys, and brain since the mechanisms for excretion of these toxins require complex nutritional support that is lacking in starvation.122-125 Because of these concerns, many practitioners of natural and functional medicine prescribe a nutritionally controlled form of fasting intended to stimulate the mobilization of xenobiotics from cells while supporting and protecting detoxification and excretory mechanisms. Rigdenlz6has described the "enterohepatic resuscitation program for chronic fatigue syndrome" and reported sigruficant improvement in the majority of patients studied. In this uncontrolled study, subjectsconsumed a limited, low-calorie diet supplemented by a medical food product designed to provide nutritional support of hepatic detoxification including phase 1 (antioxidants)and phase 2 detoxification (phase 2 conjugation substrates). Bland,Iz7 in another uncontrolled study, used a similar program with a high degree of success in 106 patients with various chronic illnesses. Using a much different approach, clinicians prescribing exercise and s a w combined with supplementaryniacin, calcium, magnesium, and polyunsaturated oil report bringing about a s i w c a n t reduction in tissue PCBs and other fat soluble xenobiotics in toxic patients.'28130 Europeans have successfully used sauna treatment to decrease mercury levels in exposed ~0rkers.I~' These approaches have not been validated with controlled clinical trials. Recent studies have reported that the sucrose polyester fat substitute olestra results in a marked loss of lipophilic xenobiotics and decreased brain levels of these agents during caloric restriction, secondary to sequestration of biliary-excreted xenobiotics and interruption of enterohepatic r e c y ~ l i n g . ' ~ ~Concerns -'~ relating to gastrointestinal side effects and marked loss

Syndromes and Special Topics of fat-soluble vitamins secondary to olestra, as well as the need to consume it as part of a snack food, limit olestra's use as a detooxlfying agent. Decreasing stool transit time and increasing dietary soluble fiber may also reduce enterohepatic recycling of xenobiotics, but further research is required. Many clinicians practicing natural or functional medicine also prescribe metaldetowfying therapies using chelating drugs such as DMSA or DMPS. Clinicians should be completely familiar with the use of these agents before prescribing them, and they should be aware, as is true with all drugs, that serious side effects can occur with these agents. DMSA is classified as a nutritional supplement in the United States, but it is a drug with potential side effects. Dosing protocols for DMSA vary depending on physician preference and individual patient need, but currently two protocols are most often used. In one protocol, 10 to 20 mg/kg per day is given in three divided doses, using a 3-days-on, 11-days-off cycle with a minimum of eight cycles. A second protocol involves giving 500 mg per day (in two or three divided doses) every other day for a minimum of 5 weeks. DMSA is best taken between meals (Box 54-3).'%

Gastrointestinal Rehabilitation Gastrointestinal rehabilitation is a concept familiar to practitioners of natural medicine. Many clinicians consider gastrointestinal rehabilitation to be an essential part of any detoxificationprogram that should OCCUT even before detoxification interventions begin. This involves therapeutic steps to reduce intestinal permeability,

Many clinicians have been successfully prescribing a program of nutritionally controlled fasting that follows this general approach: Mild to moderate caloric restriction to promote fat loss No fast foods, junk foods, deep-fried foods High quantities of fresh vegetables and often fresh vegetable juice Simple, low-processed, oligoantigenic foods (low allergy potential), protein (e.g., chicken, fish, legumes), and whole grains (e.g., brown rice, millet, quinoa) Medical food product designed to support detoxification (1-3 times daily depending on quantities of other foods eaten) Light exercise daily Sauna 3-5 times weekly The nutritionally controlled fast is continued for 5-21 days or more depending on the patient's condition and the clinician's experience.

improve nutrient absorption, and increase immune response to gut pathogens while diminishing hypersensitivities. A useful approach follows the mnemonic "ANT PIE" (Abstain, Nourish, Toxins/detoxification, Probiotics, Identdy, Eliminate). Abstain from junk foods, deep-fried foods, sugary drinks, and other foods that harm or irritate the gut, as well as unnecessary drugs or excessive alcohol. Nourish the digestive tract with nutrients that support gut healing. Medical foods that combine low allergy potential protein with a number of nutrients helpful for gastrointestinal healing are readily available. Toxins/detoxification: Nutritionally controlled fasting as described earlier begins after evidence that gut permeability has diminished and digestive processes have improved. Detoxification efforts continue simultaneously with ongoing gastrointestinal rehabilitation. In addition, chelation therapy is often started once gastrointestinal rehabilitation has progressed and the patient has shown some improvement. Probiotics are therapeutic bacteria (and some yeast), which may improve the gastrointestinal microecology, improve immune response toward gut pathogens, reduce immune hypersensitivities, and stimulate gut repair. Identify allergenic or intolerant foods and gut pathogens. Food allergies (type 1 or immediate hypersensitivity food reactions) can be identified by skin prick testing, radioallergosorbent testing, or enzyme-linked immunosorbent assay testing for IgE antifood antibodies. Patients with evidence of type 1 hypersensitivity food allergies (e.g., postprandial swelling of the lips, urticaria, wheezing) should be referred to an allergist for definitive testing, as serious anaphylaxis could occur without proper avoidance. Delayed hypersensitivity reactions (usually type 3 mediated) are best identified with a properly conducted elimination test diet followed by carefully observed reintroductions of individual food items eliminated in the test diet. IgG antifood antibodies may also be tested, but only before any dietary manipulation has occurred. Intestinal parasites, yeast, and pathogenic bacteria may also be identified by stool testing, C. ulbicuns and Helicobucter pylori serology, breath testing, and urinary organic acids. Eliminate foods found to be allergic or intolerant with elimination test diet or laboratory testing. Gut pathogens, parasites, and C. ulbicuns overgrowth may be treated.

Functional Toxicology

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118. Lee 8, Schwartz B, Stewart W, Ahn K. Provocative chelation with DMSA and EDTA evidence for differential access to lead storage sites. &cup Environ Med 1995;52:13-19. 119. Michalsen A, Weidenhammer W, Melchart D, et al. [Short-term therapeutic fasting in the treatment of chronic pain and fatigue syndromes-well-being and side effects with and without mineral supplements], (Kurzzeitiges therapeutisches Fasten in der Behandlung von chronischen Schmerz- und Erschopfungssyndromen - Vertraglichkeit und Nebenwirkungen mit und ohne begleitende Mineralstofferganzung.), Forsch Komplementarmed Klass Naturheilkd 2002;9:221-227. 120. Yoshimori T. Autophagy: a regulated bulk degradation process inside cells. Biochem Biophys Res Commun 2004;313:453-458. 121. Cahill GF Jr, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc 2003;114:149-161;discussion 162-163. 122. Beaufrand MJ, Poullain B, Klein D, Debry G. [Release of o r g a n d o r i d e pesticides during acute weight losses (author’s transl)], (Liberation de pesticides organochlores lors de pertes ponderales aigues.), Toxicol Eur Res 1978;1:39-43. 123. Imbeault P, Chevrier J, Dewailly E, et al. Increase in plasma pollutant levels in response to weight loss in humans is related to in vitro subcutaneous adipocyte basal lipolysis. Int J Obes Relat Metab Disord 2001;25:1585-1591. 124. Han S, Qiao X, Simpson S, et al. Weight loss alters organ concentrations and contents of lead and some essential divalent metals in rats previously exposed to lead. J Nutr 1996;126317-323. 12.5. Han S, Li W, Jamil U, et al. Effects of weight loss and exercise on the distribution of lead and essential trace elements in rats with prior lead exposure. Environ Health Perspect 1999;107657-662. 126. Rigden S. Entero-hepatic resuscitation program for CFIDS. CFIDS Chronicle, Spring 1995. 127. Bland J, Barrager E, Reedy R, Bland K. A medical food-supplemented detoxification program in the management of chronic health problems. Altem Ther Health Med 1995;1:67-71. 128. Kilburn K, Warsaw R, Shields M. Neurobehavioral dysfunction in firemen exposed to polychlorinated biphenyls (PCBs): possible improvement after detoxification [see comments]. Arch Environ Health 1989;44:345-350. 129. Schnare D, Robinson P. Reduction of the human body burdens of hexachlorobenzene and polychlomated biphenyls. IARC Sci Pub 1986;77:596-603. 130. Schnare D, Denk G, Shields M, Brunton S. Evaluation of a detoxification regimen for fat stored xenobiotics. Med Hypotheses 1982;9:265-282. 131. Lovejoy H, Bell ZJ, Vizena T. Mercury exposure evaluations and their correlation with urine mercury excretions. 4. Elimination of mercury by sweating. J &cup Med 1973;15:590-591. 132. Jandacek R, Anderson N, Liu M, et al. Effects of yo-yo diet, caloric restriction, and olestra on tissue distribution of hexachlorobenzene. Am J Physiol Gastrointest Liver Physiol 200.5;288: G292-GZ99. 133. Mutter LC, Blanke RV, Jandacek RJ, Guzelian PS.Reduction in the body content of DDE in the Mongolian gerbil treated with sucrose polyester and caloric restriction. Toxicol Appl Pharmacol 1988; 92428-435. 134. Moser GA, Mclachlan MS. A non-absorbable dietary fat substitute enhances elimination of persistent lipophilic contaminants in humans. Chemosphere 199939:1513-1521. 135. [No authors listed]. DMSA. Altem Med Rev 2000;5264-267.

Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease Alan L. Miller, ND Gregory S. Kelly, ND Peter B. hngiorno, ND, Dip1 Ac CHAPTER C O N T E N T S Introduction 609 Homocysteine Metabolism 609 Gender and Genetics 610 Lifestyle 610 Nutritional Relationships 610 Renal Function 614 Pharmaceutic Drug Effects on Homocysteine 615 Impact of Homocysteine on Key Nutrients 615 S-Adenosylmethionine 615 Carnitine 615 Chondroitin Sulfates, Glucosamine Sulfate, and Other Sulfated Proteoglycans 615 Coenzyme A 616 Coenzyme Qlo 616 Creatine 617 Epinephrine and Melatonin 617 Phosphatidylcholine 618 Taurine 618

INTRODUCTION Homocysteine is an intermediate in the conversion of the amino acid methionine to cysteine. Elevated homocysteine levels are now recognized as an independent risk factor for developing a heart attack, stroke, or peripheral vascular disease. In addition to its possible role in cardiovascular disease, increased homocysteine levels have been implicated in several other clinical conditions, including neural tube defects, spontaneous abortion, placental abruption, renal failm,non-insulin-dependent diabetes and complicationsof diabetes, rheumatoid arthritis,alcoholism, osteoporosis, and neuropsychiatric disorders. Interest in homocysteine started in the late 1960s Portions reprinted with permission from Alternative Medicine Review 1997; 2234-254.

Clinical Applications 618 Phase 2 Detoxification 618 Heart Disease 619 Peripheral Vascular Disease 619 Stroke 620 Pregnancy 620 Neurologic and Mental Disorders 621 Diabetes Mellitus 622 Rheumatoid Arthritis 622 Psoriasis 622 Kidney Failure 622 Alcoholism and Ethanol Ingestion 623 Gout 623 Osteoporosis 623 Drug-Induced Hyperhomocysteinemia 623 Diagnostic Considerations 624 Therapeutic Considerations 624 Therapeutic Approach 624

when Kilmer McCully, MD, a pathologist in Boston, encountered two children with homocystinuria who had advanced atherosclerosis, though the plaques contained no lipid. Homocystinuria, an autosomal disease with considerable genetic heterogeneity, is the second most common inborn error of amino acid metabolism. Although the full genetic disorder affects only 1 per 200,000 live births, abnormal homocysteine metabolismdue to enzyme dysfunction, lifestyle, or nutritional deficiencies-appears to be surprisingly common.

HOMOCYSTEINE METABOLISM Metabolism of homocysteine is by pathways that remethylate it (and require vitamin BI2 and folic acid) or by a transsulfuration pathway that requires vitamin B6. 609

Syndromes and Special Topics

Homocysteine in blood (and elsewhere) is a product of how much methionine is eaten, mainly in protein (with about three times more methionine in animal than plant protein), and how much is metabolized (metabolism may be affected by amounts of B vitamins and folate available). Homocysteine metabolism is greatly affected by enzyme function, lifestyle choices, nutritional status, renal function, and pharmaceutic effects. Following is a discussion of these factors in homocysteine metabolism.

has been reported." A marked positive dose-response relation between coffee consumption and plasma homocysteine levels was observed. The relationship was most marked in males and females consuming more than eight cups of coffee per day. The combination of cigarette smoking and high coffee intake was associated with particularly high homocysteine concentrations.12Chronic ingestion of alcohol has also been associated with increased homocysteine levels.13J4Plasma total homocysteine is inversely related to exercise.15

Gender and Genetics

Nutritional Relationships

Studies of healthy men and women indicate that certain acquired and genetic determinants may affect total plasma homocysteine. Women tend to have lower basal levels than men,' and neither contraceptives nor hormone replacement therapy seem to alter their levels sigruficantly? However, in postmenopausal women, hormone replacement therapy might slightly decrease elevated homocysteine concentrations. No siphcant lowering effect was observed in women with low homocysteine levels? Generally, homocysteine concentrations are significantly higher in postmenopausal women than in premenopausal women; however, the above-mentioned sex differences in homocysteine concentrations persist even in elderly populations.% The antiestrogen drug tamoxifen, used in the long-term treatment of breast cancer patients, is reported to decrease homocysteine levels in postmenopausal women with breast cancer.' A number of reports have also demonstrated that elevated plasma total homocysteine in children is correlated to either cardiovascular disease or death in their parents or close relatives. This relationshipwas observed in both white and black children, and in white children with hypercholesterolemia.In the latter study group, the 5,lO-methylene tetrahydrofolate reductase (MTHFR) TT genotype tended to be most frequent in children with a parental history of cardiac disease.8Epidemiologic evidence has shown homocysteine levels to be more than 45% lower in Westernized adult black Africans than in age-matched white adults, revealing racial genetic differences in homocysteine metabolism? The MTHFR gene has two different alleles where the "T" allele is associated with decreased enzyme activity, hyperhomocysteinemia, and increased risk for thromboembolism in coronary heart disease. The presence of the " C allele is correlated to lower homocysteine levels and, not surprisingly, may even provide protection against occlusion of coronary arteries. One Hungarian study concluded that the carriers of T allele with coronary heart disease died earlier due to myocardial infarction.'O

Nutrition affects homocysteine concentrations in both men and women. For example, individuals in the lowest quartiles for serum folate and vitamin B12 (nutrientsthat sigruficantly affect homocysteine metabolism) have significantly higher concentrations of homocysteine, and men in the lowest quartile of serum pyridoxal 5'-phosphate (P5P, the bioactive form of vitamin B6) also have increased homocysteine concentrations?

Lifestyle An associationbetween coffee and black tea consumption

and the concentration of total homocysteine in plasma

Methionine Metabolism of the amino acid methionine, a limiting amino acid in the synthesis of many proteins, affects several biochemical pathways involving the production of nutrients that are essential to the optimal functioning of the cardiovascular, skeletal, and nervous system. Homocysteine is an intermediate product of methionine metabolism and is itself metabolized by two pathways: the remethylation pathway, which regenerates methionine, and the transsulfuration pathway, which degrades homocysteine into cysteine and then taurine. In essence, the intermediate metabolite homocysteine is located at a metabolic crossroads, so it directly and indirectly affects all methyl and sulfur group metabolism occurring in the body. Experiments have demonstrated that high levels of K-homocysteine and adenosine in the cell inhibit all methylation reactions.16 The remethylation pathway (Figure 55-1) comprises two intersecting biochemical pathways and results in the transfer of a methyl group (CH,) to homocysteine by either methylcobalamin or betaine (trimethylglycine). Methylcobalamin originally receives its methyl group from Sadenosylmethionine(SAMe) or 5-methyltetrahydrofolate (5-methylTHF), an active form of folic acid. After remethylation, methionine can be reused to produce SAMe, the body's "universal methyl donor," which participates in several key metabolic pathways, including methylation of DNA and myelin, synthesis of camitine, coenzyme Qlo(CoQlo), creatine, epinephrine, melatonin, methylcobalamin, and phosphatidylcholine, as well as phase 2 methylation detoxification reactions. The transsulfuration pathway of methionine/homocysteine degradation (see Figure 55-1) produces the amino acids cysteine and taurine, which are important

Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease ATPIMg

CH3-group acceptor

Cysteine

1-.

Taurine

Flgure 55-1 Homocysteine metabolism. DMG, dirnethylglycine; 5-meVlylTHF; 5-methyltetrahydrofolate; f 5 R pyridoxal 5’-phosphate (vitamin Bs): SAH, S-adenosylhomocysteine;SAMe, S-adenosylmethionine; THE tetrahydrofolate.

nutrients for cardiac health, hepatic detoxification,cholesterol excretion, bile salts formation, and glutathione production. This pathway depends on adequate dietary intake and hepatic conversion of vitamin B6 into its active form, P5P. Also necessary is the amino acid serine, a down-line metabolite generated from betaine via the homocysteine-remethylationpathway. In addition to 5-methylTHF, methylcobalamin, betaine, and P5P, N-acetylcysteine has been reported to sigruhcantly lower homocysteine 1e~els.l~

Methyltetrahydrofolate Folates function as carbon donors in the synthesis of serine from glycine, directly in the synthesis of purines and pyrimidine bases and indirectly in the synthesis of transfer RNA. Folates also function as methyl donors to create methylcobalamin, which is used for remethylation of homocysteine to methionine. Dietary folic acid is a mixture of folates in the form of polyglutamates, which are readily destroyed by cooking. Synthesis of the active forms of folic acid is a complex process requiring several enzymes, as well as adequate supplies of niacin, P5P, and serine as cofactors

(Figure 55-2). In plants, folic acid is formed from a hetero-bicyclic pteride ring, para-aminobenzoic acid (PABA), and glutamic acid. Folate is initially deconjugated in the cells of the intestinal wall to the monoglutamate form. This is then reduced to dihydrofolate and then to tetrahydrofolate (THF) via folate and dihydrofolate reductase. Both enzymes require reduced nicotinamide adenine dinucleotide phosphate (niacin dependent) as a cofactor. Serine combines with P5P to transfer a hydroxymethyl group to THF.This results in the formation of 5,lO-methylene tetrahydrofolate (5,lO-methylenem) and glycine. This molecule is of central importance, being the precursor of the metabolically active 5-methylTHF, which is involved in homocysteine metabolism, and methylidynetetrahydrofolate (involved in purine synthesis), as well as functioning on its own in the generation of thymine side chains for incorporation into DNA. The following may contribute to a deficiency of folic acid: A deficient food supply A defect in utilization, as in alcoholics

Syndromes and Special Topics

Figure 55-2 Absorption and activation of folic acid. DHE dihydrofolate; 5,lO-METHE 5.10-methylenetetrahydrofolate; 5-MTHE 5-methyltetrahydrofoolate; MWFR, methylenetetrahydrofolatereductase; f5’-1? pyridoxal 5’-phosphate; R5-e riboflavin 5’-phosphate; THE tetrahydrofolate.

Malabsorption Increased needs in pregnant women and cancer patients Metabolic interference by drugs Folate losses in hemodialysis Enzyme or cofactor deficiency necessary for generation of active folic acid Individuals using supplements or consuming either breakfast cereals or green leafy vegetables have sigruficantly greater plasma folate and lower homocysteine levels than those who do not.’ Folinic acid (5-formylTHF), available supplementally as calcium folinate (also known as leucovorin calcium), is an immediate precursor to 5,lO-methylenel73 and 5-methylTHF. Folinic acid can correct deficiencies of the active forms of folic acid, is more stable than folic acid, and has a longer half-life in the body. Folinic acid also readily crosses the blood-brain barrier and is slowly cleared, compared with folic acid, which is poorly transported into the brain and, once in the central nervous system (CNS), is rapidly cleared.I8

Methylcobalamin The coenzyme form of vitamin BI2is a complex molecule containing cobalt bound to five nitrogens and one carbon. The metal-carbon bond found on this coenzyme is the only known biologic example of this type of linkage. Surrounding the cobalt is a corrin ring, which structurally resembles the porphyrin ring found in hemoglobin, the cytochromes, and chlorophyll. The use

of cobalt in the two biologically active forms of cobalamin, adenosylcobalamin and methylcobalamin, is the only known function of this metal in biologic systems. In humans the cobalt in cobalamin exists in a univalent oxidation state, designated as cob(1)alamin. The compound commonly referred to as vitamin B12 has a cyanide molecule at the metal-carbon position, and the oxidation state of the cobalt is +3 instead of the biologically active +l. In order to be used in the body, the cyanide molecule must be removed. It is thought that the compound glutathione may perform this function. Other available forms of vitamin B12 include hydroxocobalamin and the two active forms, adenosylcobalamin (cobamamide) and methylcobalamin. The absorption of dietary cobalamin requires the formation of a complex between dietary B12and R-proteins and the secretion, by the stomach mucosa, of intrinsic factor. The BI2 complex is split by pancreatic proteases, and the released BIZattaches to intrinsic factor and is absorbed in the distal ileum. The amount of cobalamin required in the diet is low, and even people with pernicious anemia can generally absorb sufficient amounts if the coenzyme is supplemented at a high enough dosage. Although the basic cobalamin molecule is only synthesized by microorganisms, all mammalian cells can convert this into the coenzymes adenosylcobalamin and methylcobalamin.Adenosylcobalamin is the major form in cellular tissues, where it is retained in the mitochondria. Methylcobalamin predominates in blood plasma and certain other body fluids, and in cells is found in the cytosol.

Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease Adenosylcobalamin functions in reactions in which hydrogen groups and organic groups exchange places. In humans, adenosylcobalamin is required in only two reactions: the catabolic isomerization of methylmalonyl CoA to succinyl CoA and interconversion of alpha- and beta-leucine. After its formation from methylmalonyl CoA, succinyl CoA is either involved in the synthesis of porphyrin molecules (along with glycine) or transfers its coenzyme A to form acetyl coenzyme A (acetyl CoA). The latter reaction is magnesium dependent, and the remaining succinate is fed into the citric acid cycle. Deficiencies in thiscoenzyme form of vitamin BIZ result in increased amounts of methylmalonyl CoA and generally an increase in glycine levels. Methylcobalamin's only known biologic function in humans is in the remethylation of homocysteine to methionine via the enzyme methionine synthase, also known as 5-methyltetrahydrofolate-homocysteine methyltransferase. In order to originally form methylcobalamin from cyanocobalamin or other Cob(III)alamin or Cob(I1)alamin precursors, SAMe must be available to supply a methyl group. Once methylcobalamin is formed, it functions in the regeneration of methionine by transferring its methyl group to homocysteine. Methylcobalamin can then be regenerated by 5-methylTHF (Figure 55-3). The cell's ability to methylate important compounds such as proteins, lipids, and myelin is compromised by a deficiency of either folate or vitamin Shortages of active folic acid, SAMe, or a dietary deficiency of cobalamin lead to a decrease in the generation of

methylcobalamin and a subsequent impairment of homocysteine metabolism. Since lack of methylcobalamin leads to depressed DNA synthesis, rapidly dividing cells in the brain and elsewhere are affected. At least 12 different inherited inborn errors of metabolism related to cobalamin are known. Abnormalities are detectable by urine and plasma assays of methylmalonic acid and homocysteine and plasma and erythrocyte analysis of cobalamin coenzymes, which can reveal deficiencies of methylcobalamin or adenosylcobalaminZ0 (see Chapter 30 for further discussion).

Betaine The metabolic pathways of betaine, methionine, methylcobalamin, and methylTHFare interrelated, intersecting at the regeneration of methionine from homocysteine. This regeneration is accomplished in one of two ways. One involves the generation in the cytosol of 5-methylTHF from methylene tetrahydrofolate and the transfer of its methyl group to regenerate methylcobalamin, which then acts as a coenzyme in the regeneration of methionine. Since tetrahydrofolate and its derivatives can only cross the mitochondria1 membrane slowly, inside the mitochondria regeneration of methionine relies on recovery of a methyl group from betaine. Betaine donates one of its three methyl groups via the enzyme betaine-homocysteine methyltransferase to homocysteine, resulting in the regeneration of methionine. After the donation of the methyl group, one molecule of dimethylglycine (DMG) remains. This molecule is

MethylrnalonylCoA Adenosylcobalamin (cobarnamide) (dibencozide)

t

7 Succinyl CoA

Cob(1)alamin

~ya-~amin (cob(lll)alamin)

+-+

t sAr f

Cob(li)alamin

A

5,lC-rnethylenetetrahydrofolate

tetrahydrofolate

? / II

Cob(1)alamin

Methionine Figure 55-3

Methyl-

i'

Tetrahydrofolate

Folinic acid -b

b

Cobalamin metabolism.

/ Homocysteine

oxidized to glycine and to two molecules of formaldehyde by riboflavin-dependent enzymes. The formaldehyde can combine with tetrahydrofolate within the mitochondria to generate one of the active forms of folic acid, methylenetetrahydrofolate,which can be converted to 5-methylTHF and subsequently used as a methyl donor (Figure 55-4). In animal studies a disturbance in the metabolism of either of the two methyl-donor pathways, due to limited availability of either betaine or folates and vitamin B1= affects levels of nutrients in the coexisting pathway, since more of a drain is placed on the other pathway as a source of methyl groups. Rats fed diets deficient in choline and methionine have hepatic folate concentrations half that of controls after 5 weeks2’ During choline deficiency, hepatic SAMe concentrations have also been shown to decrease by as much as 50%.” Similarly, THF deficiency results in decreased hepatic total choline levels.= Patients with a congenital deficiency of the enzyme methyltetrahydrofolate reductase (MTHFR), which is Acetylcholine

y

Pyridoxal 5’-phosphate

Acetyl CoA (&-dependent)

Choline

Phosphatidylcholine

SAMe

Betaine aldehyde

P

Phosphatidyldimethyl ethandamine

Homocysteine

+

Phosphatidylmethyl ethanolamine

Methionine

A

I/

DMG

SAMe Phosphatidyl ethanolamine

Sarcosine

Serine

B6

T I

Mg-

Phosphatidylserine

f Methylenetetrahydrofdate

-

T

P5P is the active coenzyme form of vitamin B6. This cofactor is involved in myriad biologic processes including the transsulfuration pathway of homocysteine. This degradation pathway involves a two-step process, resulting in the formation of cystathionine and its subsequent cleavage to cysteine. Both enzymes involved, cystathionine synthase and cystathioninase, require P5P as a cofactor, and the committed first step in the degradation of homocysteine, cystathionine synthase, also requires serine, a downstream metabolite of betaine (Figure 55-5). Some studies now suggest that cystathionine could be a useful marker to assess the effect of vitamin B6 and should be monitored with homocysteine to better elucidate clinical outcomes.29 Once cysteine is generated, it can be directed into several different pathways, including synthesis of glutathione, acetyl CoA, and taurine. Three pathways from cysteine to taurine are known; all require P5P.

kbb

Betaine

I

needed for the formation of 5-methylTHFjhave reduced levels of both methionine and SAMe in the cerebrospinal fluid and show demyelination in the brain and degeneration of the spinal cord. Methionine is effective in the treatment of some of these patients; however, betaine was shown to restore CSF SAMe levels to normal and to prevent the progress of neurologic symptoms in all patients in whom it was triedF4 Betaine supplementation has been shown to reduce homocysteine levelsz while resulting in modest increases of plasma serine and cysteine levels.26Stimulation of betaine-dependent homocysteine remethylation causes a commensurate decrease in plasma homocysteine that can be maintained as long as supplemental betaine is taken.27 Serine levels are depressed in some individuals with excess homocysteine who are treated with folic acid, cobalamin, and vitamin B6.28 Because serine is required (1)for the conversion of folic acid to its active form, (2) as a shuttle for methyl groups between the cytosol and the mitochondria, and (3) as a cofactor in the transsulfuration pathway of methionine/homocysteine metabolism, supplementation with betaine should be included with folic acid, cobalamin, and P5P in order to optimize the interrelated pathways of homocysteine metabolism.

Tetrahydrofolate

Formaldehyde

Figure 55-4 Phosphatidylcholine metabolism

RENAL FUNCTION Impaired kidney function also appears to be a factor in raised homocysteine con~entrations.~~ It has been shown that a decreased glomerular filtration rate may be a contributing factor, and some researchers suggest that hyperhomocysteinemia may actually reflect early nephrosclerosis: although other studies demonstrate only a minor renal influence3l Fenofibrate treatment, known to increase homocysteine levels, is also known to promote rises in serum creatinine (see later).32Cy~tatin C,

Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease DMG Methionine

Homocysteine Betaine Serine Pantethine

db 4

f

- - - -Cysteine

Coenzyme A Pantothenic acid

Bs

CAMP

b-

Cysteamine

.c

Other acylations Taurine - j e,o (txl.

I f

Bile acids Figure 55-5

Synthesis of taurine.

a creatinine-independent indicator of glomerular filtration rate, has also been shown to be well associated with homocysteine levels in kidney transplant patients, as well as those with coronary d i s e a ~ e ? ~ , ~ ~

PHARMACEUTIC DRUG EFFECTS ON HOMOCYSTEINE Fibrates such as Gemfibrozil are a class of drugs used to lower triglycerides and raise high-density lipoprotein levels. In a paradoxic effect working against a safer cardiac risk profile, these drugs have been observed to raise homocysteine levels up to 40%?2335 The mechanism of this observation is unknown, although it seems that renal mechanisms may be involved (see earlier). Thiazides and angiotensin-converting enzyme inhibitors are often a first-line conventional treatment to lower elevated blood pressure. One preliminary, randomized, prospective treatment study investigated 40 hypertensive patients after treatment with hydrochlorothiazide or captopril. In this study vitamins B6,BIZ,folic acid, creatinine, and cystatin C were used as parameters of renal function. For 31 and 29 days, respectively, 21 patients were prescribed hydrochlorothiazide and 19 were prescribed captopril. It was found that hydrochlorothiazide, but not captopril, raised homocysteine by l6%, as well creatinine and cystatin C. These numbers all attained significant P values.%

IMPACT OF HOMOCYSTEINE ON KEY NUTRIENTS Because of its central role in sulfur and methyl group metabolism, elevated levels of homocysteine would be expected to negatively affect the biosynthesis of all of the following: SAMe, carnitine, chondroitin sulfates,

CoA, CoQlo,creatine, cysteine, dimethylglycine,epinephrine, glucosaminesulfate, glutathione, glycine, melatonh, pantethine, phosphatidylcholine, phosphatidylserine, serine, and taurine.

S-Adenosylmethionine Methionine is a component of many proteins and cannot be manufactured from other dietary amino acids. It serves as a source of available sulfur for the synthesis of both cysteine and taurine and, as SAMe, it is the most important methyl-group donor in cellular metabolism. SAMe is formed by the transfer of an adenosyl group from adenosine triphosphate (ATP) to the sulfur atom of methionine. This reaction requires magnesium as a cofactor. When methyl groups are transferred from SAMe, Sadenosylhomocysteine is formed. This is then hydrolyzed to release the adenosine and results in the formation of homocysteine. SAMe is known to be used in the synthesis of the following compounds: carnitine, CoQlo, creatine, methylcobalamin from cob(III)alamin, l-methylnicotinamide, N-methyltryptamine, phosphatidylcholine, and polyamines. It is also used in methylation reactions as part of hepatic phase 2 detoxification.

Carnitine A trimethylated amino acid roughly similar in structure to choline, carnitine is a cofactor for transformation of free long-chain fatty acids into acyl-carnitines and their transport into a mitochondria1 matrix, where they undergo beta-oxidation for cellular energy production. Mitochondria1 fatty acid oxidation is the primary fuel source in heart and skeletal muscle. Synthesis of carnitine begins with the methylation of the amino acid L-lysine by SAMe. Methionine, magnesium, vitamin C, iron, P5P, and niacin, along with the cofactors responsible for regenerating SAMe from homocysteine (5-methylTHF, methylcobalamin, and betaine), are required for optimal carnitine synthesis (Figure 55-6). A pivotal enzyme in carnitine synthesis, betaine aldehyde dehydrogenase, is the same enzyme responsible for synthesis of betaine from choline. Two recent studies suggest that this enzyme has a preference for the choline-betaine conversion, and that choline supplementation may decrease carnitine synthesis; therefore it may be of greater benefit to supplement with betaine rather than its precursor, c h ~ l i n e , ~ ~ s

Chondroitin Sulfates, Glucosamine Sulfate and Other Sulfated Proteoglycans Proteoglycans are amino sugars found in all tissues, the highest being in cartilage, tendons, ligaments, synovial fluid, skin, fingers, toenails, heart valves, and the basement membrane of all blood vessels. Perhaps the most widely known of the amino sugars are the chondroitin

Syndromes and Special Topics Lysine

K

S-Adenosylmethionine S-Adenosylhomocysteine

Trimethyllysin

I

Fez+,ascorbic acid

f N6-Trimethyl-3-hydmxylysine

L

Pyridoxal5’-phosphate Glycine

4-Trimethylamincbulyraldehyde Betaine aldehyde dehydrogenase

2 1

B3

4-Trimethylaminobutyrate

Fez+,ascorbic acid

Camitine

Figure 556 Synthesis of carnitine.

sulfates and glucosamine sulfate (see Chapter 97 for further discussion). Chondroitin sulfates are primarily composed of alternating residues of N-acetyl-D-galactosamine and Dglucuronate. Sulfate residues are present on C-4 of the galactosamineresidues in one type of chondroitin and on C-6 in another. Glucosamine sulfate is a simple molecule composed of glucose, the amino acid glutamine, and a sulfate p u p . Other sulfated proteoglycans include dermatan sulfates, keratan sulfates, and heparan sulfates. High levels of homocysteine are likely to negatively affect the formation of the sulfated amino sugars because, although some sulfates are present in the diet, the sulfoxidation of cysteine is an important source of sulfate molecules. The sulfoxidation pathway proceeds through the toxic intermediate sulfite and requires molybdenum as a cofactor.

Coenzyme A CoA consists of an adenine nucleotide and phosphopantetheine. Contained within the structure of this coenzyme is pantothenic acid; however, the reactive component of the molecule is a sulfhydryl group that is not contained within the vitamin. In order to form the sulfhydryl-containing molecule (pantotheine), pantothenic acid must combine with cysteamine. Cysteamine is formed through conjugation and decarboxylationreactions of cysteine. As previously discussed, the metabolic stagnation implied with elevated homocysteine levels

indicates that the body has suboptimal levels of cysteine. Therefore even in the presence of adequate levels of pantothenic acid, it is possible to have inadequate biosynthesis of acetyl CoA. The disulfate form of pantetheine, known as pantethine, as opposed to pantothenic acid, bypasses cysteine conjugation and decarboxylation. This might account for some of the clinical benefits seen with pantethine supplementation that have not been reproduced with the supplementation of pantothenic acid (Figure 55-7, A to D,for the chemical structures of pantotheine, pantothine, pantothenic acid, and cysteamine).

Coenzyme Qto CoQlo is a fat-soluble quinone occurring in the mitochondria of each cell (see Chapter 82 for a full discussion). The primary biochemical action of CoQlois as a cofactor in the electron transport chain, the biochemical pathway that generates ATP. Since most cellular functions depend on an adequate supply of ATP, CoQlo is essential for the health of virtually all human tissues and organs. CoQloalso functions as an antioxidant, assisting in the recycling of vitamin E.39,40 Biosynthesis of CoQlo begins with the amino acid tyrosine. Pantothenic acid, P5P, and vitamin C are all required for the initial steps in its synthesis.An isoprenyl side chain from farnesyl &phosphate, an intermediate in cholesterol synthesis between 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)and squalene, is then added. An inadequate supply of this intermediate, which can be caused by HMG-CoA reductase inhibitors (cholesterollowering drugs of the statin family), results in decreased levels of CoQ10.41 In two of the final steps in the synthesis of CoQlo, methyl groups are provided by SAMe (Figure 55-8). Adequate dietary methionine and a sufficient supply of the nutrients required for the remethylation of homocysteine to methionine (5methylTHF, methylcobalamin, and betaine) are required to generate sufficient SAMe. Suboptimal amounts of SAMe may negatively affect the body’s ability to synthesize sufficient CoQlo. This relationship between SAMe and CoQlo has been suggested in various animal s t ~ d i e s . ~ , ~ ~

- 0 - CH, - C(CH,)’ - CH(0H) - CO - NH - CH, - CH, - CO - NH - CH,

- CH, - SH

A

-

[HO CH,

- C(CH,)‘

- CH(0H) - CO - NH - CH, - CH, - CO -NH - CH, - CH, - S -12

B - 0 - CH,

- C(CH.J2-

-

CH(0H) CO

- NH - CH, - CH, - CO

C - NH -CH,-CH,-SH

D Figure 55-7 A, Pantotheine. B, Pantothine. C, Pantothenic acid. D, Cystearnine.

Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease Acetyl CoA

4 4 Mevalonate i Polyprenyldiphosphate 4 -- - - - - - - - - Farnesyl diphosphate 3 HMG-COA

Tyrosine Pantothenic acid,B, Ascorbicaad

I

I

f

I

r

4-Hydroxybenzoate

<

I I

4-Hydroxy-5-polyprenylbenzoate S-Adenosylmethionine

f

">i

Squalene

Mg2'

S-Adenosylhornocysteine

Ubiquinone-n(CoQ,,)

f I

Methionine

Biz, fdic acid or betaine

i Cholesterol

Figure 55-8 Synthesis of coenzyme Qlo.

Creatine In humans more than 95% of the total creatine content is located in skeletal muscle, of which approximately one third is in its free form as creatine, also known as methyl-guunidinoucetic acid, while the remainder is present in a phosphorylated form as creatine phosphate (also called phosphocreutine). Creatine phosphate is used within skeletal muscle as a means of storing high-energy phosphate bonds. Creatine is formed in the liver, kidney, and pancreas, beginning with the combination of arginine and glycine to produce guanidinoacetate.A methyl group from SAMe is then transferred, resulting in the formation of creatine. The byproduct of this reaction, Sadenosylhomocysteine, is subsequentlyhydrolyzed into homocysteine and adenosine. In order to optimize endogenous production of creatine, the amino acids arginine, glycine, and methionine must be available as substrates. Additionally, cofactors needed to optimize remethylation of homocysteine to form methionine are required to recycle the homocysteine to methionine for reuse as SAMe (Figure 55-9). Serum creatine levels have been positively correlated with plasma homocysteine levels (i.e., as creatine levels rise, so do homocysteine levels).4q

a methyl group is provided by SAMe, resulting in the formation of epinephrine from norepinephrine. A number of metabolites are formed from the degradation of both norepinephrine and epinephrine. Catecholamine degradation proceeds independently, and in conjunction with monoamine oxidase, by catechol-0-methyltraferase. This enzyme catalyzes the transfer of a methyl group donated by SAMe and, depending on the substrate, results in the formation of homovanillic acid, normetanephrine, and metanephrine. The formation of melatonin from L-tryptophan proceeds through 5-hydroxytryptophan, serotonin, and N-acetylserotonin. Melatonin is then formed in the pineal gland by the donation of a methyl group. 5-methoxytryptamine, an alternate metabolite of serotonin, also requires the addition of a methyl group. Arginine + glycine d Guanidinoaceticacid + Omithine

Epinephrine and Melatonin Derivatives of the aromatic amino acids, L-tyrosine and L-tryptophan, require methylation for the biosynthesis of their down-line metabolites. The biosynthesis of catecholamines begins with the amino acid L-tyrosine and proceeds through dopa and dopamine, resulting in the formation of norepinephrine, the neurotransmitter substance found in most sympathetic nerve terminals, as well as in some synapses of the CNS. In the chromaffin cells of the adrenal medulla,

1

Creatinine Figure 55-9 Synthesis of creatine. creatine phosphate, and creatinine.

Syndromes and Special Topics Because elevated homocysteine results in suboptimal synthesis of SAMe, some impact on aromatic amino acid derivatives occurs. The exact nature of the impact on catecholamine metabolites is still unclear due to SAMe’s role in both synthesis and degradation. It appears likely that the biochemical stagnation associated with elevated levels of homocysteine would negatively affect the synthesis of melatonin.

Phosphatidylcholine Phosphatidylcholine (PC) is a primary component of lecithin. It is the most frequently encountered phospholipid in animals and is structurally related to phosphatidylserine and phosphatidylethanolamine. PC consists of a glycerol backbone that is esterified with fatty acids on carbon atoms 1 and 2, and with a phosphoric acid/choline complex in position 3. Although phosphatidylcholine is usually referred to as if it were a single compound, it is actually a group of related compounds that vary depending on the fatty acid composition at position C-1 and C-2. Dietary choline is derived primarily from PC, which, after absorption by the intestinal mucosa, is metabolized to choline in the liver by the enzyme phospholipase D. Most choline is rephosphorylated to PC; however, a small amount is carried to the brain via the bloodstream, where it is converted to the neurotransmitter acetylcholine. If PC or choline is lacking in the diet, it can be synthesized from phosphatidylserine and phosphatidylethanolamine (see Figure 55-4). Synthesis of PC depends on the availability of SAMe as a methyl donor, since synthesis involves the transfer of methyl groups from three SAMe molecules to phosphatidylethanolamine in order to generate one molecule of PC. The metabolic pathways of phosphatidylcholine, methionine, methylcobalamin, and 5-methylTHF are interrelated, intersecting at the regeneration of methionine from homocysteine by betaine (see Figure 55-1). The use of choline molecules as methyl donors in this process is probably the main factor that determines how rapidly a diet deficient in choline will induce pathologic changes.u

Taurine Taurine is a unique amino acid because it carries a sulfonic acid group (-S03H) instead of a carboxyl group (-C02H). Taurine is biosynthesized from methionine or from cysteine via the transsulfuration pathway (see Figure 55-5).As discussed previously, homocysteine can be remethylated to form methionine; however, it can also be degraded to form cysteine. Once cysteine is generated, it can be directed into several different pathways including synthesis of glutathione, acetyl CoA, 3’-phosphate 5’-phosphosdate (PAPS), and taurine. Degradation involves a two-step process resulting in the formation of cystathionine and its subsequent cleavage to cysteine.

Both enzymes involved require P5P as a cofactor, and the committed first step in the degradation of homocysteine, cystathionine synthase, also requires serine. In humans defects in both of these enzymatic reactions occur. Homocystinuria, resulting from an absence of cystathionine synthase, can lead to mental retardation. Low levels of this enzyme can also lead to abnormally high levels of homocysteine, especially when remethylation cofactors are also deficient.

CLINICAL APPLICATIONS Phase 2 Detoxification Because homocysteine is a critical intermediate in both methyl and sulfur group metabolism, elevated levels could indicate nutrient deficiencies that might compromise function in virtually all of the hepatic phase 2 detoxification reactions. Amino acid conjugation reactions require either glycine, glutamine, or taurine. Glycine functions in the conjugation of aromatic acids (e.g., benzoic acid to hippuric acid). Elevated levels of homocysteine might indicate reduced nutritional levels of betaine and subsequently its down-line metabolite glycine. Taurine functions in acylations (e.g., bile conjugation). As discussed, optimal taurine synthesis requires proper movement of homocysteine into its degradation pathway. There are no known interactions between glutamine and homocysteine. Sulfur conjugation requires N-acetylcysteine (NAC), glutathione (GSH), PAPS, or methionine/cysteine. NAC is used for mercapturic acid synthesis and is involved in detoxification of a wide variety of compounds including aromatic hydrocarbons, some phenols, halides, esters, epoxides, and caffeine. GSH is involved in dismutation reactions of organic nitrates (e.g., nitroglycerin). PAPS is used in sulfate ester synthesis, mostly with phenols, and some aliphatic alcohols (e.g., ethanol) and aromatic amines. Methionine and cysteine are used in cyanidethiocyanate detoxification. A portion of the inorganic sulfur needed for the formation of all of these compounds passes through the homocysteine cycle. Alkylation reactions require SAMe, methylcobalamin, or 5-methylTHF. These compounds provide methyl groups to detoxlfy compounds containing OH, SH, or NH2 groups. Examples of these reactions include norepinephrine to epinephrine, epinephrine to metanephrine, guanidoacetic acid to creatine, and N-acetylserotonin to melatonin. Other phase 2 detoxification reactions that might be affected by elevated homocysteine as a biologic marker of reduced nutrient formation include acetylation by acetyl CoA, which requires cysteine as a source of its cysteamine component; and the use of carnitine for the conversion of valproic acid to valpropylcarnitine.

Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease

oxidative damage to LDL cholesterol and endothelial cell membranes, hydrogen peroxide can then catalyze A sigruficant component in the pathogenesis, prevention, injury to vascular endothelium.61,62 and treatment of heart disease involves the amino acid Nitric oxide and other oxides of nitrogen released by homocysteine. Increased blood levels of homocysteineare endothelial cells (also known as endothelium-derived correlated with sigrufrcantly increased risk of coronary relaxing factor, or EDRF) protect endothelial cells from artery disease ( C A D ) : ’ ~ - myocardial ~ ~ J ~ ~ - ~infar~ti~n:~$~ ~ damage by reacting with homocysteine, forming Speripheral occlusive disease,*57 cerebral occlusive disnitrosohomocysteine, which inhibits hydrogen peroxide ease,%>’and retinal vascular occlusion (Box 55-1).% formation. However, as homocysteine levels increase, this It has been known for more than 25 years that inborn protective mechanism can become overloaded, allowing errors of homocysteine metabolism result in high levels damage to endothelial cells to Because of the of homocysteine in the blood and severe atherosclerotic role of sulfate compounds in the formation of amino disease. It is now known that, even within the range sugars needed to form the basement membrane of blood considered normal (4 to 16 pnol/L), there is a graded vessels, high levels of homocysteine are likely to conincrease in risk for CAD. In a study of 304 patients with tribute to the formation of blood vessels that are more CAD versus controls, the odds ratio for CAD increased susceptible to oxidative s t r e s ~The . ~ end result of the as plasma homocysteine increased, even within the combination of oxidative damage and endothelid collagen normal range. A 5 pmol/L increase in plasma homocysinstability can be the formation of atheroscleroticplaques. teine was correlated with an increase in the odds ratio of Decreased plasma folate levels are correlated with increased levels of homocysteine, as well as a subsequent 2.4 (p < 0.001), with no ”threshold effect.1148 increased incidence of CAD. In a 15-year Canadian study A review of numerous studies found that mild hyperof CAD mortality in 5056 men and women age 35 to homocysteinemia after a methionine load test o c a m in 21%,24%, and 32%of patients with CAD, cerebrovascular 79 years, lower serum folate levels were correlated with a disease, and peripheral vascular disease, respectively.43 sigruficantly increased risk of fatal CAD.65In a cohort from the Framingham Heart Study, concentrations of Another group of researchers found the incidence of hyperhomocysteinemia (>14 pnol/L by their definition) folate and P5P were inversely correlated with homocysin a group of 1160 elderly (ages 67 to 96) individuals in teine levels and the risk of extracranial carotid-artery stenosisMLow P5P and low vitamin BI2 have also been the Framingham Heart Study, to be 29.3%. The study also indicated that plasma homocysteine levels increase linked with hyperhomocysteinemia and a sigruficantly increased risk of CAD.48Anotherstudy of 160 cardiac with age.54 transplant patients followed for an average of 28 days A number of interrelated atherogenic mechanisms are thought to be involved with hyperhomocyteinemia. found that the high homocysteine levels seen in 99 of these patients surprisingly demonstrated no causal role These include advanced thickening and smooth muscle in the atherothrombotic vascular complications of transcell proliferation of endothelial vessel wall intima, plantation. Vitamin B6 deficiency was seen in 21% of enhanced lipid deposition in the vessel wall, forced detachment of endothelial cells, activation of leukocytes recipients with, and in 9% without, cardiovascular comand thrombocytes, increased LDL oxidation, initiation plications or death, or both. Compared with patients of platelet thromboxane synthesis, enhanced oxidative with normal B6 levels, there was a 2.7-fold increase in untoward cardiac events for those patients with B6 levels stress induced by peroxide formation during homocysless than or equal to 20 nm01/L.~ teine oxidation, and prothrombotic coagulation interRemethylation of homocysteine and the subsequent feren~e.5~@ One way homocysteine assists this process formation of SAMe is critical for biosynthesis of L-camiis by the generation of hydrogen peroxide.6l By creating tine, CoQlo, and creatine. Similarly, the transsulfuration pathway must be functioning properly for optimal biosynthesis of cysteine, GSH, pantethine, and taurine. All of these nutrients are used clinically to reduce oxidative stress, improve risk factor markers, or treat heart Generate superoxide and hydrogen peroxide, which have been disease. linked to damage to arterial endothelium

Heart Disease

Change coagulation factor levels so as to encourage clot formation Prevent small arteries from dilating, so they are more vulnerable to obstruction Cause smooth muscle cells in the arterial wall to multiply Interact with low-density lipoproteins, causing them to precipitate and damage endothelial tissue Cause platelets to aggregate

Peripheral Vascular Disease Elevated homocysteine levels have been established as an independent risk factor for intermittent claudication (IC) and deep vein thrombosis. Elevated homocysteine levels corresponded with an increased incidence of intermittent claudication and decreased serum folate

Syndromes and Special Topics levels in a study of 78 patients with IC.67A fourfold increase in risk of peripheral vascular disease was noted in individuals with hyperhomocysteinemia compared with those with normal homocysteine levels.68A group of researchers in the Netherlands found high homocysteine levels to be a significant risk factor for deep vein thrombosis, with a stronger relationship among women than me11.6~ An increased risk of peripheral vascular occlusion has been noted in women taking oral contraceptives, which might be linked to the significantly increased homocysteine levels in women so affected. It is already known that oral contraceptives can cause declines or deficiencies in vitamins B6, B1= and folate, nutrients integral to the processing of homocysteine. Laboratory assessment of plasma homocysteine levels may be helpful to detect women who may be predisposed to peripheral vascular occlusion while on oral contraceptive^.^^

Stroke Stroke patients have significantlyelevated homocysteine levels compared with age-matched with a linear relationship between risk of stroke and homocysteine levelsn and a sigruficant decrease in blood folate concentrations in those with elevated homocysteine." One investigation revealed that people with a dietary intake of at least 300 mcg per day of folic acid reduced their risk of stroke and heart disease by 20% and 13%, respectively, compared with those who consumed less than 136 mcg of folic acid per day.74

Pregnancy Biochemical enzyme defects and nutritional deficiencies are receiving increasing attention for their role in causing neural tube defects (NTDs),as well as other negative pregnancy outcomes including spontaneous abortion, placental abruption (infarct), preterm delivery, and low infant birth weight. Evidence has suggested that derangement of methionine-homocysteine metabolism could be the underlying mechanism of pathogenesis of neural tube defects and might be the mechanism of prevention observed with supplementation of folic It has been firmly established that a low dietary intake of folic acid increases the risk for delivery of a child with an NTD and that periconceptional folic acid supplementation reduces the occurrence of NTD.77-83 Research also indicates that supplemental folic acid intake results in increased infant birth weight and improved Apgar scores, along with a concomitant decreased incidence of fetal growth retardation and maternal A derangement in methionine-homocysteine metabolism has also been correlated with recurrent miscarriage and placental infarcts (abruption).@ The amino acid homocysteine, when elevated, might be a teratogenic agent contributing to congenital defects

of the heart and neural tube. Evidence from experimental animals lends support to this belief. When avian embryos were fed homocysteine to raise serum homocysteine to over 150 nmol/ml, dysmorphogenesis of the heart and neural tube, as well as of the ventral wall, was observed.89 Because homocysteine metabolism, through the remethylation and transsulfuration pathways, affects several biochemical pathways involving the production of nutrients that are essential to the optimal functioning of the cardiovascular, skeletal, and nervous systems, it is not surprising that these other nutrients have been linked to complications of pregnancy in animal models and humans. Low plasma vitamin B12levels have been shown to be an independent risk factor for NTD.90,91 Methionine has been shown to reduce the incidence of NTD by 41% in an animal model when administered This evidence indicates on days 8 and 9 of pregnancy.9293 that a disturbance in the remethylation pathway with a subsequent decrease in SAMe may be a contributing factor to these complications of pregnancy. Phosphatidylcholine, due to its role as a precursor to acetylcholineand choline, is acknowledged as a critical nutrient for brain and nerve developmentand functionP4-% Since the metabolic pathways of choline (via betaine), methionine, methylcobalamin, and 5-methylTHF are interrelated, intersecting at the regeneration of methionine from homocysteine, a disturbance in the metabolism of either of these two methyl-donor pathways, due to limited availability of key nutrients or decreased enzyme activity, directly affects the body's ability to optimize levels of SAMe. Evidence suggests that women with a history of NTDaffected pregnancies have altered folic acid metabol i ~ m . 9 ~Patients - ' ~ with a severe congenital deficiency of the enzyme MTHFR, which is needed for the formation of 5-methylTHF, have reduced levels of both methionine and adenosylmethionine in their cerebrospinal fluid and show demyelination in the brain and degeneration of the spinal cord.2J01Because of its direct impact in the activation of folic acid to its methyl derivative, a milder version of this enzyme defect is also strongly suspected to increase the incidence of NTD.lo2 It is established that high vitamin A intake during the first 2 months of pregnancy is associated with a severalfold higher incidence of birth defects.lo3JM Although the mechanism of action remains to be elicited, in an animal model the activity of hepatic MTHFR is suppressed with high vitamin A levels, suggesting that its teratogenic effect during early pregnancy may be associated with a subsequent derangement in the remethylation of homo~ysteine.'~~ Because a more significant correlation has been found between high homocysteine levels in women experiencing placental abruption, infarction, and spontaneous

Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease abortion than in control women and homocysteine and CoQlosynthesis depend on the methionine-SAMehomocysteine pathway, it is possible that low CoQloand elevated homocysteine independently found in complicated pregnancy may also, in fact, be found to be related condition~.'~~J~~ Nutritional intervention with the cofactors required for optimal metabolism of the methionine-homocysteine pathways offers a new integrated possibility for primary prevention of NTD and several other complications of pregnancy. Supplementation with betaine and the active forms of cobalamin and folic acid such as methylcobalamin and folinic acid, along with riboflavin-5'phosphate (because of its role as a cofactor for the MTHFR enzyme),may play a sigruficantrole in reducing or preventing these emotionally devastating outcomes.

Neurologic and Mental Disorders In addition to the known impact of homocysteine on the cardiovascular system and micronutrient biochemical pathways, numerous diseases of the nervous system are correlated with high homocysteine levels and alterations in B1> folate, or B6 metabolism including depression, schizophrenia, multiple sclerosis, Parkinson's disease, Alzheimer's disease (AD), and cognitive decline in the elderly. Methylation reactions via SAMe, including methylation of DNA and myelin, are vitally important in the CNS. The neurologic complications of vitamin B12 deficiency are likely due to a reduction of activity of the Blz-dependent enzyme methionine synthase and the subsequent reduction of SAMe production. The CNS lacks the alternate betaine pathway of homocysteine remethylation; therefore if methionine synthase is inactivated, the CNS has a greatly reduced methylation capacity.l@Other causes of reduced methionine synthase activity include folic acid deficiency and nitrous oxide anesthesia exposure.lB Homocysteine has also been found to be a neurotoxin, especially in conditions in which glycine levels are elevated, including head trauma, stroke, and BIZ deficiency."O Homocysteine interacts with the N-methyl-Daspartate receptor, causing excessive calcium influx and free radical production, resulting in neurotoxicity?l The neurotoxic effects of homocysteine or reduced methylation reactions, or both, in the CNS contribute to the mental symptomatology seen in B12 and folate deficiency. Increased homocysteine levels can also be seen in schizophrenics."' Sigruficant deficiencies in B12 and folate are common in the elderly population and can contribute to a decline in cognitive f u n ~ t i ~ n .An ~ ~investigation ~ - ~ ~ * of cognitive ability in older men (54 to 81 years old) found poorer spatial copying skills in those with higher homocysteine levels. Better memory performance was correlated with higher vitamin B6 levels.115

BIZ deficiency and increasing severity of cognitive impairment have been seen in AD patients compared with controls and patients with other dementias.lI6In a study of 52 AD patients, 50 hospitalized nondemented controls, and 49 elderly subjects living at home, patients with AD were found to have the highest homocysteine levels and the highest methylmalonic acid (an indicator of B12deficiency) levels.117 In another Framingham study cohort with an average of 8 years' follow-up, dementia developed in 111of 1092 nondementia subjects, including 83 who were diagnosed with AD. The adjusted relative risk of dementia was 1.4 for each increase of 1 standard deviation in the logarithmically adjusted homocysteine value. The relative risk of AD was 1.8 per increase of 1 standard deviation at base line and 1.6 per increase of 1 standard deviation 8 years before base line. Additionally, in those with a plasma homocysteine level that was greater than 14 pmol/liter, the risk of AD nearly doubled.11s In a study of 741 psychogeriatric patients, high plasma homocysteinelevels were found in demented and nondemented patients; however, only demented patients also had lower blood folate concentrations compared with controls. Patients with concomitant vascular disease had sigruficantly higher plasma homocysteine than those without diagnosed vascular disease. Sigruficantly higher homocysteine levels, compared with controls, have also been found in Parkinson disease patient^."^ Homocysteine's effects on neurotransmitter metabolism, along with its potential reduction of methylation reactions, could be a contributing factor to the etiology of depression. Folate and BIZ deficiency can cause neuropsychiatric symptoms including dementia and depression. Although no studies have been performed to date investigating depression, folate and B12 deficiency, and homocysteine levels, with what is known about these deficiencies and methionine synthase inhibition, it is suggestive that this connection will be revealed in the future. SAMe is used therapeutically as an antidepressant in Europe and is the third most popular antidepressant treatment in Italy in 1995.120~'21 As yet, SAMe is not available as a supplement in the United States. Methylation of myelin basic protein is vital to the maintenance of the myelin sheath. The worst-case scenario of folate and B,, deficiency includes demyelination of the posterior and lateral columns of the spinal cord, a disease process called subacute combined degeneration of the spinal cord (SCD).'O8 SCD can also be precipitated by nitrous oxide anesthesia, which causes an irreversible oxidation of the cobalt moiety of the B12 molecule and the subsequent inhibition of methionine synthase activity, a decrease in homocysteine remethylation, and decreased SAMe production?@ This has been treated using supplemental methionine, which further supports the theory of a nitrous oxide-induced biochemical block

Syndromes and Special Topics at methionine synthase.'22 Particularly at risk for this condition are B12-deficientindividuals who visit their dentist and receive nitrous oxide.109,123 Abnormal methylcobalamin metabolism is one of the proposed mechanisms for the pathophysiology of the demyelinating disease multiple sclerosis (MS). Deficiency of vitamin B12 has been linked to some cases of MS, and it is suggested that dietary deficiency, or more likely, a defect in R-protein-mediated absorption or methylation of BI2 might be a sigruficant contributor to the pathogenesis of MS.124

Diabetes Mellitus Homocysteine levels appear to be lower in individuals with type 1 diabetes mellitus. Forty-one type 1 diabetic subjects (age 34.8 f 12 years, duration of illness: 10.7 It 11.1 years) were compared with 40 age-matched control subjects (age 34.2 f 9.1 years). Following an overnight fast, homocysteine was sigruficantly lower (p = 0.0001) in the diabetic group (6.8 It 2.2) than in the controls (9.5 f 2.9). This difference was apparent in male and female subgroups.125However, increased levels of homocysteine have been reported in type 1 diabetics with proliferative retinopathylX and n e p h r ~ p a t h y . ' ~ ~ , ' ~ ~ Evidence to date suggeststhat metabolism of homocysteine is impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM). Following a methionine load, hyperhomocysteinemia occurred with significantly greater frequency in patients with NIDDM (39%) as comp a d with age-matched controls (7%).The area under the curve over 24 hours, reflecting the total period of exposure to increased homocysteine, was also elevated with greater frequency in patients with NIDDM and macrovascular disease (33%)as compared with controls (0'3'0). The authors concluded that hyperhomocysteinemia is associated with macrovascular disease in a sigruficant proportion of patients with NIDDM.lB Other researchers have reported a correlation between increased homocysteine levels and the occurrence of macroangiopathy in patients with NIDDM. Intramuscular injection of lo00 pg methylcobalamin daily for 3 weeks reduced the elevated plasma levels of homocysteine in these individual^.'^^ Elevated homocysteine levels appear to be a risk factor for diabetic retinopathy in individuals with NIDDM. This might be due to a point mutation on the gene for the enzyme MTHFR.130J31 A sigruficantlyhigher percentage of diabetics with retinopathy exhibit this m ~ t a t i 0 n . IElevated ~~ homocysteine levels cause cell injury to the small vessels, which may contribute to the development of retinopathy, as well as macroangiopathy in the cardiovascular system.13

Rheumatoid Arthritis Elevated total homocysteine levels have been reported in patients with rheumatoid arthritis (RA) and psoriasis.

Twenty-eight patients with RA and 20 healthy agematched control subjects were assessed for homocysteine levels while fasting and in response to a methionine challenge. Fasting levels were 33%higher in RA patients than in controls. Four hours following the methionine challenge, the increase in plasma homocysteine concentration was also higher in patients with RA.132 Another study found statistically sigruficant increases in homocysteine in RA patients (p = 0.003), with 20% of the patients having homocysteine levels above the reference range.'" A mechanism for this increased homocysteine in RA patients has not been elucidated. Penicillamine, a common sulfhydryl-containing arthritis treatment, has been found to lower elevated homocysteine levels in vivo.134

Psoriasis One study of 30 psoriasis patients and their matched controls were evaluated for blood concentrations of lipids, lipoproteins, acute phase reactants, homocysteine, and atherothrombotic markers. This study observed that more than 50% of the psoriasis patients had homocysteine levels that were higher than 15p o l / L , while only 20% of the control individuals were above this cutoff point. It was concluded that the mean levels of serum homocysteine, fibrinogen, fibronectin, intercellular adhesion molecules, plasminogen activator inhibitor, and autoantibodies against oxidized low-density lipoprotein were increased in psoriatic patients, whereas tissue plasminogen factor, vitamin B12, and folate levels were decreased ~ignificantly.5~ Further investigation into both the prevalence of hyperhomocysteinemia and the mechanism of action affecting RA and psoriasis is necessary.

Kidney Failure Because homocysteine is cleared by the kidneys, chronic renal failure, as well as absolute or relative deficiencies of 5-methylTHF, methylcobalamin, P5P, or betaine results in increased homocysteine levels. In 176 patients with end-stage renal disease on peritoneal or hemodialysis, homocysteine concentrations averaged 26.6 f 1.5 pmol/L in patients with renal failure as compared with 10.1 f 1.7 pmol/L in normals. Abnormal values exceeded the 95th percentile for normal controls in 149 of the patients with renal failre.'^^ Data also indicate that plasma homocysteine values represent an independent risk factor for vascular events in patients on peritoneal and hemodialysis. Patients with a homocysteine concentration in the upper two quintiles (>27.8 pmol/L) had an independent odds ratio of 2.9 (CI, 1.4 to 5.8; p = 0.007) of vascular complications. Vitamin B levels were also lower in patients with vascular complications than in those with0~t.l~~

Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease

Alcoholism and Ethanol Ingestion Chronic alcoholism is known to interfere with onecarbon metabolism. Because of this, it is not surprising to find that mean serum homocysteine levels are two times higher in chronic alcoholics than in nondrinkers (p < 0.001). Beer consumers have lower concentrationsof homocysteine compared with drinkers of wine or spirits (p = 0.05). In chronic alcoholics, serum P5P and red blood cell folate concentrations have been shown to be significantly lower than in control subjects.13Plasma homocysteine was sigruficantly higher, compared with controls, in 42 active alcoholics hospitalized for detoxication. In another group of 16 alcoholicswho were abstaining from ethanol ingestion, plasma homocysteine did not deviate from that of contr01s.’~ Feeding ethanol to rats produces prompt inhibition of methionine synthase, as well as a subsequent increase in activity of betaine homocysteine methyltransferase. Despite the inhibition of methionine synthase, the enhanced betaine homocysteine methyltransferase pathway uses hepatic betaine pools to maintain levels of SAMe.13’ Results indicate that ethanol feeding produces a sigzuficantloss in SAMe in the first week, with a return to normal SAMe levels in the second week. Betaine feeding enhances hepatic betaine pools in control animals, as well as ethanol-fed animals; attenuates the early loss of SAMe in ethanol-fed animals; produces an early increase in betaine homocysteine methyltransferase activity; and generates increased levels of SAMe in both control and ethanol-fed group^.'^ It has been shown that minimal supplemental dietary betaine at the 0.5% level increases SAMe twofold in control animals and fivefold in ethanolfed rats. Concomitant with the betaine-generated SAMe, ethanol-induced hepatic fatty infiltration was ameliorated.137Betaine supplementation also reduces the accumulation of hepatic triglyceride produced after ethanol inge~ti0n.I~~

Gout Although homocysteine levels have been positively correlated with increased uric acid l e ~ e l s , ” no ~ ~studies ~J~ have investigated homocysteine levels in gout patients. It is possible the increased uric acid levels in gout are due to decreased SAMe production because of the reduction in homocysteine recycling. The excess adenosine, which would have reacted with methionine to form SAMe, is degraded to form uric acid as its end product. Niacin is contraindicated in gout, a5 it competes with uric acid for e~creti0n.l~~ Animal studies have shown that increased levels of Sadenosylhomocysteine and thus homocysteine cause significant reductions in SAMe-dependent methylation reactions.I6 Therefore because degradation of the niacin-containing coenzyme nicotinamide adenine dinucleotide (NAD) is dependent on methylation by SAMe, and SAMe activity is severely

reduced in hyperhomocysteinemia, niacin levels might be higher in these people, resulting in less uric acid excretion, higher uric acid levels, and increased gout symptoms in susceptible individuals. This possibility and its mechanism need further investigation.

Osteoporosis Homocystinuria due to cystathionine synthase deficiency is an autosomal recessive error of sulfur amino acid metabolism characterized clinically by lens dislocation, mental retardation, skeletal abnormalities, and thromboembolic ~ h e n 0 m e n a . lIndividuals ~~ with this enzyme deficiency have decreased concentrations of cysteine and its disulfide form, cystine. In children with homocystinuria, osteoporosis is a common presenting symptom.143Because of the role of sulfur compounds in the formation of sulfated amino sugars, disturbed crosslinking of collagen has been proposed as a possible mechanism of action. One group of researchers studying 10 patients with homocystinuria found normal synthesis of collagen but a signhcant reduction of cross-links.lM Because of the correlation between homocystinuria and osteoporosis in children with this amino acidopathy and the increase in homocysteine concentrations in postmenopausal women, several authors have implied that elevated homocysteine levels contribute to postmenopausal osteoporosis. The Framingham study of 825 men and 1174 women, ranging from59 to 91 years old, affirmed this suspicion by evaluating plasma homocysteine levels and relative incident of hip fracture over a period of 16 to 19 years. The mean plasma total homocysteine concentrationwas 13.4 f 9.1 pmol/L with 41 hip fractures among men and 12.1 k 5.3 pmol/L and 146 hip fractures in the women’s subgroup. It was shown that both men and women in the highest quartile of plasma homocysteine indeed had a greater risk of hip fracture than those in the lowest quartile, where the risk was almost four times as high for men and 1.9 times as high for women.145Since physical activity is well known to lower homocysteine, as well as prevent falls, it may therefore influence the association between homocysteine levels and the risk of fracture.15Therefore it seems prudent to prescribe exercise, as well as appropriate supplemental therapies for women and men with high homocysteine and osteopenia/porosis.

Drug-Induced Hyperhomocysteinemia Since fibrate drugs are known to increase homocysteine levels (see ”Pharmaceutic Effects on Homocysteine” earlier), one randomized, double-blind crossover study investigated the effect using fenofibrate adjunctively with 650 pg of folic acid, 5 mg of vitamin B6, and 50 pg of B12 or just fenofibrate in hyperlipidemic men. Subjects who received the fenofibrate plus placebo had an average increase in homocysteine concentration of

Syndromes and Special Topics 44%. Subsequent to the fenofibrate plus vitamin treatment, it was 13%. In this study vitamins significantly prevented most of the homocysteine increase seen after fenofibrate plus placebo. The authors of this study suggest that routine use of these nutrients may be beneficial with this pharmaceutic therapy.32

DIAGNOSTIC CONSIDERATIONS Many studies cited herein have used a reference range, with 12 to 16 pmol/L being the upper limit of normal. This level will probably drop, as it did cholesterol testing, because researchers have found a highly sigruficant increase in relative risk of atherosclerotic cardiovascular disease and other disease processes as homocysteine levels increase, even within the "normal" range. A number of clinical laboratories currently perform plasma homocysteine determinations, by themselves or within a cardiovascular panel.

THERAPEUTIC CONSIDERATIONS Although folic acid supplementation (400 pg daily) alone can reduce homocysteine levels in many subjects, given the importance of vitamin BI2 and B6 to proper homocysteine metabolism, all three should be used together. In one study, the prevalence of suboptimal levels of these nutrients in men with elevated homocysteine levels were 56.8%, 59.1%,and 25% for folic acid, vitamin B1= and B6, respectively, indicating that folic acid supplementation alone would not lower homocysteine levels in many cases.146In other words, folic acid supplementation will only lower homocysteine levels if there are adequate levels of vitamin B12 and $. This fact could reduce the effect of folic acid fortification of food. In 1998 the FDA mandated the fortification of food products with folic acid. Although homocysteine levels have decreased modestly after the fortification of food with folic acid, the effect on mortality has been minor at best.19 This indicates the importance of more aggressive supplementary measures to reduce homocysteine-associated cardiovascular risk. In one study of 100 men with hyperhomocysteinemia, oral therapy with 650 pg folic acid, 400 pg vitamin Biz, 10 mg vitamin B6, or a combination of the three nutrients was given daily for 6 weeks. Plasma homocysteine was reduced 41.7% during folate therapy and 14.8% during B12 therapy, while 10 mg B6 did not reduce plasma

1. Tucker KL, Selhub J, Wilson PW, et al. Dietary intake pattern relates to plasma folate and homocysteineconcentrations in the Framingham Heart Study. J Nutr 1996;126:3025-3031. 2. LussierCacanS, Xhignesse M, Piolot A, et al. Plasma total homocysteine in healthy subjects: sex-specific relation with biological traits. Am J Clin Nutr 1996;61:587-593.

homocysteine significantly. The combination worked synergistically to reduce homocysteine levels by 49.80/o. 147 Several studies using folic acid, B6 B1= and betaine, either alone or in combination, have demonstrated the ability of these nutrients to normalize homocysteine levels.*Other studies confirm that oral folate supplementation alone will almost always lower high homocysteine, while B6 and B12 will lower homocysteine only in those with a genetic metabolic defect or dietary deficiency in those nutrients, or both.148J50Some studies have used high-dosage oral folate therapy (2.5 to 5 mg) to effectively reduce hyperhomocysteinemia in patients with peripheral atherosclerotic vascular disease, 50% of whom had abnormally high fasting plasma homocysteine levels, while 100% had abnormal plasma homocysteine after a methionine load. If a dietary deficiency or an increased demand resulting from genetic biochemical individuality exists for 5-methylTHF, methylcobalamin, P5P, or betaine, treatment with these active forms of mifronutrients should reduce homocysteine levels better than the nonactive forms (e.g., folic acid, cyanocobalamin, pyridoxine, betaine hydrochloride). In addition, betaine is important when there is a deficiency of the P5P-dependent enzyme cystathionine synthase-the most common genetic abnormality affecting the transsulfuration pathway of homocysteine breakdown. Betaine supplementation in combination with vitamin B6 corrects the hyperhomocysteinemia in these individuals.25J48

Therapeutic Approach Supplements Folic acid: 800 pg daily Vitamin B12:800 pg Pyridoxine: 25 to 50 mg daily If unresponsive to the previous dosages, patients may take the following: Folinic acid: 800 pg daily Methylcobalamin: 800 pg daily Pyndoxal 5'-phosphate: 20 mg daily Betaine (trimethylglycine):1200 mg daily NAC: 500 mg daily

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Hyperventilation Syndrome/Breathing Pattern Disorders Leon Chaitow, ND, DO CHAPTER CONTENTS DIAGNOSTIC SUMMARY 629 Introduction 629 HyperventilationSyndrome/Breathing Pattern Disorders Defined 629 Gender 630 Diagnostic Overview 630 General Considerations 630 Benefits of Normal Respiratory Function 630 The Carbon Dioxide-Oxygen Balancing Act 631 Pathophysiology 631 Diagnostic Considerations 635 Symptoms and Signs of Hyperventilation Syndrome/Breathing Pattern Disorders 635 Acute Hyperventilation Progression 635 Chronic Hyperventilation 636 Laboratory and Off ice Tests for Hyperventilation Syndrome/Breathing Pattern Disorders 637 The Nijmegan Questionnaire 637

Biomechanical(Structural) Considerations 638 The Structure-FunctionContinuum 638 The Muscles of Breathing 638 Structure-FunctionSummary 639 Neural Regulation of Breathing 639 Chemical Control of Breathing 639 Voluntary Control of Breathing 639 Therapeutic Considerationsand Therapeutic Approach 640 Treatment and Rehabilitation of Hyperventilation SyndromeBreathing Pattern Disorders 640 An Osteopathic/Naturopathic Protocol for Care of Hyperventilation Syndrome/Breathing Pattern Disorders 641 Breathing Rehabilitation Exercises 641 Is Breathing Retraining Effective? 641 Osteopathic Treatment of Chronic Asthma 641 Summary 642

Hyperventilation syndrome/breathing pattern disorders (HVS/BPDs) are described as follows:

which are tuned to maintain arterial carbon dioxide (PaCOz)levels within a narrow range. Although at any given time the body's carbon dioxide (CO,) production is set at a certain level, the exaggerated breathing depth and rate associated with H V S / BPDs eliminates COzat a faster pace, resulting in a fall in PaCOzand arterial hypocapnia. The arterial hydrogen ion (pH) (acid/alkaline balance) rises into the alkaline region, thus inducing respiratory alkalosis.

Hyperventilation is a pattern of overbreathing in which the depth and rate exceed the metabolic needs of the body at that time. Breathlessness usually OCCUIS at rest or with only mild exercise. Physical, environmental, or psychologic stimuli override the automatic activity of the respiratory centers,

As a direct result of HVS/BPDs, many patients present with multiple symptoms, some of which mimic serious disease. However, blood tests, electrocardiograms (ECGs), and thorough physical examinations may reveal nothing out of the ordinary. Up to 10% of patients in general internal medicine practice reportedly suffer from HVS/BPDs as their primary diagnosis.] One study

INTRODUCTION Hyperventilation Syndrome/Breathing Pattern Disorders Defined

629

Syndromes and Special Topics reported a series of 45 patients with chest pain who had normal coronary arteries on angiography and were ultimately diagnosed with HVS/BPDs. Over a 3.5-year average follow-up, 67% had made subsequent emergency visits for chest pain and 40% had been readmitted to rule out myocardial infarction.2The implications are that many individuals with HVS/BPDs experience severe and genuinely distressing symptoms, and considerable medical expenses are incurred in excluding more serious pathology.

Gender More females than males have HVS/BPDs, ranging from a ratio of 2 1 to 71. The peak age of incidence is 15 to 55 years, althoughother ages can be affected.Women may be more at risk because of hormonal influences, since progesterone stimulates respiratory rate, and in the luted (postovulation/premenstrual)phase, COz levels drop on average 25%.Additional stress can then "increase ventilation at a time when CO, levels are already Acute hyperventilation represents approximately 1% of all cases of hyperventilation, well outnumbered by chronic hyperventilation: Bradley5 stated: Unfortunately breathing pattern abnormalities and their sequelae . . . are commonly missed by doctors and health care professionals or dismissed as "over anxiousness," so that no treatment options are offered.

Diagnostic Overview

and the diaphragm ascends back to its original domed position, aided by the elastic recoil of the lung. A relaxed pause at the end of exhalation releases the diaphragm briefly from the negative and positive pressures exerted across it during breathing. *Under normal circumstances individuals are quite unaware of their breathing. Breathing rates and volumes increase or fluctuate in msponse to physical or emotional demands, but in normal subjects they return to relaxed low chest patterns after the stimuli ceases. Patients, especially those whose symptom presentation includes chronic fatigue or anxiety, or both, and who display or report a number of the following signs or symptoms, might be considered suitable candidates for respiratory treatment. The following symptoms are indications of possible breathing pattern dysfunction: A feeling of constriction in the chest Shortness of breath Accelerated or deepened breathing Inability to breathe deeply Feeling tense (the Nijmegen questionnaire avoids the use of the word anxiety) lightness around the mouth Stiffness in the fingers or arms Cold hands or feet Tigling fingers . Bloated abdominal sensation Dizzy spells Blurred vision Feeling of confusion or losing touch with environment

Presenting symptoms and observation during case taking should offer the alert clinician an opportunity to consider BPD as a factor/feature of the individual's condition. Unless it is considered, it is unlikely to be diagnosed. Various tools are available to assist in such a diagnosis, ranging from laboratory tests to simple but effective questionnaires and palpation procedures (see "Diagnostic Considerations" later). In order to recognize HVS/BPDs, one must be aware of the characteristics of a normal breathing pattern.

Details of diagnostic methods are outlined later in this chapter.

Normal Breathing Pattern

The exchange of gases involving acquisition of oxygen (0,)and elimination of CO, leads to enhanced cellular function and facilitates the following:

The breathing rate should be 10 to 14 breaths/minute, moving 3 to 5 L of */minute through the airways of the chest. During the active inhalation phase, air flows in through the nose where it is warmed filtered and humidified before being drawn in to the lungs by the downward movement of the diaphragm and outward movement of the abdominal wall and lower thoracic structures. *The upper chest and accessory breathing muscles should remain relaxed. The expiratory phase is ideally effortless as the abdominal wall and lower intercostals relax downward

GENERAL CONSIDERATIONS Benefits of Normal Respiratory Function

Normal performance of the brain, organs, and tissues of the body Normal speech and human nonverbal expression (e.g., sighing) Fluid movement (lymph, blood) Spinal mobility through regular, mobilizing, thoracic cage movement Digestive function via rhythrmc positive and.negative pl.essure fluctuations,via normal diaphragmaticfunction Any chronic alteration in breathing function automatically modifies these functions negatively.

Hyperventilation Syndrorne/Breathing Pattern Disorders

The impact of habitual BPDs such as hyperventilation on an individual’s physiology can be profound, potentially resulting in, or exacerbating, a wide range of health problems, sometimes severely, ranging from anxiety and panic attacks to fatigue and chronic pain.

The Carbon Dioxide-Oxygen Balancing Act Gilbert6 offers a reminder as to common perceptions about, and the balancing act that is manifested below the surface of, breathing function: Simply put, the body extracts oxygen from the inhaled air and excretes carbon dioxide to be exhaled. That formulation suggests that all we need to remember is that oxygen is good and carbon dioxide is bad. Yet if one considers that life-giving oxygen can also be corrosive and toxic, and that a deficiency of the waste gas carbon dioxide (COJ can cause fainting, seizures, or death, then the “good/bad” distinction must be restated as “good within certain limits” and ”bad within certain limits.” Maintaining these two gases within those limits is a complex task for the body, even more so because the supply

Breathing in excess of metabolic requirements

of each gas fluctuates with each breath. This tidal oscillation must be smoothed out so that the brain and bodily tissues and also so that C 0 2in the body receive a steady supply of 02, remains at a stable level. This need for COzstability may be less familiar than the need for stability of 0, but with respect to both of these gases, we live in a narrow zone of homeostasis bordered on both sides by physiological disaster. Much of what goes wrong with breathing involves attempts to avoid this disaster.

Figure 56-1 shows H V S symptoms.

Pathophysiology Physiologic and Pathophysiologic Causes of Altered Patterns of Breathing7 Hyperventilation can be an appropriate physiologic response to the body’s metabolic needs; for example, tachypnea (rapid breathing) or hyperpnea (increase in respiratory rate proportional to increase in metabolism) may result as the respiratory centers respond automatically and appropriately to rising COzproduction due to exercise or organic disease that may be creating acidosis.

w 1. Upper fixator overactivity shortening of accessory breathing muscles Reduced PCO, 2. Painful nodules in nape of = respiratory alkalosis neck, anterior chest and shoulder girdle 3. Temporal headaches 4. Painful legs 5. Whole body expresses *Increased neuronal tension-cannot relax in activity speeding spinal any position reflexes as well (initially) as heightened pain perception + photophobia, + hyperacusis

1

J

Increased neuronal irritability. Reduced blood flow to tachycardia

I

I

I

I

I

I

*all these symptoms are increased during progesterone phase of menstrual cycle

\ \

I

Increased circulating histamines make allergic reaction more Dizziness, lightheadedness, ”foggy brain“ Cold extremities Chest pain Anxiety, apprehension (sense of mild panic) Depressed cortical activity Vasomotor instability, blurring of consciousness and vision Loss of cortical inhibition results in emotional lability Figure 56-1 Negative health influences of a dysfunctional breathing pattern such as hyperventilation. (From Chaitow L, Bradley D, Gilbert C. Multidisciplinary approaches to breathing pattern disorders. London: Churchill Livingstone. 2002:90.)

It is therefore important to exclude organic causes that diminish arterial oxygen saturation (Pa03 or elevate PaC02 levels. Organic causes of HVS/BPDs that should be excluded/ identified before breathing rehabilitation is initiated include the following:

Respiratory: asthma, chronic obstructive respiratory disease, pneumonia, pulmonary embolus, pneumothorax, and pleural effusion Cardiovascular: acute and chronic left heart failure, right heart failure, tachyarrhythmias Hemepoeitic:anemia Renal: nephrotic syndrome, acute and chronic kidney failure Endocrine: Diabetes with ketoacidosis, pregnancy, progesterone therapy Metabolic: liver failure Pharmaceutic:aspirin, caffeine, amphetamine, nicotine Gilbert6 summarizes causes of HVS/BPDs as follows: In considering aberrations in the breathing pattern, it is helpful to keep in mind:

Adequate and inadequate compensations for pathology elsewhere (e.g., acidosis from diabetes or kidney problems) Responses to extrinsic factors (such as allergy or drugs) Responses to intrinsic factors such as progesterone Truly pathologic disorders of the breathing system itself Psychogenic or functional breathing problems

Gilbert also noted that the following factors can lead to altered breathing patterns: Ketoacidosis promotes deeper, faster breathing because the breathing centers are responding to the higher C02content. Diarrhea results in the loss of alkaline plasma bicarbonate ions, which if prolonged leads to acidosis. This stimulates corrective overbreathing in order to remove C02 (as carbonic acid) and normalize the pH. Excessive vomiting causes loss of hydrochloric acid, shifting the body toward alkalosis, slowing breathing to allow C02to build up and restore pH. Hypoventilation is the result. Use of steroids and diuretics can lead to alkalosis.

Categorization of Causes It is possible to place the common etiologic features of HVS/BPD into biomechanical, biochemical, psychologic, environmental, pathologic, and habitual categories. The reasons for an individualbreathing inappropriately can derive diredly from structural, biomechanical causes such as a restricted thoracic spine, rib immobility, or

shortness of key primary and accessory respiratory muscles. Causes of breathing dysfunction can also have a more biochemical etiology, possibly involving allergy or infection, which triggers narrowing of breathing passages, and subsequent asthmatic-type responses. Acidosis, resulting from conditions such as kidney failure, also directly alter breathing function as the body attempts to reduce acid levels via elimination of C02 through hyperventilation. The link between psychologic distress and breathing makes this another primary cause of many manifestations of dysfunctional respiration. Examining a person suffering from anxiety or depression without breathing dysfunction being noted is difficult to imagine. Other catalysts that may affect breathing function include environmental factors (e.g., altitude, humidity).8 BPDs may also emerge from a background of established pathology (e.g., asthma, cardiovascular disease, kidney failure, chronic pain). Where this is the case, the aim of this chapter is not to explore these states, as they are discussed elsewhere in this textbook. The etiology of HVS/BPD may involve combinations of the factors listed earlier; however, in most instances, altered breathing patterns, whatever their origins, seem to be maintained by nothing more sinister than pure habit.7

The Hydrogen Ion Factor Gilbert6 stated the following: The story [of HVS/BPD] might best begin with pH, because this factor influences every organ of the body. . . . The variable of relative acidity facilitates many metabolic exchanges and it must be kept in careful balance. Since pH describes proportion of hydrogen ions available for combination, and the pH is on a log scale, a small change in pH, such as 7.4to 7.2,means doubling the number of hydrogen ions present. The binding of hydrogen to negative sites helps to regulate enzymatic action, endocrine secretion, integrity of protein molecules, and cellular metabolism, including oxygen absorption and release, A pH of 7.2would seriously compromise many physiological functions. The physiological normal pH in the arterial blood is around 7.4,with an acceptable range from 7.35to 7.45.Outside these limits lie ill effects of many kinds. The body will sacrifice many other things in order to maintain proper pH.

The Carbon Dioxide-Hydrogen Ion Connection The acidity of the blood is determined mainly by C02. COz is the end-product of aerobic metabolism, deriving mainly from the mitochondria. C 0 2 is odorless; heavier than air; and, if inhaled in its pure form, causes suffocation. COz is present in the atmosphere at a concentration of around two-hundredths of 1%,harmless to humans but adequate to sustain plant life.

Hyperventilation Syndrome/Breathing Pattern Disorders

Transportation of C 0 2 occurs from the tissues into the blood and then to the lungs for exhalation. The body converts C02to carbonic acid (H2C03),of which there is a perpetual surplus. The lungs exhale around 12,000 mEq of carbonic acid per day, compared with less than 100 mEq of fixed acids excreted by the kidneys. Any increase in bodily activity produces C02, acidifying the blood, unless more C02 is excreted/ exhaled. It is therefore obvious that changes in breathing volume relative to C 0 2production regulate the momentto-moment concentration of pH of the bloodstream (longer-term regulation of pH is shared with the kidneys). It is the concentration of C02in the blood, not oxygen, that is the major regulator of breathing drive. Higher C 0 2level immediately stimulates more breathing, apparently on the assumption that abundance of C02 means oxygen-poor air is being breathed, breathing has stopped, or something else is happening that is an antecedent to suffocation.

Respiratory Homeostasis Jennett9describes the delicate homeostatic balancing act in which pH and C02are key features: When there are not other overriding drives affecting breathing, the neural control system acts to maintain a constant arterial K O 2 . This must mean that the volume of Cot expired continually balances the volume produced by tissue metabolism. Measurements show that alveolar and arterial concentrations of C02stay constant, which means that the volume of gas breathed out from the functional (alveolar)volume of the lungs must vary precisely with the rate of metabolic C02production. In rest and activity, when the system is left to itself, it is so efficient that the matching OCCUTS virtually breath-by-breath, even when metabolic activity is continually changing.

The Bicarbonate Buffer Gilbert6 explained the following: There exists a further balancing mechanism, the bicarbonate buffer. The bicarbonate ion (HCOc) is derived from C02during its ride in the bloodstream; C02 dissociates into hydrogen ions (H+)and (HC03-). This bicarbonate reserve is adjustable as needed, up to a point, and constitutes a major alkaline buffer system which opposes rises in acidity. The kidneys regulate the regulators by adjusting amount of bicarbonate returned to the bloodstream. If the kidneys detect excess acidity (a surplus of positively-charged hydrogen ions) they will try to retain more bicarbonate to balance the acid, but this is not a fast process; adjusting their filtration characteristics takes hours to days. In the short run, meanwhile, if bicarbonate buffering of excess acid is not sufficient, or if the bicarbonate is depleted, a faster back-up buffering system is available: hyperventilation. Excessive breathing exhales more C02 (acid), thereby bringing pH closer to normal.

Oxygen Delivery and Smooth Muscle Constriction The blood carries oxygen mainly in molecules of hemoglobin, which are contained in red blood cells. In an appropriate environment, hemoglobin combines readily with oxygen (to the form of oxyhemoglobin). This process varies according to local pH, as well as PO2. This ability to combine is important for both absorbing oxygen through the alveoli and also for releasing oxygen through the capillary walls, where oxygen diffuses into the tissues. These two properties are largely determined by local conditions, so that when pH is low (i.e., the blood is more acidic), hemoglobin in that area is stimulated to release additional oxygen. This is true of metabolically active tissues in general but especially of muscles. An exercising muscle needs all the oxygen it can get, and this is assisted by its chemical nature, explained by West as follows: An exercising muscle is acid, hypercarbic, and hot, and it benefits from increased unloading of O2 from its capillaries!

The effect of pH on oxyhemoglobin dissociation is called the Bohr effect. In the lungs the need is to bind oxygen to hemoglobin, not release it. Not surprisingly, the lungs have a more alkaline environment. The fact that a shift of the blood toward acidity promotes dissociation and release of oxygen from the hemoglobin is particularly important when considering hyperventilation because the resulting alkalinity causes the hemoglobin molecule to retain more oxygen than usual. With increased alkalinity encouraging smooth muscle contraction and therefore diminished diameter of blood vessels, as well as the reluctance of hemoglobin to release its oxygen, a relative oxygen deficit is likely in tissues and the brain, leading to symptoms such as fatigue, aching, cramping, and cognitive problems.

Hypoglycemia as an Exacerbating Factor Fluctuating blood glucose levels may trigger HVS/BPD symptoms in patients with high carbohydrate diets, which produce rapid rises followed by sharp falls to fasting levels or bei~w.~JO Patients are recommended to eat breakfast including protein and to avoid going without food for more than 3 hours." This fits in with a midmorning and afternoon protein snack, as well as the usual three meals a day. This is particularly relevant to patients who experience panic attacks or seizures, which have been shown more likely to strike when blood glucose levels are Referral to a nutritionist may be warranted.

Syndromes and Special Topics

Psychology and Hyperventilation SyndrornerSreathing Problem Disorders Gilbert6 described aspects of the influence of emotion on breathing: Hyperventilation as a chronic syndrome or behavioral tendency is squarely in the category of disorders often called "functional," "psychophysiological," or "psychosomatic." But it is not always so clearly delineated; disruption of the optimal breathing pattern can happen in subtler ways. Increased variability from breath to breath is known to correlate with anxiety ~tates.lZ*~ Low PCOz and increased frequency of sighing are typical of those with panic disorder even when not panicking.**These generalizations miss individuals who do not have a chronic breathing pattern disorder, but who do experience disrupted breathing under particular conditions.These "conditions" can provoke either an amygdala "alarm" discharge or some specific, learned breathing response, as well as occasional panic.

Conway and colleagues15used hypnosis to investigate the sources of hyperventilation episodes and concluded that people who hyperventilate fall into at least two groups, the chronic and the episodic, explained as follows: It has been considered that emotional events, particularly involving loss, separation and impotent anger, are the precipitating factors that may initiate a trend to hyperventilation. . . . On some occasions the important initiating event, psychological strain or life event was evident from the history, but in others questioning under hypnosis revealed psychological triggers, not elucidated previously, which provoked marked falls in PetCOz. Since it is a feature of many psychosomatic illnesses that the initiating factors are repressed and only the somatic symptoms remain, this technique may be of considerable help in some patients in whom therapy may not be progressing as well as might have been expected.

INPUT

Freeman and associates16also showed that individuals who reported several symptoms indicating hyperventilation (including chest pain/palpitations and dizzinessnot exclusively respiratory symptoms) displayed rather strong hyperventilation in response to recalling emotionally disturbing events, whereas the control subjects did not. Bereavement, loss of control, grief, and anger were common topics associated with the symptoms. Gilbert6 concludes: Aside from medical problems, there are still many factors in the psychological and behavioral realms competing for control of breathing [Figure 56-21. Successful regulation must take all factors into account, with special consideration for priorities of survival. The human brain adds a layer of complication with its power to imagine, project, and recall, often stimulating breathing reflexes without apparent reason.

Somatic Changes Due to Hyperventilation SyndromerSreathing Problem Disorders Garland" suggested that "psychology overwhelms physiology" when he described the following somatic changes that flow from a pattern of upper chest breathing, which, at its extreme, becomes hyperventilation: When faced with persistent upper chest breathing patterns, physicians should be able to identrfy reduced diaphragmatic efficiency and commensurate restriction of the lower rib cage, as these evolve into a series of changes with accessory breathing muscles being inappropriately and excessively used. A degree of visceral stasis and pelvic floor weakness will develop, as will an imbalance between increasingly weak abdominal muscles and increasingly tight erector spinae muscles.

OUTPUT

Figure 56-2 Final modulation of the breathing act includes input from many possible sources: the need for vocalization (a cry for help, a shouted warning, perhaps a growl); preparation for exertion;the need to freeze and become less noticeable;the need to maximize sensory acuity by keeping the body still; and the need to either remain calm or return to a baseline state of calmness.These inputs often conflict with each other, but if there is a hint of a threat to survival. they seem to have priority over all other considerations. (From Chaitow L. Bradley D, Gilbert C. Multidisciplinaryapproaches to breathing pattern disorders. London: Churchill Livingstone. 2002:122.)

Hyperventilation Syndrorne/Breathing

Fascia1restriction from the central tendon via the pericardial fascia, all the way up to the basi-occiput, will be noted. The upper ribs will be elevated and there will be sensitive costal cartilage tension. The thoracic spine will be disturbed by virtue of the lack of normal motion of the articulation with the ribs, and sympatheticoutflow from this area may be affected. Accessory muscle hypertonia, notably affecting the scalenes, upper trapezius, and levator scapulae will be palpable and observable. Fibrosis will develop in these muscles, as will myofascial trigger points. The cervical spine will become progressively rigid with a fixed lordosis being a common feature in the lower cervical spine. A reduction in the mobility of the second cervical segment and disturbance of vagal outflow from this region is likely. Garland concluded his listing of somatic changes associated with hyperventilationby saying that: Physically and physiologically [all of] this runs against a biologically sustainable pattern, and in a vicious cycle, abnormal function (use) alters normal structure, which disallows return to normal function.

Garland also points to the likelihood of counseling (for associated anxiety or depression) and breathing retraining, being far more likely to be successfully initiated if patients appropriately deal with the structural components, as listed.

DIAGNOSTIC CONSIDERATIONS Symptoms and Signs of Hyperventilation Syndrome/Breathing Pattern Disorders Bradley stated the following: The symptoms and signs of hyperventilation [are] diverse. None is absolutely diagnostic. Consequently clinicians rely on a suggestive group of symptoms. Each patient has a characteristic set of symptoms which can be amplified during an acute episode, or when hyperventilation is exaggerated. The intermittent nature and variable intensity of the symptoms adds to the difficulty of diagnosis. In addition, many patients will not mention some of their symptoms, either because they think they are unrelated or they are ashamed to mention them. Examples are hallucinations, phobias, sexual problems, fear of impending death or madness, and nightmares. Careful interrogation about the relationship of breathlessness to exercise usually reveals a variation in severity from day to day.

Symptoms Table 56-1 is not fully comprehensive but represents the commonest symptoms and signs of HVS/BPD.

For greater depth see T m o n s and Ley7 Gardner,18 Nix0n,19and Chaitow and colleagues?

Metabolic Disturbances and Hyperventilation Syndrome Two tests of nerve hyper excitability produced by hypocapnia-inducedhypocalcaemia are Trousseau's and Chvostek's signs. The Trousseau sign consists of occluding the brachial artery into the arm by pumping the blood pressure cuff above the systolic pressure for 2l/2 minutes. A positive sign is where paresthesia is felt severely within the period and the wrist and fingers arch in carpopedal spasm, termed main d'accoucheur or obstetrician's hand. The Chvostek sign occurs if, when tapping the facial nerve as it emerges through the parotid salivary gland, a contraction of the facial muscle twitches the side of the mouth. This is also a test for magnesium deficiency.2O Acute hypophosphatemia also contributes to weakness and tingling.

Cardiac Signs Chest pain associated with HVS/BPDs requires that heart disease is excluded as a diagnosis. Adrenalineinduced ECG changes can occur in hyperventilation, uncomplicated by coronary heart disease. One study suggests up to 90% of noncardiac chest pain is thought to be induced by WS/BPDs?* In older patients, established coronary artery disease can be exacerbated by vasoconstriction arising from hypocapnia, which puts them at risk of coronary occlusion and myocardial damage. Alternatively, hyperventilation can trigger spasms of normal caliber coronary arteries. Syndrome X refers to patients who have a history of angina, a positive exercise test (chest pain within 16 minutes), and yet a normal angiography. Thought to be a functional abnormality of coronary microcirculation, it is much more common in women than men.22

Gastrointestinal Signs Rapid breathing or mouth breathing instigates aerophagia from air gulping causing bloating, burping, and extreme epigastric discomfort. Irritable bowel syndrome is listed as a common symptom of chronic overbreathing. Fear and anxiety may induce abdominalcramps and diarrhea.] The median swallowing rate in healthy, nondyspeptic controls is 3 or 4/15 min. In the absence of food, up to 5 ml of air accompanies saliva into the gastrointestinal tract with each s w a l l ~ w . ~

Acute Hyperventilation Progression The patient presenting with an acute hyperventilation episode appears distressed.

Most common symptoms and signs of hyperventilationsyndromebreathing pattern disorders System

Symptoms

Suggested causes

Cardiovascular

Chest pain and angina, palpitation and arrhythmias, tachycardia, lightheadedness and syncope, altered ECG features

Reduced coronary blood flow, altered excitability of SA and AV nodes of cardiac muscle, reduced cardiac output, peripheralvasodilatation

Gastrointestinal

Discomfort in lower chest and epigastric area, esophageal reflux and heartburn, Moatin@distension,exacerbation of hiatal hernia symptoms, dry mouth, air swallowing and belching

Aerophagia, increased swallowing rate, mouth breathing

Neurologic

Headache, numbness and tingling (mainly involving extremities and perioral), positive Trousseau’s and Chvostek’s signs, dizzinesdgiddiness, ataxia and tremor, blurred and tunnel vision, anxiety and panic, phobias, irritability, depersonalization, detachment from reality, impaired concentration, cognition, performance, easy fatigue, insomnia, hallucinations

Cerebrovascular constriction (seenotes on smooth muscle contraction below); vasoconstrictionof vertebral or carotid arteries, or both; reduced O2 delivery, neuronal excitability resulting from alkalosis; hypocalcaemia

Respiratory

Breathlessness; restricted sensation around thorax; sighinwyawning; obvious use of upper chest, accessory breathing muscles (e.9.. scalenes) on inhalation; chest tenderness

Overuse of accessory breathing muscles and fatigue of primary respiratory muscles

Muscular

Stiffness and aching, weakness in limbs, cramping, carpopedal spasm, tetany

Hyper excitability of motor nerves, muscle fatigue, calcium/magnesium imbalance

AV; Atrioventricular; ECG, electrocardiogram: SA, sinoatrial.

The pattern of respiration is of deep, rapid breaths, using the accessory muscles visible in the neck and the upper chest. Wheezing may be heard as a result of bronchospasm triggered by hypocapnia. A stressful precipitating event is usually reported. Hypocapnia reduces blood flow to the brain (2% decrease in flow per 1mmHg reduction in arterial C q ) , causing frightening central nervous system symptoms. The reduced oxygenation of brain and tissues of the body results from contraction of smooth muscle surrounding blood vessels and a reluctance of the hemoglobin carrier molecule to release oxygen in the increasingly alkaline environmentcaused by excessive loss of COP Poor concentration and memory lapses may occur as a result, with tunnel vision and onset in those susceptible of migraine-type headaches or tinnitus. Sympathetic dominance brings on tremors, sweating, clammy hands, palpitations, and autonomic instability of blood vessels causing labile blood pressures.24 Bilateral perioral and upper extremity paresthesia and numbness may be reported. Unilateral tingling is most often confined to the left side. Dizziness, weakness, visual disturbances, tremor and confusion-sometimes fainting or even seizures-are typical symptoms.

Spinal reflexes become exaggerated through increased neuronal activity caused by loss of C02ions from the neurons. Tetany and cramping may occur in severe bouts.= On a psychologic level, Bradley5 described a ”cascade of symptoms” (see Figure 56-1) in which an original cause (emotionalor physical) leads to tension and anxiety that results in hyperventilation, possibly an acute hyperventilation attack, which (with repetition), over time, results in anticipation anxiety and avoidance behaviors or phobias, or both.

Chronic Hyperventilation The diagnosis of chronic and intermittent hyperventilation is more difficult than acute hyperventilation. A careful history and systemic inquiry, checking all other symptoms in the other body systems, usually highlights a suspicious pattern, particularly to the experienced clinician who can think beyond his or her own specialist area. Careful inquiries as to the precipitating causes of attacks helps both with the diagnosis and focusing on choice of treatment. Nixon19 suggested that there are often attacks where there is no preceding stressful event. For example, in chronic hyperventilatorsthe respiratory

Hyperventilation SyndromeBreathing Pattern Disorders

center may have been reset to tolerate a lower than normal partial pressure of PaCOz levels in the blood. In such patients, a single sigh or one deep breath may reduce the PaC02 enough to trigger symptoms. Examination must exclude organic diseases of the brain and nervous system; the heart, particularly angina and heart failure; respiratory disease; and gastrointestinal conditions, especially if there are suspicious symptoms in these systems.

Laboratory and Office Tests for Hyperventilation Syndrome/Breathing Pattern Disorderss Many possible tests for respiratory function exist, some of which require bulky or sophisticated equipment (e.g., forced expiratory volume, forced vital capacity, flowvolume curves, lung volume, gas transfer, cardiorespiratory). Some are difficult to perform (e.g., airway resistance), and some are invasive (e.g., blood gases). A selection of tests are listed as follows: Preliminary tests to exclude respiratory and cardiac disease include peak expiratory flow rate (PEFR), chest radiograph, and ECG. A PEFR measurement, compared with age, sex, and height tables, provides a simply done, quick exclusion of significant respiratory restriction in the clinic room. Where chest pain is a presenting symptom, an exercise ECG should be done. If a hyperventilation provocation test (HVPT) is performed (during which the patient is asked to voluntarily overbreathe to bring on symptoms), ECG should be monitored (see “Caution” later). Arterial blood gas determination is invasive and painful, (arterial puncture) appropriate in the emergency department, where the diagnosis of acute hyperventilation is required. For patients in whom chronic hyperventilation is suspected, the end-tidal carbon dioxide (PET C02) can be measured noninvasively from a continuous sampling through nasal prongs with the mouth occluded, or the tube can be sited in an oral airway for those with nasal obstruction to monitor C02deficits. PET C 0 2 can be evaluated following a 4-minute quiet breathing rest period, followed by exercise and recovery, or a hyperventilation provocation test can be conducted in the recovery period. Most patients with chronic hyperventilation have a PET COz at or below 30 mmHg and a markedly delayed recovery from hypocapnia after overbreathing.26 The think test2’ may be initiated 3 to 4 minutes into the recovery period. The patient is asked to recall a painful emotional experience during which symptoms developed. If the PETC02drops 10mmHg, the test supports hyperventilation. Bradley5 noted: “In some patients

with hyperventilationthe PaC02and the PET C02may be in the normal range. In those who are asymptomatic at the time of testing, this finding could be accepted. However, a normal level while experiencing symptoms negates hypocapnia as the cause of symptoms. It prompts a search for a n alternative explanation.” Palpation and observation can demonstrate a paradoxical breathing pattern in which the abdomen retracts and the upper chest expands on inhalation (as opposed to normal abdominal protrusion and lower thorax expansion). The breath-holding-time test does not require additional measurements or equipment. The time a hyperventilating patient can hold his or her breath is usually greatly reduced, often not beyond 10 to 12 seconds. Thirty seconds has been used as the approximate dividing line between hyperventilators and normals by some clinicians. It is worth noting that breathless patients without hyperventilation may have equal difficulty in breath holding.18 Buteyko performed comparative studies with a simple breath-holding technique to test C02levels and found that a simple technique of breath holding after expiration could predict the percent of alveolar C02 and therefore the degree of hyperventilation to a high degree of accuracy. According to his calculations, optimal levels of alveolar PC02 correlate to postexpiratory breath holding time of 40 to 60 seconds. Many asthmatics and hyperventilators are found to be able to hold the breath out for less than 10 seconds.2830

Caution Bradley cautioned the following: The hypervendation provocation test is best done before explanations of symptoms, to prevent suggestion and bias. Patients need to be warned only of a dry mouth. The patient is asked to concentrate on how they feel during the 1-2 minute period when they are over breathing at the rate of 30-40 per minute. The rate is set by the examiner’s hand movements. The operator must stress the importance of the test and the need to continue for as long as they can. An arterial blood gas determination at the end of the test can be of use to establish the depth of hypocapnia. Some clinicians rely on as little as 12 deep breaths which the patient can recover from easily, and subjective symptoms produced are recorded. In both the breath holding and voluntary over-breathing tests, the skills of the clinician are importantfor maintaining the trust and co-operation of patients.

The Nijmegan Questionnaire Bradley5 pointed out that: As yet there is no “gold standard” laboratory test to clinch the diagnosis of CHVS. However the questionnaire provides a non-invasive test of high sensitivity (up to 91%) and specificity up to 95%.31This easily administered internationally validated3*diagnostic questionnaireis the simplest, kindest and to

Syndromes and Special Topics

I

I I

Chest pain Feeling tense Blurred vision

Never 0

I I

I

Rare 1

I

I I I

Sometimes

2

I

Often

3

I I

I

Veryoften 4

1

I

I

I

Dizzy spells Feeling confused Faster or deeper breathing Short of breath Tight feelings in chest Bloated feeling in stomach Tingling fingers Unable to breathe deeply Stiff fingers or arms Tight feelings round mouth Cold hands or feet

'Nijmegen. Patients mark with a tick how often they suffer from the symptoms listed. A score above 23/64is diagnostic of hyperventilation syndrome.

Figure 56-3 Nijmegenquestionnaire. (From Chaitow L. Bradley D. Gilbert C. Multidisciplinaryapproachesto breathing pattern disorders, London: Churchill Livingstone. 2002: 176.)

date most accurate indicator of acute/chronic hyperventilation. It also has great educative value as patients often for the first time appreciate the widespread nature of their symptoms. Re-testing at a later date is helpful in showing patients their progress as their symptoms decrease or vanish.

Bradley noted that the results of this simple test also help indicate whether the initiating trigger causing the HVS/BPDs has been resolved, suggesting that the patient has only to deal with the '%ad breathing" habit and musculoskeletal and motor pattern changes, or whether the initiating triggers are ongoing or unresolved and may need further cognitive help (Figure 56-3).

BIOMECHANICAL (STRUCTURAL) CONSIDERATIONS The Structure-Function Continuum Nowhere in the body is the axiom of structure governing function more apparent than in its relation to respiration. Just as prolonged changes in patterns of use, such as an inappropriate [hyperventilation]breathing pattern, induce structuralchanges, involving the muscles and joints (e.g., rib) of respiration, so do these changes ultimately prevent normal function. Ultimately, the self-perpetuating cycle of functional change creating structural modification, leading to

reinforced functional tendencies, can become complete, from whichever direction dysfunction derives. Examples follow: Structural adaptations can prevent normal breathing function. Abnormal breathing function ensures continued structural adaptational stresses.17 Restoration of normal function demands restoration of adequate structural mobility, while maintenance of restored biomechanical flexibility requires that function (how the individual breathes) should be normalized through reeducation and training. Individually, neither approach is as useful as a combination of restoration of structural integrity, combined with functional improvement. It should be obvious that other underlying etiologic features, whether these relate to psychosocial, biochemical, or biomechanical factors, should be addressed as far as possible as a prerequisite of rehabilitation.

The Muscles of Breathing The muscles associated with breathing function can be grouped as either inspiratory or expiratory. They are either primary in that capacity or provide accessory support.

Hyperventilation Syndrome/

Because expiration is primarily an elastic response of the lungs, pleura, and "torsion rod" elements of the ribs, all muscles of expiration could be considered to be accessory muscles, as they are recruited only during increased demand. They include internal intercostals, abdominal muscles, transverse thoracis, and subcostales. With increased demand, iliocostalis lumborum, quadratus lumborum, serratus posterior inferior, and latissimus dorsi may support expiration, including during the high demands of speech, coughing, sneezing, singing, and other special functions associated with breathing. Space does not permit in-depth discussion of the muscles of respiration, further details of which can be found in Chaitow and colleagues.6

Structure-Function Summary Respiratory function-breathing-depends on the efficiency with which the structures constituting the pump mechanisms operate. At its simplest, the thoracic spine and the attaching ribs, together with their anterior sternal connections, along with all the soft tissues, muscles, ligaments, tendons, and fascia, need to be structurally intact, with an uncompromised neural supply, in order to function optimally. Without an efficient pump mechanism, all other respiratory functions are suboptimal. Clearly a host of dysfunctional patterns can result from altered airway characteristics, abnormal status of the lungs, or from emotional and other influences. Even if allergy or infection is causal in altering the breathing pattern, the process of breathing can usually be enhanced by relatively unglamorous nuts and bolts features such as normalization of rib restrictions or shortened upper fixator muscles.

Neural Regulation of Breathing6 Respiratory centers in the brainstem unconsciously influence and adjust alveolar ventilation to maintain arterial blood oxygen and carbon dioxide pressures at relatively constant levels, to sustain life under varying conditions and requirements. The three main groups are as follows: The dorsal respiratory group, located in the distal portion of the medulla, receives input from peripheral chemoreceptors and other types of receptors via the vagus and glossopharyngeal nerves. These impulses generate inspiratory movements and are responsible for the basic rhythm of breathing. The pneumotaxic center in the superior part of the pons transmits inhibitory signals to the dorsal respiratory center, controlling the filling phase of breathing. The ventral respiratory group, located in the medulla, causes either inspiration or expiration. It is inactive in quiet breathing but is important in stimulating

abdominal expiratory muscles during levels of high respiratory demand. The Hering-Breuer reflex prevents overinflation of the lungs and is initiated by nerve receptors in the walls of the bronchi and bronchioles sending messages to the dorsal respiratory centre, via the vagus nerve. The reflex "switches off" excessive inflation during inspiration, as well as excessive deflation during exhalation. The autonomic nervous system enables the automatic unconscious maintenance of the internal environment of the body in ideal efficiency and adjusts to the various demands of the external environment, be it sleep with repair and growth, quiet or extreme physical activity, or stress (Figure 56-4). A "third" nervous system regulating the airways has been recognized, called the nonadrenergic noncholinergic (NANC) system. Containing inhibitory and stimulatory fibers, nitric oxide (NO) has been identified as the NANC neur~transmitter?~ NANC inhibitory nerves cause calcium ions to enter the neuron, mediating smooth muscle relaxation and bronchodilation. NANC stimulatory fibers-also called C-fibers-are found in the lung supporting tissue, airways, and pulmonary blood vessels and appear to be involved in bron&wonstriction following exercise-induced asthma.32

Chemical Control of Breathing The central role of respiration is to maintain balanced concentrations of oxygen (9) and carbon dioxide (C02) in the tissues. Increased levels of C 0 2 act on the central chemo-sensitive areas of the respiratory centers themselves, increasing inspiratory and expiratory signals to the respiratory muscles. O2 on the other hand, acts on peripheral chemoreceptors located in the carotid body (in the bifurcation of the common carotid arteries) via the glossopharyngeal nerves and the aortic body (on the aortic arch), which sends the appropriate messages via the vagus nerves to the dorsal respiratory center.

Voluntary Control of Breathing Automatic breathing can be overridden by higher cortical conscious input (directly via the spinal neurones, which drive the respiratory muscles) in response to, for instance, fear or sudden surprise. Speaking requires voluntary control to interrupt the normal rhythmicity of breathing, as does singing and wind instrument playing. Evidence indicates that the cerebral cortex and thalamus also supply part of the drive for normal respiratory rhythm during wakefulness. (Cerebral influences on the medullary centers are withdrawn during sleep.) Habitual BPDs and HVS probably originatefrom some of these higher

center^.^

Syndromes and Special Topics

-........_..Parasympathetic Sympathetic

-----

Motor (to skeletal muscle)

Figure 56-4 Schema of the autonomic innervation (motor and sensory) of the lung and the somatic (motor) nerve supply to the intercostal muscles and diaphragm. (From Scanlan C, Wilkins R, Stoller J. Egan’s fundamentals of respiratory care, ed 7. St. Louis: Mosby, 1999.)

THERAPEUTIC CONSIDERATIONS AND THERAPEUTIC APPROACH Treatment and Rehabilitation of Hyperventilation SyndromeBreathing Pattern Disorders Different models of care in managing HVS/BPDs are available. It is assumed that all organic causes of breathing pattern changes have been excluded and that coexisting problems such as asthma, chronic obstructive airway disease, chronic pain, and hormonal imbalances receive appropriate specialized attention. It is also assumed that manual therapy approaches would be incorporated as an essential element of rehabilitation. Bradley described a physical therapy model of rehabilitation for HVS/BPDs as follows535: Management includes assessment and treatment involving detailed explanations of breathing pattern disorders and building an individual integrated recovery programme based on: breathing retraining tension release through talk and relaxation stress perception and management

enjoyable graduated exercise prescriptions rest/sleep guides

Apart from the essential manual therapy elements of rehabilitation (see later), Bradley noted that: As many new patients present in a state of hyper-arousal the initial assessment and treatment programmes [should] highlight this. Emphasis on de-sensitising through breathing retraining and relaxation is . . . one starting point.

B r a d l e y ’ ~ physical ~,~~ therapy rehabilitation follows stages that are summarized in the acronym BETTER Breathing retraining, Esteem/self-image, Total body relaxation, Talk/breath control, Exercise prescription, Rest /sleep. Breathing retraining incorporates a number of elements: Awareness of faulty breathing patterns Relaxation of the upper chest, shoulders, and accessory muscles Abdominal/low chest breathing pattern retraining Awareness of normal breathing rates and rhythms both at rest and during activity

Hyperventilation Syndrome/Breathing Pattern Disorders

The elements of the physical therapy protocol involving relaxation, exercise, talk/breath control, and sleep are all individualized and are not described here.

Breathing Rehabilitation Exercises Box 56-1 describesthreebreathing rehabilitation exercises.

Is Breathing Retraining Effective?

An Osteopathichlaturopathic Protocol for Care of Hyperventilation SyndromeBreathing Pattern Disorders Initial (and continual/periodic) assessment of breathing function based on functional evidence and palpation determines what needs to be done to improve breathing function. Education and information are vital for creating motivation and awareness as to why homework is essential in normalizing BPDs. The patient must understand clearly that the practitioner/therapist can do no more than create an environment, a possibility, for restoration of more normal function, but the breathing work itself is up to the patient. Treatment of muscles and joints alone, no matter how appropriate, can never restore normal breathing patterns without cooperative effort. Conversely,breathing retraining without the freeing of restricted structures is far more difficult to achieve. Psychotherapy and counseling are also unlikely to be successful unless retraining is introduced, and structural factors are dealt with. Manual attention to the upper fixators/accessory breathing muscles (upper trapezii, levator scapulae, scalenes, sternocleidomastoid, pectorals, and latissimus dorsi) is usually required. The diaphragm area also requires direct attention as a rule (lower anterior intercostals, sternum, costal margin, beneath costal margin, abdominal attachments, quadratus lumborum and psoas). Active trigger points in these muscles may need deactivating manually or via acupuncture. The thoracic spine and ribs may require mobilization (osteopathicor chiropractic adjustments). Osteopathic lymphatic pump methods may be required if there is evidence of stasis. Retraining: Various breathing exercises should be introduced, individualized to the specific needs of the patient commonly on the basis of pursed lip breathing and pranayama yoga methods (see Box 56-1 later).36-38 Relaxation methods including autogenic training or progressive muscular relaxation, or both, might usefully be introduced. Sleep pattern disturbances might require attention. Exercise of aerobic nature should be carefully introduced. Dietary advice and counseling should be introduced as appropriate.

Chronic HVS/BPDs are commonly successfully treated; however, a timeframe of 12 to 26 weeks may be required, with active patient participation throughout to break well-established habits. Lum41 discussed the reasons for people becoming hyperventilators: Neurological considerations can leave little doubt that the

habitually unstable breathing is the prime cause of symptoms. Why they breathe in thisway must be a matter for speculation, but manifestly the salient characteristics are pure habit. Lum' reported that more than 1000 anxious and phobic patients were treated using breathing retraining, physical therapy, and relaxation. Results indicated the following:

Symptoms were usually abolished in 1 to 6 months with some younger patients requiring only a few weeks. At 12 months 75%were free of all symptoms, 20%had only mild symptoms, and about 1 in 20 patients had intractable symptoms. Breathing rehabilitation therapy was evaluated in patients with HVS, the diagnosis based on the presence of several stress-related complaints, reproduced by voluntary hyperventilation." Patients with organic diseases were excluded, and most patients met the criteria for an anxiety disorder. Therapy was conducted in the following sequence: Brief, voluntary hyperventilation to reproduce the reported complaints Reattribution of the cause of the symptoms to hyperventilation Explaining the rationale of therapy involving reduction of hyperventilation by acquiring an abdominal breathing pattern, with slowing down of expiration Breathing retraining for 2 to 3 months working with a physiotherapist After breathing therapy, the sum scores of the Nijmegen Questionnaire were markedly reduced. A canonical correlation analysis relating the changes of the various complaints to the modifications of breathing variables showed that the improvement of the complaints was correlated mainly with the slowing down of breathing frequency.

Osteopathic Treatment of Chronic Asthma In a pretest/posttest crossover study using four osteopathic manipulative procedures, compared with sham

Syndromes and Special Topics

1. Pursed lip breathing3'.=

Pursed lip breathing, combined with diaphragmatic breathing, enhances pulmonary efficiency. The patient is seated or supine with the dominant hand on the abdomen and the other hand on the chest. The patient is asked to breathe in through the nose and out through the mouth, with pursed lips, ensuring diaphragmatic involvement by means of movement of the abdomen against the hand on inhalation. Exhalation through the pursed lips is performed slowly and has been shown to relieve dyspnea, slow the respiratory rate, increase tidal volume, and help restore diaphragmatic function. Author's Note: Essentially blowing firmly and slowly, through a narrow aperture such as pursed lips, effectively tones the diaphragm via eccentric isotonic activity. 2. Antiarousal breathingSas

The patient is asked to sit or recline comfortably and exhale slowly and fully through pursed lips, and the following guidance is given: Imagine a candle flame about 6 inches from your mouth, and blow a thin stream of air at it (pursed lip breathing). As you exhale, count silently to establish the length of the "out breath." When you have exhaled fully, without strain, pause for a count of '1 ," then inhale through the nose. Full exhalation creates a =coiledspring," making inhalation easier. Count to yourself to establish how long your "in breath" lasts.

procedures, involving 10 individuals diagnosed with chronic asthma, researchers demonstrated signrficant increases in both upper and lower thoracic forced respiratory excursion. Subjective evaluation of asthma symptoms ("ease of breathing") improved after treatment, but not sham treatment. However, the symptoms did not improve to a statistically sigruhcant The four procedures used were as follows: Introduction of balanced ligamentous tension at the atlantooccipital and cervicothoracicjunctions Still's method for treatment of elevated first rib Release of lower rib exhalation restriction (depressed rib status) Diaphragmatic release

Without pausing to hold the breath, exhale slowly and fully, through pursed lips, blowing the air in a thin stream, and then pause for a count of 1. Repeat the inhalation and exhalation for 230 cycles twice daily. After some weeks of daily practice you should achieve an inhalation phase that lasts 2 to 3 seconds and an exhalation phase of 6 to 7 seconds, without strain. Exhalation should always be slow and continuous; there is little value in breathing the air out in 2 seconds and then simply waiting until the count reaches 8 before inhaling again! Feelings of anxiety should reduce with this exercise. Practice twice daily, and repeat the exercise for a few minutes (6 cycles takes about 1 minute) every hour if anxious or when stress increases. Practice on waking; before bedtime; and, if possible, before meals. 3. Recitation of mantra or prayer

The respiratory (and cardiovascular) effects of rosary prayer ("Ave Maria" in Latin) and recitation of a yoga mantra were assessed.40 Results were similar, showing a slowing of respiration to approximately 6 counts per minute and synchronization of all cardiovascular rhythms (Traube-Hering-Meyer [THM] oscillations), representing blood pressure, heart rate, cardiac contractility, pulmonary blood flow, cerebral blood flow, and movement of cerebrospinalfluid. This influence on autonomic activity, represented by the THM oscillations, is clearly health enhancing, since it slows respiratory rate to the level considered optimal in breathing rehabilitati~n.'-~*~I

manipulation), as well as education combined with rehabilitation via specific home application of breathing exercises, can achieve marked benefit in HVS/BPDs, as well as breathing dysfunction with a pathologic background.

SUMMARY HVS/BPDs is a common disorder affecting up to 10% of patients in a general internal medicine practice. However, it is rarely recognized or appropriately treated. Breathing retraining is effective clinically and economically, as long as enough patience is exercised to actively engage the patient in a program requiring weeks to months of behavioral change.

The implication is that a combination of biomechanical facilitation of breathing (osseous and soft tissue

1. Lum LC.Hyperventilationsyndromes in medicine and psychiatry: a review. J R Soc Med 1987;80.229-331. 2. Newton E.Hyperventilationsyndrome. The emergency department. Available online at www.emedicine.com/EMERG/topic270.htm [accessed June29,20011. 3. Damas-Mora J,Davies L, Taylor W, JennerFA. Menstrual respiratory changes and symptoms. Br J Pyschiatry 1980;136:492497.

4. Lum LC. Hyperventilation:the tip and the iceberg. J Psychosom Res 1975;19:375-383. 5. Bradley D. Physiotherapy breathing rehabilitation strategies. In Chaitow L, Bradley D, Gilbert C, eds. Multidisciplinaryapproaches to breathing pattern disorders. Edinburgh: Churchill Livingstone, 2002. 6. Chaitow L, Bradley D, Gilbert D. Multidisciplinary approaches to breathing pattern disorders. Edinburgh: C h M Livingstone, 2002.

Hyperventilation SyndromeBreathing Pattern Disorders 7. T i o n s BH, Ley R, eds. Behavioral and psychological approaches to breathing disorders. New York Plenum Press, 1994115. 8. West J. Respiratory physiology. Philadelphia: Lippincott Williams & wilkins, 2000. 9. Jennett S. Control of breathing and its disorders. In T m o n s BH, Ley R, eds. Behavioral and psychological approaches to breathing disorders. New York Plenum Press, 1994. 10. Brostoff J. Complete guide to food allergy. London: Bloomsbury, 1993. 11. Hough A. Physiotherapy in respiratory care. London: Stanley Thornes, 1996. 12. Han JN, Stegen K, Simkens K, et al. Unsteadiness of breathing in patients with hyperventilation syndrome and anxiety disorders. Eur Respir J 1997;10167-176. 13. Beck JG, Shipherd JC, Ohtake I? Do panic symptom profiles influence response to a hypoxic challenge in patients with panic disorder? A preliminary report. Psychosom Med 2000;6267&683. 14. Wilhelm FH, Trabert W, Roth WT. Characteristics of sighing in panic disorder. Biol Psychiatry 2001;49606-614. 15. Conway AV, Freeman LJ, Nixon PG. Hypnotic examination of trigger factors in the hyperventilation syndrome. Am J Clin Hypn 1988;30296-304. 16. Freeman LJ, Conway A, Nixon PG. Physiological responses to psychological challenge under hypnosis in patients considered to have the hyperventilation syndrome: implications for diagnosis and therapy. J R Soc Med 1986;7976-83. 17. Garland W. Somatic changes in hyperventilating subject. Presentation at International Society for the Advancement of Respiratory Psychophysiology Congress, France, 1994. 18. Gardner WN. The pathophysiology of hyperventilation disorders. Chest 1996;109:516-534. 19. Nixon PG. The grey area of effort syndrome and hyperventilation: from Thomas Lewis to today. J R CONPhysicians Lond 1993;27:377-383. 20. Werbach M. Adult attention deficit disorder: a nutritional perspective. J Bodywork Mov "her 2000;4182-183. 21. De Guire S, Gervitz R, Kawahara Y, Maguire W. Hyperventilation syndrome and the assessment and treatment for functional cardiac symptoms. Am J Cardiol1992;70673-677. 22. Kumar P,Clark M. Clinical medicine, ed 4. Edinburgh: WB Saunders, 1998:687-688. 23. Calloway SP, Fonagy P. Aerophagia and irritable bowel syndrome. Lancet 1985;2:1368. 24. Magarian GJ. Hyperventilation syndromes: infrequently recognized common expressions of anxiety and stress. Medicine 1982;61:219-236. 25. Fried R, Grimaldi J. The psychology and physiology of breathing. New York Plenum Press, 1993:186-187. 26. Chambers JB, Kiff PJ, Gardner WN, et al. The value of measuring end tidal partial pressure of carbon dioxide as an adjunct to treadmill exercise testing. BMJ 1988;2961281-1285.

27. Nixon PG, Freeman LJ. The 'thinktest': a further technique to elicit hyperventilation.J R Soc Med 1988;81:277-279. 28. Courteney R. The Buteyko Method-an osteopathic approach to asthma? Osteopathy Today August 200216-19. 29. Bowler SD, Green A, Mitchell CA. Buteyko breathing techniques in asthma: a blinded randomised controlled trial. Med J Aust 1998;169575-578. 30. Buteyko K. Buteyko method; experience of application in medical practice. Moscow: Patriot, 1990. 31. Van Dixhoom J, Duivenvoorden HJ. Efficacy of Nijmegen questionnaire in recognition of the hyperventilationsyndrome.J Psychosom Res 1985;29199-206. 32. Vansteenkiste J, Rochette F, Demedts M. Diagnostic tests of hyperventilation syndrome. Eur Respir J 1991;4393-399. 33. Snyder SH. Nitric oxide: first in a new class of neurotransmitters? Science 1992;257494-496. 34.Beachey W. Respiratory care anatomy & physiology. St Louis: Mosby, 1998. 35. Bradley D. Hyperventilation syndrome/breathing pattern disorders. Auckland, N Z Tandem Press, 1998. 36. Cappo BM, Holmes DS.The utility of prolonged respiratory exhalation for reducing physiological and psychological arousal in non-threatening and threatening situations. J Psychosom Res 1984;28:265-273. 37. Faling L. Controlled breathing techniques and chest physical therapy in chronic obstructive pulmonary disease. In Casaburi R, ed. Principles and practices of pulmonary therapy. Philadelphia: WB Saunders, 1993. 38. Tiep BL, B u n s M, Kao D, Madison R, Herrera J. Pursed lip breathing using ear oximetry. Chest 1986;90:21&221. 39. Grossman P, de Swart JC, Defares PB. A controlled study of a breathing therapy for treatment of hyperventilation syndrome. J Psychosom Res 1985;2949-58. 40. Bemardi L, Sleight P, Bandinelli G, et al: Effect of rosary prayer and yoga mantras on autonomiccardiovascular rhythms: a comparative study. BMJ 2001;323:1446-1449. 41. Lum LC. Hyperventilation and anxiety state. J R Soc Med 1981; 741-4. 42. Han JN, Stegen K, De Valck C, et al.Influence of breathing therapy on complaints, anxiety and breathing pattern in patients with hyperventilationsyndrome and anxiety disorders.J Psychosom Res 1996;41:481-493. 43. Bockenhauer S, Julliard KN, Lo KS, et al. Quantifiable effects of osteopathic manipulative techniques on patients with chronic asthma. J Am osteopath Assoc 2002;102371-375.

Immune Support

CHAPTER CONTENTS Introduction 645 Psychoneuroimmunology 645 Stress 646 Cyclic Nucleotides and Immune Function 646 Lifestyle 647 Nutritional Factors 647 Nutrient Deficiency 647 Protein 647 Sugar 647 Obesity 648 Lipids 648 Alcohol 648 Vitamins 648 Minerals 649 Trace Minerals 650

EnhancingThymus Function 650 Antioxidants 650 Nutrients 651 Botanicals 651 Echinacea spp. 651 Panax ginseng 651 Astragalus membranaceus 652 Therapeutic Approach 652 General Measures 652 Supplements 652 Botanicals 652

INTRODUCTION

PSYCHONEUROIMMUNOLOGY

The immune system is a complex integration of synergistic segments that are continuously barraged by stimulifrom both internal and external sources. Immunology has continued to be a rapidly developing field in which mechanisms are continually being conceptualized and revised. For the physician interested in assessing and maintaining a patient’s health, the development of a thorough understanding of the clinical aspects of the immune system and the many factors that enhance and/or inhibit normal function is essential. The immune system is truly “holistic,” as evidenced by the close association of psychological, neurologic, nutritional, environmental, and hormonal factors with immune function. Supporting the immune system is critical to good health. Conversely, good health is critical to supporting the immune system. The best approach to supporting immune function is a comprehensive plan involving lifestyle, stress management, exercise, diet, nutritional supplementation, glandular therapy, and the use of plant-based medicines.

Psychoneuroimmunology (PNI) is the term used to describe the interactions between the emotional state, nervous system function, and the immune system. The growing body of knowledge documenting the mind’s profound influence on physiology in health and disease necessitates a fundamental change in the way physicians perceive their patients. An important step is the study of nervous system response to environmental or intrapsychic perceptions that activate endocrine and neurotransmitter processes, which in turn influence the immune system.’ A complete and detailed account of the many facets of PNI, or behavioral immunology, is beyond the scope of this chapter. The role of attitude and emotions in immune function was also discussed in Chapter 8, and the importance of stress management to a healthy immune system is discussed in Chapter 62. We focus here on the effects of stress on the immune response. 645

Syndromes and Special Topics

Stress The term stress-induced illness is certainly not a misnomer, because many clinical and experimental studies have clearly demonstrated that stress, personality, attitude, and emotion are etiologic or contributory in suppressing the immune system as well as leading to the development of many diverse diseases.' Reaction to stressful stimuli is entirely individual, reinforcing the fact that people differ sigruficantly in their perceptions and responses to various life events. The variations in response help account for the wide diversity of stress-induced illnesses. Stress-induced increases in corticosteroid and catecholamine levels lead to an immunosuppressed state, leaving the host susceptible to infectious and carcinogenic illnesses. This immunosuppression is proportional to the level of stress, and although the effects are numerous, they appear to involve a common mechanism: an increase in glucocorticoids, proinflammatory cytokines, and catecholamines resulting in significant alterations in hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal medullary (SAM)axes, leukocyte function, thymic involution, and suppressed lymphopoiesis. More than 150 clinical studies have now shown that stress can alter immune function and contribute to the development of signhcant disease and poor Lymphocytes, monocytes or macrophages and granulocytes, have receptor sites for the many regulating hormones and neurotransmitters of the HPA and SAM axes. Alterations in these compounds lead to disruption of cellular trafficking, proliferation, cytokine secretion, antibody production, and cytolytic activity. For example, glucocorticoids inhibit the production of interleukin-12 (IL-l2), interferon-gamma (IFN-y), IFN-a, and tumor necrosis factor-alpha (TNF-a) by antigen-presenting cells and type 1 helper T (Thl) cells, but upregulate the production of IL-4, IL-10, and IL-13 by Th2 cells. This mechanism systemically causes a selective suppression of the Thl-cellular immunity axis and a shift toward Th2-mediated humoral immunity, rather than generalized immunosuppression. During an immune response and inflammation, the activation of the stress system, and thus increased levels of systemic glucocorticoids through induction of a Th2 shift, may actually protect the organism from systemic "overshooting" with Thl/ proinflammatory cytokines and other products of activated macrophages with tissue-damaging potential. However, conditions associated with significant changes of glucocorticoids, such as acute or chronic stress or cessation of chronic stress, severe exercise, pregnancy, and the postpartum state, through modulation of the Thl-Th2 balance may affect the susceptibility to or the course of infections as well as autoimmune and atopic/ allergic diseases.*5 A study in medical students taking examinations found that psychological stress produced a shift in the cytokine balance toward a Th2 profile.6 The data showed decreased synthesis of Thl cytokines,

including IFN-y, and increased produdion of Th2 cytokines, including IL-10. This study and others indicate that stressinduced decrease of Thl cytokines results in dysregulation of cell-mediated immune responses. To help demonstrate causal relations between psychosocial stressors and the development of infectious illness, investigators have inoculated subjects with several different types of vaccines to demonstrate clinically relevant alterations in an immunologic response to challenge under well-controlled conditions. For example, the chronic stress associated with caring for a spouse with Alzheimer disease or, for younger people, experiencing more stressful life events was associated with a poorer antibody response to an influenza virus vaccine than in well-matched control subjects.'~The premise is that the production of a delayed, weaker, and shorter-lived immune response to a vaccine would be analogous to an impaired immune responses to other pathogens. Consistent with this concept, subjects who show poorer responses to vaccines also experience higher rates of clinical illness as well as longer-lasting infectious episodes. Fortunately, the effects of stress on the immune system can be attenuated or even overcome with positive mood, effective stress reduction techniques, humor, laughter, and guided imagery.'~~

Cyclic Nucleotides and Immune Function In addition to glucocorticoids, the catecholamines also play a role in stress-induced immune dysfunction. In many systemsof the body, cholinergic and beta-adrenergic stimulation mediate diametrically opposed actions. On the cellular level, this antagonism is mediated via cyclic adenosine monophosphate (CAMP) and cyclic guanosine monophosphate (cGMP). Beta-adrenergic stimulation of responsive target tissues causes a rise in intracellular CAMP, whereas acetylcholine acting on muscarine receptors leads to increased levels of cGMP. The immune system is also affected by this yin-yang balance, although it appears to be much more complex than in other systems. Cyclic AMP and cGMP have shown antagonistic effects in all immune functions studied to date. The immune effects of cGMP include the fo1lowing9-l5: Enhanced lymphocyte mediated cytotoxicity Stimulation of T-cell rosette formation (a measure of thymus-derived lymphocyte activity) with inhibition of B-cell rosette formation Enhanced lymphoid cell and lymphocyte proliferation Increased lymphocyte lysosomal enzyme release Increased leukocyte chemotaxis From this information, it is apparent that cGMP usually serves to enhance immune function during infection and carcinogenesis.In contrast, CAMPappears to inhibit white blood cell (WBC) proliferation and functional response, thus possibly serving to modulate the immune system.

Immune Support There are many conditions in which enhancing cGMP activity and inhibiting CAMPactivity are contraindicated (e.g., autoimmune disease, atopy, gout, and psoriasis). In acute or chronic infection, however, the cGMP/cAMP ratio should be enhanced. Although many exogenous compounds alter the cGMP/cAMP ratio, paramount in any treatment plan are adequate rest and elimination of stressful activity. These measures promote an increase in cholinergic activity while concurrently lowering betaadrenergic activity. In addition, other CAMP-promoting factors (e.g., caffeine and its analogues) should be eliminated, and cGMP stimulators (e.g. ascorbic acid) should be in~reased.*~J~

LIFESTYLE A healthy lifestyle goes a long way in establishing a healthy immune system. This benefit is perhaps most obvious when one looks at the effects of lifestyle on natural killer cell activity.'&lsBox 57-1 lists the lifestyle practices associated with higher natural killer cell activity. One particular lifestyle factor that is absolutely critical to healthy immune function is adequate sleep. In healthy humans, sleep deprivation has consistently been demonstrated to impair different parameters of immune function and mood. Interestingly, the deterioration of immune function precedes the plummeting of subjective well-being and psychosocial performance in sleepdeprived s~bjects.'~

NUTRITIONAL FACTORS The health of the immune system gland is greatly affected by a person's nutritional status. Dietary factors that depress immune function include nutrient deficiency, excess consumption of sugar, consumption of allergenic foods, and high cholesterol levels in the blood. Dietary factors that enhance immune function include all essential nutrients, antioxidants, carotenes, and flavonoids. Consistent with good health, optimal immune function requires a healthy diet that:

Is rich in whole, natural foods, such as fruits,vegetables, grains, beans, seeds, and nuts. Is low in fats and refined sugars.

Not smoking Increased intake of green vegetables Regular meals Proper body weight More than 7 hours of sleephight Regular exercise A vegetarian diet

Contains adequate, but not excessive, amounts of protein.

In addition, individuals are encouraged to drink five or six 8-ounce glasses of water (preferably pure) per day. These dietary recommendations along with a positive mental attitude, a good high-potency multivitamin and mineral supplement, a regular exercise program, daily deep breathing and relaxation exercises (meditation, prayer, etc.), and at least 7 hours of sleep daily will go a long way in helping the immune system function at an optimum level.

Nutrient Deficiency Nutrient deficiency is the most common cause of a depressed immune system. Although research relating nutritional status to immune function has historically concerned itself with severe malnutrition states (i.e., kwashiorkor and marasmus), attention is now shifting toward marginal deficiencies of single or multiple nutrients and the effects of overnutrition. The plethora of clinical and experimental data has made inevitable the conclusion that a single nutrient deficiency can impair the immune system profoundly. Given the widespread problem of subclinical nutrient deficiency in Americans, it can be concluded that many are suffering from impaired immunity amenable to nutritional supplementation. This statement is particularly true in the elderly. Numerous studies have shown that most elderly Americans are deficient in at least one nutrient. Likewise, numerous studies show that taking a multivitamin and mineral supplement enhances immune function in elderly subjects (whether they suffer from overt nutritional deficiency or These findings have considerable fundamental, clinical, and public health sigruficance.

Protein The importance of adequate protein intake to proper immune function has been extensively studied? The most severe effects of proteincalorie malnutrition (PCM) are on cell-mediated immunity, although all facets of immune function are ultimately affected. PCM is not, however, usually due to a single-nutrient deficiency. It is normally associated with multiple nutrient deficiencies, and some immune dysfunctions attributed to PCM are most likely due to these other factors. Partial deficiencies of dietary vitamins produce a comparatively greater depression in the natural and inducible levels of cytotoxic activities than do partial protein deficiencies. Nonetheless, adequate protein is essential for optimal immune function.

Sugar The oral administration of 100-g portions of carbohydrate as glucose, fructose, sucrose, honey, or orange juice significantly reduces neutrophil phagocytosis, but starch has no effect. As can be seen in Figure 57-1, effects start

usually elevated in obese individuals, which may explain their impaired immune function (see later).

Lipids Increases of cholesterol, free fatty acids, triglycerides, and bile acids inhibit various immune functions, including the following2830: V '

0

;

2

3

4

5

Hours Figure 57-1 The effects of sugar on white cell phagocytic activity.

within 30 minutes, last for more than 5 hours, and typically show a 50% reduction in phagocytic activity at the peak of inhibition (usually 2 hours after Because polymorphonuclear leukocytes (PMNs) constitute 60% to 70% of the total WBCs and are a major portion of the defense mechanism, impairment of phagocybc activity leads to an immune-compromised state. Oral administration of increasingamounts of glucose progressively lowers neutrophil phagocytosis, with maximal inhibition corresponding to maximal blood glucose levels. In addition, oral ingestion of 75 g of glucose has been shown to depress lymphocyte response to mitogens, apparently through the elevation of insulin levels.25 Other parameters of immune function are also undoubtedly affected by sugar consumption. It has been hypothesized that the ill effects of high glucose levels are a result of elevation of insulin values and competition with vitamin C for membrane transport site^?^,^^ This hypothesis is based on evidence that vitamin C and glucose appear to have opposite effects on immunologic function and the fact that both substances require insulin for membrane transport into many tissues. Considering that the average American consumes 125 g of sucrose, plus 50 g of other refined simple sugars, each day, the conclusion that most Americans have chronically depressed immune systems is inescapable. It is clear, particularly during an infection, that the consumption of simple sugars, even in the form of fruit juice, is deleterious to the host's immune status. Short-term fasting could be encouraged, particularly during the first 24 to 48 hours of an acute infectious illness, because it results in a sigruficant (up to 50%) increase in phagocytic index.= The fast should not be continued for a long period, because eventually the leukocytes' energy sources will become depleted.

Obesity Obesity is associated with decreased immune status, as evidenced by reduced bactericidal activity of leukocytes and the higher morbidity and mortality from infections in obese individuals.28Cholesterol and lipid values are

Lymphoproliferation Response to mitogens Antibody response PMN chemotaxis Phagocytosis Optimal immune function therefore depends on control of these serum components. Interestingly, L-carnitine, even at minimal concentrations,has been shown to neutralize lipid-induced This effect is probably due to carnitine's role as a rate-limiting factor in the removal of fat emulsion from the

Alcohol Alcohol increases the susceptibility to experimental infections in animals; and alcoholics are known to be more susceptible to infections, especially pneumonia. Studies of immune function in alcoholism show a profound depression in most parameters of immunity.%

Vitamins Vitamin A Vitamin A plays an essential role in maintaining the integrity of the epithelial and mucosal surfaces and their secretions. These systems constitute a primary nonspecific host defense mechanism. Vitamin A has been shown to stimulate and/or enhance numerous immune processes, including the following: Induction of cell-mediated cytotoxicity against tumors Natural killer cell activity Lymphocyte blastogenesis Mononuclear phagocytosis Antibody response These effects are not due simply to reversal of vitamin A deficiency, because many of them are further enhanced by the administration of (supposedly) excessive levels of vitamin A.22,34In addition, vitamin A prevents and reverses stress-induced thymic involution, and additional vitamin A can actually promote thymus growth.35

Carotenes Carotenes have demonstrated a number of immuneenhancing effects. In addition to being converted into vitamin A, carotenes function as antioxidants. Because the thymus gland is so susceptible to damage by free radicals, beta-carotene may be more advantageous in

Immune Support enhancing the immune system than retinol. For more information, see Chapter 138.

Vitamin C

observed in the patients receiving 200 IU daily. No effect on autoimmune antibodies was noticed. No adverse effects were observed at any of the three dosage schedules of vitamin E. In another double-blind study in 451 elderly participants in a nursing home, vitamin E supplementation (200 IU daily) demonstrated a protective effect of vitamin E supplementation against upper respiratory tract infections, particularly the common

Vitamin C (ascorbic acid) plays an important role in the natural approach to immune enhancement.Although vitamin C has been shown to be antiviral and antibacterial, its main effect is via improvement in host resistance. Many different immunostimulatory effects have been demonstrated, including enhancing lymphoproliferaPyridoxine tive response to mitogens and lymphotrophic activity A pyridoxine deficiency results in depression of cellular and increasing interferon levels, antibody responses, and humoral immunity, lymphoid tissue a trophy, immunoglobulin levels, secretion of thymic hormones, leukopenia, reduction in quantity and quality of antibody and integrity of ground substance.",36Vitamin C also has direct biochemical effects similar to those of i n t e r f e r ~ n . ~ ~production, diminished lymphoproliferative response to mitogens, and decreased thymic hormone activity? Numerous clinical studies support the use of vitamin C Factors predisposing to deficiency are low dietary in the treatment of infectious conditions. In addition to pyridoxine intake, excess protein intake, consumption of its effects on the common cold, vitamin C has also been hydralazine (yellow) dyes, and use of alcohol and oral shown to be useful in other infectious condition^.^^ contraception. Vitamin C levels are quickly depleted during the stress of an infection as well as in chronic di~ease.3~ Folic Acid and Vitamin B,, It is useful to supplement vitamin C concurrently The megaloblasticstate induced by a deficiency of vitamin with flavonoids, which raise the concentration of vitaBI2 and/or folate results in improper WBC production min C in some tissues and potentiate its effects as well as and abnormal lymphocyte responses. Folic acid deficiency exert their own effectsM (the most common vitamin deficiency in the United Vitamin E States) has been shown to result in lymphoid atrophy and decreased lymphoproliferative response to mitogens, Vitamin E enhances both humoral immunity and cellsplenic plaque-forming colonies, and antibody producmediated immunity. A vitamin E deficiency results in lymphoid atrophy and decreases of lymphoproliferative tion. A BI2 deficiency, besides producing a deficiency in folate conversion to its active tetrahydrofolate form, response to mitogens, splenic plaque-forming colonies, leads to impairment of PMN phagocytosis and bactericiand monocyte function. Vitamin E antibody response, dal action." supplementation (30-150 IU)has been shown to4': Increase lymphoproliferative response to mitogens. Prevent free radical-induced thymus atrophy. Enhance helper T-cell activity. Increase splenic plaque-forming colonies, serum immunoglobulins, antibody response, PMN phagocytosis, and reticuloendothelialsystem activity. Elderly subjects may benefit from even higher dosages of vitamin E. A recent study sought to determine the effect of vitamin E supplementation at different dosages on immune function in 88 patients older than 65 years.22,42 To determine the effect of vitamin E on immune function, the researchers measured T-cell function by assessing delayed-type hypersensitivity (DTH) skin response; antibody response to hepatitis B, tetanus, and diphtheria, and pneumococcal vaccines; and autoantibodies to DNA and thyroglobulin. Vitamin E was given at 60, 200, or 800 IU for 235 days. Although the placebo group experienced an only 8% increase in DTH, the 60-IU group had a 20% increase, the 200-IU group a 58%increase, and the 800-IUgroup a 65%increase. With regard to antibody production, the best results were

Other B Vitamins Deficiencies of thiamin, riboflavin, and pantothenic acid lead to reduced antibody response, decreased splenic plaque-forming colonies, and lymphoid atrophy.

Minerals Iron Iron deficiency is a commonly encountered isolated nutritional deficiency that causes immune dysfunction in large numbers of patients. Marginal iron deficiency, even at levels that do not lower hemoglobin values, can influence the immune system. Lymphoid tissue atrophy, decreased lymphoproliferative response to mitogens, defective macrophage and neutrophil function, and decreased T cell/B cell ratios are common experimental and clinical findings." Iron is an important nutrient for bacteria as well as for humans. During infection, one of the body's nonspecific defense mechanisms to limit bacterial growth is to reduce plasma iron, and in vitro studies have shown that the bacteriostatic effects and some of the bactericidal effects

Syndromes and Special Topics

of serum are eliminated by the addition of iron to the serum.44As temperature rises, plasma iron levels drop, and when temperature is raised to fever levels, the growth of bacteria is inhibited, but not at high iron concentrations. These observations lead us to conclude that iron supplementation is probably contraindicated during acute infection, especially in patients with low transferrin levels. However, in patients with impaired immune function, chronic infections, and subnormal iron levels, adequate supplementation is essential.

Trace Minerals Trace minerals function primarily as activators of enzyme-metal-substrate complexes in which they are loosely bound cofactors. The role of these elements in these metalloenzymes is either structural, in which they influence the reactivity of the protein by stabilizing strained configurations of binding ligands about the metal atom, or catalytic, in which they act as centers of positive charge.

Zinc The hereditary zinc deficiency disease acrodermatitis enteropathica (AE) offers an excellent model for understanding the role of zinc in immunity. In AE, the number of T cells is reduced, lymphoproliferative response to mitogens is diminished, thymic hormone levels are lower, delayed cutaneous hypersensitivity is decreased, and PMN phagocytosis, chemotaxis, and cytotoxic activities are impaired. All of these effects are reversible upon adequate administration and absorption of zinc!5 Zinc serves a vital role in many immune system reactions; for example, it promotes the binding of complement (Clq) to immune complex, acts as a protectant against iron-catalyzed damage by free radicals, acts synergistically with vitamin A, is required for lymphocyte transformation, acts independently on lymphocytes as a mitogen, and is a necessary cofactor in activating serum thymic factor. In vitro, zinc inhibits the growth of several viruses, including rhinoviruses, picornaviruses, togaviruses, herpes simplex virus, and vaccinia virus.& Adequate zinc nutriture is particularly important in the elderly, and zinc supplementation in elderly subjects results in increased numbers of T cells and enhanced cell-mediated immune responses.46 Throat lozenges containing zinc became popular in the treatment of the common cold as a result of a doubleblind clinical trial in 1984 demonstrating that zinccontaining lozenges significantly reduced the average duration of common colds by 7 d a ~ s . 4The ~ lozenges used in this study contained 23 mg of elemental zinc, which the patients were instructed to dissolve in their mouths every 2 waking hours after an initial double dose. After 7 days, 86% of the 37 zinc-treated subjects were symptom-free, compared with 46% of the 28

placebo-treated subjects. Additional studies have confirmed these results.& Because high doses of zinc can actually impair immune function, a daily intake higher than 150 mg of zinc for longer than 1 week cannot be recommended.

Selenium Selenium, in its vital role in glutathione peroxidase, affects all components of the immune system, including the development and expression of all WBCs. Selenium deficiency results in depression of immune function, whereas selenium supplementation results in augmentation and/or restoration of immune functions. Selenium deficiency has been found to inhibit resistance to infection through impairment of WBC and thymus function, whereas selenium supplementation (100-200 pg/ day) has been shown to stimulate WBC and thymus function."-52 The ability of selenium supplementation to enhance immune function goes well beyond simply restoring selenium levels in selenium-deficient individuals. For example, in one study, selenium supplementation (200 pg/day) to individuals with normal blood selenium concentrations resulted in a 118%improvement in the ability of lymphocytes to kill tumor cells and an 82.3% rise in the activity of natural killer cells.5O These effects were apparently related to the ability of selenium to enhance the expression of the immune-enhancing compound IL-2 and, consequently, the rate of WBC proliferation and differentiation into forms capable of killing tumor cells and microorganisms. The supplementation regimen did not produce sigtuficant changes in the blood selenium levels of the participants. The results indicated that the immune-enhancingeffects of selenium in humans require supplementation above the normal dietary intake.

ENHANCING THYMUS FUNCTION Perhaps the most effective method of reestablishing a healthy immune system is employing measures to improve thymus function. Promoting optimal thymus gland activity involves the following: Prevention of thymic involution or shrinkage by ensuring adequate dietary intake of antioxidant nutrients Use of nutrients that are required in the manufacture or action of thymic hormones

Antioxidants The thymus gland shows maximum development immediately after birth. During the aging process, the thymus gland undergoes a process of shrinkage, or involution. The reason for this involution is that the thymus

Immune Support

gland is extremely susceptible to free radical and oxidative damage caused by stress, radiation, infection, and chronic illness. Many patients with impaired immune function as well as conditions associated with impaired immunity (e.g., chronic fatigue syndrome, cancer, acquired immunodeficiency syndrome) suffer from a state of oxidative imbalance characterized by a greater number of prooxidants than antioxidants in their systems. This situation is quite detrimental to thymus function. One of the primary ways in which antioxidants affect the immune system, particularly cell-mediated immunity, may be by protecting the thymus gland from damage. The antioxidant nutrients most important for protecting the thymus include the carotenes, vitamin C, vitamin E, zinc, and selenium.

Nutrients Many nutrients function as important cofactors in the manufacture, secretion, and function of thymic hormones. A deficiency of any one of these nutrients results in decreased thymic hormone action and impaired immune function. Zinc, vitamin B6, and vitamin C are perhaps the most critical. Supplementation with these nutrients has been shown to improve thymic hormone function and cell-mediated immunity. Zinc is perhaps the critical mineral involved in thymus gland function and thymus hormone action. Zinc is involved in virtually every aspect of immunity. When zinc levels are low, the number of T cells is reduced, thymic hormone levels are lower, and many WBC functions critical to the immune response are severely lacking. All of these effects are reversible with adequate administration and absorption of ~ i n c . 5 ~ 3

BOTANICALS Many herbs have been shown to have antibacterial, antiviral, and immunostimulatory effects, and a complete discussion is outside the scope of this chapter (several immune-enhancing botanicals are discussed in depth in Section 5). This chapter focuses on three of the most popular immune-enhancing botanicals, Echinuceu, Punux ginseng, and Astrugalus. These three herbs were selected on the basis of their ability to exert broadspectrum effects on immune functions and recognized popularity. They stimulate the body’s natural defense mechanisms via slightly different mechanisms and are in many ways the prototypes of the hundreds of plants with known immunological a~tivity?~

Echinacea spp. Perhaps the most widely used Western herb for enhancement of the immune system is Echinuceu. The two most widely used species are Echinucea angustifoh and

Echinuceu purpureu. Both have been shown to exert profound immune-enhancing effects. Several classes of constituents contribute to this acti0n.5~3~ One of the most important immune-stimulating components of Echinuceu are large polysaccharides, such as inulin, that activate the alternative complement pathway (one of the immune system’s nonspecific defense mechanisms) and increase the production of immune chemicals that activate macrophages. The result is increased activity of many key immune parameters: production of T cells, macrophage phagocytosis, antibody binding, natural killer cell activity, and levels of circulating neutrophils. Echinuceu strengthens the immune system even in healthy people. For example, in a study of healthy volunteers aged 25 to 40 years, the fresh-pressed juice of E. purpureu extract was found to increase the phagocytosis of Cundida ulbicuns by 30% to 40%; it also enhanced the migration of WBC cells to the scene of battle by 30% to 4O%?’ Besides immune support, Echinuceu also exerts direct antiviral activity and helps prevent the spread of bacteria by inhibiting a bacterial enzyme called hyuluronidase. This enzyme is secreted by bacteria in order to break through the body’s first line of defense, the protective membranes such as the skin or mucous membranes, so that the organism can enter the body. Echinuceu is discussed fully in Chapter 89.

Panax ginseng P. ginseng has been shown to exert immunomodulating activity as evidenced by its ability to enhance the following paramaters? Antibody plaque-forming cell response Circulatory antibody titer against sheep erythrocytes Cell-mediated immunity Natural killer cell activity Production of interferon Lymphocyte mitogenesis Reticuloendothelialsystem proliferative and phagocytic functions From a clinical perspective, the long-term ingestion of ginseng by individuals with mild immunodeficiency may reduce the risk of viral infection.Use in this manner is consistent with the historical use of ginseng by debilitated individuals. There is clinical evidence of benefit in these applications. Ginseng has been shown to prevent respiratory viral infections in a nursing home environment (89% relative risk reduction) and potentiate influenza vaccinations.~~9 It should be noted that large dosages of ginseng may be contraindicated in acute infections owing to possible inhibition of immune function (see Chapter 111for more information).

Astragalus membranaceus The root of Astrugulus is a traditional Chinese medicine used for viral infections. Clinical studies in China have shown it to be effective when used prophylactically against the common cold.60It has also been shown to reduce the duration and severity of symptoms in acute treatment of the common cold as well as to raise WBC counts in persons with chronic leukopenia. Research in animals has shown that Astrugulus apparently works by stimulating several factors of the immune system, including enhancing phagocytic activity of monocytes and macmphages, increasing interferon production and ~ t u r a killer l cell activity, improving T-cell activity, and potentiatingother antiviral mechanisms.60b1Astrugalus appears particularly useful in cases in which the immune system has been damaged by chemicals or radiation. In immunodepressed mice, AstruguZus has been found to reverse the T-cell abnormalities caused by cyclophosphamide, radiation, and aging." As with Echimea, the polysaccharides contained in the root of Astrugulus membrumceus contribute to the immune-enhancing effects.

THERAPEUTIC APPROACH A major challenge to the discerning cliniaan is to determine which of the preceding factors is the key to reactivating or supportinga patient's immune system.The regimen given here is meant as a general approach and must be tailored to the patient's specific needs in order to ITlilxiRljze the desired effects and limit unnecessary treatment.

General Measures Rest (bedrest better). Drink large amount of fluids (preferably diluted vegetable juices, soups, and herb teas). Limit simple sugar consumption (including fruit sugars) to less than 50 g/day.

1. Campeau S,Day HE, Helmreich DL, et al. Principles of psychoneuroendocrinology. Psychiatr Clin North Am 1998;21:259-276. 2.Olff M. Stress, depression and immunity: the role of defense and coping styles. PsychiaQ Res 1999;85:7-15. 3.Padgett DA, Glaser R. How stress influences the immune response. Trends Immunol2003;24444-448. 4. Mulla A, Buckingham JC. Regulation of the hypothalamepituitaryadrenal axis by cytokines. Baillieres Best Prad Res Clin Endocrinol Metab 1999;13503-521. 5.Matalka KZ. Neuroendocrine and cytokines-induced responses to minutes, hours, and days of mental stress. Neuro Endocrinol Lett 2003;24283-292. 6.Elenkov IJ. Glucocorticoidsand the Thl /Th2 balance. Ann N Y Acad Sci 2004;1024138-146. 7.KiecoltGlaserJK,Glaser R, Gravenstein S, et al. Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci U S A 1996;933043-3047.

Supplements High-potency multivitamin and mineral formula Vitamin C, 500 mg every 2 hours Bioflavonoids, 1000 mg/day Vitamin A, 5000 IU/day, or beta-carotene 25,OOO IU/day Zinc, 30 mg/day

Botanicals All dosages of botanicals should be given three timedday.

Echinacea spp. Dried root (or as tea), 0.5 to 1 g Freeze-dried plant, 325 to 650 mg Juice of aerial portion of E. putpureu stabilized in 22% ethanol, 2 to 3 ml Ticture (1:5), 2 to 4 ml Fluid extract (l:l),2 to 4 ml Solid (dry powdered) extract (6.5:l or 3.5% echinacoside), 150 to 300 mg

Panax ginseng The appropriate dose of ginseng depends on the ginsenoside content; if an extract or ginseng preparation contains high concentrations of ginsenosides (and presumably other active components), a lower dose will suffice. The standard dose for high-quality ginseng root is in the range of 4 to 6 g daily. For ginseng root extract containing 5% ginsenosides, the dose is typically 100 mg one to three times daily.

Astragalus membranaceus Dried root (or as decoction), 1to 2 g Tmcture (1:5), 2 to 4 ml Fluid extract (1:1),2 to 4 ml Solid (dry powdered) extract (0.5% 4-hydroxy-3methoxy isoflavone), 100 to 150 mg

8. Bums VE,Carroll D, Drayson M, et al. Life events, perceived stress and antibody response to influenza vaccination in young, healthy adults. J Psychosom Res 2003;55:569-572. 9.MacDonald CM. A chuckle a day keeps the doctor away: therapeutic humor and laughter. J Psychosoc Nurs Ment Health Serv 2004;42:18-25. 10.Strom TB, Carpenter CB. Cyclic nucleotides in immunosuppression-neuroendocrine pharmacologic manipulation and in vivo immunoregulation of immunity acting via second messenger systems. Transplant Proc 1980;12:304-310. 11. Femera G, Brascher H, Javierre M, et al. Rosette formation by human T and B lymphocytes in the presence of adrenergic and cholinergic drugs. Experientia 19769235941596. 12.Grieco M, Siege1 I, Goel Z. Modulation of human T lymphocyte rosette formation by autonomic agonists and cyclic nucleotides. J Allergy Clin Immunol1976;58:149-159.

Immune Support 13. Gallin J, Sandler J, Clyman R, et al. Agents that increase cyclic AMP inhibit accumulation of cGMP and depress human monocyte locomotion. J Immunol1978;120492-496. 14. Stephens C, Snyderman R. Cyclic nucleotides regulate the morphologic alterations required for chemotaxis in monocytes. J Immunol 1982;128:1192-1197. 15. Singh U. In vitro lymphopoiesis in foetal thymic organ cultures: effect of various agents. Clin Exp Immunol1980;41:150-155. 16. Kusaka Y, Kondou H, Morimoto K. Healthy lifestyles are associated with higher natural killer cell activity. Prev Med 1992;21:602-615. 17. Nakachi K, Imai K.Environmental and physiological influences on human natural killer cell activity in relation to good health practices. Jpn J Cancer Res 1992;83:789-805. 18. Morimoto K, TakeshitaT, Inoue-Sakurai C, et al. Lifestyles and mental health status are associated with natural killer cell and lymphokineactivated killer cell activities. Sci Total Environ 2001;2703-11. 19. Heiser P, Dickhaus 8, Opper C, et al. Alterations of host defence system after sleep deprivation are followed by impaired mood and psychosocial functioning. World J Biol Psychiatry 2001;289-94. 20. Marcos A, Nova E, Montero A. Changes in the immune system are conditioned by nutrition. Eur J Clin Nutr 2003;57(Suppll):S66S69. 21. Chandra RK. Nutrition and the immune system from birth to old age. Eur J Clin Nutr 2002;56(Suppl3):S73-576. 22. Chandra RK. Impact of nutritional status and nutrient supplements on immune responses and incidence of infection in older individuals. Ageing Res Rev 2004;391-104. 23. Sanchez A, Reeser J, Lau H, et al. Role of sugars in human neutrophilic phagocytosis. Am J Clin Nutr 1973;26:1180-1184. 24. Ringsdorf WM Jr, Cheraskin E, Ramsay RR Jr. Sucrose, neutrophilic phagocytosis and resistance to disease. Dent Surv 1976;5246-48. 25. Bemstein J, Alpert S, Nauss K, et al. Depression of lymphocyte transformation following oral glucose ingestion. Am J Clin Nutr 1977;30613. 26. Mann G. Hypothesis: the role of vitamin C in diabetic angiopathy. Perspect Biol Med 1974;17210-217. 27. Mann G, Newton P. The membrane transport of ascorbic acid. Ann N Y Acad Sci 1975;258243-252. 28. Palmblad J, Hallberg D, Rossner S. Obesity, plasma lipids and polymorphonuclear (PMN) granulocyte functions. Scand J Haematol 1977;19:293-303. 29. Waddell CC, Taunton OD, Twomey JJ. Inhibition of lymphoproliferation by hyperlipoproteinemic plasma. J Clin Invest 197658950-954. 30.Dianzani M, Torrielli M, Canuto R, et al. The influence of enrichment with cholesterol on the phagocytic activity of rat macrophages. J Pathol1976;118:193-199. 31. De Simone C, Ferrari M, Lozzi A, et al. Vitamins and immunity. 11. Influence of L-camitine on the immune system. Acta Vitamin01 Enzym01 1982;4135-140. 32. De Simone C, Ferrari M, Meli D, et al. Reversibility by L-camitine of immunosuppression induced by an emulsion of soya bean oil, glycerol and egg lecithin. Arzneimittelforschung 1982;32: 1485-1488. 33. Frank J, Witte K, Schrodl W, et al. Chronic alcoholism causes deleterious conditioning of innate immunity. Alcohol Alcohol 2004; 39:386-392. 34. Semba RD. Vitamin A, immunity, and infection. Clin Infect Dis 1994;19:489-499. 35. Seifter E, Rettura G, Seiter J, et al. Thymotrophic action of vitamin A. Fed Proc 1973;32947. 36.Bendich A. Vitamin C and immune responses. Food Techno1 1987;41:112-114. 37. Scott J. On the biochemical similarities of ascorbic acid and interferon. J Theor Biol1982;98:235-238. 38. Bendich A, Langseth L. The health effects of vitamin C supplementation: a review. J Am Coll Nutr 1995;14124-136. 39. Jacob RA, Sotoudeh G. Vitamin C function and status in chronic disease. Nutr Clin Care 2002;5:66-74.

40. Di Car10 G, Mascolo N, Izzo AA, et al. Flavonoids: old and new aspects of a class of natural therapeutic drugs. Life Sci 1999;65: 337-353. 41. Kelleher J. Vitamin E and the immune response. Proc Nutr SOC 1991;5O:245-249. 42. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects: a randomized controlled trial. JAh4A 1997;2771380-1386. 43. Meydani SN, Leka LS, Fine BC, et al. Vitamin E and respiratory tract infections in elderly nursing home residents: a randomized controlled trial. JAMA 2004;292828-836. 44. StockmanJ. Infections and iron: too much of a good thing? Am J Dis Child 1981;13518-20. 45. Hadden JW. The treatment of zinc deficiency is an immunotherapy. Int J Immunopharmacol1995;17697-701. 46. Walker CF, Black RE. Zinc and the risk for infectious disease. Annu Rev Nutr 2004;24:255-275. 47.Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study. Antimicrob Agents Chemother 1984;2520-24. 48.Mossad SB, Macknin ML, Medendorp SV, et al. Zinc gluconate lozenges for treating the common cold: a randomized, doubleblind, placebo-controlled study. Ann Intern Med 1996;125: 81-88. 49. Kiremidjian-Schumacher L, Stotzky G. Selenium and immune responses. Environ Res 1987;42277-303. 50. Kiremidjian-SchumacherL, Roy M, Wishe HI, et al. Supplementation with selenium and human immune cell functions. II. Effect on cytotoxic lymphocytes and natural killer cells. Biol Trace Elem Res 1994;41:115-127. 51. Roy M, Kiremidjian-Schumacher L, Wishe HI, et al. Supplementation with selenium and human immune cell functions. I. Effect on lymphocyte proliferation and interleukin 2 receptor expression. Biol Trace Elem Res 1994;41:103-114. 52. Broome CS, McArdle F, Kyle JA, et al. An increase in selenium intake improves immune function and poliovirus handling in adults with marginal selenium status. Am J Clin Nutr 2004;80154-162. 53. Dardenne M, Pleau JM, Nabarra B, et al. Contribution of zinc and other metals to the biological activity of the serum thymic factor. Proc Natl Acad Sci U S A 1982;95370-5373. 54. Bogden JD, Oleske Jh4,Munves EM, et al. Zinc and immunocompetence in the elderly: baseline data on zinc nutriture and immunity in unsupplemented subjects. Am J Clin Nutr 1987;46:101-109. 55. Block IU,Mead MN. Immune system effects of echinacea, ginseng, and astragalus: a review. Integr Cancer Ther 2003;2247-267. 56. Barrett B. Medicinal properties of Echinacea: a critical review. Phytomedicine 2003;10:66-86. 57. Bauer R, Wagner H. Echinacea species as potential immunostimulatory drugs.In Wagner H, Famsworth NR,eds. Economic and medianal plant research, vol5. New York Academic Press, 1991:253-321. 58. McElhaney JE, Gravenstein S, Cole SK, et al. A placebo-controlled trial of a proprietary extract of North American ginseng (CVT-E002) to prevent acute respiratory illness in institutionalized older adults. J Am Geriatr Soc 2004;52:13-19. 59. Scaglione F, Cattaneo G, Alessandria M, et al. Efficacy and safety of the standardised ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold. Drugs Exp Clin Res 1996;22:65-72. 60. Chang HM, But PPH, eds. Pharmacology and applicationsof Chinese materia medica. Singapore: World Scientific, 1986:1041-1046. 61. Zhao KS, Mancini C, Dona G. Enhancement of the immune response in mice by Astragalus membranaceus extracts. Immunopharmacology 1990;20225-233. 62. Chu DT, Wong WL, Mavligit GM. h u n o t h e r a p y with Chinese medicinal herbs. I. Immune restoration of local xenogeneic graftversus-host reaction in cancer patients by fractionated Astragalus membranaceus in vitro. J Clin Lab Immunol 1988;25:119-123.

Intestinal Protozoan Infestation and Systemic Illness

C H A P T E R CONTENTS Introduction 655 Protozoan 655 Giardia spp. 655 Entamoeba histolytica 656

Therapeutic Considerations 657 Artemisia annua 657 Berberine 657 Allium sativum and Juglans nigra 657 Intestinal Bacterial Milieu 657

Diagnostic Considerations 657

Conclusion 657

INTRODUCTI0N The gastrointestinal tract is the largest organ of immune surveillance in the body, home to two thirds of the total lymphocyte popu1ation.l Intestinal lymphocytes manifest a variety of responses that depend on their CD phenotype, histologic location, and communication with other effector cells. Stimulation of intestinal immune response networks by lumen-dwelling microbes may produce a variety of systemic responses that are independent of gastrointestinal symptoms? Immunologic hypersensitivity to Giurdia lumbliu, for example, has been shown to provoke asthma,3~~ arthritis,"-15 and uveitis.16 Hypersensitivity reactions may occur in In none of these the absence of digestive ~omplaints.6,'~,*~ cases was the mechanism of hypersensitivity known; eosinophilia was a feature in only two cases.lo,llA high frequency of preexisting atopic disease is seen in patients with chronic giardiasis"J8 and may be a factor in susceptibility to infection.

PROTOZOAN Giardia spp. Immunologic mechanisms other than hypersensitivity reactions may also be associated with chronic giardiasis. In humans, chronic giardiasis has been associated with deficiency of secretory immunoglobulin A (IgA)19and with impaired macrophage cytotoxicity?O characteristics that may predispose to systemic illness. Athymic mice chronically infected with Giardia muris do not demonstrate mucosal darnage.2I Gillon et alZ proposed that the

release of enteropathic lymphokines by intraepithelial T cells is the cause of the intestinal injury in chronic giardiasis. In humans, the severity of malabsorption observed with chronic giardiasis is more closely related to the presence of intraepithelial lymphocytes and the antibody titer to Giardiu cyst antigen than to the estimated parasite burden.= A normal immunologic response to the parasite may be necessary to avoid chronic infection but also creates much of the tissue damage associated with chronic giardiasis. Giurdiu may provoke systemic illness by nonimmunologic mechanisms. G . lumbliu can cause intestinal protein loss without producing diarrhea.24Specific micronutrient deficiencies have also been described in chronic giardiasis. Low levels of carotene and folatG5and abnormal absorption of vitamin A, folic acid, and vitamin occur in a large minority of patients with chronic symptoms. Nutritional deficiency associated with chronic giardiasis may add to the burden of illness. Bacterial overgrowth of the small bowel has been described in giardiasis and may contribute to m a l a b ~ o r p t i o n . In ~~,~~ one study, colonization of the jejunum with Cundidu ulbicuns was reported in 30% of patients with giardiasis and was absent in A role for intestinal candidosis in provoking systemic illness has been debated for more than a quarter century (review in reference 2). Some strains of G. larnblia contain double-stranded RNA viruses?8 The role of Giurdiu as a vector for viral infection requires further study. My colleagues and I conducted a 2-year retrospective study of 218 patients who presented to our medical 655

Systemic symptoms of patients with CFIDS Symptom

With giardiasis (?!) (n= 63)

Without giardiasis (%) (n= 157)

Depression

61

Muscle weakness Headache

46

19

41

36

Sore throat

41

11

Lymphadenopathy

36

8

Arthralgia

36

27

Myalgia

34

18

Flulike symptoms

34

6

Poor exercise tolerance

30

10

41

Modified from Galland L, Lee M, Bueno H, Hiernowitz C. J Nutr M e d 1990;2:27-32. CNDS, Chronic fatigue immune dysfunction syndrome.

clinic with a chief complaint of chronic fatigue.’* G. lumbliu infection was identified in 61 patients. The symptoms of patients with and without giardiasis are shown in (Table 58-1). All patients with giardiasis and 86%of patients without giardiasis complained of digestive symptoms, but these were generally mild. The most interesting difference between the two groups lies in the positive association between giardiasis and symptoms such as myalgia, muscle weakness, flulike feelings, sweats, and adenopathy.In fact, 61%of fatigued patients with giardiasis had been diagnosed elsewhere as suffering from chronic fatigue immune dysfunction syndrome (CFIDS), compared with only 19% of fatigued patients who did not have giardiasis. Cure of giardiasis resulted in clearing of fatigue and related “viral” symptoms (myalgia, sweats, flulike feelings) in 70% of cases and in some palliation of fatigue in l8%, and was of no benefit in 12%. The association between intestinal protozoa and chronic fatigue in patients without prominent digestive complaints may not be limited to giardiasis. In an unpublished presentation, I reported that 80% of patients with a diagnosis of CFIDS who were infected with the protozoan Blustocystis hominis showed signrficant improvement of fatigue associated with treatment that cleared the protozoa from stool specimens.29

Entamoeba histolytica Chronic infestation with Entumoebu histolyticu, another common protozoan parasite, has been associated with autoimmune phenomena, including the appearance of antibodies to colonic epithelial cellsw and the development of ulcerative colitis after cure of amebic Extraintestinal autoimmune reactions to intestinal amebiasis include a case of antiphospholipid antibody syndrome with deep vein thrombosis and pulmonary

embolism3* and development of symmetrical polyarthritis very similar to rheumatoid arthritis Singh et aP measured amebic antibody levels in 41 Indian patients with a primary diagnosis of RA, 35 age- and sexmatched healthy volunteers, 162 hospital inpatients, and 26 patients with other arthritides. Amebic antibody values were elevated in 39%of patients with RA and zero to 11% of the various control groups. Only two patients with RA had experienced recent diarrheal disease. These researchers suggest that an excessive and prolonged antibody response to E. histolyticu or other enteric organisms may contribute to joint inflammation in RA. Galland15 described a patient with rheumatoid-like arthritis and antinuclear antibodies whose arthritis went into rapid and complete remission upon treatment of G. lamblia infection with metronidazole. Relapse occurred when the patient acquired E. histolyticu during a trip to Egypt; remission occurred slowly after treatment of amebiasis. Diarrhea, polyarthritis, and circulating antinuclear antibodies developed in a U.S.serviceman heavily infested with Endolimx mm,an allegedly nonpathogenic ameba?’ Metronidazole rapidly reversed all abnormalities. The reported cases of amebic arthritis may represent a variant of parasitic rheumatism, an inflammatory polyarthropathy produced by circulating antigen-antibodycomplexes.%The presence of autoantibodies, however, is not characteristicof parasitic rheumatism, and suggests other mechanisms of immune dysfunction: Either a preexisting disease is exacerbated by intercurrent amebic infection or amebic infection itself provokes autoimmunity, perhaps mediated by the action of immune response genes.= Reiter syndrome (arthritis, uveitis and urethritis) has been reported as a complication of infection with two other and Cyclosporu.40 intestinal protozoa, Cryptosp~ridium~~ Cyclospora cuyetanensis has also provoked Guillain-Bad syndrome, a severe autoimmune neuropathy4’ E. histolyticu contains a soluble lectin that is mitogenic for T lymphocytes.42*43 Activation of helper T cells by this lectin may induce replication of human immunodeficiency virus (HIV)in vivo. In one report, soluble E. histolyficu protein, although not mitogenic itself, induced HIV replication in tissue culture of lymphocytes obtained from three of seven men with chronic HIV infection.44Infection with E . histolytica and other parasites may promote the development of acquired immunodeficiency syndrome (AIDS)in HIV-infected indi~iduals.4~,~ Epidemiologic evidence associates preexisting intestinal protozoan infection with the appearance of Kaposi sarcoma among homosexual men in the United Although the influence of treating intestinal protozoan infection on the course of HIV infection has not been systematically studied, treatment of intestinal helminth infestation decreases the HIV viral load among African patients with AIDSa Synergism between intestinal parasites and other lymphotrophic retroviruses has been advanced as an explanation for the

Intestinal Protozoan Infestation and Systemic Illness

pathogenesis of Burkitt lymphoma49 and adult T-cell leukemia/lymphoma.50

DIAGNOSTIC CONSIDERATIONS Protozoan infection is usually diagnosed with stool examination; however, comparison of results of stool microscopy and duodenal aspiration has consistently shown that stool may fail to contain identifiable parasites even at the height of acute giardiasis.5lS2Collecting multiple specimens over several days increases the sensitivity to 85% to 90%.53Laboratories that specialize in tropical medicine or parasitology are more likely to find organisms in stool specimens than are general or hospital laboratories. Some authorities have suggested empirical treatment for intestinal parasites in high-risk groups, such as immigrants to the United States from Asia, the Middle east, sub-Saharan Africa, Eastern Europe, Latin America, and the Caribbean and have justified this approach on a cost-effective basis, given the safety of current medical therapies.54 A similar case might be made for treating chronically ill patients at high risk for parasitic infection because of residence, travel, sexual practices, or the context in which illness occurred.

THERAPEUTIC CONSIDERATIONS Artemisia annua Numerous naturally occurring substances have antiprotozoan activity. The most extensively studied is Artemisia unnua (sweet Annie or qinghao), a plant that yields the lactone artemisinin (qinghaosu), which is the basis for a new class of antimalarial compounds widely used in Asia and Africa.55Artemisinin is thought to owe its antiprotozoan effects to its content of endoperoxides and to kill parasites through oxidation. Its activity, at least in the treatment of Simian malaria, is enhanced by coadministration of cod liver oil and diminished by coadmjnistration of vitamin E. Artemisinin has low toxicity. In addition to its antibiotic activity, it stimulates macrophages, an important component of the immune response to protozoan infestation.% Artemisinin may induce abortion if given during pregnancy.

Berberine The alkaloid berberine can be extracted from the roots of several plant species, notably Berberis aquifolium (Oregon grape), Hydrastis canadensis (goldenseal)root, and Coptis

chinensis (goldthread). Berberine has protostatic and protocidal activity against E. histolyticu, G. Zumbliu and B. h~rninis.~’-~~ It has shown benefit in the treatment of giardiasis in children.60

Allium sativum and Juglans nigra Allium sativum (garlic) and Jugluns nigu (black walnut) have a long history of use as antimicrobials. Allicin inhibits growth of E. histolyticu in culture61and may be responsible for the antimicrobial activity of Human studies on the efficacy of garlic and black walnut in treatment of protozoan infections is lacking.

Intestinal Bacterial Milieu The intestinal bacterial milieu may be important in the treatment of protozoan infestation, especially for colonic organisms like E. histolyticu. Pathogenic strains of E. histolyticu are able to evade lysis by both classic and alternative pathways of complement. Intestinal bacteria, Escherichia coli in particular, are necessary for complement resistance and for amebic v i r ~ l e n c e . ~ ~ Gitler and MirelmarP suggested that ingested bacteria lower the redox potential within the parasite and allow the amebae to escape destruction by oxidative enzymes.@ Mirelman et alS reported that one can reversibly change the zymodeme patterns of E . histolyticu isolates from nonpathogenic to invasive by culturing amebae with the gut flora of patients who have either invasive disease or no symptoms. Optimal treatment of protozoan infection requires not only the administration of antimicrobial substances but also strategies aimed at enhancing the function of intestinal resistance factors such as secretory IgA and phagocyte function and creating a bacterial milieu that is not parasite friendly.

CONCLUSION Intestinal protozoan infestation is a significantly underrecognized cause of systemic illness. Undiagnosed infestations with Giurdiu spp., E. histolyticu, and other organisms have been associated with diverse diseases such as arthritis, asthma, Reiter syndrome, urticaria and uveitis, CFIDS, increased rate of progression of HIV infection, and a wide range of systemic dysfunction, such as fatigue, malabsorption, muscle weakness, and myalgia. Effective eradication of protozoa can result in surprisingly quick and complete clinical response.

Syndromes and Special Topics

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Maldigestion Michael T. Murray, ND Joseph E.Pizzorno Jr, ND CHAPTER CONTENTS Introduction 661 Therapeutic Considerations 661 Indigestion 661 Hypochlorhydria 662 Pancreatic lnsufficiency 663

INTRODUCTION Proper digestion, absorption, and elimination are necessary in order to gain the nutritional benefits from foods. Any disruption of these processes causes substantial, and usually progressive, health problems throughout the body. This chapter provides some overview of digestive dysfunction and ways to improve digestion. For specific digestive tract disorders (e.g., irritable bowel syndrome, peptic ulcers, inflammatory ulcers) see Section 6. For information on the various laboratory procedures for evaluation of digestive function (e.g., comprehensive digestive stool analysis, intestinal permeability assessment, small intestinal bacterial overgrowth breath test) see Section 2.

THERAPEUTIC CONSIDERATIONS Indigestion The term indigestion is often used by patients to describe a feeling of gaseousness or fullness in the abdomen. It can also be used to describe "heartburn." Indigestion can be attributed to a great many causes, including not only increased secretion of acid but also decreased secretion of acid and other digestive factors and enzymes. Indigestion is commonly treated with antacids and histamine (H2) receptor antagonists, either chosen by patients or prescribed by medical practitioners. The use of these agents will typically raise the gastric pH above 3.5, effectively inhibiting the action of pepsin, the enzyme involved in protein digestion that can be irritating to the stomach. Although raising the pH can reduce symptoms, it also substantiallyimpairs protein digestion

and mineral disassociation. In addition, the change in pH can adversely affect gut microbial flora, including the promotion of an overgrowth of Helicobucter pylori. Finally, most nutrition-oriented physicians believe that lack of acid, not excess, is the true culprit in most patients with indigestion. According to surveys, most people use antacids to relieve symptoms of reflux esophagitis.' However, reflux esophagitis is most often caused by overeating, not excessive acid production. Other common causes are as follows: Obesity Cigarette smoking Chocolate Fried foods Carbonated beverages Alcohol Coffee These factors either increase intraabdominal pressure or decrease the tone of the esophageal sphincter. Chronic heartburn may also be a sign of a hiatal hernia. However, although 50% of people older than 50 years have hiatal hernias, only 5% of patients with hiatal hernias actually experience reflux esophagitis. Perhaps the most effective treatment of chronic reflux esophagitis and symptomatic hiatal hernias is to utilize gravity. The standard recommendation is to simply place 4-inch blocks under the bedposts at the head of the patient's bed. This elevation of the head is very effective in many cases. Another recommendation to heal the esophagus is the use of deglycyrrhizinated licorice (DGL). 661

Hypochlorhydria In the patient with chronic indigestion, rather than focus on blocking the digestive process with antacids, the natural approach focuses on aiding digestion. Although much is said about hyperacidity conditions, a more common cause of indigestion is a lack of gastric acid secretion. Many symptoms and signs suggest impaired gastric acid secretion, and a number of specific diseases have been found to be associated with insufficient gastric acid output."12 They are listed in Boxes 59-1 and 59-2. Several studies have shown that the ability to secrete gastric acid decreases with Some studies found low stomach acidity in more than half of the subjects older than 60 years. The best method of diagnosing a lack of gastric acid is the Heidelberg gastric analysis (see Chapter 2l).I7 Wright1*has suggested that the response to a bicarbonate challenge during Heidelberg gastric analysis, not simply resting pH, is the true test of the functional ability of the stomach to secrete acid. Because the Heidelberg gastric acid analysis is not widely available, a clinical trial of HC1 supplements can be used as described in Appendix 7.

Etiology Like peptic ulcer disease,achlorhydria and hypochlorhydria have been linked to the overgrowth of the bacteria H. pylori. Approximately 90% to 100°/~of patients with duodenal ulcers, 70% of patients with gastric ulcers, and about 50% of people older than 50 years test positive for H. p y l ~ r i . '"he ~ presence of H. pylori is determined by measuring the level of antibodies to H. pylori in the blood or saliva or by culturing material collected during an endoscopy as well as measuring the breath for urea. More recently, a breath test has become available for assessment of current H. pylori activity. Low gastric output is thought to predispose to H.pylori colonization, and H. pylori colonization increases gastic pH, thereby setting up a positive feedback scenario and increasing the likelihood of colonization of the stomach

Bloating, belching, burning, and flatulence immediately after meals A sense of "fullness" after eating Indigestion, diarrhea, or constipation Multiple food allergies Nausea after taking supplements Itching around the rectum Weak, peeling, and cracked fingernails Dilated blood vessels in the cheeks and nose Acne Iron deficiency Chronic intestinal parasites or abnormal flora Undigestedfood in stool Chronic Candid infections Upper digestive tract gassiness

Addison's disease Asthma Celiac disease Dermatitis herpetiformis Diabetes mellitus Eczema Gallbladder disease Graves' disease Chronic autoimmune disorders Hepatitis Hyperthyroidisrdhypothyroidism Hives (chronic) Myasthenia gravis Osteoporosis Pernicious anemia Psoriasis Rheumatoid arthritis Rosacea Sjdgren's syndrome Systemic lupus erythematosus Thyrotoxicosis Vitiligo

and duodenum by other Not surprisingly, HCL antisecretory drugs (H2 receptor antagonists and proton pump inhibitors) may actually promote H. pylori overgrowth. Patients with H. pylori experience an exaggerated response in elevations of pH with antisecretory therapy.2I Although the typical conventional medicine approach is to focus only on the infective agent, the usual host defense factors are equally or more important. Unfortunately, the research has focused on eradicating the organism, and there is little information on protective factors against infectivity. Proposed protective factors against H. pylori-induced intestinal damage are maintaining a low pH and ensuring adequate antioxidantdefense mechanism~.~-" Low levels of vitamin C and vitamin E and other antioxidant factors in the gastric juice appear not only to lead to the progression of H.pylori colonization but also to contribute to the ulcer formation, because the mechanism by which H. pylori damages the stomach and intestinal mucosa is oxidative damage.25Furthermore, antioxidant status and gastric acid output appear to explain the observation that most people infected with H. pylori do not experience peptic ulcer disease or gastric cancer; for more information on natural approaches for eradicating H. pylori, see Chapter 200. One natural medicine that may be useful against H. pylori that is not discussed in Chapter 200 is bovine lactoferrin. Lactoferrin exerts broad-spectrum antimicrobial action because it has been shown to be effective in inhibiting the growth of disease-causing protozoa, yeast, bacteria, and viruses. More important than its ability to actually kill organisms is the later discovery that lactoferrin prevents the attachment of disease-causing organisms to cells that line the mouth and entire

gastrointestinal tract. At the same time, lactoferrin is a powerful booster of health-promoting bacteria like Bzj5dobacferia and Lacfobacillus species. By preventing growth of harmful bacteria while promoting the growth of beneficial bifidobacteria, lactoferrin assists in the development of a proper intestinal flora. The standard medical treatment of H. pylori infection is a 1- or 2-week course of treatment called triple therapy. It involves taking two antibiotics to kill the bacteria and an acid suppressor drug. On the basis of results of clinical trials, lactoferrin alone or in combination with triple therapy may soon be the treatment of choice. In one study, 151 patients testing positive for H. pylori and suffering from indigestion symptoms were given either triple therapy alone or with lactoferrin. H. pylori status assessed 8 weeks after the end of the treatment indicated a 95.9%eradication rate for the group receiving the lactoferrin; the other group had only a 72.5% eradication rate.26Theeffective dose of lactoferrin in this application is 300 mg a day.

Pancreatic lnsufficiency The most severe level of pancreatic insufficiency is seen in cystic fibrosis. Next in severity is the pancreatic insufficiency associated with the late stages of pancreatitis. These more severe causes of pancreatic insufficiency are most often easily recognized, but causes of mild pancreatic insufficiency are more insidious and difficult to diagnose. Both physical symptoms and laboratory tests can be used to assess pancreatic function in patients in whom mild pancreatic insuffiaency is suspected.Common symptoms of pancreatic insufficiencyare abdominal bloating and discomfort, gas, indigestion, and the passing of undigested food in the stool. For laboratory diagnosis, the comprehensivestool and digestive analysis (discussed in Chapter 14)is quite useful. In addition, the measurement of fecal elastase 1 concentrations by means of an enzyme-linked immunosorbent assay (ELISA) is an accepted indirect test of the exocrine pancreatic function.

1. Graham DY, Smith JL, Patterson DJ. Why do apparently healthy people use antacid tablets? Am J Gastroenterol 1983;78257-260.

2.Bray GW. The hypochlorhydria of asthma in childhood. Quart J Med 1931;24181-197. 3. Rabinowitch IM.Achlorhydria and its clinical significance in diabetes mellitus.Am J Dig Dis 1949;18322-333. 4. Capper WM, Butler TJ,Kilby JO, et al. Gallstones, gastric secretion, and flatulent dyspepsia. Lancet 1967;1:413-415. 5. Rawls WB, Ancona VC. Chronic urticaria associated with hypochlorhydria or achlorhydria. Rev Gastroenterol 1951;18: 267-271. 6. Giannella RA,Broitman SA, Zamcheck N. Influence of gastric acidity on bacterial and parasitic enteric infections: a perspective. Ann Intern Med 1973;78271-276.

It shows higher sensitivity and specificity for exocrine pancreatic insufficiency than the fecal chymotrypsin determination and is comparable to oral pancreatic function tests such as the pancreolauryl test.27

Pancreatic Enzyme Supplements Pancreatic enzyme products are an effective treatment for pancreatic insufficiency and are widely used. Most commercial preparations are prepared from fresh hog pancreas (i.e., pancreatin) (see Chapter 112 for a full discussion). The dosage of pancreatic enzymes is based on the level of enzyme activity of the particular product as defined by the United States Pharmacopoeia (USP). A l x pancreatic enzyme (pancreatin) product has in each milligram not less than 25 USP units of amylase activity, not less than 2.0 USP units of lipase activity, and not less than 25 USP units of protease activity. Pancreatin of higher potency is given a whole-number multiple indicating its strength. For example, a full-strength undiluted pancreatic extract that is 10 times stronger than the USP standard would be referred to as lox USP. Full-strength products are preferred to lower-potency pancreatin products because lower-potency products are often diluted with salt, lactose, or galactose to achieve desired strength (eg., 4x or lx). The dosage recommendation for a lox USP pancreatic enzyme product is typically 350 to lo00 mg three times/day immediately before meals when used as a digestive aid and 10 to 20 minutes before meals or on an empty stomach when antiinflammatoryeffects are desired. Enzyme products are often enteric-coated. However, numerous studies have shown that non-enteric-coated enzyme preparations actually outperform enteric-coated products if they are given before a meal (for digestive purposes) or on an empty stomach (for antiinflammatory effects). For vegetarians, bromelain, papain, and enzymes extracted from AspergilZus oryzae can substitute for pancreatic enzymes.

7. De Witte TJ, Geerdink PJ, Lamers CB, et al. Hypochlorhydria and hypergastrinaemia in rheumatoid arthritis. AM Rheum Dis 1979;38:1417. 8. Ryle JA, Barber HW. Gastric analysis in acne rosacea. Lancet 1920;21195-1196. 9. Ayres S. Gastric secretion in psoriasis, eczema and dermatitis herpetiformis.Arch Dermatol 1929;Jd.854-859. 10.Dotevall G, Walan A. Gastric secretion of acid and intrinsic factor in patients with hyper and hypothyroidism. Acta Med Scand 1969;186529-533. 11. Howitz J, Schwartz M. Vitiligo, achlorhydria, and pernicious anemia. Lancet 1971;1:1331-1334. 12. Howden CW, Hunt RH.Relationship between gashic secretion and infection.Gut 1987;28:96-107.

Syndromes and Special Topics 13.Rafsky HA, Weingarten M. A study of the gastric secretory response in the aged. Gastroenterology 1947;May:348-352. 15.Davies D, James TG. An investigation into the gastric secretion of a hundred normal persons over the age of sixty. Br J Med 1930; k1-14. 16. Baron JJd.Studies of basal and peak acid output with an augmented histamine test. Gut 1963;413&144. 17. Mojaverian,'F Ferguson RK,Masses PH, et al. Estimation of gastric msidence time of the Heidelberg capsule in humans: effect of varying food composition. Gastroenterology 1985;89:392-397. 18. Wright J. A proposal for standardized challenge testing of gastric acid secretory capaaty using the Heidelberg capsule radiotelemetry system. J John Bastyr Col Nat Med 1979;1:3-11. 19. Berstad K, Berstad A. Helicobacfer pylori infection in peptic ulcer disease. Scand J Gastroenterol 1993;28:561-567. 20. Sarker SA, Gyr K. Non-immunologicaldefence mechanisms of the gut. Gut 199233987-993. 21. Verdu EF, Armstrong D, Fraser R, et al. Effect of Helicobacfer pylon' status on intragastric pH during treatment with omeprazole. Gut 1995;36:539-43.

22. Shibata T, Imoto I, Taguchi Y, et al. High acid secretion may protect the gastric mucosa from injury caused by ammonia produced by Helicobacter pylori in duodenal ulcer patients. J Gastroenterol Hepatol 1996;11:674-680. 23. Rokkas T, Papatheodorou G, Karameris A, et al. Helicobucfer pylm' infection and gastric juice vitamin C levels: impact of eradication. Dig Dis Sci 1995;40:615-621. 24. Phull PS,Price AB, Thomiley MS, et al. Vitamin E concentrationsin the human stomach and duodenum: correlation with Helicobucfer pylori infection. Gut 1996;39:31-35. 25. Baik SC,Youn Hs, Chung MH, et al. Increased oxidative DNA damage in Helicobacfer pylori-infected human gastric mucosa. Cancer Res 1996361279-1282. 26. Di Mario F, Aragona G, Dal Eb N, et al. Use of bovine ladoferrin for Helicobacfer pylori eradication. Dig Liver Dis 2003;35:706-710. 27. Dominici R, Franzini C. Fecal elastase-1 as a test for pancreatic function: a review. Clin Chem Lab Med 2002;40:325-332.

Role of Dietary Fiber in Health and Disease Michael T. Murray, ND Peter B,Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS

Dietary Fiber and Chronic Degenerative Disease 666 Trends in US. Food Consumption 666

Diseases Associated with a Low-Fiber Diet 670 Diseases of the Colon and Gastrointestinal Disorders 670 Heart Disease and Gallstones 671 Obesity 671 Diabetes Mellitus 671

Definition and Composition of Dietary Fiber 666 Cellulose 667 Noncellulose Polysaccharides 667 Lignins and Lignans 669 Phytic Acid 669

Clinical Use of Dietary Fiber 671 Irritable Bowel Syndrome 672 Elevated Cholesterol Values 672 Obesity 673 Cancer Prevention 674 Dosage 674

Physiologic Effects of Dietary Fiber 669 Satiety/Palatability of Food 669 Stool Weight and Transit Time 669 Digestion 670 Short-Chain Fatty Acids 670 Intestinal Bacterial Flora 670

Toxicology 674 Mineral Malabsorption 674

Introduction 665 The Primitive Diet 665

INTRODUCTION The appreciation of the role of diet in determining the level of health deservedly continues to grow. A substantial body of research has now established well that certain dietary practices cause as well as prevent a wide range of diseases. In addition, the research is now showing that certain diets and foods can provide immediate therapeutic benefit. This chapter discusses the major diseases of Western society and how they relate to one key component of the diet: dietary fiber. The dietary fiber hypothesis has the following basic components: A diet rich in foods that contain plant cell walls (i.e., whole grains, legumes, fruits, and vegetables) is protective against a wide variety of diseases, in particular those that are prevalent in Western society. A diet providing a low intake of plant cell walls is a causative factor in the etiology of these diseases and

Drug Interactions 674 Summary 674

provides conditions under which other etiologic factors are more active. The term Wesfem diet is used throughout this chapter as well as in many other parts of the textbook. It refers to the typical diet of Western peoples, also referred to as ”foods of commerce.” This diet consists of a high intake of refined carbohydrates, saturated fats, processed foods, salt, and cholesterol and an extremely low intake of dietary fiber.

The Primitive Diet Detailed anatomic and historical evidence suggests that humans evolved as “hunter-gatherers”-that is, humans appear to be omnivores capable of surviving on both gathered (plant) and hunted (animal) foods.’ However, although the human gastrointestinal (GI) tract is capable of digesting both animal and plant foods, there are indications that it functions better with plant foods? A tremendous amount of evidence shows that deviating from a predominantly plant-based diet is a major factor 665

in the development of heart disease, cancer, strokes, arthritis, and many other chronic degenerative diseases. It is now the recommendationof many health and medical organizationsthat the human diet should focus primarily on plant-based foods: vegetables, fruits, grains, legumes, nuts, seeds, and so on. Such a diet is thought to offer significant protection against the development of chronic degenerative d i ~ 2 a . w . ~ ~

DIETARY FIBER AND CHRONIC DEGENERATIVE DISEASE The belief in the benefiaal effects of fiber in the diet goes back to at least 1585. However, the link between dietary fiber and chronic disease in the medical literature originated to a great extent from the work of two medical pioneers, Denis Burkitt and Hugh Trowell, who wrote “Western Diseases: Their Emergence and Preuenfion,” first published in 1981.3On the basis of extensive studies examining the rate of diseases in various populations (epidemiologic data) and his own observationsof primitive c u l m , Burkitt formulated the following sequence of events:

First stage. The primal diet of plant eaters contains large amounts of unprocessed starch staples; chronic degenerative diseases like osteoarthritis,heart disease,type 2 diabetes, and cancer OCCUT infrequently. Second stage. When Westernization of diet commences, obesity and diabetes commonly appear in privileged groups. Third stage. With moderate Westernization of the diet, constipation, hemorrhoids, varicose veins, and appendicitisbecome common complaints. Fourfh stage. Finally, with full Westernization of the diet, chronic degenerative diseases like osteoarthritis, rheumatoid arthritis, gout, heart disease, and cancer are extremely common. Although now extremely well-recognized, the work of Burkitt and Trowell is actually a continuation of the landmark work of Weston A. Price, a dentist and author of Nutrition and physical degeneration.6 In the early 1900s, Price traveled the world, observing changes in teeth and palate (orthodontic) structure as various cultures discarded traditional dietary practices in favor of a more ”civilized” diet. Price was able to follow individuals as well as cultures over periods of 20 to 40 years and carefully documented the onset of degenerative diseases as their diets became more westernized. It is now well documented that diet is the major factor responsible for many chronic degenerative diseases. In 1984, the National Research Council’s Food and Nutrition Board established the Committee on Diet and Health and undertook a comprehensive analysis on diet and major chronic diseases? Their findings, as well as those of the U.S. Surgeon General and other research groups, brought to the forefront the need for Americans

Metabolic Obesity, gout, diabetes, kidney stones, gallstones Cardiovascular Hypertension, cerebrovascular disease, ischemic heart disease, varicose veins, deep vein thrombosis, pulmonary embolism Colonic Constipation, appendicitis, diverticulitis, diverticulosis, hemorrhoids, colon cancer, irritable bowel syndrome, ulcerative colitis, Crohn’s disease Other Dental caries, autoimmune disorders, pernicious anemia, multiple sclerosis, thyrotoxicosis, dermatologicalconditions

to change their eating habits to reduce their risk for chronic disease. Box 60-1 lists diseases with convincing linksto a diet low in dietary fiber and plant foods. Many of these now common diseases were extremely rare before the twentieth century.

Trends in U.S. Food Consumption During the twentieth century, food consumption patterns changed dramatically in the United States (Table 60.1).Total dietary fat intake increased from 32% of the calories in 1909 to 43% by the end of the century overall; carbohydrate intake dropped from 57%to 46%; and protein intake has remained fairly stable at about 11%.Compounding these detrimental changes are the individual food choices accounting for the changes. There were sigruficant increases in the consumption of meat, fats and oils, and sugars and sweetners in conjunction with the decreased consumption of noncitrus fruits, vegetables, and whole grain products. But the biggest change in the last 100 years of human nutrition is the switch from a diet with a high level of complex carbohydrates, as found naturally occurring in grains and vegetables, to a tremendous and dramatic increase in the number of calories consumed from simple sugars. Currently, more than half of the carbohydrates being consumed are in the form of sugars such as sucrose (table sugar) and corn syrup, which are added to foods as sweetening agents. High consumption of refined sugars and a low consumption of dietary fiber is linked to many chronic diseases, including obesity, diabetes, heart disease, and cancer.

DEFINITION AND COMPOSITION OF DIETARY FIBER Generally, dietary fiber refers to the components of plant cell wall and nonnutritive residues. Originally, the

Role of Dietary Fiber in Health and Disease

Dietary fiber constituents of the food groups

Trends in quantities of foods consumed per capita (poundslyear) Foods Meat, poultry, and fish: Beef Pork Poultry Fish TOTAL

Eggs Dairy products: Whole milk Low-fat milk Cheese Other TOTAL

Fats and oils: Butter Margarine Shortening Lard and tallow Salad and cooking oil TOTAL

Fruits: Citrus Noncitrus Fresh Processed TOTAL

Vegetables: Tomatoes Dark green and yellow Other Fresh Processed TOTAL

Potatoes, white: Fresh Processed TOTAL

Dry beans, peas, nuts, andsoybeans Grain products: Wheat products Corn Other grains TOTAL

Sugar and sweeteners: Refined sugar Syrups and other sweeteners TOTAL

1909

1967

1985

1999

62 18 12

81 61 46 15

73 62 70 19

66 50 68 15

146

203

224

199

37

40

32

32

54

Food group

Main dietary fibers

Fruits and vegetables

Cellulose, hemicellulose, lignin, pectic substances, cutin, waxes

Grains

Cellulose, hernicellulose, lignin, phenolic esters

Seeds (other than grains)

Cellulose, hemicellulose, pectic substances, guar endosperm

Seed husk of Planfago

Arabinogalacturonosyl-phamno-xylan

ovafa

(mucilage) Gum arabic, alginate, carrageenan, carboxymethylcellulose

232 44 15 159 -

122 112 26 190 -

112 101 30 210 -

Food additives

339

450

450

453

18 1 8 12 2 -

6 10 16 5 16 -

5 11 23 4 25 -

5 8 22 6 29 -

41

53

68

70

17

60

72

79

154 8

73 35

87

34

115 37

179

168

193

231

46

34

36 25

38 31

55 39

definition was restricted to substances that are not digestible by the endogenous secretions of the human digestive tract. This original definition is specious, because it depends on a precise understanding of what exactly is not digestible. The composition of the plant cell wall varies according to the species of plant. Typically,the dry cell wall contains 35% cellulose, 45% noncellulose polysaccharides, 17”/0 lignins, 3% protein, and 2% ash.810It is important to recognize that dietary fiber is a complex of these constituents, and supplementation of a single component does not substitute for a diet rich in high-fiber foods. In some clinical conditions, however, the use of specific components is a useful adjunct to a healthy diet. Tables 60-2 and 60-3 summarize the classificationsof dietary fibers.

136 8

87 35

96

34

126 39

224

183

199

259

182 0

67 19

55 28 -

49 91

182

86

83

140

16

16

18

22

216 56 19

116 15 13 144

122 17 26

150 28 24 __

165

202

100 22

63 90

68 91

-

-

122

153

159

223

64 5 47

291

77 14 91

Data from United States Department of Agriculture. Food Review 2000;23:8-15.

CelIulose The best-known dietary fiber component is cellulose. This unbranched 1-4-beta-Dglucose polymer ranges in size from 3000 to 100,OOO glucose units. It is a relatively insoluble, hydrophilic material. This ability to bind water accounts for its effect of increasing fecal size and weight. Although indigestible by humans, cellulose is partially degraded by the microflora of the gut. This anaerobic process (fermentation) occurs in the colon, results in the degradation of about 50% of the cellulose, and is an important source of short-chain fatty acids (SCFAs).Sp9SCFAs have very important properties in the colon, as discussed later.

Noncellulose Polysaccharides The majority of polysaccharides in the plant cell wall are a noncellulose type, that is, they are water-soluble and posses diverse properties. Included in this class are hemicelluloses, pectin substances, gums, mucilages, and algal polysaccharides.

Hemicelluloses Hemicelluloses contain a mixture of pentose and hexose molecules in branched-chain configurations much

Classification of dietary fiber Fiber class I. Cellulose II. Noncellulose polysaccharides A. Hemicelluloses

Chemical structure

Plant part

Food sources

Physiologic effect

Unbranched 1-4-betao-glucose polymer

Principal plant wall component

Wheat bran

Increases fecal weight and size

Mixture of pentose and hexose molecules in branching chains

Plant cell walls

Oat bran

Increases fecal weight and size; binds bile acids

Karaya. gum arabic

Laxative

Guar gum, legumes, psyllium

Hydrocolloids that bind steroids and delay gastric emptying, heavy metal chelation

Citrusgum, rind, apple, onion skin

As above

B. Gums

Branchedchain uronic acid containing polymers

C. Mucilages

Similar to hemicelluloses

D.Pectins

Mixture of methyl esterified galacturan, galactan, and arabinose in varying proportions

E. Algal polysaccharides 111. Lignins

Endosperm of plant seeds

Polymerized o-mannuronic acid and L-glucuronic acid

-

Algin, agar, carrageenan

As above

Noncarbohydrate polymeric phenylpropene

Woody part of plant

Wood (40%-50%), wheat (25%), apple (25%), cabbage (6%)

Antioxidants, anticarcinogenic

smaller than cellulose. Their ability to increase fecal weight depends on the pentose fraction. The hemicelluloses are also an important source of SCFAs via bacterial degradation.

Pectin and Pectinlike Substances Pectins are found in all plant cell walls as well as in the outer skins and rind of fruits and vegetables. For example, the rind of an orange contains 30% pectin; an apple peel, 15%;and onion skins, 12%. The gel-forming properties of pectin are well known to anyone who has made a jelly or jam. These same gel-forming qualities are responsible for the cholesterol-lowering effects of pectins. Pectins lower serum cholesterol by binding the cholesterol and bile acids in the gut and promoting their excretion.

Gums Plant gums are a complex group of water-soluble, branched-chain, uronic acid-containing polymers. They are produced by the plant in response to injury and are commercially produced through incision of a plant or tree and collection of the fluid extract. Gums are used as emulsifiers, thickeners, and stabilizers by the food industry and as laxatives in pharmaceuticals.

Mucilages Structurally, mucilages resemble the hemicelluloses, but they are not classed as such because of their unique location in the seed portion of the plant. Mucilages are

generally mixed with the endosperm of the plant seeds, where they retain water, preventing seed desiccation. Guar gum, found in leguminous plants, is the most widely studied mucilage. It is isolated from the endosperm of Cyumopsis tetragonolobus, a plant cultivated in India for livestock feed. Guar gum is used commercially as a protective colloid, stabilizer, thickening, and film-forming agent for paper sizing, cheese, salad dressings, ice cream, soups, toothpaste, pharmaceutical jelly, lotion, skin cream, and tablets. It is also used as a laxative. Guar gum and other mucilages are perhaps the most potent cholesterol-lowering agents of the gel-forming hydrocolloids, including pectin and glucomannan.Guar gum has been shown to reduce fasting and postprandial serum glucose and insulin levels in both healthy and diabetic subjects;and it has reduced body weight and hunger ratings when taken with meals by obese subjects. Psyllium seed husk (Plantago ovuta) is another example of a mucilage that is widely used as a bulking and laxative agent.

Algal Polysaccharides Included in the category algal polysaccharides are alginic acid, agar, and carrageenan. Marine-derived polysaccharides are used extensively by the food industry. Alginate has been shown to inhibit heavy metal uptake in the gut, as do other gel-forming fibers. Agar is used as a thickening agent and as a gel for holding microbiologic media. It has laxative and fecal bulkincreasing activity.

Role of Dietary Fiber in Health and Disease

Carrageenan is used in milk and chocolate products because of its ability to react with milk proteins. However, unlike other plant polysaccharides, it adversely affectsthe intestinal mucosa. It has been shown in rats to induce ulcer formation in the cecum by promoting release of lysosomal enzymes by mucosal macrophages. Other rat studies have shown carrageenan to enhance carcinogen induction of neoplasia, colorectalcarcinoma, birth defects, and hepatomegaly."

Lignins and Lignans Lignins are composed of aromatic polymers of coniferyl, para-coumaryl, and sinapyl alcohols in varying ratios. Vanillin (artificial vanilla) and other aromatic chemicals are synthesized from lignins. Lignans are fiber compounds related to lignins that are typically composed of cinnamic acid, cinnamyl alcohol, propenylbenzene, and allylbenzene precursor units.Many plant lignans show important properties, such as anticancer, antibacterial, antifungal, and antiviral activities. Plant lignins are metabolized by the gut flora into the animal lignins enterolactone and enterodiol, both of which posses antiestrogenic activity and are believed to be protective against cancer.12

Phytic Acid In the plant, phytic acid (inositol hexaphosphoric acid) is responsible for storing minerals such as calcium, phosphorus, magnesium, and potassium. There is some concern that phytates can adversely affect the uptake and utilization of many minerals, including calcium, iron, and zinc. The major sources of phytate in the diet are cereal grains and legumes (Table 60-4). Phytate is destroyed by heat and by the enzyme phytase during the leavening of bread?r9 Phytic acid exerts impressive antioxidant and antitumor effects.ls15 When administered in drinking water or injected, phytic acid has demonstrated a consistent

Plant phytic acid

antitumor effect in animals against colon cancer and fibrosarcomas. Preclinical trials have yielded encouragingresults; larger, better-designed studies are in process.1s15

PHYSIOLOGIC EFFECTS OF DIETARY FIBER It is beyond the scope of this chapter to detail all known effects of dietary fiber on humans. Instead, we cover effects of greatest clinical sigruficance (stool weight, transit time, digestion, colon function, SCFAs, and colon Beneficial effects of dietary fiber are listed in Box 60-2.

Satiety/Palatability of Food High-fiber foods, because of their relatively lower energy density and overall palatability, tend to be more satiating than low-fiber foods. Furthermore, dietary fiber may promote satiety and fat oxidation through several hormonal pathways. For instance, some research has shown prolonged increases in circulating cholecystokinin concentrations after ingestion of fiber-rich meals compared with energy-matched, low-fiber meals. Fiber may also affect secretion of gut hormones, independent of glycemic response, that act as satiety factors or to alter glucose homeostasis (for more information, see Chapter 168).1618

Stool Weight and Transit Time Fiber has long been used in the treatment of constipation. Dietary fiber, particularly the water-insoluble, hydrophilic fibers such as cellulose (e.g., bran), increases stool weight as a result of water-holding properties. Transit time, the time taken for passage of material from the mouth to the anus, is greatly reduced with a high-fiber diet. Cultures consuming a high-fiber diet (100-170 g/day) usually have a transit time of 30 hours and a fecal weight of 500 g. In contrast, Europeans and Americans who eat a typical, low-fiber diet (20 g/day) have a transit time of more than 48 hours and a fecal weight of only 100 g3 Interestingly, when fiber is added to the diet of subjects

Percentage dry weight

Soybeans

1.4

Wheat

0.9

Corn

1.1

Rice

0.9

Peanuts

1.9

Sesame seeds

5.4

Lima beans

2.5

Barley

1.o

Oats

0.8

Decreased intestinal transit time Delayed gastric emptying resulting in reduced postprandial hyperglycemia Increased satiety Increased palatability Increased pancreatic secretion Increased stool weight More advantageous intestinal microflora Increased production of short-chain fatty acids Decreased serum lipids More soluble bile

with abnormally rapid transit times (less than 24 hours), it causes prolongation of the transit t i ~ n e . ~ , ~ Dietary fiber’s effect on transit time is apparently directly related to its effect on stool weight and size. A larger, bulkier stool passes through the colon more easily, requiring less intraluminal pressure and, subsequently, less straining.14 It has been hypothesized that the decreased intraluminal pressure (due to the greater leverage the colon mucosa has on a larger stool) results in less hydrostatic stress on the colon wall and therefore avoids the ballooning effect that results in diverticula. The increased intestinal transit time associated with the Western diet allows prolonged exposure of the intestinal flora to various compounds, both natural and manufactured, resulting in greater conversion of such compounds to potential ~arcinogens.~,~,”

Digestion Although dietary fiber increases the transit through the GI tract, it slows gastric emptying, thus reducing postprandial hyperglycemia in both normal and diabetic subjects. Pancreatic enzyme secretion and activity also rise in response to fiber, although excessive levels of fiber (more than 10% of the meal by weight) have a converse effedF0A number of research studies have examined the effects of fiber on mineral absorption. Although the results have been somewhat contradictory, it now appears that large amounts of dietary fiber may result in impaired absorption and/or negative balance of some minerals. Fiber as a dietary component does not appear to interfere with the minerals in other foods, but supplemental fiber, especially hemicelluloses, may cause a negative mineral balanceF4

Short-Chain Fatty Acids The fermentation of dietary fiber by the intestinal flora produces the following three main end-products: XFAs Various gases Energy The SCFAs-acetic, propionic, and butyric acids-are the main anions in the large intestine and have many important physiologic functions. SCFAs seem to decrease hepatic output of glucose and circulating concentrations of free fatty acids and stimulate secretion of glucagon-likepeptide-1. These actions may, in turn, alter insulin sensitivity, insulin secretion patterns, the partitioning of metabolic fuels, and regulation of satiety.16For every 20 g of fiber consumed each day, approximately 200 mmol of XFAs is produced, of which 62 mmol is acetate, 25 propionate, and 16 butyrate? Propionate and acetate are transported directly to the liver and utilized for energy production, whereas butyrate provides an important energy source for the

colonic mucosa. In fact, butyrate is the preferred substrate for energy metabolism in the distal ~0lon?,~2* Butyrate production may also be responsible for the anticancer properties of dietary fiber. Even at extremely low concentrations, butyrate has been shown, in vitro, to profoundly affect gene expression and other nucleic processes, such as DNA synthesis, resulting in suppressed cell proliferation in both normal and malignant cells. Butyrate has trophic effects on normal colonocytes, stops the growth of neoplastic colonocytes, inhibits the preneoplastic hyperproliferation induced by certain tumor promoters in vitro, inhibits the expression of certain protooncogenes, and promotes differentiation of colon cancer cell linesz Some of these effects are due to the acetylation of histones and the stabilization of the chromatin structure. Butyrate is also being used in enemas for the treatment of ulcerative colitis. Certain fibers appear to be more effective than others in increasing the levels of SCFAs in the colon. Pectins (both apple and citrus, guar gum, and other legume fibers) and vegetable fiber isolates produce more SCFAs than wheat fiber, corn fiber, or oat bran.8~~

Intestinal Bacterial Flora Dietary fiber appears to improve all aspects of colon function. Of central importance is the role it plays in maintaining a ”suitable” colonic bacterial flora. A lowfiber intake is associated with both an overgrowth of Enterobacteriaceae and other endotoxin-producing bacteria and a lower percentage of Lactobacillus and other acidophilic b a ~ t e r i a .A ~ ,diet ~ high in dietary fiber promotes acidophilic bacteria through the greater synthesis of colonic SCFAs, which reduces the colon pH, a condition conducive to the growth of beneficial bacteria.

DISEASES ASSOCIATED WITH A LOW-FIBER DIET Because of the important physiologic effects of dietary fiber, a diet low in dietary fiber obviously leads to altered physiology or disease. The diseases having the strongest correlation with a lack of dietary fiber are those of the colon and GI tract, heart disease and gallstones, obesity, and diabetes. Each is briefly discussed here.

Diseases of the Colon and Gastrointestinal Disorders The epidemiologic and experimental data documenting the protective effect of dietary fiber on colon cancer are overwhelming. For digestive conditions in which bacteria play a causative role, such as Crohn’s disease, fiber may inhibit the adherence of these pathogens.23There is evidence of similar strong links with other common diseases of the colon-diverticulitis, diverticulosis, irritable

Role of Dietary Fiber in Health and Disease bowel syndrome (IBS), ulcerative colitis, and appendicitis as well as hemorrhoids, peptic ulcers, and hiatal hernia.3,4,8,9Furthermore, the same diseases often respond to a high-fiber diet.

Heart Disease and Gallstones Dietary fiber has been shown to be quite protective against heart disease and gallstones. Increasing fiber intake clearly appears to be a safe and inexpensive dietary strategy for reducing the risk of coronary heart disease.2427A diet high in dietary fiber is known to reduce total serum cholesterol and triglyceride levels while raising serum high-density lipoprotein (HDL)cholesterol levels and the production and storage of less saturated bile acids. A survey of 4900 adults found that after data were controlled for demographic factors, body mass index, smoking, alcohol consumption, exercise, and total caloric intake, subjects who had the highest consumption of fiber had a sigruficantly lower C-reactive protein One cohort study of 43,757 U.S. male health professionals 40 to 75 years of age who were free of diagnosed cardiovascular disease and diabetes were asked to complete a detailed 131-item dietary questionnaire used to measure usual intake of total dietary fiber and specific food sources of fiber and then were monitored for 6 years. A 10-g increase in total dietary fiber corresponded to a 20% reduction in relative risk for myocardial. Within the three main food contributors to total fiber intake (vegetable, fruit, and cereal), cereal fiber seemed to offer the greatest protection against a cardiac event.* The binding of bile acids and micellar components to various grains, food fibers, and isolated fiber compounds leads to reduction of the enterohepatic circulation of bile salts and cholesterol. Loss of cholesterol and bile salts through the feces is the major pathway for elimination of these compounds from the body. Dietary fiber also reduces cholesterol biosynthesis and promotes the conversion of cholesterol to the bile acids via activation of the vitamin C-dependent enzyme 7-alphahydroxylase, the rate-limiting step in bile acid synthesis. This enhancement of bile acid synthesis and excretion is the result of dietary fiber’s preferential binding of deoxycholic acid, resulting in a compensatory increase in circulating levels of chenodeoxycholic acid. Chenodeoxycholic acid has been shown to inhibit cholesterol absorption and synthesis at its rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reducta~e.~ Binding of chenodeoxycholic acid by dietary fiber results in an increase in the taurocholate-toglycocholate ratio. The ultimate result of these alterations in bile salt concentrations and ratios is a less saturated bile that solubilizes cholesterol more effectively and is resistant to stone formation.

Obesity A dietary fiber-deficient diet is an important etiologic factor in the development of obesity.I8 Dietary fiber plays a role in preventing obesity by: Increasing the amount of necessary chewing, thus slowing the eating process. Increasing fecal caloric loss. Altering digestive hormone secretion. Improving glucose tolerance. Inducing satiety through greater gastric filling, stimulation of cholecystokininrelease, and intestinal bulking action. Other effects of dietary fiber on obesity are discussed here with diabetes mellitus-60% to 90% of patients with type I1 diabetes mellitus are obese.

Diabetes Mellitus Epidemiologic and experimental data show diabetes mellitus to be one of the diseases most clearly related to inadequate intake of dietary fiber.3~4,7-9 Clinical trials that have demonstrated the beneficial therapeutic effect of dietary fiber on diabetes have further substantiated this association (discussed later).29sDietary fiber’s prevention and modulation of diabetes is due to its effects on serum glucose and, subsequently, insulin levels. Fiber may account for almost half of the variance in the area under the glucose-response curve after consumption of various starchy foods. A high-complex carbohydrate, high-fiber diet reduces postprandial hyperglycemia (largely by delaying gastric emptying and thereby reducing insulin secretion) and increases tissue sensitivity to insulin (how, or whether, this relates to chromium uptake and metabolism has not been determined). Fermentation products of fiber, chiefly SCFAs, enhance hepatic glucose metabolism and may further contribute to the ameliorating effects of dietary fiber on diabetes.8r9

CLINICAL USE OF DIETARY FIBER The best and most cost-effective way of using dietary fiber in a clinical setting is via encouraging a diet rich in plant foods (Table 60-5 lists dietary fiber content of selected foods). A good goal for dietary fiber intake is 25 to 35 g daily, which can easily be achieved if the dietary focus is on whole, unprocessed, plant foods. In addition to the well-known use of dietary fiber as a laxative, the principal use of supplemental dietary fiber is in the treatment of IBS and other functional disturbances of the colon, elevated serum cholesterol values, and obesity. The best fiber sources for nonlaxative effects are psyllium, guar gum, glucomannan, gum karaya, and pectin, because they are rich in water-soluble fibers. Although there are many fiber supplements to choose from, the

Syndromes and Special Topics

Dietary fiber content of selected foods Food

Serving

Calories

Grams of fiber

Food

Serving

Fruits Apple (with skin)

1 medium

81

3.5

Banana

1 medium

105

2.4

Rice, Breads, Pastas, and Flour Bran muffins 1 muffin

Cantaloupe Cherries (sweet)

X melon

30

1.o

Bread (white)

10

49

1.2

Calories

Grams of fiber

104

2.5

1 slice

78

0.4

1 slice

61

1.4

2 crackers

50

2.0

Grapefruit

'x medium

38

1.6

Bread (whole wheat) Crisp bread, rye

Orange Peach (with skin)

1 medium

62

2.6

Rice, brown (cooked)

% cup

97

1.o

1

37

1.9

Rice, white (cooked)

% cup

82

0.2

Pear (with skin)

% large

61

3.1

Spaghetti (reg. cooked)

x cup

155

1.1

Spaghetti (whole wheat, cooked) Breakfast Cereals All-Bran

% cup

155

3.9

% cup

71

8.5

Bran Chex

55 cup 55 cup

91

4.6

Prunes

3

60

3.0

Raisins

5 cup

106

3.1

Raspberries

% cup

35

3.1

1 cup

45

3.0

'h cup

13

1.5

Corn Bran Cornflakes

10

1.1

Cucumber

x cup x cup

8

0.4

Lettuce

1 cup

10

Mushrooms

10

Pepper (green)

x cup x cup

9

0.5

Spinach

1 cup

8

1.2

Tomato Vegetables (cooked) Asparagus (cut)

1 medium

20

1.5

1 cup

30

2.0

Beans (green)

1 cup

32

3.2

Broccoli

1 cup

40

4.4

Brussels sprouts

1 cup

56

4.6

Cabbage (red)

1 cup

30

2.8

Carrots

1 cup

48

4.6

Cauliflower

1 cup

28

2.2

Corn

x cup

87

2.9

Kale Parsnip

1 cup

44

2.8

1 cup

102

5.4

Potato (with skin)

1 medium

106

2.5

Potato (without skin)

1 medium

97

1.4

Spinach

1 cup

42

4.2

Sweet potatoes Zucchini Legumes Baked beans

1 medium

Dried peas (cooked) Kidney beans (cooked)

Strawberries Vegetables (raw) Bean sprouts Celery (diced)

98

5.4

1% cups

110

0.3

Grape Nuts

% cup

101

1.4

Oatmeal

x cup

108

1.6

0.9

Raisin Bran-type

4.0

Shredded Wheat Nuts Almonds

55 cup 55 cup

115

1.5

102

2.6

79

1.1

160

3.4

1 cup

22

3.6

'h cup

155

8.8

x cup

115

4.7

% cup

110

7.3

Lentils (cooked) Lima beans (cooked)

x cup x cup

97

3.7

64

4.5

Navy beans (cooked)

'h cup

112

6.0

10 nuts

Filberts

10 nuts

54

0.8

Peanuts

10 nuts

105

1.4

clinically most effective are those that are rich in watersoluble fiber and low in added sugar or other sweeteners.

Irritable Bowel Syndrome The treatment of IBS by increasing the intake of dietary fiber has a long, although irregular, history. In general, consuming a diet rich in complex carbohydrates and dietary fiber while avoiding sugar and refined foods is effective. The most effective fiber supplements are the water-soluble forms. However, the type of fiber often used in both research and clinical practice is wheat bran. Because wheat is among the foods most commonly implicated in malabsorptive and allergic conditions, the use of wheat bran is usually not indicated in individuals with symptoms of IBS, in which food allergy is a sigruficant causative factor. Also, although patients with constipation are likely to respond to wheat bran, those with diarrhea may actually experience a worsening of their symptoms.

Elevated Cholesterol Values A review article concluded that soluble-fiber supplementation was very effective in lowering cholesterol levels.3l

Role of Dietary Fiber in Health and Disease

Specifically, a significant reduction in the level of serum total cholesterol was found in 68 of the 77 (88%)studies reviewed. The effect of soluble fiber supplementation was clearly dose-dependent. In other words, the higher the intake of soluble fiber, the greater the reduction in serum cholesterol. The average doses and reductions noted in clinical trials are shown in Table 60-6. Many of the studies utilized oat bran or oatmeal as the source of fiber. The overwhelming majority of these studies demonstrated that individuals with high cholesterol levels experiencesigruficant reductionswith frequent consumption of oatmeal or oat bran. In contrast, individuals with normal or low cholesterol levels experiencelittle change. In individualswith high cholesterol levels (above 220 mg/dl) the consumption of the equivalent of 3 g of soluble oat fiber lowers total cholesterol by 8% to 23%. This is highly sigruficant,as with each 1%drop in serum

Fiber

Typical reduction in total cholesterol (%)

Dosage (9) 50-100

20

Guar gum

Oat bran (dry)

9-15

10

Pectin

6-10

5 10-20 10

Psyllium

10-20

Vegetable fiber

27

cholesterol level, there is a 2% decrease in the risk for development of heart disease. Three grams of fiber would be provided by approximately one bowl of ready-to-eat oat bran cereal or oatmeal. Although oatmeal's fiber content (7%) is less thanthat of oat bran (15%-26%),it has been determined that the polyunsaturated fatty acids contribute as much to the cholesterol-loweringeffects of oats as the fiber content. Oat bran has a higher fiber content, but oatmeal is higher in polyunsaturated fatty acids. In practical terms, the dosage level for dry oat bran would be '/3 to 1cup; for dry oatmeal, 1to 1*/s C U ~ S . ~ ~ ~ ~

Obesity When taken with water before meals, water-soluble fiber sources bind to the water in the stomach to form a gelatinous mass that makes an individual feel full and less likely to overeat. However, the benefits of fiber go well beyond this mechanical effect. Fiber supplements have been shown to enhance blood sugar control and insulin effects as well as actually reduce the number of calories absorbed by the intestines? In some of the clinical studies demonstrating weight loss, fiber supplements were shown to reduce the number of calories absorbed by 30 to 180 calories/day. Over the course of a year, this could result in a reduction of 3 to 18 lbs. It is estimated that a person can lose 50% to 100% more weight by supplementing the diet with fiber than by simply restricting calories alone; see Table 60-7 and Chapter 194 for information on clinical studies of the treatment of obesity with dietary fiber supplements.

Clinical studies of the treatment of obesity with dietary fiber supplements

Fiber Guar

Number of subjects

Length of study

Dosage (@day)

Calorie restriction?

Average Weight Loss (Ibs) Fiber

9

2 months

20

None

9.4

7

1 year

20

None

61.9

2.5 months

20

None

15.6

21

Placebo No placebo group No placebo group No placebo group 0.9

Reference 28

29 30

33

2.5 months

15

None

5.5

20

2 months

3

None

5.5

Weight gain of 1.5 Ibs

32

20

2 months

3

None

8.14

0.44

33

Citrus pectin

14

4 weeks

5.56

Yes

12.8

34

Mixture A*

60 89

12 weeks 11 weeks

5 10

Yes Yes

18.7 13.9

No placebo group 14.7 9.2

45

3 months 3 months 6 months

7 7 7

Yes Yes Yes

13.6 10.8 12.1

Glucomannan

Mixture B'

97

52

9 7.3 6.1

'Mixture A, 80% fiber from grains/20% fiber from citrus; mixture 6, 90% insoluble/lO% soluble fiber from beet, barley, and citrus fibers.

31

35 36 37 38 39

Syndromes and Special Topics

Cancer Prevention The body of research documenting the cancer-preventing effects of a high-fiber diet has continued to accumulate. In addition to the epidemiologic associations, researchers have now also performed prospective and supplementation studies. Most, but not all, studies have shown a sigruficant protective effect of dietary fiber for a wide range of cancers. Several studies have shown benefit for prevention of breast cancer.% One representative study evaluated the association between breast cancer and dietary intake in two Chinese populations (Shanghai and Eanjin) who are at low risk for breast cancer. These populations have onefifththe rate of breast cancer for U.S.white women. There were two case-controlledstudies. In the 834 women studied, the intake of crude fiber, carotene, and vitamin C showed a strong sigruficant inverse association with breast cancer risk.The effect was closely associated with the intake of green vegetables. The women in the lowest tertile intake of crude fiber intake and the highest tertile intake of fat intake had a 2.9-fold higher risk for breast cancer relative to those in the highest tertile of crude fiber intake and the lowest tertile of fat intake.% The same protective effect has also been found in fibrocystic disease of the breast. In a study of the diet of 354 women with benign proliferative epithelial disorders of the breast who were compared with 354 matched controls and 189 unmatched controls, an inverse association between dietary fiber and the risk of benign, proliferative, epithelial disorders of the breasts was observed.% The protective effects of supplemental dietary fiber have also been demonstrated even in those with previous colon cancer. A total of 411 patients with colorectal adenomas were started on a 25%fat content diet, supplemented with 25 g of wheat bran daily and a capsule of 20 mg of beta-carotene daily. Patients with the combination of a low-fat diet and added wheat bran had no large adenomas at both 2 and 4 years, a statistically significant effect compared with the control g r o ~ p . ~

Dosage The clinician using dietary fiber supplements should encourage patients to start out with a small dose and increase gradually. Because water-soluble fibers are fermented by intestinal bacteria, a great deal of gas can be produced. If a patient is not accustomed to a high-fiber diet, an increase in dietary fiber can lead to greater flatulence and abdominal discomfort. The patient should start with a dosage between 1and 2 g before meals and at bedtime and gradually increase to 5 g.

TOXICOLOGY If a patient has a disorder of the esophagus, fiber supplements in a pill form are contraindicated because they may expand in the esophagus and lead to obstruction.3’ Fiber supplements in capsules appear to be slightly better tolerated than tablets but should still be used with caution. The difference is in how the tablets and capsules interact with water. One study showed that fiber (glucomannan) tablets swelled to seven times their original size within 1minute of coming into contact with water.= In contrast, fiber-filled gelatin capsules took 6 minutes to begin to swell. One very important recommendation is to consume sufficient amounts of water with the fiber supplement.

Mineral Malabsorption A number of research studies have examined the effects of fiber on mineral absorption. Although the results have been somewhat contradictory, it now appears that large amounts of dietary fiber may result in impaired absorption and/or negative balance of some minerals. Fiber as a dietary component does not appear to interfere with the minerals in other foods. However, supplemental fiber, especially wheat bran, may result in mineral deficiencies.

DRUG INTERACTIONS Fiber supplements may also inhibit the absorption of certain drugs. A good recommendation would be for the patient to take the fiber supplement at times separate from the taking of all medications.

SUMMARY A diet high in plant foods is associated with a decreased incidence of most of the degenerative diseases of Western society. Although this effect is largely due to increased levels of dietary fiber, such a diet is also high in other important nutrients, most of which are also deficient in the Western diet. It is clear from the literature that the best source of dietary fiber is whole foods, although fiber supplements do have a place in the treatment phase of specific diseases. It must be stressed that even with a diet high in dietary fiber and in which as little as 18% of the total calories are in the form of refined carbohydrates, many of the beneficial effects of dietary fiber are greatly reduced. There is no substitute for a healthy diet, that is, a diet composed of foods as close to their original forms as possible.

Role of Dietary Fiber in Health and Disease

1.Eaton SB, Eaton SB 3rd. Paleolithic vs. modem diets-selected pathophysiological implications. Eur J Nutr 2000;3967-70. 2. Ryde D. What should humans eat? Practitioner 1988;232415418. 3.Trowell H, Burkitt D. Western diseases: their emergence and prevention. In Trowell H, Burkitt D, Heaton K, eds. Dietary fibre, fibre-depleted foods and disease. London: Academic Press, 1985. 4. United States Public Health Service. Office of the Surgeon General. The Surgeon General’s report on nutrition and health. Washington, DC: U.S. Dept. of Health and Human Services, 1988. 5. National Research Council (US.). Committee on Diet and Health. Diet and health: implications for reducing chronic disease risk. Washington, DC: National Academy Press, 1989. 6. Price WA. Nutrition and physical degeneration; a comparison of primitive and modem diets and their effects. Santa Monica, C A Price-Pottenger Foundation, 1970. 7. United States Department of Agriculture. Major trends in U.S. food supply, 1909-1999.Food Review 2000;23&15. 8. Spiller GA. Dietary fiber in health and nutrition. Boca Raton, EX: CRC Press, 1994. Dietary fiber: the influence of dehition on analysis and 9. Devries JW. regulation. J AOAC Int 2004;87682-706. 10. Selvendran RR. The plant cell wall as a source of dietary fiber: chemistry and structure. Am J Clin Nutr 1984;39320-337. 11. Watt J, Marcus R. Harmful effects of carrageenan fed to animals. Cancer Detect Prev 1981;4129-134. 12. Setchell KDR. Discovery and potential clinical importance of mammalian lignans. In Cunnane SC,Thompson LU, eds. Flaxseed in human nutrition. Champaign, E AOCS Press, 199583-98. 13. Jariwalla RJ. Inositol hexaphosphate (IP6) as an anti-neoplasticand lipid-lowering agent. Anticancer Res 1999;19(5A):3699-3702. 14. Vucenik I, Shamsuddin AM. Cancer inhibition by inositol hexaphosphate (Ip6) and inositol from laboratory to clinic. J Nutr 2003;133:3778S3784S. 15.Shamsuddin AM. Metabolism and cellular functions of IP6 a review. Anticancer Res 1999;19:3733-3736. 16. Marlett JA, McBumey MI, SlavinJL. American Dietetic Association. Position of the American Dietetic Association: health implications of dietary fiber. J Am Diet Assoc 2002;102:993-1OOO. 17. Pereira MA, Ludwig DS.Dietary fiber and body-weight regulation: observations and mechanisms. Pediatr Clin North Am 2001;48: 969-980. 18. Howarth NC, Saltzman E, Roberts SB. Dietary fiber and weight regulation. Nutr Rev 2001;59129-139. 19. Reddy B, Engle A, Katsifis S, et al. Biochemical epidemiology of colon cancer: effect of types of dietary fiber on fecal mutagens, acid, and neutral sterols in healthy subjects. Cancer Res 1989;49: 4629435. 20. Sommer H, Kasper H. Effect of long-term administrationof dietary fiber on the exocrine pancreas in the rat. Hepatogastroenterology 1984;31:176-179.

21. Andoh A, Tsujikawa T, Fujiyama Y. Role of dietary fiber and shortchain fatty acids in the colon. Curr pharm Des 2003;9:347-358. 22. Velazquez OC, Lederer HM, Rombeau JL. Butyrate and the colonocyte: implications for neoplasia. Dig Dis Sci 1996;41: 727-739. 23. Martin HM, Campbell BJ, Hart CA, et al. Enhanced Escherichia coli adherence and invasion in Crohn’s disease and colon cancer. Gastroenterol2004;12780-93. 24. Lupton JR, Turner ND.Dietary fiber and coronary disease: does the evidence support an association? Cum Atheroscler Rep 2003;5: 500-505. 25. Rimm EB, Ascherio A, Giovannucci E, et al. Vegetable, fruit, and cereal fiber intake and risk of coronary heart disease among men. JAMA 1996;275447-451. 26. Liu S, Buring J, Sesso HD, et al. A prospective study of dietary fiber intake and risk of cardiovascular disease among women. J Am Coll Cardiol2002;3949-56. 27. Wok A, Manson JE,Stampfer MJ, et al. Long-term intake of dietary fiber and decreased risk of coronary heart disease among women. JAMA 1999;281:199&2004. 28. King DE, Egan BM, Geesey ME. Relation of dietary fat and fiber to elevation of C-reactive protein. Am J Cardiol2003;921335-1339. 29. Chandalia M, Garg A, Lutjohann D, et al. Beneficial effects of high dietary fiber intake in patients with type 2 diabetesmellitus. N Engl J Med 2000;342:1392-1398. 30.Giacco R, Parillo M, Rivellese AA, et al. Long-term dietary treatment with increased amounts of fiber-rich low-glycemic index natural foods improves blood glucose control and reduces the number of hypoglycemic events in type 1 diabetic patients. Diabetes Care 2000;23:1%1-1466. 31. Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr 1999;69: 30-42. 32. Ripsin CM, Keenan JM, Jacobs DR Jr, et al. Oat products and lipid lowering: a meta-analysis.JAMA 1992;2673317-3325. 33.Cohen LA. Dietary fiber and breast cancer. Anticancer Res 1999;19(5A):3685-3688. %.Yuan JM, Wang QS, Ross RK, et al. Diet and breast cancer in Shanghai and Eanjh, China. Br J Cancer 1995;71:1353-1358. 35. Baghurst PA, Rohan TE. Dietary fiber and risk of benign proliferative epithelial disorders of the breast. Int J Cancer 1995;63: 481-485. 36. MacLennan R, Macrae F, Bain C, et al. Randomized trial of intake of fat, fiber, and beta carotene to prevent colorectal adenomas: the Australian Polyp Prevention Project. J Natl Cancer Inst 1995;871760-1766. 37. Halama WH, Maudlin JL. Distal esophageal obstruction due to a guar gum preparation (Cal-Ban 3000).South Med J 1992;85:642-645. 38. Henry DA, Mitchell As,Aylward J, et al. Glucomannan and risk of oesophageal obstruction. Br Med J 1986;292:591-592.

Sports Nutrition Gregory S. Kelly, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Introduction 677 Sports Nutrition for Strength Athletes 677 Creatine Monohydrate 677 beta-Hydroxy-beta-Methylbutyrate 680 Whey Protein 681 Soy 682 Phosphatidylserine 683 Arginine 683 Branched-Chain Amino Acids 683 Glutamine 684 Ornithine alpha-Ketoglutarate 685 Vitamin C 685 Boron 685 Chromium 685

INTRODUCTION The greater focus on fitness and the subsequent research in the exercise field have expanded the role of nutrition in sports performance. Because there is widespread belief among athletes that special nutritional practices will enhance their achievements in competition, the use of supplements has become common. This chapter reviews the efficacy of some of supplements currently promoted to athletes. The topic has been divided into two broad categories, sports nutrition for strength athletes and sports nutrition for endurance athletes. This division is to a degree arbitrary, so some of the supplements discussed might be applicable for athletes in both categories. For more information comparing and contrasting the physiology of muscular endurance and strength, see Chapter 37.

SPORTS NUTRITION FOR STRENGTH ATHLETES Creatine Monohydrate Creatine monohydrate has become one of the most popular supplements in the history of body-building. The original version of this chapter was reprinted with permission from Alternative Medicine Review 1997:2:282-295.

Selenium 686 Vanadium (Vanadyl Sulfate) 686 Zinc 687 Summary 687 Sports Nutrition for Endurance Athletes 687 Panax ginseng 687 Eleutherococcus senticosus 689 Carnitine 689 Choline 691 Coenzyme Qjo (Ubiquinone) 691 Pyridoxal-alpha-Ketoglutarate 691 Pyruvate 692 Performance Drinks 693 Summary 695

It is used primarily to increase strength and lean body mass and may enhance muscle energy recovery.' Having been extensively studied since 1927, creatine has shown consistent results in promoting these effects in experimental subjects? In humans, more than 95% of the total creatine content is located in skeletal muscle. Approximately one third is in its free form as creatine, also known as methylguanidinoacetic acid, and the remainder is present in a phosphorylated form as creatine phosphate (also called phosphocreatine). Creatine phosphate is utilized within skeletal muscle storing high-energy phosphate bonds. Creatine is formed in the liver, kidney, and pancreas. Initially, arginine and glycine combine to produce guanidinoacetate. A methyl group from Sadenosylmethionine (SAMe) is then transferred, resulting in the formation of creatine. The by-product of this reaction, S-adenosylhomocysteine, is subsequently hydrolyzed into homocysteine and adenosine. For optimal endogenous production of creatine, the amino acids arginine, glycine, and methionine must be available as substrates. Additionally, magnesium is required as a cofactor to form SAMe from methionine, and BIZ, folic acid, and betaine are required to recycle the homocysteine to methionine for reuse as SAMe. 677

Although creatine can be synthesized endogenously as just described, it is also found in a variety of foods in varying concentrations. The richest source overall is wild game, but the richest source in domesticated animals is beef (lean red meat); 1.1 kg of fresh uncooked steak contains about 5 g of ~reatine.~ Fish is also a good source, especially herring, salmon, and tuna. However, it is believed that creatine in foods may be destroyed or reduced signhcantly by cooking. Creatine is transported to muscle tissue where it exists in equilibrium with creatine phosphate. Creatine phosphate spontaneously converts to creatinine (estimated to be at a rate of about 2 g/day for a 150-lb male) and is then excreted in the urine.4 Although part of this turnover can be replaced through dietary sources of creatine, especially meat and fish, the remainder must be supplied by endogenous synthesis. For this reason, there is a constant drain on arginine, glycine, methionine, and nutritional cofactors to maintain a supply of creatine and creatine phosphate. In vegetarians, daily needs must be met exclusively by endogenous synthesis. When dietary creatine is high, the synthetic pathway is correspondingly regulated d ~ w n w a r d . ~ In addition to its use in skeletal muscle, some creatine is used by cardiac muscle. Patients with chronic heart failure might have decreased stores of creatine and have been shown to have better exercise capacity after administration of creatine.6One week of creatine supplementation (20 g/day) to patients with chronic heart failure increased skeletal muscle energy-rich phosphagens and performance for both strength and endurance.' Creatine phosphate produces energy in the form of adenosine triphosphate (ATP) in muscle cells for about 10 seconds of activity.After it is depleted, the muscle shifts to anaerobic glycolysis for fuel. It is thought skeletal muscles are capable of storing sigruficantly more creatine than is generally supplied by the diet and by endogenous synthesis. For this reason, after an oral dose of creatine monohydrate, more serum creatine is available for storage in muscle tissue. Over time, this greater dietary consumption can allow the muscle to become saturated with creatine. When the muscle has this extra creatine, it should theoretically be able to delay fatigue and refuel itself more quickly during high-intensity, short-duration exercise and so should be capable of greater work. It is hypothesized that when muscle absorbs creatine, the creatine brings water intracellularly with it, so the muscle becomes more "hydrated." It is estimated that muscles are about 70% water, so this process results in a larger, fuller muscle. Evidence suggests when a cell is well hydrated it might accelerate its synthesis of new proteins and might also minimize protein degradation? One gram of creatine monohydrate or less in water produces only a modest rise in plasma creatine concentration; however, a 5-g oral dose has been shown to significantly

increase plasma creatine concentration. Repeated dosing with 5 g of creatine monohydrate every 2 hours sustains the plasma concentration at around 1000 mmoVL.3 Studies have shown that feeding large amounts of creatine (typically 20-30 g/day for 5 days) raises muscle total creatine (and phosphocreatine) ~ o n t e n t . ~ The ,~ extent of the rise normally observed is inversely related to the presupplementation leve1.3r8Vegetarians, because they have a very low dietary creatine intake and low to normal total creatine content, would be expected to show large increases? Muscle creatine uptake appears to be augmented substantially in individuals adhering to a program of repeated high-intensity exercise during the period of Supplementation? Resynthesis of phosphocreatine after 1 minute of recovery from intense muscular contraction is accelerated in individuals consuming creatine.8 Adequate vitamin E status might also be needed to optimize creatine uptake? In one study of eight subjects, muscle biopsy samples were taken after 5 days of ingestion of 20 g creatine per day. In five of the eight subjects, there were substantially higher muscle total creatine concentration and creatine phosphate resynthesis during recovery. In the remaining subjects, creatine supplementation slightly raised total creatine concentration but did not increase creatine phosphate resynthesis.* In three subjects measured, uptake into muscle was greatest during the first 2 days of supplementation, accounting for 32% of the total creatine monohydrate given orally per day. In these subjects, renal excretion was 40%, 6l%, and 68% of the creatine dose over the first 3 days, respectively. Approximately 20% or more of the creatine taken up was measured as phosphocreatine, but no changes were observed in the muscle ATP ~ o n t e n t . ~ Oral creatine monohydrate supplementation has also been shown, in a patient with extrapyramidal movement disorder and extremely low serum and urine creatinine concentrations, to significantly increase brain creatine levels. Phosphorus magnetic resonance spectroscopy of the brain revealed no detectable creatine phosphate before oral substitution of creatine and a sigrufrcant increase afterward. Partial restoration of cerebral creatine concentrations was accompanied by improvement of the patient's neurologic symptoms. Oral substitution of arginine, a substrate for creatine synthesis, was unable to elevate cerebral creatine levels.1° Four months of 0.10 g/kg/day of creatine monohydrate supplementation has also been shown to improve handgrip strength and increase fat free mass in the dominant hand as well as to reduce a marker of bone breakdown in boys with Duchenne muscular dystrophy.'l Creatine supplementation has been shown to improve performance in situations in which the availability of creatine phosphate is important, such as very-highintensity exercise, especially when repeated bursts of

Sports Nutrition ~

energy are required with short recovery periods.’”16 An investigation of 20 young male soccer players 15 to 19 years of age were randomly assigned to take a creatine-monohydrate supplement (three 10-g doses) or placebo for 7 days. Researchers found that supplementation with creatine resulted in soccer-specific skill performance than placebo, with no changes in endurance.17 Several studies have documented creatine monohydrate’s effect on muscle size and strength. Typically, after a 5- to 7-day loading dose, there is an increase in the amount of work done in repeated bouts of maximal exercise and a gain in body mass of between 0.5 and 1kg.13,15 One group of researchers reported that 28 days of supplementation (20 g/day) produced a fat-free mass increase of 1.7 kg.12 Although creatine supplementation improves performance in sprint-trained cyclists, it does not appear to improve endurance performance.’* One study actually reported a worsening in performance during prolonged continuous exercise after creatine supplementation. This finding remains unexplained, although the researchers believe that the increase in body mass due to supplementation might be a contributing factor.19 Research shows that creatine supplementation has no measurable effect on respiratory gas exchange and blood lactate concentrations during either incremental submaximal exercise or recovery, suggesting that creatine phosphate produces energy in the form of ATP in muscle cells for about 10 seconds of activity. After it is depleted, the muscle must shift to anaerobic glycolysis for fuel. Creatine supplementation does not influence substrate utilization during and after this type of exercise.2O Results of an unpublished human trial indicate that insulin might be a potent upregulator of a muscle’s ability to take in creatine. This has resulted in many users supplement creatine monohydrate with a simple carbohydrate (such as glucose, dextrose, or maltose), which simultaneously causes a release in insulin.In a 4-week trial, large increases in speed, anaerobic power, and lean body mass, along with a reduction in body fat, were reported in individuals receiving doses of 20 g/day of creatine for the first 5 days, followed by 10 g/day for the remainder of the 4 weeks. An even greater response in these parameters was reported in the athletes using a creatine-carbohydrate mix, which contained creatine monohydrate, dextrose, taurine, disodium phosphate, magnesium phosphate, and potassium phosphate.

Dosage Typically, dosing of creatine monohydrate follows a loading and a maintenance cycle. During the loading period, larger doses of creatine monohydrate are ingested for 5 to 7 days. A typical dose for individuals weighing less than 225 pounds is 5 g four times per day, and heavier individuals might take up to six doses per day. The maintenance

dose would be 0.03 g per kg of body weight.21*22 Larger doses are probably not of any greater benefit, because the capability of muscle to take in and store creatine is finite? In fact, this dosing schedule might exceed the ability of most individuals to incorporate creatine into muscle tissue, as evidenced by the renal excretion rate of creatine (40%-68% of the supplemented dose) reported in individuals given 30 g/day3 At least one later study supports the possible use of lower oral doses. One study reported that 3 g/day for 28 days increased muscle creatine and creatine phosphate stores to a level comparable to those in a loading phase.21 Most of the gains in size and strength occur within the first month, after which muscles are generally saturated with creatine. Evidence indicates that these gains will remain while supplementation continues but will gradually disappear after the supplement is discontinued. Typically, levels of creatine drop back to presupplementation levels about 1month after supplementation is discontinued. The increases in size and strength resulting from improved muscle cell hydration also disappear over this time. However, actual gains in muscle mass due to increased work capacity during creatine ingestion remain. Anecdotal reports suggest that 20% to 30%of individuals who take creatine do not experience an increase in muscle mass or strength. Currently, this finding is unexplained; however, individuals with lower initial tissue levels as well as those with greater ability for creatine uptake are most likely to Because of the success of creatine monohydrate, several other forms have become available, including creatine phosphate and creatine citrate. These are claimed to produce similar results; however, creatine monohydrate is the only form shown, to date, to increase strength, lean body mass, and tissue creatine phosphate levels.

Toxicity Reported side effects of creatine supplementation include gastric disturbance, headaches, heat exhaustion, muscle cramping, stroke, clenched teeth, and the sound of blood rushing in the ear. One of us (PBB) has experienced this blood rushing sound while taking a creatine supplement and found it quite disturbing; the tinnitus resolved within 2 days of discontinuing creatine use. Creatine supplementation might cause serum creatinine levels to rise. This rise is due to the increase in muscle creatine phosphate and its subsequent spontaneous conversion to creatinine. Most of the studies of creatine have supplemented creatine for only short periods. In one study, long-term supplementation with only lg/day was utilized.” In a second study, blood chemistry analyses were performed in 19 professional basketball players from Spain, who ingested 5 g of creatine monohydrate daily and were studied during three competition seasons.

Blood samples were collected in the morning after an overnight fast, five times during each of the three official competitions spanning the periods of September 1999 to June 2000, September 2000 to June 2001, and September 2001 to June 2002. Standard blood chemistry values, except levels of creatinine and creatine kinase, were found to be normal at all times.= More study is needed, but at this time, there is no indication that long-term, high-dose creatine supplementation has major adverse side effects. Creatine may serve as a precursor for amino-imidazoazaarenes, a class of mutagens found in creatine-rich foods such as fish, chicken, beef, and pork. It has been postulated that these azaarenes may form DNA adducts and subsequently could interfere with proper functionality of the nucleic acids in the cells. Conversely, some researchers consider creatine a genomeceutical, which means that it can beneficially affect gene expression? Clearly, more information is needed to resolve these apparent paradoxical effects. Some concern exists that use of caffeine(0.5 mg/kg/day) can have a negative impact on the effectiveness of creatine. However, in at least one study, participants were instructed to dissolve the creatine monohydrate in tea or coffee before ingestion. Body weight increase was still observed in seven of eight subjects, and all subjects had increased muscle total creatine and phosphocreatine resynthesis8Further studies demonstrate that there is no measurable effect of caffeine on the analysis of strength change?6 These results suggest that caffeine does not negate the effects of creatine supplementation, but until more is known it might be best to minimize caffeinated substances, or to drink them several hours away from creatine supplementation, for optimal results. Creatine supplementation is widely practiced by athletes in many sports and does not contravene current doping regulations? Because creatine supplementation does not enhance performance in endurance athletes and evidence suggests an actual decline in performance, endurance athletes should avoid creatine supplementation. In athletes concerned with improving strength, body composition, or short-duration, repetitive, high-intensity exercise, one of us (GK) recommends that creatine monohydrate be incorporated into any supplementationprotocol. Although quicker results can be seen after a loading dose, the cost-effectiveness of the 3 g/day dose might be a more appealing option for many athletes. Nursing mothers and children should never be given creatine supplementation?

beta-Hydroxy-beta-Methylbutyrate Beta-hydroxy-beta-methylbutyrate(HMB) is a relatively new product, being available in limited supply only since the end of 1995. The nutritional use of HMB for nitrogen retention has been patented by the Iowa State

University Research Foundation and is licensed to Metabolic Technologies. HMB is a leucine metabolite. How HMB is synthesized from leucine in humans has not yet been established; however, evidence in animals suggests that the majority of circulating HMB is formed after the transamination of leucine to alpha-ketoisocaproate with its subsequent oxidation to HMB.27It has not been determined, either, to what extent HMB is normally produced in vivo or which specific cofactors might influence its production. Although the mechanism of action of HMB is still equivocal, HMB is hypothesized to decrease muscle protein turnover and to possibly work primarily by minimizing protein degradation. Suggestive evidence of HMB’s blocking of catabolism is based on its ability to decrease urinary 3-methylhistidine (a marker of muscle breakdown) and to decrease plasma levels of creatine phosphokinase and lactic dehydrogenase.= Anecdotal reports indicate that individuals who work out more often and more intensely get the best results with HMB. This is important because typically, the more an individual works out, the more muscle catabolism also occurs; so at a certain point, the anabolic gains achieved by stimulating the muscles through training are offset by the catabolic effects of frequent, high-intensity workouts. HMB’s anticatabolic effects might move this balance point further in the direction of anabolic growth, allowing an individual to train more often and still receive positive results in strength and mass gains. In a human study conducted over a 3-week period, 3 g/day of oral HMB supplementation was shown to decrease body fat, increase lean mass and strength, and reduce muscle damage in individuals beginning resistance-training exercises. In this trial, participants also consumed either 117 or 175 g/day of protein. Although protein intake did not seem to affect strength, participants with higher protein intakes, independent of HMB supplementation, appeared to have greater increases in lean body massz8Because these results came from individuals who had not previously engaged in weight training, doubt existed as to whether they would be reproducible in body-builders or other athletes who had already engaged in long-term resistance training. However, in a subsequent abstract, the researchers have indicated that HMB feeding resulted in equal increases in strength, body composition, and decreased fat in both trained and untrained indi~iduals.2~A metaanalysis of HMB research considered studies involving HMB supplementation for at least 3 weeks with resistancetraining 2 or more times a week. HMB was found to sigruficantly increase net lean mass gains by 0.28% per week and strength gains by 1.09%and 1.40%per week.30 At this point, the primary concern about the usefulness of HMB is anecdotal evidence indicating that many individuals have not experienced expected results.

Sports Nutrition

or performance in trained athletes. However, whey has been shown to promote growth and enhance nitrogen balance in experimental animals, low-birth-weight infants, and burn ~ i c t i m s . 3 ~ - ~ ~ Whey protein is rich in substrates for glutathione synthesis%;it also contains substantially more cysteine, Dosage which is considered a rate-limiting step in glutathione synthesis, than casein. Whey contains high amounts of The recommended dosage for HMB is 3 g/day. Because glutamine and glycine. relatively high protein intake was reported in the study Glutathione, a powerful antioxidant, is involved in demonstrating HMB's efficacy, and because whether metabolic detoxification pathways. The role free radithe same results will occur with a low-protein diet is cals play in the development of exercise-induced tissue unknown, a similar protein intake of between 120 and damage, or the protective role antioxidants might play, 175 g/day for athletes supplementing their diets with remains to be completely elucidated. Research has indiHMB might produce best results. cated that free radical production and subsequent lipid Toxicity peroxidation are normal sequelae to the rise in oxygen consumption with e~ercise.3~ However, physical training Because HMB is such a new supplement, no information has been shown to result in an augmented antioxidant is available on its long-term safety. One analysis of nine system and a reduction in lipid peroxidation. Supple3- to 8-week studies in which subjects were fed 3 g HMB mentation with antioxidants appears to further reduce per day found that compared with the placebo, HMB lipid peroxidation but has not been shown to enhance supplementation resulted in some increase of stiff joints, exercise performance.% although the researchers believed that this effect probaGlutathione levels have been shown to diminish with bly occurred by chance. Furthermore, the subjects given e~ercise.3~ Additionally, running a marathon causes a HMB had enhanced appetite, less diarrhea, and positive large rise in the tissue content of oxidized glutathione changes in cardiovascular risk factors such as low(189%)at the expense of reduced glutathione.40Although density lipoprotein (LDL) cholesterol value and blood pressure, as well as a perception of greater ~ e l l - b e i n g . ~ ~no information is available on the effects of resistance exercise and glutathione levels, it is hypothesized that a Whey Protein higher intake of antioxidants might protect against minor muscle injuries?' Whey protein, often referred to as lactalbumin, is currently Whey protein is more efficient at inducing supernorthe supplemental protein source of choice for many bodymal glutathione levels than a cysteine-enriched casein builders and strength athletes. Whey proteins represent A whey-rich diet has been shown to increase the major proteins in human breast milk, as opposed to heart and liver tissue glutathione content in rats. The bovine milk, which is composed primarily of casein with lesser amounts of whey. Whey comprises alpha-lactoglob- whey protein diet appeared also to improve longevity when fed at the onset of senescence.Q Whey-based ulin,beta-lactoglobulin,bovine serum albumin (BSA), and formula enhances cysteine retention and results in greater immunoglobulins (Igs) ( 1 6 1 , IgG2, secretory IgA, and taurine excretion, which is thought to be a reflection IgM). Other components of the ladalbumin fraction are of greater taurine st0res.4~Whey protein fed to three enzymes, iron-binding proteins, calcium, potassium, individuals who were seropositive for human immusodium, phosphorous, and vitamins A, C, B1, BD B3, B,, BID nodeficiency virus (HIV) over a 3 months, at doses folic acid, and biotin. Whey is a balanced source of essenincreasing progressively from 8.4 to 39.2 g/day, resulted tial amino acids and peptides with a high protein effiin progressive weight gain and higher glutathione ciency ratio. It is considered an excellent source of sulfur levels.44 amino acids (methionine and cysteine) as well as Experimental studies suggest that the whey protein branched-chain amino acids (BCAAs) (leucine, isoleucine component of milk might exert an inhibitory effect on the and valine) and glutamine (see sections on BCAAs and development of several types of tumor. It is thought that glutamine for information on their potential benefits). the rich supply of substrates for glutathione synthesis Whey transits the stomach quickly and is rapidly contributes to this inhibitory effe~t.4~ In experimental absorbed from the human intestine. The beta-lactoglobanimals, a diet consisting of 20 g of whey per 100 g of ulin component remains soluble in the stomach and diet has been shown to be more protective than similar empties rapidly as an intact protein needing further diets utilizing casein, soybean, or red meat against hydrolysis by pancreatic enzymes. Casein, on the other dimethylhydrazine-induced intestinal cancers.&Peptides hand, transits the stomach slowly? from whey protein have also been shown to have No studies exist comparing the impact of different antithr~mbotic~' and immunoenhan~ing4~f'~ activities. protein sources on nitrogen balance, body composition, Because HMB is thought to function primarily as an anticatabolic substance, it is possible these individuals did not train with enough intensity to optimize its effect. The other possibility is that, like creatine monohydrate, HMB might be ineffective in some people.

Dosage The routine use of an after-workout whey protein shake might be the most important nutritional supplementation habit for enhancing body composition. It is probably in this manner that whey can be best utilized by athletes concerned with maximizing lean body mass and Strength. Amino acid availability after a workout regulates protein synthesis and degradation. Because of the anabolic effects of insulin on protein synthesis and protein degradation, a rapid synergistic response occurs when both amino acids and insulin rise after a protein-containing It is thought that the body is highly insulinsensitive after exercise and preferentially shuttles carbohydrates and protein into muscle cells rather than fat cells. Experts believe that this sensitivity gradually declines after workout for about 2 hours, until it again reaches normal sensitivity. There is evidence that protein combined with carbohydrates and/or creatine might be more effective than protein alone. A carbohydratewhey protein supplement has been shown to be more effective in generating a plasma insulin response than either a carbohydrate or a protein supplement alone during recovery from prolonged exhaustive exercise. The rate of muscle glycogen storage was also sigruficantly faster during the carbohydrate-protein treatment. The participants in this study ingested 112 g of carbohydrate and 40.7 g of protein immediately after each exercise bout.M Similar studies using protein, carbohydrates, and fats showed improvement in glycogen resynthesis using protein and carbohydrate and no change when fat was included.52 In a &week study, men who supplemented their diets with a combinationof whey protein and creatine together (1.2 g/kg/day and 0.1 g/kg/day, respectively) had significantly greater increases in lean tissue mass and bench press weight than those who took only whey protein or placebo. But not all strength measures are improved with creatine and/or whey supplementation. In this study, subjects who took creatine and/or whey supplements found no difference in squat strength and knee flexion peak torque versus those in subjects who received placebo.% Whey is an excellent choice as a protein source for the after-workout shake because of its rapid transit into the small intestine as well as its high levels of BCAAs and glutamine. Glucose polymers or maltodextrins are considered to be the best form of carbohydrates to use because of their ability to stimulate an insulin response. Fat should not be added because it might slow transit time and reduce the insulinresponse.

Toxicity The primary concerns about supplementing the diet with whey protein are the possibility of food allergies, the

lactose content, and proposed links to insulindependent diabetes mellitus (IDDM).Although the possibility of food allergies from whey must be considered, whey is probably is no more, and is possibly less, antigenic than soy, casein, or egg-based protein supplements. A significant concern might be the method of processing of the whey protein, because high temperatures during heating or drying can generate browning reaction products through covalent interaction of proteins and lactose. Browned proteins have lowered digestibility and are thought to result in greater uptake of intact protein through intestinal mucosa. All whey protein available contains some lactose, although many preparations have very low amounts. The BSA component of whey has been implicated as a possible trigger for IDDM in children. The amino acid sequences of the beta-cell protein, found on the insulinsecreting beta cells of the pancreas, and BSA are similar. Because elevations of anti-BSA antibodies have been found in sera from children who later had IDDM, it has been proposed that absorption of BSA, or partially digested fragments of BSA, stimulates the immune system, which then incorrectly destroys beta cells” One study reported the prevalence of anti-BSA antibodies as 52%in children who had IDDM for less than 1year, 47% in children with IDDM for longer than 1 year, and 28% in the control group. The researchers concluded that the prevalence of anti-BSA antibodies is higher in subjects with IDDM than in control subjects; however, because of the large overlap of antibody titers observed in patients and control subjects, anti-BSA antibodies were neither sensitive nor specific markers of IDDM?5 Other studies have found that IgG antibodies to BSA were not significantly increased at the onset of IDDM.56Currently, the exact nature of the relationship between BSA and IDDM remains unclear.

SOY Soy protein is a source of antioxidant phytochemicals. Research is beginning to show that soy supplementation may help decrease levels of lipid peroxides induced by exercise stress. One study examined the response of serum lipid peroxides to the combination of moderateintensity, weight-resistance exercise plus intake of soy protein. In this study, 18 young adult men consumed either 40 g of soy protein per day or an antioxidant-poor whey protein for 4 weeks before a session of moderateintensity weight-resistance exercise. In the soy group, values for serum lipid peroxides at 5 minutes and 3 and 24 hours after exercise were decreased, whereas the whey group showed the depression only at 24 hours. Interestingly, in both the soy and whey groups, a small rise was seen for the cytokine interleukin-8. The researchers suggest that this finding is consistent with the idea that an exercise session does induce moderate muscle stress and inflammati0n.5~

Sports Nutrition

Dosage The preceding study used 40 g per day for a young adult male. Given the benefits of soy for a number of conditions related to the menstrual cycle, soy may be a good choice for some women. As a well-known highly antigenic food, plus current controversial information regarding estrogen-dependent cancers, high-dose supplementation with soy should be considered on an individual basis.

Phosphatidylserine Phosphatidylserine is being widely used by individuals engaged in resistance training, primarily owing to its presumed ability to prevent muscle tissue degradation. Phosphatidylserinehas been shown to affect the body's production of glucocorticoids.Although the mechanism of action of phosphatidylserine is still unknown, an effect on the hypothalamic-pituitary-adrenal axis has been Phosphatidylserine is formed by adding a serine to a phosphatidyl group. This requires pyridoxal5'-phosphate (active B6) and occurs in the same biochemical loop involved with phosphatidylcholine, choline, betaine, and dimethylglycine metabolism. Physical exercise induces a sigruficant rise in plasma epinephrine,norepinephrine, adrenocorticotmpichormone (ACTH), cortisol, growth hormone (GH), and prolactin (PRL). It is theorized that preventing the increase in cortisol subsequent to intense exercise would prevent the excess muscle tissue breakdown. In one study, pretreatment of eight healthy men with either 50 or 75 mg of intravenous brain cortexderived phosphatidylserine within 10 minutes of the start of exercise blunted the ACTH and cortisol responses to physical stress.59 Oral administration of phosphatidylserinederived from brain cortex, 800 mg/day for 10 days, sigruficantly blunted the ACTH and cortisol responses to physical exercise (p = 0.003 and p = 0.03, respectively), without affecting the rise in plasma GH and PRL. Although participants also experienced reductions in plasma cortisol concentrations at a dose of 400 mg/day of phosphatidylserine, the area under the curve of plasma cortisol was sigruficantly lower after the higher dose of 800 mg/day? Although the results of this preliminary work appear promising, no trials to date have reported an increase in strength or an improvement in body composition after phosphatidylserine supplementation. Until these results are determined, claims of phosphatidylserine's ability to reduce muscle tissue catabolism should be regarded as unsubstantiated.

Arginine The amino acid arginine is used occasionally by bodybuilders to stimulate growth hormone secretion. It was very popular in the mid-198Os, but interest in it has since

waned. Arginine has been shown to stimulate wholebody protein synthesis.@Several studies have shown its ability to stimulate growth hormone and insulin-like growth factor I secretion and improve nitrogen balance after intravenous administration; however, equivocal results have been obtained after oral supplementation. Oral arginine/lysine (3 g/day of each) is apparently not a practical means of enhancing GH secretion in older men over the long term.6l Additionally, it is debatable whether increasing growth hormone levels in people not already deficient has an anabolic effect. Arginine is required for creatine synthesis, and some believe it will enhance synthesis if used as a supplement. In rats, arginine and glycine supplementation increased muscle creatine.62One study reported that individuals receiving arginine and ornithine, 5 days a week for 5 weeks, had higher gains in strength and enhancement of lean body mass than control subjects. Dosages amounted to 2 or 1g each of L-arginine and L-ornithine taken orally, and 600 mg of calcium and 1 g of vitamin C as placebos. Subjects taking the arginine and ornithine also had a significantly lower urinary hydroxyproline value, a marker of tissue breakdown, than subjects receiving placebo. The researchers of this study concluded that arginine and ornithine, in conjunction with a high-intensity strength training program, can improve strength and lean body mass and minimize tissue breakdown.@Arandomized controlled study of patients with congestive heart failure showed that supplementationof oral arginine at 9 g a day for 7 days prolonged exercise duration, probably through its nitric oxide-induced peripheral vasodilatory effects.64

Dosage The typical dosage of arginine is 2 g/day. On the basis of results reported by Elam et a1,63 a combination of arginine and ornithine might exert a positive impact on body composition and strength; however, no additional research has substantiated these findings.

Toxicity See Chapter 174 for a discussion of a possible relationship between increased dietary arginine and the incidence of herpes simplex.

Branched-Chain Amino Acids Leucine, isoleucine, and valine are regarded as BCAAs because of their similar chemical structures and interlocking methyl groups. Exercise results in marked alterations in amino acid metabolism within the body. The BCAAs, especially leucine, are particularly important because they contribute, as both energy substrates and nitrogen donors, to the formation of alanine, glutamine, and aspartate. Calculations indicate that the recommended dietary intake of leucine is inadequate, because it is lower than the measured whole-body rates of

Syndromes and Special Topics leucine oxidation. This inadequacy is exacerbated in individuals who are physically active.65 A larger supply of BCAAs appears to have a sparing effect on muscle glycogen degradation during exercise.% Short-term (3-4 hours) infusion of BCAAs has been shown to suppress muscle protein breakdown.67 In humans nourished parenterally provision of balanced amino acid solutions and of only the three BCAAs cause similar improvements in nitrogen balance for several days." Administration of BCAAs can greatly increase their concentration in plasma and subsequently their uptake by muscle during exercise.& Long-term exercise after BCAA administration results in sigruficantly greater muscle production of ammonia, alanine, and glutamine, as well as lower lactate production, than is observed during exercise without BCAA supplementation.@ Although evidence indicates that BCAAs might be significant in enhancing protein synthesis or minimizing protein degradation, supplementation with these amino acids has not produced sigruficantchanges in body composition. If whey or another top-quality protein formula is being used, adequate amounts of BCAAs are provided.

GIutamine Glutamine is the most abundant amino acid in the blood and in the free amino acid pool of skeletal muscle. Glutamine stimulates the synthesis and inhibits the degradation of proteins, is an important vehicle for the transport of nitrogen and carbon within the tissues, stimulates the synthesis of hepatic glycogen, and is an energy source for cell division.69Because glutamine deficiency can occur during periods of metabolic stress, it has led to the reclassification of glutamine as a conditionallyessential amino acid.7O Glutamine is also a precursor for the synthesis of amino acids, proteins, nucleotides, glutathione, and other biologically important molecules. Glutamine is considered to have an anabolic effect on skeletal muscle. It stimulates the synthesis and inhibits the degradation of proteins. Experiments with various animal models have demonstrated that glutamine supplementation can result in better nitrogen homeostasis with conservation of skeletal muscle?O The mechanism by which glutamine affects skeletal muscle protein turnover and, thus, muscle protein balance is unknown. However, glutamine has an anabolic effect of promoting protein synthesis and also might reduce protein breakdown?' Glutamine has been shown to increase cell volume, whereas insulin and glutamine together seem to work synergisticallyto enhance cellular hydration. The effects of glutamine in skeletal muscle include the stimulation of protein synthesis,which occurs in the absence or presence of insulin, the response being greater with insulin.n During various catabolic states, such as infection, surgery burns, and trauma, glutamine homeostasis is under stress, and glutamine reserves, particularly in

the skeletal muscle, are depleted. In these conditions, the body requirements for glutamine appear to exceed the individual's muscle deposits, resulting in a loss of muscle mass.73In critically ill patients, parented administration of glutamine reduces nitrogen loss and lowers mortality? With regard to glutamine metabolism, exercise stress can be viewed similarly to other catabolic stresses. Plasma glutamine concentrations increase during prolonged, high-intensity exercise. However, during the postexercise recovery period, plasma concentrations diminish sighcantly. Several hours of recovery are required before plasma levels are restored to preexercise levels. If recovery between exercisebouts is inadequate, the acute effects of exercise on plasma glutamine concentrations can be cumulative. It has been observed that overtrained athletes appear to maintain low plasma glutamine levels for months or ~ e a r s .Some 7 ~ experts believe that reduced concentration of plasma glutamine can provide a good indication of severe exercise stress.75Research suggests that, after exercise, greater availability of glutamine promotes muscle glycogen accumulation by mechanism possibly including diversion of glutamine carbon to After trauma there is a loss of nitrogen, with a concomitant reduction of skeletal muscle protein synthesis. This is accompanied by a decrease in the stores of muscle free glutamine. Nutritional support with either glutamine or its carbon skeleton, alpha-ketoglutarate, has been shown to counteract the postoperative drops in muscle free glutamine stores and muscle protein synthesis." One small study suggests that oral glutamine increases growth hormone release. In this work, an oral glutamine load (2 g) was administered to nine healthy subjects to determine the effect on plasma glutamine, bicarbonate, and circulating growth hormone concentrations. Eight of nine subjects responded with increases in plasma glutamine concentrations at 30 and 60 minutes before returning to the control value at 90 minutes. Ninety minutes after the glutamine administration load, concentrations of both plasma bicarbonate and circulating plasma growth hormone were elevated.78Even with this theoretical support, clinical trials studying glutamine as an exercise performance enhancer are not encouraging. In a double-blind, placebo-controlled, crossover study, six resistance-trained men performed weightlifting exercises after the ingestion of either glutamine or glycine at 0.3 g/kg body weight or of a placebo (two subjects/group). One hour after ingestion, subjects performed four total sets of exercise to momentary muscular failure, including two sets of leg presses at 200% of body weight and two sets of bench presses at 100% of body weight. Despite glutamine's possible role in exercise, there were no actual differences in the average number of maximal repetitions performed in the leg press or bench press exercises among the three group^.^ Other studies using dosages of 0.3 to 0.9 g/kg body weight

Although some advocates recommend as much as 30 g of glutamine, it is likely that only marginal benefits are found at supplementary levels higher than 2 to 3 g/day.

other hand, a suboptimal vitamin C status results in an impaired working capacity that can be normalized by restoring vitamin C body pools.83 A potent antioxidant required for collagen synthesis, ascorbic acid might help protect muscles from excessive damage due to training or trauma. Data suggest that prior vitamin C supplementation might exert a protective effect against exercise-induced muscle damage.84 Ascorbic acid also might decrease cortisol productions5 and may have a role in facilitating an adequate response to stress.%

Ornithine alpha-Ketoglutarate

Dosage

omithine alpha-ketoglutarate (OKG) is a salt formed of two molecules of ornithine and one molecule of alphaketoglutarate. OKG has been successfully used via enteral and parenteral routes in burn, trauma, and surgical patients as well as in chronically malnourished subjects. Depending on the metabolic situation, OKG treatment decreases muscle protein catabolism and/or increases protein synthesis. In addition, OKG promotes wound healing. The mechanism of action of OKG is not fully understood, but the secretion of anabolic hormones (insulin, human growth hormone), and the synthesis of metabolites (glutamine,polyamines, arginine, ketoacids) might be involved.82 This supplement has been available for more than a decade. It has been used successfully in hospitalized bum victims to slow protein loss. Only one study appears to have evaluated the effect of OKG on performance. In this study, OKG (10 g/day with 75 g of carbohydrates) was given for 6 weeks. The subjects receiving OKG experienced a significant increase in bench-press strength and biceps circumference compared with those receiving placebo. Body weight and percentage fat were not different between the groups. No differences in growth hormone levels were seen between the groups. Body composition changes were seen in several individuals in the OKG group, but no sigruficance was found either within or between experimental gr0ups.8~ Anecdotal reports from some individuals supplementing their diets with OKG indicate increased appetite and better disposition to train. Some anecdotal reports claim great results, whereas others describe no improvement.

Because of ascorbic acid’s potential for minimizing muscle damage and cortisol-induced muscle catabolism, 1to 3 g should be taken daily.

also demonstrated no changes in exercise performance, body composition, or muscle protein degradation in young healthy adults.sOfilIt is possible that beneficial effects of glutamine are best detected only in patients with chronic illness and those with compromised physiology rather than in normal, healthy individuals.

Dosage

Dosage The recommended dosage of OKG is 10 g along with a 75-g carbohydrate drink.

Vitamin C There have been several investigations during the past five decades of the potential effect of high-dose vitamin C (ascorbic acid) supplementation on physical performance. However, the results have been equivocal. Most studies could not demonstrate an effect. On the

Boron A proliferation of athletic supplements has been marketed touting boron as an ergogenic aid (a substance that can enhance work output) capable of increasing testosterone. Although this might to be true in some populations under specific conditions, boron’s impact on testosterone is still equivocal. Boron appears to raise testosterone levels in rats in a time- and dose-dependent mar1ner.8~In postmenopausal women, increasing dietary intake of boron from 0.25 to 3.25 mg/day has been reported to more than double plasma testosterone levels.88 In a subsequent study of healthy men, boron supplementation raised the plasma concentrations of both estrogen and testo~terone.~~ However, one study reported that changing boron intake had no impact on testosterone levels in postmenopausal women?O The effect of boron supplementation was investigated in 19 male body-builders age 20 to 27 years. Ten subjects were given a 2.5-mg boron supplement and nine a placebo every day for 7 weeks. Both groups demonstrated sigruficant increases in total testosterone, lean body mass, and one-repetition maximum squat and bench-press. However, analysis of variance indicated no significant effect of boron supplementation on any of the dependent variables. The researchers concluded that the gains were a result of 7 weeks of body-building, not of boron supplementation?l

Dosage It is prudent to supplement the diet with 3 mg/day of boron to ensure against deficiency; however, an expectation of increased strength and improved body composition is unrealistic.

Chromium Chromium is highly promoted in body-building circles as a fat-burning supplement and as an aid in increasing

lean mass. Available research does not support either of these claims. A meta-analysis of studies published from 1967 through 2001 found that chromium did not significantly affect lean gain or strength.3oChanges in body weight, a sum of three body circumferences, a sum of three skinfold measurements, and the one-repetition maximum for the squat and bench-press were examined in 59 collegeage students during a 12-week weight-lifting program. Half of the students were given 200 pg/day of elemental chromium as chromium picolinate, and the other half received a placebo. No treatment effects were seen for the strength measurements. The only s i g h c a n t treatment effect found was an increase in body weight observed in the women supplementing with chr0mium.9~ The effects of 9 weeks of daily chromium supplementation (200 pg chromium as picolinate) were investigated in a double-blind study in football players during sprint training. Chromium picolinate supplementation was ineffective in bringing about changes in body composition or ~trength.9~ The same results were shown in another study of 200 pg of chromium given as supplements to untrained men (23 & 4 years) in conjunction with a progressive, resistive exercise training program. Chromium supplementation was not found to promote either a significant increase in strength or lean body mass or a significant decrease in percentage of body fat.% Increasing dosage and duration of supplementation with chromium also did not help. A double-blind, placebo-controlled study conducted for 16 weeks provided 400 pg of chromium as picolinate or a placebo. At the end of 16 weeks, the chromium group did not show a sigruficantly greater reduction in either percentage body fat or body weight, or a greater increase in lean body mass, than the placebo group. The researchers concluded that chromium picolinate was ineffective in enhancing body fat reduction in this Yet another study, involving 8 weeks of daily chromium supplementation in 36 men in a double-blind design, found that strength, mesomorphy, fat-free mass, and muscle mass increased with resistance training independent of chromium supplementation (p < 0.0001). These findings suggest that routine chromium supplementation has no beneficial effects on body composition or strength gain in men, although it must be noted that the placebo group received a trace level of chromium." Evidence strongly indicates that supplementation of chromium does not enhance strength or body composition. As with boron, chromium-rich foods or a supplement containing chromium should be included in the diet to avoid deficiency; however, it is unrealistic to expect gains in strength or improvement in body composition.

Selenium Selenium is a trace mineral used as a cofactor in several enzymes. It is commonly found in antioxidant formulas because of its role as a cofactor in the enzyme glutathione peroxidase. Evidence suggests that the administration of organic selenium partially compensates for, and decreases the intensity of, oxidative stress in atI1letes.9~ Although optimal antioxidant status is critical to athletes, selenium might have an additional role in the determination of body composition. Selenium deficiency can affect the metabolism of thyroid hormones. Iodothyronine Sdeiodinase, which is mainly responsible for peripheral triiodothyronine (T3)production, has been demonstrated to be a selenium-containing enzyme?* In rats fed a selenium-deficient diet, hepatic iodothyronine 5'-deiodinase is decreased by 47%. Lower concentrations of T3and thyroxine (T4) have also been demonstrated in seleniumdeficient animals." Reduced peripheral conversion of T4 to T3 secondary to a selenium deficiency might create a functional hypothyroidism, which would be expected to adversely affect body composition.

Toxicity There are data suggesting that ingesting more than 750 to 1000 pg/day of selenium over an extended period may be harmful.

Vanadium (VanadyI SuIfate) Vanadium as vanadyl sulfate is widely utilized by athletes seeking to improve body composition. It is generally promoted as having an anabolic effect that enhances the transport of amino acids into cells. Several studies have indicated its ability to reduce fasting glucose and improve hepatic and peripheral insulin sensitivity in humans with non-insulin-dependent diabetes mellitus (NIDDM).*00-*02 However, vanadyl sulfate does not appear to alter insulin sensitivity in nondiabetic subjects.'OZ A single study reported the effect of oral vanadyl sulfate (0.5 mg/kg per day) on anthropometry,body composition, and performance in a 12-week, double-blind, placebocontrolled trial involving 31 weight-training volunteers. No sigruficant treatment effects for anthropometric parameters and body composition were observed. The two groups had similar improvements in performance in most exercises; however, a sighcant improvement in one repetition-maximum leg extension was found in the treatment group. The researchers concluded that although vanadyl sulfate was ineffective in changing body composition in weight-training athletes, its performanceenhancing effect required further investigation.lo3

Toxicity Anecdotal reports indicate that body-builders often supplement their diets with 15 mg tid of vanadium;

Sports Nutrition

however, this practice is ill-advised due to the lack of both demonstrated efficacy and information regarding long-term toxicity of high doses of vanadium. In rats, dietary concentrations of 25 mg/kg of vanadium cause mild diarrhea and growth suppression, and up to 50 mg/kg severely depressed growth and increased diarrhea and mortality. When 12 patients were fed 13.5 mg/day of vanadium for 2 weeks and then 22.5 mg/day for 5 months, 5 of the patients experienced cramps and diarrhea at the high dosage.lM

Zinc Because dietary deficiency of zinc is prevalent, zinc supplements have been widely advocated for athletes. It might not be wise to indiscriminately administer zinc, but evidence suggests that zinc might affect body composition through its interaction with a variety of hormones. It is thought that intense exercise can result in changes in zinc metabolism. Zinc has been demonstrated to be lower in trained adolescent gymnasts and even lower in females in the general population. This reduction might play a role in abnormalities of puberty, growth, or muscular performance.lo5 Some investigators have concluded that zinc might play an important role in modulating serum testosterone levels in normal men. Dietary zinc restriction in normal young men is associated with a sigruficant decrease in serum testosterone concentrations, whereas zinc supplementation of marginally zinc-deficient normal elderly men led to an increase in serum testosterone from 8.3 6.3 to 16 ? 4.4 nmol/L (p = 0.02).'06 However, although zinc deficiency might inhibit testosterone production, zinc supplementation of an individual with adequate levels has not been shown to produce excess testosterone. Zinc deficiency might result in reduced production of GH and/or insulin-like growth factor I (IGF-I).Io7Oral zinc replacement has normalized growth hormone levels and increased growth rate in teenagers found to be GHdeficient.lWZinc supplementationcauses a sigruficantrise in liver synthesis of IGF-I (somatomedin C). In chronic zinc deficiency, reduced liver produdion of IGF-I is responsible for diminished physical growth; moreover, in this situation, receptor resistance to IGF-I (in addition to GH) has been demonstrated. Receptor sensitivity is reestablished after supplementationwith zinc. Zinc might also play a role in increasing the number of receptors.'Og Zinc deficiency might affect the metabolism of thyroid hormones. The structure of nuclear thyroid hormone receptors contains zinc ions, crucial to the functional In experimental animals, zinc properties of the deficiency decreases concentrations of T3and free T4(fTJ in serum by approximately 30% when compared with zinc-adequate controls. The concentration of T4in serum was not affected by zinc deficiency. In these animals,

*

zinc deficiency also decreased the activity of hepatic iodothyronine 5'-deiodinase by 67%.*

Toxicity Zinc supplementation is generally safe if maintained at levels within two to eight times the recommended dietary allowance (RDA). Symptoms of zinc toxicity include gastrointestinal irritation, vomiting, adverse changes in ratio of high-density lipoprotein (HDL) cholesterol to LDL cholesterol, and impaired immunity. The last symptom develops when more than 180 mg/day of zinc is consumed for more than several weeks. Excess intake of zinc may either lower copper levels or aggravate an existing marginal copper deficiency. Because of the multiple interactions of zinc with hormones critical to strength and body composition, it is recommended that athletes undergo a determination of zinc nutriture and receive supplementation if required.

Summary On the basis of available information, strength athletes

are likely to obtain better results by following a supplementation routine that includes the following: Creatine monohydrate (at least 3 g/day) A postworkout protein shake (40 g of protein) Vitamin C (1-3 g/day) A multivitamin/mineral formulationcontaining approximately: 3 mg of boron, 200 pg of chromium, 200 pg of selenium, 100 Fg of vanadium, and 15 mg of zinc The published results to date on HMB are impressive; for athletes utilizing HMB, the recommended dosage is 3 g/day. Although a theoretical argument can be made for the inclusion of phosphatidylserine in a supplement routine, the high cost and the lack of information on bottom-line results in terms of improved strength or body composition make it difficult to justify its use. Compelling evidence could be used to make an argument for many of the isolated amino acids, but a high-quality protein supplement, such as whey, provides adequate levels of all of the amino acids for the majority of athletes. Because of the correlation of low glutamine levels with overtraining, supplementation with 2 g/day of glutamine in addition to a protein supplement, in individuals whose training regimen places them at risk for overtraining, seems prudent.

SPORTS NUTRITION FOR ENDURANCE ATHLETES Panax ginseng Panax ginseng, also known as Panax schinseng, is a member of the family Araliaceae. In Mandarin Chinese

it is called Ren Shen, but it is commonly referred to as Korean or Chinese ginseng.Several closely related species are also often sold as ginseng. These include Panax quinquefolium (American ginseng); Panax notoginseng, also known as Panax pseudoginseng (Himalayan ginseng), and P a m japonicum (Japanese ginseng). Ginseng was used traditionally as a tonic for a broad range of medical conditions. It was believed to be a revitalizing agent capable of enhancing health and promoting longevity (for a more detailed discussion, see Chapter 111). Soviet scholars, beginning in the early 1950s, were the first to establish the fact that many Araliaceae family plants, especially P. ginseng, are adaptogens.l1° Among their many properties, adaptogens are thought to promote regeneration of the body after stress or fatigue and to rebuild strength. Because of its reputation as an adaptogen, P. ginseng is among the most popular botanical supplements used by athletes. Many animal studies with I? ginseng, or its active components, have demonstrated an enhanced response to physical or chemical stress.111-115 In rats, the aqueous suspensions of roots of P. ginseng were tested for antistress activity by the "mice swimming endurance test" and anabolic activity by noting gain in body weights and muscle. A sigruficant increase in mice swimming time was shown by mice fed ginseng compared with the conP. ginseng extract has also been shown to trol gr0up.5~J'~ increase the activity of glutathione peroxidase and superoxide dismutase. These animals' enhanced antioxidant capacity demonstrated reduced oxidative stress after experiencing exhaustive e~ercise."~ In animal models, administration of ginseng has been shown to affect several hormones that might in turn affect performance. High doses of ginseng have been reported to increase blood testosterone level.Ils Experiments indicate that the bindjng of corticosteroid to certain brain regions is higher in adrenalectomized rats given ginseng saponin.l19Ginseng saponin has also been reported to act on the hypothalamus and/or hypophysis, stimulating ACTH secretion, which results in greater synthesis of corticosterone in the adrenal cortex.120J21 Although results of studies with animals have been compelling, ginseng's value as an ergogenic aid in humans is still equivocal.lZ Extracts of l? gznseng are reported to increase plasma total and free testosterone, dihydrotestosterone, and levels of follicle-stimulating and luteinizing hormones in infertile men.123The addition of ginseng root extract to a multivitamin base is reported to have improved subjective parameters in a population exposed to the stress of high physical and mental activity.'" In a double-blind, randomized, crossover study, 50 healthy men received either two capsules of a preparation containing ginseng extract, dimethyl aminoethanol bitartrate, vitamins, minerals, and trace elements or two capsules of placebo every day

for 6 weeks. The total workload and maximal oxygen consumption during exercise were signhcantly greater after the ginseng preparation than after placebo. The researchers also noted decreases in plasma lactate levels, carbon dioxide production, and heart rate during exercise in participants receiving the ginseng preparation.lZ A randomized controlled study of 92 moderately severe patients with chronic obstructive pulmonary disease observed that those taking 100 mg of ginseng extract twice a day for 3 months experienced improvements in parameters of pulmonary function, maximum voluntary ventilation, maximum inspiratory pressure, and maximal oxygen consumption, with no side effects.lZ6 Other researchers evaluated the effect on performance of a ginseng saponin extract (8 or 16 mg/kg body weight) ingested daily for 7 days. Although time to exhaustion was significantly less during the presupplementation control trial than during the placebo and ginseng trials, no significant difference was found between the placebo and the ginseng trials.127Another double-blind trial of 38 adults using 400 mg/day of ginseng for 8 weeks found no change in physical performance and heart rate recovery after exhaustive exercise.lZ8It should be noted that the duration of the supplementation period was only 1 week in this trial. Because historically ginseng has been used as a tonic for prolonged periods and positive results have been reported after 6 weeks of supplementation, a longer trial might have demonstrated an ergogenic effect. Research in support of the use of l? ginseng as an ergogenic aid, although equivocal, is promising. Because of the anecdotal reputation and allure this plant holds, many athletes are likely to continue to use it.

Dosage The quality of available ginseng preparations can vary greatly, so it is imperative to use I? ginseng with documented potency. A typical dose for general tonic effect would contain at least 25 mg of the saponin ginsenoside.lZ9I? ginseng contains 2% to 3% ginsenosides, so a dose of 8 to 12 g of crude herb, assuming it is of high quality, will provide adequate saponin content. Because of the variability in quality of P.ginseng available, utilizing a preparation standardized for ginsenoside content may be preferable. The dosage for a product standardized to 5% ginsenosides would be 500 mg/day, and for a product standardized to 14% ginsenosides, about 180 m g / d a ~ . For ' ~ ~anyone using ginseng for a prolonged period, some authoritieshave recommended discontinuing supplementationperiodically for 2-week intervals.

Toxicity The problem of quality control makes toxicology of ginseng difficult to address. Studies performed on standardized extracts of ginseng have demonstrated

the absence of side effects and mutagenic or teratogenic effects. However, toxicity has been reported with products of uncertified constituents.

Eleutherococcus senticosus EZeutherococcus sen ticosus, also known botanically as Acunthopunux senticosus, is a member of the Araliaceae family that also contains P.ginseng.In China, the plant is called Ci Wu Jiu;however, it is most commonly referred to as Siberian ginseng. Because of its wide availability and lower cost, the dried root and rhizome are commonly used as a ginseng substitute; however, ginsenosides, characteristic of Punux spp., are not found in the roots of Elm therococcus sentic~sus.'~~ (For a more detailed discussion of both of these botanicals, see Chapters 90 and 111.) E. senticosus is classified as an adaptogen and is believed to promote recovery and improve endurance. It has a long history of use in Chinese herbal medicine, in which it was used to enhance general health, longevity, appetite, and memory. Because of the rarity of I? ginseng, Soviet scientists shifted the focus of their research in the late 1950s to other members of the Araliaceae family in order to find suitable substitutes.Four adaptogenic plants were identified, studied, and finally introduced into therapeutic practice, between 1955 and 1964. E. senticosus was considered to be the most important of these substitutes."O Reports indicate that Eleutherococcus was used routinely by both Soviet Olympic athletes and military officers. Extracts of Eleutherococcus prolong the exercise time to exhaustion in swimming and modulate changes of the hypophyseal-adrenal system in rats under extreme condition^.'^^ Famsworth et reviewed the results of clinical trials of Eleutherococcus in humans. The data they gathered indicated that ingestion of extracts from the plant increased the ability to accommodate to adverse physical conditions, improved mental performance, and enhanced the quality of work under stressful conditions such as during athletic perf~rmance.'~~ Other researchers, however, have concluded that supplementation of E. senticosus had no ergogenic effect on the measured parameters associated with submaximal and maximal aerobic exercise tasks. The effect of this substance on performance during submaximal and maximal aerobic exercise was measured in 20 highly trained distance runners randomly assigned to matched pairs. Participants consumed either 3.4 ml of E. senticosus extract or placebo daily for 6 weeks. During the 8-week double-blind study, subjects completed five trials of 10-minute rufls on a treadmill at their 10-km race paces and a maximal treadmill test. No sigruficant differences were observed between Elmtherococcus- and placebosupplemented groups for heart rate, oxygen consumption, respiratory exchange ratio, and rating of perceived exertion during the 10-km run and maximal treadmill test.133Other human studies evaluating steady-state

substrate utilization or 10-km cycling performance time also found no benefit.lM Eleutheracoccus senticosus has received attention in the popular press under the name Ci Wu Jiu.Trials of its effect on Performance have been sponsored by PacificHealth Laboratories, Inc., the manufacturer of a standardized extract and the holder of a patent for the use of Ci Wu Jia to enhance stamina and physical performance during, and enhance recovery after cessation of, exercise. All reports on Ci Wu Jia's effect on performance have been based on information provided by this manufacturer. Ci Wu Jia reportedly has a carbohydrate-sparing action, shifting metabolism to a higher utilization of fat for energy. The carbohydrate shift is also reported to delay the lactic acid buildup associated with muscle fatigue. Reports indicate that Ci Wu Jia might slightly reduce heart rate during exercise and recovev. Participants have usually consumed 800 mg/day of the standardized extract for 2 weeks. Overall, the evidence for an ergogenic effect of E. senticosus is fair. The reported benefits Russian athletes received from supplementation remain the most compelling evidence to date of the ergogenic potential of this plant.

Dosage Recommended doses vary depending on the form of Eleutherococcus used. The dose of a 1:l fluid extract (33% ethanol) is usually between 2 and 4 ml one to three times/day; however, doses up to 16 ml have been used. A standardized 201 solid concentrate is also available. In this form, a minimum recommended dosage would be 300 mg/day, equivalent to 6 g of powdered root. Better results might be experienced at higher doses. In order to avoid accommodation, Eleutherococcus should be used for no longer than 60 consecutive days, followed by a period of 2 to 3 weeks of abstinence before resumption of ~upp1ementation.l~~

Toxicity Toxicity studies in animals have demonstrated that Eleutherococcus extracts are virtually nontoxic. Human clinical studies have shown that in the recommended dosage range, the extracts (33%ethanol) are well tolerated and side effects are infrequent. A few studies found mild side effects at higher dosages (4.5-6.0ml three times/day) when used for long periods (60 days). The symptoms included insomnia, irritability, melancholy, and anxiety.

Carnitine Carnitine is promoted as a supplement needed to improve the body's ability to use stored fat as fuel. Supplementation purportedly enhances lipid oxidation, increases maximum oxygen consumption (Vo2,,J (a measurement of maximal aerobic power), and decreases plasma lactate accumulation during exercise.

Carnitine is a trimethylated amino acid roughly similar in structure to choline. The synthesis of carnitine begins with the methylation of lysine by Sadenosylmethionine. Cofactors required for optimal synthesis of carnitine are as follows: Magnesium Iron Ascorbic acid Folic acid Methylcobalamin Betaine Pyridoxal5'-phosphate Niacin Carnitine is located in the mitochondrial membrane and is a cofactor needed for the transformation of free long-chain fatty acids (LCFAs) into acyl-camitines for subsequent transport into the mitochondrial matrix. Inside the mitochondria, LCFAs are metabolized into energy by the process of beta-oxidation. Several investigators have suggested that L-carnitine supplementation might benefit athletes. One study investigated the effect of giving 2 g/day of L-carnitine for 6 weeks to seven male marathon athletes. Improvement in running speed by 5.68% and decreases in average oxygen consumption and heart rate in the treadmill test followed supplementation. The researchers suggest that for carnitine to be effective as an ergogenic aid, several preconditions must be met: (1) a n adequate supply of lipids available as fuel, (2) shift of metabolism toward the utilization of fats as an energy source, and (3) a relative shortage of available endogenous camitine. Because the average free and total plasma carnitine levels were below the normal ranges before supplementation in these subjects, the L-carnitine might have helped them overcome a relative endogenous defi~iency.'~~ In a double-blind crossover study of 10 moderately trained male subjects, either 2 g of L-carnitine or placebo were provided orally 1hour before exercise. supplementation with L-carnitine induced a significant postexercise decrease in plasma lactate and pyruvate levels and a concurrent increase in acetylcarnitine carnithe.'% In another study, 2 g of L-camitine or a placebo was given to subjects 1 hour before they began exercise. At the maximal exercise intensity, treatment with L-carnitine increased both maximal oxygen uptake and power output. The researchers also reported that, at similar exercise intensities, oxygen uptake, carbon dioxide production, pulmonary ventilation, and plasma lactate levels were reduced in participants receiving ~-carnitine.'~' Although some of the results with L-carnitine supplementation have been promising, not all research is in

agreement. One review of carnitine and physical exercise concluded that carnitine supplernentationl3: Has an equivocal effect on performance in athletes. Does not enhance fatty acid oxidation, spare glycogen or postpones fatigue during exercise. Does not stimulate pyruvate dehydrogenase activity. Does not reduce body fat or help with weight loss. One research group found that long-term carnitine supplementation, 6 g/day, resulted in no differences in volume of oxygen consumption (Vo,), respiratory exchange ratio, heart rate, or utilization of carbohydrate and fat. They also reported that muscle carnitine concentration at rest was unaffected by ~upplementation.'~~ Similar results were reported with carnitine supplementation at 4 g/day for 14 days; although effective at increasing plasma total acid-soluble and free carnitine concentrations, this measure had no significant effect on muscle carnitine concentrations.'40Another group found that loading of athletes with L-carnitine for the 10 days before a marathon abolished the exercise-induced drop in plasma free carnitine concentration and increased the production of acetylcarnitine but yielded no detectable improvement in perf0rman~e.l~~ Still another study investigated the effects of ~-carnitine supplementation on metabolism and performance of endurance-trained athletes during and after a marathon run.In a double-blind crossover field study, seven male subjects received 2 g of L-carnitine 2 hours before the start of a marathon run and again after 20 km of running. Although the administration of L-carnitine was associated with a significant rise in the plasma concentration of all analyzed carnitine fractions, there were no significant changes in running times; plasma concentrations of carbohydrate metabolites (glucose, lactate, and pyruvate), fat metabolites (free fatty acids, glycerol, and betahydroxybutyrate), or hormones (insulin, glucagon, and cortisol); or levels of enzyme activities (creatine b a s e and lactate dehydrogenase).'" Although available data on L-carnitine as an ergogenic aid is not compelling, pretreatment has favored aerobic processes under some experimental conditions. It is possible that L-camitine might exert a beneficial effect only in persons in whom there are actual deficiencies.Availability of fat as a substrate for fuel might also affect the ability of carnitine to act as an ergogenic aid.

Dosage Ingestion of 2 g L-camitine 1hour before intensive exercise might provide some benefits; however, because of the mixed results of studies and the cost of the supplement, long-term administration of L-carnitine is difficult to justify.

Sports Nutrition

Toxicity Given twice daily at a dosage of 6 g twice daily to boys aged 6 to 13 years in a study of attention deficit hyperactivity disorder (a dosage much higher than the suggested preexercise dose for adults), L-camitine was well-t01erated.l~~ Other 3-month investigations using 2 to 3 g/day in cardiac patients also found L-carnitine safe, with no side effect^.'^,^^^ There have been some reports of excessive body odor in people taking carnitine, possibly owing to the greater formation of trimethylamines; supplemental riboflavin is thought to remedy this problem.

Choline Choline supplements have been advocated as a means of preventing the decline in choline reported to occur during exercise. Choline in the diet consists primarily of phosphatidylcholine, which after absorption by the intestinal mucosa is metabolized to choline in the liver. Most choline is rephosphorylated to phosphatidylcholine; however, a small amount of choline is carried to the brain via the blood stream, where it is converted to acetylcholine, a chemical messenger required for adequate nerve impulses and memory storage and retrieval. Running a 26-km marathon reduces plasma cholineby approximately 40% according to one study.'& The decline has been proposed to lower acetylcholine levels, resulting in a reduction in the transmission of contractiongenerating impulses across skeletal m ~ s c 1 e .Itl ~has ~ been proposed that this reduction might negatively affect endurance perf~rmance.'~,'~~ Another study investigated the effect of lecithin on the plasma choline concentrations during continuous strain in ten top-level triathletes (four women and six men). The participants received either a placebo or 0.2 g lecithin/kg body mass 1hour before each exercise. Bicycle exercise without lecithin supply decreased plasma choline concentrations in all the triathletes, on average by 16.9%.When lecithin was given before exercise, average plasma choline concentrations remained at the same level as the initial values. In a second trial, with 13 adolescent runners (three girls and ten boys), mean plasma choline concentrations remained stable when subjects were running without lecithin supplementation.lM Yet another research group, however, found that trained cyclists do not deplete choline during supramaximal brief or prolonged submaximal exercise, nor do they benefit from choline supplementation, given as choline bitartrate (2.43 g) to delay fatigue under these conditions.'" Other double-blind crossover studies of subjects participating in load carriage tests found that the placebo group did not have choline depletion, nor did intake of choline have any effect on performance of

physical reaction time, logical reasoning, vigilance, spatial memory, or working m e m ~ r y . ~ ~ J ~ ~ No evidence to date provides compelling justification for supplementation of the diet with choline as an ergogenic aid. Its potential efficacy for improving physical performance remains largely theoretical.

Coenzyme Qlo (Ubiquinone) Because of its role in mitochondria1 energy production, coenzyme Qlo (CoQlo), also known as ubiquinone, is reputed to enhance performance; however, no studies have demonstrated a sigruficant improvement in any aspect of athletic performance. Biopsy of muscle found that CoQlo levels were positively correlated to exercise capacity and marathon perf ~ r m a n c e . Providing '~~ 150 mg/day of CoQlo orally for 2 months to a group of middle-aged men resulted in higher circulating blood levels of CoQlo and improved perceived level of vigor; no improvement in aerobic capacity was found.'53 Giving cyclists 100 mg/day of CoQlo for 8 weeks produced no measurable effect on performance, Vo-, submaximal physiologic parameters, or lipid peroxidation.154Other researchers have found that oral ubiquinone was ineffective as an ergogenic aid in both young and older trained men.155 On the basis of available research, CoQlo appears to have no value as an ergogenic aid.

Pyridoxal-alpha-Ketoglutarate Pyridoxal-alpha-ketoglutarate (PAK) consists of pyridoxine (about 54%) and alpha-ketoglutarate (about 46%). It is thought to improve the generation of highenergy phosphate bonds, such as ATP and guanosine triphosphate (GTP). In addition, a higher level of alphaketoglutarate, along with pyridoxal 5'-phosphate, in the mitochondria might enhance the transamination of pyruvate to alanine, thereby possibly preventing or reducing lactic acid formation.'56 Administration of PAK was shown to reduce the plasma concentration of lactate in response to isometric exercise in a group of nonketotic patients with NIDDM.157 The administration of 30 mg/kg of PAK for 30 days has been reported to increase V h , and to decrease lactic acid accumulation during short supramaximal workloads. The administration of alpha-ketoglutarate or pyridoxine separately did not alter V b sigruficantly.156 Individually and in combination, the use of PAK and sodium bicarbonate in short-term maximal exercise capacity was studied in eight cyclists. Oral tablets of sodium bicarbonate and PAK were given in doses of 200 and 50 mg/kg, respectively. The investigators found no sigruficant differences between treatments in the ability to sustain maximum power during the exercise trial; however, the best results obtained were from individuals

Syndromes and Special Topics utilizing both PAK and bicarbonate. PAK supplements by themselves did not improve participants' ability to sustain maximum power.'"

Dosage The typical dose of PAK is 1800 to 3000 mg/day, depending on body weight. Although PAK might be complementary to athletic training, particularly in conjunction with sodium bicarbonate, available information is limited. PAK supplementation appears to positively influence some physiologic parameters associated with enhanced aerobic performance; however, to date this supplement has not been shown to produce a "bottom-line" improvement in actual performance.

Pyruvate Supplementation with pyruvate is popular with some athletes because of reports of its endurance-improving and weight loss-enhancing effects. Pyruvate is a stable salt form of pyruvic acid, the naturally occurring endproduct of the metabolism of carbohydrates. It is stabilized by the addition of sodium, potassium, calcium, or magnesium to pyruvic acid. Pyruvic acid occurs naturally in the diet, fruits and vegetables being good sources. Red apples are possibly the best source, with an estimated 450 mg of pyruvic acid per apple. Pyruvate is a three-carbon compound containing a carboxylic acid and a ketone group. During the process of glycolysis, glucose is converted to pyruvate. Pyruvate is then either converted to acetyl coenzyme A, for entry into the citric acid cycle under aerobic conditions, or to lactate under anaerobic conditions. Pyruvate's mechanism of action for weight loss and for enhancing endurance is unknown. In published research, most of which has been conducted by Stanko et a1,'59-163pyruvate has usually been given in conjunction with dihydroxyacetone. This combination has been reported to be useful in weight loss routines, in which it is partially and isocalorically substituted for glucose in obese women. Participants in one study were started on severely restrictive hypocaloric diets for 21 days while housed in a metabolic ward. In one study, participants fed dihydroxyacetone and pyruvate (DHAP) showed greater weight loss (6.5 k 0.3 kg, vs. 5.6 f 0.2 kg for the placebo group) and higher fat loss (4.3 f 0.2 kg, vs. 3.5 f 0.1 kg for the placebo In another trial, pyruvate and dihydroxyacetone, given as approximately20%of energy intake, reduced the reaccumulation of body weight (1.8 f 0.2 kg vs. 2.9 k 0.1 kg) and fat (0.8 k 0.2 kg vs. 1.8 k 0.2 kg) associated with refeeding after a calorie-restricted @ d'ei.t ' Pyruvate alone has been reported to be an effective addition to a weight loss program. In one study, participants were obese women housed in a metabolic ward and consuming a 4.25 MJ/day liquid diet for 21 days with or

without pyruvate partially and isoenergeticallysubstituted for glucose. Participants fed pyruvate showed greater weight loss (5.9 f 0.7 kg, vs. 4.3 f 0.3 kg for the placebo group) and higher fat loss (4 f 0.5 kg, vs. 2.7 f 0.2 kg for the placebo The reports indicate that pyruvate had no impact on enhancing nitrogen balance, serum protein concentrationsor lean body mass in these subje~ts.'~%'~' Because the published studies were conducted on obese women consuming calorie-restricted diets of either 500 or 1000 calories/day, these weight losses should not be extrapolated to athletes or other populations consuming normal or high-calorie diets. Also, in the published trials, pyruvate has been substituted for glucose, a substance that affects fat metabolism in overweight individuals because of its role in insulinsecretion. It is possible, under similar circumstances, that partially and isocalorically substituting protein or fat for glucose might have produced similar,if not better, results. Pyruvate has been reported to increase the time required to reach exhaustion and to decrease perceived exertion. In the published studies, pyruvate was again given in relatively high amounts in conjunction with dihydroxyacetone. In both studies, untrained men received either 100 g of DHAP or 100 g of a glucose polymer derived from the hydrolysis of cornstarch as a placebo for 7 days. Arm endurance was 133 f 20 minutes after placebo and 160 k 22 minutes after DHAP.162Leg endurance was 66 k 4 minutes after placebo and 79 k 2 minutes after DHAP.la Muscle glycogen levels, at rest and exhaustion, determined through biopsy, did not differ in the placebo and DHAP subjects.la Plasma levels of free fatty acids, glycerol, and beta-hydroxybutyrate were similar during rest and exercise for placebo and DHAP subjects in both s t u d i e ~ . ' ~ Supplementation ~J~~ of a DHAP mixture has also been reported to reduce the perceived level of exertion.Ia Feeding DHAP for 7 days appears to increase submaximal endurance in untrained athletes; however, whether similar results would be obtained with trained athletes is unresolved. In the published studies 25 g/day of pyruvate were given along with 75 g/day of dihydroxy-acetone; however, in the lay press, Stanko has been quoted as saying: "We see a linear response between 2 and 5 g a day and then the response plateaus. In other words, the response with 10 or 15 g or more is the same as with 5 g."Supporting documentation for this assertion has apparently not been published in scientific literature to date, nor has any research been published on the endurance effects of the supplementation of pyruvate without dihydroxyacetone.

Dosage Dosage recommendations for pyruvate are 2 to 5 g/day, taken with food. Better results might be obtained by dividing the 5 g into two or three doses.

Because the reported results on endurance were obtained in trials comparing DHAP with a glucose polymer, the only justifiable conclusion is that subjects consuming 100 g of DHAP rather than 100 g of hydrolyzed cornstarch, a substance with no nutritional value, experienced better endurance. Research evaluating the performance effects of adding 2 to 5 g of pyruvate to the diet of trained athletes is yet to be published. The available evidence suggesting that pyruvate acts as an ergogenic aid in high dosages in combination with dihydroxyacetone is questionable. No evidence exists in support of claims of ergogenic action for pyruvate supplementation at the recommended dose of 2 to 5 g.

Performance Drinks Performance drinks are commonly consumed as ergogenic aids during endurance sports activities. These drinks are designed to maintain normal hydration, electrolyte balance, and blood glucose levels during exercise. Current evidence indicates that ingestion of performance drinks during exercise enhances athletic performance and normalizes markers of thermoregulation. A variety of beverages formulated to provide fluid, carbohydrates, and electrolytes during and after exercise are commercially available. These beverages commonly contain 4% to 8% carbohydrate (as glucose, fructose, sucrose, or maltodextrins) and small amounts of electrolytes (most often sodium, potassium, and chloride). Contrary to popular belief, rates of sweating and urine flow are not influenced by fluid ingestion during exercise.'& Studies have shown that 5% to 10% solutions of glucose, glucose polymers (maltodextrins), and other simple sugars all have suitable gastric-emptying characteristics for the delivery of fluid and moderate amounts of carbohydrate substrate. The optimal concentration of electrolytes, particularly sodium, remains unknown. Most currently available sports drinks provide a low level of sodium (10-25 mmol/L) in recognition of the fact that sodium intake can promote intestinal absorption of fluid as well as assist in rehydration.'& Exercise and dehydration lead to increases in core temperature,body fluid osmolality, and heart rate; losses of plasma and other body fluid volumes; and depletion of glycogen. All of these homeostatic disturbances can be ameliorated by fluid consumption during exercise.167 During exercise, water and electrolytes are lost from the body in sweat. Sweat rate is determined primarily by the metabolic rate and the environmental temperature and humidity. Under some conditions, the sweat rate can exceed the maximum rate of gastric emptying of ingested fluids. If this OCCUTS, some degree of dehydration is observed. Excessive replacement of sweat losses with plain water or fluids with low sodium content after prolonged exercise has resulted in hyponatremia, so

sodium replacement is considered essential for postexercise rehydration.]@ For moderate-intensity exercise, water ingestion 30 to 60 minutes before exercise seems to minimize homeostatic disturbances;however, at higher intensitiesof athletic performance, it probably has little effect.167During exercise, ingestion of both water and carbohydratebeverages has been shown to minimize homeostatic disturbances. Subjects allowed to drink a carbohydrate-electrolyte beverage (4.85% polycose, 2.65% fructose) or distilled water ad libitum during 3 hours of continuous exercise in the heat (31.5" C) showed no significant differences between drinks for rectal temperature, heart rate, or sweat rate during exercise.169No differences in thermoregulatory responses in individuals consuming either carbohydrate beverages or water have been observed.170 The efficacy of a given drink is limited by the rate of absorption of fluid from the intestines, which is in turn limited by gastric emptying. Several factors influence gastric emptying, including exercise intensity and the carbohydrate composition of the solution.171The gastricemptymg rate might also be influenced by the caloric content, volume, osmolality, temperature, and pH of the ingested fluid; the metabolic state and biochemical individuality of the athlete; and the ambient temperature.ln The caloric content of the ingested fluid might be the most important variable governing gastric-emptying rate. At rest and during running, water has a faster gastric-emptying time than all other drinks. Gastric emptying is progressively slowed as the caloric content of the fluid rises.171During moderate exercise, gastric emptying occurs at a rate similar to that during rest; however, more intense exercise appears to inhibit gastric emptying. Evidence indicates that beverages containing less than 10% carbohydratehave gastric-emptying rates closest to that of water.ln Drinks containing less than or equal to 8% to 10% carbohydrate are absorbed into the body at similar rates and should behave similarly in replenishing body fluids lost in sweat during exercise.174 Several other factors have been shown to affect gastric emptying. Isotonic drinks appear to empty quickly throughout exercise, whereas the gastric-emptying rate of hypertonic drinks has been shown to decrease over time.175Fat is believed to delay gastric emptying; however, medium-chain triglycerides (MCTs) might not inhibit gastric emptying as most fat does. Research indicates that MCT-containing drinks have faster gastric-emptying times than drinks containing 100% maltode~trins."~ It has been suggested that maltose might be a superior source of carbohydratefor endurance athletes. Some researchers have suggested that ingestion of an 8% solution of maltodextrin or sucrose every 15 minutes during exercise might provide optimal fluid and carbohydrate rep1acement.l" The rates of gastric emptying and the

peak rates of exogenous carbohydrate oxidation are not sigruficantly different between maltose and glucose.'78 Although ingestion of 13 g carbohydrate per hour did not improve performance during prolonged moderateintensity cycling in one stUdy,ln most studies report that ingestion of carbohydrate beverages has a beneficial effect on performance. Carbohydrate ingested during exercise appears to be readily available as a fuel for the working muscles, at least when the exercise intensity does not exceed 70% to 75% of maximum oxygen uptake.ls0 Rating of perceived exertion is reported to be higher in athletes consuming water than in athletes consuming carbohydrate drinks.'81 For exercise leading to exhaustion in less than 30 minutes, carbohydrate ingestion is not effective in minimizing homeostatic perturbations or improving exercise perf~rmance'~~; however, for exercise of longer duration, ingestion of performance beverages appears to enhance performance. Research has shown that 275 ml of a 6%carbohydrate-electrolyte beverage consumed every 20 minutes maintained blood glucose levels and enhanced performance better than water during endurance cycling.182One study compared the effects of orange flavored drinks containing 0, 6.4%, and 10% carbohydrate. The solutions, given at 3 ml per kg body weight, were given in a double-blind and counter-balanced protocol at time 0 and every 20 minutes during exercise. Blood glucose and lactate levels and temperature were similar for all solutions; however, performance improved with consumption of a carbohydrate drink during exercise. The best results were obtained with ingestion of a 10% carbohydrate drink.'= In another study, eight well-trained men cycled for up to 255 minutes at a power output corresponding to V q at lactate threshold (approximately 68%Vo,,) on three occasions separated by at least 1 week. Subjects drank 5 ml per kg body weight of either a water placebo or a liquid beverage containing a moderate (6%) or high (12%) concentration of carbohydrate, beginning at minute 14 of exercise and every 30 minutes thereafter. Exercise time to fatigue was shorter in subjects receiving placebo (190 minutes) than in those receiving the 6% carbohydrate (235 minutes) and 12% carbohydrate (234 minutes) beverages.lM In a further study, 12 subjects were exercised to exhaustion on a cycle ergometer at a workload corresponding to 70%of maximum oxygen uptake. In one trial, no drinks were given, and in the other trials subjects drank 100 ml every 10 minutes. Median exercise time was greatest (110.3 minutes) for individuals receiving a hypotonic glucose-electrolyte solution (90 mmol/L glucose; 60 mmol/L Na'; 240 mosm/kg), compared with individuals receiving an isotonic glucose-electrolyte solution (200 mmol/L glucose; 35 mmol/L Na'; 310 mosm/kg) (107.3 min), water (93.1 min), and no drink (80.7 min).

Sigruficant treatment effects on heart rate, rectal temperature, and serum osmolality were also observed.185 Twelve highly trained male runners ran 15 km at selfselected pace on a treadmill in warm conditions to demonstrate differences in physiological responses, fluid preferences, and performance when ingesting sports drinks or plain water before and during exercise. One hour before the start of running, an equal volume (1000 ml) of either water or a 6% or 8% carbohydrateelectrolyte drink was ingested. Blood glucose concentration was significantly higher 30 minutes after ingestion of the 6% and 8% carbohydrate-electrolyte beverages than after water, significantly lower at 60 minutes after ingestion in subjects receiving both sports drinks than in those receiving water, but similar after 7.5 km of the run in subjects receiving all beverages. During the first 13.4 km, oxygen uptake and run times were not different between trials; however, the final 1.6-km performance run was faster with both carbohydrate-electrolytedrinks than with water.'% Research indicates that a sugar drink immediately before exercise can impair performance. Carbohydrates invoke an insulin response that increases the likelihood of hypoglycemia during exercise. A drop in blood glucose concentration results from the ingestion of glucose solutions ingested 15 to 45 minutes before prolonged exercise; however, the consumption of 18%to 50% solutions of glucose or glucose polymers 5 minutes before prolonged exercise has potential for improving endurance perf0rman~e.l~~ Many experts recommend consuming a beverage high in carbohydrates within 1 hour after exercise. Exerciseinduced depletion of muscle glycogen levels can be rapidly restored by glucose ingestion. Provided that adequate carbohydrate is consumed, the frequency of intake, the form (liquid vs. solid) and the presence of other macronutrients do not appear to affect the rate of glycogen ~ t 0 r a g e . lDuring ~~ the postexercise recovery period, ingesting a carbohydrate-electrolyte beverage is effective in minimizing physiologic disturbances. Subjects drink more; plasma volume rises to a higher level; plasma osmolality, glucose, and potassium values are greater; and body weight increases more with the ingestion of carbohydrate beverages than with pure water.lm

Dosage The optimum frequency, volume, and composition of recommended performance drinks vary widely according to the intensity and duration of the exercise, the environmental conditions, and the physiology of the individual. However, in general, isotonic beverages with glucose, glucose polymers, or maltodextrins as the carbohydrate source produce the best results. Before exercise, only water should be consumed. Drinking carbohydrate solutions 15 to 60 minutes before exercise

should be avoided because doing so can impair performance; however, their ingestion immediately prior to the start of exercise might be beneficial. This is because once endurance exercise is started, the insulin level is generally not increased, so the carbohydrates will likely be available as energy substrates. The staggered ingestion of performance drinks is beneficial when exercise duration exceeds 30 minutes; however, during shorter exercise and especially for weight-lifting, there appears to be no additional benefit in ingesting anything other than water.

Summary On the basis of available information, evidence remains mixed but promising on supplementation of the diet with I? ginseng and E. senticosus. The role of L-carnitine as an ergogenic aid remains something of a mystery; the mixed results reported in the literature and the high cost

of the supplement make it difficult to justify long-term administration of 2 g/day. No evidence to date supports supplementation with choline as an ergogenic aid. CoQl,,'s failure in several studies to demonstrate any performance-enhancing effect should end any debate or recommendations about the routine administration of this nutrient as an ergogenic aid. Although PAK supplementation has been shown to enhance certain parameters associated with aerobic exercise, it has not yet demonstrably improved performance. Evidence suggests that pyruvate acts as an ergogenic aid in high dosages in combination with dihydroxyacetone, but available evidence does not support claims of an ergogenic action for pyruvate supplementation at a dose between 2 and 5 g. The staggered ingestion of isotonic, 6% to 10% carbohydrate performance drinks should be a routine practice in endurance exercise activities of more than 30 minutes' duration.

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Stress Management Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 701 The General Adaptation Syndrome 701 Stress: A Healthy View

702

Diagnostic Considerations 702 Interpretation 702

Lifestyle Factors 704 Exercise 705 Dietary Guidelines 705 Nutritionaland Botanical Support 706 Nutritional Supplements 706 Botanical Medicines 707 Stress Management Programs 708

Therapeutic Approach 702 Calming the Mind and Body 703

INTRODUCTION Stress is defined as any disturbance-eg, heat or cold, chemical toxin, microorganisms, physical trauma, strong emotional reaction-that can trigger the ”stressresponse.” How an individual handles stress plays a major role in determining their level of health. Comprehensive stress management involves a truly holistic approach designed to counteract the everyday stresses of life. Most often the stress response is so mild it goes entirely unnoticed. However, if stress is extreme, unusual, or long-lasting, the stress response can be overwhelming and quite harmful to virtually any body system. Before one can discuss methods for helping patients deal effectively with stress, it is important to understand the stress response. Ultimately, the success of any stress management program depends on its ability to improve an individual‘s immediate and long-term responses to stress.

THE GENERAL ADAPTATION SYNDROME The stress response is actually part of a larger response known as the general adaptation syndrome, a term coined by the pioneering stress researcher Hans Selye. To fully understand how to combat stress, one must understand the general adaptation syndrome. The syndrome is composed of three phases: alarm, resistance, and exhaustion.] These phases are largely controlled and regulated by the adrenal glands. The initial response to stress is the alarm reaction, which is often referred to as the fight-or-fight response.

The fight-or-flight response is triggered by reactions in the brain that ultimately cause the pituitary gland to release adrenocorticotropic hormone (ACTH), which causes the adrenals to secrete adrenaline and other stress-related hormones. The fight-or-flight response is designed to counteract danger by mobilizing the body’s resources for immediate physical activity. As a result, the heart rate and force of contraction of the heart increase to provide blood to areas necessary for response to the stressful situation. Blood is shunted away from the skin and internal organs, except the heart and lung, while the amount of blood supplying required oxygen and glucose to the muscles and brain is increased. The rate of breathing rises to supply necessary oxygen to the heart, brain, and exercising muscle. Sweat production increases to eliminate toxic compounds produced by the body and to lower body temperature. Production of digestive secretions is severely reduced because digestive activity is not critical for counteracting stress. Blood sugar levels rise dramatically as the liver converts stored glycogen into glucose for release into the blood stream. Although the alarm phase is usually short-lived, the next phase-the resistance reaction-allows the body to continue fighting a stressor long after the effects of the fight-or-flight response have worn off. Other hormones, such as cortisol and other corticosteroids secreted by the adrenal cortex, are largely responsible for the resistance reaction. For example, these hormones stimulate the conversion of protein to energy, so that the body has a 701

Syndromes and Special Topics large supply of energy long after glucose stores are depleted, and promote the retention of sodium to keep blood pressure elevated. As well as providing the necessary energy and circulatory changes required to deal effectively with stress, the resistance reaction provides the changes required to meet emotional crisis, perform strenuous tasks, and fight infection. The effects of adrenal cortex hormones are quite necessary when the body is faced with danger, but prolongation of the resistance reaction or continued stress inmases the risk of si@cant disease (including diabetes, high blood pressure, and cancer) and results in the final stage of the general adaptation syndrome, exhaustion. Exhaustion may manifest as a partial or total collapse of a body function or specific organ. Two of the major causes of exhaustion are loss of potassium ions and depletion of adrenal glucocorticoid hormones like cortisone. Loss of potassium results in cellular dysfunction and, if severe, cell death. Adrenal glucocorticoid store depletion diminishes glucose control, leading to hypoglycemia. Another cause of exhaustion is weakening of the organs. Prolonged stress places a tremendous load on many organ systems, especially the heart, blood vessels, adrenals, and immune system, and is associated with many common diseases, as listed in Box 62-1.

STRESS: A HEALTHY VIEW The father of modem stress research was Hans %lye. Having spent many years studying this subject, Selye developed valuable insights into the role of stress in disease. According Selye, stress in itself should not be viewed in a negative context. It is not the stressor that determines the response; instead it is the individual’s internal reaction, which then triggers the response. This internal reaction is highly individualized. What one

Angina Asthma Autoimmune disease Cancer Cardiovascular disease Common cold Depression Diabetes (adult onset-type 2) Headaches Hypertension Immune suppression Irritable bowel syndrome Menstrual irregularities Premenstrual tension syndrome Rheumatoid arthritis Ulcerative colitis Ulcers Modifiedfrom Benson H. The relaxation response. New York: William Morrow, 1975.

person may experience as stress, the next person may view entirely differently. %lye perhaps summarized his view best in the following passage from his book The Stress of Life2: No one can live without experiencing some degree of stress all the time. You may think that only serious disease or intensive physical or mental injury can cause stress. This is false. Crossing a busy intersection, exposure to a draft, or even sheer joy are enough to activate the body’s stress mechanisms to some extent. Stress is not even necessarily bad for you; it is also the spice of life, for any emotion, any activity causes stress. But, of course, your system must be prepared to take it. The same stress which makes one person sick can be an invigorating experience for another.

The key statement %lye made may be ”your system must be prepared to take it.” A sigruficant body of knowledge has now accumulated delineating methodologies for helping patients develop healthful, rather than disease-facilitating, responses to both short-term and long-term stress.

DIAGNOSTIC CONSIDERATIONS Many people who are ”stressed out” may not be able to identify exactly what is causing them to feel stressed. Typical presenting symptoms are insomnia, depression, fatigue, headache, upset stomach, digestive disturbances, and irritability. To determine the role that stress may play, the “social readjustment rating scale” developed by Holmes and M e 3may be used (Table 62-1). The scale was originally designed to predict the risk of a serious disease due to stress. Various life-changing events are numerically rated according to their potential to cause disease. Notice that even events commonly viewed as positive, such as an outstanding personal achievement, carry stress. If a person is under a great deal of immediate stress or has endured a fair amount of stress for a few months or longer, it is appropriate to assess adrenal dysfunction more accurately with laboratory methods.

Interpretation The standard interpretation of the social readjustment rating scale is that a total of 200 or more units in 1year are considered to be predictive of a high likelihood of experiencing a serious disease. However, rather than using the scale solely to predict the likelihood of serious disease, the clinician can use the scale to evaluate a patient‘s level of stressor exposure, because everyone reacts differently to stressful events.

THERAPEUTIC APPROACH Whether currently aware of it or not, the patient has developed a pattern for coping with stress. Unfortunately, most people have found patterns and

Stress Management

The Social Readjustment Rating Scale Rank

1 2 3 4 5 6 7

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

Life event Death of spouse Divorce Marital separation Jail term Death of a close family member Personal injury or illness Marriage Fired at work Marital reconciliation Retirement Change in health of family member Pregnancy Sex difficulties Gain of a new family member Business adjustment Change in financial state Death of a close friend Change to different line of work Change in number of arguments with spouse Large mortgage Foreclosure of mortgage or loan Change in responsibilitiesat work Son or daughter leaving home Trouble with in-laws Outstanding personal achievement Spouse begins or stops work Beginning or end of school Change in living conditions Revision of personal habits Trouble with boss Change in work hours or conditions Change in residence Change in schools Change in recreation Change in church activities Change in social activities Small mortgage

38

Change in sleeping habits

39 40 41 42 43

Change in number of family get-togethers Change in eating habits Vacation Christmas Minor violations of the law

From HolmesTH, Rahe RH. J Psychosom Res 1967;11:213-218.

Mean value

100 73 65 63 63 53 50 47 45 45 44 40 39 39 39 38 37 36 35 31 30 29 29 29 28 26 26 25 24 23 20 20 20 19 19 18 17 16 15 15 13 12 11

methods that ultimately do not support good health. Negative coping patterns must be identified and replaced with positive ways of coping. The clinician should try to identdy any negative or destructive coping patterns listed in Box 62-2 that the patient may have developed and to replace that pattern with more positive measures for dealing with stress. Stress management can be substantially improved by assisting the patient in the following six equally important areas: Techniques to calm the mind and promote a positive mental attitude Lifestyle factors Exercise A healthful diet designed to nourish the body and support physiologic processes Dietary and botanical supplements designed to support the body as a whole, but especially the adrenal glands Supervised stress management program

Calming the Mind and Body Learning to calm the mind and body is extremely important in relieving stress. Among the easiest methods for the patient to learn are relaxation exercises. The goal of relaxation techniques is to produce a physiologic response known as a relaxation response-a response that is exactly opposite to the stress response. Although an individual may relax by simply sleeping, watching television, or reading a book, relaxation techniques are designed specifically to produce the relaxation response. Relaxation response was a term coined by Harvard professor and cardiologist Herbert Benson in the early 1970s to describe a physiologic response that is just the opposite of the stress response.' With the stress response (Box 62-3), the sympathetic nervous system dominates. With the relaxation response (Box 62-4), the parasympathetic nervous system dominates. The parasympathetic nervous system controls bodily functions such as digestion, breathing, and heart rate during periods of rest, relaxation, visualization, meditation, and sleep. Although the sympathetic nervous system is designed to protect against immediate danger, the parasympathetic

Dependence on chemicals: legal and illicit drugs, alcohol, smoking Overeating Too much television Emotional outbursts Feelings of helplessness Overspending Excessive behavior

Syndromes and Special Topics

The heart rate and force of contraction of the heart increase to provide Mood to areas necessary for response to the stressful situation. Blood is shunted away from the skin and internal organs, except the heart and lung, while at the amount of blood supplying required oxygen and glucose to the muscles and brain is increased. The rate of breathing rises to supply necessary oxygen to the heart, brain, and exercising muscle. Sweat production increases to eliminate toxic compounds produced by the body and to lower body temperature. Production of digestive secretions is severely reduced because digestive activity is not critical to counteracting stress. Blood sugar levels are raised dramatically as the liver dumps stored glucose into the blood stream.

*The heart rate is reduced and the heart beats more effectively. Blood pressure is reduced. Blood is shunted towards internal organs, especially those organs involved in digestion. The rate of breathing decreases as oxygen demand is reduced during periods of rest. Sweat production diminishes, because a person who is calm and relaxed does not experience nervous perspiration. Production of digestive secretions is increased, greatly improving digestion. Blood sugar levels are maintained in the normal physiologic range.

system is designed for repair, maintenance, and restoration of the body. The relaxation response can be achieved through a variety of techniques. The methodology should be determined by patient interest, because all techniques have the same physiologic effect-a state of deep relaxation. The most popular techniques are meditation, prayer, progressive relaxation, self-hypnosis, and biofeedback. To produce the desired long-term health benefits, the patient should use the relaxation technique for at least 5 to 10 minutes each day.

Breathing Producing deep relaxation with any technique requires learning how to breathe. One of the most powerful methods of producing less stress and more energy in the body is by breathing with the diaphragm. Diaphragm breathing activates the relaxation centers in the brain. Box 62-5 lists a 10-step technique for teaching diaphragmatic breathing.

Progressive Relaxation One of the most popular techniques for producing the relaxation response is progressive relaxation. The technique is based on a very simple procedure of comparing

1. Find a comfortable and quiet place to lie down or sit.

2.Place your feet slightly apart. Place one hand on your abdomen near your navel. Place the other hand on your chest. 3.You will be inhaling through your nose and exhaling through your mouth. 4. Concentrate on your breathing. Note which hand is rising and falling with each breath. 5.Gently exhale most of the air in your lungs. 6. Inhale while slowly counting to 4. As you inhale, slightly extend your abdomen, causing it to rise about 1 inch. Make sure that you are not moving your chest or shoulders. 7. As you breathe in, imagine the warmed air flowing in. Imagine this warmth flowing to all parts of your body. 8. Pause for 1 second, then slowly exhale to a count of 4. As you exhale, your abdomen should move inward. 9. As the air flows out, imagine all your tension and stress leaving your body. 10. Repeat the process until a sense of deep relaxation is achieved.

tension with relaxation. Many people are not aware of the sensation of relaxation. In progressive relaxation, an individual is taught what it feels like to relax by comparing relaxation with muscle tension. The basic technique is to have the patient contract a muscle forcefully for a period of 1to 2 seconds and then give way to a feeling of relaxation in that muscle. The procedure systematically goes through all the muscles of the body, progressively producing a deep state of relaxation. The procedure begins with contracting the muscles of the face and neck, then the upper arms and chest, followed by the lower arms and hands. The process is repeated progressively down the body, from the abdomen through the buttocks, the thighs, and calves to the feet. This whole process is repeated two or three times. This technique is often used in the treatment of anxiety and insomnia. Progressive relaxation, deep breathing exercises, or some other stress reduction technique is an important component of a comprehensive stress management program.

Lifestyle Factors A patient’s lifestyle is a major determinant of his or her

stress levels. The two primary areas of concern (other than addressing negative coping patterns) are time management and relationship issues. One of the biggest stressors for most people is time. They simply do not feel they have enough of it. Box 62-6 provides tips on time management for patients. Another major cause of stress for many people is interpersonal relationships. Interpersonal relationships can be divided into three major categories: marital, family, and job-related. The quality of any relationship

Stress Management

Set priorities. Realize that you can only accomplish so much in a day. Decide what is important, and limit your efforts to that goal. Organize your day. There are always interruptions and unplanned demands on your time, but create a definite plan for the day on the basis of your priorities. Avoid the pitfall of always letting the “immediate demands” control your life. Delegate authority. Delegate as much authority and work as you can. You can’t do everything yourself. Learn to train and depend on others. Tackle tough jobs first. Handle the most important tasks first, while your energy levels are high. Leave the busy work or running around for later in the day. Minimize meeting time. Schedule meetings to bump up against the lunch hour or quitting time; that way they can’t last forever. Avoid puffing things off. Work done under pressure of an unreasonable deadline often has to be redone. That creates more stress than if it had been done right the first time. Plan ahead. Don’t be a perfectionist. You can never really achieve perfection anyway. Do your best in a reasonable amount of time, then move on to other important tasks. If you find time, you can always come back later and polish the task some more.

ultimately comes down to the quality of the communication. Learning to communicateeffectivelygoes a very long way in reducing the stress and occasional (or frequent) conflicts of interpersonal relationships. Box 62-7 lists seven tips for effective communication, regardless of the type of interpersonal relationship.

Exercise The immediate effect of exercise is stress on the body. However, with a regular exercise program the body adapts, and exercise becomes an effective stress reduction technique. With regular exercise, the body becomes stronger, functions more efficiently, and has greater endurance. Exercise is a vital component of a comprehensive stress management program and overall good health. People who exercise regularly are much less likely to suffer from fatigue and depression. Tension, depression, feelings of inadequacy, and worries diminish greatly with regular exercise. Exercise alone has been demonstrated to have a tremendous effect in terms of improving mood and the ability to handle stressful life situations. This effect is seen in adolescents as well as adults. In one study, 2223 boys and 2838 girls (mean age, 16.3 years) from 10 teams and 25 different individual sports were studied for the relationship between emotional well-being and psychological well-being. The sport and vigorous recreational activity index was positively associated with emotional well-being independent of other variables?

Dietary Guidelines An individual suffering from stress or anxiety must support the biochemistry of the body by following

The first key to successful communication is the most important: Learn to be a good listener. Allow the person you are communicating with to really share his or her feelings and thoughts uninterrupted. Empathize with the person, put yourself in his or her shoes. If you first seek to understand, you will find yourself being better understood. Be an active listener. This means that you must be truly interested in what the other person is communicating. Listen to what he or she is saying instead of thinking about your response. Ask questions to gain more information or clarify what he or she is telling you. Good questions open lines of communication. Be a reflective listener. Restate or reflect back to the other person your interpretationof what he or she is telling you. This simple technique shows the other person that you are both listening to and understanding what he or she is saying. Restating what you think is being said may cause some short-term conflict in some situations, but it is certainly worth the risk. Wait to speak until the person you want to communicate with is listening. If the person is not ready to listen, your message will not be heard no matter how well you communicate. Don’t try to talk over somebody. If you find yourself being interrupted, relax; don’t try to out-talk the other person. If you are courteous and allow him or her to speak, eventually (unless extremely rude) he or she will respond likewise. If that doesn’t happen, point out that the other person is interrupting the communication process.You can do this only if you have been a good listener. Double standards in relationships seldom work. Help the other person become an active listener. This can be done by asking whether he or she has understood what you were communicating. Ask him or her to tell you what he or she heard. If the other person doesn’t seem to be understanding what you are saying, keep trying until he or she does. Don’t be afraid of long silences. Human communication involves much more than human words. A great deal can be communicated during silences; unfortunately in many situations silence can make us feel uncomfortable. Relax. Some people need silence to collect their thoughts and feel safe in communicating.The important thing to remember during silences is that you must remain an active listener.

some important dietary guidelines. Specifically, he or she must: Eliminate or restrict the intake of caffeine. Eliminate or restrict the intake of alcohol. Eliminate refined carbohydrates from the diet. Eat a diverse range of whole foods. Increase the potassium-to-sodium ratio. Eat regular planned meals in a relaxed environment. Control food allergies. According to %lye? whether or not stress is harmful is based on the strength of the system. From a purely physiologic perspective, it can be strongly argued that delivery of high-quality nutrition to the cells of the body is the critical factor in determining the strength of the system.

When the eating habits of Americans are examined as a whole, it is little wonder that so many people are suffering from stress, anxiety, and fatigue. Most Americans are not providing their bodies with the high-quality nutrition they need. Instead of eating foods rich in vital nutrients, most Americans focus on refined foods high in calories, sugar, fat, and cholesterol.

in sodium. Most Americans have a dietary potassiumto-sodium (KNa) ratio of less than 1:2.In contrast, most researchers recommend a dietary KNa ratio higher than 51 for health. However, even this recommendation may not be optimal. A natural diet rich in fruitsand vegetables can produce a K.Na ratio higher than 50:1, as most fruits and vegetables have a KNa ratio of more than 100:l.

Caffeine

Meal Planning

The average American consumes 150 to 225 mg of caffeine daily, or roughly the amount of caffeine in two cups of coffee. Although most people can handle this amount, some people are more sensitive to the effects of caffeine than other people, owing to decreased activity of phase I detoxification (see Chapter 54). Even small amounts of caffeine can affect sensitive people, whereas those with normal sensitivity respond to large amounts. Excessive caffeine consumption can produce “caffeinism characterized by symptoms of depression, nervousness, irritability, recurrent headache, heart palpitations, and insomnia.” People prone to feeling stress and anxiety tend to be especially sensitive to caffeine?”

Mealtimes should be spent in a relaxed environment. As noted previously, digestion is a process largely controlled by the parasympathetic nervous system. Eating in a rushed manner or in a noisy or hurried environment is not conducive to good digestion or good health.

Alcohol Alcohol produces chemical stress on the body. It also increases adrenal hormone output and interferes with both normal brain chemistry and normal sleep cycles. Although many people believe that alcohol has a calming effect, a study of 90 healthy male volunteers given either a placebo or alcohol demonstrated sigruficant increases in anxiety scores after consumption of alcohol?

Refined Carbohydrates Refined carbohydrates (e.g., sugar and white flour) are known to contribute to problems in blood sugar control, especially hypoglycemia. The associationbetween hypoglycemia and impaired mental function is well known. Unfortunately, most patients experiencing depression, anxiety, or other psychological condition are rarely tested for hypoglycemia, nor are they prescribed a diet that restricts refined carbohydrates. Numerous studies have shown a high percentage of hypoglycemia in depressed patients73 As depression is one of the most common causes of anxiety, this finding provides a link between hypoglycemia and feelings of stress. Simply eliminating refined carbohydrate from the diet is occasionally all that is needed for effective therapy in patients who have depression or anxiety due to hypoglycemia.

Potassium-to-Sodium Ratio One of the key dietary recommendations to support the adrenal glands is to ensure adequate potassium levels within the body. This can best be done by consuming foods rich in potassium and avoiding foods high

Food Allergies People with symptoms of anxiety or chronic fatigue must be concerned about food allergies. As far back as 1930, pioneering allergist Albert Rowe began noticing that anxiety and fatigue were key features of food allerg i e ~Originally, .~ Rowe described a syndrome known as “allergic toxemia” to describe a syndrome that included the symptoms anxiety, fatigue, muscle and joint aches, drowsiness, difficulty of concentration, and depression. Around the 1950s, thissyndrome began to be referred to as the “allergictension-fatigue syndrome.”With the popularity of chronic fatigue syndrome, many physicians and other people are forgetting that food allergies can lead to anxiety as well as chronic fatigue.

NUTRITIONAL AND BOTANICAL SUPPORT Nutritional and botanical support for the individual experiencing signs and symptoms of stress largely involves supporting the adrenal glands. Long-term stress and corticosteroids cause the adrenal glands to shrink and become dysfunctional, aggravating the stress symptoms anxiety, depression, and chronic fatigue. An abnormal adrenal response, either deficient or excessive hormone release, sigruficantly alters an individual‘s response to stress. Often the adrenals become ”exhausted” as a result of constant demands put on them. An individual with adrenal exhaustion usually suffers from chronic fatigue and may complain of feeling “stressed out” or chronically anxious. He or she typically has a reduced resistance to allergies and infection.

Nutritional Supplements The nutrients especially important for supporting adrenal function are vitamin C, vitamin B6, zinc, magnesium, and pantothenic acid. All of these nutrients play a critical role in the health of the adrenal gland as well as the manufacture of adrenal hormones. During stress, the levels of these nutrients in the adrenals decrease substantially. For example, during chemical, emotional, psychological, or physiologic stress, the urinary excretion of

Stress Management

vitamin C is increased. Examples of chemical stressors are cigarette smoke, pollutants, and allergens. Extra vitamin C in the form of supplementation and a higher intake of vitamin C-rich foods is often recommended to keep the immune system working properly during times of stress. Equally important during high periods of stress or in individuals needing adrenal support is pantothenic acid (vitamin B). Pantothenic acid deficiency results in adrenal atrophy, characterized by fatigue, headache, sleep disturbances, nausea, and abdominal discomfort. Pantothenic acid is found in whole grains, legumes, cauliflower, broccoli, salmon, liver, sweet potatoes, and tomatoes. In patients who suffer from chronic stress or have a history of corticosteroid (prednisone) use, the typical level of supplementation is 100 to 500 mg daily. The appropriate daily doses of vitamin B6 is 50 to 100 mg; of zinc, 20 to 30 mg; and of magnesium, 250 to 500 mg.

Botanical Medicines Several botanical medicines support adrenal function. Most notable are the ginsengs. Both Chinese ginseng (Punax ginseng) and Siberian ginseng (EZeutherococcus senticosus) exert beneficial effects on adrenal function and enhance resistance to stress. These ginsengs are often referred to as ”general tonics” or ”adaptogens.” The term general tonic implies that an herb will increase the overall tone of the whole body. The ginsengs are also often referred to as “adrenal tonics” because they improve the tone and function of the adrenal glands. Chinese and Siberian ginseng can be used to achieve the following goals: Restore vitality in debilitated and feeble individuals Increase feelings of energy Improve mental and physical performance Prevent the negative effects of stress and enhance the body’s response to stress Offset some of the negative effects of cortisone Enhance liver function Protect against radiation damage All of these applications are supported by good clinical

The modem term aduptogen is a more descriptive word used to describe the general tonic effects of Siberian and Chinese ginseng. An adaptogen is a substance with the following characteristics: Must be innocuous and must cause minimal disorders in the physiologic functions of an organism Must have a nonspecific action (i.e., it should improve resistance to adverse influences through a wide range of physical, chemical, and biochemical factors) Usually has a normalizing action irrespective of the direction of the pathologic state

According to tradition and scientific evidence, both Siberian and Chinese ginsengs possess this kind of equilibrating, tonic, antistress action, and so the term adaptogen is quite appropriate in describing their general effects. The ginsengs have been shown to enhance the ability to cope with various stressors, both physical and mental.1012Presumably this antistress action is mediated by mechanisms that control the adrenal glands. Ginseng delays the onset and reduces the severity of the alarm phase response of the general adaptation syndrome. People taking either of the ginsengs typically report an increased sense of well-being. Clinical studies have confirmed that both Siberian and Chinese ginsengs sigthcantly reduce feelings of stress and anxiety. For example, in one double-blind clinical study, nurses who had switched from day to night duty rated themselves for competence, mood, and general well-being, and were given a test for mental and physical performance along with blood cell counts and blood chemistry eva1uati0n.l~ The group who were given P. ginseng demonstrated higher scores in competence, mood parameters, and mental and physical performance compared with those receiving placebos. The nurses taking the ginseng felt more alert, yet more tranquil, and were able to perform better than the nurses who were not taking the ginseng. In addition to these human studies, several animal studies have shown the ginsengs to exert significant antianxiety effects. In several of these studies, the stressrelieving effects were comparable to those of diazepam (Valium); however, diazepam causes behavior changes, sedative effects, and impaired motor activity, but ginseng has none of these negative effe~ts.’~ On the basis of the clinical and animal studies, ginseng appears to offer sigrufrcant benefit to people suffering from stress and anxiety. P. ginseng is generally regarded as being more potent than E. senticosus. P. ginseng is probably better for the patient who has experienced a great deal of stress, is recovering from a longstanding illness, or has taken corticosteroids such as prednisone for a long time. For the patient who is under mild to moderate stress and is experiencing less obvious impairment of adrenal function, E. senticosus may be the better choice. Another useful botanical medicine to support stress management is Rhodiolu roseu (artic root), a popular plant in traditional medical systems in Eastern Europe and Asia, where it has traditionally been recommended to help combat fatigue and restore energy. Modem research has confirmed these effects and its qualities as an adaptogen. However, the adaptogenic actions of R. roseu are different from those of Chinese and Siberian ginsengs, which act primarily on the hypothalamus-pituitary-adrenal axis. R. roseu seems to exert its adaptogenic effects by working on neurotransmitters and endorphins. R. rosea appears to offer an advantage over other adaptogens in circumstances of acute stress because it produces a greater feeling

Syndromes and Special Topics

of relaxation and antianxiety effects. A single dose of Rhodwla extract prior to acute stressful events has been shown to prevent stress-induced disruptions in function and performance, but like the ginsengs, R. roseu has also shown positive results with long-term use.1518 On the basis of results of clinical trials with a standardized R. rosea extract, the therapeutic dose varies according to the rosavin content. For a dosage target of 3.6 to 7.2 mg of rosavin, the daily dose would be 360 to 600 mg for an extract standardized for 1%rosavin; 180 to 300 mg for 2% rosavin; and 100 to 200 mg for 3.6% rosavin. When R. roseu is used as an adaptogen, longterm administration is normally begun several weeks before a period of expected increased physiologic, chemical, or biologic strain and continued throughout the duration of the challenging event or activity. When R. roseu is used as a single dose for acute stress (e.g., for an examination or athletic competition), the suggested dose is three times the dose used for long-term supplementation. No side effects have been reported in the clinical trials, but at higher dosages, some individuals might experience greater irritability and insomnia.

Stress Management Programs Supervised stress management programs are thought to offer greater compliance and better results than unsupervised, patient-directed programs. In one study, stress management experts evaluated six widely used

1.Benson H. The relaxation response. New York William Morrow, 1975. 2.%lye H. The stress of life. New York: McGraw Hill, 1978. 3.Holmes TH, Rahe RH. The social readjustment rating scale. J Psychosom Res 1967;11:213-218. 4. Steptoe A, Butler N. Sports participation and emotional wellbeing in adolescents. Lancet 1996s71789-1792. 5. Chou T. Wake up and smell the coffee: caffeine, coffee, and the medical consequences. West J Med 1992;157544-553. 6. Monteiro MG, Schuckit MA, Irwin M. Subjective feelings of anxiety in young men after ethanol and diazepam infusions. J Clin Psychiatry 1990;51:12-16. 7. Wmokur A, Maislin G, Phillips JL, et al.Insulin resistance after oral glucose tolerance testing in patients with major depression. Am J Psychiatry 1988;145325-330. 8. Wright JH, Jacisin JJ, Radin NS, et al. Glucose metabolism in unipolar depression. Br J Psychiatry 1978;132:386-393. 9. Rowe AH, Rowe A Jr. Food allergy: its manifestations and control and the elimination diets: a compendium. Springfield, k CC Thomas, 1972. 10.Davydov M, Krikorian AD. Eleutherococcus smticosus (Rupr. & Maxim.) Maxim. (Araliaceae) as an adaptogen: a closer look. J Ethnopharmacol2OOO;72:345-393. 11. Coleman CI, Hebert JH, Reddy P. The effects of Panax ginmg on quality of life. J Clin Pharm Ther 2003;285-15. 12. Ong YC, Yong EL. Panax (ginsenghpanacea or placebo? Molecular and cellular basis of its pharmacological activity. Ann Acad Med Singapore 2O00;29424.

occupational stress management interventions (relaxation, physical fitness, cognitive restructuring, meditation, assertiveness training, and stress inoculation) on the basis of ten practicality criteria and seven effectiveness objectives. They found that relaxation was the most practical intervention, and that meditation and stress inoculation the least practical. Physical fitness was chosen to be the most effective intervention, and both meditation and assertivenesstraining were rated overall as the least effective. What these results imply is that although relaxation training may be the most practical intervention, physical exercise was the most effective intervention.l9 Meditation was shown to be the least practical and least effective method in this evaluation, but when it is part of supervised program it can be very effective. In one trial of 103 adults, 59% and 61% of the meditation and control groups, respectively, completed the studyz0 The intervention program consisted of an 8-week group stress reduction program in which subjects learned, practiced, and applied “mindfulness meditation” to daily life situations. The control group received educational materials and was encouraged to use community resources for stress management. Compared with the control group, intervention subjects reported significant decreases from baseline in effect of daily hassles (24%), psychological distress, (44%), and medical symptoms (46%)that were maintained at the 3-month follow-up.

13.Hallstrom C, Fulder S, Carruthers M. Effect of ginseng on the performance of nurses on night duty. Comp Med East West 1982;6 277-282. 14.Bhattacharya SK, Mitra SK. Anxiolytic activity of Punaw ginsmg roots: an experimental study. J Ethnopharmacol1991;34:87-92. 15. Kelly GS. Niodiola roseu: a possible plant adaptogen. Altern Med Rev 2001;6293-302. 16. Shevtsov VA, Zholus BI, Shervarly VI,et al. A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine 2003;lO 95-105. 17. Darbinyan V, Kteyan A, Panossian A, et al. Rhodiola rosea in stress induced fatigue-a double blind cross-over study of a standardized extract SHR-5with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine 2000;7365371. 18. Spasov AA, Wikman GK, Mandrikov VB, et al. A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen. Phytomedicine 2000;785-89. 19. Bellarosa C, Chen PY. The effectiveness and practicality of occupational stress management interventions: a survey of subject matter expert opinions. J Occup Health Psycho1 1997;2247-262. 20. Williams KA, Kolar MM, Reger BE, et al.Evaluation of a wellnessbased mindfulness stress reduction intervention: a controlled trial. Am J Health Promot 2001;15422-432.

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Alkylglycerols 713 AIIium cepa (Onion) 725 AIIiirm satiuum (Garlic) 729 Aloe uern (Cape Aloe) 737 Angelica Species 749 Artemisia absinthiuni (Wormwood) 755 Artemisia aiznua (Sweet Wormwood) 761 Bee Products-Pollen, Propolis, and Royal Jelly 767 Beta-carotene and Other Carotenoids 771 Boron 783 Bromelain 791 Camellia sineiisis (Green Tea) 797 Capsicumfriitescens (Cayenne Pepper) 803 Carnitine 809 Catechin [(+)-cyanidanol-31 823 Centella asiaticn (Gotu Kola) 829 Chinese Prepared Medicines 837 Cimic$iga racemosa (Black Cohosh) 847 Citicoline (CDP-Choline) 853 Coenzyme QIa 859 Coleusforskohlii 871 Cominiphora miikiil (Mukul Myrrh Tree) 877 Crataegus oxyacantha (Hawthorn) 881 Croton lechleri (Dragon’s Blood) 887 Curcuma longa (Turmeric) 893 Dehydroepiandrosterone 899 Echinacea Species (Narrow-Leafed Purple Coneflower) 907 Eleutherococcus senticosus (Siberian Ginseng) 919 Ephedra Species 925 Epilobium Species (Fireweed) 931 Fatty Acid Metabolism 935 Fish Oils (Omega-3 Fatty Acids, Docosahexaenoic Acid, Eicosapentaenoic Acid, Dietary Fish, and Fishoils) 945 Flavonoids-Quercetin, Citrus Flavonoids, and Hydroxyethylrutosides 967 Ginkgo biloba (Ginkgo Tree) 975 Glucosamine 987 Glutamine 993 Glycyrrhiza glabra (Licorice) 1003 Hydrastis canadensis (Goldenseal) and Other Berberine-Containing Botanicals 1013 5-Hydroxytryptophan 1021 Hypericum perforatirm (St. John’s Wort) 1037 Lobelia inflata (Indian Tobacco) 1049 Melaleuca alternifolia (Tea Tree) 1053 Melatonin 1057 Melissa oficinalis (Lemon Balm) 1065 Mentha piperita (Peppermint) 1071 Microbial Enzyme Therapy 1075 Naturally Occurring Antioxidants 1085 Opuntia Species (Prickly Pear) 1113 Panax ginseng (Korean Ginseng) 1119 Pancreatic Enzymes 1131 Phage Therapy: Bacteriophages as Natural, Self-LimitingAntibiotics 1147

114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142

Phosphatidylserine 1163 Piper niethysticum (Kava) 1167 Policosanol 1173 Prebiotics 1183 Probiotics 1195 Procyanidolic Oligomers 1217 Pygeum africanlrm (Bitter Almond) 1221 Ruscus acideatus (Butcher’s Broom) 1227 SAMe (S-Adenosylmethionine) 1235 Sarsaparilla Species 1241 Sereiion repens (Saw Palmetto) 1245 Silybum itiariaiizrni (Milk Thistle) 1251 Soy Isoflavones and Other Constituents 1259 Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements 1275 Tnbebrrin nuellnnedae (LaPacho, Pau D’Arco, Ipe Roxo) 1321 Tniiacetirnr parMeniirni (Feverfew) 1331 Tnraxncirm offrcinnle (Dandelion) 1335 Tnxirs brevifolia (Pacific Yew) 1339 Urtica dioico (Stinging Nettle) 1345 Urm iirsi (Bearberry) 1351 Vmciniunr macrocarpon (Cranberry) 1355 Vncciniiinr myrtillirs (Bilberry) 1365 Vnleriann oficinalis (Valerian) 1371 Viscirnr albiriii (European Mistletoe) 1375 Vitamin A 1381 Vitamin Toxicities and Therapeutic Monitoring 1389 Vitex agnirs castus (Chaste Tree) 1395 Water: The Most Basic Nutrient and Therapeutic Agent 1401 Zingibrr oficinnle (Ginger) 1411

Careful review of the scientific literature reveals a considerable amount of research documenting the clinical efficacy, pharmacologic activity, and toxicology of numerous “natural” medicines. An important purpose of this section is the substantiation, from a scientific standpoint, of the historical use of botanical medicines. Although plants have been used a s medicines since antiquity, appreciation of them as effective medicinal agents has greatly diminished recently. New to this edition is incor-poration of the research that has looked at the potential for interaction between conventional and natural interventions. Hopefully, this section will further revive the appreciation for and the safe and effective use of botanical medicines. Although some plant constituents are discussed as separate entities and in many situations may be the most appropriate therapeutic substances, we believe that the whole herb should be used whenever possible. It has been amply demonstrated that, in many instances, physiologic and pharmacologic effects of a particular plant constituent are diminished when it is given as an isolated component rather than in its naturally occurring environment. Furthermore, besides synergistic and enhancing effects, there appear to be factors in many plants that prevent

709

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many of the side effects of isolated plant constituents. In understanding the pharmacology, pharmacognosy, and historical use of plants, the student of natural medicine is once again inspired by the miracle of nature as well as the intuition and empiricism that ancient herbalists possessed. We hope that this section will help better inform our readers of the impressive uses, and potential dangers, of these

natural medicines. We also want to stress that botanical medicine should not be used simply as substitutes for the drugs commonly used to treat disease. The true physician of natural medicine will use them as part of the treatment of the whole person and in the context of removing the causes of the disease and promoting health, not simply treating symptoms.

Abortifacient a substance that induces abortion. Acrid a pungent, biting taste that causes irritation. Adaptogen a substance that is safe, increases resistance to stress, and has a balancing effect on body functions. Adjuvant a substance that enhances the effect of the medicinal agent or increases the antigeniaty of a cancer cell. Alkaloids naturally occurring amines, arising from heterocyclic and often complex structures, that display pharmacologic activity. Their trivial names usually end in - h e . They are usually classified according to the chemical structure of their main nucleus: phenylalkylamines (e.g., ephedrine), pyridine (e.g., nicotine), tropine (eg., atropine, cocaine), quinoline (e.g., quinine), isoquinolone (e.g., papaverine), phenanthrene (e.g., morphine), purine (e.g., caffeine), imidazole (e.g., pilocarpine), and indole ( e g , physostigmine, yohimbine). Alterative a substance that has a balancing effect on a particular body function. Analgesic a substance that reduces the sensation of pain. Androgens hormones that stimulate male characteristics. Anthelminthic a substance that causes the elimination of intestinal worms. Anthocyanidin a particular class of flavonoids that gives plants, fruits, and flowers colors ranging from red to blue. Antidote a substance that neutralizes or counteracts the effects of a poison. Aphrodisiac a substance that increases sexual desire. Astringent an agent that causes the contraction of tissue. Balm a soothing or healing medicine applied to the skin. Beta-carotene pro-vitamin A. A plant carotene that can be converted to two vitamin A molecules. Carminative a substance that promotes the elimination of intestinal gas. Carotenes fat-soluble plant pigments, some of which can be converted into vitamin A by the body. Cathartic a substance that stimulates the movement of the bowels, more powerful than a laxative. Cholagogue a compound that stimulates the contraction OE the gallbladder.

Choleretic a compound that promotes the flow of bile. Cholestasis the stagnation of bile within the liver. Cholinergic pertaining to the parasympathetic portion of the autonomic nervous system and the release of acetylcholine as a transmitter substance. Coenzyme a necessary nonprotein component of an enzyme, usually a vitamin or mineral. Compress a pad of linen applied under pressure to an area of skin and held in place. Decoctions dilute aqueous extracts prepared by boiling the botanical material with water for a specified period, followed by straining or filtering. Demulcent a substance soothing to irritated mucous membranes. Emulsify to disperse large fat globules into smaller uniformly distributed particles that can remain in suspension in water. Enteric-coated a special way of covering a tablet or capsule to ensure that it does not dissolve in the stomach, so it can reach the intestinal tract. Enzyme an organic catalyst that speeds chemical reactions. Essential oils also known as volatile oils, ethereal oils, or essences. They are usually complex mixtures of a wide variety of organic compounds (e.g., alcohols, ketones, phenols, acids, ethers, esters, aldehydes, oxides) that evaporate when exposed to air. They generally represent the odoriferous principles of plants. Extracts concentrated forms of natural products obtained by treating crude materials containing these substances with a solvent and then removing the solvent completely or partially from the preparation. The most commonly used extracts are fluid extracts, solid extracts, powdered extracts, tinctures, and native extracts. Flavonoid a generic term for a group of flavonecontaining compounds that are found widely in nature. They include many of the compounds that account for plant pigments (anthocyanins, anthoxanthins, apigenins, flavones, flavonols, bioflavonols, etc.). These plant pigments exert a wide variety of physiologic effects in the human body. Fluid extracts these extracts are typically hydroalcoholic solutions with a strength of one part solvent to one part herb. The alcohol content varies with

Pharmacology of Natural Medicines

each product. They are, in essence, concentrated tinctures, constructed to represent 1 grain of the crude drug to 1minim of fluid extract. Glycosides sugar-containing compounds composed of a glycone (sugar component) and an aglycone (nonsugar-containing component) that can be cleaved upon hydrolysis. The glycone portion may be glucose, rhamnose, xylose, fructose, arabinose, or any other sugar. The aglycone portion can be any kind of organic compound (e.g., sterols, triterpenes, anthraquinones, hydroquinones, tannins, carotenoids, anthocyanidins). Infusion tea produced by steeping a botanical in hot water. Laxative a substance that promotes the evacuation of the bowels. LD5,, the dosage that will kill 50% of the animals taking the substance. Lipotropic promoting the flow of lipids to and from the liver. Menstrums solvents used for extraction (e.g., water, alcohol, acetone). Metalloenzyme an enzyme that contains a metal at its active site. Native extracts high-potency extracts prepared via concentration under reduced pressure at low temperatures until all solvent is removed. Oleoresins primarily mixtures of resins and volatile oils. They either occur naturally or are made by extracting the oily and resinous materials from botanicals with organic solvents (e.g., hexane, acetone, ether, alcohol). The solvent is then removed under vacuum, leaving behind a viscous, semisolid extract that is the oleoresin. Examples of prepared oleoresins are paprika, ginger, and capsicum. Powdered extract a solid extract that has been dried to a powder. Putrefaction the process of breaking down protein compounds by rotting.

Recommended dietary allowance (RDA) recommended dietary allowance. Resins complex oxidative products of terpenes that occur naturally as plant exudates or are prepared by alcohol extraction of botanicals that contain resinous principles. Saponins nonnitrogenous glycosides, typically with sterol or a triterpene as the aglycone, that possess the common property of foaming, or making suds, when strongly agitated in aqueous solution. Solid extracts thin to thick, viscous liquids or semisolids prepared from native extracts by adjusting the latter to the specific strength with suitable diluents. Typically, these extracts are 41, that is, one part extract is equivalent to, or derived from, four parts of crude herb. Strength of an extract the potency or strength of a botanical extract is generally expressed in two ways. If they contain known active principles, their strength is commonly expressed in terms of their content of active principles. Otherwise their strength is expressed in terms of their concentration of the crude drug. Thus a strength of 4:l means one part of extract is equivalent to, or derived from, four parts of crude drug. A strength of 1:5 represents one part of extract comparable to 0.2 parts of the crude drug. This ratio method of expressing drug strength does not accurately measure potency because there may be wide variation between manufacturers. Tinctures alcoholic or hydro-alcoholic solutions usually containing the active principles of botanicals in low concentrations. They are usually prepared by maceration or percolation or by dilution of their corresponding fluid or native extracts. The strengths of tinctures are typically 1 : l O or 1:5.Alcohol content varies. Tonic a substance that exerts a gentle strengthening effect on the body.

A1kylglycerols Peter T. Pugliese, MD Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Introduction 713 History 713 Basic Chemistry of Alkylglycerol Ethers from Shark Liver Oil 714 Some Definitions 714 Absorption, Fate, and Excretion 715 Biologic Effects 716 Bacteriostatic Effects 716 Hemopoietic Effects 716 Protection Against Radiation Damage 717 Immunologic Aspects of Alkylglycerols 717 Overview of the Immune System 717 Complement 717 Macrophage 718

INTRODUCTION Sharks have existed, virtually unchanged, for some 450 million years. Some scientists attribute this long staying power to the well-developed immune system in the shark, an immune system that is quite similar to our own. Sharks have both humoral and cellular components to their immune system and therefore have B cells and T cells. They also have spleens and thymus glands just as humans do, although they possess large quantities of alkylglycerols found mainly in the liver. This chapter explores the use of alkylglycerols from sharks both as immune stimulants and as powerful agents in the treatment of neoplastic disorders.

HISTORY

~_______

Alkylglycerols are ether-linked biologic compounds that have a long and fascinating history. Much of their early history is found in the literature of histochemistry and is related to methods of staining specific cellular components. One of the greatest histologists was Robert Feulgen (1884-1955), a German physiologic chemist who devised the Feulgen reaction. (The Feulgen reaction,

Clinical Uses of Alkylglycerols 719 Cancer 719 Tumor Regression with Alkylglycerol Treatment 719 Protection Against Radiation Injuries 719 Alkylglycerols in Other Medical Conditions 720 Blood-Brain Barrier Permeability 721 Experimental Antitumor Activity with Methoxy-SubstitutedAlkylglycerol 721 Indications and Dosage 722 Toxicology of the Alkylglycerols 722 Toxicity in Animals 722 Toxicity in Humans 722 Conclusions 722

or test, is a method to detect animal nucleic acids. It involves an acid hydrolysis with HCl followed by a 1% solution of decolorized rosaniline, which yields a red color in the presence of nucleic acids.) Feulgen and K. Voit discovered plasmalogens in 1924.' At the time they thought they had discovered an aldehyde, which they called plasmal. The origin of plasmal was believed to be an unknown substance, which they called plasmaZogen. They demonstrated the presence of this compound in many tissues, from protozoa to humans. Plasmalogens, it was learned later, were ether lipid compounds that are formed in the metabolic pathway of phosphoglycerides. They differ from phosphoglycerides in that they contain an ether linkage on the C-1 of the glycerol molecule. Intensive work on the structure and formation of the plasmalogens continued over the next 35 years. It was many years before a formula for plasmalogens was finally agreed on, and the biologic function of plasmalogens and their role in organisms was finally discovered after 1960. As in many discoveries, there are always unsung heroes: scientists who work quietly in some obscure laboratory, publish a paper, and are seen no more. Such was 713

Pharmacology of Natural Medicines

the case with research on the alkylglycerols.The work of Kossel and Edbaches on the starfish Astropecten aurantiacus was unknown until 1943 when Bergmann and Stansbury3 compared their preparation of batyl alcohol, a natural alkylglycerol obtained from the starfish, to the original work of Kossel and Edbaches and found similar physical and chemical properties of both compounds. Backing up in time, in the 1920s, after World War I, to Japan, where Tsujimoto and Toyama4were working on unsaponifiable compounds from liver extracts. (Unsaponifiable fractions are those fatty compounds that do not form soaps when shaken with strong bases such as potassium or sodium hydroxide. Steroids are an example of this class of compounds.) It was the work of these two investigators that identified two major alkylglycerols in shark and ray liver oil. They called the first compound selachyl alcohol from the family name for sharks, Selachoidei, and batyl alcohol from the ray family Batoidei. They were uncertain of the exact chemical structure at the time, due to questions about the role of an oxygen atom in the molecules. In 1924 Toyama5isolated a third compound from the liver oils of the ratfish, Chimera monstrosa, which he called chimyl alcohol. Four years later Heilbron and Owens6described the crucial role of the oxygen atom as an ether linkage. They refluxed batyl alcohol with hydroiodic acid and obtained octodecyl iodide, which was conclusive evidence of a glyceryl ether structure. At about this time, a great deal of work was being conducted on shark liver oil in an attempt to isolate the fat-soluble vitamins A and D. Ether lipids consisting mainly of batyl, chimyl, and selachyl alcohols were purified from shark liver oil as a side product of this isolation. This material provided a ready source for further investigation of the ether lipids. This was fortuitous because the first therapeutic use of ether lipids was in 1930 when Giffin and Watkins7employed yellow bone marrow to treat a patient with leukopenia. At the time they did not know that the active principle in the marrow was batyl alcohol. Eight years later Marberg and Wiles* isolated batyl alcohol from the unsaponifiable fraction of yellow marrow. The biologic function of the ether lipids was not fully elucidated until after 1960, although many investigators ascribed certain biologic functions to these compounds (e.g., the antileukopenic effect described earlier; a central depressant action described by Bergergin 1948; an erythopoietic effect reported by Sandler'O in 1949; a tuberculostatic effect reported by Emmerie et all1 in 1952; a wound healing action reported by Bodman and MaisinI2 in 1958; a radioprotective effect reported by Brohult13in 1960). Alkyl glycerol ethers were found to be widespread in nature, in fact almost universal, although no clear physiologic role was defined for them.

Current research has opened many investigative channels for these compounds, and new information is beginning to shed light on the molecular action of ether lipids. A review of the chemistry of alkyl glycerol ethers helps the reader understand the physiologic action and the potential therapeutic applications.

BASIC CHEMISTRY OF ALKYLGLYCEROL ETHERS FROM SHARK LIVER OIL Some Definitions Students often view lipid chemistry as an impenetrable complexity. The terminology is indeed not easy to master at first, but with time and repetition it becomes easier. Part of this problem rests with the lipid chemists, who have some difficulty agreeing on nomenclature. In the case of ether lipids, we limit this discussion to only a few naturally occurring compounds, specifically those occurring in shark liver oil. Lipids may be broadly defined as a class of water-insoluble organic compounds. They can then be further divided into simple lipids and complex lipids. For example, simple lipids are esters of fatty acids and an alcohol, such as palmitic acid and glycerol, to form a monoglyceride. Another example of a simple lipid is a cholesterol ester. Complex lipids are esters that contain phosphorus or nitrogen bases or sugars, or all three, as well as fatty acids and an alcohol. Lecithin, which is phosphatidyl choline, is an important complex lipid. The plasmalogens, discussed later, are lipid compounds that contain an ether linkage. They also contain both a phosphorus and a nitrogen group, so they are classified as complex lipids. We also discuss neutral lipids, which are not ionically charged, and ionic lipids, or charged lipids. Fats such as common triglycerides found in lard are neutral lipids, while phospholipids are charged lipids. The term alkoxyl refers to an organic group RO, which is part of an ether group ROR. The term has been shortened to alkyl, so we denote ether lipid as alkylglyceride. Note that there is no other oxygen atom associated with the R components. The term acyl refers to R - C = 0. The term curbonyl refers to a C = 0 group, and the term carboxyl refers to a X O O H group, where one oxygen has a double bond to the carbon atom. The ether bond is the key to understanding the unique functioning of the alkylglycerol. This bond, C-O-C, is found throughout nature in many important biologic compounds, the most familiar of which is thyroxin from the thyroid gland. In the plant world, guaiacol is another familiar ether-linked substance. Glycerol ethers are quite widespread, having been isolated from many life forms and in many different molecular arrangements. The basic structure of these

Alkylglycerols compounds consists of a glycerol molecule with one or more of the hydroxyl groups being replaced by longchain fatty acids. The bonding of three fatty acid molecules to the glycerol molecule with an ester linkage is known as a triglyceride, or common fat. The ester linkage is characterized by the -COO group, in which one oxygen is linked in a double bond to a carbon atom. Figures 63-1 and 63-2 illustrate typical triglycerides and alkylglycerols, respectively. Although the chemistry of the alkylglycerols in many animals and plants has been studied extensively, we limit our discussion here to the main ether lipids found in shark liver oil. However, a note on the composition of shark liver oil is in order. Shark liver oil contains high levels of vitamins A and D, along with other constituents besides the ether lipids. In commercial preparations of the alkylglycerols extracted from shark liver oil, all of these components are removed in the extraction process. Therefore when we speak of shark liver-derived alkylglycerols in this chapter, we refer to a highly refined end product containing only the alkylglycerols. One of the major sources of natural alkylglycerols is obtained from the Greenland shark, Somniosus microcephlus, which contains up to 50% of alkylglycerols. Other sources include the elasmobranch fish such as the small shark, Chimaera monstrosu, and the dogfish, Squalus ucunthius. Cod liver oil and certain mollusks are additional sources of alkylgly~erols.'~These compounds have been found in various animal organs including bone marrow fat, spleen, liver, plasma, and erythrocytes and in milk.15J6 These compounds are found in the unsaponifiable fraction of the oils obtained from the animals. Tsujimoto and Toyama4were the first investigators to report the presence of ether lipids in shark liver oil. Three major natural alkylglycerols obtained from the Greenland shark are batyl alcohol, chimyl alcohol, and selachyl alcohol. Figure 63-3 illustrates the chemical structure of these compounds. Although chimyl and batyl alcohol are saturated chains, selachyl alcohol contains one unsaturated bond. All the ether bonds are on the number 3 carbon of glycerol. In the natural state these compounds are usually present as ester compounds, with carbons 1 and 2 esterified with c16 or C18 saturated fatty acids. A fourth natural compound is a

0 H2C-0-C-R

0

R'-

II

C -0-

I I

CH

H2C-O-

II 0

II

C -R"

Figure 63-1 Triglyceride.

H,C-0-R

0 R'-

II

C -0-

I I

CH H2C -0-

0

II

C - R" Ester bond

Figure 63-2 Alkylglycerol.

methoxy-substituted alkylglycerol, shown in Figure 63-4. This active compound comprises only a small percentage of natural shark liver oil-derived alkylglycerols, about 3%. The biologic synthesis of the lipid ethers has been well worked out. Most cells in the human body contain lipid ethers but only in small quantities. A synthesis scheme has been summarized by Mangold and PaltauP' as follows:

Step 1. Coenzyme A derivatives of long-chain fatty acids are reduced to alkyl and alkenyl chains via their alcohols, through an aldehyde. Step 2. The ether bond is formed by reaction of these alcohols with acyldihydroxyacetone phosphates, resulting in the formation of alkylacyldihydroxyacetone phosphates. Step 3. Reduction of the alkylacyldihydroxyacetone phosphates leads to the formation of alkylglycerophosphates. This may be further summarized: fatty acid + aldehyde 4alcohol + alkyl ether + 1-alkenyl ether

It is unlikely that ether lipids exist in nature as free forms; rather, they are esterified. Being ether compounds, they react as aliphatic ethers (i.e., they are stable to most oxidizing and reducing substances but undergo only one general, nonenzymatic reaction, which is acid hydrolysis). The purpose of this chapter is not to discuss the isolation and identification of the alkylglycerols. The scheme for this work is well developed and may be found in referencesby Mangold and Weber.18This chapter focuses instead on the naturally occurring alkylglycerols from shark liver oil and relates the structure and fate of these compounds to their physiologic effects and potential therapeutic use.

Absorption, Fate, and Excretion After oral ingestion of ether lipids, absorption occurs from the intestine. About 95%of radioactive (C14-labeled)

Pharmacology of Natural Medicines H2C -OH HO-

H2C-OH

I I

I CH I

HO-CH

H~C-OO-CCH~-(CH~),,-CCH~

H2C -O-CH2-(CH2)1,-CH, Chirnyl alcohol

Bawl alcohol

H2C -OH

I I

HO-

CH H2C-O-CH2-(CH2)7-

CH=CH -(CH2)7-

CH3

Selachyl alcohol Figure 63-3 Chirnyl, batyl. and selachyl alcohol.

chimyl alcohol is absorbed in the intestine, with 5% being excreted in the feces in one study.'9 In the gastrointestinal tract a large proportion of the ingested ether lipid in the form of 10alkylglycerols is cleaved at the ether bond with the alkyl moieties, giving rise to fatty acids. The remainder is incorporated into 1-0-alkyl 2,3-diacyl-sn-glycerols, l-O-alky-l-2-acyl-sn-glycerols,1-

palmitic acid (a C 16 fatty acid) during its passage through the intestinal mucosa.

BIOLOGIC EFFECTS Bacteriostatic Effects As early as 1952, the bacteriostatic effects of alkylglyc-

O-alkyl-2-acyl-sn-glycerol-3-phosphoethan0lamines.~~erols on tubercle bacillus (Mycobacteriurn tuberculosis) Ether lipids are only minor components of the human in vitro were reported." This material was isolated from diet so that the major portion of ether lipids in the body cod liver oil and consisted of the unsaponifiable fracis synthesized in the body.20Absorption of the intact ether lipid is the rule, since ether lipids are not subject to the action of lipase, which is specific for the ester bond. This means that the "fat" is absorbed rather than the fatty acids. After feeding chimyl alcohol to rats, analysis of the lymph fluid shows that 2% to 4% of the ether lipids are found as fatty acids combined in phospholipids. About 50% is found in the triglyceride fraction, while another 40% is found as the free chimyl alcohol or an esterified alcohol. In the triglyceride fraction, most of the original compound is found as palmitic acid, which indicates that the ether bound in the chimyl alcohol was split during the absorption process. The cetyl alcohol (a C 15 fatty alcohol) moiety of chimyl alcohol is oxidized to

Methoxy group

H2C -OH

I

HO -CH

I

H2C -0+H2-

CH3 A/

I I

0 CH -(CH2)13-

CH3

Figure 63-4 Methoxy-substituted alkylglycerol.

tion. Scant data have been published on the antimicrobial effects of the akylglycerols from natural sources, but a more recent report using a synthetic product, racemic sn-l(3)-dodecylglycerol, showed some activity against Streptococcus mutuns BI-X21 These investigators found that substantial decreases in the viability of this organism were associated with an accumulation of phosphatidic acid. Current research shows that antibiotic resistance in bacteria is associated with the lipid content of the bacteria in both gram-positive and gram-negative organisms.22The action of the alkylglycerol was to inhibit the synthesis of lipids in the microbial cell.

Hemopoietic Effects Bone marrow was found to be a useful therapy in treating secondary anemia more than 60 years ago. Later it was found that the unsaponifiable fraction of the marrow lipids was responsible for this action (i.e., the stimulation of erythrocyte production). Sandler'O found that batyl alcohol had a beneficial effect on erythrocyte production in rats. Further studies with subcutaneous injections in humans showed an increase in reticulocyte levels in the blood. The erythropoietic, thrombopoietic,

Alkylglycerols

and granulopoietic stimulatory activities of l-octadecylglycerol ethers was confirmed by several investigators.B25 Interestingly, chimyl alcohol can stimulate hemopoiesis, but selachyl alcohol cannot.26

Protection Against Radiation Damage The effects of 1-alkylglycerolsin the treatment of radiation-induced leukopenia have been studied extensively. Some investigators have confirmed these beneficial Work by Lorenz and while others have colleaguesmfound that lethal irradiation in mice and guinea pigs was counteracted by postirradiation injection of bone marrow. Sandler'O believed that batyl alcohol might be the active factor in bone marrow that prevented irradiation leukopenia. His observations, however, noted an increase mainly in erythropoiesis. Additional studies by Arturson and Linback3* using intraperitoneal injections of batyl alcohol in mice showed an increase in the production of both erythrocytes and reticulocytes. Other studies have confirmed the positive effect of the alkoxyglycerols on postirradiation damage. The work of Brohult and Hornberg23showed that lethal irradiation is counteracted by postirradiation injections of batyl alcohol. In 1963 BrohulP2 published a thesis on the use of alkylglycerols in radiation treatment. A summary of the major findings in this paper follows: The postirradiation decrease in thrombocytes and white cells is notably less in patients treated with alkylglycerols than in those not given alkylglycerols. Patients with low thrombocyte counts due to radiation treatment or chemotherapy had increased counts after treatment with alkylglycerols. 0 In irradiated rats pretreated with alkylglycerols, there was less of a decrease in megacaryocytes and nucleated cells in the bone marrow compared with untreated irradiated controls. Selachyl alcohol was more effective than batyl alcohol in preventing megacaryocyte decrease. A dose-related response with a maximum response at a certain level occurred, and then a decreased response occurred when that level was exceeded. The alkylglycerolsincrease the growth rate of rats after treatment and irradiation compared with untreated irradiated rats. Batyl alcohol has a greater effect than selachyl alcohol on increasing growth rate in rats. In a series of 350 patients with cervical cancer treated with alkylglycerol and given radiation therapy, there was a greater survival rate for 1year and 5 years than in untreated irradiated controls (thistopic is discussed in more detail later in the section on the clinical uses of the alkylglycerols).

IMMUNOLOGIC ASPECTS OF ALKYLGLYCEROLS Overview of the Immune System Early in the investigation and study of ether lipids, an augmentation of the immune system seen in animals that ingested these compounds was evident. Apparently the macrophage was the key cell in this reaction. A brief introduction to the immune system is provided next to acquaint the reader with the relationship of the macrophage to other immune active cells and to the immune system in general. The immune system comprises a set of physiologic responses used by the body to destroy or neutralize foreign matter, either living or nonliving. Included in this system is a process of maintaining an immune surveillance of the body's own cells to detect and destroy malignant cells. Therefore the essential role of the immune system is one of recognition of the components of "the self" and protection from "nonself entities." Our own cellular constituents make up a vast array of complex molecules to idenhfy and class*. Adding complex biochemicals from bacteria, viruses, and parasites of all kinds increases the complexity of the system manifold. The two basic responses of the immune system are (1)a nonspec$c response that protects nonselectivelyagainst foreign matter or cells without the need for recognition of specific identities (e.g., the barrier provided by the skin, the inflammatory response to injury, the complement system); and (2) a specific response that depends on recognition of a specific substance before an attack by the immune system. The specific response involves highly specialized cells and the formation of specific chemical substances employed in the attack. Among these substances are antibodies, which are adapter molecules that idenhfy foreign organisms and interact with the other components of the immune system. Each of these components has three main regions, two of which communicate with complement and the phagocytic cells, known as the biologic part. The other serves to recognize and bind to microorganisms, known as the external recognitionfunction. The body makes millions of these antibodies. The most common antibodies are the immunoglobulins, known as IgG, IgA, IgM, IgE, and IgD. Chemically, the antibody molecule consists of two active regions, known as the Fc, or constant part, and the Fab, or variable antigen-specific part. Each antibody molecule has two heavy chains and two light chains. The Fc part consists only of heavy chains, while the Fab part consists of light and heavy chains.

Complement A family of proteins known as complement provides a direct means of killing microbes without the need for phagocytosis; however, it plays an important role in

Pharmacology of Natural Medicines

phagocytosis, as discussed later in the discussion of alkylglycerols and macrophage activation. A brief review of the major steps in the complement reaction is outlined. Complement is so named because it complements and amplifies the action of the antibodies. Some of the components of the complement system circulate constantly in the bloodstream in an inactive form and are activated in the presence of infection or tissue damage. The result is a cascade reaction in which some 20 proteins are involved in generating the active moieties. However, only the major components are discussed here. Five of the active proteins resulting from the cascade form a complex known as the membrane attackgroup complex, or MAC. This MAC invades the microbial plasma membrane and disrupts it by creating a leaky channel. Other cascade-generated proteins cause vasodilatation and increased vascular permeability. The major action of the complement proteolytic cascade is to cleave a component known as C3 into two active units, C&and C3b.Complement C3 is an opsonin, a material that helps attach phagocytes to the microbe. Antibodies are required to activate complement in the classic system, but the concern here is with another complement activation pathway that does not require antibodies, the so-called alternate complement pathway. This system is triggered by certain carbohydrates on the bacterial surface that initiate the cascade at a point about halfway through the classic system to generate c3b. The interaction of complement with macrophages is a key step in many immune reactions, as complement enhances the ability of macrophages to bind, ingest, and destroy micr0organisms.3~

Macrophage The macrophage is an extremely versatile and highly regulated cellular system. Besides their microbicidal activity, macrophages are equipped to recognize and destroy both intracellular and extracellular replicating invaders, whether or not these invaders are prokaryotic or eukaryotic types. They are important scavengers for effector cells and molecules of host origin, as well as for exogenous compounds that they can take up, degrade, and detoxlfy or contain. They are known to regulate many body functions including iron and lipid metabolism. The large number of secretory products generated by the macrophage helps to regulate other cells, including the fibroblasts and cells involved in the formation of myeloid component in the bone marrow. Obviously such powerful cells need to be tightly controlled, and so they are. The resident macrophages in the tissues are usually downregulated to a high degree. The process of activation, later discussed in detail, comes from various extracellular stimuli. Over time it has become apparent that the macrophage is a multipotential cell with the capacity to develop in many ways,

depending on the specific signal it receives. This system is far from being fully understood, but the control of this delicate balance of activities is essential to life, so it has become a prime area of intensive investigation. The macrophages originate from precursor cells in the bone marrow and pass into the circulation as rnonocytes. They remain in the bloodstream for several hours and then migrate to various tissues, where they are transformed into macrophages. The macrophage is an activated monocyte and is easily distinguished from the smaller neutrophil by its size and characteristic nucleus. Although both cells are phagocytic, the macrophage has far greater potential for killing bacteria. A greater cytoplasmic volume and more cytoplasmic organelles are present in the macrophage, including more lysosomes, microtubules, microfilaments, and Golgi membranes. After leaving the bloodstream, the macrophage enters the peritoneal cavity, other serous cavities, and the red pulp of the spleen and the lymph nodes. Macrophages possess receptors for the Fc pieces of the immunoglobulins and for the Cbb complement fraction discussed earlier. The adherence of a particle to the macrophage is mediated by complement or by complement plus antibody. Either IgM or IgG is required for this reaction to take place, along with C3.If IgG is bound to the particle, it can be ingested without the addition of complement C3. The concept of immune activation is quite comprehensive in that it embodies many intercellular and molecular eventsMThe lymphocytes play a key role in activating the macrophage, particularly the T-helper lymphocytes. Macrophages are usually downregulated with respect to their surface active receptors when they are resident in most tissues (resident macrophages are usually not activated). They may be fully activated in several stages (e.g., an inflammatory response in tissues evokes a reaction that changes the C3 complement on the surface of the macrophage to fully empower the cell to engulf and destroy bacteria or red cells). They are then further activated to a high killer state by secretions from T-lymphocytes, one of which includes gamma interleukin.

Macrophage Activation by Alkylglycerols Inflamed cancerous tissue releases alkyl-lysophospholipids and other alkylglycerols, which are degradation products of alkyl phospholipids and alkyl neutral lipids. These compounds are found in cancerous tissue in high concentration but are in low concentration in normal tissues. One of these products, dodecylglycerol (DDG), is among the most potent macrophage activators The use of the natural sn-3-octylglycero1, or batyl alcohol, found in shark liver oil produced the same effect as DDG?9 The mechanism of macrophage activation by the natural alkylglycerols is most likely identical

Al kylglycerols to the action of lysophospholipids. Keeping in mind that activated macrophages exhibit increased phagocytosis, one method of assaying substances for activation potency is to measure the ingestion of various particles. Erythrocytes coated with IgG are common target particles used in this assay. Lysophosphatidylcholine has been shown to be effective in increasing macrophage ingestion of IgG-coated erythrocyte^?^,^^ Mice were treated with intraperitoneal injections of batyl alcohol in saline, and the macrophages were harvested 4 to 5 days later. Sheep erythrocyte coated with IgG showed a greatly increased ingestion of erythrocytes.There was no increased ingestion when the cells were coated with IgM or complement, which suggests that batyl alcohol activates the macrophages for Fc-mediated ingestion only. It was interesting that batyl alcohol was more effective at a lower dose than the synthetic compound.37 Evidence indicates that oral intake of natural alkylglycerols results in higher levels of plasmalogens in the erythrocytes in human subjects. (Plasmalogensare ether compounds that are formed in the metabolic pathway of phosphoglycerides. They differ from phosphoglycerides in that they contain an ether linkage on the C-1 of the glycerol molecule.) Plasmalogens protect animal cell membranes against oxidative stress. In rat studies batyl alcohol is incorporated into all tissues except brain tissue, and this action is a stereospecific It has been shown that alkylglycerols are present in human and cow milk,39,41along with other immunologic factors.@ Because the neonate has not developed a mature immune the prospect of transmitting immune functional components in the milk is a practical way to provide some protection for the newborn.44In one study lactating rats were fed alkylglycerols dissolved in corn oil; the composition of the alkylglycerols was similar to that found in shark liver oil in that batyl alcohol, chimyl alcohol, and selachyl alcohol were the major constituents.44 The findings from this study showed that although peripheral blood granulocytes were elevated, there was no elevation of peripheral lymphocytes. Plasma levels of immunoglobulins were elevated in pups whose dams were fed alkylglycerols, but not in the controls. Both IgG and IgM were elevated to a significant degree.

CLINICAL USES OF ALKYLGLYCEROLS Cancer Alkylglycerolshave been used primarily to treat various types of cancer, usually as adjunct therapy combined with radiation. This section covers the work of Brohult and colleagues45on cervical cancer tumor regression and on the decrease of complications resulting from

irradiation therapy. It also addresses a new alkylglycerol, a methoxy-substituted alkylglycerol that occurs naturally at only 3% in shark liver oil but may be available as a synthetic compound.

Tumor Regression with Alkylglycerol Treatment Patient selection was determined by stages that were defined by the International Federation of Gynecology and Obstetrics as follows: Stage I-carcinoma strictly confined to the cervix (early stage) Stage IA-cases of early stromal invasion Stage IB-all other cases of stage I Stage IIA-the carcinoma extends beyond the cervix but has not extended onto the pelvic wall; the carcinoma involves the vagina except for the lower third; no parametrial involvement Stage IIB-the carcinoma extends beyond the cervix but has not extended onto the pelvic wall; the carcinoma involves the vagina except for the lower third; parametrial involvement is noted Stage 111-the carcinoma has extended onto the pelvic wall; on rectal examination there is no cancer-free space between the tumor and the pelvic wall; the tumor involves the lower third of the vagina Stage Iv-the carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum Patients were treated with shark liver oil-derived alkylglycerol containing 100 mg of alkylglycerol, given as two capsules three times a day for a total dose of 600 mg/day. The treated group received 600 mg/day for 7 days before irradiation and for 1 to 3 months after radiation therapy. The study covered three time periods: period 1, from September 1, 1964, to February 15, 1964, comprising 458 patients; period 2, from 1970 to 1973, comprising 137 patients in a double-blind study; and period 3, from late 1973 to 1975, comprising 245 patients who were treated with alkylglycerols on as “every second patient.” The control group consisted of all patients who received radiation therapy for cervical cancer but did not receive alkylglycerols. The control group in this study consisted of 4404 patients treated during the same periods, while the total treated group was 841 patients. The mortality after 5 years was 31% for the group treated with alkylglycerols and 39.6%for the control group. The difference is statistically significant (p < 0.001).45

Protection Against Radiation Injuries Studies of patients treated from 1963-1966 and 1970-1972 by Brohult and colleagues46were aimed at evaluating

Pharmacology of Natural Medicines further the protective effects of ether lipids against irradiation injuries in patients with uterine cervix cancer. Alkylglycemls derived from Greenland shark liver oil were administered to one group of patients at a level of 600 mg/day during the radiation treatment and 300 mg/day for 1 to 3 months after treatment. Another group of patients was treated the same way during and after radiation but was also treated prophylactically 8 days before radiation with 600 mg/day of alkylglycerols. The patients receiving alkylglycerols during and after radiation treatment are referred to as the nonprophylactic group, and the patients also given alkylglycerols before the radiation as the prophylactic group. The system proposed by Kottmeier and Grap7 was used to evaluate radiation injuries that had occurred in the bladder, rectum, uterus, and intestine. Radiation injuries of grade I, with minimal objective changes in the mucosa, were excluded. Patients with radiation injuries of grades 11to IV were treated as a single group: "patients with radiation injuries." Grade II was characterized by moderate to severe changes such as necroses, ulcerations, moderate stenoses, and reactions with lengthy bleeding. Radiation complications of grade 111included injuries to the bladder, radiation fistulas from the ureters, and rectal and intestinal stenoses of such severity that colostomy or resection was needed. Grade IV was characterized by rectal and intestinal fistulas. Complications included patients with clinical features of radiation injury in whom the symptoms were found to be caused by tumor growth or a combination of tumor growth and radiation injury. These complications were termed complex injuries and represented a serious situation. AU patients with complex injuries were dead after 5 years. The incidence of radiation injuries varies with the spread of the cancer and radiation technique. The incidence is higher in the more advanced tumor stages than in the less advanced ones. It is also higher after ' T o three-beam treatment of combined high-voltage and x-ray treatment than after conventional radiographs or radium alone. When comparing the groups statistically, standardized proportions have been used in order to cancel out differences with regard to stage distribution and radiation technique. The total incidence of injuries was lower in the groups that had received alkylglycerols (18.1Y0in the prophylactic group and 24.4% in the nonprophylactic group) than in the controls (37.1%). The prophylactic group had a considerably lower incidence of complex injuries and multiple injuries than both the controls and the nonprophylactic groups. The differences were highly sigruficant (p < 0.001). Analysis of the patients divided into groups according to tumor stage or radiation technique showed that the incidence of complex injuries was lower in all subgroups of prophylactically treated patients than in the corresponding control groups. A double-blind study

from 1970-1972showed a pronounced protective effect of prophylactic treatment against injuries after radiation therapy.&The use of increased doses of radium in intracavitary irradiation was followed by a high incidence of radiation injuries, which was considerably reduced by treatment with alkylglycerols, especially when these compounds were administered prophylactically.48

Alkylglycerols in Other Medical Conditions Although few studies support the use of natural alkylglycerols in disease states other than cancer, it s e e m appropriate to consider these agents in any condition that would benefit from stimulation of an immune component. Currently the alkylglycerols are viewed as adjunct therapy rather than primary therapeutic agents, except for the methoxy-substituted alkylglycerols. Newer forms of the alkylglycerols have been synthesized and are being tested successfully with a wide range of tumor types. Conditions that are characterized by a hyperproliferative state may benefit from treatment with alkylglycerol. Considering that one possible effect of the alkylglycerols is competitive inhibition of diacylglycerol, it is plausible that protein kinase C would also be inhibited by this same action, since diacylglycerol is a stimulator of protein kinase C. Protein kinase C is essential to the oxidative burst in neutrophils, and agents that inhibit protein kinase C inhibit this acti0n.4~By inhibition (TPAFmediated of 12-0-tetradecanoylphorbol-13-acetate arachidonic acid release, studies examining the effects of synthetic alkylglycerols on the release of arachidonic acid and arachidonate metabolites from Madin Darby canine kidney cells in response to P A have suggested this same mechanism of protein kinase C inhibition.5O The work by Yamamoto and colleagues37supports the role of ether analogs as activators of macrophages and as primary cytotoxic agents. This dual role would suggest a wider application of alkylglycerol as adjunct therapy. 0 t h and JadhavS1observed that alkylglycerols given to lactating mice increase the peripheral granulocyte count, as well as the serum immunoglobulins in the pups. This action suggests the possible use of alkylglycerols in most infectious disorders.

Male Infertility In the near future, alkylglycerols may also be known to help in cases of poor sperm motility and fertility. Alkylglycerols are known to ampllfy platelet-activating The factor (PAF) biosynthesis in monocyte cell PAF produced by mammalian sperm is an important activator of sperm motility. In one in vitro study of boar spermatozoa, alkylglycerol treatment improved percentage of motility, as well as velocity parameters after 24 hours and number of boars produced. Those boars treated with PAF receptor antagonist did not show these effe~ts.5~

Alkylglycerols

Antiangiogenesis Although more clinical and in vitro studies are necessary to fully examine the usefulness of alkylglycerols, a strong body of research is being gathered. In one research project, the antitumor effects of shark liver oil and more refined alkylglycerols were analyzed in mice with Lewis lung carcinoma tumors. Purified alkylglycerols were found to sigrhcantly decrease plasmalogen content in tumors, although the shark liver oil had no such effect. In alkylglycerol-treated mice, metastasis dissemination was reduced by 64 f 8%, whereas the shark liver oil demonstrated a 30 f 9% effect below control. Lastly, after a 5-day treatment with alkylglycerols there was an attenuated presence in tumors of von Willebrand factor, a marker of endothelial cellsM The authors of this study believe these data may suggest an antiangiogenic effect of alkylglycerols. Another study of shark liver oil, as a standardized concentration of alkylglycerols and their methoxyderivates, found that prostate cancer cells demonstrated a marked colony inhibition following relatively small doses of 0.5 and 0.1 mg/ml of medium. Using flow cytometry to elucidate the mode of cell death, ovarian and prostate carcinoma exhibited an increased percentage of apoptotic cells. Interestingly, mammary carcinoma cells showed a predominantly necrotic effe~t.5~

Blood-Brain Barrier Permeability The treatment of central nervous system cancer with chemotherapeutic drugs is fraught with difficulty because low-toxicity methods that effectively traverse the blood-brain barrier are not well characterized. Alkylglycerols have demonstrated multiple biologic activities with a prominent effect on blood-brain barrier permeability56 including increasing the permeability of tight j~nctions.5~ Clinically, this effect may prove useful to improve the brain uptake of cancerostatic agents. Testing the ability to transfer methotrexate in normal rats, intracarotid short-chain alkylglycerols were shown to constitute an effective and low-toxic strategy for transient opening of the blood-brain barrier.%Another study employing intracarotid coadministration of methotrexate and 1-0-pentylglycerol in nude mice resulted in a significant increase in delivery of small and large compounds to normal brain and brain tumors, including methotrexate concentrations. These increases were found in the ipsilateral brain, compared with controls without 1-0-pentylglycerol (p < 0.005).5’

Experimental Antitumor Activity with Methoxy-Substituted Alkylglycerol About 3% of the alkylglycerols in Greenland shark liver oil consists of methoxy-substituted alkylglycerols,which have been found to inhibit tumor growth in cultured cells. Two cell lines were used, a methylcholanthrene-induced

murine sarcoma (MCGI-SS) and a juvenile osteogenic sarcoma (2T). Marked growth inhibition was noted for the mixture of 2-methoxyalkylglycerolsfrom Greenland shark liver oil, different single components derived from this oil (2-methoxyhexadecylglycerol,2-methoxyhexadecenylglycerol, and 2-methoxyoctadecenylglycerol), and various synthetic compounds including, for example, 2-ethoxyhexadecylglycerol,2-methoxyhexadecenylglycerol, and 3-methoxyhexadecylglycerol.59 In several tumor-host systems including solid tumors, leukemias, and lymphomas, the methoxy-substituted alkylglycerols were incorporated into the feed in different concentrations(0.1%to 2%, w/w). Growth inhibition was noted for melanoma B16, for a methylcholanthreneinduced sarcoma (MCG101) and Lewis lung tumor (LLT) in C57BL/6J mice, for lymphoma LAA in A/Sn mice with synthetic 2-methoxyhexadecylglycerol, and for a spontaneous mammary carcinoma in C3H mice with methoxy-substituted alkylglycerols from Greenland shark liver oil. The survival time of DBA/2J mice transplanted with lymphatic leukemia P1534 was increased by synthetic 2-methoxyhexedecylglycero1.59~aMetastases induced by the injection of MCG1-SS cells into a tail vein or into the portal vein were inhibited in the liver by methoxy-substituted alkylglycerols from Greenland shark liver Spontaneous metastasis formation from a methylcholanthrene-induced sarcoma (MCG1SS) in lymph nodes and lungs of CBA mice was inhibited by methoxy-substituted alkylglycerols derived from Greenland shark liver oil, as well as by synthetic 2-methoxyhexadecylglycerol.59Spontaneous metastasis formation from melanoma B16 was inhibited by synthetic 2-methoxyhexadecylglycerol.60 Worth noting is that the same substance can both stimulate the immune system and inhibit tumors. This has also been proven for akyllysophospholipids synthesized with a methoxy group in the 2-position of the glycerol part of the molecule. These substances have been studied at the Max-Planck Institute for Immunobiology at Freiburg and at the Department of Haematology and Oncology of the University of Munich. The German research groups have shown that even alkyllysophospholipidswithout the 2-methoxy group in the glycerol part can activate macrophages in the bone marrow. This shows that ordinary glycerol ethers, after incorporation into phospholipids, can activate the body’s immune defense system. These investigators think that the macrophage-stimulating effects of alkyllysophospholipids explain the effects of these substances on tumors and tumor spread. Tumor cells have only a low activity of enzymes that can break down ethers. This means that alkyl ethers are incorporated into the cell membrane’s phospholipids, which are then recognized and attacked by macrophages, which have a high activity of ether catabolic enzymes.

Pharmacology of Natural Medicines In experiments performed at the University of Stockholm,61 it has been shown that both types of methoxy-substituted alkylglycerols (methoxy group in the 1-position and methoxy group in the 2-position of the glycerol part of the molecule) inhibit growth of two tumor cell lines (neuroblastoma from mice and glioma cells from rats), while alkylglycerols without methoxy groups did not have any growth-inhibitingeffects on the tumor cell line studied. Interactions between different types of alkylglycerols and human neutrophil granulocytes have been studied by Palmblad and colleagues.62Platelet-activating factor (PAF) was the most potent with regard to the ability to produce an oxidative response, followed by the methoxysubstituted alkylglycerols. The study shows that there is a dissociation between the ability of an alkylglycerol to initiate oxidative and calcium responses, indicating strict structure-activity relationships for the different alkylglycerols studied.

batyl alcohol in rats at levels of 5 to 10 mg/kg of body weight had no effect on the thymus gland or on the production of adenosine triphosphate.

Toxicity in Humans BrohulP2observed that a healthy human being consumes about 10 to 100 mg/day of alkylglycerols in an average diet. Sandler'O gave healthy adult males 45 mg/day of batyl alcohol for 10 days with no ill effects. This was a relatively low dose compared with that consumed by people who eat shark meat and shark byproducts. Only the consumption of shark liver has been reported to produce ill effects, mainly diarrhea, due to the high squalene content. Alkylglycerols from the Greenland shark have been used for more than 30 years without undesirable side effects.

CONCLUSIONS

Ether lipids are well known as a new class of tumoricidal compounds, producing strong biologic signals. INDICATIONS AND DOSAGE Although many new compounds have been syntheCurrently, shark liver oil-derived alkylglycerols are not sized, natural compounds have been known for a long used as specific therapy for any medical condition. time, beginning with the work of Hanahan on plateletHowever, they may be used as ancillary, auxiliary, or activating factor, a 1-0-alkyl glycerol. This class of augmentative agents in many disorders. In cancer compound, know as plasmalogens, is known to inhibit chemotherapy or irradiation therapy, they are not only phosphorylation reactions, particularly those catalyzed protective but also additive in the overall therapeutic by protein kinase C. The dual action of alkylglycerolson effect. Any disorder that has a proliferative component, both the physical structure of the cell, such as the cell which includes most inflammatory disorders, responds membrane, and the complex biochemical pathways to alkylglycerols. Immune disorders in particular can be makes them extremely interesting as modulators of cell treated effectively with alkylglycerols. In the prevention functions. of infection or neoplastic diseases, 50 mg of alkylglycerol The biologic action of the alkylglycerols suggests they three times a day is suggested. For aggressively treated may have both prophylactic and inhibitory properties disorders, 300 mg/day or more may be necessary. The against tumors. This action is highly selective and appears use of the methoxy-derived alkylglycerols must await to be related mainly to the chemical structure of the alkylfurther research and availability of this powerful glycerol. Most clinical trials with alkylglycerolshave been with advanced cases, but these results are encouraging. alkylglycerol. The mechanisms involved in antitumor activity are many and include macrophage activation, immune cytotoxiaty, TOXICOLOGY OF THE ALKYLGLYCEROLS natural killer cell activation, enzyme inhibition and actiToxicity in Animals vation, and cell membrane disturbances. Other actions Oral toxicity studies with alkylglycerols have been include the antiinfective properties, as well as the radiaconducted on rats, mice, and dogs. Alexander and coltion protective properties of these agents. leaguesa reported that mice given a diet containing 18% Two areas that hold promise with the use of alkylglycalkyldiacylglycerolsshowed no ill effects after 2 years. erols are the suppression of autoimmune disorders and Work by Brohult,32Peifer and Carls0n,6~ the selective destruction of leukemic cells. Much of this Berger? and Bandis on oral feeding of alkylglycerols to work is covered in a report of the First International rats has shown that they are relatively nontoxic. Symposium on Ether Lipids in Oncology published Carlson6 tested dogs with chimyl, batyl, and selachyl by the American Oil Chemist Society in 1987.67Also, alcohols by feeding levels of 2.4 g/kg of body weight research in male fertility and the use of alkylglycerols and found no ill effects. in order to effectively traverse the blood-brain barrier Subcutaneous injections of batyl alcohol in mice by are other up-and-coming probabilities of employment. Bergergfound that a dose of 3 g/kg was necessary to The outlook for the use of alkylglycerols in medical obtain a subcutaneous LDm. Peritoneal injections of treatment and in the maintenance of health is optimistic.

Alkylglycerols

1.Feulgen R, Voit K. Gesamte Physiol. Menschen Xere. Pfluegers Arch 1924;206:389. 2. Kossel A, Edbacher S. Hoppe-Seyler’s. Z Physiol Chem 191594277. 3. Bergman W, Stanbury HA. Contributions to the study of marine products. J Org Chem 1943;8:283. 4.Tsujimoto M, Toyama Y. Uber die unverseifbaren Bestandteile (hoheren Alkohole) der Haifisch und Rochenleberole. Chem Umschau 1922;29:35-43. 5. Toyama Y. Chem Umsch. Geb Fette, Oele, Wachse, Harze 192491:13. 6. Heilbron IM,Owens WM. The unsaponifiable matter from the oils of the elasmobranch fish. Part Iv.The establishment of the structure of selachyl and batyl alcohols as monoglycerol ethers. J Chem Soc (Lond) 1928;942. 7. Giffin HZ,Watkins C. Treatment of secondary anemia. J Am Med Assoc 1930;95:587. 8. Marberg CM, Wiles HO. Yellow bone marrow extracts in grandocytopenia. J Am Med Assoc 1937;109:1965. 9. Berger FM. The relationship between chemical structure and central depressant action of a-substituted ethers of glycerol. J Pharmacol Exp Ther 1948;93470. 10. Sandler OE. Some experimental studies on the erythropoietic effect of yellow bone marrow extracts and batyl alcohol. Acta Med Scand 1949;22572. 11. Emmerie A, Engel C, U p W. The tuberdostatic action in vitro of the unsaponifiable fraction of cod-liver oil. J Sci Food Agr 19529:264. The a-glyceryl ethers. Clin Chim Acta 12.Bodman J, Haisin JH. 1958;3253-74. 13. Brohult A. Alkylglycerolsas growth stimulating substances. Nature (London) 1960;188:591-592. 14. Tsujimoto M. The liver oils of Elasmobranch fish. J Soc Chem Ind Japan 1932;51:317-323. 15. Holmberg J, Mysen G, Persson G. Component lipids of some food raw materials. Sixth Congress of the International Society for Fat Research, London, 1962. 16. Hallgren 8, Larsson S. The glyceryl ethers in the liver oils of elasmobranch fish. Lipid Res 1962;3:31-38. 17. Mangold HK, Paltauf F, eds. Ether lipids: biochemical and biomedical aspects. New York Academic Press, 1983Ch. 11. 18.Mangold HR, Weber N. Biosynthesis and biotransformation of ether lipids. Lipids 1987;22:789-799. 19. Bergstrom S, Blomstrand R. The intestinal absorption and metabolism of chimyl alcoholin the rat. Ada Physiol Scand 1956;38:166172. 20. Blomstrand R, Ahrens EH Jr. Absorption of chimyl alcohol in man. Proc Soc Exp Biol Med 1959;100:802-805. 21.Brissette JL, Cabacungan EA, Pieringex RA. Studies on the antibacterial activity of dodecylglycerol. Its limited metabolism and inhibition of glycerolipid and lipoteichoic acid biosynthesis in Streptococcus mutans BHT. J Biol Chem 1986;261:6338-6346. 22. Hugo WB, Stretton RJ. The role of cellular lipid in the resistance of some Gram-positive bacteria to penicillins. J Gen Microbiol 1966; 42133-138. 23. Brohult A, Holmberg J. Alkylglycerols in the treatment of leukopenia caused by irradiation. Nature 1954;1741102-1103. Hemopoietic effects of batyl alcohol. J Clin Invest 24.Linman JW. 1958;37913. 25. Osmond DG, Roylance PJ, Webb AJ, et al. The action of batyl alcohol and selachyl alcohol on the bone marrow of the guinea pig. Acta Haematol1963;29180-186. 26. Suki WN, Grollman A. The effect of batyl alcohol and related alkylglycerols on hemopoiesis in the rat. Tex Rep Biol Med 1960;18:662. 27. Alexander P, Connel DI, Brohult A, et al. Reduction of radiation induced shortening of life span by a diet augmented with alkoxy glycerol esters and essential fatty acids. Gerontologia 1959;3:147.

28. Ghys H. Effets des alkoxyglycerols (Kaby 700) sur la leucopenie consecutive a la radiotherapie. Lava1 Med 1962;33:331. 29. Snyder F, Piantadosi C, Malone B. The participation of 1- and 2isomers of Oalkylglycerolw as acyl acceptors in cell-free systems. Biochim Biophys Acta 1970;202:244-249. 30. Lorenze E, Congdon C, Uphoff D. Modification of acute irradiation injury in mice and guinea pigs by bone marrow injections. Radiology 1952;8863-877. 31. Arturson G, Lindback M. Experiments on the effect of batyl alcohol on the number of erythrocytes and reticulocytes in white mice. Acta Soc Med Upsal1951;5619. 32. Brohult A. Alkylglycerolsand their use in radiation treatment. Ada Radio1 1963;223(suppl):7-99. 33. Cohn ZA. The macrophageversatile element of inflammation. Harvey Lect 1981;77:63-80. 34. Elsbach P. Cell surface changes in phagocytosis. In Nicolson GL, Poste G, eds. Cell surface reviews, vol 4. Amsterdam: NorthHolland Publishing, 1977:363. 35. Ngwenya BZ, Yamamoto N. Activation of peritoneal macrophages by lysophosphatidylcholine.Biochim Biophs Acta 1985;839:9-15. 36. Ngwenya BZ, Yamamoto N. Effects of inflammation products on immune systems: lysophosphatidylcholine stimulates macrophages. Cancer Immunol Immunother 1986;21:174182. 37. Yamamoto N, St Clair DA Jr, Homma S, et al.Activation of mouse macrophages by alkylglycerols, inflammation products of cancerous tissues. Cancer Res 1988;48:6044-6049. 38. Adams DO, Hamilton TA. The cell biology of macrophage activation. Annu Rev Immunol1984;2283-318. 39. Hallgren 8,Niklasson A, Stallberg G, et al. On the occurrence of 1-0-alkylglycerols and lO(2-methoxyalkyl) glycerols in human colostrum, human milk, cow’s milk, sheep’s milk, human red bone marrow, red cells, blood plasma and a uterine carcinoma. Acta Chem Scand B 1974;281029-1034. 40. Das AK, Holmes RD, Wilson GN, et al. Dietary ether lipid incorporation in tissue plasmalogens of humans and rodents. Lipids 1992;27401-405. 41. Hallgren B, Larsson S. The glyceryl ethers in man and cow. J Lipid Res 19623:39-43. 42. Orga SS, Weintraub D, Orga PL. Immunologic aspects of human colostrum and milk. J Inununol1977;119245-248. 43. Quie PG.Antimicrobial defenses in the neonate. Semin Perinatol 1990;14:2-9. 44.Migliore-Samour D, Jolles P. Casein, a prohormone with an immunomodulating role for the newborn? Experientia 1988;44: 188-193. 45. Brohult A, Brohult J, Brohult S, et al. Reduced mortality in cancer patients after administration of alkoxyglycerols. Acta Obstet Gynecol Scand 1986;65:779-785. 46. Brohult A, Brohult J, Brohult S, et al. Effect of akyoxyglycerols on the frequency of fistulas following radiation therapy for carcinoma of the uterine cervix. Acta Obs Gynecol Scand 1979;58:203-207. 47. Kottmier HL, Gray MJ. Rectal and bladder injuries in relation to radiation dosage in carcinoma of the cervix. Am J Obs Gynecol 1961;827482. 48. Brohult A, Brohult J, Brohult S, et al. Effect of alkyoxyglycerols on the frequency of injuries following radiation therapy for carcinoma of the uterine cervix. Acta Obs Gynecol Scand 1977;56441-448. 49. Wilson E, Olcott MC, Bell RM, et al. Inhibition of the oxidative burst in human neutrophils by sphingoid long-chain bases. Role of protein kinase C in activation of the burst. J Biol Chem 1986;261:12616-12623. 50. Robinson M, Burdine R, Wame TR.Inhibition of phorbol ester-stimulated arachidonic acid release by alkylglycerols.Biochem Biophys Acta 1995;1254.361-367.

Pharmacology of Natural Medicines 51. Oh SY, Jadhav Ls.Effects of dietary alkylglcyerols in lactating rats on immune response in pups. Pediatr Res 1994;36:300-305. 52. P6drono F, Cheminade C, Legrand AB. Natural 1-0-alkylglycerols reduce platelet-activating factor-induced release of [3H]-serotonin in rabbit platelets. Prostaglandins Leukot Essent Fatty Acids 2004;71:19-23. 53. Cheminade C, Gautier V, Hichami A. 1-Oalkylglycerols improve boar sperm motility and fertility. Biol Reprod 2002;66:421-428. 54. Pkdrono F, Martin B, Leduc C, et al. Natural alkylglycerols restrain growth and metastasis of grafted tumors in mice. Nutr Cancer 2004;48364-69. 55. KrotkiewskiM, PrzybyszewskaM, Janik P.Cytostatic and cytotoxic effects of alkylglycerols(Ecomer).Med Sci Monit 2003;9:PI131-35. 56. Gopinath D, Ravi D, Rao BR, et al. 1-0-Alkylglycerol vesicles (Algmmes): their formation and characterization. Int J Pharm 2002;246:187-197. 57. Erdlenbruch B, Alipour M, Fricker G, et al. Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries. Br J Pharmacol2003;140.1201-1210. 58. Erdlenbruch B, Schinkhof C, Kugler W, et al. Intracarotid administration of shortchain alkylglycerols for increased delivery of methotrexate to the rat brain. Br J Pharmacol2003;139:685-694. 59. Hallgren B, Stallberg G. Occurrence,synthesis and biologicaleffects of substituted glycerol ethers. Prog Chem Fats Other Lipids 1978;164158.

60.Boeryd B, Hallgren B. The influence of the lipid composition of the feed given to mice on the immunocompetenceand tumor resistance of the progeny. Int J Cancer 1980;26241-246. 61. Brohult J. Personal communication. 62. Palmblad J, Samuelsson J, BrohultJ. Interactionsbetween alkylglycerols and human neutrophil granulocytes. %and J Clin Lab Invest 1990;50:363-370. 63. Alexander P, Connell DI, Brohult A, et al. Reduction of radiation induced shortening of life span by a diet augmented with alkyl glycerol esters and essential fatty acids. Gerontologia 1959;3: 147-152. 64.Peifer JJ, Lundberg WO, Ishio S, et al. Studies of the distributions of lipids in hypercholesteremicrats. 3. Changes in hypercholesteremia and tissue fatty acids induced by dietary fats and marine oil fractions. Arch Biochem Biophys 1965;110270. 65. Carlson WE. MSc thesis. Vancouver, Canada: University of British Columbia, 1966. 66. Bandi ZL, Mangold HK, Holmer G, et al. The alkyl and alk-1-enyl glycerols in the liver of rats fed long-chain alcohols or alkyl glycerols. FEBS Lett 1971;12217-220. 67. Baumann WJ, ed. First International Symposiumon Ether Lipids in Oncology, Gottingen, Germany, 1986. Lipids 1987;22:775-980.

Allium cepa (Onion) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 725 Chemical Composition 725

Antiasthmatic Action 726 Antitumor Effects 727 Hair Tonic Effects 727

History and Folk Use 725

Dosage 727

Pharmacology 726 Antimicrobial Activity 726 Cardiovascular Effects 726 Diabetes 726

Toxicology 727

Allium cepu (family:Amaryllidaceous or Liliaceous) Common name: onion

GENERAL DESCRIPTION Numerous forms and varieties of onion exist, as this perennial or biennial herb is cultivated worldwide. The part used is the fleshy bulb. Common varieties are white globe, yellow globe, and red globe. Onions range in size, color, and taste depending on their variety. The two general types of large, globe-shaped onions are classified as spring/summer or storage onions. The former class includes those grown in warm weather climates and mild or sweet in flavor. Included in this group are the Walla Walla, Vidalia, and Maui Sweet onion. Storage onions are grown in colder weather climates. After harvesting, they are dried out for several months to attain dry, crisp skins. They generally have a more pungent flavor and are usually named by their color: white, yellow, or red. Spanish onions fall into this classification. In addition to these large onions, there are smaller varieties such as the green onion, or scallion, and the pearl onion.

CHEMICAL COMPOSITION Onions, like garlic, contain various organic sulfur compounds: Smethylcysteine sulfoxide Trans-S(1-propenyl)cysteine sulfoxide

Summary 727

Spropylcysteine sulfoxide Dipropyl disulfide Onions also contain the enzyme alinase, which is released when the onion is cut or crushed, causing conversion of trans-S(1-propenyl) cysteine sulfoxide to the so-called lacrimatory factor (propanethialSoxide).Other constituents include the following1? Flavonoids (primarilyquercetin) Phenolic acids (e.g., caffeic, sinapic, and p-coumaric) Sterols Saponins Pectin Volatile oils

HISTORY AND FOLK USE Although not as valued a medicinal agent as garlic, onion has been used almost as widely. Like garlic (AZZium sutivum),onion has been used as an antispasmodic, carminative, dimtic, expectorant, stomachic, anthelmintic, and antiinfective agent. Externally it has been used as a rubefacient and poultice, giving relief in skin diseases and insect Onions originated in the central part of Asia, from Iran to Pakistan, and northward into the southern part of Russia. Onions have been revered throughout time not only for their culinary use but also for their therapeutic properties.As early as the sixth century, onions were used as medicine in India. Although they were popular with 725

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the ancient Greeks and Romans, they were often dressed with extra seasonings, since many people did not find them spicy enough. Yet it was their pungency that made onions popular among poor people throughout the world because this inexpensivevegetable could spark up meals. Onions were an indispensable vegetable in the cuisines of many European countries during the Middle Ages and later even served as a classic healthy breakfast food. Christopher Columbus brought onions to the West Indies, and then their cultivation spread throughout the Western hemisphere. Today China, India, the United States, Russia, and Spain are among the leading producers of onions. World onion production has increased dramatically, with current production around 44 million tons per year, making onions the second most important horticultural crop after tomatoes. Because of their storage characteristics and durability for shipping, onions have always been traded more widely than most vegetables. Onions are versatile, often used in many dishes, and accepted by almost all traditions and cultures?

PHARMACOLOGY Onions and garlic, due to their similar constituents, have many of the same pharmacologic effects. However, significant differences make one more advantageous than the other in certain conditions. One of the key nutritional qualities of onions is their high content of quercetin. To determine uptake as well as in vivo antioxidant effects of quercetin from onions, six healthy nonobese normocholesterolemic female volunteers participated in a randomized two-phase crossover supplementation trial to compare the antioxidant effects associated with (a) a meal of fried onions and (b) a meal of fried onions and fresh cherry tomatoes? Plasma flavonoids, lymphocyte DNA damage, plasma ascorbic acid, tocopherols and carotenoids, urinary malondialdehyde, and &hydroxy-2'deoxyguanosine were determined to assess flavonoid absorption and antioxidant efficacy. The results indicated that the flavonoid glucosides (quercetin-3-glucoside and isorhamnetin-4-glucoside) were sigruficantly elevated in plasma following ingestion of the onion meal, and the increases were associated with an increased resistance of lymphocyte DNA to DNA strand breakage. A significant decrease in the level of urinary 8-hydroxy-2'-deoxyguanosinewas evident 4 hours after ingestion of the onion meal. After the combined tomato and onion meal, only quercetin was detected in plasma. Endogenous base oxidation was decreased, but resistance to strand breakage was unchanged. No sigruficant change in the excretion of urinary malondialdehyde occurred following either meal. The conclusions from the study were that both meals-onions and onions

with tomatoes-led to transient decreases in biomarkers of oxidative stress, although the particular biomarkers affected differed. It is possible that the differences in patterns of response reflect the different uptakes of flavonoids, but the underlying mechanism is not yet understood.

Antimicrobial Activity Although onions exhibit antibacterial, antifungal, and anthelmintic activity, it is not nearly as potent as that of garlic. This suggests that garlic may be better indicated in cases of infection,23S6but onion can usually be consumed in larger quantities than garlic, which may increase the concentration of antimicrobial constituents in vivo to approximate those of garlic.

Cardiovascular Effects Like garlic, onions and onion extracts have been shown to decrease blood lipid levels, increase fibrinolysis, decrease platelet aggregation, and lower blood pressure in several clinical Onion oil, compared with garlic oil, is a stronger inhibitor of the enzymes cyclo-oxygenase and lipoxygenase, which mediate eicosanoid metabolism (prostaglandins, thromboxanes, and leukotrienes).1° This suggests that onions would also have a greater effect on inhibition of platelet aggregation and other events mediated by eicosanoids. Garlic and onion consumption is associated with lower levels of cholesterol and triglycerides, as well as an increase in fibrinolytic activity" (see Chapter 65 for details). As the quantity of onion consumed in the study cited was so much larger than that of garlic (600 g of onion/week compared with 50 g of garlic), an argument could be made that onion consumption was the major determinant.

Diabetes Onions have been shown to have sigruficant oral hypoglycemic action, comparableto that of the prescriptionoral hypoglycemic agents tolbutamide and phenf~rmin.'~J~ The active hypoglycemic principle in onions is believed to be ally1 propyl disulphide (APDS), although other constituents such as quercetin and anthocyanidin, may play a sighcant role as well. Experimental and clinical evidence suggests that APDS lowers glucose by competing with insulin (also a disulfide) for degradation sites, thereby increasing the half-life of insulin.Other mechanisms such as increased hepatic metabolism of glucose or increased insulin secretion have been proposed.

Antiasthmatic Action Onions have historically been used as antiasthmatic agents.2J Their action in asthma, as well as in other conditions associated with increased lipoxygenase derivatives (leukotrienes), such as psoriasis and atopic dermatitis, appears to be greater than that of garlic.

Allium cepa (Onion) 8 weeks of treatment with no sex difference. These results (As mentioned previously, onion oil is a much greater indicate that crude onion juice can be an effective topical inhibitor of cyclo-oxygenase and lipoxygenase.)’O The net effect is similar to that of cortisol, which inhibits all therapy for patchy alopecia areata. eicosanoid metabolism via inhibition of phospholipase. Lnhibition of leukotriene formation and onion’s quercetin DOSAGE and isothiocyanate content are probably the primary facOnions can be eaten liberally as part of a nutritious diet. tors responsible for onion’s antiasthmatic effects. These effects have been confirmed in experimental ~ t u d i e s . ’ ~ J ~Therapeutic dosages in the various forms are typically 50 to 150 g/day.

Antitumor Effects

An onion extract was found to be cytotoxic to tumor cells in vitro and to arrest tumor growth when tumor cells were implanted in rats.I6 The onion extract was shown to be unusually nontoxic, since a dose as high as 40 times that of the cytotoxic dose for the tumor cells had no adverse effect on the host. Another species, Allium ascalonicum (shallots), has been shown to exhibit significant antileukemic activity in mice.17 One human study evaluated onion consumption and stomach cancer in more than 120,000 men and women between 55 and 69 years of age. After a 3.3-year follow-up, 139 stomach cancers were diagnosed. The researchers found a strong inverse association between onion consumption and stomach cancer incidence but no association with the use of leeks or garlic.18

Hair Tonic Effects Topical application of onions has been shown to help alopecia areata-a patchy, nonscarring hair loss condition. Any hair-bearing surface may be involved in alopecia areata, and different modalities of treatment have been used to induce hair regrowth. One study compared the effectiveness of topical crude onion juice in the treatment of patchy alopecia areata in comparison with tap water.5 The patients were divided into two groups. The onion juice-treated group consisted of 23 patients, 16 males and 7 females ranging in age from 5 to 42 years old with a mean of 22.7 years. The control group consisted of 15patients, 8 males and 7 females ranging in age from 3 to 35 years old with a mean of 18.3 years. The two groups were advised to apply the treatment twice daily for two months. Regrowth of terminal coarse hairs started after 2 weeks of treatment with crude onion juice. At 4 weeks, hair regrowth was seen in 17patients (73.9%).At 6 weeks, hair regrowth was observed in a total of 20 patients (86.9%)and was sigruficantlyhigher among males (93.7”/0) compared with females (71.4%). In contrast, with tap water, hair regrowth was apparent in only 2 patients at

TOXICOLOGY Virtually no reports of toxicity have been reported. However, people with heartburn may note an aggravation of symptoms. One study evaluated symptoms of acid reflux in 16 normal subjects and 16 heartburn patients. Subjects were studied with an esophageal pH probe for 2 hours after eating a plain hamburger and a glass of ice water, then on another day after an identical meal plus a slice of raw onion. In the normal patients, ingestion of onions did not increase any of the variables measured (number of reflux episodes, pH <4, time of pH c4,heartburn episodes, and belches). In contrast, heartbum subjects experienced a sigruficant increase in all. Although the authors of the study concluded that onions can be a potent and long-lasting reflexogenic agent in heartburn patients,I9 an alternative explanation may be that onion simply improved digestive acid secretion, making the symptoms of reflux more noticeable.

SUMMARY This discussion of onions highlights their medicinal value, particularly in cardiovascular disease, diabetes mellitus, and inflammatory conditions. As they are chiefly regarded as food or seasoning, this and other chapters about common foods and seasonings (see Chapters 65, 87, and 142) raise questions about the medicinal effects of other common vegetables and seasonings. They also may have significant pharmacologic effects that have not been investigated. A diet rich in such foods, spices, or seasonings may offer protection and possibly treatment for a wide variety of diseases. Once again, the importance of a relatively natural, unprocessed diet to long-term health is supported. Liberal use of the Allium species appears particularly indicated considering the major disease processes of the twentieth century.

Pharmacology of Natural Medicines

1. h u n g A. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York John Wiley, 1980246-247. 2. Raj KP, Patel NN. Onion-the vegetable drug. Indian Drugs 1977; 14156-160. 3. Vahora SB, Rizwan M, Khan JA. Medicinal uses of common Indian vegetables. Planta Med 1973;23.381-393. 4. Griffiths G, Trueman L, Crowther T, et al. Onions-a global benefit to health. Phytother Res 2002;16603-615. 5. Sharquie KE, Al-Obaidi HK. Onion juice (Allium cepn L.), a new topical treatment for alopecia areata. J Dermatol2002;29:343-346. 6. Elnima EI, Ahmed SA, Mekkawi AG, Mossa JS. The antimicrobial activity of garlic and onion extracts. Pham-azie 1983;38747-748. 7. Louria DB, McAnally JF, Lasser N, et al. Onion extract in treatment of hypertension and hyperlipidemia: a preliminary communication. Curr Ther Res 1985;37127-131. 8. Mittal MM, Mittal S, Sarin JC, Sharma ML. Effects of feeding onion on fibrinolysis, serum cholesterol, platelet aggregation and adhesion. Indian J Med Sci 1974;28144-148. 9. Menon IS. Fresh onions and blood fibrinolysis. Br Med J 1969;1:845. 10. Norwell DY, Tarr RS. Garlic, vampires, and CHD. Osteopath Ann 1983;11:546-549. 11. Sainani GS, Desai DB, Gohre NH,et al. Effect of dietary garlic and onion on serum lipid profile in Jain community. Indian J Med Res 1979;69776-780.

12. Bever BO, Zahnd GR. Plants with oral hypoglycemic action. Q J Crude Drug Res 1979;17139-196. 13. Sharma KK, Gupta RK, Gupta S, Samuel KC.Antihyperglycemic effect of onion-effect on fasting blood sugar and induced hyperglycemia in man. Indian J Med Res 1977;65:422-429. 14. Dorsch W, Adam 0, Weber J, Ziegeltrum T. Antiasthmatic effects of onion extracts4etection of benzyl- and other isothiocyanates (mustard oils) as antiasthmatic compounds of plant origin. Eur J Pharmacol 1984;10717-24. 15. Dorsch W, Weber J. Prevention of allergen-induced bronchial obstruction in sensitized guinea pigs by crude alcoholic onion extract. Agents Actions 1984;14:626-630. 16. Nepkar DP, Chander R, Bandekar JR, et al. Cytotoxic effect of onion extract on mouse fibrosarcoma 180 A cells. Indian J Exp Biol 1981;19:598-600. 17. Caldes G, Prescott B. A potential antileukemic substance present in Allium ascalonicum. Planta Med 1973;23:99-100. 18.Dorant E, van den Brandt PA, Goldbohm RA, Sturmans F. Consumption of onions and a reduced risk of stomach carcinoma. Gastroenterology 1996;11012-20. 19. Allen ML, Mellow MH, Robinson MG, Orr WC. The effect of raw onions on acid reflux and reflux symptoms. Am J Gastroent 1990;85:377-380.

AUium sativum (Garlic) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 729 Chemical Composition 729 History and Folk Use 729 Pharmacology 730 Antimicrobial Activity 730 Antimicrobial Effects 730 Immune-Enhancing Effects 731 Anticancer Effects 731 Cardiovascular Effects 731 Other Effects 731

Clinical Applications 732 Cholesterol-LoweringActivity 732 Hypertension 733 Platelet Aggregation Inhibition 733 Fibrinolytic Activity 733 Prevention of Low-Density Lipoprotein Oxidation 733 Other Vascular Effects 734 Dosage 734 Toxicity

734

Drug Interactions 734 Commercial Preparations 732

Allium sativum (family: Amaryllidaceous or Liliaceous) Common names: garlic, allium

GENERAL DESCRIPTION Garlic, a member of the lily family, is a perennial plant that is cultivated worldwide. The garlic bulb is composed of individual cloves enclosed in a white skin. It is the bulb, either fresh or dehydrated, that is used as a spice or medicinal herb.

CHEMICAL COMPOSITION Garlic contains 0.1% to 0.36% of a volatile oil composed of sulfur-containing compounds including the following: Allicin Diallyl disulfide Diallyl trisulfide Garlic oil is obtained by steamed distillation of the crushed fresh bulbs.' These volatile compounds are generally considered to be responsible for most pharmacologic properties of garlic. Other constituents of garlic include the following',*:

Alliin (S-allyl-L-cysteinesulfoxide) S-methyl-L-cysteinesulfoxide

Protein (l6.8%, dry weight basis) High concentrations of trace minerals (particularly selenium) Vitamins Glucosinolates Enzymes (alliinase, peroxidase, and myrosinase) Allicin is mainly responsible for garlic's pungent odor. It is formed by the action of the enzyme alliinase on the compound alliin. The essential oil of garlic yields approximately 60% of its weight in allicin after exposure to alliinase. The enzyme is inactivated by heat, which accounts for the fact that cooked garlic produces neither as strong an odor as raw garlic nor nearly as powerful physiologic effects.'

HISTORY AND FOLK USE Garlic has been used throughout history for the treatment of a wide variety of conditions. Its usage predates written history. Sanskrit records document the use of garlic remedies approximately 5000 years ago, while the Chinese have been using it for at least 3000 years. The Codex Ebers, an Egyptian medical papyrus dating to about 1550 BC, mentions garlic as an effective remedy for various ailments including hypertension, headache, bites, worms, and tumors. Hippocrates, Aristotle, and Pliny 729

Pharmacology of Natural Medicines

cited numerous therapeutic uses for garlic. In general, garlic has been used throughout the world to treat coughs, toothache, earache, dandruff, hypertension, atherosclerosis, hysteria, diarrhea, dysentery, diphtheria, vaginitis, and many other conditions.'" Stories, verse, and folklore (such as its alleged ability to ward off vampires) give historical documentation to garlic's power. Sir John Harrington, in writing The Englishman's Doctor in 1609, summarized garlic's virtues and faults3: Garlic then have power to save from death Bear with it though it maketh unsavory breath, And scorn not garlic like some that think It only maketh men wink and drink and stink.

In 1721, during a widespread plague in Marseilles, France, four condemned criminals were recruited to bury the dead. The gravediggers proved to be immune to the disease. Their secret was a concoction they drank consisting of macerated garlic in wine. This became known as vinaigre des quatre voleurs ("four thieves" vinegar), and it is still available in France today. Garlic's antibiotic activity was noted by Pasteur in 1858. Garlic was used by Albert Schweitzer in Africa to treat amebic dysentery and as an antiseptic in the prevention of gangrene during World Wars I and II.

PHARMACOLOGY Although garlic has a wide range of well-documented effects, its most important clinical uses are in the areas of infection, cancer prevention, and cardiovascular disease.

Antimicrobial Activity Garlic has broad-spectrum antimicrobial activity against many genera of bacteria, viruses, worms, and fungi, as summarized in several These findings support the historical use of garlic in the treatment of various infectious conditions.

Antimicrobial Effects Antibacterial Activity Dating back to 1944, studies have demonstrated that both garlic juice and allicin inhibited the growth of Staphylococcus, Streptococcus, Bacillus, Brucella, and Vibrio species at low concentration^.^-^ In more recent studies using serial dilution and filter paper disk techniques, fresh and vacuum-dried powdered garlic preparations were found to be effective antibiotic agents against many bacteria, as listed in Box 65-l.47J0J1In these studies, the antimicrobial effects of garlic were compared with commonly used antibiotics including penicillin, streptomycin, chloramphenicol, erythromycin, and tetracyclines. Besides confirming garlic's well-known antibacterial effects,

Bacteria Alpha- and beta-hemolytic Streptococcus Citrobacter spp. Escherichia coli Helicobacter pylori Klebsiella pneumoniae Mycobacteria Proteus vulgaris Salmonella enteritidis Staphylococcus aureus Fungi Candida albicans Cryptococcus neoformans Helminths Ascaris lumbricoides Hookworms Viruses Herpes simplex types 1 and 2 Human rhinovirus type 2 Parainfluenza virus type 3 Vaccinia virus Vesicular stomatitis virus Data from references 4-7, 10, 11.

the studies demonstrated its efficacy in inhibiting the growth of bacteria that had become resistant to one or more of the antibiotics.' Garlic administration has also been shown to sigruficantly reduce the number of coliforms and anaerobes in the feces.I2 One clinical application of garlic's antibacterial activity may be in the treatment of Helicobacter pylori, as a clinical investigation indicated that garlic intake for long durations (years) was associated with a sigruficantly lower average antibody titer. This suggests an indirect inhibitory effect on the reproduction of H. pylori and possibly progression to more serious peptic ulcer disease^.'^

Antifungal Activity Garlic has demonstrated significant antifungal activity in many in vitro and in vivo ~tudies.4J"'~From a clinical perspective, inhibition of Candida albicans has the most significance, as both animal and in vitro studies have shown garlic to be more potent than nystatin, gentian violet, and six other reputed antifungal a g e n t ~ . 4 J ~ ' ~ Although allicin and the volatile oil fraction are clearly the most potent active anticandida components,2°,21aqueous garlic extracts have been shown in vivo to be effective, even at a dilution of 1:100,against the common tinea corporis, capitis, and cruris fungal skin infe~ti0ns.l~ In one study at a major Chinese hospital, garlic therapy alone was used effectively in the treatment of cryptococcal meningitis, one of the most serious fungal infections imaginable.18

Alliurn sativurn (Garlic)

Anthelmintic Effects Garlic extracts have anthelmintic activity against common intestinal parasites including Ascaris lumbricoides (roundworm) and hookworms.'2*22

cell a ~ t i v i t y . The ~ ~ - increase ~ in killer cell activity was a remarkable 140% in those eating the equivalent of two bulbs a day and 156% in those consuming 1800 mg of odorless, aged garlic.

Antiviral Effects

Anticancer Effects

Garlic's antiviral effects have been demonstrated by its protection of mice from infection with intranasally inoculated influenza virus and by its enhancement of neutralizing antibody production when given with influenza vaccine.= The in vitro virus-killing effects of fresh garlic, allicin, and other sulfur components of garlic were determined against Heyes simplex types 1 and 2, Parainfluenza virus type 3, Vaccinia virus, Vesicularstomatitis virus, and Human rhinovirus type 2. The order for virucidal activity was the following:

The famous Greek physician Hippocrates prescribed eating garlic as a treatment for cancer. Animal research and some human studies suggest this may have been well-founded advice. It must be kept in mind that much of garlic's anticancer effect is likely an indirect effect via its impact on the immune system. Nonetheless, several garlic components have displayed significant anticancer effects including enhancing phase I1 metabolizing enzymes, antioxidant properties, inhibition of the formation of nitrosamines, direct tumor growth inhibition, and the ability to induce apopto~is.~'"Human studies showing garlic's anticancer effects are largely based on epidemiologic These studies typically show an inverse relationship between cancer rates and garlic consumption. Human studies have also shown that garlic inhibits the formation of nitrosamines (powerful cancercausing compounds formed during d i g e s t i ~ n ) . ~ ~ , ~

ajoene > allicin > ally1 methyl thiosulfinate > methyl ally1 thiosulfinate

Ajoene was found in oil macerates of garlic but not in fresh garlic extracts. No antiviral activity was found for alliin, deoxyalliin, diallyl disulfide, or diallyl trisulfide. Fresh garlic extract was viruadal against all viruses tested. Virucidal activity of commercial products was dependent on their preparation processes. Those producing the highest level of allicin and other thiosulfinates had the best virucidal activity." The antiviral activity of an allicin-containing garlic supplement was investigated in 146 subjects randomized to receive a placebo or an allicincontaining garlic supplement, one capsule daily, over a 12-week period.= The garlic-treatment group had significantly fewer colds than the placebo group (24 vs. 65). The placebo group, in contrast, recorded sigruficantlymore days challenged virally (366 vs. 111)and a sigruficantly longer duration of symptoms (5.01 vs. 1.52 days). This study indicates that allicin-containing garlic supplements can prevent the common cold virus.

Cardiovascular Effects Garlic appears to be an important protective factor against heart disease and strokes via its ability to affect the process of atherosclerosis at many steps. As there is substantial clinical information on garlic's beneficial effects on the cardiovascular system, the pharmacology is discussed later in the section on clinical applications.

Other Effects Antiinflammatory Effects Garlic extract has demonstrated sigruficant antiinflammatory activity in experimental models of inflammation.2J2 This activity is probably a result of garlic's inhibition of the formation of inflammatory compounds.

Immune-Enhancing Effects

Hypoglycemic Action

Extensive research has shown that garlic has many immune-potentiating properties, most of which are thought to be due to volatile factors composed of sulfurcontaining compounds: allicin, diallyl disulfide, diallyl trisulfide, and others. For example, in vitro studies with allicin have shown it to stimulate enhanced cell-mediated cytotoxicity in human peripheral mononuclear cells. In animal models, multiple administration of allicin elicits marked antitumor effects via immune-stimulatory mechanisms.26Fresh garlic, commercial products containing allicin, and aged garlic preparations have all shown these immune-enhancing properties. Garlic has been shown to enhance the pathogen-attacking activity of T cells, neutrophils, and macrophages to increase the secretion of interleukin and increase natural killer

Garlic and onions have often been used in the treatment of diabetes. Allicin has been shown to have significant hypoglycemic action. This effect is thought to be due to increased hepatic metabolism, increased release of insulin,and insulin-sparing effect.50The latter mechanism appears to be the major factor, as allicin and other sulfhydryl compounds in garlic and onions compete with insulin (also a disulfide protein) for insulin-inactivating compounds, which results in an increase in free insulin. Interestingly, when allicin was administered to groups of rats fed a high-fructose diet, the control group that was fed a diet enriched by fructose alone continued to gain weight, whereas the groups fed allicin did not.51 This study indicates that garlic may have some practical use in weight control.

Pharmacology of Natural Medicines

Miscellaneous Effects Garlic possesses diuretic, diaphoretic, emmenagogue, and expectorant action.'JO It is also a carminative, antispasmodic, and digestant, making it useful in cases of flatulence, nausea, vomiting, colic, and indigestion.'252

COMMERCIAL PREPARATIONS The modern use of garlic features primarily the use of commercial preparations designed to offer the benefits of garlic without the odor. The marketplace is swamped with garlic products, and each manufacturer claims its product is the best. However, there are vital considerations when choosing a garlic product to prescribe. First, if the primary goal is to lower cholesterol or blood pressure, as well as exert immune-enhancing or antimicrobial effect, it is important to ensure that the product provides a sufficient level of allicin. Since allicin is not actually in the product at significant levels, manufacturers often refer to the a k i n potential or allicin yield. These terms signify the amount of allicin produced when allinase is activated in the garlic tablet or powder. The next issue is not so simple to tell from a label. It involves the quality and character of the enteric coating of the tablet. In order for the allicin to be liberated within the intestinal tract, the tablet must not only be resistant to the stomach's acid, it must disintegrate rapidly when it reaches the small intestine. According to research conducted by the renowned garlic expert Dr.Larry D. Lawson and ~olleagues?~ when 24 brands of entericcoated garlic were analyzed for tablet dissolution using an approved method (U.S. Pharmacopoeia [USP] dissolution method 724A), only one brand released the amount of allicjn claimed on the label. The second-best brand released only 44% of its label claim, and 75% of the brands released less than 10%of their label claim. Failure to deliver an effective dosage of allicin most assuredly does not lower cholesterol or blood pressure. Why so many garlic products fail to deliver allicin is basically due to two major problems. First, many of the garlic products contained little allinase activity. Alliin was plentiful, but since the activity of allinase was low, the level of allicin formed was also low. Next, many tablets contained excipients (e.g., binders and fillers) that actually inhibit allinase activity. The allinase activity in 63% of the brands was less than 10% of the expected activity. The inability to release an effective dose of allicin would explain why so many studies on garlic supplements fail to show benefits in lowering cholesterol or blood pressure.54For example, studies done on one particular garlic supplement before 1993 were mostly positive. In fact, the results from these positive studies were the main reason garlic supplements have been allowed to refer to cholesterol-lowering activity in Germany and in the United States. However, most studies published since

1995 have failed to show a consistent effect in lowering cholester01.~~-~' Although the authors of the negative studies on garlic believed that the underlying reason for the results was a better-designed study, a more likely explanation is that they are due to a poorer-quality tablet. Specifically, research conducted by Lawson has shown that tablets manufactured before 1993were twice as resistant to disintegration in acid as tablets manufactured after 1993 and that the older tablets released three times the amount of allicin as the more recently manufactured tablets.53Examination of the package labels shows several changes in tablet excipients between the pre-1993 and post-1993 tablets. Again, these excipients are believed to block allinase activity. Importantly, most studies that show a positive effect of garlic and garlic preparations in reducing cholesterol and blood pressure are those using products that deliver a sufficient dosage of allicin, other garlic components such as Sallylcysteine,and garlic extracts (e.g., aged garlic extract) protect against atherosclerosis via additional mechanisms including protecting against low-density lipoprotein (LDL) oxidation and improving endothelial cell function.

CLINICAL APPLICATIONS Although garlic has long been used in infectious conditions, a use supported by its antimicrobial and immuneenhancing properties, the primary clinical use of garlic has focused on its role in cardiovascular disease. Specifically, garlic is recommended primarily for its ability to lower cholesterol and blood pressure in the attempt to reduce the risk of dying prematurely from a heart attack or stroke. In addition to the use of garlic preparations, garlic consumption as a food should be encouraged, despite its odor, in patients with high cholesterol levels and high blood pressure. Garlic and garlic preparations should also be encouraged in patients with diabetes, candidiasis, asthma, infections (particularly respiratory tract infections), and gastrointestinal complaints.

Cholesterol-Lowering Activity One of the major areas of focus in garlic's ability to offer sigruficantprotection against heart disease and strokes has been the evaluation of its ability to lower blood cholesterol levels, even in apparently healthy individual~.l,~&~~ According to the results from numerous double-blind, placebocontrolled studies in patients with initial cholesterol levels greater than 200, supplementation with commercial preparations providing a daily dose of at least 10 mg alliin or a total allicin potential of 4000 pg can lower total serum cholesterol levels by about 10% to 12Y0.In addition, LDL cholesterol decreases by about 15%,

high-density lipoprotein (HDL) cholesterol levels usually increase by about lo%, and triglyceride levels typically drop by 15%.1,53,54,6246 However, most trials not using products that can deliver this dosage of allicin fail to produce a lipid-lowering e f f e ~ t . ~ ~ - ~ ~ Although the effects of supplemental garlic preparations on cholesterol levels are modest, the combination of lowering LDL and raising HDL can greatly improve the HDL-to-LDL ratio, a sigruficant goal in the prevention of heart disease and strokes. Garlic preparations standardized for alliin content exert several other beneficial effects in preventing heart disease and strokes (discussed later). In addition to taking a garlic supplement, individuals with high cholesterol levels should eat more garlic and onions, as increased dietary intake of garlic and onion can also lower cholesterol level^.^^,^^ In a 1979 population study, researchers studied three populations of vegetarians in the Jain community in India who consumed differing amounts of garlic and o n i ~ n s . ~ Numerous ,~~ favorable effects on blood lipids, as shown in Table 65-1, were observed in the group that consumed the largest amount. Blood fibrinogen (discussed later) levels were highest in the group eating no onions or garlic. The study is quite significant because the subjects had nearly identical diets, except in garlic and onion ingestion.

Hypertension Garlic has demonstrated hypotensive action in both experimental animal models and humans with hypertension.5861*70-74 An early meta-analysis of published and unpublished randomized controlled trials of garlic preparations was conducted to determine the effect of garlic on blood pressure relative to placebo.70Eight trials (seven double-blind, one single-blind)were identified as meeting analytic criteria. A total of 415 subjects were included in the analysis. All trials used a dried garlic powder standardized to contain 1.3% alliin at a dosage of 600 to 900 mg daily (corresponding to 7.8 and 11.7 mg of alliin or the equivalent of approximately 1.8 to 2.7 g of fresh garlic daily).The meta-analysis concluded that garlic preparations designed to yield allicin can lower systolic and diastolic blood pressures over a 1-to 3-month period. The typical drop from pooled data was 11mmHg in the systolic and 5 mmHg in the diastolic.This degree of blood

Effects of garlic and onion consumption on serum lipids under carefully matched diets Garlidonion

Cholesterol

Triglyceride

None

208 mg/dl

109 mg/dl

10/200g/wk

172 mg/dl

75 mudl

501600 glwk

159 mg/dl

52 rng/dl

pressure reduction in hypertensives can be quite significant. If blood pressure-lowering effects of garlic can be maintained, the risk of stroke may be reduced by an estimated 30% to 40% and the risk of heart attack by 20% to 25%.

Platelet Aggregation Inhibition Excessive platelet aggregation is strongly linked to atherosclerosis, heart disease, and strokes. Garlic preparations standardized for alliin content, as well as garlic oil and aged-garlic extract, have all demonstrated sigruficant inhibition of platelet a g g r e g a t i ~ n . ~In~ one ~,~~-~ study, 120 patients with increased platelet aggregation were given either 900 mg/day of a dried garlic preparation containing 1.3% alliin or a placebo for 4 weeks.75 In the garlic group, spontaneous platelet aggregation disappeared, the microcirculation of the skin increased by 47.6%, plasma viscosity decreased by 3.2%, diastolic blood pressure dropped from an average of 74 to 67 mmHg, and fasting blood glucose concentration dropped from an average of 90 to 79 mg/dl. In a double-blind study of aged garlic extract (Kyolic) in normal healthy individuals, dosages between 2.4 and 7.2 g per day were shown to product a dose-dependent selective inhibition on platelet aggregation and adhesion.76 S-allylcysteineis thought to be the component responsible for this effect in aged garlic extract.78

Fibrinolytic Activity Epidemiologic studies have suggested that excessive fibrinogen formation is a major primary risk factor for cardiovascular disease.79Garlic preparations standardized for alliin content and garlic oil and both fried and raw garlic have been shown to significantly increase serum fibrinolytic activity in humans.80,81This increase occurs within the first 6 hours after ingestion and continues for up to 12 hours.

Prevention of Low-Density Lipoprotein Oxidation Growing evidence indicates that LDL oxidation plays a significant role in the development of atherosclerosis. Accordingly, substances that prevent oxidation of LDL may slow down atherosclerosis. Garlic is known to exert antioxidant activity and has recently been shown to exert sigruficant effects on preventing LDL oXidation.82m-86 In one study, healthy human volunteers given 600 mg/day of a garlic preparation providing 7.8 mg alliin for 2 weeks had a 34% lower susceptibility to lipoprotein oxidation compared with controls.82These results are significant given the short amount of time in which they were produced, coupled with the importance of reducing lipoprotein oxidation. Another study was a placebo-controlled double-blind trial of 23 subjects with coronary artery disease who had

Pharmacology of Natural Medicines

one to three major comnary arteries that were 75%blocked or higher. After the subjects ingested 300 mg of garlic powder, 2 and 4 hours after a single dose, the atherogenicity of their sera was markedly decreased. Less cholesterol accumulated and there were lower levels of oxidized LDL in human aortic smooth muscle cells cultured with patients’ sera after treatment compared with those cultured with sera obtained before administration of garlic. After 3 weeks of therapy at 300 mg, three times daily, blood serum atherogenicity was decreased twofold compared with initial levels.87 As aged garlic extract has also shown an ability to prevent LDL oxidation% it is likely that Sallylcysteine and other non-allicin components of garlic play a major role in the protection against LDL oxidation.

Other Vascular Effects Studies have also shown garlic or garlic components to exert positive effects on endothelial function, vascular reactivity, and peripheral blood

DOSAGE On the basis of extensive clinical research, a commercial garlic product should provide a daily dose equal to at least 4000 mg of fresh garlic. This dosage translates to at least 10 mg alliin or a total allicin potential of 4000 pg (Figure 65-1).

0 CH-CH-

CH2-

NH2

I1

S-

CH2-

0 CH2= CH-

CH2-

I1

I

0

I

I

CH - C - OH

Alliinase

-CH2-

NH2

I

CH - CH = CH2

Figure 65-1 Conversion of alliin to allicin.

Others are apparently unable to effectively detoxify allicin and other sulfur-containingcomponents.Prolonged feeding of large amounts of raw garlic to rats results in anemia, weight loss, and failure to grow?l Although the exact toxicity of garlic has yet to be definitively determined, side effects are rare at the dosage recommended earlier. Garlic is thought to be safe during pregnancy and breastfeeding. In fact, two studies have shown that babies like breast milk better from mothers who eat garli~?~,~~

DRUG INTERACTIONS

For the vast majority of individuals, garlic is nontoxic at the dosages commonly used. For some, however, it can irritate the digestive tract and cause heartburn.

Generally, garlic supplements should not be used in patients taking anticoagulant drugs (e.g., Coumadin) or in those scheduled for an elective surgery because of garlic’s effects on platelet aggregation. Though garlic components have shown an ability to affect cytochrome P450 enzymes, they do not appear to interfere with drug metabolism

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9. Cavallito CJ, Bailey JH. Allicin, the antibacterial principle of Alliiim sativiini. I. Isolation, physical properties and antibacterial action. J Am Chem Soc 1944;66:1950-1951. 10. Sharma VD, Sethi MS, Kumar A, et al. Antibacterial property of AIIiuni sativiinr Linn: in vivo and in vitro studies. Indian J Exp Biol 1977;15:466-468. 11. Elnima EI, Ahmed SA, Mekkawi AG, et al.The antimicrobial activity of garlic and onion extracts. Pharmazie 1983;38:747-748. 12. Vohora SB, W a n M, Khan JA. Medicinal uses of common Indian vegetables. Planta Med 1973;23:381-393. 13.Salih BA, Abasiyanik FM. Does regular garlic intake affect the prevalence of Helicobacter pylori in asymptomatic subjects? Saudi Med J 2003;24:842-845. 14. h e r M, Taha M, Tosson Z. The effect of aqueous garlic extract on the growth of dermatophytes. Int J Dermatol 1980;19:285-287. 15. Venugopal PV, Venugopal Tv.Antidermatophytic activity of garlic (Alliumsativum) in vitro. Int J Dermatol 1995;34:278-279.

TOXICITY

.y43y5

Allium sativum (Garlic) 16. Sandhu DK, Warraich MK, Singh S. Sensitivity of yeasts isolated from cases of vaginitis to aqueous extracts of garlic, Mykosen 1980;23:691-698. 17. Prasad G, Sharma VD. Efficacy of garlic (Alliurn sutivum) treatment against experimental candidiasis in chicks. Br Vet J 1980;136:448-451. 18. [No authors listed]. Garlic in cryptococcal meningitis: a preliminary report of 21 cases. Chin Med J 1980;93:123-126. 19. Fromtling RA, Bulmer GS. In vitro effect of aqueous extract of garlic (Allium sativum) on the growth and viability of Cryptococcus neoformans. Mycologia 1978;70:397-405. 20. Lemar KM, Turner MP, Lloyd D. Garlic (Alliurn sativurn) as an antiCandida agent: A comparison of the efficacy of fresh garlic and freeze-dried extracts. J Appl MiCrobiol2002;93:398405. 21. Kim JW, Kim YS, Kyung KH. Inhibitory activity of essential oils of garlic and onion against bacteria and yeasts. J Food Prot 2004;67 499-504. 22. Bastidas GJ. Effect of ingested garlic on Necator americanus and Ancylostorna caninurn. Am J Trop Med Hyg 1969;18:920-923. 23. Nagai K. Experimental studies on the preventive effect of garlic extract against infection with influenza virus. Jpn J Infect Dis 1973;47321-325. 24. Weber ND,Andersen DO, North JA, et al. In vitro virucidal effects of Allium sativurn (garlic) extract and compounds. Planta Med 1992;58:417-423. 25. Josling P. Preventing the common cold with a garlic supplement: a double-blind, placebo-controlled survey. Adv Ther 2001;18:189-193. 26. Patya M, Zahalka MA, Vanichkin A, et al. Allicin stimulates lymphocytes and elicits an antitumor effect: a possible role of p2lras. Int Immunol2004;16:275-281. 27. Morioka N, Sze LL, Morton DL, et al. A protein fraction from aged garlic extract enhances cytotoxicity and proliferation of human lymphocytes mediated by interleukin-2 and concanavalin A. Cancer Immunol Immunother 1993;37316-322. 28.Lau BH, Yamasaki T, Gridley DS. Garlic compounds modulate macrophage and T-lymphocyte functions. Mol Biother 1991;3 103-107. 29. Kandil OM, Abdullah TH,Elkadi A. Garlic and the immune system in humans. Its effect on natural killer cells. Fed F'roc 1987;46:441. 30. Hirao Y, Sumioka I, Nakagami S, et al. Activation of immunoresponder cells by the protein fraction from aged garlic extract. Phytother Res 1987;1:161-164. 31. Lau BH, Tadi P, Tosk J. Allium sativurn (garlic) and cancer prevention. Nutr Res 1990;10937-948. 32. Dorant E, van den Brandt PA, Goldbohm RA, et al. Garlic and its significance for the prevention of cancer in humans: a critical review. Br J Cancer 1993;67:424-429. 33. Dausch JG, Nixon DW. Garlic: a review of its relationship to malignant disease. Prev Med 1990;19346-361. 34. Thomson M, Ali M. Garlic [Alliurn sativurnl: a review of its potential use as an anti-cancer agent. Curr Cancer Drug Targets 2003;3: 67-81. 35.Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr 2004;44: 479-488. 36. Choy YM, Kwok TT,Fund KP, et al. Effect of garlic, Chinese medicinal drugs and amino acids on growth of Erlich ascites tumor cells in mice. Am J Chin Med 1983;11:69-73. 37. Lin X, Liu J, Milner J. Dietary garlic powder suppresses in vivo formation of DNA adducts induced by N-nitroso compounds in liver and mammary tissues. FASEB J 1992;6A1392. 38. Nagabhushan M, Line D, Polverini F'J, et al. Anticarcinogenic action of diallyl sulfide in hamster buccal pouch and forestomach. Cancer Lett 1992;66:207-216. 39. Meng CL, Shyu KW. Inhibition of experimental carcinogenesis by painting with garlic extract. Nutr Cancer 1990;14207-217.

40. Niukian K, Schwartz J, Shklar G. Effects of onion extract on the development of hamster buccal pouch carcinomas as expressed in tumor burden. Nutr Cancer 1987;9:171-176. 41. Wargovich MJ. Diallyl sulfide, a flavor component of garlic (Allicrrn sativum), inhibits dimethylhydrazine-induced colon cancer. Carcinogenesis 1987;3487-489. 42. Belman S . Onion and garlic oils inhibit tumor promotion. Carcinogenesis 1983;41063-1065. 43. Weisberger AS, Pensky J. Tumor inhibition by a sulfhydryl-blocking agent related to an adive principle of garlic fANium sativum). Cancer Res 1958;18:1301-1308. 44. Kroening F. Garlic as an inhibitor for spontaneous tumors in mice. Acta Unio Int Contra Can1964;20855-856. 45. Mei X, Lin X, Liu JZ, et al. The blocking effect of garlic on the formation of N-nitrosoproline in the human body. Acta Nutrimenta Sinica 1989;11:144-145. 46. Xing M, Wang ML, Xu HX, et al. Garlic and gastric cancer-the effect of garlic on nitrite and nitrate in gastric juice. Acta Nutrimenta S i i c a 1982;453-55. 47. Sundaresan S, Subramanian P. Sallylcystehe inhibits circulatory lipid peroxidation and promotes antioxidants in N-nitrosodiethylamine-induced carcinogenesis. Pol J Pharmacol 2003;55: 37-42. 48. Ledezma E, Apitz-Castro R, Cardier J. Apoptotic and anti-adhesion effect of ajoene, a garlic derived compound, on the murine melanoma B16F10 cells: possible role of caspase-3 and the alpha(4)beta(l) integrin. Cancer Lett 2004;206:35-41. 49. Munday R, Munday CM. Induction of phase II enzymes by aliphatic sulfides derived from garlic and onions: an overview. Methods Enzymol2004;382449-456. 50. Bever BO, Zahnd GR. Plants with oral hypoglycemic action. Q J Crude Drug Res 1979;17139-196. 51. Elkayam A, Mirelman D, Peleg E, et al. The effects of allicin on weight in fructose-induced hyperinsulinemic, hyperlipidemic, hypertensive rats. Am J Hypertens 2003;161053-1056. 52. Barowsky H, Boyd LJ. The use of garlic (Allistan) in gastrointestinal disturbances. Rev Gastroenterol1944;11:22-26. 53. Lawson LD, Wang ZJ, Papadimitriou D. Allicin release under simulated gastrointestinalconditions from garlic powder tablets employed in clinical trials on serum cholesterol. Planta Medica 2001;6713-18. 54. Lawson LD, Wang ZJ. Tablet quality: a major problem in clinical trials with garlic supplements. Forsch Komplementarmed Klass Naturheilkd 2000;745. 55. Banerjee SK, Maulik SK. Effect of garlic on cardiovascular disorders: a review. Nutr J 2002;1:4. 56. Alder R, Lookinland S, Berry JA, et al. A systematic review of the effectiveness of garlic as an anti-hyperlipidemic agent. J Am Acad Nurse Pract 2003;15120-129. 57. Stevinson C, Pittler MH, Emst E. Garlic for treating hypercholesterolemia: a meta-analysis of randomized clinical trials. Ann Intern Med 2000;133:420-429. 58. Ali M, Thomson M. Consumption of a garlic clove a day could be beneficial in preventing thrombosis. Prostaglandins Leukot Essent Fatty Acids 199553211-212. 59. Lau BH, Adetumbi MA, Sanchez A. Alliurn sativum (garlic) and atherosclerosis. A review. Nutr Res 19833:119-128. 60. Kendler BS. Garlic (Alliurn sativurn) and onion (Allium cepd: a review of their relationship to cardiovascular disease. Prev Med 1987;16670-685. 61. Ernst E. Cardiovascular effects of garlic (Alliurn sativum): a review. Pharmatherapeutica 1987;583-89. 62. Kleijnen J, Knipschild P, ter Riet G. Garlic, onions and cardiovascular risk factors. A review of the evidence from human experiments with emphasis on commercially available preparations. Br J Clin Pharmacol1989;28535-544.

Pharmacology of Natural Medicines 63. Warshafsky S, Kamer RS, Sivak SL. Effect of garlic on total serum cholesterol. A meta-analysis. Ann Intern Med 1993;119599-605. 64. Jain AK, Vargas R, Gotzkowsky S, et al. Can garlic reduce levels of serum lipids? A controlled clinical study. Am J Med 1993;94 632-635. 65. Rotzsch W, Richter V, Rassoul F, et al. [Postprandial lipemia under treatment with AIIiurn sativurn. Controlled double-blind study of subjects with reduced HDLZ-cholesterol.] Arzneimittelforschung 1992;42:1223-1227. 66. Mader FH. Treatment of hyperlipidaemia with garlic-powder tablets. Evidence from the German Association of General Practitioners’ multicentric placebo-controlled double-blind study. Arzneimittelforschunng1990;40:1111-1116. 67. Bordia A. Effect of garlic on blood lipids in patients with coronary heart disease. Am J Clin Nutr 1981;34:2100-2103. 68. Sainani GS, Desai DB, Gorhe NH, et al. Effect of dietary garlic and onion on serum lipid profile in Jain community. Indian J Med Res 1979;69:776-780. 69. Sainani GS, Desai DB, Gorhe NH, et al. Dietary garlic, onion and some coagulation parameters in Jain community. J Assoc Physicians India 1979;27707-712. 70. Silagy CA, Neil HA. A meta-analysis of the effect of garlic on blood pressure. J Hypertens 1994;12:463-468. 71. Petkov V. Plants and hypotensive, antiatheromatous and coronarodilatating action. Am J Chin Med 1979;7197-236. 72. Foushee DB, Ruffin J, Banerjee U. Garlic as a natural agent for the treatment of hypertension: a preliminary report. Cytobios 1982;

34:145-152. 73. Al-Qattan KK, Khan I, Alnaqeeb MA, et al. Mechanism of garlic (Allium sativum) induced reduction of hypertension in 2K-1C rats: a possible mediation of Na/H exchanger isoform-1. Prostaglandins Leukot Essent Fatty Acids 2003;69:217-222. 74. Sharifi AM, Darabi R, Akbarloo N. Investigation of antihypertensive mechanism of garlic in 2K1C hypertensive rat.

J Ethnopharmacol2003;86.219-224. 75. f i e w e t t e r H, Jung F, Pindur G, et al. Effect of garlic on thrombocyte aggregation, microcirculation, and other risk factors. Int J Clin Pharmacol Ther Toxicol 1991;29:151-155. 76. Steiner M, Li W. Aged garlic extract, a modulator of cardiovascular risk factors: a dose-finding study on the effects of AGE on platelet functions. J Nutr 2001;131:98OS984S. 77. Rahman K, Billington D. Dietary supplementation with aged garlic extract inhibits ADP-induced platelet aggregation in humans. J Nutr 2000;1302662-2665. 78. Kodera Y, Suzuki A, Imada 0,et al. Physical, chemical, and biological properties of s-allylcysteine, an amino acid derived from garlic. J Agric Food Chem 200250622-632. 79. Emst E. Fibrinogen: an important risk factor for atherothrombotic diseases. Ann Med 1994;26:15-22.

80. Chutani SK, Bordia A. The effect of fried versus raw garlic on fibrinolytic activity in man. Atherosclerosis 1981;38:417-421. 81. Legnani C, Frascaro M, Guazzaloca G, et al. Effects of dried garlic preparation on fibrinolysis and platelet aggregation in healthy subjects. Arzneimittelforschung 1993;43119-122. 82. Phelps S, Harris WS. Garlic supplementation and lipoprotein oxidation susceptibility. Lipids 1993;28:475-477. 83. Huang CN, Horng JS, Yin MC. Antioxidative and antiglycative effects of six organosulfur compounds in low-density lipoprotein and plasma. J Agric Food Chem 2004;52:36743678. 84. Durak I, Kavutcu M, Aytac 8, et al. Effects of garlic extract consumption on blood lipid and oxidant/antioxidant parameters in humans with high blood cholesterol. J Nutr Biochem 2004;15 373-377. 85. Banerjee SK, Mukherjee PK, Maulik SK. Garlic as an antioxidant: the good, the bad and the ugly. Phytother Res 2003;1797-106. 86. Dillon SA, Burmi RS, Lowe GM, Billington D, et al. Antioxidant properties of aged garlic extract: an in vitro study incorporating human low density lipoprotein. Life Sci 2003;72:1583-1594. 87. Orekhov AN, Tertov W, Sobenin IA, et al. Garlic powder tablets reduce atherogenicity of low density lipoprotein: a placebocontrolled double-blind study. Nutr Metab Cardiovasc Dis 1996; 6 21-31. 88. Ganado P, Sanz M, Padilla E, Tejerina T. An in vitro study of different extracts and fractions of Alliurn sativum (garlic): vascular reactivity. J Pharmacol Sci 2004;94:434-442. 89. Anim-Nyame N, Sooranna SR, Johnson MR, et al. Garlic supplementation increases peripheral blood flow: a role for interleukin-6? J Nutr Biochem 2004;15:30-36. 90. Baluchnejadmojarad T, Roghani M. Endothelium-dependent and -independent effect of aqueous extract of garlic on vascular reactivity on diabetic rats. Fitoterapia 2003;74630-637. 91. Nakagawa S, Masamoto K, Sumiyoshi H, et al. [Effect of raw and extracted-aged garlic juice on growth of young rats and their organs after peroral administration (author’s trans).] J Toxicol Sci 1980;5:91-112. 92. Menneua JA, Beauchamp GK. Maternal diet alters the sensory qualities of human milk and the nursling‘s behavior. Pediatrics 1991;88:737-44. 93. Mennella JA, Beauchamp GK. The effects of repeated exposure to garlic-flavored milk on the nursling’s behavior. Pediatr Res 1993; 342305-808. 94. Gallicano K, Foster 8, Choudhri S. Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers. Br J Clin Pharmacol2003;55:199-202. 95. Markowitz JS, Devane CL, Chavin KD, et al. Effects of garlic (Alliurn sutivurn L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers. Clin Pharmacol Ther 2003; 7 4 170-177.

Aloe Vera (Cape Aloe) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 737 Aloe Vera Terminology 737 Chemical Composition 738 Anthraquinones 738 Saccharides 738 Prostanoids 738 Superoxide Dismutase 738 Other Constituents 738

Clinical Applications 741 Burns, Frostbite, and Other Tissue Damage 741 Radiation Burns 742 Psoriasis 743 Gastric Ulcers 743 Acquired immunodeficiency Syndrome 743 Asthma 744 Diabetes 744 Contraception 745 Cancer Prevention 745

History and Folk Use 738 Dosage 745 Pharmacology 739 Gastrointestinal Effects 739 Immune-Enhancing and Antimicrobial Activity 740 immunologic Effects 740 Antiinflammatory Activity 741 Other Effects 741

Aloe veru (family: Lilaceous) Common name: cape aloe

GENERAL DESCRIPTION More than 300 species of aloe plants exist, but the most popular medicinal variety is currently Aloe veru. The nomenclature of A. veru has been somewhat confused, as the plant has been known by various names, most notably Aloe burbudensis and Aloe vulguri. The geographic origination of the plant is unclear. Historical records indicate that it may have originated from Egypt or the Middle East. Aloe has been introduced and naturalized throughout most of the tropics and warmer regions of the world including the Caribbean, southern United States, Mexico, Latin America, the Middle East, India, and Asia.' A. veru is a perennial plant with yellow flowers and tough fleshy triangular or spearlike leaves arising in a rosette configuration. The leaves are up to 20 inches long and 5 inches across at the base, tapering to a point. There may be as many as 30 leaves per plant. The margins of the

Toxicology 745 Drug Interactions 745

leaf are characterized by sawlike teeth. Inside, the meaty leaf is filled with gel that arises from a clear, central mucilaginous pulp. Mature aloe measures 1.5to 4 feet long and has a base of 3 inches or greater in diameter. The leaf is composed of three distinct layers: an outer layer of tough tissue; a corrugated lining just beneath the outer layer; and the major portion of the leaf, the inner layer consisting of parenchymal cells containing large vacuoles of a semisolid, gelatinous, transparent gel. The bitter latex of the corrugated layer protects the plants from predators. Should an animal bite the leaf, the sap causes irritation. The dried latex (juice) derived from the corrugated layer is the source of the laxative properties of aloe. The parenchymal tissue or gel is the portion of the aloe used in other applications.*

Aloe Vera Terminology A. veru gel-naturally occurring, undiluted parenchymal tissue obtained from the decorticated leaves of A. Vera 737

A. veru concentrate-A. veru gel from which the water has been removed A. veru juice-an ingestible product containing a minimum of 50% A. v e r ~gel A. veru latex-the bitter yellow liquid derived from the pericyclic tubules of the rind of A. vmu, the primary constituent of which is aloin

CHEMICAL COMPOSITION The main feature of all aloe plant portions is a high water content. Aloe gel contains 99% water, while the skin and fillet fractions contain 90% and 98% water, respectively. A. veru contains numerous compounds possessing biologic activity. Although many botanical medicines suffer from substantial geographic variation in content, commercial aloe is quite consistent. One study found that the composition of the major compounds is remarkably invariable, with aloeresin A, aloesin, and aloin (both epimers A and B) contributing between 70% and 97%of total dry weight in a ratio of approximately 4:3:2,respectively. Minor compounds were less evenly distributed, with aloinoside A and aloinoside B found in higher concentrations in Western countries. The aloin content of the exudate did vary, but there were no distinct geographic discontin~ities.~

Anthraquinones In 1851the cathartic action of aloe was discovered to be due to aloin, a lemon yellow powder formed from drying of the bitter latex (Figure 66-1). From this material several anthracenes have been isolated, the major anthraquinone being barbaloin. Barbaloin and aloin are often referred to synonymously. Although aloe contains other anthraquinone derivatives, including the anthracene known as aloe-emodin, barbaloin is considered the most potent cathartic. As a whole, the anthraquinone compounds are water-soluble glycosides easily separated from the water-insoluble resinous

Saccharides Recent research on A. veru has focused on the glycoprotein, mucopolysaccharide, and polysaccharide constituents. Aloe contains the polysaccharides galactose, xylose, arabinose, and acetylated mannose. The latter, similar to guar and locust bean, has received considerable clinical research attention as an antiviral and immunopotentiating agent, especially in the treatment of acquired immunodeficiency syndrome (AIDS). Acemannan, a water-soluble, long-chain polydispersoid beta-(1,4)linked mannan polymer interspersed with 0-acetyl groups found mainly in aloe gel, is discussed later?

Prostanoids Several prostanoid compounds have been discovered in A. veru extracts? The conversion of essential fatty acids to prostanoids by the enzyme cyclooxygenase in a plant such as A. veru is rare. The major unsaturated fatty acid in the plant is gamma-linolenic acid (C18:3), which can be converted to icosatrienoic acid, the precursor to prostaglandins of the 1series. The 1series prostaglandins are known to exert more favorable effects on inflammation, allergy, platelet aggregation, and wound healing. The presence of gamma-linoleic acid or prostaglandins, or both, in a stable medium, along with inhibitors of thromboxane synthesis, may be another important chemical characteristic of aloe responsible for its antiinflammatory and wound-healing effects.

Superoxide Dismutase Extracts from the parenchymatous leaf gel and the rind of aloe (A. burbadensis Miller) have been shown to contain seven electrophoretically identifiable superoxide dismutases (SODs). Two of these seven are mangano SODs, while the other five activities are cupro-zinc SODS.~

Other Constituents Other biologic active compounds found in A. ueru include the following:

A serine carboxypeptidase Salicylates Minerals Vitamins Sterols Amino acids Box 66-1 provides a partial listing of the remarkably diverse range of compounds isolated from A. ~eru.2-~

HISTORY AND FOLK USE H

OH

Figure 66-1

Aloin and aloe-erncdin.

A. Vera has a storied history of use. Mesopotamian clay tablets dated 1750 EKindicate that A. veru was being used for medicinal purposes. Egyptian records from 550 BC

Aloe Vera (Cape Aloe)

Anthraquinones:Aloin, barbaloin, isobarbaloin, anthranol, aloetic acid, anthracene, ester of cinnamic acid, aloe-emodin, emodin, chrysophanic acid, ethereal oil, resistannol Saccharides: Cellulose, glucose, mannose, L-rhamnose, aldopentose Prostanoids:Gamma-linolenic acid Enzymes: Oxidase, amylase, catalase, lipase, alkaline phosphatase Amino acids: Lysine, threonine, valine, methionine, leucine, isoleucine, phenylalanine Vitamins: Vitamins B,, BPIB6, C, and E,folic acid, choline, betacarotene Minerals: Calcium, sodium, manganese, magnesium, zinc, copper, chromium Miscellaneous:Cholesterol, triglycerides, steroids, uric acid, lignins, beta-sitosterol. gibberellin, salicylic acid Modified from Shelton RM. Int J Dermatol 1991;30:679-683

also mentioned aloe for infections of the skin. The ancient Greeks were also aware of aloe's medicinal effects, as both Pliny (23-79 AD) and Dioscorides (first century AD) wrote of aloe's ability to treat wounds and heal infections of the skin.A. veru is still widely used in many traditional systems of medicine. In India, for example, in addition to external applications, aloe (whole leaves, the exudate, and the fresh gel) is used as a cathartic, stomachic, and anthelmintic. A. veru has been adopted into the materia medicas by many cultures of the world.' In the United States, the history of aloe can be traced as far back as the United States Phmcopot?iu of 1820, where a number of aloe preparations were described. Most of these preparations were designed to take advantage of aloe's laxative effects. By the early 1900s, more than 27 different aloe preparations were in popular use. In 1920 aloe began being cultivated for pharmaceutic use? A major development in the modern use of aloe occurred in 1935 when a group of physicians successfully used the fresh juice to treat a patient suffering from facial bums due to radiographs? The relief offered by aloe in the topical treatment of burns, minor irritations, skin ulcers, and other skin disorders is a major reason why companies supplying dematologic and cosmetic products have incorporated aloe into many of their formulations. Although more and more of aloe's medicinal effects are being confirmed, it is still predominantly administered without direct medical supervision. Therefore the history and folk use of aloe are continuing to evolve.

PHARMACOLOGY The pharmacology of aloe is surprisingly d i v e r s e laxative, immune potentiation, antimicrobial and wound-healing activities help explain its wide-ranging folk and clinical applications.

Gastrointestinal Effects Laxative Effects Although physicians have prescribed the whole aloe leaf as a cathartic for more than 2000 years, it was not until 1851 that the active principle aloin was discovered.' In small doses, aloin acts as a tonic to the digestive system, giving tone to the intestinal muscle. At higher dosages, it becomes a strong purgative. Its actions are most obvious on the large intestine, where it increases colonic secretions and peristaltic contractions. In combination with strychnine and belladonna, aloin became one of the most popular laxativesfor chronic constipation for many years. Since aloin often causes painful contractions, other anthraquinone laxatives like cascara and senna are now much more popular.'OJ1 A substantial amount of research activity continues in an effort to understand the laxative effects of aloe. Research using the rat large intestine shows that the increase in water content of the large intestine induced by barbaloin precedes the stimulation of peristalsis, attended by diarrhea. Therefore it is suggested that the increase in water content is a more important factor than the stimulation of peristalsis in the diarrhea induced by barbaloin.I2 Further studies by the same researchers suggest that aloe-emodin-9-anthrone (AE:anthrone) produced from barbaloin in the rat large intestine may be the actual chemical mediator of this effect. AE-anthrone not only caused an increase in the intestinal water content but also stimulated mucus ~ecreti0n.l~

Bowel Detoxification In 1985 Bland14 reported the effect of orally consumed A. oeru juice on urinary indican, gastrointestinal pH, stool culture, and stool specific gravity in a semicontrolled study of 10 (5 men and 5 women) healthy human subjects.14Urinary indican (see Chapter 32) is used as an indicator of the degree to which either dietary protein is malabsorbed or intestinal bacteria are engaged in putrefactive processes. After a full week of drinking 6 oz. of A. veru juice three times daily, urinary indican levels decreased one full unit. This suggests that regular A. veru juice consumption can lead to improved protein digestion and assimilation or reduced bacterial putrefaction, or both.

Inhibition of Gastric Acid Secretion With Heidelberg gastric analysis, A. vem juice was shown to increase gastric pH by an average of 1.88 units. This supports the findings of other researchers that A. veru gel can inhibit the secretion of hydrochloric acid. The Heidelberg test also demonstrated that A. veru juice can slow down gastric emptying, possibly leading to improved digestion. Six of the 10 subjects showed marked alterations in stool cultures after the week-long study. This implies that

Pharmacology of Natural Medicines

A. vma juice may exert some bacteriostatic or fungistatic activity.In the four subjectswith positive cultures for yeast, theR was a reduction in the number of yeast colonies. Stool specific gravity was reduced after the week of drinking A. Vera juice. This implies improved water retention, yet none of the subjects complained of diarrhea or loose stools.

IMMUNE-ENHANCING AND ANTIMICROBIAL ACTIVITY Immunologic Effects Antibacterial and Antifungal Activity Aloe has demonstrated activity against many common bacteria and fungiin several studies. In a detailed review of these studies, the researchers assayed the antimicrobial properties of an A. uera extract and reviewed the work of others.16-18Both mean inhibitory and mean lethal concentrationswere determined and compared with silver sulfadiazine, a potent antiseptic used in the treatment of extensive bums. As shown in Table 66-1,15 the antimicrobial effects of A. Vera compare quite favorably with those of silver sulfadiazine. A 60% A. Vera extract was found to be bactericidal against Pseudomonas aeruginosa, Klebsiella pneurnoniae, Serra tia marcescens, Citrobacter spp., Enterobacter cloacae, Streptococcus pyogenes, and Streptococcus ugaluctiae. Concentrations of 70% aloe were bactericidal for Staphylococcus uureus, 80% for E . coli, and 90% for Streptococcus faecalis and Candida albicans. Organisms inhibited in other studies include Mycobacferiurn tuberculosis, Trichophyton spp., and Bacillus s ~ b t i l i s . * ,The ~ , ~ antimicrobial activity against common

Organism

Gram-Negative Escherichia coli Enterobacter cloacae Klebsiella pneumoniae Pseudomonas aeruginosa Gram-Positive Staphylocmcus aureus Streptococcus pyogenes Streptococcus agalactiae Streptococcus faecalis Bacillus subtilis

Aloe Vera

AaSD

16

12

14

12

14

6

17

12

18

12

16

12

16

12

6

11

19

14

Modiied from Robson MC, Heggers JP, Hagstrom WJ. J Burn Care Rehabil1982; 3:157-162. Inhibition zones measured in millimeters.

skin pathogens of A. Vera gel in a cream base was shown to be slightly better than silver sulfadiazine in agar well diffusion studies.lS

Antiviral Effects Acemannan (acetylated mannose) in injectable form has been approved for veterinary use in fibrosarcomas and feline leukemia. Its action in feline leukemia is quite impressive. Feline leukemia, like AIDS, is caused by a retrovirus (feline leukemia virus, or FeLV). The virus is so lethal that once cats develop clinical symptoms, they are usually euthanized. Typically more than 70% of cats die within 8 weeks of the onset of clinical signs. In a study of 44 cats with clinically confirmed feline leukemia, acemannan was injected (2 mg/kg) weekly for 6 weeks and the cats reexamined 6 weeks after termination of i~eatment.'~ At the end of the 12-week study, 71% of the cats were alive and in good health. Acemannan has demonstrated significant antiviral activity against several viruses including feline AIDS, influenza human immunodeficiency virus type 1(W-l), virus, and measles virus.2°-z2

Immune Enhancement Acemannan is a potent i m m u n o s t i m ~ l a n t . ~Among ~,~-~ the effects noted for acemannan are the enhancement of macrophage release of interleukin (1L)-1-alpha,cytokines, tumor necrosis factor, and nitric oxide release, as well as phagocytosis and nonspecific cytotoxicity. Acemannan also enhances T-cell function and interferon production, although these actions may also be due to enhanced macrophage function. Macrophage production of cytokines IL-6 and tumor necrosis factor alpha were dependent on the dose of acemannan provided. These effects can be substantial. For example, in one study, acemannan has been shown to enhance the macrophage respiratory burst (twofold increase above the media controls), phagocytosis (45% compared with 25% in controls), and killing of C . albicuns (38% killing of C . albicans compared with 0% to 5% killing in

Hematopoietic Effects Several complex carbohydrates have been found to significantly stimulate hematopoiesis. CARN 750, a polydispersed beta-(1,4)-linked acetylated mannan isolated from the A. Vera plant, has been shown to have hemato-augmenting properties. Subcutaneous injections of 1 mg/mouse of CARN 750 optimally increased hematopoietic progenitors, measured as IL-3-supported colony-forming units, culture (CFU-C) and high proliferative potential colony-forming cell (HPP-CFC) assays in the spleen. Providing 2 mg/animal of CARN 750 optimally increased bone marrow cellularity, frequency, and absolute number of HPP-CFCs and CFU-Cs. The hematopoietic activity of CARN 750 increased with

Aloe Vera (Cape Aloe) ~

the frequency of administration. The greatest increase in activity in mice myelosuppressed with radiati~n.~'

Antiinflammatory Activity A. veru has been shown to exert a number of antiinflammatory actions, including blocking of the generation of inflammatory mediators like thromboxanes and bradykinin, reducing neutrophil infiltration during inflammation, and reducing edema.2,45J5*2831 Several compounds in aloe are responsible for these actions. The most important are glycoproteins, which inhibit and actually break down bradykinin, a major mediator of pain and inflammation; various anthraquinones; and salicylates. These antiinflammatory substances may be of significance in both topical (discussed later) and oral applications. One comprehensive study evaluated the effects of aqueous, chloroform, and ethanol extracts of A. veru gel on carrageenan-induced edema in the rat paw and neutrophil migration into the peritoneal cavity stimulated by carrageenan. Also evaluated was the capacity of the aqueous extract to inhibit cyclooxygenase activity. The aqueous and chloroform extracts decreased the edema induced in the hind paw and the number of neutrophils migrating into the peritoneal cavity, whereas the ethanol extract only decreased the number of neutrophils. The aqueous extract was also found to inhibit prostaglandin E2 production from arachidonic acid, demonstrating an inhibitory action on cyclooxygenase.The aqueous extract contained anthraglycosides, reductor sugars, and cardiotonic glycosides, while the ethanol extract contained saponins, carbohydrates, naphthoquinone, sterols, triterpenoids, and anthraquinones. The chloroform extract contained sterols and anthraquinones?2 Another useful aspect of aloe is its ability to inhibit lipid peroxidation and scavenge free radicals. One study measured the activity of seven anthraquinones and four anthrones against nonenzymatic and enzymatic lipid peroxidation in vitro and their ability to scavenge free radicals. Using rat hepatocytes exposed to strong oxidizing agents, dithranol and anthrone provided the strongest inhibition of nonenzymatic peroxidation. Rhein anthrone and aloe-emodin showed the highest inhibitory activity against peroxidation of linoleic acid catalyzed by lipoxygenase. Anthrone, dithranol, and rhein anthrone were the most effective free radical

scavenger^.^^

Other Effects Wound Healing The topical effects of A. vmu appear to be due to a combination of enhancement of wound healing along with antiinflammatory, moisturizing, emollient, and antimicrobial acti0ns?,~5J~- A. veru contains a number of compounds necessary for wound healing, including

vitamin C, vitamin E, and zinc. Unlike many other antiinflammatory substances, A. vera has been shown to stimulate fibroblast and connective tissue formation, thereby promoting wound repair. Finally, aloe appears to stimulate the epidermal growth and repair process including increasing the manufacture of supportive glycosaminoglycans, presumably due to its polysaccharides.4l Mannose-6-phosphate, the major sugar in the A. veru gel, may be its most active growth substance." Another interesting effect of aloe in wound healing is its ability to counteract the wound healing suppression effects of cortisone. In one study, A. veru at doses of 100 and 300 mg/kg daily for 4 days blocked the wound healing suppression of hydrocortisone acetate up to 100% using the wound tensile strength assay. The authors suggested this response was because of the growth factors present in A. vern masking the wound-healing inhibitors.43

Alcohol Detoxification Oral administration of aloin (300 mg/kg) given 12 hours before administration of alcohol (3 g/kg) significantly decreases the blood alcohol area under the curve by a remarkable 40%. This suggests an increase in the rate of blood alcohol elimination from the body of 45% to 50%. Analysis of hepatic triglyceride (TG) levels revealed that both ethanol and aloin given alone significantly increased the TG levels in a comparable manner. However, the level obtained by the combined treatment of aloin and ethanol was not statistically different from that produced by either treatment alone. The levels of serum L-aspartate:2-oxoglutarate aminotransferase (AST) and L-alanine:2-oxoglutarateaminotransferase (ALT) activities were not increased by acute alcohol intoxication, aloin alone, or the combined treatment of alcohol and a l o h U

CLINICAL APPLICATIONS Burns, Frostbite, and Other Tissue Damage Despite growing consumer awareness of A. veru's soothing effects on burns and wound healing during the past 40 years, few human studies have been conducted. Virtually all of the studies support the topical use of A. veru gel, especially in minor bums or skin inflammation? Recent research has supported its use for even more severe tissue damage. Although limited, the human research has been promising. For example, one study found A. veru gel quite successful in three patients with chronic leg ulcers of 5,7, and 15 years' duration." The gel was applied to the ulcers on gauze bandages. Rapid reduction in ulcer size was noted in all three subjects, and complete resolution occurred in two. Encouraging results were also reported for acne and seborrhea.

Pharmacology of Natural Medicines

In a study of 27 patients with a partial-thickness bum wound, treatment with A. veru gel was compared with Vaseline gauze. The average time of healing in the aloe gel area was a statistically sigruficant and dramatic 1 week shorter: 11.9 days compared with 18.2 days for the Vaseline gauze-treated wound. Histologic evaluation showed early epithelialization in the A. veru geltreated area.& Another study compared the therapeutic effects of systemic pentoxlfylline with topical A. veru cream in the treatment of frostbite. The frostbitten ears of 10 New Zealand white rabbits were assigned to one of four treatment groups: untreated controls, those treated with A. veru cream, those treated with pentoxifylline, and those treated with A. veru cream and pentoxifylline. The control group had a 6% tissue survival. Tissue survival was notably improved with pentoxlfylline (20%),better with A. uem cream (24%), and best with the combination therapy (30%)!’ Aloe appears to be effective even in particularly severe tissue injuries, such as those seen in necrotizing fasciitis. Necrotizing fasciitis usually manifests as a lowgrade cellulitis that quickly deteriorates to a limb- and life-threatening soft tissue infection. Immediate surgical debridement is essential, followed by aggressive wound management. An interesting report describes excellent results in two cases. Case 1 was a 72-year-old female who, upon presenting to the emergency department with a “sore bottom,” was diagnosed with five problems:

Radiation Burns

Research into the topical applications of A. veru gel began in the 1930s in the treatment of radiation burns. During the 1930s, radiographs were used therapeutically for cancer, eczema and other skin complaints, and as a depilatory agent. In 1935 Collins and Collins9 reported the success of A. veru gel in a single case, a woman with a patch of severe x-ray dermatitis on her forehead. The woman had tried various medical treatments for 8 months, only to have her condition worsen. The Collinses were going to perform a skin graft, but as a temporary measure applied a preparation of fresh whole A. veru leaves to reduce the itching. The result was that “Twenty-four hours later she reported that the sensation of itching and burning had entirely subsided,” and by 5 weeks “there was complete regeneration of the skin of the forehead and scalp, new hair growth, complete restoration of sensation, and absence of scar.” Five months after treatment was started there was complete healing. Following case reports, although not as positive as this initial study clearly indicated that A. veru was effective in some cases. Until the 1940s most of the studies on aloe were reported case histories? In order to substantiate these case studies, animal studies began to appear in the literature. Rowe and colleagues39performed several studies in rats with radiation-induced ulcers and determined that fresh aloe pulp was effective, while dried aloe powder was Anal-rectal abscess In 1953 Lushbaugh and Hale,@working for the U.S. Foumier’s gangrene Atomic Energy Commission, produced one of the most Ulcerative enterocolitis convincing studies of the efficacy of A. vera gel. Twenty Chronic blood loss/anemia albino rats were exposed to beta-radiation, and different Protein caloric malnutrition treatments were used on quadrants of the affected area of each animal. The treatments used were fresh A. veru After debridement, her anal-rectal wound extended leaf, a commercial A. veru ointment, application of a dry from the labia to the left buttock. Care was multidiscipligauze bandage, and an untreated control. Both fresh nary and included applying a water-based aloe gel and A. veru and the A. veru ointment produced clear improvesaline-soaked gauze twice a day. After 45 days, the ments. At the end of 2 months, the A. veru-treated areas wound exhibited a pink base with granulation tissue were completely healed, while the other two areas had and contraction of the wound edges. not yet healed at the end of 4 months. Case 2 was a 48-year-old male with seroma of the left Recently, a large, placebo-controlled, double-blind leg secondary to a crush injury. Within 3 days he develstudy cast doubt on the efficacy of aloe for severe radiaoped deep vein thrombosis in that leg, as well as two tion bums. Three phase III randomized trials were large seroma cavities on either side of the thigh. Care reported in this study. The first one was double-blind, included packing with aloe gel and saline-soaked used a placebo gel, and involved 194 women receiving sponges. Two weeks after admission, the anterior breast or chest wall irradiation. The second trial randomwound was covered with a split-thickness skin graft, ized 108 such patients to A. veru gel versus no treatment. while partial closure of the lateral cavity was attempted Skin dermatitis was scored weekly during both trials unsuccessfully with retention sutures. After 5 weeks, healing was complete for the anterior wound and 95% both by patients and by health care providers. Skin dermatitis scores were virtually identical on both treatment complete for the posterior wound.@ arms during both trialsw The aim of the study was to see A double-blind study showed that patients with presif topical A. veru gel would be beneficial in reducing the sure sores responded equally to an acemannan hydrogel wound dressing or a moist saline gauze wound dre~ing!~ identified skin side effects of radiation therapy including

erythema, pain, itching, dry desquamation, and moist desquamation when compared with aqueous cream. The secondary aim was to assess the effect of other factors known to predict severity of radiation skin reaction (i.e., breast size, smoking habit, and one or more drainages of lymphocele after surgery) on other skin side effects. The third study involved more than 225 patients with breast cancer after lumpectomy or partial mastectomy who required a course of radiation therapy using tangential fields. Like the other two studies, A. veru gel did not significantly reduce radiation-induced skin side effects.5l These surprising results might be explained by another recent study that compared the efficacy of commercially available gels with an acemannan-rich extract from aloe leaves in the treatment of irradiated mice. Male C3H mice received graded single doses of gamma radiation ranging from 30 to 47.5 Gy to the right leg. In most experiments the gel was applied daily, beginning immediately after irradiation. To determine the timing of application for the best effect, gel was applied beginning on days -7,0, or +7 relative to the day of irradiation (day 0) and continuing for 1, 2, 3, 4, or 5 weeks. The right inner thigh of each mouse was scored on a scale of 0 to 3.5 for severity of radiation reaction from the seventh to thirty-fifth day after irradiation. Dose-response curves were obtained by plotting the percentage of mice that reached or exceeded a given peak skin reaction as a function of dose. The researchers found that while the acemannan-rich extract gel was highly effective, the commercially available gel showed no improvement over the control. They also found that the aloe gel had to be applied immediately after irradiation and continued for at least 2 weeks. There was no effect if the aloe gel was applied only before irradiation or beginning 1 week after irradiation. Clearly, the quality and concentration of aloe constituents are crucial if clinical results are to be obtained.52

Psoriasis A recent double-blind, placebo-controlled study evaluated the clinical efficacy and tolerability of topical A. vera extract 0.5% in a hydrophilic cream and obtained impressive results. Sixty patients (36 male/24 female) aged 18 to 50 years (mean 25.6) with slight to moderate chronic plaquetype psoriasis and psoriasis area and severity index (PASI) scores between 4.8 and 16.7 (mean 9.3) were enrolled and randomized to two groups. The mean duration of the disease before enrollment was 8.5 years (range 1 to 21). Patients self-administered trial medication topically at home three times daily for 5 consecutive days/week (maximum 4 weeks active treatment). Patients were examined on a weekly basis, and those showing a progressive reduction of lesions, desquamation followed by decreased erythema, infiltration, and lowered PASI score were considered healed.

The study was scheduled for 16 weeks with 12 months of follow-up on a monthly basis. The treatment was well tolerated by all the patients, with no adverse drugrelated symptoms and no dropouts. By the end of the study, the A. vmu extract cream had cured 25 of 30 patients (83.3%)compared with the placebo cure rate of only 2 of 30 (6.6%),resulting in significant clearing of the psoriatic plaques (328 of 396, or 82.8%) versus placebo (28 of 366, or 7.7%), and a decreased PASI score to a mean of 2.2.53

Gastric Ulcers Internal use of A. veru gel to treat peptic ulcers was studied in 1963.%Twelve patients with x-ray-confirmed duodenal ulcers were given 1 tablespoon of an emulsion of A. veru gel in mineral oil once daily. At the end of 1 year, all patients demonstrated complete recovery and no recurrence. On the basis of experimental evidence, the following factors were considered responsible for the effectiveness:

A. veru gel inactivates pepsin in a reversible fashion. When the stomach is devoid of food, pepsin is inhibited by A. veru gel; however, in the presence of food, pepsin is released and allowed to digest the food. The gel inhibits the release of hydrochloric acid via interference with histamine binding to the parietal cells. A. Vera gel is an extremely good demulcent that heals and prevents aggravating irritants from reaching the sensitive ulcer.

Acquired Immunodeficiency Syndrome Although acemannan has demonstrated some direct antiviral activity against HIV-1 by inhibiting glycosylation of viral glycoproteins, its main promise in treating AIDS and HIV may be to enhance the action of azidothymidine (AZT), the antiviral drug used in AIDS. In vitro studies have shown that acemannan combined with suboptimal noncytotoxic concentrations of AZT or acyclovir acts synergistically to inhibit the replication of HIV and herpes simplex type 1 (HSV-1).2*On the basis of these studies, as well as preliminary human studies, researchers believe that the use of acemannan may reduce the amount of AZT required by as much as 90Y0,5~ which is significant. In addition to AZT being extremely expensive, its use is often associated with severe side effects including anemia and granulocytopenia due to bone marrow suppression. Preliminary clinical studies suggest that acemannan and A. veru may be beneficial when administered orally in HIV-positive individuals.5657In one study, 14 HIV patients prescribed oral acemannan (800 mg/day) demonstrated sigruficant increases in circulating monocytes/macrophages. In particular, there were significant increases in the number of large circulating monocytes,

Pharmacology of Natural Medicines

indicating improvement in phagocytizing, processing, and presenting cells in the blood.57In another study of 15 AIDS patients receiving an oral dose of acemannan (800 mg/day), the average scores of Modified Walter Reed (MWR) Clinical Evaluation scoring, absolute T-4, absolute T-8, and p24 core antigen levels all improved in those surviving (Table 66-2) at the end of 900 days. Two patients died of AIDS, and another committed suicide. From this study, as well as others, it has been suggested that prognostic criteria to determine the most responsive patients are those with an absolute T-4 count greater than 150/mm3 and p24 levels less than 300.% In another study A. vera juice (0.6 L/day) was used in conjunction with essential fatty acids and a multiple vitamin, mineral, and amino acid supplement to treat 30 patients. The 15 AIDS, 12 AIDS-related comlpex, and two I-IlV-seropositive patients continued with regular medication, including AZT.After 180 days, all patients showed clinical improvement according to modified Kamofsky Quality of Life Assessment scores and the MWR Clinical Evaluation; 25% of those positive for the p24 core antigen converted to nonreactive; anemia induced by AZT showed improvement in all patients; and the patients gained an average of 7%. Unfortunately, a follow-up study did not reproduce these early, promising results. A comprehensive study assessed the safety and efficacy of acemannan as an adjunctive to antiretroviral therapy among 63 male patients (mean age, 39 years) with advanced HIV disease receiving zidovudine (ZDV) or didanosine (ddI).% The randomized, double-blind, placebo-controlled trial provided a large dose of acemannan (400 mg orally four times daily). Eligible patients had CD4 counts of 50 to 3OO/pl twice within 1 month of study entry and had received 26 months of antiretroviral treatment (ZDV or ddI) at a stable dose for the month before entry. CD4 counts were made every 4 weeks for 48 weeks. p24 Antigen was measured at entry and every 12 weeks thereafter. Sequential quantitative lymphocyte cultures for I-IlV and ZDV pharmacokinetics were performed in a subset of patients.

of acquired immunodeficiency syndrome Test

Pretreatment

After 900 days

Modified Walter Reed Clinical Evaluation

65

2

Absolute T-4

322/mm3

324/mm3

Absolute T-8

469/mm3

660/mm3

p24 Core antigen

5115

4112

Modified from McDaniel HR. Carpenter RH, Kernp M, et al. Antiviral Res 1990; 13(suppl 1):117.

The mean baseline CD4 counts were 165 and 147/p1 in the placebo and acemannan groups, respectively; 90% of the patients were receiving ZDV at entry. Six patients in the acemannan group and five in the placebo group developed AIDSdefining illnesses. There was no statistically significant difference between the groups at 48 weeks with regard to the absolute change or rate of decline at CD4 count. Among ZDV-treated patients, the median rates of CD4 change (ACD4) in the initial 16 weeks were -121 and -120 cells/year in the placebo and acemannan groups, respectively; ACD4 decline from week 16 to 48 was 0 and -61 cells/year in the acemannan and placebo groups (p = O.ll), respectively. No statistical difference between groups occurred with regard to adverse events, p24 antigen, quantitative virology, or pharmacokinetics. Twenty-four patients, 11receiving placebo and 13receiving acemannan, discontinued study therapy prema-ly, none due to serious adverse reactions. The decreased, but not statistically significant, rate of loss of CD4 cells in the acemannan group from weeks 16 to 48 provides a possible ray of hope that long-term use, such as reported earlier, may be of value and should be investigated.

Asthma Oral administration of an extract of A. veru for 6 months was shown to produce good results in the treatment of asthma in some individuals of various age~i.5~ The exception was the fact that the A. vera extract was not effective in patients dependent on corticosteroids. The mechanism of action is thought to be via restoration of protective mechanisms followed by augmentation of the immune system. The extract used in the study was produced from the supernatant of fresh leaves stored in the dark for 7 days at 4" C. The dosage was 5 ml of a 20% solution of the aloe extract in saline twice daily for 24 weeks. Eleven of 27 patients (40%) without corticosteroid dependence reported significant improvement at the study's conclusion. Studies indicate that subjecting the leaves to dark and cold results in an increase in the polysaccharide fraction. One gram of the crude extract obtained from leaves stored in the cold and dark produced 400 mg of neutral polysaccharide, compared with only 30 mg produced from leaves not subjected to cold or dark.

Diabetes A. vera also exhibits a hypoglycemic effect in both normal and alloxan-induced diabetic mice.60 A small human study showed benefit in diabetics. Five patients with non-insulin-dependent diabetes ingested half a teaspoonful of aloe four times daily for 14 weeks. Fasting blood sugar in each patient fell from a mean of 273 to 151 mg/dl with no change in body weight. The authors concluded that aloe lowers blood glucose levels by an

Aloe Vera (Cape Aloe)

A more recent and larger study unknown (49 men and 23 women) now provides more support for the efficacy of aloe in combination with glibenclamide in diabetes. Although there was no response to glibenclamide alone, the combination was effective.62 The patients were provided with 1 tablespoon of aloe gel and 5 mg of glibenclamide twice daily, with 5 mg twice daily of glibenclamide serving as the control. After 2 weeks, fasting blood sugar decreased sigfuficantlyin the treated group, and by day 42 had decreased from an average of 289 mg% to a remarkable 148 mg%. Although the drop in serum cholesterol was insignificant, serum triglycerides decreased from 223 mg% to (again remarkable) 128 mg% by day 42. No adverse effects were noted using standard blood chemistries.

Contraception An interesting new application of aloe is as a spermicide. Twenty samples of fresh ejaculate from healthy human volunteers between 20 and 30 years of age were treated in vitro with a 1%concentration of zinc acetate combined with lyophilized A. burbudensis (at concentrations of 7.5%to 10%). The combination of zinc acetate with lyophilized A. barbudensis was shown to possess powerful spermicidal and antiviral effects. This was attributed to their concentration of minerals (boron, barium, calcium, chromium, copper, iron, potassium, magnesium, manganese, phosphorus, and zinc), which were toxic to the sperm tail, causing instant immobilization. Studies with rabbit vaginal epithelium showed no irritation. This is important because nonoxynol-9, the active spermicidal ingredient used in vaginal contraception for more than 30 years, appears to cause cell membrane damage in vaginal and cervical epithelium and may possibly have teratogenic effects.@

Cancer Prevention The antigenotoxic and chemopreventive effect of A. barbudensis on benzo[u]pyrene (B[u]P)-DNA adducts was investigated in vitro and in vivo in an animal model. Aloe showed a time-course and dose-dependent inhibition of [3H]B[u]P-DNAadduct formation in primary rat hepatocytes, inhibited cellular uptake of [3H]B[u]P in a dose-dependent manner, and significantly inhibited adduct formation in various organs (liver, kidney, forestomach and lung). When mice were pretreated with aloe for 16 days before B[u]P treatment, inhibition of BPDE-I-DNA adduct formation and persistence was enhanced. Phase I1 glutathione-S-transferaseactivity was slightly increased in the liver, but phase I cytochrome P450 activity was not affected.@ This translates into animal cancer studies as protection from Norman murine sarcoma in mice6 and efficacy in treatment of spontaneous neoplasms in dogs and cats.&

A. veru may also play a role in cancer therapy. One clinical study sought to evaluate whether the concomitant administration of aloe may enhance the therapeutic results of melatonin in patients with advanced solid tumors for whom no effective standard anticancer therapies are available. The study included 50 patients suffering from lung cancer, gastrointestinal tract tumors, breast cancer, or brain glioblastoma who were treated with melatonin alone (20 mg/day orally in the dark period) or melatonin plus A. vem tincture (1 ml twice daily). A partial response was achieved in 2 of 24 patients treated with melatonin plus aloe and in none of the patients treated with melatonin alone. Stable disease was achieved in 12 of 24 and in 7 of 26 patients treated with melatonin plus aloe or melatonin alone, respectively. Therefore the percentage of nonprogressing patients was significantly higher in the group treated with melatonin plus aloe than in the melatonin group (14 of 24 vs. 7 of 26, p < 0.05). The percentage of 1-year survival was also significantly higher in patients treated with melatonin plus aloe (9 of 24 vs. 4 of 26, p < 0.05).67

DOSAGE A. veru gel can be applied liberally for topical applications. A wide range of products are available on the market; however, simple pure A. veru gel is sufficient. A. veru juice can be consumed orally as a beverage or tonic. Although detailed information is currently lacking as to the optimal dose for these types of products, it is recommended that no more than 1 quart be consumed daily. The dose of acemannan being used in HIV/AIDS patients is 800 to 1600 mg/day. This corresponds to a dose of approximately 0.5 to 1 L/day for most A. veru juice products. However, there may be great variation in the amount of acemannan in various products.

TOXIC0LOGY Although rare, hypersensitivity reactions manifesting as generalized, nummular, eczematous, and papular dermatitis have been reported as a result of topically applied A. veru preparations. A. veru gel has been shown to delay wound healing in cases of surgical wounds such as those produced during laparotomy or cesarean deliveryM Therefore topical aloe preparations are not useful for treating deep vertical wounds.

DRUG INTERACTIONS Excessive use of aloe dried juice/latex may interact with several d r u g ~ . 6Large ~ - ~ dosages of aloe may increase the risk of toxicity of antiarrhythmic drugs. Theoretically, overuse of aloe dried juice/latex may increase the risk of

Pharmacology of Natural Medicines cardiac glycoside toxicity. Potential for adverse effects exists when aloe dried juice/latex is used excessively along with herbs containing cardiac glycosides (e.g., black hellebore, Canadian hemp roots, digitalis leaf, pheasant's eye plant, pleurisy root, squill bulb leaf scales, Strophanthus seeds) or with cardiac glycoside drugs (eg., digoxin). Overuse of aloe dried juice/latex can exacerbate the potassium loss caused by corticosteroids, diuretics, horsetail, and licorice root. Due to the hypoglycemic effects of internally consumed A. veru gel, persons using glyburide drugs to control blood sugar (e.g., DiaBeta, Micronase, Glynase) should monitor blood glucose levels closely.

Aloe dried juice/latex causes shorter gastrointestinal transit time, so it may reduce the absorption of some drugs. Theoretically, concomitantuse of aloe with other stimulant laxative herbs might increase the risk of potassium depletion. In addition to senna leaves and pods and cascara bark, the two herbs most widely used for this purpose, stimulant laxative herbs also include wild cucumber fruit (Ecboliurn eluteriurn), blue flag rhizome, alder buckthorn, European buckthorn, butternut bark, castor oil, colocynth fruit pulp, gamboge bark exudate, jalap root, black root, manna bark exudate, podophyllum root, rhubarb root, and yellow dock root.

1.Haller JS Jr. A drug for all seasons, medical and pharmacological history of aloe. Bull N Y Acad Sci 1990;66:647-659. 2. Klein AD, Penneys NS. Aloe Vera. J Am Acad Dermatol 1988;18: 714-720. 3.van Wyk BE, van Rheede, van Oudtshoom MC, Smith GF. Geographical variation in the major compounds of Aloe ferox leaf exudate. Planta Med 1995;61:250-253. 4. Grindlay D, Reynolds T. The Aloe veru phenomena: a review of the properties and modem use of the leaf parenchyma gel. J Ethnopharrnacol1986;16117-151. 5. Shelton RM. Aloe veru. Its chemical and therapeutic properties. Int J Dermatol 1991;30:679-683. 6. West DP, Zhu YE Evaluation of aloe Vera gel gloves in the treatment of dry skin associated with occupational exposure. Am J Infect Control 2003;31:40-42. 7.Afzal M, Ali M, Hassan RAH, et al. Identification of some prostanoids in Aloe Vera extracts. Planta Med 1991;5738-40. 8. Sabeh F, Wright T, Norton SJ. Isozymes of superoxide dismutase from Aloe Vera. Enzyme Protein 1996;49:212-221. 9. Collins CE, Collins C. Roentgen dermatitis treated with fresh whole leaf Aloe Vera. Am J Roentenol1935d3:396-397. 10. Godding EW. Therapeutics of laxative agents with special reference to anthraquinones. Pharmacol 1976;14(suppl 1):78-101. 11. Anton R, Haag-Berrurier MH. Therapeutic use of natural anthraquinones for other than laxative actions. Pharmacol 1976;ZO (suppl1):104-112. 12. Ishii Y, Tanizawa H, Takino Y. Studies of aloe. IV. Mechanism of cathartic effect. Biol Pharm Bull 1994;17495-497. 13. Ishii Y, Tanizawa H, Takino Y. Studies of aloe. V. Mechanism of cathartic effect. Biol Pharm Bull 1994;17:651-653. 14. Bland J. Effect of orallyconsumed Aloe veru juice on human gastrointestinal function. Natural Foods Net News1 1985;August. 15. Robson MC, Heggers JP, Hagstrom WJ. Myth, magic, witchcraft, or fact? Aloe Vera revisited. J Bum Care Rehabil1982;3:157-162. 16. Fly LB, Keim I. Tests of Aloe Vera for antibiotic activity. Econ Bot 1963;17H. 17. LJ, W b u r g R, Bed J, Baldwin JN. Bacteriostaticproperty of Aloe Vera. J Pharm Sci 1964;531287. 18. Heggers JP, Pineless GR, Robson MC. Dermaide Aloe/Aloe Vera g e l comparison of the antimicrobial effects. J A m Med Techno1 1979;41:293-294. IR. Studies of 19.Sheets MA, Unger BA, Giggleman GF, T'ard the effect of acemannan on retrovirus infections: clinical stabilization of feline leukemia virus-infected cats. Mol Biother 1991; 341-45.

20. Kemp MC, Kahlon JB, Chinnah AD, et al. In-vitro evaluation of the antiviral effects of acemannan on the replication and pathogenesis of HIV-1 and other enveloped viruses: modificationof the processing of glycoprotein precursors. Antiviral Res 1990;13(suppl 1):83. 21. Kahlon JB, Kemp MC, Carpenter RH et al. Inhibition of AIDS virus replication by acemannan in vitro. Mol Biother 1991;3:127-135. 22. Kahlon JB, Kemp MC, Yawei N, et al. In vitro evaluation of the synergistic antiviral effects of acemannan in combination with azidothymidine and acyclovir. Mol Biother 1991;3214-223. 23. 't Hart LA, Nibbering PH, van den Barselaar MT, et al. Effects of low molecular constituents from Aloe Vera gel on oxidative metabolism and cytotoxic and bactericidal activities of human neutrophils. Int J Immunolpharmac 1990;12427-434. 24. Womble D, Helderman JH. Enhancement of allo-responsiveness of human lymphocytes by acemannan (Carrisyn). Int J Immunopharmacol1988;10:967-974. 25. Zhang L, T i r d IR. Activation of a mouse macrophage cell line by acemannan: the major carbohydrate fraction from Aloe Vera gel. Immunopharmacology 1996;35119-128. 26. Stuart RW, Lefkowitz DL, Lincoln JA, et al. Upregulation of phagocytosis and candidicidal activity of macrophages exposed to the immunostimulant acemannan. Int J Immunopharmacol 1997; 19:75-82. 27. Egger SF, Brown GS, Kelsey LS, et al. Studies on optimal dose and administration schedule of a hematopoietic stimulatory beta-(l,4)linked mannan. Int J Immunopharmacol1996;18113-126. 28. Davis RH, Shapiro E, Agnew PS.Topical effect of aloe with ribonudeic acid and vitamin C on adjuvant arthritis. J Am Pod Med Assoc 1985;75:229-237. 29. Yagi A, Harada N, Yamada H, et al. Antibradykinin active material in Aloe suponaria. J Pharm Sci 1982;71:1172-1174. 30.Davis RH, Parker WL, Samson RT, Murdoch DP. Isolation of a stimulatory system in an Aloe extract. J Am Podiatr Med Assoc 1991;81:473-478. 31. Davis RH, Leiher MG, Russo JM, Byme ME. Anti-inflammatory activity of AIoe Vera against a spectrum of irritants. J Am Podiatr Med Assoc 1989;79:263-276. 32.Vazquez B, Avila G, Segura D, Escalante B. Anti-inflammatory activity of extracts from Aloe veru gel. J Ethnopharmacol 1996; 55:69-75. 33.Malterud KE, Farbrot TL, Huse AE, Sund RB. Antioxidant and radical scavenging effects of anthraquinones and anthrones. Pharmacology 1993;47(suppl 1):77-85. 34.Henry R. An updated review of Aloe veru. Cosmet Toilet 1979; 94:42-50.

~~~

Aloe Vera (Cape Aloe) 35. Shida T, Yagi A, Nishimura H, Nishioka I. Effect of Aloe extract on peripheral phagocytosis in adult bronchial asthma. Planta Med 1985;51:273-275. 36. Davis RH, Kabbani JM, Mar0 NP.Aloe Vera and wound healing. J Am Podiatr Med Assoc 1987;77%5-169. 37. Davis RH, Leitner MG, Russo JM. Aloe Vera.A natural approach for treating wounds, edema, and pain in diabetes. J Am Podiatr Med ASSN 1988;78:60-68. 38. Rowe TD. Effect of fresh Aloe Vera gel in the treatment of thirddegree Roentgen reactions on white rats. J Am Pharm Assoc 1940;29:348-350. 39. Rowe TD, Love11 BK, Parks LM. Further observations on the use of Aloe Vera leaf in the treatment of third-degree X-ray reactions. J Am Pharm Assoc 1941;30:266-269. 40. Lushbaugh CC, Hale DB. Experimental acute radiodermatitis following beta irradiation. V. Histopathological study of the mode of action of therapy with Aloe Vera.Cancer 1953;6:690-698. 41. Chithra P, Sajithlal GB, Chandrakasan G. Influence of Aloe Vera on the glycosaminoglycans in the matrix of healing dermal wounds in rats. J Ethnopharmacol1998;59:179-186. 42. Davis RH, Donato JJ, Hartman GM, Haas RC. Anti-inflammatory and wound healing activity of a growth substance in Aloe Vera.J Am Podiatr Med Assoc 1994;84:77-81. 43. Davis RH, DiDonato JJ, Johnson RW, Stewart CB. Aloe Vera,hydrocortisone, and sterol influence on wound tensile strength and antiinflammation. J Am Podiatr Med Assoc 1994;84:614-621. 44.Chung JH, Cheong JC, Lee JY, et al. Acceleration of the alcohol oxidation rate in rats with aloin, a quinone derivative of Aloe.Biochem Pharmacol1996;521461-1468. 45. ZawahryM, Hegazy MR, Helal M. Use of aloe in treating leg ulcers and dermatoses. Int J Dermatol1973;126&73. 46. Visuthikosol V, Chowchuen B, Sukwanarat Y, et al. Effect of Aloe Vera gel to healing of burn wound. A clinical and histologic study. J Med Assoc Thai 1995;78:403409. 47. Miller MB, Koltai PJ. Treatment of experimental frostbite with pentoxifylline and aloe Vera cream. Arch Otolaryngol Head Neck Surg 1995;121:678-680. 48. Ardire L. Necrotizing fasciitis. case study of a nursing dilemma. Ostomy Wound Manage 1997;43:30-4,36,38-40. 49.Thomas DR, Goode PS, LaMaster K, Tennyson T. Acemannan hydrogel dressing versus saline dressing for pressure ulcers. A randomized, controlled trial. Adv Wound Care 1998;11:273-276. 50. Williams MS, Burk M, Loprinzi CL, et al. Phase Ill double-blind evaluation of an Aloe Vera gel as a prophylactic agent for radiationinduced skin toxicity. Int J Radiat Oncol Biol Phys 1996;36:345-349. 51. Heggie S, Bryant GP, Tripcony L, et al. A phase III study on the efficacy of topical aloe Vera gel on irradiated breast tissue. Cancer Nurs 2002;25:442451. 52. Roberts DB, Travis EL. Acemannan-containing wound dressing gel reduces radiation-induced skin reactions in C3H mice. Int J Radiat Oncol Biol Phys 1995;321047-1052.

53. Syed TA, Ahmad SA, Holt AH, et al. Management of psoriasis with Aloe Vera extract in a hydrophilic cream: a placebo-controlled, double-blind study. Trop Med Int Health 1996;1:505-509. Gerard JR. Aloe vera gel in peptic ulcer therapy: 54. Blitz JJ, Smith JW, preliminary report. J Am Osteopath Assoc 1963;62731-735. 55. Anonymous. Aloe Vera may boost AZT. Med Tribune 1991;224. 56. McDaniel HR, Carpenter RH, Kemp M, et al. Extended survival and prognostic criteria for acemannan (ACE-M) treated HIV-1 patients. Antiviral Res 1990;13(suppll):117. 57. McDaniel HR, Combs C, McDaniel R, et al. An increase in circulating monocyte/macrophages (MM) is induced by oral acemannan (ACE-M) in HN-1 patients. Am J Clin Pathol 1990;94516-517. 58. Montaner JS, Gill J, Singer J, et al. Double-blind placebo-controlled pilot trial of acemannan in advanced human immunodeficiency virus disease. J Acquir Immune Defic Syndr Hum Retroviroll996; 12:153-157. 59. Shida T, Yagi A, Nishimura H, Nishioka I. Effect of Aloe extract on peripheral phagocytosis in adult bronchial asthma. Planta Medica 1985;51:273-275. 60. Ajabnoor MA. Effect of aloes on blood glucose levels in normal and alloxan diabetic mice. J Ethnopharmacol1990;28:215-220. 61. Gnhannam N, Kingston M, Al-Meshaal IA,et al. The antidiabetic activity of Aloes. Horm Res 1986;2428&294. 62. Bunyapraphatsara N, Yongchaiyudha A, Rungpitarang S, Chokechaijaroenporn 0. Antidiabetic activity of Aloe veru juice 11. Clinical trial in diabetes mellitus patients in combination with glibenclamide. Phytomedicine 1996;3:245-248. 63. Fahim MS, Wang M. Zinc acetate and lyophilized Aloe barbadensis as vaginal contraceptive. Contraception 1996;53:231-236. 64.Kim HS, Lee BM. Inhibition of benzo[a]pyrene-DNA adduct formation by Aloe barbadensis Miller. Carcinogenesis 1997;18771-6. 65. Peng SY, Norman J, Curtin G, et al. Decreased mortality of Norman murine sarcoma in mice treated with the immunomodulator, acemannan. Mol Biother 1991;3:79-87. 66. Hams C, Pierce K, King G, et al. Efficacy of acemannan in treatment of canine and feline spontaneous neoplasms. Mol Biother 1991;3 207-213. 67. Lissoni P, Giani L, Zerbini S, et al. Biotherapy with the pineal immunomodulating hormone melatonin versus melatonin plus aloe Vera in untreatable advanced solid neoplasms. Nat Immun 1998;16:27-33. 68. Schmidt JM, Greenspoon JS. Aloe Vera dermal wound gel is associated with a delay in wound healing. Obstet Gynecol1991;78:115-117. 69. Brinker F. Herb contraindications and drug interactions, ed 2. Sandy, OR Eclectic Medical Publications, 1998. 70. Klein AD, Penneys NS. Aloe Vera. J Am Acad Dermatol 1988;18: 714-720. 71. Brinker F. Herb contraindications and drug interactions. Sandy, OR Eclectic Medical Publications, 1997. 72. Blumenthal M. Herb and conventional possible interactions with drugs. Austin, Tx:American Botanical Council, 1997.

Angelica Species Michael T. Murray, ND Joseph E. Pizzorno Jr, ND C: H A P T E R C: 0 N T E N T S General Description 749 Angelica sinensis and Angelica acutiloba 749 Angelica archangelica and Angelica atropurpurea 750 Chemical Composition 750 Angelica sinensis and Angelica acutiloba 750 Angelica archangelica 750 History and Folk Use 750 Angelica sinensis and Angelica acutiloba 750 Angelica archangelica 750 Angelica atropurpurea 750

Pharmacology 750 Phytoestrogen Effects 750 Cardiovascular Effects 751 Smooth Muscle-Relaxing Activity 751 Analgesic Activity 751 Antiallergic, Immunomodulating, and Direct Antitumor Activity 751 Antimicrobial Activity 751 Clinical Application 752 Menopause 752 Dosage 752 Toxicology

Angelica sinensis or polyrnorpha (family: Umbelliferae or Apiaceae) Common names: Chinese angelica, tang-kuei (dong-quai) Angelica acutiloba (family: Umbelliferae or Apiaceae) Common name: Japanese angelica Angelica archangelica (family: Umbelliferae or Apiaceae) Common name: European angelica Angelica atropurpurea (family: Umbelliferae or Apiaceae) Common name: American angelica Angelica silves tris (family: Umbelliferae or Apiaceae) Common name: wild angelica

GENERAL DESCRIPTION Angelica spp. are biennial or perennial plants with hollow fluted stems that rise to a height of 3 to 7 feet. The umbels, or clusters, of greenish-whiteflowers bloom from May to August. The plants are found in damp mountain ravines and meadows, on river banks, and in coastal areas; angelica is also a widely cultivated species. In Asia it is grown primarily for its medicinal action, while in the United States and Europe it is cultivated for use as a flavoring agent in most major categories of food products including alcohol (e.g., bitters, liqueurs, vermouths) and nonalcoholic beverages, ice cream,

752

candy, gelatins, and puddings. With all species, the roots and rhizomes are the most extensively used portions of the plant.

Angelica sinensis and Angelica acutiloba In Asia the authentic and original medicinal angelica is Angelica sinensis (dong-quai), native to China. Although at least nine other angelica species are used in China, dong-quai is by far the most highly regarded. For several thousand years, dong-quai has been cultivated for medicinal use in the treatment of a wide variety of disorders, particularly "female" disorders. Several hundred years ago, when the supply of Chinese angelica was scarce, the Japanese began to cultivate Angelica acutiloba, an angelica species indigenous to Japan, as a substitute.' The two species appear to have similar therapeutic effects despite the following opinions: In China the Japanese angelica is thought to have no therapeutic value, while in Japan, Chinese angelica is thought to have no effect. Experimentally, both species exhibit similar therapeutic effects, so each country's claim to produce a superior dong-quai is apparently based more on emotion than scientific investigation. 749

Pharmacology of Natural Medicines

Angelica archangelica and Angelica atropurpurea Historical usage suggests that European angelica (Angelica archangelica) and American angelica (Angelica afropurpurea) have properties different from the Asian species. However, this difference has not been evaluated by chemical analysis.

CHEMICAL COMPOSITION Angelica sinensis and Angelica acutiloba Although it has been assumed that Chinese and Japanese angelica are similarly composed of various coumarins and flavonoids that are responsible for their medicinal actions, a recent analysis showed that A. sinensis contained approximately 10-fold higher levels of the key components ferulic acid and Z-ligustilide compared with roots of A. acutiloba.* Many medicinal compounds are believed to be present in the essential oil, including the following? 3n-Butylphthalide Cadinene Carvacrol n-Dodecanal Isosafrole Linoleic acid Palmitic acid Safrole Sequiterpene n-Tetradecanoyl

Angelica archangelica A. archangelica is also rich in coumarins and particularly phototoxic. Coumarins including osthole, angelicin, osthenol, umbelliferone, archangelicine, bergapten, and ostruthol are found in significant concentrations, with osthole composing nearly 0.2% of the root. The root is also a good source of flavonoids including archangelenone and caffeic acids. The root contains 0.3% to 1% volatile oil composed mainly of beta-phellandrene, alpha-pinene, bomeol, limonene, and four macrocyclic lac tone^.^,^

HISTORY AND FOLK USE Angelica sinensis and Angelica acutiloba In Asia angelica‘s reputation is perhaps second only to ginseng. Predominantly regarded as a “female” remedy, angelica has been used to treat dysmenorrhea, amenorrhea, metrorrhagia, and menopausal symptoms and to assure a healthy pregnancy and easy delivery. Angelica is also used in the treatment of abdominal pain, anemia,

injuries, arthritis, migraine headache, and many other

Angelica archangelica One of the most highly praised herbs in old herbal texts, A. archangelica was used by all Northern European countries as the following: a protection against contagion, for purrfylng the blood, and for curing every conceivable malady: it was held a sovereign remedy for poisons, a p e s and all infectious maladies.

According to one legend, A. archangelica was revealed in a dream as a cure for the plague. One explanation for the name is related to its blooming near May 8, the feast day of Michael the Archangel. It was therefore seen as a “protector against evil spirits and witchcraft.”6 A. archangelica has been used for a wide variety of conditions including flatulent dyspepsia, pleurisy, respiratory catarrh, and bronchitis. The plant was believed to possess carminative, spasmolytic, diaphoretic, expectorant, and diuretic activity.6

Angelica atropurpurea American angelica’s therapeutic use mirrors that of European angelica. Its most common use is for heartburn and flatulent colic.’

PHARMACOLOGY The pharmacology of Angelica spp. primarily relates to high coumarin content. However, unlike other scientific investigations of botanical medicines, most research on Angelica spp. has been done on plant extracts, rather than isolated constituents. The overwhelming majority of studies have been done on the Asian species. Some of the pharmacologic activities demonstrated include the following: Phytoestrogen activity Analgesic activity Cardiovascular effects Smooth muscle-relaxing effects Antiallergic, immunomodulating, and direct antitumor activity Antimicrobial activity

Phytoestrogen Effects Plant estrogenic substances or phytoestrogens are components of many medicinal herbs with a historic use in conditions that are now treated by synthetic estrogens. Chinese and Japaneseangelica contain weakly active phytoestrogens, much lower in activity than other phytoestrogens and approximately no more than 1:400 as active as estrogen? This helps to explain why angelica was used in both excessive and deficient estrogen conditions.

Angelica Species Phytoestrogens demonstrate an alterative effect by competing with estrogen for binding sites. When estrogen levels are low, they can exert some weak estrogenic activity; when estrogen levels are high, they reduce overall estrogenic activity by occupying estrogen receptor sites. This alterative action of angelica's phytoestrogens is probably the basis of much of the plant's use in amenorrhea and menopause. Japanese angelica has demonstrated uterine tonic activity, causing an initial increase in uterine contraction followed by relaxation?JOIn addition, administration of Japanese angelica to mice resulted in an increase of uterine weight, increase of the DNA content of the uterus and liver, and increase of glucose use by the liver and uterus.lt9Because of these and other effects, angelica has been referred to as a uterine tonic.

Cardiovascular Effects Although not used historically for these purposes, angelica does possess significant hypotensive a~ti0n.l.~ This is largely due to its vasodilator activity. Dihydropyranocoumarins and dihydro-furanocoumarins from Umbelliferousplants have been shown to possess significant coronary vasodilatory, spasmolytic, and cyclicAMP-phosphodiesterase inhibitory properties." The mechanism of action appears to be largely a result of calcium channel antagonism. Agents that interact with calcium channels (calcium channel blockers) are quickly coming into prominence in the treatment of wideranging conditions including hypertension and angina. Umbelliferous plants such as angelica may offer similar effects. Other cardiovascular effects noted for angelica are negative inotropic and antiarrhythmic action.'

Smooth Muscle-Relaxing Activity Calcium channel blocking compounds are also capable of relaxing the smooth muscles of visceral organs. Angelica (essential oil) has demonstrated relaxing action on the smooth muscles of the intestines and uterus, while the water extract produces an initial contraction This confirms its and then prolonged rela~ation.',~J~ historical use in the treatment of intestinal spasm and uterine cramps. Its action on other smooth muscles could explain its hypotensive action (vascular smooth muscle) and historical use in asthma (bronchial smooth muscle).

Analgesic Activity Both Chinese and Japanese angelica have demonstrated pain-relieving and mild tranquilizing effects in experimental studies in animals.19J2J3Angelica's analgesic action was 1.7 times that of aspirin in one study.13 Its analgesic activity, combined with its smooth muscle-relaxing activity, supports its historical use in

such conditions as uterine cramps, trauma, headaches, and arthritis.

Antiallergic, lmmunomodulating, and Direct Antitumor Activity Angelica has a long history of use by Chinese and Japanese herbalists in the prevention and treatment of allergic symptoms in individuals who are sensitive to various substances (e.g., pollen, dust, animal dander, food).lJ4Its action is related to its ability to inhibit the production of IgE in a selective manner. Since IgE levels in patients with atopic conditions are typically 3 to 10 times greater than the upper limit of normal, angelica may offer some benefit by reducing these elevated antibodies. Coumarin compounds have demonstrated immuneenhancing activity in both healthy and cancer patients.15J6 Coumarins have been shown to stimulate macrophages and increase phag~cytosis.'~ Such activity is thought to offer significant protection against metastasis and growth of tumor cells. Upon coumarin administration, macrophages are said to be "activated" and thus capable of entering the tumor, where a specific destruction of the tumor cells may o c c ~ r . ~ ~ J ~ Coumarin compounds of angelica and the polysaccharides of the water extract of Japanese angelica have demonstrated immune-modulating and antitumor activity. They have been shown to possess mitogenic activity to B-lymphocytes, interferon-producing activity, antitumor activity, and complement-activating (both the classical and alternative pathway) a ~ t i v i t y . ' ~ Chinese -~~,~~ angelica has been shown to increase murine IL-2 production, stimulate the reticuloendothelial system, and increase tumor necrosis factor p r o d u ~ t i o n . ~ The , ~anti~,~~ tumor effects of angelica appear to be mainly due to the polysaccharide components, as these compounds have been shown to exert antitumor effects on experimental tumor models in vivo and inhibitory effects on invasion and metastasis of cancer cells in ~itro.~~~*~Altogether these effects by coumarins, polysaccharides, and extracts of Angelica sp. would seem to support the historical use of angelica as an adjunct in cancer therapy.

Antimicrobial Activity Extracts of Chinese angelica have been shown to possess antibacterial activity against both gram-negative and gram-positive bacteria, while extracts of Japanese angelica exhibited no antibacterial action.6The inconsistency could be due to different essential oil concentrations of the extracts used in the studies. The oil of A . archangelica has also exhibited significant antifungal and anthelmintic properties but virtually no antibacterial a ~ t i v i t y . ~As, ~ ~ , ~ other herbs have much greater antimicrobial activity, Angelica spp. would be considered a less than optimum agent if this effect is desired.

Pharmacology of Natural Medicines

CLINICAL A PPLICAT10N Angelica spp. have been used worldwide to treat wide-ranging conditions. At present it appears that A. archungelicu and A. atropurpureu are most indicated as expectorants, antispasmodics, and carminatives in the treatment of respiratory ailments, gas, and abdominal spasm. Chinese angelica (A. sinensis or polymorpha) and Japanese angelica (A. acutiloba) appear most useful in the treatment of disorders of menstruation, menopause (especially hot flashes), atopic conditions, smooth muscle spasm (e.g., uterine cramps, migraines, abdominal spasm), and possibly as an immunostimulatory adjunct in cancer therapy.

Menopause By far the most popular use of Angelica spp. has been the use of A. sinensis in the treatment of menopausal complaints. Although a double-blind, placebo-controlled study in women showed no significant benefit, the traditional use of angelica has been in combination with other plants. The preparation used (a dried aqueous extract) was clearly lacking some of the important volatile compounds, though it was standardized for ferulic acid c0ntent.2~A study conducted in China showed that a combination of A. sinensis, Paeonia lactifora, Ligusticum monnieri, Atractylodes chinensis, Sclerotium poriae, and Alisma orientalis was effective in roughly 70°/"of women experiencing menopausal symptoms.30 Though not

1. Hikino H. Recent research on Oriental medicinal plants. Econ Med Plant Res 1985;1:53-85. 2. Zhao KJ, Dong IT,Tu PF, et al. Molecular genetic and chemical assessment of radix Angelica (Danggui) in China. J Agric Food Chem 2003;51:2576-2583. 3. Duke JA. Handbook of medicinal herbs. Boca Raton, FL: CRC Press, 1985:43-44. 4. Leung AY. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York: Wiley, 1980:28-29. 5.Duke JA, Ayensu ES. Medicinal plants of China. Algonac, MI: Reference Publications, 1985:74-77. 6.Grieve M. A modern herbal. New York Dover Publications, 1971:35-40. 7. Lust J. The herb book. New York Bantam Books, 1974:97-99. 8. Liu J, Burdette JE, Xu H, et al. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 2001;492472-2479. 9. Yoshiro K. The physiological actions of tang-kuei and conidium. Bull Oriental Healing Arts lnst USA 1985;10:269-278. 10.Harada M, Suzuki M, Ozaki Y. Effect of Japanese angelica root and peony root on uterine contraction in the rabbit in situ. J Phannacobiodyn 1984;7304-311. 11. Thastrup 0, Fjalland B, Lemmich J. Coronary vasodilatory, spasmolytic and CAMP-phosphodiesterase inhibitory properties of dihydropyranocoumarins and dihydrofuranocoumarins. Acta Pharmacol Toxic01 (Copenh) 1983;52:246-253.

double-blind, this study shows promise for using angelica in the management of menopausal symptoms. Interestingly, in an in vitro study with human bone, the aqueous extract of A. sinensis was found to directly stimulate the proliferation, alkaline phosphatase activity, protein secretion, and type I collagen synthesis in a dosedependent manner.31 Also, in a double-blind study, the combination of 100 mg angelica, 60 mg soy isoflavones, and 50 mg of black cohosh extract sigruficantlyreduced menstrual

DOSAGE Dried root or rhizome: 1 to 2 g orally, or by infusion, three times daily Tincture (1:5):3 to 5 ml, three times daily Fluid extract (1:l):0.5 to 2 ml, three times daily

TOXICOLOGY Angelica is generally considered to be of low toxicity. However, it contains many photoreactive substances that may induce photosensitivity.This should be kept in mind when using any Umbelliferous plant. This photoreactive activity can be used therapeutically in the treatment of vitiligo and psoriasis. Use of Angelica spp., particularly A. sinensis, in men may lead to gyne~omastia.~~

12. Tanaka S, Ikeshiro Y, Tabata M, Konoshima M. Anti-nociceptive substances from the roots of Angelica acutiloba. Arzneimittelforschung 1977;272039-2045. 13. Tanaka S, Kano Y, Tabata M, Konoshima M. [Effects of "Toki" (Angelica acutiloba Kitawaga) extracts on writhing and capillary permeability in mice (analgesic and anti-inflammatory effects).] Yakugaku Zasshi 1971;91:1098-1104. 14. Sung CP, Baker AP,Holden DA, et al. Effect of extracts of Angelica polymorpha on reaginic antibody production. J Nat Prod 1982;45:398406. 15.Casley-Smith JR. The actions of benzopyrenes on the blood-tissuelymph system. Folia Angiol 1976;247-22. 16.Berkarda B, Bouffard-Eyuboglu H, Derman U. The effect of coumarin derivatives on the immunological system of man. Agents Actions 1983;13:50-52. 17. Ohno N, Matsumoto S, Suzuki I, et al. Biochemical and physicochemical characterization of a mitogen obtained from an oriental crude drug, Tohki (Angelica actiloba Kitagawa). J Pharmacobiodyn 1983;6:903-912. 18. Yamada H, Kiyohara H, Cyong JC, et al. Studies on polysaccharides from Angelica acufiloba. Part 1. Fractionation and biological properties of polysaccharides. Planta Med 1984;50:163-167. 19. Yamada H, Kiyohara H, Cyong JC, Otsuka Y. Studies on polysaccharides from Angelica ncutiloba-IV, Characterization of an anti-complementary arabinogalactan from the roots of Angelica acutiloba Kitagawa. Mol Immunol 1985;22:295-304.

Angelica Species 20. Kumazawa Y, Mizunoe K, Otsuka Y. Immunostimdating polysaccharide separated from hot water extract of Angelica acutiloba Kitagawa (Yamato Tohki). Immunology 1982;4775-83. 21. Lu S, Huang H, Wu S. [The regulation effects of Angelica sinensis on the erythrocytic immune function and IL-2 in mice.] Zhong Yao Cai 1997;20:301-303. 22. Weng XC, Zhang P, Gong SS, Xiai SW. Effect of immuno-modulating agents on murine IL-2 production. Immunol Invest 1987167946. 23. Haranaka K, Satomi N, Sakurai A, et al. Antitumor activities and tumor necrosis factor producibility of traditional Chinese medicines and crude drugs. Cancer Immunol Immunother 1985;201-5. 24.Shan JJ, Wang Y, Wang SC, et al. [Effect of Angelica sinensis polysaccharides on lymphocyte proliferation and induction of IFNgamma.] Yao Xue Xue Bao 2002;37497-500. 25. Shang P, Qian AR,Yang TH, et al. Experimental study of anti-tumor effects of polysaccharides from Angelica sinensis. World J Gastroenterol2003;9:1963-1967. 26.Zheng M, Wang YI? [Experimental study on effect of Angelica polysaccharide in inhibitory proliferation and inducing

differentiation of K562 cells.] Zhongguo Zhong Xi Yi Jie He Za Zhi 2002;22:54-57. 27. Rhee JK, Woo KJ, Baek BK, Ahn BJ. Screening of the wormicidal Chinese raw drugs on Clonorchis sinensis. Am J Chin Med 1981;9277-284. 28. Opdyke DL. Angelica root oil. Food Cosmet Toxic01 1975;13713-714. 29. Hirata JD, Swiersz LM, Zell 8, et al. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebocontrolled trial. F e d Steril1997;68981-986. 30.Chang HM, But PPH, eds. Pharmacology and applications of Chinese Materia Medica, vol 1. Singapore: World Scientific, 1987489-505. 31. Yang Q, Populo SM, Zhang J, et al. Effect of Angelica sinensis on the proliferation of human bone cells. Clin Chim Acta 2002;32489-97. 32. Burke BE, Olson RD, Cusack BJ. Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine. Biomed Pharmacother 2002;56283-288. 33. Goh SY, Loh KC. Gynaecomastia and the herbal tonic “Dong Quai.” Singapore Med J 2001;42:115-116.

Artemsia absinthium (Wormwood)

CHAPTER CONTENTS General Description 755

Antiparasitic Effects 757 Neurologic Effects 757

Chemical Composition 755 Clinical Applications 757 History and Folk Use 755 Dosage 757 Pharmacology 756 Digestive Effects 756 Hepatic Effects 756

Toxicity 757 Drug Interactions 758

Arfemisia absinfhium (family:Asteraceae) Common names: wormwood

are absinthin, artabsin, matricin, and anabsinthin (Figures 68-1 through 68-3).

GENERAL DESCRIPTION

HISTORY AND FOLK USE

Arfemisia absinfhium generally occurs as a semiwoody, perennial subshrub reaching up to 1 m tall, particularly in its native Mediterranean habitat. The opposite, pinnatifid leaves are silvery gray and quite aromatic. The leaves and flowers are used as medicine. The stems and leaves are covered by fine, silky hairs. Tiny, dull yellowgreen flowers bloom in drooping clusters from July to September.

Wormwood was used historically as a digestive bitter in traditional herbal systems of various societies around its native Mediterranean habitat. The Ebers papyrus, an Egyptian medical treatise and one of the oldest extant pieces of writing (circa 1550 BC), mentions wormwood. Pliny the Elder discussed the use of wormwood to expel parasites, as reflected in the common name of the plant, in the first century AD. The medicinal aspects of most of the history of wormwood are unfortunately overshadowed by developments in the late eighteenth century-absinthe. The standard account of the rise of absinthe, a liqueur derived in part from wormwood, begins with French expatriate Pierre Ordinaire, who allegedly developed the first absinthe recipe in 1792 in Switzerland? Absinthe schnapps, absinthe-infused ale (known as "purl"), absinthe-infused wine, and other absinthe-containing beverages had been in use since Dioscorides' time and probably before. Absinthe was apparently made by infusing wormwood, Angelica archangelica (garden angelica) root, Pimpinella anisurn (anise) fruit, and Origanum rnaioriuna (marjoram) herb in ethanol; distilling them; and adding other flavorings including volatile The resulting product was bright green and intensely

CHEMICAL COMPOSITION The aboveground parts of wormwood contain two components considered most important to its medicinal activity: 0.15%to 0.4% volatile oil and 0.2% to 1.5%bitter sesquiterpenelactones.' The volatile oil is most notorious for its content of the terpenoids alpha- and beta-thujone, given the potential neurotoxicity of these compounds. Alpha-thujone is believed to be much more toxic and is present as 0.53%to 1.22%of the volatile oil compared with 17.5% to 42.3% for beta-thujone.2 Several chemotypes of wormwood depend on growing environment, and only certain ones contain thujon-thers have trans-sabinyl acetate, cis-epoxyocimen, or chrysanthenyl acetate instead.l Major sesquiterpene lactones present

755

Figure 681 Aipha-thujone.

.A Figure 682 Beta-thujone.

Figure 68-3 Absinthin.

The growing popularity of absinthe, combined with a fire at the Pernod Fils distillery in 1901, led to a surge of absinthelike products on the market. Unfortunately, these imitation products were often made as cheaply as possibly by simply mixing volatile oils with alcohol, adding various coloring agents to given the appropriate green hue (including copper sulfate) and antimony chloride to create the appearance of the white precipitate At the same time, a new pheformed in true ab~inthe.~ nomenon termed absinthisrn was becoming widely known. This syndrome was a result of chronic absinthe overindulgence and included bursts of violent aggressiveness followed by prolonged depression, trembling, hallucinations, seizures, and death? However, the presence of adulterated, low-quality, high-ethanol absinthe products on the market and the inability to distinguish the effects of ethanol abuse from those of other compounds in the mixture make it difficult to be certain exactly what was causing absinthism. The levels of the purported neurotoxin thujone in true absinthe were 2 to 4 mg per drink, far below the 10 mg/kg levels needed to induce neurologic damage in numerous animal experiments6 In the early twentieth century, absinthe was banned in most of Europe and the United States. It remains banned today. The Eclectics regarded wormwood as a digestive tonic useful in atonic dyspepsia, as a potential treatment for roundworms, and for topical application to sprains and bruise^.^ The dangers of absinthism were well known to these turn-of-the-century American natural physicians, but they did not seem clear on the various problematic elements in the history of absinthe discussed earlier.

bitter, formed a white precipitate, and had a high alcohol PHARMACOLOGY content (50%to 80%).4 Wormwood's actions have been studied in three major Henri Dubied and his son-in-law Henri Louis Pernod realms: digestive effects, antiparasitic effects, and effects purchased Ordinaire's formula and began producing on the central nervous system. Various reported effects large quantities of absinthe at the Pernod Fils distillery? of isolated alpha- and beta-thujone may also be relevant One client for their product was the French military, which invaded Algeria from 1844-1847 and issued to wormwood's effects. absinthe regularly to the troops to help prevent and treat Digestive Effects dysentery. These troops apparently returned to France In a controlled clinical trial, wormwood tincture and with a taste for absinthe and increased the popularity of thujone-free wormwood tincture were both shown to sigthe beverage. nificantly increase bile and pancreatic enzyme secretion Though originally absinthe was most popular with in humans compared with water.6The levels of secretion people in the lower classes, it caught on among the intelwere assessed intraduodenally. Investigations into the ligentsia in the 1860s and 1870s, a time of cultural ferment, particularly in Paris. Between 5 and 7 PM, Parisians mode of action of wormwood have not been published. These effects seem to be common to many bitter herbs would gather in cafes to sip absinthe, often diluted by that contain sesquiterpene lactones. pouring cold water over a sugar cube held in a perforated spoon into a glass containing a shot of ab~inthe.~ Hepatic Effects Numerous famous artists of the time drank absinthe regThe effect of methanol and water extracts of wormwood ularly, including Vincent van Gogh, whose insanity has on liver function in mice and rats were assessed in one been blamed on his absinthe habit.

Artemisia absinthium (Wormwood)

series of studies? Pretreatment of mice with 500 mg/kg of wormwood extract decreased the 100% lethality of 1g/kg acetaminophen to 20%. The toxicity of carbon tetrachloride was also reduced by pretreatment of rats with wormwood. Giving rats a toxic, sublethal dose of acetaminophen led to sigruficant hepatic damage; administering 500 mg/kg wormwood extract 6 hours after acetaminophen administration sigruficantly reduced this damage. Wormwood extract did not reduce the hepatotoxicity of carbon tetrachloride in this same model. Because acetaminophen and carbon tetrachloride are both converted to toxic intermediates by cytochrome P450 enzymes, and because wormwood had effects on the toxicity of both drugs, as well as lengthening pentobarbitalinduced sleep in mice (an effect possibly related to cyt P450 inhibition), it was hypothesized that the effects of wormwood may in part be mediated by inhibition of cyt P450 enzymes.

Antiparasitic Effects The effects of wormwood on various parasitic microorganisms has been assessed in vitro and in animals. These results have been of somewhat greater interest lately with the discovery of potent antimalarial compounds from Artmisiu annua (sweet Annie), a close relative of wormwood. Wormwood does not appear to contain the same active constituents as sweet Annie, which are artemisinin and related sesquiterpene lactones. Nonetheless, aqueous extracts of wormwood showed antimalarial effects in vitro.'" In mice, oral administration of extracts using 95% ethanol of wormwood was shown to have a potent schizonticidal effect against Plasmodium berghei, though not as potent as chloroquine." Although 74 mg/kg of wormwood extract suppressed 96% of schizonticide activity, chloroquine at 10 mg/kg suppressed 100% of schizonticide activity. The effects of wormwood and its constituents on various amebae have also been investigated. In vitro, aqueous and ethanolic extracts of wormwood strongly inhibited the growth of the ameba Naegleriafowleri.'2 The lowest concentration of a sesquiterpene lactone extract from wormwood that inhibited growth of the amebae to 50% or less than that of controls was 31.9 pg/ml, compared to 0.025 pg/ml for amphotericin B. Apparently research has shown an effect for wormwood against Entamoeba histolytica from India, but details of thispublication could not be ~btained.'~

Neurologic Effects Structural and biosynthetic similarities have long been noted among alpha- and beta-thujone and tetrahydrocannabinol (THC),the active hallucinogen from Cannabis sativa (marijuana).'* Though thujone does weakly bind cannabinoid receptors in animals and human receptors in vitro, it does not appear to activate these receptors to

any appreciable extent at reasonable c~ncentrations.'~ Wormwood oil also failed to have significant cannabinomimetic activity in this assay. Though thujone is widely considered to have hallucinogenic effects, these are not proven and do not appear to be mediated by cannabinoid receptors. For a discussion of the convulsant potential of thujone, refer to the toxicity section later. An 80% ethanol extract of wormwood was a strong muscarinic and nicotinic cholinergic receptor agonist in vitro.I6The effectswere due only slightly to the presence of choline in the plant, but other quaternary ammonium compounds appeared to largely account for the activity. Further research is necessary to determine if wormwood might have antidementia activity in humans.

CLINICAL APPLICATIONS Wormwood is officially approved by the German Commission E for treatment of patients with dyspepsia, loss of appetite, and biliary dy~kinesia.'~Published clinical trials were not located supporting the use of wormwood for any indication, with the exception of the paper discussed in the pharmacology section showing that wormwood could increase digestive secretions. That trial supports the use of wormwood for loss of appetite, though much more specific work is necessary for definitive proof of efficacy.

DOSAGE Wormwood is primarily used in three forms-tea, tincture, and capsule. The volatile oil is also occasionally encountered, though it is considered too toxic for use. A typical dose of tea is 1g (1tsp) dried leaf and flower per cup of water, steeped for 10 to 15 minutes.'8 The tea should be covered during steeping to retain as many volatile constituents as possible. A cup of tea is sipped before meals three times daily. Thujone is not water soluble, so aqueous extracts of the plant are generally low in thujone. A typical dose of tincture is 0.5 to 1ml threetimes daily mixed with 2 to 4 oz water, sipped before meals. A typical capsule dose is 2 to 3 g per day in divided doses.I9

TOXICITY Though much toxicity is ascribed to wormwood, details and confirmed reports are scarce. Any toxicity attributed to the use of various forms of the beverage absinthe must not be confused with use of teas or tinctures in medicinal doses. Symptoms and effects said to be caused by chronic absinthe overindulgence were discussed earlier. The toxicity of the volatile oil also cannot be easily translated to other dose forms (particularly teas) of wormwood, which contain much lower concentrations of terpenoids.

Pharmacology of Natural Medicines

Alpha-thujone is considered a neurotoxin and convulsant compound.2° Beta-thujone, present in much higher levels in wormwood, is generally considered much less In mice, alpha- and beta-thujoneboth antagonize gamma-aminobutyric acid-A (GABAA)receptors and induce seizures.22Alpha-thujone was a much stronger convulsant thanbeta-thujone in thisstudy. This study confirmed prior findings that thujone is rapidly metabolized by the liver and removed from the body in animals.23 A 31-year-old man who drank 10 ml of wormwood volatile oil, mistakenly believing it was identical to absinthe, became agitated, belligerent, and incoherent and developed tonic-clonic seizures.24 Haloperidol improved his mental function, but acute renal failure and rhabdomyolysis were discovered, becoming worse a day later. Congestive heart failure developed, in part due to aggressive alkalinization. Seventeen days after discharge from the hospital he had recovered completely. These effects have never been documented to occur in patients being treated with reasonable doses of medicinal extracts of or crude wormwood. In one naturopathic medical practice, nine patients over a 3-year period were identified who had been treated with a bitters formula including 11%tinof wormwood, generally as a treatment for dyspepsia or malabsorption.25Administered at a dose of 1 tsp (5 ml) three times daily, patients would have been exposed to approximately 500 pL wormwood tincture three times daily for weeks to months. For the eight patients with available laboratory data, there was no evidence of renal, hepatic, or other damage. One patient, in fact, showed improvement in serum liver

enzyme levels while taking the bitters formula. None of the patients developed seizures or other signs or symptoms of neurotoxicity from the use of this formula. Though retrospective, this study does support the notion that wormwood in this form and at this dose is safe for use in adults as a digestive aid, in accordance with German Commission E indications and long-standing traditional use. Controlled clinical trials on the efficacy of wormwood should also include thorough analysis of its safety at medicinal doses. Thujone stimulates 5-aminolevulinate synthase in vitro, leading to large increases in porphyrin levelsJ6 Though it seems likely that porphyrogenic levels of thujone could be achieved by drinking large volumes of absinthe, levels of intake of tincture of wormwood are far lower and unlikely to lead to such high levels. Porphyrogeniceffects have not been clearly documented to be induced by wormwood in humans, though thujone and thujone-containing herbs such as wormwood should be avoided by people with porphyria until more information is available.

1. Bisset NG, Wichtl M, eds. Herbal drugs and phytopharmaceuticals. Boca Raton, n:CRC Press, 199445-48. 2.Lawrence BM, ed. Perfumer and flavorist. Essential oils 1992-1994. Natural flavor and fragrance materials. Carol Stream, IL: Allured Publishing Corporation, 1995:ll-14. 3.Vogt DD. Absinthium: a nineteenth-century drug of abuse. J Ethnopharmacol1981;4:337-342. 4.Vogt DD, Montagne M. Absinthe: behind the emerald mask. Int J Addict 1982;171015-1029. 5. Haines JD.Absinthe-return of the green fairy. J Okla State Med Assac 1998;91:406-407. 6.Tiserand R, Balacs T. Essential oil safety: a guide for health care professionals. Edinburgh: Churchill Livingstone, 1995. 7.Felter HW. Eclectic materia medica, pharmacology and therapeutics. Sandy, OR Eclectic Medical Publications, 1922,reprinted 1998. 8.Baumann IC, Glatzel H, Muth HW.Studies on the effects of wormwood (Artemisia ubsinthium L.) on bile and pancreatic juice secretion in man. Z Allgemeinmed 1975;51:784-791. 9. Gilani AH, Janbaz KH. Preventive and curative effects of Artetnisia absinthium on acetaminophen and CCl&duced hepatotoxicity. Gen Ph~Col1995;26309-315.

10.Hernandez H,Mendiola J, Torres D, et al. Effect of aqueous extracts of Artemisia on the in vitro culture of Plasmodium falciparum. Fitoterapia 1990;61:540-541. 11.Zafar MM, Hamdard ME, Hameed A. Screening of Artemisia absinfhium for antimalarial effects on Plasmodium berghei in mice: a preliminary report. J Ethnopharmacol1990;30:223-226. 12.Mendiola J, Bosa M, Perez N, et al. Extracts of Artemisia abrotanum and Artemisin absinthium inhibit growth of Nuegleriafowleri in vitro. Trans R Soc Trop Med Hyg 1991;8578-79. 13.Tahir M, Khan AB, Siddiqui MMH. Effect of Artemisiu absinthium Linn in acute intestinal amebiasis. Conference of Pharmacology and Symposium on Herbal Drugs, New Delhi, India, 1991. 14.del Castillo J, Anderson M, Rubottom GM. Marijuana, absinthe and the central nervous system. Nature 1975;253:365-366. 15.Meschler JP,Howlett AC. Thujone exhibits low affinity for cannabinoid receptors but fails to evoke cannabimimetic responses. Pharmacol Biochem l3ehav 1999;62:473-480. 16.Wake G, Court J, Pickering A, et al. CNS acetylcholine receptor activity in European medicinal plants traditionally used to improve failing memory. J Ethnopharmacol2000;69105-114. 17. Blumenthal M, Busse WR, Goldberg A, et al, eds. The complete German Commission E monographs: therapeutic guide to

DRUG INTERACTIONS No confirmed drug interactions exist for wormwood. It should be avoided in combination with chronic ethanol abuse due to historical reports pertaining absinthe. Given the low doses of tinctures used, this should not represent any health threat related to ethanol ingestion. Wormwood may have synergistic porphyrogenic effects with other drugs that can induce porphyric attacks including barbiturates, hydantoins, and carbamazepine.

Arternisia absinthium (Wormwood) herbal medicines. Austin, Tx: American Botanical Council, 1998: 232-233. 18. Windholz M, Budavari S, Blumetti RF, Otterbein S, eds. The Merck index. Rahway, NJ:Merck & Co, 1983. 19. Duke JA. Handbook of medicinal herbs, ed 2. Boca Raton, FL.:CRC Press, 2002798-799. 20. Summary of data for chemical selection alpha-thujone 546-80-5. National Toxicology Program. Available online at http://ntp-server. niehs.nih.gov/htdocs/Chem-Background/ExecSumm/hujone. html [accessed October 20021. 21. Arnold WN. Vincent van Gogh and the thujone connection. JAMA 1988;260:3042-3044. 22. Hold Kh4, Sirisoma NS, Jkeda T, et al: Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification. Proc Natl Acad Sci U S A 2000;973826-3831.

23. Hold KM, Sirisoma NS, Casida JE. Detoxification of alpha- and beta-thujones (the active ingredients of absinthe): Site specificity and species differences in cytochrome p450 oxidation in vitro and in vivo. Chem Res Toxic01 2001;14589-595. 24. Weisbord SD, Soule JB, Kimmel PL. Poison on l i n e a c u t e renal failure caused by oil of wormwood purchased through the Internet. N Engl J Med 1997337825-827. 25. Heron S, Yamell E. Retrospective analysis of the safety of bitter herbs with an emphasis on Artemisin absinthium L (wormwood). J Naturopathic Med 2OOO;932-39. 26. Bonkovsky HL, Cable EE, Cable JW, et al. Porphyrogenic properties of the terpenes camphor, pinene, and thujone. Biochem Pharmacol 1992;432359-2368.

Artemsia annua (Sweet Wormwood) Eric L. Yarnell, N D , RH(AHG Kathy Abascal, BS, JII, RH(AHG CHAPTER CONTENTS General Description 761 Chemical Composition 761

Clinical Applications 763 Malaria 763 Schistosomiasis 763

History and Folk Use 761

Dosage 763

Pharmacology 762 Antimalarial Effects 762 Antiparasitic 762 Antineoplastic 762

Toxicity

Arfernisiu unnua (family: Asteraceae) Common names: sweet Annie, qing hao

GENERAL DESCRIPTION The genus Artemisia is named after the Greek goddess Artemis, who apparently used a plant in the genus and gave her name to it. Sweet wormwood is a large annual herb with woody stems that may attain 2 m in height. The fine leaves are dark green and have a strong, pleasant odor. The herb produces fragrant yellow flowers in late summer and early autumn. It grows as an invasive weed in many areas.

CHEMICAL COMPOSITION Sweet wormwood contains several sesquiterpene trioxane lactones, most notably artemisinin (also known as qinghaosu) but also deoxyartemisinin, artemisinic acid, and arteannuin-B.' These compounds give the plant a distinctive bitter taste. A peroxide bridge in artemisinin is vital in the antimalarial effects of the compound (Figure 69-1).2 Artemisinin is rapidly and readily reduced to dihydroartemisinin in the body. Dihydroartemisinin appears to be the active metabolite of artemisinin and all synthetic artemisinin derivatives developed to date (Figure 69-2).3

763

Drug Interactions 763

Sweet wormwood also containsa number of flavonoids.' In vitro research suggests these flavonoids potentiate the antimalarial activity of the sesquiterpene lactones.4 Three semisynthetic derivatives of artemisinin are widely available for use: artemether, artesunate, and arteether? Artemether is a lipophilic beta epimer of dihydroartemisinin and is administered intramuscularly. Artesunate is a hydrophilic hemisuccinate compound administered orally or by injection. Arteether is an ethyl ether derivative of dihydroartemisinin and is lipophilic (Figure 69-3).

HISTORY AND FOLK USE The herb, known to the ancient Chinese as qing hao, was recommended for treatment of fever as early as 341 AD, as written in the handbook for prescription for emergencies, Zhou Hou Bei Ji Fang by Ge Heng.3 Qing hao had been prescribed in traditional Chinese medicine for other problems for at least 500 years beforehand on the basis of extant written records. Qmghaosu, known as arfernisinin in the West, was isolated and identified in Sing hao in the 1970s in China.5 It was thoroughly investigated and determined to have excellent antimalarial activity. Several semisynthetic drugs have since been created as discussed above; along with artemisinin, they are used more and more in treating patients with malaria.

761

Pharmacology of Natural Medicines rapid death of all stages of malaria parasites.8 Because the presence of an oxidizing peroxide bridge appears essential to the activity of artemisinin compounds, the oxidative hypothesis is further supported. The importance of iron to this process is unclear. Some investigators suggest that iron chelators such as desferrioxamine actually increase the activity of artemisinin in vitro? Artemisinin compounds are synergistic with many other, but not all, antimalarial drugs. Low doses of mefloquine and artemisinin showed definite synergism in vitro against Plasmodiumfalciparum,while higher doses showed additive effects.'O Mefloquine, chloroquine, primaquine, and tetracycline were all potentiated by artemisinin in mice with malaria; the effects of pyrimethamine, cycloguanil, and sulphonamide antibiotics were all decreased."

Figure 69-1 Artemisinin.

Antiparasitic

I

OH Figure 69-2 Dihydroartemisinin.

Besides killing Plasmodium spp., artemisinin compounds have shown activity against Schistosoma spp. and Clonorchis sinensis. Numerous animal studies show that artemether and artesunate can prevent and cure infections by Schistosoma japonicum, Schistosoma mansoni, and Schistosoma haematobi~m.'*-'~It is not clear if artemisinin or dihydroartemisinin is effective. However, artemisinin and the various semisynthetic variants available were all effective at treating Clonorchis infections in rats with no sign of toxicity.16

Antineoplastic

Artemether: R=CH,

OR

Arteether: R=C,H, Artesunate sodium: R=COCH,CH,CO,Na Flgure 69-3

Artemisinin derivatives (artesunate,artemether, and arteether).

PHARMACOLOGY Antimalarial Effects Dihydroartemisinin preferentially accumulates in erythrocytes, and malaria-infected erythrocytes accumulate 300 times as much as uninfected erythrocytes.6 Since active artemisinin compounds all appear to be converted to dihydroartemisinin in vitro and then to act as mentioned earlier, all these compounds ultimately end up in erythrocytes. Artemisinin and related molecules appear to act in part by generation of free radicals, leading to damaging the membranes of several parasitic organisms7 This leads to

Mounting evidence suggests that artemisinin compounds have potent anticancer activity. Artemisinin and quercetagetin 6,7,3',4'-tetramethyl ether, a flavonoid found in sweet wormwood, both showed activity against several tumor types in ~ i h - 0 . Dihydroartemisinin '~ and artesunate have also been investigated and found to ~ ~presence ,~~ inhibit cancer cells sigruficantly in ~ i t r o .The of ferrous iron appears to be essential for this activity, and sufficient quantities of iron may be necessary to prevent cancer cells from becoming resistant to artemisinin compounds.'820 A combination of ferrous sulfate and dihydroartemisinin proved effective at limiting the growth of implanted fibrosarcomas in ratsz1 The combination did not appear to cause adverse effects. Ferrous sulfate or dihydroartemisinin administered alone were not effective in this model. Artemisinin inhibited human glutathione-Stransferase (GST) Al-1 in transgenic Escherichia coZi at concentrations readily achievable in humans.22This work suggests the possibility of using artemisinin to reduce drug resistance in cancer cells, which frequently protect themselves from chemotherapy agents by expressing various GST enzymes.

Arfemisiaannua (Sweet Wormwood)

CLINICAL APPLICATIONS Malaria A metaanalysis has confirmed that artemisinin; dihydroartemisinin; and the semisynthetic derivatives artemether, artesunate, and arteether are potent, effective, and safe in patients with uncomplicated malaria compared with other antimalarial agents.23In cases of severe or cerebral malaria, these agents appear to be at least as effective as quinine." No artemisinin compound has been shown to work better than any other, though there is a relative dearth of studies examining this question. It should be noted that most trials have been conducted in Southeast Asia, an area with a high incidence of multidrug-resistant malaria. Two uncontrolled trials have investigated the efficacy of an infusion of sweet wormwood leaves in patients against I? falciparurn or Plasmodium rnalariae malaria at two centers in the Democratic Republic of Congo.= The sweet wormwood was grown locally in both instances to try to determine the efficacy and cost effectiveness of this approach in Africa. In the first trial, 22 nonpregnantvolunteers older than the age of 11years with fevers higher than 38"C, evidence of parasitemia, and symptoms of malaria participated. Each received 1 L of an infusion of 5 g of sweet wormwood leaves in four divided doses for 5 days. Chromatographyshowed that thisprovided 12 mg of artemisinin total per day. Artemisinin has low water solubility, and this high degree of extraction can perhaps best be explained by the presence of nonartemisinin compounds improving artemisinin's water solubility or enhancing its efficacy.All but two patients reported complete elimination of symptoms. Five of these patients agreed to have blood smears checked daily during the trial. All five showed rapid decreases in parasite counts in the blood, and by day 4 all five patients showed complete elimination of parasitemia. In the second trial, 48 nonpregnant patients older than the age of 11 years, all with I? falcipururn and symptoms of malaria, volunteered for the study. The tea was prepared by boiling 5 g of sweet wormwood leaves in 1 L water for 5 minutes, resulting in a total of 7.2 mg of artemisinin being delivered daily for 4 days. In this group 92% had complete clearance of parasitemia by the end of the trial, and 77%were symptom free. Of the 11patients (23%)who still had parasites, only two showed evidence of parasitemia. Twelve patients complained of nausea or vomiting, or both, during the trial. The dose of artemisinin delivered in this study was substantially lower than the typical daily dose of artemisinin,which is 500 mg. This strongly suggests that compounds in sweet wormwood besides artemisinin have synergistic antimalarial activity, enhance absorption of artemisinin, or in other ways increase the effectiveness of artemisinin.

It is unknown if artemisinin would work the same way in people not chronically exposed to malaria. Artemisinin is also generally said to be ineffective at preventing malaria infection, though this does not appear to have been studied.

Schistosomiasis Several double-blind trials conducted in China and on the Ivory Coast have proven that artemether is effective at reducing the risk of developing schistosomiasis compared with placeb0.2~,~~ It is unclear if artemisinin or whole sweet wormwood would also be effective for this purpose, but trials are warranted.

DOSAGE The dose of sweet wormwood tea is 5 g/1 L water, drunk in three to four divided doses.2O The dose of a 1:5tincture of dried leaf is difficult to extrapolate from this dose because a higher ethanol concentration (60% to 70%) could be used, which would greatly improve the ability of the solvent to draw artemisinin into the final product. A rough estimate would be 1 to 3 ml three times a day for a healthy adult. The usual dose of isolated artemisinin as a prescription drug for uncomplicated malaria is 500 to 1000mg daily for 5 days.20,28 Food does not appear to significantly affect the absorption of artemi~inin.~~

TOXICITY The only common adverse effects from use of sweet wormwood are nausea, loss of appetite, and Vomiting is rare. Neurotoxic effects have been observed in experimentalanimals treated with artemisinin derivatives and in a small handful of humans.3oThese effects have not been observed during use of whole sweet wormwood or its extracts. Sweet wormwood should be avoided in pregnancy and lactation untiI more data are available regarding its safety in these situations. Artemisinin derivatives have frequently been used safely in children, particularly when administered by

DRUG INTERACTIONS Artemisinin compounds generally show more rapid parasite clearance and fever reduction when combined with mefloquine than either drug given by itself, according to a metaanalysis of clinical trials.18 Mefloquine's neurologic toxicity does not appear to be altered by combination with artemisinin compounds, though the tendency to induce severe vomiting may be slightly lessened. Artemisinin compounds can be combined safely with doxycycline and tetracycline, according to the results of

Pharmacology of Natural Medicines

two clinical trials, though at least one of these trials suggested the combination was less effective than artemether combined with m e f l o q ~ i n e . ~Another ~J~ double-blind trial found that the combination of artesunate and tetracycline is equally effective and much safer than quinine and tetracycline.34 Artemisinin may interfere slightly with sulfadoxinepyrimethamine (SP). In one trial, artemisinin by itself led to insigruficantlymore rapid parasite clearance than

artemisinin combined with SP.= Fever relief was achieved equally rapidly, and adverse effects were absent in both groups. Further research is necessary to determine for certain if there is any negative effect from combining these two agents. Grapefruit juice initially increases bioavailability of oral artemether, though it does not stop the inevitable decline in bioavailability of this compound that occurs with repeated dosing over a few days.%

1.Zheng GQ.Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med 1994;60.54-57. 2. China Cooperative Research Group. Chemical studies on qinghaosu (artemisinine). On qinghaosu and its derivatives as antimalarials. J Tradit Chin Med 1982;2:3-8. 3. Hien TT,White NJ. Qinghaosu. Lancet 1993;341:603-608. 4. Elford K, Roberts MF, Phillipson JD,Wilson RJ. Potentiationof the antimalarial activity of qinghaosu by methoxylated flavones. Trans R Soc Trop Med Hyg 1987;81:434-436. 5. CoordinatingGroup for Research on the Structure of Qmghaosu. A new type of sesquiterpenelactone-qinghaosu. Kexue Tongbao 1977; 22142. 6. Gu HM,Warhurst DC, Peters W. Uptake of 3H-dihydroartemisinine by erythrocytes infected with Plasmodium fakiparum in vitro. Trans R Soc Trop Med Hyg 1984;7826.5-270. 7. Krungkrai SR,Yuthavong Y. The antimalarial action on Plasmodium falciparum of qinghaosu and artesunate in combination with agents which modulate oxidant stress. Trans R Soc Trop Med Hyg 198731: 710-714. 8. Meshnick SR. Artemisinin antimalarials:mechanisms of action and resistance. Med Trop (Mars) 1998;5813-17. 9. Sibmooh N,Pipitapom B, Wilairatana,'F et al. Effect of artemisinin on lipid peroxidation and fluidity of the erythrocyte membrane in malaria. Biol Pharm Bull 2000;23:1275-1280. 10. Bwijo B, Alin MH, Abbas N, et al. Efficacy of artemisinin and mefloquine combinations against Plasmodium falciparum. In vitro simulation of in vivo pharmacokinetics. Trop Med Int Health 19972: 461-467. 11. Chawira AN, Warhurst DC, Robinson BL, Peters W. The effect of combinations of qinghaosu (artemisinin)with standard antimalarial drugs in the suppressive treatment of malaria in mice. Trans R Soc Trop Med Hyg 1987;81:554-558. 12. Le WJ, You JQ,Yang YQ, et al. [Studies on the efficacy of artemether in experimental schistosomiasis.] Yao Xue Xue Bao 1982;17187-193. 13. Le WJ, You JQ Mei [Chemotherapeuticeffect of artesunate in experimental schistosomiasis.] Yao Xue Xue Bao 1983;18:619-621. 14.Xiao S, Tanner M, NGoran EK, et al. Recent investigations of artemether, a novel agent for the prevention of schistosomiasis japonica, mans0n.iand haematobia. Acta Trop 2002;82175181. 15. Yang Y, Xiao S, Tanner M, et al. Histopathologicalchanges in juvenile Schistosoma haematobium harboured in hamsters treated with artemether. Ada Trop 2001;79135-141. 16.Chen RX, Qu ZQ Zeng MA, Li JY. Effectof quinhaosu and its derivatives on CIonorchis sinensis in rats. Chin Pharm Bull 1983; 18410411. 17. Zheng GQ. Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med 1994;60:54-57. 18.Singh NP, Lai H. Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. Life Sci 2001; 7049-56.

19. Efferth T, Dunstan H, Sauerbrey A, et al. The anti-malarial artesunate is also active against cancer. Int J Oncol2001;18767-773. 20. Sadava D,Phillips T, Lin C, Kane SE. Transferrin overcomes drug resistance to artemisinin in human small-cell lung carcinoma cells. Cancer Lett 2002;179:151-156. 21.Moore JC, Lai H, Li JR, et al. Oral administration of dihydroartemisinin and ferrous sulfate retarded implanted fibrosarcoma growth in the rat. Cancer Lett 1995;9883-87. 22. Mukanganyama S, Widersten M, Naik YS, et al. Inhibition of glutathione Stransferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer 200297: 700-705. 23.McIntosh HM, Olliaro P. Artemisinin derivatives for treating uncomplicated malaria (Cochrane Review). In: The Cochrane Library, Issue 3,2002. Oxford, England: Update Software. 24. McIntosh HM, Olliaro P. Artemisinin derivatives for treating severe malaria (Cochrane Review). In:The Cochrane Library, Issue 3,2002. Oxford, England: Update Sohare. 25. Mueller Ms, Karhagomba IB, Hirt HM, Wemakor E. The potential of Artemisiu annua L. as a locally produced remedy for malaria in the tropics: Agricultural, chemical and clinical aspects. J Ethnopharmacol2OOO;73:487-493. 26. Xiao SH, Booth M, Tanner M. The prophylacticeffects of artemether against Schistosoma japonicum infections. Parasitol Today 2000;16: 122-126. 27. Utzinger J, NGoran EK, N'Dri A, et al. Oral artemether for prevention of Schistosoma mansoni infection: randomised controlled trial. Lancet 2000;355: 1320-1325. 28. B a h t GA. Artemisinin and its derivatives: an important new dass of antimalarial agents. Phannacol Ther 2001;90:261-265. 29. Dien TK,de Vries PJ, Khanh NX, et al. Effect of food intake on pharmacokinetics of oral artemisinin in healthy Vietnamese subjects. Antimicrob Agents Chemother 1997;41:1069-1072. 30.Miller LG, Panosian CB. Ataxia and slurred speech after artesunate treatment for fakiparum malaria. N Engl J Med 1997;336:1328. 31. Krishna S, Planche T, Agbenyega T, et al. Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria. Antimicrob Agents Chemother 2001;45509-516. 32. Looareesuwan S,Viravan C, Vanijanonta S, et al. Randomized trial of mefloquine-doxycycline, and artesunate-doxycycline for treatment of acute uncomplicated falciparum malaria. Am J Trop Med Hyg 1994;50:784-789. 33. Than M. Unpublished data obtained from the investigator, Defence Services General Hospital, Myanmar. Cited in McIntosh HM, Olliaro P. Artemisinin derivatives for treating uncomplicated malaria (CochraneReview). In:The Cochrane Library, Issue 3,2002. Oxford, England: Update Software. 34. Duarte EC, Fontes CJ,Gyorkos TW, Abrahamowicz M. Randomized controlled trial of artesunate plus tetracycline versus standard

v.

Artemisia annua (Sweet Wormwood) treatment (quinineplus tetracycline)for uncomplicated Plasmodium falciparum malaria in Brazil. Am J Trop Med Hyg 1996;54:197-202. 35. Tran TH, Arnold K, Nguyen TH, et al. Single dose artemisininmefloquine treatment for acute uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg 1994;88:688-691.

36. van Aghnael MA, Gupta V, van der Graaf CA, van Boxtel CJ. The effect of grapefruit juice on the time-dependent decline of artemether plasma levels in healthy subjects. Clin Pharmacol Ther 1999;66:408414.

Bee Products-Pollen,

Propolis, and Royal Jelly Michael T. Murray, ND Joseph E. Pizzorno Jr, ND

C H A P T E I< C 0 N T E N T S General Description 767

Propolis 768 Royal Jelly 768

Chemical Composition 767 Dosage 768

History and Folk Use 767 Toxicity 768 Pharmacologyand Clinical Applications 768 Bee Pollen 768

GENERAL DESCRIPTION Historically, one of the most valued groups of natural medicines is that of bee pollen, propolis, and royal jelly. Bee pollen comes from the male germ cell of flowering plants. As the honeybee travels from flower to flower, it fertilizes the female germ cell. Honeybees enable the reproduction of more than 80%of the world’s grains, fruits, vegetables, and legumes. The pollen is collected and brought to the hive, where the bees add enzymes and nectar to the pollen. Propolis is the resinous substance collected by bees from the leaf buds and barks of trees, especially poplar and conifer trees. The bees use the propolis, along with beeswax, to construct the hive. Propolis has antimicrobial activities that help the hive block out viruses, bacteria, and other organisms. Royal jelly is a thick, milky substance produced by worker bees to feed the queen bee. The worker bees mix honey and bee pollen with enzymes in the glands of their throats to produce royal jelly. Royal jelly is believed to be a useful nutritional supplementbecause of the queen bee’s superior size, strength, stamina, and longevity compared with other bees.

CHEMICAL COMPOSITION Honey is composed primarily (roughly 70%) of simple sugars (mainly fructose, glucose, and maltose), but it also contains minerals including manganese, calcium, iron, and sodium; organic acids; amino acids; vitamins; and enzymes.

Drug Interactions 769

Although honey is a natural source of sugar, bee pollen is often referred to as “nature’s most perfect food” because it is a complete protein (typically containing 10% to 35% total protein), meaning it contains all eight essential amino acids. Bee pollen also provides B vitamins, vitamin C, carotenes, minerals, DNA, RNA, numerous flavonoid molecules, and plant hormones. Propolis and royal jelly have similar nutritional qualities to pollen but considerably higher levels of different biologically active compounds.’j2 Royal jelly contains approximately 12% protein, 5% to 6% lipids, and 12%to 15%carbohydrates.

HISTORY AND FOLK USE The use of bee products for medicinal purposes is as old as beekeeping itself. Chinese texts more than 2000 years old include many mentions of bee products. Hippocrates also wrote about them. Honey was so valued during Roman times that it was often used instead of gold to pay taxes. Of the bee products, propolis was the most valued as a medicinal agent. Hippocrates prescribed propolis to help heal sores, as well as external and internal ulcers. Propolis-making bees were also depicted on vases from ancient Egypt, where the sign of the bee was often interwoven with the titles of the kings and used as the motif on ornaments presented as rewards for valor. The ancient Egyptians looked upon bees and their propolis as the source of eternal health and life. In the seventeenth century, propolis was a major ingredient of healing ointments in the European pharmacopoeia.

-

767

PHARMACOLOGY AND CLINICAL APPLICATIONS The health benefits of bee products are much heralded but insufficiently researched. Some overlap exists in the clinical uses of pollen, propolis, and royal jelly. Following is a list of the principal uses for each of these bee p d ucts as shown in Box 70-1. This list is likely to grow with continued research.

Bee Pollen Little research has been done on bee pollen, probably because financial rewards to just@ such an investment are lacking. The research that does exist is limited but impressive. For example, studies in animals show that pollen can promote growth and development; protect against free radical and oxidative damage; and protect against the effects of harmful radiation, as well as toxic exposure to chemical solvents.55 A pollen extract has also been shown to produce sigruficant improvement in menopausal symptoms (headache, urinary incontinence, dry vagina, decreasing vitality) in double-blind studies? The improvements were achieved even though the pollen extract produces no estrogeniceffect, an important consideration for women who cannot take estrogens of any kind?

A key use of propolis is protection against and shortening the duration of the common cold. A preliminary human study reported that propolis extract reduced upper respiratory infections in children." In a doubleblind study of 50 patients with the common cold, the group taking propolis extract became symptom free far more quickly than the placebo group.lS Another possible application of propolis is in the treatment of inflammatory bowel diseases (IBDs) like Crohn's disease and ulcerative colitis. An anecdotal article described an interesting case of ulcerative colitis that responded to propolis therapy.19 The author suggested that the antimicrobial and antiinflammatory properties of propolis may be of value in the treatment of IBDs. The antimicrobial properties of propolis may also help protect against parasitic infections in the gastrointestinal tract. One preliminary study of children and adults with giardiasis showed a 52% rate of successful parasite elimination in children and a 60% rate in adults in those given propolis extract (amount not stated).20 However, these results are not as impressive as those achieved with conventional drugs used against giardiasis, so propolis should not be used alone for this condition without first consulting a physician about available medical treatment.

Propolis

Royal Jelly

The primary use of propolis has been in immune system enhancement and infections. Propolis has inherent antimicrobial activity that protects the hive block from viruses, bacteria, and other organisms. Propolis has shown considerable antimicrobial activity in in vitro studies.&1°Propolis also stimulates the immune system, according to preliminary human studies."J2 In vitro and animal studies have also shown that propolis exerts some antioxidant, liver protecting, antiinflammatory, and anticancer properties.1517

Some research on royal jelly has found a cholesterollowering effect. Specifically, 10 human studies have been published, 7 of which were double blind.2l Of the seven double-blind studies, only three used an oral preparation. An injectable form was used in the other four studies. Results of a detailed analysis of the double-blind studies indicate that with oral preparations, despite shortcomings in the design of the studies and lack of standardization with commercial preparations used, royal jelly can decrease total cholesterol levels by about 14%in patients with moderate to severe elevations in blood cholesterol levels (initial values ranging from 210 to 325 mg/dl). Even better results may be noted when using higherquality royal jelly products.

Bee pollen Allergies Antioxidant support Energy enhancement Menopausal symptoms Support for chemotherapy and radiation therapy Propolis Common cold Gastrointestinal infections Immune enhancement Topical antiinflammatory Upper respiratory tract infections Royal jelly Elevated cholesterol levels Energy enhancement

DOSAGE Bee pollen: usually 1to 3 tablespoons daily Propolis: 100 to 500 mg three times daily Royal jelly: 50 to 250 mg of royal jelly one to two times daily

TOXICITY Allergic reactions are the most common side effects. If there is a known allergy to conifer and poplar trees, use of bee products should be avoided. Allergic reactions

Bee Products-Pollen,

can range from mild (e.g.,mild gastrointestinal upset) to severe (e.g.,asthma, anaphylaxis [shock],intestinal bleeding, even death in people who are extremely allergic to bee products).22

1.Burdock GA. Review of the biological properties and toxicity of bee propolis (propolis).Food Chem Toxic01 1998;36347-363. 2. Hove SR, Dimick PS,Benton AW. Composition of freshly harvested and commercial royal jelly. J Apic Res 1985;2452-61. 3. Qian B, Zang X, Liu X. [Effectsof bee pollen on lipid peroxides and immune response in aging and malnourished mice.] Zhongguo Zhong Yao Za Zhi 1990;15:301-303,319. 4. Xie Y, Wan B, Li W. [Effect of bee pollen on maternal nutrition and fetal growth.] Hua Xi Yi Ke Da Xue Xue Bao 1994;25434-437. 5. Ceglecka M, Wojcicki J, Gonet B, et al. Effect of pollen extracts on prolonged poisoning of rats with organic solvents. Phytother Res 1991:5;245-249. 6. Szanto E, Gruber D, Sator M, et al. [Placebocontrolled study of melbrosia in treatment of climacteric symptoms.] Wien Med Wochenschr 1994;144:130-133. 7. Einer-Jensen N, Zhao J, Andersen KP, Kristoffersen K. Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats. Maturitas 1996;25:149-153. 8. Tosi B, Donini A, Romagnoli C, Bruni A. Antimicrobial activity of some commercial extracts of propolis prepared with different solvents. Phytother Res 1996;10335-336. Vohora SB, Sharma K, et al. Antibacterial, antifun9. Dobrowolski JW, gal, antiamebic, antiinflammatory and antipyretic studies on propolis bee products. J Ethnopharmacol19913577-82. 10. Tichy J, Novak J. Detection of antimicrobials in bee products with activity against viridans streptococci. J Altern Complement Med 2000;6:383-389. 11. Bratter C, Tregel M, Liebenthal C, Volk HD. [Prophylactic effectiveness of propolis for immunostimulation: a clinical pilot study.] Forsch Komplementarmed 1999;6256-260.

Propolis, and Royal Jelly

DRUG ~NTERAcT~oNs No drug interactions are known.

12. Crisan I, Zaharia CN, Popovici F, et al. Natural propolis extract NIVCRISOL in the treatment of acute and chronic rhinopharyngitis in children. Rom J Virol1995;46:115-133. 13.Pascual C, Gonzalez R, Torricella RG. Scavenging action of propolis extract against oxygen radicals. J Ethnopharmacol 1994; 41~9-13. 14. Lin SC,Lin YH, Chen CF, et al. The hepatoprotectiveand therapeutic effects of propolis ethanol extract on chronic alcohol-induced liver injuries. Am J Chin Med 1997;25:325-332. 15. Khayyal MT, El-Ghazaly MA, El-Khatib AS. Mechanisms involved in the antiinflammatory effect of propolis extract. Drugs Exp Clin Res 1993;19197-203. 16. Mirzoeva OK, Calder PC. The effect of propolis and its components on eicosanoid production during the inflammatory response. Prostaglandins Leukot Essent Fatty Acids 1996;55441-449. 17. Choi YH, Lee WY, Nam SY, et al. Apoptosis induced by propolis in human hepatocellular carcinoma cell line. Int J Mol Med 1999; 429-32. 18. Szmeja Z, Kulczynski B, Sosnowski Z, Konopacki K. [Therapeutic value of flavonoids in Rhinovirus infections.] Otolaryngol Pol 1989;43:180-184. 19. Golan R. Propolis. Townsend Letter for Doctors. June, 2001. 20. Miyares C, Hollands I, Castaneda C, et al. [Clinical trial with a preparation based on propolis "propolisina" in human giardiasis.] Acta Gastroenterol Latinoam 1988;18:195-201. 21. Vittek J. Effect of royal jelly on serum lipids in experimental animals and humans with atherosclerosis. Experientia 1995;51:927-935. 22. Greenberger PA, Flak MJ. Bee pollen-induced anaphylactic reaction in an unknowingly sensitized subject. Ann Allergy Asthma ImmUn012001;86239-242.

Beta-carotene and Other Carotenoids Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 771

Photoprotection 775 Commercial Forms 775

Dietary Sources 771 Metabolism 772 Absorption 772 Transformation in the Intestinal Mucosa 773 Transport, Storage, and Excretion 773

Clinical Applications 775 Prevention of Cancer 775 Prevention of Cardiovascular Disease 777 Immune Enhancement 778 Vaginal Candidiasis 778 Photosensitivity Disorders 778 Dosages 779

Physiologic Roles 774 Antioxidant Activity 774 Immune System 774 Reproduction 774

INTRODUCTION The carotenoids represent the most widespread group of naturally occurring pigments in nature. They are a highly colored (red and yellow) group of fat-solublecompounds, composed of hydrocarbons (carotenes) and their oxygenated derivatives (oxycarotenoids or xanthophylls). The basic carotenoid structure consists of eight isoprenoid units with a series of conjugated double bonds. All photosynthetic organisms, whether bacteria or plants, contain carotenoid pigments. These compounds not only function as auxiliary pigments in photosynthesis but also play a crucial role in protecting the organism or plant against photosensitization by its own chlorophyll. More than 600 carotenoids have been characterized, but only about 30 to 50 are believed to have vitamin A activity and some 20 are found in human plasma and tissues. Biologic activity of a carotenoid has historically been considered synonymous with its corresponding vitamin A activity. Beta-carotenehas been termed the most active of the carotenoids due to its higher provitamin A activity (Figure 71-1). However, recent research suggests that this function of carotenoids has been overemphasized, as they have been found to exhibit many other important physiologic activities. For a carotenoid to have

Toxicity 779 Drug Interactions 779

vitamin A activity, it must have an unaltered beta-ionone ring with an attached polyene side chain containing 11 carbon atoms. In contrast, apocarotenoids are compounds that have been shortened by the removal of at least one end of the molecule beyond a designated location (e.g.,beta-Apo-8’carotenal has been cleaved at the 8’ carbon). Apocarotenes and xanthophylls have reduced or no vitamin A activity, but many have been shown to have sigruficant antioxidant and physiologic benefits.’”

DIETARY SOURCES Among the richest sources of carotenes are green leafy vegetables. The carotenoids present in green plants are found in the chloroplastswith chlorophyll, usually in complexes with a protein or lipid. Beta-carotene is the predominant form in most green leaves. In general, the greater the intensity of the green color, the greater

Figure 71-1

Betacarotene.

771

the concentration of beta-carotene. Orange-colored fruits and vegetables (e.g., carrots, apricots, mangoes, yams, squash) typically have higher concentrations of provitamin A carotenoids, the provitamin A content again paralleling the intensity of the color. Yellow vegetables have higher concentrations of xanthophylls and hence a lowered provitamin A activity. In the orange and yellow fruits and vegetables, beta-carotene concentrations are high, but other provitamin A carotenoids typically predominate. Red and purple vegetables and fruits such as tomatoes, red cabbage, berries, and plums contain large portions of non-vitamin A-active pigments including flavonoids. Legumes, grains, and seeds are also significant sources of carotenoids. Carotenoids are also found in various animal foods such as salmon and other fish, egg yolks, shellfish, milk, and poultry. Carotenoids are also frequently added to foods as colorants. Table 71-1 lists carotenoids with provitamin A activity found in common food sources, while Table 71-2 lists some important carotenoids that have no vitamin A activity. The structures of two of these, lycopene and zeaxanthin, are illustrated in Figures 71-2 and 71-3.

According to a detailed analysis of the levels of carotenoids in 120 fruits and vegetables, lycopene is found in few." Table 71-3 lists the foods that contained lycopene. These values indicate that lycopene levels are retained in food processing.

METABOLISM Absorption Various factors are known to influence the absorption efficacy of vitamin A and carotenoids. Although retinol does not I.equirebile acids to assist absorption, carotenoids do. Other factors that affect vitamin A and carotenoid absorption include the following: The presence of fat, protein, and antioxidantsin the food The presence of bile and a normal complement of pancreatic enzymes in the intestinal lumen The integrity of the mucosal cells The absorption efficiency of dietary vitamin A is usually quite high (80% to 90%),with only a slight reduction in efficiency at high doses. In contrast, beta-carotene's

Provitamin A carotenoids and food sources Carotenoid

Vitamin A activitv (7')

Food sources Green plants, carrots, sweet potatoes, squash, spinach, apricots, green peppers

Beta-carotene

100

Alpha-carotene

50-54

Green plants, carrots, squash, corn, watermelons, green peppers, potatoes, apples, peaches

Gamma-carotene

42-50

Carrots, sweet potatoes, corn, tomatoes, watermelons, apricots

Beta-zeacarotene

20-40

Corn, tomatoes, yeast, cherries

Cryptoxanthin

50-60

Corn, green peppers, persimmons, papayas, lemons, oranges, prunes, apples, apricots, paprika, poultry

Beta-apo-W-carotenal

72

Citrus fruit, green plants

Beta-apo-l2'-carotenal

120

Alfalfa meal

.*Carotene

Vitamin A activity (%)

Food sources Green plants, carrots, sweet potatoes, squash, spinach, apricots, green peppers

Beta-carotene

100

Alpha-carotene

50-54

Green plants, carrots, squash, corn, watermelons, green peppers, potatoes, apples, peaches

Gamma-carotene

42-50

Carrots, sweet potatoes, corn, tomatoes, watermelons, apricots

Beta-zeacarotene

20-40

Corn, tomatoes, yeast, cherries

Cryptoxanthin

50-60

Lycopene

0

Corn, green peppers, persimmons, papayas, lemons, oranges, prunes, apples, apricots, paprika, poultry Tomatoes, carrots, green peppers, apricots, pink grapefruit

Zeaxanthin

0

Spinach, paprika, corn, fruits

Lutein

Green plants, corn, potatoes, spinach, carrots, tomatoes, fruits

Canthaxanthin

0 0

Crocetin

0

Saffron

Capsanthin

0

Red peppers, paprika

Mushrooms, trout, crustaceans

Beta-carotene and Other Carotenoids

Figure 71-2

Lycopene.

OH

HO Figure 71-3 Zeaxanthin.

Lycopene content of common foods Food

Lycopene (mg/lOO g)

Apricot, canned

0.06

Apricot, dried

0.8

Grapefruit (pink and raw)

3.4

Guava juice

3.3 3.1

Tomato, raw Tomato juice, canned

8.6

Tomato paste, canned

6.5

Tomato sauce, canned

6.3

Watermelon, raw

4.1

absorption efficiency is much lower (40% to 6O%), and it decreases rapidly with increasing Carotene supplementsare better absorbed than the carotenes from foods? Supplying only beta-carotene, whether natural or synthetic, may be exerting a detrimental effect to the absorption of other carotenes. For example,beta-carotene supplementation has been shown to inhibit the absorption of luteh6Studies in humans have shown that with beta-carotene supplementation, the absorption of lutein can drop by more than 50%? Interestingly the absorption of lutein from vegetables is five times greater than that of beta-carotene?

The conversion diminishes as carotene intake increases and when serum retinol levels are adequate.l0 Beta-carotene and other provitamin A carotenes were originally believed to be cleaved by carotene dioxygenase at the 15,15' double bond, which would yield two molecules of all-trans retinal. Current belief, however, is that the dioxygenase enzyme nonspecifically attacks any one of the double bonds of the beta-carotene,resulting in the formation of a corresponding apo-beta-carotenal or retinal." The apocarotenal formed can either be degraded to retinal or absorbed.The retinal formed is then converted to retinol by retinaldehyde reductase. Uncleaved provitamin A carotenoids, apocarotenoids, and non-provitamin A carotenoids like retinol are transported in the chylomicra.

Transport, Storage, and Excretion No specific carrier protein exists in the plasma for carotenoids. These compounds are typically transported in human plasma in association with the plasma lipoproteins, particularly by low-density lipoprotein (LDL). As a consequence, patients with high serum cholesterol or LDL levels tend to have high serum carotene levels. The concentrations found in the plasma usually reflect the dietary concentration, with beta-carotene typically comprising only 20% to 25% of the total serum carotene level.12 Lycopene is the most predominant carotenoid in human plasma, accounting for more than 50% of the carotenoids in human serum. Owing to its lipophilic nature, lycopene is found to concentrate in LDL and very-low-density lipoprotein (VLDL) fractions and not in high-density lipoprotein (HDL) fractions of the serum cholesterol. Interestingly, although trans-lycopene constitutes the predominant isomer in food sources, in human plasma 50%of the total lycopene has been found as cis isomers. Whether thisis due to in vivo isomerization or preferential absorption of cis-lycopene is still unclear. Little is known about in vivo metabolism of lycopene. Carotenes may be stored in adipose tissue, the liver, other organs (the adrenals, testes, and ovaries have the highest concentrations), and the skin (Table 71-4). Distribution of carotenoids in some human tissues ( W g )

Transformation in the Intestinal Mucosa As stated earlier, of the more than 600 carotenoids that have been reasonably well characterized, only about 30 to 50 are believed to have provitamin A activity. Yet carotenoids provide the majority of dietary vitamin A. Provitamin A carotene conversion to vitamin A depends on diverse factors9:

Tissue

Carotenoids

Beta-carotene

Adrenal

20.1 f 11.9 8.3 f 21.3

10.8f 5.5 4.7 f 2

Lung

5 f 7.7 3.9f 6 2.3 f 1.2 1.6 f 2.2 0.6 f 1 .O

Thyroid

0.6 f 0.4

-

Liver Testis Fat Pancreas

Protein status Thyroid hormones zinc Vitamin C

Spleen

1.3f1.1 1.1 fl 1.2f 0.5 -

Deposition in the skin results in carotenodermia. This is a benign (and probably beneficial) state. Carotenodermia not directly attributable to dietary intake or supplementation, however, may indicate a deficiency in a necessary conversion factor (e.g., zinc, thyroid hormone, vitamin C, or protein).

PHYSIOLOGIC ROLES Antioxidant Activity In general carotenes exert sigruficant antioxidant activity, while the antioxidant activity of vitamin A is relatively However, its antioxidant actions are specific in that they are involved primarily in scavenging singlet molecular oxygen and to a much lesser extent peroxyl radicals. The efficacy of the various carotenoids for physical quenching is related to the number of conjugated double bonds present in the molecule determining their lowest triplet energy level. The most efficient singlet oxygen quenching camtenoid is the open-ring camtenoid lycopene. The antioxidant activity of carotenes is thought to be responsible for their anticancer effects noted in population studies (discussed later). Because aging is associated with free radical damage, a hypothesis developed that carotenes may also protect against aging as well. Evidence seem to support this hypothesis. It appears that tissue carotenoid content is the most sigruficant factor in determining maximal life span potential (MLSP) of mammalian species (r = 0.835 for 12 mammalian species, and for primates alone, r = 0.939!).14For example, human MLSP of approximately 90 years correlates with a serum carotene level of 50 to 300 pg/dl, while other primates, such as the rhesus monkey, have an MLSP of approximately 34 years, correlating with a serum carotene level of 6 to 12 pg/dl. Although beta-carotene has received most of the attention, many carotenes that have either low or no vitamin A activity exert much greater protection compared with beta-carotene. For example, beta-carotene generates vitamin A much more efficiently than alpha-carotene, but alpha-carotene is approximately 38% stronger as an antioxidant and 10 times more effective in suppressing liver, skin, and lung cancer in animals compared with beta-~ar0tene.l~ Even more powerful are lycopene and lutein.’”20 Studies have shown lycopene to exhibit the highest overall singlet oxygen quenching of the carotenoids thus far studied.21 Its activity is roughly double that of beta-carotene. Furthermore, lycopene exerts even more impressive anticancer effects.”J8 To evaluate the role of lycopene as a protective factor in digestive tract cancers, a case-control study was conducted in northern Italy, where tomato intake is high but also heterogenous in that some people eat a lot of tomatoes while others eat few, if any. Tomatoes are a perfect

food to study as they are quite high in lycopene but low in carotene. The data were obtained from a series of hospital-based studies on various cancers of the digestive tract from 1985-1991.“ Frequency of consumption of raw tomatoes was divided into four levels: fewer than two; three to four; four; five to six; and more than seven servings per week. Results showed a consistent pattern of protection by high intake of raw tomatoes in all examined cancer sites of the digestive tract. The degree of protection was similar to, but somewhat more marked than, those afforded by green vegetables and fruit studies carried on in the same areas.The results support the findings of other researchers who found, for example, a 40% reduction in the risk of esophageal cancer by simply consuming one serving of raw tomatoes per week and a 50%reduced rate for cancers of all sites among elderly Americans reporting a high tomato intake. These results suggest that increasing dietary lycopene levels may be a sigruficant protector against cancer.17J8

Immune System Carotenes have demonstrated significant effects in enhancing immune function. Some of these effects are probably related to an ability to prevent stress-induced thymic involution, as well as promote thymus growth and function and increase interferon’s stimulatory action on the immune system.= Interferon is a powerful immuneenhancing compound that plays a central role in protection against viral infections.

Reproduction Beta-carotene reportedly has a specific effect in fertility distinct from its role as a precursor to vitamin In bovine nutritional studies cows fed beta-carotenedeficient diets exhibited delayed ovulation and an inmase in the number of follicular and luteal The corpus luteum has the highest concentration of beta-carotene of any organ The carotene cleavage activity changes with the ovulation cycle, with the highest activity occurring during the midovulation stage. It has been speculated that a proper ratio of carotene to retinol must be maintained to ensure proper corpus luteum function. As the corpus luteum produces progesterone, inadequate corpus luteum function could have significant deleterious effects. Inadequate corpus luteum secretory function is one of the characteristic features of infertile or irregular menstrual cycles, or both?’ Furthermore, an increased estrogen-to-progesterone ratio has been implicated in various clinical conditions including ovarian cysts, premenstrual tension syndrome, fibrocystic breast disease, and breast cancerF8Because supplemental betacarotene given to cows significantly reduced the incidence of ovarian cysts (42% in control group vs. 3% in the beta-carotene group), it may have a similar effect

Beta-carotene and Other Carotenoids

in humans.25,26 Another bovine condition that benefited from increased dietary betacarotene levels is cystic mastitis.27Apparently dairy farmers have a greater appreciation of beta-carotene than do many nutritionists. O f course, there are sigruficant financial reasons, as the annual monetary loss from bovine mastitis in the United Stateshas been estimated at 1.5 to 2 billion dollars, and ovarian cysts represent the major cause of infertility in cattle.

Photoprotection Photooxidative processes play a role in the pathology of light-exposed tissues including the eye and skin. Agerelated macular degeneration affects the macula lutea of the retina, the area of maximal visual acuity. It is a major cause of irreversible blindness among the elderly in the United States. Macular pigments protect against the photooxidative processes, which may be related to the antioxidant activities of the macular carotenoids or their light-filtering effects. Although lutein and zeaxanthin are responsible for coloration of the macula lutea, neither lycopene, alphacarotene or betacarotene are found in this tissue. Lutein supplementation has proven particularly beneficial in offeringprotection against macular degeneration, as well as improving visual acuity in the early stages of the disease.18J9In regard to protecting the skin against oxidative damage, though clinical applications have focused on beta-carotene, lycopene seems particularly well suited for this application.”

Commercial Forms Five primary sources of carotenes are on the market: Synthetic all-trans beta-carotene Beta- and alpha-carotene from the algae Dunaliella Mixed carotenes from palm oil Lutein Lycopene Of the three sources of beta-carotene, mixed carotenes from palm oil carotenes seem to be the best form (Table 71-5).

Palm oil carotenes appear to give much better antioxidant protection. The carotene complex of palm oil closely mirrors the pattern in high-carotene foods. In particular, unlike the synthetic version, which only provides the trans configuration of beta-carotene, natural carotene sources provide beta-carotene in both a trans and cis configuration:

60% beta-carotene (both trans and cis isomers) 34% alpha-carotene 3% gamma-carotene 3% lycopene Palm oil carotenes are absorbed about 4 to 10 times Carotenes better than synthetic all-trans beta-~arotenes.~-~~ from Dunaliella have also been shown to be well abs0rbed.3~The widespread health concerns over the use of “tropical oils” like palm and coconut do not apply to carotene products extracted from palm oil, as the fat content is minimal. In addition, the real problem with palm oil occurs when it is processed (i-e., partially hydrogenated). Lutein is used primarily for macular degenerati~n’~J~ (see Chapter 189, while lycopene is emerging as a valued carotene for protection against cancer and cardiovascular disease.

CLINICAL APPLICATIONS Prevention of Cancer Most epidemiologic studies have demonstrated a strong inverse correlation between dietary carotene intake and various cancers, especially those involving epithelial tissues (e.g., lung, skin, uterine cervix, gastrointestinal The epidemiologic association is much stronger for carotene than for vitamin A. This may reflect carotene’s superior antioxidant, immune-potentiating, and anticarcinogenic activity.37 Although there is no argument that a diet high in carotenesprotects against cancer, the big question is: “Can beta-carotene supplementationreduce the risk of cancer?” ne products (per 25,000 IU of vitamin A activity)

Source

Carotenoid

Palm oil

Alpha-carotene Beta-carotene Gamma-carotene Lycopene

Quenching rate

% in source

mg/25,000 IU

Antioxidant potential

1.9 1.4 2.5 3.1

33 63 2.5 0.1

7.36 14.04 0.56 0.02

2.6 3.66 0.26 0.01 ~~

6.53

TOTAL

Algal

Alpha-carotene Beta-carotene

1.9 1.4

4 96

0.61 14.69

1.4

100

14.97

4.05

TOTAL

Synthetic

Beta-carotene TOTAL

0.22 3.83 3.9 3.9

The answer appears to be that synthetic betatarotene supplementation does not. Three highly publicized reports on cancer prevention trials featuring synthetic alltrans beta-carotene in high-risk groups have produced negative results. Taking a close look at each of these studies is important to help put things into perspective.

The Alpha-toco herol, Beta-carotene Cancer Prevention S t u y Group

B

This study's population was 29,000 men in Finland who smoked and drank The men were given betacarotene (20 mg daily) or vitamin E, or both. The results of this study indicated an 18%increase in lung cancer in the beta-carotene group. This result was not totally unexpected, as studies in primates demonstrated that when animals were fed alcohol and beta-carotene, they experienced an increase in liver damage as a result of oxidative damage.39 Other researchers have pointed out that beta-carotene is susceptible to oxidative damage.40The protection against oxidative damage of beta-carotene is the presence of other antioxidant nutrientsjl Absence of these protective nutrients could result in formation of cancer-causing compounds, stressing the importance of relying on foods and broader-spectrum nutritional antioxidant support. Adding support to this statement is the fact that the group receiving both beta-carotene and vitamin E did not show an increase in cancer. In the group not receiving beta-carotene supplements, there was a strong protective effect of high dietary beta-carotene and blood carotenelevels against lung cancer. Altogether, these data strongly suggest that the protection offered by betacarotene is only apparent when other important antioxidant nutrients are provided and may not be provided by the synthetic forms.

Carotene and Retinol Efficacy Trial The second trial reporting on the role of beta-carotene in a high-risk group is the Carotene and Retinol Efficacy Trial (CARET)." This study comprised more than 18,000 U.S.men and women smokers and asbestos workers. It was halted 21 months prematurely in January 1996 after 4 years of intervention indicated that beta-carotene supplementation (30 mg daily) increased lung cancer by 28% and overall deaths by 17%. Although this appears dramatic, a closer look at the numbers and percentages puts them into proper perspective. Among active smokers, the risk of lung cancer during the CARET study was 5 per 1000. The 28% increase found with beta-carotene supplementation increased this number to roughly 6 per 1000.' Interestingly, once again in the group not taking betacarotene, the lowest rate of cancer was found among individuals with the highest blood beta-carotene levels; and in former smokers, beta-carotene supplementation actually reduced cancer risk by 20%.

The Physician's Health Study The Physician's Health Study was composed of 22,071 U.S.male physicians who took either 50 mg of betacarotene or a placebo every other day for 12 years. Results demonstrated no sigrufrcant effect-positive or negative-on cancer or cardiovascular disease, even in the group (11%0) that smoked."

General Comments on the "Negative" Studies Although scientific research is clear that diets high in antioxidants are protective against many cancers, the data are not as solid with antioxidant supplements. Three main points should be kept in mind when discussing research with antioxidants: The antioxidant system of the body relies on a complex interplay of many different dietary antioxidants. Taking any single antioxidant nutrient is not enough. Total protection requires a strategic, comprehensive dietary and supplement program. Although dietary supplements are important, they cannot replace the importance of consuming a diet rich in antioxidants. A shortcoming of many dietary studies is that researchers often focus on the effects of just one factor. In a way this is like judging an entire symphony by listening to a single trombone. Such research has its value, but it is not complete and often raises more questions than it answers. Another issue is that not all antioxidants are created equal.When it comes to quenching freeradicals, each may have a somewhat different (and usually narrow) range of activity. For example, beta-carotene is an effective quencher of a free radical known as singlet oxygen but is virtually powerless against the dozens of other types of free radicals. As a result, it has a narrow range of benefit and is susceptible to being damaged itself and forming a free radical without additional antioxidant support. Most antioxidants require some sort of "partner" antioxidant that allow them to work more efficiently. And research has shown that beta-carotene itself can become damaged if used alone (i.e., without its partner antioxidants vitamin C, vitamin E, and selenium).For example, while studies showed that synthetic beta-carotene supplements given alone actually increased the risk of cancer in smokers, when beta-carotene was given along with vitamin E and selenium, it reduced cancer deaths by a significant 13%.38Damaged beta-carotene is extremely toxic to the liver, the lining of the arteries, and the lungs. This fact alone may explain some of the disappointing results from recent beta-carotene studies. The results of these three studies indicate that synthetic beta-carotene supplementation may have adverse effects

Beta-carotene and Other Carotenoids

alone in the management of advanced prostate cancer.50 F&y-four patients with histologically confirmed metastatic prostatic cancer and a performance status of 0 to 2 (World Health Organization) were entered into the trial. At 6 months there was a significant reduction in PSA level in both treatments, but it was more marked in the lycopene group (mean 9.1 and 26.4 ng/ml). After 2 years these changes were more consistent in the lycopene group (mean 3.01 and 9.02 ng/ml). Eleven (40%)patients in the orchidectomy-alone group and 21 (78%) in the lycopene group had a complete PSA response, with a Other Prospective Studies partial response in 9 (33%)and 4 (15%) and progression in 7 (25%) and 2 (7%), respectively. Bone scans showed In addition to these three highly publicized studies, sevthat in the orchidectomy arm only 4 (15%)patients had a eral prospective and double-blind studies have shown complete response, versus 8 (30%)in the lycopene group, promising results. In particular, beta-carotene supplewith a partial response in 19 (70%) and 17 (63%)and promentation is especially effective in the treatment of early in 4 (15%) and 2 (7%), respectively. Of the cancerous lesions of the oral cavity and e s o p h a g u ~ . ~ t ~gression ~ 54 patients who entered the trial, 19 (35%)died, 12 (22%) Although beta-carotene has been shown to exert these in the orchidectomy group and 7 (13%) in the lycopene benefits on its own (in dosages ranging from 15to 180mg/ group. Researchers concluded that adding lycopene to day), one of the most positive studies showing a reducorchidectomy produced a more reliable and consistent tion in cancer risk with supplemental beta-carotene to date decrease in serum PSA level; it not only shrinks the priis one that featured a broader supplement program. The mary tumor but also diminishes the secondary tumors, Linxian Cancer Chemoprevention Study was a prospecproviding better relief from bone pain and lower urinary tive study of 30,000 rural Chinese adults. In one subtract symptoms and improving survival compared with study, subjects received one of four supplementprograms: orchidectomy alone. Retinol and zinc Riboflavin and niacin Prevention of Cardiovascular Disease Vitamin C and molybdenum Just as in the case of cancer prevention, while a high Beta-carotene, vitamin E, and selenium (dosages one to intake of carotene-rich foods appears to be protective, the three times greater than the U.S. recommended daily same may not be true for supplementation with synthetic allowance) beta-carotene. Double-blind trials wherein people are in high-risk groups for cancer and cardiovascular disease. These studies do not invalidate the hundreds of studies showing the preventive effect of a diet rich in carotenes and nutritional antioxidants against cancer and cardiovascular disease. These results seem to indicate the need for a diet high in carotenes and, if carotene supplementation is desired, people should not smoke, natural forms should be used, and the beta-carotene needs to be protected against the formation of toxic derivatives by taking extra vitamins C and E and selenium.

The latter group demonstrated 13% less cancer deaths These results and a reduction of 9% in overall again support the notion that a combination of antioxidants is superior to high levels of any single antioxidant.

Lycopene in the Treatment of Prostate Cancer In one of the more detailed studies of lycopene protection against cancer, Harvard researchers discovered that men who consumed the highest levels of lycopene (6.5mg per day) in their diet showed a 21% decreased risk of prostate cancer compared with those eating the lowest levels.48Men who ate two or more servings of tomato sauce each week were 23% less likely to develop prostate cancer during the 22 years of the study than men who ate less than one serving of tomato sauce each month. In addition to a protective effect, lycopene may exert a therapeutic effect as well. In a study of patients with existing prostate cancer, lycopene supplementation (15 mg daily) was shown to slow tumor growth, shrink the tumor, and lower the level of prostate specific antigen (PSA), a marker of cancer activity, by 18'70.~~ In another study, the efficacy of lycopene (4 mg daily) plus orchidectomy was compared with orchidectomy

supplemented with beta-carotene alone or placebo have not found benefit for synthetic beta-carotene supplement a t i ~ n .In ~ lfact, three of four have reported a higher risk of cardiovascular disease in the beta-carotene groups compared with those receiving placebo. The research implies that a full-spectrum of carotenes or more significant carotenes like lycopene or lutein would offer the greatest degree of pr~tection.l-~J~,~~,~~-~ Just as in cancer, a potential problem with much research on carotenes in cardiovascular disease protection has been the focus on beta-carotene. It may not be the most important marker of protection. A large clinical study evaluating the relationship between carotene status and heart attack (acute myocardial infarction) found that lycopene, but not beta-carotene, was p r ~ t e c t i v e . ~ ~ Lycopene exerts greater antioxidant activity compared with beta-carotene in general but specifically against LDL oxidation.52-M Betacarotene is likely of less importance compared with many other carotenes, especially lycopene and lutein, because it does not get incorporated into LDL effectively, though it may help protect the endothelium.&Lutein may turn out to be the most significant carotene in the battle

against atherosclerosis. On the basis of analysis of the different subtypes of LDL, it was found that lycopene, beta-carotene, and cryptoxanthin were mainly located in the larger, less-dense LDL particles, whereas lutein and zeaxanthin were found preferentially in the smaller, denser LDL parti~les.5~ Since the smaller, denser LDL subtype is most easily oxidized, lutein and zeaxanthin are particularly important in protecting against damage to LDL cholesterol. Despite the focus on protecting LDL cholesterol from damage, it appears that the protective effect of carotenes against the development of atherosclerosisdoes not occur early in the progression (i.e., they exert little effect on protecting against oxidative damage to LDL cholesterol), but rather later on by some undetermined mechanism. This conclusion is based on studies indicating that carotenoid-enriched diets are associated with less atherosclerotic plaque formation.

Immune Enhancement Carotenes have demonstrated a number of immmeenhancing effects in recent s t u d i e ~However, .~ these effects were demonstrated as far back as 1931, when it was found that a diet rich in carotenes, as determined by blood carotene levels, was inversely related to the number of school days missed by children.%Originally it was thought that the immune-enhancing properties of carotenes were due to their conversion to vitamin A. Now it is known that carotenes exert many immune system-enhancing effects independent of any vitamin A activity? In a recent study the relationship of plasma concentrations of six major carotenoids (beta-carotene, alphacarotene, beta-cryptoxanthin, lycopene, lutein, and zeaxanthin) with the incidence and severity of acute respiratory infections was determined. The incidence rate ratio of acute respiratory infections at high beta-carotene status was 0.71 (95% confidence interval [CI] 0.54 to 0.92) as compared with the low beta-carotene concentration group. Interesting, alpha-carotene, beta-cryptoxanthin, lycopene, lutein, and zeaxanthin were not related to incidence or severity of infections, indicating that beta-carotene may exert the most significant immuneenhancing effe~ts.5~ One of the most impressive studies with supplemental beta-carotene was conducted on normal human volunteers.% Results demonstrated that oral beta-carotene (180 mg/day, approximately 300,000 international unit [ILJ]) sigruficantly increased the frequency of OKT4-t (helper/inducer T cells) by approximately 30% after 7 days, and of OKT3-t (all T cells) after 14 days.“ As T4-t lymphocytes play a critical role in determining host immune status, this study indicates that oral beta-carotene may be effective in increasing the immunologic competence of the host in conditions characterized by a selective diminution of the T4 subset of T cells,

such as the acquired immunodeficiencysyndrome (AIDS) and cancer. However, rather than supplementing the diet with synthetic beta-carotene, it may be more advantageous to use natural carotene sources or to increase the intake of carotene-rich foods. In another study, 126healthy college students were randomly assigned to one of the following groups: Group A, the control group Group B, a group that used a 15-mg (25,000 IU)betacarotene supplement daily Group C, a group that consumed approximately 15mg beta-carotene per day from carrots Better results (i.e., increase in white blood cell number and function) were achieved in the group eating the carrots.59 As the absorption studies have shown supplemental beta-carotene to be much better absorbed than the carotenes from carrots and other vegetables, the differences are likely the result of form (i.e., natural is better than synthetic)?

Vaginal Candidiasis It is a well-established fact that women are more susceptible to vaginal candidiasis when the immune system is depressed, which may be due to low carotene levels. Betacarotene levels were determined in exfoliated vaginal cells in 22 women with vaginal candidiasisand compared with vaginal cells from 20 controls. The beta-carotene level per 1million cells in the women with va@ candidiasis was 1.46 ng compared with 8.99 ng in the control group (i.e., one-sixth that of normal).60 These results, coupled with beta-carotene’s known effects on enhancing the immune system, suggest that a low tissue level of beta-carotene is associated with vaginal candidiasis, and a high dietary or supplemental intake of beta-carotene may be protective against vaginal candidiasis.

Photosensitivity Disorders kta-carotene has become the treatment of choice for photosensitivity disorders. It is most effective in the treatment of erythropoieticprotoporphyria (EPP).Its effectiveness in other photosensitivity disorders such as polymorphous light eruption, solar urticaria, and discoid lupus erythematosus is sigruficant but not as great?149 Beta-carotene also has a small but sigruficant effect in increasing the exposure at which manifestations of sunburn begin, thus allowing some subjects the opportunity to stay in the sun long enough to get a “tan” for the first Patients with EPP are characterized by elevated levels of porphyrins in blood, feces, and skin and by sensitivity to visible light. This sensitivity manifests after exposure to sunlight as a burning sensation followed by swelling

Beta-carotene and Other Carotenoids

and redness. Topical sunscreens are of no value. The photosensitivity is due to excitation of the porphyrin molecule by ultraviolet radiation, resulting in the production of free radicals that are deleterious to the skin. Direct cell damage results in the release of chemical mediators, which in turn damage other cells, resulting in the manifestations of itching, burning, redness, and swelling. In EPP it appears that carotene levels must be maintained in the blood at 600 to 800 Fg/d for optimum effects and that the protective effect is not usually observed until after 4 to 6 weeks of therapy. The actions of betacarotene and other carotenes in human tissue are similar to their action in plant cells (i.e., they function as a cellular screen against sunlight-induced free radical damage).

DOSAGES For carotenes, a daily dosage of 25,000 IU (15 mg of betacarotene) appears to be reasonable for general health. Mixed carotene preparations are preferred to isolated beta-carotene supplements to provide the full range of carotenes in a natural form. For the treatment of precancerous lesions and immune enhancement, the dosage range is 25,000 to 300,000 IU. In the treatment of EPP, the dosage is based on maintaining blood carotene levels between 600 and 800 yg/dl. Again, for the best clinical impact, it appears that natural mixed forms of carotene should be used in conjunction with a broad range of other natural antioxidants (see Chapter 109).

high doses in the treatment of numerous photosensitivity disorders (see earlier discussion). Occasionally patients complain of loose stools, which usually clears spontaneously and does not necessitate stopping treatment. Elevated carotene levels in the blood do not lead to vitamin A toxiaty, nor do they lead to any other sigruficant disturbance besides yellowing of the skin (carotenodermia). The ingestion of large amounts of carrots or carrot juice (0.45 to 1 kg/day of fresh carrots for several years) has, however, been shown to cause neutropenia, as well as menstrual disorder^.^^,^^ Although the blood carotene levels of these patients did reach levels (221 to 1007 pg/ dl) similar to those of patients taking high doses of betacarotene (typically 800 pg/dl), the disturbances are due to some other factor in carrots, as neither of these effects nor any others have been observed in subjects consuming high doses of pure beta-carotene (e.g., 300,000 to 600,000 IU/day [180 to 360 mg beta-carotene], which is equivalent to 4 to 8 lb of raw carrots) over long periods of time.n-76Doses up to 1000 mg/kg have been given to rats and rabbits for long periods of time with no signs of embryotoxicity, toxicity, tumorigenicity, or interference in reproductive functions."

DRUG INTERACTIONS

Supplementing the diet with beta-carotene has not been shown to possess any sigruficant toxiaty despite its use in

One study showed that beta-carotene in combination with selenium, vitamin C, and vitamin E appeared to decrease the effectiveness of the combination of simvastatin (Zocor) and niacin. The researchers proposed that this inhibition of HMG-CoA reductase inhibitors could reduce the effectivenessof similar drugs such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), and pravastatin ( P r a v a c h ~ l ) . ~ ~

1.Krinsky NI. The antioxidant and biological properties of the carotenoids. Ann N Y Acad Sci 1998;854:443-447. 2. Russell Rh4. Physiological and clinical sigruficance of carotenoids. Int J Vitam Nutr Res 1998;68:349-353. 3. Tapiero H, Townsend DM, Tew KD. The role of carotenoids in the prevention of human pathologies. Biomed Pharmacother 2004;58: 100-110. 4. Mangels AR, Holden JM, Beecher GR, et al. Carotenoid content of fruits and vegetables: an evaluation of analytic data. J Am Diet Assoc 1993;93284-296. 5. Brown ED, Micozzi MS, Craft NE, et al. Plasma carotenoids in normal men after a single ingestion of vegetables or purified betacarotene. Am J Clin Nutr 1989;49125&1265. 6.Nierenberg DW, Dain BJ, Mott LA, et al. Effects of 4 y of oral supplementation with beta-carotene on serum concentrations of retinol, tocopherol, and five carotenoids. Am J Clin Nutr 1997;66: 315-319. 7. Kostic D, White WS, Olson JA. Intestinal absorption, serum clearance, and interactionsbetween lutein and beta-carotenewhen administered

to human adults in separate or combined oral doses. Am J Clin Nutr 1995;62604-610. 8.van het Hof KH, Brouwer LA, West CE, et al. Bioavailability of lutein from vegetables is 5 times higher than that of beta-carotene. Am J Clin N u b 1999;70261-268. 9. Brubacher GB, Weiser H. The vitamin A activity of beta-carotene. Int J Vitam Nutr Res 1984;555-15. 10. Selhorst JB, Waybright EA, Jennings S, et al. Liver lover's headache: pseudotumor m b r i and vitaminA intoxication.JAMA 1984;2523365. 11. Ganguly J, Sastry PS. Mechanism of conversion of beta-carotene into vitamin A-central cleavage versus random cleavage. World Rev Nutr Diet 1985;45198-220. 12. Olson JA. Serum levels of vitamin A and carotenoids as reflectors of nutritional status. J Natl Cancer Inst 1984;731439-1444. 13. Krinsky NI.Antioxidant function of carotenoids. Free Radic Biol Med 1989;7617-635. 14.Cutler RG. Carotenoids and retinol: their possible importance in determining longevity of primate species. Proc Natl Acad Sci U S A 1984;81:7627-7631.

TOXICIN

15. Murakoshi M, Nishino H, Satomi Y, et al. Potent preventive action of alpha-carotene against carcinogenesis:spontaneousliver carcinogenesis and promoting stage of lung and skin carcinogenesis in mice are suppressed more effectively by alpha-carotene than by betacatonene. Cancer Res 1992326583-6587. 16.Hwang ES, Bowen PE. Can the consumption of tomatoes or lycopene reduce cancer risk? Integr Cancer Ther 2002;1:121-132. 17. Weisburger JH. Lycopene and tomato products in health promotion. Exp Biol Med 2002;227924927. 18. Alves-Rodrigues A, Shao A. The science behind lutein. Toxic01 Lett 2004;15057-83. 19. Granado F, Olmediia 8, Blanco I. Nutritional and clinical relevance of lutein in human health. Br J Nutr 2003;90:487-502. 20. Mares-Perlman JA, Millen AE, Ficek TL, et al. The body of evidence to support a protective role for lutein and zeaxanthin in delaying chronic disease.J Nutr 2002;1325185524S. 21. Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophysics 1989;274532-538. 22. Franceschi S, Bidoli E, LaVecchia C, et al. Tomatoes and risk of digestive-tract cancers. Int J Cancer 1994;59:181-184. 23. Bendich A. Beta-carotene and the immune response. Proc Nutr Soc 1991;50:263-274. 24. Folman Y, Rosenberg M, Ascarelli I, et al. The effect of dietary and climatic factors on fertility, and on plasma progesterone and oestradiol-17 beta levels in dairy cows. J Steroid Biochem 1983;19 863-868. 25. [No authors listed]. Metabolism of beta-carotene by the bovine corpus luteum. Nutr Rev 1983;41:357-358. 26. Lotthammer KH. Importance of beta-carotene for the fertility of dairy cattle. Feedstuffs 1979;51:16-19. 27. O'Fallon JV, Chew BP. The subcellular distribution of betacarotene in bovine corpus luteum. Proc Soc Exp Biol Med 1984;1773 406-411. 28. Sherman BM, Korenman SG.Inadequate corpus luteum function: a pathophysiological interpretation of human breast cancer epidemiology. Cancer 1974333306-1312. 29. Ben-Amok A, Mokady S, Edelstein S, et al. Bioavailability of a natural isomer mixture as compared with synthetic all-trans-betacarotene in rats and chicks. J Nutr 1989;1191013-1019. 30. Mokady S, Avron M, Ben-Amok A. Accumulation in chick livers of 9 4 s versus all-trans beta-carotene. J Nutr 1990;120:889-892. 31. Carughi A, Hooper FG. Plasma carotenoid concentrations before and after supplementation with a carotenoid mixture. Am J Clin Nutr 1994;59:896-899. 32. Zhang J, Wang CR, Xue AN, et al. Effects of red palm oil on serum lipids and plasma carotenoidslevel in Chinese male adults. Biomed Environ Sci 2003;16:348-354. 33. Morinobu T, Tamai H, Murata T, et al. Changes in betacarotene levels by long-term administration of natural beta-carotene derived from Dunaliella bardawil in humans. J Nutr Sci Vitamin01 1994;40:421430. 34. Ziegler RG. A review of the epidemiologic evidence that carotenoids reduce the risk of cancer. J Nutr 1989;119:116-122. 35. National Research Council. Diet and health: implications for reducing chronic disease risk. Washington, DC:National Academy Press, 1989313-314. 36.Mannisto S, Smith-Warner SA, Spiegehnan D, et al. Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies. Cancer Epidemiol Biomarkers Prev 2004;13:40-48. 37. Gerster H. Anticarcinogenic effect of common carotenoids. Int J Vitam Nutr Res 1993;63:93-121. 38. [No authors listed]. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. N Engl J Med 1994;3301029-1035.

39. Leo MA, Kim C, Lowe N, et al. Interaction of ethanol with betacarotene: delayed blood clearance and enhanced hepatotoxicity. Hepatology 1992;15:883-891. 40.Krinsky NI. The biological properties of carotenoids. Pure Appl Chem 1994;66:1003-1010. 41. Krinsky NI. Antioxidant functions of carotenoids. Free Radic Biol Med 1989;7617-635. 42. Omenn GS, Goodman G, Thomquist M, et al. The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers. Cancer Res 1994;54:2038~-2043s. 43. Rowe PM. Beta-carotene takes a collective beating. Lancet 1996; 347249. 44. Garewal H, Shamdas GJ. Intervention trials with beta-carotene in precancerous conditionsof the upper aerodigestivetract. In BendichA, Butterworth CE, eds. Micronutrients in health and in disease prevention. New York Marcel Dekker, 1991:127-140. 45. Toma S, Benso S, Albanese E, et al. Treatment of oral leukoplakia with beta-carotene.Oncology 1992;4977-81. 46.Blot WJ, Li JY, Taylor PR, et al. The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr 1995;62 142451426s. 47.Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993;851483-1492. 48. Gann PH, Ma J, Giovannucci E, Wdett W, et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 1999;59:1225-1230. 49. Kucuk 0,Sarkar FH, Sakr W, et al. Phase 11 randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev 2001;10861-868. 50. Awari MS, Gupta NP.A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int 200392375-378. 51. Street DA, Comstock GW, Salkeld RM, et al. Serum antioxidants and myocardial infarction. Are low levels of carotenoidsand alphatocopheral risk factors for myocardial infarction? Circulation 1994; 901154-1161. 52.Kohlmeier L, Kark JD,Gomez-Gracia E, et al. Lycopene and myocardial infarction risk in the EURAh4IC Study. Am J Epidemiol 1997;146:61&626. 53.Rao AV, Agarwal S. Role of antioxidant lycopene in cancer and heart disease. J Am Coll Nutr 2000;19563-569. 54. Agarwal S, Rao AV. Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study. Lipids 199833: 981-984. 55. Lowe GM, Bilton RF,Davies IG, et al. Carotenoid composition and antioxidant potential in subfractions of human low-density lipoprotein. Ann Clin Biochem 1999;36323-332. 56. Clausen SW. Carotenemia and resistance to infection. Trans Am Pediatr Soc 1931;4327-30. 57. van der Horst-Graat JM, Kok FJ, Schouten EG. Plasma carotenoid concentrations in relation to acute respiratory infections in elderly people. Br J Nutr 2004;92113-118. 58.Alexander M, Newmark H, Miller RG. Oral beta-carotene can increase the number of OKTet cells in human blood. Immunol Lett 1985;9221-224. 59.Brevard PB. Beta-carotene affects white blood cells in human peripheral blood. Nutr Rep Int 1989;40:139-150. 60.Mikhail MS, Palan PR, Basu J, et al. Decreased beta-carotene levels in exfoliated vaginal epithelial cells in women with vaginal candidiasis. Am J Reprod Immunol1994;32221-225. 61. Mathews-Roth MM, Pathak UA, Fitzpatrick TB, et al. Beta-carotene as an oral photoprotective agent in erythropoietic protoporphyria. JAMA 1974;2281004-1008.

Beta-caroteneand Other Carotenoids 62. Mathews-Roth MM, Pathak UA, Fitzpatrick TB, et al. Beta carotene therapy for erythropoietic protoporphyria and other photosensitivity diseases. Arch Dermatol1977;1131229-1232. 63. Mathews-Roth MM. Photosensitization by porphyrins and prevention of photosensitization by carotenoids. J Natl Cancer Inst 1982;69:279-285. 64.Mathews-Roth MM. Treatment of erythropoietic protoporphyria with beta-carotene. Photodermatology 1984;1:318-321. 65. Wennersten G. Carotenoid treatment for light sensitivity: A reappraisal and six years’ experience. Acta Derm Vernereol 1980;60: 251-255. 66.Swanbeck G, Wennersten G. Treatment of polymorphous light eruptions with beta-carotene. Acta Derm Venereol1972;52462-466. 67. Newbold PC. Beta-carotene in the treatment of discoid lupus erythematosus. Br J Dermatol1976;95:100-101. 68. Fusaro RM, Johnson JA. Hereditary polymorphic light eruption in American Indians - photoprotection and prevention of streptococcal pyoderma and glomerulonephritis. JAMA 1980;244:1456-1459. 69. Mathews-Roth MM, Pathak MA, Parrish J ,et al. A clinical trial of the effects of oral beta-carotene on the responses of human skin to solar radiation. J Invest Dermatol1972;59349-353.

70. Shoenfeld Y,Shaklai M, Ben-Baruch N, et al. Neutropenia induced by hypercarotenemia. Lancet 1982;1:1245. 71. Kemmann E, Pasquale SA, Skaf R. Amenorrhea associated with carotenemia. JAMA 1983;249:926-929. 72. Mathews-Roth MM. Neutropenia and beta-carotene. Lancet 1982;2222. 73.Stampfer MJ, Willett W, Hennekens CH. Carotene, carrots, and white blood cells. Lancet 1982;2615. 74. Mathews-Roth MM, Abraham AA, Gabuzda TG. Beta-carotene content of certain organs from two patients receiving high doses of beta-carotene. Clin Chem 1976;22:922-924. 75. Mathews-Roth MM. Amenorrhea associated with carotenemia. JAMA 1983;250.731. 76. Poh-Fitzpatrick MB, Barbera LG. Absence of crystalline retinopathy after long-term therapy with beta-carotene. J Am Acad Dermatol 1984;11:111-113. 77. Heywood R, Palmer AK, Gregson RL, et al. The toxicity of betacarotene. Toxicology 19859691-100. 78. Brown BG, Zhao XQ, Chait A. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-1593.

Boron Peter B. Bongiorng, ND, Dip1 Ac Gregory S. Kelly, ND (:HAPTEK CONTENTS Introduction 783

Hormone Interactions 787

Sources 783

Clinical Applications 787 Osteoporosis 787 Osteoarthritis and Rheumatoid Arthritis Prostate Cancer 788

Metabolism 784 Chemical Properties 784 Biochemistry 784 Biologic Functions 785

Dosage 788

Deficiency Signs and Symptoms 785

Toxicology 788

Nutrient Interactions 786 Vitamin D 786 Calcium 786 Copper 786 Magnesium 786 Phosphorus 786 Methionine and Arginine 786

Drug Interactions 789

INTRODUCTION Boron is an ubiquitous constituent of man's external environment. It typically occurs in nature as borates hydrated with varying amounts of water. Boric acid and borax are important boron-containing compounds.' In trace amounts boron is essential for the growth of many plants, and it is found in animal and human tissues at low Concentrations.' In plasma boric acid is the predominate form, and its concentration reflects dietary intake and respiratory exposure? Although it has yet to be recognized as an essential nutrient for humans, recent data from animal and human studies suggest that boron is important for many life processes including embryogenesis; bone growth; immune function; psychomotor skill; cognitive function3; mineral metabolism; brain function and performance; and prevention of osteoporosis, osteoarthritis, and possibly prostate cancer.

SOURCES Because boron in plants depends on the availability of boron in the Samefood can greatly in boron content depending on where and how it is grown.

787

Summary 789

In general, soils exposed to high degrees of precipitation have decreased levels of boron? Food processing results in additional loss of boron? Foods of plant origin, such as leafy vegetables, noncitrus fruits, nuts, legumes, and sea vegetables are considered the best sources of boron.'J6 Wine has also been shown to contribute appreciable amounts of boron to the diet? A diet containing an abundance of these items would provide 2 to 6 mg/day of boron.6,8 Daily intake of boron depends on several variables. Concentration of boron in water varies considerably according to geographic source. In some areas boron in drinking water and water-based beverages may account for most of the total dietary boron intake. Individual food preference greatly influences daily intake of boron. Fruits, vegetables, tubers, and legumes have higher concentrations of boron than do cereal grains or animal tissues. For adults and seniors, though, the largest source of boron turns out to be instant regular coffee? Given the poor dietary intake of produce in the United States, the top two boron contributors to adult boron intake, coffee and The original version of this chapter was reprinted with permission from Alternative Medicine Review 1997;2:48-56.

783

Pharmacology of Natural Medicines milk, are actually deficient in this nutrient (Table 72-1)'O compared with other more nutritious foods. Nevertheless, these make up 12% of the total boron intake by virtue of the volume consumed.1°Boron has also been determined to be a notable contaminant or major ingredient of many personal care products, and it is occasionally used (boric acid) as a food preservative." In Sydney, Australia, 32 subjects age 20 to 53 years old were assessed over a 7-day period for their dietary intake of boron. The average boron intake in male and female subjects was found to be 2.28 k 1.3 and 2.16 f 1.1mg/day, respectively.' The boron content of selected Australian foods has been found to correlate with values in Finnish and U.S.Food and Drug Administration tables and is presented in Table 72-2.7

I

Concentration of boron in selected Australian foods

Food Almonds Apples (red) Apricots (dried) Avocados Bananas Beans (red kidney) Bran (wheat) Brazil nuts Broccoli Carrots Cashews (raw)

METABOLISM Chemical Properties

Celery Chick peas

Elemental boron was first isolated in 1808. It is the first member (atomic number 5) of the metalloid or semiconductor family of elements including silicon and germanium and is the only nonmetal of the group IIIA elements. Like carbon, boron has a tendency to form double bonds and macromolecules.'* Boron, as boric acid, acts as a Lewis acid, accepting hydroxyl (OH-) ions and leaving an excess of pr0t0ns.l~Because boron complexes with organic compounds containing hydroxyl groups, it interacts with sugars and polysaccharides, adenosine5-phosphate, pyridoxine, riboflavin, dehydroascorbic acid, and pyridine nu~leotides.'~ Borate cross-links with polysaccharides, most likely as borate di-esters, to form gels with unique properties. These gels are plastic in nature and quickly reassemble in response to externally applied stress.I3 Five naturally occurring boron ester compounds have been identified as antibiotic^.'^ ~

Coffee, from ground beans Milk, whole Apples, raw Beans, refried Potatoes, from French fries Orange juice Peanut butter Wine Apple juice Cola

Boron (mg/ml)

0.029 0.018 0.36 0.4 0.11 0.072 1.145 0.61 0.18 0.013

Modified from Rainey CJ, Nyquist LA. Christensen RE, et al. J Am Diet Assoc

1999;99:335-340.

Hazelnuts Honey Lentils Olives Onions Oranges Peaches Peanut butter Pears Potatoes Prunes Raisins Walnuts Wine (Shiraz Cabernet)

2.82 0.32 2.11 2.06 0.16 1.4 0.32 1.72 0.31 0.3 1.15 0.5 0.71 1.08 0.5 2.77 0.5 0.74 0.35 0.2 0.25 0.52 1.92 0.32 0.18 1.18 4.51 1.63 0.86

~~

Top contributors of dietary boron in the American diet Food

Dates Grapes (red)

Boron (rngll00g)

Biochemistry Boron in food, sodium borate, and boric acid are well absorbed from the digestive tract.I6 These compounds are also absorbed through damaged skin and mucous membranes; however, they do not readily penetrate intact skin.I7 No accumulation of boron has been observed in soft tissues of animals fed chronic low doses of boron; however, in acute poisoning incidents, the amount of boric acid in brain and liver tissue has been reported to be as high as 2000 ppm. Within a few days of consumption of large amounts of boron, levels in blood and most soft tissues quickly reach a plateau.18 Tissue homeostasis is maintained by the rapid elimination of excess boron, primarily in the urine, with bile, sweat, and breath also contributing as routes of e1iminati0n.I~In humans,

Boron urinary boron excretion increases over time in all boronsupplemented subjects who have been studied.I9 Evidence suggests that supplemental boron does accumulate in bone; however, cessation of exposure to dietary boron results in a rapid drop in bone boron levels. The half-life of boric acid in animals is estimated at about 1day.18

Biologic Functions Boron contributes to living systems by acting indirectly as a proton donor and exerting an influence on cell membrane structure and function.20 Although the absolute essentiality of boron for plants is well documented, studies to date have not shown it to be unequivocally essential for either animals or humans. However, boron supplementation has been shown to affect certain aspects of animal physiologic function. Experimental animals supplemented with boron demonstrate a high degree of variability in their response. In general, supplemental dietary boron has its most marked effects when the diet is deficient in known nutrients.2I Evidence suggests that boron might have a slight effect on decreasing fasting serum glucose concentrations in postmenopausal women.I5

Embryo Maturation Emerging research has shown that boron is an important player in the early stages of life? Boron defiaency negatively affects reproductive ability, as well as embryo development in both the African clawed frog (Xenopus laatis) and the zebrafish. Experimentation with Xenopus noted that dietary boron deprivation elicited necrotic egg increases combined with a high frequency of abnormal gastrulation. In the zebrafish model, 45% of borondeprived embryos died during the early postfertilization period. Conversely, only 2% of boron-supplemented embryos died. Other studies with rats and mice corroborate that low boron status may affect reproduction in mammals, although conclusions from these studies are not as clear.

Life Span Boron in an animal model has been shown to affect life span, although the process is undefined. Extremes in dietary boron, both a deficiency and an excess, decreased the median life span of Drosophila by 69%,while supplementing the diet with low levels of boron increased life span by 9.5%.=

Brain Function Brain electrophysiology and cognitive performance were assessed in response to dietary manipulation of boron (~0.25 vs. ~ 3 . 2 5mg boron/2000 kcal/day) in three studies with healthy older men and women. A low boron intake was shown to result in a decrease in the

proportion of power in the alpha band and an increase in the proportion of power in the delta band. Other changes in left-right symmetry and brain wave coherence were noted in various sites, indicating an influence on brain function. When contrasted with the high boron intake, low dietary boron resulted in significantly poorer performance (p < 0.05) on tasks emphasizing manual dexterity, eye-hand coordination, attention, perception, encoding, and short- and long-term memory. Collectively, the data from these studies indicate that boron may play a role in human brain function, alertness, and cognitive performance.23

Hematologic Boron supplementation to human subjects who had previously followed a dietary regimen deficient in boron increased blood hemoglobin concentrations, mean corpusd a r hemoglobin, and mean corpuscular hemoglobin concentration.It lowered hematocrit, red cell count, and platelet

Hepatoprotection Studies of fulminate hepatic failure in Wistar rat models have shown boron pretreatment to significantly reduce lipid peroxidation, as well as decrease serum liver enzymes in these animals. Boron pretreatment also increased the peroxide-metabolizing enzymes levels of glutathione peroxidase and catalase.%

Mineral Metabolism Boron also affects mineral metabolism and has been shown to affect levels of certain hormones in human subjects. In the first nutritional study with humans involving boron,” postmenopausal women first were fed a diet that provided 0.25 mg boron/2000 kcal for 119 days and then were fed the same diet with a boron supplement of 3 mg boron/day for 48 days. The boron supplementation reduced the total plasma concentration of calcium and the urinary excretions of calcium and magnesium and elevated the serum concentrations of 17 beta-estradiol and testosterone.6 In a study designed to determine the effects of boron supplementation on blood and urinary minerals in athletic subjects on Western diets, findings suggested that boron supplementation modestly affected mineral status.Ig

DEFICIENCY SIGNS AND SYMPTOMS Information on boron deficiency is limited, especially in humans. It is thought that insufficient intake of boron becomes obvious only when the body is stressed in a manner that enhances the need for it. When the diets of animals and humans are manipulated to cause functional deficiencies in nutrients such as calcium, magnesium,

vitamin D, and methionine, a large number of responses to dietary boron occur.26 Evidence suggests that more than 21 days on a boron-deficient diet are required to demonstrate detectable effects in humans.27The variables that are changed due to a boron-deficient diet abruptly improve about 8 days after boron supplementation is introduced.6 Evidence indicates that hemodialysis results in an excessive decrease in serum boron as compared with controls.28Although by no means is blood urea nitrogen pathognomonic for a boron deficiency, it has been found to be slightly elevated during boron depletion.B

NUTRIENT INTERACTIONS Vitamin D Considerable evidence indicates that dietary boron alleviates perturbations in mineral metabolism that are characteristic of vitamin D3 deficiency.30In one study chicks fed on a diet inadequate in vitamin D exhibited decreased food consumption and plasma calcium concentrations and increased plasma concentrations of glucose, beta-hydroxybutyrate, triglycerides, triiodothyronine, cholesterol, and alkaline phosphatase activity after 26 days. Supplementalboron returned plasma glucose and triglycerides to concentrations exhibited by chicks fed on a diet adequate in vitamin D.31 In rachitic chicks, boron elevated the numbers of osteoclasts and alleviated distortion of the marrow sprouts of the proximal tibia1 epiphysial plate, a distortion characteristic of vitamin D3 deficiency.3032Higher apparentbalance values of calcium, magnesium, and phosphorus have been observed for rats fed on a vitamin D-deprived diet if the diet is supplemented with boron.21 After supplementation with 3.25 mg boron daily, plasma levels of D2 increased in men older than age 45 and postmenopausal women on low magnesium and copper diets.33

Calcium Boron supplementation may have a favorable impact on calcium metabolism. A boron supplement of 3 mg/ day affected several indices of mineral metabolism of seven women consuming a low-magnesium diet and five women consuming a diet adequate in magnesium; the women had consumed a conventional diet supplying about 0.25 mg boron/day for 119 days. Boron supplementation modestly reduced the urinary excretion of calcium when dietary magnesium was low? In men older than age 45 and postmenopausal women, changes caused by boron supplementation include increased concentration of plasma ionized and total calcium, as well as reduced serum calcitonin concentration and urinary excretion of calcium.33 A 1993 study demonstrated that a low boron diet elevated

urinary calcium excretion. The high level of calcium excretion was maintained throughout the &week study; however, it remained elevated even after boron supplementa tion began.%

Copper Supplemental boron ads to increase serum levels of both copper and copper-dependent enzymes in humans. Boron supplementation (3 mg/day) to five men older than age 45, four postmenopausal women, and five postmenopausal women on estrogen therapy who had been fed a low boron diet (0.23 mg/2000 kcal) for 63 days resulted in higher erythrocyte superoxide dismutase, serum enzymatic ceruloplasmin, and plasma copper.33In a subsequent study, these same variables were again found to be higher during boron repletion than while subjects were fed on a diet low in boron.=

Magnesium When magnesium deprivation is severe enough to cause typical signs of deficiency, a significant interaction between boron and magnesium is found.12 A combined deficiency of boron and magnesium causes detrimental changes in the bones of animals.Supplemental boron elevates plasma Mg concentrations and enhances Boron supplementationhas resulted in inmased serum magnesium concentrations in human female subjects studied.ls Boron supplementation increases red blood cell magnesium concentrations.36It has been shown that serum magnesium concentrations are greater in sedentary females whose diets are supplemented with boron than in exercising female athletes who are supplemented with boron.37This finding, while unexplained to date, may indicate a n increased loss of boron through urine and perspiration during exercise.

Phosphorous Supplemental boron seems to lower serum phosphorus concentrations in female subjects 20 to 27 years old?’ However, exercise training diminishes these changes,’8 again possibly indicating increased losses or an increased need for boron as a result of exercise. A low magnesium status, along with supplementation of boron, may depress the urinary excretion of phosphorus. This does not occur in women with an adequate magnesium intake:

Methionine and Arginine In experimental animals, a beneficial impact is consistently observed after boron supplementation when the diet contains marginal methionine and excessive arginine. Among the signs exhibited by rats fed on a diet marginal in methionine and magnesium are depressed growth and bone magnesium concentration and elevated spleen weight/body weight and kidney weight/body weight ratios. Findings indicate that the

Boron

severity of these symptoms is alleviated with boron ~upplementation.~~

HORMONE INTERACTIONS

Boron's observed impact on

selected hormones Hormone Alkaline phosphatase

Increases

Decreases X

In rats, supplemental dietary boron substantially X Aspartate transaminase' depressed plasma insulin, plasma pyruvate concentraX Calcitonin tions, and creatine kinase activity and increased plasma X Cholecalciferol thyroxine (T4) concentrations. Boron supplementation X also decreased plasma aspartate transaminase a~tivity.3~ Creatine kinase* X 17 beta-estradiolt In animal experiments, boron supplementation offsets the elevation in plasma alkaline phosphatase caused by Insulin" vitamin D defi~iency.~~ Superoxide dismutase One researcher has hypothesized that boron might be Testosterone+ required for the synthesis of steroid hormones, as well as Thyroxine* vitamin D. Because the biosynthesis of steroids such as vitamin D, testosterone, and 17 beta-estradiol involves 'These interactions have only been demonstrated in animal models. These interactions have not been demonstrated unequivocally to date in all age one or more hydroxylation steps, and because of boron's and gender segment of a human population. ability as a Lewis acid to complex with hydroxyl groups, boron may assist the addition of hydroxyl groups to the steroid structures.6It has also been suggested that boron may act in an unspecified manner to protect hormones from rapid inactivation.6The current hypothesis suggests CLINICAL APPLICATIONS that boron can inhibit a range of microsomal enzymes Osteoporosis that insert hydroxyl groups near existing hydroxyls in steroids. These enzymes include those that catabolize A considerable body of evidence has shown that both compositional and functional properties of bone 25-hydroxyvitamin D.40Researchers supplemented boric are affected by boron statusa In experimental animals, acid to rat drinking water and observed significant histologic findings suggest that supplemental boron elevations in the plasma 1,25-dihydroxyvitamin D conenhances maturation of the growth ~ l a t e . 2Boron ~ is centration at week 2 and the plasma testosterone concenalso found at the highest concentrations in growing and tration at week 4 relative to the control gr0up.4~ calclfylng areas of long bones6 In two human studies, An increase in dietary intake of boron from 0.25 to boron deprivation caused changes in indices associated 3.25 mg/day has been reported to increaseplasma 17betawith calcium metabolism in a manner that could be estradiol by more than 50% and to more than double construed as being detrimental to bone formation and plasma testosterone levels in postmenopausalwomen. The maintenance; these changes were enhanced by a diet low elevation seemed more marked when dietary magnesium in m a g n e ~ i u m .The ~ , ~author ~ concluded that boron and was low! In a subsequent study of healthy men, boron magnesium are apparently necessary for optimal calsupplementation resulted in an increase in the concentracium metabolism and are thus necessary to prevent the tions of both plasma estrogen and testosterone; however, excessive bone loss that often occurs in postmenopausal not all published trials support these observations? women and older men.29 Ten male bodybuilders, 20 to 26 years old, were given a 2.5 mg boron supplement, while nine male bodyOsteoarthritis and Rheumatoid Arthritis builders, 21 to 27 years old, were given a placebo for A dietary boron deficiency may be a contributing factor in 7 weeks. Because both groups demonstrated sigruficant some cases of arthritis.44In areas of the world where boron increases in total testosterone (p < 0.01), lean body mass intake is routinely 1 mg/day or less, the estimated inci( p < O.Ol), one repetition maximum squat (p < 0.001), and dence of arthritis ranges from 20% to YO%, whereas in bench pressing (p < 0.01), the authors concluded that the areas where boron intake ranges from 3 to 10 mg/day, the gains were a result of 7 weeks of bodybuilding, not of estimated incidence of arthritis ranges from 0% to boron supplementation.42 Analytic evidence indicates that persons with arthritis Table 72-3 lists boron's impact on selected hormones in either animals or humans. Some of these interactions have lower boron concentrations in femur heads, bones, and synovial fluid when compared with persons withhave only been demonstrated in animal models, while out this disorder. In addition, bones of patients using others have not been demonstrated unequivocally boron supplements are more difficult to cut than those of to date in all age and gender segments of a human patients not taking boron supplements? population.

In 1961 the first anecdotal evidence suggesting that boron may be beneficial for osteoarthritis was presented when one patient had reduced swelling and stiffness and remained symptom free for 1year following supplementation with 3 mg of elemental boron twice daily for 3 weeks. A human study also offers evidence that boron supplementation may be beneficial in the treatment of this condition. In a double-blind, placebo-controlled trial of 20 subjects with osteoarthritis, 50% of subjects receiving a daily supplement containing 6 mg of boron noted a subjective improvement in their condition. Only 10% of those receiving the placebo improved during the same time interval. Greater improvement was noted in the condition of all joints (p < 0.01), as well as less pain on movement (p < 0.001) in subjects receiving the boron ~upplementation.4~ Clinical observations indicate that children with juvenile arthritis (Still disease) improve with boron supplementation (6 to 9 mg/day) in 2 to 3 weeks, while adults with osteoarthritis may require 2 to 4 months of supplementation before benefits are detected. Persons with rheumatoid arthritis may experience an aggravation of symptoms (Herxheimer response) for 1 to 3 weeks but generally notice improvement within 4 weeks of beginning boron ~upplementation.~

groups. Immunohistochemical studies demonstrated significantly less expression of IGF-1 levels, although circulating levels were unchanged among the groups.@ Although the exact mechanism to explain the antiproliferative effect is unclear, boric acid is known to bind to cis-diols on the ribose moiety of nucleotides, forming nucleotide-borate complexes including N A P and Saden~sylmethione.~’ Although not well understood, it is postulated that boric acid’s cellular effect rests in the ability of these complexes to induce changes in the function or utilization of the nucleotides.

Prostate Cancer

Although boron is potentially toxic to all organisms and, as boric acid and borax, has been used as a pesticide and food preservative, higher animals usually do not accumulate boron because of their ability to rapidly excrete it.13 Authenticated cases of poisoning in humans have been few and have primarily been the result of accidental ingestion of insecticides and household products containing borates or use of large amounts of boric acid in the treatment of b ~ r n s . 4 ~ Improper use of boric acid-containing antiseptics is still one of the most common causes of toxic accidents in newborns and infants. Sinceboric acid is readily absorbed through damaged skin, it should not be applied topically to extensive wounds.16 In animals, chronic low-level boron exposure has been shown to cause reduced growth, cutaneous disorders, and suppression of male reproductive system function?O Studies indicate that male rodents suffer testicular atrophy with dietary exposure to boric acid above 4500 ppm and have decreased sperm motility at all exposure levels above 1000 ppm-5I Goats orally dosed with toxic but sublethal amounts of boron show sigruficant increases in packed cell volume, hemoglobin, inorganic phosphate, creatine phosphokinase, conjugated bilirubin, sodium, glucose, cholesterol, and aspartate transaminase. Several serum components were significantly decreased after boron dosing including alkaline phosphatase, magnesium, glutamyltransferase, and potassium. There was also an elevation of

Given that boron may act as a possible modifier of the hormones testosterone and estrogen, some studies have looked into its possible role in prostate cancer. One controlled case study compared the boron intake of 95 prostate cancer cases with that of 8720 male controls. After controlling for age, race, education, smoking, body mass index, dietary caloric intake, and alcohol consumption, thisepidemiologic screening found the risk of prostate cancer to be inversely proportional to dietary intake of boron in a dose-responsive manner.& Other research purports that boron may act as an inhibitor of prostate specific antigen (PSA). It is thought that uninhibited PSA cleaves insulin-like growth factor binding protein-3, providing increased local levels of insulin-like growth factor 1(IGF-1),which then leads to tumor growth. Some in vitro research observes that boric acid indeed inhibits the proliferation of both the hormone-dependent and independent human prostate cancer cell lines in a dose-dependent ma1mer.4~A study of 3 groups of 10 mice were implanted subcutaneously with human prostate adenocarcinoma cells. Two of the murine groups were given boric acid solutions (at 1.7 or 9 mgB/kg/day) by gavage, whereas the control group received only water. After 8 weeks, tumor sues in the boric acid groups were decreased by 38% and 25%, respectively, and serum PSA levels decreased by 88.6% and 86.4%,respectively, as compared with the control group. Additionally, significantly less mitotic figures were seen in the boric acid

DOSAGE The optimal dose of boron for prevention of osteoporosis and proper physiologic function appears to be 3 to 6 mg/day. It is best to obtain boron by means of a diet abundant in fruits, vegetables, legumes, and nuts, but persons whose diets are limited may need a supplement containing 3 mg of elemental boron. In patients with either osteoarthritis or rheumatoid arthritis, a trial period of 2 to 4 months with a dose of 3 mg of boron three times daily seems to be indicated.

TOXICOLOGY

Boron

cerebrospinal fluid monoamine Rats given DRUG INTERACTIONS 2 mg of boron per day in their drinking water also Boron supplementation may increase serum magnesium showed decreases in HDL3 levels, which may confer and estrogen levels. However, no adverse clinical effects increased cardiovascular risk!* have been reported. Humans given 100 mg of boron intravenously or 270 mg of boric acid orally reported no discomfort and showed no obvious signs of t0xicity7~9Drinking water SUMMARY with high boron concentrations in Turkey have not been Although the skeletal response to boron is modified by shown to cause untoward effects in humans exposed other nutritional variables such as calcium, magnesium, over multiple generati0ns.5~ Airborne exposures to boron vitamin D, methionine, and arginine, considerable evioxide and its hydration product, boric acid, have been reported to cause respiratory and eye i r r i t a t i ~ n . ~ ~dence indicates that both compositional and functional properties of bone are affected by boron status. A fatal outcome has been reported following ingestion of Findings suggest that boron is an important nutrient 1g of boric acid by a child; however, adults have survived not only for mineral metabolism but also for varied acute intakes of nearly 300 g.57 aspects of optimal health in humans. Although all pubCommon signs and symptoms of acute boron toxicity lished trials are not in agreement on the impact of boron include nausea, as well as vomiting and diarrhea that supplementation on levels of 17 beta-estradiol and are blue-green in other symptoms seen with testosterone, evidence strongly suggests that boron defiacute exposure are abdominal pain, an erythematousrash ciency results in decreased levels in postmenopausal involving both the skin and mucous membranes, stimuwomen, while supplementation tends to normalize lation or depression of the central nervous system, convulsions, hyperpyrexia, renal tubular damage, abnormal levels in these same women. Boron's impact on sex liver function, and jaundice.16Increased urinary riboflavin hormones in other segments of the population is still equivocal. No evidence exists to suggest that boron supexcretion has also been reported subsequent to acute plementation acts pharmaceutically to increase levels of boric acid ingestion.58Symptoms of chronic intoxication either 17 beta-estradiol or testosterone above normal include anorexia, gastrointestinal disturbances, debility, physiologic levels. confusion, dermatitis, menstrual disorders, anemia, conOn the basis of available information, boron appears vulsions, and alopecia.I6In three cases of work-related to offer benefits in the prevention of osteoporosis and exposure, alopecia signs were reversed when boric acid arthritis. It is also a safe and potentially effective mineral exposure was reduced or elhh1ated.5~ to consider in any treatment regimen for rheumatoid, Because of its ability to increase the excretion of osteoarthritis, and prostate cancer. boron, in cases of toxicity, N-acetylcysteine is the preferred intervention.@'

of boron in nutrition and metabolism. Prog Food Nutr Sci 1993;17331-349. 2. Woods WG. An introduction to boron: history, sources, uses, and chemistry. Env Health Perspect 1994;102(suppl7):5-11. 3.Nielsen FH. The emergence of boron as nutritionally important throughout the life cycle. Nutrition 2OOO;16512-514. 4. Houng K-H. The physiology of boron and molybdenumin plants. In Okajima H, Uritani I, Houng H-K,eds. The siphcance of minor elements on plant physiology. Taipei: ASPAC, Food & Fertilizer Technology Center, 197561-66. 5. Newnham RE. The role of boron in human nutrition. J Appl Nutr 1994;46:81-85. 6. Nielsen FH, Hunt CD, Mullen LM,et al. Effect of dietary boron on mineral, estrogen, and testosterone metabolism in postmenopausal women. FASEB J 1987;1:394397. 7. Naghii MR, Wall PM, Samman S. The boron content of selected foods and the estimation of its daily intake among free-living subjects. J Am Col Nutr 1996;15:614-619. 8. McBride J. Banishingbrittle bones with boron? Agric Res 1987;Nov/ DeC12-13. 1.Naghii MR, Samman S. The role

9.Hunt CD, Meacham SL. Aluminum, boron, calcium, copper, iron, magnesium, manganese,molybdenum,phosphorus, potassium, sodium, and zinc: concentrations in common Western foods and estimated daily intakes by infants; toddlers; and male and female adolescents, adults, and seniors in the United States. J Am Diet AS= 2001;101:1058-1060. 10.Rainey CJ, Nyquist LA, Christensen RE, et al. Daily Boron Intake from the American Diet. J Am Diet Assoc 1999;99: 335-340. 11.Hunt CD, Shuler TR, Mullen LM.Concentration of boron and other elements in human foods and personal-care products. J Am Diet ASOC 1991;91:558-568. 12. Nielsen FH. Boron-an overlooked element of potential nutritional importance. Nutr Today 1988;234-77. 13. Loomis WD, Durst RW. Chemistry and biology of boron. Biofactors 19923:229-239. 14. Zittle CA. Reaction of borate with substances of biological interest. Adv Enzymol Relat Subj Biochem 1951;12:493-527. 15. Hunt CD. Biochemical effects of physiological amounts of dietary boron. J Trace Elem Exp Med 1996;9:185-213.

16. Nielsen FH. Ultratrace minerals: boron. In Shils ME, Young VR,eds. Modem nutrition in health and disease, ed 7. Philadelphia: Lea & Febiger, 198tk281-283. 17. Reynolds JE,ed. Martindale: the extra pharmacopoeia. London: Royal Pharmaceutical Society, 1996:1680. 18.Moseman RF. Chemical disposition of boron in animals and humans. Environ Health Perspect 1994;102:113-117. 19. Meacham SL, Taper LJ, Volpe SL. Effect of boron supplementation on blood and urinary calcium, magnesium, and phosphorus, and urinary boron in athletic and sedentary women. Am J Clin N u b 1995;61:341-345. 20. Barr RD, Barton SA, Schull WJ. Boron levels in man: preliminary evidence of genetic regulation and some implications for human biology. Med Hypotheses 1996;46:286-289. Keenan MJ, Hegsted M, et al. Effects of dietary boron in 21. Dupre JN, rats fed a vitamin Ddeficient diet. Environ Health Perspect 1994;102:5558. 22. Massie HR, Whitney SJ, Aiello VR,et al. Changes in boron concentration during development and ageing of Drosophila and effect of dietary boron on life span. Mech Ageing Dev 1990;53:1-7. 23. Penland JG. Dietary boron, brain function, and cognitive performance. Environ Health Perspect 1994;102(suppl7):65-72. 24. Nielsen FH, Mullen LM, Nielsen EJ. Dietary boron affects blood cell counts and hemoglobin concentrations in humans. J Trace Elem Exp Med 1991;4211-223. 25. Ali S, Pawa S, Abdulla M. Fulminant hepatic failure and its protection by boron. J Hepatol2003~8(suppl2):190. 26. Nielsen FH. New essential trace elements for the life sciences. Biol Trace Elem Res 1990;26-27599-611. 27. Nielsen FH. Facts and fallacies about boron. Nutr Today 1992;27 6-12. 28. Usuda K, Kono K, @chi K, et al. Hernodialysis effect on serum boron level in the patients with long term hemodialysis. Sci Total Environ 1996;191:283-290. 29. Nielsen FH. Studies on the relationship between boron and magnesium which possibly affects the formation and maintenance of bones. Magnes Trace Elem 1990;9:61-69. 3O.Hunt CD. The biochemical effects of physiologic amounts of dietary boron in animal nutrition models. Environ Health Perspect 1994;102(suppl7):3543. 31. Hunt CD,Herbel JL, Idso Jl?Dietary boron modifies the effects of vitamin D3 nutrition on indices of energy substrate utilization and mineral metabolism in the chick. J Bone Miner Res 1994;9:171-182. 32. Hunt CD. Dietary boron modified the effects of magnesium and molybdenum on mineral metabolism in the cholecalciferoldeficient chick. Biol Trace Elem Res 1989;22:201-220. 33. Nielsen FH, Shuler TR, Gallagher SK. Effects of boron depletion and repletion on blood indicators of calcium status in humans fed a magnesium-low diet. J Trace Elem Exp Med 19903:45-54. 34.Beattie JH,Peace HS. The influence of a low-boron diet and boron supplementation on bone, major mineral and sex steroid metabolism in postmenopausal women. Br J Nutr 1993;69871-884. 35. Nielsen FH. Biochemical and physiologic consequences of boron deprivation in humans. Environ Health Perspect 1994;102(suppl7): 59-63. %.Hunt CD, Herbel JL, Nielsen FH.Metabolic responses of postmenopausal women to supplemental dietary boron and aluminum during usual and low magnesium intake: boron, calcium, and magnesium absorption and retention and blood mineral concentrations. Am J Clin Nutr 1997;65:803-813. 37. Meacham SL, Taper LJ, Volpe SL. Effects of boron supplementation on bone mineral density and dietary, blood, and urinary calcium, phosphorus, magnesium, and boron in female athletes. Environ Health Perspect 1994;10279-82.

38.Nielsen FH, Shuler TR, Zimmerman TJ,et al. Magnesium and methionine deprivation affect the response of rats to boron deprivation. Biol Trace Elem Res 1988;1791-107. 39. Hunt CD, Herbel JL. Boron affects energy metabolism in the streptozotocin-injected, vitamin D3deprived rat. Magnes Trace Elem 1991-92;10374386. 40.h4iljkovic D, Miljkovic N, McCarty ME Up-regulatory impact of boron on vitamin D function-does it reflect inhibition of 24-hydroxylase? Med Hypotheses 2004;631054-1056. 41. Naghh MR, Samman S. The effect of boron on plasma testosterone and plasma lipids in rats. Nutr Res 1997;17523-531. 42. Ferrando AA, Green NR. The effect of boron supplementation on lean body mass, plasma testosterone levels, and strength in male bodybuilders. Int J Sport Nutr 1993;3140-149. 43. McCoy H, Kenney MA, Montgomery C, et al. Relation of boron to the composition and mechanical properties of bone. Environ Health Perspect 1994;102:49-53. 44.Newnham RE. Agricultural practices affect arthritis. Nutr Health 1991;789-100. 45.Travers RL, Rennie GC, Newnham RE. Boron and arthritis: the result of a double-blind pilot study. J Nutr Med 1990;1:127-132. 46.Cui Y, Wmton MI, Zhang ZF, et al. Dietary boron intake and prostate cancer risk. Oncol Rep 2004;11:887-892. 47.Barranco WT, Eckhert CD. Boric acid inhibits human prostate cancer cell proliferation. Cancer Lett 2004;21621-29. 48. Gallardc-Williams MT, Chapin RE, King PE, et al. Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice. Toxicol Pathol2004;32:73-78. 49. Locatelli C, Minoia C, Tonini M, et al. Human toxicology of boron with special reference to boric acid poisoning. G Ital Med Lav 1987;9:141-146. 50. Minoia C, Gregotti C, Di Nucci A, et al. Toxicology and health impact of environmental exposure to boron. A review. G Ital Med L ~ 1987;9:119-124. v 51.Chapin RE, Ku WW. The reproductive toxicity of boric acid. Environ Health Perspect 1994;102(suppl7):87-91. 52. Sisk DB, Colvin BM, Merrill A, et al. Experimental acute inorganic boron toxicosis in the goat: effects on serum chemistry and CSF biogenic amines. Vet Hum Toxicol 1990;32:205-211. 53. Jansen JA, Anderson J, Schou JS. Boric acid single dose pharmacokinetics after intravenous administration to man. Arch Toxicol 1984;55:64-67. 54. Jansen JA, Schou JS, Aggerbeck B. Gastro-intestinal absorption and in vitro release of boric acid from water-emulsdying ointments. Food Chem Toxicol 1984;22:49-53. 55.Sayli BS, Tuccar E, Elhan AH. An assessment of fertility in boron-exposed Turkish subpopulations. Reprod Toxicol 1998;12 297-304. 56. Garabrant DH, Bernstein L, Peters JM, et al. Respiratory and eye irritation from boron oxide and boric acid dusts. J Occup Med 1984;26584-586. 57. Von Burg R. Boron, boric acid, and boron oxide. J Appl Toxicol 1992;12:149-152. 58. Pinto J, Huang YP, McConnell RJ, et al. Increased urinary riboflavin excretion resulting from boric acid ingestion. J Lab Clin Med 1978;92126-134. 59. Beckett WS, Oskvig R, Gaynor ME, et al. Association of reversible alopecia with occupational topical exposure to common boraxcontaining solutions. J Am Acad Dermatol2001;42:599-602. 60.Banner W Jr, Koch M, Capin DM, et al. Experimental chelation therapy in chromium, lead, and boron intoxication with Nacetylcysteine and other compounds. Toxicol Appl Pharmacol 1986;83:142-147.

Bromelain Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 791

Antibiotic, Mucolytic, and Permeability-Modifying Activities 792

Chemical Composition 791 History 791 Pharmacology 791 Activating and Deactivating Factors 792 Activity 792 Absorption 792 Digestive Activity 792 Antiinflammatory Activity 792 Inhibition of Platelet Aggregation 792

Clinical Applications 793 Respiratory Tract Diseases 793 Thrombophlebitis 794 Surgical Procedures and Athletic injuries 794 Dysmenorrhea 794 Adjunct in Cancer Treatment 794 Dosage

794

Toxicity

795

Proteolybc enzyme of Ananas comosus (family:Bromeliaceae) Synonyms: bromelin, plant protease concentrate

and its molecular weight has been reported as 18,000 by one group of investigators and 31,000 by another.'

GENERAL DESCRIPTION

HISTORY

Bromelains are sulfhydryl proteolytic enzymes obtained from the pineapple plant. Commercial bromelain is usually derived from the stem, which differs from the bromelain derived from the fruit. Commercialbromelain is a mixture of several proteases (including carboxypeptidase) and small amounts of several nonproteolytic enzymes (acid phosphatase, peroxidase, and cellulase), polypeptide protease inhibitors, and organically bound calcium. Japan, Taiwan, and Hawaii are the major suppliers of commercial bromelain.'

Bromelain was introduced as a therapeutic agent in 1957. Since then more than 200 scientific papers on its therapeutic applications have appeared in the medical literature.*J Many early studies were with Ananase (Rorer), an enteric-coated bromelain tablet. Later studies implied that the failure of bromelain in some of these early studies was due to the enteric coating and inadequate dosages.

CHEMICAL COMPOSITION Stem bromelain (in its purified form) is a basic glycoprotein with one oligosaccharide moiety and one reactive sulfhydryl group per molecule. It has a molecular weight of 28,000, and its isoelectric point is pH 9.55. It exhibits activity over the pH range of 3 to 10, with optimal activity between 5 and 8, depending on the substrate. Fruit bromelain is an acidic protease (isoelectric point pH 4.6). Its status as a glycoprotein is still in dispute,

PHARMACOLOGY Commercial bromelain has been reported to exert a wide variety of pharmacologic Digestion assistance Antiinflammatory activity B u m dkbridement Prevention of induced pulmonary edema Smooth muscle relaxation Inhibition of blood platelet aggregation Enhancement of antibiotic absorption Cancer prevention and remission Ulcer prevention 791

Sinusitis relief Appetite inhibition Shortening of labor Enhanced wound healing

Inhibition of biosynthesis of proinflammatory prostaglandins and induction of prostaglandin El accumulation (which tends to inhibit the release of neutrophil lysosomal enzyme^)^,^,^

Bromelain is absorbed via a number of routes. It has been effectively administered orally and parenterally and through intravenous infusion.'*& Experiments with dogs have shown oral administration to result in peak levels at 10 hours, while detectable levels are still apparent at 48 hours. Intravenous infusion peaks in 50 minutes and Evidence indicates that, remains detectable for 5 in both animals and humans, up to 40% of the absorbed orally administered bromelain can be absorbed intact.&

The first hypothesis has not been substantiated, while the latter three may be part of the same mechanism of action. After tissue injury the kinin, complement, fibrinolytic, and clotting systems are activated. These systems are closely interrelated via activation of the Hageman factor (Xn) and feedback mechanisms. Fibrin's role in promotion of the inflammatory response is to form a matrix that walls off the area of inflammation, resulting in blockage of blood vessels and inadequate tissue drainage and edema. The kinin system cascade produces kinins (e.g., bradykinin, kallidin), which increase vascular permeability and cause edema, as well as evoke pain. Bromelain activates fibrinolysis by stimulating plasmin production (Figure 73-l), resulting in depolymerization of fibrin and thereby preventing fibrin-clogged venous stasis and localized edema.811 Plasmin has been shown to block the mobilization of endogenous arachidonic acid by phospholipases, thereby reducing platelet aggregation and possibly other prostaglandin-mediated phenomena.12 Bromelain has also been shown to reduce plasma kininogen, resulting in inhibition in the production of kinins.13 The depletion of kininogen has been demonstrated to significantly reduce edema. These actions, the activation of plasmin and the reduction of kinin levels, are probably the main pharmacologic effects of bromelain. Its ability to reduce inflammation has been documented in various experimental models and clinical studies.

Digestive Activity

Inhibition of Platelet Aggregation

Bromelain is effective as a substitute for trypsin or pepsin in cases of pancreatic insufficiency and postpancreatectomy.2Because of bromelain's wide pH activity, it can act on substrates in the low pH of the stomach, as well as in the high pH of the small intestine. The combination of bromelain with pancreatin and ox bile has been demonstrated via double-blind studies to be highly effective in the treatment of patients with pancreatic in~ufficiency.~

Bromelain has been demonstrated to be a potent inhibitor of platelet aggregation, both in vitro and in v~vo.'~ Again, this is probably due to its plasmin-increasing effects. Plasmin is known to inhibit platelet aggregation by blocking the mobilization of arachidonic acid from membranebound phospholipid pools.12 Platelet aggregation is a major factor in atherogenesis (seeChapter 150).Bromelain supplementation (in conjunction with potassium and magnesium) has been reported to be quite effective in treating angina (Box 73-1).15

Most of these effects are discussed later.

Activating and Deactivating Factors Being sulfhydryl proteases, like papain and ficin, both stem and fruit bromelains are inhibited by oxidizing agents such as hydrogen peroxide, methyl bromide, and iodoacetate and by metallic ions such as lead, mercury, cadmium, copper, and iron. Bromelain is also inhibited by human serum both in vivo and in vitro. Magnesium and cysteine are activators of commercial bromelain.'

Activity The activity of bromelain is expressed in various enzyme units. The use of milk-clotting units (MCUs) is the officially recognized method in the Food Chemistry Codex (FCC). Different grades of bromelain are available on the basis of MCUs.

Absorption

Antiinflammatory Activity Several mechanisms may account for bromelain's antiinflammatory effects: Activation of proteolytic activity at sites of inflammation (although bromelain's proteolytic actions are inhibited by serum factors) Fibrinolysis activity via the plasminogen-plasmin system Depletion of kininogen

Antibiotic, Mucolytic, and Permeability-ModifyingActivities Bromelain has been shown in clinical studies to increase serum levels of various antibiotics (e.g., amoxicillin, tetracycline, penicillin) in many different tissues and body fluids (e.g., cerebral spinal fluid, sputum, mucus, blood, urine, uterus, salpinx, ovary, gallbladder, appendix, and In these studies the researchers conepithelial tissue).1G18 cluded that bromelain itself possesses significant effects.

Bromelain

+ Factor Xlla

Factor XI1 (Hageman Factor)

I ' Prekallikrein activators

XI

++ Xla

(Clotting system)

II Plasminogen

++

Fibrinogen

Plasmin

\1

++

Prekallikrein

Fibrin

++ Kallikrien

Kininogen

\1

++++Kinin

+(Fibrinolysis)

T

\1

Fibrinopeptides

++ = Enhancedactivates ++ = Inhibitshlocks Figure 73-1 Bmmelain's effects on the fibrin and kinin pathways.

Angina Maldigestion Arthritis Pancreatic insufficiency Athletic injury Phytobezoar Bronchitis Pneumonia Burn debridement Scleroderma Cellulitis Sinusitis Dysmenorrhea Staphylococcal infection Ecchymosis Surgical trauma Edema Thrombophlebitis Data from references 1-36.

Bromelain was as effectiveas antibioticsin treatingvarious infectious processes (i.e., pneumonia, perirectal abscess, cutaneous staphylococcus infection, pyelonephritis, bronchitis)

Immune Modulation and Antitumor Effects Recent results from preclinical and pharmacologicstudies indicate that bromelain acts as an immunomodulator by raising the impaired immunocytotoxicity of monocytes against tumor cells from patients and by inducing the production of distinct cytokines such as tumor necrosis factor-alpha (TNF-a), interleukin-1 beta (IL-lp), IL-6,

and IL-8. In a recent clinical study with mammary tumor patients, these findings could be partially ~onfirmed.'~ Especially promising are reports on animal experiments claiming an antimetastatic efficacy and inhibition of metastasis-associated platelet aggregation, as well as inhibition of growth and invasiveness of tumor cells. Apparently, the antiinvasive activity does not depend on the proteolytic activity.lJ9

CLINICAL APPLICATIONS As is evident, bromelain has wide-ranging clinical utility. It is particularly effective in virtually all inflammatory conditions, regardless of etiology, including those resulting from physical trauma, infectious agents, surgical procedures, immunologic reactions, and prostaglandin metabolism.

RespiratoryTract Diseases Apparently bromelain's mucolytic activity is responsible for its particular effectiveness in respiratory tract diseases.20In the treatment of chronic bronchitis, bromelain was shown to have an antitussive effect and to reduce the viscosity of sputum. Spimmetricexaminationof patients before and after treatment indicated increased vital capacity and FEV1, while the residual volume was reduced. These favorable effects were believed to be the results of enhanced resolution of respiratory congestion, due to bromelain's ability to act as a mucolytic and decrease bronchial secretions. Acute sinusitis has also responded to bromelain therapy. Good to excellent results were obtained in 87'70 of bromelain-treated patients, compared with 68% of the placebo gr0up.2~

Thrombophlebitis Numerous investigators have demonstrated that orally administered bromelain has a potent favorable effect on acute thrombophlebitis, deep vein thrombosis, cellulitis, ecchymosis, and edema.15p-24 In a double-blind study involving 73 patients with acute thrombophlebitis,bromelain, as a n adjunct to analgesics, was shown to reduce all the symptoms of inflammation: pain, edema, redness, tenderness, elevated skin temperature, and disability? In thisstudy and others, the common daily dose of brome lain was 60 to 160 mg of 1200 MCU bromelain. According to some researchers, doses of 400 to 800 mg are necessary to achieve consistent results in patients with thrombophlebitis; this probably holds true for most other conditi~ns.'~

Surgical Procedures and Athletic Injuries The effect of orally administered bromelain on the reduction of edema, bruising, healing time, and pain following various surgical procedures has been demonstrated in several clinical studies.',2528Tassman's studies of patients undergoing oral surgery concluded that, although postsurgical medication alone is effective, a regimen of presurgical and postsurgical medication is recommended.25*26 In a double-blind study of patients undergoing oral surgery, bromelain was found to be sigruficantly superior to placebo: Swelling decreased in 3.8 days with bromelain, compared with 7 days for the placebo, and the duration of pain was reduced to 5.1 days in the bromelain group, compared with 8.1 in the placebo?6 Similar observations were made in studies of episiotomy cases. Bromelain reduced edema, inflammation, and pain, and preoperative administration potentiated the effects.27 Bromelain has been used in various sports-related injuries. A 1960 study involving boxers highlights its effects.28Among the 74 boxers receiving bromelain, in 58 all signs of bruising cleared completely within 4 days. In the remainder, complete clearance took 8 to 10 days. Among the 72 controls, at the end of 4 days only 10 showed bruises completely cleared, the remainder taking 7 to 14 days. Importantly, although bromelain has been shown to effectively reduce pain, this probably is the result of a reduction in tissue inflammation and edema rather than a direct analgesic effect. In an open clinical trial, 59 patients with blunt injuries to the musculoskeletal system (e.g., contusions, muscle strains, ligament tears) were given 500 mg of bromelain three times daily, 30 minutes before meals. Swelling, pain at rest and during motion, signs of inflammation, and tenderness to palpation all rapidly impr0ved.2~ Another open study investigated the effects of bromelain on mild acute knee pain of less than 3 months' duration in otherwise healthy adults.30 Two validated questionnaires (western Ontario and McMaster

Universities [WOMAC] Knee Health Index and the Psychological Well-Being Index) were completed at baseline, and after 1 month's intervention with bromelain, randomly allocated to volunteers as either 200 mg or 400 mg per day. Seventy-seven subjects completed the study. In both treatment groups all WOMAC symptom dimension scores were significantly reduced compared with baseline, with reductions in the final battery (total symptom score) of 41% and 59% in the low- and high-dose groups, respectively. In addition, improvements in total symptom score and the stiffness and physical function dimensions were sigruficantlygreater in the high-dose group (400 mg per day) compared with the low-dose group. Compared with the baseline, overall psychologic well-being was sigruficantlyimproved in both groups after treatment with a sigruficantdose-response relationship was observed.

Dysmenorrhea Bromelain and papain have been used successfully in the treatment of dy~menorrhea.~' Bromelain is believed to be a smooth muscle relaxant, since it decreases the spasms of the contracted cervix in these patients. Failure of the bromelain protease, when used alone (purified by adsorption), to produce this effect was the first indication that the pharmacologically important factor is not the main protease. The muscle-relaxing effects of bromelain on the uterus are believed to be a result of decreasing prostaglandins of the 2-series (e.g., PGF2, and PGE2), while increasing levels of PGEl-like compound^.^

Adjunct in Cancer Treatment Like other proteolytic enzymes, bromelain appears useful as an adjunct in cancer treatment. Many mechanisms appear to be responsible for the clinical benefit. In a clinical study in 16 women with breast cancer, bromelain had a sigruficant impact on monocytes, natural killer cells, and lymphocyte^.'^ When the patients were classified on the basis of bromelain effects on the monocytic cytotoxicity into bromelain responders and nonresponders, about 40% of the patients responded to bromelain with an increase of cytotoxicity from 7.8%to 54% (bh4AK-cell activity).These data suggest that bromelain stimulates the deficient monocytic cytotoxicity of cancer patients, which may partially explain its antitumor activity, though bromelain has also been shown to induce the production of distinct cytokines such as TNF-a,IL-lp, IL-6, and L-8.'

DOSAGE Unless bromelain is being used as a digestive aid, administration should be on an empty stomach (between meals). The dosage depends largely on the potency of the bromelain preparation. Most currently available bromelain is in the 1200 to 2000 MCU range, with the typical dosage being 125 to 500 mg three times a day between meals.

Bromelain

TOXICITY Large doses of bromelain (nearly 2 g) have been given with no side It is virtually nontoxic, as no LDso exists up to 10 g/kg. Chronic use appears to be well tolerated. Although no significant side effects have been noted, as with most therapeutic agents, allergic reactions may occur in sensitive individuals or with prolonged occupational exp~sure.~~Jp

1. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci 2001;58:1234-1245. 2. Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas cornosus) and its clinical application. An update. J

Ethnopharmacol1988;22.191-203. 3. Felton GE. Does kinin released by pineapple stem bromelain stimulate production of prostaglandin El-like compounds? Hawaii Med J 1977;36:39-47. 4. Miller JM, %her AW. The increased proteolyhc activity of human blood serum after oral administration of bromelain. Exp Med Surg 1964;22:277-280. 5. Izaka KI, Yamada M, Kawano T, Suyama T. Gastrointestinal absorption and antiinflammatory effect of bromelain. Jpn J Pharmacol 1972;22:519-534. 6. Seifert J, Ganser R, Brendel W. [Absorption of a proteolytic enzyme originating from plants out of the gastro-intestinal tract into blood and lymph of rats.] Z Gastroenterol1979;171-8. 7. Balakrishnan V, Hareendran A, Nair CS. Double-blind cross-over trial of an enzyme preparation in pancreatic steatorrhoea. J Assoc Physicians India 1981;29:207-209. 8. Lotz-Winter H. On the pharmacology of bromelain: an update with special regard to animal studies on dose-dependent effects. Plant Med 1990;56249-253. 9. Taussig SJ. The mechanism of the physiological action of bromelain. Med Hypotheses 1980;699-104. 10. Pirotta F, de Giuli-Morghen C. Bromelain-a deeper pharmacological study. Note I-antiinflammatory and serum fibrinolyhc activity after oral administration in the rat. Drugs Exp Clin Res 1978;41-20. 11. de Giuli-Morghen C, Pirotta F. Bromelain-a deeper pharmacological study. Note U-interaction with some protease inhibitors and rabbit specific antiserum. Drugs Exp Clin Res 1978;421-37. 12. Schafer AI, Adelman B. Plasmin inhibition of platelet function and of arachidonic acid metabolism. J Clin Invest 1985;75456-461. 13. Katori M, Ikeda K, Harada Y, et al. A possible role of prostaglandins and bradykinin as a trigger of exudation in carrageenin-induced rat pleurisy. Agents Actions 1978;8108-112. 14. Heinicke RM, van der Wal L, Yokoyama M. Effect of bromelain (Ananase) on human platelet aggregation. Experentia 1972;28: 844-845. 15. Taussig S, Nieper H. Bromelain: its use in prevention and treatment of cardiovascular disease present status. J Int Assoc Prev Med 1979;6 139-151. 16. Neubauer RA. Aplant protease for the potentiation of and possible replacement of antibiotics. Exp Med Surg 1961;19143-160. 17.Luerti M, Vignali M. Influence of bromelain on penetration of antibiotics in uterus, salpinx and ovary. Drugs Exp Clin Res 1978; 4:45-48.

Bromelain can induce IgE-mediated respiratory and gastrointestinal allergic reactions, as well as cross-react with papain, wheat flour,rye flow, grass pollen, and birch pollen.33” Although side effects are seldom observed, sensitivity manifested by urticaria or skin rash has occurred. No anaphylactic reactions have been reported. Other possible, but unconfirmed, reactions include nausea, vomiting, diarrhea, metrorrhagia, and men~rrhagia.~~

18. Tiiozzi S, Venegoni A. Effect of bromelain on serum and tissue levels of amoxicillin. Drugs Exp Clin Res 1978;439-44. 19. Eckert K, Grabowska E, Stange R, et al. Effects of oral bromelain administration on the impaired immunocytotoxicityof mononuclear cells from mammary tumor patients. Oncol Rep 1999;6:1191-1199. 20. Rimoldi R, Ginesu F, Giura R. The use of bromelain in pneumological therapy. Drugs Exp Clin Res 1978;455-66. 21. Ryan RE. A double-blind clinical evaluation of bromelains in the treatment of acute sinusitis. Headache 1967;713-17. 22. Seligman 8. Oral bromelains as adjuncts in the treatment of acute thrombophlebitis. Angiology 1969;20:22-26. 23.Seligman B. Bromelain: an anti-inflammatory agent. Angiology 1962;1350&510. 24. Felton GE. Fibrinolyticand antithrombotic action of bromelain may eliminate thrombosis in heart patients. Med Hypotheses 1980;61123-1133. 25. Tassman GC, Zafran JN, Zayon GM. Evaluation of a plant proteolytic enzyme for the control of inflammation and pain. J Dent Med 1964;19:73-77. 26.Tassman GC, Zafran JN, Zayon GM. A double-blind crossover study of a plant proteolytic enzyme in oral surgery. J Dent Med 1965;2051-54. 27.Howat RC, Lewis GD. The effect of bromelain therapy on episiotomy wounddouble blind controlled clinical trial. J Obstet Gynaecol Br Commonw 1972;79951-953. 28. Blonstein JL. Control of swelling in boxing injuries. Practitioner 1969;203206. 29. Masson M. [Bromelain in blunt injuries of the locomotor system. A study of observed applications in general practice.] Fortschr Med 1995;113303-306. 30.Walker AF, Bundy R, Hicks SM, Middleton RW. Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults. Phytomedicine 2002;9681-686. 31. Hunter RG, Henry GW, et al. The action of papain and bromelain on the uterus. Am J Obstet Gynecol1957;73:867-880. 32. Gutfreund AE, Taussig SJ, Morris AK. Effect of oral bromelain on blood pressure and heart rate of hypertensive patients. Hawaii Med J 197837143-146. 33. Baur X. Studies on the specificity of human IgE-antibodies to the plant proteases papain and bromelain. Clin Allergy 1979;9:451-457. 34.Baur X, Fruhmann G. Allergic reactions, including asthma, to the pineapple protease bromelain following occupational exposure. Clin Allergy 1979;9443-450. 35. Physicians Desk Reference. Ananase (Rorer). Boston: Medical Economics Company, 19821645. 36. Ballard T. Bromelain.J John Bastyr Col Nat Med 1979;1:37-41

Camellia sinensis (Green Tea) Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac C H A P T E R (1 0 N T E N T S General Description 797 Green Tea versus Black Tea

Photoprotective Effects 800 797

Oral Cavity Diseases 800 Chemical Composition 797 Dosage 800 Pharmacology 798 Toxicity Clinical Application 798 Cancer 798 Cardiovascular and Liver Disease 799

800

Drug Interactions 800

Camellia sinensis (family: Theaceae) Common name: green tea

countries in North Africa and the Middle East (Table 741). Consumption is increasing in the United States.

GENERAL DESCRIPTION

CHEMICAL COMPOSITION

Both green tea and black tea are derived from the same plant, the tea plant (Camellia sinensis). The tea plant originated in China but is now grown and consumed worldwide. The tea plant, an evergreen shrub or tree that can grow up to a height of 30 feet, is usually maintained at a height of 2 to 3 feet by regular pruning. The shrub is heavily branched with young hairy leaves. Parts used are the leaf bud and the two adjacent young leaves together with the stem, broken between the second and third leaves. Older leaves are considered of inferior quality.

The chemical composition of green tea varies with climate, season, horticultural practices, and age of the leaf (position of the leaf on the harvested shoot). The major components of interest are the polyphenols.'r2 The major polyphenols in green tea are the following flavonoids:

Green Tea versus Black Tea Green tea is produced by lightly steaming the freshly cut leaf, while black tea is produced by allowing the leaves to oxidize. During oxidation, enzymes present in the tea convert many polyphenolic therapeutic substances to compounds with much less activity. With green tea, oxidation is not allowed to take place because the steaming process inactivates these enzymes. Green tea is high in polyphenols with potent antioxidant and anticancer properties. Oolong tea is a partially oxidized tea. Of the nearly 2.5 million tons of dried tea produced each year, only 20%is green tea. India and Sri Lanka are the major producers of black tea. Green tea is produced and consumed primarily in China, Japan, and a few

Catechin Epicatechin Epicatechin gallate Epigallocatechin gallate Proanthocyanidins Epigallocatechin gallate is viewed as the most significant active component. The leaf bud and the first leaves are richest in epigallocatechingallate. The usual concentration of total polyphenols in dried green tea leaf is around 0% to 12%. Other compounds of interest in dried green tea leaf include the following: Caffeine (3.5%) An unusual amino acid known as theunine (one half of

the total amino acid content, which is usually 4%) Lignin (6.5%) Organic acids (1.5%) 797

World tea production by type Type

Dry weight (xlOO0tons)

Black

1940

Green

515

Oolong

60 -

TOTAL

2515

Protein (15%) Chlorophyll (0.5%) One cup of green tea usually contains about 300 to 400 mg of polyphenols and between 50 and 100 mg of caffeine. Commercial preparations that have been decaffeinated and concentrated for polyphenols to between 60%and 80% total polyphenols are available.

PHARMACOLOGY Most epidemiologicand experimental studies on tea have focused on cancer-protective aspects. Tea polyphenols are potent antioxidant compounds that have demonstrated greater antioxidant protection than vitamin C and E in experimental studies? Although the antioxidant capacity of tea is well established, some clinical trials have not found a demonstrated oxidative protection in humans? Since reliable antioxidantbiomarkers have not been established: it is questionable whether the protective benefits of green tea will be fully elucidated in the near future. In addition to exerting antioxidant activity on its own, green tea may increase the activity of antioxidant enzymes. In mice, oral feeding of a polyphenolic fraction isolated from green tea in drinking water for 30 days resulted in SigTUficantly increased activities of antioxidant and detoxifying enzymes (glutathione peroxidase, glutathione reductase, glutathione-S-transferase,catalase, and quinone reductase) in the small intestine, liver, lungs, and small bowel? With regard to cancer, a number of in vitro and experimental models of cancer have shown that green tea polyphenols may offer significant protection.'-1° Specifically, green tea polyphenols inhibit cancer by blocking the formation of cancer-causing compounds like nitrosamines, suppressing the activation of carcinogens and increasing detoxification or trapping of cancercausing agents. Numerous studies have shown that green tea (including green tea polyphenols and extracts) exerts sigruhcant inhibitory effects on the formation of nitrosamines in various animal and human models. For example, when human volunteers ingested green tea along with 300 mg sodium nitrate and 300 mg proline, nitrosoproline formation was strongly inhibited."

CLINICAL APPLICATION The primary clinical application for green tea is in the prevention of cancer. Epidemiologic studies have demonstrated that green tea consumptionmay be a major reason why the cancer rate is so low in Japan. In contrast, however, black tea consumption appears associated with a substantial increase in the risk of several forms of cancer (discussed later in the section on black tea). Green tea also appears to be of value in several chronic diseases, especially those of the heart and liver.

Cancer Green Tea Epidemiologic correlations regarding the relationship between tea consumptionand human cancer are confounded by numerous variables.12 The forms of cancer that appear to be best prevented by green tea are those of the gastrointestinal tract including cancers of the stomach, small intestine, pancreas, and colon; the lung; and estrogen-related cancers, including most breast cancers,13 skin cancer,14J5and prostate cancer. A study in Shanghai, China, found a strong inverse association between green tea consumption and various cancers.IbFor men, compared with nonregular green tea drinkers, the group with the highest green tea consumption had an 18% reduced risk for colon cancer; 28% for rectal cancer; and 37% for pancreatic cancer. In women, the highest group of green tea consumers had a reduced risk of 33% for colon, 43%for rectal, and 47% for pancreatic cancer. A second Shanghai cohort study of 18,244 men demonstrated that the presence of urinary epigallocatechins correlated with a statistically significant inverse association with gastric cancer. This conclusion came after adjustment for the presence of Helicobuctor pylori, smoking, alcohol drinking, and level of serum carotenes. Interestingly, the protective effect was primarily seen among subjects with low levels of serum carotenes." It is possible that raising carotene intake may then preclude the benefits of tea intake. A population-based study of women in Shanghai found that among nonsmokers, the consumption of green tea was associated with a clearly reduced risk of lung cancer, in a dose-dependent manner.'R One corollary to this exists with regard to smoking. Studies have shown that little benefit in antioxidant levels are found in smokers who drink green tea.19*20 In preventing breast cancer, in vitro studies have shown that green tea extracts have inhibitory effects on the growth of mammary cancer cell lines.'O The main anticancer action is inhibiting the interaction of estrogen with its receptors. Polyphenol compounds in green tea extracts block the interaction of tumor promoters, hormones, and growth factors with their receptors-a kind of sealing-off effect. This effect would account for the reversible growth arrest noted in the in vitro studies.

Camellia sinensis (Green Tea) Green tea may soon be considered as a standard treatment for early-stage breast cancer. An observational study of 1160 surgical cases of invasive breast cancers were followed for 9 years. During a review of 5264 personyears follow-up, 133 subjects (12%) were documented to suffer recurrence of breast cancer. A decreased hazard ratio for recurrence adjusted for stage was observed with consumption of three or more daily cups of green tea. Particularly in stage I, the hazard ratio was decreased quite significantly. A similar tendency was observed for stage I1 subjects but was not present among more advanced stages.20 In animal studies green tea has been shown to effectively inhibit the lung carcinogenesisinduced by injections of asbestos and benzoalphapyrene. Rats consuming water with 2% green tea experienced a cancer rate of only 16% compared with 46% for those consuming water without green tea extract.21 Green tea components such as epigallocatechin-3gallate have been shown to have antiproliferative properties through the induction of apoptosis and cell cycle arrest in cervical cancer cell lines.z Topical and oral treatments of green tea flavonoid components have also been explored to treat human papillomavirus (HPV)-related cervical cancer. A randomized controlled clinical trial of 51 patients with cervical lesions including chronic cervicitis, mild dysplasia, moderate dysplasia, and severe dysplasia were divided into four treatment groups, while 39 untreated patients served as a control. A second trial used a polyphenol ointment made with epigallocatechin-3-gallateapplied locally to 27 patients twice a week for 12 weeks. For oral delivery, 200 mg of the ointment or an epigallocatechin-3-gallate capsule was taken orally every day for 8 to 12 weeks. Overall, a 69%response rate (35/51) was noted for treatment with green tea extracts, with each treatment showing a similar response, as compared with a 10% response rate (4/39) in untreated controls. A response was considered positive when pretreatment and posttreatment biopsies and Pap smears detected an elimination of abnormal cells, a decrease in or complete elimination of HPV, or a decrease in the size of the cervical lesion. The authors of this study concluded that green tea extracts may be a potential therapy regimen for patients with HPV-infected cervical lesions.= Male reproductive tract cancer may similarly benefit from green tea. In animal studies green tea components were found to inhibit the growth of prostate cancer cells and diminish the size of existing tumors.” Green tea’s pigallocatechin gallate has shown marked inhibition of hormone-insensitive prostate cancer cells. One murine study used green tea in oral liquid extract, which was the equivalent of 6 cups of green tea daily in humans. The mice taking green tea exhibited complete inhibition of metastasis of their prostate cancer, and there was

significant apoptosis in the prostate cancer cells compared with mice given only plain water.

Black Tea In contrast to green tea, population studies analyzing black tea consumption are not as clear regarding cancer protection. Some early studies even indicated that black tea consumption may increase the risk for certain cancers (e.g., rectum, gallbladder, endometrium).25*26 For example, in one study, the relationship between black tea consumption and cancer risk was analyzed using data from an integrated series of case-control studies conducted in Northern Italy between 1983 and 1990.25 The data set included 119 biopsy-confirmed cancers of the oral cavity and throat, 294 of the esophagus, 564 of the stomach, 673 of the colon, 406 of the rectum, 258 of the liver, 41 of the gallbladder, 303 of the pancreas, 149 of the larynx, 2860 of the breast, 567 of the endometrium, 742 of the ovary, 107 of the prostate, 365 of the bladder, 147 of the kidney, 120 of the thyroid, and a total of 6147 controls admitted to the hospital for acute noncancerous conditions. The risk of developing cancer due to tea consumption was derived after allowance for age, sex, area of residence, education, smoking, and coffee consumption. Results indicated an increased risk with tea consumption for cancers of the rectum, gallbladder, and endometrium. There was no association with cancers of the oral cavity, esophagus, stomach, bladder, kidney, prostate, or any other site considered. In another study, men of Japanese ancestry were clinically examined, during the period 1965-1968.26For 7833 of these men, data on black tea consumption habits were recorded. Since 1965, newly diagnosed cancer incidence cases have been identified: 152 colon, 151 lung, 149 prostate, 136 stomach, 76 rectum, 57 bladder, 30 pancreas, 25 liver, 12 kidney, and 163 at other (miscellaneous) sites. Compared with ”almost-never” drinkers, men who habitually drink black tea more than once a day had a four times greater chance of developing rectal cancer.26

Cardiovascular and Liver Disease A prospective epidemiologic study begun in 1986 by researchers in Japan evaluated the relationship between diet and chronic disease in Japanese men aged 40 and olderF7 As daily green tea intake increased from less than three, to four to nine, to more than 10 cups, significant increases in serum high-density lipoprotein and decreases in low-density lipoproteins (LDLs) were found. In addition, green tea consumption was found to significantly improve liver profiles, with aspartate aminotransferase and alanine aminotransferase levels decreasing significantly with increasing green tea consumption.

However, one study from the Netherlands evaluating ORAL CAVITY DISEASES inflammatory markers such as interleukin (IL)-6, IL-1 Inflammatory gingival reactions, tooth decay, and oral beta, tumor necrosis factor-alpha, C-reactive protein cancer may also benefit by the use of green tea. By study(CRP), and fibrinogen found no benefit for 59 healthy ing the amount of dental plaque present, as well as a smoking volunteers who drank tea with regard to bleeding index, green tea chews and rinses have been inflammation, hemostasis, and the endothelial cardioshown to positively affect the level of gum inflammavascular risk factors measured.28Given other studies of One trial evaluated volunteers who held 2 g of green tea that show little protection for s r n o k e r ~(dis~ ~ * ~ tion.32*33 ~ brewed black tea or unbrewed green tea leaves in the cussed in the section on cancer earlier), and the strong mouth for 2 to 5 minutes. Results showed that this body of literature regarding its efficacy in nonsmoking simple use of tea leaves acted upon by salivary esterases populations, it is possible that the level of oxidative can release high levels of catechins and theaflavin galdamage sustained by regular smoking may be too great lates into the oral cavity? Routine prophylaxis, as well for tea’s demonstrated antioxidant capacities. as treatment of gum disease, may be well served by the Although not shown to have any effect on antioxidant addition of green tea support to standard brushing, status, one small study has shown black tea to exhibit flossing, and dental care regimens. benefits in reducing LDL cholesterol by 7.5% over n0nusers.2~A double-blind crossover study of 10 healthy male volunteers studied the effects of both black tea and DOSAGE separate caffeine on the flow velocity reserve of coronary The normal amount of green tea consumed by Japanese vessels before and after consumption. Two-way analysis and other green tea drinking cultures is about 3 cups of variance showed a sigruficant improvement in corodaily or about 3 g of soluble components providing nary flow before after tea consumption and was greater roughly 240 to 320 mg of polyphenols. For a green tea than caffeine by almost a factor of 4.30 extract standardized for 80% total polyphenol and 55% epigallocatechin gallate content, this would mean a daily PHOTOPROTECTIVE EFFECTS dose of 300 to 400 mg. When selecting commercial green tea extracts, it is Research has shown that topical treatment or oral important to look for the level of epigallocatechin consumption of green tea polyphenols inhibits chemical gallate, as well as total polyphenol content. carcinogen- or ultraviolet (W) radiation-induced skin tumorigenesis in different animal In one study, volunteers were treated with an extract of green tea TOXICITY or one of its constituents and subsequently exposed to Green tea is not associated with any significant side graded doses of ultraviolet radiation 30 minutes later. Weffectsor toxicity. As with any caffeine-containingbevertreated skin was examined clinically for UV-induced eryage, overconsumption may produce a stimulant effect thema, looking histologically for the presence of sunburn (e.g., nervousness, anxiety, insomnia, irritability). cells or Langerhans cell distributions for UV-induced DNA damage. On histologic examination, skin treated with green tea extracts reduced the number of sunburn DRUG INTERACTIONS cells and protected epidermal Langerhans cells from UV damage. In a dose-dependent manner, epigallocatechin- Populations with marginal or deficient iron status have been shown to have lower serum ferritin or hemoglobin 3-gallate and epicatechin-3-gallate polyphenols proved to levels, or both, presumably due to iron bindi11g.3~ be the most efficient at inhibiting erythema. It was noted Theoretic concerns have been raised for interactions that the epigallocatechin and epicatechin fractions with anticoagulants due to caffeine’s antiplatelet activity, showed almost no effect. Green tea extracts also reduced but no interactions have been reported in humans. the DNA damage that formed after UV radiation.3l

1. Graham HN. Green tea composition, consumption, and polyphenol chemistry. Prev Med 1992;21:334-350. 2. Min Z , Peigen X. Quantitative analysis of the active constituents in green tea. Phytother Res 1991;5:239-240. 3. Ho CT,Chen Q, Shi H, et al. Antioxidative effect of polyphenol extract prepared from various Chinese teas. Prev Med 1992;21:520-525.

4. HodgsonJM, Croft KD, Mori TA, et al.Regular ingestion of tea does not inhibit in vivo lipid peroxidation in humans. J Nutr 2002;13255-58. 5. Reweld A, Wiseman S. Antioxidant effects of tea: evidence from human clinical trials. J Nutr 2003;133:328553292S. 6. Khan SG,Katiyar SK, Aganval R, et al. Enhancement of antioxidant and phase II enzymes by oral feeding of green tea polyphenols in

Camellia sinensis (Green Tea) drinking water to SKH-1 hairless mice. Possible role in cancer chemoprevention. Cancer Res 1992;524050-4052. 7. Katiyar SK, Agarwal R, Mukhtar H. Green tea in chemoprevention of cancer. Compr Ther 1992;183-8. 8. Mukhtar H, Wang ZY, Katiyar SK, et al. Tea components: antimutagenic and anticarcinogenic effects. Prev Med 1992;21:351-360. 9. Wang ZY, Khan WA, Bickers DR, et al. Protection against polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice by green tea polyphenols. Carcinogenesis 1989;10411-415. 10. Komori A, Yatsumi J, Okabe S, et al. Anticarcinogenic activity of green tea polyphenols. Jpn J Clin Oncol1993;23:186-190. 11. Stich HE Teas and tea components as inhibitors of carcinogen formation in model systems and man. Pmv Med 1992;21:377-384. 12. Blot WJ, Chow WH, McLaughl~nJK. Tea and cancer-a review of the epidemiological evidence. Eur J Cancer Prev 1996;5:425-428. 13.Yang CS, Wang ZY. Tea and cancer. J NatI Cancer Inst 1993;85 1038-1049. 14. Katiyar SK, Elmets CA. Green tea polyphenolic antioxidants and skin photoprotection (Review). Int J Oncol2001;181307-1313. 15. Agarwal R, Katiyar SK, Khan SG,et al. Protection against ultraviolet B radiation-inducedeffects in the skin of SKH-1 hairless mice by a polyphenolic fraction isolated from green tea. Photochem Photobiol 1993;58:695-700. 16.Ji HT, Chow WH, Hsing A, et al. Green tea consumption and the risk of pancreatic and colorectal cancer. Int J Cancer 1997;7 255-258. 17. Sun CL, Yuan JM, Lee MJ, et al. Urinary tea polyphenols in relation to gastric and esophageal cancers: a prospective study of men in Shanghai, China. Carcinogenesis 2002;231497-1503. 18. Bong L, Goldberg MS, Gao YT, et al. A population-based casecontrol study of lung cancer and green tea consumption among women living in Shanghai, China. Epidemiology 2001;12:695-700. 19. Princen HM, van DuyvenvoordeW, Buytenhek R, et al. No effect of consumption of green and black tea on plasma lipid and antioxidant levels and on LDL oxidation in smokers. Arterioscler Thromb Vasc Biol1998;18:833-841. 20.Inoue M, Tajima K, Mizutani M, et al. Regular consumption of green tea and the risk of breast cancer recurrence: follow-up study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. Cancer Lett 2001 26;167 175-182.

21. Luo SQ, Liu XZ,Wang CJ.Inhibitory effect of green tea extract on the carcinogenesis induced by asbestos plus benzo(a)pyrenein rat. Biomed Environ Sci 1995;85458. 22. Ahn WS, Huh SW, Bae SM, et al. A major constituent of green tea, EGCG, inhibits the growth of a human cervical cancer cell line, CaSki cells, through apoptosis, G(1) arrest, and regulation of gene expression. DNA Cell Biol2003;22.217-224. 23. Ahn WS, Yoo J, Huh SW, et al. Protective effects of green tea extracts (polyphenonE and EGCG) on human cervical lesions. Eur J Cancer Prev 2003;12:383-390. 24. Rake1 D. Prostate health. Clin Fam Pract 2002;4;967. 25. La Vecchia C, Negri E, Franceschi S, et al. Tea consumption and cancer risk.Nutr Cancer 1992;1727-31. 26. Heilbrun LK, Nomura A, S t e m e r m m GN. Black tea consumption and cancer risk a prospective study. Br J Cancer 1986;54:677-683. 27. ImaiK, Nakachi K. Cross secfional study of effects of drinking green tea on cardiovascular and liver disease. BMJ 1995;310693-696. 28.de Maat MP, Pijl H, Kluft C, et al. Consumption of black and green tea had no effect on inflammation, haemostasis and endothelial markers in smoking healthy individuals. Eur J Clin Nutr 2ooO; 54:757-763. 29. Davies MJ, Judd JT, Baer DJ, et al. Black tea consumption reduces total and LDL cholesterol in mildly hypercholesterolemic adults. J Nutr 2003;133:3298S3302S. 30. Hirata K, Shimada K, Watanabe H, et al. Black tea increases coronary flow velocity reserve in healthy male subjects. Am J Cardiol 2004;931384-1388, A6. 31. Elmets CA, Singh D, Tubesing K, et al. Cutaneous photoprotection from ultraviolet injury by green tea polyphenols. J Am Acad Dermatol2001;44:425-432. 32.Wdershausen B, Gruber I, Hamm G. The influence of herbal ingredients on the plaque index and bleediig tendency of the gingiva. J C l i Dent 1991;275-78. 33. Krahwinkel T, Willershausen 8. The effect of sugar-free green tea chew candies on the degree of inflammation of the gingiva. Eur J Med Res 2000;5:463-467. 34. Lee MJ, Lambert JD, Prabhu S, et al. Delivery of tea polyphenols to the oral cavity by green tea leaves and black tea extract. Cancer Epidemiol Biomarkers Prev 2004;13132-137. 35. Temme EH, Van Hoydonck PG. Tea consumption and iron status. Em J Clin Nutr 200256379-386.

Capsicum fi-utescens (Cayenne Pepper) Michael T. Murray, ND Joseph E. Pizzorno Jr, N D CHAPTER C O N T E N T S General Description 803 Chemical Composition 803 History and Folk Use

803

Diabetic Neuropathy 805 Cluster Headaches 805 Arthritis 805 Psoriasis 805 Pruritus Ani 806

Pharmacology 803

Dosage 806

Clinical Applications 804 Postherpetic Neuralgia 804 Trigeminal Neuralgia 804 Postmastectomy Pain 804 Mouth Pain Due to Chemotherapy or Radiation 805

Toxicity 806

Capsicumfru tescens (family: Solanacea) Common names: cayenne pepper, capsicum, chili pepper, red pepper, American pepper

GENERAL DESCRIPTION Cayenne pepper (also known as chili or red hot pepper) is the fruit of Capsicum annuum, a shrubby, tropical plant that can grow up to 3 feet high. The fruit is technically a berry. Paprika is a milder and sweeter-tasting fruit produced from a different variety of Capsicum. Although cayenne pepper is native to tropical America, it is now cultivated in tropical locations throughout the world and has found its way into the cuisine of many parts of the world, particularly Southeast Asia, China, Southern Italy, and Mexico.

CHEMICAL COMPOSITION The most important constituents of cayenne pepper are the pungent compounds, with capsaicin being the most prominent (Figure 75-1). Typically, cayenne pepper contains about 1.5% capsaicin and related principles. Other active constituents present include carotenoids, vitamins A and C, and volatile oils.

Drug Interactions 806

HISTORY AND FOLK USE The folk use of cayenne pepper is quite extensive. It has been used for the following: Asthma Fever Sore throats and other respiratory tract infections Digestive disturbances Poultices Cancer It has also been used as a counterirritant in the topical treatment of arthritis and neuralgia.

PHARMACOLOGY The pharmacology of cayenne pepper centers around its capsaicin content. When topically applied to the skin or mucous membranes, capsaicin is known to stimulate and then block small-diameter pain fibers by depleting them of the neurotransmitter substance P.' Substance P is thought to be the principal chemomediator of pain impulses from the periphery. In addition, substance P has been shown to activate inflammatory mediators into joint tissues in osteoarthritis and rheumatoid arthritis.2 803

HO

-

0

Figure75-1 Capsaicin.

may offer significant benefits in a number of conditions including the pain associated with pain disorders, diabetic neuropathy, cluster headache, osteoarthritis, and rheumatoid arthritis. In addition, topically applied capsaicin may be useful in psoriasis.

Postherpetic Neuralgia

The first studies and approved use for topically applied capsaicin were in relieving postherpetic neuralgia. Numerous studies now document this Food and Drug Administration-approved application. For example, in one study 39 patients with chronic postherpetic neuralgia (average duration 24 months) were treated with 0.025%capsaicin cream for 8 weeks. During therapy the patients rated their pain. Nineteen patients (48.7”/0)substantially improved after the 8-week trial; five (12.8%) discontinued therapy due to side effects such as intolerable capsaicin-induced buming sensations (four)or mastitis (one);and 15 (38.5%)reported no benefit. The decrease in pain ratings was sigruficant after 2 weeks of continuCLINICAL APPLICATIONS ous application. Of the responders, 72.2% still reported improved 10 to 12 months after the study; with most Cayenne pepper should be recommended as a food for its beneficial antioxidant and cardiovascular effects. continuing to apply the cream regularly. In general the results of this study are consistent Although people with active peptic ulcer may be bothwith other studies (i.e., about 50% of people with posered by “spicy” foods containing cayenne pepper, spicy therpetic neuralgia respond to topically applied capsaicin foods in normal individuals do not cause ulcers. In fact, (0.025%).1419 Although this may not be a great response, cayenne pepper exerts several beneficial effects on gasit is better than the 10% response noted in the placebo trointestinal function, including acting as a digestant group. Higher concentration(0.075%vs. 0.025%)may proand carminative? Double-blind studies have shown that duce better results (as high as 75% response).20Another red pepper consumption protects against aspirin-induced study showed that capsaicin responders have been charstomach damage and improves epigastric pain, fullness, and nausea scores in people with nonulcer dy~pepsia.73,~ acterized by higher average daily pain, higher allodynia ratings, and relatively preserved sensory function at baseCapsicum does, however, lower the threshold for heartbum, presumably by direct effects on sensory neurons.1o line compared with the nonresponders. In three of the ”capsaicin responders” the area of allodynia expanded Interestingly, capsaicin, although hot to the taste, has actually been shown to lower body temperature by stim- into previously nonallodynicand nonpainful skin that had normal sensory function and cutaneous innervation?’ ulating the cooling center of the hypothalamus.” The ingestion of cayenne peppers by cultures native to the Trigeminal Neuralgia tropics appears to offer a way for these people to deal Topically applied capsaicin may be effective in reducwith high temperatures. ing the pain of trigeminal neuralgia.z In one study Capsicum ingestion may also prove to be helpful in 12 patients were followed up for 1 year after the topical promoting weight loss in obese individuals, as clinical application over the painful area of capsaicin three times studies have shown capsicum increases the basal metabolic rate while reducing appetite and caloric intake.12J3 a day for several days. Six patients had complete and four patients had partial relief of pain; the remaining two In one study, after ingesting a standardized dinner on patients had no relief of pain. Of the 10 patients who the previous evening, the subjects ate one of the followwere responsive to therapy, 4 had relapses of pain within ing for breakfast: a high-fat meal, a high-fat meal with 95 to 149 days. No relapses followed the second therapy red pepper (10 g), a high-carbohydrate meal, or a highfor the remainder of the year. These results are promiscarbohydrate meal with red pepper (10 g). Diet-induced thermogenesis was sigruficantly enhanced by the addition ing for a condition that usually does not respond to any therapy short of surgery. of red pepper to either meal, but especially the highfat meal.I4 Postmastectomy Pain Modem clinical use of cayenne pepper has focused Topically applied capsaicin may help in the relief of pain on the use of topical capsaicin-containing preparations. after breast reconstruction or mastectomy. In one Commercialointments containing 0.025% or 0.075%capdouble-blind study 23 patients with postmastectomy saicin are available over the counter. These preparations

When taken internally, cayenne pepper exerts a number of benefiaal effects on the cardiovascular system. In addition to possessing several antioxidant compounds, studies have shown that cayenne pepper reduces the likelihood of developingatherosclerosisby reducingblood cholesterol and triglyceride levels and platelet aggregation, as well as increasing fibrinolytic a~tivity.”~ (For the signhcance of these effects, see Chapter 150.) Cultures consuming large amounts of cayenne pepper have a much lower rate of cardiovascular disease.

Capsicum frutescens (Cayenne Pepper) pain syndrome (PMPS)applied either capsaicin (0.075%) days 8 to 15 of the study were significantly less severe in the capsaicin group versus the placebo group. There was or vehicle (placebo)-onlycream four times daily for 4 to also a sigruficant decrease in headache severity in the 6 weeksz3There was a significant difference in jabbing capsaicin group on days 8 to 15 compared with days 1 pain, in category pain severity scales, and in overall pain to 7, but not in the placebo group. Episodic patients relief scales in favor of capsaicin. Five of 13 patients on appeared to benefit more than chronic patients. capsaicin were categorized as good-to-excellent responses, with eight (62%) having 50% or greater improvement. Arthritis Only 1 of 10 cases had a good response to vehicle, with Topically applied capsaicin may be effective in relieving three rated as 50% or better. the pain of osteoarthritis and rheumatoid arthritis. In another study 14 patients with postmastectomy pain had sigrufcant pain relief following application of Although one study showed it to be more effective in 0.025%capsaicin cream four times daily for 4 to 6 ~ e e k s . 2 ~ osteoarthritis, another study showed just the opposite. In the double-blind study showing more effect in Unpleasant or painful sensations to light touch or pressure osteoarthritis, seven patients with rheumatoid arthritis in the painful area (hyperesthesia, allodynia) were also and 14 patients with osteoarthritis who had painful improved. involvement of the hands applied either capsaicin Mouth Pain Due to Chemotherapy 0.075% or vehicle-only cream to the hands four times or Radiation daily. Capsaicin reduced tenderness and pain associated with osteoarthritis, but not rheumatoid arthritis.% In a study conducted at the Yale Pain’ Management In the study showing greater benefit for rheumatoid Center, capsaicin was shown to dramatically reduce the arthritis, 70 patients with osteoarthritis and 31 with pain from mouth sores as a result of chemotherapy or rheumatoid arthritis received capsaicin or placebo for radiation treatment.25The interesting feature in thisstudy 4 weeks.35The patients were instructed to apply 0.025% was the vehicle used to deliver the capsaicin-taffy. The capsaicin cream or its vehicle (placebo) to painful knees researchers chose taffy because it could be held in the four times daily. Significantly more relief of pain was mouth long enough to desensitize the neurons, its sugar reported by the capsaicin-treatedpatients than the placebo decreased the initial burning sensation, and its soft edges would not aggravate sore mouths like a hard candy. All patients throughout the study; after 4 weeks of capsaicin treatment, rheumatoid and osteoarthritis patients demon11 patients in the Yale study said their pain decreasedin two cases stopping entirely-after eating the capsaicin- strated mean reductions in pain of 57%and 33%, respectively. These reductions in pain were statisticallysigrufcant laced candy. compared with those reported with placebo. According Diabetic Neuropathy to overall evaluations, 80°/0 of the capsaicin-treated patients experienced a reduction in pain after 2 weeks of Topically applied capsaicin has been shown to be of considerable benefit in relieving the pain of diabetic treatment. neuropathy in numerous double-blind In Psoriasis one large double-blind, 8-week study, investigators at 12 sites enrolled 277 men and women with painful diabetic Excessive substance P levels in the skin have been linked neuropathy of the hands and feet; 69.5% of the group to psoriasis. This finding prompted researchers to study applying the capsaicin cream (0.075%)showed improvethe effects of topically applied capsaicin. In one doublement compared with 53.4% in those applying only the blind study 44 patients with symmetrically distributed vehicle cream. psoriasis lesions applied topical capsaicin to one side of In another study 40 patients applied either 0.075% their body and a placebo to the other side.%After 3 to capsaicin cream or placebo to their affected extremities 6 weeks, sigruficantly greater reductions in scaling and daily. After 4 weeks, 76% of treated patients had some redness were observed on the capsaicin side. Burning, pain relief compared with 50% of placebo patients. In stinging, itching, and skin redness were noted by nearly addition, those responding to capsaicin said their pain half of the patients initially, but these diminished or was cut in half, while those on placebo averaged vanished upon continued application. In a later study 197 patients applied capsaicin 0.025% between 15%and 20% relief. cream or placebo cream four times a day for 6 weeks.37 Cluster Headaches Efficacy was based on a physician’s evaluation and a combined psoriasis severity score including scaling, Several studies have found that intranasal application of thickness, erythema, and pruritus. Capsaicin-treated capsaicin ointment by a physician may relieve cluster patients demonstrated sigruficantly greater improveheadaches. In one double-blind study, patients in acute ment in physician’s evaluation and in pruritus relief, as cluster were randomized to receive either capsaicin or well as a significantly greater reduction in combined placebo in the nostril for 7 days.%Patients recorded the psoriasis severity. severity of each headache for 15 days. Headaches on

Pruritus Ani Pruritus ani is a common condition that can be difficult to treat. Results from a double-blind study indicate that capsaicin is a safe and highly effective treatment for severe intractable idiopathic pruritus ani3 This study involved two 4-week treatment phases separated by a l-week washout phase. Forty-four patients were randomized to receive locally either active capsaicin (0.006%) or placebo (menthol 1%)ointment over a 4-week period. After 4 weeks of treatment and a 1-week washout period, the placebo group began to receive capsaicin while the treated group received placebo (menthol 1%)for another 4 weeks. At the end of the controlled study, responders from both groups continued with capsaicin treatment in an open-labeled manner. Results indicated that 31 of 44 patients experienced relief during capsaicin treatment periods and did not respond to menthol; all patients not responding to capsaicin also failed on menthol. In 13 patients, treatment with capsaicin was unsuccessful: 8 patients did not respond to capsaicin treatment, 1 responded equally to capsaicin

1.Szallasi A. Vanilloid (capsaicin) receptors in health and disease. Am J Clin Pathol2002;118:110-121. 2. Cordell GA, Araujo OE. Capsaicin: identification, nomenclature, and pharmacotherapy. Ann Pharmacother 1993;27330-336. 3. Kawada T, Haghara K, Iwai K. Effects of capsaicin on lipid metabolism fed a high fat diet. J Nutr 1986;116:1272-1278. 4. Wang JP, Hsu MF, Teng CM. Antiplatelet effect of capsaicin. Thromb Res 1984;36:497-507. 5. Visudhiphan S, Poohuppasit s, Piboonnukarintr, Tumliang S. The relationship between high fibrinolytic activity and daily capsicum ingestion in Thais. Am J C h Nutr 1982;35:1452-1458. 6. Horowitz M, Wishart J, Maddox A, Russo A. The effect of chilli on gastrointestinal transit. J Gastroenterol Hepatol1992;752-56. 7. Yeoh KG, Kang JY, Yap I, et al. Chili protects against aspirin-induced gastroduodenal mucosal injury in humans. Dig Dis Sci 1995;40: 5m-583.

8. Bortolotti M, Coccia G, Grossi G, Miglioli M. The treatment of functional dyspepsia with red pepper. Aliment Pharmacol Ther 2002;161075-1082. 9. Drewes AM, Schipper Is,Dimcevski G, et al. Gut pain and hyperalgesia induced by capsaicin: a human experimental model. Pain 2003;104:333-341. 10. Rodriguez-Stanley S, Collings KL, Robinson M, et al. The effects of capsaicin on reflux, gastric emptying and dyspepsia. Aliment Pharmacol Ther 2ooO;14:129-134. 11. Dib B. Effects of intrathecal capsaicin on autonomic and behavioral heat loss responses in the rat. Pharmacol Biochem Behavior 1987;28: 65-70. 12. Yoshioka M, St-Pierre S, Drapeau V, et al. Effects of red pepper on appetite and energy intake. Br J Nutr 1999;82115-123. 13.Yoshioka M, St-Pierre S, Suzuki M, Tremblay A. Effects of red pepper added to high-fat and high-carbohydrate meals on energy metabolism and substrate utilization in Japanese women. Br J Nutr 1998;80503-510.

and placebo, and 4 others dropped out because of side effects.

DOSAGE Cayenne pepper can be used liberally in the diet. Creams containing 0.025%or 0.075% capsaicin or poultices can be applied to affected areas up to four times daily.

TOXICITY Cayenne pepper is generally recognized as safe in the United States. Topically applied capsaicin may produce a local burning sensation; however, this effect goes away with time and rarely is severe enough to warrant discontinuation of use of the cream. This was the only adverse effect noted.

DRUG INTERACTIONS Although several theoretic interactions have been postulated, no clinical cases have been documented.

14. Lysy J, Sistiery-Ittah M, Israelit Y, et al. Topical capsaicin-a novel and effective treatment for idiopathic intractable pruritus ank a randomised, placebo controlled, crossover study. Gut 2003;52: 1323-1326. 15. Peikert A, Hentrich M, Ochs G. Topical 0.025% capsaicin in chronic post-herpetic neuralga: efficacy, predictors of response and long-term course. J Neurol1991;238:452-456. 16. Bjerring P, Arendt-Nielsen L, Soderberg U. Argon laser induced cutaneous sensory and pain thresholds in post-herpetic neuralgia. Quantitative modulation by topical capsaicin. Acta Derm Venereol 1990;70121-125. 17. Bemstein JE, Korman NJ, Bickers DR, et al. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol 1989; 21:265-270. 18. Watson CP, Evans RJ, Watt VR.Post-herpetic neuralgia and topical capsaicin. Pain 1988;33333-340. 19. Watson CP, Evans RJ, Watt VR, Brkett N. Post-herpetic neuralgia: 208 cases. Pain 1988;35:289-297. 20. Bemstein JE, Bickers DR, Dahl MV, et al. Treatment of chronic postherpetic neuralgia with topical capsaicin. A preliminary study. J Am Acad Dermatol1987;1793-96. 21. Petersen KL, Fields HL, Brennum J, et al. Capsaicin evoked pain and allodynia in post-herpetic neuralgia. Pain 2000;88:125-133. 22. Fusco BM, Alessandri M. Analgesic effect of capsaicin in idiopathic trigeminal neuralgia. Anesth Analg 1992;74:375-377. 23. Watson CP, Evans RJ. The postmastectomy pain syndrome and topical capsaicin: a randomized trial. Pain 1992;51:375-379. 24. Watson CP, Evans RJ, Watt VR. The post-mastectomy pain syndrome and the effect of topical capsaicin. Pain 1989;38:177-186. 25. Nelson C. Heal the burn. Pepper and lasers in cancer pain therapy. J Natl Cancer Inst 1994;86:1381-1382. 26. The Capsaicin Study Group. Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Diabetes Care 1992;15:159-165.

Capsicum frufescens (Cayenne Pepper) 27. Biesbroeck R, Bril V, Hollander P, et al. A double-blind comparison of topical capsaicin and oral amitriptyline in painful diabetic neuropathy. Adv Ther 1995;12:111-120. 28.Tandan R, Lewis GA, Krusinski PB, et al. Topical capsaicin in painful diabetic neuropathy. Controlled study with long-term follow-up. Diabetes Care 1992;15:8-14. 29. Tandan R, Lewis GA, Badger GB, et al. Topical capsaicin in painful diabetic neuropathy. Effect on sensory function. Diabetes Care 1992;15:15-18. 30. Basha KM, Whitehouse FW.Capsaicin: a therapeutic option for painful diabetic neuropathy. Henry Ford Hosp Med J 1991;39: 138-140. 31. Pfeifer MA, Ross DR, Schrage JP,et al. A highly successful and novel model for treatment of chronic p a a diabetic peripheral neuropathy. Diabetes Care 1993;16:1103-1115. 32. Forst T, PohImann T, Kunt T, et al. The influence of local capsaicin treatment on small nerve fibre function and neurovascular control in symptomatic diabetic neuropathy. Ada Diabetol2002;39:1-6.

33. Marks DR, Rapoport A, Padla D, et al. A double-blind placebocontrolled trial of intranasal capsaicin for cluster headache. Cephalalgia 1993;13:114-116. 34.McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol1992;19: 604-607. 35. Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of arthritis with topical capsaicin: a doubleblind trial. Clin Ther 1991;13:383-395. 36.Bemstein JE,Parish LC, Rapaport M, et al. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986;15:504-507. 37. Ellis CN, Berberian 8, Sulica VI, et al. A double-blind evaluation of topical capsaicin in pruritic psoriasis. J Am Acad Dermatol1993;29 438-442. 38. Lysy J, Sistiery-Ittah M, Israelit Y, et al. Topical capsaicin-a novel and effective treatment for idiopathic intractable pruritus ani: a randomised, placebo controlled, crossover study. Gut 2003;52 1323-1326.

Carnitine Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 809 Biosynthesis 810 Metabolism 810 Transportation into Tissues 810 Excretion and Degradation 810 Physiologic Functions 810 Deficiency

811

Carnitine as a Nutrient 811 Carnitine in the Infant Diet 811 Dietary Carnitine Content 812 Clinical Applications 812 Cardiovascular Disease 812 Angina 813 Recovery from Myocardial Infarction 813 Arrhythmias 813 Congestive Heart Failure 813

INTRODUCTION Camitine is an essential nutrient for the transport of long-chain fatty acids into the mitochondria1 matrix. Carnitine (beta-hydroxy/gamma-butyrobetaine) was originally isolated from meat extracts in 1905, and its exact chemical structure was determined in 1932 (Figure 76-1). However, despite extensive physiologic and pharmacologic studies in the 1930s, no physiologic role for carnitine could be Its role in human physiology remained a mystery until nearly 50 years after its discovery. The compound was virtually forgotten until Carter and colleagues4created new interest in carnitine in 1952, when they established it as a growth factor for the meal worm Tenebrio molitor (hence camitine’s other name, “vitamin BY-B for the family of vitamins and T for Tenebrio molitor). When other species of organisms were

Peripheral Vascular Disease 814 Enhancing Physical Performance 814 Alzheimer’s Disease, Senile Depression, and Age-Related Memory Defect 815 Down Syndrome 815 Kidney Disease and Hemodialysis 816 Diabetes 816 Liver Disease 816 Muscular Dystrophies 817 Low Sperm Counts and Decreased Sperm Motility 817 Chronic Obstructive Pulmonary Disease 817 Acquired ImmunodeficiencySyndrome 817 Inborn Errors of Amino Acid Metabolism 817 Protection Against Drug Toxicity 818 Attention Deficit Hyperactivity Disorder 818 Dosage 818 Toxicology 818 Drug Interactions 818

also shown to be dependent on camitine, researchers began to reexamine its role in humans. Researchers soon found that carnitine was essential in the oxidation of When the first camitinedeficient human subjects were described in 1973, it stimulated greater investigation? It had always been assumed that an individual could synthesize adequate amounts of carnitine, ingest adequate amounts of dietary camitine, or meet needs by a combination of both. The discovery that some individuals required supplemental camitine to maintain normal energy metabolism resulted in the need to consider carnitine as a vitamin or essential.6 Since camitine can be synthesized (as described later) from the essential amino acid lysine, many nutritionists and researchers have argued that it should not be considered a vitamin. Others argue that if niacin, which can be synthesized from the essential amino acid tryptophan, can be labeled a vitamin, then so should carnitine. 809

Pharmacology of Natural Medicines 0

CH3

I

II

H3C-"+-CH,-CH

I

-CH,-C-O-

I

OH

CH3 Figure 76-1

Protein bound

I I I I 1

Lysine S-adenosylmethionine SAH Trimethyllysine

L-carnitine.

Ascorbate, Fez+

BlOSYNTHESIS Carnitine is synthesized in humans from lysine with the aid of another essential amino acid, methionine. In nonmammalians, carnitine synthesis begins with stepwise methylation of free lysine by S-adenosylmethionine to produce trimethyllysine. In mammals, however, protein-bound trimethyllysine, rather than free lysine, appears to be the major precursor for carnitine ~ynthesis.*-~ Trimethyllysine is then converted through a series of enzymatic reactions to butyrobetaine. This can occur in the liver, kidney, brain, heart, and skeletal muscle. However, the conversion of butyrobetaine to camitine can only occur in the liver, kidney, and brain, as the enzyme required, butyrobetaine hydroxylase, is only present in these tissues.'" The synthesis of carnitine is largely controlled by the activity of butyrobetaine hydroxylase. This enzyme appears to be age dependent. In infancy, the activity of butyrobetaine hydroxylase has been shown to be only 12% of the normal adult mean. By 2.5 years, the activity is 30% of the adult mean, and by 15 years the level is within the standard deviation of the adult mean.1-3These data would seem to indicate the importance of preformed carnitine in breast milk. As apparent from Figure 76-2, two essential amino acids (lysine and methionine), three vitamins (ascorbate, niacin, and vitamin B6), and a metal ion (reduced iron) are required for the synthesis of carnitine. Obviously, a deficiency of any one of these nutrients would result in sigruficantly impaired carnitine ~ynthesis.'-~

METABOLISM Transportation into Tissues The heart and skeletal muscles, as well as many other tissues, depend primarily on fatty acid oxidation as a source of energy. Because they cannot synthesize carnitine, its transport into these tissues is of critical importance. Specific carnitine-binding transport proteins have been identified for several tissues (e.g., cardiac muscle, skeletal muscle, epididymis, liver, kidney).'" The transport proteins assist the transfer of carnitine from the serum into the cells via carrier-mediated transport mechanism. This active transport mechanism allows the tissues

k

Alpha-ketoglutarate + 0, Succinate + CO,

Hydroxy-trimethyllysine

Pyridoxine

Glycine

Gamma-butyrobetaine aldehyde

Gamma-butyrobetaine Ascorbate, Fez+

k

Alpha-ketoglutarate + 0, Succinate + CO,

L-carnitine 'In humans, the enzyme catalyzing this reaction occurs only in the liver, kidney, and brain Figure 76-2 Biosynthesis of carnitine.

to concentrate carnitine at levels 10 times greater than those found in the plasma.

Excretion and Degradation Urinary excretion of unchanged carnitine is the major route of elimination of carnitine. As the tubular reabsorption of camitine by the kidneys is extremely efficient, the daily turnover of carnitine is estimated to be only 4% to 6% of the total body pool of the healthy indi~ i d u a l . ' -Factors ~ that increase carnitine excretion and degradation are discussed later under causes of carnitine deficiency.

PHYSIOLOGIC FUNCTIONS Carnitine's basic function is in the transport of longchain fatty acids into the mitochondrial matrix and the facilitation of beta-~xidation.'-~ As acyl coenzyme A formed in the endoplasmic reticulum or outer mitochondrial membrane cannot penetrate the inner mitochondrial membrane to the site of fatty acid beta-oxidation, the acyl group must be transferred from CoA to carnitine. The acyl-carnitine molecule then transports the fatty acid molecule to the mitochondrial surface of the inner mitochondrial membrane and releases the fatty acid into the matrix, where beta-oxidation occurs. Figure 76-3 summarizes this process.

Carnitine CoASH

Fatty acyl-CoA

Outside mitochondrion

Mitochondria1 membrane

-

-

-

’

’

--- - - Carnitine-

Acyl-carnitine -

A---A-

- - _ _ - -

-----Inside mitochondrion

CoASH

Dietary deficiency of the precursor amino acids lysine and methionine Deficiency of any cofactor (e.g., iron, ascorbic acid, pyridoxine, niacin) required by the enzymes of the lysine to carnitine pathway Genetic defect of carnitine biosynthesis Defective intestinal absorption of carnitine Liver or kidney dysfunction that impairs carnitine synthesis Increased metabolic losses of carnitine due to catabolism, impaired tubular resorption, or genetic defect Defective transport of carnitine from tissues of synthesis to tissues where it is maximally used Increased carnitine requirement due to a high-fat diet, drugs (e.g., valproic acid), metabolic stress, or disease

Fatty acyl-CoA

Beta-oxidation of fatty acid Figure 76-3 Role of carnitine in the transport of longchain fatly acids through the inner mitochondria1membrane.

Camitinehas several other physiologicfunctionsincluding oxidation of the ketoacid analogs of the branchedchain amino acids valine, leucine, and is~leucine.~‘~ This function is extremely important during fasting, starvation, and exercise. Camitine concentrations are extremely high in the epididymis and spermatozoa, suggesting a role for carThe epididymis nitine in male reproductive functi~n.l-~ derives the majority of its energy requirements from lipids, as do the spermatozoa, during transport through the epididymis. After ejaculation, spermatocytesdepend on glycolysis of glucose and fructose and on oxidation of lactate and pyruvate. Carnitine (in the form of acetylcarnitine, which is derived from pyruvate) serves as a readily available substrate. The motility of ejaculated sperm correlates positively with acetylcarnitine ~0ntent.l.~

DEFICIENCY Carnitine deficiency may arise from several causes, as listed in Box 76-1. Carnitine deficiency states have been classified into two major groups: Systemic carnitine deficiency Myopathic deficiency Diagnosis of systemic camitine deficiency can be made using serum or 24-hour urine samples. Total, free, and esterified camitine levels should be determined. In myopathic carnithe defiaency, diagnosis quires skeletal muscle b i ~ p s y . ~ To date, no patients with primary systemic camitine deficiency have been identified. The systemic deficiency has always been secondary to some other factor rather than a defect in carnitine ~ynthesis.l-~,~fi

The consequences of systemic carnitine deficiency are impaired lipid metabolism and lipid accumulation in the skeletal muscles, myocardium, and liver. Progressive muscle weakness with lipid storage myopathy is found in all patients.’”r7 In adults, auxiliary nonmitochondrial oxidation mechanisms are apparently stimulated, resulting in some degree of adaptation. This adaptation occurs in starvation, diabetes, high-fat diets, and other causes of secondary carnitine deficiency. Systemic camitine deficiencies usually respond dramatically to orally administered supplemental ~-carnitine.’,~ Children are apparently unable to adapt to low carnitine levels as well as adults? Several cases of carnitine deficiency in children, presenting a clinical picture resembling Reye syndrome (acute encephalopathy associated with altered liver function due to lipid accumulation), have been reported.810 The clinical presentation of secondary carnitine deficiency in children includes hypotonia, failure to thrive, recurrent infections, encephalopathy, nonketotic hypoglycemia, and cardiomyopathy.7 Several fatal cases of systemic camitine deficiency have been In primary myopathic carnitine deficiency, there is an inborn error of carnitine metabolism that is limited to skeletal muscle.7,8The defect appears to be in the transport of camitine into the skeletal muscle as serum carnitine, and the camitine levels in other tissues are normal. Severe lipid-storage myopathy is the result. Supplemental camitine is generally of no value in myopathic carnitine deficiency. Rather, improvements have been noted using diets high in medium-chain triglycerides and low in long-chain triglycerides.7

CARNlTlNE AS A NUTRIENT Carnitine in the Infant Diet Oxidation of long-chain fatty acids, which requires carnitine, is well known to be critical to the survival and normal development of the newborn? Carnitine concentrations in fetal and umbilical cord blood are higher than in maternal blood, suggesting the placenta may actively

transport carnitine to the fetus, since camitine synthesis is not fully d e ~ e l o p e d .The ~ initial camitine concentration in the newborn depends on maternal camitine concentration. Supplementation of carnitine during pregnancy may be necessary to ensure adequate tissue concentrations in the fetus, as well as the mother. Serum camitine levels are typically lower in pregnant women than nonpregnant women, presumably due to increased excretion.'*J3 The newborn infant is almost entirely dependent on external sources of ~ a m i t i n eBreastfed .~ infants have the best chance of achieving optimal camitine concentrations. The bioavailability of camitine from breast milk is significantly greater than that in cow's milk-based formulas,t4 and soy-based infant formulas contain no detectable carnitine.3 Formula feeding may necessitate supplemental camitine to achieve normal carnitine concentrations in these infants. Camitine administration to preterm infants has potentiated weight gain and growth.I5 In preterm infants, serum values of carnitine decrease dramatically due to limited storage capacity coupled with a decreased ability to synthesize carnitine. Administration of L-camitine (LC) to preterm infants is considered important.

Dietary Carnitine Content Analysis of several hundred foods for carnitine content indicates that meat and dairy products are the major dietary sources of camitine.3 In general, the redder the meat, the higher the carnitine content. Cereals, fruits,and vegetables contain little or no camitine. Preliminary studies indicate that the daily diet contains 5 to 100 mg of ~arnitine.~

CLINICAL APPLICATIONS Many disease states, in addition to classical as well as secondary camitine deficiency, may benefit from camitine administration. Evidence supports the assertion that supplemental carnitine may benefit the conditions listed in Box 76-2 and discussed later. Carnitine is available in several different forms. The form being used must be LC alone or bound to either acetic or propionic acid. The D form of camitine (discussed later in the section on safety issues) should never be used. As to which form is best, it depends on the objective. For Alzheimer's disease and brain effects, it appears that L-acetylcarnitine (LAC) may provide the greatest benefit. For angina, L-propionylcamitine (LPC) may be the best choice because the myocardium appears to prefer it to L-acetylcamitine, followed by LC.16,17LC is, however, the most widely available, least expensive, and best studied form of camitine.

Cardiovascular diseases Angina pectoris Acute myocardial infarction Myocardial necrosis Arrhythmias and cardiotoxicity induced by drugs Familial endocardial fibroelastosis Cardiac myopathy Idiopathic mitral valve prolapse Elevated cholesterol levels Elevated triglyceride levels Enhancing physical performance Alzheimer's disease, senile depression, and age-related memory defects Kidney disease and hemodialysis Diabetes Liver diseases Alcohol-induced fatty liver disease Liver cirrhosis Muscular dystrophies Low sperm counts and decreased sperm motility Chronic obstructive pulmonary disease Acquired immunodeficiency syndrome Inborn errors of amino acid metabolism Organic aciduria Glutaric aciduria lsovaleric acidemia Propionicacidemia Methylmalonic aciduria Toxicity from various drugs

Cardiovascular Disease Normal heart function is critically dependent on adequate concentrations of carnitine. A deficiency of camitine in the heart would be similar to trying to run an automobile without a fuel pump. Despite plenty of fuel, there is no way to get it to the engine. Although the normal heart stores more camitine than it needs, if the heart does not have a good supply of oxygen, carnitine levels quickly decrease. This lack of oxygen leads to decreased energy production in the heart and increased risk for angina and heart disease. Camitine is useful in angina due to its ability to improve oxygen usage and energy metabolism by the myocardium. As a result of improving fatty acid usage and energy production, camitine also prevents the production of toxic fatty acid metabolites.18 These compounds are extremely damaging as they disrupt cellular membranes. Changes in the properties of cell membranes throughout the heart are thought to contribute to impaired contraction of the heart muscle and increased susceptibility to irregular beats, and eventual death of heart tissue. Supplementing the diet with carnitine increases heart camitine levels and has been shown to prevent the production of fatty acid metabolites, which

Carnitine can damage the heart, as well as boost antioxidant enzyme levels. In addition to angina, all of these effects make carnitine beneficial in recovery from a heart attack, cardiomyopathies, arrhythmias, and congestive heart failure.19,20 Carnitine also exerts a beneficial effect on blood lipids by lowering triglycerides and total cholesterol levels while raising high-density lipoprotein (HDL) cholesterol. After 4 months of therapy with LC in patients with elevated blood lipids, typical changes observed are a 20% reduction for total cholesterol, a 28% decrease in triglycerides, and a 12% increase in HDL levels.21PDue to the higher cost of carnitine compared with other natural agents (e.g., inositol hexaniacinate, garlic, and guguhpid), its use should be reserved for those cases unresponsive to these more cost-effective measures. Carnitine has also been shown beneficial in the treatment of intermittent claudication, which is a condition like angina, but, instead of the pain occurring in the heart, it occurs usually in the calf muscle. Like angina, the pain is described as a cramp or tightness. The cause of the pain is reduced oxygen delivery, along with an increase in the production of toxic metabolites and cellular free radicals. Its benefits in peripheral vascular disease are the result of improved energy production during ischemia rather than any effect on blood flow. Nonetheless, good results have been obtained in intermittent claudication and other peripheral vascular diseases (discussed later).

Angina Numerous clinical trials have demonstrated that camitine improves angina and heart disease (note that all three commercial forms have been used).19,23-29 Supplementation with carnitine normalizes heart carnitine levels and allows the heart muscle to use its limited oxygen supply more efficiently. This translates to an improvement in cases of angina. Improvements have been noted in exercise tolerance and heart function. The results indicate that carnitine is an effective alternative to drugs in cases of angina. LPC may offer the greatest benefit in angina, as well as in other cardiovascular conditions. LPC is taken up by myocardial cells much more rapidly than other forms of carnitine.16In one study LPC (15 mg/kg intravenously) significantly diminished myocardial ischemia as demonstrated by a sigruficant 12% and 50% reduction in STsegment depression and left ventricular end-diastolic pressure, respectively, during the atrial pacing test?O Left ventricular ejection fraction increased by 18%. Recovery of heart function after exercise occurred much quicker in the LPC group compared with the placebo group. LC and LAC have also shown good results. In one of the larger studies, 200 patients with exercise-induced stable angina received either standard therapy alone (e.g., nitroglycerine, calcium channel blockers, beta-blockers,

antihypertensives, diuretics, digitalis, antiarrhythmics, anticoagulants, hypolipidemics) or in combination with 2000 mg/day of LC over a 6-month period.31Compared with the control group, the patients on LC exhibited a significant reduction in premature ventricular contractions at rest, as well as an increased tolerance to exercise as demonstrated by an increased maximal cardiac frequency, increased maximal systolic blood pressure, cardiac output, and reduced ST-segment depression (70% reduction in the LC group vs. no change in the control group). Reductions in low-density lipoprotein (LDL) cholesterol (So/)and triglycerides (12%)were also noted. These results are highly significant and provide a strong rationale for the inclusion of carnitine in patients using standard medical therapy.

Recovery from Myocardial Infarction In addition to benefiting angina patients, carnitine has also been shown to be useful in helping individuals recover more quickly from a heart attack.19 In one double-blind study of 160 patients who had been released from a hospital after a heart attack, the group receiving 4 g of LC daily showed significant improvements in heart rate, blood pressure, angina attacks, rhythm disturbances, and clinical signs of impaired heart function compared with the control In Italy a larger study involving 472 patients showed additional benefits3 The study was performed to evaluate the effects of LC administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction. Placebo or LC was given at a dose of 9 g/day intravenously for the first 5 days and then 6 g/day orally for the next 12 months. Left ventricular volumes and ejection fraction were evaluated on admission, at discharge from hospital, and at 3,6, and 12 months after acute myocardial infarction. A significant attenuation of left ventricular dilation in the first year after acute myocardial infarction was observed in patients treated with LC compared with those receiving placebo. The percent increase in both end-diastolic and end-systolic volumes from admission to 3-, 6-, and 12-month evaluation was significantly reduced in the LC group.

Arrhythmias In double-blind trials, reductions in the use of conventional antiarrhythmic drugs have occurred in patients with angina who have received carnitine.19

Congestive Heart Failure Several double-blind clinical studies have shown that carnitine (again, LPC appears to be more effective than LC or LAC) improves cardiac function in patients with In one double-blind study of congestive heart fai1~re.l~ LPC versus placebo in a group of 60 patients with mild

Pharmacology of Natural Medicines

to moderate (New York Heart Association [NYHA] classes I1 and 111)congestive heart failure, LPC produced demonstrable benefit.MThe group was made up of men and women between 48 and 73 years old in chronic treatment with digitalis and diuretics for at least 3 months and who still displayed symptoms. Thirty of these patients were chosen randomly and for 180 days received 500 mg of LPC three times a day in addition to their usual treatment. At basal conditions and after 30, 90, and 180 days, the maximum exercise time was evaluated using an exercise tolerance test performed on an ergometer bicycle, and the left ventricular ejection fraction was tested by means of echocardiography. After 1 month of treatment, the patients treated with LPC, compared with the control group, showed signhcant increases in the values of both tests, increases that became even more evident after 90 and 180 days. At the stated times, the increases in the maximum exercise time were 16.4%,22.9%, and 25.9%, respectively. The ventricular ejection fraction increased by 8.4%, ll.6%, and 13.6%, respectively. In another double-blind study with similar patients, at the end of 6 months of treatment, maximum exercise time on the treadmill increased 16.4% and the ejection fraction increased by 12.1% after 180 days in the group treated with PLC at a dosage of 1 g twice Even more obvious benefits were seen in a 3-year study of 80 patients with moderate to severe heart failure (NYHA class 111 to IV)caused by dilated cardiomyopathy. After a period of stable cardiac function up to 3 months, patients were randomly assigned to receive either carnitine (2 g/day orally) or placebo. After a mean of 33.7 months of follow-up (range 10 to 54 months), 70 patients were in the study: 33 in the placebo group and 37 in the camitine group. At the time of analysis, 63 patients were alive. Six deaths occurred in the placebo group, and one death in the camitine group. Survival analysis showed that patients’ survival was statistically sigruficant in favor of the camitine group.%

Peripheral Vascular Disease All three forms of carnitine (2 to 4 g daily) have been shown to improve the walking distance without pain in patients with intermittent claudication. Presumably this improvement is the result of improved energy metabolism within the muscle, as carnitine was not shown to improve blood flow to the calf. LPC appears to offer better effects than either LC or However, in one double-blind study, LC at a dosage of 2 g twice daily demonstrated a 75% increase in walking distance after only 3 weeks of therapy.39 In the largest study with LPC, 485 patients with intermittent claudication were randomized to placebo or LPC (2 g/day) for 12 months. Maximal walking distance increased by 62% on LPC and by 46% on placebo in all

patients. However, when only those patients with more severe disease status were analyzed, the maximal walking distance increased by 98% in the LPC group compared with only 54% in the placebo g r o u ~ . ~

Enhancing Physical Performance The ability to enhance exercise tolerance and physical performance with camitine may not be limited to patients with cardiovascular disease, as carnitine supplementation has also been shown to be of benefit in healthy subjects and athletes. Efficient use of fatty acids by skeletal muscle, like the myocardium, also depends on an adequate supply of carnitine. Carnitine supplementation (usually 2 g two to three times daily) has resulted in sigruficant improvements in cardiovascular function in response to exercise in several double-blind studies in both athletes and normal subj e c t ~ ! Compared ~~~ with control groups, the subjects on carnitine have shown not only improvements in exercise intensity over time, but also evidence of improved energy metabolism within the muscle (lowered blood lactic acid and free fatty acid levels). Obviously, the improved production of energy by the exercising muscle, as well as improved heart function, could be responsible for carnitine’s ability to enhance physical performance. Although at least three studies have shown the benefits of carnitine on exercise performance to be of no more value than a placebo, carnitine supplementation should still be viewed as beneficial, especially in endurance-related events.M The reason behind this statement is the fact that studies have demonstrated carnitine improves energy-producing enzyme levels in longdistance runners.47 These athletes received either a placebo or 2 g of LC twice daily for 4 weeks. Runners receiving LC showed a significant increase in enzymes involved in energy production (cytochrome c reductase and cytochrome oxidase). In contrast, there were no changes in the placebo group. One study examined the influence of L-carnitine L-tartrate (LCLT) at a dosage of 2 g per day for 3 weeks on markers of purine catabolism, free radical formation, and muscle tissue disruption after squat exercise. Exercise-induced increases in plasma markers of purine catabolism (hypoxanthine, xanthine oxidase, and serum uric acid) and circulating cytosolic proteins (myoglobin, fatty acid-binding protein, and creatine kinase) were significantly reduced by LCLT supplementation. Exerciseinduced increases in plasma malondialdehyde returned to resting values sooner during LCLT compared with placebo. The amount of muscle disruption from MRI scans during LCLT was 41% to 45% of the placebo area. These data indicate that LCLT supplementation is effective in assisting recovery from Interestingly, normal subjects taking carnitine have improved cardiovascular function and a more rapid

Carnitine

return of heart rate to the resting rate after e~ercise.4~ The significance of these improvements is that camitine apparently mimics the benefits in heart and vascular function produced by regular exercise training without working up a sweat. Carnitine supplementation appears to be beneficial in elderly subjects complaining of muscle fatigue. In one double-blind study, 84 elderly subjects with onset of fatigue following even the slightest physical activity were randomized to receive carnitine 2 g twice daily or a placebo for 30 days. At the end of the study, compared with placebo, the carnitine-treated patients showed significant improvements in the followingparameters: total fat mass (-3.1 vs. -0.5 kg), total muscle mass (+2.1 vs. +0.2 kg), total cholesterol (-1.2 vs. +0.1 mmol/L), LDL-C (-1.1 VS.-0.2 m o l / L ) , HDL-C (+0.2 VS. +0.01 m o l / L ) , triglycerides (-0.3 vs. 0 mmol/L), apoAl(4.2 vs. 0 g/L), and apoB (-0.3 vs. -0.1 g/L). Fatigue scores decreased significantly by 40% (physical) and 45% (mental) in subjects taking carnitine, compared with 11% and 8%, respectively, in the placebo group.5o

Alzheimer’s Disease, Senile Depression, and Age-Related Memory Defect Much research has been conducted over the past 20 years with LAC in the treatment of Alzheimer’s disease, senile depression, and age-related memory defects. As described earlier, LAC is a molecule composed of acetic acid and LC bound together. This reaction occurs naturally in the human brain; therefore it is not exactly known how much greater an effect is noted with LAC versus LC or PAC. However, LAC is thought to be substantially more active than these other forms of camitine in conditions involving the brain.5152 LAC is structurally related to acetylcholine, a major neurotransmitter responsible for memory and proper brain function. In Alzheimer’s disease, and to a lesser extent the normal aging human brain, there is a defect in the utilization of acetylcholine. The close structural similarity between LAC and acetylcholine led researchers to begin testing LAC in Alzheimer’s disease. The results have been encouraging. Researchers have now shown that LAC does indeed mimic acetylcholine and is of benefit not only in patients with early-stage Alzheimer’s disease but also in elderly patients who are depressed or who have impaired memory.52It has also been shown to act as a powerful antioxidant within the brain cell, stabilize cell membranes, improve energy production within the brain cell, and enhance or mimic the function of a~etylcholine.5~ The results in delaying the progression of Alzheimer’s disease have been promising. The studies have been well controlled and extremely t h o r o ~ g h .For ~ ~example, ,~~ in one study LAC (2 g twice daily) or placebo was given to 130 patients with Alzheimer’s disease over the course

of 1 year.56The patients were evaluated by 14 different outcome measures such as assessment scales, cognitive function tests, memory tests, and physician evaluations. The group receiving the LAC had better outcome scores in all cases. Positive studies, however, have been somewhat offset by studies showing little benefit. For example, in a 1-year, multicenter, double-blind study in 229 patients with mild Alzheimer’s disease, LAC alone failed to slow decline, though it did reduce the decline in attenti0n.5~ Memory impairment need not be as severe as in Alzheimer’s disease in order for LAC to demonstrate benefit.= In one double-blind study of 236 elderly subjects with mild mental deterioration, as evident by detailed clinical assessment, the group receiving 1500 mg of LAC daily demonstrated sigruficant improvement in mental function, particularly in memory and constructional thinking.@-’ Many of the elderly suffer from depression not only as a result of experiencing a great deal of loss in their lives but also because of the biochemical changes in the brain associated with aging. LAC has been shown to improve depression in elderly subjects in double-blind studies using assessment scales standard to scientific research of antidepressant drugs (e.g., Hamilton Depression Scale, Clinical Global Impression, Sandoz Clinical Assessment). The usual dosage has been 500 mg three times daily. Elderly subjects with the highest depression scores are usually the ones who benefit the most from LAC.61*62 LAC also appears helpful in enhancing the effects of acetylcholinesterase inhibitors. In one open study, LAC (2 g/day orally for 3 months) was given to 23 patients with mild Alzheimer’s disease who had not responded to treatment in association with donepezil or rivastigmine. Clinical effects were evaluated by assessing cognitive functions, functional status, and behavioral symptoms. The response rate, which was 38% after the drug treatment alone, increased to 50% after the addition of LAC.63 This additive effect may be useful whenever a patient does not respond to either treatment alone.

Down Syndrome Given that both Down syndrome and Alzheimer’s disease are characterized by a deficit in cholinergic transmission, a study was conducted to assess the effect of a 90-day treatment with LAC in individuals with Down syndrome.” Findings were evaluated statistically and compared with three further groups of subjects: untreated Down syndrome, mental deficiency due to other cases treated, and not treated with LAC. Treated Down syndrome patients showed statistically significant improvements of visual memory and attention both in absolute terms and in comparison with the other groups. No improvement was found in mentally deficient non-Down syndrome subjects, so the favorable effect of LAC appears to be

Pharmacology of Natural Medicines specific for Down patients. An effective dosage is 20 mg of LAC per 2 lb of body weight. The action of LAC in these pathologies may be related to its direct and indirect cholinomimetic effect.

Kidney Disease and Hemodialysis Carnitine supplementation is much indicated in kidney diseases because the kidney is a major site of camitine synthesis.Damage to the kidney or reduced kidney function has a profound effect on camitine metabolism. It is well established that patients undergoing hemodialysis suffer from carnitine deficiency due to the loss of considerable quantities of camitine during dialysis, as well as decreased synthesis. Serum camitine levels drop nearly 80% during hemodialysis.’” Supplementation with LC (15 mg/kg of intravenous LC at the end of each hemodialysis) helps maintain carnitine status6 Carnitine supplementation has been extensively studied in patients undergoing hemodialysis due to chronic renal failure. These studies indicated that LC supplementation is effective in reducing triglyceride levels while raising HDL-cholesterol levels and thus helps to decrease the risk of heart disease in dialysis Carnitine-treated dialyzed patients have also shown additional benefits, including the f~llowing~O-~~: Disappearance of angina pectoris and arrhythmias occurring during dialysis Reduction of muscle symptoms including muscle cramps Increased muscle mass Sigruficant improvement of the chronic anemia seen in these patients as demonstrated by an increased hematocrit, hemoglobin, and red blood cell count Improved insulin sensitivity and reduced stress on pancreatic beta cells Since the early 199Os, a major advancement in the treatment of anemia associated with hemodialysis is recombinant human erythropoietin (EPO) therapy. However, this therapy is expensive and has side effects. In one study LC (1 g intravenously after every dialysis session) administered for 6 months led to a significantreduction in dosage, as well as improvements in membrane fragility and endogenous EPO secretion.74Given the high cost of EPO, if doctors are unwilling to follow this procedure, insurance companies should get involved and force dialysis units to employ LC.

Diabetes Patients with diabetes typically have deficient carnitine status. Studies reveal relationships between low camitine status and increased plasma fatty acids, which negatively affect insulinaction, so it has been recommended that free camitine determinations should be made even if the patient has good metabolic ~0ntr0l.7~ Given the risk of atherosclerotic cardiovascular disease and reduced

kidney and liver function found in diabetic patients, it may simply be more rational to supplement all diabetic patients with LC. Carnitine supplementation has been shown to greatly improve peripheral vascular function, as well as nerve function, in patients with In one doubleblind study, 333 patients with diabetic neuropathy were given LAC or placebo intramuscularly at a dosage of 1000 mg/day for 10 days and continued orally at a dosage of 2000 mg/day for the remainder of the 12-month study. Among the 294 patients with impaired electrophysiologic parameters at baseline, those treated with LAC showed a statistically sigruficant improvement in mean nerve conduction velocity and amplitude compared with placebo. After 12 months of treatment, mean VAS scores for pain were sigruficantly reduced from baseline by 39% in LAC-treated patients compared with 8% in placebo recipients?* Camitine supplementation may also affect blood lipids in patients with type 2 diabetes, particularly lipoprotein(a). In a study in type 2 diabetes, 2000 mg of carnitine daily lowered lipoprotein(a) levels by roughly 20% after 6 months, while in another study of patients with markedly elevated lipoprotein(a) levels, even greater reductions were n ~ t e d . ~ ~ , ~

Liver Disease Carnitine plays an extremely important role in the usage and metabolization of fatty acids in the liver. Some evidence indicates that carnitine deficiency within the liver promotes fatty infiltration (also known as steatosis or liver Alcohol ingestion is a common cause of fatty infiltration of the liver. It has been suggested that chronic alcohol consumption results in a functional deficiency of carnitine. A functional deficiency means that there is plenty of carnitine around, but its function is inhibited just as if there was a deficiency. Many commonly used agents for fatty infiltration such as choline, niacin, and cysteine appear to have little value in relieving alcohol-induced fatty liver. However, camitine sigruficantly inhibits, and reverses, alcohol-induced fatty liver disease!* Since carnitine normally assists fatty acid transport and oxidation in the mitochondria, a high liver carnitine level may be necessary to handle the increased fatty acid load produced by alcohol consumption or other liver injury.“ Supplementalcarnitine has been shown to reduce free fatty acid levels in patients with liver cirrhosis and to reduce serum triglycerides and liver enzyme levels while elevating HDL-cholesterol in alcohol-induced fatty liver di~ease.*l-~~ Camitine’s use in liver disorders associated with fatty infiltration appears warranted, especially when these changes are due to the ingestion of alcohol or exposure to xenobiotics (manmade chemicals toxic to biologic processes such as pesticides and herbicides).

Carnitine Carnitine has also proven helpful in relieving the tremendous fatigue associated with interferon-alpha (IFN-a)treatment for hepatitis C. In one study 50 patients with chronic hepatitis treated with IFN-a at a dosage of 3 million IUthree times weekly were given either carnitine (2 g daily) or placebo for 6 months. While IFN-a alone induces fatigue in the majority of cases, in contrast patients treated with IFN plus carnitine show a marked and early sigruficantreduction of both mental and physical fatigue levels.@

Muscular Dystrophies Patients with various muscular dystrophies have reduced levels of carnitine in their skeletal muscles.s87 Although levels are not as low as those observed in patients with classical myopathic carnitine deficiency, the low carnitine levels are thought to contribute to the muscular weakness experienced by these patients. Unfortunately, it is undetermined if supplemental carnitine would be of any value in patients with muscular dystrophy.

In another double-blind study, 86 men with infertility received carnitine therapy (2 g/day) or placebo for 2 months followed by a 2-month washout period, crossover, and another 2-month study. A statistically significant improvement in semen quality was seen after the LC therapy for sperm concentration and total and forward sperm motility. The increase in forward sperm motility was more significant in patients with lower initial values (i.e., <5 x lo6 or <2 x lo6 of forward motile sperm/ejaculate or sperm/ml, respe~tively).~~

Chronic Obstructive Pulmonary Disease Patients with chronic respiratory insufficiency are often severely affected by even the simplest physical activity. Treatment with LC (2 g three times/day) resulted in significant improvements in exercise ~apability.~~

Acquired Immunodeficiency Syndrome

Several reports indicate that systemic carnitine deficiency may be a problem in patients with acquired immunodeficiency syndrome (AIDS).Reduced levels of serum carLow Sperm Counts and Decreased nitine are most often found in AIDS patients. However, Sperm Motility more important is the carnitine depletion in peripheral blood mononuclear cells (PBMCs). In fact, even AIDS In the human sperm, high carnitine concentrations are patients with normal serum carnitine levels demonstrate critical to sperm energy metabolism. Several studies have low levels of carnitine in white blood ~ells.9~ Increasing the shown that the level of free carnitine in seminal fluid is content of peripheral white blood cells strongly inversely correlated with sperm count and m ~ t i l i t y . ~ ~carnitine ,~~ improved lymphocyte function, highlighting the imporThe lower the carnitine content, the more likely it is that tance of carnitine to immune function. a man is infertile. LC has been shown to prevent the toxicity of the drug Given the known physiologic role of carnitine in AZT on the mitochondria of the muscle cells.94 sperm function and its link to male infertility, a study Azidothymidine (AZT) poisons the mitochondria of the was designed to assess the therapeutic effect of carnitine muscle, leading to abnormal energy production within in men with low sperm counts and depressed sperm the muscle, which manifests clinically as muscle fatigue motility.% One hundred men selected from infertility and pain. If LC can prevent this negative effect of AZT clinics participated in the ”Italian Study Group on carniin human patients with AIDS, it would be a major tine and male infertility.” Each subject was given 3000 mg improvement in the clinical management of AIDS. of LC daily for 4 months. Preliminary studies indicate that LC supplementation The study results indicated that LC increased sperm can improve immune function and reduce the level of counts and sperm motility, in both a qualitative and a HIV-induced immune suppression. When AIDS patients quantitative manner: being treated with AZT were given 6 g of LC/day, it led The number of ejaculated sperm increased from 142 to to sigruficant increased PBMC proliferation and reduced 163 billion. blood levels of triglycerides and circulating tumor necroThe percentage of motile sperm increased from 26.9% sis fact0r.9~Given the suspected systemic carnitine defito 37.7%. ciency, along with the tremendous safety of use, The percentage of sperm with rapid linear progression carnitine supplementation appears to be warranted in increased from 10.8% to 18%. treating AIDS. The mean sperm velocity increased from 28.4% to 32.5%. The results are even more impressive if only patients with the poorest sperm motility are studied. This subgroup saw even more significant gains on all parameters. For example, the percentage of motile sperm increased from 19.3% to 40.9%, and the percentage of sperm with rapid linear progression increased from 3.1% to 20.3%.

Inborn Errors of Amino Acid Metabolism Use of carnitine to treat inborn errors of metabolism involving the urea acid cycle appears to be well justified. Preliminary studies have shown impressive therapeutic response to LC supplementation in cases of glutaric aciduria, isovaleric acidemia, propionicacidemia, and methylmalonic a ~ i d u r i a . ~ ~ ~ ~

Pharmacology of Natural Medicines

Protection Against Drug Toxicity Carnitine has been shown to protect against the damaging effectson the heart produced by the chemotherapy drug adriamycin.lmCamitine has also been shown to improve the symptoms attributed to anticonvulsant medications such as valproic acid (trade names: Depa, Depakene, Depakote, and Deproic) and carbamazepine (trade names: Epitol and Tegretol).101J02 However a subsequent study has challenged the need to administer carnitine prophylactically, since no sipficant differences were noted in well-being scores between the carnitine group and the placebo group.'O3

Attention Deficit Hyperactivity Disorder Preliminary evidence indicates that carnitine may be beneficial in attention deficit hyperactivity disorder. In one double-blind, placebecontrolled, double-crossover trial, 13 of 24 boys receiving carnitine demonstrated a significant positive response in school and home behavior.lap

and carefully monitoring patients with impaired renal function.

TOXICOLOGY LC is extremely safe, with no sigrufrcant side effects ever reported in human clinical studies. Again, only LC should be used. The D form, the mirror image of the L form, has produced side effects, indicating that it interferes with the natural L form of carnitine. Patients undergoing hemodialysis given a mixture containing D,L-camitine for 45 days experienced muscle pain and loss of muscle function presumably due to lack of energy.'" The symptoms disappeared on cessation of D,L-Carnitine supplementation. Subsequent studies showed that Dcamitine produces an LC deficiency in cardiac and skeletal rnu~c1e.'~~ Although LC results in sisruficant improvement in exercise tolerance in angina patients, D,L-carnitine actually dangerously reduces exercise tolerance in these patients.

Drug Interactions

The daily dosage of LC in all of its forms has typically been between 1500 and 4000 mg in divided doses. Given the safety of carnitine, it is better to err on the side of using too much rather than too little. The exception is in patients undergoing hemodialysis. A paradoxic effect on triglyceride levels and platelet aggregation in patients on hemodialysis has been reported.'05 Slightly higher doses were used (3 g/day) compared with other studies of supplementation in chronic renal failure (typical dose 20 mg/kg body weight or 2 g/day). In addition, the study size was extremely small, and the results conflict with other studies using similar doses. However, it appears wise to reduce the risk of this effect by using lower doses

No adverse interactions between carnitine and any drug or nutrient are known. Carnitine and coenzyme Qlo appear to work synergistically when combined.lWThe same is true for pantethine.l'O Perhaps the most important interaction is with choline. In young adult women, daily choline supplementation (20 mg/kg body weight) resulted in a 75% lower urinary carnitine excretion than in controls, without significantly altering plasma carnitine concentrations. Studies in guinea pigs demonstrated that choline supplementation resulted in a significantly lower urinary excretion and higher skeletal muscle carnitine concentrations. These studies indicate that choline supplementation results in a conservation of carnitine and may increase intracellular camitine levels.'"

1. Bremer J. Camitine-metabolism and functions.Physiol Rev 1983;63: 1420-1480. 2. Bamji MS. Nutritional and health implications of lysine camitine relationship. World Rev Nutr Diet 1984;44:185-211. 3. Borum PR. Camitine. Annu Rev Nutr 19832233-259. 4. Carter HE, Bhattacharyya PK, Weidman KR, Fraenkel G. Chemical studies on vitamin BT isolation and characterization as camitine. Arch Biochem Biophys 1952;38:405-416. 5. Engel AG, AngeLini C. Camitine deficiency of human skeletal muscle with associated lipid storage myopathy: a new syndrome. Science 1973;1798%902. 6. Borum PR, Bennett SG.Carnitine as an essential nutrient. J Am Coll Nutr 19865~177-182. 7. Gilbert EF. Camitine deficiency. Pathology 1985;17161-171. 8. Winter SC,SzabeAczel S, Curry CJ, et al. Plasma camitine deficiency, clinical observations in 51 pediatric patients. Am J Dis Child 1987; 141660-665.

9. Glasgow AM, Eng G, Engel AG. Systemic carnitine deficiency simulating recurrent Reye syndrome. J Pediatr 1980;96889-891. 10. Chapoy PR, Angelini C, Brown WJ, et al. Systemiccarnitine deficiency. A treatable inherited lipid storage disease presenting as Reye's syndrome. N Engl J Med 1980;3031389-1394. 11. Rebouche CJ, Engel AG. Camitine metabolism and deficiency syndromes. Mayo Clin Proc 1983;58:533-540. 12. Scholte HR, Stinis JT, Jennekens FG. Low camitine levels in serum of pregnant women. N Engl J Med 1979;299:1079-1080. 13. Cederblad G, Fahraeus L, Lindgren K. Plasma carnitine and renalcamitine clearanceduring pregnancy. Am J Clin Nutr 1986;44:379-383. 14. Warshaw JB, Curry E. Comparison of serum carnitine and ketone body concentrations in breast and in formula-fed infants. J Pediatr 198097122-125. 15. Ardissone P, Baccolla D, Berberis L, et al. The effects of treatment with L-carnitine of hypoglycemia in pre-term AGA infants. Curr Ther Res 1985;38:256-264.

DOSAGE

16. Siliprandi N, Di Lisa F, Pivetta A, et al. Transport and function of L-camitine and L-propionylcamitine: relevance to some cardiacmyopathies and cardiac ischemia. Z Kardioll987;76(suppl5):3440. 17.Paulson DJ, Traxler J, Schmidt M. Protection of the ischaemic myocardium by L-propionylcarnitine: effects on the recovery of cardiac output after ischaemia and repurfusion, camitine transport, and fatty acid oxidation. Cardiovasc Res 1986;20336-341. 18. Opie LH. Role of camitine in fatty acid metabolism of normal and ischemic myocardium. Am Heart J 1979;97373-378. 19. Goa KL, Brogden RN. L-camitine. A preliminaxy review of its pharmacokinetics, and its therapeutic use in ischemic cardiac disease and primary and secondary camitine deficienciesin relationship to its role in fatty acid metabolism. Drugs 1987;34:1-24. 20. Gurlek A, Tutar E, Akcil E, et al. The effects of L-camitine treatment on left ventricular function and erythrocyte supemxide dismutase activity in patients with ischemic cardiomyopathy. Eur J Heart Fail 2000;2:189-193. 21. Pola P, Tondi P, Dal Lago A, et al. Statistical evaluation of long-term L-camitine therapy in hyperlipoproteinemias. Drugs Exp Clin Res 1983;9925-934. 22. Pola P, Savi M, Grilli R, et al. Camitine in the therapy of dyslipidemic patients. Curr Ther Res 1980;27208-215. 23. Silverman NA, Schmitt G, Vishwanath M, et al. Effect of camitine on myocardial function and metabolism following global ischemia. Ann Thorac Surg 1985;4020-25. 24. Cherchi A, Lai C, Angelinno F, et al. Effects of L-camitine on exercise tolerance in chronic stable angina. A multicenter, double-blind, randomized, placebo controlled crossover study. Int J Clin Pharm Ther Toxic01 1985;23:569-572. 25. Orlando G, Rusconi C. Oral L-camitine in the treatment of chronic cardiac ischemia in elderly patients. Clin Trials J 1986;23:338-344. 26. Kamikawa T, Suzuki Y, Kobayaashi A, et al. Effects of L-camitine on exercise tolerance in patients with stable angina pectoris. Jpn Heart J 1984;25:587-597. 27. KosolcharoenP, Nappi J, Peruzzi P,et al. Improved exercise tolerance after administration of camitine. Curr Ther Res 1981;30:753-764. 28. Pola P, Savi L, Serricchio M, et al. Use of physiological substance, acetyl-camitine, in the treatment of angiospastic syndromes. Drugs Exp Clin Res 1984;X213-217. 29. Lagioia R, Scrutinio D, Mangini SG,et al. Propionyl-L-camitine. a new compound in the metabolic approach to the treatment of effort angina. Int J Cardiol1992;34:167-172. 30.Bartels GL, Remme WJ, Pillay M, et al. Effects of L-propionylcamitine on ischemia-induced myocardial dysfunction in men with angina pectoris. Am J Cardiol1994;74:125-130. 31. Cacciatore L, Cerio R, Ciarimboli M, et al. The therapeutic effect of L-camitine in patients with exercise-induced stable angina: a controlled study. Drugs Exp Clin Res 1991;17225-335. 32. Davini P, Bigalli A, Lamanna F, Boem A. Controlled study on Lcamitine therapeutic efficacy in post-infarction. Drugs Exp Clin Res 1992;18:355-365. 33. Iliceto S, Scrutinio D, Bruzzi P, et al. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: the LCarnitine Ecocardiografia Digikdizzata Marto Mocardico (CEDIM) Trial. J Am Coll Cardiol 1995;26 380-387. 34. Mancini M, Rengo F, Lingetti M, et al. Controlled study on the therapeutic efficacy of propionyl-L-camitine in patients with congestive heart failure. Arzneimittelforschung 1992;42:1101-1104. 35. Pucciarelli G, Mastursi M, Latte S, et al. [The clinical and hemodynamic effects of propionyl-L-camitine in the treatment of congestive heart failure]. Clin Ter 1992;141:379-384. 36. Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-camitine administration. Am Heart J 2000;139S120-S123. 37. Brevetti G, Perna S, Sabba C, et al. Superiority of L-propionylcamitine vs L-camitine in improving walking capacity in patients with

peripheral vascular disease: an acute, intravenous, double-blind, cross-over study. Eur Heart J 1992;13251-255. 38. Sabba C, Berardi E, Antonica G, et al. Comparison between the effect of L-propionylcamitine, L-acetylcamitine and nitroglycerin in chronic peripheral arterial disease:a haemodynamic double blind echo-Doppler study. Eur Heart J 1994;151348-1352. 39. Brevetti G, Chiariello M, Ferulano G. Increases in walking distance in patients with peripheral vascular disease treated with L-camitine: a double-blind, cross-over study. Circulation 1988;77: 767-773. 40.Brevetti G, Diehm C, Lambert D. European multicenter study on propionyl-L-camitine in intermittent claudication. J Am Coll Cardiol 1999;34.1618-1624. 41. Dragan AM, Vasiliu D, Emnia NM, Georgescu E. Studies concerning some acute biological changes after endovenous administration of 1g L-camitine, in elite athletes. Physiologie 1987;24231-234. 42. Dragan GI, Vasiliu A, Georgescu E, Dumas I. Studies concerning acute and chronic effects of L-camitine on some biological parameters. Physiologie 1987;2423-28. 43.Dragan GI, Wagner W, Ploesteaunu E. Studies concerning the ergogenic value of protein supply and L-camitine in elite junior cyclists. Physiologie 1988;25:129-132. 44. Soop M, Bjorkman 0, Cederblad G, et al. Influence of camitine supplementation on muscle substrate and camitine metabolism during exercise. J Appl Physiol1988;64:2394-2399. 45. Greig C, Finch KM,Jones DA, et al. The effect of oral supplementation with L-camitine on maximum and submaximum exercise capacity. Eur J Appl Physiol1987;56131-135. 46.Marconi C, Sassi G, Carpinelli A, Cerretelli P. Effects of L-camitine loading on the aerobic and anaerobic performance of endurance athletes. Eur J Appl Physiol1985;54:131-135. 47. Huertas R, Campos Y, Diaz E, et al. Respiratory chain enzymes in muscle of endurance athletes. Effect of L-camitine. Biochem Biophys Res Commun 1992;188:102-107. 48. Volek JS, Kraemer WJ, Rubin MR, et al. L-Camitine L-tartrate supplementation favorably affects markers of recovery from exercise stress. Am J Physiol Endocrinol Metab 2002;282:E474E482. 49. Dal Negro R. Changes in physical performance of untrained volunteers: effects of L-camitine. Clin Trials J 1986;23242-248. 50. Pistone G, Marino A, Leotta C, et al. Levocamitine administration in elderly subjects with rapid muscle fatigue: effect on body composition, lipid profile and fatigue. Drugs Aging 2003;20:761-767. 51. Bowman B. Acetyl-camitine and Alzheimer’s disease. Nutr Rev 1992;50:142-144. 52. Carta A, Calvani M, Bravi D, Bhuachalla SN. Acetyl-L-camitineand Alzheimer’s disease. Pharmacological considerations beyond the cholinergic sphere. Ann N Y Acad Sci 1993;695324-326. 53. Calvani M, Carta A, Caruso G, et al. Action of acetyl-L-camitine in neurodegeneration and Alzheimer’s disease. Ann N Y Acad Sci 1992; 663483-486. 54.Pettegrew JW, K l d WE, Panchalingam K, et al. Clinical and neurochemical effects of acetyl-L-camitine in Alzheimer’s disease. Neurobiol Aging 1995;161-4. 55. Sano M, Bell K, Cote L Dooneief G, et al. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer’s disease. Arch Neurol1992;491137-1141. 56. Spagnoli A, Lucca U, Menasce G, et al. Long-term acetyl-L-camitine treatment in Alzheimer’s disease. Neurology 1991;41:1726-1732. 57. Thal LJ, Calvani M, Amato A, Carta A. A 1-year controlled trial of acetyl-L-camitine in early-onset AD. Neurology 2000;55805-810. 58. Passeri M, Cucinotta D, Bonati PA, et al. Acetyl-L-camitine in the treatment of mildly demented elderly patients. Int J Clin Pharmacol Res 1990;1075-79. 59. Salvioli G, Neri M. L-acetylcamitine treatment of mental decline in the elderly. Drugs Exp Clin Res 1994;20169-176. 60.Cipolli C, Chiari G. [Effects of L-acetylcamitine on mental deterioration in the aged: initial results]. Clin Ter 1990;132:479-510.

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61. Garzya G, Corallo D, Fiore A, et al. Evaluation of the effects of Lacetylcamitine on senile patients suffering from depression. Drugs Exp Clin Res 1990;16101-106. 62.Tempesta E, Casella L, Pirrongelli C, et al. L-acetylcamitine in depressed elderly subjects.A cross-over study vs. placebo. Drugs Exp Clin Res 1987;13:417-423. 63. Bianchetti A, Rozzini R, Trabucchi M. Effects of acetyl-L-camitine in Alzheimer’s disease patients m s p o n s i v e to acetylcholinesterase inhibitors. Curr Med Res Opin 2003;19:350-353. 64.De Falco FA, DAngelo E, Grimaldi G, et al. Effect of the chronic treatment with L-acetylcamitine in Down’s syndrome. Clin Ter 19941M123-127. 65. Chazot C, Blanc C, Hurot JM, et al. Nutritional effects of camitine supplementation in hemodialysis patients. Clin Nephrol 2003;59: 24-30. 66.Guamieri GF, Ranieri F, Toigo G, et al. Lipid-lowering effect of camitine in chronically uremic patients treated with maintenance hemodialysis. Am J Clin Nutr 1980;331489-1492. 67. Lacour B, Di Giulio S, Chanard J, et al. Camitine improves lipid anomalies in haemodialysis patients. Lancet 1980;2:763-765. 68.Bertoli M, Battistella PA, Vergam L, et al. Camitine deficiency induced during hemodialysis and hyperlipidemia. Effect of replacement therapy. Am J Clin Nutr 1981;34:1496-1500. 69. Vacha GM, Giorcelli G, Siliprandi N, Corsi M. Favorable effects of L-camitine treatment on hypertriglyceridemia in hemodialysis patients: decisive role of low levels of high-density lipoproteincholesterol. Am J Clin Nutr 1983;38532-540. 70. Bellinghieri G, Savica V, Mallamace A, et al. Correlation between increased serum and tissue L-camitine levels and improved muscle symptoms in hernodialyzedpatients. Am J Clin Nutr 1983;38:523-531. 71. Donatelli M, Terrizzi C, Zummo G, et al. Effects of L-camitine on chronic anemia and erythrocyte adenosine triphosphate concentration in hemodialyzed patients. C u n Ther Res 1987;41:620-624. 72. Golper TA, Wolfson M, Ahmad S, et al. Multicenter trial of L-camitine in maintenance hemodialysis patients. I. Camitine concentrations and lipid effects. Kidney Int 1990;38:904-911. 73. Vazelov E, Borissova AM, Kirilov G, et al. L-camitine consecutively administered to patients on hemodialysis improves beta-cell response. Int J Artif Organs 2003;26:304307. 74. Labonia D. L-camitine effects on anemia in hemodialyzed patients treated with erythropoietin. Am J Kidney Dis 1995;26757-764. 75. Coker M, Coker C, Darcan S, et al. Camitine metabolism in diabetes mellitus. J Pediatr Endocrinol Metab 2002;15:841-849. 76. Greco AV, Mingrone G, Bianchi M, Ghirlanda G. Effect of propionylL-camitine in the treatment of diabetic angiopathy. Controlled double blind trial versus placebo. Drugs Exp Clin Res 1992; 1869-110. 77. Morabito E, Serafini S, Corsico N. Acetyl-L-camitine effect on nerve conduction velocity in streptotocin-diabetic rats. Arzneimittelforschung 1993;43343-346. 78. De Grandis D, Minardi C. Acetyl-L-camitine (levacecamine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebocontrolled study. Drugs R D 2002;3:223-331. 79. Derosa G, Cicero AF, Gaddi A, et al. The effect of L-camitine on plasma lipoprotein(a) levels in hypercholesterolemic patients with type 2 diabetes mellitus. Clin Ther 2003;25:1429-1439. 80.Sirtori CR, Calabresi L, Ferrara S, et al. L-camitine reduces plasma lipoprotein(a) levels in patients with hyper Lp(a). Nutr Metab Cardiovasc Dis 2O00;10:247-251. 81. Sachan DS,Rhew TH, Ruark RA. Ameliorating effects of camitine and its precursors on alcohol-induced fatty liver. Am J Clin Nutr 1984;39738-744. 82. Sachan DA, Rhew TH. Lipotropic effect of camitine on alcoholinduced hepatic stenosis. Nutr Rep Int 1983;271221-1226. 83. Noto R, Maugeri A, Grasso R, et al. Free fatty acids and camitine in patients with liver disease. Curr Ther Res 1986;40:35-39.

84. Neri S, Pistone G, Saracen0 B, et al. L-camitine decreases severity and type of fatigue induced by interferon-alpha in the treatment of patients with hepatitis C. Neuropsychobiology 2003;479497. 85. Borum PR, Broquist HP, Roelofs RJ. Muscle camitine levels in neuromuscular disease. J Neurol Sci 1977;34:279-286. 86. Carrier HN, Berthiller G. Camitine levels in normal children and adults and in patients with diseased muscle. Muscle Nerve 1980;3 326-334. 87. Bresolin N, Freddo L, Tegazzin V, et al. Camitine and acyltransferase in experimental neurogenic atrophies. Changes with e a t ment. J Neurol 1984;231:170-175. 88. Bomman MS, du Toit D, Otto B, et al. Seminal carnitine, epididyma1 function and spermatozoal motility. S Afr Med J 1989;75:20-21. 89. Menchini-Fabris GF, Canale D, Izzo PL, et al. Free L-camitine in human semen: its variability in different andologic pathologies. Fertil Steril 1984;42:263-267. 90.Costa M, Canale D, Filicori M, et al. L-camitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Camitine and Male infertility. Andrologia 1994;26155-159. 91.Lenzi A, Lombard0 F, Sgro P, et al. Use of camitine therapy in selected cases of male factor infertility: a double-blind crossover trial. Fertil Steril2003;79292-300. 92. Dal Negro R, Zoccatelli D, Pomari C, et al. L-camitine and physiokinesiotherapy in chronic respiratory insufficiency. Clinical Trials J 1985;22:353-360. 93. De Simone C, Famularo G, Tzantzoglou S, et al. Camitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-camitine. AIDS 1994;8:655-656. 94.Semino-Mora MC, Leon-Monzon ME, Dalakas MC. Effect of Lcarnitine on the zidovudine-induced destruction of human myotubes. Lab Invest 1994;71:102-112. 95.De Simone C, Tzantzoglou S, Famularo G, et al. High dose L-camitine improves immunologic and metabolic parameters in AIDS patients. Immunopharmacol Immunotoxicol 1993; 15:l-12. 96. Seccombe DW, James L, Booth F. L-camitine treatment in glutaric aciduria type I. Neurology 1986;36264-267. 97.de Sousa C, Chalmers RA, Stacey TE, et al. The response to Lcamitine and glycine therapy in isovaleric acidaemia. Eur J Pediatr 1986;1M451-456. 98. Roe CR, Bohon TP. L-camitine therapy in propionicacidaemia. Lancet 1982;1:1411-1412. 99. Roe CR, Hoppel CL, Stacey TE, et al. Metabolic response to camitine in methylmalonic aciduria. Arch Dis Child 1983;58:916-920. 100. Furitano G, Patema S, Perricone R, et al. Polygraphic evaluation of effects of camitine in patients on adriamycin treatment. Drugs Exp Clin Res 1984;10:107-111. 101.OConner JE, Costell M, Miguez ME’, Grisolia S. Influence of the route of administration on the protective effect of L-camitine on acute hyperammonemia. Biochem Pharmacol1986;18:3173-3176. 102. Matsuda I, Ohtani Y, Ninomiya N. Renal handling of camitine in children with camitine deficiency and hyperammonemia associated with valproate therapy. J Pediatr 1986;109:131-134. 103. Freeman JM, V i g EP, Cost S, Singhi P. Does camitine administration improve the symptoms attributed to anticonvulsant medications? A double-blinded, crossover study. Pediatrics 1994;93 893-895. 104. Van Oudheusden LJ, Scholte HR. Efficacy of camitine in the treatment of children with attention-deficit hyperactivity disorder. Prostaglandins Leukot Essent Fatty Acids 2002;6733-38. 105. Weschler A, Aviram M, Levin M, et al. High dose of L-camitine increases platelet aggregation and plasma triglyceride levels in uremic patients on hemodialysis. Nephron 1984;38:120-124. 106. Bazzato G, Mezzina C, Ciman M, Guamieri G. Myasthenia-like syndrome associated with camitine in patients on long-term dialysis. Lancet 1979;1:1041-1042.

Carnitine 107. Paulson DJ, Shug AL. Tissue specific depletion of L-camitine in rat heart and skeletal muscle by D-camitine. Life Sci 1981;28: 2931-2938. 108. Watanabe S, Ajisaka R, Masuoka T. Effects of L- and DL-camitine on patients with impaired exercise tolerance. Jpn Heart J 1995; 36319-331. 109.Bertelli A, Ronca F, Ronca G, et al. L-camitine and coenzyme Qlo protective action against ischaemia and reperfusion of working rat heart. Drugs Exp Clin Res 1992;18:431-436.

110. Gleeson JM, Wilson DE, Chan IF, et al. Effect of camitine and pantetheine on the metabolic abnormalities of acquired total lipodystrophy. Curr Ther Res 1987;41:83-88. 111.Daily JW III, Sachan DS.Choline supplementation alters camitine homeostasis in humans and guinea pigs. J Nutr 1995;125: 1938-1944.

Catechin [(+)-cyanidanol-31 Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 823 Pharmacology 823 Pharmacokinetic Studies in Humans 823 Antiviral and lmmunostimulatory Effects 823 Antioxidant 824 Antiendotoxin Effects 824 Collagen Effects 824 Histidine Decarboxylase 824

Osteogenesis lmperfecta 825 Rheumatoid Arthritis and Scleroderma 825 Cancer 826 Dosage 826 Toxicology 826 Drug Interactions 826

Clinical and Experimental Studies 824 Hepatitis 824 Alcohol-Induced Liver Disease 825 Peptic Ulcer 825 Postoperative Complications 825

INTRODUCTION This naturally occurring flavonoid has been widely used in Europe in the treatment of hepatic disease and other conditions. It is found in high concentrations in Acacia catechu (black catechu, black cutch) and Uncaria gumbier (pale catechu, gambier).’ Catechin is also found in relatively high concentrations in tea (both green and black) and red wine.

PHARMACOLOGY (FIGURE 77-1) Pharmacokinetic Studies in Humans Studies of radiolabeled catechin demonstrate that 55% of the oral dose administered to human volunteers is excreted in the urine? Of this excreted catechin, 70% was excreted within 12 hours and 90% within 24 hours. Urinary excretion of unchanged catechin was quite low (0.1%to 1.4%of oral dose).The major urinary metabolites (composing three quarters of the total urinary excretion) are glucuronides of cat& and 3’-O-methyl-catechin and its sulphate. The majority of metabolites retained the flavonol ring structure. Ring scission is a minor metabolic pathway and results in the excretion of benzoic, hippuric, and phenylpropionic acids.

Unchanged catechin is detected in the plasma between 30 minutes and 12 hours after ingestion, while metabolites persist for at least 120 hours. Researchers have concluded that the rapid rate of absorption, coupled with relatively low plasma levels of the unchanged catechin molecule, suggests that hepatic extraction and localization are extremely efficient, a desirable trait considering catechin’s hepatoprotective properties.’,*

Antiviral and lmmunostimulatory Effects Many flavonoids have been shown to possess antiviral activity, with quercetin being perhaps the most effective. Catechin has, however, been shown to inhibit infectivity by human viruses (e.g., polio virus, parainfluenza virus type 3, respiratory syncytial virus, herpes simplex type 1)3 This appears to be due to a direct flavonoid virus interaction. Perhaps more important, however, are its immune stimulationproperties! Catechin and 3’-O-methylcatechin, its major derivative, have been shown to significantly increase spontaneous pokeweed mitogen- and Staphylococcus aureus-induced lymphocyte transformation and immunoglobulin synthesis. Catechin has also been shown to increase T-cell rosette formation5; stimulate cell-mediated immune response (as measured by the 823

Pharmacology of Natural Medicines

Collagen Effects Catechin affects collagen metabolism in various ways:

OH Figure77-1 Catechin.

leukocyte migration inhibition test); and promote antigeninduced proliferative response in patients with HBsAgpositive chronic active hepatitis: Many of the immunostimulatory effects of flavonoids may be due to their ability to inhibit the catabolism of cGMP in leukocytes,’ an action known to augment many immune responses (see Chapter 57 for further discussion concerning cyclic nucleotides’ effects on immune functions).

Antioxidant Catechin has been shown, in vitro and in vivo, to be a powerful free radical scavenger and antioxidant, preventing both environmental chemical- and normal metabolism-induced oxidative damage.*Catechin has a sparing effect on glutathione metabolism as well.

Antiendotoxin Effects The role of endotoxins (lipopolysaccharide cell wall components of gram-negative bacteria) in the pathogenesis of liver diseases (particularly all types of hepatitis and alcohol-induced cirrhosis) and associated systemic disorders has been demonstrated by many investigators (see Chapter 58 for a complete discussion). Under normal conditions, endotoxins, produced by intestinal gram-negative bacteria, are absorbed into the portal venous circulation and detoxified by Kupffer cells. Impairment of the reticuloendothelial system, phage cytic function, or the portal-sinusoidal blood flow (interference of normal endotoxin clearance mechanisms) amplifies the biologic activities of endotoxins (e.g., activation of the alternative complement pathway, lipid peroxidation, promotion of such calcium-mediated phenomena as smooth muscle contraction and mast cell degranulation). Catechin’s antiendotoxin effects are both directdegradation of endotoxin and prevention of free radicalinduced damage by the lipid portion of the endotoxin molecule-and indirect-.tabilization of biomembranes and interferencewith the liver adenylate cyclase system. The latter is sigruficantbecause exotoxins such as cholera toxin from Vibrio cholerae cause their symptoms by excessive activation of adenylate cyclase, which disturbs the cyclic AMl?/ATP balance in the cells?

*Increasing cross-linkage formation in normallo and lathyritic” collagen (covalent binding of seven catechin residues per collagen alpha-chain) Reducing prolyl and lysyl hydroxylase activitiesI2 Accelerating conversion of soluble to insoluble collagen in lathyriti~,’~ diabetic>* and genetically abnormall5collagen Collagen synthesized in the presence of catechin has been shown to be resistant to the action of collagenaseI0 and pep~in.’~ Collagen biosynthesis has variously been reported to be demasedl2;unaffected17;and, in the case of adjuvant arthriti~,’~ inmased in the presence of cat&. The sigruficance of these effects is discussed as follows.

Histidine Decarboxylase This enzyme is responsible for converting histidine to histamine. Catechin and other flavonoids have been shown to be potent inhibitors of histidine decarboxylase in vitrol9and in v i v ~This . ~ action has wide clinical application (e.g., allergic conditions,peptic ulcers, inflammatory processes, other conditions where histamine is involved).

CLINICAL AND EXPERIMENTAL STUDIES Hepatitis An international workshop in 1981 on the use of cat&

in liver diseases concluded that the flavonoid was promising for the treatment of many types of hepatic disease,particularly acute and chronic viral hepatitis.’ Catechin has been shown, in numerous doubleblind clinical studies, to decrease serum bilirubin levels in patients with all types of acute viral hepatitis (i.e., types A, B, non-A, n~n-B).’Jl-~~ Furthermore, there is faster relief of clinical symptoms (i.e., anorexia, nausea, asthenia, pruritus, abdominal discomfort), a more accelerated clearance of HBsAg from the blood, and a greater reduction of SGPT and S O T levels than in control groups. The hepatoprotective effect of catechin is related to its free-radical and antioxidant properties, its antiendotoxin effects, and its ability to stabilize membranes. The most recent double-blind study using catechin involved 338 patients with chronic hepatitis B as confirmed by the presence of hepatitis B e antigen (HBeAg).27 Patients were given either catechin at a daily dose of 1.5g for 2 weeks, followed by 2.25 g for a further 14 weeks, or a placebo. The HBeAg titer decreased by at least 50% in 44 of 144 cases treated with catechin compared with 21 of 140 cases treated with placebo. The HBeAg disappeared in 16 of the catechin cases and 4 of the placebo, and a seroconversion was observed in 6 catechin patients and

Catechin [(+)-cyanidanol-31

3 placebo patients. The mean HBeAg titer in the catechin group was sigruficantly lower than that in the placebo group at the end of the 16-week therapy. The patients whose HBeAg titers were lowered were largely those with chronic active hepatitis, and they had higher initial values of SGPT, SGOT, and gamma-globulin than the patients whose HBeAg titers remained unchanged. The mean values for these liver function tests also fell SisIUfrcantly in the former subgroup. Catechin was well tolerated, the only notable side effect being a transient febrile reaction in 13 patients. These promising results need more current research.

Alcohol-Induced Liver Disease Elevated hepatic NADH:NAD ratios and decreased ATP concentrations are found during ethanol intoxication. These metabolic disturbances, along with the increased production of acetate (as a result of ethanol detoxification), produce cholestasis and induce hepatic lipid a c m u l a tion by decreasingfatty acid oxidation and favoring incorporation of fatty acids into triglycerides.28 In animal studies catechin has been shown to correct these aberration~.~*-~O However, clinical studies in humans have failed to show convincing evidence that catechin is of benefit in alcohol-related liver disease?lJ2 This could be a result of insufficient dosage. In animal studies, the dose is usually 200 mg/kg, compared with 20 to 40 mg/kg in human studies. Furthermore, the high rate of patient dropout in long-term studies has prevented adequate evaluation. A recent long-term clinical trial (6 months) demonstrated that 2 g of catechin gave some protection against ethanol-induced hepatic damage, as evidenced by lowering of hepatic enzymes (SGOT, SGPT, and gamma GT).32

Peptic Ulcer Catechin, via its ability to inhibit histidine decarboxylase, offers antiulcer activity. Experimental studies in guinea pigs and rats have demonstrated that catechin has significant antiulcer activity in various model^.'^*^^*^^ In a human clinical study, oral administration (1000 mg five times a day) resulted in reduced histamine levels in the gastric tissue (determined by biopsy) of normal patients and those with gastric and duodenal ulcers and acute gastritis.2O Histamine levels, which sigruficantly increase in patients with urticaria and food allergy after local application of the antigen to the gastric mucosa, were decreased by the prior administration of catechin.

Postoperative Complications The formation of adhesions is a common and severe problem in surgery, particularly in abdominal surgery. Lower abdominal surgery, particularly appendectomies and gynecological procedures, are often followed by adhesions

that may result in pain and obstruction. The incidence of postoperative peritoneal adhesions varies from 67% to 92%.34It has been assumed that surgery leads to the stimulation of connective tissue formation, resulting in an overproduction of procollagen and collagen and increased deposition around the damaged or ischemic area. In rats, catechin administered within the first 5 days following the procedure substantially inhibits adhesion formation following experimental adhesion induction.35 Catechin, via its inhibition of procollagen and collagen biosynthesis, should also reduce adhesion formation in humans. Intraperitonealadministration was sigruficantly more effective than the oral administration in the experimental study. However, in humans oral administration may result in sufficient tissue concentrations. Catechin has also been shown, in a double-blind study, to significantly reduce postoperative edema.35

Osteogenesis lmperfecta This heterogenous autosomal dominant bone disease is characterized by defective synthesis of collagen, resulting in impaired connective tissue and bone matrix formation. Before the use of catechin for this disorder, treatment was based solely on orthopedic measures, as no effective medical treatment was available.36The main clinical problems in osteogenesis imperfecta (01) are multiple fractures of the long bones in children and progressive collapse of the vertebral bodies in adulthood. Catechin has been shown to reduce fractures. There is also histological, electron microscopic, and biochemical evidence of improvement after t ~ e a t m e n t . ~Catechin's J~ role in improving collagen defects in 0 1 probably centers around its ability to do the following: Reduce, by its reduction of lysyl hydroxylase activity, the increased level of hydroxylysine reported in the collagen of many patients with type I 0 1 Increase the number of cross-links in the collagen matrix (which may be deficient or exhibit delayed maturation in 01) Improve the supramolecular organization and stability of collagen fibers Possibly increase the reduced collagen production occurring in 01

Rheumatoid Arthritis and Scleroderma The effects of catechin on collagen suggest that the flavonoid would have therapeutic benefit in rheumatoid arthritis and scleroderma, as well as in other collagen diseases. Inflammation and collagen are linked in several ways. Preexisting collagen is destroyed during the initial stages of inflammation, whereas its biosynthesis is increased in the later stages. Catechin appears to be an ideal agent due to its ability to inhibit the breakdown

Pharmacology of Natural Medicines of collagen caused by either free radicals or enzymes (hyaluronidase, collagenase, and pepsin), coupled with its ability to cross-link with collagen fibers and inhibit procollagen biosynthesis.12 Catechin was included in a long-term treatment program of 115 patients with generalized scleroderma that brought about arrest of progression in 89% of the patients and a subtotal or total recovery in more than 40%.% Although a number of combinations of collagen inhibitors were used in the study, the combination of catechin with Dpenidamine and L-glutamine was the most effective.Unfortunately, catechin was not used alone.

Cancer Several epidemiologic studies have now shown an inverse correlation between tea consumption and the incidence of several cancers. For example, people in Japan smoke more cigarettes than those in Western countries, yet their incidence of lung cancer is lower. Other studies show a lower incidence of colonic polyps in humans drinking green tea. This protection has been attributed in part to their high green tea consumption. This is consistent with laboratory research showing a preventive effect of green tea in animal models of lung cancer. In mice models, drinking green tea resulted in lung tumor induction being inhibited by 50"/0. Green and black tea reduced the incidence of cancer of the lung, forestoma&, esophagus, and liver in rats and mice when these were induced by carcinogens. These anticancer effects appear to be due to catechin's potent antioxidant activity of tea, lowering the modification of DNA in the tissues by hydroxyl radicals and similar active oxygen c0mpounds.3~

DOSAGE Typical dosages used have been as follows: 1g three times/day for hepatic disease 1g five times/day for peptic ulcers 500 mg three times/day for 0 1

1. COM H,ed. International workshop on (+)-cyanidanol-3in diseases of the liver. Royal Society of Medicine International Symposia Series, #47. London: Academic Press, 1981. 2. Hackett AM, Griffiths LA, Broillet A, Wermeille M. The metabolism and excretion of (+)-[14C]cyanidanol-3in man following oral administration. Xenobiotica 1983;13:279-286. 3. Kaul TN,Middleton E Jr, Ogra PL. Antiviral effect of flavonoids on human viruses. J Med Vim1 1985;15:71-79. 4. Brattig NW, Diao GJ,Berg PA. Immunoenhancing effect of flavonoid compounds on lymphocyte proliferation and immunoglobulin synthesis. Int J Immunopharmacol1984;6205-215. 5. Sipos J, Gabor V, Toth Z , et al. In vitm effect of (+)-cyanidanol-3 on rosette formation. In COM H, ed. International workshop on (+)-cyanidanol-3in diseases of the liver. Royal Society of Medicine

TOXICOLOGY Catechin was initially regarded as being remarkably free from side effects. However, soon after its introduction in France, rare but serious side effects began to be linked with catechin. Chief among the serious side effects were autoimmune hemolysis, febrile reactions, and urticaria. Catechin must be used with extreme caution. Two different series of case reports highlight the seriousness of side effects. In the first, six patients who developed hemolysis while receiving catechin were studied.40The disorder was episodic in all patients and resolved after discontinuation. The causative antibodies could be demonstrated in all six cases, even when the hemolytic episode had preceded analysis by more than 1year. It seems that the stable association of catechin with red blood cells (RBCs) generates antigenic sites against which a heterogeneous immune response is elicited, giving rise to long-lasting, drug-dependent antibodies, as well as autoantibodies. In the other series, five patients who received catechin for 4 to 36 months were presented.4l Three developed both hemolytic anemia and thrombocytopenia, while two had only thrombocytopenia. After suspending the catechin, the hematologic values returned to normal in all of the patients. Catechin-dependent platelet antibodies were detected in four of the five patients, and catechin-dependent RBC antibodies were present in three.

DRUG INTERACTIONS No drug interactions have been reported with catechin. However, sources of catechin such as green tea and Uncuriu gumbier have reportedly interacted with several drugs. These interactions are likely due to other constituents of the herbs.

International Symposia Series, #47. London: Academic Press, 1981:113-115. 6. Vallotton JJ,Frei PC. Influence of (+)-cyanidanol-3on the leukocyte migration inhibition test carried out in the presence of purified protein derivative and hepatitis B surface antigen. Infect h u n 1981;32: 432437. 7. Ruckstuhl M, Beretz A, Anton R, Landry Y. Flavonoids are selective cyclic GMP phosphodiesterase inhibitors. Biochem Phannacol1979;28 535-538. 8.Chen H, Tappell AL. Vitamin E, selenium, trolox C, ascorbic acid palmitate, acetylcysteine, co-enzyme Q, beta-carotene, canthaxanthin, and (+)-catechin protect against oxidative damage to kidney, heart, lung and spleen. Free Radic Res 1995;22: 177-186.

Catechin [(+)-cyanidan0131 9. Scevola D, Magliulo E, Barbarini G, et al. Possible antiendotoxin activity of (+)-cyanidanoi-3 in experimental hepatitis in the rat. Hepatogastroenterology 1982;29:178-182. 10. Pontz B, Krieg T, Muller PK. (+)-Cyanidanol-J changes functional properties of collagen. Biochem Pharmacol1982;31:3581-3589. 11. Orloff S, Hanumantha Rao V, Bose S. Effect of certain flavonoids on the crosslinking of lathyriticcollagen. Indian J Biochem Biophys 1974; 11~314-317. 12. Blumenkrantz N, Asboe-Hansen G. Effect of (+)
diseases of the liver. Royal Society of Medicine International Symposia Series, #47.London: Academic Press, 1981:131-134. 26. Piazza M, Guadagnino V, Picaotto L, et al. Effect of (+)-cyanidan013 in acute HAV, HBV, and non-A, non-B viral hepatitis. Hepatology 1983;345-49. 27. Suzuki H, Yamamoto S, Hirayama C, et al. Cianidanol therapy for HBe-antigen-positivechronic hepatitis: a multicentre, double-blind study. Liver 1986;635-44. 28. Gajdos A, Gajdos-TorokM, Horn R. The effect of (+)-catechinon the hepatic level of ATP and the lipid content of the liver during experimental steatosis. Biochem Pharmacol 1972;21:594-600. 29. Ryle P, Chakraborty J, Thomson A. Biochemical mode of action of a hepatoprotective drug: observations on (+)-catechin. Pharmacol Biochem Behavior 1983;18:473-478. 30.Ryle PR, Chakraborty J, Shaw G, Thomson AD. The effect of (+)-cyanidanol-3on alcoholic fatty liver in the rat. In COM H, ed. International workshop on (+)-cyanidan013 in diseases of the Catheliver. Royal Society of Medicine International Symposia Series, #47. London: Academic Press, 1981:185-193. 31. Editorial. (+)-Cyanidano1-3. Lancet 1982;i:549. 32. World MJ, Aps EJ, Shaw GK, Thomson AD. (+)-Cyanidan013 for alcoholic liver disease: results of a six month clinical trial. Alcohol 1984;19:23-29. 33. Parmar NS, Hennings G, Gulati OP. Histidine decarboxylase inhibition: a novel approach towards the development of an effective and safe gastric anti-ulcer drug. Agents Actions 1984;15494501. 34.Rivkind A, Marshood M, Durst AL, Becker Y. Cianidanol ([+I-cyanidanol-3) prevents the development of abdominal adhesions in rats. Arch Surg 1983;118:1431-1433. 35. Baruch J. Effect of Endotelon in postoperative edema. Results of a double-blind study versus placebo in 32 female patients. Ann Chir Plast Esthet 1984;29:393-395. 36. Jones C, Cummings C, Ball J, Beihgton P. A clinical and ultrastructural study of osteogenesis imperfecta after flavonoid (Catergen) therapy. S Afr Med J 1984;66:907-910. 37. Cetta G, Lenzi L, Rizzotti M, et al. Osteogenesis imperfecta: morphological, histochemical and biochemical aspects. Modifications induced by (+)
Centella asiatica (Gotu Kola) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 829 Chemical Composition 829 History and Folk Use 830 Pharmacology 830 Clinical Applications 831 Burns 831 Cellulite and Stria Gravidarum 831 Cirrhosis of the Liver 831

Keloids 831 Leprosy 832 Improving Mental Function 832 Relieving Anxiety 832 Scleroderma 832 Venous and Microcirculatory Disorders 832 Wound Healing 832

Dosage 833 Toxicology 833

CenteZZu asiaticu (family: Umbelliferae or Apiaceae) Synonym: HydrocofyZe asiaticu L. Common names: gotu kola, Indian pennywort, South African pennywort, mandukaparni

season, is approximately 0.2 inches long with seven to nine ribs and a curved, strongly thickened pericarp.' Historically, the entire plant is used medicinally, with harvesting occurring any time during the year.'

GENERAL DESCRIPTION

CHEMICAL COMPOSITION

CenteZZu usiuticu is an herbaceous perennial plant native to India, China, Indonesia, Australia, the South Pacific, Madagascar, and southern and middle Africa. This slender, creeping plant flourishes in and around water. Although it grows best in damp, swampy areas, centella is often observed growingalong stone walls or other rocky, sunny areas at elevations of approximately 2000 feet in India and Ceylon.' Depending on the environment, the form and shape of centella can change dramatically. In shallow water, centella forms floating leaves, while in dry locations the leaves are small and thin,and numerous roots are formed.' Typically, the constantly growing roots give rise to reddish stolons. The round-to-reniform, smoothsurfaced leaves, found on furrowed petioles, can reach a width of 1inch and a length of 6 inches. The leaf margin may be smooth, crenate, or slightly lobed. Usually three to six red flowers arise in a sessile manner or on short pedicels in axillary umbels at the end of 0.08-to 0.3-inchlong peduncles. The fruit, formed throughout the growing

Although the primary pharmacologically active constituents of C. usiaticu are known to be triterpenoid compounds,2 its exact chemical profile is difficult to determine due to duplicate names and contradictory findings. In addition, centella samples from India, Sri Lanka, and Madagascar apparently do not contain the same In India three (and possibly more) chem~onstituents.3,~ ically different subspeciesof C. usiuticu have been The concentration of triterpenes in centella can vary between 1.1%and 8%,with most samples yielding a concentration between 2.2% and 3.4%: Figure 78-1 illustrates the major triterpenoid components of C. asiutzcu. The Madagascar variety is most commonly used to produce standardized extracts. It yields triterpene concentrations of asiatic acid (29% to 30%),madecassic acid (29% to 30%), asiaticoside (40%), and madecassoside ( 1 Y O to 2%).2 Centella also contains a green, volatile oil composed of an unidentified terpene acetate (which accounts for 36%of the total oil), camphor, cineole, and other essential oils. Centella oil also contains glycerides of fatty acids; 829

Compound Asiatic acid Madecassic acid Asiaticoside Madecassoside

R ' R " H OH OH OH H 0-glucose-glucose-rhamnose OH 0-glucose-glucose-rhamnose

Figure 78-1 The triterpene compounds of Centella asiatica.

various plant sterols such as campesterol, stigmasterol, and sitosterol; and various polyacetylene compounds.'f Other notable compounds isolated from centella include the flavonoids keampferol, quercetin, and their glycosides; myoinositol; sugars; a bitter substance (vellarin); amino acids; and resins.'n2

HISTORY AND FOLK USE Centella has been used as a medicine in India since prehistoric times and is thought to be identical to the plant mandukapami, listed in the Susruta Samhifa (one of the valuable treatises in Ayurveda). Centella was also used extensively as a medicine, both internally and externally, by the people of Java and other islands of Indonesia. The medicinal use of centella in India and Indonesia centered around its ability to heal wounds and relieve leprosy, although it was also considered to be one of "Rasayana"(rejuvenator) herbal medicines and was used to enhance memory and prolong life.'C2 In the nineteenth century, centella and its extracts were incorporated into the Indian pharmacopeia, in which, in addition to being recommended for wound healing, it was recommended in the treatment of skin conditions such as leprosy, lupus, varicose ulcers, eczema, and psoriasis. It was also used to treat diarrhea, fever, amenorrhea, and diseases of the female genitourinary tract.' In China the leaves are prescribed for turbid leukorrhea and toxic fevers, while the shoots are used for boils and fevers. The plant is also used in the treatment of fractures, contusions, strains, and snakebites.' Centella was also used in China to delay senescence. One of the reported "miracle elixirs of life," centella's reputation as a promoter of longevity stems from the report of Chinese herbalist LiChing Yun, who reportedly lived 256 years. LiChing Yun's longevity was supposedly a result of his regular use of an herbal mixture chiefly composed of ~entella.6,~

C. asiafica was first accepted as a drug in France in the 1880s. Since then, centella extracts have been used to treat many of the same conditions listed earlier, along with those described later in the section on clinical applications. Centella, or gotu kola, has aroused much curiosity in American consumers. Many confuse gotu kola with kolanuts and assume gotu kola's rejuvenating activity is nothing more than the stimulant effect of caffeine. However, gotu kola is not related to the kolanut (CoZa nifida or Cola acuminafa),nor does it contain any caffeine.

PHARMACOLOGY The majority of pharmacologic investigations on C. asiatica have focused on the triterpene's wound-healing and venotonic activity.'P2 Although the exact mechanism of action has not yet been fully determined, a number of interesting observations have been made:

In one of the early pharmacologic investigations of centella, Boiteau and Ratshamangas demonstrated that asiaticoside substantially hastened the healing of experimentally induced wounds. These authors concluded that asiaticoside works selectively in stimulating the rapid and healthy activity of the reticuloendothelial system. Additional studies on the mechanisms of action of centella's enhancing wound healing have shown that asiaticoside given orally, by intramuscular injection or by implantation to rats, mice, guinea pigs, and rabbits produces a wide range of effects, as shown in Box 78-1. The efficacy of centella in stimulating collagen synthesis has now been demonstrated in human tissue cult u r e ~ Interestingly, .~~ this research also demonstrated an added benefit when vitamin C was added to the experimental cultures. The outcome of centella's complex actions is a balanced multiphasic effect on cells and tissues participating in the process of healing, particularly connective tissues. Enhanced development of normal connective tissue matrix is perhaps the prime therapeutic action of C. asiatica.

Stimulates hair and nail growthl.E1O Increases vascularizationof connective tissue1.8-10 Increasesthe formation of mucin and structural glycosaminoglycans like hyaluronic acid and chondroitin sulfate1,8-10,12 Increasesthe tensile integrity of the dermis1,8-i0 Increases keratinizationof epidermis through stimulation of the stratum germinati~um'.~O.~*-I~ Possesses a eutrophic or balancing effect on connective tissue1,l0

Centella asiatica (Gotu Kola) Centella has been shown to enhance the connective tissue structure of the penvascular sheath, reduce sclerosis, and improve blood flow through the affected veins.'Jo More recent investigations have focused on some of centella's effects on the central nervous system, cognitive function, stress, and anxiety? The major effects are an enhancement of cholinergic mechanisms, as well as a significant antioxidant action via increasing glutathione level^.^,^^ Presumably, these mechanisms are responsible for the improvements in mental function noted in both animal and clinical trials. Excellent results in improving cognitive function and memory were seen in animal models of Alzheimer di~ease.'~ Centella has also been shown to possess other diverse pharmacologic effects in experimental models including antiulcer, antimicrobial, immunomodulatory, and spasmolytic activity?

CLINICAL APPLICATIONS Obviously, from the brief description of centella's pharmacologic activity given earlier, it is a valuable agent for the healing of wounds and treatment of venous insufficiency and may also prove useful in improving mental function. Table 78-1 provides an abridged list of documented clinical applications of C. asiaticu. The more popular uses of this valuable plant are discussed as follows in alphabetical order.

Conditions

References

Anal fissure

15

Bladder ulcer

16, 17

Burn

18,19

Cellulite

20-25

Cirrhosis

26-28

Dermatitis

20,29

Fibrocystic breast

30

Hernorrhoid

31

Keloid

32-34

Leprosy

11, 19, 35, 36

Lupus erythematosus

37

Mental retardation

38

Mycosis fungoides

37

Peptic ulcer

39,40

Perineal lesion

41

Periodontal disease

42

Retinal detachment

43

Scleroderrna

44-47

Skin ulcer

48-55

Surgical wound

8, 43,49, 56-61

Tuberculosis

8, 62

Venous disorder

63-75, 82-86

Wound healing

8, 43, 49, 56-61

Burns The standardized extract from C. asiaticu has been effectively used in the treatment of patients with second- and third-degree burns caused by boiling water, electrical current, or gas explosion. Daily local application or intramuscular injections of the extract, or both, resulted in excellent results when the treatment was begun immediately after the accident. The extract prevented or limited the shrinking and swelling of the skin caused by skin infection, and it inhibited scar formation, increased healing, and decreased fibrosis.18J9

Cellulite and Stria Gravidarum Standardized extracts of C. asiaticu have demonstrated good results in the treatment of cellulite and prevention of stretch marks during pregnancy in a number of clinical stUdies.zJ0~025 In the treatment of cellulite, Bourguignonzo observed the action of the extract on several types of cellulite in 65 patients who had undergone other therapies without success. Over a period of 3 months, good results were produced in 58% of the patients and satisfactory results in 20%. Other investigations have shown a similar success rate (430Y0)?~-~~ The effect of centella in the treatment of cellulite appears to be related to its ability to enhance connective

tissue structure and reduce sclerosis by acting directly on fibroblasts (see Chapter 157 for further discussion).

Cirrhosis of the Liver Damis and colleaguesz6reported on the therapeutic use of an extract of C. usiaticu in alcohol-induced cirrhosis (six patients),cirrhosis of unknown etiology (two patients),and chronic hepatitis. In the cirrhosis patients, improvement in the histologic findings and regression of inflammatory infiltration were observed. No effect was observed in the patients with chronic hepatitis. Other reports have supported the use of centella in fibrotic conditions of the li~er.2~

Keloids The standardized extract of C. asiaticu has demonstrated impressive clinical results in the treatment of keloids and hypertrophic Its mechanism of action appears to be multifaceted but is basically due to reducing the inflammatory phase of scar formation while simultaneously enhancing the maturation phase of scar formation. Keloids and hypertrophic scars are characterized by a prolonged inflammatory phase that may go on for months or even years without progressing to the maturation phase.

The inflammatory phase is characterized histologically by large numbers of immature, swollen collagen bundles intermingled with inflammatory debris, while the maturation phase is characterized by mature fibrocytes, normal collagen fibers, and few inflammatory cell elements. In one study, 227patients with keloids or hypertrophic scars were treated by oral administration with a standardized centella extract (effective dosage 60 to 90 mg). The centella extract was used alone in 139 patients (the curative group), and 88 used the extract along with surgical scar revision (preventive In the curative group, 116 patients (82%) were found after 2 to 18 months to have benefited from the extract, either by relief of their symptoms or by disappearance of the inflammatory phase. In a double-blind substudy of 46 of the 139 patients, 22 of 27 receiving the extract improved, while only 9 of 19 given a placebo improved. In the preventive group, the centella extract also demonstrated a sigruficant positive effect. The therapeutic course in these patients was started a few weeks before surgery. If a positive response was observed, the patient was brought to surgery and kept on the centella extract method of preselection allowed the for 3 months. researchers to offer other forms of therapy to unresponsive patients.) Clinical improvement was observed in 72 of the 88 patients (79%).

Leprosy Several investigators have reported impressive clinical results using C. usiutica and its extracts (oral, intramuscular, or topical) in the treatment of leprosy in both The therauncontrolled and controlled studies .11J93,35 peutic response is comparable to that of dapsone, the standard allopathic drug used in the treatment of leprosy. In addition to its wound-healing activity, it appears that oxyasiaticoside, an oxidized form of asiaticoside, inhibits the growth of the tubercle bacillus in vitro and in vivo by dissolving the waxy coating of Mycobactmiurn Zeprae.8

Improving Mental Function Although long used to promote improved mental function, the first clinical investigation involving centella signhcantly increased the mental abilities of 30 developmentally disabled children.37After a 12-week period, the children were more attentive and better able to concentrate on assigned tasks. Given the growing importance of declining mental function among baby boomers, additional studies on centella's memory enhancement will hopefully be forthcoming.

Relieving Anxiety Centella is viewed as an anxiolytic on the basis of in vitro models. In an attempt to validate this effect in humans, a study was conducted to measure the effect of centella on reducing the acoustic startle response. After a single

administration of centella, subjects experienced a sigrufrcantly reduced acoustic startle response compared with the placeb-a clear indication of signrficant antianxiety action.s0

Scleroderma The standardized extract of C. asiatica has been tested in several trials in the treatment of scleroderma (including systemic sclerosis).43-46 In addition to decreasing skin induration, patients have noticed a lessening of arthralgia and improved finger motility. Presumably the positive therapeutic response is a result of centella's eutrophic effect on connective tissue, thereby preventing the excessive collagen synthesis observed in scleroderma.

Venous and Microcirculatory Disorders The most well-documented clinical utility for standardized extract of C. asiutica is in the treatment of chronic venous insufficiency, venous hypertension, and microcirculatory di~orders.6*-'~,~~~' In the treatment of chronic venous insufficiency, significant improvement in symptomatology (e.g., feelings of heaviness in the lower legs, paresthesias, nocturnal cramps); physical findings (e.g., edema, telangiectasias, trophic ulcers, vein distensibility);and functional capacity (improved venous flow) was observed in approximately 80% of patients in the clinical trials1J0t62-74 In studies of patients with venous hypertension (ambulatory venous pressure > 42 mmHg), detailed evaluations using laser Doppler flowmetry, transcutaneous oxygen and carbon dioxide tension measurements, as well as determination of capillary filtration rate, ankle circumference, and ankle edema along with detailed symptom evaluation clearly demonstrated that centella extracts are clinically effective in dealing with this The standardized extract of C. asiutica has also shown an ability to improve diabetic microangiopathy; prevent the edema and microcirculation alterations seen during medium- to long-distance flights; and normalize the echographic character of carotid arteries with significant plaq~e.8~~

Wound Healing Standardized extracts of C. asiuticu have been shown in many clinical studies to greatly aid wound repair.'3J0*42ia7-60 The types of wounds healed include the following: Surgical wounds such as episiotomies and ear, nose, and throat surgeries Skin ulcers due to arterial or venous insufficiency Traumatic injuries to the skin Gangrene Skin grafts Schistosomiasis lesions Perineal lesions produced during childbirth

Centella asiatica (Gotu Kola)

DOSAGE The majority of clinical studies on C. usiuticu used proprietary formulas available in Europe (e.g., Madecassol, TECA, Centelase). These standardized extracts contain asiaticoside (40%), asiatic acid (29% to 30%), madecassic acid (29% to 30%), and madecassoside (1%to 2%). Because the concentration of triterpenes in centella varies between 1.1%and 8%, it is difficult to calculate an appropriate dosage when simply using the crude plant material. However, because most samples yield a concentration between 2.2% and 3.4%, approximately 2 to 4 &day of crude plant material would contain an appropriate quantity of triterpenes, although it is unknown if this correlates with the clinical efficacy of the standardized extracts. Daily dosages of the various forms of centella are as follows: Standardized extract (40% asiaticoside, 29% to 30% asiatic acid, 29% to 30% madecassic acid, and 1%to 2% madecassoside): 60 to 180 mg/day

1.Kartnig T. Clinical applications of Centella asiatica (L) Urb. In Craker LE, Simon JE, eds. Herbs, spices, and medicinal plants: recent advances in botany, horticulture, and pharmacology, vol3. Phoenix: O r y Press, ~ 1986145-173. 2. Brinkhaus 8, Lindner M, Schuppan D, Hahn EG. Chemical, pharmacological and clinical profile of the East Asian medical plant Centella asiatica. Phytomedicine 2000;7427-448. 3. Battacharya SC.Constituents of Centella asiutica. I. Examination of the Ceylonese variety. J Ind Chem Soc 1956;33579-586. 4. Battacharya SC. Constituents of Centella asiafica. I. Examination of the Indian variety. J Ind Chem Soc 195633B93-898. 5.Rao PS, Seshadri TR. Variation in the chemical composition of Indian samples of Centella asiutica. Curr Sci 1969;38:77-79. 6. Duke JA. Handbook of medicinal herbs. Boca Raton, n:CRC Press, 1985. 7. Tyler V, Brady L, Robbers J. Pharmacognosy,ed 8. Philadelphia: Lea & Febiger, 1981. 8. Boiteau,'F Ratsimamanga AR. Asiaticoside extracted from Centella asiatica, its therapeutic uses in the healing of experimental or refractory wounds, leprosy, skin tuberculosis, and lupus. Therapie 1956; 11325-149. 9. Boiteau P, Nigeon-Dureuil M, Ratsimamanga AR. Action of asiaticoside on reticuloendothelial tissue. Acad Sci Compt Rend 1951;232 760-762. 10. Monograph. Centella asiatica. Milan: Indena S.p.A. 1987. 11.Abou-Chaar CI. New drugs from higher plants recently introduced into therapeutics. Leban Pharm J 1963;8:15-37. 12. Lawrence JC. The morphological and pharmacological effects of asiaticoside upon skin in vitro and in vim. Eur J Pharmacol 1967;1:414-424. 13.Bonte F, Dumas M, Chaudagne C, Meybeck A. Influence of asiatic acid, madecassic acid, and asiaticoside on human collagen I synthesis. Planta Med 1994;60:133-135. 14. May A. The effect of asiaticoside on pig skin in organ culture. Eur J Pharmacol1968;4:331-339.

Crude dried plant leaves: 2 to 4 g/day Tincture (1:5):10 to 20 ml/day Fluid extract (1:l):2 to 4 &/day

TOXICOLOGY C. asiuticu and its extracts are well tolerated, especially orally.',2 However, the topical application of a salve containing centella has been reported to cause contact dermatitis, although quite infrequently.' Although the oral administration of asiaticoside at a dose of 1 g/kg body weight has not proved toxic in toxicology studies, the toxic dose of asiaticoside by intramuscular application to mice and rabbits is reported as 40 to 50 mg/kg body weight.' Asiaticoside has been implicated as a possible skin carcinogen where repeated applications are used in an experimental animal Teratologic studies using the extract in rabbits have proved negative.31

15. Bensaude A. [The treatment of anal fissure.] Phleobologie 1980;33683-688. 16. Fam A. Use of titrated extract of Centella asiutica (TECA) in bilharzial bladder lesions. Int Surg 1973;58:451-452. 17. Etrebi A, Ibrahim A, Zaki K. Treatment of bladder ulcer with asiaticoside. J Egypt Med Assoc 1975;58:324-327. 18. Gravel JA. [Oxygen dressings and asiaticoside in the treatment of bums.] Laval Med 1965;36:413-415. 19. Boiteau P, Ratsimamanga AR. Important cicatrizants of vegetable origin and the biostimulins of Filatov. Bull Soc Sci Bretagne 1959; 34~307-315. 20. Bourguignon D. Study of the action of titrated extract of Centella asiatica. Gaz Med Fr 1975fl24579-4583. 21.Bonnett GF. Treatment of localized cellulitis with asiaticoside Madecassol. Progr Med 1974;102109-110. 22. Grosshans E, Keller F. Cellulite: reality or imposter? J Med Strasb 1983;14563-567. 23. Keller F, Grosshans E.Cellulitis: reality or fraud? Med Hyg 1983;l: 1513-1518. 24. Tenailleau A. On 80 cases of cellulitis treated with the standard extract of Centella asiatica. Quest Med 1978;31:919-924. 25. Carraro Pereira I. Treatment of cellulitis with Centella asiatica. Folha Med 1979;79401414. 26. D a d s F, Orcel L, de Saint-Maur PP, Mamou P. [Use of a titrated extract of Centelk asiutica in chronic hepatic disorders.] Sem Hop 1979;55:1749-1750. 27. El Zawahry MTI, KhaIil AM, El Banna h4H. Madecassol, a new therapy for hepatic fibrosis. Bull !%c Int Chir (Belgium) 1975;W 573-577. 28. Fmcato M. On the treatment of cutaneous lesions with extract of Centella asiutica. Minerva Chir 1960;15:1235-1238. 29. Sterkers Desagnat M, Philbert M, Moreau L. Medical treatments for benign disease of the breast. Therapeutique 1975;51:121-124. 30.Guarnerio F, Sansonetti G, Donzelli R, Marelli C. Treatment of hemorrhoids with Centella asiatica. G Ital Angiol 1986;6:46-52.

Pharmacology of Natural Medicines 31.Bosse JP, Papillon J, Frenette G, et al. Clinical study of a new antikeloid agent. Ann Plast Surg 1979;3:13-21. 32. Basset A, Ullmo A, Maleville J, Alt J. [Treatment of keloids with Madecassol per os.]Bull Soc Fr Dermatol Syphiligr 1970;77:826-827. 33. Ippolito F. Medical treatment of keloids. G Ital Dermatol 1977;112377-381. 34. Chakrabarty T, Deshmukh S. Centella asiatica in the treatment of leprosy. Sci Cult 1976;42573. 35. Chaudhuri S, Ghosh S, Chakraborty T, et al. Use of a common Indian herb "Mandukapami" in the treatment of leprosy. J Indian Med As= 1978;70177-180. 36. Wolfram VS. Erfahrungem mit Maddecassol bei der behandlung ulzereroserser hautveranderungen. Wien Med Wochenschr 1%5;115 439-442. 37.Appa Rao MVR, Srinivasan K, Koteswara RTL. The effect of Centella asiatica on the general mental ability of mentally retarded children. Indian J Psychiatry 1977;1954-59. 38. Kyoo WC. Medical treatment of peptic ulcer. J Korean Med Assoc 1980;23:31-35. 39. Pergola F. Treatment of peptic ulcer with a titrated extract of Centella asiatica. Med Chir Dig 1974;36:445-448. 40.Baudon-Glanddier B. Perineal lesions and asiaticoside. Gaz Med Fr 1963;70:2463-2464. 41. BenedicentiA, Galli D, Merlini A. [The clinical therapy of periodontal disease. The use of potassium hydroxide and the water-alcohol extract of Centella asiatica in combination with laser therapy in the treatment of severe periodontal disease.] Parodontol Stomatol 1985;24:11-26. 42. Abou-Shousha ES, Khalil HA. Effect of asiaticoside (Madecassol) on the healing process in cataract surgical wounds and retinal detachment operations (clinical and experimental study). Bull Ophthalmol Soc Egypt 1%7;60:451-470. 43. Bletry 0. Comment on the treatment of scleroderma. Gaz Med Fr 1980;871989-1990. 44.Fontan I, Rommel A, Geniaux M, Maleville J. Localized sderoderma. Concours Med 1987;109:49&504. 45. Sasaki S, Shinkai H,Akashi Y, Kishihara Y.Experimental and clinical effects of asiaticoside (Madecassol) on fibroblasts, granulomas, and sderoderma. Jap J Clin Dermatol1971;25:58!5-593. 46. Sasaki S, Shinkai H, Akashi Y, Kishihara Y. Studies on the mechanism of action of asiaticoside (Madecassol) on experimental granulation tissue and cultured fibroblasts and its clinical application in systemic s d e r o d e m . Acta Derm Venereol 1972;52141-150. 47.Balina LM, Cardama JE,Gatti JC, et al. Clinical results of an asiaticoside in cutaneous ulcerous lesions. Dia Med 1961;33: 1693-1696. 48.Bazex J, N o p e J, Peyrot J. Periulcerous eczema type cutaneous reaction during and after ulcers of the leg. Rev Med Toulouse 1982; 18171-174. 49. Dulauney MM. Postphlebitic leg ulcers and indications for therapy. Bord Med 1979;121807-1810. 50. Hanna LK, Amin L, El Serafy I. Trophic ulcers and their treatment with Madecassol. Afr Med 1969;8:315-318. 51. Huriez C. [Action of the titrated extract of Centella asiatica on cicatrization of leg ulcers (10 mg tablets). Apropos of 50 cases.] Lille Med 1971;17574579. 52.Sarteel AM, Merlen JF. [Treatment of leg ulcers. Martorell ulcer, superficial gangrene, so-called capillaritic ulcers.] Phlebologie 1983;36.375-379. 53. Thiers H, Fayolle J, Boiteau P, Ratsimamanga AR. Asiaticoside, the active principle of Centella asiatica, in the treatment of cutaneous ulcers. Lyon Med 1957;197389-395. 54. Vittori F. The treatment of ulcus cruris. J Med Lyon 1982;63:429432. 55.Castellani C, Gillet JY, Lavemhe G, Dellenbach P. [Asiaticoside and cicatrization of episiotomies.] Bull Fed Soc Gynecol Obstet 1966;18184-186.

56. Colonna d'Istria J. [Research on the healing action of Madecassol in cervical and laryngeal surgery after ionizing radiations.] J Fr Otorhinolaryngol Audiophonol Chir Maxillofac 1970;19:507-510. 57. OKeeffe P. A trial of asiaticoside on skin graft donor areas. Br J Plast Surg 1974;27194-195. 58. Pignataro 0, Teatini GP. [Clinical research on the cicatrizing action of Madecassol in comparisons of oropharyngeal mucosa.] Minerva Med 1965;56:2683-2686. 59.Riu R, Alavoine J, Auriault A, Le Moue1 C. [Clinical study of Madecassol in otorhinolaryngology.] J Med Lyon 1966;47 693-706. 60.Sevin P. Some observations on the use of asiaticoside (Madecassol) in general surgery. Progr Med (France) 1962;90:23-24. 61. King DS.Tuberculosis. N Engl J Med 1950;243:530-536,565571. 62.Allegra C. [Comparative capillaroscopic study of certain bioflavonoids and total triterpenic fractions of Centella asiatica in venous insufficiency.] Clin Ter 1984;110555-559. 63. Allegra C, Pollari G, Criscuolo A, et al. [Centella asiatica extract in venous disorders of the lower limbs. Comparative clinicoinstrumental studies with a placebo.] Clin Ter 1981;99:507-513. 64.Barletta S, Borgioli A, Corsi C. Results with Centella asiatica in chronic venous insufficiency. Gazz Med Ital1981;14033-35. 65. Basellini A, Agus GB, Antonucci E, Papacharalambus D. [Varicesin pregnancy (an update).] Ann Ostet Ginecol Med Perinat 1985; 106~337-341. 66. Boely C. Indications of titrated extract of Centella usiatica in phlebology. Gaz Med Fr 1975;82741-744. 67. Bolgert M, Gautron G. An extract from Centella asiatica in phlebology. Progr Med (France) 1972;10031-32. 68. Cappelli R. Clinical and pharmacological study on the effect of an extract of Centella asiatica in chronic venous insufficiency of lower limbs. G Ital Angiol19833:44-48. 69. Cospite M, Ferrara F, h4ilio G, Meli F. Study about pharmacologic and clinical activity of Centella asiatica titrated extract in the chronic venous deficiency of the lower limbs. Valuation with strain gauge plethysmography. G Ital Angiol1984;4200-205. 70. Frausini G, Rotatori T, Oliva S. Controlled trial on clinical-dynamic effects of three treatments in chronic venous insufficiency. G Ital Angi011985;5147-151. 71. Marastoni F, Baldo A, Redaelli G, Ghiringhelli L. [Centella asiatica extract in venous pathology of the lower limbs and its evaluation as compared with tribenoside.] Minerva-Cardioangiol 1982;30: 201-207. 72.Mariani G, Patuzzo E. Treatment of venous insufficiency with extract of Centella asiatica. Clin Eur (Italy) 1983;22:154-158. 73. Mazzola C, Gini h4M. Centella asiatica extract in treatment of chronic venous insufficiency. Clin Eur (Italy) 1982;21:160-166. 74. Pointel JP,Boccalon H, Cloarec M, et al. litrated extract of Centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. Angiology 1987;38:46-50. 75. Ramaswamy AS, Periyasamy SM, Basu N. Pharmacological studies on Centella asiatica L. (Brahma manduki) (N.O. Umbelliferae). J Res Indian Med 1970;4:160-175. 76. Laerum OD, Iversen OH. Reticuloses and epidermal tumors in hairless mice after topical skin applications of cantharidin and asiaticoside. Cancer Res 1972321463-1469. 77. Veerendra Kumar MH, Gupta YK. Effect of different extracts of Centella asiatica on cognition and markers of oxidative stress in rats. J Ethnopharmacol2002;79253-260. 78. Lee MK, Kim SR, Sung SH, et al. Asiatic acid derivatives protect cultured cortical neurons from glutamate-induced excitotoxicity. Res Commun Mol Pathol Pharmacol2O00;108:75-86. 79. Veerendra Kumar MH, Gupta YK. Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer's disease in rats. Clin Exp Pharmacol Physiol2003;30:336-342.

Centella asiatica (Gotu Kola) 80. Bradwejn J, Zhou Y, Koszycki D, Shlik J. A double-blind, placebocontrolled study on the effects of Gotu Kola (Centella asiatica) on acoustic startle response in healthy subjects. J Clin Psychopharmacol

2000;20:680-684. 81. Incandela L, Belcaro G, De Sanctis MT, et al. Total triterpenic fraction of Centella asiatica in the treatment of venous hypertension: a clinical, prospective, randomized trial using a combined microcirculatory model. Angiology 2001;52(suppl2):S61-S67. 82. De Sanctis MT, Belcaro G, Incandela L, et al. Treatment of edema and increased capillary filtration in venous hypertension with total triterpenic fraction of Centella asikticu: a clinical, prospective, placebo-controlled, randomized, dose-rangingtrial. Angiology 2001; 52(s~pp12):555-S59. 83.Cesarone MR, Belcaro G, Rulo A, et al. Microcirculatory effects of total triterpenic fraction of Centella asiatica in chronic venous hypertension: measurement by laser Doppler, TcPO2-CO2, and leg volumetry. Angiology 2001;52(suppl2):S45-S48.

84. Cesarone MR, Belcaro G, De Sanctis h4T, et al. Effects of the total triterpenic fraction of Centella usiatica in venous hypertensive

microangiopathy: a prospective, placebo-controlled, randomized trial. Angiology 2001;52(suppl2):S15-S18. 85. Cesarone MR, Incandela L, De SanctisMT, et al. Evaluation of treatment of diabetic microangiopathy with total triterpenic fraction of Centella asiatica: a clinical prospective randomized trial with a microcirculatorymodel. Angiology 2001;52(suppl2):S49-S54. 86. Cesarone MR, Incandela L, De Sanctis MT, et al. Flight microangiopathy in medium- to long-distance flights: prevention of edema and microcirculation alterations with total triterpenic fraction of Centella asiatica. Angiology 2001;52(suppl2):S33-S37. 87.Cesarone MR, Belcaro G, Nicolaides AN, et al. Increase in echogenicity of echolucent carotid plaques after treatment with total triterpenic fraction of Centella asiatica: a prospective, placebo-controlled, randomized trial. Angiology 2001;52(suppl 2): S19-S25.

Chinese Prepared Medicines Mark Harrison Nolting, ND, LAC Qiang Cao, LAC,OMD, ND CHAPTER CONTENTS Introduction 837

Adulterants, Endangered Species, and Standards 839

Global Market 838 Dispensary Guide 840 Formulationsand Preparations 838

INTRODUCTION Chinese prepared medicine (CPM) is the "over-thecounter [OK]" medicine of the traditional Chinese pharmacy, thousands of various preparations of classical and conventional Chinese herbal formulas. Much of this medicine has been in constant use for hundreds, even thousands, of years, often maintaining original formulations. One example is a frequently sold CPM called Jie Geng Wan (Platycodon Root Pills).* The source of this respiratory system medicine is the ling Kui Yao Lue Fang Lun ("synopsis of the Golden Chamber"), written by Zhang Zhong Jing in 219 AD.* Zhu? writing in his highly useful and informative Clinical Handbook of Chinese Prepared Medicines, explained the following: The overtaxed Sung-dynasty merchant, as well as the frazzled h4ing mother, appreciated the simple convenience and economy of a well-prepared herbal pill, powder, or syrup as much as does his or her modem counterpart. Yan Bian Lian, the phrase commonly used when referring to these Zhong Cheng Yuo ("Chinese Ready-to-be-Taken Medicines"), may best express fundamental reason-for-being of ready-to-take medicaments in any tradition: "Effectiveness, Convenience, Economy."

Secret family (or company) recipes called patent medicines were first produced in the Song Dynasty (960-1234 AD) and were dispensed by government agencies such as the Imperial Benevolent Prescriptions of the Taiping Period? Few true patent medicines exist anymore in the Chinese pharmacy. Many of these medicines have become part of the public domain, making it more appropriate to refer to them collectively as CPMs. Unfortunately, there are too many dubious CPMs in the worldwide market that have been adulterated in various ways, some

containing Western prescriptive medicines, toxic elements, and endangered species often hidden from the unsuspecting consumer? Consumers may find in their quest for safe, natural, and effective medicine serious medical consequences they had not expected. This is an issue that deserves scrutiny by consumers, practitioners, and regulators alike. Typical images of the U.S."Wild West" include cowboys, American Indians, farms, and the frontier life. But there was another, lesser known presence in the West, the lives of Chinese immigrants. Many had come to America seeking life on the "Gold Mountain," the view of America that had been created in China during the 1800s. According to Paul Buell? writing in his Chinese Medicine on the Golden Mountain book When in the mid-nineteenth century Chinese immigrants began to arrive in America, all kinds of traditional medical practitioners came with them . . . well-practiced Chinese medicine was often superior to contemporary western practice.

The immigrants, mostly men, left their families to mine for gold. Many ended up working as miners or other laborers. They brought their traditional form of Chinese medicine and their traditional herbal medicine, which included various forms of CPM. Chinese herbal medicine is a highly evolved system of traditional medicine that draws from a Materia Medica composed of thousands of individual herbs (herbs in traditional Chinese medicine [TCM] include plant, mineral, and animal).7 CPMs would generally be considered an adjunct to Chinese herbal medicine in most practices because they are convenient and good alternatives to the strong, bitter-tasting decoctions often used in practice. 837

Pharmacology of Natural Medicines

Many practitioners, particularly in the West, prefer to use granulated Chinese herbs or powered herbs.

GLOBAL MARKET The market for CPMs is huge. China will become the largest pharmaceutic market in the world within a few years. Chinese sales of herbal medicine alone were 2.3 billion dollars in 1995.More than 5OOO “licensed patent medicines” are estimated to exist in China.EAccording to China Today, exports of Chinese herbal medicines worldwide reached 20 billion dollars in 2002. About 5% of this amount was China’s share, and prepared medicines comprised less than one third of this.In China the famous Tong Ren Tang factory, which exports the most CPMs in China, earned 14.5 million dollars? Outside of the enormous “inside China market,” the growing interest and use of natural medicine worldwide are driving the consumption of prepared medicines rapidly upward. As mentioned already, this growth has sparked abuse and problems with product labeling and safety that the entire profession is working to counteract. Although Chinese medicine and pharmacy began to spread outside of China’s borders nearly 2000 years ago, it is only in the past 20 years that interest has grown in North America. Much of this is due to former President Richard Nixon’s trip to the People’s Republic of China in the early 1970s and subsequent reporters’ visits and articles, especially those of James Reston of the N a u York Times.The growth of acupuncture and oriental medical practices such as herbal medicine in the United States has been steady since that time. The traditional loose herb recipes used in Chinese herbal medicine are cooked and made into medicinal soups, which are often bitter and difficult for the American palate. The Chinese solution to this dilemma is to increase the use of raw licorice in the formula and to offer sugar wafers to the patient to help offset the bitter taste, although most Chinese welcome a bitter taste as a normal part of Asian cuisine. The prepared medicines offer an alternative to the traditional preparations. A number of companies, particularly in Taiwan and California, have begun to popularize the manufacture and sale of powder and tincture formulas in single herb form to help “bridge” the traditional form and the prepared, more palatable, forms of medicine. This allows the practitioner to still use the traditional approach, that of mixing and adjusting the formulas tailored to the patient’s individual diagnosis. Prepared formulas are fixed, of course, and do not allow any adjustments in the ingredients. Before the mid-l970s, the U.S. Food and Drug Administration (FDA) restricted the import and sale of traditional medicines by ethnic groups. New legislation and court rulings since then have lifted these restrictions, which, coupled with the explosion of acupuncture on

the American health scene, has opened the door to the spread of prepared medicines.* Now, due to this rapid growth in the sale and use of prepared medicines, problems with adulterants and false labeling are increasing, especially in California, where a multiagency herbal medicine task force involving numerous California and federal government agencies was formed in response. In fact, California Department of Health Services documents state that ”most imported Asian patent medicines do not fully comply with California laws.”10Although some of these violations are indeed potentially dangerous and may involve toxic ingredients and the inclusion of endangered species, many involve labeling issues and can often be sorted out by revising the labeling at the company of origin.

FORMULATIONS AND PREPARATIONS CPMs are prepared in numerous different forms. As far back as 200 BC, Chinese pharmaceutics had already developed a surprising level of sophistication. Pills were bound together using a wide variety of animal and human substances.” Box 79-1 lists 15 of the most common dosage forms of CPM. In China, the prepared medicines are produced at factories located throughout the country. Reputation and awards are important to these mainland Chinese operations. Factories such as the Chongqing Tong Jun Ge Medicine Works in Sichuan province, built in 1908, are proud of their products. This factory produces more than 200 medicines in 14 therapeutic categories.’* Roadside and rooftop billboards across China extol the benefits of ”famous” CPM, as well as displaying the awards various formulas have received over the years. Longevity is an important virtue attributed to specific herbs and formulas in Asian medicine. Ginseng, in all its many species and preparations, is surely the most

Pills Honeyed Watered Pasted Concentrated Powders Medicinal granules Tablets Troches Concentrated decoctions Glues Syrups Mixtures Dripping pills

Capsules Hard Soft Enteric Medicinal wines Tinctures Liquid extracts Plasters Adhesive plasters Ointments Medicinal distillates Medicinal teas Injections Suppositories

-

Modified from the Pharmacopeia Commission of PRC. Pharmacopeia of the People’s Republic of China (English edition 1997). VOI 1. Beijing: Chemical Industry Press, 1997:A3-A14.

revered and used herb in China. The pursuit of longevity is central to its popularity, aside from the fact that it is a highly useful and effective herb. An interesting side note is that the American species of ginseng, Panax quinquefolius,is exported in great quantitiesto China, only to be repackaged and exported back to Western markets. American ginseng is considered a milder, more "supportive" ginseng in action, making it more suitable for the elderly and weak. Ginsengs are part of the tonic herb family, a major classification that does not exist in the conventional Western pharmacy. The most famous factory for herbal medicine products in China is the Tong Ren Tang Pharmacy in Beijing. The Tong Ren Tang Pharmacy, first established in 1669, has been operated by the same family for more than 317 years. Prepared medicines produced in this factory have generally been held in the highest reputation in China, where the factory has supplied medicines to Chinese royalty over several centuries. The drug control acts implemented by the Chinese government in the 1970sand 1980s have helped to further guarantee quality control of prepared medicines in China, and companies such as the Tong Ren Tang pride themselves on following these ~tandards.'~

ADULTERANTSyENDANGERED SPECIES, AND STANDARDS The issue of adulterants and endangered species has increasingly threatened the reputation of CPM as safe and effective. The massive historical and growing contemporary usage of these products in Asia and indeed the world often obscures these quality and ethical realities. The use of tiger bone, rhino horn, bear gallbladder, and seahorse are realities in a system of medicine that spans the centuries. Raising the consciousness of practitioners who grew up in that culture is really a task of education and reshaping that culture. Trafficking of illegal products is tied to big money, and separation between this practice and the legitimate market can be challenging. Western pharmaceutics find their way into "herbal" products as "secret" ingredients that boost the effectiveness of the actions. Government control in the countries of origin is one thing, but ControlLing this globally given widespread corruption and conflicting priorities is a difficult task. The fundamental question remains: "Is the product purchased today in the Asian supermarket or local health food store free of adulterants and endangered species?" Many prepared medicines made outside mainland China lack the same quality controlsas the factories within China. Factories and sellers within China can indeed be visited and found to have goodquality products determined to be safe and free of adulterants. In 1975 an herbal-based preparation called Toukuwan was manufactured in Hong Kong by the Nan-Lien Pharmaceutical

Company and widely promoted in the United States as a treatment for rheumatism and arthritis. The FDA banned the import of Toukuwan after it discovered four drugs including Valium in the Chuifong preparation. Various prescription drugs have also been discovered in other prepared medicines. The Journal of the American Medical Association also reported four cases of agranulocytosis caused by prepared medicines in 1975 before the FDA ban. The Chuifong product has continued to appear under various names such as "miracle herb" since 1975.14J5Caution must be used when purchasing and prescribing prepared herbal medicines, and we recommend using only well-known and reputable manufacturers. If consumers are in doubt, we recommend using products produced at American companies, which typically are subject to far more quality-control standards than those in Asia, and always consulting practitioners who research the origins of various products they use and recommend. In May 1994 Traffic USA and the World Wildlife Fund published Prescription for Extinction: Endangered Species and Patented Oriental Medicines in Trade.I5 This report gave insight into the vast number of endangered species being used in natural medicine. The report indicates which products and traditional formulas contain endangered or threatened species, according to Appendices I, 11, and I11 of the Convention on International Trade in Endangered Species of Wild Fauna and Flora.16J7 Lu,18 writing in the China Daily, described new European regulations in 2004 regarding the importation of Chinese herbal medicines into the European market. He stated the following: The directive regulates that manufacturers who export herbal medicines to the EU market must get the union's GMP (Good Manufacturing Product) certificate, products quality must comply with EU phannacopoeia, and importers should have import licenses. . . . But generally speaking, the directive, which for the first time grants TCM legal status as medicines, will benefit Chinese medicine makers to explore the European market in the future.Currently, most of the TCM products exported to the EU market are under the category of food, native produce, health products, or pharmaceutical ingredients, instead of medicine. Industry experts said that when one TCM product is registered as traditional herbal medicine in the EU, it indicates great market potentials. First, the market value of TCM will be greatly lifted compared to being sold as food or pharmaceutical ingredients. Second, the legal status as medicine would allow TCM join EU countries' hospitalization insurance system. And EU's recognition of TCM will help reduce possible unfair treatment of Chinese medicines from other countries. . . . Meanwhile, domestic makers should strengthen research and development, dismiss some ingredients which are unacceptableto western people, and develop products to cater for the huge European market.

Hong Kong, long a stronghold of TCM despite a restrictive anti-TCM atmosphere under British rule, has

Pharmacology of Natural Medicines upgraded its standards for Chinese herbs. The Chinese Medicine Council of Hong Kong was formed in 1999 to protect public health and consumers’ rights and to ensure the professional standard of Chinese medicine practitioners and the trade of Chinese medicines. On the council’s website, Shawl9discusses the trailblazing approach Australia has taken to create standards for the practice and sale of Chinese herbal medicines: In that country (Australia),products were either “listed” or ”registered.” Listed products were of certified quality and were required to have supporting evidence of safety from the literature. No claims regarding efficacy could be made. Registered products equated to those with a license in the UK.

Shaw also referred to the 1996 report “Towards a Safer Choice,” which resulted from a review of the practice of TCM in Australia. The report concluded that regulation of Chinese herbal medicine and acupuncture practitioners was necessary and led to the Chinese Medicine Regulation Act 1999, which set out statutory regulation for such practitioners in the state of Victoria. The intention was that regulation would eventually be brought in on a national scale. Shaw emphasized that this was being done for the benefit of the public, not practitioners. Summing up, Shaw listed five elements for improving the safety of Chinese herbal medicines: Research into efficacy and safety Training of practitioners Quality herbs Adverse-effect monitoring Appropriate regulation

Also on the council’s website is a valuable list of safety concerns raised by AndersonI9 of the Hong Kong Medicines Control Agency, listed as follows: Lack of adequate authentication Intentional or accidental substitution Use of toxic substances and heavy metals (e.g., arsenic disulphide) Use of toxic animal materials (e.g., Bufo secretions) Use of synthetic drugs (e.g., corticosteroids, nonsteroidal antiinflammatory drugs) Inadequate or inaccurate labeling

DISPENSARY GUIDE CPM serves a number of different therapeutic purposes in and out of the practitioner’s office. First and foremost, it is best prescribed within the principles of prescribing of traditional Chinese herbal medicine. For example, clearing heat or dispelling dampness formulas require some understanding of the philosophy underlying these principles. If just prescribed cookbook style, then individual patient reactions cannot be understood and

tracked properly and the full effect of the formulas will not be appreciated. Secondly, CPM can augment and support traditional decoction-style prescribing. Thirdly, CPM is most valuable in acute prescribing and generally lends itself to OTC use. OTC use is best with input from trained Chinese medicine practitioners. In the case of Yin Chiao, described later, this widely used effective formula is most often prescribed at the onset of colds. And then there is the formula called Chuan Xin Lian (Androgrophis antiinflammatory tablets), which has tremendous effectiveness in inhibiting common bacterial infections, almost an “herbal antibiotic.”*OA final example of useful CPM in acute prescribing is the famous formula called Y m a n Baiyao. This is the most important CPM one should have at hand, at home and on the road. It is an emergency medicine useful in all cases of injury. The signature of Yunnan Baiyao as traditionally dispensed involves little bottles of yellow powder with a tiny red “emergency” pill that is said to help revive critically injured individuals. Yang and Liar@ described it as follows: Yunnan Baiyao, literally meaning Yunnan White medicine, smells like a walk through an exotic forest. That’s a clue to its composition: a dozen or so herbs from the Southwestern flora-abundant province of Yunnan-but exactly which herbs remains a state secret. Successfully used for more than 80 years, Yunnan Baiyao, now available in several forms, is a veritable cure all and an essential, trusty family medicine in China.

The 10 Chinese prepared medicines described in Table 79-1 represent a small sample of the most common and therapeutically effective formulations. Several common varieties of preparations such as pills, tablets, oral liquids, tinctures, and plasters are included. An attempt has been made to introduce preparations for cardiovascular, respiratory, central nervous system, urinary, female, and dermatological conditions. This approach of focusing on major human systems is a common method of teaching prepared medicines. Ingredients are listed with their Chinese (Pinyin) name, botanical name, and percentage in formula. Actions are listed in terms of TCM with Western activities when pertinent. Indications are given according to major Chinese sources. Administration and dosage information is provided with specific directions for adult, as well as pediatric, use. Packing information is also provided to help ensure proper recognition and dosage.A special notes section is included to highlight unique uses, cautions, and contraindications of the preparations. Due to the questionable standards of prepared medicines manufactured in Asia and generally outside China, only mainland Chinese sources known to us are listed. We also urge practitioners to scrutinize the labels of products from unknown sources. With correct labeling,

Allergic rhinitis Sinusitis Chronic rhinitis Nasal obstruction Rhinorrhea Sneezing Cough Asthma Bronchitis

Antiinflammatory Anodyne Antiasthmatic

Xanthium fruit (Cang Er Zi) Magnolia flower (Xin Yi) Angelica root (Bai Zhi) Chrysanthemum (Ju Hua) Lonicera flower (Jin Yin Hua) Pogostemon herb (Huo Xiang) Ox gallstone (Niu Huang) Bear bile (Xiong Dan Zhi) Other herbal extracts This is a widely known and used formula that is accepted as an herbal combination whose manufacturer maintains a patent on its exact formulation

Pe Min Kan Wan (nasal allergy pills)

Indications Common cold and flu Fever and sensation of chill Pain and weariness of limbs Headache Cough Swelling sore throat Mumps Parotitis

Antiphlogistic Disinfectant Carminative Refrigerant

Loniceral flower (Jin Yin Hua), 17.85% Forsythia fruit (Lian Qiao), 17.85% Arctium fruit (Niu Bang Zi), 10.72% Platycodon root (Jie Geng), 10.72% Mentha herb (Bo He), 10.72% Soja seed (Dan Dou Chi), 8.93% Licorice root (Gan Cao), 8.93% Lophaterum leaf (ZhuYe), 7.14% Scizonepeta herb (Jing Jie), 7.14%

Actions

Ingredients

Formula name

Yin Chiao Chieh Tu Pien (Lonicera and Forsythia dispel heat tablets)

Bottle of 50 tablets

Two to three tablets each dose, bid or tid Taking this medicine consistently for 30 days is considered one course of treatment

Continued

Pe Min Kan Wan is an effective remedy for the treatment of acute or chronic sinusitis and rhinitis. It is particularly effective for hypersensitive sinusitis. In hypertrophic rhinitis, it will gradually reduce the size of the polyps in the nose. Marked amelioration of the symptoms can be seen after the patient has taken this medicine for 1 week in mild cases, and one or two courses of treatment are sufficient for recovery. In serious cases, several courses of treatment should be given. Manufactured by the Fu Shan United Pharmaceutical Manufactory, Guang Dong, People’s Republic of China

Notes This formula was made for wind heat invasion of the exterior in traditional Chinese medicine. It is a very popular and commonly used medicine throughout China for early stages of common cold and flu. The Chinese hold that it is the best medicine for common cold and flu. It is most effective when taken immediately or in the first day or two after onset of cold or flu. It may also produce a diaphoretic effect, so monitor use carefully. Produced by Tien Jin Drug Manufactory, Tianjin, People’s Republic of China

Packaging 0.6 g each tablet, eight tablets per tube, 12 tubes per box

Dosage Two to four tablets bid or tid

Salviae multiorrhiza (Dan Shen) Promotes blood fanax notoginseng(San Qi) circulation Borneolum (Bing Pian) Limits blood stasis Induces resuscitation by means of aromatics Regulates the blood flow of Qi to alleviate pain

€leutherocomus senticosus (Ci Wu Jia), 100%

Dan Shen Pian (Salvia miltorrhiza compound tablets)

Wu Cha Seng tablet (Eleutherococcus senticosus tablets) Accelerates the function of the brain and kidney Improves the appetite Improves eyesight and hearing Sedative effect on the central nervous system

Strengthen vital energy Tonify the digestive system Nourish the entire system

Panax ginseng (Ren Shen) Royal Jelly (Feng Wang Jiang) In a base of honey

Renshenfengwanaiang (ginseng and Royal jelly oral liquid)

Actions

Ingredients

Formula name

Ten Chinese prepared medkines--cont’d

Bottle of 50 tablets

Clinical research in China suggested that this herb is especially effective for relieving fatigue and increasing the immune function. It can also reduce anxiety, mental depression and irritation. In China, anthropanax is preferred over ginseng in the treatment of cancer. Produced by Harbin Chinese Medicine Factory, Heilongjiang, People’s Republic of China

The most popular heart remedy in China. Laboratory and clinical research in China has shown that this remedy is able to improve heart muscle contractions, invigorate the blood, increase the blood supply to the coronary artery circulation, and regulate the heart function. This medicine may cause stomach irritation. Produced by China National Chemicals Import & Export Company, Shanghai Branch, People’s Republic of China

This is a general tonic prepared medicine and is used to treat general weakness and to strengthen the immune system. Produced by China National Medicine and Health Products Import and Export Corporation, Harbin Branch, Harbin, People’s Republic of China

Oral liquid, 10 ml each vial, 10 vials per box

Notes

Packaging

Three to four Box of 60 tablets twice tablets daily, to be taken in the morning and evening with warm boiled water Desired effect is brought about in 2-3 Weeks Of administration. Prolonged administration will give better effects.

Three tablets tid

Coronary heart disease Angina pectoris Oppressed feeling in the chest

It has therapeutic effects for coronary heart symptoms such as dyspnea, dizziness, angina pectoris, etc. Satisfactory results for general debilitation, senility, sore limbs or arthritic pains This preparation also helps stimulate and restore the functions of the organs of the infirm or aged, and of those weakened after illness or childbirth. According to the manufacturer, it is effective in curing leukopenia.

To be taken orally, one vial each time, in the morning and in the evening

Dosage

Fatigue Poor constitution Malnutrition Also used as supplementary treatment of coronary artery disease, chronic hepatitis, neurasthenia, arthritis, gastritis, stomach and duodenal ulcer, impotence, lower sexual drive

Indications

Bupleurum chinense (Chai Hu), 14.3% Angelica sinensis (Dang Gui), 14.3% Paeonia lactiflora (Bai Shao), 14.3% Atractylodes rnacrocephala (Bai Zhu), 14.3% Poria cocus (Fu Ling), 14.3% Glycyrrhiza oralensis (Gan Cao), 115% Zingiber (Sheng Jiang), 14.3% Herba rnentha (Bo He), 2.9%

Rehmannia glutinosa (Di Huang), 12% Cornus officinalis (Shan Zhu Yu), 16% Diosmrea opposita (Shan Yao), 16% Alisrna plantago (Ze Xie), 12% Poria cocas (Fu Ling), 12% Paeonia sufutricosa (Mu Dan Pi), 12%

Angelica sinensis (Dang Gui), 12.12% Ligusticum wallichii (Chuan Xiong), 9.10% White Paaeonia lactiflora (Bai ShaoYao), 12.12%

Hsiao Yao Wan (Free and Easy pill)

Liu Wei Di Huang Wan (Rehmannia six formula)

Fu Ke Ba Zhen Wan (women’s precious pills)

Continued

Produced by Lanzhou Fo Ci Pharmaceutical Factory, Lanzhou, People’s Republic of China

Gynecological disorders with loss of Mood, and deficiency of Qi and blood including pale face, fatigue, dizziness, vertigo, shortness of breath, irregular menstruation,

Replenishingboth Qi and blood

Bottle of 200 pills

Produced by Lanzhou Fo Ci Pharmaceutical Factory, Lanzhou, People’s Republic of China

Eight to 10 pills Bottle of tid, taken 200 pills with warm water

Traditionally this remedy is used to treat deficiency of kidney yin, flaming up of deficient fire, with sore and weak back and knees, feverish and painful body, dizziness, tinnitus or deafness, spontaneous or night sweating, nocturnal emission with dream, thirst, dribbling of urine, dry tongue and soreness of throat, unstable teeth, and heel pain Modern use includes treatment of nephritis, diabetes, tuberculosis, hyperthyroidism, and hypertension.

Nourishing yin Tonifying the kidney

Eight to 10 pills tid, taken with warm water

Produced by Lanzhou Fo Ci Pharmaceutical Factory, Lanzhou, People’s Republic of China

Eight to 10 pills, Bottle of tid taken 200 pills with warm water

Traditionally this remedy is used to treat depression of the liver Qi and deficiency of the liver blood which manifest as pain in the hypochondria1region, alternative fever and chills, headache, vertigo or dizziness, dry mouth and throat, fatigue, anorexia, irregular menstruation, distention of the breasts, wiry and weak pulse. Modern use includes treatment of anxiety, depression, irritability, dizziness, vertigo, PMS, and irregular menses.

Circulating the liver Qi and relieving depression of the liver; invigorating the spleen and regulating the nutrient system

Skin infections caused by fungus, tinea, or scabies Itch of toes and skin Athlete’s foot, etc.

Arthralgia Soreness of waist and pain of the back Sprain and local pain caused by rheumatism It also is used for acute bruises, sprains, fractures, and traumatic swelling.

Eliminates damp and heat in the skin: stops itching

Promotes the flow of Qi and blood circulation Dispels pathogenic factor Alleviates pain

Cortex hibisci (Tu Jin Pi), 6 cc Benzoic acid, 1.8 g Salicylic acid, 0.9 g Alcohol, suitable amount Also contains safflower, dandelion and rhubarb extracts as inert ingredients for flavor and adjuvant in a base of myrrh gum mass

Menthol, 16% Methyl salicylate, 10%

Medicated herbal plaster

Indications

Tu Jin Liniment (complex hibisci tincture)

Actions hypermenorrhea, hypomenorrhea, dysmenorrhea, general deficiency during pregnancy, general deficiency in the postpartum period, chills and fever, restlessness and thirst

Ingredients

Rehmannia glutinosa (Shou Di Huang), 18.18% Codonopis pilosulae (Dang Shen), 12.12% Atractylodes macroephala (Bai Zhu), 12.12% Poria cows (Fu Ling), 12.12% Glycyrrhiza uralensis (Gan Cao), 6.06%

Formula name

Ten Chinese prepared medicines-cont’d

Rub on the skin (it is not necessary to cover the skin), and the liquid will dry quickly. Tighten the lid after use. Not to be taken orally or dropped into eyes. Produced by The United Pharmaceutical Manufactory, Guangzhou, People’s Republic of China Administer with care to pregnant women. Contraindicated for patients with local ulceration. If skin irritation occurs, move to adjoining area or discontinue use. In the case of an allergic reaction, immediately discontinue use. Manufactured by the United Pharmaceutical Manufactory, Guang Zhong, People’s Republic of China

3.9 x 11 inches, 10 pieces per box Remove attached film and apply to affected area. For adults and children 2 years of age and older. Apply to affected area not more than three or four times daily. It will remain effective for 24 hours; more effective if used after a bath. Remove patches while bathing. If needed, cut sheet into smaller patches to save plaster.

Notes

In bottles of 15 ml: 12 bottles to a paper box

Packaging

External application one to two times a day

Dosage

Chinese Prepared Medicines

ingredients of prepared medicines should be obvious to anyone who can read Latin or Chinese herbal names. In recent years, prepared medicine companies have become well established in the United States. Several

high-quality manufacturersare now producing formulas in forms more suitable. These tinctures, powders, and capsules are usually based on the same classical formulas described in this chapter.

1.The Pharmacopeia Commission of PRC. Pharmacopeia of the People’s Republic of China (English Edition 1993, vol 1. Beijing: Chemical Industry Press, 1997162. 2.Zhu CH. Clinical handbook of Chinese prepared medicines. Brookline, MA: Paradigm Publications, 1989:77. 3.Zhu CH. Clinical handbook of Chinese prepared medicines. Brookline, MA: Paradigm Publications, 1989:2. 4. State Administration of Traditional Chinese Medicine. Advanced textbook on traditional Chinese medicine and pharmacology, vol 1. Beijing: New World Press, 1995139. 5. California Department of Health. Asian patent medicines, questions and answers. Sacramento, C A California Department of Health Food & Drug Branch, 1991. 6. Buell P. Chinese medicine on the golden mountah an interpretive guide. Seattle: Wing Luke Memorial Museum, 1984. 7. Barlow J, Richardson C. China doctor of John Day. Portland, OR Binford & Mort Publishing, 1979. 8. Traditional Chinese medicines: The Chinese market and intemational opportunities, London: Natural Medicine Marketing in Collaborationwith Sin0 European Clinics Limited, 1996. 9. Li S. Tong Ren Tang goes international: An interview with Ding Yongling, general manager of Beijing Tong Ren Tang International Co, Ltd and deputy general manager of Beijing Tong Ren Tang Group Co, Ltd. China Today, October 2003. Available online at wvw.chinatoday.corn.cn [accessedAugust 27,20041. 10. State of California, Department of Health Services. Important information for the sellers of Asian patent medicines. Sacramento, CA State of California, Department of Health Services, 1991.

11. Fu WK. Traditional Chinese medicine and pharmacology. Beijing: Foreign Languages Press, 1985. 12. Product catalog. Chongqing, Sichuan, China: Chongqing Tong Jun Ge Medicine Works, 1985. 13.Zhu CH. Clinical handbook of Chinese prepared medicines. Brookline, MA: Paradigm Publications, 1989:6. 14.Rics CA, Sahud MA. Agranulqtosis caused by Chinese herbal medicines. JAMA 1975;23352-355. 15. McCaleb R, Blumenthal M. Black pearls lose luster. HerbalGram 1990;22:45,38-39. 16. Gaski AL, Johnson KA. Prescription for extinction: endangered species and patented oriental medicines in trade. Washington, DC: Traffic USA, 1994. 17. CITES Secretariat,Convention Documents. Geneva: Conventionon InternationalTrade in Endangered Species of Wild Fauna and Flora (CITES), September 1997. 18. Yu Lu. EU regulation affects TCM exports. China Daily. Available online at zvww.ChinadaiZy.corn.cn[accessed August 7,20041. 19. Chinese Medicine Council of Hong Kong. Regulation of Chinese medicine. Available online at vwwcrnchk.org.hk (accessed August 12, 20041. 20. Zhu C-H. Clinical handbook of Chinese prepared medicines. Brookline, MA: Paradigm Publications, 1989:189. 21. Unbelievable cures and medicines from China. Beijing: New World Press, 199761-67. 22. The Pharmacopeia Commission of PRC. Pharmacopeia of the People’s Republic of China (English edition 1993, vol 1. Beijing: Chemical Industry Press, 1997A3-Al4.

Chinese Herbal Patent Formulas: APractical Guide by Jake Fratkin, 1985

Encyclopedia of Chinese and U.S. Patent Herbal Medicines by Chongyun Liu, 1999 Outline Guide to Chinese Herbal Patent Medicines in Pill Form-with Sample Pictures of the Boxes by Margaret Naeser, 1989

Chinese Patent Medicines: A Beginner’s Guide by Mark Taylor, 1998 Clinical Handbook of Chinese Prepared Medicinesby Chun-Han Zhu, 1989 The Clinical Manual of Chinese Herbal Patent Medicines by Will MacLean, 2003, ed 2

Cimicihga racemosa (Black Cohosh) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 847

Dosage 850

Chemical Composition 847

Toxicology 850

History and Folk Use 847

Drug Interactions 851

Pharmacology 848 Clinical Applications 848 Menopause 848 Effects on Bone Resorption 850

Cimicifuga racemosa (family: Ranunculaceae) Common names: black cohosh, macrotys, rattleweed, black snake root

GENERAL DESCRIPTION Cirniczfuga racemosa is a perennial herb native to North America that grows on hillsides and in woods at higher elevations from Maine and Ontario to Wisconsin, Georgia, and Missouri. The large, creeping rhizome produces stems up to 9 feet high. The ovate or oblong leaflets are 1 to 6 inches long and 4 inches wide, while the smaller leaflets are ternate, then pinnate, and sometimes even further divided. Small, white, fetid flowers grow in long racemes from May to August. The rhizome is the portion of the plant used for medicinal purposes.

CHEMICAL COMPOSITION C. racemosa contains at least three important natural product groups that contribute to its pharmacology: cycloartane triterpene glycosides such as actein, 26-deoxyactein; phenylpropanoid esters; and phenolic compounds such as caffeic acid derivatives including ferulic acid and isoferulic acid (Figures 80-1 and 80-2).’” Early reports showed that it also contained the phytoestrogen flavonoid formononetin, but more recent analysis demonstrates that this compound is not contained in

either the crude herb or standardized extracts. At this point, despite extensive chemical, biologic, and clinical studies, neither the active constituents nor the exact mode of action of black cohosh has been determined! Currently, the standardization of cimicifuga preparations is based on the content of triterpene glycosides, calculated as 26-deoxyactein. Other important triterpene glycosides include actein and cimicifugoside (aglycone cimegenol).

HISTORY AND FOLK USE The generic name cimicifuga comes from the Latin cimex, a bug, andfugo, to drive away, alluding to its use as a vermifuge. Native Americans used cimicifuga rhizomes for the relief of pain during menses and childbirth, as well as snakebite. The rhizome of C. racemosa was listed in the National Formulary from 1936 to 1950 and in the U.S. Pharmacopeia from 1820 to 1936. Eclectic physicians in the early part of the twentieth century used cimicifuga in gynecologic disorders, as well as rheumatoid and myalgic pain. Although use in the United States declined dramatically from 1950 to 1995, cimicifuga preparations have been used extensively in Europe during this same period primarily as a natural alternative to hormone replacement therapy (HRT) during menopause. This popularity is based on substantial empiric and clinical evidence. 847

Pharmacology of Natural Medicines

Constituents able to bind to estrogen receptor sites and to inhibit LH secretion Compounds that bound to estrogen receptors but did not inhibit LH secretion

Flgutr, 80-1 Cimigenol.

Flgure a 2 Formononetin.

PHARMACOLOGY The primary pharmacologic effects of cimicifuga appear to revolve around its ability to impact endocrine regulatory mechanisms.= In the past, this activity was thought to be related to various phytoestrogenic components of cimicifuga, with formononetin perhaps being the most sisrUficant-9However, thisline of reasoning has been questioned by the lack of formononetin in clinically studied cimicifuga extracts, as well as equivocal reports on phytoestrogen activity. Current thinking is that certain cimicifuga components exert selective estrogen receptor modulator (SERM) activity with no action in the uterus but beneficial effects in the hypothalamo/pituitary unit and in the b ~ n e . ~ J ~ J ~ Cimicifuga’s primary effect on endocrine regulatory mechanisms appears to be the result of complex synergistic actions of its key ingredients. Evidence suggests that these compounds act on both the hypothalamus and vasomotor centers to produce sigruficantclinical benefits in menopause. For example, one study to determine the endocrhologic actions of cimicifuga extract involved treating 110 women with either cimicifuga extract (supplying a total daily dosage of 8 mg of 27-deoxyactein) or placebo.EAfter 2 months of treatment, luteinizing hormone (LH) decreased by 20% in the cimicifugagroup compared with the placebo group. Unlike estrogens, cimicifuga does not affect the release of prolactin and folliclestimulating hormone (FSH). Researchers then divided the extract into three distinct types of active compounds on the basis of their ability to reduce LH secretion in ovariectomized rats and to compete in vitro with 17-beta-estradiol for estrogen receptor binding sites, as follows: Constituents that did not bind to estrogen receptors but did suppress LH secretion

The authors concluded that ”the LH suppressive effect of C. racemosa extracts observed in menopausal women and ovariectomized rats is caused by at least threedifferent synergistically acting compounds.” Apparently, one of cimicifuga’s key pharmacologic effects is inhibition of the secretion of LH by the pituitary gland. This effect is accomplished equally by components that do and do not bind to estrogen receptors. If cimicifuga was simply mimicking the effects of estrogen, it would certainly alter the secretion of other pituitary hormones just like estrogen, but it does not. It appears that enhancement of dopaminergic activity is the responsible mechanism for some of these central effects on menopausal symptoms.5J2 C i m i h g a extracts also appear to exert some benefiaal effects on preventing bone loss. In an experiment carried out on ovariectomized rats, cimicifuga extract increased the expression of collagen I and osteocalcin. Similarly, other animal studies have demonstrated that cimicifuga extract significantly reduces the urinary parameters of increased bone metabolism and bone loss. The effects in these animal models were similar to raloxifene, a wellconfirmed S E W . Importantly, although early studies reported a direct estrogenic effect with cimicifuga, the current perspective is that ethanol and isopropanol extracts of black cohosh do not contain formononetin or other estrogenic flavonoids and therefore do not bind to the estrogen receptor, upregdate estrogen-dependentgenes, or stimulate the growth of estrogen-dependent tumors in in vitro and animal m~dels.~J~J~

CLINICAL APPLICATIONS C. racmosu extracts are by far the most widely used and thoroughly studied natural alternatives to HRT in menopause. Clinical studies have shown cimicifuga extracts to relieve not only hot flashes but also depression and vaginal a t r ~ p h y . ~ , ’ ~ ~ ~ Although evidence indicates that cimicifuga may provide benefit in other gynecologic complaints such as premenstrual syndrome, amenorrhea (both primary and secondary), dysmenorrhea, polymenorrhea, uterine fibroids, and fibrocysticbreast disease, its primary clinical application is menopause.”-26

Menopause In one of the first clinical studies, a large open study involving 131 doctors and 629 female patients, cimicifuga extract (two tablets twice daily providing a daily

Cimicifuga racemosa (Black Cohosh)

Cimicifuga in the treatment of menopause SvmDtom

Percentaae no longer present

Percentage improved

Total Dercentaae improved

~~~~

Hot flashes

43.3 38.6 36.2 35.2 35.2 38.1 43.2 30.7 36.5

43.3 49.9 45.7 51.6 54.6 54.8 42.4 46.1 46.0

Profuse perspiration Headache Vertigo Heart palpitation Ringing in the ears Nervousnesdirritability Sleep disturbances Depressive moods

Effect on Kupperman Menopausal Index of cimicifuga compared with conjugated estrogens and diazepam Treatment group Cimicifuga Conjugated estrogens Diazepam

Beginning

At 12 wk

35 35 35

14 16 20

dosage of 4 mg 27-deoxyactein)produced clear improvement of menopausal symptoms in more than 80% of patients within 6 to 8 weeks.I8 As shown in Table 80-1, both physical and psychologic symptoms improved. Most patients reported noticeable benefits within 4 weeks after the onset of cimicifuga therapy. After 6 to 8 weeks, complete resolution of symptoms was achieved in a large percentage of patients. Cimicifuga was well tolerated, as there was no discontinuation of therapy and only 7% of patients reported mild transitory stomach complaints. In one of the first double-blind studies, 60 patients were given cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein), conjugated estrogens (0.625 mg daily), or diazepam (2 mg daily) for 12 weeks.19Results from standard indexes of menopausal symptoms indicated a clear advantage of cimicifuga extract over both drugs. Cimicifuga’s effect on relieving the depressive mood and anxiety associated with menopause was far superior to either diazepam or conjugated estrogens, as shown in Table 80-2. One of the most used assessments in clinical studies in menopause is the Kupperman Menopausal Index. This quantitative assessment of menopausal symptoms is achieved by grading in severity: severe = 3, moderate = 2, mild = 1,not present = 0. The symptoms assessed are the following: Hot flashes Depressive moods

9

86.6 88.5 81.9 86.8 90.4 92.9 85.6 76.8 82.5

Profuse perspiration Feelings of vertigo Sleep disturbances Loss of concentration Headache Joint pain Nervousness/irri tability Heart palpitation

The results of the Kupperman Menopausal Index from this trial clearly demonstrate cimicifuga extract’s superiority over conjugated estrogens and diazepam, especially when safety and side effects are taken into consideration. In another early double-blind study, 80 patients were given cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein), conjugated estrogens (0.625 mg daily), or placebo for 12 weeks.2O Cimicifuga produced better results in the Kupperman Menopausal Index, the Hamilton anxiety test, and the vaginal lining than estrogens or placebo. The number of hot flashes experienced each day dropped from an average of five to fewer than one in the cimicifuga group. In comparison, the estrogen group only dropped from 5 to 3.5. Even more impressive was the effect of cimicifuga on the vaginal lining.Although both conjugated estrogens and the placebo produced little effect, a dramatic increase in the number of superficial cells was noted in cimicifuga €PUP* In a double-blind study of 110 women, cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein) was shown to exert significant improvements in menopausal symptoms.8In addition to providing relief of hot flashes, cimicifuga once again demonstrated impressive results on the vaginal lining, as confirmed by vaginal smear. In one study, 60 women younger than the age of 40 who had hysterectomiesleaving at least one intact ovary received one of the following: cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein),estriol(1 mg daily), conjugated estrogens

Pharmacology of Natural Medicines (1.25 mg daily), or estrogen-progestin combination (Tiisequens, one tablet daily).21Although the hormone therapies produced better results as determined by a modified Kuppeman’s Menopausal Index, cimicifuga still displayed signhcant effects in relieving the symptoms of “surgical menopause.” These results indicate that cimicifuga can be a suitable alternative to estrogens in women having partial, and possibly even complete, hysterectomies. In perhaps the most detailed double-blind study to date, cimicifuga extract was evaluated for its effect on menopausal symptoms, bone metabolism and on the endometrium compared with those of conjugated estrogen (CE) and placebo.” The 62 postmenopausal women were treated either with black cohosh extract (daily dose 40 mg), 0.6 mg CE, or matching placebo for 3 months. Results indicated that the black cohosh extract was equipotent to CE and superior to placebo in reducing menopausal complaints. Both black cohosh extract and CE produced beneficial effects on bone metabolism, but the black cohosh extract had no effect on endometrial thickness, which was signrficantly increased by CE. Vaginal superficial cells were increased with cimicifuga and CE treatment. These results seem to confirm that cimicifuga extracts contain substances with SERM activity (i.e., with desired effects in the brain/hypothalamus, bone, and the vagina but without exerting uterotropic effects). Women being treated with tamoxifen most often experience symptoms similar to menopause. To examine the effect of cimicifuga extract on hot flashes caused by tamoxifen adjuvant therapy in young premenopausal breast cancer survivors, 136breast cancer survivors aged 35 to 52 years who had been treated with segmental or total mastectomy, radiation therapy, and adjuvant chemotherapywere randomly assigned to receive tamoxifen 20 mg per day orally or tamoxifen plus black cohosh extract (20 mg daily).23The duration of treatment was 5 years for tamoxifen, according to international standards for adjuvant therapies, and 12 months for the black cohosh extract. Follow-up included clinical assessment every 2 months; the primary endpoint was to record the number and intensity of hot flashes. Results indicated that almost half of the patients getting the black cohosh extract were free of hot flashes. Only 24.4% of patients taking black cohosh extract experienced severe hot flashes compared with 73.9% of the women taking tamoxifen alone.

Effects on Bone Resorption On the basis of cimicifuga’s mechanism of action, pre-

liminary experimental and clinical research, and longterm clinical experience, many experts believe it will be shown to positively influencebone resorption. In patients at high risk for osteoporosisor those with confirmed low

bone density, physicians should monitor therapy with cimicifuga by using the Osteomark-NTXor other suitable indicator of bone res0rption.2~

DOSAGE The dosage of cimicifuga is based on its content of 27-deoxyactein,which serves as an important biochemical marker to indicate therapeutic effect. The dosage of the cimicifuga extract used in the majority of clinical studies has been 40 mg of black cohosh extract supplying 2 mg of 27-deoxyacteine twice daily. Approximate dosage recommendations using other (nonstandardized) forms of C. rucmosu are as follows: Powdered rhizome: 1to 2 g Tincture (1:5): 4 to 6 ml Fluid extract (1:l):3 to 4 ml(1 tsp) Solid (dry powdered) extract (41): 250 to 500 mg The German Commission E has recommended that treatment with cimicifuga be limited to 6 months (which is also the standard recommendation for HRT); however, thisrecommendation was made before detailed toxicology studies, discussed next. Based on currently available data, cimicifuga is appropriate for long-term continued use.

TOXICOLOGY The standardized extract of C. ~ u c m o s uproviding 1 mg of 27-deoxyactein in 40 mg of extract per tablet has been used in Germany since 1956 and has a remarkable safety record. A comprehensive review including preclinical and clinical research in estrogen-sensitive populations, including women at risk for breast cancer and breast cancer survivors, as well as human cell lines most relevant to breast cancer, confirmed this safety record. No serious side effects have ever been reported.28 Cimicifuga offers a suitable natural alternative to HRT for menopause, especially where HRT is contraindicated (e.g., in women with a history of cancer, unexplained uterine bleeding, liver and gall bladder disease, pancreatitis, endometriosis, uterine fibroids, and fibrocystic breast disease). Since cimicifuga extract shows some, albeit weak, estrogenic activity, researchers have sought to determine Remefemin’s effect on an established breast tumor cell line whose growth in vitro depends on the presence of estrogens. The results from these experiments show no stimulatory effects, but rather inhibitory effects as well as an ability to promote apoptosis in these cell^.^^"^ Furthermore, combining black cohosh with tamoxifen was shown to potentiate the inhibitory effects of tamoxifen.

Cimicifuga racernosa (Black Cohosh)

Detailed toxicology studies have also been performed on black cohosh extracts. No teratogenic, mutagenic, or carcinogenic side effects have been noted. The no-effect dosage in studies in a 6-month chroNc toxicity study in rats was at 1800 mg/kg body weigh-roughly 90 times the therapeutic dose.31A 6-month toxicologic study in rats is comparable to an unlimited treatment time in humans.

Although clinical evidence is lacking, there is some theoretic concern that L-carnitine 1 g daily potentiates the anticoagulant effects of aceno~ournarol.~~

1. Chen SN, Fabricant DS,Lu ZZ, et al. Cimiracemates A-D, phenylpropanoid esters from the rhizomes of Cimicifigu racemosa. Phytochemistry 2002;61:409-413. 2. Li WK, Chen SN, Fabricant D, et al. High-performance liquid chromatographic analysis of black cohosh (Cirnicifigu rucemosa) constituents with in-line evaporative light scattering and photodiode array detection. Anal Chim Acta 2002;471:61-75. 3.Shao Y, Harris A, Wang M, et al. Triterpene glycosides from Cimicifugu racemosu. J Nat Prod 2O00;63:905-910. 4. Kennelly EJ, Baggett S, Nuntanakom P, et al. Analysis of thirteen populations of black cohosh for formononetin. Phytomediche 2002; 9~461-467. 5. Borrelli F, Izzo AA, Emst E. Pharmacological effects of Cirnicifuga rucemosa. Life Sci 2003;731215-1229. 6. Jarry H, Hamischfeger G. [Endocrine effects of constituents of Cimicifuga rucemosu. 1. The effect on serum levels of pituitary hormones in ovariectomized rats]. Planta Med 1985;1:4649. 7. Jarry H, Hamischfeger G, Duker E. [The endocrine effects of constituents of Cimicifigu rucemosa. 2. In vitro binding of constituents to estrogen receptors]. Planta Med 1985;4316-319. 8. Duker EM, Kopnski L, Jarry H, Wuttke W. Effects of extracts from Cimicifuga rucemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med 1991;57420424. 9. Mksicek RJ. Commonly occurring plant flavonoids have estrogenic activity. Mol Pharmacol 1993;443743. 10. Seidlova-Wuttke D, Hesse 0, Jarry H, et al. Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifigu racemosa) extract: comparison with estradiol-17beta. Eur J Endocrinol2003;149:351-362. 11. Nisslein T, Freudenstein J. Effects of an isopropanolic extract of Cimicifigu rucemosu on urinary crosslinks and other parameters of bone quality in an ovariectomized rat model of osteoporosis. J Bone Miner Metab 2003;21:370-376. 12.Jarry H, Metten M, Spengler B, et al. In vitro effects of the Cimicifuga rucemosu extract BNO 1055. Maturitas 2003;44:531-538. 13. Mahady GB. Is black cohosh estrogenic? Nutr Rev 2003;61:183-186. 14. Zierau 0, Bodinet C, Kolba S, et al. Antiestrogenic activities of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol 2002; 80:125-130. 15. Kligler B. Black cohosh. Am Fam Physician 2003;68:114-116. 16. Borrelli F, Ernst E. Cimicifigu racemosu: a systematic review of its clinical efficacy. Eur J Clin Pharmacol2002;58235-241. 17. McKenna DJ,Jones K, Humphrey S, Hughes K. Black cohosh efficacy, safety, and use in clinical and preclinical applications. Altem Ther Health Med 2001;793-100.

18. Stolze H. An alternative to treat menopausal complaints. Gynecology 1982;3:14-16. 19. Wamecke G. Influencing menopausal symptoms with a phytotherapeutic agent. Med Welt 1985;36:871-874. 20. Stoll W. Phytopharmacon influences atrophic vaginal epithelium. Double-blind study-cimicifuga vs. estrogenic substances. Therapeuticum 1987;1:23-31. 21. Lehmann-Willenbrock E, Riedel HH. [Clinical and endocrinologic studies of the treatment of ovarian insufficiency manifestations following hysterectomy with intact adnexa]. Zentralbl Gynakol 1988; 110:611-618. 22. Wuttke W, Seidlova-WuttkeD, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebocontrolled study: effects on menopause symptoms and bone markers. Maturitas 2003;44:%7-S77. 23. Hernandez Munoz G, Pluchino S. Cimiczfigu racemom for the treatment of hot flashes in women surviving breast cancer. Maturitas 2003;44:S59-565. 24. Bruker A. Essay on the phytotherapy of hormonal disorders in women. Med Welt 1960;44:2331-2333. 25. Schildge E. Essay on the treatment of premenstrual and menopausal moods swings and depressive states. Rigelh Biol Umsch 1964;19: 18-22. 26. Gorlich N. Treatment of ovarian disorders in general practice. Arztl Prax 1962;141742-1743. 27. Nisslein T, Freudenstein J. Effects of an isopropanolic extract of Cimicifiga rucemosa on urinary crosslinks and other parameters of bone quality in an ovariectomized rat model of osteoporosis. J Bone Miner Metab 2003;21:370-376. 28. Dog TL, Powell KL, Weisman SM. Critical evaluation of the safety of Cimicifuga racemosu in menopause symptom relief. Menopause 2003;10299-313. 29. Hostanska K, Nisslein T, Freudenstein J, et al. Cimicifrcga racemosa extract inhibits proliferation of estrogen receptor-positive and negative human breast carcinoma cell Lines by induction of apoptosis. Breast Cancer Res Treat 2004;84:151-160. 30.Nesselhut T, Borth S, Kuhn W. Influence of Cimicifigu rucemosa extracts with estrogen-like activity on the in vitro proliferation of mammary carcinoma cells. Arch Gynecol Obstet 1993;254: 817-818. 31. Kom WD. Six-month oral toxicity study with Remefemin-granulate in rats followed by an 8-week recovery period. Hannover, Germany: International Bioresearch, 1991. 32. Martinez E, Doming0 P, Roca-Cusachs A. Potentiation of acenocoumarol action by L-carnitine. J Intem Med 1993;233:94.

DRUG INTERACTIONS

Citicoline (CDP-Choline) Alexander G. Schauss, PhD, FACN CHAPTER CONTENTS Introduction 853

Alzheimer's Disease 856

Pharmacokinetics 853

BrainTrauma 856

Mechanisms of Action Plasma Choline Levels Acetylcholinesterase Production 854 Phospholipase Activity Beta-amyloid Inhibition

854 854

Glaucoma 856 Amblyopia 857

854 854

Dosage 857 Toxicology 857

Elevation of Neurotransmitters 855 Drug Interactions 857 Clinical Applications 855 Age-Related Cognitive Deficiencies 855

Summary 857

StrokeTherapy 855 Memory-Impaired Elderly 856

INTRODUCTION

PHARMACOKINETICS

Citicoline (cytidine Y-diphosphocholine)is an important organic molecule that functions as an intermediate in the biosynthesis of cell membrane phospholipids. Taken at therapeutic levels as a supplement, it is hydrolyzed in the small intestine and readily absorbed as choline and cytidine, resulting in a sparing effect on systemic choline reserves. As a choline donor, it serves as an intermediate in the biosynthesis of phospholipids and acetylcholine. At the same time, its breakdown products enter into circulation and prevent undesired loss of membrane phospholipids. In situ, citicoline is the rate-limiting step in the synthesis of phosphatidylcholine from choline.' For this reason, supplementationwith citicoline can be a useful therapeutic adjunct to practitioners treating stroke victims, in improving cognitive function in patients experiencing mild cognitive impairment, and in the treatment of senile dementia of the Alzheimer type, and memory loss. Evidence that citicoline can also play a role in the treatment and prevention of vision disorders such as glaucoma and amblyopia is growing (Figure 81-1).

A water-soluble compound, citicoline is rapidly absorbed and highly bioavailable (>90%). It is metabolized in the gut and liver via hydrolysis to choline and cytidine. After ingestion, plasma levels peak within 1 hour, followed by a second larger peak 24 hours after intake. Once absorbed, choline and cytidine enter systemic circulation; contribute to various biosynthetic pathways; and cross through the blood-brain barrier, where they are resynthesized into citicoline in the brain? Citicoline elimination occurs by respiration and urinary excretion as biphasic eliminatory peaks. Using carbon-14 radiopharmacokinetic studies, it has been determined that the half-life of citicoline is 56 hours via carbon dioxide and 71 hours via urinary e~cretion.~ The first peak and decline in plasma concentration occurs 4 to 10 hours after ingestion. The second peak occurs about 12 hours after ingestion and declines more slowly until the majority is eliminated by the twenty-fourth hour? 853

the structural and functional integrity of brain neuronal membranes by serving as a precursor for acetyl~holine.~

Acetylcholinesterase Production

OH

II,

OH

,\."'

HO

4%

OH

Figure 81-1 CDP-Ciicoline.

Another mechanism of action suggests that citicoline stimulates production of acetylcholinesterase (AChE) and Na+ATPaseand K+ATPase.In vitro work indicates that citicoline bioconverts to phosphatidylcholinewithin external leaflets of the neuronal membrane where AChE activity occurs.1oHowever, since citicoline is not known to serve as an AChE inhibitor in humans, the significance of this finding remains unknown.

Phospholipase Activity MECHANISMS OF ACTION Prolonged oral administration of citicoline for 42 to 90 days has been shown in animals to increase brain levels of phosphatidylserine, phosphatidylcholine, and phospha tidylethanolamine, three critical phospholipids found in brain cell membranes." In aged rats it has been shown that citicoline activates phosphocholine cytidylyltransferase (CTP), the rate-limiting enzyme in the citicoline to phosphatidylcholine synthesis pathway?

Plasma Choline Levels Even a single dose of citicoline has been shown by protein magnetic resonance spectroscopy to raise plasma choline levels in young and old subjects6These studies have also determined that the cytidine moiety of citicoline is responsible for stimulating phosphatidylcholine. The strongest evidence of citicoline's ability to reverse age-related cognitive deficits comes from a protein decoupled phosphorus magnetic resonance spectroscopy study that followed administration of the agent for 6 weeks, after which it was seen that brain levels of phosphodiesters, byproducts of phospholipid metabolism, increased.' However, there are other mechanisms of action of citicoline. The metabolites of citicoline metabolism including choline, methionine, betaine, and cytidine-derived nucleotides enter several metabolic pathways that are of sigruficance to cognitive and neuronal function. Degeneration of cholinergic neurons is one of the sigruficant markers associated with Alzheimer disease. If the demand for acetylcholine increases or if choline levels in the brain decrease, catabolism of neuronal membranes may scavenge yield choline from phospholipids within those membranes. Since citicoline serves as a precursor for acetylcholine, it has been demonstrated in animals that administration of citicoline can result in a modest improvement in cognitive function.s Hence regular administration of citicoline could preserve

Alteration of phospholipase activity by citicoline has also been shown. Some evidence indicates that citicoline can restore sphingornyelin levels after ischemic reperfusion, thus protecting hippocampal neurons." During brain ischemia, hydrolysis of sphingomyelin occurs due to increased production of sphingomyelinase.Citicoline's effect on phospholipase A2,combined with its inhibition of sphingomyelinaseproduction, would suggest another route providing neuroprotection, especially when administered immediately after a cerebral stroke-induced ischemic episode. Citicoline's modulation of phospholipase A2 activity contributes to yet another potential mechanism of action. The inner mitochondria1 membrane contains a phospholipid component known as cardiolipin. Studies have shown that citicoline inhibits enzymatic hydrolysis of cardiolipin by phospholipase A2 via inhibition of arachidonic acid, a substrate for phospholipaseA2.12This mechanism of action is quite interesting. The arachidonic acid content of phosphatidylcholine has been shown to decrease after postischemic reperfusion due to hydrolysis of phospholipids. Because citicoline can restore the arachidonic acid content of phosphatidylcholine, it can prevent activation of phospholipase A2.An animal study supports this mode of action by demonstrating that citicoline decreases phospholipase A2 ~timu1ation.l~

Beta-amyloid Inhibition Of particular interest to clinicians seeking to arrest the pathophysiology associated with Alzheimer's disease is the finding that citicoline counteracts the deposition of beta-amyloid,a neurotoxicprotein involved in Alzheimer's disease. A body of evidence agrees that the degree of cognitive dysfunction and neurodegeneration associated with Alzheimer's disease is proportionate to the buildup of beta-amyloid in certain brain c e l l ~ . ' ~InJ one ~ rat study it has been demonstrated that intrahippocampalinjection of beta-amyloid protein did not impair memory retention, as measured by passive avoidance learning tasks, when concurrent citicoline was administered. Not only

Citicoline (CDP-Choline) did citicoline counteract neuronal degeneration in rat hippocampus, induced by the injection of beta-amyloid protein, but the number of apoptotic cells was also reduced.16 Amyloid precursor protein (APP) contains the pep tide that forms amyloid deposits. Abnormal cleavage of APP occurs when phosphatidylcholine and phosphatidylethanolamine content is decreased, resulting in destabilization of the cell membrane. The resultant formation of amyloidogenic APP fragments is considered abnormal. It is found in older adults with Alzheimer's disease. Ordinarily,APP is cleaved in such a way that the amyloidogenic peptide is broken down and excreted as nonplaque-forming fragments. Since citicoline has been shown to maintain or restore depleted phospholipid levels in neuronal cell membranes, it may thus promote normal APP cleavage by excretion of nonplaque-forming APP fragments. In vitro work has provided some support for this hypothesis by showing an increase in the levels of phospholipids in rat brain cells induced by choline and cytidine, followed by excretion of the APP found in the lipid bilayer of neuronal mernbrane~.'~

ELEVATION OF NEUROTRANSMllTERS Evidence also indicates that citicoline can increase the levels of several neurotransmitters. In one study in rats, a dose of 100 mg/kilo of citicoline administered for 7 days resulted in an increase in norepinephrine levels in the cerebral cortex and hypothalamus, an increase in dopamine in the corpus striatum, and a concomitant increase in serotonin in the cerebral cortex, striatum and hypothalamus.16In a different study, citicoline was found to activate dopamine synthesis via stimulation of tyrosine hydroxylase activity.19 This finding may explain anecdotal reports of benefits in patients with parkinsonism following citicoline administration?O That citicoline could enhance norepinephrine release has been demonstrated in humans as well. In one study, it was shown that following citicoline administration, urinary levels of 3-methoxy4hydroxyphenylglycol (MHPG), a norepinephrine metabolite, increased.21 Further work in rats found evidence that citicoline potentiates brain dopamine synthesis by stimulating release of acetylcholine.22 A more detailed review of the mechanisms of action and therapeutic benefits of aticoline has been published.=

CLINICAL APPLICATIONS Age-Related Cognitive Deficiencies Normal cognitive function relies on the ability of neurons to transmit impulses along neuronal membranes. Agerelated cognitive deficits are associated with decreased brain cell membrane phospholipid levels. Several animal

studies have shown broad spectrum benefits in cognitive function and memory performance using various active and passive avoidance tests and via artificially induced hypoxia, electric shock, or scopolamine administration, in young and old r a t ~ ? ~ Z

STROKE THERAPY Most of the well-controlled clinical trials of citicoline involve administering it intravenously in patients in the acute stage of moderate to severe cerebral infarction with mild to moderate disturbance in consciousness.26~27 However, some studies of oral administration are available. The Citicoline Stroke Study Group, a multicentered, double-blind controlled trial conducted in the United States, examined the effects of oral citicoline on 259 stroke patients given 500,1000, or 2000 mg of citicoline within 24 hours of a stroke, continued by daily oral administration for 6 weeks?* Using any change in the Barthal Index of Neurological Function (Barthal Index) as the primary clinical endpoint and the National Institutes of Health Stroke Scale (NIHSS)score as a second variable to determine changes between baseline and follow up, patients receiving 500 or 2000 mg of citicoline were found to have twice the chance of stroke recovery compared with patients on placebo. No difference was seen in the group receiving 1000 mg of citicoline compared with placebo. Because the 2000 mg group had a higher incidence of dizziness and accidental injury, the authors concluded that the 500 mg/day dose might be the most optimal for these patients. A second controlled clinical trial was subsequently conducted by the Citicoline Stroke Study Group. This study enrolled 394 patients with acute ischemic stroke, randomly assigned to the treatment or placebo groups on a two-to-one ba~is.2~ Given the earlier advice to use a 500-mg daily dose, only this dosage level was given to the treatment group. The Barthel Index and NIHSS were used to assess efficacy.No differences were found between the treatment and placebo groups after 6 weeks of treatment and an equal 6-week follow-up period. However, the investigators noted that an inequality in baseline stroke severity was found between the two groups; 34% of the patients in the placebo group had had a mild stroke, compared with 22% in the citicoline group. The authors concluded that the baseline imbalances could have affected the overall results of the trial. The two aforementioned Citicoline Stroke Study Group trials led to a third multicentered, double-blind clinical trial. This trial enrolled 899 patients with acute stroke that occurred in the middle cerebral artery region.3oSubjects were given either 1000 mg of citicoline twice daily or placebo for 6 weeks, followed by a 6-week posttreatment follow-up. The outcome was virtually the

same for both groups. As judged by the NIHSS, 52% of subjects in the aticoline group and 51% in the placebo p u p achieved a seven-point improvement. The citicoline p u p showed a signhcant improvement on the Barthe1 Index after 6 weeks, but it was not evident at the end of 12weeks. The investigators concluded that the use of more traditional analyses might have revealed modest benefits.

Memory-Impaired Elderly A study of 95 healthy volunteers, 50 to 86 years old, looked at the effect of citicoline on verbal memoryY The study was conducted in two phases. In the first phase, all subjects took 10oO mg of citicoline or placebo daily for 3 months. Among this group of 95 subjects, a subgroup that had relatively poor memory function was identified. Those subjects identified with poor memory function were recruited for a second cross-over trial phase and given either 2000 mg of citicolineor placebo for 3 months. After the initial phase of the study, improvement was only seen in the poor memory subgroup, which found improvement in delayed recall and logical memory. At the end of the second phase of the study, a greater improvement was seen in the 2000 mg group, but then only for those with age-associated memory impairment. Another study involved 24 memory-impaired elderly subjects who were given citicoline at 500 or 1000 mg with the calcium channel blocker nimodipine, which is used to treat neurologic deficits in brain hemorrhagic patients. Pretreatment and posttreatment memory performance was In tests of recognition, no improvement was observed. However, improvements were seen in word and object recall. Positive results occurred in both treatment groups. On the basis of the role of citicoline as an intermediate in phosphatidylcholine biosynthesis, a study was carried out on 84 elderly patients with mild to moderate memory loss.% Study participants were given either loo0 mg of citicoline or placebo for 6 weeks. All subjects exhibited memory loss on the basis of their score on the Mini Mental State Examination ( M E ) and the Randt Memory Test (RMT). The FMT was only given 3 weeks into the study and again at end of treatment 3 weeks later. The RMT measures threecognitive functions: encoding and organization, cognitive efficiency, and acquisition efficiency. At the end of the study it was found that on the RMT, the citicoline group had only improved in acquisition efficiency, which is specifically related to attention skills, suggesting a dopaminergic effect of citicoline. This is because dopaminergic stimulation and improvement has been shown to be associated with attention-related cognitive mechanisms. In addition, the study showed improvements in global memory efficiency in subjects given aticoline compared with placebo. To date there is limited evidence supporting the use of citicoline to improve memory in individuals unless they have measurable deficits in memory. A study conducted

with young, 1-year-old, healthy dogs that were given citicoline over a 42-day period found that compared with control animals, the citicoline group showed superior memory processes (acquisition, retention, and retrieval) as demonstrated by a series of operant, conditionedlearning experiments.M A meta-analysis of controlled clinical trials has concluded that citicoline administration contributes to modest improvements in memory and behavioral outcomes.35Human studies of the effect of citicoline in healthy adults without cognitive impairment remains a fertile area for further investigation.

ALZHEIMER’S DISEASE Besides studies showing benefits associated with the administrationof citicoline given to Alzheimer patients%% and those suffering from age-related deficits in memory, other brain-related disorders or conditions have also been shown improvement. Citicoline may improve cognitive performance in Alzheimer patients. A 1994 double-blind study evaluated 1-month treatment with citicoline (1000 mg/day orally) on cognition in 20 Alzheimer patients. Cognitive function assessment using W E improved slightly in an early onset subgroup. MMSE scores decreased in patients in later stages of the disease. Spatial-temporal orientation improved in the total group, with a more marked difference in early-onset patients.% A later double-blind, placebo-controlled trial tested the effect of citicoline (1000 mg/day) on 30 patients with mild-to-moderate senile dementia. The overall results showed differences between the citicoline and placebo groups in the 12-week study, but the changes did not reach statistical ~igruficance.~~

BRAIN TRAUMA In a double-blind study in patients going through rehabilitation following brain trauma to restore blood flow to the site of lesion, 1month of 1000mg of citicoline administered orally was found to significantly improve recall of designs compared with placeb0.3~ However, there was no significant difference seen in either group in word recall, recall of locations, or verbal fluency. Interestingly, a greater trend was seen in patients on placebo regarding complaints of postconcussional symptoms such as headache, tinnitus, and dizziness at follow-up than among the citicoline group.

GLAUCOMA Two open clinical trials suggest that citicoline may repair damage to the optic nerve in glaucoma.40The mechanism of action appears to be related to citicoline’s ability to provide neuroprotection by enhancing

Citicoline (CDP-Choline) phosphatidylcholine synthesis. As is well known, glaucoma is the leading cause of age-related blindness and is characterized by apoptosis of retinal ganglion cells (well before visual loss is detected)!l In a double-blind, placebo-controlled trial, 1000 mg of citicoline was administered by intramuscular injection, resulting in improvement in retinal and visual function in openangle glaucoma patients." In glaucoma, as intraocular pressure builds up to abnormal levels, the resultant effect is damage to the optic disc. Continued damage to this area causes visual defects, most notably the progressive loss of peripheral vision, sometimes called "tunnel vision." If this progressive loss of vision is detected too late, it can eventually lead to permanent loss of vision.

administration by gavage of 150 mg/kg SW, 350 mg/kg BW, and 1000 mg/kg BW in 160 rats followed by histopathologies of all organs and assessment of blood, urine, ophthamology, and behavior reported no mortality, adverse events, or sigruhcant differences compared with the control ("0"dose) group.&Citicoline appears to show a low risk of toxicity in humans. One small, short-term human study did report headaches at 600mg and lo00 mg dosages in a few subjects, but this proved to be of a transient nature. No hematologic, clinical biochemistry, or neurologic abnormities were reported.44In some clinical studies, transient diarrhea and stomach pain was reported in about 5% of subjects.

DRUG INTERACTIONS AMBLYOPIA Additional research on citicoline and vision has been conducted on adults with amblyopia. In amblyopia, the condition is characterized by dimness of light entering the eye without apparent structural damage to the eye. In one small open t i a l reported by the University of Bologna, Italy, adult patients with amblyopia given citicoline showed improvement in visual acuity, contrast sensitivity, and visually evoked potentials, in addition to improved vision.

Theoretic concern has been raised over combining nootropic drugs such as citicoline with central stimul a n t ~ ?However, ~ no adverse clinical effects have been reported.

SUMMARY

Large oral dosages in animal studies have not shown toxicity. I am a co-investigator in two completed good laboratory practice (GLP)-compliantnonclinical toxicology studies in the rat. No mortality or adverse events were reported following an acute oral dose by gavage of 2000 mg/kg of body weight (BW) followed by a 14-day postadministration observation period and gross pathology on day 15 ("the limit test"). A subsequent GLP subacute toxicology study over 90 days involving daily

Citicoline appears to be a useful adjunct for improving both the structural integrity and functionality of the neuronal membrane that assists in membrane repair, particularly of brain neuron membranes. This qualifies citicoline as a nootropic agent. Its application in the treatment and possible prevention of a range of neurodegenerative diseases is apparent, especially given the many mechanisms of action of citicoline discovered to date and discussed herein. The suggestive evidence that citicoline improves performance in old but not young rats is consistent with the conception that citicoline corrects impaired phospholipid metabolism. Most likely, citicoline may also contibute to a reduction in oxidative stress by increasing glutathione, another fertile area for research on this increasingly recognized agent in the management and treatment of cognitive dysfunction, neurodegenerative diseases, and visual health. A citicoline-free base is available as an oral dietary supplement in the United States or as a drug for intravenous or intramuscular injection and oral use in other countries.

1. Weiss GB. Metabolism and actionsof CDP-choline as an endogenous compound and administered exogenously as citicoline. Life Sci 1995; 56637-660. 2. Rao AM,Hatcher JF, Dempsey RJ. CDP-choline: neuroprotedion in transient forebrain ischemia of gerbils.J Neurosci Res 199958697-705. 3. Dinsdale JR, Griffiths GK, Rowlands C, et al. Pharmacokinetics of 14C CDP-choline. Arzneimittelforschung1983;33.1066-1070. 4. Lopez-Coviella I, Agut J, Savci V, et al. Evidence that 5'cytidinediphosphocholinecan affect brain phospholipid composition

by increasing choline and cytidine plasma levels. J Neurochem 1995;65:889-894. 5. Gimenez R, Soler S, Aguilar J. Cytidine diphosphate cholie administration activates brain cytidine triphosphate: phosphocholine cytidylytransferase in aged rats. Neurosci Lett 1999;273163-166. 6. Babb SM, Appelmans KE, Renshaw PF, et al. Differentialeffect of CDPcholine on brain cytosolic levels in younger and older subjects as measured by protein magnetic rrsonanm spectroscopy. Psychopharmacol 1996;12788-94.

DOSAGE The typical dosage of citicoline in clinical students is 500 to 2000 mg/day.

TOXICOLOGY

Pharmacology of Natural Medicines 7. Babb SM, Wald LL, Cohen BM, et al. Chronic aticoline inaeasesphosphodiesten in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study. Psychopharmacol 2002; 161:248-254. 8. de la Morena E. Efficacy of CDP-choline in the treatment of senile alterations in memory. Ann N Y Acad Sci 1991;640:233-236. 9. Amenta F, Di Tullio MA, Tomassoni D. The cholinergic approach for the treatment of vascular dementia: evidence from pre-clinical and clinical studies. Clin Exp Hypertens 2002;24697-713. 10. Plataras C, Tsakiris S, Angelogianni P. Effect of CDP choline on brain acetylcholinesterase and Na’, K+-ATPase in adult rats. CLin Biochem 200033351-357. 11. Adibhatla RM, Hatcher JF, Dempsey RJ. Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem 2002;80 12-13. 12. Rao AM, Hatcher JF, Dempsey RJ. Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? Brain Res 2001;893268-272. 13.Adibhatla RM, Hatcher JF. Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia. J Neurosci Res 2003;73:308-315. 14. Nitta A, Itoh A, Hasegawa T, et al. beta-Amyloid protein-induced Alzhemer’s disease animal model. Neurosci Lett 1994;17063-66. 15. Nitta A, Fukuta T, Hasegawa T, et al. Continuous infusion of betaamyloid protein into the rat cerebral ventricle induces learning impairment and neuronal and morphological degeneration. Jpn J Pharmacol1997;7351-57. 16. Alvarez XA, k p e d r o C, Lozano R, et al. Citicoline protects hip pocampal neurons against apoptosis induced by brain beta-amyloid deposits plus cerebral hypofusion in rats. Methods Find Exp Clin Pharmacol1999;21:535-540. 17. Wang CS, Lee RK. Choline plus cytidine stimulate phospholipid production, and the expression and secretion of amyloid precursor protein in rat PC12 cells. Neurosci Lett 2000;283:25-28. 18.Petkov VD, Stancheva SL, Tocuschieva L, et al. Changes in brain biogenic monoamines induced by the nootropic drugs adafenoxate and meclofenoxate and by citicoline (experiments on rats). Gen Pharmacol1990;21:71-75. 19. Martinet M, Fonlupt P, Pacheco H. Effects of cytidine-5’ diphosphocholine on noreinephrine, dopamine and serotonin synthesis in various regions of the rat brain. Arch Int Pharmaccdyn Ther 1979; 23952-61. 20. Martinet M, Fonlupt P,Pacheco H. Interaction of CDP-choline with synaptosomal transport of biogenic amines and their precursors in vitro and in vivo in the rat corpus striaturn. Experientia 1978;34:1197-1199. 21. Lopez I, Coviella G, Agut J, et al. Effect of cytidine(5’)diphosphocholine (CDP-choline) on the total urinary excretion of 3-methoxy4hydrophenylglycol (MHPG)by rats and humans. J Neural Transm 1986;66:129-134. 22. Agut J, Coviella IL, Wurtman RJ. Cytidine(5’)diphosphocholine enhances the ability of haloperidol to increase dopamine metabolites in the striaturn of the rat and to diminish stereotyped behavior induced by apomorphine. Neuropharmacology 1984;23:1403-1406. 23. Conant R, Schauss AG. Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature. Altem Med Rev 2004;9:17-31. 24. Drago F, Mauceri F, Nardo L, et al. Effects of cytidine-diphosphocholine on acetylcholine-mediated behaviors in the rat. Brain Res Bull 199331:485-489. 25. Petkov VD, Kehayov RA, Mosharrof AH, et al. Effects of cytidine diphosphate choline on rats with memory deficits. Arzneimittelforschung 1993;43822-828. 26. Tazaki Y, Sakai F, Otomo E, et al. Treatment of acute cerebral infarction with a choline precursor in a multicentered doubleblind placebo- controlled study. Stroke 1988;19:211-216.

27. Davalos A, Castillo J, Alvarez-Sabin J, et al. Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Stroke 2002;33:2850-2857. 28. Clark WM, Warach SJ, Pettigrew LC, et al. A randomized doseresponse trial of citicoline in acute ischemic stroke patients. Neurology 1997;49:671-678. 29. Clark WM, Williams BJ, Selzer KA, et al. A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke 1999; 30:2592-2597. 30. Clark WM, Wechsler LR, Sabounjian LA, et al. A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology 2001;571595-1602. 31.Spiers PA, Myers D, Hochanadel GS, et al. Citicoline improves verbal memory in aging. Arch Neurol1996;53441-448. 32. Alvarez XA, Laredo M, Corzo D, et al. Citicoline improves memory performance in elderly subjects. Methods Find Exp Clin Pharmacol 1997;19201-210. 33. Agnoli A, Bruno G, Fioravanti M, et al. Therapeutic approach to senile memory impairment: a double-blind clinical trial with CDP choline. In Wurtman RJ, Corkin S, Growden JH,eds. Alzheimer’s disease: proceedings of the fifth meeting of the International Study Group on the Pharmacology of Memory Disorders Associated with Aging. Boston: Birkhauser, 1989:649-654. 34. Bruhwyler J, Liegeois JF, Geczy J. Facilitatory effects of chronically administered citicoline on learning and memory processes in the dog. Prog Neuropsychopharmacol Biol Psychiatr 1998;22: 115-128. 35. Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP choline) for cognitive and behavioral disturbances associated with chronic cerebral disorders in the elderly (Cochrane Review). In The Cochrane Library, Issue 3. Chichester, UK: John Wiley & Sons, 2004. 36.Caamano J, Gomez MJ, Franco A, et al. Effects of CDP-choline on cognition and cerebral hemodynamics in patients with Alzheimer’s disease. Methods Find Exp Clin Pharmacol 1994; 16~211-218. 37. Alvarez XA, Mouzo R, Pichel V, et al. Double-blind placebo controlled study with citicoline in APOE genotyped Alzheimer‘s disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Methods Find Exp Clin

Pharrnacol1999;21:633-644. 38. Cacabelos R, Alvarez XA, Franco-Maside A, et al. Effect of CDPcholine on cognition and immune function in Alzheimer’s disease and multi-infarct dementia. Ann N Y Acad Sci 1993;695: 321-323. 39. Levin HS. Treatment of postconcussional symptoms with CDPcholine. J Neurol Sci 1991;103S39-S42. 40.Grieb P, Rejdak R. Pharmacodynamics of citicoline relevant to the treatment of glaucoma. J Neurosci Res 2002;67143-148. 41. Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma: III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic optic neuropathy, papilledema, and toxic neuropathy. Arch Opthalmol1992;100:135-146. 42. Parisi V, Manni G, Colacino G, et al. Cytidine-5’-diphosphocholiie (citicoline) improves retinal and cortical responses in patients with glaucoma. Opthalmology 1999;1061126-1134. 43. Horvath K, Schauss AG, Somfai-RelleS, et al. Acute and subchronic toxicity of citicoline-free base administered orally to the rat. Manuscript submitted for publication, 2005. 44.Dinsdale JR, Griffiths GK, Castello J, et al. CDP-choline: repeated oral dose tolerance studies in adult healthy volunteers. Arzneimittelforschung 198333:lMl-1065. 45. Petkov VD, Konstantinova E, Petkov W, et al. Modulation of the effects on learning and memory of nootropic drugs and central stimulants when applied together. Acta Physiol Pharmacol Bulg 1991; 1717-26.

Coenzyme Qo Alan R.Gaby, MD Laurie K.Mischley, ND CHAPTER CONTENTS Introduction 859 Coenzyme QtoDeficiency 860 Clinical Applications 860 Mitochondria1 Diseases 860 Parkinson Disease 860 Friedrich Ataxia 860 Immune Function 860 Acquired Immunodeficiency Syndrome (AIDS) 861 Aging 861 Cancer 861 Periodontal Disease 861 Gastric Ulcer 862 Physical Performance 862 Muscular Dystrophy 862 Asthma 863 Cardiovascular Disease-General Considerations 863

INTRODUCTION Coenzyme Qlo(CoQlo)is a compound found naturally in the human body. Because of its ubiquitous presence in nature and its quinone structure (similar to that of vitamin K), CoQlois also known as ubiquinone (Figure 82-1). The primary biochemical action of CoQlois as a cofactor in the mitochondria1 electron-transport chain, the series of redox reactions that are involved in the synthesis of ATP. Since most cellular functions depend on an adequate supply of ATP, CoQlois essential for the health of virtually all human tissues and organs. In addition to its significant role in the mitochondria, CoQlois an important scavenger of reactive oxygen species. CoQlo is one of the few antioxidants that can readily regenerate to its reduced form after utilization.] Although CoQlo can be synthesized from phenylalanine or tyrosine, situations may arise in which the body’s synthetic capacity is insufficient to meet CoQlorequirements. Susceptibility to CoQlodeficiency appears to be greatest in cells that are the most metabolically active (such as those in the heart, brain, immune system, gingiva,

Cardiac Disease 863 Cardiomyopathy 863 Congestive Heart Failure 864 Angina 864 Arrhythmias 864 Prevention of Adriamycin Toxicity 864 Protection during Cardiac Surgery 865 Mitral Valve Prolapse 865 Hypertension 865 Diabetes Mellitus 865 Infertility 865 Toxicant Exposure 866 Drug Interactions 866 Dosage

866

Toxicology 867

and gastric mucosa), since these cells presumably have the highest requirements for CoQlo.Tissue deficiencies or subnormal serum levels of CoQlohave been reported to occur in a wide range of medical conditions including cardiovascular disease, hypertension, periodontal disease, asthma, Parkinson disease, and acquired immunodeficiency syndrome (AIDS).In addition, CoQlolevels decline with advancing age and this decline might contribute in part to some manifestations of aging. A need for supplemental CoQlo could theoretically result from the following: Impaired CoQlosynthesis due to nutritional deficiencies A genetic or acquired defect in CoQlo synthesis or utilization Increased tissue needs resulting from a particular illness The requirement to prevent the side effects of medical intervention Because oral administration of CoQlo can increase tissue levels of the nutrient, it is possible to correct CoQlo deficiency and its associated metabolic consequences by supplementation? 859

Pharmacology of Natural Medicines

CH20

+Fi2-

CH - C - CH2--),oH

0 Flgum 82-1 Coenzyme Qto.

Coenzyme Qlo Deficiency CoQlo participates in the citric acid cycle (Krebs cycle) enzyme known as succinate dehydrogenase-CoQlo reductase. An assay of the activity of this enzyme has been used to detect deficiencies of C0QlP3If the enzyme is fully saturated with CoQloin vivo, addition of exogenous CoQlo does not increase enzyme activity. On the other hand, exogenous CoQlo increases activity appreciably when tissue levels of CoQlo are low. Other CoQlodependent enzymes can also be measured using a similar approach? More recently, measurements of both serum and whole blood CoQlolevels have been used to detect deficiencies. Plasma CoQloreference ranges were determined to be 0.42 to 1.14mmol/Lon the basis of data for 50 healthy persons aged 20 to 64 years old. A recent study demonstrated ubiquinone-10 status was below the reference range in 40% of healthy women and 24% of men (p = 0.02):

CLINICAL APPLICATIONS Mitochondria1 Diseases Although rare, congenitalCoQlodeficiency has been documented in a few cases of mitochondrial encephalomyopathy characterized by recurrent myoglobinuria and brain involvement (seizures, ataxia, and mental retardation). Additionally, several cases of muscle C0Ql0 deficiency have been documented in patients with familial cerebellar ataxia, pyramidal signs, and seizures. In one study, all six patients determined to have low muscle CoQlo concentrations showed a clinical response to CoQlosupplementation. Clinical improvements included improvement of strength, improved ataxia, and less frequent seizures. Primary CoQlodeficiency is a potentially important and treatable cause of familial ataxia and should be considered in the differential diagnosis of this condition.

Parkinson Disease Excessive freeradical production is largely responsible for dopaminergic cell death seen in Parkinson's disease (PD). Both as a cause and an effect of the excessive oxidative stress, there is reduced activity of complex I of the mitochondrial electron transport chain. Given that CoQlo is

essential for the function of complex I and is also a powerful antioxidant, it holds therapeutic potential in the treatment of PD. Reduced levels of CoQlohave been demonstrated in the platelets of individuals with PD, and CoQlolevels were strongly correlated with activity in complexes I and II/III. Clinically, it has been demonstrated that oral CoQlo increases complex I a~tivity.~ A recent study suggests that a dose of 1200 mg/day was substantially more effective at slowing PD progression than 300 or 600 mg/day doses; indicating adequate plasma levels may need to be reached before a clinical effect is observed. Treatment is more effective if initiated early in the course of the disease.

Friedreich Ataxia Friedrich ataxia is a progressive neurologic disease characterized by loss of myelin in the central nervous system. Evidence indicates that mitochondrial oxidative stress in Friedreich ataxia may be responsible for the cardiomyocyte hypertrophy associated with this disease.' In a placebo-controlled trial, idebenone (a synthetic CoQlo analog) sigruficantly decreased heart hypertrophy (>20% decrease) in about 50% of study participants, with no adverse effects?Jo A second study combined CoQlowith vitamin E in an attempt to address two of the key features of Friedreich ataxia4ecreased mitochondrial respiratory chain function and increased oxidative stress. This therapy resulted in a rapid and sustained increase in the amount of energy generated by the diseased heart muscle, nearly returning to normal levels. The improvements in skeletal muscle energy generation paralleled those of the heart but were less substantial."

Immune Function At the mitochondrial level, CoQlo is essential for the optimal function of the immune system,12and several studies have demonstrated immune-enhancing effects of CoQlo or its analog^.^"'^ These immune-enhancing effects included increased phagocytic activity of macrophages, increased proliferation of granulocytes in response to experimental infections, and prolonged survival in mice infected with Pseudornonas ueruginosa, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Candida aZbicuns. Inoculation of animals with Friend leukemia virus reduced CoQlolevels in the blood and spleen,'6 whereas treatment of infected animals with CoQlo increased the survival rate and decreased the severity of hepatomegaly and ~plenomegaly.'~ Lmmune function tends to decline with advancing age. In a study of elderly mice, suppression of the immune response was associated with a marked decline of CoQlo levels in thymic tissue.18 This immune suppression was partly reversed by treatment with C0Q10.19In a study of eight chronically ill patients, administration of 60 mg/day

Coenzyme Qlo

of CoQlo was associated with si&cant increases in serum levels of immunoglobulin G (I&) after 27 to 98 days of treatment.20These studies suggest that CoQlo may help to prevent or reverse the immunosuppression that is associated with aging or chronic disease.

Acquired Immunodeficiency Syndrome AIDS is a complex disease associated with a wide range of nutritional defiaenaes and immunologic disorders. Although correction of nutritional defiaenaes does not cure AIDS, appropriatenutritional interventionsmay help to prevent weight loss and enhance overall immune function. In addition, since oxidative stress is believed to be involved in the pathogenesis of AIDS-related diseases, the antioxidant activity of CoQlo may be of value for individuals with AIDS.2l The T4/T8 ratios of lymphocytes are known to be low in patients with AIDS and -related complex (ARC). Several studies have demonstrated that CoQlo increases T4/T8 ratios of lymphocytes.22,23In one study, blood levels of CoQlowere sigruficantly lower in patients with ARC than in a control group and were signrficantly Six lower in patients with AIDS than in those with patients withor ARC were treated with 200 mg/day of CoQlo. T-cell helper/suppressor ratios increased in three patients, becoming normal in one case. Five patients reported symptomatic improvement, which was dramatic in some cases. Furthermore, none of the patients developed opportunistic infectionsduring a 4- to 7-month follow-up period. This study demonstrates that CoQlo deficiency is common in patients with HIV infection and that supplementation with CoQlomay improve immune function and reduce the incidence of opportunistic infections.

Aging CoQlo levels in human organs peak at 20 years of age except in the pancreas and adrenal, in which the levels seem to be highest at 1year of age. Once the peak level is achieved, levels decrease continuously with advancing age. After the age of 35 to 40, humans begin to lose their ability to synthesize CoQlo.25It has been proposed that the increase in age-associated diseases is due in part to decreased protection afforded by CoQlo as both an antioxidant and a facilitator of energy production at a cellular level. In recent years, makers of several over-the-counter skin creams have begun advertising the addition of Qlo as an ingredient capable of curbing the aging process. Research suggests there may be some truth to this claim, demonstrating topical CoQlo applied to the skin can reduce the level of oxidation normally associated with the photoaging. CoQlowas able to protect against ultraviolet A-mediated oxidative stress, suppress the expression of collagenase, and cause a reduction in wrinkle depth.26

Cancer Because of its role in enhancing immune function, CoQlo has been considered as a possible anticancer agent. Administration of CoQlo reduced tumor size and increased survival in mice exposed to a chemical carcinogen." Preliminq studies in humans, though uncontrolled, are promising. In one study, 32 women with breast cancer who were classified as "high r i s k because of tumor spread to the axillary lymph nodes received 90 mg/day of CoQlo,along with vitamins C and E, betacarotene, and essential fatty acids. In six of these women, the tumor became smaller. During the 18-month treatment period, none of the patients died (the expected number of deaths was four) and none showed signs of further distant metastases. Six patients had an apparent partial remission. In addition, patients receiving CoQlorequired fewer pain killers.27 In another report, two women with metastatic breast cancer received 390 mg/day of CoQlo.One was a 44-yearold woman with numerous liver metastases. After treatment with CoQlofor 11months, all of the liver metastases had disappeared and the patient was reported to be in excellent health. The other patient was a 49-year-old woman with breast cancer that had metastasized to the pleural cavity. After 6 months of CoQlotherapy, the pleural fluid had completely resolved and the patient was reported to be in excellent health.= Although these reports are anecdotal, the results are far better than would normally be expected. Preliminary results suggest that CoQlo might inhibit tumor-associated cyt0kines.2~Considering that CoQlois virtually free of side effects, empirical treatment of breast cancer with CoQloseems justified.

Periodontal Disease Periodontal disease affects about 60% of young adults and 90% of individuals older than the age of 65. Although proper oral hygiene is helpful, many people suffer from intractable gingivitis, often requiring surgery and resulting in eventual loss of teeth. Because periodontal disease is so common, the costs of periodontal surgery and other treatments contribute a significant amount to the overall cost of health care in the United States. Healing and repair of periodontal tissues require efficient energy production, which depends on an adequate supply of CoQlo. However, gingival biopsies revealed subnormal tissue levels of CoQloin 60% to 96% of patients with periodontal disease and low levels of CoQloin leukocytes in 86% of c a ~ e s . These 3 ~ ~findings ~ indicate that periodontal disease is frequently associated with CoQlodeficiency. Eighteen patients with periodontal disease received either 50 mg/day of CoQlo or a placebo in a 3-week double-blind tria1.3 Results were assessed according to

Pharmacology of Natural Medicines a "periodontal score," which included gingival-pocket depth, swelling, bleeding, redness, pain, exudate, and loosenessof teeth. All 8 patients receiving CoQlo improved, compared with only 3 of 10 receiving the placebo (p < 0.01). The treating dentists, who were unaware that a .study was being conducted, consistently remarked about the "very impressive" rate of healing in patients treated with CoQlo. One prosthodontist commented that the amount of healing that occurred in 3 weeks in patients receiving CoQlowould normally require about 6 months. In an open trial, administration of CoQlo produced "extraordinary postsurgical healing" (two to three times as fast as usual) in seven patients with advanced periodontal disease.34

Gastric Ulcer Susceptibility to gastric ulceration is related to the balance between ulcer-promoting factors (e.g., excessive gastric acidity, infection with Helicobucter pylori) and resistance factors (e.g., tissue integrity, production of protective mucus, repair mechanisms). Free radical damage is believed to be one of the primary mechanisms by which external factors induce gastric injury and peptic ulcerat i ~ n Since . ~ ~ CoQlo possesses antioxidant activity, it may be capable of preventing ulceration by reducing the amount of free radical damage. In addition, the production of protective mucus and the rapid cell turnover of gastric mucosa are highly energy-dependent processes requiring the presence of adequate amounts of CoQlo. The efficiency of these protective and reparative processes may be compromised in some patients with gastric ulcers. With advancing age, the fundic mucosa and its rich blood supply are gradually replaced by pyloric tissue, which has poor vascularity. This change in cell type may result in hypoxia in certain portions of the stomach. The hypoxic state of gastric tissue could explain why gastric ulcers frequently become intractable in elderly patients or in those with chronic heart or lung disease. At least one study has documented low levels of CoQloin humans with peptic ulcer disease.%The importance of CoQlo for healing of gastric ulcers has been demonstrated in animals?7Gastric ulcers were induced in mice by the application of acetic acid. The mice were then maintained either in room air (20% oxygen) or under mild hypoxic conditions (17% oxygen). Ulcers healed normally in mice exposed to room air but increased in size under hypoxic conditions. However, in hypoxic mice treated with CoQlo (50 mg/kg per day) the ulcers healed normally. This study demonstrates that hypoxia has an adverse effect on the healing of gastric ulcers in animals and that the effect of hypoxia can be prevented by administration of CoQlo.Although human studies have not been done, empirical use of CoQlo seems to be a reasonable option for elderly patients with intractable gastric ulcers,

particularly those who also have diseases likely to produce hypoxia.

Physical Performance Because CoQlo is involved in energy production and its concentration in muscle is correlated with performance, it is theoretically possible that supplementation could enhance aerobic capacity and muscle performance. In one study, six healthy sedentary men (mean age, 21.5 years) performed a bicycle ergometer test before and after taking CoQlo(60 mg/day) for 4 to 8 weeks.%CoQlotreatment improved certain performance parameters, including work capacity at submaximal heart rate, maximal work load, maximal oxygen consumption, and oxygen transport. These improvements ranged from 3% to 12% and were evident after about 4 weeks of supplementation. Although this study suggests that administration of CoQlo improves physical performance in sedentary individuals, other publications are conflicting. Until larger studies are done, the use of CoQlofor the purpose of performance enhancement cannot be considered proven.39

Muscular Dystrophy The muscular dystrophies are a group of hereditary diseases characterized by the progressive loss of muscle cells. In some types of muscular dystrophy an impairment of mitochondria1 function may contribute to the pathogenesis of the disease. Several studies have demonstrated a deficiency of CoQlo in muscle mitochondria of humans with muscular dystrophy.40In addition, serum CoQlo levels were sigruficantly (p < 0.05) inversely correlated with the degree of genetic defect.4lSQ The first double-blind trial of CoQlo in the treatment of individuals with muscular dystrophies and neurogenic atrophies concluded, "Patients suffering from these muscle dystrophies and the like should be treated with vitamin CoQloindefinitel~."~~ The same group conducted two studies on patients between 7 and 69 years of age who had diseases associated with cardiac diseases, including the Duchenne, Becker, and the limb-girdle dystrophies; myotonic dystrophy; Charcot-Marie-Tooth disease; and the Welander disease. Individuals were treated for 3 months with 100 mg daily of CoQlo or a matching placebo. In both trials, definitely improved physical performance was recorded in the groups receiving CoQlo. Cardiac function was monitored by technicians who were unaware of which treatment the patients were receiving. In each case they correctly identified the treatment group to which the patient had been assigned, on the basis of the improvement or lack of improvement in cardiac function. In a smaller double-blind study, 100 mg of CoQlo was given daily for 3 months to 12 patients with progressive muscular dystrophy. CoQlotreatment resulted in

significant improvements in cardiac output and stroke volume, as well as increased physical well-being in four of eight patients.4O Subjective improvements included increased exercise tolerance, reduced leg pain, better control of leg function, and less fatigue. Presumably, the mechanism by which CoQlo improves the symptoms of muscular dystrophies is related to an improvement in energy production in muscle cells.

Asthma The contribution of oxygen free radicals to the pathogenesis of asthma is widely k n ~ w n The . ~ modulation of antioxidant defenses by antioxidant supplementation represents a potentially important therapeutic approach. CoQlo levels, in addition to the levels of a number of other antioxidants,are decreased in asthmatics compared with c0ntrols,4~and supplementation with antioxidants including CoQlohas been shown to decrease both oxidative stress and asthma symptom^.^*^^ Results of a recent study demonstrated low concentrations of CoQloin 56 asthmatic patients compared with 25 healthy controls. In the study, mean concentrationsof CoQlo both in plasma and whole blood were significantly lower than in healthy volunteers (p < 0.001).48In a case report of a patient with chronic asthma treated with glucocorticoid for 45 years, symptoms of glucocorticoidinduced myopathy were attenuated by the administration of C O Q ~ , ,This . ~ ~ report suggests that CoQlo may decrease some long-term side effects in glucocorticoidtreated asthmatics, in addition to providing the aforementioned antioxidant protection. In a 1-year double-blind trial involving 322 patients with congestive heart failure, supplementation with CoQlo at a dose of 2 mg/kg/day for 1year decreased episodes of cardiac asthma compared with a placebo ( p < 0.001).46

Cardiovascular Disease-General Considerations Enhancing myocardial function is an important, though frequently overlooked, component of the overall prevention and treatment of cardiovascular disease. CoQlo plays a key role in energy production and is therefore essential for all energy-dependent processes including heart muscle contraction. CoQlo deficiency has been documented in patients with various types of cardiovascular disease. Whether a decline in CoQlo levels is a primary cause or a consequence of heart disease is unclear. However, given the fundamental involvement of CoQloin myocardial function, it is not unlikely that CoQlo deficiency would exacerbate heart disease and that correction of such a deficiency would have therapeutic value. In addition, CoQlo has been shown to be a potent antioxidant. In fact, ubiquinol-10, the reduced form of CoQlo,protected human low-density lipoproteins (LDLs)

more efficiently against lipid peroxidation than did vitamin E.50 Because oxidation of LDL is believed to be an initiating factor in the development of atherosclerosis, CoQlowould appear to be a preventive factor.

Cardiac Disease Circulating levels of CoQlo were significantly lower in patients with ischemic heart disease and in those with dilated cardiomyopathy (mostly New York Heart Association [NYHA] functional class I11 or IV) than in healthy c o n t r ~ l sIn . ~another ~ ~ ~ study, CoQlo levels in myocardial tissue (estimated by enzymatic methods) were low in approximately 75% of patients undergoing cardiac surgery. Concentrations of CoQlo declined progressively in both blood and myocardial tissue with increasing severity of heart disease.% Myocardial deficiencies of CoQlo were also found in the majority of patients with aortic stenosis or insufficiency, mitral stenosis or insufficiency,diabetic cardiomyopathy,tetralogy of Fallot, atrial septal defects, and ventricular septal defects.%In patients with cardiomyopathy and myocardial deficiency of CoQlo, oral administration of 100 mg/ day of CoQlofor 2 to 8 months resulted in an increase in myocardial CoQlo levels ranging from 20% to 85Y0.~~ These findings suggest that CoQlodeficiency is common in patients with various types of cardiovascular disease and that oral administration of CoQlocan increase tissue levels of this nutrient.

Cardiomyopathy In one study, 126 patients with dilated cardiomyopathy (98% of whom were in NYHA functional class I11 or IV) received 100 mg/day of CoQlo for periods of up to 66 months. After 6 months of treatment, the mean ejection fraction increased from 41% to 59% (p < 0.001) and remained stable thereafter with continued treatment. After 2 years, 84% of the patients were still alive, and at 5.5 years 52% were alive.5zThese survival rates are considerably better than the published survival statistics of patients given conventional therapy (i.e., 2-year survival rate of 50”/0for symptomatic cardiomyopathy, and 1-year survival rate of 50%for decompensated cardiomyopathy). In another study, 88 patients with cardiomyopathy received 100 mg/day of CoQlo for periods of 1 to 24 months. Significant improvements in at least two of three cardiac parameters (ejection fraction, cardiac output, and NYHA class) were seen in 75% to 85% of the patients. Approximately 80% of the patients improved to a lower (i.e., more favorable) NYHA functional class.56 In a double-blind, cross-over trial, 19 patients with cardiomyopathy (NYHA classes III and IV) received 100 mg/day of CoQlo or a placebo, each for 12 weeks. Compared with placebo, CoQlo treatment significantly increased cardiac stroke volume and ejection fraction.

Eighteen patients reported improvement in activity while taking CoQ10.57

Congestive Heart Failure The potential of CoQlo as a treatment for congestive heart failure (CHF) was suggested as early as 1967 by Japanese researchers.%In 1976 these same investigators administered 30 mg/day of CoQlo to 17 patients with CI-IF.All of the patients improved, and nine (53%)became asymptomatic after 4 weeks of treatment.59 In an open trial of 34 patients with refractory NYHA class IV CHF, administration of 100 mg/day of CoQlo resulted in sustained improvement in cardiac function in 28 cases (82%).The survival rate after 2 years was 62%' compared with an expected 2-year survival rate of less than 25% for similar patients.@ In another study, 12 patients with advanced CHF who had failed to respond adequately to digitalis and diuretics received 100 mg/day of CoQlofor 7 months. Two thirdsof the patients showed definite clinical improvement after a mean treatment period of 30 days. In these patients, dyspnea at rest disappeared and energy level and tolerance for activity increased. Objective improvements included decreased hepatic congestion, reductions in heart rate and heart volume, and a decline in systolic time intervals (suggesting improved myocardial performance). Withdrawal of CoQlowas followed by severe clinical relapse, with subsequent improvement on resumption of treatment.6l In a large multicenter trial, 1113 CHF patients received 50 to 150 mg/day of CoQlofor 3 months (78% of the patients received 100 mg/day). The proportion of patients with improvements in clinical signs and symptoms were as follows62: Cyanosis, 81% Edema, 76.9% Pulmonary rales, 78.4% Enlargement of the liver area, 49.3% Jugular reflux, 81.5% Dyspnea, 54.2% Palpitations, 75.7% Sweating, 82.4% Arrhythmia, 62% Insomnia, 60.2% Vertigo, 73% Noduria, 50.7% The results of these uncontrolled studies were confirmed more recently in a double-blind trial. Some 641 patients with CHF (NYHA classes lll or IV)were randomly assigned to receive placebo or CoQlo (2 mg/ kg/day) for 1 year. Conventional therapy was continued in both groups. The number of patients requiring hospitalization during the study for worsening heart

failure was 38% less in the CoQlo group than in the placebo group (p < 0.001). Episodes of pulmonary edema were reduced by about 60% in the CoQlo group, compared with the placebo group (p < 0.001).46

Angina Twelve patients with stable angina pectoris were randomly assigned to receive 150 mg/day of CoQlo or a placebo in a Cweek, double-blind, cross-over trial. CoQlo treatment sigruficantly increased exercise tolerance on a treadmill (time before onset of chest pain) and sigruficantly increased the time until ST-segment depression occurred. Compared with placebo, there was a 53% reduction in the frequency of anginal episodes and a 54% reduction in the number of nitroglycerin tablets needed during CoQlotreatment; however, these differences were not statistically significant.63 These results suggest that CoQlois a safe and effective treatment for angina pectoris. Although the amelioration of anginal attacks was not statistically sigruficant, the magnitude of the effect was large. It would therefore be worthwhile to perform a similar study with a larger number of patients.

Arrhythmias Twenty-seven patients with ventricular premature beats (VPBs) and no evidence of organic heart disease received a placebo for 3 to 4 weeks, followed by 60 mg/day of CoQlofor 4 to 5 weeks. The reduction in VPBs was significantly greater after CoQlo than after placebo. The beneficial effect of CoQlowas seen primarily in diabetics, in whom the mean reduction in VPB frequency was 85.7V0.A sigruficant reduction in VPBs also occurred in 1 (11%) of 9 otherwise healthy patients and in 4 (36%) of 11 patients with hypertension.@

Prevention of Adriamycin Toxicity The clinical value of Adriamycin as an anticancer agent is limited by its toxicity, which includes cardiomyopathy and irreversible heart failure. Adriamycin-induced cardiotoxicity is believed to be caused, at least in part, by a reduction in CoQlo levels and by inhibition of CoQlodependent enzymes. In rats treated with Adriamycin, administration of CoQlorestored the levels of thisnutrient to normal and prevented Adriamycin-induced morphologic changes in the heart.65Treatment with CoQlo also prevented Adriamycin-induced cardiotoxiaty in rabbits.% Cancer patients receiving Adriamycin had lower myocardial levels of CoQlothan did controls. The magnitude of CoQlo depletion was directly related to the severity of cardiac im~airment.6~ To determine the effect of CoQlosupplementation on Adriamycin cardiotoxicity, seven patients receiving Adriamycin were also given 100 mg/day of CoQlo, beginning 3 to 5 days before

Coenzyme Qto

Adriamycin was started. Another seven patients (control group) received Adriamycin without CoQlo. Cardiac function deteriorated significantly in the control group, whereas patients given CoQlo had little or no cardiotoxicity, even though the cumulative dose of Adriamycin in the CoQlogroup was 50% greater than that in the control group.@Despite the small number of patients in thisstudy, the results are highly encouraging.Because administration of CoQlodoes not appear to affect the antitumor activity of Adriamycin, CoQloprophylaxis seems appropriate for all patients receiving Adriamy~in.6~

Protection during Cardiac Surgery Postoperative low cardiac output is a major cause of early death following cardiac surgery. Fdty patients undergoing cardiac surgery for acquired valvular lesions were randomly assigned to receive 30 to 60 mg/day of CoQlo for 6 days before surgery or to a control group that did not receive CoQlo.Postoperatively, a state of severe low cardiac output developed in 48% of the patients in the control group, compared with only 12% of those in the CoQlo group. These results suggest that preoperative administration of CoQlo increases the tolerance of the heart to ischemia during aortic cross-clamping.7°

Mitral Valve Prolapse Cardiac performance was evaluated using an isometric hand-grip test in 194 children with symptomatic mitral valve prolapse. Before treatment, all patients had an abnormal hand-grip test. Sixteen children received 2 mg/ kg/day of CoQlo or a placebo for 6 weeks in a singleblind trial. Hand-grip strength became normal in seven of the patients receiving CoQloand in none of the placebotreated patients.71 However, the relevance of this study to the treatment of mitral valve prolapse in adults is doubtful. Aside from the study's inadequate blinding, isometrichand-grip may not be a reliable test of cardiac function. Furthermore, impaired cardiac function is not typical of mitral valve prolapse in adults, and the symptoms associated with this condition do not appear to be caused by diminished cardiac function.

Hypertension Enzymatic assays revealed a deficiency of CoQloin 39% of 59 patients with essential hypertension, compared with only 6% of healthy controls. In animal models of hypertension including spontaneously hypertensive rats, uninephrectomized rats treated with saline and deoxycorticosterone, and experimentally hypertensive dogs, orally administered CoQlo significantly lowered blood Twenty-six patients with essential hypertension received 50 mg of CoQlo twice daily. After 10 weeks of

treatment, mean systolic blood pressure decreased from 164.5 to 146.7 mmHg and mean diastolic blood pressure decreased from 98.1 to 86.1 mmHg (p < 0.001). The fall in blood pressure was associated with a sigruficant reduction in peripheral resistance, but there were no changes in plasma renin activity, serum and urinary sodium and potassium, and urinary aldosterone. These results suggest that treatment with CoQlo decreases blood pressure in patients with essential hypertension, possibly because of a reduction in peripheral resistanceT6 In another study, 109patients with essential hypertension received CoQlo(average dose, 225 mg/day) in addition to their usual antihypertensive regimen. The dosage of CoQlowas adjusted according to clinical response and blood CoQlo levels (the aim was to attain blood levels >2 pg/ml). The need for antihypertensive medication declined gradually, and after a mean treatment period of 4.4 months, about half of the patients were able to discontinue between one and three drugs." Similar results have been reported by others.76 It should be noted that the effect of CoQlo on blood pressure was usually not seen until after 4 to 12 weeks of therapy. That observation is consistent with the delayed increase in enzyme activity that results from administration of CoQlo.Thus CoQlois not a typical antihypertensive drug; rather, it s e e m to correct some metabolic abnormality involved in the pathogenesis of hypertension.

Diabetes Mellitus Low tissue levels of CoQlo have been consistently reported in diabetic patients. There are several mechanisms by which CoQlo may be of therapeutic value in Improved blood pressure and long-term glycemic control have been reported with CoQlosupplementation (100 mg twice Enhancement of endothelial function may offer some protection against arteriopathies.84A recent study of 80 dyslipidemic type 2 diabetics found that CoQlo (200 mg/day) in combination with fenofibrate (200 mg/day) sigruficantly improved endothelial and nonendothelial forearm vasodilatory functi011.8~This effect was not found with either therapy alone or in a placebo group. An accumulating body of research demonstrates a link between mitochondria1 dysfunction and type 2 diabetes. The mitochondrial enhancement offered by supplemental CoQloappears to offer some therapeutic value against a defect in cellular energy p r o d u ~ t i o n . ~ ~ , ~ f i ~

InfertiI ity Peroxidation in sperm cells is an important factor associated with male infertility. Sperm function in infertile men has been associated with lipid peroxidation and decreased antioxidant defenses in spermatozoa.88

A statistically significant correlationbetween CoQlolevels and sperm count was found in 32 patients with a history of infertility. The association was direct for reduced (p < 0.05) CoQloand indirect for oxidized (p < 0.01) CoQ10.88 Recent research suggests that sperm cells with low motility and abnormal morphology have low levels of CoQ10.2 Consequently, sperm cells with low CoQlo concentrations might be less capable of quenching free radicals. Some authors have suggested using the reduced-to-oxidized CoQloratio as a diagnostic test for asthenozoospennia.@ In a &month, uncontrolled open trial, in which infertile men were supplemented orally with CoQlo,sperm cells demonstrated a sigruficant increase in motility and both seminal plasma and sperm cell quantity of CoQlo increased.g0 This supports previous studies on both sperm motility and fertilization rates?l

Toxicant Exposure Many ambient and occupational exposures to environmental toxicants affect the mitochondrial respiratory chain.92-%Damage to the respiratory chain can decrease mitochondrial membrane potential, leading to upregulated apoptosis; CoQlohas demonstrated the ability to reduce thismembrane-potential damage.97-101 Although current diagnosis and treatment of environmentally related illnesses remain controversial, cytoprotection with CoQlo may be an effective therapeutic method to reduce mitochondrial damage due to toxicants, both acute and chronic, and should be a focus of further research.Io2

Drug Interactions Cholesterol-lowering Statin drugs such as lovastatin and pravastatin inhibit the enzyme 3-hydroxy-3-methylglutaryl(HMG)-CoA reductase, which is required for biosynthesis of both cholesterol and CoQlo.Thus administration of these drugs might compromise CoQlostatus by decreasing its synthesis. Supplementation of the diet of rats with lovastatin (400 mg/kg of diet) for 4 weeks reduced the concentration of CoQlo in the heart, liver, and blood.Io3In another study, administration of lovastatin to five patients receiving CoQlo for heart failure was followed by a reduction in blood levels of CoQloand a sigruficant deterioration of clinical status. Some of these patients improved after the dosage of CoQlowas increased or the lovastatin was discontinued.lap These results suggest that people who have low CoQlo levels and suboptimal cardiac function might develop clinically sigruficant CoQlo depletion after taking an HMG-CoA reductase inhibitor. Although individuals with high CoQlolevels and good cardiac function may be more resistant to this side effect, it is recommended that all patients being treated with HMG-CoA reductase inhibitors also receive CoQloprophylactically.

The beta-blockers propranolol and metoprolol have been shown to inhibit CoQlo-dependentenzymes.lo5The antihypertensive effect of these drugs might therefore be compromised in the long run by the development of CoQlo deficiency. In one study, administration of 60 mg/day of CoQlo reduced the incidence of druginduced malaise in patients receiving propranolol.106 A number of phenothiazines and tricyclic antidepressants have also been shown to inhibit CoQlo-dependent enzymes. It is therefore possible that CoQlo deficiency may be a contributing factor to the cardiac side effects that are frequently seen with these drugs. In two clinical studies, supplementation with CoQlo improved electrocardiographic changes in patients on psychotropic dmgs.lo7 Several case reports describing potential interactions between CoQloand warfarin have been reported. CoQlo is structurally related to menaquinone (vitamin K2)and may have procoagulant effects." In each of these patients the international normalized ratio (INR),which had been stable and therapeutic, fell below the therapeutic range within 2 weeks of beginning CoQlosupplementation (as low as 30 mg/day).lm The INR returned to the therapeutic range after CoQlo was discontinued. It is recommended that the INR be monitored closely if these agents are to be used concomitantly. See also the earlier discussion on prevention of Adriamycin toxicity.

DOSAGE The optimal dose of CoQlo is not known and probably varies according to the severity of the condition being treated. For example, 30 mg/day of CoQlo was reportedly effective in the treatment of mild congestive heart failure, 90 mg/day resulted in improvements in some cases of cancer, 390 mg/day was associated with complete regression of liver metastases in a patient with breast cancer, and 1200 mg/day proved the most advantageous dose for slowing the progression of Parkinson disease. The plasma and presumably brain levels of CoQlo may be the primary determinant of efficacy, rather than the dose.8J10Research indicates that therapeutic blood levels of CoQlo should be at least 2.5 pg/mL to elicit a therapeutic result56 and that optimum improvement in neurodegenerative diseases and myocardial function may occur at plasma levels greater than 3 pg/mL.8Jl0 Unfortunately, few laboratories offer plasma analysis of CoQloat this time. The usual dosage of CoQlois 60 mg/day, with a range of 30 to 1200 mg/day. The dosage of CoQlo should be adjusted according to the response of the patient. Because the synthesis of new CoQlo-dependentenzymes is a slow process, a clinical response might not occur until 8 or more weeks after therapy is begun."'

Coenzyme Qlo

TOXICOLOGY CoQlois generally well tolerated, and no serious adverse effects have been reported with long-term use. Because safety during pregnancy and lactation has not been proven, CoQlo should not be used during these times unless the potential clinical benefit outweighs the risks. CoQlo is contraindicated in cases of known

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hypersensitivity. In a series of 5143 patients treated with 30 mg/day of CoQlo, the following incidence of side effects was reported70: Epigastric discomfort, 0.39% Loss of appetite, 0.23% Nausea, 0.16% Diarrhea, 0.12%

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56. Langsjoen PH, Folkers K, Lyson K, et al. Effective and safe therapy with coenzyme QlO for cardiomyopathy. Klin Wochenschr 1988;66:583-590. 57. Langsjoen PH, Vadhanavikit S, Folkers K. Effective treatment with coenzyme QlO of patients with chronic myocardial disease. Drugs Exp Clin Res 1985;11:577-579. 58.Ymamura Y, Ishiyama T, Yamagami T, et al. Clinical use of c0enzyme-Q for treatment of cardiovascular disease. Jpn Circ J 1967; 31:168. 59. Ishiyama T, Morita Y, Toyama S, et al. A clinical study of the effect of coenzyme Q on congestive heart failure. Jpn Heart J 1976;17 32-42. 60.Anonymous. Coenzyme aids cardiomyopathy. Med World News 19852669. 61. Mortensen SA, Vadhanavikit S, Baandrup, et al. Long-term coenzyme QlO therapy: a major advance in the management of resistant myocardial failure. Drugs Exp Clin Res 1985;11:581-593. 62. Baggio E, Gandini R, Plancher AC, et al. Italian multicenter study on the safety and efficacy of coenzyme QlO as adjunctivetherapy in heart failure (interim analysis). The CoQlO Drug Surveillance Investigators.Clin Investig 1993;71(suppl8):S145-S149. 63. Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme QlO on exercise tolerance in chronic stable angina pectoris. Am J Cadi01 198556247-251. 64.Fujioka T, Sakamoto Y, Mimura G. Clinical study of cardiac arrhythmias using a 24-hour continuous electrocardiographicrecorder (5th report)-antiarrhythmic action of coenzyme QlO in diabetics. Tohoku J Exp Med 1983;141(suppl):453-463. 65. Ogura R, Toyama H, Shimada T, et al. The role of ubiquinone (coenzyme QlO) in preventing Adriamycin-induced mitochondrial disorders in rat heart. J Appl Biochem 1979;1:325-335. 66. Domae N, Sawada H, Matsuyama E, et al. Cardiomyopathy and other chronic toxic effects induced in rabbits by doxorubicin and possible prevention by coenzyme QlO. Cancer Treat Rep 1981; 65:79-91. 67. Karlsson J, Astrum H, et al. Effect of Adriamycin on heart and skeletal muscle coenzyme Q (CoQlO) in man. In Folkers K, ed. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 1986. 68. Judy WV, Dugan W, et al. Coenzyme QlO reduction of Adriamycin cardiotoxicity. In Folkers K, Yamamura Y, eds. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 1984: 231-241. 69. Cortes EP, Gupta M, Chou C, et al. Adriamycin cardiotoxicity: early detectionby systolic time interval and possible prevention by coenzyme QlO. Cancer Treat Rep 1978;62:887-891. 70. Tanaka J, Tominaga R, Yohitoshi M, et al. Coenzyme Q10 the prophylactic effect on low cardiac output following cardiac valve replacement. Ann Thorac Surg 1982;33145-151. 71. Oda T, Hamamoto K. Effect of coenzyme QlO on the stress-induced decrease of cardiac performance in pediatric patients with mitral valve prolapse. Jpn Circ J 1984;48:1387. 72. Yamagami T, Iwamoto Y, Folkers K, et al. Reduction by coenzyme QlO of hypertension induced by deoxycorticosterone and saline in rats. Int J Vitam Nutr Res 1974;44:487-496. 73. Igarashi T, Nakajima Y, Tanaka M, et al. Effect of coenzyme QlO on experimental hypertension in rats and dogs. J Pharmacol Exp Ther 1974;189:149-156. 74. Iwamoto Y, Yamagami T, Folkers K, et al. Deficiency of coenzyme QlO in hypertensive rats and reduction of deficiency by treatment with coenzyme QlO. Biochem Biophys Res Commun 1974;58:743-748. 75. Okamoto H, Kawaguchi H, Togashi H, et al. Effect of coenzyme QlO on structural alterations in the renal membrane of stroke-prone spontaneously hypertensive rats. Biochem Med Metab Biol 1991;45:216-226.

76. Digiesi V, Cantini F, Oradei A, et al. Coenzyme QlO in essential hypertension.Mol Aspects Med 1994;15(suppl):S257-S263. 77. Langsjoen P, Langsjoen P, Willis R, et al. Treatment of essential hypertension with coenzyme QlO. Mol Aspects Med 1994;(suppl 15):5265-5272. 78. Kishi T, &hi H, Watanabe T, et al. Bioenergetics in clinical medicine. XI. Studies on coenzyme Q and diabetes mefitus. J Med 1976;7307-321. 79. Kucharska J, Braunova Z, Ulicna 0, et al. Deficit of coenzyme Q in heart and liver mitochondria of rats with streptozotocin-induced diabetes. Physiol Res 2000;49411-418. 80. Eriksson JG, Forsen TJ, Mortensen SA, et al. The effect of coenzyme QlO administration on metabolic control in patients with type 2 diabetes mellitus. Biofactors 1999;9:315-318. 81. Hodgson JM, Watts GF, Playford DA, et al. Coenzyme QlO improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr 2002;561137-1142. 82. McCarty ME Toward practical prevention of type 2 diabetes. Med Hypotheses 2000;51:786-793. 83. McCarty MF. Toward a wholly nutritional therapy for type 2 diabetes. Med Hypotheses 2000;54:483-487. 84. Watts GF, Playford DA, Croft KD, et al. Coenzyme Q(l0) improves endothelial dysfunction of the brachial artery in type II diabetes mellitus. Diabetologia 2002;45420-426. 85. Playford DA, Watts GF, Croft KD, et al. Combined effect of coenzyme QlO and fenofibrate on forearm microcirmlatoIy function in type 2 diabetes. Atherosderosis 2003;168:169-179. 86. Lamson DW, Plaza SM. Mitochondrial factors in the pathogenesis of diabetes: a hypothesis for treatment. Altem Med Rev 2002;7 94-111. 87. Silvestre-Aillaud P, BenDahan D, Paquis-Fluckinger V, et al. Could coenzyme QlO and L-camitine be a treatment for diabetes secondary to 3243 mutation of mtDNA? Diabetologia 1995;38: 1485-1486. 88. Alleva R, Scaramucci A, Mantero F, et al. The protective role of ubiquinol-10 against formation of lipid hydroperoxides in human seminal fluid. Mol Aspects Med 1997;(suppl18):S221-S228. 89.Balercia G, Amaldi G, Fazioli F, et al. Coenzyme QlO levels in idiopathic and varicmle-associated asthenomspermia. Andrologia 2OO2;M107-111. 90. Balemia G, Mosca F, Mantero F, et al. Coenzyme Q(l0) supplementation in infertile men with idiopathicasthenozoospermk an open, uncontrolled pilot study. Fertil Steril2004;81:93-98. 91. Lewin A, Lavon H. The effect of coenzyme QlO on sperm motility and function. Mol Aspects Med 1997;(suppl18):S213-S219. 92.Greenamyre JT, Betarbet R, Sherer TB. The rotenone model of Parkinson’s disease: genes, environment and mitochondria. Parkinsonism Relat W o r d 2003;(suppl9)2S59-S64. 93. Dorta DJ, Leite S, DeMarco KC, et al. A proposed sequence of events for cadmium-induced mitochondrial impairment. J Inorg Biochem 200397251-257. 94. Peraza MA, Carter DE, Gandolfi AJ. Toxicity and metabolism of subcytotoxic inorganic arsenic in human renal proximal tubule epithelial cells (HK-2).Cell Biol Toxicol 2003;19:253-264.

95. Robertson JD, OrreniUs S. Molecular mechanisms of apoptosis induced by cytotoxic chemicals. Crit Rev Toxicol 2000;30609-627. 96. Robertson JD, OrreniUs S. Role of mitochondria in toxiccell death. Toxicology 2002;181:491496. 97. Femandez-Ayah DJ, Martin SF, Barroso MP, et al. Coenzyme Q protects cells against serum withdrawal-induced apoptosis by inhibition of ceramide release and caspase-3 activation. Antioxid Redox Signal 2OOO;2263-275. 98. Kagan T, Davis C, LinL, et al. Coenzyme QlO can in some circumstances block apoptosis, and this effect is mediated through mitochondria. Ann N Y Acad Sci 1999;88731-47. 99. Menke T, Gille G, Reber F, et al. Coenzyme QlO reduces the toxicity of rotenone in neuronal cultures by pmerving the mitochondrial membrane potential. Biofactors 2003;1865-72. 100. Papucci L, Schiavone N, Witort E, et al. Coenzyme q10 prevents apoptosis by inhibiting mitochondria1 depolarization independently of its free radical scavenging property. J Biol Chem 2003; 27828220-28228. 101. Merlo Pich M, Castagnoli A, Biondi, et al. ubiquinol and a coenzyme Q reducing system protect platelet mitochondrial function of transfusional buffy coats from oxidative stress. Free Radic Res 2002;36:429-436. 102. Piotrowska D, Dlugosz A, Pajak J. Antioxidative properties of coenzyme QlO and vitamin E in exposure to xylene and gawline and their mixture with methanol. Acta Pol Pharm 200259: 427432. 103. Willis RA, Folkers K, Tucker JL, et al. Lovastatin decreases c m zyme Q levels in rats. Proc Natl Acad Sci U S A 1990;87:892& 8930. 104. Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci U S A 1990;8789318934. 105. Kishi T, F o k K. Inhibition of cardiac CoQlO-enzymesby clinically used drugs and possible prevention. In Folkers K, ed. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 1977. 106. Hamada M, Ochi T, et al. Correlation between serum CoQlO level and myocardial contractility in hypertensive patients. In Folkers K, Yamamura Y, eds. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 1984. 107. Kishi T, Okamoto T, et al. Inhibition of myocardial respiration by psychotherapeutic drugs and prevention by coenzyme Q. In Folkers K, Yamamura Y, eds. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 1984A39-154. 108. Morton RA. Ubiquinones, plastoquinones and vitamins K. Biol Rev Camb PMOSSoc 1971;46:47-96. 109. Spigset 0. Reduced effect of warfarin caused by ubidecmone. Lancet 1994;344:1372-1373. 110. Sinatra ST. Coenzyme QlO and congestive heart failure. Ann Intern Med 2000;133745-746. 111. Kishi T, Okamoto T. Metabolism of exogenous coenzyme QlO in vivo and the bioavailability of coenzyme QlO preparations in Japan. In Follcers K, ed. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 19M131-142.

Coleus forskohlii Michael T. Murray, NI) Joseph E. Pizzorno J r , ND CHAPTER CONTENTS General Description 871 Chemical Composition 871 History and Folk Use

871

Hypothyroidism 874 Malabsorption and Digestive Disorders 874 Depression 874 Cancer Metastases 874 Immune System Enhancement 874

Pharmacology 872

Dosage 874

Clinical Applications 872 Inflammatory Conditions 872 Cardiovascular Effects 873

Toxicology

874

Drug Interactions 874

Other Clinical Applications 874 Glaucoma 874 Weight Loss Programs 874

Coleusforskohlii (family: Labiatae) Synonyms: Coleus barbatus, Plectranthus barbatus, I? forskohlii Common name: coleus

GENERAL DESCRIPTION Coleus forskohlii, a perennial, is a small member of the mint (Labiatae)family. It grows on sun-exposed, dry hill slopes between an altitude of 1000 and 6000 feet in the subtropical, temperate climactic zone. Thus it is found in India, Nepal, Sri Lanka, and Thailand. Its Latin name comes from the word coleos, which means "sheath" and refers to the fused filaments that form a sheath around the stylus of the flower. The epithet, forskohlii, commemorates the Finnish botanist Forskal, who traveled extensively in Egypt and Arabia in the eighteenth century. The radially spread rootstock is the portion of the plant that has been used for medicinal purposes. The rootstock is also the source of a compound of unique biologic importance, forskolin. No other species of Coleus contains forskolin.

CHEMICAL COMPOSITION The primary chemical of clinical interest contained in C. forskohlii is the diterpine forskolin (Figure 83-1). In 1974 forskolin was discovered during a large-scale screening of medicinal plants by the Indian Central Drug Research Institute. The screening revealed the presence of a hypotensive and spasmolytic component, which was initially named coleanol.' Additional investigation determined the exact chemical structure, and the name was changed to forskolin. From 1981 to 2003, forskolin was used in more than 13,000 in vitro and in vivo experimental studies designed to better understand the cellular processes governed by CAMP(discussed later). Although most of these studies have used this isolated constituent, there is evidence that other components within the plant extract enhance the absorption and biologic activity of forskolin. However, no detailed analysis of the chemical composition of C. forskohlii could be found.

HISTORY AND FOLK USE C. forskohlii has a long history of use in Ayurvedic, Siddha, and Unani systems of medicine. Studies of the 871

Pharmacology of Natural Medicines

OCOCH, OH Flgum 83-1 Forskolin.

pharmacologic activity of forskolin substantiate the traditional uses of C. forskohlii in such conditions as': Cardiovascular disease Eczema Abdominal colic Respiratory disorders Painful urination himnnia Convulsions

PHARMACOLOGY As noted in a landmark experiment in 1981, the basic mechanism of action of forskolin is the activation of adenylate cyclase, which increases cyclic adenosine monophosphate (CAMP)in cells? CAMPis perhaps the most important cell-regulating compound. Once formed, it activates many other enzymes involved in diverse cellular function^.^ Under normal situations, CAMP is formed when an activating hormone (e.g., epinephrine) binds to a receptor site on the cell membrane and stimulates the activation of adenylate cyclase. This enzyme is found in all cellular membranes, and only the specificity of the receptor site determines which hormone will activate it in a particular cell. In contrast, forskolin appears to directly activate adenylate cyclase, bypassing hormonal transmembrane activation of adenylate cyclase. The physiologic and biochemical effects of a raised intracellular CAMPlevel include the following: Inhibition of platelet activation and degranulation Inhibition of mast cell degranulation and histamine release Increased force of contraction of heart muscle Relaxation of the arteries and other smooth muscles Increased insulin secretion Increased thyroid function Lipolysis Forskolin possesses additional mechanisms of action independent of its ability to directly stimulate adenylate cyclase and CAMP-dependent physiologic responses! Specifically, forskolin has been shown to inhibit a number of membrane transport proteins and channel proteins through a mechanism that does not involve the

production of CAMP. The result is again a transmembrane signaling that results in activation of other cellular enzymes. Research is under way to determine the exact receptors to which forskolin is binding. Another action of forskolin is the inhibition of platelet-activating factor (PAF) by interfering with PAF binding to receptor sites? PAF plays a central role in many inflammatory and allergic processes including neutrophil activation, increasing vascular permeability, smooth muscle contraction such as bronchoconstriction, and reduction in coronary blood flow. Treatment of platelets with forskolin before PAF exposure results in a 30% to 40% decrease in PAF binding. This decrease in PAF binding caused by forskolin was concomitant with a decrease in the physiologic responses of platelets induced by PAF. However, this forskolin-induced decrease in PAF binding was not a consequence of CAMPformation, as the addition of a CAMPantagonist did not inhibit the action of forskolin. In addition, the inactive analog of forskolin, dideoxyforskolin, which does not activate adenyl cyclase, also reduced PAF binding to its receptor. Researchers speculate that the action of forskolin on PAF binding is due to a direct effect of this molecule and its analog on the PAF receptor itself or to components of the postreceptor signaling for PAF.

CLINICAL APPLICATIONS The therapeutic ramifications of C.forskoh2ii based on the pharmacology of forskolin are immense. In many conditions a decreased intracellular CAMPlevel is thought to be a major factor in the development of the disease process. C. forskohlii appears to be especially well indicated in the following types of conditions: Atopic dermatitis Asthma Psoriasis Angina Hypertension Although C. forskohlii can be used alone, it may prove to be most useful when combined with other botanicals or measures, or both, in the treatment of these disorders.

Inflammatory Conditions Allergic conditions such as asthma and eczema are characterized by a relative decrease in CAMPin both the bronchial smooth muscle and the skin. As a result, mast cells degranulate and smooth muscle cells contract more readily. In addition, these allergic conditions are also characterized by excessive levels of PAF.

Asthma and Eczema Current drug therapy for allergic conditions like asthma and eczema is largely designed to increase CAMPlevels

Coleus forskohlii

by using substances that either bind to receptors to stimulate adenylate cyclase (e.g., corticosteroids) or inhibit the enzyme phosphodiesterase,which breaks down CAMP once it is formed (e.g., methylxanthines). These actions are different than forskolin's ability to increase the production of CAMPvia transmembraneactivation of adenylate cyclase. The CAMP-elevating action of forskolin supports the use of C. forskohlii extracts alone or in combination with standard drug therapy in the treatment of virtually all allergic conditions. C. forskohlii extracts may be particularly useful in asthma, as increasing intracellular levels of cAMP result in relaxation of bronchial muscles and relief of respiratory symptoms. Forskolin has been shown to have remarkable effects in relaxing constricted bronchial muscles in asthmatics.G8This type of smooth muscle is also found in the gastrointestinal tract, uterus, bladder, and arteries. Forskolin has been shown to have tremendous antispasmodic action on these various smooth muscles. This antispasmodic action of forskolin supports the folk medicine use of C. forskohlii in the treatment of not only asthma, but also intestinal colic, uterine cramps (menstrual cramps), painful urination, angina, and hypertension. In addition to forskolin's ability to relax smooth muscle, its other antiallergic activities, such as inhibiting the release of histamine and synthesis of allergic compounds, are also beneficial in treating asthma? One double-blind clinical study sought to compare the antiasthmatic effects of forskolin with the drug fenoterol. Sixteen patients with asthma were studied using three different preparations: Single inhalation doses of fenoterol Dry powder capsules of fenoterol(O.4 mg) Metered doses of fenoterol (0.4 mg) and forskolin dry powder capsules (10 mg) All three preparations caused sigrufrcant improvement in respiratory function and bronchodilation. However, while the fenoterol preparations caused tremors and decreased blood potassium levels, no such negative effects were seen with forskolin. In another study, the bronchodilating effect (after 5 minutes) of forskolin was as good as that produced by fenoterol in 12 healthy volunteers (nonsmokers),as determined by whole body plethysmography.lo Both substances were administered by metered dose inhalers. At the beginning (after 3 and 5 minutes), the protective effect of forskolin against inhaled acetylcholine was as good as that produced by fenoterol, while later on (after 15 and 30 minutes), fenoterol provided stronger protection. Whether orally administered forskolin in the form of C. forskohlii extract would produce similar bronchodilatory effects is yet to be determined. However, based on the plant's historical use and additional mechanisms of action, it appears likely.

Psoriasis Psoriasis is a common skin disorder that seems to be caused by a relative decrease in cAMP as compared with cyclic guanine monophosphate (cGMP). The result is a tremendous increase in cell division. In fact, cells divide in psoriasis at a rate 1000 times greater than normal. Preliminary studies have indicated that forskolin may be of great benefit to individuals with psoriasis via its ability to reestablish the normal balance between cAMP and cGMP.'

Cardiovascular Effects Perhaps the most useful clinical applications of C. forskohlii extracts will be for cardiovascular diseases such as hypertension, congestive heart failure, and angina. The cardiovascular effects of C. forskohIii and its components have been studied in great detail.'J1J2 Its basic cardiovascular actions involve lowering of blood pressure along with improving contractility of the heart. Again, this is related to increasing cAMP levels throughout the cardiovascular system, which results in relaxation of the arteries and increased force of contraction. The net effect is sigruficant improvement of cardiovascular function.

Hypertension and Cardiac Failure Several clinical and animal studies have supported the use of forskolin in hypertension and cardiac failure."-14In one human study involving seven patients with dilated cardiomyopathy, forskolin was shown to improve left ventricular function primarily via reduction of preload and without raising metabolic costs.I3 This study confirmed earlier animal studies showing forskolin increases the contractile force of heart muscle.12 In another human study, the hernodynamic effects of intravenous (3 pg/kg/min) forskolin given to patients with dilated cardiomyopathy was e~a1uated.l~ Although systemic vascular resistance and diastolic pressure fell, forskolin had no effect on cardiac index, ejection fraction, or myocardial oxygen consumption at this low dosage. However, when a small dosage of dobutamine was given along with the forskolin, an increase of all four parameters was observed. At a higher dosage (4 pg/kg/min), forskolin increased heart function by 19% and produced a 16% rise in heart rate. However, these changes were associated with symptomatic flush syndromes. These results indicate that forskolin may best be used in congestive heart failure in combination with other botanicals such as Crutaegus (see Chapter 85). Forskolin has also been shown to be a direct cerebral vasodilator, indicating that it may prove to be useful in cerebral vascular insufficiency and poststroke re~overy.'~

An additional mechanism of action particularly beneficial in a wide range of cardiovascularconditions is inhibition of platelet aggregation. In this area, the evidence indicates that the standardized C. forskohlii extract is superior to pure forskolin.16 In an animal model for evaluating in vivo inhibition of platelet aggregation, rats were divided into four groups: Group 1 received C. forskohlii extract (480 mg/kg supplying 20 mg/kg of forskolin);group 2 received forskolin (20 mg/kg); group 3 received dipyridamole; and group 4 served as the control. All treatments were given orally once daily. ADPinduced platelet aggregation was measured on odd days 1 through 15. All three treatments produced signhcant inhibition of platelet aggregation. On day 15, the inhibitions were approximately 42% for group 1, 37% for group 2, and 52% for group 3. Hence the extract of C. forskohlii produced greater inhibition than the pure forskolin.

OTHER CLINICAL APPLICATIONS C.forskohlii extracts concentrated and standardized for forskolin content may prove to be useful in a number of other clinical applications, including the following: Weight loss programs Hypothyroidism Malabsorption and digestive disorders Depression Prevention of cancer metastases Immune system enhancement

Glaucoma In clinical studies, forskolin has been shown to greatly reduce intraocular pressure (IOP) when it is applied This effect indicates that topical directly to the eye~.'~-~O forskolin preparations may be of benefit in the treatment of glaucoma. Unlike current drug therapy, forskolin actually increases intraocular blood flow, has no side effects, and does not induce miosis.

Malabsorption and Digestive Disorders Forskolin stimulates digestive secretions including the release of hydrochloric acid, pepsin, amylase, and pancreatic e n z y r n e ~ Forskolin . ~ ~ ~ ~ has been shown to promote nutrient absorption in the small intestine.29 C.forskohliiextracts may prove to be quite useful in treating dry mouth, as forskolin increases salivation.30

Depression Forskolin has been shown to exert antidepressant activity in animal studies.31

Cancer Metastases Forskolin has been shown to be a potent inhibitor of cancer metastasis in mice injected with malignant cells.32 As little as 82 mcg administered to mice inhibited metastasis by over 70%.

Immune System Enhancement Forskolin exhibits potent immune system enhancement (primarily through activation of macrophages and lymphocytes) in several m ~ d e l s . ~ - ~ ~

DOSAGE The recommended dosage should be based on the level of forskolin. As the forskolin content of coleus root is typically only 0.2% to 0.3%,crude coleus products may not be sufficient to produce a pharmacologic effect. The safety of the whole root at high dosages is not as well studied. It is best to use standardized extracts that have known forskolin content. Daily dosages follow: Forskolin: 5 to 10 mg two to three times daily Standardized extract (18% forskolin): 50 mg two to three times daily Dried root: 2 to 5 g two to three times daily

Weight Loss Programs

TOXIC0LOGY

Lipolysis, the breakdown of stored fat, is regulated by CAMP.Forskolin has been shown to stimulate lipolysis, as well as inhibit the synthesis of fat in adipocytes?l-" Forskolin has also been shown to counteract the agerelated decreased response of fat cells to lipolytic hormones like epinephrine.25

The animal studies on forskolin indicate low toxicity. The pharmacology of forskolin suggests it would be wise to restrict the use C.forskohlii preparations in patients with low blood pressure and peptic ulcers.

Hypothyroidism

C.forskohlii preparations should be used cautiously in patients on prescription medications, especially antiasthmatics and antihypertensives, due to its ability to potentiate these and other drugs' effects.

Forskolin has been shown to increase thyroid hormone production, as well as stimulate thyroid hormone release.26

DRUG INTERACTIONS

Coleus forskohlii

1.Ammon HIT, Muller AB. Forskoh. from ayurvedic remedy to a modem agent. Planta Med 1985;51:473-477. 2. Seamon KB, Daly JW. Forskolin: a unique diterpene activator of cyclic AMP-generating systems. J Cyclic Nucleotide Res 1981;7 201-224. 3. Insel PA, Ostrom RS. Forskolin as a tool for examining adenylyl cyclase expression, regulation, and G protein signaling. Cell Mol Neurobiol2003;23:305-314. 4. Laurenza A, Sutkowski EM, Seamon KB. Forskolin. A specific stimulator of adenyl cyclase or a diterpene with multiple sites of action. Trends Pharmacol Sci 1989;10442-447. 5. Wong S, Mok W, Phaneuf S, et al. Forskolin inhibits platelet-activating factor binding to platelet receptors independently of adenylyl cyclase activation. Eur J Pharmacol1993;245:55-61. 6. Wong S, Mok W, Phaneuf S. Forskolin inhibits platelet-activating factor binding to platelet receptors independently of adenylyl cyclase activation. Eur J Pharmacol1993;24555-61. 7. Lichey J, Friedrich T, Priesnitz M, et al. Effect of forskolin on methacholine-induced bronchoconstridion in extrinsic asthmatics. Lancet 1984;2167. 8. Bauer K, Dietersdorfer F, Sertl K, et al. Phannacodynamic effects of inhaled dry powder formulations of fenoterol and colforsin in asthma. Clin Pharmacol Ther 1993;5376-83. 9. Marone G, Columbo M, Triggiani M, et al. Forskolin inhibits the release of histamine from human basophils and mast cells. Agents Actions 1986;18:96-99. 10. Kaik G, Witte PU. Protective effect of forskolin in acetylcholine provocation in healthy probands. Comparison of 2 doses with fenoterol and placebo. Wien Med Wochenschr 1986;136637-641. 11. Dubey MP, Srimal RC, Nityand S, Dhawan BN. Pharmacological studies on coleonol, a hypotensive diterpene from Coleus forskohlii. J Ethnopharmacology 1981;31-13. 12. Lindner E, Dohadwalla AN, Bhattacharya BK. Positive inotropic and blood pressure lowering activity of a diterpene derivative isolated from Coleus forskohlii. Forskolin. Arzneimittelforschung 1978; 28284-289. 13.Kramer W, Thormann J, Kinder M, Schlepper M. Effects of forskolin on left ventricular function in dilated cardiomyopathy. Arzneimittelforschung 1987;37364-367. 14. Schlepper M, Thormann J, Mitrovic V. Cardiovascular effects of forskolin and phosphodiesterase-III inhibitors. Basic Res Cardiol 1989;84:197-212. 15. Wysham DG, Brotherton AF, Heistad DD. Effects of forskolin on cerebral blood flow. Implications for a role of adenylate cyclase. Stroke 1986;171299-1303. 16. Wysham DG, Brotherton AF, Heistad DD. Effects of forskolin on cerebral blood flow. Implications for a role of adenylate cyclase. Stroke 1986;171299-1303. 17. Potter DE, Burke JA, Temple JR. Forskolin suppresses sympathetic neuron function and causes ocular hypotension. Curr Eye Res 1985;487-96. 18. Caprioli J, Sears M. Forskolin lowers intraocular pressure in rabbits, monkeys, and man. Lancet 1983;1:958-960.

19. Meyer BH, Stulting AA, Muller FO. The effects of forskolin eye drops on intra-ocular pressure. S Afr Med J 1987;71:570-571. 20. Seto C, Eguchi S, Araie M, et al. Acute effects of topical forskolin on aqueous humor dynamics in man. Jpn J Ophthalmol 1986;30: 238-244. 21. Allen DO, Quesenberry JT.Quantitative differences in the cyclic AMP-lipolysis relationships for isoproterenol and forskolin. J Pharmacol Exp Ther 1988;244%52-858. 22. Allen DO, b e d B, Naseer K. Relationships between cyclic AMP levels and lipolysis in fat cells after isoproterenol and forskolin stimulation. J Pharmacol Exp Ther 1986;238:659-664. 23. Okuda H, Morimoto C, Tsujita T. Relationship between cyclic AMP production and lipolysis induced by forskolin in rat fat cells. J Lipid Res 1992;33225-231. 24. Bianco AC, Kieffer JD, Silva JE. Adenosine 3’,5’-monophosphate and thyroid hormone control of uncoupling protein messenger ribonucleic acid in freshly dispersed brown adipocytes. Endocrinology 1992;1302625-2633. 25. Hoffman BB, Chang H, Reaven GM. Stimulation and inhibition of lipolysis in isolated rat adipocytes. Evidence for age-related changes in responses to forskolin and PGEl. Horm Metab Res 1987;19:358-360. 26. Saunier B, Dib K, Delemer B, et al. Cyclic AMP regulation of Gs protein. Thyrotropin and forskolin increase the quantity of stimulatory guanine nucleotide-binding proteins in cultured thyroid follicles. J Biol Chem 1990;265:19942-19946. 27. Roger PP,Servais P,Dumont JE. Regulation of dog thyroid epithelial cell cycle by forskolin, an adenylate cyclase activator. Exp Cell Res 1987;172282-292. 28. Haye B, Aublin JL, Champion S, et al. Chronic and acute effects of forskolin on isolated thyroid cell metabolism. Mol Cell Endocrinol 1990;43:41-50. 29.Reymann A, Braun W, Woermann C. Proabsorptive properties of forskolin. Disposition of glycine, leucine and lysine in rat jejunum. Naunyn W e d e b e r g s Arch Pharmacol1986;334:110-115. 30.Larsson 0, Detsch T, Fredholm BB. VIP and forskolin enhance carbachol-induced K+ efflux from rat salivary gland fragments by a Ca2(+)-sensitive mechanism. Am J Physiol 1990;259: C904C910. 31. Wachtel H, Loschmann PA. Effects of forskolin and cyclic nucleotides in animal models predictive of antidepressant activity. Interactions with rolipram. Psychopharmacol (Berl) 1986;90: 430-435. 32. Agarwal KC, Parks RE Jr. Forskolin: a potential antimetastatic agent. Int J Cancer 1983;32:801-804. 33. Schorlemmer HU. Forskolin for immune stimulation. Chem Abstr 1985;1021009. 34. KraU JE Femandey EI, Connolly-Filtingoff M. Human aging: effect on the activation of lymphocyte cyclic AMP-dependent protein kinase by forskolin. Proc Soc Exp Biol Med 1987;184:396-402. 35. Chang J, Chemey ML, Moyer JA. Effect of forskolinon prostaglandin synthesis by mouse resident peritoneal macrophages. Eur J Pharmacol1984;103:303-312.

c0mrm;ohora mukd (Mukul Myrrh Tree) Michael T. Murray. NI) Joseph E. I'izzorno Jr. XI) CHAPTER CONTENTS General Description 877

Additional Antiatherosclerotic Effects 879 Antiinflammatory Effects 879

Chemical Composition 877 Dosage 879 History and Folk Use 877

Toxicology 879 Pharmacology 878 Lipid Disorders 878

Commiphora mukul (family: Burseraceae) Common name: mukul myrrh tree

GENERAL DESCRIPTION Commiphoru mukul, a small, thorny tree that grows 4 to 6 feet tall, is native to Saudi Arabia and India. In its natural setting, the tree remains essentially free of foliage for most of the year. Its bark is ash colored and comes off in rough flakes, exposing the under-bark, which also peels off. When injured, the tree exudes a yellowish gum resin that has a balsamic odor. This oleoresin is referred to as "gum guggul" or "guggulu." This resin is used for medicinal purposes. When tapped during the winter, the average tree yields 1.5 to 2 lb of resin.'

CHEMICAL COMPOSITION Guggulu contains a mixture of diverse chemical constituents that can be separated into several fractions.' The first step in the fractionation process involves mixing guggulu with ethyl acetate to yield soluble and insoluble fractions (Figure &I-1).The insoluble fraction, containing the carbohydrate constituents, is regarded as toxic and is the major reason why extracts of the soluble portion are preferred to crude gum guggul for medical use. The insoluble portion has no demonstrable pharmacologic activity other than toxicity.' In contrast, the soluble portion possesses sigruficant cholesterol-lowering and antiinflammatory activity. The soluble portion can be further separated into base, acid,

and neutral fractions. The neutral portion possesses almost all of the cholesterol-loweringactivity, while the acid portion possesses the antiinflammatory components.' On further purification of the neutral portion, it was determined that the ketone fraction contains the most potent cholesterol-lowering components. The ketone fraction is composed of Czl or Cz7steroids, with the major components being Z- and E-guggulsterone (Figure 84-2). These compounds are considered the major active components of gum guggul and its extracts.' For medicinal purposes, a standardized extract known as gugdipid, which is standardized to contain a minimum of 50 mg of guggulsterones/g, is regarded as the most beneficial in terms of safety and effectiveness.'P2 In addition to guggulsterones, gugullpid contains various diterpenes, sterols, esters, and fatty alcohols. These accessory components appear to exert a synergistic effect.'tZ

HISTORY AND FOLK USE Guggulu is a highly valued botanical medicine in the Indian system of medicine, Ayurveda. It is included in formulas for various health conditions including rheumatoid arthritis and lipid disorders. The classic Ayurvedic medical text, the Sushru tusumhitu, describes in detail the usefulness of guggul in the treatment of obesity and other disorders of fat metabolism including "coating and obstruction of channels."',2 Inspired by thisdescription, researchers began examining, in well-designed scientific studies, the clinical effectiveness of gum guggul and its extracts in disorders of 877

Insoluble (55%) gum carbohydrates

D

Bases (.3%)

Soluble (45%') gugulipid (antiinflammatory and hypocholesterolemic activities) Guggulsterones

\ Diterpenes, lignans,

Figure 84-1 Chemical segregation of gum guggulu.

Guggul preparations appear most indicated in type IIb (increased LDL, VLDL, and triglycerides) and type IV (increased VLDL and triglycerides) hyperlipidemias. Preliminary human clinical trials using gugulipid found that cholesterol levels showed typical reductions of 14% to 27"/0 in total cholesterol levels in a 4- to 12-week period, while triglyceride levels dropped Figure 84-2 Guggulsterone. from 22 to 30Y0.'~-'~ However, a larger double-blind study did not show either of two doses of a standardized guggul extract (guggulipid, containing 2.5% guggulslipid metabolism-specifically, its ability to lower cholesterol and triglyceride levels and promote weight terones) in lowering LDL-C levels healthy adults with hyperli~idemia.'~ loss. This research resulted in the development of a natSubjects received either standard-dose guggulipid ural cholesterol-lowering substance that is safer and more effective than many cholesterol-lowering drugs (1000 mg), high-dose guggulipid (2000 mg), or matching placebo three times daily for 8 weeks. LDL-C levels including niacin. Gugulipid was granted approval in India for marketing as a lipid-lowering drug in 1986.'~~ decreased by 5% in the placebo group. Both standarddose guggulipid and high-dose guggulipid raised levels of LDL-C by 4%, respectively. There were no significant PHARMACOLOGY changes in levels of total cholesterol, HDL-C, triglycerides, Lipid Disorders or VLDL-C in response to treatment with guggulipid in Numerous studies in humans and animals have shown the intention-to-treat analysis. Although guggulipid was that gum guggul (both crude and purified alcohol generally well tolerated, six participants treated with guggulipid developed a hypersensitivity rash compared extract),37its petroleum ether extract (referred to asfmcwith none in the placebo group. These results call into tion A)?-" and gugulipid (standardized ethyl acetate question the clinical effectiveness of guggulipid despite extract)'*J3all exert effective lipid-lowering activity. All plausible mechanisms of action. lower both elevated cholesterol and triglyceride levels. The effect on cholesterol is particularly beneficial, as In vitro studies have shown that the primary mechaguggul lowers very low-density lipoprotein cholesterol nism of action involves guggulsterones acting as an (VLDL-C) and low-density lipoprotein cholesterol antagonist ligand for the farnesoid X receptor (FXR)(i.e., (LDL-C), while simultaneously elevating high-density guggulsterones promote the conversion of cholesterol to lipoprotein cholesterol (HDL-C),thus offering protection bile acids and increase the uptake of LDL-C from the against heart disease due to atherosclerosis. blood by the li~er).'~*"j-'~ Another possible action of

Cornrniphora rnukul (Mukul Myrrh Tree) guggulsterones in affecting lipid levels is their ability to stimulate thyroid fun~tion.'~

Additional Antiat herosclerotic Effects In addition to lowering lipid levels, gum guggul and its extracts including gugulipid have been shown to prevent the formation of atherosclerosis and aid in the regression of preexisting atherosclerotic plaques in animals. This implies that they may have similar effects in humans. Gum guggul and gugulipid have also been shown to prevent the heart from being damaged by freeradicals and to improve the metabolism of the heart?J4 Gum guggul and its extracts have a mild effect in inhibiting platelet aggregation and promoting fibrinolysis, implying that it may also prevent the development of a stroke or ernboli~m.~J~ This research indicates that guguhpid offers considerable benefit for preventing and treating atherosclerotic vascular disease, the leading cause of death in the United States.

Antiinflammatory Effects The guggulsterone fraction of gum guggul has been shown to exhibit sigruficant antiinflammatory action in experimental models of inflammation (e.g., raw paw edema and adjuvant arthritis method).20-22 Its activity in models of acute inflammation is comparable to approximately one fifth that of hydrocortisone and equal to phenylbutazone and ibuprofen.2O In models of chronic inflammation, it was shown to be more effective than hydrocortisone, phenylbutazone, and ibuprofen in reducing the severity of secondary lesions. The antiinflammatory action is thought to be due to inhibition of delayed hypersensitivity reactions.21,22 The clinical application of these effects may include osteoarthritis. In an open trial of 30 patients with osteoarthritis of the knee, 500 mg of the concentrated exact three times daily produced significant improvements in the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Total Score and subscales, visual analog scale (VAS), and 6-minute

1. Satyavati GV. Gugulipid. A promising hypolipidaemic agent from gum guggul (Cornrniphora wightii). Econ Med Plant Res 1991; 547-82. 2. Satyavati GV. Gum guggul (Cornrniphoru rnukul)-The success story of an ancient insight leading to a modem discovery. Indian J Med Res 1988;87327-335. 3. Satyavati GV, Dwarakanath C, Tripathi SN. Experimental studies of the hypocholesterolemic effect of Cornrniphoru rnukul. Indian J Med Res 1969371950-1962. 4. Khana DS, Agarwal OP, Gupta SK, Arora RB. A biochemical approach to anti-atherosclerotic action of Comrniphoru-rnukul.

walk-test. WOMAC subscales were used as outcome mea~ures.2~

DOSAGE Although the crude oleoresin (gum guggul), alcohol extract, and petroleum ether extract all exert lipid-lowering and antjinflammatory action, they are associated with side effects (e.g., skin rashes, diarrhea) at the doses required to produce a clinical effect. Interestingly, in classic Ayurvedic texts the purification of crude guggul in Triphala kashaya is recommended to eliminate these side effects2 Guguhpid, the standardized ethyl acetate extract of the gum guggul, has demonstrated not only greater clinical efficacy but also much greater patient tolerance than crude or purified gum guggul. The dosage of guguhpid is based on its guggulsterone content. The typical dosage, 25 mg of guggulsterone three times per day, is an effective treatment for elevated cholesterol levels, elevated triglyceride levels, or both. For a 2.5% guggulsterone content extract, this translates to an effective dose of 1000 mg three times/day. For comparison, the daily dosages of the other forms follow: Crude gum guggul-10 g Alcoholic extract-4.5 g Petroleum ether extract-1.5 g

TOXICOLOGY ~~~~

The side effects of crude gum guggul and alcoholic and petroleum ether extracts were discussed earlier. In clinical studies, gugulipid has not displayed any untoward side effects, nor has it adversely affected liver function, blood sugar control, kidney function, or hematologic parameters.11-13 Safety studies in rats, rabbits, and monkeys have demonstrated gugulipid to be n0nt0xic.l~It does not possess any embryotoxic, fetotoxic effects and is therefore considered safe to use in pregnancy. In mice the oral and intraperitoneal LDS0values are 1600 mg/kg.'

An Indian indigenous drug in Indian domestic pigs. Indian J Med

Res 1969;57900-906. 5. Nityand S, Kapoor NK. Hypocholesterolemic effect of Cornrniphoru mukul resin (guggal). Indian J Exp Biol1971;9:376-377. 6. Kuppurajan K, RajagopalanSS, Koteswara RT, SitaramanR. Effect of guggul (Cornrniphora rnukul-Engl.) on serum lipids in obese, hypercholesterolemic and hyperlipidemic cases. J Assoc Physicians India 1978;26367-371. 7. Baldwa VS, Bhasin V, Ranka PC, Mathur KM. Effects of Comrniphora rnukul (Guggul) in experimentally induced hyperlipidernia and atherosclerosis.J Assoc Physicians India 1981;29:13-17.

8. Malhotra SC, Ahuja Mh4S Comparative hypolipidaemic effectiveness of gum guggulu (Cornmiphoru mukill) fraction "A," ethylp-chlorophenoxyisobutyrate and Ciba-13437-Su. Indian J Med Res 1971;101621-1632. 9. Arora RB, Das D, Kapoor SC,Sharma RC. Effect of some fractions of Comrniphora rnukul on various serum lipid levels in hypercholesterolemic chicks and their effectiveness in myocardial infarction in rats. Indian J Exp Biol1973;11:166-168. 10. Malhotra SC, Ahuja MMS, Sundaram KR. Long term clinical studies on the hypolipidaemic effect of Commiphoru mukul (guggulu) and clofibrate. Ind J Med Res 1977;65390-395. 11. Vema SK, Bordia A. Effect of Cornrniphoru mukul (gum guggulu) in patients of hyperlipidemia with special reference to HDL-cholesterol. Indian J Med Res 1988;87356-360. 12. Agarwal RC, Singh SP, Saran RK, et al. Clinical trial of guguhpida new hypolipidemic agent of plant origin in primary hyperlipidemia. Ind J Med Res 1986;&4:626-634. 13. Nityanand S, Srivastava JS, Asthana OF'. Clinical trials with guguhpid. A new hypolipidaemic agent. J Assoc Physicians India 198937323-328. 14. [No authors listed]. Gugulipid. Drugs Fuhire 1988;13:618-619. 15.Szapary PO, Wolfe ML, Bloedon LT, et al. Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial. JAMA 2003;290:765-772. 16. Singh V, Kaul S, Chander R, Kapoor NK. Stimulation of low density lipoprotein receptor activity in liver membrane of guggulsterone treated rats. Pharmacol Res 1990;22:37-44.

17. Cui J, Huang L, Zhao A, et al. Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump. J Biol Chem 2003;278 1021410220. 18. Urizar NL, Liverman AB, Dodds DT, et al. A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 2002;2961703-1706. 19. Tripathi YB, Tripathi P, Malhorta OF,' Tripathi SN. Thyroid stirnulatory action of (Z)-guggulsterone: mechanism of action. Planta Med 1988;54:271-277. 20.Arora RB, Kapoor V, Gupta SK, Sharma RC. Isolation of a crystalline steroidal compound from Cornmiphora rnukul and its anti-inflammatory activity. Indian J Exp Biol1971;9:403-404. 21.Arora RB, Taneja V, Sharma RC, Gupta SK. Anti-inflammatory studies on a crystalline steroid isolated from Cornmiphoru mukul. Indian J Med Res 1972;60:929-931. 22. Sharma JN, Sharma JN. Comparison of the anti-inflammatory activity of Cornmiphoru mukul (an indigenous drug) with those of phenylbutazone and ibuprofen in experimental arthritis induced by mycobacterial adjuvant. Arzneimittelforschung 1977;271455-1457. 2 3 . S i g h BB, Mishra LC, Viijamury SP, et al. The effectiveness of Cornmiphoru mukul for osteoarthritis of the knee:an outcomes study. Altem Ther Health Med 2003;974-79.

Crataegus oxyacantha (Hawthorn) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER C O N T E N T S General Description 881 Chemical Composition 881

Clinical Applications 883 Atherosclerosis 883 Hypertension 883 Congestive Heart Failure 883

History and Folk Use 881 Dosage 884 Pharmacology 882 Synergism with Vitamin C 882 Collagen-Stabilizing Action 882 Cardiovascular Effects 882

Crutuegus oxyucuntha (family: Rosacea) Synonym: Crutuegus luevigitu Common names: hawthorn, may bush, whitethorn, haw

GENERAL DESCRIPTION Crutuegus oxyucunthu is a spiny tree or shrub that is native to Europe. It may reach a height of 30 feet but is often grown as a hedge plant. Its common name, hawthorn, is actually a corruption of ”hedgethorn,” as it was used in Germany to divide plots of land. Its botanical name, C. oxyucuntha, is from the Greek krutos, meaning hardness (of the wood); oxus, meaning sharp; and ukunthu, meaning a thorn. The fruit and blossoms are used medicinally.’ Other species of Crataegus (e.g., Crutuegus rnonogyna, Crutuegus pentugynu) contain similar constituents and likely have similar pharmacologic actions to C. oxyucunthu, so they may be suitable alternatives?J

Side Effects and Drug Interactions 884 Toxicology

884

but also of blackberries, cherries, blueberries, grapes, and many flowers as well. These compounds are highly concentrated in hawthorn berry and flower extracts. High-performance liquid chromatography and thin-layer chromatography (of crataegus extracts) have demonstrated that extracts of the flowers are particularly rich in flavonoids (e.g., quercetin, quercetin3-galactosidefvitexin, vitexin-4’-rhamnoside),procyanidins (Figure 85-2),and oligomers of procyanidins.5T6 In addition to flavonoids, crataegus extracts also contain7: Cardiotonic amjnes (e.g., phenylethylamine, o-methoxyphenylethylamine, tyramine, isobutylamine) Choline and acetylcholine Purine derivatives (e.g., adenosine, adenine, guanine, caffeic acid) Amygdalin Pectins Triterpene acids (ursolic, oleonolic, and crategolic acids)

CHEMICAL COMPOSITION Hawthorn leaves, berries, and blossoms contain many biologically active flavonoid compounds, particularly anthocyanidins and proanthocyanidins (polymers of anthocyanidins, also known as bifluvuns or procyanidins) (Figure 85-1).2-5These flavonoids are responsible for the red to blue colors not only of hawthorn berries,

HISTORY AND FOLK USE Crataegus flowers and berries have been used primarily as cardiac tonics and mild diuretics in organic and functional heart disorders. They are also used for their astringent qualities to relieve sore throat pain.’ 881

The prevention of free radical damage, due to potent antioxidant and free radical scavenging action2,4,810 The inhibition of enzymatic cleavage by enzymes secreted by leukocytes during infla~~tmation~ The prevention of the release and synthesis of compounds that promote inflammation, such as histamine, serine proteases, prostaglandins, and leukotrienes4

OH Flgure 851 Proanthocyanidin 82.

rhamnoside

These effects on collagen and their potent antioxidant activity make hawthorn extracts extremely useful in the treatment of a wide variety of inflammatory conditions. Hawthorn berries, like cherries," are particularly effective in the treatment of gout, as their flavonoid components reduce uric acid levels, as well as reduce tissue destruction.

Cardiovascular Effects The beneficial effects of crataegus in the treatment of cardiovascular conditions appear to be a result of the following pharmacologic actions:

HowoH

I

I OH

OH

0

Figure 85-2 Vitexin4-rhamnoside.

PHARMACOLOGY The pharmacology of crataegus centers on its flavonoid components.23 The proanthocyanidins in crataegus are largely responsible for its cardiovascular activities.

Synergism with Vitamin C As stated earlier, crataegus is particularly rich in anthocyanidins and proanthocyanidins. These flavonoids have strong "vitamin P" activity. Included in their effects are the abilities to increase intracellular vitamin C levels, stabilize vitamin C (by protecting it from oxidation), and decrease capillary permeability and frag~lity.~,~-~

Collagen-Stabilizing Action Crataegus's flavonoid components possess significant collagen-stabilizing action. Collagen is the most abundant protein of the body and is responsible for maintaining the integrity of ground substance, tendons, ligaments, and cartilage. Collagen is destroyed during inflammatory processes that occur in rheumatoid arthritis, periodontal disease, and other inflammatory conditions involving bones, joints, cartilage, and other connective tissue. Crataegus procyanidins affect collagen metabolism in many ways including the following: Reinforcement of the natural cross-linking of collagen that forms the collagen matrix of connective tissue (e.g., ground substance, cartilage, tendon)2A

Improvement of the blood supply to the heart by dilating the coronary v e ~ s e l s ~ * ~ J * - ~ ~ Improvement of the metabolic processes in the heart, which results in an increase in the force of contraction of the heart muscle and elimination of some types of rhythm d i ~ t u r b a n c e s ~ , ~ J ~ J ~ - ' ~ Inhibition of angiotensin-converting enzyme (ACE)20 Crataegus's ability to dilate coronary blood vessels has been repeatedly demonstrated in experimental studies. This effect appears to be due to relaxation of vascular smooth muscle by a combination of direct effects on both the vascular endothelium and smooth muscle. In addition, various flavonoid components in crataegus have been shown to inhibit vasoconstriction by various substances including hypophysin, histamine, and acetylcholine. In addition, procyanidins have been shown to inhibit ACE (discussed later).2*3"1 Improvement in cardiac metabolism has been demonstrated in humans and animalswho have received crataegus extracts2J The improvement is not only a result of increased blood and oxygen supply to the myocardium, but also a result of flavonoid-enzyme interactions. In particular, crataegus extracts and various flavonoid components in crataegus have been shown to inhibit cyclic AMP phosphodiesterase (CAMP-PDE).~ This results in increased levels of CAMPwithin the myocardium, leading to a positive inotropic effect (i.e., an increase in the force of contraction). This is particularly beneficial in cases of congestive heart failure (discussed later). The procyanidins of crataegus have demonstrated a specific inhibition of ACE similar to synthetic ACE inhibitors widely used in the treatment of hypertension.2I The proanthocyanidins that appear to have the highest activity are proanthocyanidins 8-5 3,3'-di-O-gallate and C-1 3,3',3''-tri-O-gallate. It is not surprising that

Crataegus oxyacantha (Hawthorn)

these proanthocyanidins are found in relatively high concentrations in hawthorn berries, flowers, and their extract^.^,^

CLINICAL APPLICATIONS The clinical use of crataegus revolves around its cardiovascular effects. Its use in atherosclerosis, hypertension, congestive heart failure, and arrhythmias is discussed as follows.

Atherosclerosis Crataegus preparations, although in a supplement form, should be thought of as a necessary food in the prevention and treatment of atherosclerosis. Increasing the intake of flavonoid compounds by taking crataegus extracts has numerous health-promoting effects including reducing cholesterol levels and decreasing the size of existing atherosclerotic plaques.= This effect is probably a result of collagen stabilization. A decrease in the integrity of the collagen matrix of the artery results in cholesterol deposition. Many researchers believe that if the collagen matrix of the artery remains strong, the atherosclerotic plaque will never develop. Crataegus flavonoids, by increasing the integrity of collagen structures, may offer sigruficant protection against atherosclerosis. In addition, feeding proanthocyanidin extracts to animals has resulted in reversal of atherosclerotic lesions, as well as decreased serum cholesterol levels. Flavonoids contained in hawthorn extracts appear to offer significant prevention, as well as potential reversing effects, in the treatment of atherosclerotic processes, which are still the major causes of death in the United States.

Hypertension Crataegus exerts a mild antihypertensive effect, which has been demonstrated in both experimental and clinical studies? Its action in lowering blood pressure is unique in that it produces a number of diverse pharmacological effects. Specifically, it dilates the coronary vessels, inhibits ACE, acts as an inotropic agent, and possesses mild diuretic activity. Its clinical effects in lowering blood pressure, however, are generally mild.*O Crataegus’s effects generally require prolonged administration, and in many instances it may take up to 2 weeks before adequate tissue concentrations are achieved. It should be kept in mind that as beta-blockers lower blood pressure by reducing cardiac output, crataegus administration to patients on these drugs may produce a mild hypertensive response.

Congestive Heart Failure Crataegus has a long history of use in the treatment of congestive heart failure, particularly in combination with

digitalis or other herbs containing cardiac glycosides such as Cereus grandiflorus, also known as Cactus grundifloris, and Convallaria mjalis. It potentiates the action of the cardiac glycosides,presumably via its ability to inhibit CAMP-PDEand to interact with calcium channels. Because of this enhancing effect, lower doses of cardiac glycosides can be used. In addition, magnesium has also been shown to augment digitalis action. For mild to moderate cases of CHF, crataegus extract used alone may be sufficient, but for moderate to severe CHF it should be used in combination with other cardiac glycosides. In early or mild stages of CHF, the effectiveness of crataegus has been repeatedly demonstrated in doubleblind ~ t u d i e s . 2 ” ~In~ ~a detailed metaanalysis, eight trials involving 632 patients with chronic heart failure (New York Heart Association [ M A ] classes I to 111) demonstrated that crataegus extract was more beneficial than placebo as shown by improvements in maximal workload, pressure-heart rate product, and symptoms such as dyspnea and fatigue. In an earlier double-blind study, 30 patients with congestive heart failure (NYHA stage 11) were assessed in a randomized, double-blind study.27Treatment consisted of a crataegus extract standardized to contain 15 mg procyanidin oligomers per 80 mg capsule. Treatment duration was 8 weeks, and the substance was administered at a dose of one capsule taken twice a day. The group receiving the crataegus extract showed a statistically significant advantage over placebo in terms of changes in heart function as determined by standard testing procedures. Systolic and diastolic blood pressures were also mildly reduced. Like all other studies with crataegus extracts, no adverse reactions occurred. In another study, 78 patients with CHF (NYHA stage 11) were given either 600 mg of extract standardized to contain 18.8%procyanidolic oligomers or placebo daily.28 The parameter used to measure effectiveness was the patient’s working capacity (W) on a bicycle ergometer. After 56 days of treatment, the crataegus p u p had a mean increase of 25 W compared with the placebo group’s increase of only 5 W. In addition, the crataegus group also experienced a mild, though sigruficant, reduction in systolic blood pressure (from 171 to 164 mmHg) and heart rate (from 115 to 110 beats/&). There was no change in blood pressure or heart rate in the placebo group. Crataegus provides a definite dose response. Individuals with more severe CHF require higher dosages in order to experience the most benefit. This comment is based on an important finding in a double-blind study of 209 patients with NYHA class III CHF. Although those receiving 900 mg of a crataegus extract standardized to contain 18.8%procyanidolic oligomers demonstrated improvement in all parameters tested, those receiving 1800 mg showed even better results.3o

Pharmacology of Natural Medicines

DOSAGE Clearly, the dosage depends on the type of preparation and source material. The amount of crataegus extract used in various clinical studies on CHF has been equivalent to 30 to 169 mg of epicatechin or 3.5 to 19.8 mg of flavonoids, usually administered in two or three doses. Standardized extracts are preferred, as flavonoid content in crude preparations can vary tremendously. The dosages listed for the various crataegus formulas are for use three times a day: Berries or flowers (dried): 3 to 5 g or as infusion Tincture (1:5): 4 to 5 ml (alcohol may elicit pressor response in some individuals) Fluid extract (1:l): 1to 2 ml Freeze-dried berries: 1 to 1.5 g Flower extract (standardized to contain 1.8%vitexin4'-rhamnoside or 18% procyanidolic oligomers): 200 to 600 mg

as unlikely. In another postmarketing surveillance study of 3664 patients who were treated with 900 mg of crataegus extract for 8 weeks, 48 patients (1.3%) reported adverse events including hot flushes, stomach complaints, palpitations, dizziness, dyspnea, headache, and epistaxis. In 19 patients, this resulted in discontinuationof the treatment.24 Hawthorn may potentiate or inhibit the actions of anticoagulants, antihypertensives, and cardiac glycosides. This concern is based primarily on theoretic grounds rather than clinical reports. Importantly, in a randomized, crossover trial with eight healthy volunteers, hawthorn did not signhcantly alter the pharmacokineticparameters for digoxin. This suggests that both hawthorn and digoxin may be coadministered safely?

TOXICOLOGY

Postmarketing surveillance studies report only mild and infrequent side effects with crataegus extract. In a study of 1011 patients, 14 adverse events (1.4%) occurred after the administration of 900 mg of hawthorn extract for 24 weeks. In two patients, a causal relation with crataegus was suspected but regarded by the treating doctors

Crataegus has been shown to have low t0xicity.3~In a human study in patients with CHF, dosages at levels 100 times the typical dosage did not produce any evidence of toxicity. Although some studies have shown that proanthocyanidins may be carcinogenic, more careful evaluation has indicated that the carcinogenicity was probably due to nitrosamines found in the extracts used.% Purified proanthocyanidins have been found to be nonmutagenic, according to the Salmonella mutagenicity assay system.

1. Grieve M. A modem herbal, vol 1. New York Dover Publications, 1971:385-386. 2. Chang Q,Zuo Z, Harrison F, Chow MS. Hawthorn. J Clin Pharmacol 2002;42:605-612 Sweet BV. Hawthorn: pharmacology and therapeutic 3. Rigelsky JM, uses. Am J Health Syst Pharm 2002;59:417-422. 4. Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000;52: 673-751. 5. Svedstrom U,Vuorela H, Kostiainen R, et al. Isolation and identification of oligomeric procyanidins h m Crataegus leaves and flowers. Phytochemistry 2002;60:821-825. 6. Ficarra P, Ficarra R, Tommasini A, et al. High-performance liquid chromatography of flavonoids in Cratnegrts oxyacanthn L. I. Reversedphase high-pressure liquid chromatography. Farmaco [Prat] 1983; 39:148-157. 7. Wagner H,Grevel J. [Cardiotonic drugs IV.Cardiotonic amines from Crataegus oxyacantha]. Planta Medica 1982;459&101. 8. Quettier-Deleu C, Voiselle G, Fruchart JC, et al. Hawthorn extracts inhibit LDL oxidation. Pharmazie 2003;58:577-581. 9. Bahorun T, Aumjaud E, Ramphul H, et al. Phenolic constituents and antioxidant capacities of Crntnegus rnonogyna (Hawthorn) callus extracts. Nahrung 2003;47191-198.

10. Nijveldt RJ, van Nood E, van Hoom DE, et al. Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 2001;74:418-425. 11. Blau LW. Cherry diet control for gout and arthritis. Tex Rep Biol Med 1950;8:309-311. 12.Schussler M, Hob1 J, Fricke U. Myocardial effects of flavonoids from Crataegus species. Arzneimittelforschung 1995;45:842-845. 13. Kim SH, Kang KW, Kim KW, Kim ND. Procyanidins in crataegus extract evoke endothelium-dependent vasorelaxation in rat aorta. Life Sci 2OOO;67121-131. 14. Mavers VWH, Hensel H. [Changes in local myocardial blood flow following oral administration of a Crataegus extract in non-narcotized dogs. Arzniemittelforschung 1974;24:783-785. 15. Roddewig C, Hensel H. Reaction of local myocardial blood flow in non-anesthetized dogs and anesthetized cats to oral and parented application of a Crataegus fraction (oligomere procyanidins). Arzneimittelforschung 1977;271407-1410. 16. Vierling W, Brand N, Gaedcke F, et al. Investigation of the pharmaceutical and pharmacological equivalence of different Hawthorn extracts. Phytomedicine 2003;10:8-16. 17. Schwinger RH, Pietsch M, Frank K, Brixius K. Crataegus special extract WS 1442 increases force of contraction in human myocardium CAMP-independently. J Cardiovasc Pharmacol 200035 700-707.

SIDE EFFECTS AND DRUG INTERACTIONS

Crataegus oxyacantha (Hawthorn 18. Muller A, Linke W, Klaus W. Crataegus extract blocks potassium currents in guinea pig ventricular cardiac myocytes. Planta Med 1999;65:335-339. 19. Schussler M, Holzl J, Fricke U. Myocardial effects of flavonoids from Crataegus species.Arzneimittelforschung 1995;45:842-845. 20. Walker AF, Marakis G, Morris AP,Robinson PA. Promising hypotensive effect of hawthorn extract: a randomized double-blind pilot study of mild, essential hypertension. Phytother Res 2002;1648-54. 21. Lacaille-Dubois, Franck U, Wagner H. Search for potential angiotensin converting enzyme (ACE)-inhibitors from plants. Phytomedicine 2001;8:47-52. 22.Petkov E, Nikolov N, Uzunov P. Inhibitory effect of some flavonoids and flavonoid mixtures on cyclic AMP phosphodiesterase activity of rat heart. Planta Medica 1981;43183-186. 23. Wegrowski J, Robert AM, Moczar M. The effect of prqanidolic oligomers on the composition of normal and hypercholesterolemic rabbit aortas. Biochem Pharm 19843334914497. 24.Pittler MH, Schmidt K, Emst E. Hawthorn extract for treating chronic heart failure: meta-analysis of randomized trials. Am J Med 2003;114665-674. 25.0Conolly VM, Jansen W, Bemhoft G, Bartsch G. [Treatment of decreasing cardiac performance. Therapy using standardized crataegus extract in advanced age]. Fortschr Med 1986;104:805-808. 26.0Conolly VM, Jansen W,Bemhoft G, Bartsch G. [Treatment of decreasing cardiac performance. Therapy using standardized crataegus extract in advanced age]. Fortschr Med 1986;104:805-808.

27.Leuchtgens H. [Crataegus Special Extract WS 1442 in NYHA 11 heart failure. A placebo controlled randomized double-blind study]. Fortschr Med 1993;111:352-354. 28.Schmidt U, Kuhn U, Ploch M, Hubner WD. Efficacy of the hawthorn (Crataegus) preparation LI 132 in 78 patients with chronic congestive heart failure defined as NYHA functional class II. Phytomedicine 1994;1:17-24. 29.Zapfe jun G. Clinical efficacy of crataegus extract WS 1442 in congestive heart failure NYHA class II. Phytomedicine 2001;8: 262-266. 30. Tauchert M. Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in patients with chronic stable New York Heart Association class-III heart failure. Am Heart J 2002;143: 910-915. 31. Degenring FH, Suter A, Weber M, Saller R. A randomised double blind placebo controlled clinical trial of a standardised extract of fresh Crataegus bemes (Crataegisan) in the treatment of patients with congestive heart failure NYHA 11. Phytomedicine 2003;lO: 363-369. 32.Tankanow R, Tamer HR, Streetman DS, et al. Interaction study between digoxin and a preparation of hawthorn (Crataegus oxyacuiitha). J Clin Pharmacol2003;43437-642. 33. Schlegelmilch R, Heywood R. Toxicity of crataegus (hawthorn) extract (WS 1442).J Am Coll Toxicol 1994;13:103-111. 34. Yu CI, Swaminathan 8. Mutagenicity of proanthocyanidins. Food Chem Toxicol 1987;25135-139.

Croton lechleri (Dragon's Blood) Kathy Abascal, BS,JD, RH(AHG) Eric L. Ymell, ND, RH(AHG) CHAPTER CONTENTS General Description 887

Antiviral Effect 888 Cicatrizant Effect 889

Chemical Composition 887 History and Folk Use 887 Pharmacology 888 Analgesic Effect 888 Antidiarrheal Effect 888 Antimicrobial Effect 888 Antiproliferative or Cytotoxic Effect, or Both 888 Antiulcerogenic Effect 888

Croton spp. (family: Euphorbiaceae) Synonym: Many Crofon species are identified as dragon's blood, including Croton Zechleri, Croton sordidus, Croton urucurana, Croton draco. (Croton draconoides, Croton palantostigma), Croton xalapensis, and Croton eythrochikl-" Common names: dragon's blood, sangre de drago, sangre de grado, Lora sangre (sp.), sangre de perro (sp.)

GENERAL DESCRIPTION Dragon's blood comes from species of Euphorbiaceae trees that produce a red sap? The trees are native to Bolivia, Brazil, Columbia, Ecuador, and Peru and generally range in height from 3 to 25 meters, although they occasionally reach heights of 35 meters. The young trees have a sympodial branching pattern with three to five branches protruding off the trunk.The leaves are large, three veined, ellipsoid, and glandular at the base. The flowers are white and unisexual, and the fruit is three parted. The sap ranges in color from faint to deep red and occasionally a slight orange.

CHEMICAL COMPOSITION The sap, the part used medicinally, contains a single alkaloid, taspine.6The leaves contain additional alkaloids

Clinical Applications 889 Analgesic 889 Diarrhea 889 Herpes Simplex Viral Lesions 889 Dosage 889 Toxicology 889 Drug Interactions 889

(isoboldine, norisoboldine, manoflorine, thaliporphine, glaucine, and taspine). The sap consists primarily of proanthocyanidins (90%) but also contains crolechinol; crolechinic acid; korberin A and B; 3',4-0-dimethylcedrusin; simple phenols and diterpenes; phytosterols; and trace amounts of 1,3,5-trimethoxybenzene and 2,4,6-trimethoxyphenol?BThe air-dried, pulverized bark contains campesterol, beta-sitosterol, stigmasterol, acetyl aleuritolicacid, catechin, gallocatechin, and beta-sitosterol glucoside (Figure 86-1).9

HISTORY AND FOLK USE Dragon's blood is widely used by the indigenous peoples of the Amazon basin, and the Spaniards reported that it was widely used in the Amazon region in the 1600~.'~JThe sap is applied to the skin for abrasions, cuts, scratches, blisters, bites, and strings. It is taken internally in dilute form for gastrointestinal distress (e.g., gastritis, gastric ulcer, intestinal infections and inflammation, diarrhea). It is used as a gargle for sore throat; a vaginal antiseptic; a hemostatic after childbirth; a topical hemostatic for severe cuts and lacerations; and an analgesic applied directly to molar toothaches.12It is also taken internally for wound healing. The sap is used for various respiratory infections (tonsiltitis,pharyngitis, lung infections/pneumonia, influenza, and colds). 887

Antipro1iferative or Cytotoxic Effect, or Both Taspine, a dragon’s blood alkaloid, was cytotoxic in vitro against KB and V-79 cells in ~ i t r 0 . lDragon’s ~ blood induced apoptosis in human gastrointestinal cells in a dose-dependent manner, and cell proliferation decreased in all cells exposed to dragon’s blood for 48 hours.’* Overall, the effects were deemed similar to those observed with paclitaxel (Taxol).A sigruficant alteration of microtubular architecture was observed. Dragon’s blood significantly reduced cancer cell adhesion with more than 85% of cells remaining in suspension. When cells were transferred to another medium, they were unable to regain their ability to adhere.

Flgum 86-1 Taspine.

PHARMACOLOGY Analgesic Effect Dragon’s blood balm* had a sigruficant analgesic effect compared with a placebo balm in a series of animal e~periments.’~ Dragon’s blood completely prevented hyperalgesia induced by a protease and blocked hyperalgesia induced by prostaglandin. Dragon’s blood was analgesic even if the hyperalgesic stimuli were applied intradermally, suggesting that its active components can cross the skin. Dragon’s blood inhibited the responses of mesenteric arteries to calcitonin generelated peptide (a primary neurotransmitter of sensory afferent nerves) and attenuated the epithelial secretory response to capsaicin in guinea pigs, but not that of neurokinin-1 antagonist, suggesting a unique prejunctional and postjunctional effect on sensory afferent nerves. On the basis of pharmacologic results, researchers suggested that topical use of dragon’s blood may offer relief for conditions characterized by itching, pain, edema, redness, and discomfort.

Antidiarrheal Effect SP-303, a patented extractt from dragon’s blood sap, restored intestinal fluid accumulation to near-normal levels in mice administered cholera t0xin.14 Cholera toxin-induced diarrhea results from the irreversible activation of adenylate cyclase leading to elevated cyclic adenosine monophosphate (CAMP).SP-303 did not affect CAMPlevels, suggesting that it acts at a distal site.

Antimicrobial Effect Several phenolic compounds and diterpenes isolated from dragon’s blood demonstrated potent activity against Bacillus subtilis and Escherichia coli in ~ i t r 0 . IDragon’s ~ blood sap sigruficantlyinhibited growth of gram-positive and gram-negative organisms in vitro, including Proteus vulgaris, E. coli, and Staphylococcus aureus.16 ~

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‘1% Zangrado Bute Bite Balm. Rainforest Phytoceuticals,LLC, Delmar, NY. +SP-303 is available as a topical drug (Wend) and an internal drug (Pmvir),

Shaman Pharmaceuticals.South San Francisco, Calif.

Antiulcerogenic Effect Dragon’s blood administered at dilutions of 1:lOOO and 1:10,000in drinking water assisted the healing of ulcers in rats with acetic acid-induced gastric ulcers.19 These doses are equivalent to the doses used in traditional medicine for the treatment of gastric disorders. Dragon’s blood also reduced myeloperoxidase activity, the upregulation of proinflammatory genes tumor necrosis factoralpha, inducible nitric oxide synthase, interleukin-1-beta, and cyclooxygenase 2. Its healing of ulcers was comparable to that of a combination of penicillin and streptomycin and resulted in ulcers that were smaller, less inflamed, and possessing lower bacterial content. The authors note that the dragon’s blood in its natural, whole resin form is effective at lower doses than the patented extract of dragon’s blood (SP-303). They speculate that dragon’s blood’s polyphenolic fraction activates fibroblasts, resulting in improved wound healing, and note that the sap contains trace amounts of compounds that are 30 times more potent than penicillin.

Antiviral Effect Various compounds in dragon’s blood have shown antiviral activity against influenza, parainfluenza, herpes simplex viruses types I and II, and hepatitis A and B in vitro?O A patented extract of dragon’s blood sap (SP-303) showed antiviral activity against respiratory syncytial virus (RSV) and appeared to inhibit viral penetration of the host cell.2l SP-303 also showed antiviral activity against two strains of herpes simplex virus (HSV) type 1,as well as a strain of HSV type 2 at a dose comparable to that of acyclovir.” The compound significantly reduced HSV lesion formation in the mouse vaginal model (applied topically in a 5% to 10% preparation). At aerosol doses of 0.5 to 9.4 mg/kg/day, SP-303 significantly increased the survival of mice lethally infected with RSV? At aerosol doses of 1.3 to 9.8, it sigruficantly reduced lung titers of RSV in infected rats. SP-303 administered intraperitoneally also significantly reduced

Croton lechleri (Dragon’s Blood) pulmonary RSV titers in infected rats with a minimum efficacious dose of 3 mg/kg.” SP-303 administered once daily for 8 days beginning before or after influenza A infection in mice significantly reduced lung consolidationbut was lethally toxic at the dose of 30 mg/kg/day. The drug administered as an aerosol (2.5,5,10 mg/ml) for 1hour twice daily also reduced lung consolidation in animals. However, when administered before virus exposure, SP-303 treatment resulted in sigruficant increases in mean day to death but did not inhibit lung virus titer.%

Cicatrizant Effect Dragon’s blood forms a barrier by coprecipitating with proteinsand other matrix elements and, in the process, fosters accelerated wound healing with reduced pain, inflammation, and scarringF6 Taspine showed a dose-related cicatrizant effect when administered in vivo to mice.27

CLINICAL APPLICATIONS Analgesic Dragon’s blood sap offered rapid symptomaticrelief in a placebo-controlled study of its effect on insect Ten Terminex workers (who often suffer insect bites in their work) applied either dragon’s blood balm* or placebo balm to bites and recorded the results over a 3-month period. When workers suffered multiple simdtaneous bites, they used both balms on different bites and compared the results. Most of the treated bites were caused by fire ants that elicit initial pain, followed by intense itching that can persist for weeks.

Diarrhea SP-303, a patented compound extracted from dragon’s blood sap, shortened by 21%the duration of diarrhea in a double-blind, randomized, placebo-controlled study of 184 patients suffering diarrhea after traveling to Jamaica and Mexic0.2~Patients were treated four times a day for 2 days with 125 mg, 250 mg, or 500 mg doses or placebo. The drug was most effective at the 125- and 250-mg doses and was well tolerated. In another doubleblind, randomized, placebo-controlled study, SP-303 significantly reduced stool weight and abnormal stool frequency in HIV-positive patients with diarrhea.30Positive results were seen by day 4 in the 26 members of the active group treated with 500 mg orally of SP-303every 6 hours compared with the 25 patients in the placebo group.

Herpes Simplex Viral Lesions Virend (a topical formulation of SP-303) showed a trend toward decreased lesion pain in a double-blind,

‘1% Zangrado Bute Bite Balm, Rainforest Phytoceuticals,LLC. Delmar, NY.

placebo-controlledstudy of 45 patients positive for HIVantibody with active-phase, culture-positive genital or perineal herpes simplex viral lesions, or both.3I A statistical analysis showed Virend to be more active in patients with overall smaller lesion areas. Two patients experienced pain and burning after applying Virend, and one withdrew from the study for this reason. In another open-label study, nine AIDS patients with herpes simplex virus unresponsive to acyclovir were treated with SP-303.32The drug showed a transient positive effect but failed to completely heal or cause cessation of virus shedding. Several patients complained that SP-303 caused pain or burning on application.

DOSAGE In traditional medicine, the internal dose is 3 to 20 drops mixed in a beverage, 1 to 3 times daily for up to 3 ~ e e k s . ~The N pure sap is applied topically as needed. Doses of 125 and 250 mg of SP-303, administered every 6 hours, were more effective at reducing the duration of traveler’s diarrhea than the 500 mg dose.35

TOXlCOLOGY Dragon’s blood, used topically or at low internal doses, is considered nontoxicx Mice treated with dragon’s blood or taspine hydrochloride for 17 months evidenced a lack of carcinogenic or tumor-promoting effe~ts.3~ Taspine was nontoxic to human foreskin fibroblasts at concentrationsbelow 150 ng.= The alkaloid had no effect in vitro on cell proliferation and did not have a carcinogenic or tumor-promoting effect in vitro. The compound 3’,4-0-dimethycedrusin, isolated from dragon’s blood, did not stimulate cell proliferation but instead inhibited thymidine incorporation while protecting cells against degradation in a starvation medium.39 In another in vitro experiment, dragon’s blood had a negligible effect on proliferation of endothelial cells and was not cytotoxic.40SP-303, a patented dragon’s blood extract, was toxic to mice at 16 mg/kg/day, as evidenced by weight loss and a decrease in survival time compared with controls.41A similar weight loss occurred in rats at a dose of 18.7 mg/kg. SP-303 injected intraperitoneally caused sigruficant weight loss and death in rats at doses of 30 mg/kg/day. However, no toxicity was observed following oral administration of up to 270 mg SP-303 daily.“

LDesmarchelier C, Schaus FW. Sixty medicinal plants from the Peruvian Amazon, ecology, ethnomedicine and bioactivity. Lima, Peru: Grafica Bellido, 2000:12&129. 2. BorgesJR, King SR,Hughes K, et al. Conservationof b i d t u r a l diversity and benefit sharing mechanisms in the Amazon: C m t a leddm’,a traditional indigenous resource. presented at the INPI/EC meeting ‘‘Role of intellectd property protection in the field of biodiversity and traditional knowledge,” Manaus, Brazil, September 9-11,2001. 3. Miller MJ, Vergnolle N, McKnight W, et al. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado. J Invest Dennatol2001;117:725-730. 4. Pieters L, de Bruyne T, Claeys M, et al. Isolation of a dihydrobenzofuran lignan from South American dragon’s blood (Croton spp.) as an inhibitor of cell proliferation. J Nat Prod 1993;56:899-906. 5.Desmarchelier C, Schaus FW. Sixty medicinal plants from the Peruvian Amazon, ecology, ethnomedicine and bioactivity. Lima, Peru: Grafica Bellido, 2000:126-129. 6.Milanowski DJ, Winter RE, Elvin-Lewis MP, Lewis WH. Geographic distribution of three alkaloid chemotypes of Croton lechleri. J Nat Prod 2002;65:814819. 7. Cai Y, Evans FJ,Roberts MF, et al. Polyphenolic compounds from Croton Zechlm’. Phytochemistry 1991;30:2033-2040. 8. Miller MJ, MacNaughton WK, Zhang XJ, et al. Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado. Am J Physiol Gastrointest Liver Physiol 2000;279: G192G200. 9.Lopes Pereira Peres MT, Delle Monache F, Pizzolatti MG, et al. Analgesic compounds of Croton urucurunu Baillon. Pharmco-chemical criteria used in their isolation. Phytother Res 1998;12209-211. 10. Miller MJ, MacNaughton WK, Zhang XJ, et al. Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado. Am J Physiol Gastrointest Liver Physiol2OOO;279:G192-G200. 11. Milanowski DJ, Winter RE, Elvin-Lewis MP, Lewis WH. Geographic distribution of three alkaloid chemotypes of Croton lechleri. J Nat Prod 2002;65:814819. 12. BorgesJR,King SR, Hughes K, et al. Conservation of b i d t u r a l diversity and benefit sharing mechanisms in the Amazon: Croton lechlm’,a traditional indigenous resource.Prepared for the INPI/EC meeting “Role of intellectual property protection in the field of biodiversity and traditional knowledge,” Manaus,Brazil, September 9-11,2001. 13.Miller MJ, Vergnolle N, McKnight W, et al. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado. J Invest Dennatol2001;117725-730. 14.Orozco-Topete R, Sierra-Madero J, et al. Safety and efficacy of V i i n d for topical treatment of genital and anal herpes simplex lesions in patients with AIDS.Antiviral Res 199735:91-103. 15.Chen ZP,Cai Y, Phillipson JD.Studies on the anti-turnour, antibacterial, and wound-healing properties of dragon’s blood. Planta Med 1994;60:541-545. 16. Carpenter MR, Goodman-Snitkoff GW, et al. Antibacterial effects of sangre de grado on gram-positive and gram-negative bacteria. Abstr Gen Meet Am Soc Microbiol2001;101:38. 17.Itokawa H, Ichihara Y, Mochizuki M, et al. A cytotoxic substance from sangre de grado. Chem Pharm Bull (Tokyo) 199139:1041-1042. 18. Sandoval M,Okuhama NN, Clark M, et al. Sangre de grado Croton pulunostigma induces apoptosis in human gastrointestinal cancer cells. J Ethnopharmacol2002;80.121-129. 19. Miller MJ, MacNaughton WK, Zhang XJ, et al. Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado. Am J Physiol Gastrointest Liver Physiol2000;279:G192-G200. 20. Williams JE. Review of antiviral and immunomodulating properties of plants of the Peruvian rainforest with a particular emphasis on una de gato and sangre de grado. Alt Med Rev 2001;6567-579.

21. Bamard DL, Huffman JH, Meyerson LR, Sidwell RW. Mode of inhibition of respiratory syncytial virus by a plant flavonoid, SP-303. Chemotherapy 1993;33212-217. 22. Bamard DL, Smee DF, Huffman JH, et aI. Antiherpesvirus activity and mode of action of SP-303, a novel plant flavonoid. Chemotherapy 1993;39:203-211. 23. Gilbert BE, Wyde PR, Wilson SZ, Meyerson LR. SP-303 small-particle aerosol treatment of influenza A virus infection in mice and respiratory syncytial virus in cotton rats. Antiviral Res 1993;21: 37-45. 24. Wyde PR, Ambrose MW,Meyerson LR, Gilbert BE. The antiviral activity of SP-303, a natural polyphenolic polymer, against respiratory syncytial and parainfluenza type 3 viruses in cotton rats. Antiviral Res 1993;20:145-154. 25. Sidwell RW, Huffman JH, Moscon BJ, Warren Rl? Influenza virusinhibitory effects of intrapentoneally and aerosol-administered SP-303, a plant flavonoid. Chemotherapy 1994;4042-50. 26. Miller MJ, Vergnolle N, McKnight W, et al. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado. J Invest Dermatol2001;117725-730. 27. Vaisberg AJ, Milla M, Planas MC, et al. Taspine is the cicatrizant principle in sangre de grado extracted from Croton lechleri. Planta Med 198955140-143. 28. Miller MJ, Vergnolle N, McKnight W, et al. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado. J Invest Dermatol2001;117725-730. 29. DiCesare D, DuPont HL, Mathewson JJ, et al. A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am J Gastroenterol2002;972585-2588. 30. Holodniy M, Koch J, Mistral M, et al.A double blind, randomized, placebo-controlled phase 11 study to assess the safety and efficacy of orally administered SP-303 for the symptomatic treatment of diarrhea in patients with AIDS. Am J Gastroenterol 1999;94: 3267-3273. 31. Orozco-Topete R, Sierra-Madero J, Cano-Dominguez C, et al. Safety and efficacy of Virend for topical treatment of genital and anal herpes simplex lesions in patients with AIDS. Antiviral Res 1997;3591-103. 32. Safrin S, McKinley G, McKeough M, et al. Treatment of acyclovirunresponsive cutaneous herpes simplex virus infection with topically applied SP-303. Antiviral Res 1994;25185-192. 33. Miller MJ, MacNaughton WK, Zhang XJ, et al. Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado. Am J Physiol Gastrointest Liver Physiol 2000;279: G192G200. 34.Borges JR, King SR, Hughes K, et al. Conservation of biocultural diversity and benefit sharing mechanisms in the Amazon: Crotun lechlm‘, a traditional indigenous resource. Prepared for the INPI/EC meeting “Role of intellectual property protection in the field of biodiversity and traditional knowledge,” Manaus,Brazil, September 9-11,2001. 35. DiCesare D, W o n t HL, Mathewson JJ, et al. A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am J Gastroenterol2002;97:2585-2588. 36. Duke JA. Handbook of medicinal herbs, ed 2. Boca Raton, Fla: CRC Press, 2002256. 37. Villegas LF, Frenandez ID, Maldonado H, et al. Evaluation of the wound-healing activity of selected traditional medicinal plants from Peru. J Ethnopharmacol1997;55193-200. 38.Vaisberg AJ, Milla M, Planas MC, et al. Taspine is the cicatrizant principle in sangre de grado extracted from Croton lechleri. Planta Med 1989;55:140-143.

Croton lechleri (Dragon’s Blood) 39. Sandoval M, Okuhama NN, Clark M, et al. S a n p de grado Croton palanosfigma induces apoptosis in human gastrointestinal cancer cells. J Ethnophamacol2002;80:121-129. 40.Chen ZP, Cai Y, Phillipson JD.Studies on the anti-hunour, antibacterial, and wound-healing properties of dragon’s blood. Planta Med 1994;60:541-545. 41.Gilbert BE, Wyde PR, Wilson SZ, Meyerson LR. SP-303 smallparticle aerosol treatment of influenza A virus infection in mice and

respiratory syncytid virus in cotton rats. Antiviral Res 1993;21: 37-45. 42. Wyde PR, Ambrose W ,Meyerson LR, Gilbert BE. The antiviral activity of SP-303, a natural polyphenolic polymer, against respiratory syncytial and parainfluenza type 3 viruses in cotton rats. Antiviral R ~ s199330145-154.

Curcuma longa (Turmeric) Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS General Description 893

Neuroprotective Effects 896 Antimicrobial Effects 896

Chemical Composition 893 History and Folk Use 893 Pharmacology 893 Antioxidant Effects 894 Anticarcinogenic Effects 894 Antiinflammatory Effects 894 Cardiovascular Effects 895 Hepatic Effects 895 Gastrointestinal Effects 895

Curcuma longu (family: Zingiberaceae) Common names: turmeric, curcuma, Indian saffron

GENERAL DESCRIPTION Curcuma longu, a perennial herb of the ginger family, is cultivated extensively in India, China, Indonesia, and other tropical countries. It has a thick rhizome from which arise large, oblong, and long-petioled leaves. The rhizome is the part used; it is usually cured (boiled, cleaned, and sun dried) and polished.'

CHEMICAL COMPOSITION Turmeric contains the following*,2: 4% to 14% of an orange-yellow volatile oil that is composed mainly of turmerone, atlantone, and zingiberone 0.3% to 5.4% curcumin Sugars (28% glucose, 12% fructose, 1%arabinose) Resins Protein Vitamins Minerals

Figure 87-1 shows the chemical structure of turmeric.

Clinical Applications 896 Cancer Prevention and Treatment Adjunct Inflammation 896

896

Toxicology 897 Drug Interactions 897 Dosage 897

HISTORY AND FOLK USE Turmeric is the major ingredient of curry powder and is also used in prepared mustard. It is extensively used in foods for both its color and flavor. In addition, turmeric is used in both the Chinese and Indian (Ayurvedic) systems of medicine as an antiinflammatoryagent and in the treatment of numerous conditions including flatulence, jaundice, menstrual difficulties, bloody urine, hemorrhage, toothache, bruises, chest pain, and colic.' Turmeric poultices are often applied locally to relieve inflammation and pain.

PHARMACOLOGY Turmeric and its derivatives have a great deal of pharmacologic activity? Although a number of components have demonstrated activity, the volatile oil components and curcumin are believed to be the most active components. Turmeric has been described as follows: An effective antioxidant Anticarcinogenic Antiinflammatory A cardiovascular protectant Hepatoprotective 893

Pharmacology of Natural Medicines The protective effects of turmeric and its derivatives are only partially explained by its direct antioxidant and fwe radical-scavenging effects. It also inhibits nitrosamine formation, enhances the body’s natural antioxidant system, increases the levels of glutathione and other nonprotein sulfhydryls, and acts directly on several enzymes and gene loci. A gastrointestinal carminative and protectant Neuroprotective An antimicrobial agent

Antioxidant Effects Turmeric extracts exert significant antioxidant activity. Although both water- and fatsoluble extracts have been shown to be effective antioxidants in various in vitro and in vivo models, CurCulTLinis the most potent component.% The antioxidant activity of curcumin is comparable to standard antioxidants like vitamins C and E and butylated hydmxyanisole (BHA) and butylated hydroxytoluene (Bm.33 Because of its bright yellow color and antioxidant properties against lipid peroxidation, m u m i n is used in butter, margarine, cheese, and other food products. For active oxygen species, curcumin is slightly weaker than vitamin C but stronger than vitamin E and superoxide dismutase. Against hydroxyl radicals, curcumin offers greater effectiveness than these ita am ins.^,^,^ Not all of the antioxidant properties of turmeric are due to curcumin alone, as the aqueous extract of turmeric is more effective against superoxide than curcumin and is much stronger in inhibiting oxidative damage to DNA.5,6 The antioxidant activities of curcumin may in part explain the anticarcinogenic and cardioprotective capacity of this spice (see later). In vitro and in vivo studies have also shown this antioxidant action to be neuroprotective as well.8

Anticarcinogenic Effects The antineoplasticeffects of turmeric and curcumin have been demonstrated at all steps of carcinogenesis: initiation, promotion, and progression. In addition to inhibiting the development of cancer, several studies suggest that curcumin can also promote cancer regression. Turmeric and curcumin are nonmutagenic and have been shown to suppress the mutagenicity of several common mutagens (e.g., cigarette smoke condensates, benzopyrene, 7,12-dimethylbez[a]anthracene), as do chili and capsaicin?-” Turmeric and curcumin compounds have been found to induce apoptosis in lung and colon tumor cell l i n e ~ . ’ ~Turmeric J~ and curcumin have also demonstrated impressive anticancer effects against a number of chemical carcinogens on a wide range of cell types in both in vitro and in vivo Curcumin has demonstrated an impressive ability to reduce the levels of urinary mutagens.22D

Antiinflammatory Effects The volatile oil fraction of C. longu has been demonstrated to possess antiinflammatory activity in various experimental models (e.g., Freund’s adjuvant-induced arthritis,formaldehyde- and carrageenan-induced paw edema, and cotton pellet and granuloma pouch tests).”z Its effects in these studies were comparable to cortisone and phenylbutazone. Even more potent in acute inflammation is curcumin.2628Curcumin is as effective as cortisone or phenylbutazone in models of acute inflammation but only half as effective in chronic models. However, while phenylbutazone and cortisone are associated with significant toxicity, curcumin displays virtually no toxicity (see later discussion on toxicology). The rank in order of potency of curcumin analogs, cortisone, and phenylbutazone in carrageenan-induced paw edema is as follow^^^,^^: sodium curcuminate > tetrahydrocurcumin > curcumin > cortisone > phenylbutazone > triethylcurcumin Sodium curcuminate can be produced by mixing turmeric with slaked lime. This mixture, applied as a poultice, is an ancient household remedy for sprains, muscular pain, and inflamed Curcumin’s counterirritant effect may also be a major factor in its topical antiinflammatory acti0n.2~ Capsaicin, a similar pungent principle from Capsicum frutescens (cayenne pepper), has been shown to be quite effectiveas a topical pain reliever in cases of postherpetic neuralgia and arthritis. Both capsaicin and curcumin deplete nerve endings of the neurotransmitter of pain, substance P.29 Used orally, curcumin exhibits many direct antiinflammatory effects Inhibition of leukotiene formation Inhibition of platelet aggregation Promotion of fibrinolysis Inhibition of neutrophil response to various stimuli involved in the inflammatory process Stabilization of lysosomal membranes In addition to its direct antiinflammatory effects, curcumin also appears to exert some indirect effects. In models of chronic inflammation, curcumin is much less active in adrenalectomized animals.Possible mechanisms

of action include the following: with a curcuma extract (turmeric) on abnormally high plasma fibrinogen levels (values in mg/dl before and after a 15-day treatment)

Stimulation of the release of adrenal corticosteroids ”Sensitizing” or priming cortisol receptor sites, thereby potentiating cortisol action Increasing the half-life of endogenous cortisol through alteration of hepatic degradation Subiect number

Sex

Aae (vr) Before

After

Cardiovascular Effects

1

M

The effects of turmeric and curcumin on the cardiovascular system include the lowering of cholesterol level^^"^ and the inhibition of platelet aggregation.%J7 This is of great sigruficance in preventing atherosclerosis and its complications. In one small study, 10 healthy volunteers received 500 mg of curcumidday for 7 days.35A significant decrease in the level of serum lipid peroxides of 33%, increase in high-density lipoprotein cholesterol of 29%, and a decrease in total sem cholesterol of 11.63%was observed. Given the side-effect profile of standard cholesterol-lowering medications, more studies on this effect of curcumin are necessary. As an acute phase reactant, the protein fibrinogen circulates in the blood and provides the material from which insoluble fibrin clots can form during coagulation. It has been shown that high levels of plasma fibrinogen concentration can predict future coronary heart disease in men and women.%In a preliminary study of 30 apparently healthy volunteers, baseline levels of fibrinogen were recorded, and 8 subjects were found to have high plasma fibrinogen (above 350 11g/m1).3~These subjects were given a hydroalcoholic extract of C. longu containing 20 mg of curcumin for 15 days. Impressively, curcuma administration decreased the fibrinogen levels to values in the 240 to 290 mg/dl range (Table 87-1). In other studies, adding as little as 0.1% curcumin to a high-cholesterol rat diet decreases cholesterol levels to one half of those found in rats fed cholesterol but no c u r ~ u m i n .This ~ indicates that even at small doses, curcumin may be effective. Curcumin’s cholesterol-lowering actions include interfering with intestinal cholesterol uptake; increasing the conversion of cholesterol into bile acids by increasing the activity of hepatic cholesterol-7-alpha-hydroxylase, the rate-limiting enzyme of bile acid synthesis; and increasing the excretion of bile acids via its choleretic

2

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31

476

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Turmeric’s and curcumin’s action on inhibiting platelet aggregation appears mediated by inhibiting the formation of thromboxanes (a promoter of aggregation) while simultaneously increasing prostacyclin (aninhibitor of aggregati~n).~J’

Hepatic Effects Curcumin has exhibited hepatoprotection similar to that of glycyrrhizin and silymarin (see Chapters 99 and

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125 for further discussion) against carbon tetrachloride and galactosamine-induced liver injury.2~~~ This protection is largely a result of its potent antioxidant activity. Similar results are seen with Javanese turmeric (Curcurnu xunthorrhiziu). Mice given intraperitoneal injections of the hepatoxic drugs carbon tetrachloride (32 mg/kg) and acetaminophen (600 mg/kg) experienced significantly decreased liver damage, as measured by serum glutamate oxaloacetate (SGOT)and serum glutamate pyrur m (SGPT) when treated with 100 mg/kg vate t of turmeric.“ The antioxidant and hepatoprotective effects alone would support turmeric’s historical use in liver disorders; however, turmeric and curcumin also exert antiinflammatory and choleretic effects. The increases of SGOT and SGPT commonly seen in experimental models of inflammation have been prevented by curcumin.26 Curcumin is an active choleretic, increasing bile acid output by more than 100Y0.~ In addition to increasing biliary excretion of bile salts, cholesterol, and bilirubin, curcumin also increases the solubility of the bile.4O This suggests a benefit in the prevention and treatment of cholelithiasis.

Gastrointestinal Effects Turmeric and its components exert a number of beneficial effects on the gastrointestinal system. Turmeric’s long use as a carminative has significant research support.2 Specifically, curcumin has been shown to inhibit

Pharmacology of Natural Medicines gas formation by Clostridium petfringens and in rats given diets rich in flatulence-producing foods. In addition, sodium curcuminate has been shown to inhibit intestinal spasm, and another compound from turmeric, p-tolymethylcarbinol, has been shown to increase the secretion of secretin, gastrin, bicarbonate, and pancreatic enzymes? As a component of curries and spicy foods, there is some concern that turmeric may be irritating to the stomach. However, several studies have shown turmeric to be beneficial to gastric integrity. Turmeric and curcumin have been shown to increase the mucin content of the stomach and exert gastroprotective effects against ulcer formation induced by stress, alcohol, indomethacin, pyloric ligation, and re~erpine.2,~~ However, at high doses, curcumin or turmeric may be ulcerogenic (see later discussion on toxicology).

Neuroprotective Effects A number of animal studies have explored the effect of curcumin on nervous tissue pathology. For example, studies have suggested a neuroprotective role of curcumin in stroke models! Curcumin has been shown to reduce plaque burden in models of Alzheimer’s disease.44 Curcumin has also been shown to decrease naphthalene and 4hydroxy-2-nonenal-induced cataract formation on the lens by decreasing the rate of apoptosis and subsequent opacification resistance of the The authors postulate that induction of the glutathione Stransferase, which acts to decrease lipid peroxidation, was probably responsible for the cataractogenesisinhibiting effects.

Antimicrobial Effects Alcohol extracts and the essential oil of C. longu were shown in one study to inhibit the growth of most organi s m occurring in cholecystitis (i.e., Sarcinu, G u m u , Corynebuctm’um, and Clostridium)? Other microorganisms that are inhibited include Stuphylococcus, Streptococcus, Bacillus, Entumoebu histolyticu, and several pathogenic f ~ n g i .The ~,~ concentrations ~ used in these studies were relatively high 0.5 to 5 mg/ml of the alcohol extract and essential oil, and 5 to 100 mg/ml of curcumin.

CLINICAL APPLICATIONS Turmeric and curcumin have several clinical applications. Most notable are the following: Cancer prevention and treatment adjunct Inflammation Atherosclerosis Liver disorders Cholelithiasis Irritable bowel syndrome

Cancer Prevention and Treatment Adjunct As discussed earlier, turmeric and cucurninhave demonstrated sigruficant protective effects against cancer development in experimental studies in animals. Human research is showing similar results. In one human study, 16 chronic smokers were given 1.5 g of turmeric daily while a group of 6 nonsmokers served as a control g r o u ~At. ~the end of the 30-day trial, the smokers receiving the turmeric demonstrated significant reduction in the level of mutagens excreted in the urine. These results are quite significant, as the level of urinary mutagens is thought to correlate with the systemic load of carcinogens and the efficacy of detoxification mechanisms. Due to widespread exposure to smoke, aromatic hydrocarbons, and other environmental carcinogens, the frequent use of turmeric as a spice appears warranted. Turmeric extracts and curcumin have demonstrated direct antitumor results in a number of experimental models of skin, epithelial, stomach, lung, and liver cancers.12r18APJ This effect has also been substantiated in a human Sixty-twopatients with either ulcerating oral or cutaneous squamous cell carcinomas who had failed to respond to the standard treatments of surgery, radiation, and chemotherapy were given either an ethanol extract of turmeric (for oral cancers) or an ointin Vaseline. The ointment containing 0.5% curcment or extract was applied topically three times daily. At the end of the 18-month study, the treatment was found to have been effective in reducing the smell of the lesion (90%), itching, exudate (70%), pain (so%), and size of the lesion (10%).Although these are not spectacular results, it must be pointed out that this patient population had failed to respond to standard medical treatment. Although more human studies on the use of turmeric and curcumin in cancer are necessary, ample evidence supports their use in cancer prevention and as adjuncts in an overall cancer treatment plan.

Inflammation C. longu has been used in Ayurvedic medicine, both locally and internally, in the treatment of sprains and inflammation. This use seems to be substantiated not only by the experimental studies described earlier, but also by clinical inve~tigations.~~3 In one double-blind crossover clinical trial in patients with rheumatoid arthritis, curcumin (1200 mg /day) was compared with phenylbutazone (300 mg/day). The improvements in the duration of morning stiffness, walking time, and joint swelling were comparablein both groups.53However, although phenylbutazone is associated with sigruficant adverse effects, curcumin has not been shown to produce any side effects at the recommended dosage level.

Curcurna longa (Turmeric)

In another study, which used the postoperative inflammation model for evaluating nonsteroidal antiinflammatory drugs (NSAIDs), curcuinin was again shown to exert comparable antiinflammatory action to phenylbutazone.59Although c urhas an antiidlammatory effect similar to phenylbutazone and various NSAIDs, it does not possess dired analgesic action. Most likely due to its antiidammatory effects, topical application appears to be of benefit in wound The results of these studies indicate that turmeric or curcumin may provide benefit in the treatment of inflammation. Furthermore, the safety and excellent tolerability of curcumin compared with standard drug treatment is a major advantage.

DRUG INTERACTIONS No drug interactionshave been reported. Some theoretic concern has been raised that curcumin might increase the risk of bleeding of anticoagulant drugs due to its ability to decrease platelet aggregation.62

DOSAGE

Toxicity has not been reported at standard dosage levels. The oral LDNlevels for turmeric, its alcohol extracts, and curcumin have not been determined, as 2.5 g/kg fed to mice, rats, guinea pigs, and monkeys and 3 g/kg sodium curcuminate fed to rats resulted in neither mortality nor chromosomal aberrations in teratology tests?%% At high doses, curcumin or turmeric may damage the gastrointestinal system, as curcumin, with doses of 100 mg/kg body weight, is ulcerogenic in rats? Some studies have found sensitivity of mice to turmeric that resulted in hepatotoxi~ity.5~f" Curcumin toxicity has not been found in rats or other mammals, even at very high doses (5%to 10% by weight of diet).13Human studies suggest that curcumin is nontoxic to humans up to 8000 mg/day when taken by mouth for 3 months.61

On the basis of the evidence presented earlier, turmeric should be consumed liberally in the diet. When specific medicinal effects are desired, higher doses of turmeric can be given or extracts of C. Iongu or curcumin can be used. The recommended dosage for curcumin as an antiinflammatory is 200 to 400 mg three times a day. To achieve a similar amount of curcumin using turmeric would require a dosage of 4000 to 40,000 mg. Because the absorption of orally administered curcumin may be limited (pharmacokinetic studies in animals show that 40% to 85% of an oral dose of curcumin passes through the gastrointestinaltract u n ~ h a n g e d ~ 5 ~ ) , curcumin is often formulated in conjunction with bromelain to possibly enhance absorption. In addition, bromelain also has antiinflammatory effects (see Chapter 73). A curcumin-bromelaincombination is best taken on an empty stomach20 minutesbefore meals or between meals. Providing curcumin in a lipid base such as lecithin, fish oils, or essential fatty acids may also increase absorption. This combination is probably best absorbed when taken with meals.

1.h u n g A. Encyclopedia of common ~ t u r ai ln e e n t s used in food, drugs, and cosmetics. New York Wdey, 1980:313-314. 2. Ammon W, Wahl MA. Pharmacology of Curcum Zongu. Planta Med 1991571-7. 3. Toda S, Miyase T, Arichi H, et al. Natural antioxidants.Antioxidative compounds isolated from rhizome of Curcum Zonga L. Chem Pharmacol Bull (Tokyo)1985;33:1725-1728. 4. Zhao B, Li XJ, He RG, et al. Scavenging effect of extracts of green tea and natural antioxidants on active oxygen radicals. Cell Biophys 1989;14175-185. 5. Shalini VK, Srinivas L. Lipid peroxide induced DNA damage: pmtection by turmeric (Curcum Zongu). Mol Cell Biochem 1987;77:3-10. 6. SrinivasL, Shalini VK. DNA damage by smoke. Protection by turmeric and other inhibitors of ROS. Free Radical Biol Med 1991;11:277-283. 7. Sharma OP. Antioxidant properties of curcumin and related compounds. B i d e m Pharmacol1976;25:1811-1825. 8. Thiyagarajan M, Sharma SS. Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci 2004;74969-985. 9. Jensen NJ. Lack of mutagenic effect of turmeric oleoresin and curcumin in the salmonella/mammalian microsome test. Mutat Res 1982;105:393-396.

10. Nagabhushan M, Amonkar AJ, Bhide SV.In vitro antimutagenicity of curcuminagainst environmentalmutagens. Food Chem Toxic01 1987;25:545-547. 11. Nagabhushan M, Bhide SV.Nonmutagenicity of curcurnin and its antimutagenicaction versus chili and capsaicin. Nutr Cancer 1986; 8201-210. 12. Radhakrishna Pillai G, SrivastavaAs,Hassanein TI, et al. Induction of apoptosis in human lung cancer cells by curcumin. Cancer Letters 2004;208163-170. 13. Samaha H!3, Kelloff GJ, Steele V, et al. Modulation of apoptosis by sulindac, curcumin,phenylethyl-3-methylcaffeate,and 6-phenylhexyl isothiocyanate:apoptotic index as a biomarker in colon cancer chemopmention and promotion. Cancer Res 1997571301-1305. 14. Jiang TL, Salmon SE, Liu RM. Activity of camptothecin, harringtonin, catharidin and cucumae in the human tumor stem cell assay. Eur J Cancer Clin Oncol1983;19263-270. 15.Mehta RG, Moon RC. Characterization of effective chemopreventive agents in mammary gland in vitro using an initiationpromotion protocol. Anticancer Res 1991;11:593-596. 16.Kuttan R, Bhanumathy ,'F Nirmala K, et al. Potential anticancer activity of turmeric (Curcum Zongu). Cancer Lett 1985;29: 197-202.

TOXICOLOGY

17. Soudamini NK,Kuttan R Inhibition of chemical carcinogenesis by curcumin.J EthnophannaCOl1989;27227-233. 18. Azuine M, Bhide S. Chemopreventive effect of turmeric against stomach and skin tumors induced by chemical carcinogens in Swiss mice. Nutr Cancer 1992;1777-83. 19.Nagabhushan N, Bhide SV. Curcumin as an inhibitor of cancer. J Am Coll Nutr 1992;11:192-198. 20. Azuine MA, Kayal JJ,Bhide SV. Protective role of aqueous turmeric extract against mutagenicity of direct-acting carcinogens as well as benzo [alpha] pyrene-induced genotoxicity and carcinogenicity. J Cancer Res Clin Oncol1992;118:447-452. 21. Boone CW,Steele VE,Kelloff GJ. Screeningof chemopreventive (antiCarcinogenic)compounds in rodents. Mutat Res 1992;267251-255. 22. Polasa K, Raghuram TC, Krishna TP, et al. Effect of turmeric on urinary mutagens in smokers. Mutagenesis 1992;7107-109. 23. Polasa K, Sesikaran B, Krisha TP,et al. Turmeric (Curcumlongdinduced reduction in urinary mutagens. Food Chem Toxic 1991; 29699-706. 24. Chandra D, Gupta SS. Anti-inflammatory and anti-arthritic activity of volatile oil of curcuma longa (Haldi). Indian J Med Res 1972;~138-142. 25. Arora RB, Kapoor V, Basu N, et al. Anti-inflammatory studies on Curcum longu (turmeric).Ind J Med Res 197159:1289-1295. 26.Srimal R, Dhawan B. Pharmacology of diferuloyl methane (curcumin),a non-steroidal anti-inflammatory agent. J Pharm Pharmacol 1973;25:447-452. 27. Mukhopadhyay A, Basu N, Ghatak N, et al. Anti-inflammatory and irritant activities of CurCuIILin analogues in rats. Agents Actions 1982; 12508-515. 28. Ghatak N, Basu N. Sodium curcuminate as an effective anti-inflammatory agent. Indian J Exp Biol1972;10235-236. 29. Patacchini R,Mag@ CA, Meli A. Capsaicin-Like activity of some natural pungent substances on peripheral ending of visceral primary afferents. Arch Pharmacoll990;342:72-77. 30.Srivastava R, Srimal RC. Modification of certain inflammationinduced biochemical changes by cumurnin.Indian J Med Res 1985; 81:215-223. 31.Srivastava R. Inhibition of neutrophil response by curcumin. Agents Actions 1989;28:29&303. 32.Flynn DL, Rafferty MF, Boctor AM. Inhibition of 5-hydroxyeicosatetraenoicacid (5-HITE)formation in intact human neutrophils by naturdy-occurring dmyheptanoids. Inhibitory activities of curcuminoids and yakuchinones. Prostaglandins Leukot Med 1986; 2357-360. 33. Rao DS,Sekhara NC, SatyanarayanaMN, et al. Effect of Ncumin on serum and liver cholesterol levels in the rat. J Nutri 1970;loO: 1307-1315. 34.Srinivasan K, Samaiah K. The effect of spices on cholesterol 7 alphahydroxylase activity and on serum and hepatic cholesterol levels in the rat. Int J Vitam Nutr Res 1991;61:364-369. 35. Soni KB, Kuttan R. Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers. Indian J Physiol Pharmacol1992;36:273-275. 36. Srivastava R, W h i t M, Srimal RC, et al. Anti-thrombotic effect of curcumin.Thmmb Res 1985;40:413-417. 37. Srivastava R, Puri V,Srimal RC, et al. Effect of curcuminon platelet aggregation and vascular prostacyclin synthesis. Arzneimittelforschung 1986;36:715-717. 38.Stone MC, Thorp JM. Plasma fibrinogen-a major coronary risk factor. J R Coll Gen Pract 198535565-569. 39. Ramirez Bosca A, Soler A, CarrionCutierrez MA, et al. An hydroalcoholic extract of Curcum h g u lowers the abnormally high values of human-plasma fibrinogen. Mech Ageing Dev 2OOO;114:207-210. 40.Ramprasad C, Sirsi M. Curcuma longu and bile secretion. Quantitative changes in the bile constituents induced by sodium curcuminate. I Sci Ind Res 1957:16C:108-110.

41. Kiso Y, Suzuki Y, Watanabe N, et al. Antihepatotoxic principles of Curcum Zongu rhizomes. Planta Med 1983;49185187. 42. Lm SC,Lin CC, Lin YH, et al. Protective and therapeutic effects of Curcum xanthom'hza on hepatotoxin-induced liver damage. Am J Chi Med 1995;23243-254. 43. Rafatullah S, Tariq M, Al-yahya MA, et al. Evaluation of turmeric c cur cum longa) for gastric and duodenal antiulcer activity in rats. J Ethnopharmacol1990;2925-34. 4.4.Lim GP, Chu T, Yang F, et al. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 2001;21:8370-8377. 45. Pandya U, !%h MK, i Jin GF, et al. Dietary curamin prevents ocular toxiaty of naphthalene in rats. Toxicol Lett 2000;115195-204. 46.Awasthi S, Srivastava SK, Piper JT, et al. Curcumin protects against 4-hydroxy-2-trans-nonenal-inducedcataract formation in rat lenses. Am J Clin Nutr 1996;64:761-766. 47. Lutomski J, Kedzia B, Debska W.[Effect of an alcohol extract and active ingredients from Curcum Zonga on bacteria and fungi]. Planta Med 1974;269-19. 48. Huang MT, Smart RC, Wong CQ, et al. Inhibitory effect of curcumin, chlorogenic aad, caffeic acid, and ferulic acid tumor promotion in mouse skin by 12-0-tetradecanoylphorbol-13-acetate. Cancer Res 1988;48:5941-5946. 49. Mukundan MA, Chacko MC, Annapurna W. Effect of turmeric and curcuminon BP-DNA adduds. Carcinogenesis 1993;14:493-496. 50. Singh SV, Hu X, Srivastava SK, et al. Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin. Cardnogenesis 1998;19:1357-1360. 51. Banerji A, Chakrabarti J, Mitra A, et al. Effect of curcumin on gelatinase A (MMP-2) activity in B16F10 melanoma cells. Cancer Lett 2004;211:235-242. 52. Kuttan R, Sudheeran PC, Josph CD. Turmeric and curcumin as topical agents in cancer therapy. Tumori 1987;7329-31. 53.Deodhar SD, Sethi R, Srimal RC. Preliminary studies on antirheumatic activity of curcumin (diferuloylmethane).Ind J Med Res 1980;71:632-634. 54.Satoskar RR, Shah !3J, Shenoy SG.Evaluation of anti-infhnmatory property of CurCuIILin(diferuloyl methane) in patients with postoperative inflammation. Int J Clin Pharmacol Ther Toxicol 1986;24.651-654. 55. Gopinath D, Ahmed MR, Gomathi K, et al. Dermal wound healing processes with curcumin incorporated collagen films.Biomaterials 2004;25:1911-1917. 56.Shankar TN, Shantha NV, Ramesh HP,et al. Toxicity studies on turmeric (CurcumZonga): acute toxicity studies in rats, guinea pigs & monkeys. Indian J Exp Biol1980;1873-75. 57. Wahlstrom B, Blennow G. A study on the fate of curamin in the rat. Ada Pharmacol Toxicol (Copenh) 1978;4386-92. 58. Ravindranath V, Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicology 1980;16259-265. 59. Deshpande SS,Lalitha VS, Ingle AD, et al. Subchmnic oral toxicity of turmeric and ethanolic turmeric extract in female mice and rats. Toxicol Lett 1998;95183-193. 60.Kandarkar SV, Sawant SS, Ingle AD, et al. Subchronic oral hepatotoxicity of turmeric in mice-histopathological and ultrastructural studies. Indian J Exp Biol1998;36:675-679. 61. Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of Curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001;21:2895-2900. 62. Shah BH, Nawaz Z, Pertani SA. Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling. Biochem Pharmacol 1999581167-1172.

Dehydroepiandrosterone Laurie I<. Mischley, NI) ,Alan K. Gaby, MI> CHAPTER CONTENTS Introduction 899

Dehydmepiandrosterone-sulfate Biochemistry 899 Clinical Applications 900 Aging 900 Depression 901 Alzheimer's Disease 901 Osteoporosis 901 Sexual Function 902 Cardiovascular Disease 902 Myotonic Dystrophy 902

INTRODUCTION Dehydroepiandrosterone (DHEA) is a steroid hormone secreted by the adrenal glands and to a lesser extent by the testes and ovaries. Circulating levels of DHEA and its ester, DHEA-sulfate (DHEA-S) are 20 times higher than those of any other adrenal steroid. Until recently, this hormone was considered to function primarily as a reservoir on which the body drew as a precursor for the formation of other hormones. Only in recent years has a physiologic role for DHEA begun to be elucidated. Although first identified in 1934, DHEA did not gain popularity until 1993, when French scientists claimed it was a cure for aging' based on the observation that DHEA levels peak in the late 20s and steadily decline thereafter. Indeed, epidemiologic evidence suggests that higher DHEA levels are associated with increased life expectancy2and enhanced well-being?" It has therefore been postulated that some of the manifestations of aging may be caused by the decline in DHEA that occurs with age. DHEA-S production varies profoundly throughout life. Circulatinglevels are high at birth but quickly decline to the point of being almost undetectable within a few months. Levels begin to increase in children 8 to 10 years of age (adrenarche) and peak in the second decade. Beginning in the early 30s, levels decline by 10% per

Cancer 902 Immunology 903 Systemic Lupus Erythematosus 903 Rheumatoid Arthritis 903 Inflammatory Bowel Disease 903 Toxicity 904 Drug Interactions 904 Dosage 904 Summary 904

decade (adrenopause) and then plateau around the age of 80 years?~~ Adrenopause results in an 80%loss of total DHEA production compared with young-adult values. Interestingly, these age-associated fluctuations (including the eventual decline) do not occur with any other adrenal steroid (Figure 88-1).

DEHYDROEPIANDROSTERONE-SULFATE BIOCHEMISTRY DHEA and its ester, DHEA-S, are the most abundant hormones in the blood stream. DHEA and DHEA-S undergo continuous interconversion with DHEA-S, representing approximately 80%of the total pool and acting primarily as a storage form.5 Because DHEA-S is present in much greater quantity than DHEA, has a longer half-life, and lacks the circadian fluctuation seen with DHEA, it is more reliably used in clinical laboratory assessment.6 Despite DHEA-S's status as the major secretory product of the human adrenal, an understanding of its physiologic roles remains elusive. Assessing whether the effects of DHEA are a direct result of the hormone, its metabolites, or a combination of the two has been difficult? Although often chemically classified as a weak androgen, little evidence of direct androgenic activity exists. Any androgenic activity is most likely mediated through its conversion to other, more potent androgens. 899

The biosynthesis of all sex steroids in humans proceeds through DHEA.8 As a steroid precursor, DHEA is converted to both estrogens and androgens, depending on the requirements of the target tissue. The majority of DHEA conversion to metabolites occurs within peripheral cells via the enzymes aromatase and steroid Men

30

1

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25

CLINICAL APPLICATIONS Previous studies have demonstrated a wide variety of beneficial effects in conditions such as diabetes, obesity, decreased immune function, atherosclerosis,and many of the disorders associated with normal aging. The problem with many of these studies is that they have been conducted using rodent models. Rodents have little endogenous DHEA and do not have levels that decrease with age. DHEA in rodent studies is often administered at supraphysiologic doses, calling into question the relevance to humans at physiologic doses.This review intends to base recommendationson human studies to the extent possible.

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sulfatase (STS), which are present in the majority of human cells (Figure 88-2). Effects of DHEA in humans vary significantly depending on the individual's age, gender, menopausal status, and DHEA levels. On a cellular level, the target tissue and intracellular enzyme availability shape the fate of the molecule? Given the variability of DHEA's metabolism, one should exercise caution when considering supplementation at high dosages (>lo mg/day for women and 30 mg/day for men).

O 20 30 40 50 60 70 80

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Figum 861 Decline of dehydroepiandrosterone in men and women with age. (From Labrie F, Luu-TheV, Labrie C, Simard J. Frontiers Neuroendocrinology 2001;22:185-212.)

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Preliminary results suggest DHEA may retard the aging process. In a study of 75 healthy subjects age 90 to 106 years, men with the highest DHEA-S levels had the highest level of functioning.1oSeveral other studies in

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Dehydroepiandrosterone elderly humans have supported an inverse correlation between DHEA levels and the degree of dependence in activitiesof daily living and mobility. In one study, plasma DHEA level was low in 80% of the male nursing home residents who required total care compared with 40% low in other nursing home residents and 6%in independently living men of comparable age."" In men older than 90 years of age, higher DHEA-S levels were associated with a higher body mass index and waist-to-hip ratio, taken as indices of the body's energy (fat) reserves. In women older than 90 years of age, DHEA-S levels were positively correlated with serum-free triiodothyronine (FT3) and inversely with triglycerides.1° In an attempt to determine whether DHEA supplementation would counteract defects associated with aging, 280 healthy individuals between the ages of 60 and 79 years old were given 50 mg of DHEA daily or placebo for a year. In women older than 70 years of age, there was a reduction in the amount of bone loss and an increase in most libido parameters. Women also showed improvements of skin status including greater hydration, epidermal thickness, sebum production, and pigmentation.12 Although DHEA levels do not appear to correlate significantly with cognitive f u n ~ t i o n ? , ~low J ~ serum DHEA-S has been associated with decreased psychologic well-being and symptoms of depression?

Depression An extensive study of depression in adolescents showed

approximately 30%have abnormally low DHEA level^,'^ and mean levels of DHEA in the saliva of depressed adults are lower than those in normal control subjects.15 Improvements in cognition have been observed after oral administration of DHEA to middle-aged and elderly depressed patients,16 and the antidepressant actions of DHEA have been demonstrated in several randomized controlled trial^.'^,'^ The ability of DHEA to affect depressive symptomatology seems to be most substantial where DHEA levels are low or in those with an elevated cortisol-to-DHEA ratio. Cerebrospinal fluid DHEA-S levels are highly correlated with serum levels? DHEA easily crosses the blood-brain barrier, and evidence suggests the brain synthesizes DHEA from ch~lesterol.'~The ability of DHEA to enhance mood may be related to its role in the central nervous system. As a neurosteroid, research suggests the hormone may play a vital role in regulation of neuronal excitability. DHEA supplementation has been shown to increase levels of beta-endorphin, bind NMDA receptors, act as an antagonist at GABA receptors, and protect against the deleterious effects of glucocorti~ o i d s . ' ~ In J ~rats, , ~ ~ DHEA has been shown to increase hypothalamic serotonin levels.2l These pharmacologic properties may help explain the efficacy of DHEA in mood disorders.

Depression Associated with Aging Results from several studies suggest that DHEA treatment (30 to 150 mg/day) may decrease depressive symptomatology in age-advanced patients with major depression or d y ~ t h y m i a . ~ ~Replacement J~,~D of DHEA (50 mg/day) in 50-year-olds for 6 months resulted in a significant increase in the sense of well-being in both men and women. Another study demonstrated that supraphysiologic dosages of 90 and 450 mg/day of DHEA was associated with a substantial benefit in the treatment of midlife-onset dysthymia in both men and women."

Hypoadrenalism Individuals with reduced adrenal function, and thus low DHEA production, commonly report symptoms of depression and dysthymia. Studies in hypoadrenal patients have demonstrated that replacement with 50 mg/day DHEA results in an improvement in mood and overall sense of well-being3

Elevated Cortisol-toDehydroepiandrosterone Ratio Elevated cortisol levels are well documented in depression, occurring in approximately 50% of cases.15 Hypercortisolemia has been shown to impair learning and memory in humans, and prolonged exposure to excess glucocorticoids leads to neuronal a t r ~ p h y .The ~ ~ ,neu~ rocognitive deficits observed in depressive disorder, therefore, may be partially attributable to glucocorticoid hypersecretion. DHEA possesses significant antiglucocorticoid activityF6 and it may be via this mechanism that administration of DHEA reduces neurocognitive deficits in major d e p r e s s i ~ n . ~ ~ ~ ~ ~

Alzheimer's Disease Low DHEA-S plasma levels appear to be a risk factor A decreased for the development of Alzheimer's di~ease.2~ concentration of DHEA-S in patients with Alzheimer's disease has been reported, but the significance of DHEA in dementia remains u n ~ l e a r . Several ~ ~ , ~ small studies using DHEA in the treatment of Alzheimer's disease have produced unimpressive r e s ~ l t s . 3 ~ - ~ ~

Osteoporosis The possible relationship between DHEA deficiency and osteoporosis was suggested by a study of women with Addison disease. In these patients, the onset of menopause was followed by an unusually rapid rate of bone loss. This accelerated bone loss was associated with marked reductions in plasma concentrations of DHEA and testosterone (94% and 63%lower, respectively, than those of healthy postmenopausal women).MThese findings suggest that DHEA or testosterone, or both, are essential for the maintenance of bone mass in postmenopausal women.

When bone mineral density was measured at the lumbar spine, hip, and radius in women 45 to 69 years old, 55 of the 105 women in the study were found to have low bone density. The average serum DHEA-S level was 60% lower in the women with low bone density than in those with normal bones. Women with low DHEA-S values were 40 times more likely to have osteoporosis than were women with normal DHEA-S levels. In contrast, there was no relationship between estrogen levels and bone density.35Another study of 29 postmenopausal women demonstrated a significant positive correlation between bone mineral content of the distal radius and ulna and age-adjusted serum DHEA levels.% DHEA might prevent osteoporosis by several mechanisms. At the time of menopause, the amount of DHEA manufactured by the ovaries declines by more than 60Y0.~~ As an important precursor molecule, this reduction affects the formation of other sex steroids known to contribute to bone formation. A doubleblind, placebocontrolled study of 50 mg/day DHEA supplementation demonstrated improved bone turnover and decreased osteoclastic activity in women older than 70 years.'* Treatment using transdermal DHEA cream for 1 year in postmenopausal women demonstrated sigruficantly increased serum osteocalcin levels and bone mineral density of the femur, while the bone alkaline phosphatase levels decreased.%

Sexual Function Treatment with 50 mg DHEA each morning in 24 women with adrenal insufficiency significantly increased the frequency of sexual thoughts, sexual interest, and satisfaction for both the mental and physical aspects of sexuality in a double-blind study.39

Erectile Dysfunction The first study to describe an inverse correlation between DHEA-S levels and the incidence of erectile dysfunction (ED) was the Massachusetts Male Aging Study, a community-based,random-sample observational survey of men 40 to 70 years old conducted from 1987 to 1989. More than half (52%) of the men in the study had minimal, moderate, or complete impotence.40In these men the degree of impotence was directly correlated with low serum DHEA-S levels. Follow-up research suggests that this is especially true for men younger than the age of 60 years.4I Additional double-blind, placebo-controlled studies have demonstrated that 50 mg DHEA/day given orally for 6 months resulted in improvement in all five domains of the International Index of Erectile Function (IIEF), which quantitatively describes an individual's ability to achieve or maintain an erection sufficient for satisfactory sexual perf~rmance.",~~ Response was most

substantial in individuals with hypertension or lack of an organic etiology for their condition.42There was no impact of DHEA treatment on serum prostate specific antigen, prolactin, testosterone, mean prostate volume, or mean postvoid residual urine v0lume.4~

Cardiovascular Disease Mean plasma DHEA-S levels were significantly lower in men with a history of heart disease than in men without such a history. In men with no history of heart disease as a baseline, a low plasma DHEA-S level (440p,g/dl) was associated with a more than threefold increase in the age-adjusted risk of death from cardiovascular disease.44 Similar findings were reported by although another epidemiologic investigation found only a modest protective effect of DHEA.& In women, no inverse association was found between DI-EA-S and cardiovascular disease. In fact, cardiovascular death rates were highest in women in the highest tertile of DHEA-S levels and lowest in the middle tertile (a U-shaped di~tribution).~~ Since the highest serum DHEA-S levels are often present in women with PCOS, and PCOS is associated with insulin resistance and hypothyroidism, this could explain why very high DHEA-S levels are associated with heart disease.

Myotonic Dystrophy Myotonic dystrophy is an autosomal dominant multisystem disorder characterized by muscle weakness and myotonia. Myotonic dystrophy is associated with low DHEA levels, and DHEA has thus been proposed as a therapeutic option. DHEA receptors have been identified on skeletal muscle, and their presence may account for some of the benefit of DHEA seen in such conditions.@ The intravenous administration of DHEA-S (200 mg/ day for 8 weeks) in 11 patients with myotonic dystrophy induced an improvement in muscle strength and a decrease of myotonia. Improvement in the activities of daily living occurred, and in the four patients with cardiac involvement, the symptoms of conduction block and a premature heartbeat also impr0ved.4~

Cancer Premenopausal women with breast cancer had significantly lower plasma levels of DHEA than age-matched controls without breast cancer, whereas postmenopausal women had significantly higher DHEA levels than agematched controls.50 In another study, women with DHEA levels in the highest tertile were 60% less likely to develop breast cancer than were women in the lowest In a prospective case-control study, serum DHEA and DHEA-S levels were significantly lower in individuals who subsequently developed bladder cancer than in those who did

These findings suggest that DHEA has anticancer activity and that low DHEA levels may be a risk factor for cancer, except in postmenopausal women. However, further research is required before guidelines can be developed regarding DHEA therapy and cancer. The observation that some postmenopausal women with breast cancer have elevated DHEA levels, as well as the fact that DHEA is converted in part to estrogen and testosterone, should be cause for concern. It is unknown whether the anticancer effects of DHEA are stronger than the potential prostate cancer-promoting effects of additional testosterone or the breast cancer-promoting effects of additional estrogen. This is a complicated issue, since the metabolism of DHEA is usually ”crossgender” (i.e., women get an increase in testosterone, whereas estrogen levels often do not change, and vice versa for men). Until those questions can be answered, DHEA therapy should be approached with caution in patients who are at risk for developing hormonedependent cancers.

Immunology Serum levels of DHEA-S and interleukin-6 (IL-6) are inversely correlated. IL-6 is one of the pathogenic mediators in inflammatory and age-related diseases such as polymyalgia rheumatica, rheumatoid arthritis, inflammatory bowel disease, osteoporosis, atherosclerosis, and possibly Alzheimer’s disease, Parkinson’s disease, and beta-cell malignan~ies.~~ IL-6 is a cytokine that stimulates hepatocytes to produce acute-phase reactants and B-lymphocytes to produce immunoglobulin. Levels of IL-6 correlated strongly with the erythrocyte sedimentation rate and rheumatoid factor titers.% It has been theorized that the increase in IL-6 production during the process of aging might be due, in part, to diminished DHEA secretion.53This theory is based on research demonstrating serum DHEA correlates negatively with serum IL-6. Exogenously administered DHEA inhibits IL-secretion in a U-shaped fashion, with serum concentrations equaling that of healthy controls exerting the greatest effect.53 In a double-blind study, administration of 50 mg/day of DHEA to postmenopausal women produced a twofold increase in natural killer cell activity and a 6% decrease in the proportion of T helper ~ells.5~ Although the increase in natural killer cell activity might be expected to enhance immune surveillance against cancer and viral infections, the decline in T helper cells could have adverse consequences. On the other hand, since DHEA is known to mediate T-cell responses156 the decline in T helper cells could merely be a reflection of enhanced T-cell function. Activation of immune function by DHEA has also been demonstrated in ageadvanced men.57

Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a chronic inflammatory connective tissue disorder that occurs predominantly in women. Several studies have demonstrated efficacy in patients with SLE when treated with 50 to 200 mg D H E A / ~ ~ Y .A~ *double-blind, -~~ placebocontrolled trial of women with SLE demonstrated the group receiving DHEA had a significant reduction in the number of disease flares and serious lupus-related adverse events, as well as improvement in the person’s global assessment.61 The effects of DHEA in autoimmune conditions such as SLE are likely due to a decrease in inflammatory cytokines such as IL-6. DHEA appears to decrease IL,-6 production (which is responsible for stimulating antibody production). IL-6 inhibition may curb antibody production and thus clinical manifestations of antibody-mediated disease^.^^,^^

Rheumatoid Arthritis A decreased DHEA-S serum concentration is found in patients with rheumatoid arthritis (RA)64,65; however, low levels may be a consequence of RA rather than predisposing to the disease.65The decrease in DHEA-S is most probably due to increased aromatase activity in synovial tissue of RA patients. Thus an available steroid precursor, such as DHEA, may be rapidly converted to proinflammatory estrogens in the synovial tissue, which may in turn stimulate the inflammatory process in patients with RA.& Patients with RA have a high frequency of osteoporosis, which may be due, in part, to reduced levels of DHEA-S.@This is an key example of the intricacies of DHEA physiology: The use of DHEA offers protection against osteoporosis, which is common in RA, but the increase in synovial aromatase may excessively convert DHEA to estrogen, exacerbating the inflammatory process of arthritis. Despite these concerns, some practitioners have observed that patients with rheumatoid arthritis improve clinically after treatment with DHEA; however, those observations have not been investigated in controlled trials.

Inflammatory Bowel Disease DHEA-S concentrations are decreased in patients with both Crohn‘s disease and ulcerative colitis.67 In one study, 200 mg DHEA/day were given orally for 56 days to 7 patients with active Crohn’s disease and 13 patients with active ulcerative colitis (UC), all of whom were refractory to other drugs. Some patients went into remission: 6 of 7 Crohn’s patients and 6 of 13 UC patients. The treatment response rate was 85.7% for Crohn’s disease and 61.5%for UC. No patient withdrew from the study because of side effects.@

The mechanism of action may result from the ability of DHEA to decrease mediators of inflammation. It has been shown that DHEA inhibits the activation of nuclear factor-kappa-beta and the secretion of IL-6 and IL-12.53

Steroid sulphatase (STS) inhibitors are currently being developed for use in breast cancer therapy. STS controls the hydrolysis of DHEA-S.R DHEA may potentiate the action of thyroid hormones.n

DOSAGE

TOXICITY

Although DHEA appears to be safe, the long-term effects For a steroid hormone, DHEA appears to be relatively of moderate to high dosages are unknown. It is therefore safe. Cardiac arrhythmias have been exacerbated by important that this hormone is treated with respect and DHEA supplementation, according to several r e ~ o r t s . ~ ~ * ~ toOerr on the side of caution. In the elderly 50 mg/day Administration of 1600 mg/day for 28 days to healthy will increase DHEA levels into the reference range of volunteers resulted in some degree of insulin resistance, young adults? Although some practitioners are roubut no other sigruficant side effects. In the SLE studies, tinely prescribing 50 mg/day for healthy women and 200 mg/day given for a number of months was well tol100 mg/day for healthy men, such doses may be supraerated, with the exception of mild to moderate acne and physiologic. The safe dosage appears to be 5 to 15mg/day occasional mild hirsutism. Another study reported interfor women and 10 to 30 mg/day for men. Patients with mittent nausea, perioral dermatitis, subjective feelings of SLE or other autoimmune diseases sometimes need as aggressiveness, and intermittent hoarseness.@ Because much as 100 mg/day or more to obtain benefit. Large of DHEA’s role as a precursor to more potent sex doses should be split into twice-a-day dosing, usually hormones, it should be used with extreme caution in morning and evening. individuals with hormone-sensitive cancers. After oral administration, studies show that most DHEA is ab~orbed,’~ and that once in circulation, DHEA readily penetrates the blood-brain ~~

~

DRUG INTERACTIONS

Estrogen (oral contraception pills, hormone replacement therapykFree-testosterone and DHEA levels are reduced in women taking estrogen.71 Aromatase inhibitors-These drugs are used to interrupt the growth of hormone-dependent cancers. Aromatase is the enzyme responsible for many of the conversions in the steroid pathway.

In conclusion, DHEA appears to be one of the major therapeutic advances of the past two decades. However, we must treat this powerful hormone with caution and respect in order to maximize its benefits and minimize its risks.

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SUMMARY

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Echinacea Species (Narrow-Leafed Purple Conef lower ) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER C O N T E N T S General Description 907 Chemical Composition 907 Polysaccharides 908 Alkylamides 909 Caffeic Acid Derivatives 909 Flavonoids 909 Polyacetylenes 909 Miscellaneous 910 History and Folk Use 910 Pharmacology 910 Tissue Regeneration and Antiinflammatory Properties 910 lmmunostimulatory Properties 910 Antiviral Properties 911 Antibacterial Properties 911 Antineoplastic Activity 912

Echinuceu spp. (family: Asteraceae) Echinaceu ungustifoliu Common names: narrow-leafed purple coneflower, black sampson, snakeroot Echinuceu purpureu Common name: purple coneflower Echinucea pallidu Common name: pale purple coneflower

GENERAL DESCRIPTION Echinaceu spp. are perennial herbs native to Midwestern North America, from Saskatchewan to Texas. The genus derives its name from the Greek echinos, meaning sea urchin. This refers to the prickly scales of the dried seed head portion of the flower. Nine species of Echinuceu have been taxonomically classified by McGregor on the basis of comparative anatomy and morphology (Table 89-1)' Of the nine species, Echinuceu angustifolia, Echinacea purpureu, and Echinaceu pullidu are the most commonly

Clinical Applications 912 The Common Cold 913 Candidiasis 914 Snakebites 914 Wound Healing 914 Arthritis 914 Cancer 914 Commercial Preparations 914 Species 915 Part of the Plant to Use 915 Preparations 915 Solvents 915 Dosage 915 Toxicology 915 Drug Interactions 916

used clinically? E. angustifoh, with a typical height of up to 2 feet, is shorter than E. purpureu (1.5 to 5 feet) and E. pullidu (1to 3 feet). Another key to species identification is that E. angustifoh and E. purpureu have yellow pollen, while E. pullidu is noticeably paler and has white pollen. The portions of the plant used for medicinal purposes include the aerial portion, the whole plant including the root, and the root itself. The tap root of E. ungustifoliu can reach a length of 3 to 4 feet.3 E. ungustifoliu has thick, hairy, 1- to 3-inch-long leaves found at the base of a purple seed head shaped like a cone. The only exception to the family of "purple" coneflower is Echinaceu parudoxu, which has a yellow flower.

CHEMICAL COMPOSITION Analysis of Echinucea spp. has yielded a wide assortment of chemical constituents with pharmacologic activities. From a pharmacologic perspective, the important 907

SDecies

Svnonvms

~~

Echinacea angustifolia

Brauneria angustifolia

Echinacea atrorubens

Rudbeckia atrorubens

Echinacea laevigata

Brauneria laevigata

Echinacea pallida

Rudbeckia pallida

Brauneria pallida Echinacea paradoxa

Brauneria paradoxa

Echinacea purpurea

Rudbeckia purpurea

Rudbeckia hispida Rudbeckia serotina Echinacea speciosa Echinacea intermedia Echinacea simulata

Echinacea speciosa

Echinacea sanguinea Echinacea tennesseensis

Bra uneria tennesseensis

Modified from McGregor RL. Univ Kansas Sci Bull 1968;48:113-142.

constituents of Echinacea spp. can be divided into seven categories: Polysaccharides Alkylamides Caffeic acid derivatives Flavonoids Essential oils Polyacetylenes Miscellaneous chemicals

In the case of echinacea, it appears that while individual immune enhancing compounds produce significant effects when they are combined in meaningful amounts, there is an additive effect. The immune-enhancingcomponents of echinacea work together in a harmonious fashion to produce the phenomena of synergy. A key manner in which echinacea affects immune function is via enhancing the ability of macrophages to engulf and destroy particulate matter. The specific components of echinacea that possess this action are the polysaccharides, alkylamides, and cichoric acid. Although each component is effective alone, the greatest degree of enhancement was noted when the three active components were used in a specific ratio (0.25,2.5, and 25 mg/ml).4This phenomena of synergy was noted with a clear dose-dependent effect. In other words, the effects with the three actives were greater than any individual active and the higher the dosage, the greater the effect on enhancing macrophage function. A similar effect was noted in the ability of macrophages to detect the presence of foreign matter in the blood and

signal the other components of the immune system to mount an attack via interleukin-1 (IL-1) and granulocyte colony-stimulating factor (G-CSF). Because echinacea contains a wide assortment of chemical constituentswith confirmed immune-enhancing effects, it is important for manufacturers to recognize to ensure sufficient levels of all these active compounds. Unfortunately, most echinacea products on the market do not speclfy the levels of active compounds because they have not been analyzed for them. In addition, when manufacturers do state the level of a particular marker compound, most consumers fail to realize that concentrating only for one particular active compound of echinacea results in loss of other constituents and, as a result, all of the synergisticeffects. For example, some manufacturers standardize for "total phenolic content" or the compound echina~oside.~ Although these types of echinacea extracts were found to have some antioxidant properties, recent studies have found them to have no effect on enhancing immune function in experimental animal Growing understanding of the chemical composition of echinacea requires manufacturers to perform quality control tests not only on the finished product, but also on the plant to ensure that it is being grown properly and harvested at the exact time for maximal levels of all active compounds. It is imperative that echinacea be treated properly after harvesting. In addition, studies indicate that a significant amount of the active ingredients are destroyed in the drying process. If the fresh plant material is not processed immediately, the content of several key components-especially cichoric acid and alkylamides-will be low (as much as 80% will be lost).810 Chemical analysis of commercial echinacea preparations has demonstrated tremendous variation in the levels of key compounds. For example, one analysis of various commercial echinacea products found that there was not only tremendous variation in the level of cichoric acid, with most products containing either none or little, but even within the same product there was tremendous interbatch variation."

Polysaccharides A number of immunostimulatory and mild antiinflammatory polysaccharides have been isolated from Echinacea ~ p p . ~ , ~ JMost * - ' ~ notable are h u h , which is found in a high concentration (5.9%)in E . angustifoh root, and the high-molecular-weight (25,000 to 50,000) polysaccharides found in the aerial part of E. purpurea, as these components possess significant immuneenhancing properties. Typically the most potent immune-enhancing polysaccharidesare the water-soluble, acidic, branched-chain heteroglycans composed of many types of sugars rather than the polyfructose content of inulin.

Echinacea Species (Narrow-Leafed Purple Coneflower)

Alkylamides

0

Alkylamides typically exert a tingling sensation on the tongue, which is representative of their mild anesthetic effect. These compounds are found in highest concentrationsin the roots. The roots of E. angustifoh contain higher concentrations (0.004% to 0.039%) than E . purpurea (0.009% to 0.151%) and E. paZZida (0.001%).16~'7 Alkylamides are among the most active constituents of echinacea on macrophage function.18

Caffeic Acid Derivatives Caffeic acid serves as the backbone for a number of important medicinal plant compounds in other plants, as well as Echinacea spp. (Figure89-1). The first compound believed to be unique to Echinacea was echinacoside, a compound eventually shown to be composed of caffeic acid, a caffeic acid derivative (similar to catechol), glucose, and rhamnose, all attached to a central glucose molecule (Figures 89-2 and 89-3).19 Echinacoside accumulates in the roots but is also found in smaller concentrations in the flowers. The roots of E . angustifoh contain 0.3% to 1.3%,while the roots of E. pallida contain a similar concentration of 0.4% to 1.7Y0.l~It is assumed that E. purpurea has similar echinacoside levels as well. Other caffeic acid derivatives important in the pharmacology of Echinacea include cichoric acid, chlorogenic acid, and ~ y n a r i nCichoric .~ acid was originally isolated from E . purpureu and is found in much higher concentrations in this species compared with E. angustifolia and E . p ~ l l i d a . However, ~,~~ E. a n g u s t i f o h and E . pallida have

U

OH

R'

R"' R"

Compound

R

3-0-Caffeoyl- OH quinic acid (chlorogenic acid) lsochlorogenic OH acids OH OH Cynarine Caffeic acid

R'

R"

R"'

Caffeic acid

OH

OH

Caffeic acid Caffeic acid OH Caffeic acid OH Caffeic acid Caffeic acid Caffeic acid Caffeic acid Caffeic acid OH Caffeic acid

Figure 89-3 Other caffeic acid derivatives.

higher amounts of other types of caffeic acid derivatives. These differences are not thought to have much clinical sigruficance;rather, they may prove to be valuable in quick chemical differentiation of species.

Flavonoids The leaves and stems of E. angustifoh and E. purpurea have been shown to contain numerous flavonoids, with rutoside being the most a b ~ n d a n tThe . ~ total flavonoid content (calculated as quercetin) for E. angustifolia and E. purpureu was 0.48% and 0.38%, respectively3

Essential Oils The essential oil content varies among the three common speciesz1:

Figure 89-1 Caffeic acid.

E. angustifolia root and leaves contain less than 0.1%. E. purpurea root contains 0.2%,and flowers and leaves contain 0.6%. E. pullida root contains up to 2%, and the leaves contain less than 1%.

OR

Interestingly, in one study the essential oil content of E. pallida root was found to rise to 3.5% to 4% in April and May but fall to 1% to 1.5%for the rest of the year.u The major essential oil components are sesquiterpene derivatives, borneol, alpha-pinine, and related aromatic

compound^.^

Compound

R

R'

Echinacoside 6-0-Caffeoylechinacoside Verbascoside Desrhamnosylverbascoside

Glucose (1,6-) 6-0-Caffeoyl-glucose

Rharnnose (1,3-) Rharnnose (1,3-)

H H

Rharnnose (1,3-) H ~

Figure 89-2 Echinacoside and similar compounds.

Polyacetylenes A number of polyacetylenes have been identified from the roots of all three commercial ~pecies.2~ The difference in the type of polyacetylene and susceptibility to breakdown may help to differentiate which species is best for commercial use. Because the polyacetylenes of E. pallida

Pharmacology of Natural Medicines are quite susceptible to autoxidation, E. angitstifolia may be better for commercial products.” Research has shown that long-term storage greatly decreases the content of polyacetylenes to only trace levels at best. However, the polyacetylene derivatives of autoxidation of E. pallida are quite characteristic and useful in differentiating E. pallida from E . angustifolia.

Miscellaneous Undoubtedly, other constituents contribute to the pharmacology of echinacea. The occurrence of a “colorless alkaloid” was first reported by the great John Uri Lloyd in 1897 and substantiated recently by the isolation of the alkaloids tussilagine and isotussilagine.25Other compounds isolated from Echinacea spp. include the following? Resins Glycoproteins Sterols Minerals Fatty acids

HISTORY AND FOLK USE

among naturopathic physicians until around 1980 when it was rediscovered due to the increased consumer interest in immune system disorders such as candidiasis, chronic fatigue syndrome, AIDS, and cancer. Although interest in echinacea decreased in America between the 1930s and 1980s, European physicians continued research. Much of this research was initiated by a 1932 study by Gerhard Madaus, who demonstrated immune-enhancing effects of a preparation from the fresh juice of the aerial portion of E. purpurea. This was followed by development of a commercial product (Echinacin) and a great deal of scientific study. Thus E. purpurea began to be as respected as E. angitstifolia among herbal practitioners in E ~ r o p e . ~

PHARMACOLOGY The chemistry, pharmacology, and clinical applications of echinacea have been the subject of more than 300 scientific ~ t u d i e s . ~This , ~ , section ~~ summarizes some of the pharmacological information on Echinacea with attention to the species used, part of the plant used, solvent used for extraction, and other relevant features. When no species delineation is made, the activity described is similar in all species.

Echinacea was used extensively by the Native Americans Tissue Regeneration and living in areas where it grew. In fact, American Indians Antiinflammatory Properties used echinacea against more illnesses than any other Echinacin (a commercial product consisting of the plant. The root was used externally for the healing of wounds, burns, abscesses, and insect bites; internally for freshly pressed juice of E. purpurea stabilized in ethanol) infections, toothache and joint pains; and as an antidote as well as polysaccharide components of echinacea have for rattlesnake bites.26 been shown to promote tissue regeneration and reduce H.C.F. Meyer, a German lay healer, introduced a cominflammation in experimental studies.30This effect mercial product containing echinacea to Americans is apparently largely due to inhibition of the enzyme around 1870. He recommended ”Meyer’s blood ~ u r i f i e r ” ~ hyaluronidase via formation of a polysaccharide complex with hyaluronic acid, thereby maintaining the structure as a wonder cure for almost every conceivablemalady, and and integrity of the collagen matrix in connective tissue there were numerous case reports of successful treatments and ground substance. In addition to increased hyaluronic for snakebites, typhus, diphtheria, and other infections. acid stabilization, echinacea also stimulates fibroblast E. angustifoh became a favorite with eclectic physicians, growth and manufacture of glycosaminoglycans, a critias it was thought to be greater in activity than other cal goal in wound healing. species. Eclectics used it externally as a local antiseptic, Echinacea exerts a mild, direct cortisone-like effect stimulant, deodorant, and anesthetic and internally for and enhances the secretion of adrenal cortex hormones? “bad blood” (i.e., to correct ”fluid depravation with The polysaccharide portion appears to be responsible for tendency to sepsis and malignan~y”).~’,~ the direct antiinflammatory effects, although the alkyAlthough many physicians began to investigate and lamide fraction has also demonstrated some activity.3l use echinacea as a serious medicine, in 1909 the Council on Pharmacy and Chemistry of the American Medical lmmunostimulatory Properties Association refused to recognize echinacea as an active drug, stating: “Ln view of the lack of any scientific scrutiny Echinacea possesses a broad spectrum of effects on the of the claims made for it, Echiizacea is deemed unworthy immune system as a result of its content of a diverse range of active components affecting different aspects of of further consideration until more reliable evidence is immune f ~ n c t i o n .For ~ , ~example, inulin, the major compresented in its favor.” Despite this opposition, echiponent in the root of E. angustifoh, activates the alternanacea was included in the National Formulary of the United States and remained there until 1950.3 tive complement pathway and thus promotes chemotaxis of neutrophils, monocytes, and eosinophils; solubilizaWith the demise of the eclectic movement, the popution of immune complexes; neutralization of viruses; larity of echinacea in the United States waned except

Echinacea Species (Narrow-Leafed Purple Coneflower) and bacteriolysis. Echinacea also increases the levels of properdin, the normal serum globulin that stimulates the alternative complement pathway2JJ2Another nonspecific immune enhancement is echinacea's enhancement of serum leukocyte and granulocyte ~ o u n t s . " ~ , ~ ' ~ ~ The high-molecular-weight heteroglycan polysaccharide components of echinacea have profound immunostimulatory effects.The majority of these effects appear to be mediated by the binding of active echinacea polysaccharides to carbohydrate receptors on the cell surface of macrophages and T-lymphocytes. However, some of the T-cell activation in early studies is now thought to be due to a contaminantprotein. Later studies using a purer polysaccharide fraction have not shown si@cant results? Echinacea promotes nonspecific T-cell activation (i.e., transformation, production of interferon, and secretion of lymphokines). The resultant effect is enhanced T-cell mitogenesis, macrophage phagocytosis, antibody binding, natural killer cell activity; and increased numbers of circulating n e ~ t r o p h i l s . ~ , ~ ~ Echinacea polysaccharides have also been shown to enhance macrophage phagocytosis and stimulate macrophages to produce increased amounts of tumor necrosis factor (TNF), interferon, and IL-1; destroy tumor cells in tissue culture; and inhibit Candida albicans infection in rats infected intravenously with a lethal dose (3 x lo5 cells) of C. albicans?J3 The interactions with macrophages are most likely responsible for much of the immune system enhancement of echinacea polysaccharides. In addition to the polysaccharides, lipophilic alkylamides and caffeic acid derivatives like cichoric acid are thought to contribute to the immunostimulatory aspects of echinacea, especially alcoholic extract^.^"^^ Although most research has been devoted to the water-soluble components such as polysaccharides, the lipophilic fraction yields the most potent enhancement of macrophage phagocyt~sis.~,~ The carbon clearance test is often used to measure systemic macrophage activation. The method involves measuring the rate of disappearance of carbon granules from the blood at varying intervals following administration of the test substance. Root extracts of echinacea administered orally tend to yield greater effects on phagocytic activity than the aerial portion, with E . purpurea > E . angustifolia > E . p ~ l l i d a . ~ Many studies have used injectable preparations, but oral preparations are generally thought to yield similar or even better results, although direct comparisons are apparently not available. For example, intramuscular Echinacin administered to healthy males on 4 successive days was shown to increase granulocytic phagocytosis by nearly %YO, while the oral administration of an E. purpurea root extract at a dose of 30 drops three times daily to healthy males for 5 consecutive days resulted in an increase O.~ this difference may be due to the of ~ ~ O Y However,

differing constituents of the forms used. The expressed juice of the aerial portion E . purpurea, as found in Echinacin, has lower concentrations of several of the phagocytosis-stimulating compounds characteristic to echinacea including polysaccharides, alkylamides, and caffeic acid derivatives like cichoric acid compared with alcoholic extract? In general, echinacea appears to offer benefits for all infectious conditions. An exception to this statement may be acquired immunodeficiency syndrome (AIDS). It is unclear at this time if echinacea should be recommended for AIDS. Although this condition is associated with widespread depression of the immune system, presumably due to the human immunodeficiency virus (HIV),stimulation of T-cell replication may also stimulate replication of the virus as well. In addition, echinacea has been shown to lower T helper cells and decrease T helper cell-to-suppressor cell ratios.2JAlthough there are anecdotal reports of echinacea's efficacy in HIV-infected individuals, more research is necessary.

Antiviral Properties The juice of the aerial portion of E. purpurea, along with alcoholic and aqueous extracts of the roots, have been shown to possess antiviral activity. Some of the viruses inhibited in cell cultures include influenza, herpes, and vesicular stomatitis viruses?,34 Although certain Echinacea components (e.g., echinacoside, other caffeic acid derivatives, polysaccharides)may block virus receptors on the cell surface, the antiviral effects may also be due to inhibition of hyaluronidases. The viralinhibiting action of echinacea is significantly diminished when hyaluronidase is added to the cell culture^.^ Many organisms secrete hyaluronidase, which increases connective tissue permeability and allows the organism to become more i n ~ a s i v e . ~ ~ Clinically, the inhibition of hyaluronidase coupled with general immunostimulation of echinacea is probably more important than direct antiviral activity. The nonspecific antiviral action of echinacea enhances cytotoxic killing of virus-infected cells and the release of interferon. Interferons bind to cell surfaces, where they stimulate synthesis of intracellular proteins that block the transcription of viral ribonucleic acid (RNA).

Antibacterial Properties The direct antibacterial activity of echinacea is quite mild. This is somewhat surprising, as echinacea has a long history of effective use in both internal and external bacterial infections. Possibly, it possesses antiinfective properties that prevent bacterial adherence, though this has yet to be determined. Clearly, its clinical efficacy is due to its strong immune-potentiating actions. Echinacea possesses mild antibacterial action due largely to echinacoside, the complex caffeic acid derivative,

Pharmacology of Natural Medicines found in highest concentrations in the root of E. ungustifoliu. Echinacoside and caffeic acid have been shown to have antibacterialaction against Stuphylococcus uureus, Coynebucterium diphtheria, and Proteus vulgaris. Approximately 6.3 mg of echinacoside is equivalent to 10 Oxford units of ~enicillin.~,'~

Antineoplastic Activity Obviously, echinacea possesses indirect, antineoplastic activity via its general immuno-enhancing effects. Specifically important is its stimulation of macrophages to greater cytotoxic activity against tumor cells. (Z)-1,8pentadecadiene, a lipid-soluble component found in the root of E. angustifoh and E. pullufu, has been shown in vivo to possess signhcant direct antineoplastic activity.%

CLINICAL APPLICATIONS Echinacea has long been used clinically for conditions where its pharmacologic actions have proven efficacy, especially in infections. Clinical studies have demonstrated effectivenessin a number of infectious conditions using all three routes of administration: injectable, oral, and topical. However, not all of the clinical studies have been positive. Mixed results from clinical studies with echinacea are most likely due to lack of or insufficient quantity of active compounds. The axiom for effectiveness of any herbal product is its ability to deliver an effective dosage of active compounds. If the product, by chance, had sufficient levels of active compounds, it would be effective. If not, it would likely be no more effective than a placebo. For example, the most recent clinical trial using a well-defined echinacea extract containing alkamides, cichoric acid, and polysaccharides at concentrations of 0.25, 2.5, and 25 mg/ml, respectively, prepared from freshly harvested E. purpureu plants (commercially available as Echinilin), showed excellent results.37In this randomized, doubleblind, placebo-controlled trial, 282 subjects 18 to 65 years old with a history of two or more colds in the previous year, but otherwise in good health, were randomized to receive either echinacea extract or placebo. They were instructed to start the echinacea or placebo at the onset of the first symptom related to a cold, consuming 10 doses the first day and four doses per day on subsequent days for 7 days. Severity of symptoms (10-point scale: 0, minimum; 9, maximum) and dosing were recorded daily. A nurse examined the subjects on the mornings of days 3 and 8 of their cold. A total of 128 subjects contracted a common cold (59 echinacea, 69 placebo). The total daily symptom scores were found to be 23.1%lower in the echinacea group than in the placebo group. Throughout the treatment period, the response rate to treatments was greater in the echinacea group. This study indicated that early intervention with a

standardized formulation of echinacea resulted in reduced symptom severity in subjects with naturally acquired upper respiratory tract infection. In contrast to this positive result, several studies with less welldefined echinacea products showed little benefit, especially in experimentally induced rhinovirus infections. For example, in one double-blind study 160 subjects were given either echinacea or placebo and then exposed to a common cold virus. Infection occurred in 44 and 57%and illness occurred in 36 and 43% of the echinaceaand placebo-treated subjects, respectively. However, the preparation contained no echinacosides or alkamides and contained only 0.16%cichoric acid. In another double-blind study illustrating the problems with clinical research on echinacea, 302 volunteers from four military institutions and one industrial plant in Germany were given either a placebo or alcohol-based tinctures from either E. purpureu or E. angustifilia for 12 weeks.38The main outcome measure was time until the first upper respiratory tract infection. The secondary outcome measures were the number of participants with at least one infection, global assessment, and adverse effects. The time until occurrence of the first upper respiratory tract infection was 66 days in the E . angustifoh group, 69 days in the E. purpureu group, and 65 days in the placebo group. In the placebo group 36.7% had an infection, while in the E . ungustifoliu group it was 32% and in the E. purpureu group it was 29.3%.These results indicate that there was no significant benefit with either form of echinacea, although there was an approximately 20% reduced risk of infection in the echinacea groups. In addition, 70% of the E. purpureu and 78% of the E. angustifoh group felt they had benefited from treatment compared with 56% in the placebo group. The E. ungustifolia had a slightly higher percentage of subjects experiencing side effects (18%)compared with the E. purpureu (10%) and placebo (11Y0)groups. On the surface, these results do not seem to support the effectiveness of echinacea preparations in the prevention of upper respiratory infections. However, both echinacea preparations used were weak ethanol-based tinctures. The herb-to-solvent ratio was 1:11, meaning that for every gram of herbal material there were 11 ml of the water and alcoholic (30% ethanol) solution. The dosage that was administered was 50 drops twice daily, supplying a daily dosage of approximately 2 ml (or, using the herb-to-solvent ratio, about 200 mg of echinacea, hardly a therapeutic dose). Furthermore, the starting material of both forms of echinacea was dried root and neither preparation was analyzed for active compounds. If they had been, it is likely that neither would have contained sufficient levels to produce an effect. At present, although the results from clinical research are mixed, given the long history, safety, and confirmed

Echinacea Species (Narrow-Leafed Purple Coneflower) immune-enhancing effects in experimental modes, as well as the numerous clinical studies that have shown positive results, the clinical applications of echinacea include the following: Treatment of the common cold and other viral respiratory tract infections Possible prevention of the common cold and viral respiratory tract infections Treatment of temporary immune deficiency and increased susceptibility to infections Children in daycare or nurseries Adults experiencing undue stress Sport-induced immunodeficiency Supportive therapy to enhance the effectiveness of antibiotics in bacterial infections Chemotherapy and radiation-induced immune suppression Herpes simplex infections

The Common Cold One of the most popular uses of echinacea is in the treatment of the common cold. This application has been extremely difficult to venfy in clinical studies for several reasons beyond the issue of quality control and dosage given earlier. Nonetheless, reasonably large and welldesigned, double-blind, placebo-controlled studies have found echinacea effective for aborting, as well as reducing the symptoms and duration of ~ o l d s . * ~ ”These 3~ studies have used all various species and extracts of the herb. In one study, 180 patients with influenza were given either an extract of E. purpureu root at a daily dose of 450 mg or 900 mg or a placebo. The 450-mg dose was found to be no more effectivethan a placebo; however, the group taking the 900-mg dose had a sigruficant reduction in cold symptoms.40 In the other study, 108 patients with colds received either an extract of the fresh-pressed juice of E. purpureu (4 ml twice daily) or placebo for 8 weeks.4l The number of patients remaining healthy was as follows: echinacea, 35.2%; placebo, 25.9%. The length of time between infections was: echinacea, 40 days; placebo, 25 days. When infections did occur in patients receiving echinacea, they were less severe and resolved quicker. Patients showing evidence of a weakened immune system (CD4CD8 ratio < 1.5) benefited the most from echinacea. The results from one trial were especially encouraging, as they suggested that echinacea can not only make colds shorter and less severe, it can sometimes stop a cold that is just starting.42In this study, 120 people were given E. purpureu or a placebo as soon as they started showing signs of getting a cold. Participants took either echinacea or placebo at a dosage of 20 drops every 2 hours for 1 day, then 20 drops 3 times a day for 9 more days.

Fewer people in the echinacea group felt that their initial symptoms actually developed into “real” colds (40% of those taking echinacea vs. 60% taking the placebo actually became ill).Also, among those who did come down with ”real” colds, improvement in the symptoms started sooner in the echinacea group (4 days instead of 8 days). Both results were statistically sigruficant. However, echinacea’s ability to shorten the duration of colds was more dramatic. On the other end of the spectrum, a trial of the freshpressed juice of €. purpureu in reducing the duration or severity, or both, of upper respiratory infections in children 2 to 11 years old was quite disappointing. The results from the trial indicated that E. purpureu, as dosed in this study, was not only ineffective, but its use was associated with an increased risk of r a ~ h . 4 ~ In another double-blind trial, 128 patients received either 100 mg of E. purpureu (freeze-dried pressed juice from the aerial portion of the plant) or a placebo three times daily until cold symptoms were relieved or until the end of 14 days, whichever came first.41Symptoms (sneezing, nasal discharge, nasal congestion, headache, sore or scratchy throat, hoarseness, muscle aches, and cough) were scored subjectively by the patient and recorded daily in a diary. No statistically sigruficant difference was observed between treatment groups for either total symptom scores or mean individual symptom scores. The time to resolution of symptoms was also not statistically different. Clearly, more research using well-characterized echinacea preparations at appropriate dosages are necessary in well-designed trials. Currently, the “gold standard” for evaluating cold remedies involves inoculating healthy individuals with rhinovirus. Though the concentration of viral assault is much greater than what one might encounter in the real world, any substance showing efficacy in this model is regarded as being highly efficacious. In one study, 48 healthy adults received echinacea or placebo, 2.5 m13 times per day, for 7 days before and 7 days after intranasal inoculation with rhinovirus (RV-39)j5A total of 92% of echinacea recipients and 95% of placebo recipients were infected. However, colds developed in 58% of echinacea recipients compared with 82% of placebo recipients. Although administration of echinacea before and after exposure to rhinovirus did not decrease the rate of infection, it did appear to reduce the clinical development of a cold. However, because of the small sample size, statistical hypothesis testing had relatively poor power to detect statistically significant differences in the frequency and severity of illness. The only other experimental rhinovirus infection and echinacea study was seriously marred. In this trial, 160 subjects were given either echinacea or placebo and then exposed to rhinovirus. Infection occurred in 44%

Pharmacology of Natural Medicines and 57% and illness occurred in 36% and 43% of the echinacea- and placebo-treated subjects, respectively.& These results indicate that eclunacea was not very effective; however, the preparation used contained no echinacosides or alkamides and contained only 0.16%cichoric acid.

Candidiasis Echinacea’s effect against C. ulbicuiis noted in animal studies has been confirmed in several human clinical ~ t u d i e sA . ~ study featured in Table 89-2 demonstrated that Echinacin greatly accentuated the efficacy of a topical antimycotic agent (econazole nitrate), decreasing reoccurrence from 60.5% to 5% to 16.7%.The researchers used standardized skin tests to show that this enhancement was due to echinacea’s boosting of cell-mediated imm~nitY.4~ Also of interest is the similarity in the efficacies of the oral and injectable forms.

Arthritis Echinacea’s antiinflammatory activity has been shown in uncontrolled studies to be useful in rheumatoid arthritis. In one study, 15 drops of Echinacin three times daily resulted in a 21.8% decrease in inflammation. Although this improvement was less than cortisone (42%) and prednisone (49.2%),no side effects are associated with Echinacin while the drugs have well-known side effects.50

Cancer

Several studies have noted a stimulatory effect of echinacea on leukocyte counts in patients receiving radiation for cancer therapyM5’A study using the commercial preparation Esberitox demonstrated that 85% of 55 patients showed a stabilization of leukocyte counts compared with the control group, which showed a steady decline in levels (starting at 6000 and decreasing to 2500 after Snakebites 45 days).ls This strongly supports the recommendation of echinacea to patients undergoing orthodox cancer Echinacea has quite a reputation among naturopathic treatments. physicians and native American healers for the treatment of snakebites. No studies of this use have been carried In an open prospective study with matched historical out, but echinacea’s inhibition of hyaluronidase might controls, an injection of polysaccharide fraction isolated account for much of its reputed efficacy, since most snake from the herb E. purpureu was shown to counteract the venoms permeate the system as a result of hyaluronidase undesired effects of chemotherapy? Fifteen patients in the venom breaking down connective tissue of the with advanced gastric cancer undergoing palliative ground substance. chemotherapy with etoposide, leucovorin, and 5-fluorouracil (ELF) received for 10 days (beginning 3 days Wound Healing before chemotherapy) daily intravenous injections of 2 mg of a polysaccharide fraction isolated from E . purpureu herb Several uncontrolled clinical studies have been reported to substantiateechinacea’s wound-healing a~tivities?J6,~*~~ cell cultures. The median number of leukocytes 14 to The largest (4598 patients) demonstrated that a salve of 16 days after chemotherapy was 3630/pl in the patients the juice of the aerial portion of E. piirpureu had an 85% receiving echinacea polysaccharide compared with 2370/p1(870 to 3950) in the patients of the historical conoverall success rate in the treatment of inflammatory skin conditions such as abscesses, folliculitis, wounds trol group. These results suggest that echinacea might be of all kinds, eczema, burns, herpes, and varicose ulcers effective in reducing chemotherapy-induced leukopenia. of the leg3

COMMERCIAL PREPARATIONS

Therapeutic scheme

No. of patients

Recurrence rate (%)

Topical antimycotic alone

43

60.5

Topical antimycotic + subcutaneous Echinacin

20

15

Topical antimycotic + intramuscular Echinacin

60

5

Topical antimycotic + intravenous Echinacin

20

15

Topical antimycotic + oral Echinacin

60

16.7

Modified from Coeugniet EG. Kuhnast R. Therapiewoche 1986:36:3352-3358.

As evident from the above information, determining which Echinacea preparation is best is difficult to determine. It is not only difficult to determine which species is most effective, the portion of the plant used and how it is prepared are also seriousissues. Dosage recommendations for all currently available forms follow, along with a few observations regarding the ”preparations controversy.” Another problem that needs to be addressed is quality control. Since as early as 1904, many commercial sources of echinacea have contained adulterants and no echinacea. For example, it has been estimated that due to supplier errors in collection, more than 50% (and possibly as high as 90% at times) of the echinacea sold in the United States from 1908 to 1991 has actually been Purthenium integrifolium, or Missouri ~ n a k e r o o tSome .~~ suggest that this adulteration is due to confusion of the common names. Others point out that although the

Echinacea Species (Narrow-Leafed Purple Coneflower)

Parthenium integrifolium plant looks quite different ". . . once the root is cut and sifted it has an uncanny resemblance to E. angustifoh or E. PaZZida roots, though it possesses its own characteristic flavor and fragrance."53 From practical and clinical viewpoints, physicians should require from suppliers adequate documentation that they are, in fact, supplying echinacea, as well as its species.

Species Although studies have shown various echinacea species, or components found in higher concentrations in one species, to be more effective than others, each commercial species has its advantages and disadvantages. No "best" species can be recommended at this time, as differing experimental models have yielded inconsistent results. Rather, the clinician must recognize the unique value of each species. Although E. angustifoliu has long been considered the best species and to possess the greatest activity, some studies dispute this.For example, several studies have shown E. purpurea to demonstrate greater enhancement of phagocytosis. In fact, in one study, an aqueous extract of E. angustifoh did not demonstrate any impact on phagocytic function in rats, whether it was administered orally, intraperitoneally, or intravenously? As E. purpurea is the easiest to grow commercially, it may become the most used in the United States, as it is in Europe.

Part of the Plant to Use The portion of the plant that possesses the greatest immune-enhancing properties depends on the experimental model. The key points, as described earlier, are that various echinacea components have exerted immuneenhancing effects and there is clearly a synergistic effect among these constituents.

Preparations Echinacea products are available in many different forms: Crude plant in either ground or powdered form Freeze-dried Alcohol-based tinctures and liquid extracts Aqueous tinctures and liquid extracts Dry, powdered alcoholic or aqueous It is popular to standardize hydro/alcoholic extracts for echinacoside (for E . angustifolia) or cichoric acid (for E. purpurea). Although these extracts are thought by their proponents to be the most potent, it must be noted that even 4-10 X homeopathic preparations have been shown to produce activity.31

Solvents Which solvent is best to use? Again, this question is extremely difficult to answer, as both hydrophilic

and lipophilic components have been shown to possess immune-enhancing activities. Even a small amount of ethanol results in precipitation or breakdown of the immuno-active polysaccharides, suggesting that aqueous extracts may be best. However, an aqueous extract would leave behind valuable lipophilic immuneenhancing alkylamides and caffeic acid derivatives. To optimize an extract's immune-enhancing effects, many manufacturers use low ethanol (10% to 20%) hydro/ alcoholic mixtures or combine a low ethanol extract with a high ethanol extract. Both products typically contain both polar and lipophilic compounds.

DOSAGE Box 89-1 lists dosages of echinacea as a general immune stimulant during infection. The question of whether echinacea should be used on a long-term or continual basis really depends on the need. In a healthy individual with no apparent depression of the immune system, continual administration is certainly not indicated. However, as recent studies have shown, patients with impaired immune function experience longterm benefit.4O The usual recommendationwith long-term use is 8 weeks on, followed by 1week off.

TOXIC0LOGY When used at the recommended doses, there is no danger of toxicity, as no studies have reported acute or chronic toxicity reactions due to Echimcea extracts. Echinacin, given intravenously, has resulted in the production of fever (0.5" C to 1" C elevation in body temperature) on occasion. This is presumably a result of secretion of interferon-alpha and IL-1 by activated macrophages.3 The median lethal dose (LDm)of intravenous Echinacin has been determined to be 50 d / k g body weight in mice and rats. The polysaccharides in E. purpurea (aerial portion) were shown to have an LDm of 1000 to 2500 mg/kg when given peritoneally to mice. Chronic administration of Echinacin to rats at doses many times the human therapeutic doses gave no evidence of any toxic effects." Mutagenic tests with Echinacin demonstrated no mutagenic activity?

Dried root (or as tea): 0.5-1 g Freeze-dried plant: 325-650 mg Juice of aerial portion of Echinacea purpurea stabilized in 22% ethanol: 2-3 ml (0.5-0.75 tsp) Tincture (15): 2-4 ml (1-2 tsp) Fluid extract (1:l):1-2 ml ('12-1 tsp) Solid (dry-powdered) extract (6.51 or 3.5% echinacoside): 150-300 mg

Pharmacology of Natural Medicines

Modem reviews of the safety and efficacy of Echirzacea are theoretic, as there is no evidence that echinacea use spp. have found no toxicity in both adults and children in has actually harmed anyone with these diseases. cases of both acute and long-term a d m i n i ~ t r a t i o n . ~ - ~ ~ * ~ 5~ Echinacea appears to be safe even for pregnant or lactatReported side effects are also uncommon and usually ing women based on both animal studies and evaluation limited to minor gastrointestinal symptoms, increased studies in women using echinacea during pregnancy urination, and mild allergic reactions. However, severe showing no harmful effects.59 allergic reactions have occurred occasionally, some of them life threatening. Allergic reactions have most often DRUG INTERACTIONS been reported in people who are also allergic to other members of plants in the daisy (Compositae) family Theoretically, echinacea may interfere with drugs that (e.g., daisy, ragweed, marigolds).% are purposely used to suppress the immune system. The German Commission E warns against using echiThese include cyclophosporin, which is used in patients nacea in cases of autoimmune disorders such as multiple who have had organ transplants to prevent the immune sclerosis, lupus, and rheumatoid arthritis. These warnings system from rejecting the transplanted organ.

1. McGregor RL. The taxonomy of the genus Echinncen (Compositae). UNv Kansas Sci Bull 1968;48:113-142. 2. Barrett 8. Medicinal properties of Echinacea: a critical review. Phytomedicine 2003;10:66-86. 3. Bauer R, Wagner H. Echinacea species as potential immunostimulatory drugs. In Wagner H, Famsworth NR,eds. Economic and medicinal plant research, vol5. New York: Academic Press, 1991:253-321. 4. Gwl V, Chang C, Slama J, et al. Echinacea stimulates macrophage function in the lung and spleen of normal rats. J Nutr Biochem 2002; 13487. 5. Perry NB,Burgess EJ, Glennie VL. Echinacea standardization: analyhcal methods for phenolic compounds and typical levels in medicinal species. J Agric Food Chem 2001;49:1702-1706. 6. Pellati F, Benvenuti S, Magro L, et al. Analysis of phenolic compounds and radical scavenging activity of Echiiiacea spp. J Pharm Biomed Anal 2004;35:289-301. 7. Rininger JA,Kickier S, Chigurupati P, et al. Immunopharmacological activity of Echinacea preparations following simulated digestion on murine macrophages and human peripheral blood mononuclear cells. J Leukoc Biol2000;68:503-510. 8.Perry NB, van Klink JW, Burgess EJ, et al. Alkamide levels in Echinucea purpurea: effects of processing, dqmg and storage. Planta Med 2000;66:54-56. 9. Kim HO,Durance TD, Scaman CH, et al. Retention of caffeic acid derivatives in dried Echinacea purpurea. J Agric Food Chem 2000; 4tk41824186. 10. Stuart DL, Wills RB. Effect of drying temperature on alkylamide and cichoric acid concentrations of Echinacea purpurea. J Agric Food Chem 2003;51:1608-1610. 11. Bauer R. Standardization of Echinacea purpurea expressed juice with reference to cichoric acid and alkamides. J Herbs Spices Medicinal Plants 1999;651-61. 12. Wagner H,Proksch A, Riess-Maurer I, et al. [Immunostimulating action of polysaccharides (heteroglycans) from higher plants. Arneimittelforschung 1985;35:1069-1075. 13. Stimpel M. Proksch A, Wagner H, et al. Macrophage activation and induction of macrophage cytotoxicity by purified polysaccharide fractions from the plant Echinacea purpurea. Infect Immun 1984; 46: 845-849. 14. Luettig B, Steinmuller C, Gifford GE, et al. Macrophage activation by the polysaccharide arabinogalactan isolated from plant cell cultures of Echinacea purpurea. J Natl Cancer Inst 1989;81:669-675.

15. Tubaro A,Tragni E, Del Negro P, et al. Anti-inflammatory activity of a polysaccharide fraction of Echinacea angustifolia. J Pharm Pharmacol 1987;39:567-569. 16. Clifford LJ, Nair MG, Rana J, et al. Bioactivity of alkamides isolated from Echinucea piirpurea (L.) Moench. Phytomedicine 2002;9:249-253. 17. Bauer R, Remiger P. TLC and HPLC analysis of alkylamindes in echinacea drugs. Planta Med 1989;55367-371. 18. Goel V, Chang C, Slama JV, et al. Alkylamides of Echinacea purpurea stimulate alveolar macrophage function in normal rats. Int Immunopharmacol2002;2:381-387. 19. Stoll A, Renz J, Brack A. Antibacterial substances 11. Isolation and constitution of echinacoside, a glycoside from the roots of Echinacea angustifoh. Helv Chim Acta 1950;33:1877-1893. 20. Bauer R, Reminger P, Alstat E. Alkamides and caffeic acid derivatives from the roots of Echinacea tennesseensis. Planta Med 1990;56:533-534. 21. Neugebauer H. The constituents of Echinacea. Pharmazie 1949;4: 137-140. 22. Heinzer F, Meusy JP, Chavanne M. Echinacea pallida and Echinacea purpurm. Follow-up of weight development and chemical composition for the first two culture years. Proceedings of the 36th Annual Congress of the Society of Medicinal Plant Research. Freiburg, Germany, September 12-16,1988. 23. Schulte KE, Rucker G, Perlick J. [The presence of polyacetylene compounds in Echinacea purpura Mnch and Echinacea angustifolia DC.]Arzneimittelforschung 1967;17825-829. 24. Bauer R, Khan IA,Wagner H. TLC and HPLC analysis of Echinacea pallida and E. angustifoh roots. Planta Med 1988;54:426-430. 25. Roder E, Wiedenfeld H, Hille T, et al. Pyrrolizidine in Echinucea angustifoh DC,und Echinacea purpurea MOENCH-Isolierung und Analytik. Dtsch Apoth Ztg 1984;1242316-2318. 26. Vogel VJ. American Indian medicine. Norman, OK University of Oklahoma Press, 1970:356-357. 27. Felter H.The eclectic materia medica, pharmacology and therapeutics. Portland, OR Eclectic Medical Publications, 1983547-351. 28. KutsCheraux AW. Naturae medicina and naturopathic dispensatory. Yellow Springs, OH: Antioch Press, 1953. 29. Percival SS. Use of echinacea in medicine. Biochem Pharmacol 2000;60:155-158. 30. Tragni E, Tubaro A, Melis S, et al. Evidence from two classic irritation tests for an anti-inflammatory action of a natural extract, Echinacina B. Food Chem Toxic01 1985;23:317-319.

Echinacea Species (Narrow-Leafed Purple Coneflower) 31. Wagner H,Breau W, Wder F, et al. In v i h inhibition of arachidonate metabolism by some alkamides and phenylated phenols. Planta Med 198935566-567. 32. Mose JR. [Effect of echinacin on phagocytosis and natural killer cells.] Med Welt 1983;34:1463-1467. 33. Roesler J, SteinmullerC, Kiderlen A, et al.Application of purified polysaccharides from cell cultures of the plant Echinacea purpum to mice mediates protection against systemic infections with Listerin monocytogenes and Candida albicuns. Int J Immunopharmacol1991;1327-37. 34. Wacker A, Hilbig W. [Virus-inhibitionby Echinucea purpurea.] Planta Med 1978;33:89-102. 35. Hopp ES, Bum HF. Ground substance in the nose in health and infection. Ann Otol Rhino1 Laryngol1958;67480-490. 36. Voaden D, Jacobson M. Tumor inhibitors. 3. Identification and synthesis of an oncolytic hydrocarbon from American coneflower roots. J Med Chem 1972;15:619-623. 37. Goel V, Lovlin R, Barton R, et al. Efficacy of a standardized echinacea preparation (Echinilin) for the treatment of the common cold: a randomized, double-blind, placebc-controlled trial. J Clin Pharm Ther 2004;2975-83. 38.Melchart D, Linde K, Worku F, et al. Immunomodulation with Echinacea-a systematic review of controlled clinical trials. Phytomedicine 1994;1:245-254. 39. Melchart D, Linde K, Fischer P, et al. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2000;Z: CDO00530. 40.Braunig B, Dom M, Limburg E, et al. Echinacea purpurea radix for strengthening the immune response in flu-like infections. Z Phytother 1992;13:7-13. 41. Schoneberger D.The influence of immune-stimulating effects of pressed juice from Echinucea purpureu on the course and severity of colds. Results of a double-blind study. Forum Immunologie 1992; 8: 2-12. 42. Hoheisel 0,Sandberg M, Bertram S, et al. Echinagard treatment shortens the course of the common cold: a double-blind, placebocontrolled clinical trial. Eur J Clin Res 1997;9:261-268. 43. Taylor JA, Weber W, Standish L, et al. Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial. JAMA 2003;290:28242830. 44.Yale SH,Liu K. Echinacea purpurea therapy for the treatment of the common cold: a randomized, double-blind, placebo-controlled clinical trial. Arch Intem Med 2004;162:1237-1241.

45. Sperber SJ,Shah LP, Gilbert RD, et al. Echinaceu purpureu for prevention of experimental rhinovirus colds. Clin Infect Dis 2004; 38:1367-1371. 46. Turner RB, Riker DK, Gangemi JD. Ineffectiveness of eclunacea for prevention of experimental rhinovirus colds. Antimicrob Agents Chemother 2000;441708-1709. 47. Coeugniet EG, Kuhnast R. Recurrent candidiasis: adjuvant immunotherapy with different formulations of Echinacin. Therapiewoche 1986363352-3358. 48. Pohl P. [On the therapy of irradiation-induced leukopenia with Esberitox.] Med Klin 1969;62:1546-1547. 49. Kinkel HJ, Plate M, Tullner HU. [Effect of Echinacin ointment in healing of skin lesions.] Med Klin 1984;79:580-583. 50.Seidel K, Knobloch H. [Determination & comparison of the antiphlogistic effects of antirheumatic drugs.] Z Rheumaforsch 1957;16:231-238. 51. Chone B, Manidakis G. [Echinacintest for the provocation of leukocytes in effective radiotherapy.] Dtsch Med Wochenschr 1969;94: 1406-1410. 52. Melchart D, Clemm C, Weber B, et al.Polysaccharides isolated from Echinacea purpum herba cell cultures to counteract undesired effects of chemotherapy-a pilot study. Phytother Res 2002;16:138142. 53. Foster S. Echinacea. Nature's immune enhancer. Rochester, VT: Healing Arts Press, 1991. 54. SchumacherA, Friedberg KD. [The effect of Echinaceu ungrrstifoliu on non-specific cellular immunity in the mouse.] Arzneimittelforschung 1991;41:141-147. 55. Mengs U,Clare CB, Poiley JA. Toxicity of Echinuceu purpurea. Acute, subacute and genotoxicity studies. Arzneimittelforschung 1991; 41:1076-1081. 56. Pamham MJ. Benefit-risk assessment of squeezed sap of the purple coneflower (Echinaea purpurea) for long-term oral immunostimulation. Phytomedicine 19963:95-102. 57. Giles JT,Palat CT ID,Chien SH, et al. Evaluation of echinacea for treatment of the common cold. Pharmacotherapy 2000;20:690-697. 58. Mullins RJ, Heddle R. Adverse reactions associated with echinacea: the Australian experience. Ann Allergy Asthma Immunol 2002; 88:42-51. 59. Gallo M, KO= G. Can herbal produds be used safely during pregnancy? Focus on echinacea.Can Fam Physiaan 2001;471727-1728.

Eleuthermoccws senticosws (Siberian Ginseng) Michael T. Murray, ND Joseph E.Pizzorno Jr, ND CHAPTER C O N T E N T S General Description 919 Chemical Composition 919

Clinical Applications 922 Adaptogenic Activity in Healthy Individuals 922 Adaptogenic Activity in Disease States 922

History and Folk Use

Dosage 923

919

Pharmacology 921 Adaptogenic Activity 921 Stress Control 922 Radiation Protection 922 Carcinogenesis Inhibition 922

Eleutherococcus or Acanthopanax senticosus (family: Araliaceae) Common names: Siberian ginseng, touch-me-not, devil's shrub, eleuthero ginseng

GENERAL DESCRIPTION Eleutherococcus senticosus, or Siberian ginseng, is a shrub that grows 5 to 8.5 feet high. Its erect, spiny shoots, 1.5 to 2.5 inches in diameter, are covered with a light gray or brownish bark. The leaves are long petioled in a compound, palmate configuration. The five leaflets are elliptic and finely serrated at the margins on both sides, with scattered, minute spinules along the veins.' Eleuthero grows abundantly in parts of the Soviet Far East, Korea, China, and Japan, north of latitude 38. Its distribution is much greater than that of Panax ginseng (see Chapter l l l ) . I The root is the most widely used component, with the highest concentration of biologically active substances occurring in the fall, just before defoliation. The leaves are also used medicinally, with their highest concentration of biologically active substances occurring in July, just before flowering.

CHEMICAL COMPOSITION The initial phytochemical report on eleuthero was published in 1965 by members of the Institute of

Toxicology 923 Drug Interactions 923

Biologically Active Substances in Vladivostok, Russia.' Seven compounds, termed eleutherosides A-G, were isolated from a physiologically active fraction of the methanol extract of eleuthero. The total eleutheroside content of the root ranges from 0.6% to 0.9%, and of the stems it ranges from 0.6% to 1.5%. The ratio of the eleutherosides A-G obtained is approximately 8:30:10:12:4:2:1,respectively. Figure 90-1 illustrates structure of a key type of constituent. Table 90-1, modified from reviews of eleuthero, summarizes what is currently known about the components of E. senticosus.' It is important to recognize that thin-layer chromatographic analysis has shown that the ginsenosides characteristic of Panax sp. (American, Chinese, Korean, Japanese ginsengs) are not present in the roots of

E. senticosus.

HISTORY AND FOLK USE Ginseng plants, members of the family Araliaceae including Eleutherococcus senticosus, are among the most ancient and esteemed of all medicinal herbs. Their use in Chinese herbal medicine dates back more than 4000 years.lr2 References in ancient documents to members of the Araliaceae family were imprecise, giving rise to some confusion in modem interpretation. However, the value of eleuthero as a medicinal agent was certainly known to the Chinese, as evidenced by the following ode [Ode to Wujia ( E . senticosus) by 919

Pharmacology of Natural Medicines

p - D - Glucoside

Ye Zhishen (Qmg Dynasty)12:

V '

From earth and heavens the quintessence originates, Five folioles clustering your leaves, And pretty little thorns wrapped whole your shoots; Oh what a jackal's gaunt leg looks much alike. How wonderful is Winzhang-grass, the Eleutheroginseng Dispensing in liquor for drinking, And decocting with burnet for daily using, It will keep your virgin face younger And prolong your life for ever and ever; Even i f a cartload of gold and jewels, That cannot estimate your price of nature.

CH,OH

OCH,

Flgure 90-1 Eleuthemside 6.

Compoundsfound in €leuthemcoccus senticosus Compound

Type

Location

Eleutheroside A (daucosterol)

Sterol

Roots, stems

Eleutheroside B(syringin)

Phenylpropanoid

Roots, stems

Eleutheroside B, (isofraxidin-7-0-alpha-L-glumside;also known as beta-calycanthoside)

Coumarin

Roots

Eleutheroside 82

Unknown

Roots

Eleutheroside 83

Unknown

Roots

Eleutheroside B4 [(-)-sesamin]

Lignan

Eleutheroside C (methyl-alpha-D-galactoside) Eleutheroside D [(-)-Syringarsinoldi-0-beta-D-glucoside]

Sugar Lignan

Roots Roots, stems

Eleutheroside E (different crystalline form of D; also known as acanthoside D)

Lignan

Roots, stems

Eleutheroside F

Unknown

Roots

Eleutheroside G Eleutheroside I (=mussenin B)

Unknown

Roots

Triterpene

Leaves

Triterpene Triterpene

Leaves Leaves

Triterpene

Leaves

Triterpene

Vitamin E

Benzofuran

Leaves Roots

Beta-carotene

Carotenoid

Roots

lsofraxidin

Coumarin

Roots

Coumarin X

Coumarin

Roots

Complex mixture

Essential oil

Roots

Copper (-)-Syringaresinol

Mineral

Roots

Lignan

Caffeic acid Caffeic acid ethyl ester

Phenylpropanoid

Roots Roots

Eleutheroside K Eleutheroside L Eleutheroside M (= hederasaponin B) Senticosides A-D (may be identical to eleutherosid

nd M)

Roots, stems

Phenylpropanoid Phenylpropanoid Phenylpropanoid

Roots Roots

Sterol

Roots

Polysaccharides

Sugar

Galactose Glucose (alpha and beta)

Sugar

Roots, fruit Roots

Sugar

Roots

Maltose (alpha and beta) Sucrose

Sugar Sugar Triterpene

Roots Roots

Coniferyl aldehyde Synapyl alcohol Beta-sitosterol

Oleanolic acid Modified from Davydov M, Krikorian AD. J Ethnopharmacol2OOO;72:345-393.

Roots

Roots

Eleutherococcus senticosus (Siberian Ginseng)

The Chinese have long believed that the regular use of eleuthero would increase longevity, improve general health and appetite, and restore memory. The Russians have a separate history of eleuthero and even claimed, despite a long history of use by Chinese herbalists (references date back to 2000 BC), that "Eleutherococcus was not known in Oriental folk medicine." The Russian history of eleuthero begins in 1855 when a pair of Russian scientists, C. I. Maximovich and L.I. Shrenk, traveled from St. Petersburg to the Ussuri region of Russia on the Amur River. It was in this area that Maximovich observed a vast thicket of unusual plants, with leaves resembling horse chestnut and young shoots resembling ginseng. Unable to idenhfy the plant, the two scientists brought back samples to St. Petersburg for classification. The plant was given the genus name of EZeuthero, or "free-berried shrub," and the species name of senticosus, which means "thorny" in Latin. Not until the middle of the twentieth century was eleuthero again "discovered," when Russian scientists began investigating substances that produce a "state of nonspecific resistance" in the body. Substances with this effect were termed adapfogens.In 1958Brekhman described an adaptogen as It must be innocuous and cause minimal disorders in the physiologic functions of an organism. It must have a nonspecific action (i.e., it should increase the resistance to adverse influences by a wide range of physical, chemical, and biochemical factors). It usually has a normalizing action irrespective of the direction of the pathologic state (alterative action). Brekhman's research with adaptogens began with P. ginseng, since this was the best-known natural adaptogen. After confirming the adaptogenic action of panax in human studies, Brekhman began searching for an alternative to this plant because of the difficulty and expense in obtaining panax. Initially, all six species of Araliaceae native to Russia were investigated and eleuthero was found to be the most promising. Numerous studies (in vivo, in vitro, and human studies) have been conducted since the late 1950s, nearly all in the Soviet Union. They are not referenced here as they are not translated and not widely available. Instead, review articles and original articles in English are ~ i t e d . l - ~

Adaptogenic Activity An important characteristic of an adaptogen is its ability

to "normalize," irrespective of the direction of pathology. E. senticosus has been found to do the following in experimental models: Impede the adrenal hypertrophy induced by adrenocorticotropic hormone and the adrenal atrophy induced by cortisone Impede the thyroid hypertrophy induced by thyroidin and thyroid gland atrophy induced by 6-methylthiouracil Reduce blood glucose levels in alimentary and adrenal hyperglycemia and increase glucose levels in insulininduced hypoglycemia Reduce leukocytosis induced by the parenteral administration of milk, as well as leukopenia induced by endotoxins Reduce erythrocytosis induced by cobaltous nitrate and erythropenia induced by phenylhydrazine These are summarized in Table 90-2. Similar results have been obtained with I? ginseng (see Chapter 111).

Function

Normalization action of Eleutherococcus senticosus

Adrenal

Impedes hypertrophy induced by ACTH Impedes atrophy induced by cortisone

Thyroid

Impedes hypertrophy induced by thyroidin Impedes atrophy induced by 6-methylthiouracil

Kidney

Increases renal capacity in pyelonephritis

Blood pressure

Decreases high blood pressure through improvement of atherosclerosis Increases pressure in hypotension

Blood glucose

Reduces alimentary and adrenal hyperglycemia Increases blood sugar in insulin-induced hypoglycemia

Leukocyte

Reduces leukocytosis induced by the administration of milk Reduces leukopenia induced by endotoxins

Erythrocyte

Reduces erythrocytosis induced by cobaltous nitrate Reduces erythropenia induced by phenylhydrazine

Stress

Reduces activation of the adrenal cortex in response to stress Prevents stress-induced thymic and lymphatic involution

Radiation

Protects against radiation exposure

Cancer Cholesterol

Inhibits carcinogenesis from urethane, 6-methylthiouracil indole Reduces hepatic biosynthesis

DNA

Stimulates synthesis

PHARMACOLOGY As mentioned earlier, a number of experimental and clinical studies have demonstrated that eleuthero possesses adaptogenic properties (i.e., the ability to increase nonspecific body resistance to stress, fatigue, and disease). Additional experimental and clinical research supports other therapeutic applications of E. senticosus.

ACTH, Adrenocorticotropic hormone; DNA, deoxyribonucleic acid.

Pharmacology of Natural Medicines

Stress Control Another important action of adaptogens is the inhibition of the alarm phase of the stress reaction. Eleuthero has shown similar action to P. ginseng in experiments designed to demonstrate an antialarm action. Specifically, eleuthero has been shown to increase the swimming time of rats, reduce activation of the adrenal cortex in response to stress (alarm phase reaction), and prevent stress-induced thymic and lymphatic involution.'"

Radiation Protection In addition to its confirmed adaptogenic activity, eleuthero has also demonstrated both protective and therapeutic actions in animals exposed to both single and prolonged x-ray radiation. In one study, both E. senticosus and P. ginseng were found to double the life span of rats exposed to prolonged radiation (total doses of 1620 to 7000 rads). When eleuthero was combined with antibiotics, the lifetime of irradiated rats (total dose of 3000 rads over 60 days) increased threefold.' These results suggest that eleuthero may be of benefit in protecting against harmful radiation and as an adjunctive aid in radiation therapy in oncology. The latter suggestion is further supported by studies of eleuthero that have demonstrated an inhibition of carcinogenesis.

Carcinogenesis Inhibition Eleuthero preparations have been shown in experimental studies in animals to inhibit'? Urethane-induced lung adenomas 6-methylthiouracil-induced tumors of the thyroid Myeloid leukemia induced by indole The formation of spontaneous mammary gland tumors and leukemia Transplantation of various tumors As is evident from the discussion of eleuthero's adaptogenic activities, it shares many features with P. ginseng. In addition to adaptogenic activities, eleuthero, like panax, has been shown to do the following': Increase resistance to infection in animals Reduce hepatic cholesterol biosynthesis Increase reproductive capacity and sperm counts in bulls Possess sigruficant antioxidant activity Stimulate DNA synthesis and cellular repair enzymes Part of eleuthero's anticancer effects may be due to its immune-stimulating effects. In vitro, it increases phagocytosis of Candida albicans by granulocytes and monocytes from healthy donors by 30% to 459'0.*,~In vitro studies have shown that whole ethanolic fluid extract of E. senticosus can induce and enhance interleukin-1 and interleukin-6 but not interleukin-2 production.'0

CLINICAL APPLICATIONS Adaptogenic Activity in Healthy Individuals A fluid extract (33% ethanol) of E. senticosus root has been administered to more than 2200 human subjects in clinical trials conducted in Russia designed to evaluate the "adaptogenic" effects of eleuthero. The data indicated that eleuthero had the following effects: Increased the ability of humans to withstand many adverse physical conditions (e.g., heat, noise, motion, work load increase, exercise, decompression) Increased mental alertness and work output Improved the quality of work under stressful conditions and improved athletic performance The male and female subjects ranged in age from 19 to 72 years. Dosages of the fluid extract (33%ethanol) ranged from 2 to 16 ml, one to three times a day, for periods of up to 60 consecutive days. Results from research outside of Russia have been mixed, with little evidence to support that eleuthero improves physical performance in athletes."-13

Adaptogenic Activity in Disease States A fluid extract (33% ethanol) of E. senticosus root has been administered to more than 2200 human subjects with various illnesses including angina, hypertension, hypotension, acute pyelonephritis, various types of neuroses, acute craniocerebral trauma, rheumatic heart disease, chronic bronchitis, and cancer.] Eleuthero appears to be effective in atherosclerotic conditions, as evidenced by its ability to lower elevated serum cholesterol and prothrombin levels, reduce blood pressure, and eliminate anginal symptoms in human subjects. Its action on blood pressure is truly adaptogenic, as eleuthero has also been shown to increase blood pressure in subjects with hypotension? Its effect in regulatingblood pressure may be indicative of improved renal function; it has been demonstrated that patients with acute pyelonephritis given eleuthero extract demonstrate increased renal capacity, as measured by an increased secretion of phenol red.' Eleuthero appears to have some psychotropic action, as it has been proven effective in the treatment of various psychologic disturbances. Eleuthero has consistently demonstrated an ability to increase one's sense of wellbeing, regardless of the psychologic complaint (e.g., insomnia, hypochondriasis, various neuroses). A possible explanation of this effect is improved balance of the biogenic amines including serotonin, dopamine, norepinephrine, and epinephrine, as eleuthero extract administered to rats has been shown to increase biogenic amine content in the brain, adrenals, and urine.'

Eleutherococcus senticosus (Siberian Ginseng)

Data are insufficient enough to fully evaluate eleuthero's action in other disease states. However, it must be kept in mind that an adaptogen is nonspecific in its action and possesses a normalizing action irrespective of the direction of the changes from physiologic norms.

DOSAGE The standard dosage of the fluid extract (33%ethanol) of E . senticosus roots used in the majority of studies ranged from 2 to 4 ml (up to 16 ml), one to three times a day, for periods of up to 60 consecutive days. In multiple dosing regimens, there is usually a 2- to 3-week interval between course^.^,^

Dosages are as follows: Dried root: 2 to 4 g Tincture (1:5):10 to 20 ml Fluid extract (1:l):2 to 4 ml Solid (dry-powdered) extract (20:l): 100 to 200 mg

TOXIC0LOGY Toxicity studies in animals have demonstrated that eleuthero extracts are virtually nontoxic. The median lethal dose of the 33% ethanol extract of eleuthero is 14.5 ml/kg in mice and greater than 20 ml/kg in rats. No long-term toxicity was observed when a daily dose of 5 ml/kg of the fluid extract was administered to rats.

1. Davydov M, Krikorian AD. Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. (Araliaceae) as an adaptogen: a closer look. J

Ethnopharmacol2000;72:345-393. 2. Duke JA. CRC handbook of medicinal herbs. Boca Raton, n. CRC Press, 1985:337-338. 3.Baranov AI. Medicinal uses of ginseng and related plants in the Soviet Union. Recent trends in the Soviet literature. J Ethnopharmacol 1982;6:339-353. 4. Brekhman 11, Dardymov Iv.New substances of plant origin which increase nonspecific resistance. Ann Rev Pharmacol 1969;9: 419-430. 5. Brekhman 11, Dardymov Iv.Pharmacological investigation of glycosides from ginseng and Eleutherococcus. Lloydia 1969;32:46-51. 6. Brekhman 11, Kirillov 01.Effect of eleutherococcus on alarm-phase of stress. Life Sci 1969;8:113-121. 7. Ben-Hur E, Fulder S. Effect of Panax ginseng saponins and Eleutherococcus senticosus on survival of cultured mammalian cells after ionizing radiation. Am J Chin Med 1981;948-56. 8. Windfeuer A, Mayerhofer D. [The effects of plant preparations on cellular functionsin body defense]. Arzneimittelforschung Mar 1994; M361-366.

Teratogenicity has been studied in three species (rats, rabbits, and minks), with no adverse effects observed.' In human clinical studies, it was demonstrated that eleuthero extracts (33% ethanol) in the recommended dosage range are well tolerated and side effects are infrequent. A few studies found mild side effects at higher dosages (4.5 to 6 ml three times daily) when used for long periods (60 days). The symptoms included insomnia, irritability, melancholy, and anxiety. In individuals with rheumatic heart disease, pericardial pain, headaches, palpitations, and elevations in blood pressure have been reported.' These symptoms are probably due to the mild stimulating effects of eleuthero and, although not serious, indicate the need to decrease the dosage or allow a washout period, or both.

DRUG INTERACTIONS A clinical study in healthy humans indicated that extracts of eleuthero at generally recommended doses are unlikely to alter the levels of drugs primarily dependent on the CYP2D6 or CYP3A4 pathways for eliminati~n.'~However, in one case report, although a clear relationship could not be established, a person taking eleuthero with digoxin (Lanoxin) developed dangerously high serum digoxin levels.15 Therefore simultaneous use with digoxin requires close medical supervision and regular monitoring of blood digoxin levels.

9. Wagner H, Proksch A, Riess-Maurer I, et al. [Immunostimulating action of polysaccahrides (heteroglycans) from higher plants]. Arzneimittelforschung 198535:1069-1075. 10. Steinmann GG, Esperester A, Joller P. Immunopharmacological in vitro effects of Eleutherococcus senticosus extracts. Arzneimittelforschung 2001;51:76-83. 11. Gafhey BT, Hugel HM, Rich PA. The effects of Eleutherococcus senticosus and Panax ginseng on steroidal hormone indices of stress and lymphocyte subset numbers in endurance athletes. Life Sci 2001;70431-442. 12. Szolomicki J, Samochowiec L, Wojcicki J, et al. The influence of active components of Eleutherococcus senticosus on cellular defence and physical fitness in man. Phytother Res 2000;1430-35. 13.Eschbach LF, Webster MJ, Boyd JC, et al. The effect of Siberian ginseng (Eleutherococcus senticosus) on substrate utilization and performance. Int J Sport N u b Exerc Metab 2000;10444-451. 14.Donovan JL, DeVane CL, Chavin KD, et al. Siberian ginseng (Eleutherococcus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers. Drug Metab Dispos 2003;31:519-522. 15.McRae S. Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. CMAJ 1996;155293-295.

Ephedra Species* Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 925

Dosage 927

Chemical Composition 925

Toxicology

History and Folk Use

Drug Interactions 928

926

927

Pharmacology 926 Ephedrine 926 Pseudoephedrine 926 Clinical Applications 926 Asthma and Hay Fever 926 Common Cold 927 Weight-Loss Aid 927

Ephedru sinicu (family: Ephedraceae) Common names: Chinese ephedra, Ma Huang, Chinese joint fir Related species: Ephedru distucha (European ephedra) Ephedra trifurcu or Ephedra viridis (desert tea) Ephedru nevudensis (Mormon tea, cay note, canutillo, whorehouse tea, tapopote, teamster's tea) Ephedru umericunu (American ephedra) Ephedru gerurdiuna (Pakistani ephedra)

GENERAL DESCRIPTION Ephedru spp. are erect, branching shrubs found in desert or arid regions throughout the world. The 1.5-to 4-foot shrubs typically grow on dry, rocky, or sandy slopes.

'On February 6,2004, the U.S. Food and Drug Administration (FDA) issued a ban on the sale of dietary supplements containing ephedra. This ban was finalized on April 6, 2004.The FDA made this decision on the basis of clinical studies and adverse event. Dietary supplements containing ephedrine alkaloids, like other sympathomimetics. raise blood pressure and increase heart rate. The FDA thought ephedrine-based products exposed users to several risks including the consequences of a sustained increase in blood pressure (e.g., serious illnesses or injuries including stroke and heart attack that can result in death). There was also a risk of increased morbidity and mortality from worsened heart failure and proarrhythmic effects in susceptible individuals.

The many slender, yellow-green branches of ephedra have two small leaf scales at each node. The mature, double-seeded cones are visible in the fall.

CHEMICAL COMPOSITION The chemical analysis of the stems and branches of Ephedru spp. has focused on their alkaloid content. In Ephedreu sinicu, the total alkaloid content can be up to 3.3%, with 40% to 90% of this being ephedrine. The remaining alkaloids are primarily pseudoephedrine and norpseudoephedrine.'J2In Ephedru gerurdiunu, the alkaloid content usually varies from 0.8%to 1.4%,about half ephedrine and half other alkaloids (e.g., pseudoephedrine, N-methylephedrine, norephedrine) Ephedru nevudensis contains little or no ephedrine. Depending on species, parts used (aerial, stem, leaf or a combination of stem and leaf), harvesting, and extraction techniques, the alkaloid content of the commercially available ephedra products varies considerably. In a series of studies, the alkaloid content in ephedra-based products varied by as much as fivefold with different brands exhibiting lot-to-lot differences ranging from 44% to 260%. Although some products listed the ephedrine content on the label, many did not. In addition to the variations in alkaloid content, commercial ephedra products .*j3

925

Pharmacology of Natural Medicines

usually contained other highly active botanicals including kola nut, guarana, and St. John's wort, as well as many contaminants (e.g., heavy metals).3A

CH3

I

HOCHCH,NHCH,

I

HISTORY AND FOLK USE E. sinicu has been used for medicinal purposes in China since approximately 2800 BC. Ma Huang (the stem and branch) was used primarily in the treatment of the common cold, asthma, hay fever, bronchitis, edema, arthritis,fever, hypotension, and urticaria.' The Chinese believed the effect of the root and rhizome (Ma Huanggen) to be the opposite of the stem and branches and limited its use to the treatment of profuse night sweating.' Two hypotensive principles (ephedradine A and B) have since been isolated from ephedra root, along with a hypertensive compound (1-tyrosine betaine or maokine).I Western medicine's interest in ephedra began in 1923 with the demonstration that the isolated alkaloid ephedrine possessed a number of pharmacologic effects. Ephedrine was synthesized in 1927 and has since been used extensively for clinical conditions in which sympathomimetic effects are d e ~ i r e d . ~

PHARMACOLOGY The pharmacology of ephedra centers around its ephedrine content. Ephedrine and pseudoephedrine have been extensively investigated and are widely used in both prescription and over-the-counter (OTC)medications for asthma, hay fever, and rhinitis. In 1973 more than 20 million prescriptions contained one of these alkaloids. In 2000 ephedra was found in at least 200 over-thecounter products, and it was estimated that as many as two to three billion doses were consumed that year in the United States.

Ephedrine Ephedrine's basic pharmacologic action is that of a sympathomimetic. Ephedrine stimulates both alphaand beta-adrenergic receptors, as well as the release of norepinephrine. Ephedrine shares many pharmacologic actions with epinephrine, although ephedrine is much less active. Ephedrine also differs from epinephrine in its ability to be absorbed orally, its longer duration of action, and its more pronounced effect upon the central nervous system (CNS). The CNS effects of ephedrine are similar to those of amphetamines but, again, are much less potent.14 Figure 91-1 illustrates its chemical structure. The cardiovascular effects of ephedrine are also similar to those of epinephrine. It increases both diastolic and systolic blood pressure, cardiac output, and heart rate, but for a longer (about 10 times) period. Like epinephrine, ephedrine increases coronary, cerebral, and

Figure 91-1 Ephedrine.

muscle blood flow at the expense of renal and splanchnic blood flow.'-5 The bronchial muscle relaxation induced by ephedrine is much less than epinephrine, but, again, the duration of action is much longer. Other smooth muscles, with the exception of the human uterus, are generally affected by ephedrine in the same manner (mild relaxation) as epinephrine. Ephedrine relaxes the human uterus, where the effects of epinephrine are more complex.14 Extracts of ephedra have been shown to inhibit complement in vitro, and a Chinese herbal medicinal prescription, Makyo-kanseki-to, has been found to inhibit cyclic adenosine monophosphate activity?r7 The principle adverse effects of ephedrine are CNS stimulation, nausea, tremors, tachycardia, and urinary retention.'r2 The major route of elimination of ephedrine is as the unchanged drug in the urine. The average half-life is 6 hours, although acidifymg the urine decreases the halflife considerably. Alkalinization increases the ha1f-life.*p9

Pseudoephedrine Pseudoephedrine exhibits bronchodilating activity similar to ephedrine but has weaker pressor, cardiac, and CNS effects. Pseudoephedrine is often recommended over ephedrine in the treatment of chronic asthma, as it has fewer side effects. Pseudoephedrine has also demonstrated sigruficant antiinflammatory effects in various experimental models.g'O Other ephedra alkaloids, including ephedrine, also exhibited antiinflammatory activity, although at much lower potency. As the antiinflammatory effect of pseudoephedrine is essentially identical in normal and adrenalectomized mice, the antiinflammatory activity is not exerted via the adrenal glands. Instead, it appears that the antiinflammatory activity of pseudoephedrine and other ephedra alkaloids is due to inhibition of prostaglandin E2 synthesis.

CLINICAL APPLICATIONS Asthma and Hay Fever Ephedra and its alkaloids have proven effective as bronchodilators for the treatment of mild to moderate asthma and hay fever. The peak bronchodilation effect occurs in 1 hour and lasts about 5 hours after administration.

Ephedra Species The therapeutic effect of ephedra diminishes if used over a long period of time due to the weakening of the adrenal gland caused by ephedrine. Therefore it is often necessary to use ephedra in combination with herbs such as GZycyrrhizu glubru and Pumx ginseng and nutrients such as vitamin C, magnesium, zinc, vitamin B6, and pantothenic acid, which all support the adrenal glands. The folklore herbal treatment of asthma involved the use of ephedra in combination with herbal expectorants. (Expectorants are herbs that modify the quality and quantity of secretions of the respiratory tract, resulting in the expulsion of the secretions and an improvement in respiratory tract function.) Commonly used expectorants include the following:

Glycyrrhizu glubru (licorice) Grindeliu camparum (grindelia) Euphorbiu hirtu (euphorbia) Droseru rotundifolia (sundew) Polygulu senegu (senega)

Common Cold Ephedrine and pseudoephedrine are components of many OTC products for the self-treatmentof the common cold. In China ephedra, in combination with various other herbs, has been found to be clinically effective in the treatment of cold symptoms, as well as those of influenza, pneumonia, whooping cough, and bronchitis.'

Weight-Loss Aid In both human and animal studies, ephedrine has been shown to promote weight ~oss?,'~-'~ Although ephedrine has demonstrated an anorectic effect," its main mechanism for promoting weight loss appears to be increasing the metabolic rate of adipose tissue."-16 Therefore ephedra's weight-reducing effects are most significant in those individuals with a low basal metabolic rate.13 These effects can be greatly enhanced when used in combination with methylxanthines, caffeine, and theophylline, as well as aspirin,1~'8~20 which potentiates the action of ephedrine and other ephedra compounds. In one animal study, when ephedrine was used alone, it resulted in a 14%decrease in body weight and a 42% decrease in body fat. However, when used in combination with caffeine or theophylline, the decreases were 25% and 75%, re~pective1y.l~ However, when either caffeine or theophylline was used alone, there was no significant loss in body weight. The reason for the greater decrease in body weight is the increased metabolic rate and fat cell breakdown promoted by ephedrine and enhanced by caffeine and theophylline. It is recommended that, for methylxanthines, Camellia sinensis (green tea) or extracts of Cola sp. be used rather than coffee or black tea.

One of the better-designed studies on the use of an ephedrine/caffeine combination determined the safety and efficacy of an herbal supplement containing Ma Huang (90 mg/day ephedrine) and kola nut (192 mg/day caffeine)given to subjects for 6 months for weight loss. A total of 167 subjects were randomized to receive either a placebo or ephedrine/caffeine combination. The subjects were monitored primarily for changes in blood pressure, heart function, and body weight. In addition to these parameters, body composition and metabolic changes were studied. The results of this study demonstrated significant beneficial effects on body weight, body fat, and blood lipids of the herbal supplement in overweight men and women who were otherwise healthy. Herbal versus placebo treatment decreased body weight (-5.3 vs. -2.6 kg), body fat ( 4 . 3 vs. -2.7 kg) and low-density lipoprotein cholesterol (-8 vs. 0 mg/dl), and increased high-density lipoprotein cholesterol (+2.7 vs. -0.3 mg/dl, p = 0.004). The ephedrine/caffeine mixture produced small changes in blood pressure variables (+3 to -5 mm Hg) and increased heart rate ( 4 f 9 beats/min), but cardiac arrhythmias were not increased. Compared with placebo treatment, the herbal supplement produced no adverse events and only minimal side effects consistent with the known stimulant action of ephedrine and caffeine (e.g., dry mouth,

DOSAGE The optimum dosage of ephedra depends on the alkaloid content in the form used. The average total alkaloid content of E. sinicu is 1%to 3%.When used in the treatment of asthma or as a weight-loss aid, the ephedra dose should have an ephedrine content of 12.5 to 25 mg and be taken two to three times daily. For the crude herb, an equal dose would be approximately 500 to 1000 mg three times/day. Standardized preparations are often preferred, as they have more dependable therapeutic activity.

TOXICOLOGY Ephedra can obviously produce the same side effects as ephedrine (e.g., increased blood pressure and heart rate, insomnia, anxiety). The FDA advisory review panel on nonprescription drugs recommended that ephedrine not be taken by patients with heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland. Nor should ephedrine be used in patients on antihypertensive or antidepressant drugs. Pregnant women should also avoid the use of ephedra and ephedrine. Ephedrine administered to chick embryos has resulted in cardiovascular teratogenicity and

Pharmacology of Natural Medicines embryotoxicity at doses as low as 1 pmol/egg.21The teratogenic effect of ephedrine is potentiated by caffeine.u Presumably, this activity of ephedrine is the result of the production of nitrosamines.23Simultaneousvitamin C administration might reduce the formation of nitrosamines from ephedra A key reason that the FDA issued the ban on ephedra products was the tremendous amount (more than 2000) of adverse event reports filed with the FDA related to the use of supplements containing ephedra alkaloid^.*^,^^ However, when the Council of Responsible Nutrition studied the adverse event reports (AERs) filed with the FDA, it found that 98% of the AERs did not contain complete information and in 81% of the reports, information on total daily intake of ephedra was not provided.28Of the 1173reports, 121 were selected for further evaluation. Of the 121 selected cases, 47 were considered to contain serious adverse events including 15 cases of stroke and strokelike symptoms, 13 cases of seizures, 15 cases of cardiac arrest, and 2 cases of individuals who collapsed. From the selected 121 cases, there were 8 reports of death: 6 were cardiovascular, 1 occurred in an automobile accident, and 1was a spontaneous abortion. Among the six cardiovascular-related deaths, five were males

and one was female. All five males who died from cardiovascular problems were using dietary supplements containing ephedra as an athletic performance enhancer. Additionally, four of the five were simultaneously using other performance-enhancing products such as caffeine; therefore their deaths cannot be directly attributed to the use of ephedra. The report concluded that after extensive examination of these adverse event reports, it was not possible to conclusively determine if there were any unexpected toxicologic effects due to the ephedra contained in the dietary supplements solely on the basis of the information presented in the adverse event reports.

1.Chang Hh4, But PP. Pharmacology and applications of Chinese Materia Medica. Philadelphia: World Scientific, 1986:1119-1124. 2. Abourashed EA, El-AIfy AT, Khan IA,et al. Ephedra in perspective a current review. Phytother Res 2003;17703-712. 3. Gurley BJ, Gardner SF, Hubbard MA. Content versus label claims in ephedra-containing dietary supplements. Am J Health Syst P h m 200057963-969. 4. Haller CA, Duan M, Benowitz NL, et al. Concentrations of ephedra alkaloids and caffeine in commercial dietary supplements. J Anal Toxicol 2004;28:145-151. 5. White LM, Gardner SF,Gurley BJ, et al. Pharmacokinetics and cardiovascular effects of ma-huang (Ephrdm sinicn) in normotensive adults. J Clin Pharmacol1997;37116-122. 6. Ling M, Piddlesden SJ, Morgan BP. A component of the medicinal herb ephedra blocks activation in the classical and alternative pathways of complement. Clin Exp Inmuno1 1995;102:582-588. 7.Nikaido T,Iizuka S, Okada N, et al. [The study of Chinese herbal medicinal prescription with enzyme inhibitory activity. VI. The study of makyo-kanseki-to with adenosine 3’,5’-cyclic monophosphate phosphodiesterase.] Yakugaka Zasshe 1992;112:124-128. 8. W h o n GR, Beckett AH. Absorption metabolism and excretion of the ephedrines in man. I. The influence of urinary pH and urine volume output. J Pharmacol Exp Ther 1968;162139-147. 9. Pickup ME, May CS, Sendagire R, et al. The pharmacokinetics of ephedrine after oral dosage in asthmatics receiving acute and chronic treatment. Br J Clin Pharmacol 1976;3:123-134. 10. Hikino H, KOMO C, Takata H, et al.Anti-inflammatory principle of ephedra herbs. Chem Pharm Bull 1980;28:2900-2904. 11. Kasahara Y, Hikino H, Tsuru S, et al. Anti-inflammatory actions of ephedrines in acute inflammations. Planta Med 1985;54: 325-331.

12. Zarrindast MR, Hosseini-Nia, Farnoodi F. Anorectic effect of ephedrine. Gen Pharmacol1987;18:559-561. 13. Ashup A, Madsen J, Holst JJ, et al. The effect of chronic ephedrine treatment on substrate utilization, the sympathoadrenal activity, and expenditure during glucose-induced thermogenesis in man. Metabolism 1986;35:260-265. 14. Bailey CJ, Thombum CC, Flatt PR. Effects of ephedrine and atenol on the development of obesity and diabetes in ob/ob mice. Gen Pharmacol 1986;17:243-246. 15. M o o AG, Miller DS.The thermogenic properties of ephedrine/ methylxanthine mixtures: animal studies. Am J Clin Nutr 1986; 43:388-394. 16. Pasquali R, Cesari MP, Melchionda N, et al. Does ephedrine promote weight loss in low-energy-adapted obese women? Int J Obesity 1987;11:163-168. 17. Miller DS.A controlled trial using ephedrine in the treatment of obesity. Int J Obesity 1986;10:159-160. 18. Dulloo AG, Mdler DS.Aspirin as a promoter of ephedrine-induced thermogenesis: potential use in the treatment of obesity. Am J Clin Nutr 1987;45:564-569. 19. Boozer CN, Daly PA, Home1 P, et al. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int J Obes Relat Metab Disord 2002;26:593-604. 20. Daly PA, Krieger DR, Dulloo AG, et al. Ephedrine, caffeine and aspirin. Safety and efficacy for the treatment of human obesity. Int J Obes Relat Metab Disord 1993;17 Suppl 1:S73-S78. 21. Kalix P. The pharmacology of psychoactive alkaloids from ephedra and catha. J Ethnopharmacol1991;32:201-208. 22. Nishikawa T, Bruyere HJ Jr, Takagi Y, et al. Cardiovascular teratogenicity of ephedrine in chick embryos. Toxicol Lett 1985;29: 59-63.

DRUG INTERACTIONS As mentioned earlier, ephedrine should not be taken by patients with heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland. Nor should ephedrine be used in patients on antihypertensive or antidepressant drugs. Ephedrine will potentiate other stimulant/ sympathomimetic drugs and will likely counteract antihypertensives.

Ephedra Species 23. Nishikawa T, Bruyere HJ Jr, Gilbert EF, et al. Potentiating the effects of caffeine on the cardiovascular teratogenicity of ephedrine in chick embryos. Toxicol Lett 1985;2965-68. 24. Alwan SM, Al-Hindawi MK, Abdul-Rahman SK, et al. Production of nitrosamines fiom ephedrine, pseudoephedrine and extracts of ephedra foliata under physiological conditions. Cancer Lett 1986; 31:221-226. 25. Sever PS,Dring LG, Williams RT. The metabolism of (-)-Ephedrine in man. Eur J Clin Pharmacol1975;9193-198.

26. SON MG, Carabin IG, Griffiths JC, et al. Safety of ephedra: lessons learned. Toxicol Lett 2004;15097-110. 27. Schulman S. Addressing the potential risks associated with ephedra use: a review of recent efforts. Public Health Rep 2003;118:487-492. 28. Council for Responsible Nutrition. Safety Assessment and Determination of a Tolerable Upper Limit for Ephedra. Cantox Health Sciences International, 20009-169.

Epilobium Species (Fireweed) Kathy Abascal, BS, JD, RH(AHG) Eric L. Yarnell, ND, RH(AHG) CHAPTER CONTENTS General Description 931

Effect on Prostate and Prostatic Enzymes 932

Chemical Composition 931 Clinical Applications 933 History and Folk Use 931 Dosage 933 Pharmacology 932 Analgesic Effect 932 Antiinflammatory Effect 932 Antimicrobial Effect 932 Antitumor Effect 932

Epilobium spp. (family: Onograceae) Synonym: Chamaenerion spp. Common names: fireweed, willow herb, great willow herb (Epilobiumangustifoliurn),rose-bay (Epilobiumangustfoliurn),wickup (Epilobiurn angustfolium);small-flowered willow herb (Epilobium parvijlorum), marsh epilobium (Epilobium palustre), wickop (Epilobium palustre), swamp willow herb (E. palustre)

GENERAL DESCRIPTION Epilobium is a genus of some 200 species that typically grow at relatively high latitudes or high altitudes.’ This plant is found in all parts of the world. Fireweed is a perennial that grows in colonies connected by underground roots. It has tall, erect, and somewhat woody stems, from 2 to 7 feet tall, crowded with long, narrow, alternate leaves that are from 2 to 6 inches long. The leaves are dark green on the upper surface and silverydowny on the underside. Its flowers range from lavender to pink to carmine-purple, and its pods are long, narrow, and filled with feathery seeds? The Latin name Epilobium derives from Greek words that describe how the flower sits on long, thin, podlike seed cases. Most species have small flowers (e.g., Epilobium parviflorum, known as small-flowered willow herb). A few have large flowers (e.g., Epilobium angustifoliurn,known as great willow herb). Despite the use of the term “willow,” there is no relationship between Epilobium spp. and Salix spp. (willow).

Toxicology 933 Drug Interactions 933

CHEMICAL COMPOSITION The aerial parts are rich in flavonoids (quercitrin, isoquercitrin, myricitrin, isomyrcitrin, myricetin 3-O-betaD-glucoronide),3 and the various species contain at most seven flavonol glycosides based on kaempferol, quercetin, and myricetin skeletons: The plants contain complex tannins such as ellagitannins (oenothein A and B) and gallotannins5;beta-sitosterol; triterpenes (taraxasterol, oleanolic acid)6;fatty acids (linolenic acid, palmitic acid, linoleic acid); and gallic, chlorogenic, and ellagic acids.’ The small-flowered species contain myricitrin, quercitrin, and isomyricitrin, with myricitrin present in the largest amount. The large-flowered species have a completely different flavonoid pattern, with isoquercitrin being predominant. The plant contains the highest content of the flavonoid myricetin 3-O-beta-~-glucoronide shortly after flowering (Figure 92-1).

HISTORY AND FOLK USE Fireweed has been widely used as a medicine and as a food in many parts of the world. Native Americans used it for burning urination, male urination problems, coughs and sore throats, stomachaches and intestinal discomfort, bowel hemorrhages, gastritis, tuberculosis, and as a panacea for pain? It was used as a poultice for boils; abscesses; carbuncles; bruises; infected sores, cuts, and wounds; and other skin ailments. Various Eskimo 931

OH

OH

0

Figure 92-1 Quercitrin.

and Siberian tribes also used the plant to treat sores? Young shoots were widely consumed as food and fodder, as were the roots and leaves. The seed fluff was used for weaving cloth, making thread, and starting fires. Fireweed is named mjoelke in Scandinavia, a derivation of the word milk, because of centuries of observation that cows grazing on the plant produce more milk. Eclectic physicians considered fireweed unequaled as a treatment for summer bowel troubles and also used it in other types of diarrhea including cholera infantum and typhoid dysentery.'O The Eclectics often administered fireweed as an infusion, using frequent small doses (up to every 10 minutes). Epilobium hirsutism was used in Egyptian and European folk medicine to treat inflammation, adenoma, and prostate tumors." Europeans also used the plant to treat eczema, seborrhea, other skin conditions, and menstrual disorders.I2

20% of the effect on prostaglandin release. Experiments show that flavonoids and sitosterol derivatives are not responsible for these actions. Myricetin-3-0- beta-^ glucuronide, isolated from fireweed, was 10 times more effective than indomethacin at inhibiting carrageenaninduced edema in rats, was equally effective at inhibiting prostaglandin biosynthesis, and had a dose-related antiarthritic effect.15J6 The compound inhibited both cyclooxygenase-1 and -2 nearly equivalently. It inhibits 5-lipooxygenase comparably to the reference compound nordihydroguaiaretic acid. It significantly and dosedependently inhibited platelet aggregation equivalently to indomethacin but, in contrast to indomethacin, induced no gastric ulcers in rats. We speculatethat the compound may have greater safety than nonsteroidal antiinflammatory drugs because it prevents the arachidonic shunting that results in the formation of leukotrienes.

Antimicrobial Effect Dilute ethanolic extracts of fireweed ( E . angustifolium, Epilobium hirsutum, Epilobium palustre, Epilobium tetragonum, and Epilobium rosmarinifolium) are antimicrobial in ~ i t r 0 . IE.~ angustifolium and E . rosmarinifolium have the broadest spectrum of action, inhibiting bacteria, yeast, and h g i . E. angustifolium and E. hirsutum inhibited Microspontm canis at concentrations as low as 10 pg/ml. In another study, a methanolic extract of E. angustfohn failed to inhibit mold (Aspergillus niger) but somewhat inhibited Candida albicans while strongly inhibiting Staphylococcus aureus and Escherichia coli.18

PHARMACOLOGY

Antitumor Effect

Analysis of studies on fireweed may be complex given subtle differences among species and differences in the actions of aqueous and alcoholic extracts. Overall, though, most species in this genus appear to have analgesic, antiinflammatory, antimicrobial, antineoplastic, and prostate-related activities.

Oenothein B, isolated from fireweed, showed some antitumor activity against sarcoma 180 in mice and some selectivity in vitro against lung cancer cells and two colon cancer lines but did not have a noticeable effect on the prostate cancer lines tested.I9 In another series of experiments, the alcoholic extract of E . angustifolium had a specific and signhcant antiproliferative effect on human prostate epithelial cells.2O In addition, several of its flavonoids were potent growth inhibitors when tested on various hormone-sensitive and hormone-nonsensitive cell lines.

Analgesic Effect Ethanolic extracts of E. angustifolium injected subcutaneously had a weak analgesic effect on mice in the hot plate test, while its analgesic effect on mice injected intraperitoneally with acetic acid was greater than that of a~etylsalicylate.'~ The latter test is more sensitive for nonsteroidal analgesics.

Antiinflammatory Effect Aqueous extracts of E. angustifolium strongly reduce the release of prostaglandins and strongly depress carrageenan-induced edema when administered orally (40mg/kg) in animal models.I4The effect on edema formation was equivalent to that of indomethacin (2 mg/kg). E. parviflorum did not suppress edema and had about

Effect on Prostate and Prostatic Enzymes The aqueous-methanolic extracts of various fireweed species inhibit aromatase in vitro.2l This action is primarily attributed to the ellagitannins oenothein A and 8, but other fireweed flavonoids (kaempferol, quercetin, myricetin) also inhibit aromatase. Both oenothein A and B had a considerably greater inhibitory action on 5 alphareductase in vitro than the reference drug hestride. The aqueous extract and ultrafiltrate of E. angustifolium had an antiandrogenic effect in intact rats, and the aqueous extract had a proandrogenic effect in castrated rats.22

The hexane extract did not have similar effects. In another study, alcoholic extracts of fireweed failed to inhibit 5-alpha-reductase, while the aqueous extract showed sigruficant inhibition.23This action was attributed to the compound oenothein B.

CLINICAL APPLICATIONS No clinical studies were found on any of the fireweed species. This is unfortunate, as preliminary studies indicate that fireweed may be more effective than drugs such as finestride and indomethacin, as discussed earlier. The existing pharmacologic research supports fireweed’s well-established use in traditional medicine as a treatment for prostate disorders and as a topical medicine in various skin conditions.

DOSAGE

as needed.” The suggested dose for an aqueous/alcoholic tincture is 2 to 6 ml three times a day. Aqueous/alcoholic tinctures appear more effective than tinctures with a high alcohol concentrat i ~ n 26 . ~No ~, widely accepted standardization exists to ensure quality fireweed extracts, although flavonoid profiles can be used to distinguish the various specie^.*^^^^ Species grown in Africa appear to have a significantly higher content of oenothein B than the same species grown in Europe.29

TOXICOLOGY Fireweed has no known toxic effects, and its lack of toxicity is underscored by a worldwide use as both food and fodder. The median lethal dose for injected ethanol extract in mice is 1.4 g/kgW

DRUG INTERACTIONS

Dosages for fireweed are not well established. Fireweed is traditionally administered as a standard infusion using 2 to 3 teaspoons of herb to 1 cup of boiling water, taken

There are no documented drug interactions with fireweed.

1. Averett JE, Kerr BJ, Raven PH. The flavonoids of Onagraceae, tribe Epilobieae: Epilobium sect. Epilobium. Am J Bot 1978;65:567-570. 2. Moore M. Medicinal plants of the Pacific West. Santa Fe, NM: Red Crane Books, 1995136-138. 3. Ducrey 8, Marston A, Gohring S, et al. Inhibition of 5 alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobium species. Planta Med 1997;63:111-114. 4. Averett JE, Kerr BJ, Raven PH. The flavonoids of onagraceae, tribe Epilobieae: Epilobiurn sect. Epilobium. Am J Bot 1978;65:567-570. 5. Ducrey B, Marston A, Gohring S, et al. Inhibition of 5 alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobium species. Planta Med 1997;63:111-114. 6.Glowniak K, Zareba S, Kozyra M, Turewicz K. P23 sterols and triterpenoids from Epilobium sp. and some other medicinal plants. [poster] Eur J Pharm Sci 1994;2124. 7. Lesuisse D, Berjonneau J, Ciot C, et al. Determination of oenothein B as the active 5-alpha-reductase-inhibitingprinciple of the folk medicine Epilobium paruiflorum. J Nat Prod 1996;59:490-492. 8. Moerman DE. Native American ethnobotany. Portland, OR T i b e r Press, 1998212-213. 9. Kallman S. [Wild Plants as Food & Medicine.] Vasteras, Sweden: ICA Bokforlag, 1997152-155 [in Swedish]. 10. Felter HW,Lloyd JU. King’s American Dispensatory,vol 1. Sandy OR Eclectic Medical Publications, 1993:711-712. 11. Barakat HH, Hussein S A M , Marzouk MS, et al. Polyphenolic metabolites of Epilobium hirsutum. Phytochem 1997;&935-941. 12. Battinelli L, Tita B, Evandri MG, Mazzanti G. Antimicrobial activity of Epilobium spp. extracts. Farmaco 200156345-348. 13.Tita B, Abdel-Haq H, Vitalone A, et al. Analgesic properties of Epilobium angustifolium, evaluated by the hot plate test and the writhing test. Farmaco 2001;56:341-343.

14. Hiermann A, Juan H, Sametz W. Influence of Epilobium extracts on prostaglandin biosynthesis and carrageenin induced oedema of the rat paw. J Ethnopharmacol1986;17161-169. 15. Hiermann A, !khramm HW,Laufer S. Anti-inflammatoryactivity of myricetin-3-0-beta-D-glucuronide and related compounds. Inflamm Res 1998;47421-427. 16. Hiermann A, Reidlinger M, Juan H, Sametz W. [Isolation of the antiphlogistic principle from Epilobium angustifolium.] Planta Med 199157357-360, 17. Battinelli L, Eta B, Evandri MG, Mazzanti G. Antimicrobial activity of Epilobium spp. extracts. Farmaco 2001;56:345-348. 18. Rauha JP, Remes S, Heinonen M, et al. Antimicrobial effects of Finnish plant extracts containing flavonoids and other phenolic compounds. Int J Food Microbiol2000;563-12. 19. Ducrey 8, Marston A, Gohring S, et al. Inhibition of 5 alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobium species. Planta Med 1997;63111-114. 20. Vitalone A, Bordi F, Baldazzi C, et al. Anti-proliferative effect on a prostatic epithelial cell line (PZ-HPV-7) by Epilobium angustifolium L. Farmaco 200136483-489. 21. Ducrey 8, Marston A, Gohring S, et al. Inhibition of 5 alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobium species. Planta Med 1997;63:111-114. 22. Hiermann A, Bucar F. Studies of Epilobium angustifolium extracts on the growth of accessory sexual organs in rats. J Ethnopharmacol 1997;55179-183. 23. Lesuisse D, Berjonneau J, Ciot C, et al. Determination of oenothein B as the active 5-alpha-reductase inhibiting principle of the folk medicine Epilobiurn parviflorum. J Nat Prod 1996;59:490-492. 24. Moore M. Medicinal plants of the Pacific West. Santa Fe, N M Red Crane Books, 1995:136-138.

Pharmacology of Natural Medicines 25. Hiermann A, Bucar F. Studies of Epilobiuni aiigustifoliurn extracts on the growth of accessory sexual organs in rats. J Ethnopharmacol 199755179-183. 26. Lesuisse D, Berjonneau J, Ciot C, et al. Determination of oenothein B as the active 5-alpha-reductase inhibiting principle of the folk medicine Epilobium pawiflorum. J Nat Prod 1996;59:490-492. 27. Slacanin I, Marston A, Hostettmann K, et al. Isolation and deterrnination of flavonol glycosides from Epilobiurn species. J Chromatol 1991557391-398.

28.Averett JE, Kerr BJ, Raven PH. The flavonoids of onagraceae, tribe Epilobieae: Epilobiurn sect. Epilobium. Am J Bot 1978;65: 567-570. 29. Ducrey B, Marston A, Gohring S, et al. Inhibition of 5 alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobiirrn species. Planta Med 1997;63111-114. 30.Tita 8, Abdel-Haq H, Vitalone A, et al. Analgesic properties of Epilobiitrn nngustifolium, evaluated by the hot plate test and the writhing test. Farmaco 2001;56:341-343.

Fatty Acid Metabolism Richard S. Lord, PhD J. Alexander Bralley, PhD CHAPTER CONTENTS Introduction 935 Fatty Acid Structure and Metabolism 935 Saturated Fatty Acids 936 Unsaturated Fatty Acids 936 Trans Fatty Acids 938 Polyunsaturated Fatty Acids 939

Fatty Acids and Human Diseases 941 Developmental Disorders 942 Heart Disease 942 Cancer 943 Neurologic Disorders 943 Summary

943

Control of Fatty Acid Supply and Distribution 940 Digestion and Assimilation 940 Synthesis and Distribution 941 Effect of Low-Fat Diets 941

INTRODUCTION Fatty acids are common denominators for all life forms. The same oleic acid that is found in the cell membranes of olive trees is also critical for the cellular structure and functions of bacteria, fungi, and humans. Thin layers of fatty acids provide the separation of the inside from the outside of living cells. Plants fill their seeds with fatty acids because they are the most efficient storage form of energy. Although a growing body of research is now documenting the critical importance of fatty acids for maintaining health, common food choices in modern society do not lead to appropriate levels or balances of these nutrients. Years of negative associations of dietary fat with calories, cholesterol, and cancer have resulted in a general public attitude that foods containing fats should simply be avoided. Many food manufacturers have taken advantage of this attitude by modifying fat content and labeling, wherever possible, to tout "low-fat" foods. Advertisements for such foods further instill the notion that dietary fat is bad. Amid the clamor over the largely mistaken problems associated with dietary fats, many problems have been created by the large-scale use of modified fats by food suppliers. Individuals do not feel the effects of abusing dietary fats on the short term because of the presence of many protective mechanisms that make health threats from fat abuse an insidious process.

Modem diets of fast foods and packaged dinners tend to be rich in saturated fats and hydrogenated oils and lacking in essential fatty acids (EFAs). We now know that the amount and type of dietary fat play major roles in maintaining health. Some saturated fatty acids stimulate cholesterol formation, but most do not. The old concept of three EFAs has been replaced by recognition of critical roles for multiple polyunsaturated fatty acids (PUFAs).Dietary fats simultaneously provide the major cellular energy source, control the passage of compounds into and out of cells, determine the integrity of nerve tissue, and serve to form powerful hormones. The essential hormone function is mediated by some special fatty acids that affect energy flow, cell division, immune responses, and many other body controls. These critical fatty acids are used to make powerful tissuespecific compounds called eicosanoids. Figure 93-1 illustrates the various roles of fatty acids. This chapter discusses more about these functions after some basic fatty acid relationships are explained.

FATTY ACID STRUCTURE AND METABOLISM About 30 structural isomers and homologs of fatty acids occur in human tissues. They are named in various ways, including those with Latin prefixes such as pentaand hexa- for the number of carbon atoms. These are the 935

Pharmacology of Natural Medicines

chemical names approved by the International Union of Pure and Applied Chemists. Many also have common names. Because common names are in widest use among clinicians, they are used here. Table 93-1 provides a lexicon of fatty acid terms.

Saturated Fatty Acids Fatty acids containing the maximum number of carbonhydrogen bonds are called saturated. They have a higher energy or caloric yield than corresponding unsaturated fatty acids. They are present as major components of most foods and are high in manufactured foods such as candy bars. The most abundant members in human tissues are those that are 14 (myristic),16 (palmitic),or 18 (stearic)carbons long. The elongation process can be repeated to yield members that are 20, 22, and 24 carbons long. Although such longchain fatty acids are minor components of the lipid membranes of the body they undoubtedly perform valuable functions, apparently helping to stabilize membranes, especially those in peripheral nerve cells.

Unsaturated Fatty Acids

Blood Lipoproteins

Three major families of unsaturated fatty acids (UFAs)

A

Diet

Figure 93-1

Hepatic Synthesis Elongation, Desaturation

Metabolic roles of fatly acids.

are found in human tissues: the omega-9, omega-6, and omega-3 UFAs (or n-9, n-6, and n-3). The omega-6 and omega-3 PUFAs are defined by the position of the double bond closest to the terminal methyl group of the fatty acid molecule. In the omega-6 family, the first double bond occurs between the sixth and seventh carbons from the methyl group end of the molecule, whereas in the omega-3 family, the first double bond occurs between the third and fourth carbons (Figure 93-2 provides naming conventions).

Lexicon of fatty acid terms Term or abbreviation

Definition or explanation

AA

Arachidonic acid

A M

Alpha-linolenic acid

Alpha-linolenic acid

Delta 9,12,15 octadecatrienoic acid; 18:3 omega-3

Arachidonic acid

Delta 5,8,11,14 eicosatetraenoic acid; 20:4 omega-6

Beta-oxidation

The mitochondrial metabolic pathway whereby fatty acids are converted into acetyl coenzyme A (acetyl CoA) which enters the citric acid cycle to ultimately yield adenosine triphosphate. The carbon atoms of the fatty acid are oxidized to C02.

Carnitine

The molecule to which fatty acids are attached in the process of their enzyme-mediated entry into the mitochondrial matrix. This enzyme is inhibited by malonyl coenzyme A (malonyl CoA) formed during fatty acid synthesis from carbohydrates.

Cerebronic acid

The 2-hydroxy derivative of lignoceric acid (24:O); found in glycosphingolipids in the brain

Cervonic acid

Another name for docosahexaenoic acid

cis

Geometrical isomer in which two groups are on the same side of a double bond

Clupanodonic acid

Another name for delta 7.10.1 3,16,19-docosapentaenoicacid (DPAS), an omega-3 series, long-chain, highly unsaturated fatty acid; found in fish oils and phospholipids in the brain

Delta

Used to describe the position of double bonds relative to the carboxyl end of a fatty acid

Desaturase

Tightly bound to the endoplasmic reticulum membrane, this enzyme, in association with cytochrome b5 and cytochrome b5 reductase, uses reduced nicotinamide adenine dinucleotide and O2to introduce

Fatty Acid Metabolism . a

-

*

Lexicon of fatty acid terms-cont'd

Term or abbreviation

Definition or explanation double bonds into fatty acids. There are at least four separate desaturases, named according to the position of inserted double bonds. Delta-9-desaturase, delta-6-desaturase,and delta-5(4) desaturase act on fatty acetyl CoA thioesters, always inserting double bonds between the thioester bond (carboxylate group) and the double bond closest to it, leaving a three-carbon gap. Activities of these enzymes fluctuate according to dietary fat intake to maintain optimal fluidity state of the membrane lipids. Their concentrations decrease in starvation and increase greatly on refeeding carbohydrates. They are suppressed when dietary unsaturatedfatly acid intake (including trans isomers) is high.

DGLA

Dihomogammalinolenic acid

Dihomogammalinolenic acid

Delta 8,11,4 eicosatrienoicacid; 20:3 omega-6

DHA

Delta 4,7,10,13,16,19 docosahexaenoic acid; 22:6; an omega-3 series long-chain, highly unsaturated fatty acid; found in fish oils and the phospholipidsin the brain (also known as cervonic acid)

Dienoic

Contains two double bonds

EFA

Essential fatty acid

Eicosanoid

A product of the specific, enzyme-directedoxidation of polyunsaturatedfatty acids containing 20 (eicosa) carbons. This term encompasses the prostaglandins, thromboxanes, and leukotrienes.

Eicosapentaenoic acid

Delta 5,8,11,14,17 eicosapentaenoic acid; 20:5 omega-3; one of the most abundant fatty acids in fish oils

Elongase

An enzyme that adds 2-carbon units (acetate) to the carboxyl end of an existing saturated or unsaturated fatty acid. Mitochondria1form uses acetyl CoA, while endoplasmic form has malonyl CoA as substrate.

EPA

Eicosapentaenoic acid

Gamma linolenic acid

Delta 6,9,12 octadecatrienoic acid; 18:3 omega-6

GLA

Gamma-linolenic acid

HUFA

Highly unsaturatedfatty acid; generally having five or six double bonds

LA

Linoleic acid

Lauric acid

Tetradecanoic acid; C12:O; first isolated and identified from the laurel plant

LCP

Long-chain polyunsaturated fatty acid

Linoleic acid

Delta 9,12 octadecadienoic acid; 18:2 omega-6

Meads acid

Delta 5,8,11 eicosatrienoicacid; 20:3 omega-9. This compound is not normally produced in appreciable amounts due to the preferential loading of the desaturase enzymes with the more strongly binding essential fatty acids and their metabolic products. It accumulates, however, in essential fatty acid deficiency, making it a marker for this condition.

Monoenoic

Containing one double bond

MUFA

Monounsaturated fatty acid

Omega

Used to describe the position of double bonds relative to the methyl end of a fatty acid

P + MIS ratio

Polyunsaturated + monounsaturated to saturated fatty acid ratio

PIS ratio

Polyunsaturated-to-saturatedfatty acid ratio

Phospholipase A2

An enzyme that catalyzes the hydrolysis of the fatty acid ester from position 2 of phosphoglycerides. Dependent on calcium, this enzyme is responsive to intracellular calcium, calmodulin, etc. It releases primarily polyenoic fatty acids (arachidonicacid, etc.) from membranes for eicosanoid synthesis.

PUFA

Polyunsaturated fatty acid

Phosphatide

Diacylglycerolphosphate, to which various groups may be attached through phosphoester linkage; the principal components of cell membranes

Polyenoic

Containing two or more double bonds

Saturated fatty acid

A fatty acid in which all of the carbon atoms except for the carboxyl carbon are fully hydrogenated as -CHr (and 4 H 3 )

Stearidonic acid

Delta 6,9,12,15 octadecatetraenoic acid; 18:4 omega-3; a product of elongation of ALA and a precursor to EPA. A good source is black currant seed oil.

Timnodonic acid

Another name for eicosapentaenoic acid (EPA) or 20:4 omega-6

Trans

Geometrical isomer in which two groups are on opposite sides of a double bond

Unsaturatedfatty acid

A fatty acid in which two or more adjacent pairs of carbon atoms are lacking hydrogen atoms, having instead an additional carbon-carbon bond or double bond

A

The Greek letter delta

0

The Greek letter omega

Dihomogammalinolenicacid

or 8,11,14-eicosatrienoicacid or 20:3A8,11,14 or 20:306 Figure 93-2 Naming conventions for unsaturated fatty acids.

Saturated

Monounsaturated Myristoleic (n-5)

Myristic Palmitic Stearic Figure 93-3

L?E!E%E.

Palmitoleic (n-7) Oleic (n-9)

Formation of monounsaturatedfatty acids.

The older delta (A) naming scheme gives the positions of all double bonds, counting from the carboxyl or number 1carbon. The omega (a)scheme takes advantage of the fact that the double bonds are always separated by three carbons and simply gives the total length and number of double bonds separated by a colon. The number following the o symbol gives the position of the first double bond counting from the omega-1 carbon. Fatty acids can be synthesized from acetyl coenzyme A derived from carbohydrate, protein, and other nonlipid sources. This pathway produces saturated fatty acids, predominantly palmitic acid (16:O). Palmitic acid can be desaturated, forming palmitoleic acid of the omega-7 class of unsaturated fatty acids. Palmitic acid can also be lengthened to stearic acid (180) and desaturated to form oleic of the omega-9 class. Under ordinary metabolic conditions, these two classes are not further lengthened or desaturated to any appreciable extent. The omega-6 and omega-3 classes of unsaturated fatty acids are derived from dietary polyunsaturated fats. These classes can be further lengthened and desaturated. None of the four

omega classes of unsaturated fatty acids, however, is interconvertible. These reactions can be repeated in various combinations, giving an array of saturated and unsaturated fatty acids for use in the essential functions of tissue maintenance. The desaturase enzymes function to place double bonds at positions up to nine carbons from the carboxyl end of the molecules. When you count from the other end, the position varies, depending on the length of the fatty acid. Thus for stearic acid with 18 carbons, a desaturase can form a double-bond nine carbons from the carboxyl end, which is also nine carbons from the methyl end (18 - 9 = 9). These differences become important because the type of eicosanoid hormones that can be formed later depend on the position of the first double bond from the methyl end. The geometry of the desaturase will not allow insertion farther than nine carbons (A9) from the carboxyl group. This is the reason that linoleic acid (LA, A9, 12) cannot be synthesized in humans. Fatty acids of various chain lengths can act as desaturase substrates, as well as those that already possess double bonds at other positions. Figure 93-3 shows the products of the A9 desaturase acting on three saturated fatty acids. The activity of the desaturase enzymes is critical for maintaining the ratio of saturated and unsaturated components in cell membranes. Tumor tissue and virustransformed cells have a higher content of unsaturated fatty acids, especially oleic acid, which increases relative to the amount of stearic acid. Such shifts increase the metabolic rates of many lipid-dependent enzymes and are associated with a higher capacity for cell division.’ Individuals with recurrent tumors may already have too much oleic acid relative to stearic acid, and encouraging a diet high in olive oil or other highly unsaturated fatty acids may be contraindicated.

Trans Fatty Acids In the tissues of plants and higher animals, the insertion of double bonds always results in the cis geometry. The phrase “partiallyhydrogenated vegetable oil” on food labels indicates that a natural oil has been chemically modified in a process that converts some of the cis unsaturated fatty acids to the trans form. Oleic acid is changed into its trans isomer, elaidic acid, which is the most abundant trans fatty acid in most hydrogenated oils. In human metabolism, trans unsaturated fat behaves similar to saturated fat, meaning more risk of heart disease, etc. Adverse effects of trans fatty acids on high-density lipoprotein or low-density lipoprotein cholesterol are well documented in the medical research literature.24 Interference with eicosanoid production is also suspected, and research in the area of health risks of trans fatty acids is accelerating. Trans fatty acid levels in cell membranes are determined by dietary intake of

Fatty Acid Metabolism

hydrogenated A person eating a doughnut for breakfast (3.19 g of trans fatty acids), a small order of French fries with lunch (3.43 g), two teaspoons of margarine on bread with dinner (1.24 g), and two cookies for a snack (1.72 g) would ingest a total of 9.58 g of trans fatty acids, enough to negate the serum cholesterollowering effects of a decrease in saturated fat of 10% of total energy intake.6 Elaidic acid is generally the most abundant of the trans fatty acids because it is produced by the hydrogenation of the most common oils used in the food industry including corn, soybean, and safflower.These oils contain relatively high amounts of oleic and linoleic acids, both of which may convert to elaidic acid during the hydrogenation process. Hard margarine may contain as much as 60% of the total unsaturated fatty acids as elaidic acid. Palmitelaidic acid is a trans fat that can be formed from hydrogenation of natural fatty acids containing palmitoleic acid or partial saturation of PUFAs with isomerization. The plasma level reflects body burden of trans fatty acids and is useful in monitoring intake of hydrogenated oils.

Family

Configuration

Omega-6

Name

18:2 18:3 20:3

Linoleic acid (LA) Gamma linolenic acid (GLA) Dihornogarnmalinolenic acid (DGW Arachidonic acid (AA)

20:4 Omega-3

18:3 205

Alpha-linolenic acid ( A M ) Eicosapentaenoic acid (EPA) Docosapentaenoic acid (DPA-3) Docosahexaenoic acid (DHA)

225 22:6

Polyunsaturated Fatty Acids Dietary PUFAs are largely composed of two classes of fatty acids, the omega-6 family (e.g., LA), which is abundant in vegetable seed oils, and the omega-3 family (e.g., alpha-linolenic acid [ALA]), which is high in vegetable leaves and modest in soybean oil.' Table 93-2 lists other members of these classes. When the diet supplies adequate LAs and ALAS, they may be used to form the other members in their classes by repeated desaturation and elongation reactions. The delta-6 desaturase enzyme acts as a gateway for the flow of fatty acids through the desaturation and elongation pathway. Although it can act on any longchain fatty acid, the substrate binding affinity increases greatly with the number of double bonds already present (Figure 93-4). Thus 18:3 binds stronger than 18:2, which binds stronger than 18:l. The result is that ALA is quickly converted to EPA, while oleic acid is slowly converted into 20:309 in the presence of appreciable amounts of either LA or ALA. When the two EFAs are absent, however, 20:309 accumulates because the desaturase is free to act on oleic acid. Elevated 20:309 (Mead or eicosatrienoicacid) is a marker that can be used to detect EFA deficiency in addition to the actual concentrationsof the EFAs in plasma and erythrocyte membranes. The delta-6 desaturase enzyme requires the zinc ion for activity. For this reason, supplementing a patient with sources of LA and ALA does little good if zinc deficiency is present. The changes in body growth, organ weights, and lipid concentrations of plasma and liver produced by zinc deficiency are reversed by the addition of GLA-rich primrose oil, but not LA-rich safflower oil,

Delta-6-desaturase

I

I

I

I

I

Elongase

1

1

I

Delta-Sdesaturase

1

I

f pi-lpi Figure 93-4 Formation of longer and more saturated fatty acids. The line thicknesses for the arrows that run from top to bottom indicate the relative binding strengths to the desaturase enzymes.

showing the role of zinc in the delta-6 desaturase enzyme.8The enzyme is also inhibited by high concentrations of saturated fatty acids, monounsaturated acids, and trans fatty acids, all of which compete for the enzyme binding site and yield products that are of less sigruficance to the cell.

Pharmacology of Natural Medicines The primary function of the pathway described earlier is to supply the parent compounds for the 1-, 2-, and 3-series prostanoid and leukotriene pathways (see later). The PUFAs have great impact on health due to their conversion to these compounds, collectively called eicosanoids. They possess extremely potent biologic activities, and their homeostatic functions in regulating blood vessel leaking, lipid accumulation, inflammation, and immune cell behavior are relevant to the initiation and progress of heart and blood vessel disease? These compounds, in turn, are used to amplify and balance signals to the organs, the blood clotting system, and the immune system. Production of eicosanoid hormones is shown in Figure 93-5. The parent compounds are the PUFAs, DGLA, AA, and EPA, and the pathway uses the same enzyme for all three series of products. The concentrations of the three fatty acids present in the phospholipid of the cell membranes where the hormones are produced determine which product will predominate. There is direct substrate competition for the active site on the enzyme, as depicted in Figure 93-5. In a similar manner, the lipoxygenase enzyme initiates the sequence of reactions leading to leukotriene formation. The 2-series that is derived from AA is by far the most proinflammatory. The effects of GLA and DGLA on rheumatoid arthritis and many other inflammatory diseases are mediated via this mechanism. Since dietary intake is a primary determinant of the fatty acids that go into this pathway, there is a direct link between the balance of specific fats in the diet and inflammatory responses and other local control processes. Long-term health maintenance is highly dependent on proper balance of dietary fatty acids. Many people do not eat the fresh nuts, seeds, whole grain breads, and seafood products that are the rich sources of EFAs. The same individuals are likely to have high intakes of saturated and trans fatty acids. The recognition of vast health effects has led to the recent surge of interest in fatty acids. It is no longer adequate (or even correct) simply to recommend the replacement of fats high in saturated fatty acids with those that are high in unsaturated fatty acids. Balanced intake of the unsaturated fatty acids, not just a high PUFA-to-saturated ratio, is required for optimal control of every tissue in the body.1° Although the actions needed to correct fatty acid abnormalities are quite straightforward, the subject of clinical applications of fatty acid profiling is complex. Those who seek to understand the underlying biochemical and physiologic concepts are generally in need of good reference sources. Some that we have found helpful are listed later in “Further Reading.” In addition, Chapter 17 discusses the interpretation of fatty acid testing and clinical interventions.

Figure 93-5

Fatty acid relationships to eicosanoid formation.

Dietary sources of even-numbered medium- and long-chain saturated fatty acids No. of carbons

Common name

Source

10

Capric (C1O:O)

Most plants and butter

12

Lauric (C12:O)

Palm kernel, coconut, laurels

14

Myristic (C14:O)

Nutmeg, palm kernel, coconut, myrtle

16

Palmitic (C16:O)

Common in all animal and plant fats

18

Stearic (C18:O)

Common in all animal and plant fats

20

Arachidic (C20:O)

Peanut (arachis) oil

22

Behenic (C22:O)

Seeds

24

Lignoceric (C24:O)

Cerebrosides, peanut oil

CONTROL OF FAlTY ACID SUPPLY AND DISTRIBUTION Fatty acids are present in the diet in the form of triglycerides in solid fats or liquid oils and as phosphatides in cell membranes of whole foods. They are rarely present in nature as free fatty acids. Table 93-3 lists food sources of the more abundant fatty acids. Foods always contain complex mixtures of fatty acids with enrichment of any single fatty acid rarely exceeding 70%.

Digestion and Assimilation Fats are first digested by the action of bile acids and then pass into intestinal epithelial cells along with cholesterol, where they are associated with proteins, becoming particles called chylomicrons. These are passed into the lymphatic system to flow directly through the heart into systemic circulation. Enzymes in capillary cell walls cause the transfer of fatty acids from the chylomicrons, which become greatly reduced in size and return for

Fatty Acid Metabolism uptake by the liver as chylomicron remnants. By this process, the fatty acids in foods become directly incorporated into the membranes of all tissues.

carbohydrate fat, or protein

Synthesis and Distribution Because of the critical life-supporting functions in forming cell membranes and supplying energy sources and hormone controls, several mechanisms assure that the supply of fatty acids will be continuous, even during short intervals between meals (Figure 93-6). In the fasting state, fatty acids are either produced from carbohydrates or protein or mobilized from adipose stores. The liver handles the role of supply depot by forming another class of lipid-protein particles called very low density lipoproteins (VLDLs). These particles deliver fatty acids and cholesterol to the tissues by mechanisms similar to those for chylomicrons, except that the remnant LDL particles are taken up in total by binding to receptor sites on cell surfaces. By ensuring a constant supply of fatty acids, the body controls one of the most critical materials for carrying out the various life-sustaining functions of growth and repair.

+ 1 Malonyl CoA

Fatty acylcarnitine

i

Fatty acid

Citrate

fatty acid synthesis cycle

a

IStearic (18carbons long) I Figure 93-7

Carbohydrate conversion to fat; inhibition of fatty acid oxidation.

Effect of Low-Fat Diets An individual on a low-fat, high-carbohydrate diet uses the fatty acid synthetic pathway extensively. As shown in Figure 93-7, this pathway requires citrate to leave the mitochondria to generate malonyl coenzyme A (malonyl CoA). The resultant high concentrations of malonyl CoA inhibit the activity of the enzyme that is

I

FOOD

I-Gut Lymphatics

Chylomicrons

the gateway to fatty acid oxidation. For this reason, very low-fat diets do not result in weight loss nearly as fast as one might expect. The burning of excess fat is actually inhibited by the high carbohydrate intake. In individuals with low body fat and good lean mass, high carbohydrate intake spares the use of fatty acids. In more sedentary individuals with lower rates of fatty acid oxidation, the medium-chain fatty acids that are otherwise so quickly used for energy may accumulate above normal levels in membranes. Many other factors influence the rate of oxidation of fatty acids. Dramatically increased fatty acid oxidation occurs in starvation and diabetes mellitus with production of large amounts of ketone bodies that accumulate to give the ketoacidotic condition. Carnitine deficiency results in impairment of fatty acid oxidation and failure of gluconeogenesis, leading to hypoglycemia.

FArrY ACIDS AND HUMAN DISEASES distribution fatty acids (FASTING)

Liver Figure 93-6

Mechanisms for continuous supply of fatty acids to all tissues.

Quantification of the approximately 30 fatty acids present in human tissues is now routinely available. Both deficiencies and excesses of individual fatty acids lead to metabolic problems. A brief discussion of a few highly relevant conditions affected by fatty acid intake is presented here (see Chapter 17 for additional discussion of specific fatty acid imbalances). Table 93-4 lists typical signs and symptoms of fatty acid abnormalities, while Table 93-5 lists some well-documented clinical applications of supplemental fatty acids.

Pharmacology of Natural Medicines Signs and symptoms associated with fatty acid abnormalities Sians and symptoms

Fatty acid association

Action

Emaciation, weakness, disorientation

Caloric deprivation

Add sources of balanced omega-3 and omega-6 fatty acids

Reduced growth, renal dysplasia, reproductive deficiency, scaly skin

Classic essential fatty acid deficiency

Add good quality fats and oils

Eczema-like skin eruptions, loss of hair, liver degeneration, behavioral disturbances, kidney degeneration, increased thirst, frequent infections, poor wound healing, sterility (male) or miscarriage (female), arthralgia, cardiovascular disease, growth retardation

Linoleic acid insufficiency

Add corn or safflower oils

Growth retardation, weakness, impairment of vision, learning disability, poor coordination, tingling in armdegs, behavioral changes, mental disturbances, low metabolic rate, high blood pressure, immune dysfunction

Alpha- or gamma-linolenic acid insufficiency

Add flax, primrose, borage, or black currant oils

Depression, anxiety, learning and behavioral disorders, age-related eye disorders

Longchain PUFA-dependent neuromembrane function

Add fish oils, avoid hydrogenated oils

Cardiovascular disease risk

Prostanoid balance

Add omega-3 PUFAs

Cancer

Low stearic to oleic ratio

Use omega-6 PUFAs with caution

Rheumatoid arthritis

Low GLA and DGLA

Add primrose oil

Deficiency of vitamin B12or carnitine, or both

Increased odd-numbered FAs

Add B12or carnitine, or both

Myelinated nerve degeneration

Increased long-chain FAs

Add high-erucate canola or mustard oils

Fatty liver

Saturated and omega-9 accumulation in liver

Restrict alcohol, add lecithin, increase methionine

Accelerated aging

High PUFA intake without increased antioxidants

Add vitamins E and C, Se, Mn, and Zn

DGLA, Dihomogamma-linolenic acid; FAs, fatty acids; GLA, gamma-linolenic acid; PUFA, polyunsaturated fatty acid.

Developmental Disorders The very-long-chain PUFA docosahexaenoic acid (DHA) has a special role in the formation of the developing nervous system."J2 Children with attention-deficit hyperactivity disorder have lower concentrations of key fatty acids in plasma and in red blood cells.I3 Preterm infants deprived of EFAs during late pregnancy are likely to have failures of normal development, especially the visual system, unless omega-3 fatty acids are ~upp1emented.l~

Heart Disease As mentioned earlier, the general association of dietary fat rather than the specific association of the type of dietary fat with heart disease is a misguided notion that has affected public health for several decades. The notion apparently stems from biochemical studies showing the potential conversion of fatty acids into cholesterol and from blood lipid abnormalities involving familial

hypertriglyceridemias, in which heart disease is a frequent clinical outcome. In the general population the cardiovascular disease association is not with total dietary fat but with fatty acid composition of the diet. We are now seeing the emergence of firm conclusions about the decades-long encouragement of intake of hydrogenated oils in the form of hard margarines and bakery products. By the late 1960s, processed vegetable fats had displaced animal fats in the diets of most people in industrialized countries due to lower costs and purported health benefits. Increased tissue levels of the trans fatty acids from hydrogenated oils is clearly a factor in the etiology of heart di~ease.'~,'~ Higher palmitic and lower omega-3 fatty acids in serum are correlated with higher incidence of coronary heart disease in middle-aged men at high risk for cardiovascular disease." Improvements in plasma fatty acids and vitamins E and C were the only factors found to be related to improvements in life expectancy and 70% lowering of heart disease in a study population.l8

Fatty Acid Metabolism Clinical use of gamma-linolenic acid and alpha-linolenic acid Application

Gamma-linolenic acid

Alpha-linolenic acid

X

xx

Lower blood pressure, lower blood cholesterol, and lower risk of stroke and heart attack Normalize fat metabolism in diabetes and decrease the amount of insulin required by diabetics

X

Prevent liver damage due to alcoholism and decrease withdrawal symptoms after discontinuing the habitual use of alcohol

X

Cancer Because of the pivotal role in tumorigenesis of cellcell recognition factors and the membrane-associated functions controlling that process, changes in the fatty acid composition of cell membranes signal tumor activity. Tumor tissue and virus-transformed cells have a higher content of unsaturated fatty acids, especially oleic acid, which increases relative to-the amount of stearic acid. Such shifts increase the metabolic rates of many lipid-dependent enzymes and are associated with a higher capacity for cell division.19 Changes in dietary fatty acid intake cause alterations in immune response, including antitumor activity?O

Neurologic Disorders

Provide adjunctive treatment for schizophrenics

X

xx

Cause weight loss by increasing metabolic rate and fat burn-off

X

xx

Relieve premenstrualbreast pain (mastalgia) and premenstrual syndrome of bloating, irritability, depression, and aggressive behavior

xx

Prevent drying and atrophy of tear and salivary glands (Sjogren's syndrome)

X

Prevent arthritis in animals

X

X

Improve the condition of hair, nails, and skin

X

xx

Improve certain kinds of eczema

X

X

Slow down or stop deterioration in multiple sclerosis

X

X

Help treat diabetic neuropathy in type II diabetes

X

X

Kill cancer cells in tissue culture without harming normal cells

X

xx

X

Adrenal leukodystrophy and related conditions are associated with the accumulation in nerve sheath membranes of fatty acids more than 20 carbons longz1This situation may be made worse by the lack of sufficient long-chain PUFAs. The indicator for this situation is the sum of the 22-26 carbon length even-numbered fatty acids. Fatty acids have long been known to be important in brain function. The brain has a high content of lipid, and the fatty acid composition is unique in the high content of very-long-chain PUFAs, especially DHA. Strong evidence suggests a relationship between depleted DHA levels in postpartum depression and other forms of depression.22 These results have led to acceleration of studies of the proper clinical application of essential fatty acid therapies in depressed

~

Many health problems are related to inappropriate fat intake and suboptimal fatty acid composition of the body. The therapeutic value of oils rich in specific fatty acids is being reported in the research literature with increasing frequency for a wide range of diseases. The availability of laboratory methodologies for accurate evaluation of fatty acid status now allows for sophisticated clinical manipulation of these important nutrients . ~~

x, Moderate; xx, strong clinical response.

1. Wood CB, Habib NA, Apostolov K, et al. Reduction in the stearic to oleic acid ratio in human malignant liver neoplasms. Eur J Surg On~011985;11:347-348. 2. Mensink RP, zodc PL, Katan MB, Hornstra G. Effect of dietary cis and trans fatty acids on serum lipoprotein[a] levels in humans. J Lipid Res 1992;331493-1501. 3. Longnecker M. Do trans fatty acids in margarine and other foods increase the risk of coronary heart disease? Epidemiology 1993;4 492-495.

4. Lichenstein A. Trans fatty acids, blood lipids, and cardiovascular risk. Where do we stand? Nutr Rev 1993;51:340-343. 5. Pettersen J, Opstvedt J. Fatty acid composition of lipids of the brain and other organs in suckling piglets. Lipids 1992;27761-769. 6. Litin L, Sacks F. Trans fatty acid content of common foods. N Engl J Med 1993;329:1969-1970. 7. Kinsella JE. Requirements and sources of n-3 polyunsaturated fatty acids in the human diet. In Karel M, Lees R, eds. Proceedingsof the MIT conferenceon fish oils. New York Marcel Dekker, 1989.

Pharmacology of Natural Medicines ~

~~

8. Huang YS, Cunnane SC,Horrobin DF, Davignon 1. Most biological effects of zinc deficiency corrected by g-linolenic acid, (18:3 omega 6) but not by linoleic acid (18:2 omega 6). Atherosclerosis 1982;41: 193-207. 9. Stamler J. Nutrition related risk factors for the atherosclerotic diseases-present status. Prog Biochem Pharmacol1983;19:245-308. 10. Horrobin DF, ed. Clinical uses of essential fatty acids. Montreal: Eden Press, 1981. 11. Green P, Glozman S, Kamensky B, Yavin E. Developmental changes in rat brain membrane lipids and fatty acids. The preferential prenatal accumulation of docosahexaenoic acid. J Lipid Res 1999;40:960-966. 12. Farkas K, Noble RC, Speake BK. Developmental changes in the levels of molecular species of triacylglycerol that contain docosahexaenoic acid in adipose tissue of the chick embryo. Comp Biochem Physiol B Biochem Mol Biol 1996;115:1-6. 13. Stevens LJ,Zentall SS, Deck JL, et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr 1995fi2761-768. 14.Innis SM. n-3 Fatty acid requirements of the newborn. Lipids 1992;27879-887. 15. Ascherio A, Katan MB, Zock PL, et al. Trans fatty acids and coronary heart disease. N Engl J Med 1999;3401994-1998. 16. Nelson GJ. Dietary fat, trans fatty acids, and risk of coronary heart disease. Nutr Rev 199856250-252. 17. Simon JA, Fong J, Bernert JT, Browner WS. Serum fatty acids and the risk of stroke. Stroke 1995;26:778-782.

18. Renaud S, de Lorgeril M, Delaye J, et al. Cretan Mediterranean diet for prevention of coronary heart disease. Am J Clin Nutr 1995;61: 36OS376S. 19. Wood CB, Habib NA, Apostolov K, et al. Reduction in the stearic to oleic acid ratio in human malignant liver neoplasms. Eur J Surg Oncol 198531LM7-38. 20.Erikson KL, Hubbard NE, Chakrabarti R. Modulation of signal transduction in macrophages by dietary fatty acids. J Nutr 1995;125: 1683s-16865. 21.van Gee1 BM, Assies J, Haverkort EB, et al. Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with "Lorenzo's oil." J Neurol Neurosurg Psychiatry 1999;67 290-299. 22. Mischoulon D, Fava M. Docosahexanoic acid and omega-3 fatty acids in depression. Psychiatr Clin North Am 2000;23:785-794. 23.Locke CA, Stoll AL. Omega-3 fatty acids in major depression. World Rev Nutr Diet 2001;89:173-185. 24. [No authors listed.] Omega-3 fatty acids in the treatment of depression. Harv Ment Health Lett 2001;184-5. 25.Stoll AL, Damico KE, Daly BP, et al. Methodological considerations in clinical studies of omega 3 fatty acids in major depression and bipolar disorder. World Rev Nutr Diet 2001;

Erasmus U. Fats that heal, fats that kill. Bumaby, Canada: Alive Books, 1986. Murray RK, Granner DK, Mayes PA, Rodwell VW. Harpers illustrated biochemistry, ed 26. Stamford, CT Appleton and Lange, 2003.

Spiller GA. Handbook of lipids in human nutrition. Boca Raton, n: CRC Press, 1996.

88:58-67.

Fish Oils (Omega-3 Fatty Acids, Docosahexanoic Acid, Eicosapentaenoic Acid, Dietary Fish, and Fish Oils) Alexander G.Schauss, PhD, FACN CHAPTER C O N T E N T S Introduction 945 Description 946 Dietary Requirement 946 Explaining Inconsistent Results of Fish Oil SupplementationTrials 948 Pharmacology

Rheumatoid Arthritis 954 Psoriasis 955 Cancer 956 Migraine Headache 958 Diabetes 958 Raynaud Disease 958 Malaria 958

948

Clinical Applications 949 Cardiovascular Disease 949 Elevated Serum Lipids 950 Hypertension 951 Angina Pectoris 951 Stroke 952 Bypass Patients 952 Myocardial Infarction 952 Immune Function 953 Pregnancy and Lactation 953 Nephrotic Syndrome 953 Autoimmune Diseases 954

INTRODUCTION A significant body of scientific evidence indicates that consumption of fish oil rich in dietary omega3 fatty acids is beneficial to human health. The health benefits of fish oil, particularly the association between consumption of omega3 long-chain polyunsaturated fatty acids (PUFAs) and cardiac disease, have long been suspected. Millions of people were given cod liver oil as a fish oil supplement decades ago in the belief that fish oil had health maintenance benefits. Provocative scientific evidence of fish oil’s benefits appeared in the late 1970s when it was claimed that fish oil consumption among Greenland Eskimos and other fish-eating populations might convey a lifetime protective effect against coronary heart disease (CHD).’”

Toxicity 959 Bleeding Time 959 Toxin Contamination 959 Oxidation 959 Measurement of Lipid Oxidation Products in Essential Fatty Acid Supplements 960 Dosage 961 Drug Interactions 961 Conclusion

961

The findings among Greenland Eskimos were particularly intriguing. Greenland Eskimos were found to have low rates of CHD despite a diet rich in saturated animal fats derived from seal and whale meat. It was eventually determined that the Greenland Eskimos’ diet was also rich in fish and that the oil in fish contained large quantities of omega3 fatty acids abundant in docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA). A large study in the United States, the Diet and Reinfarction Trial (DART),”5and two studies in Europe, the GISSI-Prevenzione Trial and the Lyon Diet Heart StudyG8have demonstrated that by increasing dietary omega3 fatty acid intake, a significant decrease in ischemic heart disease occurs.

945

Pharmacology of Natural Medicines

These studies and many others have had a profound effect on public health policy makers' perceptions of the importance of fish and fish oil to human health. For example, on February 8,2002, the U.S. Food and Drug Administration (FDA) announced that it would permit the claim "consumption of omega3 fatty acids may reduce the risk of CHD," to appear on labels of omega3 fatty acid supplements containing a dose level of DHA and EPA of up to 2000 mg per day. The FDA's decision to permit such a claim is sigruficant and timely in that by 2000, one million Americans were reported to suffer heart attacks annually. Approximately one third of these heart attacks, or 300,000, were of the "sudden death" variety, in which individuals die within 2 to 3 hours of their heart attack. A significant body of evidence from the Thrombosis Prevention Trial, the Antiplatelet Trial Collaboration, and the U.S. Physicians Health Study now indicates that including fish rich in omega3 fatty acids with meals just twice a week could significantly reduce the incidence of sudden death from a heart a t t a ~ k . ~On - ' ~the basis of these and several other studies, it is now estimated that this one change in diet could save at least 150,000 people annually from fatal heart attacks.lS1*However, increased daily intake of 5 to 7 servings of fruits, vegetables, and nuts rich in antioxidants may also reduce the incidence of heart attacks. The ratio of omega3 fatty acids to omega-6 (18:2n-6) fatty acids has been the subject of considerable study. Several investigations have shown that a decrease in omega-6 fatty acids combined with an increase in omega3 fatty acids can result in a sigruficant decrease in sudden cardiac death in men.19,20 However, the reduction in risk of a sudden cardiac attack causing death following an increase in omega-3 fatty acid consumption does not occur overnight, but rather after several years of weekly intake. With about 20% to 40% of human body mass being adipose tissue and 15% to 20% of body fat being omega-6 (18:2n-6) in composition, an adult may have more than 3 kg of omega-6 fatty acids in his or her body. This large reservoir of omega-6 may need 3 years to equilibrate with improved dietary lipid intake.21 Hence the recommendation to increase intake of omega3 €atty acids could not come soon enough. Dietary fish oil and fish oil supplements have also been found to ameliorate the signs and symptoms of other diseases and conditions. The EPA and DHA found in fish oil have been shown in various studies to reduce the pain of rheumatoid arthritis by decreasing inflammation, the pain associated with menstrual cramps, the risk of premature delivery in pregnancy, and low birth weights. Beneficial effects have also been reported in the treatment or management of bipolar (manic-depressive) disorder, mild to moderate depression, Raynaud disease, lupus, IgA nephropathy, chronic fatigue syndrome,

Crohn's disease, type 2 diabetes, kidney stones, cystic fibrosis, psoriasis, and ulcerative colitis. Additionally, DHA has been shown to be important for neurogeneses of neuronal synapses and healthy eye development of fetuses and infants.

DESCRIPTION Marine life is generally rich in two omega3 fatty acids (also referred to as n-3fatty acids), EPA and DHA. These long-chained and highly PUFAs contain, respectively, 20 and 22 carbons and 5 and 6 double bonds, also referred to as 20:5n-3 PUFA and 22:6n-3 PUFA. The 20:5n-3 PUFAs and 22:6n-3 PUFAs are abundant in shellfish, sea mammals, and fish, hence the reason Greenland Eskimos' diet is rich in EPA and DHA. By comparison, EPA and DHA levels are low or absent in domesticated land animals. The source of the EPA and DHA found in most marine foodstuffs is phytoplankton, which serves as food for various sea creatures. Fish oil from herring, cod liver, wild salmon, mackerel, and sardines is particularly rich in omega3 fatty acids containing EPA and DHA. Table 94lZ7lists the relative concentration of fatty acids in various common fish species. The habitat in which fish grow has a major impact on their fatty acid composition.22In the wild, fish consume food sources that contain high levels of alpha-linolenic acid (18:3n-3). Fish raised in "fish farms" deserve mention. It has been reported that salmon raised in fish farms receive a steady diet of synthetic pigment to give them a rich pink hue; otherwise, they would be unappetizing given their rather morbid, pale gray appearance. In the natural ocean environment, phytoplankton, which are rich in EPA and DHA, form the basis of the food chain for salmon and contribute to its pink color. Commercial fish foods contain less DHA and EPA and hence lower concentrationsof omega3 fatty acids. Studies have shown that wild fish have higher concentrationsof omega3 fatty acids than pond-reared/cultured fish grown in fish farms and fed commercial feedstuffs that are devoid of EPA and DHA.= For individuals who do not or cannot consume seafood, foods such as tofu, canola oil, black currant oil, flaxseed oil (the best nonfish source), nuts, and soybeans are important sources of alpha-linolenic acid (18:3n-3). However, soy-derived oils and foods and most nuts contain large amounts of omega-6 fatty acids that can reduce some of the therapeutic benefits of the omega3 fatty acids, so finding a prudent balance between omega3 and omegad fatty acids is suggested.

Dietary Requirement Omega3 fatty acid requirements in humans remain controversial. The first suspected case of omega3 fatty acid

Fish Oils ration of fatty acids in fish oils

Oil

Cholesterol (mg/lOO 9)

Unsaturated Mono- ( 5 )

n-3 PUFAs

Poly- (%)

18:3 (5)

205 (I)

22:6 (%)

Cod liver

570

18

51

0.7

9

9.5

Herring

760

19

60

0.6

7.1

4.3

Menhaden

600

34

32

1

Salmon Pilchard

485

24

40

1

-

25

29

Trace

17

9

Mackerel

21

43

Trace

11

11

Anchovy

-

28

29

Trace

17

9

Sardine

-

24

34

Trace

15

10

12.7

8

8

11

Modified from Kinsella JE, Lokesh B, Stone RA. Am J Clin Nutr 1990;52:1-28. PUfAs, Polyunsaturated fatty acids.

deficiency in humans was not reported until 1988.” The patient was a 7-year-old girl with retarded growth who had been fed solely by gastric tube since 3 years of age. A deficiency of omega-3 fatty acid was suspected. Soon after taking cod liver oil and linseed oil supplements, she began to experience normal growth. Some investigators contend that as little as one meal containing fish rich in omega-3 fatty acid a week is sufficient, while others suggest that a much higher intake level of three meals of fish a week is necessary for individuals to benefit from its attributes. An expert workshop held in Europe in 1998 agreed that consumption of omega-3 fatty acids may reduce the risk of CHD.= One year later a similar agreement was published by another expert workshop that addressed the question of what is an adequate intake of essential fatty acids in the United States.26By 2004, evidence was pointing toward the consumption of two to three portions (>8 oz) of fish per week. The United Kingdom Food Standards Agency has recommended that men eat no more than four portions of fish per week and women and children no more than two.* Because the concentration of EPA and DHA in fish can vary depending on its growth environment, fish oil supplements can offer a viable and reliable source of omega3 fatty acid standardized around the content of EPA and DHA. The most popular combination of EPA and DHA found in fish oil supplements remains the brand ”MaxEPA,” which contains 18% EPA and 12% DHA. Eskimo3 is another brand similar to MaxEPA in that it contains 19% EPA and 13% DHA. Other fish oil supplements such as blue-fin tuna oil generally contain ‘Food Standards Agency. Oily fish advice: your questions answered. Available [accessed online at www.food.gov.uWnews/newsarchive/2O~~un/oi/~ishfaq July 7, 20051.

7% EPA and 25% DHA. However, this does not imply that omega-3 fish oil supplements are always derived from pelagic fish (i.e., from deep oceanwater fish), since some freshwater fish contain higher levels of EPA and DHA than some saltwater species (see Table 94-1). Most fish oil capsules contain between 300 and 500 mg of omega-3 fatty acid per gram. Patients using fish oil at the therapeutic levels discussed herein may require between 15 and 30 capsules daily to derive the described benefits, depending on their DHA-to-EPA ratio. At 9 calories/g of oil, this can represent a significant increase in caloric intake and may necessitate an increase in energy expenditure to avoid weight gain. EPA- and DHA-rich fish oil should be kept in capsules (such as soft gelatin with minimal plasticizer contenP; see later discussion on oxidation) capable of providing an oxygen barrier. Otherwise, toxic lipid peroxides (e.g., malondialdehyde)and anisidine isomers may form. Encapsulated liquid sources generally do not have this protection unless they contain antioxidants. Emulsified fish oils are preferred as they are better absorbed in humans. Encapsulated products typically contain fish oil, not fish liver oil. This distinction is important because fish liver oil contains the fat-soluble vitamins A and D, which, if taken in excessive amounts, can cause vitamin A or D toxicity. The lowest consistently reported daily intakes associated with chronic toxicity in adults are 50,000 IU for vitamin A and 10,000 IU for vitamin D. However, there is mounting evidence that vitamin D from sunlight and DHA found in fish oil may reduce the incidence of certain cancers, such as breast cancer. Hence some vitamin D residuals in the fish oil may actually increase its protective value against cancer, as well as CHD. Researchers at the Italian National Cancer Institute completed an investigation aimed at clarifymg

the association between fat intake and breast cancer risk. A total of 4052 postmenopausal women were followed for an average of 5.5 years. During this time 71 cases of invasive breast cancer were diagnosed. The cancer patients were matched with 141 controls. All study participants had blood samples drawn, and red blood cell (erythrocyte) membranes were analyzed for their fatty acid content. The researchers pointed out that erythrocyte membranes are good biomarkers not only for dietary fat intake but also for other dietary and hormonal factors. Women with DHA concentrations in the highest tertile had less than half the risk of breast cancer than did women in the lowest tertile. Polyunsaturated fatty acids overall were also protective, with omega-3 acids being somewhat more protective than omega-6 acids. Saturated fatty acid concentrations were not significantly related to breast cancer risk. A higher concentration of monounsaturated fats, especially oleic acid, was associated with a significantly increased risk. The researchers pointed out that most oleic acid in mammalian tissue is derived from saturated stearic acid through a process involving the enzyme delta 9-desaturase. Saturated fatty acids, cholesterol, carbohydrates, insulin,testosterone, and estrogen all activate this enzyme, whereas dietary polyunsaturated fatty acids and fasting deactivate it. The researchers concluded that the delta 9-desaturase enzyme may be an important link between breast cancer risk and dietary fat c ~ n s u m p t i o n . ~ ~

Explaining Inconsistent Results of Fish Oil Supplementation Trials A number of papers in the fish oil literature have reported equivocal or contradictory results. Many of these differences in outcomes can be explained by the use of olive oil as a placebo or the lack of control for saturated or omega-6 fatty acid intake. Olive oil cannot be considered an inert placebo in trials that investigate effects on platelet function or CHD risk. Several studies have shown that olive oil supplementation has similar inhibitory effects on various aspects of platelet function, including decreased platelet aggregation and thromboxane A2 (TXA2) release, increased platelet membrane oleic acid content, and decreased platelet membrane arachidonic acid c ~ n t e n t .Further, ~,~~ an excess of oleic acid impairs incorporation of arachidonic acid into platelet phospholipids. Another possible complicating factor is the squalene found in olive oil and some deepwater fishes but not in other vegetable 0ils.3~ Other problems include the differing ratios of fatty acids, the position of the fatty acids on the glycerol backbone, and the susceptibility to peroxidation of the various fish oil p r e p a r a t i ~ n s . ~ ~ Also, overprocessing of fish oil supplements can result in a loss of its active constituents and hence an attendant decrease in its efficacy. This has been demonstrated in

at least two studies that looked at such variables as how processing affects levels of triglycerides, cholesterol, lipoprotein(a), atherogenic index, and fibrinogen, following fish oil s ~ p p l e m e n t a t i o n . ~ , ~ ~

PHARMACOLOGY ~~

In general, the effects of supplemental and dietary m a t urated fatty acids appear to be mediated through changes in serum lipids, altered ratios of prostaglandins, decreased platelet aggregation, and modification of cell membrane activity.33 Fish oils appear to reduce undesirable circulating fats and decrease the production of the prothrombotic substance TXA2 by occupying TXA2 receptors and enhancing the production of the platelet antiaggregatory substance prostacyclin. These actions play an important role in inflammation, atherogenesis, thrombosis, and CHD. Fish meals that provide an average of 3.6 g a day of omega-3 fatty acids reduce platelet aggregation and platelet TXB2responses.% Significant decreases in platelet sensitivity to collagen, serum TXB2 levels, and urinary TXB2 metabolites have been observed following omega-3 fatty acid treatment.37EPA supplementation has been shown to decrease synthesis of the omega-6 platelet agonist TXA2 coincident with formation of the inactive omega-3 form, TXA3.38,39 A longitudinal study has shown a pronounced action of dietary omega-3 fatty acids to diminish platelet formation and endothelial deposition that could lead to thrombosis.4o Through the vasodilatory effects of prostacyclin PG13, fish oils may improve peripheral circulation, thereby assisting very low density lipoprotein (VLDL) cholesterol removal. This may be accomplished by altering membrane fluidity in a specific manner, thus affecting the activity of membrane-bound enzymes and resulting in changes in receptor activity, specificity, and signal transduction. Evidence also suggests that fish oils decrease hepatic synthesis of fatty acids and triglycerides and reduce secretion of VLDL cholesterol while displacing arachidonic acid from tissue phospholipids. This results in omega-3 EFA levels that inhibit thromboxane synthesis. Researchers have noted that fish oil effects are selective. EPA and DHA not only displace arachidonic acid from phospholipid pools and inhibit cyclooxygenase, but EPA also becomes a preferred substrate for cyclooxygenase when peroxide tone is high. This results in decreased production of the vasoactive and aggregatory prostacyclin PG12 and increased production of PGI3 that has more potent antiaggregatory effects. According to some researchers, increased bleeding time is due to either less TXA2 or higher prostacyclin I3 levels:' although others contend that EPA conversion to PG13 is the primary cause.42Many researchers believe this

Fish Oils change is one of the primary factors that decreases the risk of atherosclerosis and t h r o m b ~ s i sThese . ~ ~ findings may explain some of the epidemiologic evidence of decreased coronary artery disease and prolonged bleeding time seen in some Eskimos and in those Japanese found eating a diet rich in fish.% Fish oils rich in EPA and DHA have also been found to suppress production of inflammatory mediators found in patients with rheumatoid arthritis and psoriasis. The antiinflammatory effect of the omega3 fatty acids is probably due to reduced production of leukotrienes, interleukin-2, and tumor necrosis factor-alpha (TNF-a), all principal mediators of inflammation. A recent study has found that the ability of fish oil to decrease TNF-a production is influenced by an inherent TNF-a production and by polymorphisms in the TNF-a and lymphotoxin alpha genes (also known as tumor necrosis factor-beta).51 In relation to coronary artery disease, ingestion of fish oil and its effect on platelets, erythrocytes, neutrophils, monocytes, and liver cells are considered to be important in explaining its benefits. The increased concentrations of EPA and DHA from the ingestion of fish oil have been shown to do the following: Decrease production of prostaglandin E2 (PGE2) metabolites Decrease production of TXA, (an active vasoconstrictor and platelet aggregator) Increase prostacyclin PGIB(an active vasodilator and inhibitor of platelet aggregation) Increase production of leukotriene B5 (a weak inducer of inflammation; weak chemotactic agent) Decrease production of leukotriene B4 (a weak inducer of inflammation; inducer of leukocyte adherence and chemotaxis)

CLINICAL APPLICATIONS Cardiovascular Disease The EPA and DHA in fish oil inhibits the development of atherosclerosis, which can increase the risk of primary cardiac arrest?, Evidence from large animal studies indicates that fish oil prevents atherosclerosis by mechanisms other than simply lowering cholesterol, including the following: Stimulation of endothelial production of nitric acid Decrease of cytokine and interleukin-1production Inhibition of monocyte migration into the plague These three events can, when uncontrolled, contribute to the characteristic yellowish plaques (atheromas) that contain the combination of cholesterol, lipophages, and lipoid material seen in the intima and inner media of largeand medium-sized arteries found in atherosclerosis.

Hence the demonstrated ability of fish oil to control all three, combined with its ability to lower VLDL and elevated triacylglycerols, can be a useful approach in the prevention of ventricular fibrillation and sudden death. That fish oil can perform this favorable reduction in risk of sudden death, not shown to be possible by the consumption of linolenic acid or linoleic acid from vegetable oils, has been shown in several double-blind, placebo-controlled, randomized trials conducted in human subjects, especially when compared with vegetable oils.& Increased stiffness in the large arteries can lead to systolic hypertension and increased pulse pressure (which is the difference between diastolic and systolic pressure), both factors that can contribute to increased risk of CHD. Whether DHA or EPA can improve systolic and pulse pressure and vascular resistance has been studied. Thirty-eight middle-aged men and women with elevated plasma total cholesterol consumed a DHA, EPA, or placebo supplement during a 7-week intervention. In contrast to the placebo group, and showed no changes, systemic arterial compliance rose 36% in the EPA group and 27% in the DHA group, and there was a trend toward a reduction in pulse and systolic pressure.'* Also, both the EPA and DHA groups experienced significant declines in plasma total triacylglycerol concentrations. In addition, diets rich in omega-3 fatty acids from fish oil lower triglyceride levels, especially in those with severe hypertriglyceridemia, for whom attempts to correct the cause through exercise, the drug gemfibrozil, or other dietary modifications have proven inadequate. This benefit is not seen with plant source oils containing land-based alpha-linolenic fatty acid-rich polyunsaturated fat sources ( e g , flaxseed oil) or via reduction of saturated animal fatty acids k1take.4~ At a 1994scientificmeeting on the role of fish oil in cardiovascular health, the following favorable mechanisms of action of omega-3 fatty acids in humans were reported inhibition of VLDL triglyceride synthesis; decreased apoprotein B synthesis; enhancement of VLDL turnover with an increased fractional catabolic rate of VLDL; depression of LDL synthesis; and reduction of postprandial li~idemia.4~ The therapeutic use of fish oil supplements is essential in patients with type 5 hyperlipidemia. All benefits of fish oil may not be conferred by only eating fish. Favorable therapeutic and preventive effects may require between 5 and 20 g/day of linolenic acid and fish oil, which is unlikely in contemporary diets consumed in industrialized societies-hence the use of fish oil supplements. The prevention of thrombosis by fish oil consumption is suggested by a number of studies, particularly in patients receiving coronary bypass surgery. In a randomized controlled trial of bypass patients who received

Pharmacology of Natural Medicines ~

warfarin or aspirin as anticoagulants, those subjects who also received fish oil had significantly fewer vein graft

occlusion^.^^ Despite all of these findings related to CHD by 1996, a 1997American Heart Association (AHA) science advisory report on fish oil consumption stated: ”There is no convincing role for fish oil supplements in the prevention of CHD.’” The AHA report did accept mounting evidence that sudden cardiac deaths may be prevented but took the position nevertheless by stating that “further studies are needed to explore the potential of fish oil in the prevention of sudden cardiac death.” Apparently, the AHA’S scientists require ”compelling evidence” before they would recommend general usage of fish oil supplements to reduce CHD or sudden death, despite the conclusion of one of the studies they cited that found that fish oils reduce myriad potential atherogenic processes associated with atherosclerosis, CHD, and sudden cardiac-related deaths.55 Research has focused more on fish oil supplements than on fish consumption. This may be due to dietary surveys that have found that less than half of Australians, Americans, and Canadians regularly eat fish. In addition, fish is a generalized term and some popular species of fish contain low levels of omega-3 fatty acids.

ELEVATED SERUM LIPIDS The most consistent effect of fish oils on serum lipids is a reduction in total triglycerides and VLDL cholesterol, especially in patients with severe hypertriglyceridemia. In general, dietary fish oils appear to both reduce undesirable serum-circulating fats and decrease the production of the prothrombotic thromboxanes. In most studies, fish oil supplementation causes a sigruficant reduction of VLDL cholesterol, plasma triglycerides, plasma cholesterol, and LDL cholesterol. In hypertriglyceridemic patients, fish oil supplementation typically results in a significant decline in VLDL cholesterol levels because large decreases in triglyceride levels lead to a decrease in VLDLS.@~~-~~ Some studies have not found decreases of total cholesterol or LDL cholesterol following fish oil supp l e m e n t a t i ~ nHowever, .~~~ these equivocal studies used olive oil as a placebo, whch, as discussed earlier, is a confounder. For patients with elevated serum cholesterol (>7.75mmol/L) or triglycerides (>5.64mmol/L), there is sufficient evidence to consider fish oil supplementation of 5 to 10 g/day.@In one study of 365 patients, supplementation with 10 ml/day (9.2 g) of MaxEPA resulted in significant reductions in triglyceride levels, which were maintained over a period of 4 years.65Continuing

~~

reductions were observed in persons remaining in the study more than 4 years. The authors concluded: “For triglycerides to remain depressed it seemed necessary to maintain a daily intake of 9.2 g MaxEPA.” In a Canadian study, triglyceride levels decreased 31% in 9 days following fish oil supplementation.66 However, total and HDL cholesterol levels did not change. Nine days after supplementation ceased, triglyceride levels showed a trend of returning to baseline. As total cholesterol and LDL cholesterol levels are predictors of death from cardiovascular and CHD, their control is crucial. Almost all epidemiologic studies show that populations eating fish have a reduced death rate from CHD. By 1990,22 primary and secondary prevention trials demonstrated that lowering serum total cholesterol and LDL cholesterol through either diet or drugs reduced the incidence of CHD among survivors of myocardial infarction. A 10-year prospective study of male mortality rates due to cardiovascular disease found that LDL cholesterol, HDL cholesterol, and total cholesterol levels are the most predictive indices of subsequent mortality from cardiovascular disease among men with and without preexisting cardiovascular disease.67 Support for fish oil intake in the reduction of CHD comes primarily from epidemiologic studies’” and clinical and experimental studies in animals and A 20-year prospective study conducted in the Netherlands found that consuming as little as 35 g/day of fish (0.5 lb/wk) might be of benefit in preventing, and reducing mortality from, CHD.” In contrast, two epidemiologic studies found no relationship between fish consumption and cardiovascular The effect of fish oil consumption on lowering serum lipids may account for the lower mortality rate due to cardiovascular disease found in coastal Alaskan natives, who, compared with mainland Americans, eat a diet rich in fish and other sea creatures. Autopsies on 339 Alaskan natives found that only 10.3% died of cardiovascular causes, compared with 50% of all deaths among those subjects who lived on the American mainland.n The possibility of fewer fatal arrhythmias due to high fish consumption has also been proposed to explain the lower death rate of native Two studies involving rats have shown that ingestion of either as much as 30% or as low as 0.4% of energy in the form of omega-3 fatty acids from fish decreased the incidence of ventricular f i b r i l l a t i ~ n .The ~ ~ ,antiarrhythmic ~~ aspects of PUFAs are supported by a number of clinical and experimental studies in animals and human^.^^-^* Some investigators conclude that fish oil is more effective at reducing ventricular arrhythmias than pharmacologic agents in the prevention and management of cardiovascular disease.”

Hypertension

Another proposed mechanism is that fish oils may facilitate excretion of sodium and fluid by the kidneys. This is supported by a reported but unpublished, double-blind, cross-over study in which researchers placed healthy, nonhypertensive men and women on a diet supplemented with approximately 1 g/day of PUFAs for 28 days.95Each participant received capsules with either fish oil or safflower oil. The fish oil dose was similar to the amount consumed in a single daily serving of tuna, lake trout, or salmon. After 2 weeks, the subjects crossed over to the other supplement. The study found an average 2 to 3 mmHg drop in both diastolic and systolic blood pressure in those who received fish oil supplements. The researchers also found that fish oil increased urine output by approximately lo%, performing much like a low-sodium diet. This resulted in a reduction in fluid volume. Unlike diuretics, the fish oil supplementation did not increase potassium excretion.

There is some evidence from placebo-controlled studies that fish oil reduces blood pressure in a dose-response fashion,especially in patients with hypercholesterolemia and hypertension, but not in subjects with normal blood pressure.83 Fish oil seems to have hypotensive effects, ranging from limited (dosages of 5 g/day or less) to substantially larger d o ~ a g e s ?although ~ , ~ ~ ~ there is some conflicting evidence.93It has been proposed that fish oil depresses vascular response to the hormones involved in hypertension." Another suggestion is that fish oil acts by increasing vasodilatory prostaglandins PGIl and PG13, and that this increase accounts for observed reductions in blood pressure." To test this hypothesis, one study examined the effect of fish oil on blood pressure in men with mild, essential hyperten~ion.9~ One group received 10 ml of fish oil (3 g of omega3 fatty acids), a second group received 50 ml (9 g of EPA and 6 g of DHA), a third group received 50 ml of safflower oil (39 g of omega-6 fatty acids), and a fourth group received 50 ml of a mixture of coconut, olive, and safflower oils. The latter group represented the approximate amount and ratio of fatty acids consumed in the average American diet (39%saturated fat, 46% monounsaturated fat, and 15%polyunsaturated fat). The group receiving the highest dose of fish oil (50 ml) had an average reduction of 6.5 mmHg in systolic pressure and 4.4 mmHg in diastolic pressure. None of the other groups, including the low fish oilsupplemented group, demonstrated blood pressure reductions in the aggregate. The study did not find the expected association between increased production of PGI, and PG13and sustained reduction in blood pressure. This suggests that vasodilatory prostaglandins are probably not the primary mediators of blood pressure reduction by fish oil consumption, although they may play a role.

A number of studies have shown that fish oil supplementation reduces the number of angina attacks and reduces mortality in men recovering from myocardial i n f a r ~ t i o n . 9Significant ~~~ rheological improvements in patients with stable angina pectoris may occur following daily fish oil supplementation with 2.8 g of EPA and 1.8 g of DHA (equivalent to 15 capsules of M ~ X E P A ) . ~ ~ In a double-blind, placebo-controlled study, fish oil supplementation resulted in increased red cell deformability, reduced whole blood viscosity, and prolonged bleeding time compared with olive oil supplementation. The frequency of angina attacks decreased in both groups. However, neither type of oil affected exercise capacity or hemodynamic response to exercise. In 1999 a group of researchers in Italy reported that supplementation with fish oil (containing580 mg of EPA and 290 mg of DHA) sigmficantly reduced mortality among patients who survived a first heart attack.6 This resulted in an editorial comment on the study in the Lancet that wondered if fish oil could protect against ischemic heart disease.%Two years later the researchers reanalyzed their data to determine how fish oil exerts its protective effect.'@They found that the reduction in mortality occurred after only 3 months of supplementation and continued thereafter. The reduction in the incidence of sudden cardiac death accounted for about 57% of the total improvement in mortality rates. At the end of the study 2.7%of the placebo group participants had died from sudden cardiac death as compared with only 2% in the fish oil group. Overall, cardiovascular death (including stroke) at the end of the study was 6.5% in the placebo group versus 5.5% in the fish oil group. There was no statistical significant difference in the incidence of nonfatal heart attacks between the fish oil

Recent evidence also suggests fish oil may prevent cardiovascular disease in Rhesus monkeys and hyperlipidemic pigs despite lack of improvement in serum cholesterol levels.81,82 This retardation in the initiation and progression of atherogenesismay be due to fish oil's depression of inflammatory eicosanoid metabolism in platelets, macrophages, and monocytes. The therapeutic dosage of fish oil for the treatment of cardiovascular disease should be 5 g/day or m0re.4~One researcher has suggested that for both prophylactic and therapeutic applications, the most efficacious use of fish oil would be to concomitantly lower total fat intake to no more than 30%of calories and saturated fatty acids to no more than 30%of total fat, while limiting omega-6 fatty acids (vegetable oils) to a maximum of 10% of total fat intake.49

Angina Pectoris

Pharmacology of Natural Medicines

and placebo groups. The researchers concluded that fish oils exert their protective effect by preventing fatal ventricular arrhythmias rather than through an improvement in cholesterol profile. They did note a small drop in triglyceride levels of 4.6%in the fish oil group but found no significant differences in LDL and HDL cholesterol between the two groups. They also point out that the number of lives per 1000 patients that could be saved every year by giving heart attack survivors fish oil exceeds the number of lives per 1000 patients estimated to be saved by treating heart disease patients with high cholesterol levels with pravastatin. This puts fish oil supplements squarely in the category of a highly effective unpatentable heart drug. Evidence is growing that high blood levels of C-reactive protein (CRP)are associated with an increased risk of CHD and heart attacks. Danish research has revealed that CRP levels can be kept lowered by regular consumption of fish or fish oils.1o1The investigators studied 269 patients with suspected coronary artery disease based on angiography and found that patients with one or more blocked coronary arteries had significantly higher CRP blood levels than patients with no sigrulicant blockages, followed by the observation of an inverse correlation between CRP blood levels and the level of DHA in granulocytes. The level of DHA in granulocytes was found to closely correlate with fish consumption. This led the researchers to conclude that DHA has an antiinflammatory effect that can result in lower CRP levels, thereby suggesting that fish or fish oil consumption may decrease the risk of coronary artery disease.

Stroke A 1995 study found that men who ate fish five or more times a week had a 40% lower risk of experiencing a stroke than men who ate fish less than once a week. A similar study in women by researchers at Harvard Medical School found even more impressive results for women.1o2In this study 79,839 female nurses between the ages of 34 and 59 were followed for 14 years, by which time 574 had experienced a stroke; 303 of the strokes were caused by blood clots, while another 181 were caused by a ruptured artery, and the remaining 90 were of undetermined origin. It was determined that women who ate fish once a week lowered their risk of a stroke of any kind by 22%. However, women who consumed fish five or more times per week reduced their risk by 52%. The investigators concluded that women whose intake of fish oils is 0.5 g per day or more have a 30% lower risk of a stroke than women whose intake is below 0.1 g per day. Of particular interest was the finding that in those women who had a high fish or fish oil consumption, there was no evidence of an increased risk of hemorrhagic stroke. The researchers

concluded that the protective effect of fish oils are due to their ability to inhibit platelet aggregation, lower blood viscosity, suppress formation of leukotrienes, reduce fibrinogen levels, reduce blood pressure, and reduce insulin resistance. Curiously, the beneficial effects were substantially more likely in women who did not take aspirin on a regular basis.

Bypass Patients Some studies have demonstrated that fish oil supplementation may help prevent reclosing (restenosis) of the arteries after angioplasty. In one such study bypass patients were supplemented with 4 g of fish oil a day.Io3 One year later those patients who consumed the fish oil supplements had an occlusion rate of 27%,while control patients had a 33% rate of occlusion, or a 23% relative improvement. On the basis of a postoperative evaluation 3 weeks after patients had cardiac transplants, it was found that patients who consumed fish oil supplements had normal endothelium-dependent coronary vasodilation, which remained abnormal in patients who did not consume fish oil.

Myocardial Infarction

Several studies of rodents have shown that dietary fats modulate the electrical stability of the myocardium. The appropriate fatty acids can reduce the vulnerability to arrhythmia during myocardial i s ~ h e m i a . ~ ~ , ~ ~ , ' ~ Raising the omega-3 fatty acids to higher levels in the myocardium may also prevent postinfarction ventricular fibrflation.7L10531C6 One study evaluated the effect of dietary intervention in 2033 men recovering from myocardial infarction? Patients were randomly allocated to receive one of four types of dietary advice: 1. Lowered intake of dietary fat 2. Consumption of at least two portions of fatty fish (200 to 400 g) a day 3. Supplementation with three capsules (1.5 g) of MaxEPA a day 4. Increased dietary fiber intake At the end of 2 years, the group consuming fish were found to have increased their EPA intake to four times that of other subjects. This group also experienced sigruficantly lower mortality. The fat and fiber advice groups showed no differences in mortality. Although the rate of recurrence of heart attack was similar in all groups, the fish and fish oil group had a 29% reduction in risk of death compared with the other groups. These findings are in direct conflict with an earlier study showing no such benefits.lo7However, it may be sigruficant that the earlier study was conducted over the short period of 6 weeks. Even in patients with no apparent clinical evidence of arterial disease, fish consumption has been shown to

Fish Oils

improve arterial wall function. One study found that in both healthy and non-insulin-dependent diabetes mellitus patients, those who ate fish showed significantly better compliance of their left subclavian artery and femoral arteries.lo8

Immune Function Research in both animals and humans has not yet determined whether fish oil supplementation suppresses or enhances immune function. For example, recent laboratory animal experiments show that supplementation with gamma-linolenic acid or fish oil results in marked changes in the structure and function of leukocyte membranes consistent with improved immune response.10g In addition, animal studies have shown enhancement of the metabolic processes associated with resistance to infection and such diseases as cancer."O However, longterm supplementation with EPA results in pronounced inhibition of the oxidative processes necessary for the immune response. In humans an omega-3enriched, low-fat, low-cholesterol diet suppresses immune function, possibly increasing susceptibility to infection. For example, increasing the typical American diet content of omega-3 fatty acid intake from 1%to 2.5% over a 6-week period results in decreased PGE2 levels, helper cell activity, and other indices of immune function.lWMore research is necessary to clarify the differences in animal and human responses to fish oils.

Pregnancy and Lactation In recent years an extensive number of studies have been published on the effect of DHA and fish oil on pregnancy and During pregnancy, growth of new tissue raises the requirement for essential fatty acids, as mobilization moves polyunsaturated fatty acids from maternal tissue stores to the fetus. A study of 19 normal pregnant women found an increased requirement for omega-3 EFA intake during pregnancy, lactation, and infancy.l17 The authors stated that because omega-3 fatty acids decrease in maternal circulation during pregnancy and remain low for at least 6 weeks after pregnancy, "it may be reasonable to increase the omega-3 PUFA in the diet before, during, and after pregnancy." The authors further suggest that "dietary supplementation may be indicated," since maternal levels of EPA were 42%of normal value. The study further concluded the following: It seems reasonable to suggest that 18:3 omega-3 intake be increased during pregnancy, lactation, and infancy, when requirements for omega-3 PUFA are highest, during the development of the nervous system, which is rich in lipids containing high proportions of omega-3 PUFA.The mental apparatus of the coming generation is developed in utero, and the time to begin supplementation is before conception. A normal brain

cannot be made without an adequate supply of omega3

PUFA, and there may be no later opportunity to repair the effects of an omega-3 fatty acid deficiency once the nervous system is formed. Supplementation with either ALA or EPA may restore EFA levels in such deficient individuals.

In a study of 9000 pregnant women, investigators report that women who consume fish once a week during the first 16 weeks of pregnancy have a 3.6 times lower risk of giving birth to a low-birth-weight infant (>2500 g) or premature delivery (born before 259 days) than those women who ate no fish or seafood during this same time period.118The researchers also found that women whose daily intake of fish was less than 15 g were significantly more likely to give birth to a preterm or underweight baby than women who had higher intakes of fish. This would suggest that even small amounts of fish taken during the early stages of pregnancy can protect against preterm deliveries and low-birth-weight infants. However, recent reports of mercury contamination of some species of fish urge caution. Mercury is a known neuro- and feto-toxic heavy metal. There is no safe intake level of mercury. Fish oil supplements have been found to contain undetectable mercury levels, hence offering a compelling substitute source of omega-3 fatty acids for females of childbearing age. Another study has looked at DHA intake and lactation in lactating women 4 to 6 weeks after delivery.l19 Those women who supplemented their diet with 200 mg of DHA/day had 28% more breast milk than a placebo group consuming 200 mg of a corn/soy oil mixture.

Nephrotic Syndrome Both hypertriglyceridemia and hypercholesterolemia are common in patients with nephrotic syndrome. This association results in an increased risk of CHD. Fish oils have been found to lower serum triglycerides in patients with nephrotic syndrome and may therefore be of clinical benefit.& IgA nephropathy is a kidney disease that can follow a viral infection of the gastrointestinal or upper respiratory tract. The disease has no known cure. Treatment with steroids, antibiotics, anticoagulants, antiplatelet drugs, and phenytoin have been found largely ineffective. About 20% to 40% of all IgA nephropathy patients develop renal failure 5 to 25 years after diagnosis. One study at the Mayo Clinic has found that fish oil supplementation can be effective in slowing down the progression of the disease.120 The progression of the disease was judged by regularly measuring the level of creatinine in blood serum during the 2 years of the trial. A clear difference was observed. The patients in the fish oil group receiving 12 fish oil capsules a day containing 1.9 g of EPA and 1.4g of DHA had an average median increase in serum creatinine of only 0.03 mg/dL, while the patients in the placebo group experienced an increase

placebo control group rather than any improvement by the fish oil Other studies did not suffer from this confounder. A double-blind, placebo-controlled study of patients with rheumatoid arthritis found sigruhcant improvements in several clinical indices during 12 weeks of fish oil supplementati~n,'~~ as did another study of patients Autoimmune Diseases with either rheumatoid arthritis or psoriasis who reported i r n p r o ~ e m e n tPatients .~~ taking 18 g of fish oil Fish oils may play a role in the treatment of autoimmune (containing 153 mg EPA and 103 mg DHA) for 6 weeks disease (e.g., lupus erythematosus, dermatomyositis, reported significant improvement in symptoms. Samautoimmune nephritis, multiple s c l e r ~ s i s ) ~ and ~~-'~~ ples of peripheral blood mononuclear cells from these inflammatory disorders (e.g., rheumatoid arthritis,Iz4 patients showed suppressed synthesis of the two mediapsoriasis,lE atopic dermatitis'). The evidence of fish oil's tors of inflammation, IL-l-@ and TNF-a, compared with possible benefits is derived f?om animal studies using patients receiving placebos. Of particular interest was inbred mice strains.@ Observational studies and anecthe finding that the antiinflammatory effect of the fish dotal reports by lupus patients suggest some benefit. oils continued for up to 4 weeks after cessation of supRheumatoid Arthritis plementation. In another randomized, double-blind, placebo-controlled study conducted over a 24-week Rheumatoid arthritis is uncommon among Eskimos, period, 49 patients with rheumatoid arthritis experiyet by comparison 2% of the world's population suffers enced significant clinical benefit, particularly in tender from rheumatoid arthritis, which is three times prevalent joints, from supplementation of either a low dose of in females more than in males. The disease can strike at 27 mg/kg EPA and 18 mg/kg DHA or a high dose of any age due to inflammation of joint tissues associated with production of toxic substances in the synovium that 54 mg/kg EPA and 36 mg/kg DHA. Interleukin-1 levels can lead to cartilage destruction. (An interesting footnote decreased 54.7% in the high-dose group and 40.6% in the low-dose group.91 is a study from Spain that found decreased levels of In another 15-week study involving 50 patients who omega3 fatty acids in the blood and synovial fluids of male and female rheumatoid arthritis patients compared had been diagnosed with rheumatoid arthritis, fish oil with healthy controls.'26) supplementation was studied. The patients were all The usual symptoms associated with rheumatoid consuming a diet that contained less than 10 g/day of omega-6 fatty acids. These fats are known to promote arthritis are swelling of the affected joints; fatigue; general malaise; and morning stiffness, in particular. inflammation through their eicosanoid metabolites. Half Evidence is mounting that omega3 fatty acids found the patients were given fish oil capsules to provide a in fish oil may beneficially influence the course of treatdaily intake of 40 mg/kg body weight (about 2.8 g for a ment in patients with rheumatoid arthritis due to their 70-kg person); the other half received placebo capsules inhibition of inflammation and incorporation into cell containing 50/50 corn/olive oil. All subjects continued membrane^.'^^ A considerable body of evidence indicates with their regular diet and medications. About half the that rheumatoid arthritis is caused by oxidative stress patients dropped out during the experiment, mainly due involving excessive production of proinflammatorycomto changes in their medications. Complete clinical evalupounds such as interleukin-l-beta (IL-1-p) and TIW-a. ations were carried out at baseline, 4, 8, and 15 weeks. Although there were no significant changes after 4 or Further support comes from a population-based, case-controlled study in women that found a decreased 8 weeks, after 15 weeks major improvements were noted risk of rheumatoid arthritis in those who consumed the in the group receiving fish oil. Particularly impressive most while other studies have shown that fish was the decrease in morning stiffness and overall assessoil supplementation can reduce IL-1-p production, ment of disease activity by both the patients and physiresulting in a reduction in morning stiffness and painful cians. Significant improvements were noted in 6 of the points.'28 9 evaluation parameters in the fish oil group, while no In addition, 14 randomized, controlled clinical trials improvements were noted in the control group. Only have reported significant benefits from fish oil supplethe total number of joints affected, the erythrocyte sedimentation in rheumatoid arthritis patients. A doublementation rate, and the CRP level were unaffected by blind, placebo-controlled study of rheumatoid arthritis supplernentation.lm patients given 1.8 g/day of fish oil showed less morning Dr.Joel Kremer of Albany Medical College in New York stiffness and tender joints. Analysis of this study has concluded that taking 3 to 6 g daily of omega3 fatty showed that the purported benefits of fish oil could have acid fish oils for 12 weeks or more will significantly been due to the unusually high dropout rate of the diminish joint pain and morning stiffness in rheumatoid

of 0.14 mg/dL annually, indicating that their disease was progressing significantly faster. After 4 years, 40% of the patients in the placebo group had died or developed end-stage renal disease compared with only 10% in the fish oil group. No adverse effects of fish oil supplementation were observed.

Fish Oils arthritis patients. Several studies have shown that the improvement in some patients is sigruficant enough to allow them to materially reduce or completely discontinue their use of nonsteroidal antiinflammatory drugs (NSAIDs) such as diclofenac and naproxen. Dr. Kremer also points out that fish oil supplementation has been found to benefit patients with inflammatory bowel disease.131Kremer 's assertion is based on a double-blind, placebo-controlled study involving 66 patients with active rheumatoid arthritis indicated by the presence of at least three of the following symptoms: six or more tender joints; three or more swollen joints; 30 minutes or more of morning stiffness; and a sedimentation rate of 28 mm/hr or higher. The patients were weaned off their antiinflammatory medications and then started on the NSAID diclofenac (75 mg twice a day). After 2 weeks the subjects were randomized into two groups receiving either 130 mg/kg per day of either fish oil (EPA + DHA ethyl esters) or corn oil (an omega-6 fatty acid). The daily dose of fish oil corresponds to about 9 g/day for a person weighing 70 kg. After 18 or 22 weeks, the diclofenac was replaced by a placebo and the fish and corn oil supplementation continued for another 8 weeks, after which all patients were switched to the corn oil plus diclofenac placebo until the end of the study at week 48. The researchers found that the fish oil group achieved a significant lessening of their symptoms from the start of supplementation and until the replacement of diclofenac with the placebo. No statistically significant benefits were observed in the corn oil group. Several patients in the fish oil group maintained their improved status even after diclofenac withdrawal. The researchers concluded that some rheumatoid arthritis patients using fish oil supplementation may be able to discontinue nonsteroidal antiinflammatory drugs without experiencing a flare-up of their disease. They also noted that the benefits achieved from supplementing with 9 g/day of fish oil were no greater than those observed in other studies using only 3 to 6 g/day.

Psoriasis Psoriasis is a skin disease characterized by thick silvery white scales that are surrounded by a red inflamed border. Psoriasis is accompanied by high concentrations of arachidonic acid in the plaques and profound changes in the metabolism of eicosanoids, leading to an increase in proinflammatory agents. Fish oils presumably improve the condition by decreasing the levels of inflammatory leukotriene compounds, especially leukotriene B4r a lipoxygenation product of arachidonic acid. The EPA in fish oil replaces the arachidonic acid in phospholipids, leading to the formation of leukotriene B5rather than Blr resulting in a much weaker inflammatory response.132 This effect has been demonstrated in neutrophils isolated from the peripheral blood of patients given fish oil

to treat their psoriasis.133Patients who showed evidence of clinical response to fish oil therapy for their psoriasis were shown to have higher levels of leukotriene B5 than those failing to improve. Patients with psoriasis (vulgaris) have been successfully treated with a low-fat diet supplemented with fish An impressive 77% (23% were nonresponders) of the patients reported either excellent, moderate, or mild improvement. It was interesting to note that a number of patients did not show improvement until at least 4 months of supplementation. This may indicate the importance of allowing adequate time for clinical improvement after initiating fish oil therapy. Etretinate is a powerful drug used to treat skin disorders such as psoriasis. It can cause serious adverse effects, however, when used in the regularly prescribed dose of about 1 mg/kg per day. One study has shown that a combination of EPA and etretinate at a lower dose (0.3 to 0.5 mg/kg per day) works as well as the pure, high dose and has significantly fewer side effects.lMThe clinical trial included 40 psoriasis patients who were randomly assigned to receive either 20 mg etretinate daily (in capsules) or 20 mg etretinate plus 1800 mg of EPA ethyl ester (in capsules). After 12 weeks the participants were examined to determine the extent of improvement. Forty-five percent of the patients in the combination group showed excellent improvement (>75%)compared with 15%in the pure etretinate group. The time to achieve a 50% improvement in symptoms was also considerably shorter in the combination group (5.1 weeks) than in the monotherapy group (7.6 weeks). Adverse reactions such as inflammation of the lips, dry mouth and eyes, and scaling were observed in both groups but were mild and tolerable. The researchers conclude that the combination regimen is effective in the treatment of psoriasis without marked adverse reactions. Another study investigated whether topical application of fish oil to skin areas affected by psoriasis would alleviate symptoms. The clinical trial involved 25 patients with psoriasis who were randomly assigned to apply either fish oil or liquid paraffin to their psoriatic plaques and leave them covered for 6 hours overnight under an occlusive dressing.135The treatment was repeated daily for a 4-week period. Fish oil proved highly effective in reducing scaling (severity of scaling went from an average rating of 2.91 to 0.32 on a scale from 0 to 4), plaque thickness (from a rating of 2.21 to 0.52), and erythema (from a rating of 2.71 to 0.90). Itching was not relieved by the fish oil treatment. The 4-week liquid paraffin treatment was also effective in reducing erythema but was significantly inferior to the fish oil treatment in reducing scaling and had no significant effect on itching or plaque thickness. Both treatments were well accepted by the patients, and the researchers concluded that they are

both clinically effective with the fish oil treatment being superior to the paraffin treatment.

Cancer Numerous animal studies have demonstrated anticancer activity by fish oil.'% Experimental studies in rats have demonstrated that while corn oil-fed rats show an increased risk for colon cancer, fish oil-fed rats show both decreased risk and slowed progression of this cancer.137Fish oil appears to exert this anticancer effect by altering carcinogen metabolism and modifying prostaglandin synthesis. In Japan, which has the lowest breast cancer rate of any industrialized country, fish consumption is the highest among such countries. Conversely, in those countries where the risk of breast cancer is highest, the proportion of calories in the diet from fish is relatively low. A large epidemiologic study of 23 dietary factors in countries with high and low risks of cancer found a strong association between the percentage of calories from fat and the risk of breast cancer.138Fish consumption was found to have the next most sigruficant association, a negative correlation. A British investigation of the association between a high dietary fat intake and the risk of developing breast and colon cancer revealed interesting findings conceming the incidence of cancer. The study compared cancer mortality rates in 24 European countries, Canada, and the United States with fish consumption and the intake of animal fats.139In countries where the animal fat intake was high, the researchers found a clear inverse correlation between the ratio of fish fat to animal fat and the risk of developing breast cancer in women and colon cancer in both men and women. A similar correlation was found between cancer risk and the ratio of fish fat to total fat intake. This led the investigators to conclude that fish and fish oils not only protect against colon cancer in men but also against colon and breast cancer in women. This protective effect, however, is only apparent in countries where the intake of animal fats is high. In other words, a high intake of fish or fish oils counteracts the detrimental effects of a high animal fat consumption. The researchers further concluded that a 15%decrease in animal fat intake combined with a threefold increase in fish oil intake could possibly reduce male colon cancer risk by as much as 30% in countries with a high animal fat intake. A threefold increase in fish oil intake could be achieved by eating fish three times a week or by taking two standard fish oil supplements containing EPA and DHA. The presence of benign polyps or adenomas is known to be a sigruficant risk factor for the development of fullblown rectal or colon cancer. One study aimed at determining if polyunsaturated fatty acids played a role in the progression of benign polyp adenomas to colon cancer. The study investigators included 27 patients with sporadic

benign polyps of the rectum or colon, 22 patients with cancer of the colon or rectum, and 12 subjects with a normal colon.lmThe researchers measured the fatty acid profile of blood plasma and biopsied samples of the lining of the colon from both diseased and normal areas. They found no differences between polyp patients and those patients with a normal colon as far as plasma profile and normal colon lining profile were concerned. However, there was found a significant difference between the fatty acid profile of normal colon tissue and diseased colon tissue in the adenoma patients. Diseased tissue was found to have higher levels of linoleic acid, dihomogammalinolenic acid, and EPA and lower levels of alpha-linolenic and arachidonic acids. A sigruficant stepwise reduction also existed in EPA content of diseased colon lining from the benign polyp stage to endstage colon cancer. The researchers concluded that there are significant changes in the levels of omega-3 and omega-6 fatty acids early on in the sequence leading from benign polyps to colon cancer and speculated that these changes might participate in the progression to colon cancer. They recommended further work to investigate the benefits of long-term dietary manipulation in view of the finding that low-dose fish oil supplementation normalizes the cell proliferation pattern in patients with sporadic polyps. These kinds of findings have motivated others to conduct intervention trials to see if increasing fish oil via supplementation would reduce the number of abnormal cells in the colon. One such study set out to determine if fish oil supplementation would inhibit the development of benign polyps, the precursors of colon cancer. In this study, 34 men and 26 women who had just undergone surgery to remove benign polyps from their colon were studied.141 Patients were divided into four groups. Group 1was supplemented with 1.4 g of EPA and 1.1 g of DHA/day, group 2 with 2.7 g of EPA and 2.4 g of DHA, and group 3 with 4.1 g of EPA and 3.6 g of DHA. Group 4 received placebo-capsules containing olive oil. Biopsy samples from the lower part of the colon and blood samples were taken and analyzed at the start of the trial and 30 days. Overall, patients in the fish oil groups experienced a significant decline in the number of abnormal cells in their colon lining compared with the placebo group. Further analysis showed that the reduction in the number of abnormal cells was limited to patients who had a large number of abnormal cells at the beginning of the trial. The researchers also noted a significant increase in EPA and DHA levels and a significant drop in arachidonic acid level in the biopsy samples from the fish oil-supplemented patients. A separate 6-month trial involving 15 patients taking 1.4 &day of EPA and 1.1g/day of DHA also showed a significant drop in the number of abnormal colon-lining cells. The researchers concluded that low-dose supplementation with fish oils inhibit the proliferation of those

Fish Oils abnormal cells associated as precursors to polyps in patients at risk for colon cancer and that this effect can be maintained with long-term treatment. Similar to several others studies concerned with oxidation of fish oil in vivo, the authors cautioned that it may be advisable to increase vitamin E intake during fish oil administration. Lung cancer is the leading cause of cancer deaths in Japan even though the incidence and mortality is still less than two-thirds that found in the United States and the United Kingdom. Japanese researchers completed a study aimed at determining the association between lung cancer and diet.’& Their study involved 748 men and 297 women age 40 to 79 years who had been diagnosed with lung cancer and 2964 male and 1189 female cancer-free controls. The researchers found that both men and women who ate cooked or raw fish five times a week or more had half the incidence of lung adenocarcinoma when compared with participants who ate cooked or raw fish less than once a week. Women who consumed tofu (soybean curds) five times a week or more were found to have half the risk of adenocarcinomas compared with women who consumed tofu less than once a week. Frequent consumption of carrots was found to be beneficial for women but detrimental for men, especially smokers. Green vegetables were found to be highly beneficial for men but not statistically so for women. There was also some evidence that increased coffee consumption is associated with an increased risk of squamous cell and small cell lung carcinomas in men. Increased consumption of dried or salted fish was not beneficial for men or women. The researchers speculate that this is because the processing destroys the omega-3 oils present in raw and cooked fish. Animal studies have shown that an increase in fat intake can decrease the number of natural killer (NK) cells found in the blood and spleen. NK cells are an integral part of the natural immune response to virus infections and certain types of cancer. Researchers at Oxford University found that fish oil sigruficantly decreases NK cell activity in healthy human subjects.’43Their clinical trial involved 48 men and women age 55 to 75 years. The participants were randomized to receive one of six supplements for 12 weeks. The supplements were all provided in the form of capsules, three of which were to be taken with each meal. The nine capsules (daily intake) contained either a total of 2 g alpha-linolenic acid, 770 mg gamma-linolenic acid (fromevening primrose oil), 680 mg arachidonic acid, 720 mg DHA, 720 mg EPA+ 280 mg DHA (fish oil), or a placebo (8020 mix of palm and sunflower oils). All the participants had blood samples taken 4 weeks before the start of supplementation, immediately before the start of supplementation, and then every 4 weeks during the trial, as well as after a 4-week washout period. The researchers found no changes in killer cell activity except in the group taking fish oil. The researchers observed an average decline of 20% after

8 weeks and 48% after 12 weeks. The decline was completely reversed after the washout period. The fact that no decline was observed with pure DHA strongly suggests that EPA was responsible. The researchers concluded that excessive EPA intake could have adverse effects for people at risk of viral infections and some cancers. The British researchers’ speculation about fish oils perhaps affecting the effectiveness of NK cells in killing cancer cells is at odds with the results of many other studies. At least a dozen studies show a clear protective effect of fish or fish oil against colon, breast, and prostate cancer. Preliminary evidence indicates that diet can influence the risk of developing melanoma. An estimated 1 in 75 Americans will develop cutaneous malignant melanoma in their lifetime. It is believed that a high intake of omega-6 fatty acids can stimulate the growth of melanoma and other cancers, whereas DHA found in omega-3 fatty acids may suppress the growth of cancer cells. In an in vitro experiment, researchers treated 12 different human metastatic melanoma cell cultures with DHA and observed that more than 50% of these cells stopped growing.’@The investigators urged further testing of their findings in a clinical trial setting. The authors concluded that “if DHA is capable of suppressing cell and tumor growth and metastatic potential in in vivo models of melanoma, a clinical trial of DHA would be warranted as an adjuvant to current surgical and chemotherapeutic interventions.” Cachexia is an abnormal rate of weight loss commonly experienced by many cancer patients, especially those with pancreatic cancer. Several studies have demonstrated that supplementing the diet with around 2.2 g of EPA and 1.4 g of DHA assists stabilization of weight in patients with inoperable pancreatic cancer. One study has shown that such patients can gain weight by consuming a nutritional supplement fortified with fish oils. In this study, 20 patients (age 18 to 80) with inoperable pancreatic cancer were given two cans of a fish-oil enriched nutritional supplement each day, added to their daily food intake. The supplement contained 310 kilocalories per can, composed of 49.7 g of carbohydrate, 16.1 g of protein, 6.5 g of fat, 1 g of EPA, 0.5 g of DHA, and 28 essential vitamins and minerals. After 3 weeks the median weight gain for the group was 1 kilo, and 2 kilos after 7 weeks. A marked improvement in appetite was also noted. Of further interest was the finding that these patients survived an average of 8 months, compared with the expected survival time of 4.1 months, typically reported for patients given ~hemotherapy.’~~ In another study, 18 patients with inoperable pancreatic cancer, including nine patients with stage 4 tumors, were started on a dose of 2 g of fish oils (containing 360 mg of EPA and 240 mg of DHA/day).’% The dose was subsequently increased by 2 g/day every week until the patients’ body tolerance was reached. The average final intake was 12 &day. Before entering the trial,

the mean weight loss among the patients was 2.9 kilos per month. After 3 months of fish oil supplementation, a n average weight gain of 0.3 kilos a month was observed. Overall, 11 patients (61%) gained weight, 3 became weight stable, and 4 continued to lose weight, but at a sigruficantly reduced rate. The concentration of EPA in plasma phospholipids increased from 0% to 5.3% of total fatty acids after 1 month of supplementation, while the concentration of DHA increased to 6.6%from a base level of 3.5%.The researchers concluded that fish oil supplementation arrests weight loss in cancer patients with cachexia. Similar improvements in survival time have also been seen in patients with other end-stage cancers with generalized malignancies. In one study, 60 patients with generalized solid tumors were divided into two groups: one group received 18 g of fish oil containing 170 mg of EPA and 115 mg of DHA per capsule, while the other received a ~ 1 a c e b o .The l ~ ~ fish oil group also received 200 mg of vitamin E daily to reduce oxidation in vivo from the effect of so much fish oil. Each group included 15 well-nourished and 15 malnourished patients. None of the well-nourished patients suffered from cancer cachexia (abnormally low weight and general weakness). The researchers measured the level of T cells, NK cells, and the synthesis of interleukin and TNF before the start of the supplementation and on day 40 of the trial. The study followed all patients until they died. Malnourished patients were found to have a considerably impaired immune function and a decreased production of TNF; both parameters were restored through fish oil supplementation. Malnourished patients overall had a much shorter survival time than well-nourished ones (mean of 213 days vs. 481 days). Both malnourished and well-nourished patients who received fish oil and vitamin E survived significantly longer than did patients on placebo. The researchers speculate that fish oils exert their beneficial effect by decreasing the body’s production of prostaglandin E2, which is believed to play an important role in the initiation and progression of cancer. They concluded that supplementation with dietary omega-3 polyunsaturated fatty acids, specifically fish oils with an antioxidant such as vitamin E, may offer significant palliative support to cancer patients with end-stage metastatic disease. Despite the mounting evidence for a beneficial effect of fish oil in the prevention and treatment of various cancers discussed earlier, some conflicting evidence on the role of fish oil in oncogenic processes requires resolution, particularly for those cancers for which limited research has been performed.=

Migraine Headache Anecdotal reports indicate that patients suffering from migraine headaches who are given 1 g/day of MaxEPA,

particularly males, have significantly less frequent or less intense, or both, episodes. These results might be due to changes in prostaglandin synthesis or reduction, or both, in platelet serotonin release, with resultant reduction in cerebral vasospasm.

Diabetes The incidence of diabetes is also low in Greenland Eskimos. Studies have shown that the type of fat consumed by humans may have a profound effect on insulin action in tissues. Patients with insulin-dependent diabetes mellitus (IDDM) are prone to disorders of lipoprotein and lipid metabolism, especially hyperlipidemias. The combination of low-density lipoprotein (LDL) cholesterol and elevated plasma cholesterol (hypertriacylglyceridemia) is associated with an increased risk of CHD. This combination is a major contributor to the morbidity and mortality associated with non-insulin-dependent diabetes mellitus (NIDDM) patients.148In individuals with NIDDM, fish oil ingestion has been demonstrated to favorably alter arterial wall compliance without adversely affecting cholesterol levels, blood pressure, or fasting blood sugar levels, thereby contributing to a reduced risk of vascular complications seen in IDDM and NIDDM patient^.'^^,'^^ One study has even shown a desirable significant decrease in VLDL triglyceride and cholesterol concentrations in NIDDM patients consuming three fish oil capsules a day containing 320 mg EPA and 530 mg DHA.151

Raynaud Disease Raynaud disease is characterized by periods of disrupted blood flow to the fingers caused by exposure to cold or stress. The condition is usually relieved by warming of the affected body part. Secondary Raynaud disease occurs in association with progressive systemic sclerosis or connective tissue disease. Preliminary evidence indicates that symptoms of Raynaud disease improve in primary but not secondary Raynaud phenomenon, on the basis of a double-blind, placebocontrolled clinical trial involving 32 patients.120Patients were given either 12 one-gram fish oil capsules daily for 12 weeks containing 4 g of EPA and 2.6 g of DHA or a placebo. The group receiving the fish oil supplements reported significant alleviation of symptoms associated with Raynaud disease at the end of the study, including 5 patients, who developed symptoms before the experiment began but could not induce symptoms at all after either 6 or 12 weeks of supplementation.

Malaria Malaria afflicts more than 500 million people worldwide, with about 5% of victims dying each year. Unpublished studies at the U.S. Department of Agricultural Research Service Center in Beltsville, MD, have found evidence

that the omega-3 fatty acids in fish oil may be beneficial in the treatment of malaria.lS2In their research, mice were fed dietary fish oils for 4 weeks and then inoculated with parasites, either Plasmodium yoelii or Plasmodium berghei. As the mice continued to eat the high-fish oil diet, the parasites multiplied as usual. However, after 3 to 4 weeks, the mice were free of the parasites. The researchers suspected that the cause of the parasite’s death was rupture of the parasites’ cell membranes or red blood cell hosts. The researchers theorized that infected cells are more susceptible to rupture because the parasites foster a number of destructive oxidative reactions to which a diet high in fish oils makes them more vulnerable. This finding is particularly promising since there is now a strain of P. berghei that is chloroquine resistant to malaria. The World Health Organization is currently examining the benefits of treating malaria with dietary fish oil and qinghaosu, a Chinese botanical.

(ESKIMO-3: 35% n-3 fatty acids, 18% EPA, and 12% DHA) given for both short (4 weeks) and long (6 months) durations resulted in no changes in bleeding time.46 Another controlled study used 1.5, 3, or 6 g of fish oils (SuperEPA)as a supplement for 3 months and found no effect on bleeding time in 45 healthy male volunteers with normal trig1~cerides.l~~ Evidence as to the degree to which fish oil may affect fibrinolysis is conflicting. Plasma PAI-1 is an inhibitor of fibrinolysis. Increased PAI-1 activity has been linked to the development of myocardial infarction and thrombosis by several investigators. In at least one double-blind, randomized study conducted on an untreated essential hypertensive population, a modest increase in fibrinogen levels was observed after fish oil and corn oil intake was increased by 4 g of omega-3 PUFAs.170However, no change in PAI-1 activity or tissue plasminogen activator (PA) activity was found.

TOXIN CONTAMINATION TOXICITY A review of fish oil supplementation and CHD found that 10 MaxEPA capsules or 25 ml/day of cod liver oil (providing 1.8 g of EPA) is “safe over a long term.”lS3 Long-term studies of potentially adverse effects of fish oil supplementation in humans have not been published. However, this is also true of all other oils, such as vegetable oils and most currently prescribed hypolipidemic drugs.“ Not until 2004 did increased risk and incidence of deaths associated with statius and some other classes of hypolipidemic drugs become well known. Care must also be taken to use fish oil, not fish liver oil, as the latter can be excessively high in vitamins A and D and possibly result in toxicity. Finally, large dosages of fish oil supplements may result in a significant increase in total caloric intake, which can be ameliorated by an increase in energy expenditure.

Although increased bleeding may not be a problem, there may be other risks from increased consumption of fish.171For example, some fish may be contaminated from industrial effluents and toxins. Many of these toxicants, such as polychlorinated biphenyl, are known to increase the risk of cancer. In animal experiments it has been demonstrated that eating such contaminated fish as infrequently as once a week may increase the risk of developing cancer and create a significant risk to pregnant women and i n f a n t ~ . * ” JWith ~ ~ the growth of aqua businesses, or fish farms, it remains unknown whether such exposure is being reduced. Some transgenic fish varieties grow so quickly in fish farms that the opportunity for toxic buildup in organs and fat may be decreased. However, as noted earlier, the EPA and DHA concentration and fatty acid balance of farm fish may be adversely affected by commercial food-fed fish.

Bleeding Time

Oxidation

Concerns have been expressed about prolonged bleeding time in populations having a relatively high intake of fish. Several studies have shown that this effect appears to be dose dependent, although collagen-induced platelet aggregation was not shown to be inhibited.’% Many studies have shown that fish oil supplements prolong bleeding time, inhibit platelet aggregation, and decrease TXA2p r o d u ~ t i o n . ~ ~ f i J ~ ~ ~ @ Recent research suggests that the effect of fish oil supplementation on bleeding time is largely determined by the dosage, duration, and composition of the supplement, and the typical treatment regimens are safe. In one double-blind, placebo-controlled trial, daily supplementation with 30 ml of a Scandinavian fish oil formulation

It has been reported in a pig study that a diet rich in fish oil taken for many months can induce a deficiency of vitamin E, leading to cardiac n e c r o ~ i s . ’ ~For ~ J ~this ~ reason, periodic vitamin E (mixed tocopherol or gamma tocopherol) supplementation may be warranted. However, there is no evidence that the incidence of cardiac necrosis is higher in Eskimos. The omega-3 fatty acids found in fish oil are susceptible to oxidative breakdown. For this reason they must be protected from oxidation by proper extraction and storage, encapsulation, or stabilization with an antioxidant such as vitamin E. Inappropriately stored fish oils (i.e., exposure to oxygen) may result in the formation of toxic lipid peroxides over time.

MEASUREMENT OF LIPID OXIDATION PRODUCTS IN ESSENTIAL FATTY ACID SUPPLEMENTS The consumption of essential fatty acid supplements and vegetable oils is increasing. This is in part due to the perception that consumption of these lipids is beneficial to health. However, the high concentration of unsaturated fatty acids in these products compared with animal fats make these products more susceptible to spoilage and oxidative damage. A number of factors accelerate spoilage of these oils, including the presence of reactive metals, high water content, or high temperatures during processing and storage. Consumers perceive oxidative damage as rancidity or off-flavors and off-odors. Health implications for this damage are important. Oxidative damage diminishes the nutritional value of these oils by destroying vitamins and other nutrients. Oxidative products may also interact with protein and carbohydrates. In addition, the byproducts of lipid oxidation may pose a health risk to consumers. Some edible oils are more resistant to oxidative damage. For example, vegetable oils may naturally contain antioxidants such as tocopherols or vitamin E. Antioxidants prevent the oxidative reactives that can lead to rancidity. Many pathways of oxidation of lipids are not completely understood. Two pathways that have received attention are oxidative and hydrolytic rancidity. Hydrolytic rancidity results in the production of free fatty acids and their salts (soaps). This reaction, also called saponification, is due to a reaction of the lipids with water and typically requires the presence of catalysts or enzymes. Oxidative reactions tend to be more complex, and their byproducts are difficult to measure. Initially, oxygen combines with free fatty acids to form hydroperoxides and free radicals. These reactions are d u e n c e d by many factors: the percentage of unsaturated fatty acids present in the oil; processing and storage temperatures; oxygen concentration; light exposure; presence of antioxidants in the oil; moisture content of the oil; and the presence of reactive transition metals such as iron, nickel, or copper. The primary oxidative products are unstable. Hydroperoxides are rapidly degraded to aldehydes, ketones, alcohols, and hydrocarbons. These secondary products are relatively stable and are responsible for the characteristic flavor and odor associated with rancid oils. Historically, manufacturers of edible oils have relied on two analytic tests to determine the level of oxidation in oil: the free fatty acid percentage and peroxide value. More recently, two additional measures, the anisidine value and the total oxidation value, have been the focus of attention.

The percentage of free fatty acids in oil is an indication of freshness. As oil ages, triglycerides are cleaved to glycerol and free fatty acids through hydrolysis. Free fatty acids are more prone to oxidation than triglycerides, so their presence in oils increases the possibility of rancidity. A fresh, carefully processed oil has a free fatty acid percentage of less than 0.05%. The peroxide value measures the level of hydroperoxides in oil. Hydroperoxides are the primary byproduct of oxidation. Peroxide value alone is not indicative of the actual oxidative state of the oil because hydroperoxides decompose rapidly to secondary byproducts such as aldehydes. Therefore an oil might also have a low peroxide value as a result of extensive oxidation rather than due to low levels of oxidation. In theory, a fresh oil would have a peroxide value of zero. In practice, most vegetable oils have peroxide values ranging from 0.1 to 1. Besides the peroxide value, the anisidine value also must be calculated. The anisidine value is a measure of the amount of alpha- and beta-unsaturated aldehydes. Anisidine is an aromatic amine. Synonyms for anisidine include: aminoanisole, methoxyaniline, methoxyphenylamine, and methoxybenzenamine. Anisidine has two isomeric forms. Both have been reported to enhance mutagenicity in bacterial strains.17hThe ortho-anisidine isomer has been associated with bladder tumors. Data on carcinogenicity is almost exclusively on the ortho-isomer, not the para-isomer, which most companies focus on when they measure anisidine values in fish oils. The total oxidative value (TOV) used to express the extent of oxidation of an oil is the sum of the peroxide value and the anisidine value. Tests for peroxide value should comply with AOCS [American Oil Chemists Society] Oficial Method Cd 8-53 and not exceed a maximum of 5 mEq/kg, while the para-anisidine value should comply with AOCS OfficialMethod 18-90 and not exceed a maximum of 20. Many commercially available oils contain high levels of hydroperoxides and secondary byproducts of oxidation. During the past decade, Shukla and PerkinsIn have analyzed various oils for oxidative stability. The results show that fish oils are more prone to oxidation than vegetable oils. The total oxidation values of fish oils ranged from 20 to 60 compared with 5 to 20 for vegetable oils (Tables 94-2 and 94-3).27 Shukla and Perkins made the following recommendations to prevent oxidation during the manufacturing process28: Always use top-quality, freshly produced raw materials stored in temperature- and humidity-controlled facilities. Prevent exposure to oxygen by using closed, impermeable containers.

Fish Oils

Product

Peroxide value (Px)

Anisidine value (Av)

Total oxidation value (2Px + Av)

Iodine value

Percentage of free fatty acids

5.4 1.5 6.9 3.4

6 4.4 4.8 0

16.8 7.4 18.6 6.8

151.5 146.2 178.6 152

4.1 0.14 0.80

3.7 2.7 20.8 2.2

30.2 14.3 17.9 29.2

37.6 19.7 59.5 33.6

189 196.5 241.7 199.4

0.10 0.09 0.25 0.31

Vegetable oils A

B

C D

1.02

Fish oils

E F

G H

Modified from Kinsella JE, Lokesh B, Stone RA. Am J Clin Nutr 1990;52:1-28

Avoid exposure of raw materials to sunlight. Use stringent quality control. Use stainless steel equipment. Minimize heating of oil during processing. ‘e Use antioxidants to prolong shelf life. When using soft gelatin capsules, choose a shell with the lowest concentration of plasticizer possible.

Country England The Netherlands

By the early twenty-first century, manufacturers of fatty acid supplements and vegetable oils have taken the lead to protect consumers by producing oils with the lowest levels of oxidative byproducts possible. Consumer education and accurate measurement of peroxide and anisidine values are vital to this effort.

DOSAGE The dosages reported to be most effective for most conditions responsive to fish oil are in the range of 5 to 15 g of fish oil/day. EPA and DHA concentrations depend on the intended use. Clinical improvement may require 4 to 6 months to manifest, so patient compliance is important.

DRUG INTERACTIONS Fish oil has eicosanoid-modifying effects. Caution should be taken when recommending fish oil supplementation to pregnant women (studies to date on bleeding time have all been carried out on males). Nearly all fish contain methyl mercury. However, pregnant women can protect their unborn child by not eating large fish that can contain higher levels of methyl mercury, such as king mackerel, shark, swordfish, and tilefish. It is prudent for nursing mothers and young children not to eat these fish as well. Individuals known or suspected to have a bleeding disorder, as well as those prescribed

Denmark United States

Peroxide value (Px)

Anisidine value (Av)

3.8 1.8 3.7 2.2

16.6 34 30.2 20.6

Total oxidation value (2Px + Av)

24.2 37.6 37.6 25

Modified from Kinsella JE, Lokesh B,Stone RA. Am J Clin Nutr 1990;52:1-28.

therapeutic levels of aspirin or warfarin, should consult their physician. Patients may benefit from fish oil when taking cyclosporine.*78Fish oil may also inhibit the cholesterol- and triglyceride-lowering effect of the drugs pravastatin and ~imvastatin?’~

A substantial body of evidence now documents the beneficial effects of fish and fish oil consumption. The link between consumption of dietary long-chain omega-3 fatty acids and cardiac disease was shown when the Physicians’ Health Study in particular demonstrated that fish consumption was inversely associated with the incidence of sudden death ( p = 0.004 before adjustment for potential confounders and p = 0.007 and 0.001 after adjustment for such confounders as aspirin use, body mass index, diabetes, hypertension, hypercholesterolemia, beta-carotene use, and alcohol consumption), similar to the original findings reported for Greenland Eskimos. It is now believed that the omega-3 fatty acids EPA and DHA are the components in fish oil responsible for

its preventative, mitigative, and therapeutic benefits, not only in the management of cardiovascular disease but in the prevention and treatment of various cancers, diabetes, rheumatoid arthritis, and other diseases.’@’ However, determining which source of fish oil (i.e., eating fish or supplementing with fish oil) and which fish species is most desirable is difficult, as the various species and sources have different levels and ratios of eicosanoid metabolites, in addition to the influence of storage, handling procedures, and processing methods. In an effort to resolve the question of which source of fish oil is most beneficial, one study compared the effects of fish oil (4.5 g EPA/DHA) from fish with fish oil supplements in 25 mildly hyperlipidemic men over a 5-week period. Both fish and fish oil supplements lowered serum triglycerides and raised HDL cholesterol. There was no difference between the two treatments in their effects on total cholesterol, apolipoprotein-B, LDL cholesterol, or blood pressure. However, dietary fish did lower fibrinogen (15.6%) and thromboxane (10.5%)and increase bleeding time (10.8%),as compared with both controls and those receiving fish oil supplements.’*’ These findings suggest that although both fish consumption and fish oil supplementation produce desirable

effects on lipids and lipoproteins, fish consumption is more effective in improving several of the hemostatic factors involved in cardiovascular disease. Which fish or fish oil products produce the most desirable combination of therapeutic effects remains unknown. Further research is necessary. In the interim, it s e e m evident that humans can benefit from a diet containing fresh or fresh/frozen fish consumed at least three to five times a week, with additional fish oil supplementationwhen warranted. To ensure that fish is safe for consumption, both continued vigdance by regulatory agencies and effective quality control procedures and standards are required to prevent contaminated fish containing toxicants, such as mercury, from reaching the marketplace. Fish oil supplement manufacturers should provide sufficient information on labels about the source of the fish oil and species to enable consumers to make informed decisions. Information on the fish oil’s source, EPA and DHA concentration and ratio, toxic residual levels (if any), and risk of oxidative activity (total oxidative value) should be provided. Total evidence to date suggests that omega-3 fish oil from dietary fish or fish oil supplements is a beneficial intervention that can be applied to improve population health at reasonable cost and with low risk.la2

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135. Escobar SO, Achenbach R, Iannantuono R, Torem V. Topical fish oil in psoriasis: a controlled and blind study. Clin Exp Dermatol 1992;17159-162. 136. Karmali RA. Fatty acids: inhibition. Am J Clin Nutr 1987;45: 225-229. 137. Reddy BS, Burill C, Rigotty J. Effects of diets high in omega-3 and omega-6 fatty acids on initiation and postinitiation stages of colon carcinogenesis. Cancer Res 1991;51:487-491. 138. Kaizer L, Boyd NF, Kriukov V, Tritchler D. Fish consumption and breast cancer risk an ecological study. Nutr Cancer 1989;1261-68. 139. Caygill CP, Charlett A, Hill MJ. Fat, fish, fish oil and cancer. Br J Cancer 1996;74:159-164. 140. Femandez-Banares F, Esteve M, Navarro E, et al. Changes of the mucosal n-3 and n-6 fatty acid status occur early in the colorectal adenoma-carcinoma sequence. Gut 1996;38:254-259. 141. Anti M, Annelao F, Marra G, et al. Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas. Gastroenterology 1994;107:1709-1718. 142. Takezaki T, Hirose K, Inoue M, et al. Dietary factors and lung cancer risk in Japanese: with special reference to fish consumption and adenocarcinomas. Br J Cancer 2001;&2:1199-1206. 143. Thies F, Nebe-von-Caron G, Powell JR, et al. Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 years. Am J Clin Nutr 2001;73:539-548. 144. Albino AP, Juan G, Traganos F, et al. Cell cycle arrest and apoptosis of melanoma cells by docosahexaenoic acid: association with decreased pRb phosphorylation. Cancer Res 2000;604139-4145. 145 Barber MD, Ross JA, Voss AC, et al. The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. Br J Cancer 1999;81:80-86. 146. Wigmore SJ, Ross JA, Falconer JS, et al. The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer. Nutrition 1996;12:S27-S30. 147. Gogos CA, Ginopoulos P, Salsa B, et al. Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy. Cancer 1998;82:395-402. 148. Goh YK, Jumpsen JA, Ryan EA, Clandinin MT. Effect of omega-3 fatty acid on plasma lipids, cholesterol and lipoprotein fatty acid content in NIDDM patients. Diabetologia 1997;4045-52. 149. McVeigh GE, Brennan GM, Cohn JN, et al. Fish oil improves arterial compliance in non-insulin-dependent diabetes mellitus. Arterioscler Thromb 1994;14:1425-1429. 150. Luo J, Rizkalla SW, Vidal H, et al. Moderate intake of n-3 fatty acids for 2 months has no detrimental effect on glucose metabolism and could ameliorate the lipid profile in type 2 diabetic men. Diabetes Care 1998;21:717-724. 151. Rivellese AA, Maffettone A, Iovine C, et al. Long-term effects of fish oil on insulin resistance and plasma lipoproteins in NIDDM patients with hypertriglyceridemia. Diabetes Care 1996;19: 1207-1213. 152. Anonymous. Fish oil: new hope in fighting malaria. Sci News 1989;135:237. 153. Neutze JM, Starling MB. Fish oils and coronary heart disease. N Z Med J 1986;99:581-583. 154. Ahmed AA, Holub BJ. Alteration and recovery of bleeding times, platelet aggregation and fatty acid composition of individual phospholipids in platelets of human subjects receiving a supplement of cod-liver oil. Lipids 1984;19617-624. 155. Goodnight SH Jr, Harris WS, Connor WE. The effects of dietary omega 3 fatty acids on platelet composition and function in man: a prospective, controlled study. Blood 1981;58880-885. 156. Sanders TA, Roshanai F. The influence of different types of omega 3 polyunsaturated fatty acids on blood lipids and platelet function in healthy volunteers. Clin Sci (Lond) 1983;64:91-99.

157. Ahmed AA, Holub BJ. Alteration and recovery of bleeding times, platelet aggregation and fatty acid composition of individual phospholipids in platelets of human subjects receiving a supplement of cod-liver oil. Lipids 1984;19:617-624. 158. Knapp HR, Reilly IA,Alessandrini P, Fitgerald GA. In vivo indexes of platelet and vascular function during fish oil administration in patients with atherosclerosis.N Engl J Med 1986;314:937-942. 159. Siess W, Roth P, s e r e r B, et al. Platelet-membrane fatty acids, platelet aggregation, and thromboxane formation during a mackerel diet. Lancet 1980;1:441-444. 160. Brox JH, Killie JE, Gunnes S, Nordoy A. The effect of cod-liver oil and corn oil on platelets and vessel wall in man. Thromb Haemost 1981;46604-611. 161. Hirai A, Terano T, Hamazaki T, et al. The effects of the oral administration of fish oil concentrate on the release and the metabolism of 14C-arachidonicacid and 14C-eicosapentaenoicacid by human platelet. Thromb Res 1982;28:285-298. 162. Bradlow BA, Chetty N, van der Westhuyzen J, et al. The effects of a mixed fish diet on platelet function, fatty acids and serum lipids. Thromb Res 1983;29:561-568. 163. Schimke E, Hildebrandt R, Ekitz J, et al. Influence of a cod liver oil diet in diabetics type I on fatty acid patterns and platelet aggregation. Biomed Biochim Acta 1984;43:S351-353. 164. Lands WE, Culp BR, Hirai A, Gorman R. Relationship of thromboxane generation to the aggregation of platelets from humans: effects of eicosapentaenoic acid. Prostaglandins 1985;30:819-825. 165. Von Schacky C, Fischer S, Weber PC. Long-term effects of dietary marine omega-3 fatty acids upon plasma and cellular lipids, platelet function, and eicosanoid formation in humans. J Clin Invest 1985;761626-1631. 166. Srivastava KC. Docosahexaenoic acid ( C 2 6 omega 3) and linoleic acid are anti-aggregatory and alter arachidonic acid metabolism in human platelets. Prostaglandins Leukot Med 1985;17319-327. 167. Sanders TA, Hochland MC. A comparison of the influence on plasma lipids and platelet function of supplements of omega 3 and omega 6 polyunsaturated fatty acids. Br J Nutr 1983;50521-529. 168. Croft KD, Beilin LJ, Vandongen R. The effect of dietary fish oil on platelet metabolism of 14C arachidonic acid. Thromb Res 1986; 42~99-104.

169. Blonk MC, Bilo HJ, Nauta JJ. Dose-response effects of fish41 supplementation in healthy volunteers. Am J Clin Nutr 1990;52: 120-127. 170. Toft I, Bonaa KH, Ingebretsen OC, et al. Fibrinolytic function after dietary supplementation with omega-3 polyunsaturated fatty acids. Arterioscler Thromb Vasc Biol1997;17814-819. 171. Foran JA, Glenn BS, Silverman W. Increased fish consumption may be risky. JAMA 1989;26228. 172. Foran JA, Cox M, Croxton D. Sport fish consumption advisories and projected cancer risks in the Great Lakes basin. Am J Public Health 1989;79:322-325. 173. Foran JA, VanderPlwg D. Consumption advisories for sport fish in the Great Lakes basin. J Great Lakes Res 1989;15:476-485. 174. Ruiter A, Jongbloed AW, van Gent CM, et al. The influence of dietary mackerel oil on the condition of organs and on the blood lipid composition in the young growing pig. Am J Clin Nutr 1978;31:2159-2166. 175. Gudbjarnason S, Hallgrimsson J. The role of myocardial membrane lipids in the development of cardiac necrosis. Acta Med %and SUPPI 1976;587:17-27. 176. Thompson DC,Josephy PD, Chu JW, Eling TE. Enhanced mutagenicity of anisidine isomers in bacterial strains containing elevated N-acetyltransferase activity. Mutat Res 1992;279:83-89. 177. Shukla VK, Perkins EG. Rancidity in encapsulated health food oils. Inform 1998;9:955-961. 178. Andreassen AK, Hartmann A, Offstad J, et al. Hypertension prophylaxis with omega-3 fatty acids in heart transplant recipients. J Am Coll Cardiol 1997;29:13241331. 179. Nakamura N, Hamazaki T, Ohta M, et al. Joint effects of HMGCoA reductase inhibitors and eicosapentaenoic acids on serum lipid profile and plasma fatty acid concentrations in patients with hyperlipidemia. Int J Clin Lab Res 1999;29:22-25. 180. Connor WE. Importance of n-3 fatty acids in health and disease. Am J Clin Nutr 2000;71:171S175S. 181. Cobiac L, Clifton PM, Abbey M, et al. Lipid, lipoprotein, and hemostatic effects of fish vs fish-oil n-3 fatty acids in mildly hyperlipidemic males. Am J Clin Nutr 1991;53:1210-1216. 182. Jones PJ, Lau VW. Effect of n-3 polyunsaturated fatty acids on risk reduction of sudden death. Nutr Rev 2002;60407-409.

Flavonoids-Quercetin, Citrus Flavonoids, and Hydroxyethylrutosides Michael T. h4urray. SI) Peter B. Bongiorno, NL), Dip1 Ac CHAPTER CONTENTS Introduction 967

Diabetes 971 Thalassemias 971

Historical Perspective 967 Chemical Descriptions 968 Quercetin 968 Citrus Bioflavonoids 968

Commercially Available Forms 971 Quercetin 971 Citrus Bioflavonoids 971 Dosages 971

Pharmacology 968 Quercetin 968 Citrus Flavonoids 970

Toxicity 972 Drug Interactions 972

Clinical Applications 970 Allergic and Inflammatory Conditions 970 Capillary Fragility, Excessive Bruisability, and Hemorrhoids 971

INTRODUCTION Flavonoids, a group of plant pigments, are largely responsible for the colors of many fruits and flowers. Recent research suggests that flavonoids may be useful in the treatment and prevention of many health conditions. In fact, many of the medicinal actions of foods, juices, herbs, and bee pollen are now known to be directly related to their flavonoid content. More than 4000 flavonoid compounds have been characterized and classified according to chemical structure. Flavonoids are a bit of an enigma to scientists, as they are quite reactive compounds. They can enter into almost any type of reaction known to organic chemistry such as oxidationreduction reactions, carbonyl reaction, acid-base reactions, free-radical reaction, hydrophobic interactions, tautomery, and isomerizations.' As such, characterizationof the many diverse physiologic properties of flavonoids is a considerable challenge to biochemists and researchers alike. This chapter discusses a few representatives of this class of useful clinical agents (quercetin, citrus bioflavonoids, and hydroxyethylrutosides). One of the most beneficial groups of plant flavonoids are the proanthocyanidins(alsoreferred to as procyanidins).

The most potent proanthocyanidins are those bound to other proanthocyanidins. Collectively, mixtures of proanthocyanidin dimers, trimers, tetramers, and larger molecules are referred to as procyanidolic oligorners (PCOs). Chapter 119 discusses PCOs.

HISTORICAL PERSPECTIVE Flavonoids, as well as vitamin C, were discovered by Albert Szent-Gyorgyi (1893-1986), one of the most respected and honored biochemists of the twentieth century. Szent-Gyorgyi received the Nobel Prize in 1937 for his discovery of some of the properties of these molecules. Szent-Gyorgyi discovered the flavonoids while isolating vitamin C. A friend with bleeding gums had stopped the bleeding by taking a crude vitamin C preparation isolated from lemon. When the problem reappeared, Szent-Gyorgyigave his friend a purer form of vitamin C. He expected to observe an even more impressive result, but the purer form of vitamin C did not work. SzentGyorgyi then isolated the flavonoid fraction from the original crude vitamin C preparation, gave it to his friend, and observed complete healing. 967

Szent-Gyorgyi termed his discovery “vitamin P” due to its ability reduce vascular permeability, one of the hallmark features of scurvy. He went on to show that the clinical symptoms of scurvy are the result of a combined deficiency of vitamin C and flavonoids. However, because flavonoids could not fulfill all the requirements of a vitamin, the designation as vitamin P was abandoned. Although flavonoids are often referred to as “semiessential” nutrients, their importance in human nutrition appears to be as important to good health as the essential vitamins and minerals. Good dietary sources of flavonoids include citrus fruits, berries, onions, parsley, legumes, green tea, and red wine. The average daily intake in the United States for flavonoids is estimated to be between 150 and 200 mg.

CHEMICAL DESCRIPTIONS Quercetin Quercetin (Figure 95-1) is a flavonoid that serves as the aglycone for many other flavonoids, including the citrus flavonoids rutin, quercitrin, and hesperidin. These derivatives differ from quercetin in that they have sugar molecules attached to the quercetin backbone. Quercetin is consistently the most active of the flavonoids in experimental studies, and many medicinal plants owe much of their activity to their high quercetin content.

Citrus Bioflavonoids Citrus bioflavonoid preparations can include rutin, hesperidin, quercitrin, and naringin. Most of the clinical research on rutin and crude bioflavonoid complexes occurred before 1970. Since then, most of the clinical research has used a standardized mixture of rutinosides known as hydroxyethylrutosides (HERS). Impressive clinical results have been obtained in the treatment of capillary permeability, excessive bruisability, hemorrhoids, and varicose veins with HERS (discussed later). Citrus bioflavonoids can be viewed as providing similar effects to, but probably not as potent as, HERS or quercetin.

OH

OH

0

Flgure 95-1

Quercetin.

PHARMACOLOGY As a class of compounds, flavonoids have been referred to as ”nature’s biologic response modifiers” because of their ability to mod* the body’s reaction to other compounds such as allergens, viruses, and carcinogens, as evidenced by their antiinflammatory, antiallergic, antiviral, and anticarcinogenic properties? In addition, flavonoids act as powerful antioxidants, providing remarkable protection against oxidative and free radical damage: and have the ability to traverse the blood-brain barrier, thus exerting a neuroprotective effect: Flavonoids are known to form strong ligand complexes with heavy metal ions and may prove to be a good agent of heavy metal detoxification.’ The practical aspect of this antioxidant activity is highlighted by the results of a study in 805 men designed to determine the effect of dietary flavonoids on protecting against heart disease. The study demonstrated an inverse correlation between flavonoid intake and death from a heart a t t a ~ kThis . ~ effect is probably a result of the potent antioxidant effects of the flavonoids preventing, similar to vitamins C and E, the formation of oxidized cholesterol. However, the antioxidant activity of flavonoids is generally more potent and effective against a broader range of oxidants than traditional antioxidant nutrients like vitamins C and E, selenium, and ~ i n c . ~ ! ~ Because different flavonoids tend to provide different benefits, additional and more specific beneficial effects are discussed under the key selected flavenoid categories. There is significant overlap among these flavonoids, however.

Quercetin Quercetin consistently demonstrates the greatest activity among the flavonoids studied in experimental models, particularly in vitro studies. The primary actions that are briefly reviewed here are its antiinflammatoryeffects, inhibition of aldose reductase, antiviral activityrand anticancer properties.

Antiinflammatory Effects Quercetin has demonstrated significant antiinflammatory activity due to direct inhibition of several of the initial processes of inflammation via interaction with calcium channels or calmodulin (the intracellular calcium-binding protein), or both, as well as through other mechanisms such as by inhibiting mast cell and basophil degranulation, neutrophil and monocyte lysosomal secretion, prostaglandin (most notably, leukotriene) formation, lipid peroxidation, and the resultant cascade of effects that are often a result of these processes. For example, it inhibits both the manufacture and release of histamine and other allergic/inflammatory mediators. In addition, it exerts potent antioxidant activity and vitamin C-sparing action.”I4

Flavonoids-Quercetin, Citrus Flavonoids, and Hydroxyethylrutosides

Effect on Histamine Release

Inhibition of Aldose Reductase

The release of histamine and other inflammatory mediators from mast cells and basophils is involved in the pathogenesis of acute allergic and inflammatory responses. Mast cells are widely distributed throughout the human body but are found in higher concentrations in the blood vessels of the subepithelial connective tissue of the respiratory tract, conjunctiva, gastrointestinal tract, and skin. Mast cell and basophil degranulation is an active process that requires calcium influx. Quercetin and many other flavonoids have been shown to be potent inhibitors of mast cell, neutrophil, and basophil degran~lation.'~-'~ A generally accepted hypothesis for this action is that quercetin inhibits receptor-mediated calcium influx, thereby inhibiting the primary signal for degranulation. However, quercetin is also active under conditions in which the calcium channel mechanism is not operative, indicating that other mechanisms are responsible as well.

Quercetin is a strong inhibitor of aldose reductase, the enzyme responsible for the conversion of blood glucose to sorbitol. This compound is strongly implicated in the development of diabetic complications such as diabetic cataracts, neuropathy, and retinopathy.17 The mechanism by which sorbitol is involved in the development of diabetic complications is best understood by considering its involvement in cataract formation. Although the lens does not have any blood vessels, it is an actively metabolizing tissue that continuously grows throughout life. Elevated blood sugar levels result in shunting of glucose to the sorbitol pathway. Because the lens membranes are virtually impermeable to sorbitol and lack the enzyme required to break down sorbitol (polyol dehydrogenase), sorbitol accumulates to high concentrations. These high concentrations persist even if glucose levels return to normal. This accumulation creates an osmotic gradient that results in water being drawn into the cells to maintain osmotic balance. As the water is pulled in, the cell must release small molecules like amino acids, inositol, glutathione, niacin, vitamin C, magnesium, and potassium in order to maintain osmotic balance. Because these latter compounds function to protect the lens from damage, their loss results in an increased susceptibilityto damage. As a result, the delicate protein fibers within the lens become opaque and a cataract forms. Quercitrin, which is hydrolyzed by gut bacteria to yield quercetin and a sugar moiety, was shown to significantly decrease the accumulation of sorbitol in the lens of diabetic animals, effectively delaying the onset of cataracts.18In addition to its effect on aldose reductase, quercetin is also of value in diabetes for its ability to enhance insulin secretion and protect the pancreatic p cells from the damaging effects of free radicals, and for its inhibition of platelet a g g r e g a t i ~ n . ~ , ~

Membrane Stabilization, Antioxidant Activity, and Hyaluronidase Inhibition Quercetin inhibits many of the inflammatory processes attributed to activated ne~trophi1s.l~ This is probably due to its membrane-stabilizing action, potent antioxidant effect (whichprevents the production of free radicals and inflammatory leukotrienes), and inhibition of the enzyme hyaluronidase (thus preventing the breakdown of the collagen matrix of connective tissue and ground substance).Quercetin's membrane-stabilizingeffect could also account for its action in preventing mast cell and basophil degranulation. This effect also inhibits inflammation by decreasing neutrophil lysosomal enzyme se~retion.'~ Neutrophils and monocytes contain lysosomes that, on secretion of their contents, contribute greatly to the inflammatory process.

Effects on Eicosanoid Metabolism Excessive leukotriene formation has been linked to asthma, psoriasis, atopic dermatitis, gout, ulcerative colitis, and possibly cancer.15J6Quercetin has been shown to inhibit many steps in eicosanoid metabolism. Probably of most significanceis its inhibition of phospholipase A2 and lipoxygenase enzymes (see Chapter 149 for diagram).6,7J4 The net result is a significant reduction in the formation of leukotrienes. The leukotrienes C4, D4, and E4 (composing the slow-reacting substances of anaphylaxis [SRS-A]) are derived from arachidonic acid and are 1000 times as potent as histamine in promoting inflammation. Leukotrienes promote inflammation by causing vasoconstriction (thereby increasing vascular permeability) and bronchoconstriction (thus inducing asthma) and by promoting white blood cell chemotaxis and aggregation. The reduction of leukotriene formation has significant antiinflammatory effects.

Androgen Receptor Inhibition The androgen receptor is involved in the development and progression of prostate cancer. In vitro research on androgen-sensitive prostate cancer cell lines using Western blot analyses found quercetin able to inhibit the transcription of the receptor gene in a dose-dependent fashion. Additionally, quercetin inhibited the secretion of the prostate-specific, androgen-regulated tumor markers PSA and hK2. The messenger ribonucleic acid levels of androgen-regulated genes such as PSA, NKX3.1, as well as ornithine decarboxylase, were also downregulated by q~ercetin.'~ Although clinical trials are necessary to evaluate and characterize this effect in men, quercetin may prove to have a beneficial effect on prostate cancer.

Pharmacology of Natural Medicines

Antiviral Activity

Cardiovascular Effects

Flavonoids as a group possess sigruficant antiviral activity, with quercetin having the greatest antiviral activity against herpes virus type I, para-influenzae 3, polio vints type I, and respiratory syncytial virus.2oz Quercetin has been shown, in vitro, to inhibit both viral replication and infectivity. In vivo studies in animals have also shown quercetin to inhibit viral infection.’*23 This would suggest that quercetin may be of some benefit in viral infections including the common cold.

Animal studies have also elucidated other uses for citrus bioflavonoids that beneficially affect cardiovascular risk factors and bone density. Increases in high-density lipoprotein and decreases in low-density lipoprotein cholesterol, total lipid, and triglyceride plasma levels in normolipidemic rats and in rats with diet and induced hyperlipidemia have been observed.29Antihypertensive effects have been demonstrated by evaluating long-term administration of hesperidin and its water-soluble analog, glucosyl hesperidin, to spontaneously hypertensive rats and normotensive rats. Animals were fed diets containing 30 mg/day/kg body weight of either hesperidin or its glucosyl analog for 25 weeks. Blood pressure and heart rate of the hypertensive animals administered the bioflavonoids were measured. Both of these measurements decreased as compared with the control group. In comparison, the blood pressure and heart rate of the controls were not changed by the long-term administration of the bioflavonoid

’

Anticancer Properties Many flavonoids have also been shown to inhibit tumor formation, but again quercetin has consistently been the most effective. In experimental models, quercetin has demonstrated significant antitumor activity against a wide range of cancers including squamous cell carcinoma, leukemia, and cancers of the breast, ovaries, colon, rectum, and brain. Unfortunately, there are no human studies to support the impressive results noted in animal and in vitro studies.2427

Citrus Flavonoids Collagen Matrix Support In addition to possessing antioxidant activity and an ability to increase intracellular levels of vitamin C, rutin, hesperidin, and HER exert many beneficial effects on capillary permeability and blood flow, primarily via strengthening endothelial cells and supporting collagen structures. Collagen, the most abundant protein of the body, is responsible for maintaining the integrity of “ground substance,” as well as the integrity of tendons, ligaments, and cartilage. Collagen is also the support structure of the skin and blood vessels. Citrus flavonoids affect collagen metabolism in several ways. They reinforce the natural cross-linlung of collagen that forms the so-called collagen matrix of connective tissue and protect against free radical damage with their potent antioxidant and free radical scavenging action. They also inhibit enzymatic cleavage of collagen by enzymes secreted by leukocytes during inflammation and microbes during infection. Like quercetin, citrus flavonoids also prevent the release and synthesis of compounds that promote inflammation and allergies such as histamine, serine proteases, prostaglandins, and leukotrienes.8 It is believed that the citrus bioflavonoid hesperidin possesses antihistaminic activity through its metabolite heparitin, a weak inhibitor of cyclooxygenase 2 enzymes. This metabolite is produced as a product of intestinal bacteria, which underscores the need for a balanced intestinal flora in order to gain the antihistamine benefits of citrus bioflavonoids.zs

Bone Metabolism Effects Histornorphometric research on ovariectomized mice has shown that marked decreases in trabecular bone volume and trabecular thickness of the femoral distal metaphysis were sigruficantly prevented by hesperidin. Additionally, calcium, phosphorus, and zinc concentrations in the femur were significantly higher in the hesperidin-fed group while serum and hepatic lipids were lower in mice that consumed the hesperidin-containing diets.31

CLINICAL APPLICATIONS There is much overlap among the clinical uses of flavonoid preparations. Most of the clinical research has focused on HER products.

Allergic and Inflammatory Conditions Largely on the basis of in vitro studies, quercetin appears to be indicated in virtually all inflammatory and allergic conditions including asthma, hay fever, rheumatoid arthritis, and lupus, as well as in diabetes and cancer. However, the main shortcoming is the limited number of clinical studies and poor absorption. Earlier pharmacokinetic studies in animals and humans indicated that little quercetin is absorbed intact, with the majority of the oral dose (53%) being excreted in the f e ~ e s . ~ ~ , ~ ~ One of the main problems in studying the absorption of quercetin and other flavonoids is their degradation by microorganisms in the colon. To sidestep this issue, a recent study examined the absorption of quercetin in healthy ileostomy patients with complete small intestinesM

Flavonoids-Quercetin, Citrus Flavonoids, and Hydroxyethylrutosides The study examined the absorption of quercetin from fried onions (a rich source of quercetin glycosides),rutin, or 100 mg of pure quercetin. Absorption was defined as oral intake minus ileostomy excretion and corrected for degradation within the ileostomy bag. Absorption results were as follows: 52% from onions, 17% from quercetin rutinoside, and 24% for pure quercetin. These results indicate that humans do absorb appreciable amounts of quercetin and that absorption (but not necessarily pharmacologic activity) may be enhanced when quercetin is bound to glucose. In other words, citrus bioflavonoid preparations or HERs, or both, may prove to be more effective clinically.

Capillary Fragility, Excessive Bruisability, and Hemorrhoids

Thalassemias Although it may be difficult to treat the long-term outcomes of thalassemia conditions, it is possible that quercetin may serve to protect abnormally sensitive lymphocytes from common dietary substances. An in vitro study evaluated the effect of food mutagens on the lymphocytes from three different types of thalassemia patients: beta-thalassemia major, beta-thalassemia/Hb E, and an alpha-thalassemia trait with a 3.7-kb deletion. When the mutagen exposure was combined with quercetin, reduced sensitivities among the various thalassemic genotypes were observed in a dose-dependent manner.51 Although human studies are necessary to confirm this beneficial effect, quercetin might be worth a try to attenuate the toxic mutagenic effects commonly found in these susceptible patients.

A deficiency of hesperidin in the diet has been linked with abnormal capillary leakiness, as well as pain in COMMERCIALLY AVAILABLE FORMS the extremities, causing aches, weakness, and night leg Quercetin cramps.35Early studies demonstrated rutin to be effective Quercetin is available alone in powder and capsule in reducing capillary fragility, easy bruising, swelling and bruising after sports injuries, and n0sebleeds.3~~~form. However, if quercetin is being used for its antiinflammatory properties, products that combine with More recent and much more extensive studies have been the pineapple enzyme bromelain may provide addiperformed with HERs. Positive double-blind clinical tional benefit. Bromelain exerts antiallergy and antiinstudies exist in the treatment of venous insufficiency flammatory activity on its own and may also enhance including varicose veins, hemorrhoids, diabetic vascular the absorption of quercetin. Combination preparations disease, and diabetic retinopathy? of protein-digesting enzymes, like bromelain, and In double-blind studies of patients with chronic flavonoids have been shown to potentiate each other's venous insufficiency, HER improves microvascular antiinflammatory activity.52 blood flow and clinical symptoms (pain, tired legs, night cramps, and restless legs) in 73% to 100% of patients.4146 Citrus Bioflavonoids Several studies were conducted on pregnant women, in Mixed preparations of citrus bioflavonoids are the most whom HER was shown to be of great benefit in improving widely used and least expensive flavonoid sources. venous function, as well as in helping to relieve hemorHowever, mixed citrus flavonoids are the least active rhoidal signs and symptoms. In one study, 90% of the and generally the least quantified source of flavonoids, women given HER (1000 mg daily for 4 weeks) had as most commercially available sources of mixed citrus improved symptoms compared with only 12% in the flavonoids only contain 50% flavonoids. Preparations placebo group.47 Similar results in hemorrhoids not containing pure rutin and hesperidin or those that clearly associated with pregnancy have been reported.40,48 state the levels of rutin and hesperidin are better than Diabetes products that do not quantify the amount of the individual flavonoid components. HERs are probably the better Flavonoids appear to be important in the long-term care choice when opting for the benefits in this class of of diabetes. One of the hallmark features of diabetes is a flavonoids. sigruficant disturbance of blood flow through small blood vessels. HERs appear to improve blood flow in diabetics significantly and can be useful in the treatment of diabetic DOSAGES microvascular disease and retinopathy. Flavonoids can The recommended dosage range for quercetin is 200 to also stimulate an otherwise weak insulin effect in several 400 mg 20 minutes before meals (three times/day). If ways. For example, they can influence the protein phosquercetin is being used for its antiinflammatory properphokinases, which modulate second messenger pathways ties and bromelain supplementation is also indicated, known to up-regulate the gene encoding the glucose administration with bromelain may enhance absorption. transporters.' Combination preparations of proteolytic enzymes PCO or bilberry extracts may be better than quercetin, and flavonoids have been shown to have significant citrus flavonoids, and HER in diabetics.4850

Pharmacology of Natural Medicines antiinflammatory activity in experimental studies?* If used with bromelain, the amount of bromelain (1800MCU activity) should be equal to the amount of quercetin. Dosages used for HERS in double-blind clinical studies on the treatment of venous insufficiency and hemorrhoids have ranged from 1000 to 3000 mg daily. This translates to a dosage of citrus bioflavonoids, rutin, and hesperidin of 3000 to 6000 mg daily.

DRUG INTERACTIONS

Quercetin appears to be well tolerated in humans. Carcinogenic and teratogenic studies in rats and rabbits have shown that quercetin is without apparent side effects, even when consumed in large quantities (2000 mg/kg body weight and 5% to 10% of total diet) for long periods In addition, quercetin adminof time (up to 2 istration (up to 2000 mg/kg body weight) to pregnant rats had no teratogenic effects.59As is true of any other compound, allergic reactions may occur. Although uncommon, if they occur, discontinue use. Citrus bioflavonoids, rutin, hesperidin, and HER appear to be extremely safe and without side effects even during ~ r e g n a n c y . ~ , ~ ~

Quercetin, rutin, hesperidin, HER, and green tea polyphenols do not appear to interact with any drug. Citrus bioflavonoid preparations, if they contain naringin, may interact with drugs. This flavonoid is found in grapefruit juice but not orange juice. Naringin has been found to activate phosphoglycoprotein in the epithelial cells of the intestine and suppress the expression of the cytochrome P450 3A4 gene. The phosphoglycoprotein enhances the uptake from the intestine of many drugs including vinblastine, cyclosporine, digoxin, fexofenadine, and losartan' and can increase the oral bioavailability of drugs like nifedipine, felodipine, verapamil, and terfenadine, as well as inhibit the breakdown of various drugs, particularly caffeine, coumarin, and estrogens.60 In addition, the suppressed expression of the P450 gene can enhance oxidative decomposition of some drugs.' Because the drugs mentioned are used frequently in the therapy of cancer, human immunodeficiency virus, immune disorders, hypertension, and other serious conditions, avoidance of grapefruit juice and flavonoid preparations containing naringin is recommended when taking any of these drugs.

1. Havsteen BH. The biochemistry and medical sigruhcance of the flavonoids. Pharmacol Ther 2002;9667-202. 2.Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000;52: 673-751. 3. Rice-Evans C. Flavonoid antioxidants. Curr Med Chem 2001;8: 797-807. 4.Youdim KA, Dobbie MS, Kuhnle G, et al. Interaction between flavonoids and the blood-brain barrier: in vitro studies. J Neurochem 2003;85180-192. 5. Hertog MG, Feskens EJ, Hollman PC, et al. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993;3421007-1011. 6. Rice-Evans CA, Miller NJ, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 1996;20933-956. 7. Havsteen B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharmacol 1983;32:1141-1148. 8. Ferrandiz ML, Alcaraz MJ. Anti-inflammatory activity and inhibition of arachidonic acid metabolism by flavonoids. Agents Actions 199132283-288. 9. Middleton E Jr, Drzewieki G. Flavonoid inhibition of human basophil histamine release stimulated by various agents. Biochem Pharmacol1984;333333-3338. 10. Middleton E Jr, Drzewieki G. Naturally occurring flavonoids and human basophil histamine release. Int Arch Allergy Appl Immunol 1985;77:155-157. 11. Amella M, Bronner C, Briancon F, et al. Inhibition of mast cell histamine release by flavonoids and bioflavonoids. Planta Med 1985;51:16-20.

12. Pearce FL, Befus AD, BienenstockJ. Mucosal mast cells. III. Effect of quercetin and other flavonoids on antigen-induced histamine secretion from rat intestinal mast cells. J Allergy Clin Immunol 1984; 73:819-823. 13.Busse WW, Kopp DE, Middleton E Jr. Flavonoid modulation of human neutrophil function. J Allergy Clin Immunol 1984;73 801-809. 14. Yoshimoto T, Furukawa M, Yamamoto S, et al. Flavonoids: potent inhibitors of arachidonate 5-lipoxygenase. Biochem Biophys Res CO~UTUII1983;116:612-618. 15. Ford-Hutchinson AW. Leukotrienes: their formation and role as inflammatory mediators. Fed Proc 1985;44:25-29. 16. Ford-Hutchinson AW. Leukotriene involvement in pathologic processes. J Allergy Clin Immunol1984;74:437-440. 17. Chaudhry PS,Cabrera J, Juliani HR,et al. Inhibition of human lens aldose reductase by flavonoids, sulindac and indomethacin. Biochem Pharmacol1983321995-1998. 18.Varma SD, Mizuno A, Kinoshita JH. Diabetic cataracts and flavonoids. Science 1977;195:205-206. 19. Xing N, Chen Y, Mitchell SH, et al. Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis 2001;22409-414. 20. Mucsi I, Pragai BM. Inhibition of virus multiplication and alteration of cyclic AMP level in cell cultures by flavonoids. Experientia 1985; 41:93O-931. 21. Kaul TN, Middleton E Jr, Ogra PL. Antiviral effects of flavonoids on human viruses. J Med Virol1985;15:71-79. 22. Beladi I, Mucsi I, Pusztai R, et al. In vitro and in vivo antiviral effects of flavonoids. In Farkas L, Gdbor M, KBllay F, eds. Flavonoids and bioflavonoids, 1981: proceedings of the International Bioflavonoid Symposium (6th Hungarian Bioflavonoid Symposium)

TOXICITY ~

~~~~

Flavonoids-Quercetin, Munich, F.R.G., September 6-9, 1981. New York Elsevier, 1982 443-450. 23.Guttner J, Veckenstedt A, Heinecke H, et al. Effect of quercetin on the course of mengo virus infection in immunodeficient and normal mice. A histologic study. Acta Virol 1982;26:148-155. 24. Elangovan V, Balasubramanian S, Sekar N, et al. Studies on the chemopreventive potential of some naturally-occurring bioflavonoids in 7,12-dimethylbenz(a)anthracene-inducedcarcinogens in mouse skin. J Clin Biochem Nutr 1994;17153-160. 25.Verma AK, Johnson JA, Gould MN, et al. Inhibition of 7,12-dimethylbenz(a)anthracene- and N-nitrosomethylureainduced rat mammary cancer by dietary flavonol quercetin. Cancer Res 1988;48:5754-5758. 26. Stavric 8. Quercetin in our diet: from potent mutagen to probable anticarcinogen. Clin Biochem 1994;27245-248. 27. Larocca LM, Giustacchini M, Maggiano N, et al. Growth-inhibitory effect of quercetin and presence of type I1 estrogen binding sites in primary human transitional cell carcinomas. J Urol 1994;152: 1029-1033. 28. Lee NK, Choi SH, Park SH, et al. Antiallergic activity of hesperidin is activated by intestinal microflora. Pharmacology 2004;71:174-180. 29. Monforte MT, Trovato A, Kirjavainen S, et al. Biological effects of hesperidin, a citrus flavonoid. (Note II): hypolipidemic activity on experimental hypercholesterolemia in rat. Farmaco 1995;50: 595-599. 30. Ohtsuki K, Abe A, Mitsuzuwi H, et al. Effects of long-term administration of hesperidin and glucosyl hesperidin to spontaneously hypertensive rats. J Nutr Sci Vitamin01 (Tokyo) 2002;48: 420-422. 31. Chiba H, Uehara M, Wu J, et al. Hesperidin, a citrus flavonoid, inhibits bone loss and decreases serum and hepatic lipids in ovariectomized mice. J Nutr 2003;133:1892-1897. 32. Petrakis PL, Kallianos AG, Wender SH, et al. Metabolic studies of quercetin labeled with C14. Arch Biochem Biophys 1959;85:264-271. 33. Gugler R, Leshik M, Dengler HJ. Disposition of quercetin in man after single oral and intravenous doses. Eur J Clin Pharmacol 1975; 9529-234. 34.Hollman PC, de Vries JH, van Leeuwen SD, et al. Absorption of dietary quercetin glycosides and quercetin in health ileostomy volunteers. Am J C l i Nutr 1995;621276-1282. 35. Garg A, Garg S, Zaneveld LJ, et al. Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytother Res 2001;15:655-669. 36. Lagrue G, Behar A, Maurel A. [Edematous syndromes caused by capillary hyperpermeability. Diffuse angioedema.] J Ma1 Vasc 1989; 14231-235. 37. Horoschak A. Nocturnal leg cramps, easy bruisability and epistaxis in menopausal patients: treated with hesperidin and ascorbic acid. Del Med J 1959;31:19-22. 38. Cragin RB. The use of bioflavonoids in the prevention and treatment of athletic injuries. Med Times 1962;90:529-532. 39. Beretz A, Cazenave J. The effect of flavonoids on blood vessel wall interactions. In Cody V, Middleton E Jr, Harbome JB, et al, eds. Plant flavonoids in biology and medicine II: biochemical, cellular, and medicinal properties. Proceedings of a Meeting on Plant Flavonoids in Biology and Medicine, Strasbourg, France,August 31-September3, 1987. New York Liss, 1988:187-200. 40. Wadworth AN, Faulds D. Hydroxyethylrutosides. A review of its pharmacology, and therapeutic efficacy in venous insufficiencyand related disorders. Drugs 1992;441013-1032.

Citrus Flavonoids, and Hydroxyethylrutosides 41. Poynard T, Valterio C. Meta-analysis of hydroxyethylrutosides in the treatment of chronic venous insufficiency. Vasa 1994;23:244-250. 42. Boisseau MR, Taccoen A, Garreau C, et al. Fibrinolysis and hemorheology in chronic venous insufficiency: a double blind study of troxerutin efficiency. J Cardiovasc Surg (Torino) 1995;36 369-374. 43.Neumann HA, van den Broek MJ. A comparative clinical trial of graduated compression stockings and 0-(beta-hydroxyethy1)rutosides (HR) in the treatment of patients with chronic venous insufficiency. Z Lymphol1995;19:8-11. 44. Renton S, Leon M, Belcaro G, et al. The effect of hydroxyethylrutosides on capillary filtration in moderate venous hypertension: a double blind study. Int Angiol 1994;13:259-262. 45. MacLennan WJ, Wilson J, Rattenhuber V, et al. Hydroxyethylrutosides in elderly patients with chronic venous insufficiency: its efficacy and tolerability. Gerontology 1994;40:45-52. 46. Bergstein NA. Clinical study on the efficacy of 0-(beta-hydroxyethy1)rutoside(HR) in varicosis of pregnancy. J Int Med Res 1975; 3:189-193. 47.Annoni F, Boccasanta P, Chiurazzi D, et al. [Treatment of acute symptoms of hemorrhoid disease with high dose oral 0-(betahydroxyethy1)-rutosides.] Minerva Med 1986;771663-1668. 48. Wijayanegara H, Mose JC, Achmad L, et al. A clinical trial of hydroxyethylrutosides in the treatment of haemorrhoids of pregnancy. J Int Med Res 1992;20:54-60. 49. Belcaro G, Candiani C. Chronic effects of 0-(beta-hydroxyethy1)rutosides on microcirculation and capillary filtration in diabetic microangiopathy. Curr Ther Res 1991;49:131-139. 50. Agolini G, Cavallini GM. [Long-term therapy of retinal vasculopathies with oral administration of high doses of 0-(betahydroxyethy1)-rutoside.] Clin Ter 1987;120101-110. 51. Ruf AA, Webb J, Anderson D. Modulation by flavonoids of the effects of a food mutagen in different thalassaemia genotypes in the Comet assay. Teratog Carcinog Mutagen 2003;suppl 2: 93-102. 52. Tarayre,’lJ Lauressergues H. Advantages of a combination of proteolytic enzymes, flavonoids and ascorbic acid in comparison with non-steroid anti-inflammatory agents. Arzneimittelforschung 1977;271144-1149. 53. Stoewsand GS, Anderson JL, Boyd JN, et al. Quercetin: a mutagen, not a carcinogen, in Fischer rats. J Toxicol Environ Health 1984;14 105-114. 54. Hirono I, Ueno H, Hosaka S, et al. Carcinogenicity examination of quercetin and rutin in ACI rats. Cancer Lett 1981;13:15-21. 55. Kato K, Mori H, Fujii M, et al. Lack of promotive effect of quercetin on methylazoxymethanol acetate carcinogenesis in rats. J Toxicol Sci 1984;9:319-325. 56. Kato K, Mori H, Tanaka T, et al. Absence of initiating activity by quercetin in the rat liver. Ecotoxicol Environ Saf 1985;10:63-69. 57.Hosaka S, Hirono I. Carcinogenicity test of quercetin by pulmonary-adenoma bioassay in strain A mice. Gann 1981;72:327-328. 58. Hirose M, Fukushima S, Sakata T, et al. Effect of quercetin on twostage carcinogenesis of the rat urinary bladder. Cancer Lett 1983;21: 23-27. 59. Willhite CC. Teratogenic potential of quercetin in the rat. Food Chem Toxicol 1982;20:75-79. 60.Fuhr U, Kummert AL. The fate of naringin in humans: a key to grapefruit juice-drug interactions? Clin Pharmacol Ther 1995;58: 365-373.

Ginkgo biloba (Ginkgo Tree) MichaelT. Murray, ND Joseph E. Pizzorno Jr, ND Peter B. hngiorno, ND, Dip1 Ac CHAPTER CONTENTS General Description 975 Chemical Composition 975 History and Folk Use 976 Pharmacology 976 Tissue Effects 976 Nerve Cell Effects 976 Vascular Effects 977 Platelet Effects 977 Absorption and Distribution of Gingko biloba Extract 977 Clinical Applications 979 Cerebral Vascular Insufficiency and Impaired Mental Performance 979 Alzheimer‘s Disease 981 Tinnitus 981

Ginkgo bilobu (family: Ginkgoaceae) Common names: @go tree, maidenhair tree

GENERAL DESCRIPTION Ginkgo bilobu is a deciduous tree that lives up to 1000 years old and grows to a height of 100 to 122 feet and a diameter of 3 to 4 feet. The ginkgo has short horizontal branches with short shoots bearing fan-shaped leaves that measure 2 to 4 inches across. Because the leaf resembles a maidenhair fern, the @go has been called ”maidenhair tree.” Ginkgo bears an inedible foulsmelling fruit and an edible ivory-colored inner seed that is sold in marketplaces in the Orient. Extracts from the leaves of the &go tree are used medicinally.

CHEMICAL COMPOSITION The active components of ginkgo leaves are the ginkgo-flavone glycosides or ginkgo heterosides (flavonoid molecules with sugars attached, which are

Cochlear Deafness/Ototoxicity 982 Senile Macular Degeneration and Diabetic Retinopathy 982 Peripheral Arterial Insufficiency 982 Sexual Dysfunction 983 Premenstrual Syndrome and Idiopathic Cyclic Edema 983 Antidepressant Effects 983 AllergiedAsthma 984 Raynaud’s Disease 984 High Altitude Sickness 984 Future Applications of Gingko biloba Extract 984 Dosage 984 Toxicity 985

unique to the ginkgo), several terpene molecules unique to ginkgo (ginkgolides and bilobalide), and organic acids.’ The G. bilobu extract (GBE),marketed in Europe under the trade names Tanakan, Rokan, Ginkgobil, Kaveri, Seredrin, and Tebonin, is a well-defined and complex product prepared from the green leaves. Extracts identical to these preparations are available in the United States as food supplements. The culturing, harvesting, and extracting techniques have been thoroughly standardized and require careful control. GBE is standardized to contain 24% flavone glycosides, as these molecules represent a convenient analytic reference group. Although they play a major role in the pharmacologic activity of GBE, other components are also important. The three major backbone flavonoids of the G. bilobu flavonols are quercetin, kaempferol, and isorhamnetine (Figure 96-1). The sugar (glucoside) components are glucose and rhamnose, which are present as single sugars or disaccharides (two attached sugar molecules). 97s

R

OH

0

ComDound

R

R'

R"

Kaempferol Quercetin lsorhamnetine

H OH

OH

OCH3

OH

H H H

OH

Figure 961 The major backbone flavonoids of Gingko biloba extract

The ginkgo is now planted throughout much of the United States as an ornamental tree. The ginkgo, which is the tree most resistant to insects, disease, and pollution, is frequently planted along streets in cities.' The first green growth to reappear at the center of Hiroshima in 1946 was the sprout of a gingko tree that grew to be a normal, full-size tree.2 G. biloba's medicinal use can be traced back to the oldest Chinese materia medica (2800 BC). The @go leaves have been used in traditional Chinese medicine for their ability to "benefit the brain," relieve the symptoms of asthma and coughs, and help the body eliminate filaria. Ginkgo leaf extracts are now among the leading prescription medicines in both Germany and France, where they account for 1% and 1.5%, respectively, of total prescription sales. In America, it was the top-selling botanical medicine in 1999 with $148 million in sales3

PHARMACOLOGY

Figure 96-2

Bilobalide.

Other sigruficant flavonoid components of the extract include proanthocyanidins, largely composed of dimers and oligomers of delphinoidine and cyanidine. The major terpene molecules of GBE, which account for 6% of the extract, are the gnkgolides and bilobalide (Figure 962). These substances are unique to ginkgo and are not found in any other plants. Other constituents of GBE include a number of organic acids. These compounds contribute valuable properties to the extract by making the usually water-insoluble flavonoid and terpene molecules of ginkgo water soluble.

HISTORY AND FOLK USE G. biloba is the world's oldest living tree species. The sole surviving species of the family Ginkgoaceae, the ginkgo tree can be traced back more than 200 million years to the fossils of the Permian period, and for this reason it is often referred to as "the living fossil." Once common in North America and Europe, the @go was almost destroyed during the Ice Age in all regions of the world except China, where it has long been cultivated as a sacred tree. In the late seventeenth century, Engelbert Kaempfer, a German physician and botanist, became the first European to discover and catalog the @go tree. The flavonoid kaempferol is named after Kaempfer. In 1771 Linnaeus named the tree G. biloba. The ginkgo tree was brought to America in 1784 to the garden of William Hamilton near Philadelphia.

The standardized concentrated extract of the leaves of G. biloba (24% @go flavone glycoside content) has demonstrated remarkable pharmacologic effects. Interestingly, the total extract is more active than single isolated component^.',^ This suggests synergism between the various components of GBE, an explanation that is well supported in more than 400 clinical and experimental studies using the extract.'TM

Tissue Effects GBE exerts profound, widespread tissue effects including membrane-stabilizing, antioxidant, and free radicalscavenging effects. GBE also enhances the use of oxygen and g l u c ~ s e . ' , ~ , ~ Cellular membranes provide the first line of defense in maintaining the integrity of the cell. Largely composed of fatty acids (phospholipids), cellular membranes also serve as fluid barriers, exchange sites, and electrical capacitors. These membranes are fragile and vulnerable to damage, especially the lipid peroxidation induced by oxygenated free radicals. GBE is an extremely effective inhibitor of lipid peroxidation of cellular mernbrane~.',~ Red blood cells provide excellent models for evaluating the effects of substances on membrane functions. Red blood cell studies using GBE have demonstrated that, in addition to directly stabilizing membrane structures and scavenging free radicals, GBE also enhances membrane transport of potassium into the cell and sodium out by activating the sodium pump. In essence, GBE leads to better membrane polarization. This effect is particularly important in excitable tissues such as nerve cells.',4

Nerve Cell Effects GBE's membrane-stabilizing and free radical-scavenging effects are perhaps most evident in the brain and nerve

Ginkgo biloba (Ginkgo Tree) cells. Brain cells contain the highest percentage of unsaturated fatty acids in their membranes of any cells in the body, making them highly susceptible to free radical damage. The brain cell is also highly susceptible to hypoxia. Unlike most other tissues, the brain has little energy reserve. Its functions require large amounts of energy, which must be supplied by a constant supply of glucose and oxygen. Diminished circulation to the brain sets off a chain of reactions that disrupt membrane function and energy production and ultimately lead to cellular death. GBE is remarkable in its ability to prevent metabolic and neuronal disturbances in experimental models of cerebral i~chemia.',~,~-'~ It accomplishes this by enhancing oxygen utilization and increasing cellular uptake of glucose, thus restoring energy production. All of the above-mentioned metabolic effects are in addition to GBE's ability to reestablish effective tissue perfusion. Particularly interesting is GBEs ability to normalize the circulation in areas most affected by microembolization, namely the hippocampus and ~triatum.',~ Discussion of additional nervous tissue actions of GBE is incorporated later in the section on clinical indications. Briefly, GBE promotes an increased nerve transmission rate, improves synthesis and turnover of brain neurotransmitters, normalizes acetylcholine receptors in the hippocampus (the area of the brain most affected by Alzheimer disease),l" and inhibits beta-amyloid deposition.l1

Vascular Effects

ischemic vascular area than on a normally perfused area.]* However, despite intense investigation, many of GBE's tonic effects on vascular components are still largely unexplained. Remarkably, GBE can simultaneously combat the phenomena resulting from vascular spasm and, with the same efficiency, restore circulation to areas subject to vasomotor paralysis. The importance of this dual action is becoming more apparent in cerebral insufficiency, as single-direction drugs (i.e., vasodilators)can often aggravate the condition by preferentially dilating the healthy areas, thereby deflecting blood and oxygen away from the ischemic area.

Platelet Effects GBE and isolated pkgolides have profound effects on platelet function including inhibition of platelet aggregation, adhesion, and degran~lation.~ These effects appear to be due to direct membrane and antioxidant effects, increased synthesis of prostacyclin, and an antagonism of a substance known as platelet-activating factor (PAF). GBE and the pkgolides have been shown to be potent inhibitors of I'AF?J3.l5 PAF is a potent stimulator of platelet degranulation and is involved in many inflammatory and allergic processes including neutrophil activation, increasing vascular permeability, smooth muscle contraction including bronchoconstriction,and reduction in coronary blood flow. GBE and ginkgolides compete with PAF for binding sites and inhibit the various events These actions may be responsible induced by PAF.'J~,'~,'~ for many of GBEs clinical effects. Interestingly, despite these effects on PAF, GBE exerts no inhibition of platelet aggregation in humans.

The mechanisms of GBE's vascular effects have been Absorption and Distribution investigated using a number of in vivo and in vitro techof Ginkgo biloba Extract niques (Table 96-1).'t4 Isolated vessel techniques allow The pharmacokinetics (absorption, distribution, and for separation of GBE's effects on different parts of the vascular system (e.g., arterial, arteriolar, microcircula- elimination) of GBE have been studied in rats using radiolabeled extra~ts.'*~5 Following oral administration, tory, venular, and venous components), while in vivo studies provide information on the total circulatory pheat least 60% of the radiolabeled extract was absorbed. Since blood levels peaked after 1.5hours, upper gastroinnomena (i.e., GBE's ability to increase the perfusion rate testinal tract absorption was suspected. to various regions). In general, GBE exerts its vascular effects primarily The flavonoids appear to have an affinity for organs rich in connective tissues such as the aorta, eyes, skin, through its effects on the lining of the blood vessels and lungs. Levels of radioactivity in these tissues are two (vascular endothelium) and the system that regulates to three times higher than those in blood and decrease blood vessel tone. Its vasodilating action is explained by direct stimulation of the release of endothelium-derived little over the course of time. Retained specific activity in the heart is twice that found in the skeletal muscles. relaxing factor (EDRF) and prostacyclin (a beneficial Of the glands, the adrenals retained the greatest level of prostaglandin). In addition, GBE inhibits 3',5'-cyclic radioactivity. GMP (guanosine monophosphate) phosphodiesterase, At 72 hours, the hippocampus and striated bodies an enzyme that results in relaxation of blood vesse1s.l~~ On the venous system, GBE stimulates greater tone, show radioactivity five times greater than that of the blood. This deposition pattern, which parallels the circuthus aiding the dynamic clearing of toxic metabolites lation improvement observed after ischemia due to that accumulate during ischemia (Figure 96-3).'" blood clotting in rats, is alleviated by GBE extracts. GBE normalizes circulation by producing tonic Other areas of the brain such as the cerebral cortex, effects. These effects are much more apparent in an

h

a

e

c

h

a

Release of PG12

Direct membrane effect

Release of EDRF from endothelium

Inhibition of PDE

Cellular and membrane mechanisms explaining Ginkgo biloba's effects

m

Debilitated capillary walls

Increased capillary resistance

Direct membrane effect

Capillary hyperpermeability and plasma

Amelioration of capillary hyperpermeability

Direct membrane effect

Hypoxic vasoparalysis

Diminished accumulation of toxic wastes: K+,COP,and lactate Consequence of venous tonic effect

Mitochondria1 metabolic restart

Vascular atony

Restitution of arterial tone

Direct effect

Potentiation of alphaadrenergic effects'

Exchange area (capillary)

s of the vasoregulatory effects of Ginkgo bi/oba extract

EDRF; Endothelium-derivedrelaxing factor: PDE, phosphodiestefase; PGI,, prostaglandin 12. 'Partly through COMT inhibition.

Potentiation of alpha-adrenergic effects'

Diminished platelet hyperaggregability

s

Vasorelaxation

i

Effects found with Ginkgo biloba extract

n

Arterial thrombosis

Upstream flow (arteriole)

m

Arterial spasm

n

Tissue pathologic condition

~

Site of action

c

Inhibition of PDE (?)

Release of dilating prostaglandins Indirect effect via alphaadrenergic effects

Antagonism of experimental venous spasms

Venular spasms

Direct effect

Venous tonic effect

Venous relaxation and vasoparalysis extravasation

Downstream flow (venous)

Ginkgo biloba (Ginkgo Tree)

Figure 96-3

Gingko biloba extract's impact on ischemia.

brainstem, and cerebellum do not show such high levels of radioactivity.

CLINICAL APPLICATIONS GBE's primary clinical application has been in the treatment of vascular insufficiency. In more than 50 doubleblind clinical trials, both patients with chronic cerebral (brain) arterial insufficiency and peripheral arterial insufficiency have responded favorably to GBE. As described earlier, GBE exerts an extraordinary array of pharmacologic activities that imply a broad spectrum of possible clinical applications, an implication borne out by the new applications of GBE, which are constantly being discovered.

Cerebral Vascular lnsufficiency and Impaired Mental Performance Cerebral vascular insufficiency is an extremely common condition in the elderly of developed countries due to the high prevalence of atherosclerosis (hardening of the arteries). In well-designed studies, GBE has displayed a statistically sigruficant regression of the major symptoms of cerebral vascular insufficiency and impaired mental performance. The following symptoms were reported1,46,1"21: Short-term memory loss Vertigo Headache Ringing in the ears

Lack of vigilance Depression The sigruficant regression of these symptoms by GBE suggests that vascular insufficiency may be the major causative factor accounting for these so-called age-related cerebral disorders versus a true degenerative process. In a comprehensive review, the quality of research on more than 40 clinical studies with GBE in the treatment of cerebral insufficiency was analyzed. The results indicate that GBE is effective in reducing all symptoms of cerebral insufficiency including impaired mental function (senility), and the quality of research was comparable to Hydergine (dihydroergotamine), an FDA-approved drug used in the treatment of cerebral vascular insufficiency and Alzheimer's disease. Eight studies stood out as being extremely well designed and are summarized in Table 96-2.1421 It appears that by increasing cerebral blood flow, and therefore oxygen and glucose utilization, GBE offers relief from these presumed "side effects" of aging and may offer significant protection against their development. Furthermore, G. biloba's antiaggregatory effect on platelets offers additional protection against a stroke. This has been supported in a clinical study of poststroke patients, which demonstrated that GBE improved blood flow and blood viscosity.22 In addition to improving blood supply to the brain, experimental and clinical studies show that GBE increases the rate at which information is transmitted at the nerve cell l e ~ e l . ~One * ~ ~study investigated the

1989 1977 1978

1975

1983 1977 1979 1976 1985 1977

Hofferberth

Moreau

Pidoux

12 20 19 20 112 50 50

CCI

CCI CCT

CCI

Misc

CVA

CCI

30

36 48 27

30 80 99 14 40 47 48 20 25 19

No. of patients

CCI

CVA

D

cos

Senescence

CVA

CCI

CCI

CCI, cv

CCI CCI

Misc

CCI

CCI

Diagnosis

87 47-86 67 59-84 55-94 50 50

84

53-69 72 78

60 40-80 77 65 67 35-80 65-95 62 60 57-88

Age (YO

Placebo (n = 19) Nicergoline (n = 19) DB

Open Open

Open, M

Open

Open

55% 68% 76% 72%

85% 76%

Placebo DB

160 35 (IV) 160 17.5(IV) 120 160 160

Open

79%

Placebo (n= 30) ED ( n = 30) DB

NS

83%

120

Open

Placebo (n = 18)

Placebo (n = 20) DB

DB, CS

Placebo (n = 20) DB

Open

74%

12 2 8 1-3 52 27 27

DB Open

Raubasine + ED ( n = 24)

12

Placebo (n= 14) ED ( n = 19)

DB

Open

Placebo (n = 90)

DB, CS

76% 65% 44% 65% 90% 80% 60% 80% 92% 69%

Placebo (n = 30) Placebo (n = 40)

DB, CS

Efficacy

Compared with:

Type

DB

120 240 120

120 120 120 120 120 120 360 160 120 120

Dosage (mg)

8 8 8

4 7 24 5 5 3 8 5 4 12

Duration (weeks)

CCI, Chronic cerebral insufficiency; COS,cerebral organic syndrome: CS, crossover; CVA, cerebral vascular accident: 0,dementia; D6,double-blind; ED,ergot derivatives; M, multicenter; NS,not specified.

Wackenheim

Vorberg

Terasse

Tea

Safi

Leroy

Israel

Gessner

Eckmann

Dieli

Choussat

1975 1977 1981 1982 1983

1984 1984 1976 1975

Year

Boudouresques

Bono

Augustin

Arrigo

Agnoli

Principal author

Studies demonstrating the significant regression of the major symptoms of cerebral vascular insufficiency through the use of Gingko biloba extract

Ginkgo biloba (Ginkgo Tree)

effects of acute doses of standardized GBE on memory and psychomotor performance in 31 healthy volunteers who were 30 to 59 years old. The study was randomized, double-blind, and placebo-controlled with a five-way crossover design. Gingko improved working memory in all volunteers, especially those who were 50 to 59 years However, GBE’s memory-enhancing effects are not limited to the elderly. In another double-blind study, the reaction time in healthy young women performing a memory test was improved sigruficantly after the administration of GBE.25

Alzheimer’s Disease GBE is showing great benefit in many cases of senility including Alzheimer’s d i s e a ~ e . ~ ,In~ ,addition ~ , ~ ~ to GBE’s ability to increase functionalbrain capacity via the mechanisms described earlier, it has been shown to normalize the acetylcholine receptor in the hippocampus of aged animals, increase cholinergic transmission, inhibit beta-amyloid deposition,” and address many of the other major elements of Alzheimer’s disease.’r4 Although preliminary studies in established Alzheimer’s patients are quite promising, at this time it appears that GBE only helps to reverse or merely delay mental deterioration in the early stages of Alzheimer’s disease. This may help enable the patient to maintain a normal life for a while and avoid being institutionalized. The benefits of GBE in early-stage Alzheimer’s disease are quite evident when looking at the results of two recent double-blind studies. In the first study, 216 patients with Alzheimer’s disease or multiinfarct dementia were given either 240 mg/day of GBE or placebo for 24 weeksz8 Improvements were noted in several clinical parameters including the Clinical Global Impressions (CGI) scale, as shown in Table 96-3. The second study, published in the Journal of the American Medical Association, was the first U.S. clinical study on GBE.29The study was conducted at six research centers. Harvard Medical School and the New York Institute for Medical Research approved the design of the study, in which 202 patients with Alzheimer’s disease

1 cardiovascular performance measures Time of Measurement

Parameter Pain-free walking distance (m)

Week 0

Week 104

62.9

172.4

Rest flow (rnVl00 rnl/rnin)

113.8 1.6

Peak flow (mlll00 mllmin)

3.7

6.9

46.5

72.6

Total walking distance (rn)

Doppler measurement after strain (mmHg)

384

2.7

were given either a modest dose of GBE (120 mg/day) or a placebo for 1 year. GBE not only stabilized Alzheimer’s disease but also led to significant improvements in mental function in 64% of the patients. There were no side effects with GBE. Direct comparison studies on gingko versus standard pharmaceutic regimens have been recently completed. A comparison of placebo-controlled efficacy studies of at least 6 months in duration demonstrated that GBE and second-generation cholinesterase inhibitors (tacrine, donepezil, rivastigmine, metrifonate) were equally effective in treating mild to moderate Alzheimer dementia. In this study, it was observed that no major differences occurred between the four cholinesterase inhibitors and GBE. Additionally, tacrine exhibited a high dropout rate due to adverse drug reactions. In conclusion, the author called for a critical review of the use of new secondgeneration cholinesterase inhibitor prescriptions for mild to moderate Alzheimer’s disease in light of gingko’s equivalent effectiveness.30 A metaanalysis surveyed 50 articles to examine the effect of g d g o on objective measum of cognitivefunction in patients with Alzheimer’s disease.31In the 212 subjects in the placebo and @go groups, a significant overall effect size that was comparable with the benefits of standard cholinesteraseinhibitors was found. In this analysis, standardized measures of cognition were measured including the Alzheimer’s Disease Assessment Scalecognitive subscale. In addition to being beneficial in early-stage Alzheimer’s disease, if the mental deficit is due to vascular insufficiency or depression and not Alzheimer’s disease, GBE is usually effective in reversing the deficit.’tM Importantly,GBE should be taken consistently for at least 12 weeks in order to determine its effectiveness. Although some people with Alzheimer’s disease report benefits within a 2- to 3-week period, most will need to take GBE for a longer period of time.

Tinnitus Permanent, severe tinnitusis an extremely difficult condition to treat. Previous studies have shown contradictory results of GBE in the treatment of tinnitus. For example, in M e y e r ‘ ~study, ~ ~ GBE improved the condition in all patients regardless of prognostic factor. However, in Coles’s3 study, 21 patients with tinnitus took GBE for 12 weeks: 11 reported no change, 4 reported slight to very slight improvement, and 5 reported that their tinnitus was worse. The explanation for these different results is that in Meyer’s study the patients had recent onset tinnitus,while in Coles’s study 18 patients had tinnitusfor at least 3 years. A 1994 study of GBE in tinnitus used a two-part design: the first part was an open part, without a placebo control; the second part was a double-blind, placebocontrolled, cross-over study? The 80 patients in the

open study had been referred to the Department of Audiology, Sahlgren’s Hospital, Goteborg, Sweden, due to permanent severe tinnitus. Twenty patients reporting a positive effect to GBE (14.6 mg twice daily) after 2 weeks were recruited for the double-blind study. Patients were given either the GBE or placebo for 2 weeks and then crossed over into the other group. Evaluation indicated that six patients preferred GBE, seven preferred placebo, and seven had no preference. On the surface, this study seemingly indicates that GBE is ineffective for permanent, severe tinnitus. However, the study was really designed for the GBE to fail. First, the dosage used (14.6 mg twice daily or 29.2 mg daily) is far less than the standard dosage of 40 mg three times daily (or roughly four times the daily dosage used in the study). Secondly, in studies on patients with cerebral vascular insufficiency, it is well established that GBE often takes at least 2 weeks before benefits become apparent. The longer that GBE is used, the more obvious the benefit. In a condition like permanent, severe tinnitus,2 to 4 weeks is simply not enough time. However, given the small, insufficient dosage, it probably would not have mattered if the subjects had been studied for a longer period of time. A more recent study of 1121 healthy people between 18 and 70 years old with tinnitus that was comparatively stable showed no benefit over placebo when given 50 mg of standardized gingko three times a day. Although these data are discouraging, it should be noted that outcome measures were obtained through questionnaires and phoned-in patient reports, without objective audiometric meterh1g.3~ The degree to which GBE is of benefit in permanent, severe tinnitus remains to be determined, but given GBE’s excellent safety profile, it is certainly worth a try.

Cochlear Deafness/Ototoxicity Ischemia is usually the underlying factor in acute cochlear deafness. GBE has improved recovery in cases of acute cochlear deafness due to unknown factors or due to sound trauma or pressure (barotrauma).%GBE has also been shown to be a protective agent against ototoxicity from treatment with the chemotherapeutic agent cisplatin, without decreasing antineoplastic efficacy.37

Senile Macular Degeneration and Diabetic Retinopathy GBE appears to address the multifactorial pathophysiol-

ogy of senile macular degeneration, the most common cause of blindness in adults, quite effectively. In doubleblind studies, GBE demonstrated a statistically significant improvement in long-distance visual acuity in both macular degeneration and diabetic retinopathy.1,4*38 GBE has demonstrated impressive protective effects against free radical damage to the retina in experimental studies. Furthermore, GBE has been shown to prevent

diabetic retinopathy in diabetic rats, suggesting it may have a protective effect in human diabetics as

Peripheral Arterial lnsufficiency Peripheral arterial disease has as its primary lesion the same cholesterol-containing plaque that is responsible for other conditions associated with atherosclerosis (e.g., coronary artery disease, cerebral vascular insufficiency). The arterial obstruction or narrowing causes a reduction in blood flow during exercise or at rest. Clinical symptoms are caused by the consequent ischemia. The most common symptom of peripheral arterial disease is pain during exertion as a result of intermittent claudication. The pain usually occurs in the calf and is described as cramping, tightness, or severe fatigue. The pain is usually bilateral. The cause of the pain is not only reduced oxygen delivery but also an increase in the production of toxic metabolites and cellular free radicals. These free radicals accumulate and react with the lipid constituents of the cell membrane. Pain at rest indicates serious reduction in resting blood flow. It is obviously a sign of severe disease. The pain may be localized to one or more toes, or it may have a stocking-type distribution. The character of the pain is usually described as burning or gnawing and is generally worse at night. Cyanosis or pallor of the extremity is usually apparent. In moderate to severe narrowing of the artery, there are trophic changes including a dry, scaly, and shiny epidermis. The hair may disappear, and the toenails may become brittle, ridged, and deformed. The standard medical approach to peripheral vascular disease and intermittent claudication includes avoidance of tobacco (which causes vasoconstriction), a regular exercise program consisting of walking, and the prescription drugs pentoxifylline (Trental) or cilostazol (Pletal). Surgery is also an option, though most patients with intermittent claudication need not take this risk.’9 Trental has emerged as the “drug of choice” in the standard medical treatment of intermittent claudication.40 A total of 17 placebo-controlled trials have shown that Trental prolongs the total and pain-free walking distance in patients with intermittent claudication. However, the level of improvement (approximately 65% for pain-free walking distance) is less than that achieved with exercise or with GBE. In nine double-blind, randomized clinical trials of GBE versus placebo in two matched groups of patients with peripheral arterial insufficiency of the leg, GBE was shown to be quite active and superior to placebo (eight studies) and equal to pentoxifylline (one ~ t u d y ) . ~ , ~ j , ~ l * Not only did measurements of pain-free walking distance (75% to 110%) and maximum walking distance (52.6% to 119%) dramatically increase, but plethysmographic and Doppler ultrasound measurements also

Ginkgo biloba (Ginkgo Tree)

demonstrated increased blood flow through the affected limb. Blood lactate levels also dropped.g10,12-*8 The demonstration that GBE improves limb blood flow, as well as improved walking tolerance (in studies following strict methodology and with sufficient patients for reliable evaluation), indicates that GBE is far superior to pentoxifylline and standard medical therapy in peripheral arterial insufficiency. This includes other peripheral vascular disorders such as diabetic peripheral vascular disease, Raynaud’s disease, acrocyanosis, and postphlebitis syndrome. Cilostazol is the newest of the drugs used to treat intermittent claudication. Comparison studies between pentoxyfylline and cilostazol have shown greater efficacy for the group treated with cilostazol in a 24-week study.47Although cilostazol and gingko have not been directly compared, evidence indicates that cilostazol’s ability to increase total walking distance (143%) and pain-free walking distance (163%) is inferior to that of gingko’s longer-term record of efficacy (approximately 330% and 271%, respectively). Additionally, patient reports showed no improvement in general health perception for patients taking cilostazol and reported a 34% incidence in headaches at the recommended dosage.@ Importantly, although @go was well tolerated and less expensive than the two FDA-approved drugs, the effect was still somewhat modest, especially compared with exercise pr0grams.4~~ The longer the period over which GBE is used, the greater the benefit. Table 96-3 summarizes a 2-year trial of GBE (160 mg/day) in the treatment of peripheral arterial disease (Fontaine’s stage IIb). Pain-free walking distance increased by more than 270%.’ The usual daily dosage of GBE is 120 mg (40 mg three times a day); however, some of the studies employed a dosage of 160 mg/day, including the study summarized in Table 96-3.

According to preliminary study results, GBE appears to be effective in the treatment of erectile dysfunction due to lack of blood flow. The improvement of the arterial inflow to erectile tissue is assumed to be due to the known effect of GBE on enhancing blood flow through both arteries and veins without any change in systemic blood pressure. Ginkgo’s effects are more apparent with long-term therapy, and better results may have been obtained with a 120 mg/day dose in order to take full advantage of its effect on improving blood flow. With the current epidemic use of antidepressant medications including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and tricyclics for various conditions, antidepressant-induced sexual dysfunction is becoming a prevalent side effect. A study of 33 women and 30 men showed an overall 84% effectiveness rate at curbing symptoms with G. bilobu extract exhibiting a positive effect on all four phases of the sexual response cycle: desire, excitement (erectionand lubrication), orgasm, and resolution This research group also demonstrated the efficacy of @go for these side effects after other management trials of cyproheptadine, yohimbine, amantadine, and buspirone hydrochloride had

Premenstrual Syndrome and Idiopathic Cyclic Edema

Premenstrual syndrome (PMS) is often characterized by fluid retention, vascular congestion, increased capillary permeability, and breast tenderness. A recent doubleblind, placebo-controlled study sought to determine the effectiveness of GBE on these symptoms.54The population studied was a group of 165 women between the ages of 18 and 45 years who had suffered from congestive symptoms for at least three cycles. The patients were then assigned to receive either the &go extract (80 mg twice Sexual Dysfunction daily) or placebo from the sixteenth day of the period to day 5 of the next. On the basis of extensive symptom Most cases of impotence (erectile dysfunction) are due evaluation by patients and physicians, it was concluded to impaired blood flow to erectile tissue. Evidence indithat the GBE was effective against congestive symptoms cates that GBE may be extremely beneficial in the treatment of erectile dysfunction due to lack of blood fl0w.5~ of PMS, particularly breast pain or tenderness. Patients taking the @go extract also noted improvementsin neuSixty patients with proven erectile dysfunction who had ropsychologic assessments. These results indicate that not reacted to papaverine injections up to 50 mg GBE may hold some promise in the treatment of PMS. were treated with GBE in a dose of 60 mg/day for 12 to 18 months. The penile blood flow was reevaluated by Antidepressant Effects duplex sonography every 4 weeks. The ability of GBE to improve general mood in patients The first signs of improved blood supply were seen suffering from cerebral vascular insufficiency in doubleafter 6 to 8 weeks. After 6 months’ therapy, 50% of the blind studies has led researchers to begin investigating patients had regained potency and in 20% a new trial of GBE’s antidepressive effects. In a recent double-blind papaverine injection was then successful; 25% of the study, 40 elderly patients (ranging from 51 to 78 years patients showed an improved blood flow, but papaverold) with depression who had not benefited fully from ine was still not successful. The remaining 5% were standard antidepressant drugs were given either 80 mg unchanged.

of GBE three times daily or a placeb0.5~By the end of the eighth week, the total score of the Hamilton Rating Scale for Depression in the GBE group had dropped from 14 to 4.5. In comparison, the placebo group dropped from 14 to only 13. This study indicated two things: GBE can be used with standard antidepressants. GBE enhance the effectiveness of standard antidepressants, particularly in patients older than 50 years of age. Importantly, the dosage used in the study (80 mg three times daily) is higher than the standard dosage of 40 mg three times daily. See the previous section on "sexual dysfunction" regarding grnkgo's ability to decrease unwanted side effects of standard antidepressant medications.

AllergiedAsthma Mixtures of gmkgolides, as well as the GBE standardized to contain 24% ginkgoflavonglycosides, have shown clinical effects in allergic conditions due to their inhibition of PAF, a key chemical mediator in asthma, inflammation, and allergie~.'~,'~ In one double-blind placebo study, the ability of a mixture of grnkgolides to block the effects of PAF when PAF was injected into the skin was investigated.16Normally, when PAF is injected it causes an immediate formation of a hive (classic wheal and flare reaction). However, if the pkgolide mixture (120 mg) was given before PAF injection, it effectively counteracted the wheal and flare reaction. Specifically, the grnkgolide reduced the flare (reddened) area by a mean of 62.4%and the wheal (hive) volume by a mean of 60%. A study from the Qmgdao Hospital of Integrated Traditional and Western Medicine in Shandong, China assessed the efficacy of an oral gingko liquor to alleviate airway hyperreactivity. It was found that the treatment sigruficantlyreduced airway inflammation and improved pulmonary function and clinical symptoms of asthmatic patients.% Mixtures of gmkgolides, as well as purified gmkgolides, are under investigation in several European countries. The hope is that they will be proven clinically effective in eczema, allergies, and many other conditions in which PAF plays a central r ~ l e . ~ ~ , ~ '

Raynaud's Disease Most common in young women (60%to 90% of reported cases), Raynaud's disease is a condition of vasospastic response that causes areas of the body including the fingers, toes, and tips of the nose and ears to feel numb and cool in response to cold temperatures or stress. During a Raynaud attack, these blood vessels that supply the skin narrow, limiting blood circulation to affected areas. Gingko's vasodilating activity is most likely responsible for its effectiveness in treating this problem.

Given the side-effect profile of pharmaceutic treatments for Raynaud's disease, a recent double-blinded, placebocontrolled study evaluated the use of GBE to treat this difficult condition. A 10-week trial revealed a 56% reduction in the number of weekly attacks, whereas placebo reduced the number by 27Y0.~~ The World Health Organization has recommended the use of ginkgo in Raynaud's disease, acrocyanosis, and postphlebitic syndrome.58

High Altitude Sickness A recent study demonstrated the usefulness of gingko to prevent symptoms of acute mountain sickness. For a Himalayan expedition of moderate altitude with gradual exposure, 44 volunteers were divided into a placebo group and a group that received 80 mg of gingko twice a day. No subject in the gingko group developed acute mountain sickness, unlike 40.9% of subjects in the placebo group. Vasomotor disorders of the extremities were also prevented in the gingko

FUTURE APPLICATIONS OF GINKGO BILOBA EXTRACT Experimental studies, as well as some preliminary clinical evidence, indicate that GBE may be of benefit in cases of angina, congestive heart failure, and acute respiratory distress syndrome. Its action on PAF may also make it useful for a great number of other applications in addition to allergies including various types of shock, thrombosis, graft protection during organ transplantation, multiple sclerosis, and burns.'r4

DOSAGE Most of the clinical research on G. bilobu has used a standardized extract, containing 24% ginkgo flavone glycosides, at a dose of 40 mg three times a day. However, some studies have used the higher dosage of 80 mg two to three times daily. Devising a dosage schedule using other forms of ginkgo is difficult due to extreme variation in the content of active compounds in dried leaf and crude extracts. Whatever form of @go is used, it appears to be essential that it is standardized for content and activity. For example, a standard 1:5 tincture obtained from the highest possible flavonoid content crude ginkgo leaf would require 1oz /day to provide the equivalent dosage level of the standardized extract. Clinical research clearly shows that GBE should be taken consistently for at least 12 weeks in order to determine effectiveness.Although most people report benefits within 2 to 3 weeks, some may take longer to respond.

GBE is extremely safe, and side effects are uncommon. In 44 double-blind studies involving 9772 patients taking GBE, the number of side effects reported was extremely small. The most common side effect, gastrointestinaldiscomfort, occurred in only 21 cases, followed by headache (seven cases) and dizziness (six cases).& Due to its inhibition of PAF, many practitioners are concerned that gingko may increase bleeding risk when used concurrently with warfarin (Coumadin),aspirin, and other antiplatelet therapies. A recent study evaluating the use of @go and warfarin concurrently revealed no change in the international normalized ratio, which is the blood test chosen to monitor the patient's possible bleeding risk in response to anticoagulation therapy@ . '

In contrast to the tolerance of the leaf extract, contact with or ingestion of the fruit pulp has produced severe allergic reactions.61t62Contact with the ginkgolic acids in the fruit pulp causes erythema and edema, with the rapid formation of vesicles accompanied by severe itching. This is similar to an allergic reaction to the poison ivy-oak-sumac group, suggesting cross-reactivity between G. bilobu fruit and this family. Ingestion of as little as two pieces of fruit pulp has been reported to cause severe gastrointestinal irritation from the mouth to the anus. Because the gingko leaf does have a low level of irritative ginkgolic acids, animal studies have been conducted to examine the possibility of adverse reactions from using gingko leaf extract. It was concluded that extracts of G. bilobu taken orally be considered

1. DeFeudis FV,ed. Ginkgo biloba extract (EGb 761). Pharmacological activities and clinical applications. Paris: Elsevier, 1991. 2.Tesch BJ. Herbs commonly used by women: an evidence-based review. Am J Obstet Gynecol2003;188(suppl5):544-S55. 3. Blumenthal M. Herb sales down 3% in mass market retail storessales in natural food stores still growing, but at lower rate. Herbal Gram 2000;49:68. 4. Funfgeld EW, ed. Rokan (Ginkgo biloba). Recent results in pharmacology and clinic. New York: Springer-Verlag, 1988. 5. Kleijnen J, Knipschild P. Ginkgo biloba. Lancet 1992;340:1136-1139. 6. Kleijnen J, Knipschild P. Ginkgo biloba for cerebral insufficiency. Br J C h Pharmacol 1992;34:352-358. 7. Sckaffler VK,Reeh PW.[Doubleblind study of the hypoxia protective effect of a standardized Ginkgo biloba preparation after repeated administration in healthy subjects]. Arzneimittelforschung 1985; 35:1283-1286. 8. Chatterjee SS, Gabard B. Studies on the mechanism of action of an extract of Ginkgo biloba, a drug for the treatment of ischemic vascular diseases. Naunyn-Schmiedebergs Arch Pharmacol 1982; 320R52. 9. Le Poncin Lafitte M, Rapin J, Rapin JR. Effect of Ginkgo biloba on changes induced by quantitative cerebral microembolization in rats. Arch lnt Pharmacodyn Ther 1980;243:236-244. 10. Karcher L, Zagerman P,Krieglstein J. Effect of an extract of Ginkgo biloba on rat brain energy metabolism in hypoxia. Naunyn Schmiedebergs Arch Pharmacol1984;32731-35. 11.Watanabe CM, Wolffram S, Ader P, et al. The in vivo neuromodulatory effects of the herbal medicine gingko biloba. Proc Natl Acad Sci U S A 2001;98:6577-6580. 12. Schmidt U, Rabinovici K, Lande S. Einfluss eines Ginkgo biloba specialextraktes auf doe befomdlickeit bei zerebraler onsufficizienz. Munch Med Wochenschr 1991;133S15-S18. 13. Bruchert E, Heinrich SE, Ruf-Kohler P. Wirksamkeit von LI 1370 bei alteren patienten mit himleistungsschwache. Multizentrische doppelblidstudie des fachverbandes Deutscher Allegemeinaezte. Munch Med Wochenschr 1991;133:59-S14. 14.Meyer B. [Multicenter randomized double-blind drug vs. placebo study of the treatment of tinnitus with Ginkgo biloba extract.] Presse Med 1986,151562-1564. 15. Taillandier J, Ammar A, Rabourdin JP, et al. [Treatment of cerebra1 aging disorders with Ginkgo biloba extract. A longtiudinal

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TOXICITY

study on different levels of investigation. Hum Psychopharmacol 1994;9215-222. 28. Kanowski S,Hermann Wh4, Stephan K, et al. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Phytomedicine 1997;4:3-13. 29. Le Bars PL, Kak MM, Berman N, et al. A placebo-controlled, doubleblind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA 1997;278: 1327-1332. 30. Wettstein A. Cholinesterase inhibitors and Ginkgo extracts-are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months’ duration. Phytomedicine 2000;6:393-401. 31. Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 199855: 1409-1415. 32. Meyer 8. A multicenter randomized doubleblind study of Ginkgo biloba extract versus placebo in the treatment of tinnitus. In results in pharmaFunfgeld EW, Rokan eds.(Ginkgo biloba)-recent cology and clinic. New York Springer-Verlag, 1988:245-250. 33. Coles RRA. Trial of an extract of Ginkgo biloba (EGB) for tinnitus and hearing loss. Clin Otolaryngol1988;13:501-504. 34. Holgers KM, Axelsson A, Pringle I. Ginkgo biloba extract for the treatment of tinnitus. Audiology 1994;3385-92. 35. Drew S,Davies E. Effectiveness of Ginkgo biloba in treating tinnitus: double blind, placebo controlled trial. BMJ 2001;332:73. 36. Bascher V, Steinert W. Differential diagnosis of sudden deafness and therapy with high dose infusions of Ginkgo biloba extract. In Clausen CF, Kirtane MV, Schlitter K, eds. Vertigo, nausea, tinnitus, and hypoacusia in metabolic disorders. Amsterdam: Elsevier Science, 1988575-582. 37. Fukaya H,Kanno H. [Experimental studies of the protective effect of ginkgobiloba extract (GBE)on cisplatin-induced toxicity in rats]. Nippon Jibiinkoka Gakkai Kaiho 1999;102907-917. 38. Lanthony P, Cosson JP. [The course of color vision in early diabetic retinopathy treated with Ginkgobiloba extract.A prelurunary doubleblind versus placebo study]. J Fr Ophtalmol 1988;11:671-674. 39.De Felice M, Gallo P, Masotti G. Current therapy of peripheral obstructive arterial disease. The non-surgical approach. Angiology 199O;41:1-11. 40.Ernst E. Pentoxlfylline for intermittent claudication. A critical review. Angiology 1994;45339-345. 41. Schneider B. [Ginkgo biloba extract in peripheral arterial diseases. Meta-analysis of controlled clinical studies]. Arzneimittelforschung 1992;42:428-436. 42. Thomson GJ, Vohra RK, Carr MH, Walker MG. A clinical trial of Gingko biloba exkact in patients with intermittent claudication. Int Angi01 1990;9:75-78. 43.Saudreau F, Sense JM, Pillet J, et al. Efficacy of Ginkgo biloba extract in the treatment of chronic obliterating arteriopathies of the lower limbs in stage Ill of Fontaine’s classification. J Ma1 Vasc 1989;14177-182.

44.Rudofsky VG. [Effect of Ginkgo biloba extract in arterial occlusive disease. Randomized placebo controlled crossover study]. F0rtscl-u Med 1987;105:397-400. 45. Bauer U.Ginkgo biloba extract in the treatment of arteriopathy of the lower limbs. A 65-week trial.] Presse Med 1986;15:1546-1549. 46.Bauer U.&month doubleblind randomized clinical trial of Ginkgo biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency.Arznehittelforschung 1984;34:71&721. 47. Dawson, DL, Cutler BS, Meissner MH, Strandess DE Jr. Cilostazol has beneficial effects in the treatment of intermittent claudication. Circulation 1998;98:67&686. 48. Mosby’s Drug Consult. St Louis: Mosby, 2003. 49. Pittler MH,Emst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med 2O00;108:276-281. 50. Jacobs BP, Browner WS. Ginkgo biloba: a living fossil. Am J Med 2OOO;108:341-342. 51. Sikora R, Sohn M, Deutz FJ, et al. Ginkgo biloba extract in the therapy of erectile dysfunction. J Urol1989;141:188A. 52. Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther 1998;24:139-143. 53. Cohen AJ, Bartilik BD. Gingko biloba for drug-induced sexual dysfunction. Presented at the American Psychiatric Association Annual Meeting, San Diego, CA, 1997. 54.Tamborini A, Taurelle R. [Value of standardized Ginkgo biloba extract (Egb 761) in the management of congestive symptoms of premenstrual syndrome]. Rev Fr Gynecol Obstet 1993;88: 447-457. 55. Schubert H, Halama P. Depressive episode primarily unresponsive to therapy in elderly patients. Efficacy of Ginkgo biloba (Egb 761) in combination with antidepressants. Geriatr Forsch 1993;3: 45-53. 56. Li M, Yang B, Yu H, B a n g H. Clinical observation of the therapeutic effect of ginkgo leaf concentrated oral liquor on bronchial asthma. Chinese J Integr Med 1997;3264-267. 57. Muir AH, Robb R, McLaren M, et al. The use of Ginkgo biloba in Raynaud’s disease: a double-blind placebollontrolled trial. Vasc Med 2002;7265-267. 58. World Health Organization. WHO monographs on selected medicinal plants, vol 1. Geneva: World Health Organization, 19W154-167. 59. Roncin JP, Schwartz F, DArbigny P. EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure. Aviat Space Environ Med 1996;67445-452. 60.Engelsen J, Nielsen JD, Winther K. Effect of coenzyme QlO and Ginkgo biloba on warfarin dosage in stable, long-term warfarin treated outpatients. A randomised, double blind, placebo-crossover trial. Thromb Haemost 2002;87:1075-1076. 61. Becker LE, Skipworth GB. Ginkgo-tree dermatitis, stomatitis, and proctitis. JAMA 1975;231:1162-1163. 62. Hausen BM. The sensitizing capacity of ginkgolic acids in guinea pigs. Am J Contact Dermat 1998;9:146-148.

Glucosamine Michael T. hlurray, ND Joseph E. Pizzorno Jr, NI> CHAPTER CONTENTS General Description 987

Dosage 991

Available Forms 987 Glucosarnine Sulfate versus Nacetylglucosarnine 987 Glucosarnine Sulfate versus Glucosarnine Hydrogen Chloride 988

Toxicity 991 Drug Interactions 991

Clinical Applications 988 Osteoarthritis 988

GENERAL DESCRIPTION Glucosamine is a simple molecule, manufactured in the body from glucose and an amine. One of the primary physiologic roles of glucosamine is in the joints, where it stimulates the manufacture of glycosaminoglycans (GAGS),key structural components of cartilage. Glucosamine also promotes the incorporation of sulfur into cartilage. Because of this effect, glucosamine sulfate (GS) is thought to be the best source of glucosamine (Figure 97-1). As some people age, they apparently lose the ability to manufacture sufficient levels of glucosamine. The result is that synthesis of GAGS does not keep up with degradation. The inability to manufacture glucosamine at an adequate rate has been suggested to be the major factor leading to osteoarthritis. There are no food sources of glucosamine. Commercially available sources of glucosamine are derived from chitin-the exoskeleton of shrimp, lobsters, and crabs.

AVAILABLE FORMS Glucosamine is commercially available as glucosamine sulfate, glucosamine hydrochloride, and N-acetylglucosamine (NAG). GS, the only form of glucosamine that has been the subject of more than 300 scientific investigations and more than 20 double-blind studies, is the preferred form. GS has also been used by millions of

people worldwide and is registered as an aid in osteoarthritis in some 70 countries. When authors or manufacturers discuss glucosamine hydrochloride or NAG, they often cite references of clinical studies that have used GS or the combination of glucosamine hydrogen chloride (HC1) and chondroitin sulfate. On the basis of currently available clinical evidence, it appears that only GS provides proven clinical effectiveness when administered as an isolated agent (numerous studies show the combination of glucosamine HC1 and chondroitin sulfate to be effective).

Glucosamine Sulfate versus /V-acetylglucosamine NAG differs from GS in that instead of a sulfur molecule, NAG has a portion of an acetic acid molecule attached to it. GS and NAG are different molecules and appear to be handled by the body differently. Companies marketing NAG claim that this form is better absorbed, more stable, and better used than glucosamine sulfate. These contentions are without support in the scientific literature. Detailed human studies on the absorption, distribution, and elimination of orally administered GS have shown an absorption rate of as high as 98% and that, once absorbed, it is then distributed primarily to joint tissues, where it is incorporated into the connective tissue matrix of cartilage, ligaments, and tendons.',* In addition, there are impressive clinical studies on thousands of patients. In contrast, the only clinical study with NAG used it 987

sulfur has been shown to inhibit the various enzymes that lead to cartilage destruction in osteoarthritis (e.g., collagenase, elastases, and hyalur~nidase).~',~~ Because one of the primary effects of GS is to promote OH the manufacture of GAGs, a lack of the sulfur moiety may mean less GAG synthesis when glucosamine HC1 is Figure 97-1 Glucosamine. used. Therefore it is unlikely that glucosamine HC1 will show the same excellent clinical results achieved with as a polymer that is not yet available ~ommercially.~ GS because it lacks this critical element. Polymerization is thought to be necessary due to the In fact, results from double-blind studies indicate that poor oral availability of unbound NAG. glucosamine HC1 may be no more effective than a placebo in relieving osteoarthritis. One double-blind, placeboFurther evidence of the superiority of GS to NAG is controlled, 10-week study examined the effects of gluoffered by studies on laboratory animals. Several studies cosamine HC1 in patients with osteoarthritis of the have demonstrated that glucosamine absorption and utilization is at least twice that of NAG."15 The researchers knee.2I Patients received either 500 mg of glucosamine concluded that glucosamine is a more efficient precursor HCl or a placebo three times daily. Forty-five patients of macromolecular hexosamine (GAG) than NAG. It received glucosamine HC1, while 53 received the placebo. The results indicated that 49% of patients receiving gluis possible that NAG does not penetrate the cell membranes and, as a result, is unavailable for incorporation cosamine HC1 felt they had improved compared with 45% of the placebo group who said they felt improved. into glycoproteins and mucopolysaccharides.6The body preferentially uses GS rather than NAG. This preference However, the difference between the two groups was appears largely due to the active processes that enhance not statistically sigruficant. What these results call into absorption of GS in the intestines.1b question is the viability of glucosamine HC1 as an effective form of glucosamine. The absorption of NAG by humans is poor for several More than 30 published, double-blind clinical trials reasons: with GS have demonstrated a success rate of 72% to 95% NAG is quickly digested by intestinal bacteria. in various forms of osteoarthritis. In osteoarthritis of the NAG binds with dietary lectins in the gut, resulting in knee, the success rate is more than 80%. Clearly, the suca lectin-NAG complex, which is excreted in the feces. cess rate noted by glucosamine HCl in this preliminary A large percentage of NAG is metabolized by intestinal study is much less than the rate reported with glucells. cosamine sulfate. In addition to the question of absorption, several studies have shown that the articular tissue cannot use CLINICAL APPLICATIONS NAG as well as it does glu~osamine.~,~ These absorption The primary use for GS is in the treatment of osteoarthritis. and utilization problems suggest NAG is highly unlikely to possess the same kind of antiarthritic and antiinflamGlucosamine is a safe and effective natural alternative to aspirin and other nonsteroidal antiinflammatory drugs matory properties that GS has been shown to possess. (NSAIDs) in the treatment of osteoarthritis. Clinical and Glucosamine Sulfate versus experimental research indicates that current drugs used Glucosamine Hydrogen Chloride in osteoarthritis may be producing short-term benefit but actually accelerating the progression of the joint Research has shown that sulfur is an extremely impordestruction. NSAIDs tend to inhibit cartilage repair by tant component in the therapeutic effect of GS, and its inhibiting glycosaminoglycan synthesis and the incorposubstitution is likely to decrease the efficacy of supplemental glu~osamine.'~ Sulfur is an essential nutrient ration of sulfur into Because osteoarthrifor joint tissue, where it functions in the stabilization of tis is caused by a degeneration of cartilage, it appears that while NSAIDs are fairly effective in suppressing the connective tissue matrix of cartilage, tendons, and the symptoms, they possibly worsen the condition by ligaments. Even healthy humans have low serum sulfate inhibiting cartilage formation and accelerating cartilage (0.3 to 0.4 mM) and synovial sulfur levels, but in destruction (see Chapter 195 for further d i s c u ~ s i o n ) . 2 ~ ~ ~ osteoarthritis these concentrations are even lower. As far back as the 1930s, researchers demonstrated that indiOsteoarthritis viduals with arthritis are commonly deficient in this essential nutrient.18J9 Restoring sulfur levels brought Numerous double-blind studies have shown GS to about significant benefit to these patient^.'^ In addition produce much better results compared with NSAIDs to sulfur playing a critical role in the manufacture and placebos in relieving the pain and inflammation of of GAGs like chondroitin sulfate and keratan sulfate, osteoarthritis. In one of the classic studies comparing GS

with a placebo, 252 patients with osteoarthritis of the knee were given either a placebo or 500 mg of GS three times daily for 4 weeks.28Results indicated that GS was significantly more effective than the placebo in improving pain and movement after 4 weeks. Previous studies have shown that the longer GS is used, the greater the therapeutic benefit. The rate and severity of side effects with glucosamine did not differ from the placebo. These results are consistent with other double-blind studies versus a p l a ~ e b o . ~A~few - ~ ~studies , ~ ~ have shown no greater benefit than a p l a ~ e b o . ~ , ~ ~ The two longest placebo-controlled trials are of three years in d ~ r a t i o n . ~The , ~ ’results from these studies show quite convincingly that GS slows down the progression of osteoarthritis and in many cases produces regression of the disease, as noted by radiologic improvements. In the first long-term study, 212 patients with knee osteoarthritis were randomly assigned 1500 mg sulphate oral glucosamine or placebo once daily for 3 years. Weightbearing, anteroposterior radiographs of each knee in full extensionwere taken at enrollment and after 1and 3 years. Mean joint-space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis, whereas minimum joint-space width (i.e., at the narrowest point) was measured by visual inspection with a magnifying lens. Symptoms were scored by the Western Ontario and McMaster Universities (WOh4AC) osteoarthritisindex. The 106 patients on placebo had a progressive joint-space narrowing, with a mean joint-space loss after 3 years of -0.31 mm. No sigruficantjoint-space loss occurred in the 106 patients on GS: -0.06 mm. Similar results were reported with minimumjoint-space narrowing. As assessed by WOMAC scores, symptomsworsened slightly in patients on placebo compared with the clinical improvement observed in the group receiving GS. To investigate the relationship between baseline radiographic severity of knee osteoarthritis (OA) and the importance of long-term joint space narrowing in more detail, a subanalysis of data from the 3-year trial was p e r f ~ r m e dMeasurements .~~ of mean joint-space width (JSW), assessed by a computer-assistedmethod, were performed at baseline and after 3 years, on weight-bearing anteroposterior knee radiographs. Those receiving GS demonstrated a trend for significant reduction in jointspace narrowing in patients in the highest quartile of baseline mean JSW (>6.2 mm). In these patients, a joint space narrowing of 14.9% occurred in the placebo group after 3 years, while patients from the GS group only experienced a narrowing of 6%. Insight into who might best respond to GS was provided in another analysis from this 3-year study that examined the ability of GS to improve a biochemical marker of collagen type I1 degradation (CTX-II).39 At baseline the 212 patients had an average concentration of urinary CTX-II of 222.4 ng/mmol creatinine. This was

sigruficantly above the CTX-I1 levels measured in urine samples from 415 healthy controls (169.1 ng/mmol). Although there was no sigruficant difference in the CTX-II response in the placebo group and the glucosaminetreated group, those with high cartilage turnover presented a sigruficant decrease in CTX-I1 after 12-month glucosamine treatment. The group with CTX-11 concentrations above normal average plus 1standard deviation decreased 15.5% after 12-month therapy. The change in CTX-I1 in these patients correlated with the change in average JSW observed after 36 months. Increased baseline levels of CTX-11 in the placebo group were associated with a worsening of the WOMAC index. These data indicate that measurement of urinary collagen type 11 C-telopeptide fragments enables the identification of patients with high cartilage turnover who appear to be most responsive to GS therapy. In the second study, 202 patients with knee osteoarthritis were randomized to receive oral GS (1500 mg once a day) or placebo. Changes in computed tomography radiographic minimumjoint space width were measured in the medial compartment of the tibiofemoral joint, and symptoms were assessed using the Lequesne and WOMAC. Though symptoms improved more significantly in the GS group, the most telling result was the fact that progressive joint space narrowing with placebo use was -0.19 mm after 3 years, while there was no average change with GS sulfate use (an increase of 0.04 mm was the a ~ e r a g e ) ? ~ Head-to-head, double-blind studies have also shown GS to produce much better results compared with NSAIDs in relieving the pain and inflammation of osteoarthritis, despite the fact that GS exhibits little direct antiinflammatory effect and no direct analgesic or pain-relieving effects.4043Although NSAIDs offer purely symptomatic relief and may actually promote the disease process, GS appears to address the cause of osteoarthritis. By promoting cartilage synthesis, thus treating the root of the problem, GS not only relieves the symptoms but also helps the body to repair damaged joints. The clinical effect is impressive, especially when glucosamine’s safety and lack of side effects are considered. In one of the earlier comparative studies in which GS (1500 mg/day) was compared with ibuprofen (1200 mg/day), pain scores decreased faster in the first 2 weeks in the ibuprofen group. However, by week 4 the group receiving GS experienced a significantly better improvement than the ibuprofen group.4o Physicians rated the overall response as good in 44% of the glucosamine sulfate-treated patients as compared with only 15%of the ibuprofen group. Additional studies designed to further evaluate the comparative effectiveness of GS to NSAIDs provide even better evidence.41“ One study consisted of 200 subjects with osteoarthritis of the knee given either GS (500 mg three times daily) or ibuprofen (400 mg three times daily)

for 4 weeks.4l Consistent with previous studies, the ibuprofen group experienced quicker pain relief. However, by the end of the second week, the group taking GS experienced as good results as the ibuprofen group with one major exception-although the rate of side effects with glucosamine were mild and only affected 6% of the group, ibuprofen produced more significant side effects much more frequently, with 35% of the group experiencing them. In another study, 329 patients were given 1500 mg GS, 20 mg piroxicam, both compounds, or a placebo for 90 days.42The main efficacy variable was represented by the Lequesne index, a standard method of assessing disease activity. As can be seen in Figure 97-2, the results of the study were strikingly in favor of GS alone. These impressive results with GS were achieved without side effects. In fact, patients on GS had fewer side effects than the placebo and no dropouts. (Table 97-1 provides the side effect and dropout values among the four groups.) In another study in osteoarthritis of the knee (Table 97-2) GS showed comparable symptomatic relief, but was better tolerated and produced residual benefit after di~continuation.4~ Another study showed an obvious advantage of GS over ibuprofen in patients diagnosed with temporomandibular joint (TMJ) osteoarthritis. In the doubleblind study, 40 women and 5 men received either GS (500 mg) or ibuprofen (400 mg) three times daily for 90 days. Fifteen patients taking GS (71%)and 11 taking ibuprofen (61%)improved, with positive clinical response taken as a 20% decrease in TMJ pain and function. Between-group comparison revealed that patients taking GS had a significantly greater decrease in TMJ pain with function, effect of pain, and acetaminophen used between days 90 and 120 compared with patients taking ibuprofen.44 In addition to showing benefit in double-blind studies, oral GS was shown to offer significant benefit in an open 121

Dropouts

Placebo

GS

Piroxicam

GS + piroxicam

24.4%

14.8%

40.9%

5.9%

20

3

0

3

GS,Glucosamine sulfate.

Time

Glucosamine sulfate

Ibuprofen

8.42 5.54 3.60 3.26

8.46 5.63 4.18 3.84

1.43 0.77 0.47 0.36

1.48 0.89 0.48 0.54

Knee Pain (Average Score) Before treatment Wk 2 Wk 4

2 wk after treatment Knee Swelling (Average Score) Before treatment Wk 2 Wk 4

2 wk after treatment Clinical Improvement Glucosamine sulfate

Ibuprofen

Effectiveness

After 4 wk

After 6 wk

After 4 wk

After 6 wk

Symptom free

45% 39% 1 1 o/o 5%

55%

32% 45% 15% 8%

36% 41% 14% 9%

Improved Unchanged Worsened Side Effects

32% 7% 6%

Glucosamine sulfate

Ibuprofen

Side effects

6%

Dropouts

0%

16% 10%

Modified from Qiu GX, Gao SN, Giacovelli G, et al. Arzneirnineiiorschung 1998;48: 469-474.

-@U-

Placebo

+Piroxicam -A-

4 0

Incidence of side effects

15

30

60

90

GS + Pir

1 120 150

Day Figure 97-2 Symptom relief (Lequesne index) from glucosamine compared with piroxicam and placebo.

trial involving 252 doctors and 1506 patients in P0rtugal.4~ This large study provides valuable clinical information on the appropriate use of GS. The patients received 500 mg of GS three times daily over a mean period of 50 days. Symptoms of pain at rest, on standing, and on exercise, as well as limited active and passive movements, all improved steadily throughout the treatment period. Objective therapeutic efficacy was rated by doctors as "good" in 59% of the patients and "sufficient" in a further 36%. Although not a controlled study, a 95%

G lucosarnine response rate is impressive. The results with GS were rated by both doctors and patients as being sigruficantly better than those obtained with previous treatment including NSAIDs, vitamin therapy, and cartilage extracts. GS produced good benefit in a significant portion of patients who had not responded to any other medical treatment. In the study, obesity was associated with a significant shift from good to fair. This finding may indicate that higher dosages may be required for obese individuals or that oral glucosamine is not enough to counteract the added stress of obesity on the joints. Patients with peptic ulcers and individuals taking diuretics were also associated with a shift from good to sufficient in efficacy, as well as tolerance. Individuals with current peptic ulcers should take glucosamine sulfate with foods. Individuals taking diuretics may need to increase the dosage to compensate for the reduced effectiveness. The improvement with glucosamine lasted for 6 to 12 weeks after the end of treatment.

GS has an excellent safety record in animal and human studies. On the basis of these studies, many experts have recommended that GS “be considered as a drug of choice for prolonged oral treatment of rheumatic disorders.” Side effects, when they do appear, are generally limited to light to moderate gastrointestinal symptoms including stomach upset, heartburn, diarrhea, nausea, and indigestion. If these symptoms occur, GS should be taken with meals. Regarding people who are “sulfur sensitive,” an important distinction must be made. When patients report they are allergic to sulfur, what they usually mean is that they are allergic to the so-called sulfa drugs or sulfite-containing food additives. It is impossible to be allergic to sulfur, as sulfur is an essential mineral. The sulfate form of sulfur is present in human blood. In short, GS is extremely well tolerated and no allergic reactions have been reported.

DOSAGE

DRUG INTERACTIONS

The standard dosage for GS is 1500 mg daily. It may be administered as a single or divided dosage with equal effectiveness. Obese individuals may need higher dosages on the basis of body weight (e.g., 20 mg/kg body weight daily). Also, individuals taking diuretics may also need to take higher dosages.

Concern has been expressed that glucosamine may influence insulin secretion or action, or both, in humans primarily on the basis of in vitro studies. However, human studies do not support that at recommended levels GS has any impact on insulin secretion or action in either health subjects or those with type 2

1.Setnikar I, Palumbo R, Canali S, Zanolo G. Pharmacokinetics of glucosamine in man. Arzneimittelforschung 1993;43:1109-1113. 2. Setnikar I, Giacchetti C, Zanolo G. Pharmacokinetics of glucosamine in the dog and man. Arzneimittelforschung 1986;36: 729-735. 3. Rubin BR, Talent JM, Kongtawelert P, et al. Oral polymeric N-acetyl-D-glucosamine and osteoarthritis. J Am Osteopath Assoc. 2001;101:339-344. 4. Setnikar I. Antireactive properties of ”chondroprotective” drugs. Int J Tissue React 1992;14:253-261. 5. Karzel K, Domenjoz R. Effect of hexosamine derivatives and uronic acid derivatives on glycosaminoglycan metabolism of fibroblast cultures. Pharmacology 1971;5:337-345. 6. Vidal y Plana RR, Bizzarri D, Rovati AL. Articular cartilage pharmacology. I. In vitro studies on glucosamine and non steroidal anti-inflammatory drugs. Pharmacol Res Commun 1978;10557-569. 7. Capps JC, Shertlar MR, Bradford RH. Hexosamine metabolism. II. Effect of insulin and phlorizin on the absorption and metabolism, in vivo, of D-glucosamine and N-acetyl-D-glucosamine in the rat. Biochim Biophys Acta 1966;127205-212. 8. Capps JC, Shetlar MR, Bradford RH. Hexosamine metabolism. I. The absorption and metabolism, in vivo of orally administered D-glucosamine and N-acetyl-D-glucosamine in the rat. Biochim Biophys Acta 1966;127194204. 9. Shetlar MR, Capps JC, Hem DL. Incorporation of radioactive glucosamine into the serum proteins of intact rats and rabbits. Biochim Biophys Acta 1964;8393-101.

10. Richmond JE. Studies on the metabolism of plasma glycoproteins. Biochemistry 1963;128:676-683. 11. Capps JC, Shetlar MR. In vivo incorporation of D-glucosamine-1-C14 into acid mucopolysaccharides of rabbit liver. Proc SOCExp Biol Med 1963;114:118-120. 12. Shetlar MD, Hem DL, Bradford RH, et al. Fate of radioactive glucosamine administered parenterally to the rat. Proc SOCExptl Biol Med 1962;109:335-337. 13. Kohn P, Winzler RJ, Hoffman R. Metabolism of D-glucosamine and N-acetyl-D-glucosaminein the intact rat. J Biol Chem 1962;237 304-308. 14.McGarrahan JF,Maley F. Hexosamine metabolism. J Biol Chem 1962;2372458-2465. 15. Shetlar MD, Hem DL, Bradford RH, Endecott 8. Incorporation of [1-14C]glucosamine into serum proteins. Biochim Biophys Acta 1961;53:615-616. 16. Tesoriere G, Dones F, Magistro, Castagnetta L. Intestinal absorption of glucosamine and N-acetylglucosamine. Experientia 1972;28770-771. 17. Annefeld M. Personal communication. February 28, 1997, Chicago. 18. Sullivan MX, Hess WC. Cystine content of finger nails in arthritis. J Bone Joint Surg Am 1935;16:185-188. 19. Senturia BD. Results of treatment of chronic arthritis and rheumatoid conditions with colloidal sulphur. J Bone Joint Surg Am 1934; 16119-125. 20. Vignon E, Richard M, Annefeld M. An in vitro study of glucosamine sulfate on human osteoarthritic cartilage metabolism. Manuscript in preparation.

TOXICITY

Pharmacology of Natural Medicines ~

21.Houpt JB, Mch4iUan R, Wein C, et al. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol1999;262423-2430. 22. Brandt KD. Effects of nonsteroidal anti-inflammatory drugs on chondrocyte metabolism in vitro and in vivo. Am J Med 1987;83 29-34. 23. Shield MJ. Anti-inflammatory drugs and their effects on cartilage synthesis and renal function. Eur J Rheumatol Inflamm 1993; 13:7-16. 24. Brooks PM, Potter SR, Buchanan WW. NSAID and osteoarthritishelp or hindrance? J Rheumatol 1982;93-5. 25. Newman NM, Ling RS.Acetabular bone destruction related to nonsteroidal anti-inflammatory drugs. Lancet 1985;2;11-14. 26. Solomon L. Drug-induced arthropathy and necrosis of the femoral head. J Bone Joint Surg Am 197355246-251. 27.Ronningen H, Langeland N. Indomethacin treatment in osteoarthritis of the hip joint. Acta Orthop S a n d 1979;50:169-174. 28.Noack W, Fischer M, Forster KK, et al. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;251-59. 29. Crolle G, DEste E. Glucosamine sulfate for the management of arthrosis: a controlled clinical investigation. Curr Med Res Opin 1980;7104-109. 30.Pujalte Jh4,Llavore EP, Ylescupidez FR. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis. Curr Med Res Opin 1980;7110-114. 31. Drovanti A, Bignamini AA, Rovati AL. Therapeutic activity of oral glucosamine sulfate in osteoarthrosis: a placebecontrolled doubleblind investigation. Clin Ther 1980;3:260-272. 32. DAmbrosia E, Casa B, Bompani R, et al. Glucosamine sulphate: a controlled clinical investigation in arthrosis. Pharmatherapeutica 1982;2:504-508. 33. Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med 2003;37:45-49. 34. Hughes R, Carr A. A randomized, double-blind, placebocontrolled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology 2002;41:279-284. 35. Rindone JP, Hiller D, Collacott E, et al. Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee. West J Med 2000;17291-94. 36. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357251-256.

~

~~~

37. Paveka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis:a >year, randomized, placebocontrolled, double-blind study. Arch Intern Med 2002;162: 2113-2123. 38. Bruyere 0, Honore A, Ethgen 0, et al. Correlation between radiographic severity of knee osteoarthritis and future disease progression. Results from a 3-year prospective, placebo-controlled study evaluating the effect of glucosamine sulfate. Osteoarthritis Cartilage 2003;l:l-5. 39. Christgau S, Henrotin Y, Tank0 LB, et al. Osteoarthritic patients with high cartilage turnover show increased responsiveness to the cartilage protecting effects of glucosamine sulphate. Clin Exp Rheumatol 2004;22:36-42. 40.Lopes Vaz A. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulfate in the management of osteoarthrosis of the knee in out-patients. Curr Med Res Opin 1982;8:145-149. 41. Muller-Fassbender H, Bach GL, Haase W, et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;2:61-69. 42. Rovati LC, Giacovelli G, Annefeld M, et al. A large, randomized, placebo controlled, double-blind study of glucosamine sulfate vs piroxicam and vs their association, on the kinetics of the symptomatic effect in knee osteoarthritis. Osteoarthritis Cartilage 1994;2 (suppl 1):56. 43. Qiu GX, Gao SN, Giacovelli G, et al. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Armeimittelforschung 1998;48:469-474. 44. Thie NM, Prasad NG, Major PW. Evaluation of glucosamine sulfate compared to ibuprofen for the treatment of temporomandibular joint osteoarthritis: a randomized double blind controlled 3 month clinical trial. J Rheumatol2001;28:1347-1355. 45. Tapadinhas MJ, Rivera IC, Bignamini AA. Oral glucosamine sulfate in the management of arthrosis: report on a multi-centre open investigation in Portugal. Pharmatherapeutica 1982;3:157-168. 46. Monauni T, Zenti MG, Cretti A, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000;49:926-935. 47. Scroggie DA, Albright A, Harris MD. The effect of glucosaminechondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163: 1587-1590.

Glutamine Peter B.Bongiomo, ND, Dip1 Ac CHAPTER CONTENTS introduction 993 Food Sources 993 Forms 993 Physiologic Effects 993 Clinical Applications 995 Intestinal Permeability-Related Conditions 995 Infectious Diarrhea 995 Postsurgical Complications of the Gastrointestinal Tract 995 Chemotherapy and Radiation Side Effects 996 Cachexia 997

INTRODUCTION Glutamine (Figure 98-1) is the most abundant amino acid in the blood and muscle tissue. It comprises approximately 6% of mixed whole body protein and is unique among amino acids in that it is a preferred fuel of rapidly dividing cells such as intestinal and immune cells and is important in maintaining pancreatic function.’” Glutamine is involved in the transport of circulating amino nitrogen and is an important intermediary that allows for accelerated gluconeogenesis from amino acids that are released by the skeletal muscle during stress state^.^ In addition, glutamine is used as a precursor for DNA and glutathione ~ynthesis.~ As one of the principal fuels used by the cells of the intestinal lining, it accounts for 35% of enterocyte energy production. Although readily available in the diet and synthesized in the body from glutamate and ammonia, supplementation is known to enhance the energy metabolism of the gastrointestinal mucosa, thus stimulating regeneration.6 Although glutamine is not considered essential in healthy people, there is evidence that the increased need for glutamine in stressed states such as burns, septicemia, endotoxemia, intestinal failure, and critical illness may result in it being ”conditionally e~sential.”~,~,~

Human ImmunodeficiencyVirus 997 Peptic Ulcers 998 Severe Burns 998 Low-Birth-Weight Infants 998 Exercise and Weight Lifting 998 Cardiac Disease 999 Other Conditions 999 Dosage 999 Toxicity

1000

Drug Interactions 1000

Food Sources Typical food sources of glutamine include animal and plant proteins. Typical foods are cabbage, beef, chicken, fish, legumes, miso (a salty, fermented bean product), and dairy products.

Forms The nomenclature of L-glutamine and glutamine are used interchangeably. Dglutamine is the stereoisomer of L-glutamine and does not have any known biologic activity. L-glutamine is not very soluble in water, and aqueous solutions are unstable at temperatures of 22 to 24 degrees Celsius. As a result, the more soluble and more stable dipeptides such as alanyl-glutamine are used as delivery forms of L-glutamine in total parenteral nutrition s o l u t i ~ n s . ~ J ~

Physiologic Effects Intestinal Repair and Protection Animal and human studies suggest that glutamine stimulates intestinal mucosal growth1’ and protects from mucosal atrophy. Glutamine prevents intestinal mucosal damage and has been shown to decrease bacterial leakage across the intestines after they are damaged, presumably by stimulating repair.12 Glutamine is thought to accomplish this by strengthening epithelial tight 993

0

0

NH, Figure 98-1

L-glutamine.

junctions and also by preventing paracellular permeabilities through an epidermal growth factor receptordependent mechanism. In one tissue culture experiment, intestinal epithelium cells were treated with acetaldehyde in order to compromise barrier function. These cells were treated with L-glutamine, D-glutamine, L-asparagine, L-arginine, L-lysine, or L-alanine. Only the L-glutamine demonstrated a benefit by decreasing aldehyde effects on transepithelid resistance. Furthermore, L-glutamine-treated cells had decreased permeability that was dose dependent. L-glutamine reduced the acetaldehyde-induced disturbance of transmembrane structures such as occludin, zonula occludens-1, E-cadherin, and beta-catenin from the intercellular junctions. Lastly, L-glutamine induced a rapid increase in the tyrosine phosphorylation of epidermal growth factor receptor. No other amino acids demonstrated this effect.l3

Acid Base Balance Glutamine plays an important role in acid-base homesta as is.^^ Glutamine is synthesized from glutamate and the toxic alkaline waste product ammonia by the enzyme glutamine synthetase, which requires magnesium and adenosine triphosphate. When ammonia levels are elevated, the body effectively removes ammonia from the blood by synthesizing glutamine. Conversely, if the blood is too acidic, the glutamine can be broken down into glutamate and ammonia, which increases blood pH. Ammonia can bind hydrogen ions to produce ammonium cations, which are excreted in the urine along with chloride anions. Bicarbonate ions are simultaneously released into the bloodstream. Clinical studies have shown that relatively small oral doses of glutamine can elevate plasma bicarbonate concentrations in healthy adults. In one study 2 g of glutamine were dissolved in a cola drink and ingested over a 20-minute period 45 minutes after a light breakfast. Control subjects were given soda only. Blood samples were taken 1 week before, at baseline, and subsequently at three separate 30-minute intervals after ingestion of the glutamine drink or placebo. Eight of nine subjects responded to the oral glutamine load with a sigruhcant increase in plasma glutamine at 30 and 60 minutes before returning to the baseline value at 90 minutes. Ninety minutes after the glutamine was

administered, plasma bicarbonate concentration was found to be increased. Additionally, circulating plasma growth hormone concentration was elevated as well. Concomitant with enhanced renal acid secretion, glutamine ingested also caused an increase in glomerular filtration rate.15 The authors of this study explained that their results show that it is unlikely L-glutamine is a direct precursor of bicarbonate. Instead, L-glutamine appears to play an indirect role in accelerating acid secretion through mechanistic changes in the kidneys. Human studies have shown that urinary ammonium excretion is altered by changes in glutamine intake.16 Chronic metabolic acidosis is a common clinical problem encountered in catabolic states such as sepsis, shock, and diabetes and is a major factor in many biologic derangement^.'^ Because glutamine becomes an essential amino acid in catabolic states when the increased demand exceeds the body’s capability to synthesize it,’* glutamine supplementation may be quite useful to maintain pH homeostasis in patients with acidotic conditions.

Glutathione Repletion Glutathione is a tripeptide consisting of glutamate, cysteine, and glycine. As a reservoir source for glutamate in the body, the availability of glutamine appears crucial for the regeneration of glutathione stores in the liver during hepatic injury; in skeletal muscle following major trauma, sepsis, or surgery; and in chemotherapy-injured heart muscle.1Y-21 Glutamine can enhance intracellular repletion of glutathione, an important scavenger of reactive oxygen species.= Rat studies have demonstrated that during 5-flurouracil-induced free radical-mediated hepatic injury, glutamine increases glutathione biosynthesis and preserves the glutathione stores in hepatic tissue.19Human studies of 17 patients undergoing a standardized surgical procedure were prospectively given 0.56 g/kg body weight/day of glutamine or a placebo. Employing percutaneous muscle biopsies and blood samples, it was observed that 24 and 72 hours after an operation, there were no significant decreases in total or reduced glutathione in the glutamine-supplemented group. In contrast, the placebo group experienced total muscle glutathione losses of 47”/0k 8% and 37%f 11%, as well as reduced glutathione decreases of 53% f 10% and 45%f l6%, at 24 and 72 hours, respectively.

Protein Sparing Glutamine is a regulator of muscle prote0lysis,2~and supplementation can attenuate loss of protein in the muscle. Experiments using animal cancer models have demonstrated decreased protein loss and simultaneous protection of immune and gut-barrier function during radiation therapy in patients with advanced c a n ~ e r . ~

Glutamine In children with severe muscle wasting, 5 hours of oral glutamine has shown to have protein-sparing effect (see later discussion on cachexia).24

Immune Support Although poorly understood, it appears that glutamine has an immune-modulating effect by enhancing interleukin (1L)-6 levelsz and lymphocyte function?6 IL-6 plays an essential role in the final differentiation of beta cells into immunoglobulin-secreting cells, nerve cell differentiation, and acute phase reactants in hepatocytes. Exercise by itself is known to induce an elevenfold increase in plasma IL-6.Glutamine supplementation further enhances IL-6 levels.= The ability of lymphocytes to proliferate and generate lymphokine-activated killer cell activity in vitro has been found to be glutamine dependent.27Additionally, glutamine-enriched parental nutrition has demonstrated enhanced lymphocyte activity in patients undergoing high doses of chemotherapy after stem cell transplantation for hematologous malignancy.

CLINICAL APPLICATIONS Intestinal Permeability-Related Conditions A number of conditions are linked to intestinal permeabilities including chronic urticariaF8 inflammatory bowel disease (Crohn's disea~e)F~-~I celiac liver and biliary cirrhosis and cases of portal hypertension,=a systemic scler0sis,3~ rheumatologic disordersP7J8cystic alcohol overuse,4oadult and child asthma:' human immunodeficiency virus (HIv)/ acquired immune deficiency syndrome,42nonsteroidal antiinflammatory drug-treated arthritis patients,a moderate to major burn injuries,"" corticosteroid use,& cardiopulmonary bypass patient^,^,^^ and acute metal toxicities.48 In order to evaluate these permeabilities, sucrose has served as a marker for gastroduodenal permeability and the urinary lactulose/mannitol ratio for intestinal permeability, after administration of these sugars.28From a naturopathic perspective, the underlying cause of many of these conditions may stem from food allergies, which contribute first to chronic inflammation in the intestinal tract28and then to systemic endotoxemia.Certain conditions such as cardiopulmonary bypass can cause intestinal i~chemia:'~which is then the primary insult that causes permeabilities in these patients. The use of glutamine can help heal these permeabilities, thus removing a mode of pathogenesis in these variegated conditions.

Infectious Diarrhea Animal models have definitely shown the usefulness of glutamine in diarrhea to augment sodium and water absorption and to enhance blood glucose and body weight.%A rat model of cholera toxin-induced diarrhea has shown that glutamine was able to improve water

and electrolyte intestinal absorption even better than the traditional glucose solutions.10One placebocontrolled, double-blind, randomized trial human study evaluated glutamine to treat acute diarrhea in 128 otherwise healthy children. O f these 6- to 24month-olds, 63 received 0.3 g/kg/day of glutamine and 65 controls received a placebo for 7 days. The average duration of diarrhea in the glutamine-treated group was signhcantly shorter than that of the placebo group (3.40 f 1.96 days vs. 4.57 f 2.48 days, respectively). However, no differences in serum IL-8 and secretory immunoglobulinA were found between groups at the beginning of treatment or 1week later.5l Clearly, glutamine holds promise for enhancing repair of mucosal injury caused by a wide range of infections or toxic agents and thus has great potential as a nutritional therapeutic for patients with enteric

Postsurgical Complications of the Gastrointestinal Tract Patients undergoing abdominal surgeries such as gastrectomies, sigmoidectomies, cholecystectomy, colectomies, and rectal resections are at risk for the development of intestinal failure or short bowel syndrome (SBS). In SBS a serious malabsorption of fluid, electrolytes, and other nutrients can occur, placing the patient at higher morbidity and mortality r i ~ k . 5 Trauma ~ from abdominal surgery may also compromise the intestinal mucosa to the point where bacteria and endotoxins can easily transfer through the intestinal wall and invade tissue and blood in an event called bacterial translocation. Through inflammatory mechanisms, bacteria, and endotoxic septic conditions, the intestinal mucosal barrier can be adversely affected and cause further damage, thus forming a vicious circle. Severe cases result in systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS).% In a regimen that includes growth hormone and diet changes, glutamine can help difficult cases to enhance bowel adaptation. In one study of 10 patients with SBS who had previously failed to adapt to enteral nutrients, 8 subjects received exogenous growth hormone, supplemental glutamine, and a modified high-carbohydrate, high-fiber diet. Two patients were treated with the modified diet alone. Three weeks of treatment with growth hormone, glutamine, and a modified diet sigruficantly increased total caloric absorption from approximately 60%to 75%, protein absorption from 48.8%to 63%, and carbohydrate absorption from 60% to 81.5%. Water absorption increased from 45.7% to 65%, and sodium from 49% to 69%. Fat absorption did not change. Diet alone did not influence nutrient absorption or stool output. After 28 days of therapy, the patients were discharged and instructed to continue the diet and glutamine treatment.55It is unknown whether glutamine and

Pharmacology of Natural Medicines diet changes alone, without concomitant growth hormone administration, would have the same positive effect. In a second study, 20 patients having just undergone abdominal surgery were randomized into two groups receiving oral administration of 30 g of glutamine or a placebo in divided doses for 7 days. Serum glutamine concentration was significantly decreased in the placebo group and increased in the glutamine group after 7 days. Markers of intestinal permeability were sigruficantly increased in the placebo group and decreased in the glutamine group. Additionally, the serum markers of endotoxin, diamine oxidase, and malondialdehyde concentrations were sigruficantly decreased in the glutamine group compared with those in the placebo group. Temperatures, heart rates, and white blood cell counts were also sigruficantly lower in the glutamine group.% Ischemia-reperfusion of the gut is also a common event in various clinical conditions such as trauma, burn, septic shock, cardiac or aortic surgery, and liver or small bowel transplantation and is associated with a high death rate. Intestinal ischemia-reperfusion can cause edema and disruption of the structural integrity and function of the intestinal mucosa and associated vascular tissue. It may set the stage for endotoxemic translocation of a number of bacterium, including Escherichia coli, Enterococcus, Pseudomonas, Proteus, and Staphylococcus. Studies of animal models demonstrate that glutamine, when supplemented as total parenteral nutrition, protects the intestines from morphologic and functional mucosal injury after intestinal ischemia-reperfusion. Furthermore, intestinal permeabilities and the incidence of bacterial translocation in the intestinal ischemiareperfusion animals are also prevented by glutamine supplementation.56 The gastrointestinal tract is susceptible to SBS, severe intestinal permeabilities, ischemia perfusion damage, systemic inflammatory response during trauma, various medical conditions, and abdominal postoperative periods. Glutamine can decrease intestinal permeability, maintain an intestinal barrier, and attenuate systemic inflammatory response in early postoperative patients.

Chemotherapy and Radiation Side Effects Standard cancer therapies often include the use of chemotherapy and radiation, which can injury rapidly dividing intestinal cells. It has been shown that during chemotherapeutic and radiotherapy insult, glutamine can reduce degeneration of intestinal mucosa in rats, prevent intestinal mucosal injury,%protect liver function through enhanced glutathione biosynthesis and storage in hepatic tissue, increase immune function, and reduce permeability of the g ~ t . ~ ~ 3 In one investigation, 70 patients with colorectal cancer were randomly assigned to oral glutamine at 18 g/day or placebo before the first regimen of 5-flurouracil and

folinic acid administered intravenously for 5 days. Glutamine was given 5 days before, during, and after chemotherapy. Using D-xylose urinary excretion and cellobiose-mannitol evaluation, damage to the intestines was assessed at baseline, as well as 4 and 5 days after the end of the first cycle of chemotherapy. After one cycle of chemotherapy, the reduction in Dxylose absorption and reduction of mannitol was sigruficantly greater in the placebo group (7.1%vs. 3.8%and 9.2% vs. 4.5%, respectively). Urinary recovery of cellobiose was not different between the study arms. Accordingly, the cellobiosemannitol ratio increased more in the placebo treatment group. Furthermore, diarrhea parameters, as well as the average number of antidiarrheal opiate loperamide tablets needed, were reduced in the glutamine arm, thus supporting the positive clinical effect of this low-cost supplement." Oropharyngeal mucositis, or mouth sores, and accompanying swallowing difficulty are other untoward results of radiotherapy and can be a major source of suffering in patients with head and neck cancer. Glutamine during and after chemotherapy appears to be an excellent way to safely decrease the incidence of mouth sores. One investigation of 17 patients with head and neck cancer who received primary or adjuvant mouth irradiation for 5 days a week were randomized to either adjunctive glutamine suspension of 16 g in 240 ml normal saline or a saline placebo. Patients were instructed to swish the test solutions (30 ml) four times daily. The duration of objective oral mucositis was sigruficantly shorter in the glutamine arm.57A second randomized, double-blind crossover trial observed 24 patients who were given a glutamine or placebo suspension to swish and swallow on days of chemotherapy administration and for at least 14 days following. Significant improvement was observed in the glutamine group. Additionally, the duration of mouth pain was 4.5 days less in chemotherapy courses with concomitant glutamine supplementation. The severity of oral pain was reduced so significantly when glutamine was used that a patient could venture past soft foods 4 days sooner compared with placebo.% Glutamine studies validating its use are also beginning to emerge in other areas of oncology. In a study of esophageal cancer patients, 13 patients were randomized into two groups, control and a group that received oral glutamine supplemented at a dosage of 30 g/day for 4 weeks. It was observed that supplementation of glutamine enhanced lymphocyte mitogenic function and reduced permeability of the gut during radiochemothe rap^.^ Patients undergoing bone marrow transplant and myelosuppressive chemotherapy for acute myeloid leukemia have also found that parenteral glutamine therapy can improve neutrophil recovery, although no change in neutropenic fever had been shown.59Given that glutamine improves the structure and function of

Glutamine

the gut, it is understandable that multiple parameters and markers of healthy physiologic function will improve with its use. It should be noted that glutamine’s efficacy may depend on a number of other factors, including the specific chemotherapeutic prescribed and dosage. A study of 65 patients with advanced breast cancer receiving doxifluridine were prescribed 30 g a day of glutamine in three divided doses of 10 g each or a placebo for 8 consecutive days during each interval between chemotherapy, which was administered from days 1 to 4. In this case there was no statistical difference with regard to diarrhea morbidity, nor did glutamine affect the severity and duration of tumor growth.@Interestingly, a study of bone marrow transplant patients found that allogeneic transplant patients (those receiving bone marrow from another individual) did not have the same beneficial mouth pain reduction that autologous transplant patients (those who donated their own marrow) experienced when receiving glutamine support. However, in the work mentioned previously, the amounts of glutamine were less than those used in other studies. It was also theorized that methotrexate use in the allogeneic patients may be responsible for the decreased protection. Nevertheless, in the allogeneic patients, the 28-day survival was still increased.61A third multicenter study of 129 patients found no protection against diarrhea when used adjunctively with pelvic radiation therapy. These patients received 4 g of glutamine or a placebo by mouth, which is also a significantly lower dose than the more successful studies employed.62 Although intestinal function is greatly compromised with chemotherapy and radiation treatment, cardiac function is commonly affected as well. The use of doxorubicin therapy for breast cancer is often limited by cardiomyopathic heart changes that often result in congestive heart failure. One rat study simulated doxorubicin treatment with and without glutamine support and found that oxidative damage to the heart was diminished in the glutamine-treated group, probably as a result of glutamine’s ability to maintain cardiac tissue glutathione levels (see later discussion on cardiac disease)?l

Cachexia Cancer-related cachexia is caused by a diverse combination of accelerated protein breakdown and slowed protein synthesis.63 There has been considerable interest in giving supplemental glutamine to cancer patients because glutamine is taken up by the growing tumor, and any subsequent deficiency of glutamine in the host may cause cancer cachexia? One animal study found that glutamine levels in plasma and skeletal muscle were indeed decreased in tumor-bearing rats, while glutamine production and the conversion of arginine to glutamine were increased.

In rats supplemented with glutamine, total parenteral nutrition demonstrated a reduced whole-body protein breakdown rate during chemotherapy5 A clinical study of patients with stage lV solid malignancies who had demonstrated weight loss of at least 5% were randomly assigned in a double-blind fashion to either a control mixture of nonessential amino acids or treatment of 14 g of glutamine/day, along with the leucine metabolite betahydroxy-beta-methylbutyrate (3 g/day) and L-arginine (14 g/day). Within 4 weeks, the patients supplemented with the glutamine mixture gained 0.95 f0.66 kg of body mass, whereas control subjects lost 0.26 k 0.78 kg during the same time period. This effect continued over the 24 weeks with no negative effect of treatment on the incidence of adverse effects or quality of life measures.63 Because the glutamine derived from skeletal muscle is trapped by the tumor, there is a theoretic concern that glutamine supplementation in cancer patients could potentially encourage tumor growth. One research group, however, has shown that glutamine supplementation does not appear to enhance DNA content in tumor Additionally, some tissue culture studies provide evidence that glutamine may even inhibit cancer promotion.65Although research is necessary to clarify this point, given the immediate risk of mortality due to protein loss in cancer patients, it still would seem prudent in those patients at greater immediate risk of cachexia-related death.

Human ImmunodeficiencyVirus Loss of body cell mass and drug-associated gastrointestinal problems often occur in patients with HIV infection. In these cases the patient’s ability to survive can be affected in the long term. Given the role glutamine plays in cachexic body mass loss (see earlier discussion), reversal of malabsorption,66and protection of the small intestine:’ glutamine deficiency is a probable causal factor in HIV-associated wastinga Preliminary clinical studies suggest improvements in HIV-positive patients dosed at 8 g a day with regard to intestinal permeability and intestinal absorption. The authors of this study correctly suggest that at least 20 g/day may be necessary for more significant improvement~A . ~ double-blind, ~ placebo-controlled trial of 26 patients with greater than 5% weight loss since their disease onset used a glutamine and antioxidant regimen including 40 g of glutamine/day in divided doses or 40 g of a glycine placebo for 12 weeks. Over 3 months, the glutaminelantioxidant group gained 2.2 kg in body weight or 3.2%, whereas the control group gained only 0.3 kg or 0.4%. The glutamine-antioxidant group gained 1.8 kg in body cell mass, whereas the control group gained 0.4 kg. Of note, the intracellularwater increased in the glutamineantioxidant group but not in the control

Pharmacology of Natural Medicines Glutamine can help HIV patients decrease the severity of iatrogenic diarrhea. Twenty-five patients suffering for more than a month from nelfinavir-associated diarrhea were randomized in a double-blind, placebo-controlled, crossover trial to receive L-glutamine at 30 g/day or a placebo for 10 days. In this study the L-glutamine significantly reduced the severity of nelfinavir-associated diarrhea and produced improved quality of life compared with placebo.71

Another study of 45 severely bumed adults found that those randomized to receive enteral glutamine experienced a reduction in blood infection by a factor of 3, and mortality risk was lowered.” Another investigation of burned patients whose total body surface bums ranged from 50% to 80% and third-degree burns ranged from 20% to 40% but who did not have respiratory injuries found improved gut permeability, initially decreased plasma endotoxin levels, and reduced ho~pitalization.7~

Peptic Ulcers

Low-Birth-Weight Infants

Cabbage juice, a key source of glutamine, has been well documented as having remarkable success in treating peptic ulcers. One liter per day of the fresh juice, taken in divided doses, resulted in total ulcer healing in an average of only 10 days. Further research has shown that the high glutamine content of the juice is probably responsible for the efficacy of cabbage in treating these ulcers. In a double-blind clinical study of 57 patients, 24 using 1.6 g/day of glutamine and the rest using conventional therapy (antacids, antispasmodics, milk, and bland diet), glutamine proved to be the more effective treatment. Half of the glutamine patients showed complete healing (according to radiographic analysis) within 2 weeks, and 22 of the 24 showed complete relief and healing within 4 weeksu Although the mechanism for these results is unknown, it is postulated by the authors to be due to the role of glutamine in the biosynthesis of the hexosamine moiety in certain mucoproteins. These moieties may stimulate mucin synthesis, which would benefit peptic ulcer patients.

Infants with a birth weight of less than 1000 to 1500 g may be especially susceptible to glutamine depletion, as nutritional supply of glutamine is limited in the first weeks after birth. This may increase morbidity by contributing to problems with gut integrity, as well as immune suppre~sion.~ One study of 35 ill preterm neonates of less than 1000 g were randomized to receive either glutamine-supplemented parenteral nutrition or standard parenteral nutrition. Although there were no significant differences between the groups in white cell count, differential white cell count, blood urea nitrogen, plasma ammonia, lactate, pyruvate, plasma glutamine, or glutamate, the median time to achieving full enteral nutrition was shorter in the glutamine group (13 days vs. 21 days). Parenteral glutamine was well tolerated and considered safe for these preterm neonates.75 However, other studies have found that formula supplemented with glutamine in growing preterm infants is entirely metabolized in the gut and does not have a discernable effect on whole-body protein and nitrogen kinetic^.'^ A large multicenter, double-blind, randomized trial of infants with a birth weight of 401 to 1000 g were given either a control or 20% isonitrogenous solution by parenteral nutrition for up to either 120 days of age, death, or discharge from the hospital. Of the 721 infants who were assigned to glutamine supplementation, 370 (51%)died or developed late-onset sepsis, as compared with 343 of the 712 infants (48%) assigned to control. Although no adverse effects were noted as a result of being given glutamine, this study demonstrated that glutamine did not decrease mortality. This study and others also found no reduction in the incidence of sepsis in these young patient^.^,^^

Severe Burns Plasma glutamine levels have been demonstrated to be profoundly decreased after severe bums in adults. This may at least partially explain the impaired cellular immunity that is seen in bum patients. Bum victims given glutamine have shown better intestinal repair, a higher quality of wound healing, and reduced hospitalization. In one study, 48 severe bum patients were randomly divided into two groups: a control group that took a placebo and a glutamine-treated group that received 0.5 g of glutamine/kg body weight/day, both for 14 days. After taking glutamine for 14 days, plasma glutamine concentration was sigruf~cantly increased in the glutamine group than in the control group. In addition, a greater quality of wound healing as well as shorter hospital stays were experienced in the glutamine-treated bum patients.“ In another study, dosage of L-glutamine at 0.6 g/kg/ day did not result in an immediate whole body protein gain (an important factor in a bum patient’s convalescence) and resulted in an insignificant increase in plasma glutamine? However, this study measured only the first 48 hours, which may not have been enough time to show a long-term benefit.

Exercise and Weight Lifting Glutamine is considered to have an anabolic effect on skeletal muscle. Given the benefits on glutathione reserves, protein catabolism, and intestinal integrity, some glutamine enthusiasts believe that glutarnine supplementation may be useful for exercise and strength training as well. One small study suggests that oral glutamine increases growth hormone re1ea~e.I~ Even so, clinical trials studying glutamine as an exercise performance enhancer are not encouraging.

A double-blind, placebo-controlled, crossover study had six resistance-trained men lift weights after the ingestion of glutamine or glycine at 0.3 g/kg body weight or a placebo. One hour after ingestion, subjects performed four total sets of exercise to momentary muscular failure including two sets of leg presses at 200% of body weight and two sets of bench presses at 100% of body weight. Despite glutamine's possible role in exercise, there were no actual differences in the average number of maximal repetitions performed in the leg press or bench press exercises among these three groups.79Other studies using 0.3 to 0.9 g per kilogram of body weight also demonstrated no changes in exercise performance, body composition, or muscle protein degradation in young healthy adults.8°,81It is possible that beneficial effects of glutamine are best detected only in patients with chronic illness and those with compromised physiology instead of normal, healthy individuals.

Cardiac Disease Cardiac disease is a recognized stress on the physiology of the gastrointestinal and immune system. Animal studies have supported the notion that glutamine can help recovery from cardiac ischemia and help the heart recover after reperfusion injury.82,83As noted earlier, glutamine can protect the heart from damage due to chemotherapy regimens by its glutathione-replenishing effect (see earlier discussion on chemotherapy and radiation side effects).19Also noted earlier are the benefits to the gastrointestinal system in those heart patients experiencing ischemic gut episodes after cardiac by pas^.^"^ Animal research shows that greater levels of plasma glutamine also prevent decreases in the ratio between adenosine triphosphate to adenosine diphosphate in myocardial tissue.83 Unfortunately, little research has been done to evaluate the clinical use of glutamine in various cardiac situations. One investigation of patients with chronic stable angina received a single 80 mg/kg oral dose of glutamine or a placebo in a double-blind, random fashion 40 minutes before a standard exercise test. This single dose of glutamine significantly increased plasma glutamine concentration from 419 to 649 pmol/L. Moreover, the glutamine appeared to encourage positive changes in ST depression on the echocardiogram.83 Clearly, more research is required, but given that heart disease is the leading reason for mortality, natural and safe treatments like glutamine should be further explored.

Other Conditions A number of other medical conditions such as alcoholism, pancreatitis, and brain injury will further adversely affect the health of a patient who already has protein and energy

needs and is more susceptible to infection. Although more studies are necessary, the following includes a few interesting conditions not mentioned earlier. In alcoholics, glutamine supplementation (1 g/day) has been shown to reduce voluntary alcohol consumption in uncontrolled human studies and experimental animal ~ t u d i e s . ~ Despite -~' the fact that this research is about 50 years old, there has never been any follow-up to these preliminary studies. This is unfortunate, as the results were quite promising, finding glutamine to be safe and relatively inexpensive. Related to alcoholism in many patients, individuals with acute pancreatitis have also benefited from parenteral glutamine treatment with improvement in immune function, decreased systemic inflammation, and a trend toward shorter hospital stays.' In an interesting study of 20 brain injury patients, 10 subjects were randomized to receive either an early enteral diet or the same formula with glutamine and probiotic added for a range of 5 to 14 days. The infection rate was found to be loo%, but only 50% in the glutamine group. The median number of infections per patient was significantly greater in the control group compared with the study group. Critical care stay and ventilation requirements were more than halved in the treatment group (10 days vs. 22 days, and 14 days vs. 7 days, respectively). Interestingly, probiotics were also used in the treatment group. This synergistic enhancement in gut flora may be useful to augment the already known benefits of glutamine.88

DOSAGE The typical oral dosage of glutamine is 100 mg three times a day, although the delivery method and actual effective dosage should be condition specific, meaning dosages are often much higher. The following points serve as guidelines: Severebums: enteral dosage for individuals with severe burns has been approximately 0.5 g/kg/day in most studies Preventing and treating the side effects of chemotherapy involves the following: Patients treated with 5-flurouracil have received up to 18 g/day 5 days before, then during, and 5 days after treatment" High-dose chemotherapy after stem cell transplantation: total parenteral nutrition enriched with glutamine 20 gZ6 Oral mucositis: 16 g in 240 ml normal saline is mixed, and 30 ml is swished four times a d a y 7 Esophageal cancer radiotherapy: was given with a successful adjunctive oral glutamine supplement of 30 g/day for 4 weeks5

Cachexia patients have been tested with dosages of 14 g/day combined with other amino acids63 Pediatric oncology patients: 0.65 g/kg was found to be a safe dose of glutamine to use in a clinical study in pediatric oncology patientss9 Children with acute diarrhea: 0.3 g/kg/day has been used suc~essfully~~ Peptic ulcers: drinking 1 L a day in divided doses is sufficient or 1.6 g/day for 1 monthB HIV patients: 30 to 40 g glutamine/day to prevent medication associated diarrhea, and to improve intestinal permeability70*71; coadministration of antioxidants may also be helpful Postabdominal surgeries: glutamine can be dissolved in warm water and taken orally or by gastric tube after the operation at 30 g/day for 7 daysM

In one pediatric oncology patient, a single dose of 0.75/kg was found to raise the blood ammonia level to an unacceptably high limit. Related to this, it was difficult to disperse the glutamine adequately at this dose, resulting in the suspension being found unpalatable.

Glutamine, even at high doses, is without apparent side effects and is well tolerated.4S2

In cancer treatment, glutamine does not appear to change the efficacy of cancer drugs, rate of relapse, or progression of malignancy.61Some animal studies suggest that glutamine supplementation may even preferentially increase tumor retention of methotrexate, thus increasing the therapeutic window of this drug?O Many antiseizure medications including phenobarbital, phenytoin, carbamazepine, primidone, and valproic acid work to block glutamate activity in the brain. Because glutamine can convert to glutamate, clinicians should be cautious when using glutamine in patients using these medications.

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TOXICITY

Glutamine standard peptide-based feeding in critically ill patients. Am J Clin Nutr 1996;64:615-621. 25. Hiscock N, Petersen EW, Krzywkowski K, et al. Glutamine supplementation further enhances exercise-induced plasma IL-6.J Appl Physiol2003;95145-148. 26. Piccirillo N, De Matteis S, Laurenti L, et al. Glutamine-exuiched parenteral nutrition after autologous peripheral blood stem cell transplantation: effects on immune reconstitution and mucositis. Haematologica 2003;88192-200. 27. Noyer CM, Simon D, Borczuk A. A doubleblind placebo-controlled pilot study of glutamine therapy for abnormal intestinal permeability in patients with AIDS.Am J Gastroenterol1998;93972-975. 28. Buhner S,Reese I, Kuehl F, et al. Pseudoallergicreactions in chronic urticaria are assodated with altered gastroduodenal permeability. Allergy 2004;591118-1123. 29. Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: the role of environmental factors.Autoimmun Rev 2004;3394-400. 30. Peeters M, Geypens B, Claus D, et al. Clustering of increased small intestinal permeability in families with Crohn‘s disease. Gastroenterology 1997;113802-807. 31. Puspok A, Oberhuber G, Wyatt J, et al. Gastroduodenalpermeability in Crohn’s disease. Eur J Clin Invest 1998;2867-71. 32. Smecuol E, Bai JC, Vazquez H, et al. Gastrointestinal permeability in celiac disease. Gastroenterology 1997;112:1129-1136. 33. Di Leo V, Venturi C, Baragiotta A, et al. Gastroduodenaland intestinal permeability in primary biliary cirrhosis.Eur J Gastroenterol Hepatol2003;15967-973. 34.Campillo B, Pemet F’, Bories PN, et al. Intestinal permeability in liver cirrhosis: relationship with severe septic complications.Eur J GastroenterolHepatol1999;11:755-759. 35. Catanoso M, Lo Gull0 R, Giofre MR, et al. Gastro-intestinalpermeability is increased in patients with limited systemic sclerosis. Scand J Rheumatol2001;30:77-81. 36. Vaarala 0. The gut immune system and type 1 diabetes. Ann N Y Acad Sci 2002;958:39-46. 37. Katz JP, Lichtenstein GR. Rheumatologic manifestations of gastrointestinal diseases. Gastroenterol Clin North Am 1998;27 533-562. 38. Parke AL. Gastrointestinal disorders and rheumatic diseases. Curr Opin Rheumatol1991;3160-165. 39. van Elburg RM, Uil JJ, van Aalderen WM, et al. Intestinal permeability in exocrine pancreatic insufficiencydue to cystic fibrosis or chronic pancreatitis. Pediatr Res 1996;39:985-991. 40.KeshavarzianA, Holmes EW, Pate1 M, et al. Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage. Am J Gastroenterol1999;94200-207. 41. Hijazi 2, Molla AM, Al-Habashi H, et al. Intestinal permeability is increased in bronchial asthma. Arch Dis Child 2004;89227-229. 42. Uil JJ, van Elburg RM, van OverbeekFM, et al. Clinical implications of the sugar absorption test intestinal permeability test to assess m u d barrier function. Scand J Gastroenterol Suppll997;223:70-78. 43. Weber P, Brune T, Ganser G, et al. Gastrointestinal symptoms and permeability in patients with juvenile idiopathic arthritis. Clin Exp Rheumatol2003;21:657-662. 44.Deitch EA. Intestinal permeability is increased in burn patients shortly after injury. Surgery 1990;107411-416. 45. Kiziitas S, Imeryuz N, Gurcan T, et al. Corticosteroid therapy augments gastroduodenal permeability to sucrose.Am J Gastroenterol 1998;932420-2425. 46.Riddington DW, Venkatesh B, Boivin CM, et al. Intestinal permeability, gastric intramucosal pH, and systemic endotoxemia in patients undergoing cardiopulmonary bypass. JAh4A 1996;275 1007-1012. 47. Sindair DG, Haslam PL, Qumlan GJ, et al. The effect of cardiopulmonary bypass on intestinal and pulmonary endothelial permeability. Chest 1995;10871&724.

48. Gotteland M, Araya M, Pizarro F, et al. Effect of acute copper exposure on gastrointestinalpermeability in healthy volunteers. Dig Dis Sci 2001;46:1909-1914. 49. Videm V, SvennevigJL, Fosse E, et al. Plasma endotoxin concentrations during cardiac surgery may be related to atherosclerosis. Perfusion 2000;15:421426. 50. Brooks HW,White DG, Wagstaff AJ, et al. Evaluation of a glutamine-containing oral rehydration solution for the treatment of calf diarrhea using an Escherichia coli model. Vet J 1997;153: 163-169. 51. Yalcin SS,Yurdakok K, Tezcan I, et al. Effect of glutamine supplementation on diarrhea, interleukin-8 and secretory immunoglobulin A in children with acute diarrhea. J Pediatr Gastroenterol Nutr 20O4;38494501. 52. Majamaa H, Isolauri E, &elin M, et al. Lactic acid bacteria in the treatment of acute rotavirus gastroenteritis. J Pediatr Gastroenterol Nutr 1995;20333-338. 53. Matarese LE, Seidner DL, Steiger E. Growth hormone, glutamine, and modified diet for intestinal adaptation. J Am Diet Assoc 2004;104:1265-1272. 54.QUan ZF, Yang C, Li N, et al. Effect of glutamine on change in early postoperative intestinal permeability and its relation to systemic inflammatory response. World J Gastroenterol 2004;lO: 1992-1994. 55. Byme TA, MorrisseyTB, Nattakom TV,et al. Growth hormone, glutamine, and a modified diet enhancenutrient absorption in patients with severe short bowel syndrome. JF’EN J Parenter Enteral Nutr 1995;19296-302. 56. Wu GH, Wang H, Zhang YW, et al. Glutamine supplemented parenteral nutrition prevents intestinal ischemia-reperfusioninjury in rats. World J Gastroenterol2004;10:2592-2594. 57. Huang EY, Leung SW, Wang CJ, et al. Oral glutamine to alleviate radiation-induced oral mucositk a pilot randomized trial. Int J Radiat Oncol Biol Phys 2OOO;46535-539. 58. Anderson PM, schrwder G, Skubitz KM. Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy.Cancer 1998;831433-1439. 59. Scheid C, Hermann K, Kremer G, et al. Randomized, double-blind, controlled study of glycyl-glutamine-dipeptidein the parenteral nutrition of patients with acute leukemia undergoing intensive chemotherapy.Nutrition 2004;20249-254. 60.Bozzetti F, Biganzoli L, Gavazzi C, et al. Glutamine supplementation in cancer patients receiving chemotherapy: a double-blind randomized study. Nutrition 1997;13748-751. 61. Anderson PM, Ramsay NK,Shu XO, et al. Effect of low-dose oral glutamine on painful stomatitisduring bone marrow transplantation. Bone Marrow Transplant 1998;22339-344. 62. Kozelsky TF, Meyers GE, Sloan JA. North Central Cancer Treatment Group. Phase III double-blind study of glutamine versus placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy. J Clin Oncol2003;21:1669-1674. 63. May PE, Barber A, DOlimpio JT, et al. Reversal of cancer-related wasting using oral supplementation with a combination of betahydroxy-beta-methylbutyrate,arginine, and glutamine. Am J Surg 2002;183471-479. 64.Klimberg VS, Souba WW, Salloum RM, et al. Glutamine-enriched diets support muscle glutamine metabolism without stimulating tumor growth. J Surg Res 1990;48:319-323. 65. Kaufmann Y, Kornbluth J, Feng 2,et al. Effect of glutamine on the initiation and promotion phases of DMBA-induced mammary tumor development.JPEN J Parenter Enteral Nutr 2003;27411-418. 66. Dwyer JT. Nutrition support of HIV+ patients. Henry Ford Hosp Med J 1991;39:60-65. 67. Klimberg VS, Souba WW, Dolson DJ, et al. Prophylactic glutamine protects the intestinal mucosa from radiation injury. Cancer 1990;6662-68.

Pharmacology of Natural Medicines 68. Shabert JK, W h o r e DW. Glutamine deficiency as a cause of human immunodeficiencyvirus wasting. Med Hypothe~e~ 1996;46:252-256. 69. Noyer CM,S i o n D, Boruuk A, et al. A double-blind placebocontrolled pilot study of glutamine therapy for abnormal intestinal permeability in patients with AIDS. Am J Gastroenterol 199893: 972-975. 70. Shabert JK, Wmlow C, Lacey JM, et al. Glutamineantioxidant supplementationincreases body cell mass in AIDS patients with weight loss: a randomized, double-blind controlled trial. Nutrition 1999; 15860-864. 71. Huffman FG, W a l ME. ~ L-glutamine supplementation improves nelfinavir-associated diarrhea in HIV-infected individuals. HIV C l i Trials 2003;4324329. 72. Peng X, Yan H, You Z, et al. Effects of enteral supplementation with glutamine granules on intestinal mucosal barrier h c t i o n in severe burned patients. Bums 2004;30:135-139. 73. Garrel D, Patenaude J, Nedelec B, et al. Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial. Crit Care Med 200331:2444-2449. 74. Zhu M, Tang D, Zhao X, et al. [Impact of glutamine of gut permeability and clinical prognosis on the aging patients undergoing gastric-intestinal operation.] Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2000;22:425-427. 75.Thompson SW, McClure BG, Tubman TR. A randomized, controlled trial of parenteral glutamine in ill, very low birth-weight neonates. J Pediatr Gastroenterol Nutr 200337550-553. 76. Parimi PS,Devapatla S, Gruca LL, et al. Effect of enteral glutamine or glycine on whole-body nitrogen kinetics in very-low-birthweight infants. Am J Clin Nutr 2004;79:402-409. 77. Poindexter BB, Ehrenkranz RA, Stoll BJ, et al. National Institute of Child Health and Human Development Neonatal Research Network. Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants. Pediatrics 2004;113:1209-1215.

78. Vaughn P, Thomas,'F Clark R, et al. Enteral glutamine supplementation and morbidity in low birth weight infants. J Pediatr 2003;142:662-668. 79. Antonio J, Sanders MS, Kalman D, et al. The effects of high-dose glutamine ingestion on weightliftingperformance. J Strength Cond R ~ s2002;16157-160. 80. Candow DG, Chilibeck PD, Burke DG, et al. Effect of glutamine supplementation combined with resistance training in young adults. Eur J Appl Physiol2001;86:142-149. 81. Haub MD, Potteiger JA, Nau KL, et al. Acute L-glutamine ingestion does not improve maximal effort exercise. J Sports Med Phys Fitness 1998;38:240-244. 82. Khogali SE, Harper AA, LyaU JA, et al. Effects of L-glutamine on post-ischaemic cardiac fundion: protection and rescue. J Mol Cell Cardiol199830819-827. 83. Khogali SE, Pringle SD, Weryk BV, et al. Is glutamine beneficial in ischemic heart disease? Nutrition 2002;18:123-126. 84. Rogers LL, Pelton RB, Williams RJ. Voluntary alcohol consumption by rats following administration of glutamine. J Biol Chem 1955;214503-506. 85. Rogers LL, Pelton RB. Glutamine in the treatment of alcoholism; a preliminary report. Q J Stud Alcohol 1957;18581-587. 86. Ravel JM, Felsing B, Lansford EM, et al. Reversal of alcohol toxicity by glutamine. J Biol Chem 1955;214497-501. 87. Rogers LL, Pelton RB, Williams RJ. Voluntary alcohol consumption by rats following administration of glutamine. J Biol Chem 1955;214503-506. 88. Falcao de Arruda IS, de Aguilar-Nascimento JE.Benefits of early enteral nutrition with glutamine and probiotics in brain injury patients. Clin Sci (Lond) 2004;106:287-292. 89. Ward E, Picton S, Reid U, et al. Oral glutamine in pediatric oncology patients: a dose finding study. Eur J Clin Nutr 2003;57 31-36. 90. Rubio lT,Cao Y, Hutchins LF, et al. Effect of glutamineon methotrexate efficacy and toxicity. Ann Surg 1998;227772-778,

Glycyrrhiza glabra (Licorice) Mchael T. Murray, ND Joseob E. Pizzorno Jr, ND

C H A P T E R C 0 N T E N TS General Description 1003 Chemical Composition 1003 History and Folk Use

1004

Pharmacology 1004 Estrogenic Activity 1004 Pseudoaldosterone Activity 1004 Antiinflammatory and Antiallergic Activity 1004 lmmunostimulatory and Antiviral Effects 1005 Anticancer Effects 1005 Antibacterial Activity 1005 Antihepatotoxic Activity 1005 Memory-EnhancingEffect 1005 Antinephritic Activity 1005 Clinical Applications

Oral Licorice Preparations Containing Glycyrrhizin 1007 Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 1007 Hepatitis 1007 Acute Intermittent Porphyria 1007 Obesity and Syndrome X 1008 Addison's Disease 1008 Inflammation 1008 Sweetening Agent 1008 Topical Applications 1008 Eczema and Psoriasis 1008 Herpes Simplex 1008 Melasma 1008 Dosage 1008 Dosage Instructions for Deglycyrrhizinated Licorice 1009

1005 Side Effects and Toxicology

Deglycyrrhizinated Licorice 1006 Gastric Ulcers 1006 Duodenal Ulcers 1006 Aphthous Ulcers 1006

Glycyrrhiza glabra (family: Leguminosae) Common names: licorice, glycyrrhiza

GENERAL DESCRIPTION Glycyrrhiza glabra is a perennial, temperate zone herb or subshrub, 3 to 7 feet high, with a long, cylindrical, branched, flexible, and burrowing rootstock with runners. The parts used are the dried runners and roots, which are collected in the fall.

CHEMICAL COMPOSITION The major active component of licorice root is the triterpenoid saponin glycyrrhizin (also known as glycyrrhizic acid or glycyrrhizinic acid, Figure 99-l), which is usually

1009

Drug Interactions 1009

found in concentrations ranging from 6% to 10%. The intestinal flora is believed to hydrolyze glycyrrhizin, yielding the aglycone molecule (glycyrrhetinic acid) and a sugar moiety, resulting in absorption of both.' A processed licorice extract, deglycyrrhizinated licorice (DGL), which is used in the treatment of peptic and aphthous ulcers, is made by removing the glycyrrhizin molecule. The active components of DGL are flavonoids. These compounds have demonstrated impressive protection against chemically induced ulcer formation in animal studies? Other active constituents of licorice include isoflavonoids (e.g., isoflavonol, kumatakenin, licoricone, glabrol), chalcones, coumarins (e.g.,umbelliferone, herniarin), triterpenoids and sterols, lignins, amino acids, amines, gums, and volatile oils?

1003

Pharmacology of Natural Medicines

from soy) are known to possess estrogenic effect. The estrogenic activity of the isoflavones appears to be more sigrulicantthan the estrogen antagonism of glycyrrhetinic acid? Interestingly,these same components inhibit breast cancer cell

Pseudoaldosterone Activity Figure -1

Glycyrrhizinicacid.

HISTORY AND FOLK USE The medicinal use of licorice in both Western and Eastern cultures dates back several thousand years. It was used primarily as a demulcent, expectorant, antitussive, and mild laxative. Licorice is one of the most popular components of Chinese medicines. Its traditional uses include treating peptic ulcers, asthma, pharyngitis, malaria, abdominal pain, insomnia, and

PHARMACOLOGY Licorice is known to exhibit many pharmacologic actions including the following? Estrogenic Aldosterone-like action Antiinflammatory (cortisol-likeaction) Antiallergic Antibacterial, antiviral, and antitrichomonas Antihepatotoxic Anticonvulsive Choleretic Anticancer Expectorant Antitussive activities The majority of these actions are discussed individually later. Although much of the pharmacology focuses on glycyrrhizin and glycyrrhetinic acid, it is worth remembering that licorice has many other components such as flavonoids, which may have significant pharmacologic effects.

Estrogenic Activity Most herbalists generally believe that glycyrrhiza exhibits alterative action on estrogen metabolism (i.e., when estrogen levels are too high, it inhibits estrogen action, and when estrogens are too low, it potentiates estrogen action when used in greater amounts)! Glycyrrhetinic acid has been shown to antagonize many of the effects of estrogens, particularly exogenous e~trogens.~ The estrogenic action of glycyrrhiza is due to its isoflavone content, as many isoflavone structures (e.g., daidzein and genistein

The chronic ingestion of glycyrrhiza in large doses leads to a welldocumented pseudoaldosteronism syndrome (i.e., hypertension,hypokalemia, sodium and water retention, low plasma renin activity, and suppressed urine and serum aldosterone levels).813In normal subjects, the amount of glycyrrhizin needed to produce these side effects is between 0.7 and 1.4 g, which corresponds to approximately 10 to 14 g of the crude herb? Although glycyrrhiza possesses mineralocorticoid activity (about four orders of magnitude lower than aldosterone) and binds to aldosterone receptors, it is largely without effect in adrenalectomized animals or in patients with severe adrenocorticoid insufficiency. Therefore it can be concluded that its primary effects are largely as a result of glycyrrhetinic acid inhibiting the breakdown of aldosterone in the 1i~er.l~ Glycyrrhizin and glycyrrhetinic acid have been shown to suppress 5-beta-reductase, the main enzyme in humans responsible for inactivating cortisol, aldosterone, and progesterone. These effects can be put to good use in the treatment of Addison disease, a severe disease of adrenal insuffi~iency.'~

Antiinflammatory and Antiallergic Activity Glycyrrhiza has signhcant antiinflammatoryand antiallergic activity.15J6 Although both glycyrrhizin and glycyrrhetinicacid bind to glucocorticoid receptors, and much of glycyrrhiza's antiinflammatory activity has been explained by its "cortisol-like effects," many of the effects of glycyrrhiza actually antagonize or counteract Included are antagonism to such actions of cortisol as activation of tryptophan oxygenase, accumulation of hepatic glycogen, stimulation of hepatic cholesterol synthesis, inhibition of thymus atrophy, and inhibition of ACTH synthesis and secretion. Glycyrrhizin does, however, reinforce cortisol's inhibition of antibody formation, stress reaction, and inflammation. Like its mineralocorticoid effect, glycyrrhiza'smajor influence on glucocorticoid metabolism is probably related to its suppression of 5-beta-reductase activity, thus increasing the half-life of cortisol. Glycyrrhetinic acid can also increase the conversion of cortisol to the more powerful cortisone.18 Glycyrrhiza'smajor cortisol-likeeffect relates to its ability to inhibit pho~pholipase-A2.~~ This enzyme is responsible for cleaving lipids from biomembranes for eicosanoid metabolism. In addition to this effect, glycyrrhizin has also been shown to inhibit cyclic adenosine monophosphate (CAMP)-phosphodiesterase,thereby raising CAMP levels and prostaglandin formation by activated

Glycyrrhiza glabra (Licorice)

peritoneal macrophages from rats.20f21Glycyrrhizin has been shown to inhibit experimentally induced allergenic reactions such as the Arthus’ phenomenon, the Schwartzman’s phenomenon, and Forssman’s anaphylaxis and to be an antidote against many toxins including diphtheria, tetanus, and tetrodotoxin.21*22 Glycyrrhizin has exerted antithrombotic effects but does not potentiate the inhibitory activity of antithrombin I11 or heparin cofactor I1 toward thrombinB

lmmunostimulatory and Antiviral Effects Glycyrrhizin and glycyrrhetinic acid have been shown to induce i n t e r f e r ~ nThe . ~ ~induction of interferon leads to significant antiviral activity, as interferons bind to cell surfaces, where they stimulate synthesis of intracellular proteins that block the transcription of viral DNA. The induction of interferon is also followed by activation of macrophages and augmentation of natural killer cell activity. Glycyrrhizin has been shown to directly inhibit the growth of several DNA and FWA viruses in cell cultures (vaccinia, Epstein-Barr, Herpes simplex, Newcastle disease, vesicular stomatitis viruses, SARS-associated coronavirus, and human immunodeficiency virus [HIV]) and to inactivate herpes simplex virus 1 (HSV-1) irreversibly.2528Administration of glycyrrhizin to mice suffering from herpetic encephalitis increased their survival rate on average about 2.5 times, while it reduced HSV-1 replication in the brain to 45.6% of the control.29 Glycyrrhizin, as stated earlier, also inhibits the thymolytic and immunosuppressive action of cortisone. Other licorice components have exerted immunomodulatory effects as well.30

strains), Streptococcus mutans, Mycobacterium smegmatis, Bacillus subtilis, Streptococcus pyogenes, Haemophilus influenzae, Moraxella catarrhalis, and Candida a l b i ~ a n s . ~ ~ , ~ ~ The majority of the antimicrobial effects are due to isoflavonoid components, with the saponins having a lesser antibacterial effect.

Antihepatotoxic Activity Glycyrrhetinic acid inhibits carbon tetrachloride and galactosamine-induced liver damage. The mechanism of action is prevention of nonenzymatic lipid peroxidation and inhibition of the production of free radicals by the enzymatic action of NADPH-cytochrome P450 reductase on CC14.40

Memory-Enhancing Effect Licorice may exert some memory-enhancing effects. In a study in mice, licorice was shown to enhance learning and memory in mice as determined by the elevated plus-maze and passive avoidance paradigm. Furthermore, licorice significantly reversed the amnesia induced by diazepam and scopolamine. Although antiinflammatory and antioxidant properties may contribute favorably to the memoryenhancement effect, since scopolamine-induced amnesia was reversed as well, it is possible that the beneficial effect on learning and memory was due to facilitation of cholinergic transmission.4l

Antinephritic Activity Glabridin, an isoflavan isolated from G. glabra, improved urinary protein excretion, total cholesterol, serum creatinine, and blood urea nitrogen levels after its oral administration to mice with glomerular disease.42

Anticancer Effects

CLINICAL APPLICATIONS

Licorice components exert a wide range of anticancer effects.31The most active appear to be the flavonoids and coumarins. For example, isoliquiritigenin has been shown to suppress colon cancer in mice via markedIy decreasing both prostaglandin E2 and nitric oxide (NO) production in mouse macrophage Isoliquiritigenin was also shown to significantly inhibit the proliferation of prostate and breast cancer cell lines in dosedependent and time-dependent manners.7~~~ Isoliquiritigenin also signhcantly reduced pulmonary metastasis in mouse renal cell carcinoma and prevented the leukocytopenia caused by administration of 5-fl~orouracil.~ A coumarin compound, identified as licocoumarone, was shown to the factor in licorice that induces a p o p t ~ s i s . ~ ~

Licorice is a component of more traditional Chinese and Japanese herbal formulas than any other herb. Though extremely pharmacologically diverse, the current clinical applications of licorice can be divided into three main categories:

Antibacterial Activity Alcohol extracts of glycyrrhiza have displayed antimicrobial activity in vitro against Helicobacter pylori, Staphylococcus aureus (including antibiotic resistant

Use of DGL Use of oral licorice preparations containing glycyrrhizin Use of topical preparations containing glycyrrhetinic acid The key use of DGL is in ulcerative conditions of the gastrointestinal tract (e.g., peptic ulcers, canker sores, inflammatory bowel disease), while the key uses of oral licorice containing glycyrrhizin include viral infections (e.g., the common cold, HIV, and acquired immunodeficiency syndrome (AIDS), viral hepatitis); premenstrual syndrome (PMS) and menopause; acute intermittent porphyria; Addison’s disease; inflammation; syndrome X; and as a sweetening agent. Topical preparations

containing glycyrrhetinic acid can be used in eczema, psoriasis, herpes, and melasma.

DEGLYCYRRHIZINATED LICORICE By far, the most popular medicinal use of licorice in the United States is in the treatment of peptic ulcers with DGL (deglycyrrhizinated licorice). Although glycyrrhetinic acid was the first drug proven to promote healing of gastric and duodenal ulcers,43most physicians using licorice in the treatment of peptic ulcers now use DGL. DGL was actually shown to be more effective than glycyrrhetinic acid, without side effects.44 DGL's mode of action is different than that of current drugs such as antacids and H2-receptor antagonists, which focus on reducing gastric acidity. Though effective, these treatments can be expensive, carry some risk of toxicity, disrupt normal digestive processes, and alter the structure and function of the cells that line the digestive tract. The latter factor is just one of the reasons why peptic ulcers develop again if antacids, cimetidine, ranitidine, and similar drugs are used. Rather than inhibit the release of acid, DGL stimulates the normal defense mechanisms that prevent ulcer formation and stimulate healing of the damaged mucous membranes. Specifically,DGL increases the following45,&: The blood supply to the damaged mucosa The number of cells producing the mucous that protects the mucous membranes The amount of mucous the cells produce The life span of the intestinal cell

In addition, several flavonoid components of G. glubra have shown significant activity against H.pylori including antibiotic-resistant strains.%

Gastric Ulcers Nunemus clinical studies over the years have found DGL to be an effective antiulcer compound. DGL has been shown to be extremely effective in the treatment of gastric In one study, 33 gastic ulcer patients were ulcer~.4~-~l treated with either DGL (760 mg, three times a day) or a placebo for 1 month.50There was a sigruficantly greater reduction in ulcer size in the DGL group (78%)than in the placebo group (34%).Complete healing occurred in 44% of those receiving DGL, but only in 6% of the placebo group. In several head-to-head comparison studies, DGL has been shown to be more effective than cimetidine (Tagamet), ranitidine (Zantac), or antacids in both shortterm treatment and maintenance therapy of peptic u l ~ e r s . 4 ~However, ,~5~ although these drugs are associated with sigruficant side effects (see earlier), DGL is extremely safe and is only a fraction of the cost. Subsequentstudieshave shown DGL to be as effective as Tagamet and Zantac for both short-term treatment and

maintenance therapy of gastric For example, in a head-to-head comparison with Tagamet, 100 patients received either DGL (760 mg, three times a day between meals) or Tagamet (200 mg, three times a day, and 400 mg at bedtime).4sThe percentage of ulcers healed after 6 and 12 weeks were similar in both groups. Whereas Tagamet is associated with some toxicity, DGL is extremely safe to use. Gastric ulcers are often a result of using alcohol, aspirin or other nonsteroidal antiinflammatory drugs, caffeine, and other factors that decrease the integrity of the gastric lining. As DGL has been shown in human studies to reduce the gastric bleeding caused by aspirin, DGL is strongly indicated for the prevention of gastric ulcers in patients requiring long-term treatment with ulcerogenic drugs such as aspirin, nonsteroidal antiinflammatory agents, and corticosteroids.5l

Duodenal Ulcers DGL is also effective in duodenal ulcers. This is perhaps best illustrated by one study in patients with severe duodenal ulcers: 40 patients with chronic duodenal ulcers of 4 to 12 years' duration and more than six relapses during the previous year were treated with All of the patients had been referred for surgery because of relentless pain, sometimes with frequent vomiting, despite treatment with bed rest, antacids, and anticholiiergic drugs. Half of the patients received 3 g of DGL daily for 8 weeks; the other half received 4.5 g/day for 16 weeks. All 40 patients showed substantial improvement, usually within 5 to 7 days, and none required surgery during the 1year follow-up. Although both dosages were effective, the higher dose was sigruficantly more effective than the lower dose. In another more recent study, the therapeutic effect of DGL was compared with that of antacids or cimetidine in 874 patients with confirmed chronic duodenal ulcers.52 Ninety-one percent of all ulcers healed within 12 weeks; there was no sigruficant difference in healing rate in the groups. However, there were fewer relapses in the DGL group (8.2%) than in those receiving cimetidine (12.9%) or antacids (16.4%).These results, coupled with DGL protective effects, suggest that DGL is a superior treatment of duodenal ulcers.

Aphthous Ulcers Recurrent aphthous stomatitis (canker sores) is a common problem. DGL may be effective in promoting healing. In one study, 20 patients were instructed to use a solution of DGL as a mouthwash (200 mg powdered DGL dissolved in 200 ml warm water) four times daily? Fifteen of the 20 (75%)experienced 50%to 75%improvement within 1 day, followed by complete healing of the ulcers by the third day. DGL in tablet form may produce even better results.

Glycyrrhiza glabra (Licorice)

The result of glycyrrhizin in HIV-positive and AIDS patients is almost immediate improvement in immune function. In one study, nine symptom-free HIV-positive patients received 200 to 800 mg glycyrrhizin in vitro The most popular use of oral licorice preparations containing glycyrrhizin is in the treatment of viral illnesses, daily. After 8 weeks, the groups had increased T helper cells, improved helper /suppressor ratios, and improved particularly the common cold. Licorice has long been liver function.60 used in this application. This historical use is justified by In another study, six AIDS patients received 400 to its immune-enhancing and antiviral effects. In addition, licorice components were shown to exert antibacterial 1600 mg glycyrrhizin in vitro daily61After 30 days, five of the six showed a reduction or disappearance of the action against the common pathogens Streptococcus pyogenes, Haemophilus influenzae, and Moraxella ~atarrhalis.5~ P24 antigen, which indicates active disease. The results of these studies and others in HIV-positive and AIDS Another popular use of licorice is in the treatment of patients are encouraging. gynecologic issues, primarily PMS and menopause. Regarding PMS, because glycyrrhizin and glycyrrhetinic Hepatitis acid possess antiestrogeniceffect and suppress the breakSome studies of HIV patients used an intravenous glydown of progesterone, administration of licorice 2 weeks cyrrhizin-containingp d u c t , Stronger NeominophagenC before the onset of menstruation (the midluteal phase) (SNMC), consisting of 0.2% glycyrrhizin, 0.1% cysteine, may help to reduce PMS symptomatology. Clinical trials and 2.0%glycine in physiologic saline solution. This prcdhave shown that taking licorice containing herbal combiuct is used in Japan primarily for the treatment of hepanations is useful in dysmenorrhea.% Isoflavones from glycyrrhiza have shown an ability to inhibit serotonin titis. The other components, glycine and cysteine, appear to modulate glycyrrhizin's actions. Glycine has been reuptake and therefore may also exhibit some antideshown to prevent the aldosterone effectsof glycyrrhizin, pressant effects in PMS.57 while cysteine aids the liver in detoxification reactions. Human ImmunodeficiencyVirus and In addition to AIDS,SNMC has demonstrated benefiAcquired Immunodeficiency Syndrome cial results in treating chronic hepatitis B and c, often difficult infections for the body to clear.22,62-61 Specifically, Glycyrrhizin-containing preparations are showing promise in the treatment of HIV-related diseasesincluding SNMC has been shown to improve liver function and lower levels of liver enzymes. Glycyrrhizin therapy AIDS. Although much of the research has featured intraappears particularly helpful in patients with chronic venous administration, this route of administration may hepatitis C who fail to respond to interferon and in those not be necessary, as glycyrrhizin and glycyrrhetinic acid who cannot be treated with it for various reasons. are easily absorbed orally and are well tolerated. This is most evident in a recent double-blind study on the clinical effectiveness of glycyrrhizin by long-term oral adminis- Acute Intermittent Porphyria This disorder of heme biosynthesis is characterized by tration to 16 hemophiliac patients with evidence of HIV recurrent attacks of neurologic and psychiatric dysfuncinfection.58Patients received daily doses of 150 to 225 mg tion. The symptoms include the following: of glycyrrhizin for 3 to 7 years. Helper and total T-lymphocyte numbers, other immune Abdominal complaints of nausea, vomiting, and colicky system parameters, and glycyrrhizin and glycyrrhetinic pain, occasionallysevere enough to present as an acute acid levels in the blood were monitored. The results indiabdomen without fever or leukocytosis cated that orally administered glycyrrhizin was converted Variable neurologic signs and symptoms (e.g., paresinto glycyrrhetinic acid, which was detected in sera, thesia, hypesthesia, neuritic pain, wrist or foot drop, without manifesting any side effect. None of the patients loss of deep tendon reflexes) given the glycyrrhizin had progression of immunologic Variable mental and emotional disturbances, typically abnormalities or development to AIDS. In contrast, the restlessness, disorientation, and visual hallucinations group not receiving glycyrrhetinicacid showed decreases (seen in one third of patients) in helper and total T-cell counts and antibody levels. Two of the 16 patients in the control group develAs estrogens are known to exacerbate or induce acute oped AIDS. intermittent porphyria (AIP), it is quite possible that In another study, 10 HIV positive patients without some of the so-called PMS symptoms are exacerbations AIDS took 150 to 225 mg glycyrrhizin daily.59After 1to of AIP due to the midcycle estrogen surge. A partial (50%) deficiency of uroporphyrinogen I 2 years, none developed symptoms associated with AIDS synthase results in increased inducibility of aminoleor Armrelated complex (ARC), while 1 of 10 patients vulinic acid (ALA) synthase by drugs and foreign chemof a matched control group developed ARC and 2 proicals and by 5-beta-reductase steroid metabolites (potent gressed to AIDS and subsequently died.

ORAL LICORICE PREPARATIONS CONTAINING GLYCYRRHIZJN

inducers of ALA synthase). AIP is also associated with a marked deficiency in the activity of 5-alpha-reductase, resulting in increased 5-beta-reductase activity? Glycyrrhetinic acid and glycyrrhizin have been shown to sigruficantly reduce 5-beta-reductase while increasing 5-alpha-red~ctase.~ (Lead also increases 5-beta-reductase activity, resulting in a presenting picture similar to AIP.& Chronic or acute lead toxicity must be ruled out in these patients.)

Obesity and Syndrome X Preparations containing glycyrrhetinic acid may be effective in reducing various issues related to syndrome X or metabolic syndrome. For example, in a preliminary study, 15 normal-weight subjects (7 males, 22 to 26 years old, and 8 females, 21 to 26 years old) who consumed for 2 months 3.5 g a day of a commercial preparation of licorice containing glycyrrhetinic acid reduced body fat mass by 1.2%in men and 2.8% in w0men.6~This weight loss may be mediated not only via suppressing renin activity and aldosterone levels via inhibition of ll-betahydroxysteroid dehydrogenase, but also via improving blood glucose control-a key goal in syndrome X.@-’O In another study, supplementation of a licorice root extract to moderately hypercholesterolemic patients for 1 month reduced plasma susceptibility to oxidation (by 190/,).It also increased resistance of plasma LDL against three major atherogenic modifications: oxidation (by 55%), aggregation (by 28%), and retention (by 25%). It reduced plasma cholesterol levels (by 5%), which was due to a 9% reduction in plasma LDL cholesterol levels, and reduced (by 14%) plasma triglyceride levels. Licorice extract supplementation also reduced systolic blood pressure by

Addison’s Disease As described earlier, licorice exerts an ”aldosterone-like effect” that is useful in treating Addison‘s disease.

Inflammation Virtually any inflammatory or allergic condition may be reduced by licorice by the mechanisms discussed earlier in the section on pharmacology. Historically, licorice has been successfully used for treating asthma and other atopic c~nditions.~**~ Licorice has been shown to enhance the action of corticosteroids like prednisone and prednisolone, as well as the levels of the body’s own corticosteroids.R,n In one study, six subjects received an intravenous dose of prednisolone with or without 200 mg glycyrrhizin. Glycyrrhizin was found to increase significantly the concentration of total and free prednisolone by inhibiting its breakdown. Furthermore, the effects of prednisolone appeared to be potentiated by glycyrrhizin.”

Sweetening Agent As glycyrrhizin is 50 to 100 times sweeter than sucrose, licorice can be used as a sweetening or flavoring agent to mask the bitter taste of other medications3

TOPICAL APPLICATIONS Eczema and Psoriasis Glycyrrhetinicacid exerts an effect similar to that of topical hydrocortisone in the treatment of eczema, contact and allergic dermatitis, and psoriasis. In fact, in several studies, glycyrrhetinic acid was shown to be superior to topical cortisone, especially in chronic cases. For example, in one study of patients with eczema, 93% of the patients applying glycyrrhetinic acid demonstrated improvement compared with 83% using cortisone.74 In another study, a topical gel containing 2% glycyrrhetinic acid was shown to be effective for treatment of atopic dermatitis and was more effective than in reducing the scores for erythema, edema, and itching over 2 weeks compared with preparations containing 1% glycyrrhetinic acid.75 Glycyrrhetinic acid can also be used to potentiate the effects of topically applied hydrocortisone by inhibiting the ll-beta-hydroxysteroid dehydrogenase, which catalyzes the conversion of hydrocortisone to an inactive ~ O I T I It - Ialso . ~ ~increases ,~ the permeation of topically applied steroids. In one study, glycyrrhetinic acid in a concentration of 0.1% in gel increased diclofenac sodium flux value 10-fold compared with a control gel.78

Herpes Simplex Clinical studies have shown topical glycyrrhetinic acid and derivatives to be quite helpful in reducing the healing time and pain associated with cold sores and genital herpes.m*sO As mentioned earlier, glycyrrhizin inactivates HSV-1 irreversibly and stimulates the synthesis and release of interferon.25

Melasma Two components, glabrene and isoliquiritigenin, can inhibit tyrosinase-a key enzyme in melanin biosynthesis.8I Dermatologic disorders such as melasma, age spots, and sites of actinic damage arise from the accumulation of melasma. Glabrene and isoliquiritigenin may serve as candidates for skin-lightening agents.

DOSAGE The dosage of licorice for most clinical applications is based on the content of glycyrrhetinic acid. The exception is in the treatment of peptic ulcer. In this application, deglycyrrhizinated licorice (DGL) is preferred, as it

Glycyrrhiza glabra (Licorice)

produces equally effective results compared with glycyrrhetinic acid but is free from any side effects. For most purposes, the goal is to achieve a high level of glycyrrhetinic acid in the blood without producing side effects (discussed later). In general, the following dosages three times a day are safe and effective in raising glycyrrhetinic acid levels: Powdered root: 1to 2 g Fluid extract (1:l):2 to 4 ml Solid (dry powdered) extract (4:l): 250 to 500 mg In the treatment of AIDS, pure glycyrrhetinic acid products or extracts standardized for glycyrrhetinic acid are recommended. Toxicity can become a problem for patients taking licorice for any period longer than 1month (see Side Effects and Toxicology).

Dosage Instructions for Deglycyrrhizinated Licorice In order to be effective in healing peptic ulcers, it appears that DGL must mix with saliva. DGL may promote the release of salivary compounds, which stimulate the growth and regeneration of stomach and intestinal cells. DGL in capsule form has not been shown to be effective?2,83 The standard dosage for DGL is two to four 380-mg chewable tablets between or 20 minutes before meals. Taking DGL after meals is associated with poor results.84 DGL should be continued for 8 to 16 weeks, depending on the response.

SIDE EFFECTS AND TOXICOLOGY The main hazards of licorice administration are due to the aldosterone-like effects of glycyrrhetinic acid. If ingested regularly, licorice root (>3 g/day for more than 6 weeks) or glycyrrhizin (>lo0 mg/day) may cause sodium and water retention, hypertension, and hypokalemia.8,9,s87 Individuals with existing hypertension may be more predisposed to this effect via increased sensitivity to the inhibition of 11-beta-hydroxysteroiddehydrogenase by glycyrrhetinic acid.fsJ”’ Monitoring of blood pressure and electrolytes and increasing dietary potassium intake is suggested, as the pseudoaldosterone effects can be quite sigruficant. The maximal effect on blood pressure with chronic ingestion is observed after 2 weeks of use?9 There is great individual variation in the susceptibility to the symptom-producing effects of glycyrrhizin, primarily due to differences in pharmacokinetics and conversion to the more potent glycyrrhetinic acid (100 to 200 times more active in suppressing 11-beta-hydroxysteroid-dehydrogenase).90Adverse effects are rarely observed at levels below 100 mg/day, while they are

quite common at levels above 400 mg/day9 However, some persons may be susceptible to chronic dosages at even lower levels, especially if the more potent glycyrrhetinic acid is available in free form. One study determined a no-effed level of glycyrrhetinic acid as 2 mg/kg, from which an acceptable daily intake (ADI) of 0.2 mg/kg body weight can be extrapolated with a safety factor of 10. This translates to a consumption of 12 mg glycyrrhetinic acid/day for a person with a body weight of 60 kg?I Prevention of the side effects of glycyrrhizin may be possible by following a high-potassium, low-sodium diet. Although no formal trial has been performed, patients who normally consume high-potassium foods and restrict sodium intake, even those with high blood pressure and angina, have been reported to be free from the aldosterone-like side effects of glycyrrhi~in.~~ Licorice should probably not be used in patients with a history of hypertension or renal failure or in those who currently use digitalis preparations. Licorice preparations containing glycyrrhizin may reduce serum and salivary testosterone levels in men. In one study, men consuming the equivalent of 500 mg of glycyrrhizin experienced a drop of 26% in serum testosterone le~els.9~ However, in another study, no sigruficant effect was noted.% Licorice intake during pregnancy is generally regarded safe unless hypertension becomes an issue. There has been one detailed study on maternal consumption of glycyrrhizin and how it affects birth ~ e i g h t . 9 Glycyrrhizin ~ intake was calculated from detailed questionnaires on licorice consumption.Glycyrrhizin exposure was grouped into three levels: low (<250 mg/week), moderate (250 to 499 mg/week), and heavy (2500 mg/week). Birth weight and gestational age (from ultrasound measurements) were obtained from hospital records. Babies with heavy exposure to glycyrrhizin were not significantly lighter at birth, but they were significantly more likely to be born earlier-2.52 days earlier. No other associations could be made.

DRUG INTERACTIONS No significant reports of drug interactions have appeared, although on theoretic grounds licorice components have shown considerable interactions with various enzyme systems. Licorice root extract and purified glabridin were shown to inhibit P450 3A4, the major human drug metabolizing P450 enzyme, in time- and concentration-dependent manners, thereby potentiating the action of many drugs.%Glycyrrhizin intake may be problematic for people on digitalis, diuretics, or antihypertensive medications. Also, individuals using oral hypoglycemic drugs or insulin need to monitor blood sugar levels closely when using glycyrrhiza.

Pharmacology of Natural Medicines

1.Hattori M, Sakamoto T, Kobashi K, et al. Metabolism of glycyrrhiziiby human intestinal flora. Planta Med 1983;48:38-42. 2. Yamamoto K, Kakegawa H, Ueda H, et al. Gastric cytoprotective anti-ulcerogenic actions of hydroxychalcone in rats. Planta Med 1992;58:389-393. 3. Chandler RF. Licorice, more than just a flavour. Can Pharm J 1985; 118421-424. 4. Kumagai A, Nishino K, Shimomura A, et al. Effect of glycyrrhizin on estrogen action. Endocrinol Jpn 1967;1434-38. 5.Kraus S, Kaminskis A. The anti-estrogenic action of betaglycyrrhetinic acid. Exp Med Surg 1969;27411420. 6.Tamir S, Eizenberg M, Somjen D, et al. Estrogen-like activity of g l a b m e and other constituents isolated from licorice root. J Steroid Biochem Mol Biol2001;78291-298. 7. Maggiolini M, Statti G, Vivacqua A, et al. Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. J Steroid Biochem Mol Biol2002;82:315-322. 8.Farese RV Jr, Biglieri EG, Shackleton CH, et al. Licorice-induced hypermineralocorticoidism. N Engl J Med 1991;325:1223-1227. 9. Stormer FC, Reistad R, Alexander J. Glycyrrhizic acid in l i q o u r i c e evaluation of health hazard. Food Chem Toxicol 1993;31:303-312. 10. Takeda R, Morimoto S, Uchida K, et al. Prolonged pseudoaldosteronism induced by glycyrrhizin. Endocrinol Jpn 1979;26541-547. 11. Baron J. Side-effects of carbenoxolone.Acta Gastroenterol Belg 1983; 46:469-4&4. 12. Epstein MT, Espiner EA, Donald RA, et al. Effect of eating liquorice on the renin-angiotensin aldosterone axis in normal subjects. Br Med J 1977;1:488-490. 13. Armanini D, Karbowiak I, Funder JW. Affinity of liquorice derivatives for mineralocorticoid and glucocorticoid receptors. Clin Endocrinol (Oxf) 1983;19:609-612. 14. Tamura Y, Nishikawa T, Yamada K. Effects of glycyrrhetinic acid and its derivatives on delta 4 5 alpha- and 5 beta-rrductase in rat liver. Arzneimittelforsdlungung1979;29:647-649. 15. Kuroyanagi T, %to M. [Effect of prednisolone and glycyrrhizin on passive transfer of experimental allergic encephalomyelitis.] Arerugi 1966;1567-74. 16. Cyong J, Otsuka Y. A pharmacological study of the anti-inflammatory activity of Chinese herbs. A review. Acupunct Electrother Res 1982;7173-202. 17. Kumagai A, Nanaboshi M, Asanuma Y, et al. Effects of glycyrrhizin on thymolytic and immunosuppressive action of cortisone. Endocrinol Jpn 1967143942. 18. van Uum SH, Walker BR, Hermus AR, et al. Effect of glycyrrhetinic acid on 11beta-hydroxysteroid dehydrogenase activity in normotensive and hypertensive subjects. Clin Sci (Colch) 2002;102: 203-211. 19. Okimasa E, Moromizato Y, Watanabe S, et al. Inhibition of phosphclipase A2 by glycyrrhizin, an anti-inflammatory drug. Acta Med Okayama 1983;37385-391. 20. Amer MS, Mckinney GR, Akcasu A. Effect of glycyrrhetinic acid on the cyclic nucleotide system of the rat stomach. Biochem Pharmacol 197423~3085-3092. 21.Ohuchi K, Kamada Y, Levine L, et al. Glycyrrhizin inhibits prostaglandin E2 production by activated peritoneal macrophages from rats. Prostaglandins Med 1981;7457-463. 22.Suzuki H, Ohta Y, Takino T, et al. Effects of glycyrrhizin on biochemical tests in patients with chronic hepatitisdouble blind trial. Asian Med J 1984;26423-438. 23. Mendes-Silva W, Assafim M, Ruta B, et al. Antithrombotic effect of Glycyrrhizin, a plant-derived thrombin inhibitor. Thromb Res 2003; 11293-98.

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47.Morgan AG, Pacsoo C, McAdam WA. Maintenance therapy. A two year comparison between Caved-S and cimetidine treatment in the prevention of symptomatic gastric ulcer. Gut 1985;26 599-602. 48. Morgan AG, McAdam WA, Pacsoo C, et al. Comparison between cimetidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy. Gut 1982;23:545-551. 49. Glick L. Deglycrrhizinated liquorice for peptic ulcer. Lancet 1982; 2817. 50. TurpieAG, RuncieJ, Thornson TJ. Clinical trial of deglydymhizinized liquorice in gastric ulcer. Gut 1969;10299-303. 51. Rees WD, Rhodes J, Wright JE,et al. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gastroent 1979;14605-607. 52. Kassir ZA. Endoscopic controlled trial of four drug regimens in the treatment of chronic duodenal ulceration. Ir Med J 1985;78:153-156. 53. Tewari SN, Wilson AK. Deglycyrrhizinated liquorice in duodenal dcer. Practitioner 1973;210820-823. 54. Das SK, Das V, Gulati AK, et al. Deglycyrrhizinated liquorice in aphthous ulcers. J Assoc Physicians India 198937647. 55. Tanaka Y, Kikuzaki H, Fukuda S, et al. Antibacterialcompounds of licorice against upper airway respiratory tract pathogens. J Nutr Sci Vitamin01(Tokyo) 2001;47:270-273. 56. Tanaka T. A novel anti-dysmenorrhea therapy with cyclic administration of two Japaneseherbal medicines. Clin Exp Obstet Gynecol 2003;3095-98. 57. Ofir R, Tamir S, Khatib S, et al. Inhibition of serotonin re-uptake by licorice constituents. J Mol Neurosci 2003;20135-140. S, et al. Prophylacticeffect of long58. Ikegami N, Akatani K, Yam& term oral administration of glycyrrhizin on AIDS development of asymptomatic patients. Int Conf AIDS 1993;9:234 [abstract no. POA25-05961. 59. Ikegami N, Akatani K, Yamazaki S, et al. Clinical evaluation of glycyrrhizin on HIV-infected asymptomatic hemophiliac patients in Japan. Fifth International Conference on AIDS.Abstract W.B.P. 298, June 1989. Cited in AIDS Treatment News #lo3 May 18, 1990. 60. Mori K, Sakai H, Suzuki S, et al. [The present status in prophylaxis and treatment of HIV infected patients with hemophilia in Japan.] W h o Byhori 1989;371200-1208. 61.Hattori T, Ikematsu S, Koito A, et al. Preliminary evidence for inhibitory effect of glycyrrhizin on HIV replication in patients with AIDS. Antiviral Res 1989;11:255-261. 62. Eisenburg J. [Treatment of chroNc hepatitis B. Part 2. Effect of glycyrrhizinic acid on the course of illness.] Fortschr Med 1992;llO: 395-398. 63. Acharya SK, Dasarathy S, Tandon A, et al. A preliminary open trial on interferon stimulator (SNMC) derived from Glycyrrhiza glabra in the treatment of subacute hepatic failure. Indian J Med Res 1993;98: 69-74. 64.Kumada H. Long-term treatment of chronic hepatitis C with glycyrrhizin [stronger neo-minophagen C (SNMC)] for preventing liver cirrhosis and hepatocellular carcinoma. Oncology 2002;62 94100. 65. Anderson K, Bradlow H, Sassa S, et al. Studies in porphyria W. Relationship of the 5 alpha-reductive metabolism of steroid hormones to clinical expression of the genetic defect in acute intennittent porphyria. Am J Med 1979;66:644-650. 66. Tomita T, Sat0 T, Saito K, et al. Effects of lead and arsenic on the formation of 5 beta-H steroids. Toxicol Lett 19793:291-297. 67. Armanini D, De Palo CB, Mattarello MJ, et al. Effect of licorice on the reduction of body fat mass in healthy subjects. J Endocrinol Invest 2003;26646-650. 68. K d a M, Mimaki Y , Sashida Y, et al. phenolics with PPAR-gamma ligand-biding activity obtained from licorice (Glycyrrhiza uralensis

roots) and ameliorative effects of glycyrin on genetically diabetic KK-A(y) mice. Bioorg Med Chem Lett 2003;134267-4272. 69. Mae T, Kishida H, Nishiyama T, et al. A licorice ethanolic extract with peroxisome proliferator-activated receptor-gamma ligandbinding activity affects diabetes in KK-Ay mice, abdominal obesity in diet-induced obese C57BL mice and hypertension in spontaneously hypertensive rats. J Nutr 2003;133:3369-3377. 70. Armanini D, Fiore C, Mattarello MJ, et al. History of the endocrine effectsof licorice. Exp Clin Endocrinol Diabetes 2002;110257-261. 71. F~~hrman B, Volkova N, Kaplan M, et al. Antiatheroscleroticeffects of licorice extract supplementationon hypercholesterolemic patients: increased resistance of LDL to atherogenic modifications, reduced plasma lipid levels, and decreased systolicblood pressure. Nutrition 2002;18:268-273. 72. MacKenzie MA, HoefnagelsWH, Jansen RW, et al. The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers. J Clin Endocrinol Metab 1990;701637-1643. 73. Chen W, Shimada F, Kato H, et al. Effect of glycy-rrhizin on the pharmacokinetics of prednisolone following low dosage of prednisolone hemisuccinate.Endocrinol Jpn 1990;37331-341. 74. Evans FQ. The rational use of glycyrrhetinicacid in dermatology.Br J Clin Pract 1958;12269-274. 75. S a d M, Morteza-SemnaniK, Ghoreishi MR. The treatmentof atopic dermatitiswith licorice gel. J Dermatolog Treat 2003;14153-157. 76. Teelucksigh S, Mackie AD, Burt D, et al. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990;335: 1060-1063. 77. SigUjonsdottir HA, Manhem K, Axelson M, et al. Subjects with essential hypertension are more sensitive to the inhibition of 11 beta-HSD by liquorice.J Hum Hypertens 2003;17125-131. 78. Nokhodchi A, Nazemiyeh H, Ghafourian T, et al. The effect of glycyrrhizin on the release rate and skin penetration of diclofenac sodium from topical formulations.Farmaco 2002;57883-888. 79.Partridge M, Poswillo D. Topical carbenoxolone sodium in the management of herpes simplex infection. Br J Oral Maxillofac Surg 1984;22.138-145. 80.Csonka GW, Tyrrell DA. Treatment of herpes genitalis with carbenoxoloneand cicloxolone creams. A double blind placebo controlled trial. Br J vener Dis 1984;60:178-181. 81. Nerya 0, Vaya J, Musa R, et al. Glabrene and isoliquiritigenin as tyrosinase inhibitors from licorice roots. J Agric Food Chem 2003;51:1201-1207. 82. Bardhan KD, Cumberland DC, Dixon RA, et al. Clinical trial of deglycyrrhizinised liquorice in gastric ulcer. Gut 1978;19779-782. 83. MulticentreTrial. Treatmentof duodenal ulcers with glycyrrhmizin acid-reduced liquorice. Br Med J 19733:501-503. 84. Feldman H, Gilat T. A trial of deglycyrrhizinated liquorice in the treatment of duodenal ulcer. Gut 1971;12499-555. 85.Belhadj-Tahar H, Nassar B, Coulais Y, et al. Acute pseudoaldosteronism syndrome induced by liquorice. Therapie 2003;58: 375-378. 86. Lin SH, Yang SS, Chau T, et al. An unusual cause of hypokalemic paralysis: chronic licorice ingestion.Am J Med Sci 2003;325:153-156. 87.Al-Qarawi AA, Abdel-Rahman HA, Ali BH, et al. Liquorice (Glycyrrhiza glabra) and the adrenal-kidney-pituitaryaxis in rats. Food Chem Toxicol 2002;40:1525-1527. 88. TanahashiT,Mune T, Morita H, et al. Glycyrrhizicacid suppresses type 2 11 beta-hydroxysteroid dehydrogenase expression in vivo. J Steroid Biochem Mol Biol2002;80441-447. 89.SigUjonsdottir HA, Franzson L, Manhem K, et al. Liquoriceinduced rise in blood pressure: a linear dose-response relationship. J HW H y ~ e r t e 2001;15549-552. n~ 90. Ploeger B, Mensinga T, Sips A, et al. The pharmacokinetics of glycyrrhizic acid evaluated by physiologicallybased pharmacokinetic modeling. Drug Metab Rev 200133125-147.

Pharmacology of Natural Medicines 91. van Geldem CE, Bijlsma JA, van Dokkum W, et al. Glycyrrhizic acid the assessment of a no effect level. Hum Exp Toxic01 2000;19 434-439. 92. Baron J, Nabarro J, Slater J, et al. Metabolic studies, aldosterone secretion rate, and plasma renin after carbenoxolone sodium as bicgastmne. Br Med J 1969;2793-795. 93. Annanini D, Bonanni G, Mattarello MJ, et al. Licorice consumption and serum testosterone in healthy man. Exp Clin Endocrinol Diabetes 2003;111:341-343.

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Hydrastis canadensis (Goldenseal) and Other Berberine-Containing Botanicals Michael T. Murray, ND Joseph E. Pizzorno Jr, ND C H A P T E R CONTENTS Introduction 1013 General Description 1013 Hydrastis canadensis 1013 Berberis vulgaris 1014 Berberis aquifolium 10 14 Coptis chinensis 10 14 Chemical Composition 1014 Hydrastis canadensis 1014 Berberis vu/garis 10 14 Berberis aquifolium 1014 Coptis chinensis 1014 History and Folk Use 1014 Hydrastis canadensis 1014 Berberis vulgaris 1014 Berberis aquifolium 1014 Coptis chinensis 1014

lmmunostimulatory Activity 1016 Anticancer Effects 1016 Antipyretic Activity 1016 Antidiabetic Actions 1016

Clinical Applications 1016 Infectious Diarrhea 1016 Trachoma 1017 Cholecystitis and Cirrhosis of the Liver Cancer 1017 Congestive Heart Failure 1018

1017

Dosage 1018 Toxicity 1018 Drug Interactions 1018

Pharmacology 1014 Antimicrobial Activity 1014 Antiinfective Activity 1015

Hydrastis canadensis (family: Ranunculaceae) Common names: goldenseal, yellow root, Indianturmeric, eye root, jaundice root Berberis vuZguris (family: Berberidaceae) Common name: barberry Berberis aquifolium (family: Berberidaceae) Common names: Oregon grape, trailing mahona Coptis chinensis (family: Ranunculaceae) Common name: goldthread

INTRODUCTION The plants goldenseal (Hydrastis canadensis), barberry (Berberisvulgaris), Oregon grape Ukrberis aquifolium),and goldthread (Coptis chinensis) share similar indications and effects due to their high content of berberis alkaloids.

The chief berberis alkaloid, berberine, has been studied extensively in both experimental and clinical settings. Its pharmacologic effects are reviewed later. The general description, history and folk use, chemical composition, and specific clinical indications for each plant are presented here. The pharmacology of these plants is primarily discussed in terms of the activity of berberine.

GENERAL DESCRIPTION Hydrastis canadensis Goldenseal is native to eastern North America and is cultivated in Oregon and Washington. It is a perennial herb with a knotty yellow rhizome from which arises a single leaf and an erect hairy stem. In early spring, it bears two five- to nine-lobed rounded leaves near the top, 1013

Pharmacology of Natural Medicines which are terminated by a single greenish-white flower. The parts used are the dried rhizome and roots.12

Berberis vulgaris The common barberry is a deciduous spiny shrub that may reach 16 feet in height. Native to Europe, it has been naturalized in eastern North America. Parts used are the barks of the stem and root.l.2

Berberis aquifolium The Oregon grape is an evergreen, spineless, ornamental shrub, 3 to 7 feet in height. It is native to the Rocky Mountains from British Columbia to California. Parts used are the rhizome and roots.'"

Coptis chinensis Goldthread is a perennial herb native to China. The parts used are the rhizomes and

CHEMICAL COMPOSITION (FIGURE 10011) Hydrastis canadensis Alkaloids isolated from hydrastis include the following: Hydrastine (1.5%to 4%) Berberine (0.5%to 6%) Berberastine (2% to 3%) Canadine Candaline Hydrastinine Other related alkaloids Other constituents include meconin, chlorogenic acid, phytosterins, and resins.12

Berberis vulgaris Barberry contains several alkaloids in its roots: Jatrorrhizine Berberine Berberubine Berbamine Bedcine Palmatine Columbamine Oxyacanthine

Berberis aquifolium Oregon grape contains the alkaloidsberbamine, berberine, canadine, corypalmine, hydrastine, isocorydine, mahonine, and oxyacanthine. Resins and tannins have also been reported

Coptis chinensis Goldthread root contains berberine (5%to 8%)and other alkaloids similar to those found in goldenseal?

HISTORY AND FOLK USE Hydrastis canadensis Native to North America, hydrastis was used extensively by American Indiansas an herbal medication and clothing dye. Its medicinal use centered around its ability to soothe the mucous membranes of the respiratory, digestive, and genitourinary tracts in inflammatory conditions induced by allergy or infection. The Cherokee and other Indian tribes used hydrastis in disorders of the eye and skin.lj2

Berberis vulgaris This plant is native to most of Europe. Similar species are found in North Africa and Asia. Barberry's historic use is as an antidiarrheal agent, bitter tonic, antipyretic, and antihemorrhagic.',*

Berberis aquifolium Oregon grape's historic and folk use is similar to that of hydrastis. In addition, Oregon grape was used in the treatment of chronic skin conditions such as acne, psoriasis, and eczema.'r2

Coptis chinensis In China goldthread was used in the traditional medicine system to "drain fire." It was used primarily in infectious conditions, similar to the historic use of goldenseal. Specific uses included fever, dysentery, gastrointestinal infection, furuncles, boils, and eye infection^.^

PHARMACOLOGY

It also contains chelidonic, citric, malic, and tartaric acids.'J

The medicinal value of hydrastis, barberry, Oregon grape root, and goldthread is thought to be due to their high content of isoquinoline alkaloids, of which berberine has been the most widely studied. Berberine has demonstrated antibiotic, immunostimulatory, anticonvulsant, sedative, hypotensive, uterotonic, choleretic, and carminative activity. Berberine's pharmacologic activities support the historic use of the berberine-containing herbs.

Antimicrobial Activity Figure 1W1 Berberine.

Perhaps the most celebrated of berberine's effects has been its antibiotic activity. Although not as potent as many prescription antibiotics, berberine exhibits a broad

Hydrastis canadensis (Goldenseal) and Other Berberine-Containing Botanicals spectrum of antibiotic activity. Berberine has shown antimicrobial activity against bacteria, protozoa, and fungi including the

Staphylococcus sp. Streptococcus sp. Chlamydia sp. Corynebacterium diphtheria Escherichia coli Salmonella typhi Vibrio cholerae Diplococcus pneumonia Pseudomonas sp. Shigella dysenteriae Entamoeba histolytica Trichomonas vaginalis Neisseria gonorrhoeae Neisseria meningitidis Treponema pallidum Giardia lamblia Leishmania donovani Candida albicans Its action against some of these pathogens is actually stronger than that of prescription antibiotics commonly used for these pathogens. Berberine's action in inhibiting Candida, as well as other pathogenic bacteria, prevents the overgrowth of yeast that is a common side effect of antibiotic use. Table 100-1 lists the in vitro sensitivity of various organisms to berberine sulfate. The antimicrobial activity of berberine increases with pH in all organisms studied? At a pH of 8, its antimicrobial activity in vitro is typically two to four times greater than it is at pH 7, which in turn is one to four times greater than at pH 6. This suggests that alkalinization will improve its clinical efficacy, particularly in the treatment of urinary tract infections.

Antiinfective Activity Researchersinvestigated berberine's ability to inhibit the adherence of group A streptococci to host cells on the basis that the therapeutic effect of berberine appeared to be greater than its direct antibiotic effects.14Recent studies have shown that certain antimicrobial agents can block the adherence of microorganisms to host cells at doses much lower than those needed to kill cells or to inhibit cell growth. Berberine's ability to inhibit the adhesion of streptococa to host cells has several modes of action. First, berberine causes streptococci to lose lipoteichoic acid (LTA). LTA is the major substance responsible for adhesion of the bacteria to host tissues. Another important action of berberine is preventing the adhesion of fibronectin to the streptococci, as well as eluting already bound fibronectin. The results of thisstudy are quite profound. They raise many questions and force researchers and practitioners to look at the treatment of bacterial infections in a new

Organism

Bacteria Bacillus cereus Bacillus subtilis Corynebacterium diphtheria Enterobacter aerogenes Escherichia coli Klebsiella sp. Klebsiella pneumoniae Proteus sp. Pseudomonas mangibrae Pseudomonas pyocyanea Salmonella paratyphi Salmonella typhimurium Shigella boydii Staphylococcus aureus Streptococcus pyogenes Vibrio cholerae Fungi Candida utilis Candida albicans Cryptococcus neoformans Microsporum gypseum Saccharomyces cerevisiae Sporothrix schenkii Trchophyton mentagrophytes Other Entamoeba histolytica Erwinia carotovora Leishmania donovani Mycobacterium tuberculosis Xanthomonas citri

Inhibitory concentration (mg/ml)*

25 25 6.2 2500.05 600.05 >loo 25 >loo >loo >loo >loo 2100 12.5 6.2-50 12.5 25 12.5 12.5 150t 50t 1 OOt 6.2 1 OOt 200 100

5.08 200+ 3.1

Data from references 5, 6, and 9. 'Minimum concentration that totally inhibits growth in a liquid medium at pH 8. Maximum concentration tested was 100 pg/ml, unless otherwise noted. Vested in a solid medium, which typically requires a 4 to 10 times greater concentration for the same level of inhibition.

light. Is it better to use a substance with bactericidal or bacteriostatic action over a substance that prevents the adherence of bacteria to host cells? Is the true value of botanicals with "antiinfective" actions a multifactorial effect on all aspects of infections from immune stimulation to antimicrobial and antiadherence actions? The results of the study indicate that berberine interferes with infections due to group A streptococci not only by inhibiting streptococcal growth but also by blocking these organisms to host cells. The study implies

Pharmacology of Natural Medicines

that berberine-containing plants may be ideal in the treatment of “shvp throat,” a condition historically treated with goldenseal by American naturopathic physicians. Berberine’s action in inhibiting C. albicans prevents the overgrowth of yeast, which is a common side effect of antibiotic use.

lmmunostimulatory Activity Berberine has been shown to increase the blood supply This improved blood supply may promote to the ~p1een.l~ optimal activity of the spleen by increasing the release of compounds, such as tuftsin, that potentiate immune function. Berberine has also been shown to activate macrophages, via both enhanced priming and triggering.16

CLINICAL APPLICATIONS The broad antimicrobial effects of berberine, combined with its antiinfective and immune-stimulating actions, support the historic use of berberine-containingplants in infections of the mucous membranes. Berberine-containing plants may also be useful as an adjunct to standard cancer therapy.

Infectious Diarrhea

Berberinehas shown sigruficantsuccessin the treatment of acute diarrhea in several clinical studies. It has been found effective against diarrheas caused by E . coli (traveler’s diarrhea), Shigellu dysenteriae (shigellosis), Salmonella paratyphi (food poisoning), Klebsiellu sp., G. lamblia (giarAnticancer Effects diasis), and V.cholerae (cholera).2636 Studies in hamsters and rats have shown that berberine also has significant Berberine exhibits potent anticancer activity both directly activity against Entamoeba histolytica, the causative by killing tumor cells and indirectly by stimulating white organism of amebiasis.’,8 blood cells.1620The most impressive effect was noted in It appears that berberine is effective in treating the a study demonstrating antitumor activity against human majority of common gastrointestinal infections. Clinical and rat malignant brain tumors.18Several experimental studies have produced results with berberine comparable approaches were used in the study. In vitro studies were to standard antibiotics in most cases. In fact, in several performed on a series of six human malignant brain tumor studies results were better. cell lines and rat 9L brain tumor cells. Berberine used For example, in a study of 65 children younger than alone at a dose of 150 pg/ml showed an average cancer 5 years of age with acute diarrhea caused by E. coli, cell kill of 91%. This kill rate was more than twice that of Shigella, Salmonella, Klebsiella or Faecalis aerogenes, those 1,3-bis(2-chloro-ethyl)-l-nitrosourea(BCNU),the standard given berberine tannate (25 mg/6 hr) responded better chemotherapeutic agent for brain tumors, which had a than those treated with standard antibiotic therapy31 cell kill rate of 43%.Studies in rats harboring solid 9L brain In another study, 40 children who were 1 to 10 years tumors also showed that berberine has antitumor effects. old and infected with the parasite Giardia received either Rats treated with berberine, 10 mg/kg, had an 81% cell berberine (5 mg/kg body weight each day), the drug kill. However, the combination treatment of berberine metronidazole (10 mg/kg body weight each day), or a and BCNU exhibited additive effects on killing cancer placebo of vitamin B syrup in three divided cells. These results indicate that berberine may prove to After 6 days, 48%of patients treated with berberine were be more effective than BCNU or, at the least, a valuable symptom free and, on stool analysis, 68% were giardia therapeutic addition in the treatment of difficult brain free. In the metronidazole (Flagyl)group, 33%of patients cancers. were without symptoms and, on stool analysis, all were Berberine has also exhibited unique antioxidant and giardia free. In comparison, 15% of patients on placebo antimutagenic effects.21*22 were asymptomatic and, on stool analysis, 25% were giarAntipyretic Activity dia free.These results indicate that berberine was actually more effective than metronidazole in relieving sympHistorically, berberine-containingplants have been used toms at half the dose but less effective than the drug in as febrifuges. Berberine produces an antipyretic effect clearing the organism from the intestines. three times as potent as aspirin in a pyretic model in And finally, in a study of 200 adult patients with acute rats.= However, while aspirin suppresses fever through diarrhea, the subjects were given standard antibiotic its action on prostaglandins, berberine appears to lower treatment with or without berberine hydrochloride fever by increasing the immune system’s handling of (150 mg/day). The patients receiving berberine recovfever-producing compounds from microorganisms. ered quicker.% An additional 30 cases of acute diarAntidiabetic Actions rhea were treated with berberine alone. Berberine arrested diarrhea in all of these cases with no mortality Berberine has been shown to possess antidiabetic effects or toxicity. related to its ability to stimulate insulin secretion, block Despite these results, due to the serious consequences glucose absorption via inhibition of alpha-glucosidaseand of an ineffectivelytreated infectious diarrhea due to highly epithelial glucose transport, and reduce serum lipid levels in animal models of impaired glucose toleran~e.*~S pathogenic organisms, the best approach may be to use

berberine-containing plants as an adjunct to standard antibiotic therapy. Much of berberine’s effectiveness is undoubtedly due to a combination of its direct antimicrobial activity, inhibition of microbial attachment to mucous membranes, and blocking of the action of toxins produced by several pathogenic b a ~ t e r i a . ~The ~ ” ~toxin-blocking effect is most evident in diarrheas caused by enterotoxins (e.g., V.cholerue, E . coli), cholera, and traveler’s diarrhea, re~pectively.~~’ Although cholera is a serious disorder that needs standard antibiotic therapy, traveler’s diarrhea is usually selflimiting. Good results with berberine in the treatment of traveler’s diarrhea have been obtained. In one study, patients with traveler’s diarrhea randomly received 400 mg of berberine sulfate in a single dose or served as controls.36In treated patients, the mean stool volumes were significantlyless than those of controls during three consecutive 8-hour periods after treatment. At 24 hours after treatment, siphcantly more treated patients stopped having diarrhea as compared with controls (42%vs. 20%). For people planning to travel to an underdeveloped country or an area of poor water quality or sanitation, the prophylactic use of berberine-containingherbs 1week before, during, and 1week after visiting may be useful.

Trachoma Water extracts of berberine-containing plants have been employed to treat various eye complaints including infectious processes by cultures throughout the world. Recently, berberine has shown remarkable effect in the treatment of t r a ~ h o m a . ~Trachoma, ,~’ an infectious eye disease due to the organism Chlamydia truchomutis, is a major cause of blindness and impaired vision in underdeveloped countries. It affects approximately 500 million people worldwide and results in blindness in 2 million. The drug sulphacetamide is currently the most widely used antitrachoma drug. In clinical trials comparing berberine (0.2%) and sulphacetamide (20% solution), sulphacetamide showed the best improvement (decrease in conjunctivaldischarge, edema, and papillary reactions), but the conjunctival scrapings of all patients receiving sulphacetamide were still positive for C. truchomutis. These patients had a high rate of recurrence of symptoms. In contrast, patients treated with the berberine solution showed mild ocular symptoms, which disappeared more gradually, but their conjunctival scrapings were always negative for C. trachomatis. Thesepatients did not suffer relapse even 1year after treatment, which suggests that berberine is probably curative for trachoma.Q4’ Berberine’s efficacy is believed to be due to stimulation of some host defense mechanism, rather than simply a direct action on the organism. As the berberine concentration used in these studies was 100 times less than the concentration of sulphacetamide, and berberine is much

cheaper, it may be more cost-effective than other treatments for trachoma. Berberine (0.2% solution) is an appropriate therapy for many types of conjunctivitis.

Cholecystitis and Cirrhosis of the Liver Berberine has been shown in several clinical studies to stimulate the secretion of bile (choleretic effect) and bilirubina4 In one study of 225 patients with chronic cholecystitis, oral berberine doses of 5 to 20 mg three times a day before meals caused, over a period of 24 to 48 hours, a disappearance of clinical symptoms, a decrease in bilirubin level, and an increase in the bile volume of the gall bladder. Berberine has been shown to correct the hypertyraminemia of patients with liver cirrhosis. It prevents the elevation of serum tyramine following oral tyrosine load by inhibiting the enzyme tyrosine decarboxylase found in bacteria in the large intestine.&Berberine inhibits tyrosine decarboxylase and tryptophanase activities of Streptococcusfuecdis and E. coli but not those of animal enzymes. Tyramine is believed to be responsible for some of the cardiovascular and neurological complications of liver disease, such as hepatic encephalopathy. The accumulation of tyramine and its derivatives may cause lowering of peripheral resistance, with resultant high cardiac output, reduction in renal function, and cerebral dysfunction. Berberine, by lowering plasma tyramine levels, helps prevent the complications of cirrhosis. This tyramine-lowering effect of berberine may have significance in other conditions as well.

Cancer Berberine and another alkaloid found in berberinecontaining plants, berbamine, have been shown to exert beneficial effects as adjuncts in cancer therapy. In fact, berbamine has been used in China since 1972 in the treatment of depressed white blood cell (WBC) counts due to chemotherapy and radiation. In one study, 405 patients with WBC counts less than 4000 were given 150 mg of berbamine daily (50 mg orally three times daily) for 1 to 4 weeks. Berbamine was viewed as “significantly effective” if WBC increased to greater than 4000 after 1 week or increased to greater than 1000 after 2 weeks; ”effective” if WBC increased to greater than 4000 after 2 weeks or increased greater than 1000 after 4 weeks; and “ineffective” if there was no change in WBC after 4 weeks of treatment. The overall results for the 405 patients are as follows: Sigruficantly effective in 163 cases (40.2%) Effective in 125 cases (38.8%) Ineffective in 117 cases (29%) The total effective rate was 71%. However, WBC before therapy was related to overall effectiveness. The effective rate was only 54.8%in 31 cases where WBC was

Pharmacology of Natural Medicines

less than 1000 and 82.7% in cases where WBC count was between 3100 and 3800.45

Congestive Heart Failure Berberine-containing plants may exert beneficial effects in chronic congestive heart failure (CHF). In one doubleblind study, 156 patients with CHF and more than 90 ventricular premature complexes (VPCs) or nonsustained ventricular tachycardia (VT), or both, on 24-hour Holter monitoring were randomly divided into two groups. All patients were given conventional therapy for CHF, consisting of angiotensin-converting enzyme inhibitors, digoxin, diuretics, and nitrates. Patients were given berberine 1.2 to 2 g/day or a placebo. Symptoms, a 6-minute walk test, left ventricular ejection fraction (LVEF), frequency and complexity of VPCs, and quality of life were assessed after 8 weeks of treatment and during a mean 24month follow-up. After treatment with berberine, there was a sigruficantly greater increase in LVEF, exercise capacity, improvement of the dyspnea-fatigue index, and a decrease of frequency and complexity of VPCs compared with the control group. There was also a si@cant decrease in mortality in the berberine-treated patients during long-term follow-up (7 patients receiving treatment died vs. 13 on placebo). There were no apparent side effects in the berberine group. Researchers concluded that berberine improved quality of life and decreased VPCs and mortality in patients with cHF.46

DOSAGE As no detailed clinical studies have differentiated which berberine-containing herb to use for specific conditions, the following is offered only as a guideline based on experimental studies and historical use. In general, the plants can be viewed as interchangeable. H . canadensis:

Infective, congestive, and inflammatory states of the mucous membranes Digestive disorders Gastritis Peptic ulcers Colitis Anorexia Painful menstruation Berberis vulgaris: The treatment of gallbladder disease including gallstones and as a less expensive form of berberine in the treatment of the conditions listed earlier for hydrastis. Berberis aquifoliurn: Best used in the treatment of chronic skin diseases and in the conditions listed earlier for hydrastis.

Coptis chinensis: Can be used in the treatment of infective, congestive, and inflammatory states of the mucous membranes, fever, and infectious disorders of the skin. The dosage should be based on berberine content. As there is a wide range of quality in goldenseal preparations, standardized extracts are recommended. In one study of 20 products purchased at local pharmacies or health food stores, 17 were labeled as containing goldenseal root and 3 contained goldenseal herb as the sole active herbal ingredient." The berberine concentration varied from 0.82% to 5.86%, while the hydrastine concentration ranged from 0 to 2.93%. Only 10 of 17 products met proposed U.S. Pharmacopeia (USP)standards for the hydrastine and berberine content of goldenseal root. Five products contained little or no hydrastine, unusual berberine-to-hydrastine ratios, and additional peaks not observed with other products. Dosages three times a day are as follows: Dried root or infusion (tea): 2 to 4 g Tincture (1:5):6 to 12 ml(1.5 to 3 tsp) Fluid extract (1:l):2 to 4 ml(0.5 to 1tsp) Solid (powdered dry) extract (4:l or 8%to 12% alkaloid content): 250 to 500 mg

TOXICITY Berberine and berberine-containing plants are generally nontoxic at the recommended dosages. However, berberine-containing plants are not recommended for use during pregnancy and higher dosages may interfere with B vitamin metabolism. Berberine is excreted via hepatobiliary mechanism^.^^ The oral median lethal dose in rats for berberine is greater than 1000 mg/kg body weight, indicating that the toxicity is extremely 10w.4~

DRUG INTERACTIONS Berberine-containing plants may interfere with the absorption of tetracycline and related antibiotics. In one double-blind study, giving subjects 100 mg of berberine at the same time as 500 mg of tetracycline four times daily led to a reduction in the efficacy of tetracycline in subjects with cholera.32 However, another double-blind study showed no interaction.34Nonetheless, simultaneous use is not recommended until this issue is clarified. Berberine-containing plants may enhance the effects of oral hypoglycemic drugs.

1.Duke JA. Handbook of medicinal herbs. Boca Raton, n:CRC Press, 1985:78,238-289,287-288. 2. Leung AY. Encyclopediaof common natural ingredients used in food, drugs, and cosmetics. New York John Wdey, 1980:52-53,189-190. 3. Chang HM, But PPH. Pharmacology and applications of Chinese materia medica, vol2. Teaneck, NJ: World Scientific, 19871029-1040. 4. Hahn FE, Ciak J. Berberine. Antibiotics 1976;3:577-588. 5. Amin AH, Subbaiah TV, Abbasi KM. Berberinesulfate.Antimicrobial activity, bioassay, and mode of action. Can J Microbiol 1969;15: 1067-1076. 6. Johnson CC, J o h n G, Poe CF. Toxicity of alkaloids to certain bacteria. II. Berberine, physostigmine, and sanguinarine. Acta Pharmacol Toxic01 1952;8:71-78. 7. Kaneda Y, Toni M, Tanaka T. In vitro effects of berberine sulphate on the growth and structure of Entamoeba histolytica, Giurdia lamblia and Tricomonas vaginalis. Ann Trop Med Parasitol1991;85:417-425. 8. Subbaiah TV, Amin AH. Effect of berberine sulfate on Enfamoeba histolytica. Nature 1967;215:527-528. 9. Ghosh AK, Rakshit MM, Ghosh DK. Effect of berberine chloride on Leishmania donovani. Indian J Med Res 1983;78:407416. 10. Majahan VM, Sharma A, Rattan A. Antimycotic activity of berberine sulphate: an alkaloid from an Indian medicinal herb. Sabouraudia 1982;20:79-81. 11. Kim SH, Shin DS,Oh MN, et al. Inhibition of the bacterial surface protein anchoring transpeptidase sortase by isoquinoline alkaloids. Biosci Biotechnol Biochem 2004;68:421-424. 12. Freile ML, Giannini F, Pucci G, et al. Antimicrobial activity of aqueous extracts and of berberine isolated from Berberis heterophylla. Fitoterapia 2003;74702-705. 13. Hwang BY, Roberts SK, Chadwick LR, et al. Antimicrobial constituents from goldenseal (the Rhizomes of Hydrustis canadensis) against selected oral pathogens. Planta Med 2003;69:623-627. 14. Sun D, Courtney HS,Beachey EH. Berberine sulfate blocks adherence of Streptococcus pyogenes to epithelial cells, fibronectin, and hexadecane. Antimicrob Agents Chemother 1988;321370-1374. 15.Sabir M, Bhide NK. Study of some pharmacological actions of berberine. Indian J Physiol PharmacoI1971;15111-132. 16.Kumazawa Y, Itagaki A, Fukumoto M, e t al. Activation of peritoneal macrophages by berberine-type alkaloids in terms of induction of cytostatic activity. Int J Immunopharmacol 1984;6: 587-592. 17. Sabir M, Akhter MH, Bhide NK.Further studies on pharmacology of berberine. Indian J Physiol Pharmacol 1978;22:9-23. 18. Zhang RX, Dougherty DV, Rosenblum ML. Laboratory studies of berberine used alone and in combination with 1,3-bis(2-chloroethyl)1-nitrosourea to treat malignant brain tumors. Chin Med J 1990; 103658-665. 19. Corder0 CP, Gomez-Gonzalez S, Leon-Acosta CJ, et al. Cytotoxic activity of five compounds isolated from Colombian plants. Fitoterapia 2004;75225-227. 20. Jantova S, Cipak L, Cemakova M, et al. Effect of berberine on proliferation, cell cycle and apoptosis in HeLa and L1210 cells. J Pharm Pharmacol2003;551143-1149. 21. Yokozawa T, Ishida A, Kashiwada Y, et al. Coptidis Rhizoma: protective effects against peroxynitrite-induced oxidative damage and elucidation of its active components. J Pharm Pharmacol 2004; 56547-556. 22. Cemakova M, Kost’alova D, Kettmann V, et al. Potential antimutagenic activity of berberine, a constituent of Muhoniu aquifolium. BMC Complement Altem Med 2002;19;2:2. 23. Nishino H, Kitagawa K, Fujiki H, Iwashima A. Berberine sulfate inhibits tumor-promoting activity of teleocidin in two-stage carCinogenesis on mouse skin. Oncology 1986;43:131-134.

24. Leng SH, Lu FE, Xu LJ. Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion. Acta Pharmacol Sin 2004;25:496-502. 25. Pan GY, Huang ZJ,Wang GJ, et al. The antihyperglycemic activity of berberine arises from a decrease of glucose absorption. Planta Med 2003;69:632-636. 26. Gupte S. Use of berberine in the treatment of giardiasis. Am J Dis Child 1975;129:866. 27. Bhakat MP, Nandi N, Pal HK,et al. Therapeutic trial of berberine sulphate in non-specific gastroenteritis. Indian Med J 1974;68:19-23. 28. Kamat SA. Clinical trial with berberine hydrochloride for the control of diarrhoea in acute gastroenteritis. J Assoc Physicians India 1967;15:525-529. 29. Desai AB, Shah KM, Shah DM. Berberine in the treatment of diarrhoea. Ind Pediatr 1971;8:462-465. 30. Sharma R, Joshi CK, Goyal RK. Berberine tannate in acute diarrhoea. Ind Pediatr 1970;7496-501. 31. Sack RB, Froehlich JL. Berberine inhibits intestinal secretory response of Vibrio cholerae toxins and Escherichia coli enterotoxins. Infect Immun 1982;35:471-475. 32. Choudry VP, Sabir M, Bhide VN. Berberine in giardiasis. Indian Pediatr 1972;9:143-146. 33. Kamat SA. Clinical trial with berberine hydrochloride for the control of diarrhoea in acute gastroenteritis. J Assoc Physicians India 1967;15525-529. 34. Khin-Maung-U, Myo-Khin, Nyunt-Nyunt-Wai, et al. Clinical trial of berberine in acute watery diarrhoea. Br Med J 1985;291:1601-1605. 35. Gupte S. Use of berberine in treatment of giardiasis. Am J Dis Child 1975;129:866. 36. Rabbani GH, Butler T, Knight J, et al. Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichiu coli and Vibrio cholerae. J Infect Dis 1987;155:979-984. 37. Akhter MH, Sabir M, Bhide NK. Possible mechanism of antidiarrhoeal effect of berberine. Indian J Med Res 1979;70233-241. 38. Tai YH, Feser p, Memane WG, et al. Antisecretory effects of berberine in rat ileum. Am J Physiol1981;241:G253-G258. 39. Swabb EA, Tai YH, Jordan L. Reversal of cholera toxin-induced secretion in rat ileum by luminal berberine. Am J Physiol1981;241: G2484252. 40. Babbar OP, Chhatwal VK,Ray IB, et al. Effect of berberine chloride eye drops on clinically positive trachoma patients. Indian J Med Res 1982;76:83-88. 41.Mohan M, Pant CR, Angra SK, Mahajan VM. Berberine in trachoma. Indian J Ophthalmol1982;3069-75. 42. Preiniiger V. The pharmacology and toxicology of the papaveraceae alkaloids. Alkaloids 1975;15:207-251. 43. Chan MY. The effect of berberine on bilirubin excretion in the rat. Comp Med East West 1977;5:161-168. 44.Watanabe A, Obata T, Nagashima H. Berberine therapy of hypertyraminemia in patients with liver cirrhosis. Acta Med Okayama 1982;36:277-281. 45. Liu CX, Xiao PG,Liu GS. Studies on plant resources,pharmacology and clinical treatment with berbamine. Phytother Res 1991;5:228-230. 46. Zeng XH, Zeng XJ, Li YY. Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol2003,92:173-176. 47. Edwards DJ, Draper EJ. Variations in alkaloid content of herbal products containing goldenseal. J Am Pharm Assoc (Wash) 2003;43:419-423. 48. Tsai PL, Tsai TH. Hepatobiliary excretion of berberine. Drug Metab Dispos 2004;32405-412. 49.Kowalewski Z, Mrizikiewicz A, Bobkiewicz T, et al. Toxicity of berberine sulfate. Acta Pol Pharm 1975;32113-120.

5 -Hydroxytryptophan

CHAPTER CONTENTS Introduction 1021 Tryptophan and 5-Hydroxytryptophan Metabolism 1021 Pharmacology 1022 5-Hydroxytryptophanversus L-Tryptophan

1022

Clinical Applications 1022 Depression 1023 L-Tyrosine: An Adjunct to 5-Hydroxytryptophan 1026 Anxiety and Panic Disorder 1026

INTRODUCTION 5-Hydroxytryptophan( 5 - H " ) (Figure 101-1) is the intermediate between tryptophan and serotonin. Although the use of 5-HlT may be relatively new to most clinicians, it has been available through pharmacies for several years and has been intensely researched for the past three decades. It has been used clinically since the 1970s.

TRYPTOPHAN AND 5HYDROXYTRYPTOPHAN METABOLISM Once tryptophan is absorbed from the intestines, it is carried by the blood to the liver, along with other amino acids consumed during the meal. Ingested tryptophan can pass into the general circulation, metabolize into blood proteins, or convert to kynurenine (which then goes on to form nicotinic acid, picolinate, and other important metabolites) in the liver. After conversion to kynurenine, it cannot be converted to serotonin. The same is likely true if the tryptophan is incorporated into blood proteins. Unchanged tryptophan can be converted to 5-HTP and then to serotonin. However, if this conversion OCCUTS outside the brain, brain chemistry will not be influenced. Even under the best-case scenario, only 3% of a dosage of L-tryptophan in supplemental or dietary form is likely to be converted to serotonin in the brain.'

Weight Loss 1027 insomnia 1029 Migraine and Tension Headache 1029 Juvenile Headache 1030 Fibromyaigia 1030 Parkinson's Disease 1031 Seizure Disorders 1032 Dosage 1032 Toxicology

1032

Drug Interactions 1033

The manufacture of serotonin from tryptophan within the brain is highly dependent on the level of tryptophan or 5-HTP that crosses the blood-brain barrier. While 5-HTP easily crosses the blood-brain barrier, the delivery of tryptophan into the brain depends on several factors. The first factor of importance is the level of free tryptophan in the blood. In a number of situations the liver's conversion of tryptophan to kynurenine occurs at an elevated rate (i.e., stress, elevated cortisol levels, low B-vitamin status, and high dosages of L-tryptophan [>2000 mg]). All of these situations lead to increased activity of tryptophan oxidase and kynurenine formamidase, which convert tryptophan to kynurenine. Elevated levels of kynurenine block the entry of tryptophan into the brain and lower brain serotonin levels. Increasing tryptophan intake makes matters worse when tryptophan oxidase activity is increased. Unlike 5-HTP, which easily enters the brain, the transport of tryptophan across the blood-brain barrier involves the binding of tryptophan to a transport molecule. As tryptophan shares this transport vehicle with several other amino acids, when the ratio of tryptophan to these other amino acids is low, little tryptophan is transported into the brain. The protein in almost all foods contains relatively small amounts of tryptophan and larger proportions of other amino acids. This generally leads to low serotonin levels with

1021

0

H Figure 101-1 5-Hydroxytryptophan.

a high-protein intake. The opposite occurs with a highcarbohydrate meal.

PHARMACOLOGY Several pharmacokinetic studies have shown that about 70% of a dosage of 543" taken orally is delivered to the bloodstream.z--' The remaining 30% is metabolized by intestinal cells. Ample evidence from these pharmacokinetic studies, as well as the clinical studies, indicates that once absorbed, 5-HTl' is delivered to the brain, resulting in increased formation of not only serotoninbut also other brain chemicals (e.g., the monoamines melatonin, endorphins, dopamine, and norepinephrine). By raising brain serotonin levels, as well as by other effects, 5-HTP has shown positive effects in the various conditions associated with low serotonin levels. Besides raising serotonin and melatonin levels, 5-HTP has been shown to raise beta-endorphin levels. Many pain-relieving and mood-elevating benefits of 5-HTP may be related more to its ability to enhance endorphin levels than to its ability to increase serotonin levels. This endorphin-increasingaction is useful for both migraine and tension headache, fibromyalgia, and other painful situations. In addition, raising endorphin levels produces sigxuficant effects on mood and behavior. By raising serotonin, melatonin, and beta-endorphin levels, 5-HTP has a sigruficant impact on helping to regulate and improve brain chemistry. 5-HTP has also been shown to raise the levels of other important neurotransmitters such as dopamine and norepinephrine.4The ability of 5-HTP to increase both serotonin (and other indolamines) and catecholaminesis quite sigruficantand unique to 5-HTP. It is an effect that 5-HTP does not share with L-tryptophan.The effective treatment of depression requires more than simply raising serotonin levels; catecholamine levels must also be increased. 5 - H " provides the brain with both sets of tools.

5-Hydroxytryptophan versus L-Tryptophan Nutrition-oriented physicians have long used precursor therapy for affecting brain chemistry. Unfortunately, L-tryptophan has produced inconsistent results. These inconsistent results are likely due to its inconsistent elevation of brain serotonin level.

In a head-to-head comparison study of 5-HTP and L-tryptophan in the treatment of depression, 5-HTP proved superior? The proposed reason is the fact that 5-HTP easily crosses the blood-brain barrier and is not affected by competing amino acids and 5-HTP affects brain chemistry in a broader and more positive fashion. L-Tryptophan is often effective in cases of low serotonin, especially insomnia, but 5 H T P is more broadly effective. There are many advantagesof 5HTP over L-tryptophan. Chief among them are that 5-HTP easily crosses the blood-brain barrier and is one step further on the path to serotonin synthesis. The conversion of tryptophan to 5-HTP by tryptophan hydrolase is the most important step in the manufacture of serotonin. This enzyme is inhibited by a number of factors including the following: Stress Vitamin B6 insufficiency Low magnesium levels Insensitivity to insulin Various hormones Genetic factors

In addition, as noted earlier, these same factors and others are known to increase the activity of tryptophan oxygenase, increasing the conversion of L-tryptophan to kynurenine. Perhaps the biggest advantage of 5-HTP over L-tryptophan is that it is safer. Although L-tryptophan is safe if properly prepared and free of the contaminants linked to eosinophilia myalgia syndrome (EMS), 5 - H " is inherently safer. The reasons are that taking L-tryptophan to produce positive effects in the treatment of depression, insomnia, and other low serotonin conditions requires a relatively high dosage (e.g., a minimum of 2000 mg in insomnia and 6000 mg in depression). At high dosages such as these, L-tryptophan is potentially problematic, as more L-tryptophanwill be shunted toward the kynurenine pathway and L-tryptophan promotes oxidative damage. Excessive levels of dietary tryptophan or high dosages of L-tryptophan result in tryptophan actually acting as a free radical? By contrast, 5-HTP is an anti~xidant.~ This antioxidant difference is due to the additional molecule of oxygen and hydrogen in 5-HTP. This simple change in molecular structure allows the phenolic ring structure to effectively accept or quench the unpaired electron of a free radical.

CLINICAL APPLICATIONS A massive amount of evidence suggests that low serotonin levels are a common consequence of modern living. The lifestyle and dietary practices of many people living in this stress-filled era result in lowered levels of serotonin within the brain. As a result, many people are overweight, crave sugar and other carbohydrates, experience bouts of depression, get frequent headaches,

5-H ydroxytryptophan

and have vague muscle aches and pain. All of these maladies are correctable by raising brain serotonin levels. The primary therapeutic applications for 5-HTP are low serotonin states, as listed in Box 101-1.

Depression Some of the first clinical studies on 5-HTP for the treatment of depression began in the early 1970s in Japan. The first study involved 107 patients with either unipolar depression or manic bipolar depression! These patients received 5-HTP at dosages ranging from 50 to 300 mg/day. The researchers observed a quick response (within2 weeks) in more thanhalf of the patients. Seventyfour of the patients either experienced complete relief or

Depression Anxiety Obsessive compulsive disorder Obesity Carbohydrate craving Bulimia Insomnia Narcolepsy Sleep apnea Migraine headaches Tension headaches Chronic daily headaches Premenstrual syndrome Fibromyalgia Epilepsy Myoclonus Chronic pain disorders

were sigruficantlyimproved, and none experienced significant side effects. These promising results were repeated in several other Japanese studies. An interesting aspect in two of these studies was the fact that 5-HTP was shown to be effective in some patients (50%in one study, 35%in another) who had not responded positively to any other antidepressant agent?Jo The most detailed of the Japanese studies was conducted in 1978." The study enrolled 59 patients with depression: 30 male and 29 female. The groups were mixed in that both unipolar and bipolar depressions were included, along with a number of other subcategories of depression. The severity of the depression in most cases was moderate to severe. Patients received 5-HTP in dosages of 50 or 100 mg three times daily for at least 3 weeks. The antidepressant activity and clinical effectiveness of 5-HTP was determined by using a rating scale developed by the Clinical Psychopharmacology Research Group in Japan. The improvements among the various patients are detailed in Table 101-1.These results indicate that 5-HTP was helpful in 14 out of 17 patients with unipolar depression and 12 out of 21 patients with bipolar depression. The degree of improvement in most cases ranged from excellent to very good. The results achieved in this open study are quite good, given how rapidly they were achieved. Thirty-two of the 40 patients who responded to 5-HTP did so within the first 2 weeks of therapy. Typically, in most studies with antidepressant drugs, the benefits are not apparent until after 2 weeks to 1month of use. For this reason, the length of study when assessing antidepressant drugs should be at least 6 weeks because it may take that long to sigruficantlyaffect brain chemistry in a positive manner.

Improvement in various subtypes of depression 1 + 2 + 3/total+

Subtype First-episode depression

1

2

3

4

5, 6, 7

8

1

1

0

1

0

0

2/13

Unipolar depression

3

8

3

1

2

0

14/17

Bipolar depression

6

4

2

3

3

3

12/21

Mixed depression Presenile or senile depression Neurotic depression

0 3

1 2

0

1

0

0

112

0

3

1

0

519

0

1

2

1

0

0

314

Reactive depression

0

1

1

0

0

0

2IZ

Schizophrenic depression

0 -

1 -

TOTAL

13

19

% of total

22

32.2

0 -

8 13.6

0 10 16.9

0 6

0 -

3

40159

10.2

5.1

67.8

'Improvement: 1, marked improvement; 2, moderately improved; 3, slightly improved; 4, unchanged: 5, 6, 7, felt worse; 8, dropped out. T h e number of subjects that improved (improvement scores 1, 2, or 3) compared with the total number of subjects in that subtype.

111 -

Pharmacology of Natural Medicines

In contrast, many of the studies with 5-HTP were shorter than 6 weeks because statistically significant results were achieved so soon (Table 101-2).However, the longer 5H" is used, the better the results. Some people may need to be on 5-HTP for at least 2 months before they experience benefits. The only major side effect noted in this study was mild nausea. The Occurrence of nausea due to 5-HTP is actually less frequent than that experienced with other antidepressant drugs (roughly 10% of subjects taking 5-HTP at a daily dosage 1300 mg experience nausea compared with about 23% taking Prozac) and about the same as that which occurs with a placebo. In double-blind studies, about 10% or so of people taking the placebo typically complain of nausea. Nonetheless, mild nausea may be a natural consequence of elevated serotonin levels with 5HTP. About 30% of the 5-HTP taken orally is converted to serotonin in the intestinal tract. This can lead to a mild case of nausea. Fortunately, this effect wears off after a few weeks of use. A 5-HTP dosage of 150 to 300 mg daily is sufficient in most cases. For example, in one study it was shown that 13 out of 18 subjects with depression given 5-HTP at a level of 150 or 300 mg/day experienced good to excellent results.12 This percentage of responders is quite good, but if the level of serotonin in the blood is viewed as a rough indicator of brain serotonin levels, some interesting conclusions can be made (Table 101-3). In some cases a higher dosage may be necessary. The measurements in Table 101-3suggest that serotonin levels in depressed individuals are considerably lower

Improvement group Day 1 Day 2 Day 3 Days 4-7 Days 8-14 1

3

2

5

2

0 0 -

1

13

1

4

2 8

1 7

Marked Moderate Slight TOTAL

1

2 6

2 17

Day 15

0 0 1 1

Level of serotonin in blood (ng/ml): controls, responders,and nonresponders Before Normal subjects

than those found in normal subjects and that individuals who respond to 5-HTP show a rise in serotonin to levels consistent with normal subjects. The level of serotonin in those who do not respond to 5-HTP remained quite low. These results imply that nonresponders may require higher dosages to raise serotonin levels or that additional support may be necessary. When prescribing higher doses, it is important that the 5-HTP be taken in divided dosages not only to reduce the problem with nausea but also because the rate of brain cell uptake of 5-HTP is limited. The first studies of 5-HTP in a double-blind format (the Japanese studies) were open trials.I3 The antidepressive effects of 5-HTP were also compared with L-tryptophan in the early 1 9 7 0 ~In . ~one study, 45 subjects with depression were given L-tryptophan (5 g/day), 5-HTP (200 mg/day), or a placebo. The patients were matched in clinical features (e.g., age, sex) and severity of depression. The main outcome measure was a rating scale called the Hamilton Depression Scale (HDS), the most widely used assessment tool in clinical research on depression. The HDS score is determined by having the test subject complete a series of questions in which he or she rates the severity of symptoms on a numerical basis, as follows: 0-not present 1-present but mild 2-moderate 3-severe 4-very severe Symptoms assessed by the HDS include depression, feelings of guilt, insomnia, gastrointestinal symptoms and other bodily symptoms of depression (e.g., headaches, muscle aches, heart palpitations), and anxiety. The HDS is popular in research because it provides a good assessment of the overall symptoms of depression. Table 101-4 shows the results of the study. A review of head-to-head comparison studies showed that 5-HTP, at a dosage of 200 mg/day, produced therapeutic success on a par with tricyclic antidepressant drugs.I4Research has also shown that combining 5-HTP with clomipramine and other types of antidepressant drugs produces better results than any of the compound

HDS from a comparative study of 5-HTP, L-tryptophan,and placebo

After 1 wk (150 or 300 rndday 5-HTP)

150

Beginning of the study

Responders

78

148

Nonresponders

56

77

End of the study (30 days)

5-HTP

L-Tryptophan

Placebo

26

25

23

9

15

19

HDS, Hamilton Depression Scale; 5-HTF: 5-hydroxytryptophan.

5Hydroxytryptophan

5-HTP versus fluvoxamine in percentage changes in the HDS

for depression 5-HTP + MA0

MA0 + placebo

Initial measurement

28.67

26.33

After 8 days

16.67

19.23

After 15 days

11.77

6.03

Modified from Alino JJ, Gutierrez JL, lglesias ML. Int Pharmacopsychiatry 1976; 11s-15. B-HTFI 5-Hydroxytryptophan; MAO, monoamine oxidase.

given a l ~ n e . ' ~For -~~ example, in one study, 5-HTP combined with a monoamine oxidase (MAO) inhibitor demonstrated significant advantages compared with the MA0 inhibitor alone (Table 101-5).19 This line of research suggests that 5-HTP might also be used in conjunction with St. John's wort extract and Ginkgo bilobu extract, two herbal medicines with proven antidepressant activity. Because 5-HTP was expensive in 1972, researchers developed a test to determine who was most likely to respond to it, so that it would not be wasted on people who were unlikely to r e ~ p o n d . ' ~ , The ~ ' - ~test involved the patients first having a spinal tap to measure the level of 5-hydroxyindoleacetic acid (5-HIAA, the breakdown product of serotonin) in the cerebrospinal fluid (CSF). The drug probenecid, which prevents the transport of 5-HIAA from the CSF to the bloodstream, was given for the next 3 days. As a result of this blocking action, the amount of serotonin produced over a 4-day period could be calculated by a repeat spinal tap on day 4. Since the 5-HIAA could not leave the CSF, it accumulated and provided a measure of serotonin manufacture. The researchers discovered that the average level of 5-HIAA after 3 days of probenecid was sigruficantly lower in depressed individuals than in controls matched for age, sex, and weight. This low level of serotonin reflected a decreased rate of manufacture within the brain. 5-HTP was most effective in patients with a low 5-HIAA response to 3 days of probenecid.21-23In other words, 5-HTP is most effective as an antidepressant when the amount of serotonin manufactured in the brain is reduced. As stated earlier, 5-HTP often produces good results in patients who are unresponsive to antidepressant drugs. One of the more impressive studies involved 99 patients described as suffering from "therapy-resistant" depression." These patients had not responded to any previous therapy including all available antidepressant drugs and electroconvulsive therapy. These therapyresistant patients received 5-Hm at dosages averaging 200 mg/day but ranging from 50 to 600mg/day. Complete recovery was seen in 43 of the 99 patients, and sigruficant improvement was noted in 8 more. Such sigruficant

Decrease in HDS

5-HTP ( n = 34)

Fluvoxamine (n = 29)

After 2 wk

Mean decrease ("10) decrease ~35% 35%-50% decrease 50%-75% decrease

23 20 10 4

18.9 19 8 2

After 4 wk

Mean decrease (Yo) ~35% decrease 35%-50% decrease 50%-75% decrease >75% decrease

46.2 2 7 12 3

46.1 8 3 13 5

After 6 wk

Mean decrease ("h) <35% decrease 35%-50% decrease 50%-75% decrease >75% decrease

60.7 4 8 12 10

56.1 5 3 8 13

HDS, Hamilton Depression Scale; BHTR 5-hydroxytryptophan.

improvement in patients suffering from long-standing, unresponsive depression is quite impressive, prompting the author of another study to state the following? L-~-HTPmerits a place in the front ranks of antidepressants instead of being used as a last resort. I have never in 20 years used an agent that (1) was effective so quickly; (2) restored patients so completely to the persons they had been and their partners had known; and (3) was so entirely without side effects. A 1987 review article on 5-HTP in depression highlighted the need for welldesigned, double-blind, head-tohead studies of 5-H" versus standard antidepressant Although 5-H" was viewed as an antidepressant agent with few side effects, the authors of this review felt that the big question to answer was how 5-H" compared with the new breed of antidepressant drugs, the selective serotonin reuptake inhibitors(SSRk) like Prozac, Paxil,and Zoloft. In 1991 a doubleblind study comparing 5-HTP with an SSRI was conducted in Swit~erland.~~ 5-H" was compared in the study with the SSRI fluvoxamine (Luvox). Fluvoxamine is used primarily in the United States as a treatment for obsessive compulsive disorder (OCD), an anxiety disorder characterized by obsessions and compulsions affecting an estimated 5 million Americans. Fluvoxamine exerts antidepressant activity comparable to (if not better than) other SSRk like Prozac, Zoloft, and Paxil. In the study, subjects received either 5-HTP (100 mg) or fluvoxamine (50 mg) three times daily for 6 weeks. The assessment methods used to judge effectiveness included the HSD, self-assessment depression scale (SADS), and physician's assessment (Clinical Global Impression). As indicated in Table 101-6, the percentage decrease in depression was slightly better in the 5-HTP group

Pharmacology of Natural Medicines

(60.7% vs. 56.1%). 5-HTP was quicker acting than the fluvoxamine, and a higher percentage of patients responded to 5-HTP than to fluvoxamine. The advantages of 5-HTP over fluvoxamine are evident when looking at the subcategories of the HDS depressed mood, anxiety, physical symptoms, and insomnia. For depressed mood, 5-HTF’ produced a 65.7% reduction in severity compared with 61.8% for fluvoxamine; for anxiety, 54%” produced a 58.2% reduction in severity compared with 48.3%for fluvoxamine; for physical symptoms, 5-HTP produced a 47.6%decrease in severity compared with 37.8% for fluvoxamine; and for insomnia, 5-HTJ? produced a 61.7%decrease in severity compared with a 55.9% decrease for fluvoxamine. However, perhaps more important than simply relieving insomnia is 5-H”’s ability to improve the quality of sleep. By contrast, antidepressant drugs greatly disrupt sleep processes. On the SADS, 5-HTP produced a 53.3%drop in SADS values compared with a drop of 47.6% for the fluvoxamine group. A drop greater than 50% is an excellent result. In fact, a 50%drop is the best SSRIs generally produce. 5-HTP is equal to or better than standard antidepressant drugs, and the side effects are much less severe (Table 101-7). In the study comparing 5-HTP with fluvoxamine, this is how the physicians described the differences among the two groups: Whereas the two treatment groups did not differ signhcantly in the number of patients sustaining adverse events, the interaction between the degree of severity and the type of medication

I

5-HTP versus antidepressant drugs: comparison of side effects

Percentage of Patients Experiencing Side Effects Side effects

5-HTP

Tricvclics

SSRls

Nausea

9

15

23

Headache

5

16

20

Nervousness

2.5

11

16

Insomnia

2.5

7

17

Anxiety

2.5

Drowsiness Diarrhea

7

9

14 11

2.5

23 4

Tremor

0

18

11

Dry mouth

7

64.5

12

Sweating

2.5

15

9

Dizziness

5

25.5

7

Constipation

5

25

Vision changes

0

14.5

5.5 4

12

BHTF: 5-Hydroxytryptophan; SSFlls, selective serotonin reuptake inhibitors.

was highly significant: fluvoxamine predominantly produced moderate to severe side effects; oxitriptan (5-HTP) produced primarily mild forms of adverse effects. Fourteen (38.9%) of the patients receiving 5-HTP reported side effects compared with 18 patients (54.5%) in the fluvoxamine group. The most common side effects with 5-HTP were nausea, heartburn, and gastrointestinal problems (flatulence, feelings of fullness, and rumbling sensations). These side effects were rated as being very mild to mild. In contrast, most of the side effects experienced in the fluvoxamine group were of moderate to severe intensity. The only subject to drop out of the 5-Hm group did so after 35 days (5 weeks), while four subjects in the fluvoxamine group dropped out after only 2 weeks. On the basis of studies on weight loss, the longer that 5-H” is used (e.g., after 4 to 6 weeks of use), the less the problem with mild nausea. 5-HTP has been shown to have “equipotency” with SSRIs and tricyclic antidepressants in terms of effectiveness but offers several advantages in that it is better tolerated and associated with fewer and much milder side effects. In addition, many people prefer to use a natural substance like 5-HTP over synthetic drugs.

L-Tyrosine: An Adjunct to 5-Hydroxytryptophan In the early 1970s, researchers discovered that, in about 20%of patients who responded well to 5-HTP, the results tended to decrease after 1 month of treatment. The antidepressant effects of 5-HTP in these subjects began to wear off gradually after the first month despite the fact that the level of 5-HlT in the blood, and presumably the level of serotonin in the brain, remained at the same level as when they were experiencing benefits? The researchers discovered that although serotonin levels appeared to stay at the same levels after 1month of treatment, the levels of the other important monoamine neurotransmitters, dopamine and norepinephrine, declinedF8As discussed earlier, when depressed patients are treated with 5-HTP, they experience a rise not only in serotonin but also in catecholamines like dopamine and norepinephrine. In about 20% of subjects, the catecholamine-enhancingeffects of 5-HTP tended to wear off. Providing these patients with L-tyrosine, the amino acid precursor to the catecholamines, helped to reestablish the efficacy of 5-HTP.6,28 The dosage was 200 mg/day for 5 - H ” and 100 mg/kg body weight for L-tyrosine. This dosage for L-tyrosine is quite high and would require substantial clinical supervision.

Anxiety and Panic Disorder 5-HTP has shown an ability to relieve anxiety in studies in depressed individuals. It may also be helpful in relieving panic attacks. Lowering the availability of serotonin to the

5-H ydroxytryptophan brain by tryptophan depletion increases the vulnerability of panic disorder patients for an experimental carbon dioxide panic challenge, and increasing the availability of serotonin inhibits the response to such a challenge. When 5-HTP or placebo was given to 24 panic disorder patients and 24 healthy volunteers before panic challenge, 5-HTP significantly reduced the reaction to the panic challenge in panic disorder patients regarding subjective anxiety, panic symptom score, and number of panic attacks, as opposed to placebo.29These results indicate that 5-HTP may be helpful in relieving panic attacks.

Weight Loss A considerable body of scientific evidence documents the major role serotonin in the brain plays in influencing eating behavior. A key finding is that when animals and humans are fed tryptophan-free diets, appetite is sigruficantly increased, resulting in binge eating4arbohydrates would be preferable, but in fact the animals binge on whatever is available.I.2 A diet low in tryptophan leads to low brain serotonin levels; as a result, the brain senses it is starving and stimulates the appetite control centers in a powerful way. This stimulation results in a preference for carbohydrates. Researchers discovered that when animals or humans are fed a carbohydrate meal, more tryptophan is delivered to the brain, resulting in more serotonin being manufactured. This scenario has led to the idea that low serotonin levels lead to "carbohydrate craving" and play a major role in the development of obesity, as well as bulimia.30 Cravings for carbohydratescan be mild or quite severe. They may range in severity from the desire to nibble one piece of bread or cookie to uncontrollable binging. At the upper end of the spectrum of carbohydrate addiction is bulimia, a potentially serious eating disorder characterized by binge eating and purging of the food through forced vomiting or the use of laxatives. The serotonin theory of bulimia is that low serotonin levels trigger the binge eating, which leads to a rush of serotonin being produced and released in the brain.31J2 This increased serotonin effect produces a brief reduction in feelings of stress and tension. This serotonin "fix" is short-lived and followed by feelings of @t and low self-esteem. The current medical treatment for bulimia is the use of drugs that enhance the effects of serotonin. Although there are no reports in the medical literature of 5-HTP being used in the treatment of bulimia, given its effects on serotonin levels, it merits consideration. 5-HTP may help to prevent the decline in serotonin levels associated with a reduced calorie intake. Concentrations of tryptophan in the blood stream and subsequentbrain serotonin levels plummet with dieting.% In response to severe drops in serotonin levels, the brain puts out a strong message to eat. This situation sets up the scenario to explain why most diets do not work.

As far back as 1975, researchers demonstrated that giving 5-HTP to rats who were genetically bred to overeat and be obese resulted in sigruficant reduction in food intake.34It tums out that these rats bred to be fat have decreased activity of the enzyme that converts tryptophan to 5 - H " and subsequently to serotonin. There is circumstantialevidence that many humans are genetically predisposed to obesity. This predisposition may involve the same mechanism as rats genetically predisposed to obesity. By providing preformed 5-HlT, this genetic defect is bypassed and more serotonin is manufactured. The early animal studies with 5-HTP as a weightloss aid have been followed by a series of three human clinical studies. The first study involved 19 significantly overweight female subjects with a body mass index ranging from 30 to 40.% Analysis of the pretreatment dietary intake concluded that these women tended to overeat carbohydrates. Food intake and eating behavior were assessed using a 3-day diet diary at the beginning and end of the two treatment periods. AU food was carefully weighed before meals and weighed again if there were any leftovers. Participants also filled out a self-evaluation of appetite and satiety twice weekly, and mood was evaluated using standard psychologic tests. The daily dosage of 5-HTP used in the study was 8 mg/kg body weight. Patients were given either the 5-I-I"or a placebo 20 minutes before meals for 5 weeks, and after a 1-week interval were switched to receive the other treatment. No dietary restrictions were prescribed because the researchers wanted to answer the question, "Does 5-HTP reduce appetite and promote weight loss without any conscious effort?" To make sure that the women actually took the 5-HTP, researchers measured the level of the serotoninbreakdown product, 5-hydroxy3-indole acetic acid (5-HIAA), in the urine. Table 101-8 lists the results of the study. These results with 5-Hm were achieved without the women making any conscious effort to reduce food consumption. The average amount of weight loss during the 5-week period of 5-H" supplementation was a little more than 3 lb, compared with less than 1 lb of total weight loss during the placebo period.

Food intake (caloriedday)

Protein intake (g/day)

Carbohydrate intake @/day)

2903 2327

101

274

Placebo

85

223

5-HTP

1819

79

176

Pretreatment

5-HTe 5-Hydroxytryptophan.

Pharmacology of Natural Medicines

Interestingly, evaluation of the various self-tests indicated that appetite or degree of initial hunger did not differ between the two groups. What differed was satiety. In other words, the 5-HTP did not reduce the appetite before a meal, but after consuming an adequate amount of food, the satiety centers in the brain were stimulated and the women did not feel hungry. As a result, their caloric intake was dramatically reduced. The level of 5-HIAA, the breakdown product of serotonin, in the group receiving the 5-HTP increased by more than 50-fold over the control group. This increase provided two things: (1)It assured researchers that subjects actually took the 5-HTP, and (2) it clearly indicated that 5-HTP increased serotonin manufacture. The next study sought to determine if 5-HTP helped overweight individuals adhere to dietary recommendations.%Fourteen overweight female subjects with a body mass index between 30 and 40 were enrolled in the double-blind study.*Again, analysis of the pretreatment dietary intake concluded that these women tended to overeat. The women were randomly assigned to receive either 5-HTP (300 mg) or placebo 30 minutes before meals. The 12-week study was divided into two 6-week periods. For the first 6 weeks there were no dietary recommendations, and for the second 6 weeks the women were placed on a 1200-caloriediet. The women were seen every 2 weeks to evaluate body weight, diet diaries, self-evaluations of appetite, and satiety. The women were also asked if they experienced the presence of meat aversion; taste or smell alterations; early satiety; and nausea or vomiting, or both. To verify patient compliance, urinary measurement of 5-HIAA was again determined. As shown in Table 101-9, the women taking the placebo lost 2.28 lb, while the women taking the 5-HTP lost 10.34 lb. Like the previous study, 5-HTP appeared to promote weight loss by promoting satiety. Although some women reported some aversion to meat or altered taste and smell, each woman (lOOo/~)reported early satiety (Table 101-10). Most of the women receiving 5-HTP also experienced mild nausea during the first 6 weeks of the

Impact of 5-HTP on weight loss Placebo

5-HTP

Weight (lb) Baseline

207.68

229.46

After 6 wk

206.58

225.94

After 12 wk Total Weight Loss (Ib) After 6 wk

205.4

219.12

After 12 wk 5-HTF: 5-Hydroxytryptophan.

1.1

3.52

2.28

10.34

5-HTP

Placebo

Wk 1-6

Wk7-12

Wkl-6

Wk7-12

Taste alteration

2l7

ID

Off

Smell alteration

2l7

ll7

Off

Meat aversion

317

ll7

OR

Early satiety

717

6ff

Nausea

5/7

Off

2l7 ll7

Ol7 Ol7 Ol7 2l7 2l7

5 - M R 5-Hydroxytryptophan

trial, but during the last 6 weeks none complained of nausea. The fact that weight loss is accelerated during the second 6-week period makes it highly unlikely that 5-HTP promotes weight loss as a result of producing nausea. One study with 5-HTP enrolled overweight women with a body mass index ranging between 30 and 40 and an overactive appetite.37The 28 subjects of the study were given either 5-HTP (300 mg three times daily before meals) or a placebo. For the first 6 weeks there were no dietary restrictions, and for the second 6 weeks the women were placed on a diet of 1200 calories/day. Carbohydrates contributed to 53% of the calories, fats comprised 29%, and proteins provided 18%. No carbohydrate-rich foods were permitted between meals. Subjects were examined every 2 weeks to evaluate food intake and body weight. Routine blood measurements were also performed at the beginning, at 6 weeks, and at the end of the study. To venfy patient compliance, urinary measurement of 5-HIAA was determined. The results from this study were even more impressive than the previous studies for several reasons. The group receiving the 5-HTP lost an average of 4.39 lb after the first 6 weeks and an average of 11.63lb after 12weeks. In comparison, the placebo group lost an average of only 0.62 lb after the first 6 weeks and 1.87 lb after 12 weeks. The lack of weight loss during the second 6-week period in the placebo group obviously reflects the fact that the women had difficulty adhering to the diet. Early satiety was reported by 100% of the subjects during the first 6-week period. During the second 6-week period, even with severe caloric restriction, 90% of the women taking 5-HTP reported early satiety. Once again, many of the women receiving the 5-HTP reported mild nausea during the first 6 weeks of therapy. However, the symptom was never severe enough for any of the women to drop out of the study. No other side effects were reported. On the basis of the urinary measurements of 5-HIAA, the women took their 300 mg of 5-HTP with meals and, as a result, achieved weight loss. The amount of weight loss was amplified by a better capability to adhere to

5-H ydroxytryptophan a 1200-calorie diet. The structure of the dietary changes reflected primarily a reduction in pasta, bread, and other carbohydrate-rich foods (the study was conducted in Rome). In the latest study, 25 overweight non-insulin dependent diabetic outpatients were enrolled in a double-blind, placebo-controlled study and randomized to receive either 5-HTP (750 mg/day) or placebo for 2 consecutive weeks, during which no dietary restriction was preResults again indicated that patients receiving 5-HTP sigruficantly decreased their daily energy intake, by reducing carbohydrate and fat intake, and reduced their body weight.

Insomnia Several clinical studies have shown 5-HTP to produce good results in promoting and maintaining sleep in normal subjects, as well as in those experiencing i n ~ o m n i a ? ~One ~ , of ~ ~the , ~key benefits with 5-HTp in the treatment of insomnia is its ability to increase sleep quality. This effect is evident by its ability to increase REM sleep (typically by about 25%) while simultaneously increasing deep sleep stages 3 and 4 without increasing total sleep time.37,40 The sleep stages that are reduced by 5-HTP to compensate for the increases are non-REM stages 1 and 2, the least important stages of sleep. In one of the studies, the subjects receiving 200 mg of 5-HTP increased their amount of REM sleep by 15.5 minutes during the five-night study.37 Subjects taking 600 mg of 5-HTP increased REM sleep time by an average of 20 minutes for the five-night study. These results indicate that 5-HTP increases the amount of dream time by about 3 to 4 minutes a night. Although there was a clear dose-related effect, the lower dosage is sufficientin most cases. In addition, taking too much 5-HTP may increase REM sleep to an abnormal level, lead to an increased risk for nightmares, and cause mild nausea.

Migraine and Tension Headache The relationship of serotonin and headaches is fully described in Chapter 191. Because migraine sufferers have low levels of serotonin in their tissues, some researchers refer to migraine as a ”low serotonin syndrome.”44 Although the primary benefit of 5-HTP in the prevention of both migraine and tension headache is related to its ability to normalize underlying imbalances in the serotonin system, it also influences the endorphin system in a positive way. Several clinical studies on using 5-HTP for headaches, both vascular and nonvascular, have shown excellent results. In particular, the use of 5-HTP in the prevention of migraine headache offers considerable advantages over drug therapy. Although a number of drugs have been shown to be useful in the prevention of migraine headaches, all of them carry significant side effects.

The problem with drug therapy in the prevention of migraine headaches is perhaps best exemplified by one of the most commonly used drugs, methysergide (Sansert). Methysergide therapy for the prevention of migraine attacks is effective in about 60% to 80% of cases. However, this effectiveness is not without a high price, as side effects are quite common and can be severe. Retroperitoneal fibrosis, pleuropulmonary fibrosis, and fibrotic thickening of cardiac valves may occur in patients receiving long-term methysergide maleate therapy. Therefore this preparation must be reserved for prophylaxis in patients whose vascular headaches are frequent or severe and uncontrollable and for those who are under close medical supervision. Several studies have compared 5-HTP with methysergide in the prevention of migraine headaches. In one of the largest double-blind studies, 124 patients received either 5-HTP (600 mg daily) or methysergide (3 mg daily) in identically looking pills for 6 m0nths.4~Treatment was determined to be successful if there was a reduction higher than 50% in the frequency of attacks or in the number of severe attacks. Although 75% (30 of the remaining 40 patients) taking methysergide demonstrated significant improvement compared with 71% (32 of the 45 patients), this difference was not viewed as being statistically significant (Table 101-11). The advantage of 5-HTP over methysergide was demonstrated when researchers looked at side effects. Side effects were more frequent in the group receiving methysergide than in the 5-HTP group. In fact, five patients in the methysergide group had to withdraw during the trial because of side effects. Two other studies comparing 5-HTP with drugs used in the prevention of migraine headaches (pizotifen and propranolol) demonstrated that 5-HTP compared quite favorably in terms of effectivene~s.~,~~ Although these drugs have sigruficant side effects, 5-HTP is extremely well tolerated even at dosages as high as 600 mg/day. One of the other key differences noted in these studies between 5-HTP and the drugs was 5-HTP’s ability to improve mood and relieve feelings of depression. In a doubleblind study of 5-HTP in chronic tension headache, 78 patients with chronic tension-type headaches

5-HTP versus methysergide:clinical effects of treatment in 124 Patients Methysergide

No attacks (100% reduction) Improvement (>50% reduction) No improvement Withdrawal due to side effects 5-HTF:5-Hydroxytryptophan.

5-HTP

35%

25%

40% 12.5%

46%

12.5%

0%

29%

achieved without side effects. Not a single child reported a side effect while taking 5-HTP. Interestingly, for some reason, children rarely experience even mild nausea from 5-HTP. The possible benefits of using 5-Hm in children with recurrent headaches or sleep disorders, or both, is far-reaching. Evaluation of the 48 children in the trial demonstrated inadequate school progress compared with their classmates. The children were shown to be of normal intellectual capacity but demonstrated inattentiveness similar to that observed in depression. Many of the Juvenile Headache children may have been suffering from depression. The unwillingness of the nine subjects in Group C to switch One of the best uses of 5-HTP is in chronic headaches in to the other unknown medication (which was, in fact, children. These headaches are a big problem because of the placebo) is a strong indicator that these children and the tremendous risk for side effects of the current drugs their parents noted some rather dramatic improvements used to treat, as well as prevent, them. Several studies beyond simply a reduction in headaches or improved of 5-HTP in the treatment of chronic headaches in children and adolescents have shown excellent r e ~ u l t s . 4 ~ - ~sleep. ~ The manner in which 5-HTP may be of benefit in Given the risks of current drugs used in chronic childmigraine headaches may not simply be the overcoming hood headaches, a trial of 5-HTP for 2 months certainly seems reasonable. If the headaches are also accompanied of some defect in serotonin synthesis. As noted previously, part of the clinical benefit of 5-HTP may be via an by sleep disorders, 5HTP appears to be especially well ability to increase the levels of beta-endorphin. A decrease suited. in beta-endorphin level in migraine, as-well as tension In one study, 48 elementary and junior high students headache sufferers, has been demonstrated by several suffering from recurrent headaches (at least one headache investigators.5253 every 2 weeks) and sleep disorders including difficulty A clinical trial measured the effects of 5-HTP on seroin getting to sleep, frequent awakenings, sleep walking, tonin and beta-endorphin levels in 20 juvenile patients nightmares, and bedwetting were divided into two suffering from migraine or tension-type headaches.% groups." Group A was given 5-HTP for 2 months, folPatients were monitored and evaluated for frequency lowed by a placebo for 2 months, while group B received and intensity of headache attacks for 3 months before just the opposite. It was necessary to divide group A into 5-HTP treatment and 3 months of therapy. The researchers a nine-patient subgroup, Group C. These nine patients reported a statistically significant reduction in the did so well on the 5-HTP that they did not want to switch headache score with 5-HTP treatment in both migraine over to the other medication, even though they had no and tension-type sufferers. These improvements were idea whether they were, in fact, taking 5-HTP or were on likely due to increased beta-endorphin levels, as noted in a placebo. The dosage of 5-HTP was based on the child's Table 101-12. However, the level of beta-endorphin weight: 4.5 mg/kg/day. achieved with 5-HTP, especially as measured in the The headache index was reduced by about 70% when the kids were taking 5-HTP compared with an 11.5% white blood cell, was still far less than that observed in control patients not suffering from recurrent headache. drop when they were taking the placebo. In the nine These results imply that longer periods of 5-HTP supplepatients in group C, there was an 81.8% decrease in the mentation may be required before there is a normalization headache index after the second month. Interestingly, of beta-endorphin levels in children prone to headaches. these same patients only exhibited an 18.2% reduction These results may indicate that 5-HTP alone is not after the first month. These results indicate that evalable to raise beta-endorphin levels sufficiently to reduce uation of the benefits of 5-HTP in the treatment of or eliminate headaches, suggesting that other therapies headaches requires at least a 2-month trial. The failure designed to increase beta-endorphin levels should be to show benefit with 5-HTP in some studies in used along with 5-HTP. Examples of other therapies headaches may be due to the fact that they lasted less that have been shown to raise beta-endorphin levels are than 2 months. The 25 patients experienced a modest exercise, acupuncture, and biofeedback. reduction in frequent awakenings, nightmares, sleep walking, and talking while asleep and no change in Fibromyalgia difficulty falling asleep or in bedwetting. The history of the development of 5-HTP as an effective Overall, this study demonstrated very good effects in treatment for fibromyalgia began with studies on the these children. Perhaps the most impressive aspect to drug f e n ~ l o n i n e This . ~ ~ drug blocks the enzyme that consider, however, was the fact that these benefits were were treated with 5-HTP (300 mg/day) or placebo for 8 weeks.@In comparison with the group treated with placebo, there was no statistically significant change in the number of days with headache or in headache intensity in the group treated with 5-H"; however, there was a significant decrease in the consumption of analgesics. During the 2 weeks after treatment, there was also a significant decrease in the number of days with headache. Subjective opinion during this latter period was also favorable to 5-HTP.

5-H ydroxytryptophan Patients’and physicians’opinions on the effectiveness of 5-HTP versus placebo in fibromyalgia ResDonse Serotonin (serum, PdL) Migraine (13 Subjects) Before After Tension-Type (7 Subjects) Before After Total (20 Subjects) Before After Controls (17 subjects)

Betaendorphin (plasma, pmoVL)

Beta-endorphin (white blood cells, pmoll 1O6 GB/L)

104.6

16.2

110.5

115.7

19.4

120.3

90.7

14.5

142.3

97.2

17.6

152.4

100.5

15.7

129.3

108.3

18.4

140.4

96

21.3

359.3

5-HTe 5-Hydroxytryptophan.

inhibits the conversion of tryptophan to 5-HTP and, as a result, blocks serotonin production. During the late 1960s and early 1970s, it was thought that increased serotonin formation may promote migraine headaches (the opposite of what was later proved, i.e., increasing serotonin levels reduce migraine headache occurrence). The researchers discovered that providing headache sufferers with fenclonine resulted in severe muscle pain. This effect was the exact opposite of what was expected but led to some important advances in the understanding of fibromyalgia-a way to induce its severe symptoms of (as well as symptoms nearly identical to) EMS, the condition caused by contaminated L-tryptophan. The researchers also discovered that migraine sufferers had a greater reaction to the drug than nonheadache sufferers. In fact, in most normal subjects fenclonine produced no fibromyalgia. These Occurrences highlight just how sensitive migraine sufferers are to low serotonin levels. Migraine headaches and fibromyalgia share a common feature: Both are low serotonin syndromes.56After more than 25 years of research, one of the lead researchers stated: ”In our experience, as well as in that of other pain specialists, 5-HTP can largely improve the painful picture of primary fibr~myalgia.”~~ A double-blind study in 50 patients with fibromyalgia found that 100 mg of 5-HTP three times per day As shown significantly improved their in Table 101-13, 5-HTP was rated substantially better than placebo by subjects and evaluating physicians. Improvements were noted in all symptom categories: number of painful areas, morning stiffness,sleep patterns, anxiety, and fatigue. In another study, 100 mg of

Good

5-HTP

Placebo

11

Fair

8

Poor

4

None

0

5-HTP taken three times daily demonstrated maximum results by day 30 of the 90-day trial.59 One of the primary benefits with 5-HTP in fibromyalgia may be its ability to improve sleep quality. A key finding in patients with fibromyalgia is a reduced REM sleep and an increase in non-REM sleep.60In addition, the deeper levels (stages III and IV)are not achieved for long enough periods. As a result, people with fibromyalgia wake up feeling fatigued and in pain. The severity of the pain of fibromyalgia correlates with the rating of sleep quality. For example, a study of 50 women with fibromyalgia syndrome recorded their sleep quality, pain intensity, and attention to pain for 30 days, using palm-top computers programmed as electronic interviewers.6l They described their previous night’s sleep quality within 30 minutes of awakening each day and at randomly selected times in the morning, afternoon, and evening rated their present pain. The researchers found that a night of poor sleep was followed by a significantly more painful day, and a more painful day was followed by a night of even poorer sleep. 5-HTP may help to break the cycle by addressing the low serotonin level, as well as by promoting a restful sleep.

Parkinson’s Disease The use of 5-HTP in Parkinson’s disease provides some benefit, but only if used in combination with the drug Sinemet (the combination of L-dopa with the decarboxylase inhibitor carbidopa). Although brain levels of serotonin are decreased in Parkinson’s disease, the reduction in dopamine receptors is more severe. Increasing serotonin levels with 5-H” in patients not taking Sinemet are associated with worsening of symptoms, especially rigidity.62 One of the key benefits of taking 5-HTP in Parkinson’s disease is that it can help to counteract the negative effects that the L-dopa in the Sinemet has on sleep and mood.In addition, 5-HTP has also been shown to improve the physical symptoms of Parkinson’s disease. About 9 out of 10 people with Parkinson’s disease suffer from depression. The degree of depression in Parkinson’s disease is a reflection of their serotonin levels. The lower the level of serotonin, the more severe is

Pharmacology of Natural Medicines

DOSAGE

Patient no. 1

L-dopa (mg/day) 1000

Carbidopa (mdday) 175

5-HTP (mg/day) 125

HDS Before After 11 22

2

300

75

75

14

3

3

400

150

100

21

13

4

1000

100

100

12

6 22

5

500

125

500

18

6

1125

112.5

300

18

7

7

500

50

100

17

13

HDS, Hamilton Depression Scale.

The dosage should be started at 50 mg three times/day. If the response is inadequate after 2 weeks, increase the dosage to 100 mg three times/day. This recommendation will greatly reduce the mild symptoms of nausea often experienced during the first few weeks of 5-HTP therapy. Because 5-HTP does not rely on the same transport vehicle as L-tryptophan, it can also be taken with food. Enteric-coated preparations are preferred. For insomnia, the general recommendation is 100 to 300 mg, 30 to 45 minutes before retiring. Start with the lower dosage for at least 3 days before increasing dosage.

TOXICOLOGY their depression. One study examined the effect of 5-HTP in seven Parkinson’s disease patients, all of whom were on Sinemet.@The initial dosage of 5-HTP was 75 mg, which was increased by 25 mg every 3 days until the patients reported a relief of their depression, or up to a maximum of 500 mg/day for 4 months. The impressive results obtained in these patients are shown in Table 101-14. Six out of seven patients responded to 5-HTP. Note that the dosages of 5-HTP in these five out of the six patients who responded ranged from only 75 to 125 mg. The only patient who did not respond took 500 mg of 5-HTP.

Seizure Disorders Most of the recent research on 5-HTP has focused on its use in the treatment of several seizure disorders.67o 5-HTP has shown good results in most (but not all) studies in patients suffering from diseases characterized by myoclonus, with the exception of epilepsy, which is not helped by 5-HTP. The best response to 5-HTP for myoclonus occurs in people who have intention myoclonus, which is most often produced as a result of ischemic damage to the brain.33 Intention myoclonus can be a problem after a stroke or heart attack, overdosage of a drug such as heroin, a severe asthma attack, or an adverse reaction to anesthesia or another chemical. Improvements in intention myoclonus with 5-HTP have been demonstrated in patients. 5-Hmhas also produced good results in patients with progressive myodonus epilepsy, essential myoclonus, palatal myoclonus, and Friedreich ataxia.’I In a 1983article, one researcher of 5-HTP stated: ”Some helpless bedridden patients dramatically improved to the extent that they could walk again and resume independent living.”RBecause of the phenomenal results, 5-HTP was the first compound to be evaluated as an orphan drug by the Pharmaceutical Manufacturing Associations Commission on Drugs for Rare Diseases.

The major concern with 5-HTP is a possible link to L-tryptophan and EMS. However, an important distinction must be made in the manufacturing process. While L-tryptophan is produced via bacterial fermentation and filtration, 5-HTP is commercially available through an extraction process from the seed of Grifonia simplicifolia, an African plant. 5-HTP extracted from thisnatural source avoids the contamination problem associated with past manufacturing of L-tryptophan. Detailed analyses of all evidence by the Centers for Disease Control and Prevention (CDC) and other experts have led to the conclusion that the cause of the EMS epidemic could be traced to a single Japanese manufacturer, Showa D e n k ~ .Of ~ the , ~ ~six Japanese companies that supplied L-tryptophan to the United States, Showa Denko was the largest (50% to 60% of all the L-tryptophan). The L-tryptophan was used not only as a nutritional supplement but also in infant formulas and nutrient mixtures for intravenous feeding. A single case report linked 5-H” to a condition similar to EMS in 1980.75However, this case involved the use of high dosages of 5-Hm (1400 mg) over a 20-month period. Further examination of the patient indicated a defect in tryptophan metabolism that resulted in elevations in kynurenine. Such defects in tryptophan metabolism are common in patients with scleroderma, which shares many common features with EMS. It appeared that either the 5-HTP may have contained a contaminant to which this man was sensitive or that taking such high dosages of 5-HTP over a prolonged period of time aggravated his abnormal handling of L-tryptophan. There has also been a report of a 28-year-old woman, her husband, and her two sons, 33 and 13 months old, developing an EMS-like illness in response to contaminated 5-HTP? The young boys had inherited the inability to convert tryptophan to 5-Hm.As a result, they required daily administration of 5-HTP (5 to 7 mg/kg). Both boys had been receiving the 5-HTP almost from birth.

5-H ydroxytryptop han

who received only uncontaminated L-tryptophan or 5-hydroxtryptophan (5-HTP).”78 Furthermore, researchers at the NIH studying the effects of uncontaminated 5-HTP on various metabolic conditions have not observed a single case of EMS, nor has a case of elevated eosinophils been attributed to 5-HTP in these studies.76 In short, there has never been a report of uncontaminated 5-HTP causing EMS. Although there has never been a single person developing EMS from 5-HTP products proven to be free from the contaminants, long-term continual use of 5-HTP should be monitored by regular (every 6 months) eosinophil determination. For any person suffering from scleroderma due to the problem with tryptophan metabolism noted in these patients, an eosinophil determination after the first month of 5-HTP use is indicated, especially if dosages are greater than 500 mg/day In addition is the following advice:

The mother was not taking 5-HTp, but she was preparing it for the young boys by opening the capsules, mixing the powder in juice or water, and giving it to them orally with a syringe. She never took the 5-HTP; she only touched it with her hands as she emptied the capsules. When the second boy was about 9 months old, the mother began experiencing symptoms of EMS. After consulting a physician in July of 1991, it was noted that her eosinophil count was well over 30%. She continued to worsen and was hospitalized in August of 1991 with a tentative diagnosis of EMS. At this time she was referred to the National Institutes of Health (NIH) for further evaluation. Because of the possible link between the mother‘s symptoms and the 5-HTP, the boys and the father were also evaluated. The older boy had an eosinophil count of 9% (normal is 1%to 4%), and the younger boy had a count of 6%. The father had no abnormalities. The 5-HTP that the boys were using was analyzed by High Pressure Liquid Chromatography and found to contain an impurity not found in the 5-HTP that the NIH was using in its studies for ataxia and myoclonus. Switching the boys to the contaminant-free 5-HTP brought about normalization of eosinophil counts. The mother’s case is interesting because she was the most severely affected and she was only coming into contact with the contaminated 5-HTP through her skin. In 1998 researchers at the Mayo Clinic identified trace levels of a compound termed “peak X as the key contaminant using a sensitive laboratory technique.n As a result, manufacturers of 5-HTP now screen for the presence of this compound to ensure that all of the 5-HTP on the marketplace is free from peak X as outlined in current FDA methodology. There have been no reports of a single person developing EMS from 5-HTP despite its popularity. Nonetheless, to be on the safe side, some experts recommend that long-term continual use of 5-HTP be monitored by regular (every 6 months) eosinophil determination. Evidence that uncontaminated 5-HTP does not cause EMS is also provided by researchers who have been using 5-HTP for more than 25 years. They state that: ”EMS has never appeared in the patients of ours

Because 5-HTP is the direct precursor to serotonin, it shouId not be used by individuals taking antidepressant drugs without close medical supervision. Although 5-HTP has been used safely in combination with prescription antidepressant drugs in clinical studies, taking this combination could result in too much serotonin in the body The result is a condition known as the “serotonin syndrome,” characterized by confusion, fever, shivering, sweating, diarrhea, and muscle spasms. 5-HTP may antagonize the effects of drugs used in migraine headaches like methysergide and cyproheptadine, which block serotonin effects. The drug carbidopa greatly enhances the half-life and produces an apparent clearance at least 14 times smaller, as well as a 15.4 times greater area under the curve, compared with 5-HTP100 mg given without carbidopa.79

1. Filippini GA, Costa CVL, Bertazzo A, eds. Recent advances in tryptophan research, tryptophan and serotoninpathways. Exp Biol Med 1996;398:1-762. 2. MagnussenIE,Nielsen-Kudsk F. Bioavailability and related pharmacokinetics in man of orally administered L-5-hydroxytryptophan in steady state. Ada Pharmacol Toxicol (Copenh) 1980;46:257-262. Van Woert MH. Plasma accumu3. Magnussen I, JensenTS,Rand JH, lation of metabolism of orally administered single dose L-5hydroxytryptophan in man. Ada Pharmacol Toxicol 1981;49184-189.

4. van Praag HM, Lemus C. Monoamine precursors in the treatment of psychiatric disorders. In Wurtman RJ, Wurtman JJ, eds. Nutrition and the brain, vol7. New York Raven Press, 1986:89-139. 5.van Praag HM. Studies on the mechanism of action of serotonin precursors in depression. Psychopharmacol Bull 1984;20 599-602. 6.Aviram M, Cogan U, Mokady S. Excessive dietary tryptophan enhances plasma lipid peroxidation in rats. Atherosclerosis 1991;88: 29-43.

Do not use 5-HTP during pregnancy or lactation. Do not use 5-HTP in Parkinson disease unless the patient is on Sinemet. Do not use 5-HTP in patients with scleroderma.

DRUG INTERACTIONS

7. Simic MG, al-Sheikhly M, Jovanovic SV. Inhibition of f r e radical processes by antioxidants-tryptophan and 5-hydroxytryptophan. Bib1 Nutr Dieta 1989;43:28&289. 8. Sano I. [L5hydroxutrvptophan-(L-5-HTP)therapy]. Folia Psychiatr Neurol Japan 1972;267-17. 9. TakahashiS, Kondo H, Kato N. Effect of L-5-hydroxytryptophanon brain monoamine metabolism and evaluation of its clinical effect in depressed patients. J Psychiatr Res 1975;12177-187. 10. Fujiwara J, Otsuki S. Subtype of affective psychosis classified by response on amine precursors and monoamine metabolism. J Oral Pathol1973;2:93-100. 11. Nakajima T, Kudo Y, Kaneko Z. Clinical evaluation of 5-hydroxyL-tryptophan as an antidepressant drug. Folia Psychiatr Neurol Jpn 197832223-230. 12. Kaneko M, Kumashiro H, Takahashi Y, Hoshino Y. L-5-HTP treatment and serum 5-HTP level after L-5-HTP loading on depressed patients. Neuropsychobiology 19795232-240. 13. van Praag HM,Korf J, Dols LC, Schut T. A pilot study of the p d c tive value of the probenecid test in application of 5-hydroxytryptophan as antidepressant.Psychopharmacologia 1972;2514-21. 14. van Praag HM. Management of depression with serotonin precursors.Biol Psychiatry 1981;16291-310. 15. Robie TR, Flora A. Antidepressant chemotherapy, 1965. Rapid response to serotonin precursor potentiated by Ritalin. Psychosomatics 1965;6351-354. 16. Nardini M, De Stefan0 R, Iannuccelli M, et al. Treatment of depression with L-5-hydroxytryptophan combined with chlorimipramine, a double-blind study. Int J Clin Pharmacol Res 1983;3:239-250. 17. Rousseau JJ. Effects of a levo-5-hydroxytryptophan-dihydroergoaistine combination on depressionand neuropsychic performance. A double-blind placebocontrolled clinical trial in elderly patients. Clin Ther 1987;9:267-272. 18. Mendlewicz J, Youdim MB. Antidepressant potentiation of 5hydroxytryptophan by L-deprenil in affective illness. J Affect Disord 1980;2137-1%. 19. Alino JJ,Gutierrez E,Iglesias ML. 5-Hydroxytryptophan (5HTF') and a MA01 (nialamide)in the treatment of depressions. A doubleblind controlled study. Int Pharmacopsychiatry 1976;11:&15. 20. Angst J, Woggon B, Schoepf J. The treatment of depression with L-5hydroxytryptophan versus imipramine. Results of two open and one double-blind study. Arch Psychiatr Nervenkr 1977; 224175-186. 21. van Praag Hh4, Korf J. 5-Hydroxytrytophan as an antidepressant. The predictive value of the probenecid test. J Nerv Ment Dis 1974; 158331-337. 22. van Praag HM, Korf J. Serotonin metabolism in depression: clinical application of the probenecid test. Int Pharmacopsychiatry 1974;935-51. 23. van Praag HM. Central monoamine metabolism in depressions. 1. Serotonin and related compounds. Compr Psychiatry 1980;21: 30-43. 24. van Hiele JJ.L-5-hydroxytryptophan in depression. The first substitution therapy in psychiatry? Neuropsychobiology 1980;6: 230-240. 25. Kielholz P. Treatment for therapy-resistant depression. Psychopathology 1986;19:194200. 26.Byerley WF, Judd LL, Reimherr FW, Grosser BI. 5-Hydroxytryptophan. A review of its antidepressant efficacy and adverse effects. J Clin Psychopharmacol1987;7127-137. 27. Poldinger W, Calanchjni B, Schwarz W. A functional-dimensional approach to depression: serotonin deficiency as a target syndrome in a comparison of 5-hydroxytryptophan and fluvoxamine. Psychopathology 1991;24:53-81. 28. van Praag HMC. In search of the mode of action of antidepressants: 5-HTP/tyroSinemixtures in depression. Adv Biochem Psychopharmacol1984;39301-314.

29. Schruers K, van Diest R, Overbeek T, Griez E. Acute Ld-hydroxytryptophan administration inhibits carbon dioxide-induced panic in panic disorder patients. Psychiatry Res 2002;113237-243. 30.Wurtman RJ, Wurtman JJ. Brain serotonin, carbohydrate-craving, obesity and depression. Adv Exp Med Biol1996;398:35-41. 31. Weltzin TE, Fernstrom MH, Kaye WH. Serotonin and bulimia nervosa. Nutr Rev 199452399408. et al. Acute tryptophan 32. Weltzin TE, Femstrom MH, Femstrom JD, depletion and increased food intake and irritability in bulimia nervosa. Am J Psychiatry 1995;152:166&1671. 33. Goodwin GM, Cowen PJ, Fairbum CG, et al. Plasma concentrations of tryptophan and dieting. BMJ 1990;300:1499-1500. 34.Blundel JE, Leshem MB. The effect of 5-H" on food intake and on the anorexic action of amphetamine and fenfluramine. J Pharm Pharmacol 1975;2731-37. 35. Ceci F, Cangiano C, Cairella M, et al. The effects of oral 5-hydroxytryptophan administration on feeding behavior in obese adult female subjects. J Neural Transm 1989;76109-117. 36. Cangiano C, Ceci F, Cairella M, et al. Effects of 5-hydroxytryptophan on eating behavior and adherence to dietary prescriptions in obese adult subjects. Adv Exp Med Biol1991;294:591-593. 37. Cangiano C, Ceci F, Cascino A, et al. Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydr0xytryptophan.Am J Clin Nutr 1992;56863-867. 38. Cangiano C, Laviano A, Del Ben M, et al. Effects of oral 5-hydroxytryptophan on energy intake and macronutrient selection in noninsulin dependent diabetic patients. Int J Obes Relat Metab Disord 1998;22:648-654. 39. GuilleminaultC, Cathala HP,CastaigneP. Effects of 5-HTPon sleep of a patient with brain stem lesion. Electroencephalog Clin Neurophysiol1973;34:177-184. 40. Wyatt RJ, Zarcone J, Engelman K. Effects of 5hydroxytryptophan on the sleep of normal human subjects. Electroencephalogr Clin

Neurophysiol1971;30505-509. 41. Autret A, Minz M, Bussel B, et al. Human sleep and 5-HTF! Effects of repeated high doses and of association with benserazide. ElectroencephalogrClin Neurophysiol1976;41:408-413. 42. Zarcone VP Jr, Hoddes E. Effects of 5hydroxytryptophan on fragmentationof REM sleep in alcoholics. Am J Psychiatry 1975;1327476. 43. Soulairac A, Lambinet H. [Effect of 5-hydroxytryptophan, a serotonin precursor, on sleep disorders]. Ann Med Psycho1 (Paris) 1977;1:792-798. 44.Sicuteri F. Hypothesis: migraine, a central biochemical dysnociception. Headache 1976;16:145-149. 45. Titus F, Davalos A, Alom J, Codina A. IHydroxytryptophan versus methysergide in the prophylaxis of migraine. Randomized clinical trial. Eur Neurol1986;25327-329. %. Bono G, Criscuoli M, Martignoni E, et al. Serotonin precursors in migraine prophylaxis. Adv Neurol1982;33:357-363. 47. Maissen CP, Ludin HP. [Comparisonof the effect of 5-hydroxytryptophan and propranolol in the interval treatment of migraine]. Schweiz Med Wochenschr 1991;121:1585-1590. 48.Ribeiro CA. L-5-Hydroxytryptophan in the prophylaxis of chronic tension-type headache: a double-blind, randomized, placebocontrolled study. For the Portuguese Head Society. Headache 2000;40:451-456. 49. De Giorgis G, Miletto R, Iannuccelli M, et al. Headache in association with sleep disorders in children. A psychodiagnostic evaluation and controlled clinical study-L-5-HTP versus placebo. Drugs Exp Clin Res 1987;13:425-433. 50.Santucci M, Cortelli P, Rossi PG, et al. L-5-hydroxyhyptophan versus placebo in childhood migraine prophylaxis: a double-blind crossover study. Cephalgia 1986;6155-157. 51. Longo G, Rudoi I, Iannuccelli M. [Treatment of essential headache in developmental age with L-5-HTP (cross over double-blind study versus placebo)].Pediatr Med Chir 1984;6241-245.

5-H ydroxytryptop han 52.Fettes, Gawel M, Kuzniak S. Endorphin levels in headache syndromes. Headache 1985;25:37-39. 53. Leone M, Sacerdote P, DAmico, et al. Beta-endorphin levels are reduced in peripheral mononuclear cells of cluster headache patients. Cephalgia 1993;13:413-416. 54. Battistella PA, Bordin A, Cemetti R, et al. Beta-endorphin in plasma and monocytes in juvenile headache. Headache 1996;36:91-94. 55. Sicuteri F. The ingestion of serotonin precursors (L-5-hydroxytryptophan and L-tryptophan) improves migraine. Headache 1973;13 19-22. 56. Nicolodi M, Sicuteri F. Fibromyalgia and migraine, two faces of the same mechanism. Serotonin as the common clue for pathogenesis and therapy. Adv Exp Med Biol1996398373-379. 57. Nicolodi M, Sicuteri F. Eosinophilia myalgia syndrome. The role of contaminants, the role of serotonergic metabolism set up. Adv Exp Med Biol 1996;398351-357. 58. Caruso I, Sarzi PuttiniP, Cazzola M, Azzolini V. Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome. J Int Med Res 1990;18201-209. 59. Puttini PS, Caruso I. Primary fibromyalgia syndrome and 5-hydroxy-L-tryptophan: 90-day open study. J Int Med Res 1992;20: 182-189. 60. White KP, Harth M. An analytical review of 24 controlled clinical Pain 1996;64:211-219. trials for fibromyalgia syndrome (M). 61. Affleck G, Urrows S, Tennen H, et al. Sequential daily relations of sleep, pain intensity, and attention to pain among women with fibromyalgia. Pain 1996;68363-368. 62.Chase TN, Ng LK, Watanabe AM. Parkinson’s disease. Modification by 5hydroxytryptophan. Neurology 1972;22479-484. 63. Mayeux R, Stem Y, Sano M, et al. The relationship of serotonin to depression in Parkinson’s disease. Mov Disord 1988;3:237-244. 64.Bastard J, Truelle JL, Emile J. [Effectivenessof 5 hydroxytryptophan in Parkinson’s disease]. Nouv Presse Med 1976;5:1836-1837. 65. Sano VI,Taniguchi K. [L-5hydroxytryptophan (L-5-HTP) therapy of Parkinson’s disease]. Munch Med W d e n s c h r 1972;1141717-1719. 66. Pranzatelli MR, Tate E, Galvan I, Wheeler A. A controlled trial of 5-hydroxy-L-tryptophan for ataxia in progressive myoclonus epilepsy. Clin Neurol Neurosurg 1996;98161-164.

67.Trouillas P, Serratrice G, Laplane D, et al. Levorotatory form of 5-hydroxytryptophan in Friedreich‘s ataxia. Results of a doubleblind drug-placebo cooperative study. Arch Neurol 1995; 52:456-460. 68. Wessel K, Hermsdorfer J, Deger K, et al. Double-blind crossover study with levorotatory form of hydroxytryptophan in patients with degenerative cerebellar diseases. Arch Neurol1995;52451-455. 69. Pranzatelli MR, Tate E, Huang Y, et al. Neuropharmacology of progressive myoclonus epilepsy. Response to 5-hydroxy-L-tryptophan. Epilepsia 1995;36:783-791. 70. Trouillas P, Brudon F, Adeleine P. Improvement of cerebellar ataxia with levorotatory form of 5-hydroxytryptophan. Arch Neurol1988; 451217-1222. 71.Van Woert MH, Jutkowitz R, Rosenbaum D, Bowers MB Jr. Serotonin and myoclonus. Monogr Neural Sci 1976;3:71-80. 72. Van Wwrt MH. Myoclonus and L-5-hydroxytryptophan (L-5HlT). Prog Clin Biol Res 1983;12743-52. 73. Kilboume EM. Eosinophilia-myalgia syndrome: coming to grips with a new illness. Epidemiologic Rev 1992;1416-36. 74. Kilboume EM, Philen RM, Kamb ML. Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome. J Rheumatol Suppl1996;46:81-88. 75. Stemberg EM, Van Woert MH, Young SN, et al. Development of a scleroderma-like illness during therapy with Ld-hyrdoxytryptophan and carbidopa. N Engl J Med 1980;303:782-787. 76. Michelson D, Page SW, Casey R, et al. An eosinophilia-myalgia syndrome related disorder associated with exposure to L-5hydroxytryptophan. J Rheumatol1994;21:2261-2265. 77. Klarskov K, Johnson KL, Benson LM, et al. Eosinophilia-myalgia syndrome case-associated contaminants in commercially available 5-hydroxytryptophan. Adv Exp Med Biol1999;467461-468. 78. Nicolodi M, Sicuteri F. Eosinophilia myalgia syndrome. The role of contaminants, the role of serotonergic metabolism set up. Adv Exp Med Biol 1996;398:351-357. 79. Gijsman HJ, van Gerven JM, de Kam ML, et al. Placebo-controlled comparison of three dose-regimens of 5-hydroxytryptophan challenge test in healthy volunteers. J Clin Psychopharmacol2002;22: 183-189.

H-ypencum perforaturn (St. John's Wort) Michael T. Murray, ND Peter 3. Bongiorno, ND, Dip1 Ac CHAPTER C O N T E N T S General Description 1037 Chemical Composition 1037 History and Folk Use

1038

Pharmacology 1038 Antidepressant Activity 1039 Antiviral Activity 1040 Antibacterial Activity 1041 Pharmacokinetic Studies 1041 Clinical Applications 1041 Depression 1041 Seasonal Affective Disorder 1043

Hypericurn perforaturn (family: Hypericaceae) Common names: St. John's wort, Klamath weed, hypericum

GENERAL DESCRIPTION St. John's wort (Hypericum perfiraturn) is a shrubby perennial plant with numerous bright yellow flowers. It is commonly found in dry, gravelly soils, fields, and sunny places. St. John's wort is native to many parts of the world including Europe, Asia, and the United States. It grows especially well in northern California and southern Oregon.' The plant is glabrous throughout, green or sometimes glaucescent; the stems are erect, branched at the top and 30 to 100 cm long. The leaves are either (1)oval or elliptic; (2) oblong-ovate or rather narrow, oblong-linear, subotuse, and flat; or (3) more or less revolute-marginated with numerous pellucid and a few black granular dots. The yellow flowers are numerous, forming a broad, paniculate, almost corymbose inflorescence, 7 to 11cm long and 5 to 11 cm broad. The lanceolate bracts are 0.5 cm long and acute. The calyx is deeply parted, 5 mm long and about two to three times shorter than the corolla. The sepals are lanceolate or narrow lanceolate 4 to 5 mm

Insomnia 1043 Mental Function 1043 Acquired Immunodeficiency Syndrome and Other Viral Infections 1043 Topical Application 1044

Dosage 1044 Toxicity 1044 Photosensitivity 1045 Pregnancy and Nursing 1045 Drug Interactions 1045

long, 1 mm broad, as long as the ovary, acute or acuminate, sparingly furnished with black oval dots, with a smooth or sparsely toothed margin. The petals are oblong to oblong-elliptic, 1.2 to 1.5 cm long and 0.5 to 0.6 cm broad, with or without numerous black granular dots and lines on the margin in the upper part, while the surface is full of yellow glandular dots, thin lines, and stripes. The three-bundled stamens are numerous; the ovary is ovoid, 3 to 5 mm long. The seed is 1 rnm long, cylindric, brown, and minutely pitted longitudinally.' The whole plant is used medicinally. Harvesting time is generally July through August. The plant must be dried immediately to prevent degradation of active principles.'

CHEMICAL COMPOSITION The major compounds of interest have been hypericin (Figure 102-1) and pseudohypericin. These compounds are typically found in low concentrations, ranging from 0.0095% to 0.466%in the leaves and as much as 0.24% in the flowers.' More recently, researchers have been interested in the other chemical constituents (especially the various flavonoids and xanthones). The interest in these other components stems largely from pharmacologic studies 1037

Pharmacology of Natural Medicines OH

0

OH

Figure 102-1 Hypericin.

with commercially available extracts demonstrating effects and benefits beyond hypericin and pseudohypericin. For example, amentoflavone has been shown to bind to benzodiazepine receptors and act as a modulator of gamma-aminobutyncacid, which may be a major anxiolytic mechanism? The active components include*3: 0

Flavonoids (flowers l6%, leaves 12%, and whole herb 9%) Xanthones Phenolic carboxylic acids (caffeic, chlorogenic, ferulic, and gentisic acids) Essential oils (whole herb content 0.13%) Carotenoids Alkanes Phloroglucinol derivatives Phytosterols Medium-chain fatty acid alcohols

HISTORY AND FOLK USE St. John’s wort has a long history of folk use. Dioscorides, the foremost physician of ancient Greece, as well as Pliny and Hippocrates, used St. John’s wort in the treatment of many illnesses. Its Latin name, H.perforutum, is derived from Greek and means “over an apparition,” a reference to the belief that the herb was so obnoxious to evil spirits that a whiff of it would cause them to depart. The naming of St. John’s wort has its origins in folk traditions. One claims that red spots, symbolic of the blood of St. John, appeared on the leaves of the plant on the anniversary of the saint’s beheading. Another comes from a common medieval belief that if one slept with a piece of the plant under a pillow on St. John’s Eve, “the Saint would appear in a dream, give his blessing, and prevent one from dying during the following year.” Many people from the time of the ancient Greeks through the Middle Ages believed St. John’s wort to have magical powers. Recent research on St. John’s wort appears to offer some explanation of this ”magical” power. On the basis of a long history of use as a

mood-elevating substance and preliminary in vitro experiments and clinical studies, in 1984 the German Commission E permitted the medicinal use of St. John’s wort for depression, anxiety, or nervous excitement. The commission E evaluates efficacy of herbal medicines on the basis of a doctrine of reasonable certainty versus the U.S.Food and Drug Administration’s doctrine of absolute proof. Herbal products can be marketed with drug claims if they have been proven to be safe and effective. Whether the herbal product is available by prescription or over the counter is based on its application and safety of use. Herbal products sold in German pharmacies are reimbursed by insurance if they are prescribed by a physician. Because the German system allowed companies to market their products according to the guidelines of the Commission E, many companies achieved success with their products, allowing them to fund the necessary research to gain greater acceptance within mainstream conventional medicine. The case of St. John’s wort extract in the treatment of depression is a perfect case in point to illustrate how the Commission E monographs have fueled the science of botanical medicine. For example, originally it was thought that hypericin acted as an inhibitor of the enzyme monoamine oxidase (MAO), thereby resulting in the increase of central nervous system (CNS) monoamines such as serotonin and dopamine. However, newer information indicates that St. John‘s wort possesses no in vivo inhibition of MA0 (discussed later). Apparently the antidepressant activities are related more to modulating the relationship between the immune system and mood, as well as by inhibiting serotonin reuptake (discussed later). In addition, it appears that although hypericin is an important marker, other compounds such as flavonoids are thought to play a major role in the pharmacology of St. John’swort. More than 27 double-blind randomized trials involving more than 2200 patients with mild to moderately severe depression have shown St. John’s wort extracts standardized for hypericin to yield excellent results in the treatment in depression with far fewer side effects than standard antidepressant medications: For patients with preexisting conductive heart dysfunction or elderly patients, high-dose hypericum extract is safer with regard to cardiac function than tricyclic antidepressant~.~ It is no coincidence that St. John’s wort extracts became among the most widely used antidepressants in Germany with a market share of more than 25% in 1997.‘r7

PHARMACOLOGY St. John’s wort extracts (primarily of the flowering tops) have shown a wide variety of effects in experimental and

Hypericum perforatum (St. John’s Wort)

clinical studies. Some of the activities demonstrated include the f~llowing’,~: Antidepressant effects Antiviral effects Antibiotic effects Increased healing of wounds and burns

Antidepressant Activity Among the different biologic hypotheses for depression, the biogenic amine hypothesis is the most widely accepted. This hypothesis suggests that depression is the result of a deficiency in function of the biogenic amines (e.g., serotonin, catecholamines, dopamine). These neurotransmitters are stored in granules within neurons. After stimulation of the neurons, these neurotransmitters are released into the synaptic cleft via exocytosis. After binding to postsynaptic receptors, the neurotransmitters are either taken up again and restored in the vesicles or they are catabolized by the enzymes MA0 or catechol0-methyltransferase (COMT). Most antidepressant drugs increase the availability of these amines, particularly serotonin, by either inhibiting the reuptake or blocking MAO. As stated earlier, initial studies indicated that St. John’s wort extract’s antidepressant action was based on the ability of crude hypericin preparations to inhibit both types A and B r n O . 8 As ~ ~a result of this inhibition, there is an increase in the level of neurotransmitters within the brain that maintain normal mood and emotional stability including serotonin, catecholamines, and dopamine. These preliminary results identified hypericin as the supposed active constituent. However, later chemical analysis of these crude hypericin prepara tions identified a content of as much as 20% of other St. John’s wort constituents, with the flavonoids being the most imp0rtant.l In other words, it is unknown to what extent hypericin or the flavonoids individually contribute to any M A 0 inhibition. To better understand the influence of hypericin, hypericum total extract, and hypericum fractions on the activity of M A 0 and COMT, a study was conducted.1° An inhibition of M A 0 could be shown in the following concentrations: Hypericin to mol/L Hypericum total extract to 10-4mol/L One extract fraction up to mol/L A COMT inhibition could not be shown for hypericin, with hypericum extract to 10-4 mol/L and with two extract fractions also up to 1W mol/L. The MA0 inhibiting fraction contained hyperich, as well as flavonols, the COMT-inhibition fraction being mainly flavonols and xanthones. The key result from this study, as well as in another in vitro/ex vivo study, is the demonstration

that the concentrations of inhibition shown, particularly with regard to the inhibition of MA0 activity, are likely insufficient to explain the clinically proven antidepressive effect of St. John’s wort extract.lOJ1Therefore additional mechanisms are likely responsible for these clinical benefits. At least three other mechanisms have been proposed: modulation of interleukin-6 (IL-6) activity, inhibition of the reuptake of serotonin, and agonist action of sigma receptors. The modulating effect of St. John’s wort extract on IL-6 is the most interesting, as it proposes a mechanism by which St. John’s wort interacts with the link between the immune system and mood. The immune system and the nervous system share many common biochemical features and regulatory interactions. Regarding IL-6, this cytokine is heavily involved in the communication between cells within and outside the immune system. With regard to the nervous system, IL-6 is known to modulate hypothalamic-pituitary-end organ axes, especially the hypothalamic-pituitary-adrenal (HPA) axis. The hypothesis is that an elevation in IL-6 results in activation of the HPA axis, leading to elevations in corticotropin-releasing hormone (CRH) and other adrenal regulatory hormones-hallmark features in depression. St. John’s wort extract has shown an ability to reduce IL-6 levels, and hence this action may explain the clinical effectiveness of St. John’s wort extract.I2 Animal studies comparing the effects of hypericum in mice who produce normal IL-6 levels versus IL-6 knockout mice (those with no IL-6 expression), found higher levels of serotonin produced in the former group.13An in vitro study demonstrating reduction of IL-6 levels involved taking blood samples from five healthy volunteers and four depressive patients.12The release of IL-6, interleukin-1-beta (IL-1-p), and tumor necrosis factoralpha was measured quantitatively after an incubation time of 24 hours on microtiter plates. A massive suppression of the IL-6 release was found for PHA-stimulated St. John’s wort extract. If these effects can be duplicated in vivo, it would provide a mechanism by which St. John’s wort extract modulates CRH release and, subsequently, mood. St. John’s wort extract has also been shown to inhibit the reuptake of serotonin similar in fashion to drugs like fluoxetine (Prozac), paroxetine (Pad), and sertraline (Zoloft). The study demonstrating a 50% serotonin reuptake inhibition used the 0.3% hypericin content standardized extract at a concentration of 6.2 y g / d and did not attempt to identdy the active inhibitor^.'^ The authors of the study concluded that “the antidepressant activity of hypericum extract is due to inhibition of serotonin uptake by postsynaptic receptors.’’ Overall, though, results are conflicting with regard to the effect of acute doses of St. John’s wort extracts on the serotoninergic system in rodents.15 A marked increase of both

Pharmacology of Natural Medicines serotonin (5-I-IT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) was reported in rat brain cortex. Other researchers report high 5-HIAA and 5-I-IT levels in mouse hypothalamus and hippocampus but not in the cerebral cortex, where only 5-HIAA increased. However, other research found no significant changes in either 5-HT or 5-HIAA after a schedule of treatment during the forced swimming test. One study of the rat locus coeruleus did show that systemic hyperforin induced a lasting and marked (lOOo/o to 200%) increase in the extracellular concentrations of 5-HT, but not 5-HIAA.16 There is gathering information that St. John’s wort may affect function via sigma receptors. Sigmal-receptors have been shown to play an important role in antidepressive effects since selective sigmal-receptor agonists, as well as typical antidepressants, reduced the immobility time in the forced swimming and tail suspension tests.” Research demonstrates that the pretreatment of rats with St. John’s wort extracts or hyperforin trimethoxybenzoate can block other ligand binding to sigma receptors. The antidepressant-like activity of hyperforin trimethoxybenzoate was completely antagonized by pretreating rats with BD 1047, a selective sigmal antagonist. These results, together with the previous observation that agonists at sigmal receptors are active in antidepressant models in rats, suggest that St. John’s wort’s antidepressant effects might be mediated in part by an indirect action on sigma

receptor^.'^ A fascinating study evaluated the effect of both St. John’s wort and imipramine on gene transcription in the rat hypothalamus.6 The depressed patient’s hypothalamus is known to manifest changes associated with food intake, decreased libido, and abnormal circadian rhythms. This research found a sigruficant correlation of six genes directly modulated by both these test compounds. The probability of this occurring by chance was 1.14 x The functions of these specific genes include protein synthesis and degradation, cellular scaffolding and intracellular transport, mitochondria1 and glycolytic energy metabolism, and cellular signaling through modulation of calcium-binding proteins. Although the implication of this research is not totally clear, the authors postulate that these modulated gene functions may relate to immune and inflammatory downregulation with neuronal protection from cellular injury. Amentoflavone, one of the many flavone contents in St. John’s wort, has been shown to cross the blood-brain barrier by passive diffusion.’*This may account for the ability of this botanical to travel into the brain and affect CNS gene transcription. Nevertheless, one point regarding the probable synergistic effects of the St. John’s wort constituents should be underscored: given the multitude of active components in this botanical medicine, it is likely that synergistic sites of action outside the CNS,

in accordance with CNS effects, account for the complete and effective global actions of St. John’s wort. Extracts of St. John’s wort have been tested in various animal models designed to study its antidepressant effects. In these studies, St. John’swort extract was found to enhance the exploratory activity of mice in a foreign environment, extend the narcotic sleeping time in a dosedependent fashion, antagonize the effects of reserpine, and decrease aggressive behavior in socially isolated male mice.’J9 These activities are consistent with the expected effects of antidepressant compounds and appear to be the result of increased monoamine activity.

Antiviral Activity In vitro studies have shown that hypericin and pseudohypericin exhibit strong antiviral activity against herpes simplex virus I and 11, as well as influenza types A and B, and vesicular stomatitis virus.2oThese compounds have also demonstrated remarkable antiviral activity against Epstein-Barr virus (EBV).*l Researchers from New York University Medical Center and the Weizmann Institute of Science in Israel generated a tremendous amount of excitement when they demonstrated the antiretroviral activity of hypericin and pseudohypericin.z This preliminary study examined the effect of these compounds on two animal retroviruses, Friend leukemia virus and radiation leukemia virus, both in vitro and in vivo (in mice). The researchers found the effective dose of hypericin in mice to be 1.5 to 2 pg/ml. The researchers concluded the following: Hypericin and pseudohypericin display an extremely effective antiviral activity when administered to mice after retroviral infection. . . . The antiviral activity is remarkable both in its mechanism of action. . . and in the potency of one administration of a relatively small dose of the compounds.Availability. . . and the relatively convenient and inexpensive procedure for the extraction and purification of hypericin and pseudohypericin further enhance the potential of these compounds. Later, two possible mechanisms were described to explain the antiviral activity of both hypericin and pse~dohypericin.~~ First was inhibition of assembly or processing of intact virions from infected cells-released virions contain no detectable activity of reverse transcriptase. Second, these compounds also directly inactivate mature and properly assembled retroviruses. The antiviral activity of hypericin against human immunodeficiency virus (HIV) appears to require interaction with light to activate the h y p e r i ~ i n . Another ~~,~~ requirement is sufficient concentrations, as entry of hypericin into infected cells depends on the concentration of hypericin in the blood. At sufficient concentrations, hypericin incubated with HIV-infected whole blood decreases culturable HIV, indicating significant antiviral activity.26

Hypericurn perforaturn (St. John’s Wort)

Antibacterial Activity St. John’s wort extracts have broad-spectrum antimicrobial activity against both gram-negative and gram-positive bacteria.27The organisms they studied included Staphylococcus aureus, Streptococcus mufans, Proteus vulgaris, Escherichia coli, and Pseudornonas aeruginosa.

Pharmacokinetic Studies Recent pharmacokinetic studies have been published using the 0.3% hypericin content standardized extract.’rz8 The major drawback of these studies is the focus on hypericin and pseudohypericin. Nonetheless, these studies effectively demonstrated that hypericin and pseudohypericin are absorbed. In one study, it was shown that after 4 days of taking the standard dosage of the extract (300 mg three times daily), a steady state is reached with mean maximal plasma levels during the steady-state period of 8.5 ng/ml for hypericin and 5.8 ng/ml for pseudohypericin.z8 Interestingly, even though pseudohypericin is found in higher concentrations in the extract than hypericin, higher blood levels are achieved with hypericin, indicating that hypericin is more bioavailable than pseudohypericin.

CLINICAL APPLICATIONS The primary use of St. John’s wort is in the treatment of depression. It may also be of benefit in the treatment of chronic viral infections and, topically, in various skin products.

Depression Extracts of St. John’s wort standardized for hypericin content (most studies used the 0.3% hyperich content extract) have sigruficant support in the treatment of mild to moderate antidepressant.l*s The officialGerman Commission E monograph for St. John’s wort lists psychovegetative disturbances, depressive states, fear, and nervous disturbances as clinical indications for St. John’s wort. The clinical evaluation of St. John’s wort extract began with an initial clinical study of six depressed women, ages 55 to 65 years, which measured the change in urinary metabolites of noradrenaline and dopamine following administration of a standardized extract of St. John’s wort extract (0.14% hypericin content)?’ Researchers found a significant increase in the catecholamine metabolite 3-methoxy-4-hydroxyphenylglycol,a marker commonly used to evaluate the efficacy of antidepressant therapy. A follow-up study by the same researchers followed 15 women with depression taking the same standardized e~tract.~’ The results demonstrated a significant improvement in symptoms of anxiety, apathy, hypersomnia and insomnia, anorexia, psychomotor retardation, depression, and feelings of worthlessness. No side effects were observed.

Since this initial study, a total of 1592 patients have been studied in 25 double-blind controlled studies (15 compared with placebo, 10 compared with antidepressant drugs including 5 studies comparing St. John’s wort to tricyclics: two vs. imipramine; two vs. amitriptyline; and one vs. d e ~ i p r a m i n e ) . ’ ~ ~ ~ ~ ~ ~ ~ ~ ~ In these studies, St. John’s wort extract improved many psychologic symptoms, including the following: Depression Anxiety Apathy Sleep disturbances Insomnia Anorexia Feelings of worthlessness Even more impressive is that St. John‘s wort extract was able to achieve these benefits without producing significant side effects. The scientific investigation of St. John’s wort is not complete. From a clinical perspective, the major shortcomings of the existing clinical trials are their relatively short terms (8 weeks) and lack of studies in severely depressed patients.32Given the growing popularity of hypericum, studies that address these shortcoming are necessary. The currently available information clearly supports the short-term use of St. John’s wort extract as an alternative to standard antidepressant drugs in cases of mild to moderate depression. Whether it will be shown to be suitable in the treatment of serious depressions (i.e., those associated with psychotic symptoms or depressions with serious risk of suicide) remains to answered. As stated earlier, there have been more than 25 double-blind studies with St. John’s wort extract in the treatment of depression. The methodologic quality of this research, particularly the studies since 1989, has been judged as being acceptable by strict ~riteria.*~J”,~~ The overall results have also been judged as providing good documentation of antidepressant a ~ t i v i t y ? ~ a , ~ ~ Two well-publicized clinical studies proffer that St. John’s wort is ineffective in the treatment of depression. One &week trial3 employed suboptimal doses of St. John’s wort, using 900 to 1200 mg, which is less than the standard 1800-mg dose used in most trials. Given that the trial was funded by a company that makes antidepressant medications, and in light of the plethora of positive St. John’s wort trials, it is dubious whether this study should be seriously considered. The second 8-week study34 made the similar mistake of dosing 900 mg to 1500 mg. A valuable note in this study is that the comparison drug sertraline, a drug with a much stronger side-effect profile than hypericum, was not any more effective than St. John’s wort or the placebo. The doubleblind studies with the highest methodologic quality

clinical trials with St. John’s wort extract in depression No. of Baseline Trial (ref no.) patients HDS Trials Comparing St. John’s Wort with Placebo Halamas 50 18 Hansgren et ales Harrer & SommeP’ Hubner et aI.= Quandt et al.39 Reh et aLM Schmidt & SommeP Schmidt et at.“ Sommer & HarreP TOTALS

72 120 40 88 50 65 40

105 630

20.4 20.9 12.4 17.3 20 16.4 29.5 15.8

Dose (muday)

Duration (wk)

1.08 2.7 0.75 2.7 0.75 1 1.08 0.75 2.7

4 4 6

4 4 8 6 4 4

Trials comparing St. John’s Wort Extract with an Antidepressant Drug Bergman et al.” 80 15.4 0.75 Harrer et al.45 Vorbach et at.& TOTALS

102 135 317

19.4 9.4

2.7 2.7

6 4 4

Responder rate (St. John’s wort)

Responder rate (placebo)

10125 27/34 22/58 14/20 29/44 20125 20132 15/25 28/50 1851313 (59%)

0125 9/38 9/58 9/20 3/44 1 1/25 6/33 3/24 13/55 631322 (20%)

32/40 27/51 42/67 1011158 (64%)

28/40(amitryptiline) 28/51 (maprotiline) 37/68(imipramine) 931159 (58%)

Responder rate, a decrease in the Hamilton Depression Scale (HDS) of ~50%or achieving a value 40.

rating are listed in Table 102-1. Several of the better studies are discussed later. In the study with the highest methodologic rating, 135 depressed patients were treated in 20 centers.* Patients were given either St. John’s wort extract (0.3%hypericin content, 300 mg threetimes daily) or imipramine (25mg threetimes daily) for a period of 6 weeks. Inclusion diagnoses were typical depressions with a single episode, several episodes, depressive neurosis, and adjustment disorder with depressed mood in accordance with DSM-111-R. Main assessment criteria were the Hamilton Depression Scale (HDS), the Depression Scale according to von Zerssen (D-S), and the Clinical Global Impressions (CGIs). In both treatment groups, there were sigruficant decreases in the HDS from 20.2 to 8.8 in the St. John’s wort group, and from 19.4 to 10.7 in the imipramine group. The D-S point value also dropped from 39.6 to 27.2 in the St. John’s wort group, and 39 to 29.2 in the imipramine group (Table 102-2). The analysis of CGIs revealed comparable results in both treatment groups. The main advantage, however, was not so much a difference in therapeutic outcome but rather a significant advantage in terms of lack of side effects and excellent patient tolerance in the St. John’s wort group. Another high-quality, randomized, double-blind study examining the effectiveness and tolerance of the 0.3% hypericin content standardized St. John’s wort extract compared with maprotiline was performed in a group of 102 patients with depression.* Patients were given either St. John’s wort extract (300 mg three times

Hypericum compared with imipramine St. John’s wort

Hamilton Depresslon Scale Initial measurement Week 6 Depression Scale (von Zerssen) Initial measurement Week 6

ImiDramine

20.2 8.8

19.4 10.7

39.6 27.2

39 29.2

daily) or maprotiline (25 mg three times daily) for a period of 4 weeks. Effectiveness was determined using the HDS, D-S, and CGIs. The total score of the HDS dropped during the 4 weeks of therapy in both treatment groups by about 50%.The mean values of the D-S and the CGI scales showed similar results, and after 4 weeks of therapy, no sigruficant differences in either treatment group were noticed. The onset of the effects occurred up to the second week of treatment but were observed earlier with maprotiline than with the St. John’s wort extract. However, maprotiline treatment resulted in the typical side effects with tricyclics (e.g., tiredness, mouth dryness, heart complaints), while St. John’s wort caused no significant side effects. In a multicenter, double-blind study, 72 depressive patients with a HDS greater than 16 were given either St. John’s wort extract (0.3%hypericin content, 300 mg)

Hypericurn perforaturn (St. John’s Wort) or placebo three times daily for 4 ~ e e k s . At 4 ~the end of the trial period, there was a signrficant advantage for the St. John’s wort group, as 27 out of 34 (81%)patients in this group responded on the basis of an HDS score less than 10, compared with 9 out of 38 (26%) in the placebo group. Another way of looking at the results in this study is to examine the drop in the average HDS in both groups. In the treatment group, the HDS dropped from an average of 20.8 at the beginning of the trial to 9.2 after 4 weeks, while in the placebo group the drop was from 20.4 to 14.7. At the end of the 4-week trial, the placebo group and treatment group were subsequently treated for an additional 2 weeks with St. John‘s wort extract in both groups, with the average HDS in the treatment group dropping below 6 and the original placebo group dropping below the responder rate of 10. In another double-blind study, 105 patients with different types of mild to moderate depressions were given either 300 mg of the St. John’s wort extract standardized to contain 0.3% hypericin or an identically looking placebo three times daily for 4 weeksa The effectiveness of treatment was judged after 2 and 4 weeks according to the HDS, the standard measure to assess an antidepressant’s effectiveness. The results are shown in Table 102-3. Using the criteria of a decrease in the HDS of greater than 50% or achieving a value less than 10 as identification of responders, 28 out of 42 patients (67%) in the St. John’s wort group responded, compared with 13 of 47 patients (27.7%) in the placebo group. The results of this study are consistent with other well-designed studies comparing St. John’s wort with placebo.

Seasonal Affective Disorder Seasonal affective disorder (SAD) represents a subgroup of major depression with a regular occurrenceof symptoms in autumn/winter and full remission in spring/summer. Light therapy has become the standard treatment for this type of depression. Apart from this, pharmacotherapy with antidepressants also seems to provide an improvement of SAD symptoms. The aim of a controlled, singleblind study was to evaluate if St. John’swort could be beneficial in treating SAD patients and whether the combination with light therapy would be additionally ad~antageous.4~ Patients who fulfilled DSM-111-R criteria for major depression with a seasonal pattern were randomized in a 4-week treatment study with 900 mg of St. John’s wort extract/day (0.3% hypericin content) pericum compared with placebo St. John’s wort

Baseline Week 2 Week 4

Placebo

15.81

15.83

9.64 7.17

12.28 11.30

combined with either bright (3000 lux, n = 10) or dim light (<300 lux therapy). The significant reduction in the HDS in both groups (72% and 6O%, respectively) indicates that St. John’s wort extract may benefit patients with SAD as a sole therapeutic agent, as well as in combination with light therapy.

Insomnia St. John’s wort has been shown to improve sleep quality and well-being in healthy elderly With antidepressant drugs, particularly tricyclic antidepressants and MA0 inhibitors, REM (rapid eye movement) sleep is reduced. St. John’s wort did not interfere with REM sleep like other antidepressants and was shown to increase the intensity of deep sleep during the total sleeping period as demonstrated by brain wave studies. Although St. John’s wort improved sleep quality, it did not act as a sedative (i.e., it did not reduce sleep onset), nor did it change total sleep duration.

Mental Function One of the most interesting comparative studies was a double-blind study in which St. John’s wort extract (0.3% hypericin content) was compared with maprotiline in 24 healthy volunteers by measuring resting brain wave (EEG) tracings and mental activity (visual and acoustic evoked potential^)?^ Interpretation of the differences in reactions indicated that, unlike maprotiline, which interferes with mental function, St. John’s wort actually improves memory and other mental activities.Long-term administration of St. John’s wort in rats can improve learning and spatial memory with significant changes in the content of monoamines in several brain regions.%

Acquired Immunodeficiency Syndrome and Other Viral Infections Research suggests that St. John’swort may be a useful adjunctive treatment for herpes simplex, mononucleosis, and influenza, although further human studies are necessary to establish the optimal dosage of the standardized extract. Combined with its antidepressant activity, St. John’s wort also appears to be a promising treatment for chronic fatigue syndrome. The greatest promise of St. John’s wort, however, may be in the treatment of acquired immunodeficiency syndrome (AIDS). In response to the in vitro and animal studies, many AIDS patients began self-administering St. John’s wort. Although most patients reported feeling better with a more positive outlook, more energy, and less fatigue, it was not known to what degree this was due to a placebo e f f e ~ t . ~In l 3vitro ~ studies have reported St. John’s wort‘s ability to inhibit light-induced activation of HIV gene expressi0n.5~ To better determine the benefits, a number of trials evaluated the efficacy of standardized extracts of St. John’s wort in the treatment of HIV-infected individuals.

Pharmacology of Natural Medicines In one study, St. John’s wort extracts providing approximately 1 mg of hypericin/day were studied in 31 patients.% Baseline and 4-monthly measurements including physical examination, T-cell subsets, and other laboratory parameters were performed. Concomitant use of azidothymidine (AZT)and other treatments was permitted. The results of the study were encouraging. In the subgroup of 10 patients who took no AZT either before or during the study (“AZT virgins”; none had AIDS), the mean helper T-cell count increased 13%from baseline after 1month on St. John‘s wort and maintained this increase for 4 months. Although these increases were not statistically sigruhcant, in contrast, T helper cell counts of the 10 patients using AZT throughout the study fell sigruhcantly after an initial mild rise. Side effects were limited to reversible liver enzyme elevations in five patients, with all levels returned to baseline after 1month without St. John’s wort extract. In another open pilot study, 18 HIV patients (3 with the CDC II, 8 with CDC 111, 4 with CDC IV 8, and 3 with CDC IV C1 classification) were treated solely with standardized St. John’s wort extract (weekly intravenous injection and daily oral intake), providing a daily intake of 2 mg of h y p e r i ~ i n The . ~ ~ 16/18 patients with good compliance showed stable or even increasing counts of absolute T helper cells over the 40 months of observation. Also, the helper-to-suppressor T-cell ratio showed an improvement in the majority of these patients. Clinically, it was noteworthy that only 2 of these 16 patients encountered an opportunistic infection during the 40 months of observation. The other 14/16 patients remained clinically stable and active in work and life. This steady-state situation of the HIV infection also correlated with stable values of hemoglobin, leukocytes, and platelets. Furthermore, none of the otherwise known viral complications due to cytomegalovirus, herpes, or EBV were encountered in these 16 patients. Despite these good preliminary results, the trials proved disappointing, as significant blood levels of hypericin could not be achieved using the extract either orally or intravenously. Use of the standardized extract for the treatment of HIV infection has since been replaced by the use of intravenously administered synthetic hypericin. Preliminary studies are again producing some encouraging results with good safety, although photosensitivity may occur (see later discussion on toxicity) and long-term controlled evaluation is necessary (for further discussion, see Chapter 175).”s5’

Topical Application St. John’s wort has a historical use as an aid in wound healing. Research has demonstrated antibacterial and wound healing activity? St. John’s wort preparations have also been used in bums, as a sunscreen, and in the treatment of muscular pain? Oil-based preparations are preferred for topical applications.

DOSAGE The dosages of St. John’swort preparations are based on their hypericin content. The overwhelming majority of the studies in depression have used St. John’s wort extract standardized to contain 0.3% hypericin and 3%to 5% hyperforin. This extract is produced via an extraction with 80% methanol (which is subsequently removed). Although hypericin and hyperforin are key components, this extract is composed of a wide range of compounds constituting the remaining 95% of the extract. Manufacturers of these standardized extracts employ high-performance liquid chromatography (HPLC) techniques to identify not only the hypericin, pseudohypericin, and hyperforin but also related compounds, flavonoid components, xanthones, cinnamic acid, and several other key components. The point is that although the dosage is based on hypericin levels, assuring appropriate levels of these other constituents is also vitally important. To achieve the benefits noted in the clinical trials, it is difficult to recommend any other forms beyond standardized extracts. Nonetheless, here are dosage recommendations for various forms of St. John’s wort: Dried flowers: 2 to 4 g three times daily Tincture (1:5): 3 to 6 ml three times daily Fluid extract (1:l):1to 2 ml three times daily Standardized solid (dry-powdered) extract (0.3% hypericin and 3% to 5% hyperforin): 300 mg three times daily

TOXICITY No significant side effects have been reported in the numerous double-blind studies, but perhaps the best demonstration of the excellent safety record of St. John’s wort extract is a large-scale study conducted in Germany involving 3250 patients.58 Results were analyzed by means of a patient questionnaire. Pooled data indicated that symptoms of depression were reduced in frequency and intensity by approximately 50%. The frequency of undesired side effects was reported in 79 patients (2.43%), and 48 (1.45%) discontinued therapy. The most frequently noted side effects were gastrointestinal irritation (0.55%), allergic reactions (0.52%), fatigue (0.4%), and restlessness (0.26%). A review of three 6-week, randomized, doubleblind studies comparing St. John’s wort to placebo or synthetic antidepressants found no difference in sideeffect profile from placebo.59 In this review St. John’s wort was also found to not cause the sedation, anticholinergic reactions, gastrointestinal disturbances, and sexual dysfunction often found in patients treated with tricyclic antidepressants or selective serotonin reuptake inhibitors.

The frequency and severity of side effects with St. John’s wort extract are clinically insignificant, especially when compared with the well-known side effects of tricyclics and other antidepressants. There have been no deaths due to St. John’s wort toxicity, a stark contrast to the 31 deaths per 1 million prescriptions produced by synthetic antidepressantsP

Photosensitivity There is considerable evidence that St. John’s wort can cause severe photosensitivity in animals grazing extensively on the plant. The term ”hypericism” has been used to describe a skin disease found in animals who graze on large quantities of St. John‘s wort?’ However, reports of photosensitivity in humans have been rare and have been limited to those taking excessive quantities for HIV infection.62St. John’s wort is unlikely to be toxic to humans when used at recommended medicinal doses.@However, individuals with AIDS taking large amounts of St. John’s wort extracts (or hypericin) have developed phot~sensitivity?~ Because of the possibility of photosensitivity, avoidance of exposure to strong sunlight and other sources of ultraviolet light when using St. John’s wort is often recommended to individuals, especially those with fair skin. However, although this recommendation may be appropriate, it must be pointed out that the therapeutic dosage of 2.7 mg/day of hypericin is about 30 to 50 times below the level required to produce phototoxicity.64

DRUG INTERACTIONS Historically, those taking St. John’s wort have been advised to avoid foods and medications that are known to negatively interact with MAO-inhibiting drugs such as tyramine-containing foods (e.g., cheeses, beer, wine, pickled herring, yeast). Drugs such as L-dopa and 5-HT should be avoided. However, given recent research demonstrating the lack of in vivo M A 0 inhibition, this recommendation is no longer justified. Strong evidence warrants precaution when combining St. John’s wort with pharmaceutic therapies. St. John’s wort has been found to decrease the plasma concentrations of alprazolam, amitriptyline, digoxin, cyclosporine, indinavir, irinotecan, methadone, nevirapine, simvastatin, tacrolimus, theophylline, warfarin, phenprocoumon, and oral contraceptives. In the case of cyclosporine, the interaction resulted in some transplant graft rejections. Hypericum has also been shown to decrease the bioavailability of the R and S forms of

erap pi mil?',^

One study evaluating the safety of St. John’s wort while nursing studied 33 breastfeeding women over a 2-year peri0d.6~Compared with 101 disease-matched and 33 age-matched controls, there were no statistically sigruficant differences found in maternal or infant demographics or maternal adverse events. No sigruficant difference was observed in the frequency of maternal report of decreased milk production among the groups, nor was a difference found in infant weight over the first year of life. Data regarding hypericum use and pregnancy/ reproductive safety are scant.%At this point, St. John’s wort cannot be recommended as a safe therapy during pregnancy.

When combined with serotonin reuptake inhibitors, antidepressants (e.g., sertraline, paroxetine, nefazpdone) or buspirone, hypericum can theoretically contribute to ”serotonergic syndrome,”68a syndrome caused by excess serotonin levels. This syndrome has been iatrogenically induced by psychotropic and nonpsychotropic pharmaceutic coadministration and may include symptoms such as agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fe~er.6~ Women on oral contraception should also be informed regarding the possible decrease in birth control efficacy with hypericum. St. John’swort causes an induction of ethinyl estradiol and norethindrone metabolism consistent with increased CYP3A activity and can contribute to intracyclicbleeding.7O One study evaluated the use of St. John’s wort and oral contraception. St. John’s wort appeared to contribute to breakthrough bleeding in 7 of 12 women (vs. 2 of 12 women in the oral contraception-only group). When taking oral contraceptive pills with st. John’s wort, women may experience breakthrough bleeding and should consider adding a barrier method of c~ntraception.~~

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Pharmacology of Natural Medicines relevant to antidepressant action and novel pharmacogenetic candidates for the phenotype of antidepressant treatment response. Mol Psychiatry 2004;9:237-251. 7. De Smet PA, Nolen WA. St John’s wort as an antidepressant. BMJ 1996313241-242. 8.Suzuki 0, Katsumata Y, Oya M, et al. Inhibition of monoamine oxidase by hypericin. Planta Medica 1984;50:272-274. 9. Holzl J, D e m k h L, Gollnik 8. Investigations about antidepressive and mood changing effects of Hypericirm perforaturn. Planta Med 1989;55:643. 10. Thiede HM, Walper A. Inhibition of MA0 and COMT by hypericum extracts and hypericin. J Geriatr Psychiatry Neurol1994;7s54-56. 11. Bladt S, Wagner H. Inhibition of MA0 by fractions and constituents of hypericum extract. J Geriatr Psychiatry Neurol1994;7S57-59. 12. Thiele 8, Brink I, Ploch M. Modulation of cytokine expression by hypericum extract. J Geriatr Psychiatry Neurol1994;7s60-62. 13.Calapai G, Crupi A, Firenzuoli F, et al. Interleukin-6 involvement in antidepressant action of Hypericum perforatum. Pharmacopsychiatry 2001~supp11):s8-10. 14.Perovic S, Muller WE. Pharmacological profile of hypericum extract. Effect of serotonin uptake by postsynaptic receptors. Arzneimittelforschung 1995;45:1145-1148. 15. Mennini T, Gobbi M. The antidepressant mechanism of Hypericum perfoaturn. Life Sci 2004;75:1021-1027. 16. Kaehler ST, Sinner C, Chatterjee SS, et al. Hyperforin enhances the extracellular concentrations of catecholamines, serotonin and glutamate in the rat locus coeruleus. Neurosci Lett 1999; 262199-202. 17. Noda Y, Kamei H, Nabeshima T. [Sigma-receptor ligands and antistress actions.] Nippon Yakurigaku Zasshi 1999;114:43-49. 18.Gutmann H, Bruggisser R, Schaffner W, et al. Transport of amentoflavone across the blood-brain barrier in vitro. Planta Med 2002;68:804-807. 19. Okpanyi SN, Weischer ML. [Animal experiments on the psychotropic action of a Hypericum extract.] Arzneim Forsch 19873710-13. 20. Muldner H, Zoller M. [Antidepressive effect of a Hypericum extract standardized to an active hypericine complex. Biochemical and clinical studies.] Armeimittelforschung 1984;34:918-920. 21. Lavie D. Antiviral pharmaceutical compositions containing hypericin or pseudohypericin. European Patent Application, No. 87111467.4, filed 8/8/87, European Patent Office. Pub1 No. 0 256 A2. 175-177. 1987. 22. Someya H. Effect of a constituent of Hypericirm erectitm on infection and multiplication of Epstein-Barr virus. J Tokyo Med Coll 1985;43:815-826. 23. Meruelo D, Lavie G, Lavie D. Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses. Aromatic polycyclic diones hypericin and pseudohypericin. Proc Natl Acad sci U S A 1988;855230-5234. 24. Lavie G, Valentin F, Levin B, et al. Studies of the mechanism of action of the antiretroviral agents hypericin and pseudohypericin. Proc Natl Acad Sci U S A 1989;86:5963-5967. 25. Degar S, Prince AM, Pascual D, et al. Inactivation of the human immunodeficiency virus by hypericin. Evidence for photochemical alterations of p24 and a block in uncoating. AIDS Res Human Retroviruses 1992;8:1929-1936. 26.Valentine FT, Lavie G, Levin B, et al. Synthetic hypericin enters blood lymphocytes and monocytes in vitro and decreases culturable HIV in blood obtained from infected individuals. Int Conf AIDS 1991;7:97 (abstract no. W.A.1022). 27. Barbagallo C, Chisari G. Antimicrobial activity of three Hypericum species. Fitoterapia 1987;58175-177. 28. Staffeldt B, Kerb R, Brockmoller J, et al. Pharmacokinetics of hypericin and pseudohypericin after oral intake of the Hypericum perforaturn extract LI 160 in healthy volunteers. J Geriatr Psychiatry Neurol 1994;7 Suppll:S47-53.

29. Ernst E. St John’s wort, an antidepressant? A systematic, criteriabased review. Phytomedicine 1995;2:67-71. 30.Muldner VH, Zoller M. [Antidepressive effect of a Hypericum extract standardized to an active hypericine complex. Biochemical and clinical studies.] Arzneimittelforschung 1984;34:918-920. 31.Hamr G, Schulz V. Clinical investigation of the antidepressant effectiveness of Hypericum. J Geriatr Psychiatry Neurol 1994;7(suppl 1):s-8. 32. Linde K, Ramirez G, Mulrow CD, et al. St John’s wort for depression-an overview and meta-analysis of randomised clinical trials. BMJ 1996;313:253-258. 33.Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St. John‘swort in major depression: a randomized controlled trial. JAMA 2001;2851978-1986. 34.Hypericum Depression Trial Study Group. Effect of Hypericum perforaturn (St John’s wort) in major depressive disorder: a randomized controlled trial. JAMA 2002;2871807-1814. 35. Halama P. [Efficacy of the Hypericum extract LI 160 in the treatment of 50 patients of a psychiatrist.] Nervenheikunde 1991; 10305-307. 36. Hansgren D, Vesper J, Ploch M. Multicenter double-blind study examining the antidepressant effectiveness of the hypericum extract LI 160. J Geriatr Psychiatry Neurol1994;7(suppl 1):S15-18. 37. Harrer G, Sommer H. Treatment of mild/moderate depressions with Hypericum. Phytomedicine 1994;1:3-8. 38. Hubner WD, Lande S, Podzuweit H. Hypericum treatment of mild depressions with somatic symptoms. J Geriatr Psychiatry Neurol 1994;7(~~ppl l):S12-14. 39. Quandt J, Schmidt U, Schenk N. Ambulante behandlung leichter und mittelschwerer depressiver verstiimmungen. Der Allgemeinarzt 1993;297-102. 40. Reh C, Laux P, Schenk N. Hypericum-extrakt bei depressioneneine wirksame alternative. Therapiewoche 1992;421576-1581. 41. Schmidt U, Sommer H. [St. John’s wort extract in the ambulatory therapy of depression. Attention and reaction ability are preserved.] Fortschr Med 1993;111:339-342. 42. Schmidt U, Schenk N, Schwarz N et al. The therapy of depressive moods. Psycho 1989;15:665-671. 43. Sommer H, Harrer G. Placebocontrolled double-blind study examining the effectiveness of an hypericum preparation in 105 mildly dep& patients. J Geriatr Psychiatry Neurol1994;7(suppll):S9-11. 44.Bergman. R, Nubner J, Demling J. Behandlung leichter gis mittelschwer depressionen. Therapiewoch Neurologie/Psychiatrie 1993;7235-240. 45. Harrer G, Hubner WD, Podzuweit H. Effectiveness and tolerance of the hypericum extract LI 160 compared to maprotiline. A multicenter double-blind study. J Geriatr Psychiatry Neurol 1994;7 (suppl l):S24-28. 46. Vorbach EU, Hubner WD, Arnoldt KH. Effectivenessand tolerance of the hypericum extract LI 160 in comparison with imipramine. Randomized double-blind study with 135 outpatients. J Geriatr Psychiatry Neurol 1994;7(suppl l):S19-23. 47. Martinez B, Kasper S, Ruhrmann S, et al. Hypericum in the treatment of seasonal affective disorders. J Geriatr Psychiatry Neurol 1994;7(~~ppl l):S29-33. 48. Schulz H, Jobert M. Effects of hypericum extract on the sleep EEG in older volunteers. J Geriatr Psychiatry Neurol 1994;7(suppl 1): 539-43. 49. Johnson D, Ksciuk H, Woelk H, et al. Effects of hypericum extract LI 160 compared with maprotiline on resting EEG and evoked potentials in 24 volunteers. J Geriatr Psychiatry Neurol 1994; 7(suppl 1):S44-46. 50. Widy-Tyszkiewicz E, Piechal A, JoNec I, et al. Long term administration of Hypericum perforaturn improves spatial learning and memory in the water maze. Biol Pharm Bull 2002;251289-1294. 51. James JS. Report. AIDS Treat News 1989;74.

Hypericum perforaturn (St. John’s Wort) 52. James JS. Report. AIDS Treat News 1989;91. 53. Taher MM, Lammering GM, Hershey CM, et al. Mood-enhancing antidepressant St. John’s wort inhibits the activation of human immunodeficiency virus gene expression by ultraviolet light. IUBMB Life 2002;54:357-364. 54. Cooper WC, James J. An observational study of the safety and efficacy of hypericin in HIV? subjects. Int Conf AIDS 1990;6:369 (abstract no. 2063). 55. Steinbeck-Hose A, Wemet P. Successful long term treatment over 40 months of HIV-patients with intravenous Hypericin. Int Conf AIDS 1993;9:470 (abstract no. PO-B26-2012). 56. Fumer V, Bek M, Gold J. A phase I/LI unblinded dose ranging study of hypericin in HIV-positive subjects. Int C o d AIDS 1991;7199 (abstract WB 2071). 57. Gulick R, Lui H, Anderson R, et al. Human hypericism: a photosensitivity reaction to hypericin (St John’s wort). Int Conf AIDS 1992;8:B90 (abstract no. FOB3018). 58. Woelk H, Burkard G, Grunwald J. Benefits and risks of the hypericum extract LI 160: drug monitoring study with 3250 patients. J Geriatr Psychiahy Neurol1994;7 (Suppll):S34-38. 59. Trautmann-Sponsel RD, Dienel A. Safety of Hypericum extract in mildly to moderately depressed outpatients: A review based on data from three randomized, placebo-controlled trials. J Affect Disord 2004;82:303-307. 60. Henry JA, Alexander CA, Sener EK. Relative mortality from overdose of antidepressants. BMJ 1995;310:221-224. 61. Araya OS, Ford EJ. An investigation of the type of photosensitization caused by the ingestion of St. John’s Wort (Hypericum perforaturn) by calves. J Comp Path01 1981;91:135-141.

62. Gulick RM, McAuliffe V, Holden-Wdtse J, et al. Phase I studies of hypericin, the active compound in St. John’s wort, as an antiretroviral agent in HIV-infected adults. AIDS Clinical Trials Group Protocols 150 and 258. Ann Intern Med 1999;130:510-514. 63. Schempp CM, Winghofer B, Muller K, et al. Effect of oral administration of Hypericum perforaturn extract (St. John’s Wort) on skin erythema and pigmentation induced by UVB, UVA, visible light and solar simulated radiation. Phytother Res 2003;17141-146. 64.Siegers CP, Biel S, Wihelm Kp. Zur frage der phototoxizitat von hypericum. Nervenheilkunde 1993;12:320-322. 65. Lee A, Minhas R, Matsuda N, et al. The safety of St. John’s wort (Hypericum perforatum) during breastfeeding. J Clin Psychiatry 2003;64:966-968. 66. Goldman RD, Koren G; Motherisk Team. Taking St John’s wort during pregnancy. Can Fam Physician 2003;49:29-30. 67. Tannergren C, Engman H, Knutson L, et al. St John’s wort decreases the bioavailability of R- and Sverapamil through induction of the first-pass metabolism. Clin Pharmacol Ther 2004;75:298-309. 68.1220 AA. Drug interactions with St. John’s wort (Hypericunz perforaturn): a review of the clinical evidence. Int J Clin Pharmacol Ther 2004;42:139-148. 69. Houlihan DJ. Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine. Ann Pharmacother 2004;38:411-413. 70. Pfrunder A, Schiesser M, Gerber S, et al. Interaction of St John’s wort with low-dose oral contraceptive therapy: a randomized controlled trial. Br J Clin Pharmacol2003;56683-690. 71. Hall SD, Wang Z, Huang SM, et al. The interaction between St John’s wort and an oral contraceptive. Clin Pharmacol Ther 2003;74525-535.

Lobelia infla ta (Indian Tobacco) Michael T. Murray, ND JosephE. Pizzorno Jr, ND CHAPTER CONTENTS General Description 1049

Gastrointestinal Effects 1050 Central Nervous System Effects 1050

Chemical Composition 1049 Clinical Applications 1050 History and Folk Use

1049 Dosage 1050

Pharmacology 1049 Respiratory Effects 1049

Lobelia infiafa (family: Campanulaceae) Common names: Indian tobacco, pukeweed, asthma weed, gagroot, vomitwort

GENERAL DESCRIPTION Lobelia is an indigenous North American annual or biennial plant with an erect, angular, hairy stem that contains a milky sap and grows from 6 inches to 3 feet in height. Numerous small, two-lipped, blue flowers grow in spikelike racemes from July to November.

CHEMICAL COMPOSITION Lobelia contains about 0.48% pyridine (piperidine) alkaloids composed mainly of lobeline (Figure 103-1) with lesser amounts of lobelanine, lobelanidine, and other alkaloids.’ Other constituents include resin, gum, lipids, and chelidonic acid?

HISTORY AND FOLK USE Lobelia was named after Matthias de Lobe1 (1570-1616), a famous French botanist and physician to the court of King James I. After chewing the plant, early settlers noted that the taste was similar to tobacco and produced effects like that of nicotine, the principal alkaloid in domestic tobacco, Nicotiana tobaccum. Also, Native Americans smoked the dried leaves to obtain the central nervous system effects of the alkaloids in the plant. Thus lobelia was commonly referred to as “Indian tobacco.”

Toxicology

1050

Lobelia became one of the most commonly used herbs by Thomsonians, who used it as an emetic, diaphoretic, expectorant, sedative, antispasmodic, and antiasthmatic. It has been used for the following conditions: Asthma Whooping cough Bruises Sprains Ringworm Insect bites Poison ivy symptoms Thomson stated: “There is no vegetable which the earth produces more harmless in its effect on the human system, and none more powerful in removing disease and promoting health than 10belia.”~

PHARMACOLOGY Lobeline has been regarded to possess many of the same pharmacologic actions as nicotine, only less potent. However, its complex actions cannot be explained simply as being a weaker version of nicotine. Detailed pharmacologic investigation comparing the effects of lobeline to nicotine indicate that lobeline possesses novel effects on nicotinic receptors!>

Respiratory Effects One of the earliest known uses of lobeline was as a safe, short-acting respiratory stimulant. This respiratory stimulation has been shown to be due to direct stimulation of 1049

I

unresponsive to any other medication. Furthermore, although lobeline causes bronchoconstriction in dogs and rats, in guinea pigs and (presumably) humans the opposite-bronchodilation-occurs.lo Although effective when used alone in the treatment of asthma, it has traditionally been used in combination with other botanical agents including Cupsicurnfitescens and Syrnphlocurpus fuctidu. Lobelia has also been used as an aid in stopping smoking with equivocal results from clinical trials."

H5c6mc6 Figure 103-1 Lobeline.

the carotid body chemoreceptors. The powerful respiratory stimulant action of lobeline has been used for stimulation of respiration in fever cases, cases of paralysis of respiratory centers due to narcotic poisoning, alcohol, soporifics, morphine, narcosis, or spinal anesthesia. Lobeline has also been used to treat accident victims who have been buried, nearly drowned, hit by lightning or electrically shocked, and poisoned by asphyxiating gases.

Gastrointestinal Effects The emetic action of lobeline is mediated by its stimulation of the emetic chemoreceptor trigger zone in the area postrema of the medulla oblongata (outside the blood-brain barrier) and activation of the vagal and spinal afferent nerves that form the sensory input of the reflex pathways involved in vomiting:

Central Nervous System Effects One of the more promising lines of research with lobeline is that it appears to disrupt the fundamental mechanisms of dopamine storage and release. This action may help in antagonizing the neurochemical and behavioral effects of the psychostimulants amphetamine and methamphetamine. Lobeline has been found to inhibit the amphetamine-induced release of dopamine in vitro and amphetamine-induced hyperactivity, drug discrimination, and self-administration in animal experiment~.~fi Since lobeline is not addictive itself, it may reduce the abuse liability of these psychostimulants.

CLINICAL APPLICATIONS

DOSAGE Dried herb: 0.2 to 0.6 g three times daily Ticture: 15 to 30 drops three times daily Fluid extract: 8 to 10 drops three times daily

TOXICOLOGY Although lobelia has a reputation for being toxic, a thorough review of the medical literature was unable to find any well-documented case of serious problems or death due to lobelia.12 The main reason may be that lobelia causes nausea and vomiting when the amount used is too high, thereby avoiding absorption of toxic amounts. In general, a dosage of more than 1 ml of tincture one time is enough to produce sigruficant nausea and possibly vomiting. Lobelia should not be used for more than 1 month consecutively and should be avoided during pregnancy and breastfeeding. Like nicotine poisoning, toxic symptoms of lobelia include the following: Nausea Salivation Diarrhea Disturbed hearing and vision Mental confusion Marked weakness

Lobelia is primarily used as an expectorant in such conditions as pneumonia, asthma, and bronchitis. It appears that some of its actions may be mediated by the adrenal cortex? Experimentally induced lung edema in rats is responsive to lobeline in many models that are

Faintness and prostration ensue; blood pressure falls; the pulse becomes weak, rapid, and irregular; breathing is difficult; and collapse occurs, followed by convulsions. Death may conceivably result from respiratory failure. The antidote in acute poisoning is 2 mg of atropine, which is given subcutaneously.

1. Karawya MS, Abdel-Wahab SM, Zaki AY. Colorimetric method for the estimation of alkaloids in lobelia and its pharmaceuticalpreparations.J Assoc off Anal Chem 1971;54:1423-1425. 2. Leung A. Encyclopediaof common natural ingredientsused in food, drugs, and cosmetics. New York Wiley, 1980220-223.

3. Christopher J. School of natural healing. Provo, UT: BiWorld Publishers, 1976358-367. 4.Da~najMI, Patrick GS, Creasy KR, Martin BR. Pharmacology of lobeline, a nicotinic receptor ligand. J Pharmacol Exp Ther 1997;282:410-419.

Lobelia inflafa (Indian Tobacoo) 5. Miller DK, Harrod SB, Green TA, et al. Lobeline attenuates locomotor stimulation induced by repeated nicotine administration in rats. Pharmacol Biochem Behav 2003;74279-286. 6.Laffan RJ, Borison HL. Emetic action of nicotine and lobeline. J Pharmacol Exp Ther 1957;121:468-476. 7. Dwoskin LP, Crooks PA. A novel mechanism of action and potential use for l o b e h e as a treatment for psychostimdant abuse. Biochem Pharmacol2002;63:89-98. 8.Harrod SB, Dwoskin LP, Crooks PA, et al. Lobeline attenuates d-methamphetamine self-administration in rats. J Pharmacol Exp Ther 2001;298:172-179.

9. Halmagyi DF, Kovacs A, Neumann P. Adrenocortical pathway of lobeline protection in some forms of experimental lung edema of the rat. Dis Chest 1958;33285-296. 10. Cambar PJ, Shore SR, Aviado DM. Bronchopulmonary and gastrointestinal effects of lobeline. Arch Int Pharmacodyn Ther 1969;177:1-27. 11. Stead LF, Hughes JR.Lobeline for smoking cessation. Cochrane Database Syst Rev 2000;(2):CwoO124. 12. Bergner P. Is lobelia toxic? Med Herbal 1998;101,15-32.

Melaleuca alternifolia (Tea Tree) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND C H A P T E K C 0 N T E N TS General Description 1053 Chemical Composition 1053 History and Folk Use 1053

Dandruff 1055 Acne 1055 Common Foot Problems 1055 Fungal Nail Infection 1055 Vaginal Infections 1056

Pharmacology 1054

Dosage 1056

Clinical Applications 1054 Skin Infections 1054 Oral Infections 1055

Toxicity

Melaleuca alternifolia (family: Myrtaceae) Common name: tea tree

GENERAL DESCRIPTION Tea tree (Melaleuca alternifolia) is a small tree native to only one area of the world: the northeast coastal region of New South Wales, Australia. The leaves, the portion of the plant that is used medicinally, are the source of a valuable therapeutic oil. Although there are more than 50 members of the Melaleuca family, the oil from the leaf of M . alfernifoliahas received the most research attention.

CHEMICAL COMPOSITION Tea tree leaves contain about 1.8%of oil obtained via steam distillation.' This oil contains more than 48 compounds, but is chiefly composed of the following2: l-terpinen-4-01 18-cine01 Gamma-terpinene (see Figure 104-1) p-cymene Other terpenes The Australian standard (AS 2782-1985) for "Oil of Melaleuca (Terpinen-4-ol type)" sets a minimum content of terpinen-4-01 at 30% and a maximum 1,8-cineol content of 15%.'

1056

Drug Interactions 1056

HISTORY AND FOLK USE The medicinal properties of crushed tea tree leaves were known to the Bundjalung Aborigines of northern New South Wales, Australia. In fact, the waters of a lagoon where tea tree leaves had fallen and decayed for hundreds of years were viewed as having tremendous healing properties.' The popular name of tea tree was first reported in 1777, in Captain Cook's account of his second voyage, entitled A Voyage to the South Pole': [W]e at first made it [somebeer] of a decoctionof the spruce leaves;but finding that this alone made the beer too astringent, we afterwards mixed with it an equal quantity of the tea plant (a name it obtained in my former voyage from OUT using it as tea then, as we also did now), which partly destroyed the astringency of the other, and made the beer exceedingly palatable, and esteemed by everyone on board.

The leaves of M . aZternifolia were also used by the early settlers of Australia to make tea; hence the further use of the popular name "tea tree."' The first report of tea tree's medicinal use appeared in the Medical Journal of Australia in 1930.3 A surgeon in Sydney reported impressive results using a solution of tea tree oil to clean surgical wounds. According to thisreport? The results obtained in a variety of conditions when it (tea tree oil) was first tried were most encouraging, a striking 1053

Pharmacology of Natural Medicines CH3

I

Q

H3C

CH3

Figure 104-1 Gamma-terpinene.

feature being that it dissolved pus and left the surface of infected wounds clean so that its germicidal action became more effective without any apparent damage to the tissues. This was something new, as most efficient germicides destroy tissue as well as bacteria.

During World War II, tea tree oil was issued to soldiers to use as a disinfectant. The Australian Army went so far as to commandeer supplies of the oil and exempt leaf cutters from national service in order to maintain production. The production of tea tree oil during World War 11was regarded as an "essential" industry.' After World War 11, the tea tree oil industry stagnated for more than 30 years. There were a number of reasons for this, including the general trend away from natural medicines and toward synthetic medical drugs. However, during the late 1970s and early 1980s, the Australian tea tree oil industry was reborn as successful plantations growing M. alternifolia were established.' Tea tree oil has been used in the treatment of the following conditions': Acne Aphthous stomatitis Boils Burns Carbuncles Corns Gingivitis Herpes Impetigo Infections of the nail bed Insect bites Lice Mouth ulcers Pharyngitis Psoriasis Ringworm Root canal treatment Sinus infections Skin and vaginal infections Thrush Tiiea pedis (athlete's foot) Tonsillitis A variety of tea tree oil-based cosmetic products exist in the marketplace, including toothpastes, shampoos

and conditioners, creams, hand and body lotions, soaps, gels, liniments, and nail polish removers.

PHARMACOLOGY Tea tree oil possesses signrficant antiseptic properties and is regarded by many as the ideal skin disinfectant. This claim is supported by its efficacy against a wide range of organisms, its good penetration, and its lack of skin irritation.' The therapeutic uses of tea tree oil are based largely on its antiseptic and antifungal properties. Organisms inhibited by tea tree oil are listed in Table 104_1.1~4-6

CLINICAL APPLICATIONS The historical usesof tea tree oil demonstrateits wide range of applications as an antiseptic. Three of the more popular and documented uses are in the treatment of skin infections, vaginal infections,and common foot complaints.

Skin Infections Tea tree oil is useful in a broad range of dermal infections, not only because of its broad-spectrum antiseptic properties, but also because of its capacity to m i x with sebaceous secretions and penetrate the epidermis. A clinical trial in patients with furuncles demonstrated that tea tree oil encouraged more rapid healing without scarring than was seen in matched control subject^.^ Presumably the positive clinical effects were due to the oil's germicidal activity against Staphylococcus aureus. The method of application consisted of cleaning

Organism

Mean inhibitory zone (mm)

Bacillus subtilis

Mycobacterium smegmatis

24.1 26.1 56.4 20.3 27.9 16.9 33.9 27.1 31 .O

Propionibacterium acnes

Not determined

Bacteroides fragilis Branhamella catarrhalis Candida albicans Clostridium perfringens Enterococcus faecalis Escherichia coli Lactobacillus acidophilus

Pseudomonas aeruginosa

Not determined

Serratia marcescens Staphylococcus aureus

24.8 25.4

Streptococcus pyrogenes

Not determined

Trichomonas vaginalis

Not determined

Trichophytonmentagrophytes

Not determined

Data from references 1 and 4-6.

Melaleuca alternifolia (Tea Tree)

the site followed by painting the surface of the furuncle freely with tea tree oil two or three times a day. For most skin infections, the most effective treatment appears to be direct application of full-strength, undiluted oil at the site of infection. If irritation occurs, diluted preparations may be tried.

Oral Infections Tea tree oil has been shown to exert sigruficant activity against oral pathogens, both bacterial and fungal, and has been suggested to be a suitable alternative to chlorhexidine? From a clinical perspective, these effects may best be utilized in the treatment of oral candidiasis (thrush). In one open study, 27 patients with acquired immunodeficiency syndrome (AIDS)and oral candidiasis that was clinically refractory to fluconazole were randomly assigned to receive either an alcohol-based or an alcoholfree melaleuca oral solution four times daily for 2 to 4 weeks. Overall, 60% of patients demonstrated a clinical response to the melaleuca oral solution (7 cases cured and 8 cases clinically improved) at the 4-week evaluation?

Dandruff There is evidence that dandruff appears to be related to the yeast Pityrosporurn ovule. Because tea tree oil has antifungal activity against I? ovule, a 4-week study was designed to investigate the efficacy and tolerability of 5%tea tree oil shampoo versus a placebo in 126 male and female patients, aged 14 years and older, with moderate dandruff. The 5% tea tree oil shampoo group showed a 41% improvement in the quadrant-area-severity score, compared with 11%improvement in the placebo group. Statistically sigruficantimprovementswere also observed in the total area of involvement score, the total severity score, and the itchiness and greasiness components of the patients' self-assessments. The scaliness component of patient self-assessment improved but was not statistically sigruficant. There were no adverse effects.'O

Acne Topical application of tea tree oil is a suitable alternative to benzoyl peroxide preparations. In one study, 124 patients with mild to moderate acne randomly received either a 5% gel of tea tree oil or 5% benzoyl peroxide lotion to be applied topically every day. After 3 months, both treatments produced a signhcant improvement in the mean number of both noninflamed and inflamed lesions, although with noninflamed lesions, benzoyl peroxide was found to be more effective. An important finding was that there were fewer reports of side effects (dryness, pruritus, stinging, burning, and skin redness) with tea tree oil (44%vs. 79%)."

Common Foot Problems Tea tree oil, in emollient form (8% tea tree oil) or in solution (40%),can be massaged into the feet daily for the

treatment of tinea pedis, foot irritation, and bromhidrosis (severely foul-smelling feet). One researcher concluded, after 6 years of using different concentrations and preparations, that tea tree oil eradicates or improves the symptoms of tinea pedis when used daily by patients at home? He also reported that even undiluted forms had little effect on onychomycosis (discussed further later). Diluted tea tree oil in solution was found to reduce foot irritation and promote wound healing with surgical incision in cases of corns, calluses, bunions, and hammer toes, and was extremely effective in diminishing bromhidrosis. In tinea pedis, one double-blind study found that 10% tea tree oil cream compared quite favorably with the antifungal tolnaftate in relieving symptoms but was less effective in eliminating the fungi from culture^.^ Specifically, both the tea tree group (24 out of 37) and the tolnaftate group (19 out of 33) showed significant improvement in the four clinical parameters scaling, inflammation, itching, and burning, but only 30% of the subjects applying tea tree oil cream tested culture negative, compared with 85%in the tolnaftate group. In another double-blind trial, 158 patients with tinea pedis were randomly assigned to receive either placebo or 25% or 50% tea tree oil solution.12Patients applied the solution twice daily to affected areas for 4 weeks and were assessed after 2 and 4 weeks of treatment. A marked clinical response was seen in 68%of the 50%tea tree oil group and in 72% of the 25% tea tree oil group, compared with 39% in the placebo group. Mycological cure was assessed by culture of skin scraping taken at baseline and after 4 weeks of treatment. The mycological cure rate was 64% in the 50% tea tree oil group, compared with 31% in the placebo group. Four (3.8%) patients applying tea tree oil experienced moderate to severe dermatitis that improved quickly upon cessation of the study medication.

Fungal Nail Infection Fungal nail infections (onychomycosis) are the most common cause of nail disease, affecting approximately 2% to 13% of the population. Standard medical treatments include dbbridement, topical antifungals, and systemic antifungals. All current therapies have high recurrence rates. Oral therapy has the added disadvantages of high cost and potentially serious adverse effects. One study compared the efficacy and tolerability of the topical application of 1% clotrimazole solution with that of 100% tea tree oil for the treatment of toenail onych~mycosis.'~ The 117 patients received twice-daily applications of either 1% clotrimazole (CL) solution or 100%tea tree (IT) oil for 6 months. Wbridement and clinical assessment were performed at 0,1,3,and 6 months. Culture specimens were obtained at 0 and 6 months. Each patient's subjective assessment was also obtained

Pharmacology of Natural Medicines

3 months after the conclusion of therapy. After 6 months of therapy, the two treatment groups were comparable on the basis of culture cure (CL = 11%,TT = 18%) and clinical assessment documenting partial or full resolution (CL= 61%,TT = 60%).Three months later, about half of each group reported continued improvement or resolution (CL = 55%,TT = 56%).These results indicate that topical therapy with tea tree oil, in conjunction with dGbridement, provides excellent improvement in nail appearance and symptomatology.

DOSAGE A number of commercial products contain tea tree oil. Tea tree oil can be used as a topical antiseptic for reducing microbial counts in wounds, surgical incisions, and skin and vaginal infections. In addition, tea tree leaves can be used to make teas that may be of benefit in cases of sore throat, tonsillitis, sinus infections, and colitis.

Vaginal Infections

TOXICITY

Tea tree oil demonstrates germicidal activity against a number of common vaginal pathogens and opportunistic organisms, including Trichomonas vaginalis and Cundida albi~ans.'~ A 40% solution of tea tree oil emulsified with isopropyl alcohol and water was found in a clinical study to be highly effective for the treatment of cervicitis, chronic endocervicitis, trichomonal vaginitis, and vaginal candidiasis.14Weekly in-office treatment (usually four to six were necessary) involved thorough washing of the perineum, labia, and vagina with a suitable scrub (the commercial product pHisoHex was used in the study). After drying, the affected areas were washed with a 1%tea tree oil solution. This was followed by insertion of a tampon (three 4 x Pinch sponges) saturated with the 40% tea tree oil solution. Patients were instructed to remove the tampon after 24 hours. For infectious processes-trichomonas and candidiasis-daily vaginal douches containing 1 quart of water with a 0.4% concentration of the oil were prescribed. No irritation, burning, or other side effects were reported or observed with either the office applications or the douches.

Tea tree oil is extremely safe for use as a topical antiseptic. However, it may cause allergic contact dermatitis in some individuals. During a 3-year period, seven patients were seen in an outpatient dermatology clinic in Kona, Hawaii, for contact dermatitis due to the use of commercially available product containing 100% tea tree oil.l5 The patients were treating preexisting skin conditions, which included foot fungus, dog scratches, insect bites, and rashes. All patients presented with an eczematous dermatitis. Patch tests indicated that all patients were sensitive to a 1% solution of tea tree oil. It is recommended that individuals apply the oil to a small area of skin before using tea tree oil for the first time so as to avoid the bother of experiencing contact dermatitis over a larger area. The oral ingestion of tea tree oil cannot be recommended because it could lead to a toxic reaction. However, folk use suggests that oral ingestion of tea from the leaves is reasonably safe.

1.Altman PM. Australian tea tree oil. Australian J Pharmacy 1988; 69276-278. 2.Swords G, Hunter GLK. Composition of Australian tea tree oil (Melaleuca altemfolia). J Agric Food Chem 1978;26:734-737. 3.Humphery EM. A new Australian germicide. Med J Australia 1930;1:417-418. 4. Walker M. clinicalinvestigation of Australian Melaleuca alternifolia oil for a variety of common foot problems. Current Podiatry 1972;18:30-35. 5. Tong MM, Altman PM, Barnetson RS.Tea tree oil in the treatment of tinea pedis. Australas J Dermatol1992;33:145-149. 6. Carson CF, Riley Tv. The antimicrobial activity of tea tree oil. Med J Aust 1994;160:236. 7. Feinblatt Hh4. Cajeput-type oil for the treatment of furunculosis. J Nat Med Assoc 1960;5232-34. 8. G m p p FC, Ramacciato JC, Sioes RP, et al. Antimicrobial activity of garlic, tea tree oil, and chlorhexidine against oral microorganisms. Int Dent J 2002;52433-437. 9. Vazquez JA, Zawawi AA. Efficacy of alcohol-based and alcohol-he melaleuca oral solution for the treatment of fluconazole-refractory

oropharyngeal candidiasis in patients with AIDS. HIV Clin Trials 2002;3379-385. 10. Satchell AC, Saurajen A, Bell C, Barnetson RS.Treatment of dandruff with 5% tea tree oil shampoo. J Am Acad Dermatol 2002; 47852-855. 11. Bassett IB, Pannowitz DL, Barnetson RS. A comparative study of tea-tree oil versus benzoylperoxide in the treatment of acne. Med J Aust 3990;153:455-458. 12. Satchell AC, Saurajen A, Bell C, Bametson RS. Treatment of interdigital tinea pedis with 25% and 50% tea tree oil solution: a randomized, placebo-controlled, blinded study. Australas J Dermatol 2002;43175-178. 13.Buck DS, Nidorf DM, Addino JG. Comparison of two topical preparations for the treatment of onychomycosis.Melaleuca alternifolia (tea tree) oil and clotrimazole. J Fam Pract 1994;38:601-605. 14. Pena EF. Melaleuca alternifolia oil: its use for trichomonal vaginitis and other vaginal infections.Obstet Gynecol1962;19:793-795. 15. Knight TE, Hausen BM. Melaleuca oil (tea tree oil) dermatitis. J Am Acad Dermatol1994;30:423-427.

DRUG INTERACTIONS No drug interactions have been reported for tea tree oil.

Melatonin Michael T. Murray, ND Joseph E. Pizzorno Jr, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS General Description 1057 Synthesis and Secretion 1057 Clinical Evaluation of Melatonin Secretion 1058

Depression 1060 Multiple Sclerosis 1061 Coronary Artery Disease 1061 Alzheimer's Disease 1062

Pharmacology 1058

interactions 1062

Clinical Applications 1058 Jet Lag 1058 Insomnia 1059 Cancer 1059

Dosage 1062 Toxicology 1062

GENERAL DESCRIPTION

SYNTHESIS AND SECRETION

Melatonin (not to be confused with melanin, the compound responsible for skin pigment) is a hormone manufactured from serotonin and secreted by the pineal gland (Figure 105-1).The pineal gland, a pea-sized gland at the base of the brain, has been a source of curiosity since antiquity. The ancient Greeks regarded the pineal gland as the seat of the soul, a concept that was extended by the philosopher Descartes. In the seventeenth and eighteenth centuries, physicians associated "madness" with the pineal gland. Physicians in the early 1900s believed the pineal gland was somehow involved with the endocrine system. The identification of melatonin in 1958 provided the first solid scientific evidence of an essential role for the gland. It is now thought that the sole function of the pineal gland is to manufacture and secrete melatonin. The exact function of melatonin is still poorly understood, but it is critically involved in the synchronization of hormone secretion. The natural biorhythm of hormone secretion is referred to as the "circadian rhythm." The human body is governed by an internal clock that signals the secretion of various hormones at different times to regulate body functions. Melatonin plays a key role as the biologic timekeeper of hormone secretion. Melatonin also helps control sleep-wake cycles. Release of melatonin is stimulated by darkness and suppressed by light via a mdtisynaptic pathway that connects the pineal gland to the retina.

Melatonin secretion is related largely to the length of the night, because most of the melatonin synthesis occurs during the dark phase as a result of increased activity of the enzyme serotonin-N-acetyltransferase.'Hence, there is a normal circadian pattern of melatonin synthesis and secretion (Figure 105-2).The longer the night, the longer the duration of synthesis and secretion. The most consistent observation in humans is that melatonin profiles show a phase change from winter to summer, with earlier secretion in summer than in winter. When humans are kept strictly in darkness for 14hours a day for a period of 2 months, the melatonin secretion pattern expands to cover almost the entire dark period, and concomitantly, in extended periods of 14 hours of light, the rhythm contracts to less than 10 hours, with accompanying changes in body temperature and sleep? Light of sufficient intensity at night rapidly reduces melatonin prod~ction.~ The spectrum of light that most effectivelyproduces lowering of melatonin production is the green band (540 nm), corresponding to the rhodopsin H

/On-rNy N

H Flgure 105-1 Melatonin.

1057

Pharmacology of Natural Medicines AcCoA

CoA

SAM

SAH

Kacetyl serotonin

Serotonin Kacetyltransferase

Melatonin HIOMT

Figure 105-2 Melatonin synthesis.

absorption spectrum in the human eye? This observation is of considerable importance to understanding not only the physiologic effects of melatonin but also its importance in the control of circadian rhythms and the treatment of seasonal affective disorder (SAD; discussed further in Chapter 144).5Theantidepressanteffect of light therapy in the treatment of SAD is probably due to balancing of the altered circadian rhythm by restoration of proper melatonin synthesis and secretion by the pineal gland. Disruption of pineal function is thought to be a major reason for SAD as well as jet lag.'" Another factor governing melatonin secretion may be the amount of food a person eats. The age-related reductions in melatonin observed both in humans and rhesus monkeys were shown to decrease by 30% in rhesus monkeys given calorie-restricted diets for 12 years.' Although more studies are needed to clanfy the relationship between food and melatonin, this finding has many implications for anti-aging medicine, which might use melatonin as both a biomarker and therapy.

CLINICAL EVALUATION OF MELATONIN SECRETION The circadian pattern of melatonin secretion and the response of body tissues to orally administered melatonin can be monitored by measurement of either salivary or serum levels, because saliva and serum melatonin concentrations correlate well! However, salivary melatonin is preferable because it eliminates the need for multiple blood samples and allows the patient the luxury of collecting the sample at home. Typically, patients are asked to collect saliva according to the particular laboratory's technique (either soaking a swab or simply expectorating saliva into a small container) at four different times (includingnocturnal determination). Monitoring of the circadian secretion of melatonin is clinically indicated for the conditions listed in Box 105-1 and can assist the clinician in proper timing of melatonin dosage.

PHARMACOLOGY In addition to its role in synchronizing hormone secretion, melatonin has been shown to possess antioxidant effects9 This action may explain the studies in rats showing that melatonin supplementation led to longer lives (31 months vs. 25 months). However, the clinical

Insomnia related to disturbed circadian rhythm Seasonal affective disorder Delayed sleep phase syndrome stress Cancer Multiple sclerosis Abnormal sexual development Administration and monitoring of melatonin therapy

sigruficance of melatonin's antioxidant effects has not been fully determined. It is hard to imagine that its antioxidant effects would have greater sigruficance than those of vitamin C, vitamin E, and a host of other antioxidants that can be delivered at much higher concentrations. Melatonin has also been shown to exert some sedative and anticancer effects (discussed later). The pharmacokinetics of orally administered melatonin has been studied. Daytime serum melatonin levels in normal adults are in the range of 20 pg/ml, rising to levels of about 150 pg/ml at night.'O Oral doses of 0.1 to 0.3 mg produce serum concentrations that are equivalent to normal physiologic night-time melatonin levels." However, because melatonin demonstrates a large hepatic first-pass effect and a biphasic elimination pattern, therapeutic doses are typically 1to 3 mg?J2J3

CLINICAL APPLICATIONS The primary clinical uses of melatonin are in the treatment of jet lag and insomnia and as an adjunct in cancer therapy. In addition, the role of melatonin in depression and Alzheimer's disease is discussed. There are other possible indications for melatonin based on very preliminary studies. For example, low melatonin levels have been found in multiple sclerosis, coronary artery disease, epilepsy, postmenopausal osteoporosis, and liver disease.14J5The studies in multiple sclerosis and coronary artery disease are also briefly discussed here as is the relationship between vitamin B12 and melatonin secretion.

Jet Lag Several double-blind studies have shown melatonin to be very effective in relieving jet lag.'"19 Different dosage

Melatonin

recommendations have been given. Some researchers have recommended that melatonin be taken at the beginning of the sleep period based on the point of departure starting a few days before departure (especially for passengers traveling eastward). Others have recommended taking melatonin just one time on the first evening upon arriving at the new destination. The latter recommendation avoids the problem of extreme drowsiness sometimes produced by melatonin at an unwanted time. One study was designed to answer the question In of optimal timing of melatonin the study, 52 members of an airline cabin crew flying an international route were randomly assigned to the following three groups: Early melatonin: 5 mg from 3 days before arrival until 5 days after return home Late melatonin:placebo for 3 days then 5 mg melatonin for 5 days at new destination Placebo Daily ratings in jet lag, mood, and sleepinessmeasures demonstrated that the best recovery was in the late melatonin group. The early melatonin group actually demonstrated a worse recovery than the placebo group. This study suggests that the best way to use melatonin for jet lag is to take 5 mg in the evening at the new destination for 5 days.

Insomnia Melatonin plays an important role in the induction of sleep. Low melatonin secretion at night can be a cause of insomnia. Several double-blind trials have shown melatonin supplementation to be very effective in promoting sleep.21-25 However, it appears that the sleep-promoting effects of melatonin are most apparent when melatonin levels are l0w.2~In other words, using melatonin is not like taking a sleeping pill. It produces its effects only when melatonin levels are low. When melatonin is given just before bedtime in normal subjects or in patients with insomnia who have normal melatonin levels, it has no sedative effect. This is because, normally, just prior to going to bed, there is a rise in melatonin secretion. Melatonin supplementation is effective as a sedative only when the pineal gland’s own production of melatonin is very low. However, low melatonin levels are thought to be an extremely common cause of insomnia in childrenz7and the elderly.% Conducted in a Dutch sleep center, a randomized, double-blind,placebocontrolled trial involved 62 children 6 to 12 years of age who had suffered for more than a year from idiopathic chronic sleep-onset insomnia. The children received either 5 mg melatonin or placebo at 7 PM, and melatonin was measured in their saliva. The children treated with melatonin slept better, ate better, seemed to be less sick and tired, were more lively,

responded better to attention, and were considered to be healthier than those treated with placebo. Melatonin supplementation advanced the onset of sleep by 57 minutes, advanced the end of sleep, and decreased sleep latency. A few subjects dropped out of the study, but none because of melatonin-related problems.z7The researchers noted a high degree of attention deficit hyperactivity disorder (ADHD) in the study group, suggesting a possible role for melatonin in children with insomnia as well ADHD. Older people typically exhibit poor sleep efficiency and reduced nocturnal plasma melatonin levels. In one of the most interesting studies, 26 elderly insomniacs with lower than normal melatonin levels were given 1to 2 mg of melatonin 2 hours before the desired bedtime for 1 week. Rapid-release and slow-release melatonin preparations were used. Both sleep latency and sleep quality were evaluated. Although there was no discernible difference in sleep onset and sleep efficiency (percentage of time asleep of total time in bed) between the two forms, the slow-release form yielded better results for sleep maintenan~e.2~ Another study examined the ability of similar, physiologic doses to restore nighttime melatonin levels and sleep efficiencyin insomniac subjects older than 50 years. In a double-blind, placebo-controlled study, 15 subjects who slept normally and 15 subjects who exhibited confirmed decreases in sleep efficiency received, in randomized order, a placebo and three melatonin doses (0.1,0.3, and 3.0 mg) orally 30 minutes before bedtime for 1week. Treatments were separated by 1-week “washout” periods. The physiologic melatonin dose, 0.3 mg, showed sigruficant restoration of sleep efficiency, principally in the midportion of the night. It also raised plasma melatonin levels to normal. The pharmacologically higher dose, 3.0 mg, like the 0.1-mg dose, also improved sleep. However, the 3.0-mg dose induced hypothermia and caused plasma melatonin to remain elevated into the daylight hours. The melatonin treatment did not mod* sleep efficiency or alter sleep architecture for older people in whom sleep was already normal.3oThis study does support the rationale of using the lowest fully effective dose of melatonin for the elderly and provides a word of caution: The clinician must watch for hypothermia and daytime melatonin excess when using higher melatonin doses to gain a greater antioxidant effect in patients with cancer.

Cancer There is a growing body of evidence which shows that a good night’s sleep may help prevent canceP and that a lack of melatonin may encourage cancer. Melatonin has been shown to inhibit several types of cancers, particularly hormone-related cancers like those of the breast and prostate.32It has also been shown to inhibit both the

initiation and promotion of cancer. The higher cancer incidence reported in individuals living or working in an environment in which they are exposed to higher than normal artificial electromagnetic fields has been theorized to be caused by suppression of melatonin synthesis.%The exposure of humans or animals to light (visible electromagnetic radiation) at night rapidly depresses pineal melatonin production and blood melatonin levels. Likewise, the exposure of animals to various pulsed static and extremely low-frequency magnetic fields also reduces melatonin levels. Reduction of melatonin by artificial electromagnetic field exposure may be a sigruficant risk factor for cancer. Two studies show that decreased melatonin due to nighttime work is associated with higher rates of breast cancers. The first study found that the risk was higher with more years of graveyard shift work. The investigators theorized that nighttime light exposure can reduce melatonin levels, thus increasing estrogen exposure to breast tissue. Breast cancer risk was higher among subjects who frequently did not sleep during the period of the night when melatonin levels are typically at their highest. Although the risk did not increase with interrupted sleep accompanied by turning on a light, there was an indication of higher risk among subjects who had the brightest bedrooms.M A second prospective study reported on 78,562 nurses, of whom 2411 had primary breast cancer. Nurses who had been on rotating shifts had an 8% increase in relative risk compared with nurses on day shifts. For nurses with more than 30 years of night work, the increase was 36Y0.~~ Clinical and animal studies corroborate the preceding findings. Research shows that melatonin works with the hypothalamic-pituitary-gonadal axis by downregulating some of the pituitary and gonadal hormones that control mammary gland development and m o d e tumor activity. Studies using estrogen receptor-positive human breast cancer cell lines demonstrate that melatonin could act directly on tumoral cells as a naturally occurring antiestrogen, thereby influencing their proliferative rate.% Melatonin has also been shown to exert anticancer effects in clinical trials in patients with cancer. In these studies, melatonin has been given at moderate (e.g., 10 mg daily) to extremely high (i.e., more than 40 mg daily) levels. Melatonin has most often been used in combination with other anticancer agents, including interleukin-2 (IL-2) and interferon. The results are promising. Although interferon and IL-2 are often ineffective when used alone, very good results have been obtained from their use in combination with melatonin. For example, in one study, 80 patients with advanced solid n e e plasm were randomly assigned to receive IL-2 either alone (3 million KJ/day for 6 days a week for 4 weeks) or in

combination with melatonin (40mg/day orally at 8 PM)?~ A complete response was obtained in 3 of 41 patients treated with IL-2 plus melatonin but in none of the patients receiving IL-2 alone. A partial response was achieved in 8 of 41 patients treated with IL-2 and melatonin, compared with only 1 patient in the IL-2 only group. The survival rate after 1 year was 19 of 41 in the IL-2 plus melatonin group, compared with only 6 of 30 in the IL-2 only group. In another study of 100 patients with metastatic solid tumors, for which no standard therapy was available, survival at 1 year was s i g h cantly higher in patients treated with IL-2 and melatonin (21/52) than in those receiving the supportive care alone (5/48).38 Similar results have been shown with melatonin in combination with interferon, tumor necrosis factor, and tamoxifen, as well as when melatonin was used These preliminary results are quite encouraging, as improvements in survival time and quality of life assessments have been produced in approximately 30% of patients taking anywhere from 10 to 50 mg daily (at 8.00 PM). However, although melatonin has been shown to increase survival time in these studies, the results are good but not earth-shattering. For example, in one study of patients with solid tumors and brain metastasis, 15 of 24 patients (63%) died within 1 year in the melatonin group, compared with 21 of 26 (88%)in the group receiving supportive care only. These studies, although randomized, were not double-blind, indicating that a placebo response may have been partially responsible for some of the improvements noted. Additionally, studies are also suggesting a link between the cancer progression and depression (see later), in which severe depression may be associated with elevated cancer risk. Although the impact a cancer diagnosis can have on a patient’s psychological response confounds results, research is beginning to show a relationship between cancer and depression with diurnal variations in melat0nin.4~

Depression When melatonin was first evaluated in depression, the low levels were believed led to the ”low melatonin syndrome” and low levels of melatonin were believed contribute to the higher cortisol levels observed in depressed individuals. The realization is now emerging that melatonin may not necessarily be lower in depressed individuals; instead, the timing of melatonin release may be altered. Initial studies performed in the 1980s demonstrated that melatonin levels were typically below normal in patients with clinical depression.However, in all of these studies it tumed out that antidepressant drugs or other factors were responsible for the depressed melatonin levels. Later studies have not supported the common

Melatonin

presence of low melatonin levels in patients with clinical depre~sion.4~ These studies measured melatonin levels in drug-free, depressed patients and the subjects were carefully matched with a comparable control group. In addition, it has been demonstrated that normal subjects secreting no melatonin do not frequently suffer from depression.’ It was also initially thought that melatonin may affect mood as a result of reducing cortisol levels by inhibiting the secretion by the pituitary hormone adrenocorticotropic hormone (ACTH), which then signals the adrenal glands to secrete cortisol. With melatonin deficiency, cortisol levels would be expected to be increased. This appears to be the case in many depressed patients, in whom both decreased melatonin and increased cortisol concentrations are frequently However, it is unlikely that melatonin supplementation can significantly lower cortisol levels, because research has shown that melatonin supplementation does not suppress either ACTH or cortisol Interestingly, as techniques to examine hormone secretion are improving, support is emerging for the observation that even though melatonin levels are not actually lower in depressed patients, there is a sigruficant shift in peak secretion of the hormone. One study evaluated 14 drug-free depressive patients. Compared with a control group the depressed subjects demonstrated a 77-minute peak time delay of serum melatonin, which was corroborated by evaluation of the urinary melatonin metabolite 6-sulfato~ymelatonin.~ This finding suggests that an understanding of the noradrenergic pathways that stimulate melatonin secretion as well as development of more elegant ways to moaberrant circadian rhythms are needed to improve treatment in depressed patients. Although direct treatment with melatonin is unlikely to have any sigruficant positive effects on the treatment of depression in most patients, melatonin in the future may be used in combination with specifically timed light therapy and lifestyle and environmental changes to modify peak secretion times in order to alter the course of this illness. A note of caution is important for anyone using melatonin to treat depression, because one double-blind study conducted in 1973 demonstrated that melatonin supplementation actually worsened clinical depression dramatically in some cases.54Obviously worsening of depression is quite serious as it increases the risk for suicide. A possible explanation for the worsening is the fact that the melatonin was given two to four times during the day, a time when melatonin levels are typically low. Another study in nondepressed subjects demonstrated that melatonin given during the day tended to cause fatigue, confusion, and ~leepiness.5~

Multiple Sclerosis Multiple sclerosis (MS) is the most common of the demyelinating diseases of the central nervous system. The clinical course and prognosis of the disease is extremely variable. The illness typically tends to progress in a series of relapses and remissions. The patient with MS seems, in most cases, to enter a phase of slow and steady deterioration of neurologic function. The pineal gland has been implicated in the pathogenesis and clinical course of MS. In one study, 32 patients with MS who were randomly selected from consecutive hospital admissions to a neurology service due to exacerbation of symptoms underwent monitoring of nocturnal melatonin The study revealed that the progressive decline in melatonin may be relevant to the pathophysiology, and specifically to the course, of the disease. The specific role of melatonin in remission of MS is unknown, but what is known is that when melatonin levels decline it is associated with an exacerbation of symptoms. Patients with chronic progressive MS have been shown to have lower melatonin levels than patients with a relapsing/remitting course. Because activation of melatonin receptors enhances the release of type 1helper T cell (Thl)cytokines, such as gamma-interferon and L-2, there is some evidence that melatonin might be proinflammatory in certain autoimmune conditions, and therefore blockage of its activity might be useful in other autoimmune diseases, such as rheumatoid arthritis.5’ The balance between type 1 and type 2 helper T cells is not well characterized in MS, so whether melatonin therapy would have any benefit in MS is not yet known.

Coronary Artery Disease Melatonin levels are sigruficantlylower in patients with coronary heart disease than in healthy controls. In one study, nocturnal melatonin levels in patients with coronary heart disease were one-fifth the levels in healthy controls. The absence of melatonin would cause increased night-time sympathetic activity, which would in turn raise the risk for coronary disease. Melatonin serves as a suppressor of sympathetic activity nocturnally. Lower levels of melatonin may lead to increased circulating epinephrine and norepinephrine, which has been implicated in damage to vessel walls. Atherogenic uptake of low-density lipoprotein cholesterol is accelerated by these amines at pathophysiologic concentrations.%In another study, melatonin was found to inhibit platelet aggregation.%Melatonin not only may play a preventive role in heart disease but also may be of use during invasive surgical procedures. In patients who undergo cardiopulmonary bypass, melatonin levels are disrupted by the procedure and during the postoperative period for up to 2 daysm Given this information,

Pharmacology of Natural Medicines more research is warranted to find out whether patients benefit from supplemental melatonin before undergoing surgery.

Alzheimer's Disease Although studies show no correlation with a melatonininduced increase in cerebrovascular blood there is evidence to support the role of melatonin as a protector of neuronal cells. Cobalt is a transition metal found to be in high levels in patients with Alzheimer's disease (AD). Cobalt has been found to induce oxidative damage and beta-amyloid release, both of which are prevented with melatonin treatment. Because cobalt is an essential nutrient, melatonin may prove an important preventive treatment in people susceptible to AD.62 Research in patients with AD reveals a poorly understood underlying noradrenergic dysfunction that leads to decreased melatonin levels63;replacing melatonin can reverse some of the cognitive loss. In one double-blind, placebo-controlled study, researchers who previously reported on bright light therapy as a means to improve cognitive function in AD evaluated the effectiveness of melatonin. Three milligrams of melatonin were given to 11 subjects at 8:30 PM every day for a month, and 9 other subjects were given placebo (mean age 79.2 years). Using standard dementia and AD assessment scales, the researchers found that the melatonin group had a sigruficantly longer sleeping time and less nighttime activity, with improved levels of cognitive and noncognitive functions. Even though the researchers noted that these results were sigruficant and clearly supported the use of melatonin in AD, they acknowledged that moming bright light therapy still achieved even greater improvement in patients with AD.61 However promising the notion, whether all patients with AD would benefit from melatonin is still unclear. A multicenter, randomized, placebo-controlled clinical trial of 157 subjects showed no statistical benefit for melatonin therapy. Subjects were given either placebo, 2.5 mg melatonin in a timed-release dose, or 10 mg melatonin. Even though no statistically sigruficant differences in objective sleep measures were seen between baseline and treatment periods for the any of the three groups, nonsignificant trends for longer nocturnal total sleep time and decreased wake time after sleep onset were observed in the melatonin groups compared with the placebo group. Although this appears initially to be a negative result, the researchers did report trends toward a greater percentage of subjects having more than a 30-minute increase in nocturnal total sleep time in the 10-mg melatonin group and for a decline in the day-night sleep ratio in the 2.5-mg sustained-release melatonin group, compared with placebo. Additionally, patient

caregivers also described improvements in sleep quality for the 2.5-mg sustained-release melatonin group compared with the placebo group.65Because melatonin in this and other studies has had an excellent safety profile, it seems reasonable to try melatonin in patients with AD.

INTERACTIONS Vitamin B12 has been shown to influence melatonin secretion.& The low levels of melatonin in the elderly may be a result of low vitamin BI2 status. Vitamin BI2 (1.5 mg/day of methylcobalamin) has been shown to produce good results in the treatment of sleep-wake rhythm disorders, presumably as a result of improving melatonin ~ e c r e t i o n . ~ ~

DOSAGE At this time, melatonin therapy appears most appropriate for use when low melatonin levels are suspected, as occurs in some patients with insomnia and in jet lag. Evaluation of salivary melatonin levels can provide valuable diagnostic insight as to the likely success or failure of melatonin in the treatment of insomnia. A dose of 3 mg at bedtime is more than enough, as doses as low as 0.1 mg and 0.3 mg have been shown to produce a sedative effect when melatonin levels are low." One study of children 6 to 12 years of age with insomnia used 5 mg.27 Higher dosages may be required to produce the anticancer benefits noted previously.

TOXICOLOGY Although melatonin appears to have no serious side effects at recommended dosages in adults and children, melatonin supplementation could conceivably disrupt the normal circadian rhythm. In one study, a daily dosage of 8 mg/day for only 4 days resulted in sigruficant alteration of the circadian rhythm?* It is not known what sort of effect would occur at commonly recommended dosages (i.e., 3 mg). As described, depression worsened in some patients when they were given melatonin during the day. Higher than normal physiologic doses have also been shown to cause hypothermia and daytime melatonin excess in some elderly individuals.30 Additionally, there is some concern that elevated melatonin values may contribute to proinflammatory reactions in rheumatoid arthritis57 as well as increased airway inflammation in patients with nocturnal exacerbations of a ~ t h m a . Therefore ~,~~ practitioners may want to avoid giving this supplement to patients with these conditions until more studies of melatonin's immunotherapeutic effect have been conducted.

Melatonin

1. Yu HS, Reiter RJ, eds. Melatonin biosynthesis, physiological effects and clinical applications. Boca Raton: CRC Press, 1993. 2. Wehr TA. The durations of human melatonin secretion and sleep respond to changes in daylength (photoperiod). J Clin Endocrinol Metab 1991;73:1276-1280. 3.Illnerova H. Entrainment of mammalian circadian rhythms in melatonin production by light. Pineal Res Rev 1988;6173-217. 4. Reiter RJ. Action spectra, dose response relationships and temporal aspects of light’s effects on the pineal gland the medical and biological effects of light. Ann N Y Acad Sci 1985;453215230. 5. Rosenthal NE, Sack DA, GiUin JC, et al. Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984;41:72-80. 6. Waldhauser F, Ehrhart B, Forster E. Clinical aspects of the melatonin action. Experentia 1993;49:671-681. 7. Roth GS, Lesnikov V, Lesnikov M, et al. Dietary caloric restriction prevents the age-related decline in plasma melatonin levels of rhesus monkeys. J Clin Endocrinol Metab 2001;863292-3295. 8.Vakkuri 0, Leppaluoto J, Kauppila A. Oral administration and distribution of melatonin in human serum, saliva and urine. Life Sci 1985;37489-495. 9. Reiter RJ, Melchiorri D, Sewerynek E, et al. A review of the evidence supporting melatonin’s role as an antioxidant. J Pineal Res 1995;181-11. 10. Waldhauser F, Waldhauser M, Liebennan HR, et al. Bioavailability of oral melatonin in humans. Neuroendocrinology 1984;39: 307-313. 11. Dollins AB, Zhdanova N, Wurtman RJ, et al. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci U S A 1994;91:18241828. 12. Mallo C, Zaidan R, Galy G, et al. Pharmacokinetics of melatonin in man after intravenous infusion and bolus injection. Eur J Clin Pharmacol 1990;38297-301. 13. Lane EA, Moss HB. Pharmacokinetics of melatonin in man: first pass hepatic metabolism. J Clin Endocrinol Metab 1985;61: 1214-1216. 14. Bruck R, Aeed H, Avni Y, et al. Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats. J Hepatol2004;40:86-93. 15. Koc M, Taysi S, Buyukokuroglu ME, Bakan N. Melatonin protects rat liver against irradiation-induced oxidative injury. J Radiat Res (Tokyo)2003;44:211-215. 16. Arendt J, Braodway J. Some effects of jet-lag and their alleviation by melatonin. Ergonomics 1987;301379-1393. 17. Claustrat B, Brun J, David M, et al. Melatonin and jet-lag: confirmatory result using a simplified protocol. Biol Psychiatry 1992; 32705-711. 18.Petrie K, Conaglen JV,Thompson L, Chamberlain K. Effect of melatonin on jet-lag after long haul flights. BMJ 1989;298705-707. 19. Lmo A, Silvy S, Condorelli L, Rusconi AC. Melatonin and jet-lag: treatment schedule. Biol Psychiatry 1993;34:587. 20. Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet-lag in international cabin crew. Biol Psychiatry 1993;33:526-530. 21. Waldhauser F, Saletu B, Trinchard-Lugan I. Sleep laboratory investigations on hypnotic properties of melatonin. Psychopharmacology 1990;100222-226. 22. Zhdanova N, Wurtman RJ, Lynch HJ, et al. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther 199557552-558. 23. Dahlitz M, Alvarez 8, Vignau J, et al. Delayed sleep phase syndrome response to melatonin. Lancet 1991;3371121-1124.

24. MacFarlane JG, Cleghorn JM, Brown GM, Streiner DL. The effects of exogenous melatonin on the total sleep time and daytime alertness of chronic insomniacs. A preliminary study. Biol Psychiatry 1991;30371-376. 25. James SP, Sack DA, Rosenthal NE, Mendelson WB. Melatonin administration in insomnia. Neuropsychopharmacology 1990; 319-23. 26. Nave R, Peled R, Lavie P. Melatonin improves evening napping. Eur J Phannacol1995;275213-216. 27. Smits MG, van Stel HF, van der Heijden K, et al. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 2003;42:1286-1293. 28. Haimov I, Laudon M, Zisapel N, et al. Sleep disorders and melatonin rhythms in elderly people. BMJ 1994;309:167. 29. Haimov I, Lavie P, Laudon M, et al. Melatonin replacement therapy of elderly insomniacs. Sleep 1995;18598-603. 30. Zhdanova N, Wurtman RJ, Regan MM, et al. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab 2001;86: 4727-4730. 31. A good night’s sleep may help prevent cancer. lime, p 96, Oct 13, 2003. 32. Molis TM, Spriggs LL, Jupiter Y, Hill SM. Melatonin modulation of estrogen-regulated proteins, growth factors, and proto-oncogenes in human breast cancer. J Pineal Res 1995;18:93-103. 33. Reiter RJ. Melatonin suppression by static and extremely low frequency electromagnetic fields: relationship to the reported increased incidence of cancer. Rev Environ Health 1994;10171-186. 34. Davis S, Mirick DK, Stevens RG. Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 2001;93:1557-1562. 35. Stephenson J. Epidemiological studies reveal link between night work and breast cancer. Lancet Oncol2001;2:S1470-S2045. 36. Sanchez-BarceloEJ, Cos S, Fernandez R, Mediavilla MD. Melatonin and mammary cancer: a short review. Endocr Relat Cancer 2003;10153-159. 37. Lissoni P, Barni S, Tanchi G, et al. A randomized study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma. Br J Cancer 1994;69 196-199. 38. Lissoni P, Bami S, Fossati V, et al. A randomized study of neuroimmunotherapy with lowdose subcutaneous interleukin-2 plus melatonin compared to supportive care alone in patients with untreatable metastatic solid tumour. Support Care Cancer 1995;3:194-197. 39.Neri B, Fiorelli C, Moroni F, et al. Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma: a phase II study. Cancer 1994;73:3015-3019. 40.Brackowski R, Zubelewicz B, Romanowski W, et al. Preliminary study on modulation of the biological effects of tumor necrosis factor-alpha in advanced cancer patients by the pineal hormone melatonin. J Biol Regul Homeost Agents 1994;8:77-80. 41. Lissoni P, Bami S, Meregalli S, et al. Modulation of cancer endocrine therapy by melatonin: a phase Il study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer 1995;71:854-856. 42. Lissoni P, Bami S, Ardizzoia A, et al. Randomized study with the pineal hormone melatonin versus supportive care alone in advanced nonsmall cell lung cancer resistant to a first-line chemotherapy containing cisplatin. Oncology 1992;49336-339. 43. Lissoni P, Bami S, Cattaneo G, et al. Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 1991;48448-450.

Pharmacology of Natural Medicines 44.Lissoni P, Bami S, Ardizzoia A, et al. A randomized study with the pineal hormone melatonin versus supportive cape alone in patienk with brain metastases due to solid neoplasms. Cancer 1994;7369!3-701. 45. Spiegel D, Giese-DavisJ. Depression and cancer: mechanisms and disease p r o p s i o n . Biol Psychiatry 2003;54:269-282. 46.Maurizi CP. Disorder of the pineal gland associated with depression, peptic ulcers, and sexual dysfunction. South Med J 1984;77: 1516-1518. 47. Wetterberg L. The relationship between the pineal gland and the pituitary-adrenal axis in health, endocrine and psychiatric conditions. Psychoneuroendocrinology 1983;8:75-80. 48. Beck-Friis J, Kjellman BF, Aperia B, et al. Serum melatonin in relation to clinical variables in patients with major depressive disorder and a hypothesis of a low melatonin syndrome. Ada Psychiatr %and 1985;71:319-330. 49. Rubin RT, Heist EK, McGeoy SS, et al. Neuroendocrine aspects of primary endogenous depression. XI. Serum melatonin measures in patients and matched control subjects. Arch Gen Psychiatry 1992;4955&567. 50. Thompson C, Franey C, Arendt J, Checkley SA. A comparison of melatonin secretion in depressed patients and normal subjects. Br J Psychiatry 1988;152260-265. 51. Waterman GS, Ryan ND,Perel JM, et al. Nocturnal urinary excretion of 6-hydroxymelatonin sulfate in prepubertal major depressive disorder. Biol Psychiatry 1992;31:582-590. 52. Mallo C, Zaidan R, Faure A, et al. Effects of a four-day nocturnal melatonin treatment on the 24 h plasma melatonin, cortisol and prolactin profiles in humans. Acta Endocrinol (Copenh) 1988;119: 474-480. 53. Crasson M, Kjiri S, Colin A, et al. Serum melatonin and urinary 6sulfatoxymelatonin in major depression. Psychonemndocrinology 2004;291-12. 54. Carman JS, Post RM, Buswell R, Goodwin FK. Negative effects of melatonin on depression.Am J Psychiatry 1976;1331181-1186. 55. Dollins AB, Lynch HJ, Wurtman RJ, et al. Effect of pharmacological daytime doses of melatonin on human mood and performance. Psychopharmacology (Berl) 1993;112490-496. 56. Sandyk R, Awerbuch GI. Relationship of nocturnal melatonin levels to duration and course of multiple sclerosis. Int J Neurosci 1994; 75229-237.

57. Maestroni GJ. The immunotherapeutic potential of melatonin. Expert Opin Investig Drugs 2001;10467-476. 58.Brugger P, Marktl W, Herold M. Impaired nocturnal secretion of melatonin in coronary heart disease. Lancet 1995;345:1408. 59.Cardinali DF', Del Zar MM, Vacas MI. The effects of melatonin in human platelets. Acta Physiol Pharmacol Ther Latinoam 1993; 431-13. 60.Guo X, Kuzumi E, Charman SC,Vuylsteke A. Perioperative melatonin secretion in patients undergoing coronary artery bypass grafting. Anesth Analg 2002;941085-1091. 61. Van Der Helm-Van Mil AH, Van Someren EJ, Van Den Boom R, et al. No influence of melatonin on cerebral blood flow in humans. J Clin Endocrinol Metab 2003;88:5989-5994. 62. Olivieri G, Hess C, Savaskan E, et al. Melatonin protects SHSY5Y neuroblastoma cells from cobalt-induced oxidative stress, neurotoxicity and increased beta-amyloid secretion. J Pineal Res 2001; 31:320-325. 63. Wu YH, Feenstra MG, Zhou JN, et al. Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab 2003;88:589&5906. 64.Asayama K, Yamadera H, It0 T, et al. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and noncognitive functions in Alzheimer type dementia. J Nippon Med Sch 2003;70334-341. 65. Singer C, Tractenberg RE, Kaye J, et al. A multicenter, placebocontrolled trial of melatonin for sleep disturbance in Alzheimer's disease. Sleep 2003;26893-901. 66.Honma K, Kohsaka M, Fukuda N, et al. Effects of vitamin B12 on plasma melatonin rhythm in humans: increased li&t sensitivity phase-advances the circadian clock? Experentia 1992;48: 716720. 67. Okawa M, Mishima K, Nanami T, et al. Vitamin B12 treatment for sleep-wake rhythm disorders. Sleep 1990;13:15-23. 68. Sutherland ER, Ellison MC, Kraft M, Martin RJ. Elevated serum melatonin is associated with the nocturnal worsening of asthma. J Allergy Clin Immunol2003;112513-517. 69.Sutherland ER, Martin RJ, Ellison MC, Kraft M. Immunomodulatory effects of melatonin in asthma. Am J Respir Crit Care Med 2002;166:1055-1061.

Melissa ofiCicinalis(LemonBalm) Eric L. Yarnell, ND, RH (AHG) Kathy A h l , BS, JD, RH (AHG) CHAPTER CONTENTS General Description 1065 Chemical Composition 1065

Clinical Applications 1066 Herpes Simplex 1066 Anxiety, Agitation, Insomnia 1067 Dyspepsia 1067

History and folk Use 1065 Dosage 1067 Pharmacology 1066 Sedative Effects 1066 Antiviral Effects 1066 Thyroid Effects 1066 Other Effects 1066

Melissa oficinalis (family: Lamiaceae) Common names: lemon balm, balm, melissa, balm mint

Toxicology 1068 Drug Interactions 1068

More than 3% of the dry weight of lemon balm is composed of rosmarinic acid, a phenylpropanoid derivative4 (Figure 106-1).

GENERAL DESCRIPTION Melissa oficinalis, like most mints, displays square stems and opposite leaves. The leaves, which are the part used medicinally, are green with serrated edges and exude a lemony odor when brushed or crushed. This southern Eurasian native, now naturalized in much of the world, produces small yellow-white flowers at leaf nodes throughout the summer and fall. Typical plants reach 0.5 to 1 m in height. Unlike most mints it does not produce stolons. Lemon balm is native to southern Eurasia. The world balm is derived from the term “balsam,” referring to the delightful odor of the plant. The genus name Melissa derives from a Greek word for bees, which are strongly attracted to this plant.

HISTORY AND FOLK USE

Lemon balm has been employed in the traditional herbal medicine of Europe for millennia. It was used primarily for people suffering from dyspepsia and nervou~ness.~ It was discussed 2000 years ago in the works of ancient Greek and later Roman herbalists and physicians for these purposes as well as for wound healing and insect bites.6 The seventeenth century herbalist Nicholas Culpeper lauded the benefits of lemon balm in enhancing digestion, relieving melancholy, and ”opening the brain.”’ The Basque used lemon balm as a digestive for nervous stomachs and as a sedative for insomnia, hysteria, and depression as well as for heart palpitations caused by nerves. They also used it for neuralgias and to reguCHEMICAL COMPOSITION late menses, and combined it with cloves as a topical for Several groups of constituents endow lemon balm toothaches.8 with its medicinal characteristics. The leaves contain The Eclectic physicians in North America used lemon balm as a moderate stimulant, diaphoretic, and antispas0.02% to 0.15% volatile oil, accounting for the lemon modic? The standard infusion was often combined with odor. Two major classes of terpenoids are found in this lemon juice to treat fevers and painful menstruation. The oil-hydrocarbon terpenes, particularly citral a and b, Cherokee used the plant similarly, and the Costanoan and sesquiterpenes, particularly beta-caryophyllene.’ tribe used the decoction for infant’s colic and stomach Lemon balm is also a rich source of flavonoid glycosides such as luteolin-3’-glucuronide and a~igenin.2,~ aches.1° 1065

0

antibacterial and antiparasitic activity of lemon balm is warranted.

Thyroid Effects Tannins, rosmarinic acid, luteolin, and other phenolic compounds as well as aqueous extracts of lemon balm Figure 1061 ciiral.

PHARMACOLOGY The pharmacodynamics of lemon balm are complex because of the large number of active and secondary constituentspresent in the plant. The volatile oil fraction appears to have antimicrobial, antiviral, and antiparasitic activity and to contribute to the anxiolytic and relaxing effects of lemon balm. The flavonoids and rosmarinic acid are antioxidant. Rosmarinic acid and related polyphenolic compounds also are anxiolytic, sedative, and antiviral, and they inhibit both complement and protein synthesis. Various extracts containing some or all of these constituents show similar properties as well as having antithyroid effects.

Sedative Effects Animal studies confirm that lemon balm constituents and extracts have a calming effect on the central nervous system. For instance, a tincture of lemon balm was sedative, analgesic, and hypnotic in mice and potentiated the effects of phenobarbital." On the basis of historical descriptions of lemon balm as a prime remedy for dementia and anxiety, researchers began to investigate whether this herb might have cholinergic activity. In vitro studies on human neurons with ethanolic extracts of lemon balm have confirmed this theory.12 The inhibitory concentration of 50% (ICm) for binding to nicotinic and muscarinic receptors was less than 1mg/ml in the assay used with some of the most potent extracts, with nicotinic activity being somewhat stronger.

Antiviral Effects Consistent in vitro data show that lemon balm has antiviral and antiretroviral effects, particularly against herpes ~implex.'~J~ Terpenoids and tannins have been implicated, with later data suggesting that water-soluble compounds (i.e., not terpenoids) are the most important, at least in lemon balm's ability to inhibit human immul ~ mechanodeficiency virus type 1 (HIV-1) in ~ i t r 0 .The nism by which lemon balm interferes with various viruses has not been established. The volatile oil of lemon balm killed blood stream forms of the parasitic organism Trypanosom brucei but had minimal activity against Leishmania major.l6 Further research on the

have diverse effects on the thyroid gland and thyroid hormones. They inhibit rat iodothyronine deiodinase in vitro and prevent bovine thyroid-stimulating hormone (TSH) from stimulating human thyroid membranes in ~ i t r o . l The ~ J ~latter effect was due to adduct formation between polyphenols and TSH, thereby preventing TSH receptor binding. Adducts also form with immunoglobulin G antibodies formed in patients with Graves' disease that mimic TSH, blocking their binding to the TSH receptor in ~ i t r 0 . l ~

Other Effects Preliminary laboratory investigations suggest a wealth of other miscellaneous effects of lemon balm. Rosmarinic acid inhibits C3 and C5 convertases, suggesting an antiinflammatory effect for lemon balm.2°*21Lemon balm flavonoids show potent antiperoxidant activity? Lemon balm was antiulcerogenic in rats in one trial, both alone and in combination with various other herbs traditionally used to treat patients with ulcers.23Lemon balm extracts did not exhibit spasmolytic a~tivity.2~

CLINICAL APPLICATIONS Lemon balm has been shown to be effective in treating herpes simplex when applied topically, and to counteract anxiety, insomnia, and dyspepsia when taken internally, according to clinical trials. Other uses, including for hyperthyroidism and as topical treatment for neuralgia, have not been investigated in humans but are promising.

Herpes Simplex Two clinical trials have investigated the effect of various topical preparations of lemon balm on herpes labialis lesions. In one double-blind trial, 116 patients who had an outbreak of herpes within 72 hours of admission to the study were randomly assigned to receive treatment with a cream containing a 70:l extract of lemon balm or placebo (cream base alone).25Redness was relieved significantly better in the lemon balm group than in the placebo group; other symptoms were not sigruficantly different between the groups. After 5 days of treatment, 24 patients in the lemon balm group were healed completely, compared with 15 in the placebo group (no statistical analysis of this difference was offered). Physicians and patients were significantly more likely to rate lemon balm as more effective than placebo. No major adverse effects occurred, and there

Melissa officinalis (Lemon Balm) was no difference between the groups in the rate of adverse effects. In a second double-blind trial, 66 men and women were randomly assigned to apply either a lemon balm cream similar to the one studied in the first trial or Global average daily symptomatic relief was sigruficantly better in those given lemon balm. Other measures of efficacy, including physician rating of global outcomes and number of vesicles, were not signhcantly different between the groups but showed a consistent trend in favor of lemon balm. No adverse effects were reported. The effects of lemon balm creams on herpes lesions are mild and reduce symptoms only in a minority of patients. Nevertheless, the harmlessness and low cost of the therapy recommend it for at least a therapeutic trial in patients with mild symptoms.

Anxiety, Agitation, Insomnia Several clinical trials have evaluated the effects of lemon balm extracts in people with mild anxiety and in relaxing otherwise healthy people. In an older double-blind German study, 102 men and women with ”vegetative dystonia” (mild anxiety) were randomly assigned to receive either a lemon balm-containing product or pla~ebo.~’ The lemon balm product contained, per 5 ml, 27 mg lemon balm volatile oil,36 mg orange peel volatile oil, 4 mg nutmeg volatile oil, and 16 mg cinnamon volatile oil.Participants took 0.23 ml per kg body weight three times daily for 8 weeks. Several psychological tests showed that subjects taking the lemon balm product had significantly less overall anxiety, nervousness, excitability, and emotional lability than subjects taking the placebo. Adverse effects were not reported. A later double-blind crossover trial randomly assigned 20 healthy young men and women to receive either a single dose of an unspecified extract of lemon balm at one of three levels (300, 600, or 900 mg) or placebo.28 Subjects went through a 7-day washout period, then crossed over to another group, until each subject had taken each of the four possible agents. Various assessments undertaken immediately after intake of each agent and for the next 6 hours showed that the 600-mg dose most effectively improved attention compared with placebo. The 300-mg dose increased calmness, whereas the 900-mg dose reduced alertness compared with placebo. In vitro investigations suggested that these results may have been mediated by the cholinergic effects of lemon balm constituents. This mechanism of action has led researchers to investigate the effects of lemon balm volatile oil applied as lotion in a double-blind trial of patients with Alzheimer’s di~ease.2~ The relaxing effects of lemon balm have also led to interest in its potential for patients with insomnia. A double-blind trial in 98 generally healthy women and

men with mild insomnia was undertaken, comparing a combination of Valerianu officinalis (valerian) root and lemon balm with placebo for 1month.30The herbal product contained 120 mg of a 4.5:l valerian root extract and 80 mg of a 5:l lemon balm leaf extract. Three tablets were to be taken 30 minutes before bed. The extract was sigruficantly more effective than placebo in improving subjectively rated sleep quality, although recordings of sleep quality on a visual analog scale did not show any differences between the two groups. There was no difference between the groups in rates of intolerability or adverse effects. The equivocal results of this trial and the fact that lemon balm was combined with valerian make it difficult to assess the true efficacy of lemon balm in relieving insomnia. Note that lemon balm is approved by the German Commission E, an official body of the German government that reviewed available medical evidence and then decided which herbs were allowed for treatment of which conditions, for the treatment of nervous sleeping disorder^.^^

Dyspepsia Lemon balm leaf is approved by the German Commission E for treatment of “functional gastrointestinal complaints,” which presumably refers to dyspepsia and possibly irritable bowel syndrome (IBS)?] No clinical trials documenting the efficacy of lemon balm for dyspepsia were retrieved by a literature search. Lemon balm has been studied only as part of the product Iberogast, which also contains lberis amaru (bitter candytuft), Mutricaria recutitu (chamomile),Mentha x piperitu (peppermint), Carurn cuwi (caraway), Glycyrrhizu glubru (licorice), Angelica archangelica (garden angelica), Chelidonium rnujus (greater celandine), and Silybum muriunum (milk thistle). In a double-blind trial, 60 patients with dyspepsia were randomly assigned to receive Iberogast, Iberogast without Zberis umara (IWI), or placebo for 4 weeks.32Both Iberogast and IWI relieved symptoms significantly better than placebo, though Iberogast led to significantly more rapid improvement than IWI. There were no major adverse effects. Clearly this trial does not address the efficacy of lemon balm in isolation, although it does support the concept that a combination of carminative herbs such as lemon balm and peppermint can have a beneficial effect on the health of patients with dyspepsia. More research on lemon balm in patients with dyspepsia and IBS is required at this point.

DOSAGE Lemon balm is traditionally employed as a tea or tincture. The dried leaf should still smell strongly of lemon and should be dark green; if not, it is of inferior quality. For a tea, 2 to 3 tsp of herb is steeped in 1cup hot water for 10 to 15 minutes; three cups of this sort are drunk daily?

Pharmacology of Natural Medicines

The dose of a tincture,made preferably from fresh material and as concentrated as possible (1:2 to 1:3 weighttu-volume ratio), is taken 2 to 6 ml three times daily? There is no widely accepted standardization to ensure quality lemon balm extracts, although a minimum 0.05% volatile oil content is recommended by the German Commission E.3l Pure volatile oil of lemon balm may also be utilized at a dose of 1 to 3 drops taken internally three times daily in adults, or by topical application to the skin in a cream, lotion, or fixed oil base. Because of the expense of extracting the oil from this plant, however, there are many adulterated products on the market that contain lemon scent, lemon grass, or other lemonscented herbs and not lemon balm.

in euthyroid or hypothyroid patients, on the basis of in vitro reports of thyrosuppressive effects discussed previously, there are no published reports of thisoccurrence. Controlled trials in humans have proved that lemon balm, combined with extracts of V. oficinalis (valerian) root, do not interfere with the ability to drive or operate heavy machinery?

DRUG INTERACTIONS

Lemon balm has no known toxic effects. Despite the theoretical concern that it might suppress thyroid function

There are no documented drug interactions for lemon balm. Given its effects on thyroid function in vitro, there is a theoretical concern that the herb may have additive or synergistic effects with thyrosuppressive drugs and may interact in unpredictable ways with thyroid hormone replacement agents. Lemon balm should be combined with these classes of drugs only under careful supervision by an experienced health care professional.

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16. Mikw J, Harkenthal M, Steverding D, Reichling J. In vitro effect of essential oils and isolated mono- and sesquiterpenes on Leishmania mjor and Typanosoma brucei. Planta Med 2000;66:366-368. 17. Auf’mkolk M, Kohrle J, Gmbinger H, et al. Antihormonal effects of plant extracts: iodothyronine deiodinase of rat liver is inhibited by extracts and secondary metabolites of plants. Horm Metab Res 1984;1618&192. 18. Auf’mkolk M, Ingbar JC, Amir SM, et al. Inhibition by certain plant extracts of the binding and adenylate cyclase stimulatory effect of bovine thyrotropin in human thyroid membranes. Endocrinology 1984;115527-534. 19.Auf‘mkolk M, Ingbar JC, Kubota K, et al. Extracts and autooxidized constituents of certain plants inhibit the receptorbinding and the biological activity of Graves’ immunoglobulins. Endocrinology 1985;116:1687-1693. 20. Englberger W, Hadding U,Etschenberg E, et al. Rosmarinic acid: a new inhibitor of complement C3-convertase with anti-inflammatory activity. Int J Immunopharmacol1988;10729-737. 21.Peake PW, Pussell BA, Martyn P, et al. The inhibitory effect of rosmarinic acid on complement involves the C5 convertase. Int J Immunopharmacol1991;13853-857. 22.Hohmann J, Zupko I, Redei D, et al. Protective effects of the aerial parts of Salvia officinalis, Melissa oficinalis and hvandula angustifolia and their constituents against enzyme-dependent and enzyme-independent lipid peroxidation. Planta Med 1999;65: 576-578. 23. Khayyal MT, el-Ghazaly MA, Kenawy SA, et al. Antiulcerogenic effect of some gastrointestinally acting plant extracts and their combination. Arzneimittelforschung 2001;51:545-553. 24. Forster HB, Niklas H, Lutz S. Antispasmodic effects of some medicinal plants. Planta Med 1980;40:309-319. 25. Wolbling RH, Leonhardt K. Local therapy of herpes simplex with dried extract of Melissa officinalis. Phytomedicine 1994; 1:25-31. 26. Koytchev R, Alken RG, Dundarov S. Balm mint extract (Lo-701) for topical treatment of recurring herpes labialis. Phytomedicine 1999;6225-230.

TOXICOLOGY

Melissa officinalis (Lemon Balm) 27.Biichner KH, Hellings H, Huber M, et al. [Double blind study as evidence of the therapeutic effect of Melissengeist on psychovegetative syndromes.]Med Klin 1974;69:1032-1036. 28. Kennedy DO, Scholey AB, Tidesley NT, et al. Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm). Pharmacol Biochem Behav 2002;72953-964. 29. Ballard CG, OBrien JT,Reichelt K, Perry EK. Ammatherapy as a safe and effective treatment for the management of agitation in severe dementia: the results of a double-blind, placebo-controlled trial with Melissa. J Clin Psychiatry 2002;63:553-558. 30. Cemy A, Schmid K. Tolerability and efficacy of valerian/lemon balm in healthy volunteers (a double-blind, placebo-controlled, multicentre study). Fitoterapia 1999;70221-228.

31. Blumenthal M, Busse WR, Goldberg A, et al, eds. The complete German commission E monographs: therapeutic guide to herbal medicines. Austin, Tx: American Botanical Council, 1998:16(1161. 32. Madisch A, Melderis H, Mayr G, et al. [A plant extract and its modified preparation in functional dyspepsia: results of a double-blind placebo controlled comparative study.] Z Gastroenterol 2001;39: 511-517. 33. Hoffmann D. The new holistic herbal. New York Barnes & Noble Books, 1990177. 34.Albrecht M, Berger W, et al. [Psychopharmaceuticals and safety in traffic.] Z Allegmeinmed 1995;71:1215-1221.

Mentha piperita (Peppermint) Michael T. h3urray, ND Joseph E. Pizzorno Jr, NI) CHAPTER CONTENTS General Description 1071 Chemical Composition 1071 History and Folk Use 1071 Pharmacology 1072 Carminative Effects 1072 Antispasmodic Effects 1072 Choleretic Effects 1072 External Analgesic Effects 1072

Mentha piperitu (family: Labitae) Common name: peppermint

Clinical Applications 1072 Irritable Bowel Syndrome 1072 Nonulcer Dyspepsia 1072 Cholelithiasis 1073 External Analgesic 1073 The Common Cold 1073 Headache 1073 Dosage 1073 Toxicology

1073

Drug Interactions 1074

Peppermint is a natural hybrid of garden spearmint (Mentha spicutu) and water mint ( M e n t h uquutica). First described in England in 1696, peppermint now grows all over the world.' The two most popular varieties are white peppermint (Mentha piperita var. oficinalzs) and black peppermint (M. piperita var. vulgaris). Both are typical members of the mint family, that is, herbs with square stems, horizontal rhizomes, and lanceolated leaves with a serrated edge. Black peppermint has deep red stems with purplish-tinged dark green leaves, whereas white peppermint has green stems with lighter green leaves. Both varieties produce purple flowers during the summer months. For medicinal effects, the aerial portion of the plant is the most widely used.

chromatographic analysis of peppermint oil typically shows more than 40 different peaks. Most of the volatile oil components are terpenoids.' The composition of menthol and other volatile oil components is sensitive to climate and latitude as well as to the maturity of the plant. Pharmaceutical-grade peppermint oil is produced by distilling the fresh aerial parts of the plant harvested at the very beginning of the flowering cycle. The oil is standardized to contain not less than 44% free menthol and a minimum of 5% esters calculated as menthyl acetate. The ketone component (calculated as menthone) usually ranges from 15% to 30%, with the remainder of the oil being composed of various terpenoids.' Menthol is also synthesized by hydrogenation of thymol. Other components of peppermint herb that may contribute to its medicinal effects are polymerized polyphenols (19% of dry weight), flavonoids (12%), tocopherols, carotenes, betaine, and choline.2

CHEMICAL COMPOSITION

HISTORY AND FOLK USE

The major medicinal component of peppermint is its volatile oil, which can be found in concentrations of up to 1.5% in the herb, but is usually present in the range 0.3% to 0.4%. The principal components of the oil are menthol (28%-29%) (Figure 107-l), menthone (20%-31%),and menthyl acetate (3%-10%),although gas

Although peppermint was not officially recognized until the seventeenth century, mints have been used for their medicinal effects for thousands of years. Records from the ancient Egyptian, Greek, and Roman eras show that other members of the mint family, particularly spearmint (M. spicutu), were used.l

GENERAL DESCRIPTION

1on

Pharmacology of Natural Medicines

for pain. The initial cooling effect is followed by a period of warmth.

CLINICAL APPLICATIONS H,C

A

CH3

Figure 107-1 Menthol.

The most popular uses of peppermint for medicinal purposes were in the treatment of indigestion and intestinal colic, colds, fever, and headache.

PHARMACOLOGY The pharmacology of peppermint is attributed almost entirely to its menthol components. The major categories of actions for peppermint and menthol are as follows: Carminative Antispasmodic Choleretic External analgesic Nasal decongestant

Carminative Effects Carminatives promote the elimination of intestinal gas. Peppermint and peppermint oil are well-accepted carminatives. Although the exact mechanism of action has not been determined, one proposed mechanism is relaxation of the esophageal sphincter, which leads to the release of gas pressure in the stomach?

Antispasmodic Effects The mechanism behind peppermint oil’s antispasmodic effects has been determined. Researchers have concluded that peppermint oil inhibits contractions of isolated smooth muscles by blocking the influx of calcium into the muscle ~ells.~5 The researchers hypothesized that the clinical effectiveness of peppermint oil in the treatment of the irritable bowel syndrome is a result of inhibition of the hypercontractility of intestinal smooth muscle, thereby returning the muscle to its proper tone.

Choleretic Effects Choleretics stimulate the flow of bile. Menthol and related terpenes have been shown to exert a choleretic effect as well as to improve the solubility of the

External Analgesic Effects The external analgesic and counterirritant effects of menthol are well accepted. When applied to the skin, peppennint oil or menthol stimulates the nerves that perceive cold and simultaneously depresses those

Peppermint oil is the most extensively used of all the volatile oils. Pharmaceutical preparations often utilize peppermint oil or menthol for its therapeutic and flavoring properties. For example, it is used extensively in antacid products and irritant laxatives for both its flavor and its therapeutic effects. The same is true for its inclusion in mouthwash preparations and after-dinner mints. The pharmacologic effects of peppermint and peppermint oil are useful in a number of clinical situations. The most notable are as follows: Irritable bowel syndrome Intestinal colic Gallstones Musculoskeletal pain The common cold

Irritable Bowel Syndrome Enteric-coated peppermint oil (ECPO) has been shown to be quite helpful in improving gastrointestinal (GI) function in individuals suffering from the irritablebowel syndrome (IBS), a common functional disorder of the large intestine characterized by some combination of (1)abdominal pain, (2) altered bowel function, constipation, or diarrhea, (3) hypersecretion of colonic mucus, (4)dyspeptic symptoms (flatulence, nausea, anorexia), and (5)varying degrees of anxiety or depression. Several double-blind studies have shown ECPO to be effective in relieving all symptoms of IBS in approximately 70% to 85% of cases within 2 to 4 weeks.11-15In one trial, 42 children between 8 and 10 years old with IBS were given ECPO or placebo for 2 weeks. Dosage was one capsule three times daily for children weighing 30 to 45 kg and two capsules three times daily for children weighmg more than 45 kg. After 2 weeks, 76% of the ECPO p u p reported sisruficant improvements, compared with only 19%in the placebo group.l5 One of the central findings in IBS is a hypercontractility (excessive contraction) of intestinal smooth muscle. Peppennint oil, especially when combined with caraway oil, inhibits the hypercontractility of intestinal smooth muscle, making it useful in IBS as well as esophageal spasm and intestinal colic.16 Although effective on its own, ECPO is best used within a comprehensive treatment protocol for IBS (see Chapter 183).

Nonulcer Dyspepsia In addition to its effects in IBS, enteric-coated peppermint oil has benefits in nonulcer dyspepsia (NUD),

Mentha piperita (Peppermint)

gastroesophageal reflux disorder (GERD), and intestinal overgrowth of Cundidu ulbicuns (a common yeast implicated in many cases of IBS) and Helicobuctw pylori. NUD and GERD are basically catch-all terms that reflect a kind of wastebasket diagnosis that doctors use when they cannot find any real reason for a patient’s upper GI dysfunction, just as IBS is used as a wastebasket diagnosis for lower GI dysfunction. Symptoms of NUD and GERD include heartburn as well as difficulty swallowing, feelings of pressure or heaviness after eating, sensations of bloating after eating, stomach or abdominal pains and cramps, and of the symptoms of IBS. About three of every ten patients with NUD and GERD also meet the criteria for IBS. Several of the clinical studies in patients with IBS featured the combination of peppermint oil and caraway oil in an enteric-coated capsule (ECPCO).The results of these trials indicate that this combination produces better results than peppermint oil alone for symptoms of IBS. Later studies also indicate that the combination of peppermint and caraway oils is quite helpful in improving NUD.17,18 In one double-blind study, 120 patients with NUD were given either the peppermint and caraway seed oil combination or cisapride (Propulsid)for 4 weeks.18 The mean reduction of pain score was comparable in the two groups (4.62 for ECPCO; 4.6 for cisapride). Other symptoms of NUD also improved in a similar fashion. Positive results were also found in H.pylori-positive individuals. Although the enteric-coated peppermint and caraway oil combination is extremely safe at recommended levels, cisapride caused fatal heart rhythm problems. According to the U.S. Food and Drug Administration, at least 111people died as a result of cisapride use, and nearly 400 experienced heart abnormalities. Cisapride (Propulsid)has subsequently been taken off the market.

Cholelithiasis Several studies have shown that a formula containing menthol and related terpenes (menthone, pinene, borneol, cineol, and camphene) demonstrates efficacy in dissolving gallstones.”1° This approach to gallstone removal offers an effective alternative to surgery and has been shown to be safe even when the formula is consumed for prolonged periods (up to 4 years). Terpenes, like menthol, help dissolve gallstones by reducing bile cholesterol levels while increasing bile acid and lecithin levels in the gallbladder. Because menthol was the major component of this formula, peppermint oil, especially if enteric-coated, may offer similar benefits.

External Analgesic Menthol and related substances can be used as counterirritants in the treatment of arthritis, fibromyositis, tendonitis, and other inflammatory conditions involving the musculoskeletal system.

The Common Cold Menthol and peppermint oils are often employed in the treatment of the common cold as components of topical nasal decongestants, cough and throat lozenges, ointments, salves, and inhalants. Whether the use of these products is of benefit has not been proven in clinical studies. However, their popularity appears to represent their ability to help make breathing easier during the common cold. The best method for using menthol or peppermint oil is to apply commercial preparations to the upper chest during periods of rest so that the vapors can be inhaled continuously. Peppermint tea may also be of benefit during the common cold. Peppermint as well as other members of the mint family has demonstrated significant antiviral activity as well as a mild diaphoretic effect.I9The most active antiviral components, the polyphenols, are concentrated in the tea.*Peppermint oil has shown antiviral activity against Newcastle disease, herpes simplex, and vaccinia.

Headache In a double-blind, placebo-controlled, randomized crossover trial, topical application of peppermint oil to the forehead and temples resulted in a statistically significant decrease in muscle tension as reported subjectively and measured objectively by electromyographic activity of the temporal muscle. In addition, the oil application decreased sensitivity to pain.2O

DOSAGE Peppermint is most widely used as a tea (infusion), on its own or in Combination with other botanicals. The infusion is usually prepared with 1 to 2 teaspoons of the dried leaves per 8 ounces of water. The dosage of peppermint oil administered in an enteric-coated capsule for the treatment of the irritable bowel syndrome is one to two capsules (0.2 ml/capsule) three times daily between meals. This dosage is also appropriate for the treatment of gallstones. The dosage of menthol as an external analgesic is 1.26% to 16% applied to the affected area no more than three or four times daily.

TOXICOLOGY Peppermint herb is generally regarded as safe (GRAS) when used as a tea; however, hypersensitivity reactions have been reported. Adverse reactions to ECPO capsules are rare but include hypersensitivity reactions (rash), heartburn, bradycardia, and muscle tremor. When applied topically, peppermint oil or menthol can induce contact dermatitis and hypersensitivity reactions. The likelihood of development of such a reaction

Pharmacology of Natural Medicines is enhanced when heating pads are used in conjunction with topically applied preparations containing menthol.21 In rats the lethal dose for 50% of subjects (LD,) of menthol is 3280 mg/kg. The fatal oral dose in humans is calculated at 1g/kg. In one study, repeated high-dose feeding of rats for 28 days with peppermint oil produced signs of dose-related brain lesions, but the dosage (40mg/kg) given to the rats far exceeded those used in

1.Briggs C. Peppermint medicinal herb and flavoring agent. Can P h J 1993;M~ch:89-92. 2. Duband F, Camat AP,Camat A, et al. [Aromatic and polyphenolic composition of infused peppermint, Menthu x piperitu L.] Ann Pharm Fr 1992;50:146-155. 3. GiachettiD, Taddei E,Taddei I. Pharmacological activity of essential oils on Oddi’s sphincter. Planta Med 1988;54.389-392. Aaronson PI. The mechanism of action of peppermint oil 4. Hills JM, in gastrointestinal smooth muscle: an analysis using patch clamp electrophysiology and isolated tissue pharmacology in rabbit and guinea pig. Gastroenterology 1991;101:55-65. 5.Hawthome M, Ferrante J, Luchowski E, et al. The actions of peppermint oil and menthol on calcium channel dependent processes in intestinal, neuronal and cardiac preparations. Aliment Pharmacol Ther 1988;2101-118. 6. Hodinsky BZ. Terpenes in the treatment of gallstones. Minn Med 1971;54:649-652. 7. Bell GD, Doran J. Gall stone dissolution in man using an essential oil preparation. Br Med J 1979;1:24. 8. Doran J, Keighley RB, Bell GD. Rowachol-a possible treatment for cholesterolgallstones. Gut 1979;20312-317. 9. Ellis WR, Bell GD. Treatment of biliary duct stones with a terpene preparation. Br Med J 1981;282611. 10. SomervilleKW, Ellis WR, Whitten BH, et al. Stones in the common bile duct: experience with medical dissolution therapy. Postgrad Med J 1985;61:313-316. 11.Mascher H, Kikuta C, %el H. Pharmacokinetics of menthol and carvone after administration of an enteric coated formulation containing peppermint oil and caraway oil. Armeimittelforschung 2001;51:465-469. 12. SomervilleK, Richmond C, Bell G. Delayed release peppermint oil capsules (Colpermin)for the spastic colon syndrome: a pharmacckinetic study. Br J Clin Pharmacol1984;18:638-640.

DRUG INTERACTIONS Peppermint oil may enhance the oral bioavailability of certain drugs.Most notably, in a study in rats, peppermint oil (100 mg/kg) tripled the mean cyclosporinemaximum concentration and increased the area under the concentrationversus-time c~rve.2~ This dosage does not reflect the dosage used in clinical studies; however, physiciansshould be aware that peppermint oil may raise serum levels of certain drugs when the agents are coadministered.

13.Rees W, Evans B, Rhodes J. Treating irritable bowel syndrome with peppermint oil. Br Med J 1979;2835-836. 14. Lech Y, Olesen KM, Hey H, et al. [Treatmentof irritablebowel syndrome with peppermint oil: a doubleblind study with a placebo.] Ugeskr Laeger 1988;1502388-2389. 15.Kline RM, Kline JJ,Di Palma J,et al. Fnteric-coated, pHdependent peppermint oil capsules for the treatment of irritable bowel syndrome in children. J Pediatr 2001;138:125-128. 16.Micklefield GH, Greving I, May B. Effects of peppermint oil and caraway oil on gastroduodenal motility. Phytother Res 2000; 1420-23. 17. May B, Kuntz HD, Kieser M, et al. Efficacy of a fixed peppermint oil/caraway oil combination in non-ulcer dyspepsia. Arzneimittelforschung1996;46:1149-1153. 18.May B, Kohler S, Schneider B. Efficacy and tolerability of a fixed combination of peppermint oil and caraway oil in patients suffering from functional dyspepsia. Aliment Pharmacol Ther 2000;14 1671-1677. 19. Herrmann EC, Kucera L. Antiviral substances in plants of the mint family (Labiatae). 3. Peppermint (Menthu pipen’tu) and other mint plants. Proc Soc Exp Biol Med 1967;124:874-878. 20. Gobel H, Sdunidt G, Dworshak M, et al. Essential plant oils and headache mechanisms. Phytomedicine 1995;2:93-102. 21. Heng MC. Local necrosis and interstitial nephritis due to topical methyl salicylate and menthol. Cutis 1987;39442-444. 22. Olsen P,Thorup I. Neurotoxicity in rats dosed with peppermint oil and pulegone. Arch Toxicol 1984;Supp17408-409. 23. Thorup I, Wurtzen G, Carstensen J, et al. Short term toxicity study in ratsdosed with peppermint oil. Toxicol Lett 1983;19211-215. 24.Wacher VJ, Wong S, Wong HT. Peppermint oil enhances cyclosporine oral bioavailability in rats: comparison with c-alphatocopheryl poly(ethy1ene glycol 1000) succinate (TF’GS) and ketoconazole. J Pharm Sci 2002;91:77-90.

Microbial Enzyme Therapy Corey Resnick, ND CHAPTER CONTENTS Introduction 1075 Pharmacology 1076 Intact Protein Absorption 1076 Comparison of Fungal Lipase and Pancreatin 1077

Lactose Intolerance 1078 Vascular Disease 1079 Celiac Disease 1080 Food Allergies 1081 Summary 1081

Clinical Applications 1077 Malabsorptionand Steatorrhea 1077

INTRODUCTION Enzymes derived from microbial species, such as Aspergillus o y m e and Rhizopus arrhizus are safe and effective in the treatment of a wide variety of disorders. In certain cases, microbial enzymes are sigruficantly more effective than animal-derived enzymes or other available therapies. Some microbial enzyme preparations are particularly well suited for clinical application because of their ability to hydrolyze physiologically and/or pathologically important substrates over a wide pH range and their inherent ability to resist degradation by stomach acid. Clinically, microbially derived enzyme preparations have most often been used in oral administration at mealtimes to aid digestion through hydrolyzing of dietary substrates such as fats, carbohydrates, and proteins. Of additional interest, however, is the potential usefulness of microbial enzymes administered orally between meals. On the basis of the theory that some portion of orally administered enzymes is absorbed intact into the blood stream, these enzymes can act systemically to hydrolyze substrates of therapeutic importance (e.g., fibrin). Indirect evidence in support of this theory is presented later in this chapter. Although relatively new to many clinicians in the United States, microbial enzymes have been used in ethnic food production for many centuries, and in clinical practice and research for more than 50 years. In Japan for example, A. oyzae has a long history of use in the

fermentation of soybeans to produce soy sauce, tamari, and miso. Beginning around the 1950s, published research in Europe and Scandinavia reported on the therapeutic use of purified, concentrated preparations of enzymes from A. oyzae and other fungal species. Bergkvist was among the first to report on the isolation and purification of individual enzymes produced by A. oyzae. Wolf and Ransberger studied the effects of enzymes from AspergilZus and other plant species (e.g., Lens esculenta and Pisum safivum) along with animal enzymes (e.g., trypsin, chymotrypsin) in the treatment of cancer. Roschlau and others studied the effectiveness of intravenously administered proteolytic enzymes from A. oryzae in the treatment of vascular disease in humans and animals. Later research has studied increasingly diverse types and sources of microbially derived enzymes, including various protease, lipase, carbohydrase, and cellulase preparations. Controlled in vivo studies using enteral and parenteral routes and in vitro studies have examined the effectiveness of these enzymes in a wide range of conditions, including the following: Maldigestion Malabsorption Pancreatic insufficiency Steatorrhea Celiac disease Lactose intolerance 1075

Arterial obstruction Ischemic disease Thrombotic disease Inflammatory disorders Rheumatoid arthritis Anecdotal reports indicate that enzymes derived from both microbes and plants are being used in an even broader spectrum of clinical conditions. This chapter reviews published clinical and experimental research in the emerging field of microbial enzyme therapy. Theoretical discussions are presented on the oral administration of microbially derived enzymes for therapeutic purposes, with suggested areas for further research.

PHARMACOLOGY Intact Protein Absorption Contrary to long-held theories that the healthy intestinal mucosa is an essentially impermeable barrier to proteins and large polypeptides, there is now irrefutable evidence that macromolecules can and do pass intact from the human gut into the blood stream under normal conditions.’-8 This fact may help explain the apparent effectiveness of enzyme therapy in the nutritional management of a number of conditions, including vascular disease, maldigestion/malabsorption, food allergies, inflammatory bowel disease, immune dysfunction, and certain inflammatory disorders.1,2*818

Evidence for Intestinal Absorption of Intact Proteins Numerous whole proteins, including plant and animal enzymes, have been shown in human and animal studies to be absorbed intact into the blood stream after oral administration. Examples are human albumin and lactalbumin, bovine albumin, ovalbumin, lactoglobulin,ferritin (molecular weight 500,000 DALT), chymotrypsinogen, elastase, and other large molecules, such as botulism toxin (1,000,000 DALT).1-3J9-22 Even inert particles, such as carbon particles from India ink’and whole viruses,u can cross the healthy intestine. Immunoglobulins have been detected in peripheral tissues after oral administration. In a study conducted in rats, 5% of an oral dose of bovine immunoglobulin G was found substantially intact in peripheral tissuese6 Studies have demonstrated the intact absorption of plant enzymes, such as bromelain derived from pineapple and peroxidase (40,000 DALT) from horseradish. An in vivo study in fish showed that 0.7%of a dose of horseradish peroxidase was detected intact in examined peripheral tissues after oral Proteins and polypeptides absorbed intact from the gut can exert pharmacologic effects in target tissues.

Several peptide hormones are known to be biologically active when administered orally, including luteinizing hormonereleasing factor and thyrotropin-releasing hormone.2526Even insulin can cross the intestinal mucosa intact and produce sigruficanthypoglycemia under limited circumstances (e.g., in the presence of protease inhibitors or hypertonic solutions in the intestinal lumen).27B It now appears probable that enzymes such as acid-stable protease from A. oryme (molecular weight -35,000 DALT) are absorbed intact after oral administration. To the extent that such absorption does occur, Aspergillus-derived proteases may exhibit properties in the blood stream that they are known to possess in other applications. Such properties include the ability to hydrolyze dietary proteins and polypeptides that have leaked into the blood stream as food antigens. Protease from Aspergillus is also known to possess thrombolytic, fibrinolytic, and antiinflammatory properties29-35 and has been shown to be effective when administered intravenously in reestablishing circulation through chronically obstructed arteries in humans (see

Mechanism for Intestinal Absorption of Macromolecules Two general types of mechanisms have been suggested to account for the intact absorption of macromolecules and particles.1,2,8 In the ”transcellular route,” macromolecules are believed to penetrate the brush-border membrane of intestinal mucosal cells by the following mechanisms: Diffusion through aqueous “pores” or through lipid regions in the membrane Pinocytosis (endocytosis)or phagocytosis Carrier-mediated transport systems Some combination of these routes

A “paracellular” or intercellular route also appears likely, in which molecules pass between mucosal cells. This route includes passage through so-called extrusion zones, which occur as old cells are displaced by new ones in the rapidly proliferating mucosal tissue. A specialized cell type has been identified overlying Peyer ’s patches (subepithelial lymphoid tissue) throughout the small intestine. These so-called M cells permit subepithelial tissue lymphocytes to come extremely close to the intestinal lumen, apparently facilitating lymphocyte “sampling” of luminal antigens and thereby stimulating an immune response. A number of studies have shown rapid passage through M cells (by pinocytosis) of macromolecules such as horseradish peroxidase and solid particles such as viruses.1*234

Pancreatic Recycling of Enzymes There is strong evidence that the body seeks to conserve its digestive enzymes by absorbing intact endogenous

and exogenous enzymes. Several human studies have shown that exogenous pancreatic enzymes trypsin and chymotrypsinare absorbed intact into the blood stream in an enzymatically active form after oral administration!14 Even more dramatic is the finding that both endogenous and exogenous pancreatic enzymes not only are absorbed intact from the gut but also are transported through the blood stream, taken up intact by pancreatic secretory cells, and re-secreted into the intestinal lumen by the pancreas, to be mixed with newly synthesizedpancreatic enzymesMThe existence of this enteropancreatic circulation of proteolytic enzymes is closely analogous to the recycling of bile salts by the liver. Of further interest is the possibility that oral supplementation with enzymes may have a sparing effect on the body’s own digestive enzymes, perhaps aiding organ regeneration, by hydrolyzing substrates (foods) for which endogenous enzyme would otherwise be required. Support for this hypothesis may also be found in the phenomenon of adaptive secretion, by which the pancreas, stomach, and possibly other organs secrete specific digestive enzymes in direct response to the type and amount of food substrate pre~ent.4~t~

Comparison of Fungal Lipase and Pancreatin pH Range Many of the enzymes derived from A. oryzae and related fungal species possess unusually high stability and activity under a broad range of pH conditions. These properties distinguish them from animal enzymes such as pepsin, pancreatin, trypsin, chymotrypsin, pancrelipase, and pancreatic amylase, which require pH conditions often lacking in persons with impaired health. For example, pepsin is active only below a pH of about 4.5, whereas pancreatin has optimum digestive activity only in an alkaline medium. In contrast, some preparations of microbe- and plant-derived enzymes are stable and active throughout a range as broad as pH.”7,9-13

Enzyme Replacement Therapy Human and animal studies have compared the effectiveness of acid-stable lipase from various fungal species with that of pancreatin in the treatment of malabsorption and steatorrhea due to pancreatic insufficiency. Administered orally at mealtime, fungal lipase has been found to be effective in these conditions and to offer certain advantages over both conventional and enteric-coated pancreatic enzyme replacement therapy. Treatment of steatorrhea using pancreatic enzyme replacement therapy is often unsatisfactory because of several factors. Gastric acid destroys up to 90% of the lipase content of exposed pancreatic enzymes (i.e., conventional pancreatin administered in powder, capsule, or tablet f ~ r m ) > ~Large - ~ ’ dosages are therefore required

for efficacy and contribute to increased expense, large number of tablets or capsules required, and poor patient ~ o m p l i a n c e . ~Furthermore, ~>~ pancreatin can cause hyperuricosuria and renal damage in large doses owing to its high purine contenLMAlthough H2receptor antagonists such as cimetidine are often used along with pancreatin to lessen intragastric ina~tivation,5~$~ this approach is unsuccessful in improving lipid digestion in many patients57and carries the risk of possible adverse side effects. Various forms of enteric-coated pancreatin (i.e., enteric-coated capsules, tablets, granules and microspheres) are formulated to dissolve above pH 5.5-6.0 and are intended to protect orally administered pancreatin against gastric a~idity.5~3 These often lack optimum efficacy, however, because most patients with pancreatic insufficiency have hyperacidity in the upper small intestine owing to decreased bicarbonate secretion. As a result, enteric-coated tablets or capsules often fail to dissolve and deliver their enzymes in the duodenum or jejunum as h1tended.5~In addition, phthalate derivatives and other excipients required for enteric coatings may cause reactions in chemically sensitive individuals. By contrast, a lipase preparation from A. oryzae is resistant to inactivation by gastric acidity and is enzymatically active in pH ranging from 2 to 10. It digests dietary fat, beginning in the stomach and continuing in the small intestine.52,60It is water-soluble, heat-stable, nontoxic, and free of some of the potential drawbacks of pancreatin replacement therapy?

CLINICAL APPLICATIONS Malabsorption and Steatorrhea Chronic panmatitis and cystic fibrosis are the most common causes of pancreatic exocrine insufficiency. Pancreatogenic steatorrhea results from failure of fat digestion, leading to lipid malabsorption, impaired nutrition, weight loss, and considerable social embarra~sment.4~6~ Lipase preparations from fungal sources have been shown to be highly effective in treating malabsorption and steatorrhea under a wide variety of conditions.m*626 A 1985 crossover control clinical trial compared the effectiveness of 10 teaspoons of a conventional pancreatic enzyme preparation (360,000 lipase units) with that of 10 capsules of enteric-coated pancreatin (100,000 lipase units) and 10 capsules of acid-stable fungal enzymes (75,000 lipase units) in patients with chronic pancreatitis, severe pancreatic exocrine insufficiency, and steatorrhea.60Seventeen patients in the study were divided into two treatment groups on the basis of surgical status. Nine patients had undergone Whipple’s procedure (bowel resection with partial duodenopancreatectomy)

3 to 8 months before the study (group A). This group had shown a preoperative reduction in stimulated pancreatic enzyme secretion to less than 10% of normal. In the remaining eight, nonsurgical patients (group B), stimulated secretion was reduced to between 4% and 28% of normal. All patients were given a diet containing 100 g fat/day; 5 days after discontinuation of all medications (pancreatic enzymes, antacids, and H2receptor antagonists), stools were collected for 72 hours. Thereafter, each group was started on identical 2-week periods of treatment using enteric-coated pancreatin first, then conventional pancreatin, and, finally, acid-stable fungal enzymes. Stools were collected for the last 3 days of each treatment period and analyzed for stool weight, fat concentration, and total fecal fat excretion. Before treatment, atl fecal parameters were pathologically elevated in all 17 patients, diarrhea and characteristic abdominal symptoms were present, and the patients had a tendency to lose weight. All three treatment protocols led to a significant reduction in total daily stool weight and total daily fecal fat excretion in comparison with controls in both groups. Perhaps more importantly, all patients in both groups became virtually symptom-free with each of the three treatment protocols. Table 108-1 shows fecal fat excretion and stool weight for controls and for each treatment protocol in group A and group B. Individual patient results in each group have been averaged together. It is interesting to note that the fungal lipase controlled signs and symptoms about as well as a 33% larger dose of entericcoated pancreatin and a 380% larger dose of conventional pancreatin. A 1988 placebo-controlled, randomized, crossover study in England compared the effectiveness of 400 mg (4800 lipase units) of acid-stable lipase from A. oryzue with that of 10,000 mg (60,000 lipase units) of pancreatin in the treatment of chronic pancreatic exocrine insufficiency in dogs.52Eleven dogs (weighing 15 to 21 kg) used in the study underwent total pancreatectomy to produce pancreatic exocrine insufficiency. All animals received intrasplenic autografts of islet of Langerhans

tissue to preserve pancreatic endocrine function. Animals served as their own controls through the use of preoperative data. The dogs were maintained on fixed diets containing 46 g/day fat. Each treatment protocol lasted 3 weeks, beginning and ending with weighing of animals and %day specimen collections for determination of fecal fat excretion and stool volume. Dogs in the untreated placebo group experienced sigruficant weight loss (p < 0.01) due to malabsorption averaging 0.9 kg over a 3-week period. Dogs receiving either 400 mg/day of A. oryzue lipase or 10,000 mg/day of pancreatin did not show significant weight loss. Similarly, both fecal fat excretion and stool volume were pathologically elevated in the placebo group. Significant reductions occurred in both fecal fat and stool volume, with no sigruficant difference between fungal lipase and pancreatin treated animals. A significant finding of the English study was the fact that a small dose of acid-stable lipase from A. oryzue (400 mg) was as effective as a dose of conventional pancreatin 25 times larger (10,000 mg) in the treatment of malabsorption, malnutrition, and steatorrhea due to pancreatic exocrine insufficiency in dogs. Unlike pancreatin, A. oryzue lipase delivers enzyme activity in the broad range from pH 2 to 10. It safely digests dietary fat, beginning in the stomach and continuing in the small intestine, and may be more effective than pancreatin in the abnormal acidic conditions commonly found in the duodenum and jejunum of patients with pancreatic insufficiency.

Lactose Intolerance Lactose intolerance produces symptoms such as abdominal pain, bloating, cramping, flatulence, belching, and diarrhea.&Maldigestion of lactose is a common problem in children and adults, occurring in 76% of apparently healthy children in one study and 56% in another singleblind, controlled trial.67Lactose maldigestion can result from genetic nonpersistence of intestinal lactase activity at some time after weaning as well as from secondary lactase deficiencies. It may or may not produce symptoms of lactose

Stool weight and fecal fat in patients with steatorrhea Fecal Fat (glday)

Stool Weight (@day)

Group A

Group B

Group A

Group B

180

82

906

675

Entericcoated pancreatin (1 00,OOOlipase units)

75

39

494

324

Pancreatin (360,000lipase units)

55 87

48

437

345

48

51 9

316

Treatment protocol Control

Fungal lipase (75,000lipase units)

The upper limit of the normal range for fecal fat excretion is 7 @day, and for stool weight is 250 @day.

Microbial Enzyme Therapy

A lactase enzyme derived from A. oryzae is effective in the treatment of lactose maldigestion and lactose intolerance when taken orally at the time of milk Moreover, this enzyme aids in the in vivo digestion of milk sugar even in healthy individuals classified as normal lactose digesters. Furthermore, the A. oryzae-derived lactase is more effective in the digestion of lactose than a similar enzyme derived from the yeast Kluyveromyces l a c t k g It is known that milk prehydrolyzed in vitro by being incubated under refrigeration with lactase is effective in the prevention of lactose intolerance in susceptible individuals. A 1986 single-blind, controlled study was designed to determine whether ingestion of lactase at mealtime was equally as effective in the treatment of lactose intolerance as prehydrolyzed milk, because the latter requires refrigeration, which is difficult to obtain in ”underdevelopedff parts of the world. The hydrogen breath test was used as an accurate and sensitive measurement of lactose digestion in vivo (see Chapter 25). The study included 48 healthy Guatemalan preschool children. The ability of participants to digest lactose from ingested whole cow’s milk was tested against four treatment protocols as follows (each protocol included 240 ml of whole cow’s milk containing 12 g of lactose): 1.Whole, intact cow’s milk 2. Milk prehydrolyzed in vitro with lactase enzyme 3. Varying amounts of lactase from K. lactis administered orally with milk 4.Varying amounts of lactase from A. oryzae administered orally with milk

Twenty-seven of the children (56%) proved to be maldigesters of lactose from the ingestion of intact milk. Twenty-five of these lactose maldigesters (93%) were found to show no lactose maldigestion (i.e., successfully treated) after the ingestion of milk prehydrolyzed with lactase in vitro for 24 hours. Rehydrolyzed milk was used as the standard for successful treatment in comparing the effectiveness of lactase enzymes derived from A. oryzue and K. 1actis.g All experimental dosages of in vivo lactase from both A. oryzae and K. lactis si@cantly reduced the volume of post-challenge hydrogen excretion as compared with intact milk (p < 0.05). However, la@ from A. oryzue was found to be equally as effective as prehydrolyzed milk, whereas K. lactis lactase was only 82%as effective. This research supports the addition of microbial betagalactosidase (lactase) to milk at mealtimes as effective in the prevention of signs and symptoms of lactose maldigestion. Ingestion of lactase with milk at mealtime avoids the inconvenience of refrigerated 24hour incubation as well as the sweeter flavor produced when milk is prehydrolyzed. In a somewhat surprising result, A. oryzae lactase was also found to improve the extent of lactose digestion in

the 21 children classified as normal, complete digesters. This finding demonstrates that the capacity for lactose digestion is actually a continuum, even in lactasepersistent subjects, rather than an all-or-none phenomenon. The efficacy of these enzymes in lactose-intolerant children and adults has now been replicated in several ~tudies.~,~~

Vascular Disease Numerous crossover, single-blind and placebo-controlled studies have confirmed the effectiveness of a proteolytic enzyme derived from A. oryzae in treating chronically obstructed arteries in humans.29-333,37,7478 In fact, intravenous therapy with fungal protease from A. oryzue is dramatically more effective than anticoagulant therapy (e.g., heparin, warfarin) at recanalizing obstructed arteries and improving blood flow through stenosed arterial ~ e g m e n t s . ~ 3 ~ , ~ ~ A 1978 controlled, single-blind crossover study evaluated the effectiveness of protease from A. oryzae versus anticoagulant therapy and placebo in 18 patients (ages 63 to 75 years) with stable intermittent claudication of at least 6 months’ duration.%Patients were divided into two groups, and a full assessment of each patient was carried out before testing. Translumbar aortogram, Doppler ultrasonographic scanning, and peripheral systolic blood pressure were used to assess the patency of eight different arterial segments in each patient (a total of 72 segments in each group). Anticoagulation therapy with warfarin was introduced after assessment and continued throughout an observation period of 3 months and subsequent trial periods. Assessment of peripheral circulation was repeated after the %month observation period of anticoagulant therapy. Thereafter, a series of six intravenous infusions of fungal protease and normal saline was given to experimental and control groups, respectively, at regular intervals over the next 2 weeks. Assessment of peripheral circulation was repeated at the end of the protease infusion treatment. No other form of therapy was given, except warfarin for anticoagulation. On admission to the study, the first group of patients receiving fungal protease therapy showed 27 obstructed segments (completely obstructed), 34 stenosed segments (partially obstructed), and only 11 patent arterial segments. The 9 patients receiving saline (placebo) showed 25 obstructed,26 stenosed, and 21 patent arterial segments before treatment (Table 108-2). At the end of the %month observation period (anticoagulation therapy only), no changes in Doppler ultrasonography findings or ankle/arm blood pressure ratios were found in either group. At the end of the 2-week trial period, 3 of the 72 arterial segments in the saline group had progressed to increased obstruction (i.e., 4% worse). In contrast, treatment with the fungal protease infusion improved patency of 33 of 72 arterial

segments after placebo or fungal

Placebo Arterial status

Treated

Initial

Final

Initial

Final

No. patients

21

21

11

27

No. stenosed

26

23

34

35

No. obstructed

25

28

27

10

segments (i.e., a 46% improvement). These changes were sigruficant at the 0.1% level (p c 0.001). The saline group was offered the opportunity to receive a further course of treatment without disclosure of a change in regimen from saline to fungal protease infusion. Five patients declined further treatment, but four patients with 32 arterial segments subsequently received the crossover fungal protease infusion protocol. After treatment, 5 completely obstructed segments were found to have recanalized. This research demonstrated that 3 months of anticoagulant therapy produced no improvement whatsoever in peripheral nor did subsequent infusions of saline (placebo) during a 2-week period. Six intravenous infusions of a fungal protease derived from A. oryzue given within 2 weeks sigruficantly improved peripheral circulation in more than half of the chroNcally obstructed arterial segments in these patients. Furthermore, detailed analysis of study results suggested that an increase in the number and/or dosage of protease infusions might have resulted in even greater improvement in obstructed and stenosed arterial segments. Other studies have shown fungal protease to be effective in the treatment of arterial obstruction in patients with more advanced conditions, such as gangrene and other severe ischemic disea~e?’,~,~

Celiac Disease It has been known since the 1950s that the gluten found in wheat, rye, and other grains is the cause of intestinal damage in celiac disease, with the gliadin fraction of gluten being the source of its toxicity.79” By the 1970s, fractionation studies had succeeded in identifying the components of gliadin involved in the toxic mechanism. The carbohydrate moiety, consisting mainly of glucose, galactose, xylose, and arabinose, is the source of gluten’s gastrointestinal toxicity in the patient with celiac disease, rather than the protein fraction as had been previously suspected?l* Carbohydrase enzymes from microbial sources are effective in vitro in the treatment of celiac disease, because they enzymatically cleave the toxic carbohydrate portion of gliadin. Fungal carbohydrase preparations

render grains like wheat and rye virtually harmless to individuals with gluten enteropathy?1fi2 A 1977 study attempting to identdy the source of gliadin toxicity used a preparation of amylytic enzymes from Aspergillus niger to remove the carbohydrate portion of gliadin in vitro.8l To ascertain the variables being tested, native gliadin underwent chromatography, which showed that carbohydrate was associated with four main protein bands. When the carbohydrase-treated gliadin underwent chromatography, no alteration was detected in the protein pattern, but carbohydrate was completely absent. To further establish that the protein makeup remained unchanged compared with native gliadin, peptide mapping of the treated gliadin was carried out with electrophoresis followed by chromatography. Peptide maps showed no differencebetween the treated and untreated gliadins, confirming that no alteration had occurred in the primary structure of the protein. Gliadin treated in this manner was baked into loaves of bread made with gluten-free flour. The study compared the effect of bread with treated versus untreated gliadin on four patients with previously diagnosed celiac disease. All four patients had been following gluten-free diets for at least 3 months before the study and were virtually symptom-free. Previously, their clinical and physical signs and symptoms had included the diarrhea, malabsorption, decreases in body weight and height, anemia, tetany, impaired Dxylose absorption, decreased intestinal mucosal enzyme secretion, flattened mucosal brush border, and subepithelial tissue lymphocytosis typical of celiac disease. During the test period, patients 1,2, and 3 received a total of 50 g of treated gliadin baked into loaves of bread (10 g gliadin/450-g loaf). Xylose absorption tests and intestinal biopsies from jejunal villi were performed before and after each test period. The celiac patient receiving untreated gliadin (patient4) experienced a return of signs and symptoms of celiac disease-diarrhea, abdominal pain, low values on xylose absorption studies, decreased mucosal enzyme secretion (alkaline phosphatase, lactase, sucrase) and characteristic histologic damage (mucosal lymphocytosis and loss of enterocyte height). The patients who received the treated gliadin remained symptom free during the test period and showed no abnormalities in histologic parameters (i.e., general morphology, epithelial cell height, and tissue lymphocytes were normal in these patients). This study demonstrated that carbohydrate-digesting enzymes from Aspergillus spp. can be used in vitro to remove the toxicity of gluten to patients with celiac disease and supports the hypothesis that carbohydrate components of gliadin are responsible for its toxicity rather thanthe protein components previously suspected.

Microbial Enzyme Therapy

It appears that no controlled studies have been performed to evaluate the effectiveness of amylytic fungal enzymes at reducing gluten toxicity to patients with celiac disease by administering these enzymes with gluten-containing foods at mealtime. It should be noted that although patients with celiac disease show intolerance to the carbohydrate portion of gliadin, this is likely not the only source of gluteninduced disease. A number of studies suggest that protein components of gluten produce systemic allergic manifestations in some patients.* It appears that both gastrointestinal intolerance and immunologic hypersensitivity are capable, either individually or in concert, of producing disease symptoms in susceptible individuals. Future studies may also show that both pathologic mechanisms are amenable to treatment by hydrolysis of the offending portions of gluten with the appropriate orally administered fungal enzymes. This possibility, however, remains to be proven.

including the increased supply of dietary antigens that leak into the blood stream as a result of inadequate protein digesti~n.lJt~t~-~*,~ By digesting dietary protein, fungal enzymes administered orally at mealtime work to decrease the supply of antigenic macromolecules available to leak into the blood stream. In addition, orally administered fungal enzymes that have themselves been absorbed intact may help ”digest” antigenic dietary proteins that they encounter in the blood stream. Further research is needed to evaluate the role of fungal enzymes in the treatment of food allergies.

SUMMARY

‘References 1, 2. 9, 10, 14, 84, 85.

Although the intact absorption of orally administered protein, including enzymes, can no longer be reasonably denied, the quantitative significance of this process requires additional study. It appears unlikely that this route of absorption is sigrufrcant from the standpoint of overall nutritional status, but considerable evidence supports the biologic and therapeutic importance of intact protein absorption and the role of fungal enzyme therapy. The emerging field of fungal enzyme therapy holds promise as an effective therapy or adjunct in a wide range of conditions, including maldigestion, malabsorption, pancreatic insufficiency, steatorrhea,celiac disease, lactose intolerance, arterial obstruction, and thrombotic disease.

1. Gardner ML. Gastrointestinal absorption of intact proteins. Ann Rev Nutr 1988;8:329-350. 2. Gardner ML. Intestinal assimilation of intact peptides and proteins from the diet-a neglected field? Biol Rev Camb PMOSSoc 1984; 59289-331. 3. Warshaw AL, Walker WA, Isselbacher KJ. Protein uptake by the intestine: evidence for absorption of intact macromolecules. Gastroenterology 1974;66987-992. 4. Udall JN, Walker WA. The physiologic and pathologic basis for the transport of macromolecules across the intestinal tract. J Pediatr Gastroenterol Nutr 1982;1:295-301. 5. Loehry CA, Axon AT, Hilton PJ, Hider RC, Creamer B. Permeability of the s m a l l intestine to substances of different molecular weight. Gut 1970;11:466-470. 6. Hemmings WA, Williams EW. Transport of large breakdown products of dietary protein through the gut wall. Gut 1978;19715-723. 7. Menzies IS. Transmucosal passage of inert molecules in health and disease. In Skadhauge E, Heintze K, eds. Intestinal absorption and secretion. Lancaster, PA MTP Press, 19W527-543. 8. Gardner MLG, Steffens KJ, eds.Absorption of orally administered enzymes. Berlin: Springer-Verlag, 1995. 9. Ferguson A, Carswell F. Precipitins to dietary proteins in serum and upper intestinal secretions of coeliac children. Br Med J 1972;1:75-77. 10. Husby S, Foged N, Host A, Svehag SE. Passage of dietary antigens into the blood of children with coeliac disease: quantification and size distribution of absorbed antigens. Gut 1987;281062-1072.

11. Husby S, Jensenius JC, Svehag SE. Passage of undegraded dietary antigen into the blood of healthy adults: further characterization of the kinetics of uptake and the size distribution of the antigen. Scand J Immunol1986;24447-455. 12.WaUcer WA. Antigen absorption from the small intestine and gastrointestinaldisease.Pediatr Clin North Am 1975;22:731-746. 13. Hamilton I, Fairris GM, Rothwell J, et al. Small intestinal permeability in dermatological disease. Q J Med 1985;56.559-567. 14. Lambert MT, Bjamason I, Connelly J, et al. Small intestine permeability in schizophrenia.Br J Psychiatry 1989;155619-622. 15. Heatley RV, et al. Inflammatory bowel disease. In Losowsky MS, Heatley RV, eds. Gut defenses in clinical practice. Edinburgh Churchill Livingstone, 1986225-277. 16. Shorter RG, Huizenga KA, Spencer RJ. A working hypothesis for the etiology and pathogenesis of nonspecific inflammatory bowel disease. Am J Dig Dis 1972;1710241032. 17. Jackson PG, Lessof MH, Baker RW, et al. Intestinal permeability in patients with eczema and food allergy. Lancet 1981;1:1285-1286. 18.Hemmings WA. The absorption of large breakdown products of dietary proteins into the body tissues including the brain. In Hemmings G, Hemmings WA, eds. The biological basis of schizophrenia. Lancaster, PA h4TP Press,1978239-257. 19. Jakobsson I, Lindberg T, Lothe L, et al. Human alpha-ladalbumin as a marker of macromolecular absorption. Gut 1986;271029-1034. 20.Bockman DE, Winborm WB. Light and electron microscopy of intestinal ferritin absorption: observations in sensitized and non-sensitized hamsters. Anat Rec 1966;155:603-622.

Food Allergies Antigen sampling by subepithelial immune tissue in the gut helps, under normal conditions, to program the body’s defenses and protect against exposure to “foreign” dietary proteins and polypeptides. Under pathologic conditions, food allergies can be caused by several factors,

Pharmacology of Natural Medicines 21. Andre C, Lambert R, Bazin H, Heremans JF.Interference of oral immunization with the intestinal absorption of heterologous albumin. EUI J Imm~n011974;4701-704. 22.Dannae1.1~A, Inganas M, Johansson SG, Foucard T. Intestinal uptake of ovalbumin in malabsorption and food allergy in relation to serum IgG antibody and orally administered sodium cromoglycate. Clin Allergy 1979;9:263-270, 23. Wolf JL, Rubin DH, Fmberg R, et al. Intestinal M cells a pathway for entry of retrovirus into the host. Science 1981;212:471-472. 24. McLean E, Ash R. The time-course of appearance and net accumulation of horseradish peroxidase ( H R P )presented orally to juvenile carp, Cyprinus curpio. Comp Biochem Physiol A 1986;84:687-690. 25. Ormiston BJ. Clinical effects of TRH and TSH after i.v. and oral administration in normal volunteers and patients with thyroid disease. In R Hal et al, eds. Thyrotropin releasing hormone (Frontiers of hormone research,vol. I). Basel: Karger, 197245-52. 26. boss M, Rivier J, Guillemin R. Release of gonadotrophins by oral administration of synthetic LRF or tripeptide fragment of LRF. J Clin Endocrinol Metab 197235175177. 27. Siefert J, et al. Mucosal permeation of macromolecules and particles. Science 1975;127505-513. 28. Laskowski M Jr, Haessler HA, Miech RP, et al. Effect of trypsin inhibitor on passage of insulin across the intestinal bamer. Science 1958;1271115-1116. 29. Bergkvist R, Svaed PO. Studies on the thrombolytic activity of a protease from Aspergillus o r y m . Acta Physiol Scand 1964;60:363-371. 30. Verstraefe M, Verhaege R, Schetz J, et al. Clinical trial of Brinase and anticoagulents as a method of treatment for advanced limb ischemia. Eur J Clin Pharmacol1979;16165-170. 31. Kiessling H, Svensson R. Influence of an enzyme from Aspergillus oryzae, protease I, on some components of the fibrinolytic system. Acta Chem Scand 1970;24569-579. 32. Larsson LJ, Frisch EP, Tomeke K, et al. Properties of the complex between alpha-2-macroglobulin and brinase, a proteinase from Aspergillus oyzae with thrombolytic effect. Thromb Res 1988; 4955-68. 33. Vanhove P, Donati MB, Claeys H, et al. Action of brinase on human fibrinogen and plasminogen. Thromb Haemost 1979;42571-581. 34.Kiessling H. Some properties of a complex between alpha2-macroglobulin and brinase. Protides Biol Fluid Proc Colloq 1975;2347-52. 35.Bergkvist R The proteolytic enzymes of Aspergillus o r y m II: properties of the proteolytic enzymes. Acta Chem Scand 1963;17 1541-1551. 36.Fitzgerald DE, Frisch EP, Milliken JC. Relief of chronic arterial obstruction using intravenous brinase: a control study. Sand J Thorac Cardiovasc Surg 1979;13327-332. 37. Verhaeghe R, Verstraete M, Schetz J, et al. Clinical trial of brinase and anticoagulants as a method of treatment for advanced limb ischemia. Eur J Clin Pharmacol1979;16165-170. 38. Keljo DJ, Hamilton JR. Quantitative determination of macromolecular transport rate across intestinal Peyer's patches. Am J Physiol 1983;244:G637-G644. 39. Wolf JL, Bye WA. The membranous epithelial (M) cell and the mucosal immune system. Annu Rev Med 1984;35:95-112. 40.Bjamason I, Peters J. Helping the mucosa make sense of macromolecules.Gut 1987;281057-1061. 41. Ambrus JL, Lassman HB, DeMarchi JJ.Absorption of exogenous and endogenous proteolytic enzymes. Clin Pharmacol Ther 1967;8:362-368. 42.Kabacoff BL, Wohlman A, Umhey M, Avakian S. Absorption of chymotrypsin from the intestinal tract. Nature 1963;199:815. 43.Martin GJ, et al. Further in vivo observations with radioactive trypsin. Am J Pharm 1964;129386-392. 44.Avakian S. Further studies on the absorption of chymotrypsin. Clin Pharmacol Ther 1964;66:712-715.

45. Miller JM, Wfiard RF, Polachek AA. An investigation of trypsin 1-131 in patients. Exp Med Surg 1960;18352-370. 46.Leibow C, Rothman SS. Enteropancreatic circulation of digestive enzymes. Science 1975;189472-474. 47. Guyton AC, ed. Textbook of medical physiology, ed 4, Philadelphia: WB Saunders, 1971:761. 48. Bore1 P, Armand M, senft M, et al. Gastric lipase: evidence of an adaptive response to dietary fat in the rabbit. Gastroenterology 1991;100:1582-1589. 49. DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973;288.813-815. 50. Heizer WD,Cleaveland CR, Iber F'L. Gastric inactivation of pancreatic supplements. Bull Johns Hopkins Hosp 1965;116261-270. 51.Go VL, Poley JR, Hofmann AF, Summerskill WH. Disturbances in fat digestion induced by acidic jejunal pH due to gastric hypersecretion in man. Gastroenterology 197058638-646. 52.Griffin SM, Alderson D, Famdon JR. Acid resistant lipase as replacement therapy in chronic pancreatic exocrine insufficiency: a study in dogs. Gut 1989;301012-1015. 53. DiMagno EP. Controversies in the treatment of exocrine pancreatic insufficiency. Dig Dis Sci 1982;27481-484. 54.Stapleton FB, Kennedy J, Nousia-Arvanitakis S, Linshaw MA. Hyperuricosuria due to high dose pancreatic extract therapy in cystic fibrosis. N Engl J Med 1976;295246-248. 55.Gow R, Bradbear R, Francis P, Shepherd R. Comparative study of varying regimens to improve steatorrhea and creatorrhea in cystic fibrosis: effectiveness of an enteric-coated preparation with and without antacids and cimetidine. Lancet 1981;2:1071-1074. 56.Graham DY. Pancreatic enzyme replacement: the effect of antacids or cimetidine. Dig Dis Sci 1982;27485-490. 57. Staub JL, Sarles H, Soule JC, et al. No effects of cimetidine on the therapeutic response to oral enzymes in severe pancreatic insufficiency. N Engl J Med 1981304:1364-1365. 58. Regan FT,Malagelada JR, Dih4agno EP, et al. Comparative effects of antacids, cimetidine and enteric coating on the therapeutic response to oral enzymes in severe pancreatic insufficiency. N Engl J Med 1977;297854-858. 59. htler-Munro PL, Fitzpatrick WJ, Batten JC, Northfield TC. Effect of intrajejunal acidity and aqueous bile acid and lipid concentrations in pancreatic steatorrhea due to cystic fibrosis. Gut 1984;25:500-507. 60.Schneider Mu, Knoll-Ruzicka ML, Domschke S, et al. Pancreatic enzyme replacement therapy: comparative effects of conventional and enteric-coated microspheric pancreatin and acid-stable fungal enzyme preparations on steatorrhea in chronic pancreatitis. Hepatogastroenterology1985;3297-102. 61. Ladas SD, Giorgiotis K, Raptis SA. Complex carbohydrate malabsorption in exocrine pancreatic insufficiency. Gut 1993;34:984-987. 62.Nakamura T, Takeuchi T, Tando Y. Pancreatic dysfunction and treatment options. Pancreas 1998;16:329-336. 63.Roberts IM.Enzyme therapy for malabsorption in exocrine pancreatic insufficiency. Pancreas 1989;4:496-503. 64.Zom J. [Experienceswith substitution therapy using a new pancreatic enzyme of plant origin.] Fortschr Med 1978;96:1941-1943. 65.Pointner H, Flegel U. [Treatment of exocrine pancreatic insufficiency with fungal lipase.] Arzneimittelforschung 1975;25: 1833-1835. 66. Medow MS, Thek KD, Newman LJ, et al. Beta-galactosidase tablets in the treatment of lactose intolerance in pediatrics. Am J Dis Child 1990;144:1261-1264. 67. Barillas C, Solomons NW. Effective reduction of lactose maldigestion in presd-1001children by direct addition of beta-galactosidases to milk at mealtime. Pediatrics 1987;79:766-772. 68. Rosado JL, Solomons NW, Lisker R, Bourges H. Enzyme replacement therapy for primary adult lactase deficiency: effective

Microbial Enzyme Th ~

reduction of lactose malabsorption and milk intolerance by direct addition of beta-galactosidases to milk at mealtime. Gastmenterology 1984;871072-1082. 69. Rosado JL, Deodhar AD, Bourges H, Solomons NW. The effect of the digestion products of lactose (glucose and galactose) on its intraintestinal, in vivo hydrolysis by exogenous microbial betaD-galactosidase. J Am Coll Nutr 1986;5:281-290. 70.Corazza GR, Benati G, Sorge M, et al. Beta-galadosidase from Aspergillus niger in adult lactose malabsoxption: a double-blind crossover study. Aliment Pharmacol "her 1992;661-66. 71. OKeefe S. The use of lactase enzyme in feeding malnourished lactose intolerant patients. XIII International Congress of Nutrition. Brighton, England, 1985190. 72. Rand AG Jr. Enzyme technology and the development of lactosehydrolyzed milk. In Paige DM, Bayless TM, eds. Lactose digestion: clinical and nutritional implications. Baltimore: Johns Hopkins University Press, 1981:219-230. 73. Lactose intolerance [editorial].Lancet 1991938:1280. 74. Frisch El', Fitzgerald DE. Relief of chronic peripheral artery obstruction by intravenous brinase. J Ir Med Assoc 1973;66: 313-318. treatment 75. Lund F, Ekestrom S, Frisch EP,Magaard F. Thrombolyt~c with i.v. brinase of advanced arterial obliterative disease of the limbs. Angiology 1975;26534-556. 76. Frisch EP, Blomback M, Ekestrom S, et al. Dosage of i.v. brinase in man based on brinase inhibitor capacity and coagulation studies. hgi010gy 1975;26:557-563.

77. Roschlau WH, Fisher AM. Thrombolytic therapy with local perfusions of CA-7 (fibrinolytic enzyme from Aspergillus myme) in the dog. Angiology 1966;17670-682. 78.Frisch EP, Blomback M. Blood coagulation studies in patients treated with brinase. In Davidson JF, ed. Progress in chemical fibrinolysis and thrombolysis, vol Iv.Edinburgh, Churchdl Livingstone, 1979184187. Weijers HA, Dicke WK. Coeliac disease. Iv.An 79. Van De Kamer JH, investigation into the injurious constituents of wheat in connection with their action on patients with coeliac disease. Acta Paediatr 1953;&223-231. 80. Van De Kamer JH,Weijers HA. Coeliac disease. V. Some experiments on the cause of the harmful effect of the gliadin. Acta Paediatr 1955;44:465-469. 81. Phelan JJ,Stevens FM, McNicholl B, et al. Coelic disease: the abolition of gliadin toxicity by enzymes from Aspergillus niger. Clin Sci Mol Med 1977;5335-43. 82. McCarthy CF. Nutritional defects in patients with malabsorption. Proc Nutr Soc 197635:37-40. 83. Phelan JJ. The nature of gliadin toxicity in coeliac disease. Biochem Soc Trans 1974;2:136&1370. 84. Hekkens WTJM. Antibodies to gliadin in serum of normals, coeliac patients and schizophrenics. Nature 1963;199:259-261. 85. Hekkens WTJM, et al. Antibodies to wheat proteins in schizophrenia: relationship or coincidence? In Hemmings G, ed. The biochemistry of schizophrenia and addiction. Lancaster, PA: MTP Press, 1980125-133.

Naturally Occurring Antioxidants Robert A. Ronzio. PhD CHAPTER CONTENTS Introduction 1085 Free Radicals and Reactive Oxygen Species 1085 Free Radicals 1085 Reactive Oxygen Species 1086 Formation of Free Radicals and Reactive Oxygen Species 1086 Functions of Free Radicals and Reactive Oxygen Species 1087 Inflammation 1087 Antioxidants 1088 Enzyme Antioxidants 1088 Nutrient Antioxidants 1090 Antioxidants Produced by the Body 1093

INTRODUCTION Mitochondria use oxygen to maximize production of adenosine triphosphate (ATP) in oxidizing fuel molecules to carbon dioxide. Paradoxically, oxygen is such a powerful reactant that it can disrupt cellular function and impair homeostatic mechanisms primarily through oxygen radicals. Research suggests that free radical attack and cumulative oxidative damage are associated with many diseases and chronic conditions, including cancer,'r2 cardiovascular disease,3r4cataracts? inflammation and autoimmune disease,6v7lung disease? neurologic disorders?JO aging,11J2 he pa ti ti^,'^ and cell death.I4 Box 109-1 summarizes prominent examples of the more than 100 conditions that reflect oxidative damage. Free radicals may be a consequence of the disease process, or they may be a cause. The following discussion focuses on the formation and physiologic effects of free radicals and oxygen-based reactants, and then addresses cellular antioxidant mechanisms and the use of antioxidant supplements.

Nonnutritive Antioxidants 1096 Botanical Extracts 1096

Comparison of Antioxidants 1098 Antioxidants and Regulation of Cell Function 1099 The Adequacy of Antioxidant Defenses 1100 Guidelines for Use of Antioxidants 1101 Precautions in Using Antioxidant Supplementation 1101 Selecting Antioxidants

1102

FREE RADICALS AND REACTIVE OXYGEN SPECIES Free Radicals Free radicals are highly reactive molecules. Unlike most molecules, which contain pairs of electrons, free radicals possess at least one unpaired electron, an unstable condition. Consequently, free radicals remove electrons from bystander molecules indiscriminately to make up for their own deficiency. Lipid peroxidation remains the best-studied example of molecular modifications induced by reactive oxygen species (see later) and free radicals. An initial event generates free radicals, and propagation steps repeated many times perpetuate their formation. Thus, free radical reactions tend to "snowball'' unless held in check by antioxidant defenses.15 Nitric oxide (NO.) and superoxide (O,.-), are examples of physiologically important radicals. When present at low levels, these species play regulatory roles, but excessive concentrations lead to cell damage. The hydroxyl radical (*OH)is one of the most reactive radicals occurring in the body. Its high degree of chemical reactivity precludes any useful physiologic role. 1085

ROS sources

Alcohol-induced damage Atherosclerosis Autoimmune diseases (rheumatoid arthritis and others) Cancer Contact dermatitis Coronary artery bypass Diabetic cataracts Drug toxicity Emphysema Hypertensivecerebrovascular injury immune deficiency of aging Inflammatory bowel disease Iron overload disease Liver cirrhosis Myocardial infarction Nephrotoxicity Nutrient deficiencies Obstructive lung disease Parkinson's disease Prematureaging Premature retinopathy Senile dementia and neurologic degeneration Stroke Systemic lupus erythematosus Thermal injury Viral infections, including acquired immunodeficiencysyndrome

I

Of+ H202

ROS targets Protein

DNA

Lipiddmembranes

-OH I

I

@= Chain breakers @ = Preventive antioxidants

1

I

'ROOH

Flgure 1041 Sources, targets, and sites of antioxidant neutralization for reactive oxygen species (ROS).

Reactive Oxygen Species In addition to these free radicals, the body generates an array of oxidizing agents, including hydrogen peroxide (H202),lipid peroxide (ROOH),and hypochlorite (OC-). Although 02.-and H202are not very reactive chemically, they can yield hydroxyl radical in the presence of transition metal ions. Reduced iron catalyzes the conversion of superoxide to singlet oxygen, an activated oxygen molecule with an unstable electron configuration. Furthermore, nitric oxide and superoxide, in excess, form peroxynitrite ( O N W ) , an extremely powerful oxidizing agent and radical generator. It is useful to regard these metabolites collectively as reactive oxygen species (ROS) to include the various forms of more or less reactive oxidizing agents, whether or not they are free radicals.15 Likely targets of free radicals and ROS include polyunsaturated fatty acids in membrane lipids, serum lipoproteins, proteins, and even DNA (Figure 109-1). The oxidation products include lipid peroxides and hydroperoxides, protein carbonyls, and altered purines such as &oxo-2-deoxyguanosine."J6 The consequences of attack by free radicals and ROS are often subtle: Increased membrane fluidity and damage to (1)membrane receptor proteins may alter cellular regulatory mechanisms such as signal transduction, (2) inactivation of proteins required for All' production, leading to an energy deficit, and (3)inactivation of calcium ATPase, changing

calcium homeostasi~.'~ Mitochondria as principal radical generators represent especially important targets of free radical attack. ROS damage could trigger apoptosis by altering mitochondria1 membrane permeability, leading to the release of apoptogenic substances such as cytochrome c. There is strong circumstantial evidence that ROS and free radicals also play a role in cancer initiation and promotion. Although ROS often damage DNA and induce malignant transformation, the development of cancer depends on many factors, including the rates of damage and repair, the status of defenses, and alternative pathways for initiation and promotion.

Formation of Free Radicals and Reactive Oxygen Species Although not plentiful, free radicals are surprisingly common in the body. Free radicals and ROS arise through a variety of mechanisms. Some sources are spontaneous chemical accidents: Free radicals are generated by air pollutants such as ozone, by nitric oxides in air pollutants such as cigarette smoke, and by cosmic rays and radiation. On the other hand, oxygen may react with heme proteins such as myoglobin, hemoglobin, and cytochrome c as well as with iron (F$+) to generate superoxide, which yields H202. The extremely reactive hydroxyl radical can be formed from H202in the

Naturally Occurring Antioxidants

presence of Fe2+or copper (Cu’).Therefore, the release of these ions from storage sites during inflammation and injury may promote the spontaneous production of free radicals. In addition, normal metabolism yields free radicals and ROS in the following ways: As noted previously, mitochondria mishandle oxygen. Approximately 1%to 3% of oxygen molecules passing through mitochondria end up as superoxide owing to the leakage of electrons from the electron transport chain during damage, generating about 10 g/day of superoxide.18 The aging process may be related to cumulative mitochondria1 deterioration. Cells contain peroxisomes, organelles that oxidize fatty acids while producing H202 Drugs that cause peroxisome proliferation, such as clofibrate, may act as promoters by stimulating the production of hydrogen peroxide. The oxidation of purines from DNA, RNA, and ATP relies on xanthine oxidase, an enzyme that produces superoxide. Various cytoplasmic oxidases generate ROS, including dopamine oxidase, beta hydroxylase, and urate oxidase. The detoxication of metabolites and xenobiotics by microsomal mixed function oxidases (cytochromeP450) can generate ROS (1 mole of free radical is generated for each mole of toxin metabolized). Furthermore, drugs such as penicillamine and phenylbutazone can be metabolized to free radicals. Also, several xenobiotics, such as paraquat and alloxan, catalyze the formation of superoxide through cyclic reactions (“redox recycling”),promoting autooxidation. A number of pesticides and drugs are hepatotoxins for these rea~0ns.l~ It is worth noting that certain phenolic compounds in plant-derived foods, such as chlorogenic acid and caffeic acid, can also generate oxidants through redox cycling.

Functions of Free Radicals and Reactive Oxygen Species It is important to emphasize that ROS serve many useful functions. NO* functions as a neurotransmitter, a hormone, and a paracrine molecule as well as a messenger and may regulate processes as diverse as vasodilation and memory?O Furthermore, hydrogen peroxide and superoxide may regulate cellular redox balance and levels of key cellular antioxidants such as glutathione, thereby functioning as second messengers to alter signal transduction and gene expre~sion.’~ The mechanisms entail activation of transcription factors, regulated in turn by stimulating calcium (Caz+)signaling and protein phosphorylation via the activation of protein kinases and inhibition of phosphatases. Thus ROS may be second messengers for apoptosis, cell growth, and chemotaxis.21”

Superoxide,hydrogen peroxide, and nitric oxide serve as defensive compounds. Phagocytic cells, including macrophages, monocytes, neutrophils, and eosinophils, create ROS as part of their defensive mechanism. The binding of immune complexes, bacterial endotoxins, or other inflammatory agents to cell surface receptors triggers a respiratory burst in phagocytic cells. This localized production of highly reactive chemicals species oxidizes viruses, bacteria, and other foreign substances. Production of ROS follows a definite sequence: Initially, plasma membrane nicotinamide adenine dinucleotide phosphate (NADPH) oxidase releases superoxide, which undergoes dismutation to H2O2.Myeloperoxidase in lysosomes then transforms H202and chloride ion to hypochlorite, the same powerful oxidizer found in commercial bleach. Hypochlorite spontaneously reacts with amines and ammonia to produce very reactive chloramines. Furthermore, nitric oxide is produced, which reacts with molecular oxygen to yield nitrogen oxides NOz and N203,which are potent oxidizing agents. Note that the respiratory burst can activate xenobiotics.=

Inflammation Inflammation represents a major source of oxidants. Infection, toxic exposure, ischemia, and trauma activate phagocytic cells? Inappropriate activation of ROS production is potentially dangerous. Inflammation activates the arachidonic acid cascade, which converts polyunsaturated fatty acids to eicosanoids, lipid peroxides such as prostaglandjn (PG) G2and PGH, leukotrienes, and hydroxyeicosatetraenoic acid (HETE) via cyclooxygenase and lipoxygenase. The autooxidation of polyunsaturated fatty acids with three or more double bonds in membranes yields proinflammatory PGG2-likeisomers called F2 isoprostanes.” Isoprostanes represent important markers of radical-induced lipid peroxidation. The more or less continuous production of ROS by activated phagocytes during chronic, possibly low-level, inflammation may eventually deplete antioxidant Ensuing defenses, thus allowing ROS to attack ~ells.2~ tissue injury often impairs function in a downward spiral from health to disease. For example, free radicals and ROS are present at high levels in the colons of patients with ulcerative colitis.26

Oxidative Stress In an attempt to help develop theoretical models, certain global terms have been formulated. The term oxidative stress refers to a shift in the ratio of prooxidant/antioxidant balance and its consequence^.^^ Although cell damage may be implied, tissue changes that favor prooxidants are not necessarily detrimental. A redox imbalance can be due to excessive ROS production and/or to limited antioxidant defenses. Furthermore, endogenous defenses may be consumed or impaired by

ROS attack. Inadequate antioxidants could also be the result of inadequatedietary intake of antioxidant nutrients or chronic conditions such as malabsorption syndromes.

ANTIOXIDANTS Antioxidants are substances that inhibit the oxidation of a target molecule, often induced by free radical attackF8 Thus oxidative damage due to exposure to environmental pollutants such as ozone can be ameliorated with antioxidant^.^^ Antioxidants are both lipid-soluble and water-soluble. In addition, there is a "pecking order" among antioxidants; some are more readily oxidized than others and will be consumed rapidly unless replenished or recycled.30 Box 109-2 lists the primary and secondary antioxidant defenses, including enzymes,

Detoxication Enzymes Superoxide dismutases (copper, zinc, manganese) Catalases (iron) Glutathione peroxidases (selenium) Glutathione transferase (glutathione)

Auxiliary Proteins Glutathione reductase (niacin, glutathione) Glucose-6-phosphate dehydrogenase (niacin) Albumin Transferrin (iron) Ferritin (iron) Ceruloplasmin (copper) Metallothionein (cysteine)

Vitamin Antioxidants Betacarotene (provitamin A) Vitamin C Vitamin E (tocopherols)

Plant Antioxidants (Nonvitamins)

nutrients, and metabolites, that protect against free radicals and ROS. Certain antioxidants are preventive inhibitors, which block the initiation of free radical attack (Figure 109-2). Preventive inhibitors include defensive enzymes such as catalase, superoxide dismutase (SOD), and peroxidases as well as the tripeptide glutathione. Beta-carotene, chelating agents such as organic acids, and plant polyphenols also represent preventive antioxidants when they quench singlet oxygen or sequester metal catalysts. Other antioxidants function us chain breakers, which convert free radicals to stable products and thus block free radical chain reactions. Vitamin E and ascorbic acid are essential chain-breaking antioxidants (Figure 109-3).

Enzyme Antioxidants Antioxidant enzymes either neutralize a free radical, superoxide, or they catalyze the breakdown of peroxides which can generate free radicals. Furthermore, viable antioxidant enzyme production decreases with age?* The following three types of enzymes detoxify ROS are recognized:

SOD Catalase Glutathione peroxidase These enzymes occur throughout the body in cells, tissues and fluids.

Superoxide Dismutase SOD very rapidly converts superoxide to H2OPBecause H202may yield dangerous hydroxyl radicals if allowed to accumulate, SOD cooperates with catalase to break down H202to water and with glutathione peroxidases to inactivate both H202and lipid peroxides. By "dismutating" superoxide to H20> SOD intervenes before ROS causes damage. The mitochondria1

Carotenoids and xanthophylls Phenolic acids and polyphenols Diketones Tocotrienols

ROH + 0 2

'ROOH

02-*uperoxide

Metabolites Coenzyme Qlo Uric acid Cysteine Glutathione Polyfunctional organic acids (citric acid, malic acid) Bilirubin, biliverdin Alpha-lipoic acid Histidine Melatonin Peptides (carnosine, anserine)

GSH p e r o x i d a s e h H2O + 0 2

H202-(6atalase,

dismutas*

H202 + 0,

Figure 1042 Preventive antioxidants.

RO HQ

0,

-[ (

Beta-carotene Tocopherol \->H20+ROH Coenzyme Q , ~)

Figure 109-3 Chain-breaking antioxidants.

enzyme requires manganese, whereas the cytoplasmic form requires copper and zinc. These trace mineral nutrients are often classified as antioxidants, although it is their enzyme host that more accurately deserves this classification. Evidence for the role of SOD in preventing damage comes from a variety of sources. Aorta from copper-deficient rats contains less Cu-SOD activity and more lipid peroxidation than nondeficient ExtracellularSOD found in vessel walls may have a major role in regulating the vascular level of superoxide.33 Manganese (Mn) SOD is induced during acute inflammation.34Patients with a familial dominant form of amyotrophic lateral sclerosis (ALS) possess a defective gene that decreases cytoplasmic SOD by 40Y0.~Although mutations in the SOD gene account for only 1%of ALS cases, this area has been key in understanding the pathology of the disease. The level of SOD in the cerebral cortex of patients with Alzheimer's disease is 25% to 35%lower than in the brains of healthy people.%Further evidence for the involvement of SOD in neurologic abnormalities comes from studies with transgenic animals that overexpress SOD or knockout animals that are enzyme-deficient as well as from SOD mutations in some cases of familial ALS, although the precise mechanism is Administering SOD bound to polyethylene glycol together with catalase reduces reperfusion injury in heart and kidney and induces lung injury in animals.% The SOD gene has been cloned and is being studied. As an example, premature infants have been treated with prophylactic recombinant human SOD in pilot studies.39Oral supplementation with coated plant or liver Cu/Zn SOD has anecdotally been noted to ameliorate symptoms in some patients with inflammatory conditions and sunburn. Unlike mammalian enzymes, a coated, non-soy legume-derived SOD resists the action of pancreatic enzymes, and a small double-blind, placebo-controlled study suggested that oral ingestion of this material can increase the activity of erythrocyte SOD within 4 hours.40

Catalase An iron-dependent enzyme, catalase occurs widely in

cells and is a component of peroxisomes, which generate H202 through oxidative metabolism. Catalase seems specifically designed to prevent a buildup of H20p Animal studies with catalase, usually in conjunction with SOD, suggest protection against ischemic injury to the retina;' intestinal ROS damagela and radiation.& The transcytosis of catalase and SOD across capillaries has also been observed.MExamination of human atherosclerotic coronary arteries revealed that vascular antioxidant enzymes including catalase were selectively elevated in smooth muscle cells and macrophages in atheroscleroticlesi0ns.4~

Glutathione Peroxidases A family of enzymes known as glutathione peroxidases functions with catalase. They require reduced glutathione to reduce cytoplasmic H202 as well as lipid peroxides. Unlike catalase and SOD, glutathione peroxidases use the trace mineral nutrient selenium in the form of selenocysteine. For this reason, selenium is sometimes referred to as an antioxidant nutrient. Glutathione peroxidases exist as several isofonns. Phospholipid hydroperoxide glutathione peroxidase can reduce membrane lipid peroxides to readily metabolized, nontoxic fatty acid alcohols.46In the lung, antioxidant enzymes, including extracellular glutathione peroxidase, are induced by exogenous oxidative stress, such as associated with lung diseases." Lipoxygenase and phospholipid glutathione peroxidase constitute a "yin-yang" regulatory mechanism controlling the oxygenation of polyunsaturated lipids and regulation of cell function.& Selenium plays a role in the induction of glutathionerequiring enzymes, including five peroxidases. Thioredoxin reductase is a selenocysteine-containingenzyme that catalyzes the reduction of thioredoxin. Nearly 60% of plasma selenium is represented by selenoprotein P, which seems to function in protecting endothelial cells of the liver and glomerular capillaries from oxidative damage independent of peroxidases." In vitro, selenoprotein P protects against peroxynitrite-induced damage and reduces phospholipid hydroperoxides.5" More than 30 mammalian selenoproteins have been detected, but the functions of most of them remain unkn0wn.5~ Defensive enzymes are often inducible. For example, in animal models, exhaustive exercise causing oxidative stress was found to raise levels of SOD, glutathione peroxidase, and glutathione transferase; however prior supplementation with vitamin E and selenium reduced ROS production, and lesser amounts of detoxification enzymes were induced.52 In human atherosclerotic coronary arteries, catalase, glutathione peroxidase, and SOD were upregulated in atherosclerotic lesions, possibly as the result of oxidative stress.45Deprenyl, a monoamine oxidase B inhibitor, has been shown to increase the lifespans of several animal species. This drug upregulates SOD and catalase in the brain as well as the heart, kidneys, adrenals, and spleen, leading to the proposal that deprenyl may protect the neuroimmunoendocrine system against oxidative stress in the aging pr0cess.5~ Results of studies of the effects of training on antioxidant capacity have been mixed. As examples, a study of a cohort of Canadian men and women found no significant correlation between erythrocyte glutathione peroxidase and exercise level.% In marathon runners and sprint-trained athletes, SOD activity was significantly higher than in controls at rest. In marathon runners SOD rose immediately after strenuous exercise, but lipid

peroxidation increased early in the postexercise period. SOD was not altered by sprints in sprint-athletes, and lipid peroxidation also increased early after exercise, suggesting that both strenuous exercise and exhaustive exercise may temporarily overwhelm antioxidant defenses in trained athletes.55When male volunteers were subjected to a 10-week endurance training program, selenium supplementation with 180 kg selenomethionine daily had no effect on exercise-induced adaptations, nor did muscle glutathione peroxidase activity respond to exercise or to selenium supplementation.56

Other Defensive Enzymes Glutathione transferase adds glutathione to potentially toxic substances and is considered a component of phase II detoxificationenzymes. Non-selenium-dependent glutathione peroxidase reduces aldehydes produced by radical-induced fragmentation of polyunsaturated fatty acids, and epoxides produced during detoxification, in addition to peroxides. Like glutathione peroxidase, glutathione transferase requires a ready supply of reduced glutathione, produced by the action of glutathione reductase from oxidized glutathione. In turn, glutathione reductase requires NADPH, dependent on a robust glucose metabolism. NADPH and glutathione serve other reductases that help regenerate tocopherol and ascorbate, demonstrating the principle that overall metabolic balance is a prerequisite for adequate antioxidant defense.15Our knowledge of innate antioxidant defenses continues to expand. For example, recent research indicates that antibodies are able to catalyze the conversion of singlet oxygen, a reactive form, to hydrogen peroxide, which can be neutralized by ~ a t a l a s e . ~ ~

Nutrient Antioxidants Vitamin E (Tocopherols) Vitamin E refers to eight fat-soluble compounds, of which alpha-tocopherol is the most active in the usual biologic test systems (although some human models, such as the red blood cell [RBC] membrane stabilization test, suggest that other forms may be more active). Vitamin E is acknowledged as the primary chain-breaking antioxidant of lipids, lipoproteins, and membranes. In addition, vitamin E contributes to membrane r e p a p ; it blocks the formation of nitro~oamines,5~ helps protect low-density lipoprotein (LDL) against oxidative damage,60,61 reduces symptoms of tardive dyskinesiaperhaps by reducing nerve damage62-and decreases platelet aggregation and blood clot formation.63Vitamin E also acts as an antiinflammatory agent and can promote beta cell activity. Supplementation of patients with type 2 diabetes with 800 IU vitamin E/day for 1month significantly reduced serum lipid peroxidation and

improved beta cell function in comparison with control subjects." Although several studies have indicated that supplementation with vitamin E can improve various aspects of the immune resp0nse,6~supplementation of apparently well-nourished elderly individuals with 200 mg vitamin E daily did not reduce the incidence of upper respiratory tract infections.& Patients with rheumatoid arthritis treated daily with 1200 mg vitamin E in addition to standard drug treatment experienced improvement in symptoms, decreased lipid peroxidation, and increased glutathione peroxidase activity.67 Vitamin E has been implicated in the reduction of cardiovascular disease. Observational studies of women and men suggest that increasing dietary vitamin E intake to more than 20 times the usual intake in a Western-type diet can reduce the risk of heart disease and its manifestations, such as myocardial infarction, among low-risk

population^.^,^^ Nevertheless, most randomized trials with patients at risk for congestive heart disease (CHD) have found that even high-dose vitamin E supplementation did not differ from placebo in terms of cardiovascular disease mortality in subjects monitored for several years.70Thus supplementation with 400 IUvitamin E/day in high-risk patients did not improve outcomes after a mean followup of 4.5 years.7I Similar results were reported by the Collaborative Group of the Primary Prevention Project." In the Alpha Tocopherol Beta Carotene trial, there was no marked association between supplementation with 50 mg vitamin E/day and coronary heart disease or angina in male smoker^.^*^^ The Cambridge Heart Antioxidant Study demonstrated a large, sigruficant reduction in nonfatal myocardial infarction among patients with atherosclerosis who had been supplemented with vitamin E (400 or 800 IU) compared with those receiving a placebo for a median of 1.4 years.75However, there was no reduction in cardiovascular mortality. On the other hand, when a large population at high risk of dying from coronary disease was treated with a combination of 600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily for 5 years, there was no sigruficant reduction in 5-year mortality according to a recent Large-scale randomized primary trials currently under way may help resolve remaining issues. The Heart Outcome Prevention Evaluation trial was extended (median follow-up of 7 years). In this randomized trial, 3994 patients with either diabetes or heart disease received placebo or 400 IU/day natural vitamin E. In these patients with advanced disease, vitamin E did not reduce the incidence of cancer or major cardiovascular events. The authors reported a somewhat increased risk of heart failure in the vitamin E group."

Naturally Occurring Antioxidants

How might antioxidants reduce the risk of heart disease?According to the ”oxidation hypothesis’’ of cardiovascular disease, the oxidation of LDL and other lipoproteins helps initiate atherosclerosis. Each molecule of LDL possesses an average of seven molecules of alpha-tocopherol, but less than one molecule of betacarotene. On the other hand, vitamin E accounts for only 30%of total antioxidants present in LDL in some people. Supplementation with 800 IU of alpha-tocopherol daily for 3 months increased the tocopherol level in isolated LDL and decreased the rate of LDL lipid peroxidation by 40y0.~~ Vitamin E may reduce the risk of neurodegenerative disease. A high intake of vitamin E and vitamin C was associated with a reduced risk of Alzheimer’s disease according to the Rotterdam studyn In a controlled trial, alpha-tocopherol was administered at a daily level of 2000 IU to patients with moderately severe Alzheimer’s disease.s0With vitamin E supplementation, there was a 230-day delay in the onset of severe dementia or death in comparison with controls, although there was no improvement in cognition with supplementation. These data lend support to the possible involvement of oxidative stress in neurodegenerative disease and a role for antioxidant supplementation in therapeutic programs. A protective role of vitamin E in cancer is less clear: The Nurses’ Health Study failed to confirm a reduced risk of breast cancer in patients with high intakes of vitamins E and C.81In the Alpha Tocopherol Beta Carotene trial, treatment with 50 mg vitamin E/day decreased the incidence of prostate cancer as well as mortality due to this disease in heavy male smokers.n Other studies suggest an inverse association between vitamin E intake8* and supplemental vitamin E on the risk of prostate cancer, especially sm0kers.8~ Whole foods provide mixtures of tocopherols, including alpha, beta, and gamma isomers, and the typical U.S. diet supplies twice as much gamma-tocopherol as the alpha form. Alpha-tocopherol predominates in the body, probably owing to selection by tocopherol-binding protein in the liver. Gamma-tocopherol,not the alpha form, selectively blocks peroxynitrite, although it is a weaker antioxidant than alpha-tocopherol. Gamma-tocopherol seems to complement the actions of alpha-tocopherol in blocking ”electron-loving” mutagens and acting as an antioxidant.84 Supplementing with alpha-tocopherol, a form common in commercial supplements, may not be as effective as using natural mixed tocopherols. One study found no correlation between body stores of gamma-tocopherol and the risk of heart attack, suggesting that this isomer may not offer protection against heart disease.% Tocotrienols are a form of vitamin E having an unsaturated side chain. The antioxidant literature on these

compounds is meager compared with vitamin E. They appear to complement tocopherols. Tissue distribution of tocotrienols, coenzyme Qlo (CoQlo),and vitamin E differ, suggesting that selective mechanisms maintain the lipid antioxidants in various tissues.86 In vitro tocotrienols are potent antioxidants. In addition, they can inhibit human breast cancer cell line, possibly by mechanisms independent of their antioxidant properties. They can also inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase and thus potentially could inhibit cholesterol synthesis.87However, treatment of hypercholesterolemic patients with 250 mg mixed tocotrienyl acetatedday for 8 weeks did not reduce cholesterol levels, although this treatment lowered the rate of LDL oxidation and improved resistance to lipid peroxidation by 22%.88 Tocopherol and other chain-breaker antioxidants become radicals as they deactivate potentially toxic substances. The tocopheryl radical (chromanoxyl radical) does not readily attack lipids and proteins and will decompose unless converted back to tocopherol by ascorbic acid, glutathione, and CoQlo, illustrating the theme that antioxidant defenses complement one The dietary reference intake (RDI) for vitamin E is 15mg. This intake is believed adequate to prevent myopathy and neuropathy. An earlier study found that healthy people consuming balanced diets supplying the daily requirement of vitamin E experienced less oxidative damage when supplemented with 100 mg vitamin E dailyg1The daily vitamin E requirement can vary dramatically according to factors that increase oxidative stress, including an increased consumption of polyunsaturated fatty acids, even with as little as 2.5 g of fish oil daily.92 The best sources of vitamin E-such as unrefined vegetable oils, wheat germ, liver and eggs-represent high-fat foods, and it is difficult to provide high levels of vitamin E in the usual diet without supplementation. Synthetic alpha-tocopherol contains a mixture of D and L isomers; only the D form (actuallyRRR-alpha-tocopherol) is active in the body. Esterified alpha-tocopherol is considerably more stable than unesterified tocopherol, and supplemental forms incorporate acetate, succinate, or palmitate, which are readily hydrolyzed and absorbed during digestion. As with other fat-soluble vitamins, absorption of vitamin E depends on fat digestion and absorption. Therefore conditions that impair fat digestion and assimilation reduce tocopherol uptake, and supplementation is prudent in patients with malabsorption syndromes.

Ascorbic Acid (Vitamin C) A prominent, water-soluble antioxidant, ascorbic acid (vitamin C) occurs in body fluids and the cytoplasm.

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Ascorbic acid is one of the most efficient chain-breaking antioxidants in human plasmag0;it can react with a wide range of ROS and other oxidants, including superoxide, singlet oxygen, hypochlorite, and sulfur radicals.91 Ascorbic acid protects lipids and membrane from oxidative damage by scavenging peroxyl and hydroxyl radicals.% It is also reported to reduce the risk of cataracts and retinal increase immune function and detoxi~ation,9~ and decrease heavy metal Ingested ascorbic acid reduces the gastrointestinal production of nitrosamines and fecal mutagens." These factors help explain why higher ascorbic acid intake is linked to a reduced risk of cancers of the oral cavity and esophagus," stomach,* colon, and lung.'O0 Observational studies suggest that ascorbic acid has at most only a modest effect on the risk of coronary heart disease. Ascorbate supplementation can reduce plasma LDL oxidation.'O' A combination of ascorbate with vitamin E is possibly more effective than ascorbate alone for older adults.'02 In other research, patients who had recently undergone heart transplant surgery were supplemented with 1000 mg vitamin C and 800 IU vitamin E or placebo daily. After 1 year, arteries had narrowed by 8% in controls, compared with no arterial narrowing in supplemented patients.lo3Serum ascorbic acid is depleted in patients with inflammation in peripheral arterial disease and reduced lower limb blood flow.'04 There is some evidence that supplementation with ascorbic acid may lower blood pressure in hypertension. However, the effect of 500 mg vitamin C/day was sigruficant only during the first month of treatment, suggesting only a short-term benefit.lo5Current randomized trials may clanfy the role of ascorbic acid supplementation on cardiovascular disease risk. Data from the Rotterdam Study suggest that a high intake of ascorbic acid and vitamin E is associated with a reduced risk of Alzheimer's disease, especially among cigarette smokersn Plasma ascorbic acid is a biomarker of oxidative stress. For example, cigarette smoking depletes the ascorbic acid pool and decreases the body's capacity to maintain plasma ascorbic acid in the reduced (bioactive) form.lMLike the tocopheryl radical, the ascorbyl radical is relatively stable and has little tendency to attack cells. Dehydroascorbate can be reduced back to ascorbate by glutathione and NADPH by redox recycling. In animal models, high levels of ascorbate can compensate for low glutathione production, and vice versa. Ascorbic acid functions with glutathione and lipoic acid to regenerate alpha-tocopherol. Possibly during inflammation or injury, released iron or copper and ascorbate play a prooxidant role. Note that supplemental antioxidants may transiently increase oxidative stress after strenuous exertion. In a study of acute muscle injury due to eccentric exercise in volunteers,

supplementation immediately after injury with vitamin C, 12.5 mg/kg, and N-acetylcysteine, 10 mg/kg, transiently induced oxidative stress compared with p1aceb0.l~' Excessive dietary iron or iron accumulation could also promote ascorbate-induced oxidation. The DRI for vitamin C is 90 mg for men and 75 mg for women. However, convincing evidence that the recommended dietary allowance for (healthy young) men should be at least 200 mg is based on careful tissue saturation studies.lo8 Similar studies found that young healthy women may require 90 mg ascorbic acid/day.lW Lifestyle choices such as cigarette smoking increase the need for vitamin C.

Carotenoids and Vitamin A Carotenoids represent more than 500 different (red, orange, yellow) plant pigments and are conveniently divided into carotenes and xanthophylls (oxygenated carotenes). The best-known carotenoid is beta-carotene. Although it is the most abundant in nature, betacarotene does not stand alone: In green leafy vegetables xanthophylls make up 90% of the carotenoids. Betacarotene represents only one quarter to one third of the carotenoids in plasma.'1° Carotenoids exhibit tissue specificity. Thus, betacarotene is the major carotenoid in liver, adrenal gland, kidney, ovary, and adipose tissue, and lycopene, a red carotene from tomatoes, is prevalent in testes and human plasma."' Lycopene effectively quenches free radicals, although it does not form vitamin A.112 Lutein and zeaxanthin are xanthophylls that accumulate in the body: They are the only carotenoids found in the retina and macula of primates. Lutein and lycopene are plentiful in blood. Levels of these carotenoids in blood are not affected by vitamin A status. Plasma alpha-carotene,beta-carotene, and lutein are useful biomarkers of carotenoid-rich food consumption, and lutein may serve as an intake biomarker for the Cruciferae (cabbage) farnily.Il3There is a preferential uptake of lutein and zeaxanthin from the intestine into chylomicrons, a general carrier of lipid nutrients.'14 In general, carotenoids are versatile antioxidants; lycopene, lutein, zeaxanthin, and others complement the antioxidant activity of beta-carotene. Beta-carotene absorbs energy from singlet oxygen and releases it as heat. This carotenoid is especially effective at low oxygen tension, as found in tissues, where it can scavenge peroxyl radicals and alkoxyl radicals.l15 Carotenoids also enhance immune function, regardless of their provitamin activity. They quench ROS due to inflammation, help maintain membrane receptors, and modulate the release of prostaglandins and leukotrienes.116,117 Increased carotenoid levels have been associated with decreased LDL oxidation.118The greater consumption of carotenoids, especially lutein and zeaxanthin, correlates with a lower

Naturally Occurring Antioxidants

risk of advanced, age-related macular degenerati~n."~ In one study, supplementing with beta-carotene in combination with vitamin E, vitamin C, zinc, and copper slowed the progression of advanced, age-related macular degeneration. Several epidemiologic studies suggested an inverse correlation between carotenoid consumption and several forms of cancer, including lung cancer.121,122 Later cohort studies found an inverse association between lycopene and alpha-carotene intake, but not betasarotene intake, and the risk of lung cancer. Lung cancer risk was reduced by a diet that provided a variety of carotenoids.lZ Increased serum levels of beta-carotene, lycopene, and lutein/zeaxanthin were shown to be inversely related to mortality from all causes and to cancer mortality in Japanese subjects.l" The beneficial effects of carotenoids in chemoprevention of cancer are thought to occur through protection against oxidative stress and immune enhancement.lZ Nonetheless, the results of intervention studies with beta-carotene supplementation in cancer have been mixed. A study of Finnish men who had a decade-long history of heavy cigarette smoking and alcohol use found an increased risk of lung cancer with betacarotene supplementation, but not in subjects administered both vitamin E and beta-carotene.lZ6Subjects who had the highest level of serum beta-carotene at the beginning of the study-indicative of a greater intake of fruits and vegetables-had the lowest risk for development of lung cancer. Another intervention trial suggested that beta-carotene raised the risk of cancer in high-risk groups (smokers or persons exposed to asbest~s).'~' In contrast, the Linxian, China, study, which involved administering beta-carotene, vitamin E, and selenium to marginally malnourished people, lowered the risk of cancer mortality.lZ8The Physicians' Health Study did not detect any positive or negative effects on the incidence of cancer or heart disease after 12 years of supplementation with beta-carotene.IB Overall, intervention studies have not demonstrated that supplemental vitamin E and beta-carotene can prevent or treat coronary disease." The failure to find a reduced risk of lung cancer with beta-carotene supplements is consistent with the generally accepted view of the chemopreventive properties of antioxidants: They can block cancer initiation and early promotion but are less effective during very late stages of carcinogenesis. Increased serum/plasma levels of carotenoids have been associated with a reduced risk of coronary heart disease.131 Although the antioxidant properties of carotenoids were hypothesized to prevent coronary heart disease, five primary prevention trials with betacarotene found no reduction in the risk of this disease with beta-carotene supplementation, such as 50 mg/day. As examples, men and women enrolled in a study to

prevent nonmelanoma skin cancer experienced no reduction in mortality from all causes or from cardiovascular disease when supplemented with 50 mg beta-carotene daily for a mean of 4.3 years and &year follow-up.132 The Physician's Health Study I did not detect any significant effect on the incidence of cancer or heart disease after more than 12 years of treatment with 50 mg betacarotene (alternate days) and follow-up.133The second study of this series, PHS II, examines the effects of betacarotene as well as vitamin E, vitamin C, and multivitamins on the incidence of prostate cancer and age-related eye diseases, in addition to cardiovascular disease.133 The synthetic form of beta-carotene represents the all trans isomer, whereas fruits, vegetables and algae provide varying amounts of the 9-cis isomer together with minor carotenoids. The 9 4 s isomer appears to be a somewhat more efficient antioxidant.lMNatural mixed carotenoids containing alpha- and beta-carotenes as well as xanthophylls were better absorbed, and they functioned as more effective antioxidants in vivo than synthetic (all trans) beta-~arotene.'~~ (For additional discussion of the broad impact of carotenoids on health, see Chapter 71.) Vitamin A can act as a free radical trap and lipid peroxyl radical scavenger; it contributes to the antioxidant status of LDL, for e ~ a m p 1 e .Cutaneous l~~ vitamin A and vitamin E may be complementary antioxidants to reduce ultraviolet light-induced damage.13' Vitamin A analogues, such as 1 3 4 s retinoic acid and trans retinoic acid, can also reduce lipid peroxidation in vitro. However, the major role of vitamin A and its derivative in most tissues remains the regulation of transcription and translation in differentiation.

Antioxidants Produced by the Body Glutathione A sulfhydryl-reducing agent, glutathione is a tripeptide that contains cysteine. Glutathione occurs in high (millimolar) concentrations in most cells and plays many roles. It serves as a detoxifying agent, assists amino acid transport, quenches free radicals, and helps regulate the internal redox environment of cells. As a substrate for glutathione peroxidases, glutathione plays a key role in antioxidant defenses. In addition, glutathione reacts directly with singlet oxygen, hydroxyl radicals, and superoxide radicals to form oxidized glutathione (GSSG).l%Glutathione reductases regenerate reduced glutathione (GSH) and the ratio of GSH to GSSG is normally more than 100:1.138 Together with ascorbate, GSH participates in the regeneration of vitamin E, which emphasizes the cooperation of antioxidants. Oxidative stress reduces this ratio, activates transcription factors, and increases production of interleukin-1 and tumor necrosis f a ~ t 0 r .Depletion l~~ of intracellular glutathione is associated with immunodeficiency.

Pharmacology of Natural Medicines

Patients with acquired immunodeficiency syndrome

(AIDS)appear to have low levels of reduced glutathione, which could activate transcription factor NF (nuclear factor) kappaB to increase transcription of the human immunodeficiency virus (HN) genome." A clinical study demonstrated that low GSH levels in CD4 T cells from HIV-infected subjects is associated with a decreased survival of 2 to 3 years.14' Low glutathione levels are also associated with a variety of chronic conditions, such as diabetes, age-related macular degeneration, gastrointestinal disorders, and neurodegenerative disease, although cause and effect remain to be established in this disease state. N-Acetylcysteine is an effective precursor for glutathione, and oral supplementation with this substance can raise intracellular GSH'" in model systems and in healthy individuals,'43 but not necessarily in patients with AIDS.14 Indeed, HIV in clinically stable patients may not be specifically associated with oxidative stress.145

Higher blood levels of glutathione correlate with higher levels of health in elderly subjects.'& Whether glutathione concentrations predict aging and whether low glutathione is a cause of aging remain to be determined. Initial research suggested that oral glutathione can increase plasma glutathione concentrations in animals.147However, it now seems unlikely that orally administered reduced glutathione can raise tissue glutathione levels in humans, on the basis of the observation that a 3-g bolus did not increase plasma glutathione or cysteine.l& Certain cancer chemotherapiesas well as radiotherapy rely on induced apoptosis and other free radical actions, and debate regarding the safety of providing antioxidants during chemotherapy continues. Intravenous glutathione has been used prior to cisplatin administration in order to reduce the severity of cisplatin-induced nephrotoxicity in patients with ovarian cancer,'49 and before oxaliplatin administration to reduce the druginduced nephrotoxicity. Significantly, GSH did not diminish the effects of chemotherapy on the colonic tumors.lm Further clinical studies are needed to clarify the safety and efficacy of antioxidant treatment with chemotherapy. The use of doxorubicin (Adriamycin), an effective chemotherapeutic agent, is limited by cardiotoxicity, and antioxidants may be effective in reducing the drug-induced oxidative stress.'51 Intramuscular glutathione injection, 600 mg on alternate days for 2 months, has been used for ir~ferti1ity.l~~

Coenzyme Qlo (Ubiquinone) Ubiquinones are a family of fat-soluble antioxidants containing 1 to 12 isoprene units. The predominant form in humans is ubiquinone 10, or CoQlo. Long recognized

as a lipophilic electron carrier in mitochondria1ATP production, CoQloalso stabilizes membranes and functions as an important antioxidant that can recycle tocopher01.I~~ CoQlois also involved in the regulation of gene expression, possibly via superoxide as a second messenger.'% CoQlocan enhance the immune system,155and it has been used to improve the health statusin patients with angina,'56 hypertension and insulinre~istance,l~~ and various cardiornyopathies.lMCoQlois generally recognized as an adjuvant therapy for chronic heart failure.'59J60In addition, CoQlosupplementation before cardiac surgery can improve cardiac function and reduce postoperative stress.'61 CoQlo may also improve immune function in patients with HIV infection."j2Ubiquinol, the reduced form of CoQlo, protects LDL against lipid peroxidation.'@ Patients with cancer are often low in CoQlo, and preliminary studies suggest that treatment with CoQlo may be helpful in treating patients with advanced breast cancer.164 The largest benefits of CoQlosupplementation apparently occur in those who are the most deficient in this coenzyme.'65 CoQlo synthesis requires vitamins B2, B6, B12 and folate, and synthesis may not be optimal in people with a low intake of these important vitamins. The normal value for CoQloin plasma is approximately 0.4lmol/L, mostly in the reduced form. Ubiquinol is readily oxidized, and dietary forms are ubiquinones, which are readily reduced after absorption. A decline in lipid peroxidation in plasma after supplementation with CoQlo supports an antioxidative role for CoQ10.166 Certain drugs also lower serum levels of C O Q ~ OThey .~~~ include beta blockers and HMG-CoA reductase inhibitors. However, the necessity of CoQlo supplementation in these situations has not yet been established.

Alpha-Lipoic Acid Alpha-lipoic acid (ALA) was initially classified as a vitamin. However, later research demonstrated that ALA is synthesized in humans and animals. As a coenzyme of pyruvate dehydrogenase and alpha-ketoglurate dehydrogenase, ALA is required in the catabolism of carbohydrate and fatty acids. Isolated ALA exists in the oxidized or disulfide form. This is reduced to the sulfhydryl form, dihydrolipoic acid, by many tissues indicating its antioxidant potential. Exogenous ALA is both watersoluble and fat soluble. In tissues, ALA is able to regenerate endogenous antioxidants, including ascorbic acid and glutathione, which in turn recycle vitamin E. Furthermore, ALA scavenges hydroxyl radicals, peroxynitrite, superoxide, and peroxyl radicals-all strong oxidizing agents.la Pharmacologic doses of ALA have been used to treat a number of disease states. The derived benefits probably reflect the antioxidant potential of this compound.

Naturally Occurring Antioxidants

The antioxidant capacity of plasma increases after tea Intravenous ALA has been used to treat diabetic peripheral neuropathy. In one study doses of 600 mg IV or consumption, and most of this increase is due to higher 1800 mg orally daily for 3 weeks led to sigruficant uric acid concentrations.l@ improvement in Total Symptom S ~ 0 r e s .ALA l ~ ~ was also found to improve glucose tolerance and insulin sensitiv- Polyfunctional Organic Acids Citrate, fumarate, succinate, malate, and tartrate can ity in patients with type 2 diabetes when administered either 1200 mg/day orally for 4 weeks or 500 mg/day IV bind (chelate) transition metal ions and block ROS production, thus acting as preventive antioxidants. These for 10 ~ e e k s . ' ~ ~ Although J'~ placebo-controlled studies showed that neuronal conduction improved in diabetic acids require the presence of chain-breaking antioxidants for maximum effectiveness. Not all chelates confer patients with neuropathy following oral ALA treatment, properties; for example, iron-ascorbate and there was no sigruficantimprovement in ~ y m p t o m s . l ~ ~ antioxidant J~ iron EDTA complexes catalyze oxidation. Tartaric acid High-dose ALA is approved in Germany for the treatcan enhance the bioavailability of wine polyphenols.184 ment of diabetic neuropathy. ALA has also been used to treat radiation poisoning Melatonin and HIV infection. Children exposed to radiation during In addition to helping set the body biorhythms, endocrine the Chemobyl disaster who were treated with ALA secretion, and sleep patterns, the hormone melatonin alone or with vitamin E experienced better organ funcalso acts as an antioxidant in vitro and in vivo.185The cention and less oxidative stress.In A small open trial with HIV-positive patients suggested that ALA supplementatral nervous system consumes 20% of the oxygen used daily and thus is likely to generate ROS at a high rate. tion might reduce lipid peroxidation, improve antioxidant status, and increase ratios of helper-to-suppressor Hypothetically, conditions involving damage by free radicals to DNA could be aggravated by light suppresT cells.174Whether ALA can reverse age-related organ sion of melatonin.ls6 Melatonin production and sleep decline in humans remains unknown. Resultsof animal studies are provocative. Mitochondria may play a pivotal part in preventing oxidative damage decay with age, due to oxidation of their constituent of nerves.IE7In senescence-accelerated mice, long-term administration of physiologic levels of melatonin cormacromolecules, including catabolic enzymes. Feeding rected hepatic mitochondria1 dysfunction, suggesting rats very high doses of acetylcamitine and ALA (0.5%in chow) partially reversed this decay as indicated by that melatonin may reduce oxidative damage associated with aging.Iss In addition, pretreatment with melatonin reduced oxidative stress, partial reversal of the decline in sigruficantly reduced cardiac damage resulting from activities of key enzymes, as well as increases in hepatic cellular respiration and ambulatory activity.175Feeding ischemia-reperfusion injury in rats.189Whether melatonin is effective in treating or preventing neurodegenerhigh-dose ALA to aged rats for 2 weeks reduced myocardial oxidant production to levels observed in healthy ative disease such as Alzheimer's disease remains to be established. Although melatonin is sometimes sold as a young rats.176Aging is also associated with neurodegeneration, and animal studies suggest that high-dose ALA food supplement, it is actually a potent hormone. and/or acetyl-L-camitine can improve brain function, Storage and Transport Proteins: increase the activity of key catabolic enzymes,ln Ferritin, Transfernn, Ceruloplasmin, decrease brain lipid peroxidation, and increase brain Metallothionein antioxidant enzyme activities.178 Free iron and copper ions catalyze the conversion of Uric Acid (Urate) H202to hydroxyl radicals; therefore proteins that bind Uric acid is a waste product of a purine metabolism these ions help protect tissues against ROS. Under that occurs in high levels in plasma. Urate is a broadnormal circumstances, it is questionable whether unbound iron is normally present in cells. However, spectrum antioxidant capable of scavengingfree radicals and of chelating transition metals.179Uric acid is responwith chronic inflammation, iron may be released from ferritin, and potentially this unbound iron may pose a sible for 21% to 34% of the total plasma antioxidant hazard. Iron storage disease is linked to oxidative activity, in which it appears to protect alpha-tocopherol damage. Transferrin (which has a high affinity for iron) from peroxyl radicals." Also, assays of total antioxidant and ceruloplasmin (which binds copper) can be considcapacity (TAC) based on crocin bleaching indicated ered part of the antioxidant defenses." Iron stored in that 49% of the TAC activity in human plasma is due to ferritin does not participate in generation of free radiuric acid.181 In patients with acute ischemic stroke, cals. Another intracellular cysteine-rich protein, metalserum TAC strongly correlated with uric acid levels. lothionein, binds many metals, including copper. It is Levels of both vitamin C and uric acid were lower in patients who had experienced stroke than in controls.182 induced by cytokines, toxic metals, and oxidative stress.

Pharmacology of Natural Medicines Mitochondrial-specific ROS generators can increase the production of metallothioneinin liver by 3.7- to 11.8-fold in mice, far more than SOD or glutathione peroxidase.lg1 Similarly, acute ethanol-induced hepatotoxicity and associated oxidative stress were curtailed in mice that had been genetically manipulated to overexpress metallothionein, compared with wild-type mice.192

Whether higher consumption of flavonoids can reduce the risk of cancer and cardiovascular disease is not clear from currently available studies.202Among Finnish men and women, individuals with increased quercetin intake had lower mortality due to heart disease, and the risk of cerebrovascular disease was inversely related to intake of kaempferol, naringenin, and hesperidin. Men with the highest intake of quercetin Nonnutritive Antioxidants had a lower incidence of lung cancer, and those with the Flavonoids highest intake of myricetin had a reduced risk of The typical diet provides a wide range of substances of prostate cancer. In addition, the incidence of asthma was plant origin that play important roles in maintaining lower with greater intakes of quercetin, naringenin and health. Many act as antioxidants. One of the largest he~peridin.2~~ classes is the flavonoids, found mainly in fruits, leaves, On the other hand, there was no strong relationship stems, and roots of vegetables, legumes, and tea. between flavonoid intake and total coronary heart Flavonoids potentiate the effects of vitamin C and prodisease among American male health professionals?04 tect other easily oxidizable substances. More than 40oO Among elderly Dutchmen dietary catechins were not flavonoids have been reported; undoubtedly more associated with a reduced risk of lung cancer or epithelial cancers.2o5In a cohort of postmenopausal American remain to be discovered. Natural phenolics include flavonoids (anthocyanidins, catechins, flavanones, women, dietary catechins were inversely proportional only with the incidence of rectal cancer.2o6Quercetin can flavones, flavonols, and isoflavones); tannins (ellagic Ascorbic acid enhances the inhibit melanoma ~ells.2~' acid, gallic acid); phenyl isopropenoids (caffeic acid, inhibition of cancer cells by fisetin and quercetin in vitro, coumaric acids, ferulic acid); lignans; and other substances, including catechol, resveratrol (grape skins), suggesting that ascorbate potentiates the action of flavonoids as chemoprotective agents?08 Case-control and rosmarinic acid (rosemary). Substantial amounts of ingested quercetin, a common flavone, are absorbed studies suggest a protective effect of apple and red wine by the gastrointestinal tract in humans.'" Quercetin consumption on asthma severity in adults; this associaand kaempferol, another flavone, are among the most tion may reflect their flavonoid content.209 abundant flavonoids in the diet. Previous estimates of daily consumption of total Antioxidant properties are the best-documented charflavonoids ranged from 200 to 1000 mg daily. However, acteristic of flavonoids. Antioxidant properties, physioaccurate food consumption data and refined analytical logic activities, bioavailability, and other properties are methods based on high-performance liquid chromatogfunctions of the chemical structure of flavonoids." The raphy indicate that for northern European elderly men, total phenolic content of common plant foods and beverthe mean daily intake of the putative anticancer ages has been found to correlate with total antioxidant flavonoids was only about 23 mg daily, with quercetin activity in ~ i t r 0 . l ~ ~ being the predominant flavonoid?10 Though quercetin Various flavonoids inhibit peroxidation in vitro by consumption was low, this flavonoid level represents scavenging ROS, superoxide, hydroxyl radical, and sinsubstantially more antioxidant activity than the typical glet oxygen. For example, rutin, myricetin, and quercetin daily consumption of vitamin E or beta-carotene.Furtherscavenge s ~ p e r o x i d e 'and ~ ~ block LDL 0xidati0n.l~~ more, this level of flavonoid consumption correlated Flavonoids from bilberries and grapes were able to with a decreased risk of cardiovascular disease2I0but not protect collagen from superoxide-induced damage.19* of cancer?ll Flavonoids can also bind transition metals, limiting Botanical Extracts their ability to catalyze free radical formation.199Some flavonoids also inhibit the induction of nitric oxide Botanical extracts have been used for centuries by natusynthase, for example during ischemia-reperfusion ral health care practitioners. Research has now demoninjury.2ooExcessive nitric oxide poses a potential probstrated that much of their clinical efficacy is due to their lem because it reacts with radicals to form peroxynitrite, flavonoid constituents, which are often organ specific. which can severely damage cells. Xanthine oxidase Silybum marianum and Other releases superoxide, and this activity can be inhibited Hepatoprotective Botanicals by quercetin, among others.2ooSeveral flavonoids possess antiinflammatory properties. They may inhibit Milk thistle extracts containing silymarin,212extracts of both the cyclooxygenase and 5-lipoxygenase pathways, Indian herbs such as Picrorhiza kurroa,213 Eclipta a1ba,2l4 thus limiting the production of proinflammatory and Tinosporu c0rd@fOlia,2~~ and combinations of these eicosanoids.201 extracts concentrate flavonoids in the liver, where they

Naturally Occurring Antioxidants

exert hepatoprotectiveeffects. Oxidative stress is a prime feature of liver disease, and antioxidantsmay potentially play important therapeutic roles.216Because liver detoxication promotes autoxidation due to ROS produced by cytochrome Pqm,217 the antioxidant properties of these botanical flavonoids largely explains the beneficial effects of these plant extracts in normalizing liver function. In addition to scavenging ROS and inhibiting the 5-lipoxygenase pathway, silymarin has other properties, such as modification of gene expression. The preponderance of evidence suggests that silymarin is a useful adjunct in the treatment of alcoholic liver Tinospora cordifolia extract has been found to reduce lipid peroxidation and increase glutathione, catalase, and superoxide dismutase levels in diabetic rats.219 Pretreatment with extracts of Picrorhiza kurroa can protect against experimentalhepatic ischemia-reperfusion injury in part through its antioxidantproperties.220 In vitro studies with human cells found these extracts to reduce oxidant-induced DNA damage and cytotoxicity.221

Proanthocyanidins and Anthocyanidins A variety of plant sources yield a family of flavonoids called proanthocyanidins. Often they are chained together (oligomers); hence the name oligomeric proanthocyanidins (OPCs).Pine bark and grape seeds are typical commercial sources. Animal experiments indicate that grape seed extracts can limit lipid peroxidation in the brain, suggesting that constituents or their colonic fermentation products are absorbed and cross the blood-brain barrier.w Short- and long-term exposure studies have not indicated appreciable toxicity or side effects for grape seed O P C S . ~ Laboratory animals fed OPCs from grape seeds demonstrated cardioprotection against ischemia-reperfusion compared with control animals.224Furthermore, pretreatment with grape seed OPCs protected against experimentally induced hepatotoxicity, pulmonary toxicity, doxorubicin-induced cardiotoxicity, and drug-induced immunotoxicity in mice.225 Preparations of European pine bark (Pycnogenol) have been used as supplements for capillary dysfunction in patients with diabetes and for other venous abnormalities, including retinal hemorrhage.226Pycnogenol protects against ROS and raises levels of antioxidant enzymes in vitro. It can also help regenerate vitamin E and attenuate vitamin C.226Pycnogenol can inhibit the production of ROS in cultured macrophages as well as the activation of nuclear transcription factors involved in the expression of proinflammatory cytokines, such as interleukin-l-beta.=' These observations suggest that OPCs may be useful in reducing inflammation, and a pilot study reported that Pycnogenol si&cantly reduced inflammation associated with systemic

lupus erythematosus.22sFurthermore, cell culture experiments demonstrated that Pycnogenol may prevent neurons from amyloid-beta-induced apoptosis by suppressing ROS and reducing DNA f r a g m e n t a t i ~ n . ~ ~ O K s are also major constituents of legume-derived polyphenols, which inhibit peroxynitrite-induced apoptosis in human colonic cells, a model system for gut inflammation.m French men consume a high-fat diet yet appear to have a lower mortality due to heart disease. Several explanations have been proposed for the so-called French paradox. Of particular interest is the correlation of heart protection with red wine consumption, although the mechanism is u n k n ~ w n . ~ ' The cholesterol-lowering effect of spirits is not unique to wine. However, red wine contains abundant tannins and other polyphenols, including caffeic acid and anthocyanidins, and drinking red wine increases the antioxidant capacity of serum.232,233 In animal models, grape polyphenols protect against ethanolinduced neuronal damage.= Such experiments suggest the absorption of polyphenols and related derivatives. Red wine has a higher phenol antioxidant index as measured against isolated LDL than white wine.235 Red wine polyphenols can inhibit vascular smooth muscle cells but not endothelial cells in vitro. The mechanism may involve downregulation of expression of cyclin A gene, a cell cycle regulator.% Grape skins and red wine contain resveratrol, a polyphenolic compound, and phytoalexin, a compound produced by plants in response to environmental stressors. Exposure to resveratrol correlates with a decrease in myocardial damage associated with ischemiareperfusion and inhibition of LDL oxidation.237This substance apparently inhibits platelet aggregation and eicosanoid syntheses and blocks cellular events linked to tumor initiation, promotion, and progression.238 These effects seem to be independent of its antioxidant properties.

Catechins Tea is a rich source of polyphenols that are highly substituted with hydroxyl groups. Catechin and gallic acid derivative-including epigdocatechin, epigdocatechin3 gallate, and epicatechin-3 gallatefunction as radical quenchers in vitr0.239,240 Tea consumption has been linked to a lower risk of cancer, and antiproliferative effects seem to be a function of polyphenol content."' There is also in vitro evidence that green tea catechins may block signal transduction pathways and induce apoptosis in tumor cells?@Green tea polyphenols may also block nitric oxide production implicated in inflammation243 and reduce DNA oxidation, lipid peroxidation, and free radical production in smokers?44The relationship between catechins and cancer incidence

Pharmacology of Natural Medicines is conflicting. For example, cat& intake was found to be inversely associated only with redal cancer risk among postmenopausal women in the United Urokinase, a proteolytic enzyme overexpressed in many cancers, can be inhibited by green tea flavonoids. In addition, green tea prevented loss of liver superoxide dismutase, glutathione peroxidase, and catalase activities, which were due to chronic alcohol consumption in laboratory animals, while protecting membrane lipids from peroxidation.246Thus, green tea polyphenols probably have multiple effects in the body, including quenching of radicals. Green tea extracts free of caffeine are now commercially available (see Chapters 74 and 77).

Infusion of amyloid beta protein has been used in a rat model of neurotoxicity. Dietary curcumin suppressed both microgliosis oxidative damage and neuropathology and prevented Abeta-induced spatial memory deficits, which are relevant to Alzheimer’s disease.= Rabbits fed an atherogenic diet with curcuminoids exhibited lower levels of plasma lipid peroxides and had higher levels of CoQlo and alpha-tocopherol than controls lacking curcuminoids. The supplemented animals also had fewer aortic fatty streak lesions.257 Curcuminoids are diketones, not flavonoids, emphasizing the point that many other plant ingredients besides polyphenols may function as antioxidants and as anticarcinogens. Garlic serves as a second example of this class of Other Botanicals botanicals. Garlic contains a wide range of organosulfur Extracts of Ginkgo biloba have long been known to supcompoundswith multiple physiologicactivities, including port vascular function and cerebral insufficiency. It antioxidant properties. Allicin inhibited nitric oxide proseems probable that active constituents, gdgolides, duction in stimulated cardiac myocytes by inhibition and related flavonoids reduce oxidative ~ t r e s s . 2 ~ As~ 2 ~of nitric oxide synthase, while Sally1 cysteine inhibited oxidant-induced damage to cultured endothelial cells examples of this research, pretreatment with the extract and inhibited the formation of hydrogen peroxide EGb 761 reduced skin damage induced by ultraviolet B light in laboratory Mice supplemented with induced by oxidized LDL.258z9Rabbits fed an atherogenic diet and garlic extract had sigruficantly better EGb 761 also had less ROSinduced apoptosis in lymphocytes than untreated mice; this result was larger in antioxidant status and reduced plaque area compared old mice than in young animals.25o with animals not fed garlic.260In addition, aged garlic Cell culture studies suggest that EGb 761 can generacts as an antioxidant in vivo. A pilot study of smokers ally raise glutathione levels and induce gammaand nonsmokers found that supplementation daily glutamylcysteinyl synthetase, the rate-limiting enzyme with aged garlic extract for 2 weeks lowered levels of 8-iso-prostaglandin FZ, a rather specific marker of in glutathione synthesis.251Rats treated with EGb 761 radical-induced lipid oxidation.261 had increased catalase and superoxide dismutase activity and reduced lipid peroxidation in the hippocampus, striatum, and substantia nigra than controls.252 COMPARISON OF ANTIOXIDANTS Culinary herbs contain potent antioxidants. A comparison of culinary and medicinal herbs found that There are several points to consider in comparing antioxthe phenolic content and radical-quenching properties idants. Studies of the quenching activity of antioxidants of ahnary herbs were appreciably higher. The most frequently employ single time points measured at a potent culinary herbs were dill, oregano, marjoram, and single concentration of antioxidant (end-point assay). sweet bay Among medicinal herbs, thyme, peppermint, This practice can lead to erroneous conclusions in comand St. John’s wort were notable. The total radical parisons of the effectiveness of antioxidants. A far more absorbance capacity was directly proportional to the reliable approach evaluates the IC%,the concentration of total phenolic content of both types of herbs.253Turmeric antioxidant yielding 50% inhibition of a given oxidant has a long history of use in Eastern traditions as a or radical. The smaller the ICw, the more efficient the seasoning and as a medicinal herb. Curcuminoids antioxidant. Using DPPH (diphenyl picrylhydrazyl are the bright yellow pigments isolated from this radical), one of the test systems used for measuring free source. These lipids limit the metabolism of environradical quenchingF6*pine bark OPCs, a study found that mental mutagens and they possess antioxidant and grape seed OPCs and polyphenols from lentil effectively antiinflammatory activities. Consumption of 200 mg quench organic free radicals.230It is important to comof curcuma daily by healthy subjects decreased serum pare antioxidant activity in several systems, such as lipid peroxide levels and in HDL and LDL lipid superoxide, lipid peroxidation in LDL or microsomes, peroxidation.254Animal studies suggest that consump- and chemiluminescenceto detect the formation of reaction of curcumin can limit lipid peroxide-induced tive oxygen species. The order of decreasing effectivecataracts and that curcumin may suppress colon ness of these superoxide quenchers is as follows: ~ancer.25~ lentil-derived polyphenols > ascorbic acid > quercethB1

Naturally Occurrin On the basis of ICs0 values calculated from radical

quenching with spin-labeled substrate, epicatechin gallate was shown to be the most effective catechin in human blood plasma. It was also the most effective in protecting alpha-to~opherol.~~~ Using inhibition of NADPH-dependent lipid peroxidation of rat liver microsomes, one study found that catechins have IC5,, values between 10 and 51 pM, and galloyl catechins were more effective than simple catechins. In this membrane system, antioxidant activity was a function of lipophilicity as well as ease of

Antioxidants and Regulation of Cell Function After the in vitro effectivenessof an antioxidant has been demonstrated, the following question arises: “Does this antioxidant improve cellular function?” Antioxidants possess multiple actions that may or may not be directly related to their free radical scavenging activity and the curtailment of oxidative damage. Current interest focuses especially on molecular mechanisms affecting the redox status of the cell and the regulation of redoxdependent gene expression. The transcription factor IW-kappaB regulates the production of multiple inflammatory cytokines and adhesion molecules. This factor is upregulated during aging and may contribute to age-related chronic diseases such as rheumatoid arthritis. In human monocytes alphalipoic acid can prevent tumor necrosis factorstimulated production of intracellular adhesion molecule (ICAh4-1 expression). It does so by inhibiting the binding of NF-kappaB to DNA?6 Apoptosis (programmed cell death) is also regulated by a complex pathway involving activation of transcription factors, and relies on the cellular redox balance. Oxidative stress induced by ROS triggers apoptosis in several model systems, and apoptosis may be regulated by antioxidant^.^^^,^^^ Indeed, conditions ranging from diabetes mellitus and heart failure to HIV infection may entail altered apoptosis.267 Thioredoxin and thioredoxin reductase represent a widespread endogenous redox-regulating system with multiple roles in intracellular signaling and resistance to oxidative stress. Thioredoxin is a small sulfhydryl protein capable of recycling antioxidants by reducing oxidized forms of ascorbic acid, alpha-lipoic acid, CoQlo, as well as selenocysteine-dependentenzymes and regulatory proteins. Thioredoxin also promotes the activation of several transcription Antioxidant vitamins can have far-reaching effects on tissues. Thus vitamin E supplementation can reduce the induction of the protein kinase C pathway in hyperglycemic aortas. This pathway regulates endothelial cell permeability and cell proliferation, and in this case,

vitamin E inhibits the migration and proliferation of vascular smooth muscle cells, opening the possibility of reducing the risk of vascular disease associated with type 2 It is of interest that alpha-tocotrienol inhibited monocyte adhesion by endothelial cells more than alpha-tocopherol. The mechanism of inhibition of expression of adhesion molecule-1 and E-selectin was found to be NF-kappaB dependent.270It is worthwhile to note that ascorbic acid plays critical roles in hormone synthesis and wound healing in serving as a cofactor for hydroxylation reactions. Phytochemicals have multiple effects, ranging from enzyme inhibition to enzyme induction via alteration of signal transduction. Certain carotenoids enhance immune function, regardless of their provitamin activity. For example, supplementation of healthy male nonsmokers with 15 mg of beta-carotene daily for 26 days increased the function of isolated blood monocytes, suggesting that higher beta-carotene consumption may enhance cell-mediated immunity.lE Flavonoids, in particular, often have multiple effects, so they are often regarded as “biologic response modifiers.” Furthermore, there are indications that certain polyphenols can alter several enzyme activities, and interactions with cell receptors as well as enzymes remain an important arena of flavonoid research. There is a growing awareness of the necessity of understanding the impact of flavonoids on the oxidative stress that contributes to mutagenesis and apoptosis. Consumption of green tea and red wine flavonoids as well as of oligomeric proanthocyanidins can lower various indices of oxidative stress, such as plasma malondialdehyde and F2-isoprostanes (from fatty acid peroxidation), tissue inflammation, and urinary output of oxidized DNA bases. Effectiveness of an antioxidant in vivo relies on adequate absorption and assimilation. Water solubility of polyphenols would likely favor intestinal uptake; however, quercetin is readily absorbed despite its minimal water solubility.193The effects of bioactive ingredient or ingredients in botanical extracts are seldom completely understood. An additional complication is the fact that intestinal bacteria degrade complex polyphenols to simple phenolic acids, which may be more bioactive than the starting material. For example, red wine polyphenols are absorbed and metabolized to glucuronide conjugates, which possess antioxidant activity in pla~ma.2’~ Gastric cleavage of higher procyanidin oligomers to monomers and dimers increases their bioavailability. Flavonol monomers including epicatechin are extensively 0-methylated, sulfated, or conjugated as glucuronides during absorption into the circulation. However, studies of the in vivo properties of these derivatives is in its infancy2”

Pharmacology of Natural Medicines

The Adequacy of Antioxidant Defenses Protection by free radical scavengers is limited, and free radical damage is not completely prevented even in healthy people. All cells lack an enzyme defense against hydroxyl radicals, the most damaging species. Therefore when free radical production exceeds the scavenging systems, hydroxyl radicals can be released, causing severe cellular damage. The body's ability to respond to oxidative stress is a function of age, inheritance, medical history, level of exposure to pollutants and other environmental stressors, and diet.

Age Because repair mechanisms decline with age, the body gradually loses functional resiliency, especially to oxidative stress. According to the free radical theory of aging, aging represents progressive oxidative damage." Ames et all1 have estimated that the average human cell sustains 10,000 DNA "hits" per day. Although most of this damage is repaired, unrepaired damage accumulates with age. Subtle structural alterations occur first, leading to decreased repair of damaged membranes and DNA, ultimately limiting the function of the nervous, endocrine, and immune systems." The rate of free radical formation by mitochondria in nondividing tissues is negatively related to animal longevity. Thus long-lived animals have less oxidation of mitochondria1 DNA, but not of nuclear DNA, than short-lived animals.274The production of superoxide anions and expression of SOD are common denominators of various degenerative processes. Studies with genetically engineered laboratory animals (both transgenic and knockout) as well as human SOD mutations provide a direct link between free radical scavenger enzymes and aging.275Evidence suggests that cumulative ROS damage to mitochondria leads to the decrease in ATP production associated with aging. Supplemental antioxidants result in the sign& cant extension of the mean lifespan in laboratory animals. Potentially antioxidants could block ROS at their sites of production, the mitochondria.276

Inheritance Owing to heredity, the levels of protective enzymes can vary among individuals.People who possess low levels of these enzymes face greater risks of free radical-induced disease. This distinction is blurred somewhat because these enzymes are often inducible, and greater enzyme synthesis occurs in many organs, such as liver and lung, as they adapt to increased oxidative burden (upregulation of antioxidant defense enzymes)."

Medical History and Environmental Exposure Processes such as trauma, inflammation, and infection generally increase ROS production. Oxidative stress

sometimes accompanies drug treatment. Cigarette smoke, ozone, oxides of nitrogen, solvents, and pesticides can cause toxicity when radicals are created during their detoxification. The gut epithelium does not appear to adapt to long-term oxidative stress and, because of low initial levels of defensive enzymes, may be especially susceptible to oxidative damage with even moderate inflammation.278 Strenuous physical exercise increases ROS production, and supplementing with antioxidant vitamins such as E, C and CoQlo may decrease associated oxidative damage, especially in older people?79 and increase LDL antioxidant capacity in endurance However, the conflict between exercise-induced oxidative stress and the obvious benefits of exercise has not been entirely resolved. Indeed, certain benefits of exercise may be oxidant-mediated. Whether supplemental antioxidants are needed to counteract the increase in oxidative stress has not yet been established, but athletes who exercise strenuously are likely to benefit from higher antioxidant intake.281In addition, antioxidants may attenuate muscle cell damage following strenuous exercise. Thus supplementation with 1200 IU alpha-tocopherol daily for 4 weeks before 6 days of endurance running reduced the leakage of creatine b a s e and lactate dehydrogenase compared with placebo.282

Nutritional Status Americans do not consume enough antioxidants, and the trend seems unlikely to change in the foreseeable future. Perhaps only 10% to 20% of adults eat a minimum of five daily servings (3 to 5 cups) of fruits and vegetables.283a World Health Organization recornmendations for fruits and vegetables entail a minimum combined intake of about 400 g/day/person, as 250 g vegetables and 150 gfruit per person. Median intakes of key antioxidants indicate that the consumption of vitamins C and E, betacarotene, zinc, selenium, copper, and manganese are low for specific segments of the population, and far below the recommended daily allowances (RDAs) for some. Furthermore, the RDAs do not address contributing factors related to chronic diseases, lifestyle choices, or medical history, nor do they address the issue of the mutually supportive roles of antioxidants. Europeans may not consume enough antioxidants. On the basis of the 1998 German Nutrition Survey, substantial numbers of healthy women and men do not consume recommended intakes for several vitamins, including antioxidants such as vitamin E.285The immune system, in particular, requires ample antioxidant nutrients.286The health of the immune system represents a key predictor of longevity. Antioxidants protect immune cells against oxidative damage and limit the production of noninflammatory eicosanoids. For example, supplementing apparently healthy, elderly people

Naturally Occurring Antioxidants

(who were consuming an otherwise typical diet) with 60 to 800 mg vitamin E improved several aspects of cellSeveral mediated immunity within 6 to 12 studies also suggest that consumption of 200 mg/day vitamin E may be more effective than 800 mg/day. In other research, ingestion of 268 mg natural vitmin E per day for 8 months sigxuficantly reduced serum immunoglobulin E with apparently normalization of most lesions in patients with atopic d e r m a t i t i ~If. ~one ~ extrapolates from such data, antioxidant supplements may profoundly affect healthy aging. Overall the studies suggest that the RDAs for this nutrient and other antioxidants are inadequate for optimal immune function for certain groups.

GUIDELINES FOR USE OF ANTIOXIDANTS Antioxidants represent powerful additions to the health care practitioner’s armamentarium. However, their application in treatment protocols requires an understanding of their strengths and limitations. No single supplement, nutrient, or food can maintain the body’s antioxidant defenses: There are simply too many oxidants to be neutralized and too many layers of antioxidant defenses to be sustained, and the range of reactivities of water- and lipid-soluble ROS is far too great. Thus it is unrealistic to expect that one or more antioxidants will be completely effective in disease prevention or treatment. Indeed, the often negative or conflicting results reported from clinical trials may reflect wide variations in the nutritional status and heterogeneity of antioxidant intake in the study populations. Clearly, multiple nutrients, including vitamins, minerals, and other food factors, are essential to ensure normal function of organ systems such as the cardiovascular system. A basic strategy is to gear supplementation to correct any imbalances in an individual’s nutritional status. Multiple, complementary antioxidants are far more effective than large amounts of a single antioxidant. Often antioxidants work synergistically. An additional consideration is that antioxidant requirements should be balanced against oxidant burden. Thus, exposure to pollutants such as cigarette smoke, nitric oxides, and ozone as well as chronic inflammation raises oxidative stress. High intake of fish oil and polyunsaturated fatty acids increases the need for vitamin E. The goal is to support the body’s defense system rather than to quench all free radicals in the body, which would be counterproductive. Superoxide and nitric oxide play essential roles in maintaining the body’s defenses and homoeostatic mechanisms, for example. Greater consumption of antioxidant-rich foods-especially colored fruits, vegetables and legumes, and beverages such as green tea-may

generally be the most effect way to increase intake of a broad spectrum of defined and undefined antioxidants. Analysis of vegetable and fruit intake from a cohort of American male nonsmokers supports the contention that vitamin C is an especially critical antioxidant for health-promoting effects of fruits and vegetables.2N

PRECAUTIONS IN USING ANTIOXIDANT SUPPLEMENTATION The clinician should take the following precautions when using antioxidant supplementation in patients: 1. The uptake, assimilation and disposal, dosage, duration of treatment, effects of mixtures, and longterm safety of polyphenols are generally not well studied.291 2. Flavonoids are metabolized and detoxified by liver enzymes, and pharmacologic doses may increase toxin burden. Some flavonoids can induce phase I detoxification enzymes, increasing the ability to transform toxins. The tradeoff lies in the possible greater sensitivity to mutagens. In this context, quercetin at typical dietary levels appears to be a possible anticarcinogen in V ~ V O . ~ ~ ~ 3. Vitamin E can exacerbate hypertension in susceptible people. High levels may antagonize other fat-soluble vitamins, thus decreasing bone mineralization. This vitamin may be contraindicated in patients receiving anticoagulants or in those with a vitamin K def i~iency.2~~ 4.Large doses of vitamin C rarely increase oxalate production; the effects seems to be counterbalanced by increased vitamin B6h1take.2~~ 5. Excessive iron and iron overload may cause hydroxyl radical production in viv0.2~~ 6. Beta-carotene could act as a prooxidant, unless protected by other antioxidants such as vitamin E, when there is excessive oxidative stress (smoking, alcohol consumption) and when diets are inadequate. Beta-carotene may raise the risk of lung cancer in high-risk populations unless protected by antioxidants like vitamin E.296In addition, betacarotene may exacerbate liver abnormalities in patients with alcoholic liver disease. In one study, the rate of fatal coronary heart disease rose in patients receiving 20 mg/day beta-carotene (with or without alpha-to~opherol).~~ High levels of betacarotene may be contraindicated in smokers with myocardial infarctions. 7 . h antioxidant in one system is not necessarily an antioxidant in all systems. For example, vitamin C and vitamin E exhibit prooxidant activity in vitro under certain conditions. When exposed to catalytic levels of

iron or copper ions, ascorbate promotes the formation of H202 and hydroxyl radicals."JMIn vitro studies suggest that ascorbic acid can decompose lipid peroxides to gen0toxins.2~~ In vivo, these effects would likely require high ascorbate concentrations coupled with the depletion of tocophero1.l" 8. Prooxidant effects of carotenoids are poorly understood, and consumption of large amounts could be hazardous themselves in susceptible individuals. Carotenoids generally lose their effectiveness at high concentrations and at high partial pressures of oxygen. This feature may account for the possible benefits of consumption of carotenoid-rich foods even though therapeutic doses of isolated carotenoids may be deleterious.298Depending on the concentration of supporting antioxidants, even flavonoids can become prooxidants. Prooxidant activity of polyphenolic radicals is well documented.299 9. Vitamin A is a teratogen when the intake is 25,000 IU or more per day for several months. The general advice to women who are or who might become pregnant is to limit both their daily intake of vit& A from supplements to no more than 5000 IU/day (1500 pg) and their consumption of liver and liver products.300The current tolerable upper intake level for vitamin A is 3000 pg (10,000 IU).301 10. Nutrient-drug interactions and phytochemical-drug interactions are additional important considerations. The literature in this area, although steadily growing, remains incomplete. A number of reviews have been published.302mThe following examples are illustrative of such interactions: Taking vitamin C with flavonoids can stabilize the vitamin and increase its uptake.= Lycopene reacts synergisticallywith either vitamin E, rosmarinic acid (from rosemary), glabridin (from licorice), or garlic to block LDL oxidation.N5 Studies with transformed cell lines suggest that flavonoids such as myricetin and quercetin can inhibit the uptake of dehydroascorbate and ascorbic acid, potentially reducing intracellular ascorbic acid.% Silybin can potentiate the activity of the chemotherapeutic agent cisplatin in animal models.N7 Certain flavonoids can decrease cyclosporin uptake in laboratory animals.308 Quercetin inhibits the sulphation of certain drugs (dopamine, salbutamol, paracetamol, minoxidil) in the duodenum and liver of rats.Molecular modeling studies suggest that flavones can interact with benzodiazepine-binding sites and thus may compete with this class of drugs.310 Oral tangeretin seems to inhibit the tumor inhibition actions of tamoxifen in animal models.3lI

-

SELECTING ANTIOXIDANTS The traditional definition of an essential nutrient (e.g., mineral or vitamin) is too restrictive from the perspective of lifelong protection against chronic disease. The presence of vast numbers of nonvitamin antioxidantsin addition to established nutrients in vegetables, legumes, fruits, and grains-poses the question whether those antioxidants are in fact essential in the diet for optimal health and disease prevention. The consumption of vegetables and fruits by well-nourished individuals reduces the risk of radical-induced DNA damage. Because short-term interventions with vitamin C or E, beta-carotene, or flavonoids have not demonstrated this benefit, the data suggest that other plant food factors account for such protection.312 Consequently, antioxidant supplementation cannot substitute for a prudent diet, cessation of smoking, and regular exercise. Supplementation may be most effective for those individuals with the lowest baseline antioxidant levels whether from genetic or environmental causes. Foods supply a rich assortment of substances that can function as antioxidants. As an example, the total oxygen radical capacity of certain fruits has been determined.313 Strawberry, plum, orange, red grapes, kiwi fruit, and grapefruit possess high radical-quenching activity. Blackberry, blueberry, raspberry, strawberry, plums, red wine, and red grapes contain large amounts of anthocyanidins with strong antioxidant ~roperties.3~~ Further research will undoubtedly uncover many more phytochemical interactions. Though the picture is far from complete, antioxidants apparently operate ~ynergistically.~~~ Thus, animal studies indicate that consumption of a greater diversity of antioxidants provides more antioxidant protection than Even members of the vitamin B single complex, such as pantothenic acid, may indirectly stimulate antioxidant prod~ction.3'~ A number of studies recognize the importance of supplementation with complementary antioxidants.For example, daily supplementation with vitamin C (500 mg), vitamin E (400 IU), beta-carotene (15 mg), zinc (80mg), and copper (2 mg) sigruficantly slowed the progression of advanced agerelated macular degeneration. In one study, however, this regimen did not affect the risk of cataracts or loss of visual acuity.121In other research CoQlo,vitamin E, and alpha-lipoic acid synergistically protect LDL against lipid peroxidation in vitro?l8 It should be emphasized that many ingredients in foods play important physiologic roles in addition to their properties as antioxidants. Furthermore, their effects may be indirect; antioxidants and response elements help the cell adapt to ROS exposure and correct ROS-induced damage.319Exploration of the role of

Naturally Occurring Antioxidants

I

Recommended safe upper intake levels for antioxidant nutrients

Vitamin E

1000 mg'

Vitamin C

2000 mg'

Vitamin A

3000 pg*

Beta carotene

None established (Five or more servings of fruits and vegetables would provide an estimated 3-6 mg beta carotene daily.)

Copper

10 mg*

Magnesium

250 mg+

Selenium

300 pg*

Zinc

40 mg'

From Flynn A, Moreiras 0.Stehle I? et al. Eur J Nutr 2003;42:118-130. "US. Food and Nutrition Board, Institute of Medicine Tolerable Upper intake Levels. +EuropeanCommission SCF, Tolerable Upper Intake Level.

1.Kovacic P, Jacinth0 JD.Mechanisms of carcinogenesis: focus on oxidative stress and electron transfer. Curr Med Chem 2001;8: 773-796. 2. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002;82:47-95. 3.Ross JS, Stagliano NE, Donovan MJ, et al. Atherosclerosis and cancer: common molecular pathways of disease development and progression. Ann N Y Acad sci 2001;947271-292. 4. Iuliano L. The oxidant stress hypothesis of atherogenesis. Lipids 2001;36S41-S44. 5. Ottonello S, Foroni C, Carta A, et al. Oxidative stress and agerelated cataract. Ophthalmologica 2000;2147&85. 6. DOdorico A, Bortolan S, Cardin R, et al. Reduced plasma antioxidant concentrations and increased oxidative DNA damage in inflammatory bowel disease. Scand J Gastroenterol 2001;36: 1289-1294. 7. Tak PP,Zvaifler NJ, Green DR, Firestein GS. Rheumatoid arthritis and p53 how oxidative stress might alter the course of inflammatory diseases. Immunol Today 2000;21:7&82. 8.Rahman I. Oxidative stress, transcription factors and chromatin remodeling in lung inflammation. Biochem Pharmacol 2002;64: 935-942. 9. Esposito E, Rotilio D, Di Matteo V,et al. A review of specific dietary antioxidants and the effects on biochemical mechanisms related to neurodegenerativeprocesses. Neurobiol Aging 2002;23:719. 10. Moosmann B, Behl C. Antioxidantsas treatment for neurodegenerative disorders. Expert Opin Investig Drugs 2002;11:1407-1435. 11. Ames BN, Shigenaga h4K, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A 1993;90:7915-7922. 12. Wei YH, Lee HC. Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med 2002;227671-682.

a major oxidant, peroxynitrite, and nitrogen oxides as NRS ("nitrogen reactive species") in chronic degenerative diseases is still in its infancy3" Consequently, the antioxidants that best defuse these reactive compounds have not yet been established. Table 109-1 provides a s u m m a r y of a recommended intake of antioxidants for maintenanceas compiled by the European Federation of Health Product Manufacturers.301 The levels often prescribed in treatment protocols may be considerably higher than those listed in the table. Thus, the consumption of a broad spectrum of antioxidants in amounts geared to meet an individual's oxidant burden and nutritional status appears to be essential to promote optimal health and to minimize the effects of genetic predisposition that compromise defenses against aging, degenerative disease, and toxic chemical exposure. Future health claims for antioxidants must await additional studies, including intervention clinical trials demonstrating better function with supplementation and prospective studies exploring risk reduction for degenerative diseases.321

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251. Rimbach G, Gold K, Matsugo S, et al. Induction of glutathione synthesis in human keratinocytes by Ginkgo bilobu extract (EGb 761). Biofactors 2001;1539-52. 252. Bridi R, Crossetti FP, Steffen VM, Henriques AT. The antioxidant activity of standardized extract of Ginkgo bilobu (EGb 761) in rats. Phytother Res 2001;15449451. 253. Zheng W, Wang SY. Antioxidant activity and phenolic compounds in selected herbs. J Agric Food Chem 2001;49:5165-5170. 254. Miquel J, Bemd A, Sempere JM, et al. The curcuma antioxidants: pharmacological effects and prospecs for future chemical use. A review. Arch Gerontol Geriatr 2002;34:3746. 255. Awasthi S, Srivatava SK,Piper JT, et al. Curcumin protects against 4-hydroxy-2 trans nonenal-induced cataract formation in rat lenses. Am J Clin Nutr 1996;64:761-766. 256. Frautschy SA, Hu W, Kim P, et al. Phenolic antiinflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging 2001;22:993-1005. 257. Quiles JL, Mesa MD, Ramirez-Tortosa CL, et al. Curcum longu extract supplementation reduces oxidative stress and attenuates aortic fatty streak development in rabbits. Arterioscler Thromb Vasc Biol2002;22:1225-1231. 258. Schwartz IF, Hershkovitz R, Iaina A, et al. Garlic attenuates nitric oxide production in rat cardiac myocytes through inhibition of inducible nitric oxide synthase and the arginine transporter CAT2 (cationic amino acid transporter-2). Clin Sci 2002;102 487493. 259. Ho SE, Ide N, Lau BH. Sally1 cysteine reduces oxidant load in cells involved in the atherogenic process. Phytomedicine 2001; 8:3946. 260. Durak I, Ozturk HS,Olcay E, et al. Effects of garlic extract on oxidant/antioxidant status and atherosclerotic plaque formation on rabbit aorta. Nutr Metab Cardiovasc Dis 2002;12141-147. 261. Dillon SA, Lowe GM, Billington D, Rahman K. Dietary supplementation with aged garlic extract reduces plasma and urine concentrations of 8-isoprostaglandin F(2alpha) in smoking and nonsmoking men and women. J Nutr 2002;132168-171. 262. Halliwell B. How to characterize a biological antioxidant. Free Radic Res Commun 1990;9:1-32. 263. Lotito SB, Fraga CG. Catechins delay lipid oxidation and alpha tocopherol and beta carotene depletion following ascorbate depletion in human plasma. Proc SOCExp Biol Med 2000; 225:32-38. 264. Yang 8, Kotani A, Arai K, Kusu F. Relationship of electrochemical oxidation of catechins on their antioxidant activity in microsomal lipid peroxidation. Chem Phann Bull 2001;49747-751. 265. Lee HA, Hughes DA. Alpha-lipoic acid modulates NF-kappaB activity in human monocytic cells by direct interaction with DNA. Exp Gerontol200237401-410. 266. Roberts RA, Soames AR, James NH, et al. Dosing-induced stress causes hepatocyte apoptosis in rats primed by the rodent nongenotoxichepatocarcinogen cyproterone acetate. Toxic01 Appl Pharmacol1995;135192-199. 267. Narula J, Haider N, V i i a n i R, et al. Apoptosis in myocytes in end stage heart failure. N Eng J Med 1996;3351182-1189. 268. Nordberg J, Arner ES. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 2001;31:1287-1312. 269. Kunisaki M, Bursell SE, Umeda F, et al. Normalization of diacylglycerol-proteinkinase C activation by vitamin E in aorta of diabetic rats and cultured rat smooth muscle cells exposed to elevated glucose levels. Diabetes 1994;43:1372-1377. 270. Theriault A, Chao JT, Gapor A. Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes. Atherosclerosis 2002; 160.21-30.

Pharmacology of Natural Medicines 271. Yamashita S, sakane T, Harada M, et al. Absorption and metabolism of antioxidative polyphenolic compounds in red wine. Ann N Y Acad Sci 2002;957325-328. 272. Spencer JP,Schroeter H, Rechner AR, Rice-Evans C. Bioavailability of flavan-Sols and procyanidins: gastrointestinal tract influences and their relevance to bioactive forms in vivo. Antioxid Redox Signal 20013:1023-1039. 273. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol1956;11:298-300. 274.Baja G. Endogenous oxidative stress: relationship to aging, longevity and caloric restriction. Ageing Res Rev 2002;1:397-411. 275. Levin ED, Christopher NC, Lateef S, et al. Extracellular superoxide dismutase overexpression protects against aging-induced cognitive impairment in mice. Behav Genet 200292:119-125. 276. Miquel J. Can antioxidant supplementation protect against a g e related mitochondrial damage? Ann N Y Acad Sci 2002;959:508-516. 277.Visner GA, hugall WC, Wilson JM, et al. Regulation of manganese superoxide dismutase by lipopolysaccharide, interleukin-1 and tumor necrosis factor. J Biol Chem 1990;265:2856-2864. 278. Grisham MB, MacDermott RP,Deitch EA. Oxidant defense mechanisms in the human colon. Inflammation 1990;14669-680. 279. Goldfarb AH. Antioxidants: role of supplementation to prevent exercise induced oxidative stress. Med Sci Sports Exerc 1993; 25232-236. 280. Vasankari TJ, Kujala UM,Vasankari TM, et al. Increased serum and low density lipoprotein antioxidant potential after antioxidant supplementation in endurance athletes. Am J Clin Nutr 1W7;65:1052-1056. 281. Sen CK. Antioxidants in exercise nutrition. Sports Med 2001;31: 891-908. 282. Itoh H, Ohkuwa T, Yamazaki Y, et al. Vitamin E supplementation attenuates leakage of enzymes following 6 successive days of running training. Int J Sports Med 2000;21:369-374. 283.Block G. Antioxidant intake in the US. Toxicol Ind Health 1993;9:295-301. 284. Patterson BH, Block G, Rosenberger WF, et al. Fruit and vegetables in the American diet: data from the NHANES II Survey. Am J Public Health 1990;801443-1449. 285.Beitz R, Mensink GB, Fischer B, Thamm M. Vitamins-dietary intake and intake from dietary supplements in Germany. Eur J Clin Nutr 200256539-545. 286.Meydani SN, Santos MS, Wu D, Hayek MG. Antioxidant modulation of cytokines and their biologic function in the aged. Z Emahrungswiss 1998;3735-42. 287. Bogden JD, Bendich A, Kemp FW,et al. Daily micronutrient supplements enhance delayed hypersensitivity skin test responses in older people. Am J Clin Nutr 1994;60:437-447. 288. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. JAh4A 1997;277:1380-1386. 289. Tsoureli-Nikita E, Hercogova J, Lotti T, Menchini G. Evaluation of dietary intake of vitamin E in the treatment of atopic dermatitis. a study of the clinical course and evaluation of the immunoglobulin E serum levels. Int J Dermatol2002;41:146-150. 290. Block G, Norkus E, Hudes M, et al. Which plasma antioxidants are most related to fruit and vegetable consumption? Am J Epidemiol 2001;154:1113-1118. 291. Canada AT, Watkins WD, Nguyen TD. The toxicity of flavonoids to guinea pig enterocytes. Toxicol Appl Pharmacol 1989;99: 357-361. 292. Stavric B. Quercetin with our diet: from potent mutagen to probable anticarcinogen. Clin Biochem 1994;27245-248. 293. Meydani M. Vitamin E. Lancet 1995;345:170-175. 294.Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol 1999;10:840-845.

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Opuntia Species (Prickly Pear) Kathy Abascal, BS, JD, KH(AHG) Eric L. Yarnell, NI), RH(AHG) CHAPTER C O N T E N T S General Description 1113 Chemical Composition 1113 History and Folk Use 1113 Pharmacology 1114 Analgesic Effect 1114 Antiinflammatory Effect 1114 Antiviral Effect 1114 Cicatrizant Effect 1114 Diuretic and Other Renal Effects 1114 Hypoglycemic Effect 1114 Hypocholesteremic Effects 1115

Opuntia spp. (family: Cactaceae) Common names: prickly pear, nopal

GENERAL DESCRIPTION There are about 260 species of Opuntia.' These cacti are shrubs with many stems branching at their bases. The flat, pear-shaped pads are stems or branches, not leaves as many suppose. The true leaves are small and scalelike, and they wither away quickly. Some prickly pear varieties form thickets many feet tall and many feet across. Prickly pear's thorns are simple spines-they do not have radial or central spines. Their flowers range from yellow through orange and red to rose. Their fruits also come in shades of yellow through red to purple. Most species have glochids, sometimes referred to as tiny spines although they are actually leaf hairs with tiny retrorsed barbs.2 The stems, fruits, and flowers are all used as medicines.

CHEMICAL COMPOSITION Data comparing the constituents of the many prickly pear species are sparse to nonexistent, and there is no indication that any particular species is a better medicinal plant. The pad is high in mucilage, consisting of carbohydrate-containing polymers that typically have

Clinical Applications 1115 Diabetes (Adult-Onset Non-lnsulin-Dependent) 1115 Hyperlipidemia 1115 Prostatic Hyperplasia 1115 Weight Loss 1115 Dosage 1116 Toxicology

1116

Drug Interactions 1116

an alternating galacturonic acid-rhamnose backbone, although the polysaccharide structure of the mucilage varies in different species? The pads also contain a mixture of saturated and unsaturated long-chain aliphatic esters, malonyl daidzen, genistein, beta-sitosterol, and vanillic, ferulic, myristic, palmitic, and stearic acid^.^-^ Prickly pearfruits are high in carbohydrates and contain the pigments indicaxanthin, betanin, three varieties of methyl citrate, and l-methyl malate.7 The flowers contain flavonoids (quercitin and isorhamnetin-3 glucosides and 3-rutinosides, isorhamnetin 3-rhamnosylgalactoside, and kaempferol 3-galactoside) in varying amounts.8

HISTORY AND FOLK USE Prickly pear has a long history of medicinal use. The Aztecs used prickly pear root with Geranium spp. (cranesbill) as a febrifuge, to alleviate hernias, and to soothe irritated livers? The fruit and seeds were used to prevent diarrhea. Indigenous peoples along the Yaqui River used the fluid from roasted prickly pear pads to relieve pain.*O In New Mexico, prickly pear pads were used as poultices for painful, inflamed skin conditions, for swollen glands in the neck, and for congested, purplish breasts in lactating women. The pads were also used as emollients for tumors, warts, and calluses. The Tarahumara used 1113

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the pads for the pain of bites and burns, and the Paipai used them to heal festering wounds. The Yaqui and the Hispanics in New Mexico soak diced pads in water and drink the liquid for thirst and diabetes; they also use the roasted pad to treat diabetic infections. Prickly pear was brought from the Americas to Africa and Europe, and its medicinal uses followed." Today, the Moors apply the heated pads to swellings on the body, the South African Bantu use prickly pear for a variety of tumors, and Zimbabweans use prickly pear internally as a treatment for pain in gouty arthritis.12J3In the Canary Islands, prickly pearfruits are used topically for a variety of inflamed wounds and internally for gastrointestinal and bronchial problems. In the Mediterranean region, prickly pear pads are used to treat gastric ulcers, and in Sicilian folk medicine, a flower infusion is used for its diuretic and relaxant action on the kidneys.I4

PHARMACOLOGY Analgesic Effect Prickly pear fruits and pads had sigruficant analgesic effects in mice in the hot plate and writhing tests.15 Prickly pear fruit injected intraperitoneally (400 mg/kg) had an analgesic effect comparable to that of aspirin (70 mg/kg) in mice in the writhing test.

Antiinflammatory Effect Prickly pear sigruficantly reduced carrageenan-induced edema in rat paws and showed an antiinflammatory effect in the adjuvant-induced chronic inflammation model in mice.16 The active constituent was isolated and identified as beta-sitosterol. Another study showed that prickly pear (Opuntiu dillenii) fruit extract injected intraperitoneally (100 to 400 mg/kg) had an antiinflammatory action in mice.17 Pretreatment with prickly pear significantly reduced edema in a dose-dependent manner, and its maximal effect was similar to that of indomethacin. However, the fruit extract induced a much more transient effect than the reference drug.

Antiviral Effect Preliminary pharmacologic studies show prickly pear pad to have antiviral effects.18These effects were investigated after a patient with mild diabetes who suffered frequent recurrences of herpes genitalis reported that taking 2 g prickly pear a day stopped the herpes outbreaks. In vitro studies indicate that prickly pear displays some antiviral activity: In hamster kidney cells, prickly pear sigruficantly and specifically reduced herpes simplex virus type 2 (HSV-2) replication at 3.5 mg/ml and completely inhibited replication at 15 mg/ml. Also, prickly pear sigruficantly inhibited other herpes viruses (pseudorabies virus, bovine mammillitis virus, equine

herpes virus type 1 as well as the more cell-associated human herpes virus, cytomegalovirus, and varicella zoster virus). Prickly pear inhibited replication by HSV-2 in infected human cervix tissue at 15 mg/ml, and inhibited RNA virus replication, although inhibition was greater aftei pre-infection incubation in prickly pear medium." Testing involved a laboratory strain of influenza A virus, an isolate of respiratory syncytial virus, and strains oj encephalomyocarditis (EMC) virus and human immm odeficiency virus type 1 (HN-1). The only virus thai prickly pear failed to inhibit was the picomavirus EMC The researchers concluded that fresh prickly pear extraci showed significant inhibition of virus replication and that the inhibitory activity resided in the wall of thc plant. They found prickly pear to be a promising antiviral agent deserving of more study, because it combines a breadth of in vitro reactivity with a high index of clinical safety. However, prickly pear pads combined with freslCapsicumfrutescms (cayenne) fruit and fresh Citrus Iimon (lemon) did not protect chickens from Newcastle virus.'!

Cicatrizant Effect When administered by mouth, dried prickly pear pac (Opuntiuficus indicu) signhcantly inhibited hydrochloride induced, aspirin-induced, and ethanol-induced gastric lesions in rats.20,21 Prickly pear did not affect gastric juice secretion, acid output, or stomach pH in the rats Extracts of 0. ficus indicu showed significant wound healing activity in rats.=

Diuretic and Other Renal Effects Fruit and flower infusions of 0.ficus indicu significantlq increase diuresis in rats, and the fruit infusion had ar antiuric effect.= Infusions of the pad, fruit, and flowei have each showed a modest but statisticallyinsigruficani increase in natriuresis and kaluresis. Prickly pear pad: (20 mg per 100 g body weight daily for 5 weeks) sigrufi cantly decreased uric acid levels and increased watei intake while only slightly raising urine output in rats? Although the rise in urine flow was slight, the investiga tors suggest that it could account for the greater excretion of uric acid. Opuntia megacantha pads (20 mg/kg daily for 5 weeks) significantly increased urinarj sodium output in diabetic rats and normal rats compared with controls.25Prickly pear did not alter plasma aldosterone concentrations. In earlier studies by the samc researchers, prickly pear extract administered orallj (20 mg per 100 g body weight) increased creatinine clear. ance in diabetic rats and raised plasma creatinine anc urea levels in all rat^.^*,^^

Hypoglycemic Effect Animal studies show prickly pear pad to have a hype glycemic effect in streptozotocin-induced diabetes ir

Opuntia Species (Prickly Pear)

rats and rabbits, although one study showed no effect if the rabbits’ pancreatic beta cells were completely ~ b l i t e r a t e d . ~In~ -one ~ ~ rabbit study, prickly pear’s hypoglycemic effect was comparable to that of tolbutamide.27Prickly pear and insulin equivalently reduced, but did not normalize, glucose and insulin levels in diabetic rats. Interestingly, prickly pear combined with insulin had a synergistic effect. Diabetic rats being given the combination rapidly achieved normal glucose levels and at 7 weeks became hypoglycemic. At that point, prickly pear alone was sufficient to maintain normal glucose levels.28

Hypocholesterolemic Effects Prickly pear pectin had a hypocholesterolemic effect in guinea pigs in several studies conducted by the same research g r o ~ p .In~ each , ~ ~study, prickly pear reduced blood cholesterol levels, reduced low-density lipoprotein (LDL) cholesterol and increased its density. Highdensity lipoprotein (HDL) cholesterol levels were not affected significantly. Isotope studies indicated that prickly pear’s effect on blood fats was due to decreases in hepatic cholesterol concentrations and homeostasis rather than a change in cholesterol absorption.

CLINICAL APPLICATIONS Diabetes (Adult-Onset Non-Insulin-Dependent) There are a number of clinical trials on the effect of prickly pear pad in non-insulin-dependent diabetes A preliminary metaanalysis of mellitus (NIDDM).32-38 the clinical trials on prickly pear’s benefit in NIDDM concluded that the intervention data showed it to lower blood glucose levels by 10 to 30 mg/dl in patients with NIDDM and supported claims that prickly pear has a However, the control true metabolic effect in data were insufficient for a full metaanalysis. Most of these studies are very small, and many lacked valid placebo controls. Nonetheless, a statistically significant reduction of blood glucose and, when tracked, insulin levels was seen consistently when broiled prickly pear was administered to volunteers with NIDDM. Glucose levels dropped in the first hour after ingestion but typically reached sigruficance 2 to 3 hours later in one study, indicating an action that was measurable over a span of 6 hours. The magnitude of the hypoglycemic effect varied from mild to moderate depending on dose. For example, a 300-g dose of broiled pad acutely lowered blood glucose levels by 30 mg/dl in 8 subjects, whereas 500 g lowered levels by an average of 45 mg/dl in the same subjects. Most studies used broiled pads. One that used homogenized prickly pear pad preparation did not find a hypoglycemic effect.% However, when the pad was

ground in a regular blender rather than ultrahomogenized, it had an effect equivalent to that of broiled Capsules of dried prickly pear did poorly in a small, crossover, single-blind study in which a single dose of 30 capsules had no hypoglycemic effect.40Only a mild effect was seen in volunteers taking 30 capsules per day for 10 days-an impractical dose for most people. In contrast, prickly pear has been shown to affect glucose levels mildly or not at all in normal individuals.3335f” In two studies, prickly pear pad did not reduce glucose or insulin levels in healthy volunteers. In a third study, nondiabetic individuals who ate broiled prickly pear pads before meals for 10 days showed a mild but significant reduction in fasting glucose levels, but prickly pear pad had a significant hypoglycemic effect in volunteers in an induced hyperglycemic state.w In three studies using oral glucose loading, glucose levels dropped signhcantly, but in one test in which the glucose was administered intravenously, prickly pear had no effect.

Hyperlipidemia Prickly pear pads lowered cholesterol levels, improved ratios of cholesterol, and reduced triglyceride levels in a small, non-placebo-controlled clinical trial?5 Eight healthy patients, fourteen obese patients (18% to 70% overweight), and seven patients with NIDDM ate 100 g of broiled prickly pear pads before meals three times a day for 10 days. Each group experienced a sigruficant reduction in total cholesterol levels compared with their entry values. Levels of beta-cholesterol diminished significantly in the obese and diabetic patients, and the ratio of beta to alpha cholesterol showed a mild but significant drop. Triglyceride levels also diminished significantly in obese and diabetic patients (23%0-27%)but remained unchanged in healthy patients.

Prostatic Hyperplasia Dried prickly pear flowers improved subjective symptomology of prostatic hyperplasia in a preliminary open study.@ Eighty-eight patients at two centers took two 250-mg capsules of flower three times daily for 2 to 6 months. Many patients reported decreases in urgency, emergency urinations, and the sensation of fullness in the bladder, but not all patients experienced relief.

Weight Loss In a small, open-label study, prickly pear pads significantly reduced body weight of obese and diabetic subjects and showed a trend toward weight loss in normal ~ubjects.3~ Fourteen obese patients, seven patients with NIDDM, and eight healthy patients ate 100 g of broiled prickly pear pad before meals three times a day for 10 days. Each group showed a mean reduction in weight of 1.5 kg while maintaining their usual diets.

DOSAGE Studies of the use of this plant have used a variety of forms of prickly pear pad. Most have used broiled or grilled pads, whereas some studies have used juiced slurries. These studies used 100 to 500 g (3-170 2 ) of pads three times a day, taken before meals. There is little information on dried preparations, but as mentioned previously, such preparations did not achieve results in some small trials.

TOXICOLOGY Prickly pear showed a high degree of safety in studies of mice, horses, and humansB It has a long history of use as a food, a factor that also indicates a high level of safety. Most adverse events involving the plant are the result of its glochids (tiny,nearly invisible spines),which can become embedded in the skin.45Sabra dermatitis is an occupational disease among prickly pear fruit handlers, in which the glochids cause a widespread skin eruption resembling scabies that in chronic cases involves granuloma formation. However, in two animal

1.Thomber JJ, Bonker F. The fantastic clan: the cactus family. New York Maanillan, 1932. 2. Moore M. Medicinal plants of the desert and canyon west. Santa Fe: Museum of New Mexico Press, 1989. 3.Smestad PB, Steinar W.Watersoluble polysaccharides of Opuntia fius-indicn cv “Burbank‘sspineless.”Phytochemishy 1%’9;18:569-571. 4. Munoz EC, Millan AL, Braverman V, et al. Isoflavones in Mexican foods and soy products. FASEB J 2001;15:A286. 5.Abramovitd-1 RA, Coutts RT, Knaus EE. Identification of constituents of Opuntiafragilis. Planta Med 1968;16147-157. 6.McGarvie D, Parolis H. The mucilage of Opuntia aurantiaca. Carbohydrate Res 19819467-71. 7. Femandez-Lopez JA, Almela L. Application of high-performance liquid chromatography to the characterization of the betalain pigments in prickly pear fruits. J Chromatog A 2001;913415-420. 8. Clark DW, Parfitt BD. Flower flavonoids of Opuntia series Opuntiae. Phytochemistry 1980;191856-1857. ’ WW, liemey GD. Wild plants of the Pueblo province. 9. Dunrmre Santa Fe: Museum of New Mexico Press, 199531-34. 10. Curtin LSM, Moore M, eds. Healing herbs of the upper Rio Grande: traditional medicine of the Southwest. Santa Fe: Western Edge Press, 1997116-120. 11. Kay MA. Healing with plants in the American and Mexican west. Tucson: University of Arizona Press, 1996, pp 201-202. 12. Dimmitt MA. Genus Opuntia (incl. Cylindropuntia, Grusonia, and Corynopuntia). In Phillips SJ, Comus PW, e d s A natural history of the Sonoran desert. Tucson: Arizona-Sonoran Desert Museum Press, 2000:209-218. 13.Hartwell JL. Plants used against cancer. Lawrence, MA: Quarterman Publications, 198286. 14.Galati EM, Tripodo MM, Trovato A, et al. Biological effect of Opuntia ficus indica (L.) Mill. (Cactaceae) waste matter. Note 1: D i w t i c activity. J Ethnopharmacol2002;7917-21.

studies, prickly pear sigmfmntly raised blood urea and creatinine levels in rats, and increased urinary creatinine clearance rates in diabetic rats ~ n l ~The . ~researchers ~p expressed concern that prickly pear perhaps caused an early stage of kidney dysfunction in rats. However, the same researchers did not report similar results in a subsequent study, and no other studies have reported such eff ectsZ6

DRUG INTERACTIONS No human data on drug interaction are available for prickly pear. All herbs rich in complex carbohydrates may affect transit time and thus may alter absorption of practically any medication. Many of the diabetes trials of this plant included patients who were taking oral hypoglycemic agents (tolbutamide, glyburide, chlorpropamide), and no adverse interactions were rep~rted.=~~J’,% Prickly pear and insulin had a synergistic effect in rats, first normalizing blood sugar levels and then inducing hypoglycemiaF8 The effect of combining prickly pear and insulin in human subjects has not been studied.

15. Choi J, Chung KL, Young CL, et al. [Screening on biological activities of the extracts from fruit and stem of prickly pear (Opuntiaficus indica var. saboten).] Korean J Pharmacogn 2001;32;330-337. 16.Park EH, Kahng JH, Lee SH, Shin KH. An anti-inflammatory principle from cactus. Fitoterapia 2001:72:288-290. 17. Lon, JF,del Rio I, Perez-Santana L. Preliminary studies of analgesic and anti-inflammatory properties of Opuntia dillenii aqueous extract. J Ethnopharmacol1999;67213-218. 18. Ahmad A, Davies J, Randall S, Skinner GR. Antiviral properties of extract of Opuntia strepfacantha.Antiviral Res 1996;3075-80. 19. Mtambo MM, Mushi El,Kinabo LD, et al. Evaluation of the efficacy of the crude extracts of Capsicumfrutescens, Citrus Zimon and Opuntia vulgaris against Newcastle disease in domestic fowl in Tanzania.

J Ethnopharmacol1999;68:55-61. 20. Lee EB, Hyun JE,Li da W, Moon M.Effects of Opuntiaficus-indica var. Saboten on gastric damage in rats. Arch Pharmacal Res 2002;25:67-70. 21.Galati EM, Monforte MT, Tripodo MM, et al. Antiulcer activity of Opuntia ficus indica (L.) Mill. (Cactaceae): Ultrastructural study. J Ethnopharmacol2001;761-9. 22. Park EH, Chun MJ. Wound healing activity of Opuntiaficus indica. Fitoterapia 2001;72:165-167. 23. Galate EM, Tripod MM, Trovata A, et al. Biological effect of Opuntia ficers indica (L.) Mill. (Cactaceae waste matter: Note I: diuretic activity). J Ethnopharmacol2002;79:17-21. 24.Bwititi P, Zamurawo M, Mabhachi G, Mashanga N. Toxic and hypericaemic effects of Opuntia megacantha extract in rats. Phytother Res 1997;11:389-391. 25. Bwititi PT, Machakairr T, Nhachi CB, Musabayane CT. Effects of Opuntia megacantha leaves extract on renal electrolyte and fluid handling in stmptozotocin (STZ)-diabetic rats. Renal Fail 2001;23:149-158. 26. Bwititi,’l Musabayane CT, Nhachi CF. Effects of Opuntia megacantha on blood glucose and kidney function in streptozotocin diabetic rats. J EthnopharmacolZO00;69:247-252.

Opuntia Species (Prickly Pear) 27. Trejo-GonzalezA, Gabriel-Ortiz G, Puebla-Perez AM, et al. A purified extract from prickly pear (Opuntia fuliginosa) controls experimentally induced diabetes in rats. J Ethnopharmacol 1996;55:27-33. 28. Ibanez-Camacho R, Roman-Ramos R. Hypoglycemic effect of Opuntia cactus. Arch Invest Med (Mex) 1979;10223-230. 29. Ibanez-Camacho R, Meckes-Lozoya M, MelladoCampos V. The hypoglucemic effect of Opuntia streptacantha studied in different animal experimental models. J Ethnopharmacol1983;7175-181. 30. Femandez ML, Trejo A, McNamara DJ. Pectin isolated from Prickly Pear (Opuntia sp.) modifies low density lipoprotein metabolism in cholesterol-fed guinea pigs. J Nutr 1990;1201283-1290. 31.Femandez ML, Lin EC, Trejo A, McNamara DJ. Prickly pear (Opuntia sp.) pectin reverses low density lipoprotein receptor suppression induced by a hypercholesterolemic diet in guinea pigs. J Nutr 1992;1222330-2340. 32. Frati AC, Jimenez E, Ariza CR. Hypoglycemic effect of Opuntia ficus-indica in non insulin-dependent diabetes mellitus patients. Phytotherapy Res 1990;4195-197. 33. Frati AC, Gordillo BE, Altamirano P, et al.. Acute hypoglycemic effect of Opuntia streptacantha Lemaire in NIDDM. Diabetes Care 1990;13:455-456. 34. Frati-Munari AC, Gordillo BE, Altamirano P, Ariza CR. Hypoglycemic effect of Opuntiu streptucantha Lemaire in NIDDM. Diabetes Care 1988;11:63-66. 35. Frati-Munari AC, Femandez-Harp JA, De La Riva H, et al. [Effects of nopal (Opuntia sp.) on serum lipids, glycemia and body weight.] Arch Invest Med (Mex) 1983;14117-125. 36. Frati-Munari AC, Del Valle-Martinez LM, Ariza-Andraca CR, et al. [Hypoglycemic effect of different doses of nopal (Opuntia streptacantha Lemaire) in patients with type ll diabetes.] Arch Invest Med (Mex) 1989;20197-201.

37. Frati-Munari AC, Gil UR, Ariza-Andraca CR, et al. [Duration of hypoglucemic action of Opuntia strepfacantha Lem.] Arch Invest Med (Mex) 1989;20297-300. 38. Frati-Munari AC, Altamirano-BustamanteE, Rodriguez-BarcenasN, et al. [Hypoglycemic action of Opuntia streptacantha Lemaire: study using raw extracts.] Arch Invest Med (Mex) 1989;20321-325. 39. Aguilar C, Ramirez C, Castadeda-Andrade I, et al. Opuntia (prickly pear cactus) and metabolic control among patients with diabetes mellitus. Annu Meet Int Soc Techno1Assess Health Care 1996;1214. 40. Frati-Mumari AC, Vera-Lastra 0, Ariza-Andraca CR. [Evaluation of nopal capsules in diabetes mellitus.] Gac Med Mex 1992;128 431-436. 41. Frati-Munari AC, Yever-Garces A, Islas-Andrade S, et al. [Studies on the mechanism of ‘hypoglycemic’ effect of nopal (Opuntia sp.,.] Arch Invest Med (Mex) 1987;187-12. 42. Frati-Munari AC, Quuoz-Lazar0 JL, Altamirano-Bustamante P, et al. [The effect of various doses of nopal (Opuntia streptacantha Lemaire) on the glucose tolerance test in healthy individuals.] Arch Invest Med (Mex) 1988;19143-148. 43.Frati-Munari AC, Licona-Quesada R, Araiza-Andraca C, et al. [Activity of Opuntia streptucantha in healthy individuals with induced hyperglycemia]. Arch Invest Med (Mex) 1990;21:99-102. 44. Palevitch D, Earon G, Levin I. Treatment of benign prostatic hypertrophy with Opuntia ficus-indicu (L.) Miller. Journal of Herbs, Spices 81 Medicinal Plants 1993;24549. 45. Whiting DA, Bristow JH. Dermatitis and keratoconjunctivitis caused by a prickly pear (Opuntia rnicrodasys). S Afr Med J 1975; 49~1445-1448. 46. Meckes-Lozyoa M, Roman-Ramos R. Opuntia streptacantha:a coadjutor in the treatment of diabetes mellitus. Am J Chin Med 1986;14116-118.

Panax ginseng (Korean Ginseng) hlichael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 1119 Chemical Composition 1119 History and Folk Use

1120

Pharmacology and Clinical Indications 1120 Adaptogenic Activity 1121 Cognitive Performance 1122 Antistress Activity 1122 As an Ergogenic Aid 1123 Diabetes 1123 Reproductive Effects 1124 Menopause 1124

Panax ginseng C.A. Meyer (family: Araliaceae) Synonym: Panax schinseng Nees Common names: Korean ginseng, Chinese ginseng, Asiatic ginseng, Oriental ginseng

GENERAL DESCRIPTION Korean or Chinese ginseng is a small perennial plant that originally grew wild in the damp woodlands of northern China, Manchuria, and Korea. Wild ginseng is now extremely rare. However, ginseng is a widely cultivated plant, especially in Korea but also in Russia, China, and Japan. In addition to Panax ginseng C.A. Meyer, the following four other, closely related species are often used:

Panax quinquefolius (American ginseng) Panax juponicum C.A. Meyer (Japanese ginseng) Panax pseudoginseng (Himalayan ginseng) Panax trifoliurn

I? ginseng C.A. Meyer is the most widely used and most extensively studied species.l” Its pharmacology is the major focus of this chapter. Fully mature, Korean ginseng is an herbaceous plant with a taproot, five-lobed palmate leaves, and greenishwhite flowers in an umbel. In the first year, ginseng bears only a single leaf with three leaflets. In the second

Cell-Proliferating, Antioxidant, and Antiaging Effects 1124 lmmunomodulating Effects 1125 Anticancer Properties 1125 Cardiovascular Effects 1125 Hepatic Effects 1126 Radiation-ProtectingEffects 1126

Toxicology Dosage

1126

1126

Drug Interactions 1127

year it bears a single leaf with five leaflets, and in its third year it bears two leaves with five leaflets. It usually starts flowering in its fourth year, while bearing three leaves. The roots of the cultivated plant are 3 to 4 mm in diameter and 10 cm long, and the roots of wild plants may attain 10 cm in diameter and a length of 50 to 60 cm. Ginseng is often processed in two forms, white and red. White ginseng is the dried root whose peripheral skin is frequently peeled off. Red ginseng is the steamed root, which has a caramel-like color.2 There are many types and grades of ginseng and ginseng extracts, which vary according to the source, age, and parts of the root used, where it was grown, the time of harvesting, and the methods of preparation.’” Old, wild, well-formed roots are the most valued, whereas rootlets of cultivated plants are considered the lowest grade. High-quality preparations are usually in the form of extracts of the main root of plants between 4 and 6 years old that have been standardized for ginsenoside content (see later) and ratio to ensure optimum pharmacologic effect.

CHEMICAL COMPOSITION Ginseng contains at least 13 different triterpenoid saponins, collectively known as ginsenosides, which are 1119

believed to be the most important active constituents. The usual concentration of ginsenosides is between 2% and 3%.The ginsenosides have been designated &, hI, h~krR, R+ %I Rtl 2O-glucO-Rf,$1, and $2. The ginsenosides originate from the following three fundamental aglycones: Oleanolic acid (ginsenoside &) 20-S-protopanaxadiol (ginsenosides to &) 20-Sprotopanaxatriol(ginsenosides& to $2)

As can be seen from Figure 111-1, the ginsenosides differ primarily in their sugar groups. Ginsenosides h1, F&2r R,%, and are present in sigruficantconcentrations in Korean ginseng. In contrast, American ginseng (Punax quinqu#oliurn) contains primarily ginsenosidesb1and F& and does not contain ginsenosides Rf, hBor, in some instances, These features allows for easy detection of species with high-pressure liquid chromatography (HPLC). Other components of ginseng are as follows'2:

s1.4

Panacene, a volatile oil Free and glucoside-bound sterols (e.g., beta-sitosterol and its beta-glucoside) Polyacetylene derivatives beta-elemene and panaxynol 8% to 32% starch Low-molecular-weight polysaccharides Pectin Vitamins (e.g., thiamine, riboflavin, B12,nicotinic acid, pantothenic acid, biotin)

R"

Ginsenoside

R

R'

R"

R,,

CIC-~GIC CIC-~GIC Cb2Glc CIC-~GIC CIC-~GIC CIC-~GIC Cb2Glc H H H H H H

H H H H

Xyl-4Ara(p)-6Glc Xyl-4Ara(f)-6Glc GIC-~GIC Am( )-6Glc Xyl- GIC Ara(f)-6Glc Glc Glc H Glc

Rbl Rb2

Rb3

Rc R,

Re Rf 3 1 x~GI~CO-R, Rhl

H H H Rha-2Glc-0 GIc-~GIc-O Glc-0 Rha-2Glc-0 GIc-~GIc-O Glc-0

Although it had been reported that ginseng contains large amounts of germanium (i.e., 300 parts per million), a follow-up study using highly sensitive (detection limit of 1 part per billion [ppb]), flameless atomic absorption spectrometry combined with solvent extraction demonstrated that the highest concentration of germanium measured in samples of ginseng purchased in the Osaka market was only 6 ~ p bMore . ~ research is needed to accurately determine the germanium content of botanical medicines, as the reported concentrations vary widely. Such low levels suggest that a connectionbetween the pharmacology of ginseng and its germanium content is unlikely,

HISTORY AND FOLK USE Perhaps the most famous medicinal plant of China, ginseng has been generally used alone or in combination with other herbs to restore the "Yang" quality. It has also been used as a tonic for its revitalizing properties, especially after a long illness. Conditions for which ginseng is used in folk medicine are shown in Box 111-1. It has been used as an alterative, anodyne, aperitif, aphrodisiac, cardiotonic, carminative, emetic, estrogenic, expectorant, gonadotrophic, nervine, sedative, sialogogue, stimulant, stomachic, and tranquilizer.l.2As can be seen from this list, ginseng has been used for most conditions, reflecting a broad range of nutritional and medicinal properties.

PHARMACOLOGY AND CLINICAL INDICATIONS

R

Ra2

0.1% to 0.2% choline Minerals (including germani~m)~ Simple sugars (glucose, fructose, sucrose, maltose, trisaccharides, etc.) Unique proteins (e.g., panaxagin, a protein that possesses antifungal, antiviral, translation-inhibiting, and ribonuclease activities)6 Various flavonoids

f

H Glc H

Am, Arabinose; Glc, glucose; Rha, rhabinose; Xy/, xylose. Figure 111-1 Ginsenosides of Panax ginseng.

Since the 1950s, a great amount of research has been conducted worldwide to determine whether the therapeutic properties attributed to ginseng belong in the realm of legend or fact. Unfortunately, inconsistent results (due mostly to different procedures in the preparation of extracts, use of nonofficial parts of the plant, use of adulterants, and lack of quality control in the ginseng used) have made determination of ginseng's true properties difficult. Nonetheless, enough good research does exist to indicate that ginseng possesses pharmacologic activity consistent with its near-legendary status, especially when high-quality extracts, standardized for active constituents, are used.

Panax ginseng (Korean Ginseng

Amnesia Anemia Anorexia Asthma Atherosclerosis Boils Bruises Cachexia Cancer Convulsions Cough Debility Diabetes Diuretic Divination Dysentery Dysmenorrhea Dyspepsia Enterorrhagia Epilepsy Epistaxis Fatigue Fear Fever Forgetfulness Gastritis Hangover Headache

Heart Hematoptysis Hemorrhage Hyperglycemia Hypertension Hypotension Impotence Insomnia Intestinalcomplaints Longevity promotion Malaria Menorrhagia Nausea Neurasthenia Palpitations Polyuria Pregnancy Puerperium Rectocele Rheumatism Rhinitis Shortness of breath Sores Spermatorrhea Splenitis Swelling Vertigo

Over the years, ginseng has been reported to have numerous pharmacologic effects in humans and laboratory animals, including the f~llowing'J*~: General stimulatory effects during stress Decrease in sensitivity to stress Increase in mental and physical capacity for work Improved endocrine system function Amelioration of radiation sickness, experimental neurosis, and cancer Enhanced protein synthesis and cell reproduction Improved glucose control in diabetes Modulation of various immune system parameters Lowering of serum cholesterol Protection of the liver from hepatotoxins Some of these actions are discussed in greater detail here.

Adaptogenic Activity Ginseng was originally investigated for its adaptogenic qualities.An aduptogen was defined in 1957by the Russian pharmacologist 1.1. B r e w 2 as a substance with the following properties: It must be innocuous and cause minimal disorders in the physiologic functions of an organism. It must have a nonspecific action (i.e., it should increase resistance to adverse influences through a

wide range of physical, chemical, and biochemical factors). It usually has a normalizing action irrespective of the direction of the pathologic state. According to tradition and scientific evidence, ginseng possesses thiskind of equilibrating, tonic, antistress action, and so the term adaptogen is quite appropriate to describe its general effects?r73 From a clinical perspective, ginseng can be used as a general tonic, especially in debilitated and feeble individuals. Use in this manner is consistent with its historic application.

Antifatigue (Mental and Physical) Activity Some of the first studies of ginseng's adaptogenic activities were performed during the late 1950s and early 1960s by Brekhman and Dardymov7fiin the USSR, and by Petkov9-" in Bulgaria. In one of Brekhman's experiments, Soviet soldiers given an extract of ginseng ran faster in a 3-km race than those given a placebo. In another, radio operators tested after administration of ginseng extract transmitted text significantly faster and with fewer mistakes than those given placebo. These and similar results found reported by European researchers, who demonstrated improvement in human physical and mental performance after the administration of ginseng extracts, prompted researchers to confirm the results in experimental models using m i ~ e ? , ~ - ~ In perhaps the best known of these experiments, mice were subjected to swimming in cold water or runningup an apparently endless rope to determine whether ginseng could lengthen the time to exhaustion. The results indicated that ginseng possessed sigruficant antifatigue activity, because a clearly dose-dependent increase in time to exhaustion was noted in mice receiving ginse~~g?fi,'~-~~ In one study, the time to exhaustion was lengthened by up to 183%in the mice given ginseng 30 minutes before exercising compared with controls? Experimental animal studies indicated that much of the antifatigue action of ginseng was due to the stimulant effect of ginseng on the central nervous system (CNS). Stress coupled with ginseng ingestion induced alterations in energy metabolism during prolonged exercise.'@15 Ginseng has been shown to improve locomotor activity>6 mod+ electroencephalography (EEG) tracing~,'~ improve metabolic activity in the CNS,'7 and affect the hypothalamic-pituitary-adrenal axis (discussed later), all of which could be largely responsible for ginseng's antifatigue activity in mental and physical performance. The CNS activity of ginseng is essentially different from that of the usual stimulants. Although stimulants are active under most situations, ginseng reveals its stimulatory action only with the challenge of ~tress.'~

On the physical level, ginseng's antifatigue properties appear to be closely related to its ability to spare glycogen utilization in exercising mu~cle.'~ Exercise physiologists have clearly established that during prolonged exercise, the development of fatigue is closely related to the depletion of glycogen stores and the buildup of lactic acid, both in skeletal muscle and in the liver. If an adequate supply of oxygen is available to the working muscle, nonesterified fatty acids are the preferential energy substrate, thus sparing utilization of muscle glycogen, blood glucose, and, consequently, liver glycogen. The greater the ability to conserve body carbohydrate stores through mobilization and oxidizing of fatty acids, the greater the amount of time to exhaustion. Ginseng enhances fatty acid oxidation during prolonged exercise, thereby sparing muscle glycogen stores.14 Mental and physical antifatigue activity effects have been demonstrated in both animal studies and doubleblind, clinical trials in humans. In one double-blind clinical study, nurses who had switched from day to night duty rated themselves for competence, mood, and general well-being, and were evaluated with an objective test of psychophysical performance, blood cell counts, and blood chemistry analysis. The group administered ginseng demonstrated higher scores in competence, mood parameters, and objective psychophysical performance than those receiving a placebo.18 From a clinical standpoint, ginseng's antifatigue properties may be useful whenever fatigue or lack of vigilance is apparent. Athletes in particular may derive some benefit from ginseng use (see later). Another important clinical indication appears to be chronic obstructive pulmonary disease (COPD). In one doubleblind study, 92 adults with COPD were randomly assigned to receive either ginseng or pla~ebo.'~ Pulmonary function tests (PFTs), maximum voluntary ventilation 0, maximum inspiratory pressure (MIP) and maximal oxygen consumption (Vqmax) were studied before treatment and every 2 weeks for the %month study period. In the ginseng group, but not in the control group, all parameters were significantly higher than baseline and than parameters in the placebo group. Maximum increases, in comparison with baseline, were FVC 32.5'/0, FEVl,o 27.0%, M w 40.4%, MIP 47.0% and Vozmax 37.5%. No side effects were observed.

Cognitive Performance Standardized extracts of P. ginseng alone or in combination with Ginkgo biloba (a formula called Gincosan) have been shown to improve cognitive performance in animal and clinical s t u d i e ~ . ~In@one ~ ~ of the earlier studies (a double-blind, crossover design) in university students in Italy, ginseng extract alone was compared with placebo in various tests of psychomotor performance. A favorable effect of ginseng relative to baseline performance was observed in attention (cancellation test), mental

arithmetic, logical deduction, integrated sensorimotor function (choice reaction time), and auditory reaction time. However, statistically significant superiority of the ginseng group over the placebo group was noted only for mental arithmetic. It is interesting to note that during the course of the trial, the students taking ginseng reported a greater sensation of well-being." Later studies in college-aged students showed similar results with a clear dose d e p e n d e n ~ y .However, ~ ~ - ~ unlike for studies in older subjects, no positive effect on mood or quality of life has yet been demonstrated with ginseng administered to healthy young adults. The benefits of ginseng on cognitive performance, mood, and quality of life assessment are considerably greater in middle-aged adults than in younger adults. In several studies of the administration of ginseng alone or in combination with G. biloba extract, significant improvements have been noted not only in tests of cognition and memory but also in social functioningand mental health?&%In one study however, the results attenuated after 4 weeks of use,indicating that cotherapy with G. biloba may be more efficacious or that cycling of the ginseng dosage may be necessary to produce a prolonged effect.% Both G. biloba and P. ginseng have been shown to modulate aspects of cognitive performance, including effects on EEG recordings. One double-blind, placebocontrolled, balanced crossover experiment assessed, in 15 healthy volunteers, the effects of single doses of G. biloba extract (360 mg), P. ginseng extract (200 mg G115), and an identical placebo on auditory-evoked potentials, contingent negative variation (CNV), and resting power within the delta, theta, alpha, and beta wavebandsz9The results showed that ginseng led to a significant shortening of the latency of the P300 component of the evoked potential. Both ginseng and @go also led to significant reductions in frontal "eyes closed" theta and beta activity, with additional reduction for ginseng in the alpha waveband. These findings demonstrated for the first time that P. ginseng can directly modulate EEG activity and that these effects are more pronounced than those that follow ingestion of G. biloba.

Antistress Activity Ginseng has been shown to enhance the ability to cope with various stressors, both physical and mental. Presumably, as has been demonstrated in several animal studies, this is a result of delaying the alarm phase response in Selye's classic model of stress. These studies found that adrenal cholesterol levels are many times higher in animals given ginseng than in their matched controls, indicating greater tolerance of stress and delayed alarm phase re~ponse.~~3O,~~ Italian researchers have studied the effect of a standardized ginseng extract, the ginsenoside composition of which was accurately determined, on the adrenal functions of rats exposed to cold.30The ginseng extract

significantly counteracted body temperature decline without affecting blood glucose or cortisone levels. In a group of adrenalectomized rats, the ginseng extract had no significant effects. Administration of hydrocortisone to the adrenalectomized rats did, however, cause body temperature to be maintained when the rats were exposed to cold. Histologic findings in this study were as follows: Evidence of hyperfunctioning in the supraoptic and paraventricular nuclei of the hypothalamus in rats fed the ginseng extract Remarkable increase in corticotropic basophilic cells (adrenocorticotropic hormone [ACTHI-producing) in the pars distalis of the pituitary gland Hyperplasia of the adrenal zona fasciculata, indicating that hyperfunctioning of the adrenal was promoted by the administration of the ginseng extract Other researchers have demonstrated that ginseng saponins significantly increase plasma ACTH and corticosteroids (in a parallel kinetic pattern).3z,33 Because this effect could be blocked by dexamethasone (which acts on the hypothalamus and pituitary to prevent ACTH release), it was concluded that ginsenosides act predominantly on the hypothalamus or pituitary to promote secretion of ACTH. This conclusion has been further confirmed by indirect studies. ACTH first stimulates an increase in cyclic adenosine monophosphate (CAMP)in the adrenal and then promotes corticosteroid synthesis. Ginseng administration has been shown to increase adrenal CAMP in normal rats, but not in hypophysedomized rats. These investigations make quite clear that ginseng’s antistress action is mediated by the hypothalamicpituitary-adrenal axis, as follows: The antistress action of ginseng is greatly reduced by adrenalectomy. Ginseng continues to exert its antistress action after hypophysectomy only if ACTH is administered. Histologic and chemical evidence demonstrates a strong link between ginseng and the hypothalamicpituitary-adrenal axis. Dexamethasone blocks the effects of ginseng. This release of ACTH and associated pituitary substances (e.g., beta-lipoprotein, endorphins, enkephalins) coupled with their end-organ effects is probably responsible for many of the antifatigue and antistress actions of ginseng, because ACTH and corticosteroids have been shown to bind directly to brain tissue to increase mental activities during stress. From a clinical perspective, it is apparent that ginseng has a balancing effect or alterative action on the hypothalamic-pituitary-adrenalaxisthrough adjustment of metabolic and functional systems governing hormonal control of homeostasis. This effect assists the body’s response to the challenge of stress and therefore is indicated when disruption of this axis is apparent.

Ginseng may prove especially effective in restoration of normal adrenal function and prevention of adrenal atrophy associated with corticosteroid administration. In rats, ginseng has been found to inhibit cortisone-induced adrenal and thymic atrophy?

As an Ergogenic Aid The benefits of ginseng on athletic performance are not clear. Results of later double-blind studies have been negative. For example, one study, in which 36 healthy young men received a standardized ginseng extract (Ginsana)at a dosage level of 400 mg/day, showed that ginseng had no effect on any exercise-related parameter (e.g., blood lactic acid concentration, heart rate, and perceived exert i ~ n ) Similar ?~ results were seen in a study in women and an even more comprehensive laboratory evaluation in 38 health adults also showed no improvement in any ~arameter.~J’ The totality of results at this time do not offer support for claims that ginseng improves athletic performance. However, other benefits have been noted, such as an ability to protect against muscle injury and inflammation in athletes as well as improve psychomotor performance at rest during a graded exercise te~t.%3~

Diabetes Ginseng, used either alone or in combination with other botanicals, has a long folk use in the treatment of diabetes. This hypoglycemic activity has been confirmed in both experimental and clinical trials. In one double-blind study in type 2 diabetes, ginseng therapy reduced fasting blood glucose levels, elevated mood, improved psychophysical performance, and lowered body weight and glycosylated hemoglobin.4o The chief constituents responsible for this effect are as follow^^*^^: Five glycans (polysaccharides designated panaxans A to E) Adenosine A carboxylic acid A peptide A fraction designated DPG-3-2 The ratio of ginsenosides also appears to be an important factor. In one human study, the ratio of protopanaxadiol to protopanaxatriol was the sole predictor of whether or not a ginseng preparation would exert hypoglycemic effects.&It appears that it is important to utilize crude, standardized extracts having a higher protopanaxadiol-protopanaxatriol ratio, such as those from American ginseng extract, in order to produce the desired benefit. Powdered American ginseng root (P.quinquefoliurn)at a dosage of about 3 g before each meal has been shown to reduce postprandial blood sugar signrficantly in patients with type 2 diabetes. It has been determined that American ginseng works through the stimulation of pancreatic beta cells with a subsequent increase in

Pharmacology of Natural Medicines insulin secretion. This substance also has sigruficant antioxidantproperties and improves cognitive function. In addition, American ginseng has been shown to possess nerve protection and regeneration properties. This could prove to be valuable in diabetes, in which peripheral and autonomic nerve damage so often occurs.4749 It is interesting to note that ginseng raises serum cortisol levels in nondiabetic individuals but reduces serum cortisol levels in patients with diabetesw Because cortisol antagonizes insulin,this is presumably a beneficial effect. This action again demonstrates ginseng’s nonspecific balancing effect, which is baffling to researchers accustomed to investigating compounds with consistent pharmacologic effects. Ginseng is indicated as an adjunctive therapy in the treatment of diabetes, both for its hypoglycemic effect and for its ability to decrease the atherogenic index (see later). Although the root has received the most attention, animal studies indicate that extracts from ginseng berry may even be more beneficial owing to a higher concentration of ginsenoside %.sosl

or hypofunction, other organic causes of male infertility, ovarian atrophy or hypofunction, amenorrhea, and other organic causes of female infertility. It should be noted that several reports of mastalgia have been reported in women taking ginse11g.5~3’ Most of the later clinical studies involving reproductive effects have focused on ginseng’s effect on erectile dysfunction. A plausible mechanism involves evidence that ginsenosides can facilitate penile erection by directly inducing the vasodilatation and relaxation of penile corpus cavernosum mediated by the release and/or modification of the release of nitric oxide from endothelial cells and perivascular In one double-blind, crossover study a total of 45 patients with clinically diagnosed erectile dysfunction showed significantly higher Mean International Index of Erectile Function scores with Korean red ginseng than those who received placebo. In response to the global efficacy question 60% of the patients answered that Korean red ginseng improved erection.b0

Reproductive Effects

Ginseng has also been a popular treatment for menopausal symptoms. One double-blind study in 384 menopausal women was performed to compare the effects of a standardized ginseng extract with those of a placebo on quality of life, menopausal symptoms, and physiologic markers of menopause (follicle-stimulating hormone and estradiol levels, endometrial thickness, maturity index, and vaginal pH). Although the ginseng extract showed only a tendency for a slightly better overall symptomatic relief, it was associated with statistically sigrulicant improvements in mood and well-being. No statistically significant effects were seen for the physiologic parameters, including vasomotor symptoms (hot flushes). The results of this study suggest that the beneficial effects of ginseng in menopause are most likely not mediated by phytoestrogen or hormone replacementlike effects.6I

Although it is claimed to be a ”sexual rejuvenator” and aphrodisiac, human studies supporting this belief are scanty. In animal studies, however, ginseng has been shown to have the following a f f e c t ~ ~ ~ s ~ : Promotes the growth of the testes and increase spermatogenesis in rabbits Accelerates the growth of the ovary and enhance ovulation in frogs Stimulates egg-laying in hens Facilitates lordotic response in female rats Increases gonadal weight in both male and female rats Raises testicular nucleic acid content in rats Increases sexual activity and mating behavior in male rats These animal study results seem to support ginseng‘s

use as a fertility and virility aid. In other experimental animal studies, ginseng has been shown to increase testosterone levels while reducing prostate weight.%This finding suggests that ginseng should have favorable effects in the treatment of benign prostatic hyperplasia; however, no clinical trials have yet been reported. Ginsenosides have also been shown to bind to human myometrial receptor proteins, and they apparently exert estrogen-like action on the vaginal epithelium. These activities are sigruficant enough to prevent the atrophic vaginal changes associated with postmenopause and other menopausal symptoms.55 Other clinical indications involving the reproductive system (based on historical use and experimental evidence) are decreased sperm counts, testicular atrophy

Menopause

Cell-Proliferating, Antioxidant, and Antiaging Effects Ginseng has a dual effect on cell growth: It stimulates cell division in an adequate nutritional environment but acts cytostatically under adverse conditions (as described previously).61Furthermore, ginseng has yielded impressive results in lengthening the lifespan of cells in culture.6* This enhancement of cellular proliferation and function has been shown in a variety of cell types (epithelial, hepatic, lymphocyte, fibroblast, thymic, etc.), but especially nerve cells, which appears to be a result of potentiation of nerve growth factor (NGF) by ginsenosides?rM Clinically, these results indicate a potential use of ginseng in healing damage to virtually all tissue types, but especially the brain. In animal studies, ginseng has been

Panax ginseng (Korean Ginseng) shown to reduce oxidative stress, scavenge free radicals directly, protect endothelial cells from damage, and increase cellular antioxidant enzymes like superoxide dismutase Again these effects demonstrate ginseng’s nonspecific action.

in vitro, this has not been the observed effect in vivo, in which lymphocyte proliferation has been enhanced.74

These effects may be related to a dose-dependent ginseng-induced elevation of interferon (which inhibits lymphocyte proliferation).

lmmunomodulating Effects

Anticancer Properties

That ginseng possesses immunomodulating activity is evidenced by its ability to enhance the following immune function^^-^^:

Regular ginseng consumption may protect against cancer. In two large population studies, the risk for development of cancer was sigruficantly lower among people who consumed ginseng on a regular basis. Ginseng extract and powder were shown to be more effective than fresh sliced ginseng, ginseng juice, or ginseng tea in reducing the cancer risk. A statistically highly significant dose-response relationship between ginseng intake and cancer risk was observed. These results support the preventive and anticancer effects of ginseng demonstrated in animal and in vitro studies.8749 Long-term oral administration of ginseng to newborn mice has been shown to reduce the incidence and also to inhibit the proliferation of tumors induced by various chemical carcinogens, including DMBA (7,12-dimethylbenz[a]anthracene), urethane, and aflatoxin B1.39 The anticancer effects of ginseng in other experimental models can be summarized as follow^^-^^:

Antibody plaque-forming cell response Circulatory antibody titer against sheep erythrocytes Cell-mediated immunity Natural killer (NK) cell activity The production of interferon Lymphocyte mitogenesis Reticuloendothelial system proliferativeand phagocytic functions

In addition to these immunostimulatory aspects, ginseng components have been shown to exert antiallergy and antijnflammatory effects in experimental models.sOsl From a clinical perspective, the long-term ingestion of ginseng by individuals with mild immunodeficiency may reduce the risk of viral infection. It use in this manner is consistent with the historical use of ginseng by debilitated individuals. There is clinical evidence of benefit in these applications. Extracts of l? ginseng were found to stimulate NK function in normal individuals and patients with either chronic fatigue syndrome or acquired immunodeficiencysyndrome (AIDS)F2Ginseng has been shown to prevent respiratory viral infections in a nursing home environment (89% relative risk reduction) and potentiate influenza vaccinations.mB It should be noted that large dosages of ginseng may be contraindicated in acute infections. The reason may be its in vitro inhibition of lymphocyte transformation (similarto cortisone) at high (i.e., >1 mg/ml), but not low concentrations.85,s6 In fact, in vitro, ginseng at 1.6 pg/ml has been shown to inhibit phytohemagglutinin-induced transformation of peripheral blood lymphocytes to a greater degree than cortisone at 500 pg/mLS The greatest level of inhibition, however, was observed when ginseng was used in combination with cortisone. These results suggest that ginseng at high doses may be effective against T cell-mediated inflammatory diseases without producing glucocorticoid-like side effects. It also suggests that a lower dose of cortisone could be used if ginseng were given simultaneously. When using ginseng, the clinician must remember (1)that ginseng’s in vim effect on lymphocyte proliferation is biphasicthat is, it exerts a strong inhibition at high concentrations and a moderate stimulation at low concentrations-and (2) that although ginseng has demonstrated significant inhibition of lymphocyte proliferation

Ginseng promotes apoptosis. The effect is observed only in slow-growing tumors, such as Ehrlich and sarcoma 180 ascites tumor. The effect is not observed in rapidly growing tumors, such as 11210 and p388, and Walker carcinoma. There is no dose-response relationship or cumulative effect. The lack of a dose-response relationship suggests that ginseng’s anticancer effects are indirect and subject to a threshold mechanism. Thus, ginseng once again appears to demonstrate nonspecific effects. In addition to a possible role in cancer prevention, some researchers are investigating P. ginseng extracts as a possible adjunct in cancer t~eatment.9~ Exerting some direct and indirect anticancer actions, ginseng may also offer protection against chemotherapy-induced damage to normal cells. In one animal study, l? ginseng extract was shown to protect against cisplatin nephrot~xicity.~~

Cardiovascular Effects From a clinical perspective, ginseng may offer some protection against atherosclerotic disease, further supporting its use as a general tonic. It may also possess a blood pressureregulating effect via improvement in the endothelial dysfunction underlying many cases of hypertension.% Ginseng administered to human subjects with hyperlipidemia has been shown to reduce total serum Cholesterol, triglyceride, and nonesterified fatty acid levels

Pharmacology of Natural Medicines while raising serum high-density lipoprotein (HDL) cholesterol levels. Platelet adhesiveness was also decreased.97 These results in humans confirmed earlier studies on rats fed high-cholesterol The mechanism of action appears to be through accelerated degradation, conversion, and excretion of cholesterol and triglyceride despite increased lipogenesis and cholesterogenesis. Ginseng has also been shown to be effective in lnhibiting platelet aggregation and the conversion of fibrinogen to fibrin@ .' '

Hepatic Effects

the Journal of the American Medical Association (JAMA) titled "Ginseng Abuse Syndrome."107 In this article, a number of side effects of commercial preparations of ginseng are reported, including the following: Hypertension Euphoria Nervousness Insomnia Skin eruptions Morning diarrhea

Given the extreme variation in quality of ginseng in the American marketplace and the use of both nonofficial Obviously, any adaptogenic substance must affect the parts of the plant and adulterants, it is not surprising that liver because of this organ's central role in metabolic and detoxification reactions. Ginseng affects the liver in sevside effects were noted. None of the commercial preparaeral ways. Perhaps the most important is its ability to tions used in the trial had been subjected to controlled produce a marked hyperplasia of the Kupffer cells of the analysis. Furthermore, the species of ginseng used liver and of the folliculi in the spleen and lymph nodesN included P. ginseng, Panax quinquefolius, Eleutherococcus The hyperplastic folliculi show an increase in the senticosus, and Rumex hymenosepalus in a variety of differnumber and volume of light centers, thus demonstrating ent forms-roots, capsules, tablets, teas, extracts, cigamorphologic evidence of increased host defense capacity rettes,chewing gum, and candies. It is virtually impossible against a wide variety of external assaults. Because these to derive any firm conclusions from the data presented cells are responsible for filtering out much of the toxins in the J A M A article. The author's final words do, and debris from the portal circulation, increasing their however, seem sensible and appropriate: number and activity could have profound effects. An important caveat is that these GAS [ginseng abuse synGinseng has also been shown to increase nuclear drome] effects are neither uniformly negative nor uniformly RNA biosynthesis, indicating greater protein synthepredictable. Nevertheless, long-term ingestion of large sis.3*101 In fact, ginseng has been shown to increase not amounts of ginseng should be avoided, as even a panacea can only nuclear RNA synthesis, but also ribosomal and cause problems if abused. messenger RNA, the amount of rough endoplasmic reticulum, and the activity of RNA p o l y m e r a ~ e . ~ J ~ ' - ~Studies ~~ performed on standardized extracts of These results indicate that ginseng activates virtually ginseng demonstrate the absence of side effects and every step in protein biosynthesis. As protein synthesis mutagenic or teratogenic effects.'08110These studies differ is often reduced in the elderly, the significance of the markedly from the trial reported in JAMA in that highquality extracts were used. An extensive review of the described effects on enhancement of hepatic protein synthesis would be extremely high. However, these results safety of P. ginseng concluded, "Data from clinical trials have yet to be confirmed by clinical studies. suggest that the incidence of adverse events with ginseng Ginseng has also been shown to reverse diet-induced monopreparations is similar to that with pla~ebo."'~' fatty liver in animals and to possess significant antihepatotoxic action.Io4 The clinical indications of these DOSAGE hepatic actions of ginseng are quite broad and support its general tonic/adaptogen properties. The dosage of ginseng is inversely proportional to the ginsenoside content; that is, if an extract or ginseng Radiation-Protecting Effects preparation contains high concentrations of ginsenoGinseng has been shown to offer some protection sides (and presumably other active components), a lower dose suffices. The standard dose for ginseng is in against harmful radiation, both in vivo and in vitro, and to hasten recovery from radiation s i c k n e ~ s . In ~ ~the ~ J ~ the range of 4.5 to 6 g daily. presence of ever-increasing environmental radiation Currently, there is almost a total lack of quality control contamination, ginseng may be an appropriate prophyin ginseng products marketed in the United States. lactic against radiation exposure. Independent research and published studies have clearly documented a tremendous variation in the ginsenoside content of commercial preparations. In fact, TOXICOLOGY many products on the market contain only trace amounts of p e n o s i d e s , and some formulations contain no ginThe problem of quality control makes toxicology difficult to address. This is exemplified by a 1979 article in seng at all. This situation has led to several problems,

Panax ginseng (Korea lower dose and increase it gradually. The Russian approach for long-term administration is to use ginseng cyclically for a period of 15 to 20 days followed by a 2-week interval without any ginseng.

ranging from toxicity reactions (discussed later) to lack of medicinal effect. The widespread disregard for quality control in the health food industry has done much to tarnish the reputation of ginseng as well as other important botanicals. We recommend the use of standardized ginseng preparations to ensure sufficient ginsenoside content, consistent therapeutic results, and reduced risk of toxicity. Products should be standardized in their ginsenoside content. The typical dose (taken one to three times daily) for general tonic effects should contain a saponin content of at least 5 mg of ginsenosides with an &,-$,ratio of 2:l. For example, for a high-quality ginseng root powder containing 5% ginsenosides, the dose would be 100 rng.”O Because each individual’s response to ginseng is unique, the patient should be monitored for signs of possible ginseng toxicity (see later). It is best to begin at a

glyburide (Diabeta, Micronase). It is important to discuss proper monitoring of blood sugar levels with patients who have diabetes before prescribing ginseng. Ginseng may interferewith the anticoagulant drug warfarin (Coumadin). People taking this agent should not use ginseng unless they are being closely monitored by a physician. I? ginseng may potentiate the monoamine oxidase inhibitor phenelzine (Nardil) to produce maniclike symptoms.11o

1. Leung AY, Foster S. Encyclopedia of common natural ingredients used in food, drugs and cosmetics. New York: John Wiley, 1996277-281. 2.Shibata S, Tanaka 0, Shoji J, et al. In Wagner H, Hikino H, Farnsworth NR,eds. Economic and medicinal plant research, vol 1. London: Academic Press, 1985217-284. 3. Dong TT,Cui XM, Song ZH, et al. Chemical assessment of roots of Panax notoginseng in China: regional and seasonal variations in its active constituents. J Agric Food Chem 2003;51:4617-4623. 4. Assinewe VA, Baum BR, Gagnon D, et al. Phytochemistry of wild populations of Punax quinquefolius L. (North American ginseng.) J Agric Food Chem 2003;51:4549-4553. 5. Mino Y, Oto N, Sakao S, et al. Determination of germanium in medicinal plants by atomic absorption spectrometry with electrothermal atomization. Chem Pharm Bull (Tokyo) 1980;28: 2687-2691. 6. Ng TB, Wang H. Panaxagin, a new protein from Chinese ginseng, possesses anti-fungal, anti-viral, translation-inhibiting and ribonuclease activities. Life Sci 2001;68:739-749. 7. Brekhman 11, Dardymov IV.New substances of plant origin which increase nonspecific resistance. Annu Rev Pharmacol 1969;9: 419-430. 8. Brekhman 11, Dardymov IV. Pharmacological investigation of glycosides from ginseng and Eleutherococcus. Lloydia 1969;3246-51. 9. Petkov W. [Pharmacology of the drug Panax ginseng.] Arzneimittelforschung 1959;9:305-311. 10. Petkov W. [Onthe mechanism of action of Punaxginseng C.A. Mey: on the problem of a pharmacology of reactivity.2.1Arzneimittelforschung 1961;11:288-295,418-422. 11. Petkov V. Effect of ginseng on the brain biogenic monoaxnines and 3’,5’-AMP system. Experiments in rats. Arzneimittelforschung 1978;28:388-393. 12. Saito H, Yoshida Y,Takagi K. Effect of Panaxginseng root on exhaustive exercise in mice. Jpn J Pharmacol1974;24119-127. 13. Kaku T, Miyata T, Uruno T, et al. Chemico-pharmacologicalstudies on saponins of Panax ginseng C.A. Meyer. II. Pharmacological part. Arzneimittelforschung 1975;25:539-547. 14. Avakian EV Jr, Evonuk E. Effect of Panax ginseng extract on tissue glycogen and adrenal cholesterol depletion during prolonged exercise. Planta Med 19793643-48.

15. Sterner W, Kirchdorfer AM. Comparative work load tests on mice with standardized ginseng extract and a ginseng containing pharmaceutical preparation. Z Gerontol1970;3:307-312. 16. Cicero AF, Bandieri E, Arletti R. Orally administered Panax notoginseng influence on rat spontaneous behaviour. J Ethnopharmacol 2000;73387-391. 17. Samira MM, Attia MA, Allam M, et al. Effect of the standardized ginseng extract G115 on the metabolism and electrical activity of the rabbit’s brain. J Int Med Res 1985;13:342-348. 18.Hallstrom C, Fulder S, Carruthers M. Effect of ginseng on the performance of nurses on night duty. Comp Med East West 1982;6277-282. 19. Gross D, Shenkman Z, Bleiberg B, et al. Ginseng improves pulmonary functions and exercise capacity in patients with COPD. Monaldi Arch Chest Dis 2002;57242-246. 20. Petkov VD, Belcheva S, Petkov W. Behavioral effects of Ginkgo bilobu L., Panax ginseng C.A. Mey. and Gincosan. Am J Chin Med 2003;31:841-855. 21. Petkov VD,Kehayov R, Belcheva S, et al. Memory effects of standardized extracts of Punux ginseng (G115), Ginkgo biloba (GK 501) and their combination Gincosan (PHL-00701). Planta Med 1993;59:106-114. 22.DAngelo L, Grimaldi R, Caravaggi M, et al. A double-blind, placebo-controlled clinical study on the effect of a standardized ginseng extract on psychomotor performance in healthy volunteers. J Ethnopharmacol 1986;16:15-22. 23. Scholey AB, Kennedy DO. Acute, dose-dependent cognitive effects of Ginkgo biloba, Punax ginseng and their combination in healthy young volunteers: differential interactions with cognitive demand. Hum Psychopharmacol2002;17354. 24. Kennedy DO, Scholeya AB, Wesnes KA. Dose dependent changes in cognitive performance and mood following acute administration of ginseng to healthy young volunteers. Nutr Neurosci 2001; 4295-310. 25. Cardinal BJ, Engels HJ. Ginseng does not enhance psychological well-being in healthy, young adults: results of a double-bliid, placebo-controlled, randomized clinical trial. J Am Diet Assoc 2001;101:655-660. 26. Coleman CI, Hebert JH,Reddy P. The effects of Punax ginseng on quality of life. J Clin Pharm Ther 2003;28:5-15.

DRUG INTERACTIONS Taking ginseng preparations may increase the effectiveness of insulin and drugs that lower blood sugar levels such as

Pharmacology of Natural Medicines 27. Ellis JM, Reddy P. Effects of Panax ginseng on quality of life. Ann Pharmacother 2002;36:375-379. 28. Wesnes KA, Ward T, McGity A, et al. The memory enhancing effects of a Ginkgo biloba/Panax ginseng combination in healthy middle-aged volunteers. Psychopharmacology (Berl) 2000;152 353-361. 29. Kennedy DO, Scholey AB. Ginseng: potential for the enhancement of cognitive performance and mood. Pharmacol Biochem Behav 2003;75687-700. 30. Bombardelli E, Cristoni A, Lietti A. The effect of acute and chroNc ( P a m ) ginseng saponins treatment on adrenal function; biochemical and pharmacological. In Proceedings of the 3rd International Ginseng Symposium. Seoul: Korean Ginseng Research Institute, 1980:9-16. 31. Fulder SJ. Ginseng and the hypothalamic-pituitarycontrol of stress. Am J Chin Med 1981;9:112-118. 32. Hiai S, Yokoyama H, h a H. Features of ginseng saponin-induced corticosterone secretion. Endocrinol Jpn 1979;26737-740. 33. Hiai S, Yokoyama H, Oura H, et al. Evaluation of corticosterone secretion-inducing activities of ginsenosides and their prosapogenins and sapogenins. Chem Pharm Bull (Tokyo) 1983;31: 168-174. 34. Tanizawa H, Numano H, Odani T, et al. [Study of the saponin of Panax ginseng C.A. Meyer. I. Inhibitory effect on adrenal atrophy, thymus atrophy and the decrease of serum K+ concentration induced by cortisone acetate in unilateral adrenalectomized rats.] YakUgakU k h i 1981;101:169-173. 35. Engels HJ, Wirth JC. No ergogenic effects of ginseng ( P a w ginseng C.A. Meyer) during graded maximal aerobic exercise. J Am Diet As= 1997;971110-1115. 36. Engels HJ, Fahlman MM, Wirth JC. Effects of ginseng on secretory IgA, performance, and recovery from interval exercise. Med Sci Sports Exerc 200335:690-696. 37. Engels HJ, Kolokouri I, Cieslak TJ2nd, et al. Effects of ginseng supplementation on supramaximal exercise performance and short-term recovery. J Strength Cond Res 2001;15:290-295. 38. Cabral de Oliveira AC, Perez AC, Merino G, et al. Protective effects of P a m ginseng on muscle injury and inflammation after eccentric exercise. Comp Biochem Physiol C Toxic01 Pharmacol 2001;130: 369-377. 39. Ziemba AW, Chmura J, Kaciuba-Uscilko H, et al. Ginseng treatment improves psychomotor performance at rest and during graded exercise in young athletes. Int J Sport Nutr 1999;9:371-377. 40.Sotaniemi EA, Haapakoski E, Rautio A. Ginseng therapy in non-insulin-dependent diabetic patients. Diabetes Care 1995;18: 1373-1375. 41. Ng TB, Yeung HW. Hypoglycemic constituents of Punax ginseng. Gen Pharmacol1985;16549-552. 42. Waki I, Kyo H, Yasuda M, et al. Effects of a hypoglycemic component of ginseng radix on insulin biosynthesis in normal and diabetic animals. J Pharmacobiodyn 19825547-554. 43. Konno C, Sugiyama K, Kano M, et al. Isolation and hypoglycaemic activity of panaxans A, B, C, D and E, glycans of Panax ginseng mots. Planta Med 19843:434-436. 44.Kimura M, Waki I, Tanaka 0, et al. Pharmacological sequential trials for the fractionationof components with hypoglycemic adivity in alloxan diabetic mice from ginseng radix. J Pharmacobiodyn 1981;4402-409. 45. Kimura M, Waki I, Chujo T, et al. Effects of hypoglycemic components in ginseng radix on blood insulin level in alloxan diabetic mice and on insulin release from perfused rat pancreas. J Pharmacobiodyn 1981;4410-417. 46.Sievenpiper JL, Amason JT, Leiter LA, et al. Decreasing, null and increasing effects of eight popular types of ginseng on acute postprandial glycemic indices in healthy humans: the role of ginsenosides. J Am Coll Nutr 2004;23:24&258.

47. Vuksan V, Sievenpiper J, Koo VY, et al. American ginseng (Panax quinquefolius L) reduces postprandial glycemia in nondiabetic subjects with type 2 diabetes mellitus. Arch Intern Med 2000; 160:1009-1013. 48. Vuksan V, Stavro MP, Sievenpiper JL, et al. Similar postprandial glycemic reductions with escalation of dose and administration time of American ginseng in type 2 diabetes. Diabetes Care 2000; 23:1221-1226. 49.Franz MJ, Bantle JP, Beebe CA, et al. Nutrition principles and recommendations in diabetes. Diabetes Care 2004;27(Suppl 1): s36-s46.

50. Dey L, Xie JT,Wang A, et al. Anti-hyperglycemic effects of ginseng: comparison between root and berry. Phytomedicine 2003;lO: 600-605. 51. Attele AS, Zhou YP,Xie JT, et al. Antidiabetic effects of Panax ginseng berry extract and the identificationof an effective component. Diabetes 2002;51:1851-1858. 52. Nocerino E, Amato M, Izzo AA. The aphrodisiac and adaptogenic properties of ginseng. Fitoterapia 2000;71(Suppl l):Sl-S5. 53. Kim C, Choi H, Kim CC, et al. Influence of ginseng on mating behavior of male rats. Am J Chin Med 1976;4163-168. 54. Fahim MS, Fahim Z, Harman JM, et al. Effect of Punax ginseng on testosterone level and prostate in male rats. Arch Androl 1982;8261-263. 55. Punnonen R, Lukola A. Oestrogen-like effect of ginseng. Br Med J 1980;281:1110. 56. Yonezawa M. Restoration of radiation injury by intraperitoneal injection of ginseng extract in mice. J Radiat Res (Tokyo)1976;17111-113. 57. Palmer BV, Montgomery AC, Monteiro JC. Gin Seng and mastalgia. Br Med J 1978;1:1284. 58. Murphy LL, Lee TJ.Ginseng, sex behavior, and nitric oxide. Ann N Y Acad Sci 2002;962:372-377. 59. Price A, Gazewood J. Korean red ginseng effective for treatment of erectile dysfunction. J Fam Pract 2003;52:20-21. 60.Hong B, Ji YH, Hong JH, et al. A double-blind crossover study evaluating the efficacy of Korean red ginseng in patients with erectile dysfunction: a preliminary report. J Urol2002;168:2070-2073. 61. Wiklund M,Mattsson LA, Lindgren R, et al. Effects of a standardized ginseng extract on quality of life and physiological parameters in symptomatic postmenopausal women: a double-blind, placebocontrolled trial. Swedish Alternative Medicine Group. Int J Clin Pharmacol Res 1999;19:89-99. 62. Fulder SJ. The growth of cultwed human fibroblasts treated with hydrocortisone and extracts of the medicinal plant Panax ginseng. Exp Gerontol1977;12:125-131. 63. Yamamoto M, Masaka M, Yamada K, et al. Stimulatoryeffect of ginsenosides on DNA, protein and lipid synthesis in bone marrow and participation of cyclic nucleotides. Arzneimittelforschung 1978;282238-2241. 64.Radad K, Gille G, Moldzio R, et al. Ginsenosides Rbl and Rgl effects on survival and neurite growth of MPP+-affected mesencephalic dopaminergic cells. J Neural Transm 2004;111:37-45. 65. Mizumaki Y, Kurimoto M, Hirashima Y, et al. Lipophilic fraction of P a m ginseng induces neuronal differentiation of PC12 cells and promotes neuronal survival of rat cortical neurons by protein kinase C dependent manner. Brain Res 2002;950254-260. 66. Fu Y, Ji LL. Chronic ginseng consumption attenuates age-associated oxidative stress in rats. J Nutr 2003;1333603-3609. 67. Liu ZQ, Luo XY,Sun YX, et al. Can ginsenosidesprotect human erythrocytes against free-radical-inducedhemolysis? Biochim Biophys Acta 2002;157258-66. 68.Siddique MS, Eddeb F, Mantle D, et al. Extracts of Ginkgo biloba and Panax ginseng protect brain proteins from free radical induced oxidative damage in vitro. Acta Neur& Suppl2000;76:87-90. 69. Kim YK, Guo Q, Packer L. Free radical scavenging activity of red ginseng aqueous extracts. Toxicology 2002;172:149-156.

Panax Ginseng (Korean Ginseng) 70.Kwan CY, Kwan TK. Effects of Panax notoginseng saponins on i n 2000;21: vascular endothelial cells in vitro. Acta Pharmacol S 1101-1105. 71. Kim SH, Park KS. Effects of Panax ginseng extract on lipid metabolism in humans. Pharmacol Res 2003;48:511-513. 72. Jie YH, Cammisuli S, Baggiolini M. Immunomodulatory effects of Panax ginseng C.A. Meyer in the mouse. Agents actions 1984; 15:386-391. 73. Gupta S, Agarwal SS, Epstein LB, et al. Panax. A new mitogen and interferon producer. Clin Res 1980;28504A. 74. Singh VK,Agarwal SS, Gupta BM. Immunomodulatory activity of Panax ginseng extract. Planta Med 1984;50:462-465. 75. Shin JY, Song JY, Yun YS, et al. Immunostimulating effects of acidic polysaccharides extract of Panax ginseng on macrophage function. Immunopharmacol Immunotoxicol2002;24:469482. 76. Assinewe VA, Amason JT, Aubry A, et al. Extractable polysaccharides of Panax quinquefolius L. (North American ginseng) root stimulate TNFalpha production by alveolar macrophages. Phytomedicine 2002;9398-404. 77. Lim DS,Bae KG, Jung IS, et al. Anti-septicaemic effect of polysaccharide from Panax ginseng by macrophage activation. J Infect 2002;45:32-38, 78. Cho JY, Kim AR, Yo0 ES, et al. Ginsenosides from Panax ginseng differentially regulate lymphocyte proliferation. Planta Med 2002; 68:497-500. 79. Lim TS, Na K, Choi EM, et al. Immunomodulating activities of polysaccharidesisolated from Panax ginseng. J Med Food 2004;71-6. 80.Park EK, Choo MK, Han MJ, et al. Ginsenoside Rhl possesses antiallergic and anti-inflammatory activities. Int Arch Allergy Immunol2004;133113-120. 81. Choo MK, Park EK, Han MJ, et al. Antiallergic activity of ginseng and its ginsenosides. Planta Med 2003;6951&522. 82. See DM, Broumand N, Sahl L, et al. In vitro effects of Echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients. Immunopharmacology 1997;35:229-235. 83. McElhaney JE,Gravenstein S, Cole SK, et al. A placebo-controlled trial of a proprietary extract of North American ginseng (CVT-E002) to prevent acute respiratory illness in institutionalized older adults. J Am Geriatr SIX 2004;5213-19. 84. Scaglione F, Cattaneo G, Alessandria M, et al. Efficacy and safety of the standardised ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold. Drugs Exp Clin Res 1996;22.65-72. 85. Chong SK, Brown HA, Rimmer E, et al. In vitro effect of Panax ginseng on phytohaemagglutinin-induced lymphocyte transformation. Int Arch Allergy Appl Immunol1984;73:216-220. 86.Yeung HW, Cheung K, Leung KN. Immunopharmacology of Chinese medicine. 1. Ginseng induced immunosuppression in virus-infected mice. Am J Chin Med 1982;10:44-54. 87. Yun TK, Choi SY. Non-organ specific cancer prevention of ginseng: a prospective study in Korea. Int J Epidemiol1998;27359-364. 88. Yun TK. Panax ginseng-a non-organ-specific cancer preventive? Lancet Oncol2001;249-55. 89. Shin HR, Kim JY, Yun TK, et al. The cancer-preventive potential of Panax ginseng: a review of human and experimental evidence. Cancer Causes Control 2000;11:565-576.

90. Kim HS, Lee EH, KO SR, et al. Effects of ginsenosides Rg3 and Rh2 on the proliferation of prostate cancer cells. Arch Pharm Res 2004;27:429435. 91. Liu WK,Xu SX, Che CT.Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sci 2000;671297-1306. Anticarcinogenic effect of long-term oral 92. Yun TK, Yun YS, Han IW. administration of red ginseng on newborn mice exposed to various chemical carcinogens. Cancer Detect Prev 1983;6515-525. 93.Lee KD, Huemer RP. Antitumoral activity of Panax ginseng extracts. Jpn J Pharmacol1971;21:299-302. 94. Chang YS, Seo EK, Gyllenhaal C, et al. Panax ginseng: a role in cancer therapy? Integr Cancer Ther 2003;213-233. 95. Liu SJ, Zhou SW. Panax notoginseng saponins attenuated cisplatininduced nephrotoxicity. Acta Pharmacol Sin 2000;21:257-260. 96. Sung J, Han KH, Zo JH, et al. Effects of red ginseng upon vascular endothelial function in patients with essential hypertension. Am J Chin Med 2O00;28:205-216. 97. Yamamoto M, Uemura T, Nakama S, et al. Serum HDL-cholesterol-increasing and fatty liver-improving actions of Panax ginseng in high cholesterol diet-fed rats with clinical effect on hyperlipidemia in man. Am J Chin Med 1983;11:96-101. 98. Yamamoto M, Kumagai A, Yamamura Y. Plasma lipid-lowering actions of ginseng saponins and mechanisms of the action. Am J Chin Med 1983;11:84-87. 99. Joo CN. The preventative effect of Korean (P. ginseng) saponins on aortic atheroma formation in prolonged cholesterol-fed rabbits. In Proceedings of the 3rd International Ginseng Symposium. Seoul Korean Ginseng Research Institute, 1980:27-36. 100. Matsuda H, Namba K, Fukuda S, et al. Pharmacological study on Panax ginseng C.A. Meyer. III. Effects of red ginseng on experimental disseminated intravascular coagulation. (2). Effects of ginsenosides on blood coagulative and fibrinolytic systems. Chem Pharm Bull (Toyko) 1986;34:1153-1157. 101.Oura H, Hiai S, Sen0 H. Synthesis and characterization of nuclear RNA induced by radix ginseng extract in rat liver. Chem Pharm Bull (Tokyo) 1971;19159&1605. 102. Oura H, Hiai S, Nabetani S, et al. Effect on ginseng extract on endoplasmic reticulum and ribosome. Planta Med 1975;28:76-88. 103. Oura H, Nakashima S, Tsukada K, et al. Effect of radix ginseng extract on serum protein synthesis. Chem Pharm Bull (Tokyo) 1972;20:980-986. 104.Hikino H, Kiso Y, Kinouchi J, et al. Antihepatotoxic actions of ginsenosides from Panax ginseng roots. Planta Med 1985;1:62-64. 105. Kim TH, Lee YS, Cho CK, et al. Protective effect of ginseng on radiation-induced DNA double strand breaks and repair in murine lymphocytes. Cancer Biother Radiopharm 1996;11:267-272. 106.Ben-Hur E, Fulder S. Effect of Panax ginseng saponins and Eleutherococcus senticosus on survival of cultured mammalian cells after ionizing radiation. Am J Chin Med 1981;9:48-56. 107. Siege1 RK. Ginseng abuse syndrome: problems with the panacea. JAMA 1979;241:16141615. 108. Hess FG Jr, Parent RA, Stevens KR, et al. Effects of subchronic feeding of ginseng extract G115 in beagle dogs. Food Chem Toxicol 1983;21:9597. 109. Hess FG Jr, Parent RA, Cox GE, et al. Reproduction study in rats of ginseng extract G115. Food Chem Toxicol 1982;20189-192. 110. Coon JT, Emst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Safety 2002;25:323-344.

Pancreatic Enzymes Anthony J. Cichoke, DC, PhD, DACBN CHAPTER CONTENTS Inhibitors 1135 Supplement Coating

Introduction 1131

1135

History 1131 Measuring Enzyme Activity

1136

Pancreatic Enzyme Supplements 1132 Enzyme Extraction Processes 1132 Rupturing the Cell Membrane 1133 Fractionation 1133 Crystallization 1133 Enzyme Isolation 1133 Absorption of Proteins 1133 Understanding the Absorption of Enzymes 1134

Clinical Applications 1136 Digestive Disorders 1137 Inflammatory Diseases 1138 Cancer 1138 Autoimmune and Immune Complex-Mediated Diseases 1139 Cardiovascular Disorders 1139 Viral and Bacterial Disorders 1139 Other Conditions 1139 Dosage 1139

Factors Affecting Enzyme Activity Optimal pH Range 1135 The Effects of Temperature 1135 Substrate Concentration 1135 Cofactors 1135 Metal Ions 1135

1134

INTRODUCTION Pancreatic enzymes produced by the body are well known for the integral role they play in the digestion of proteins, fats, and carbohydrates. Pancreatic juice contains numerous enzymes, including amylase, lipase, ribonuclease, and deoxyribonuclease'; and the proenzymes trypsinogen, chymotrypsinogen, and procarboxypeptidase, which are converted in the small intestine to their active forms trypsin, chymotrypsin, and carboxypeptidase, respectively. Protein leaves the stomach primarily in the form of proteases, peptones, and large polypeptides? Upon reaching the small intestine, they are further digested by the proteolytic enzymes, trypsin, chymotrypsin, and carboxypolypeptidase. Protein digestion occurs mainly in the duodenum and jejunum. Carbohydrates are digested by a-amylase in the pancreatic juice, which breaks down starches (converting them into maltose and other small glucose polymers), whereas pancreatic lipase digests fats?

Toxicology 1140 Oral Enzymes 1140 Enzyme Enemas 1141 Topical Application 1141 Injectable Enzymes 1141

Although critical for proper digestion, pancreatic enzymes also aid in a surprising variety of bodily functions, including detoxification, immunity, aging, blood fluidity, and tissue repair. Unfortunately, an inadequate production of, or an excessive need for, pancreatic enzymes can occur for a variety of reasons, including genetics, illness, injury, exercise, aging, and toxins (both endogenous and exogenous). In fact, many authorities believe that a deficiency of pancreatic enzymes, for whatever reason, may be a cause of numerous illnesses and degenerative conditions. When a deficiency occurs, enzymes from an external source may be necessary.

HISTORY Pancreatic enzymes have a long history of clinical use. In the early twentieth century, John Beard, a Scottish embryologist, successfully treated cancer using a pancreatic 1131

Pharmacology of Natural Medicines

extract, which he described in his book, The Enzyme Treatment of Cancer and its Scientific Basis. In 1934, Emst Freund, a Viennese physician, found a substance in the blood of people free from cancer that was able to dissolve cancer cells. Patients with cancer did not have this material, which Freund called "normal substance." In the early 1930s, Professor Doctor Max Wolf worked with Freund in Vienna and successfully identified "normal substance" as an enzyme that decomposes fatty materials and proteins. For his work in the field of enzymes, Wolf is generally considered the father of modem enzyme therapy. The work of Freund and John Beard sparked Wolf's interest in the possibilities of treating malignant diseases with enzymes. He subsequently founded the Biological Institute of New York City and, after studying various enzymes and enzyme combinations, developed what he regarded as an optimal preparation for the treatment of various acute and chronic conditions. His preparation was a combination of a fractionated hydrolysate of beef pancreas, calf thymus, Pisum sativum (common pea), Lens esculenta (edible lentil), mannitol, and papaya. In the 1960s, Irving Innerfield conducted landmark research in the area of pancreatic enzymes, primarily relating to the clinical use of trypsin, chymotrypsin, and pancreatin as well as streptokinase (a microbial proteolytic enzyme). In 1971, the late Professor Heinrich Wrba, at the time head of the Austrian Cancer Research Institute at the University of Vienna, stated, "Our present knowledge allows us to include this [enzyme] therapy into the small list of highly-effective causal anticancer compounds. It [enzyme therapy] will certainly play an important role in cancer treatment over the next few years." Dr. Wrba's interest in cancer was piqued when he lost a daughter to leukemia. He devoted his life to educating oncologists in Germany and around the world about enzyme therapy. It was the late Karl Ransberger, however, who continued and refined Wolf's research, bringing it to doctors, hospitals, and patients throughout the world. Ransberger encouraged and funded research projects in numerous hospitals and universities in Europe, the Americas, and elsewhere. His research, and that of others, has validated enzyme therapy's effectiveness in treating numerous conditions, including arthritis, cancer, multiple sclerosis, cardiovascular disease, human immunodeficiency virus (HIV), and acquired immunodeficiency syndrome (AIDS).

PANCREATIC ENZYME SUPPLEMENTS The pancreatic enzyme supplements most commonly used & health care are chymotrypsin, trypsin, and pancreatin (which contains proteolytic, amylolytic and lipolytic

properties), as well as pancrelipase (similar to pancreatin, but with a higher proportion of lipase). Chymotrypsin and trypsin are proteolytic enzymes that break proteins down into peptides. Chymotrypsin liberates the amino acids L-tyrosine, L-tryptophan, and L-phenylalanine and other molecules, including several synthetic esters and amides.' Trypsin hydrolyzes primarily lysyl and argjnyl residues. Pancreatin contains amylase, lipase, and protease. Amylase breaks down starch; lipase breaks down fats; and protease breaks down proteins. Pancrelipase is similar to panmatin, but with a higher concentration of lipase. These enzymes are primarily obtained from hog or ox pancreas, but some (such as lipase) can also be obtained from microbial sources (e.g., Aspergillus niger and Aspergillus oyzae). According to the U.S. Pharmacopoeia (USP), chymotrypsin and trypsin are routinely crystallized from ox pancreas gland extract, and pancreatin from both hog and ox sources, whereas pancrelipase is derived from hog pancreas? Porcine pancreas is especially rich in amylase and lipase and is similar to human pancreas.' Bovine pancreas contains considerable amounts of proteolytic enzymes but substantially lower amounts of lipase and amylase.' Germany, Japan, England, India, and other countries utilize their own pharmacopoeia, and foreign companies may use other sources to formulate their enzyme products. Age, sex, and species of pork or ox can affect enzyme concentration and activity levels. For example, sow glands (from pork) are high in lipase, whereas butcher hogs (young male hogs, up to 90 kg in weight and 6 months of age) are high in protease. Beef cows and bulls have different enzyme levels from those in steers or heifers. Beef, though providing all three basic enzyme types, does not exhibit the activity levels of pork (which has an activity level one third to one half higher). Furthermore, physiology of hogs is more similar to that of humans than to that of any other animal.

ENZYME EXTRACTION PROCESSES Enzymes are particularly sensitive to environmental changes, so it is especially important during extraction to control pH (usually with buffers), temperature (using precooled solutions and apparatus), substrate, and proteolysis (controlled through the use of inhibitors) to render a product that is enzymatically active: The following steps are typically involved in the production of pancreatic enzyme supplements: 1. Cell membrane rupture 2. Fractionation 3. Crystallization 4. Enzyme isolation

Pancreatic Enzymes

Rupturing the Cell Membrane

Pancreatin

Although many methods are employed in enzyme extraction, most entail rupturing the cell membrane of the animal tissue. Rupture can be achieved through mincing, homogenizing, shaking with fine glass beads (at high speed), grinding with sand, &zing (and subsequent thawing), oscillations(ultrasonicor sonic),autolysis (either alone or with toluene, ethyl acetate, or sodium sulfide), treatment with solvents (e.g., acetone), or lysis with added enzymes? Extracting enzymes from animal tissues is easier than extracting them from microorganisms.5In fact, in many cases, simple extraction with water may be sufficient. All extraction processes, however, must control pH and temperature to protect the enzymes from deactivation.

Pancreatin extraction can involve eliminating the insoluble tissue, then treating the mixture with organic solvents to dissolve the tissue and precipitate the enzymes.' However, because part of the lipase and other enzymes are inactivated during the manufacturing process, pancreatin that is isolated in this way is not very active.' Pancreatin can also be produced through lyophilization, that is, by drying under reduced pressure or with acetone. At this low temperature, the enzymes are more stable and less likely to be denatured.' After proper defatting, the pancreatin is stable, provided that it contains not more than a small percentage of m0isture.l However, it may contain undesirable microorganisms (such as Salmonella) and must, therefore, be decontaminated.' Under carefully controlled conditions, pancreatin can be decontaminated with a terminal heat treatment.' According to the USP,3 each milligram of pancreatin should exhibit the following characteristics:

Fractionation Once the enzyme is brought into a solution, it must be separated from the other substances in the solution. Gel filtration or dialysis can be used to remove the small molecules, leaving large molecules (primarily proteins, with some polysa~charides).~ Various fractionation methods can be employed for purifying the enzymes, including changing the pH, heating, using organic solvents and/or salts, adsorption, column chromatography, and electroph~resis.~ Inhibitor affinity chromatography and substrate affinity chromatography are also used? as is magnetic affinity separation7

Crystallization After an enzyme has been purified, it may be possible to crystallize it. Dixon and Webb5 regard crystallization as a final-stage method of fractionation. Crystallization can be achieved with ammonium sulfate solutions (the typical method) or at a constant salt concentration through a gradual change in the temperature or the pH.5

Enzyme Isolation Because each enzyme has its own distinct properties, isolation methods can vary by enzyme, as seen in the following discussion.

Chymotrypsin One method (used in Germany) for extracting chymotrypsin (in the form of its inactive precursor chymotrypsinogen) is by fractionated extraction, ultrafiltration, and subsequent chromatographic purification of pancreatic juice. The chymotrypsinogen is converted to the active chymotrypsin by treatment with trypsin in an acid environment.

Tiypsin Trypsinogen can be isolated from the animal pancreas by fractionated precipitation and then activation to trypsin in a slightly alkaline environment.

Not less than 25 USP units of amylase activity Not less than 2.0 USP units of lipase activity Not less than 25 USP units of protease activity The USP states, "One USP unit [or 1x1 of amylase activity is contained in the amount of pancreatin that decomposes starch at an initial rate such that one microequivalent of glucosidic linkage is hydrolyzed per minute" under the conditions listed in the USP to assay for amylase activity. "One USP unit [or 1x1 of lipase activity is contained in the amount of pancreatin that liberates 1.0 pEq of acid per minute at a pH of 9.0 and 37" C" under the conditions detailed in the USP to assay for lipase activity. "One USP unit [or 1x1 of protease activity is contained in the amount of pancreatin that digests 1.0'mg of casein" under the conditions enumerated in the USP to assay for protease a~tivity.~ Therefore a product labeled "4x" would be four times stronger than a product labeled "lx."

Pancrelipase Since it is isolated from the same organs, pancrelipase is isolated in much the same way as pancreatin. Pancrelipase is similar to pancreatin and according to the USP should exhibit the following characteristics: Not less than 100 USP units of amylase activity Not less than 24 USP units of lipase activity Not less than 100 USP units of protease activity

ABSORPTION OF PROTEINS In the past, the efficacy of enzyme therapy has been discounted, because the intestinal epithelial mucosa

Pharmacology of Natural Medicines had been thought to be impermeable to large protein molecules.g10 However, research over the past several decades has shown that the intestinal epithelium can be crossed by macromolecules, including intact proteins such as proteolytic enzymes.” These macromolecules normally penetrate the mucosal surface via the transcellular route as, in the healthy mucosa, the tight junctions (zonula occludens) between the enterocytes prohibit paracellular Binding to the luminal membrane of the enterocyte is followed by phagocytosis.16Some of the vacuole membrane vesicles formed fuse with lysosomes, and within the resulting phagolysome, the peptides and proteins may be hydrolyzed by lysosomal enzymes.14 Other macromolecules avoid intracellular digestion and are passed from the enterocytesthrough the basolateral membrane into the interstitial space.17In the interstitial space, the macromolecules become available to macrophages and lymphoid cells.’* Those molecules not taken up by macrophages or lymphatic cells eventually pass from the interstitial space into the blood or 1 y m ~ h . l ~ The transport of macromolecular material from the lumen to the interstitium has been extensively studied in the epithelium covering the lymphatic structures, such as Peyer’s patches and isolated follicles.16In these regions, specialized enterocytes, the follicle-associated epithelium cells (FAE cells)I3 or M cellsz0 (so called because of their occurrence in the microfolds of the luminal surface), transport macromolecular material in both dire~ti0ns.l~ The gut-associated immune system is thus supplied with antigenic macromolecules from the intestinal lumen.21-23The immunoglobulins (Igs) produced by the plasma cells in the lumina propria (mainly IgA) are transported transcellularly to the luminal surface. The exact level of intestinal absorption of intact molecules or large breakdown products of dietary proteins is not yet totally clear and can vary by individual.”s Although it is generally assumed that, apart from a very small proportion, all protein is hydrolyzed into amino acids or low-molecular-weight peptides before absorption by the mucosa, some research supports the hypothesis that a considerable proportion of dietary protein is taken up in the form of macromolecules and is only then hydrolyzed intercellularly in the peripheral tissue into amino acids (a process called “distributed digestion”).2628 Regardless of the nutritional significance, the transepithelial transfer of particulate matter is at least antigenically sufficient to elicit a response from the gutassociated immune system.I3 The production and secretion of the immunoglobulins promote binding and proteolysis of the antigen material on the mucosal brush border, thereby reducing its absorption (immunologic barrier).29

Understanding the Absorption of Enzymes Understanding the intestinal transport of macromolecules is especially important for understanding the functions and absorption of enzymes spe~ifically.~~ Hydrolases such as trypsin and elastase can be transported functionally intact into the blood from the lumen of the gut. These circulating proteinases are bound to antiproteinases such as alphas macroglobulin or alphal antiproteinasesl and can be resorbed from the main blood stream by pancreatic cells (enteropancreatic circulation as an enzyme conservation process).30Thus, the intestinal absorption of intact enzymes appears to be important for the balance between hydrolases and antiproteinases in the intracellular space31and is an important factor for the establishment and maintenance of the internal stability of the body. It should be kept in mind that, although there are a number of absorption mechanisms, the primary mechanism for enzymes and other macromolecular enteral absorption is pinocytotic transfer by the M cells of the small intestinal epithelium. After connection to a receptor in the mucosa of the intestinal wall, the enzymes are absorbed into the wall by pinocytosis, guided through the intestinal cells in vesicles, and finally released into the blood by exocyt~sis.~lJ~ To clarify rate of absorption, Steffen et aP3 investigated the absorption of an enzyme mixture “A” (EMA, which contained pancreatin, 100 mg; papain, 60 mg; lipase, 10 mg; amylase, 10 mg; trypsin, 24 mg; chymotrypsin, 1mg; bromelain, 45 mg; and the bioflavonoid rutin, 50 mg) in rabbits. Using electrophoresis, these researchers found that entire enzyme molecules were absorbed. Although enzyme particles were also present, the ratio to the entire amount administered was not measured. EMA was found in both lungs and liver after 1 to 2 hours. After 1 to 4 hours, approximately twice as much EMA was found in the liver as in the lungs. The absorption maximum in all animals occurred approximately 1hour after administration. After 24 hours, EMA was no longer found in either the lungs or liver. The absorption rate of individual and combined enzymes can be seen in Table 112-1.343The absorption rate of orally ingested EMA is more than 20% within 6 hours.= (For additional discussion of the intestinal absorption of intact macromolecules, see Chapters 19 and 53.)

FACTORS AFFECTING ENZYME ACTIVITY Numerous factors can affect the activity of supplemental enzymes; they include the following: PH Temperature Substrate and substrate concentration Cofactors

Pancreatic Enzymes

Absorption rate of individual and combined enzymes (within 6 hours) Enzvme Amylase

AbsorDtion rate (%) 45

Chymotrypsin

14-16

Pancreatin

18-19

Papain

6

Trypsin

26-28

Enzyme combination (bromelain, chymotrypsin, pancreatin, papain, and trypsin, with the bioflavonoid rutin)

22

Data from references 34 and 35.

Metal ions Inhibitors and coating

Optimal pH Range Each enzyme has an optimal pH range, depending on such variables as temperature and substrate concentration, at which the enzymatic catalytic reaction occurs most rapidly. Chymotrypsin is stable at a pH of 3 or 4, suffers reversible denaturation at a pH below 3.0, and becomes inactive at a pH above 10.0.' Trypsin, stable at a pH of 3.0 (and at low temperature), is irreversibly denatured at a pH of 8.0 or higher.l One must remember that enough the pH of the normal stomach is 1.5 to 3.03640~ to denature or inactivate some or all of the pancreatic enzyme supplement if it is not enterically coated or otherwise treated to protect it from a low-pH environment.

The Effects of Temperature In general, an increase of 50" F (10" C) in the enzymatic environment approximately doubles the rate of the chemical reaction.37 However, because enzymes are proteins, excessively high temperatures can denature them, thus destroying their activity. Optimal temperature or an enzyme is the temperature at which the catalyzed enzymatic reaction progresses most rapidly without damage to the enzyme. This is a good rationale for avoiding hot beverages when taking enzyme supplements. The enzymes in the human body develop high levels of activity at about body temperature, increasing to maximum at about the temperature of a severe fever, that is, 104" F (40" C).

accelerated by the addition of more substrate. This is why it is particularly important to ingest sufficient quantities of supplemental enzymes (which vary according to the condition being treated).

Cofactors Although all enzymes consist of protein, some are complex proteins, that is, they have a protein component and a "cofactor." If the cofactor is removed, the protein (no longer active enzymatically) is called the apoenzyme. A cofactor might be a metal (e.g., iron, magnesium, copper, or zinc), a prosthetic group (a moderately sized organic molecule), or a coenzyme (small organic compound). Prosthetic groups and metals can aid in the catalytic function of the enzyme, whereas coenzymes take part in the enzymatic reaction. Many vitamins, trace elements, and minerals essential to human bodily function are part of enzymatic cofactors. So the physician must ensure that his or her patients take multivitamins and multiminerals to "feed" their enzymes. Coenzymes are essential for the activity of many enzymes and serve as a type of substrate in certain reactions. In these reactions, the coenzyme is converted to a form no longer active in catalyzing the reaction. The reaction requires a mix that contains one molecule of cofactor for every molecule of substrate to be converted.

Metal Ions Specific metal ions are required for the activity of many enzymes. Some metal ions increase enzyme activity and others decrease or inhibit it. Calcium, cobalt, copper, iron, magnesium, manganese, molybdenum, potassium, and zinc are the most common enzyme activators in humans. Certain heavy metal ions inhibit enzyme reactions; they are barium, lead, and mercury, and they combine with the sulfhydryl reactive group (-SH) that is part of the active site of many enzymes.

Inhibitors Ions, atoms, or molecules that terminate or retard enzyme activity are called inhibitors. They are classified as either noncompetitive or competitive. A noncompetitive inhibitor combines with the enzyme at a location other than the active site. The noncompetitive inhibitor retards the conversion of the substrate by the enzyme, although it does not affect the bonding of the substrate of the enzyme. An inhibitor is classified as competitive if it combines with the active site of the enzyme, preventing the substrate from having access to the active site.

Substrate Concentration

Supplement Coating

The rate of any reaction is accelerated by raising the substrate concentration until the enzyme is saturated by substrate. At this level, the rate of reaction becomes independent of substrate concentration and is no longer

The normal human stomach has a pH of approximately 1.5 to 3.0.% This low pH inhibits bacterial growth and activates certain enzymes. This acidic nature, however, can destroy pH-sensitive supplemental enzymes. For this

Pharmacology of Natural Medicines reason, many enzyme products are enterically coated. The coating allows the product to reach the small intestine before disintegrating.’ Other products are encapsulated in “microspheres,”delaying disintegration. In one study, cellulose acetate phthalate (CAP) and maize starch were used as the coating materials to encapsulate pancreatic protease.% Results indicate that the coating materials were stable for at least 3 hours (time to pass through each part of the gastrointestinal tract) in simulated gastric conditions (pH 3.97) but disintegrated rapidly under simulated intestinal conditions (pH 6.82 and temperature 39.5”C).

MEASURING ENZYME ACTIVITY When considering enzymes and enzyme applications, the physician must understand the variables affecting their performance. Selection of an enzyme for therapeutic purposes requires more than knowing whether a given product contains amylase, protease, lipase, or other enzymes. The activity levels of the enzymes are critical. Unfortunately, the labels on most enzyme products sold in the United States do not indicate the activity levels of the enzymes contained therein. In addition, when the activity is stated, the consumer has no way of knowing which enzyme assay the manufacturer used unless the label also indicates that the product conforms to the guidelines of the USP. This is particularly confusing because activity levels are greatly affected by the conditions under which the assay was performed (including temperature, pH, and substrate). Adding to the confusion, enzyme manufacturers utilize diverse assay methodologies. Therefore directly comparing the enzymatic activity of competing products is difficult, if not impossible.The utilization of a single assay system (suchas detailed in the USP) is probably necessary to directly compare competitive products. Several standardized assay systems are available for enzyme suppliers and are found in the USP (for a definitive assay), the National Food Ingredients Association (NFIA) Laboratory Methods Compendium, and the Food Chemical Codex. Incomplete labeling and the inconsistent use of standardized assay methodologies make evaluation of competitive products extremely challenging. Price could be the first indication of inequities in assay procedures. For example, if company A is selling a product at 1000units/g for $30 a bottle and company B is selling a product at 5000 units/g for $10 a bottle, the units are most likely not the same. For clinical reliability, one must use only appropriately labeled products or obtain the assay procedures from each of the manufacturers. If possible, competitor products should be compared by means of assays performed in an independent laboratory.

CLINICAL APPLICATIONS Historically, enzyme therapy has been used in a wide variety of applications, ranging from the classic substitution of enzymes for intestinal deficiency to the centuries-old external application of enzymes to treat leg ulcers, topical wounds, wrinkles, blemishes, episiotomies, scars, and so on. Enzymes can be used individually or in complex enzyme mixtures. Because trypsin, chymotrypsin, lipase, and amylase are substratespecific, combinations of enzymes are frequently employed for a broader spectrum of activity. In addition, when combined, some enzymes act synergistically with others-hence the use of pancreatin (from animal pancreas) as well as products that include both enzymes from different sources and activating substances. For example, one German product contains an enzyme extract consisting of proteinases, triacylglycerol lipase, and alpha-glycosidase (amylase), minor amounts of elastase, nuclease, and carboxypeptidase, and calcium ions to boost activity. Enzyme combinations should not be viewed as simply intensified forms of pancreatin. An enzyme combination has a number of therapeutic advantages over a preparation with only one or two components. Combining enzymes from diverse sources-animal, plant, and fungi-results in a wider range of optimal pH, synergism of the combined enzymes, greater absorption, higher level of effectiveness, and broader range of application. Furthermore, as S t r e i ~ h h a nstates, ~ ~ enzyme combinations are better than single enzymes for the following reasons: Isoenzymatic activity differences of single biocatalysts are more readily balanced by combining uniformly acting hydrolases of varying origins. Giant molecular substrates are more quickly and more intensively fragmented by a multihydrolytic preparation because the differently acting hydrolases are able to simultaneously disintegrate the giant molecular substrates at many different locations. Certain enzymatic mixtures have a broader range of action than pancreatin, bromelain, or any other standardized monohydrolytic preparation-this is because certain enzyme mixtures characteristically possess differences in optimal pH and also differences in reactive properties of the proteolytic, lipolytic, and/or glycolytic acting hydrolases. Clinical uses of individual enzymes can be seen in Boxes 112-1 through 112-5,m95while clinical uses of combinations can be seen in Box 112-69”178(for more information on how enzymes can treat more than 150 conditions, please see my book, The Complete Book of Enzyme Therapy).

Pancreatic Enzymes

In debridement, treatment of abscesses and ulcerations, liquefaction of mucous secretionsm In ophthalmic cataract surgeries and therapy of eyeball hematomas and ophthalmorrhagia~~.~~ Before and after tooth extraction as well as in operative dentistvz$4 After episiotomy procedures" As an anthelmintic against enterozoic wormse In early recognition of tumor cellsM In histologic gastroenteric diagnosis47 In inflammatory conditions (local and systemic) to promote the dispersion of blood extravasates and effusions from fracture^^',^-^^ Surgical Sporting Accidental soft tissue trauma48-52*55 lntervertebraldisc lesionss For uveitis vitreous hemorrhage, diabetic retinopathy, and asthmatic symptoms57

In debridement of necrotizing wounds, ulcerations, abscesses, empyemas, hematomas, fistulas, and decubitus ulcers5s41 To accelerate healing in injuries, inflammations, phlogistic edemas, and traumatic changes*% As an auxiliary agent in meningitis therapyp2 As an ointment or dressing (wet or dry)' As a liquid or an aerosol to liquefy sputum in bronchial disorders and in the preparation of sputum for cytologic examination' As an antiinflammatory agent; oily suspensions are injected intramuscularly' As an aid in the treatment of intraocular hemorrhage, thrombophlebitis, intestinal obstruction (due to cirrhosis or carcinoma)63

Needs calcium ions for enzymatic activity Acts on starch, glycogen, and related polysaccharides and oligosa~charides~ In combination with other enzymes, as a digestanPs64.ffi As an antiinflammatory64 In treatment of deficiencies of exocrine pancreas, amylaceous dyspepsia, and cystic fibrosis'

-

In pancreatin-containing remedies to increase pancreaticllipolytic activities (replacement therapy)When given with pancreatin in combined preparations, it reduces fat level in stools7o7z Synergistically intensifiesthe activity of lipoproteid-lipase in the blood73and migration of agran~locytes~~ As a digestive aid7'

In pancreatic insufficiency, inadequate secretion of exocrine pancreas, and disturbed digestion, and after g a ~ t r e c t o m f ~ . ~ ~ - ~ ~ In chronic pancreatitis@and after surgery for chronic pancreatiti~~~ After pancreatectomy'V@ In ductal obstruction from neoplasm (e.g., of the pancreas or common bile duct)@ *To treat severe cases of steatorrhea (as found in cystic f i b r o s i ~ ) ~ - ~ ~

Soft tissue i n j u r i e ~ ~ . ~ ~ Sprained ankle97-w Reabsorption of hematomas96.1w Sports m e d i ~ i n e ' ~ ' - ' ~ ~ Meniscectomy (preoperative and postoperative therapy)108*i09 Traumatologyllo Prevention of posttraumatic and postoperative swelling1i1 Pancreatitisll' S~rgery~.~~~ Lower extremity bypass ~ u r g e r y " ~ Operative dentistry1I5 Proctology116 SinusitisIl7-120 Acute and chronic b r o n ~ h i t i s ~ ~ ~ - ~ ~ ~ Cystitis and lower urinary tract infections117~124~125 Prostatitis' 17.124.126 Pelvic inflammatory Postthrombotic syndrome124133 Pathologic venous p r o c e s s e ~ ~ ~ ~ ~ ~ ~ - ~ ~ Occlusive arterial disease139 Lymphedema140-145 Soft tissue rheumatism (nonarticular rheumatoid ~ y n d r o m e ) ' ~ * ~ ~ ~ Rheumatoid arthritis (chronic polyarthritis)'17~i22~131~142~148~i49~150-163 Ankylosing spondylitis (Bekhterev's d i ~ e a ~ e ) ~ ~ ~ ~ ~ ~ , ~ ~ Degenerative rheumatic joint d i s e a ~ e ' ~ , ~ ' ~ Monoarticular, activated o ~ t e o a r t h r o s i s ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ Multiple s ~ l e r o s i s ~ ~ ~ ~ ~ ~ ~ ~ ~ HIV infection^^^^-^^^ Fibrocystic breast d i s e a ~ e ~ " . ~ ~ ~ Ulcerative colitis and Crohn's disease117.122.1TI-178

.

Most conditions treated by enzymes can be assigned to one or more of the following categories: Digestive conditions Inflammatory conditions Cancer Autoimmune or immune disorders Cardiovascular disorders Viral and bacterial disorders Other conditions

Digestive Disorders Pancreatic enzymes have a long history of use in treating a myriad of digestive conditions, including indigestion,

Pharmacology of Natural Medicines pancreatic insufficiency, steatorrhea, pancreatitis, heartburn, gas, diarrhea, constipation-the list seems endless. Supplementing the diet with pancreatic enzymes can improve food digestion and therefore nutrient assimilation.This is especially true if the body’s own pancreatic enzyme production and/or supply is deficient, as can occur with age or because of an underlying health condition such as pancreatic insufficiency, chronic pancreatitis, steatorrhea, biliary tract disease, celiac disease, lactase deficiency or cystic fibrosis. In fact, individuals suffering from cystic fibrosis almost always take large quantities of pancreatin or pancrelipase to improve digestion. Any condition that can be improved by better nutrition can benefit from the addition of enzyme supplements. This is particularly true of those suffering from chronic pancreatitis-a condition marked by poor digestion. Enzyme therapy can help increase body weight and improve serum albumin levels (low levels reflect protein calorie maln~trition).”~

Inflammatory Diseases The inflammatory process is involved in numerous diseases and conditions, from sports injuries to arthritis to sinusitis to fibrositis. One of the basic concepts in systemic enzyme therapy is that all kinds of inflammatory processes respond to enzymes. The following steps describe the postulated mechanism of action:

1. In the damaged area, various repair mechanisms are activated, resulting among other effects in surrounding of the traumatized region by fibrin. 2. After having been partly or completely sealed off by microthrombi and/or a fibrin web, the injured area is cut off from the normal circulatory system. Stasis results, inhibiting the repair processes (nutrients cannot get into the damaged area and waste products cannot be removed). Pressure rises in the damaged capillaries, the blood vessels become highly permeable, and fluid is forced out into the surrounding tissue. The result is increased pressure, swelling, and pain. 3. Supplemental enzymes, after absorption, are bound in complexes (e.g., alpha2 macroglobulin-hydrolase) and circulate to the injured area from the blood stream. 4. Proteolytic enzymes directly attack the microclots and fibrin formation, lysing the fibrin and breaking open the clogged vessels, thus reestablishing circulation.

By restoring normal blood flow, postinflammatory pain and edema are reduced more rapidly and, equally important, the essential physiological inflammatory repair process is not blocked or diminished (as with antiinflammatory agents), but rather is accelerated and reinforced.

Even inflammatory diseases, such as arthritis and herpes zoster, have been shown to respond to the systemic application of enzymes.148J80J81 Despite the supportive research, the administration of enzymes in traumatology and injuries is not widely used. All types of injuries-sprains, strains, hematomas, dislocations, and even postoperative conditions-can be treated effectively with enzymes. Individual enzymes and enzyme combinations (particularly those including trypsin, chymotrypsin, pancreatin, amylase, lipase, papain, and bromelain, with rutin) are effective in treating inflammation because they help limit the injury, aid its rectification, and promote new, healthy tissue formation. They are inflammation activators, not inflammation inhibitors, effectively accelerating the inflammatory process (a necessary component of wound healing). This acceleration means, on the one hand, that the work of damage control, damage repair, and new tissue construction is carried out more actively and thus completed more swiftly. On the other hand, it means that there can be a temporary increase in the visual and sensory effects produced by the inflammation (i.e., more redness, swelling, heat, and pain). Because the inflammatory reaction is so universal, it appears that enzymes and enzyme mixtures can be effectively used to treat a wide variety of chronic disorders.

Cancer Just as Beard researched the effect of enzymes on cancer, so have modem researchers. Dr.William Kelley devised an anticancer program that employed detoxification, pancreatic enzymes (and other nutritional supplements), improved enzyme-rich nutrition, and coffee enemas.lS2 He started his treatment program in response to his own bout with pancreatic cancer. Pancreatic cancer is the fourth leading cause of cancer death in the United States, affecting nearly 30,000 people every year.183Unfortunately, survival rates for this disease are extremely low; in fact, most people do not live even 5 years after diagnosis. The survival rate is abysmal probably because pancreatic cancer is usually not diagnosed until it is quite advanced. Standard medical treatment for pancreatic cancer involves surgery, radiation therapy, and chemotherapy. However, even with treatment, pancreatic cancer still claims 99% of those diagnosed with the disease; hence, its reputation as one of the deadliest cancers.l@ Dr. Nicholas Gonzalez became aware of Kelley’s work in the 1980s and began reviewing the case histories of Kelley’s patients. He and Dr. Linda Isaacs are now using their own version of the Kelley program to treat pancreatic cancer with enzyme therapy. They have conducted a 2-year-long pilot study on 11 patients with inoperable, biopsy-proven pancreatic adenocarcinoma to see whether therapy with enzyme supplements

Pancreatic Enzymes

could help. Nine (81%)of the patients survived 1 year, five (45%)survived 2 years, and 4 survived 3 years.185 This compares favorably with survival rates reported in the National Cancer Data Base from 1995; 25% at 1year and 10%at 2 years." In fact, patients lived an average of 17 months, which is three times longer than patients with this type of cancer usually survive.187Researchers are currently conducting a Phase I11 clinical trial funded by the National Institute of Health's National Center for Complementary and Alternative Medicine to compare the effectiveness of pancreatic enzymes and dietary supplements with that of standard gemcitabine-containing chemotherapy regimens in the treatment of advanced pancreatic cancer. The trial is ongoing and, although no results have yet been released, we anxiously await the outcome of this trial.

Autoimmune and Immune Complex-Mediated Diseases In autoimmune disease, tissue-bound immune complexes activate the complement system. Activation of the enzyme cascade results in an intense protein-destroying inflammatory response leading to signhcant local tissue destruction. For instance, when immune complexes collect in the kidneys, complement activation causes inflammation, resulting in glomerulonephritis. Research shows that some enzymes can inhibit immune complex-mediated diseases, such as glomerulonephritis, by interrupting the complement cascade. Other disorders with similar mechanisms also respond to supplemental enzymes. Some of these conditions, such as Crohn's disease, pulmonary fibrosis, chronic rheumatism, and ankylosing spondylitis, have not responded well to conventional medical treatments.

Cardiovascular Disorders Cardiovascular disease, the primary killer in the United States, kills nearly a million Americans every year,'87 almost as many as cancer, accidents, pneumonia, influenza, and all other causes of death combined. But cardiovascular disease is not limited to the elderly; nearly 175,000 Americans younger than age 65 die from this disease every year.188 In normal circulation, there is a constant dynamic balance between blood clotting and fibrinoly~is.'~~ If fibrinolysis is impaired, clot formation is abnormal. If fibrinolysis increases, a tendency toward excessive bleeding results. Therefore, maintenance of proper equilibrium is extremely important for the circulatory system. One study examined the effects of various enzyme combinations on fibrinolysis and fibrin formation. The researchers induced fibrin deposition with calcium ions or staphylocoagulase in the plasma of centrifuged, acellular citrated blood from humans or rabbits and treated the clot with various concentrations of enzyme

suspensions. The higher the enzyme content of the solution, the more rapidly clots were deg~-aded.'*~J~~

Viral and Bacterial Disorders Enzyme therapy can be beneficial in treating infection caused by viruses or bacteria. But as more and more bacteria become resistant to antibiotics, researchers and physicians are looking for new treatment alternatives. Enzyme therapy is a valuable alternative to antibiotics in treating many conditions because it can help stimulate the immune system and strengthen the body as a whole. Enzymes also reduce inflammation and improve circulation. Many conditions can be helped with enzymes, including abscesses, acne, adenoiditis, adnexitis, bladder infection, boils, conjunctivitis, diarrhea, ear infections, empyemas, epididymitis, gingivitis, kidney disorders, laryngitis, pneumonia, rheumatic fever, sinusitis, staphylococcalinfections, and tonsillitis. Enzyme therapy can also aid in the treatment of viruses. The human body defends against viruses with the help of macrophages or natural killer (NK) cells. Oral enzyme combinations (such as papain, trypsin, and chymotrypsin) synergisticallyincrease the antiviral effects of tumor necrosis factor (TNF), macrophages, and NK cells and the breakdown of circulating immune complexes (CICs). Enzymes can aid in the treatment of numerous viral conditions including AIDS, chancre sores, chickenpox, colds and coughs, hepatitis, herpes simplex, herpes zoster, influenza, measles, pneumonia (viral), and warts.

Other Conditions Enzyme therapy may be of value in conditionsthat do not easily fit into one of the preceding categories. Autism is just one example. No causative agent has been found for this developmental disease, although many theories abound, including vaccinations, a genetic link,nutritional deficiencies, and reactions to chemicals or other environmental factors. Some research indicates that enzyme therapy to improve protein digestion may be of particular benefit in autism as well as many other conditions.1go

DOSAGE Enzymes may be administered rectally, topically, orally, or by injection, depending on the condition being treated. Rectal administration involves a retention implant. Topical treatment consists of ointment spread over the involved area. Oral forms include lozenges (dissolved in the mouth), oral tablets, and enteric-coatedtablets. A wide range in daily dosage has historically been used for the following reasons: There are individual differences in patient health. *The level of effective absorption in tablet strength can vary.

Pharmacology of Natural Medicines

There are a wide variety of influencing ranges in pH. Enzyme activity levels vary between products.

Composition of enzyme combinations (mg) Enzyme

A

B

100

100

0

Papain

60

60

100

Bromelain

45

45

0

Lipase

10

10

0

Amylase

10

10

0

Trypsin

24

24

40

1

1

40

50

0

0

0

0

40

Pancreatin

Chymotrypsin Rutin Thymus extract

For example, pancreatin dosage depends on the condition being treated as well as on the patient's diet and digestive requirements. Dosage can vary because of pancreatin's susceptibilityto inactivationin the stomach and duodenum.lY1 Table 112-2lY2indicatesthe composition of threeenzyme combinations(A, B, and C), whereas Table 112-3 lists some of the conditions effectively treated with these products, the dose required, and the treatment p e r i ~ d . ' ~ ' ~ ~

C

Modified from Stauder G, Pollinger W, Fruth C. Allgemein Medizin 1990; 19:188-191.

TOXICOLOGY Oral Enqmes In general, side effects of orally administered enzymes are few and due primarily to excessive dosages or hypersensitivity reactions. According to Wolf and

Dosage programs for specific conditions Condition

Frequency x dosage

Treatment period

Postthrombotic syndrome193

3x5

As needed

Oncology194

2x11

6 weeks or as needed

A

Lyrnphedemal4'

2x5

2 years

A

Fibrocystic breast disease175

2x10

6 weeks or as needed

Experimental hematomaw

3 x 10

24 hours

A A

Prophylactic treatment of karate injurieslal

3x5

During the season

Trauma and meniscus operationlW

3 x 10

Average of 17.7 days

Combination' A

Soft tissue injuries and distortions of the ankleg7

3 x 10 initially, then 3 x 1

As needed

Athletic soft tissue injuries'"

2x5

Spring football season

Dental ~ u r g e r y " ~

4x5

Day before surgery to seventh postoperative day

A

Sports injurieslm

3x10

As needed

Chronic polyarthritislH

4x8

6 months

A A

Active arthroseslg6

4x7

6 weeks

Extraarticular rheumatism146

3 x 10

As needed

Adnexitis'"

3x5

10-14 days

Prostatitis' l7.lz4

3x5

10 days

MastopathylS7

2x10

Multiple sclerosis167-170~178 Initially As symptoms improve

2 ampoules injection 2 ampoules injection

On injection-free days Later Finally

Daily Every 2 to 3 days, then at longer intervals

3 x 10 3x5 3x3

C C A A A

Herpes zoster18' Initially First 2 days

2 ampoules injection 3-4 x 1

First 2 days As indicated to 14 days

C A

HIV

25lday

12 months

A

'For composition of combination, see Table 112-2.

Ran~berger,'~~ high dosages (70 tablets of 17.5 g each) of a proteolytic enzyme mixture have been given without long-term side effects. Studies and literature searches commissioned by regulatory authorities such as the U.S. Food and Drug Administration (FDA) have apparently confirmed that enzyme preparations obtained from suitable sources (e.g., nontoxic, nonpathogenic sources) are safe to consume.199There is some indication that patients with cystic fibrosis who are undergoing long-term highdose pancreatic enzyme therapy may demonstrate colonic wall thickening, a condition called fibrosing colonopathy; however, the copolymer coating on the tablet, rather than the tablet's contents, may be the culprit.2O0 With normal use of pancreatic enzymes, stools can be pale or have a pungent odor. Transient intestinal upset, such as diarrhea and gas, may result from excessive dosage of pancreatin. Hypenuicosuria (excess uric acid in the urine) and hypenuicemia (excess uric acid in the blood) have been associated with extremely high doses of exogenous pancreatic enzymes. If the pancreatin preparations are held in the mouth before swallowing, stomatitis can result as can ulcerations and irritation of the mucosa, particularly in infants, in whom pancreatin may also cause perianal soreness.l~ol It is not known whether pancreatin given to pregnant women can harm the fetus, because animal reproductive studies have not been conducted. Therefore, pancreatin should probably not be used during pregnancy.2o1Also, because whether pancreatin is distributed into mother's milk is not known, caution should be exercised with use of this substance in nursing women.2o1 Sneezing, lacrimation, rash, and other hypersensitivity reactions have been reported in sensitive individuals. Pancrelipase (and any other enzyme derived from pork sources) is contraindicated in those who are hypersensitive or allergic to pork products. Enzymes should not be used by hemophiliacs, nor immediately before or after those surgical procedures with an increased risk of bleeding. Trypsin is especially contraindicated in those with blood-clotting mechanism disorders, in liver disease, and as an aerosol within a week of pulmonary hemorrhage.' A note about supplement safety: During the last few years, there has been increased concern regarding mad cow disease (also called bovine spongform encephalopathy [BSE]).In humans, this disease is called CreutzfeldtJakob disease (CJD). The disorder can be caused by eating beef that is infected with BSE, but it can also be transmitted through corneal transplant tissue, from hormone extracts (such as human growth hormone), and

possibly from ingesting contaminated glandular products. It may take as long as 20 years after infection for the characteristic symptoms of CJD to manifest. Since 1995, FDA has required that manufacturers of supplements ensure that any animal products used in their supplements do not originate in BSE countries (which as of this writing include the European Union countries and Japan).202Unfortunately, there is no test to see whether a supplement is infected with BSE. On an "up" note, the FDA considers tissues from cow pancreas (the source of some pancreatic enzymes) to be "low In addition, many manufacturers use pork sources for pancreatic enzymes. For anyone who is concerned about pancreatic supplements the National Nutritional Foods Association suggests checking the supplement's label to see whether a bovine source and a country of origin are listed.204If neither is indicated on the label, one can contact the manufacturer. One should also contact the manufacturer to see what measures they use to ensure BSE-free products.

Enzyme Enemas Enzyme enemas can sometimes cause the rectum or anus to itch or b u m . However, these are only minimal side effects in relation to the positive benefits obtained.

Topical Application Enzymatic activity directed toward proteinaceous components of the epithelium can cause irritation. For example, prolonged skin contact with proteolytic enzymes may cause irritation of the skin, mucous membranes of the throat, nose, and eyes.lW

Injectable Enzymes Injectable forms require more care, which is why they are normally administered in a hospital setting. Chymotrypsin, when injected, can occasionally create anaphylactic reactions.' Trypsin is more toxic when injected, and rapid infusion is far more toxic than slower infusion.' In addition, trypsin must not be administered intravenously.' Further, intradermal or scratch testing is advised before parenteral administration.' Other contraindications to trypsin's use are pork allergy and pancreatitis. It should be remembered that, at the beginning of therapy, an individual's symptoms may occasionally become more severe. This is a sign that a therapeutic reaction is occurring and should be evaluated positively. The medication need not be discontinued, although a temporary reduction in dose might be advisable.

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135. Mahr H. Zur enzymtherapie entzundlicher venenerkrankungen der tiefen beinvenenthrombose und des postthrombotischen syndroms. Erfahrungsheilkunde 1983;117. 136.Maehder K. Enzymtherapie venoser gefasserkrankungen. Die Arztpraxis 1972;2. 137. Kluken N. Venose krankheiten in klinik und praxis, systemische enzymtherapie, medizinische woche Baden-Baden, 1990.Natur und Ganzheitsmedizin 1991;28. 138. Vogler W. Enzymtherapie. Hessen Hausarz 1989;4116. 139. Rokitansky 0, v. Ozontherapie und enzyme bei der chronischarteriellen verschlusskrankeit. Systemische Enzymtherapie am 31.10.90. Medizinixhe Woche, Baden-Baden, 1990, Natur- und Ganzheitsmedizin 1991;(Suppl 14). 140.Keim H, et al. Methode zur lindecung der lymphstauung am arm nach behandlung des mammakarzinoms. Rontgenberichte 1972;l:l. 141. Scheef W, Pischnamazadeh M. Proteolytische enzyme als einfache und sichere methode zur verhutung des lymphodems nach ablatio mammae. Med Welt 1984;35:1032. 142. Streichhan P, Inderst R. Konventionelle und enzymtherapeutische massnahmen bei der behandlung brustkrebsbedingter armlymphodeme. Der Prakt Arzt 1991;13:37-38. 143. Ransberger K, Stauder G, Streichhan P. Wissenschaftliche monographie zur praklinik Wobenzym@N, Mulsal@N, Phlogenzym@. Forum Medizin, 1991. 144. Konig W. Erfahrungen der Robert-Janker-Klinik, Bonn, mit systemischer enzymtherapie und emulgierten vitaminen. Acta Medica Emperica 1988;3711. 145. Konig W. Proteolytische enzyme verhindern lymphodem. In Medizinische Enzym-Forschungesgellschaft e.V., ed.Systemische Enzymtherapie, Symposium Munich, 1986; Medizin Aktuell (Enzyme Series,) Informed International Congress Report 53,1986. 146. Uffelmann K, Vogler W, Fruth C. Der eisatz hydrolytischer enzyme beim extraartikularen rheumatismus. Allgemeinmedizin 1990;19:151-153. 147. Vogler W. Der stellenwert der enzymtherapie bei entzundlichrheumatischen erkrankungen. Systemische Enzymtherapie, Medizinische Woche, Baden-Baden, 1990. Natur- und Ganzheitsmedizin 1991;223. 148. Miehlke K. Enzymtherapie bei rheumatoider arthritis. Natur- und Ganzheitsmedizin 1988;108-111. 149. Inderst R. Enzymtherapie. Erfahrungsheilkunde 1989;38:305. 150. Horger I, Moro V, van Schaik W. Zirkulierende immunkomplexe bei polyarthritis-patienten.Natur-und Ganzheitsmedizin 1988; 1:117. 151. Steffen C, Smolen J, Miehlke K, Horger J, Menzel J. Enzymtherapie im vergleich mit immunkiomplexbestimmungenbei chonischler polyarthritis. Zeitschr f Rheumatologie 1985;44:51. 152. Reinbold H. Die biologische alternative in der therapie entzundlicher rheumatischer erkrankungen. Zeitschr Allgemeinmedizin 1981;34. 153. Reinbold H. Die therapie des morbus bechterew mit enzymen. Erfahrungsheilkunde 1980;lO. 154. Ekerot L, Ohlsson K, Necking L. Elimination of protease-inhibitor complexes from the arthritic joint. Int J Tissue React 1985;7 391-395. 155. Ballachi G. Hydrolytische enzyme bei aktivierten polyarthrosen. Rheuma 1988;8. 156. Goebel KM. Enzymtherapie bei spondylitis ankylosans. Lecture given at 17th Systemische Enzymtherapie Symposium, Vienna, 1991. 157. Horger I. Enzymtherapie bei einem rheumakollektiv. Therapiewoche 1983;33:3948. 158. Panijel M. Entzundlich-rheumatische erkrankungen. Zeitschr f Allgemeinmedizin 1985;61:1305.

Pancreatic Enzymes 159. Steffen C, Zeitlhofer J, Menzel J, Smolen J. Die antigen-induzierte experimentelle arthritis als prufverfahren fur entzundungshemmung durch oral appliqierte substanzen. Zeitschr Rheumatologie 1979;38:264. 160. Miehlke K. Enzymtherapie bei chronischer polyarthritis. Der Kassenarzt 1989;46. 161. Miehlke K. Rheumabahandlung mit enzymen ist mehr als nur antiphlogistische therapie. Lecture given at 17th Systemische Enzymtherapie Symposium, Vienna, 1991. 162. Klein G, Schwann H, Kullich W. Enzymtherapie bei chronischer polyarthritis. Natur-und Ganzheitsmedizin 1988;1:112. 163. Klein K. Behandlung der rheumatoiden arthritis mit Wobenzym@ im vergleich zur basistherapie mit gold. Lecture given at 17th Systemische Enzymtherapie Symposium, Vienna, 1991. 164. Singer F. Aktivierte arthrosen knorpelschonend behandeln. Lecture given at 10th Systemische Enzymtherapie Symposium, Frankfurt, Germany, 1990. 165. Tilwe GH, Beria S, Tutrakhia NH,et al. Efficacy and tolerability of oral enzyme therapy as compared to diclofenac in active osteoarthritis of knee joint an open randomized controlled clinical trial. J Assoc Physicians India 2001;49617-621. 166. Masuhr KF. Eurologie. Stuttgart Hippokrates, 1989. 167. Neuhofer CH, van Schaik W, Stauder G, Pollinger W. Pathogenetic immune complexes in MS: their elimination by hydrolytic enzymes. A therapeutic approach. International Multiple Sclerosis Conference, Rome. Bologna: Monduzzi Editore SPA, 1988. 168. Ransberger K, van Schaik W. Enzymtherapie bei multipler sklerose. Der Kassenarz 1986;41:42. 169. Neuhofer CH. Enzymtherpie bei multipler sklerose. Hufeland J 1986;47. 170. Neuhofer CH. Systemische enzymtherapie bei encephalomyelitis disseminata. Der Prakt Arzt 1991;702. 171. Dirringer H. Unkonventionelle viruserkrankungen. Bundesgesundhbl1990;33188. 172. Inderst R, Ransberger K, Brand G. Fortschritte in der therapie der envorbenen immunschwache durch naturheilkundliche methoden. Naturheilpraxis 1988;41:1050. 173. Jager H, Popescu M, Samtleben W, Stauder G. Hydrolytic enzymes as biological response modifiers (BRM) in HIV-infection. In San Marino Conferences-highlights in medical virology, immunology and oncology, vol. 1. Oxford Pergamon Press, 1988. 174. Jager H. Hydrolytische enzyme in der therapie der hiverkrankung. Zeitschr Allgemeinmedizin 1990;19:160. 175. Ransberger K. Naturheilkundliche therapie von AIDS mit enzympraparaten. Forum des Prakt und Allgemeinarztes 1988; Heft 4.27, Jahrgang, April 1988. 176. Scheef W. Gutartige veranderungen der weiblichen brust. Therapiewoche 1985;5090. 177. Inderst R. Colitis ulcerosa und morbus crohn systemische enzymtherapie, medizinische woche Baden-Baden, 1990. Naturund Ganzheitsmedizin 1991;228. 178. Neuhofer CH. Autoimmunerkrankungen. Multiple sklerose, amyotrophe lateralsklerose, colitis ulcerosa. Erfahrungsheilkunde 1988;38:451. 179. Trolli PA, Conwell DL, Zuccaro G Jr. Pancreatic enzyme therapy and nutritional status of outpatients with chronic pancreatitis. Gastroenterol N u s 2001;24:84-87. 180. Kleine MW,Pabst H. Enzymtherapie der lateralen sprunggelenksdistorsion. Dtsch Z Sportzmed 1990;41:126-134. 181. Kleine MW. Therapie des herpes zoster mit proteolytischen. Enzymen Therapiewoche 1987;37110&1112. 182. Kelley WD. One answer to cancer. Ontario, OR The Kelley Foundation, 1974. 183. Pancreatic Cancer: Pancreatica-FAQ. Available online at: http://www..pancreaticn.org/faq.html[accessed April 10,20031.

184. Lillemoe LD, Ye0 CJ, Cameron JL. Pancreatic cancer : state-of-theart care. CA Cancer J Clin 2000;50241-268. 185. Gonzalez NJ, Isaacs LL. Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer 1999;33117-124. 186. Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base report on pancreatic cancer. Cancer 1995;761671-1677. 187. Preventing heart disease and stroke: Addressing the nation‘s leading killers. National Center for Chronic Disease Prevention and Health Promotion. Centers for Disease Control and Preventing. Available online at www.cdc.gov/nccdphp/nng/nng-cvd.htm [accessed April 10,20031. 188. 1991 Heart and stroke facts. Dallas: American Heart Association, 1991. 189. Haid-Fischer F, Haid H. Venenerkrankungen. Stuttgart: Thieme, 1985. 190. Brudnak MA, Rimland B, Kerry RE, et al. Enzyme-based therapy for autism spectrum disorders-is it worth another look? Med Hypotheses 2002;58:422-428. 191. Worschhauser S. [Conservativetherapy for sports injuries. Enzyme preparations for therapy and prophylaxis.] Allgemeinmedizin 1990;19:173-177. 192. Stauder G, Pollinger W, Fruth C. Systemische Enzymetherapie. Eine Ubersicht uber Neue Klinische Studient. Allgemein Medizin 1990;19:18&191. 193. Inderst R. Enzymtherapie bei Gefasserkrankungen [Enzyme therapy in vascular diseases]. Allgemein Medizin 1990;19: 154-157. 194. Wrba H. Kombinierte tumortherapie. Stuttgart: Hippokrates, 1992. 195. Klein G, Pollmann G, Kullich W. Klinische Erfahrungen mit der Enzymtherapie bei Patienten mit Chronischer Polyarthritis im Vergleich Zur Oralen Goldtherapie [Clinical experience with enzyme therapy in patients with rheumatoid arthritis in comparison with oral gold]. Allgemein Medizin 1990;19:144-147. 196. Gallacchi G. Der Einsatz Hydrolytischer Enzyme bei der Aktivierten Arthrose [The use of hydrolytic enzymes in activated arthrosis]. Allgemein Medizin 1990;19:148-150. 197. Dittmar F-W, Luh W, Phillipp E.Wobenzym@zur Behandlung der Mastopathie. Working paper, 1993. 198. Wolf M, Ransberger K. Enzyme therapy. Los Angeles: Regent House, 1972. 199. Sears A, Walsh G. Biotechnology in the feed industry: proceedings of Alltech’s ninth annual symposium. Nicholasville, KY Alltech Technical Publ, 1993. 200. Ramsden WH, Moya EF, Littlewood JM. Colonic wall thickness, pancreatic enzyme dose and type of preparation in cystic fibrosis. Arch Dis Child 1998;79:339-343. 201. McEvoy GK, ed. AHFS ’94 Drug Information, American Hospital Formulary Service. Bethesda, MD: American Society of Hospital Pharmacists, 1994. 202. Number of reported cases of bovine spongiform encephalopathy (BSE) worldwide. Office International des epizooties. Available [accessed April 10, online at www.oie.int/engln~/en-esbmo~ide.htm 20031. 203. Letter to Reiterate Certain Public health and safety concerns to firms manufacturing or importing dietary supplements that contain specific bovine tissues, US Food and Drug Administration, Center for Food Safety and Applied Nutrition, November 14,2000. Available online at wwzu.http:/~m.cfsan.fda.gov/-dms/dspltro5.html [accessed April 10,20031. 204. Mad Cow Disease and dietary supplements. National Nutritional Foods Association (“FA). Available online at http://www.nnfn. org/seruies/publication/fux/2001/02-20-01.hfm [accessed April 10, 20031.

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~~

Cichoke, AJ. The complete book of enzyme therapy. New York Avery Publishing, 1999. Cichoke AJ. Enzymes and enzyme therapy: how to jump start your way to lifelong good health, ed 2. New Canaan, CT: Keats, ZOOO. Cichoke AJ.Acute trauma and systemic enzyme therapy. Portland, OR Seven C's Publishing, 1993.

Cichoke AJ. A new look at chronic disorders and enzyme therapy. Portland, OR: Seven C's Publishing, 1993. Cichoke AJ. A new look at enzyme therapy. Portland, OR Seven C's Publishing, 1993.

Phage Therapy: Bacteriophages as Natural, Self-Limiting Antibiotics Elizabeth Kutter. PhI) CHAPTER CONTENTS Introduction

1147

Historic Context 1147 Discovery 1147 Early Research 1147 Initial Attempts at Commercialization 1148 Specific Problems of Early Phage Therapy Work 1149

Toxicology 1158 Drug Interactions 1159 Conclusion

Bacteriophage Physiology 1149 Properties of Phages 1150 Phages and the Immune System

Clinical Applications 1153 Current Research 1153 Bacterial Pathogenicity 1157 Advantages of Phages 1158

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1152

INTRODUCTlON Phage therapy involves the use of specific virusesviruses that can attack only bacteria-to kill pathogenic microorganisms. The art was first developed early in the twentieth century, but since the advent of chemical antibiotics in the 1940s, it has been little used in the West. Today, however, the growing incidence of bacteria that are resistant to most or all available antibiotics is leading to widespread renewed research interest in the possibilities of phage Most of the recent articles appearing in the West reflect little knowledge of the extensive Eastern European research and clinical utilization of phage therapy. The good clinical results of Eastern European research provide a substantial basis for optimism and complement the limited animal work in the West. We need to draw as much as possible on the largely unknown body of knowledge that has accumulated in Poland and the former Soviet Union as we again explore phage therapy and to give credit where it is due for the many years of hard, careful work in the field even though it has primarily been done in a clinical rather than controlled-research mode. This chapter has been written to put phage therapy into historical and ecologic context and to explore some of the most interesting and extensive research in Eastern Europe, with the hope that

this modality will soon be available for implementation by physicians of all schools.

HISTORIC CONTEXT Discovery More than a century ago, Hankinlo reported that the waters of the Ganges and Jumna rivers in India had a marked antibacterial action that could pass through a porcelain filter, and then could be destroyed by boiling. He particularly studied the water’s effects on Vibrio cholerue and suggested that the substance responsible was what kept cholera epidemics from being spread by ingestion of the water of these rivers. However, he did not explore the phenomenon further. Edward Twort and Felix d’Herelle independently reported the isolation of filterable entities capable of lysing bacterial cultures and of producing small cleared areas on bacterial cultures, implying that discrete particles were involved.ll They are jointly given credit for the discovery of bacteriophages.

Early Research It was d’Herelle, a Canadian working at the Pasteur Institute in Paris, who gave these newly discovered organisms the name bacteriophages-using the suffix phage 1147

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”not in its strict sense of to eat, but in that of developing at the expense He carefully characterized them as viruses that multiply in bacteria, and he worked out the details of infection of different bacterial hosts by various phages under a variety of environmental conditions. The 90th Annual Meeting of the British Medical Association in Glasgow featured a very interesting discussion among d’Herelle, Twort, and several other eminent scientists of the day on the nature and properties of bacteriophages. The main question was whether the observed bacteriolytic principle was an enzyme produced by bacterial activity or a form of tiny virus. Gradually, it became clear that the phage is indeed viral in nature, able to reproduce and direct the synthesis of its own enzymes. DHerelle summarized the early phage work in a 300-page book, The Bacteriophage: Its Role in Immunity.12 He wrote classic descriptions of plaque formation and composition, infective centers, the lysis process, host specificity of adsorption and multiplication, the dependence of phage production on the precise state of the host, isolation of phages from sources of infectious bacteria, and the factors controlling stability of the free phage. He quickly became fascinated with the apparent role of phages in the natural control of microbial infections. He noted, for example, the frequent specificities of the phages isolated from recuperating patients for disease organism infecting them and the rather rapid variations over time of the phage populations. Throughout his life, he worked to develop the therapeutic potential of properly selected phages against the most devastating health problem of the day. However, he initially focused on simply understanding phage biology. Thus, the first known report of successful phage therapy came from Bruynoghe and Maisin,13who used phage to treat staphylococcal skin infections. After much travel, including the study of epidemics in Latin America and a year at the Pasteur branch in Saigon, d’Herelle left the Pasteur Institute in 1922. He worked in Holland and then became employed as a health officer by the League of Nations, based in Alexandria, Egypt. Phage therapy and sanitation measures were the primary tools in his arsenal to deal with major outbreaks of infectious disease throughout the Middle East and India. In 1928, he was invited to Stanford to give the prestigious Lane lectures; his discussions were published as the monograph The Bacteriophage and its Clinical Applicati~ns.’~ He gave many lectures for medical schools and societies as he crossed the country. He accepted a regular faculty position at Yale, where he was supported by George Smith, translator of his first two books into English. DHerelle continued to spend summers in Paris working with the phage company he had established there and returned permanently to France in 1933, with excursions to Tbilisi, Georgia, to help establish phage work there.

George Eliava, director of the Georgian Institute of Microbiology, saw bacteriocidal action of the water of the Koura River in Tbilisi (Tiflis) that he could not explain until he became familiar with d’Herelle’s work while spending 1920 to 1921 at the Pasteur Institute. He became a very early collaborator of d’Herelle’s; several of his phage papers are cited by d’Herelle.12 The two developed the dream of founding an Institute of Bacteriophage Research in Tbilisi-to be a world center of phage therapy for infectious disease, including scientific and industrial facilities, and supplied with its own experimental clinics. The dream quickly became a reality through the support of Sergo Oqonikidze, the People’s Commissar of Heavy Industry, despite KGB opposition to this ”foreign project.’’ A large campus on the river Mtkvari was allotted for the project in 1926. DHerelle sent supplies, equipment, and library materials. In 1934 and 1935, he visited Tbilisi for a total of 6 months and wrote a book, The Bacteriophage and the Phenomenon of R e c o ~ e t ywhich , ~ ~ was translated into Russian by Eliava. DHerelle intended to move to Georgia; in fact, a cottage built for his use still stands on the institute’s grounds. However, in 1937, Eliava was arrested as a ”people’s enemy” by Beria, then head of the KGB in Georgia and soon to direct the Soviet KGB as Stalin’s much-feared henchman. Eliava was soon executed, sharing the tragic fate of many Georgian and Russian progressive intellectuals of the time, and d’Herelle, disillusioned, never returned to Georgia. However, their institute survived and is still functioning at its original site on the Mtkvari (which it now shares with the more modem Institute of Molecular Biology & Biophysics and Institute of Animal Physiology). In 1938, the Bacteriophage Institute was merged with the Institute of Microbiology & Epidemiology under the direction of the People’s Commissary of Health of Georgia. In 1951, it was formally transferred to the AllUnion Ministry of Health set of Institutes of Vaccine and Sera, taking on the leadership role in providing bacteriophages for therapy and bacterial typing throughout the former Soviet Union. Under orders from the Ministry of Health, hundreds of thousands of samples of pathogenic bacteria were sent to the institute from throughout the Soviet Union to isolate more effective phage strains and to better characterize their usefulness. In 1988, an official Scientific Industrial Union ”Bacteriophage” was formed, centered in Tbilisi with branches in Ufa, Habarovsk, and Ghorki. Their later work is further discussed here.

Initial Attempts at Commercialization From the beginning, a major commercial use of phages has been for bacterial identification through a process called phage typing-the use of patterns of sensitivity to a specific battery of phages to precisely identify microbial strains. This technique takes advantage of the fine

Phage Therapy: Ba

specificity of many phages for their hosts and is still in common use around the world. However, the sophisticated ability of phages to destroy their bacterial hosts can also have a very negative commercial impact; phage contaminants occasionally spread havoc and financial disaster for the various fermentation industries that depend on bacteria, such as cheese production and fermentative synthesis of chemicals and medications.16 Phage therapy has been evaluated extensively, with many successes being reported for a variety of diseases, including dysentery, typhoid and paratyphoid fevers, pyogenic and urinary tract infections, and cholera. Phages have been given orally, through colon infusion, and as aerosols as well as poured directly into lesions. They have also been given as injections: intradermal, intravascular, intramuscular, intraduodenal, intraperitoneal, and even into the lung, carotid artery, and pericardium. The early strong interest in phage therapy is reflected in some 800 papers published on the topic between 1917 and 1956. Many of these works have been reviewed in some detail by Ackermann and DuBow.I7 The reported results were quite variable. Many of the physicians and entrepreneurs who initially became excited by the potential clinical implications jumped into applications with very little understanding of phages, microbiology, or basic scientific process. Thus, many of the studies were anecdotal and/or poorly controlled; many of the failures were predictable, and some of the reported successes did not make much scientific sense. Often, uncharacterized phages, at unknown concentrations, were given to patients without specific bacteriologic diagnosis, and there is no mention of follow-up, controls, or placebos. Much of the understanding gained by d’Herelle was ignored in this early work, and inappropriate methods of preparation, “preservatives,” and storage procedures were often used. On one occasion, d’Herelle reported testing 20 preparations from various companies and finding that not one of them contained active phages! On another occasion, a preparation was advertised as containing a number of different phages, but it turned out that the technician responsible had decided it was easier to grow them up in one large batch than in separate batches. Not surprisingly, a check of the product showed that one phage had out-competed all the others, and this was not, in fact, a polyvalent preparation. In general, there was no quality control except in a few research tenters. Large clinical studies were rare, and the results of those that were carried out were largely inaccessible outside Eastern Europe.

Specific Problems of Early Phage Therapy Work Many still believe (erroneously)that phage therapy was proven not to work; however, it simply was never

adequately researched, and the work that was done well is not known widely enough. It is thus important to carefully consider the reasons for the early problems and the question of efficacy. They were as follows: Paucity of understanding of the heterogeneity and ecology of either the phages or the bacteria involved Failure to select phages of high virulence against the target bacteria before using them in patients Use of single phages in infections that involved mixtures of different bacterial species and strains Emergence of resistant bacterial strains, which can occur through selection of resistant mutants (a common occurrence if only one phage strain is used against a particular bacterium) or through lysogenization (if temperate phages are used, as discussed later) Failure to appropriately characterize or titer phage preparations, some of which were totally inactive Failure to neutralize gastic pH prior to oral phage administration Inactivation of phages by both specific and nonspecific factors in bodily fluids Liberation of endotoxins as a consequence of widespread lysis of bacteria within the body (the herxheimer reaction), which can lead to toxic shock (which can also be caused by antibiotics) Lack of availability or reliability of bacterial laboratories for carefully iden-g the pathogens involved (necessitatedby the relative specificity of phage therapy)

BACTERIOPHAGE PHYSIOLOGY Viruses are like spaceships that are able to carry genetic material between susceptible cells and then reproduce in those cells, just as human immunodeficiency virus (HIV) specifically infects human T lymphocytes that carry the CD4 surface protein. In the case of bacteriophages, the targets are specific kinds of bacterial cells; they cannot infect the cells of more complex organisms. Each virus consists of a piece of genetic information, determining all of the properties of the virus, which is carried around packaged in a protein coat (Figure 113-1). Most phages have tails, the tips of which have the ability to bind to specific molecules on the surfaces of their target bacteria (Figure 113-2). The viral DNA is then ejected through the tail into the host cell, where it directs the production of progeny phages; often more than 100 are produced in just half an hour. Each strain of bacteria has characteristic protein, carbohydrate, and lipopolysaccharide molecules present in large quantities on its surface. These molecules are involved in forming pores, motility, and binding of the bacteria to particular surfaces. Each such molecule can act as a receptor for particular phages. Development of resistance to a particular phage generally reflects mutational loss of its specific receptor; this

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is then transferred to a fresh culture of the bacteria in a liquid medium, allowing the culturing of a homogeneous stock of that particular phage, whose properties can then be studied.

Properties of Phages

Figure 113-1

Phage diagram (bacteriophage T4).

Figure 113-2 Electron micrograph of phage infecting a bacterium.

loss often has negative effects on the bacterium and does not protect it against the many other phages that use different receptors. Each kind of bacterium has its own phages, which can be isolated wherever that bacterium grows: from sewage, feces, soil, even ocean depths and hot springs. The process of isolation is easy. The sample is placed in an appropriate salt solution; the supernatant is separated and then is passed through a filter with a pore size small enough to remove the bacteria. The solution is then mixed (at several different dilutions) with a culture of the bacteria in question. A few drops are spread on a block of appropriate nutrient-agar medium. The next day, a dense lawn of bacteria is seen, dotted with round cleared areas called plaques. Each plaque contains about a billion phages, all of them progeny of a single initial phage that multiplied at a high rate and destroyed the bacteria there in the process. An individual plaque

One major source of confusion in the early phage work was the perception that all phages were fundamentally similar, though subject to adaptive change according to the recent conditions of growth. One consequence of this belief was that new phages were often isolated for each series of experiments, so there was little continuity or basis for comparison. Phages specific for virtually every studied bacterial species have now been isolated, but few have been well classified. A second early source of confusion affecting therapeutic use of phages was the question whether the lytic principle termed bacteriophage simply reflected an inherent property of the specific bacteria or required regular reinfection by an external agent. During the 1930s and 1940s, it became increasingly clear that in some senses both were true-that there were in fact two quite fundamentally different groups of bacteriophages. Lytic phages always have to infect from outside, reprogram the host cell, and release a burst of phage through breaking open, or lysing, the cell after a relatively fixed interval. Temperate phages, on the other hand, have another option; they can actually integrate their DNA into the host DNA, much as HIV can integrate the DNA copy of its RNA. Key technical developments that helped clarify the general nature and properties of bacteriophages were (2) the concentration and purification of some large phages by means of very-high-speed centrifugation and the demonstration that they contained equal amounts of DNA and proteinls and (2) visualization of phages by means of the electron microscope (EM).'9,20 Soon after these developments, RuskaZ1reported the first attempts to use the electron microscope for phage systematics. This has since become a key tool of the field.17 Each phage was found to have its own specific shape and size, from the "lunar lander"-style complexity of T4 and its relatives to the globular heads with long or short tails of lambda and T7, to the small filamentous phages that looked much like bacterial pili (Figure 113-3).

Lytic Phages A much better understanding of the interactions between lytic phages and bacteria began with one-step growth curve experiment^.^,^^ These demonstrated an eclipse period, during which the DNA began replicating and there were no free phages in the cell; a period of accumulation of intracellular phages; and a lysis process that released the phage to go in search of new hosts. This phage infection cycle is illustrated in Figure 113-4.

Phage Therapy: Bacteriophages as Natural, Self-Limiting Antibiotics

In 1943, an event occurred that was to have a major impact on the orientation of phage research in the United States and much of western Europe, strongly shifting the emphasis from practical applications to basic science. Physicist-turned-phage - - biologist - Max Delbruck

d M

0 Mi

0 L

0 CY

Lysogenic Phages SSVl Figure 113-3

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met with Alfred Hershey and Salvador Luria to form the “Phage Group,” which eventually expanded largely through the influence of the summer “Phage Course” at Cold Spring Harbor, Long Island, in 1945. The influence of this group on the origins of molecular biology has been well d o c ~ u n e n t e d . ~A~ major , ~ ~ element of the successes of phages as model systems for working out fundamental biologic principles was that Delbruck persuaded most phage biologists in the United States to focus on one bacterial host (Escherichiu coli B) and seven of its lytic phages. These were arbitrarily chosen and named types T1 through T7. As it turned out, T2, T4,and T6 were quite similar to one another, defining a family now called the T-men phages. These phages were key in demonstrating that DNA is the genetic material, that viruses can encode enzymes, that gene expression is mediated through special copies in the form of ”messenger RNA,” that the genetic code is triplet in nature, and many other fundamental concepts. The negative side of this strong focus on a few phages growing under rich laboratory conditions, however, was that there was very little study or awareness of the ranges, roles, and properties of bacteriophages in the natural environment, or of potential applications.

LI

II Various phages.

The integration of lysogenic phage DNA into the host DNAleadsto virtually permanent association of a prophage

I

I

I

I

I

5

10

15

20

25

Minutes after Infection Figure 113-4 Bacteriophageintracellular growth cycle. Noteworthy features: nucleolytic action on host chromosome furnishes DNA precursors; replicating DNA is much longer than virion DNA; several phagecoded proteins become associated with the host membrane: maturation of phage head occurs at a membrane site.

I

Pharmacology of Natural Medicines with a specific bacterium and all its progeny. The prophage diredsthe synthesis of a repressor, which blocks the reading of the rest of its own genes and also those of any closely related lysogenic phages-a major advantage for the bacterial cell, giving it protection it from infection by a signrficant class of phages as well as a potential weapon against many competing bacteria. Occasionally, a prophage escapes from regulation by the repressor, cuts its DNA back out of the genome by a sort of site-specific recombination, and goes ahead to make progeny phage and lyse open the cell. Sometimes the cutting-out process makes mistakes, and a few bacterial genes are carried along with the phage DNA to its new host; this process, called transduction, plays a significant role in bacterial genetic exchange. Such lysogenic phages are bad candidates for phage therapy, owing both to their mode of inducing resistance and to the fact that they can potentially lead to transfer of genes involved in bacterial pathogenicity; this issue is discussed in more detail later. However, their specificity often makes them very useful for phage typing in distinguishing between bacterial strains.

PHAGES AND THE IMMUNE SYSTEM A number of early experiments involving the injection of phages into animals led to the widespread impression that phage therapy could not in fact succeed because the phages were too rapidly cleared by the immune system; the remarks in thisregard by Gunter StentZ6had a particularly strong impact on the phage community. Two early experiments involving rabbits showed rapid disappearance of the particular phages used from the blood and organs, but long-term survival in the Subsequent experiments in rats and mice also showed rapid loss from the circulation. When Nungester and WatrousZ9ainjected lo9 plaque-forming units (pfu) of a staphylococcal (staph) phage intravenously into albino rats, a blood concentration of only 105 pfu/ml was seen after 5 minutes, which dropped to 40 pfu/ml by 2 hours. There is one major concern with these early articles on phage pharmacokinetics in animal models: The experiments were done in the absence of host bacteria in which the phage could multiply and find protection. Furthermore, they were carried out by the very unnatural mode of intravenous injection, exposing the phage almost immediately to the reticuloendothelial system. Results of many later studies have made it clear that phages are often seen in the mammal circulatory system; however, this generally occurs under conditions in which they are entering the circulatory system from some sort of reservoir in other tissues and in which the mammal is dealing with an infection by a bacterium that they can infect-precisely the sort of situation seen in gene therapy as currently practiced in Eastern Europe.

One of the best early sets of experiments was published in 1943 by the noted Harvard bacteriologist Renb Dubos and They injected white mice intracerebrally with a dose of a smooth Shigella dysenteriae strain that was sufficient to kill more than 95% of the mice in 2 to 5 days and treated them with intraperitoneal injection of a phage mixture isolated from New York City sewage, grown in the same bacteria, and purified only by sterile filtration. With no treatment or when treated with filtrates of staph cultures or with heat-killed phage, only 3 of 84 mice (3.6%)survived; in contrast, 46 of 64 (72%) of the mice given lo7 to lo9phages survived. These researchers also carried out pharmacokinetic studies. When phages were given to uninfected mice, they appeared in the blood stream almost immediately, but the levels started to drop within hours and very few were seen in the brain. In the infected animals, however, brain phage levels quickly greatly exceeded blood levels; around lo7 to 109phage/g were often seen between 8 and 114 hours after administration, with the level starting to drop anywhere between 75 and 138 hours. After the first 18 hours, blood levels were far lower than brain levels, but phages were still present in blood at 104 to lo5 phage/ml in those subjects in which the brain levels were still more than lo9phage/g. These findings clearly established that (1)the phages themselves were responsible, not something in the lysate that just stimulated normal immune mechanisms, (2) phages could rapidly find and multiply in foci of infection anywhere in the body, and (3) phages could be maintained in the circulation as long as there was a privileged reservoir of infection where phages were continually being produced. Without providing data or pharmacokinetics, the researchers mention that the mice were also rescued by phages administered subcutaneously or intravenously but not by stomach tube or in drinking water. Carefully controlled experiments carried out in 1943 through 1945 by Henry Morton and Enrique Perez-Otero at the University of Pennsylvania supported those of Dubos et al. These investigators further showed the lack of any protection when lysates of phage with inappropriate host specificities were used. A final review authorized by the Council on Pharmacy and Chemistry discussed the major advantages of phages, such as the ability to replicate into problem areas and treat localized infections that are relatively inaccessible via the circulatory system and the fact that their high specificity greatly aided in reducing later resistance problems.32The review also emphasized that almost all of the earlier research had been so poorly conceived and/or carried out that it offered no proof either for or against the promise of phages as antibiotics. The background of these experiments, as described by Hausler,” is very interesting. In 1942, both The Lancet and the British Medical Journal published editorials about

Phage Therapy: Bacteriophages as Natural, Self-Limiting Antibiotics

the apparently successful use of antidysentery phages by the Soviet military in the Middle and Far East. The U.S. National Research Council Committee on Medical Research (NRC/CMR) immediately approached Morris Rakieten, d‘Herelle’s close associate in his phage work at Yale, to discuss the possibilities offered by phages for dealing with this perpetual scourge of armies. (The German army was already producing massive amounts of phage, without prior efforts at research, because 155,000 German soldiers had been affected by dysentery in World War I, with 8600 deaths). By November of 1942, the NRC was supporting antidysentery phage research in several top U.S. bacteriology laboratories that do not appear to have previously been engaged in phage work; the group at University of Pennsylvania mentions that their work was started in November of 1942 with NRC support, but they were initially required to keep the results secret. Others involved in this NRC-supported work were Arthur Schade and Leona Caroline at the Overly Biochemical Research Foundation, New York. U.S. work with dysentery phages largely ended in 1944, when the end of World War I1 made penicillin available to the general public. The military secrecy, the end of the war emergency funding, the rapid rise in antibiotic availability and their broad spectra, and Max Delbruck’s success in persuading the phage community to shift its focus to basic mechanistic research involving a few model systems probably all contributed to the fact that there was little U.S. follow-up to these interesting and successful results; few people even knew about them or about two successful subsequent human applications. Penicillin worked against only some kinds of bacterial infections. Typhus, for example, was not treatable, and some excellent phage work was carried out in the interim. It was known that the strains of Salmonella fyphi that created the main pathogenicity problems were those carrying one particular antigen, named Vi (for “virulence”). In 1936, a pair of Canadians had identified phages specific against the Vi antigen. In the early 1940s, Walter Ward,%of the Los Angeles County Hospital, was trying to deal with repeated serious outbreaks of typhoid that were killing one in five of those afflicted. He tested the Vi-specific phages against mouse typhus and found that the death rate fell to 6%, versus 93% in the controls. Some of his colleagues then used these phages to treat patients with typhoid; only 3 of their 56 treated patients died, compared with the 20% mortality for the other treatments available at the time?5 Most impressively, the rest of the patients receiving phage therapy rapidly changed from being largely comatose to full of vigor, with renewed appetite, in 24 to 48 hours. In 1948-1949, near Montreal, Desranleau treated nearly 100 patients with dysentery by giving them a cocktail of six Vi-specific phages, and the death rate dropped from

20% to 2%. By 1947, however, chloramphenicolhad been shown to work well against typhoid, and it was much easier for pharmaceutical companies to deal with, so that seems to have been the end of phage clinical trials in the Western hemisphere. The high specificity of phages still plays a strong role in the Phage Typing sets used for detecting and following problem strains of such bacteria as Shigella, Salmonella, and Cholera, but phage therapy itself is only beginning to stage a comeback.

CLINICAL APPLICATIONS Current Research The growing understanding of phage biology has the potential to facilitate more rational thinking about the therapeutic process and the selection of therapeutic phages. However, there was generally little interaction between those who were so effectively using phages as tools to understand molecular biology and those working on phage ecology and therapeutic applications. Many in the latter group were spurred on by a concern about the rising incidence of nosocomial infections and of bacteria resistant against most or all known antibiotics as well as by the fact that phages are far more effective than antibiotics in areas of the body where the circulation is bad and in not disrupting normal flora. This strong sense of the potential importance of phages was particularly seen in Poland, France, Switzerland,and the former Soviet Union, where use of therapeutic phages never fully died out and there has been some ongoing research and clinical experience. In France, Dr. JeanFranqois Vieu led the therapeutic phage efforts until his retirement some 15 years ago. He worked in the Service des Entirobactiries of the Pasteur Institute in Paris and, for example, prepared Pseudomonas phages on a caseby-case basis for patients. His experience there is discussed in two arti~les.~J’ In Vevey, Switzerland, the small pharmaceutical firm Saphal made “Coliphagine,” “Intestiphagine,” ”Pyophagine,” and “Staphagine” in drinkable and injectable forms, salves, and sprays into the 1960~:~The owner, Harrmann Glauser, had been encouraged and trained by d’Herelle’s old colleague Paul Hauduroy, who had become a professor of microbiology at the University of Lausanne during the second world war, The preparations were officially approved and were paid for by insurance there. Phage therapy was used extensively in many parts of eastern Europe as a regular part of clinical practice, and companies in Russia now make phages for this purpose. However, most of the research and much of the phage preparation came under the direction of key centers in Tbilisi, Georgia, and Wroclaw, Poland. In both cases, the close interactions between research scientists and physicians play an important role in the high degree

Pharmacology of Natural Medicines

of success obtained, just as appears to have been the case for d’Herelle’s early work.

Institute of Immunology and Experimental Medicine, Polish Academy of Sciences The most detailed publications documenting phage therapy have come from the group led by Stefan Slopek, director for many years of the Institute of Immunology and Experimental Medicine, Polish Academy of Sciences, Wroclaw. They published a series of extensive papers describing work carried out from 1981 to 1986 with 550 patients.This set of studies involved 10 Polish medical centers-including the Wroclaw Medical Academy Institute of Surgery Cardiosurgery Clinic, Children’s Surgery Clinic, and Orthopedic Clinic, the Institute of Internal Diseases Nephrology Clinic, and Clinic of Pulmonary Diseases. The patients ranged in age from 1 week to 86 years. In 518 of the cases, phage use followed unsuccessful treatment with all available other antibiotics. The major categories of infections treated were as follows: Long-persisting suppurative fistulas Septicemia Abscesses Respiratory tract suppurative infections and bronchopneumonia Purulent peritonitis Furunculosis

In a final summary paper, these investigators carefully analyzed the results with regard to such factors as nature and severity of the infection and monoinfection versus infection with multiple bacteria.40Rates of success ranged from 75% to 100% (92%overall), as measured by marked improvement, wound healing, and disappearance of titratable bacteria; 84% of subjects demonstrated full elimination of the suppurative process and healing of local wounds. Infants and children did particularly well. Not surprisingly, the poorest results occurred in elderly patients and those in the final stages of extended serious illnesses, two groups with weakened immune systems and generally poor resistance. The bacteriophages all came from the extensive collection of the Bacteriophage Laboratory of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw. In the later studies, some of the specific phages were named. All were virulent, capable of completely lysing the bacteria being treated. In the first study alone, 259 different phages were tested (116 for Staphylococcus, 42 for Klebsiella, 11 for Proteus, 39 for Escherichia, 30 for Shigella, 20 for Pseudomonas, and 1 for Salmonella); 40% of them were selected to be used directly for therapy. All of the treatment was conducted in a research mode, with the phage prepared at the institute by standard methods and tested for sterility.

Treatment generally involved 10 ml of sterile phage lysate given orally half an hour before each meal, with gastric juices neutralized by the taking of (basic) Vichy water, baking soda, or gelatum. In addition, phagesoaked compresses were generally applied three times a day where dictated by localized infection. Treatment ran for 1.5 to 14 weeks, averaging 5.3 weeks. For intestinal problems, short treatment sufficed, whereas long-term use was necessary for such problems as pneumonia with pleural fistula and pyogenic arthritis. Bacterial levels and phage sensitivity were continually monitored, and the phage(s) were changed if the bacteria lost their sensitivity. Therapy was generally continued for 2 weeks beyond the last positive test result for the bacteria. Few side effects were observed; those that were seen seemed to be directly associated with the therapeutic process. On about days 3 to 5, pain in the liver area lasting several hours was often reported. The investigators suggested that this pain might be related to the extensive liberation of endotoxins as the phage is destroying the bacteria most effectively. In severe cases of sepsis, patients often ran a fever for 24 hours on about days 7 to 8.38 Various methods of administration were successfully used, including oral, aerosols, and infusion either rectal or in surgical wounds. Intravenous administration was not recommended for fear of possible toxic shock from bacterial debris in the l y s a t e ~ However, .~~ it was clear that the phages readily entered the body from the digestive tract and multiplied internally wherever appropriate bacteria were present, as measured by their presence in blood and urine as well as by therapeutic effects.4l This interesting and rather unexpected finding has been replicated in many studies and systems.“-45 Detailed notes were kept throughout on each patient. The final evaluating therapist also filled out a special inquiry form that was sent to the Polish Academy of Science research team along with the notes. The Computer Center at Wroclaw Technical University carried out extensive analyses of the data. These researchers used the categories established in the World Health Organization (WHO) (1977) International Classification of Diseases in assessing results. They also looked at the effects of age, severity of initial condition, type(s) of bacteria involved, length of treatment, and other concomitant treatments. The reports included many specific details on individual patients that helped to give some insight into the ways phage therapy was used as well as an in-depth analysis of difficult cases. After Slopek’s retirement, Dr. Beatta WeberDabrowska carried on with the treatment work, publishing a summary in English of the results for the next 16 patients.& In 1998, immunologist A. G6rski took over as Institute director and revived a strong focus on phage work, with special emphasis on the immunologic

consequences of phage treatment?’ These researchers are also now working with the basic phage group of Dr.M. Lobocka in Warsaw to sequence and further characterize key phages-an important step in eventually making them available to the outside world.

Bacteriophage Institute, Tbilisi The most extensive and least widely known work on phage therapy was carried out under the auspices of the Bacteriophage Institute at Tbilisi, in the former Soviet republic of Georgia. According to various physicians there, phage therapy is part of the general standard of care, used especially extensively in pediatric, bum, and surgical hospital settings. Phage preparation was carried out on an industrial scale, employing 700 people in the factory and several hundred more in the research arm of the Institute just before the breakup of the Soviet Union, and many tons of a variety of products were regularly shipped throughout the former Soviet Union. They were available both over the counter and through physicians. The largest use was in hospitals, to treat both primary and nosocomial infections, alone or in conjunction with other antibiotics and particularly when antibioticresistant organisms were found. The military is still one of the strongest supporters of phage therapy research and development, because phages have proved so useful for wound and burn infections as well as for preventing debilitating gastrointestinal epidemics among the troops. The International Science and Technology Centers program, set up jointly by the United States, Europe, and Japan to give constructive opportunities to scientists formerly working with Soviet military projects, is now one of the strongest supporters of basic and applied research in this area in Tbilisi. From the Bacteriophage Institute’s inception, the industrial part was run on a self-supporting basis, and its scientific branch was government supported. The latter included the electron microscope facility, permanent strain collection, laboratories studying phages of the enterobacteria, staphylococci, and pseudomonads, and formulating new phage cocktails, and p u p s involved in immunology,vaccine production, Lactobacillus work, and other therapeutic approaches. The Institute also carried out the very extensive studies needed for approval by the Ministry of Health in Moscow of each new strain, therapeutic cocktail, and means of delivery. This careful study of the host range, lytic spectrum, cross-resistance, and other fundamental properties of the phages being used was a major factor in the reported successes of the phage therapy work carried out through the institute, as was their method for initially selectinghighly virulent phages from among the myriad potentially available against any given host. All of the phages used for therapy are lytic, avoiding the problems engendered by lysogeny. The problems of bacterial resistance were

largely solved through the use of well-chosen mixtures of phages with different receptor specificities against each type of bacterium as well as of phages against the various bacteria likely to be causing the problem in multiple infections. The situation was further improved whenever the clinicians typed the pathogenic bacteria and monitored their phage sensitivity. Where necessary, new cocktails were then prepared to which the given bacteria were sensitive. Not infrequently, using a phage in conjunction with carefully chosen other antibiotics was shown to give better results than either the phage or the antibiotic alone. The depth and extent of the work involved are very impressive. For example, in 1983 through 1985 alone, the Institute’s Laboratory of Morphology and Biology of Bacteriophages carried out studies of growth, biochemical features, and phage sensitivity on 2038 strains of Stuphylococcus, 1128 of Streptococcus, 328 of Proteus, 373 of P. ueruginosa, and 622 of Clostridium received from clinics and hospitals in towns across the former Soviet Union. New broader-acting phage strains were isolated using these and other institute cultures and were included in a reformulation of their extensively used Piophage preparation; it now inhibited 71% of their Staphylococcus strains instead of 58%; 76% of Pseudomonas instead of 55%;51% of E. coli instead of 11%;30%of Proteus instead of 3%: 60% of Streptococcus instead of 38%; and 80% of Enterococcus instead of 3%.& In the years since, the formulation has continued to be improved on the basis of further studies, and phages against Klebsiellu and Acinetobucter have been isolated and developed into therapeutic preparations. The other major product, used very extensively by the military, by pediatric centers, and in regions with extensive diarrheal problems, is IntestiPhge, which consists of 23 different phages active against a range of enteric bacteria and was often prepared in tablet form. A good deal of work has gone into developing and providing the documentation for Ministry of HeaIth approval of specialized new delivery systems, such as a spray for use in respiratory tract infections, in treating the incision area before surgery, and in sanitation of hospital problem areas such as operating rooms. An enteric-coated pill was also developed, using phage strains that could survive the drying process, and accounted for the bulk of the shipments to other parts of the former Soviet Union. Much of the focus in the last 20 years has been on combating nosocomial infections, in which multidrugresistant organisms have become a particularly lethal problem and it is also easier to cany out proper long-term research. Clinical studies of the effectivenessof the phage treatment and appropriate protocols were carried out in collaboration with a number of hospitals, but little has been published in accessible form. Zemphira Alavidze

Pharmacology of Natural Medicines

and her colleagues, who are currently doing most of the actual therapeutic development and clinical application, have manuscripts in preparation that describe their work in institutions such as the Leningrad (St. Petersburg) Intensive Burn Therapy Center, the Academy of Military Medicine in Leningrad, the Karan Trauma Center, and the Kemerovo Maternity Hospital. Some of the most intensive studies were carried out in Tbilisi at the Pediatric Hospital, the Burn Center, the Center for Sepsis, and the Institute for Surgery. Special mixtures were developed for dealing with strains causing nosocomial infections in various hospitals, and they were very effectively used in sanitizing operating rooms and equipment, water taps, and other sources of spread of the infections (most of them predominantly involving Staphylococcus). The number of sites testing positive for the problem bacteria decreased by orders of magnitude over the several months of the trial at each site. An exciting new product completed the approval process and was licensed in 2000 by the Georgian Ministry of Health. PhagoBioDerm is a biodegradable, nontoxic polymer composite that is impregnated with the Pyophage cocktail of phages, along with other antimicrobial age11ts.4~ Markoishvilim reported the results of a study of PhagoBioDerminvolving 107patients with ulcers that had failed to respond to conventional therapysystemic antibiotics, antibiotic-containing ointments, and various phlebotonic and vascular-protecting agents. The ulcers were treated with PhagoBioDerm alone or in combination with other interventions during 1999 and 2000. The wounds or ulcers healed completely in 70% of the 96 patients for whom there was follow-up data. In the 22 cases for which complete microbiologic analyses were available, healing was associated with the concomitant elimination or very marked reduction of the pathogenic bacteria in the ulcers.

Recent Work in the West Levin and Bull' and Barrow and Soothil14have provided good reviews of much of the animal research carried out in Britain and the United States since interest in the possibilities of phage therapy began to resurface in the early 1980s. The results, in general, are in very good agreement with the clinical work just described in terms of efficacy, safety, and importance of appropriate attention to the biology of the host-phage interactions, reinforcing trust in the reported extensive eastern European results. In Britain, Smith and H ~ g g i n s " carried ~~ out a series of excellent, well-controlled studies on the use of phages in systemic E. coli infections in mice and then in diarrhetic disease in young calves and pigs. For example, they found that injecting 106colony-forming units (CFUs) of a particular pathogenic strain intramuscularly killed 10 out of 10 mice, but none died if the researchers simultaneously injected 104 pfu of a phage selected against the

K1 capsule antigen of that bacterial strain. This phage treatment was more effective than using such antibiotics as tetracycline, streptomycin, ampicillin, and trimethoprim/ sulfafurazole. Furthermore, the resistant bacteria that emerged had lost their capsule and were far less virulent. In calves, these researchers found very high and specific levels of protection. They had to isolate different phages for each of their pathogenic bacterial strains, because they did not succeed in isolating phages specific for more general pathogenicity-related surface receptors such as the K88 or K99 adhesive fimbriae, which play key roles in attachment to the small intestine. Still, the phage was able to reduce the number of bacteria bound there by many orders of magnitude and to virtually stop the fluid loss. The results were particularly impressive if (1)the phage was present before or at the time of bacterial presentation and (2) multiple phages with different attachment specificities were used. Furthermore, the phages could be transferred from animal to animal, supporting the possibility of their prophylactic use in a herd. If the phages were given only after the development of diarrhea, the severity of the infection was still substantially reduced, and none of the animals Levin and Bull' carried out a detailed analysis of the population dynamics and tissue phage distribution of the 1982 Smith and Huggin@ study, which can be helpful in assessing the parameters involved in successful phage therapy and its apparent superiority to antibiotics. They have gone on to perform interesting animal studies of their own and conclude that phage therapy is at least well worth further study.' Barrow and So0thill4 carried out a series of studies preparatory to using phages for infections in bum patients. Using guinea pigs, they showed that skin graft rejection could be prevented by prior treatment with phages against Pseudomonas aeruginosu. They also saw excellent protection of mice against systemic infections with both Pseudomonas and Acinetobucter when appropriate phages were used.4 In the latter case, as few as 100 phages protected against infection with lo8 bacteriaseveral times the LDW(dose at which 50% of the subjects died)! Merrill et al5I have carried out a series of experiments designed to better the understanding of the interactions of phages with the human immune system, and helped Richard Carlton, MD, start a company called Exponential Therapeutics to explore the possibilities of phage therapy. They initially worked with lytic derivatives of the lysogenic phages lambda and P22-a poor choice for therapeutic use, as discussed earlier and later in this chapter-but they gathered some very interesting data about factors affecting interactions between these phages and the innate immune system and patented a process for isolating longer-circulating phages. They have now published successful animal studies with

Phage Therapy: Bacteriophages as Natural, Self-Limiting Antibiotics

phages against vancomycin-resistant Enterococcus, and Exponential Biotherapies has completed successful phase 1clinical trials with these phages.

Bacterial Pathogenicity Most bacteria are not pathogenic; in fact, they play crucial roles in the ecologic balance in the digestive system, mucous membranes, and all body surfaces. They often actually help protect against pathogens. This is one reason why broad-spectrum antibiotics have such a broad range of side effects and why more narrowly targeted bacteriocidal agents would be highly advantageous. Interestingly, most of the serious pathogens are close relatives of nonpathogenic strains. Studies clarifying the mechanisms of pathogenesis at the molecular level have progressed remarkably in recent years, crowned by the determination of the complete sequence of (nonpathogenic) E. coli K12 and several other bacterial species, and extensive cloning and sequencing of pathogenicity determinants. Generally, a number of genes are involved, and they are clustered in so-called pathogenicity islands, or Pais, which may be 50,000 to 200,000 base pairs long. They generally have some unique properties, indicating that the bacterium itself probably acquired them as a sort of “infectious disease” at some time in the past and then kept them because they helped the bacterium infect new ecologic niches where there was less competition. Many of these Pais are carried on small extrachromosomal circles of DNA called plusmids, which can also be carriers of drugresistance genes. Others reside in the chromosome, where they are often found embedded in defective lysogenic prophages that have lost some key genes in the process and cannot be induced to form phage particles. However, the prophages can sometimes recombine with related infecting phages. Therefore it makes sense to avoid using lysogenic phages or their lytic derivatives for phage therapy to avoid any chance of picking up and moving such pathogenicity islands. For bacteria in the human gut, pathogenicity involves the following two main factors: The production of toxin molecules, such as shiga toxin (from Shigellu and some pathogenic E. coli) or cholera toxin; these toxins mod* proteins in the target host cells and thereby cause the problem The acquisition of cell-surface adhesions that allow the bacterium to bind to specific receptor sites in the small intestine, rather than just moving on through to the colon They also all contain the components of so-called type 111 secretion machinery, related to those involved in the assembly of flagella (for motility) and of filamentous phages, and instrumental in many plant pathogens. For all the pathogenic enteric bacteria, the infection process

triggers changes in the neighboring intestinal cells. They include degeneration of the microvilli, formation of individual ”pedestals” cupping each bacterium above the cell surface, and, in the case of Sulrnonel2u and Shigellu, induction of cell-signaling molecules that trigger engulfment of the bacterium and its subsequent growth inside the cell. Recently, E. coli 0157 has been the subject of much concern, its contamination of such products as hamburgers and unpasteurized fruit juices leading to serious problems. Particularly in young children and the elderly, deaths have occurred from hemorrhagic colitis (bloody diarrhea) and from hemolytic-uremic syndrome, in which the kidneys are affected. Antibiotic therapy has shown no benefit; it is actually generally contraindicated because it leads to increased toxin release.52My colleagues and I have isolated a phage from sheep resistant to inoculation with E. coli 0157H7 at the U.S. Department of Agriculture in College Station, Texas. A major concern of this facility is to eliminate this human pathogen, which is found in the normal flora of one quarter of the cattle in the United States, from which it contaminates water sources and creates massive recalls for industries from meat packers to apple juice producers; this phage turns out to also be T4-like and to infect virtually all tested 0157 strains. Studies are suggesting that this and additional phages we have isolated from sheep are good candidates for controlling 0157 in the gastrointestinal tracts of nun in ant^.^^,^

T-Even Phages A substantial fraction of the phages in the therapeutic mixes for gram-negative bacteria are relatives of bacteriophage T4, which has played such a key role in the development of molecular biology. This family is often called the T-even phages, from an historical accident reflecting the fact that T2, T4, and T6 from the original collection of Delbruck‘s Phage Group all turned out to be related. Large sets of T-even phages have been isolated for study from all over the world: Long Island sewage treatment plants, animals in the Denver Zoo, and patients with dysentery in eastern Europe (the last using Shigellu as host). The laboratory of Harald Bruessow at Nestle, Inc., in Lausanne, Switzerland, has become interested in the possibility of using phages to treat infant diarrhea in underdeveloped countries-a longstanding concern of theirs, and no other approaches have worked for the 27% that involve coliform bacteria. These researchers have isolated a number of broad-spectrum phages from patients at the world-famous Diarrheal Center in Bangladesh; all of them are T4-like They have now selected a group of therapeutic candidates and are carrying out various in vitro and animal studies in preparation for potential human trials.

Pharmacology of Natural Medicines T4-like phages are found infecting all of the enteric bacteria and their relatives.57Most of the T-even phages use 5-hydroxymethylcytosine instead of cytosine in their DNA, which protects them against most of the restriction enzymes that bacteria make to protect themselves against invaders and gives them a much more effective host range. T4's entire DNA sequence is known, and we know a great deal about its infection process in standard laboratory conditions and about the methods it uses to target bacteria so effectively.5859We can potentially use this knowledge to develop more targeted approaches to phage therapy, particularly as more is learned about the similaritiesand differences in its extended family.60*61 We know that different members of the T-even phage family use different outer membrane proteins and oligosaccharides as their receptors, and we understand the tail-fiber structures involved well enough to potentially predict which phages will work on given bacteria and to engineer phages with new specificities.6*@ The T-even bacteriophages share a unique ability that contributes significantly to their widespread occurrence in nature and to their competitive advantage. There have still been far too few studies of T4 ecology and its behavior under conditions more closely approaching the natural environment and the circumstances it will encounter in phage therapy, often anaerobic and/or with frequent periods of starvation. The limited available information in that regard has been summarized by A variety of studies are shedding light on the ability of these highly virulent phages to coexist in balance with their hosts in nature. For example, they can reproduce in the absence of oxygen as long as their bacterial host has been growing anaerobically for several generations. They are also able to control the timing of lysis in response to the relative availability of bacterial hosts in their environment. When E . coli are singly infected with T4, they lyse after 25 to 30 minutes at body temperature in rich media, releasing about 100 to 200 phages/cell. However, when additional T-even phages attack the cell more than 4 minutes after the initial infection, the cell does not lyse at the normal time. Instead, it continues to make phages for as long as 6 h o ~ r s .We ~ ,have ~ ~ found that the phages can also survive for a period of time in a hibemation-like state inside starved cells, allowing their host to readapt when nutrients are again supplied, and produce a few additional phages. This is particularly interesting and important because bacteria undergo many drastic changes to survive periods of starvation that increase their resistance to a variety of environmental insults.% Thus, for many reasons, the T4-like phages make excellent candidates for therapeutic and prophylactic use against enteric and other gram-negative bacteria, and studies of their ecology and distribution are now being carried out with these goals in mind in Tbilisi,

Bangladesh, Lausanne, and College Station, Texas, and at The Evergreen State College.

Advantages of Phages Phages have many potential advantages, as follows: They are self-replicating but also self-limiting because they multiply only as long as sensitive bacteria are present. They can be targeted far more specifically than most antibiotics to the problem bacteria, causing much less damage to the normal microbial balance in the gut. The bacterial imbalance or "dysbiosis" caused by many antibiotic treatments can lead to serious secondary infections involving relatively resistant bacteria, and often increasing hospitalization time, expense, and mortality (see Chapters 12 and 14).Particular resultant problems are Pseudomonads, which are especially difficult to treat, and Clostridium dzficile, the cause of serious diarrhea and membranous c0litis.6~ Phages can often be targeted to receptors on the bacterial surface that are involved in pathogenesis, so any resistant mutants are attenuated in virulence. Few side effects have been reported for phage therapy. Phage therapy would be particularly useful for people with allergies to antibiotics. Appropriately selected phages can easily be used prophylactically to help prevent bacterial disease at times of exposure or to sanitize hospitals and help protect against hospital-acquired (nosocomial) infections. Especially for external applications, phages can be prepared fairly inexpensively and locally, facilitatingtheir potential applications to underserved populations. Phages can be used either independently or in conjunction with other antibiotics to help reduce the development of bacterial resistance.

TOXIC0LOGY From a clinical standpoint, phages appear to be very safe. This feature is not surprising, given that humans are exposed to phages from birth. Bergh et a P reported that nonpolluted water contains about 2 x 108phages/ml. Phages are normally found in the gastrointestinal tract, skin, urine, and mouth, where they are harbored in saliva and dental p l a q ~ e . ~They ~ - ~also l have been shown to be unintentional contaminants of sera and thence of commercially available vaccines,"-75 which were given dispensation to be sold despite this discovery because of the general consensus that phages are safe for humans. Extensive preclinical animal testing was required for approving new phage formulations in the former Soviet Union, but few of these studies were published. Bogovazova et a176*"evaluated the safety and efficacy of Klebsiella phages produced by the Russian company

Phage Therapy: Bacteriophages as Natural, Self-LimitingAntibiotics Immunopreparat. Pharmacokinetic and toxicologic studies using intramuscular, intraperitoneal, or intravenous administration of phages were carried out in mice and guinea pigs. The researchers found no signs of acute toxicity or gross or histologic changes, even using a dose/g 3500-fold higher than the projected human dose. They then evaluated the safety and efficacy of the phages in treating 109 patients infected with Klebsiellu. The phage preparation was reported to be nontoxic for humans and to be effective in treating Klebsiellu infections, as manifested by marked clinical improvements and bacterial clearance in the phage-treated patients. Side effects such as occasional liver pain and fever reported in the early days of Western phage therapy may have been due to bacterial byproducts contaminating phage preparations used i n t r a v e n o ~ s l yConcern . ~ ~ ~ for this possibility is a major reason that the Polish phage therapy group never administers their phages intravenously. The same is true for almost all of the therapeutic work carried out in Tbilisi and probably helps explain the group’s virtually total lack of significant problems. Because the phage readily enter the blood stream after infusion in or near wounds and other sites of localized infection and then travel to sites of infection throughout the body, as discussed previously in descriptions of the work by DuBow, there generally seems to be no particular reason for undergoing the extra risks of intravenous administration.

DRUG INTERACTIONS No negative effects on the efficacy or safety of other drugs have been reported as a result of phage administration in the long history of work in Eastern Europe. No systematic studies have been carried out in this regard, but phages are so specific in their actions that it is hard to see where such interactions might be predicted to occur. On the other hand, at least some antibiotics would tend to interfere with phage treatment of localized infections in areas with poor circulation, by killing off the most accessible of the bacteria in which the phages need to multiply as they work their way deeper into the lesion; this would be a particular problem in cases in which the phages can still attach and infect but cannot complete their replication cycle. (Many of the Georgian physicians believe that antibiotics should never be used topically for wounds and deep-seated infections, because the decrease in antibiotic concentration below the surface provides a strong selection for antibiotic resistance and this problem does not occur with phages.)

CONCLUSION Clearly the time has come to look more carefully at the potential of phage therapy, both by strongly supporting

new research and by scrutinizing the research already available: such as the very interesting human antityphoid phage research carried out in this country in the 1940s that has come to lighP5 as well as the earlier European work and the very extensive applications in the former Soviet Union. As Barrow and So0thill4conclude: Phage therapy can be very effective in certain conditions and has some unique advantages over antibiotics. With the increasing incidence of antibiotic-resistant bacteria and a deficit in the development of new classes of antibioticsto counteract them, there is a need to investigate the use of phage in a range of infections. Phages are quite specific as to the bacteria they attack, and the stipulations of Ackermann & DUBow[”~ are important here. The specificity of phages means that: Phages have to be tested against the patient’s bacteria] just as antibiotics [should be], and the indications have to be right, but this holds everywhere in medicine. However, phage therapy requires the creation of phage banks and a close collaboration between the clinician and the laboratory. Phages have at least one advantage. . . . While the concentration of antibiotics decreases from the moment of application, phage numbers should increase. Another advantage is that phages are able to spread and thus prevent disease. Nonetheless, much research remains to be done . . . on the stability of therapeutic preparations; clearance of phages from blood and tissues; their multiplication in the human body; inactivation by antibodies, serum or pus; and the release of bacterial endotoxins by lysis. . . . In addition, therapeutic phages should be characterized at least by electron microscopy.

With the exploding possibilities and decreasing costs of genomic analysis since the last edition of this book, it is now possible to perform at least partial genomic sequencing of phages to be included in general cocktails so as to know more about the phage families involved and exclude phages from temperate families and those likely to carry or acquire genes related to pathogenicity or toxin production; this is now standard done procedure for phages being developed in the West. Such modern techniques are now also being applied to some of the Georgian phage preparations with help from grants from the International Science and Technology Centers (ISTC) and Civilian Research and Development Foundation (CRDF) programs, both of which were set up to support civilian applications of science formerly funded by the Soviet military. This is an important step in considering the importation of such phages for topical use in the Western world. Although it seems premature to broadly introduce injectable phage preparations in the West without further extensive research, their carefully implemented use in external applications and for a variety of agricultural purposes could potentially help reduce the emergence of antibiotic-resistant strains and deal with problems we have difficulty handling today. Furthermore, compassionate use of appropriate phages seems warranted

Pharmacology of Natural Medicines

Special thanks to Drs. Liana Gachechiladze, Zemphira Alavidze, Davi Gamrekeli, Guram Gvasalia, Ramaz Katsarava, lnga Georgadze, Mzia Kutateladze, Rezo Adamia, Amiran Meipariani, Taras Gabisonia, Teimuraz and Nino Chanishvili and their colleagues in Tbilisi, and to Beata Weber-Dabrowski and Andre Gorski in Wroclaw for their

hospitality and efforts to help me understand the extensive therapeutic work carried out there. Others who have been particularly helpful with information and communication include Dr. Marina Shubladze, pediatrician in Tbilisi for 10 years, now residing in Seattle; Nino Mzavia, Nino Trapaidze, Timur and Natasha Zurabishvili, who have worked in my laboratoy ; Bill Summers (Yale), Hans-Wolfgang Ackermann (Lava1 University), Eduard Kellenberger (Basel) and Bruce Levin (Emory); Kathy d'Acci, clinical laboratoy director, St Peter's Hospital, Olympia; physicians Jess Spielholz, MD, and Robin Moore, ND; and especially, the many colleagues and students involved in our laboratory in Olympia, particularly Barbara Anderson, Burt Guttman, Pia Lippincot, Mark Mueller, Stacy Smith, Elizabeth and Chelsea Thomas, Jim Neitzel, Andrew Brabban, and Raul Raya.

1. Levin B, Bull JJ. Phage therapy revisited: the population biology of a bacterial infection and its treatment with bacteriophage and antibiotics.Am Nat 1996;147881-898. 2. LederbergJ. Smaller fleas ...ud infiniturn: therapeutic bacteriophage redux. Proc Natl Acad Sci U S A 1996;933167-3168. 3. Radetsky P.The good virus.Discover 1996;1750-58. 4. Barrow PA, Soothill JS. Bacteriophage therapy and prophylaxis: rediscovery and renewed assessment of the potential. Trends Microbiol1997;5:268-271. 5.Alisky J, Iczkonski K, Rapoport A, et al. Bacteriophage shows promise as antimicrobial agents. J Infection 1998;36:5-13. 6.Sulakvelidze A, Alavidze Z, Moms J. Bacteriophage therapy. Antimicrobial Agents Chemother 2001;45:649-659. 7.Summers WC. Felix d'Herelle and the origins of molecular biology. New Haven, CT: Yale University Press, 1999. 8. Kutter E, SulakvelidzeA. Bacteriophages: biology and applications. Boca Raton, FL: CRC Press, 2004. 9. Merril CR, M o l l D, Adhya SL. The prospect for bacteriophage therapy in Western medicine. Nat Rev Drug Discov 2003;2:489-497. 10. Hankin EH. L'action bactericide des eaux de la Jumna et du Gange sur le vibrion du cholera. Ann de l'lnst Pasteur 1896;10511. 11. D'Herelle F, Twort FW,Bordet J, et al. Discussion on the bacteriophage (bacteriolysin): from the Ninetieth Annual Meeting of the British Medical Association, Glasgow, July, 1922. Br Med J 1922;2:289-97; reproduced in Stent G. Papers on bacterial viruses, 2nd ed. Boston: Little, Brown, 1965. 12. DHerelle F (SmithGH, trans). The bacteriophage: its role in immunity. Baltimore: Williams & Wilkins, 1922. 13. Bruynoghe R, Maisin J. Essais de therapeutique au moyen du bacteriophage du staphylocoque. C R Soc Biol 1921;85:1120-1121. 14. DHerelle F. The bacteriophage and its clinical applications. Springfield, IL:CC Thomas, 1930. 15. Eliava G. Bakteriofagi fenomenvyzdorovieniya. Tbilisi, Georgia: Tbilis National University Publications, 1935. 16.Saunders ME. Bacteriophages in industrial fermentationsin. In Webster RG, Granoff A, eds. Encyclopedia of virology. San Diego: Academic Press, 1994116-121. 17. Ackermann HW,DuBow MS. V i s of prokaryotes. I. General properties of bacteriophages. In Practical applications of bacteriophages. Boca Raton, FL:CRC Press, 1987.

18. Schlesinger M. Reindarstellungeines bakteriophagen in mit freiem auge sichtbaren mengen. Biochem Z 1933;264:6. 19. Ruska H. Die sichtbarmachung der bakteriophagen lyse im ubermikroskop.Naturwissenxhaften 1940;28:45. 20. Pfankuch E, Kausche G. Isolierung U. Uebermikroskopische abbildung eines bakteriophagen. Natunvissemchaften 1940;28:46. 21. Ruska H. Ergeb. Hyg BakteriolImmunforsch Exp Ther 1943;25:437. 22. Ellis EL, Delbrueck M. The growth of bacteriophage. J Gen Physiol 1939;22:365-384. 23. Doermann AD. The intracellular growth of bacteriophages. I. Liberation of intracellular bacteriophage T4 by premature lysis with another phage or with cyanide. J Gen Physiol1952;35645-656. 24. Caims J, Stent GS, Watson JD. Phage and the origins of molecular biology. Long Island, Ny: Cold Spring Harbor Laboratory Press, 1966. 25. Fischer E, Lipson C. Thinking about science: Max Delbrueck and the origins of molecular biology. New Yolk Norton, 1988. 26.Stent G. Molecular biology of bacterial viruses. San Francisco: WH Freeman, 1963:8. 27. Appelmans R. Le bacteriophage dans l'organisme. C R Seances Soc Biol Fil 1921;85722-724. 28. Evans AC. Inactivationof antis~ptococcusbacteriophageby animal fluids. Public Health Reports 1933;48:4114. Cited by Merril C, S Adhya S. Phage therapy. In Calendar R, ed. The Bacteriophages ed 2. Oxford: Oxford University Press, in press. 29.Nungester WJ, Watrous RM. Accumulation of bacteriophage in spleen and liver following its intravenous inoculation. Proc Soc Exp Biol Med 193431:901-905. 30.Geier MR, Trigg ME,Merril CR. Fate of bacteriophage lambda in non-immune germ-free mice. Nature 1973;246:221-223. 31. Dubos RJ, Straus JH, Pierce C. The multiplication of bacteriophage in vivo and its protective effects against an experimental infection with Shigellu dysenteriue. J Exp Med 1943;78:161-168. 32.Morton HE, Engely FB. Dysentery bacteriophage: review of the literature on its prophylactic and therapeutic uses in man and in experimental infections in animals. J Am Med Assoc 1945;127 584-891. 33. Hausler T. Gesund durch Viren. Miinchen, Germany: Piper, 2003. 34. Ward WE. Protective action of VI bacteriophage in Eberthella typhi infections in mice. J Infect Dis 1943;72:172-176.

in cases in which bacteria resistant to all available antibiotics are causing life-threatening illness. Phages are especially useful in dealing with recalcitrant nosocomial infections, in which large numbers of particularly vulnerable people are being exposed to the same strains of bacteria ina closed hospital setting. In this case, the environment as well as the patients can be effectively treated.

Acknowledgments

Phage Therapy: Bacteriophages as Natural, Self-Limiting Antibiotics 35. Knouf EG, Ward WE, Reichle PA, et al. Treatment of typhoid fever with type specific bacteriophage. J Am Med Assoc 1946;132 134-138. 36. Vieu JF. Les bacteriophages. In Fabre J, ed. Traite de therapeutique, Serums et vaccins. Paris: Flammarion, 1975:337-430. 37. Vieu JF, Guillermet F, Minck R, et al. Donn&s actuelles sur les applications therapeutiques des bacteriophages. Bull Acad Natl Med 1979;163:61. 38. Slopek S, Durlakova I, Weber-Dabrowska B, et al. Results of bacteriophage treatment of suppurative bacterial infections. I. General evaluation of the results. Arch Immunol Ther Exp 1983;31:267-291. 39. Slopek S, Kucharewica-Krukowska A, Weber-Dabrowska 8, et al. Results of bacteriophage treatment of suppurative bacterial infections. Vl. Analysis of treatment of suppurative staphylococcalinfections. Arch Immunol Ther Exp 1985;33261-273. 40. Slopek S, Weber-Dabrowska B, Dabrowski M, et al. Results of bacteriophage treatment of suppurative bacterial infections in the years 1981-1986.Arch Immunol Ther Exp 1987;35:569-583. 41. Weber-Dabrowska B, Dabrowski M, Slopek S. Studies on bacteriophage penetration in patients subjected to phage therapy. Arch Immunol Ther Exp (Warsz) 1987;35:363-368. 42. Smith HW, Huggins RB. Successful treatment of experimental E. coli infections in mice using phage: its general superiority over antibiotics. J Gen Microbiology 1982;128:307-318. 43. Smith HW, Huggins RB. Effectiveness of phages in treating experimental E. coli diarrhoea in calves, piglets and lambs. J Gen Microbiology 1983;129:2659-2675. 44.Smith HW, Huggins RB. The control of experimental E. coli diarrhea in calves by means of bacteriophage. J Gen Microbiology 1987; 13311111-1126. 45. Smith HW, Huggins RB, Shaw KM. Factors influencing the survival and multiplication of bacteriophages in calves and in their environment. J Gen Microbiology 1987;1331127-1135. 46. Weber-Dabrowska 8, Mulczyk M, Gorski A. Bacteriophage therapy of bacterial infections: an update of our institute’s experience. Arch Immunol Ther Exp 2000;48:547-551. 47. Weber-Dabrowska B, Zimecki M, Mdczyk M, et al. Effect of phage therapy on the turnover and function of peripheral neutrophils. FEMS Immunol Med Microbiol2002;34:135-138. 48. Alavidze Z. Personal communication, 1998. 49. Katsarava R, Beridze V, Arabuli N, et al. Amino acid-based bioanalogous polymers. Synthesis and study of regular poly(ester amide)s based on bis(a-amino acid), alpha, omega-alkylene diesters, and aliphatic dicarboxylic acids. J Polymer Sci 1999;37391407. 50. Markoishvili K., Tsitlanadze G, Katsarava R, et al. A novel sustained-release matrix based on biodegradable poly(ester amide)s and impregnated with bacteriophages and an antibiotic shows promise in management of infected venous stasis ulcers and other poorly healing wounds. Int J Dermatol2002;41:453458. 51. Merrill C, Biswis B, Carlton R, et al. Long-cirdating bacteriophages as antibacterial agents. Proc Natl Acad Sci U S A 1996;93: 3188-3192. 52.Greenwald D, Brandt L. Recognizing E. coli 0157:H7 infection. Hosp Pract (Off Ed) 1997;32123-6,129-30,133. 53. Wendelsdorf K, Hoyle N, DiSalvo S, et al. Characterization of bacteriophages against Pseudomonus ueruginosu for therapeutic uses. Presented to American Society for Microbiology General Meeting, New Orleans, May 2427,2004. 54. Raya R, Dyen M, Callaway TR, et al. Isolation of phages from sheep and their use in in vitro and in vivo assays to reduce contamination levels of Escherichiu coli 0157H7 in ruminants. Presented to American Society for Microbiology General Meeting, Washington DC,May 18-22,2003. 55. Chibani-chennoufi S, Sidoti J, Bruttin A, et al. Isolation of T4like bacteriophages from the stool of pediatric diarrhea patients in Bangladesh. J Bacteriol2004;186:8287-8294.

56. Chibani-Chennoufi S, Sidoti J, Bruttin A, et al. In vitro and in vivo bacteriolytic activities of Escherichin coli phages: implications for phage therapy. Antimicrob Agents Chemother 2004;48:2558-2269. 57. Ackermann H, Krisch H. A catalogue of T4-type bacteriophages. Archi Virol1997;142:2329-2345. 58.Kutter E, Kellenberger E, Carlson K, et al. Effects of bacterial growth conditions and physiology on T4 infection. In Karam JD, Drake J, eds. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology, 1994406-420. 59. Kutter E, Stidham T, Guttman B, et al. Genomic map of bacteriophage T4. In Karam JD, Drake J, eds. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology, 1994~491-519. 60. Jacob F, Monod J. Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol1961;3:318-356. 61.Kutter E, Gachechiladze K, Poglazov A, et al. Evolution of T4-related phages. Virus Genes 1995;11:285-297. 62. Henning U, Hashemolhosseini S. Receptor recognition by T-even-type coliphages. In Karam JD, Drake J, eds. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology, 1994291-298. 63. Tetart F, Desplats C, Krisch HM. Genome plasticity in the distal tail fiber locus of the T-even bacteriophage: recombination between conserved motifs swaps adhesin specificity.J Mol Biol1998;282:543-556. 64.Doermann AH. Lysis and lysis inhibition with E. coli bacteriophage. J Bacteriol 1948;55:257-275. 65.Abedon S. Lysis and the interaction between free phages and infected cells. In Karam JD,Drake, J, eds. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology, 1994397-405. 66. Kolter R. Life and death in stationary phase. ASM News 1992; 58:75-79. 67. Fekety R. Antibiotic-associated diarrhea and colitis. Cur Opin Infect Dis 1995;8:391-397. 68. Bergh 0,Borsheim KY, Bratbak G, et al. High abundance of viruses found in aquatic environments. Nature 1989;340:467-468. 69. Caldwell JA. Bacteriologic and bacteriophagic study of infected urines. J Infect Dis 1928;43:353-362. 70. Yeung MK, Kozelsky CS. Transfection of Actinornyces spp. by genomic DNA of bacteriophages from human dental plaque. Plasmid 1997;37141-153. 71. Bachrach G, Leizerovici-Zigmond M, Zlotkin A, et al. Bacteriophage isolation from human saliva. Lett Appl Microbiol 2003;36:50-53. 72. Merril CR, Friedman TB, Attallah AF, et al. Isolation of bacteriophages from commercial sera. In Vitro 1972;8:91-93. 73. Geier MR, Attallah AF, Menil CR. Characterization of Escherichin coli bacterial viruses in commercial sera. In Vitro 1975;11:55-58. 74. Milch H, Fomosi F. Bacteriophage contamination in live poliovirus vaccine. J Biol Stand 1975;3307-310. 75. Moody EE, Trousdale MD, Jorgensen JH, et al. Bacteriophages and endotoxin in licensed live-virus vaccines. J Infect Dis 1975;131: 588-591. 76. Bogovazova GG, Voroshilova NN, Bondarenko VM. The efficacy of Klebsiellu pneumonine bacteriophage in the therapy of experimental Klebsiellu infection. Z h Mikrobiol Epidemiol Immunobiol 1991;5-8. 77.Bogovazova GG, Voroshilova NN, Bondarenko VM, et al. [Immunobiological properties and therapeutic effectiveness of preparations from Klebsiellu bacteriophages.] Zh Mikrobiol Epidemiol Immunobiol1992;Mar:30-33. 78. Larkum NW. Bacteriophage as a substitute for typhoid vaccine. J Bacteriol1929;1742. 79. Larkum NW. Bacteriophage from Public Health standpoint. Am J Pub Health 1929;19:31-36. 80.King WE, Boyd DA, Conlin JH. The cause of local reactions following the administration of Stuphylococcirs bacteriophage. Am J Clin Pathol1934;4336-345.

Phosphat idylserine Parris

M.Kidd. PhD

CHAPTER CONTENTS Introduction 1163

Clinical Applications 1164

Physiologic Roles 1163

Dosage 1164

Pharmacology

Toxicology and Drug Interactions 1164

1163

INTRODUCTION Phosphatidylserine ("1 is a phospholipid substance ubiquitous in all known life forms, including all human are moleCdeS/ each with a characteristic headgroup, a middle piece derived from glycerol, and one or two tailpieces that usually consist of fatty acids.' Phospholipids have unique self-assembly and side-by-side packing properties that suit them for making cell membranes, the predominant cellular matrices on which energy is generated and utilized to promote metabolism. Phosphatidylserine is functionally and structurally indispensable for the membranes of all known cells; toget6er with other phospholipids PS makes up the bulk matrix of the membrane, into which are inserted a plethora of proteins that catalyze cell-level biochemistry. Phosphatidylserine's clinical benefits are most apparent in brain-related functions, including cognition, mood, and stress management? The substance occurs most abundantly in nervous tissues, wherein it facilitates electrical stimulus initiation, cell-tocell stimulus transmission by way of synapses, and electrical circuit integration across the brain? These prohomeostatic central nervous system benefits translate into a clinically unique, optimizing and revitalizing effect on the brain.

PHYSIOLOGIC ROLES The involvement of PS in life processes is profound, because all known life forms rely on the cell-level membrane systems for which PS is structurally and functionally essential. Through its characteristic headgroup shape and molecular charge distribution, PS defines many of the physical and chemical characteristics of cell

membranes.' Membrane-level processes specifically linked to PS include the f0llowing3r4: The movement of electrolytes into and out of cells (especially sodium, potassium, magne~ium)~ The reception of molecularmessages from outside the cell (receptor functions)6 Signal transduction, via the enzymes adenylate cyclase and protein kinase C73 The secretion process, via intracellular vesicle fusion with the outer cell membrane The recognition and recycling of dead and dying body cells by immune cells Another, perhaps underrecognized function of PS is in energetics. PS is utilized by mitochondria as a backup metabolic source of phospholipids for their membrane systems. The mitochondria1 membranes have a central role in generating the energy required to sustain life. Though not an enzyme, PS plays a quasicatalytic role in normal clotting. It also aids in the routine elimination of nonfunctional cells from the body. PS is normally located in the inner leaflet of the cell's outermost membrane, bordering the cytoplasm. It is held there by an active enzymatic process. As the cell begins to die, it can no longer keep the enzyme active, and PS flips from the inner leaflet to the outer. There it is recognized by circulating immune cells as a signal to eliminate the cell. This phenomenon facilitates timely clearance of nonproductive cells from the tissues.

PHARMACOLOGY The pharmacology of PS is consonant with its many known roles in membrane functions. These contribute to the efficiency of initiation and propagation of electrical 1163

stimuli, and their subsequent passage from cell to cell via chemical transmitter release at the synapses, involving membrane vesicle fusion also facilitated by PS. By enabling membrane-to-membrane fusion processes, PS uniquely facilitates the cellular secretion of transmitters, hormones, and other messenger substances.' In animal studies PS enhanced the synaptic release, turnover, or receptor actions of at least nine major transmitter system^.^,^ There are also indications that PS has a trophic effect in the brain. In aging rats, PS both conserved the youthful densities of receptors for nerve growth factor and protected the nerve circuits against the usual age-related atrophy.'O PS is well absorbed by mouth. With its absorption into the intestinal lining cells (enterocytes) the fatty acid component at position 2 in the molecule is cleaved from the glycerol backbone. After absorption, this fatty acid position as well as position 1 can be substituted with other fatty acids, in a kind of tail group shuffling facilitated by transacylase enzymes. This enables local modification of the molecule to facilitate its optimal use by that particular cell and tissue. The specific fatty acid profile of PS thus varies with the tissue location: For example, in the brain positions 1and 2 are mostly oleic acid (18:ln6) and docosahexaenoic acid (C22:6n3) (DHA), whereas in the platelets they are mostly stearic acid (18:O) and arachidonic acid (C20:4n6).11 Oripally,PS was prepared through laborious isolation from bovine brain, but with the advent of "mad cow disease'' alternative commercial preparation from soybean lecithin became necessary. Phosphatidylserine is now usually available as a PSenriched soy lecithin complex that also contains the other phospholipids phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol. Responsible manufacturers list the amounts of each on the product label. Although the earlier, definitive clinical trials on PS were conducted with bovine brain PS, which carries some DHA, the effectiveness of soy-derived phosphatidylserine has now been proven in double-blind However, other lines of research indicate that PS and DHA have synergistic roles in brain cell metabolism.15 With DHA so undersupplied in the Western diet, cosupplementation with DHA should predictably improve the overall benefit of PS supplementation.

CLINICAL APPLICATIONS The primary use of PS has been for the treatment of impaired mental function in the middle-aged and elderly, and especially for the mild to moderate cognitive impairments that presage Alzheimer's disease and other dementias. In 13doubleblind trials,PS administered as a dietary supplement produced consistent improvement in memory, learning, word recall, and other cognitive functions, most markedly in the middle-aged and elderly.l2JGB

For the most severely cognitively impaired, the benefits of PS generally were modest, but activities of daily living and other performance in daily life were someIn the largest such trial, a total times of 425 elderly patients (between ages 65 and 93 years) with moderate to severe senility were given either PS (100 mg three times daily) or a placebo for 6 Statistically sigruficant (p c 0.01) improvements in mental function, mood, and behavior were noted in the P S treated group compared with placebo. Phosphatidylserine appears to positively affect mood in depressed elderly s u b j e ~ t s . 2This ~~~ effect ~ ~ could also explain some of its positive effects on memory and cognition-the link between depression and impaired mental function is well-established in the geriatric population. In one small double-blind study of 10 depressed elderly patients, PS was shown to improve depressive symptoms, memory, and behavior.30Unlike typical antidepressant drugs, PS promoted this improvement without influencing the levels of serotonin and other monoamine neurotransmitters, suggesting another mechanism of action. Improved brain cell membrane function is one obvious rationale. Another is the repeated finding that PS can d u c e cortisol secretion in response to stress in both young and aging subjects21-3 Typically, cortisol levels are elevated in depressed patients. PS has improved adaptation to stressful challenges in four double-blind trials.13J4,31,32 Another, controlled study indicated PS lessened anxiety, insomnia, and difficulty with recall in feeble elderly women.% Dietary PS supports hypothalamic-pituitary-adrenal integration (the HPA axis)3335*36 as well as daily hormone rhythms from the pit~itary.3~ Human electroencephalographicand imaging studies indicate that PS improves energy production and utilization throughout the brak1.3~

DOSAGE ~

~~

The standard dosage recommendation for phosphatidylserine is 100 mg by mouth with meals, three times daily. Intake up to 500 mg daily is well tolerated.

TOXICOLOGY AND DRUG INTERACTIONS No adverse side effects or adverse drug interactions have been reported for PS. This is consistent with PS's being an orthomolecule, its molecular structure being familiar to living cells ever since life began. Animal studies determined that PS (bovine) given orally was extremely well tolerated. Dogs tolerated up to 70 g per day for 1 year without any apparent side effect. In more than 35 clinical studies PS was administered to more than 900 subjects, without major side effect at standard dosage (100 mg three times daily). Stomach upset has been reported, but very rarely.

Phosphatidylserine

1. Alberts B, Johnson A, Lewis J, et al. Molecular biology of the cell. New York: Garland Science, 2002. 2. Kidd PM. The phospholipids as anti-aging nutraceuticals. In Klatz RM, Goldman R, eds. Anti-aging medical therapeutics, vol IV. Chicago: American Academy of Anti-Aging Medicine, 2000. 3. Nunzi MG, et al. Therapeutic properties of phosphatidylserine in the aging brain. In Hanin I, Pepeu G, eds. Phospholipids: biochemical, pharmaceutical, and analytical considerations. New York: Plenum Press, 1990. 4. Borghese CM, Gomez RA, Ramirez OA. Phosphatidylserine increases hippocampal synaptic efficacy. Brain Res Bull 1993;31: 697-700. 5. Morrot G, Zachowski A, Devauz PF. Partial purification and characterization of the human erythrocyte Mg2tATPase: a candidate aminophospholipid translocase. FEBS Lett 1990;26629-32. 6. Cohen SA, Miiller WE. Age-related alterations of NMDA-receptor properties in the mouse forebrain: partial restoration by chronic phosphatidylserine treatment. Brain Res 1992;584:174180. 7. Malkiewicz-Wasowicz B, G m t 0, Stromme JH. The influence of changes in the phospholipid pattern of intact fibroblasts on the activities of four membrane-bound enzymes. Biochim Biophys Acta 1977;482358-369. 8. Newton AC, Johnson JE. Protein kinase C: a paradigm for regulation of protein function by two membrane-targeting modules. Biochim Biophys Acta 1998;1376155-172. 9. Samson JC. The biological basis of phosphatidylserine pharmacology. Clin Trials J 1987;241-8. 10. Nunzi MG, Guidolin D, Petrelli L, et al. Behavioral and morphofunctional correlates of brain aging: a pmlinical study with phosphatidylserine. In Bazan NG, Murphy MG, Toffano G, eds. Neurobiology of EssentialFatty Acids. New York Plenum Press, 1992. 11. Alling C, Jonsson G, Gustavsson L, et al. Anionic glycerophospholipids in platelets from alcoholics. Drug Alcohol Depend 1986; 16309-320. 12.Gindin J, Novikov M, Kedar D, et al. The effect of plant phosphatidylserine on age-associated memory impairment and mood in the functioning elderly. Rehovot, Israel Geriatric Institute for Education and Research, and Department of Geriatrics, Kaplan Hospital, 1995. 13. Fahey TD, Pearl MS. The hormonal and perceptive effects of phosphatidylserine administration during two weeks of resistive exercise-induced overtraining. Biol Sport 1998;15135-144. 14. Benton D, Donohue RT, SiLlance B, Nabb S. The influence of phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. Nutr Neurosci 2001;4169-178. 15. Salem N, Niebylski CD. The nervous system has an absolute molecular species requirement for proper function. Mol Membr Biol 1995;12131-134. 16. Amaducci L, Crook TH, Lippi A, et al. Use of phosphatidylserine in Alzheimer’s disease. Ann N Y Acad Sci 1991;640245-249. 17.Crook TH, Tinklenberg J, Yesavage J, et al. Effects of phosphatidylserine in age-associated memory impairment. Neurology 1991;41:644-649. 18. Crook T, Petrie W, Wells C, Massari DC.Effects of phosphatidylserine in Alzheimer’s disease. Psychopharmacol Bull 1992;28:61-66. 19. Crook TH. Treatment of age-related cognitive decline: effects of phosphatidylserine. In Klatz RM, Goldman R, eds. Anti-aging medical therapeutics, vol II. Chicago: American Academy of AntiAging Medicine, 1998. 20. Cennacchi T, Bertoldin T, Farina C, et al. Cognitive decline in the elderly: a double-blind, placebo-controlled multicenter study on

efficacy of phosphatidylserine administration. Aging (Milano) 1993;5:123-133. 21. Delwaide PJ, Gyselynck-Mambourg AM, Hurlet A, Ylieff M. Double-blind randomized controlled study of phosphatidylserine in demented patients. Acta Neurol Scand 1986;73136-140. 22. Engel RR, Satzger W, Gunther W, et al. Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type. Eur Neuropsychopharmacol 1992;2149-155. 23. Fuenfgeld EW. Double-blind study with phosphatidylserine (PS)in parkinsonian patients with senile dementia of Alzheimer’s type (SDAT).Prog Clin Biol Res 1989;3171235-1246. 24. Nerozzi D, Aceti F, Melia E, et al. [Phosphatidylserine and memory disorders in the aged]. Clin Ter 1987;120399-404. 25. Palmieri G, Palmieri R, Inzoli MR, et al. Double-blind controlled trial of phosphatidylserine in patients with senile mental deterioration. Clin Trials J 1987;2473-83. 26.Ransmayr G, Plorer S, Gerstenbrand F, Bauer G. Doubleblind placebo-controlled trial of phosphatidylserine in elderly patients with arteriosclerotic encephalopathy. Clin Trials J 1987; 2462-72. 27.Villardita C, Grioli S, Salmeri G, et al. Multicentre clinical trial of brain phosphatidylserine in elderly patients with intellectual deterioration. Clin Trials J 1987;2484-93. 28. Hershkowitz M, Fisher M, Bobrov D, et al. Long-term treatment of dementia Alzheimer type with phosphatidylserine: effect on cognitive functioning and performance in daily life. In Bazan NG, Horrocks LA, Toffano G, eds. Phospholipids in the nervous system: biochemical and molecular pathology. Padova: Liviana Press, 1989. 29. Amaducci L. Phosphatidylserine in the treatment of Alzheimer’s disease: results of a multicenter study. Psychopharmacol Bull 1988; 24:130-134. 30.Maggioni M, Picotti GB, Bondiolotti GP, et al. Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand 1990;81:265-270. 31. Monteleone P, Beinat L, Tanzillo C, et al. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans. Neuroendocrinology 1990;52:243-248. 32. Monteleone P, Maj M, Beinat L, et al. Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenalaxis in healthy men. Eur J Clin Phannacol 1992;42:385-388. 33.Nerozzi D, Magnani A, Sforza V, et al. Early cortisol escape phenomenon reversed by phosphatidylserine (Bros) in elderly normal subjects. Clin Trials J 1989;26:33-38. 34. Manfredi M, Pranteda G, Sacca A, et al. [Clinical results of phosphatidylserine in 40 climacteric and elderly women with psychoorganic disorders]. Clin Ter 1987;120:33-36. 35. Masturzo P,Murialdo G, de Palma D, et al. TSH circadian secretions in aged men and effect of phosphatidylserine treatment. Chronobiologia 1990;17267-274. 36. Rabboni M, Maggioni FS, Giannelli A, Beinat L. Neuroendocrine and behavioural effects of phosphatidylserine in elderly patients with abiotrophic or vascular dementia or mild depression. Clin Trials J 1990;27230-240. 37. Klinkhammer P, Szelies 8, Heiss WD. Effect of phosphatidylserine on cerebral glucose metabolism in Alzheimer’s disease. Dementia 1990;1:197-201.

Piper methysticum (Kava) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Analgesic Effects 1170 Anxiolytic Effects 1170 Antiischemia Effects 1 170

General Description 1167 Chemical Composition 1167 History and Folk Use 1167 The Kava Ceremony 1168 The Effects of Drinking Kava

Clinical Applications

1169

Pharmacology 1169 Isolated Kavalactones Compared with Crude Extracts 1169 Sedative Effects 1170

Piper rnethysticum (family: Piperaceae) Common name: kava

GENERAL DESCRIPTION Kavu is a hardy, slow-growing perennial that generally resembles other members of the pepper family. It is an attractive shrub and can attain heights of more than 9 feet. The plant does not have many leaves, but those it does have are thin, single, heart-shaped, alternate, petiolate, 4 to 10 inches long, and sometimes wider than they are long. Although Piper rnethysticurn does flower, it is incapable of self-reproduction; its propagation is vegetative and now due solely to human effort.l s 2 For medicinal purposes, it is the rootstock that is used. The rootstock is knotty, thick, and sometimes tuberous with holes or cracks created by partial destruction of the parenchyma. In other words, the rootstock is often somewhat pithy. From the main rootstock, there are extensions of lateral roots up to 9 feet long.*,2

CHEMICAL COMPOSITION Analysis of the composition of the dried kava rootstock indicates that it contains approximately 43% starch, 12% water, 3.2%simple sugars, 3.6%proteins, 3.2%minerals (primarily potassium), and 15% kavalactones (Table 115-1).1,2

Dosage

1170

1171

Side Effects and Toxicology

1171

Drug Interactions 1172

On the basis of detailed analysis of the active ingredients of kava, a laborious process over the past 110 years, many experts now believe that the pharmacologic activities of kava are due mostly, if not entirely, to the presence of compounds known as kuvuluctones (also referred to as kava alpha-pyrones). These compounds are found in the fat-soluble resin of the root. Although the kavalactones are the primary active components, other components appear to contribute to the sedative and anxiolytic activities of kava, as one study found the sedative activity of a crude preparation to be more effective than the isolated kavalactones (Figure 115-1).3 The kavalactone content of the root can vary between 3% and 20%.

HISTORY AND FOLK USE Oceania-the Pacific island communities of Micronesia, Melanesia, and Polynesia-is one of the few geographic areas of the world that did not have alcoholic beverages before European contact in the eighteenth century. However, these islanders did possess a "magical" drink used in ceremonies and celebrations because of its calming effect and ability to promote sociability. The drink, also called kava, is still used today in this region of the world, where the people are often referred to as the happiest and friendliest in the world. The origins of kava use are not known as it predates written history in Oceania.lt2It was first described for

1167

Pharmacology of Natural Medicines Kavalactones R

ComDound

R”

R’

R”’

C5-6

C7-8

Kavain 7,8-Di hydrokavain 5,6-Dihydrokavain Yangonin

OMe

5,6,7,8-Tetrahydroyangonin Methysticin Dihydromethysticin 5,6-Dehydromethysticin 5,6-Dihydroyangonin

OMe

7,8-Dihydroyangonin

OMe

10-Methoxy-yangonin

OMe

11-Methoxy-yangonin

OMe

OMe

11-Hydroxy-yangonin

OMe

HO

OH

OMe

0-CH2-0 0-CHZ-0 0-CH2-0 OMe OMe

Hydroxykavain 11-Methoxy-1Phydroxy dehydrokavain

‘Single dashes represent a single band, and double dashes represent a double band.

OCH,

R’ Figure 115-1 Kavalactones.

the Western world by captain James Cook in the account of his voyage to the South Seas in 1768. Many myths and legends surround the early use of kava. The plant itself probably originated in the New Guinea/Indonesia area and was spread from island to island by early Polynesian explorers in canoes, along with other plants. Each culture has its own story on the origins of kava. For example, in Samoa a story is told about the origins of kava and sugar cane. The story goes that a Samoan girl went to Fiji where she married a great chief. After some time, she returned to Samoa, but before doing so, she noticed two plants growing on a hill. She saw a rat chewing on one of the plants and noticed that the rat seemed to go to sleep. She concluded that the plant was a comforting food. She decided she would take this plant, sugar cane, back to Samoa, but then she noticed that the rat awoke and began to chew the root of another plant, kava. The animal that had been weak and shy became bold, strong, and more energetic. She decided that she would take both plants back with her to plant in Samoa. The plants grew very well in Samoa,

and soon a chief from a neighboring island exchanged two laying hens for roots of the two plants. Hence, the Samoans take credit for the spread of both sugar cane and kava. In Tonga, a legend is told about a great chief named Loau who lived on the island of Euaiki. He went to visit his servant Feva’anga, who wanted to give a feast in honor of the chief, but it was a time of great famine. In desperation, he and his wife killed and cooked their only daughter to be served to the chief. However, Loau recognized the human flesh in the food when it was served and would not eat it. He instructed Feva’anga to plant the food in the ground and to bring him the plant that would spring forth. On receiving the mature plant, Loau instructed that a drink be prepared from it and consumed with due ceremony.

The Kava Ceremony Regardless of exactly how kava originated, it has been used in ceremonies by the Oceanic people for thousands of years. There are three basic kava ceremonies: the full ceremonial as enacted on every formal occasion, the one performed at the meeting of village elders, chiefs, and nobles and for visiting chiefs and dignitaries, and the less formal kava circle common on social occasions.lP2 The first step of any kava ceremony was the preparation of the beverage. The following description of the classic process was written in 1777 by Georg Forster, a young naturalist on James Cook‘s second Pacific voyage: [Kava] is made in the most disgustful manner that can be imagined, from the juice contained in the roots of a species of pepper-tree. This root is cut small, and the pieces chewed by several people, who spit the macerated mass into a bowl,

Piper rnefhysficurn (Kava) where some water (milk) of coconuts is poured upon it. They then strain it through a quantity of fibres of coconuts, squeezing the chips, till all their juices mix with the coconut-milk; and the whole liquor is decanted into another bowl. They swallow this nauseous stuff as fast as possible; and some old topers value themselves on being able to empty a great number of bowls.

As this traditional method of preparation became frowned upon or made illegal by colonial governments and missionaries, more "sanitary" methods of preparation, involving grinding or grating, took its place in many parts of Oceania. The full kava ceremony, reserved for very highly honored guests, involves leading all the guests to a platform. The ceremony begins with the arrival of a group of young men dressed in ceremonial attire and carrying a bowl of the kava drink and necessary utensils. The bowl is placed between the kava preparers and the visitors. The kava is poured in a cup by a specially selected individual who then turns and faces the visitor and delivers the beverage to the chief guest. The guest is instructed to hold the cup with both hands and drink from it. If the whole cup is drained without stopping, everyone says "a maca" (pronounced "a matha," meaning "it is empty") and claps three times with cupped hands. The cupbearer then returns to the kava bowl and proceeds to serve the person next in rank or importance. Important people who visit Fiji and other islands of Oceania still participate in the kava ceremonies. For example, during a 1992 presidential campaign visit to Hawaii, Hillary Clinton participated in a kava ceremony conducted by the Samoan community on Oahu.

The Effects of Drinking Kava Kava drinkers relate a pleasant sense of tranquility and sociability upon consumption. Subjective reports given by scientists who have sampled kava themselves are relatively abundant. One of the first scientific studies of kava was performed by the noted pharmacologist Louis Lewin in 1886. A later description written in 1927 is as followsl: When the mixture is not too strong, the subject attains a state of happy unconcern, well-being and contentment, free of physical or psychological excitement. At the beginning, conversation comes in a gentle, easy flow and hearing and sight are honed, becoming able to perceive subtle shades of sound and vision. Kava soothes temperaments. The drinker never becomes angry, unpleasant, quarrelsome or noisy, as happens with alcohol. Both natives and whites consider kava as a means of easing moral discomfort. The drinker remains master of his consciousnessand his reason. When consumption is excessive, however, the limbs become tired, the muscles seem no longer to respond to the orders and control of the mind, walking becomes slow and unsteady and the drinker looks partially inebriated. He feels the need to lie down. . . . He is overcome by somnolence and finally drifts off to sleep.

A later description is provided by researcher R. J. Gregory, who writes the following from his own experience: Kava seizes one's mind. This is not a literal seizure, but something does change in the processes by which information enters, is retrieved, or leads to actions as a result. Thinking is certainly affected by the kava experience, but not in the same ways as are found from caffeine, nicotine, alcohol, or marijuana. I would personally characterize the changes I experienced as going from lineal processing of information to a greater sense of "being" and contentment with being. Memory seemed to be enhanced, whereas restriction of data inputs was strongly desired, especially with regard to disturbances of light, movements, noise and so on. Peace and quiet were very important to maintain the inner sense of serenity. My senses seemed to be unusually sharpened, so that even whispers seemed to be loud while loud noises were extremely unpleasant.

Drinking about half a coconut shell (100 to 150 ml) of certain varieties of kava is enough to put most people into a deep, dreamless sleep within 30 minutes. Unlike alcohol and other sedatives, kava does not produce a morning hangover. The kava drinker awakens having fully recovered normal physical and mental capacities.

PHARMACOLOGY Many of the first comprehensive studies on the activities of kavalactones were conducted by a team of scientists from the Freibwg University Institute of Pharmacology in Germany, led by Hans J. Meyer, during the 1950s and 1 9 6 0 ~ .This ~ research determined that kavalactones exhibit sedative, analgesic, anticonvulsant, and musclerelaxing effects in laboratory animals. These studies seemed to confirm earlier empirical and subjective observations. Later studies have utilized better-defined kava extracts.

Isolated Kavalactones Compared with Crude Extracts Some evidence suggests that the whole complex of kavalactones and other compounds naturally found in kava produce greater pharmacologic activity. In addition, studies have shown that kavalactones are more rapidly absorbed when given orally as an extract of the root rather than as the isolated kavalactones. The bioavailability of lactones, as measured by peak plasma concentrations, is up to 3 to 5 times higher from the extract than when given as isolated s~bstances.~ Further evidence that kava root extracts are superior to isolated kavalactones is offered by an animal study showing that although isolated kavalactones are well absorbed by brain, crude kava preparations produce brain concentrations of lactones 2 to 20 times higher! This evidence suggests that crude extracts standardized for kavalactone content may offer the greatest therapeutic benefit.

Pharmacology of Natural Medicines Several clinical trials have featured a kava extract standardized to contain 70% kavalactones. However, this high percentage of kavalactones may be sacrificing some of the other constituents that may contribute to the pharmacology of kava. More important than the actual percentage of kavalactones is the total dosage of the kavalactones and the assurance that the full range of kavalactones and other important constituents are present. Standardized preparations of kava are now gaining greater popularity in Europe and the United States as mild sedatives and anxiolytics.

Sedative Effects Recent studies have confirmed and/or elaborated on the sedative effects of kava. Most notable are studies demonstrating that kavalactones exert many of their effects through nontraditional mechanisms. For example, most sedative drugs, including the benzodiazepines (e.g., diazepam, triazolam, cloraepate dipotassium) work by binding to specific receptors (benzodiazepine or GABA receptors) in the brain, leading to the neurochemical changes (potentiation of GABA effects) that promote sedation. Studies in animals have shown that the kavalactones do not bind to benzodiazepine or GABA receptors? Instead, the kavalactones are thought to somehow m o d e receptor domains rather than interact specifically with receptor binding sites. In addition, other studies have indicated that the kavalactones appear to act primarily on the limbic system, the ancient part of the brain that affects all other brain activities and is the principal seat of the emotions.6 It is thought that kava may also promote sleep by altering the way in which the limbic system modulates emotional processes. It appears that many of the laboratory models of identifying how a substance works to promote a calming effect are simply not sophisticated enough to evaluate the physiologic effects of kava.

Analgesic Effects In another example of the unusual pharmacologic qualities of kava, a study designed to evaluate its pain-relieving effects could not demonstrate any binding to opiate receptors? The signhcance of this finding is that the study used experimental models in which nonopiate analgesics like aspirin and other nonsteroidal antiinflammatory drugs are ineffective. In addition, it was determined that the sedative or muscle-relaxing effects were not responsible for the pain-relieving effects. These findings indicate that kava reduces pain in a manner unlike morphine, aspirin, or any other pain reliever.

Anxiolytic Effects An interesting difference of kava from other anxiolytics is that unlike the drugs, kava does not lose effectiveness

with time. Kavalactones, even when administered in large dosages, demonstrated no loss of effectiveness in animal studies.8 This is another example of the unusual qualities of kava.

Antiischemia Effects Another pharmacologic activity of kava of importance is its ability to protect against brain damage due to i ~ h e r n i a .This ~ effect has been demonstrated in two animal models of focal cerebral ischemia. The effectiveness of the kavalactones was due to their ability to limit the infarct area as well as to provide a mild anticonvulsant effect. Kava extract may prove useful in the recovery from a stroke.

CLINICAL APPLICATIONS The primary clinical application of kava is in the treatment of anxiety. This application is well-supported by clinical research.'O Early clinical trials used D,L-kavain, a purified kavalactone, at a dosage of 400 mg/day. For example, in one double-blind placebo-controlled study of 84 patients with anxiety symptoms, kavain was shown to improve vigilance, memory, and reaction time." In another double-blind study, kavain was compared with oxazepam (a drug similar to diazepam [Valium])in 38 patients.12 Both substances caused progressive improvements in two different anxiety scores (Anxiety Status Inventory and the Self-rating Anxiety Scale) over a 4week period. However, although oxazepam and similar drugs are addictive and cause side effects, kavain appeared to be free of these complications. In one of the early studies with kava extracts, a 70% kavalactone extract was shown to exhibit significant therapeutic benefit in patients suffering from anxiety.13 The study was double-blind; 29 patients were assigned to receive 100 mg of the kava extract three times daily and 29 other patients received a placebo. Therapeutic effectiveness was assessed using several standard psychological assessments, including the Hamilton Anxiety Scale (HAMA).The result of this 4-week study indicated that individuals taking the kava extract had a statistically significant reduction in symptoms of anxiety, including feelings of nervousness, and somatic complaints, such as heart palpitations, chest pains, headache, dizziness, and feelings of gastric irritation. No side effects were reported with the kava extract. Studies have also compared the effects of a kava extract standardized to contain 30% kavalactones with buspirone and omipramol. In the double-blind study, 129 patients with generalized anxiety disorder were given either 400 mg kava (30%kavalactones), 10 mg buspirone, or 100 mg opipramol daily for 8 weeks. Detailed analysis showed that no significant differences could be observed regarding all efficacy and safety measures.

Piper rnethysticum (Kava)

traditionally prepared kava drink contains approxiAbout 75% of patients were classified as responders mately 250 mg of kavalactones, and in Oceania, several (50% reduction of the HAMA score) in each treatment bowls may be consumed at one sitting. Dosages are as group, and about 60%achieved full remis~i0n.l~ Kava has also been shown to be particularly effective follows: in relieving anxiety in perimenopausal and postAnxiolytic dosage: 45-70 mg of kavalactones three menopausal women.15-17In one double-blind study, two times/ day groups of 20 women with menopause-related symptoms Sedative dosage: 180-210 mg of kavalactones 1 hour were treated for a period of 8 weeks with the 70%kavalacbefore retiring tone extract (100 mg three times daily) or placebo.18The measured variable was once again the HAMA. The group receiving the kava extract demonstrated significant SIDE EFFECTS AND TOXICOLOGY improvement at the end of the very first week of treatIn November 2001, German health authorities anment. Scores continued to improve over the course of the nounced that 24 cases of liver disease (including hep8-week study. In addition to symptoms of stress and anxatitis, liver failure, and cirrhosis) associated with the use iety, a number of other symptoms also improved. Most notably there was an overall improvement in subjective of kava had been reported in Germany; of the affected well-being, mood, and general symptoms of menopause, persons, one died and three required a liver transplant. The true nature of kava-induced liver damage is clouded including hot flashes. As with previous studies, no side by the fact that in 18 of these cases, conventional preeffects were noted. scription or over-the-counter pharmaceutical drugs with Additional studies have shown that unlike benzodiknown or potential liver toxicity were also being used. It azepines, alcohol, and other drugs, kava extract is not is entirely possible that the use of kava by these individassociated with depressed mental function or impairment in driving or the operation of heavy e q ~ i p m e n t . ' ~ , ~uals ~ was a coincidence rather than the cause of the liver problem; alternatively, the problem may have stemmed In one of these studies, 12 healthy volunteers were tested in a double-blind crossover manner to assess the effects from using kava well above recommended levels or from an interaction with some of these hepatotoxic drugs, of oxazepam (placebo on days 1to 3/15 mg on the day before testing, 75 mg on the morning of the experiment), thereby increasing their toxicity.A survey of 400 German the extract of kava standardized at 70% kavalactones medical practices showed that 78% of the kava prescriptions that were written sigruficantlyexceeded the recom(200 mg three times daily for 5 days), and a placebo on mended intake." Nonetheless, there have been reports behavior and event-related potentials (ERPs) in electroencephalographic (EEG) readings on a recognition of hepatitis in patients using kava at dosages equal to or only slightly higher than recommended levels.= memory task. The subjects' task was to identdy within a High daily dosages of kava consumed over a prolist of visually presented words those that were shown for the first time and those that were being repeated. longed period (a few months to a year) are associated Consistent with other benzodiazepines, oxazepam with a number of side effects beyond liver damage, including the development of "kava dermopathy"-a inhibited the recognition of both new and old words as condition of the skin characterized by a peculiar genernoted by Em.In contrast, kava allowed a slightly greater alized scaly eruption known as kar~i.*~ The skin becomes recognition rate and a larger ERP difference between old dry and covered with scales, especially the palms of the and new words. The results of this study once again hands, soles of the feet, forearms, the back, and shins. It demonstrate the unusual effects of kava. In this case, it was thought at one time that kava dermopathy may be improves anxiety, but unlike standard anxiolytics, kava due to interference with niacin. However, in a doubleactually improves mental function and, at the recomblind, placebmontrolled study niacinamide (100 mg/day) mended levels, does not promote sedation. Another demonstrated no therapeutic effect.= It appears that the study indicated that kava helped improve reflex vagal only effective treatment for kava dermopathy is reduction control of heart rate in generalized anxiety disorder or cessation of kava consumption. No cases of kava patients.2I dermopathy have been reported in persons taking standardized kava extracts at recommended levels. DOSAGE Other reported adverse effects of extremely high doses of kava (e.g., more than 310 g/week) for prolonged In clinical studies using pure kavalactones or kava periods are as followsz6: extracts standardized for kavalactones, the dosage is based on the level of kavalactones. Because the kavalacBiochemicalabnormalities(low levels of serum albumin, tone content of the root varies between 3% and 20%, protein, urea, and bilirubin) preparations standardized for kavalactone content are Elevated liver enzymes preferred to crude preparations. A standard bowl of

Presence of blood in the urine Increased red blood cell volume Decreased platelet and lymphocyte counts Shortness of breath

Kava is not recommended for use by pregnant or breastfeeding women.

DRUG INTERACTIONS

At this time, kava is not recommended for use by anyone who has any liver problems or who is a regular consumer of alcohol. Use of kava for more than 4 weeks requires close monitoring of liver enzymes (once every 4 to 6 weeks). Patients should be instructed to discontinue use of kava if symptoms of jaundice (e.g., dark urine, yellowing of the eyes) occur. Nonspecific symptoms of liver disease include nausea, vomiting, light-colored stools, unusual tiredness, weakness, stomach or abdominal pain, and loss of appetite.

Kava may potentiate the effects of benzodiazepines, barbiturates, and prescription sedatives. Kava also inhibits a number of the cytochrome enzymes that play a role in the breakdown of many medi~ations.~~ Therefore it has the potential to interact with a wide range of medications. There is evidence that kava interferes with dopamine or other drugs used in the treatment of Parkinson’s disease; therefore until this issue is resolved, kava extract should not be used by patients with Parkinson’s disease.24

1.Lebot V, Merlin M, Lindstrom L. Kava. The pacific drug. New Haven, CT:Yale University Press, 1992. 2. Sin& Y. Kava: an overview. J Ethnopharmacol1992;3713-45. 3. Meyer HJ.Pharmacologyof kava. In Efron D, Holmstedt B, Kline NS, eds. Ethnopharmacologic search for psychoactive drugs. New York: Raven Press. 1979133-140. 4. Keledjian J, Duffield PH, Jamieson DD. Uptake into mouse brain of four compounds present in the psychoactive beverage kava. J Pharm Sci 1988;7731003-1006. 5. Davies LP, Drew CA, Duffield P, et al. Kava pyrones and resin: studies on GABAA, GABAB and benzodiazepine binding sites in rodent brain. Pharmacol Toxic01 1992;71:120-126. 6. Holm E, Staedt U, Heep J, et al. [The action profile of D,L-kaVain. Cerebral sites and sleep-wakefulness-rhythm in animals.] Arzneimittelforschung 1991;41:673-683. 7. Jamieson DD, Duff3eld PH. The antinociceptive action of kava components in mice. Clin Exp Pharmacol Physiol1990;17495-507. 8. Duffield PH, Jamieson D. Development of tolerance to kava in mice. Clin Exp Pharmacol Physiol 1991;18:571-578. 9. Backhauss, Krieglstein J. Extract of kava (Piper methysticum) and its methysticum constituents protect brain tissue against ischemic damage in rodents. Eur J Pharmacol1992;215265-269. 10. Pittler MH, Emst E. Efficacy of kava extract for treating anxiety: systematic review and meta-analysis. J Clin Psychopharmacol 2000;2084-89. 11. Scholing WE, Clausen HD. [On the effect of D,L-kavain: experience with neuronika (author’s transl).] Med Klin 1977;721301-1306. 12. Lindenberg D, Pitule-Schodel H. [D,L-kavain in comparison with oxazepam in anxiety disorders. A double-blind study of clinical effectiveness.] Forschr Med 1990;108:49-50, 53-54. 13. Kinzler E, Kromer J, Lehmann E. [Clinical efficacy of a kava extract in patients with anxiety syndrome. Double-blind placebo controlled study over 4 weeks.] Arzneimittelforschung 1991;41:584-588. 14. Boemer RJ, Sommer H, Berger W, et al. Kava-Kava extract LI 150 is as effective as opipramol and buspirone in generalised anxiety disorder-an %week randomized, double-blind multi-centre clinical trial in 129 out-patients. Phytomedicine 2003;1O(Suppl4):38-49.

15. Cagnacci A, Arangino S, Renzi A, et al. Kava-Kava administration reduces anxiety in perimenopausal women. Maturitas 2003;44: 103-109. 16. De Leo V, la Marca A, Morgante G, et al. Evaluation of combining kava extract with hormone replacement therapy in the treatment of postmenopausal anxiety. Maturitas 2001;39:185-188. 17. De Leo V, La Marca A, Lanzetta D, et al. [Assessment of the association of Kava-Kava extract and hormone replacement therapy in the treatment of postmenopause anxiety.] Minerva Ginecol 2000;52263-267. 18. Wamecke G. [Psychosomatic dysfunctions in the female climacteric. Clinical effectiveness and tolerance of kava extract WS 1490.1 Fortxhr Med 1991;109:119-122. 19. Herberg KW. [Effect of kava-special extract WS 1490 combined with ethyl alcohol on safety-relevant performance parameters.] Blutalkohol 1993;30:96-105. 20. Munte TF, Heinze HJ, Matzke M, et al. Effects of oxazepam and an extract of kava roots (Piper methysticum) on event-related potentials in a word recognition task. Neuropyschobiology 1993;2746-53. 21. Watkins LL, Connor KM, Davidson JR. Effect of kava extract on vagal cardiac control in generalized anxiety disorder: preliminary findings. J Psychopharrnacol2001;15283-286. 22. Schroder-Bemhardi D, Dietlein G. Compliance with prescription recommendations by physicians in practices. Int J Clin Pharmacol Ther 2001;39:477-479. 23. Escher M, Desmeules J, Giostra E, Mentha G. Hepatitis associated with kava, a herbal remedy for anxiety. BMJ 2001;322:139. 24.Schelosky L, Raffauf C, Jendroska K, et al. Kava and dopamine antagonism [letter]. J Neurol Neurosurg Psychiatry 1995;58: 639-640. 25.Norton SA, Ruze P. Kava dermopathy. J Am Acad Dermatol 1994;31:89-97. 26. Ruze P. Kava-induced dermopathy. A niacin deficiency. Lancet 1990;335:1442-1445. 27. Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab Dispos 2002;301153-1157.

Policosanol hfichael T. hlurray, N D Joseph E. Pizzorno Jr, N D C: H A P T E R C: 0 N T E N T S General Description 1173 Chemical Composition 1173 History and Folk Use 1173 Pharmacology 1173 Clinical Applications 1174 Cholesterol Lowering 1174 Diabetes 1176

GENERAL DESCRIPTION Policosanol refers to a patented mixture of higheraliphatic primary alcohols isolated and purified from the wax of sugar cane (Saccharurn oficinarum, L.).

CHEMICAL COMPOSITION As the name implies, policosanol is a mixture of many (poly) cosanols, cosanols being long-chain alcohols (LCAs). The components of policosanol are 1-octacosanol, 1-dotriacontanol, 1-triacontanol, 1-tetracosanol, 1-tetratriacontanol, 1-hexacosanol, 1-heptacosanol, and 1-nonacosanol. The patented Cuban policosanol contains eight LCAs in specific amounts. Erroneously, the term ”octacosanol” is sometimes used to refer to policosanol, even in the biomedical literature. Although octacosanol is contained in policosanol, studies show that octacosanol has only mild, if any, blood lipid-modifying effects compared with results of studies on the patented material.’

HISTORY AND FOLK USE The development of policosanol began in 1964 when Che Guevara, Cuba’s minister of industry, created the first postrevolution state-sponsored research center, the Cuban Institute for Research on Sugar Cane Derivatives.2 The Institute’s intent was to identify high-value bioactive sugar cane derivatives that would

Hypertension 1176 Elderly Patients 1177 Type I1 Hypercholesterolemia and Disturbances of Hepatic Function 1177 Antiplatelet Effects 1177 Angina 1178 Intermittent Claudication 1178

Toxicology 1178 Drug Interactions 1179

ultimately surpass the value of refined white sugar. The first product with such potential was policosanol. It is sold as a patented agent for lowering cholesterol in more than 40 countries. One notable exception is the United States, a result of this country’s current trade embargo against Cuba. The sources for imitation policosanol products marketed in the United States include sugar cane wax extracts produced outside Cuba, rice bran wax, and beeswax. However, it must be kept in mind that the clinical research on policosanol is with the Cuban policosanol derived from sugar cane wax?

PHARMACOLOGY The pharmacologic effects of policosanol, derived from experimental models, can be summarized as follows: Policosanol produces a dose-dependent and significant reduction of serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. High-density lipoprotein cholesterol (HDL-C) values are also increased in a dose-dependent manner. Triglycerides are also signhcantly reduced, but the reduction is not dose-dependent.45 Policosanol lowers serum total cholesterol and LDL-C by (1)inhibiting cholesterol synthesis at a point between the formations of acetate and mevalonate, (2) exerting no direct inhibition on 3-hydroxy-3-methylglutaryl 1173

Pharmacology of Natural Medicines

coenzyme A (HMG-CoA) reductase, and (3) sigruficantly increasing LDL-receptor dependent processing as demonstratedby increasing the incorporationof LDL into the hepatocyte and stimulating its ~atabolisrn.6,~ Policosanol not only effectively decreases serum cholesterol levels but also reduces the cholesterol content in different tissues, such as liver, heart, and fatty tissue? The cholesterol-lowering effects of policosanol are persistent, and it does not lose its effect over time. Policosanol diminishes platelet aggregation by altering prostaglandin synthesis. Specifically, policosanol lowers sem levels of the proaggregatory thromboxane A2 and raises those of the antiaggregatory prostaglandin prostacyclin?-" Policosanol prevents and reverses atherosclerotic lesions and thrombosis.12-16 Policosanol prevents intimal thickening and smooth muscle cell proferati~n.'~J~ Policosanol is an effective antioxidant in preventing LDL 0xidation.'~2O Pharmacokinetics indicate that Policosanol is rapidly absorbed, on the basis of radioactive absorption studies in experimental animals (rats, rabbits, and monkeys) and humans. Peak levels have been achieved from 30 to 120 minutes after treatment in different animal species and humans. Radioactivity is distributed mainly in the liver, but radioactivity levels in the systemic circulation are low. This effect is an advantage for a cholesterol-lowering agent because the liver is the main organ for synthesis and regulation of cholesterol metabolism. Excretion studies in animals and human healthy volunteers have demonstrated that feces is the main route for radioactivity excretion after oral administration; urinary excretion is not relevant.

CLINICAL APPLICATIONS The primary application of policosanol is as a cholesterollowering agent. However, it also exhibits antiplatelet

effects and has shown clinical usefulness in angina and intermittent claudication.

Cholesterol Lowering Exceptional clinical documentation demonstrates the efficacy, safety, and tolerability of policosanol in patients with type I1 hypercholesterolemia and in patients with secondary hypercholesterolemia associated with diabetes mellitus or nephrotic syndrome.3J1-26 This agent works to lower cholesterol levels by several mechanisms. It inhibits cholesterol manufacture but does so before the level of HMG-CoA reductase. In addition, policosanol affects LDL-C metabolism. Specifically, policosanol increases LDL receptor processing. It exerts this effect by increasing the binding of LDL to its receptor, improving the transport of LDL into the liver cell, and significantly enhancing the breakdown of LDL-C. In addition to lowering LDL, policosanol has also been shown to increase HDL, to protect against free radical damage to LDL-C, and to inhibit excessive platelet aggregation. All together, policosanol exerts many pharmacologic actions of benefit in the prevention and treatment of atherosclerosis. The clinical research into this agent included shortand long-term, randomized, placebo-controlled studies as well as studies comparing it with statins (lovastatin, pravastatin, and simvastatin), fibrates (bezafibrate and gemfibrozil), acipimox, and probucol that have involved nearly 3000 subjects. In these studies, policosanol in dosages ranging from 5 to 20 mg/day has demonstrated significant improvements in LDL-C, total cholesterol, HDL-C, and the ratios of total cholesterol to HDL-C and LDL-C to HDL-C. Policosanol produces cholesterol-lowering effects within the first 6 to 8 weeks of use. At doses of 10 to 20 mg per day, policosanol lowers total cholesterol by 17%to 21% and LDL-C by 21% to 29%and raises HDL-C by 8% to 15%.3 The combined LDL reduction and HDL increase can produce dramatic improvements in the LDL/HDL ratio. Although the effects are somewhat dose-dependent (Figure 116-1),27a 40-mg dose has no

Figure 116-1 The lipid-lowering effects of policosanol are dosedependent percent changes compared to placebo in 8 weeks treatment periods). (Data from Pons P, Rodriguez M. Robaina C, et al. Int J Clin Pharmacol Res 1994;14:27-33.)

Policosanol advantage over a 20-mg dose according to the results of a double-blind study?* These improvements in lipid profiles compare quite favorably to results observed with statin drugs. From comparative studies it can be concluded that 10 mg of policosanol is equivalent in efficacy to 20 mg lovastatin, 10 mg pravastatin, or 10 mg simvastatin. Although these drugs have well-known side effects, policosanol is apparently safe. It has not been shown to produce any adverse drug interaction, and it can be used in diabetic patients, elderly patients, and even patients with impaired liver function or severe liver damage. In addition to its effects on cholesterol levels, policosanol also exerts additional positive effects in atherosclerosis. It prevents excessive platelet aggregation without affecting coagulation, prevents smooth muscle cell proliferation into the intima of the artery, and exerts good antioxidant effects in preventing LDL oxidation (Figure l16-2).29

Double-Blind Comparative Studies Policosanol has been compared with statin drugs (lovastatin, simvastatin, and pravastatin), fibrates (gemfibrozil), acipimox, and probucol in randomized, doubleblind, short-term clinical trials conducted in patients with type I1 hypercholesterolemia.

Versus Lovastatin In two studies, policosanol administered for 8 weeks at 10 mg/day has shown an efficacy similar to that of lovastatin administered at 20 mg/day.3031 In the first study, 36 patients were randomly assigned to receive either policosanol(10mg/day) or lovastatin (20 mg/day) tablets for 8 weeks. Policosanol significantly lowered serum LDL by 29.9%, total cholesterol by 21.1, triglycerides by 13.6%,and the LDL/HDL ratio by 36.7Y0 and raised HDL by 12.5%.In contrast, lovastatin significantly lowered LDL by 25%, total cholesterol by l8%, triglycerides by 10.9%,and the LDL/HDL ratio by 30.4% and raised HDL by 8.3%.Policosanol, but not lovastatin, significantly lengthened the lag time (20.9%) of CU+~-

induced LDL peroxidation and increased total plasma antioxidant activity by 24.2%. These results clearly demonstrate that policosanol (10 mg/day) was slightly more effective than lovastatin (20 mg/day). Another advantage for policosanol is that it has no hepatotoxic effect. Lovastatin sigruficantly, but moderately, raised serum transaminase and creatine phosphokinase values but policosanol did not. Other side effects were also more common in lovastatin-treated patients. In the second study, policosanol was compared with lovastatin in patients with moderately severe intermittent claudication. Twenty-eight patients were randomly assigned to receive either policosanol10 mg or lovastatin 20 mg tablets once daily. Walking distances on a treadmill (constant speed 3.2 km/hr, slope 10 degrees, temperature 25" C) were assessed before and after 20 weeks of treatment. In comparison with baseline values, policosanol sigruficantly increased the initial claudication distance from 160.39 m to 211.31 m (+33.7"/0) and the absolute claudication distance from 236.39 m to 288.09 m (+24.3%).In contrast, there was no change in the group receiving the lovastatin. In this study, policosanol sigruficantly lowered total cholesterol and LDL levels by 17.5% and 31.0%, respectively, and also increased HDL levels by 31.5%. Lovastatin reduced total cholesterol 18.0%, LDL 22.6%,and triglycerides 9.8%;no effect was seen on HDL. In addition, policosanol, but not lovastatin, moderately but siphcantly reduced fibrinogen levels. Versus Atomastatin In a single-blind, parallel-group study conducted in older patients (60-80 years) with type I1 hypercholesterolaemia after 4 weeks of a cholesterol-lowering diet, 75 patients were randomly assigned to receive either policosanol or atorvastatin, 10-mg tablets taken once daily with the evening meal for 8 ~ e e k s . 3 After ~ 8 weeks, policosanol had lowered total cholesterol and LDL levels by 16.4% and 23.1%, respectively, whereas atorvastatin reduced them by 22.6% and 29.8%, respectively. However, policosanol, but not atorvastatin, significantly increased serum HDL-C levels by 5.3%. Policosanol was better

Figure 116-2 The efficacy of 10 mg of policosanoldaily is maintained in long-term therapy (comparisonvs placebo).(Data from Canetti M, Morera M, Mas R. et al. Int J Clin Pharmacol Res 1995;15:159-165.)

Pharmacology of Natural Medicines tolerated than atorvastatin, as revealed by patient withdrawal analysis and overall frequency of adverse events.

Versus Pravastatin Policosanol administered at 10 mg/day was compared with the same dosage of pravastatin for 8 weeks.33The policosanol group demonstrated greater changes in LDL-C and HDL-C than the pravastatin group. Side effects were more common in the pravastatin group. Although pravastatin signhcantly increased the serum levels of alanine and aspartate aminotransferases (ALT and AST, respectively), policosanol exhibited no hepatotoxicity (Figure 116-3). Versus Simvastatin Policosanol and simvastatin were found to be equally effective at dosages of 10 mg/day for 8 weeks in In patients patients with type II hypercholester~lernia.~~~ with type II hypercholesterolemia and concomitant noninsdindependent diabetes mellitus (NIDDM), policosanol, but not simvastatin, significantly raised HDL-C levels.%As with the other agents, more adverse experiences were and have been reported in simvastatin-treated patients than in policosanol-treated patients. Versus Fibrates Different studieshave compared the effects of policosanol and fibrates, such as gemfibrozil and bezafibrate.sB The results have shown that policosanol produces slightly higher reductions of serum total cholesterol, LDL-C, apolipoprotein B (ApoB), and the atherogenic ratios of cholesterol to HDL-C and LDL-C to HDL-C, whereas the fibrates have reduced triglycerides more effectively. The two agents had similar results in raising HDL-C levels. However, as with the statin drugs, fibrates but not policosanol have increased serum transaminase levels, and the adverse experiences reported by fibrate-treated patients have been more common than those reported by policosanol-treated patients. Versus Acipimox A comparative double-blind clinical trial of policosanol versus acipimox for 8 weeks in patients with type Il

hypercholesterolemia has shown that policosanol is more effective than acipimox in reducing LDL-C and total chole~terol.~~ In addition, serum lipoprotein(a) (Lp(a))levels were significantly reduced by policosanol treatment in both the whole study population (32.6% reduction) and the stratum showing initial high Lp(a) levels (>30 mg/dl) (57.4%reduction). Lp(a) is a plasma lipoprotein that in structure and composition closely resembles LDL, but with an additional molecule of an adhesive protein called apolipoprotein(a).Elevated plasma levels of Lp(a)are an independent risk factor for coronary heart disease, particularly in patients with elevations of LDL-C. In fact, a high level of Lp(a) has been shown to carry a ten times greater risk for heart disease than an LDL-C elevation. That is because LDL on its own lacks the adhesive apolipoprotein(a).As a result, LDL does not easily stick to the walls of the artery. Levels of Lp(a) below 20 mg/dl are associated with a low risk for heart disease; levels between 20 and 40 mg/dl with a moderate risk; and levels exceeding 40 mg/dl with an extremely high risk.

Versus Probucol A comparative study of policosanol (10 mg/day) and probucol (1000 mg/day) for 8 weeks in patients with type I1 hypercholesterolemia showed that policosanol was more effective in reducing LDL-C and total cholesterol than probucol.40Both drugs were safe and well tolerated (Figure 116-4).

Diabetes Policosanol administered to patients with NIDDM and type II hypercholesterolemia sigruficantlylowered LDL-C, serum total cholesterol, and atherogenic ratios while raising HDL-C levels. In addition, policosanol does not impair glycemic control in diabetic patients, as assessed through the evaluation of its effects on blood glucose and glycosylated hemoglobin (HgbA,,) values (Table 116-1).41*a

Hypertension Policosanol has been studied specifically in patients with hypertension and hypercholesterolemia. In the first

Flgure 116-3 The efficacy of policwanol vs. pravastatin in type II hypercholesterolemia. (Data from Benitez M, Romero C. Mas R. et al. Cum Ther Res 1997;58:859-867.)

Policosanol

Figure 116-4

The efficacy of policosanol vs. probucol in type I I hypercholesterolemia. (Data from Pons P, lllnait J, Mas R, et al. Curr Ther Res 1997;58:26-35.)

study policosanol sigrulicantly reduced LDL-C (-19.1Y0), total cholesterol (-13%) and the ratios of cholesterol to HDL-C (-20%) and LDL-C to HDL-C (-24.2%) in hypertensive patients with hypercholesterolemia while significantly raising HDL-C levels (+17.1’%0)!~ After 12 months of therapy the policosanol group had significantly lower systolic pressure (-10 mm Hg), but the values in the placebo group remained unchanged. Many of the patients were also taking beta-blockers and diuretics, two classes of drugs known to adversely affect blood lipid levels. In the second study after 6 weeks of a standard step I cholesterol-lowering diet, 589 patients were randomly assigned to receive either policosanol (5 mg) or placebo tablets, to be taken once daily for 12 months.44The dosage of placebo or policosanol was doubled to 10 mg/day if total cholesterol values were higher than 6.1 mmol/L after 6 months of therapy. Policosanol significantly lowered LDL by 20.5%, total cholesterol by 15.4%, triglycerides by 11.9%, and the LDL/HDL ratio by 22.2% and raised the HDL level by 12.7%.The frequency of vascular and all-cause serious adverse events (SAEs) was lower in the policosanol recipients (2 vascular SAEs, 0.7”/,; 5 all-cause SAEs, 1.7%) than in the placebo recipients (6 vascular SAEs, 2.0%; 12 all-cause SAEs, 4.1%). Policosanol sigrulicantly decreased systolic blood pressure to 10 mmHg lower than baseline and placebo values, which could be an additional advantage in this population at high risk of coronary events.

Elderly Patients

Treatment

Baseline

Total Cholesterol (mmoUL) Policosanol 7.51

12 weeks

Percent change

5.35

-28.9

Placebo LDL-C (mmoUL) Policosanol

7.94

8.01

+0.4

5.27

3.05

-44.4

Placebo HDL-C (mmolk) Policosanol

5.32

5.56

+3.4 +23.5

1.47

1.58

Placebo 1.51 Triglycerides (mmoVL) Policosanol 2.06

1.52

+0.7

1.96

-2.4

Placebo 2.45 Total Cholesterol to HDL-C Policosanol 5.88

2.1 1

+6.5

Placebo LDL-C to HDL-C Policosanol

5.72

6.03

4.25

2.01

-51.6

Placebo

3.99

4.16

+2.9

Modified from Torres 0, Agramonte 18~393-397.

-38.3

3.52

AJ, Illnail J.

+3.8

et al. Diabetes Care 1995;

Type II Hypercholesterolemia and Disturbances of Hepatic Function

The efficacy pattern of policosanol in patients with type II Policosanol administered for short- or long-term therhypercholesterolemia and concomitant disturbances of apy in patients older than 60 years with hypercholesterolemia has been effective, safe, and well t0lerated.4~~~hepatic function is similar to that shown in hypercholesterolemic patients without impairment of liver In this population policosanol has a similar efficacy profile to that observed in younger patients. Table 116-2 function.48Policosanol reduced total cholesterol (-13.6%), LDL-C (-19.1Y0), and the LDL-C/HDL-C ratio (-25.5%) summarizes the major results obtained at months 6 and and raised HDL-C (+11.5%). In addition, policosanol 12 in a long-term study of performed in elderly patients. was shown to reduce levels of ALT and gammaOf particular importance in this population is the fact glutamyl transpeptidase (GGT) toward normal. that no drug-related adverse experiences occurred. Elderly patients are at risk for such problems because Antiplatelet Effects of impaired renal and hepatic clearance as well as a high Policosanol reduces platelet aggregation by altering coexistence of concomitant diseases and medication prostaglandin synthesis. Specifically, this agent lowers consumption.

Pharmacology of Natural Medicines

Effect of policosanol on the serum lipid profile in elderly patients with hypercholesterolemia Treatment

Baseline

Total Cholesterol (mmoVL) Policosanol 7.68

6 months

12 months

6.67

6.43

Percent change -16.4

Placebo LDL-C (mmovl) Policosanol

7.33

7.46

7.57

+0.03

5.40

4.34

4.10

Placebo HDL-C (mmoVL) Policosanol

4.99

5.22

5.24

+4.8

1.28

1.28

1.36

+5.9

Placebo

1.28

1.25

1.25

-2.4

-24.1

serum levels of the proaggregatory thromboxane A2while raising levels of the antiaggregatoryprostaglandin prostacyclin. Clinical trials in humans have shown that policosanol sigruficantlyinhibits platelet aggregation without affecting coagulation Policosanol's effects on platelet aggregation compare quite favorably with those of low-dose aspirin."B Similar to its effects in lowering cholesterol, taking 40 mg of policosanol does not increase the effect of taking 20 mg. In both healthy volunteers and patients with hypercholesterolemia, policosanol at 20 mg/day and 40 mg/day inhibited aggregation induced by a variety of agents at nearly identical levels in the two groups.51

showed considerable benefit. The study consisted of a 6-week single-blind, placebo-controlled run-in phase followed by a 2-year double-blind, randomized treatment step. Fm-six patients with intermittent claudication were randomly assigned to receive placebo or policosanol 10 mg twice daily. Walking distances on a treadmill (constant speed 3.2 km/hr, slope 10 degrees, temperature 25" C) were assessed before and after 6,12,18, and 24 months of treatment. After 6 months of therapy, policosanol significantly increased (p < 0.01) the initial claudication distance from 125.9 m to 201.1 m and the absolute claudication distance from 219.5 m to 380.7 f 50.2 m. The two variables remained unchanged in the placebo group. These effects did not wear off but improved after long-term therapy, so that final values were increases of 333.5 m for the initial claudication distance and 648.9 m for the absolute claudication distance; both sigruficantly greater (p < 0.0001) than those obtained in the placebo group, which showed values of 137.9 m for the initial claudication distance and 237.7 m for the absolute claudication distance. Policosanol, but not placebo, sigruficantly increased the ankle/arm pressure index. In addition, from month 6 to study completion, the frequency of patients reporting improvement of lower limb symptoms was greater in the policosanol group than in the placebo group. Sixteen patients withdrew from the study (12 placebo, 4 policosanol). Eight patients in the placebo group experienced a total of 10 serious adverse events, 8 of which were vascular events, compared with none in the policosanol gr0up.5~

Angina

TOXICOLOGY

Policosanol was shown to improve the clinical evolution, and exercise-electrocardiography(ECG)testing responses of patients with coronary heart disease (CHD) and myocardial ischemia,documented by exercise myocardial perfusion s~intigraphy.~~ In the double-blind study, 15 patients were treated with 5 mg of policosanol twice daily; another 15 patients were administered the same dose plus 125 mg aspirin; and a third group of 15 patients received placebo plus the same aspirin dose. They were monitored for 20 months, and results of treadmill exercise and serum lipid measurementswere compared with baseline values. Beneficial changes among the two policosanol groups and the placebo group showed an increment on functional capacity class, a decrement on rest and exercise angina, and a significant decrease in cardiac events, and in ischemic ST segment response, especially in the policosanol plus aspirin group.

Policosanol exhibits an exemplary safety profile. In all controlled studies, policosanol has exerted no negative effect on any clinical or laboratory parameter. Side effects were comparable to a placebo. In fact, the withdrawal rate for policosanol in short- and long-term clinical studies was comparable to or even lesser than that of placebo; only 0.2% policosanol-treated patients withdrew before conclusion of a study as a result of an adverse experience, compared with 0.6% of the placebo group. Comparative studies have shown the rate of dropout due to side effects of 0.9%in policosanol-treated patients compared with a 4.4% rate for those treated with other lipid-lowering drugs (e.g., statins, fibrates, probucol, and acipimox). In a large postmarketing surveillance study, the tolerability of policosanol was assessed in 27,879 patients (17,225patients for 2 years and 10,654 patients for 4 years). All of the patients had been treated for at least 1month. During the study, 86 patients (0.31%) reported adverse effects, the most common of which was weight loss. Twenty-two (0.08%) discontinued treatment because of presumed side effects.%

Intermittent Claudication Policosanol is showing promise in the treatment of intermittent claudication. In addition to the study comparing it with lovastatin already described, another study

Policosanol A single dose (1000 mg/day) as much as 50 times the maximum recommended dose (20 mg/day) administered to healthy volunteers produced no adverse reaction; hence no overdose symptoms have been detected. Animal studies show that policosanol is virtually nontoxic; the oral LDso (dosage at which 50% of the animals died) in rats, mice, rabbits, and dogs was more than 5000 mg/kg. Body weight gain, behavioral assays, and biochemical and hematologic determinations in surviving animals at the end of the test (14 days) did not reveal differences between treated and control groups. Moreover, weight organ analysis and histopathologic study did not reveal differences between gr0ups.5~S The effects of successive dosage increases of policosanol administered orally to Macaca arctoides monkeys demonstrated that even the highest dose administered (500 mg/kg) policosanol was tolerated. Similar results have been shown in oral subchronic and chronic toxicity models in rats, dogs, and monkey^?^-^^ Policosanol did not produce any adverse effects on fertility and reproduction in animal studies, nor has it exerted any mutagenic or carcinogenic Specifically, policosanol administered orally up to 1000 mg/kg during the organogenesis period did not produce embryotoxic nor teratogenic effects in rats or rabbits, and a multigenerational study did not show any toxicity. Although policosanol neither induced teratogenic effects in rats or rabbits nor affected rat fertility and reproduction, policosanol is not recommended for use in pregnant women. The reason for this restriction is that cholesterol and associated metabolic products are required for adequate fetal development. Because hypercholesterolemia and atherosclerosisare chronic diseases, the suspension of lipid-lowering therapy for 9 months cannot be considered an additional coronary risk factor. It is not known whether the product or some active metabolite

is excreted via the human milk during nursing, so policosanol therapy during lactation is also not recommended. Efficacy and safety of policosanol in children has not been well established. Thus, treatment of children with policosanol is not recommended at present.

Policosanol has demonstrated synergism with the antiplatelet properties of aspirin in experimental animal models and healthy human volunteers as well as in different experimental animal models of ischemia and thrombosis. Pretreatment with policosanol inhibited aspirin-induced gastric ulcer in experimental animals. Single or repeated doses of policosanol administered orally did not significantly affect fibrinolytic activity or bleeding time in rats. In these studies interaction between policosanol and heparin or warfarin have been ruled out.65 Antipyrine is a model drug used to investigate interaction with drugs metabolized by liver microsomal enzymes (the Pm system). Policosanol administered orally to Beagle dogs for 3 to 4 weeks did not affect antipyrine or theophylline pharmacokinetics, suggesting that it does not interact with drugs metabolizing processes involving the microsomal system. No specific clinical trials have been developed to evaluate the possible pharmacologic interactions of policosanol, but in short and long-term clinical studies, this agent has been employed simultaneously with calcium antagonists, inhibitors of angiotensin-convertingenzyme, beta-blockers, meprobamate, diuretics, nitroderivative vasodilators, nonsteroidal antiinflammatorydrugs, anxiolytics, antidepressants, neuroleptics, oral hypoglycemic agents, digoxin, warfarin, thyroid hormones, antiulcer drugs, as well as others without evidence of clinically relevant adverse interactions.

1.Castano G, Femandez L, Mas R, Illnait J, et al. Comparison of the efficacy, safety and tolerability of original policosanol versus other mixtures of higher aliphatic primary alcohols in patients with type II hypercholesterolemia. Int J Clin Pharmacol Res 2002; 255-66. 2.Carr K. Cuban biotechnology treads a lonely path. Nature 1999;398:A22-A23. 3. Gouni-Berthold I, Berthold HK. Policosanol clinical pharmacology and therapeutic significance of a new lipid-lowering agent. Am Heart J 2002;143356-365. 4. Arruzazabala ML, Carbajal D, Mas R, et al. Cholesterol-lowering effects of policosanol in rabbits. Biol Res 199427205-209. 5. Menendez R, Arruzazabala ML, Mas R, et al. Cholesterol-lowering effect of policosanol on rabbits with hypercholesterolemia induced by a wheat starch-casein diet. Br J Nutr 1997;77:923-932.

6. Menendez R, Femandez L, Del Rio A, et al. Policosanol inhibits cholesterol biosynthesis and enhances LDL processing in cultured human fibroblasts. Biol Res 1994;27199-203. 7. Menendez R, Amor AM, Gonzilez RM, et al. Effect of policosanol on the hepatic cholesterol biosynthesis of normocholesterolcmic rats. Biol Res 1996;29253-257. 8. Cruz Bustillo D, Mederos CM, Mas R, et al. Efecto hipocolesterol mico del Ateromixol (PPG) en el cerdo en ceba. Rev. CENIC Cien Biol1991;262-63. 9. Arruzazabala ML, Valdes S, Mas R, et al. Effect of policosanol succesive dose increases on platelet aggregation healthy volunteers. Pharmacol Res 1995;34:181-185. 10. Valdes S, Arruzazabala ML, Femandez L, et al. Effect of policosanol on platelet aggregation in healthy volunteers. Int J Clin Pharmacol Res 1996;1667-72.

DRUG INTERACTIONS

Pharmacology of Natural Medicines 11.Carbajal D, Arruzazabala ML, Valdes S, Mas R. Effect of policosanol on platelet aggregation and sem levels of arachidonic acid metabolites in healthy volunteers. Prostaglandins Leukot Essent Fatty Acids 1998;58:61-64. 12. Noa M, Herrera M, Magraner J, Mas R. Effect of policosanol on isoprerdine-induced myocardial necrosis in rats. J Pharm Pharmacol 1998;46:282-285. 13.Carbajal D, Anuzazabala ML, Mas R, et al. Effects of policosanol on experimental thrombosis models. Prostaglandins Leuko Essent Fatty Acids 1994;50:249-251. 14. Arruzazabala ML, Molina V, Carbajal D, et al. Effect of policosanol on cerebral ischemia in Mongolian gerbils: role of prostacyclin and thromboxane A*. Prostaglandins Leuko Essent Fatty Acids 1993; 49:695-697. 15. Noa M, Mas R, de la Rosa MC, Magraner J. Effect of policosanol on lipofindin-induced artherosclerotic lesions in rats. J Pharm Pharmacol1995;47289-291. 16. Noa M, Mas R, Mesa R. Effect of policosanol in circulating endothelid cell in experimental models in Sprague-Dawley rats and in rabbits. J Pharm Pharmacol1997;49999-1002. 17. Noa M, Mas R, Mesa R. Effect of policosanol on intimal thickening in rabbit cuffed carotid artery. Int J Cardiol1998;67125-132. 18. Batista J, Stusser IL, Penichet M, Uguet E. Doppler-ultrasound pilot study of the effects of long-term policosanol therapy on carotidvertebral atherosclerosis. Curr Ther Res 1995;56906-914. 19. Fraga V, Menendez R, Amor AM, et al. Effect of policosanol on in vitro and in vivo rat liver microsomal lipid peroxidation. Arch Med Res 1997;28:355-360. 20. Menendez R, Mas R, Amor AM, et al. Effects of policosanol treatment on the susceptibility of low density lipoprotein (LDL) isolated from healthy volunteers to oxidative modification in vitro. Br J Clin Pharmacol2OOO;W255-262. 21. Soltero I, Fuenmayor I, Colmenares J. Ensayo doble ciego para la evalaucion del policosanol en el tratamiento de la hiperlipoproteinemia tip0 II. Arch Venezol Farmacol Terap 1993;1265-70. 22.Aneiros E, Calderon B, Mas R, et al. Effects of successive dose increases of policosanol on the lipid profile and tolerability of treatment. Curr Ther Res 1993;54:304-312. 23. Aneiros E, Calderon B, Mas R, et al. Effect of policosanol in lowering cholesterol levels in patients with type-II hypercholesterolemia. Curr Ther Res 1995;56:176-182. 24. Pons P, Rodriguez M, Mas R, et al. One-year efficacy and safety of policosanol in patients with type-II hypercholesterolemia. Curr Ther Res 1994;55:1084-1092. 25. Castano G, Mas R, Nodarse M, et al. One-year study of the efficacy and safety of policosanol (5 mg twice daily) in the treatment of type II hypercholesterolemia. Curr Ther Res 1995;56:296-304. 26. Canetti M, Morera M, Illnait J, et al. One year study on the effect of policosanol (5 mg-twice-a-day) on lipid profile in patients with type II hypercholesterolemia. Adv Ther 1995;12245-254. 27. Pons P, Rodriguez M, Robaina C, et al. Effects of successive dose increases of policosanol on lipid profile of patients with type-II hypercholesterolaemia and tolerability to treatment. Int J Clin Pharmacol Res 1994;1427-33. 28.Castano G, Mas R, Femandez L, et al. Effects of policosanol 20 versus 40 mg/day in the treatment of patients with type Il hypercholesterolemia: a &month double-blind study. Int J Clin Pharmacol Res 2001;21:43-57. 29. Canetti M, Morera M, Mas R, et al. A two year study on the efficacy and tolerability of policosanol in patients with type 11 hyperlipoproteinaemia. Int J Clin Pharmacol Res 1995;15:159-165. 30.Castano G, Menendez R, Mas R, et al. Effects of policosanol and lovastatin on lipid profile and lipid peroxidation in patients with dyslipidemia associated with type 2 diabetes mellitus. Int J Clin Pharmacol Res 2002;22:89-99.

31. Castano G, Mas R, Femandez L, et al. Effects of policosanol and lovastatin in patients with intermittent claudication: a double-blind comparative pilot study. Angiology 2003;54:25-38. 32. Castano G, Mas R, Femandez L, et al. Comparison of the efficacy and tolerability of policosanol with atorvastatin in elderly patients with type I1 hypercholesterolaemia. Drugs Aging 2003;20:153-163. 33.Benitez M, Romero C, Mas R, et al. A comparative study of policosanol vs pravastatin in patients with type-II hypercholesterolemia. Curr Ther Res 1997;58:859-867. 34.Ortensi G, Gladstein J, Vail H, Tesone PA. A comparative study of policosanol versus simvastatin in elderly patients with hypercholesterolemia. Curr Ther Res 1997;58:390-401. 35. Prat H, Roman 0,Pino E. Comparative effects of policosanol and two HMGCoA reductase inhibitors on type II hypercholesterolemia.Rev Med Chil 1999;127286-294. 36. Canetti M, Morera M, Illnait J, et al. Estudio comparativo de 10s efectos del policosanol y el gemfibrozil on pacientes con hipercolesterolemia primaria tip0 II. Rev CENIC Cien Biol1996;27&70. 37. Soltero I, Fuenmayor I, Colmenares J. Estudio comparativo doble ciego de la eficacia y tolerancia del policosanol vs. bezafibrato en pacientes con hiperlipidemia tip0 II. Arch Venezol de Farmacol Terap 1993;1271-76. 38. Pons P, Femandez L, Mas R, et al. Estudio comparativo de 10s efectos del policosanol y el bezafibrato en pacientes con hipercolesterolemia primaria tip0 II. Rev CENIC Cien Biol1996;2771-77. 39. Alcocer L, Femandez L, Campos E, Mas R. A comparative study of policosanol versus acipimox in patients with type I1 hypercholesterolemia. Int J Tissue React 1999;21:85-92. 40.Pons P, Illnait J, Mas R, et al. A comparative study of policosanol versus probucol in patients with hypercholesterolemia. Curr Ther Res 1997;58:26-35. 41. Torres 0, Agramonte AJ, Illnait J, et al. Treatment of hypercholesterolemia in NIDDM with policosanol. Diabetes Care 1995;18: 393-397. 42. Crespo N, Alvarez R, Mas R, et al. Effect of policosanol on patients with non-insulin-dependent diabetes mellitus and hypercholesterolemia: A pilot study. Curr Ther Res 1997;58:44-51. 43. Castano G, Tula L, Canetti M, et al. Effects of policosanol in hypertensive patients with type II hypercholesterolemia. Curr Ther Res 1996;57691-699. 44.Castano G, Mas R, Fernandez JC, et al. Effects of policosanol on older patients with hypertension and type 11 hypercholesterolaemia. Drugs R D 2002;3:159-172. 45. Pons P, Jimenez A, Rodriguez M, et al. Effects of policosanol in elderly hypercholesterolemic patients. Curr Ther Res 1993;53: 265-269. 46. Castano G, Canetti M, Morera M, et al. Efficacy and tolerability of policosanol in elderly patients with type-11 hypercholesterolemia: a 12 months study. Curr Ther Res 1995;56819-828. 47. Castano G, Mas R, Femandez JC, et al. Effects of policosanol in older patients with type II hypercholesterolemia and high coronary risk. J Gerontol A Biol Sci Med Sci 2001;56M186-M192. 48. Zardoya R, Tula L, Castano G, et al. Effects of policosanol on hypercholesterolemic patients with disturbances on serum biochemical indicators of hepatic function. Curr Ther Res 1996;57568-577. 49. Arruzazabala ML, Mas R, Molina V, et al. Effect of policosanol on platelet aggregation in type II hypercholesterolemic patients. Int J Xssue React 1998;20119-124. 50. Arruzazabala ML, Valdes S, Mas R, et al. Comparative study of policosanol, aspirin and the combination therapy policosanolaspirin on platelet aggregation in healthy volunteers. Pharmacol Res 1997;36:293-297. 51. Arruzazabala ML, Molina V, Mas R, et al. Antiplatelet effects of policosanol(20 and 40 mg/day) in healthy volunteers and dyslipidaemic patients. Clin Exp Pharmacol Physiol2002;29891-897.

52. Stusser R, Batista J, Padron R, et al. Long-term therapy with policosanolimproves treadmiu exercise-ECG testingperformance of coronary heart disease patients. Int J Clin Pharmacol Ther 1998;36:469473. 53. Castano G, Mas Ferreiro R, Femandez L, et al. A long-term study of policosanol in the treatment of intermittent claudication. Angiology 2001;52115-125. 54.Femandez L, Mas R, Illnait J, Femandez JC. Policosanol results of a postmarketing surveillance study of 27,879 patients. Curr Ther Res 1998595'717-7722. 55. Aleman CL, Mas R, Rod& L, et al.Toximlogia aguda del Ateromixol (PFG) en roedores. Rev CENIC Cien Bio11991;22:102-105. 56. Aleman CL, Mas R, Rodeiro I, et al. Acute, subchronic and chronic toxicology of policosanol in rats. Toxicol Letters 1992;Suppl2:248. 57. Rodriguez C, Mesa R, Mas R, et al. Study of policosanol oral chronic toxicity in male monkeys (Mucacu arcfoides). Food Chem Toxicol 1994;32565-575. 58. Mesa AR, Mas R, Noa M, et al. Toxicity of policosanol in Beagle dogs: one year study. Toxicol Lett 1994;73131-190.

59. Aleman CL, Mas R, Hernandez C, et al. A 12 months study of policosanol oral toxicity in Sprague-Dawley rats. Toxicol Lett 1994;70 77-87. 60.Aleman CL,Puig MN, Elias EC, et al. Carcinogenicityof policosanol in mice: an 18 month study. Food Chem Toxicol 199533: 573-578. 61. Aleman CL, Mas Femiro R, Noa Puig M, et al. Carcinogenicity of policosanol in Sprague Dawley rats: a 24 month study. Teratog Carcinog Mutag 1994;14239-249. 62. Rodriguez MD, Garcia H. Teratogenic and reproductive studies of policosanol in the rat and rabbit. Teratog Carcinog Mutag 1994; 14:107-113. 63. Rodriguez MD, Garcia H. Evaluation of pen- and post-natal toxicity of policosanol in rats. Teratog Carcinog Mutagen 1998;18:1-7. 64.Rodriguez MD, Sanchez M, Garcia H. Multigeneration reproduction study of policosanol in rats. Toxicol Lett 1997;90:97-106. 65.Carbajal D, Arnuazabala ML, Valdes S, Mas R Interaction policosanol-warfarin on bleeding time and thrombosis in rats. Phannacol Res 1998;38:89-91.

Prebiotics Jason A . Hawrelak, HNat (Hons 1, 1’hI)c CHAPTER CONTENTS Introduction 1183 Fructooligosaccharides 1183 Description 1183 Commercial Forms 1184 Clinical Applications 1185 Dosage 1187 Toxicity 1187

INTRODUCT10N Two main tools are available to beneficially alter the gastrointestinal tract (GIT) microflora-probiotics and prebiotics. The focus of this chapter is to review the beneficial actions and safety profile of the latter. A prebiotic is defined as “a nondigestible food ingredient that beneficially effects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the coIon.”l For a food ingredient to be classified as prebiotic, it must satisfy the following requirements: 1. Be neither digested nor absorbed in the stomach or small intestine.2 2.Act as a selective food source for one or a limited number of potentially beneficial commensal bacteria in the large intestine.2 3. Change the colonic microflora ecosystem toward a healthier composition.2 4.Induce luminal or systemic changes that improve the health of the host.3

Most emphasis at this stage has been on finding and studying food sources that are used by lactic acid-producing bacteria, a choice that is due to the health-promoting properties of these organisms? The best-known lactic acid-producing bacteria belong to the genera Lactobacillus and Bifdobac terium. Not all food ingredients that travel to the colon undigested are prebiotics. Only compounds that are selectively consumed by beneficial members of the microflora while being ignored by potentially pathogenic ones can truly be termed prebiotics. When prebiotics reach the colon, they are preferentially utilized by those organisms that have the capacity to hydrolyze their bonds.

Lactulose 1188 Commercial Forms 1188 Clinical Applications 1188 Dosage 1191 Toxicity 1191 Colonic Foods 1191

The metabolism of the prebiotic results in the increased growth and activity of the beneficial organisms, often at the expense of other components of the microflora.4 Food ingredients that make it to the colon undigested but lack the selectivity of fermentation are termed colonic foods; they are discussed in more depth at the end of this chapter. Numerous compounds have the potential to be called prebiotics. Table 117-1 lists those compounds and the type of microorganisms whose growth they p r o r n ~ t e . ~ - ~ However, the best-researched prebiotics are the fructooligosaccharides and lactulose, both of which are the focus of this chapter.

FRUCTOOLIGOSACCHARIDES Description Fructooligosaccharides (FOSs) are linear or branched chains of fructose and glucose molecule^.^ The number of fructose units contained in a compound determines the name of the FOS. Oligofructose is generally composed of between 2 and 7 units, whereas inulin is composed of up to 60.1°FOSs are found in varying percentages in foods and are present in more than 36,000 plant species, where they function primarily as storage carbohydrates.” FOSs are found in many common vegetables, including asparagus, onion, leek, garlic, artichoke, Jerusalem artichoke, and chicory root. But it is from chicory root (Cichorium intybus) that most of the commercially produced inulin and oligofructose is manufactured. Shortchain fructans, such as oligofructose, are produced from inulin through a process of partial enzymatic hydrolysis? 1183

Pharmacology of Natural Medicines Prebiotic substances and the organisms whose growth they promote Prebiotic compound

Food sources

Targeted microorganisms

Fructooligosaccharides

See TaMe 1 17-2

Bifidobacterium spp.

LaCtUlose

Ultra-heat-treated milk Unknown

Lactobacillus spp., Bifidobacterium spp.

Lactitol Beta-glucooligomers

Oats

Lactobacillus spp.

Raffinose Galactooligosaccharides

Legumes, beets Cow's milk, yoghurt; human milk

Lactobacillus spp., Bifidobacterium spp.

Xylooligosaccharides

Oats

Bifidobacterium spp.

Lactosucrose Galactosyl lactose

None Human milk

Bifidobacteriumspp.

Lactobacillus spp., Bifidobacterium spp.

Bifidobacterium spp.

Bifidobacteriumspp.

Data from references 5-8.

Commercial Forms There are two ways in which FOSs can be consumed, in supplements and in foods.

Fructooligosaccharide Supplements The most commonly employed method to p u d y and concentrate FOSs for supplement use via a hot water extraction of fresh chicory roots. This process results in inulin (a.k.a. Raftdine, a long-chain FOS) as the end product. Some manufacturers utilize enzymatic hydrolysis to produce oligofructose (a.k.a., Raftilose, a medium-chain FOS) from i n ~ . ' OOther manufacturers synthesize FOSs from sucrose by using the fungal enzyme fructosyltransferase (from Aspergdlus niger). This last process involves chemical synthesis of a new compound (called Neosugar or Actilight, a short-chain FOS) from two other natural compounds (fructose and glucose). The finished compound is similar to naturally obtained FOS, only smaller? FOSs are resistant to digestion in the upper GIT because of the beta-configuration of the bonds between the fructose units.Human digestive enzymes are specific in requiring alpha linkages; thus FOSs are classified as nondigestible oligosaccharides?

Foodstuff

Form

Asparagus

Raw Boiled

Banana

Raw Dried (raw) Raw kernels Cooked kernels

Barley Burdock

Root (raw)

Chicory

Root (raw) Roasted (as coffee) Leaves (raw)

Dandelion

Root (raw)

Garlic

Raw

Globe artichoke

Boiled

Jerusalem artichoke

Tubers (raw)

Leek

Raw

Onion

Raw Cooked

Rye Salsify

Flour (raw)

Wheat

Bran (raw) Flour (baked)

Yacon

Root (raw)

Food Sources of Fructooligosaccharides As previously mentioned, FOSs are common food ingredients. Individuals consuming the standard Western diet consume an average of 5.1 g FOSs per day.I2 However, this amount can easily be increased if foods rich in FOSs are consumed on a daily basis. Foods containing FOSS are listed in Table 117-2.12J3 Other Fos-Containing foods are honey,14beer, Chinese chives, and maple syrup.15 There is no particular advantage to the consumption of FOSs as supplements rather than in FOSrich foods. As long as the amount of FOSs consumed in a food form is similar to that used in clinical studies, it will promote

Root (raw)

Data from references 12 and 13.

g FOS per 100 g fresh weiaht

Average percentage of fresh weiaht (%)

2.0-3.0 1.4-2.0 0.3-0.7 0.9-2.0 0.5-1.O 0.1-0.2 12.0-17.0 15.2-20.5 35.747.6 12.0-15.0 7.9 9.8-16.0 2.0-6.8 16.0-20.0

2.5 1.7 0.5 1.5 0.75 0.15 14.5 17.5 41.7 13.5 7.9 12.9 4.4 18.0

3.0 1.1-7.5 0.8-5.3 0.5-1.O 4.2 1.040 1 .O-3.8 3.0-19.0

3.0 4.3 3.1 0.7 4.2 2.5 2.4 11.0

Prebiotics

identical effects, because all FOSs consumed reach the colon intact, whether ingested in whole foods or as supplements.

Clinical Applications

bifidobacteria have relatively high beta-fructosidase activity that is specific for the fructose bonds present in FOSS.~~

In Vivo Evidence of a Prebiotic Eflect In a human trial utilizing oligofructose (8 g/day over a 2-week period), Mitsuoka et all5also found a 0.9 log unit increase in bifidobacteria numbers with oligofructose consumption (p < 0.005). The trial also showed a decrease in enterobacteria numbers. Buddington et alZ reported a 0.8 log increase in bifidobacteria ( p < 0.03) using a smaller dosage level of Enhanced resistance to enteric pathogens, due to colooligofructose (4 g/day). Oligofructose was administered nization resistance provided by the increased growth of over a period of 25 days. There appeared to be no change lactic acid-producing bacterial6 in other microflora populations. Increased resistance to infections, due to the nonspeUtilizing fairly large doses of inulin, Kleeson et al’ cific stimulation of the immune systernl6 noted a decrease in Bucteroides numbers and an increase Modification of carcinogen metabolism16 in bifidobacteria levels over a 19-day trial. With 20 g/day Enhanced absorption of mineralsI6 dosage levels, bifidobacteria levels increased by 0.9 log Improved serum lipid parameters16 units, and with 40 g/day, by 1.3 log units (p < 0.05). Treatment of atopic eczema and prevention of atopy In an attempt to determine the optimal dose of development” oligofructose, in terms of maximizing bifidobacteria Increased intestinal mucin production and trophic numbers and minimizing side effects, Bouhnik et a121 effects on the colonic epithelium, secondary to the designed a trial that used five different dosage levels. The increased production of SCFAs18 oligofructose dosages used were 20 g/day, 10 g/day, 5 g/day, and 2.5 g/day, with 0 &day as the placebo. The This review focuses primarily on the ability of FOSs to duration of the trial was 7 days. The data indicated enhance bifidobacterial growth, mineral absorption, and that bifidobacteria counts did not change in subjects serum lipid parameters as well as on the possibility of receiving 0 g or 2.5 g/day of oligofructose, but that in using FOSs in the treatment and prevention of atopic those subjects ingesting 5, 10, or 20 g/day, counts were diseases. sigruficantly greater (p < 0.05) at day 8 than at baseline. Enhanced Growth of Bifidobacteria A significant correlation between the ingested dose In Vitro Evidence of a Prebiotic ESfect of oligofructose and fecal bifidobacterial counts was observed at day 8 (p < 0.01). In terms of side effects, all Gibson and Wang conducted the initial in vitro experigroups, including the placebo group, experienced mild ments on the fermentation of oligofructose and inulin. Anaerobic batch culture fermenters were inoculated abdominal symptoms such as bloating, excess flatus, borborygmi, and mild abdominal pain. In general, the with both types of FOSs and mixed fecal organisms. higher the dose of oligofructose, the more side effects The results indicated that both oligofructose and inulin experienced. The investigators concluded that 10 g/day are completely and quickly metabolized by the fecal fl~ra.’~,~~ was well-tolerated and that this dose is probably the optimal dose of oligofructose, as it leads to a significant This initial research was later followed up in order to increase in colonic bifidobacteria with minimal side ascertain which of the fecal microorganisms could utilize effects. FOSs as growth substrates. Data indicated that FOSs are efficient substrates for the majority of bifidobacteria In a study reported by Gibson et al,” both oligofrucstrains tested (except Bifidobucteriurn bifidum). In pure tose and inulin were tested to assess their effects on bificultures, many other organisms showed an ability to utidobacteria levels and the populations of other members lize FOSs as substrates, including Klebsiella pneurnoniue, of the intestinal microflora. Eight subjects participated in the 45-day trial in which they ate controlled diets. For Staphylococcus epidermis, Staphylococcus aureus, Bacteroides the first 15 days, all the subjects ate 15 g/day of sucrose. fragilis, Bacteroides ovutus, Bucteroides thetaiotaomicron, Bacteroides vulgatus, En terococcus faecalis, Enterococcus For the middle 15 days, the sucrose was substituted with faecium, Lactobacillus acidophilus, and Clostridium ~ p p . ~15 g of oligofructose. For the final 15 days, four of the participants were given 15 g/day of inulin. A marked However in mixed cultures,which mimic the real situation effect was noted in bifidobacteria numbers, which in the colon, bifidobacteria become the dominant microorganisms present, suggesting an ability to “out-compete” increased 0.7 log units with oligofructose (p < 0.01) and 0.9 log units with inulin (p < 0.001). There was also these other organisms for the available FOSs. Indeed The health benefits claimed for prebiotics stem mainly from their ability to increase numbers of beneficial organisms in the colon, to reduce numbers of potentially pathogenic microorganisms (PPMs), and to stimulate production of short-chain fatty acids (SCFAs). These health benefits are as follows:

Pharmacology of Natural Medicines ~

a sigruficant decrease in bacteroides (p < 0.01), clostridia (p < 0.05), and fusobacteria (p < 0.01) in the oligofructosefed subjects, whereas levels of gram-positive cocci decreased in the inulin-fed group (p c 0.001). Inulin administration also increased lactobacilli numbers, although not sigruficantly (p < 0.075). In both groups, bifidobacteria became the numerically predominant species in the feces (Figure 117-1).24*25

Enhanced Mineral Absorption Studies utilizing animal models have demonstrated that microfloral degradation of FOSs sigruficantly increases calcium and magnesium absorption.26-28 Human studies have also shown that FOS consumption improves calcium abs0rption.2~~~ The proposed mechanism by which mineral absorption is enhanced by FOSs is the action of protonated SCFAs. Protonated SCFAs are absorbed across the apical membrane of colonocytes by direct diffusion. Owing to the low pK, values of the SCFA in relation to the intracellular pH, the SCFA dissociates once it has entered the cell. This results in the release of a hydrogen ion. The hydrogen ion is subsequently secreted from the cell in return for a cation, which may be a magnesium or calcium ion. The hydrogen ion is then available to protonate another SCFA and enable it to diffuse into the cellz9Other mechanisms may also be involved, however, such as the decrease in colonic pH that results in greater solubility of calcium, higher colonic venous blood flow, enlarged colonic villi, and enhanced expression of

calbindin-D9k (the active calcium transport These effects are more pronounced in the colon and some are calcium-specific, explaining why calcium absorption is increased even though there is very little impact on the absorption of other minerals (e.g., iron and ~ i n c ) . ~

Lipid-Lowering Effects Animal studies have demonstrated that the consumption of FOSs lowers serum triacylglycerol and total and very-low-density lipoprotein (VLDL) cholesterol levels.3e36Human trials have produced mixed results, with one study showing improved lipid profiles after FOS consumption (specifically, higher fasting insulin levels and plasma triacylglycerol levels)34and others finding no significant effect^?^,^ The differences in results may be explained by the varying duration of treatment in these trials. The positive result was found in an 8-week-long trial, and the two trials with negative results were shorter (20 and 28 days). Thus long-term consumption of FOSs may beneficially affect dyslipidemia, although the effects appear to be fairly modest. Further trials in hyperlipidemic individuals are needed to clanfy the role of FOSs in the management of lipid disorders.

Improved Bioavailability of Phytoestrogens An interesting animal (rat) study has found that concurrent consumption of FOSs and the soy-isoflavones

Flgure 117-1 The prebiotk concept: The effects of sucrose, oligofructose and inulin on the intestinal ecosystem. Pie diagrams illustrate how the microflora can develop during the feeding of sucrose and the prebiotics oligofructose and inulin (From Gibson GR. Br J Nutr 1998;80:S209-S212. Used with permission).

Prebiotics genistein and daidzein significantly improved the bioavailability of these compounds. The relative absorption of genistein was ~ 2 0 %higher in FOS-fed rats than in controls. In addition, the presence of both phytoestrogens in serum was maintained for longer in FOSfed rats than in controls, suggesting that FOSs enhanced colonic absorption of these c0mpounds.3~ This result may be especially relevant to women who have just finished antibiotic therapy, in whom the metabolism and subsequent absorption of phytoestrogens appears to be impaired.40Bifidobacteria have been demonstrated to possess beta-glucosidase activity and FOS administration has resulted in enhanced betaglucosidase activity in animal models41 in addition to So, FOS improved phytoestrogen bioa~ailability.~~ consumption not only aids in the reestablishment of a healthy GIT microflora; its consumption also increases colonic beta-glucosidase activity, resulting in enhanced deglycosylation and, thus, increased colonic concentrations of the medicinally active aglycones. Hence, FOSs increase both the metabolism and the absorption of phytoestrogens.

Treatment of Atopic Eczema and Prevention of Atopy Development A number of studies have found an aberrant composition of the GIT microflora in infants who later experience food allergies and atopic More specifically, the development of atopic eczema has been correlated with higher colonic concentrations of Bacferoides spp., Clostridiu spp., and E. coli and a decreased concentration of bifidobacteria. This change in microbial composition is theorized to deprive the developing immune system from counter-regulatorysignals against responses mediated by helper type 2 T (Th2) cells and, hence, to promote Th2-type immunity?5 Infantile atopic eczema is characterized by a Th2-dominated immune response as well as excessive intestinal inflammation and aberrant macromolecular absorption across the intestinal mucosa.These latter characteristics may also be caused by the dysbiotic condition. Bacteroides, clostidia and E. coli all have the potential to trigger inflammatory responses in the gut and can release toxins that can impair intestinal permeability, leading to increased exposure to potential antigens.& Supplementation with FOSs has been to demonstrated to reduce colonic concentrations of both Bacteroides and clostridia as well as to promote a bifidobacteria-dominated colonic Hence FOSs use may bring the aberrant intestinal flora back into balance, thereby improving gut barrier function. The promotion of an intestinal flora dominated by grampositive bacteria may also promote a shift towards Thl immunity via an enhanced production of interleukin-12 and interferon-y.%

Two other studies have demonstrated the ability of B$dobacteriurn spp. (Bifidobucteriurn lactis strain Bb12) to alleviate the symptoms of infantile atopic e ~ z e m a . 4 ~ 5 ~ Thus, there is the potential for FOSs to be used in the treatment of atopic eczema, because stimulation of the growth of endogenous strains of bifidobacteria may produce similar results. FOS treatment has not yet been studied but it could prove to be very effective.

Dosage Studies have shown a bifidogenic effect in dosages of 4 to 40 g/day of FOSs. The optimum dosage, in terms of side effect profile and increases in bifidobacteria concentration, is considered to be 10 g/day. The physician should start with a lower dose and slowly increase it to reduce chances of adverse GIT reactions. Dosages smaller than 3 g/day are unlikely to cause significant alterations in the GIT microecology.

Toxicity FOSs are components of many common foods. No genotoxic, carcinogenic, mutagenic, teratogenic, or toxicologic effects are associated with the ingestion of any FOS.1652 Oligofructose and inulin are officially recognized as natural food ingredients in most European countries and have a self-affirmed GRAS (generally regarded as safe) status in the United States? A 2000 published case study described an instance of anaphylaxis attributed to inulin found in vegetables and processed foods. This was later confirmed with skin-prick testing and blinded food-provocation testing.53 This allergy does appear to be extremely rare, however, considering the widespread consumption of FOScontaining foods. The only side effects noted with administration of FOSs are mild digestive symptoms, such as flatulence, borborygmi, abdominal bloating, and abdominal discomfort. However these effects are dose-dependent and occur less regularly with smaller doses. Over time, these symptoms diminish as the intestinal flora adjusts to the greater amount of substrate available." However, some individuals may continue to experience mild abdominal bloating and discomfort even with continued use. Some concerns have been put forth in the literature regarding the ability of K. pneurnoniae to utilize FOS as a growth sub~trate.%5~ FOS has indeed been shown to stimulate the growth of K. pneurnoniae in Petri dishes; however, this occurred only when Klebsiella was grown in isolation, with no other competing organisms present. In mixed-culture experiments, in which KZebsieZZa was grown in the presence of many other human GIT microorganisms, this growth stimulation did not O C C U T . ~ ~ In these situations, which more closely resemble the environment of the human GIT (where more than

Pharmacology of Natural Medicines

500 species of bacteria compete for available growth substrates)%,FOS did not stimulate the growth of Klebsiella? In addition, no human or animal experiment has ever reported the Klebsiella concentration in the GIT to rise after FOS consumption.

LACTULOSE Lactulose is a semisynthetic disaccharide composed of the monosaccharides fructose and galactose. It was first synthesized from lactose in 1929 by Montgomery and Huds0n.5~The human digestive system lacks the ability to break down lactulose into its component hexose and pentose moieties. Hence, lactulose is neither catabolized nor absorbed in the small intestine. Once lactulose reaches the large intestine, it is fermented by the normal intestinal microflora. Fermentation is the process through which the normal intestinal microflora catabolizes carbohydrates in order to obtain energy for growth and maintenance of cellular functions. The end products of lactulose fermentation include SCFAs, lactic acid, and the gases hydrogen and carbon dioxide.% In vitro experiments have demonstrated that overall SCFA production is increased twofold to threefold by the addition of lactulose, and acetate synthesis fourfold to si~fold.5~*~ Within the large intestine, these SCFAs are avidly absorbed by colonocytes and used as a source of energy, either locally or systemically. The production of SCFAs also results in the acidification of the colonic contents.% Brown et a161have demonstrated that a daily dose of 30 to 40 g of lactulose reduces the pH of the proximal colon from 6.0 to 4.85.

Commercial Forms Lactulose is available in two forms, syrup and crystalline powder. Lactulose syrup generally contains between 50% and 67Y0 ladulose (in addition to some lactose and galactose), whereas the crystalline powder is composed of 99% lactulose. The only food source of lactulose thus far identified is ultra-heat-treated milk, although lactulose is present only in insignificant amounts in this substance?

Clinical Applications Lactulose has a wide variety of clinical applications, including: Promoting growth of lactobacilli and bifidobacteria Decreasing growth of intestinal pathogens Constipation Preventing colon cancer Liver disease Endotoxemia Preventing urinary tract infections

Promoting Growth of Lactobacilli and Bifidobacteria In Vitro Evidence of a Prebiotic Elypect Lactulose can be fermented by only a limited number of intestinal microorganisms. These microorganisms are Lactobacillus spp., Bifidobacterium spp., and Enterococcus spp. Studies have found that these three types of microorganisms readily metabolize lactulose, producing mainly lactic and acetic acids as end products. In these same experiments, E. coli, Proteus spp., Salmonella spp., and Shigella spp. were unable to utilize lactulose as a growth substrate.62 In vitro experiments conducted by Kontula et alG demonstrated the growth of some species of lactic acid-producing bacteria on lactulose. Lactobacillus species acidophilus, rhumnosus, and lactis ssp lactis, Enterococcus species faecalis and hirae, and various Streptococcus species were shown to be able to utilize lactulose as a growth substrate. In another in vitro study, It0 et alM found that the addition of lactulose to fecal samples resulted in a sigruficant alteration in the fecal microbial population. The growth of Clostridium dificicile, Bacteroides spp., Enterobacteriaceae, and Bifidobacterium spp. was significantly suppressed in the lactulose samples compared with controls, and lactobacilli became the dominant component of the fecal flora. The suppressed growth of the former organisms appears to be caused by the decrease in fecal pH caused by the metabolism of lactulose. The end products of ladulose metabolism-lactic acid and SCFAs-raise the hydrogen ion concentration in the intestinal lumen and hence lower the fecal pH. This decrease in pH appears to inhibit the metabolism and growth of various intestinal microorganisms, including the PPMs C. dificile and Bacteroides spp.@ The suppressive effect of lactulose on the growth of Bifidobacteriurn spp. in this last experiment appears to conflict with earlier data. However, the investigators believe that this inconsistency can be explained by the environmental pH in the fecal incubation system used in the study. Brown et a16 have reported that the pH in the proximal colon drops to a maximum of 4.85 after lactulose administration.61In the It0 in vitro study, the pH was measured at below 4.0.Vince et a16 have previously reported the growth of Bifidobucterium spp. to be suppressed when such acidic conditions develop. Thus this effect would not occur in vivo, where the pH is more alkaline. In Vivo Evidence of a Prebiotic Eflect In one of the original studies utilizing lactulose to change the fecal flora, MacGillivray et a1%assessed the effects of lactulose feeding on infants. All infants were formula fed and younger than 4 months old. After a feeding period of 2 days, the lactulose-containing formula

Prebiotics produced a preponderance of Lactobacillus bifidus (now known as B. bifidum) in the stools of 88% of the infants. In 66% of the infants, B. bifidum dominated the fecal flora at concentrationsgreater than 90%. None of these infants had a bifidobacteria-dominated flora at baseline. Terada et aF7reported that 3 &day of lactulose taken over a 2-week period altered intestinal microflora and fecal bacterial metabolism in adults. The study was conducted in 8 healthy volunteers. During the intake of lactulose, the number of bifidobacteria increased significantly (p < 0.001), as did the lactobacilli population (p < 0.05), whereas the number of Bacteroidaceae and clostridia decreased (p < 0.05) compared with baseline values. Bifidobacteria became the numerically dominant microorganism in the fecal flora after 14 days of lactulose administration. The fecal metabolites skatol, indole, and phenols were also significantly reduced with lactulose intake ( p < 0.05). Fecal betaglucuronidase, azoreductase, and nitroreductase activities also decreased significantly (p < 0.05) after 14 days of treatment. These latter results indicate reduced metabolism of putrefactive (protein-fermenting) organisms of the microflora. The mean fecal pH also dropped from 7.0 to 6.4. Ballongue et a P conducted an in vivo study to assess the effects of lactulose on the intestinal microbial ecosystem. In a double-blind, randomized, placebo-controlled trial, they measured the effects of a daily dose of 20 g lactulose on the gastrointestinal microbiota. After 4 weeks of treatment, populations of Bucteroides, Clostridium, coliforms, and Eubucterium had decreased by 4.1, 2.3, 1.8, and 3.0 log units, respectively, and populations of Bifidobucterium, Lactobucillus, and Streptococcus had increased by 3.0, 1.9, and 1.2 log units, respectively, in comparison with placebo; all the differences were statistically sigruficant (p < 0.01). The fecal pH also fell from a baseline of 6.9 to 5.8 by the end of the treatment period (p < 0.01). Acetic acid production was increased 33%, and lactic acid production by 30% (p < 0.01) by lactulose administration.

Decreasing Growth of Potentially Pathogenic Microorganisms Research suggests that lactulose not only enhances the growth of beneficial members of the GIT microflora but also inhibits the growth of potential intestinal pathogens. Studies have demonstrated that lactulose consumption can decrease colonic concentrations of clostridia, Bucteroides spp., and coliformsM as well as eradicate carrier states involving SulrnoneIlu spp.69*70 The ability of lactulose to increase numbers of lactobacilli and bifidobacteria and to diminish numbers of gram-negative bacteria is believed to be due to two mechanisms. The first is lactulose’s ability to act directly as a food source for lactobacilliand bifidobacteria

organisms while being only weakly metabolized by gram-negative organism^.^' The second mechanism is the change in colonic pH caused by the end products of lactulose metabolism-lactic acid and SCFAs. The coupled effect of SCFA production and pH decrease has been shown to inhibit the growth of gram-negative bacteria. The diminished pH resulting from lactulose administration has been shown to raise the total concentration of the undissociated forms of SCFAS.~These lipophilic acids can penetrate the microbial cell membrane and, at the higher intracellular pH, dissociate to produce hydrogen ions. The hydrogen ions interfere with essential metabolic functions, such as substrate translocation and oxidative phosphorylation, and hence inhibit the growth of gram-negative microbes.n In vitro experimentshave also demonstrated the ability of lactulose to inhibit the growth of Cundidu ulbicuns. A continuous-flow culture was used as a model of the human GIT ecosystem. Within 24 hours after the input of 0.25% lactulose, C. ulbicuns numbers were reduced by 97%. The reduction in Cundidu numbers was believed to be caused by the increase in the growth of lactic acidproducing bacteria and the overall drop in pH.73

Constipation Lactulose is used in conventional medicine mainly for its laxative effects. It works primarily as an osmotic laxative, but the greater production of SCFAs may also play a role.58t74 Ingestion of lactulose has been found to cause statistically sigruficant rises in the frequency, weight, volume, and water content of stools and to produce stools of softer consistency compared with both baseline and placebo.”

Preventing Colon Cancer Lactulose may protect against the development of colon cancer via a number of different mechanisms, four of which are discussed here. First, lactulose administration has been found to decrease the production of secondary bile acids in the intestinal tract (secondary bile acids have been postulated to be promoters of colonic carcinogenesis). This effect is thought to be mediated by the reduction in luminal pH caused by lactulose fermentati~n.~~ Second, lactulose also has the ability to decrease the metabolism of PPMs. This action appears to be directly related to lactulose’s ability to reduce colonic pH. The low pH suppresses overall metabolism of these organisms, which can be indirectly measured by the drop in fecal enzymatic activity by the microorganisms. In an in vivo study, Ballongue et alMdemonstrated a statistically significant decrease in the specific activity of a number of bacterial enzymes that are believed to be involved in the genesis of colon cancer. Activity of azoreductase was lowered by 45%, that of 7-alpha-dehydroxylase by 40%,

Pharmacology of Natural Medicines that of beta-glucuronidaseby 38%,that of nitroreductase by 36%, and that of urease by 27% (all, p < 0.01). Facultative anaerobes like coliforms and anaerobes like Clost ridiurn and Bacteroides normally produce betaglucuronidase, 7 - d p h d & y d 1 ~ ~ and ~1n ~i~h d , uctase. The decreased activity of these enzymes correlates with the reduced numbers of Bacteroides, Clostridiurn, and colifonns found in this clinical trial after administration of lactulose. Third, lactulose appears to inhibit the formation of ammonia within the intestinal tract.n Ammonia has been shown to alter the morphology and intermediary metabolism of intestinal cells as well as to increase DNA synthesis in and reduce the lifespan of mucosal cells.78It is also considered to be more toxic to healthy mucosal cells than to transformed cells, and thus, ammonia may potentially select for neoplastic gr0wth.7~Thus, any inhibition of ammonia production should be of benefit in the prevention of colon tumorigenesis. Additionally, a randomized, clinical trial conducted by Roncucci et alm demonstrated the ability of lactulose to prevent the growth of resected colorectal polyps. Lactulose administration (20 g/day) reduced the recurrence rates of colonic polyps by 66% (p < 0.02) compared with controls.

Hepatic Encephalopathy Hepatic encephalopathy is often found as a complication of liver cirrhosis. It is considered the totality of nervous system manifestations of liver failure. Symptoms include tremors, mental confusion, memory loss, and personality changes. The exact cause of hepatic encephalopathy is not known. However, an accumulation of neurotoxins (particularly ammonia) in the cerebral circulation is commonly believed to be the main causative factor.61 A number of studies have found lactulose to be effective in the management of this condition?”@ Lactulose is believed to work via a number of different mechanisms. First, lactulose fermentation results in the production of SCFAs and a subsequent decrease in colonic pH. This causes the protonation of potentially toxic ammonia (produced via the fermentation of proteins and blood in the intestinal lumen) to produce ammonium ions, which are unable to diffuse through to the portal circulation. Hence, systemic and cerebral ammonia levels de~rease.8~ Second, lactulose administration in cirrhotic individuals results in the beneficial modification of the microflora, so that non-proteinfermenting organisms (e.g., bifidobacteria) dominate the colonic flora, thereby reducing ammonia production in the ~ o l o n . ~Third, f i ~ the low colonic pH secondary to lactulose fermentation prevents the putrefaction of amino acids, proteins, and blood within the colon, reducing the luminal production of ammonia.=

Endotoxemia Endotoxins are lipopolysaccharide constituents of the outer membranes of gram-negative bacteria. Gramnegative bacteria continuously shed components of their outer cell membranes, resulting in the release of an enormous quantity of endotoxin. Gram-negative bacteria compose a sigruficant proportion of the intestinal microflora (e.g., Bacferoides spp., Fusobacteriurn spp., and Enteroba~teriaceae)~~~~~; thus, this membrane shedding results in release of significant quantities of endotoxin into the intestinal lumen. In healthy individuals, luminal endotoxin causes minimal systemic effects. However, in individuals with a compromised intestinal barrier or suboptimal liver function, this intestinal endotoxin can have pathologic consequences?l Liehr et a192 demonstrated that lactulose possesses antiendotoxin activity. When rats were fed lactulose over a 4 or 8 days before intravenous administration of galactosamine, the liver damage that normally develops was prevented. Because galactosamine-induced liver necrosis and inflammation are mediated by systemic endotoxemia of intestinal origin, the prevention of liver inflammation and necrosis after lactulose consumption suggests an antiendotoxin effect. This effect was most likely mediated by an alteration of the intestinal microecology, which indirectly diminished the intestinal pool of endotoxin. However the researchers also suggest a direct antiendotoxin effect, because intravenous administration of lactulose also prevents galactosamineinduced hepatitis. This work was followed by a prospective, controlled trial assessing the use of lactulose in endotoxemia secondary to obstructivejaundice. Oral lactulose (30 ml/6 hours) was given to 12 patients for 3 days before surgery, and another 12 patients were used as controls. Lactulose administration sigruficantly reduced the incidence of endotoxemia in the portal blood during the operation and in the systemic blood after the operation (both, p < 0.05). Interestingly, lactulose appear to both decrease the luminal pool of endotoxin and directly prevent endotoxin absorpti0n.9~

Preventing Urinary Tract Infections Two human studies have demonstrated the efficacy of lactulose therapy in the prevention of urinary tract infections. McCutcheon and F ~ l t o nconducted ~~ a retrospective study with 45 elderly, long-term hospital patients as subjects. They found that daily lactulose therapy for 6 months (30 ml lactulose syrup per day) led to a sigruficant reduction in rate of urinary tract infections (UTIs) compared with controls (p < 0.025). Sixteen of the 17 lactulose-treated patients (94%) remained infection free over the 6 months, compared with only 16 of the 28 control subjects (57%) (p < 0.005). In addition, there were significant reductions in the number of antibiotic

Prebiotics

prescriptions ( p < 0.05) and in the number of patients receiving antibiotics ( p < 0.005) in the lactulose group.” In the second study, Mack and colleagues (cited in enrolled 75 elderly, hospitalized patients in a randomized, placebo-controlled trial. Thrty-eight patients received the placebo, and 58 lactulose therapy. Only 12% of the lactulose group experienced UTIs during the period of follow-up, compared with 32% in the control group (p < 0.01). Thus lactulose consumption demonstrates sigruiicant protection against the development of UTIs. The intestinal microflora appears to act as a reservoir for urinary tract pathogens. Microorganisms such as E . coZi, E. faecaZis, E . faecium, and K. pneumoniae are all common urinary tract pathogens, and these organisms are also commonly found in the GIT. The organisms can escape the confines of the large bowel and, in susceptible individuals, colonize the vagina, periurethral area, and distal urethra. From these areas they can ascend into the bladder. Thus, interventions that can inhibit the growth of these organisms in the GIT should result in decreased numbers organisms available to colonize the genitourinary tract.89This is likely to be the mechanism by which lactulose therapy prevents UTIs. Ingestion of lactulose acidifies the large bowel and sigruficantly increases the production of SCFA.61*68 At a low pH, these SCFAs (particularly butyrate) inhibit the growth and metabolism of enterococci and E. coZi, substantially reducing their overall populations in the large bowels9and decreasing the intestinal reservoir of urinary tract pathogens.

constipation the recommended dose is 15 to 40 g/day.75,96 For the management of liver disease, higher dosages have usually been employed (-35 g/day).%

Toxicity Therapeuticuse of lactulose is considered to be extremely safe, with adverse reactions generally being mild and few. Side effects consist of vomiting, nausea, diarrhea, and abdominal However, these reactions tend to occur only with single doses larger than 60 g, which appears to be the maximum load of lactulose that the intestinal flora is able to metabolize to SCFAs at one time. When the bacterial fermentation capacity is exceeded, osmotic diarrhea, abdominal cramping, and nausea may result. These symptoms are most likely caused by the interference with net fluid absorption in the colon owing to the osmotic effect of malabsorbed and intact sugars?* Nonetheless, flatulence, abdominal bloating, and discomfort are common symptoms at the start of lactulose therapy. Gastrointestinal symptoms diminish, however, as the colonic microflora adapts to the greater amount of fermentable substrate.97

COLONIC FOODS

Colonzcfoods are defined as ”foods entering the colon and serving as substrates for the endogenous colonic bacteria, thus indirectly providing the host with energy, metabolic substrates and essential micronutients.”85By definition, then, colonic foods escape digestion and absorption in the Dosage upper GIT to reach the colon intact. Here members of the colonic microflora ferment the foods to produce SCFAs, Doses of lactulose as low as 3 g/day have been shown to cause beneficial alterations in the intestinal mi~roflora.~’ hydrogen, methane, and carbon dioxide. Through the production of SCFAs, the ingestion of colonic foods plays However, higher doses (e.g., 10 g/bid) appear to proa pivotal role in the health of the host.74 duce more substantial changes.@For the treatment of

.*

~

Other foods that may produce beneficial changes in the intestinal microflora

Food or food-component

Type of study

Observed changes

Oat bran

In vitro

Increased growth of Lactobacillus rhamnosus, Lactobacillus plantarum, and Lactococcus lactis1O0

Rat feeding study

Increased growth of lactobacilliand bifidobacteria; decreased numbers of coliformsIo1

Carrot

Human feeding study

Increased growth of bifidobacteriaIo2

Brown rice

Human feeding study

Increased numbers of Bifidobacterium adolescentis and Enterococcus faecalis; decreased counts of bacteroides, Eubacterium aerofaciens, Escherichia coli, and Clostridium spp.Io3

Tea polyphenols

Pig feeding study

Chicken feeding study

Increased numbers of lactobacilli;decreased counts of bacteroides and lecithin-positive clostridia; decreased fecal concentrations of ammonia, phenol, cresol, and skato1104 Enhanced growth of lactobacilli; reduced bacteroides numbersIo5

Human flora-associated rat feeding study

Increased growth of lactobacilli, bifidobacteria, and staphylococci; decreased counts of enterobacteria”

Resistant starch

Pharmacology of Natural Medicines

Colonic foods lack the specificity of fermentation that prebiotics possess. Thus their ingestion promotes the growth and/or metabolic activity of a number of different bacterial species within the large bowel, including species that are potentially harmful. Colonic foods include resistant starch, plant cell wall polysaccharides (e.g.,cellulose),hemicelluloses, pectins, and gums.@ Commonly used fibers, such as slippery elm, pectin, psyllium husks, and p a r gum, should all be considered colonic foods, not prebiotics,because they are utilized by a number of different bacterial species in the bowel.

1.Roberfroid MB. Prebiotics and synbiotics: concepts and nutritional properties. Br J Nutr 1998;80:S197-S202. 2.Collins MD, Gibson GR. Probiotics, prebiotics, and synbiotics: approaches for modulating the microbial ecology of the gut. Am J Clin Nutr 1999;691052!5-1057s. 3.Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995;125:1401-1412. 4. Goldin BR, Gorbach SL. Prebiotics: A review of their effects on the intestinal flora and health benefits. Gastroenterol Int 1998;ll (SUppll):l-3. 5. Van Loo J, CummingsJ, Delzenne N, et al. F~nctionalfood properties of non-digestible oligosaccharides: a consensus report from the ENDO project (DGW AIRIIcT94-1095). Br J Nutr 1999;81:121-132. 6. Hudson MJ, Marsh PD. Carbohydrate metabolism in the colon. In Gibson GR, Macfarlane GT, eds. Human colonic bacteria: role in nutrition, physiology, and pathology. Boca Raton, W. CRC Press, 1995. 7.Teramoto F, Rokutan K, Kawakami Y, et al. Effect of 4G-beta-cgalactosylsucrose (lactosucrose) on fecal microflora in patients with chronic inflammatory bowel disease. J Gastroenterol1996;31:33-39. 8. Teuri U, Korpela R. Galacto-oligosaccharidesrelieve constipation in elderly people. Ann Nutr Metab 1998;42.319-327. 9.Roberfroid MB, Delzenne NM. Dietary fructans. Ann Rev Nutr 1998;18117-143. 10. Roberfroid MB, Van Loo JA, Gibson GR. The bifidogenic nature of chicory inulin and its hydrolysis products. J Nutr 1998;12811-19. 11.Nmess KR. Inulin and oligofructose: what are they? J Nutr 1999;129140251406s. 12. Moshfegh AJ, Friday JE, Goldman JF', Ahuja JK. Presence of inulin and oligofructose in the diets of Americans. J Nutr 1999;129 1407S1411S. 13. Van Loo J, Coussement P, De Leenheer L, et al. On the presence of inulin and oligofructose as natural ingredients in the Western diet. Crit Rev Food Sci Nutr 1995;35:525-552. 14. Swallow KW, Low NH.Analysis and quantitation of the carbohydrates in honey using high-performance liquid chromatography. J Agric Food Chem 1990;38:1828-1832. 15. Mitsuoka T, Hidaka H, Eida T. Effect of fructooligosaccharides on intestinal microflora. Nahrung 1987;31:427-436. 16.Macfarlane GT, Cummings JH. Probiotics and prebiotics: can regulating the activities of the intestinal bacteria benefit health? BMJ 1999318:999-1003. 17. Laiho K, Ouwehand A, Salminen S, Isolauri E. Inventing probiotic functional foods for patients with allergic disease. Ann Allergy Asthma Immuno12002;89(Suppl1):75-82. 18. Latella G. Effects of SCFA on human colonocytes. Gastroenterol Int 1998;11(Suppl 1):76-79.

For example, guar gum is metabolized by Bucteroides spp. ~ is fermented by and Rurninococcus S P P . , ~pectin Bucteroides spp., Bifidobucteriurn spp., Eubucteriurn spp., and Clostridium spp.,* and psyllium husks are fermented solely by Bucteroides ~ p p . 9 ~ Some colonic foods, however, have demonstrated the ability to promote the growth of beneficial species of bacteria, although their effects are not as specific as with prebiotics. Foods and food constituents that promote the growth of beneficial bacteria are listed in Table 117-3.1m106

19. Wang X, Gibson GR. Effects of the in vitro fermentation of oligofructose and inulin by bacteria growing in the human large intestine. J Appl Bacteriol1993;75373-380. 20. Gibson GR, Wang X. Bifidogenic properties of different types of fructose containing oligosaccharides. Food Microbiol1994;11:491-498. 21. Bouhnik Y,Vahedi K, Achour L, et al. Short-chain fructmligosaccharide administration dose-dependently increases fecal bifidobacteria in healthy humans. J Nutr 1999;129113-116. 22.Buddington RK, Williams CH, Chen SC, Witherly SA. Dietary supplement of neosugar alters the fecal flora and decreases activities of some reductive enzymes in human subjects. Am J Clin Nutr 1996;63:709-716. 23. Kleessen B, Sykura B, Zunft HJ, Blaut M. Effects of inulin and lactose on fecal microflora, microbial activity, and bowel habit in elderly constipated persons. Am J Clin Nutr 1997;65:1397-1402. 24. Gibson GR, Beatty ER, Wang X, CummingsJH. Selectivestimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology 1995;108:975-982. 25. Gibson GR. Dietary modulation of the human gut microflora using prebiotics. Br J Nutr 1998;80:S209-S212. 26.Ohta A, Ohtsuki M, Baba S, et al. Calcium and magnesium absorption from the colon and rectum are increased in rats fed fructooligosaccharides.J Nutr 1995;1252417-2424. 27. Younes H, Coudray C, Bellanger J, et al. Effects of two fermentable carbohydrates(inulin and resistant starch) and their combination on calcium and magnesium balance in rats. Br J Nutr 2001;86479-485. 28.Takahara S, Morohashi T, Sano T, et al. Fructooligosaccharide consumption enhances femoral bone volume and mineral concentrations in rats. J Nutr 2O00;1301792-1795. 29.Trinidad Tp, Wolever TM, Thompson LU. Effect of acetate and propionate on calcium absorption from the rectum and distal colon of humans. Am J Clin Nutr 1996;63:574-578. 30.van den Heuvel EG, Muys T, van Dokkum W, Schaafsma G. Oligofructosestimulates calcium absorption in adolescents.Am J Clin Nutr 1999;69:544-548. 31. Griffin IJ, Davila I'M, Abrams SA. Non-digestible oligosaccharides and calcium absorption in girls with adequate calcium intakes. Br J Nutr 2002;87(Suppl2):S187-S191. 32. Scholz-AhrensKE, SchaafsmaG, van den Heuvel EG, SChreZenmeir J. Effects of prebiotics on mineral metabolism. Am J Clin Nutr 2001; 733459S-464s. 33. Coudray C, Bellanger J, Castiglia-DelavaudC, et al. Effect of soluble or partly soluble dietary fibres supplementation on absorption and balance of calcium, magnesium, iron and zinc in healthy young men. Eur J Clin Nutr 199751:375-380. 34.Jackson KG, Taylor GR, Clohessy AM, Williams CM. The effect of the daily intake of inulin on fasting lipid, insulinand glucose concentrations in middle-aged men and women. Br J Nutr 1999;8223-30.

Prebiotics 35.Kok N, Roberfroid M, Robert A, Delzenne N. Involvement of lipogenesis in the lower VLDL secretion induced by oligofructose in rats. Br J Nutr 1996;76881-890. 36. Fiordaliso M, Kok N, Desager JP, et al. Dietary oligofructose lowers triglycerides, phospholipids and cholesterol in serum and very low density lipoproteins of rats. Lipids 1995;30163-167. 37.Alles MS, de Roos NM, Bakx JC, et al. Consumption of fructooligosaccharides does not favorably affect blood glucose and serum lipid concentrations in patients with type 2 diabetes. Am J Clin Nutr 1999;69:64-69. 38. Pedersen A, Sandstrom 8, van Amelsvoort JM. The effect of ingestion of inulin on blood lipids and gastrointestinal symptoms in healthy females. Br J Nutr 1997;78:215-222. 39. Uehara M, Ohta A, Sakai K, et al. Dietary fructooligosaccharides modify intestinal bioavailability of a single dose of genistein and daidzein and affect their urinary excretion and kinetics in blood of rats. J Nutr 2001;131:787-795. 40. Kilkkinen A, Pietinen P, Klaukka T, et al. Use of oral antimicrobials decreases serum enterolactone concentration. Am J Epidemiol2002; 155:472477. 41.Rowland IR, Rumney CJ, Coutts JT, Lievense LC. Effect of Bifidobacteriurn longurn and inulin on gut bacterial metabolism and carcinogen-induced aberrant crypt foci in rats. Carcinogenesis 1998;19:281-285. 42. Ohta A, Uehara M, Sakai K, et al. A combination of dietary fructooligosaccharides and isoflavone conjugates increases femoral bone mineral density and equol production in ovariectomized mice. J Nutr 2002;132:2048-2054. 43. Bjorksten B, Sepp E, Jdge K, et al. Allergy development and the intestinal microflora during the first year of life. J Allergy Clin Immunol 2001;108516-520. 4.4.Kalliomaki M, Kirjavainen P, Eerola E, et al. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol2001;107129-134. 45. Kqavainen PV, b o l a T, Salminen SJ, Isolauri E. Aberrant composition of gut microbiota of allergic infants: a target of bifidobacterial therapy at weaning? Gut 2002;51:51-55. 46. Eigenmann PA, Calza AM. Diagnosis of IgE-mediated food allergy among Swiss children with atopic dermatitis. Pediatr Allergy Lmmunol2000;11:95-100. 47.Majamaa H, Laine S, Mettinen A. Eosinophil protein X and eosinophil cationic protein as indicators of intestinal inflammation in infants with atopic eczema and food allergy. Clin Exp Allergy 1999;29:1502-1506. 48. Van Der Velden VH, Laan MI', Baert MR, et al. Selective development of a strong Th2 cytokine profile in high-risk children who develop atopy: risk factors and regulatory role of IFN-y, IL-4and IL-10. Clin Exp Allergy 2001;31:997-1006. 49. Gibson GR, Beatty ER, Wang X, Cummings JH. Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology 1995;108:975-982. 50. Kujavainen PV, Apostolou E, Arvola T, et al. Characterizing the composition of intestinal microflora as a prospective treatment target in infant allergic disease. E M S Immunol Med Microbiol2001;321-7. 51. Isolauri E, b o l a T, Sutas Y, et al. Probiotics in the management of atopic eczema. Clin Exp Allergy 2O00;30:1604-1610. 52. Roberfroid MB. Chicory fructooligosaccharides and the gastrointestinal tract. Nutrition 2000;16677-679. 53. Gay-Crosier F, Schreiber G, Hauser C. Anaphylaxis from inulin in vegetables and processed food. N Engl J Med 2000;342:1372. 54. Trenev N. Probiotics: Nature's internal healers. Garden City Park, W. Avery Publishing, 1998126127. 55. Miller AL. The pathogenesis, clinical implications, and treatment of intestinal hyperpermeability. Altern Med Rev 1997;2:330-345. 56. Moore WE, Holdeman LV Human fecal flora: the normal flora of 20 Japanese-Hawaiians. Appl Microbiol 1974;27961-979.

57. Montgomery E, Hudson CS. Transformation of lactose to a new disaccharide, lactoketose. Science 1929;69:556-557. 58. Clausen MR, Mortensen PB. Lactulose, disaccharides and colonic flora. Clinical consequences. Drugs 1997;53:930-942. 59. Mortensen PB, Rasmussen HS, Holtug K. Lactulose detoxifies in vitro short-chain fatty acid production in colonic contents induced by blood implications for hepatic coma. Gastroenterology 1988; 94~750-754. 60.Mortensen PB, Rasmussen HS, Holtug K. Short-chain fatty acid production from mono- and disaccharides in a fecal incubation system: implications for colonic fermentation of dietary fiber in humans. J Nutr 1988;118321-325. 61. Brown RL, Gibson JA, Sladen GE, et al. Effects of lactulose and other laxatives on ileal and colonic pH as measured by a radiotelemetry device. Gut 1974;15:999-1004. 62. Liao W, Cui XS, Jin XY, Floren CH. Lactulose-a potential drug for the treatment of inflammatory bowel disease. Med Hypotheses 1994; 43:234-238. 63. Kontula P, Suihko ML, Von Wright A, Mattila-Sandholm T. The effect of lactose derivatives on intestinal lactic acid bacteria. J Dairy Sci 1999;82:249-256. 64.It0 Y, Moriwaki H, Muto Y, et al. Effect of lactulose on short-chain fatty acids and lactate production and on the growth of faecal flora, with special reference to Clostridiurn dzficile. J Med Microbiol 1997;46:80-84. 65. Vince A, Killingley M, Wrong OM. Effect of lactulose on ammonia production in a fecal incubation system. Gastroenterology 1978;74544-549. 66. MacGillivray PC, Finlay HVL, Binns TB. Use of lactulose to create a preponderance of lactobacilli in the intestine of bottle-fed infants. Scott Med J 1959;4182-189. 67. Terada A, Hara H, Kataoka M, Mitsuoka T. Effect of lactulose on the composition and metabolic activity of the human faecal flora. Microb Ecol Health Dis 1992;5:43-50. 68. BallongueJ, SchumannC, Quignon P. Effects of ladulose and lactitol on colonic microflora and enzymatic activity. Scand J Gastroenterol Suppl1997;222:4144. 69. Knothe H, Knapp G, Meyer M, et al. [Therapy of salmonella enteritis with special reference to lactulose] [abstract]. Infection 1980; 8(Suppl3):S294S298. 70. Hoffmann K. [Treatment of healthy salmonella carriers with lactulose beta-galactosido-fructose] [abstract]. Dtsch Med Wochensch 1975;100:1429-1431. 71. Salminen S, Salminen E. Lactulose, lactic acid bacteria, intestinal microecology and mucosal protection. Scand J Gastroenterol Suppl 1997;222:45-48. 72. Naidu AS, Bidlack WR,Clemens RA. Probiotic spectra of lactic acid bacteria (LAB). Crit Rev Food Sci Nutr 1999;39:13-126. 73. Bernhardt H, h o k e M. Mycological aspects of gastrointestinal microflora. Scand J Gastroenterol Suppl1997;222102-106. 74. Topping DL. Short-chain fatty acids produced by intestinal bacteria. Asia Pac J Clin Nutr 1996;5:15-19. 75. Bass P, Dennis S. The laxative effects of lactulose in normal and constipated subjects. J Clin Gastroenterol1981;3(Suppl 1):23-28. 76. Nagengast FM, Hectors MP, Buys WA, van Tongeren JH. Inhibition of secondary bile acid formation in the large intestine by lactulose in healthy subjects of two different age groups. Eur J Clin Invest 1988;1856-61. 77. Bird SP, Hewitt D, Ratcliffe 8, Gurr MI. Effects of lactulose and lactitol on protein digestion and metabolism in conventional and germ free animal models: relevance of the results to their use in the treatment of portosystemic encephalopathy. Gut 1990;31: 1403-1406. 78. Macfarlane GT, Gibson SA. Metabolic activities of the normal colonic flora. In Gibson SA, ed. Human health the contribution of microorganisms. London: Springer-Verlag,1994.

79. Madarlane S, Madarlane GT. Proteolysis and amino acid fermentation. In Gibson GR, Madarlane GT, eds. Human colonic bacteria: role in nutrition, physiology, and pathology. Boca Raton, n:CRC Press, 1995. 80.Roncuca L, Di Donato P, Carati L, et al. Antioxidant vitamins or lactulose for the prevention of the rrcurrrnce of colorectal adenomas. Coloredal Cancer Study Group of the University of Modena and the Health Care District 16. Dis Colon Redurn 1993;36227-234. 81. Porth C, ed. Pathophysiology: concepts of altered health states, ed 5. Philadelphia: Lippincott, 1998764-765. 82. Horsmans Y, Solbreux PM, Daenens C, et al. Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy. Aliment Pharmacol Ther 1997;11:165-170. 83. Watanabe A, Sakai T, Sat0 S, et al. Clinical efficacy of ladulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 1997;261410-1414. 84. Dhiman RK, Sawhney MS,Chawla YK, et al. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Dig Dis Sci 2OOO;451549-1552. 85.Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995;125:1401-1412. 86. Riggio 0, Varriale M, Testore GP, et al. Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients. J Clin Gastroenterol1990;12433-436. 87. Murawaki Y, Kobayashi M, Koda M, Kawasakia H. Effects of lactulose on intestinal bacterial flora and fecal organic acids in patients with liver cirrhosis. Hepatol Res 2OOO;1756-64. 88. Mortensen PB, Holtug K, Bonnen H, Clausen MR. The degradation of amino acids, proteins, and blood to shortchain fatty acids in colon is prevented by lactulose. Gastroenterology 1990;98:353-360. 89. Tannock GW. The bowel mimflora: an important source of urinary tract pathogens. World J Urol1999;17339-344. 90.salminen S, Isolauri E, Onnela T. Gut flora in normal and disordered states. Chemotherapy 1995;41(Suppll):5-15. 91. Houdijk AF',Meijer C, Cuesta MA, et al. Perioperative anti-endotoxin strategies.Scand J Gastroenterol Suppl 1997;222:93-97. 92. Liehr H, Englisch G, Rasenack U. L a c t u l o e a drug with antiendotoxin effect. Hepatogastroenterology 1980;27356-360.

93. Pain JA, Bailey ME. Experimental and clinical study of lactulose in obstructivejaundice. Br J Surg 1986;73:775-778. 94. McCutcheon J, Fulton JD. Lowered prevalence of infection with lactulose therapy in patients in long-term hospital care. J Hosp Infect 1989;1381-86. 95. Conn HO. A clinical hepatologist's predictionsabout non-absorbed carbohydrates for the early twenty-first century. Scand J GastroenterolSuppl 1997;222:88-92. 96.Sanders JF. Lactulose syrup assessed in a double-blind study of elderly constipated patients. J Am Geriatr Soc 1978;26236-239. 97. Flourie B, Briet F, Florent C, et al. Can diarrhea induced by lactulose be reduced by prolonged ingestion of lactulose? Am J Clin Nutr 1993;58:369-375. 98. Myers AA, Leedle JAZ. Carbohydrate metabolism in the human colon. In Hentges DJ, ed. Human intestinal microflora in health and disease.New York Academic Press, 1983. 99. Bemalier A, Dore J, Durand M. Biochemistry of fermentation. In Gibson GR, Roberfroid M, eds. Colonic microbiota, nutrition and health. Dordrecht: KLuwer Academic Publishers, 1999. 100.Kontula P, Von Wright A, Mattila-Sandholm T. Oat bran P-glucoand xylo-oligosaccharides as fermentativesubstrates for lactic acid bacteria. Int J Food Microbiol1998;45:163-169. 101.Ryhanen EL. Studies on probiotic bacterial supplementationin rats fed different diets with special reference to dietary fiber. Finnish J Dajr Sci 1996;52131-136. 102.Tamura Z. Nutriology of bifidobacteria. Bifidobaderia Microflora 1983;2:3-16. 103.Benno Y, Endo K, Miyoshi H, et al. Effect of rice fiber on human fecal microflora. Microbiol Immunol1989;33435-440. 104.Hara H, Orita N, Hatano S, et al. Effect of tea polyphenols on fecal flora and fecal metabolic products of pigs. J Vet Med Sci 1995; 5745-49. 105.Terada A, Hara H, Nakajyo S, et al. Effect of supplements of tea polyphenols on the caecal flora and caecal metabolites of chicks. Microb Ecol Health Dis 1993;63-9. 106. Silvi S, Rumney CJ, Cresci A, Rowland IR. Resistant starch modifies gut microflora and microbial metabolism in human flora-associated rats inoculated with faeces from Italian and UK donors. J Appl Microbiol 1999;86:521-530.

Probiotics Jason A. Hawrelak, BNat (Hons), PhDc CHAPTER CONTENTS Introduction 1195 Description 1196 Proposed Mechanisms of Action

1196

Probiotics Characteristics 1197 Desirable Properties of Probiotics 1 197 Probiotics in Common Use 1197 Issues in Probiotic Nomenclature 1198 The Importance of Strain 1198 Commercial Forms 1199 Fermented Foods 1 199 Supplements 1200 Clinical Applications 1200 Promotion of Proper Intestinal Environment 1201 Stabilization and Recolonization of Gastrointestinal Tract Flora after Antibiotic Therapy 1201 Urinary Tract Infection 1202 Vaginal Yeast Infections and Bacterial Vaginosis 1203 Prevention of Atopic Disease 1203

Atopic Eczema 1204 Cancer 1204 Irritable Bowel Syndrome 1204 Inflammatory Bowel Disease 1205 Ulcerative Colitis 1205 Crohn’s Disease 1205 Traveler’s Diarrhea 1206 Lactose Intolerance 1206 Stimulation of Gastrointestinal Tract and Systemic Immunity 1207 Using the Right Strain

1207

Dosage 1207 Supplements 1207 Yogurts 1209 Fermented Vegetables

1209

Promoting Growth of Lactobacilli and Bifidobacteria 1209 Oligosaccharides and Disaccharides 1209 Spirulina 1209 Toxicity

1209

Drug Interactions 1209

specific supplements containing freeze-dried bacteria. The microorganisms found in these products are usually lactobacilli and bifidobacteria.4 The term probiotic is derived from the Greek and literally Humans have been consuming probiotics for many means “for life.” It was first coined in 1965by Lilley and thousands of years, and fermented foods have been, and Stillwell’ to describe substances secreted by one microstill are, of great importance to the diets of most of the organism that stimulate the growth of another. In 1974, world’s people. Microbial cultures have been used to Parkel.2 modified this definition to ”organisms and subproduce beer, wine, yogurt, tempeh, sauerkraut, olives, stances which contribute to intestinal microbial balance.” cheese, and many other fermented foods.3Thus the symA more comprehensive definition has been put forth by biotic relationship between humankind and probiotic Naidu et a1,3 that is, ”microbial dietary adjuvants that microorganisms has a long history of important nutribeneficially affect the host physiology by modulating tional and therapeutic benefits for humans. mucosal and systemic immunity,as well as improving nutritional and microbial balance in the intestinal t r a ~ t . ” ~ Currently there is renewed interest in the field of fermented foods and probiotics. This interest has been stimuIn broad terms, this last definition includes fermented lated by the explosion of research in thisarea. This chapter foods such as yogurt, sauerkraut, and kefir as well as

INTRODUCTION

1195

Pharmacology of Natural Medicines focuses on the health benefits and therapeutic uses of probiotic-containing foods and supplements.

DESCRIPTION At the tum of the century, Metchnikoff5 asserted that yogurt is the elixir of life. He theorized that putrefactive bacteria in the large intestine produce toxins that invite disease and shorten life. He believed that the eating of yogurt would cause lactobacilli to become dominant in the colon and displace the putrefactive bacteria. For years, these claims of healthful effects from fermented foods were considered unscientific folklore. However, a substantial and growing body of scientific evidence has now demonstrated that lactobacilli, bifidobacteria, and fermented foods play a significant role in human health. The genus Lactobacillus is characterized by considerable heterogeneity. Bacteria are classified as lactobacilli if they are gram-positive, nonsporing, and rod-shaped organisms that produce lactic acid as the major end product of carbohydrate fermentation. Lactobacilli appear to be fairly unique in that they have been isolated from a number of diverse environments, such as fermented vegetables and dairy foods, as well as the human gastrointestinal tract (GIT) and vagina? On the other hand, bifidobacteria are not found in natural fermentative processes, but are native to the GIT and ~ a g i n a Bifidobacteria .~ are also gram-positive, nonsporing bacteria, but they are Y-shaped instead of rod-shaped, and their major fermentative end product is acetic acid.8 Intestinal colonization by lactobacilli and bifidobacteria begins during the birthing process. Prior to birth, the GIT of the neonate is completely sterile. During delivery, the newborn is inoculated with microorganisms from the birth canal and the mother’s fecal flora as well as from organisms in the environment. In the first week, the organisms that are best suited to the intestinal environment become established. Initially there is often a predominance of Escherichia coli, enterococci, and streptococci. A diet of breast milk creates a colonic environment that favors the growth of a simple flora of bifidobacteria and a few other anaerobes. Breast milk contains many bifidogenic oligo~accharides~ as well as living bacteria. Amazingly, breast milk from healthy women can contain up to lo9 bacteria/L, including various strains of lactobacilli and bifidobacteria.lOJ In formula-fed infants the microbiota is more complex (resemblingthe adult flora), containing far fewer bifidobacteria and more Bacteroides spp., clostridia, and anaerobic streptococci. The introduction of solid food to the breast-fed infant causes major changes in the microflora. A rapid rise in the numbers of enterococci and enterobacteria is followed by increases in Bacteroides spp. anaerobic streptococci, and clostridia. As the amount of solid food increases in the diet, the bacterial

Lactobacillus Species reuteri crispatus acidophilus jensenii gasseri plantarum casei rharnnosus paracasei ruminis Bifidobacterium Species adolescentis infantis longum bifidum breve catenulaturn pseudocatenulatum angulatum ruminantium dentium Data from references 11 and 15-19.

flora of formula-fed and breast-fed infants approaches that of adu1ts.l2-l4Common species of lactobacilli and bifidobacteria found in the infant and adult human GIT are listed in Box 118-1.11J5-19

PROPOSED MECHANISMS OF ACTION The exact mechanisms by which probiotics accomplish their beneficial actions have not been well documented. However, several postulated mechanisms explain many of the favorable effects. One such mechanism is competition for adhesion sites. Many pathogenic organisms must associate with the GIT epithelium in order to colonize effectively. However, some strains of bifidobacteria and lactobacilli can adhere to the epithelium and act as “colonization barriers” by preventing pathogens from adhering to the mucosa.20 This effect has been demonstrated with Lactobacillus rhumnosus strain GG and Lactobacillus plantarurn 299v. Both of these organisms have shown the ability to inhibit attachment of E . coli to human colon cells.21 Another possible mechanism of action is the modification of the microbial flora through the synthesis of antimicrobial compounds. Many types of lactobacilli and bifidobacteria produce bacteriocins or other antimicrobial compounds. Bacferiocins are defined as ”compounds produced by bacteria that have a biologically active protein

Probiotics

Other biologically moiety and a bactericidal active compounds produced by lactic acid-producing bacteria (LAB) are hydrogen peroxide (H202),diacetyl, and short-chain fatty acids (SCFAs). The release of these compounds by probiotic organisms results in a beneficial modification of the microflora.23However, not all strains of lactobacilli or bifidobacteria produce antimicrobial compounds, and some produce compounds that are fairly nonspecific in their activity, so that beneficial bacteria as well as pathogenic organisms may be negatively affected. It has also been observed that probiotics can stimulate the immune response. This immune response may take the form of increased secretion of immunoglobulin (Ig) elevated numbers of natural killer cells, or enhanced phagocytic activity of macrophages.25Increased secretion of IgA may reduce the numbers of pathogenic organisms in the gut, thus improving the composition of the microflora.2°,26 Probiotics may also compete for nutrients that would otherwise be utilized by path0gens.2~This situation occurs with Clostridiurn dificile, a potentially pathogenic organism that depends on monosaccharides for its growth. Probiotic organisms in sufficient numbers can utilize most of the available monosaccharides, resulting in the inhibition of C . dificile.=

PROBIOTIC CHARACTERISTICS Probiotic organisms require certain characteristics to enable them to exert maximum therapeutic effects. These qualities are summarized in Table 118-1F9

Desirable Properties of Probiotics Of these characteristics of probiotics, the following are considered almost essential for a probiotic to have therapeutic effects: (1)gastric acid and bile salt stability, (2) an ability to adhere to the intestinal mucosa, and (3) an ability to colonize the intestinal tract. Another vital characteristic is the ability to produce antimicrobial compounds and directly antagonize more pathogenic organisms.3oUnfortunately, many commercially available probiotic supplements and yogurts contain organisms that do not exhibit these vital characteristics. A probiotic strain that does not exhibit these characteristics, it will be nowhere near as effective as those that do. Thus some specific strains of bacteria will be more effective probiotics than others.

Probiotics in Common Use Many different microorganisms are currently used as probiotics. Box 118-2 lists commonly used probiotic spe~ies.2~3~~~ To enhance the reader’s understanding of how bacteria are named and classified, the following summary may be helpful. Genus is the first name of a bacterium (e.g., Lactobacillus). It is somewhat general and refers to a grouping of organisms based on similarity of qualities, such as physical characteristics, metabolic needs, and metabolic end products. Species is a bacterium’s second name (e.g., acidophilus). It is a much more narrow classification based on shared common characteristics that distinguish them from other species. Strain is an even more specific classification that divides members of the

The desirable characteristics of effective probiotic organisms Probiotic characteristic

Functional benefit

Human origin

Human origin should translate to ability to survive conditions in the human gastrointestinal tract (GIT) as well as the possibility of species-specific health effects.

Gastric acid and bile salt stability

Survival through stomach and small intestine

Adherence to intestinal mucosa

Essential for immune cell modulation and competitive inhibition of pathogens

Colonization of intestinal tract

Multiplicationin the intestines suggests that daily ingestion may not be needed; immune cell modulation.

Safety in food and documented clinical safety

Adverse effects absent or minimal; accurate identification (genus, species, strain)

Production of antimicrobial compounds

Normalization of GIT flora; suppressed growth of pathogens

Antagonism against pathogenic organisms

Prevention of adhesion and toxin production by pathogens

Clinically documented and validated health effects

Clinicians can be confident of therapeutic effects; dose-response data for minimum effective dosage in different formulations is known.

Increased shelf-life and stability during processing

All of the preceding properties should be maintained during storage and processing.

Adapted from Mattila-Sandholm T, Salminen S. GastroenterologyInternational 1998;ll(Suppl 1):8-16.

Pharmacology of Natural Medicines ~~

familiaris. Within this one species is great diversity in size, shape, strength, and other physical characteristicsranging from the Irish wolfhound to the Chihuahua. A similar division occurs within species of bacteria. Lactobacilus species Bacillus Species Within each species of bacteria there is a multitude of acidophilus johnsonii coagulans strains. Some probiotic strains are resilient and strong, plantarum brevis able to survive passage through the upper GIT and rhamnosus casei Streptococcus Species paracasei lactis inhibit pathogenic bacteria, and others are weak and thermophilus fermentum delbrueckii cannot survive the upper GIT or kill pathogenic bacteria. reuteri Also important to note is that just because one strain of Enterococcus Species bacteria in a given species has a proven action does not Blffdobacterium Species faecium mean that another strain will as well, even if they are breve adolescentis closely related. Furthermore, actions found in one strain Sacchammyces Species infantis animalis of L. rhamnosus cannot be extrapolated to a strain of longum lactis cerevisiae L. acidophilus or L. plantarum. Actions and qualities are bifidum thermophihm fundamentally strain specific.39 Therefore strains of bacteria within the same species can have significantly Data from references 29,31,and 32. different actions, proper ties, and characteristics. Unfortunately, this strain specificity is not well known, leading to inaccurate extrapolations from the literature. For example, some supplement manufacturers same species into subgroups on the basis of several quote a study that utilized L. rhumnosus strain GG and properties that these bacteria have in common that distinguish them from other members of the species then say that their probiotic supplement containing a strain of L. acidophilus or another strain of L. rhamnosus (e.g.,strain LA5).33 will do the same. This is quite incorrect. Unless the feaIssues in Probiotic Nomenclature ture is proven, one cannot assume that a given strain of L. acidophilus, B. bifidum, or any other species of lactic The reader should note changes in nomenclature, some acid bacteria will survive transit through the upper recent and some fairly antiquated, so as to make better GIT, let alone colonize the intestines or have specific sense of the probiotic literature; they are as follows: therapeutic actions. The species might, but unless they are proved to have such features, it is impossible to The species Lactobacillus bulguricus is now referred to as know. Two recent studies have demonstrated this strain Lactobacillus delbrueckii ssp. bulgaricus.34 specificity. Lactobacillus bifidus (also known as "bifidus") was One trial assessed the efficacy of two strains of renamed Bifuobucterium bifidum more than 30 years L. rhamnosus in the treatment of viral gastroenteritis. One ago, but the improper nomenclature continues to be strain was L. rhamnosus strain GG (LGG), the other was widely used.% a strain found in a supplemental product (Lactophilus). Many strains of bacteria that were once classified as LGG accelerated recovery from the diarrhea, whereas Lactobacillus casei have been reclassified as strains of the closely related strain did not.40 Lactobacillus rhamnosus (e.g., L. rhamnosus GG) or Additional in vitro research using two closely related Lactobacillus paracasei (e.g., L. paracusei Shirota strain).35 strains of B. bifidum (CIDCA 537 and 5310) found that Strains of Lactobacillus sporogenes have been renamed one strain (CIDCA 5310) inhibited enterocyte invasion Bacillus coagulans (they are not true lactobacilli because by Salmonella arizonae, whereas the other had no effect!' they form spores).% The results of both of these studies demonstrate the Bacterial strains that were once classified as Lactobacillus principle of strain specificity-that is, different bacterial acidophilus (often referred to as "acidophilus") have now strains within the same species can have sigruficantly been divided into six species: L. acidophilus, Lactobacillus different actions and therapeutic effects. gusswi, Lactobacillus amylovorus, Lactobacillus gallinarum, Thus clinicians are urged to use well-researched proLactobacillus johnsonii, and Lactobacillus ~ r i s p a t u s . ~ ~ biotic strains whenever possible. By choosing wellStrains of Sacchurornyces boulardii are now definitively researched strains one can be assured of using probiotics regarded as a distinct group within the species that have documented gastric acid and bile tolerance, can Saccharomyces cermisiae.37,3a adhere to the intestinal mucosa, can temporarily colonize The Importance of Strain the intestinal tract, and have proven therapeutic actions, thus increasing the probability of achieving good clinical Strains of bacteria can be likened to different breeds of dogs. All dogs belong to the genus Canis and the species outcomes. ~

~

~~

~

Probiotics

COMMERCIAL FORMS There are two main forms in which probiotic organisms can be ingested, fermented foods and supplements. Fermented foods can be of both dairy and vegetable origin, the most commonly known of each being yogurt and sauerkraut, respectively. Probiotic supplements consist of freeze-dried (lyophilized) bacteria in powder, capsule, or tablet form. Regardless of the form in which the microorganisms are consumed, products containing probiotic organisms must provide live organisms in sufficient numbers to exert therapeutic effects in order to have clinical efficacy. Both types of fermented foods and supplements do so.

Fermented Foods Fermented Dairy-Yogurt The origin of fermented dairy products is somewhat obscure, but their consumption is believed to date back to at least 5000 BC." Sour milks have always been popular throughout Europe, Asia, and Africa as nutritious, long-lasting foodstuffs. Fermented milks were also considered medicine, ancient physicians like Hippocrates, Galen, and Avicenna advocating their use for the treatment of gastrointestinal ills.43 Early in the twentieth century, Nobel prize laureate Elie Metchnikoff popularized the idea that fermented milk products could beneficially alter the microflora of the GIT. He attributed the long life of Bulgarian peasants to their consumption of soured milk, which he believed to arrest the abnormal putrefaction of proteins within the bowel.5 Metchnikoff later researched the bacteria found in this Bulgarian milk-Bacillus bulguricus (now known as Lactobacillus delbrueckii subspecies bulguricus) and a type of cocci (now known as Streptococcus thermophil~s)!~ He used these cultures in the manufacture of a type of sour milk he launched in Paris at the beginning of the twentieth century? These same species of bacteria are still used today in the manufacture of commercial yogurts. These two bacterial species (L. delbrueckii ssp. bulguricus and S. therrnophilus) are responsible for the taste, consistency, and smell that we associate with yogurt.44It is now known, however, that these species lack the ability to survive in the human GIT. Hence, yogurt manufacturers now routinely add additional probiotic species of bacteria to yogurt in an attempt to enhance its therapeutic effects (e.g., Lactobacillus acidophilus and Bifidobacterium bifdu rn) .* The therapeutic efficacy of a specific yogurt depends substantially on the characteristics of the strains of bacteria that it contains as well as on the number of viable bacteria present at the point of consumption. A therapeutic yogurt contains bacterial strains with the desired characteristics outlined in Table 118-1, and these strains

should be in sufficient numbers to exert therapeutic effects once consumed (i.e., >lo6 bacteria/ml of each bacterial strain)?5 Recent market-basket surveys have shown that some yogurts do achieve and maintain this level of bacterial viability throughout their shelf life, and furthermore, these same brands of yogurt often use bacterial strains with the desired probiotic characteristics.% A number of studies have attested to the therapeutic efficacy and ability of yogurt and fermented milks to successfully deliver probiotic bacteria to the human GIT.47-55 Yogurt appears to act as an ideal transport medium for probiotic bacteria, because it has been shown to enhance the survival of bacteria through the upper GIT.45 In fact, one study found that 10s bacteria given in a milk-base demonstrated greater fecal recovery after oral administration than 1O1O organisms given as a freeze-dried powder. Thus sigruficantly smaller numbers of probiotic bacteria can be given in yogurt than in supplements to achieve similar numbers of viable organisms in the lower GIT.%

Fermented Vegetables-Sauerkraut and Kimchi Fermented plant foods have always been an important component of the human diet and are still common food items throughout the world, from sauerkraut in Eastern Europe to kimchi in Southeast Asia. Traditionally prepared, both of these foods contain large amounts of probiotic bacteria. Strains of L. plantarurn are involved in the h a l stages of fermentation in both kimchi and sauerkraut, and they typically reach populations of >1@ bacteria/ml by the end-stages of f e r m e n t a t i ~ n ~ and ~ . ~thus ~ are present in sufficient quantities to have therapeutic effects when consumed. Additionally, research has found that many of the L. plantarurn strains isolated from fermented foods can survive exposure to gastric acid and bile salts, thereby indicating an ability to survive transit through the upper GIT. These same strains have also been found able to adhere to intestinal epithelial cells, thus fulfilling three of the main criteria needed by desirable probiotic 0rganisms.5~Kimchi and sauerkraut can be used as therapeutic tools much like probiotic supplements and yogurts. However, the characteristics of the bacterial strains found in these fermented foods will not be known, so their therapeutic effects will not be as certain. Some strains of L. plantarurn isolated from fermented foods also use a mannose-specific mechanism to adhere to human intestinal cells. Many pathogenic bacteria and parasites (e.g., enterotoxigenic E . coli, Shigellu spp., Vibrio cholerue, Salmonella spp., and Giurdiu lurnbliu) also utilize a mannose-specific binding mechanism.60,61 Hence strains of L. plan tarurn compete directly with these microorganisms for a limited number of binding sites along the

Pharmacology of Natural Medicines

human GIT. The consumption of traditionally prepared kimchi and sauerkraut may thus play a role in the prevention and treatment of gastroenteritis caused by these pathogens.

Supplements The quality of probiotic supplements depends on two main factors, (1) the characteristics of the strains contained in the supplement and (2) adequate viability, so that sufficientnumbers of bacteria are viable at the point of consumption. Bacterial strains used in probiotic supplements should ideally demonstrate all the characteristics outlined in Table 118-1,but as a minimum should at least survive transit through the stomach and proximal small intestine. Viability at consumption depends on a number of factors, such as proper manufacturing and the "hardiness" of the strain, as well as packaging and storage of the product in the right amount of moisture and at the correct temperature. Many strains of lactobacilli and bifidobacteria do not respond well to freezedrying (lyophilization), spray drying, or conventional frozen storage, and too high a temperature during packaging or storage can dramatically reduce viability. Typically, unless the product has been shown to be stable, refrigeration is necessary during storage and ideally during transport. Some products may not have to be refrigerated until after their container has been opened, however. Some manufacturers utilize enteric coatings on their tablets and capsules to improve survival through the acidic medium of the stomach. Recent research suggests that this practice does indeed enhance survival through the upper although enteric coatings are not necessary if the strain has demonstrated satisfactory tolerance to gastric acid. A number of excellent companies provide highquality probiotic products, but it is difficult to sort through all of manufacturer's claims of superiority. Additionally, market-basket surveys have found that some supplements contain potentially pathogenic contaminantsta but the majority fails to contain the species and quantity of bacteria listed on the label.@In fact, a 1990 study concluded, "Most of the lactobacilli-containing products currently available either do not contain the Lactobacillus species advertised and/or contain other bacteria of questionable benefit."* Another study evaluated 16 commercial probiotic products for actual microbial content. Four contained L. acidophilus as stated on the label, but 11 were found to be contaminated with pathogens." Clearly, the clinicians need documentation of strain characteristics, product quality/viability, and microbiologic content of a product before prescribing it for their patients.

CLINICAL APPLICATIONS The intestinal flora plays a major role in the health of the h 0 ~ t . The l~~ beneficial ~~ effects of the intestinal flora are (1) stimulation of the immune system, (2) synthesis of vitamins (B group and K), (3)enhanced GIT motility and function, (4) improved digestion and nutrient absorption, (5)relief of gas-induced abdominal distention, (6) inhibition of pathogens (colonizationresistance), (7) metabolism of important plant compounds/drugs, and (8) the production of SCFAs and p o l y a m i n e ~ . ~Because ~ , ' ~ , ~ of the important role of lactobacilli and bifidobacteria within the human GIT microflora, and thence to human health, probiotic supplements can be used to promote overall good health. There are, however, several specific uses for probiotics (Box 118-3).432,69-n

Treatment of intestinal Disorders Constipation Lactose intolerance Prevention and treatment of gastrointestinaltract (GIT) infections Flatulence Diarrhea: infantile, antibiotic-associated,traveler's Inflammatory bowel disease Irritable bowel syndrome Intestinal hyperpermeability Other Conditions and Uses Treatment of hypercholesterolemia Prevention and treatment of vaginal infections Prevention and treatment of urinary tract infections Treatment of hepatic encephalopathy Prevention of alcohol-inducedliver disease Stimulation of gastrointestinaland systemic immunity Prevention of cancer Improvement in digestion Prevention of atopic disease Alleviation of atopic eczema Treatment of food allergies Recolonization of GIT and vagina after antibiotic use Stabilization of GIT flora Data from references 4, 32, and 69-72.

The primary areas of probiotic use discussed here are: Promotion of proper intestinal environment Stabilization and recolonization of GIT flora after antibiotic therapy For irritable bowel syndrome (IBS) For inflammatory bowel disease For traveler's diarrhea For lactose intolerance For cancer prevention For urinary tract infections

Probiotics

For vaginal yeast infections Prevention of atopic disease For atopic eczema Stimulation of gastrointestinal and systemic immunity

Promotion of Proper Intestinal Environment Lactobacilli and bifidobacteria have long been known to play important roles in the prevention of, and defense against, diseases, particularly those of the GIT and vagina. As part of the ”normal flora,” they inhibit the growth of other organisms through competition for nutrients, alteration of pH and oxygen tension to levels less favorable to pathogens, prevention of attachment of pathogens by physically covering attachment sites, and production of limiting factors such as antimicrobial Lactobacilli and bifidobacteria produce a variety of factors that inhibit or antagonize other microorganisms. These include metabolic end products, such as organic acids (lactic and acetic acid), carbon dioxide, and hydrogen peroxide, as well as other antimicrobial compounds, such as ba~teriocins.’~-~* It should be noted, however, that the ability to produce bacteriocins, hydrogen peroxide, and other antimicrobial compounds is extremely strain-dependent. Some of the antimicrobial activity of lactobacilli has been shown to be due to their production of hydrogen peroxide.78However, this reaction requires folic acid and riboflavin; if they are in short supply, H202production will be reduced. The earliest reported therapeutic uses of lactobacilli in the 1920s suggested that their proliferation in the gut was associated with a concomitant decrease in potentially harmful coliform bacteria. This effect has since However, it is believed that many of been the earlier commercial products were less reliable than those used in later published clinical trials because of inappropriate strains and problems in production, storage, and distribution to consumers?l Later research has demonstrated a possible role of probiotics in the management of both Helicobacter pylori and G. lamblia infections. Epidemiologic research has found an inverse association between fermented milk intake and peptic ulcer disease, suggesting a protective effect from lactobacilli in the Additionally, in vitro research has found that L. acidophilus DDS1, L. acidophilus NAS, L. delbrueckii ssp bulgaricus LB-51,83 L. acidophilus LB,84 and L. johnsonii La-1 can inhibit the growth of H. pylori.85 Michetti et alss followed up on the original in vitro work with L. johnsonii La-1 to assess whether such growth inhibition occurred in vivo. Twenty individuals with

documented H. pylori infection consumed 200 ml/day of L. johnsonii Supernatant.After 3 days, urea breath tests documented signrficantly decreased H . pyZori growth and activity. This decrease in activity remained for 6 weeks after administration of the probiotic.8s This promising result gave rise to a randomized, double-blind, placebo-controlled trial. Fifty-three subjects consumed either 180 ml twice daily of acidified milk (containing>lo7 L. johnsonii La-1 per ml) or placebo for 3 weeks. During the last 2 weeks, all subjects received clarithromycin (500 mg bid). After the 3-week time period, the La-1 group showed significant reductions in H. pylori density, of 34.2%in the antrum and of 39.2%in the corpus, compared with baseline ( p = 0.02 and p = 0.04, respectively), and there were no significant changes in the placebo group. Additionally, the La-1 group had a significant decrease in gastric inflammation in the antrum ( p = 0.02) and in the activity of inflammation in the antrum ( p = 0.01) and corpus ( p = 0.02), but the placebo group had no significant changes.86Thus L. johnsonii La-1 may play an adjunct role in the management of H. pylori-related gastritis and peptic ulcer disease. L. johnsonii La-1 has also been shown to inhibit the growth of G. lamblia trophozoites (the adult form of the parasite). L. johnsonii La-1 has demonstrated the ability to produce a combination of substances that inhibits growth of G. larnblia in vitro. Substances found in La-1 supernatant impaired the ability of Giardia to replicate and encyst. These products also caused dramatic alterations in the morphology of trophozoites. Thus consumption of L. johnsonii La-1 may help arrest the proliferation of Giardia and prevent encystation,consequently breaking the lifecycle of the para~ite.8~

Stabilization and Recolonization of GastrointestinalTract Flora after Antibiotic Therapy Antibiotic use is the most common and significant cause of major alterations in the normal GIT microbiota.88The potential for an antimicrobial agent to influence the gut microflora is related to its spectrum of activity, pharmacokinetics, and length of administration.’O In regard to an agent’s spectrum of activity, an antimicrobial agent that is active against both gram-positive and gram-negative organisms has a greater impact on the intestinal flora.88In terms of pharmacokinetics, the rate of intestinal absorption plays a fundamental role, but whether the drug is excreted in active form in either the bile or saliva is also important. Both of these pharmacokinetic factors determine the drug’s ultimate concentration in the intestinal lumen and, hence, the severity of the microfloral alteration.88 In general, oral antimicrobials that are well absorbed in the small intestine have minor affect on the colonic

Pharmacology of Natural Medicines flora, whereas agents that are poorly absorbed can cause sigrulicant changes. Parenteral administration of antimicrobial agents is not free of these consequences, because some agents can be secreted in the bile or saliva or from the intestinal mucosa and thus can still cause considerable alterations in the colonic flora?l The dosage of the agent as well as the length of its administration also determine the magnitude of the impact on the intestinal flora. In general, the greater the dosage and the longer its administration, the larger the effect on the microflora.gO If an antimicrobial agent does severely affect the microflora, negative repercussions on the host's health can result. These repercussions include the overgrowth of already present microorganisms, such as fungi and C. dificile,92 the establishment of new, resistant pathogenic bacteria that can colonize other areas of the a decrease in the production of SCFAs, which can lead to electrolyte imbalances and and a greater susceptibility to intestinal and genitourinary pathogens owing to the decrease in colonization re~istance.9~ Probiotic supplementation can attenuate the impact of antibiotics on the GIT environment. A number of probiotic strains have proven effective in the prevention and treatment of antibiotic-associated diarrhea, including S. cerevisiae (Hansen CBS 5926),95,96 L. rlmmnosus GG,51*97,98 and L. acidophilus LA5.99These results demonstrate the ability of probiotics to stabilize the GIT microflora during antibiotic administration. Probiotics may also produce or enhance endogenous production of SCFAs, a feature that may also explain their antidiarrheal activity during antibiotic therapy. O0 Additionally, some probiotic strains have proven efficacious in the treatment and prevention of C. dificile overgrowth after antibiotic use. C. dificile superinfection is considered the most common cause of antibioticassociated diarrhea, and severe infections can result in pseudomembranous colitis and even death. Probiotic agents such as L. rhamnosus GG101J02, L. plarzfariinz 299v,lo3 have been shown and S. cerevisiae (Hansen CBS 5926)1M,105 to play important roles in the prevention and treatment of C. dzficiZe infection. L. acidophilus LA5@JMand L. rhanznosus GG'O' and have also demonstrated anti-Cundidu activity and thus may play a role in the prevention and treatment of antibioticinduced candidal overgrowth in the GIT and vagina. Although it is commonly believed that probiotics are not effective if taken during antibiotic therapy, the research actually supports the use of probiotics during antibiotic administrati~n.~~,~~,~~J~~ Reductions of friendly bacteria and/or superinfection with antibiotic-resistant flora may be prevented by administering probiotics products during antibiotic therapy. Probiotics should, however, be taken as far away in time from the antibiotic doses as possible.

Urinary Tract Infection Lactobacilli play a significant role in the prevention of urinary tract infections (UTIs). The normal urogenital microflora is dominated by lactobacilli. Strains of L. crispatus and Lactobacillus jensenii usually predominate in this environment, and most of these strains appear to produce H202.1D9 Hydrogen peroxide plays an important microbial-balancing role in the urogenital region, and its production helps maintain a healthy lactobacillipredominant flora. Unfortunately, factors such as antibiotic and spermicide use lead to the disruption of this flora and a predisposition to UTIS.~*OJ~' Recent research has found an inverse association between vaginal E. coli colonization and the presence of H202-positive lactobacilli within the vagina. In fact, women who did not have H202-positivelactobacilli in their vaginal flora were 650% more likely to have vaginal E. coli colonization. Because E. coli colonization of the vagina appears to be the critical initial step in the pathogenesis of both acute and recurrent UTIs, reestablishing a flora dominated by H202-producinglactobacilli should help prevent UTIs.l12 A number of studies have also demonstrated the efficacy of some strains of lactobacilli in preventing UTIs. Reid et a1113conducted a placebo-controlled trial assessing the effects of lactobacillus suppositories on the recurrence of UTIs after administration of antibiotics. The suppositories contained 1.6 x lo9 colony-forming units (CFU), consisting of L. rhamnosus GR-1 and Lactobacillus ferrnenf u m B-54. Thirty-one participants applied either the placebo or lactobacilli suppositories twice weekly for 2 weeks and then once a month for 2 months. Treatment with the lactobacillus suppositories resulted in 45% fewer UTI recurrences than the placebo. In addition, no side effects or candidal superinfections occurred in the lactobacillus-treated group. The researchers theorized that more frequent administration would produce even greater re~u1ts.l~~ A study conducted by Bruce et a P 4 also investigated the activity of L. rhanznosus GR-1 and L. ferrnentum 8-54 suppositories on UTI recurrence. Ten women with a history of recurrent UTIs took part in the study. Participants administered one suppository containing more than 1.6 x lo9 freeze-dried lactobacilli each week for 12 months. Results indicated a substantial reduction in the infection rate (66.3%)with no side effects. Additional research using L. rhamnosus GR-1 and L.ferrnentum RC-14 found that oral consumption of these strains resulted in vaginal colonization within 7 days. In some cases, colonization persisted for 10 weeks after administration. Oral administration of these probiotics also resulted in an improvement in vaginal flora (as measured by the Nugent scoring system). Thus some strains of orally administered lactobacilli can survive

Probiotics

douche twice a day with a lactobacilli solution containing los live organisms per ml. However, the right strains must be used (see the important criteria previously listed for Vns). Hydrogen peroxide-producing lactobacilli are present in the majority of normal vaginas but are absent in women suffering from chronic v a g i n o ~ i s . ' ~The ~ J ~pro~ duction of H202by lactobacilli is toxic to pathogens such Not all women's vaginas are as Gardnerella v~ginalis.'~~ colonized by the right strains of lactobacilli, however. One study evaluated the lactobacilli population in 275 women in the second trimester of pregnancy by obtaining vaginal culture specimens to detect H202production status as well as the presence of pathologic organisms. Women colonized by H2O2-positivelactobacilli were less likely to have bacterial vaginosis, symptomatic candidiasis, and vaginal colonization by G. vaginalis, Bacteroides spp., Peptostreptococcus spp., Mycoplasrna horninis, Adherence to uroepithelial and vaginal cells Ureaplasma urealyticum, and viridans streptococci.132The Colonization of the vagina women who did not have any vaginal lactobacilli were Inhibition of urogenital pathogen growth and/or also more likely to have Chlamydia trachomatis. The attachment researchers also reported that most commercially availProduction of hydrogen peroxide able products contain either lactobacilli that do not If the probiotic preparation is to be orally consumed, produce H202or Lactobacillus strains derived from dairy the strains must have gastric acid and bile salt foods, which are unable to bind to vaginal epithelial stability cells. Although intravaginal application of probiotics Bacterial strains that exhibit these characteristics will be appears to be the preferred therapy for vaginal infections, more effective in the treatment and prevention of UTIs even simple consumption of appropriate yogurts appears than those that do not. Hence, selection of strains with beneficial. For example, one study of 33 patients with these characteristics is e~sential."~ recurrent Candida vaginitis found a threefold decrease in Vaginal Yeast Infections infections when the patients consumed 8 ounces/day of and Bacterial Vaginosis yogurt containing H202-producingL. acidophilus (strain LA5) for a period of 6 months. The mean number of Many strains of lactobacilli have been shown to retard infections per 6 months was 2.54 in the control group the growth of Candida albicans, the major yeast involved and 0.38 in the yogurt-treated group. Candida colonizain vaginal yeast i n f e ~ t i o n s . * ~ JClinical ~ ~ J ' ~ studies have tion occurred with a mean of 3.23 per 6 months in the suggested that the ingestion or introduction of yogurt or control group and of 0.84 per 6 months in the yogurt lactobacilli into the vagina can assist in clearing up and group. Lactobacilli concentrationsin the vagina rose as a preventing recurrent vaginal yeast infections as well as result of yogurt ingestion, suggesting that L. acidophilus bacterial vaginosis.48J20-122 LA5 colonized the The normal urogenital microflora is dominated by A later trial evaluated the capability of orally adminlactobacilli, the function of which is to maintain an environment that limits the growth of potentially pathogenic istered probiotic strains to reestablish eubiosis in women with bacterial vaginosis. Ten women with a recent microorganisms. Lactobacilli do this through the maintenance of an acidic environment (via the fermentation history of urogenital infections consumed L. rhamnosus of vaginal glycogen to lactic acid) and the production of GR-1 and L.femzmturn RC-14 in a skim milk base. Within 1 week the bacterial strains were recovered from the H202.112,123 It was previously believed that the vaginal vagina in all 10 subjects. After 14 days of treatment, six flora was dominated by strains of L. a~idophiZus'~~J~; however, research has found that L. mspatus and L. jmsenii of the subjects who had had abnormal vaginal flora at baseline were found to have normal lactobacilliare the predominant vaginal lactobacilli.lWJz6 dominated Antibiotic use has been shown to suppress the growth of vaginal lactobacilli and raise the pH of the vagina as Prevention of Atopic Disease well as increase the growth of yeast, E. coli, and other Two recent groundbreaking studies have demonstrated gram-negative b a ~ t e r i a . Reestablishment ~~~J~~ of normal the ability of probiotics to prevent the development of vaginal lactobacilli can be aided by having the woman transit through the GIT, colonize the vagina, and beneficially alter the microecology of the genitourinary tract.'15 On the other hand, Baerheim et reported that vaginal application of an unknown strain of L. rhamnosus (Gynophilus)failed to decrease the incidence of UTIs over a 6-month period compared with placebo. Interestingly, twice-weekly application of Gynophilus did not affect the periurethral lactobacilli population, suggesting that this strain was unable to adhere to and colonize the urogenital environment. Additional in vitro research demonstrated that the bacterial strain found in Gynophilus was unable to inhibit the growth of E. coli.116 Thus this research highlights the need to use bacterial strains with the specific characteristics needed for success in urogenital applications. The critical properties needed for a bacterial strain in urogenital applications are as follows:

atopic disease in infants. In a randomized, double-blind, placebo-controlled trial, either placebo or L. rhamnosus GG was administered prenatally (for the last month of pregnancy) to mothers who had at least one first-degree relative (or partner) with allergic rhinitis, asthma, or atopic eczema and then postnatally (for 6 months) to their infants. When the infants were 2 years old, the frequency of atopic eczema in the probiotic group was half that of the placebo group (relative risk [RR] 0.51; 95% confidence interval [CI] 0.32-0.84; p = 0.008).133 The second study reported similar results. In this randomized, double-blind, placebo-controlled trial, either L. rkamnosus GG or a placebo was administered to 159 mothers who were at high risk of giving birth to an atopic child, for the last month of pregnancy and then for the 3 months after birth. At the end of a 2 years, the rates of chronic relapsing atopic eczema in the children were compared in the two groups. Maternal intake of probiotics was associated with a 2/3 reduction in the prevalence of atopic eczema in comparison with placebo (RR 0.32; 95% CI 0.12-0.85; p = 0.0098). In addition, the concentration of transforming growth factor-beta2 (TGF-P2; a key immunoregulatory factor involved in the induction of oral tolerance and IgA production) was significantly greater in the breast milk of the probiotic group than that of the control group ( p = 0.018). This latter finding is highly sigruficant because hgher concentrationsof TGF-P? in breast milk and colostrum have been correlated with an infant's ability to produce specific IgA antibodies against dietary antigens and to prevent development of atopic disease during breast feeding.'%

Atopic Eczema Atopic eczema is a common, chronically relapsing skin disorder particularly prevalent in infancy and childhood. It is characterized by hypersensitivity reactions to environmental allergens. In children, the relationship between environmental allergens, such as dietary antigens, and exacerbation of symptoms is especially apparent. The pathophysiology of atopic eczema consists of excessive intestinal inflammation, aberrant macromolecular absorption across the intestinal mucosa, and an immune response dominated by type 2 helper T (Th2) cells.135-138 Probiotics have the potential to moderate all three of these underlying pathophysiologic processes. For instance, L. rkamnosiis GG has demonstrated a capacity to decrease interleukin-4production,'3ysuppress lymphocyte proliferation,'" increase intestinal IgA secretion,"" enhance allergen degradation by the intestinal mucosa,142 normalize increased intestinal permeability, and alleviate intestinal inflammation.143 All of these actions promote a shift toward type 2 helper T (Thl)cell immune responses and improve macromolecule handling in the gut. A recent clinical trial assessed the potential of Bifdobacterium lactis Bb12 and L. rkamnosus GG in the

management of infantile atopic eczema. After &weeks administration, B. lactis Bb12 reduced the SCORAD score (a measure of the extent and severity of atopic eczema symptoms) by loo%, and L. rhamnosus GG reduced the score by 9470, as compared to baseline. The improvement in symptoms in both treatment groups was significantly greater than in the control group (p = O.Ol)."

Cancer A series of population studies have suggested that the consumption of high levels of cultured milk products may reduce the risk of colon L. delbrueckii ssp. bulgaricirs strain LB-51, a strain of the primary lactobacilli used in traditional yogurt, has demonstrated potent antitumor activity.14*Feeding colostrum fermented with L. acidopkilus D D S l and milk fermented with L. acidophilus (strain Delvo Pro LA-1) has been reported to result in a reduction in tumor proliferation in animal s t ~ d i e s . ' ~ ~ , ' ~ ~ In human studies, ingestion of L. acidophilus NCFM,151 L. rlmmnosus GG,49and L. paracasei Shirota50has resulted in reduced activity of bacterial enzymes associated with the formation of cancer-causing compounds in the gut. The beneficial effects of lactobacilli against cancer appear to extend well beyond the colon. In a double-blind trial conducted in 138 patients surgically treated for bladder cancer, the patients were divided into three groups: (A) those with primary multiple tumors, (B) those with recurrent single tumors, and (C) those with recurrent multiple tumors. In each group, patients were randomly allocated to receive either the oral L. paracasei strain Shirota (LPS) or placebo. LPS showed a better effect than placebo in preventing cancer recurrences in groups A and B. However, no significant effect was noted in group C.152 Probiotic preparations are also of value in patients with cancer who were undergoing either chemotherapy or radiation therapy involving the gastrointestinal tract. In one study, 24 patients scheduled for internal and external irradiation of the pelvic area for gynecologic cancers were selected for a controlled study to test the prevention of intestinal side effects by administration of L. acidopkilus. The test group received 150 ml/day of a fermented milk product supplying them with live L. acidophilus (strain NCFB-1748) in a 6.5% lactulose substrate. Lactobacilli administration resulted in the prevention of radiotherapy-associated diarrhea.153

Irritable Bowel Syndrome Probiotics appear to have a promising role in the management of IBS. Studies and case series conducted in the 1950s and 1960s repeatedly demonstrated the beneficial effects of probiotic administration on IBS symptoms.'"" This initial research has been followed by more rigorous examination in later clinical trials. Bazzocchi et al7I performed an open study assessing the effects of a probiotic preparation on the course of IBS. They used a freeze-dried probiotic preparation called

Probiotics

VSL# 3, which contained 5 x 10” cells/g of three strains of bifidobacteria (B. longurn Y10, B. infanfis Y1, and B. breve Y8), four strains of lactobacilli (L. acidophilus, L. casei, L. delbrueckii ssp bulguricus, and L.plantarum) and one strain of Streptococcus salivarius ssp. t h o p h i l u s . Forty-two patients who satisfied the Rome I criteria for diagnosis of IBS received 3 g of the preparation per day for 1month. At the end of the trial, only 19%of the study participants still fulfilled all the criteria for IBS (p < 0.01). Fecal concentrations of bifidobacteria, lactobacilli, and S. salivarius all sigruhcantly rose from baseline values ( p < 0.01). In addition, two experimental objective measurements-intestinal contractile response and visceral response to mechanical colonic stimulationwere significantly reduced (p < 0.04).” Thus this probiotic preparation appears to improve both objective and subjective measures of IBS symptomatology. A second randomized, placebo-controlledtrial was conto investigate the effects of ducted by Noebaek et L. plantarurn 299v on IBS. The subjects were 60 patients with IBS as defined by the Rome I criteria, who were randomly divided into two groups. One group received 400 ml/day of a rose hip drink containing 5 x lo7CFU/ml of L. plantarurn 299v, and the other group received a plain rose hip drink comparable in texture, color, and taste. Administration lasted 4 weeks. No adverse effects were reported in either group. Rectal biopsies confirmed the growth of L. plantumm 299v in the intestinal mucosa of the treated group. Abdominal pain was sigruficantlyand rapidly reduced in the treated group (p < 0.01), as was flatulence (p < 0.05). At 12-month follow-up, patients who had received L. plantarurn maintained their improvement in overall GIT function compared with the placebo

Inflammatory Bowel Disease

Ulcerative Colitis Venturi et aP9 performed an open trial assessing the effects of a multiple-strain probiotic preparation (VSL# 3; for specific contents see the IBS discussion) in patients with ulcerative colitis. Twenty patients who were allergic or intolerant to 5-aminosalicylic acid (5-ASA) were treated with VSL# 3 for 12 months. Fecal concentrations of lactobacilli and bifidobacteria rose significantly from baseline values by the 20th day of treatment (p < 0.05). At the end of the 12 months, 15 of the 20 participants remained in remi~sion?~ a finding that compares favorably with rates of remission observed during long-term mesalazine therapy.*&Thus long-term administration of VSL# 3 may protect against relapse in quiescent ulcerative colitis. Rembacken et a P 7performed a randomized, doubleblind trial with 116 subjects to compare the efficacy of mesalazine and a nonpathogenic strain of E . coli (strain Nissle 1917) in the prevention of relapse of ulcerative colitis. All subjects were initially treated with an initial course of antibiotics (oral gentamicin for 7 days) and corticosteroids until remission of the active disease was induced. Fifty-nine subjects were then allocated to mesalazine treatment and 57 to E. coli administration. In the mesalazine group, 73% of subjects experienced a relapse within 12 months, whereas in the E . coli group, only 67% did so. The mean duration of remission was 206 days in the mesalazine group and 221 days in the E. coli group. Statistical analysis indicated that the two treatments were equivalent. These results suggest that daily treatment with E . coli (Nissle 1917)is as efficacious as mesalazine in maintaining remission in patients with ulcerative ~ 0 l i t i s . l ~ ~

Crohn’s Disease Intestinal dysbiosis may be one of the etiologic factors In a randomized, double-blind, placebo-controlled trial, involved in the pathogenesis of both ulcerative colitis and 20 subjects who had Crohn’s disease and were suffering Crohn’s disease. According to Campieri and Gionchetti,l= from diarrhea and moderate GI complaints (as measured “the onset of inflammation may be associated with an by the BEST Crohn’s Disease Activity Index) were imbalance in the intestinal microflora with relative pretreated with S. cereuisiue (Hansen CBS 5926) for 2 weeks dominance of ’aggressive’ bacteria and an insufficient concentration of ’protective’species.”158In support of this in combination with basic treatment (either salazosulfapyridine or 5-ASA). Treatment resulted in a significant theory, research has found that patients with ulcerative colitis have lower colonic concentrations of la~tobacilli,’~~reduction in the frequency of bowel movements have higher colonization by sulfate-reducingbacteria,lm (p < 0.01) and the BEST index ( p < 0.05) in comparison with baseline. After this initial period, participants were and may also have pathogenic strains of E . coli in greater assigned to either the placebo group or the verum (i.e., concentrations than healthy controls.*61Patients with active agent) group, and both groups took their respecCrohn’s disease have been found to have decreased tive medications for 7 weeks. At the end of the trial, parnumbers of bifidobacteria162and elevated numbers of ticipants in the verum group had a further reduction in Bacteroides spp in their feces as well as to have pathogenic strains of E . coli in greater amounts than healthy populastool frequency and BEST index, whereas in the placebo group, the two parameters returned to baseline levels. tions.161 In addition, research conducted in animal Hence, this strain of S. cerevisiue appears of benefit in the models of inflammatory bowel disease has achieved sucmanagement of Crohn’s disease and can be given concessful outcomes with administration of probiotics, and currently with orthodox treatment to improve clinical human research has also demonstrated some level of outcomes.

Pharmacology of Natural Medicines The efficacy of L. rharnnosus GG in Crohn’s disease was evaluated in a small, open study. Four children with mildly to moderately active Crohn’s disease were given L. rhumnosus GG enterocoated tablets (each tablet contained > 10’O viable bacteria) twice daily for 6 months. Clinical improvement was noted 1 week after the commencement of therapy. After 4 weeks, the Pediatric Crohn’s Disease Activity Index (PCDAI) scores were 73% lower than at baseline, an improvement that was sustained throughout the study period. Intestinal permeability improved in similar fashion (in particular, paracellular permeability). Thus L. rhamnosus GG administration appeared to improve both clinical symptoms and gut barrier function in children with Crohn’s d i s e a ~ 2 . l ~ ~ These promising results contrast sharply with the findings from a double-blind, placebo-controlled trial that assessed the efficacy of L. rhumnosus GG in preventing relapses of Crohn’s disease. Before trial commencement, all study participants underwent extensive intestinal resections to remove all diseased intestinal tissue. Fortyfive subjects were then assigned to either the placebo group or the L. rhamnosus GG group (LGG). After 12 months, clinical and endoscopic remission rates were equivalent in the two groups, suggesting that LGG had no beneficial effect in this cohort of patients.”O Interestingly, a clinical trail using mesalazine in a cohort of patients with Crohn’s disease who had just undergone surgical resection also did not demonstrate significant benefit of the medication over pla~ebo.’~’ Thus this subgroup of cases of Crohn‘s disease may be fairly nonresponsive to therapeutic intervention, which may explain why LGG administration had no significant benefits.

Traveler’s Diarrhea Probiotics are routinely recommended by nutritionally oriented doctors to their patients who travel to developing countries. However, one published report casts doubt on this practice. A randomized, double-blind, placebocontrolled trial was conducted on 282 British soldiers deployed to Belize. They received two capsules containing L. fermenturn (strain KLD), L. acidophilus (unknown strain), or a placebo daily for 3 weeks. L.fermentum KLD was a human isolate, able to adhere to intestinal cells and inhibit pathogenic bacteria, and was acid and bile tolerant; hence, it displayed many of the characteristics of a successful probiotic strain. No information was provided regarding the characteristics of the L. acidophilus strain. Each capsule contained 10” CFU of bacteria. No protection from traveler’s diarrhea was provided by either strain.In This was a surprising result, given the characteristics of L. ferrnentum KLD, indicating that in vitro antimicrobial activity against intestinal pathogens does not always translate into in vivo results. However, other research using L. rhamnosus GG demonstrated better results. Eight-hundred and twenty

Finnish travelers holidaying in two locations in Turkey completed the trial. Subjects received either L. rhamnosus GG powder (daily dose 2 x lo9 CFU) or placebo. Interestingly, subjects who traveled to one distinct location in Turkey had a modest, yet statistically significant benefit, whereas travelers to the other location did not receive significant protection. This result suggests that L. rhamnosus GG protects against the development of traveler’s diarrhea in some locations but will have little effect in others.’73 Strains of L. plan tarum may have greater benefit in the prevention of traveler’s diarrhea. The main causative organisms of this disorder are enterotoxigenic E . co2i (= 40% of cases), Salmonella spp., Entamoeba histolytica, and G. l~mblia.’~~ E. coli, Salmonella sp., and G. lamblia all use a mannose-specific mechanism to adhere to enterocytes.60,61 Many, but not all, strains of L. plantarum also use a mannose-specificadherence mechanism (including strains isolated from traditional fermented foods, like sauerkraut and Nigerian ogi). This characteristic appears to be rather unique, as no other species of lactobacilli or bifidobacteria adhere to human enterocytes in this manner. Direct competition for a limited number of mannosespecific adhesion sites between strains of L. plantarum and enteropathogens may limit the ability of the pathogens to bind to the intestinal mucosa, which is a necessary prerequisite to infection.6oAs yet, however, no clinical trials have been conducted using strains of L. plantarum.

Lactose Intolerance Lactose intolerance is a fairly common condition, affecting up to 70% of the world’s adults,’75although its prevalence is far lower in communities from Northern European descent (15% to 25%).’76It is caused by a deficiency of the enzyme lactase, which is usually located on the brush border of the small intestine. In the absence of lactase, lactose remains in the gut and osmotically draws water into the intestines. When lactose reaches the large intestine, it is avidly fermented by the colonic microflora into SCFAs, lactic acid, C02, and hydrogen gas. These processes result in the symptoms of lactose intolerance-bloating, diarrhea, flatulence, and abdominal discomfort.’” A number of studies have shown that lactose in ”living” yogurt is better tolerated by lactose-intolerant individuals than lactose in other dairy food^."^-'^^ This difference is primarily due to the activity of microbial beta-galactosidase, which breaks down lactose in vivo. However, yogurt consumption also significantly slows gastrointestinal transit compared with . unfermented dairy foods. This delay in gastrointestinal transit also contributes to the improvement in lactose tolerance.lT Most, if not all, strains of the typical yogurt-producing bacteria (L. delbrueckii ssp. bulgaricus and S. thermophilus) appear to possess sigruficantbeta-galactosidase a~itivity.’~~

Probiotics development of atopy if consumed during pregnancy and the early months of b r e a ~ t f e e d i n g . l Other ~ ~ J ~ strains of L. rharnnosus cannot be assumed to act in a similar manner. The clinician who chooses to use the exact strain that had the effects in clinical trials can be confident of similar results. Using another closely-related strain may or may not have any effects.Whenever possible, use the exact strain used in the research, because other strains, even closely related ones, may not have the same effects. Even a strain that has a proven effect in one area may not be the best strain for another application. For instance, L. rharnnosus GG has been shown to be useful in the treatment of infantile eczema,’2 but it does not appear to be of any benefit in the treatment of U T I S . ’ ~This ~ situation is somewhat analogous to the use of specific breeds of dog for specific jobs. For instance, if a guard dog is needed, a German Shepherd or Rottweiler would be far more useful than a Labrador or Scottish terrier. That is not to say that a Labrador is not a “good” or useful breed of Stimulation of Gastrointestinal Tract dog; it is merely that Labradors may not be the best and Systemic Immunity breed available for this task. All probiotic strains similarly have areas of strengths and weaknesses. As more A number of probiotic strains have demonstrated an abilresearch is conducted on each strain, it will become ity to enhance indices of both gastrointestinal and sysclearer which strains are best suited for specific health temic immune function in humans. Administration of conditions. Unfortunately, much of the earlier probiotic L. joknsonii La1251mand L. rharnnosus GG1411@resulted in research failed to delineate the bacterial strain used, so enhanced gut IgA response to antigens. Phagocytic activthe findings are hard to place in the context of later ity of peripheral blood leukocytes has been increased research. by consumption of L. johnsonii La1,183J85-187 B. lactis Table 118-2193-236 outlines the most appropriate probiBb12,183J87 L. rhurnnosus HNO01,188B. Zacfis HN019,189J90 otic strains available for some common health condiand L. rharnnosus GG.191B. Zucfis HN019 also improves natural killer cell tumor-killing a c t i ~ i t y ’ ~and J ~ ~ tions. If it is not possible to locate and utilize the specific strains delineated in this table, the best option is to use enhances phagocyte-mediated bactericidal activity.lE9 an alternative bacterial strain that possesses the characOne double-blind, placebo-controlled trial was teristics listed in Table 118-1. designed to assess whether this enhancement of immune indices translated to decreased rates of infection and/or severity of infection. Five-hundred seventy-one children DOSAGE enrolled in daycare took part in the trial. Children were randomly assigned to drink L. rharnnosus G G The dosage of probiotic foods and supplements is based solely on the number of live organisms present in the containing milk (LGG) or probiotic-free milk (PFM) as product. Successful results have been attained in clinical the control. After 7 months, the LGG group were found trials using between lo7 and 10” viable bacteria per to have significantly fewer days of absence from daycare day.47,71,216 Interestingly, it appears that 100 times less due to illness (4.9 [95% CI 4.4-5.51 versus 5.8 [95% CI viable bacteria need to be given in a dairy medium than 5.3-6.41 days, 16% difference;p = 0.03) than the PFM group. in a freeze-dried supplement to achieve similar numbers There were also relative reductions of 17”/0in the number of live bacteria in the lower Dairy appears to of children suffering from complications from respiratory work as an ideal transport medium for the bacteria, infections and lower respiratory tract infections (p = 0.05), and of 19%in antibiotic use in the LGG group (p = 0.03).47 enhancing their survival through the upper GIT?5 When consumed in a yogurt medium, most of the bacteria survive transit through the stomach to the small intestine. In the proximal small intestine, they are exposed to large quantities of bile salts. However, bacterial strains from these two species are typically intolerant to bile salts, and exposure to these salts results in cell death and lysis. Microbial beta-galactosidase is an intracellular enzyme, so cell lysis results in the liberation of this enzyme into the intestinal lumen, where it can function to digest lactose. Microbial beta-galactosidase has been shown to be metabolically active in the middle and distal small intestine, contributing to the digestion of lactose before it reaches the large intestine, where its fermentation causes symptoms.1n In addition to the yogurt-producing bacteria, two specific probiotic strains have demonstrated their usefulness in the management of lactose intolerance, L. ucidophilus NCFM178J81 and L. johnsonii La1.1E2

USING THE RIGHT STRAIN To achieve successful and reproducible clinical outcomes, it is imperative to use the exact probiotic strain that has been proven to have the specific therapeutic action that is desired. For example, two trials have demonstrated that L. rhurnnosus GG can prevent the

Supplements

Supplements are best consumed with meals in order to take advantage of the greater alkalinity of the gastric environment (which equates to greater bacterial survival).237 A dosage of lo8 bacteria per sitting is often mentioned in the probiotic literature as the minimum quantity of bacteria needed to produce therapeutic e f f e ~ t s . ~ ~ , ~ ~ ~

Therapeutic application

Most appropriate probiotic strain@)

Reference(@

Hypercholesterolemia

Lactobacillus plantarum 299v, Bacillus coagulans ATCC # 31284, Lactobacillus acidophilus L1

53, 193-195

Prevention of atopy

Lactobacillus rhamnosus GG

133, 134

Eczema

L. rhamnosus GG, Bifidobacterium lactis Bbl2, Lactobacillusparacasei Shirota

72, 142, 143, 196-198

Food allergies

L. rhamnosus GG, B. lactis Bb12, L. paracasei Shirota

70, 72, 139, 140, 142, 143, 191, 197-199

Nonsteroidal antiinflammatory drug use/erosive gastritis

L. rhamnosus GG

200

Antibiotic use (during and afler)

L. rhamnosus GG, Saccharomyces cerevisiae (Hansen CBS 5926), L. acidophilus LA5, L. plantarum 299v

51, 95-99, 101, 103, 201-204

Lowered immunity

L. rhamnosus GG, B. lactis HN019 (DRlO), Lactobacillusjohnsonii La1, L. rhamnosus HNOOl (DR20), L. acidophilus LA5

47, 183, 187-190, 205-209

Intestinal hyperpermeability

L. rhamnosus GG, S. cerevisiae (Hansen CBS 5926)

142, 143,210,211

Gastroenteritis

L. rhamnosus GG, Lactobacillus reuteri MM53, L. paracasei CRL431, L. acidophilus CRL730, L. johnsonii La1, B. lactis Bb12, L. plantarum 299v, L. paracasei Shirota

21, 54,55, 184, 212-219

Giardia infection

L. johnsonii La1, L. plantarurn 299v. L. rhamnosus GG

21, 60, 87

Intestinal dysbiosis

L. rhamnosus GG, L. johnsonii La1, L. plantarum 299v, L. paracasei Shirota, L. acidophilus LA5

50, 52, 101, 202, 220-224

Irritable bowel syndrome

L. plantarum 299v, VSL# 3

71, 157, 225

Traveler's diarrhea

L. rhamnosus GG, 6.lactis Bb12, L. acidophilus LA5, S. cerevisiae (Hansen CBS 5926), L. plantarum 299v

21, 173, 186, 218, 226

Lactose intolerance

L. acidophilus NCFM, L. johnsonii La1, L. acidophilus LA5

178, 181, 182,227,228

Peptic ulcer diseasehonerosive gastritis

L. johnsonii La1, L. acidophilus LB, L. acidophilus strain NAS, L. acidophilus DDS-1, L. rhamnosus GG

47. 83-86

Crohn's disease

L. rhamnosus GG, S.cerevisiae (Hansen CBS 5926)

141,168,169,229

Ulcerative colitis

Escherichia coli strain Nissle 1917, VSL# 3, L. plantarum 299

69, 167, 230-232

Prevention of colon cancer

L. rhamnosus GG, L. acidophilus NCFM, L. paracasei Shirota, L. acidophilus DDS-1, L. acidophilus Delvo Pro LA1, Lactobacillus delbrueckii ssp. bulgaricus strain LB-51

49, 148-151

Urinary tract infection

L. rhamnosus GR-1, Lactobacillus fermenturn 6-54, L. fermentum RC-14. L. acidophilus NCFM

111, 113-115, 117, 233-235

Vaginal candidiasis (thrush)

L. acidophilus LA5, L. acidophilus strain NAS, L. rhamnosus GG, L. rhamnosus GR-1, L. fermentum RC-14

48, 106, 107, 119, 122,236

Probiotic strains are listed in decreasing order of appropriateness. For instance, strains listed first generally have the most evidence supporting their use in that condition. (Note: This table highlights only those strains widely discussed in the peer-reviewed literature.)

Also, a handful of studies have demonstrated therapeutic effects utilizing lo7 to lo8 viable bacteria per dose.47,216,239 However, most of the successful probiotic research has utilized more than lo9 bacteria per dose. The minimum concentration of probiotic bacteria needed to achieve therapeutic effects appears to be somewhat strain dependent, in that for some strains (e.g., L. reuteri MM53), lo7bacteria is a sufficient quantity to produce beneficial effects,2I6but for other strains, lo9 viable bacteria is needed (e.g., L. rharnnosus GG, if given as lyophilized b a ~ t e r i a )This . ~ ~ situation, unfortunately, makes it hard to give firm dosage recommendations;

the minimum effective dosage appears to differ by strain. Thus it is best practice to ensure that supplements contain bacteria in concentrations greater than lo9bacteria per dose, unless research has demonstrated that the specific strain contained in the supplement is effective in smaller amounts. Therefore, the dosage of viable bacteria given in supplemental forms should generally be lo9 to 10" bacteria per dose. If a formulation contains multiple strains, each strain must be present in amounts higher than lo9, because smaller doses of living bacteria may not produce therapeutic effects.

Probiotics

Yogurts The minimum dosage of viable bacteria needed in a dairy medium is lo8 per dose. Therapeutic yogurts contain more than lo6 viable bacteria per mL, so a 100-g serving (= '/2 cup) will provide sufficient probiotic bacteria for therapeutic effe~ts.2~~ Unfortunately, many so-called acidophilus and/or bifidus yogurts do not Only yogurt brands that contain this minimum are guaranteed to contain this level of viable bacteria, or those that have done so in market-basket surveys, should be utilized. A serving of yogurt containing less than lo8 viable bacteria is unlikely to have any medicinal effects beyond its inherent nutritional content. A 100-g serving of yogurt contains only 3.1 to 3.5 g of lactose,"' well below the threshold level for people with lactose intolerance. Hence lactose-intolerant individuals should be able to consume the minimum amount of yogurt without ill effe~ts.2~~

Fermented Vegetables Traditionally prepared fermented vegetables generally contain more than lo8 living bacteria per gram, so 10 grams is the minimum dosage r e q ~ i r e d . ~ ~ B For applications in the mouth, esophagus, and stomach, supplement powders, therapeutic yogurts, or fermented vegetables are the best forms of administration, as administration in these forms will allow the probiotic bacteria to come into direct contact with the areas where they are needed. For applications in the small and large intestine, however, there is no advantage of one form of administration over another (assuming an adequate dose is prescribed).

oligosaccharides. For further details, please refer to Chapter 117.

Spirulina Another possible way to improve the intestinal ecology is through the consumption of spirulina. Although no human studies appear to have been published, intriguing veterinary research has shown that providing horses with spirulina stimulates the growth of lactobacilli in the cecum. The researchers suggest that this result may be due to the mucopolysaccharides in ~ p i r u l i n a . ~ ~ ~

TOXICITY Lactobacilli have been consumed in large numbers throughout recorded history. The fermentation of foodstuffs is one of the oldest known uses of biotechnology, and even today fermented foods and beverages constitute 20% to 40% of the human food supply worldwide. Thus lactobacilli have a long history of safe use.3 In a 1999 article, Naidu et aP reviewed the safety profile of lactobacilli and bifidobacteria. No adverse effects or events were reported by any of the 7526 subjects who participated in the 143 human trials r e ~ i e w e d . ~ A number of cases of fungemia from the oral administration of S. cermisiae (aka S. boulardii)have been reported in the literature. These cases have occurred almost exclusively in immunocompromised or critically ill individuals. Thus, administration of strains of S. cereuisiae should be given only to immunocompetent i n d i ~ i d u a l s ? ~ , ~ ~ ~

DRUG INTERACTIONS

A number of different sugars can stimulate the growth of endogenous strains of lactobacilli and bifidobacteria, including fructooligosaccharides,lactulose, and soybean

Lactobacilli and bifidobacteria are negatively affected by alcohol and antibiotic^.^^,^^^ Although there is no evidence that L. acidophilus interferes with the activity of most antibiotics, some strains affect the metabolism of sulfasalazine, chloramphenicol palmitate, and phthalylsulfathiazole?48Concurrent administration of S. cerevisiae (Hansen CBS 5926) with monoamine oxidase inhibitors may increase blood pressure.249

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PROMOTING GROWTH OF LACTOBACILLI AND BlFlDOBACTERlA Oligosaccharides and Disaccharides

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204. Cremonini F, Di Car0 S, Covino M, et al. Effect of different probiotic preparations on anti-Helicobacter pylori therapy-related side effects: a parallel group, triple blind, placebo-controlled study. Am J Gastroenterol2002;972744-2749. 205. Perdigon G, Nader de Macias ME, Alvarez S, et al. Enhancement of immune response in mice fed with Streptococcus therrnophilus and Lncfobncillus acidophilus. J Dairy Sci 1987;70:919-926. 206. Tejada-Simon MV, Lee JH, Ustunol Z, Pestka JJ. Ingestion of yogurt containing Lnctobncillus acidophilus and BiFdobacteriurn to potentiate immunoglobulin A responses to cholera toxin in mice. J Dairy Sci 1999;82:649-660. 207. Hatcher GE, Lambrecht RS.Augmentation of macrophage phagocytic activity by cell-free extracts of selected lactic acid-producing bacteria. J Dairy Sci 1993;762485-2492. 208. Marteau P, Vaerman JP, Dehennin JP,et al. Effects of intrajejunal perfusion and chronic ingestion of Lactobacillus johnsonii strain La1 on serum concentrations and jejunal secretions of immunoglobulins and serum proteins in healthy humans. Gastroenterol Clin Biol 1997;21:293-298. 209. Gill HS, Rutherford KJ, Prasad J, Gopal PK. Enhancement of natural and acquired immunity by Lactobacillus rhamnosus (HNOOl), Lnctobncillrts acidophilus (HN017) and Bifdobacteriurn lactis (HN019). Br J Nutr 2000;83:167-176. 210. Jahn HU, Ullrich R, Schneider T, et al. Immunological and trophical effects of Sncchnromyces boulardii on the small intestine in healthy human volunteers. Digestion 1996;5795-104. 211. Buts JP, De Keyser N, De Raedemaeker L. Saccharornyces boulardii enhances rat intestinal enzyme expression by endoluminal release of polyamines. Pediatr Res 1994;36:522-527. 212. Isolauri E, Juntunen M, Rautanen T, et al. A human Lactobacillus strain (Lactobacillus casei strain GG) promotes recovery from acute diarrhea in children. Pediatrics 1991;88:90-97. 213.Shomikova AV, Isolauri E, Burkanova L, et al. A trial in the Karelian Republic of oral rehydration and Lactobacillus GG for treatment of acute diarrhoea. Acta Pediatr 1997;86460-465. 214. Isolauri E, Kaila M, Mykkanen H, et al. Oral bacteriotherapy for viral gastroenteritis. Dig Dis Sci 1994;39:2595-2600. 215. Saavedra JM, Bauman NA, Oung I, et al. Feeding of Bifdobacterium bifdrtm and Streptococcus therrnophilus to infants in hospital for prevention of diarrhoea and shedding of rotavirus. Lancet 1994344:1046-1049. 216. Shomikova AV, Casas IA, Mykkanen H, et al. Bacteriotherapy with Lactobncillrrs reirtrri in rotavirus gastroenteritis. Pediatr Infect Dis J 1997;16:1103-1107. 217. Sugita T, Togowa M. Efficacy of Lactobacillus preparation Biolactis powder in children with rotavirus enteritis. Jpn J Pediatr 1994;47213-220. 218. Michail S, Abemathy F. Lactobacillus plantarurn reduces the in vitro secretory response of intestinal epithelial cells to enteropathogenic Escherichin coli infection.J Pediatr Gastroenterol Nutr 2002;35:350-355. 219.Ogawa M, Shimizu K, Nomoto K, et al. Protective effect of Lactobacillus casei strain Shirota on Shiga toxin-producing Eschrrichin coli 0157:H7 infection on infant rabbits. Infect Immun 2001;69:1101-1108. 220.Silva M, Jacobus NV, Deneke C, Gorbach SL. Antimicrobial substance from a human Lactobacillus strain. Antimicrob Agents Chemother 1987;31:1231-1233. 221.Bemet-Camard MF, Lievin V, Brassart D, et al. The human Lnctobncillus ncidophilus strain LA1 secretes a nonbacteriocin antibacterial substance(s) active in vitro and in vivo. Appl Environ Microbiol 1997;63:2747-2753. 222.Bernet MF, Brassart D, Neeser JR, Servin AL. Lactobacillus acidophilus LA1 binds to cultured human intestinal cell lines and inhibits cell attachment and cell invasion by enterovirulent bacteria. Gut 1994;35:483-489.

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Procyanidolic Oligomers Michael T. Murray, ND JosephE. Pizzorno Jr, ND CHAPTER CONTENTS General Description 1217 Chemical Composition 1217

Clinical Applications 1219 Venous and Capillary Disorders 1219 Visual and Function and Retinopathy 1219 Atherosclerosis 1219

History and Folk Use 1217 Dosage 1219 Pharmacology 1218 Protection of Collagen 1218 Antioxidant and Free Radical Scavenging Activity 1218

GENERAL DESCRIPTION The proanthocyanidins (also referred to as "procyanidins") are one of the most beneficial groups of plant flavonoids. The most active proanthocyanidins are those bound to other proanthocyanidins. Collectively, mixtures of proanthocyanidin dimers, trimers, tetramers, and larger molecules are referred to as procyanidolic oligorners (PCOs).'J Although PCOs exist in many plants as well as red wine, commerciallyavailable sources of PCOs include extracts from grape seed skin (Vitex v i n f i a ) and the bark of the maritime (Landes)pine.'$ This chapter reviews the benefits of PCOs from grape seeds and pine bark.

CHEMICAL COMPOSITION Grape seed and pine bark PCO extracts are well defined chemically.Grape seed extracts are available that contain 92% to 95%PCOs, whereas the PCO content of pine bark extracts varies from 80% to 85%. Proanthocyanidin B2 is shown in Figure 119-1.

HISTORY AND FOLK USE In 1534, French explorer Jacques Cartier led an expedition up the Saint Lawrence River in what would become North America. Trapped by ice, Cartier and his crew were forced to survive on a ration of salted meat and biscuits. Cartier's crew began to exhibit signs and symptoms of scurvy, the cause of which was unknown at that time. Fortunately for Cartier and the surviving members

Toxicity

1220

Drug Interactions 1220

of his crew, they met a Native American who advised them to make a tea from the bark and needles of pine trees. As a result, Cartier and his men survived. More than 400 years later, Professor Jacques Masquelier of the University of Bordeaux, France, read the book Cartier wrote detailing his expedition. Intrigued by Cartier's story, Masquelier and others concluded that pine bark must contain some vitamin C as well as bioflavonoids, which can exert vitamin C-like effects. Masquelier termed the active components of the pine bark pycnogenols.'J This term was used to describe an entire complex of proanthocyanidin complexes found in a variety of plants, including pine bark, grape seeds, lemon tree bark, peanuts, cranberries, and citrus peels. The term pycnogenol has been replaced in the scientific community by the terms proanthocyanidis,oligorneric prounthocyanidin complex (OPC),and PCO. In the United States, Pycnogenol is a registered trademark of Horphag Ltd of Guernsey, UK, and refers to the PCO extracted from the bark of the French maritime pine. Masquelier patented the method of extracting PCOs from pine bark in France in 1951, and from grape seeds in 1970. The PCO extract from grape seed emerged as the preferred source on the basis of research conducted between 1951 and 1971 as well as intensive research from 1972 to 1978.' The 1970s research was conducted with the goal of gaining approval for PCO as a medicinal agent by the French equivalent of the U.S. Food and Drug Administration (FDA). During this time, detailed analytical, toxicity, pharmacologic, and clinical studies were performed on PCOs derived from grape seeds. 1217

Increase intracellular vitamin C levels Decrease capillary permeability and fragility Scavenge oxidants and free radicals Inhibit destruction of collagen Data from references 1 and 2.

I

OH Figum 119-1 Proanthocyanidin B2

PCOs from both grape seeds and pine bark have been marketed in France for decades, where they have been promoted to improve retinopathies, venous insufficiency, and vascular fragility.

PHARMACOLOGY

Trap hydroxyl free radicals Trap lipid peroxides and free radicals Markedly delay the onset of lipid peroxidation Chelate free iron molecules, thereby preventing iron-induced lipid peroxidation Inhibit production of free radicals by noncompetitively inhibiting xanthine oxidase Inhibit the damaging effects of the enzymes (e.g., hyaluronidase, elastase, collagenase) that can degrade connective tissue structures

Extracts of PCOs have demonstrated a wide range of activity, as listed in Box 119-1.

Protection of Collagen Collagen, the most abundant protein of the body, is responsible for maintaining the integrity of ground substance as well as the integrity of tendons, ligaments, and cartilage. Collagen is also the support structure of the dermis and blood vessels. PCOs are remarkable in their effects of supporting collagen structures and preventing collagen destruction. They affect collagen metabolism in several ways. They have the unique ability to cross-link collagen fibers, resulting in reinforcement of the natural cross-linking of collagen that forms the so-called collagen matrix of connective tissue.45 They also protect against free radical damage with their potent antioxidant and free radical scavenging action, and they inhibit enzymatic cleavage of collagen by enzymes secreted by leukocytes during inflammation and microbes during infection.6~~ PCOs also prevent the release and synthesis of compounds that promote inflammation and allergies such as histamine, serine proteases, prostaglandins, and leuk0trienes.'2,~,~

Antioxidant and Free Radical Scavenging Activity Perhaps the most celebrated effects of PCOs in the United States are their potent antioxidant and free radical scavenging activity. Free radical damage has been linked to the aging process and virtually every chronic degenerative disease, including heart disease, arthritis, and cancer. Fats and cholesterol are particularly

susceptible to free radical damage. When damaged, fats and cholesterol form toxic derivatives known as lipid peroxides and cholesterol epoxides, respectively. The antioxidant and free radical-scavenging effects of PCOs were discovered by Masquelier in 1986.' One study evaluated the free radical-scavenging activity of PCOs and determined their inhibitory effects on xanthine oxidase (a primary generator of oxygenderived free radicals) and the lysosomal enzyme system (which governs the release of enzymes that can damage the connective tissue framework acting as a protective sheath around capillary walls).' This research, summarized in Box 119-2, provides a detailed explanation of the vascular protective action of PCOs and a strong rationale for their use in vascular disease. In experimental models, the antioxidant activity of PCOs is much greater (approximately 50 times) than that of vitamin C and vitamin E. From a cellular perspective, one of the most advantageous features of PCOs' free radical scavenging activity is that, because of their chemical structure, they are incorporated into cell membranes. This physical characteristic, along with their ability to protect against both water- and fat-soluble free radicals, provides significant cellular protection against damage by free radicals. The researchers concluded their discussion with the following comment: "These findings, together [with]those of other investigators, provide a strong rationale for using these compounds in the therapeutic management of microvascular disorder^."^

Procyanidolic Oligomers

CLINICAL APPLICATIONS Venous and Capillary Disorders The primary clinical applications of PCOs are in the treatment of the following conditions: Venous and capillary disorders including venous insufficiency Varicose veins Capillary fragility Disorders of the retina, including diabetic retinopathy and macular degeneration Good clinical studies have shown positive results in the treatment of these c~nditions.'J@*~ PCO extracts have also been helpful in improving sperm quality and function (see discussion of male infertility) and melasma, presumably as a result of their antioxidant effect^.'^,'^

Visual Function and Retinopathy Increased intake of PCO is likely to benefit almost everyone. This suggestion is perhaps best illustrated by research evaluating the effects of grape seed PCOs extract on visual function in healthy subjects.2°,21In the studies, 100 normal volunteers with no retinal disorder received either 200 mg/day of PCOs or placebo for 5 or 6 weeks. The group receiving PCOs demonstrated significant improvement in visual performance in dark and after-glare tests compared with the placebo group. PCO extracts have also been shown to be of benefit in treating retinopathies, especially diabetic retinopathy. In one study, 40 patients with diabetes, atherosclerosis, and other vascular diseases involving the retina were randomly treated with placebo or PCO extract (50 mg x 3/day for 2 months). The results demonstrated a beneficial effect of PCOs on the progression of retinopathy. In patients without any treatment (placebo)the retinopathy progressively worsened during the trial and the visual acuity significantly decreased; on the contrary, the PCOtreated patients showed no deterioration of retinal function, and a sigruficant recovery of visual acuity was also obtained. The fluorangiography showed an improvement of retinal vascularization and a reduced endothelial permeability and leakage in the PCO group, but not in the placebo-treated patients. The ophthalmoscopy and the electroretinogram also confirmed the beneficial effects of PCOs. In addition to the PCOs exerting free radicalscavenging, antiinflammatory, and capillary protective activities, it has been suggested that Pycnogenol may bind to the blood vessel wall proteins and mucopolysaccharides and produce a capillary "sealing" effect, leading to a reductions in capillary permeability and edema f~rmation.'~

Atherosclerosis There are now numerous studies demonstrating that an individual's level of antioxidants may be a more significant factor in determining the risk of heart disease than cholesterol levels. Antioxidants prevent both the oxidation of cholesterol and its carrier proteins and the initial damage to the artery that ultimately leads to the process of atherosclerosis.Several studies have shown the protective effects of red wine against heart disease and stroke through protection against low-density lipoprotein (LDL) oxidation.22 The active components in the wine are thought to be proanthocyanidins.Also, a study of 805 men beginning in 1985 and published in 1993demonstrated an inverse correlation between flavonoid intake and death due to heart atta~k.2~ Clinical studies have shown that PCO extract supplementation enhances the oxygen radical absorbance capacity (ORAC) in plasma throughout the supplementation peri0d.2~'~ In one double-blind study, the effect of a standardized formulation of a PCO extract bound to phosphatidylcholine (Leucoselect-Phytosome)was determined on susceptibility of LDL to oxidation in a group of heavy smokers. Among oxidative indices, the concentration of thiobarbituric acid-reactive substances (TBARS) was sigruficantly reduced in subjects taking the PCO extract, and the lag phase prolonged, compared with the values in subjects taking placebo as well as with baseline values. In addition to preventing damage to LDL and the lining of the artery, PCO extracts have been shown to lower blood cholesterol levels and shrink the size of cholesterol deposits in arteries in animal and human s t ~ d i e s . ' , ~Additional ~J~ mechanisms of PCOs useful in preventing atherosclerosis include inhibition of platelet aggregation and inhibition of angiotensin-I-converting e n ~ y m e . Presumably, ~~J~ PCO extracts may exert similar benefits in humans. PCO extracts appear to be helpful in improving endothelial function in patients with hypertension. In one double-blind study in 58 patients with hypertension who received supplementation with 100 mg PCOs over a period of 12 weeks, endothelin-1 concentrations were significantly lower, and concentrations of 6-keto prostaglandin F1, in plasma significantly higher, in the PCO group than in the placebo group, and the PCOs helped reduce the effective dose of the calcium antagonist nifedipine in a statistically significant manner.16 PCO extracts, although in a supplement form, should be regarded as a necessary food in the prevention and treatment of atherosclerosis.

DOSAGE As antioxidant support, a daily dose of 50 mg of either the grape seed or pine bark extract is suitable.

For comparison, it is now estimated that the average daily intake of total flavonoids in the United States is about 25 mg. An intake greater than 30 mg offers a simificant reduction in risk for cardiovascular mGrtality.23 When PCO extracts are being used for therapeutic purposes, the daily dosage should be increased to150 to 300 mg.

1. Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther 2002;40:158-168. 2. Schwitters 8, Masquelier J. OPC in practice: biflavanols and their application. Rome: Alfa Omega, 1993. 3. Masquelier J. [Procyanidolic oligomers.] J Parfums Cosmetiques Aromes 1990;95:89-97. 4. Masquelier J, Dumon MC, Dumas J. [Stabilization of collagen by procyanidolic oligomers.] Acta Therap 1981;7101-105. 5. lixier JM, Godeau G, Robert AM. Evidence by in vivo and in vitro studies that binding of pymogenols to elastin affects its rate of degradation by elastases. Biochem Pharmacol1984;333933-3939. 6. Meunier MT, Duroux E, Bastide P. Free-radical scavenger activity of procyanidolic oligomers and anthocyanosides with respect to superoxide anion and lipid peroxidation. Plant Med Phytother 1989; 4~267-274. 7. Maffei Facino R, Carini M, Aldini G, et al. Free radicals scavenging action and anti-enzyme activities of procyanidines from Vitis viniferu. A mechanism for their capillary protective action. Arneimitteforschung 1994;44:592-601. 8. Sharma SC,Sharma S, Gulati OP. Pycnogenol inhibits the release of histamine from mast cells. Phytother Res 2003;1766-69. 9.Cho KJ, Yun CH,Packer L, Chung AS. Inhibition mechanisms of biotlavonoids extracted from the bark of Pinus maritima on the expression of proinflammatory cytokjnes.Ann N Y Acad Sci 2001,928:141-156. 10. Henriet JI? Veno-lymphatic insufficiency:4,729 patients undergoing hormonal and procyanidol oligomer therapy. Phlebologie 1993; %313-325. 11. Baruch J. Effect of Endotelon in postoperative edema: results of a doubleblind study versus placebo in 32 female patients. Ann Chir Plast Esthet 1984;29393-395. 12. Lagrue G, Oliver-Martin F, Grillot A. A study of the effects of procyanidol oligomers on capillary resistance in hypertension and in certain nephropathies. Sem Hop 1981;571399-1401. 13. Petrassi C, Mastromarho A, Spartera C. Pycnogenol in chronic venous insufficiency. Phytomedicine 2OOO;7383-388. 14. Soyeux A, Segiun JP, Le Devehat C, Bertrand A. Endotelon: diabetic retinopathy and hemorheology (preliminary study). Bull Soc Ophtalmol Fr 1987;871441-1444. 15. Proto F, et al. Electrophysical study of Vitis viniferu procyanoside oligomers effects on retinal function in myopic subjects. Ann Ott Clin Ocul 1988;11485-93.

TOXICITY PCO extracts are without known side effects.

DRUG INTERACTIONS There are no documented drug interactions for the procyanidins.

16. Liu X, Wei J, Tan F, et al. Pycnogenol@,French maritime pine bark extract, improves endothelial function of hypertensive patients. Life Sci 2004;74:855-862. 17. Spadea L, Balestrazzi E. Treatment of vascular retinopathies with Pycnogenol. Phytother Res 2001;15:219-223. 18. Roseff SJ. Improvement in sperm quality and function with French maritime pine tree bark extract. J Reprod Med 2002;47 821-824. 19. Ni Z, Mu Y, Gulati 0. Treatment of melasma with Pycnogenol. Phytother Res 2002;16567-571. 20. Corbe C, Boissin JP, Siou A. [Light vision and chorioretinalcirculation: study of the effect of procyanidolic oligomers (Endotelon).] J Fr Ophtalmol 1988;11:453-460. 21. Boissin JP, Corbe C, Siou A. Chorioretinal circulation and dazzling: use of procyanidol oligomers. Bull Soc Ophtalmol Fr 1988;88: 173174,177-179, 22. Frankel EN, Kanner J, German JB, et al. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet 1993;341:454-457. 23. Hertog MG, Feskens EJ, H o h a n PC, et al. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993;3421007-1011. 24. Devaraj S, Vega-Lopez S, Kaul N, et al. Supplementation with a pine bark extract rich in polyphenols increases plasma antioxidant capacity and alters the plasma lipoprotein profile. Lipids 2002;37 931-934. 25.Vigna GB, Costantini F, Aldini G, et al. Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers. Metabolism 2003;52 1250-1257. 26. Nuttall SL, Kendall MJ, Bombardelli E, Morazzoni P.An evaluation of the antioxidant activity of a standardized grape seed extract, Leucoselect. J Clin Pharm Ther 1998;23:385-389. 27. Wegrowski J, Robert AM, Moczar M. The effect of procyanidolic oligomers on the composition of normal and hypercholesterolemic rabbit aortas. Biochem Pharmacol1984;333491-3497. 28. Chang WC, Hsu FT.. Inhibition of platelet aggregation and arachidonate metabolism in platelets by procyanidins. Prostagland Leukot Essent Fatty Acids 1989;38181-188. 29. Meunier MT, V i e F, Jonadet M. Inhibition of angiotensin I converting enzyme by flavanolic compounds: in vitro and in vivo studies. Planta Med 1987;54:12-15.

Pygeum africmum (Bitter Almond) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 1221

Male Infertility and Impotence 1224 Pygeum versus Serenoa 1224

Chemical Composition 1221 Dosage 1224 History and Folk Use 1221 Toxicology 1224 Pharmacology 1221 Ferulic Acid Esters 1222 Other Components 1222

Drug Interactions 1224

Clinical Applications 1222 Prostate Disorders 1222

Pygeum ufricunum (family: Rosaceae) Synonym: Prunus ufricunum Common names: bitter almond, red stinkwood

GENERAL DESCRIPTION Pygeum ufricunum is an evergreen tree native to Africa that can grow to a height of 120 to 150 feet. It has pendulous branches with thick, oblong, leatherlike, mat-colored leaves and creamy white flowers. The fruit (drupe)resembles a cherry when ripe. The dark brown to gray bark of the trunk is the part used for medicinal purposes.

CHEMICAL COMPOSITION The major active components of the bark are as follows: Lipid-soluble pentacyclic triterpenes Sterolic triterpenes Fatty acids Esters of ferulic acid (Figure 120-1) The pentacyclic triterpenic components are ursolic acid (Figure 120-2), oleanolic acid, crataegolic acid, and their derivatives. The sterolic fraction is composed mainly of beta-sitosterol and beta-sitosterone (Figure 120-3). The fatty acids range from C12 to C24 and the important ferulic acid esters are those bound to n-tetracosanol and n-doc~sanol.'~

HISTORY AND FOLK USE The powdered bark of P. ufricunum was used by the natives of tropical Africa as a treatment for urinary disorders. It was often given with palm oil or milk. Since about 1970, the bark has been entirely wild-collected, with the major exporters being Cameroon, Madagascar, Equatorial Guinea, and Kenya. Two companies, Groupe Fournier of France and Indena of Italy, produce 86% of the world's bark extract, both for their own products and for the free market. Worldwide exports of dried bark in 2000 were estimated at 1350 to 1525 metric tons per year, down from its peak of 3225 tons in 1997. Bark extracts (6370 to 7225 kg/year) are worth an estimated $4.36 million US.dollars per year. However, wild collection of the bark is no longer sustainable. Since 1995, P. ufricunum has been declared an endangered species. Alternatives to wild collection to meet future market demand include conservation practices, enrichment plantings, and smalland large-scale production. Currently, the species is at the beginning of a transition from an exclusively wild-collected species to that of a cultivated medicinal tree?

PHARMACOLOGY Pharmacologic screening of various extracts prepared with solvents of differing degrees of polarity indicated that the highest activity was found in lipophilic extracts.l 1221

0

11

H HC=C-C-OH

h OH Figure 120-1

Ferulic acid.

CH3 I

H3cA COOH

HO

Figure 120-2 Ursolic acid.

0

M Figure 120-3 Beta-sitosterone.

This finding is interesting in light of pygeum's historical administration in lipophilic media (palm oil or milk). Virtually all of the pharmacologic research has featured a pygeum extract standardized to contain 14% triterpenes including beta-sitosterol and 0.5% n-docosanol. This extract has been extensively studied in both experimental animal studies and clinical trials with humans. The primary target organ for pygeum's effects in men is the prostate. The three major active components of pygeum appear to exert different, yet complementary, effects in benign prostatic hyperplasia (BPH).In addition, pygeum has been shown to enhance the secretions of the prostate and bulbourethral glands, in terms of both quantity and quality.

Ferulic Acid Esters The esters of ferulic acid act primarily on the endocrine system. Studies in animals have shown docosanol to reduce levels of luteinizing hormone and testosterone while raising adrenal steroid secretion of both adrenal

androgens and cortico~teroids.~~~ Docosanol also significantly lowers serum prolactin levels. This reduction of prolactin is quite significant because prolactin increases both the uptake of testosterone and the synthesis of dihydrotestosterone within the prostate. The accumulation of testosterone within the prostate and its subsequent conversion to the more potent dihydrotestosterone is thought to be the major contributing factor to the hyperplasia of the prostatic cells observed in BPH.8 Although traces of docosanol are present in pygeum, the esterification with ferulic acid results in greater bioavailability and a c t i ~ i t y . ~ , ~ , ~ Ferulic acid esters and the sterol fraction of pygeum exert cholesterol-lowering action systemically as well as within the prostate? Breakdown products of cholesterol have been shown to accumulate in the prostate tissue affected with either BPH or cancer." These metabolites of cholesterol initiate degeneration of prostatic cells, which can promote prostatic enlargement. Drugs that lower cholesterol levels have been shown to have a favorable influence on BPH, preventing the accumulation of cholesterol in the prostatic cells and limiting subsequent formation of damaging cholesterol metabolites. The lowering of intraprostatic cholesterol content is an important aspect of the pharmacology of pygeum. The sterolic fraction is also endowed with competitive action against testosterone accumulation within the prostate. In addition, the sterols of pygeum have also been shown to reduce inflammation by preventing the intraprostatic formation of inflammatory prostaglandins?JO

Other Components Other components of pygeum are also important. For example, the pentacyclic triterpenes exhibit antiinflammatory effects within the prostatic epithelium and may be responsible for stimulation of the secretory cells of the prostate, seminal vesicles, and bulbourethral glands?-" Finally, the fatty acid components are similar to those of Serema repens (see Chapter 124) and may exert similar effects as well as improve the oral bioavailability of other components of the lipophilic extract.

CLINICAL APPLICATIONS Prostate Disorders The pharmacologic actions of the standardized pygeum extract support its use in prostate disorders, BPH in particular. Adding further support are the results of numerous clinical trials in more than 600 patients.12-M Consistently, these studies have demonstrated pygeum to effectively reduce the symptoms and clinical signs of BPH, especially in early cases. However, it must be pointed out that improvement is largely symptomatic, because the reductions in size of the prostate and in residual urine content of the bladder are modest. The results

Pygeum africanum (Bitter Almond)

Patients Showing Reduction (%) Study Open Trials Guillernin12 Lange & MureP Werneau et all4 Vi~llet~~ Lhez & LeguevagueI6 Thomas & RouffilangeI7 HuetI8 RornettilS Gallizia & Gallizia’O Durval2’ Pansadoro & BenincasaZ2 Double-BlindedTrials Maverz4

BongiZ5 Dorernieux et a126 Del Valio‘’ Colpi & Farinaz8 Donkervoort et alz9 Dufour et aPO Legromandi et aP1 Ranno et Frasseto et al3 Bassi et at3

Dosage (mg/day)

No. of days

100 100 100 75 75 75 50 100 100 100 75

30 30 45 60 90 50 30 50 60 90 90

100 75 100 100 150 150 100 100 200 200 200

60 60 60 60 45 90 45 45 60 60 60

No. of patients in study

Residual urine

Prostate volume

Dysuria

Nocturia

Frequency

25 25 27 20 52 33 55 25 19 23 35

80 72 60 64 69 60 85 72 90 72 94

80

80

NC

NC

NC

NC

80 72 71 64

60 50 77 30 47 20 120 104 39 20 40

77 88 85

-

NC NC

NC

NC

NC

NC

NC

NC

NC

57 85 72 85 72 94

57 85 72 70 72 94

NC

20 72 94

70 88

57 88

23 88

NC -

NC

48

NC -

-

76

NC

NC

NC

65

NC

NC

NC

-

70

NC

89 75

-

-

-

NC -

70

70

70

70

-

80 45 89 75

20 25

NC

70 80 78 89 75

80

NC

-

NC NC

-

88 NC

-

NC

-, not measured;NC,no change.

of the clinical trials on pygeum are given in Table 120-1. A discussion of some of the most important aspects of these studies follows. One of the major findings in evaluating the effectiveness of pygeum in BPH has been the high rate of response to placebo. This is well-demonstrated in one of the larger double-blind studiesm As in other double-blind studies, pygeum extract was shown to be statistically superior to placebo in reducing the major symptoms of BPH (nocturnal frequency, difficulty in starting micturition, and incomplete emptying of the bladder). However, there was a high percentage of responses to the placebo (Table 120-2). It seems that simply taking a capsule provides relief to many sufferers. Another study highlights the importance of doubleblind studies that feature both objective and subjective findings. In the study, both patients and physicians rated the placebo and pygeum extract to be effective in improving subjective symptoms, which were daytime frequency, nocturia, weak stream, after-dribbling, hesitation, and

Patients showing response to

SvmDtom

Placebo arouD

Pvaeurn arow

26/52= 50% 16/50= 33% 14/40= 35% 15/34= 44% 1 1/43= 26%

44/56= 78% 27/54= 50% 21/32= 66% 13/33= 39% 21/38= 55%

~

Nocturia Daytime frequency Incompletevoiding Dribbling Urine flow rate

Data from references 12-22 and 24-34.

interruption of fl0w.2~However, urodynamic variables (flow, frequency, and histogram) clearly demonstrated the superiority of pygeum over placebo. One of the shortcomings of some of the clinical research on pygeum is the lack, in many of the studies, of objective measures such as urine flow rate (ml/sec),

residual urine content, and prostate size. Studies that have used objective measurements have shown some good results. For example, in one open trial, 30 patients with BPH who were given 100 mg/day of the pygeum extract for 75 days demonstrated significant improvements in objective parameters: Maximum urine flow rate increased from 5.43 to 8.20 ml/sec and the residual urine volume dropped from 76 to 33 ml.=

Male Infertility and Impotence Pygeum may be effective in improving fertility when diminished prostatic secretion plays a significant role in the problem. Pygeum has been shown to increase prostatic secretions and improve the composition of the seminal Specifically,pygeum administration to men with decreased prostatic secretion has led to higher levels of total seminal fluid plus rises in alkaline phosphatase and protein levels. Pygeum appears to be most effective in cases in which the level of alkaline phosphatase activity is reduced (i.e., less than 400 IU/cm3) and there is no evidence of inflammation or infection (i.e., absence of white blood cells and immunoglobulin A [IgA]).The lack of IgA in the semen is a good predictor of clinical success. In one study, the patients with no IgA in the semen demonstrated an alkaline phosphatase increase from ~ ~ ~ subjects whose semen 265 to 485 I U / C ~In. contrast, contained IgA showed only a modest increase, from 213 to 281 IU/cm3. Pygeum extract has also shown an ability to improve the capacity to achieve an erection in patients with BPH or prostatitis, as determined by nocturnal penile tumescence in a double-blind clinical trial.% BPH and prostatitis are often associated with erectile dysfunction and other sexual disturbances. Presumably by improving the underlying condition, pygeum can improve sexual function.

Pygeum versus Serenoa

was better tolerated.39In addition, the improvement of objective parameters, especially urine flow rate and residual urine content, is better in the clinical studies of serenoa. However, there may be circumstances in which pygeum is more effective than serenoa. For example, serenoa has not been shown to have the effects on prostate secretion that pygeum has. Although the two extracts have somewhat overlapping mechanisms of actions, they can be used in combination.

DOSAGE The dosage of the lipophilic extract of P. africunurn standardized to contain 14% triterpenes including betasitosterol and 0.5% n-docosanol is 100 to 200 mg/day. Typically the dosage has been divided for twice-daily administration; however, results were similar in a double-blind study with 100 mg given once daily and 50 mg twice daily, indicating that taking pygeum once daily is equivalent to using divided doses.40The crude herb is not used.

TOXICOLOGY Tests for acute and chronic toxicity in the rat and mouse have shown that the standardized extract of P.ufricunum bark is nontoxic. Raising the dosage from 1to 6 g/kg in the mouse and from 1 to 8 g/kg in the rat caused no deaths within 48 hours. In chronic toxicity studies, giving the animals from 60 to 600 mg/kg for 11 months did not produce any negative effects. In the human clinical trials, the pygeum extract also demonstrated no sigruficant toxicity. The most common side effect is gastrointestinal irritation, resulting in symptoms ranging from nausea to severe stomach pains; however, the presence of these side effects rarely leads to discontinuation of therapy.

The standardized liposterolic extract of Serenou repens is another popular botanical treatment for BPH (see Chapter 124). In a double-blind study that compared pygeum extract with extract of serenoa, the serenoa extract produced a greater reduction of symptoms and

There are no documented drug interactions for l? africanum.

1. Long0 R, lira S. Steroidal and other components of Pygeum africanum bark. Farmaco 1983;38:28&292. 2.Martinelli EM, Seraglia R, Pifferi G. Characterization of Pygeum africanum bark extracts by HRGC with computer assistance. HRC & CC 1986;9106-110. 3. Pierini N, Citti F, Di Marzio S, et al. Identificationand determination of n-docosanol in the bark extract of Pygeum africanum and in patent medicines containing it. Boll Chim Farm 1982;121:27-34. 4. Uberti E, Martinelli EM, Pifferi G, Gagliardi L. HPLC analysis of n-docosyl ferulate in Pygeum afrzcanum extracts and pharmaceutical formulations.Fitoterapia 1990;61:342-347.

5. Stewart KM.The African cherry (Prunus africana): can lessons be learned from an over-exploited medicinal tree? J Ethnopharmacol 2003;893-13. 6. Muntzing J, Eneroth P, Gustafsson JA, Liljekvist J. Direct and indirect effects of docosanol (IK.2),the active principle in Tadenan, on the rat prostate. Invest Urol1979;17176-180. 7. Thieblot L. Preventive and curative action of a bark extract of an African plant, Pygeum afrzcanurn: experimental prostatic adenoma in the rat. Therapie 1971;26575-580. 8. Hinman F. Benign prostatic hyperplasia. New York Springer-Verlag, 1983.

DRUG INTERACTIONS

9. Bombardelli E. Methods, composition and compounds for the treatment of prostatic adenoma. EP Appl 8330491.3, June 10, 1985. 10. Marcoli M. Anti-inflammatory and antiedemigenic activity of extract of Pygeum africunum in the rat. New Trends Androl Sci 1985; 1239-93. 11. Latalski M. The ultrastructure of the epithelium of bulbomthral glands after administrationof the Tadenan preparation. Folia Morphol 19799:193-201. 12.Guillemin P. Clinical trials of V1326, or Tadenan, in prostatic adenoma. Med Prat 1970;386:75-76. 13. Lange J, Muret P. Clinical trial of V1326 in prostatic disease. Med 1970;11:2807-2811. 14. Wemeau L, Delmay J, Blankaert J. Tadenan in prostatic adenoma. Vie Medicale 1970;Jan:585-588. 15. Viollet G . Clinical experimentation of a new drug from prostatic adenoma. Vie Medicale 1970;June:3457-3458. 16.Lhez A, Leguevague G. Clinical trials of a new lipid-sterolic complex of vegetal origin in the treatment of prostatic adenoma. Vie Medicale 197O;Dec:5399-5404. 17.Thomas JP, Rouffilange F. [The action of Tadenan in prostatic adenoma]. Rev Int Serv 1970;43:43-45. 18. Huet JA. Prostatic disease in old age. Med Intern 1970;5:405-408. 19. Rometti A. [Medical treatment of prostatic adenoma]. Prov Med 1970;38:49-51. 20. Gallizia F, Gallizia G. Medical treatment of benign prostatic hypertrophy with a new phytotherapeutic principle. Recent Med 1972; 9:461-468. 21. Durval A. [On the use of a new drug in the therapy of prostatic adenoma: Tadenan. Clinical considerations on 23 cases]. Minerva Urol1970;22:106-111. 22. Pansadoro V, Benincasa A. Prostatic hypertrophy. Results obtained with Pygeum africunum extract. Minerva Med 1972;11:119-144. 23. Zurita IE,Pecorini M, Cuzzoni G. Treatment of prostatic hypertrophy with Pygeum africanum extract. Rev Bras Med 1984;41:364-366. 24. Maver A. Medical treatment of fibroadenomatous hypertrophy of the prostate with a new plant substance. Minerva Med 1972;63: 2126-2136. 25. Bongi G. Tadenan in the treatment of prostatic adenoma: anatomoclinical study. Minerva Urol 1972;24:129-139. 26. Doremieux J, Masson JC, Bollack C. [Prostatic hypertrophy, clinical effects and histological changes produced by a lipid complex extracted from Pygeum africanum]. J Med Strasbourg 1973;4253-257.

27. Del Valio B. Use of a new drug in the treatment of chronic prostatitis. Minerva Urol1974;26:81-94. 28. Colpi G, Farina U. [Study of the activity of chloroformic extract of Pygeum africunum bark in the treatment of urethral obstructive syndrome caused by non-cancerous prostapathy]. Urologia 1976;43: 441-448. 29. Donkervoort T, Sterling J, van Ness J, Donker PJ. A clinical and urodynamic study of Tadenan in the treatment of benign prostatic hypertrophy. Eur Urol1977;8218-225. 30. h f o u r B, Choquenet C, Revol M, et al. Controlled study of the effects of Pygeum africanum extract on the functional symptoms of prostatic adenoma. Ann Urol1984;18:193-195. 31. Legramandi C, Ricci-Barbini V, Fonte A. [The importance of Pygrum africunum in the treatment of chronic prostatitis void of bacteria]. Gazz Med Ital 1984;143:73-76. 32. Ranno S, Minaldi G, Viscusi G, et al. [Efficacy and tolerability in the treatment of prostatic adenoma with Tadenan 501. Progr Med 1986;42165-169. 33. Frasseto G, Bertoglio S, Mancuso S, et al. [Study of the efficacy and tolerability of Tadenan 50 in patients with prostatic hypertrophy]. Progr Med 1986;42:49-52. 34. Bassi P, Artibani W, De Luca V, et al. Standardized extract of Pygerrm uficunum in the treatment of benign prostatic hypertrophy: controlled clinical study vs. placebo. Minerva Urol1987;39:45-50. 35. Lucchetta G, Weill A, Becker N, et al. Reactivation of the secretion from the prostatic gland in cases of reduced fertility: biological study of seminal fluid modifications. Urol Int 1984;39222-224. 36. Menchini-Fabris GF, Giorgi P, Andreini F, et al. New perspectives on the use Pygeurn ufricunum in prosato-bladder pathology. Arch Int Urol Nefrol Androl1988;60.313-322. 37. Clavert A, Cranz C, Riffaud JP, et al. Effects of an extract of the bark of Pygeum ufricanum (V.1326) on prostatic secretions in the rat and man. Ann Urol1986;20341-343. 38. Carani C, Salvioli C, Scuteri A, et al. Urological and sexual evaluation of treatment of benign prostatic disease using Pygeum ufiicunum at high doses. Arch Ital Urol Nefrol Androl1991;63341-345. 39. Duvia R, Radice GP, Galdini R. Advances in the phytotherapy of prostatic hypertrophy. Med Praxis 1983;4:143-148. 40. Chatelain C, Autet W, Brackman F. Comparison of once and twice daily dosage forms of Pygeum africunum extract in patients with benign prostatic hyperplasia: a randomized, double-blind study, with long-term open label extension. Urology 1999;54473-478.

Ruscus aculeatus (Butcher’s Broom) Kathy Abascal, BS, JD, RH(AHG) Eric L. Yamell, ND, RH(AHG) CHAPTER CONTENTS General Description

1227

Chemical Composition History and Folk Use

1227 1227

Pharmacology 1227 Anticancer Effect 1227 Antielastase Effect 1227 Ahtihypoxic Effect 1228 Antiinflammatory Effect 1228 Antimicrobial Effect 1228 Fibirinolytic Effect 1228 Lymphatic Flow Effect 1228 Vasoconstrictive Effect 1228

Clinical Applications 1228 Chronic Venous Insufficiency 1228 Edema and Varicosities 1230 Hemorrhoids 1230 Diabetic Retinopathy 1230 Premenstrual Syndrome 1230 Soft Tissue Injuries 1230 Dosage 1230 Toxicology

1230

Drug Interactions

1230

Ruscus uculeutus (family: Liliaceae) Common names: butcher’s broom, box holly, knee holly, kneeholy, kneeholm, Jew’s myrtle, sweet broom, pettigree, Maeusedornwurzelstock (German)

coumarins, sparteine, tyramine, and glycolic See Figure 121-1.

GENERAL DESCRIPTION

In ancient Greece, butcher’s broom was used as a laxative and to treat kidney stones.6In European botanical medicine, a wine decoction of butcher’s broom was used as a diuretic to treat urinary obstructions, kidney stones and gravel. It was also used to regulate menses, ameliorate jaundice, and treat headaches. In South America, the roasted root was made into a beverage for prostate tumors.7

Ruscus aculeatus is an evergreen shrub native to Mediterranean Europe and Africa from the Azores islands to Iran in southwesternAsia.’ Butcher’s broom has tough, green, erect, striated stems that do not have bark. Its leaves are rigid and terminate in a single sharp spine. It has large berries that remain attached to the plant through the winter. The root is thick, typically 2 to 4 inches long with many woody rootlets growing on its lower surface. The root is the part used medicinally.

CHEMICAL COMPOSITION The primary active ingredients of butcher’s broom are the steroidal saponins ruscogenin and neoruscogenin (up to 6%). The plant also contains other steroidal sapogenins and saponins (such as ruscin and ruscoside), fatty acids (mainly tetracosanoic acid), sterols (including sitosterol, campesterol, stigmasterol), flavonoids,

HISTORY AND FOLK USE

PHARMACOLOGY Anticancer Effect Butcher’s broom saponins have a cytostatic effect on leukemia HL-60 cells in vitro.8

Antielastase Effect Ruscinogens isolated from butcher’s broom have a remarkable antielastase in ~ i t r oThe . ~ author noted that the concentration of ruscinogen that will reach the perivascular matrix of the subpapillary derma after

1227

Vasoconstrictive Effect

HO Figure 121-1 Ruscogenin.

topical application of the herb in vivo is greater than the concentration tested in this study.

Antihypoxic Effect Hypoxia-induced activation of endothelial cells may be a cause of venous disease. A proprietary extract of butcher’s broom known as Cyclo 3 fort dose-dependently protected human endothelial cells from induced hypoxia in vitro.”

Antiinflammatory Effect Butcher’s broom extract and its isolated steroidal saponins had an antiinflammatory effect in several animal models.’0 Injected intravenously, it inhibits the permeability-increasing effects of bradykinin, leukotriene B4, and histamine in hamster cheek pouch preparations.”

Antimicrobial Effect Butcher‘s broom showed a very low activity against Candida albicans.’2

Fibrinolytic Effect Thrombosis in chronic venous insufficiency is associated with reduced levels of tissue plasminogen activator in varicose veins. In a small study (20 patients), patients scheduled for vein stripping surgery were administered butcher’s broom (150 mg) and methylhesperidine chalcone (150 mg) or placebo 3 times daily for 14 days prior to ~urgery.’~ Segments of the great saphenous vein removed from patients in the active group had enhanced levels of tissue plasminogen activator and enhanced fibrinolytic activity compared to placebo.

Lymphatic Flow Effect Butcher’s broom dose-dependently enhanced the duration and flow intensity of the lymphatic vessels in dogs.14This effect did not change when the calcium channel antagonist nifedipine was injected, indicating that butcher’s broom’s lymphatic effect does not involve the opening of calcium channels but appears to act directly on peripheral lymphatics.

Topical administration of butcher’s broom extract in a hamster cheek preparation dose-dependently inhibited histamine-induced increases in ~ermeabi1ity.I~ This action was inhibited by the alpha-1 adrenoceptor antagonist prazosin and the calcium channel blocker diltiazem but was not affected by the alpha-2 adrenoceptor antagonist rauwolscine. This suggests that butcher’s broom’s vasoconstrictive effect is mediated by calcium and alpha-1 adrenergic receptors. Heat increases, and cold decreases, butcher’s broom’s ability to increase the release of norepinephrine from the ad re no receptor^.'^

CLINICAL APPLICATIONS There are few clinical studies on the effect of butcher’s broom alone. Instead, most of the clinical studies investigate a proprietary combination formula known as Cyclo 3 fort by Pierre Fabre Medicament, Paris, France, or Phlebodril by Pierre Fabre Pharma GmbH, Frieburg, Germany. These formulas combine butcher’s broom with trimethylhesperidin chalcone (a flavonoid precursor) and ascorbic acid. Butcher’s broom has an action independent of the other compounds in the formula, and some studies indicate that butcher’s broom used alone may have a stronger effect. Yet other studies indicate that the combination may have a synergistic effect. All discussions of butcher’s broom trials below therefore include the possibility that it was not butcher’s broom by itself that was active. Butcher’s broom is also paired with Melilotus spp. (sweet clover) in some topical preparations. There are no studies indicating whether butcher’s broom alone would achieve the same results.

Chronic Venous lnsufficiency Butcher’s broom is most commonly used to alleviate the symptoms of chronic venous insufficiency (CVI), including ankle edema, itching, tension, and cramping of the legs. Both animal and clinical studies support its effectiveness in CVI, and the German Commission E approved butcher’s broom as an adjunct treatment for this condition.’ There are seven clinical trials on the use of butcher’s broom combination extracts in CVI. These studies consistently found the herb to have a positive effect, and are summarized in Table 121-1.1”22All but two were randomized, double-blind trials; however, both the quality of the trials and the butcher’s broom preparations vary from trial to trial. Nonetheless, butcher’s broom’s ability to improve venous circulation is well accepted. In one large multi-center trial, 81.6% of treating physicians rated its efficacy as excellent and the remaining physicians rated it as good.20Butcher’s broom acts most strongly when

30

80

Kiesewetter et alls

Beltramino et aIz0 Open-label, randomized, multicenter

Random selection, uncontrolled

Placebo-controlled, double-blind

CW,Chronic venous insufficiency.

36

Randomized, double-blind, placebo-controlled

20

Haas et all8

Randomized, doubleblind, multicenter

Seydewitz et aIz2

141 +20 healthy volunteers

Rudofsky17

Double-blind,crossover, placebo-controlled, prospective

Randomized, double-blind, placebo-controlled

40

Cappelli et all6

TvDe

Le Devehat et aIz1 60 + 7 healthy volunteers

No. of DarticiDants

Studv

2 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) daily: Control 2 tablets of 500 mg hydroxyethyl rutoside daily 2 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) daily 3 capsules (150 mg ruscus, 150 mg trimethylhesperidin chalcone) daily

3 ruscus capsules twice daily for 5 weeks, then 2 capsules twice daily; amount of ruscus in capsules not stated

1 capsule (150 mg ruscus, 150 mg methylhesperidin chalcone) 3 times a day

2 capsules (450 mg ruscus extract) 3 times daily for 4 weeks, then 2 capsules 2 times daily for 8 weeks

2 capsules (16.5 mg ruscinogens, 75 mg hesperidin, 50 mg ascorbic acid) 3 times a day

Product

Stage IV varicosities w/stage I or stage II CVI, scheduled for vein stripping

CVI; blood samples drawn from foot before and after provoked venous stasis

CVI (heavy, tired, swollen or painful legs)

CVI

CVI stage I and II, scheduled for surgery

CVI

CVI, varicosities

Focus

cher’s broom in chronic vascular insufficiency (CVI)

Increase in enzyme activity in the proximal segment of the vein, distinctly higher incidence of subjective improvement of symptoms

Improved blood viscosity disturbances caused by venous stasis

Significant improvement in symptoms, reduction in limb circumference; physicians and patients had a more favorable opinion of ruscus than of rutoside

Reduced circumferences of lower legs and malleoli, subjective complaints; greater rheologic improvement in patients with advanced stages of CVI

Significantly increased fibrinolytic activity of removed great saphenous vein

Continuous decrease in foot and ankle volume, decrease in leg swelling, improved venous pumping

Itching, edema, and paresthesia improved greatly

Result

4 weeks

4 weeks

90 days

5 months

14 days

2 weeks’ washout followed by 12 weeks’ treatment

2 months withl 15-day washout and 2 months’ crossover

Duration

Pharmacology of Natural Medicines

circulation is impaired, but some researchers caution that it is less effective when the disease has compromised venous wall receptor activity.’*

Edema and Varicosities Butcher’s broom shows promise as a treatment for a wide variety of edemas and circulatory disturbances of the venous system. The results of these clinical trials are summarized in Table 121-2.B32 As mentioned above, these trials were on combination extracts with butcher’s broom as a major component. Many of the studies are small and some are poorly designed, but the overall picture supports the ability of butcher’s broom to reduce swelling and discomfort associated with primary and secondary edema. It has positive effects in pregnancyrelated venous insufficiency, varicosities, lymphedema, symptoms of swelling of ankles and breast tenderness in premenstrual syndrome, edema secondary to calcium channel antagonist therapy of hypertension, and swelling secondary to soft tissue injury.

Hemorrhoids The German Commission E has approved butcher’s broom as a treatment for hemorrhoids.’ In an open-label multi-center study of 124 patients with hemorrhoids, 69% of patients and 75% of the treating physicians rated the butcher’s broom combination extract Cyclo 3 fort as having good or excellent efficacy.33Ninety-two percent of physicians rated the treatment as safe and well tolerated. Significant positive effects were observed after 7 days of treatment. Though controlled trials are warranted, butcher’s broom may be a useful treatment for patients with hemorrhoids.

duration of 67 months.32The amount of butcher’s broom administered for 90 days was not stated. Eighty percent of the women in the active group reported a complete resolution of PMS symptoms of mastalgia and breast tension. Unexpectedly, butcher’s broom also had a dramatic effect on some of the psychological symptoms associated with PMS (e.g., complete resolution in 85% of the subjects of symptoms such as irritableness, “hairtrigger temper,” ”temporary alienation”). In vitro research indicates that butcher’s broom acts more efficiently in the presence of progesterone; butcher’s broom may be most effective during the luteal phase of a woman’s menstrual cycle.

Soft Tissue Injuries In a small study, butcher’s broom applied topically reduced swelling and pain caused by soft tissue sports injuries.2s Several in vitro studies show that butcher’s broom’s action is enhanced by heat, suggesting that it may be advantageous to apply heat to the site of the injury when using the herb.

DOSAGE Most clinical studies administered 150 mg butcher’s broom three times daily with meals. The German Commission E recommends extracts and preparations standardized to contain 7 to 11 mg total ruscogenin (sum of neoruscogenin and ruscogenin) per dose.’ A typical dose of tincture of the dried root is 1to 2 ml three times daily.35

Diabetic Retinopathy

TOXICOLOGY

Diabetic retinopathy can abruptly cause severe deterioration of vision, and it is estimated that the incidence of retinopathy may be as high as 80% in patients with longstanding, poorly controlled diabetes. In a study of 60 patients with non-insulin-dependent diabetes, butcher’s broom compared favorably with troxerutin.34 Butcher’s broom produced a 23% regression of negative changes in the fundus of the eye with no sign of progression. Troxerutin produced a somewhat larger regression (27.8%) but also had a greater (5.8%) progression rate. Butcher’s broom also decreased blood glucose and cholesterol levels and significantly increased high density lipoproteins in this preliminary study.

Butcher’s broom is generally considered very safe. It occasionally causes gastrointestinal distress, and in rare instances causes lymphatic ~ o l i t i s . ’ ,Thus ~ ~ , ~butcher‘s ~ broom should probably not be combined with nonsteroidal antiinflammatory drugs or other drugs linked with lymphatic colitis, and use should be discontinued if negative gastrointestinal symptoms are severe or persist. One author cautions against the use of butcher’s broom in pregnancy based on a lack of proof of safety3 While not definitive, preliminary animal and clinical studies cited above indicate that butcher’s broom does not have negative effects when used during pregnancy.

Premenstrual Syndrome

DRUG INTERACTIONS

Butcher’s broom sigruficantly reduced symptoms of breast tenderness in women with diagnosed premenstrual syndrome (PMS) in a randomized, placebo-controlled, double-blind study of 40 women with PMS of an average

In an in vitro study, adenosine, cocaine, phentolamine, prazosin, and verapamil reduced butcher’s broom’s vasoconstrictive effect.3*Acetylcholine and rauwolscine potentiated its vasoconstrictive action. No studies have

Double-blind, placebocontrolled

9

48

57

12

12

50

11

25 + 20 healthy controls

Bergz3

BohmeP

Cluzan et aIz6

Cossio et alz7

Jager et aI2*

Weindorf et atz9

Lagrue et aPO

Le Devehat et a P

Monteil-Seurin 40 and L a d ~ r e ~ ~

Open, uncontrolled

20

Baudet et al 24

Randomized, double-blind, placebocontrolled

Double-blind, placebocontrolled

Open, uncontrolled

2 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) daily

2 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) daily

150 mg hesperidin methylchalchone, 100 mg ascorbic acid) daily

3 capsules (150 mg ruscus,

3 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) 3 daily plus physiotherapy Drinkable ampules; 1st week: 180 mg ruscus and 900 mg hesperidin methylchalchone per day; weeks 2-8 120 mg ruscus and 600 mg hesperidin methylchalchone per day 3 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) per day 450 mg ruscus, 450 mg hesperidin, 300 mg ascorbic acid daily

Placebocontrolled, double-blind Uncontrolled

4 g ruscus cream (1.6 g ruscus and 1.6 g melilot per 100 g) 3 times daily

Compression stocking, kinesitherapy, and melilot and ruscus cream (4 to 6 g creadday)

2 capsules of ruscus extractlday (amt. not stated) from week 21 to 24 of pregnancy

Melilot and ruscus cream (4 to 6 g creamJday)

Product

Placebocontrolled

Placebocontrolled

Uncontrolled

Placebocontrolled

18

Bergz3

Type

participants

Study

No. of

Premenstrual syndrome symptoms for at least 60 months (breast tension, pelvic heaviness, “menstrual psychopathic disorder,” ankle edema)

Venous insufficiency characterized by varicose veins; blood samples drawn before and after provoked venous stasis

Edema secondary to calcium antagonist treatment of hypertension

Trunk or branch varicose veins

Primary varicosity of greater saphenous vein

Lymphedema of extremities

Lymphedema after mastectomy

Sports injuries, patients w/sprain or contusions of lower limb or ankle

Pregnant women with painful pregnancy-relatedvaricosity of one limb

Pregnancy-relatedsymptoms of venolymphatic insufficiency

Effect of cream on size of femoral veins in healthy volunteers

Focus

Clinical studies on butcher’s broom in edema and varicosities

~

14 days

Increased muscle strength, reduced swelling, decreased temperature, and resolved pain more quickly

Significantly reduced breast tension, pelvic heaviness, and menstrual “psychopathic disorder”

Significant improvement in several microrheologic factors of blood viscosity

90 days

Not found

6-8 weeks 4/9 showed complete improvement; 3/9 showed partial improvement; 2/9 showed no change in edema

* 1 days 2 weeks

7

2 months

Venous capacity and improved at rest; expelled blood volume during exercise improved

Significant changes in some venous parameters

Significant improvement in symptoms, reduction of edema in 81% of participants

90 days

Treatment beginning in second trimester

Statistically significant reduction in size of femoral vein and pain

Reduced edema by second month, positive subjective improvement in symptoms

Women monitored from early pregnancy; infants studied before and after birth

1 day

Length

Improved symptoms based on subjective criteria; “absolute harmlessness” to infant

Change in size of femoral vein

Result

-

been conducted to determine whether butcher's broom in turn interferes with or affects the action of the aforementioned drugs. One author cautions against the use of butcher's broom for patients on alpha-adrenergic

antagonistic therapy for benign prostatic hyperplasia or hypertension, or for patients taking monoamine oxidaseinhibiting drugs.3In vitro, animal, and clinical studies overall do not provide support for this view.

1. Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal medicine: expanded Commission E monographs. Newton, MA: Integrative Medicine Communications, 2000:40. 2. Duke JA. Handbook of medicinal herbs, ed 2. Boca Raton, n:CRC PRSS, 2002130-131. 3. Fetrow CW,Avila Jl7.Professional's handbook of complementary and alternative medicines. Springhouse, PA: Springhouse Corp, 1999. 4. Rauwald HW,Grunwidl J. Ruscus uculeutus extract: unambiguous proof of the absorption of spirostanol glycosides in human plasma after oral administration. Planta Med 1991;57A75-A76. 5. Dunouau C, Belle R, W a d - A h A, et al. Triterpenes and sterols from Ruscus uculeutus. Planta Med 1996;62:189-190. 6. Potterton D. Culpeper's color herbal. New York Sterling Publishing, 198335. 7. Hartwell JL. Plants used against cancer. Lawrence, MA: Quarterman Publications, 1982340. 8. Mimaki Y, Kuroda M, Kameyama A, et al. New steroidal constituents of the underground parts of Ruscus muleutits and their cytostatic activity on HL-60 cells. Chem Pharm Bull (Tokyo) 1998;46298-303. 9. Baurain R, Dom G, Trouet A. Protecting effect of Cyclo 3 Fort and its constituents for human endothelial cells under hypoxia. Clin Hemorheol 1994;14:S15. 10. Mimaki Y, Kuroda M, Kameyama A, et al. Steroidal saponins from the underground parts of Ruscus uculeatus and their cytostatic activity on HL-60 cells. Phytochemistry 1998;48:485-493. 11. Bouskela E, Cyrino FZ, Marcelon G . Inhibitory effect of the Ruscus extract and of the flavonoid hesperidine methylchalcone on increased microvascular permeability induced by various agents in the hamster cheek pouch. J Acardiovasc Pharmacol 1993;22:

19. Kiesewetter H, Scheffler P, Jung F, et a1 Effect of Ruscus extract in chronic venous insufficiency stage I, II,and III. In Vanhoutte PM, ed. Return circulation and norepinephrine. Pans: John Libbey Eurotext, 1991:163-169. 20. Beltramino R, l'enenory A, Buceta AM. An open-label, randomized multicenter study comparing the efficacy and safety of Cyclo 3 Fort versus hydroxyethyl rutoside in chronic venous lymphatic insufficiency. Angiology 2OOO;51:535-544. 21. Le Devehat C, Khodabandehlou T, Dougny M. The effects of Cyclo 3 Fort treatment on hemorheological disturbances during a provoked venous stasis in patients with chronic venous insufficiency. Clin Hemorh 1994;14(Suppll):S53-563. 22. Seydewitz V, Berg D, Welbers P, Staubesand J. Biochemical investigations on the action of Ruscus extract and trimethylhesperidinchalcon (TMHC). In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:151-156. 23. Berg D. First mults with Ruscus extract in the treatment of pregnancy related varicose veins. In Vanhoutte PM, ed. Return circulation and norepinephrine. Park John Libbey Eurotext, 1991:5561. 24. Baudet JH, Collet D, Aubard Y, Renaudie P. Therapeutic test of Ruscus extract in pregnant women: evaluation of the fetal tolerance applying the pulse Doppler's method of the cord. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:63-71. 25. Bohmer D. Action of Ruscus extract cream in the treatment of acute sport injuries. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:171-179. 26. Cluzan RV, AUiot F, Ghabboun S, Pascot M. Treatment of secondary lymphedema of the upper limb with Cyclo 3 Fort. Lymphology 1996;29:29-35. 27. Jimenez Cossio JA, Magallon Ortin PJ, Capilla Montes MT, Coya Vina J. Therapeutic effect of Ruscus extract in lymphedemas of the extremities. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:lll-119. 28. Jager K, Eichlisberger R, Jeanneret CH, Lobs KH. Pharmacodynamic effects of Ruscus extract (Cyclo 3 Fort) on superficial and deep veins in patients with primary varicose veins assessment by duplex sonography. Clin Drug Invest 1999;17 265-273. 29. Weindorf N, Schultz-Ehrenburg U.Kontrollierte studie zur oralen venentonisierung der primaeren varikosis mit Ruscus uculeutus und trimethylhesperdinechalckon.Z Huutkr 1987;622&38. 30. Lagrue G, Behar A, Chaabane A, Laurent J. Edema induced by calcium antagonists: effects of Ruscus extract on clinical and biological parameters. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:105-109. 31.Le Devehat C, Khodabandehlou T, Vimeux M, Bondoux G. Hemorheological concepts in venous insufficiency and implications for treatment with Ruscus extract. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991225-236. 32. Monteil-Seurin J, Ladure PH. Efficacy of Ruscus extract in the treatment of the premenstrual syndrome. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:43-53.

225-230.

12. Ali-Shtayeh MS, Yaghmour Rh4, Faidi YR, et al. Antimicrobial activity of 20 plants used in folkloric medicine in the Palestinian area. J Ethnopharmacol1998;60:265-271. 13.Facino RM, Carini M, Stefani R, et al. Anti-elastase and antihyaluronidase activities of saponins and sapogenins from Hederu helix, Aesculus hippocastunum, and Ruscus uculeutus: factors contributing to their efficacy in the treatment of venous insufficiency. Arch Pharm 1995;328:720-724. 14. Pouget G, Ducros L, Marcelon G. Effect of Ruscus extract on peripheral lymphatic vessel pressure and flow. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libby Eurotext, 1991~89-95. 15. Bouskela E, Cyrino FZ, Marcelon G. Effects of Ruscus extract on the internal diameter of arterioles and venules of the hamster cheek pouch microcirculation.J Cardiovasc Pharmacol 1993;22:221-224. 16. Cappelli R, Nicora M, Di Perri T. Use of extract of Ruscus nculeufus in venous disease of the lower limbs. Drugs Exp Clin Res 1988;14:277-283. 17. Rudofsky G. Efficacy of Ruscus extract in venolymphatic edema using foot volumetry. In Vanhoutte I'M, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:121-130. 18. Haas S, Lill G, Stiller A, et al: Influence of Ruscus extract and methylhesperidine chalcone on the fibrinolytic activity of the vein wall. In Vanhoutte PM, ed. Retum circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:157-162.

Ruscus aculeatus (Butcher’s Broom) 33. Bennani A, Biadillah MC, Cherkaoui A, Sebti M. [Acute attack of hemorrhoids: Efficacy of Cyclo 3 Fort based on results in 124 cases reported by specialists.] Phlebologie 1999;52:89-93. 34. Archimowicz-CyrylowskaB, Adamek B, Drozdzik M, et al. Clinical effect of buckwheat herb, Ruscus extract and Troxerutin on retinopathy and lipids in diabetic patients. Phytother Res 1996;10659-662. 35. Moore M. Herbal materia medica. Bisbee, Az: Southwest School of Botanical Medicine, 1995:25.

36. Dharancy S, Dapvril V, Dupont-Evrard F, Colombel JF. ICyclo 3 Fortinduced lymphocytic colitis associated with ileal villous atrophy.] Gastroenterol Clin Biol2000;24:134-135. 37. Mennecier D, Thiolet C, Bredin C, et al. [Lymphocyticcolitis after ingestion of Rustacea flavonoid extract.] Presse Med 2001;301063. 38.Rubanyi G, Marcelon G, Vanhoutte PM. Effect of temperature on the responsiveness of cutaneous veins to the extract of Rirscus aculeatus. Gen Pharmacol 1984;15:431-434.

SAMe (S-Adenosylmethionine) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 1235 Pharmacology 1235 Available Forms 1235 Clinical Indications 1235 Depression 1235 Osteoarthritis 1236 Fibrornyalgia 1237

INTRODUCTION S-Adenosylmethionine (SAMe) is an important physiologic agent formed in the body through combination of the essential amino acid methionine with adenosyl triphosphate (ATP) (Figure 122-1). SAMe was discovered in Italy in 1952. Not surprisingly, most of the research on SAMe has been conducted in the country of its discovery. Because SAMe is manufactured from methionine, one would think that dietary sources of methionine would provide the same benefits as SAMe. However, high doses of methionine have not been shown to raise levels of SAMe, nor do they provide the same pharmacologic activity as SAMe. High doses of methionine are associated with some degree of t0xicity.l Normally the body manufactures all the SAMe it needs from the amino acid methionine. However, a deficiency of methionine, vitamin BI2, or folic acid can result in decreased SAMe synthesis. In addition, tissue levels of SAMe are typically low in the elderly and in patients with osteoarthritis, depression, and various liver disorders.

PHARMACOLOGY SAMe is involved in more than 40 biochemical reactions in the body. It functions closely with folic acid and vitamin BIZin “methylation” reactions. Methylation is the process of adding a single carbon unit (a methyl group) to another molecule. SAMe is many times more effective in transferring methyl groups than other methyl donors.

Liver Disorders 1238 Migraine 1238

Dosage 1238 Toxicology 1238 Interactionsand Contraindications 1239

Methylation reactions are critical in the manufacture of many body components, especially brain chemicals, as well as in detoxification reactions. SAMe is also required in the manufacture of all sulfurcontaining compounds in the human body, including glutathione (discussed later) and various sulfur-containing cartilage components. The beneficial effects of SAMe supplementation are far-reaching owing to this agent’s central role in so many metabolic processes.

Available Forms SAMe has been available commercially in Europe since 1975 and in the United States since 1999. The commercial form of SAMe is a stabilized salt produced under U.S. patents no. 3,954,726 (1976) and no. 4,057,686 (1977).

CLINICAL INDICATIONS The five principal uses of SAMe are in depression, osteoarthritis, fibromyalgia, liver disorders, and migraine headaches.

Depression SAMe is necessary in the manufacture of important brain compounds, such as neurotransmitters and phospholipids like phosphatidylcholine and phosphatidylserine. Supplementing the diet with SAMe in depressed patients raises levels of serotonin, dopamine, and phosphatidylserine and improves binding of neurotransmitters to receptor sites, resulting in increased 1235

Pharmacology of Natural Medicines

I

CHZ

H,C--Sf

CH20

I/

HO

\

I

OH

Figure 122-1 S-Adenosylmethionine (SAMe)

SAMe has also been shown to produce sigruficant effects on other conditions associated with depression, such as during the postpartum (after pregnancy) period and in drug rehabilitation. SAMe's benefits in these conditions are probably a combination of its effect on brain chemistry and liver function (discussed later). In the study in postpartum depression (after-pregnancy "blues"), the administration of SAMe (1600 mg/day) was associated with significantly better mood scores In another study, SAMe compared with a placeb~.'~ (1200 mg/day) was shown to sigrhcantly reduce psychologic distress (chiefly anxiety and depression) in the detoxification and rehabilitation of opiate abusers.16 Detailed clinical evaluations utilizing electroencephalograms (EEGs), event-related potentials (EMS), and low-resolution brain electromagnetic tomography (LORETA) have clearly indicated a central nervous system antidepressant action of SAMe.14

serotonin and dopamine activity and better brain cell membrane fluidity, leading to significant clinical improvement.22 The antidepressiveeffects of folic acid (seeChapter 144) are mild compared with the effects noted in clinical trials Osteoarthritis using SAMe. On the basis of results from a number of clinical studies it appears that SAMe is perhaps the most SAMe has also demonstrated impressive results in the effective natural antidepressant (although a strong argutreatment of o~teoarthritis."-'~A deficiency of SAMe in ment could be made for the extract of St. John's wort the joint tissue, just like a deficiency of glucosamine, standardized to contain 0.3% hypericin)."s leads to loss of the gel-like nature and shock-absorbing Although most of the early studies utilized injectable qualities of cartilage. As a result, osteoarthritis can SAMe, the later studies have used an oral dose of 400 mg develop. four times daily (1600 mg total) and have demonstrated In vitro studies have shown that SAMe exerts a that SAMe is just as effective given orally as when given number of effects that appear to be highly relevant in intraven~usly.~-'~ the treatment of osteoarthritis. First, the agent has been Several studies have compared SAMe with tricyclic shown to be very important in the manufacture of cartiantidepressants. These studies have shown that SAMe lage components.20This effect has been demonstrated is better tolerated and has a quicker onset of anti very well in humans. In one double-blind study condepressant action. In one study comparing SAMe with ducted in Germany, the 14 patients with osteoarthritis of the hands who were given SAMe showed greater desipramine in addition to determining the clinical response, the blood level of SAMe was determined in cartilage formation on magnetic resonance imaging (MRI).*' These results indicate that SAMe is capable both groups. At the end of the 4-week trial, 62% of the of improving the structure and function of cartilage patients treated with SAMe and 50% of the patients treated with desipramine had significantly improved. in joints affected by osteoarthritis. Second, SAMe has Regardless of the type of treatment, patients with a 50% shown some mild pain-relieving and anti-inflammatory decrease in Hamilton Depression Scale score showed effects in animal studies.' All of these effects combine a sigruficant rise in plasma SAMe concentration. These to produce exceptional clinical benefits. results suggest that one of the ways that tricyclic antideA total of 21,524 patients with osteoarthritis have pressant agents exert their antidepressive effects utilized SAMe in detailed clinical trials. In double-blind is by raising SAMe 1e~els.I~ trials, SAMe has demonstrated similar reductions in In two separate double-blind studies, SAMe was pain scores and clinical symptoms to those produced by nonsteroidal antiinflammatory drugs (NSAIDs) like given orally (1600 mg daily) or intramuscularly (400 mg ibuprofen, indomethacin, naproxen, and piroxicam. daily) and compared with 150 mg imipramine given orally daily. In both studies, the results of SAMe and In one double-blind study, SAMe was compared imipramine treatment did not differ significantly for any with ibuprofen.22The 36 subjects with osteoarthritis of efficacy measure. However, significantly fewer adverse the knee, the hip, and/or the spine received a daily oral events were observed in the patients treated with SAMe. dose of 1200 mg of SAMe or 1200 mg of ibuprofen for The researchers concluded that the antidepressive 4 weeks. Morning stiffness, pain at rest, pain on motion, efficacy of 1600 mg SAMe orally and 400 mg SAMe crepitation (crackling noise upon movement of a joint), intramuscularly is comparable with that of 150 mg swelling, and limitation of motion of the affected joints imipramine, but SAMe is sigruficantly better t01erated.I~ were assessed before and after treatment. The total

SAMe (S-Adenosylmethionine)

score obtained by the evaluation of all the individual clinical parameters improved to the same extent in patients treated with SAMe and in those treated with ibuprofen. In two other studies, SAMe was actually shown to produce slightly better results.2324 SAMe has also been compared with naproxen (Naprosyn). In one double-blind study, 20 patients with osteoarthritis of the knee were given either SAMe or naproxen for 6 weeksE During the first week, SAMe was administered at a dose of 400 mg three times daily and afterwards at a dose of 400 mg twice daily, whereas the dose of naproxen during the first week was 250 mg three times daily and subsequently 250 mg twice daily. During the first 2 weeks, the patients were allowed to take the drug paracetamol as an additional analgesic if the pain was severe. The patients were examined at the beginning of the study and after 2,4, and 6 weeks. The parameters tested were pain, crepitation, joint swelling, circumference of joint, extent of motility, and walking time over 10 meters. At the end of the sixth week no statistically sigruficant difference between the two patient groups treated was found; both groups exhibited a marked improvement on all parameters. Another double-blind study compared SAMe with both naproxen and a placebo in the treatment of osteoarthritis of the hip, knee, spine, and hand. The study involved 33 rheumatologic and orthopedic medical centers and a total of 734 subjects. SAMe administered orally at a dose of 1200 mg daily was shown to exert the same analgesic (pain-relieving) activity as naproxen at a dose of 750 mg daily. However, SAMe was significantly better than naproxen, both in terms of physicians’ and patients’ judgments and in terms of the number of patients with side effects. In fact, SAMe was better tolerated than the placebo. Ten patients in the SAMe group and 13 in the placebo group withdrew from the study because of intolerance to the Other double-blind studies have shown SAMe to offer the pain-relieving and antiinflammatory benefits of drugs like indomethacin and piroxicam but is generally much better tolerated than these potent N S A I D S . ~ ~ , ~ ~ Perhaps the most meaningful study of SAMe in the treatment of osteoarthritis was a long-term, multicenter, open 2-year trial involving 97 patients with osteoarthritis of the knee, hip, and spine.29The patients received 600 mg of SAMe daily (equivalent to three tablets of 200 mg each) for the first 2 weeks and thereafter 400 mg daily (equivalent to two tablets of 200 mg each) until the end of the 24th month of treatment. Separate evaluations were made for osteoarthritis of the knee, hip, cervical spine, and dorsal/lumbar spine. The severity of the clinical symptom (morning stiffness, pain at rest, and pain on movement) was assessed with scoring before the start of the treatment,

at the end of the first and second weeks of treatment, and then monthly until the end of the 24-month period. SAMe showed good clinical effectiveness and was well tolerated. The improvement of the clinical symptoms during therapy with SAMe was already evident after the first weeks and continued to the end of treatment. Nonspecific side effects occurred in 20 patients, but in no case did therapy have to be discontinued. Most side effects disappeared during the course of therapy. Moreover, during the last 6 months of treatment, no adverse effect was recorded. Detailed laboratory tests carried out at the start and after 6,12,18, and 24 months of treatment showed no pathologic changes. SAMe administration also improved the depressive feelings often associated with osteoarthritis. And finally, in the largest study, 20,641 patients with osteoarthritis of the knee, the hip, and the spine and also with osteoarthritic polyarthritis of the fingers, were studied over 8 weeksN The patients were given 400 mg three times daily for the first week, 400 mg twice daily for the second week, and 200 mg twice daily from the third week on. No additional analgesic/ anti-inflammatory treatment was allowed. The efficacy of SAMe was comparable to results achieved with NSAIDs. Efficacy was described as very good or good in 71% of cases, as moderate in 21%, and as poor in 9%; tolerance to the agent was assessed as very good or good in 87Y0, as moderate in 8%, and as poor in 5%. What all of these studies indicate is that SAMe appears to offer significant advantages over NSAIDs. The drugs are associated with sigruhcant risk of toxicity, side effects, and actual promotion of the disease process in osteoarthritis, but SAMe offers similar benefits without risk or side effect.

Fibromyalgia SAMe has been shown in four double-blind clinical studies to produce excellent benefits in patients suffering from f i b r ~ m y a l g i a .In ~ ~two - ~ of the studies, injectable SAMe (200 mg daily) was used. During treatment, subjects demonstrated sigruficant in reduction in the number of trigger points and painful areas as well as improvements in m ~ ~ d . ~ ~ , ~ ~ In one of the studies oral SAMe (800 mg daily) was compared with a placebo for 6 weeks in 44 patients with fibromyalgia.33Tender point score, muscle strength, disease activity, subjective symptom, mood parameters, and side effects were evaluated. Patients given SAMe demonstrated improvements in clinical disease activity, pain experienced during the last week, fatigue, morning stiffness, and mood; however, the tender point score and muscle strength did not differ in the two treatment groups. SAMe was without side effect. In one of the studies, SAMe was compared with transcutaneous electrical nerve stimulation (TENS)-a

Pharmacology of Natural Medicines popular treatment for fibromyalgia-in 30 patients with this disorder.34Patients receiving SAMe (200 mg by injection and 400 mg orally daily) experienced significantly greater clinical benefit as shown by a decreased number of tender points, diminished subjective feelings of pain and fatigue, and improved mood. TENS offered little benefit for most symptoms, whereas SAMe was deemed “effective in relieving the signs and symptoms of primary fibromyalgia.”w

Liver Disorders SAMe has been shown to be quite beneficial in several liver disorders, including cirrhosis, Gilbert syndrome, and oral contraceptiveinduced liver damage. Its benefits are related to its function as the major methyl donor in the liver as well as its lipotropic activity. One of the leading contributors to impaired liver function is diminished bile flow, or cholestasis. SAMe is beneficial for a variety of liver disorders because of its ability to promote bile flow and relieve chole~tasis.~~3 One of the key functions of SAMe in the liver is the inactivation of estrogens. Clinical studies have shown that SAMe is quite useful in protecting the liver from damage and improving liver function in conditions associated with estrogen excess-namely, oral contraceptive use, pregnancy, and premenstrual ~yndrome.~’-~~ Another key indication for the use of SAMe is in the treatment of Gilbert syndrome, a common disorder characterized by a chronically elevated serum bilirubin level (1.2 to 3.0 mg/dl). Previously considered rare, this disorder is now known to affect as much as 5% of the general population. The condition is usually without symptoms, although some patients complain about loss of appetite, malaise, and fatigue (typical symptoms of impaired liver function). SAMe at a dosage of 400 mg three times daily has resulted in a significant decrease in serum bilirubin in patients with Gilbert syndrome.& In addition to these relative minor disturbances in liver function, SAMe offers benefits in the treatment of more severe liver disorders including cirrhosis. Its effect in cirrhosis appears to be due to an abihty to overcome the SAMe depletion characterized by the disorder. Because SAMe is involved in so many liver processes, depleted levels of SAMe within the liver has serious consequences. Supplementation with SAMe in patients with liver cirrhosis not only improves bile flow and clinical signs and symptoms, but also promotes membrane function and increases levels of glutathione>14 Glutathione assumes a critical role in detoxification as well as in the defense against a variety of injurious agents by combining directly with these toxic substances to eventually form water-soluble compounds.

Because many of the toxic compounds are lipid (fat) soluble, conversion to water-soluble compounds results in more efficient excretion via the kidneys. When higher levels of toxic compounds are present or when the liver function is impaired, higher glutathione levels are required. One of the greatest risks of chronic liver diseases such as chronic hepatitis is liver cancer. Supplementation with SAMe appears to be very much indicated in patients with such diseases in the attempt to reduce the risk for liver cancer. Animal studies have shown a significant protective effect of supplemental SAMe against liver cancer in animals exposed to liver ~arcinogens.4~

Migraine SAMe has also been shown to be of benefit in the treatment of migraine headaches. The benefit arises gradually, and long-term treatment is required for therapeutic eff ectiveness.46

DOSAGE In general, the longer SAMe is used, the more beneficial the results. This agent is perfectly suited for longterm use because of its excellent safety profile. The dosage ranges for the various clinical indications are as follows:

Depression. 400 mg three to four times daily. Because SAMe can cause nausea and gastrointestinal disturbances in some people, it is recommended that SAMe be started at a dosage of 200 mg twice daily for the first day, increased to 400 mg twice daily on day 3, then 400 mg three times daily on day 10, and finally to the full dosage of 400 mg four times daily after 20 days if needed. Osteoarthrifis. Start out as above for depression. After 21 days at a dosage of 1200 mg daily, reduce to the maintenance dosage of 200 mg twice daily. Fibromyalgia. 200 mg to 400 mg two times daily. Liver Disorders. 200 mg to 400 mg two to three times daily. Migraine Headaches. 200 mg to 400 mg two times daily.

TOXICOLOGY No significant side effects have been reported with oral SAMe other than the occasional nausea and gastrointestinal disturbances. However, individuals with bipolar (manic) depression should not take SAMe unless

SAMe (S-Adenosylmethionine)

under strict medical supervision because SAMe‘s antidepressant activity may lead to the manic phase in these individuals; this effect is exclusive to some people with bipolar depression.

INTERACTIONS AND CONTRAINDICATIONS SAMe functions very closely with vitamin BI2, folic acid, vitamin B6, and choline in methylation reactions. Because of SAMe‘s effects on the liver, it may enhance the elimination of various drugs from the body!’ The clinical significance of this effect has not been fully determined.

1.Stramentinoli G. Pharmacologic aspects of Sadenosylmethionine. Pharmacokinetics and pharmacodynamics. Am J Med 1987;83 35-42. 2. Bottiglieri T, Hyland K, Reynolds EH. The clinical potential of

ademetionine (Sadenosylmethionine) in neurological disorders. Drugs 1994;48:137-152. 3. Fava M, Rosenbaum JF, MacLaughlin R, et al. Neuroendocrine effects of Sadenosyl-L-methionine, a novel putative antidepressant. J Psychiatr Res 1990;24:177-184. 4. Bressa GM. Sadenosyl-L-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl 1994; 154:7-14. 5. Janicak PG, Lipinski J, Davis JM, et al. Parenteral Sadenosylmethionine (SAMe) in depression: literature review and preliminary data. Psychopharmacol Bull 1989;25:238-242. 6. Friedel HA, Goa KL, Benfield P. Sadenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs 1989;38:389-416. 7. Carney MW, Toone BK, Reynolds EH. Sadenosylmethionine and affective disorder. Am J Med 1987;83:104-106. 8. Vahora SA, Malek-Ahmadi P. Sadenosylmethionine in the treatment of depression. Neurosci Biobehav Rev 1988;12:139-141. 9. Kagan BL, Sultzer DL, Rosenlicht N, et al. Oral Sadenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 1990;147591-595. 10. Rosenbaum JF, Fava M, Falk WE, et al. An open-label pilot study of oral Sadenosylmethionine in major depression: interim results. Psychopharmacol Bull 1988;24189-194. 11. De Vanna M, Rigamonti R. Oral S-adenosyl-L-methionine in depression. Curr Ther Res 1992;52:478-485. 12. Salmaggi E Bressa GM, Nicchia G, et al. Double-blind, placebocontrolled study of Sadenosyl-L-methionine in depressed postmenopausal women. Psychother Psychosom 1993;59:34-40. 13. Bell KM, Potkin SG, Carreon D, et al. Sadenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl1994;15415-18. 14. Delle Chiaie R, Pancheri P,Scapicchio P. Efficacy and tolerability of oral and intramuscular Sadenosyl-L-methionine 1,4butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr 2OO2;76:117251176s.

It has been cautioned that SAMe be avoided in patients Parkinson’s disease. Animal studies indicate that excessive methylation is associated with Parkinson’s disease and SAMe excess has caused Parkinson’s disease-like effects in animal In addition, both animal and human studies indicate that increased methylation can cause the depletion of dopamine and block the effects of do dopa.^,*^,^ This line of research is contradicted, however, by preliminary evidence that SAMe may improve the emotional depression and the impaired mental function that are often associated with the disorder.50 Nonetheless, it is recommended that patients with Parkinson’s disease avoid supplementing with SAMe until more is known.

15. Cerutti R, Sichel MP, Perin M, et al. Psychological distress during puerperium: A novel therapeutic approach using Sadenosylmethionine. Curr Ther Res 1993;53:707-717. 16. Lo Russo A, Monaco M, Pani A, et al. Efficacy of SadenosylL-methionine in relieving psychological distress associated with detoxification in opiate abusers. Curr Ther Res 1994;55:905-913. 17.Soeken KL, Lee WL, Bausell RB, et al. Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J Fam Pract 2002;51:425-430. 18. Schumacher HR Jr. Osteoarthritis: the clinical picture, pathogenesis, and management with studies on a new therapeutic agent, Sadenosylmethionine. Am J Med 1987;83:1-4. 19. Montrone F, Fumagalli M, Sarzi Puttini P, et al. Double-blind study of Sadenosyl-methionine versus placebo in hip and knee arthrosis. Clin Rheumatol1985;4:484-485. 20.Harmand MF, Vilamitjana J, Maloche E, et al. Effects of Sadenosymethionine on human articular chondrocyte differentiation. An in vitro study. Am J Med 1987;83:48-54. 21. Konig H, Stahl H, Sieper J, et al. Magnetic resonance tomography of finger polyarthritis: morphology and cartilage signals after ademetionine therapy. Aktuelle Radio1 1995;5:36-40. 22. MulIer-Fassbender H. Double-blind clinical trial of Sadenosylmethionine versus ibuprofen in the treatment of osteoarthritis. Am J Med 1987;8381-83. 23. Glorioso S, Todesco S, Mazzi A, et al. Double-blind multicentre study of the activity of Sadenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharmacol Res 1985;5:39-49. 24. Marcolongo R, Giordano N, Colombo B, et al. Double-blind multicentre study of the activity of Sadenosyl-methionine in hip and knee osteoarthritis. Curr Ther Res 1985;3782-94. 25. Domljan Z, Vrhovac B, Durrigl T, et al. A double-blind trial of ademetionine vs naproxen in activated gonarthrosis. Int J Clin Pharmacol Ther Toxic01 1989;27329-333. 26. Caruso I, Pietrogrande V. Italian double-blind multicenter study comparing Sadenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease. Am J Med 1987;83:66-71. 27. Vetter G. Double-blind comparative clinical trial with Sadenosylmethionine and indomethacin in the treatment of osteoarthritis. Am J Med 1987;83:78-80. 28. Maccagno A, Di Giorgio EE, Caston OL, et al. Double-blind controlled clinical trial of oral Sadenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med 1987;83:72-77.

29. Konig B. A long-term (two years) clinical trial with Sadenosylmethionine for the treatment of osteoarthritis. Am J Med 1987; 83:89-94. 30.Berger R, Nowak H. A new medical approach to the treatment of osteoarthritis. Report of an open phase IV study with ademetionine (Gumbaral)..AmJ Med 1987;8384-88. 31. Tavoni A, Vitali C, Bombardieri S, et al. Evaluation of Sadenosylmethionine in primary fibromyalgia. A double-blind crossover study. Am J Med 1987;83:107-110. 32. Volkmann H, Norregaard J, Jacobsen S, et a]. Double-blind, placebo-controlled cross-over study of intravenous Sadenosyl-Lmethionine in patients with fibromyalgia. Scand J Rheumatol 1997;26206-211. 33. Jacobsen S, Danneskiold-Samsoe B, Andersen RB. Oral Sadenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. S a n d J Rheumatol1991;20294-302. 34. Di Benedetto P, Iona LG, Zidarich V. Clinical evaluation of Sadenosyl-L-methionine versus transcutaneous nerve stimulation in primary fibromyalgia. Curr Ther Res 1993;53:222-229. 35. Frezza M, Surrenti C, Manzillo G, et al. Oral Sadenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A doubleblind, placebo-controlled study. Gastroenterology 1990;99:211-215. 36. Avila MA, Garcia-Trevijano ER, Martinez-Chantar ML, et al. SAdenosylmethionine revisited: its essential role in the regulation of liver function. Alcohol 2002;27163-167. 37.Di Padova C, Tritapepe R, Di Padova F, et al. Sadenosyl-Lmethionine antagonizes oral contraceptive-induced bile cholesterol supersaturation in healthy women: preliminary report of a controlled randomized trial. Am J Gastroenterol1984;79:941-944. 38. Nicastri PL, Diaferia A, Tartagni M, et al. A randomised placebccontrolled trial of ursodeoxycholic acid and Sadenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol 1998;105:1205-1207. 39. Frezza M, Pozzato G, Pison G, et al. Sadenosylmethionine counteracts oral contraceptive hepatotoxicity in women. Am J Med Sci 1987;293:234-238.

40.Bombardieri G, Milani A, Bemardi L, et al. Effects of Sadenosylmethionine (SAMe) in the treatment of Gilbert’s syndrome. Curr Ther Res 1985;37580-585. 41.Angelico M, Gandin C, Nistri A, et al. Oral S-adenosyl-Lmethionine (SAMe) administration enhances bile salt conjugation with taurine in patients with liver cirrhosis. Scand J Clin Lab Invest 1994;54:459-464. 42. Kakimoto H, Kawata S, Imai Y, et al. Changes in lipid composition of erythrocyte membranes with administration of Sadenosyl-Lmethionine in chronic liver disease.GastroentemlJpn 1992;2750&513. 43.Loguercio C, Nardi G, Argenzio F, et al. Effect of SadenosylL-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease. Alcohol Alcohol 1994;29597-604. 44. Mato JM, Camara J, Femandez de Paz J, et al. Sadenosylmethionine in alcoholic liver cirrhosis: a randomized, placebocontrolled, double-blind, multicenter clinical trial. J Hepatol1999;30:1081-1089. 45. Pascale RM, Marras V, Simile MM, et al. Chemoprevention of rat liver carcinogenesis by S-adenosyl-L-methionine: a long-term study. Cancer Res 1992;52:4979-4986. 46.Gatto G, Caleri D, Michelacci S, et al. Analgesizing effect of a methyl donor (Sadenosylmethionine) in migraine: an open clinical trial. Int J Clin Pharmacol Res 1986;6:15-17. 47. Reicks M, Hathcock JN. Effects of methionine and other sulfur compounds on drug conjugations. Pharmacol Ther 1988;3767-79. 48. Cheng H, Gomes-Trolin C, Aquilonius SM, et al. Levels of L-methionine Sadenosyltransferase activity in erythrocytes and concentrations of Sadenosylmethionine and Sadenosylhomocysteine in whole blood of patients with Parkinson’s disease. Exp Neurol 1997;145580-585. 49.Charlton CG, Crowell B Jr. Parkinson’s disease-like effects of Sadenosyl-L-methionine: effects of L-dopa. Pharmacol Biochem Behav 1992;43:423-431. 50. Di Rocco A, Rogers JD,Brown R, et al. SAdenosyl-methionine improves depression in patients with Parkinson’s disease in an open-label clinical trial. Mov Disord 2000;15:1225-1229.

Sarsaparilla Species Michael T. Murray, ND JosephE. Pizzorno Jr, ND CHAPTER C O N T E N T S General Description 1241

Clinical Application 1242 Psoriasis 1242

Chemical Composition 1241 Dosage History and Folk Use 1241 Historical Use in the Treatment of Syphilis 1241

1242

Toxicology

1242

Drug Interactions 1242 Pharmacology 1242 Endotoxin Binding 1242

Smilax aristolochiifoliu (family: Liliaceae) Synonym: Smilax medica Common name: Mexican sarsaparilla Smilax ofzcinalis (family: Liliaceae) Synonym: Smilax regelii Common name: Honduras sarsaparilla

GENERAL DESCRIPTION Sarsaparilla is a tropical American perennial plant. Its long slender root and short thick rhizomes produce a vine that trails on the ground and climbs by means of tendrils growing in pairs from the petioles of the alternate, obicular to ovate, evergreen leaves. The root is the part of the plant utilized for medicinal purposes.

CHEMICAL COMPOSITION Sarsaparilla contains 1.8% to 2.4% steroid saponins, including the following: Sarsaponin Smilasaponin Sarsaparilloside and its aglycones, sarsapogenin (Figure 123-l), smilagenin, and pollinastanol Other constituents are starch, resins, and a trace of volatile oi1.l

HISTORY AND FOLK USE Sarsaparilla’s medicinal use has been as a tonic and blood purifier. Tonics are defined as agents that ”permanently exalt the energies of the body at large, without vitally affecting any one organ in particular. . . . In short, tonics tone the whole system. A blood purifier or depurative refers to an agent which cleanses and purifies the system.”2Sarsaparilla’s reputation in this regard probably stems from its importation from the Caribbean and South America to Europe in the sixteenth century for the treatment of ~yphilis.~

Historical Use in the Treatment of Syphilis A French physician, Nicholas Monardes, published a comprehensive account of sarsaparilla and several other “new” drugs for the treatment of syphilis in 1574. Many Europeans at the time believed that syphilis had come to Europe from the West Indies with Columbus’s sailors, and because there was a general belief that whatever disease was native to a country might be cured by the medicinal herbs growing in that region, it was only natural for sarsaparilla to become a popular remedy. Furthermore, the standard treatment for syphilis, mercury, often resulted in greater morbidity and mortality than the disease itself. Sarsaparilla was a welcome alternative, but despite initial excitement, Monardes’ sarsaparilla cure sank in favor. This was probably due to other aspects of the cure,

1241

Pharmacology of Natural Medicines

R

HO Figure 123-1

Sarsasapogenin.

which involved confinement to a warm room for 30 days followed by 40 days of abstinence from both wine and sexual inter~ourse.~ However, sarsaparilla continued to be used in the treatment of syphilis. During military operations in Portugal in 1812, a British Inspector General of Hospitals noted that the Portuguese soldiers suffering from syphilis who used sarsaparilla recovered much faster and more completely than their British counterparts, who were treated with m e r c ~ r y . ~ Sarsaparilla was also used by the Chinese in the treatment of syphilis. Clinical observations in China show that sarsaparilla is effective, according to blood tests, in about 90% of acute cases and 50% of chronic Although sarsaparilla was clearly more beneficial in the treatment of syphilis, it was mercury that established itself as the standard treatment for more than four-anda-half centuries. It has been stated that “the use of mercury in the treatment of syphilis may have been the most colossal hoax ever perpetrated” in the history of medi~ine.~ Mercury represented a new kind of medicine, one formulated and prepared in a laboratory using the new techniques of chemistry. It helped prepare the way for the future use of drugs rather than herbal medicines. An interesting note is that sarsaparilla species have been used all over the world in many different cultures for the same conditions, namely gout, arthritis, fevers, digestive disorders, skin disease, and cancer.’

PHARMACOLOGY

compounds before they reach the general circulation. If the amount of endotoxin absorbed is excessive or if the liver is not functioning adequately, the liver can become overwhelmed, and endotoxins spill into the blood. If endotoxins are allowed to circulate, activation of the alternate complement system occurs. This system plays a critical role in aggravating inflammatory processes, and activation of complement is responsible for much of the inflammation and cell damage that occur in many diseases, including gout, arthritis, and psoriasis. Historically, these conditions have been treated with sarsaparilla. In further support of sarsaparilla’s effect as a binder of endotoxin is its historical use in the treatment of fever, because absorbed endotoxins produce fever. Sarsaparilla also exhibits some antibiotic activity, but it is probably secondary to the endotoxin-binding action.’

CLINICAL APPLICATION Sarsaparilla’s medicinal action appears to be a result of its binding of bacterial endotoxins in the gut, which makes them unabsorbable. This action greatly reduces the stress on the liver and other organs and is probably responsible for sarsaparilla’s historical use as a tonic and blood purifier. The ability to bind endotoxins is also probably the reason that sarsaparilla is effective in many cases of psoriasis, gout, and arthritis.

Psoriasis Individuals with psoriasis have been shown to have high levels of circulating endotoxins. Binding of endotoxin in the gut is associated with clinical improvement in these individuals. In a controlled study of 92 patients, an endotoxin-binding saponin (sarsaponin) from sarsaparilla greatly improved the psoriasis in 62% of the patients and resulted in complete clearance in 18Yk6

DOSAGE Dried root: 1 to 4 g or by decoction three times/day Liquid extract (1:l):8 to 15 ml three times/day Solid extract (4:l):250 mg three times/day

Sarsaparilla’s mechanism of action is largely unknown, although the plant does contain several saponins and has been shown to be clinically effective in the treatment of ps~riasis.’,~,~ This evidence points to a possible effect on binding of cholesterol and bacterial toxins in the intestines. Sarsaparilla has also demonstrated hepatoprotective effects.’

TOXICOLOGY

Endotoxin Binding

No drug interactions have been reported for sarsaparilla. However, it has been theorized that sarsaparilla may increase the absorption of certain drugs, notably digitalis and bismuth, thereby potentially increasing the chance of drug toxicity.

Evidence seems to support sarsaparilla as an endotoxin binder. Endotoxins are cell wall constituents of bacteria that are absorbed from the gut. Normally, the liver plays a vital role by filtering these and other gut-derived

Although no adverse effects have been reported for sarsaparilla, it is possible that problems could arise if large doses are used over a long time.

DRUG INTERACTIONS

1. Leung AY, Foster S. Encyclopedia of common natural ingredients used in food, drugs and cosmetics, ed 2. New York JohnWdey, 1996. 2. Felter HW. The eclectic materia rnedica, pharmacology and therapeutics. Portland, OR Eclectic Medical Publications, 1983. 3. Van der Zee B, Griggs B. Green pharmacy: A history of herbal medicine. London: Jill Norman & Hobhouse, 1981. 4. Bensky D, Gamble A. Chinese herbal medicine: materia medica. Seattle, WA: Eastland Press, 1986.

5. Duke JA. CRC handbook of medicinal herbs. Boca Raton, FL: CRC Press, 1985. 6. Thurmon FM. The treatment of psoriasis with sarsaparilla compound. N Engl J Med 1942;337128-133. 7. Rafatullah S, Mossa JS,Ageel AM, et al. Hepatoprotective and safety evaluation studies on sarsaparilla. Int J Pharmacognosy 1991;29: 296-301.

Serenoa repens (Saw Palmetto) Eric L. Yarnell, ND, RH(AHG) Kathy Abascal, BS, JD, RH(AHG) CHAPTER CONTENTS General Description 1245 Chemical Composition 1245

Clinical Applications 1246 Benign Prostatic Hyperplasia 1246 Male-Pattern Baldness 1248

History and Folk Use

Dosage 1248

1245

Pharmacology 1246

Serenoa repens (family: Arecaceae) Common names: saw palmetto, palmetto scrub, Saba2 serrulafa

GENERAL DESCRIPTION Serenoa repens is a small palm tree native to the West Indies and the Atlantic coast of North America from South Carolina to Florida. The plant grows from 6 to 10 feet high, with a crown of large spiny-toothed leaves, 2 to 4 feet high, that form a circular, fan-shaped outline. The fruit of the plant, commonly called a berry, is the component used for medicinal purposes. The deep red-brown to black berries are wrinkled and oblong, measuring 0.5 to 1 inch in length with a diameter of 0.5 inch.l

CHEMICAL COMPOSITION Saw palmetto berries contain about 1.5% of a fruitysmelling oil containing saturated and unsaturated fatty acids and sterols.' About 63% of this oil is composed of free fatty acids, including capric, caprylic, caproic, lauric, palmitic, and oleic acids. The remaining portion is composed of ethyl esters of these fatty acids and sterols, including beta-sitosterol and its glucoside. The lipidsoluble compounds are thought to be the major phannacologic components. Other components of the berries are proanthocyanidins, carotenes, lipase, tannins, and sugars. The purified fat-soluble extract, the most-researched medicinal product, contains 85% to 95% fatty acids and sterols. It is made up predominantly of a complex

Toxicology

1249

mixture of saturated and unsaturated free fatty acids, their methyl- and ethyl-esters (approximately 7%), longchain alcohols in free and esterified forms, and various free and esterified sterol derivatives. The free fatty acids in this extract are identified by gas chromatography and mass spectrometry as follows: Caproic acid (C6) Capric acid (C8) Caprylic acid (C10) Lauric acid (C12) Myristic acid (C14) Isomyristic acid (C14) Palmitic acid (C16) Oleic acid (C18:l) Stearic acid (C18) Lauric and myristic acid are the major fatty acids, accounting for approximately 30% of the fatty acid content. The identified alcohols include those with n-C22, n-C23, n-C24, n-C26, n-C28, and n-C30 chains, phytol, famesol, and geranylgeraniol, in addition to high-molecularweight unsaturated polyphenols. The sterolic fraction is composed of beta-sitosterol, stigmasterol, cycloartenol, lupeol, lupenone, and 24-methylcycloarteno1. Many of these sterols are esterified with the fatty acids of the extract.

HISTORY AND FOLK USE The American Indians, and later Eclectic and Naturopathic physicians, used saw palmetto berries in the treatment of genitourinary tract disturbances and as 1245

a tonic to support the body nutritionally.2,3This substance was strongly recommended as a remedy for symptoms of benign prostatic hyperplasia as early as 1919.4It was used in men to increase the function of the testicles and relieve irritation in mucous membranes, particularly those of the genitourinary tract and prostate. Saw palmetto has been used in women with disorders of the mammary glands; long-term use was reputed to cause the breasts to enlarge slowly? Many herbalists have regarded saw palmetto as an aphrodisiac.’

PHARMACOLOGY A standardized liposterolic (fat-soluble) saw palmetto berry extract has demonstrated numerous pharmacologic effects relating to its primary clinical application in the treatment of the common disorder of the prostate gland, benign prostatic hyperplasia (BPH). BPH is a complex disease process in which testosterone in the prostate (primarily when converted to the more potent dihydrotestosterone [DHT]) plays a permissive role, but other factors are critical in its pathogenesis.’ The primary therapeutic action of saw palmetto extract in the treatment of BPH has been thought to be inhibition both of the intraprostatic conversion of testosterone to DHT and of its intracellular binding and tran~port.~,’However, later research suggested additional mechanisms of action, including antiestrogenic and receptor site-binding effects.s Estrogen may contribute to BPH because it inhibits the hydroxylation and subsequent elimination of DHT. Serenoa appears to inhibit the activity of estrogen in the prostate. For example, in a double-blind study of 35 men with BPH, 18 were given the saw palmetto extract at 160 mg twice daily, and 17 were given placebo.6 At the end of the 90-day study, androgen, estrogen, and progesterone receptors from prostate tissue samples were evaluated with two different techniques. The men receiving the saw palmetto extract had significantly lower cytosol and receptor values for estrogen and progesterone than the placebo group. Because the progesterone receptor content is linked to estrogenic activity, the results of the evaluation imply that at least part of the efficacy of the saw palmetto extract is through its antiestrogenic effect. The results of the androgen receptor analysis were quite interesting: There was no change in the number of cytosol androgen receptors, but the number of nuclear androgen receptors was significantly lower in the saw palmetto group (60% of the placebo group tested positive for the nuclear receptor, compared with 10% of the saw palmetto group). These results indicate that the saw palmetto extract probably competitively blocks the translocation of the cytosol androgen receptor to the nucleus.

The overall results of the study show that the standardized extract of saw palmetto exerts both antiandrogenic and antiestrogenic activities. Preliminary analysis of the extract demonstrates that separate fractions are responsible for these effects. Researchers in this study concluded, ”It cannot be excluded, however, that the primary effect is antiestrogenic and that the inactivation of androgen receptors and progesterone receptors and of the 5-alpha-reductase activity is secondary to the estrogen receptor blockade.”8 Serenoa standardized extracts do not affect systemic levels of androgens, follicle-stimulating hormone, or luteinizing hormone in men with BPH.9 This may help explain the relatively low incidence of adverse effects of this substance in clinical trials. These findings do not, however, rule out localized effects of saw palmetto on androgen or estrogen effects in other tissues of the body. Endocrinologic factors in addition androgens and estrogen play a role in the pathogenesis of BPH. Various locally produced growth factors are important, and liposterolic extracts of Serenoa block the ability of one of them, basic fibroblast growth factor, to induce prostatic hyperplasia in vitro.’” High prolactin levels may also stimulate prostate hyperplasia; Serenoa extracts interfere with this process in rats but the drug finasteride does not.” Saw palmetto extracts exert antispasmodic effects on smooth muscle. Rat smooth muscle was originally shown to be inhibited by two Serenoa extracts owing to inhibition of calcium ion influx.12A later study found that Serenoa extract, but not pumpkin seed extract, stinging nettle root extract, or beta-sitosterol, consistently inhibited human alphal-adrenergic receptors in ~ i t r 0 . I ~ Whether this effect is relevant clinically is still unknown. The standardized extract has demonstrated antiedematous effects, and the polysaccharide components have been shown to have immunostimulatory effect^.'^,'^ Serenoa extract and myristoleic acid induced apoptosis and necrosis in an androgen-sensitive human prostate cancer cell line in vitro.”j

CLINICAL APPLICATIONS Currently, the primary clinical application of saw palmetto berries (specifically the fat-soluble extract) is in the treatment of BPH. There is initial evidence that saw palmetto may also help counter androgenetic andropecia (male-pattern baldness). On the basis of its pharmacology, this extract may also be of benefit in conditions of androgen excess in women, such as hirsutism and polycystic ovarian disease.

Benign Prostatic Hyperplasia In the United States, between 50% and 60% of men between the ages of 40 and 59 years have BPH. This disorder is characterized by increased urinary frequency,

Serenoa repens (Saw Palmetto) linical studies demonstrating the efficacy of Serenoa repens extract* No. of patients

Study

Type of study

Length of study

Results

Boccafoschi and Annoscia”

Double-blind, placebo-controlled

22

60 days

Significant difference for volume voided, maximum flow, mean flow, dysuria, nocturia

Cirillo-Maruccoet all8

Open

47

4 months

Significant difference for dysuria, nocturia, urine flow

Tripodi et all9

Open

40

30-90 days

Significant difference for dysuria, nocturia, volume of prostate, voiding rate, residual urine

Emili et aIz0

Double-blind, placebo-controlled

30

30 days

Significant difference for number of voided, strangury, maximum and mean urine flow, residual urine

Greca and VolpiZ1

Open

14

1-2months

Significant difference for dysuria, perineal heaviness, nocturia, volume of urine per voiding, interval between two diurnal voidings, sensation of incomplete voiding

Duvia et alzz

Controlled

30

30 days

Significant difference for voiding rate vs. Pygeum africanum

Tasca et a P

Double-blind, placebo-controlled

30

31-90 days

Significant difference for frequency, urine flow measurement

Cukier et aIz4

Double-blind, placebocontrolled

168

60-90 days

Significant difference for dysuria, frequency, residual urine

Champault et alz5

Double-blind, placebo-controlled

168

60-90 days

Significant difference for objective and subjective parameters

Crimi and RussoZ6

Open

32

4 weeks

Significant difference for dysuria, nocturia, volume of prostate, voiding rate

Champault et aIz7

Double-blind, placebo-controlled

110

28 days

Significant difference for dysuria, nocturia, flow measurement, residual urine

Mattei et aIz8

Double-blind

40

3 months

Significant difference for dysuria, nocturia, residual urine

BraeckmanZ9

Open

305

3 months

Significant difference for maximum urine flow, prostate volume, international prostate score

‘85% to 95% fatty acids and sterols at a dosage of 320 mgday.

nighttime awakening to empty the bladder, and reduced force and caliber of urination (see Chapter 154). These major symptoms have been shown to be significantly improved in more than a dozen double-blind, placebocontrolled clinical trials (summarized in Table 124-1).17-29 At least two metaanalyses have combined data from these and other trials and concluded that, despite some limitations in trial design, Serenoa extracts have been shown to reduce symptoms of BPH and increase urine flow in comparison with p l a c e b ~ .One ~ , ~of ~ these also concluded that Serenoa extracts are as effective as the 5-alpha-reductase-inhibiting drug finasteride (Proscar) with sipficantly fewer adverse effects.31 In one of the larger studies, involving 110 patients with BPH, impressive clinical results were reported: Nocturia decreased by more than 4570, flow rate (ml/sec) rose by

more than 50%, and postmicturition residue (ml) diminished by 42% in the group receiving the Serenoa extract.26 In contrast, those being given placebo showed no significant improvement in nocturia or flow rate, and postmicturition residue actually worsened. Sigruficant improvements were also noted in selfrating by the patients and global rating by the physicians. Of the 50 treated subjects completing the 30-day study, physicians rated 14 greatly improved, 31 improved, and only 5 unchanged or worse. In contrast, no subjects in the placebo group had greatly improved, 16 showed some improvement, and 28 remained unchanged or worse. Although the saw palmetto extract has shown excellent results in numerous double-blind, placebo-controlled clinical trials, results from a recent open, multicenter study are perhaps the most revealing.29 The results

Pharmacology of Natural Medicines

corroborate those from numerous double-blind, controlled studies showing that the liposterolic extract of saw palmetto (S. repens) standardized to contain 85% to 95% fatty acids and sterols is an effective treatment for BPH. Whereas drugs like finasteride typically take up to a year to show sigrulicant benefit, the saw palmetto extract produces better results in a much shorter time. Most patients experience some relief of symptoms within the first 30 days of treatment with the saw palmetto extract. In this study, 305 men were given a dosage of 160 mg twice daily. The subjective evaluations of treatment made by patients after 45 and 90 days of treatment were quite favorable. After 45 days, 83% of patients estimated that the drug was effective. After 90 days, 88% did so. Similarly, global evaluations made by physicians after 45 and 90 days demonstrated 81% and 88% effectiveness, respectively. The objective evaluations demonstrated remarkable improvements in all measurements. Maximum urinary flow increased from 9.8 to 12.2 ml/sec, mean urinary flow rate increased from 5.8 to 7.4 ml/sec, prostatic volume decreased from 40,348 to 36,246 mm3, and the International Prostate Symptom Score decreased from 19.0 to 12.4. No serious adverse reactions were reported. Although these results are impressive, perhaps the most profound changes occurred in the quality of life scores, as shown in Table 124-2. These improvements in quality of life scores demonstrate just how powerful an effect improving bothersome symptoms such as nocturia can have on an individual’s mental outlook. Another important finding was that the saw palmetto extract had no demonstrable effect on serum prostatic specific antigen levels. A further study evaluated the long-term efficacy of saw palmetto.32This 3 year, multicenter, open-label study evaluated 160 mg of a standardized extract (Strogen)in 435 men (age 41 to 89 years) with stage I or stage I1 BPH. By the end of the study, 120 patients had withdrawn-12 for lack of efficacy, 41 because of the need for surgery, 41 lost to follow-up, and 8 owing to

Evaluation Delighted Happy Satisfied Mitigated Unsatisfied Unhappy Hopeless

Responses on Day 0 (%)

Responses on Day 90 (%)

0.6 2.3 9.7 22.7 43.8 18.5 2.3

5.4 24.0 36.8 20.9 9.5 2.4 1 .o

adverse reactions. In the remaining 315 subjects, the following results were reported: Nocturia normalized or improved in 73% Daytime frequency improved in 54% Feeling of incomplete emptying improved in 75% Rectal examination revealed improvement in prostate congestion in 55% *Average residual volume decreased from 64 to 38 ml Peak urine flow increased by an average of 6.1 ml/sec A total of 14.7% of the men experienced a continued deterioration of prostate function. The primary adverse events were mild gastrointestinal disturbance. In a comparison double-blind trial, 542 men with BPH symptoms were randomly assigned to receive either the alpha blocker tamsulosin or Serenoa extract for 1 year.33 The two groups showed identical levels of improvement in symptoms. Tamsulosin was more frequently associated with ejaculatory disorders than Serenoa extract. In a separate double-blind trial involving 329 men with BPH symptoms, tamsulosin combined with placebo was just as effective as tamsulosin combined with Sereiiou extract at relieving symptoms.M Adding Serenoa extract to tamsulosin caused no alteration in adverse effects.

Male-Pattern BaIdness A combination of 400 mg Serenou extract and 100 mg beta-sitosterol daily was found effective for male-pattern baldness in a pilot double-blind, placebo-controlled trial.35The trial lasted 5 months and involved 19 men with mild to moderate baldness. Sixty percent (6/10) of men in the treatment group were rated as having improved by blinded observers, whereas only 11%(1/9) of men in the placebo group were rated as improved. Thirty-three percent (3/9) of men in the placebo group showed deterioration compared with none in the treatment group. There were no major adverse effects, although two men originally entered into the study dropped out because of adverse effects (it is not clear from the study report which group these men had been assigned to).

DOSAGE The dosage for the liposterolic extract of saw palmetto berries (containing 85% to 95% fatty acids and sterols) is 160 mg twice daily or 320 mg daily; the two regimens have been shown to be equally e f f e ~ t i v eA. ~similar ~ dose using fluid extracts and tinctures would require extremely large quantities of alcohol if the liposterolic components are the primary active constituents. The Eclectics used comparatively small dosages of saw palmetto in crude extracts effectively for BPH with

Serenoa repens (Saw Palmetto) apparent clinical success. Ellingwood4lists as his dose as 10 drops to 1dram of specific Serenou (meaning basically a fresh berry tincture). We are unaware of any published clinical study of a crude extract. Dosages are as follows:

The dose of fluid extracts or tinctures is unknown owing to a lack of research.

TOXICOLOGY

Crude berries: 10 g twice daily Liposterolic extract (standardized at 85-95% fatty acids and sterols): 160 mg twice daily or 320 mg once daily

No significant adverse effects have been reported in the clinical trials of the saw palmetto berry extract or for saw palmetto berry ingestion. Mild gastrointestinal upset and erectile dysfunction (in approximately 1%of users in clinical trial^)^ occasionally occur.

1.Duke JA. CRC Handbook of medicinal herbs. Boca Raton, F L CRC Press, 1985:118. 2. Felter HW, Lloyd JU. King’s American dispensatory (1898). Portland, OR: Eclectic Medical Publications (reprint), 1983: 1750-1752. 3. Kuts-Cheraux AW. Naturae medicina and naturopathic dispensatory. Yellow Springs, OH: Antioch Press, 1953:249. 4. Ellingwood F. American materia medica, therapeutics and pharmacognosy. Sandy, OR Eclectic Medical Publications, 1919, reprinted 1998457459. 5. Sant GR, Long JP. Benign prostatic hyperplasia. In Sant GR, ed. Pathophysiologic principles of urology. Boston: Blackwell Scientific Publications, 1994123-154. 6. Carilla E, Briley M, Fauran F, et al. Binding of Permixon, a new treatment for prostatic benign hyperplasia, to the cytosolic androgen receptor in the rat prostate. J Steroid Biochem 1984;20:521-523. 7. Sultan C, Terraza A, Devillier C, et al. Inhibition of androgen metabolism and binding by a liposterolic extract of “Serenou repens B” in human foreskin fibroblasts. J Steroid Biochem 1984;20515-519. 8. Di Silverio F, DEramo G, Lubrano C, et al. Evidence that Serenou repens extract displays antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy. Eur Urol1992;21:309-314. 9. Casarosa C, Cosci di Coscio M, Fratta M. Lack of effects of a liposterolic extract of Serenou repens on plasma levels of testosterone, follicle-stimulating hormone, and luteinizing hormone. Clin Ther 1988;10585-588. 10. Paubert-Braquet M, Cousse H, Raynaud JP, et al. Effect of the lipidosterolic extract of Serenou repens (Permixon) and its major components on basic fibroblast growth factor-induced proliferation of cultures of human prostate biopsies. Eur Urol1998;33340-347. 11.Van Coppenolle F, Le Bourhis X, Carpentier F, et al. Pharmacological effect of the lipidosterolicextract of S m o n repens (Permixon) on rat prostate hyperplasia induced by hyperprolactinemia. comparison with finasteride. Prostate 2000;43:49-58. 12.Gutierrez M, Garcia de Boto J, Cantabrana B, Hidalgo A. Mechanisms involved in the spasmolyhc effect of extracts from Subal serrulutu fruit on smooth muscle. Gen Pharmacol1996;27171-176. 13. Goepel M, Hecker U, Krege S, et al. Saw palmetto extracts potently and noncompetitively inhibit human alpha-1-adrenoceptors in vitro. Prostate 1999;38208-215. 14.Tarayre JF‘, Delhon A, Lauressergues H, et al. [Anti-edematous action of a hexane extract of the stone fruit of Serenou repens Barb]. Ann Pharm Fr 1983;41:559-570. 15. Wagner H, Proksch A. Immunostimulatory drugs of fungi and higher plants. Econ Med Plant Res 1985;1:113-153. 16. Iguchi K, Okumura N, UsUi S, et al. Myristoleic acid, a cytotoxic component in the extract from Serenou repens, induces apoptosis

and necrosis in human prostatic LNCaP cells. Prostate 2001; 4759-65. 17. Boccafoschi C, Annoscia S. Comparison of Serenou repens extract with placebo by controlled clinical trial in patients with prostatic adenomatosis. Urologia 1983;50:1257-1268. 18. Cirillo-Marucco E, Pagliarulo A, Tritto G, et al. Extract of Serenou repens (PermixonR)in the early treatment of prostatic hypertrophy. Urologia 1983;5:1269-1277. 19. Tripodi V, Giancaspro M, Pascarella M, et al. Treatment of prostatic hypertrophy with Serenoa repens extract. Med Praxis 1983;4:41-46. 20. Emili E, Lo Cigno M, Petrone U. Clinical trial of a new drug for treating hypertrophy of the prostate (Permixon). Urologia 1983;501042-1048. 21. Greca P, Volpi R. Experience with a new drug in the medical treatment of prostatic adenoma. Urologia 1985;52532-535. 22. Duvia R, Radice GP, Galdini R. Advances in the phytotherapy of prostatic hypertrophy. Med Praxis 1983;4143-148. 23. Tasca A, B a d M, Cavazzana A, et al. [Treatment of obstructive symptomatology caused by prostatic adenoma with an extract of Serenou repens: double-blind clinical study vs. placebo]. Minerva Urol Nefrol 1985;3787-91. 24. Cukier J, Ducassou J, Le Guillou M, et al. Permixon versus placebo. C R Ther Pharmacol Clin 1985;415421. 25. Champault G, Patel JC, Bonnard AM. A double-blind trial of an extract of the plant Serenoa repens in benign prostatic hyperplasia. Br J Clin Pharmacol1984;18:461-462. 26. Crimi A, Russo A. Extract of Serenou repens for the treatment of the functional disturbances of prostate hypertrophy. Med Praxis 1983;4:47-51. 27. Champault G, Bonnard AM, Cauquil J, Patel JC. Medical treatment of prostatic adenoma. Controlled trial. PA 109 vs placebo in 110 patients. Ann Urol (Pans) 1984;18:407-410. 28. Mattei FM, Capone M, Acconcia A. Serenoa repens extract in the medical treatment of benign prostatic hypertrophy. Urologia 1988;55547-552. 29. Braeckman J. The extract of Serenoa repens in the treatment of benign prostatic hyperplasia. A multicenter open study. Curr Ther 1994;55:776-785. 30. Boyle P,Robertson C, Lowe F, Roehrbom C. Meta-analysis of clinical trials of Permixon in the treatment of symptomatic benign prostatic hyperplasia. Urology 2000;55533-539. 31. Wilt TJ, Ishani A, Stark G, et al. Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 1998;2801605-1609. 32. Bach D, Ebeling L. Long-term drug treatment of benign prostatic hyperplasia-results of a prospective 3-year multicenter study using Sabal extract IDS89. Phytomedicine 1996;3105-111.

33. Debruyne F, Koch G, Boyle P, et al. [Comparison of a phytotherapeutic agent (Permixon)with an alpha-blocker (Tamsulosin)in the treatment of benign prostatic hyperplasia: a 1-year randomized international study.] Eur Urol2002;41:497-506. 34.Glemain P, Coulange C, Billebaud T, et al. [Tamsulosin with or without Serenoa repens in benign prostatic hyperplasia: the OCOS trial.] Pmg Urol2002;12:395-403. 35. Prager N, Bickett K, French N, Marcovici G. A randomized, doubleblind, placebocontrolled trial to determine in the effectiveness

of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia. J Altem Complement Med 2002;8:143-152. 36. Braeckman J, Bruhwyler J, Vandekerckhove K, GPczy J. Efficacy and safety of the extract of Serenoa repens in the treatment of benign prostatic hyperplasia: therapeutic equivalence between twice and once daily dosage forms. Phytother Res 1997;11:55&563.

Silybum maximum (Milk Thistle) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Viral Hepatitis 1254 Gallstones 1254 Psoriasis 1254 Protection against Chemical-Induced Renal Damage 1254 Silybin Bound to Phosphatidylcholine 1254

General Description 1251 Chemical Composition 1251 History and Folk Use 1251 Pharmacology 1251 Hepatoprotection Effects 1251 Other Pharmacologic Actions 1252

Dosage 1255 Toxicity

Clinical Applications 1253 Chemical-Induced Liver Damage Cirrhosis 1253

1253

Silybum marianum (family: Compositae) Synonym: Carduus marianus Common names: milk thistle, marian thistle, St. Mary's thistle

GENERAL DESCRIPTION Silybum rnarianum is a stout, annual or biennial plant found in dry rocky soils in southern and Western Europe and some parts of the United States. The branched stem grows 1 to 3 feet high and bears alternate, dark green, shiny leaves with spiny, scalloped edges that are markedly streaked with white along the veins. The solitary flower heads are reddish purple with bracts ending in sharp spines. Flowering season is from June to August. The seeds, fruit, and leaves are used for medicinal purposes.

CHEMICAL COMPOSITION SiZybum mariunum contains silymarin, a mixture of flavanolignm, consisting chiefly of silybin, silydianin, and ~ilychristine.'-~ The concentration of silymarin is highest in the fruit, but it is also found in the seeds and leaves. Other flavanolignans contained in Silybum include silandrin, silyhermin, silymonin, and neosilyhermin.' Silybin is the silymarin component with the greatest degree of biologic activity (Figure 125-1).

1255

Drug Interactions 1255

HISTORY AND FOLK USE Perhaps the most widespread folk use of this plant has been in assisting the nursing mother in the production of milk. It was also used in Germany for curing jaundice and biliary derangements. It is interesting to note that the discovery of the liver-protecting flavanolignans in S. marianum was the result not of systemic pharmacologic screening but rather of investigation of SiZybum's empirical effects in liver disorders.'

PHARMACOLOGY Currently S. marianum extracts (usually standardized to contain 70% silymarin) are widely used in European pharmaceutical preparations for hepatic disorders. Silymarin is one of the most potent liver-protecting substances k110wn.l~

Hepatoprotection Effects Free Radical Scavenging Silybum's ability to prevent liver destruction and enhance liver function is due largely to silymarin's inhibition of the factors that are responsible for hepatic damage-free radicals and leukotrienes-coupled with its ability to stimulate liver protein synthesis. Silybum components prevent free radical damage by acting 1251

Pharmacology of Natural Medicines

as antioxidants.I4 Silymarin is many times more potent in antioxidant activity than vitamin E.

the patients. Treatment with intravenous silybinin at a dose of 20 mg per kg body weight, penicillin, and glucose for 3 days resulted in reversal of both the organ failures and encephalopathy. Silymarin may also be of great value as an adjunct in patients receiving long-term drug therapy. A very interesting study found that silymarin, in an unusually high dose of 800 mg/day, given to psychiatric patients receiving phenothiazines or butyrophenones resulted in significant protection of the liver as measured by malondialdehyde serum liver enzyme levels? The silymarin did not interfere with the efficacy of the antidepressants.

Effects on Hepatic Glutathione

Stimulation of Hepatic Protein Synthesis

Silymarin prevents the depletion of glutathione (GSH) induced by alcohol and other liver toxins. Even in normal people, silymarin has been shown to raise the basal GSH level in the liver by 35%.

Perhaps the most interesting effect of Silybum components on the liver is their ability to stimulate protein synthe~is.~,'~," This results in an increase in the production of new liver cells to replace the damaged old ones. Sonnenbichler and Zetl" have suggested that "silybinin imitates in some way a physiological regulator in animal cells, so that the structure fits into a specific binding site on the polymerase and in such a way causes the observed effects on rRNA synthesis making the drug from Silybum marianum indeed interesting for liver therapy." Interestingly, silybinin does not have a stimulatory effect on malignant hepatic tissue.'O

CH2OH

FvOY

OH

0 Figure 125-1

Silybin.

Protection from Liver-Damaging Chemicals and Drugs

The protective effect of Silybum against liver damage has been demonstrated in a number of experimental and clinical studies. Experimental liver damage in animals can be produced by such diverse toxic chemicals as carbon tetrachloride, galactosamine, ethanol, and praseodymium nitrate. Silymarin has been shown to protect the liver Antiinflammatory Effects from all of these Perhaps the most impressive of silymarin's protective Leukotrienes, key chemical mediators of inflammaeffects is against the severe poisoning by Arnanifa phalloides tion that are produced by the transfer of oxygen to (the death cap or toadstool mushroom), an effect that polyunsaturated fatty acids (a reaction catalyzed by the has long been recognized in folk medi~ine."~ Ingestion enzyme lipoxygenase), can also damage the liver. of A. phalloides or its toxins causes severe poisoning and, Silymarin has been shown to be a potent inhibitor of this in approximately 30%of victims, death. enzyme, thereby inhibiting the formation of damaging leukotrienes. Among the experimental models for measuring protection against liver damage, those based on amanitin or Silymarin has also been demonstrated to inhibit phalloidin toxicity are the most important, because these prostaglandin synthesis during inflammati~n.'~ Free radical damage to membrane structures due to organic two peptides from A. phalloides are the most powerful liver-damaging substances known. Silymarin has demondisease or intoxication results in increased release, strated impressive results in these experimental models. through lipolysis, of fatty acids. This leads, among other When silymarin was administered before amanita toxin things, to greater prostaglandin and leukotriene synthepoisoning, it was 100% effective in preventing toxi~ity.~,~sis. Silymarin counteracts this deleterious process by suppressing the pathologic decomposition of memEven if given 10 minutes after the amanita toxin, it combrane lipids and inhibiting prostaglandin f0rmati0n.l~ pletely counteracted the toxic effects. In two cases reported in the literature, silymarin Leukotrienes and inflammatory prostaglandins are also involved in the damage of the liver by toxins, so their prevented death and greatly reduced the amount of neutralization by silybin is another mechanism for its liver damage as long as 24 hours after ingestion.6 This protection of the liver. study reported on a husband and wife who ate toxic mushrooms and experienced gastrointestinal symptoms Other Pharmacologic Actions 18 hours later. Despite initial conventional treatment with gastric emptying, intravenous fluids, activated Silymarin has demonstrated several other physiologic charcoal, and a duodenal tube, both patients' laboratory effects. In animal studies it has been shown to increase parameters showed deteriorating liver and renal funclymphocyte proliferation as well as increase in interferontion. Mild hepatic encephalopathy developed in one of gamma, interleukin-4 (IL-4), and IL-10 cytokines in a

Silyburn rnarianurn (Milk Thistle)

dose-dependent manner.14It has also shown a broad range of anticancer effects in various animal models and in vitro studies.’”” Silymarin is a strong inhibitor of cyclic adenosine monophosphate (CAMP)phosphodiesterase, being 13 to 50 times more active than theophylline and 1to 3 times more active than papaverine.18 Silymarin has also been shown to prevent the toxic effects of a variety of compounds, such as hemolysis induced by phenylhydrazine, damage from x-irradiation, and brain edema induced by Presumably, these effects are triethyltinsulfate (TZS).19-21 related to silymarin’s sigruhcant membrane-stabilizing and antioxidant actions. Its action in increasing the osmotic resistance of red blood cells is also quite Silymarin has also been shown to lower cholesterol levels in animal studies and may block cholesterol synthesis.23

CLINICAL APPLICATIONS Silymarin’s primary use is as an aid to the liver, although additional clinical applications are regularly being discovered. This substance can be used to support detoxification reactions or in the treatment of more severe liver disease. In numerous clinical studies, silymarin has been shown to have positive effects in treating several types of liver disease, including the following2‘%

9

Cirrhosis Chronic hepatitis Fatty infiltration of the liver (chemical- and alcoholinduced fatty liver) Subclinical cholestasis of pregnancy Cholangitis and pericholangitis

The therapeutic effect of silymarin in these disorders has been confirmed by histologic, clinical, and laboratory data. Silymarin may also be useful in improving the solubility of the bile in the treatment of gallstones as well as in psoriasis.

Chemical-Induced Liver Damage In one of the first extensive double-blind clinical trials investigating silymarin’s therapeutic effect in liver disorders, the substance demonstrated impressive results in 129 patients with toxic metabolic liver damage, fatty degeneration of the liver of various origin, or chronic hepatitis, who were compared with a control group of 56 patients. The results might have been even more impressive if the study had lasted longer than 35 days.24 A follow-up study of patients with liver damage due to alcohol, diabetes viruses, or toxic exposure yielded even more striking results. Patients were monitored for a long time (7 weeks). Not only were clinical findings markedly improved in the silymarin-treated groups,

but laboratory and liver biopsy data improved as well. Highly sigruficant results were obtained in bromsulphalein retention as well as in measurements of alanine transaminase (ALT), iron, and cholesterol levels. Biopsy showed remarkable tissue restorative effects. Upon completion of silymarin therapy, restitution of normal cell structure was found even in severely damaged livers. These effects on the tissue level correlated well with improvements in blood chemistry values.25 Another study highlighted the benefit of silymarin in individuals exposed to toxic chemicals. In this study, abnormal results of liver function tests (elevations levels of AST, ALT activity), and/or abnormal hematologic values (low platelet counts, increased white blood cell [WBC] counts, and a relative increase of lymphocytes compared with other WBCs) were observed in 49 of 200 workers exposed to toxic toluene and/or xylene vapors for 5 to 20 years.%Thirty of the affected workers were treated with silymarin, and the remaining 19 were left without treatment. Under the influence of silymarin, the liver function parameters and platelet counts significantly improved. The WBC counts also showed a tendency toward improvement. Pooled data from case record studies involving 452 patients with A. phalloides poisoning show a highly sigruficant difference in mortality in favor of silymarin therapy. The mortality rate for silymarin therapy is 9.8%,compared with 18.3%for standard treatment.“

Cirrhosis As previously described, silymarin is quite effective in treating alcohol-related liver disease. There is a tremendous range in severity of alcohol-related liver disease, from relatively mild to serious damage such as cirrhosis. Even in this severe state, silymarin has shown benefit. Perhaps the most significant benefit is extending the life span of patients with these disorders. In one study, 87 patients with cirrhosis (46 with alcoholic-related cirrhosis) received silymarin, whereas 83 patients (45 with alcoholic cirrhosis) received a pla~ebo.~’ The mean observation period was 41 months. In the treatment group, there were 24 deaths, 18 related to liver disease; in the control group, there were 37 deaths, 31 related to liver disease. The Cyear survival rate was 58% in the treatment group compared with 39% in the controls. Analysis performed on results of five trials involving a total of 602 patients with liver cirrhosis demonstrated that, although it produced a statistically insignificant reduction of total mortality by 4.2%in comparison with placebo, silymarin did lead to a statistically sigruficant reduction in liver-related mortality of 7%.“ Silymarin can also improve immune function in patients with cirrhosis.38

Viral Hepatitis Silymarin is useful in helping reverse virally induced liver damage. It is effective in both acute and chronic viral hepatitis. In one study of acute viral hepatitis, 29 patients treated with silymarin showed a definite therapeutic influence on the characteristic increased serum levels of bilirubin and liver enzymes compared with a placebo The laboratory parameters had regressed more in the silymarin group than in the placebo group by the fifth day of treatment. The number of patients attaining normal liver values after 3 weeks of treatment was significantly higher in the silymarin group than in the placebo group. In a study of chronic viral hepatitis, silymarin was shown to result in dramatic improvement. Used at a high dose (420 mg) for periods of 3 to 12 months, silymarin resulted in a reversal of liver cell damage (as noted on biopsy), a rise in protein level in the blood, and a lowering of liver enzyme values. Common symptoms of hepatitis (e.g., abdominal discomfort, decreased appetite, and fatigue) were all improved.J0

Gallstones Silymarin may help prevent or treat gallstones through its ability to increase the solubility of the bile. In one study, the composition of the bile was assayed in 19 patients with a history of gallstones (4patients) or removal of the gallbladder due to gallstones (15) before and after silymarin (420 mg/day for 30 days) or placebo. Silymarin treatment led to significant reduction in the biliary cholesterol concentration and bile saturation index.41

Psoriasis Correction of abnormal liver function is indicated in the treatment of psoriasis. Silymarin has been reported to be of value in the treatment of psoriasis, and this effect may be due to its ability to inhibit the synthesis of leukotrienes and improve liver function.43 The connection between the liver and psoriasis relates to one of the liver’s basic tasks, filtering the blood. Psoriasis has been shown to be linked to high levels of circulating endotoxins, such as those found in the cell walls of gut bacteria. If the liver is overwhelmed by an increased number of endotoxins or chemical toxins, or if the liver’s functional ability to filter and detoxify is decreased, the psoriasis is aggravated. Another factor in psoriasis is excessive production of leukotrienes. Silymarin has been shown to reduce leukotriene formation by inhibiting lipooxygenase.12Therefore, silymarin would inhibit one of the causes of the excessive cellular replication. Silymarin has other effects of value in patients with psoriasis. Most of them revolve around correcting the abnormal ratio of cAMP to cyclic guanosine monophosphate (cGMP) observed in the skin of patients with

psoriasis. The ratio of these two cellular control agents controls cellular replication. In psoriasis, cGMP levels are high relative to cAMP levels. Silymarin works to lower cGMP levels and raise cAMP levels.18

Protection against Chemical-Induced Renal Damage Some research has indicated that the antitoxin, free radical-scavenging effects of silymarin may be of value in protecting the kidneys.44In a very provocative study, female rats were given the anticancer drug cisplatin either with or without silybinin (300 mg/kg). Compared with the drug-only group, the silybinin-treated group lost significantly less weight and experienced no loss in creatinine clearance, no changes in urea level or magnesium excretion, and only slight degenerative changes in the glomerulus and tubules. Considering the significant problem of serious nephrotoxicity from cisplatin and other chemotherapeutic agents, silybinin may be of great value as an adjunct in the treatment of cancer.

Silybin Bound to Phosphatidylcholine One form of silymarin has emerged that may provide the greatest benefit. This form binds silybin to phosphatidylcholine. Preliminary research indicates that phosphatidylcholine-bound silybin is better absorbed and produces better clinical results.

Absorption Studies Several human and animal studies have shown that phosphatidylcholine-bound silybin is better absorbed. In one study, the excretion of silybin, the major component of silymarin, in the bile was evaluated in patients undergoing gallbladder removal (cholecystectomy). A drainage tube, the T-tube, was used to sample the bile. Patients were given either a single oral dose of the silybin-phosphatidylcholine complex or silymarin. The amount of silybin recovered in the bile in free and conjugated form within 48 hours was 11%for the silybin-phosphatidylcholine group and 3% for unmodified ~ilybin.4~ One of the significant features of this study is the fact that silymarin has been shown to improve the solubility of the bile. Because more silybin is being delivered to the liver and gallbladder when the phosphatidylcholine-bound silybin is used, this form is ideal for individuals with gallstones or fatty infiltration of the liver, two conditions characterized by decreased bile solubility. In another study, plasma silybin levels were determined after administration of single oral doses of silybinphosphatidylcholine complex and a similar amount of silymarin to nine healthy volunteers. Although absorption was rapid with both preparations, the bioavailability of the silybin-phosphatidylcholine complex was

Si/ybum marianum (Milk Thistle)

much greater than that of silymarin, as indicated by higher plasma silybin levels at all sampling times after intake of the complex. The researchers in this study concluded that complexation with phosphatidylcholine greatly increases the oral bioavailability of silybin, probably by facilitating its passage across the gastrointestinal m~cosa.~~

Clinical Studies Several clinical studies have shown phosphatidylcholinebound silybin to be more effective. In one study, eight patients with chronic viral hepatitis (three with hepatitis 8, three with both hepatitis B and hepatitis C, and two with hepatitis C) were given one capsule of phosphatidyl-choline-boundsilybin (equivalentto 140 mg silymarin)between meals for 2 months.47After treatment, serum malondialdehyde levels (an indicator of lipid peroxidation) decreased by 36% and the quantitative liver function evaluation, as measured by galactose elimination capacity, increased by 15%. A statistically significant reduction of liver enzymes was also seen: AST diminished by 17%and ALT rose by 16%. In another study designed primarily to evaluate the dose-response relationship of phosphatidylcholinebound silybin, positive effects were again displayed.48 In this study, patients with chronic hepatitis due to either a virus or alcohol were given different doses for 2 weeks: 20 patients received 80 mg twice daily, 20 patients received 120 mg twice daily, and 20 patients received 120 mg three times daily. At all tested doses, phosphatidylcholine-boundsilybin produced a remarkable and statistically significant decrease in mean serum and total bilirubin levels. When used at the dose of 240 or 360 mg/day, it also resulted in a remarkable and statistically significant decrease in the liver enzymes ALT and gamma-glutamyl-transpeptidase (GGTP). These results indicate that even short-term treatment of viral- or alcohol-induced hepatitis with relative low doses of phosphatidylcholine-bound silybin can be effective, but that for the best results, higher doses are needed.

DOSAGE The standard dose of milk thistle is based on its silymarin content (70 to 210 mg three times daily). For this reason, standardized extracts are preferred. The best results are achieved at higher dosages-140 to 210 mg of silymarin three times daily. The dosage for silybin bound to phosphatidylcholine is 120 to 240 mg twice daily. Alcohol-based extracts are virtually always contraindicated in liver disease, because a relatively large amount of alcohol is administered to obtain an adequate dose of silymarin in this form.

TOXICITY Silymarin preparations are widely used medications in Europe, where a considerable body of evidence points to very low toxicity.' When used at high doses for short periods, silymarin given by various routes to mice, rats, rabbits, and dogs has shown no toxic effects. Studies in rats receiving silymarin for protracted periods have also demonstrated a complete lack of toxicity.' Because silymarin possesses choleretic activity, it may produce a looser stool as a result of greater bile flow and secretion. If higher doses are used, it may be appropriate to use bile-sequesteringfiber compounds (e.g., guar gum, pectin, psyllium, oat bran) to prevent mucosal irritation and loose stools. Because of silymarin's lack of toxicity, its long-term use is feasible when necessary.

DRUG INTERACTIONS Although silymarin components have been shown to interact with drug-metabolizing cytochrome PjSO enzymes in in vitro studies, the concentrations showing an inhibitory effects are not achieved with normal dosage recommendations." Clinical studies have shown that coadministration of silymarin with drugs metabolized by enzymes (e.g., indinavir) cause no adverse interaction^.^^,^^

Pharmacology of Natural Medicines

1.Wagner H. Antihepatotoxic flavonoids. In Cody V, Middleton E Jr, Harboume JB, eds. Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure-activity relationships. New York Liss, 1986545-558. 2. Adzet T. Polyphenolic compounds with biological and pharmacclogical activity. Herbs Spices Medicinal Plants 1986;1:167-184. 3. Hikino H, Kiso Y, Wagner H, Fiebig M. Antihepatotoxic actions of flavonolignans from Silybum marianum fruits. Planta Med 19843: 248-250. 4. Wagner H. Plant constituents with antihepatotoxic activity. In Bed JL, Reinhard E, eds. Natural products as medicinal agents. Stuttgart: Hippokrates-Verlag, 1981. 5.Vogel G, Tuchweber B, Trost W, Mengs U. Protection against Amanita phalloides intoxication in beagles. Toxic01Appl Pharm 1984; 73355-362. 6. Seme EH, Toorians AWF, Gietema JA, et al. Amanifa phlloides, a potentially lethal mushroom: its clinical presentation and therapeutic options. Neth J Med 1996;49:19-23. 7.Vogel G, Trost W, Braatz R, et al. [Pharmacodynamics, site and mechanism of action of silymarin, the antihepatoxic principle from Silybum mar. (L.) Gaertn]. Arzneimittelforschung 1975;25:82-89. 8. Poser G. [Experiencein the treatment of chronic hepatopathies with silymarin]. Arzneimittelforschung 1971;21:1209-1212. 9. Palasciano G, Portincasa P, Palmieri V, et al. The effect of silymarin on plasma levels of malondialdehyde in patients receiving longterm treatment with psychotropic drugs. Curr Ther Res 199455: 537-545. 10. Sonnenbichler J, Goldberg M, Hane L, et al. Stimulatory effect of silybinin on the DNA synthesis in partially hepatectomized rat livers: non-response in hepatoma and other malignant cell lines. Biochem Pharmacol1986;3553&541. 11. Sonnenbichler J, Zetl I. Biochemical effects of the flavanolignane silybinin on RNA, protein and DNA synthesis in rat livers. In Cody V, Middleton E, Harboume JB, eds. Plant flavonoids in biology and medicine: biochemical, pharmacological, and s t r u c t u r e activity relationships. New York Liss, 1986:319-331. 12.Fiebrich F, Koch H. Silymarin, an inhibitor of lipoxygenase. Experientia 1979;351548-1550. 13.Fiebrich F, Koch H. Silymarin, an inhibitor of prostaglandin synthetase. Experientia 1979;35:1150-1152. 14. Wilasrusmee C, Kittur S, Shah G, et al. Immunostimulatory effect of Silybum marianum (milk thistle) extract. Med Sci Monit 2002;8: BR439-BR443. 15. Tyagi A, Bhatia N, Condon MS, et al. Antiproliferative and apoptotic effects of silybinin in rat prostate cancer cells. Prostate 200233: 211-217. 16.Kohno H, Tanaka T, Kawabata K, et al. Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethaneinduced colon carcinogenesis in male F344 rats. Int J Cancer 2002;lOl: 461-468. 17. Yanaida Y, Kohno H, Yoshida K, et al. Dietary silymarin suppresses 4nitroquinohe l-oxide-induced tongue carcinogenesis in male F344 rats. Carcinogenesis 2002;23:787-794. 18. Kock HP,Bachner J, Loffler E. Silymarin: potent inhibitor of cyclic AMP phosphodiesterase. Methods Find Exptl Clin Pharmacol 1985;7:409413. 19. Valenzuela A, Barria T, Guerra R, Garrido A. Inhibitory effect of the flavonoid silymarin on the erythrocyte hemolysis induced by phenylhydrazine. Biochem Biophys Res Comm 1985;126712-718. 20. Flemming K. [Therapeutic effect of silymarin on X-irradiated mice]. Arzneimittelforschung 1971;21:1373-1375. 21. Zoltan OT, Gyori I. [Studies on the brain edema of the rat induced by triethyltinsulfate. Part 7 The therapeutic effect of silymarin,

theophylline, and mannitol in the conditioned reflex test]. Arzneimittelforschung 1970;201248-1249. 22. Seeger R. [Effect of silymarin on osmotic resistance of erythrocytes]. Arzneimittelforschung 1971;21:1599-1605. 23. Skottova N, Krecman V. Silymarin as a potential hypocholesterolaemic drug. Physiol Res 1998;471-7. 24. Schopen RD, Lange OK, Panne C, Kimberger EJ. Searching for a new therapeutic principle: experience with hepatic therapeutic agent Legalon. Med Welt 1969;20888-893. 25. Schopen RD, Lange OK. [Therapy of hepatoses: therapeutic use of silymarin]. Med Welt 1970;21:691-698. 26.Canini F, Bartolucci, Cristallini E, et al. [Use of silymarin in the treatment of alcoholic hepatic steatosis]. Clin Ter 1985; 114307-314. 27. Salmi HA, Sama S. Effect of silymarin on chemical, functional, and morphological alteration of the liver: a double-blind controlled study. Scand J Gastroenterol1982;17517-521. 28. Scheiber V, Wohlzogen FX. Analysis of a certain type of 2 x 3 tables, exemplified by biopsy findings in a controlled clinical trial. Int J Clin Pharmacol Biopharm 1978;16:533-535. 29. Boari C, Montanari M, Galleti GP, et al. [Occupational toxic liver diseases: therapeutic effects of silymarin]. Minerva Med 1981; n.2679-2688. 30. Grossi F, Viola F. [Membrane protectors and silymarin in herpatology therapy]. Clin Ter 19819611-23. 31. Maneschi M, Tiberio C, Cittadini E. [Metabolic impairment of the hepatocyte in pregnancy: prevention and therapy with a membranestabilizing drug]. Clin Ter 198197625-630. 32. Bulfoni A, Gobbato F. Evaluation of the therapeutic activity of silymarin in alcoholic hepatology. Gazz Med Ital 1979;138: 597-608. 33. Cavalieri S. A controlled clinical trial of Legalon in 40 patients. Gazz Med Ital 1974;133:62&635. 34. Saba P, Galeone GF, Salvadorini F, et al. Therapeutic effects of silymarin in chronic liver diseases due to psychodrugs. Gazz Med Ital 1976;135236-251. 35. De Martiis M, Fontana M, Sebastiani F, Parenzi A. [Silymarin, a membranotropic drug: clinical and experimental observations]. Clin Ter 1977;81:333-362. 36. Szilard S, Szentgyorgyi D, Demeter I. Protective effect of Legalon in workers exposed to organic solvents. Acta Med Hung 1988;45: 249-256. 37. Ferenci P, Dragosic SB, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol1989;9:105-113. 38. Deak G, Muzes G, Lang I, et al. [Immunomodulator effect of silymarin therapy in chronic alcoholic liver diseases]. Orv Hetil 1990;131:1291-1296. 39. Magliulo E, Gagliardi B, Fiori GP. [Results of a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres]. Med Klin 1978;73:1060-1065. 40.Berenguer J, Carrasco D. Double-blind trial of silymarin versus placebo in the treatment of chronic hepatitis. Munch Med Wochenschr 1977;119:240-260. 41. Nassauto G, Iemmolo RM, Strazzabosco M, et al. Effect of silybinin on biliary lipid composition: experimental and clinical study. J Hepatol 1991;12:290-295. 42. Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs 2001;61:2035-2063. 43. Weber G, Galle K. The liver-a therapeutic target in dermatoses. Med Welt 1983;34:108-111. 44. Gaedeke J, Fels LM, Bokemeyer C, et al. Cisplatin nephrotoxicity and protection by silybinin. Nephrol Dial Transplant 1996;11:56-62.

Silybum marianum (Milk Thistle) 45. Schandalik R, Gatti G, Perucca E. Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients. Arzneimittelforschung 1992;42.964-968. 46. Barzaghi N, Crema F, Gatti G, et al. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidykhohe complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet 1990;15:333-338. 47. Moscarella S, Giusti A, Marra F, et al. Therapeutic and antilipoperoxidant effects of silybin-phosphatidylcholinecomplex in chronic liver disease: preliminary results. Curr Ther Res 1993;53:98-102. 48.Vailati A, Aristia L, Sozze E, et al. Randomized open study of the dose-effect relationship of a short course of IdB 1016

in patients with viral or alcoholic hepatitis. Fitoterapia 1993;64: 219-228. 49. Zuber R, Modriansky M, Dvorak Z, et al. Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 2002;16632-638. 50. DiCenzo R, Shelton M, Jordan K, et al. Coadministration of milk thistle and indinavir in healthy subjects. Pharmacotherapy 2003;23866-870. 51. Piscitelli SC,Formentini E, Burstein AH, et al. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002;22:551-556.

Soy Isoflavones and Other Constituents Kathleen A. Head, ND

JulieS. 3urenka, BS, MT(ASCP) CHAPTER C O N T E N T S Introduction 1259 Chemical Composition 1259 lsoflavones 1259 Other Soy Constituents 1261 Pharmacology 1262 Hormonal Effects in Infants 1262 Hormonal Effects in Adults 1263 Mechanisms of Action of Soy lsoflavones 1265

INTRODUCTION In the past several years, soy and its constituents have received considerable attention, from both researchers and health practitioners. Epidemiologic data indicating that people from Asian cultures have lower rates of certain cancers, including cancer of the breast, prostate, and colon, sparked an interest in soy as a contributing factor. Although soy constituents-saponins, lignans, phytosterols, protease inhibitors, and phytates-have come under investigation, the constituents that seem to hold the most promise from a therapeutic standpoint are the two isoflavones, genistein and daidzein. Numerous epidemiologic, human, animal, and in vitro studies have demonstrated that soy isoflavones are effective chemopreventive agents for certain types of cancer. Mechanisms involved include the following: Antiangiogenesis Estrogen receptor binding Enhanced immune response due to increased interleukin-6 (IL-6) levels Modulation of sex hormone-binding globulin (SHBG) Antiinflammatory and antioxidant effects Inhibition of the enzymes protein tyrosine b a s e (pn<)and 5-alpha-reductase Interaction with many other enzymes has been suggested. Evidence also points to the beneficial effects Portions of this chapter reprinted with permission from Alternative Medicine Review 1997;2:433-450.

Clinical Applications 1265 Cancer 1265 Cardiovascular Disease 1268 Menopause 1269 Osteoporosis 1270 Thyroid Effects 1270 Other Potential Therapeutic Effects

1270

Drug-Nutrient Interactions 1271 Conclusion

1271

of soy, particularly the isoflavones, in prevention of cardiovascular disease. Isoflavones appear to inhibit platelet-activating factor and thrombin formation. They also increase high-density lipoprotein (HDL) cholesterol and decrease triglycerides as well as low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, and total cholesterol. Other potential health benefits of soy are prevention of osteoporosisvia the phytoestrogen effects of isoflavones, alleviation of some menopausal symptoms, possible attenuation of some aspects of cognitive disorders, and prevention of neovascularization in ocular conditions, via inhibition of angiogenesis.

CHEMICAL COMPOSITION Interest in the constituents of soybeans, particularly the isoflavones, has catapulted soy to the status of a promising nutrient with potentially significant health benefits. The principal isoflavones in soy are genistein (4’,5,7trihydroxyisoflavone),daidzein (4’,7-dihydroxyisoflavone) (Figure 126-l), and their metabolites. In addition, soy products are a source of lignans, coumestans, saponins, plant sterols, phytates (inositol hexaphosphate), and protease inhibitors, all of which are also receiving attention for their health-promoting benefits.

lsoflavones Classification Fluvonoids are a subgroup of the larger group of plant constituents, the polyphenols. Flavonoids are further 1259

Pharmacology of Natural Medicines

Approximately 600 isoflavonoids have been identified. They are divided into subclasses according to the oxidation level of the central pyran ring. Isoflavones are the most abundant of the subclasses of isoflavonoids. Genistein and daidzein are two important isoflavones in soy. As can be seen in Figure 126-1, genistein has a hydroxy group in the 5 position, giving it three hydroxy groups, but daidzein has just two. Due to the fact that the 5-hydroxy group on the genistein binds to the 4ketonic oxygen, genistein is a more hydrophobic molecule than daidzein. This gives genistein some of its unique therapeutic effects.

differentiated into isoflavonoids, with isoflavones a subcategory of isoflavonoids (Figure 126-2). Isoflavonoids differ from other classes of flavonoids through having greater structural variability, being frequently present in plants in free form rather than as glycosides, and having a higher frequency of isoprenoid substitution. They are not as ubiquitous in nature as some of the other flavonoids, such as flavones and flavonols, being found primarily in one subfamily of Leguminosae, the Papilionoideae.2

Absorption, Metabolism, and Excretion OH

Figure 126-1

0

Isoflavones undergo extensive metabolism in the intestinal tract prior to absorption. Genistein is formed from biochanin A, and daidzein from formononetin.' Genistein and daidzein also occur in soy products in the form of their glycosides, genistin and daidzin. In the case of the glycosides, intestinal bacterial glucosidases cleave the sugar moieties, releasing the biologically active isoflavones genistein and daidzein. In adults, these are further transformed by bacteria to specific metabolites: equol, 0-desmethylangolensis, dihydrogenistein, and

-OH

Structure of genistein and daidzein.

Polyphenols

I

Enterolactone

Flavones Flavans

Aaphthoquinones

Xanthones Hydroxycinnamic acid Lignans

I

I

I

1

Tannins

Condensed (proanthocyanidins)

Hydrolyzable

,

Flavonones Neoflavonoids

Hydroxybenzoic acid

,

Flavonoids Enterodiol

I

I

I

I

Stilbenes

Flavonols

lsoflavanones

lsoflavonoids

lsoflavans

lsoflavones

Diadzein (from formononetin)

Genistein (from biochanin A)

I

I

metabolized Equol 0-desmethylangolensis Dihydro enestein P-ethjphenol Figure 126-2

I

I

Chalones

Flavonolols

Polyphenol classification.

Anthocyanidins

Catechins

Pterocarpans

Rotenoids

Nonso isoflavones irXone* pratensein) lute one^ (e.g.* prunetin,

Aurons

Soy lsoflavones and Other Constituents

p-ethylphenol. Due to soy intake by livestock, people also consume isoflavone metabolites indirectly if they eat a diet high in dairy products and meat.3 In at least one study, genistein was found to be well absorbed in the small intestines by human subjects fed a soy beverage! After absorption, the isoflavones are transported to the liver, where they are removed from the portal blood. However, a percentage of the isoflavones in the portal blood can escape uptake by the liver and enter the peripheral circulation. The effectiveness of this hepatic first-pass clearance influences the amount that reaches peripheral tissue^.^ The isoflavones are then eliminated, primarily via the kidneys, like endogenous estrogen^.^ After examining plasma, fecal, and urinary concentrations of isoflavones in healthy volunteers, Xu et a16 concluded that the bioavailability of soy isoflavones is influenced by an intact, healthy gut, with microflora capable of converting these isoflavones to their active forms. Wheat fiber appears to reduce the bioavailability of genistein. A small crossover study involving seven healthy women found that a diet higher in fiber resulted in 55% less plasma genistein 24 hours after soy intake and a 20% reduction in total urinary genistein. The researchers postulated that fairly insoluble wheat fiber reduced the absorption of genistein by its bulking effect and hydrophobic binding7 Karr et a18 found urinary excretion of isoflavones to be reflective of the type and amount of soy ingested. A study conducted on healthy male subjects (age 20 to 40 years) found that urinary excretion of genistein and daidzein was greater after consumption of 112 g of tempeh, a fermented soy product, than after 125 g of unfermented soy piece^.^ This finding seems to indicate that fermentation of soy products increases bioavailability of the isoflavones. Plasma levels of soy isoflavones are also higher after consumption of soy and certain other leguminous plants, such as clover.1°

Isoflavone Content of Soy Products Fukutake et all1analyzed soy products for genistein and genistin content; their results are outlined in Table 126-1.

- -

I

In general, they found that fermented soy products contain more genistein than soybeans, soy milk, and tofu. Alcohol extraction, a process used in the production of many soy protein concentrates and isolates (used in soy protein powders), results in the removal of up to 90%of the isoflavones.12 The isoflavone content of soybeans varies considerably, depending on the variety of soybean (there are more than 10,000 varieties of soybeans), the year harvested, geographic location, and the plant part in question.I3Nonsoy legumes, such as lentils and other beans, do not contain appreciable amounts of isoflav~nes.'~

Other Soy Constituents Protease Inhibitors Researchers have looked with interest at protease inhibitors (PIS)and their potential anticancer and antiinflammatory effects. Two prominent protease inhibitors from soybeans are Bowman-Birk inhibitor (BBI) and Kunitz-Trypsin inhibitor (KTI). BBI is a 71-residue inhibitor that has two independent inhibitory sites involving binding with the proteases, trypsin, and ~hymotrypsin.'~ BBI has been found to inhibit expression of certain oncogenes in irradiated animal models16 and to inhibit chemically induced carcin~genesis.'~J~ Both in vitro and in vivo animal models have demonstrated that BBI appears to exert its effects directly on the target organ rather than nonspecifically affecting rnetab~lisrn.~~~~~ Some researchers have hypothesized that the dietary intake of exogenous PISindirectly increases endogenous PI formation.*' Other researchers have questioned the concept that PIScontribute significantly to the anticancer effectsof soy. This is due, in part, to the fact that raw and cooked soy products are equally effective in reducing cancer incidence even though heating destroys virtually all PI activity? Another reason for skepticism is that ingested PIS (such as purified BBI) are very poorly absorbed from the digestive tract.22Some investigators have postulated that the formation of these proteaseprotease inhibitor complexes might interfere with protein absorption, offering some protection against cancer

Levels of genistein and its glycoside, genistin, in soy foods

Foods

Genistein

Genistin

Soybeans, soy nuts, soy powder

4.6-18.2 ps/g'

200.6-968.1 pg/g*

Soy milk, tofu

1.9-13.9 pg/g

94.8-137.7 ps/g

Fermented soy miso and nattot

38.5-229.1ps/g

71.7-492.8 ps/g

Calculated daily Japanese dietary intake

1.5-4.1 rndday

6.3-8.3 rnglday

Modified from Fukutake M, Takahashi M, lshida K, et al. Food Chem Toxic01 1996;34:457-461. '@g raw food. +Soy sauce contains both genistein and genistin, but at lower levels than other fermented soy products.

Pharmacology of Natural Medicines (epidemiologic studies indicate that high-fat, highprotein diets raise cancer risk).u Protease inhibitors in soy products have been implicated in pancreatic hypertrophy and hyperplasia in animal models.” Whether it is the protease inhibitors and whether this hyperplasia contributes to increased rates of pancreatic cancer in these animals are still subjects of debate.

Lignans Lignans are capable of exerting a phytoestrogenic effect in humans. In addition, they exhibit antitumor and antiviral activity.2 The most prevalent lignans in mammals are enterolactone and enterodiol, which are formed by gut bacteria from the plant precursor lignans matairesinol and secoisolariciresinol, re~pectively.~ Oil seeds, such as flaxseed, have about 100 times the lignan content of other plants. Other sources of lignans, in descending order of importance, are dried seaweed, whole legumes (including soy), cereal bran, legume hulls, whole-grain cereals, vegetables, and fruit.’ Gender differences in urinary lignan excretion have been observed, with men excreting more enterolactone and less enterodiol than women. The researchers believed that this finding implied a difference in colonic bacterial metabolism of lignans between the genders.25 Administration of antibiotics nearly completely eliminates the formation of these mammalian lignans from their precursor^.^

Phytosterols Phytosterols, such as beta-sitosterol, are found in high concentrations in soy products. Although poorly absorbed, they bind cholesterol in the Dietary content of phytosterols differs widely among populations. The typical Western diet contains about 80 mg/day of phytosterols, whereas the traditional Japanese diet contains approximately 400

Coumestans The phytoestrogen coumestrol and other coumestan isoflavonoids have been found by some researchers in significant quantities in soy foods of all types.28On the other hand, Adlercreutz and MazuIj report its presence only in soy sprouts. The most abundant source is mung bean sprouts. Coumestan is also found in significant quantities in other members of the Leguminosae family, including Trifolium and Medicago ~ p p . ~

Saponins Saponins are distributed widely in the plant h g d o m , including in soybeans. They appear to have anticancer properties by virtue of their antioxidant and antimutagenic proper tie^.^^ They also bind cholesterol and bile

acids in the gut.22An in vitro study demonstrated that saponins isolated from soybeans exhibited potent antiviral effects on the human immunodeficiency virus (HIV). Saponin B1 completely inhibited HIV-induced cytopathic changes and virus-specific antigen expression within 6 days of infection. Saponin B2 exhibited similar, although less potent, effects.30

Phytates Although phytic acid (inositol hexaphosphate) has been implicated in blocking the absorption of minerals, the phytate content of plants, including soy, seems to be responsible for some of the anticancer properties of vegetable-based foods. Phytic acid is a highly charged antioxidant, capable of scavenging hydroxyl radicals and chelating metal ions such as the prooxidant iron. Graf and Eaton3I reported the iron-chelating ability of phytate to be more important than the fiber in prevention of dietary colon cancer. Vucenik et aP2reported antitumor effects of phytic acid both in vitro and in animal models. Phytates also appear to enhance natural killer cell activity.33Rao et al” found that these potent antioxidant effects protect against cardiac ischemia and reperfusion injury in animal models. For a summary of soy constituents and their functions, see Table 126-2.

PHARMACOLOGY Soy constituents have been shown to have estrogenic, antiestrogenic, anticarcin~genic,”~~ bacteriocidal, and antifungaP9effects. Isoflavones also have antimutagenic?’ a n t i ~ x i d a n t , ~mild , ~ ’ antiinflammatory,42 and antiproliferative effect^.^^,^^ This chapter focuses primarily on isoflavones because they are the constituents found in greatest quantity in soy products.

Hormonal Effects in Infants Advances in understanding of the phytoestrogen content of soy foods have led researchers to examine the isoflavone content in commonly consumed infant formulas. One study examined the isoflavone content of 25 randomly selected samples from five major brands of soy-based infant formula^.^ There were significant levels of isoflavones, particularly in the form of the glycosides of genistein and daidzein, in all samples tested. The plasma concentrations of genistein and daidzein were compared in 4-month-old infants fed exclusively soy formula, cow‘s milk formula, and breast milk. A 4-monthold infant consuming soy milk was estimated to be ingesting between 4.5 and 8.0 mg/kg body weight per day of total isoflavones. This is a proportionately greater concentration per body weight than that found in adults consuming soy foods.

Soy lsoflavones and Other Constituents

Constituent

Function

Protease inhibitors (Bowman-Birk inhibitor, Kunitz-Trypsin inhibitor)

Inhibit oncogene expression Inhibit chemically induced carcinogenesis Implicated in pancreatic hypertrophy (animal studies)

Lignans (enterolactone, enterodiol)

Phytoestrogen effects (agonistic/antagonistic) Antitumor Antiviral

Phytosterols, beta-sitosterol

Binds cholesterol in the gut

Coumestans (coumestrol)

Phytoestrogen effects (agonistic/antagonistic) Antioxidant Bind cholesterol and bile acids in the gut Antiviral (human immunodeficiency virus)

Saponins

Phytates

Antioxidant Chelate metal ions (e.g., iron) Enhance natural killer cell activity

lsoflavones (genestein, daidzein, and their metabolites)

Phytoestrogen effects (agonisticJantagonistic) Antimutagenic Antioxidant Antiinflammatory Antiproliferative Antihypertensive Angiogenesis inhibition

Additionally, the researchers estimated that the daily exposure of infants to soy isoflavones was 6 to 11times higher, with body weight factored into the equation, than the typical dose necessary to exert hormone-like effects in adults. They found negligible concentrations of isoflavones in breast milk and cow’s milk.5 There was some evidence of the daidzein metabolite equol in the infants who were fed cow’s milk, confirming previous observations that cow‘s milk also contains some isoflavones. In this study, the plasma concentration of isoflavones in breast-fed babies was l/200 the level in soy-formula-fed babies. Franke and Custer,44however, reported in 1996 that human breast milk from mothers consuming soy foods provided significant levels of isoflavones. Some researchers have concluded that the isoflavone content of human breast milk appears to be a reflection of the mother ’s diet. These findings have raised some interesting questions and stimulated lively debate. Adverse effects of phytoestrogens on development and reproductive capacity of livestock, wildlife, and experimental animals have been reported.45There has been very little clinical experience with human infants and phytoestrogens, however.

In animal models, phytoestrogens have had effects similar to those of other estrogens, including interference with normal reproductive system development.&On the other hand, phytoestrogenic isoflavones have been found to possess some important anticancer properties. Genistein, given in only three doses to newborn mice, decreased breast cancer incidence and tumor numbers significantly.44Although millions of Asians have consumed large quantities of soy foods for hundreds of years without any apparent health risk and seemingly with health benefits, long-term studies are needed to clardy the safety of using soy-based infant formulas and to assess the potential beneficial or adverse effects of consuming phytoestrogens in the form of soy isoflavones early in life.

Hormonal Effects in Adults Plant lignan and isoflavonoid glycosides are converted by gut bacteria in the intestines to compounds with molecular weights and structures similar to those of steroid hormones (Figure 126-3).The pattern of isoflavonoid and lignan excretion in the urine is similar to that seen with endogenous estrogens!’ Studies of the effects of phytoestrogens on hormone levels are conflicting. Lu et a P found that the consumption of soy products by premenopausal women resulted in decreased circulating ovarian steroids and adrenal androgens as well as longer menstrual cycles. Six healthy females, age 22 to 29 years, were given 12 ounces of soy milk three times daily with meals for 1month. Daily isoflavone intake was approximately 100 mg each of daidzein and genistein (in the form of their glycosides, daidzin and genistin). The estradiol levels diminished by 31% on days 5 to 7 of the menstrual cycle, by 81% on days 12 to 14, and 49% on days 20 to 22. Luteal phase progesterone levels decreased by 35%, and dehydroepiandrosterone sulfate (DHEAS) levels decreased progressively during the month by 14% to 30%. The length of the menstrual cycle increased during the soy feeding month from 28.3 k 1.9 to 31.8 x 5.1 days. In a second group of 68 premenopausal women given 40 mg genistein daily for only 12 weeks, the menstrual cycle lengthened by 3.52 days and the follicular phase by 1.46 days. Levels of serum hormone-binding globulin, free estradiol, and estrone were also in~reased.4~ In another study of premenopausal women, Cassidy et a150 found that 60 g of soy protein, with 45 mg of isoflavones daily, resulted in the suppression of midcycle surges of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Plasma concentrations of estradiol rose during the follicular phase in the soy group, whereas cholesterol values decreased by 9.6%. The researchers noted that a similar effect occurs in women given tamoxifen. There were no significant differences in estradiol levels between the soy and control

0

Estriol HO Figure 126-3

Structure of soy isoflavones compared with estrogens.

groups at midcycle or during the luteal phase.w At least one study reported soy protein isolate to have a stimulatory effect on breast tissue in premenopausal women, characterized by increased breast secretions, epithelial cell hyperplasia, and elevations of serum estradi01.~~ Wang et a152 found that genistein competed with the binding estradiol of to estrogen receptors, with 50% M. inhibition occurring at 5 x A study in which postmenopausal women received soy supplementation found a small estrogenic effect on vaginal cytology. However, no difference between soy-supplemented subjects and controls, with regard to serum levels of FSH, LH, sex hormone-binding globulin, endogenous estradiol or body weight, was 0bserved.5~ A double-blind, placebo-controlled trial of 94 healthy postmenopausal women was conducted in which women received either 118 mg soy isoflavones daily or a casein placebo for 3 months. Both groups reported improvements in libido, amount of facial hair, and dry skin, but the women in the soy treatment group also reported a significant improvement in vaginal dryness that was not seen in the placebo group.% Many studies of phytoestrogens focus on the use of coumestrol, because it has more potent phytoestrogenic effects than lignans, genistein, and daidzein. In vitro studies have found that both genistein and coumestrol inhibit the conversion of estrone to 17-beta estradiol. Coumestrol exhibited the strongest i n h i b i t i ~ n .An ~~ in vitro study monitoring the expression of the estrogenresponsive protein pS2 in breast cancer cell MCF-7 tissue culture, to assess the estrogenic response of various

plant substances, found that the following substances elicited estrogen-like activity: Daidzein Equol Nordihydroguaiaretic acid Enterolactone Kaempferol The substances tested that did not appear to have estrogen-like activity were quercetin and enterodi01.~~ The effects of phytoestrogens vary greatly according to the species of animal, the particular phytoestrogen compound being tested, the age of the animal, the duration of ingestion, the presence or absence of exogenous estrogen, the target tissue in question, and the dosage used. The phytoestrogen coumestrol was found to have an estrogenic effect, as demonstrated by changes in uterine and brain tissue, when given to prepubescent rats; however, when it was given to adult female rats, ovarian cycling was mhibited. When coumestrol was given for 10 days to neonatal rats, there was no effect on estrous cycling, but when given for 21 days, it interfered with normal cycling once the rats reached adulthood. The females exlubited persistent estrous and lack of an LH surge, and the males demonstrated a decrease in sexual behavior.57 Historically, the consumption of soy products in Asian cultures from a very young age has not had any apparent negative effects related to hormone imbalances. It is unlikely that animal studies are effective at predicting the effects of phytoestrogens in the human

Soy lsoflavones and Other Constituents

The mechanism for the antiestrogenic effect of phytoestrogens are largely unknown, but some experts believe it is unlikely to be a direct receptor-mediated e f f e ~ t .One ~ mechanism of action of lignans and isoflavonoids is to stimulate synthesis of sex hormonebinding globulin (SHGB; also known as sex steroidbinding protein) in the liver. SHBG binds to cell surface receptors, resulting in regulation of bioavailability and activity of hormone^.^ An in vitro study in MCF-7 human breast cancer cells, found that SHBG downregulated estradi01.~~ Phytoestrogens appear to exert mild agonistic and antagonistic effects on estrogen, depending on the level of endogenous estrogen present and on the tissue being tested. In vitro studies demonstrate an estrogenic effect in the absence of endogenous estrogen, and an antiestrogenic effect in the presence of estrogen? Much research in this area remains to be done. Much of the effect of phytoestrogens might be due to enzyme inhibitions. Phytoestrogens apparently have an inhibitory effect on many enzymes involved in the biosynthesis and metabolism of steroid hormones. The effect on enzymes is further discussed later.

Mechanism of Action of Soy lsoflavones The many proposed mechanisms for the therapeutic effects of isoflavones include the following: Inhibition of PTK Binding of estrogen receptors (although soy's inhibition of cancer cell growth does not seem to be entirely estrogen dependent)'jO Inhibition of production of reactive oxygen species'jl Induction of DNA strand breakage resulting in apoptosis or cell death60 Inhibition of angiogenesis'j2 Modulation of SHBGa Inhibition of 5-alpha-reductaseH Inhibition of P-form phenolsulfotransferase (PST)mediated sulfation6 Inhibition of thrombin formation and platelet activation6'j Increased LDL receptor activiV7 The therapeutic implications of each of these mechanisms is elaborated in the next section.

CLINICAL APPLICATIONS Cancer The first clues that soy diets might provide protection from cancer came from epidemiologic studies, in which people from Asian cultures eating a diet high in soy foods such as tofu demonstrated lower rates of several types of cancers, including types not typically considered to be related to hormones or diet. Messina et a16*

reviewed 21 epidemiologic studies that evaluated the effect of soy diets on 26 different cancer sites. An evaluation of the effect of nonfermented soy products in these studies found that 10 showed decreased risks for rectal, stomach, breast, prostate, colon, and lung cancers, and 15 showed no sigruficant effect. Only one, in which fried bean curd was evaluated, showed an increased risk for esophageal cancer. On the other hand, the effects of fermented soy products-miso soup and soybean pastewere much less consistent. In 21 studies evaluating fermented soy products involving 25 cancer sites, a higher cancer risk was found in 4, mixed results were obtained in 4, no significant effects were found in 14, and a decreased risk was found in 3. The higher risks of cancer from consumption of fermented soy products appear to involve primarily the gastrointestinal tractesophageal, stomach, colorectal, and pancreatic cancers.'j6These studies are summarized in Table 126-3. A community-based prospective study of more than 30,000 Japanese adults (35 years and older) was conducted over 7 years. Data on soy and isoflavone intake from food frequency questionnaires determined that men in the highest tertile of soy intake had a significant inverse risk of death from stomach cancer. The same was seen in women, although the inverse association was of marginal significance. These results suggest that soy intake may reduce the risk of death from stomach cancer.'j9 Citing several other findings will put the epidemiologic studies into some perspective. Adlercreutz et a170 found high urinary excretion of the soy isoflavones equol, daidzein, and 0-desmethylangolensin, in both men and women living in rural Japan. Most soy foods contain about 1 to 2 mg genistein per g of soy. In Asian cultures people tend to consume 20 to 80 mg/day. The usual dietary intake of genistein in Western cultures is 2 to 3 mg/day. Messina et a1& examined 26 animal studies and reported that 17 (65%) of them demonstrated a protective effect of soy against experimental carcinogenesis. There are many proposed mechanisms for the anticancer benefits of soy-based foods. Inhibition of PTK activity has been proposed as a major mechanism in the prevention of carcinogenesis. Although synthetic PTK inhibitors have been proposed for the treatment of cancer, expected toxicity has restricted their development. In 1987, genistein was discovered to be a natural PTK inhibitor.6oTyrosine kinase inhibition results in the inhibition of leukotriene production (products of inflammation implicated in the stimulation of tumor growth). In vitro studies found that pretreatment of cancer cell lines with genistein completely inhibited leukotriene prod~ction.~~ Influence on a number of other enzymes has been suggested as a possible mechanism for the anticancer

Summary of epidemiologic studies of soy and cancer

Cancer location

Fermented misolsoybean paste

Unfermented tofuhean curd

Breast (five studies)

1. Risk

5. Risk

Other soy products

2.Risk, premenopausal No effect, postmenopausal 3. Risk 4.No significant effect' 1. No significant effect 2. No significant effect

Prostate (three studies)

3. No significant effect

3. No significant effect Colorectal (six studies)

1. No significant association* 2. Risk (colon) 3. Risk (rectal) 5.No significant association

3. No significant association 4. Risk (not significant) 6. Risk (rectal, colon, not significant)

3. No significant association 5. Risk (rectal, not colon)

Lung (four studies)

1. No significant association

1. No significant association 2. Risk 3. Risk

4. Risk (soy in general)

Stomach (16 studies)

1. Risk (miso) 1. No effect (bean paste) 2. Risk (not significant) 3. No significant association 4. Risk (soybean paste) 5. Risk (miso) 6. Risk 7. Risk 8.No significant association 9. No significant association 10. Risk

Esophageal (two studies)

1. Risk (males; no effect in females)

Gallbladderbile duct (two studies)

1. No significant effect (all soy products) 2. Risk (bile duct, not significant) No effect (gallbladder)

Liver (one study)

1. No significant association

1. Risk

2.Risk 3. Risk (not significant) 12. Risk 14. No significant association

1. No significant association

1. No effect (soybean, fried curd) 11. Risk (soybean) 13. Risk (soy milk) 15. No significant association (nonmiso soy products) 16. Risk (soy milk, other soy products)

2. Risk (fried bean curd)

1. Risk

Pancreatic (one study) ~~

From Messina MJ, Persky V, Setchell KD. Barnes S Nutr Cancer 1994;21.113-131. 'Type of soy not reported

In vitro studies have found genistein to be a very properties of isoflavones. Some of the enzymes are DNA to poi some rase^,^,^^ ribosomal S6 kinase activity,'4 phos- potent inhibitor of neovascularization or angiogenesis, pholipase C - g a m n ~ a ,phosphatidylinositol ~~ k i n a ~ e s , ~ ~one of the proposed mechanisms for cancer growth inhibition.62Isoflavone's effects on hormone regulation, and mitogen-activated protein kinase.n In addition, expression, and metabolism have been elaborated previgenistein demonstrated in vitro inhibition of phenolsulously and are discussed further in the sections on breast fotransferase, an enzyme involved in sulfation-induced and prostate cancer. carcinogensis.@j At issue in the study of soy isoflavones in the treatJenkins et a178also showed that in postmenopausal, women high levels of isoflavone intake appear to raise ment of cancer is whether the concentration achieved by dietary consumption of soy products is enough to influserum concentrations of IL-6, an effect that in turn may enhance immune surveillance, resulting in lower ence tumor growth. Studies on human volunteers conincidence of certain cancers in soy-eating parts of the suming soy beverages, which provided 42 mg genistein and 27 mg daidzein daily, resulted in peripheral blood ~orld.'~

Soy lsoflavones and Other Constituents concentrations of 0.5 to 1.0 pM,4 a concentration much lower than that necessary to inhibit growth of cultured cancer cells.79 However, the same researchers found nontransformed mammary epithelial cell cultures to be much more sensitive to genistein, with inhibition of growth stimulation occurring in the range of 1 to 2 pM. This finding suggests a role for isoflavones in chemoprevention rather than as chemotherapeutic agents.

Breast Cancer Case-controlled, epidemiologic, in vitro, and animal studies point to the effectiveness of soy isoflavones in the prevention of breast cancer. One case-controlled study examined the effect of phytoestrogens on breast cancer risk, pairing 144 women who had early diagnoses of breast cancer with controls matched for age and area of residency. Before treatment, a questionnaire and 72-hour urine and blood tests were administered. Urine was assayed for the isoflavones daidzein, genistein, and equol as well as for the lignans enterodiol, enterolactone, and matairesinol. Adjustments were made for age at menarche, parity, and alcohol and total fat intake. Increased excretion of daidzein, equol, and enterolactone was associated with a reduction in the risk for development of breast cancer. The most significant correlation was between the levels of the soy isoflavone equol and the risk of breast cancer, with subjects in the highest quartile of equol excretion exhibiting only one-quarter the risk of those in the lowest quartile-a fourfold reduction in risk. The lignan enterolactone and the isoflavone daidzein were associated with a threefold reduction in risk. The daidzein results were insignificant after correction for confounding variables. Similar trends were noted for both premenopausal and postmenopausal groups. Unfortunately, no reliable data for genistein were available owing to instability of the derivative of genistein being tested and interference by an unknown compound.@' Two case-controlled studies, one conducted in Singapore8Iand one in found sigruficant protection from soy intake for premenopausal but not postmenopausal women. Epidemiologic studies demonstrate an inverse relationship between soy intake and incidence of breast cancer (see Table 126-3). Americans have two to three times the breast cancer rate of Asians eating a traditional Asian diet.83An epidemiologic study of Asian-American women found tofu intake to correlate inversely with breast cancer incidence, after adjustment for other dietary, menstrual, and reproductive factors.84 This effect was observed in both premenopausal and postmenopausal women. A case-controlled study of 1095 Asian-Americans in Los Angeles County, CA, found that breast cancer risk was sigruficantly inversely associated with soy intake during both adolescence and adult life.

Median soy intake in the study group was 12 mg isoflavones daily? In summary, all five of the human studies examined seemed to indicate a protective effect of soy against breast cancer in premenopausal women. The effect on postmenopausal women was significant in two of the five studies. In vitro experiments with human breast cancer cells confirm genistein to be a potent inhibitor of cell growth regardless of estrogen receptor status. Other isoflavones, daidzein and biochanin A, demonstrated weaker growth inhibition.- Pagliacci et aP9 reported that the in vitro inhibition of MCF-7 human breast cancer cells occurred through blocks at critical points in cell cycle control as well as via induction of apoptosis. Wang et a152found that genistein had a concentration-dependent effect on breast cancer cell cultures. At lower concentrations (1o-S to 10-6M), genistein stimulated growth, whereas at it inhibited growth. The higher concentrations (>lP5), researchers concluded that the effect of genistein at the lower concentrations appeared to be estrogen receptormediated but that the effects at higher concentrations were independent of estrogen receptors. Genistein, when administered to neonatalg0or prepubescent rats?l suppressed the development of chemically induced mammary tumors without causing toxicity to the development of the endocrine or reproductive systems. Barnes et a192found that soy in the form of raw soybeans as well as soy protein isolate inhibited mammary tumors in experimental models.

Prostate Cancer Epidemiologicevidence points to the benefits of soy constituents in the prevention of prostate cancer. Japanese men who consume a low-fat, high-soy diet have low mortality rates from prostate cancer. Isoflavones in the plasma of Japanese men were between 7 and 110 times higher than in Finnish men, with genistein present in the highest ~oncentrations.9~ Suggested mechanisms of protection include genistein-induced prostate cancer cell adhesion, direct growth inhibition, and induction of apoptosis. Growth inhibition appears to be independent of genistein's estrogenic effe~ts.9~ An in vitro study indicated that the isoflavones genistein, biochanin A, and equol were potent inhibitors of 5-alpha-reductase,@the enzyme necessary for conversion of testosterone to dihydrotestosterone (implicated in prostate cancer). Studies have found that animals fed soy isolates high in the isoflavones genistein and daidzein demonstrated a lower incidence of prostate cancer and a 27% longer disease-free period after exposure to chemical carcinogens than animals fed a soy isolate low in is0flavones.9~ This finding not only points to the potential chemoprotectiveeffects of soy but seems to highlight the importance of the isoflavones over other soy constituents.

Pharmacology of Natural Medicines Peterson and Barnes96found that the isoflavones genistein and biochanin A, but not daidzein, inhibited several human prostate cancer cell lines.

National Institutes of Health Recommendations The committee of the National Institutes of Health (NIH) studying chemoprevention from soy products made the following recommendations: Future dietary studies involving soybeans should use soy products rather than isolated compounds, because soybeans appear to contain several potential anticarcinogens. Standardized and improved analytical methods are needed so that the contents of all soy-based materials employed in soybean research, whether soybean fractions or soy products, can be accurately described. Basic research in the absorption, metabolism, and physiology of potential anticarcinogens in humans should be conducted.

Cardiovascular Disease Studies of monkeys have confirmed the cardioprotective effects of soy. Soy protein diets, compared with casein diets, resulted in significant improvements in lipid profiles and insulin sensitivity and a decrease in arterial lipid per~xidation.~~ Furthermore, animal studies indicate that the isoflavone content of the soy is an important factor. In addition to reducing elevations of blood cholesterol, isolated soy protein may decrease oxidation of LDL cholesterol, impede the formation of arteryblocking blood clots, improve dilator response in arteries already exhibiting plaque formation, reduce restenosis after balloon angioplasty, and generally decrease atheroscler~sis.~~~~

Lipid-Lowering Effects A large meta-analysis of 38 controlled studies comparing soy- and animal-protein diets found a statistically significant decrease in serum lipids in the soy group. The changes were most significant in subjects with

hypercholesterolemia (Table 126-4).99The intakes of energy, total fat, saturated fat, and cholesterol were similar in the two groups. Gooderham et allm reported no effect on platelet aggregation or serum lipid levels in healthy, normocholesterolemic men fed soy protein in comparison with casein. One of the proposed mechanisms for the hypoEpidemic effect involves an increase in LDL receptor activity in both humans and animal^.^' Other metabolic changes that have been noted in animals and humans on soy diets are increases in bile acid synthesis and apolipoprotein B and E receptor activity, and a decrease in hepatic secretion of lipoproteins (associated with greater clearance of cholesterol from the blood stream).lo1 Proposals for the specific constituents involved include the amino acid profile, saponins, phytic acid, and fiber as well as the effects of isoflavones discussed later.lo1 In one study, monkeys were fed soy isolates high in isoflavones and results were compared in a crossover trial with those of a soy isolate in which the isoflavones had been removed via alcohol extraction. Serum LDL and VLDL levels and ratio of total to HDL cholesterol were significantly lowered, but HDL levels were significantly elevated in the group consuming the isoflavonerich diet.12 No lipid-lowering effect occurred in a third group on a casein diet. Two separate clinical trials completed in 2002 demonstrated the beneficial effects of soy isoflavones on lipid profiles in humans. Uesugi et all0*demonstrated that in healthy perimenopausal women, 61.8 mg soy isoflavones daily resulted in sigruficant decreases in total and LDL cholesterol.102Another study involved 41 hyperlipidemic men and postmenopausal women who were given one of three diets for 4 weeks: a low-soy isoflavone diet (10 mg isoflavones daily), a high-soy isoflavone diet (73 mg isoflavones daily), or a control diet of low-fat dairy food. Examination of the results found no significant differences between the lowand high-isoflavone diets. Both soy diets, however, resulted in significantly lower calculated coronary artery disease risk, total cholesterol level, and ratios of total to HDL cholesterol, LDL to HDL cholesterol, and

Results of a metaanalysis of the effects on serum lipids of soy-protein diet in comparison with meat-protein diet LiDid

Sov diet

Meat Drotein diet

Total cholesterol

23.2 mg/dl decrease

9.3% decrease

Low-density lipoprotein cholesterol

21.7 mg/dl decrease

12.9% decrease

Trig1ycerides

13.3 mg/dl decrease

10.5% decrease

High-density lipoprotein cholesterol

1.2 mg/dl increase (not significant)

2.4% increase

Modifiedfrom Anderson JW, Johnstone BM, Cook-NewellME. N Engl J Med 1995;333:276-282.

Soy lsoflavones and Other Constituents

of soy milk consumption (isoflavonecontent unknown) on hypertension. Three months of soy milk consumption resulted in decreases in diastolic, systolic, and mean blood pressure values compared with those in subjects in a cow's milk (placebo) group. Urinary genistein measurements showed significant association with the decrease in blood pressure, particularly for the diastolic values, suggesting a hypotensive effect of isoflav~nes.'~~ In a previously cited study measuring the effects of soy isoflavones on lipid values and blood pressure, a significant hypotensive effect was seen in men consuming soy isoflavone diets.lo3

apolipoprotein B to apolipoprotein A-1 compared with placebo. No significant sex differences were observed, with the exception of systolic blood pressure, which was significantly lower in men, but not women, eating the soy diets.lo3 In Finland 60 patients in a primary care clinic were enrolled in a double-blind, placebo-controlled, 6-week trial. Patients in the treatment group received Abacor, a product based on isolated soy protein, in addition to their regular diet. Although the soy isoflavone content was not noted, the Abacor diet sigruficantly reduced both total and LDL cholesterol levels.'04

Effects on the Atherosclerotic Process

Menopause

Arterial thrombus formation is generally initiated by an injury to the endothelial cells lining the blood vessels. One of the first events after an injury is thrombin formation. This leads to a cascade of events including platelet activation and resulting in thrombus formation. Genistein has been found to inhibit thrombin formation and platelet activation.&The pathogenesis of atherosclerotic plaque formation involves, in addition to lipid accumulation, the infiltration of monocytes and T lymphocytes into the artery wall, which contributes to the thickening of the wall and eventual occlusion of the vessel. Monocytes and lymphocytes are able to adhere to the endothelial cell surfaces via the expression of certain "adhesion molecules." The infiltration and proliferation appear to be controlled by peptide growth factors. Increased levels of isoflavones, genistein in particular, appear to alter the platelet growth factor activity and to inhibit cell adhesion and proliferation, all activities necessary for lesion formation in the intima of the blood vessels (Figure 126-4).98

A review of clinical trials studying the effects of soy isoflavones on menopausal symptoms yielded mixed results. Observational data indicate that Japanese women, who consume 50 to 100 times greater amounts of soy isoflavones than women consuming Western diets, have a nearly tenfold lower incidence of vasomotor symptoms, such as hot flashes.lo6In a 2-month study 20 menopausal women were given a daily soy drink containing 80 mg soy isoflavones. A significant decline in hot flashes, compared with the placebo group given a casein drink, was observed. The soy group also exhibited lower total cholesterol and LH levels and higher prolactin and growth hormone levels.107 A double-blind Brazilian study of 80 menopausal women showed that 100 mg soy isoflavone daily for 4 months resulted in a decrease in menopausal symptoms as measured by endogenous hormone levels. An additional benefit was a sigruficant decrease in LDL and total cholesterol.lo8 Conversely, other studies have not shown soy isoflavone consumption to be of benefit in reducing menopausal symptoms. In a double-blind, placebocontrolled study of 94 healthy menopausal women, Kotsopoulos et a P found that soy isoflavone supplementation consisting of 118 mg daily did not provide

Hypotensive Effects Dietary soy may help modulate blood pressure. One double-blind randomized trial of 40 men and women with mild to moderate hypertension examined the effect

Thrombus formation

Infiltrationand proliferation of monocytes and T-lymphocytes

xxx

+

.1 XXX

T

Inhibits thrombus formation Flgure 126-4

Atheroscleroticplaque

Lipid accumulation

Inhibits proliferation and adhesion to vessel walls

+xxx

T

Improves lipid profile Impact of soy on atherosclerotic plaque formation.

Pharmacology of Natural Medicines

signhcant symptomatic relief compared with placebo. The one parameter that yielded positive results was a decrease in vaginal dryness.54Furthermore, a study conducted in 123 postmenopausal women with moderate hot flushes did not show benefit of soy consumption. Fifty-nine of the women consuming a soy beverage containing 90 mg isoflavones for 12 weeks, and the remaining 64 received a rice beverage. There was no difference in hot flashes between the soy and rice beverage groups.’Og

Osteoporosis An animal study indicated that soy isolates may enhance bone density. Ovariectomized rats fed a high-soy diet demonstrated enhanced bone density of the vertebral bodies and femoral bone compared with the group fed a casein diet. Although there was considerable bone turnover in the soy-fed group, bone densities suggest that formation exceeded resorption.”” A review of research over the past 35 years showed that genistein, which appears to bind estrogen receptors, stimulates protein synthesis in osteoblast cell lines in vitro.”’ Clinical studies of the effect of soy isoflavone’s on bone density have confirmed a protective effect in older women but not in healthy younger women. One study involving 208 postmenopausal women examined the effect of dietary soy on markers of bone turnover over 1 year. Examination of both markers of bone resorption and bone formation showed that women with the highest level of isoflavone consumption possessed greater spinal bone density.112A community-based cohort study found that premenopausal, but not perimenopausal, Japanese-American women with genistein intake in the highest tertile had higher spinal and femoral bone mineral density than women in the lowest tertile.lI3 However, a clinical trial in which 28 young, healthy, menstruating women were given 90 mg soy isoflavones daily for 12 months found no differences in bone mineral content or bone mineral density compared with the control group (receiving soy protein with isoflavones rem~ved).”~

Thyroid Effects Emerging epidemiologic and pathologic data suggest that thyroid cancer may be an estrogen-dependent disease. A popula tion-based, case-controlled study conducted in the San Francisco Bay area examined 817 cases of thyroid cancer diagnosed between 1992 and 1998. The study concluded that intake of the isoflavones daidzein and genistein in soy-based food and alfalfa sprouts was associated with a lower risk of thyroid cancer. Findings were similar for both white and Asian women and for premenopausal and postmenopausal women.115 The effect of soy isoflavones on thyroid hormone levels was studied in 73 hypercholesterolemic, postmenopausal women in a 6-month, double-blind trial.

Patients were assigned to one of three diets: control (casein from nonfat dry milk), isolated soy protein containing 56 mg isoflavones, and isolated soy protein containing 90 mg isoflavones. Slight rises were observed in thyroid hormone levels in both groups consuming soy diets compared with placebo. Results did not, however, provide evidence of changes in a variety of other endogenous hormones, including estrogens, DHEAS,and i n ~ u l i n . ” ~ On the other hand, there is some evidence that soy isoflavone supplementation may inhibit thyroid funct i ~ and n ~cause ~ ~ diet-induced goiter. In vitro analysis found that both daidzein and genistein blocked iodination of tyrosine and that genistein inhibited thyroxine synthesis.118A study of 37 healthy Japanese adults demonstrated that 30 g per day of soybeans for 3 months led to a slight elevation in thyroid-stimulating hormone (TSH)values.119Another study from Cornell University’s Department of Pediatrics also found that the frequency of feedings with soy-based formulas early in life was significantly higher in children with autoimmune thyroid disease (31%) than in siblings (12%) and unrelated controls (130/,).120

Other Potential Therapeutic Effects Although research on the health benefits of soy constituents has focused primarily on the chemopreventive effects for cancer, cardiovascular disease, and women’s health issues, a few other conditions might benefit from the addition of soy isoflavones to the diet.

Eye Disorders Neovascularization complicates many eye disorders, such as proliferative diabetic retinopathy, and is responsible for corneal transplant rejection. Substances that exhibit the capacity to inhibit angiogenesis could play an important role in preventing this vascularization. An animal study demonstrated that genistein, when injected subconjunctivally, inhibited corneal neovascularization.Iz1Although this was not a human study with the use of oral doses, the findings open the door for future investigation.

Cognitive Function Studies examining the effect of soy intake on cognitive function are limited, and results have varied. However, preliminary animal studies indicate that soy isoflavones may attenuate hyperphosphorylation of the tau protein, a hallmark of Alzheimer’s disease and several other human dementias.l’ On the other hand, an analysis from a large longitudinal study of 764 elderly men, originally conducted to assess diet, heart disease, stroke, and cancer, demonstrated that poor cognitive performance, enlargement of ventricles, and low brain weight were sigrulicantly and independently associated with high

Soy lsoflavones and Other Constituents levels of midlife tofu consumption. Although it is unclear which soy constituents in the tofu were responsible for these results, these findings suggest a need for further study.123

inhibition of dysplastic and malignant epithelial breast cancer cells. The addition of tamoxifen to the cell cultures had a synergistic and additive effect that was independent of estrogen receptor status.12'

DRUG-NUTRIENT INTERACTIONS

CONCLUSION

Dietary supplementation of soy protein concurrent with oral levothyroxine therapy appears to decrease absorption of levothyroxine and lead to the need for higher oral dosing to achieve therapeutic levels of free thyroxine (T4) and TSH. Temporal separation of levothyroxine intake and soy protein supplements results in suppressive serum levels of T4 and TSH with lower doses of levothyro~ine.~~~ Genistein has been shown to inhibit breast cancer cell growth in vitro at doses of 10 pM or above. In a model of estrogen receptor-positive postmenopausal breast cancer, lower doses of genistein have been shown to inhibit the therapeutic effects of tamoxifen therapy.'= An animal study demonstrated that tamoxifen suppression of breast tumor growth in ovariectomized athymic mice was negated by the administration of 1000 ppm dietary genistein.'26 Therefore, postmenopausal women undergoing tamoxifen therapy for estrogen-responsive breast cancer should use caution when consuming dietary genistein. However, in contrast, another in vitro study of genistein (doses of 1 to 10 pg/ml) showed growth

Research indicates that soy and its individual constituents have several potential health benefits. The primary isoflavones, genistein and daidzein, as well as their metabolites exert a wide array of effects that may offer protection against cancer, cardiovascular disease, and osteoporosis. Soy and its constituents also appear to have therapeutic applications in menopause and ocular neovascularization. Whether soy has a negative or positive effect on thyroid and cognitive functions remains to be elucidated. Many of the studies to date have been epidemiologic, animal, or in vitro. Controlled human trials are emerging, and some confirm the preliminary findings reported in earlier studies. Soy constituents, particularly the isoflavones, have come under scrutiny owing to their phytoestrogen effects. Because in some cases they act as estrogen agonists, and in others as antagonists, the use of these isoflavones in patients with cancer and in infant formulas remains controversial. Further study to determine whether their use in these situations is harmful or beneficial is indicated.

1. Knight DC,Eden JA. A review of the clinical effects of phytoestrogens. Obstet Gynecol1996;87897-904. 2. Harbone JB, Baxter H, eds. Phytochemical dictionary. Basingstoke, England: Burgess Science Press, 1995. 3. Adlercreutz H, Mazur W. Phyto-oestrogens and Western diseases. Ann Med 1997;29:95-120. 4. Barnes S, Sfakianos J, Coward L, Kirk M. Soy isoflavonoids and

11. Fukutake M, Takahashi M, Ishida K, et al. Quantification of genistein and genistin in soybeans and soybean products. Food Chem Toxic01 1996;34:457-461. 12. Anthony MS, Clarkson TB, Hughes CL Jr, et al. Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys. J Nutr 1996;12643-50. 13. Messina M, Barnes S. The role of soy products in reducing risk of cancer. J Natl Cancer Inst 1991;83541-546. 14.Franke A. Isoflavone content of breast milk and soy formulas: benefits and risks. Clin Chem 1997;43850-851. 15. Hatano K, Kojima M, Tanokura M, Takahashi K. Solution structure of bromelain inhibitor IV from pineapple stem. Structural similarity with Bowman-Birk trypsin/chymotrypsin inhibitor from soybean. Biochemistry 1996;30:5379-5384. 1 6 . 9 Clair WH, St Clair DK. Effect of the Bowman-Birk protease inhibitor on the expression of oncogenes in the irradiated rat colon. Cancer Res 1991;51:4539-4543. 17. St Clair WH, Billings PC, Carew JA, et al. Suppression of dimethylhydrazine-induced carcinogenesis in mice by dietary addition of the Bowman-Birk protease inhibitor. Cancer Res 1990;50: 580-586. 18. Messadi DV, Billings,'F Shklar G, Kennedy AR. Inhibition of oral carcinogenesis by a protease inhibitor. J Natl Cancer Inst 1986;76 447-452. 19. Oreffo VI, Billings PC, Kennedy AR, Witschi H. Acute effects of the Bowman-Birk protease inhibitor in mice. Toxicology 1991;69: 165-176.

cancer prevention. Underlying biochemical and pharmacological issues. Adv Exp Med Biol1996;401:87-100. 5. Setchell KD, Zimmer-Nechemias L, Cai J, Heubi p.Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet 1997;350:23-27. 6.Xu X, Harris KS, Wang HJ, et al. Bioavailability of soybean isoflavones depends upon gut microflora in women. J Nutr 1995;125:2307-2315. 7. Tew BY, Xu X, Wang KJ, et al. A diet high in wheat fiber decreases the bioavailability of soybean isoflavones in a single meal fed to women. J Nutr 1996;126871-877. 8. Karr SC,Lampe JW, Hutchins AM, Slavin JL. Urinary isoflavonoid excretion is dose dependent at low to moderate levels of soyprotein consumption. Am J Clin Nutr 1997;6646-51. Urinary isoflavonoid phyto9. Hutchins AM, Slavin JL, Lampe JW. estrogen and lignan excretion after consumption of fermented and unfermented soy products. J Am Diet Assoc 1995;95:545-551. 10. Morton MS, Wilcox G, Wahlqvist ML, Griffiths K. Determination of lignans and isoflavonoids in human female plasma following dietary supplementation. J Endocrinol 1994;142:251-259.

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85. Wu AH, Wan P, Hankin J, et al. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Carcinogenesis 2002;23:1491-1496. 86. Peterson G, Barnes S. Genistein inhibition of the growth of human breast cancer cells: independence from estrogen receptors and the multi-drug resistance gene. Biochem Biophys Res Commun 1991;179:661-667. 87. Peterson G, Barnes S. Genistein inhibits both estrogen and growth factor-stimulated proliferation of human breast cancer cells. Cell Growth Differ 1996;71345-1351. 88. Peterson TG, Coward L, Kirk M, et al. The role of metabolism in mammary epithelial cell growth inhibition by the isoflavones genistein and biochanin A. Carcinogenesis 1996;171861-1869. 89. Pagliacci MC, Smacchia M, Migliorati G, et al. Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. Eur J Cancer 1994;30A:1675-1682. 90. Lamartiniere CA, Moore J, Holland M, Barnes S. Neonatal genistein chemoprevents mammary cancer. Proc Soc Exp Biol Med 1995; 208:120-123. 91. Murrill WB, Brown NM, B a n g JX, et al. Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats. Carcinogenesis 1996;171451-1457. 92. Barnes S, Grubbs C, Setchell K, Carlson J. Soybeans inhibit mammary tumors in models of breast cancer. Prog Clin Biol Res 1990;347239-253. 93. Adlercreutz H, Markkanen H, Watanabe S. Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 1993;342:1209-1210. 94. Kyle E, Neckers L, Takimoto C, et al. Genistein-induced apoptosis of prostate cancer cells is preceded by a specific decrease in focal adhesion kinase activity. Mol Pharmacol1997;51:193-200. 95. Pollard M, Luckert PH. Influence of isoflavones in soy protein isolates on development of induced prostate-related cancers in L-W rats. Nutr Cancer 1997;28:41-45. 96.Peterson G, Barnes S. Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. Prostate 1993;22335-345. 97. Wagner JD, Cefalu WT, Anthony MS, et al. Dietary soy protein and estrogen replacement therapy improve cardiovascular risk factors and decrease aortic cholesteryl ester content in ovariectomized cynomolgus monkeys. Metabolism 1997;46:698-705. 98. Raines EW, Ross R. Biology of atherosclerotic plaque formation. Possible role of growth factors in lesion development and the potential impact of soy. J Nutr 1995;125:S624S630. 99. Anderson JW, Johnstone BM, Cook-Newel1 ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995;333:276-282. 100. Gooderham MH, Adlercreutz H, q a l a ST, et al. A soy protein isolate rich in genistein and daidzein and its effects on plasma isoflavone concentrations, platelet aggregation, blood lipids and fatty acid composition of plasma phospholipid in normal men. J Nutr 1996;1262000-2006. 101. Potter SM. Overview of proposed mechanisms for the hypocholesterolemic effect of soy. J Nutr 1995;125S606-5611. 102. Uesugi T, Fukui Y, Yamori Y. Beneficial effects of soybean isoflavone supplementation on bone metabolism and serum lipids in postmenopausal Japanese women: a four-week study. J Am Coll Nutr 2002;21:97-102. 103. Jenkins DJ, Kendall CW, Jackson CJ, et al. Effects of high- and lowisoflavone soyfoods on blood lipids, oxidized LDL, homocysteine, and blood pressure in hyperlipidemic men and women. Am J Clin Nutr 2002;76:365-372. 104. Puska P, Korpelainen V, Hoie LH, et al. Soy in hypercholesterolemia: a double-blind, placebo-controlled trial. Eur J C l i Nutr 2002;56:352-357.

Pharmacology of Natural Medicines 105.Rivas M, Garay RP, Escanero JF, et al. Soy milk lowers blood pressure in men and women with mild to moderate essential hypertension. J Nutr 2002;1321900-1902. 106. Brzezinski A, Adlercreutz H, Shaoul R, et al. Short-term effects of phytoestrogens-rich diet on postmenopausal women. Menopause 1997;4:89-94. 107. McMichael-Phillips DF, Harding C, Morton M, et al. Effects of soyprotein supplementation on epithelial proliferation in the histologically normal human breast. Am J Clin Nutr 1998;68: 1431S1435S. 108. Han KK, Soares JM Jr, Haidar MA, et al. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol 200299389-394. 109.Van Patten CL, Olivotto LA, Chambers GK, et al. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial. J Clin Oncol 2002;201449-1455. 110. Aqmandi BH, Alekel L, Hollis BW, et al. Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis. J Nutr 1996;126161-167. 111. Albertazzi P. Purified phytoestrogens in postmenopausal bone health: is there a role for genistein? Climacteric 2002;5:190-196. 112. Kritz-Silverstein D, Goodman-Gmen DL. Usual dietary isoflavone intake, bone mineral density, and bone metabolism in postmenopausal women. J Womens Health Gend Based Med 2002;11:69-78. 113. Greendale GA, FitzGerald G, Huang WI, et al. Dietary soy isoflavones and bone mineral density: results from the study of women’s health across the nation. Am J Epidemiol2002;155:7&754. 114. Anderson JJ, Chen X, Boass A, et al. Soy isoflavones: no effects on bone mineral content and bone mineral density in healthy, menstruating young adult women after one year. J Am Coll Nutr 2002;21:388-393. 115. Horn-Ross PL, Hoggatt KJ, Lee MM. Phytwstrogens and thyroid cancer risk the San Francisco Bay Area thyroid cancer study. Cancer Epidemiol Biomarkers Prev 2002;11:4-49.

116. Persky VW, Turyk ME, Wang L, et al. Effect of soy protein on endogenous hormones in postmenopausal women. Am J Clin Nutr 2002;75:145-153. 117. Doerge DR, Sheehan DM. Goitrogenic and estrogenic activity of soy isoflavones. Environ Health Perspect 2002;1105349-S353. 118. Divi RL, Chang HC, Doerge DR. Anti-thyroid isoflavones from soybean: isolation, characterization, and mechanisms of action. Biochem Pharmacol1997;54:1087-1096. 119. Ishizuki Y, Hirooka Y, Murata Y, Togashi K. [The effects on the thyroid gland of soybeans administered experimentally in healthy subjects.] Nippon Naibunpi Gakkai Zasshi 1991;67622-629. 120. Fort P, Moses N,Fasano M, et al. Breast and soy-formula feedings in early infancy and the prevalence of autoimmune thyroid disease in children. J Am Coll Nutr 1990;9164-167. 121. Kruse FE, Joussen AM, Fotsis T, et al. [Inhibition of neovascularization of the eye by dietary factors exemplified by isoflavonoids.] Ophthalmologie 1997;94:152-156. 122. Kim H, Xia H, Li L, Gewin J. Attenuation of neurodegenerationrelevant modifications of brain proteins by dietary soy. Biofactors 2000;12243-250. 123. White LR, Petrovitch H, Ross GW, et al. Brain aging and midlife tofu consumption. J Am Coll Nutr 2OOO;19:242-255. 124. Bell DS, Ovalle F. Use of soy protein supplement and resultant need for increased dose of levothyroxine. Endocr Prad 2001;7 193-194. 125. Jones JL, Daley BJ, Enderson BL, et al. Genistein inhibits tamoxifen effects on cell proliferation and cell cycle arrest in T47D breast cancer cells. Am Surg 2002;68:575-577. 126. Ju YH, Doerge DR, Allred KF, et al. Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice. Cancer Res 2002;62:2474-2477. 127. Tanos V, Brzezinski A, Drize 0,et al. Synergistic inhibitory effects of genistein and tamoxifen on human dysplastic and malignant epithelial breast cells in vitro. Eur J Obstet Gynecol Reprod Biol 2001;102:188-194.

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements Alexander G . Schauss, PhD, FACN CHAPTER C O N T E N T S Introduction 1275 The Recommended Daily Allowances 1275 The Need for a Guideline to Optimal Intake Levels of Nutrients 1277 The Development of Suggested Optimum Nutrient Intakes 1277 Revelations from the Birmingham Study 1278 Survey Questionnaire for Suggested Optimum Nutrient Intake 1278

INTRODUCTION In 1998, the Food and Nutrition Board of the U.S. Institute of Medicine recommended that to reduce the likelihood of neural tube defects offspring, women should eat a varied diet and take an extra 400 vg of folic acid to be absolutely sure that they get enough of the nutrient.* Further, the Board found that “the evidence for a protective effect from folate supplements is much stronger than for food folate.”’ That the public should use a dietary supplement, not just food, to ensure that they are consuming the necessary level of a nutrient to prevent a disease or condition is nothing less than a paradigm shift in official public health policy concerning the issue of nutrient supplementation. In recent years a convincing link between the intake of folic acid and neural tube defects has been established. As a result the National Institutes of Health and U.S. Department of Health and Human Services gave special attention to the need for folic acid in the diet in the prevention of such neural tube defects as spina bifida Folic acid is but one of the B vitamins that has been the subject of research on the role nutrients play in the prevention, mitigation, or treatment of cancers, cardiovascular diseases, mental disorders, and other diseases and condition^."'^ For example, researchers are continuing to unravel the association between levels of folate, pyridoxine (vitamin B6), and inositol and the reduction ?p3

Dietary Supplementation: An Idea Whose Time Has Come? 1279 The Suggested Optimum Nutrient Intakes 1279 Fat-Soluble Vitamins 1280 Water-Soluble Vitamins 1284 Minerals 1290

of excessive levels of blood homocysteine, a marker associated with the risk for cardiovascular disease. This chapter discusses the daily suggested optimal nutrient intake (SONI) of nutrients necessary to maintain health and reduce the risk of disease. The conclusion I have reached for each nutrient is based on a review of thousands of epidemiologic, clinical, and experimental papers, offering evidence for optimal versus minimal intake levels to maintain health and reduce the risk of disease in humans of 27 vitamins, minerals, and trace elements.

The Recommended Daily Allowances Since the mid-l940s, the U.S. Recommended Daily Allowances (RDAs) have served as a nutritional guideline.I3These guidelines were developed from minimalist criteria aimed solely at the prevention of nutritionally related clinical deficiencies. In the late 1990s the RDAs were gradually replaced with new nutritional guidelines, the Recommended Daily Intakes (RDIs).’~Curiously, the RDIs show no more promise than the RDAs did in providing the public with useful information on the intake of nutrients in the prevention, mitigation, and treatment of a wide range of conditions and diseases for which diet does or may play a role. Hence, it is worthwhile to understand the limits of the RDAs and RDIs to fully appreciate the need for SONIs. Because our understanding of the optimal level of each nutrient in the prevention, mitigation, and treatment of disease

1275

Pharmacology of Natural Medicines

remains a somewhat primitive science, the discussion is framed around the concept of SONIs. As our understanding of the role of each nutrient in disease processes becomes more sophisticated, the values for the SONIs are certain to change, yet they certainly provide us better guidelines to maintain health than the minimalist basis from which the RDAs were constructed.

The History In May 1941, a committee of the National Academy of Sciences (NAS) suggested for the first time that a ”Recommended Daily Dietary Allowance” of essential nutrients be established. These guidelines were developed with the goal of reducing the incidence of nutritional deficiency diseases in the general population such as scurvy (deficiency of vitamin C), pellagra (deficiency of niacin), and beriberi (deficiency of vitamin BJ. Over time, nutritionists, dietitians, and physicians have relied on the RDAs, through nine revisions, as a guideline for advising public health officials and the public about recommended nutrient intake levels. According to the committee that established them, RDAs were intended (1) as guidelines for the prevention of nutritional deficiencies and (2) to be related to the nutrient status of population groups, not individuals. In essence, the RDAs provide no information on the role of nutrients in the prevention, amelioration, or treatment of conditions or diseases.

The Weaknesses A common mistake made by many public health practitioners is to use the RDAs to evaluate the adequacy of an individual‘s diet. Even worse is the assumption that maintaining a diet that provides an RDA level of nutrients will somehow ensure wellness over an individual’s lifetime. Only recently has it become apparent that “healthy normal people” are an ideal population group to study. Among Americans 60 years and older, more than 80% suffer from at least one or more chronic diseases, such as cancer, atherosclerosis, osteoporosis, macular degeneration, osteoarthritis, rheumatoid arthritis, diabetes, and hypertension, and age-related degenerative diseases, such as presbycusis (hearing loss). Since at least 1951, critics of the RDA have asserted that the RDA’s lack the abillty to recommend levels of nutrients sufficient to maintain health for a person seeking a healthy lifespan that is associated with a morbidity-free existence. Studies that have been used to determine the level of a nutrient sufficient to prevent a nutritional deficiency is typically conducted for only 6 to 9 months, about 1% of the average person‘s lifespan. This fact suggests that these minimalist dietary standards are based on data incapable of determining levels of nutrients essential to prevent many conditions and diseases associated with morbidity over a lifetime.

Even more germane to this issue is the attention focused in recent years on the role of substances not generally recognized as nutrients that appear to be directly involved in the prevention or mitigation of a diverse host of diseases from colon cancer to coronary heart disease, cataracts, birth defects, and stroke. Early editions of the RDAs, published in the 1940s, clearly stated that the RDAs “vary greatly in disease.” In spite of this realization, the RDAs continued to focus only on the prevention of nutritional deficiencies in population groups. This focus began to change in 1989 with the release of the tenth edition of the RDA by the National Academy of Sciences. The tenth edition acknowledged for the first time that levels of a nutrient, specifically the nutrient vitamin C, may need to be higher than the RDA for groups at risk for development of chronic diseases, particularly smokers. This recommendation opened the door to an entirely new paradigm, namely, the determination of optimal nutrient intake levels to minimize the risk of development of conditions and diseases affecting various population groups (i.e., women at risk for birth defects). Unfortunately, the NAS’s noble attempt to keep up with the science of nutrition continues to be inadequate because of its minimalist foundation. A higher level of vitamin C intake for smokers is in indeed suggested in the tenth edition, but studies of smokers‘ blood levels of vitamins and minerals have shown that levels of other nutrients, such as beta-carotene, zinc, vitamin Bb and vitamin E, also may have to be significantly higher than that recommended for vitamin C or prescribed by the RDAs. Mounting evidence suggests that all of these nutrients, not just vitamin C, and probably many other nutrients and nonnutritive substances found in food, may have to be taken by smokers to compensate for the nutrient loss their habit produces. Chromium intake is another area in which the RDAs fall short. The RDA for chromium is 35 pg/day for adult men. Clinical trials have confirmed the safety of up to loo0 pg/day of supplemental chromium. Hence, individuals consuming diets containing less then 50 pg/day of chromium might benefit from a supplement containing an additional 200 to 500 pg/day to reduce the risk of type 2 diabetes while helping maintain normal blood glucose levels, because of chromium’s role in insulin regulation. The RDAs also fail to address the excessive use of alcohol, yet another example of a common addiction that raises nutrient requirements. Individuals who habitually consume excessive amounts of alcohol have been found to have lower levels of folate, vitamin BI, vitamin B6, vitamin A, beta-carotene, zinc, and vitamin C. The lifestyles of individuals are also neglected in the RDA. Dieters, for example, commonly consume inadequate levels of nutrients. Studies have shown that it is extremely difficult, if not impossible, for someone

Suggested Optimum Nutrient intake of Vitamins, Minerals, and Trace Elements

consuming less than 1200 calories/day to meet the RDAs. An analysis of 11major reducing diets shows that none can provide 100% of the RDAs for vitamins. What about individuals with eating disorders (i.e., bulimia nervosa)? Individuals who work under conditions of chronic stress? Individuals who smoke cigarettes? People who get insufficient vitamin D from sunlight or have darker skin pigmentation and need more vitamin D to reduce cancer risk? We have come to realize that people with habits or lifestyles require nutrient levels well above those recommended by the RDAs. It is important to understand the limits of the RDAs and to appreciate the potential benefits of higher nutrient intake levels, when prudent. Box 127-1 outlines seven limitations of the RDAs as dietary intake guidelines in the prevention of conditions and diseases that affect the quality of life, morbidity, and mortality. Item number 7 on the list found in Box 127-1 is an important point. It identifies the folly of relying on RDAs or the most recent guideline, the RDI, as a yardstick to determine safe or adequate intake of a nutrient. There is no known toxicity associated with vitamin B12. The adult RDA for vitamin BIZ is 2 to 2.5 pg/day. Conventional foods such as liver provide nearly 100 pg of this vitamin per 100-g serving, more than 40 times the RDA! Would we recommend that individuals should avoid eating liver because it contains so much vitamin B12 (cobalamin)? Yet for decades the RDAs have been used by critics of dietary supplementation as a tool to warn people that nutrient intakes higher than RDA levels are not safe and may actually have serious adverse effects. If the level of various nutrients in foods can be significantly higher than the RDAs, why support this

1. They are meant to serve as a guideline for the prevention

of nutritional diseases, not the promotion of health. 2. The recommendations are based on the nutrient status of large

population groups numbering in the millions, not as a guideline to determine individual dietary-nutrient requirements. 3. The estimates of the RDAs are based only on short-term research that represents less than 1% of the average person’s life span, so they cannot provide nutrient recommendations that may be of benefit over a lifetime in the prevention or amelioration of diseases associated with aging or certain life styles. 4. They do not make adjustmentsfor variations in nutrient needs associatedwith conditions or diseases that affect nutrient requirements. 5. They provide no data on compensatory levels of nutrient intake needed to compensate for nutrient-demanding lifestyle factors such as: chronic stress, chronic intense exercise, cigarette smoking, alcoholism, restrictive dieting routines, polluted environments, exposure to chemical carcinogens, etc. 6. They neither define nor identify a safety limit for total or supplemental nutrient intake. 7. They do not relate to levels of nutrients found in food.

minimalistic approach to nutrient intake levels? And why do so for more than 50 years? Especially in the face of mounting evidence, for almost all of the nutrients for which an RDA has been set, that higher levels may prevent, mitigate, or treat a wide range of diseases? Each discussion of vitamin, mineral or trace element, has a separate titled section in the reference list. Although it is a standard practice to report the latest studies on a subject in the scientific literature, I have intentionally included references to papers several decades old to illustrate how long ago our knowledge about the benefits of these nutrients above the RDA was gained. These historical references place the concept of suggested optimal nutrient intakes in perspective.

The Need for a Guideline to Optimal Intake Levels of Nutrients A growing body of evidence indicates that intakes of certain vitamins and minerals at levels well above the RDAs may be necessary to protect against the development of certain conditions and diseases that affect the quality of life and/or lifespan. For example, antioxidants such as vitamin C, beta-carotene, vitamin E, and selenium may prevent free radical damage to vascular endothelial cells associated with the most common form of cardiovascular disease, atherosclerosis. These vitamins and minerals may be required in much higher amounts to prevent atherosclerosis than the RDAs, which were determined to prevent deficiency symptomsunless, of course, the development of atherosclerosis is a symptom of vitamin/mineral deficiencies, a concept well worth exploring. The same might be said of many cancers, heart disease, birth defects, eye diseases (e.g., macular degeneration and cataracts), hearing loss, diabetes, and other maladies and diseases.

The Development of Suggested Optimum Nutrient Intakes As a result of numerous epidemiologic, clinical, and experimental studies, it is now possible to create SON1 levels for the vitamins, minerals, and trace elements essential to health. Nearly 20 years ago, an effort was made by Drs. Cheraskin and Ringsdorf at the University of Alabama School of Medicine in Birmingham to establish optimum nutrient intake levels. Their prospective study of the intake levels of vitamins and minerals in humans spanned 15 years. They examined the dietary intake and physiologic levels of nutrients in more than 13,500 subjects, male and female, living in six diverse regions of the United States. The results of their multimillion dollar study was compiled into 153 volumes containing more than 49,000 pages of data. Only a small but sigruficant portion of their findings were ever released. A series of some 100 research papers

Pharmacology of Natural Medicines were published during a 20-year span ending in the early 1990s, but it seems that their work has been neglected because it is rarely cited in the literature. Cheraskin and Ringsdorf 's research, with the assistance of specialists in various disciplines, investigated the health status of study participants through a timeconsuming evaluation of each person's health status over a 15-year period. Each subject completed the following tests and procedures: 1. The 195-item Cornell Medical Index Health Questionnaire (CMI) 2. Physical and anthropometric measurements 3. Dental examination 4. Eye examination 5. Cardiac function tests, including an electroencephalogram (EEG) 6. Glucose tolerance test (GTT) 7. Panel of 50 blood chemistry analyses 8. A comprehensive study of the diet, including a study of food intake over 7 days This study attempted to find evidence whether there existed an "ideal" combination of macronutrients, micronutrients, carbohydrates, protein, and fat that would suggest which nutrients contributed to health and longevity, and at what level. The hypothesis of the study was that relatively symptomless and disease-free individuals are healthier than those with clinical symptoms and signs and that this difference was due to the intake of nutrients from the diet and/or dietary supplementation. Of course, any study, even one involving some 13,500 subjects studied prospectively in six diverse geographical regions over 15 years has inherent weaknesses and shortcomings. But it remains the only study of its nature that made its findings available to researchers to analyze and mine for data on what optimal nutrient levels in humans living in a Western culture might be.

Revelations from the Birmingham Study Cheraskin and Ringsdorf's 15-year study of 13,500 subjects found that the healthiest individuals, meaning those with the fewest clinical symptoms and signs over the life of the study, were those who had consumed dietary supplements and eaten a diet nutritionally dense in nutrients relative to their caloric intake. Nutritional density of the diet proved to be a key variable among the healthiest subjects. For example, Cheraskin and Ringsdorf discovered that the "healthiest" subjects had a mean vitamin C intake of 410 mg/day, a good portion of which was consumed in food and the balance from supplementation. The finding of a vitamin C intake just above 400 mg/day is particularly interesting in light of anthropologic evidence of vitamin C intake in preagricultural ancestral diets studied by coprologists. One study found that humans living before the dawn of agriculture (before 10,000 BC)

consumed approximately 392 mg of vitamin C a day on the basis of the composition of their diet, well above the 60 mg level suggested by the RDAs. (These and many other studies are cited in the relevant vitamin and mineral discussion sections that follow.) The Birmingham Study results for vitamin C represents only a 4% difference in daily vitamin C intake between humans living today and those who lived more than 12,000 years ago. Equally intriguing is emerging evidence that cancer and other chronic diseases of modern civilization are relatively rare in ancestral humans, who lived before the advent of agriculture.Could the higher intake of vitamin C and other nutrients in primitive diets be related to the lower incidence of such chronic degenerative diseases? This is a question that may take years to resolve, but it does warrant research interest, especially given what we now know about vitamin C. Epidemiologic evidence of a protective effect of vitamin C for non-hormone-dependent cancers is strong, according to a 1991 National Cancer Institute report. Of the 46 studies in which dietary vitamin C was calculated, 33 found statistically significant protection against cancer, with the highest vitamin C intake conferring the most protection. Of 29 additional studies that assessed fruit intake, 21 found significant protection. For cancers of the esophagus, larynx, oral cavity, and pancreas, evidence for a protective effect of vitamin C or some component in fruit ( e g , polyphenols, flavonoids, and carotenoids) remained strong and consistent. For cancers of the stomach, rectum, breast, and cervix there has also emerged strong evidence of a protective effect against these cancers. Several recent lung cancer studies, for example, have found evidence suggesting a protective effect of vitamin C. Therefore the concept of an "ideal" level or SON1 of 410 mg of vitamin C or more per day may not be out of line, even though it is more than four times higher than the RDA or the more recently created RDI." The evidence in support of vitamin C at higher intake levels, along with similar findings for other nutrients such as selenium and chromium, suggests that the RDAs and RDIs may represent the nutritional equivalent of the minimum wage. Clearly, if the emerging research suggesting a preventive role and even mitigative role for higher nutrient intake levels is correct, there is a profound need for a new paradigm to replace the minimalistic and outmoded RDAs and RDIs. SONI represents an estimate of the vitamin and mineral intake levels that may reduce the risk of maladies and diseases that impair our ability to function or remain healthy or that increase the risk of various diseases.

Survey Questionnaire for Suggested Optimum Nutrient Intake The following questions can serve as a guideline to determine whether higher nutrient requirements than the RDAs/RDIs for an individual are warranted.

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements If the patient answers "yes" to any of the 16 items listed, the SONI that follows in the next section of this chapter may be of benefit in determining a reasonable and safe daily intake of the respective nutrient. It should be noted that for each question in the questionnaire there exists a reasonable body of scientific evidence to support that a nutrient intake of some vitamins and/or minerals above the RDAs is worth considering.

1. Are you under chronic emotional stress? 2. Do you have frequent colds and flus (more than 3 per year)? 3. Do you wish to reduce your risk for development of cardiovascular disease? 4. Do you wish to reduce your risk for development of cancer? 5. Do you wish to reduce your risk for development of 0steoporosis? 6. Do you wish to reduce your risk for development of macular degeneration of the eye? 7. Do you have skin problems? 8. Do you smoke cigarettes? 9. Are you regularly exposed to sidestream smoke at home or work? 10. Do you frequently drink alcohol? 11. Do you take birth control pills? 12. Are you pregnant? 13. Are you older than 50 years? 14. Are you postmenopausal? 15. Do you exercise more than three times a week for 1 hour at a time? 16. Is the air you breath polluted?

Dietary Supplementation: An Idea WhoseTime Has Come? In June 2002, the Journal of the American Medical Association (JAMA) published a two-part paper by two researchers associated with Harvard Medical School that sparked widespread media attenti~n.'~,'~ The abstract of that paper reads as follows: Vitamin deficiency syndromes such as SCUNY and beriberi are uncommon in Western societies. However, suboptimal intake of some vitamins, above levels causing classic vitamin deficiency, is a risk factor for chronic diseases and common in the general population, especially the elderly. Suboptimal folic acid levels, along with suboptimal levels of vitamins B, and B1= are a risk factor for cardiovascular disease, neural tube defects, and colon and breast cancer; low levels of vitamin D contribute to osteopenia and fractures; and low levels of the antioxidant vitamins (vitamins A, E, and C) may increase risk for several chronic diseases. Most people do not consume an optimal amount of all vitamins by diet alone. Pending strong evidence of effectiveness from randomized trials, it appears prudent for all adults to take vitamin supplements. The evidence base for tailoring the contents of multivitamins to specific characteristics of patients such as age, sex, and physical

activity and for testing vitamin levels to guide specific supplementation practices is limited. Physicians should make specific efforts to learn about their patients' use of vitamins to ensure that they are taking vitamins they should, such as folate supplementation for women in the childbearing years, and avoiding dangerous practices such as high doses of vitamin A during pregnancy or massive doses of fat-soluble vitamins at any age.12

This paper is the first report to appear in a leading peer-reviewed medical journals to state that "most people do not consume an optimal amount of all vitamins by diet alone" and that it would be "prudent for all adults to take vitamin supplements."12The IAMA report is the beginning of a paradigm shift in public health thinking on this subject that is long overdue. The health care system can no longer disregard or argue against the mounting evidence that something more than guidelines for preventing nutrient deficiencies are needed. If one looks into the future, it is likely that this shift will take the form of new recommendations that will identify upper limits through risk assessment, rather than by the minimalistic orientation that has been employed to create the RDA and RDI in the past. Even the National Academy of Sciences' Committee on Use of Dietary Reference Intakes at the Institute of Medicine, Food and Nutrition Board, has admitted that since the publication of the tenth and final edition of the RDA in 1989, "there has been a significant expansion and evolution of the research based toward defining functional endpoints that are relevant to the understanding of nutrient requirements and food constituents and their relationship to a number of aspects of human health.""

THE SUGGESTED OPTIMAL NUTRIENT INTAKES The section that follows is divided into various nutrients according to categories. A SONI is provided on the basis of my review of the literature for each nutrient. The evaluation of the literature began with submission of the first edition of this work, nearly 10 years ago, and is an ongoing project. The format for each nutrient is identical, allowing the reader to contrast the RDA and RDI with the SONI for the nutrient. SONIs are divided by gender and age along the same parameters as the RDAs for easy comparison. Some liberty has been taken with the RDIs to fit them into the same age range as the RDAs for convenience. The recommendations made are based on the median weight and height for each designated age group, as listed in Table 127-1. If the patient's height and weight are significantly higher or lower than the figures found for the age group, the SONI should be adjusted accordingly. Given that the prevalence of overweight and obesity in the United States and many other Western countries has reached critical

Ipopulation of designated age Gender Male

Female

Age (Yr)

Weight (Ib)

Height (in)

15-18

145

69

19-24

160

70

25-50

174

70

51+

170

68

11-14

101

62

15-18

120

64

19-24

128

65

25-50

138

64

51+

143

63

Fat-Soluble Vitamins

Minerals

Carotenedbetacarotene Vitamin A Vitamin D Vitamin E Vitamin K

Boron Calcium Chromium Copper Iodine Iron Magnesium Manganese Phosphorus Potassium Selenium Sodium Vanadium

Water-Soluble Vitamins Ascorbic acid (vitamin C) Cyanocobalamin (vitamin B12) Folic Acid Niacidniacinamide (vitamin B3) Pyridoxine (vitamin B), Riboflavin (vitamin B2) Thiamin (vitamin B,)

7i-e Ic.

LII

levels, it is very likely that the SONI underestimates requirements. The nutrients discussed in the following section are divided into three nutrient classifications with nutrients presented in alphabetical order in each classification (Box 127-2). The reference list is divided in the same way and order. Each nutrient section contains a table listing the following values for each gender and age group: RDA: as defined earlier. EAR: Estimated Average Requirement, the daily intake value that is estimated to meet the requirement, as defined by the specified indicator or criterion of adequacy, in half of the apparently healthy individuals in a life stage or gender group. 0 DRI/RII: DRI is Dietary Reference Intakes; RII is Recommended Intakes for Individuals; a set of reference values for specific nutrients, each category of which has

special uses. The development of the DRIs replaces the reports on RDAs issued periodically from 1941 to 1989; hence those that have not been issued are included in the table but designated as not available (n/a). UL (some tables): Tolerable Upper Intake Level, the maximum level of daily nutrient intake that is likely to pose no risk of adverse effects. The UL represents total intake from food, water, and supplements. SONI: defined earlier; also represents the total intake from food, water, and supplements.

Fat-Soluble Vitamins Vitamin A Vitamin A is a fat-soluble vitamin that is measured as retinol activity equivalents (RAEs). 1RAE = 1 pg retinol, 12 pg beta-carotene, 24 pg alpha-carotene, or 24 pg beta-cryptoxanthin. The RAE for dietary provitamin A caroteinoids is twofold greater than retinol equivalents (RE), whereas the RAE for preformed vitamin A is the same as RE.] To determine the bioavailability of fat-soluble vitamins, one must know the plasma response and plasma clearance curves. The importance of this information has been eloquently demonstrated in a study in which both curves were determined in young and old adults? It was shown that although older individuals had a greater small intestinal absorption of vitamin A, their clearance of the vitamin in circulation was significantly delayed compared with that in young adults. Such factors explain why care must be taken in the consideration of supplementation with vitamin A; once the vitamin in the form of retinyl esters enters the circulation, it can be carried around in the blood for of days, not just hours, eventually building up toxic precursors. Reports of vitamin A toxicity, nevertheless, remain rare, owing to either increasing knowledge about the risks associated with prolonged intake of foods rich in the vitamin or vitamin A-containing supplements or to a lower order of risk than might be suggested by experimental evidence. Estimates of the number of adverse events associated with excessive vitamin A intake are unreliable, especially the adverse events reporting system managed by the U.S. Food and Drug Administration. This system has been criticized by toxicologists and public health officials as an unreliable passive reporting system that lacks validation. Large intake of vitamin A, but not of the provitamin A carotenoids, can cause toxicity, the most serious of which are birth defect^.^ Hence, women of childbearing age should show prudence in taking large amounts of vitamin A without the advice of a health practitioner. Pregnant women should preferentially ingest foods rich in carotenoids or should consume beta-carotene or a mixed carotene supplement to ensure adequate

Suggested Optimum

vitamin A supplies, given the role of vitamin A in cell differentiation. Vitamin A toxicity in adults is uncommon at doses below 100,000 IU/day. If any symptoms of toxicity develop, such as nausea, abdominal cramps, and severe headaches, they will quickly dissipate after vitamin A intake is discontinued. Vitamin A is required for reproduction, embryonic development, maintenance of epithelial tissue (i.e., skin, lung, vagina, uterus, gastrointestinal tract), cell differentiation, and Vitamin A may also play an important role in cancer prevention and the treatment of precancerous conditions. Illness, in particular febrile conditions, and lipid malabsorption can markedly raise vitamin A requirement^.^-'^ Low intakes of vitamins A, C, and E, have been found in premenopausal women diagnosed with breast cancer and in women treated for m e l ~ n o m a . ' ~The J ~ value of vitamin A and associated retinoids in health maintenance has been recognized since the early 198Os.l5 The mean intakes of vitamin A in the United States, based on the NHANES for 1999-2000, were 961 RE and 916 RE, for males and females of all ages, respectively.16 Given the evidence for a protective role for this vitamin, especially against diseases associated with aging,I7 a higher optimal intake level for vitamin A is suggested for all age groups than that recommended by the RDA, EAR or DRI. This suggestion is supported by the 15-year prospective Birmingham Study, which found levels of vitamin A intake higher than the RDA required to support health maintenance (Table 127-2).18

Carotenes and Beta-carotene Carotene is an unsaturated hydrocarbon pigment found in many plants. It is a class of carotenoids that include

Gender

Aae Ivr)

Male

11-14 15-18 19-24 25-50 51+ 11-14 15-18 1 9-24 25-50 51+

Female

RDA

_____

1000 1000 1000 1000 1000 800 800 800 800 800

EAR

DRI/RII

445 630 625 625 625 420 485 500 500 500

600 900 900 900 900 600 700 700 700 700

~ _ _ _ _ _

~~

Ootimal

UL

~

1000 1000 2000 2000 1750 800 800 2000 2000 1800

1700 2800 2000 3000 3000 1700 2800 2000 3000 3000

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DRVRII, Dietary Reference IntakedRecommended Intakes for Individuals;RE, retinol equivalent(s): 1 RE = 1 pg retinol or 6 l g betacarotene; UL, Tolerable Upper Intake Level.

alpha-, beta-, gamma-, and zeta-carotene, which have provitamin A activity. Some carotenes, however, such as lycopene, do not have provitamin A activity. Most carotenes are found in fruits and leafy vegetables. Carotene is thought to assist in trapping light energy for photosynthesis or to aid in reduction-oxidation (redox) reactions; hence its interest to researchers studying antioxidants.'" The main dietary source of vitamin A it is produced by splitting one molecule of carotene into two molecules of vitamin A in either the intestinal wall or the liver, explaining why it is called provitamin A. The absorption of carotene is less efficient than that of vitamin A. The absorption of dietary carotene depends on the action of bile acid. Beta-carotene is a known source of vitamin A, because it is the most nutritionally active vitamin A precursor among the carotenes. Of the nearly 600 carotenoids, a family of natural pigments found in plants and animals, less than 50 are vitamin A precursors like beta-carotene.4 Animal studies have shown that beta-carotene is not mutagenic, teratogenic, embryotoxic, or carcinogenic,nor does it cause hypervitaminosis A (vitamin A t~xicity).~ N o signs of organ toxicity have been found in subacute, subchronic,or chronic oral toxicity studies in experimental animals receiving doses of up to 1000 mg/day betacarotene per kilogram of body weight via the diet. Even synthetic beta-carotene has not been shown to exert any carcinogenic effect in rodents or in CD1 mice in particular. Two studies have reported a n enhanced risk of lung cancer in human intervention studies? "Although dose and timing of exposure, smoking status, and imbalance of antioxidant defense have been recognized as potential factors accounting for the outcome of these studies,"6 no conclusive explanation has not yet been promulgated to explain these findings. However, examination of the design of these studies, particularly the use of a single carotenoid (beta-carotene) at a low supplemental dose, may explain the anomaly, especially given the lack of any evidence from animal toxicology studies that synthetic beta-carotene is carcinogenicat even exceptionally high intake levels7 More likely the administration of beta-carotene may have been administered too late in the carcinogenicprocess to be of any benefit for smokers. That human studies found a slightly increased risk of lung cancer in long-term smokers may discourage smokers from maintaining optimal levels of carotene, including beta-carotene. This possibility is worrisome, in that epidemiology studies have found an inverse correlation between high dietary beta-carotene intake and cardiovascular disease, particularly angina pectoris and myocardial infarction, conditions associated with smoking.&" Beta-carotene and its related carotenoids have been shown to protect against various cancers and to enhance cancer resistance directly as an antimutagen and anticarcinogen or indirectly as an antioxidant by reducing

cell damage.12-22 In particular, increased beta-carotene levels seem to reduce the risk of development of lung cancer, important information for cigarette smokers and people regularly exposed to sidestream smoke. Individuals with low intakes of beta-carotene have a 30%to 220% higher risk of lung cancer than those with a high intake of this nutrient. A 12-year study of almost 3000 men living in Switzerland found an association between low blood levels of vitamin A and beta-carotene and higher risk of lung cancer and death from all cancers.= Men with low carotene levels had nearly twice the risk of lung cancer compared with men who had normal levels, and nearly 3.5 times the risk of stomach cancer. Lycopene is not a provitamin but is a carotene, but it should be mentioned that epidemiologic studies suggest a link between lycopene intake and lower risk of both pancreatic, prostate, and stomach cancers and myocardial infarction.2427 Beta-carotene also has non-vitamin A functions, on the basis of its ability to act as an antioxidant by scavenging free r a d i ~ a l s . For ~ , ~example, ~ carotenoids protect against the damage from excessive exposure ultraviolet light that can lead to ultraviolet light-related tissue damage and skin cancer.M31 No RDA or RDI intake level for carotenes or betacarotene has been determined, although the mean intakes of carotenes in the United States, based on the NHANES for 1999-2000, were 426 RE and 480 RE, for males and females of all ages, respectively (Table 127-3).32

Vitamin D Vitamin D is a prohormone classified as a vitamin. Vitamin D3 (the natural form) is more effective at raising serum 25(OH)D concentrations than vitamin D2. Important for bone maintenance and the metabolism

Recommended intake of beta-carotene (mg) Gender

Age (Yr)

RDA

Optimal

Males

11-14

n/a

50

15-18

n/a

70

Females

19-24

n/a

100

25-50

n/a

100

51+

nla

100

11-14

n/a

50

15-18

n/a

60

19-24

n/a

25-50

n/a

80 80

51+

n/a

80

n/a, Not available; Optimal, Suggested RDA, Recommended Daily Allowance.

Optimal

Nutrient

Intake;

and absorption of phosphorus and calcium, vitamin D also contributes to the functioning of the reproductive system, the digestive system, and the immune system.'" Vegetarians, the elderly, and individuals who have limited exposure to sunlight or ultraviolet light or dark skin pigmentation may be at risk of inadequate vitamin D The elderly may be at particular risk of poor vitamin D status due to decreases in exposure to sunlight, intake of vitamin D-fortified foods, absorption of the nutrient in the gastrointestinal tract, and caloric intake. The skin of elderly individuals also produces approximately half the vitamin D after exposure to the sun as that of a young pers0n.5,~ Good bone mineral density is known to reduce the risk of fractures and osteoporosis. There is considerable experimental and epidemiologic evidence to support the need for calcium and vitamin D supplementation to reduce the risk of fracture and o s t e o p ~ r o s i s . ~ ~ ~ ~ ~ These studies have found that a daily dose of 800 IU of vitamin D, or 100,000 IU given three times a year, reduces the frequency of both falls and factures. Ensuring adequate levels of vitamin D throughout adulthood and as one ages is important, especially give the prevalence of vitamin D deficiency in virtually all institutionalized elderly persons.I6 Even in infants and adolescents, vitamin D supplementation can ensure higher bone mineral density, especially in prepubertal g i r l ~ . ' ~ ItJremains ~ unclear whether vitamin D alone reduces fracture rates or whether supplemental calcium is required. Optimal vitamin D status may be associated with a reduced risk of hypertension and also plays a role in regulating blood p r e s s ~ r e . ' ~ , ~ ~ There is also growing evidence that vitamin D combined with calcium might reduce the number of colorectal t ~ m o r s . ~Some l - ~ ~ evidence suggests that adequate vitamin D intake and/or production (via the skin) may decrease the risk of breast ~ancer.2~ At physiologic concentrations, vitamin D has been found to protect cell proteins and membranes from oxidative stress. When levels are optimal, vitamin D probably induces apoptosis of certain cancer cells. It is hoped that future research into vitamin D regulation of genes involved in neoplastic processes will elucidate its role in reducing malignancies. Patients with multiple sclerosis who are given vitamin D, calcium, and magnesium supplements have experienced a lower rate of relapse.25Women who were found to have the highest vitamin D intake via supplements (400 Tu or higher per day) were found to be 40% less likely to have multiple sclerosis than women not taking vitamin D supplements.26Interestingly, this finding did not hold if the vitamin was derived from food. Sunlight ultraviolet exposure on the skin promotes vitamin D production. It is important to note that this process is self-limiting and will not cause vitamin D

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements

toxicity (hypervitaminosis D) in healthy people or the elderly.27~28 One hour of total-body sun exposure can provide the equivalent of 10,000 IU of vitamin without

Gender

Ape (vr)

RDA

DRI/RII

Optimal

UL

Male

11-14

10

5

10

50

Vitamin D can be toxic at prolonged (several months) 5 15-18 10 10 50 high intakes. However, the data to support this finding 19-24 10 12 50 5 come wholly from literature reporting on the use of 20 50 5 25-50 10 vitamin DZ.No adverse effects have been reported in 24 50 51+ 5 10 healthy adults who have consumed up to 62 times the RDA of this nutrient. Because vitamin D has been shown Female 11-14 10 10 50 5 to be teratogenic in animals, a pregnant or potentially 5 15-18 10 12 50 pregnant woman should take vitamin D supplements 19-24 10 12 50 5 with caution, although doses as high as 600,000 IU have 5 25-50 5 18 50 been given to women during their seventh and eighth 51+ 5 22 50 10 months of pregnancy without evidence of harm.29 There is controversy about the risk of sunlight expoOptimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DRVRU, Dietary Reference IntakedRecommended Intakes for sure and melanoma.30 Evidence from several studies Individuals; UL, Tolerable Upper Intake Level. has found that non-sun-exposed areas of the skin have 'As cholecalciferol in pg. 10 pg cholecalciferol = 400 IU of vitamin D. a higher incidence of melanoma, including malignant melanoma, than sun-exposed area^.^'-^^ A very large with a free radical, the tocopherol molecule is converted epidemiologic study of U.S. Navy personnel found that adequate vitamin D levels may decrease the chance of into the tocopheroxyl radical, which can then be development of certain lethal skin melanomas (skin reduced back to harmless tocopherol by either vitamin C cancers) in adults with occupations and lifestyles that or glutathione. Any deficiency of this vitamin can affect prevent regular exposure to sunlight for up to 15 minutes the life span of red blood cells. a day? All of the cases of vitamin D toxicity with hyperVitamin E contributes to human health in numerous For example, it plays a role in preventing calcemia involve intakes higher than 40,000 IU a day. A careful examination of the vitamin D toxicity literamutagenesis, in the repair of membranes and DNA, and ture found that the consumption of more than 4000 IU a in maintenance of immunocompetence, especially as it day of vitamin D3caused no harm but raised 25(OH)Dto relates to normal T-lymphocyte function. high-normal concentrations in practically all a d ~ l t s . 3 ~ Many studies have found that the incidence of variFor individuals living in northern latitudes, daily ous cancers is higher in individuals with low levels of vitamin D3 supplementation is indicated to overcome vitamin E. Evidence to date is strong that a low intake the decline in 25(OH)D and to control parathyroid of vitamin E is a risk factor for cancer in many, but hormone levels in postmenopausal women.% not all, organs. The expression of its protective effect A dose of vitamin A at levels corresponding to may depend on the primary cause, which vanes. This is particularly important for smokers and persons exposed approximately one serving of liver has been found to to cigarette smoke, because vitamin E is a respiratory interfere with the action of vitamin D. It has been demonstrated that a dose of vitamin A antagonizes the tract antioxidant.%" There is evidence that vitamin E serum calcium response to vitamin D (Table 127-4).37 inhibits platelet aggregation, thereby reducing the risk of blood clots that can potentially lead to myocardial Vitamin E (Tocopherols and Tocotrienols) infarcts or s t r ~ k e . l ~ - ' ~ Vitamin E a fat-soluble vitamin essential to all mammals. Adequate vitamin E levels may protect against The term vitamin E applies to a family of eight related cataract de~elopment.'~J~ In one study, vitamin E supplecompounds, the tocopherols and the tocotrienols. The mentation reduced the risk of cataracts by more than four major forms of vitamin E are designated alpha, half. The benefit of vitamin E supplementation is unclear for both recreational exercisers and high-intensity beta, delta, and gamma. The tocotrienols are less widely athletes. However, vitamin E may play an important distributed in nature, and less biologically active, than the tocopherols. Although vitamin E is required role in preventing exercise-inducedmuscle and throughout an individual's life span, its levels decline coronary heart disease.20,21 There is mounting evidence that immune function with aging, probably owing to lowered caloric intake or can be enhanced by vitamin E supplementation.22 poor food choices. Vitamin E may prevent and reduce the risk of cancer, on One of the most important functions of vitamin E is to protect cell membranes from damage by reactive oxygen the basis of numerous cohort studies and randomized species (ROS),known as oxidative damage. By reacting trials.=%

Vitamin E supplementation raises plasma tocopherol concentration?' In general, high intake of vitamin E seems very safe.% Very few side effects have been reported in any scientifically controlled studies, with intakes as high as 3200 mg (3200 IU)?9,40Vitamin E supplementation is not, however, recommended for individuals undergoing anticoagulant therapy, who may also be vitamin K deficient. The suggested optimal levels are for natural vitamin E (d-alpha-tocopherol, d-alpha-tocopheryl acetate, or d-alpha-tocopheryl succinate). AU forms of natural vitamin E become active antioxidants (free radical scavengers) inside the body. The synthetic forms of vitamin E have the dl- designations in front of the form provided. The mean intakes of Vitamin E (total alpha-tocopherol equivalents in mg) in the United States based on the N H A N E S for 1999-2000 were 9.6 mg and 8 mg, for males and females of all ages, respectively (Table 127-5).4l

There is no known toxicity association with the administration of high doses of phylloquinone. However, patients undergoing warfarin therapy who are taking vitamin K should know that the vitamin can inhibit the vitamin K-dependent gamma-carboxylation of coagulation factors n, W, IX,and X. Even dietary variation in vitamin K intake can lead to difficulty in warfarin dosing.18 There is insufficient evidence to support supplemental intake of vitamin K beyond that found in most diets, except possibly in postmenopausal women and in women suffering from menorrhagia. Phylloquinone is the natural form of the vitamin and the primary dietary source of vitamin K. A normal mixed diet contains 300 to 500 pg of vitamin K per day, well in excess of the RDA. The RDA is 1 pg of phylloquinone per kilogram of body weight for adults and children. No tolerable upper intake level has been determined for vitamin K (Table 127-6).

Vitamin K (Phylloquinone)

Water-Soluble Vitamins Ascorbic Acid (Vitamin C)

Vitamin K is a fat-soluble vitamin found in food and created by bacteria in normal intestines.14 It is essential for normal clotting, particularly for the production of prothrombin and proteins C and S, as well as normal bone metabolism and development, especially loss of bone mass in postmenopausal osteoporosis.51o Studies show that women with low intakes of vitamin K may be at higher risk of hip fracture." It has also been reported that the vitamin helps maintain good bone mineral density and lower the risk of One study suggests that vitamin K may play a role during the acute insulin response associated with glucose t01erance.l~

Vitamin C (ascorbic acid) is a water-soluble antioxidant that acts as a cofactor in hydroxylation reactions required for collagen synthesis. Adequate vitamin C (ascorbic acid) intake is necessary for immunity, maintenance of bones, formation of collagen, and a broad range of other biologic functions.'-* In a study that measured the vitamin C intake of 1038 doctors and their wives, subjects with the fewest signs and symptoms of illness or degenerative diseases consumed an average of 410 mg of vitamin C a day, about seven times the RDA, which is 60 mg?-16To achieve this level of intake, supplementation would be required.

Recommended intake of vitamin E (mg tocopherol)* Gender

Aae (vr)

RDA

EAR

DRVRII

Optimal

UL

Male

11-14 15-18 19-24 25-50 51+ 11-14 15-18

10 10 10 10 10 8 8 8 8 8

9 12 12 12 12 9 12 12 12 12

11 15 15 15 15 11 15 15 15 15

70 100 400 400 800 70 90 400 400 800

600 800 1000 1000 1000 600 800 1000 1000 loo0

Female

19-24

25-50 51+

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance: DR//R//, Dietary Reference IntakedRecommendedIntakes for Individuals; UL. Tolerable Upper Intake Level. 'Alpha-tocopherol equivalents: 1 mg d-alpha tocopherol = 1 IU alpha-tocopherol.

Gender

Age (Yr)

RDA

DRllRll

Optimal

Male

11-14 15-18 19-24 25-50 51+ 11-14 15-18 19-24 25-50 51+

45 65 70 80 80 45 55 60 65 65

60 75 120 120 120 60 75 90 90 90

45 64 70 80 80 45 55 60 65 65

Female

Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DR//Rl/, Dietary Reference Intakes/Recommended Intakes for Individuals.

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elem Cigarette smoking is associated with a sigruficant drop in vitamin C levels. For a typical smoker to attain the same vitamin C level as a nonsmoker requires consumption of three to four times as much vitamin C.17-25 The third NHANES (NHANES 111) showed that 11%of nonsmoking women and 21% of nonsmoking men in the United States do not get enough vitamin C. Alcoholics, many of whom smoke, have low vitamin C status and require considerably more vitamin C. The elderly may especially benefit from vitamin C s u p p l e m e n t a t i ~ n .Increased ~ ~ , ~ ~ lipid (fat) peroxidation has been associated with accelerated aging and degeneration. One study demonstrated that supplementation 1 year for with vitamin C at levels much higher than RDA significantly decreased lipid peroxide levels in elderly subjects.28 Research suggests that vitamin C may reduce the risk of cataracts, cancers of the gastrointestinal tract, and cardiovascular disease.2945In a 12-year study of 3000 men living in Switzerland, the subjects with low blood levels of vitamin C had a higher risk of stomach and intestinal cancers. For people older than 60 years, low vitamin C levels are associated with nearly a threefold increased risk of stomach cancer and twice the risk for intestinal cancer. The interest in vitamin C in the treatment of cancer is partially based on studies showing significantly reduced levels in patients with malignancies. Most evidence suggests that doses of vitamin C larger than RDA may be beneficial in reducing the risk of various cancers, rather than in treating them. The reason may be that higher levels of vitamin C improve certain indices of immune competence and response that boost disease resistance. High dietary intake of vitamin C has been reported to be associated with lower rates of death from cerebrovascular and cardiovascular diseases. A cohort study of 11,348 noninstitutionalized U.S. adults found that women and men with the highest vitamin C intake derived from food and/or vitamin C supplements had, respectively, a 25% and 42% decrease in cardiovascular mortality. Vitamin C supplementation may reduce the risk of cardiovascular mortality by influencing cholesterol levels, platelet values, and even blood pressure.4649 Because the levels of vitamin C decline with age after midlife, there is evidence that suboptimal levels of vitamin C may raise the risk of cataract^.^^,^ People who consume the lowest levels of vitamin C seem to have the highest incidence of cataractous lenses. Whether this is due to other components in food (i.e., antioxidants such as polyphenols) or vitamin C alone is not known. One study has shown that subjects who supplemented with vitamin C significantly lowered their risk of cataracts. Vitamin C markedly increases nonheme iron absorption.m51In some diets, only 3% of nonheme iron is absorbed, compared with as much as 23% of the heme

iron form. The addition of 50 to 100 mg of vitamin C to meals can double or triple nonheme iron absorption. Two grams (2000 mg) of vitamin C taken throughout the day with meals increases the absorption of nonheme iron fivefold. Bone density and vitamin C status decline after age 35. Vitamin C is an important nutrient in bone metabolism, especially in the synthesis of collagen, which forms the structural framework of bones. A number of studies show that vitamin C supplementation results in improved maintenance of bone mineral density in postmenopausal Studies have also shown reductions in healing time of wounds with high-dose vitamin C ~ u p p l e m e n t a t i o nand ~ ~ , enhancement ~ of the bactericidal activity of le~kocytes.5~ The vitamin’s ability to prevent the common cold or shorten its duration continues to be controversial.56 Vitamin C supplementation has been shown to improve glucose metabolism and lower blood sugar levels associated with h y p e r g l ~ c e m i a . ~ ~ ; ~ ~ Vitamin C taken at optimal ranges or at less than 1000 mg/day is virtually free of any known or observed side effects. Doses in excess of 1000 mg at a time have been known to cause diarrhea (bowel tolerance), hyperuricosuria, and hyperoxaluria in healthy individuals. There is also evidence that doses as high as 10,000 mg/day have no adverse side effects, but long-term studies to support this position are lacking. The mean intakes of vitamin C in the United States, based on the NHANES for 1999-2000, were 103 mg and 91 mg, for males and females of all ages, respectively? Higher recommended levels of vitamin C for adults, 200 mg/day, have been suggested by the U.S. Department of Agriculture and the National Cancer Institute, because fruit and vegetable consumption results in vitamin C intakes exceeding 210 mg/day. However, these higher levels have not become part of the RDIs. Instead the RDIs have raised the vitamin C intakes to 90 mg and 75 mg for adult men and women, respectively, well below the level that is optimal (Table 127-7).61

Cyanocobalamin (Vitamin BIZ) Vitamin B12 (cyanocobalamin)is water soluble, is synthesized by bacteria, and is found in virtually all animals but rarely in any plant foodstuffs. Vitamin BI2is essential for the functioning of the central nervous system and a number of enzymes involved in amino acid, nucleic acid, and fatty acid metabolism. It is also necessary in the metabolism of folic acid (folate), which is essential for thymidine and, thus, DNA synthesis. The vitamin acts as a coenzyme for fat and carbohydrate metabolism, hematopoiesis, and protein synthesis.’-3 Vitamin BI2 deficiency is common among the elderly, in whom it can cause macrocytic anemia and neurologic abnormalities (loss of proprioception and vibration sense),

Pharmacology of Natural Medicines Recommended intake of vitamin BI2 (cyanocobalamin) (pg) Gender Male

Female

Age(yr)

RDA

EAR

DRllRll

Optimal

UL

11-14

50

39

45

150

1200

15-18

60

63

75

200

1800

19-24

60

75

90

200

2000

25-50

60

75

90

400

2000

51+

60

75

90

800

2000

11-14

50

39

45

150

1200

11-14

2.0

15-18

60

56

65

200

1800

15-18

2.0

19-24

60

75

200

2000

19-24

2.0

25-50

60 60

60

75

400

2000

25-50

51+

60

60

75

1000

2000

51+

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DRMRII. Dietary Reference IntakedRecommended Intakes for Individuals; UL, Tolerable Upper Intake Level. 'A new RDA for adults for vitamin C of 200 mg/day has been suggested, following US. Department of Agriculture and National Cancer Institute recornmendations for fruit and vegetable consumption that results in vitamin C intakes of greater than 210 maday.

owing to an absence of intrinsic factor.& In the elderly, it often results in neurologic, cerebral, and psychiatric abnormalities? Any assessment of elderly patients with depression or impaired memory should include a determination of vitamin B12status.a1oIndividuals who suffer depression with a history of gastric or ileal disease may also experience a deficiency of this vitamin." Many elderly patients who had a "normal" serum vitamin B12 concentration were found to be metabolically deficient in cobalamin.12This finding would suggest that deficiency of vitamin BI2 is often ~nderdiagnosed.'~ In some cases fatigue may suggest the presence of pernicious anemia, along with neurologic indication^.'^ In such cases, treatment with vitamin B12 and folic acid should begin im~nediately.'~,'~ Some evidence shows that after the development of pernicious anemia, risk of cancer is increased.17 There is now convincing evidence that vitamin BI2 may reduce one risk factor for arteriosclerosis, the accumulation of homocysteine (homocysteinemia). High levels of homocysteine has been associated with an increased risk of cardiovascular disease. Vitamin B12 levels have been found to be inversely related to homocysteine concentration^.'^^^ When a vitamin deficiency is diagnosed, administration of vitamin B12injections has proven superior to oral vitamin BI2 supplement. Yet there is growing evidence that oral vitamin B12 (cyanocobalamin) is a completely safe alternative to vitamin B12 injections. One study has found that some individuals with gastric disease who absorb vitamin BI2from food poorly can absorb the

Gender

Age (yr)

RDA

EAR

DRI/RII

Optimal

Male

11-14

2.0

1.5

1.8

2.0

15-18

2.0

2.0

2.4

2.0

19-24

2.0

2.0

2.4

25-50

2.0

2.0

2.4

51+

2.0

2.0

2.4

3.0

1.5

1.8

2.0

2.0

2.4

2.0

2.0

2.4

2.0

2.0

2.0

2.4

2.0

2.0

2.0

2.4

3.0

Female

2.0 .

2.0

EAR. Estimated Average Requirement; Opfimal, Suggested Optimal Nutrient Intake; RDA. Recommended Daily Allowance; DRVRII, Dietary Reference IntakedRecommendedIntakes for Individuals.

crystalline supplement form. Some experts have argued that the only legitimate need for vitamin B12supplementation is in patients with a congenital defect of vitamin B12 metabolism, such as vitamin BI2-responsive methylmalonic acidemia. Vitamin B12 deficiency is more likely in very strict vegetarians, because the best sources of vitamin BI2 are meat and meat products and, to a lesser extent, milk and milk products, some seafoods, and egg yolk. There is growing evidence that vitamin BI2 may play a role in the prevention of some types of cancers. Smokers, for example, have been found to have significantly lower levels of precancerous bronchial squamous metaplasia when given vitamin B12 (500 yg/day) and folic acid supplements than those receiving placebo.3O Other benefits of vitamin B12supplementation reported in the literature are the treatment of osteoarthritic anorexia nerv0sa,3~and chronic exposure to gaseous nitric oxide.34 There is insufficient evidence to advocate an intake of vitamin B12 above the RDA in any population group except the elderly or the patient with evidence of pernicious anemia. For the patient with pernicious anemia, vitamin BI2 injections (parenteral cobalamin) or weekly oral doses of 1000 yg is suggested. During such treatment, however, the patient should take care to not to consume large amounts of folic acid, which might mask the nerve damage associated with vitamin B12deficiency. Nevertheless, persons with atrophic gastritis should consume oral vitamin B12supplements to ensure normal vitamin B12n ~ t r i t u r e . ~ ~ Vitamin B12 is not carcinogenic, teratogenic, or mutagenic.%It is considered safe in doses up to 1000 times the RDA. The UL has not been determined (Table 127-8).

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements

Folk Acid (Pteroylglutamic Acid) Recognition of the critical importance of folate for maintaining health is growing. Folic acid is required in the metabolism of some amino acids, for the synthesis of nucleic acids, and in a number of enzyme cofactors.I4 Certain population groups are at particular risk for development of folate deficiency, especially pregnant Like newborn infants, women and adolescent who are also at risk, these groups experience considerable growth, confirming the importance of folic acid in protein synthesis and DNA and RNA replication required in cell growth. Inadequate folic acid is also seen in the elderly, in whom it is less well Because folic acid deficiency is a well-documented cause of birth defects in animals, numerous studies have looked at its role in such human congenital malformations as neural tube defects, cleft palate, and cleft lip.12J3 Folic acid and multivitamin supplementation have been demonstrated in numerous studies to decrease or eliminate the recurrence of neural tube defects or cleft palate/ cleft lip in human Folic acid deficiency rises in prevalence with age.22,23 The vitamin may also reduce a risk factor associated with atherosclerosis, in that folic acid is required for the conversion of homocysteine to methionine." A deficiency of folic acid is associated with elevated homocysteine (homocystinemia),which is a risk factor for atheroscleroS ~ SNormal . ~ ~ subjects given 5 mg/day of folic acid for 2 weeks had significant decreases in homocysteine levels, especially those whose initial homocysteine levels were high.26 There is also mounting evidence that smokers and heavy coffee drinkers require a higher intake of folic acid.27 Given the growing popularity of coffee as a beverage consumed in most homes and offices and neighborhood coffee houses and chains, its influence on folic acid status, especially among heavy consumers, needs to be considered. Folate is required for critical brain metabolic functions. A wide range of neuropsychiatric disorders has been linked to folic acid deficiency including, insomnia, depression, myelopathy, peripheral neuropathy, restless leg syndrome, dementia, irritability, and organic psychosis.28 Low folate levels have been implicated to poorer antidepressant response to selective serotonin reuptake inhibitors.29Borderline to deficient serum or red blood cell folate levels have been detected in from 15% to 38% of adults diagnosed with depressive disorders. The risk associated with the development of cataracts may be reduced by maintaining folic acid (and vitamin BIZ) levels.30Folic acid taken with cobalamin has been found to be helpful in the treatment of osteoarthritis of the hands.3I There are two reports of its benefits in the treatment of bronchial squamous metaplasia in heavy smokers using folic acid along with vitamin B12t h e r a ~ y . ~ ~ J ~

Folic acid supplementation in healthy adults is safe even at high levels of intake, although such supplementation can mask clinical signs of pernicious anemia, which if left untreated can lead to permanent nerve damageM There is also continuing controversy about whether folic acid supplementation of 400 pg or more reduces zinc absorption. Folate catabolism progressively rises during pregnancy, reaching a peak in the third trimester when maximal fetal growth is 0ccurring.3~This is due to increased demand for folate in cellular bio~ynthesis.~~ For lactating and pregnant women, the RDAs are inadequate; at least 600 pg folic acid should be taken as a dietary supplement daily to ensure adequate supplies for the mother, her fetus, and then her infant during brea~tfeeding.~' For individuals with elevated plasma total homocysteine concentration who are at risk for cardiovascular disease, a minimum of 250 pg of folic acid as a supplement should be taken in addition to a diet providing at least an additional 400 pg of f01ate.~~ Folic acid is particularly important for people with defects in the absorption and metabolism of folate, an essential nutrient that is a contributing factor in agi11g.3~Studies have shown that folate from dietary sources alone results in a modest reduction in the risk of colon cancer. However, the benefit of long-term folic acid intake has been demonstrated in the Nurses' Health Study involving 88,756 women. Women who consumed a multivitamin for more than 15 years had substantially reduced their risk for colon cancer.40The researchers concluded that this effect may be related to the folic acid contained in multivitamins. The mean intakes of folate in the United States, based on the NHANES for 1999-2000, are 405 pg and 319 pg, for males and females of all ages, respectively (Table 127-9).4]

Gender

Age (yr)

RDA

EAR

DRI/RII

Optimal

UL

Male

11-14 15-18 19-24 25-50 51+ 11-14

150 200 200

250 330

200 150

320 320 320 250

300 400 400 400 400 300

15-18 19-24 25-50 51+

180 180 180 180

330 320 320 320

400 400 400 400

500 750 1000 2000 2000 500 750 1000 1000 2000

600 800 1000 1000 1000 600 800 1000 1000 1000

Female

200

EAR, Estimated Average Requirement: Optimal, Suggested Optimal Nutrient Intake: RDA, Recommended Daily Allowance; DRlVRll, Dietary Reference IntakeslRecommended Intakes for Individuals; UL, Tolerable Upper Intake Level.

Pharmacology of Natural Medicines

Niacin (Nicotinic Acid) and (Niacinamide) Nicotinamide

in humans supplementing with the esterified form of vitamin B3 (inositol hexaniacinate). The mean intakes of niacin in the United States, based on the NHANES for 1999-2000, were 25.9 mg and 18.9 mg for males and females of all ages, respectively (Table 127-10).20

Niacin is a water-soluble vitamin. The term is the generic descriptor for nicotinic acid (pyridine-3-carboxylicacid) and derivatives exhibiting biologic activity of nicotinamide (nicotinic acid amide). Niacin is critical in many biochemical processes, Vitamin B6 particularly those involving energy metabolism and lipid rnetabolism.'s2 The requirement for niacin in Vitamin B6 is a water-soluble vitamin comprising the humans is met in part by conversion of the essential group of nitrogen-containing compounds (pyridoxine, amino acid tryptophan to niacin? Several studies have pyridoxal, pyridoxal-5'-phosphate, pyridoxamine, and corresponding phosphorylated forms) that occur natucalculated that from 39 to 86 mg of tryptophan produces rally in the following three primary forms: pyridoxine, the same levels of niacin metabolites as 1 mg of niacin. pyridoxal, and pyridoxamine. Vitamin B6 is required for For this reason the convention is to consider 1 mg of growth and maintenance of almost every bodily funcniacin as equivalent to 60 mg of tryptophan. Because tion, amino acid metabolism, and production of neuromost proteins contain at least 1%to 2% tryptophan, it is transmitters derived from amino acids. It also plays a possible to maintain adequate niacin status with a diet role in glycogen breakdown, fatty acid metabolism, relatively devoid of niacin but containing at least 100 g hormone metabolism, heme biosynthesis, and purine of protein a day: bio~ynthesis.'-~ The use of niacin as a druglike agent-it lowers serum levels of low-density lipoprotein (LDL) and very-LDL Various studies have found the prevalence of vitamin B6 deficiency to vary from 9% in preschool children to 68% (VLDL) cholesterol and triglycerides while raising the in low-income pregnant women. The average prevalence level of high-density lipoprotein (HDL) cholesterol-has generated much i n t e r e ~ tNicotinic .~~ acid given in doses of vitamin B6 deficiency is 25% in adult^.^ Studies in humans indicate that the bioavailability of of 1.5 to 3 g per day has been shown to decrease total vitamin B6 from natural sources is limited. For example, and LDL cholesterol values and increase HDL cholesterol concentration.There is also interest in its notorious, the vitamin B6 in whole wheat bread and peanut butter is 75% and 63%, respectively, as available as the vitamin B6 but not harmful, vasodilatory or "flushing" effect in increasingblood flow to the extremities in certain circulafrom tuna. Supplementation of vitamin B6 has been used in the tory disorders. This effect comes only from the nicotinic acid form, not the amide. There is no evidence that treatment of premenstrual syndrome: cardiovascular disorders? and diabetic neuropathy? The vitamin has levels above twice the RDA for niacin in healthy persons prevents disorders associated with high cholesterol (hypercholesterolemia) or other hyperlipidemias. The only evidence for a significantly higher intake of niacin above the RDA in healthy asymptomatic individuals comes from the prospective Birmingham Study.'O Researchers found that individuals with the least number of signs and symptoms associated with physical RDA EAR DRllRll Optimal UL Gender Age (yr) illness or degeneration were consuming an average of Male 11-14 17 9 12 25 20 115 mg of niacin a day, or approximately six or seven 30 30 15-18 20 12 16 times the RDA. 19-24 19 12 16 30 35 There has been considerable use of niacin as a treat12 25-50 19 16 30 35 ment for some forms of schizophrenia, first espoused 51+ 15 12 16 30 35 in the early 1950~."-'~ Niacinamide supplementation 25 20 Female 11-14 15 9 12 has also been suggested in the treatment of rheumatoid 30 11 14 25 15-18 15 arthriti~,'~,'~ and inositol nicotinate in intermittent 15 11 19-24 14 25 35 ~1audication.I~ 35 15 11 14 25 25-50 Because nicotinic acid can raise blood glucose levels, nicotinic acid supplementation is contraindicated in the 51+ 15 11 14 25 35 treatment of diabetes. Also, large intakes of nicotinic acid EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient (>lo00 mg) have been associated with stomach pain, Intake; RDA, Recommended Daily Allowance; DR//R//, Dietary Reference diarrhea, cardiac arrhythmias, itching, and n a ~ s e a . ' ~ J ~IntakedRecommended Intakes for Individuals; UL, Tolerable Upper Intake Level. '1 niacin equivalent = 1 mg niacin or 60 mg dietary tryptophan. These side effects have not been observed, however,

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements also been demonstrated to treat carpal tunnel s y n d r ~ m e . ~Elderly - ' ~ people may have a greater requirement for vitamin B6 to maintain health, particularly for their immune systems. In one study, healthy elderly people were given either 50 mg/day of vitamin B6 or placebo. Those receiving the supplement had significant improvement in immunocompetence, especially lymphocytic a~tivity.'~ There is some emerging evidence that inadequate vitamin B6 status may contribute to the development of coronary heart disease through a rise in plasma homocysteine.'"" Homocysteine has been found to be highly atherogenic in animals and may contribute to atherosclerosis and myocardial infarction in humans.18Added evidence that vitamin B6 might be important in preventing cardiovasculardiseases comes from experimental studies in animals. When animals are given vitamin B6 deficient diets they demonstrate atherosclerotic lesions similar to those found in human atherosclerosis. Many women taking oral contraceptives have been shown in various studies to have low levels of vitamin B6.19-22Levels of this vitamin have also been found to be low in cigarette smokers.23Some evidence has been reported suggesting that inadequate vitamin B6 levels may raise the risk of some cancer^.^^,^ Although there is growing evidence for a role of vitamin B6 supplementation in preventing some kinds of cardiovascular diseases, and for e n h a n h g immunity, levels in healthy individualsneed not exceed 12to 15times the RDA, even in the elderly. Supplementation of vitamin B6 up to 200 mg/day is safe for most individuals. Very high doses of vitamin B6 have been associated with sensory and motor impairment.2"28Daily intakes up to 500 mg/day, which is 250 times the RDA, for up to 6 months appear to be safe.29Supplements of pyridoxal-5'-phosphate may be preferred over pyridoxine hydrochloric acid supplements in individuals wishing to avoid any reversible side effects from vitamin B6 supplementation. The mean intakes of vitamin B6 in the United States, based on the NHANES for 1999-2000, were 2 mg and 1.6 mg for males and females of all ages, respectively (Table 127-11).30

Riboflavin (Vitamin B2) The water-soluble vitamin riboflavin is a precursor of two coenzymes (riboflavin-5'-phosphate and flavin mononucleotide) needed for a wide variety of enzymes in intermediary metabolism. Riboflavin is also required as a precursor of several flavoenzymes that are needed by tissue proteins.'" Riboflavin is especially important for tissue repair, vision, and blood. The need for riboflavin varies with energy requirements, explaining why riboflavin-deficient people tire

Gender

Male

Female

Age (yr)

RDA

EAR

DRI/RII

Optimal

UL

11-14

1.7

0.8

1.o

2

60

15-18

2.0

1.1

1.3

5

80

19-24

2.0

1.1

1.3

10

100

25-50

2.0

1.1

1.3

10

100

51+

2.0

1.4

1.7

25

100

11-14

1.4

0.8

1.o

2

60

15-18

1.5

1.0

1.2

5

80

19-24

1.6

1.1

1.3

10

100

25-50

1.6

1.1

1.3

10

100

51+

1.6

1.3

1.5

20

100

EAR, Estimated Average Requirement: Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance: DRVRII, Dietary Reference Intakes/Recommended Intakes for Individuals; UL, Tolerable Upper Intake Level.

easily and have a poor appetite. Worldwide, intakes of riboflavin are OW.^-^ There is growing evidence that riboflavin may be important in preventing the development of cataracts, which are commonly associated with a g i ~ ~ gThere . ~ , ~is equivocal evidence that riboflavin supplementation may be required in people who exercise reg~larly.~J~ This latter issue may be more of a consideration if the exerciser is on a calorie-restrictive diet." Intakes of riboflavin significantly higher than SON1 or RDA have been employed in the treatment of migraine prophylaxis, with promising results. In one open pilot trial involving 25 patients with a history of migraine related to either the syndrome of mitochondria1 encephalomyopathy, lactic acidosis, or strokelike episodes (MELAS), 400 mg/day of riboflavin was given as a prophylactic treatment for migraine.12 On average, 68% of patients reported improvement on an index of severity. A second randomized, placebo-controlled trial involving 55 patients with similar migraines reported a 50% improvement among those receiving riboflavin, versus a 15% response in the placebo group.13It is theorized that in some migraine patients, riboflavin may correct a mitochondrial dysfunction resulting from impaired oxygen metabolism. Evidence is building for a role of riboflavin as an antioxidant owing to its role as a precursor for glutathione reductase, the enzyme that reduces oxidized glutathione (GSSG) formed via the glutathione reductase reaction with the concomitant oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH).14This finding may have implicationsin the management of rheumatoid arthriti~.'~

Pharmacology of Natural Medicines

A number of studies have demonstrated that certain vitamins, particularly riboflavin and retinol and their derivatives, have the ability to modify molecular reactivity and response to ~arcinogens.'~,'~ Dietary riboflavin has such an important role.I8 The mechanism of action is control of the induction of repair enzymes (poly[ADP-ribose]polymerase, DNA polymerase beta, and DNA ligase) responsive to carcinogens that cause damage to DNA. Studies have shown that DNA damage increases proportionate to a deficiency of riboflavin and that greater damage to DNA is reversed via riboflavin s~pplementation.'~ Riboflavin has no known toxicity, although the photosensitizing properties of the vitamin raise the possibility of some theoretical risks. There is insufficient evidence to support riboflavin supplementation in healthy adults to more than twice the RDA. However, in cases of traumatic tissue damage, riboflavin supplementation at several times the RDA is indicated because the vitamin can protect tissue from oxidative injury.20*21 No adverse events have been reported for riboflavin supplementation. It is of the lowest order of potential toxicity. The mean intakes of riboflavin in the United States, based on the NHANES for 1999-2000, were 2.2 mg and 1.7 mg for males and females of all ages, respectively? A UL has not been determined for riboflavin (Table 127-12).

Thiamin (Vitamin B,) Thiamin is a water-soluble vitamin consisting of one pyrimidine ring and one thiazole ring linked by a methylene bridge. This is important to know because many processed foods are rich in sulfites that split the

thiamine molecule into the pyrimidine and thiazole moieties, thus destroying its biologic a~tivity.l-~ In a study of 1009 dentists and their wives evaluated for daily thiamin intake, the subjects having the least number of signs or symptoms associated with illness or degenerative diseases consumed an average of 9 mg of thiamin a day, approximately eight times greater than the RDA for this n ~ t r i e n t . There ~ , ~ is insufficient evidence to suggest intakes of thiamin above eight times the RDA in healthy persons. However, individuals regularly consuming high intakes of refined carbohydrates (i-e., refined sugar-sucrose, wheat flour products made with unfortified 70% extraction flour) may require supplemental intake of thiamin in the range of 5 to 15 mg/day until such time as a more nutrient-dense, fiber-rich diet is consumed on a regular basis."1° Manifestations of thiamin deficiency (beriberi) can be induced by chronic alcoholism." Thiamin deficiency has been seen in patients with Alzheimer Is-type dementia.12 To date, thiamin, when taken orally, has been reported harmless in humans, although gastric upset can be experienced at doses exceeding 100 to 200 times the RDA.' Ageing itself may be a risk for thiamin deficiency, on the basis of evidence of comorbidity of thiamin deficiency and age-related degenerative disease^.'^ Individuals displaying marginal or pronounced functional neurosis, including impulsive behavior, may have subclinical thiamin deficiency.'JO There is a growing appreciation for the association between thiamin status and mood and cognitive fun~tioning.'~ Physical activity places a burden on thiamin requirements.l5,I6 The mean intakes of thiamin in the United States, based on the NHANES for 1999-2000, were 1.8 mg and 1.4mg for males and females of all ages, re~pective1y.l~ A UL has not been determined for thiamin (Table 127-13).

Minerals Gender Male

Female

Aae (vr)

RDA

EAR

DRllRll

Optimal

11-14

1.5

0.8

0.9

2.0

15-18

1.8

1.1

1.3

2.2

19-24

1.7

1.1

1.3

2.5

25-50

1.7

1.1

1.3

2.5

51+

1.4

1.1

1.3

2.5

11-14

1.3

0.8

0.9

1.8

15-18

1.3

0.9

1.o

1.8 2.0

19-24

1.3

0.9

1.1

25-50

1.3

0.9

1.1

2.0

51+

1.2

0.9

1.1

2.0

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DR//R//. Dietary Reference IntakedRecommended Intakes for Individuals.

The author of this section is also the author of Minerals, Trace Elements and Human Health, ed 4, Tacoma, W A Biosocial Publications, 1999 (for more information contact infoaa ibrnrmrn).

Boron Boron has only recently been established to be of nutritional significance to humans. Evidence suggests that signs and symptoms of insufficiency manifest only when the body is stressed in some way that enhances the need for boron. Boron influences the activity of a number of enzymes as well as being involved in the metabolism of steroid hormones and such nutrients as vitamin D, calcium, and magnesium. In animals it has been shown to strengthen bones; boron affects bone mineral density, along with calcium, phosphorus, and magnesium. In young women boron supplementation has a beneficial

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements

Recommended intake of thiamin (mg) Gender Male

Female

Age (yr)

RDA

EAR

DRIIRII

Recommended intake of boron (ma) Optimal

Gender

RDA

Ootimal

UL 11

11-14

1.3

0.7

0.9

3.3

11-14

n/a

1.5

15-18

1.5

1.o

1.2

3.5

15-18

nla

2.0

17

19-24

1.5

1.o

1.2

3.5

19-24

nla

2.5

20

25-50

1.5

1.o

1.2

7.5

25-50

n/a

2.5

20

51+

1.2

1.o

1.2

9.2

51+

n/a

2.5

20

11-14

1.1

0.7

0.9

3.1

11-14

nla

1.5

11

15-18

1.1

0.9

1.o

3.1

15-18

nla

2.0

17

19-24

1.1

0.9

1.1

3.1

19-24

nla

2.5

20

25-50

1.1

0.9

1.1

7.1

25-50

n/a

3.0

20

51+

1.o

0.9

1.1

9.0

51+

n/a

3.0

20

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DRVRll, Dietary Reference IntakeslRecommended Intakes for Individuals.

effect on serum phosphorus and magnesium concentrations; the effect can be modified by exercise. In animals such as rodents, and in humans, it plays a beneficial role in arthritis, brain function, and lipid ratios.'-12 Most persons eating Westernized diets consume between 0.1 and 0.5 mg of boron a day. Human studies indicate that people consuming less than 0.25 mg of boron a day, or less than one-half the estimated average minimum requirement for humans, would benefit from supplementation or consumption of foods rich in boron, particularly apples and pears grown in dry areas, since boron is more easily leached out of the soil in wet climates. No evidence has been reported to date to suggest that a boron intake above 10 mg/day is beneficial. Supplementation with 3 mg of boron a day for postmenopausal women has resulted in improvement in retention of both calcium and magnesium and elevation in circulating serum concentrations of testosterone and estrogen (17-beta-estradiol).13This improvement is more marked in women who have been consuming lowmagnesium diets. Similar improvements might also be true if the women were vitamin D defi~ient.'~ There is preliminary evidence based on animal studies that in males, boron has an effect on steroidogenesis ( e g , production of testosterone) and testicular function and that development is proportional to the boron concentration in the testes.15 There is increasing interest in the role of boron on brain function.16Results in animals and humans indicate that dietary boron influences brain electrical activity.l7 Individuals in a low state of alertness consume less boron (0.5 mg/day) than those found to be more alert (>3 mg/day). It has also been concluded that adequate boron intake improves psychomotor skills and cognitive processes of attention and rnemory.l7-l9

Male

Aae (vr)

Female

Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; UL, Tolerable Upper Intake Level.

Preliminary evidence in animals has demonstrated that boron may modulate immune function that might be of significance to humans.12 Adequate boron suppresses inflammatory processes. There is some evidence that boron (as sodium tetraborate decahydrate) may prevent arthritis in sheep.'r6 In a randomized double-blind clinical trial of 20 patients with severe osteoarthritis given either 6 milligrams of boron or placebo, five improved and five did not, but only one of the 10patients taking the placebo improved.20 Boron deficiency in chicks results in a syndrome that resembles human arthritis.21,22 The evidence continues to grow that boron status may play a role in the prevention and treatment of arthritisu There is also preliminary evidence of an association between sufficient boron intake and resistance to dental canes (tooth decay).2427 Other studies have reported that boron may reduce the risk of human prostate canceP as well as the risk factors associated with cardiovascular di~ease.2~ Considering how many other studies have been conducted on boron to determine the scope of its benefits in animal and human physiology,304 it would not be surprising that at some point this provisionally essential trace element will be declared essential. In human studies to date, no side effects have been reported at intake levels up to 13 mg of boron per day (Table 127-14).

Calcium Calcium is primarily stored in bones (99%), where the ratio of calcium to phosphorus is nearly constant at slightly greater than 2:l. Calcium is involved in numerous vital functions throughout the body, including protein and fat digestion, energy production, nerve transmission, neuromuscular activity, and the absorption of other nutrients, such as vitamin B12.14

Estimates of adult calcium requirements in humans vary from 300 to 400 mg/day to between 1200 and 1500 mg/day. The lowest requirements are usually seen in populations with low protein intakes.’ In general, persons with very low protein intakes require less calcium per day. High levels of protein, which are usually also high in phosphorus, require higher calcium intakes. A rise in protein intake affects urinary calcium concentration and calcium retention. It is recommended that calcium intake be increased during adolescence, pregnancy, and lactation. Of particular interest is the use of calcium supplements to increase daily calcium intake.5,6 Various calcium supplements claim higher absorbability. There seems very little advantage to improved absorbability because unabsorbed calcium exhibits valuable functionality in its own right. Heaney7explained this concept as follows: Calcium remaining in the food residue forms complexes with harmful substances left over from digestion, such as oxalic acid, unabsorbed fatty acids and bile acids. This complexation is the mechanism by which high calcium diets reduce the risk of kidney stones and colon cancer. [Incidentially, the latter protection provides another illustration of the functional role of the accompanying anion. Calcium phosphate has been shown to be more efficacious at preventing colon cancer in animal models than the same amount of calcium as the carbonate.]

age group or gender. Both late menarcheal age and low calcium intake during growth are risk factors for osteoporosis, probably through impairment of peak bone mass. The level of calcium intake immediately preceding puberty may influence the timing of menarche, which in turn could influence long-term bone mass gain in response to calcium supplementation. Thus determinants of early menarcheal age and high calcium intake may positively interact to affect bone mineral mass accrual.30 Some new supplements incorporating the nutrients required for bone, including hydroxyapatite, may be an alternative to calcium supplementation to ensure the adequate nutrient needs for bone. New studies show that even moderate consumption of calcium in foods or as supplements can reduce both heme and nonheme iron a b s o r p t i ~ n . These ~ ~ ” ~reductions could have important nutritional implications, especially for premenstrual and pregnant women, who are already at risk for iron deficiency and may be advised to take calcium supplements (Table 127-15).

Chromium Trivalent chromium is a trace element essential to the metabolism of lipids (e.g., cholesterol), glucose, and insulin The long-term effects of a suboptimal intake of chromium has been related to a decrease in tissue chromium associated with aging and a higher incidence of diabetes and atherosclerosis, particularly in developed nations. Illness, aging, stress (i.e., trauma, surgery, intense heat or cold), and strenuous exercise seem to increase chromium losses or needs. Studies of humans with heart disease have demonstrated that chromium deficiency is associated with

Calcium has received considerable attention in the mass media because of the rising prevalence of agerelated osteoporosis, which has been described as epidemic. Articles and advertisements suggest that high intakes of calcium via supplementation or enrichment of fooddbeverages is essential to the development and maintenance of strong, healthy bones. The attention this nutrient has received is most important to women.813 Women are more prone to osteoporosis that men because of smaller skeletal mass at maturity and because the most rapid period of bone loss occurs after men~pause.’~J~ However, many studies do not show a relationship RDA Optimal DRVRII UL Gender Age (yr) between levels of dietary calcium intake and the inci1200 1000 2500 1300 Male 11-14 dence of osteoporosis.1~z9 In the largest prospective scientific study of bone in premenopausal women aged 15-18 1200 1300 1000 2500 20 to 40 years, no relationship could be found between 19-24 1200 1000 1000 2500 calcium intake and bone mineral density; this finding 800 1000 700 2500 25-50 has been reported by many studies published since 1985. 51 + 800 1200 700 2500 When developing or maintaining bone mineral Female 11-14 1200 1300 1200 2500 density is a goal, optimal intake of all nutrients essential 1200 1300 1200 15-18 2500 to bone formation and homeostasis is required. Diet, 19-24 1200 1000 1200 2500 hormones, age, and gender are just some of the factors 800 800 2500 25-50 1000 that influence calcium requirements and metabolism. 800 800 2500 51+ 1200 Because of these variables and the interrelationships among calcium, protein, phosphorus, magnesium, zinc, Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily vitamin D, boron, and the other elements, it remains Allowance; DRMRll, Dietary Reference Intakes/Recommended Intakes for Individuals; UL, Tolerable Upper Intake Level. difficult to select a single calcium requirement for any

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements

chromium picolinate daily for 4 months; the supplement atherosclerosis, suggesting that optimal chromium levels may reduce the risk of heart disease.8-12Tissues of caused no sigruficant adverse events in this study4*nor in two other studies involving older men and women humans who have died of heart disease have been found to have less chromium than tissues of humans who died given 924 pg chromium picolinate of accidental causes. In tissues of patients with atheroThere have also been studies showing the importance sclerotic plaque who died of heart disease, no detectable of maintaining adequate chromium status in the chromium was found. There is also evidence in humans elder1+45 and in male runners.& In the span of some 40 years, a considerable body that a diet sufficient in chromium along with selenium, copper, potassium, magnesium, and calcium reduces of evidence has shown the importance of trivalent the risk of cardiovascular disease through a beneficial chromium as an essential trace element, with multiple effect on serum cholesterol and triglyceride levels.'>16 roles in human physiology. Chromium taken with nicotinic acid (niacin) or the No UL has been determined for chromium chromium supplement chromium picolinate (200 to (Table 127-16). 400 pg/day), has been shown to lower cholesterol levels Copper in individuals with elevations in serum cholesterol. Traces of chromium have been shown to be required Copper is an essential element in the human body. for health as part of the glucose tolerance factor (GTF) About 95% of copper is found in serum as part of ceruloplasmin. Copper is needed by all tissues but is present involved in the regulation of blood glu~ose.'~ However, in highest levels in the liver, where it contributes to it is worthwhile to state that GTF has never been synenergy and detoxification mechanisms. The element thesized in its pure form or definitively characterized despite repeated attempts.ls The brain has high requireis also required to absorb, utilize, and synthesize hemoments for blood glucose as a fuel. The amount of globin, maintain the integrity of the outer covering chromium in foods decreases with processing. The wideof nerves (myelin), metabolize vitamin C, and oxidize fatty acids. Both excess and deficiency of copper can spread tendency to greater consumption of highly result in problems such as bone/joint and connective processed foods, particularly refined sugar, which tissue disturbances, cardiovascular degeneration, stimulates urinary losses of chromium, may result in a marginal intake of chromium and depletion of tissue abnormal electrocardiogram, accelerated aging, depigchromium stores. There is considerable evidence that mentation and dermatitis, anemia, and neurologic refined carbohydrate-rich diets that are low in fiber impairments. Proper balance of copper with zinc (and and chromium are contributing to the growing prevaother trace elements) is necessary for good health. A low lences of overweight, obesity, and type 2 diabete~.'~-*~ratio of copper to zinc can result from dietary deficiency Despite some studies reporting no benefit from the use of copper or excessive zinc intake, and may lead to of chromium supplementation in the amelioration of hypercholesterolemia, myocardial and arterial damage, and higher mortality. High levels of serum copper found disorders of glucose metabolism,28the majority of studies have demonstrated a role for chromium in improving glucose utilization and/or blood profile~.2~-~~ The supplement chromium picolinate has received considerable research in use as an adjunct to the treatment of type 2 diabetes.33 The safety of chromium supplementationis well estabGender Age (yr) RDA DRI/RII Optimal lished. Even in pharmacologic doses (50 to 1000 mg/day for 1 to 3 months), it has no toxicity in cats, rats, or mice. Male 11-14 50-200 25 200 Several reports have found DNA damage or signs of 15-18 50-200 35 200 oxidative stress in vitro after exposure to high concen19-24 50-200 35 300 trations of chromium picolinate, including one study 25-50 50-200 35 300 in fruit flies exposed to chromium picolinate but not 51+ 50-200 30 300 an equivalent amount of chromium Female 11-14 50-200 21 200 Countering these concerns are a number of studies 50-200 24 200 15-18 supporting the safe use of chromium picolinate in vivo. 19-24 50-200 25 200 A rat study found no pathologic changes after 6 weeks 25-50 50-200 25 300 of daily oral administration of chromium pi~olinate.~~ 300 51+ 50-200 20 Two months of daily oral administration of 400 pg of chromium picolinate to 10 obese women found no signs Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily of oxidative damage to DNA.40 Sixty subjects with Allowance; DRl/RIl, Dietary Reference IntakeslRecommended Intakes for type 2 diabetes were given oral doses of 1000 pg of Individuals.

in humans living in areas with low selenium levels in the Recommended intake of soil and high copper content in drinking water have copper (mg) been associated with a significantly elevated incidence of atherosclerosis. The ideal zinc-to-copper ratio should Gender Age (yr) RDA DRVRII Optimal UL be between 8:l and 14:1.1-6 Male 11-14 1.5-3.0 0.7 1.5-4 5.0 Excess fructose consumption in the presence of inad8.0 1.5-3.0 0.9 1.5-4 15-18 equate copper intake has been shown in several mam0.9 1.5-4 10.0 19-24 1.5-3.0 malian species to lead to heart arrhythmias (in humans) 10.0 1.5-3.0 0.9 1.5-4 25-50 and even heart failure (in animal^).^-'^ The homeostasis 10.0 1.5-3.0 0.9 1.5-4 51+ of hormones is impaired by the consumption of fructose Female 11-14 1.5-3.0 0.7 1.5-4 5.0 with a low-copper diet, which in animal studies has been 15-18 1.5-3.0 0.9 1.5-4 8.0 shown to decrease levels of plasma thyroid hormones, 0.9 1.5-4 10.0 1.5-3.0 19-24 insulin,epinephrine, and norepinephrine, and to increase 10.0 1.5-3.0 0.9 1.5-4 25-50 glucocorticoids. How a deficiency of copper and excessive dietary fructose intake can result in such cardiovas10.0 1.5-3.0 0.9 1.5-4 51+ cular problems in humans remains a matter for further Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily research for well over a decade.I4l9In a study performed Allowance; DRVRIl, Dietary Reference IntakedRecommended Intakes for by the U.S.Department of Agriculture Human PerforIndividuals; UL, Tolerable Upper Intake Level. mance Laboratory, examining the effect of fructose consumption on copper, arrhythmias developed in some subjects within several weeks. known to be bactericidal. This bactericidal activity is It has been known for some years that dietary fructose accomplished by an abundant cellular halide, the exacerbates the signs associated with copper deficiency, chloride including anemia, hypercholesterolemia, impaired gluDeficiencies of iodine, iron, and vitamin A are the cose tolerance, pancreatic atrophy, cardiomyopathy, and three most common micronutrient deficiencies in develincreased mortality. In the last 25 years there has been oping countries. A study in an iodine-sufficient area of a dramatic rise in the use of fructose as a sweetener in Sudan that was nevertheless known as a goiter endemic beverages, particularly sodas, fruit juices, and processed area, consumption of millet was one of the etiologic foods. How much the higher intake is related to the rise factors suggested.'O This may be possible because in obesity, diabetes, and coronary diseases is being quessorghum contains dhurrin, a cyanogenic glucoside that tioned by researchers worldwide. Fructose consumption could raise the iodine-to-thiocyanate ratio above a critiduring lactation also produces a significant reduction in cal level found in goiter. In another study conducted copper concentrations in breast milk. in the Ivory Coast (Cote d'Ivoire), when iodine was There is no evidence of a decline in copper status with given to children at high risk of goiter, the therapeutic Copper supplementation should be approached response to oral iodine was impaired if the child was with caution because copper is among the most powerful also iron deficient." This finding suggests that the presproducers of free radicals. However, when copper is in ence of iron deficiency anemia in children might limit proper balance with zinc, the two elements act as antioxthe effectiveness of iodine supplementation. idants by removing damaging free radicals such as the Iodine in large amounts disturbs all thyroid functions. superoxide radical. Excess copper supplementation supLow thyroid function is often associated with low body presses immune function,22*u whereas copper deficiency can have adverse effects on immune f u n ~ t i o nand ~ ~ , ~ temperature. Twenty-four patients who had consistently subnormal temperatures were treated with 1500 pg neutropenia (Table 127-17).26 of iodine per day. Twelve subjects underwent thyroid Iodine hormone analysis, results of which were normal in all. Eleven of these 12 also had low urinary iodine levels. Iodine accumulates in thyroid tissue and is incorporated Fifteen of the 24 patients' temperature returned to into thyroxine and triiodothyronine, the hormones of the normal within 1 month.I2 The investigators suggested thyroid gland. Iodine deficiency is the most common that low body temperature may indicate iodine deficause of endemic goiter and cretinism. Milk and dairy ciency and/or some other metabolic abnormality. For products as well as bread and bakery products are the people who have subnormal temperatures and do not main sources of iodine in human food. Iodine is concenhave a palpable multinodular goiter, iodine supplement trated in milk and eggs, which are second only to seafood may be metabolically beneficial and safe. as the richest sources of iodine. Marine (sea) salt is a The RDA for iodine is 2 pg/kg of body weight in poor source of iodine. In conjunction with two enzymes adults and somewhat more in children. This amount (myeloperoxidase and hydrogen peroxide), iodine is

I

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements

seems adequate to provide for the biosynthesis of the thyroid hormones. Additional intakes of 25 and 50 pg, respectively, may be required during pregnancy and lactation. The most common supplementation method for iodine is via iodized salt, 1 g of which supplies approximately 75 yg of iodine. In the event of a nuclear reactor accident, a single dose of 300 mg of potassium iodide may help block the uptake of radioactive iodine (I3II) by the thyroid (Table 127-18).

Iron Most iron in the body is found in the hemoglobin of red blood cells. Some iron is also found in the myoglobin found in skeletal muscles and the heart. The remaining iron is found in enzymes essential to energy Iron deficiency is one of the most common deficiency diseases in the world. Even in the United States, repeated dietary surveys have found inadequate iron intake to meet even the RDA. The most common cause of this inadequacy is nutritional, including inadequate absorption of iron due to poor iron intake, and reduced bi~availability.~ Iron loss, resulting from pregnancy, internal bleeding, menstruation (in women),'O parasitic infections (e.g., hookworm), low stomach acid (e.g., hypochlorhydria, achlorhydria), and malabsorption are also important factors in iron deficiency. Some data suggest that iron deficiency anemia may be a secondary outcome of vitamin A deficiency, which contributes to defective iron transport.'lJ2 The risk of iron deficiency is relatively high in menstruating women eating a diet inadequate in iron. This is one reason the RDA for iron is higher for adolescent and adult women than for men. However, many women are following reduced-calorie diets that are unable to provide enough iron to maintain

homeostasis; for this reason, such women need to consider iron supplementation. Nonheme iron is the main source of iron in the diet, although it is much more poorly absorbed than heme iron, which is found only in animal sources. Meat, fish, and vitamin C enhance the absorption of nonheme iron. However, new studies are showing that even moderate consumption of calcium in foods or as supplements can reduce both heme and nonheme iron a b s ~ r p t i o n . ' ~ ' ~ These reductions could have important nutritional implications, especially for people such as premenstrual women and pregnant women, who may already be at high risk for iron deficiency. Symptoms of iron deficiency anemia include fatigue, irritability, paleness, intolerance to cold, and a general sense of lack of well-being. Brain function can also be impaired by iron d e f i c i e n ~ y . 'Inadequate ~~~ iron levels tend to effect the right hemisphere of the brain and have been linked to cognitive impairment, poor attention span, restlessness, and the inability to concentrate. Optimal levels of iron are also essential to immune function. Because iron is an essential trace element vital to human health, there has been extensive study of its role in humans, from conception through pregnancy (including middle- and upper-income womenz5) to old Iron supplementation is not safe for individuals with any iron storage disorder, such as hemosiderosis, idiopathic hemochromatosis, or a thalassemia (Table 127-19).

Magnesium The mineral magnesium, half of which is in bones, is required for many metabolic functions. One of its most important is in maintaining the function of the nervous

Recommended intake of iodine (pg) Gender Male

Female

Age (yr)

RDA

EAR

DRI/RII

11-14

150

73

120

15-18

150

95

150

UL

Gender

150

600

Male

150

900

Optimal

Age (yr)

RDA

EAR

DRllRll

Optimal

UL

11-14

12

5.9

8

15

40

15-18

12

7.7

11

15

45

19-24

150

95

150

150

1100

19-24

10

6.0

8

20

45

25-50

150

95

150

150

1100

25-50

10

6.0

8

20

45

51+

150

95

150

150

1100

51+

10

6.0

8

20

45

11-14

150

73

120

150

600

11-14

15

5.7

8

20

40

15-18

150

95

150

150

900

15-18

15

7.9

15

20

45

19-24

150

95

150

150

1100

19-24

15

8.1

18

22

45

25-50

150

95

150

150

1100

25-50

15

8.1

18

22

45

51+

150

95

150

150

1100

51

+

15

5.0

8

20

45

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DRl/Rll, Dietary Reference IntakedRecommended Intakes for Individuals; UL. Tolerable Upper Intake Level.

Female

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DR//R//, Dietary Reference IntakedRecommended Intakes for Individuals; UL, Tolerable Upper Intake Level.

Pharmacology of Natural Medicines

system and neuromuscular transmission and activity. Magnesium deficiency is associated with tremors, muscle spasms, convulsions, neuropsychiatric disturbances, coronary artery disease, angina pectoris, cardiac arrhythmias, and hypertension. Along with calcium, sodium, and potassium, magnesium affects the muscle tone of blood Blood levels of magnesium are low in patients with myocardial ischemia, coronary artery spasm, mitral valve prolapse, and cardiac tachyarrythmias. Low tissue and blood levels have also been observed in patients prior to, during, and after myocardial infarction. Magnesium insufficiency directly and indirectly affects cardiac function through its effect on potassium, sodium, and calcium concentrations in cells and surrounding fluids. Given that coronary and heart disease contributes profoundly to morbidity and mortality in developed countries, an intake of magnesium higher than RDA could have a profound impact on early Studies have also implicated lack of sufficient magnesium as a cause of preeclampsia and hypertension in pregnant women.26Low levels of magnesium combined with an altered calcium/magnesium ratio has been found in severe dementia of the Alzheimer's type.27 The prevalence of hypomagnesemia is widespread throughout the world, particularly in a range of patients with various maladies and diseases.2a31This is not surprising when one realizes that in the United States magnesium intake from the diet has declined from more than 400 mg/day in the beginning of the twentieth century to around 250 mg/day at the end of the century. Given the growing prevalence of individuals with airway respiratory problems, it is interesting that merely increasing magnesium intake by 100 mg/day has been shown to improve lung function while reducing wheezing and airway hyperreacti~ity.~~ There is a consensus of opinion in the health care community that magnesium ranks among the most important of all nutrients. It is involved in more than 200 enzyme reactions in the human body, and magnesium deficiency contributes to or causes a wide range of degenerative diseases, particularly cardiovasculardisease, to which the World Health Organization attributes onethird of all deaths globally (15.3 million people). A higher optimal daily intake of magnesium is without doubt one of the most important pieces of advice a clinician can suggest to a patient (Table 127-20).33

Manganese Manganese is involved in protein, fat, and energy metabolism and is required for bone growth and development as well as reproduction. Diets high in refined carbohydrates may provide inadequate intake of manganese. Addition of supplemental iron to the diet can depress manganese retention if iron nutriture is

poor. Concentrations of manganese in tissues and organs remain relatively constant with age.1-6 Patients with osteoporosis have been found to have low levels of manganese. There is emerging evidence that manganese supplementation, alone or combined with other nutrients, may reduce the risk of bone loss and fracture^.^-'^ There is some evidence that managanese alone or in combination with several other vitamins and minerals can treat tardive dy~kinesia."-*~ Given manganese recognition as an essential trace element, research showing its importance to human health is extensive and growing. Sources of dietary manganese are mainly plant foods, because animal tissue contains very low amounts of this nutrient. One exceptionally rich dietary source for manganese is tea. However, tea can inhibit the uptake of iron (Table 127-21).

Phosphorus Approximately 85% of the phosphorus in the body is in bone as calcium phosphate and/or hydroxyapatite. Deficiencies of this nutrient are extremely rare because foodstuffs seem to provide an ample supply. Both animal and plant foods are rich in phosphates. However, a vitamin D deficiency may reduce absorption of phosphorus. Most adults consume between 1000 and 1500 mg of phosphorus each day, 50% to 60% of which is normally ab~0rbed.I-l~ A phosphorus intake greatly in excess of calcium intake, especially if the calcium intake is minimal (400 mg/day or less), can reduce calcium availability and contribute to calcium deficiency. In general, the calcium-tophosphorus ratio should be about 1:l and definitely not above 1:2 (Table 127-22).

Gender Male

Female

Age (yr)

RDA

EAR

DRI/RII

Optimal

UL

11-14 15-18 19-24 25-50 51+ 11-14 15-18 19-24 25-50 51+

270 400 350 350 350 280 300 280 280 280

200 340 330 350 350 200 300 255 265 265

240 410 400 420 420 240 360 310 320 320

300 400 500 500 600 300 400 450 450 550

350 350 350 350 350 350 350 350 350 350

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DR//R//, Dietary Reference IntakedRecommended Intakes for Individuals; UL, Tolerable Upper Intake Level.

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements

Gender Male

Female

DRI/RII

Optimal

UL

2-5

1.9

5

6

2-5

2.2

5

9

19-24

2-5

2.3

5

11

Age (yr)

RDA

11-14 15-18 25-50

2-5

2.3

5

11

51+

2-5

2.3

10

11

11-14

2-5

1.6

5

6

2-5

1.6

5

9

15-18 19-24

2-5

1.8

5

11

25-50

2-5

1.8

5

11

51+

2-5

1.8

10

11

Opfimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DRl/Rl/, Dietary Reference IntakedRecornmended Intakes for Individuals; UL, Tolerable Upper Intake Level.

Gender Male

Female

Aae (vr)

RDA

EAR

DRI/RII

Optimal

UL

11-14

1200

1055

1250

1200

4000

15-18

1200

1055

1250

1200

4000

19-24

1200

580

700

1200

4000

25-50

800

580

700

800

4000

51+

800

580

700

800

3000

11-14

1200

1055

1250

1200

4000

15-18

1200

1055

1250

1200

4000

19-24

1200

580

700

1200

4000

25-50

800

580

700

800

4000

51+

800

580

700

800

3000

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DRVRll, Dietary Reference IntakedRecommendedIntakes for Individuals; UL,Tolerable Upper Intake Level.

Potassium Potassium is an essential element in maintaining fluid balance in the cells, transmission of nerve impulses, skeletal muscle contractility, and normal blood pressure. However, it must exist in balance with sodium. During nerve transmission and muscle contraction, potassium and sodium exchange places. Together with high sodium intake, decreased potassium intake may be implicated in hypertension and heart disease. Potassium is also a catalyst in protein and carbohydrate metabolism. Diuretic drugs can deplete potassium and so can be dangerous. When sodium is lost with water from the body, the ultimate damage comes when potassium moves out of the cells with cell water.

There is no RDA for potassium. However, some authorities believe that the minimum requirement should be between 1600 and 2000 mg/day. An intake of about 1600 mg/day is required just to maintain normal body stores and a normal concentration in plasma and fluid, so a higher intake for many lifestyles involving loss of water would ensure optimal body levels. According to some researchers, a diet rich in fruits and vegetables and low in sodium should ensure maintenance of optimal potassium levels.*-22 However, it has been calculated that due to the poor absorbability of potassium in fruit without chloride, only 40% of the potassium (e.g., in a banana) is retained. Unfortunately this finding is often not calculated into food value tables that estimate total potassium intake from foods. This is one reason that when potassium supplementation is suggested, potassium chloride is recommended. A low-sodium diet enhances potassium conservation, whereas a high-sodium diet promotes potassium excretion. In a study comparing vegetarians with nonvegetarians, sigruhcantly lower blood pressure was found in every decade of age in the vegetarians, only 2%of whom had hypertension (higher than 160 mm Hg systolic/95 mm Hg diastolic) compared with 26% of the nonvegetarians.2ltZ This study further confirms the important role that potassium plays in the regulation of blood pressure. In a study of 10,000 subjects in the United States, it was found that persons with the highest levels of calcium, potassium, vitamin A, and vitamin C had the lowest incidence of hypertension, suggesting that potassium is not the only essential nutrient in maintaining normotensive status in humans.23It has also been shown, in a population consuming a high-sodium and low-potassium diet (in China), who were given either 60 mmol of potassium chloride or placebo in a randomized trial, that potassium effected a significant reduction in systolic blood pressure but not diastolic blood pressure.” Because potassium is one of the nutrients along with magnesium in fruits and vegetables, it has been hypothesized that bone mineral functions as a buffer base and that lifetime buffering of the acid load from the ingestion of mixed diets leads to gradual and accumulated bone loss. This hypothesis suggested that it might be worthwhile to consider decreasing the rate of bone loss through the use of a diet favoring alkaline ash. Since potassium is one of the two minerals that has a known buffering effect, a study reported that greater potassium intake was sigruficantly associated with greater bone mineral density and less decline in bone mineral density for both men and women.= Given the increased consumption of carbonated beverages (sodas), which contributes to acid ash, individuals insisting on consuming these drinks should consider potassium and magnesium supple mentation and/or a diet containing at least seven to nine portions of fruits and vegetables a day.

Pharmacology of Natural Medicines

Observational studies have identified an inverse association between dietary intake of potassium and blood pressure level. Randomized trials have demonstrated that potassium supplementation lowers blood pressure in both hypertensive and normotensive persons. Clinical trials have also shown that a low dietary potassium intake raises blood pressure.26In a prospective study of 19 years of follow-up in 9805 men and women who participated in the first " E S (NHANES I) found that stroke hazard was sigruficantly more likely among participants consuming a low-potassium diet, after adjustment for established cardiovascular disease risk fact0rs.2~ These findings suggest that there is an association between low dietary potassium intake and an higher risk of stroke. The greatest benefit of potassium supplementation, however, remains among individuals with a high intake of sodium. Increased potassium intake should be included as a recommendation for prevention and treatment of hypertension, especially in individuals unable to reduce their intake of sodium.28Neither an N D I nor a UL has been determined for potassium (Table 127-23).

Selenium Selenium is a cofactor for enzymes and proteins with significant importance in free radical scavenging, thyroid hormone and insulin function, regulation of cell growth, and maintenance of fertility. Selenium is found in food primarily in the form of selenomethionine and selenocysteine-the former the prime form in plants, and the latter the main form in foods of animal origin. The concentration of selenium in foods depends on the selenium content of the soil and of animal feeds. Little is known about the mechanism that maintains selenium homeostasis. Several selenium enzymes contain selenocysteine, which is involved in the maintenance of sulfhydryl groups in reduced form and as a defense against free

Gender

Age (yr)

RDA

Optimal

Male

11-14

2

2

15-18

2

2

19-24

2

3

25-50

2

3

Female

51+

2

3

11-14

2

2

15-18

2

2

19-24

2

3

25-50

2

3

51+

2

3

Optimal, Suggested Optimal Nutrient Intake; RDA. Recommended Daily Allowance.

radicals. Selenium enzymes include glutathione peroxidase, hydroxyperoxides, and thioredoxin reductase.'-14 Epidemiologic studies show that a high intake of antioxidant-rich foods is inversely related to cancer risk.15z6Although animal and cell cultures confirm the anticancer effects of antioxidants, intervention trials to determine their ability to reduce cancer risk have been inconclusive. A meta-analysis found that in four trials, selenium showed sigruficant beneficial effect on the incidence of gastrointestinal cancer?' A prospective study involving 1312 subjects (75% of whom were male) found that individuals who took daily selenium supplementation at triple the RDA had 63% fewer cases of prostate cancer, 58%fewer colon or rectal cancers, and 47% fewer lung cancers than those who took the placebo. Overall there were 50% fewer cancer deaths in the selenium group than in the placebo group.28A reanalysis of the reduction in lung cancers found that the most significant decrease occurred among individuals with low baseline selenium concentration^.^^ Interest in the chemopreventive effects of selenium involves some 100 studies that have investigated its effects in carcinogen-exposed animals; two thirds have observed a reduction in tumor incidence and/or preneoplastic end points. These promising findings have encouraged the study of selenium supplementation's cancer-preventive attributes. Among a number of randomized, placebo trials in humans is the Nutritional Prevention of Cancer Trial (NPCT), the first results of which described a protective effect of selenium on cancer incidence, although not all site-specific cancers exhibited a reduction in incidence. The treatment effect with 200 pg of selenium (as selenium yeast) daily was restricted to males and to those with lower baseline plasma selenium concentration^.^^ The NPCT also reported a sigruficant protective effect of selenium supplementation on the overall incidence of prostate cancer, although the effect was restricted to those with lower baseline prostate-specific antigen and plasma selenium concentration^.^^ Additionally, the NPCT found that among individuals at high risk of nonmelanoma skin cancer, selenium supplementation was ineffective at preventing basal cell carcinoma and raised the risk of squamous cell carcinoma and total nonmelanoma skin cancer?' It has been demonstrated that lipid peroxidation increases in vivo in selenium-deficient rats.= Selenium has also been reported to inhibit ultraviolet light-induced skin carcinogenesis in hairless mice.% It is believed that selenium may inhibit tumor growth and induce suicide in malignant cells, possibly owing to the activities of the selenium-dependent enzymes glutathione peroxidase and superoxide d i ~ m u t a s e . ~ ~ One interesting study found a role for selenium supplementation in improving mood and decreasing anxiety. Using a double-blind cross-over design, the researchers

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements gave 50 subjects either a placebo or 100 pg selenium on a daily b a s i ~ . ~On , ~ ’three occasions the subjects filled in the Profile of Moods States (POMS). A food frequency questionnaire was used to estimate the intake of selenium in the diet. Intake was associated with a general elevation of mood and in particular, a decrease in anxiety. The change in mood in persons taking the active tablet was correlated with the estimated level of selenium in the diet. The lower the level of selenium in the diet, the more reports of anxiety, depression, and tiredness, which decreased after 5 weeks of selenium therapy. These findings were reevaluated some years later in a study that attempted to examine the impact of 200 pg/day selenium supplementation on levels of psychological burden (anxiety, depression, and mood state) in patients with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), using a randomized, double-blind, placebo-controlled design3*At the 12-monthevaluation, participants who received selenium reported greater vigor and had less state and trait changes in mood compared with the placebo-treated individuals. No apparent selenium-related effect on depression or distress was observed. The risk for state anxiety was almost four times higher, and nearly nine times greater for trait anxiety in the placebo-treated group, when data were controlled for antiretroviral therapy, CD4 cell decline (>50cells) and years of education. Selenium therapy may be a beneficial treatment to decrease anxiety in HIV-positive patients who exhibit a high prevalence of psychological burden. Selenium deficiency has been implicated in myocarditis and cardiomyopathy. This might be particularly significant for schizophrenic patients being treated with drugs such as clozapine that have been associated with the pathogenesis of life-threatening cardiac side effects. To compare plasma and red blood cell (RBC) selenium concentrations of schizophrenic patients treated with clozapine, with healthy controls and patients with mood disorders, a study measured plasma and RBC selenium concentrations in each g r o ~ p . Selenium 3~ concentrations in plasma and red cells were found to be significantly lower in schizophrenic patients treated with clozapine than in all other groups. The metabolism of selenium by the brain differs from that of other organs, in that at times of deficiency the brain retains selenium to a greater extent. The preferential retention of selenium in the brain suggests that the element plays important functions. To date mood is the clearest example of an aspect of psychological functioning that is modified by selenium intake. Five studies have reported that a low selenium intake was associated with poorer mood. The underlying mechanism is unclear, although a response to supplementation was found with doses greater than those needed to produce maximal activity of the selenoprotein glutathione peroxidase.40

Alcohol use has been shown to affect selenium status.41The effects of alcohol intake on mood, behavior, and cognition may be partly mediated by biologic changes related to selenium deficiency. It has been observed that there is a trend toward the normalization of selenium levels in patients with alcoholism after a relatively short period of abstinence from alcohol. It has also been observed that when depression develops in persons with alcoholism, they are likely to improve fairly rapidly after a relatively short period of abstinence from alcohol without therapy aimed at the depressive symptoms. Depression and behavioral problems are common in patients undergoing dialysis. It has also been suggested that dialysis-related selenium loss may play a role in biological mechanisms of psychiatric disorders in dialysis The argument supporting higher selenium intake via supplementation is becoming increasingly persuasive. Selenium supplementation appears to enhance the immune response. Selenium appears to counteract certain viral infections; thus, in a selenium-deficient host the benign coxsackie virus becomes virulent, causing heart damage, the influenza virus causes more serious lung disease, and HIV infection progresses more rapidly to AIDS. Long recognized as essential for successful animal reproduction, selenium is required for human sperm maturation and sperm motility and may reduce the risk of miscarriage. Findings have been equivocal in linking selenium to cardiovascular disease risk, although other conditions involving oxidative stress and inflammation have shown some association with selenium status. A deficiency of selenium has been linked in several studies to an impairment in mood states. There is growing evidence that higher selenium intakes are associated with reduced cancer r i ~ k . 4Adequate ~ levels of selenium taken with chromium, copper, potassium, magnesium, and calcium have been found to lower the risk of cardiovascular disease. There is evidence that in elderly people, several hundred micrograms of selenium and 400 mg of vitamin E improve mental status, motivation, initiation, emotional stability, mental alertness, interest in the environment, and self-care while reducing anxiety, depression, poor appetite, and fatigue. This finding suggests that optimal selenium nutriture is increasingly important in the latter decades of life. The preferred form of selenium in a dietary supplement is selenomethionine. Vitamin C intake of 600 mg/day has been shown to increase dietary selenium absorption by nearly 100%. There is data suggesting that ingesting more than 750 to 1000 pg of selenium per day over an extended period may be harmful. Therefore optimal levels must remain below this level until evidence suggests that a higher upper intake level is safe (Table 127-24).

Pharmacology of Natural Medicines

Gender Male

Female

Age(yr)

RDA

EAR

DRllRll

Optimal

UL

Gender

11-14 15-18

40

35

50

45

40

75

280

Male

55

150

400

19-24

70

45

55

200

400

25-50 51+

70

45

55

200

70

45

55

250

11-14

45

35

40

75

280

15-18

50

45

55

100

400

Age (yr)

RDA

Optimal

11-14

500

400

15-18

500

400

19-24

500

400

400

25-50

500

400

400

51+

500

400

11-14

500

400

15-18

500

400

Female

19-24

55

45

55

150

400

19-24

500

400

25-50

55

45

55

175

400

25-50

500

400

51+

55

45

55

200

400

51+

500

400

EAR, Estimated Average Requirement: Optimal, Suggested Optimal Nutrient Intake: RDA, Recommended Daily Allowance; DRl/R/l, Dietary Reference IntakedRecommendedIntakes for Individuals; UL, Tolerable Upper Intake Level.

SodiudSodium Chloride Sodium chloride is the primary source of sodium (39%sodium by weight). The healthy adult can maintain sodium balance with an intake of approximately that required by an infant. Close regulation of the concentration and content of sodium within the body is crucial for health. Disorders of sodium regulation are a central feature of many human diseases. In general, the regulation of sodium in the body involves two processes, the control of sodium loss and the control of sodium intake. Sodium chloride occurs naturally in most foods. The problem is that sodium chloride is also added to most processed foods, often in amounts well in excess of that required physiologically or to maintain health. This added intake has been the subject of numerous studies, which have frequently found that the level of sodium chloride ingested by Americans is 10 to 20 times the level required to maintain Many studies have found an association between excessive intake of salt and hypertension.*I6 The highest intakes (28 g/day) have been found in northern Japan where it is estimated that 38% of the population is hypertensive. In contrast, Alaska natives consume only 4 g/day and rarely have hypertension. However, some studies do not show an association between salt and hypertension. These studies tend to be too small to discover the association and frequently fail to consider dietary potassium intake. Numerous studies have shown that potassium can limit some of the toxic effects of excessive sodium ingestion. For most individuals, the most prudent approach would be to limit salt intake by restricting salted processed foods. This alone should reduce daily salt intake by between 3 and 5 g, or about one third the daily salt intake of the average American (10 to 14.5 g/day).

Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance.

Refraining from adding salt to food at the table would reduce salt intake another third. The remaining one third is approximately the amount of salt per day found in populations with very low incidence of hypertension. Potassium chloride may be an acceptable substitute for sodium chloride, especially when other agents, such as citric acid and other acids, have been added to mask its unpleasant bitter taste. However, it is important to recognize that some individuals with hypotension (low blood pressure) may benefit from added salt. Nevertheless, there remains no known benefit from large intake of either sodium or sodium chloride. Maintaining a low salt intake throughout life may decrease the risk of hypertension in the portion of the population at risk.” Neither an RDI nor a UL as been determined for sodium. (Table 127-25)

Vanadium Vanadium belongs to a group of three elements, chromium (Cr), titanium (Ti), and vanadium (V) that are aligned next to each other on the periodic table of elements and share many of characteristics. Vanadium has an unusually large number of different oxidation states. It combines with nearly all nonmetals. That explains why there are so many vanadium compounds. The important forms of vanadium in biologic systems are the tetravalent (4) and pentavalent (+5) states. The former complexes with such substances as hemoglobin to stabilize cells membranes against oxidation. Vanadium has been shown to be an essential trace element in the growth of animals since 1973.’” Trace amounts of vanadium appear to be needed for human health, although no specific essential function has been found for it to date.4Adults consume

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements

between 10 and 100 pg/day from food, of which a small fraction (1%to 5%)is absorbed. Vanadate can be reduced nonenzymatically to vanadyl by ascorbic acid, the reduced form of nicotinamide adenine dinucleotide, or glutathione. Most vanadium is stored in bone in the range of 0.1 to1 mg. Vanadium complexes with cis-diols and other compounds and competes with transition metals for binding to metalloproteins and adenosine triph~sphate.~ A deficiency disease associated with vanadium has not been identified in humans. In rats, vanadium deficiency has been found to increase thyroid weight and decrease thyroid peroxidase content. Vanadium may be essential to human health through its contribution to the efficiency of insulin action inside the cell. To understand why requires a review of animal studies examining its role in insulin regulation and the possible treatment of diabetes. Starting in 1971 and continuing for two decades thereafter, a series of papers reported that vanadium (as vanadate) had an insulin-mimetic effe~t."~ A 1983 study showed vanadium toxicity (at 1.1 mg of vanadium as oral sodium orthovanadate decahydrate [4 mg]).IoIn 1985, a study showed lipid peroxidation in the kidneys of rats and mice after vanadium ingestion." In 1985, a paper reported that when diabetic rats were given drinking water containing vanadium, blood glucose levels were reduced.lZ By 1988 several studies had confirmed these results. Of all forms of vanadium, vanadyl sulfate was reported as most effective. Additionally, a 3-month subacute toxicity study in rats given sodium metavanadate 0, 5, 10, and 50 ppm followed by histopathologic examination showed no mortality, only mild dose-dependent lesions in kidneys and spleen, and an increased concentration of urea and uric acid in the group with the highest exp~sure.'~ An acute toxicity study found that most animals died within 24 hours, when sodium metavanadate or vanadyl sulphate pentahydate was administered orally to rats and mice at 448 mg/kg (rats) and 467 mg/kg (mice).14 However, between 1989 and 1991, researchers attempting to replicate the earlier reports of its insulinmimetic effect began to report negative side effects, including animal deaths.15-18 These findings led to growing concern about the long-term risks associated with vanadium supplementation in humans. The enthusiasm for vanadium as a treatment for diabetes was tempered in 1989, when researchers of the original 1985 paper12reported that the concentration of vanadate used in the drinking water was toxic to some animals and did indeed result in severe diarrhea and death because of dehydration (which they had not reported). As more studies from 1989 on reported signs of toxicity in all of the vanadium-treated animals, some toxicologists concluded that oral vanadium administration was not a suitable therapy for diabetes mellitu~.'~ By 1993,

the list of vanadium toxicity symptoms and signs had grown to include the following: inhibits feeding; DNA damage; generates hydroxyl radicals; induces lipid peroxidation; causes red blood cell destruction, cells rupture; causes immunosuppression; and, induces death in animal studies. By late 1994, Malabu et a120reported as follows: With the possible exception of cytotoxic drugs, it must be almost unprecedented for an agent with such an impressive record of morbidity and mortality to reach the point of being tested in humans. Doming0 and Keen et a1 have stated repeatedly that they do not regard vanadium as a viable option to treat human diabetes, and we can only echo these sentiments. Of particular concern is the tendency of vanadium to accumulate in a time and dose-dependent fashion, notably in the kidney and other tissues.

Nevertheless, the evidence for its efficacy continued to be reported, without mention of side effects, as shown in the following quotationz1: Our results suggest that the oral administration of vanadyl sulphate has a beneficial effect on blood sugar homeostasis, restores the ability of skeletal muscles to accumulate glycogen efficientlyin response to circulating insulin, and may compensate for the loss of hormone sensitivityin the peripheral tissues of senescent animals.

Because of concerns about the toxicity of vanadium, newer and safer forms of vanadium have been developed, including the following vanadium complexes: bis(1-oxy-2-pyridinethiolato)oxovanadium; a vanadylemethylpicolinatecomplex; a vanadium ligand L-glutamic acid gamma-monohydroxamate;and, peroxovanadiums. One of the promising forms is a vanadyle-methylpicolinate complex, which has long-acting characteristics and low toxicity.It has been shown in preliminaryin vivo work in rats to be beneficial in the treatment of both type 1 and type 2 diabetes mellitus when administered orally. Vanadium is now considered by some to be an essential trace element. Intake of 10 kg/day is thought to meet the body's needs (U.S. diets contain between 10 and 53 pg/day). Some body-building and diabetic-oriented dietary supplements contain vanadium at levels exceeding 100 mg, although dietary needs are likely to be in microgram amounts (some 1000 times lower). It is not possible to determine an optimal level of vanadium because of the lack of sufficient evidence for its essentiality in humans. The UL for vanadium has been determined only for adults: 1.8 mg/dayZ3No RDA or DRI has been determined for vanadium. The optimal intake level cannot be determined, but should stay below the UL of vanadium for adults.

Zinc An adequate supply of zinc is essential for growth and

physical development as well as for the metabolism of

Pharmacology of Natural Medicines proteins, fats, and carbohydrates. Most aspects of reproduction in both males and females requires zinc. This mineral is also vital to the immune system. Virtually every enzyme reaction in the brain involves zinc, and its essentiality in the development and function of the central nervous system and brain is uncontested. Zinc is antagonistic to such toxic elements as cadmium, mercury, and lead.14 The highest concentrations of zinc are in the ear and Disorders associated with impairment of either organ may benefit from continuous optimal intakes of zinc over a lifetime. Zinc supplementation has been demonstrated as a treatment for presbycussis.'2 The typical intake of zinc in Western diets is around 10 mg, two thirds the RDA. The elderly often consume less than half the RDA for zinc.13 Although some individuals seem to be poor absorbers, most cases of zinc deficiency, whether chronic or marginal, are self-inflicted. This may result from weight loss efforts, vegetarianism, or other lifestyle habits (e.g., alcoholism, excessive exercise). However, in some cases relative zinc deficiencies are induced by exposure to toxic metals, such as cadmium in cigarette smoke and excess copper from copper water pipes. There is increasing evidence that zinc levels decline after physical stress or injury. Zinc is one of the few minerals lost rapidly in the urine after acute or chronic psychologic stress, which can lead to inadequate zinc status, despite RDA intake. To maintain homeostasis in an adult, at least 5 mg/day of zinc in the diet

is needed. In the United States, inadequate zinc intake (5 pg/day) is found in 18% to 80% of various population groups. To enable the reader to gain an appreciation of the function of zinc in human health, Table 127-26 lists a few of the zinc metalloenzymes and binding proteins and their function. Impairments of taste, vision, smell, and appetite can be early signs of inadequate zinc status. There is a simple test for zinc status (Zinc Status, Ethical Nutrients, San Clemente, CA) that evaluates the ability to taste a premixed solution of zinc sulphate.14Individuals unable to taste this solution have been found to be zinc deficient, in some cases despite being asymptomatic. Insufficient zinc has multiple effects on the immune system, particularly T lymphocytes, decreased number and activity of killer cells, and impaired antibody production. Zinc deficiency is common in anorexia nervosa and is often seen both in bulimia nervosa and obesity.15,16 During an infant's first year of life, the newborn has an excess of copper, which needs to be balanced by zinc; otherwise it could lead to irritable behavior, because excessive copper levels can act as a neurotoxic agent in the central nervous system. During any period of rapid growth in the child, the daily requirement for zinc rises. After age 10 to 12 years, zinc is required for normal pubertal development, or else a lag in growth can occur. In adolescent females, zinc tends to be lower and copper higher, which can contribute to increased menstrual

Zinc-dependent enzyme or binding-protein

Function

Alcohol dehydrogenase

Metabolize alcohol

Alkaline phosphatase

Hydrolyze phosphate group

Angiotensin-converting enzyme

Regulate blood pressure; maintain salt balance

Carbonic anhydrase

Conversion of carbon dioxide and bicarbonate

Carboxypeptidase A and B

Digest protein from the diet

Catecholamine vesicles

Enhance protein matrix holding catecholamines

Component 9 of complement

Support immune function

Cytochrome c

Electron transport and energy production

Fructose-1,bdiphosphatase

Gluconeogenesis

Glyoxalase

Detoxification of aldehydes

Insulin

Part of the molecule

Lactate dehydrogenase

Convert pyruvate to lactic acid during anaerobic energy production

Malate dehydrogenase

Support energy production in the Krebs cycle

Metallothionein

Storage, transport, and excretion of zinc

Polymerase (ADP-ribose)

Repair damaged DNA

Sphingomyelinase

Catalyze sphingomyelin

Thymulin

Immune system hormone

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements tension. From adolescence on, stress of any kind can cause greater loss of zinc; urinary zinc excretion can increase threefold. Stress increases utilization and loss of zinc. Shortage of zinc before birth can predispose one's sensitivity to stress later in life. Zinc deficiency in stressed animals produces loss of appetite or erratic eating patterns. Moderate zinc deficiency reduces emotional stability. Chronic zinc deficiency is associated with various mental health problems, including lethargy, mild to moderate depression, mood instability, and impairment of both concentration and abstracting thinking (reasoning). Lack of zinc can bring about a poor emotional response to stress. Zinc loss in adult females can alter personality by increasing and decreasing energy production, producing changes in mood. Metabolically, zinc functions indirectly as an antioxidant by protecting sulfhydryl groups against oxidation and inhibiting electron transfers by prooxidant metals. Zinc is a binder to cysteine, histidine, and the albumins (glycoproteins in plasma), where it assists in binding nucleo-proteins to help maintain stability of RNA structures in protein synthesis. The trace element is also required to maintain insulin activity as well as for DNA and protein synthesis. Ensuring that a pregnant woman has adequate zinc status can reduce infant morbidity and mortality so that the infant is born within normal weight range. There is insufficient evidence to suggest zinc intake should be twice the RDA for zinc. However, because repeated studies of westernized diets indicate that most populations consume less than the RDA of this essential mineral, it seems prudent that some supplementation of zinc and/or an increase in zinc-rich foods be considered a part of maintaining an optimal level of this nutrient over a lifetime. Zinc supplementation is generally safe if maintained at levels within two to eight times the RDA. Symptoms of zinc toxicity include gastrointestinal irritation, vomiting, adverse changes in HDL/LDL cholesterol ratios,

Introduction 1. National Research Council, Committee on Diet and Health. Diet and health: implications for reducing chronic disease risk. Washington, DC: National Academy Press, 1989. 2. U.S. Department of Health and Human Services. The Surgeon General's report on nutrition and health. (DHHS publication [PHS] 50210). Washington, DC: Government Printing Office 1988. 3. Verschuren Wh4, Jacobs DR, Bloemberg BP, et al. Serum total cholesterol and long-term heart disease mortality in different cultures. Twenty-five year follow-up of the Seven Countries Study. J A M 1995;274:131-136.

and impaired immunity.17The latter develops when levels above 180 mg/day are consumed for more than several weeks. Excess intake of zinc may either lower copper levels or aggravate an existing marginal copper deficiency. Zinc status is subject to strong homeostatic regulation.1a As stated in the 10th edition of the RDA: Small amounts of zinc are more efficiently absorbed than large amounts, and persons in poor zinc status absorb more efficiently than those in good status. . . . Because of such efficient regulation, a person's zinc requirements depend predominantly on that person's zinc status or body pool of

mobilized zinc.19 Given the multitudinous requirements of zinc in the human body and the extensive amount of research conducted on this mineral in animals and humans, maintaining optimal zinc status is essential (Table 127-27).2M5

Recommended intake of zinc (mg) Gender Male

Female

Age (yr)

RDA

EAR

DRllRll

Optimal

UL 23

11-14

15

7.0

8

15

15-18

15

8.5

11

18

34

19-24

15

9.4

11

20

40

25-50

15

9.4

11

20

40

51+

15

9.4

11

20

40

11-14

12

7.0

8

12

23 34

15-18

12

7.3

8

15

19-24

12

6.8

8

17

40

25-50

12

6.8

8

17

40

51+

12

6.8

8

17

40

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DRI/RII, Dietary Reference IntakedRecommendedIntakes for Individuals; UL, Tolerable Upper Intake Level.

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Pharmacology of Natural Medicines 7. Chandra RK. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet 1992;211241127. 8. Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1933281450-1456. 9. Food and Nutrition Board, National Research Council, National Academy of Science. Recommended dietary allowances, loth ed. Washington, DC:National Academy Press, 1989. 10. Kumpulainen, JT, Salonen, JT, eds. Natural antioxidants and food quality in atherosclerosis and cancer prevention. London: The Royal Society of Chemistry, 1996. 11. Committee on Use of Dietary Reference Intakes in Nutrition Labeling, Food and Nutrition Board, Institute of Medicine, National Academies of Science. Dietary reference intakes: guiding principles for nutrition and labeling fortification. Washington, DC: National Academy Press, 2003. 12. Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: clinical applications. JAMA 2002;2873127-3129. 13. Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: scientific review. JAMA, 2002;2873116-3126.

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Carotenes and Beta-Carotene 1. Burton GW, Ingold KU. Beta-carotene: an unusual type of lipid antioxidant. Science 1984;224569-573. 2. Mobarhan S, Bowen P, Andersen B, et al. Effects of beta-carotene repletion on beta-carotene absorption, lipid peroxidation, and neutrophil superoxide formation in young men. Nutr Cancer 1990;14:195-206. 3. Pryor WA. The antioxidant nutrients and disease prevention-what do we know and what do we need to find out? Am J Clin Nutr 1991;53:3915393S. 4. Oson JA. Provitamin A function of carotenoids: the conversion of &carotene to Vitamin A. J Nutr 1989;119:105-108. 5. Connett JE, Kuller LH, Kjelsberg MO, et al. Relationship between carotenoids and cancer. The multiple risk factor intervention trial (MRFIT) study. Cancer 1989;64:126-134. 6. Woutersen RA, Wolterbeek AP,Appel MJ, et al. Safety evaluation of synthetic beta-carotene. Crit Rev Toxic01 1999;29:515-542. 7.Schauss AG. Beta-carotene and the incidence of lung cancer in Finnish male smokers: a critique. Q Rev Natural Med 1994; 191-195. 8. Riemersma RA, Wood DA, MacInytre CCA, et al. Risk of angina pectoris and plasma concentrations of vitamins A, C and E and carotene. Lancet 1991;3371-5. 9. Gaziano JM, Manson JE, Branch LG, et al. A prospective study of consumption of carotenoids in fruits and vegetables and decreased cardiovascular mortality in the elderly. Ann Epidemiol 1995;5: 255-260. 10. Klipstein-Grobusch K, Geleijnse JM, den Breeijen JH, et al. Dietary antioxidants and risk of myocardial infarction in the elderly: the Rotterdam study. Am J Clin Nutr 1999;69;261-266. 11. Pandey DK, Shekelle R, Selwyn BJ, et al. Dietary vitamin C and beta-carotene and risk of death in middle-aged men: the Western Electric study. Am J Epidemiol1995;142:1269-1278. 12. Pet0 R, Doll R, Buckley JD, Spom MB. Can dietary beta-carotene materially reduce human cancer rates? Nature 1981;290:201-209. 13.Ziegler RG. Vegetables, fruits and carotenoids and the risk of cancer. Am J Clin Nutr 1991;53:2515259S. 14. Manson JE, Jonas MA, Hunter DJ, et al. Prospective cohort studies of vitamins and cancer. In Bray GA, Ryan DH, eds. Vitamins and cancer prevention. Pennington Center nutrition series, vol3. Baton Rouge: Louisiana University Press, 1993237-109. 15. Hennekens CH. Antioxidant vitamins and cancer. Am J Med 1994; 97(Suppl3A):2S4S. 16. Van Poppel G. Epidemiological evidence for beta-carotene in prevention of cancer and cardiovascular disease. Eur J Clin Nutr 1996;5O(S~ppl3):S57-S61. 17. Cook NR, Stampfer MJ, Ma J, et al. Beta-carotene supplementation for patients with low baseline levels and decreased risks of total and prostate carcinoma. Cancer 1999;86:1783-1792. 18. Dugas TR, Morel DW, Harrison EH. Dietary supplementation with beta-carotene, but not with lycopene, inhibits endothelial cellmediated oxidation of low-density lipoprotein. Free Rad Biol Med 1999;26:1238-1244. 19. Bendich A. Symposium conclusions: Biological actions of carotenoids. J Nutr 1989;119:112-115. 20. DiMascio P, Murphy ME, Sies H. Antioxidant defense systems: the role of carotenoids, tocopherols and thiols. Am J Clin Nutr 1991;53(Suppl):l94s-2rn. 21.Colditz GA, Branch LG, Lipnick RJ, et al. Increased green and yellow vegetable intake and lowered cancer deaths in an elderly population. Am J Clin Nutr 1985;41:32-36.

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28. Clark L, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996;2761957-1963. 29. Reid E, Duffield-Lillico AJ, Garland L, et al. Selenium supplementation and lung cancer incidence: an update of the nutritional prevention of cancer trial. Cancer Epidemiol Biomarkers Prev 2002;ll: 1285-291. 30.Duffield-LillicoAJ, Reid ME, Turnbull BW, et al. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemol Biomarkers Prev 2002;11:630-639. 31. Duffield-Lillico AJ, Dalkin BL, Reid ME, et al. Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU Int 2003;91: 608-612. 32. Duffield-Lillico AJ, Slate EH, Reid ME, et al. Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial. J Natl Cancer Inst 2004 96333-334. 33. Sword J, Pope A, Hoekstra W. Endotoxin and lipid peroxidation in vivo in selenium- and vitamin E-deficient and -adequate rats. J Nutr 1991;121:251-257. 34. Overad K, Thorling EB, Bjerring P, Ebbesen P. Selenium inhibits UV-light-induced skin carcinogenesis in hairless mice. Cancer Lett 1985;27163-170. 35. L'Abbe M, Fischer W, Trick K, et al. Dietary Se and tumor glutathione peroxidase and superoxide dismutase activities. J Nutr Biochem 1991;2:430-436. 36. Benton D, Cook R. Selenium supplementation improves mood in a double-blind cross-over trial. Psychophannacology (Berl) 1990;102:549-550. 37. Benton D, Cook R. The impact of selenium supplementation on mood. Biol Psychiatry 1991;291092-1098. 38. Shor-Posner G, Lecusay R, Miguez MJ, et al. Psychological burden in the era of HAART impact of selenium therapy. Int J Psychiatry Med 2003;3355-69. 39. Vaddadi KS, Soosai E, Vaddadi G. Low blood selenium concentrations in schizophrenic patients on clozapine. Br J Clin Pharmacol 2003;55:307-309. 40.Benton D. Selenium intake, mood and other aspects of psychological functioning. Nutr Neurosci 2002;5:363-374. 41.Sher L. Role of selenium depletion in the etiopathogenesis of depression in patients with alcholism. Med Hypotheses 2002;59:330-333. 42. Sher L. Role of selenium depletion in the effects of dialysis on mood and behavior. Med Hypotheses 2002;59:89-91. 43. Rayman MP, Rayman MI'. The argument for increasing selenium intake. Proc Nutr Soc 2002;61:203-215. SodiurnlSoditim Chloride 1. Grollman A. The role of salt in health and disease. Am J Cardiol 1961;8:593-602. 2. Luft FC. Sodium. In Brown ML, ed. Present knowledge in nutrition, ed 6. Washington, DC: Nutrition Foundation, 1990: 233-240. 3. Luft FC. Salt, water, and extracellular volume regulation. In Ziegler EE, Filer LJ Jr, eds. Present knowledge in nutrition, ed 7. Washington, DC:International Life Sciences Press, 1996265-271. 4. Meneely GR, Ball COT. High sodium-low potassium environment and hypertension. Am J Med 1958;25:713-725. 5. Gros G, Weller JM, Hoohler SW. Relationship of sodium and potassium intake to blood pressure. Am J Clin Nutr 1971;24:605-608. 6. Dahl LK. Salt and hypertension. Am J Clin Nutr 1972;25:231-244.

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements 7. Meneely GR, Battarbee HD. High sodium-low potassium environment and hypertension. Am J Cardiol 1976;38:768-785. 8. Marsh AC, Koons PC. The sodium and potassium content of selected vegetables. J Am Diet Assoc 1983;83:2427. 9. Cutler, JA, Follman D, Elliott P. An overview of randomized trials of sodium reduction and blood pressure. Hypertension 1991; 17(S~ppl1):1-27-1-33. 10. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (DASH) diet. N Engl J Med 2001;344:3-10. 11. Weinberger WH, Fineberg NS, Finberg SE, Weinberger M. Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension 2001;37429432. 12. Dahl LK. Salt in processed baby foods. Am J Clin Nutr 1968;21: 787-792. 13. Sanchez-Castillo CP, Branch WJ, James Wl? A test of the validity of the lithium-marker technique for monitoring dietary sources of salt in man. Clin Sci 1987;72:87-94. 14. Sanchez-Castillo CP, Warrender S, Whitehead TI', James WP. An assessment of the sources of dietary salt in a British population. Clin Sci 1987;72:95-102. 15.Miyajima E, Yamada Y. Reduced sympathetic inhibition in saltsensitive Japanese young adults. Am J Hypertens 1999;12: 1195-1200. 16. The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels: results of the trials of hypertension prevention, phase I. Trials of Hypertension Prevention Collaborative Research Group. JAMA 1992;2671213-1220. 17.Battarbee HD, Meneely GR. The toxicity of salt. CRC Crit Rev Toxicol 1978;5:355-376.

15. Ramanadham S, Monggold JJ,Brownsey RW, et al. Oral vanadyl sulfate in treatment of diabetes mellitus in rats. Am J Physiology, 1989;257H904-H911. 16. Domingo JL, Gomez M, Llobet JM, Corbella J. Chelating agents in the treatment of acute vanadyl sulphate intoxication in mice. T O ~ ~ C O1990;62:203-11. ~O~Y 17. Domingo JL, Gomez M, Llobet JM, et al. Improvement of glucose homeostasis by oral vanadyl or vanadate treatment in diabetic rats is accompanied by negative side effects. Pharmacol Toxicol 1991;68:249-53. 18. Domingo JL, Gomez M, Llobet JM, et al. Oral vanadium administration to streptozotocin-diabetic rats has marked negative side-effects which are independent of the form of vanadium used. Toxicology 1991;66:279-287. 19. French RJ, Jones PJ. Role of vanadium in nutrition: metabolism, essentiality and dietary considerations. Life Sci 1993;52:339-346. 20. Malabu UH, Dryden S, McCarthy HD, et al. Effects of chronic vanadate administration in the STZ-induced diabetic rat. The antihyperglycemic action of vanadate is attributable entirely to its suppression of feeding. Diabetes 1994;43:9-21. 21. De Tata V, Novelli M, Cavallini G, et al. Beneficial effects of the oral administration of vanadyl sulphate on glucose metabolism in senescent rats. J Gerontology 1993;48B191-B195. 22. Sasagawa T, Yoshikawa Y, Kawabe K, et al. Bis(6-ethylpicolinato) oxovanadium(IV)complex with normoglycemic activity in KK-A(y) mice. J Inorg Biochem 2002;88:108-112. 23.Committee on Use of Dietary Reference Intakes in Nutrition Labeling, Food and Nutrition Board, Institute of Medicine, National Academies of Science. Dietary reference intakes: guiding principles for nutrition and labeling fortification. Washington, DC: National Academy Press, 2003:191.

Vanadium 1. Dimond EG, Caravaca J, Benchimol A. Vanadium. Excretion, toxicity, lipid effect in man. Am J Clin Nutr 1963;1249-53. 2.Byme AR. Vanadium in foods and in human body fluids and tissues. Sci Total Environ 1978;1017-30. 3. Nielsen FH. Vanadium. In Mertz W, ed. Trace elements in human and animal nutrition, vol 1. New York: Academic Press, 1987: 275-300. 4.Harland BF, Harden-Williams BA. Is vanadium of human nutritional importance yet? J Am Diet Assoc 1994;94:891-894. 5. Barceloux DG. Vanadium. J Toxicol Clin Toxicol 1999;37265-278. 6. Meeks MJ, Landolt RR, Kessler WV, Born GS. Effect of vanadium on metabolism of glucose in the rat. J Pharm Sci 1971;60482483. 7. Dubyak GR, Kleinzeller A. The insulin-mimetic effects of vanadate in isolated rat adipocytes. Dissociation from effects of vanadate as a (NA+ - K K+)ATPaseinhibitor. J Biol Chem 1980;255:5306-5312. 8.Shecter Y, Karlish SJ. Insulin-like stimulation of glucose oxidation in rat adipocytes by vanadyl(IV) ions. Nature 1980;284: 556-558. 9. Degani H, Gochin M, Karlish SJ, Shechter Y. Electron paramagnetic resonance studies and insulin-like effects of vanadium in rat adipocytes. Biochemistry 1981;29:5795-5799. 10. MacDonald E, Hellevuo K. Vanadate and cardiac glycosides. Lancet 1983;11:579-580. 11. Donaldson J, Hemming R, LaBella F. Vanadium exposure enhances lipid peroxidation in the kidney of rats and mice. Can J Physiol Pharm 1985;63:196-199. 12.Heyliger CE, Tahiliani AG, McNeill JH. Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. Science 1985;2271474-1477. 13. Domingo JL, Llobet JM, Tomas JM. Short-term toxicity studies of vanadium in rats. J Appl Toxicol 1985;5:418-421. 14. Llobet JM, Domingo JL. Acute toxicity of vanadium compounds in rats and mice. Toxicol Lett 1984;23:227-231.

Zinc 1.Sandstead HH. Trace element interactions. J Lab Clin Med 1981;98 457-462. 2. Prasad ASP. Clinical biochemical and nutritional spectrum of zinc deficiency in human subjects: an update. Nutr Rev 1983;41:206. 3. Cunnigham-Rundles S, Cunningham-Rundles WE Nutrition and immunology. New York Alan R Liss, 1988:197-214. 4. Cousins RJ, Hempe JM. Zinc. In Brown ML, ed. Present knowledge in nutrition, ed 6. Washington, DC: Nutrition Foundation, 1990: 251-260. 5. Tuormaa TE. Adverse effects of zinc deficiency: a review from the literature. J Orthomol Med 1995;10149-164. 6. Berg JM, Shi Y. The galvanization of biology: a growing appreciation for the roles of zinc. Science 1996;271:1081-1085. 7. Nishi Y. Zinc and growth. J Am Col Nutr 1996;15:340-344. 8. Cousins RJ. Zinc. In Ziegler EE, Filer LJ Jr, eds. Present knowledge in nutrition, ed 7. Washington, DC: International Life Sciences Press, 1996:293-306. 9. Shambaugh GE Jr. Zinc and presbycusis. Am J Otol 1985;6:116-117. 10. Shambaugh GE Jr. Zinc for tinnitus, imbalance, and hearing loss in the elderly. Am J Otol 1986;7476-477. 11. Shambaugh GE Jr. Zinc: the neglected nutrient. Am J Otol 1989;10:156-160. 12. Shambaugh GE. Zinc, an essential nutrient for hearing and balance. Int J Biosocial Med Res 1991;13:192-199. 13.Undenvood EJ. Trace elements in human and animal nutrition, ed 4. New York Academic Press, 1977. 14. Schauss AG, Bryce-Smith D. Nutrients and brain function. Basel, Karger, 1987151-162. 15. Schauss AG, Costin C. Zinc and eating disorders. New Caanan, CT Keats Publishing, 1985. 16. Schauss AG, Costin C. Anorexia and bulimia. New Canaan, CT Keats Publishing, 1997.

Pharmacology of Natural Medicines 17. Fosmire GJ. Zinc toxicity. Am J Clin Nutr 1990;51:225-227. 18. Taylor CM, Bacon JR, Aggett PJ, Bremner I. Homeostatic regulation of zinc absorption and endogenous losses in zinc-deprived men [erratum in Am J Clin Nutr 1992;56:462]. Am J Clin Nutr 1991;53:755-763. 19. Food and Nutrition Board, National Research Council, National Academy of Science. Recommended dietary allowances, ed 10. Washington, DC National Academy Press, 1989. 20. Simmer K, Thompson Rl? Maternal zinc and intrauterine growth retardation. Clin Sci 1985;68:395-399. 21. Meadows NJ, Ruse W, Smith ME Zinc and small babies. Lancet 1981;21135-1137. 22. Masters DG, Keen CL, hnnerdal B, Hurley LS. Zinc deficiency teratogenicity: the protective role of maternal tissue catabolism. J Nutr 1983;113905-912. 23. Wagner PA, Bailey LB, Christakis GJ, Dinning JS. Serum zinc concentrations in adolescents as related to sexual maturation. Human Nutr Clin Nutr 1985;39C:459. 24. Takihara H, Cosentino MJ, Cockett AT. Effect of low-dose androgen and zinc sulfate on sperm motility and seminal zinc levels in infertile men. Urology 1983;22:160. 25. Soltan MH, Jenkins DM. Maternal and fetal plasma zinc concentration and fetal abnormality. Br J Obstet Gynaecol 1982;89:56. 26. Sandstead HH. WO Atwater memorial lecture. Zinc: essentially for brain development and function. Nutr Rev 1985;43129-137. 27. Aamodt RL, Rumble WF, et al. Absorption of orally administrated 65% by normal human subjects. Am J Clin Nutr 1981;34:2648-2652. 28. Taper LJ, Oliva JT,Ritchey SJ. Zinc and copper retention during pregnancy: the adequacy of prenatal diets with and without dietary supplementation. Am J Clin Nutr 1985;41:1184-1192. 29. Gibson RS,Anderson BM, Scythes CA. Regional differences in hair zinc concentrations: a possible effect of water hardness. Am J Clin Nutr 1983;37:37-42. 30. Haring BSA, Van Delft W. Changes in the mineral composition of food as a result of cooking in ‘hard’ and soft‘ waters. Arch Environ Health 1981;36:33-35. 31. Moser-VeillonPB, Reynolds RD. A longitudinal study of pyridoxine and zinc supplementation of lactating women. Am J Clin Nutr 199052135-141.

32. Bales CW, Freeland-Graves JH, Askey S, et al. Zinc, magnesium, copper, and protein concentrations in human saliva: age- and sex- related differences. Am J Clin Nutr 1990;51:462-469. 33. Thomas EA, Bailey LB, Kauwell GA, et al. Erythrocyte metallothionein response to dietary zinc in humans. J Nutr 1992;122: 2408414. 34.King JC, Hambidge KM, Westcott JL, et al. Daily variation in plasma zinc concentrations in women fed meals at six-hour intervals. J N U ~ 1994;124508-516. I 35. Nishi Y. Anemia and zinc deficiency in the athlete. J Am Col Nutr 1996;15:323-324. 36. Reunanen A, Knekt P, Mamiemi J. Serum calcium, magnesium, copper and zinc and risk of cardiovascular death. Eur J Clin Nutr 1996;50;431-437. 37. Hambidge KM. Zinc deficiency in young children. Am J Clin Nutr 1997;65:160-161. 38. Mossad SB, Macknin ML, Medendorp SC,Mason P. Zinc gluconate lozenges for treating the common cold a randomized, placebocontrolled study. Ann Intern Med 1996;12581-88. 39.King JC. Does poor zinc nutriture retard skeletal growth and mineralization in adolescents? Am J Clin Nutr 1996;64:375-376. 40.Mahajan S, Prasad A, Brewer G, et al. Effect of changes in dietary zinc intake on taste acuity and dark adaptation in normal human subjects. J Trace Elem Exp Med 1992;5:33-45. 41. Kondo T, Toda Y, Matsui H. Effects of exercise and sleep deprivation on serum zinc. J Trace Elem Exp Med 1990;3:324354. 42. Zlotkin SH, Casselman CW. Urinary zinc excretion in normal subjects. J Trace Elem Exp Med, 1990;313-21. 43. Krebs NF, Reidinger CJ, Hartley S, et al. Zinc supplementation during lactation: effects on maternal status and milk zinc concentrations. Am J Clin Nutr 1995;61:1030-1036. 44.Stumiolo GC, et al. Inhibition of gastric acid secretion reduces zinc absorption in man. J Am Coll Nutr 1991;4372-375. 45. Koyana H, Hosokai H, Tamura S, Satoh H. Positive association between serum zinc and apolipoprotein A-II concentrations in middle-aged males who regularly consume alcohol. Am J Clin Nutr 1993;57657-661.

Tabebuia avellanedae (LaPacho, Pau D’Arco, Ipe Roxo) Terry Willard, CIH, PhD Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Introduction

Antineoplastic Effects 1325 Antiinflammatory Activity 1326

1321

General Description

1321 Clinical Applications

Chemical Composition

Dosage History and Folk Use

1327

1321 1327

1322 Toxicology

Pharmacology 1322 Antimicrobial Activity 1322

Tabebuia avezlanedae (family: Bignoniaceae) Tabebuia ipe Tabebuia cassinoides Tecoma ochracea Common names: LaPacho, Pau DArco, Ipe Roxo

INTRODUCTION The taxonomic division of plants with medicinal uses in the Bignoniaceae family is confused. The literature often interchanges the genera of Tecoma and Tabebuia. At least four species have been called LaPacho, as follows:

Tecoma ochracea Tecoma ipe Tabebuia cassinoides Tabebuia avellanedae

This chapter considers the Tabebuia genus.

GENERAL DESCRIPTION The tree from which LaPacho is obtained is a member of the Bignoniaceae family known as Tabebuia avellanedae or Tabebuia ipe. This tropical tree, native to Brazil, can grow up to 125 feet tall and has rose- to violet-colored flowers that bloom in profusion just before the new leaves appear. There are about 100 species of these evergreen trees or shrubs, native to tropical America. The leaves are

1327

Drug Interactions

1327

opposite, long-petiolate, digitately five- or seven-foliate. The leaflets are entire or toothed; the flowers are large in terminal cymes or panicles; the calyx is tubular or campanulate, closed in bud, variously cleft or toothed in anthesis; the corolla tubes are ampliate, the limb somewhat bilate; the stamens are four; the capsule is slender, cylindric, and suterete; and the seeds are broadly winged. The trees of this genus are very showy when in flower because they usually blossom when leafless. Because the taxonomy of these plants is so difficult, it is quite possible that there is confusion among even trained gatherers. One specific way to distinguish the species is at the seedling stage. The four-leaf-clover-like cotyledons are distinctive in being deeply cleft.’

CHEMICAL COMPOSITION Many of the studies and chemical analyses on Tabebuia spp have been performed on the heart wood, but the bark is the product available in the marketplace and the part utilized in folklore. The major components of T. avellanedae are 16 quinones (mostly with CISskeleton) containing both naphthoquinones (seven, Cloto C,) and anthraquinones (nine, C14to Cl). Both of these groups of quinones rarely occur in the same plant. The lapachol content is usually 2% to 7%. The quinones are listed in Box 128-1. Other compounds found in the heart wood are lapachenole, quercetin, and 0- and p-hydroxybenzoic acids.2 1321

Naphthoquinones Lapachol Menaquinone-I Deoxylapachol Beta-lapachone Alpha-lapachone Dehydro-alpha-lapachone

Anthraquinones 2-Methylanthraquinone 2-Hydroxymethylanthraquinone 2-Acetoxymethylanthraquinone Anthraquinone-2-aldehyde 1-Hydroxyanthraquinone 1-Methoxyanthraquinone 2-Hydroxy-3-methylquinone Tabebuin (a newly discovered compound)

Lapachol content can be estimated through study of the yellowish flaky powder found on the surface of the fractured wood chips or bark. If the lapachol content exceeds 1%to 270, mixing with dilute (5%) NaOH generates a red-brown solution owing to a litmus-type reaction. There is no color if the content is less than 0.5%. Exact concentration can be determined by titrating the NaOH reaction or through chromatography? Evaluation of lapachol with high-pressure liquid chromatography (HPLC) found that lapachol is only a minor constituent of the inner bark and is not detectable in aqueous extracts! A recent analysis of 10 products found in the marketplace showed that only one contained lapachol (and only in trace amounts) and the other nine had none. This finding suggests that many of the products now available on the market are not truly Tabebuiu spp., that the wrong part of the plant is being marketed, or that processing and transportation have damaged the product. This might explain the variation in results practitioners have experienced. Standardization of LaPacho products for lapachol or naphthoquinone content is needed to solve this problem.

HISTORY AND FOLK USE The native Indians of Brazil also refer this tree as Pau DArco or Ipe Roxo. The inner bark has been used for medicinal purposes for centuries as a folk remedy for a wide variety of afflictions, including the following?

Enuresis Fever Pharyngitis Snakebite Syphilis Wounds Ulcers Respiratory problems Arthritis Cystitis Constipation Prostatitis Poor circulation Constipation Cancer of the esophagus, head, intestine, lung, prostate, and tongue LaPacho is reported to be alexiteric, analgesic, anodyne, antidotal, antimicrobial, diuretic, and fungicidal?

PHARMACOLOGY During the previous century, LaPacho was subjected to scientific scrutiny. The first active constituent to be studied, lapachol, was isolated by Patemo in 1882 (Figure 128-1). Its structure was determined by Hooker in 1896. In 1927, Fieser synthesized lapachol. It has since been studied by numerous researchers. It is interesting to note that many of the scientific studies have found LaPacho and lapachol to be more effective in treating malaria and cancerous tumors through oral ingestion rather than intravenous or intramuscular inje~tion.~ An herbalist’s interpretation would be that the body‘s recuperative powers are more effectively stimulated by the more natural route of nutrient plant material absorption through the digestive tract. Although most of the studies have been of individual chemicals, some show significantly better results with the whole extract and diminishing effectiveness as the extracts are refined or individual chemicals are t e ~ t e d . ~

Antimicrobial Activity Antibacterial Activity In 1956, a research team at the Universidade do Recife in Brazil reported that lapachol isolated from the 0

&OH

Boils Chlorosis Colitis Diarrhea Dysentery

0 Flgure 128-1

Lapachol.

Tabebuia avellanedae (LaPacho, Pau D'Arco, Ipe

T. avellanedaetree exhibited antimicrobial activity against gram-positive and acid-fast bacteria, and Brucellu species.'O It is important to note that the research team found that progressive purification reduced the antimicrobial activity of the extract. This finding led to the conclusion that more than one active substance was present in the original extract. Later that year the same researchers published a paper proclaiming a new antibiotic substance from T. avellanedae that demonstrated "strong anti-Brucella activity and fungistatic behavior."" They eventually found that, along with lapachol, the extract of the Tabebuia tree contained alpha-lapachone, beta-lapachone, and a newly discovered quinone that they named xyloidone. In 1967, another group of researchers discovered seven naphthoquinones, nine anthraquinones, lapachenole, quercetin and 0- and p-hydroxybenzoic acids in the heartwood of the tree.2 Several of these exhibit strong microbicidal and fungicidal activities (Table 128-1). Naphthoquinones are highly effective against Candidu albicans and Trichophyton mentagrophytes.12 Lapachol has been shown to have both antimicrobial and antiviral a~tivity.'~,'~,~~ Beta-lapachone shows diversified antiparasitic activity as well as antiviral action.15J6 Alpha-lapachone is also active against certain parasites, and xyloidone is active against numerous bacteria

.a

~

~J~ LaPacho component, the flavonoid and f ~ n g i . ' Another quercetin, is cytotoxic for certain parasites.19 Xyloidone is effective against a wide array of organism, such as Staphylococcus aureus and the Brucella species. This component also inhibits the causative agents of tuberculosis, dysentery, and anthrax. Mechanism of Action Lapachol, like many naphthoquinones, acts as a respiratory poison by interfering with electron transport in microbes.20Research in 1946 showed that drug suppression of malarial parasites could usually be correlated with the inhibition of their oxygen uptake.21 In 1947, lapachol was found, at concentrations of 100 mg/L, to inhibit O2uptake by Plasmodium knowles by 74% and succinate oxidase systems by 26%.= In the following year, lapachol was found to exhibit antimalarial activity against Plasmodium 10phurae,2~suggesting respiratory poisoning as a likely mechanism. Mitochondria1 respiration is inhibited by 50% at a lapachol concentration of less than 110 y m ~ l / L . ~ ~ Increasing doses of lapachol produced progressive respiratory inhibition in tumor cells isolated from animals. Oxygen consumption and oxygen metabolite production are inhibited in neutrophils upon administration of lapachol.25

: r m Antimicrobial activity of Tabebuia avellanedae'

Microorganism

6.subtilis 6.mycoides 6.anthracis S. aureus Sar. lutea

S.hemolyticus M. tuberculosis

M.smegmatis N. asteroides N. catarrhalis

E.coli K. pneumoniae

S. fyphosa

Br. suis Br. abortus Br. melitensis C. albicans C. krusei C. neoformans

Lapachol

Chorohidro-lapachol

60.0-80.0 40.0-60.0 40.0-60.0 60.0-80.0 40.0-60.0 >100.0 80.0-100.0 80.0-100.0

8.0-10.0 10.0-15.0 20.0-30.0 30.0-40.0 15.0-20.0 60.0-80.0 40.0-60.0 60.0-80.0 40.0-60.0 30.0-50.0 >100.0 >100.0 >100.0 2.0-4.0 2.0-4.0 2.0-4.0 40.0-60.0 40.0-60.0 40.0-60.0

>loo 40.0-60.0 >100.0 >100.0 >100.0 15.0-20.0 15.0-20.0 10.0-15.0 >100.0 B100.0 >100.0

'Minimum concentration of inhibition (pcjml).

Alpha-lapachone

40.0-50.0 40.0-50.0 40.0-50.0 30.0-40.0 30.0-40.0 60.0-80.0 30.0-50.0 30.0-50.0 60.0-80.0 80.0-100.0 >100.0 21 00.0 >100.0 20.0-30.0 30.0-40.0 30.0-40.0 80.0-100.0 80.0-100.0 50.0-80.0

Beta-lapachone

1 .o-2.0 5.0-8.0 4.0-6.0 2.0-4.0 4.0-6.0 10.0-15.0 10.0-15.0 15.0-20.0 10.0-1 5.0 10.0-15.0 >100.0 >100.0 >100.0 0.6-1.O 1 .o-2.0 1 .o-2.0 80.0-100.0 80.0-100.0 30.0-50.0

Xyloidone

4.0-6.0 20.0-30.0 20.0-30.0 15.0-20.0 20.0-30.0 >50.0 10.0-1 5.0 15.0-20.0 20.0-30.0 c20.0 >100.0 >100.0 >100.0 0.8-1.O 1.5-2.0 1.5-2.0 30.0-50.0 50.0-60.0 40.0-60.0

The exact site at which lapachol acts has been the subject of some controversy. Some researchers have concluded that 2-hydroxy-3-alkyl-l,4 naphthoquinones, such as lapachol, act just after cytochrome c in the respiratory chain:1 whereas others suggest that lapachol exhibits an oligomycin-like action in mitochondria, acting just after cytochrome b.20It has been hypothesized that naphthoquinones either prevent an interaction between cytochromes b and c or act directly on an unknown enzyme between the tw0.2~The inhibitory action can be reversed by the addition of 2,4-dinitrophenol, suggesting that lapachol may act on energy conservation rea~ti0ns.l~ Lapachol has now been shown to act as an uncoupler of oxidative phosphorylation. Lapachol prevents synthesis of adenosine triphosphate (ATP) by stimulating respiration in the absence of a phosphate acceptor. This effect is most pronounced at a high pH, at which lipid solubility is the lowest.27 Hadler and Moreau2*studied lapachol in combination with showdomycin and demonstrated that lapachol exposes a mitochondrial thiol group that occupies a pivotal position between the cycle that meshes with the respiratory chain and the cycle that meshes with ATP. These researchers believe that the side chain acts as a swinging arm and that the remainder of the lapachol molecule is embedded in a lipid matrix. In addition to inhibiting cellular respiration and uncoupling oxidative phosphorylation, lapachol inhibits certain enzymes. In particular, it is a competitive inhibitor of glycolase I in erythrocytes. The side chain is again thought to be significant in this action. Lapachol also demonstrates noncompetitive inhibition of alpha-keto-aldehyde dehydrogenase, leading to the accumulation of toxic alpha-ketoaldehydes.28Lapachol demonstrated 64% inhibition of 3-alpha-hydroxysteroidmediated transhydrogenase at a concentration of 10-5M (well within dosage range).29

Antiviral Activity Lapachol has proven to be active against certain viral strains, including herpes virus hominis types I and II.29 Hydroxynaphthoquinone has been shown to effectively inhibit four influenza viruses. Lapachol also significantly inhibits poliovirus and vesicular stomatitis virus.13 Studies of beta-lapachone's antiviral activity have offered insights into the mechanism of this powerful quinone. In experiments with viruses, beta-lapachone demonstrated its ability to inhibit certain enzymes, such as DNA and RNA polymera~es.~~ Beta-lapachone was tested against avian myeloblastosis virus and Rauscho murine leukemia virus and found to inhibit retrovirus reverse trans~riptase.~~ In the presence of dithioreitol, beta-lapachone inhibits eukaryotic DNA polymerasealpha activity. Although the mechanism of action for enzyme inhibition is complex, it may be related to

superoxide production.30This finding in turn may help explain the structural changes in the DNA of the epimastigotes. The site of action appears to be the enzyme protein. This issue has great sigruficance for possible treatment of both human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) (the implicated viruses in acquired immunodeficiency syndrome [AIDS] and Epstein-Barr syndrome, respectively). Beta-lapachone also inhibits Friend virus and was the only substance among a number tested that prolonged survival time of chickens infected intraperitoneally with Rous sarcoma virus.32

Antiparasitic Activity The trematode Schistosoma mansoni is the causative agent of the common tropical disease schistosomiasis. The cercariae of this blood fluke live in water and enter the host by penetrating the skin. This debilitating disease, a serious problem in many tropical areas, causes weakening of the host and increases susceptibility to a variety of other pathogens, some of which may be fatal. Lapachol has been tested as a topical barrier to the cercariae and has been found to be highly effective at preventing its p e n e t r a t i ~ n . Oral ~ , ~ ~lapachol was also tested and found to significantly reduce penetration. After being consumed, the lapachol was secreted onto the skin, apparently by the sebaceous glands, where it again acted as a topical barrier. The cercariae seek to penetrate the host through or near the sebaceous glands, suggesting that dietary administration of lapachol would be an efficient means of protecting against infection. Although the mechanism for this anti-schistosomal activity is relatively unknown, Pinto et all7 thought that the side chain was involved and noted that effective barriers are liposoluble. Alpha-lapachone and beta-lapachone, also components of LaPacho, both exhibited activity against S. mansoni.'O The activity of beta-lapachone against viruses and parasites has been studied in an attempt to understand the mechanism by which this quinone works. Beta-lapachone is notably effective against Typan~somacruzi, a zoomastigote responsible for trypanosomiasis, or Chagas' disease, which occurs in both acute and chronic forms and has no known cure. Beta-lapachone causes complete inhibition of T. cruzi at concentrations of 0.8 to 5.0 pg/ml and progressively inhibits motility with increasing concentrations. When T. cruzi epimastigotes were incubated with the quinone, they were subject to nuclear, mitochondrial, endoplasmic reticular, and cytoplasmic membrane damage and underwent alterations in the chromatin distribution. Respiration rates were lowered, the mitochondria became swollen, and glucose and pyruvate oxidation was inhibited. Lipid peroxidation was stimulated, leading to decreased cell viability.

Tabebuia avellanedae (LaPacho, Pau D'Arco, Ipe Roxo)

In addition, in vitro testing resulted in the rapid decay of DNA, RNA, and protein, and DNA breakage in T. cruzi. This was accompanied through inhibition of DNA, RNA, and protein synthesis and instigation of "unscheduled" DNA synthesis.34 It is thought that this toxic action against parasites is at least partly due to superoxide prod~ction.3~ Both 0; and H202are intermediates of oxygen reduction, and both are toxic to living organisms. When betalapachone is introduced to T. cruzi, it rapidly enters the epimastigote and is reduced to its semiquinone form in the mitochondria and microsomes of the pathogen.36 Superoxide is produced by the reduction of molecular oxygen, which is facilitated by autooxidation of the semiquinone free radical. Superoxide is then converted to hydrogen peroxide via superoxide dismutase (SOD). Stimulation of lipid peroxidation follows, and the cell degenerates.

Antifungal Activity In addition to its activity against a variety of bacteria, components of LaPacho are known to possess potent antifungal ~ a p a b i l i t i e s .The ~ ~ ,quinone ~ xyloidone inhibits several species of fungus (including Candida albicans, Candida krusei, and Cryptococcus n e o f ~ m a n s )The . ~ ~ antifungal activity of aqueous, dichloromethane, and methanol extracts from T. avellanedae were also compared, and it was shown that the aqueous and methanol extracts of showed the highest antifungal activity.39 T. avellanedae bark was found to be active against Aspergillus fumigatus, C. neofomzans, Microsporum gypseum, Penicillium purpurogenum, Saccharomyces cermisiae, and Trichophyton mentagrophyte~.~~

Antineoplastic Effects Because of the folklore information surrounding the tumor-reducing qualities of the herb LaPacho, it underwent extensive study by the National Cancer Institute (NCI).After initial positive results, lapachol was judged to be the most active antineoplastic agent. Lapachol entered phase I clinical trials at the NCI in 1968, on the basis of its activity against Walker 256 tumors (with a confidence rate exceeding 90%). During these trials it was difficult to obtain therapeutic blood levels of lapachol without some mild toxic side effects, such as nausea, vomiting, and anti-vitamin K activity. This is quite hard to understand, because later studies found the toxicity to be very low, with an LD5,, (dose at which 50% of organisms died) of 487 mg, about the same as caffeit~e.~ The IND (investigative new drug) status for the drug was closed in 1970.40 It has been shown, however, that some of the anthraquinones in LaPacho have vitamin K activity; therefore use of the whole herb would compensate for lapachol's effect on vitamin K.41

An analogue, dichloroallyl lawsone (DCL),which had a better in vivo activity in the Walker 256 system, was selected to replace lapachol with IND approval in 1975. Like lapachol, DCL was found to be an inhibitor of oxidative phosphorylation. In Rhesus monkeys the agent was observed to have some cardiac toxicity. It was decided subsequently that there was little point to any further analogue development, and the case was closed." The approach just described indicates a flaw in the underlying philosophy of the pharmaceutical sciences and the NCI program. Because the initial studies came from a whole plant, the detailed studies should have been undertaken on the whole plant: Some of the other quinones have also been shown to have antineoplastic activities. Was it too complex to consider the chemical reactions of the more than 20 components found in LaPacho? Or was the standard economic/political incentive for patenting an analogue an impediment to the investigation of a plant species? Lapachol is rapidly absorbed through the gastrointestinal tract after oral administration to rats bearing W256 tumors. It is taken up by all tissues except the brain and blood cells. A significant amount appears in the tumor after 6 hours, with most of the drug disappearing from the other body tissue. The half-life of intravenous lapachol is 33 minutes in mice (75 minutes in dogs). Lapachol is extensively metabolized and excreted mostly in the feces.' Beta-lapachone has been shown to inhibit growth of a large variety of tumor cells, including epidermoid laryngeal cancer, prostate, colon, ovary, and breast cancer, and also different types of leukemia cells.43 Most other analogues had little effect on cancer.44 The theories on how lapachol works as an antineoplastic agent vary considerably. One of the most prominent involves reduction-oxidation (redox) cycle capabilities. The redox function of lapachol was known as early as 1936.45In 1947, Ball et a12 studied the respiratory poison mechanism of naphthoquinones in the intravenous killing of malarial parasites. In 1966, lapachol was shown to stimulate mitochondria1 ATPase activity (in the general fashion of uncouplers), but had no effect on ATPase stimulation by dinitrophenol. Its maximum activity is at a high pH, at which lipid solubility might be expected to be lowest." Lapachol was found to be an in vivo inhibitor of respiration at chemotherapeutic doses.* Later, lapachol was shown to augment the flow of electrons from reduced nicotinamide adenine dinucleotide phosphate (NADP) to form oxygen-related free radicals. These seem to be site-specific free radicals that bind to the cancerous DNA or RNA, producing either superoxides or free hydroxyl There seems to be a redox potential that is important for the inhibition of electron transfer in coenzyme Qlo.@ Bennett et a149argued that this respiration poisoning is

Pharmacology of Natural Medicines

not the mechanism of antitumor activity. In their study, lapachol was shown to sigruficantly reduce the pool of uridine triphosphate (UTP), the largest pool of the pyrimidine nucleotides (exposure time was very short, 2-4 hours). Lapachol is theorized to be like DCL in that it blocks pyrimidine biosynthesis through inhibition of dihydroorotate dehydrogenase.20It is also believed that the antineoplastic activities of lapachol might stem from its interaction with nucleic acids:’ and it has been proposed that interaction of the naphthoquinone moiety between base-pairs of the DNA helix occurs with subsequent inhibition of DNA replication and/or RNA synthesis. Free amino groups in the sugar moiety are necessary for DNA binding.% Beta-lapachonehas an effect on the modulation of cell growth and apoptosis in human colon carcinoma tumor (HCT-116) cell lines. Exposure of HCT-116 cells to betalapachone resulted in growth inhibition and induction of apoptosis in a dose-dependent manner. This upregulated apoptotic activity was also associated with a decrease in Bcl-2 protein expression, an increase in caspase-3 activity, a decrease in intact poly (ADP-ribose) polymerase protein levels, and degradation of betacatenin. The nuclear protein levels of nuclear factorkappaB (NF-kappaB) and the activity of NF-kappaB DNA binding were markedly reduced after betalapachone treatment. Beta-lapachone treatment also resulted in inhibition of the transcriptional activity of NF-kappaB-luciferase reporter plasmid. The researchers suggest, therefore, that beta-lapachone-induced apoptosis may be partly regulated through the inactivation of the second messenger NF-kappaB system.51 Beta-lapachonewas also shown to decrease the viability of sarcoma cells by stimulating lipid peroxidation. This was accomplished through the following activities? Reduction of lapachone at the mitochondria1 and microsomal membranes with generation of the semiquinone form Autooxidation to produce O2 Production of H202via SOD

G protein for this Two animal studies using carrageenan-induced subplantar edema has also exhibited the antiinflammatory abilities of l a p a ~ h o l .In ~ one ~,~ study, the second phase of inflammation, which is correlated with the appearance of prostaglandins and kinins, was where lapachol seemed to exert the greatest antiinflammatory effect.56Lapacho compounds have also demonstrated potent activity against the growth of human keratinocytes and appear to be promising as effective antipsoriatic agents; beta-lapachone displayed activity comparable to that of the antipsoriatic drug anthralin. Treatment of keratinocytes with these potent lapacho compounds caused remarkable damage to the plasma membrane like that observed with anthralin. This finding was documented by leakage of lactate dehydrogenase into the culture medium, which significantly exceeded that of the vehicle control and may serve as a caution when this agent is being considered for in vivo use.57

Quercetin Quercetin is a highly active flavonoid that inhibits a wide range of enzymes and suppresses the synthesis of DNA, RNA, and proteins.58Quercetin’s cytotoxicity may be due to the fact that it inhibits mitochondrial electron transport.59Hodnick et a159have noted that quercetin produced a substrate-independent, potassium cyanide (KCN)-insensitive, respiratory burst in mitochondria. Other flavonoids that demonstrated this activity produced 02-and H202,suggesting that quercetin may also generate these cytotoxic chemicals. The following are among the enzymes inhibited by quer~etin~,~~,~~: Nicotinamide adenine dinucleotide (NADH) oxidase Phosphodiesterase Cyclic adenosine monophosphate (CAMP)-independent protein kinases Ca2+phospholipid-dependent protein kinase Tyrosine protein kinases

Shapiro et all9 suggested that the cytotoxicity of quercetin may be due toits chelating abilities. This agent is trypanocidal to Trypanosoma brucei, a livestock parasite Antiinflammatory Activity belonging to the same genus as T. cruzi. Soon after the parasite enters the host, the host’s unsaturated ironExtracts of the bark from T. auellanedae demonstrate clear building proteins remove iron from the hemoflagellate. antiinflammatory activity with low Pau Because the parasite is unable to synthesize heme, it D’Arco douching and the use of tampons soaked in an encounters a shortage of iron. By chelating the host’s iron, alcoholic extract of LaPacho have been shown to be very quercetin blocks utilization of iron by the parasite yet successful against a wide range of inflammations, such as vaginitis, cervicitis, and cervic~vaginitis.~~~~~~~ does not adversely affect the host. This flavonoid is also cytotoxic against Crithidia fasciculata. The fact that Aqueous extract of the inner bark of T. auellanedae has quercetin is small and lithophilic seems to be significant demonstrated antinociceptive and antiedematogenic to its activity. activities in mice models, with a possible antinociceptive Like lapachol, quercetin inhibited O2 consumption effect correlated with the adenosine system.53Adenosine and H202production in neutrophils.26Many flavonoids itself is posited to interact with receptors coupled with

Tabebuia avellanedae (LaPacho, Pau D'Arco, Ipe Roxo) exhibit antiviral activity. When mice that had been intracerebrally infected with attenuated viruses, including rabies, were given quercetin in their diet, a prophylactic effect was observed.61 Quercetin inactivates the following viruses (inactivation is defined as reducing viral infectivity tenfold): Herpes simplex type 1 Respiratory syncytial virus Pseudorabies/Aujesky's virus Poliovirus type 1 Parainfluenza type 3 Sindbis virus Potato virus x

CLINICAL APPLICATIONS The spectrum of clinical applications of T.uvellunedae is quite broad. Current use has focused on LaPacho's antineoplastic and antimicrobial activity. Its use is extremely popular in the treatment of intestinal candidiasis and vaginal candidiasis (both topical and internal). Research has also focused on antipsoriatic and antiedema properties. There are also many anecdotal reports of remission of different forms of cancer with use of this botanical.26 Unfortunately, because of lack of quality control and confusion about the portion of the plant to use (any of the studies and chemical analyses have been done on the heartwood, but the bark is the product available in the market place and discussed in the folklore), it is highly likely that most practitioners are not using effective materials. This likelihood could explain varying clinical results.

1 pint of water for 5 to 15 minutes three to four times daily. Dosages of other forms (aqueous extract, fluid extract, solid extract) should be based on lapachol content, providing a daily lapachol intake of 1.5-2 g/day. A tampon that has been soaked in the decoction or fluid extract is used in the treatment of vaginitis and cervicitis. The tampon is inserted vaginally and changed every 24 hours until resolution.

TOXICOLOGY Although anti-vitamin K activity has been reported for lapachol, the presence of several vitamin K-like substances in the whole plant suggests that this activity is not a problem. Lapachol has been reported to have an oral LD5, of 1.2 to 2.4 g/kg in albino rats and 487 to 621 mg/kg in mice." In comparison, the oral LDsOof caffeine is 192 mg/kg in rats and 620 mg/kg in mice.6 Long-term administration of lapachol at a dose of 0.0625 to 0.25 g/kg/day to monkeys was found to produce moderate to severe anemia. The anemia was most pronounced during the first 2 weeks of treatment. Death occurred in monkeys after six doses of lapachol at 0.5 g/kg per day and after five doses of 1 g/kg per day? There have been no reports in the literature of human toxicity when the whole bark as a decoction is used. Because low doses have been reported to cause nausea and vomiting," only a qualified naturopathic physician, herbalist, or other practitioner experienced in its use should attempt to treat using this botanical medicine.

DRUG INTERACTIONS

DOSAGE The usual form of administration of LaPacho is as a decoction, with the standard dose being 1 cup of decocted bark two to eight times per day. The decoction is made by boiling 1 tsp of LaPacho for each cup of water for 5 to 15 minutes. A more precise dosage based on a lapachol content of 2% to 4% would be 15 to 20 g of bark boiled in 500 ml or

No interactions with pharmaceutical drugs have been reported, but because of its known anti-vitamin K-like activity, there may be an interaction with anticoagulant medications, such as warfarin, that could theoretically result in increased bleeding tendencies. This effect would probably be minimized if treatment involved the whole herb rather than specific components. Regardless, caution is warranted.

1. Duke JA. Interview. Saturday, February 24,1984. 2. BurnettAR,ThomsonRH.Naturally occurring quinones.Part X. The quinonoid constituents of Tabebuia avellanedae (Bignoniaceae). J Chem Soc 1967;(C):2100-2104. 3. Pfizer C. Antitumor composition from lapachol and its salts. CA70: 90758,156. 4. Steinert J, Khalaf H, Rimpler M. HPLC separation and determination of naphtho[2,3-b]furan4,9-dionesand related compounds in

extracts of Tabebuia avellanedae (Bignoniaceae).J Chromatogr A 1995; 693:281-287. 5. Canadian Health Protection Branch. Herbs and botanical preparations. Information Letter 1987;Aug 13:726. 6.Duke JA. CRC handbook of medicinal herbs. Boca Raton, FL: CRC Press, 1985:470473. 7. Bemardes A. A pocket book of Brazilian herbs (folkloehistoryuses). Rio de Janeiro:Shogun Editora, 198422-23.

Pharmacology of Natural Medicines 8. Hartwell JL. Plants used against cancer: a survey. Lawrence, MA: Quarterman Publications, 1982. 9. Morrison RK, Brown DE, Oleson JJ, et al. Oral toxicology studies with lapachol. Toxic01 Appl Pharmacol 1970;171-11. 10.de Lima OG, $Albuquerque IL, Machado MP, et al. Primeiras observacoes sobre a acao antimicrobiana do lapachol. Anais da Sociedade de biologica de pernambuco 1956;XIV129-135. 11. de Lima OG, d’Albuquerque IL, Machado MP, et al. Uma nova substancia antibiotica isolada do “Pau D’Arco,” Tabebuia sp. Anais da Sociedade de biologica de pemambuco 1956;XW136-140. 12. Gershon H, Shanks L. Fungitoxicity of 1,4naphthoquinones to Candida albicans and Trichophyton mentagrophytes. Can J Microbiol 1975;21:1317-1321. 13.Lagrota M, et al. Antiviral activity of lapachol. Rev Microbiol 1983;14:21-26. 14.Guiraud P, Steiman R, Campos-Takaki GM, et al. Comparison of antibacterial and antifungal activities of lapachol and betalapachone. Planta Med 1994;60:373-374. 15. Lopes JN, Cruz FS,Docampo R, et al. In vitro and in vivo evaluation of the toxicity of 1,4naphthoquinone and 1,Z-naphthoquinone derivatives against Trypanosoma cruzi. Ann Trop Med Parasitol 1978;72:523-531. 16. Schuerch AR, Wehrli W. beta-Lapachone, an inhibitor of oncornavirus reverse transcriptase and eukaryotic DNA polymerasealpha. Inhibitory effect, thiol dependence and specificity. Eur J Biochem 1978;84:197-205. 17.Pinto AV, Pinto MD, Gilbert B, et al. Wstosomiasis mansoni: blockage of cercarial skin penetration by chemical agents. I. Naphthoquinones and derivatives. Trans R Soc Trop Med Hyg 1977;71:133-135. 18. de Lima OG, d’Albuquerqu1 IL, de Lima CG, et al. Antividade antimicrobiana de alguns derivados do lapachol em comparacao com a xiloidona, Nova ortonaftoquinona natural isolada de extractos do cerne do “Pau d’Arco“ roxo, Tabebuia aoellanedae Lor. ex. Griseb. Substancias antimicrobianas de plantas superiores. Revista d o Instituto de Antibioticos Recife 1962;4. 19.Shapiro A, Nathan HC, Hutner SH, et al. In vivo and in vitro activity by diverse chelators against Trypanosonm brucei brttcei. J Protozool 1982;29:85-90. 20. Howland F.Uncoupling and inhibition of oxidative phosphorylation by 2-hydroxy-3-alkyl-l,4naphthoquinones. Biochim Biophys Ada 1963;m659-662. 21. Wendel WB. The influence of naphthoquinones upon the respiratory and carbohydrate metabolism of malarial parasites. Fed Proc 1946;5:406407. 22.Ball EG, Anfinsen CB, Cooper 0. The inhibitory action of naphthoquinones on respiratory processes. J Biol Chem 1947;168: 257-270. 23. Fieser LF, Richardson AP. Naphthoquinone antimalarials. 11. Correlation of structure and activity against Plasmodiiini lophrcrae in ducks. J Am Chem Soc 1948;70:3156-3165. 24. Gosalvez M, Garcia-Caner0 R, Blanco M, et al. Effects and specificity of anticancer agents on the respiration and energy metabolism of tumor cells. Cancer Treat Rep 1976;60:1-8. 25. Crawford DR, Schneider DL. Identification of ubiquinone-50 in human neutrophils and its role in microbicidal events. J Biol Chem 1982;2576662-6668. 26. Weed B. Second opinion: Lapacho fight against cancer. Vancouver: Rostrum Communication, 1984. 27. Howland JL. Influence of alkylhydroxynaphthoquinones on the mitochondria1 oxidation of tetramethyl-p-phenylenediamine. Biochim Biophys Acta 1967;131:247-254. 28. Hadler HI, Moreau TL. The induction of ATP energized mitochondrial volume changes by the combination of the two antitumour age agents showdomycin and lapachol. J Antibiot (Tokyo) 1969;22:513-520.

29. Koide SS. Inhibition of 3alpha-hydroxysteroid-mediatedtranshydrogenase of rat liver by various quinones and flavonoids. Biochim Biophys Acta 1962;59:708-710. 30. Austin FG. Schistosoma mansoni chemoprophylaxis with dietaIy lapachol. Am J Trop Med Hyg 1974;23:412-419. 31. Wanick MC, Bandeira JA, Femandes RV. Acao antiinflamatoria e cicatrizante do extrato hidroalcoolico d o liber d o pau darco roxo (Tabebuia avellanedae), em pacientes portadoras d e cervicites e cervico-vaginites. Separata da Revista do Instituto de Antibioticos 1970;10:41-46. 32.Schaffner-Sabba K, Schmidt-Ruppin KH, Wehrli W, et al. betaLapachone: synthesis of derivatives and activities in tumor models. J Med Chem 1984;27990-994. 33. Gilbert B, de Souza JP, Fascio M, et al. Schistosomiasis: protection against infection by terpenoids. An Acad Bras Cienc 1970;42: 39740. 34. Goijman SG, Stoppani AO. Oxygen radicals and macromolecule turnover in Trypanosoma cruzi. Life Chem Rep 1984;2: 216-221. 35. Docampo R, Cruz FS, Boveris A, et al. beta-Lapachone enhancement of lipid peroxidation and superoxide anion and hydrogen peroxide formation by sarcoma 180 ascites tumor cells. Biochem Pharmacol 1979;28:723-728. 36. Boveris A, Stoppani AO, Docampo R, et al. Superoxide anion production and trypanocidal action of naphthoquinones on Trypanosoma crtizi. Comp Biochem Physiol C 1978;61:327-329. 37. Genet J. [Natural remedies for vaginal infections.] Sidahora 1995;Winter:40-41. 38.Guiraud P, Steiman R, Campos-Takaki GM, et al. Comparison of antibacterial and antifungal activities of lapachol and betalapachone. Planta Med 1994;60:373-374. 39. Portillo A, Vila R, Freixa B, et al. Antifungal activity of Paraguayan plants used in traditional medicine. J Ethnopharmacol 2001; 7693-98. 40.Block JB, Serpick AA, Miller W, et al. Early clinical studies with lapachol (NSC-11905). Cancer Chemother Rep 2 1974;427-28. 41. Preusch PC, Suttie JW. Lapachol inhibition of vitamin K epoxide reductase and vitamin K quinone reductase. Arch Biochem Biophys 1984;234:405-412. 42. McKelvey EM, Lomedico M, Lu K, et al. Dichloroallyllawsone. Clin Pharmacol Ther 1979;25:586-590, 43. Dubin M, Fernandez Villamil SH, Stoppani AO. [Cytotoxicity of beta-lapachone, an naphthoquinone with possible therapeutic use.] Medicina (B Aires) 2001;61:343-350. 44.Rao KV. Quinone natural products: streptonigrin (NSC-45383) and lapachol (NSC-11905) structure-activity relationships. Cancer Chemother Rep 2 1974;411-17. 45. Ball EG. Studies on oxidation-reduction. XXII. Lapachol, lomatiol, and related compounds. J Biol Chem 1936;114:649-655. 46.Bachur NR, Gordon SL, Gee MV, et al. NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals. Proc Natl Acad Sci USA 1979;76954-957. 47. Bachur NR, Gordon SL, Gee MV. A general mechanism for microsoma1 activation of quinone anticancer agents to free radicals. Cancer Res 1978;38:174550. 48. Iwamoto Y, Hansen IL, Porter TH, et al. Inhibition of coenzyme Qlo-enzymes, succinoxidase and NADH-oxidase, by adriamycin and other quinones having antitumor activity. Biochem Biophys Res Commun 1974;58:633-638. 49. Bennett LL Jr, Smithers D, Rose LM, et al. Inhibition of synthesis of pyrimidine nucleotides by 2-hydroxy-3-(3,3-dichloroallyl)-1,4naphthoquinone. Cancer Res 1979;39:4868-4874. 50. Lee SH, Sutherland TO, Deves R, et al. Restoration of active transport of solutes and oxidative phosphorylation by naphthoquinones in irradiated membrane vesicles from Mycobacteriurn phlei. Proc Natl Acad Sci U S A 1980;77:102-106.

Tabebuia avellanedae (LaPacho, Pau D’Arco, Ipe Roxo) 51. Choi BT, Cheong J, Choi YH. beta-Lapachone-induced apoptosis is associated with activation of caspase-3 and inactivation of NF-kappaB in human colon cancer HCT-116 cells. Anticancer Drugs 2003;14845-850. 52. Oga S, Sekino T. Toxicidade e atividade anti-inflamatoria de Tabebuia avellanedae Lorentz e griesebach (“Ipe Roxo”). Rev Farm Bioquim Univ Sao Paulo 1969;747-53. 53.de Miranda FG, Vilar JC, Alves IA,et al. Antinociceptive and antiedematogenic properties and acute toxicity of Tubebuiu avellanedue Lor. ex Griseb. inner bark aqueous extract. BMC Pharmacol 2001;1:6. 54. Fredholm BB, Gustafsson LE, Hedquist P, et al. Adenosine in the regulation of neurotransmitter release in the peripheral nervous system. In Beme RM, RaU TW, Rubio R, eds. Regulatory function of adenosine: proceedings of the International Symposium on Adenosine, Charlottesville, Virginia, June 7-11, 1982. Boston: M Nijhoff Publishers, 1983:479-493. 55. Daval JL, Nehlig A, Nicolas F. Physiological and pharmacological properties of adenosine: therapeutic implications. Life Sci 1991; 49:1435-1453. 56. de Almeida ER, da Silva Filho AA, dos Santos ER, et al. Antiinflammatory action of lapachol. J Ethnophamcol 1990;29 239-241. 57. Muller K, Sellmer A, Wiegrebe W. Potential antipsoriatic agents: lapacho compounds as potent inhibitors of HaCaT cell growth. J Nat Prod 1999;62:1134-1136.

58. Graziani Y. The effect of quercetin of pp60v-sr kinase activities. In Cody V, Middleton E Jr, Harbome JB, eds. Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure-activity relationships: proceedings of a symposium held in Buffalo, New York, July 22-26, 1985. New York Liss, 1986: 301-313. 59. Hodnick WF, Roettger WJ, Kung FS. Inhibition of mitochondria1 respiration and production of superoxide and hydrogen peroxide by flavonoids: a structure activity study. In Cody V, Middleton E Jr, Harbome JB, eds. Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure-activity relationships: proceedings of a symposium held in Buffalo, New York, July 22-26, 1985. New York Liss, 1986:249-252. 60. Srivastava AK, Chiasson JL. Effect of quercetin on serine/threonine and tyrosine protein kinases. In Cody V, Middleton E Jr, Harbome JB, eds. Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure-activity relationships: proceedings of a symposium held in Buffalo, New York, July 22-26, 1985. New York Liss, 1986315-318. 61. Selway JWT. Antiviral activity of flavones and flavins. In Cody V, Middleton E Jr, Harbome JB, eds. Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure-activity relationships: proceedings of a symposium held in Buffalo, New York, July 22-26,1985. New York Liss, 1986:521-536. 62. Questionable methods of cancer management: ’nutritional’ therapies. CA Cancer J Clin 1993;43:309-319.

Tanaceturnparthenium (Feverfew) Kathy Abascal, BS, JD, RH(AHG)

Eric L. Yarnell, ND, RH(AHG) CHAPTER CONTENTS General Description

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Chemical Composition History and Folk Use Pharmacology

1331 1331

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Tanacetu m partheniu m (family: Asteraceae) Synonym: Chysanthemum parthenium Common names: feverfew, featherfew

GENERAL DESCRIPTION Feverfew (Tanacetum parthenium) is a composite plant that is cultivated in flower gardens throughout Europe and the United States. The round, leafy, branching stems bear alternate, bipinnate leaves with ovate, hoary-green leaflets. The flowers are small and daisylike, with yellow disks and from 10 to 20 white, toothed rays. The name feverfew is a corruption of the word febrifuge, used to signify its tonic and fever-dispelling properties.

CHEMICAL COMPOSITION The major active chemicals in the plant have been hypothesized to be sesquiterpene lactones, principally parthenolide. However, many investigators have found evidence of other active constituents, including both lipophilic compounds (like sesquiterpene lactones) and hydrophilic compounds, though their exact identity has not been determined.’” The flowering herb also contains 0.02% to 0.07% volatile oils (Lamphor, ~-bomeol,&penes, and miscellaneous esters)+$ Various compounds in the volatile oil have shown pharmacologic activity?

HISTORY AND FOLK USE Feverfew has been used for centuries as a febrifuge and for the treatment of migraines and arthritis. Other historical uses of feverfew have been in the treatment of

Clinical Applications 1332 Migraine Headache 1332 Rheumatoid Arthritis 1332 Dosage

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Toxicity

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anemia, earache, dysmenorrhea, dyspepsia, trauma, and intestinal parasites4 It has also been used as an abortifacient and in gardens to control noxious pests (its pyrethrin component is an effective insecticide and herbicide).

PHARMACOLOGY Feverfew has demonstrated some remarkable pharmacologic effects in experimental studies. Its long folk history of use in the treatment of inflammatory conditions such as fever, arthritis, and migraine suggests that it acts in a fashion similar to that of the more common nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin. Extracts of feverfew have been shown to inhibit the synthesis of compounds that promote inflammation, including inflammatory prostaglandins, leukotrienes, and thromboxanes. No adverse effects reported for feverfew mimic those of aspirin or NSAIDs, suggesting that the effects of feverfew are in some way distinct from those of the drugs. Inhibition by feverfew at the initial stage of synthesis, particularly inhibition of phospholipase A= is more like that exerted by corticosteroids than by NSAIDs and may partially explain the differences? Feverfew also has favorable effects on the behavior of blood platelet^.^,^ These effects include inhibition of platelet aggregation and the secretion of inflammatory and allergic mediators like histamine and serotonin. Parthenolide components also exert a tonic effect on vascular smooth muscle? The combined effect on smooth muscle and platelets is probably the factor responsible for feverfew’s effect in preventing and treating migraine headaches. 1331

Pharmacology of Natural Medicines

CLINICAL APPLICATIONS Feverfew has been used for centuries to relieve fever, migraines, and arthritis.The only condition with confirmed scientific documentation at present is in the prevention and treatment of migraine headache.

Migraine Headache Physician John Hill, in his book The Family Herbal (1772), noted, "In the worst headache this herb exceeds whatever else is known." Recently, there has been tremendous increase in the interest in feverfew for migraine headache. This renewed interest began in 1970s in Britain. Greater public awareness of the herb led to scientific investigation. A 1983 survey found that 70% of 270 migraine sufferers who had eaten feverfew daily for prolonged periods claimed that the herb decreased the frequency and/or intensity of their attacks.1° Many of these patients had shown no response to orthodox medicines. This prompted clinical investigations of the therapeutic and preventive effects of feverfew in the treatment of migraine. Numerous double-blind trials have now been conducted on the efficacy of feverfew in migraine the results of which have been assessed in three metaana1y~es.l~'~ The first two metaanalyses concluded that the majority of studies show that feverfew extracts are superior to placebo for decreasing the frequency and severity of migraine headaches, though most of the studies were of relatively low methodologc quality and that efficacy was not proved beyond a reasonable doubt.'"16 The third metaanalysis concluded that feverfew extracts have not been proven in controlled trials to prevent migraine better than p1aceb0.I~ The highest quality study among fever clinical trials used a granulated ethanol extract of feverfew and found it ineffective compared with placebo, whereas all the other trials used unextracted, powdered feverfew. As a result, careful attention must be paid in future studies to the types of products utilized, and the results of trials using different products should probably not be combined in metaanalyses. One double-blind, randomized clinical trial compared the effects of a combination of a feverfew extract (100 mg) with riboflavin 400 mg and magnesium 300 mg daily to riboflavin 25 mg daily.Is The control, riboflavin 25 mg, appeared to be just as active as the combination formula, and the trial showed that combining feverfew and magnesium with riboflavin adds no additional benefits for preventing migraine headaches.

and cellular damage found in rheumatoid arthritis. The inhibition of the release of inflammatory particles by feverfew is much greater than that achieved by NSAIDs like aspirin8This finding, coupled with many of feverfew's other effects, indicates that feverfew could greatly reduce inflammation in rheumatoid arthritis. Although a double-blind, placebo-controlled study demonstrated no apparent benefit from oral feverfew in rheumatoid arthritis, the dosage used was small (76 mg dried, powdered feverfew leaf, corresponding to two medium-sized leaves), the level of parthenolide was not determined in the product, and patients continued to take NSAIDs, a practice that has been suggested to reduce the efficacy of feverfew.19 Therefore the benefit of feverfew in rheumatoid arthritis has not yet been determined.

DOSAGE The effectiveness of feverfew depends on adequate levels of parthenolide, the active principle. Unfortunately, analyses of the parthenolide content of more than 35 different commercial preparations indicate a wide variation in the amount of this agent.20The majority of products contained no parthenolide or only traces. Knight,2l however, found that the addition of an oxidizing agent and a weak base to powdered feverfew leaves led to regeneration of large amounts of parthenolide.2IThere are plausible mechanisms, according to Knight,21 whereby parthenolide could also be regenerated in vivo. It is therefore difficult to determine the relevance of measurement of parthenolide in extracts; assessments of activity of extracts would perhaps be superior though more expensive. The preparations used in successful clinical trials had a parthenolide content of 0.4% to 0.66%. In order to achieve the benefits noted in the migraine studies, the dosage of parthenolide must be similar. The dosage of feverfew used in the London Migraine Clinic study was one capsule containing 25 mg of the freeze-dried pulverized leaves twice daily.6In the Nottingham study it was one capsule containing 82 mg of dried powdered leaves once daily.7 Therefore the daily dosage of parthenolide that may be effective in the prevention of a migraine headache is roughly 0.25 to 0.5 mg. Although these low dosages may be effective in preventing an attack, a higher dose (1 to 2 g) is necessary during an acute attack: dried pulverized leaves, 25 to 50 mg two times/day.

Rheumatoid Arthritis

TOXICITY

Inflammatory compounds released by white blood cells and platelets contribute greatly to the inflammation

There were no reports of toxic reactions in patients taking feverfew in the 6-month migraine study. Feverfew has

~~

~

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Tanaceturn partheniurn (Feverfew)

been used by large numbers of people for many years without reports of toxicity. Chewing the leaves, however, may result in aphthous ulcerations, and some sensitive persons experience an exudative dermatitis from

external contact.= In clinical trials, neither mouth ulcers nor dermatitis was more common in the feverfew groups than the placebo groups; in one trial, aphthous ulcers were actually more common in the placebo group.”

1. Brown AMG, Edwards CM, Davey MR, et al. Pharmacological activity of feverfew (Tunaceturn purtheniurn (L) Schultz-Bip.): assessment by inhibition of human polymorphonuclear leukocyte chemiluminescencein-vitro. J Pharm Pharmacol1997;49:558-561. 2.Sumner H, Salan U, Knight DW, Hoult JRS. Inhibition of 5-lipoxygenase and cyclo-oxygenase in leukocytes by feverfew. Involvement of sesquiterpene lactones and other components. Biochem Pharmacol1992;43:2313-2320. 3. Marles RJ, Kaminski J, Amason JT, et al. A bioassay for inhibition of serotonin release from bovine platelets. J Nat Prod 1992;55: 1044-1056. 4. Duke JA. CRC handbook of medicinal herbs. Boca Raton, FL: CRC Press, 1985:118. 5. Bohlmann F, Zdero C. Sesquiterpene lactones and other constituents from Tunaceturn purtheniurn. Phytochemistry 1982;21:2543-2549. 6.Pugh WJ, Sambo K. Prostaglandin synthetase inhibitors in feverfew.J Pharm Pharmacol1988;40743-745. 7. Makheja AN, Bailey JM. A platelet phospholipase inhibitor from the medicinal herb feverfew (Tunaceturnpurthenium). Prostaglandins Leukot Med 1982;8653-660. 8. Heptinstall S, White A, Williamson L, Mitchell JRA. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leukocytes. Lancet 1985;1:1071-1074. 9. Barsby RW, Salan U,Knight DW, Hoult JR. Feverfew and vascular smooth muscle: extracts from fresh and dried plants show opposing pharmacological profiles, dependent upon sesquiterpene lactone content. Planta Med 1993;59:20-25. 10.Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efficacy of feverfew as prophylactic treatment of migraine. Br Med J (Clin Res Ed)1985;291:569-573. 11. Murphy JJ, Heptinstall S, Mitchell JRA.Randomized double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet 1988;2:189-192.

12. Palevitch D, Earon G, Carasso R. Feverfew (Tunaceturn purtheniuni) as a prophylactic treatment for migraine: a double-blind placebocontrolled study. Phytother Res 1997;11:508-511. 13.De Weerdt CJ, Bootsma HPR, Hendriks H. Herbal medicine in migraine prevention. Randomized double-blind placeboiontrolled crossover trial of a feverfew preparation. Phytomedicine 1996;3: 225-230. 14. Kuritzky A, Elhacham Y, Yerushalmi Z, Hering R. Feverfew in the treatment of migraine: its effect on serotonin uptake and platelet activity. Neurology 1994;44(Suppl2):293P. 15. Pittler MH, Vogler BK, Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev 2000;CW02286. 16. Vogler BK, Piffler MH, Emst E. Feverfew as a preventive treatment for migraine: a systematic review. Cephalalgia 1998;18: 704-708. 17. Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev 2004;(1):CW02286. 18. Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache 2004;44:885-890. 19. Pattrick M,Heptinstall S, Doherty M. Feverfew in rheumatoid arthritis: a double blind, placebo controlled study. Ann Rheum Dis 1989;48547-549. 20. Heptinstall S, Awang DV, Dawson BA, et al. Parthenolide content and bioactivity of feverfew (Tunaceturn purtheniurn (L.) Schultz-Bip.). Estimation of commercial and authenticated feverfew products. J Pharm Pharmacol1992;44:391-395. 21. Knight DW. Feverfew: chemistry and biological activity. Nat Prod Reports 1995;12271-276. 22. Awang DVC. Feverfew. Can Pharm J 1989;122:266-270.

Taraxacum officinale(Dandelion) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Anticancer and Immune-Enhancing Effects Kidney Stones 1337

General Description 1335 Chemical Composition History and Folk Use

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1336 Clinical Applications 1337 Liver Conditions 1337

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Pharmacology 1336 Digestive Effects 1336 Diabetes 1337 Liver Tonic 1337 Diuretic and Weight-Loss Effects

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Taraxacum officinale (family: Compositae) Common names: English: dandelion, wet-a-bed, lion’s tooth French: dent-de-lion, pissenlit German: lowenzahn, pfaffenrohrlein Spanish: diente de leon Italian: tarassaco Chinese: p’u kung ying, Ching p’o PO, chiang-nouts’ao, huang-hua-tii-ting

GENERAL DESCRIPTION Dandelion (Taraxucum officinale) is a member of the Compositae family and is closely related to chicory.’ Several origins have been attributed to the name Taraxacum, among them the most likely being from the Greek taraxo (”disorder,” ”disturbance”), and akos (”remedy”), and akeomai (”I heal”) and from tharakhcharkon, possibly a derivative of a Persian-Arabic word for “edible” and the name by which the plant is referred to in a thirteenth-century Arabian botanical work. Taraxacum is known around the world by a variety of names. In English-speaking countries, dandelion (from the French dent-de-Zion, referring to the plant’s lion’s tooth leaves) is its most common name. It is also known as wet-a-bed (after its diuretic action), lion’s tooth, fairy clock, priest’s crown, swine’s snout, blowball, milk gowan, wild endive, white endive, cankerwort, puffball, and Irish daisy1

Dosage

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Drug Interactions 1338

Dandelion is a variable perennial, growing to a height of 12 inches. Its spatula-like leaves are deeply toothed, shiny, and hairless and are arranged in a ground-level rosette. The yellow flowers bloom for most of the year and are sensitive to light and weather-opening at daybreak and closing at night fall, and opening in dry weather and closing in wet (a closed dandelion flower signals rain). When the flower matures, it closes up, the petals wither, and it forms into a puffball containing seeds that are dispersed by the breeze. The rosette formation of grooved leaves channels rainwater into the center and down to a taproot, which is thick and dark brown, almost black on the outside. The root is cylindrical, tapering, and somewhat branched. It has a slight odor and a sweetish taste. The inside of dried dandelion root is yellowish, very porous, and without pith. It is believed that the plant originated in Central Asia and spread throughout most of the world, preferring the cooler climates.’ Although Taruxacum is very adaptable, it prefers moist nitrogen-rich soils at altitudes less than 6000 feet. Most species occur in the temperate zones of the northern hemisphere, with the greatest concentration in northwest Europe. The portion of the plant that is most commonly used is the root; however, the leaves and whole plant can also be used. In addition to its medicinal use, dandelion is a nutritious food and beverage. Tender leaves are used raw in salads and sandwiches, or lightly cooked as 1335

Pharmacology of Natural Medicines a vegetable. Tea is made from the leaves, coffee substitute from the roots, and wine and schnapps from the flowers.

CHEMICAL COMPOSITION Dandelion root‘s calorie count is exceptionally low-a cup is only 25 calories-and its nutrient content is exceptionally high.’ In fact, dandelion root contains greater nutritional value than many other vegetables. It is particularly high in vitamins and minerals, protein, choline, inulin, and pectin. Its carotenoid content is extremely high, as reflected by its having a higher vitamin A content than carrots (dandelion has 14,000 IU of vitamin A per 100 grams, compared with 11,000 W for carrots). Dandelion greens are an outstanding source of vitamin A, and an excellent source of vitamin C, riboflavin, Bb and thiamin as well as calcium, copper, manganese, and iron.I.2 The primary therapeutic actions of dandelion are believed to be due to the bitter principle taraxacin, various terpenoids, inulin, and its high concentration of nutrients, especially choline.’ Other constituents of dandelion that may contribute to its pharmacology are resins, pectin, taraxanthin (a carotenoid pigment in the flowers), fatty acids, and flavonoids. The roots of T.oficinale roots contain the triterpenes P-amyrin, taraxasterol, and taraxerol and the sterols sitosterin, stigmasterin, and phytosterin (Figures 130-1 and 130-2): Later research has elicited several compounds that are likely to be clinically significant. Three flavonoid glycosides-luteolin 7-glucoside and two luteolin 7-diglucosides-have been isolated from dandelion flowers and leaves, together with free luteolin and

chrysoeriol in the flower tissue. Three hydroxycinnamic acids-chicoric acid, monocaffeyltartaric acid, and chlorogenic acid-have been found throughout the plant, and the coumarins, cichoriin and aesculin, have been identified in leaf extracts. Chicoric acid and the related monocaffeyltartaric acid were found to be the major phenolic constituents in flowers, roots, leaves, and involucral bracts and also in the medicinal preparations tested?

HISTORY AND FOLK USE Although many individuals may consider the common dandelion an unwanted weed, herbalists all over the world have revered this valuable herb. Generally regarded as a liver remedy, dandelion has a long history of folk use throughout the word. In Europe, dandelion was used in the treatment of the following conditions: Fevers Boils Eye problems Diarrhea Fluid retention Liver congestion Heartburn Various skin problems

In China, dandelion has been used to treat the following disorders: Breast problems (cancer, inflammation, lack of milk flow, etc.) Liver diseases Appendicitis Digestive ailments Dandelion’s use in India, Russia, and most other parts of the world revolved primarily around its action on the liver.

PHARMACOLOGY The primary pharmacologic activities of dandelion relate to digestion, liver function, and diuresis. Figure 130-1 Taraxerol.

Figure 130-2 Taraxasterol

Digestive Effects Bitter herbs like dandelion are used to aid digestion on the basis of the belief that bitter principles stimulate the initial phase of digestion, including the secretion of salivary and gastric juices. Dandelion goes beyond this initial stimulation by stimulating the release of bile by the liver and gallbladder. The digestive tonic properties attributed to dandelion are now thought to be due to a bitter principle researchers have named turuxucin and have identified as belonging to a class of active substances called guaianolides, which have intestinal antiseptic, germicidal, and expectorant effects.6

Taraxacum officinale (Dandelion) Dandelion root contains a very high concentration (up to 40%) of an indigestible carbohydrate called inulin, which serves as food source for and thus promotes the growth of the “friendly” colonic bacteria species Bifidobacterium and Lactobacillus. When these beneficial bacteria are encouraged to proliferate, they crowd out other harmful bacteria, thus acting like a natural protective antibiotic and improving the health of the digestive tract.

Diabetes Inulin is also helpful in improving blood sugar control and diabetes. In one study, dandelion given to diabetic rats in the form of a water extract significantly improved the rats’ production of antioxidant liver enzymes; it also decreased their blood sugar, total cholesterol, and triglyceride levels, and raised their concentrations of beneficial high-density lipoprotein ch~lesterol.~

Liver Tonic Studies in humans and laboratory animals have shown that dandelion root enhances the flow of bile, improving such conditions as liver congestion, bile duct inflammation, hepatitis, gallstones, and jaundice.*-’O Dandelion’s action in increasing bile flow is twofold: It has a direct effect on the liver, causing rises in bile production and flow to the gallbladder (choleretic effect), and a direct effect on the gallbladder, causing contraction and release of stored bile (cholagogue effect). The high choline content of the root may be a major factor in dandelion’s ability to act as a “tonic” to the liver. Historically, dandelion’s positive effect on such a wide variety of conditions is probably closely related to its ability to improve the functional ability of the liver. In one animal study, dandelion sigruficantlyimproved the liver’s ability to clear toxins by 244%.Dandelion’s effectiveness in improving the liver’s ability to clear potentially toxic agents was also demonstrated in a study in which rats were given the antimicrobial drug ciprofloxacin. In those rats that also received dandelion, levels of the drug were rapidly and significantly lowered by 73%.”

Diuretic and Weight-Loss Effects The leaves of dandelion have confirmed diuretic activity. In one study in mice, dandelion exerted a diuretic activity comparable to that of furosemide (Lasix).I2Because dandelion replaces potassium lost through diuresis, it does not have the potential side effects of furosemide, such as hepatic coma and circulatory collapse. The dose given was 8 ml/kg body weight of the aqueous fluid extract of the leaves. This dose produced a 30% loss of body weight in mice and rats in a 30-day period. Much of the weight loss was attributed to the significant diuretic effects.

Anticancer and Immune-Enhancing Effects Various dandelion extracts and components have demonstrated antitumor properties in animal experiments.l3-lS Evidence also indicates that dandelion enhances cellmediated, humoral, and nonspecific immunity, induces the secretion of tumor necrosis factor-alpha, and influences production of nitric oxide.16J7

Kidney Stones One study using female Wistar rats evaluated the following seven botanicals historically used to prevent and treat kidney-stone formation:

Verbena oficinalis Lithospermum oficinale Taraxacum oficinale Equisetum arvense Arctostaphylos uva ursi Arctium lappa Silene saxifiaga Variations of the main urolithiasis risk factors-itraturia, calciuria, phosphaturia, pH, and diuresis-were measured. The researchers concluded that the beneficial effects of these herbal infusions on urolithiasis can be attributed to some disinfectant action, and, tentatively, to the presence of saponins.’*

CLINICAL APPLICATIONS Dandelion’s specific action is on the liver, but as an alterative or tonic it benefits the body as a whole. It is often used as: A diuretic A laxative A cholagogue A general stimulant for the urinary system A choleretic A depurative (purifier) A hypoglycemic An antitumor agent

Liver Conditions Two human studies have demonstrated the liver-healing properties of dandelion. In a 1938study in Italy, 12 patients with severe liver imbalances, many exhibiting classic symptoms such as loss of appetite, low energy, and jaundice, were treated with dandelion extract (one 5-ml injection/day for 20 days).’ Eleven of the 12 patients showed a considerable drop in blood cholesterol. In the other study, dandelion extract was shown to successfully treat hepatitis, swelling of the liver, jaundice, and dyspepsia with deficient bile secretion.8 Dandelion’s effects on the liver, particularly its lipotropic effects, may be put to good use in the treatment of premenstrual syndrome. Decreased clearance of

Pharmacology of Natural Medicines estrogen and other hormones by the liver is believed to be responsible for these symptoms in some women. If dandelion can improve the liver's ability to detoxify these hormones, symptoms may be likewise improved.

DOSAGE As a general tonic and mild liver remedy, the dandelion root can be used at the following dosages three times per day: Dried root 2 to 8 g by infusion or decoction Fluid extract (1:l):4 to 8 ml(1 to 2 tsp) Tincture: Alcohol-based tinctures of dandelion are not recommended because of the extremely high dosage required Juice of fresh root: 4 to 8 ml(1 to 2 tsp) Powdered solid extract (4:l):250 to 500 mg

safe to use even in large amounts, with virtually no documented side effects reported.' There has been one case report of an atopic individual experiencing an anaphylactic reaction after the oral ingestion of an herbal combination containing T. oficinale. In this case, the herbal compound was found to have trace amounts of pollen from T. oficinale and several other medicinal plants, which resulted in this systemic reaction.19 This single case report indicates a possible need for caution in individuals with pollen allergy to other plants of the Compositae family. The carcinogenicity of T. oficinale has been investigated in an animal model. No carcinogenic activity was observed after 120 days of administration.20

DRUG INTERACTIONS

No toxic or adverse effects have been reported for either external or internal use of dandelion. It is considered

In an animal study, administration of an extract of the whole dandelion plant concomitantly with ciprofloxacin decreased absorption of the drugz1 The investigators found that this effect was due to the high mineral content of the dandelion herb. Until further information is available, ciprofloxacin should not be taken within 2 hours of any dandelion supplement, including teas. In general, it is often recommended that botanical medicines that have a diuretic effect should be avoided by anyone taking diuretic medications, because they may enhance the effect of these drugs and lead to possible cardiovascular side effects.

1. Hobbs C. Turuxacum oficinule: a monograph and Literature review. In Alstadt E, ed. Eclectic dispensatory. Portland, OR: Eclectic Medical, 1989. 2. h u n g AY, Foster S. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York John Wdey, 1996: 205-207. 3.Broda 8, Andrzejewska E. Choline content in some medicinal plants. F m POI 1966;22:181-184. 4. Devys M. Triterpene alcohols from dandelion (T. dens-leonis) pollen. CR Acad Sci Ser D 1969;269:798-801. 5. Williams CA, Goldstone F, Greenham J. Flavonoids, cinnamic acids and coumarins from the different tissues and medicinal preparations of Taraxucum oficinule. Phytochemishy 1996;42:121-127. 6. Ahmad W, Yasmeen S, Ali Z, et al. Taraxacin, a new guaianolide from Taruxucurn wullzchii. J Nat Prod 2O00;63:1010-1011. 7. Yamashita K, Kawai K, Itakura M. Effects of fructo-oligosaccharides on blood glucose and serum lipids in diabetic subjects. Nutr Res 1984;4:961-966. 8. Faber K. [The dandelion Turaxucum oflicinule.] Pharmazie 1958;13:423-436. 9.Susnik F. Present state of knowledge of the medicinal plant Turuxucurn oficinale Weber. Med Razgl 1982;21:323-328. 1O.Bohm K. [Choleretic action of various plant drugs.] Arzneimittelforschung 1959;9:376-378. 11. Cho SY, Park JY, Park EM, et al. Alternation of hepatic antioxidant enzyme activities and lipid profile in streptozotocin-induced

diabetic rats by supplementation of dandelion water extract. Clin Chim Acta 2002;317109-117. 12. Racz-Kotilla E, Racz G, Solomon A. The action of Turuxacum oficinale extracts on the body weight and diuresis of laboratory animals. Planta Med 1974;26:212-217. 13. Sieyaku KK. Taraxacurn extracts as antihunour agents. Chem Abstr 1981;94374. 14. Takasaki M, Konoshima T, Tokuda H, et al. Anti-carcinogenic activity of Turuxucum plant. 11. Biol Pharm Bull 1999;22:606-610. 15. Takasaki M, Konoshima T, Tokuda H, et al. Anti-carcinogenic activity of Turaxucum plant. I. Biol Pharm Bull 1999;22:602-605. 16. Kim HM, Shin HY, Lim KH, et al. Turuxucum oficinale inhibitstumor necrosis factor-alpha production from rat astrocytes. Immunopharmacol Immunotoxicol2000;22:519-530. 17. Kim HM, Lee EH, Shin TY, et al. Turaxacum oficinale restores inhibition of nitric oxide production by cadmium in mouse peritoneal macrophages. Immunopharmacol Immunotoxicol1998;20:283-297. 18. Grases F, Melero G, Costa-Bauza A, et al. Urolithiasis and phytotherapy. Int Urol Nephrol1994;26507-511. 19. Lovell CR, Rowan M. Dandelion dermatitis. Contact Dermatitis 1991;25:185-188. 20. Hirono I, Mori H, Kato K, et al. Safety examination of some edible plants, Part 2. J Environ Pathol Toxicol 1978;1:71-74. 21. Zhu M, Wong PY, Li RC. Effects of Turuxucum mongolicum on the bioavailability and disposition of ciprofloxacin in rats. J Pharm Sci 1999;88:632-634.

Preparations of the leaves can be used as a mild diuretic and weight-loss agent at the following dosages three times per day: Dried leaf: 4 to 10 g by infusion Fluid extract (1:l):4 to 10 ml

TOXICITY

T a u s brevifolia (PacificYew) Cathryn M. Flanagan, ND CHAPTER CONTENTS General Description

1339

Chemical Composition History and Folk Use

1340 1340

Tuxus brevifoliu (family: Taxaceae) Common names: Pacific yew, taxol, paclitaxel

GENERAL DESCRIPTION Paclitaxel (Taxol) and complex diterpenoid taxanes are compounds found in Tuxus brevifoliu, the Pacific yew. Docetaxel (Taxotere) is a semisynthetic agent derived from 10-deacetyl baccatin 111, a taxane isolated from the needles of Tuxus buccutu, the English yew. These compounds have been cited as some of the most promising plant compounds tested for anticancer properties to date.’ Pacific yew was first collected in 1962 by a U.S. Department of Agriculture team in Washington State as part of the large natural products screening program of the U.S.National Cancer Institute. Confirmed activity by a bark extract against the KB cell line in tissue culture was reported in 1964. Isolation studies began in 1965, and by 1971, Wall et a12at the Research Triangle Institute (Durham, NC) had identified paclitaxel as the active constituent.* Paclitaxel became big news in 1989, when investigators at the Johns Hopkins Oncology Center in Baltimore reported a 30% response rate in cases of refractory ovarian cancer, a remarkable rate for this type of ~ a n c e rThe . ~ development of docetaxel began in 1981 in France. Taxanes used in conjunction with chemotherapy and irradiation have demonstrated improved results to either therapy alone as well as better tolerance of the therapies. Yews are evergreen trees or shrubs that produce a seed surrounded by an edible red fleshy aril. The yew is difficult to class taxonomically because it looks like conifers but, because of the absence of cones and resin ducts, it is placed in a separate order.

Pharmacology

1341

Clinical Applications Toxicity

1341

1341

Although the yew appears to be tenacious, it is slow to reproduce. The species is dioecious, with female trees producing relatively scarce fruits. Seedlings are rare. Most often, new yew trees come from offshoots of a ”mother tree,” which is why they are usually found in clusters. They grow best on deep, moist, rich rocky or gravelly soils. The largest known living Pacific yew is in Lewis County, Washington, near Mount Rainier. It stands 21.3 m tall, has a girth of 4.5 m, and is estimated to be 1000 years old.2 Although paclitaxel is found in species other than the Pacific yew, its concentration is too low to warrant the extensive extraction processing required. Initially, it was thought that the most consistently stable and highly active constituent came from bark isolates, followed by root isolates. Currently, paclitaxel and another compound, baccatin III (from the English yew, T. buccutu), are being extracted from needles and twigs of 3- to 5-year-old cuttings being grown for this purpose. Paclitaxel, a complex molecule, can be synthesized from baccatin 111, but only recently has total synthesis been achieved.45 Harvesting of a sufficient natural source is unrealistic for long-term use, because the Pacific yew, an inhabitant of old-growth stands, is in limited supply. The demand for taxol is estimated at 50 to 200 kg/patient, which would require 500,000 to 635,000 kg of bark yearly. One 200-year-old tree with a 25-cm diameter yields only 2.7 kg of bark.2 The National Cancer Institute had requested 340,200 kg of dried bark in 1991 for 25 kg to be used in clinical trials alone. Environmentalists are concerned about the devastation of the little old-growth habitat that has survived logging efforts. Ironically, the Pacific yew had been previously regarded as a trash tree, left behind or burnt after logging operations. Now it 1339

Pharmacology of Natural Medicines is sought for its bark, and accessible stands are being harvested for maximum yield. The future of paclitaxel as a viable anticancer agent depends either on synthetic production of it or of a molecule similar enough to retain the therapeutic properties produced or on improvements in harvesting and extraction techniques that will maximize yield while perpetuating the natural source. Researchers at Stanford University have overcome many hurdles in the synthesis but have not yet been totally successful. Extraction from needles looks promising, as it takes only 27.2 kg of foliage (produced from one tree), versus 4.1 kg of bark (consuming three trees), to obtain 2 g of paclitaxel, the necessary dose for one patient. Harvesting trees in a manner that allows for sprouting of new trees is another way to sustain a supply and the survival of the species. Another natural source of paclitaxel is the fungus Tuxornyces undreunue, originally isolated from the inner bark of the Pacific yew. When grown in artificial medium, Tuxomyces produces paclitaxel.6 As yet, this finding does not appear to have been developed commercially but is a promising and more sustainable source of paclitaxel. A collaborative research and development agreement between the National Cancer Institute and the BristolMyers Squibb Company has made it possible for paclitaxel to be the first drug available through the treatment referral center to designated comprehensive cancer centers for eligible patients before being commercially a~ailable.~ The National Cancer Institute announced (newsletter, September 1992) that paclitaxel had been reclassified as a group C drug, making it available with Medicare reimbursement to women with refractory ovarian cancer.

CHEMICAL COMPOSITION Yew is poisonous because of at least 11 alkaloids, known collectively as tuxines. The structure of only two of the alkaloid constituents is known, taxine A, which accounts for 30%, and taxine B, which accounts for 2%. Paclitaxel (Figure 131-1) is a pseudoalkaloid but not a constituent of taxine because its nitrogen is acylated with benzoic acid and has no basic principle. The concentration of paclitaxel in yew bark is low, only 0.01%. Taxanes have now been found in species other than the Pacific yew, but at lower concentrations. The harvesting of 500,000 to 635,000 kg/year of the bark is required to provide the estimated paclitaxel needed. Therefore, development of analogues synthesized from natural terpenes is important for long-term use. In the search for precursors for paclitaxel synthesis, the much more prevalent yew needles have been analyzed for paclitaxel analogues. Several have been identified (e.g., 10-deacetyltaxol 111, cephalmannine,

O b '

10-Deacetylbaccatin 111

Taxol

R'

R"

H

H

Q

A

OANH o

Figure 131-1 Paclitaxel.

10-deacetyltaxol, 10-deacetylcephalomannine,and baccatin-111). Because all yew species contain these highly oxygenated diterpenoids based on the unique taxane skeleton, most of the more than 100 yew varieties are being screened, as are other members of the Tuxus species. Other analogues, like docetaxel, are made through alteration of compounds extracted from the yew tree needles. It is possible that taxanes in Tuxus besides paclitaxel have an important secondary effect, preventing induction of P-glycoprotein, a molecule that effluxes paclitaxel and docetaxel out of cancer cells. Synthetic taxanes have been shown to be able to reduce taxol resistance in vitro and are now in clinical trial^.^ Paclitaxel is synthesized from cyclization of the universal diterpenoid precursor, geranylgeranyl diphosphate, to taxa-4(5),11(12)-diene.This olefin is hydroxylated via cytochrome P450 catalysts to taxa-4(20),11(12)-dien5-alpha-01. Then this alcohol is converted via an acetyl coenzyme A-dependent process to the corresponding acetate ester. Further genetic identification and isolations are targeted to improve the yield of paclitaxel from the Trzxus species.8

HISTORY AND FOLK USE Historically, the yew has been highly valued for its dense, resilient, decay-resistant, tight-grained wood and

Taxus brevifolia (Pacific Yew)

its medicinal properties. The Greeks named the yew foxus in reference to its use for making strong bows (toxon), and its poisonous nature (toxikon)? It was used as an animal and fish poison by primitive cultures as well as for murder and suicide. In the 1st century AD, Claudius suggested its use as an antidote for viper bites. Europeans used it as an abortifacient, and for heart ailments and hydrophobia.2Native Americans used the yew for many ailments as follows: Rheumatism Lung ailments Colds Fever Pain scurvy Numbness Paralysis Stomach ache Bowel ailments Dysmenorrhea Clots Gonorrhea Women ate yew berries to prevent conception. Youths rubbed smooth sticks of yew on their developing bodies to gain its strength. Both the bark and the leaves have been brewed for tea, and powders made from the bark alone. The fleshy red aril (berry) that surrounds the seed is not poisonous, although the seed itself is? There is a lot of folklore about the yew's supernatural powers. Because it is a slow-growing, long-lived tree, it was associated with immortality and used in spells to raise the dead.1° Because it was regarded as among the most potent of trees for protection against evil, it was considered unlucky to cut down or damage a yew tree. Many were planted in churchyards/graveyards and alongside homes for protection. Specimens survive today in spite of main trunks being hollowed out from decay following hundreds of years of existence.

PHARMACOLOGY Paclitaxel's anticancer action is unique in that it inhibits cell division by promoting the formation of microtubules, the rodlike structures that function as a cell skeleton, making cells more stable and resistant to depolymerization. In contrast, other anticancer phytoagents (e.g., colchicine and vinca alkaloids) induce polymerization of microtubules. In addition, under the influence of paclitaxel, the microtubules polymerize independently of the microtubule-organizing center (MTOC), which is in a perinuclear area, and instead localize predominantly in the cell periphery." This interferes with the mitotic spindle and selectively blocks cells in the G2 and M phases of the cell cycle, the most radiosensitive

phases. Additionally, paclitaxel induces the formation of abnormal spindle asters that do not require centrioles for enucleation and are reversible after treatment.l2J3 Discovery of this unique mechanism of action by Horowitz et a1 in 1979 kindled interest in paclitaxel, despite the inherent problems in the utilization of a scarce natural product.14J5 In addition, paclitaxel has demonstrated, in vivo, an ability to activate a local release of an apoptosisinducing cytokine.16Studies on cancer cell lines induced with gml, a novel gene, demonstrated a marked increase in sensitivity to paclitaxel via apoptosis. An assay for gml expression could serve as a clinically useful predictor of chemotherapeutic ~ensitivity.'~ Docetaxel manifests its maximum inhibitory effect against cells that are in S phase.ls Other analogues (particularly IDN5109) are showing antiproliferative activity 20- to 30-fold higher than paclitaxel in cancer cells that test positive for multiple-drug resi~tance.'~

CLINICAL APPLICATIONS Paclitaxel has demonstrated a broad spectrum of antitumor activity. Phase I trials, which began in 1983, demonstrated paclitaxel's antineoplasticactivity against several tumor types, such as the f~llowing~O-~~: Melanoma Adenocarcinoma of unknown origin Refractory ovarian carcinoma Small cell and non-small cell lung carcinoma Gastric, colon, prostate, breast, and head and neck carcinomas Lymphoblastic and myeloblastic leukemias Trials are also being conducted with impressive results using paclitaxel in combination with other antineoplastic agents, such as cisplatinz8The Gynecology Oncology Group (GOG) reported a 33% response rate in patients who were previously resistant to cisplatin, when they are treated with the combination of cisplatin and pa~litaxel.2~ Trials are being conducted on small cell and non-small cell lung, renal, gastric, breast, advanced ovarian, colon, and cervical carcinomas; head and neck cancers; small cell lung and prostate carcinomas; and low-grade non-Hodgkin's Table 131-1 lists the short-term partial or complete response rates of various types of cancer to paclitaxel alone or in combination with other chemotherapeutic drugs.

TOXlCITY ~~

~

Human poisoning from the deliberate consumption of yew leaves or seeds is now rare. Published cases involving psychiatric patients and prisoners describe the first

Cancer type

Response range ("10)

Ovarian cancer

20-50

Breast cancer

56-62

Lung cancer

21-46

Melanoma

28

Renal carcinoma

0 (small numbers)

Prostate

50 (small numbers)

Modified from Appendino G. Fitoterapia 1993;&4:5-25.

been evident in ulcerated mucosa, indicating that the cell cycle was arrested in mitosis.38 Paclitaxel has been known to inhibit neurite growth and induce prominent morphologic effects, such as microtubule bundles in neurons, in satellite cells, and in Schwann cells in organotypic dorsal root ganglion cultures.394 Clinically, the most common symptoms have been glove-and-stocking paresthesia and perioral numbness. Distal sensory loss to large-fiber (proprioception, vibration) and small-fiber (pin-prick, temperature) modalities and loss or decrease of distal deep tendon reflexes have been noted, although motor nerves seem to be spared. In general, the clinical incidence and severity of peripheral neurotoxicity have been doserelated. Patients with a history of substantial alcohol use have appeared to be more predisposed to the development of neurosensory toxic effects of cisplatin and

symptoms of intoxication as appearing 1 hour after ingestion. The manifestations include mydriasis, nausea, vomiting, abdominal cramping, and arrhythmia. Death occurs from cardiac arrest 3 to 24 hours after i n g e ~ t i o n . ~ ~ The development of a suitable clinical formulation has been hampered by paclitaxel's poor aqueous solubility. The lethal dose in humans is approximately four or five Cremophor is being used as the vehicle for administrahandfuls of leaves, corresponding to 150 needles. No tion and has been implicated in side effects such as type 1 specific antidote is known. hypersensitivity reactions.48Neutropenia, the principle Paclitaxel binds 95% to 98% with plasma proteins dose-limiting toxic effect of paclitaxel, resolves rapidly yet is readily eliminated through hepatic metabolism, (15 tn 21 days) after treatment is st~pped.4~ The major biliary excretion, and/or extensive tissue binding. Tntal clinical risk factor for neutropenia seems to be the extent urinary excretion has been insignificant, indicating of prior myelotoxic chemotherapy and/or irradiation. that renal clearance contributes minimally to systemic Bradyarrhythmias, which have been noted as tran~ l e a r a n c e . ~ ~Hepatic , " ~ ~ ~ metabolism via cytochrome sient and asymptomatic, have been reported during P450 (CYP) is involved for both paclitaxel and docetaxel. paclitaxel infusions in at least 29%of patients with ovarHowever, the former is hydroxylated by CYP2C8, ian cancer, as reported by McGuire et al.45This developwhereas the latter is hydroxylated by CYP3A4.35 ment appears to be related more to paclitaxel, because Toxicity in clinical trials manifests as follows: other agents formulated with Cremophor have not been Bone marrow suppression associated with similar arrhythmias. Atypical chest Hypersensitivity pains during paclitaxel infusion have been observed, but Cardiovascular abnormalities they are believed to be a manifestation of a hypersensiNeurotoxicity tivity reaction.'*S4 Arthralgias and myalgias Other paclitaxel- or Cremophor-related side effects Alopecia are sudden and complete alopecia-often occurring in a Gastrointestinal upset single day-local venous toxic effects such as erythema, tenderness, and cellulitis in areas of dermal extravasaJunctional tachycardia via conduction block rather tion, fatigue, headaches, taste perversions, significant than direct primary toxicity on myocytes has been elevations in serum triglycerides, and minor rises in suggested.%Hypersensitivity, skin reactions, and accuhepatic and renal function values?' mulated fluid retention syndrome are minimized with a Lipid-coated microbubbles may be an effective way 3- to 5-day regimen of corticosteroids prior to paclitaxel of providing selective affinity for tumor cells, thus infusions.37 reducing systemic effects while maintaining antitumor Patients with leukemia who are treated with lugh doses actions.I8 Additional precautions may be necessary of paclitaxel exhibited mucositis, which also appeared in with the concurrent use of the medications listed in response to lower, cumulative dosing. An accumulation BOX 131-1. of epidermal cells with paclitaxel-induced asters has

Taxus brevifolia (Pacific Yew)

Arnphotericin B by injection (e.g., Fungizone) Antithyroid agents Azathioprine (e.g., Imuran) Chloramphenicol (e.g., Chloromycetin) Colchicine Flucytosine (e.g., Ancobon) Ganciclovir (e.g., Cytovene) Interferon (e.g., lntron A, Roferon A) Plicarnycin (e.g., Mithracin) Zidovudine (e.g., AZT, Retrovir)

Modified from US Pharrnacopeia. Drug interactions, vol. II. Rodolille. MD: United States Pharmacopeial Convention, 1997:1237-1238.

1.Bolsinger C, Jaramillo AE. Taxus brevifolia Nutt. Pacific Yew, 1990. In Bums RM, Honkala BH. Silvics of forest trees of North America (rev.). Portland, OR Pacific Northwest Research Station, USDA Forest Service, 199017. 2.Hartzell H Jr. The yew tree: a thousand whispers. Eugene, OR Hulogosi, 1991:31,80,154-156,176,230, 3. Rowinsky EK, Donehower RC. Taxol: twenty years later, the story unfolds. J Natl Cancer Inst 1991;83:1778-1781. 4. Denis JN, Greene AE, Guenard D, et al. Highly efficient, practical approach to natural taxol. J Am Chem Soc 1988;110:5917-5919. 5. Blume E. Investigators seek to increase taxol supply. J Natl Cancer Inst 1989;81:1122-1123. 6. Stierle A, Strobel G , Stierle D. Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew. Science 1993;260214-216. 7.Geney R, Ungureanu M, Li D, q i m a I. Overcoming multidrug resistance in taxane chemotherapy. Clin Chem Lab Med 2002;40: 918-925. 8. Hezari M, Croteau R. Taxol biosynthesis: an update. Planta Med 1997;63:291-295. 9. Duke J. Handbook of northeastern Indian medicinal plants. Lincoln, MA: Quarterman, 1986:156. 10.Cunningham S. Encyclopedia of magical herbs. St. Paul, M O Llewellyn Publications, 1985:228. 11. Wehland J, Henkart M, Klausner R, Sandoval n! Role of microtubules in the distribution of the Golgi apparatus: effect of taxol and microinjected anti-alpha-tubulin antibodies. Proc Natl Acad Sci U S A 1983;80:4286-4290. 12. Rowinsky EK, Donehower RC, Jones RJ, Tucker RW. Microtubule changes and cytotoxicity in leukemic cell lines created with taxol. Cancer Res 1988;48:4093-4100. 13. De Brabander M, Geuens G, Nuydens R, et al. Taxol induces the assembly of free microtubules in living cells and blocks the organizing capacity of the centrosome and kinetochores. Proc Natl Acad Sci U S A 1981;78:560&5612. 14. Brasch RC, Rockoff SD, Kuhn C, Chraplyvy M. Contrast media as histamine liberators. II. Histamine release into venous plasma during intravenous urography in man. Invest Radio1 1970;5:510-513. 15. Shedadi WH. Adverse reactions to intravenous administration of contrast media: a comparative study based on a prospective study. Am J Roentgen01 1975;124:145-151.

Chickenpox Herpes zoster Cardiac arrhythmias Infection

Medical problems that may affect the use of paclitaxel are listed in Box 131-2. Studies in rats and rabbits have shown that paclitaxel causes miscarriages and fetal deaths. Breastfeeding is contraindicated during paclitaxel thera~y.4~

16. Lanni JS, Lowe SW, Licitra EJ, et al. p53-independent apoptosis induced by paclitaxel through an indirect mechanism. Proc Natl Acad Sci U S A 1997;949679:683. 17. Kimura Y, Furuhata T, Shiratsuchi T, et al. GML sensitizes cancer cells to taxol by induction of apoptosis. Oncogene 1997;15: 1369-1374. 18. Ho SY, Barbarese E, DArrigo JS, et al. Evaluation of lipid-coated microbubbles as a delivery vehicle for Taxol in brain tumor therapy. Neurosurgery 1997;40:1260-1266. 19. Distefano M, Scambia G, Ferlini C, et al. Anti-proliferative activity of a new class of taxanes (14-beta-hydroxy-10-deacetylbaccatinI11 derivatives) on multidrug-resistance-positivehuman cancer cells. Int J Cancer 1997;72:844-850. 20. Koeller J, Brown T, Havlin K, et al. A phase I/pharmacokinetic study of taxol given by prolonged infusion without premedication. Proc ASCO 1989;8:82. 21. Donehower RC, Rowinsky EK, Grochow LB, et al. Phase I trial of taxol in patients with advanced cancer. Cancer Treat Rep 1987; 71:1171-1177. 22. Wiemik PH, Schwartz EL, Strauman JJ, et al. Phase I clinical and pharmacokinetic study of taxol. Cancer Res 1987;472486-2493. 23. Wiemik PH, Schwartz EL, Einzig A, et al. Phase I trial of taxol given as a 24-hour infusion every 21 days: responses observed in metastatic melanoma. J Clin Oncol 1987;51232-1239. 24. Legha SS, Tenney DM, Krakoff IR. Phase I study of taxol using a 5-day intermittent schedule. J Clin Oncol 1986;4:762-766. 25. Grem JL, Tutsch KD, Simon KJ, et al. Phase I study of taxol administered as a short i.v. infusion daily for 5 days. Cancer Treat Rep 1987;71:1179-1184. 26. Ohnuma T, Zimet AS, Coffey VA, et al. Phase I study of taxol in a 24-hour infusion schedule. Proc Am Assoc Cancer Res 1985;26662. 27. Kris MG, OConnell JP,Gralla RJ, et al. Phase I trial of taxol given as a 3-hour infusion every 21 days. Cancer Treat Rep 1986;70:605-607. 28. Belani C. TAX 326 Study Group. Phase III randomized trial of docetaxel in combination with cisplatin or carboplatin or vinorelbine plus cisplatin in advanced non-small cell lung cancer: interim analysis. Semin Oncol 2001;28(3suppl9):lO-14. 29.Thigpen JT, Blessing JA, Ball H, et al. Phase I1 trial of taxol as second-line therapy for ovarian carcinoma: a gynecologic oncology group study. Proc Am SOCClin Oncol1990;9:604. 30. Dustin P. Microtubules. Sci Am 1980;243:66-76.

Pharmacology of Natural Medicines 31. Appendino G. Taxol (paclitaxel): Historical and ecological aspects. Fitoterapia 1993;64:5-25. 32. Jacmt M, Riondel J, Picot F, et al. [Action of taxol on human tumors transplanted in athymic mice.] C R Seances Acad Sci In 1983;297597-600. 33. Riondel J, Jacrot M, Nissou MF, et al. Antineoplastic activity of two taxol derivatives on an ovarian tumor xenografted into nude mice. Anticancer Res 1988;8:387-390. 34. Stemberg CN, Sordillo PP, Cheng E, et al. Evaluation of new anticancer agents against human pancreatic carcinomas in nude mice. Am J Clin On~011987;10219-221. 35. Dorr RT. Pharmacology of the taxanes. Pharmacotherapy 1997;1796S104S. 36. Faivre S, Goldwasser F, Soulie P, Misset JL. Paclitaxel (Taxo1)associated junctional tachycardia. Anticancer Drugs 1997;8:714-716. 37. Von Hoff DD. The taxoids: same roots, different drugs. Semin Oncol 1997;24S3-510. 38. Hruban RH, Yardley JH, Donehower RC, Boitnott JK. Taxol toxicity. Epithelial necrosis in the gastrointestinal tract associated with polymerized microtubule accumulation and mitotic arrest. Cancer 1989;6331944-1950. 39. Masurovsky EB, Peterson ER, Crain SM, Horwitz SB. Microtubule arrays in taxol-treated mouse dorsal root ganglion-spinal cord cultures. Brain Res 1981;217392-398. 40.Masurovsky EB, Peterson ER, Crain SM, et al. Morphological alterations in satellite and Schwann after exposure of fetal mouse dorsal root ganglia-spinal cord culture to taxol. IRCS Med Sci Libr Compend 1981;9:968-969.

41.Masurovsky EB, Peterson ER, Crain SM, Horwitz SB. Morphological alterations in dorsal root ganglion neurons and supporting cells of organotypic mouse spinal cord-ganglion cultures exposed to taxol. Neuroscience 1983;10491-509. 42. Letoumeau PC, Ressler AH. Inhibition of neurite initiation and growth by taxol. J Cell Biol1984;98:13551362. 43. Letoumeau PC, Shattuck TA, Ressler AH. Branching of sensory and sympathetic neuritis in vitro is inhibited by treatment with taxol. J Neurosci 1986;6:1912-1917. 44.Roytta M, Horwitz SB, Raine CS. Taxol-induced neuropathy: shortterm effects of local injection. J Neuroqtol1984;13685-701. 45. McGuire WP, Rowinsky EK, Rosenshein NB,et al. Taxol: a unique antineoplastic agent with signhcant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 1989;111:273-279. 46.Rowinsky EK, Burke PJ, Karp JE, et al. Phase I and pharmacodynamic study of taxol in refractory acute leukemias. Cancer Res 1989;49:4640-4647. 47. Burgoyne RD, Cumming R. Taxol stabilizes synaptosomal microtubules without inhibiting acetylcholine release. Brain Res 1983; 280190-193. 48. Laussus M, Scott D, Leyland-Jones 8. Allergic reactions (ar) associated cremophor (c) containing antineoplastic (anp). Proc Am Soc Clin Oncol 1985;4:1042. 49. US Pharmacopeia. Drug interactions, vol II. Rockville, MD: United States Pharmacopeial Convention, 19971237-1238.

Urtica dioica (Stinging Nettle) Eric L. Yarnell, ND, RH(AHG) Kathy Abascal, BS, JD, RH(AHG) CHAPTER CONTENTS General Description 1345 Chemical Composition History and Folk Use Pharmacology

1345 1345

1346

Clinical Applications

1347

Urticu dioicu ssp. dioicu (family: Urticaceae) Synonym: Urticu dioicu Common names: stinging nettle, nettle, great nettle

Benign Prostatic Hyperplasia Arthritis 1348 Allergic Rhinitis 1348 Dosage

1348

Toxicity

1348

1347

Drug Interactions 1349

Additionally, this species is monoecious, male and female flowers appearing on the same plant.

CHEMICAL COMPOSITION GENERAL DESCRIPTION Urticu dioicu is a prolific Eurasian perennial that has become naturalized around the globe. Two major subspecies are recognized as important in medicine in the West: dioicu, the standard stinging nettle, and grucilis, the California nettle. Urticu urens, the dwarf or dog nettle, is also used interchangeably. The leaves, fruit (often inappropriately called seeds), and root are all used, each somewhat differently. U.dioicu reaches up to 2 m in height with large cordate leaves. The dark green opposite or whorled leaves have serrated margins and are covered with tiny, visible stinging hairs, as are the stems. The leaves are lighter green on the underside. Stinging nettle produces dangling clusters of tiny, dull white-green flowers that extend from leaf nodes throughout the summer. Male flowers appear yellow when pollen is present. The flowers are dioecious, having male and female parts on separate plants-hence the species name. The fruit is a l-mm-wide, single-seeded nutlet with a yellow-brown color when ripe. The roots grow in extensive networks; coupled with its easily spread seed, this feature leads to formation of large patches and spread to disturbed areas of soil. U. urens appears similar to U . dioicu, though it never grows taller than 30 to 40 cm and is less hairy.

Nettle leaves are known to contain the glycosides of flavonoids (including quercetin and kaempferol), phenylpropanoids (including caffeic malic acid), sterols, carotenoids, vitamins, and minerals.' The stinging hairs contain formic acid, histamine, serotonin, and choline among other irritants. Very little is known about the chemistry of the fruits, except that they contain protein, carbohydrate, and 30% fixed oil.' The chemistry of the roots of stinging nettle has been the most thoroughly examined. Acidic polysaccharides, lectins, sterols including beta-sitosterol, triterpenoids, the coumarin-like compound scopoletin, phenylpropanoids, ceramides, and lignans are all potentially related to the physiologic effects of the roots (Figures 132-1 and 132-2).2 Lignans of potential importance include neoolivil and secoisolariciresinol,which are metabolized by human gut flora to enterodiol and enterolactone, well-characterized phytoestrogenic compound^.^

HISTORY AND FOLK USE Urticu species have long been employed as medicine in Europe and Asia. The steamed or dried leaves were eaten as a vegetable or seasoning, and often still are.4 Nettle fiber was formerly processed into thread used to make clothing, rope, and sailcloth, though it was 1345

Pharmacology of Natural Medicines

Figure 132-1 Scoploetin.

HO

u Flgure 132-2 Sitosterol

ultimately replaced by flax. The source of the fiber known as "ramie" comes from the plant Boehrneriu niveu, which is also in the Urticaceae family. The word nettle appears to be derived from the old Anglo-Saxon noedl, "needle," and even before that to the common IndoEuropean verb ne, "to spin/sew." There is little record of use of the roots in traditional cultures, except as a source of yellow dye! Medicinally, stinging nettle leaves were once considered a spring tonic, taken each year in particular by patients with chronic skin or rheumatic conditions? The leaves' diuretic (also ascribed to the fruits), tonifying, lactagogue, antiasthmatic, antihemorrhagic, and "bloodbuilding" properties are consistently referenced by European herbalist^.^ Up to modem times, there are descriptions of applications of fresh leaves to aching joints, intentionally causing stings to relieve symptoms. Stinging nettle leaves are also frequently said to promote hair growth.

PHARMACOLOGY The two principal effects of stinging nettles leaves are inhibition of inflammation and promotion of diuresis. Most research has involved a proprietary 50% ethanol 1O:l extract of the leaves known as IDS 23 (Strathmann AG & Co, Hamburg, Germany). In vitro, IDS 23 extract and caffeic malic acid inhibit 5-lipoxygenase and cyclooxygenase (isotype not determined); the whole extracts are more potent than caffeic malic acid alone.6 IDS 23 also inhibits tumor necrosis factor-alpha and interleukin-1-beta secretion induced by lipopolysaccharide in human blood; phenylpropanoids and flavonoids isolated from the leaves were not effective in this ~ y s t e mPerhaps .~ even more important, IDS 23 has been

shown to inhibit activation of nuclear factor kappaB (NFkappaB)by preventing degradation of its inhibitory subunit, IkappaB, in vitro. The immunologic effects of leaf extracts may extend beyond inhibition of arachidonic acid-metabolizing enzymes and NFkappaB to isotype switching of helper T cells. In vitro, IDS 23 stimulated production of IL-4 by monocytes and inhibited production of IL-2 and interferon-gamma (IFN-gamma)? IL-4 production promotes formation of type 2 helper T cells, which are associated with much less inflammation than type 1 helper T cells. Preliminary in vitro research also shows that nettle leaves are strong antioxidants.'O The multiple antiinflammatory, immunomodulating, and antioxidant effects of stinging nettle leaves help explain how they could be helpful for so many inflammatory diseases. Stinging nettle leaves increase the volume and quality of urine in animal and human studies. A continuous intravenous infusion of an aqueous stinging nettle leaf extract increased natriuresis and urine volume in rats, leading to a reduction in blood pressure." In a small uncontrolled trial of patients with congestive heart failure, stinging nettle leaf juice showed a diuretic effect.I2 Though much more work is needed, existing data support the traditional belief that stinging nettle leaves are a mild diuretic. Nettle fruits are also believed to have this action but have not been studied. Stinging nettle roots have a variety of effects in the prostate that counteract hyperplasia. An extract combining stinging nettle root and Prunus ufricunurn (pygeum) bark weakly inhibited 5-alpha-reductase and moderately inhibited aromatase in prostate tissue.13A separate study found that stinging nettle root extract inhibited aromatase in vitro, although much less potently than Sereiiou repens (saw palmetto) extract.14 The two combined showed some additive effects. No effect was noted for another stinging nettle root extract on prostatic alphaladrenergic receptor^.'^ Most research on stinging nettle root extracts suggests that its primary effects are mediated by sex hormonebinding globulin (SHBG). In vitro, ethanolic extracts were shown to decrease the binding of dihydrotestosterone by SHBG.16 Lignans and trihydroxyoctadecenoic acids, but not triterpenoids, were active in this study. A different study found that only an aqueous extract of stinging nettle root blocked binding of SHBG to its receptor on prostate cells in ~ i t r 0 . These l~ results clearly suggest that multiple active compounds in stinging nettle give this medicinal plant a broad spectrum of effects. Stinging nettle root extracts have also been repeatedly shown to interfere with binding of epidermal growth factor (EGF) to its receptor on prostate cells.2Js EGF is a major stimulus of prostatic hyperplasia. Lectins appeared to be the most active compounds isolated in these studies.

Urtica dioica (Stinging Nettle)

CLINICAL APPLICATIONS The major uses of stinging nettle, organized according to the part being used and the route of administration are shown in Table 132-1.19 Published clinical trial data are available on three of these indications, as discussed here.

Benign Prostatic Hyperplasia Extracts of stinging nettle root have been the subject of a number of clinical trials showing it beneficial for symptoms of benign prostatic hyperplasia (BPH).In one doubleblind trial, 50 men with stage I or I1 (mild to moderate) BPH symptoms were randomly assigned to receive either placebo or 300 mg of an extract of stinging nettle root standardized to an unspecified amount of an unspecified steroid glycoside twice daily.2O SHBG levels were significantly lower, and urine volume and maximum flow (but not average flow) significantly higher, in the stinging nettle group than in the placebo group. Residual urine volume rose slightly and nonsignificantly in both groups. No adverse effects were reported. In a one-year trial involving 246 men, 459 mg of a stinging nettle root extract was shown to be sigruficantly more effective than placebo at improving BPH symptoms.21Urine flow and residual volume were minimally affected with no statistical difference between the nettle extract and placebo. Adverse effect rates did not differ between the treatment groups. This is the most rigorous trial conducted to date and strongly supports the efficacy of stinging nettle root extracts for relieving irritative BPH symptoms. An uncontrolled trial using 5 ml of tincture (40% ethanol, 1:5 weight-to-volume ratio) of stinging nettle

Plant Dart

Route of administration

Maior action

Internal

Antiinflarnmatory, diuretic

and dwarf nettle root three times daily found that it could relieve nocturia and reduce residual bladder volume in men with three or fewer micturitions per night in a clinically significantly manner.22The trial ran for 6 months. The extract was less effective in men with more than three nightly voids at baseline. Stinging nettle had no effect on prostate volume. Stinging nettle combined with saw palmetto was as effective as and had significantly fewer adverse effects than finasteride in a double-blind trialF3This trial ran for 1 year and involved 543 men with symptomatic BPH. An uncontrolled postmarketing study that monitored 2080 patients with mildly symptomatic BPH who took the same saw palmetto and stinging nettle The ~ extract documented only 15 mild adverse e ~ e n t s . 2 extract combination was very helpful in relieving symptoms. Stinging nettle has been investigated in combination with pygeum. In a double-blind trial, 134 men with symptomatic BPH were randomly assigned to take either 300 mg stinging nettle extract combined with 25 mg pygeum extract twice daily or half this dose.25After 2 months, urinary flow, residual urine volume, and nocturia were sigruficantly improved in both groups, with no clear difference between the groups. There were no serious adverse effects. In summary, these trials support the notion that stinging nettle root has some benefit in men with symptomatic BPH. More controlled clinical trials of higher quality would help confirm this conclusion. Of particular importance are trials comparing stinging nettle extracts with other phytomedicines for BPH (saw palmetto, pygeum, and beta-sitosterol) and combination extractions. If it

Main indications

Level of clinical SUDDO~~'

Commission E aDDroved+ Yes

~

Folium and fructus

Urinary tract Infection

Absent

Allergic rhinitis

Poor

No

Arthritis

Poor

Yes

Kidney stone prevention

Absent

Yes

Folium

Topical

Antiinflamrnatory, counterirritant

Arthritis

Poor

No

Radix

Internal

Interference with sex hormonebinding globulin and growth factors, aromatase inhibition

Benign prostatic hyperplasia

Good

Yes

'Level of clinical support refers to the number of published clinical trials with positive results. Fbor, 1 or 2 trial(s) and mostly of low quality; Good. more than 2 trials of good or high quality. tBlumenthal M, Busse WR, Goldberg A, et al, eds. the complete German Commission E monographs: therapeutic guide to herbal medicines. Boston: Integrative Medicine Communications, 1998216-217.

Pharmacology of Natural Medicines

stinging nettle could be definitively shown to be just as effective as these other medicines, this highly sustainable, cheap herb could reduce the need for reliance on the other three, less sustainable or more expensive extracts.

Arthritis Stinging nettle leaves have been used internally and topically to treat arthritis. An initial uncontrolled clinical trial found that 1340 mg daily of a nettle leaf extract (6.4:l-8.l:l) reduced the need for nonsteroidal antiinflammatory drugs (NSAIDs) by 50% in patients with osteoarthritis of the knee.26 A subsequent open trial involving patients with acute exacerbations of various forms of arthritis compared the use of a standard 200-mg dose of the NSAID diclofenac with a subtherapeutic 50-mg dose of diclofenac combined with 50-g freeze-dried nettle daily for 2 weeks.27 The two groups had similar levels of improvement (no significant differences between the groups) compared with baseline on various pain rating scales. There were no serious adverse events. Double-blind trials to confirm these results are warranted. Two case studies published in 1994 heralded the first mention of topical stinging nettles as potentially effective pain relievers for patients with arthritis in the modem medical literature.28The practitioner who noted these cases went on to publish a case series, again showing that many patients treating themselves with topical nettle stings were experiencing noticeable pain relief, allowing for reductions in NSAID doses.29 The nature of the therapy made designing a doubleblind trial seem a near impossibility. However, such a trial has been conducted in patients with osteoarthritis of the thumb or index finger.30The placebo chosen was Lumium album (white deadnettle) leaf, a plant that has evolved to mimic stinging nettle in appearance, presumably to deter herbivores from eating it, without actually having stings. Patients were told that two types of nettle were being studied and that harmless stings might occur. Each patient applied the leaf of the plant they

were being treated with once daily, applying the leaf to three different spots for 30 seconds each. After 1 week of treatment, there was a 5-week washout period; then all patients “crossed over” for another week‘s treatment with the other plant. When patients were treated with stinging nettle, their pain and disability scores were significantly better than during deadnettle treatment. Although the use of a nonstinging placebo may have compromised this trial, it does provide support for the folk use of topical application of nettles to reduce arthritis symptoms.

Allergic Rhinitis A single double-blind trial has been reported on the efficacy of stinging nettle leaves for allergic r h i n i t i ~A . ~total ~ of 69 patients with acute onset of allergic rhinitis symptoms took 600 mg freeze-dried stinging nettle or placebo at the onset of symptoms, then recorded their response 1 hour later. The total number of doses and general responses were recorded over the remaining week. Overall assessment of efficacy of stinging nettle was better than that of placebo, though differences in daily symptom logs did not show a strong difference. No statistical analysis was provided. Two patients in the nettle group dropped out owing to intensification of symptoms, but no other signhcant adverse effects were noted.

Stinging nettle leaf and root are available in a number of dose forms, summarized in Table 132-2.31J2Fresh leaves are applied one to two times daily to every few days depending on symptoms, so treatment obviously requires ongoing access to growing plants.

TOXICITY Oral use of stinging nettle leaf, fruit, or root is not associated with any significant adverse effects. Topical application of fresh leaf raises mildly painful, inflamed

Dose form

Leaf

Root

Tea

Infuse 4 g in 150 ml water three times daily3*

Decoct 4-6 g in 150 ml water once daily3z

Freeze-dried capsules

300 mg twice daily, up to 50 g once

Not available

Concentrated extracts

Not available

51-1O:l extract 500 mg three times dailyz6

Tincture

30% ethanol, 1 :2-1:5 weight-to-volume, 3-14 ml three times dailg3

50% ethanol, 1:2-1:5, 4-9 ml three times daily33

Urtica dioica (Stinging Nettie) wheals because of the stinging hairs. AS previously noted, this effect is sometimes exploited therapeutically. The welts usually clear completely within 2 hours with lessening of symptoms after 30 minutes. As with all herbal medicines, it is possible for patients to be allergic to stinging nettle, although this reaction is exceedingly rare.

There are no documented negative interactions between stinging nettle and any other medication. Some open trials (described previously) suggest that stinging nettle leaves potentiate NSAIDs, allowing for dose reductions in these agents.

1.Bisset NG, Wichtl M, eds. Herbal drugs and phytophannaceuticals. Stuttgart: Medpharm Scientific Publishers, 1994. 2. Wagner H, Willer F, Samtleben R, Boos G. Search for the antiprostatic principle of stinging nettle (Urticu dioicu) roots. Phytomedicine 1994;1213-224. 3. Schottner M, Gansser D, Spiteller G. Lignans from the roots of Urtica dioicu and their metabolites bind to human sex hormone binding globulin (SHBG). Planta Med 1997;63529-532. 4. Foster S. Herbal renaissance: growing, using & understanding herbs in the modem world. Salt Lake City, UT: Gibbs-Smith, 1993. 5. Grieve M. A modem herbal, vol2. New York Dover Publications, 1971. 6. Obertreis B, Giller K, Teucher T, et al. [Anti-inflammatory effects of Urtica dioicu folia extract in comparison to caffeic malic acid.] Arzneimittelforschung 1996;46:52-56. 7. Obertreis B, Ruttkowski T, Teucher T, et al. Ex-vivo in-vitro inhibition of lipopolysaccharide stimulated tumor necrosis factor-alpha and interleukin-1 beta secretion in human whole blood by extractum Urticae dioicae foliorum. Arzneimittelforschung 1996;46:389-394. 8. Riehemann K, Behnke B, Schulze-Osthoff K. Plant extracts from stinging nettle (Urticu dioicu), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB. FEBS Lett 1999;442:89-94. 9. Klingelhoefer S, Obemeis B, Quast S, Behnke 8. Antirheumatic effect of IDS 23, a stinging nettle leaf extract, on in vitro expression of T helper cytokines. J Rheumatol1999;262517-2522. 10. Pieroni A, Janiak V, Durr CM, et al. In vitro antioxidant activity of non-cultivated vegetables of ethnic Albanians in southern Italy. Phytother Res 2002;16:467-473. 11. Tahri A, Yamani S, Legssyer A, et al. Acute diuretic, natriuretic and hypotensive effects of a continuous perfusion of aqueous extract of Urticu dioicu in the rat. J Ethnopharmacol2000;73:95-100. 12. Kirchhoff HW.[Nettlejuice as a diuretic.] Z Phytother 1983;4621-626. 13. Hartmann RW, Mark M, Soldati F. Inhibition of 5 alpha-reductase and aromatase by PHL-00801 (Prostatonin), a combination of PY 102 (Pygeum ufricanum) and UR 102 (Urtica dioica) extracts. Phytomedicine 1996;3:121-128. 14. Koch E, Biber A. Pharmacological effects of Subal and Urtica extracts as basis for a rational medication of benign prostatic hyperplasia. Urologe 1994;334:90-95. 15. Goepel M, Hecker U, Krege S, et al. Saw palmetto extracts potently and noncompetitively inhibit human alpha-1-adrenoceptorsin vitro. Prostate 1999;38:208-215. 16. Gansser D, Spiteller G. Plant constituents interfering with human sex hormone-bindmg globulin. Evaluation of a test method and its application to Urticu dioicu root extracts. Z Naturforsch 1995;50: 98-104. 17. Hryb DJ, Khan MS, Romas NA, Rosner W. The effect of extracts of the roots of the stinging nettle (Urtica dioicu) on the interaction of SHBG with its receptor on human prostatic membranes. Planta Med 1995;61:31-32.

18. Wagner H, Geiger WN, Boos G, Samtleben R. Studies on the binding of Urtica dioicu agglutinin (UDA) and other lectins in an in vitro epidermal growth factor receptor test. Phytomedicine 1995;Z: 287-290. 19. Blumenthal M, Busse WR, Goldberg A, et al, eds. The complete German Commission E monographs: therapeutic guide to herbal medicines. Boston: Integrative Medicine Communications, 1998: 216-217. 20.Vontobel HP, Herzog R, Rutishauser G, Kres H. [Results of a double-blind study on the effectiveness of ERU (extractum radicis urticae) capsules in conservative treatment of benign prostatic hyperplasia.] Urologe A 1985;24:49-51. 21. Schneider T, Rubben H. Stinging nettle root extract (Bazoton-uno) in long term treatment of benign prostatic syndrome (BPS). Results of a randomized, double-blind, placebo controlled multicenter study after 12 months. Urologe A 2004;43302-306. 22. Belaiche P, Lievoux 0. Clinical studies on the palliative treatment of prostatic adenoma with extract of Urtica root. Phytother Res 1991;5:267-269. 23.Sokeland J, Albrecht J. [Combination of Subd and Urticu extract vs. finasteride in benign prostatic hyperplasia (Aiken stages I to 11). Comparison of therapeutic effectiveness in a one year double-blind study.] Urologe A 1997;36:327-333. 24. Schneider HJ, Honold E, Masuhr T. [Treatment of benign prostatic hyperplasia. Results of a treatment study with the phytogenic combination of Subul extract WS 1473 and Urtica extract WS 1031 in urologic specialty practices.] Fortschr Med 1995;113:37-40. 25.Krzeski T, Kazon M, Borkowski A, et al. Combined extracts of Urticu dioicu and Pygeum ufricanum in the treatment of benign prostatic hyperplasia: double-blind comparison of two doses. Clin Ther 1993;15:1011-1020. 26. Ramm S, Hansen C. [Nettle leaf extract for arthrosis and rheumatoid arthritis.] Therapiewoche 1996;28:3-6. 27. Chrubasik S, Enderlein W, Bauer R, Grabner W. Evidence for antirheumatic effectivenessof herba Urticae dioicae in acute arthritis: a pilot study. Phytomedicine 1997;4105-108. 28. Randall CF. Stinging nettles for osteoarthritis pain of the hip. Br J Gen Pract 1994;44:533-534. 29. Randall C, Meethan K, Randall H, Dobbs F. Nettle sting of Urtica dioicu for joint pain-an exploratory study of this complementary therapy. Complement Ther Med 1999;7126-131. 30. Randall C, Randall H, Dobbs F, et al. Randomized controlled trial of nettle sting for treatment of base-of-thumb pain. J R Soc Med 2000;93:305-309. 31. Mittman P. Randomized, double-blind study of freeze-dried Urticu dioica in the treatment of allergic rhinitis. Planta Med 1990; 5644-47. 32. Tyler V. Herbs of choice: the therapeutic use of phytomedicinals. New York Pharmaceutical Products Press, 1994. 33. Mills S, Bone K. Principles and practice of phytotherapy: modem herbal medicine. Edinburgh: Churchill Livingstone, 2OOO.

DRUG INTERACTIONS

Uva ursi (Bearberry) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 1351 Chemical Composition

Clinical Applications 1352 Urinary Tract Infections 1352

1351 Dosages

History and Folk Use

1352

1351 Toxicology

Pharmacology 1351 Antimicrobial Effects 1351 Antiinflammatory Effects 1351 Inhibition of Melanin Synthesis 1352

1352

Drug Interactions 1352

Arctosfaphylos uva ursi (family: Ericaceae) Common names: bearberry, upland cranberry

PHARMACOLOGY Antimicrobial Effects

GENERAL DESCRIPTION

Although pharmacologic research has focused primarily on arbutin, the pharmacology of the whole plant is different from that of arbutin alone. The crude plant extracts are much more effective medicinally than the isolated constituent a r b ~ t i n This . ~ fact appears to be related to the activity of gallic acid, which prevents the splitting of arbutin by such enzymes as beta-glucosidase contained in gut bacteria.* Arbutin undergoes hydrolysis in the stomach or intestinal tract to produce its aglycone, hydroquinone, which has urinary antiseptic properties.6 The hydrolysis of arbutin is responsible for much of the therapeutic effect of U'DU ursi.'e6 By preventing the splitting of arbutin, the flavonoid components allow more arbutin to be hydrolyzed and absorbed than when arbutin is administered as an isolated component. Arbutin alone has been reported to be an effective urinary antibiotic, but only if taken in large doses and if the urine is alkaline (once again documenting the value of whole-plant medicines).' It is reported to be active against Candida albicans and Staphylococcus aureus, and especially active against Escherichia ~ o l i . Uva ~ , ~ ursi also has diuretic properties.'

Arctostaphylos uva ursi is a small evergreen shrub found in the northern United States and in Europe. A single long, fibrous main root sends out several prostate or buried stems 4 to 6 inches high. The bark is dark brown, the leaves are obovate to spatulate and 0.5 to 1 inch long, the flowers are pink or white and grow in sparse terminal clusters, and the fruit is a bright red or pink.

CHEMICAL COMPOSITION The most active ingredient of uva ursi is arbutin, which typically composes 7% to 9% of the leaves. Other constituents are as follows'4: Tannins (6%to 7%) Flavonoids (quercetin) Allantoin Gallic and ellagic acids Volatile oils A resin (urvone)

HISTORY AND FOLK USE

Antiinflammatory Effects

This plant has a long history of use for its diuretic and astringent properties. Conditions for which uva ursi was used include chronic cystitis, nephritis, kidney stones, and bronchitis.'

Some early animal research is now showing that arbutin, and possibly other constituents of uvu ursi, potentiate the activity of commonly prescribed antiinflammatory drugs. One study found that an aqueous extract 1351

Pharmacology of Natural Medicines increased the inhibitory activity of dexamethasone in allergic and inflammatory models without increasing any of the side effects.aSimilar results have been demonstrated with isolated arbutin when combined with indomethacin?

Inhibition of Melanin Synthesis Uva ursi extract has been shown to inhibit the enzyme tyrosinase.1° This effect impairs melanin synthesis, which indicates that uvu ursi extracts may be effective as a whitening agent for the skin. In fact, hydroquinone is approved by the U.S.Food and Drug Administration as an agent in over-the-counter skin products for bleaching age spots and hyperpigmentation.

CLINICAL APPLICATIONS Crude extracts are widely used in Europe as components in certain diuretic and laxative products, but the major use of uvu ursi is as a urinary disinfectant in cases of urinary tract infection.'

Urinary Tract Infections Uva ursi is reported to be especially active against E. cok6 As well as exerting direct antibiotic effects, uvu ursi extract promotes the aggregation of E. coIi in vitro.' These combined effects indicate that uvu ursi can be used both in the immediate treatment and in the prevention of recurrent cystitis. In one double-blind study, the prophylactic effects of a standardized uvu ursi extract and a placebo on recurrent cystitis were evaluated in 57 women." At the end of 1 year, 5 of 27 women in the placebo group had a recurrence, whereas none of the 30 women receiving uvu ursi extract had a recurrence. No side effects were reported in either group. These impressive results indicate that regular use of uvu ursi is a safe and effective measure to prevent recurrent cystitis. In a study of normal subjects, consuming uvu ursi tea was shown to be more bacteriostatic than normal urine? The effectiveness in inhibiting bacterial growth (S. uureus and E. coli) depended on adequate excretion products of arbutin (hydroquinone paired with glucuronate or sulfur) and a pH above 8. Alkalinization of the urine with bicarbonate or citrate salts in conjunction with uvu ursi may enhance the therapeutic effects in acute urinary tract infections.

DOSAGES The dosages for uvu ursi are as follows: Dried leaves or as an infusion: 1.5 to 4.0 g (1 to 2 tsp) three times daily

Freeze-dried leaves: 500 to 1000 mg three times daily Tincture (1:5):4 to 6 ml(1 to 1.5 tsp) three times daily Fluid extract (1:l):2 to 4 ml (1/2 to 1 tsp) three times daily Powdered solid extract (10% arbutin): 250 to 500 mg three times daily

TOXICOLOGY The toxicology of uvu ursi is proportional to the conversion of arbutin to hydroquinone. Exactly how much arbutin is converted to hydroquinone has not been sufficiently determined, but pharmacokinetic data in humans indicate that uvu ursi intake definitely increases the urinary excretion of hydroquinone metabolites.'* Hydroquinone is metabolized in the liver by phase I1 enzymes into hydroquinone glucuronate or sulfate and then excreted in the urine. In various laboratory animals, the oral LDW(dose at which 50% of the subjects are killed) of hydroquinone in 2% aqueous solution is between 320 and 550 mg/kg body weight. Signs and symptoms of toxicity to uvu ursi include the following:

Tinnitus Nausea Vomiting Sense of suffocation Shortness of breath Cyanosis Convulsions Delirium Collapse

DRUG INTERACTIONS An extract of uvu ursi has been found to markedly potentiate the effects of beta-lactam antibiotics, such as oxacillin and cefmetazole, against methicillin-resistant S. u ~ r e u s The . ~ ~ effective compound was identified as corilagin. Corilagin reduced the mean inhibitory concentrations (MICs) of various beta-lactams 100- to 2000-fold, but not the MICs of other antimicrobial agents tested. The effect of corilagin and oxacillin was synergistic. Corilagin showed a bactericidal action when added to the growth medium in combination with oxacillin.

Uva ursi (Bearberry)

1.Leung AY, Foster S. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York John Wiley, 1996: 505-506. 2. Budvari S, ed. Merck index: an encyclopedia of chemicals, drugs, and biologicals, ed 12. Rahway, NJ:Merck, 1996:131. 3. Parejo I, Viladomat F, Bastida J, et al. Single extraction step in the

quantitative analysis of arbutin in bearberry (Arctostaphylos uvn-ursi) leaves by high-performance liquid chromatography. Phytochem Anal 2001;12:336-339. 4. Veit M, Van Rensen I, Kirch J, et al. HPLC analysis of phenolics and flavonoids in Arctostuphylos uvne-ursi. Planta Med 1992;58: A687-A688.

5. Jahodar L, Jilek P, Pdktova M, et al. [Antimicrobial effect of arbutin and an extract of the leaves of Arctostnphylos uvu-ursi in vitro.] Cesk Farm 1985;34:174-178. 6. Frohne D. [The urinary disinfectant effect of extract from leaves of uva ursi.] Planta Medica 1970;18:1-25 7. Turi E, Turi M, Annuk H, et al. Action of aqueous extracts of bearberry and cowberry leaves and wild camomile and pineapple-weed flowers on Escherichia coli surface structures. Pharmaceut Biol 1999;37127-133.

8. Matsuda H, Nakamura S, Tanaka T, et al. [Pharmacologicalstudies on leaf of Arctostuphylos uvn-ursi (L.) Spreng. V. Effect of water extract from Arctostnphylos uvn-ursi (L.) Spreng. (bearberry leaf) on the antiallergic and antiinflammatory activities of dexamethasone ointment.] Yakugaku Zasshi 1992;112:673-677. 9. Matsuda H, Tanaka T, Kubo M. [Pharmacological studies on leaf of Arctostnphylos uvu-ursi (L.) Spreng. 111. Combined effect of arbutin and indomethacin on immuno-inflammation.] Yakugaku Zasshi 1991;111:253-258. 10. Matsuda H, Higashino M, Nakai Y, et al. Studies of cutical drugs from natural sources. IV. Inhibitory effects of Arctostnyhylos plants on melanin biosynthesis. Biol Pharm Bull 1996;19:153-156. 11. Larsson B, Jonasson A, Fianu 5. Prophylactic effect of UVA-E in women with recurrent cystitis: a preliminary report. Curr Ther Res 1993;53:441-443. 12. Paper DH, Kwhler J, Franz G. Bioavailability of drug preparations containing a leaf extract of Arctostnphylos uvn-ursi (Uvae ursi folium). Planta Med 1993;59:A589. 13. Shimizu M, Shiota S, Mizushima T, et al. Marked potentiation of activity of beta-lactams against methicillin-resistant Stnyhylococcus nurt-us by corilagin. AntimicrobAgents Chemother 2001;45:3198-3201.

..

Vaccuuummacrocapon (Cranberry) Rhonda Dorren, BSc Pharm Sherry Torkos, RPh Michael T. Murray, ND CHAPTER CONTENTS General Description 1355

Dosage 1361

Chemical Composition 1355

Adverse Effects 1362

History and Folk Use

Drug Interactions 1362

1356

Pharmacology 1356 Clinical Applications 1356 Urinary Tract Applications 1356 Other Clinical Applications 1359

GENERAL DESCRIPTION The shiny, scarlet cranberry, like its cousin the blueberry, belongs to the genus Vuccinium and is found growing in the wild in northern Europe, northern Asia, and North America. Cultivated cranberries are grown in huge sandy bogs on low, trailing vines. Cranberries have also been called ”bounce berries,” because ripe berries bounce, and “crane berries,” a reference to the cranberry shrub’s pale pink blossoms, which resemble the heads of the cranes that frequent cranberry bogs. Cranberry is gaining a lot of attention as a possible alternative to antibiotics in the prevention and treatment of urinary tract infections (UTIs). The emergence of multiple antibiotic-resistant organisms in the general community is a potentially serious threat to public health.’ Although encouraging a revision of the utilization of antibiotics, this surfacing of resistance has also prompted the development of additional antibiotics. A paradigm shift in the treatment of infectious disease, particularly chronic infections, may be required to prevent antibiotics from becoming obsolete; where appropriate, alternatives to antibiotics require consideration? As a result, there has been an increase in the use of natural products as well as the consumption of cranberries (processed and fresh) in North America. The majority of research on cranberry involves urinary tract health. However, the historical bibliography of investigations on cranberry also includes, but is not limited to, type 2 diabetes, prevention of blocked urinary

catheters, deodorizing of offensive urine, healing skin around urostomy stomas, and as an anticarcinogen, antifungal agent, and an anti~xidant.~-~

CHEMICAL COMPOSITION In addition to ascorbic acid, cranberry juice contains a variety of substances that may be biologically active. Cranberries contain flavonoids and other phenolic compounds.1° The quantity of flavonoids in cranberry juice ( ~ 3 1 . 9mg per serving) is higher than in red wine (~22.0mg), but lower than in chocolate ( ~ 1 6 5mg) and apples (~147 mg). In a sample of freshly squeezed cranberry juice, one study found 400 mg of total flavonoids and phenolic compounds per liter of sample, was which was distributed as about 44% of phenolic acids and 56% of flavonoids. Benzoic acid was the major phenolic compound and the major flavonols were quercetin and myricetin. Cranberries also contain organic acids, including quinic, malic, and citric acid.” Cranberries contain proanthocyanidins (also referred to as condensed tannins), which are linked anthocyanidins. Anthocyanidins are an aglycone form (without any attached sugars) of anthocyanins, which are among the types of flavonoids found in cranberry. Anthocyanins in the form of cyanidin are found in cranberry; they are glycosides (sugar groups attached).I2J3These different forms of polyphenols are often made mention of in the scientific literature on cranberry. 1355

Pharmacology of Natural Medicines

HISTORY AND FOLK USE Native Americans used cranberry both as food and for the treatment of bladder and kidney diseases. Over time, as trade with Europe grew, the Pilgrims learned about cranberry from local tribes for a condition referred to as ”bladder gravel” (small bladder stones) and to remove blood toxins. Cranberries were served to ships’ crews as a source of vitamin C to prevent SCUNY. Other documented medical applications in the seventeenth century include the relief of stomach ailments, liver problems, blood disorders, and cancer. The boiled berry and seal oil were used to reduce the severity of gallbladder attacks.14 Cranberry’s beneficial effects on urinary tract health were researched during the 1700s and 1800s. It was proposed that the mechanism of action for its positive outcomes was its ability to acidify the urine. Direct antibacterial and antifungal effects of cranberry juice have been shown, although the potential mechanism(s) for its effects remain unpro~en.’~-’’ Hippuric acid, converted from the quinic and benzoic acids is cranberry, is a strong bacteriostatic agent, and its potential to acidify urine has been i n ~ e s t i g a t e d . ~ JIn & ~brief, ~ these early studies focused on the ability of cranberry juice to lower urinary pH, theorizing its ability to suppress infections and enhance antibiotic activity.2’-24The concentration of hippuric acid is unlikely to reach levels adequate for antibacterial action. Further research failed to validate the proposed theory that the mechanism of action was a reduction in urinary pH, and for decades, cranberry continued to be popular while its true mechanism remained a mystery. Current evidence is strongest for its effectiveness in promoting urinary tract health with the optimistic anticipation of sparing the patient the experience of unwanted side effects and continuing use of prescription

PHARMACOLOGY The primary application of cranberry is in the treatment of UTIs. Cranberry components interfere with bacterial adherence to mucosal cells-an important step in the development of infection. In fact, bacterial adherence to the uroepithelium is now recognized as a critical step in the initiation and pathogenesis of UTIs. For bacteria to successfully attach to the host, they must identify and attach to epithelial cells receptor sites. Bacterial virulence depends on their ability to recognize and attach to these receptors. Proteinaceous fibers on the bacterial cell wall, called firnbriae, produce adhesion molecules that attach to these monosaccharide or oligosaccharide receptors on uroepithelial cells. Two different fimbriae have been defined and studied: type 1 fimbriae, which adhere to mannose specific receptors, and P fimbriae, which adhere

to the disaccharide alpha-~-Gal(l,4)-beta-~-Gal (Gal-Gal) receptors. Although early research on cranberry for urinary health had focused on its acidification properties, later investigations revealed that the proanthocyanidins (condensed tannins) in cranberries can inhibit the uropathogenic P-fimbriated strains of Escherichiu coli.26-28 Cranberry cocktail contains two different inhibitors: fructose, effective for inhibiting the type 1 fimbriae, and a second, unidentified inhibitor that is effective for obstructing the Gal-Gal-specific fh1briae.2~In addition, scientific evidence suggests that cranberry acts on the cell wall not only by preventing attachment of the fimbrial subunits but also by serving as a genetic control, preventing the expression of normal fimbrial subunits, or both.30-33 In animal models, investigations of approximately 77 clinical isolates of E. coli demonstrated that cranberry juice inhibited bacterial adhesion to the bladder by more than 75% for more than 60% of the strains of bacteria.34 Further research demonstrated that cranberry signrficantly reduced the adherence of pathogens to urinary epithelial cells isolated from patients with UTIs, including Proteus mirnbilis, Staphylococcus aureus, Klebsiellu pneumoniae, Eiiterobacter spp. and Pseudomonas ~ e r u g i n o s a . ~ ~ ~ ~ ~ ~ The cumulative effects of cranberry have now been demonstrated as successfully acting on cell walls preventing proper attachment of the fimbrial subunits, inhibiting bacterial adherence to uroepithelial cells, and cellular e l ~ n g a t i o nCellular .~~ elongation is an effect that is observed in bacteria treated with ampicillin. It has been postulated that cranberries may share an antibacterial effect similar to that of antibiotics.%The question whether urinary concentrations of the active constituents reach bactericidal levels is currently a topic of research.39 Regarding recurrent UTIs (RUTIs) and cranberry, emerging concepts regarding treatment considerations for the management of RUTIs suggest taking cranberry supplements as part of the protocol.4° Numerous investigations have been completed on cranberry.The following discussion provides an overview of some of the preliminary and current data, including a review on cranberry and urinary tract health.

CLINICAL APPLICATIONS Urinary Tract Applications Reduction of Bacteriuria and Pyuria after Ingestion of Cranberry Juice One of the most promising studies was conducted by Avorn et al4I in a double-blind randomized clinical trial involving 153 elderly women. Participants consumed 300 ml/day of either a commercially available cranberry beverage or a synthetic placebo drink that was

Vaccinium macrocarpon (Cranberry)

similar-tastingand contained vitamin C but lacked cranberry content?] Upon investigation, 15% of the urine samples of those who had been drinking cranberry juice had bacteriuria with pyuria, compared with 28% of the urine samples from the placebo group. The difference became apparent after 1 month of cranberry use. Most patients with bacteriuria were asymptomatic. Although statistical significance was not achieved, there was a trend toward less antibiotic use for treatment of UTIs in the cranberry group (1.7 versus 3.2 antibiotics per 100 patient-months). The chief criticism of this trial is that the control group had a higher rate of urinary infection before the study, suggesting there may have been sampling bias, and the main outcome, identified as asymptomatic bacteriuria, does not generally need treating.42Even though there was trend toward fewer clinically relevant urinary infections, the study was not designed to demonstrate that effect. This trial, in common with others, had a high dropout rate, which casts doubt on the long-term tolerability of cranberry

Trials Involving Catheterization, Neurogenic Bladders, and Spinal Cord-Injured Patients

Rates of bacteriuria and symptomatic UTIs in individuals who receive clean intermittent catheterization are an enduring concern. Schlager et a P completed a doubleblind placebo-controlledcrossover trial of children (n = 15) that compared cranberry with placebo for 3 months in a crossover study of children with neurogenic bladders treated with intermittent catheterization.The researchers reported that 75% of 151 cultures indicated bacteriuria at both sample intervals. In this case, there was no difference whether the children were drinking cranberry concentrate or placebo. Later research by Morris and SticklelA9studied volunteers who were inoculated with Proteus rnirabilis for 24 to 48 hours and then examined for the extent of catheter encrustation. Findings in volunteers who drank 500 ml of cranberry juice did not differ significantly from those in volunteers who drank 500 ml of water. It was noted that participants who drank either cranberry juice or water had less encrustation than volunteers who did not supplement their normal fluid intake. First-Time Urinary Tract Infection Reid et a P examined 15 spinal cord-injured patients and Sexual Behavior to ascertain whether cranberry juice altered bacterial biofilm load in the bladder. They found that cranberry Another promising application for cranberry was juice sigruficantly diminished biofilm load, with reducdemonstrated by Foxman et al,45 who randomly Samtion in adhesion of both gram-positive and gram-negative pled 288 control subjects from a student body, studying bacteria to cells, compared with baseline. Water intake first-time UTIs in young unmarried women. Participants did not change bacterial adhesions. from a university health service were recruited, and the Linsenmeyer et a151completed a prospective, doublewomen had engaged in sexual intercourse at least once. blind, placebo-controlled, crossover study of 21 individVaginal intercourse raised the risk of UTI, which was uals with neurogenic bladders secondary to spinal cord further increased with condom use. Compared with the injury who were randomly assigned to receive either general population of students, the study found that 400 mg cranberry tablets or placebo three times a day for intercourse significantly increased the risk of UTIs (43%), as did drinking carbonated soft drinks (23770)~ 4 weeks.51Cranberry tablets did not modify urinary pH but that drinking cranberry juice reduced the risk (52%). or reduce bacterial counts, urinary white blood cell counts, or number of UTIs in individuals with neuroCranberry Juice and Adhesion genic bladders. of Antibiotic-Resistant Uropathogens Further long-term studies evaluating specific types of bladder management and UTIs will help to determine Howell et a P carried out an in vitro study that verified the role of cranberries in individuals who have neurocranberry's ability to prevent the adhesion of certain genic bladders, require catheterization, or have spinal E. coli strains that are resistant to trimethoprimcord injuries. sulfamethoxazole.46The researchers obtained 39 uropathogenic P-fimbriated E. coli isolates, 24 of which were Comparative Trial Subsequent resistant, from women with culture-confirmed UTIs. to Antibiotic Therapy Exposure to cranberry juice prevented adhesion in 31 of The use of cranberry supplements in women with UTIs 39 isolates, including 19 of 24 resistant isolates; antiafter antibiotic treatment may reduce the recurrence of adhesion activity began within 2 hours of exposure and UTIs. In an open-label trial in Finland, Kontiokari et a15* persisted for up to 10 hours. Because the mechanism treated 150 women with UTIs due to E. coli with a stanof action is not bacteriocidal, the use of cranberry may dard antimicrobial regimen; then the participants impede the development of bacterial resistance. A reducwere randomly assigned to receive 50 ml of cranberrytion in the frequency of infections may decrease the reglingonberry juice concentrate daily for 6 months, ularity of antibiotic use, saving first-line antibiotics for 100 ml of Lactobacillus drink 5 days a week for 1 year, or other infecti0ns.4~

Pharmacology of Natural Medicines no intervention. At 6 months, 16%of the women in the cranberry group, 39%in the Lactobacillus group, and 36% in the control group had UTIs. This finding demonstrates that regular drinking of cranberry juice but not Lactobacillus seems to reduce the recurrence of UTI.

and stinging sensation were monitored. Participants completed the questionnaire before and after taking the proprietary cranberry extract capsule, at a dose of 500 mg daily. After 6 months, more than 90% of the subjects experienced improvement.

Ingestion of Cranberry Juice Reduces the Incidence of Urinary Tract Infections in Geriatric Patients

Reviews of Clinical Studies of the Use of Cranberries for Treating Urinary Tract Infection

In Russia, Kirchhoff et a153compared UTI rates in two geriatric units. Patients on one unit drank cranberry juice, and those on the other drank the usual mixed-berry juice for 4 weeks. In all cases of suspected infection, urine samples were cultured; a signhcant growth of bacteria was found in 54% (140/338) of cases, and this information led to antibiotic treatment in 44% of cases. There was no difference in the rates of infections in the two units, suggesting no effect of cranberry juice intake on UTI rate.

A Cochrane Review of clinical trials conducted in 2004 by Jepson et a156on the use of cranberries for preventing or treating UTIs is summarized in Table 134-1. This review is promising, and further well-designed trials providing relevant outcomes are warranted and needed.

Effectiveness as a Prophylactic against Urinary Tract Infection StotherP executed a randomized placebo-controlled trial that demonstrated, from a societal perspective, the comparative effectiveness and cost-effectiveness of concentrated cranberry tablets, cranberry juice, and placebo used as prophylaxis against lower UTI in adult women. Sexually active women ( n = 150)aged 21 to 72 years were randomly assigned for 1 year to one of the following three groups of prophylaxis: Placebo juice + placebo tablets Placebo juice + cranberry tablets Cranberry juice + placebo tablets The tablets were a proprietary extract of cranberry (30:1), given twice daily. The juice was a pure unsweetened cranberry juice (not cranberry cocktail) given in doses of 250 ml three times daily. Outcome measures demonstrated greater than 50% decreases in both symptomatic UTIs per year and annual antibiotic consumption. Both cranberry juice and cranberry tablets, in a statistically significant manner, decreased the number of patients experiencing at least one symptomatic UTI per year (20% and l8%, respectively) compared with placebo (32%).Total annual antibiotic consumption was lower in both treatment groups than in the placebo group. Cost-effectiveness ratios showed that cranberry tablets were twice as cost-effective as organic juice, providing evidence that cranberry tablets are the most cost-effective prevention of UTIs. In a pilot study by 60 women with symptoms of chronic UTI and urethritis were evaluated through a questionnaire format. Symptoms such as frequency of urination, sensation of not emptying, voiding in small amounts, intermittent urination, difficulty in holding, weakness in stream, straining, and burning

Prevention of Urinary Tract Infection Nutritional intervention for the prevention of UTIs using cranberry supplements in elderly subjects may be useful and inexpensive.%Use of cranberry to prevent UTIs, as reviewed by Harkins,28 has been studied in long-term care facility residents and aging adults. There are valid criticisms against some studies, particularly in consideration of the evidence and urinary tract health strategies in the elderly. However, specific issues in the elderly population may make the use of cranberry valuable. For example, the randomized studies of cranberry by Avom et a14' and StotherP showed a trend toward reduced antibiotic use that, if further confirmed in a larger study of the elderly population, would be of immense value in and of it~elf.4~ Antibiotic use is associated with numerous adverse effects, drug interactions, and precautions for use-especially in elderly patients, who may have impaired kidney and liver function. Furthermore, many studies have shown that asymptomatic bacteriuria in elderly persons does not require therapy. However, the clinical dilemma is in mildly symptomatic elderly adults (e.g., those with slightly reduced activities of daily living or oral intake, or low-grade temperature elevations). Such elderly people often receive prescribed treatment in attempt to clear the symptoms. Use of cranberry to manage these conditions may be warranted.28

Reduction in Urinary Odor Urinary odor, common in elderly people, may be reduced after administration of ~ r a n b e r r y . 4 * ~One ~ , ~ ~possible ,~* method for reducing antibiotic use in older adults could be a reduction in malodorous urine, a common trigger for urinalysis and urine culture for institutionalized elderly persons.**

Continuing Research Studies are currently under way to compare cranberry with prescribed antibiotics for patients with diagnosed UTIs. The outcome will assess cranberry not only in preventing UTIs but also as a potential alternative to

Vaccinium macrocarpon (Cranberry) Summary of Cochrane Review of cranberries for treating urinary tract infections (UTls) Study information

Cranberry product

Effect(s) on UTls

Comments

Seven trials met the inclusion criteria

Six trials compared cranberry juice (or cranberry-lingonberry juice) vs. placebojuice or water

Two good-quality randomized controlled trials (RCTs) demonstrated that cranberry products significantly reduced the incidence of UTls at 12 months compared with placebo/control in women

Minor side effects reported in all trials

Four trials were crossover design

Two trials compared cranberries tablets vs. placebo

There was no significant difference between cranberry juice and cranberry capsules in the incidence of UTls

Undetermined whether cranberry juicekapsule is effective for other groups, such as children and elderly men and women

Three trials were parallel group design

One study evaluated both juice and tablets

One trial reported significant results for the outcome of symptomatic UTls

The large number of dropouts and withdrawals suggest that cranberry juice may not be acceptable over long periods

Five trials were not included in the metaanalyses owing to methodologic flaws or lack of available data

Dosages: 7.5 g cranberry concentrate daily (50 ml) 1:30 concentrate given either in 250 ml juice or in capsule form

Two good-quality RCTs demonstrated that cranberry juice may decrease the number of symptomatic UTls over a 12-month period in women

Optimum dosage and method of administration remain inconclusive

Modified from Jepson FIG, Mihaljevic L, Craig J. Cochrane Database Syst Rev 2004;2:CD001321. Boldface type indicates important points of the study.

antibiotic use in the treatment of UTIs. In Canada a pilot study is in progress by KapooP9at McMaster University to determine the effectiveness of a concentrated proprietary cranberry extract (Cran-Max) as a prescribed method of treatment for current UTIs. Preliminary results suggest that Cran-Max may have utility in treating selected patients with uncomplicated UTIs. Another study, being conducted at the Veterans Medical Center in West Roxbury, MA, is evaluating the use of the same proprietary cranberry extract (CranMax) for the prevention of UTIs in spinal cord-injured patients with neurogenic bladders. Such patients are at risk for development of UTIs for a number of reasons, including abnormal bladder pathophysiology and frequent instrumentation. This study came about as a result of the institution's treatment of approximately 100 patients with this proprietary extract of cranberry product, and reports of a significant reduction in the frequency of UTIs. The study involves 150 subjects in a double-blind, placebo-controlled, crossover design for 6 months@ . ' The National Institutes of Health (NIH) and National Center for Complementary and Alternative Medicine (NCAM) have launched an initiative to provide approximately $2.6 million in grants for research into products for cranberry (Vaccinium macrocarpon) and their matching placebos. The investigations will include basic and clinical research on the role of cranberry in the

prevention and treatment of UTI, other infections, and other conditions for which there is credible evidence of efficacy. For clinical trials, preference will be given to those that also test mechanistic hypotheses. This research may lead to definitive Phase 3 trials to determine the efficacy, safety, dosage, and timing, and duration of intervention of cranberry in the prevention and/ or treatment of UTI or other conditions. Products of primary interest are: cranberry juice cocktail, encapsulated powders, and their matching placebos.61

Other Clinical Applications Although much of the focus on the benefits of cranberry has been on UTIs, cranberry could influence other conditions as well. Examples of other areas of cranberry research follow. This representation of scientific literature is not meant to be exhaustive.

Antioxidant Cranberry has antioxidants that can scavenge free radicals. Of the berries, blackberries, blueberries, cranberries, and raspberries have the highest antioxidant capacity.62-61 Pedersen et a16 studied the effects of blueberry and cranberry consumption on the plasma antioxidant capacity of healthy female volunteers.6 Daily ingestion of 500 ml of cranberry juice increased plasma phenolic content and antioxidant capacity. Consumption of a similar amount of blueberry did not have this effect.

Cancer Antiangiogenic approaches to prevent and treat cancer represent a priority area in investigative tumor biology. Vascular endothelial growth factor (VEGF) plays a crucial role for the vascularization of tumors. In vitro research on human dermal microvascular endothelial cells showed that edible berries impair angiogenesis.M Several in vitro studies on cranberry have reported similar promising outcomes. Researchers at the University of Western Ontario discovered that mice receiving cranberry juice and cranberry products had a significantly lower number of breast cancer tumors than the control group, and the development of tumors was delayed in the cranberryfed group. The incidence of the proliferation of tumors to the lungs and lymph nodes was markedly reduced in the cranberry-fed group. A greater effect was demonstrated by the cranberry solids than the juice. Ongoing research is examining whether the activity of the berry solids traces largely to one component or to several potentially acting in As evaluated in vitro, a proanthocyanidin fraction, an extract of concentrated flavonoids and triterpenoid esters of cranberry, exhibited potential anticarcinogenic activity, demonstrating an ability to inhibit tumor cell A synergistic or additive antiproliferative interaction of the anthocyanins, proanthocyanidins, and flavonol glycosides within cranberry extract have also been demonstrated by in vitro research on human tumor cells.7l A combination of six berry extracts (wild blueberry, bilberry, cranberry, elderberry, raspberry seeds, strawberry) were studied for antioxidant efficacy, cytotoxic potential, cellular uptake, and antiangiogenicproperties. The combination of anthocyanin-rich berries was reported to show antiangiogenic, antioxidant, and anticarcinogenic potentials.”

Vascular Disease Atherosclerosis causes cardiovascular disease, which may begin with the uptake of oxidized low-density lipoprotein by endothelial macrophages, the accumulation of foam cells in the intima of the artery, and the formation of fatty streaks. Research indicates that consumption of flavonoids in foods and beverages may reduce the risk of atheroscler~sis.~~ Cranberries contain the flavonoids anthocyanins, flavonols, and proanthocyanidins. In vitro and in vivo experiments with flavonoids demonstrate that they: inhibit low-density lipoprotein (LDL) oxidation, platelet aggregation and adhesion, and enzymes involved in lipid /lipoprotein metabolism (affects the immune response to oxidized LDL and their uptake by endothelial macrophages); may induce endothelium-dependent vasorelaxation; and may increase reverse cholesterol transport, thereby

decreasing total and LDL cholesterol values. Wilson et a174showed in vitro that cranberry extracts reduce oxidation of LDL.74A review by Reed75examined the effects of flavonoids on atherosclerosis with a n emphasis on the positive potential effects of the flavonols and proanthocyanidins in cranberrie~.~~ Youdim et a176investigated the putative antioxidant and antiinflammatory effects of blueberry and cranberry anthocyanins and hydroxycinnamic acids. The polyphenols isolated from both berries were able to afford protection for endothelial cells against stressor-induced upregulation of oxidative and inflammatory insults. This may have beneficial actions against the initiation and development of vascular diseases and may be a contributing factor in the reduction of age-related deficits in neurologic impairment^.^^

Helicobacter pylori Burger et al” argue that because cranberry has been shown to inhibit bacterial adhesion to uroepithelial cells, it may also be useful as antiadhesion therapy in Helicobacfer pylori infections. In a number of small in vitro studies, the investigators demonstrated that a high-molecular-weight (HMW) constituent of cranberry inhibits sialyllactose-specific adhesion of H. pylori to a human gastric cell line and mucus as well as human erythrocytes.n This research warrants further investigation into the use of cranberry as it relates to H. pylori.

Oral Bacteria As a result of cranberry’s purported antiadhesive properties, the effect of cranberry on the coaggregation (massing together) of oral bacteria was tested. Weiss et a178discovered an HMW nondialyzable material they isolated from cranberry juice. Although the molecular structure of this material and its mechanism of action are not known, in vitro studies showed that coaggregation of pairs of bacteria were inhibited, and pilot in vivo studies showed that coaggregation of a large number of different pairs was reversed.79 Studies using mouthwash demonstrated positive results and warrant additional research. WeissSoconducted a small pilot study of individuals (n = 59) using a standard mouthwash that contained this HMW constituent.80After 6 weeks of daily use, results showed a reduction in colony-forming units of bacteria in saliva compared with placebo. These data and those of other similar studies prompt the theory that inhibition of oral streptococci to colonization and attachment to the tooth surface in vivo is due to the antiadhesion activity of the cranberry constituent.81 Another study hypothesized the inhibition of extracellular polysaccharide synthesis, which promotes the sucrose-dependent adhesion of oral bacteria.82

Vaccinium macrocarpon (Cranberry)

Peristomal Problems Tsukada et a16conducted a small study on the incidence of peristomal problems in 13 patients who had undergone urostomy. Patients drank 160 to 320 g/day of cranberry juice for an average of 6 months. Four of 6 patients who initially had erythema, maceration, or pseudoepithelial hyperplasia at the stoma site showed improvement after the cranberry juice regimen. This apparent protective effect for the skin against urine may be relevant for patients who are immobile and incontinent and suffer skin damage as a result. Additional studies to confirm this finding are warranted.28

Managing Calcium Oxalate Urolithiasis Investigations of the potential influence of cranberry juice on urinary biochemical and physicochemical risk factors associated with the formation of calcium oxalate kidney stones have been reported. Older research on patients with renal stones reported a reduction in urinary calcium excretion in people after drinking cranberry juice and suggested that it may be useful in the treatment of some patients with recurrent renal stones.83 Urinary variables were assessed by McHarg et a P in a randomized crossover trial (n = 20) in participants with no previous history of kidney stones.The ingestion of cranberry juice significantly and uniquely altered three key urinary risk factors. Oxalate and phosphate excretion decreased, whereas citrate excretion increased. In addition, there was a reduction in the relative supersaturation of calcium oxalate, which tended to be significantly lower than that induced by water alone. Each of these outcomes is desirable in patients at risk for nephrolithiasis (urolithiasis). The investigators concluded that cranberry juice has antilithogenic properties and deserves consideration as a conservative therapeutic protocol in managing calcium oxalate urolithiasis. The use of cranberry may be warranted in some patients with recurrent renal stones, but supplementary research is needed.28 A small earlier investigation by Terris et al,85 also of healthy ( n = 5 ) participants, reported changes in urinary markers for urolithiasis. Conversely, this preliminary evidence noted that cranberry may boost urinary oxalate concentrations, suggesting the promotion of kidney stones. At the same time, however, there was a boost in the concentration of inhibitors of stone formation, magnesium and potassium. These researchers concluded that because cranberry juice has a moderately high concentration of oxalate, a common component of kidney stones, limiting its consumption may be advisable in patients with a history of nephrolithiasis.%Formation of kidney stones has not been presented as a dilemma in any of the studies to date.%

DOSAGE There are a variety of cranberry products to choose from that vary greatly in quality, potency, and activity. Research as demonstrated no significant difference in incidence of UTIs between cranberry juice and cranberry capsules.56Differences do exist, however, between the concentrations of cranberry (extract ratio) in commercially available tablets and capsules. Most products on the market are not standardized, being either dried whole fruit powders or juice powders made from spraying cranberry juice onto maltodextrin powder. One standardized cranberry extract (available commercially as Cran-Max), provides a minimum 34:l extract of cranberry and is standardized to 1ppm anthocyanosides. This extract is manufactured with a patented technology to produce a more concentrated and stable form of cranberry extract. The technology utilizes the whole cranberry-seeds, pulp, skins, and juice-to form a lignan-cellulose matrix that protects the bioactive components (condensed tannins) from destruction in the stomach. This more potent form of cranberry has been the source of several previous and ongoing clinical ~tudies.54,55,86,87 Although drinking cranberry juice for health is one way to get the health benefits of this berry, it may not be the ideal method. Most commercial cranberry juice cocktails contain only 27% to 33% pure cranberry juice, sugar and water making up the rest of the volume. Drinking large amounts of cranberry cocktail not only is inconvenient but can be expensive and high in calorie count. In a 1-year study in 150 women, StotherP found that cranberry tablets provided the most cost-effective prevention of UTI? For these reasons, oral cranberry capsules/tablets may be preferred. To limit sugar and calories, several forms of cranberry juice are available either unsweetened or sweetened with noncaloric sweeteners. Health care providers directing their patients in selecting effective products should ensure that they find the most palatable product and should encourage long-term adherence. In the case of UTI prevention, this strategy may reduce an individual’s potential for development of the disorder as well as decrease the need for antibiotics. On the basis of the clinical studies, the amount of cranberry juice recommended for prevention of UTIs is 1 to 10 oz daily; however, the ideal dose has not yet been deter1nined.~~5~,~~ For those unable to drink this amount of juice, or for those concerned about the sugar or calorie content, a quality cranberry supplement can be considered. In successful studies utilizing capsules, one of the products used 250-mg capsules, which provided a 30:l extract of cranberry and were given twice daily.

The juice used was a pure unsweetened cranberry juice (not cranberry cocktail) and was given as 250 ml three times daily? For use as a urinary deodorizer for incontinent patients, 3 to 6 oz (90 to 180 ml) per day of cranberry juice has been used.58 Encapsulated formulations are often taken in doses of 300 to 500 mg once to twice daily depending on the concentration of cranberry extract provided in the capsule. Approximately 1500 g of fresh fruit produces 1L of j U i ~ e . ' ~ * ~ The National Kidney Foundation suggests that drinking a 10-oz (300-ml) glass of cranberry juice cocktail daily may help prevent UTIs. The Produce for Better Health Foundation, in partnership with the National Cancer Institute, recommends eating 5 servings of fruit a day. One serving of cranberries is '/2 cup (55g) of whole fruit or 3/4 cup (180 ml) of 100% juice.

Most monographs on cranberry report a high oxalate content; therefore in theory regular intake may precipitate urinary stone formation. Urinary oxalate excretion does not rise after the drinking of cranberry juice, however, and none of the studies has reported stone formation as a complication. There are no reported adverse effects from long-term consumption of cranberry juice in moderate amounts.28

DRUG INTERACTIONS

Taken orally, cranberry is generally well tolerated. None of the clinical trials reported significant side effects with 300 to 500 ml of cranberry juice consumption. Cranberry juice at doses of 3 to 4 L per day may cause gastrointestinal upset and diarrhea? Patients with diabetes should not consume cranberry juice sweetened with sugar or fruit juice, in consideration of its sugar content.@

There are no known interactions of cranberry with herbs or supplements.@Interaction with warfarin is biologically plausible because cranberry juice contains antioxidants, including flavonoids, which are known to inhibit cytochrome P450 enzymes, and warfarin is predominantly metabolized by P450form 2C9 e n ~ y m e s . 8The ~-~~ constituents of different brands of cranberry juice may vary, affecting their potential for interacting with drugs. Whether the constituents of cranberry juice inhibit 2C9 and therefore the metabolism of warfarin, or interact in another way, calls for further investigation. Until then, patients taking warfarin would be prudent to limit their intake of cranberry.92The preliminary evidence that flavonoids found in cranberry may inhibit cytochrome P450 form 2C9 enzymes also suggests that the enzymes may affect other drugs they process (e.g., amitriptyline, diazepam); further investigation is required.89

1. Cunha BA. Strategies to control antibiotic resistance. Semin Respir MWt 2002;17250-258. 2. Carson CF, Riley TV. Non-antibiotic therapies for infectious diseases. Commun Dis Intell 2003;27(Suppl):S143-S146. 3. Chambers BK, Camire ME. Can cranberry supplementation benefit adults with type 2 diabetes? Diabetes Care 2003;26:2695-2696. 4. Rogers J. Pass the cranberry juice. Nurs Times 1991;87:36-37. 5. Jackson B, Hicks LE. Effect of cranberry juice on urinary pH in older adults. Home Healthc Nurse 1997;15198-202. 6. Tsukada K, Tokunaga K, Iwama T, et al. Cranberry juice and its impact on peristomal skin conditions for urostomy patients. Ostomy Wound Manage 1994;40:60-62,64,66-68. 7. Bomser J, Madhavi DL, Singletary K, et al. In vitro anticancer activity of fruit extracts from Vaccitiitrm species. Planta Med 1996; 62212-216. 8. Swartz JH, Medrek TF.Antifungal properties of cranberry juice. Appl Miaobiol1968;161524-1527. 9. Wilson T, Porcari JP, Harbin D. Cranberry extract inhibits low density lipoprotein oxidation. Life Sci 1998;62:PL381-PL386. 10. Chen H, Zuo Y, Deng Y. Separation and determination of flavonoids and other phenolic compounds in cranberry juice by highperformance liquid chromatography. J Chromatogr A 2001;913: 387-395. 11. Coppola ED, Conrad EC, Cotter R. High pressure liquid chromatographic determination of major organic acids in cranberry juice. J Assoc Off Anal Chem 1978;61:1490-1492.

12. Flavonoids. In The phytochemistry of herbs. Available online at wziw.herbalchem.net [accessed June 4,20041. 13. Manach C, Scalbert A, Morand C, et al. E'olyphenols: food sources and bioavailability. Am J Clin Nutr 2004;79:727-747. 14. Consumer Lab. natural products encyclopedia: cranberry monograph. Available online at wwzu.consumerlab.com [accessed June 4, 20041. 15. Swartz JH, Medrek TF. Antifungal properties of cranberry juice. Appl Microbiol 1968;16:1524-1527. 16. Borukh IF, Kirbaba VI, Senchuk GV. [Antimicrobial properties of cranberry.] Vopr Pitan 1972;31:82. 17. Ibragimov DI, Kazanskaia GB. [Antimicrobial action of cranberry bush, common yarrow and Achillea biebersteinii.] Antibiotiki 1981; 26:10&109. 18. Kinney AB, Blount M. Effect of cranberry juice on urinary pH. Nurs Res 1979;28:287-290. 19. Kahn HD, Pananello VA, Saeli J, et al. Effect of cranberry juice on urine. J Am Diet Assoc 1967;51:251-254. 20. Bodel F T,Cotran R, Kass EH. Cranberry juice and the antibacterial action of hippuric acid. J Lab Clin Med 1959;54881-888. 21. Nahata MC, C u m i n s BA, McLeod DC, et al. Effect of urinary acidifiers on formaldehyde concentration and efficacy with methenamine therapy. Eur J C l i Pharmacol1982;22:281-284. 22. S i p s o n GM, Khajawall AM. Urinary acidifiers in phencyclidine detoxification. Hillside J Clin Psychiatry 1983;5:161-168. 23. Walsh BA. Urostomy and urinary pH. J ET Nurs 1992;19:110-113.

ADVERSE EFFECTS

Vaccinium macrocarpon (Cranberry) 24. Chernomordik AB, Vasilenko EG. [Increase in novobiocin activity and an expansion of its antimicrobial action spectrum.] Antibiotiki 1981;26456-460. 25. Jones AH. The next step in infectious disease: taming bacteria. Med Hypotheses 2003;60171-174. 26.Ofek I, Mirelman D, Sharon N. Adherence of Escherichia coli to human mucosal cells mediated by mannose receptors. Nature 1977;265:623-625. 27. Burger 0,Ofek I, Tabak M, et al. Ahigh molecular mass constituent of cranberry juice inhibits Helicobacter pylori adhesion to human gastric mucus. FEMS Immunol Med Microbiol2O00;29:295-301. 28.Harkins K. What’s the use of cranberry juice? Age Ageing 2000;29:9-12. 29. Zafriri D, Ofek I, Adar R, et al. Inhibitory activity of cranberry juice on adherence of type 1 and type P fimbriated Escherichia coli to eucaryotic cells. Antimicrob Agents Chemother 19893392-98. 30.Ahuja S, Kaack 8, Roberts J. Loss of fimbrial adhesion with the addition of Vaccinum macrocarpon to the growth medium of P-fimbriated Escherichia coli. J Urol1998;159559-562. 31. Foo LY, Lu Y, Howell AB, et al. The structure of cranberry proanthocyanidins which inhibit adherence of uropathogenic P-fimbriated Escherichia coli in vitro. Phytochemistry 2000;54:173-181. 32. Foo LY, Lu Y, Howell AB, et al. A-type proanthocyanidin trimers from cranberry that inhibit adherence of uropathogenic P-fimbriated Escherichia coli. J Nat Prod 2000;63:1225-1228. 33.Reid G. The role of cranberry and probiotics in intestinal and urogenital tract health. Crit Rev Food Sci Nutr 2002;42(Suppl): 293-300. 34. Sobota AE. Inhibition of bacterial adherence by cranberry juice: potential use for the treatment of urinary tract infections. J Urol 1984;131:1013-1016. 35.Sdunidt DR, Sobota AE. An examination of the anti-adherence activity of cranberry juice on urinary and nonurinary bacterial isolates. Microbios 1988;55:173-181. 36. Habash MB, Van der Mei HC, Busscher HJ, et al. The effect of water, ascorbic acid, and cranberry derived supplementation on human urine and uropathogen adhesion to silicone rubber. Can J Microbiol 1999;45691-694. 37.Sharon N, Ofek I. Fighting infectious diseases with inhibitors of microbial adhesion to host tissues. Crit Rev Food Sci Nutr 2002;42(S~pp1):267-272. 38. Sandberg T, Stenqvist K, Svanborg-Eden C. Effects of subminimal inhibitory concentrations of ampicillin, chloramphenicol, and nitrofurantoin on the attachment of Eschetichia coli to human uroepithelial cells in vitro. Rev Infect Dis 1979;1:838-844. 39.Lee YL, Owens J, Thrupp L, et al. Does cranberry juice have antibacterial activity? JAMA 2000;2831691. 40. Gormley EA. Recurrent urinary tract infection concepts regarding etiology and treatment Urol Rep 2003;4399-403. 41. Avom J, Monane M, Gurwitz JH, et al. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 1994;271: 751-754. 42. Nicolle LE, Mayhew WJ, Bryan L. Prospective randomized comparison of therapy and no therapy for asymptomatic bacteriuria in institutionalized elderly women. Am J Med 1987;83:27-33. 43.High KF. Nutritional strategies to boost immunity and prevent infection in elderly individuals. Clin Infect Dis 2001;33:1892-1900. 44.Fleet JC. New support for a folk remedy: cranberry juice reduces bacteriuria and pyuria in elderly women. Nutr Rev 1994;5216&170. 45. Foxman B, Geiger AM, Palin K, et al. First-time urinary tract infection and sexual behavior. Epidemiology 1995;6:162-168. 46. Howell AB, Foxman B. Cranberry juice and adhesion of antibioticresistant uropathogens. JAMA 2002;287:3082-3083. 47. Walsh N. Growing evidence: cranberry juice tied to lower UTI risk-NM undertakes large study. Ob Gyn News 2003;38:18.

48. Schlager TA, Anderson S, Trudell J, et al. Effect of cranberry juice on bacteriuria in children with neurogenic bladder receiving intermittent catheterization. J Pediatr 1999;135:698-702. 49. Morris NS, Stickler DJ. Does drinking cranberry juice produce urine inhibitory to the development of crystalline, catheter-blocking Proteus mirabilis biofilms? BJU Int 2001;88:192-197. 50. Reid G, Hsiehl J, Potter P, et al. Cranberry juice consumption may reduce biofilms on uroepithelial cells: pilot study in spinal cord injured patients. Spinal Cord 2001;3926-30. 51. Linsenmeyer TA, Harrison B, Oakley A, et al. Evaluation of cranberry supplement for reduction of urinary tract infections in individuals with neurogenic bladders secondary to spinal cord injury. A prospective, double-blinded, placebo-controlled, crossover study. J Spinal Cord Med 2004;2729-34. 52. Kontiokari T, Sundqvist K, Nuutinen M, et al. Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ 2001; 322:1571. 53. Kirchhoff M, Renneberg J, D w a e r K, et al. [Can ingestion of cranberry juice reduce the incidence of urinary tract infections in a department of geriatric medicine?] Ugeskr Laeger 2001;163: 2782-2786. 54.Stothers L. A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women. Can J Urol 2002;9 1558-1562. 55. Wheeler R. Outcome pilot study following women with symptoms of chronic urinary tract infections and urethritis with taking Cran-Max. 1998. Available online at zuunu.cranmax.com [accessed June 4,20041. 56. Jepson RG, Mihaljevic L, Craig J. Cranberries for treating urinary tract infections. Cochrane Database Syst Rev 2004;2:CDO01321. 57. Kraemer RJ. Cranberry Juice and the reduction of ammoniacal odor of urine. Southwest Med 1964;45211-212. 58.DuGan CR, Cardaciotto €5.Reduction of ammoniacal urinary odors by the sustained feeding of cranberry juice. J Psychiatr Nurs 1966;8:467-470. 59. Kapoor A. Effectiveness of Cran-Max (a concentrated cranberry extract) as a prescribed method of treatment for current urinary tract infections (study in progress). Dept. of Urology, McMaster University, Hamilton, Ontario, Canada. 60. Veterans Affairs, Boston Healthcare System. Evaluation of CranMax tablets for the prevention of UTI’s in spinal cord injured (SCI) patients with neurogenic bladders. 2004 (study complete, awaiting final release). 61. National Institute of Health. Research grants. Available online at

http://grants2.nih.gov/grants/guide/rfaTfiles/RFA-AT-03-004.htmlnm [accessedJune 4,20041. 62. Wang SY, Jiao H. Scavenging capacity of berry crops on superoxide radicals, hydrogen peroxide, hydroxyl radicals, and singlet oxygen. J Agric Food Chem 2000;4&5677-5684. 63. Kahkonen MP, Hopia AI, Heinonen M. Berry phenolics and their antioxidant activity. J Agric Food Chem 2001;49:4076-4082. 64.Zheng W, Wang SY. Oxygen radical absorbing capacity of phenolics in blueberries, cranberries, chokebemes, and lingonberries. J Agric Food Chem 2003;51:502-509. 65. Pedersen CB, Kyle J, Jenkinson AM, et al. Effects of blueberry and cranberry juice consumption on the plasma antioxidant capacity of healthy female volunteers. Eur J Clin Nutr 2000;54:405-408. 66. Roy S, Khanna S, Alessio HM, et al. Anti-angiogenic property of edible berries. Free Radic Res 2OO2;36:1023-1031. 67. Guthrie N. Effect of cranberry juice and products on human breast cancer cell growth (abstract 531.13). FASEB J 2000;14. 68. Ferguson PJ, Kurowska E, Freeman DJ, et al. A flavonoid fraction from cranberry extract inhibits proliferation of human tumor cell lines. J Nutr 2004;134:1529-1535.

Pharmacology of Natural Medicines 69. B o a r J, Madhavi DL, Sigletary K, et al. In vitro anticancer activity of fruit extracts from Vaccinium species. Planta Med 1996;62212-216. 70. Murphy BT, MacKinnon SL, Yan X, et al. Identification of triterpene hydroxycinnamates with in vitro antitumor activity from whole cranberry fruit Wacciniitm macrocnryonl. J Agric Food Chem 2003; 51:3!541-3545. 71. Seeram NP,Adams LS, Hardy ML, et al. Total cranberry extract versus its phytochemical constituents: antiproliferative and synergistic effects against human tumor cell lines. J Agric Food Chem 2004;52:2512-2517. 72. Bagchi D, Sen CK, Bagch M, et al. Anti-angiogenic, antioxidant, and anti-carcinogenic properties of a novel anthocyanin-rich berry extract formula. Biochemistry (Mosc) 2004;69:75-80. 73. Yan X,Murphy BT, Hammond GB, et al. Antioxidant activities and antitumor screening of extracts from cranberry fruit Wnccitiiirni mncrocarpon). J Agric Food Chem 2002;50:5844-5849. 74. Wilson T, Porcari JP, Harbin D. Cranberry extract inhibits low density lipoprotein oxidation. Life Sci 1998;62:PL381-PL386. 75. Reed 1. Cranberry flavonoids, atherosclerosis and cardiovascular health. Crit Rev Food Sci Nutr 2002;42(Suppl):301-316. 76. Youdim KA, McDonald J, Kalt W, et al. Potential role of dietary flavonoids in reducing microvascular endothelium vulnerability to oxidative and inflammatory insults. J Nutr Biochem 2002;13: 282-288. 77. Burger 0, Weiss E, Sharon N, et al. Inhibition of Hdicobncfer yylori adhesion to human gastric mucus by a high-molecular-weight constituent of cranberry juice. Crit Rev Food Sci Nutr 2002; 42(Suppl):279-284. 78. Weiss EI,Lev-Dor R, Kashamn Y, et al. Inhibiting interspecies coaggregation of plaque bacteria with a cranberry juice constituent [errata J Am Dent Assoc 1999;130:36 and 1999;130:332].J Am Dent ASSW1998;129:1719-1723. 79. Weiss EL, Lev-Dor R, Sharon N, et al. Inlubitory effect of a highmolecular-weight constituent of cranberry on adhesion of oral bacteria. Crit Rev Food Sci Nutr 2002;42(Suppl):285-292. 80. Weiss EI, Kozlovsky A, Steinberg D, et al. A high molecular mass cranberry constituent reduces mutans streptococci level in saliva

and inhibits in vitro adhesion to hydroxyapatite. FEMS Microbiol Lett 2004;232:89-92. 81. Yamanaka A, Kimizuka R, Kato T, et al. Inhibitory effects of cranberry juice on attachment of oral streptococci and biofilm formation. Oral Microbiol Immunol2004;19150-154. 82. Steinberg D,Feldman M, Ofek I, et al. Effect of a high-molecularweight component of cranberry on constituents of dental biofilm. J Antimicrob Chemother 2004;5486-89. 83. Light I, Gursel E, Zinnser HH. Urinary ionized calcium in urolithiasis. Effect of cranberry juice. Urology 1973;1:67-70. 84.McHarg T, Rodgers A, Charlton K. Influence of cranberry juice on the urinary risk factors for calcium oxalate kidney stone formation. BJU Int 2003;92:765-768. 85. Terris MK, Issa MM, Tacker JR. Dietary supplementation with cranberry concentrate tablets may increase the risk of nephrolithiasis. Urology 2001;5726-29. 86. Poduska J. Cran-Max clinical trial. Central Military Hospital, Prague, Czech Republic, 1999. Available online at: www.crnniiinx.com [accessed June 4,20041. 87. Hejzlar L, Podusak J. The effect of prophylactic administration of Cran-Max on the occurrence of recurring infections of the urinary tract. Available online at zuzuzu.crutimux.com [accessed June 4,20041. 88. Natural Medicines comprehensive database. Monograph cranberry. Available online at zuz~~~.n~t~rruldutabuse.com [accessed June 4,20041. 89. Hodek P, Trefil P, Stiborova M. Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450. Chem Biol Interact 2002;139:1-21. 90. Rettie AE, Korzekwa KR, Kunze KL, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992;5:54-59. 91. Grant P. Warfarin and cranberry juice: an interaction? J Heart Valve Dis 2004;13:25-26. 92. Suspected warfarinxranberry juice interaction. Canadian Adverse Reaction Newsletter 2004;14:3. Available online at http://zuzuw. I i c - s c . ~ c . c u ~ 1 p ~ - ~ ~ ~ s a / t y d - d p f html / n d ~[accessed l 4 n 3 ~ e .June 4,20041.

Vacciniummyrtillillus (Bilberry) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 1365 Chemical Composition 1365

Clinical Applications 1367 Ophthalmologic Applications 1367 Other Clinical Applications 1368 Other Effects 1368

History and Folk Use 1366 Dosage 1369 Pharmacology 1366 Collagen-StabilizingAction 1366 Normalization of Capillary Permeability 1366 Antiaggregation Effect on Platelets 1367 Effects on Cancer Cells 1367

Toxicology 1369 Drug Interactions 1369 Summary 1369

Vaccinium myrtillus (family: Ericaceae) Common names: bilbeq, huckleberry, European blueberry, whortleberry, blueberry

GENERAL DESCRIPTION The genus Vaccinium in the family Ericaceae comprises nearly 200 species, most of which are found in the Northern Hemisphere. This chapter focuses on Vaccinium myrtillus and the medicinal use of extracts of its fruit. V. myrtillus, or bilberry, is a shrubby perennial plant that grows in the sandy areas of the northern United States and in the woods and forest meadows of Europe. The angular, green, branched stem grows from a creeping rootstock to a height of 1 to 1.5 feet. The 0.5- to l-inch-long leaves are oval, slightly dentate, and bright green, whereas the flowers are reddish- or greenish-pink and bell-shaped. The bilberry's flowering season is April through June. The fruit is a blue-black berry.'

CHEMICAL COMPOSITION The pharmacologically active constituents of bilberries are its flavonoid components, specifically its anthocyanosides. An anthocyanoside is composed of an aglycone (e.g., anthocyanidin) bound to one of three glycosides (arabinoside, glucoside, or galactoside). More than 15 different anthocyanosides originate from the five

aglycones found in V. myrtillus (Figure 135-1).2 Other members of the genus Vaccinium as well as Ribes nigrurn (black currant) and Vitis vinifera (grape) contain similar anthocyanosides? Extracts of these fruits are also used for medicinal purposes in Europe. The concentration of anthocyanosides in the fresh fruit is approximately 0.1% to 0.259'0, whereas concentrated extracts of V. myrtillus are produced that yield an anthocyanidin content of 25%? An extract with an anthocyanidin content of 25% actually contains about 37% anthocyanosides owing to the conjugation of the anthocyanidin with a glycoside. (For analytical purposes, the anthocyanosides content should always be expressed in terms of anthocyanidin.) Only very small amounts of free anthocyanidins exist in nature and in V.myrti2lus extracts. Bilberries are also good sources of bioavailable resveratro14 and quercetin? though the level of these compounds is less than that found in other foods (e.g., the level of reservatrol in bilberry is
Pharmacology of Natural Medicines R

extracts have been shown to affect collagen metabolism in the following ways:

OH Anthocyanin

R

R ' R "

Delphinidin 3-0-glycoside Cyanidin 3-0-glycoside Petunidin 3-0-glycoside Peonidin 3-0-glycoside Malvidin 3-0-glycoside

OH

OH OH

OH

OH

OCH,

OH OH

OCH,

OH OH

OCH, OCH,

H

H

Figure 135-1 Vacchum myfti//is anthocyanosides. (From Eaj A, Bombardeili E. (Greek) Gabetta 6. Martinelli M.J Chromatogr 1983;279:365-372.)

consumption, period the mean serum concentrations of quercetin ranged between 21.4 and 25.3 pg/L in the berry group, which translated to being 32% to 51% higher than in the control group-indicating that the berries used in this study are a good source of bioavailable quercetin.

HISTORY AND FOLK USE Bilberries have, of course, been used as food and for their high nutritive value. Medicinally, they have been utilized in the treatment of scurvy and urinary complaints (including infection and stones).' The dried berries have been used primarily for their astringent qualities in the treatment of diarrhea and dysentery. Decoctions of the leaves have been used in the treatment of diabetes.'

PHARMACOLOGY The pharmacology of V. rnyrtillus is discussed almost entirely in relationship to its anthocyanoside content, as research has focused primarily on the anthocyanosides.

Collagen-Stabilizing Action Anthocyanosides possess sigruficant collagen-stabilizing action.G12 Collagen, the most abundant protein of the body, is responsible for maintaining the integrity of "ground substance" as well as tendons, ligaments, and cartilage. Collagen is destroyed during the inflammatory processes that occur in rheumatoid arthritis, periodontal disease, and other inflammatory conditions involving bones, joints, cartilage, and other connective tissue. Anthocyanidins, proanthocyanidins, and other flavonoids are remarkable in their ability to prevent collagen destruction. The anthocyanidins in V. rnyrtillus

Anthocyanosides cross-link collagen fibers, resulting in strengthening of the natural cross-linking of collagen that forms the collagen matrix of connective tissue (ground substance, cartilage, tendon, etc.).6-10 Anthocyanosides prevent free radical damage with their potent antioxidant and free radical scavenging a~tion.~-~Jl Anthocyanosides inhibit enzymatic cleavage of collagen by enzymes secreted by leukocytes during inflamation.6-8,10-12 Anthocyanosides and other flavonoid components of V. myrtiZZzts prevent the release and synthesis of compounds that promote inflammation, such as histamine, serine proteases, prostaglandins, and l e u k ~ t r i e n e s . ~ ~ J ~ J ~ Anthocyanosides promote mucopolysaccharide and collagen biosynthesis and stimulate reticulation of collagen fibrils.'517

Normalization of Capillary Permeability Anthocyanosides have strong "vitamin P" activity.6 Included in their effects are an ability to raise intracellular vitamin C levels and to reduce capillary permeability and fragility.6-8Their effect in reducing capillary fragility and permeability is roughly twice that of rutin, in both intensity and duration of action.ls V. nzyrtillus extracts have been widely used in Europe in the treatment of various arterial, venous, and capillary disorders. Clinical studies have demonstrated a positive effect in the treatment of the following condition^'^-^^: Capillary fragility Blood purpuras Various encephalic circulation disturbances (similar to Ginkgo biloba) Venous insufficiency Varicose veins Microscopic hematuria caused by diffused and kidney capillary fragility V. myrtillus's efficacy in the treatment of a variety of venous- disorders relates to the ability of anthocyanosides to protect altered veins (postphlebotic veins as well as varicose veins) via two rne~hanisms'~: (1)increasing the endothelium barrier effect through stabilization of the membrane phospholipids and (2) increasing the biosynthesis of the acid mucopolysaccharides of the connective ground substance, thus restoring the altered mucopolysaccharidepericapillary sheath. This latter effect leads to a marked increase in newly formed capillaries and collagen fibrils. One interesting effect of the normalization of collagen structures and capillaries is the demonstration that

Vaccinium myrti//us(Bilberry)

anthocyanosides from V. myrtillus reduce the permeability of the blood-brain Greater blood-brain permeability has been linked to autoimmune diseases of the central nervous system, schizophrenia, ”cerebral allergies,” and a variety of other central nervous system disorders. Presumably, the anthocyanosides inhibit both enzymatic and nonenzymatic degradation of the basement membrane collagen of brain capillaries, thus helping maintain or restore the brain’s protection from drugs, pollutants, naturally occurring degradation products, and other cerebral toxin^.^-'^*^ Another recent study further demonstrates the remarkable efficacy of bilberry in protecting and strengthening the capillaries and microcirculation. In this study, the effects of anthocyanidins on hamster cheek microcirculation were investigated after ischemia and reperfusion. The treated group had diminished adherence of leukocytes to the venules after reperfusion, resulting in prevention of the markedly increased capillary permeability seen in the placebo group.26

Antiaggregation Effect on Platelets Anthocyanosides, like many other flavonoids, have been shown to have sigruficant antiaggregation effects on platelet^.^^-^^ Their action in vivo appears to be direct antiaggregation effects on the platelets and an indirect effect via prostacyclin-like acti0n.2~-~~ Prostacyclin (PG12) is a potent stimulator of adenyl cyclase, the enzyme that catalyzes the production of cyclic adenosine monophosphate (CAMP)from adenosine triphosphate (ATP). Cyclic AMP prevents platelets from aggregating and adhering to the endothelial surface.

Smooth Muscle-Relaxing Activity Anthocyanoside extracts have demonstrated sigruficant vascular smooth muscle-relaxing effects in a variety of experimental models.3032The clinical application of this research may be in the treatment of dysmenorrhea, for which a preliminary study demonstrated positive effects.=

Effects on Cancer Cells An in vitro study demonstrated that among ethanol

extracts of 10 edible berries, bilberry extract was the most effective at inhibiting the growth of human leukemia cells and colon carcinoma cells.M Bilberry extract was shown to possess dual action in this regard through induction of apoptosis (programmed cell death) and promotion of nucleosomal DNA fragmentation. The reason bilberry extract was the most potent of the extracts tested was that it contained the largest amounts of phenolic compounds, including anthocyanins, and showed the greatest free radical scavenging activity. Pure delphinidin and malvidin, like the glycosides isolated from the

bilberry extract, induced apoptosis in the leukemia cells, but only pure delphinidin and the glycoside isolated from the bilberry extract, but not malvidin and the glycoside, inhibited the growth of human colon cancer cells.

CLINICAL APPLICATIONS The primary clinical application of bilberry extracts has been in the prevention and treatment of a diverse group of disorders of the eye and vision. However, the same mechanisms of action that benefit the eye are of value to other health problems, especially those involving capillary dysfunction or inflammation.

Ophthalmologic Applications Night Vision Perhaps the most sigruficant clinical applications for V. myrtillus extracts are in the field of ophthalmology.Interest in V. myrtillus anthocyanosides was first aroused when it was observed that the administration of bilberry extracts to healthy subjects resulted in improved nighttime visual acuity, quicker adjustment to darkness, and faster restoration of visual acuity after exposure to glare33 Further studies confirmed these r e ~ u l t s . 3Results ~ ~ were most impressive in individuals with pigmentary retinitis and hemeralopia. (Hemerulopia refers to “day blindness,” or an inability to see as distinctly in bright light as in dim light.) It appears that, in addition to their effect on capillaries, V. myrtillus anthocyanosides have an affinity for the pigmented epithelium of the retina, which composes the optical or functional part of the retina.4I This feature is consistent with several of the clinical effects observed. Anthocyanoside extracts of V. myrtillus appear to be of great value in both poor night vision and poor day vision.

Glaucoma V. myrtillus may play a significant role in the prevention and treatment of glaucoma via its effect on collagen structures in the eye. In the eye, collagen provides tensile strength and integrity to the tissues-cornea, sclera, lamina cribrosa, trabecular meshwork, and vitreous. Morphologic changes in the collagen of the eye precede clinically detectable abnormalities. These changes may result in elevated intraocular pressure (IOP) readings or, perhaps more significantly, the progression of peripheral vision loss. Changes in collagen structure would explain the following observations:

Similar peripheral vision loss in patients with normal and elevated IOP Cupping of the optic disc even at low IOP levels No apparent anatomic reason for decreased aqueous outflow (see Chapter 170 for complete discussion and references)

Therefore, primary prevention of glaucoma involves maintaining ground substance and collagen framework integrity. It appears that the prevention of collagen matrix breakdown is important here, as it is in other conditions involving collagen abnormalities, such as atherosclerosis, rheumatoid arthritis, and periodontal disease. Consumption of V. myrtillus may offer significant protection against the development of glaucoma, because of its collagen-enhancing actions. In addition, anthocyanosides may be of benefit in the treatment of chronic glaucoma, as rutin has been demonstrated to lower IOP when used as an adjunct in cases unresponsive to miotics V. myrtillus anthocyanosides are, in general, much more biologically active than rutin.lS

Cataracts and Retinal Degeneration V myrtillus anthocyanosidesmay offer significant protection against the development of retinal (macular) degeneration and cataracts, particularly diabetic retinopathy and cataracts. Both the rate of retinal degeneration and the occurrence of cataracts in rats can be retarded by changing their diet from a commercial laboratory chow to a "welldefined diet."@S4 Preliminary research suggests that flavonoid componentsin the well-defined diet may be responsible for the protective effects against cataracts and retinal degeneration.& Limited research has shown that, when combined with vitamin E, bilberry significantly slows the progression of senile cataracts in humans.& V myrtillus anthocyanoside extracts are widely used in Europe in the prevention of diabetic retinopathy.The positive effects noted in clinical trials may be due to improved capillary integrity as well as inhibition of sorbitol production (see Chapter 163). Flavonoids have been shown to be potent in vitro and in vivo inhibitors of sorbitol accumulation. In laboratory experiments they have been found capable of inhibiting the development of diabetic ~ataracts?~-~l

Other Clinical Applications Diabetes Mellitus A decoction of blueberry leaves has a long history of folk use in the treatment of diabetes. This use is supported by research, which has shown that oral administration reduces hyperglycemia in normal and depancreatized dogs, even when glucose is concurrently injected intravenously.@52 The anthocyanoside myrtillin (3-glucosideof delphinidin) is apparently the most active hypoglycemic component of V myrtillus. Upon injection, it is somewhat weaker than insulin, but it is also less toxic, even at 50 times the 1 g/day therapeutic dose. It is of interest to note that a single dose can have beneficial effects lasting for several weeks.@ The most important benefits from use of anthocyanosides in the treatment of diabetes, however, relate to

their ability to improve collagen integrity and capillary permeability. Benefit also possibly derives from their ability to inhibit sorbitol accumulation, thus providing protection from the serious vascular and neurologic sequelae of diabetes. V myrtillus anthocyanosides have also been shown to have a protective effect on capillary fraghty in diabetes and to reduce serum cholesterol and triglyceride levels in primary dy~lipidemia.~~ Although studies in rabbits have not confirmed a cholesterol-lowering effect, the anthocyanosides significantly decrease the intimal proliferation, extracellular matrix production, and calcium and lipid deposition found in the aorta of untreated atherosclerotic rabbits. Presumably, this decrease is a result of greater collagen cross-linking, which thus diminishes the permeability in small and large blood vessels.%

Inflammatory Joint Disease The effects of anthocyanosides on collagen structures and their potent antioxidant activity make V myrtillus anthocyanoside extracts very useful in the treatment of a wide variety of inflammatory conditions, most notably rheumatoid arthritis. Bioflavonoids have been found to increase collagen synthesis and inhibit collagen catabolism in rats with adjuvant-induced arthritis (a chronic progressive polyarthritis with some similarities to rheumatoid arthriti~).'~ Blueberries, like cherries, are particularly indicated in the treatment of gout, because their flavonoid components are able to reduce both uric acid levels and tissue destruction (see Chapter 171).55

Microscopic Hematuria The effect of V myrtillus in the reduction of microscopic hematuria may reflect its tissue distribution. Pharmacokinetic studies in rats have demonstrated an affinity for the skin and kidneys.56Anthocyanosides' affinity for these tissues reflects the high concentration of collagen and mucopolysaccharides in the skin and kidneys and the fact that they are excreted via the kidneys.

Other Effects As mentioned previously, the smooth muscle-relaxing effects of bilberry extract have been put to good use in the treatment of dy~menorrhea.3~ A significant improvement in pelvic/lumbosacral pain, mammary tension, nausea, and lower limb heaviness was noted when women with dysmenorrhea were given bilberry extract (115 mg anthocyanosides per day) for 3 days before and during menstruation. Bilberry extracts have demonstrated antiulcer effects in various experimental models and have been promoted as an ulcer medication in Italy.57

Vaccinium myrtillus (Bilberry)

DOSAGE

SUMMARY

The standard dose for V rnyrtillus is based on its anthocyanoside content, as calculated from its anthocyanidin percentage. Widely used pharmaceutical preparations in Europe are typically standardized for a 25% anthocyanidin content. Dosages are as follows:

V rnyrtillus anthocyanosides exhibit significant pharmacologic activity, particularly on collagen structures. Research has demonstrated a positive effect in the treatment of the following problems:

Anthocyanosides (calculated as anthocyanidin): 20 to 40 mg three times/day Vacciniurn myrtillus (25% extract): 80 to 160 mg three times/day Fresh berries: 55-115 g three times/day

TOXICOLOGY Extensive toxicologic investigation has demonstrated that V. myrtillus anthocyanoside extracts are devoid of toxic effects. Administration to rats of dosages as high as 400 mg/kg has no apparent side effects, and excess levels are quickly excreted through the urine and bile.l8TZ6

DRUG INTERACTIONS

Capillary fragility Blood purpuras Various encephalic circulation disturbances Venous insufficiency Varicose veins Microscopic hematuria caused by diffused and kidney capillary fraghty Poor night vision Hemeralopia Diabetic retinopathy Experimental studies indicate that anthocyanoside should also be useful in most inflammatory or degenerative conditions involving connective tissues (e.g., osteoarthritis, gout, rheumatoid arthritis, periodontal disease) as well as in glaucoma, diabetes, cataracts, retinal degeneration, and schizophrenia.

No drug interactions have been reported for V. rnyrtillus.

1. Grieve M. A modem herbal, vol. 1. New York Dover Publications, 1971:385-386. 2. Baj A, Bombardelli E, Gabetta B, Martinelli EM. Qualitative and quantitative evaluation of Vaccinium myrtillus anthocyanins by high-resolution gas chromatography and high-performance liquid chromatography. J Chromatogr 1983;279:365-372. 3. Andersen OM. Anthocyanins in fruits of Vaccinium uliginosum L. (bog whortleberry). J Food Sci 1987;52665-656,680. 4. Lyons MM, Yu C, Toma RB, et al. Resveratrol in raw and baked blueberries and bilberries. J Agric Food Chem 2003;51:5867-5870. 5. Erlund I, Mamiemi J, Hakala P, et al. Consumption of black currants, lingonberries and bilberries increases serum quercetin concentrations. Eur J Clin Nutr 2003;5737-42. 6. Kuhnau J. The flavonoids. A class of semi-essential food components. Their role in human nutrition. World Rev Nutr Diet 1976; 24117-191. 7. Gabor M. Pharmacologic effects of flavonoids on blood vessels. Angiologica 1972;9:355-374. 8. Havsteen B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharmacol1983;32:1141-1148. 9. Monboisse JC, Braquet P, Randoux A, Borel JP. Non-enzymatic degradation of acid-soluble calf skin collagen by superoxide ion protective effect of flavonoids. Biochem Pharmacol 1983;32: 53-58. 10. Detre A, Jellinek H, Miskulin M, Robert AM. Studies on vascular permeability in hypertension: action of anthocyanosides. Clin Physiol Biochem 1986;4143-149. 11. Monboisse JC, Braquet P,Borel Jl?Oxygen-free radicals as mediators of collagen breakage. Agents Actions 1984;15:49-50. 12. Jonadet M, Meunier MT, Bastide J, Bastide P. Anthocyanosides extracted from Vitis vinifer, Vaccinium myrtillus and Pinus maritimus.I.

Elastase-inhibiting activities in vitro. II. Compared angioprotective activities in vivo. J Pharm Belg 1983;38:41-46. 13. Middleton E. The flavonoids. Trends Pharm Sci 1984;5:335-358. 14.Amella M, Bronner C, Briancon F, et al. Inhibition of mast cell histamine release by flavonoids and bioflavonoids. Planta Med 1985;51:16-20. 15. Rao CN, Rao VH, Steinman B. Influence of bioflavonoids on the collagen metabolism in rats with adjuvant induced arthritis. Ital J Biochem 1981;30:54-62. 16. Ronziere MC, Herbage D, Garrone R, Frey J. Influence of some flavonoids on reticulation of collagen fibrils in vitro. Biochem Pharmacol1981;30:1771-1776. 17. Mian E, Curri SB, Lietti A, Bombardelli E. Anthocyanosides and the walls of the microvessels. further aspects of the mechanism of action of their protective effect in syndromes due to abnormal capillary fragility. Minerva Med 1977;68:3565-3581. 18. Lietti A, Cristoni A, Picci M. Studies on Vaccinium myrtillus anthocyanosides. I. Vasoprotective and anti-inflammatory activity. Arzneim Forsch 1976;26:829-832. 19. Ghiringhelli C, Gregoratti L, Marastoni F. [Capillarotropic action of anthocyanosides in high doses in phlebopathic statis.] Minerva Cardioangiol1978;26255-276. 20. Treviso A. Therapeutic value of the association of anthocyanin glucosides with glutamine and phosphorylserine in the treatment of learning disturbances at different ages. Gazz Med Ital 1979;138:217-232. 21. Grismondi GL. [Treatment of phlebopathies caused by stasis in pregnancy.] Minerva Ginecol1981;33221-230. 22. Piovella F, Almasio P, Ricetti MM, et al. Results with anthocyanidins in the treatment of haemorrhagic diathesis due to defective primary haemostasis. Gazz Med Ital1981;140:445-449.

Pharmacology of Natural Medicines 23. Pennarola R, Roc0 P, Matarazzo G, et al. The therapeutic action of the anthocyanosides in microcirculatory changes due to adhesive-induced polyneuritis. Gazz Med Ital1980;139:485-491. 24. Amouretti M. Therapeutic value of Vaccinium myrtillus anthocyanosides in an internal medicine department. Therapeutique 1972; 48~579-581. 25.Robert AM, Godeau G, Moati F, Miskulin M. Action of the anthocyanosides of Vaccinium myrtillus on the permeability of the blood brain barrier. J Med 1977;8:321-332. 26. Bertuglia S, Malandrino S, Colantuoni A. Effect of Vaccinium rnyrtillus anthocyanoside on ischemia reperfusion injury in hamster cheek pouch microcirculation. Pharmacol Res 1995;31:183-187. 27.Zaragoza F, Iglesias I, B e n d J. Comparative study of the antiaggregation effects of anthocyanosides and other agents. Arch Pharmacol Toxic01 1985;11:183-188. 28. Morazzoni P, Magistretti MJ. Effects of Vaccinium myrtillus anthocyanosides on prostacyclin like activity in rat arterial tissue. Fitoterapia 1986;5711-14. 29.Bottecchia D, Bettini V, Martino R, Camerra G. Preliminary report on the inhibitory effect of Vuccinium rnyrtillus anthocyanosides on platelet aggregation and clot retraction. Fitoterapia 1987; 483-8. 30. Bettini V, Mavellaro F, Ton P, Zanella P. Effects of Vacciniurn myrtillus anthocyanosides on vascular smooth muscle. Fitoterapia 1984;55:265-272. 31. Bettini V, Mavellaro F, Patron E, et al. Inlubition by Vaccinium myrtillus anthocyanosides of barium-induced contractions in segments of internal thoracic vein. Fitoterapia 1984;55:323-327. 32. Bettini V, Mayellaro F, Pilla I, et al. Mechanical responses of isolated coronary arteries to barium in the presence of Vaccinium myrtillus anthocyanosides. Fitoterapia 1985;56:3-10. 33. Colombo D, Vescovini R. Controlled clinical trial of anthocyanosides from Vacciniurn myrtillus in primary dysmenorrhea. G Ital Obstet Ginecol 1985;71033-1038. 34. Katsube N, Iwashita K, Tsushida T, et al. Induction of apoptosis in cancer cells by bilberry (Vaccinium myrtillus) and the anthocyanins. J Agric Food Chem 2003;51:6&75. 35. Jayle GE, Aubert L. Action of the anthocyanin glycosides on the scotopic and mesopic vision of the normal subject (des glucosides d’anthocyanes sur la vision scotopique et mesopique du sujet normal). Therapie 1964;19:171-185. 36. Terrasse J, Moinade S. Premiers resultats obtenus avec un nouveau facteur vitamininique P ’les anthocyanosides’ extraits du Vaccinium myrtillus. Presse Med 1964;72:397-400. 37. %la D, Roland0 M, Rossi PL, Pissarello L. Effect of anthocyanosides on visual performance at low illumination. Minerva Oftalmoll979; 21:283-285. 38. Gloria E, Peria A. Effect of anthocyanosides on the absolute visual threshold. Ann Ottalmol Clin Ocul1966;92595-607.

39.Junemann G. On the effect of anthocyanosides on hemeralopia following quinine poisoning. Klin Monatsbl Augenheilkd 1967; 151:891-896. 40.Caselli L. Clinical and electroretinographic study on activity of anthocyanosides. Arch Med Intern 1985;3729-35. 41. Wegmann R, Maeda K, Tronche P, Bastide P. Effects of anthocyanosides on photoreceptors. Cytoenzymatic aspects. Ann Histochim 1969;14:237-256. 42. Stocker F. New ways of influencing the intraocular pressure. N Y St J Med 1949;4958-63. 43. Pautler EL, Ennis SR. The effect of diet on inherited retinal dystrophy in the rat. Curr Eye Res 1984;3:1221-1224. 44.Hess H, Knapka JJ, Newsome DA, et al. Dietary prevention of cataracts in the pink-eyed RCS rat. Lag Anim Sci 198535:47-53. 45. Pautler EL, Maga ]A, Tengerdy C.A pharmacologically potent natural product in the bovine retina. Exp Eye Res 1986;42:285-288. 46.Bravetti G. [Preventive medical treatment of senile cataracts with vitamin E and anthocyanosides.] Clinical evaluation. Ann Ottalmol Clin Ocul 1989;115:109. 47.Scharrer A, Ober M. Anthocyanosides in the treatment of retinopathies. Klin Monatsbl Augenheilkd 1981;178:386-389. 48. Bever 8,Zahnd G. Plants with oral hypoglycemic action. Q J Crude Drug Res 1979;17:139-196. 49. Chaundry PS,Cambera J, Juliana HR,Varma SD. Inhibition of human lens aldose reductase by flavonoids, sulindac and indomethadn. Biochem Pharmacol1983;32:1995-1998. 50.Varma SD, Mizuno A, Kinoshita JH. Diabetic cataracts and flavonoids. Science 1977;195:87-89. 51. Varma SD, El-aguizy HK, Richards RD. Refractive change in alloxan diabetic rabbits. Control by flavonoids I. Acta Ophthalmol 1980;58:748-759. 52. Allen FM. Blueberry leaf extract. Physiologic and clinical properties in relation to carbohydrate metabolism. JAMA 1927;89: 1577-1581. 53. Passariello N, Bisesti V, Sgambato S. Influence of anthocyanosides on the microcirculation and lipid picture in diabetic and dyslipidic subjects. Gazz Med Ital 1979;138:563-566. 54. Kadar A, Robert L, Miskulin M, et al. Influence of anthocyanoside treatment on the cholesterol-induced atherosclerosis in the rabbit. Paroi Arterielle 1979;5:187-206. 55. Blau LW. Cherry diet control for gout and arthritis. Tex Rep Biol Med 1950;8:309-311. 56. Lietti A, Fomi G. Studies on Vaccinium rnyrtillus anthocyanosides. 11. Aspects of anthocyanins pharmacokinetics in the rat. Armeimittelforschung 1976;26:832-835. 57. Magistretti MJ, Conti M, Cristoni A. Antiulcer activity of an anthocyanidin from Vaccinium myrtillus. Arzneimitteforschung 1988; 38:686-690.

Valeriana officinalis (Valerian) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS

Chemical Composition 1371

Clinical Applications 1372 Insomnia 1372 Anxiety and/or Depression 1373

History and Folk Use

Dosage 1373

General Description 1371

1371

Pharmacology 1371

Valeriana officinalis (family: Valerianaceae) Common names: valerian, all heal

GENERAL DESCRIPTION Valerian is a perennial plant native to North America and Europe. The yellow-brown tuberous rootstock produces a flowering stem 2 to 4 feet high. The stem is round, but grooved and hollow, with leaves arranged in pairs. The small rose-colored flowers are in bloom from June to September. The rootstock is the portion used medicinally.

CHEMICAL COMPOSITION The important active compounds of valerian are the valepotriates (iridoid molecules; Figure 136-1) and valerenic acid. These compounds are found exclusively in valerian. Originally it was thought that just the valepotriates were responsible for valerian’s sedative effects, but an aqueous extract of valerian has also been shown to have a sedative effect. Because the valepotriates are not soluble in water, it was concluded that valerenic acid also possesses sedative action and is the chemical factor responsible for the sedative effect noted in human clinical trials with aqueous extracts of valerian root (see later). Moreover, because the safety of valepotriates was questioned after studies demonstrated mutagenicity, most commercial extracts feature water-soluble extracts standardized for valerenic a ~ i d s . l - ~ Other components of valerian are a volatile oil (0.5% to 2%),choline (3%), flavonoids, sterols, and several alkaloids (actinidine, valerianine, valerine, and chatinine).’

Toxicity

1374

HISTORY AND FOLK USE Valerian’s primary traditional use has been as a sedative for the relief of insomnia, anxiety, and conditions associated with pain. Specific conditions for which it was used are migraine, insomnia, hysteria, fatigue, intestinal cramps, and other nervous conditions.

PHARMACOLOGY Valerian has demonstrated a number of pharmacologic effects, such as the f ~ l l ~ ~ i n g d - ~ : Normalizing of the central nervous system (it acts as a sedative in states of agitation and as a stimulant in cases of extreme fatigue) Lowering of blood pressure Enhancement of the flow of bile (choleretic effect) Relaxing intestinal muscles Antitumor and antibiotic activity Its prime pharmacologic effect, however, is consistent with its historical use as a sedative. Pharmacologic studies indicated that both valepotriates and valerenic acid are capable of binding to gamma-aminobutyric acid (GABA) receptors much like the benzodiazepines.8 However, valerian does not appear to act in a similar fashion, in that side effects such as impaired mental function, morning hangover, and dependency have not been reported with valerian. In addition, valerian compounds which do not bind to GABA receptors have also been shown to produce sedative effects. Therefore other mechanisms may be more important. 1371

Compound

R

R'

R"

Valtrate lsovaltrate Homovaltrate AcevaRrate

lsovaleroyl lsovaleroyl lsovaleroyl lsovaleroyl

lsovaleroyl Acetyl Methyl-valeroyl 0-acetyl-valeroyl

Acetyl lsovaleroyl Acetyl Acetyl

Figure 136-1 Valeopotriates in Valeriana officinalis.

One key mechanism of action of valerian components is acting as an agonist to adenosine receptors. Adenosine is not a typical hormone or neurotransmitter,but is probably the most important neuromodulator in the central and peripheral nervous systems. A neurornodulator is a compound that has a modulatory effect on neuronal activity, increasing or decreasing the rate at which a nerve cell fires. Neuromodulators are distinct from neurotransmitters (e.g., glutamate), which are typically stored in the presynaptic specialization, are released into the synaptic cleft, and then interact with postsynaptic receptors and are either taken up or metabolized. A neuromodulator, such as adenosine, is more likely to be either constitutively released or released at times of high or low metabolic activity. Neuromodulators may act presynaptically or postsynaptically and may then be either taken up or metabolized. The therapeutic exploitation of adenosine receptors is still in its infancy, although the stimulant properties of the methylxanthines (caffeine, theophylline, theobromine, etc.) are partially explained by antagonizing adenosine receptors. In contrast, valerian has been shown to act as an adenosine agonist.'*10

CLINICAL APPLICATIONS The primary clinical application for valerian is as a sedative in the treatment of insomnia. It can also be used in the treatment of stress and anxiety.

Insomnia More than 20 double-blind clinical studies have now substantiated valerian's ability to improve sleep quality and relieve insomnia.11-22 The initial studies were performed on subjects who did not have insomnia. These studies showed quite clearly that extracts of valerian root improved subjective ratings for sleep quality and sleep latency (the time required to go to sleep) but left no "hangover" the next morning." In one early study, the effects of valerian on sleep were studied in two groups of healthy young

subjects.I2One group slept at home, the other in a sleep laboratory. Sleep was evaluated on the basis of questionnaires, self-rating scales, and night-time motor activity. Under home conditions, both doses of an aqueous valerian extract (450 and 900 mg) reduced perceived sleep latency and wake time after sleep onset. Nighttime motor activity was enhanced in the middle third of the night and reduced in the last third. The data suggest a dose-dependent effect. In the sleep laboratory, where only the higher dose of valerian was tested, no significant differences from placebo were obtained. However, the direction of the changes in the subjectiveand objective measures of sleep latency and wake time after sleep onset, as well as in night-time motor activity, corresponded to that observed under home conditions. There was no evidence for a change in sleep stages or electroencephalogram (EEG)spectra. The results indicate that the aqueous valerian extract exerts a mild sedative effect. Although the initial studies demonstrated that valerian could improve sleep quality in normal subjects, they failed to answer the question whether valerian could improve sleep patterns in people suffering from insomnia. In a follow-up to these two preliminary studies, valerian extract has been shown to significantly reduce sleep latency, improve sleep quality, and reduce nighttime awakenings in sufferers of insomnia in more than 15 double-blind studies.I3 These studies were usually performed under strict laboratory conditions and demonstrated quite clearly that valerian is as effective in reducing sleep latency as small doses of barbiturates or benzodiazepines. However, although these latter compounds also increase morning sleepiness,valerian usually reduces morning sleepiness. In one of the better-designed double-blind trials, patients age 18 to 73 years and diagnosed with nonorganic insomnia according to In ternational Classification of Diseases, Tenth Edition were treated at night with either 600 mg of valerian extract or 10 mg of oxazepam for 6 weeks.I6A total of 202 outpatients with a mean duration of insomnia of 3.5 months at baseline were involved in the study. Sleep quality after 6 weeks measured by Sleep Questionnaire B showed that the 600 mg of valerian extract was at least as efficacious as a treatment with 10 mg oxazepam. Both treatments markedly increased sleep quality compared with baseline ( p < 0.01). The other sleep function subscales-feeling of refreshment after sleep (GES), psychic stability in the evening (PSYA), psychic exhaustion in the evening (PSYE), psychosomatic symptoms in the sleep phase (PSS), dream recall (TRME), and duration of sleep-confirmed similar effects of both treatments. Clinical Global Impressions scale (CGI) and Global Assessment of Efficacy by investigator and patient, again, showed similar effects of both treatments. No significant side effects or serious adverse drug reactions were reported in either

Valeriana officinalis (Valerian) group. Most patients assessed their respective treatment as very good (82.8% in the valerian group, 73.4% in the oxazepam group). These results show that valerian extract displays a comparable efficacy to that of 10 mg oxazepam in the therapy of non-organic insomnia. In another study comparing the effects of valerian and oxazepam, 75 patients with nonorganic and nonpsychiatric insomnia between 18 and 70 years old were randomly allocated either to receive 600 mg of valerian extract or 10 mg of oxazepam every day 30 minutes before going to bed over a period of 28 days. The results of this study were consistent with those of the other, in that both groups all measures of sleep quality improved significantly, but there was no statistically sigruficant difference between groups.21 Valerian extract has also been shown to help improve sleep and relieve insomnia in people withdrawing from chronic benzodiazepine use.17 The study consisted of patients with insomnia who complained of poor sleep despite long-term use of benzodiazepines. These patients had taken benzodiazepines nightly for an average of 7 years. Sleep EEGs of the patients were analyzed with period amplitude analysis (PAA) and associated algorithms, during chronic benzodiazepine use (night l), and then after 15 days of a valerian placebo trial (initiated after washout of benzodiazepines; night 2). The subjects given valerian extract reported significantly better subjective sleep quality than given the placebo. The EEG results also showed significant less wake time after sleep onset (WASO) in valerian subjects than in placebo subjects and that the valerian-treated patients experienced longer sleep latency and increased alpha count in slow-wave sleep. Altogether these results indicate that valerian extract has a positive effect on withdrawal from benzodiazepine use. Valerian extract also appears to be quite effective in children. Serious sleep disturbances are particularly problematic for children with an intellectual deficit and are often the source of much distress for both the child and caregivers. Conventional drugs are not suitable for long-term treatment, making valerian an attractive alternative. In one small double-blind study in five children with varying intellectual deficits and different primary sleep problems, treatment with valerian extract led to significant reductions in sleep latencies and nocturnal time awake, lengthened total sleep time, and improved sleep quality.Is The treatment was apparently most effective in children with deficits that involved hyperactivity. Although the findings were preliminary and in need of replication, the results imply that valerian may be quite useful in the safe and effective long-term treatment of sleep difficulties in children with intellectual deficits. One of the major advantages of valerian extract is that it rarely has a negative affect on reaction time, alertness,

or concentration the morning after intake. In one doubleblind trial, 102 male and female volunteers were studied to determine whether reaction time, alertness, and concentration might be impaired by treatment with a valerian root extract.= The effect was first examined the morning after a single evening dose of either valerian extract (600 mg), flunitrazepam (1mg), or a placebo and then after 2 weeks of evening administration of valerian extract (600 mg) or a placebo. Evaluation of the primary criterion (the median of reaction time measured with the Vienna Determination Test [VDT])and secondary criteria (alertness test, tracking test, sleep quality, further VDT parameters, and safety criteria) all demonstrated that neither a single administration nor 14 days of valerian extract treatment produced an impairment in reaction abilities, concentration, or coordination.

Anxiety and/or Depression Valerian extracts are also proving to be quite helpful in treatment of generalized anxiety and depression in preliminary studies. For example, in one study involving 36 outpatients with generalized anxiety disorder, patients underwent a 2-week washout period and then were randomly assigned to one of the following three treatments for 4 weeks: valepotriates (mean daily dose: 81.3 mg), diazepam (mean daily dose: 6.5 mg), and placebo." Although no sigruficant difference was observed among the three groups at baseline or in the change from baseline on the Hamilton Anxiety Scale (HAMA)-probably because of the small sample size in each group-there was some evidence of benefit nonetheless. Specifically, only the diazepam and valepotriates groups showed a sigruficantreduction in the psychic factor of the HAMA. In one interesting study, valerian extract was shown to be effective in reducing the physiologic effects of psychological stress induced under laboratory conditions in a group of healthy volunteer^.^^ Valerian extract produced significant decrease in systolic blood pressure responsivity, no significant reductions in diastolic blood pressure, and a decrease in the heart rate reaction to mental stress. Valerian may prove quite useful in relieving anxiety in a patient with comorbid depression. In an open clinical trial, the combination of valerian with St. John's wort was found to improve symptoms more quickly than with St. John's wort monotherapy? The combination therapy was well tolerated, and no sigruficant side effects occurred.

DOSAGE As a mild sedative, valerian may be taken at the following dosages 30 to 45 minutes before bedtime: Dried root (or as tea): 1to 2 g Tincture (1:5): 4 to 6 ml(1to 1.5 tsp)

Pharmacology of Natural Medicines

A major concern for any sedative or antianxiety medication is its potential to affect a person’s ability to drive or operate potentially dangerous machinery. A randomized, placebo-controlled, double-blind study evaluated the impact of a valerian-lemon balm preparation on psychomotor and mental performance tests.28 For the rare patient with increased morning sleepiness, No effect was found on reaction time, concentration, reducing the dosage will eliminate the problem. For best or attentiveness. results, dietary factors such as caffeine and alcohol, which One case of valerian overdose has been reported disrupt sleep (see Chapter 182), should be eliminated. in the literat~re.~~ The patient presented with mild all of which disappeared within 24 hours symptoms, TOXICITY after the patient had taken an overdose-approximately Valerian is generally regarded as safe and is approved 20 times the recommended therapeutic dose of for food use by the U.S. Food and Drug Admini~tration.2~ valerian. Fluid extract (1:l):1 to 2 ml (0.5 to 1 tsp) Solid (dry powdered) extract (4:l):250 to 500 mg Valerian extract (1.0 to 1.5%valtrate or 0.5% valerenic acid):150 to 300 mg

1. Houghton PJ.The biological activity of Valerian and related plants.

J Ethnopharmacol1988;22.121-142. 2.von der Hude W, Scheutwinkel-Reich M, Braun R. Bacterial mutagenicity of the tranquilizing constituents of Valerianaceae roots. Mutat Res 1986;169:23-27. 3.von der Hude W, Scheutwinkel-Reich M, Braun R. In vitro mutagenicity of valepotriates. Arch Toxicol 1985;56:267-271. 4. Takeda S, Endo T, Aburada M. Pharmacological studies on iridoid compounds. III. The choleretic mechanism of iridoid compounds. J Pharmacobiodyn 1981;4612-623. 5. Hendriks H, Bos R, Allersma DP, et al. Pharmacological screening of valerenal and some other components of essential oil of Valerianu ofiicindis. Planta Med 1981;42:62-68. 6. Hazelhoff B, Malingre TM, Meijer DK. Antispasmodic effects of valeriana compounds: an in-vivo and in-vitro study on the guinea pig ileum. Arch Int Pharmacodyn 1982;257274287. 7. Bounthanh C, Bergmann C, Beck JP, et al. Valepotriates, a new class of cytotoxic and antitumor agents. Planta Med 1981;41:21-28. 8. Mennini T, Bemasconi F‘, Bombardelli E, et al. In vitro study on the interaction of extracts and pure compounds from Vulerium officinalis roots with GABA, benzodiazepine and barbiturate receptors in rat brain. Fitoterapia 1993;64:291-300. 9.Schumacher B, Scholle S, Holzl J, et al. Lignans isolated from valerian: identificationand characterization of a new olivil derivative with partial agonistic activity at A(1) adenosine receptors. J Nat Prod 2002;65:1479-1485. 10. Muller CE, Schumacher B, Brattstrom A, et al. Interactions of valerian extracts and a fixed valerian-hop extract combination with adenosine receptors. Life Sci 2002;71:1939-1949. 11. Leathwood F’, Chauffard F, Heck E, Munoz-Box R. Aqueous extract of valerian root (Valerianu oficcinalis L.) improves sleep quality in man. Pharmacol Biochem Behav 1982;17:65-71. 12.Balderer G , Borbely AA. Effect of valerian on human sleep. Psychopharmacology (Berl) 1985;87406409. 13. Leathwood PD, Chauffard F. Aqueous extract of valerian reduces latency to fall asleep in man. Planta Med 1985;54:144148. 14. Lindahl 0,Lindwd L. Double blind study of a valerian preparation. Pharmacol Biochem Behav 1989;321065-1066. 15. Dressing H, Riemann D, Low H. Insomnia. Are Valerian/Melissa combinations of equal value to benzodiazepine? Therapiewoche 1992;42:726-736. 16. Ziegler G, Ploch M, Miettinen-Baumann A, Collet W. Efficacy and tolerability of valerian extract LI 156 compared with oxazepam in

the treatment of non-organic insomnia-a randomized, doubleblind, comparative clinical study. Eur J Med Res 2002;7480-486. 17. Poyares DR, Guilleminault C, Ohayon MM, Tufik S. Can valerian improve the sleep of insomniacs after benzodiazepine withdrawal? Prog Neuropsychopharrnacol Biol Psychiatry 2002;26: 539-545. 18. Francis AJ, Dempster RJ. Effect of valerian, Valerianu edulis, on sleep difficulties in children with intellectual deficits: randomised trial. Phytomedicine 2002;9:273-279. 19. Herrera-Arellano A, Luna-Villegas G, Cuevas-Uriostegui ML, et al. Polysomnographic evaluation of the hypnotic effect of Valerianu edulis standardized extract in patients suffering from insomnia. Planta Med 2001;67695-699. 20. Wheatley D. Kava and valerian in the treatment of stress-induced insomnia. Phytother Res 2001;15:549-551. 21. Dom M. [Efficacy and tolerability of Baldrian versus oxazepam in non-organic and non-psychiatric insomniacs: a randomised, doubleblind, clinical, comparative study.] Forsch Komplementarmed Klass Naturheilkd 2000;779-84. 22. Donath F, Quispe S, Diefenbach K, et al. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry 2000;33:47-53. 23. Kuhlmann J, Berger W, Podzuweit H, Schmidt U. The influence of valerian treatment on ”reaction time, alertness and concentration” in volunteers. Pharmacopsychiatry 1999;32:235-241. 24. Andreatini R, Sartori VA, Seabra ML, Leite JR. Effect of valepotriates (valerian extract) in generalized anxiety disorder: a randomized placebo-controlled pilot study. Phytother Res 2002;16: 650-654. 25. Cropley M, Cave Z, Ellis J, Middleton RW. Effect of kava and valerian on human physiological and psychological responses to mental stress assessed under laboratory conditions. Phytother Res 2002;16:23-27. 26. Muller D, Pfeil T, von den Driesch V. Treating depression comorbid with anxiety-results of an open, practice-oriented study with St John’s wort WS 5572 and valerian extract in high doses. Phytomedicine 2003;10(Suppl4):25-30. 27. Leung A. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York: Wiley, 1980. 28. Albrecht M, Berger W, et al. [Psychopharmaceuticals and safety in traffic.] Zeits Allegrneinmed 1995;71:1215-1221. 29. Wiley LB, Mady SP, Cobaugh DJ, Wax PM. Valerian overdose: a case report. Vet Hum Toxicol 1995;37364-365.

Viscumalbum (European Mistletoe) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 1375 Chemical Composition History and Folk Use

1375 1375

Pharmacology 1376 Cardiovascular Effects 1376 Antineoplastic and lmmunostimulatory Effects 1376

Viscum album L. (family: Loranthaceae) Common names: European mistletoe, all-heal, birdlime, devil's fuge

GENERAL DESCRIPTION Viscum album, or European mistletoe, is an evergreen, semiparasitic plant found on the branches of deciduous trees in Europe and northern Asia. The roots of the plant penetrate through the bark into the wood of the host tree. The green branches are 1 to 2 feet long and form pendent bushes with leaves that are opposite, leathery, yellow-green and narrowly obovate. Inconspicuous pale yellow or green flowers appear from March to May, the female developing into sticky white berries that ripen from September to November.'I2 Viscum is most commonly seen on old apple, ash, and hawthorn trees. Traditionally, mistletoe from oak has been the most widely used, although it does not grow as well on oak as on the previously mentioned trees.'r2

CHEMICAL COMPOSITION V. album contains a variety of pharmacologically active substances, including alkaloids, polysaccharides, phenylpropanes, lignins, lectins, and viscotoxins.3-1° Some specific compounds found in viscum are as folloWs2~5~6~'0: A wide range of carbohydrates, including simple sugars as well as polysaccharides

Clinical Applications 1377 Cancer 1377 Immune Support 1378 Dosage

1378

Toxicity

1378

Drug Interactions 1378

Phenolic compounds such as flavonoids, caffeic acid, syringin, and eleutherosides Sterols, including beta-sitosterol, stigmasterol, and triterpenes Various amino acids as well as vasoactive amines, including tyramine, phenylethylamine, and histamine Fatty acids such as linoleic, palmitic, and oleic acids The alkaloids isolated from viscum appear to be related to those found in the host ~ l a n t .For ~ , ~example, mistletoes growing on Solanaceae shrubs contain nicotine alkaloids like hyoscine, anabasine, and isopelletierine. Cardiac glycosides have been found in mistletoe growing on Nerium oleander; strychnine has been found in mistletoe growing on Stychnos species; and caffeine has been found in mistletoe growing on coffee plants. Because pharmacologically active compounds appear to be concentrated within the mistletoe, different host trees, providing diverse chemical constituents, could be used for different therapeutic action. Also of importance is the fact that the proteins/lectins are present only in aqueous extracts, indicating that therapeutic activity would differ from the alcoholic/aqueous extracts. The alcoholic/aqueous extracts also demonstrate considerably less toxicity.

HISTORY AND FOLK USE Mistletoe was held in great reverence by the Druids who, dressed in white robes, would search for the 1375

Pharmacology of Natural Medicines sacred plant. When some was discovered, a great ceremony would ensue, culminating in the mistletoe's separation from the oak tree with a golden knife. The Druids believed that mistletoe protected them from all evil and that the oaks on which it was seen growing were to be respected because of the wonderful cures that the priests were able to produce with it.' Mistletoe's use has been recorded in the Middle East, Africa, India, and Japan, and it was mentioned as an anticancer drug by Pliny, Dioscorides, and Galen.3In 1720, an English physician, Sir John Colbatch, extolled the virtues of viscum in a pamphlet titled The Treatment of Epilepsy by Mistletoe. For many years, mistletoe was used in the treatment of a variety of nervous system disorders, including convulsions, delirium, hysteria, neuralgia, and nervous debility.'f3 It has been used in naturopathic medicine in the treatment of hypertension and vascular disorders of the uterus, bladder, and intestines. Probably because of viscum's potential toxicity, its use appears to have fallen into some disrepute shortly after Colbatch's work. For many years it was used only in external preparations for the treatment of dermatitis. Then, in 1906, a study demonstrating viscum's hypotensive effect in animals and humans was published. This paper appears to have restored viscum's medical prestige, initially in France and eventually throughout E~rope.~

PHARMACOLOGY V. album exhibits diverse pharmacologic actions. The herb and various extracts have demonstrated the following activities: Hypotensive Vasodilating Cardiac depressant Sedative Antispasmodic Immunostimulatory Antineoplastic It is interesting to note that purified mistletoe lectins are, in general, not as active in experimental studies as crude preparations.",'* Presumably, the crude preparations contain a number of compounds in viscum acting synergistically.It has also been proposed that alkaloidal components are responsible for the maintenance of lectin structure and activity? During isolation and purification procedures, alkaloidal linkages are cleaved from the lectins, resulting in a loss of specificity for target molecules. Unfermented viscum preparations typically demonstrate a greater direct cytotoxicity to tumor cells due to higher concentrations of the viscotoxin mistletoe lectin I (ML I).1s15

Cardiovascular Effects Viscum has exhibited a variety of effects on components of the cardiovascular system.3J6In particular, viscum has repeatedly demonstrated hypotensive action in animal studies. The mechanism of action for its hypotensive effect is still not entirely clear, and no recent investigations have been published. Viscum has been shown to inhibit the excitability of the vasomotor center in the medulla oblongata and to possess cholinomimetic activity.I6 The hypotensive activity may depend on the form in which the mistletoe is administered and the host tree from which it was collected. Studiesindicate that aqueous extracts are more effective; the highest hypotensive activity was demonstrated by a macerate of leaves of mistletoe parasitizing on willow and gathered in January.I6 Viscum's nonprotein components-flavonoids, phenol carboxylic acids, phenylpropanes, and lignins-have been shown to possess hypotensive action. Alcoholic solutions (tinctures and fluid extracts) contain these compounds, but not viscotoxins or lectins. As previously stated, however, aqueous extracts appear to be more effective. Several viscum preparations for hypertension are currently available in Europe. In fact, in Britain alone, more than 150 different mistletoe preparations can be found in the marketpla~e.~ These preparations typically have small amounts of viscum in combination with other botanicals with hypotensive action, such as garlic, Crataegus oxyacantha, and Tilia platyphyllos.

Anti neoplastic and lmmunostimulatory Effects Viscum preparations have been used clinically in Europe for the treatment of cancer since 1926, when Iscador, a fermented product made from the crude pressed juice, was introduced as an immunotherapeutic agent for cancer. This work was carried out under the direction of Rudolph Steiner. Since that time, numerous studies have shown that Iscador, and other viscum preparations and components, are effective antineoplastic and immunostirnulatory a g e n t ~ . " - ' ~ J ~ - ~ ~ Iscador and other fermented viscum preparations differ from nonfermented extracts in their greater effectiveness and their lower toxicity.I7Specifically, the major viscotoxin, ML I, is not found in Iscador.'* It is thought that fermentation transforms ML I to its A and B chains, which have important immunologic proper tie^.'^ The A chain has mitogenic effects, and the B chain stimulates macrophages and the release of lymphokines. In addition, there is a rapid decrease of lectin concentration during fermentation. The pharmacologic activity of Iscador has been shown to be due to its viscum components rather than to other constituents, such as lactobacilli, which possess

Viscum album (European Mistletoe) adjuvant activity. The lectins have been clearly demonstrated to be the viscum components largely responsible for Iscador's adjuvant activity. Although in vitro unfermented plant juice has demonstrated a tenfold greater cytotoxicity to tumor cells than Iscador, fermented Iscador contains a great number of substances that may act synergistically. In vivo studies in mice have demonstrated Iscador to be of greater adjuvant activity than purified mistletoe lectin and to be without secondary toxic effect^.'^,^^ Viscum's adjuvant activity is demonstrable in both delayed-type hypersensitivity and antibody responses of mice to sheep red blood cell^.'^^^^ Like other adjuvants (bacille Calmette-Guerin, levamisole, muramyl dipeptide, bacterial and yeast components, etc.), Iscador is most effective when administered near the tumor, although systemic administration has also yielded positive results. Upon local administration, an inflammatory process ensues that promotes white blood cell (WBC) infiltration and an encapsulation of the tumor. The nonspecific host defense factors stimulated by Vzscum album include the following: Enhanced macrophage phagocytic and cytotoxic a~tivity'~,~~ Increased neutrophil production17 Increased thymic weight and enhanced cortical thymocyte activity and proliferation2lTu Enhanced natural killer (NK) cell a ~ t i v i t y ' ~ , ~ , ~ ~ Increased antibody-dependent, cell-mediated cytotoxi~ity'~,~~ Iscador's effects on these immunologic parameters have been confirmed in patients with c a n ~ e r . ~ ~ , ~ Iscador's effect on stimulating the thymus gland has been demonstrated in several s t u d i e ~ ? Its ~ , ~ability ~ to induce hyperplasia of the thymic cortex and to accelerate the regeneration of hematopoietic cells after X irradiation is much greater than that of any other agent reported to date.21 In addition, thymic lymphocytes became 29 times more responsive to concanavalin A as a result of Iscador administration. In summary, V. album exhibits numerous cytotoxic, adjuvant, and immunostimulatory effects that indicate a therapeutic effect in human cancer. These effects have been confirmed in vivo against murine tumors, Lewis lung carcinoma, colon adenocarcinoma 38, and C3H mammary adenocarcinoma 16/C.4

CLINICAL APPLICATIONS Cancer The clinical application with the most significant scientific documentation is the use of viscum preparations as adjuncts in cancer therapy. It must be pointed out that the route of administration of viscum preparations

used in published studies as adjuncts in cancer treatments is subcutaneous or intravenous. It is not known to what degree (if any) the effects noted for Iscador, as well as other preparations and viscum compounds, can be achieved with oral administration, although one study has shown an enteric-coated, specially prepared viscum preparation to lead to absorption of intact 1e~tin.s.~~ Early clinical investigations of viscum preparationsIscador-were not very well documented. Owing to the shortage of acceptable controlled clinical trials, the use of Iscador and other viscum preparations as cancer treatment in Europe has remained controversial, even though positive effects with Iscador in the postoperative treatment of lung, breast, colon, and cervical carcinomas has been shown in several controlled studies.25The problem is that the methodologic criteria in these studies are quite poor. Until their benefits are better documented, mistletoe preparations appear most useful as adjuncts to standard therapy. The results of a prospective study indicate that Iscador is quite helpful in increasing the survival rate for various ~ancers.3~ The prospective long-term epidemiologic study sought to determine whether Iscador treatment prolongs survival time of patients with carcinoma of the colon, rectum, or stomach; breast carcinoma with or without axillary or remote metastases; or small cell or non-small cell bronchogenic carcinoma. A total of 10,226 patients with cancer were evaluated. Of these patients, 1668 had been treated with Iscador and 8475 had taken neither Iscador nor any other mistletoe product (control patients). In the nonrandomized, matchedpair study, survival time of patients treated with Iscador was longer for all types of cancer studied. In the pool of 396 matched pairs, mean survival time in the Iscador groups (4.23 years) was roughly 40% longer than in the control groups (3.05 years). Perhaps even more beneficial than Iscador are the new generation of mistletoe preparations standardized on ML I (e.g., Eurixor). This greater standardization offers significant advantages. ML I is a potent inducer of cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor. Its cytotoxic effects are also related to its ability to induce apoptosis (programmed cell death).26 In one study, the effect of Eurixor was examined in 40 patients with advanced carcinoma of the breast. Along with standard chemotherapy (VEC regimen), 21 patients were assigned to receive mistletoe (treatment group) and 19 patients were given a placebo (control After the fourth cycle of chemotherapy, the treatment group had statistically significantly higher leukocyte levels ( p < 0.001) than the control group; the treatment group had an average WBC count of 3000 cells/mm3, and the control group an average count of 1000 cells/mm3. Furthermore, the parameters of the quality of life and anxiety strain revealed significantly

Pharmacology of Natural Medicines better values in the treatment group than in the control group. These results show that the adjuvant treatment with mistletoe extracts, in this case Eurixor, is a valuable addition to standard chemotherapy for patients with advanced breast cancer. These results are quite important, because advanced breast cancer carries a very poor prognosis. Similar results in better-designed studies have been shown with various viscum preparations in advanced pancreatic, colon, and liver cancer.28,34-36 The results are quite encouraging.

Immune Support The immune-enhancing effects of viscum preparations will likely extend to conditions beyond cancer. For example, Iscador was shown to reduce the rate of recurrent respiratory infections (RRIs)in children 5 to 14 years old living in areas exposed to the radioactive fallout from the Chernobyl nuclear reactor a~cident.~’ The dosage was two subcutaneous injections a week for 5 weeks. One year after a single treatment course, the frequency of RRI relapses decreased by 75%. Furthermore, V. album therapy resulted in normalization of initial immune indices that were either below or above the normal ranges. This immunomodulatory effects was assessed by investigation of lymphocyte subsets, NK cell activity, phagocytic and oxidative activity of polymorphonuclear leukocytes, and antiviral activity of serum before and 1week after treatment. Clearly, additional investigations into the pharmacology of V; album are needed. Specifically,it must be determined whether the effects noted both in vitro and in vivo in animals, as well as in patients receiving injectable viscum preparations, can be attained with oral administration. In addition, greater clarification is needed to determine optimal viscum preparations. What host tree should be selected for which condition? What is the optimal harvesting time? In what form should the viscum be administered-crude herb, aqueous or alcoholic extract, fermented or nonfermented? Viscum is undoubtedly one of the most complex botanicals, yet examination of currently available data allows one to say with much confidence that the future medicinal use of V. album is quite promising.

Fluid extract 1:l (25% alcohol): 0.5 ml three times/day Dried aqueous extract 4:l: 100 to 250 mg three times/day

TOXICITY V; album possesses significant toxicity. Historically, the berries have been regarded as being considerably more toxic than the leaves and stems despite the fact that they all contain similar toxic compounds. The berries are considered to be more toxic probably because of the fatal poisonings of children who ingest the berries. Lethal doses of viscum lectins administered by various routes to mice produce the following two types of toxicity: (1)a typical type characterized by death after 3 to 4 days with marasmus-like symptoms and (2) an atypical type characterized by immediate death from respiratory paralysis.23In mice, the dose that is fatal to 50% of the subjects (LD%)of the plant juice administered intraperitoneally is 32 mg (dry weight)/kg of body weight.29 The LDm values of V. album, either orally administered or in extracts form, have not yet been determined. As stated earlier, alcohol-based extracts contain virtually no viscum proteins. This fact would imply significantly less toxicity with these preparations; however, it would also imply loss of activity, because much of the pharmacology of viscum relates to its protein content, especially immune-enhancing activity. It is interesting to note that the toxicity of Korean mistletoe, Viscum album coloratum, appears to be lower than that of European mistletoe.’J* This other species has also demonstrated anticancer effects, but they appear to be due to highly cytotoxic alkaloids rather than to l e c t i n ~ . Studies ~,~ comparing Korean viscum extracts with European extracts, as well as their alkaloid components, have demonstrated that the Korean mistletoe has greater activity in inhibiting cancer cells. In addition, fresh Korean mistletoe extracts exhibited In the future greater activity than fermented extract~.~JO Korean mistletoe may prove to be superior to European mistletoe.

DRUG INTERACTIONS DOSAGE The standard dose of V.album, based on the British Herbal Pharmacopoeia,38is as follows: Dried leaves: 2 to 6 g (or by infusion) three times/day Tincture 1:5(45% alcohol): 1 to 3 ml three times/day

There is some theoretical concern that mistletoe’s hypotensive effects might be additive with conventional antihypertensive drugs and that its immunostimulant effects could counter immunosuppressant drugs. However, there appear to be no reported clinical cases.

Viscum album (European Mistletoe)

1.Grieve M. A modern herbal. New York, Ny: Dover Publications,

1971:547-548. 2. Becker H. Botany of European mistletoe (Viscum album L.). Onc010g~1986;43:2-7. 3. Anderson LA, Phillipson JD.Mistletoe-the magic herb. Pharm J 1982;229:437439. 4.Khwaja TA, Dias CB, Pentecost S. Recent studies on the anticancer activities of mistletoe (Viscum album) and its alkaloids. Oncology 1986;43:42-50. 5. Jordan E, Wagner H. Structure and properties of polysaccharides from Viscum album (L.). Oncology 1986;43:8-15. 6. Wagner H, Jordan E, Feil 8. Studies on the standardization of mistletoe preparations. Oncology 1986;4316-22. 7. Franz H, Ziska P, Kindt A. Isolation and properties of three lectins from mistletoe (Viscum album L.). Biochem J 1981;195:481-484. 8. Olsnes S, Stirpe F, Sandvig K, Phil A. Isolation and characterization of viscumin, a toxic lectin from Viscum album L. (mistletoe). J Biol Chem 1982;25713,263-270. 9. Petricic J, Kalogjera Z. Isolation of glucosides from mistletoe leaves (Viscum album L.). Acta Pharm Jugosl1980;30:163. 10. Wagner H, Feil B, Kalogjera Z, Petricic J. Phenylpropanes and lignins of Viscum album cardioactive drugs. Planta Medica 1986;2:102. 11. Evans MR, Preece AW. Viscum album-a possible treatment for cancer? Bristol Med Chir J 1973;88:17-20. 12. Klamerth 0, Vester F, Kellner G. Inhibitory effects of a protein complex from Viscum album on fibroblasts and HeLa cells. Hoppe Seylers Z Physiol Chem 1968;349:863-864. 13. Ribereau-Gayon G, Jung ML, Di Scala D, Beck JP.Comparison of the effects of fermented and unfermented mistletoe preparations on cultured tumor cells. Oncology 1986;433541. 14. Hulsen H, Doser C, Mechelke F. Differences in the in vitro effectiveness of preparations produced from mistletoes of various host trees. Arzneimitteforschung 198696433436. 15.Hulsen H, Mechelke F. The influence of a mistletoe preparation on suspension cell cultures of human leukemia and human myeloma cells. Arzneimitteforschung 1982;32:1126-1127. 16. Petkov V. Plants with hypotensive, antiatheromatous and coronarodiiatating action. Am J Chin Med 1979;7:197-236. 17.Hajto T. Immunomodulatory effects of Iscador: a Viscum album preparation. Oncology 1986;4351-65. 18.Jordan E, Wagner H. Detection and quantitative determination of lectins and viscotoxins in mistletoe preparations. Arzneimitteforschung 1986;36:428433. 19. Bloksma N, Dijk HV,Korst P, Willers JM. Cellular and humoral adjuvant activity of a mistletoe extract. Immunobiology 1979;156 309-319. 20. Bloksma N, Schmiermann P, deReuver MD, et al. Stimulation of humoral and cellular immunity by viscum preparations. Planta Med 1982;46221-227. 21. Rentea R, Lyon E, Hunter R. Biological properties of Iscador. A Viscum album preparation I. Hyperplasia of the thymic cortex and accelerated regeneration of hematopoietic cells following X-irradiation. Lab Invest 1981;44:43-48.

22. Hajto T, Lanzrein C. Natural killer and antibody-dependent cellmediated cytotoxicity activities and large granular lymphocyte frequencies in Viscum album-treated breast cancer patients. Oncology 1986;43:93-97. 23.Nienhaus J, Stoll M, Vester F. Thymus stimulation and cancer prophylaxis by Viscum proteins. Experientia 1970;26523-25. 24. Hamprecht K, Handretinger R, Voetsch W, Anderer FA. Mediation of human NK-activity by components in extracts of Viscum album. Int J Immunopharmacol1987;9:199-209. 25. Kleijnen J, Knipschild P. Mistletoe treatment for cancer. Review of controlled trials in humans. Phytomedicine 1994;1:255-260. 26. Janssen 0, Scheffler A, Kabelitz D. In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis). Arzneimitteforschung 1993;43:1221-1225. 27. Heiny BM. [Adjuvant treatment with standardized mistletoe extract reduces leukopenia and improves the quality of life of patients with advanced carcinoma of the breast getting palliative chemotherapy (VEC regimen).] Krebsmedizin 1991;12:3-14. 28. Friess H, Beger HG, Kunz J, et al. Treatment of advanced pancreatic cancer with mistletoe: results of a pilot trial. Anticancer Res 1996;16915-920. 29. Duke JA. Handbook of medicinal herbs. Boca Raton, FL: CRC Press, 1986, pp 512-513. 30.Khwaja TA, Varven JC, Pentecost S, Pande H. Isolation of biologically active alkaloids from Korean mistletoe Viscum album, coloratum. Experientia 1980;36599-600. 31. Manjikian S, Pentecost S, Khwaja TA. Isolation of cytotoxic proteins from Viscum album, coloratum. Proc Am Assoc Cancer Res 1986; 27266. 32.Lyu SY, Kwon YJ, Joo HJ, Park WB. Preparation of alginate/ chitosan microcapsules and enteric coated granules of mistletoe lectin. Arch Pharm Res 2004;27118-126. 33. Grossarth-Maticek R, Kiene H, Baumgartner SM, Ziegler R. Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nomandomized and randomized matchedpair studies nested within a cohort study. Altern Ther Health Med 2001;757-66,68-72,7476. 34. Cazacu M, Oniu T, Lungoci C, et al. The influence of isorel on the advanced coloredal cancer. Cancer Biother Radiopharm 2003;1827-34. 35. Mabed M, El-Helw L, Shamaa S . Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma. Br J Cancer 2004;9065-69. 36. Kovacs E, Kuehn JJ. Measurements of IL-6, soluble IL-6 receptor and soluble gp130 in sera of B-cell lymphoma patients. Does viscum album treatment affect these parameters? Biomed Pharmacother 2002;56152-158. 37.Chemyshov VP, Heusser P, Omelchenko LI, et al. Immunomodulatory and clinical effects of Viscum album (Iscador M and Iscador P) in children with recurrent respiratory infections as a result of the Chemobyl nuclear accident. Am J Ther 2000;7195-203. 38. British Herbal Medicine Association, Scientific Committee. British herbal pharmacopoeia. Cowling, British Herbal Medicine Association, 1983:235-236.

Vitamin A Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 1381 Nomenclature 1381 Recommended Dietary Allowance Dietary Sources 1382

1381

Deficiency 1382 Immune System Effects 1382 Other Effects 1383 Determination of Deficiency 1383 Metabolism 1383 Absorption 1383 Transformation in the Intestinal Mucosa 1383 Transport, Storage, and Excretion 1383 Physiologic Roles of Vitamin A Vision 1384

1384

INTRODUCTION

Growth and Development 1384 Development and Maintenance of Epithelial Tissue 1384 Reproduction 1384 Immune System 1385

Clinical Applications 1385 Viral Illnesses 1385 Skin Disorders 1386 Dry Eyes 1386 Dosage 1387 Toxicity

1387

Drug Interactions 1387

Nomenclature

the retina of the eye. All-trans retinol is found in nature primarily as long-chain retinyl esters. The aldehyde form of all-trans retinol is commonly designated retinaldehyde or retinal, while the acidic form is termed retinoic acid. It has been suggested that retinol serves only as a precursor to these two active forms of vitamin Aretinal being primarily involved with vision and reproduction, and retinoic acid being important in other somatic functions, such as growth and differentiation (Figure 138-1). Synthetic derivatives of retinoic acid have been developed to treat many dermatological conditions and, more recently, certain forms of cancer. Isotretinoin (134s retinoic acid) is used in treating severe cystic acne and disorders of keratinization, such as Darier disease and lamellar ichthyosis. Etretinate, an aromatic derivative of retinoic acid, has no appreciable activity against acne but is claimed to be more potent than isotretinoin in the treatment of psoriasiform diseases. These compounds, however, are not without side effects.'p2

When isolated in its pure form, vitamin A is a pure, lipid-soluble, yellow crystal with a condensed formula C20H290H. Vitamin A is termed retinol, signifying that it is an alcohol that is intricately involved in the function of

Vitamin A was originally measured in international units (IUs), with 1 IU being defined as 0.3 pg of crystalline

Vitamin A was the first fat-soluble vitamin to be recognized. Although identified as a necessary growth factor in 1913, it was not chemically characterized until 1930. The initial discovery of vitamin A was made almost simultaneously by two groups of research workers, McCollum and Davis at the University of Wisconsin, and Osborne and Mendel at Yale University. They found that young animals fed a diet deficient in natural fats became very unhealthy, as evidenced by inability to grow and poor immune function. These researchers also noted that the animals' eyes would become severely inflamed and infected with the restricted diet and that this condition could be quickly relieved by the addition to the diet of either butterfat or cod liver oil. Once known as the "antiinfective vitamin," vitamin A has recently regained recognition as a major determinant of immune status.

Recommended Dietary Allowance

1381

Pharmacology of Natural Medicines

Group

Retinol equivalents

Infants 0-1 year Children 1-3 years

Figure 138-1

International units

375

1875

400

2000

4-6 years

500

2500

7-10 years Young Adults and Adults Males 11+ years

700

3500

1.000

5000

Females 11 + years

800

4000

Pregnancy

800

4000

Forms of vitamin A.

all-trans retinol or 0.6 pg beta-carotene. In 1967, an Expert Committee of the United Nations Food and Agriculture Organization and World Health Organization (FAO/ WHO) recommended that vitamin A activity be referred to in terms of retinol equivalents rather than in IU,with 1 pg of retinol being equivalent to 1 retinol equivalent (RE). The amount of beta-carotene required for 1 RE is 6 pg, whereas the amount required for other provitamin A carotenoids is 12 pg. In 1980, The Food and Nutrition Board of the National Research Council/National Academy of Sciences adopted this recommendation, and the 1980 recommended dietary allowance (RDA) for vitamin A is stated in pg and RE. For the adult male the RDA is set at 1000 RE (750 as retinol and 250 as betacarotene, 5000 IU), whereas that for women is lower at 800 RE (4000 IU). Children need 400 to 1000 RE (2000 to 5000 IU), the amount increasing with growth from infancy to 14 The RDAs for different age groups are shown in Table 138-1.

Food sources of vitamin A Food

Portion size

Meats Beef liver, fried

100 g

Calf liver, cooked

100 g

26,872

Chicken liver, cooked Vegetables Sweet potatoes, baked Carrots, raw

2 livers

25,760

1 medium

14,600

1 large

11,000

Spinach, raw

100 g

8100

Carrots, cooked

lh cup 'h cup 'h cup 'h cup

8000

Pumpkin, cooked Spinach, cooked Collard greens

IlJ/portion 50,375

8000 7300 5400

Broccoli, cooked Fruits Watermelon

lh cup

1900

'he melon

5310

Dietary Sources

Cantaloupe

'14

The most concentrated sources of preformed vitamin A are liver, kidney, butter, whole milk, and fortified skim milk, whereas the leading sources of provitamin A are dark green leafy vegetables (collards and spinach) and yellow-orange vegetables (carrots,sweet potatoes, yams, and squash) (Table 138-2). Ingestion of excessive amounts of liver-2.7 to 11 kg/week-has been reported to cause hypervitaminosis A.4

Apricots, dried

4 halves

2275

Apricots, raw

2-3 medium

2700

Nectarines, raw

1 medium

1650

DEFICIENCY Vitamin A deficiency may be due to inadequate dietary intake (primary deficiency) or to some secondary factor that interferes with the absorption, storage, or transportation of vitamin A. Some factors known to induce a vitamin A deficiency are as follows: Malabsorption due to bile acid or pancreatic insufficiency

melon

3400

Modified from Selhorst JB, Waybright EA, Jennings S, et al. JAMA 1984;252:3365.

Protein-energy malnutrition Liver disease Zinc deficiency Abetalipoproteinemia

Immune System Effects Immune system abnormalitiesassociated with a vitamin A deficiency include impaired ability to mount an effective antibody response, decreased levels of helper T cells, and alterations in the mucosal linings of the respiratory and gastrointestinal tracts. Vitamin A-deficient individuals

Vitamin A

are more susceptible to infectious diseases and have higher mortality rates. It appears that although a vitamin A deficiency may predispose an individual to an infection, vitamin A stores are also severely depleted during the course of an infection. Thus, a vicious circle ensues. Infectious conditions associated with vitamin A deficiency include measles, chickenpox, respiratory syncytial virus (RSV), acquired immunodeficiency syndrome (AIDS), and pneumonia.

Other Effects Prolonged vitamin A deficiency results in the characteristic signs of follicular hyperkeratosis (buildup of cellular debris in the hair follicles, giving the skin a goose-bump appearance, which occurs most often at the back of the upper arm), night blindness, and higher rate of infection. As the condition worsens, the mucous membranes of the respiratory tract, gastrointestinal tract, and genitourinary tract also become affected, and the classic eye disease known as xerophthalmia due to vitamin A deficiency ensues. Even a mild vitamin A deficiency is associated with a significant rise in mortality. This association is extremely significant, because vitamin A deficiency is particularly widespread in developing countries, especially in Asia, where as many as 10 million children have xerophthalmia every

year.'^^,^

Xerophthalmia The term xerophthalmia is generally used to cover all the ocular manifestations of vitamin A deficiency. Blindness is one of the most serious consequences of vitamin A deficiency. Although it rarely occurs in the United States, it is the major preventable cause of blindness in Asia. The xerophthalmia of vitamin A deficiency is staged as shown in Table 138-3.

f the xerophthalmias Staae

Diaanosis

Sians and SymDtoms

xo

Night blindness

Poor dark adaptation

XlA

Xerosis of conjunctiva

Dryness with "lackluster" appearance, thickening, wrinkling, and diffuse pigmentation of conjunctiva

~

X1B

Bitot spots

Usually triangular collections of desquamated, keratinized epithelial cells and mucus

x2

Xerosis of cornea

Dryness of cornea leading to keratinization and a hazy, milky appearance

x3

Keratomalacia

Ulceration, distortion, and softening of the cornea with eventual perforation and iris prolapse and infection

In an effort to prevent vitamin A deficiency in underdeveloped countries, large prophylactic doses (200,000 IU) are given by the WHO to children every 6 months.

Determination of Deficiency The rapid dark adaptation test (see Chapter 29) is perhaps the most sensitive of the currently available tests designed to determine vitamin A deficiency. Measurement of serum retinol levels is usually not useful, because they may not drop until marked deficiency occurs. Deficiency in the United States and other developed countries is usually secondary to malabsorption, liver disease, or proteinuria.'e2

METABOLISM Absorption A variety of factors are known to influence the absorption efficacy of vitamin A and carotenoids. Although retinol does not require bile acids to facilitate absorption, carotenoids do. Other factors that affect vitamin A and carotenoid absorption are as follows: The presence of fat, protein, and antioxidants in the food The presence of bile and a normal complement of pancreatic enzymes in the intestinal lumen The integrity of the mucosal cells The absorption efficiency of dietary vitamin A is usually quite high (80% to 90%), with only a slight reduction in efficiency at high doses. In contrast, beta-carotene's absorption efficiency is much lower (40% to 6O%), and it diminishes rapidly with increasing dosage.'T2 Carotene supplements are better absorbed than the carotenes from foods?

Transformation in the Intestinal Mucosa The majority of absorbed retinol is esterified with palmitic acid or another free fatty acid within the intestinal mucosal cells. It is then incorporated, along with triglycerides, phospholipids, and cholesterol esters, into chylomicra. Each chylomicron is transported through the lymphatic channels into the general circulation and eventually is removed from the circulation by the liver.

Transport, Storage, and Excretion Upon reaching the liver, vitamin A is stored primarily in special perisinusoidal lipocytes (It0 cells); the hepatocytes contain only a minor fraction of the total vitamin A stored in the liver. Although small amounts of vitamin A are found in most tissues (Table 138-4), more than 90% of the total body vitamin A content is stored in the liver. It is stored as a lipoglycoprotein complex consisting of 96% retinyl esters and 4% unesterified retinol. The retinyl esters are hydrolyzed by a tightly bound retinyl ester hydrolase, which transfers the released all-trans

the rods. The three iodopsins, as follows, are in the cones:

Tissue

Vitamin A

Adrenal gland

10.4 k 7.1

Liver

149 k 132

Testis

1.14 k 1.23

+ 1.55

Fat

1.46

Pancreas

0.52 f 0.28

Spleen

0.89 k 0.88

Lung

0.91 & 1.89

Thyroid

0.43 & 0.33

retinol to intracellular retinol-binding protein (RBI'). The bound retinol is then processed through the Golgi apparatus and secreted into the plasma, where it forms a reversible 1:l molar complex with prealbumin.1,2 Adequate dietary protein, iron, and zinc are necessary for proper retinal mobilization. The half-lives of RBP and prealbumin are less than 12 hours, making them particularly likely to be deficient during protein-calorie malnutrition or other situations in which protein metabolism is abnormal. A zinc, iron, or vitamin E deficiency also severely impairs vitamin A metabolism, because these nutrients function synergistically in many physiologic processes of vitamin A metabolism (absorption, transport, and mobilization in partic~lar).~*~fi Retinol is transferred into the cell after RBP binds to a cell surface receptor. The retinol is then quickly bound by cellular retinol-binding protein (CRBP) in the cell cytosol. Retinoic acid is metabolized differently from retinol. It is absorbed through the portal system and transported in the plasma bound to albumin. It does not accumulate in the liver or other tissues in any appreciable amounts. It is metabolized quite rapidly to more polar oxygenated compounds. Intracellularly, it is bound to the cellular retinoic acid-binding protein (CRABP)? Vitamin A metabolites are excreted mainly through the feces (via the bile) and the urine. During periods of deficiency there appears to be an adaptation in utilization, as evidenced by a reduction in the rate of vitamin A

Blue cones (maximum absorption 420 nm) Green cones (maximum absorption 534 nm) Red cones (maximum absorption 563 run) The vitamin A form found in these pigments is the 11-cis isomer of vitamin A aldehyde (retinal). When a photon of light strikes the dark-adapted retina, the 11-cis configuration is converted to the all-trans form of the retinaldehyde and split from the rhodopsin molecule to yield opsin and all-trans retinol. This leads to a change in membrane potential and subsequent visual excitation. During light adaptation, because the visual processes largely depend on the cone cells, the released all-trans retinal or retinol from the rod cells is transported to pigment epithelial cells and stored as retinyl palmitate. During dark adaptation these processes are reversed, and the retinal is isomerized to the 114s form. The rod cells are particularly sensitive to vitamin A deficiency, so night blindness or poor dark adaptation is an early consequence of vitamin A deficiency (see Chapter 29).'f12

Growth and Development Vitamin A is believed to affect growth and development through its necessary role in the synthesis of many glycoproteins (eg., mucus), some of which may control cellular differentiation, and by its function as CRBP in controlling gene expression.'t2 The adhesion between cells is apparently related to glycoprotein synthesis, which is markedly depressed in vitamin A deficiency. Consequently, there is a loss of normal stimuli for cellular growth and differentiation during deficiency. CRBP is transferred directly into the nucleus and may function in a fashion much like some of the steroid hormones. The effects of a vitamin A deficiency most readily seen at the cellular level are in those differentiating tissues that have a rapid turnover rateepithelial cells of the oral cavity, respiratory tract, urinary tract, and ducts of secretory

Development and Maintenance of EpithelialTissue

PHYSIOLOGIC ROLES OF VITAMIN A Vision

The role of vitamin A and carotenoids in the development and maintenance of epithelial tissue cannot be overstated. Vitamin A status determines whether much or keratin is synthesized in epidermal cells-the presence of adequate vitamin A results in mucin production, whereas a lack leads to hyperkeratinization of the skin, cornea, upper respiratory tract, and genitourinary tract. Mucopolysaccharide synthesis also appears to depend on adequate vitamin A status.1,2J0

The best-understood physiological role of vitamin A is its effects on the visual system. The human retina has four kinds of vitamin A-containing photopigments: Rhodopsin, maximum absorption at 498 nm, is present in

The requirement of vitamin A for reproductive functions in higher animals has been known since 1922.*

Reproduction

Vitamin A Beta-carotene has also been reported to have a specific effect in fertility distinct from its role as a precursor to vitamin A."-13 In bovine nutritional studies, cows fed beta-carotene-deficient diets exhibited delayed ovulation and an increase in the number of follicular and luteal cysts."J2 The corpus luteum has the highest concentration of beta-carotene of any organ measured.13The carotene cleavage activity changes with the ovulation cycle, the highest activity occurring during the midovulation stage. It has been speculated that a proper ratio of carotene to retinol must be maintained to ensure proper function of the corpus luteum. The corpus luteum produces progesterone, so inadequate corpus luteum function could have significant deleterious effects. Inadequate corpus luteum secretory function is one of the characteristic features of infertile and/or irregular menstrual cycles.14 Furthermore, an increased estrogen/progesterone ratio has been implicated in a variety of clinical conditions, including ovarian cysts, premenstrual tension syndrome, fibrocystic breast disease, and breast cancer.15Because supplemental betacarotene given to cows significantly reduced the incidence of ovarian cysts (42%in control group vs. 3% in the beta-carotene group), it may have a similar effect in h~mans.'~ Another J~ bovine condition that benefited from higher levels of dietary beta-carotene is cystic mastitis.'* It appears that farmers have a greater appreciation of beta-carotene than many nutitionists. Of course, there are si@cant financial reasons, because the annual monetary loss from bovine mastitis in the United States has been estimated to be at least 1.5 to 2 billion dollars, and ovarian cysts represent the major cause of infertility in cattle.

Immune System Vitamin A is absolutely essential to proper immune function. Vitamin A plays an essential role in maintaining the epithelial and mucosal surfaces and their secretions. These parts of the immune system constitute a primary nonspecific host defense mechanism. Furthermore, vitamin A has been shown to stimulate and/or enhance numerous immune processes, including induction of antitumor activity, enhancement of WBC function, and increase in antibody response.I6These effects are not due simply to a reversal of vitamin A deficiency, because many are further enhanced by (supposedly) excessive amounts of vitamin A. Retinol has also demonstrated significant antiviral activity and has prevented the immunosuppression induced by glucocorticoids, severe burns, and surgery. Some of these effects are probably related to vitamin A's ability to prevent stress-induced thymic involution and to promote thymus growth. The carotenes, which are better antioxidants, may turn out to be even more effective in protecting the thymus gland than vitamin A, because the thymus gland is particularly susceptible to free radical and oxidative damage.

CLINICA L A PPLICAT10 NS Adequate tissue vitamin A levels are vital for optimum health. In addition, this nutient can be used beyond its "physiologic" role in the treatment of various conditions. Supplemental vitamin A is used primarily to enhance the immune system in viral illnesses to treat numerous skin disorders. Natural vitamin A is available as either retinol or retinyl-palmitate. Absorption may be improved via micellization or emulsification. Micellizatzon is the process of making the fat-soluble vitamin A into very small droplets (micelles) so that the material is dispersed in water. Emulsification is the process of suspending vitamin A into a colloidal mixture with another chemical (such as lecithin) so that it can mix with water. Despite manufacturers' claims, it is important to remember that regular vitamin A is absorbed at a rate of 80% to 90%.

Viral Illnesses As discussed previously, vitamin A is absolutely critical to a healthy, functioning immune system. Vitamin Adeficient individuals are more susceptible to infectious diseases in general, but especially viral infections. Although vitamin A deficiency may predispose an individual to an infection, vitamin A stores are severely depleted during an infection.

Measles Vitamin A deficiency is a major problem in many developing countries, in which 5 to 10 million children exhibit severe vitamin A deficiency. A number of well-designed studies have confirmed an effect first noted in 1932vitamin A supplementation can significantly reduce infant mortality due to measles by at least 50%. Typically the dosage of vitamin A in double-blind studies has been 200,000 to 400,000 IU administered only once or twice to replenish body stores."J* The benefit of vitamin A supplementation in the treatment of measles is not limited to developing countries. A study of "well-nourished" children in Long Beach, CA, suffering from measles indicated that 50% were deficient in vitamin A.19 This finding supports the use of vitamin A supplementation even in the United States.

Infants with Respiratory Syncytial Virus Infections Wide-scale immunization programs have reduced the risk of measles in children. However, vitamin A therapy appears appropriate for other childhood viral illnesses. One of the more common viruses is the respiratory syncytial virus (RSV), a common cause of severe respiratory disease in young children. Studies have shown that children with RSV have low serum levels of vitamin A.

Pharmacology of Natural Medicines Furthermore, the lower the vitamin A level, the greater the severity of the disease, similar to the relationship shown in measles. Because vitamin A supplementation diminishes the morbidity and death caused by measles, a group of researchers decided to determine vitamin A's safety and absorption pattern in RSV as a first step in assessing the therapeutic effectiveness.20 Twenty-one children with a mean age of 2.3 months (range, 1 to 6 months) with mild RSV infection were treated with 12,500 to 25,000 IU of oral micellized vitamin A. Baseline vitamin A levels were shown to be low; however, within 6 hours of administration of 25,000 IU, but not 12,500 IU, of vitamin A, normal levels were reestablished. Despite their young age, none of the children experienced any obvious signs or symptoms of vitamin A toxicity. Although the study was not designed as a therapeutic trial, the subjects receiving vitamin A had shorter hospital stays than children with a similar severity of illness who were not enrolled in the study. Although vitamin A supplementation is an attractive treatment of RSV infections because of its low cost, wide availability, and ease of administration, placebocontrolled trials have suggested that it may be of value only in the most severe cases. A placebo-controlled study of 180 children in Chile with RSV provided 50,000 to 200,000 IU of retinyl palmitate (according to age) within 2 days of Supplementation resulted in no significant benefit, except for those children suffering from hypoxemia. These children experienced substantial benefit, consisting of a more rapid resolution of tachypnea and shortening of their hospital stay from 9.3 to 5.5 days. Similar results were seen in a study involving hospitalized pediatric patients with nonspecific upper respiratory infections.22

Acquired Immunodeficiency Syndrome Patients with AIDS may also benefit from vitamin A supplementation. One study showed that a vitamin A deficiency is quite common during human immunodeficiency virus (H.IV) infection and that vitamin A deficiency is clearly associated with a decreased level of circulating helper T cells, one of the hallmarks of AIDS.23 Analysis of vitamin A levels, helper T cells, and other blood parameters in individuals with HIV indicated that more than 15% had low serum vitamin A levels. Helper T-cell levels were much lower in patients with HIV infection whose vitamin A levels were low than in who had normal levels of vitamin A. Vitamin A deficiency was also shown to be associated with a higher rate of mortality due to HIV. Increasing betacarotene may be the preferred form of vitamin A for supplementation in patients with HIV, because of that retinoic acid, the active form of vitamin A, may actually increase HJY replication in humans. Low beta-carotene levels are common in AIDS, presumably as

a result of fat malabsorption. Low beta-carotene levels are associated with greater impairment of immune

Skin Disorders The use of high-dose vitamin A therapy for acne and other skin disorders was introduced in dermatology in the late 1930s. It is still used by a few dermatologists, although this type of therapy is not as popular as before the advent of synthetic retinoids. Vitamin A therapy has been shown to be quite effective in treating skin conditions associated with excessive formation of keratin (hyperkerutosis), a skin protein that can clog the pores of the skin to produce a "goose bump" effect. Examples of some skin conditions associated with hyperkeratosis include acne, psoriasis, ichthyosis, lichen planus, Darier disease, palmoplantar keratoderma, and pityriasis rubra pilaris. The dosages of vitamin A used to treat these conditions have typically been quite high (300,000 to 500,000 IU/day for 5 to 6 months in the treatment of acne; 1 to 3.5 million IU/day for 1 to 2 weeks for the other conditions).s28 The use of these high dosages usually results in the development of significant toxicity (see later). Although there is some evidence that carotenes may be more useful and less toxic in some of these conditions, the pharmacologic activity responsible for the effects of vitamin A in hyperkeratosis is believed to occur when serum retinol levels exceed serum RBP capacity, causing destabilization of membranes and destruction of the keratin-producing cells.24 In monitoring for vitamin A toxicity, laboratory tests appear unreliable until obvious toxicity symptoms are apparent. The first significant toxic symptom is usually headache, followed by fatigue, emotional instability, and muscle and joint pain. Chapped lips (cheilitis) and dry skin (xerosis) generally occur in the majority of patients, particularly in dry weather. Because high doses of vitamin A during pregnancy can cause birth defects, women of child-bearing age should use effective birth control during vitamin A treatment and for at least 1month after discontinuation. High doses of vitamin A may not be necessary if other nutritional factors, like zinc and vitamin E, are included. These nutrients work with vitamin A in promoting healthy skin. A safe and effective recommendation for vitamin A in the treatment of acne is less than 25,000 IU/day.

Dry Eyes Dry-eye disorders are a complex group of diseases characterized by a localized water deficiency in the tear ducts, a mucin deficiency, or a combination of the two. Despite the diversity of underlying causes, the changes in the conjunctiva of the eye are similar in all cases-loss of goblet cells (mucin-producing cells), abnormal enlargement of nongoblet epithelial cells, and increases in cellular layers, keratin deposition and stratification, and keratinization.

Vitamin A Apart from topical vitamin A therapy, all other nonsurgical therapies of dry eye (i.e., the frequent application of artificial tears, lubricants, or slow-releasing polymers, and the therapeutic use of soft contact lenses) are not directed toward reversing the underlying process, but rather toward alleviating the symptoms. The hypothesis that a localized vitamin A deficiency in the lining of the outer eye may be responsible for dry eye, based on vitamin A's vital role in epithelial tissue, seems obvious. Clinical studies featuring commercial vitamin A eye drops (Viva-Drops from Vision Pharmaceuticals) have yielded impressive clinical results in the treatment of dry eye^.*^,^

such as occurs in cirrhosis of the liver, hepatitis, or protein calorie malnutrition, and in children and adolesc e n t ~ .Signs ~,~~ of vitamin A toxicity generally include the following:

DOSAGE

Serum levels of vitamin A between 250 and 6600 IU/dl are typical of toxicity. Prolonged, severe hypervitaminosis A leads to bone fraghty and thickening of the long bone. Toxicity is typically encountered during high-dose vitamin A therapy for various skin conditions.Although dosages smaller than 300,000 IU/day for a few months rarely cause toxicity symptoms, early recognition is still very important. Cheilitis (chapped lips) and xerosis (dry skin) generally appear in the majority of patients, particularly in dry weather. The first sigruficant toxicity symptom is usually headache, followed by fatigue, emotional lability, and muscle and joint pain. Laboratory tests are of little value in monitoring toxicity, because serum vitamin A levels correlate poorly with toxicity, and serum glutamic-oxalo-acetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) values are elevated only in symptomatic ~atients.2~

Dosage ranges for vitamin A reflect the intent of use. For general health purposes, a dosage of 5,000 IU for men and 2,500 IU for women appears reasonable. During an acute viral infection, a single oral dosage of 50,000 IU for 1 or 2 days appears to be safe even in infants (note, however, that women who might be pregnant must not use vitamin A supplements; beta-carotene is fine). For the treatment of acne and hyperkeratotic skin disorders, high-dose therapy may be useful but should be monitored closely by a physician.

TOXICITY Vitamin A supplementation must be avoided during pregnancy, because large doses have been shown to be teratogenic. Unfortunately, the safe dosages for pregnant women have not yet been determined, though combined human and animal data suggest that 30,000 IU/day should be considered safe.3l Nonetheless, women who are at risk of becoming pregnant should keep their supplemental vitamin A levels below 5,000 IU or, better yet, switch to Excess dietary intake of vitamin A has been associated with birth defects in humans in fewer than 20 reported cases over the past 30 years.%Acute toxicity with vitamin, which is most often seen in children as a result of the accidental ingestion of a single large dose of vitamin A (100,000 to 300,000 IU), manifests as follows:' Raised intracranial pressure with vomiting Headache Joint pain Stupor Occasional papilledema Symptoms rapidly subside upon withdrawal of the vitamin, and complete recovery always results.' Vitamin A toxicity may occur in adults who have taken an excess of 50,000 IU/day for several years. Smaller daily doses may produce toxicity symptoms if there are defects in storage and transport of vitamin A

Dry, fissured skin Brittle nails Alopecia Gingivitis Cheilosis Anorexia Irritability Fatigue Nausea

DRUG INTERACTIONS Vitamin E and zinc are particularly important to the proper function of vitamin A. A deficiency of zinc, vitamin C, protein, or thyroid hormone will impair the conversion of provitamin A carotenes to vitamin A. Excessive vitamin A intake can inhibit vitamin Dmediated calcium absorption, accelerate bone loss, and inhibit formation of new bone.%3' All of these actions may raise the risk of osteoporosis and hip fracture. In one prospective study, a vitamin A intake greater than 5000 IU/day, compared with a lower intake, was associated with a reduction in bone mineral density that approximately doubled the risk of hip fracture.% Studies have demonstrated a link between exposure to toxic chemicals and vitamin A nutrition. Administration of compounds such as polybrominated biphenyls, dioxin, and other toxic chemicals to rats leads to decrease in the hepatic content of vitamin A. Concurrent administration of vitamin A and the xenobiotics partially prevents the symptoms of toxicity. Exposure to these compounds results in an increased vitamin A requirement because of the enhanced degradation of vitamin A in the l i ~ e r . ~ ~ , ~

Pharmacology of Natural Medicines

1.Olson R, ed. Nutrition reviews' present knowledge in nutrition, ed 6. Washington, DC:Nutrition Foundation, 1989:96107. 2.Undenvood B. Vitamin A in animal and human nutrition. In Spom M, Robe& AB, DeWitt S, eds. The retinoids, vol 1. Orlando, l% Academic Press, 1984:282-392. 3. Krause MV, Mahan LK. Food, nutrition and diet therapy, ed 7. Philadelphia: WB Saunders, 1984:103-107,224. 4. Selhorst JB,Waybright EA, Jennings S, et al. Liver lover's headache: pseudotumor cerebri and vitamin A intoxication. JAMA 1984; 252:3365. 5. Sommer A, Tanvatjo I, Hussaini G, et al. Increased mortality in children with mild vitamin A deficiency. Lancet 1983;2:585-588. 6.Brown ED, h4icozzi MS, Craft NE, et al. Plasma carotenoids in normal men after a single ingestion of vegetables or purified beta-carotene. Am J Clin Nutr 1989;49:1258-1265. 7. Rahman MM, Wahed MA, Fuchs GJ, et al. Synergistic effect of zinc and vitamin A on the biochemical indexes of vitamin A nutrition in children. Am J Clin Nutr 2002;75:92-98. 8. Muxioz EC, Rosado JL, Lopez P, et al. Iron and zinc supplementation improves indicators of vitamin A status of Mexican preschoolers. Am J Clin NU&2000;71:789-794. 9. Goodman Ds.Overview of current knowledge of metabolism of vitamin A and carotenoids. J Natl Cancer Inst 1984;73:1375-1379. 10. Zile MH,Cullum ME. The function of vitamin A: current concepts. Proc Soc Exp Biol Med 1983;172:139-152. 11. Folman Y, Rosenberg M, Axarelli I, et al. The effect of dietary and climatic factors on fertility, and on plasma progesterone and wstradiol-178 levels in dairy cows. J Steroid Biochem 1983;19: 863-868. 12. Metabolism of beta-carotene by the bovine corpus luteum. Nutr Rev 1983;41:357-358. 13. Lotthammer KH. Importance of beta-carotene for the fertility of dairy cattle. Feedstuffs 1979;51:16-19. 14. O'Fallon JV,Chew BP. The subcellular distribution of betacarotene in bovine corpus luteum. Proc Soc Exp Biol Med 1984;177 406-411. 15. Sherman BM, Korenman SG.Inadequate corpus luteum function: a pathophysiological interpretation of human breast cancer epidemiology. Cancer 1974;33:1306-1312. 16.Semba RD. Vitamin A, immunity, and infection. Clin Infect Dis 1994;19:489-499. 17. Fawzi WW, Chalmers TC, Herrera MG, et al. Vitamin A supplementation and child mortality. JAMA 1993;269:898-903. 18. Hussey GD, Klein M. A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 1990;323:160-164. 19. Arrieta AC, Zaleska M, Stutman HR, et al. Vitamin A levels in children with measles in Long Beach, California. J Pediatr 1992;121:75-78. 20. Neuzil KM,Gruber SC, Chytil F, et al. Safety and pharmacokinetics of vitamin A therapy for infants with respiratory syncytial infections. Antimicrob Agents Chemother 1995;39:1191-1193.

21. Dowell SF, Papic Z, Bressee JS, et al. Treatment of respiratory

syncytial virus infection with vitamin A. A randomized, placebocontrolled trial in Santiago, Chile. Pediatr Infect Dis J 1996;15782-786. 22.Julien MR, Gomes A, Varandas L, et al. A randomized, doubleblind, placebo-controlled clinical trial of vitamin A in Mozambican children hospitalized with nonmeasles acute lower respiratory tract infections. Trop Med Int Health 1999;4794-800. 23. Semba RD, Graham NM, Caiaffa WT, et al. Increased mortality associated with vitamin A deficiency during human immunodeficiency virus type 1infection.Arch Intern Med 1993;1532149-2154. 24. Ullrich R, Schneider T, Heise W, et al. Serum carotene deficiency in HIV-infected patients. AIDS 1994;8:661-665. 25. Kligman AM, Mills OH, Leyden JJ, et al. Oral vitamin A in acne vulgaris. Preliminary report. Int J Dermatol 1981;20:278-285. 26. Thomas JR 3rd, Cooke JP, Winkelmann RK. High-dose vitamin A in Darier 's disease. Arch Dermatol1982;118891-894. 27. Randle HW,Diaz-Perezk,Winkelmann RK. Toxic doses of vitamin A for pityriasis rubra pilaris. Arch Dermatol 1980;116:888-892. 28. Winkelmann RK,Thomas JR 3rd, Randle HW.Further experience with toxic vitamin A therapy in pityriasis rubra pilaris. Cutis 1983; 31~621-632. 29. Rengstorff RH. Topical treatment of external eye disorders with preparations containing vitamin A. Practical Optometry 1993;4 163-165. 30. Westerhout D. Treatment of dry eyes with aqueous antioxidant eye drops. Contact Lens J 1989;19:165-173. 31. Wiegand UW, Hartmann S, Hummler H. Safety of vitamin A: recent results. Int J Vitam Nutr Res 1998;68:411-416. 32. Rothman KJ, Moore LL, Singer MR, et al. Teratogenicity of high vitamin A intake. N Engl J Med 1995;333:1369-1373. 33. Azais-Braesco V, Pascal G. Vitamin A in pregnancy: requirements and safety limits. Am J Clin Nutr 2000;7l(Suppl):1325S-l333S. 34. Hatoff DE, Gertler SL, Miyai K, et al. Hypervitaminosis A unmasked by acute viral hepatitis. Gastroenterology 1982;82124128. 35. Farris WA, Erdman JWJr. Protracted hypervitaminosis. Afollowing long-term, low level intake. JAMA 1982;2471317. 36. Genaro Pde S, Martini LA. Vitamin A supplementation and risk of skeletal fracture. Nutr Rev 2004;62:65-67. 37. Johansson S,Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res 2001;16:1899-1905. 38. Melhus H, Michaelsson K, Kindmark A, et al. Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med 1998;129770-778. 39. Cullum ME, Zile MH. Acute polybrominated biphenyl toxicosis alters vitamin A homeostasis and enhances degradation of vitamin A. Toxicol Appl Pharmacol 1985;81:177-181. 40. Thunberg T,Ahlborg Ug, Wahlstrom B. Comparison of the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxinand six other compounds on vitamin A storage, the UDP-gluconosyltransferase and aryl hydrocarbon hydroxylase activity in the rat liver. Arch Toxicol 1984;55:16-19.

Vitamin Toxicities and Therapeutic Monitoring Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Introduction 1389

LaboratoryTests for Vitamin Toxicity 1392

Vitamin Toxicity 1389 Lipid-Soluble Vitamins 1389 Water-SolubleVitamins 1391

INTRODUCTION When nutrients such as vitamins are being used at high doses for pharmacologic effects, the physician must be vigilant for possible toxicity or side effects. In general, vitamin therapy is virtually "nontoxic" and the small risk of development of any toxicity can be further reduced by careful monitoring of the patient. The physician should also be aware of toxicity resulting from selfadministered vitamins. The primary signs and symptoms of vitamin toxicity are listed in Tables 139-1 and 139-2, which are complemented by a more detailed discussion of toxicity and guidelines for monitoring selected vitamins.

VITA MIN TOXlCITY Lipid-Soluble Vitamins Vitamin A The majority of the cases of hypervitaminosis A involve ingestion of a large quantity at one time by a young child.'T2 Adverse reactions to such ingestion in children can occur with intakes as low as 1,500 IU/kg/daf and are usually transient. Signs of acute hypervitaminosis A include headache (probably resulting from intracranial pressure elevations), nausea, vomiting, occasional dizziness, visual disturbances, and fever. Long-term ingestion of large quantities of vitamins by children, usually a result of administration by a parent, may result in long-lasting changes in bone formation with occasional fractures. Chronic vitamin A excesses can precipitate alopecia, erythema, skin peeling, thickened epithelium, and fatty liver as well as heart, kidney, and testicular defects, anemia, and hypercholesterolemia.Usually, most of the untoward effects of excess vitamin A are resolved with cessation of ingestion. The bone modifications can

be the longest lasting although irrevocable changes are seldom. Some studies also show irreversible liver damage.3 Excessive intake of vitamin A has also been suggested to have a detrimental effect on bone by inducing osteopor~sis.~,~ However, one 9.5-year study involving almost 35,000 postmenopausal women with hip and non hip fractures found little evidence of an increased risk of hip or all fractures with higher intakes of vitamin A or retinol. There was also no evidence of a dose-response relationship in hip fracture risk with increasing amounts of vitamin A or retinol from supplements. Furthermore, the results showed no association between vitamin A ingestion from food and supplements, or food only, and the risk of hip or any other fractures.6 When large doses of vitamin A are being given, careful monitoring is necessary. Rather than sudden ingestion of large doses, a gradual stepwise increase in dosage is indicated, with a symptom evaluation made before the dosage is increased. Usually, the first-recognized symptom of hypervitaminosis is frontal headache. If signs or symptoms appear, supplementation should be discontinued until they disappear. Therapy may be carefully resumed at a lesser dose. Periodic liver enzyme levels should be determined to check for hepatic damage. Typically, serum glutamic-oxalo-acetic transaminase (SGOT) levels are the first to be affe~ted.',~,'sPatients whose liver function is compromised by viral hepatitis, protein-energy malnutrition, cirrhosis, or hemodialysis seem to be the most vulnerable to vitamin A toxicity and to require close m~nitoring.~ Vitamin A levels during pregnancy must be carefully assessed, because both deficiency and an excess can bring about undesirable results. It is known that 1389

Pharmacology of Natural Medicines

Vitamin

Toxic dosaae

Toxic sians and sYmDtoms

Carotene

Long-term: none

No apparent toxicity, even at large doses (250 mg/day); synthetic form may be a problem for heavy smokers not taking other antioxidants

Vitamin A

Short-term: Infants: 75-300,000IU Adults: 2-5million IU Long-term: Infants: 18,000-60,000 IU/day Adults: 100,000 IU/day

Anorexia, bulging fontanelles, hyperirritability, vomiting Headache, drowsiness, nausea, vomiting Premature epiphyseal bone closing, long bone growth retardation Anorexia, headache, blurred vision, loss of hair, bleeding lips, cracking and peeling skin, muscular stiffness and pain, severe hepatic damage and enlargement, anemia, teratogenesis

Vitamin D

Short-term: 1000-3000IU/kg Long-term: 10,000-50,000 IU/day

Anorexia, nausea, vomiting, diarrhea, headache, polyuria, polydipsia Weight loss, pallor, constipation, fever, hypercalcemia, calcium deposits in soft tissues

Vitamin E

Long-term: >BOO IU/day

Severe weakness, fatigue, exacerbation of hypertension, potentiationof anticoagulants

Vitamin K

Long-term: none

Phylloquinone (K,),unlike menadione (K3), is not associated with side effects when given orally

Toxic dosages and side effects of water-soluble vitamins Vitamin

Toxic dosage

Toxic signs and symptoms

Ascorbic acid

Short-term: usually >10 g Long-term: >3 @day

Nausea, diarrhea, flatulence Increased urinary oxalate and uric acid levels in extremely rare cases, impaired carotene utilization, chelation and resultant loss of minerals

Biotin

Long-term: >10 mg/day

No reported side effects from oral administration at therapeutic doses

Folic acid

Long-term: 15 mg/day

Abdominal distension, anorexia, nausea, sleep disturbances (see text)

Niacin

Short-term: >lo0mg Long-term: 3-7g/day

Transient flushing, headache, cramps, nausea, vomiting Anorexia, abnormal glucose tolerance, increased plasma uric acid levels, gastric ulceration, liver enzyme elevations

Niacinamide

Long-term: >lo00mg/day

Same as for niacin

Pantothenic acid

Long-term

Occasional diarrhea

Pyridoxine

Short-term Long-term: 300 mg/day

No acute effects are noted at therapeutic doses Sensory and motor neuropathy

Riboflavin

Long-term

No toxic effects have been noted

Thiamin

Long-term

No toxic effects noted for humans after oral administration

Vitamin B,2

Long-term

No side effects from oral administrationhave been reported

almost all steps in organ formation are controlled by vitamin A-derived retinoic acids.3This fact suggests that vitamin A is indeed necessary for the proper development of embryonic tissues. The main effect of low vitamin A during pregnancy is a deficient vitamin A status for the child at birth and for the following few months. Deficient levels are associated with depressed immune function and higher morbidity and mortality due to infectious diseases such as diarrhea, measles, and respiratory infections. Vitamin A deficiency is also related to an higher rate of mother-to-child transmission

of human immunodeficiency virus type 1 (HIV-l)? Nonetheless, vitamin A has been shown to have teratogenic effects in animals (e.g., resorption of fetus, cleft palate, spina bifida, anencephaly), so supplementation above the recommended dietary allowance (RDA) is not warranted in pregnant, or potentially pregnant, women. According to some studies (see Chapter 71), dosages of vitamin A greater than 10,000 IU during pregnancy (specifically during the first 7 weeks after conception) have probably been responsible for 1 of every 57 cases of birth defects in the United States.

Vitamin Toxicities and Therapeutic Monitoring

Despite the significant growth in production and use of vitamin A supplements over the past 50 years, the number of reported cases of hypervitaminosis A has remained relatively ~onstant.~

Carotenoids Carotenoids appear to be without toxic effects at the therapeutic doses customarily used and are therefore more appropriate than vitamin A for most conditions. The only effect of large dosages of carotenoids is an apparently benign yellowing of the skin. Three large, recent, widely publicized therapeutic trials with synthetic beta-carotene have found that it appears to raise the risk of cancer for heavy smokers. However, several factors complicate the interpretation of these results. The significance of these trials is fully discussed in Chapter 71.

Vitamin D Large doses of vitamin D (e.g., 50,000 IU) are now often used in the initial treatment of osteoporosis. Toxic dosing can also result from overtreatment of hypoparathyroidism or from production by granulomas in certain diseases such as sarcoidosis.1° Toxicity is characterized by hypercalcemia, deposition of calcium into internal organs, and kidney stones. It has also been suggested that long-term overconsumption of vitamin D2 (the synthetic form) in fortified foods contributes to atherosclerosis and heart disease, possibly as a result of diminished magnesium absorption." Generally, single or short-term (i.e., up to 7 days) administration of large doses of vitamin D up to 100,000 IUare well tolerated. For long-term administration, dosages are generally kept below 1200 IU/day.

Vitamin E Although fat soluble, vitamin E has an excellent safety record. Recent clinical trials of vitamin E supplementation at doses as high as 3200 IU/day in a wide variety of subjects for periods of up to 2 years have not shown any unfavorable side effects. Detailed safety assessments have been carried out in several studies. For example, in one double-blind trial in 32 elderly (>60 years old) people, the effect of daily supplementation of 800 IU of D,L-alpha-tocopheryl acetate for 30 days was assessed through measuring general health, nutrient status, liver and kidney function, metabolism, blood cell status, blood nutrient and antioxidant status, thyroid hormones, and urinary function.12The only significant effect noted was an increase in serum vitamin E levels. Vitamin E at this dose was extremely well-tolerated, and no side effects were reported. The results of this study are not surprising and are consistent with a large body of knowledge demonstrating that vitamin E supplementation is extremely safe.

Vitamin K Large doses of the synthetic water-soluble vitamin K3 (menadione), when administered to infants, may cause hemolytic anemia, hyperbilirubinemia, hepatomegaly, and possibly death. Adults with glucose-6-phosphate dehydrogenase (G6PD) deficiency may show hemolytic reactions.13The natural vitamin K1 (phytadione or phylloquinone) does not appear to have any toxicity when given orally, unless huge doses (200 mg) are given.14

Water-Sohble Vitamins Ascorbic Acid Vitamin C has been reported to have perhaps the lowest toxicity of all vitamins. Diarrhea and intestinal distension or gas are the most common complaints when it is consumed at higher dosages. High doses of vitamin C have been shown to have the following effects: Increase the urinary excretion of calcium, iron and manganese Increase the absorption of iron Raise urinary oxalate or uric acid levels, but only in an extremely small subgroup of the population Alter many routine laboratory parameters (e.g., serum B12 aminotransferases, bilirubin, glucose, stool occult blood) The clinician must take these effects into consideration when supplementing with megadoses of vitamin C. One concern with high dosages of vitamin C often cited in the medical literature is the development of calcium oxalate kidney stones. However, numerous studies have now demonstrated that in persons not undergoing hemodialysis or suffering from recurrent kidney stones, severe kidney disease, or gout, high-dose vitamin C therapy will not cause kidney stones. Vitamin C administration of up to 10 g/day has not shown any effect on urinary oxalate levels.15J6 A second, more theoretical concern about vitamin C relates to its excess use in progressive inflammatory diseases such as rheumatoid arthritis and Crohn's disease. It is theorized that available surplus vitamin C may interact with metal ions, eliciting a proantioxidant consequence." Although no clinical information is available to support this thinking, it may be prudent to consider limiting the megadosing of vitamin C in patients with unresponsive or worsening chronic inflammatory conditions and to be cautious of large doses of vitamin C in patients with known iron or copper excess conditions. There have been reports that abrupt cessation of high-dose vitamin C intake leads to "rebound scurvy"; rebound scurvy has also been reported to occur after birth in the babies of pregnant women who have been taking high doses. However, other studies do not support

the existence of rebound scurvy with sudden cessation or after pregnancy with high doses of vitamin C. Although the existence of rebound scurvy is controversial (some experts question its existence), it is better to err on the side of caution. At this time a safe recommendation to pregnant women would be a daily dosage of 500 mg vitamin C.

Folic Acid It has been reported that 8 out of 14 healthy human subjects who consumed 15 mg/day of folic acid for 1month experienced abdominal distension, flatulence, nausea, anorexia, sleep disturbances with vivid dreams, malaise, and irritability.'* This report, however, has not been confirmed in a double-blind clinical study'9 and other Folic acid supplementation appears to be without side effects, even at high doses (e.g., 15 mg/day).

Niacin The acute side effects of niacin are well known. The most common and bothersome is the skin flushing that typically occurs 20 to 30 minutes after the niacin is taken. Long-term consequences of niacin therapy include gastric irritation, nausea, and liver damage. In an attempt to combat the acute reaction of skin flushing, several manufacturers began marketing "sustained-release," "timed-release" or "slow-release" niacin products. These formulations allow the niacin to be absorbed gradually, thereby reducing the flushing reaction. However, although these forms of niacin reduce skin flushing, they have actually proved to be more toxic to the liver. A recent study strongly recommended that the use of sustained-releaseniacin be restricted because of the high percentage (78%)of patient withdrawals from the study due to side effects; 52% of the patients taking the sustained-releaseniacin had liver damage, compared with none of the patients taking immediate-releaseniacinu Because niacin can impair glucose tolerance, it should probably not be used in diabetics unless they are under close observation. Niacin should also not be used in patients with preexisting liver disease or elevation in liver enzyme values, gout, or peptic ulcers. Side effects can occur with any form of niacin, including niacinamide. Although niacinamide does not cause the acute flushing of the skin, it can cause liver damage. Inositol hexaniacin is the safest form of niacin currently available. Both short- and long-term studies have shown it to be virtually free of side effects other than an occasional mild gastric upset or mild flushing of the skin. Regardless of the form of niacin being used, periodic checking (at least every 3 months) of liver function values are indicated when high-dose (i.e., 2 to 6 g/day)

niacin, inostitol hexaniacinate, or niacinamide therapy is being used.

Pyridoxine Vitamin B6 is one of the few water-soluble vitamins that is associated with some toxicity when taken in large doses or in moderate dosages for long periods. Large doses of vitamin B6 are currently being used for a wide variety of conditions. Doses greater than 2000 mg/day can produce symptoms of nerve toxicity (tingling sensations in the feet, loss of muscle coordination, and degeneration of nerve tissue) in some individuals. Long-term intake of dosages greater than 500 mg/day can be toxic if taken daily for several months.24There are also a few rare reports of toxicity occurring at chronic long-term dosages as low as 150 m g / d a ~ . One ~ * ~animal study reports the increased possibility of nerve toxicity in patients with renal failure who have uremia owing to decreased pyridoxine excretion, which induces an increase in susceptibility to pyridoxine-induced neuropathy? Because patients with renal failure are commonly given long-term pyridoxine therapy, caution is advised to look for neuropathic signs in pyridoxine supplemented uremic renal failure patients. Toxicity is thought to be a result of supplemental pyridoxine's overwhelming the liver's ability to add a phosphate group to produce the active form of vitamin B6 (pyridoxal-5-phosphate). As a result, it is speculated either that pyridoxine is toxic to the nerve cells or that it actually acts as an antimetabolite by binding to pyridoxal-5-phosphate receptors, thereby creating a relative deficiency of vitamin B6. It appears to make sense to limit dosages to 50 mg. If more than 50 mg is desired, then the doses should be spread throughout the day. Alternatively, the activated form could be used.

LABORATORY TESTS FOR VITAMIN TOXICITY Only a limited number of routine laboratory tests are available for detecting vitamin toxicity. These are presented in Table 139-3.

Vitamin

Laboratory measurement

Vitamin A

SGOT, serum vitamin A

Vitamin D

Serum calcium

Niacin

SGOT, SGPT

Vitamin C

Urinary oxalate and uric acid

SGOS; Serum glutamic-oxalo-acetic transaminase; SGPT; serum glutamate pyruvate transaminase.

Vitamin Toxicities and Therapeutic Monitoring

1. Miloslav R, ed. CRC handbook series in nutrition and food, section E: nutritional disorders, vol. 1. West Palm Beach, FL: CRC Press, 1978. 2.Omaye S. Safety of megavitamin therapy. Adv Exp Med Biol 1984;177169-203. 3. Perrotta S, Nobili B, Rossi F, et al. Vitamin A and infancy: biochemical, functional, and clinical aspects. Vitam Horm 2003;66:457-591. 4. Feskanich D, Singh V, Willett WC, et al. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002;28747-54. 5.Melhus H, Michaelsson K, Kindmark A, et al. Excessive detary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture.Ann Intern Med 1998;129:770-778. 6. Lim LS, Harnack LJ, Lazovich D, et al. Vitamin A intake and the risk of hip fracture in postmenopausal women: the Iowa Women’s Health Study. Osteoporos Int 2004;15:552-559. 7. DiPalma J, Ritchie D. Vitamin toxicity. Annu Rev Pharmacol Toxicol 1977;17:133-148. 8. Buist R. Vitamin toxicities, side effects and contraindications. Int Clin Nutr Rev 1984;4:159-171. 9. Azais-Braesco V, Pascal G. Vitamin A in pregnancy: requirements and safety limits. Am J Clin Nutr 2000;7l(Suppl):132551333S. 10. Johnson KA, Bernard MA, Funderburg K. Vitamin nutrition in older adults. Clin Geriatr Med 2002;18:773-799. 11.Seelig MS. Magnesium deficiency with phosphate and vitamin D excess: role in pediatric cardiovascular nutrition. Cardio Med 1978; 3:637-650. 12. Meydani SN, Meydani M, Rall LC, et al. Assessment of the safety of high-dose, short-term supplementation with vitamin E in healthy older adults. Am J Clin Nutr 1994;60:704-709. 13. Krupp MA, Chatton MJ. Current medical diagnosis and treatment. Los Altos, CA. Lange Medical, 1984, pp 803-808.

14. Bicknell F, Prescott F. The vitamins in medicine, ed 3. New York Grune & Stratton, 1953:694. 15. Rivers JM. Safety of high level vitamin C ingestion. Int J Vitamin Nutr Res Suppl1989;3095-102. 16. Wanzilak TR, DAndre SD, Davis PA, et al. Effect of high dose vitamin C on urinary oxalate levels. J Urol 1994;151:834-837. 17. Fisher AE, Naughton DE Vitamin C contributes to inflammation via radical generating mechanisms: a cautionary note. Med Hypotheses 2003;61:657-660. 18. Hunter R, Barnes J, Oakeley HF. Toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet 1970;1:61-63. 19. Hellstrom L. Lack of toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet 1971;1:59-61. 20. Sheehy TW. Folic acid. Lack of toxicity. Lancet 1973;1:37. 21. Richens A. Toxicity of folic acid. Lancet 1971;1:912. 22. Boss G, Ragsdale R, Zettner A, et al. Failure of folic acid (pteroglutamic acid) to affect hyperuricemia. J Lab Clin Med 1980;96783-789. 23.McKenney JM, Proctor JD, Harris S. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994;271:672-677. 24. Cohen M, Bendich A. Safety of pyridoxine: a review of human and animal studies. Toxicol Lett 1986;34.129-139. 25. Parry GJ, Bredesen DE. Sensory neuropathy with low-dose pyridoxine. Neurology 1985;35:1466-1468. 26. Waterston JA, Gilligan BS. Pyridoxine neuropathy. Med J Aust 1987;146640-642. 27. Dalton K, Dalton MJ. Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol Scand 1987;76:8-11. 28. Levine S, Saltzman A. Pyridoxine (vitamin B6) toxicity: enhancement by uremia in rats. Food Chem Toxicol 2002;401449-1451.

Vitex agnus castus (Chaste Tree) Donald J. Brown, ND CHAPTER C O N T E N T S General Description 1395 Chemical Composition 1395 History and Folk Use

Premenstrual Syndrome and Cyclical Mastalgia 1397 Hyperprolactinemia 1398 Infertility and Secondary Amenorrhea

1398

1395 Dosage 1398

Pharmacology 1396 Toxicology 1398 Clinical Applications 1396 Corpus Luteum Insufficiency 1396

Vitex ugnus custus (family: Verbenaceae) Common name: chaste tree

Drug Interactions 1399

17-hydroxyprogesterone.Testosterone and epitestosterone were also presumed to be p r e ~ e n tAdditional .~ research is needed.

GENERAL DESCRIPTION Vitex ugnus custus, also known as chaste tree, is a shrub with finger-shaped leaves and slender violet flowers. It grows in creek beds and on river banks in valleys and lower foothills in the Mediterranean and central Asia. The plant blooms in high summer and, after pollination, develops dark-brown to black fruit the size of peppercorns. The fruit possesses a pepper-like aroma and flavor. The ripe, dried fruit of V: agnus custus is the part of the plant used in medicinal preparations today.'

CHEMICAL COMPOSITION The fruit of Vitex contains essential oils, iridoid glycosides, and flavonoids.* The essential oils include limonene, 1,&cineole, and ~ a b i n e n e .The ~ primary flavonoids are castican, orientin, and isovitexin. The two isolated iridoid glycosides are agnuside and aucubin (Figures 140-1 and 140-2): Agnuside serves as a reference material for quality control in the manufacture of Vitex extracts. One study found delta-3-ketosteriods in the flowers and leaves of Vitex. The researchers reported (albeit in a somewhat vague manner) that this fraction of the leaves and flowers "probably" contained progesterone and

HISTORY AND FOLK USE The genus name Vitex is derived from the word vitilium, which means "plaiting." The flexible, but tough and hard, branches were used for construction of wattle fences. Plinius, first century AD, has the earliest reference to the plant as Vitex. The species name u p u s custus originates from the Latin custitus ("chastity") and the equating of the Greek ugnos with the Latin ugnus ("lamb"). V; agnus custus belonged to the official medicinal plants of antiquity and is mentioned in the works of Hippocrates, Dioscorides, and Theophrast. The first specific medicinal indications can be found in the writings of Hippocrates, fourth century BC. He recommends the plant for injuries, inflammation, and swelling of the spleen, and the leaves in wine for hemorrhages and the "passing of afterbirth." In the Corpus Hippocratum he states, "If blood flows from the womb, let the woman drink dark red wine in which the leaves of the chaste tree have been steeped. A draft of chaste leaves in wine also serves to expel a chorion held fast in the womb." Dioscorides attributed to the fruit a hot and astringent activity and recommended it for wild animal bites, swelling of the spleen, and dropsy. Decoctions of the fruit and plant were used as sitz baths for diseases of the uterus. 1395

The English name for V. ugnzis custus, ”chaste tree,” is derived from the belief that the plant would suppress libido in women who took it. In Greek cities, festivals in the honor of Demeter included a vow of chastity by the local women. The Catholic Church in Europe developed a variation on this theme by placing the blossoms of the plant in the clothing of novice monks to supposedly suppress libido. It is interesting to note that another common name for V. ugnus custus, “monk’s pepper,” derived from the fact that monks in southern Europe commonly used the fruit as a spice in their cooking.

PHARMACOLOGY According to Dr Rudolf Fritz Weiss, Vitex acts on the diencephalohypophysial system. Vitex increases production of luteinizing hormone (LH) (Figure 140-3). The result is OH

Figure 140-1 Aucubin.

OH

0 Figure 140-2 Agnuside.

d u

FSH

a shift in the estrogen/progesterone ratio in favor of progesterone. This is, in fact, a corpus luteum-like hormone effect.6The ability of Vitex to increase or modulate progesterone levels in the body is therefore an indirect effect and not a direct hormonal a ~ t i o n . ~ Vitex also modulates the secretion of prolactin from the pituitary gland. In studies with rats, Vitex was shown to inhibit prolactin release by the pituitary glandparticularly in conditions of stress. The mechanism of action appears to involve the ability of Vitex to directly bind dopamine receptors and subsequently inhibit prolactin release in the pituita~y.~,~

CLINICAL APPLICATIONS The causes of menstrual disorders are multifaceted and can vary greatly in manifestations. Frequently, therapeutic interventions must be used on a trial-and-error basis over a number of menstrual cycles to determine their efficacy. Nutritional interventions like vitamin B6, magnesium, and vitamin E, as well as evening primrose oil for cyclical mastalgia, have all shown greater efficacy when used over periods of several months. This characteristic reflects the gradual balancing effect that many of these interventions have on the female hormonal system. Vitex certainly fits this mold. The majority of earlier clinical studies completed with Vitex were uncontrolled studies with large populations of female patients in European gynecology practices. Vitex, which has a Commission E Monograph in Germany, is commonly used in these practices as an initial intervention in a number of menstrual disorders, as follows: Anovulatory cycles Hypermenorrhea Hyperprolactinemia Infertility Mastalgia Polymenorrhea premenstrual syndrome Secondary amenorrhea

Pituitary

Many of these conditions have been linked to corpus luteum insufficiency.

LH

Corpus Luteum lnsufficiency

Prolactin

Figure 140-3 Effect of Vitex on pituitary hormone secretion.

Corpus luteum insufficiency (also referred to as luteal phase defect) is a manifestation of suboptimal ovarian function. In laboratory terms, corpus luteum insufficiency is usually defined as an abnormally low progesterone level 3 weeks after the onset of menstruation (serum progesterone below 10 to 12 ng/ml). This state is normal during puberty and at menopause; however, it is usually considered abnormal in women between ages 20 and 40 years.’O Corpus luteum insufficiency points to abnormal formation of ovarian follicles, an abnormality that may be

Vitex agnus castus (Chaste Tree)

so pronounced that no secondary or tertiary follicles are produced, with a resulting lack of ovulation (anovulation). Corpus luteum insufficiency also leads to a relative deficiency of progesterone. Insufficient levels of progesterone may also result in the formation of ovarian cysts. Corpus luteum insufficiency may give rise to a myriad of menstrual abnormalities. Table 140-1 lists the most common clinical conditions in 1592 women diagnosed with corpus luteum insufficiency. Foremost are hypermenorrhea (heavy periods), polymenorrhea (abnormally frequent periods), and persistent anovulatory bleeding. It is interesting to note that secondary amenorrhea (lack of a period) may sometimes be observed in women with corpus luteum insufficiency. Disturbances of other hormones may also be associated with corpus luteum insufficiency. One study found hyperprolactinemia in 70% of cases." Also noted is an exaggerated response to the thyroid-releasing hormone (TRH) test, which is associated with manifest or latent hypothyroidism.

Premenstrual Syndrome and Cyclical Mastalgia Premenstrual syndrome (PMS) is one of the most common complaints found in gynecology practices. According to some estimates, 30% to 40% of menstruating women are affected by PMS.12 Table 140-2 lists the different subgroups of PMS and the symptoms associated with them. In a double-blind study 170 women (mean age 36 years) with a diagnosis of PMS were randomly assigned to receive either 20 mg of a Vitex extract (dried, ethanolic extract [6-12:1]) or placebo once daily for three menstrual cycles. Twenty-three women were taking oral

The most common clinical conditions in 1592 women diagnosed with corpus luteum insufficiency No. of patients

Percentage of total

418

26.3

Polymenorrhea

369

23.2

Persistent anovulatory bleeding

216

13.6

Secondary amenorrhea

202

12.7

Dysmenorrhea

186

11.7

Anovulatory cycles

175

11.0

Involuntary sterility

Diagnosis Hypermenorrhea

145

9.1

Oligomenorrhea Menorrhagidmetrorrhagia

69

4.3

66

4.1

Irregular menstrual cycles

32

2.0

1

0.1

Primary amenorrhea

contraceptives (11 in the Vitex group and 12 in the placebo group) during the study period. At the end of the treatment period, women taking the Vitex extract had a significantly greater reduction in overall PMS symptom score than those taking placebo ( p < 0.001). Five of the six self-assessment items indicated a significantly greater reduction for the Vitex group with the exception of the item listed "others and bloating," which was measured as unaffected by treatment with Vitex. The Clinical Global Impressions (physician assessment) also showed a significantly greater reduction of PMS symptoms in the Vitex group than in the placebo group ( p < 0.001). The overall responder rate was 52% for the Vitex group compared with 24% for the placebo group.I3 One study compared the efficacy of Vitex (3.5 to 4.2 mg/day of dried fruit extract) with vitamin B6 (200 mg/day) in 175 women with premenstrual tension ~yndr0me.l~ Although both agents were effective (symptom scale decreased from 15.2 to 5.1 in the Vitex group and from 11.9 to 5.1 in the B.5 group), 24.5% Of subjects reported excellent results for Vitex, compared with only 12.1% for B6.However, more than twice as many women (12) reported side effects from Vitex than from B6 (5). Other studies with Vitex for PMS have been uncontrolled or clinical monitoring trials. A monitoring survey of gynecology practices in Germany examined the effect of Vitex on 1542 women with a diagnosis of PMS.I5 The mean age of the patients was 34.7 years, with a range of 13 of 62 years. Additional diagnoses noted in these patients included corpus luteum insufficiency ( n = 1016) and uterine fibroids (n = 170).Patients were instructed to

Subgroups of premenstrual

Prevalence (%)

Subgroup

Svmptoms

PMS-A

Anxiety Nervous tension

75-80

PMS-H

Irritability Fluid retention Weight gain Swollen extremities Abdominal bloating Breast tenderness

60-70

PMS-C

Increased appetite Sweet craving Headache Fatigue Fainting spells

35-40

PMS-D

Depression Insomnia Forgetfulness

30-35

Infertility and Secondary Amenorrhea

Efficacy of Vifex Outcome Patient Assessment improved Relieved

Percentage of patients

57 33

No change

4

No data Physician Assessment Very good/good

5 71

Satisfactory

21

Unsatisfactory

4

No data

3

take 40 drops per day of a Vifexliquid extract. The average duration of treatment was 166 days. The efficacy of treatment was assessed by both patients and their physicians. These assessments are listed in Table 140-3. In more than 90% of the cases, symptoms were completely relieved, with a report of side effects in only 2% of patients (listed in Table 140-3).Only 17 of the 1542 women studied had to stop treatment because of side effects. Improvement in symptoms began after an average treatment duration of 25.3 days. After completion of the monitoring period, 562 patients continued taking Vitex. Similar results have been reported in three uncontrolled ~tudies.’”’~ Another benefit for women taking Vitex for PMS has been reduced cyclical breast pain (mastalgia). A liquid product combining 32.4 mg of Vitex with assorted homeopathic ingredients has been researched for cyclical breast painz0 and is approved in Germany and other countries specifically for that indication. Clinicians should expect it to take three or four cycles for Vitex to work for this condition as well.

Hyperprolactinemia A mentioned previously, Vitex has shown a modulating effect on prolactin. A double-blind, placebo-controlled study examined the effect of Vitex on 52 women with luteal phase defects due to latent hyperprolactinemia. The daily dose of the Vitex extract was 20 mg and the study lasted for 3 months. Hormonal analysis was performed at days 5 through 8 and day 20 of the menstrual cycle before and after 3 months of therapy. After 3 months of therapy, 37 cases were available for analysis (20 placebo and 17 Vitex). Prolactin release was significantly reduced in the Vitex group. Both shortened luteal phases and deficits in progesterone production were normalized. No side effects were noted, and two women in the Vitex group became pregnant.21

Twenty patients with secondary amenorrhea were enrolled in a 6-month study using Vitex liquid extract at 40 drops daily. Laboratory monitoring of progesterone, follicle-stimulating hormone (FSH), and LH values and Papanicolaou smears were performed before the study and at 3 and 6 months. At the end of the study, data were available in 15 patients. The onset of cycles with menstruation was observed with Vitex treatment in 10 of the 15 patients. The hormone values showed increased values for progesterone and LH, but FSH values either did not change or dropped slightlyz A nonblinded, uncontrolled trial studied the effect of Vitex on corpus luteum function in 48 infertile women between 23 and 39 years of age. The inclusion criteria were normal prolactin levels (<20 ng/ml), normal results in the prolactin and thyroid-stimulating hormone (TSH) stimulation tests, and an abnormally low serum progesterone level ( 4 2 . 0 ng/ml on the twentieth day of the cycle). Treatment consisted of Vitex liquid extract, 40 drops daily, without any other medication for 3 months. Fortyfive women completed the trial (3 were excluded because of concurrent hormone use). The outcome of therapy was assessed through evaluation for normalization of the midluteal progesterone level and correction (lengthening) of any preexisting shortening of the phases of the cycle. Treatment was deemed successful in 39 of the 45 patients. Seven women became pregnant, serum progesterone was restored to normal (>12 ng/ml) in 25 patients, and there was a trend toward normalization of progesterone levels in 7 patients.23 A double-blind, placebo-controlled study involving 89 women with infertility, luteal phase defect, or secondary amenorrhea looked at the effect off a liquid Vitex extract (32.4 mg) with homeopathic ingredients on progesterone, LH, and prolactin levels and conception rates over a 3-month span. Of the 66 women evaluated at the end of the study, 31 had normal hormone values. More importantly, 15 women (7 with amenorrhea, 4 with infertility, and 7 with luteal phase defect) conceived during the studyz4

DOSAGE The recommended daily dose for Vitex is a dried or liquid extract delivering the equivalent of 30 to 40 mg of the dried fruit Vitex is typically taken once in the morning before breakfast and should be taken for at least three menstrual cycles to evaluate efficacy.

TOXICOLOGY Human and animal studies have determined Vitex to be safe for most women of menstruating age.

Side effect

No. of patients reporting

No information

7

Nausea

5

Gastric complaints

3

Acne

3

Changes in menses rhythm

2

Diarrhea

2

Erythema

2

Allergy

1

Weight gain

1

Giddiness

1

Heartburn

1

Hypermenorrhea

1

Pruritus

1

Alopecia

1

Cardiac palpitations

1

1.Agni casti fructus (Chastetree fruits). Bundesanzeiger No. 90, May 15, 1985. 2. Agni casti fructus (Chaste tree fruits). Commission E Monograph, December 2, 1992. 3. Kustrak D, Kuftinec J, Balzevic N. The composition of the essential oil of Vitex agnus castus. Planta Med 1992;58:A681. 4. Gomaa CS. Flavonoids and iridoids from V i t a agnus castus. Planta Med 1978;33:277. 5. Saden-Krehula M, Kustrak D, Blazevic N. Delta-3-ketosteroids in flowers and leaves of V i t a agnus castus. Acta Pharmaceutica Jugoslavica 1991;41:237-242. 6. Weiss RF. Herbal medicine. Gothenburg, Sweden: Ab Arcanum, 1988. 7.Amann W. [Elimination of ostipation with Agnolyt.] Ther Ggw 1965;1041263-1265. 8. Sliutz G, Speiser P, Schultz AM, et al. Agnus castus extracts inhibit prolactin secretion of rat pituitary cells. Horm Metab Res 1993; 25253-255. 9. Jarry H, Leonhardt S, Wuttke W. [Agnus castus as dopaminergous effective principle in mastodynon N.] Zeitschrift Phytother 1991;1277-82. 1O.Propping D, Katzorke T, Bekien L. Diagnosis and therapy of corpus luteum deficiency in general practice. Therapiewoche 1988;38:2992-3001. 11. Muhlenstedt D, Wutke W, Schneider HPG. Short luteal phase and prolactin. Int J Fertil1978;23:213-217. 12. Lurie S, Borenstein R. The premenstrual syndrome. Obstet Gynecol SUW1990;45:220-228. 13. Schellenberg R. Treatment of the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study. BMJ 2001;322:134-137. 14. Lauritzen C, Reuter HD, Repges R, et al. Treatment of premenstrual tension syndrome with Vitex agnus castus: controlled, double-blind study versus pyridoxine. Phytomedicine 1997;4:183-189.

Vitex is not recommended for use during and its use during lactation is being questioned owing to its possible dopaminergic actions, which might lead to a suppression of lactation. Safety of Vitex in children has also not been determined. Side effects noted in one large population study are listed in Table 140-4. Common side effects noted in other clinical observations have included urticaria (rash with itching), mild gastrointestinal upset, and intermenstrual bleeding.

DRUG INTERACTIONS Because of theoretical interactions, some authorities suggest that Vitexbe avoided by women taking oral contraceptives or hormone therapy.*' However, two clinical studies have found no adverse interactions in women taking oral contraceptive concomitantlywith Vitex.I3J9 The potential dopaminergic action of Vitex also suggests that it should not be used concomitantly with dopamine antagonist drugs, such as haloperidol and metoclopramide.

15. Dittmar FW,Bohnert KJ, et al. Premenstrual syndrome: treatment with a phytopharmaceutical. Therapiewoche Gynakol1992;5:60-68. 16. Coeugniet E, Elek E, Kuhnast R. Premenstrual syndrome (PMS)and its treatment. Arztezeitchr Naturheilverf 1986;27619-622. 17. Peteres-Welt C, Albrecht M. Menstrual abnormalities and PMS: V i t a agnus-castus. Ther Gynakol 1994;7:49-52. 18. Loch EG, Selle H, Boblitz N. Treatment of premenstrual syndrome with a phytopharmaceutical formulation containing Vitex agnus castus. J Womens Health Gend Based Med 2000;9:315-320. 19. Berger D, Schaffner W, Schrader E, et al. Efficacy of Vitex a p f s castus L. extract ZE 440 in patients with premenstrual syndrome (PMS). Arch Gynecol Obstet 2000;264:150-153. 20. Hal&a M, Beles P, Gorkow C, Sieder C. Treatment of cyclical mastalgia with a solution containing Vita agnus castits extract: results of a placebo-controlled doubleblind study. Breast J 1999;8:175-181. 21. Milewicz A, Gejdel E, Sworen H, et al. [Vitex u p u s castus extract in the treatment of luteal phase defects due to hyperprolactinemia. Results of a randomized placebo-controlled double-blind study.] Arzneimittelforschung 1993;43:752-756. 22. Losh EG, Kayser E. Diagnosis and treatment of dyshormonal menstrual periods in the general practice. Gynakol Prax 1990;14: 489-495. 23. Propping D, Katzorke T. Treatment of corpus luteum insufficiency. Z Allgemeinmed Zeits Allgemeinmedizin 1987;63932-933. 24. Gerhard I, Patek A, Monga B, et al. [Mastodynon" for female infertility.] Forsch Komplementarmed 1998;5272-278. 25. Blumenthal M, Busse WR, et al, eds. The Complete Commission E Monographs. Boston: Integrative Medicine Communications, 1998:108. 26. Blumenthal M, Goldberg A, Brinkmann J, eds. Herbal Medicine: Expanded Commission E Monographs. Newton, MA: Integrative Medicine Communications, 2000:62-64. 27. Bohnert KJ. The use of Vitex agnits castus for hyperprolactinemia. Q Rev Natural Med 1997;Spring:19-21.

Water: The Most Basic Nutrient and Therapeutic Agent Herb Joiner-Bey, ND CHAPTER CONTENTS Introduction

1401

Water and the Human Body 1401 Signs and Symptoms of Dehydration 1402 Thirst: The Sense That Cannot Be Trusted 1402 Ideal Water Intake 1402 Pure Water versus Other Beverages 1402 Water Temperature

1403

Special Needs 1403 Physiology of Water Metabolism 1403 Aquaporins: Getting Water into the Cell Interior 1403 Oxygen Transport 1403 Role of Water in Protein, DNA, and RNA Metabolism 1404 Energy of Hydrolysis 1404

INTRODUCTION Although the therapeutic use of water may appear foolishly simplistic to those schooled in the "high-tech precision of modern medicine, pure water can be of significant value in healing what ails human beings. Pure water has been undervalued as a therapeutic tool because of a number of false assumptions and beliefs, according to Fereydoon Batmanghelidj, MD. Conceptual fallacies held by conventional medicine in regard to the body's need for and use of water are as follows':

Dry mouth is the only or predominant symptom of water need. Water is merely a passive solvent with no chemical properties of its own. The human body can never become depleted of water if it is readily available.

Clinical Applications 1404 Hydration and the Elderly 1404 Winter Hydration 1405 Dehydration and Jet Lag 1405 Multiple Organ System Effects of Chronic Subclinical Dehydration 1405 Subclinical Dehydration (Hypohydration): The Missing Diagnosis 1406 Common Conditions Improved by Water Coronary Heart Disease and Fatal Myocardial Infarction 1406 Hypertension 1407 Peptic Ulcers and Dyspepsia 1407 Asthma and Allergies 1407 Migraine Headache 1407 Chronic Fatigue Syndrome 1408 Concluding Thoughts

1406

1408

The water needs of the body can be easily met by any commercially prepared fluid. All of these beliefs, commonly held by professionals and nonprofessionalsalike, are false. The importance of hydration to health is given recognition in systems of natural medicine, but among naturopathic physicians, pure water's power and potential as an internal healing modality has been widely underutilized.

WATER AND THE HUMAN BODY Water is the predominant compound in the human body. At birth, a baby's body is 78% water by weight. The average young adult is 70% water, and although the body's water content declines with age, water content remains at no less than 50% even in the geriatric patient.

1401

Pharmacology of Natural Medicines During youth, most cells, with the exception of adipose cells, are 90% water. Even bone tissue is 22% water. We tend to take for granted the many fluids and compartments within the body of which water is the major constituent. Any nook not occupied by protein, mineral crystals, fat deposits, cell membrane fatty acids, glycogen stores, or solutes is occupied by water molecules. Water is primarily dispersed in the following compartments: Blood Lymph Perspiration Tears Digestive secretions: gastric juice, bicarbonate with pancreatic enzymes, bile Urine Cerebrospinal fluid Fluid transport channels of peripheral nerves Lubricating fluids: pericardium, pleura, peritoneum Synovial fluid Mucous-lungs, vagina Vitreous humor of eye Cartilage and disks 90% of cell interiors

Signs and Symptoms of Dehydration Clinical dehydration is a serious medical condition that must be treated immediately. Indications are as follows: Fatigue and weakness Headaches Rough, dry skin Dry mucous membranes in nose, mouth, or throat Nosebleeds (especially in dry interior air during winter) Dark, concentrated, strong-smelling urine in small quantities Irritability Irrational behavior Constipation Nausea Intestinal cramps Weak, irregular pulse Low blood pressure Shallow, rapid breathing

Thirst: The Sense That Cannot Be Trusted The osmoreceptors in the hypothalamus are sensitive only to certain solutes in the blood (e.g., sodium) and are insensitive to others (e.g., urea)? Thus, the osmoreceptors are not very accurate gauges of blood solute

concentration and water need at the cell level. The thirst center of hypothalamus, triggered by osmoreceptor reaction to solute concentration, is distinct from the osmoreceptors. Unfortunately for optimal hydration, the sense of thirst in the mouth (dryness) is quickly and easily satiated by small amounts of water stimulating the moisture receptors within the mucus membranes of the mouth, throat, and upper gastrointestinal tract. Although thirst returns fairly quickly if the osmoreceptors and thirst center are only marginally satiated, the body will continue to suffer the ill effects of marginal hydration if a continuous state of optimal hydration is not provided.

Ideal Water Intake Water intake requirements vary according to individual needs and circumstances. For an average individual in moderate temperature and humidity conditions, optimal water intake can be determined by dividingbody weight (in pounds) in half. The resulting number is the number of fluid ounces of pure water the individual should consume daily. For example, a 200-pound person should drink 100 fluid ounces (about 12 &ounce glasses) of pure water each d a ~ . ~ A

PURE WATER VERSUS OTHER BEVERAGES By definition, osmosis is the diffusion of water molecules from a place of relative high concentrationacross a semipermeable membrane to a place of relatively low concentration. The amount of pressure that must be applied against this osmotic movement of water is called osmotic pressure. The difference in water concentration across membranes defines the water concentration gradient across that membrane. Thus, the osmotic pressure is proportional to the concentration gradient. The higher the water concentration on one side of the membrane relative to the other side, the higher the osmotic pressure and the greater the vigor of movement of water molecules across the membrane. Any solutes dissolved in water outside the membrane decrease the water concentration gradient across the membrane and the vigor of water movement. If the concentration of solutes in the exterior water is less than the concentration of solutes in the interior cell water, the concentration of water molecules is greater outside the cell than inside. Therefore, through osmosis, water molecules will move down their concentration gradient from the exterior to the interior, and the cell will be hydrated. Conversely, if the concentration of solutes is higher in the exterior than the interior, water molecules are

Water: The Most Basic Nutrient and Therapeutic Agent in higher concentration within the cell. Therefore water molecules will move out of the cell to lower their concentration gradient from the interior to the exterior. Thus, the cell becomes dehydrated. Obviously, the beverage that has the least amount of solutes and, therefore, the highest osmotic drive to hydrate the body at the cellular level is pure water. If anything is dissolved in water (coffee, tea, sugar, flavorings, colors, protein, etc.), osmosis is reduced. Body and cell hydration are, therefore, inhibited by the consumption of beverages containing solutes. Thus, the basic principles of physiology indicate that pure water is the beverage of choice for optimal hydration of the body?

WATER TEMPERATURE According to the principles of traditional Chinese medicine, the consumption of cold food and drink is a bane of optimal health and wellness among people in Western civilization. The interior temperature of the body is higher than oral, axial, or rectal temperature. For example, the interior temperature of the stomach is about 102" F, and that of the heart is approximately 106" F. These warm temperatures are appropriate for the optimal physiologic functions and biochemical processes that sustain life. The ingestion of large amounts of cold food and beverages tends to inhibit the optimal physiologic functioning of these processes. For this reason, it is prudent to ensure that water consumed is at room temperature or warmer.

SPECIAL NEEDS Particular care must be taken to adequately hydrate people who, because of special circumstances, may need an even greater intake of water than already recommended. These persons include the following: Infants fed high-protein formulas (care should be taken not to overhydrate infants) Persons eating high-protein diets Patients suffering from disorders with symptoms such as fever, vomiting, diarrhea, respiratory discharges, and other avenues of water loss Patients taking diuretic medicines People living in environments with high atmospheric temperatures People engaged in strenuous physical activity, such as athletes and physical laborers Athletes and other individuals performing high-exertion activities should weigh themselves before and after exertion. For every pound of weight lost, they should drink two 8-ounce glasses of pure water to ensure adequate rehydration.

PHYSIOLOGY OF WATER METABOLISM Aquaporins: Getting Water into the Cell Interior Most of the biochemical action in the body occurs within cells. For a cell to be well hydrated, water must overcome the following obstacles: Mucous membrane of gastrointestinal tract Capillary wall Connective tissue Cell membrane The ability to control water intake and release through membranes made of fatty acids is fundamental to the life of human cells. The exact mechanism of water flux through membranes was not discovered until 1992. Aquuporin water channels are the means by which water traverses membranes and satisfy the need for control of water movement. Aquaporins constitute a large family of protein channels that span cell membranes. It has been estimated that an aquaporin can transport up to 3 billion water molecules per second. This system is so efficient that water flow is effectively limited only by the rate of diffusion of water molecules (osmosis).There are at least ten distinct categories of aquaporins, and at least 200 different forms. Aquaporins are found in a wide variety of organisms-humans, animals, bacteria, and plants. The average red blood cell (RBC) may have as many as 150,000 aquaporins on its cellular membrane. At its narrowest point, an aquaporin has a diameter of only 3 angstroms (A). A single water molecule has a diameter of 2.8 A. Therefore the size of the aquaporin opening is just large enough to allow the passage of water and oxygen molecules single file, but small enough to exclude larger ions and molecules. Water influx through aquaporins is inhibited in vitro by the addition of mercury and other heavy metals. A cysteine bonding unit that projects into the pore is the site of inhibition. When a heavy metal bonds to the cysteine unit, the pore is induced to close, terminating the flow of water through that channel. Researchers have concluded that the aquaporin system is Nature's filtration system for purrfylng water before it enters the cell. Operating optimally, the aquaporin system is equipped to handle the flux of water molecules at the rate at which water naturally diffuses without delaying

Oxygen Transport The transport of gase-xygen toward cells and carbon dioxide away from cells-is a bedrock biologic function for all animal species on Earth. Modem physiology has focused on hemoglobin, located inside RBCs, as the

major carrier of oxygen in the body. However, water, the carrier of gases to and from RBCs, plasma, and tissue cells, has received little focused attention. In the alveoli and in tissue capillaries and connective tissue, water is the medium in which the diffusion of gas exchange occurs. Without the ready solubility of oxygen and carbon dioxide in water, gas exchange in living systems would not be possible. Oxygen diffuses from atmospheric air into the water of alveolar tissues and plasma before it associates with hemoglobin in RBCs. After being carried to peripheral tissue capillaries, oxygen dissociates from hemoglobin into the water of plasma and connective tissue and is carried into the cell by water diffusing through membrane aquaporins.

Role of Water in Protein, DNA, and RNA Metabolism Protein is the next most abundant substance, after water, in the body. Protein constitutes the major structural and functional components of every cell, and its range of functions is correspondingly immense. As in the architectural design of buildings, a protein's form is determined by its function. The form of a protein, its three-dimensional shape, is a unique sequence of amino acids determined by the unique sequence of coding genes on chromosomal DNA that initiates the synthesis of that protein.14J5Protein synthesis and the achievement of its active forms cannot take place without the medium of water. Water molecules provide the environment that not only allows proteins to function but also supports their activities in numerous ways. In order to fulfill their respective missions, the amino acid strands of proteins must bend, twist, and contort their primary linear structure into secondary, tertiary, and quaternary forms. The hydrophobic and hydrophilic interactions between water and amino acid strands drive the conformational changes necessary for proteins to realize their ultimate functional shapes. The final shape of a protein is determined by the manner in which water and amino acid strands are bonded to each other. As a lubricating agent, water facilitates the breaking and reestablishment of hydrogen bonds and other links between the various parts of protein. Once the appropriate bonding is in place, water molecules are critical to the continued integrity and stability of protein ~tructure.'~,'~ Because of the flexibility of the bonds among various portions of protein strands, large protein molecules have, under ideal conditions, the flexibility for dynamic action during rapid, life-sustaining biochemical interactions. Flexibility within structural integrity requires optimal hydration of protein, with water molecules serving as flexible, reinforcing,hydrogenbonded bridges between segments of amino acid strands within proteins.

Water is also essential to activity within the nucleus. Chromosomal DNA and messenger RNA (mRNA) are intimately bound to water molecules by hydrogen bonds in a manner that facilitates their critical functions. Even the separation of the matching helical strands of DNA, essential for exposing genome codons for mRNA transcription, is facilitated by water molecules. The structure and function of the endoplasmic reticulum (ER) and transfer RNA (tRNA) are similarly supported. The genetic code defines the structure of proteins by delineating unique sequences of amino acids. Water molecules drive the amino acid strands into their functional shapes using hydrophobic and hydrophilic forces. It can, therefore, be suggested that the DNA genetic code is arranged in a fashion that specifically anticipates the conformational interaction of water molecules required to finish protein-generating tasks. This interdependent interaction among DNA, mRNA, ER, tRNA, protein, and water defines a fundamental biochemical relationship that generates and sustains life.

Energy of Hydrolysis One of the most critical chemical reactions in the body is the liberation of energy stored in adenosine triphosphate (ATP) and creatine phosphate. When cells need to retrieve this stored energy, the high-energy phosphate bonds must be broken by enzymes, which add water molecules to replace the disconnected phosphate groups. For this reason, optimal hydration is essential at the mitochondrial level if energy is to be efficientlyextracted from All' and creatine phosphate. An intracellular water deficit thus inhibits mitochondrial energy production throughout the body.

CLINICAL APPLICATIONS Hydration and the Elderly Dehydration is one of the most common causes of hospitalization among persons older than 65 years. It has been estimated that half of the elderly patients admitted for clinical dehydration die within 1year of admission. The following factors lead to clinical and subclinical dehydration among seniors: Lower percentage of body water Lack of awareness of hydration needs Lack of mental clarity and attentiveness to personal needs Illnesses that accelerate water loss by inducing vomiting, fever, and/or diarrhea Decline of thirst sensation with age As we age, the water content of our bodies declines from a high of about 78% at birth to a low of about 50% in the senior years. Gradual total-body dehydration is

Water: The Most Basic Nutrient and Therapeutic Agent

a hallmark of the aging process. In addition, the preponderance of body water shifts gradually with age from cell interiors to the exterior connective tissue. Long-term chronic disease eventually wears the body down to the point at which patients can no longer ingest water and food; thus, they ultimately succumb to dehydration. To make matters worse, sense of thirst declines with age. The adverse effect of aging on thirst was demonstrated in a study comparing the responses of elderly men (ages 67 to 75 years) and young men (ages 20 to 31 years). After a period of water deprivation, the older men had larger increases in plasma solutes, sodium concentration, and antidiuretic hormone (ADH) levels than the younger men. Yet the older men were less thirsty and drank less after water deprivation than the younger men. The older men did not drink enough to dilute their plasma and urine to pre-dehydration levels. Researchers concluded that after water deprivation, ’Ithere is a deficit in thirst and water intake in healthy elderly men, as compared with younger men.”18 This is true even though the ADH response is maintained. As with other nutritional deficiencies, chronic subclinical dehydration (or hypohydration) contributes to the aging process. In its struggle for survival, the body is designed to adjust metabolic processes to compensate for deficits in nutritional intake, including water, but the adjustment comes at a high price. Energy and biochemical resources, which could have been used to maintain a more youthful tissue integrity and physical vigor, must be redirected. These resources are shifted away from processes that increase longevity toward those that improve the odds for short-term survival. For example, intracellular deficits can impair the functioning of antioxidant enzymes such as catalase and superoxide dismutase. Consequently, free radical damage proliferates, cell and tissue structure, including that of DNA, is compromised, metabolic residues and debris (lipofuscin) accumulate more rapidly within cells, and the process of aging accelerates.

Winter Hydration Although most people try to attend carefully to hydration during hot summer months, many neglect hydration during winter months. This tendency is unfortunate because the human body loses water in many ways during winter. Some are obvious; others are not, as follows: Exercising in cold weather mutes the experience of sweating in many people, deceiving them into thinking their bodies are not losing much water. Cold air cannot hold as much moisture as warm air, so winter air is drier than summer air. The drier air draws more water from the lungs as we breathe, so we exhale more moisture during winter months.

Interior environments are usually very dry in the winter because of the use of dehumidif;ing methods of heating. The lower interior humidity increases water loss from the lungs and the skin. When the body gets chilled, blood is shifted away from the periphery toward the interior organs to preserve vital heat. The shunting of blood to the interior increases renal arterial flow, glomerular filtration rate, and urine output, an effect called cold diuresis. Cold weather raises body metabolism and associated water needs required to maintain healthy body temperature. Respiratory illnesses more typical of winter cause the body to generate large amounts of mucus to rid itself of pathogens. The water in these discharges must be replaced. Intestinal influenza, with diarrhea and vomiting, requires additional water and, perhaps, electrolyte replacement.

Dehydration and Jet Lag The cabin atmospheric pressure of modem passenger jets is equivalent to that found on land at an elevation of 8000 feet above sea level. Although the relative humidity of the Sahara Desert is typically 20% to 25%, the humidity of jet cabin air can be as dry as 1%to 10%. For these reasons, dehydration is a major factor in the experience of jet lag. People traveling in airplanes should keep thoroughly hydrated with pure water and avoid the other beverages offered by flight attendants. It is prudent to drink at least 8 ounces of pure water per hour.

Multiple Organ System Effects of Chronic Subclinical Dehydration The insidious effects of chronic hypohydration are wide-ranging and staggering. Consider the following effects: Cell structural disintegration Impaired flow of nutrients into the cell due to compromised membrane protein channels and insufficient carrier solvent (water) Local tissue resistance to endocrine hormones due to faulty integrity and responsiveness of membrane receptors Chronic fatigue due to lack of enzyme-catalyzed energy produ~tion’~ Free radical damage to cell structures, including DNA, due to reduced enzymatic free radical scavenging Inadequate repair of nuclear DNA damage due to faulty enzyme repair activity Reduced production of key bioactive compounds, such as hormones, digestive enzymes, and neurotransmitters

Pharmacology of Natural Medicines Accumulation of toxins within cells Increased synthesis of histamine within the central nervous system20 Long-term elevations of vasopressin (ADH) Long-term elevations of cortisol with adverse effects on bone integrity, muscle mass, connective tissue, hypertension, and immunity2 The numerous consequences of neglecting optimal hydration can interact in synergistic ways, with tragic results. For example, uncontrolled free radical damage, inadequate DNA repair, and weakened immune response can combine to promote the development of cancer. Faulty membrane receptor construction can contribute to such tissue resistance hormonal disorders as type 11 diabetes mellitus. Errors in receptor synthesis can also lead to mistakes by the immune system, such as misreading of cell membrane proteins as foreign invaders, triggering autoimmune attack. (This last problem is compounded by the inappropriate union of glucose molecules with cell membrane proteins, owing to high intake of refined carbohydrates.)

Subclinical Dehydration (Hypohydration): The Missing Diagnosis Years of research with inmates of an Iranian prison have led Dr.Fereydoon Batmanghelidj to propose that hypohydration at the cellular level is a major contributing factor in many ailments and that the suffering associated with many disorders is triggered or worsened by dehydration. The underlying rationale for Batmanghelidj’s claim is that to alleviate the stress caused by dehydration, the body takes desperate measures to conserve water. Part of dehydration management involves the synthesis and release of histamine. Histamine release appears to activate other systems designed to save body water. ADH reduces water loss in urine. Histamine and kinin compounds influence the escape of water from capillaries into connective tissue. Decreasing blood water content diminishes blood volume and raises plasma sodium concentration, activating the renin-angiotensin system and vasopressin to elevate blood pressure.45 A key concept of Dr.Batmanghelidj’s theory is based on his years of clinical observation and practice with only the simplest, crude healing tools at his disposal. He writes, “Chronic cellular dehydration painfully and prematurely kills. Its initial outward manifestations have until now been labeled as diseases of unknown Recurrent noninfectious conditions associated with pain and discomfort in various parts of the body, which cannot be explained by other identifiable causes, can be interpreted as expressions of water deficits at the sites of tissue manifesting symptoms.4*21

COMMON CONDITIONS IMPROVED BY WATER On the basis of empirical experience, the scope of appli-

cation of water as a therapeutic tool is immense. The only caveat is that kidney filtration must be intact and

healthy to allow excretion of water and accompanying toxins. The following is a list of disorders in which water therapy is indicated: Coronary heart disease Peptic ulcers Arthritis Hypertension Low back pain Intermittent claudication Fibromyalgia Migraine headache Hangover headache Constipation Colitis discomfort Obesity Edema of unknown origin Chronic fatigue syndrome

Coronary Heart Disease and Fatal Myocardial Infarction It has been known for some time that high viscosity of blood and plasma, high hematocrit, and high blood concentrations of fibrinogen are well correlated with coronary heart disease. Even high ”normal” levels of these parameters are considered independent risk factors.22-28 Some researchers consider these factors to be as harmful as smoking, high blood pressure, and high low-density lipoprotein (LDL) cholesterol. Viscosity, hematocrit, and fibrinogen are found to be elevated years before the appearance of major circulatory events. The elevations are also implicated in the early stages and development of atherosclerosis as well as the prognosis of patients diagnosed with atherosclerosis. In addition, these factors have also been linked to intermittent ~laudication.2~ High hematocrit has been associated with tachycardia, magnitude of heart tissue damage from myocardial infarction, reduced oxygen transport, and diminished blood supply to heart tissue. Researchers at the Heart Institute of Loma Linda University analyzed data that had been available to them for 20 years to determine what influence the consumption of pure water and other beverages would have on the risk of fatal myocardial infarction. The database arose from 6 years of monitoring (1976-1982)the lifestyle choices of more than 8000 men and 12,000 women aged 25 and older. The subjects were Seventh Day Adventists (a population that tends to make healthier than average lifestyle choices)and their houseguests. Researchersnoted

Water: The Most Basic Nutrient and Therapeutic Agent

what lifestyle factors seemed to correlate with the 246 fatal myocardial infarctions that occurred in this group during that period. The results were striking. Compared with those who drank 2 or fewer glasses of pure water daily, men who drank 5 or more glasses had only 46%, and women only 59%, of the risk of having a fatal heart attack. Compared with those who drank 2 or fewer glasses of fluids other than pure water, women who drank 5 or more had a 147% greater risk, and men a 46%greater risk. Moreover, these relative risk relationships held regardless of adjustments for any other factors. In essence, consumption of pure water was shown to significantly reduce the risk of fatal heart attack. According to the researchers, who included cardiologists and public health experts, failing to drink enough water can be as harmful to cardiovascular health as smoking. Just by increasing pure water intake, one can reduce risk of death from heart attack by half. This amount of benefit is greater than that gained by ceasing smoking, reducing cholesterol, exercising, or maintaining ideal body weight. According to one researcher, increasing intake of pure water could be the cheapest and simplest method of reducing fatal heart attack risk imaginable.m

Hypertension Dehydration reduces blood volume, and the reduced blood volume in turn lowers blood pressure. This reduction in blood pressure triggers kidney release of renin to restore blood pressure. Renin initiates the conversion of angiotensinogen to angiotensin 11, a powerful vasoconstrictor. This process also enhances salt and water retention by the kidneys. And, of course, the result is elevated blood pressure. Concurrently, ADH (vasopressin) is released by the pituitary to reabsorb water from fluids filtered by kidney glomeruli. This processes increases blood volume and blood pressure. In addition to reducing heart attack risk from coronary artery disease, optimal hydration with pure water can lower stress on the heart and arteries by minimizing stimulation of the renin-angiotensin system and vasopressin. Greater intake of pure water must be a cornerstone of an effective regimen for essential hypertension.

Peptic Ulcers and Dyspepsia Peptic ulcers and dyspepsia were the first conditions that brought hidden, subclinical dehydration to the attention of Dr. Batmanghelidj in the Iranian prison where he practiced. Thousands of cases successfully treated with water therapy lend credence to this modality. Chronic inflammation of the stomach and duodenum with heartburn and acid reflux are prime indications for water intervention. This concept does not seem far-fetched when we remember that the

gastrointestinal mucous membranes must produce sufficient mucus to protect themselves from damage by digestive fluids. All of these secretions are water-based. Hypohydration inhibits both digestion and membrane protection. In addition, water deficits reduce the volume of bicarbonatecontainingfluids released from the pancreas. This deficit results in a failure of proper neutralization of stomach acid, leading to duodenal ulcers.31

Asthma and Allergies Histamine is a prime mediator of allergy and asthma. It is generated in the central nervous system when the body is dehydrated. It is also released by mast cells located on the mucous membranes of the respiratory and gastrointestinal systems. Histamine works with the immune system, facilitating the movement of white blood cells to sites of microbe invasion. Anecdotal evidence, from practitioners and patients across the United States, confirms the efficacy of pure water as a therapeutic agent in these cases. Of course, identifying and eliminating allergens and triggering agents is a major aspect of intervention. Nevertheless, in addition to vitamin BIZ, omega-3 fatty acids, flavonoids, and botanical medicines, pure water should be a key component of regimens for states of hypersensitivity such as asthma and allergy. Of particular note is the new scientific light being shed on exercise-induced asthma. Studies indicate that dehydration during exercise can raise the intensity of asthma symptoms in persons subject to asthmatic attacks. Dehydration can increase spasm of bronchial smooth muscle because of overly dry airway membranes. Dehydration of mucous membranes occurs before the asthmatic athlete even begins training. Dehydrated asthma sufferers begin exercise with reduced hydration capacity; therefore, a pathologic respiratory state occurs more rapidly. Researchers have concluded that "Exercise induced asthma is an exaggerated airway response to airway dehydration." Airway narrowing from exercise in elite athletes and otherwise healthy subjects is now considered a physiologic response to pathologic changes in airway cells resulting from "dehydration injury."32 These changes occur in healthy subjects who are exercising intensely for long periods and who are breathing air that is cold, dry, or both.33 In order to minimize risk of asthmatic attack during exercise, it is imperative for the athlete to be in a state of optimal hydration before training begins and for good hydration status to be maintained throughout the exercise and during recovery. Optimal hydration with pure water is essential for the asthmatic athlete.

Migraine Headache As with allergies and asthma, histamine is believed to be a contributing factor in migraine headache.MHypohydration

Pharmacology of Natural Medicines

induces the central nervous system to increase its synthesis of histamine. Thus, optimal hydration should minimize histamine synthesis as well as associated migraine headache. Anecdotal clinical evidence is also accumulating in support of pure water as a very helpful adjunct to other natural approaches in the treatment of migraine.

CONCLUDING THOUGHTS

Plasma volume is subnormal in up to 52% of patients with chronic fatigue syndrome (CFS). Total blood volume is below normal in up to 63% of patients with CFS. In addition, 90% or more experience delayed orthostatic hypotension, which may be caused by low blood volume. Interestingly, some cases respond well to intravenous fluids. In fact, some patients with CFS recover from total disability after 6 to 9 months of daily IV infusion.21These facts indicate that pure water can be a useful adjunct to other interventions for chronic fatigue.

This chapter merely opens the door of possibility in the mind of the reader to the restorative potential of pure water. New possibilities are being uncovered daily. In Taoism, the major spiritual philosophy indigenous to China, sages encourage us to know the Absolute (the Creator of the Universe) by observing deeply Its creation-Nature. We take for granted so much that is precious. We may note the wild flowers in the field, but we are oblivious to the moist, nutrient-rich soil that allows them to flourish. Water is the most underappreciated healing tool at our disposal. As humanity is being forced by health crises to revisit the healing power of Nature, its traditional medical "roots," let us be constantly mindful of what nourishes those roots. As Dr.Batmanghelidj and his colleagues at the Foundation for the Simple in Medicine implore, let us use pure water as the foundation of health and wellness it was intended to be.

1. Meyerowitz S. Water: The ultimate cure. Summertown, TN: Book Publishing, 2001:7. 2.Beme RM, Levy MN. Principles of physiology, ed 3. St. Louis: Mosby, 2000:418,434-454. 3. Batmanghelidj F. Your body's many cries for water. Vienna, VA: Global Health Solutions, 1997. 4. Batmanghelidj F. ABCs of asthma, allergies and lupus. Vienna, VA: Global Health Solutions, 2ooO. 5. Borgnia M, Nielsen S, Engel A, Agre P. Cellular and molecular biology of the aquaporin water channels. Annu Rev Biochem 1999;68:425-458. 6.Echevarria M, Ilundain AA. Aquaporins. J Physiol Biochem 1998;54:107-118. 7. King LS,Agre P. Pathophysiology of the aquaporin water channels. Annual Rev Physiol1996;58:619-648. 8. Ma T, Verkman AS. Aquaporin water channels in gastrointestinal physiology. J Physiol1999;517317-326. 9.Venero JL, Vizuete ML, Machado A, Can0 J. Aquaporins in the central nervous system. Prog Neurobiol2001;63321-336. 10. Verkman AS, Mitra AK. Structure and function of aquaporin water channels. Am J Physiol Renal Physiol2000;278:F13-F28. 11. Verkman AS, Matthay MA, Song Y. Aquaporin water channels and lung physiology. Am J Physiol Lung Cell Mol Physiol 2000;278 L867-L879. 12. Van 0s CH, Kamsteeg EJ, Marr N, Deen PM. Physiological relevance of aquaporins: luxury or necessity? Pflugers Arch 2ooO;440:513-520. 13.Yamamoto T, Sasaki S. Aquaporins in the kidney: emerging new aspects. Kidney Int 1998;54:1041-1051. 14. Champe P, Harvey R. Lippincott's illustrated reviews: biochemistry, ed 2. Philadelphia: JB Lippincott, 199413. 15.Garrow JS, Ralph JA, eds. Human nutrition and dietetics, ed 10. London: Churchill Livingstone, 2000:149. 16.Chaplin M. Water Structure and Behavior. School of Applied Sciences, South Bank University, UK.Available online at wuwsbu. ac.ukhuft-r [accessed March 25,20031.

17. Watterson JG. The role of water in cell architecture. Mol Cell Biochem 1988;79101-105. 18. Phillips PA, Rolls BJ, Ledingham JG, et al. Reduced thirst after water deprivation in healthy elderly men. N Engl J Med 1984 Sep 20;311:753-759. 19.Streeten D, Bell D. Circulating blood volume in chronic fatigue syndrome. J Chronic Fatigue Syndr 1998;43-12. 20. Kjaer A, Larsen PJ, Knigge U, Warberg J. Dehydration stimulates hypothalamic gene expression of histamine synthesis enzyme: importance for neuroendocrine regulation of vasopressin and oxytocin secretion. Endocrinology 1995;1362189-2197. 21. Batmanghelidj F. Pain: a need for paradigm change. Anticancer Res 1987~7971-989. 22.de S i o n e G, Devereux RB, Chien S, et al. Relation of blood viscosity to demographic and physiologic variables and to cardicvascular risk factors in apparently normal adults. Circulation 1990;81:107-117. 23. Lowe GD, Lee AJ, Rumley A, et al. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol 1997;96:16&173. 24. Lee AJ, Mowbray PI, Lowe GD, et al. Blood viscosity and elevated carotid intima-media thickness in men and women: the Edinburgh Artery Study. Circulation 1998;971467-1473. 25. Lowe GD, Drummond MM, Lorimer AR, et al. Relation between extent of coronary artery disease and blood viscosity. Br Med J 1980;280673-674. 26.Koenig W, Emst E. The possible role of hemorheology in atherothrombogenesis. Atherosclerosis 1992;9493-107. 27. Erikssen G, Thaulow E, Snadvik L, et al. Haematocrit: a predictor of cardiovascular mortality? J Intern Med 1993;234:493499. 28. Resch KL, Emst E, Matrai A, et al. Can rheologic variables be of prognostic relevance in arteriosclerotic diseases? Angiology 1991;42963-970. 29. Kannel WB,McGee DL. Update on some epidemiologic features of intermittent claudication: the Framingham Study. J Am Geriatr Soc 1985;33:13-18.

Chronic Fatigue Syndrome

Water: The Most Basic Nutrient and Therapeutic Agent 30. Chan J, Knutsen SF, Blix GG, et al. Water, other fluids, and fatal coronary heart disease: the Adventist Health Study. Am J Epidemiol2002;155827-833. 31. Batmanghelidj F. A new and natural method of treatment of peptic ulcer disease. J Clin Gastroenterol 1983;5:203-205. 32. Medrala W, Wolanczyk-Medrala A, Tomkowicz T, et al. [Pathogenesis of exercise induced asthma.] Pol Merkuriusz Lek 2001;11:203-205.

33. Anderson SD, Holzer K. Exercise-induced asthma: is it the right diagnosis in elite athletes? J Allergy Clin Immunol 2000;106: 419-428. 34. Pizzorno J, Murray M, eds. Textbook of natural medicine, ed 2. London: Churchill Livingstone, 1999:1401-1412.

Zinpiber officinale(Ginger) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 1411 Chemical Composition 1411 History and Folk Use 1412 Pharmacology 1412 Antioxidant Effects 1412 Effects on Prostaglandin and Leukotriene Metabolism 1412 Effects on Platelets and Fibrinolysis 1413 Cholesterol-Lowering and Hepatic Effects 1413 Cardiotonic and Hypotensive Properties 1413 Analgesic Effects 1413

Zingiber oficinale (family: Zingiberaceae) Common name: ginger

GENERAL DESCRIPTION Ginger is an erect perennial herb with thick tuberous rhizomes (underground stems) from which the aerial stem grows to a height of 2 to 4 feet. Grasslike alternate leaves, 6 to 12 inches long and 0.75 inch wide, shoot off from the aerial stem. Wild ginger produces a beautiful flower, but cultivated ginger rarely flowers. Although ginger is native to southern Asia, it is now extensively cultivated throughout the tropics (e.g., India, China, Jamaica, Haiti, and Nigeria). Jamaica is the major producer, with exports to all parts of the world amounting to more than 2 million pounds annually. The knotted and branched rhizome, commonly called the "root," is the portion of ginger used for culinary and medicinal purposes. Extracts and the oleoresin are produced from dried unpeeled ginger, because peeled ginger loses much of its essential oil content.'f2 Ginger oil is produced from the fresh ginger via steam distillation.

Gastrointestinal Smooth Muscle Effects 1413 Antiulcer Effects 1413 Thermogenic Properties 1413 Antibiotic Activity 1414 Anticancer Effects 1414

Clinical Applications 1414 Motion Sickness 1414 Nausea and Vomitina 1415 Inflammatory Condigons 1415 Dosage 1416 Toxicology

1416

CHEMICAL COMPOSITION The following compounds have been isolated from ginger? Starch (up to 50%) Protein ( ~ 9 % ) Lipids (6% to 8%)composed of triglycerides, phosphatidic acid, lecithins, and free fatty acids A protease (2%) Volatile oils (1%to 3%), the principal components of which are sesquiterpenes (bisabolene, zingiberene, and zingiberol) and various "pungent" principles, aromatic ketones, known collectively as gingerols vitamins (especially niacin and vitamin A) Resins The pungent principles are thought to be the most pharmacologicallyactive components of ginger. Gingerol and its derivatives can be found in concentrations as high as 33% in ginger oleoresin (Figure 142-1). The fresh oleoresin will have a higher percentage of the more pungent gingerol, as gingerol can be dehydrated during storage to form shogaol or have its fatty acid moiety cleaved to form zingerone (Figures 142-2 and 142-3). 1411

Pharmacology of Natural Medicines Ginger is widely used as a spice, especially in Asian and Indian dishes. It is also used in many baked goods, beverages (ginger ale), candy, liqueurs, and cosmetic products (perfumes, soaps, creams, etc.). C

- CH,

- CH

I

II

OH

0 Flgure 142-1 Gingerol.

C -CH,

II

0 Figure 142-2 Zingerone.

PHARMACOLOGY Ginger possesses numerous pharmacologic properties; the following are most relevant: Antioxidant effects Inhibition of prostaglandin, thromboxane, and leukotriene synthesis Inhibition of platelet aggregation Cholesterol-lowering actions Choleretic effects Cardiotonic effects Gastrointestinal actions Thennogenic properties Antibiotic activities

Antioxidant Effects

C - CH=CH

II 0 Figure 142-3 Shogaol.

The oleoresin is made by extracting the oily and resinous materials with the aid of a solvent (alcohol, hexane, or acetone).

HISTORY AND FOLK USE Ginger has been used for thousands of years in China for medicinal purposes. Chinese records dating from the fourth century BC indicate that it was used to treat the following conditions': Stomach ache Diarrhea Nausea Cholera Hemorrhage Rheumatism Toothache

It was used by Eclectic physicians in the United States in the late 1800s as a carminative, diaphoretic, appetite stimulant, and local counterirritant?

Ginger has shown antioxidant effects in experimental studies! In a study in rats, ginger sigruficantly lowered lipid peroxidation by maintaining the activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. The blood glutathione content was significantly increased in ginger-fed rats. To achieve a similar effect with vitamin C, the dosage required was 100 mg/kg body weight? Ginger's strong antioxidant properties have led to its being investigated for preventing the development of rancidity in meat products6 Ginger has been shown to prolong the shelf life of fresh, frozen, and precooked pork patties. Because the use of many synthetic antioxidants is prohibited by law, ginger may one day be used commercially to extend the shelf life of meats and other foods.

Effects on Prostaglandin and Leukotriene Metabolism Numerous constituents in ginger have been shown to be potent inhibitors of prostaglandin and leukotriene synthesis through blocking of the cyclooxygenase enzymes.'-'* The most potent components appear to be the pungent principles, although the aqueous extract has also demonstrated inhibition. Inhibition of prostaglandin and leukotiene formation could explain some of ginger's historical use as an antiinflammatory agent. However, ginger and its extracts also have strong antioxidant activities, and fresh ginger contains a protease with action that may be similar to that of other plant proteases (e.g., bromelain, ficin, papain) on inflammation.'

Effects on Platelets and Fibrinolysis Ginger, like garlic and onions, is an inhibitor of platelet aggregation.'O However, ginger's effects may be far more powerful. In a comparison, an aqueous extract of ginger was shown to exert greater inhibitory effects on platelet aggregation than aqueous garlic and onion extract^.'^ Ginger was shown to produce a greater inhibition on thromboxane formation and proaggregatory prostaglandins. Ginger, but not onion or garlic, also significantly reduced platelet lipid peroxide formation. In another model, gingerol compounds and their derivatives were more potent antiplatelet agents than aspirin.'O The superiority of ginger over onions was also demonstrated in a controlled study.I4Female volunteers given either 70 g raw onions or 5 g raw ginger demonstrated that ginger has a pronounced effect in lowering platelet thromboxane production, whereas onion actually produced a mild elevation (pooled results). In addition to acting on platelets, ginger promotes fibrinolysis. In one study, administration of 50 g of fat to 30 healthy adult volunteers decreased fibrinolytic activity from a mean of 64.20 to 52.10 units.15Supplementation of 5 g of ginger powder with the fatty meal not only prevented the drop in fibrinolytic activity but actually increased the activity sigruficantly.

Cholesterol-Lowering and Hepatic Effects Ginger has been shown to significantly reduce serum and hepatic cholesterol levels in cholesterol-fed rats by impairing cholesterol absorption as well as stimulating cholesterol-7-alpha-hydroxylase,the rate-limiting In addition, ginger has enzyme of bile acid been shown to increase bile se~retion.'~ Therefore, ginger works to lower cholesterol by promoting excretion and impairing absorption.

Cardiotonic and Hypotensive Properties Gingerol has shown potent cardiotonic activity (positive inotropic and chronotropic effects) on isolated guinea pig left atria.20,21 These effects are a result of acceleration of calcium uptake by the sarcoplasmic reticulum. Gingerol was the first substance shown to produce these effects. Individuals with heart problems or high blood pressure are probably better off using fresh ginger rather than the dried preparation. This recommendation is based not only on the fact that gingerol is the more potent cardiotonic but also on the demonstration that shogaol has a blood pressure-elevating effect in animals.22Gingerol is found predominantly in fresh ginger, whereas shogaol is rarely found in dried ginger.

Analgesic Effects Ginger has demonstrated analgesic effects in experimental studies in animals.= This effect is thought to be

a result of inhibition by shogaol of the release of substance P much like that by capsaicin, the pungent principle of red pepper (Capsicum frutescens).

Gastrointestinal Smooth Muscle Effects One interesting aspect of ginger is its ability to simultaneously improve gastric motility and exert antispasmodic effects. This action is consistent with its use as a gastrointestinal tonic. A lipophilic ginger extract was shown in one study to enhance gastric motility, as evidenced by increased intestinal transport of a charcoal meal fed to rats," and various fat-soluble components of ginger, such as galanolactone, demonstrated antagonism of serotonin receptor sites.25This latter mechanism may be responsible for ginger's antispasmodic effects on visceral and vascular smooth muscle. Ginger has also been shown to inhibit serotonin-induced diarrhea and exert anti-emetic effects in experimental m o d e l ~ . 2 ~ * ~ ~ Ginger also prevents the slow wave dysrhythmias produced by acute gastrointestinal hyperglycemia via inhibition of prostaglandin production.28Oral ginger extract was also shown to improve gastroduodenal motility in the fasting state and after a standard test meal in healthy human ~olunteers.2~

Antiulcer Effects Ginger has demonstrated sigruficant antiulcer effects in a variety of animal m 0 d e l s . 3 ~Ginger ~~ prevents ulcer formation due to ethanol, indomethacin, aspirin, and other common ulcerogenic compounds. The pungent principles appear to be responsible for this effect. Interestingly, in one study, roasted ginger inhibited ulcer formation in three gastric ulcer models, but dry ginger had no such effect.% A methanol extract of the dried powdered ginger rhizome, fractions of the extract, and the isolated constituents, gingerol and shogaol, were tested against 19 strains of Helicobacter pylori-a bacterium associated with peptic ulcers and gastric cancer. The methanol extract of ginger rhizome inhibited the growth of all 19 strains in vitro with a minimum inhibitory concentration range of 6.25 to 50 pg/ml. One fraction of the crude extract, containing the gingerols, was active and inhibited the growth of all strains with a minimum inhibitory concentration (MIC) range of 0.78 to 12.5 pg/mLX

Thermogenic Properties Ginger is noted for its apparent ability to subjectively warm the body and has historically been used as a diaphoretic. In animal studies, ginger has been shown to help maintain body temperature and to inhibit serotonininduced hypothermia.26s Crude extracts and the pungent components of ginger have been shown to increase oxygen consumption,

follow-up studies have evaluated the effectiveness of ginger as a motion sickness medication. The appearance of motion sickness trials using ginger prompted an interest in ginger by the National Aeronautics and Space Administration (NASA), which subsequently funded a study at Louisiana State University. This study compared ginger, both fresh and dried powdered, with scopolamine by measuring the number of head movements experimental subjects could make in a rotating chair until they reached an end point defined as motion sickness short of vomiting. Ginger was not shown to produce any protection against motion sickness in this model or in two additional protocols (vestibular stimulation only and combined vestibular-visual stimulation)." However, in perhaps a more "real life'' test, ginger (1 g) given to naval cadets unaccustomed to sailAntibiotic Activity ing in heavy seas was shown to reduce the tendency to vomiting and cold sweating in comparison with a Ginger, shogaol, and zingerone have been shown to be placebo in a double-blind trialj3 strongly inhibitory against Salmonella typhi, Vibrio cholerue, Mowrey and Clayson41proposed that the anti-motion and Trichophyton violaceurn, whereas aqueous extracts at 2.5%,5%, and 25%concentration have been shown to be sickness effects of ginger were due to local gastrointestinal tract effects rather than to central nervous system effective against Trichornonas vaginalis.38 Ginger and its (CNS)effects. Although ginger's mechanism of action in pungent principles were also demonstrated to possess sigruficant antifungal activity against pathogenic y e a ~ t . 3 ~ alleviating gastrointestinal distress has yet to be fully elucidated, there is evidence to support this hypothesis. Anticancer Effects Ginger has been shown to partially inhibit the excessive gastric motility characteristic of motion sickness." To Ginger extracts and some pungent constituents present further support a gastric versus a CNS mechanism of in ginger have exhibited anti-tumor-promoting activity action, one study clearly demonstrated that neither the in experimental models of carcinogenesis.40 vestibular system nor the oculomotor system, both of which are critical in the Occurrence of motion sickness, CLINICAL APPLICATIONS was influenced by ginger (1g).44However, in a doubleblind cross-over placebo-controlled study, ginger (1 g) Ginger is widely used as a condiment for its unique flawas shown to significantly reduce induced vertigo, but vors, but from the previously described pharmacology, not ny~tagmus.4~ it obviously has important medicinal effects as well. It has been hypothesized by others that ginger ameIn general, like many other culinary herbs and spices, liorates the nausea associated with motion sickness such as garlic and onions, ginger provides many healthby preventing the development of gastric dysrhythmias promoting effects. Specifically, ginger provides benefit to and the elevation of plasma vasopressin. To test this many body systems, including the digestive, hepatobilhypothesis, 13 volunteers with a history of motion sickiary, and cardiovascular systems. ness underwent circular vection, during which nausea Historically, the majority of complaints for which (scored 0 to 3, i.e., none to severe), electrogastrographic ginger was used concerned the gastrointestinal system. recordings, and plasma vasopressin levels were assessed A clue to ginger's efficacy in alleviating gastrointestiwith or without ginger pretreatment in a cross-over, nal distress is offered in several double-blind studies in double-blind, randomized, placebo-controlled study.& motion sickness, hyperemesis gravidum, and postoperaCircular vection induced a maximal nausea score of tive nausea and vomiting. Human studies have also 2.5 and increased tachygastric activity and plasma vasoshown a positive effect in arthritis and migraine pressin. Pretreatment with ginger (1000 and 2000 mg) headaches. These studies are discussed below. effectively reduced nausea, tachygastric activity, and Motion Sickness vasopressin release induced by circular vection. The overall effectiveness of ginger in motion sickness Ginger was first shown to be effective in treating has yet to be definitively determined. Issues that the motion sicknessby Mowrey and C l a y ~ o nin~1982. ~ In their studies have raised include the variability in the quality study, ginger (940 mg) was shown to be far superior to of commercial ginger preparations and the time required Dramamine (100mg) in relieving symptoms of nausea and for ginger to produce its effects. Commercial preparations vomiting. Since this initial study, several better-designed

perfusion pressure, and lactate production in the perfused rat hind limb.% These effects signify increased thermogenesis. Gingerol is the most potent thermogenic component of ginger. A human study demonstrated that consuming a ginger sauce (containing unspecified amounts of ginger principles) with a meal had no sigxuficant effect on metabolic rate.37However, there were two problems with this study: (1)the concentration of gingerol in the preparation used was probably low or zero and (2) the effective concentration range of gingerol for its thermogenic effects is quite narrow. Given ginger's historical use as a "warming" substance, these scientific investigations appear to support its use as a diaphoretic and thermogenic aid, although confirmation in humans is still lacking.

Zingber officinale (Ginger) ~

vary widely in chemical composition and often contain adulterants, and in the ginger study conducted at sea, ginger reduced symptoms of cold sweating and vomiting only at the end of 4 hours. In other words, it appears that ginger may prove to be more effective when welldefined preparations are given at least 4 hours before motion is experienced.

Nausea and Vomiting

ginger and the comparison groups were the numbers of low-birth-weight infants (< 2500 g)-only 3 in the ginger group compared with 12 in the comparison The antiemetic action of ginger has also been observed in women who had undergone major gynecologic surgery. In two double-blind studies, 1000 mg of dried powdered ginger root was shown to significantly reduce the incidence of nausea compared with placebo in a manner similar to the drug meto~lopramide.~~5~

Ginger’s antiemetic action has been studied in hyperemeInflammatory Conditions sis gravidum, the most severe form of pregnancy-related Ginger’s ability to inhibit the formation of inflammatory nausea and vomiting. This condition usually requires prostaglandins, thromboxanes, and leukotrienes, along hospitalization. In a double-blind randomized cross-over with its strong antioxidant activities and protease trial, ginger root powder at a dose of 250 mg four times a component, suggests a possible benefit in inflammatory day brought about a sigruficant reduction in both the conditions. To test this hypothesis, a preliminary clinical severity of the nausea and the number of attacks of vomstudy was conducted in seven patients with rheumatoid iting in 19 of 27 cases of early pregnancy (< 20 arthritis, in whom conventional drugs had provided Another natural approach to nausea and vomiting of pregnancy is vitamin Bg.In one double-blind study, 138 only temporary or partial relief.% One patient took 50 g/day of lightly cooked ginger, and the other six took women were given either 500 mg of ginger or 10 mg of either 5 g of fresh or 0.1 to 1g of powdered ginger daily. vitamin B6three times daily for 3 days.&Subjects graded All patients reported substantial improvement, includthe severity of their nausea using visual analog scales ing relief of pain, greater joint mobility, and decreased before treatment and recorded the number of vomiting swelling and morning stiffness. episodes in the previous 24 hours and again during three In the follow-up to this study, 28 patients with consecutive days of treatment. The ginger and Vitamin B6 rheumatoid arthritis, 18 with osteoarthritis, and 10 with sigruficantlyreduced the nausea scores from 5 to 3.6 and muscular discomfort who had been taking powdered 5.3 to 3.3, respectively, and the number of vomiting ginger for periods ranging from 3 months to 2.5 years episodes from 1.9 to 1.2 and 1.7 to 1.2, respectively. were evaluated. On the basis of their clinical observaThere was no significant difference between ginger and tions, Srivastava and M ~ s t a f reported a~~ that 75% of the vitamin B6 for the treatment of nausea and vomiting patients with arthritis and 100% of the patients with during pregnancy. muscular discomfort experienced relief in pain or swellIn another study, 70 women with nausea and vomiting ing. The recommended dosage was 500 to 1000 mg/day, of pregnancy were randomly assigned to receive either oral ginger 1 g/day or an identical placebo for 4 d a ~ s . 4 ~ but many patients took three to four times this amount. Patients taking the higher dosages also reported quicker Subjects graded the severity of their nausea using visual and better relief. analog scales and recorded the number of vomiting Three double-blind studies with standardized and episodes in the 24 hours before treatment, and again highly concentrated extracts of ginger provide addiduring 4 consecutive days during treatment. At a followtional support for the usefulness of ginger in osteoarthriup visit 7 days later, the number of vomiting episodes tis, although in one study ginger was effective only after had decreased sigruficantly in the ginger group; 28 of In the largest of the three studies 3 months of 32 in the ginger group had improvement in nausea with the concentrated ginger extract, 261 patients with symptoms compared with 10 of 35 in the placebo group. These clinical results and those reported by 0thers,5~,~* osteoarthritis of the knee were given either ginger extract or placebo twice daily, with acetaminophen along with the safety and the relatively small dose of allowed as rescue medi~ation.~’ The primary efficacy ginger required and the problems (e.g., teratogenicity) variable was the proportion of responders experiencing with antiemetic drugs in pregnancy, support the use of a reduction in ”knee pain on standing,” with use of an ginger for nausea and vomiting in pregnancy. This recintent-to-treat analysis. The percentage of responders ommendation is becoming a well-accepted prescription experiencing a reduction in knee pain on standing was even in orthodox obstetrical practices. superior in the ginger extract group to that in the control Ginger appears very safe for use during pregnancy. In group (63% vs. 50%).Analysis of the secondary efficacy a cohort study of women exposed to ginger during pregvariables revealed a consistently greater response in the nancy, all of whom used it during the first trimester, the ginger extract group compared with the control group, results indicated that there is not a higher risk for major in analysis of the following mean values: reduction in malformations with ginger use. In fact, the only statistical knee pain on standing (24.5 mm vs. 16.4 mm), reduction differences between the pregnancy outcomes of the

Pharmacology of Natural Medicines

in knee pain after walking 50 feet (15.1 mm vs. 8.7 mm), and reduction in the Western Ontario and McMaster Universities osteoarthritis composite index (12.9 nun vs. 9 mm). Change in global status and reduction in intake of rescue medication were also numerically greater in the ginger extract group. It has also been reported that ginger is beneficial in migraine heada~he.5~ Given ginger's effects on platelets, eicosanoids, and serotonin inhibition, this recommendation makes sense.

motion sickness or nausea and vomiting would be 100 to 200 mg. For other applications, the dosage is 100to 200 mg three times daily.

TOXICOLOGY

Many questions remain concerning the best form of ginger and the proper dosage. Most research studies have used 1g of dried powdered ginger root. Practically speaking, this is a small dose of ginger. For example, ginger is commonly consumed in India at a daily dose of 8 to 10 g. Furthermore, although most studies have used powdered ginger root, fresh (or possibly freeze-dried) ginger root or extracts concentrated for gingerol at an equivalent dosage may yield even better results because they may deliver higher levels of gingerol as well as the active protease. In the treatment of nausea and vomiting due to motion sickness or pregnancy or after surgery, a dosage of 1 to 2 g of dried powdered ginger may be effective. This would be equivalent to approximately 10 g or 1/3 oz of fresh ginger root, roughly a '/,-inch slice. For inflammatory conditions like rheumatoid arthritis, the dosage should be double this amount. For ginger extracts standardized to contain 20% gingerol and shogaol, an equivalent dosage in treating

Ginger does not appear to produce any toxicity problems when used at normal dosages. Although ginger extracts and several components in ginger have been shown to possess potent mutagenic activity, ginger also contains several equally potent antimutagenic substances.60*61 The sigruficance of this mutagenicity (the study was conducted in Escherichiu coli and did not use the Ames test) has not been entirely determined, but the long history of use and lack of carcinogenic or toxic effect in animals suggest that it is not a problem. In acute toxicity tests in mice, ginger extract administered as a lavage was tolerated up to 2.5 g/kg with no mortality or side effects during a 7-day trial period?* Increasing the dosage to 3 to 3.5 g/kg resulted in a 10% to 30% mortality. In comparison, 0.6 g/kg of aspirin produced mortality in 25%, stomach ulcers in 40%, and hypothermia in 60% of subjects. Some individuals consuming high doses-more than the equivalent of 6 g of dried powdered ginger-alone on an empty stomach may experience some gastrointestinal discomfort. Administration of 6 g of dried powdered ginger has been shown to increase the exfoliation of gastric surface epithelial cells in human subjects.@ This effect may cause some gastric distress and ultimately could lead to ulcer formation. Therefore, it is recommended that dosages consumed on an empty stomach be less than 6 g.

1. AfA M, Al-Hadidi D, Menon M, et al. Ginger: an ethnomedical, chemical and pharmacological review. Drug Metab Drug Interact 2001;18:159-190. 2. Tyler V, Brady L, Robbers J. Pharmacognosy, ed 8. Philadelphia: Lea & Febiger, 1981:156-157. 3. Fdter H. The eclectic materia medica, pharmacology and therapeutics. Portland, OR Eclectic Medical Publications, 1983:702. 4. Reddy AC, Lokesh BR. Studies on spice principles as antioxidants in the inhibition of lipid peroxidation of rat liver microsomes. Mol Cell Biochem 1992;111:117-124. 5. Ahmed RS,Seth V, Banerjee BD. Influence of dietary ginger (Zingiber oficcinale Rosc) on antioxidant defense system in rat: comparison with ascorbic acid. Indian J Exp Biol2O00;383604-606. 6. Lee YB, Kim YS, Ashmore CR. Antioxidant property in ginger rhizome and its application to meat products. J Food Sci 1986;51:20-23. 7. Kiuchi F, Iwakami S, Shibuya M, et al. Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids. Chem Pharm Bull 1992;40:387-391. 8.Kiuchi F, Shibuyu M, Sankawa U. Inhibitors of prostaglandin biosynthesis from ginger. Chem Pharm Bull 1982;30:754-757.

9. Srivastava KC. Isolation and effects of some ginger components of platelet aggregation and eicosanoid biosynthesis. Prostaglandins Leukot Med 1986;25:187-198. 10. Nqahja-Tjendraputa E, Ammit AJ, Roufogalis BD, et al. Effective anti-platelet and COX-1enzyme inhibitors from pungent constituents of ginger. Thromb Res 2003;111:259-265. 11. Thomson M, Al-Qattan KK, Al-Sawan SM, et al. The use of ginger (Zingiber oficinale Rosc.) as a potential anti-inflammatory and antithrombotic agent. Prostaglandins Leukot Essent Fatty Acids 2002;67475-478. 12. Tjendraputra E, Tran VH,Liu-Brennan D, et al. Effect of ginger constituents and synthetic analogues on cyclooxygenase-2 enzyme in intact cells. Bioorg Chem 2001;29156-163. 13. SrivastavaK. Effects of aqueous extracts of onion,garlic and ginger on the platelet aggregation and metabolism of arachidonic acid in the blood vascular system. In vitro study. Prostaglandins Leukot Med 1984;13227-235. 14. Srivastawa KC. Effect of onion and ginger consumption on platelet thromboxane production in humans. ProstaglandinsLeukot Essent Fatty Acids 198935183-185.

DOSAGE

Zingiber ohkinale (Ginger) 15. Verma SK, Bordia A. Ginger, fat and fibrinolysis. Indian J Med Sci 2001;55:83-86. 16. Gujral S, Bhumra H, Swaroop M. Effect of ginger (Zingiber oficinale Roscoe) oleoresin on serum and hepatic cholesterol levels in cholesterol fed rats. Nutr Rep Int 1978;17183-189. 17.Giri J, Sakthi Devi TK, Meerarani S. Effect of ginger on serum cholesterol levels. Indian J Nutr Diet 1984;21:433-436. 18.Srinivasan K, Sambaiah K. The effect of spices on cholesterol 7 alpha-hydroxylase activity and on serum and hepatic cholesterol levels in the rat. Int J Vitam Nutr Res 1991;61:364-369. 19. Yamahara J, Miki K, Chisaka T, et al. Cholagogic effect of ginger and its active constituents. J Ethnopharmacol1985;13:217-225. 20. Shoji N, Iwasa A, Takemoto T, et al. Cardiotonic principles of ginger (Zingiber oficinale Roscoe). J Pharm Sci 1982;1011741175. 21. Kobayashi M, Ishida Y, Shoji N, Ohizumi Y. Cardiotonic action of [8]-gingerol, an activator of the Ca++-pumpingadenosine triphosphatase of sarcoplasmic reticulum, in guinea pig arterial muscle. J Pharmacol Exp Ther 1988;246:667-673. 22. Suekawa M, Aburada M, Hosoya E. Pharmacological studies on ginger. II. Pressor action of (6)-shogaol in anesthetized rats, or hindquarters, tail and mesenteric vascular beds of rats. J Pharmacobiol1986;9:842-860. 23. Onogi T, Minami M, Kuraishi Y, Satoh M. Capsaicin-like effect of (6)shogaol on substance P-containing primary afferents of rats: a possible mechanism of its analgesic action. Neuropharmacology 1992;31:1165-1169. 24.Yamahara J, Huang QR, Li YH, et al. Gastrointestinal motility enhancing effect of ginger and its active constituents. Chem Pharm Bull 1990;38:430-431. 25. Huang QR, Iwamoto M, Aoki S, et al. Anti-5-hydroxytryptamine effect of galanolactone, diterpinoid isolated from ginger. Chem Pharm Bull 1991;39397-399. 26. Huang Q, Matsuda H, Sakai K, et al. [The effect of ginger on serotonin induced hypothermia and diarrhea.] Yakugaku Zasshi 1990;110936-942. 27. Vishwakarma SL, Pal SC,Kasture VS, Kasture SB. Anxiolytic and antiemetic activity of Zingiber oficinale. Phytother Res 2002;16: 621-626. 28. Gonlachanvit S, Chen YH, Hasler WL, et al. Ginger reduces hyperglycemia-evoked gastric dysrhythmias in healthy humans: possible role of endogenous prostaglandins. J Pharmacol Exp Ther 2003;307 1098-1103. 29.Micklefield GH, Redeker Y, Meister V, et al. Effects of ginger on gastroduodenal motility. Int J Clin Pharmacol Ther 1999;37 341-346. 30. a1 Yahya MA, Rafatullah S, Mossa JS, et al. Gastroprotective activity of ginger, Zingiber oficimle ROSC.,in albino rats. Am J Chin Med 1989;1751-56. 31. Yamahara J, Mochizuki M, Rong HQ, et al. The anti-ulcer effect in rats of ginger constituents. J Ethnopharmacol1988;23:299-304. 32.Yamahara J, Hatakeyama S, Taniguschi K, et al. [Stomachic principles in ginger. II. Pungent and anti-ulcer effects of low polar constituents isolated from ginger, the dried rhizome of Zingiber officinaleRoscoe cultivated in Taiwan. The absolute stereostructure of a new diarylheptanoid.] J Pharm Soc Japan 1992;112 645-655. 33. Wu H, Ye D, Bai Y, Zhao Y.Effect of dry ginger and roasted ginger on experimental gastric ulcers in rats. China J Chinese Materia Medica 1990;5278-280,317-318. 34. Mahady GB, Pendland SL, Yun GS, et al. Ginger (Zingiber oficinale Roscoe) and the gingerols inhibit the growth of Cag A+ strains of Helicobacter pylori. Anticancer Res 2003;233699-3702. 35.Kano Y, Zong QN, Komatsu K. Pharmacological properties of galenical preparation. XN. Body temperature retaining effect of the Chinese traditional medicine, "goshuyu-to" and component crude drugs. Chem Pharm Bull 1991;39:690-692.

, Colquhoun EQ, Dora KA, et al. Pungent principles ' I 36. Elderhsaw T of ginger (Zingiber oficinale) are thermogenic in the perfused rat hind limb. Int J Obes Relat Metab Disord 1992;16:755-763. 37. Henry CJ, Piggott SM. Effect of ginger on metabolic rate. Human Nutr Clin N ~ t 1987;41:89-92. r 38. Chang HM, But PPH. Pharmacology and applications of Chinese materia medica, vol. 1. Philadelphia: World Scientific, 1986: 366-369. 39. Ficker C, Smith ML, Akpagana K, et al. Bioassay-guided isolation and identification of antifungal compounds from ginger. Phytother Res 2003;17897-902. 40.Surh YJ, Lee E, Lee JM. Chemoprotective properties of some pungent ingredients present in red pepper and ginger. Mutat Res 1998;402259-267. 41. Mowrey DB, Clayson DE. Motion sickness, ginger, and psychophysics. Lancet 1982;1655-657. 42. Stewart JJ, Wood MJ, Wood CD, Mims ME. Effects of ginger on motion sickness susceptibility and gastric function. Pharmacology 1991;42.111-120. 43. Grontved A, Brask T, Kamskard J, Hentzer E. Ginger root against seasickness. A controlled trial on the open sea. Acta Otolaryngol 1988;10545-49. 44. Holtman S, Clarke AH, Scherer H, Hohn M. The anti-motion sickness mechanism of ginger. A comparative study with placebo and dimenhydrinate. Acta Otolaryngol 1989;108:168-174. 45.Grontved A, Hentzer E. Vertigo-reducing effect of ginger root. A controlled clinical study. ORL J Otorhinolaryngol Relat Spec 1986;48:282-286. 46. Lien HC, Sun WM, Chen YH, et al. Effects of ginger on motion sickness and gastric slow-wave dysrhythmias induced by circular vection. Am J Physiol Gastrointest Liver Physiol 2003;284: G4814489. 47. Fischer-Rasmussen W, Kjaer SK, Dahl C, Asping U. Ginger treatment of hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 1990;38:19-24. 48.Sripramote M, Lekhyananda N. A randomized comparison of ginger and vitamin B, in the treatment of nausea and vomiting of pregnancy. J Med Assoc Thai 2003;86:846-853. 49. Portnoi G, Chng LA, Karimi-Tabesh L, et al. Prospective comparative study of the safety and effectiveness of ginger for the treatment of nausea and vomiting in pregnancy. Am J Obstet Gynecol 2003;189:13741377. 50.Vutyavanich T, Kraisarin T, Ruangsri R. Ginger for nausea and vomiting in pregnancy: randomized, double-masked, placebocontrolled trial. Obstet Gynecol2001;97:577-582. 51. Keating A, Chez RA. Ginger syrup as an antiemetic in early pregnancy. Altem Ther Health Med 2002;8:89-91. 52.Bone ME, Wilkinson DJ, Young JR, et al. Ginger root-a new antiemetic. The effect of ginger root on postoperative nausea and vomiting after major gynecological surgery. Anaesthesia 1990;45: 669-671. 53. Pongrojpaw D, Chiamchanya C. The efficacy of ginger in prevention of post-operative nausea and vomiting after outpatient gynecological laparoscopy. J Med Assoc Thai 2003;86244-250. 54. Srivastava KC, Mustafa T. Ginger (Zingiber oficinnle) and rheumatic disorders. Med Hypotheses 1989;29:25-28. 55. Srivastava KC, Mustafa T. Ginger (Zingiber oficinale) in rheumatism and musculoskeletal disorders. Med Hypotheses 1992;39:342-348. 56. Altman RD, Marcussen KC. Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum 2001;442531-2438. 57. Wigler I, Grotto I, Caspi D, Yaron M. The effects of Zintona EC (a ginger extract) on symptomatic gonarthritis. Osteoarthritis Cartilage 2003;11:783-789. 58. Bliddal H, Rosetzsky A, Schlichting P, et al. A randomized, placebocontrolled, cross-over study of ginger extracts and ibuprofen in osteoarthritis. Osteoarthritis Cartilage 2000;8:9-12.

Pharmacology of Natural Medicines 59.Mustafa T, Srivastava KC. Ginger (Zingiber oficinale) in migraine headaches. J Ethnopharmacol1990;29267-273. 60.Nakamura H, Yamamoto T. Mutagen and antimutagen in ginger, Zingiber officimle. Mutation Res 1982;103119-126. 61. Nagabhushan M, Amonkar AJ, Bhide SV. Mutagenicity of ginger01 and shogaol and antimutagenicity of zingerone in salmonella/ microsome assay.Cancer Lett 19873221-233.

62.Macolo N, Jain R, JainSC,Capasso F. Ethnopharmacologic investigation of ginger (Zingiber oficinale). J Ethnopharmacol 1989;27 129-140. 63. Desai HG,Kalro RH, Choksi AP. Effect of ginger & garlic on DNA content of gastric aspirate. Indian J Med Res 1990;92139-141.

Specific Health Problems 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195

Acne Vulgaris and Acne Conglobata 1421 Affective Disorders 1427 Alcoholism 1449 Alzheimer’s Disease 1459 Angina 1473 Aphthous Stomatitis 1481 Asthma 1485 Atherosclerosis 1501 Atopic Dermatitis (Eczema) 1525 Attention Deficit Hyperactivity Disorder in Children 1533 Bacterial Sinusitis 1545 Benign Prostatic Hyperplasia 1549 Carpal Tunnel Syndrome 1557 Celiac Disease 1563 Cellulite 1567 Cervical Dysplasia 1571 Chronic Fatigue Syndrome 1579 Congestive Heart Failure 1591 Cystitis 1597 Dermatitis Herpetiformis 1605 Diabetes Mellitus 1607 Endometriosis 1643 Epilepsy 1649 Erythema Multiforme 1663 Fibrocystic Breast Disease 1665 Fibromyalgia Syndrome 1671 Gallstones 1687 Glaucoma: Acute (Angle Closure) and Chronic (Open Angle) 1697 Gout 1703 Hair Loss in Women 1711 Hepatitis 1715 Herpes Simplex 1723 HIV/ AIDS Naturopathic Medical Principles and Practice 1727 Hypertension 1757 Hyperthyroidism 1771 Hypoglycemia 1781 Hypothyroidism 1791 Infectious Diarrhea 1801 Inflammatory Bowel Disease (Crohn’s Disease and Ulcerative Colitis) 1813 Insomnia 1829 Irritable Bowel Syndrome 1837 Kidney Stones 1843 Leukoplakia 1853 Lichen Planus 1855 Macular Degeneration 1859 Male Infertility 1865 Menopause 1877 Menorrhagia 1901 Migraine Headache 1907 Multiple Sclerosis 1925 Nausea and Vomiting of Pregnancy 1941 Obesity 1947 Osteoarthritis 1961

196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 21 1 212 213 214 215 216

Osteoporosis 1977 Otitis Media 1991 Parkinson’s Disease 1999 Pelvic Inflammatory Disease 2015 Peptic Ulcer-Duodenal and Gastric 2025 Periodontal Disease 2031 Pneumonia: Bacterial, Mycoplasmal, and Viral 2039 Porphyrias 2045 Premenstrual Syndrome 2053 Proctologic Conditions 2067 Psoriasis 2079 Rheumatoid Arthritis 2089 Rosacea 2109 Seborrheic Dermatitis 2113 Senile Cataracts 2117 Streptococcal Pharyngitis 2123 Trichomoniasis 2127 Urticaria 2133 Uterine Fibroids 2149 Vaginitis and Vulvovaginitis 2155 Varicose Veins 2167

This section is both a therapeutic handbook and a study of the origins and causes of disease. Each disease is thoroughly discussed, with particular emphasis on the biochemistry of the altered physiology leading to the symptomatology and pathology. We also discuss, as appropriate, the aspects of genetics and lifestyle leading to the disorder. Finally, we present a comprehensive therapeutic regimen using relatively natural and nontoxic therapies. Although we believe this to be the most effective way to present the material, we are extremely concerned that it could continue to promote the disease orientation of the current dominant medical system. We can only offer the following suggestion: Always treat the patient, not the disease! All recommendations made here should be considered in the context of the whole patient. Our purpose is to help our patients to become well, not to simply alleviate symptoms and allow the true cause(s) of their disease to continue unabated. We therefore recommend that readers carefully study Sections 1 and 4 be before reading this section, and that the psychological and spiritual reasons people may have for being sick always be considered.

ORGANIZATION In general, each chapter is divided into the following five parts: Diagnostic summary-a brief list of the key diagnostic elements General considerations-a discussion of the underlying pathology and altered physiology Therapeutic considerations-a discussion of the correctable deficiencies and various natural therapies that may be used to treat the underlying pathophysiology Therapeutic approach-a concise therapeutic regimen References-thorough referencing of our discussion to aid those who seek further study of our treatment rationale

1419

Specific Health Problems The section is arranged alphabetically by disease name. Please also use the Index to look for diseases, as some are addressed in other disease chapters or within a grouping; for example, depression is discussed in the chapter ”Affective Disorders.”

To aid us in the further development of this textbook, we welcome comments. In particular, we are greatly interested in well-documented successes, and failures, of the use of these procedures. We would also appreciate recommendations for therapeutic and diagnostic approaches not included here.

Acne Vulgaris and Acne Conglobata Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

1421

General Considerations 1421 Endocrinologic Aspects 1422 Therapeutic Considerations 1422 Diet 1422 Sugar, Insulin, and Chromium 1422 Nutrients 1422 Vitamin A 1422 Zinc 1422 Vitamin E and Selenium 1423 Pyridoxine 1423 Pantothenic Acid 1423

DIAGNOSTIC SUMMARY Open comedones-dilated follicles with central dark, horny plugs (blackheads) Closed comedones-small follicular papules with (red papules) or without (whiteheads) inflammatory changes Superficial pustules-collections of pus at follicular opening Nodules-tender collections of pus deep in dermis Cysts-from nodules that fail to discharge contents to the surface Large deep pustules-from nodules that break down adjacent tissue, leading to scars

GENERAL CONSIDERATIONS Acne is the most common of all skin problems. Acne vulgaris is characterized as a pilosebaceous disease with comedones, papules, and pustules, while acne conglobata is a more severe form, with cyst formation and subsequent scarring. The lesions occur predominantly on the face and, to a lesser extent, on the back, chest, and shoulders. It is more common in males, and onset is typically at puberty (somewhat later for the conglobata form).

Miscellaneous Factors 1423 Topical Treatments 1423 Tea Tree Oil 1423 Azelaic Acid 1424 Therapeutic Approach 1424 Diet 1424 Supplements 1424 Physical Medicine 1424 Topical Treatments 1424

In acne vulgaris the onset reflects an increase in pilosebaceous gland size and sebum secretion due to androgenic stimulation. The severity and progression are determined by a complex interaction among hormones, keratinization, sebum, and bacteria. The lesions begin in the upper portion of the follicular canal, with hyperkeratinizationbeing the first microscopic change. This leads to blockage of the canal, resulting in dilation and thinning. Eventually a comedone is formed. The formation of open or closed comedones appears to be related to the degree of keratinization and the level of blockage of the duct. Despite a large amount of purulent exudate in pustular and cystic lesions, the only bacteria commonly cultured are normal skin species: Propionibacterium acnes (Coynebacteriurn acnes) and Staphylococcus albus. l? acnes is believed to release lipases that hydrolyze sebum triglycerides into free fatty acid lipoperoxides, thus promoting an inflammatory cascade. Acnelike lesions can occur in response to various compounds: corticosteroids, halogens, isonicotinic acid, diphenylhydantoin, and lithium carbonate. Exposure to various industrial pollutants also causes acne: machine oils, coal tar derivatives, and chlorinated hydrocarbons. Cosmetics, pomades, overwashing, and repetitive rubbing can produce acne. 1421

Endocrinologic Aspects

Sugar, Insulin, and Chromium

Acne is considered to be an androgen-dependent condition, and androgen excess, either systemic or local, is associated with more severe forms of the disease. Androgens control sebaceous gland secretion and exacerbate the development of abnormal keratinizing follicular epithelium.Endocrine disordersproducing excess androgens are important etiologic factors: idiopathic adrenal androgen excess, partial defect in 21-hydroxylase, and polycystic ovarian syndrome. Free testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and low sex-hormone-binding globulin levels have all been impli~ated.'-~ The skin of acne patients shows greater activity of 5-alpha-reductase, the enzyme that converts testosterone to a more potent androgen, dihydrotesto~ t e r o n eThis . ~ ~ increased activity is independent of systemic levels of androgens and may explain the poor correlation between systemic levels of androgens and the severity of the acne lesions.

Many dermatologists have reported that insulin is effective in the treatment of acne, suggesting impaired cutaneous glucose tolerance or insulin insensitivity, or b~th.~JO The insulin was either given systemically (5 to 10 units two to three times a week) or injected directly into the lesion. One study comparing the results of oral glucose tolerance tests in acne patients showed no differences from controls. However, repetitive skin biopsies revealed that the acne patients' skin glucose tolerance was significantly impaired." One researcher of the role of glucose tolerance in acne coined the term "skin diabetes" to describe the disorder of acne.'* Considering the known immunosuppressive effects of sugar (see Chapter 57), all concentrated carbohydrates should be strictly eliminated. High-chromium yeast is known to improve glucose tolerance and enhance insulin sensitivity13 and has been reported in an uncontrolled study to induce rapid improvement in patients with acne.14

THERAPEUTIC CONSIDERATIONS

NUTRIENTS Vitamin A

Effective treatment of acne is a significant clinical challenge. Success can only be obtained by a rigorous, comprehensive application of dietary, nutritional, and botanical interventions.

Diet Although there is some controversy when diet is discussed in the etiology of acne, there is clear evidence of an association. In Westernized societies, acne vulgaris is a nearly universal skin disease afflicting 79% to 9.570of the adolescent population. In men and women older than 25 years, 40% to 54% have some degree of facial acne, and clinical facial acne persists into middle age in 12% of women and 3% of men. In contrast, epidemiologic evidence suggests that acne incidence rates are considerably lower in non-Westernized societies. For example, in an examination of acne prevalence in the Kitavan Islanders of Papua New Guinea and the Ache hunter-gatherers of Paraguay, researchers found no cases of acne.6 The exact diet for acne sufferers to follow has not been evaluated, but foods high in iodine should be eliminated and milk consumption (due to possible hormone content) should be limited.7Trans fatty acids and high-fat foods should also be eliminated because of their possibility of disrupting sebaceous secretions. The composition of the diet should be in the range of 45% protein, 35% carbohydrate, and 20% fat, as such a composition produces substantially less 5-alpha-reduction of testosterone and enhanced cytochrome P450 hydroxylation of estradiol, both therapeutic goals.8 A high carbohydrate diet (10% protein, 70% carbohydrate, and 20% fat) has the opposite effect.

Many studies have demonstrated that retinols including oral vitamin A reduce sebum production and the hyperkeratosis of sebaceous follicles. Retinol has been shown to be effective in treating acne when used at high, and potentially toxic, dosages (i.e., 300,000 to 400,000 IU/day for 5 to 6 months).I5 Although dosages of vitamin A below 300,000 IU/day for a few months rarely cause toxic symptoms,15 early recognition is important. Cheilitis (chapped lips) and xerosis (dry skin) generally occur in the majority of patients, particularly in dry weather. The first sigruhcant toxic symptom is usually headache followed by fatigue, emotional lability, and muscle and joint pain. Laboratory tests appear unreliable for monitoring toxicity, since serum vitamin A levels correlate poorly with toxicity, and serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) are elevated only in symptomatic patients. Of far greater concern is the teratogenicity of massive dosages of vitamin A. Women of childbearing age should use effective birth control during treatment and for at least 1 month after discontinuation. In our opinion, massive doses should be reserved for intractable cases and retinol therapy should not be used alone. The major problem with many clinical studies using retinol and retinol analogs has been their simplistic use as isolated agents. As noted later, many other factors are of critical importance.

Zinc Zinc is vitally important in the treatment of acne. It is involved in local hormone activation, retinol-binding

Acne Vulgaris and Acne Conglob

protein formation, wound healing, immune system activity, and tissue regeneration. Zinc supplementation in the treatment of acne has been the subject of much controversy and many doubleblind studies. Inconsistent results may be due to the differing absorbability of the various zinc salts used. For example, studies using effervescent zinc sulfate show efficacies similar to tetracycline, with fewer side effects from chronic use,16 while those using plain zinc sulfate have shown less beneficial re~u1ts.l~ The majority of patients required 12 weeks of supplementation before good results were demonstrated, although some showed dramatic improvement immediately. In another study, 66 patients with inflammatory acne were given zinc gluconate (30 mg elemental zinc) or placebo for 2 months.lS On the basis of the number and severity of lesions, an ”inflammatoryscore” was attributed to each patient. In the placebo group the inflammatory score dropped from 58 to 47 in the 2-month period, while in the treatment group the score dropped from 49 to 27. Physicians rated 24 of 32 patients in the zinc group as responders compared with only 8 of 34 in the placebo group. At least two additional double-blind studies with zinc gluconate provide additional s ~ p p o r t , ’ ~but ,~~ unfortunately there have been no studies to date using better absorbed forms of zinc such as zinc picolinate, acetate, or monomethionine. The importance of zinc to normal skin function is well recognized, especially in light of the zinc-deficient syndrome acrodermatitis enteropathica. Zinc is essential for retinol-binding protein and thus for serum retinol levels.21Although low levels of zinc increase 5-alphareduction of testosterone, high concentrations significantly inhibit this reaction.22Serum zinc levels are lower in 13- and 14-year-old males than in any other age group.23

Vitamin E and Selenium Serum vitamin A levels in rats on a vitamin E-deficient diet remain low regardless of the amount of oral or intravenous vitamin A supplementation. Serum levels return to normal after vitamin E is restored to the diet. Vitamin E has been shown to regulate retinol levels in humans. Male acne patients have sigruficantly decreased levels of erythrocyte glutathione peroxidase, which normalizes with vitamin E and selenium treatment. The acne of both men and women improves with this treatment.” This improvement is probably due to inhibition of lipid peroxide formation and suggests the use of other free radical quenchers.

Pyridoxine Women with premenstrual aggravation of acne often respond to vitamin B6 supplementation, reflecting its role in the normal metabolism of steroid hormones.25

In rats a vitamin B6 deficiency appears to cause an increased uptake and sensitivity to testosterone.26 In some patients, thyroid therapy has resulted in marked impro~ernent.~~

Pantothenic Acid Pantothenic acid, which is physiologically active in the synthesis of cholesterol and steroid hormones, may be of value at high dosages in the treatment of acne. This was evaluated in a study of 100 Chinese patients (45 males and 55 females) between 10 and 30 years of age (80% were between the ages of 13and 23) with varying ranges of acne lesions. They were provided 10 g/day of pantothenic acid in four divided doses, and a cream consisting of 20% by weight pantothenic acid was applied four to six times a day. Within 1 or 2 days of starting, there was a noticeable decrease in sebum secretion. Within 1to 2 weeks, the frequency of new acne eruptions began to decline and existing lesions started to regress. No side effects were noted.28

MISCELLANEOUS FACTORS One study showed that 50% of patients with severe acne had a positive microclot test, indicating circulating endot0xins.2~This is important because circulating endotoxins have been shown to cause an increased copper-to-zinc ratiom and enhance tissue destruction via activation of the alternate complement pathway and formation of fibrin.

TOPICAL TREATMENTS Various topical gels, ointments, and creams containing natural products are available to treat acne. The goal of these preparations is the same as benzoyl peroxide (i.e., to reduce both the bacteria level and inflammation). Although there are many choices, the most popular formulas are those with either tea tree oil or azelaic acid.

Tea Tree Oil Meluleucu ulternifoliu, or “tea tree,” is a small tree native to only one area of the world: the northeast coastal region of New South Wales, Australia. The leaves, the portion of the plant that is used medicinally, are the source of a valuable therapeutic oil. Tea tree oil possesses sigruficant antiseptic properties and is regarded by many as the ideal skin disinfectant. This claim is supported by its efficacy against a wide range of organisms (including27 of 32 strains of I? ~ c n e s ) ~ l and its good penetration and lack of irritation to the skin. The therapeutic uses of tea tree oil are based largely on its antiseptic and antifungal properties. In a study conducted at the Royal Prince Hospital in New South Wales, a 5%tea tree oil solution demonstrated

similar beneficial effects as 5% benzoyl peroxide in acne, but with substantially fewer side effects.” However, this 5% tea tree oil solution is probably not strong enough for moderate to severe acne. Stronger solutions (up to 15%) should provide even better results. Numerous studies have shown that tea tree oil is extremely safe for use as a topical antiseptic, but it can occasionally produce contact dermatitis.

Azelaic Acid This naturally occurring nine-carbon dicarboxylic acid has exerted much pharmacologic activity including antibiotic activity against P. acnes. Clinical studies with 20% azelaic acid cream have shown it to produce results equal to those achieved with benzoyl peroxide, tretinoin, and oral tetracy~line.3~ It has been shown to be effective in all of the different forms of acne. In order to achieve benefits, azelaic acid must be applied to affected areas twice daily continuously for a period of at least 4 weeks. Treatment usually must be continued for at least 6 months to maintain the benefits produced after the first month. One review article found topical cream containing 20% azelaic acid to be as effective as 5% benzoyl peroxide, ~ O / O hydroquinone cream, 0.05% tretinoin, 2% erythromycin, and 0.5 to 1 g/day oral tetracycline in ameliorating comedonal, papulopustular, and noddocystic acne but less effective than oral isotretinoin at a dose of 0.5 to 1 mg/kg per day in reducing conglobate acne. The authors suggested that the few side effects of topical azelaic acid and lack of overt systemic toxicity made it a better choice for chronic use than other agents. The lower incidence of allergic sensitization, exogenous ochronosis, and residual hypopigmentation offer a clear advantage over conventional drugsM

underlying hormonal abnormalities before specific therapies are initiated. Also, considering the widespread use of long-term, broad-spectrum antibiotics, systemic candidiasis must be ruled out (see Chapter 52). The most popular acne medication is isotretinoin (Accutane), a derivative of vitamin A. It is approved only for severe acne and recalcitrant nodular acne. Concern over the safety and widespread use of this drug is growing. Specifically, reports of intracranial hypertension, depression, and suicidal ideation with Accutane use have prompted an examination of its serious and lifethreatening potential. Although a warning was added to its product label for signs of depression and suicidal ideation, the overprescription of this drug in less severe forms of acne including mild and moderate cases gives rise for concern. Depression and suicide can follow in patients with no prior history of psychiatric symptoms or suicide attempts.19

Diet Eliminate all refined and concentrated carbohydrates and limit high-fat and high-carbohydrate foods. Avoid foods containing trans fatty acids and iodine.

Supplements Vitamin A: 100,000 IU/day for 3 months Vitamin E: 400 IU/day Vitamin C : 1000 mg/day Zinc: 50 mg/day (picolinate is best30) Selenium: 200 pg/day Yeast (brewer’s)-1 tablespoon twice a day (if patient is susceptibleto gout, use chromium supplement instead)

Physical Medicine Sun or ultraviolet lamp

THERAPEUTIC APPROACH Acne is a multifactorial disease requiring an integrated therapeutic approach in order to avoid supplement toxicity while attaining the desired clinical results. Patients should be checked for treatable causes and

1. Pochi PE. Acne: endocrinologic aspects. Cutis 1982;30:212-214, 216217,219. Z.!khiavone FE, Rietschel RL, Squotas D, Harris R. Elevated free testosterone levels in women with acne. Arch Dermatol 1983;119: 799-802. Besser GM, et al. Andmgen status in women with 3. Darley CR,Moore JW, late onset or persistent acne vulgaris. Clin Exp Dermatol1984,9:2835. 4. Takayasu S, Wakimoto H, Itami S, Sano S. Activity of testosterone 5-alpha-reductase in various tissues of human skin. J Invest Dermatol1980;74187-191.

Topical Treatments Tea tree oil (5y0 to 15%)preparations Azelaic acid (20%) preparations Thorough daily cleansing with calendula soap Drain comedones with comedo extractor

5. Sansone G, Reisner RM.Differential rates of conversion of testosterone to dihydrotestosterone in acne and normal human skin-a possible pathogenic factor in acme. J Invest Dermatol1971;56:366-372. 6. Cordain L, Lindeberg S, Hurtado M, et al. Acne vulgaris: a disease of Western civilization.Arch Dermatol2002;138:1584-1590. 7. Ayrts S, M a n R. Acme vulgaris: therapy directed at pathophysiologic defects. Cutis 1981;28:41-42. 8. Kappas A, Anderson K, Conney A, et al. Nutrition-endocrine interactions:induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cyt&ome P-450-dependent oxidation

Acne Vulgaris and Acne Conglobata of estradiol by dietary macronutrients in man. Proc Natl Acad Sci U S A 1983;807646-7649. 9. Semon H, Herrmann F. Some observations on the sugar metabolism in acne vulgaris, and its treatment by insulin. Br J Derm 1940;52: 123-128. 10.Grover RW, Arikan N. The effect of intralesional insulin and glucagon in acne vulgaris. L Invest Derm 1963;40:259-261. 11. Kader MM, El-Mof%y AM,Ismail AA, Bassili F. Glucose tolerance in blood and skin of patients with acne vulgaris. Ind J Derm 1977;22 139-149. 12. Cohen JL, Cohen AD. Pustular acne staphyloderma and its treatment with tolbutamide. Can Med Assoc J 1958;80629-632. 13. Offenbacher EG, Pi-Sunyer FX. Beneficial effect of chromium-rich yeast on glucose tolerance and blood lipids in elderly patients. Diabetes 1980;29919-925. 14. McCarty M. High-chromium yeast for acne? Med Hypotheses 1984; 14307-310. 15. Kilgman AM, MiUs OH Jr, Leyden JJ, et al. Oral vitamin A in acne vulgaris. A preliminary report. Int J Dermatol1981;20278-285. 16. Michaelsson G, Juhlin L, Ljunghall K. A double-blind study of the effect of zinc and oxytetracycline in acne vulgaris. Br J Dermatol 1977;97561-566. 17. Weimar VM, Puhl SC,Smith WH, tenBroeke JE. Zinc sulphate in acne vulgaris. Arch Dermatol1978;114:1776-1778. 18. Dreno B, Amblard P, Agache P,Litoux P. Low doses of zinc gluconate for inflammatory acne. Acta Derm Venereol1989;69:541-543. 19.Meynadier J. Efficacy and safety study of two zinc gluconate regimens in the treatment of inflammatory acne. Eur J Dermatol 2000;10:269-273. 20. Kobayashi H, Aiba S, Tagami H. Successful treatment of dissecting cellulitisand acne conglobata with oral zinc. Br J Dermatol1999;141: 1137-1138. 21. Michaelsson G, Juhlin L, Vahlquist A. Effects of oral zinc and vitamin A in acne. Arch Dermatol 1977;113:31-36.

22. Leake A, Chisholm GD, Habib FK. The effect of zinc on the 5-alphareduction of testosterone by the hyperplastic human prostate gland. J Steroid Biochem 1984;20:651-655. 23. Michaelsson G, VahlquistA, Juhlin L. Serum zinc and retinol-binding protein in acne. Br J Dermatol1977;96283-286. 24. Michaelsson G, Edqvist L. Erythrocyte glutathione peroxidase activity in acne vulgaris and the effect of selenium and vitamin E treatment. Acta Derm Venerol1984;64:9-14. 25. Snider BL, Dieteman DF. Letter: Pyridoxine therapy for premenstrual acne flare. Arch Dermatol1974;110130-131. 26. Symes EK, Bender DA, Bowen JF, Coulson WE Increased target tissue uptake of, and sensitivity to, testosterone in the vitamin B6 deficient rat. J Steroid Biochem 1984;201089-1093. 27. Barnes B. Thyroid therapy in dermatology. Cutis 1971;8:581-583. 28. Leung LH. Pantothenic acid deficiency as the pathogenesis of acne vulgaris. Med Hypotheses 1995;44:490-492. 29. Juhlin L, Michaelsson G. Fibrin microclot formation in patients with acne. Acta Derm Venereol 1983;63:538-540. 30. Etzel KR, Swerdel MR, Swerdel JN, Cousins RJ. Endotoxin-induced changes in copper and zinc metabolism in the Syrian hamster. J Nutr 1982j1122363-2373. 31. Carson CF, Riley TV The antimicrobial activity of tea tree oil. Med J Australia 1994;160.236. 32. Bassett IB, Pannowitz DL, Barnetson RS.A comparative study of tea-tree oil versus benzoyl peroxide in the treatment of acne. Med J Aust 1990;153:455-458. 33.Nazzaro-Porro M. Azelaic acid. J Am Acad Dermatol 1987;17 1033-1041. 34. Nguyen QH, Bui TP.Azelaic acid. Pharmacokinetic and pharmacodynamic properties and its therapeutic role in hyperpigmentary disorders and acne. Int J Dermatol 1995;34:75-84.

Affective Disorders Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary 1427 Depression 1427 Dysthymia 1427 Manic Phase 1428 Seasonal Affective Disorder 1428 Introduction 1428 DEPRESSION 1428 General Considerations 1428 The Learned Helplessness Model 1429 Therapeutic Considerations 1429 Counseling 1430 Hormonal Factors 1430 EnvironmentalToxins 1431 Lifestyle Factors 1431 Nutrition 1433 Monoamine Metabolism and Precursor Therapy 1436 Botanical Medicines 1441 Therapeutic Approach 1442 Diet 1442 Lifestyle 1442 Supplements 1442 Botanical Medicines 1442

DIAGNOSTIC SUMMARY Depression The official definition of clinical depression, according to the American Psychiatric Association in its Diagnostic and Statistical Manual of Mental Disorders (DSM-ZV), is based on the following eight primary criteria: Poor appetite with weight loss or increased appetite with weight gain Insomnia or hypersomnia Physical hyperactivity or inactivity Loss of interest or pleasure in usual activities or decrease in sexual drive Loss of energy and feelings of fatigue

BIPOLAR (MANIC) DEPRESSION AND HYPOMANIA 1442 General Considerations 1442 Therapeutic Considerations 1443 Tryptophan 1443 Phosphatidylcholine 1443 Omega-3 Fatty Acids 1443 Vanadium 1443 Circadian Rhythms 1444 Therapeutic Approach Diet 1444 Supplements 1444

1444

SEASONAL AFFECTIVE DISORDER 1444 General Considerations 1444 Therapeutic Considerations 1444 Melatonin 1444 Light Therapy 1444 ~-Tryptophan/5-Hydroxytryptophan 1444 Hypericum perfoliatum 1444 Therapeutic Approach 1445

Feelings of worthlessness, self-reproach, or inappropriate guilt Diminished ability to think or concentrate Recurrent thoughts of death or suicide The presence of five of these eight symptoms definitely indicates clinical depression; the individual with four is probably depressed. According to the DSM-ZV, the symptoms must be present for at least 1month to be called depression. Clinical depression is also referred to as major depression or unipolar depression.

Dysthymia Like clinical depression, dysthymia is diagnosed according to DSM-IV criteria. In order to be officially diagnosed

1427

as dysthymic, a patient must be depressed most of the time for at least 2 years (1year for children or adolescents) and have at least three of the following symptoms: Low self-esteem or lack of self-confidence Pessimism, hopelessness, or despair Lack of interest in ordinary pleasures and activities Withdrawal from social activities Fatigue or lethargy Guilt or ruminating about the past Irritability or excessive anger Lessened productivity Difficulty in concentrating or making decisions

Manic Phase Mood is typically elation, but irritability and frank hostility are not uncommon. Inflated self-esteem, grandiose delusions, boasting, racing thoughts, decreased need for sleep, psychomotor acceleration, weight loss due to increased activity and lack of attention to dietary habits

Seasonal Affective Disorder Regularly occurring winter depression frequently associated with summer hypomania

modify the functional state of the brain, thus affecting mood and behavior: The individual genetic makeup The particular age of neuronal development, which results in age-specific variability The functional plasticity of the brain during development, which contributes to the functional and structural shaping of the system The motivational state, affected by various biologic drives, which channels behavior toward specific goals by setting priorities or prejudicing the context of particular types of incoming information The availability of memory-stored information and related processing strategies *The environment, which can adjust the incoming information depending on its momentary significance Disease or lesion of the brain, which could cause aberrant functional states Conditions of the metabolic/hormonal system or the internal biochemical environment of the central nervous system (CNS) This chapter focuses on the nutritional, environmental, and lifestyle factors that contribute to affective disorders, as well as specific therapies to alter brain neurotransmitter levels.

INTRODUCTlON Affective disorders are disturbancesin mood. Used in this context, mood is a prolonged emotional tone dominating an individual’s outlook. Normal, typically transient moods (e.g., sadness, grief, elation) are a part of everyday life, making the demarcation between “normal” and ”pathologic” often difficult to determine. Depression and mania, either alone or in alternation, are the most common affective disorders, with depression alone being much more common. In order to separate states of depression that alternate with mania from the more common types of depression (i.e., those uncomplicated by mania), the terms ”unipolar” and “bipolar” are commonly used. A unipolar depressive suffers from depression alone, while the bipolar depressive suffers from either mania alone or mania alternating with depression. Many nutritional, environmental, and lifestyle factors are discussed in this chapter, and it is important to recognize that they have a much broader scope of clinical application than simply depression and mania. This chapter is really a compilation of many chapters that address factors associated with mood disturbance. As the biochemistry of mood and behavior have become better understood, many conditions once thought of as having a psychologic or sociologic etiology are now being shown to have a physiologic or biochemical basis as well. There appear to be at least eight factors that

Obviously, there is a spectrum of clinical depression that ranges from mild feelings of depression to serious considerations of suicide. Mild depression is also known as dysthyrnilz. Dysthymia is a term coined in the 1980s that replaced the term depressive neurosis, which was used in the 1950s, and the term depressive personality, which was used in the 1970s.

GENERAL CONSIDERATIONS Depression is a major problem in the United States. Approximately 20 million Americans suffer true clinical depression each year, and more than 30 million Americans take antidepressant drugs or anxiolytics. The obvious question is: “Why are so many Americans depressed?’’ Five basic theoretic models of depression attempt to answer this question: The “aggression-turned-inward” construct, which, although apparent in many clinical cases, has no substantial proof The ”loss model,” which postulates that depression is a reaction to the loss of a person, thing, status, selfesteem, or even a habit pattern

Affective Disorders

The “interpersonal relationship” approach, which uses behavioral concepts (i.e., the person who is depressed uses depression as a way of controlling other people (including doctors). It can be an extension and outgrowth of such simple behavior as pouting, silence, or ignoring something or someone. It fails to serve the need, and the problem worsens. The “learned helplessness” model, which theorizes that depression is the result of habitual feelings of pessimism and hopelessness The “biogenic amine” hypothesis, which stresses biochemical derangement characterized by imbalances of biogenic amines Although the biogenic amine model of depression is the dominant medical model of depression, there is much value to counseling, especially in clear cases of psychologic etiology. Of the various psychologic theories of depression, the one that we feel has the most merit is the learned helplessness model developed by Martin Seligman, PhD. During the 1960s, Dr.Seligrnan discovered that animals could be trained to be helpless. His animal model provided a valuable clue to human depression, as well as serving as a model to test antidepressant drugs.’

The Learned Helplessness Model Seligrnan’s early experiments were performed on three groups of dogs. The first group of dogs received an escapable electrical shock. The dogs could turn off the shock by simply pressing a panel with their noses. This group of dogs would thus have control. The second group of dogs was “yoked” to the first group. They got exactly the same shocks as the first group but could not turn off the shock. The shock would cease only when the “yoked” dog in the first group would press its nose to the panel. Thus the second group of dogs had no control over the degree of shock they received. The third group of dogs received no shocks at all. Once the dogs went through this first part of the experiment, they were placed in a “shuttle box,” a box separated in the middle by a small barrier that the dogs could jump over. The dogs would be electrically shocked but could escape the shock by simply jumping over the barrier to the other side. Seligman hypothesized that the first and third groups would quickly figure this out but that the second group of dogs would have learned to be helpless in that they would believe nothing they would do mattered. Seligman thought that the dogs in the second group would simply lie down and accept the shock. As predicted, the first and third groups of dogs learned within seconds that they could avoid the shock by jumping over the barrier, while the dogs in the second group would simply lie down and not even make an effort to jump over the barrier, though they could see the shockless side of the shuttle box. Seligman and his

colleagues went on to show that many humans react in an identical fashion to animals in these experiments. The adoption of Seligman’s model was revolutionary in psychopharmacology, as it became an effective experiment to test antidepressive drugs. Basically, when animals that had learned to be helpless were given antidepressant drugs, they would unlearn helplessness and start exerting control over their environment. Researchers discovered that when animals learned to be helpless, it resulted in alteration of brain monoamine content. The drugs would restore proper monoamine balance and alter the animals’ behavior. Researchers also discovered that when animals with learned helplessness were taught how to gain control over their environment, their brain chemistry also normalized. The alteration in brain monoamhe content in the animals with learned helplessness mirrors the altered monoamine content in human depression. Although most physicians look quickly to drugs to alter brain chemistry, helping patients to gain greater control over their lives actually produces even greater biochemical changes. One of the most powerful techniques to produce the necessary biochemical changes in the brains of depressed individuals is to teach them to be more optimistic. Outside the laboratory setting, Seligman discovered that the determining factor on how a person would react to uncontrollable events, either “bad” or “good,” was their explanatory style-the way in which they explained events. Optimistic people were immune to becoming helpless and depressed. However, individuals who were pessimistic were extremely likely to become depressed when something went wrong in their lives. Seligman and other researchers also found a direct correlation between an individual’s level of optimism and the likeliness of developing not only clinical depression but other illnesses as well? In one of the longer studies, patients were followed for a total of 35 years. Optimists rarely got depressed, but pessimists were extremely likely to battle depression and other psychologic disturbances.

THERAPEUTIC CONSIDERATIONS Modern psychiatry focuses on manipulating neurotransmitter levels in the brain rather than identifying and eliminating the psychologic factors that are responsible for producing the imbalances in serotonin, dopamine, gamma-aminobutyricacid, and other neurotransmitters. Depression can often be due to an underlying organic or physiologic cause (Box 144-1).Identification and elimination of the underlying cause should be the primary therapy. The depressed individual needs a comprehensive clinical evaluation. The basic clinical approach to a person suffering from depression is to ascertain what nutritional, environmental, social, and psychologic factors are involved in the disease process. After the diagnosis of depression has

Specific Health Problems

Preexisting physical condition Diabetes Heart disease Lung disease Rheumatoid arthritis Chronic inflammation Chronic pain Cancer Liver disease Multiple sclerosis Prescription drugs Antihypertensives Antiinflammatory agents

Birth control pills Antihistamines Corticosteroids Tranquilizers and sedatives Premenstrual syndrome Stressnow adrenal function Heavy metals Food allergies Hypothyroidism Hypoglycemia Nutritional deficiencies Sleep disturbances

been made, it is important to rule out the simple organic factors that are known to contribute to the depression: Nutrient deficiency or excess Drugs (e.g.,prescription, illicit, alcohol, caffeine, nicotine) Hypoglycemia Consumption Hormonal derangement Allergy Environmental factors Microbial factors Each factor is discussed later. Regardless of whether there is an underlying organic cause, counseling is always recommended for the depressed individual.

Counseling Although many counseling techniques are useful, the one with the most merit and support in the medical literature is cognitive therapy. In fact, cognitive therapy has been shown to be as effective as antidepressant drugs in treating moderate depre~sion.~,~ However, while there is a high rate of relapse of depression when drugs are used, the relapse rate for cognitive therapy is much lower. People taking drugs for depression tend to stay on them for the rest of their lives. That is not the case with cognitive therapy because the patient is taught new skills to deal with depre~sion.~ Psychologists and other mental health specialists trained in cognitive therapy seek to change the way the depressed person consciously thinks about failure, defeat, loss, and helplessness. Cognitive therapists employ five basic tactics. First, they help patients recognize the negative automatic thoughts that flit through the consciousness when the patient feels the worst. The second tactic is disputing the negative thoughts by focusing on contrary evidence. The third tactic is teaching the patient a different explanation to dispute the negative automatic thoughts. The fourth tactic involves learning how to

avoid rumination (the constant churning of a thought in one’s mind) by helping the patient better control his or her thoughts. The final tactic is questioning depressioncausing negative thoughts and beliefs and replacing them with empowering positive thoughts and beliefs. Cognitive therapy does not involve the long, drawn-out process of psychoanalysis. It is a solution-oriented psychotherapy designed to help the patient learn skills to improve the quality of his or her life.

Hormonal Factors Many hormones are known to influence mood; however, it is beyond the current scope of this text to address all of them. Instead, the focus is on the effects of the thyroid and adrenal hormones.

Thyroid Function Depressive illness is often a first or early manifestation of thyroid disease, as even subtle decreases in available thyroid hormone are suspected of producing symptom^.^,^ The link between hypothyroidism and depression is well known, but whether the thyroid hypofunction is a result of depression-induced hypothalamicpituitary-thyroid (HPT) dysfunction, or of thyroid hypofunction, remains to be definitively determined. It is probably a combination. Depressed patients should be screened for hypothyroidism, particularly if they complain of fatigue or have any other symptoms suggestive of hypothyroidism.

Stress and Adrenal Function Like the thyroid gland, dysfunction of the adrenal gland is closely associated with depression. Often this dysfunction is the result of stress-a major factor to consider in the depressed individual. The patient’s level of, and response to, stress can be measured with the adrenal stress index. This test measures the level of the cortisol and dehydroepiandrosterone (DHEA) in the saliva. The typical pattern found in depression is an elevated morning cortisol level and a decreased DHEA level. That elevations in cortisol reflect a disturbance in the hypothalamic-pituitary-adrenal (HPA) axis is the basis of the dexamethasone suppression test (discussed later). Defects in HPA regulation seen in affective disorders include excessive cortisol secretion, which is independent of stress responses, abnormal nocturnal release of cortisol, and inadequate suppression by dexamethasone.8 The CNS effects of increased endogenous release of cortisol mirror the effects of exogenous cortisol: depression, mania, nervousness, insomnia, and, at high levels, schizophrenia. The effects of glucocorticoids on mood are related to their induction of tryptophan oxygenase (Figure 144-1).This results in shunting of tryptophan to the kynurenine pathway at the expense of serotonin and melatonin synthesis?

Affective Disorders

EnvironmentalToxins

S-Adenosyl-

7 methionine \

Y

S-Adenosylhomocysteine

Methionine Serine Tetrahvdro-

CH3-R

b

Glycine Homocysteine 5-10-Methylene tetrahydrofolate

5-Methyl tetrahydrofolate

\

FADH,

FAD

Figure 144-1 Tryptophan metabolism.

Tests of Hypothalamic-Pituitary Function The two tests widely used as aids in class@g psychiatric conditions are the dexamethasone suppression test (DST) and the thyrotropin-releasing hormone (TRH) The basic function of these tests is to determine if the condition is a result of hypothalamic dysfunction and to categorize the psychiatric illness (e.g., severe major affective disorders versus severe psychotic disorders). It is generally held that the DST is of little clinical value as a screening test, and it is debatable whether it offers more information than urinary free cortisol. Because thyroid hormone assays cannot detect all cases of thyroid hypofunction, they are not an effective screening procedure. The TRH test is sigruficantly more sensitive in diagnosing ”subclinical hypothyroidism.”ll A grading system for hypothyroidism as determined by the TRH test has been proposed as follows: Grade 3 (subclinical hypothyroidism-4%). Patients are usually without classic signs of thyroid failure and have normal T3RU,Tb and thyroid-stimulatinghormone (TSH) levels but definitely abnormal TSH response to the TRH test. Grade 2 (mild hypothyroidism-3.6%). Patients may have mild isolated clinical signs or symptoms of hypothyroidism but demonstrate normal T3RU and T4 levels. Baseline TSH levels are elevated, and there is an abnormal TRH test. Grade 1 (overt hypothyroidism-1 %). Patients demonstrate signs and symptoms of classical hypothyroidism along with abnormal laboratory values (i.e., reduced Tau and T4levels, increased TSH levels, and abnormal TRH response).

The TRH test may have wide clinical use,as dysfunction of the thyroid gland is implicated in many conditions.

Heavy metals (lead, mercury, cadmium, arsenic, nickel, and aluminum), as well as solvents (e.g., cleaning materials, formaldehyde, toluene, benzene), pesticides, and herbicides have an affinity to nervous tissue. As a result, various psychologic and neurologic symptoms can occur, including the f~llowing’”’~: Depression Headaches Mental confusion Mental illness Tingling in extremities Abnormal nerve reflexes Other signs of impaired nervous system function (See Chapters 26 and 36 for further discussion.) Detailed medical history and hair mineral analysis are good screening mechanisms for environmental toxicity. If the hair mineral analysis is inconclusive, a more sensitive indicator is the 8-hour lead mobilization test. This test employs the chelating agent ethylenediamine tetraacetic acid (EDTA) and measures the level of lead excreted in the urine for a period of 8 hours after the injection of EDTA.

Lifestyle Factors A health-promoting lifestyle and diet are important in the treatment of depression. Particularly important is the cessation of smoking, excessive alcohol consumption, decreased sugar intake, and the intake of caffeine. These lifestyle changes, coupled with regular exercise and a healthful diet, are more than likely to produce better clinical results than Prozac, with no side effects and no cost.

Smoking Cigarette smoking is one of the major factors contributing to premature death in the United States. Cigarette smoking is also a significant factor in depression. Central to the effect of nicotine is the stimulation of adrenal hormone, including cortisol, secretion. Elevated cortisol levels are a well-recognized feature of depression.2 One of the key effects of cortisol (and stress) on mood is activation of tryptophan oxygenase, resulting in less tryptophan being delivered to the brain. Because the level of serotonin in the brain depends on the amount of tryptophan delivered to the brain, cortisol dramatically reduces the level of In addition, cortisol also serotonin and rnelat~nin.~ “down-regulates’’ serotonin receptors in the brain, making them less sensitive to the serotonin that is available. Cigarette smoking also leads to a relative vitamin C deficiency, as the vitamin C is used to detoxify the cigarette smoke. Low levels of vitamin C in the brain can result in depression and hysteria.15

Alcohol Alcohol, a brain depressant, increases adrenal hormone output, interferes with many brain cell processes, and disrupts normal sleep cycles. Alcohol ingestion also leads to hypoglycemia. The resultant drop in blood sugar produces a craving for sugar because it can quickly elevate blood sugar. Unfortunately, increased sugar consumption ultimately aggravates the hypoglycemia. Hypoglycemia aggravates the mental and emotional problems of the alcoholic. Treatment options that can address both the depression and addiction of the individual simultaneously are best.I6 Supplementation with selenium in alcoholics can improve mood stability and help change drinking habits as well (see the section on selenium later).

Caffeine Although caffeine is a well-known stimulant, the intensity of response to caffeine varies greatly, with people prone to feeling depressed or anxious tending to be especially sensitive to caffeine. The term “caffeinism” is used to describe a clinical syndrome similar to generalized anxiety and panic disorders; its symptoms include depression, nervousness, palpitations, irritability, and recurrent heada~he.’~ Several studies have looked at caffeine intake and depression. For example, one study found that, among healthy college students, moderate and high coffee drinkers scored higher on a depression scale than did low users. Interestingly, the moderate and high coffee drinkers also tended to have sigruficantly lower academic performance.18Several other studies have shown that depressed patients tend to consume fairly high amounts of caffeine (e.g., >700 mg/day).Iy2OIn addition, caffeine intake has been positively correlated with the degree of mental illness in psychiatric patients.21z The combination of caffeine and refined sugar seems to be even worse than either substance consumed alone. Several studies have found an association between this combination and depression. In one of the most interesting studies, 21 women and 2 men responded to an advertisement requesting volunteers “who feel depressed and don’t know why, often feel tired even though they sleep a lot, are very moody, and generally seem to feel bad most of the time.”= After baseline psychologic testing, the subjects were placed on a caffeine- and sucrose-free diet for 1 week. The subjects who reported substantial improvement were then challenged in a double-blind fashion. The subjects took either a capsule containing caffeine and a Kool-Aid drink sweetened with sugar or a capsule containing cellulose and a Kool-Aid drink sweetened with NutraSweet. Each challenge lasted up to 6 days. About 50% of test subjects became depressed during the test period with caffeine and sucrose. Another study using a similar format as the Kool-Aid study described earlier found that 7 of 16 depressed

patients were depressed with the caffeine and sucrose challenge but symptom free during the caffeine- and sucrose-free diet and cellulose and NutraSweet test period.24 The average American consumes 150 to 225 mg of caffeine daily, or roughly the amount of caffeine in one to two cups of coffee. Although most people appear to tolerate this amount, some people are more sensitive to the effects of caffeine than others. Even small amounts of caffeine, as found in decaffeinated coffee, are enough to affect some people adversely. Patients with depression or any psychologic disorder should be advised to avoid caffeine completely.

Exercise Regular exercise may be the most powerful natural antidepressant available. In fact, many of the beneficial effects of exercise noted in the prevention of heart disease may be related just as much to its ability to improve mood as to its improvement of cardiovascular function.25 Furthermore, obesity is associated with Various community and clinical studies have clearly indicated that exercise has profound antidepressive effects.27These studies have shown that increased participation in exercise, sports, and physical activities is strongly associated with decreased symptoms of anxiety, depression, and malaise. Furthermore, people who participate in regular exercise have higher self-esteem, feel better, and are much happier than people who do not exercise. Much of the mood-elevating effects of exercise may be attributed to the fact that regular exercise has been shown to increase the level of endorphins, which are directly correlated with mood.28One of the most interesting studies that examined the role of exercise and endorphins in depression compared the beta-endorphin levels and depression profiles of 10 joggers with those of 10 sedentary men of the same age. The 10 sedentary men tested were more depressed, perceived greater stress in their lives, and had a higher level of cortisol and lower levels of beta-endorphins. As the researchers stated, this “reaffirms that depression is very sensitive to exercise and helps firm up a biochemical link between physical activity and depression.”2y At least 100 clinical studies have now evaluated the efficacy of an exercise program in the treatment of depression. In an analysis of the 64 studies before 1980, physical fitness training was shown to relieve depression and improve self-esteem and work behavior.3O Unfortunately, the quality of many of the studies was less than ideal. However, because of the good results noted in the analysis of these studies, there was a flurry of well-designed studies conducted in the 1980sto better determine how effective exercise could be as a therapy. These studies used stricter scientific criteria than the

Affective Disorders earlier ones, yet they produced similar results. It was of nutrients are quite common in depressed individuals. The most common deficienciesare folic acid, vitamin BIZ, concluded that exercise can be as effective as other antiand vitamin B6. The significance of these deficiencies is depressants, including drugs and p~ychotherapy.~~ More discussed later. recently, even stricter studies have further demonstrated that regular exercise is a powerful a n t i d e p r e s ~ a n t . ~ ~ , ~ ~ , ~ ~ Dietary Guidelines The best exercises are either strength training (weight lifting) or aerobic activities such as walking briskly, jogBecause the brain requires a constant supply of blood ging, bicycling, cross-country skiing, swimming, aerobic sugar, hypoglycemia must be avoided. Symptoms of hypoglycemia can range from mild to severe and include dance, and racquet sports. the following:

Nutrition

A deficiency of any single nutrient can alter brain function and lead to depression, anxiety, and other mental disorders (Table 144-1). However, the role of nutrient deficiency is just the tip of the iceberg with regard to the role of nutrient effects on the brain and mood. Melvin Werbach, MD, stated the following34: It is clear that nutrition can powerfully influence cognition, emotion, and behavior. It is also clear that the effects of classical nutritional deficiency diseases upon mental function constitute only a small part of a rapidly expanding list of interfaces between nutrition and the mind. Even in the absence of laboratory validation of nutritional deficiencies, numerous studies utilizing rigorous scientific designs have demonstrated impressive benefits from nutritional supplementation.

A high-potency multiple vitamin provides a good nutritional foundation on which to build. When selecting a multiple vitamin and mineral formula, it is important to make sure that it provides the fullrange of vitamins and minerals at high potency levels. Deficienciesof a number

Behavioral effects of some vitamin deficiencies Deficient vitamins

Behavioral effects

Thiamin

Korsakoff’spsychosis, mental depression, apathy, anxiety, irritability

Riboflavin

Depression, irritability

Niacin

Apathy, anxiety, depression, hyperirritability, mania, memory deficits, delirium, organic dementia, emotional lability

Biotin

Depression, extreme lassitude, somnolence

Pantothenic acid

Restlessness, irritability, depression, fatigue

B6

Depression, irritability, sensitivity to sound Forgetfulness, insomnia, apathy, irritability, depression, psychosis, delirium, dementia

Folic acid 812

Psychotic states, depression, irritability, confusion, memory loss, hallucinations, delusions, paranoia

Vitamin C

Lassitude, hypochondriasis,depression, hysteria

Depression, anxiety, irritability, and other psychologic disturbances Fatigue Headache Blurred vision Excessive sweating Mental confusion Incoherent speech Bizarre behavior Convulsions Several studies have shown hypoglycemia to be common in depressed individuals.3538A study of six countries showed a highly sigrulicantcorrelationbetween sugar consumption and the annual rate of depre~sion.3~ Simply eliminating refined carbohydrate from the diet is occasionally all that is necessary for effective therapy in patients who have depression due to reactive hypoglycemia. The dietary guidelines for depression are identical to the dietary guidelines for optimal health. It is now a well-established fact that certain dietary practices cause, while others prevent, a wide range of diseases. Quite simply, a health-promoting diet provides optimal levels of all known nutrients and low levels of food components that are detrimental to health such as sugar, saturated fats, cholesterol, salt, and food additives. A health-promoting diet is rich in whole “natural” and unprocessed foods. It is especially high in plant foods such as fruits, vegetables, grains, beans, seeds, and nuts, as these foods contain not only valuable nutrients but also additional compounds that have remarkable health-promoting properties.

Folic Acid and Vitamin BI2 Folic acid and vitamin B12 function together in many biochemical processes. Folic acid deficiency is the most common nutrient deficiency in the world. In studies of depressed patients, 31% to 35% have been shown to be deficient in folic acid.- In elderly patients this percentage may be even higher. Studies have found that among elderly patients admitted to a psychiatric ward, the number with folic acid defiaency ranges from 35% to 9 2 . 6 Y 0 . ~ , ~ Depression is the most common symptom of a folic acid deficiency. Vitamin B12 defiaency is less common than that of folic acid defiaency, but it can also cause depression, especially in the elderly.46,47Correcting folic acid

Specific Health Problems

>-

Tryptophan /

Excretion products (skatole, indican)

5-Hydroxytryptophan th

\

I

Jaaad

Kynurine

Serotonin

*/,kh

3-Hydroxykynureine

Melatonin

5-Methoxytryptamine

/,

mao

Xanthurenic acid

3-Hydroxyanthranilic acid

5-Hydroxyondoleacetic acid

I (several steps)

Quinolinic acid

Picolinic acid

Niacin Pyridoxal-5-phosphate (PLP) dependent step aaad Aromatic amino acid decarboxylase, PLP dependent step; the rate for decarboxylation of 5-hydroxytryptophanis 16% of the rate of DOPA kh Kynurenine k Kynureninase, PLP dependent ka Kynurenine aminotransferase, PLP dependent mao Monoamine th Tryptophan hydroxylase, tetrahydrobiopterindependent tp Tryptophan pyrolase (oxygenase), inducible Figure 144-2 Relationshipamong folate cycle, S-adenosylmethionine, and transmethylation.

and vitamin BI2 deficiencies results in a dramatic improvement in mood. Folic acid, vitamin BI2, and a form of the amino acid methionine known as SAMe (Sadenosylmethionine) function as “methyl donors” (Figure 144-2). They carry and donate methyl molecules to important brain compounds including neurotransmitters. SAMe is the major methyl donor in the body. The antidepressant effects of folic acid appear to be a result of raising brain SAMe content. One of the key brain compounds dependent on methylation is tetrahydrobiopterin (BH,). This compound functions as an essential coenzyme in the activation of enzymes that manufacture monoamine neurotransmitters

like serotonin and dopamine from their corresponding amino acids. Patients with recurrent depression have been shown to have reduced BH4 synthesis, probably as a result of low SAh4e levels. BH4 supplementation has been shown to produce dramatic results in these Unfortunately, BH4 is not currently available commercially. However, since BH, synthesis is stimulated by folic acid, vitamin BI2, and vitamin C , it is possible that increasing these vitamin levels in the brain may stimulate BH, formation and the synthesis of monoamines like serotonin.50 Some evidence supports the contention that supplementing the diet with folic acid, vitamin C, and vitamin B12 can increase BH4 levels. In addition, the folic acid

Affective Disorders

supplementation and the promotion of methylation reactions have been shown to increase the serotonin c ~ n t e n t . ~The l - ~serotonin-elevating ~ effects are undoubtedly responsible for much of the antidepressive effects of folic acid and vitamin BI2. One review of three folate trials involving 247 depressed patients has been published.% Two of the studies involving 151people assessed the use of folate in addition to other treatment and found that adding folate reduced Hamilton Depression Scale (HDS) scores on average by a further 2.65. One of the studies, involving 96 people, assessed the use of folate instead of the antidepressant trazodone. This study did not find a sigruficant benefit from the use of folate. Although the authors of this analysis considered these data "limited," they acknowledged the potential role of folate as a supplement to treat depression. No side effects or toxicities were noted in any of the studies reviewed. Typically the dosages of folic acid in the antidepressant clinical studies have been high: 15 to 50 mg. High-dose folic acid therapy is safe (except in patients with epilepsy) and has been shown to be as effective as antidepressant drugs.55 A dosage of 800 pg of folic acid and 800 pg of vitamin B12should be sufficient in most circumstances to prevent deficiencies. Folic acid supplementation should always be accompanied by vitamin B12supplementation to prevent folic acid from masking a vitamin BI2deficiency.

Vitamin B6 B6 levels are typically quite low in depressed patients, especially women taking birth control pills or PremarinW Considering the many functions of vitamin B6 in the brain, including the fact that it is absolutely essential in the manufacture of all monoamines, it is likely that many of the millions of people taking Prozac may be suffering depression simply as a result of low vitamin B6. Patients with low B6 status usually respond well to supplementation. The typical effective dosage is 50 to 100 mg.

Zinc Zinc serves as the mineral cofactor in more than 70 metalloenzymes. Severe zinc deficiency is manifested by bullous-pustular dermatitis, diarrhea, alopecia, and recurrent infections.61A growing body of evidence implicates a derangement of zinc homeostasis in mood disorders. Interestingly, it has been shown that depressed patients who have low baseline levels of zinc experience increases in these concentrations in the hippocampus and other brain regions after being given prescription antidepressant therapies.62It has been postulated that zinc may act as an antagonist of the N-methyl-paspartate glutamate receptor.63 One small, placebo-controlled, double-blind pilot study of zinc supplementation in antidepressant therapy

was conducted in patients who were diagnosed with major (unipolar) depression. Six patients received 25 mg of zinc supplementation per day, while eight patients took a placebo. These patients were also treated with standard antidepressant therapy such as tricyclic antidepressants and selective serotonin reuptake inhibitors (SRIs). Using standard Hamilton Depression and Beck Depression Inventory Scales to assess efficacy of these antidepressant therapies, zinc supplementation significantly reduced scores in both measures after 6- and 12-week supplementation when compared with placebo treatment.64Although this was a small trial, it seems reasonable to use zinc as part of a multinutrient supplementation regimen for depressed patients. Long-term supplementation should be properly balanced with copper.

Selenium Plasma selenium is clearly lower in alcoholic patients. Serum, erythrocyte, and whole blood levels of selenium are also decreased in patients with alcoholism.65Low selenium status encourages depressed mood, whereas high dietary or supplementary selenium has been shown to improve mood.% Research has consistently reported that low selenium status was associated with a significantly increased incidence of depression, anxiety, confusion, and hostility.65Furthermore, when alcoholism and depression occur together in an individual, there is an increased risk for suicide.67 Given the propensity for low selenium status in alcoholic patients and the relationship between selenium levels and mood disorder, selenium supplementation is warranted in an attempt to ameliorate the untoward comorbid psychologic and physical profile of patients with alcohol abuse or dependence.

Chromium As increased sugar intake is correlated with depression, the essential trace mineral chromium may be a useful means to balance insulin levels. One small study evaluated the effects of chromium supplementation for atypical depression, which is characterized by mood reactivity, increased appetite and weight gain, hypersomnia, leaden paralysis, and interpersonal rejection sensitivity and is associated with earlier onset, greater chronicity, disability, and suicidality than other forms of depression. It is estimated that more than one fifth of all depressive illness falls into this category. A placebo-controlled, double-blind, pilot study of chromium picolinate was conducted in 15 patients with atypical types of major depressive disorder. Ten patients started with a dose of 400 pg, which increased to 600 pg for the remainder of the study. The other five patients took a placebo. Seventy percent of the patients on the chromium versus 0% of the placebo patients

Specific Health Problems responded positively to the treatment. Other outcomes were consistent with greater effect of chromium. Three patients on chromium failed to show any improvement. The chromium picolinate was well tolerated, with no attrition due to side effects.68 Another successful study of eight patients with depression found some enhanced dreaming and mild psychomotor a~tivation.6~ Chromium’s mechanism of action may be by alteration of brain serotonin levels,7O as well by increasing insulin insensitivity.7l

Omega-3 Fatty Acids An insufficiency of omega-3 oils has been linked to

depression.” Studies have also reported that countries with high rates of fish oil consumption have low rates of depressive disorder.%This may be related to the impact of dietary fatty acids on the phospholipid composition of neurologic cell membranes. Although it is thought that the cell is programmed to selectively incorporate the different fatty acids it needs to maintain optimal function, the lack of essential fatty acids (particularly the omega-3 oils) and excess of saturated fats and animal fatty acids lead to the formation of cell membranes that have much less fluid than normal. A relative deficiency of essential fatty acids in cellular membranes substantially impairs cell membrane function. Because the basic function of the cell membrane is to serve as a selective barrier that regulates the passage of molecules into and out of the cell, a disturbance of structure or function disrupts homeostasis. The medical literature has demonstrated that there are changes in fatty acid levels in the red blood cells of depressed patients and in serum fatty acid composition in depressive disorder.73 Because the brain is the richest source of phospholipids in the human body and proper nerve cell function is critically dependent on proper membrane fluidity, alterations in membrane fluidity affect behavior, mood, and mental function. Studies have shown that the biophysical properties, including fluidity, of brain cell membranes directly influence neurotransmitter synthesis, signal transmission, uptake of serotonin and other neurotransmitters, neurotransmitter binding, and the activity of monoamine oxidase. All of these factors have been implicated in depression and other psychologic disturbances. In one small study, 20 patients diagnosed with major depressive disorder participated in a 4-week, double-blind evaluation of either placebo or an eicosapentaenoic acid addition to their ongoing antidepressant therapy. The effect of eicosapentaenoic acid was sigruficant from week 2 of treatment, similar to the time course for effectiveness of antidepressant medications. The effect of the placebo was minimal. Item analysis showed that eicosapentaenoic acid also affected core depressive symptoms

such as depressed mood, guilt feelings, and worthlessness, as well as Because omega-3 fatty acids may play a key mechanistic role in the pathophysiology of depression,” it is possible that they may reduce the development of depression just as they reduce the development of coronary artery disease.72This conclusion was based on several factors: Studies have suggested that lowering plasma cholesterol by diet and medications increases suicide, homicide, and depression. *The quantity and type of dietary fats consumed influence serum lipids and alter the biophysical and biochemical properties of cell membranes. Dietary advice to lower cholesterol levels tends to increase the ratio of omega-6 to omega-3 fatty acids and decreases the level of the essential omega-3 fatty acid, docosahexanoic acid. Epidemiologic studies in various countries and the United States have indicated that decreased consumption of omega-3 fatty acids correlates with increasing rates of depression. A consistent association between depression and coronary artery disease also exists.

Food Allergies Depression and fatigue have been linked to food allergies for more than 65 years. In 1930 Rowe coined the term ”allergic toxemia” to describe a syndrome that included the symptoms of depression, fatigue, muscle and joint aches, drowsiness, difficulty in concentration, and n e w o u s n e s ~Although .~~ the term allergic toxemia is not used anymore, food allergies still play a major role in many people with depression.n

Monoamine Metabolism and Precursor Therapy The use of monoamine (MA) precursors, particularly tryptophan, 5-hydroxytryptophan (5-Hm),and tyrosine, has offered a more “natural way“ of influencing MA metabolism than monoamine oxidase inhibitors or tricyclic antidepressants.

The Tryptophan Catastrophe For more than 30 years, L-tryptophan was used by millions of people in the United States and around the world safely and effectively for insomnia and depression. But in October 1989, some people taking tryptophan started reporting strange symptoms to physicians-severe muscle and joint pain, high fever, weakness, swelling of the arms and legs, and shortness of The syndrome was dubbed eosinophilia-myalgiasyndrome (EMS). Laboratory studies showed that the blood of subjects with EMS contained a high level of eosinophils.

Affective Disorders

In patients with EMS, eosinophil levels rose to greater than 1000/mm3, roughly double the normal level, and the percentage of eosinophils often increased to levels above 30%. The problem with such severe elevations in eosinophils is that these white blood cells contain packets that have high levels of histamine and other allergic and inflammatory compounds. When these compounds are released by eosinophils, this leads to intense symptoms of an allergic and inflammatory nature (e.g., severe muscle and joint pain, high fever, weakness, swelling of the arms and legs, skin rashes, and shortness of breath)-the same symptoms as those experienced by people with EMS. It was suspected that one or more newly introduced contaminants that activated eosinophils and other white blood cells had to be the reason behind EMS because L-tryptophan had been used successfully by more than 30 million people worldwide without side effects. Detailed analysis of all evidence by the Centers for Disease Control and Prevention (CDC) led to the conclusion that the cause of the EMS epidemic could be traced to one Japanese manufacturer, Showa Denko.79,80 Of the six Japanese companies supplying L-tryptophan to the United States, Showa Denko was the largest, supplying 50% to 60%. The L-tryptophan was used not only as a nutritional supplement but also in infant formulas and nutrient mixtures used for intravenous feeding. The L-tryptophan produced from October 1988 to June 1989 by Showa Denko became contaminated with substances now linked to EMS due to changes in the bacteria being used to produce the L-tryptophan and in the filtration process. The change in the filtration process resulted in the L-tryptophan being contaminated with impurities linked to EMS. Examination of the prefiltered material indicated that it had no detectable levels of the impurities linked to EMS. Somehow the filtration process produced the contaminants. Although the epidemic of EMS during the last half of 1989 was clearly related to the contaminated L-tryptophan produced by Showa Denko, there have been a handful of other reported cases of EMS in people who never took L-tryptophan and in people who took L-tryptophan before the contaminated batch manufactured by Showa Denko hitting the shelves. It is likely that in these earlier reports of EMS-like illnesses among L-tryptophan users, the subjects were also using contaminated L-tryptophan and they also had a predisposition to EMS (discussed later).81,82 This conclusion is based on the fact that uncontaminated tryptophan 5-HTI’ has never produced EMS. Clearly, it is absolutely essential that uncontaminated L-tryptophan be used to avoid the possibility of EMS. The total number of reported cases of EMS in the United States eventually reached 1511. Included in this number were 36 deaths attributed to L-tryptophan. In Europe the total number of cases was 171and there were

no death^.^^-^^ The difference between the U.S. and the European experiences is that the dominant L-tryptophan supplement in Europe was Optimax, a product marketed by Merck, the largest pharmaceutic company in the world. The supplier of the tryptophan used in the Merck product was Ajimomato. An interesting aspect of the entire L-tryptophan catastrophe is that it did not affect more people. Based on very detailed studies, it was concluded that EMS affected 144 out of every 100,000 men and 268 out of every 100,000 women taking ~-tryptophan.~~ If 50% of these L-tryptophan users were taking Showa Denkosupplied L-tryptophan,we can assume that EMS affected 144 of every 50,000 men and 268 of every 50,000 women taking contaminated L-tryptophan. In other words, roughly 1 of every 250 people who took the contaminated L-tryptophan developed EMS. The obvious question is: “Why didn’t everyone taking the contaminated L-tryptophan experience EMS?” The answer appears to be that only those with an abnormal activation of the kynurenine pathway reacted to the contaminant.&4 Kynurenine and its metabolites (especially quinolic acid) are also linked to other EMSrelated illnesses including the toxic oil syndrome, one of the largest food-related epidemics to date. This syndrome occurred in Spain during May 1991. It affected more than 20,000 people and caused more than 12,000 hospitalizations. It was caused by the ingestion of canola oil contaminated with a compound similar to one found in the contaminated Showa Denko L-tryptophan.= An interesting finding from studies conducted by researchers from the Centers for Disease Control was that people who took a multivitamin preparation were extended some protection against EMS.% When regular vitamin users did develop EMS, it was less severe than the EMS experienced in non-vitamin users. A likely explanation for this occurrence is that either the vitamins (particularly vitamin B6 and niacin) shunted tryptophan metabolism away from the kynurenine pathway or the contaminants are somehow metabolized by vitamindependent enzymes.

L-Tryptophan The basic theory of tryptophan supplementation in depression (and insomnia) is that it will increase the level of serotonin and melatonin in the brain. This theory is supported by the considerable evidence that many depressed individuals have low tryptophan and serotonin levels. Unfortunately, supplementation with L-tryptophan in depressed patients has produced mixed results in the published clinical trials. In only two out of eight studies comparing L-tryptophan with a placebo was L-tryptophan shown to be more effective than the placebo. But interestingly, 9 of 11 studies comparing L-tryptophan with conventional antidepressant drugs showed no differen~e.8~-~~

Among the many factors to consider when looking at these studies are study size, severity of depression, duration, and dosage. In addition, a number of factors such as hormones like estrogen and cortisol, as well as tryptophan itself, stimulate the activity of tryptophan oxygenase, which results in tryptophan being converted to kynurenine and less tryptophan being delivered to the brain (Figure 144-1shows the metabolism of tryptophan). Evidence linking digestive dysfunction and abnormal serotonin levels is also emerging. Twenty percent of patients with functional bowel disorders also have psychiatric ~ornorbidities.9~ Effectively treating digestive dysfunction may also rebalance tryptophan and serotonin levels, thus working to alleviate depressive illness. The naturopathic notion of "treating the gut" may be of use in treating primary mechanisms of depression. In summary, L-tryptophan is only modestly effective in the treatment of depression when used alone. In order to gain any real benefit from L-tryptophan, it must be used along with vitamin Bb and the niacinamide form of vitamin B3 to help block the kynurenine pathway to provide better results. Better yet is the use of 5-HTP.

5-Hydroxytryptophan As the pharmacology of 5-hydroxytryptophan is fully described in Chapter 101, only a concise summary is presented here. Unlike tryptophan, 5-HTP cannot be converted to kynurenine and easily crosses the bloodbrain barrier. As a result, while only 3% of an oral dose of L-tryptophan is converted to serotonin, more than 70% of an oral dose of 5-HTP is converted to serotonin. In addition to increasing serotonin levels, 5-HTP causes an increase in endorphin and catecholamine levels. Numerous double-blind studies have shown that 5-HTP has "equipotency" with SRIs and tricyclic antidepressants in terms of effectiveness and is less expensive, better tolerated, and associated with fewer and much milder side effe~ts.9"~~

Phenylalanine and Tyrosine Although the number of clinical studies using phenylalanine or tyrosine for depression does not approach the number using tryptophan and 5-HTP, there is evidence that these monoamine precursors may be effective in some individuals.99J00General catecholamine metabolism is briefly illustrated in Figure 144-3. Phenylalanine, besides being hydroxylated to tyrosine and degraded to phenylketonic acids, can be decarboxylated to phenylethylamine (PEA).%Th~scompound has amphetamine-like stimulant properties and is suggested to be an endogenous stimulatory or antidepressive substance in humans. (Note that this biogenic amine is found in high concentrations in chocolate, which might explain the latter's addictiveness.) Low urinary PEA levels are found in depressed patients, while high levels

are found in schizophrenia.99J00Phenylalanine, both D and L- forms, has been demonstrated to increase

urinary PEA output and CNS PEA concentrations. As phenylalanine is a tyrosine hydroxylase inhibitor, it is expected that more shunting of phenylalanine to PEA synthesis will occur with supplementation. The pharmacologic activity of supplemental tyrosine in depressives may be related to its increasing of "trace amine" levels (octopamine, tyramine, and PEA), rather than just its enhancement of catecholamine synthesis or possibly its stimulation of thyroid hormone synthesis. The largely negative results using L-dopa alone in affective disorders tend to substantiate this Central norepinephrine turnover, however, is decreased in depressed patients. This may be a result of the low serum tyrosine levels seen in some depressed individuals.'@' Like tryptophan, the brain tyrosine content is best determined by the ratio of serum tyrosine concentration to the sum of its brain-uptake competitors (i.e., leucine, isoleucine, valine, tryptophan, phenylalanine). Tyrosine ratios are increased by high-protein meals. Tyrosine supplementation results in increased levels of 3-methoxy-4hydroxyphenethylene glycol (MHPG) in the urine. This compound is believed to be the principal breakdown product of norepinephrine in the CNS and may provide a biochemical marker for determining which amino acid to supplement. Table 144-2 summarizes clinical studies using phenylalanine or tyrosine, or both, for depression. These results indicate that phenylalanine and tyrosine supplementation offer encouraging alternatives to tricyclics and MA0 inhibitors. In the early 1970s, van Praag and colleagues discovered that about one in five patients who responded well to 5-HTP tended to relapse after 1 month of treatment. The antidepressant effects of 5-HTP in these subjects began to wear off gradually after the first month despite the fact that the level of 5-HTP in the blood, and presumably the level of serotonin in the brain, remained at the same level as when they were experiencing the The researchers discovered that although serotonin levels appeared to stay at the same levels after 1month of treatment, the levels of the other important monoamine neurotransmitters, dopamine and norepinephrine, declined.l0' These patients responded to supplemental tyrosine.

S-Adenosylmethionine SAMe was discussed briefly earlier with vitamin BI2and folic acid in its methylation role. SAMe is involved in the methylation of monoamines, neurotransmitters, and phospholipids like phosphatidylcholine and phosphatidylserine. Normally, the brain manufactures all the SAMe it needs from the amino acid methionine. However, SAMe synthesis is impaired in depressed patients.

Phenylalanine+ Ph

I

I

Tyrosine 4 L-Dopa I th

+Dopamine+

I

do

dc

/

/com

Phenylethylamine +Tyramine

Noroxyandelic acid

I Phenylethanol-+Octopamine I amine

Hydroxvphenyl-acetic acid-

Norepinephrine \

\ mao

Epinephrine

Pt

>

'ram

/

\

/ma0

3,4 Dihydroxyandelic /o

\corn Metanephrine

4-Hydroxy-3-methoxyandelic acid I

4-Hydroxy-3-methoxyphenylglycol

Hydroxymandelic acid

I

J/

Vanillic acid com dc do mao Ph Pt th

Catechol-0-methyl-transferase; SAMe dependent Dopa decarboxylase (aaad); pyridoxal-5-phosphatedependent ascorbate, copper and iron dependent; tryptamine and histamine inhibit Dopamine oxidase; 02, Monoamine oxidase; many drugs and plant compounds are inhibitory dihydrobiopterindependent Phenylalaninehydroxylase; 02, Phenylethanol-amine Kmethyltransferase;low activity in CNS; S-adenosylmethionine (SAMe) dependent; inhibited by tyramine, dopamine Tryptophan hydroxylase; inhibited by tryptophan, phenylalanine, dopa and dopamine; Fe dependent; rate limiting enzyme for dopamine synthesis tetrahydrobiopterin,02, Figure 144-3

Catecholamine metabolism.

Phenylalanineand tyrosine in depression No.of Datients

Dosages (mddav)

Duration (davs)

Clinical effects and comments

Yaryura et al. (1974)

15

200-400

14

(D,L-P)10 severely depressed patients responded

Fischer et al. (1975)

23

100

1-13

(D- or D,L-P)A complete response was observed in 17 patients previously unresponsive to tricyclics and MA0 inhibitors

Beckman et al. (1977)

20

75-200

20

(D,L-P) Eight complete remissions, four showed marked improvement; used Hamilton Depression Scale and von Zerssen self-ratingquestionnaire

Heller (1978)

55

100-400

60-180

(D-P)73% recoveredcompletely after 15 days, 23% had marked improvement, 4% failed to respond

Heller (1978)

60

100

30

(D-P)Complete remission and improvement in 83% for the phenylalanine group compared with 73% for the imipramine group; double-blind controlled study-no diagnostic criteria or rating scales were reported

Beckman (1979)

27

200

30

(D,L-P)No significant difference between phenylalanineand imipramine groups

9

300

Ongoing

(T) Double-blind, placebo-controlledstudy; tyrosine demonstrated a rate of response (60-70%) typical of most major antidepressantswithout side effects

References*

Gibson et al. (1983)

MAO, Monoamine oxidase; R phenylalanine; 1; tyrosine. 'References from Beckman H. Adv Biol Psychiat 1983;10:137-147 and Gelenberg AJ, Gibson CJ. Nutr Health 1984;3:163-173.

The results of a number of clinical studies suggest that Supplementing the diet with SAMe in depressed patients SAMe is one of the most effective natural antidepresresults in increased levels of serotonin, dopamine, and Unfortunately, its use is still limited due to its phosphatidesand improved binding of neurotransmitters sants.10510g high price. Tables 144-3 and 144-4 summarize doubleto receptor sites, resulting in increased serotonin and dopamine activity and improved brain cell membrane blind studies comparing SAMe with either a placebo or fluidity, and thus sigruficant clinical improvement.102-104 a tricyclic drug such as imipramine.

References'

SAMe responders

Fazio et al. (1973)

Not quantified

Placebo responders

Conclusion SAMe superior to placebo based on Hamilton Depression Scale (HDS)

Agnoli et al. (1976)

20120

1/10

SAMe superior to placebo

Muscettola et al. (1982)

4110

0110

SAMe superior to placebo

Janicak (1982)

5/7

015

SAMe superior to placebo

Caruso et al. (1984)

Not quantified

SAMe superior to placebo based on HDS

Carney et al. (1986)

Not quantified

SAMe superior to placebo based on HDS and Beck Scale

De Leo (1987)

Not quantified

SAMe superior to placebo based on Clinical Global Impression Scale

TOTAL

29/37 (78%)

1/25 (4%)

SAMe dramatically more effective than placebo

'References from Janicak PG. Lipinski J, Davis JM. et al. Psychopharmacol Bull 1989;25:238-242.

References.

SAMe responders

Drug responders

Conclusion

Mantero et al. (1975)

11/16

9115

SAMe comparable to imipramine (75 mg/day)

Barberi et al. (1978)

10/10

8/10

SAMe more effective than amitriptyline (100 mg/day)

5114

4110

SAMe comparable to clomipramine (100 mg/day)

Del Vecchio et al. (1978)

35/45

30141

SAMe comparable to clomipramine (100 mg/day)

Scarzella et al. (1978)

9110

9110

SAMe comparable to clomipramine (100 mg/day)

Scaggion et al. (1982)

18/22

10118

719

619

SAMe comparable to clomipramine (50 mg/day)

Plotkin (1988)

919

2/9

SAMe more effective than imipramine (150 mg/day)

Janicak (1988)

5l7

2/3

SAMe comparable to imipramine (150 mg/day)

Miccoli et al. (1978)

Kufferle et al. (1982)

TOTAL

1091142 (76%)

801124 (61Yo)

SAMe more effective than nomifensine (200 mg/day)

SAMe significantly more effective than antidepressant drugs

'References from Janicak PG, Lipinski J. Davis JM.et al. Psychopharmacol Bull 1989:25:238-242.

The studies cited in these tables used injectable SAMe. However, more recent studies using a new oral preparation at a dosage of 400 mg four times daily (1600mg total) have demonstrated that SAMe is just as effective orally as it is when given intraven~usly."~"~ SAMe is better tolerated and has a quicker onset of antidepressant action than tricyclic antidepressants. One study compared SAMe with the tricyclic desipramine. In addition to clinical response, the blood level of SAMe was determined in both groups. At the end of the 4-week trial, 62% of the patients treated with SAMe and 50% of the patients treated with desipramine had sigruficantly improved. Regardless of the type of treatment, patients with a 50% decrease in their HDS score showed a sigruficant increase in plasma SAMe

concentration.These results suggest that one way tricyclic drugs exert antidepressive effects is by raising SAMe 1e~els.l~~ No sigruficant side effects have been reported with oral SAMe. However, because SAMe can cause nausea and vomiting in some people, it is recommended that it be started at a dosage of 200 mg twice daily for the first day, increased to 400 mg twice daily on day 3, then to 400 mg three times daily on day 10, and finally to the full dosage of 400 mg four times daily after 20 days. Individuals with bipolar (manic) depression should not take SAMe. Because of SAMe's antidepressant activity, these individuals are susceptible to experiencing hypomania or mania. This effect is exclusive to some individuals with bipolar depression.

Affective Disorders

Botanical Medicines Hypericum perforatum St. John's wort is now becoming a standard treatment consideration for antidepressant the rap^,"^ Extracts of St. John's wort standardized for hypericin are the most thoroughly researched natural antidepressants. Mechanisms of action may include serotonin reuptake modulation, increases in interleukin-6 activity, and agonist action of sigma receptors. Past information implicating the inhibition of MA0 activity as a suggested mechanism is largely disproven. See Chapter 102 for more information. More than27 double-blind, randomized trials involving more than 2200 patients with mild to moderately severe depression have shown St. John's wort extracts standardized for hypericin to yield excellent results in the treatment in depression with far fewer side effects than standard antidepressant medications.116 A total of 1592patients have been studied in 25 doubleblind, controlled studies (15 compared with placebo, 10 compared with antidepressant drugs including 5 studies comparing St. John's wort extract with tricyclics: two versus imipramine, two versus amitriptyline, and one versus In these studies, St. John's wort extract was shown to produce improvements in many psychologic symptoms including the following: Depression Anxiety Apathy Sleep disturbances Insomnia Anorexia Feelings of worthlessness The main advantage of St. John's wort extract over antidepressant drugs was not so much a difference in therapeutic outcome but rather a sigruficant advantage in terms of side effects, cost, and patient satisfaction. For example, in a study of 102 patients, slightly better results were obtained with maprotiline (a tetracyclic) in the HDS, Discomfort Scale, and Clinical Global Impression scale, but when side effects and patient tolerance were added to the equation, St. John's wort was considered superior.lZ0Maprotiline treatment resulted in the typical side effects of tricyclics (e.g., tiredness, mouth dryness, heart complaints).It should be noted that St. John's wort has been known to decrease the efficacy of certain drugs including oral contraceptivesand may cause photosensitivity when dosed in high amounts.For more information on St. John's wort, consult Chapter 102.

Piper mythisticum Kava extracts, like St. John's wort, are gaining in popularity in Europe in the treatment of anxiety and depression.

Several European countries (e.g., Germany, the United Kingdom, Switzerland, Austria) have approved kava preparations in the treatment of nervous anxiety, insomnia, depression, and restlessness on the basis of detailed phannacologic data and favorable clinical studies. In fact, kava extract compares quite favorably with benzodiazepines in effectivenessbut does not possess the major drawbacks of these drugs (e.g., impaired mental acuity, addicti~eness).'~~-'~~ These approved kava preparations are extracts standardized for kavalactone content (usually 30% to 70%).Since a German study reported a high incidence of improper dosing of kava extract, it is important that practitioners be aware of how to use this botanical properly for best efficacy.'" Kava appears most useful in cases of depression with severe anxiety (for more information on kava, see Chapter 115).

Ginkgo biloba The extract of Ginkgo bilobu leaves standardized to contain 24% ginkgo flavonglycosides and 6% terpenoids exerts good antidepressant effects, especially in patients older than 50 years of age. Researchers became interested in the antidepressive effects of G. bilobu extract as a result of the improvement in mood reported by patients suffering from cerebrovascular insufficiency who were treated with @go in double-blind studies.15128These observations led to several double-blind studies of the efficacy of @go in depression. In one of the more recent doubleblind studies, 40 older patients (ranging from 51 to 78 years old) with depression who had not benefited fully from standard antidepressant drugs were given either 80 mg of G. bilobu extract three times daily or a p1aceb0.l~~ By the end of the fourth week of the study, the total score on the HDS was reduced on average from 14 to 7. At the end of the 8-week study, the total score in the G. bilobu extract group had dropped to 4.5. In comparison, the placebo group only dropped from 14to 13. This study indicates that G. bilobu extract can be used with standard antidepressants and may enhance their effectiveness, particularly in patients older than 50 years of age. In addition to human studies, G. bilobu extract has also demonstrated antidepressant effects in a number of animal models including the learned helplessness model. The most interesting of these studies demonstrated that G. bilobu extract was able to counteract one of the major changes in brain chemistry associated with aging-the reduction in the number of serotonin receptor sites.130 Typically, with aging there is a significant reduction in the number of serotonin receptor sites on brain cells. As a result, the elderly are more susceptible to depression, impaired mental function, insomnia, and sleep disturbances. The study was designed to determine whether G. bilobu extract could alter the number of serotonin receptors in old (24-month-old) and young (4-month-old)rats.

At the beginning of the study, the older rats had a 22% lower number of serotonin binding sites compared with the younger rats. The results of chronic treatment with G. bilobu extract for 21 consecutive days demonstrated that there was no change in receptor binding in young rats, but in the older rats there was a statistically sigruficant increase (by 33%) in the number of serotonin binding sites. These results indicate that G. bilobu extract may counteract at least some, if not all, of the age-dependent reductions of serotonin binding sites in the aging human brain as well. The exact mechanism of G. bilobu extract’s effect on increasing serotonin receptors has not yet been determined; however, G. bilobu extract may address two major reasons why serotonin receptors decline with age: impaired receptor synthesis or changes in cerebral neuronal membranes or receptors as a result of free radical damage. G. bilobu extract has demonstrated an ability to increase protein synthesis. The flavone amentoflavone, also found in H. perforufurn, binds to benzodiazepine receptors and is a modulator of GABA, which may be a major anxiolytic me~hanism.’~~ In addition, G. bilobu extract is known to be a potent antioxidant. The most likely explanation is that it is a combination of these two effects (and others) rather than one single mechanism (see Chapter 96 for further discussion).

Supplements High-potency multivitamins and minerals Vitamin C: 500 to 1000 mg three times daily Vitamin E: 200 to 400 IU/day Selenium: 200 pg/day Chromium: 400 to 600 pg/day Zinc: 25 mg/day Flaxseed oil: 1 tbsp/day 5-HTP: 100 to 200 mg three times daily Folic acid and vitamin BIZ: 800 pg of each daily

Botanical Medicines If a patient is younger than 50 years of age, St. John’s wort extract (0.3% hypericin) should be used at a dosage of 900 to 1800 mg daily. In severe cases, St John’s wort extract can be used in combination with 5-HTP or at a dosage of 50 to 100 mg three times daily. If older than 50 years of age, G. bilobu extract (24% @go flavonglycosides)should be used at a dosage of 240 to 320 mg daily. In severe cases, this can be used in combination with St. John’s wort or 5-HTE or both. If anxiety is a significant factor, kava extract standardized for kavalactone content should be used at a dosage of 45 to 70 mg kavalactones three times daily.

THERAPEUTIC APPROACH Treatment depends largely on accurate determination of which factors are contributing to the patient’s depression; balancing of errant neurotransmitter levels; and optimizing the patient’s nutrition, lifestyle, and psychologic health.

Diet Patients should increase their consumption of fiber-rich plant foods (fruits,vegetables, grains, legumes, and raw nuts and seeds) and avoid caffeine, nicotine, other stimulants, and alcohol. Their food allergies must be identified and controlled. Patients should increase their consumption of cold water fish to at least twice per week.

Lifestyle Patients should be referred to a counselor or helped in developing a positive, optimistic mental attitude. This can be accomplished by helping them set goals, use positive self-talk and affirmations, identify selfempowering questions, and find ways to inject humor and laughter into their lives. Patients should exercise at least 30 minutes at least three times a week. *Patients should spend 10 to 15 minutes daily on relaxation/ stress reduction techniques.

GENERAL CONSIDERATIONS Bipolar depression is a disorder characterized by periods of major depression alternating with periods of elevated mood. If the elevated mood is relatively mild and lasts for 4 days or less, it is referred to as hypornuniu. Mania is longer and more intense. To be diagnosed as a bipolar depressive, an individual would be expected to have at least three of the following symptoms: Excessive self-esteem or grandiosity Reduced need for sleep Extreme talkativeness, excessive telephoning Extremely rapid flight of thoughts along with the feeling that the mind is racing Inability to concentrate, easily distracted Increase in social or work-oriented activities, often with a 60- to 80-hour working week Poor judgment, as indicated by sprees of uncontrolled spending, increased sexual indiscretions, and misguided financial decisions A full-blown manic attack requires hospitalization. Manic people have lost control, and they may hurt

themselves or others. The standard treatment for bipolar depression is lithium. Lithium stabilizes mood. It is especially useful in preventing the manic phase. Lithium is used either alone or in combination with an antidepressant like Prozac. However, because Prozac and other antidepressant drugs can occasionallyinduce mania and hypomania, it is often difficult to effectively control the lows in bipolar depressives with drug therapy.

THERAPEUTIC CONSIDERATIONS Patients experiencing a manic syndrome usually require hospitalization to prevent impulsive and aggressive behavior from ruiningtheir careers or injuring themselves or others. Lithium has become the drug of choice for these patients. Typically, manic patients are initially hospitalized for 2 weeks and kept under sedation with antipsychotic drugs until lithium levels reach acceptable blood levels. Referral seems warranted for most cases until mood can be stabilized. Many of the principles outlined in the discussion of depression are applicable to mania as well. However, due to the seriousness of this condition, it is more appropriate to use nutritional therapy as an adjunct, rather than as the primary therapy. Also, as SRIs like Prozac, Zoloft, and Paxil are often helpful when used in combination with lithium, 5-HTP and botanical medicines such as St. John's wort extract may prove useful as adjuncts to lithium as well, without the side effects.

Omega-3 Fatty Acids One 4-month, double-blind, placebo-controlled study found marked therapeutic efficacy and no side effects of omega-3 fatty acids in the prevention of bipolar manic-depressive illness. Using 9.6 g/day of omega-3 fatty acids or an olive oil control, the patient group had a significantly longer period of remission than the placebo group. Furthermore, for nearly every other outcome measure, the omega-3 fatty acid group performed better than the placebo group.14' The authors of this study also postulated that omega-3 fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate.

Vanadium

Vanadium's role in mania has been researched primarily by Naylor and colleagues.142-144 Increased levels of vanadium are found in hair samples from manic patients, and these values fall toward normal levels with recovery.142 In contrast, depressed patients typically have normal hair concentrationsand elevated whole blood and serum vanadium levels.lQ Their levels also return to normal on recovery. Vanadium, as the vanadate ion, is a strong inhibitor of Na+,K+ATPase. Lithium has been reported to reduce this Therapies designed to reduce vanadate to the less inhibitory vanadyl form have used ascorbic acid, methylene blue, and EDTA separately and in combinat i ~ n . ' ~ Ascorbic ~,'~ acid (3 g/day) was shown in a Tryptophan double-blind, cross-over study to result in significant clinical impr~vement.'~~ Although patients have responded to tryptophan supThe use of a "low-vanadium diet" has also been plementation, the effective doses were generally quite advocated by Naylor. However, his dietary suggestions large (i.e., 12 g/day ~ - t r y p t o p h a n ) . ' ~A~better J ~ ~ choice for low vanadium intake are not consistent with the appears to be 5-HTP, which has been shown to be helpvanadium content of foods, as determined by flameless ful in the treatment of bipolar depression when used atomic absorption spectro~copy.'~~ Using this method, in combination with lithium at a much lower dosage (e.g., 100 mg three times daily) than ~-tryptophan.'~,'~~low-vanadium foods (1to 5 ng/g) include fats, oils, fresh fruits, and vegetables. Whole grains, seafood, meat, and PhosphatidyIcholine dairy products are in the range of 5 to 30 ng/g, while prepared foods such as peanut butter, white bread, Supplementation with large amounts of phosphatidyland breakfast cereals range from 11 to 93 r ~ g / g . 'The ~~ choline (15 to 30 g/day in both the pure form and as benefit of the low-vanadium diet used in Naylor's study lecithin) has shown better results than monoamine was probably due to his simultaneous administration precursors in the treatment of mania.'&'% Lithium is of EDTA. believed to promote increased CNS cholinergic activity If Naylor's hypothesis is correct, perhaps other factors via inhibition of choline flux across the blood-brain known to affect Na+,K+ATPase activity are involved barrier.139J40 Evidence indicates that mania is associated in some cases. Those factors associated with decreased with a reduced CNS cholinergic a c t i ~ i t y . ' ~The ~ , ' ~use of activity would include uremia, hypothyroidism, and phosphatidylcholineto increase CNS choline may result catecholamine insensitivity. From a therapeutic aspect, in significant improvement or amelioration of symptoms correction of these underlying factors may be of some in some Details of the basic defect in the aid. Vitamins E and B6 have been demonstrated to one-carbon cycle and the cholinergic system need to be increase Na+,K+ATPase activity in vitro, and vitamin E worked out, but the defect appears to be a valuable clue stabilizes membranes as well.'& to the etiology of mania.

Specific Health Problems

Circadian Rhythms

Light Therapy

Manic depressive patients have disturbed circadian rhythms, seasonal patterns of exacerbations, and supersensitivity to light, suggesting that alteration of circadian light-dark cycles through light therapy may be of clinical utility (see the section on seasonal affective disorder later).147

The antidepressive effects of full-spectrum light therapy have been demonstrated in well-monitored, controlled studies not only in SAD but also in clinical The antidepressant effect of light therapy is probably due to restoring proper melatonin synthesis and secretion by the pineal gland, leading to reestablishment of the proper circadian rhythm. Light therapy has also been shown to decrease TSH levels in SAD patients.'% Light therapy consists of using full-spectrum lighting (Vitalite is a popular brand). The typical protocol used in clinical studies involved placing full-spectrum fluorescent tubes in regular fluorescent fixtures (eight tubes total). Patients were then instructed to sit 3 feet away from the light from 5 AM to 8 AM and again from 5:30 PM to 8:30 PM. They were free to engage in activities as long as they glanced at the light at least once per minute. Obviously, to adopt this treatment protocol would greatly restrict social activities. Something that may work just as well is simply replacing standard light bulbs with full-spectrum light bulbs.

THERAPEUTIC APPROACH In general, the same dietary and lifestyle guidelines given in the section on depression are appropriate here.

Diet A low-vanadium diet is recommended. This entails eliminating all refined and processed foods and promoting the consumption of fresh fruits and vegetables.

Supplements Phosphatidylcholine: 10 to 25 g/day (phosphatidylcholine may induce depression in some patients? if this occurs, it should be discontinued immediately) Vitamin C: 3 to 5 g/day in divided doses Vitamin E: 400 to 800 IU/day Pyridoxine: 100 mg/day

GENERAL CONSIDERATIONS Seasonal affective disorder (SAD) is associated with winter depression and summer hypomania. Typically, these individuals feel depressed, slow down, and generally oversleep, overeat, and crave carbohydrates in the winter. In the summer, these same patients feel elated, active, and energetic.

THERAPEUTIC CONSIDERATIONS Melatonin Although many variables may be responsible for SAD, light exposure is the most logical explanation. Many mammals exhibit seasonal variation in activity level, sleep patterns, and appetite and are extremely sensitive to changes in day length. The key hormonal change may be a reduced secretion of melatonin from the pineal gland and an increased secretion of cortisol by the adrenal glands. Melatonin supplementation is thought to improve SAD because it increases brain melatonin levels, but it may also suppress cortisol se~reti0n.I~~

~-Tryptophan/5-Hydroxytryptophan An open-label trial of 16 patients with SAD who responded only somewhat, or not at all, to bright light therapy were given 1g of L-tryptophan three times a day in addition to 10,000 lux cool-white fluorescent light therapy for 30 minutes every morning. Two patients discontinued medications within 3 days because of side effects. In the 14 patients who completed their treatment, the addition of L-tryptophan significantly reduced mean depression scores. Overall, 9 of 14patients (64%)showed good clinical responses to combined treatment and minimal side effects.155Corroborating work also found that tryptophan depletion in drug-free depressed patients induced a sigruficant decrease in plasma-free and total tryptophan levels, with peak effects occurring 5 hours after ingestion of a tryptophan-free amino acid drink. A transient depressive relapse was observed within a day after the tryptophan depletion, although the same group also found no change in behavior in a subsequent trial, despite similar plasma tryptophan decrease^.'^^ By modulating serotonergic mechanisms, L-tryptophan may be a reasonable addition to a protocol for those patients who have minimal responses to light therapy. Another more effective therapeutic alternative may be to try 5 4 3 " (see earlier).

Hypericum perfoliatum St. John's wort extract, standardized to contain 0.3% hypericin (see Chapter 101), at a dosage of 300 mg three times daily, has been shown to improve SAD.'57 However, although effective on its own, St. John's wort

extract is more effective when used in combination with light therapy. This was demonstrated in a doubleblind study in which patients with SAD were randomized in a 4-week treatment study with 900 mg/day of St. John’s wort extract (0.3% hypericin content) combined with either bright (3000 lux, n = 10) or dim light (<300 lux therapy). There was a significant reduction in the HDS in both groups (72% and 60%, respectively), demonstrating that the efficacy of St. John’s wort extract in SAD is enhanced with light therapy.

Because the cause of SAD is related to light, the treatment goal is to extend light exposure on winter days. This can be accomplished by using full-spectrum lighting as described earlier. However, it may be unrealistic to expect most patients to comply fully. Therefore have the patient introduce full-spectrum lighting throughout his or her indoor environment and prescribe conjunctive therapy with nighttime melatonin (3 mg 45 minutes before retiring) and daytime St. John’s wort or 5-HTP.

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65.Sher L. Role of selenium depletion in the etiopathogenesis of depression in patient with alcoholism. Med Hypotheses 2002;59: 330-333. 66. Finley JW, Penland JG. Adequacy or deprivation of dietary selenium in healthy men: clinical and psychological findings. J Trace Elem Exp Med 1998;ll:ll-27. 67. Cornelius JR, Salloum IM,Mezzich J, et al. Disproportionate suicidality in patients with comorbid major depression and alcoholism. Am J Psychiatry 1995;152:358-364. 68.Davidson JR, Abraham K, Connor KM, et al. Effectiveness of chromium in atypical depression: a placebo-controlled trial. Biol Psychiatry 2003;53:261-264. 69. McLeod MN, Golden RN. Chromium treatment of depression. Int J

Neuropsychopharmacol2000;3:311-314. 70. Attenburrow MJ, Odontiadis J, Murray BJ, et al. Chromium treatment deavases the sensitivity of 5HTW receptors. Psychophannacology 2002;159:432-436. 71. Anderson RA. Chromium, glucose intolerance and diabetes. J Am Coll Nutrition 1998;17548-555. 72. Hibbeln JR, Salem N Jr. Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy. Am J Clin Nutr 1995;62:1-9. 73. Maes M, Christophe A, Delanghe J, et al. Lowered omega-3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res 1999;85:275-291. 74. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159:477-479. 75. Severus WE, Ahrens B, Stoll AL. Omega-3 fatty acids: the missing link? Arch Gen Psychiatry 1999;56:380-381. 76. Rowe AH, Rowe A, Jr. Food allergy. Its manifestations and control and the elimination diets. A compendium. Springfield, IL: CC Thomas, 1972. 77. Brostoff J, Challacombe SJ, eds. Food allergy and intolerance. Philadelphia: WB Saunders, 1987. 78. Hertzman PA, Blevins WL, Mayer J, et al. Association of the eosinophiha-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 1990;322:869-873. 79. Kilboume EM. Eosinophilia-myalgia syndrome: coming to grips with a new illness. Epidemiol Rev 1992;14:16-36. 80. Kilbourne EM, Philen RM, Kamb ML, et al. Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome. J Rheumatol Suppl1996;46:81-88. 81.Filippini GA, Costa CVL, Bertazzo A, eds. Recent advances in tryptophan research tryptophan and serotonin pathways. Exp Biol Med 1996;398:1-762. 82. Proceedings.Eosinophilic-MyalgiaSyndrome:Review and reappraisal of clinical, epidemiologic and animal studies symposium.Washington, DC,December 743,1994. J Rheumatol Suppl1996;463-110. 83. Belongia EA, Hedberg CW, Gleich GJ, et al. An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 1990;323357-365. 84. Silver RM, McKinley K, Smith EA, et al. Tryptophan metabolism via the kynwnine pathway in patients with the eosinophilia-myalgia syndrome. Arthritis Rheum 1992;35:1097-1105. 85. Hertzman PA. The eosinophilia-myalgia syndrome and the toxic oil syndrome. Pursuing parallels. Adv Exp Med Biol 1996;398: 339-342. 86. Hatch DL, Goldman LR. Reduced severity of eosinophilia-myalgia syndrome associated with the consumption of vitamin-containing supplements before illness. Arch Intern Med 1993;153:2368-2373. 87. Boman B. L-tryptophan: a rational anti-depressant and a natural hypnotic? Aust N Z J Psychiatry 1988;22:83-97. 88. Moller S, Kirk L, Brandrup E, et al. Tryptophan availability in endogenous depression-relation to efficacy of L-tryptophan treatment. Adv Biol Psychiat 1983;10:30-46.

Affective Disorders 89. d’Elia G, Hanson L, Raotma H. L-tryptophan and 5-hydroxytryptophan in the treatment of depression. A review. Acta Psychiatr Scand 1978;57239-252. 90. Carroll BJ. Monoamine precursors in the treatment of depression. Clin Pharmacol Ther 1971;12:743-761. 91. van Praag HM. Studies in the mechanism of action of serotonin precursors in depression. Psychopharmacol Bull 1984;20599-602. 92.van Praag HM. Central monoamine metabolism in depressions. I. Serotonin and related compounds. Compr Psychiatry 1980; 21:30-43. 93. Agazzi A, De Ponti F, De Giorgio R, et al. Review of the implications of dietary tryptophan intake in patients with irritable bowel syndrome and psychiatric disorders. Dig Liver Dis 2003;35590-595. 94. van Hiele LJ. 1-5-Hydroxytryptophanin depression: the first substitution therapy in psychiatry? The treatment of 99 out-patients with ’therapy-resistant’depressions.Nmpsychobiology 1980;6230-240. 95. Byerley WF, Judd LL, Reimherr FW,et al. 5-Hydroxytryptophan: a review of its antidepressant efficacy and adverse effects. J Clin Psychopharmacol1987;7127-137. 96. van Praag HM. Management of depression with serotonin precursors. Biol Psychiatry 1981;16:291-310. 97. Poldinger W, Calanchini 8, Schwarz W. A functional-dimensional approach to depression: serotonin deficiency as a target syndrome in a comparison of 5-hydroxytryptophan and fluvoxamine. Psychopathology 1991;2453-81. 98. van Praag HM, Lemus C. Monoamine precursors in the treatment of psychiatric disorders. In Wurtman RJ, Wurtman JJ, eds. Nutrition and the brain, vol7. New York Raven Press, 198689-139. 99. Gelenberg AJ, Gibson CJ. Tyrosine for the treatment of depression. Nutr Health 1984;3:163-173. 100. Beckman H. Phenylalanine in affective disorders. Adv Biol Psychiat 1983;10:137-147. 101.van Praag HM. In search of the mode of action of antidepressants: 5 - m / t y r o s i n e mixtures in depression. Adv Biochem Psychopharmacol1984;39:301-314. 102. Baldessarini RJ. Neuropharmacology of Sadenosyl-L-methionhe. Am J Med 1987;83(suppl5A):95-103. 103. Reynolds E, Carney M, Toone B. Methylation and mood. Lancet 1984;2196-198. 104.Bottiglieri T, Laundy M, Martin R, et al. Sadenosylmethionine influences monoamine metabolism. Lancet 1984;2224. 105.JanicakPG, LipinskiJ, Davis JM, et al. Parenteral Sadenosyl-methionine (SAMe) in depression: literature review and preliminary data. Psychopharmacol Bull 1989;25:238-242. 106.Friedel HA, Goa KL, Benfield P. Sadenosyl-L-methionine. Drugs 1989;38:389-416. 107. Carney M W , Toone BK, Reynolds EH. Sadenosylmethionine and affective disorder. Am J Med 1987;83(suppl5A):104-106. 108.Vahora SA, Malek-Ahmadi P. Sadenosylmethionine in the treatment of depression. Neurosci Biobehav Rev 1988;12139-141. 109. Nguyen M, Gregan A. Sadenosylmethionine and depression. Aust Fam Physician 2002;31:339-343. 110. Kagan BL, Sultzer DL, Rosenlicht N, et al. Oral Sadenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 1990;147591-595. 111. Rosenbaum JF, Fava M, Falk WE, et al. An open-label pilot study of oral Sadenosyl-L-methionine in major depression: interim results. Psychopharmacol Bull 1988;24:189-194. 112.De Vanna M, Rigamonti R. Oral Sadenosyl-L-methionine in depression. Curr Ther Res 1992;52478-485. 113. Salmaggi P, Bressa GM, Nicchia G, et al. Double-blind, placebocontrolled study of S a d e n o s y l - L - m e t e in depressed postmenopausal women. Psychother Psychosom 1993;59:34-40. 114. Bell KM, P o t h SG,Carreon D, et al. Sadenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl1994;154:15-18.

115. Buttenveck V. Mechanism of action of St. John’s wort in depression: what is known?CNS Drugs 2003;17539-562. 116. Linde K, Mulrow CD. St John’s wort for depression. Cochrane Database Syst Rev 2000;(2):CW00448. 117. Morazzoni P, Bombardell E. Hypericum perforatum. Fitoterapia 1995;6643-68. 118. Harrer G, Schulz V. Clinical investigation of the antidepressant effectiveness of Hypericum. J Geriatr Psychiatry Neurol 1994;7 (suppl 1):S6-8. 119. De Smet PA, Nolen WA. St. John’s wort as an antidepressant. BMJ 1996i313241-242. 120.Harrer G, Hubner WD, Podzuweit H. Effectiveness and tolerance of the hypericum extract LI 160compared with maprotiline: a multicenter double-blind study. J Geriatr Psychiatry Neurol 1994;7 (suppl 1):S24-28. 121. Singh YN. Kava: an overview. J Ethnopharmacol1992;3713-45. 122. Lindenberg D, Pitule-Schodel H. [D,L-kavain in comparison with oxazepam in anxiety disorders. A double-blind study of clinical effectiveness.]Fortschr Med 1990;108:49-50,53-54. 123. Kinzler E, Kromer J, Lehmann E. [Effect of a special kava extract in patients with anxiety-, tension-, and excitation states of non-psychotic genesis. Double blind study with placebos over 4 weeks] Arzneimittelforschung 1991;41:584-588. 124.Dietlein G, Schoder-Bemhardi D. Doctors‘prescription behaviour regarding dosage recommendations for preparations of kava extracts. Pharmacoepidemiol Drug Saf 2003;12:417-421. 125. DeFeudis FV,ed. Ginkgo biloba extract (EGb 761). Pharmacological activities and clinical applications. Paris: Elsevier, 1991. 126. Funfgeld EW, ed. Rokan (Ginkgo bilobu). Recent results in pharmacology and clinic. New York Springer-Verlag, 1988. 127. KleijnenJ, Knipschild P. Ginkgo biloba. Lancet 1992;340:1136-1139. 128. Kleijnen J, Knipschild P. Ginkgo biloba for cerebral insufficiency. Br J Clin Pharmacol1992;34:352-358. 129. Schubert H, Halama P. Depressive episode primarily unresponsive to therapy in elderly patients. Efficacy of Ginkgo biloba (Egb 761) in combination with antidepressants. Geriatr Forsch 1993;3 45-53. 130.Huguet F, Drieu K, Piriou A, et al. Decreased cerebral 5-HT1, receptors during aging: reversal by Ginkgo biloba extract (EGb 761). J Pharm Pharmacol1994;46316-318. 131.Hanrahan JR, Chebib M, Davucheron NL, et al. Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors. Bioorg Med Chem Lett;13:2281-2284. 132. Growden J. Neurotransmitter precursors in the diets. Their use in the treatment of brain diseases. In Wurtman R, Wurtman J, eds. Nutrition and the brain, vol3. New York Raven Press, 1979:117-182. 133. Chouinard G, Young SN, Annable L. Tryptophan in the treatment of depression and mania. Adv Biol Psychiat 1983;10:47-66. therapy.] Folia Psychiatr 134. Sano I. [L-5-hydroxytryptophan-(L-5-HTP) Neurol Jpn 1972;267-17. 135.van Praag HM. Central monoamine metabolism in depressions. I. Serotoninand related compounds. Compr Psychiatry 1980;21:30-43. 136. Wurtman R, Barbeau A, Growdon J. Choline and lecithin in brain disorders. In Wurtman R, Wurtman J, eds. Nutrition and the brain, vol5. New York Raven Press, 1979. 137. Cohen 8, Miller A, Lipinski J, et al. Lecithin in mania: a preliminary report. Am J Psychiatry 1980;137242-243. 138.Cohen B, Lipinski J, Altesman R. Lecithin in the treatment of mania: double-blind, placebo-controlled trials. Am J Psychiatry 1982;1391162-1164. 139.Jope R, Tolbert L, Wright S, et al. Biochemical RBC abnormalities in drug-free and lithium-treated manic patients. Am J Psychiatry 1985;142:356-358. 140.Jenden D, Jope R, Fraser S. A mechanism for the accumulation of choline in erythrocytes during treatment with lithium. Commun Psychopharmacol1980;4:339-344.

Specific Health Problems 141.Stoll A, Severus WE, Freeman MP, et al. Omega-3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56:407-412. 142.Naylor G, Smith A, Bryce-Smith D, et al.Tisue vanadium levels in manic-depressive psychosis. Psycho1 Med 1984;14:767-772. 143.Naylor G. Vanadium and manic depressive psychosis. Nutr Health 19843:79-85. 144.Naylor G. Vanadium and affective disorders. Biol Psychiatry 1983; 18103-112. 145.Myron D, Givand S, Nielsen F. Vanadium content of selected foods as determined by flameless atomic absorption spectroscopy. J Agric Food Chem 1977;25:297-300. 146.Nadiger H, Rao S, Sadasivudu 9. Effect of simultaneous administration of vitamin E and pyridoxine on erythrocyte membrane Na' K+ATPase activity. Int J Vitam Nutr Res 1984;54:307-311. 147.Lewy A, Wehr T, Goodwin F, et al. Manic-depressive patients may be supersensitiveto light. Lancet 1981;1:383-384. 148.Tamminga C, Smith R, Chang S, et al. Depression associated with oral choline. Lancet 19762905. 149.Yu HS, Reiter RJ, eds. Melatonin: biosynthesis, physiological effects and clinical applications. Boca Raton, FL:CRC Press, 1993. 150. Miles A, Philbrick DR. Melatonin and psychiatry. Biol Psychiatry 1988;23:405-425.

151.Rosenthal N, Sack D, Carpenter C, et al. Antidepressant effects of light in seasonal affective disorders. Am J Psychiatry 1985;142: 163-170. 152.Rosenthal N, Sack D, Gillin J, et al. Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 1984;41:72-80. 153.Leppamaki SJ, Partonen lT,Hurme J, et al. Randomized trial of the efficacy of bright-light exposure and aerobic exercise on depressive symptoms and serum lipids. J Clin Psychiatry 2002; 63:316-321. 154.Martiny K, Simonsen C, Lunde M, et al. Decreasing TSH levels in patients with Seasonal Affective Disorder (SAD) responding to 1 week of bright light therapy. J Affect Disord 2004;79: 253-257. 155. Lam RW, Levitan RD, Tam EM, et al. L-tryptophan augmentation of light therapy in patients with seasonal affective disorder. Can J Psychiatry 1997;42:303-306. 156.Neumeister A, Praschak-Rieder N, Hesselmann B, et al. Rapid tryptophan depletion in drug-free depressed patients with seasonal affective disorder. Am J Psychiatry 1997;154:1153-1155. 157.Kripke D, Risch S, Janowsky D. Bright white light alleviates depression. Psychiatry Res 1983;10105-112.

Alcoholism Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER C O N T E N T S Diagnostic Summary

1449

General Considerations 1449 Intoxication and Withdrawal

Therapeutic Considerations 1452 Nutrition 1452 Psychosocial Aspects 1454 Miscellaneous Factors 1455

1451

Metabolic Effects of Alcohol and Alcoholism 1451 Ethanol Metabolism 1451 Fatty Liver 1451 Hypoglycemia 1452

DIAGNOSTIC SUMMARY Alcohol dependence manifested when alcohol is withdrawn: tremulousness, convulsions, hallucinations, delirium Alcoholit binges, benders (248 hours of drinking associated with failure to meet usual obligations), or blackouts Evidence of alcohol-induced illnesses: cirrhosis, gastritis, pancreatitis, myopathy, polyneuropathy, cerebellar degeneration Physical signs of excess alcohol consumption: alcohol odor on breath, flushed face, tremor, ecchymoses Psychologic/social signs of excess alcohol consumption: depression, loss of friends, arrest for driving while intoxicated, surreptitious drinking, drinking before breakfast, frequent accidents, unexplained work absences

GENERAL CONSIDERATIONS The World Health Organization has defined alcoholism as alcohol consumption by an individual that exceeds the limits accepted by the culture or injures health or social relationships. As indicated in Box 145-1, the health, social, and economic consequences of alcoholism are alarming. With more than 100,000 deaths annually attributed to alcohol misuse, alcohol-related problems are a cause of considerable morbidity and mortality2Current estimates

Therapeutic Approach 1455 Recommendations for All Four Stages 1455 Specific Recommendations for Each Stage 1456

indicate that 18 million persons in the United States are alcoholics, making alcoholism one of the most serious health problems facing the physician today.’ The total number of Americans affected, either directly or indirectly, is much greater when one considers disruption of family life, automobile accidents, crime, decreased productivity, and mental and physical disease. Doctors should consider alcoholism when the information provided by the patient and the doctor’s own analysis seem to indicate a missing factor. Often, alcoholism is a “hidden” disease. The natural consequences of the alcoholic’s behavior may be disguised by sympathetic family and friends. This allows the alcoholic to target other factors as the “real problem” without identifying his or her drinking behavior. Table 145-1 provides an alcoholism-screening questionnaire. The etiology of alcoholism remains obscure. It represents a multifactorial condition with genetic, physiologic, psychologic, and social factors, all of which seem to be equally important. Serious drinking often starts in younger people; approximately 35% of alcoholics develop their first symptoms between 15 and 19 years of age, and more than 80%develop their first symptoms before age 30.3 Although alcoholism is most common in men, the incidence has been increasing in women. Once at more disparate figures, the female-to-male ratio for alcohol dependence has tapered to 12.2 Women generally seem to develop disease at a lower quantity of intake than

1449

Specific Health Problems

Modifiedfrom Hyman SE. Cassem NH. Alcoholism. In Dale DC,Federman DD. eds.Scientific American medicine. New York: Scientific American 1997;111:1-12:13.

The brief Michigan Alcoholism Screening Test 1. Do you feel you are a normal drinker?

Yes (0)

2. Do friends or relatives think you are a normal drinker?

Yes (0)

3. Have you ever attended a meeting of Alcoholics Anonymous (AA)?

Yes (5)

4. Have you ever lost friends or girlfriends or boyfriends because of drinking?

Yes (2)

5. Have you ever gotten into trouble at work because of drinking?

Yes (2)

6. Have you ever neglected your obligations, your family, or your work for 2 or more days in a row because you were drinking?

Yes (2)

7. Have you ever had delirium tremens (DTs), severe shaking, heard voices, or seen things that weren’t there after heavy drinking?

Yes (2)

8. Have you ever gone to anyone for help about your drinking?

Yes (5)

9. Have you ever been in a hospital because of drinking?

Yes (5)

10. Have you ever been arrested for drunk driving or driving after drinking?

Yes (2)

Modified from Hyman SE,Cassem NH. Alcoholism. In Dale DC. Federman OD, eds. Scientlic American medicine. New Yo&: Scientific American, 1997:13, 111:1-12. Alcoholism is indicated by a score of >5.

men do. This may be partially due to women’s lower volume of distribution for alcohol and may also be related to increased gut permeability to endotoxins.4 Research indicates genetic factors may be most import a r ~ t The . ~ finding of a genetic marker for alcoholism could result in the diagnosis of the disease in its initial and most reversible stage. Some case-control studies suggest that non-gender-based gene polymorphisms encoding cytokines and other immune modulators may play a role in alcoholic predispositions.The gene patterns associated with risk reveal that antibody-mediated mechanisms

could play a role in disease path~genesis.~ Interestingly, genetic studies have also shown that the major alcoholismrelated genes that have so far been identified are those protective against alcoholism. For example, approximately half of all Southeast Asians have genetic variants of alcohol-metabolizing enzymes such that after drinking only small amounts of alcohol, they experience an unpleasant facial flushing, tachycardia, nausea, and headaches. These symptoms and signs are a result of the accumulation of the toxic metabolite acetaldehyde? It is probable that people predisposed to alcoholism are either

less sensitive to these toxic accumulations or better able to clear these metabolites, or both. Therefore they may continue drinking comfortably way beyond the ability of a nonalcoholic. The genetic basis of alcoholismhas also been supported by the following: Genealogic studies showing that alcoholism is a family condition Studies of adopted children of alcoholic parents raised by foster parents demonstrating continued higher risk of alcoholism Twin studies showing differences between identical and nonidentical twins Association with genetic markers: color vision, nonsecretor ABH, HLA-BI3, and low platelet monoamine oxidase (MAO) Biochemical studies showing the importance of alcohol dehydrogenase polymorphism in racial susceptibility to alc~holism.~ A number of studies have shown that the incidence of alcoholism is four to five times more common in the biologic children of alcoholic parents than those of nonalcoholic parent^.^ Although it would be ultimately useful, knowledge of family history suggests that clear evidence of a biologic marker may not be necessary for the implementation of a relatively innocuous primary prevention program.

INTOXICATION AND WITHDRAWAL The signs of alcoholic intoxication are typical of a central nervous system depressant: drowsiness, errors of commission, disinhibition, dysarthria, ataxia, and nystagmus. Fifteen milliliters of pure alcohol (the equivalent of 1 oz of whiskey, 4 oz of wine, or 10 oz of beer) raise the blood level of alcohol by 25 mg/dl in a 70-kg person. Table 145-2 shows the effects of varying blood levels of alcohol. Effects of varying levels of blood alcohol Blood level (ma/dl)

Effect

<50

No significant motor dysfunction

100

Mild intoxication-decreased inhibitions, slight visual impairment, slight muscular incoordination, slowing of reaction time Legally intoxicatedin most jurisdictions

150 350

500

Ataxia, dysarthria, slurring of speech, nausea and vomiting Marked muscular incoordination,blurred vision, approaching stupor Coma and death

Withdrawal symptoms usually occur 1 to 3 days after the last drink. They typically range from anxiety and tremulousness to mental confusion, tremor, sensory hyperactivity, visual hallucinations, autonomic hyperactivity, diaphoresis, dehydration, electrolyte disturbances, seizures, and cardiovascular abnormalities.

METABOLIC EFFECTS OF ALCOHOL AND ALCOHOLISM Ethanol Metabolism Tne primary metabolic processes that regulate the rate of alcohol catabolism in normal individuals are6: The rate of ethanol absorption The concentration and activity of liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) The reduced nicotinamide adenine dinucleotide (NADH)/nicotinamide adenine dinucleotide (NAD)+ ratio in the liver mitochondria It is generally accepted that the availability and regeneration of NAD+ are the dominant rate-limiting factors for ethanol ~xidation.~ Ethanol is converted to acetaldehyde by ADH, with NAD+ as a necessary cofactor. The aldehyde product of ethanol metabolism is believed to be responsible both for many of the harmful effects of alcohol consumption and for the addictive process itself. Higher than normal blood aldehyde levels have been found in alcoholics and their relatives after alcohol cons~mption.~ This suggests either increased ADH activity or depressed ALDH activity in people susceptible to alcoholism. Acetaldehyde is converted by ALDH to acetate with little entering the Krebs cycle; most is converted to long-chain fatty acids.6

Fatty Liver All active alcoholics display fatty infiltration of the liver, with the severity roughly proportional to the duration and degree of alcohol excess. Even moderate doses of ethanol may produce both acute and chronic fatty liver infiltrates. The pathogenesis is due to the following6~*: Increased endogenous fatty acid synthesis Diminished triglyceride utilization Impaired lipoprotein excretion Direct damage to endoplasmic reticulum by free radicals produced by ethanol metabolism The high-fat diet of the alcoholic (as is typical of the average American diet) Leptin is a peptide hormone involved in the regulation of appetite and energy metabolism. It is most likely directly related to liver pathology in alcoholics. High levels of leptin are known to contribute to liver pathology including increased rates of fibrosis, a known factor in liver steatosis? Research has demonstrated increased

Specific Health Problems

circulating leptin levels in a dose-dependent manner in chronic alcoholism, regardless of nutritional status.1°

Hypoglycemia Alcohol induces reactive hypoglycemia. The resultant drop in blood sugar produces a craving for food, particularly foods that quickly elevate blood sugar (i.e., sugar and alcohol). Increased sugar consumption aggravates the reactive hypoglycemia, particularly in the presence of alcohol, due to alcohol-induced impairment of gluconeogenesis.6 Hypoglycemia aggravates the mental and emotional problems of the alcoholic and the withdrawing alcoholic with such symptoms as the following': Sweating Tremor Tachycardia Anxiety Hunger Dizziness Headache Visual disturbance Decreased mental acuity Confusion Depression

THERAPEUTIC CONSIDERATIONS Nutrition Although many of the nutritional problems of alcoholics relate directly to the effects of alcohol, a major contributing factor is that alcoholics tend not to eat. They substitute alcohol for food. As a result, the alcoholic not only has to deal with nutritional deficiencies caused by excessive alcohol consumption, but also true nutritional deficiencies due to inadequate intake.

Zinc One of the key nutrients involved in the metabolic handling of alcohol is zinc, as both ADH and ALDH are zinc-dependent enzymes, with the latter being more sensitive to deficiency." Both acute and chronic alcohol consumption result in zinc deficiency."J2 Several factors contribute to the development of zinc deficiency in alcoholics: Decreased dietary intake Decreased ileal absorption (probably due to interference with the zinc-binding ligand, picolenic acid, and nonspecific mucosal damage) Hyperzincuria Both higher hair zinc and copper values have been observed in a study of 43 male alcoholics, versus no higher levels in 39 nonalcoh~lics.~~ Hair copper was sigruficantly related to the amount of ethanol consumed, whereas hair

zinc was higher in consumers of distilled beverages. These data may indicate abnormal metabolism and loss of these minerals in the alcoholic. Low serum zinc levels are associated with impaired alcohol metabolism, a predisposition to cirrhosis, impaired testicular function, and other complications of alcohol abuse."J4 Zinc supplementation, particularly when combined with ascorbic acid, greatly increases alcohol detoxification and survival in rats.I5

Vitamin A Vitamin A deficiency is also common in alcoholics and appears to work synergistically with zinc deficiency to produce the major complications of alcoholism!J4 The mechanism has been hypothesized as follows: reduced intestinal absorption of zinc and vitamin A, in conjunction with impaired liver function (reduced extraction of zinc, mobilization of retinol binding protein [RBP], and storage of vitamin A), results in reduced blood levels of zinc, vitamin A, RBP, and transport proteins, as well as a shift to nonprotein ligands. These cause the tissues to have reduced concentrations of zinc and vitamin A, abnormal enzyme activities and glycoprotein synthesis, and impaired DNA/RNA metabolism and cause the kidneys to increasingly lose zinc. These metabolic abnormalities then lead to the common disorders of a l c o h ~ l i s m ~ ~ : Night blindness Skin disorders Cirrhosis of the liver Reduced skin healing Decreased testicular function Impaired immune function Vitamin A supplementation ir- ibits alcohol consumption in female rats, and the effect is inhibited by testosterone administration.16 Other research on rats further supports the sigruficance of the endocrine system on alcohol preference. Ovariectomized and adrenalectomized rats show decreased preference for alcohol, while corticosterone injections increase alcohol preference.17 Vitamin A supplementation in the alcoholic has corrected vitamin A deficiency as noted by improvements in night blindness and sexual function! Despite the importance and benefits to the alcoholic, great care must be employed when recommending vitamin A supplementation. Excessive amounts of vitamin A are contraindicated due to the fact that a liver damaged by excessive alcohol consumption sigruficantly loses its ability to store vitamin A. As a result, the alcoholic is at great risk for developing vitamin A toxicity when supplemented at dosages above the recommended dietary allowance of 5000 IU.

Antioxidants Ethanol consumption increases lipid peroxidation in humans, resulting in increased lipoperoxidelevels in both

Alcoholism the liver and serum. Matters are made even worse by the fact that alcoholics are typically deficient in key antioxidant nutrients, particularly vitamin E, selenium, and vitamin C.lSJ9There is a significant correlation between serum lipid peroxide levels, serum glutamate oxaloacetate transaminase (SGOT) activity, and liver cell Antioxidant administration, either before or simultaneous with ethanol intake, inhibits lipoperoxide formation and prevents fatty infiltration of the liver.2l Effective antioxidants include vitamins C and E, zinc, selenium, and cysteine.

Carnitine Although the use of lipotropic agents appears warranted in treating alcoholic fatty liver disease, many commonly used lipotropic agents (e.g., choline, niacin, cysteine) appear to have little value.",23 One lipotropic agent, carnitine, significantly inhibits alcohol-induced fatty liver disease. It has been suggested that chronic ethanol consumption results in a functional deficiency in carniBecause carnitine normally facilitates fatty acid transportation and oxidation in the mitochondria, a high liver camitine level may be necessary to handle the increased fatty acid load produced by alcohol consumption. Supplemental carnitine reduces serum triglycerides and SGOT levels while elevating HDL chole~terol.~~

Amino Acids Amino acid chromatography patterns are aberrant in alcoholics; restoration to normal levels greatly aids the alcoholic ~ a t i e n t . ~ Because ~ - ~ O the liver is the primary site for amino acid metabolism, it is not surprising that alcoholics develop abnormal amino acid patterns. Normalization of plasma amino acids is particularly indicated in those patients showing signs or symptoms of hepatic cirrhosis or depression. The branched-chain amino acids (BCAAs)-valine, isoleucine, and leucineinhibit the hepatic encephalopathy and increased protein catabolism that are common sequelae of cirrhosis.30 Methionine, a known lipotropic, must be activated to S-adenosylmethionine. However, in severe liver disease, the activity of the corresponding enzyme is depressed. In this case, supplementation with methionine is not as useful. Sadenosylmethioninewould be indicated to ameliorate associated deficiencies and resulting Derangement of neurotransmitter profiles, particularly due to the low plasma levels of tryptophan typically seen in withdrawing alcoholics, will result if not normalized, leading to depression, encephalopathy, and Anomalous amino acid profiles are aggravated by the low-protein diet used as standard therapy for cirrhosis but can be avoided through the use of free-form amino acids without the risk of hepatic en~ephalopathy?',~~ (See the section on depression later for further discussion of amino acid imbalances.)

Although there are some characteristic amino acid abnormalitiesin alcoholics, an individual approach is indicated due to differences in nutritional status, biochemistry, and the amount of liver damage. Correction of the imbalances probably requires amino acid chromatography for best results.

Vitamin C In one study, a deficiency of ascorbic acid (AA) was found in 91% of patients with alcohol-related diseases.32 Supplemental AA helped ameliorate the effects of acute and chronic ethanol toxicity in experimental studies involving humans and guinea pigs, two species unable to There is a direct correlation synthesize their own AA.15,33 between leukocyte ascorbic acid levels (a good index of actual body AA status), the rate of ethanol clearance from the blood, and the activity of hepatic ADH.I4The evidence suggests that AA, a strong reducing agent, can function as an electron donor similar to NAD in ethanol metabolism, thereby increasing the conversion of ethanol to acetaldehyde and the further catabolism of a~etaldehyde.'~3~

Selenium Plasma selenium is clearly lower in alcoholic patients. Serum, erythrocyte, and whole blood levels of selenium are also decreased in patients with a l c o h ~ l i s m Low .~~ selenium status encourages depressed mood, whereas high dietary or supplementary selenium has been shown to improve mood.MResearch has consistently reported that low selenium status was associated with a significantly increased incidence of depression, anxiety, confusion, and h0~tility.l~ Furthermore, when alcoholism and depression occur together in an individual, there is an increased risk for ~uicide.3~ Given the propensity for low selenium status in alcoholic patients, and the rela tionship between selenium levels and mood disorder, selenium supplementation is warranted in an attempt to ameliorate the untoward comorbid psychologic and physical profile of patients with alcohol abuse or dependence.

B Vitamins Alcoholics are classically deficient in most of the B These deficiencies result from various mechanisms: Low dietary intake Deactivation of the active form Impaired conversion to the active form by ethanol or acetaldehyde Impaired absorption Decreased storage capacity Alcohol diminishes thiaminabsorption in the intestine and reduces hepatic thiamin storage. It also decreases phosphorylation of thiamin,leading to a reduction of the

active form of thiamin that also may contribute to development of thiamin defi~iency.~~ A thiamin deficiency is both the most common (55% in one study32)and the most serious of the B vitamin deficiencies, since a deficiency causes beriberi and the Wernicke-Korsakoff syndrome. In addition, evidence indicates that a thiamin deficiency results in greater intake of alcohol, suggesting that thiamin deficiency is a predisposing factor for a l c ~ h o l i s m .It~ ~should be noted that once present, Wernicke-Korsakoff syndrome is refractory to oral doses of thiamin,so rapid replacement of depleted brain thiamin levels by repeated parenteral therapy is required.% A functional pyridoxine deficiency is also common in alcoholics, due not so much to inadequate intake as to impaired conversion to its active form, pyridoxalIn addition to 5-phosphate, and enhanced degradati~n?~ inhibiting conversion to more active forms, alcohol also decreases the absorption and utilization by the liver and increases the urinary excretion of many B vitamins, especially folic acid.*lM

Magnesium Magnesium deficiency is common in alcoholics. In fact, hypomagnesemia is present in as many as 60% of alcoholics and is strongly linked to delirium tremens.4' It is thought to be the major reason for the increased cardioThis deficiency is vascular disease noted in due primarily to a reduced magnesium intake coupled with alcohol-induced renal hyperexcretion of magnes i ~ m , ' ,which ~ ~ continues during withdrawal despite low serum magnesium levels. Alcoholic cardiomyopathy, often associated with thiamine deficiency, may instead be due to a magnesium deficiency.

Essential Fatty Acids Ethanol has been shown to interfere with essential fatty acid (EFA) metabolism and, as a result, may produce symptoms of EFA deficiency if consumed in excess.43 A 5-year study of alcohol-consuming rhesus monkeys linked a marginal EFA diet to alcoholic amblyopia, a rare neuropathy characterized by blurred vision, diminished retinal function, and a reduction in visual acuity.@Brain biopsies showed the fatty acyl docosahexaenoic acid (DHA) composition of brain specimens had decreased significantly compared with controls. In the retinas of the alcohol-consuming animals at 5 years, there was a similar decrease in DHA. It may be useful to support neurologic function by giving EFAs in order to prevent these ophthalmologic sequelae.

Glutamine Glutamine supplementation (1 g/day) has been shown to reduce voluntary alcohol consumption in uncontrolled human studies and experimental animal studies!H7 Although this research occurred more than 50 years ago,

there has never been any follow-up to these preliminary studies. This failure to follow up this line of research is unfortunate, as the results were promising and showed the supplement to be safe and relatively inexpensive.

Psychosocial Aspects Psychologic and social measures are critical in the treatment of the alcoholic patient. It is important for the physician to maintain a nonjudgmental, but not passive, attitude toward the patient. Alcoholism should be viewed as a chronic, progressive, addictive, and potentially fatal disease, although many aspects of the alcoholic's behavior may make it difficult to maintain this objectivity.' Social support for both patient and family is important, and success often appears proportional to the involvement of Alcoholics Anonymous (AA), counselors, and other social agencies. Because most physicians have not had adequate training or experience in handling the psychosocial aspects of this problem, it is important to establish a close working relationship with an experienced counselor and AA. Al-Anon and Ala-Teen are useful resources for family members. Successfulinitiation of treatment requires the following: The patient's agreement that he or she has an alcohol problem Education of the patient and family about the physical and psychosocial effects of alcoholism Immediate involvement of the patient in a treatment program Successful programs (such as AA) usually include strict control of drinking and replacement of the alcohol addiction with another addiction that is nonchemical, time consuming, and heavily supported by family, friends, and peers. Although strict abstinence may not be absolutely necessary, at this time it appears the safest and most effective choice.'

Depression Depression is common in alcoholics and is known to lead to the high suicide rate. Many alcoholics are depressed first and later become alcoholic (primary depressives), while others become alcoholic first and later develop a depressive condition in the context of their alcoholism (secondary depressives). Alterations in the metabolism of serotonin and the availability of its precursor, tryptophan, have been implicated in some forms of depression, while other forms have been linked to alterations in catecholamine metabolism and tyrosine availability. Alcoholicshave severely depleted levels of tryptophan, which may explain both the depression and sleep disturbances common in alcoholism, since brain serotonin levels depend on circulating tryptophan levels.48Ethanol impairs tryptophan transport into the brain. The enzyme tryptophan pyrrolase, considered to be rate limiting in

Alcoholism tryptophan catabolism, is more active in rats during alcohol withdrawal.28In one study, five of six chronic alcoholics had no detectable plasma tryptophan on withd r a ~ a 1The .~~ tryptophan levels returned to normal after 6 days of treatment and abstinence. Another factor influencing tryptophan uptake into the brain is competition from amino acids that share the same transport-tyrosine, phenylalanine, valine, leucine, isoleucine, and methioninemany of which are elevated in malnourished alcoholic^?^,^ Alcoholics have sigruficantly depressed ratios of tryptophan to these amino acids when compared with normal controls, with depressed alcoholics having the lowest ratios.% The major amino acids, whose elevated levels help to lower this ratio, are the catecholamine precursors, tyrosine and phenylalanine. Elevated plasma catecholamine levels are common in alcoholics and may contribute to the depressi0n.4~An interesting finding is that taurine is also low in depressed alcoholics, with the lowest levels being reported in psychotic alcoholic^.^^

Miscellaneous Factors Intestinal Flora The intestinal microflora is severely deranged in alcoholics.50 Colonization of the small intestine by endotoxin-producingbacteria may lead to malabsorption of fats, carbohydrates, protein, folic acid, and vitamin BIZ, This is probably the cause of the abnormalitiesof the small intestine commonly found in alcoholics. Alcohol ingestion also increases intestinal permeability to endotoxins and macromolecules, allowing increased toxic and antigenic effects.51The ensuing allergic reactions and deposition of immune complexes probably contribute to the many complications of alcoholism, and, considering the addictive tendency of food allergies, may also contribute to alcoholic cravings.

Exercise The involvement of the alcoholic patient in a graded, individually tailored fitness program has been shown to improve the likelihood of maintaining Research has shown that regular exercise is effective in alleviating anxiety and depression and enables individuals to respond better to stress. Improved fitness may allow more effective responses to emotional upset, thereby reducing the likelihood of resorting to alcohol when involved in conflict.

Silybum marianum The flavonoid complex of milk thistle (silymarin) appears to be useful for the alcoholic, especially in the presence of considerable liver involvement or cirrhosis. Silymarin has been shown to be effective in the treatment of the fullspectrum of alcohol-related liver disease from relatively mild to serious cirrhosis. Perhaps the

most sigruficant benefit is extending the life span of these patients. In one study 87 cirrhotics (46 with alcoholic cirrhosis) received silymarin, while 83 cirrhotics (45 with alcoholiccirrhosis) received a placebo.53The mean observation period was 41 months. In the treatment group, there were 24 deaths with 18 related to liver disease, while in the controls, there were 37 deaths with 31 related to liver disease. The 4-year survival rate was 58% in the treatment group, compared with 39% in the controls. Silymarin can also improve immune function in patients with cirrhosis.54Whether this effect is involved in the hepatoprotective action or a result of improved liver function has yet to be determined.

THERAPEUTIC APPROACH Alcoholism is a difficult disease to treat. Although many therapeutic regimens have been attempted, there has been little documented long-term success, except for that of AA (and even the overall success of this program is highly controversial). The approach presented here is unique in that we have attempted to develop an integrated, whole-person, stage-oriented program. The treatment of the alcoholic patient must be optimized for the four stages of alcoholism: active alcohol consumption, withdrawal, recovery, and recovered. The recovery stage is defined here as the period between withdrawal and fullreestablishment of normal metabolic function. All alcoholics, at whatever stage, benefit the most by employing simultaneous counseling, lifestyle, and metabolic-balancing therapies. Following are the recommended therapies in the usual context, with additional recommendations for each stage. Also, a complete diagnostic work-up is necessary due to the high risk that the alcoholic patient will develop a wide variety of clinical and subclinical diseases.

Recommendations for All Four Stages Diet Stabilization of blood sugar levels is critical to successful treatment. Although a strict hypoglycemic diet may not be warranted, most of the dietary guidelines must be followed. These include elimination of all simple sugars (foods containing added sucrose, fructose, or glucose; fruit juice; dried fruit; and low-fiber fruits such as grapes and citrus fruits); limitation of processed carbohydrates (e.g., white flour, instant potatoes, white rice); and an increase in complex carbohydrates (e.g., whole grains, vegetables, beans).

Supplements Vitamin A: 5000 IU/day Vitamin B complex: 20 times the recommended daily allowance Vitamin C: 1 g two times/day

Specific Health Problems

Vitamin E 400 IU/day (d-alpha-tocopherol) Magnesium: 250 mg two times/day Selenium: 200 pg/day Zinc: 30 mg/day (picolinate) Camitine: 500 mg two times/day (L-camitine) Glutamine: 1g/day Lactobacillus acidophilus: 1tsp/day

Exercise Establish a graded program using heart rate response to determine intensity. The patient should exercise five to seven times per week, for 20 to 30 minutes, at an intensity sufficient to raise the heart rate to 60% to 80% of maximum for the age group.

Counseling Establish a good working relationship with AA and an experienced counselor who has particular expertise in working with alcoholics. Additional recommendations for the four stages follow.

Specific Recommendations for Each Stage Stage I: Active Alcohol Consumption Work with family, peers, social contacts, and whomever else is involved with the patient to elicit his or her recognition of an alcohol problem and willingness to enter a treatment program. Additional supplements include the following: Pyridoxal-5-phosphate:20 mg/day Riboflavin: 100 mg/day Vitamin A: 50,000 KJ/day Zinc: 30 mg/day

1. Hyman SE, Cassem NH. Alcoholism. In Dale DC, Federman DD, eds. Scientific American medicine. New York Scientific American 1997;IIk1-1213. 2. Enoch MA, Goldman D. Problem drinking and alcoholism: diagnosis and treatment. Am Fam Physician 2002;65441-448. 3. Rohde P, Lewinsohn PM, Kahler CW,et al. Natural course of alcohol use disorders from adolescence to young a d u l t h d . J Am Acad Child Adolesc Psychiatry 2001;40:83-90. 4.Day CP. Who gets alcoholic liver disease: nature or nurture? J R Coll Physicians Lond 2000;34:557-562. 5. CruzCoke R. Genetics and alcoholism. Neurobehav Toxic01 Teratol I 983;5: 179-180. 6. Pohorecky LA, Brick J. Pharmacology of ethanol. Pharmacol Ther 1988;36:335427. 7. Tipton KF, Heneman GTM, McCrodden JM. Metabolic and nutritional aspects of alcohol. Biochem Soc Trans 1983;11:59-61. 8.Lieber CS. Alcohol, liver, and nutrition. J Am Coll Nutr 1991;lO: 602-632.

Stage 11: Withdrawal Severity of symptomatology vanes widely, although it is usually proportional to the degree of physiologic dependence and duration of the disease. Milder cases usually start within a few hours after cessation of drinking and typically resolve within 48 hours. More severe cases usually occur only in patients older than 30 years of age and usually develop after about 48 hours of abstinence. These patients should be admitted to an inpatient facility. Some institutions may not allow the use of supplements; this should be checked before a patient is admitted. Additional supplements include the following: Tryptophan: 3 g/day Riboflavin: 100 mg/day Electrolyte replacement as necessary

Stage 111: Recovering Establish a strong network of caring family, friends, and peers to regularly support the patient. Get the patient involved and busy with intense, people-oriented activities. Help the patient recognize that alcohol is no answer to the stresses of life; aid him or her in developing more effective ways of handling adversity. An additional supplement is flaxseed oil, 1 tbsp three times/day.

Stage IV: Recovering The patient’s support group must always be maintained. Continued total abstinence is the best policy, although carefully controlled drinking may be possible. Slowly reduce supplement dosages, after a 6-month abstinence, to 25% of the previously mentioned dosages.

9. Piche T, Vandenbos F, Abakar-Mahamat A, et al. The severity of liver fibrosis is associated with high leptin levels in chronic hepatitis C. J Vial Hepat 2004;11:91-96. Femandez-Sola J, Fatjo F, et al. Increased circulating leptin 10. Nicolas JM, levels in chronic alcoholism. Alcohol Clin Exp Res 2001;25:83-88. 11. Das I, Burch RE, Hahn HK.Effects of zinc deficiency on ethanol metabolism and alcohol and aldehyde dehydrogenase activities. J Lab Clin Med 1984;104:610-617. 12. Wu CT, Lee JN, Shen WW, et al. Serum zinc, copper, and ceruloplasmin levels in male alcoholics. Biol Psychiatry 1984;19:1333-1338. 13. Gonzalez-Reimers E, Aleman-Valls MR, Barroso-Guerrero F, et al. Hair zinc and copper in chronic alcoholics.Biol Trace Elem Res 2002; 85269-275. 14.Scholmerich J, Lohle E, Kottgen E, et al. Zinc and vitamin A deficiency in liver cirrhosis. Hepato-Gastroenterol1983;30:119-125. 15. Yunice AA,Lindeman RD. Effect of ascorbic acid and zinc sulphate on ethanol toxicity and metabolism. Proc Soc Exp Biol Med 1977; 154.146-150.

Alcoholism 16. Messiha FS. Vitamin A, gender and ethanol interactions.Neuorbehav

Toxic01 Teratol1983;5:233-236. 17. Morin LP, Forger NG. Endocrine control of ethanol intake by rats or hamsters: relative contributions of the ovaries, adrenals and steroids. Pharmacol Biochem Behav 1982;17529-537. 18. Lecomte E, Herbeth B, Pirollet P. Effect of alcohol consumption of blood antioxidant nutrients and oxidative stress indicators. Am J Clin Nutr 1994;60255-261. 19.Sher L. Role of selenium depletion in the etiopathogenesis of depression in patients with alcoholism. Med Hypotheses 2002;59: 330-333. 20. Suematsu T, Matsumura T, Sat0 N, et al. Lipid peroxidation in alcoholic liver disease in humans. Alcohol Clin Exp Res 1981;5427-430. 21. DiLuzio NR. A mechanism of the acute ethanol-induced fatty liver and the modification of liver injury by antioxidants. Am J Pharm Sci Support Public Health 1966;1550-63. 22. Stanko RT, Mendelow H, Shinozuka H, et al. Prevention of alcoholinduced fatty liver by natural metabolites and riboflavin. J Lab Clin Med 1978;91:228-235. 23. Hartroft WS, Porta EA, Suzuki M. Effects of choline chloride on hepatic lipids after acute ethanol intoxication. Q J Stuc Alcohol 1964;25:427-437. 24. Sachan DS,Rhew TH, Ruark RA. Ameliorating effects of camitine and its precursors on alcohol-induced fatty liver. Am J Clin Nutr 1984;39:738-744. 25. Hosein EA, Bexton B. Protective action of camitine on liver lipid metabolism after ethanol administration to rats. Biochem Pharmacol 1975;24:1859-1863. 26. Sachan DA, Rhew TH. Lipotropic effect of camitine on alcoholinduced hepatic stenosis. Nutr Rep Int 1983;271221-1226. 27. Majumdar SK, Shaw GK, Thomson AD. Changes in plasma amino acid patterns in chronic alcoholicpatients during ethanol withdrawal syndrome: their clinical implications. Med Hypotheses 1983;12: 239-251. 28. Branchey L, Branchey M, Shaw S, et al. Relationship between changes in plasma amino acids and depression in alcoholic patients. Am J Psychiatry 1984;141:1212-1215. 29.Rosen HM, Yoshimura N, Hodgman JM, et al. Plasma amino acid patterns in hepatic encephalopathy of differing etiology. Gastroenterology 1977;72:483-487. 30. Fischer JE, Rosen HM, Ebeid AM, et al. The effect of normalization of plasma amino acids on hepatic encephalopathy Surgery 1976;80:7%91. 31. Lieber CS. Hepatic, metabolic, and nutritional disorders of alcoholism: from pathogenesis to therapy. Crit Rev Clin Lab Sci 2000;37 551-584. 32. Baines M. Detection and incidence of B and C vitamin deficiency in alcohol-related illness. Ann Clin Biochem 1978;15:307-312. 33. Yunice AA, Hsu JM, Fahmy A, et al. Ethanol-ascorbate interrelationship in acute and chronic alcoholism in the guinea pig. Proc SOC Exp Biol Med 1984;177:262-271. 34. Finley JW, Penland JG. Adequacy or deprivation of dietary selenium in healthy men: clinical and psychological findings. Trace Elem Exp Med 1998;ll:ll-27. 35. Cornelius JR, Salloum IM, Mezzich J, et al. Disproportionate suicidality in patients with comorbid major depression and alcoholism. Am J Psychiatry 1995;152358-364.

36. Koike H, Mori K, Misu K, et al. Painful alcoholic polyneuropathy with predominant small-fiber loss and normal tluamine status. Neurology 2001;56:1727-1732. 37. Zimatkin SM, Zimatkina TI. Thiamine deficiency as predisposition to, and consequence of, increased alcohol consumption. Alcohol Alcohol 1996;31:421427. 38. Thomson AD. Mechanisms of vitamin deficiency in chronic alcohol misusers and the development of the Wemicke-Korsakoff syndrome. Alcohol Alcohol 2000;35(~~ppl1):2-7. 39. Lumeng L. The role of acetaldehyde in mediating the deleterious effect of ethanol on pyridoxal 5’-phosphate metabolism.J Clin Invest 1978;62:286-293. 40. McMartin KE, Collins TD, Bairnsfather L. Cumulative excess urinary excretion of folate in rats after repeated ethanol treatment. J Nutr 1986;1161316-1325. 41. Jermain DM, Crismon ML, Nisbet RB. Controversies over the use of magnesium sulfate in delirium tremens. Ann Pharmacother 1992; 26650-652. 42. Abbott L, Nadler J, Rude RK. Magnesium deficiency in alcoholism: possible contribution to osteoporosis and cardiovascular disease in alcoholics. Alcohol Clin Exp Res 1994;18:1076-1082. 43. Horrobin DF. A biochemical basis for alcoholism and alcoholinduced damage including the fetal alcohol syndrome and cirrhosis: interference with essential fatty acid and prostaglandin metabolism. Med Hypotheses 1980;6929-942. 44.Pawlosky RJ, Bacher J, Salem N Jr. Ethanol consumption alters electroretinograms and depletes neural tissues of docosahexaenoic acid in rhesus monkeys: nutritional consequences of a low n-3fatty acid diet. Alcohol Clin Exp Res 2001;25:1758-1765. 45. Rogers LL, Pelton RB, Williams RJ. Voluntary alcohol consumption by rats following administration of glutamine. J Biol Chem 1955; 214:503-506. 46. Rogers LL, Pelton RB. Glutamine in the treatment of alcoholism. Q J Stud Alcohol 1957;18:581-587. 47. Ravel JM, Felsing B, Lansford EM Jr., et al. Reversal of alcohol toxicity by glutamine. J Biol Chem 1955;214:497-501. 48. Branchey L, Shaw S, Lieber CS. Ethanol impairs tryptophan transport into the brain and depresses serotonin. Life Sci 1981;29: 2751-2755. 49. Ireland MA, Vandongen R, Davidson L, et al. Acute effects of moderate alcohol consumption on blood pressure and plasma catecholamines. Clin Sci (Lond) 1984;66:643-648. 50. Bode JC, Bode C, Heidelbach R, et al. Jejunal microflora in patients with chronic alcohol abuse. Hepatogastroenterology 1984;31:30-34. 51. Worthington BS, Meserole L, Syrotuck JA. Effect of daily ethanol ingestion on intestinal permeability to macromolecules. Am J Dig Dis 1978;2323-32. 52. Sinyor D, Brown T, Rostant L, et al. The role of a physical fitness program in the treatment of alcoholism. J Stud Alcohol 1982;43: 380-386. 53. Ferenci P, Dragosics B, Dittrich H. Randomized controlled trial of Silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989;9:105-113. 54. Deak G, Muzes G, Lang I, et al. [Immunomodulator effect of silymarin therapy in chronic alcoholic liver diseases.] Orv Hetil 1990; 131:1291-1292,1295-1296.

Alzheimer’s Disease Michael T. Murray, ND Joseph E. Pizzorno Jr, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

1459

General Considerations 1459 Neuropathology 1459 Etiology 1460 Aluminum 1460

Vitamin BI2 1464 Zinc 1465 Phosphatidylcholine 1466 Phosphatidylserine 1466 L-Acetylcarnitine 1466

Diagnostic Considerations 1461 Recognizing Reversible Causes 1462 Fingerprint Patterns 1462

Other Therapies 1467 Dehydroepiandrosterone 1467 Melatonin 1467 Botanical Medicines 1467

Therapeutic Considerations 1462 Diet 1462 Estrogen 1463 Aluminum 1463

Therapeutic Approach 1469 Dietary and Lifestyle Recommendations Supplements 1469 Botanical Medicine 1469

1469

Nutritional Considerations 1463 Antioxidants 1463 Thiamin 1464

DIAGNOSTIC SUMMARY Progressive mental deterioration, loss of memory and cognitive functions, inability to carry out activities of daily life Characteristic symmetrical, usually diffuse electroencephalogram (EEG) pattern Diagnosis usually made by exclusion Definitive diagnosis can be made only by postmortem biopsy of brain, demonstrating atrophy, senile plaques, and neurofibrillary tangles

GENERAL CONSIDERATIONS Alzheimer’s disease (AD)is a neurodegenerative disorder that clinically manifests itself as a progressive deterioration of memory and cognition or dementia. In the United States, 5% of the population older than 65 suffer from severe dementia, while another 10% suffer from mild to moderate dementia. With increasing age, there is a rise in frequency. For example, in people older than 80 years of age, the frequency rate for dementia is higher than 25%. Postmortem studies have shown that 50% to 60%of all

cases of dementia, in both the senile and presenile periods, are the result of AD. The tremendous increase (tenfold)of AD in this century in the U.S. population older than 65 years of age is one reason why AD is referred to as “the disease of the twentieth century.” Many believe that AD will reach epidemicproportions by the end of thiscentury.

Neuropathology AD has distinctive neuropathologic features, including the following*: Plaque formation Amyloid deposition Neurofibrillary tangles Granulovacuolar degeneration The massive loss of telencephalic neurons These findings are particularly evident in the cerebral cortex and hippocampal formation. The clinical features of AD are believed to be related to cholinergic dysfunction due to appreciable reductions in the activity of the enzyme choline acetyltransferase, the enzyme that synthesizes acetylcholine, and the neuronal transfer of choline. 1459

Specific Health Problems

Etiology The etiology of AD is being extensively researched. Genetic factors play a major role with several genes being linked to AD: the amyloid precursor protein on chromosome 21 (explainingthe close association between Down syndrome and AD); the presenilin genes on chromosomes 14 and 1; and the apolipoprotein E (ApoE) gene on chromosome 19. The first two mutations are rare and associated with symptoms developing before the age of 50. The most significant genetic finding is the link with the ApoE. One form of ApoE, the e4type, is linked to a sigruficantlygreater risk for AD; another, the eZtype, is associated with significant protection. Literature is accumulating regarding the role of genetically linked aberrant immune system regulation of inflammation as a possible contributor to AD, as we are now observing for cardiovascular disease conditions such as atherosclerosis. Although innate immune function in the brain is normally modulated to remove plaque formation in an attempt to maintain health, research is beginning to characterize a chronic and excessive reaction to immune protofibrils of amyloid proteins in the brain that can promote disease.* As a result, immunotherapeutic approaches have recently been developed for the treatment of AD. These studies led to human trials that resulted in both beneficial and adverse effect^.^ The findings further encourage natural therapeutic considerations including a greater role of antioxidant protection from untoward immune processes and may lead to employing the natural antiinflammatory therapeutics currently being considered for cardiovascular disease. Although genes play a significant role in determining susceptibility to AD, like most chronic degenerative disease, lifestyle and environmental factors also play a sigruficant role. Emerging research reveals that dietary factors are important. Poor-quality diets with excess saturated or trans fatty acids may predispose neurons to aluminum-induced toxicities.45 Some data suggest that abnormal sleep-wake cycles and decreased morning light exposure may play a role in the expression of AD (see the section on melatonin later). Traumatic injury to the head; chronic exposure to aluminum or silicon, or both; exposure to neurotoxins from environmental sources; and free radical damage have all been implicated as causative factors as well. Like other chronic degenerative diseases, there is considerable evidence that increased oxidative damage plays a central role in the pathophysiology. Therapies designed to support antioxidant mechanisms (discussed later) may be quite helpful in the prevention of AD?

Aluminum Considerable attention has been focused on the association of aluminum concentration in the neurofibrillary tangle (NFT). Whether the aluminum concentration

develops in response to AD or whether it initiates the lesions has not yet been determined, but sigruficant evidence shows that it contributes, possibly significantly, to the disease. Aluminum has a strong affinity for the paired helical filament-tau (PHF-r), which is involved in the formation of the neurofibrillary tangles. In fact, studies have demonstrated that aluminum is the cofactor along with this tau filament in the formation of the neurofibrillary tangles.’ The aluminum selectively binds to PHF-r, induces PHF-z to aggregate, and retards the brain’s ability to break down PHF-r. Corroboration of aluminum’s role in AD is further supported by a recent animal study that evaluated long-term exposure to ecologic doses of aluminum. In this study, researchers found ghostlike neurons with cytoplasmic and nuclear vacuolations, with aluminum deposits. The hippocampus contained neuritic plaques, while the cerebrovasculature exhibited amyloid deposits. The authors also found behavioral changes in these rats that are reminiscent of those observed in AD.8 A great deal of circumstantial evidence links chronic aluminum exposure to AD. Increasing aluminum concentrations in the brain could explain why AD increases with increasing age. A study of 356 healthy people has shown that serum aluminum concentration increases as people age.9 Those with AD have significantly higher aluminum levels than both normal people and patients with other types of dementias, such as those from alcohol, atherosclerosis, and stroke. Trying to remove the aluminum appears to help some, but it is probably too late after the disease is well established. For example, intramuscular injections of desferrioxamine (a chelating agent for the removal of iron and aluminum) over a 2-year period showed a significant slowing of the rate of decline in 48 AD patients.1° Even in those without mental disease, elevated aluminum levels are associated with poorer mental function. For example, in a study of dialysis patients, the 13 patients who had a positive aluminum deferoxamine test (a measure of the amount of aluminum in the body) were compared with 13 who had a negative test. Subjecting the entire group to four attention tests and two memory tests revealed that those with higher levels of aluminum had a moderate to considerable disturbance of mental function.1° The aluminum appears to come from the water supply, food, antacids, and deodorants. The most sigruficant source is probably drinking water, as the aluminum in water is in a more bioavailable, and thus potentially toxic, form. Researchers measured the aluminum absorption of tap water by adding a small amount of soluble aluminum in a radioactive form to the stomachs of animals. They discovered that the trace amounts of aluminum from this single exposure immediately entered the animals’ brain tissue. The frightening news is that aluminum in

water not only occurs naturally but is also added (in the form of alum) to treat some water supplies.”

Causes and mechanisms of development of senile dementia

DIAGNOSTIC CONSIDERATIONS

Etiology

Pathogenesis

Because only about 50% of patients with dementia actually have AD, a comprehensive diagnostic work-up is paramount in the approach to the demented patient. The diagnosis of AD chiefly depends on clinical judgment. Complete evaluation of a patient who may have dementia includes the following:

Degenerative etiology

Disturbancesof gene expression and thus of protein metabolism

Altered genetic code

Disturbanceof the synthesis of specific proteins

Alzheimer’s disease

Reduction in acetylcholinesynthesis resulting from decreased choline acetyltransferase activity

Huntington chorea

Disturbanceof the GABA-nergic system

A detailed history Neurologic and physical examination Psychologic evaluation with particular attention to depression A general medical evaluation with emphasis on the detection of subtle metabolic, toxic, or cardiopulmonary disorders that can precipitate confusion, especially in the elderly A series of neurophysiology tests to document the type and severity of cognitive impairment Evaluation by a social worker or other qualified individual who can mobilize community resources Appropriate laboratory studies, including an electrocardiogram, EEG, computed tomography scan, and magnetic resonance spectroscopy

Idiopathic dementia Localized form

Decline in cognitive function

Parkinson’s disease

Reduction in dopamine turnover

Pick’s disease

Reduction in cholinergic activity

Loss of neuronal redundancy

Disturbanceof cerebral metabolism following infection or trauma Reduction in cholinergic activity caused by loss of neurons and synapses

Cerebrovascular disease Chronic meningitis Tuberculous, mycotic Encephalomyelitis Encephalopathy following head injury (boxers) Epileptic dementia Virus encephalopathy

The diagnostic process in AD is one of exclusion. Nutritive etiology The first step is to diagnose dementia. Error rates of Chronic alcoholism 10% to 50% have been reported when the diagnosis Diabetes mellitus of dementia is based only on the first eval~ation.’~~’~ Most of these misdiagnosed patients are found, on Disturbances of electrolyte metabolism further evaluation, to have a pseudodementing funcHypoglycemia tional illness.I2 Depression, which can mimic dementia in the elderly, is common. Table 146-1 lists possible Hyponatremia causes. Hypothyroidism A careful neurologic examination is required for every Korsakoff syndrome subject suspected of dementia.l The examination will Nicotinamidedeficiency reveal one of the following: Vitamin B deficiency 1.Clear evidence of focal, circumscribed brain disease 2. Clear evidence of diffuse, bilateral brain dysfunction 3. No evidence of neurologic dysfunction

The ”routine” neurologic examination described in most physical diagnosis textbooks is designed to effectively recognize ”1”and “3,” but it will not accurately assess diffuse brain dysfunction, the evidence for which is subtle. The diagnosis of diffuse brain dysfunction is made through careful attention to the patient’s level of consciousness, attentiveness to the examiner, comprehension, and performance of tasks. Note is also made of facial expressions, quality of speech, posture, respiratory rhythm, and gait.

Toxic etiology Addiction to barbiturates, psychotropic drugs, etc. Chronic carbon monoxide intoxication Chronic cesium intoxication Mycotoxins RenaVhepatic encephalopathy Vincristine intoxication

Insulin, starvation Diuretics Thiamine transketolase deficiency Disturbancesof energy formation

Specific Health Problems Specific signs of diffuse brain dysfunction include the following: Persistence of glabella-tap response (light tapping above the bridge of the nose produces a blink, which normally fatigues rapidly) Corneomandibular reflex (ipsilateral strong blink and contralateral movement of the chin in response to a firm stimulus applied quickly to the cornea) Sucking reflex Snout reflex Palmomental reflex (ipsilateral contraction of mentalis muscle in responseto stimulation of the t h e m eminence) Grasp reflex

Recognizing Reversible Causes Once the diagnosis of dementia is made, the next step is to rule out reversible causes of dementia. The most common reversible cause is drug toxicity. Other important causes are metabolic and nutritional disorders such as hypoglycemia; thyroid disturbances; and vitamin BI2/ folate, or thiamine deficiencies.Also to be considered are neurosyphilis and a number of disorders that can cause dementia: Huntington's chorea, cerebral vascular disease, normal pressure hydrocephalus, and intracranial masses. Table 146-2 lists recommended tests. The EEG is an important diagnostic tool in differentiating dementia. Although a normal EEG does not rule out the diagnosis of dementia, particularly in its early stages, it does provide valuable information. AD is associated with a characteristic symmetrical, usually diffuse slowing of the EEG. More importantly, the EEG

differentiates focal (e.g., intracranial mass or vascular disease) versus diffuse (e.g., metabolic disorders or normal pressure hydrocephalus) brain dysfunction. The CT scan is included in the diagnostic protocol due to the high incidence (4% to 5%)of silent brain tumors or other masses (e.g., subdural hematoma) in patients seen for the diagnosis of dementia. The CT scan is of limited usefulness in AD, since atrophy of the brain is part of the "normal" aging process. More recent advances using nuclear magnetic resonance spectroscopy of the brain can provide useful diagnostic information in minutes. This noninvasive tool employs simple measurements to characterize neuronal markers and neurotransmitters (glutamate, gammaaminobutyric acid), thus providing more advanced information in the differential diagnosis of this often confounding ~0ndition.l~

Fingerprint Patterns Abnormal fingerprint patterns are associated with both AD and Down ~yndrome.'~ Compared with the normal population, Alzheimer and Down patients show an increased number of ulnar loops on the fingertips, with a concomitant decrease in whorls, radial loops, and arches. Ulnar loops (pointing toward the ulnar bone, away from the thumb) are frequently found on all 10 fingertips. Radial loops (pointing toward the thumb), when they do appear, tend to be shifted away from the index and middle fingers-where they most commonly ocm-to the ring and little fingers. In patients with this fingerprint pattern characteristicof AD, it is recommended that an aggressive, preventive approach be instituted immediately.

THERAPEUTIC CONSIDERATIONS

Test

Rationale

CBC

Anemia, infection

VDRL

Syphilis

Electrolytes

Metabolic dysfunction

Liver function tests

Hepatic dysfunction

BUN

Renal dysfunction

TSH, T4, T3, T3U Serum B,2 and RBC folate

Thyroid dysfunction Deficiency

Urinalysis

Renalhepatic dysfunction

Hair mineral analysis

Heavy metal intoxication

ECG

Heart function

EEG

Focal vs. diffuse

CT scan

Atrophy, intracranial mass

SUN, Blood urea nitrogen; CBC,complete blood cell count: C7;computed tomography; ECG, electrocardiogram; EEG, electroencephalogram; RSC. red blood count; TSH, thyroid-stimulating hormone; VDRL, Venereal Disease Research Laboratory.

The primary areas of intervention from a natural medicine perspective involve prevention by addressing suspected pathophysiology and using natural measures to improve mental function in the early stages of the disease. In the advanced stages of AD, natural measures will provide only limited benefit.

Diet Dietary factors are clearly important in the etiology of AD. Food choices consistent with the standard American diet are associated with significant risk for the development of AD, while fish consumption and high monounsaturated fatty acids intake typically seen with the Mediterranean diet appear to be associated with high protection against cognitive decline. A diet high in saturated fat, trans fatty acids, and low in dietary antioxidants may lead to increased serum and brain concentrationsof aluminum and transition metal ions, which are implicated in oxidative stress, potentially leading to the neurologic damage characteristic of AD.

Alzheimer's Disease Many risk factors for AD such as cholesterol and saturated fat and risk reduction factors such as whole grain cereals and vegetables are shared with atherosclerosis. Poor-quality diets may also increase the prevalence of AD by eliciting inflammation, which may cause the neurologic damage that results in AD?> Additionally, studies comparing whole foods to intake of individual antioxidant nutrient supplements are also reporting a synergistic activity found among whole food products that are not available when given single antioxidant nutrients alone.16

Estrogen Estrogen has been promoted to offer protective and possibly therapeuticbenefits in AD. However, the epidemiologic and clinical evidence to support the potential benefits of estrogen is weak, especially as there is little evidence of major sex differences in the rate or severity of AD.17 Twelve population-based studies indicate that women on hormone replacement therapy (HRT) have a lower rate of AD.17-20 The problem with these studies is that women taking HRT are much healthier before taking the hormones?' This situation has clouded much of the research on HRT, not only in its role against AD but also in its role against cardiovasculardisease. If women taking estrogens have a lower risk for AD before taking HRT, it is difficult to fully evaluate the protective role of HRT, especially in light of a possible increased risk for breast cancer. The most recent, published, randomized, controlled trials demonstrate no evidence of HRT benefit in women with established vascular disease or in apparently healthy women. The increased risks of breast cancer and thromboembolic disease have been confirmed in these trials, with evidence of increased risk of stroke. Observational data suggest there may also be a small increased risk of ovarian cancer associated with longer-term use of HRT. The premature termination of one arm of the Women's Health Initiative randomized controlled trial caused concern among patients, doctors, and pharmaceutic companies." In previous clinical trials, estrogen therapy had been shown to improve mental function in some studies but not in other^.'^-^^ It is likely that estrogen produces some benefits, but several natural products discussed in this chapter exert greater benefit without the potential side effects of estrogens. The benefits of estrogen in AD could be related to many different factors, but the one that appears most likely is its antioxidant effect.21However, a safer and probably better recommendation for this effect is vitamin E. The protective role of vitamin E against heart disease, for example, is generally greater than that offered by HRT (see Chapter 150).Given the plethora of information regarding the risks associated with long-term use of HRT and the increased benefit-to-risk ratio of a number of natural therapies, it seems most reasonable to consider that at this point the risks of estrogen therapy outweigh the benefits.

Aluminum Encouraging the avoidance of all known sources of aluminum-aluminum-containing antacids, aluminumcontaining antiperspirants, cooking in aluminum pots and pans, wrapping food with aluminum foil, and nondairy creamers-certainly seems appropriate. Aluminum is also found in baking powder and table salt, as it is added to keep them from becoming lumpy. In addition, citric acid, as well as calcium citrate supplements, appear to increase the efficiency of absorption of aluminum (but not lead) from water and food.= Aluminum absorption can be decreased by magnesium, because magnesium competes with aluminum for absorption, not only in the intestines but also at the blood-brain barrier." A diet rich in magnesium is recommended. Have the patient focus on unprocessed foods; avoid milk and dairy products; and increase the consumption of vegetables, whole grains, nuts, and seeds-all good sources of magnesium.

NUTRITIONAL CONSIDERATIONS Nutritional status is directly related to cognitive function in the elderly.= Given the frequency of nutrient deficiency in the elderly population, it is likely that many cases of impaired mental function may have a nutritional etiology.

Antioxidants Considerable evidence indicates that oxidative damage plays a major role in the development and progression of AD.6~26,27 Epidemiologic evidence suggests that antioxidant nutrients offer sigruficant protection against AD.4,28 Researchers are beginning to show that antioxidant nutrients, especially vitamin E, may help to prevent AD in the same way that they help against heart disease, cancer, Parkinson's disease, and other diseases linked to inflammation and excessive oxidation. As digestive functions tends to diminish in the elderly population, there is a propensity toward fat malabsorption. Since vitamin E is a fat-soluble vitamin, neuronal symptoms of vitamin E deficiency including ataxia, proprioceptive and vibratory sense impairment, and gait disturbance are commonly seen in the aged population. Because of these known deficiency symptoms, the use of supplemental vitamin E has been investigated to prevent or treat AD. The recommended daily allowance (RDA) of vitamin E is 15 mg (22 W). Intakes as high as 2000 IU per day have been shown to slow the progression of Alzheimer dementia.BOnestudy alsoshowed a protective effect of vitamin E for vascular and other non-Alzheimer dementia in elderly men. An important note to this study was that the use of vitamin E was significant only when combined with vitamin C. The same study also demonstrated that, even in elderly men with no cognitive

Specific Health Problems impairment, extra vitamin E or extra vitamin C is associated with significantly better cognitive performance.30 Studies are also reporting the benefits of using vitamin E with standard pharmacologic treatment. One retrospective chart review was performed on 130 patients from the Ohio State University Memory Disorders Clinic to examine the long-term effects of combination therapy of donepezil and vitamin E on patients with AD. Confirmed Alzheimer subjects were included if they had taken at least 5 mg donepezil and at least loo0 U vitamin E daily. These patients were then compared to data for patients who had not taken the vitamin E with the donepezil. It was discovered that patients who had taken both the donepezil and the vitamin E had declined at a sigruficantlylower rate compared with their counterparts who did not take vitamin E. Although this was not a controlled comparison study, given vitamin E’s safety and cost effectiveness, it makes sense to use vitamin E therapy in patients taking donepezil for AD?’ As discussed earlier in the etiology section, it is known that presenilin gene expression is found to be decreased in brain areas affected by AD. The latest research is elucidating mitochondrial dysfunction as a factor in decreasing presenilin production. Although AD is a condition governed in part by genetic makeup, researchers are finding that antioxidant use can support mitochondrial function, which in turn increases presenilinproduction, effectively changing genetic expression. It was shown that when mitochondrial energy metabolism was suppressed by the agent sodium azide, a known supressor of mitochondrial function, presenilin expression decreased. Azide effect on presenilin messenger RNA expression, a marker of presenilin production, was completely inhibited by the addition of antioxidants, suggesting that the imbalance of the cellular homeostasis due to the presence of oxidants can modulate the expression of this gene and change factors contributing to AD.32 What this teaches us is that even though there are inborn genetic predispositions that may not be changeable at the genetic level, environmental and lifestyle choices that include a good antioxidant regimen can indeed make a difference in how one’s genetic inheritance is expressed. As melatonin is becoming a recognized antioxidant for many clinical conditions, its use should also be considered for AD (see the section on melatonin later).

Thiamin Although severe thiamin deficiency is relatively uncommon (except in alcoholics), many Americans do not consume even the RDA of 1.5 mg, especially the elderly. In an attempt to gauge the prevalence of thiamin deficiency in the geriatric population, 30 unselected consecutive outpatients visiting a university outpatient clinic in Tampa, Florida, were tested for thiamin levels. Depending on the thiamin measurement (plasma vs. red blood cell thiamin),

low levels (defined as a level below the lowest reference range for younger-aged groups) were found in 57% and 33%, re~pectively.~~ In addition to its role as a nutrient, thiamin also demonstrates some pharmacologic effects on the brain. Specifically it mimics the important neurotransmitter involved in memory-acetylcholine. Thiamin has been shown to potentiate and mimic the effects of acetylcholine in the brain.% This effect explains the positive clinical results that have been noted for thiamin (3 to 8 g/day) in improving mental function in AD and age-related impaired mental function ( ~ e n i l i t y ) . High-dosage ~~,~~ thiamin supplementation exerts its benefits without side effects. These results highlight the growing body of evidence that a significant percentage of the geriatric population is deficient in one or more of the B vitamins. Given the essential role of thiamin and other B vitamins to normal human physiology, especially cardiovascular and brain function, routine B vitamin supplementation appears to be worthwhile in this age group. AD may simply be the result of chronic low intake of essential nutrients-key among which are the B vitamins.

Vitamin BI2 Another key B vitamin linked to AD is vitamin BIZ. Vitamin B12deficiency results in impaired nerve function, which can cause numbness, paresthesias, or a burning feeling in the feet, as well as impaired mental function, which in the elderly can mimic AD. Vitamin BI2 deficiency is thought to be quite common in the elderly and is a major cause of depression in this age group. Determination of vitamin B12deficiency is best achieved by measuring the level in the blood (serum cobalamin) or the level of methylmalonic acid in the urine. In addition, measuring the level of plasma homocysteine is emerging as a method to determine the status of both vitamin BIZ and folate. Several investigators have found that the level of vitamin BI2 declines with age and that vitamin B12 deficiency is found in 3% to 42% of persons aged 65 and older. Diagnosing cobalamin deficiency early in the elderly is important because it is easily treatable and, if left untreated, can lead to impaired neurologic and cognitive fun~tion.~~*~* In one study, among 100 consecutive geriatric outpatients who were seen in office-based settings for various acute and chronic medical illnesses but not for vitamin B12 deficiency-related diseases like pernicious anemia, 11 patients had serum cobalamin levels at 148 pmol/L or below; 30 patients had levels between 148 and 295 pmol/L; and 59 patients had levels above 296 pm0l/L.3~After the initial cobalamin determination, the subjects were followed for up to 3 years. The patients with cobalamin levels below 148 pmol/L were treated

Alzheimer's Disease and not included in the analysis of declining cobalamin levels. The average annual serum cobalamin level decline was 18 pmol/L for patients who had higher initial serum cobalamin levels (actual range from 224 to 292 pmol/L). For patients with lower initial cobalamin levels, the average annual serum cobalamin decline was much higher, at 28 pmol/L. These results indicate that measuring the level of vitamin B12in the blood (serum cobalamin) or measuring the urinary excretion of methylmalonic acid or the level of homo~ysteine~~ as screening tests for vitamin B12deficiency appears to be indicated in the elderly given the positive cost-benefit ratio.*l," To test for B12 deficiency, the urinary methylmalonic acid assay is perhaps the best in that it is sensitive, as well as being noninvasive and relatively convenient for the patient. Correction of an underlying vitamin BI2 deficiency can significantly improve mental function and quality of life in these patients. Serum homocysteine is also being studied, for a growing body of literature demonstrates clear correlations between high levels of this marker and cardiovascular disease and, more recently, dementia and AD. A Boston University study published in the New England Journal of Medicine concluded that high homocysteine levels (>14 pmol/L) nearly doubled the risk of ADA3 The importance of detailed examination in elderly patients with mental symptoms is highlighted by results from a study that analyzed the plasma homocysteine, serum cobalamin, and blood folate in 296 consecutive patients referred to a geriatric psychiatric ward in Sweden for diagnosis of mental disease.P4Patients who were deficient in vitamin BIZor folic acid or who had elevated levels of homocysteine were given vitamin B12 (dosage not specified) or folic acid (10 mg/day), or both. When individuals with low cobalamin levels were supplemented with vitamin B12, significant clinical improvements were noted. In other studies, supplementation with vitamin B12 has shown tremendous benefit in reversing impaired mental function as a result of low levels of vitamin B12?7 In one large study, a complete recovery was observed in 61% of cases of mental impairment due to low levels of vitamin B12.45The fact that 39% did not respond is probably a result of long-term low levels of vitamin B12. Several studies have shown that the best clinical responders are those who have been showing signs of impaired In one study, mental function for less than 6 rn~nths.'~ 18 subjects with low serum cobalaminlevels and evidence of mental impairment were given vitamin B12. Only those patients who had symptoms for less than 1year showed i m p r ~ v e m e n t .The ~ ~ importance of diagnosing and correcting low vitamin B12levels in the elderly cannot be overstated. Serum vitamin B12 levels are significantly low, and vitamin B12 deficiency is significantly common in AD

patient^.^^,^^,^ It has recently been demonstrated that an oral daily dose as low as 50 yg can significantly increase serum vitamin B12 levels in vitamin Blz-deficientelderly persons.49Supplementation of BIZ or folic acid, or both may result in complete reversal in some patients, but generally there is little improvement in patients who have had Alzheimer symptoms for more than 6 months. It has been hypothesized that prolonged low levels of vitamin B12may lead to irreversible changes that will not respond to supplementation. Vitamin B12 is available in several forms. The most common form is cyanocobalamin; however, vitamin B12 is active in the human body in only two forms: methylcobalamin and adenosylcobalamin. Although methylcobalamin and adenosylcobalamin are active immediately on absorption, cyanocobalamin must be converted to either methylcobalaminor adenosylcobalaminby removing the cyanide molecule and adding either a methyl or adenosyl group. This conversion may be reduced with aging and may be another factor responsible for the vitamin B12disturbances noted in the elderly population.

Zinc Zinc deficiency is one of the most common nutrient deficiencies in the elderly and has been suggested to be a major factor in the development of AD.50Included in the list of zinc-containing enzymes are most enzymes involved in DNA replication, repair, and transcription. It has been suggested that dementia, possibly because of a long-term zinc deficiency, may represent the long-term cascading effects of error-prone or ineffective DNAhandling enzymes in nerve cells.5l In addition, zinc is required by many antioxidant enzymes including superoxide dismutase. The end result could be the destruction of nerve cells and the formation of neurofibrillary tangles and plaques. The levels of zinc in the brain and cerebrospinal fluid in patients with AD are markedly decreased, and there is a strong inverse correlation between serum zinc levels and the senile plaque count.52 Zinc supplementation has demonstrated good benefits in AD. In one study, 10 patients with AD were given 27 mg/day of zinc (as zinc aspartate). Only two patients failed to show improvement in memory, understanding, communication, and social contact. In one 79-year-old patient, the response was labeled "unbelievable" by both medical staff and family.53Unfortunately, there does not seem to be much interest in the scientific community in following up these impressive results with zinc therapy. The most recent medical literature acknowledges zinc's apparent duality as "The Zinc Paradox."54Fueling this ambivalence is conflicting information that zinc may be problematic for Alzheimer patients as, in vitro, it accelerates the formation of insoluble beta-amyloid ~eptide.5~ Although zinc is neurotoxic at high concentrations and accumulates at sites of degeneration, total tissue zinc is

Specific Health Problems

markedly reduced in the brains of Alzheimer patients. Other research has shown a much higher concentration of copper-zinc superoxide dismutase in and around the damaged brain tissue of AD patients.% This suggests that the increased concentration of zinc in the damaged areas is due to the body’s efforts to neutralize free radicals through the increased local production of dismutases. A possible corollary is that the higher focal levels of zinc result in increased amyloid formation when the free radical scavenging mechanisms have been inadequate.

Phosphatidylcholine Because dietary phosphatidylcholine can increase acetylcholine levels in the brain in normal patients and AD is characterized by a decrease in cholinergic transmission, it seems reasonable to assume that phosphatidylcholine supplementation would benefit Alzheimer patients. However, the basic defect in cholinergic transmission in AD relates to impaired activity of the enzyme acetylcholine transferase. This enzyme combines choline (as provided by phosphatidylcholine) with an acetyl molecule to form acetylcholine, the neurotransmitter. Providing more choline does not necessarily increase the activity of this key enzyme, so phosphatidylcholine supplementation is not beneficial in the majority of patients with AD. Not surprisingly, clinical trials using phosphatidylcholine have largely been disappointing. Studies have shown inconsistent improvements in memory from choline supplementation in both normal and Alzheimer ~ a t i e n t s . 5The ~ ~ studies have been criticized for small sample size, low dosage of phosphatidylcholine, and poor design. Furthermore, some researchers are questioning the form of choline that is used.61Other forms such as phosphatidylserine (see later) or choline alphoscerate62 may prove more useful in supporting cholinergic transmission. In a patient with mild to moderate dementia, the use of a high-quality phosphatidylcholine preparation may be worth a try. A dosage of 15 to 25 g/day of phosphatidylcholine is required. If there is no noticeable improvement within 2 weeks, supplementation should be discontinued.

Phosphatidylserine Phosphatidylserineis the major phospholipid in the brain, where it plays a major role in determining the integrity and fluidity of cell membranes. Normally, the brain can manufacture sufficient levels of phosphatidylserine, but a deficiency of methyl donors like Sadenosylmethionine (SAMe), folic acid, and vitamin BIZor essential fatty acids may inhibit the production of sufficient phosphatidylserhe. Low levels of phosphatidylserine in the brain are associated with impaired mental function and depression in the elderly. The primary use of phosphatidylserine is in the treatment of depression or impaired mental function, or both, in the elderly, including AD. To date, the 11double-blind

published studies have all reported the successful use of phosphatidylserine in the treatment of age-related cognitive decline, AD, or d e p r e ~ s i o n . ~In” the largest study a total of 494 elderly patients (between 65 and 93 years old) with moderate to severe senility were given either phosphatidylserine (100 mg three times daily) or a placebo for 6 months.” The patients were assessed for mental performance, behavior, and mood at the beginning and end of the study. Statistically significant (p < 0.01) improvements were noted in mental function, mood, and behavior for the phosphatidylserine group.

L-Acetylcarnit ine A great deal of research has been conducted over the past decade with L-acetylcamitine (LAC) in the treatment of AD, senile depression, and age-related memory defects. LAC is composed of acetic acid and L-camitine bound together. This reaction occurs naturally in the human brain. Therefore it is not exactly known how much greater of an effect is achieved with LAC versus L-carnitine. However, LAC is thought to be substantially more active than other forms of carnitine in conditions involving the The close structural similarity between LAC and acetylcholine led to an interest in using LAC in AD. Research has shown that LAC does mimic acetylcholine and is of benefit not only in patients with early-stage AD but also in elderly patients who are depressed or who have impaired mem0ry.7~It has also been shown to act as a powerful antioxidant within the brain cell, stabilize cell membranes, and improve energy production within the brain cell, as well as enhance or mimic the function of a~etylcholine.~~ The latest metaanalysis involving studies of LAC in mild cognitive impairment and mild (early) AD is promising in terms of showing both clinical and psychometric improvements. Double-blind, placebo-controlled, prospective, parallel group comparison studies of at least 3 months’ duration were studied. Using a dose range of 1.5 to 3 g a day, treatment time points were assessed at 3,6,9, and 12 months. This analysis showed a significant advantage for acetyl-L-carnitine compared with placebo. The advantage for acetyl-L-carnitine was seen by the time of the first assessment at 3 months and increased over time. Additionally, acetyl-L-carnitinewas well tolerated in all studies.76 Further studies also show efficacy regarding the use of LAC in situations where AD patients were unresponsive to acetylcholinesterase inhibitors. One study evaluated the effect of LAC using 2 g/day orally for 3 months in association with donepezil or rivastigmine in 23 patients with mild AD who had not responded to treatment with acetylcholinesterase inhibitors (AChE-Is). Clinical effects were evaluated by assessing cognitive functions, functional status, and behavioral symptoms. The response rate, which was 38% after AChE-I treatment,

Alzheimer’s Disease increased to 50% after the addition of LAC, indicating that the combination of both the pharmaceutic and LAC works better than the pharmacologic treatment alone.” The memory impairment need not be as severe as in AD in order for LAC to demonstrate benefit.7880In one double-blind study of 236 elderly subjects with mild mental deterioration, as evidenced by detailed clinical assessment, the group receiving 1500 mg/day of LAC demonstrated significant improvement in mental function, particularly in memory and constructional thinking.80

OTHER THERAPIES Dehydroepiandrosterone Dehydroepiandrosterone (DHEA) is the most abundant hormone in the blood stream and is found in extremely high concentrationsin the brain. As DHEA levels decline dramatically with aging, low levels of DHEA in the blood and brain are thought to contribute to many symptoms associated with aging including impaired mental function. Although DHEA itself has no known function, it does serve as the source for all other steroid hormones in the body including sex hormones and corticosteroids. Therefore the function of DHEA seems to be supplying the body with what it needs to maintain optimum levels and balance of all the steroid hormones that regulate the body’s activities. Over the past 15 years it has been demonstrated that declining levels of DHEA are linked to such conditions as diabetes, obesity, elevated cholesterol levels, heart disease, arthritis, and other age-related diseases. In addition, DHEA shows promise in enhancing memory and improving cognitive function.81-83 As of this writing, the only double-blind, placebo-controlled study was a small pilot study (58 subjects) in which 50 mg of DHEA was given twice a day. Although some benefit was reported at 3 months, DHEA did not significantly improve cognitive performance or overall ratings of change in severity in this small-scale pilot studyM The levels of DHEA necessary to improve brain power in men older than the age of 50 appear to be 25 to 50 mg/day. For women, a dosage of 15 to 25 mg appears to be sufficient in most cases. As men and women reach their 70s, they may require higher levels (e.g., 50 to 100 mg). Excessive dosages of DHEA can cause acne and, in women, menstrual irregularities. Although most elderly people probably need DHEA, laboratory assessment before prescription may help one decide if DHEA would be beneficial in an individual case and better assess the needed dosages.

Melatonin Formed by the body from serotonin and released by the pineal gland, melatonin is considered by many to be “the master hormone” of the body. It is well known for its use

in normalizing circadian rhythms and sleep cycles and, more recently, as a powerful antioxidant for cancer therapies. Virtually ignored in conventional textbooks until only relatively recently, medical research is beginning to its value its ostensibly commanding role in many physiologic processes. In vitro studies have shown that melatonin protects neuronal cells from heavy metal cobalt damage. Cobalt is a transition metal found to be in high levels in AD patients. It was found that the induction of oxidative damage and beta amyloid release were both avoided with melatonin treatment. Since cobalt is an essential nutrient, often bound to vitamin BIB melatonin may prove an important preventive treatment in AD-susceptible indi~iduals.~~ One double-blind, placebo-controlled study has studied melatonin in AD patients. Researchers from Nippon medical school, who previously reported on bright light therapy as a means to improve cognitive function in AD, evaluated the effectiveness of melatonin. Three milligrams of melatonin were given to 11 subjects at 8:30 PM every day for a month, while 9 other subjects were given placebo (mean age of 79.2 years old). Based on standard dementia and AD assessment scales, the melatonin group had a sigruficantly increased sleeping time and decreased nighttime activity, with improved levels of cognitive and noncognitive functions. Even though the authors noted that these results were significant and clearly supported the use of melatonin in AD, they acknowledged that morning bright light therapy still showed greater improvements in AD patients.%

Botanical Medicines Ginkgo biloba Extract The Ginkgo biloba extract (GBE) standardized to contain 24% @go flavonglycosides is showing great benefit in many cases of senility including AD. In addition to GBE’s ability to increase the functional capacity of the brain via the mechanisms described earlier, it has also been shown to normalize the acetylcholine receptor in the hippocampus of aged animals, increase cholinergic transmission, inhibit beta-amyloid dep0sition,8~and address many of the other major elements of ADBrE9(see Chapter 96 for a full discussion). Although preliminary studies in established Alzheimer patients are quite promising, at this time it appears that GBE only helps to reverse or delay mental deterioration in the early stages of AD. This improvement may enable the patient to maintain a normal life and avoid a nursing home. The benefits of GBE in early-stage AD are quite evident when looking at the results of two recent doubleblind studies. In the first study, 216 patients with AD or multiinfarct dementia were given either 240 mg/day of GBE or placebo for 24 weeks.% Improvements were noted in several clinical parameters including the

I

ilobal Impression ratings: GBE versus placebo GBE (%)

Placebo (%)

3

1

Much improved

29

16

Slightly improved

41

Unchanged

28

38 30

Moderately worse

0

14

Much worse

0

1

Very much improved

GEE, Ginkgo biloba extract.

Clinical Global Impressions (CGI) scale, as shown in Table 146-3. The second study, published in the Journal of the American Medical Association, was the first clinical study on GBE conducted in the United States?l The study was conducted at six research centers. Harvard Medical School and the New York Institute for Medical Research approved the design of the study, in which 202 patients with AD were given either a modest dose of GBE (120 mg/day) or a placebo for 1 year. GBE not only stabilized AD but also led to significant improvements in mental function in 64% of the patients. There were no side effects with GBE. Direct comparison studies looking at gingko versus standard pharmaceutic regimens have been completed recently. A comparison of placebo-controlled efficacy studies of at least 6 months in duration demonstrated that GBE and second-generation cholinesterase inhibitors (tacrine, donepezil, rivastigmine, metrifonate) were equally effective in treating mild to moderate Alzheimer dementia. This study found no major differences between the four cholinesterase inhibitors and GBE. Additionally, tacrine exhibited a high dropout rate due to adverse drug reactions. In conclusion, the author called for a critical review of the use of new second-generation cholinesterase inhibitor prescriptions for mild to moderate AD in light of gingko’s equivalent effectiveness?* A meta-analysis surveyed 50 articles to examine the effect of @go on objective measures of cognitive function in patients with AD.93In the 212 subjects in the placebo and @go groups, a sigruficant overall effect size that was comparable with the benefits of standard cholinesterase inhibitors was found. In this analysis, standardized measures of cognition were measured including the Alzheimer’s Disease Assessment Scalecognitive subscale. In addition to offering benefit in early-stage AD, if the mental deficit is due to vascular insufficiency or depression and not AD, GBE is usually effective in reversing the defi~it.9”~~ It must be pointed out that GBE should be taken consistently for at least 12 weeks in order to determine

effectiveness. Although some people with AD report benefits within a 2- to 3-week period, most will need to take GBE for a longer period of time.

Huperzine A Huperzine A is an alkaloid isolated from the moss Huperzia serruta, long used in China to treat primarily fever and inflammation. Although it has been shown to have no antipyretic or antiinflammatory properties in experimental models, Huperzine A has been shown to be a potent inhibitor of acetyl-cholinesterase. In fact, it is significantly more selective and substantially less toxic than the acetylcholine esterase (ACE) inhibitors currently used in conventional medicine (physostigmine, tacrine, and donepezil). Toxicity with synthetic ACE inhibitors has been a major drawback in their clinical use. In contrast, Huperzine A, purified from H. serrata, has been used as a prescription drug in China since the early 1990s and has reportedly been used by more than 100,000 people with no serious adverse effect?’ First studied for use in myasthenia gravis, clinical studies conducted in China have shown considerable benefit in the treatment of dementia. One double-blind clinical study found that Huperzine A at a dose of 200 yg twice daily produced measurable improvements in memory, cognitive function, and behavioral factors in 58% of Alzheimer patients?8 In contrast, in the placebo group 36% showed improvement. No sigruficant side effects occurred in either group.

Other Promising Botanicals Although long-term clinical trials have not yet been conducted, two herbs from Asia and one from Northern Europe show great promise according to preliminary reports, as well as historical use. Bacopa monniera (BM)is an Ayurvedic botanical medicine used for memory enhancement, epilepsy, insomnia, and as a mild sedative. Additionally, it has been able to reduce the memory dysfunction in rat models of AD. One recent study evaluated an extract of BM on a culture of purified rat astrocytes exposed to toxins mimicking the effect of excess nitric oxide exposure, a condition shown to be a factor in AD. Results showed that the extract of BM inhibited the formation of reactive species and DNA damage in a dose-dependent manner. These data support the traditional use of BM and indicate that this medicinal plant has therapeutic potential in treatment or prevention of AD.w,’OO Kempo, an ancient Japanese botanical medicine, has been shown to normalize neurons subjected to stressinduced damage of brains with a genetically induced propensity for seizures. Most notably the researchers observed complete suppression effects on amyloid beta protein-induced neuron death.’O’ Galanthus nivalis (the common snowdrop) has been studied for its alkaloid content of galanthamine. In vivo

Alzheimer’s Disease

and in vitro research confirms the inhibition of human cholinesterases.102~103 Huperazine A (see earlier) shares common binding sites with galanthamine.’” Although none of the three botanical medicines described here have large-scale trials to support their use, it seems reasonable that these natural substances may support standard allopathic therapeutics in an effort to lower the dose and side effects of pharmacologic treatments and may in the future be considered as a safer method of supplanting current drug options.

THERAPEUTIC APPROACH The primary therapeutic goal is prevention or beginning therapy as soon as any dementia is noted.

Dietary and Lifestyle Recommendations Avoid aluminum (found in many antiperspirants, antacids, and cookware). Follow a generally healthful dietary and lifestyle plan. Increase whole food products including fish, cereals, vegetables, and monosaturated fats.

1.Dmasio AR. Alzheimer’s disease and related dementias. In Bennett CJ, Plum F, eds. Cecil textbook of medicine, ed 20. Philadelphia: Saunders, 1996:1992-1996. 2. Wick G, Berger P, Jansen-Durr F’, Grubeck-Loebenstein B. A Darwinian-evolutionary concept of age-related diseases. Exp Gerontol2003;38:13-25. 3. Monsonego A, Weiner HL. Immunotherapeutic approaches to Alzheimer’s disease. Science 2003302834-838. 4. Solfrizzi V, Panza F, Capurso A. The role of diet in cognitive decline. J Neural Transm 2003;11095-110. 5. Grant WB, Campbell A, Itzhaki RF, Savory J. The significance of environmental factors in the etiology of Alzheimer’s disease. J Alzheimers Dis 2002;4:179-189. 6. Markesbery WR. Oxidative stress hypothesis in Alzheimer’s disease. Free Radical Biol Med 1997;23:134-147. 7. Shin RW. Interaction of aluminum with paired helical filament tau is involved in neurofibrillary pathology of Alzheimer’s disease. Gerontology 1997;43(suppl1):16-23. 8. Miu AC, Andreescu CE, Vasiu R, Olteanu AI.A behavioral and histological study of the effects of long-term exposure of adult rats to aluminum. Int J Neurosci 2003;1131197-1211. 9. Zapatero MD, Garcia de Jalon A, Pascual F, et al. Serum aluminum levels in Alzheimer’s disease and other senile dementias. Biol Trace Elem Res 1995;47235-240. 10. Frolich L, Riederer P. Free radical mechanisms in dementia of the Alzheimer’s type and the potential for antioxidative treatment. Arzneimittelforschung 1995;45443-446. 11. Walton J, Tuniz C, Fink D, et al. Uptake of trace amounts of aluminum into the brain from drinking water. Neurotoxicology 1995; 16187-190. 12. Garcia CA, Reding MJ, Blass JP.Overdiagnosis of dementia. J Am Geriatr Soc 1981;29407410. 13.Smith JS, Kiloh LG. The investigation of dementia: results in 200 consecutive admissions. Lancet 1981;1:824-827.

Decrease total calories and unhealthy fats. Use morning light therapy.

Supplements High-potency multivitamin and mineral supplement according to guidelines given in Chapter 44 Vitamin C: 500 to 1000 mg three times/day Vitamin E: 400 to 800 IU/day Flaxseed oil: 1tbsp/day Thiamin: 3 to 8 &day Phosphatidylserine: 100 mg three times/day L-Acetylcamitine:500 mg three times/day Methylcobalamin: 1000 pg twice daily Melatonin: 3 mg in the evening at least a half hour before bed

Botanical Medicine GBE (24%@go flavonglycosides):80 mg three times/ day Huperzine A: 200 pg twice daily

14. Ross BD, Bluml S, Cowan R, et al. In vivo MR spectroscopy of human dementia. Neuroimaging Clin N Am 1998;8:809-822. 15. Weinreb HJ. Fingerprint patterns in Alzheimer’s disease. Arch Neurol1985;42:50-54. 16. Liu RH. Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals. Am J Clin Nutr 2003;78(suppl3):517S520S. 17. Kuller LH. Hormone replacement therapy and its potential relationship to dementia. J Am Geriatr Soc 1996;44:878-880. 18. Paganini-Hill A. Oestrogen replacement therapy and Alzheimer’s disease. Br J Obstet Gyn 1996;103(suppl13):80-86. 19.Honjo H, Tanaka K, Kashiwagi T, et al. Senile dementiaAlzheimer‘s type and estrogen. Horm Metab Res 1995;27: 204-207. 20.Smalheiser NR, Swanson DR. Linking estrogen to Alzheimer’s disease. An informatics approach. Neurology 1996;47809-810. 21. Matthews KA, Kuller LH, Wing RR, et al. Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol1996;143971-978. 22. Annitage M, Nooney J, Evans S. Recent concerns surrounding HRT. Clin Endocrinol (Oxf) 2003;59145-155. 23. Nolan CR, DeGoes JJ, Alfrey AC. Aluminum and lead absorption from dietary sources in women ingesting calcium citrate. South Med J 1994;87894-898. 24. Glick JL. Dementias. The role of magnesium deficiency and hypothesis concerning the pathogenesis of Alzheimer’s disease. Med Hypotheses 1990;31:211-225. 25. Tucker DM, Penland JG, Sandstead HH, et al. Nutrition status and brain function in aging. Am J Clin N u b 1990;52:93-102. 26. Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A 1993; 907915-7922. 27.Smith MA, Perry G, Richey PL, et al. Oxidative damage in Alzheimer’s. Nature 1996;382:120-121.

Specific Health Problems ~

28. Jama JW, Launer LJ, Witteman JC, et al. Dietary antioxidants and cognitive function in a population-based sample of older persons. Am J Epidemiol1996;144:275-280. 29. Johnson KA, Bernard MA, Funderburg K. Vitamin nutrition in older adults. Clin Geriatr Med 2002;18:773-799. 30. Masaki KH, Losonczy KG, Izmirlian G, et al. Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 2000;54:1265-1272. 31. Klatte ET, scharre DW, Nagaraja HN, et al. Combination therapy of donepezil and vitamin E in Alzheimer disease. Alzheimer Dis Assoc Disord 2003;17113-116. 32.Ghidoni R, Gasparini L, Alberici A, et al. Inhibition of energy metabolism down-regulates the Alzheimer related presenilin 2 gene. J Neural Transm 2003;1101029-1039. 33. Chen MF, Chen LT, Gold M, et al. Plasma and erythrocyte thiamin concentration in geriatric outpatients. J Am Coll Nutr 1996;15 231-236. 34. Meador KJ, Nichols ME, Franke P, et al. Evidence for a central cholinergic effect of high dose thiamine. Ann Neurol1993;34:724726. 35. Meador K, Loring D, Nichols M, et al. Preliminary findings of highdose thiamine in dementia of Alzheimer’s type. J Geriatr Psychiatry Neurol 1993;6222-229. 36.Benton D, Fordy J, Haller J. The impact of long-term vitamin supplementation on cognitive functioning. Psychopharmacol (Berl) 1995;117298-305. 37. van Goor L, Woiski MD, Lagaay AM, et al. Review: cobalamin deficiency and mental impairment in elderly people. Age Ageing 1995; 24536-542. 38.Shevell MI, Rosenblatt Ds. The neurology of cobalamin. Can J Neurol Sci 1992;19:472-486. 39. Yao Y, Lu-Yao G, Mesches DN, Lou W. Decline of serum cobalamin levels with increasing age among geriatric outpatients. Arch Fam Med 19943:91&922. 40.Aronow WS. Homocysteine. The association with atherosclerotic vascular disease in older persons. Geriatrics 20035822-24,27-28. 41.Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin deficiency. Am J Med 199496239-246. 42. Norman EJ, Morrison JA. Screening elderly populations for cobalamin (vitamin BI2) deficiency using the urinary methylmalonic acid assay by gas chromatography mass spectrophotometry. Am J Med 1993;94589-594. 43. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002; 346:476483. 44. Nilsson K, Gustafson L, Faldt R, Gustafson L. Plasma homocysteine in relation to serum cobalamin and blood folate in a psychogeriatric population. Eur J Clin Invest 1994;24600-606. 45. Healton EB, Savage DH, B r u t JC, et al. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore) 1991;70229-245. 46.Martin DC, Francis J, Protetch J, Huff FJ. T i e dependency of cognitive recovery with cobalamin replacement. A report of a pilot study. J Am Geriatr Soc 1992;40:168-172. 47. Levitt AJ, Karlinsky H. Folate, vitamin B12 and cognitive impairment in patients with Alzheimer’s disease. Acta Psychiatr Scand 1992;86301-305. 48. Kristensen MO, Gulmann MC, Christensen JE, et al. Serum cobalamin and methylmalonic acid in Alzheimer dementia. Acta Neurol Scand 1993;87475-481. 49. Seal EC, Metz J, Flicker L, Melny J. A randomized, double-blind, placebo-controlled study of oral vitamin B12 supplementation in older patients with subnormal or borderline serum vitamin B,, concentrations. J Am Geriatr Soc 2002;50:146-151. 50. Constantinidis J. The hypothesis of zinc deficiency in the pathogenesis of neurofibrillary tangles. Med Hypoth 1991;35319-323.

51. Burnet FM. A possible role of zinc in the pathology of dementia. Lancet 1981;1:186-188. 5 2 . T d y CL, Snowdon DA, Markesbery WR. Serum zinc, senile plaques, and neurofibrillary tangles: findings from the Nun Study. Neuroreport 1995;6:2105-2108. 53. Constantinidis J. Treatment of Alzheimer’s disease by zinc compounds. Drug Develop Res 1992;271-14. 54. Cuajungco MP, Faget KY. Zinc takes the center stage: its paradoxical role in Alzheimer’s disease. Brain Res Brain Res Rev 2003;41: 44-56. 55. Cuajungco MP, Lees GJ. Zinc and Alzheimer’s disease: is there a direct link? Brain Res Brain Res Rev 1997;23219-236. 56. Furuta A, Price DL, Pardo CA, et al. Localization of superoxide dismutases in Alzheimer’s disease and Down’s syndrome neocortex and hippocampus. Am J Pathol1995;146357-367. 57.Rosenberg G, Davis KL. The use of cholinergic precursors in neuropsychiatric diseases. Am J Clin Nutr 1982;36709-720. 58. Levy R, Little A, Chuaqui P, Reith M. Early results from double-blind, placebo controlled trial of high dose phosphatidylcholine in Alzheimer‘s disease. Lancet 1983;1:987-988. 59. Sitaram N, Weingartner B, Caine ED, a Gillin JC. Choline: selective enhancement of serial learning and encoding of low imagery words in man. Life Sci 1978;22:1555-1560. 60.Higgins JP, Flicker L. Lecithin for dementia and cognitive impairment. Cochrane Database Syst Rev 2003;3CW01015. 61. Amenta F, Pametti L, Gallai V, Wallin A. Treatment of cognitive dysfunction associated with Alzheimer’s disease with cholinergic precursors. Ineffective treatments or inappropriate approaches? Mech Ageing Dev 2001;122:2025-2040. 62. Parnetti L, Amenta F, Gallai V. Choline alphoscerate in cognitive decline and in acute cerebrovasculardisease: an analysis of published clinical data. Mech Ageing Dev 2001;122:2041-2055. 63. Cenacchi T, Bertoldin T, Farina C, et al. Cognitive decline in the elderly. A double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration. Aging (Milano)1993; 5123-133. 64.Engel RR, Satzger W, Gunther W, et al. Doubleblind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type. Eur Neuropsychopharmacoll992; 2149-155. 65. Crook T, Petri W, Wells C, Massari DC.Effeds of phosphatidylserine in Alzheimer’s disease. Psychopharmacol Bull 1992;2861-66. 66.Crook TH, T i e n b e r g J, Yeseavage J, et al. Effects of phosphatidylserine in age-associated memory impairment. Neurology 1991;41:644-649. 67. Funfgeld EW, Baggen M, Nedwidek P, et al. Double-blind study with phosphatidylserine (PS)in parkinsonian patients with senile dementia of Alzheimer’s type (SDAT). Prog Clin Biol Res 1989;317 1235-1246. 68. Amaducci L. Phosphatidylserine in the treatment of Alzheimer’s disease: results of a multicenter study. Psychopharmacol Bull 1988; 24:1030-1034. 69. Nerozzi D, Aceti F, Melia E, et al. [Phosphatidylserine and memory disorders in the aged.] Clin Ter 1987;120:399-404. 70. Palmieri G, Palmieri R, Inzoli MR, et al. Double-blind controlled trial of phosphatidylserine in patients with senile mental deterioration. Clin Trials J 1987;2473-83. 71. Villardita C, Grioli S, Salmeri G, et al. Multicentre c l i c a l trial of brain phosphatidylserine in elderly patients with intellectual deterioration. Clin Trials J 1987;2484-93. 72. Delwaide PJ, Gyselynck-Mambourg AM, Hurlet A, Ylieff M. Double-blind randomized controlled study of phosphatidylserine in demented patients. Acta Neurol Scand 1986;73:136-140. 73. Bowman B. Acetyl-carnitine and Alzheimer’s disease. Nutr Rev 1992;50:142-144.

Alzheimer’s Disease 74. Carta A, Calvani M, Bravi D, Bhuachalla SN. Acetyl-L-camitine and Alzheimer’s disease. Pharmacological considerations beyond the cholinergic sphere. Ann N Y Acad Sci 1993;695:324326. 75. Calvani M, Carta A, Caruso G, et al. Action of acetyl-L-camitine in neurodegeneration and Alzheimer’s disease. Ann N Y Acad Sd 1992; 663483436. 76. Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-camitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol2003;1861-71. 77.Bianchetti A, Rozzini R, Trabucchi M. Effects of acetyl-L-camitinein Alzheimer’s disease patients unresponsive to acetylcholiiesterase inhibitors. Curr Med Res Opin 2003;19:350-353. 78. Vecchi GP, Chiari G, Cipolli C, et al. Acetyl-L-carnitinetreatment of mental impairment in the elderly. Evidence from a multicenter study. Arch Gerontol Geriatr 1991;2:159-168. 79. Salvioli G, Neri M. L-acetylcamitine treatment of mental decline in the elderly. Drugs Exp Clin Res 1994;20169-176. 80. Cipolli C, Chiari G. [Effects of L-acetylcamitineon mental deterioration in the aged. Initial results]. Clin Ter 1990;132(suppl6):479-510. 81. Kalimi M, Regelson W. The biologic role of dehydroepiandrosterone (DHEA).New York W de Gruyter, 1990. 82. Yen SS, Morales AJ, Khorram 0. Replacement of DHEA in aging men and women. Potential remedial effects. Ann N Y Acad Sci 1995; 774128-142. 83. Morales AJ, Nolan JJ, Nelson JC, Yen SS. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994;78:1360-1367. 84. Wollcowitz OM, Kramer JH, Reus VI, et al. DHEA treatment of Alzheimer’s disease:a randomized, doubleblind, placekontrolled study. Neurology 2003;60:1071-1076. 85. Olivieri G, Hess C, Savaskan E, et al. Melatonin protects SHSY5Y neuroblastoma cells from cobalt-induced oxidative stress, neurotoxicity and increased beta-amyloid secretion. J Pineal Res 2001;31: 320-325. 86. Asayama K, Yamadera H, It0 T, et al. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch 2003; 70:334-341. 87. Watanabe CM, Wolffram S, Ader P, et al. The in vivo neuromodulatory effects of the herbal medicine gingko biloba. Proc Natl Acad Sci U S A 2001;986577-6580. 88. DeFeudis FV,ed. Ginkgo biloba extract (EGb 761).Pharmacological activities and clinical applications. Paris: Elsevier, 1991. 89. Kleijnen J, Knipschild P. Ginkgo biloba. Lancet 1992;340:1136-1139.

90. Kanowski S, Herrmann WM, Stephan K, et al. Proof of the efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type of multi-infarct dementia. Phytomedicine 1997; 43-13. 91. Le Bars PL, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American Egb Study Group. JAMA 1997;278:1327-1332. 92. Wettstein A. Cholinesterase inhibitors and Ginkgo extracts-are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months’ duration. Phytomedicine 2000;6393401. 93. Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 199855: 1409-1415. 94. SpagnoliA, Lucca U, Menasce G, et al. Long-term acetyl-L-camitine treatment in Alzheimer’s disease.Neurology 1991;41:1726-1732. 95.Pettegrew JW,Klunk WE, Panchalingam K, et al. Clinical and neurochemical effects of acetyl-L-camitine in Alzheimer’s disease. Neurobiol Aging 1995;16:1-4. 96. Sano M, Bell K, Cote L, et al. Double-blind parallel design pilot study of acetyl levocamitine in patients with Alzheimer’s disease. Arch Neurol1992;49:1137-1141. 97. Skolnick A. Old Chinese herbal medicine used for fever yields possible new Alzheimer disease therapy. JAMA 1997;277:776. 98. Xu SS, Gao W, Weng Z, et al. Efficacy of tablet huperzine-A on memory, cognition and behavior in Alzheimer’s disease. Zhongguo Yao Li Xue Bao 1995;16391-395. 99.Colasanti M, Suzuki H. The dual personality of NO. Trends Pharmacological Science 2000;21:249-252. 100. Russo A, Borrelli F, Campisi A, et al. Nitric oxide-related toxicity in cultured astrwytes: effect of Bacopa monniera. Life Sci 2003; 73~1517-1526. 101. Sugaya E, Sugaya A, Kajiwara K, et al. Nervous diseases and Kampo gapanese herbal) medicine: a new paradigm of therapy against intractable nervous diseases. Brain Dev 1997;19:93-103. 102.Thomsen T, Kewitz H. Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo. Life Sci 1990; 461553-1558. 103. Howes MJ, Perry NS, Houghton PJ. Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders. Phytother Res 2003;171-18. 104.Greenblatt HM, Kryger G, Lewis T, et al. Structure of acetylcholinesterasecomplexed with (-)-galanthamineat 2.3 A resolution. FEBS Lett 1999;463:321-326.

Angina Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary 1473 General Considerations 1473

Botanical Medicines 1477 Other Therapies 1478 Intravenous EthylenediamineTetraacetic Acid Chelation Therapy 1478

Diagnostic Considerations 1473 Therapeutic Considerations 1474 Coronary Angiogram, Artery Bypass Surgery, and Angioplasty 1474 Nutritional Supplements for Angina 1475

DIAGNOSTIC SUMMARY Squeezing or pressurelike pain in the chest appearing immediately after exertion. Other precipitating factors include emotional tension, cold weather, or a large meal. Pain may radiate to the left shoulder blade, left arm, or jaw. The pain typically lasts for only 1to 20 minutes. Stress, anxiety, and high blood pressure are typically present. The majority of people demonstrate an abnormal electrocardiographic reading (transient ST segment depression) in response to light exercise (stress test).

Therapeutic Approach 1479 Diet 1479 Lifestyle 1479 Nutritional Supplements 1479 Botanical Medicines 1479

in Chapter 150) and coronary artery spasm. Prinzmetal’s variant angina, the most commonly recognized form of coronary artery spasm, is not due to plaque in the coronary arteries and is more apt to occur at rest or at odd times during the day or night. It is more common in women younger than age 50. Magnesium insufficiencyinduced coronary artery spasm, more common in men than women, is now recognized as an important cause of myocardial infarction (MI) and may be of significance in angina pectoris.

DIAGNOSTIC CONSIDERATIONS GENERAL CONSIDERATIONS Angina pectoris results when the supply of oxygen, and occasionally other nutrients, is inadequate to meet the metabolic needs of the heart muscle. The primary cause is atherosclerosis, although platelet aggregation, coronary artery spasm, nonvascular mechanisms such as hypoglycemia, and increased metabolic need (such as in hyperthyroidism) can also be important. The primary lesion of atherosclerosis is the atheromatous plaque, which progressively narrows and ultimately blocks the coronary artery, resulting in a decreased supply of blood and oxygen to the heart tissue. Symptoms typically begin to appear after a major coronary artery is blocked by more than 50%. Blood flow to the heart may also be compromised by transient platelet aggregation (discussed in more detail

The diagnosis of angina is frequently made by history alone. Clinical evaluation of all patients with angina should include an electrocardiogram (ECG) at rest and a chest radiograph. Because more than half of patients with typical angina and confirmed coronary atherosclerosis have normal 12-lead ECG readings at rest, diagnosis must often be confirmed using electrocardiographic stress testing or 24-hour Holter monitoring (ambulatory electrocardiography). The most common diagnostic electrocardiographic changes associated with angina are evidence of previous MI and ST-segment and T-wave changes that occur during attacks of pain. The most characteristic change is displacement of the ST segment, with or without T-wave inversion.Complicating diagnosis, however, is the observation that hypoglycemia-induced angina does not manifest with rate or ST-segment abnormalities.’ 1473

THERAPEUTIC CONSIDERATIONS Angina is a serious condition that requires careful treatment and monitoring. In the severe case, as well as in the initial stages in the mild to moderate patient, prescription medications may be necessary. Eventually the condition should be controlled with the help of natural measures. If there is sigruficant blockage of the coronary artery, intravenous ethylenediamine tetraacetic acid (EDTA) chelation therapy, angioplasty, or coronary artery bypass may be appropriate. From a natural perspective, there are two primary therapeutic goals in the treatment of angina: improving energy metabolism within the heart and improving blood supply to the heart. These goals are interrelated, as an inmased blood flow means improved energy metabolism and vice versa. The heart uses fats as its major metabolic fuel. It converts free fatty acids to energy in much the same way as an automobile uses gasoline. Defects in the utilization of fats by the heart greatly increase the risk of atherosclerosis, heart attacks, and angina pains. Specifically, impaired utilization of fatty acids by the heart results in accumulation of high concentrations of fatty acids within the heart muscle. This makes the heart extremely susceptible to cellular damage, which ultimately leads to a heart attack. Carnitine, pantethine, and coenzyme Qlo(CoQlo)are essential compounds in normal fat and energy metabolism and are of extreme benefit to sufferers of angina. These nutrients prevent the accumulation of fatty acids within the heart muscle by improving the conversion of fatty acids and other compounds into energy.

Coronary Angiogram, Artery Bypass Surgery, and Angioplasty According to the American Heart Association’s Heart Disease and Stroke Statistics 2003 Update: 1,025,000 angioplasties were done in the United States in 2000. Of these, 561,000 were percutaneous transluminal coronary angioplasties (PTCAs). 655,000 men and 370,000 women had angioplasties. 519,000 cardiac revascularizations (also known as coronary artery bypass graft [CABG] operations) were done in the United States in 2000. CABGs were performed on 371,000 men and 148,000 women. The rapidly expanding use of PCTA is based on a perceived benefit in comparison with the use of CABG or pharmacologic treatment, but these perceptions have not been confirmed by clinical studies. In fact, to date no study has demonstrated a mortality benefit of CABG or PCTAs over nonsurgical interventions in patients with stable coronary artery disease (CAD). The Medicine, Angioplasty, or Surgery Study (MASSII) showed no difference in cardiac death or acute MI among patients

in the CABG, PCTA, or medical treatment (MT) group. However, it did show a sigruficantly greater need for additional revascularization procedures in patients who underwent PCTAs. The finding of comparable mortality and morbidity rates for patients who underwent CABG or MT suggests that MT is a reasonable alternative for patients with multivessel CAD? There is no question that when appropriate, these procedures save lives. Yet several studies have challenged the widespread recommendation for an angiogram given by most cardiologists. One landmark study evaluated 168 patients who were told they needed to have an angiogram to determine the degree of blockage and consequent need for bypass surgery or angioplasty? Using noninvasive tests, such as the exercise stress test, the echocardiogram, and the Holter heart monitor that is worn for 24 hours, Graboys and colleagues determined that 134, or 8O%, did not need the catheterization. These 168 patients experienced only a 1.1% annual fatal heart attack rate over a 5-year period. This rate is much lower than the mortality rates associated with either CABG (5% to 10%) or angioplasty (1%to 2%). The researchers concluded: “In a large fraction of medically stable patients with coronary disease who are urged to undergo coronary angiography (heart catheterization), the procedure can be safely deferred.” Noninvasive testing to determine the functional state of the heart is far more important in determining the type of therapy that is necessary than the dangerous search for blocked arteries. If the heart is not functioning well, then the angiogram may be necessary to see if surgery should be done. Furthermore, the blockages found by the angiogram are usually not relevant to the patient’s risk of heart attack. For instance, in a sophisticated study of bypass surgery, the Coronary Artery Surgery Study (CASS), it was demonstrated that heart patients with healthy hearts but with one, two, or all three of the major heart vessels blocked did surprisingly well without surgery45 Regardless of the number or severity of the blockages, each group had the same low annual death rate of 1%. Importantly, the severity of blockage does not estimate reduction in blood flow in the artery. In one study, Iowa researchers measured blood flow in more than 44 blockages demonstrated by angiogram.6 Much to their surprise, they found no correlation between blood flow and the severity of the heart artery blockage. In other words, the angiogram did not provide clinically relevant information. The researchers found that the majority of coronary arteries with 96% blockage had the fastest blood flows, while arteries with only 40% blockage had severe blood flow restriction. The authors concluded that the blockages found on the heart catheterization simply do not correlate with blood flow restriction, saying: “The results of these studies should be profoundly disturbing . . .

Angina information cannot be determined accurately by conventional angiographic approaches.” The critical factor in whether a patient needs coronary artery bypass surgery or angioplasty is how well the left ventricular pump is working, not the degree of blockage or the number of arteries affected. Bypass is only helpful Up to 90% of when the ejection fraction is less than 40Y0.~ all bypass procedures are done when the ejection fraction is greater than 50%, which is adequate for circulatory needs. In other words, up to 90% of all bypass procedures may be unnecessary. When coronary artery bypass surgery or angioplasty, or both, are necessary based on these accepted criteria, they definitely increase long-term survival and relieve symptoms for 85%. However, these procedures are not without risk. Complications are common. In one study, 61%of the patients having coronary artery bypass surgery suffered nervous system disorders as a result? Another study found that 2% to 5% of individuals having coronary bypass surgery die during or soon after the operation and 10% have MIS? Considering the cost of these procedures, the lack of long-term survival benefit, and the high level of complications, it appears that electing to have these procedures when they are less than absolutely necessary (e.g., ejection fraction <40%) is unwise for the majority of patients. This is particularly true in light of the availability of effective ”natural” alternativesto coronarybypass surgery. Numerous studies have shown that dietary and lifestyle changes can sigruficantly reduce the risk of heart attacks and other causes of death due to atherosclerosis (see Chapter 150).Simple dietary changes, such as decreasing the amount of saturated fat and cholesterol,and increasing the amount of dietary fiber, complex carbohydrates, fish oils, and magnesium in the diet, along with eliminating alcohol consumption and cigarette smoking and reducing high blood pressure, would greatly reduce the number of coronary bypass operations performed in Westernized countries. In addition, several nutritional supplements and botanical medicines have been shown in clinical studies to improve heart function in even the most severe angina cases. Another possible alternative is intravenous EDTA chelation therapy (discussed later). When a cardiac procedure cannot be prevented, the goal is then to prevent the damaging effects produced by this procedure. In particular, the goal is to prevent restenosis. This can be accomplished by prescribing a high-potency multivitamin and mineral formula, along with additional vitamin C (500 mg one to three times daily) and CoQlo (100 mg daily 2 weeks before surgery and for 3 months after). Note that it is generally recommended that garlic supplementationand high dosages of vitamin E (>200 IU)should be avoided before any surgery due to their ability to inhibit platelet aggregation. Vitamin C supplementation is rarely employed in hospitals, despite the fact that it may provide significant

benefits, and low vitamin C status is common in hospitalized patients. In a study analyzing the vitamin C status of patients undergoing coronary artery bypass, the plasma concentration of vitamin C was shown to plummet by 70% 24 hours after coronary artery bypass surgery and persisted in most patients for up to 2 weeks after surgery.IOIn contrast, vitamin E and carotene levels did not change to any sigruficant degree presumably because they are fat soluble and are therefore retained in the body for longer periods of time. Given the importance of vitamin C, the serious depletion of vitamin C may deteriorate defense mechanisms against free radicals, infection, and wound repair in these patients. Supplementation appears to be essential in patients recovering from heart surgery, or any surgery for that matter. CoQlo is recommended in an attempt to prevent oxidative damage during reperfusion. Return of blood flow after coronary artery bypass surgery results in oxidative damage to the vascular endothelium and myocardium and thus increases greatly the risk for subsequent CAD. CoQloprevents reperfusion injury in patents undergoing coronary artery bypass surgery or angioplasty. In one study, 40 patients undergoing elective surgery received either 150 mg of CoQlo each day for 7 days before the surgery or served in the control group.” The concentrations of lipid peroxides and an enzyme (creatine kinase) indicating myocardial damage were significantly lower in patients receiving CoQlo than in the control group. The treatment group also showed a statistically significant lower incidence of ventricular arrhythmias during the recovery period. These results clearly demonstrate that pretreatment with CoQlocan play a protective role during routine bypass surgery by reducing oxidative damage. In addition to vitamin C and CoQlo, a mixture of highly purified bovine-derived glycosaminoglycans (GAGs) naturally present in the aorta including dermatan sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, and related hexosaminoglycans is also of benefit in preventing reperfusion injury and restoring proper structure, integrity, and function of the coronary vascular endothelium.12The dosage of purified aortic GAGs is 100 mg daily.

Nutritional Supplements for Angina Using antioxidant supplementation in patients with angina is important. In an analysis of normal controls and patients with either stable or unstable angina, the plasma level of antioxidants has been shown to be a more sensitive predictor of unstable angina than the severity of atheroscler~sis.~~J~ One group of researchers concluded: “These data are consistent with the hypothesis that the beneficial effects of antioxidants in CAD may result, in part, by an influence on lesion activity rather than a reduction in the overall extent of fixed di~ease.”’~

Specific Health Problems

Antioxidant nutrients are also important in preventing nitrate tolerance. Oral nitrates are widely used in the conventional treatment of angina, but their continuous administration can result in rapid development of tolerance. Experimental findings indicate that nitrate tolerance is associated with increased vascular production of superoxide. The superoxide anions generated quickly degrade the nitric oxide formed from the administration of nitroglycerine and result in lower levels of cGMP (an important intracellular regulator that promotes vasorelaxation). Because vitamin C is the main aqueous phase antioxidant and free radical scavenger of superoxide and vitamin E is the main lipid phase antioxidant, their importance in preventing nitrate tolerance is obvious. Clinical trials have upheld this connection, showing that high-dose vitamin C and E supplementation can prevent nitrate tolerance.15J6

Carnitine Carnitine, a vitamin-like compound, stimulates the breakdown of long-chain fatty acids by the energyproducing units in cells-the mitochondria. Carnitine is essential in the transport of fatty acids into the mitochondria. A deficiency in camitine results in a decrease in fatty acid concentrations in the mitochondria and reduced energy production. Normal heart function is critically dependent on adequate concentrationsof carnitine.Although the normal heart stores more camitine than it needs, if the heart does not have a good supply of oxygen, carnitine levels quickly decrease. This leads to decreased energy production in the heart and increased risk for angina and heart disease. Since angina patients have a decreased supply of oxygen, carnitine supplementation makes good sense. Several clinical trials have demonstrated that carnitine improves angina and heart disea~e.'~-~' Supplementation with carnitine normalizes heart carnitine levels and allows the heart muscle to use its limited oxygen supply more efficiently. This translates to an improvement in cases of angina. Improvements have been noted in exercise tolerance and heart function. The results indicate that carnitine is an effective alternative to drugs in cases of angina. In one study of patients with stable angina, oral administration of 900 mg of L-camitine increased mean exercise time and the time necessary for abnormalities to occur on a stress test (6.4 minutes in the placebo group compared with 8.8 minutes in the carnitine-treated group).2' These results indicate that carnitine may be an effective alternative to other antianginal agents such as beta-blockers, calcium-channel antagonists, and nitrates, especially in patients with chronic stable angina pectoris.

Carnitine, by improving fatty acid utilization and energy production in the heart muscle, may also prevent the production of toxic fatty acid metabolites. These compounds are extremely deleterious as they activate various phospholipases and disrupt cellular membrane structures. The changes in the properties of cardiac cell membranes induced by fatty acid metabolites are thought to contribute to impaired heart muscle contractility and compliance, increased susceptibility to irregular beats, and eventual death of heart tissue. Supplemental carnitine increases heart camitine levels and prevents the production of toxic fatty acid metabolites. This has been demonstrated clinically where the early administration of L-camitine (40mg/kg per day) in patients having heart attacks was found to considerably reduce heart damage."

Pantethine Pantethine is the stable form of pantetheine, the active form of pantothenic acid, which is the fundamental component of coenzyme A (CoA).CoA is involved in the transport of fatty acids to and from cells, as well as to the mitochondria. The synthetic pathway from pantethine to CoA is much shorter than that of pantothenic acid, making pantetheine the preferred therapeutic substance. In addition, pantetheine has significant lipid-lowering activity while pantothenic acid has very little (if any) effect in lowering cholesterol and triglyceride levels. The standard dose for pantethine is 900 mg/day. Like carnitine, pantethine has been shown in clinical trials to significantly reduce serum triglyceride and cholesterol levels while increasing high-density lipoprotein cholesterol levels.B25Its lipid-lowering effects are most impressive when its toxicity (virtually none) is compared with that of conventional lipid-lowering drugs. Its mechanism of action is due to inhibiting cholesterol synthesis and accelerating fatty acid breakdown in the mitochondria. Pantethine is well indicated in angina. Like carnitine, heart pantethine levels decrease during times of reduced oxygen supply. Demonstrated effects in animals indicate that it would greatly benefit individuals with angina.26

Coenzyme Qlo CoQlo,also known as ubiquinone, is an essential component of the mitochondria, where it plays a major role in energy production. Like carnitine and pantethine, CoQlo can be synthesized within the body. Nonetheless, deficiency states have been reported. Deficiency can be a result of impaired CoQlo synthesis due to nutritional deficiencies, a genetic or acquired defect in CoQlo synthesis, or increased tissue needsF7 Cardiovascular diseases including angina, hypertension, mitral valve prolapse, and congestive heart failure are examples of diseases that require increased tissue levels of C O QIn~addition, ~ ~ ~ many of the elderly may

Angina have increased CoQlorequirements: the decline of CoQlo levels that occurs with age may be partly responsible for the age-related deterioration of the immune system. CoQlodeficiency is common in individuals with heart disease. Heart tissue biopsies in patients with various heart diseases show a CoQlodeficiency in 50% to 75% of cases.27One of the most metabolically active tissues in the body, the heart may be unusually susceptible to the effects of CoQlo deficiency. Accordingly, CoQlo has shown great promise in the treatment of heart disease. In one study 12 patients with stable angina pectoris were treated with CoQlo (150 mg/day for 4 weeks) in a double-blind, cross-over Compared with placebo, CoQloreduced the frequency of anginal attacks by 53%. In addition, there was a significant increase in treadmill exercise tolerance (time to onset of chest pain and time to development of ECG abnormalities) during CoQlotreatment. The results of this study and others suggest that CoQlois a safe and effective treatment for angina pectoris. Camitine, pantethine, and CoQloshould be considered in all heart disorders, not just angina.

Magnesium

Reduce the size of the infarct (blockage) Improve heart rate and arrhythmias

Botanical Medicines Crataegus Species Hawthorn berry and flowering tops extracts are widely used in Europe for their cardiovascular activity. They exhibit a combination of effects that are of great value to patients with angina and other heart problems. Studies have demonstrated that hawthorn extracts are effective in reducing angina attacks, as well as in lowering blood pressure and serum cholesterol level^.^^-^^ The beneficial effects in the treatment of angina are due to improvement in the blood and oxygen supply of the heart resulting from dilation of the coronary vessels, as well as improvement of the metabolic processes in the heart.36-39 Crataegus sp.’s ability to dilate coronary blood vessels has been repeatedly demonstrated in experimental studies.538 In addition, crataegus extracts have been shown to improve cardiac energy metabolism in human and experimental studies. This combined effect is extremely important in the treatment of angina, as it results in improved myocardial function with more efficient use of oxygen. The improvement results not only from increased blood and oxygen supply to the heart muscle but also from hawthorn flavonoids interacting with key enzymes to enhance myocardial contractility (see Chapter 85 for a comprehensive discussion of this important botanical).

Magnesium deficiency may play a major role in angina, including Prinzmetal’s variant. A magnesium deficiency has been shown to produce spasms of the coronary arteries and is thought to be a cause of nonocclusive heart attacksz9Furthermore, it has been observed that men who die suddenly of heart attacks have sigruficantly lower levels of heart magnesium, as well as potassium, than matched controls.3o Making magnesium the treatment of choice for angina due to coronary artery spasm has been s~ggested?O-~~Ammi visnaga Khella is an ancient medicinal plant native to the Magnesium administration has also been found to be helpful in the management of arrhythmias and in angina Mediterranean region, where it has been used in the due to atherosclerosis. Its benefit in these situations is treatment of angina and other heart ailments since presumably via the same mechanisms responsible for its the time of the pharaohs. Several of its components have effects in an acute MI. demonstrated effects in dilating the coronary arteries. Its Since the mid-l980s, eight well-designed studies mechanism of action appears to be similar to the calcium involving more than 4000 patients have demonstrated channel blocking drugs. Since the late 1940s,there have been numerous scientific that intravenous magnesium supplementation during studies on the clinical effect of khella extracts in the treatthe first hour of admission to a hospital for an acute MI ment of angina. More specifically khellin, a derivative of produces a favorable effect in reducing immediate and the plant, was shown to be extremely effective in relievlong-term complications, as well as death rates.3s35 ing angina symptoms, improving exercise tolerance, and The beneficial effects of magnesium in an acute MI relate to its ability to the following: normalizing electrocardiographic tests. This is evident by the concluding statements in a study by Osher and Improve energy production within the heart colleagues39in 1951: “The high proportion of favorable Dilate the coronary arteries, resulting in improved results, together with the striking degree of improvement frequently observed, has led us to the conclusion that delivery of oxygen to the heart Reduce peripheral vascular resistance, resulting in khellin, properly used, is a safe and effective drug for the reduced demand on the heart treatment of angina pectoris.” Inhibit platelets from aggregating and forming blood At higher doses (120 to 150 mg/day), pure khellin clots was associated with mild side effects such as anorexia,

Specific Health Problems

nausea, and dizziness. Although most clinical studies used high dosages, several studies show that as little as 30 mg of khellin per day appear to offer as good results with fewer side e f f e ~ t s . ~ , ~ ~ Rather than using the isolated compound khellin, khella extracts standardized for khellin content (typically 12%)are the preferred form. A daily dose of such an extract would be 250 to 300 mg. Khella appears to work well with hawthorn extracts.

Other Therapies Acupuncture Several studies have shown acupuncture to be of benefit in improving angina, specifically in reducing nitroglycerin use, decreasing the number of angina attacks, and improving exercise tolerance and ECG readings.4245

Relaxation and Breathing Exercises Relaxation and breathing exercises may be helpful in improving angina symptoms, especially when anxiety is a significant c ~ n t r i b u t o r .In ~ ,one ~ ~ study in patients with cardiac syndrome X, a form of angina in people with otherwise normal coronary arteries, transcendental meditation (20 minutes twice daily of silently chanting a mantra with eyes closed) was found to reduce angina-like chest pain and to normalize ECGs.&

Intravenous EthylenediamineTetraacetic Acid Chelation Therapy EDTA chelation therapy is an alternative to coronary artery bypass surgery and angioplasty, which may prove to be more effective and is definitely safer and less expensive. EDTA is an amino acid-like molecule that, when slowly infused into the bloodstream, binds with minerals such as calcium, iron, copper, and lead and carries them to the kidney, where they are excreted. EDTA chelation has been commonly used for lead poisoning, but in the late 1950s and early 1960s it was found to help patients with atherosclerosis. The discovery of EDTA chelation therapy in the treatment of angina and other conditions associated with atherosclerosis happened accidentally. In 1956 a battery worker whom Dr. Norman Clarke was treating with EDTA for lead poisoning noticed that his symptoms of angina disappeared. Clarke and others began using EDTA chelation therapy in patients with angina, cerebral vascular insufficiency, and occlusive peripheral vascular disease. In a series of 283 patients treated by Clarke and his colleagues from 1956 to 1960,87% showed improvements in their symptoms. Heart patients improved, and patients with blocked arteries in the legs, particularly those with diabetes, avoided a m p ~ t a t i o n . ~ , ~ ~ It was originally thought that EDTA opened blocked arteries by chelating out the calcium deposits in the

cholesterol plaque. However, it now seems more related to chelating out excess iron and copper, minerals that, in the presence of oxygen, stimulate free radicals. Free radicals damage the cells in the artery and are a primary reason for atherosclerosis. In a review of the progression and regression of atherosclerosis, the authors write that the process of atherosclerosis is "dependent on the presence of some metals (copper and iron) and can be completely inhibited by chelating agents such as EDTA."50 Despite obvious benefits to heart patients, EDTA fell out of favor in the mid-1960s. Advocates believe thisoccurred for two reasons: (1) the lucrative surgical approach to heart and vessel disease was on the rise and (2) the patent on EDTA that was held by Abbott Laboratories expired, so there was no financial interest for drug companies to fund any research. Fortunately, in 1972 a small group of practicing physicians using EDTA chelation therapy founded an organization now called the American College for the Advancement of Medicine to continue education and research in this important area. In the early days of EDTA chelation therapy, several serious problems were discovered. Giving too much EDTA or giving it too fast was soon noted to be dangerous. In fact, several deaths attributed to kidney failure were caused by toxicity to EDTA. Fortunately, additional research resulted in more appropriate protocols, and EDTA chelation therapy as used now is safe. No deaths or significant adverse reactions have occurred in more than 500,000 patients who have undergone EDTA chelation therapy. Because EDTA chelation improves blood flow throughout the body, the "side effects" are usually beneficial and only a few adverse effects are noticed. A substantial body of scientific evidence exists on the use of EDTA chelation therapy in the treatment of angina, peripheral vascular disease, and cerebral vascular disease.51 Since 1987, numerous Food and Drug Administration-approved studies have demonstrated some rather impressive r e s ~ l t s . ~ l - ~ ~ Nonetheless, there is a paucity of well-designed, placebo-controlled studies to definitively assess the efficacy of this approach. This is unfortunate considering the early successes. The conclusion from a recent Cochran review summarizes the situation well: "At present, there is insufficient evidence to decide on the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes of patients with atherosclerotic cardiovascular disease." For more information, the reader is referred to the American College of Advancement in Medicine (ACAM), 23121 Verdugo Drive, Suite 204, Laguna Hills, CA, 92653; 1-800-532-3688 (outside California) or 1-800-4356199 (inside California);www.acam.org.

THERAPEUTIC APPROACH The primary therapy for angina is prevention because angina is usually secondary to atherosclerosis. Once angina has developed, restoring proper blood supply to the heart and enhancing energy production within the heart are necessary. Particularly important nutrients for accomplishing these results are vitamins C and E, carnitine, pantethine, CoQlo, and magnesium. Magnesium is of additional benefit because of its ability to relax spastic coronary arteries and improve heart function. Hawthorn berries or extracts offer a number of benefits to individuals with angina, including coronary artery dilation and improved heart muscle metabolism. Patients with unstable angina pectoris (characterized by a progressive increase in the frequency and severity of pain, increased sensitivity to precipitating factors, progression of symptoms over several days, and prolonged coronary pain) should be hospitalized.

Diet The dietary guidelines given in Chapter 44 are appropriate here. In particular, an increase of dietary fiber is recommended, especially the gel-forming or mucilaginous fibers (e.g., flaxseed, oat bran, pectin). Onions and garlic (both raw and cooked), vegetables, and fish should also be increased, while reducing the consumption of saturated fats, cholesterol, sugar, and animal proteins. All fried foods and food allergens should be avoided. Patients with reactive hypoglycemia should eat regular meals and carefully avoid simple carbohydrates of all forms (e.g., sugar, honey, dried fruit, fruit juice).

1.Bansal S, Toh SH, LaBresh KA. Chest pain as a presentation of reactive hypoglycemia. Chest 1983;84:641-662. 2. Hueb W, Soares PR, Gersh BJ, et al. The medicine, angioplasty, or surgery study (MASSII): a randomized, controlled clinical trial of three therapeutic strategies for multivessel coronary artery disease: one-year results. J Am Coll Cardiol2004;43:1743-1751. 3. Graboys TB, Headley A, Lown B, et al. Results of a second opinion program for coronary artery bypass surgery. JAMA 1987;258: 1611-1614. 4. Alderman EL, Bourassa MG, Cohen LS, et al. Ten-year follow-up of survival and myocardial infarction in the randomized Coronary Artery Surgery Study. Circulation 1990;821629-1646. 5. Myocardial infarction and mortality in the coronary artery surgery study (CASS) randomized trial. N Engl J Med 1984;310750-758. 6. White CW, Wright CB, Doty DB, et al. Does visual interpretation of the coronary angiogram predict the physiologic importance of a coronary stenosis. N Engl J Med 1984;310819-824. 7. Winslow CM, Kosecoff JB,Chassin M, et al. The appropriateness of performing coronary artery bypass surgery. JAMA 1988;260505-509. 8. Shaw PJ, Bates D, Cartlidge NE, et al. Neurological complications of coronary artery bypass graft surgery. six month follow-up study. Br Med J (Clin Res Ed) 1986;293165-167.

Lifestyle The individual with angina should not smoke or drink alcohol and coffee. Stress should be decreased by using stress management techniques such as progressive relaxation, meditation, or guided imagery. A carefully graded, progressive, aerobic exercise program (30 minutes three times/week) is a necessity. Walking is a good exercise with which to start.

Nutritional Supplements Vitamin C: 500 to 1500 mg daily Vitamin E: 400 to 800 IU daily CoQI0:150 to 300 mg daily L-Carnitine: 500 mg three times/day Pantethine: 300 mg three times/day Magnesium, preferably bound to aspartate, citrate, or other Krebs cycle intermediate: 200 to 400 mg three times/day

Botanical Medicines Crutuegus oxyucuntha (three times/day) Berries or flowers (dried): 3 to 5 g or as a tea Tincture (1:5):4 to 6 ml(1to 1.5 tsp) Fluid extract (1:l): 1to 2 ml(0.25 to 0.5 tsp) Solid extract (10% procyanidins or 1.8% vitexin-4’rhamnoside): 100 to 250 mg Ammi visnugu (three times/day) Dried powdered extract (12% khellin content): 100mg three times/day

9. Long-term results of prospective randomized study of coronary artery bypass surgery in stable a n e a pectoris. Lancet 1982;21173-1180. 10.Ballmer PE, Reinhart WH, Jordan P, et al. Depletion of plasma vitamin C but not vitamin E in response to cardiac operations. J Thorac Cardiovasc Surg 1994;108:311-320. 11. Chello M, Mastroroberto P, Romano R, et al. Protection of coenzyme Qlo from myocardial reperfusion injury during coronary artery bypass grafting. Ann Thorac Surg 1994;581427-1432. 12. Laurora G, Cesarone MR, DeSanctis MT, et al. Delayed arteriosclerosis progression in high risk subjects treated with mesoglycan. Evaluation of intima-media thickness. J Cardiovasc Surg (ToMo) 1993;34:313-318. 13. Kostner K, Hornykewycz S, Yang P, et al. Is oxidative stress causally linked to unstable angina pectoris? A study in 100 CAD patients and matched controls. Cardiovasc Res 1997;36:330-336. 14. Vita JA, Keaney JF Jr, Raby KE, et al. Low plasma ascorbic acid independently predicts the presence of an unstable coronary syndrome. J Am Coll Cardiol1998;31:980-986. 15. Watanabe H, Kakihana M, Ohtsuka S, et al. Randomized, doubleblind, placebo-controlled study of ascorbate on the preventive effect of nitrate tolerance in patients with congestive heart failure. Circulation 1998;97886-891.

Specific Health Problems ~~

16.Watanabe H, Kakihana M, Ohtsuka S, et al. Randomized, double-blind, placebc-controlled study of supplemental vitamin E on attenuation of the development of nitrate tolerance. Circulation 19979625452550. 17. Lagioia R, Scritinio D, Mangini SG,et al. Propionyl-L-camitine. A new compound in the metabolic approach to the treatment of effort angina. Int J Cardiol1992;34:167-172. 18. Bartek GL, Remme WJ, Pillay M, et al. Effects of L-propionylcamitine on ischemia-induced myocardial dysfunction in men with angina pectoris. Am J Cardiol1994;74:125-130. 19. Cacciatore L, Cerio R, Ciarimboli M, et al. The therapeutic effect of L-camitine in patients with exercise-induced stable angina. A controlled study. Drugs Exp Clin Res 1991;17225-235. 20. Davini P, Bigalli A, Lamanna F. Controlled study on L-camitine therapeutic efficacy in post-infarction. Drugs Exptl Clin Res 1992; 18:355-365. 21. Kamikawa T, Suzuki Y, Kobayashi A, et al. Effects of L-camitine on exercise tolerance in patients with stable angina pectoris. Jpn Heart J 1984;25:587-597. 22. Rebuzzi AG, khiavoni G, Amico CM, et al. Beneficial effects of L-carnitine in the reduction of the necrotic area in acute myocardial infarction. Drugs Exp Clin Res 1984;10:219-223. 23. Arsenio L, Bodria P, Magnati G, et al. Effectiveness of long-term treatment with pantethine in patients with dyslipidemias. Clin Ther 1986;8:537-545. 24. Miccoli R, Marchetti P, Sampietro T, et al. Effects of pantethine on lipids and apolipoproteins in hypercholesterolemic diabetic and non-diabetic patients. Curr Ther Res 1984;36545-549. 25. Gaddi A, Descovich GC, Noseda G, et al. Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia. Atherosclerosis 198450 73-83. 26. Hayashi H, Kobayashi A, Terad H, et al. Effects of pantethine on action potential of canine papillary muscle during hypoxic perfusion. Jpn Heart J 1985;26289-296. 27. Folkers K, Yamamura Y, eds. Biomedical and clinical aspects of coenzyme Q: proceedings of the International Symposium on Coenzyme Q, vols 1-4. Amsterdam: Elsevier Scientific, 1977 (vol l), 1980 (vol 2), 1982 (vol3), 1984 (vol4). 28. Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Qla on exercise tolerance in chronic stable angina pectoris. Am J Cardiol1985;56:247-251. 29. Turlapaty PD, Altura BM. Magnesium deficiency produces spasms of coronary arteries. Relationship to etiology of sudden death ischemic heart disease. Science 1980;208:198-200. 30. Altura BM. Ischemic heart disease and magnesium. Magnesium 1988;757-67. 31. McLean RM. Magnesium and its therapeutic uses: a review. Am J Med 1994;9663-76. 32. Purvis JR, Movahed A. Magnesium disorders and cardiovascular disease. Clin Cardiol 1992;15:556-568. 33.Hampton EM, Whang DD, Whang R. Intravenous magnesium therapy in acute myocardial infarction. Ann Pharmacother 1994;28: 220-226. 34. Teo KK, Yusuf S. Role of magnesium in reducing mortality in acute myocardial infarction. A review of the evidence. Drugs 1993;46: 347-359.

35. Schecter M, Kaplinsky E, Rabinowitz B. The rationale of magnesium supplementation in acute myocardial infarction. A review of the literature. Arch Intern Med 1992;1522189-2196. 36. Ammon HPT, Handel M. [Crataegus, toxicology and pharmacology. Part I: Toxicity.] Planta Med 1981;43:105-20; Part 11: Pharmacodynamics. Planta Med 1981;43:209-239; Part IIk Pharmacodynamics and pharmacokinetics. Planta Med 1981;43 313-322. 37. Blesken R. [Crataegus in cardiology.] Fortschr Med 1992;llO 290-292. 38.Nasa Y, Hashizume H, Hoque AN, et al. Protective effect of Crataegus extract on the cardiac mechanical dysfunction in isolated perfused working rat heart. Arzneimittelforschung 1993;43: 945-949. 39. Osher HL, Katz KH, Wagner DJ. Khellii in the treatment of angina pectoris. N Engl J Med 1951;244:315-321. 40. Anrep GV, Kenawy MR, Barsoum GS. Coronary vasodilator action of khellin. Am Heart J 1949;37531-542. 41. Conn JJ, Kissane RW, Koons RA, et al. Treatment of angina pectoris with khellin. Ann Intern Med 1952;361173-1178. 42. Ballegaard 5, Karpatschoff B, Holck JA, et al. Acupuncture in angina pectoris do psychosocial and neurophysiological factors relate to the effect? Acupunct Electrother Res 1995;20101-116. 43. Meng J. The effects of acupuncture in treatment of coronary heart diseases. J Tradit Chin Med 2004;2416-19. 44.Ballegaard S, Jensen G, Pedersen F, et al. Acupuncture in severe, stable angina pectoris: a randomized trial. Acta Med %and 1986; 220307-313. 45. Richter A, Herlitz J, Hjalmarson A. Effect of acupuncture in patients with angina pectoris. Eur Heart J 1991;12:175-178. 46.Cunningham C, Brown S, Kaski JC. Effects of transcendental meditation on symptoms and electrocardiographic changes in patients with Cardiac Syndrome X. Am J Cardiol2000;85:653-655,A10. 47. Gilbert C. Clinical applications of breathing regulation. Beyond anxiety management. Behav Modif 2003;27:692-709. 48. Clarke CN, Clarke NE, Mosher RE. Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. Am J Med Sci 1956;232:654-666. 49. Clarke NE Sr. Atherosclerosis, occlusive vascular disease and EDTA. Am J Cardiol1960;6233-236. 50. Steinberg D, Parthasarathy S, Carew TE, et al. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320915-924. 51. Cranton EM, Frackelton JP. Current status of EDTAchelation therapy in occlusive arterial disease. J Adv Med 1989;2107-119. 52. Olszewer E, Carter JP.EDTA chelation therapy. A retrospective study of 2,870 patients. J Adv Med 1989;2197-211. 53. Olszewer E, Sabbag FC, Carter JP. A pilot double-blind study of sodium-magnesium EDTA in peripheral vascular disease. J Nat Med Assoc 1990;82:173-177. 54. Olszewer E, Carter JF'. EDTA chelation therapy in chronic degenerative disease. Med Hypotheses 1988;2741-49. 55. Casdorph HR. EDTA chelation therapy, efficacy in arteriosclerotic heart disease. J Holistic Med 1981;3:53-59. 56. Vilarruz MV, Dans A, Tan F. Chelation therapy for atherosclerotic cardiovascular disease. Cochrane Database Syst Rev 2002;(4): CW02785.

Aphthous Stomatitis Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

1481

General Considerations 1481 Therapeutic Considerations 1481 Food and Environmental Allergens 1481 Gluten Sensitivity 1482 Stress 1482

Nutrient Deficiency 1482 Quercetin 1482 Deglycyrrhizinated Licorice 1482 Therapeutic Approach Diet 1483 Supplements 1483

1482

DIAGNOSTIC SUMMARY Single or clustered, shallow, painful ulcers found anywhere in the oral cavity Lesions are from 1 to 15 mm in diameter, have fairly even borders, are surrounded by an erythematous border, and are often covered by a pseudomembrane Lesions usually resolve in 7 to 21 days but are often recurrent

GENERAL CONSIDERATIONS Recurrent aphthous stomatitis (also called common canker sore and ulcerative stomatitis) is a common condition, estimated to affect 20% of the population. The etiology, based on studies of initiating factors, appears to be related to food sensitivities (especially gluten sensitivity), stress, and nutrient deficiency. These factors U I U f y the key underlying feature of recurrent aphthous stomatitis (RAS)-dysregulation of the immune system in the oral mucosa. Histologically, RAS consists of mucosal ulcerations with mixed inflammatory cell infiltrates. T helper cells predominate in the preulcerative and healing phases, while T suppressor cells predominate in the ulcerative phase. Other findings associated with immune dysregulation include the following: Lymphomononuclear infiltrate and hemagglutination antibodies against oral mucosa Reduced response of lymphocytes to mitogens Increased levels of circulating immune complexes Alterations in natural killer (NK)cell activity in various stages of disease

Increased adherence of neutrophils Release of tumor necrosis factor-alpha (TNF-a) Signilficant involvement of mast cells in the pathogenesis of RAS

THERAPEUTIC CONSIDERATIONS Food and Environmental Allergens The oral cavity is obviously the first site of contact for ingested, and many inhaled, allergens. The histologic appearance of the lesions and the association of RAS with increased serum antibodies to food antigens and atopy strongly suggest that an allergic reaction is involved.' Furthermore, immunoglobulin E-bearing lymphocytes are significantly increased in aphthous lesions, and mast cells are increased in tissue sections from prodromal stages of recurrent ulcers.* Mast cell degranulation plays an important role in the production of the aphthous lesion? An elimination diet has been shown to have good therapeutic results? The allergen is not necessarily a food. Frequent allergens inducing RAS are as follows5: Benzoic acid Cinnamaldehyde Nickel Parabens Dichromate Sorbic acid Elimination of allergens usually brings complete resolution or significant improvement. 1481

Specific Health Problems

Gluten Sensitivity Considerable evidence indicates that sensitivity to gluten is the primary cause of RAS. The incidence of RAS is increased in patients with celiac di~ease."~ Jejunal biopsy of 33 patients with RAS showed 8 to have the villous atrophy typical of celiac disease, along with histologic signs of immunologic reactions to food antigens? The remaining patients also exhibited these types of signs, but to a lesser degree. Although villous atrophy is a prerequisite for the diagnosis of celiac disease, gluten sensitivity may take other forms: Gluten may act directly on the oral mucosa or produce functional changes in the small intestine by immunologic or other mechanisms that are distinct from those causing the characteristic abnormalities of celiac disease? An underlying glutensensitive enteropathy would also contribute to nutritional deficiencies. Withdrawing gluten from the diet results in complete remission of RAS in patients with celiac disease and some improvement in the rest of the patientsG9 Even in the absence of villous atrophy, gluten sensitivity can definitely produce RAS. For example, in one small study, three of four gluten-sensitive patients identified by positive antibodies to alpha-gliadin,but with normal small intestinal biopsy, responded dramatically to a gluten-free diet.'O

We strongly recommend measuring alpha-gliadin antibodies in any patient presenting with M S .

Stress Stress is often a precipitating factor in RAS, suggesting a breakdown in normal host protective factors."

Nutrient Deficiency The oral cavity is often the first place nutritional deficiency becomes visible to the physician because of the high turnover rate of the mucosal epithelium. Although a number of nutrient deficiencies can lead to aphthous stomatitis, thiamin appears to be the most sigrhcant. In one study seeking to examine whether thiamin deficiency is associated with RAS, the levels of transketolase (a thiamin-dependent enzyme) were determined in 70 patients with RAS and 50 patients from a control group.12Low levels of transketolase were found in 49 of 70 patients with RAS compared with only 2 of 50 in the control. These results clearly demonstrate an association between low thiamin levels and RAS. Several other studies show that nutrient deficiencies are much more common in RAS sufferers. For example, a study of 330 patients with RAS found that 47 (14.2%) were deficient in iron, folate, or vitamin B12,or a combinaIn another study of 60 patients, tion of these n~trients.'~ 28.2% were deficient in thiamin, riboflavin, or pyridoxine.I4 When these patients' deficiencies were corrected, the majority had complete remission. Other studies have

shown similar deficiency rates for the same nutrients and equally good response to s~pplementation.'~ Zinc supplementation has also been shown to be helpful. In one double-blind study, 40 patients with RAS were given either zinc sulfate (220 mg providing 50 mg of elemental zinc) or a placebo once daily for 1month.16 Results showed that the levels of serum zinc before treatment were under the normal value in the 42.5% of the patients with RAS. After 1month of zinc therapy, the aphthae reduced and did not reappear for 3 months. Low nutrient status may explain why patients with RAS have an increased oxidant/antioxidant status in comparison with healthy controls. In one study, superoxide dismutase, glutathione peroxidase (GSHPx) and catalase (CAT) activities, and malondialdehyde (MDA) and antioxidant potential (AOP) levels were measured in plasma and erythrocytes from 22 patients with RAS and 23 control^.'^ Researchers found decreased CAT and GSHPx activities and AOP levels in the erythrocytes, as well as decreased AOP and increased MDA plasma levels, in patients with RAS in comparison with control subjects. This study clearly demonstrated that enzymatic and nonenzymatic antioxidant defense systems are impaired in patients with RAS.

Quercetin Quercetin is known to inhibit mast cell degranulation, basophil histamine release, and the formation of other mediators of inflammation.18The antiallergy drug disodium cromoglycate, a compound similar in structure and function to quercetin, has been shown to be effective in the treatment of RAS, resulting in an increase in the number of ulcer-free days and in mild symptomatic relief.19 Other flavonoids (acacetin, apigenin, chrysin, and phloretin, but not catechin, flavone, morin, rutin, or taxifolin) have also shown antiallergy effects similar to disodium cromoglycate.18

Deglycyrrhizinated Licorice Deglycyrrhizinated licorice (DGL) may be effective in promoting healing of RAS. In one study, 20 patients were instructed to use a solution of DGL as a mouthwash (200 mg powdered DGL dissolved in 200 ml warm water) four times dailyz0Of the 20 patients, 15 (75%) experienced 50% to 75% improvement within 1 day, followed by complete healing of the ulcers by the third day. DGL in tablet form may be more convenient and effective.

THERAPEUTIC APPROACH These data suggest that no single factor is solely responsible for the initiation of the aphthous lesion in any specific patient. However, an underlying tendency to ulceration may be present, the expression of which is facilitated by these factors. Considerable evidence suggests that the

Aphthous Stomatitis

underlying problem may be a gluten sensitivity. In addition, nutrient deficiencies need to be corrected and antiinflammatory nutrients prescribed.

Diet The patient’s diet should be low in animal products, high in complex carbohydrates, and free of known allergens and all gluten sources (i.e., grains).

1.Wilson CWM. Food sensitivities, taste changes, aphthous ulcers and atopic symptoms in allergic disease. Ann Allergy 1980;44:302-307. 2. Bays RA, Hamerlinck F, Cormane RH. Immunoglobulin-bearing lymphocytes and polymorphonuclear leukocytes in recurrent aphthous ulcers in man. Arch Oral Biol1977;22147-153. 3. Wray D, Vlagopoulos TP, Siraganian RP. Food allergens and basophil histamine release in recurrent aphthous stomatitis. Oral Surgery Oral Med Oral Pathol1982;54:388-395. 4. Hay KD, Reade PC. The use of an elimination diet in the treatment of recurrent aphthous ulceration of the oral cavity. Oral Surg Oral Med Oral Pathol1984;57504-507. 5. Nolan A, Lamey PJ, Milligan KA. Recurrent aphthous ulceration and food sensitivity. J Oral Pathol Med 1991;20473-475. 6.Ferguson R, Basu MK, Asquith P, Cooke WT. Jejunal mucosal abnormalities in patients with recurrent aphthous ulceration. Br Med J 1976;l:ll-13. 7. Ferguson MM, Wray D, Carmichael HA, et al. Celiac disease associated with recurrent aphthae. Gut 1980;21:223-226. 8. Wray D. Gluten-sensitive recurrent aphthous stomatitis. Dig Dis Sci 1981;26:737-740. 9. Walker DM, Rhodes J, Llewelyn J, et al. Gluten hypersensitivity in recurrent aphthous ulceration. J Dent Res 1979;58:1271. 10. OFarrelly C, OMahony D, Graeme-Cook F, et al. Gliadin antibodies identify gluten-sensitive oral ulceration in the absences of villous atrophy. J Oral Pathol Med 1991;20476-478. 11. Ship II, Merritt AD, Stanley HR. Recurrent aphthous ulcers. Am J Med 1962:3232-43.

.

Supplements Vitac: 1000 mg/day High-potency multivitamin and mineral according to guidelines given in Chapter 44 DGL: one to two 380 mg chewable tablets 20 minutes before meals

12. Haisraeli-Shalish M, Livneh A, Katz J. Recurrent aphthous stomatitis and thiamine deficiency. Oral Surg Oral Med Oral Pathol Oral Radio1 Endod 1996;82634-636. 13. Wray D, Ferguson MM, Hutcheon AW, Daag JH. Nutritional deficienciesin recurrent aphthae. J Oral Path 1978;7418-423. 14. Nolan A, McIntosh WB, Allam BF, Lamey PJ. Recurrent aphthous ulceration. Vitamin B,, Bb and B6 status and response to replacement therapy. J Oral Pathol Med 1991;20:389-391. 15. Wray D, Ferguson MM, Mason DK, et al. Recurrent aphthae: treatment with vitamin B1%folic acid, and iron. Br Med J 1975;2490-493. 16. Orbak R, Cicek Y, Tezel A, Dogru Y. Effects of zinc treatment in patients with recurrent aphthous stomatitis. Dent Mater J 2003; 22:21-29. 17. Cimen MY, Kaya TI, Eskandari G, et al. Oxidant/antioxidant status in patients with recurrent aphthous stomatitis. Clin Exp Dermatol 2003;28:647-650. 18. Pearce FL, Befus AD, Bienenstock J. Mucosal mast cells. 111. Effect of quercetin and other flavonoids on antigen-induced histamine secretion from rat intestinal mast cells. J Allergy Clin Immunol1984;73 819-823. 19. Kowolik MJ, Muir KF, MacPhee IT. Di-sodium cromoglycate in the treatment of recurrent aphthous ulceration. Br Dent J 1978;lM 384-389. 20. Das SK, Das V, Gulati AK, Singh W.Deglycyrrhizinated liquorice in aphthous ulcers. J Assoc Physicians India 1989;37647.

Asthma Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

1485

General Considerations 1485 Major Categories 1486 Mediators 1486 Lipoxygenase Products 1486 Autonomic Nervous System 1487 Adrenal Gland 1487 Pertussis Vaccine 1487 InfluenzaVaccine 1488 Therapeutic Considerations 1488 General 1488 Diet 1489

DIAGNOSTIC SUMMARY Recurrent attacks of dyspnea, cough, and expectoration of tenacious mucoid sputum Prolonged expiration phase with generalized wheezing and musical rales Eosinophilia, increased serum immunoglobulin (Ig) E, positive food/inhalant allergy tests

GENERAL CONSIDERATIONS Bronchial asthma is a hypersensitivity disorder characterized by bronchospasm, mucosal edema, and excessive excretion of a viscous mucus that can lead to ventilatory insufficiency. Its prevalence is approximately 3% of the US. population, and although it occurs at all ages, it is most common in children younger than 10. There is a 2:l male-to-female ratio in children, which equalizes by the age of 30. Major factors involved in asthma are the following:

9

Hypersensitivity of the airways Beta-adrenergic blockade Cyclic nucleotide imbalance in airway smooth muscle Release of inflammatory mediators from mast cells

The incidence of asthma is rising rapidly in the United States, especially in children. Reasons often

Nutrition 1490 Botanical Medicines 1493 Acupuncture and Acupressure

1495

Therapeutic Approach 1495 Environment 1495 Diet 1495 Supplements 1495 Botanical Medicines 1496 Counseling 1496 Acupuncture and Acupressure 1496 In Acute Attack 1496

given to explain the rise in asthma include the following: Increased stress on the immune system due to factors such as greater chemical pollution in the air,] water, insect allergens from mites and cockroaches, and food Earlier weaning and earlier introduction of solid foods to infants Food additives Higher incidence of obesity2 Genetic manipulation of plants, resulting in food components with greater allergenic tendencies In addition, multiple genetic variables may make certain individuals more susceptible to asthma. Mexican researchers have demonstrated that a deficiency in the glutathione S-transferase M1, a gene involved in response to oxidative stress, may also make those with this deletion more susceptible to asthmatic attacks, thus supporting the need for antioxidant therapy in these individuals? The ADAM33 gene on chromosome 2Op13 has been linked to the pathogenesis involved in airway remodeling (see mediator section later) and is probably a factor in corticosteroid resistance in some asthmatic^.^ Other research teams have also identified genes on chromosomes 7 and 12 as probable players in the pathogenesis of a ~ t h m a . ~ , ~ 1485

Major Categories Asthma has typically been divided into two categories: extrinsic and intrinsic. Extrinsic or atopic asthma is generally considered an immunologically mediated condition with a characteristic increase in serum IgE. Intrinsic asthma is associated with a bronchial reaction that is due, not to antigen-antibody stimulation, but rather to such factors as chemicals, cold air, exercise, infection, agents that activate the alternative complement pathway, and emotional upset.

Causes Inflammation and ThllTh2 Balance Imbalances in T helper cell immune responses appear to be a fundamental mechanism of immunologically mediated airway inflammation. CD4’ T helper cells are generally categorized into Thl and Th2 cells. Via the release of interferons and interleukin 2, the Thl pathway is increased in immunologic response of cancer, multiple sclerosis, viruses, and type IV hypersensitivities. Th2 responses are related to increases in interleukins 4, 6, 9, and 13; IgE, eosinophilia; and activated B cell humoral immunity. Clinical conditions that reflect increased Th2 responses include asthma and atopic syndromes and allergies. Research involving asthmatic subjects demonstrates a normal Thl gene expression, but a constant upregulation of Th2-specific genes, leading to Th2 pred~minance.~ Although it is unclear what the cause of this exaggerated Th2 response is in asthma, it seems that genetics, fungi, heavy metal toxicities, nutrition, viruses, and pollution are factors in this upregulation? The “hygiene hypothesis” is also gaining ground in standard medical literature. It asserts that minimizing exposure to infectious agents due to lifestyle choices based on hygienic concerns has favored the dominance of Th2 immune responses to environmental allergens and the probable encouragement of asthma and atopic diseases?*I0

Mediators Both extrinsic and intrinsic factors involved primarily with Th2 imbalances trigger the cytokine activated release of mast cell-derived chemical mediators. These mediators are responsible for bronchoconstriction, mucus production, and other signs and symptoms in the majority of cases. These mediators are either preformed within granules or generated from membrane-bound phospholipids. The preformed mediators include histamine, various chemotactic peptides such as eosinophilic chemolactic factor (ECF) and high-molecular-weight neutrophil chemotactic factor (NCF), proteases, glycosidases, and heparin proteoglycan. The membranederived agents include lipoxygenase products such as leukotrienes (LTs) and the so-called slow-reacting

substance of anaphylaxis (SRS-A),prostaglandins (PGs), thromboxanes (Txs), and platelet-activating factor (PAF). These mediators are diverse in chemical composition and modes of action and account for many of the signs and symptoms of asthma. The actions include bronchial smooth muscle constriction (histamine, LTC4, LTD, and LTE4, PGF2, PGD2, and PAF), mucosal edema (increased permeability histamine, LTC4, LTD4, and PAF), vasodilation (PGD2and PGE2), mucous plugging (histamine, HETEs, and LTC,), inflammatory cell infiltrate (NCF, ECF-A, HETEs, LTB,, and PAF), and desquamation of epithelium (proteases and glycosidases, together with lysosomal enzymes and basic proteins derived from neutrophils and eosinophils). In chronic asthma, eventual airway remodeling is a consequence of these mediator effects. The cellular and mediator elements responsible for airway remodeling involve anomalous interface between the airway epithelium and the underlying mesenchymal tissues. This process is highlighted by the induction of growth factors that encourage fibroblastic and smooth muscle proliferation and the deposition of matrix proteins, which cause the airway wall thickening linked to bronchial hyperresponsiveness and fixed airflow obstruction? Mild episodic asthma differs from moderate to severe sustained asthma in that the latter is largely dependent on a subacute/chronic inflammation of the bronchi with infiltration of eosinophils, neutrophils, and mononuclear cells, while episodic asthma is due primarily to bronchial smooth muscle contraction.

Lipoxygenase Products The most potent chemical mediators in asthma are the lipoxygenase products (i.e., leukotrienes, Figure 149-1). The leukotrienes composing SRS-A (LTC,, LTD4, LTE,) are 1000 times more potent as stimulators of bronchial constriction than histamine. Researchers have observed that asthmatics have an imbalance in arachidonic acid metabolism, leading to a relative increase in lipoxygenase products.” Platelets from asthmatic patients show a 40% decrease in cyclooxygenase-derived metabolites and a 70% increase in lipoxygenase products. This pathophysiologic alteration is further aggravated in ”aspirin-induced asthma.” Aspirin and other nonsteroidal antiinflammatory drugs (e.g., indomethacin, phenylbutazone) inhibit cyclooxygenase while promoting lip~xygenase.’~J~ The net result is a shunting of arachidonic acid toward the lipoxygenase pathway and the production of excessive levels of leukotrienes. Tartrazine (yellow dye no. 5) is also a cyclooxygenase inhibitor and known inducer of asthma, particularly in children.12 Tartrazine is ubiquitous in processed foods and can even be found in vitamin preparations and antiasthmatic prescription drugs (e.g., aminophylline).

Asthma Arachidonic acid

. 1

Cyclooxygenase

Prostaglandin G,

Lipoxygenase 5-HPETE

Leukotriene A4

+

Thromboxane 4 > -

LTB,

\I/ TXB,

Leukotriene C,

Figure 149-1 Arachidonic acid metabolism.

Tartrazine may also indirectly support the asthmatic process via its role as an antimetabolite of vitamin Bb (see later discussion of tryptophan).

a decrease in the cAMP-to-cGMP ratio, resulting in bronchial constriction.

Autonomic Nervous System

An evaluation of health criteria in a total of 448 children

The relationship between the autonomic nervous system and bronchial asthma represents an interaction between parasympathetic and sympathetic innervation and beta-Zadrenergic receptors (which are localized in lung tissue and which react to circulating cate~holamines).'~ Stimulationof the parasympathetic vagus nerve results in airway constriction. This vagal mechanism involves the following: release of acetylcholine at the synapse, subsequent binding to its receptor on smooth muscle tissue, and subsequent formation of cyclic guanosine monophosphate (cGMP). Accumulation of cGMP or a relative deficiency in cyclic adenosine monophosphate (CAMP),or both, result in constriction of the airway smooth muscle, as well as degranulation of mast cells and basophils. Decreased sympathetic activity or diminished beta-2 receptor numbers or sensitivity also promote the cyclic nucleotide imbalance. Some of the mediators discussed earlier block beta-2 receptors and both directly and indirectly elevate cGMP levels.

and adolescents in Britain who had received only breast milk for the first 6 months of life, and in particular on the first day after birth, produced some interesting findings. All of the children were weaned after 1 year of age and were older than 4 years at the time the parents responded. The mean age was 7.87 years. In response to the question "Has your child ever been diagnosed as asthmatic?" there were 30 positive answers (6.72%).The surprise came when the researchers classified the respondents according to whether or not they had received the pertussis ~accine.'~ Among the 243 immunized children, 26 were diagnosed as having asthma (10.69%). In contrast, of the 203 children who had not been immunized, only 4 had asthma (1.97%).The relative risk of developing asthma from the pertussis vaccine was 5.43 in this study. The sigruficance of this finding was at the p = 0.0005 level. Even though all of the children who received the pertussis vaccine received other vaccinations, the researchers suspected that the statistical evidence focused on pertussis. Among the children who did not receive the pertussis vaccine, most had received some other vaccination. Of the 91 subjects of the study who received no vaccines, only 1had asthma, compared with 3 with asthma in the 112 who had other vaccinations. Therefore the relative risk of developing asthma is about 1% in children receiving no immunizations, 3%in those receiving vaccinations other than pertussis, and 11%for those receiving pertussis. Another finding to weigh, in the group not immunized to pertussis, is that 16 developed whooping cough compared with only 1 in the immunized group.

Adrenal Gland The activity of the adrenal gland is important in asthma due to its hormones cortisol and epinephrine. Cortisol is an effective prime activator of beta receptors, and epinephrine is considered to be the prime stimulator of beta receptors. It has been suggested that during asthmatic attacks there is a relative deficiency of cortisol and epinephrine (which stimulates beta-2 receptors to catalyze the formation of cyclic adenosine monophosphate from adenosine monophosphate [AMP]).This leads to

Pertussis Vaccine

Specific Health Problems

Influenza Vaccine One evaluation of more than 9600 children was employed to determine the safety of cold-adapted trivalent intranasal influenza virus vaccine in children. Although this relatively new vaccination was deemed safe for children and adolescents, a significantly increased relative risk of 4.06 was observed in children 18 to 35 months of age for asthma and associated reactive airway disease.I6

THERAPEUTIC CONSIDERATIONS As with many complex diseases, the initial cause or causes of asthma (e.g., hypochlorhydria) may initiate a sequence of events that becomes self-propagating (e.g., hypochlorhydria-induced food allergies leading to increased intestinal permeability and then to increased susceptibility to food allergy). Effective treatment requires control of both the initiating cause or causes and the induced physiologic abnormalities.

General Hypochlorhydria

are widely used in foods, beverages, and drugs. The most common coloring agents are azo dyes-tartrazine (orange), sunset yellow, amaranth, and coccine (red)and the nonazo dye pate blue. The most commonly used preservatives in food are sodium benzoate, 4-hydroxybenzoate esters, and sulfur dioxide. Various sulfites are commonly used in prepared foods. Tartrazine, benzoates, sulfur dioxide, and sulfites in particular have been reported to cause asthma attacks in susceptible individuals.2°J It is estimated that 2 to 3 mg of sulfites are consumed each day by the average U.S. citizen, while an additional 5 to 10 mg are ingested by wine and beer drinkers.21The largest sources are the salads, vegetables (particularly potatoes), and avocado dip served in restaurants. A customer can ingest 25 to 100 mg of metabisulfite in as little as one restaurant meal. It has been postulated that a molybdenum deficiency may be responsible for sulfite sensitivity.22 Sulfite oxidase, the enzyme responsible for neutralizing sulfites, is molybdenum dependent.

Salt

Fractional gastric analyses in 200 asthmatic children by Bray in 1931 showed that 80% of them had gastric acid secretions below normal 1e~els.l~ This high occurrence suggests that decreased gastric acid output may predispose these children to food allergies and has a major impact on the success of rotation or elimination diets, or both, and, if not corrected, on the development of additional food allergies.

Strong evidence indicates that an increased intake of salt increases bronchial reactivity and mortality from a ~ t h m a .The ~ , ~degree ~ of bronchial reactivity to histamine is positively correlated with the 24-hour urinary sodium excretion and rises with increased dietary sodium. Because the severity of asthma correlates with the degree of bronchial reactivity, the severity of asthma can clearly be influenced by alterations in dietary sodium consumption.

Increased Intestinal Permeability

Estrogen and Progesterone

The presence of food allergies is thought to be responsible for asthmatics having been shown to have “leaky guts.”18As a result of increased gut permeability, there is increased antigen load on the immune system. This subsequently overwhelms the immune system, increasing the likelihood of developing additional allergies, as well as increasing bronchoconstrictive compounds into the circulation. It is essential to idenhfy offending foods as soon as possible to avoid the development of further allergies.

For female patients who experience severe asthma symptoms, it may be useful to consider therapeutic regimens that encourage a decrease in hormonal fluctuations. Some studies find estrogen withdrawal to increase lung contra~tility.~~ However, other studies find little relationship between estrogen use and asthmatic symptoms.2628Estrogen29and progesterone are both known to act as smooth muscle relaxants. It may be that the airways of premenopausal and postmenopausal women may respond differently to exogenous hormone replacement and need to be assessed independently with this intervention. One interesting review of more than 90 papers published from 1966 to 2001 found that during the premenstrual and menstrual phase, when hormonal levels are low, asthmatic women have been found to experience increased asthma exacerbations, increased hospitalizations for asthma, and decreased pulmonary function. Additionally, women who experienced decreased fluctuations in hormonal levels either by becoming pregnant or by starting oral contraceptive therapy tended to have improvements in pulmonary

Candida albicans An overgrowth of the common yeast Cundidu albicuns in the gastrointestinal tract has been implicated as a

causative factor in allergic conditions including asthma. Apparently the acid protease produced by C. albicuns is the responsible allergen.19 Appropriate anti-Cundidu therapy may result in significant clinical improvement of asthma in many cases.

Food Additives Vitally important in the control of asthma is the elimination of food additives.20Artificial dyes and preservatives

function and fewer requirements for m e d i ~ a t i o n . ~ ~One epidemiologic revied8found that among children, consumption of fresh fruit, particularly fruit high in Natural hormone replacement may offer a safer vitamin C, has been related to a lower prevalence of approach than synthetic hormones, although no studies asthma symptoms and higher lung function. This effect to verify the safety or efficacy of these natural forms of was observed even at low levels of fruit consumption female sex hormones have been conducted. In the longer (one or two servings per week vs. fewer than one servterm, natural therapeutics designed to balance estrogen and progesterone along with specific recommendations ing per week), which suggests that a small increase in fruit intake could be beneficial. This same review disfrom this chapter may offer the most risk-free relief for those premenopausal and postmenopausal women who cussed consumption of fish as also being related to lower airway hyperreactivity among children and higher lung suffer from asthmatic exacerbations (see Chapters 189 function in adults. and 204). A study of Scottish adults also found a dose/response Dehydroepiandrosterone relationship between fruit consumption and pulmonary function, whereby increased fruit consumption led to Decreased levels of dehydroepiandrosterone (DHEA) decreases in phlegm and better pulmonary have been shown to be quite common in postmenopausal women with asthma compared with matched controls.3o In addition, a "reasonable" intake of fruit (>180 g/day), One study of 55 asthmatic and 20 healthy postwhole grains (>45 g/day), and moderate alcohol consumption (one to three glasses/day) was associated menopausal women aged 48 to 60 before hormone with a 139-mlhigher FEV and a 50%lower prevalence of replacement therapy and after 6 months of transdermal chronic obstructive pulmonary disease (COPD) symp17b-estradiol (E2) and medroxyprogesterone acetate toms versus diets that did not meet these intake requiretreatment demonstrated a significant increase in serum ments.%Finally, one study of 607 asthma patients and DHEA levels in the asthmatic group, with no change 864 controls highlighted apples and moderate red wine in the control Whether DHEA itself produces consumption as sources of antioxidants that decreased any therapeutic benefit in asthma remains to be demonasthma severity? strated; however, given its importance to proper immune function, a n ability to produce positive effects is cerFood Allergy tainly possible. Many studies have indicated that food allergies play an Melatonin important role in asthma (see Chapter 53).4145Adverse reactions to food may be immediate or delayed. DoubleThere is some concern regarding elevated melatonin levels contributing to increased airway inflammation blind food challenges in children have shown that immediate onset sensitivities are usually due (in in patients with nocturnal asthmatic exa~erbations,3**~~ decreasing order of frequency) to egg, fish, shellfish, as well as proinflammatory reactions in rheumatoid nuts, and peanuts, while foods most commonly associarthritis.34In the study of nocturnal asthmatics, peak ated with delayed onset include (in decreasing order measured serum melatonin level was significantly and of frequency) milk, chocolate, wheat, citrus, and food inversely correlated with overnight change in forced colorings.43Elimination diets have been successful in expiratory volume (FEV) in subjects with nocturnal identifying allergens and treating asthma and are a asthma, but not in subjects with nonnocturnal asthma or particularly valuable diagnostic and therapeutic tool healthy controls. An interesting note is that this study in infants.46Elimination of common allergens during observed a delayed release of melatonin in the nocturnal infancy (first 2 years) has been shown to reduce allergic asthma patients. Therefore it is theoretically possible tendencies in high-risk children (e.g., strong familial that supplementation combined with an earlier sleep hist01-y):~ regimen may help regulate this late peaking of melatonin and possibly mitigate symptoms. Nevertheless, Breastf eeding the practitioner may want to avoid giving this supplement to patients with asthma, especially the nocturnal Many studies have demonstrated the protective effect of type, until more studies are conducted regarding breastfeeding in the prevention of asthma. One study melatonin's immunotherapeutic effect. examined the association of breastfeeding and the presence of chronic respiratory symptoms among Diet 5182 Brazilian schoolchildren 7 to 14 years of age. Ninety Beneficial Foods percent of the mothers in this population had breastfed A number of publications corroborate the notion that their child. After adjusting for potential confounding factors, these researchers revealed that children who had people who have a diet rich in fruit and vegetables have not been breastfed were more likely to have a medical a lower risk of poor respiratory health.35-37 This effect is most likely due to the increased levels of antioxidants. diagnosis of asthma.48One Iraqi study additionally

Specific Health Problems ~~

showed that the vitamin C content of breast milk was significantly correlated with the maternal intake of vitamin C: Low vitamin C intake by mother translates to low intake by the child, thus leaving him or her more susceptible to oxidative ~tress.4~ The Canadian Asthma Primary Prevention study collected 2 years of data in which researchers chose 545 infants who were considered at high risk of asthma on the basis of a history of familial atopy. These children were broken down into control and intervention groups. The interventionsincluded (1)house dust control measures; (2) recommendations for avoidance of pets, envirorunental tobacco smoke, and day care during the first year; and (3) only breastfeeding or use of partially hydrolyzed whey formula until at least the age of 4 months. At 1year of age, asthma was significantly reduced by 34%. At 2 years of age, sigruficantly fewer children had asthma in the intervention group than in the control group (16.3% vs. 23'/0), and 60% less of the intervention group children had persistent asthma. A 90% reduction for recurrent wheeze occurred in the intervention group compared with that seen in the control g r o u ~Multifactorial .~ studies like these are quite useful in order to elucidate the multitude of changes necessary to affect multifactorial diseases like asthma in an effective manner.

Vegan Diet A long-term trial of a vegan diet (elimination of all animal products) provided sigruficant improvement in 92% of the 25 treated patients who completed the study (9 dropped Improvement was determined by a number of clinical variables including vital capacity, FEV at 1 second, and physical working capacity, as well as by biochemical indices such as haptoglobin, IgM, IgE, cholesterol, and triglyceride levels in the blood. The researchers also found a reduction in the tendency to infectious disease. Importantly, however, although 71% of the patients responded within 4 months, 1year of therapy was required before the 92% level was reached. The diet excluded all meat, fish, eggs, and dairy products. Drinking water was limited to spring water (chlorinated tap water was specifically prohibited), and coffee, ordinary tea, chocolate, sugar, and salt were excluded. Herbal spices were allowed, and water and herbal teas were allowed up to 1.5 L/day. Vegetables used freely were lettuce, carrots, beets, onions, celery, cabbage, cauliflower, broccoli, nettles, cucumber, radishes, Jerusalem artichokes, and all beans except soya and green peas. Potatoes were allowed in restricted amounts. A number of fruits were also used freely: blueberries, cloudberries, raspberries, strawberries, black currants, gooseberries, plums, and pears. Apples and citrus fruits were not allowed, and grains were either restricted or eliminated.

The beneficial effects of this dietary regimen are probably related to three areas: Elimination of food allergens Altered prostaglandin metabolism Increased intake of antioxidant nutrients and magnesium The importance of avoiding food allergies was discussed earlier. In regards to altered prostaglandin metabolism, the avoidance of dietary sources of arachidonic acid (derived from animal products) appears to be quite significant. The prostaglandins and leukotrienes derived from arachidonic acid contribute significantly to the allergic reaction in asthma. Decreasing the availability of arachidonic acid as a substrate of these inflammatory compounds appears to explain some aspects of the efficacy of the vegan diet. The benefits of altering prostaglandin metabolism are further discussed later, as is the role of increased dietary antioxidants in preventing asthma. Perhaps the most significant effect noted in the trial of the vegan diet, besides the patients' improvement in health, was the great reduction in health care costs (the patients had been receiving corticosteroids and other drugs and therapies for an average of 12 years) and, according to the authors, the changed attitude toward increased responsibility for their own health.

Nutrition Omega-3 Essential Fatty Acids Epidemiologic studies have shown that children who eat fish more than once a week have one third the risk for asthma of children who do not eat fish regularly? Several clinical studies have shown that increasing the intake of omega-3 fatty acids through supplementation with fish oils containing eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) offers significant benefits in asthma as noted by improvements in airway responsiveness to allergens, as well as improvements in respiratory fun~tion.5~3 These benefits are related to increasing the ratio of omega-3 to omega-6 fatty acids in cell membranes, thereby reducing the availability of arachidonic acid. In particular, omega-3 fatty acid ingestion leads to a significant shift in leukotriene synthesis from the extremely inflammatory 4-series to the less inflammatory 5-series leukotrienes. This shift is directly related to improvements in asthma symptoms.55The benefits may take as long as 1year before they are apparent, as it apparently takes time to turn over cellular membranes in favor of the omega-3 fatty acids.

Tryptophan Metabolism and Pyridoxine Supplementation Children with asthma have been shown to have a metabolic defect in tryptophan metabolism and reduced

Asthma platelet transport for s e r ~ t o n i n .Tryptophan ~ ~ ~ ~ ~ is converted to serotonin, a known bronchoconstricting agent in asthmatics. High serotonin levels in the blood and sputum are common findings in asthmatics and are reflected by an elevated urinary level of 5-hydroxyindoleacetic acid (5-HIAA), the breakdown product of serotonin. The levels of 5-HIAA in the urine correlate well with the severity of asthmatic symptoms. Double-blind clinical studies have shown that patients benefit from either a tryptophan-restricted diet56 or pyridoxine supp l e m e n t a t i ~ n ~to~ ,correct ~~ the blocked tryptophan metabolism. Pyridoxine may also be of direct benefit to asthmatic patients. In one study, plasma and erythrocyte pyridoxal phosphate (PLP) levels in 15 adult patients with asthma were significantly lower than in 16contr~ls?~ Oral supplementation with 50 mg of pyridoxine twice daily to seven of the patients failed to produce a substantial elevation of these low levels. However, all patients reported a dramatic decrease in frequency and severity of wheezing and asthmatic attacks while taking the supplements. In a study of 76 asthmatic children, pyridoxine at a dosage of 200 mg daily produced sigruficant reductions in symptoms and dosages of bronchodilators and corticosteroids. However, a double-blind study failed to demonstrate any significant improvement with B6 supplementation in patients who depended on steroids for control of symptoms.59 Although vitamin B6 supplementation may not help patients on steroids, it is definitely indicated in asthmatics being treated with the drug theophylline. Theophylline significantly depresses pyridoxal-5-phosphate levels.60 In addition, another study has shown that vitamin B6 supplementation can significantly reduce the typical side effects of theophylline (e.g., headaches, nausea, irritability, sleep disorders).61

Antioxidants The substantial increase in the prevalence of asthma over the past 20 years can be partially explained by the reduced dietary intake of antioxidant nutrients like betacarotene and vitamins A, C, and E, as well as the mineral cofactors essential for antioxidant defense mechanisms Patients undergoing such as zinc, selenium, and acute asthmatic distress are known to have lowered serum total antioxidants.@Genetic influences may also play a role in the need for antioxidants as well (see the section on general considerations earlier).3 One study of 158 children with moderate to severe asthma revealed that supplementation of 50 mg/day of vitamin E and 250 mg/day of vitamin C conferred significant protection against ozone-induced reduction in pulmonary Antioxidants are thought to provide important defense mechanisms for maintaining the redox state of the lung. This protection is sigruficant

because oxidizing agents can both stimulate bronchoconstriction and increase hyperactivity to other agents. Asthma appears to be another disease process that is influenced greatly by antioxidant mechanisms. Analgesics like acetaminophen, known to deplete antioxidant levels such as glutathionein animals, should be used with caution in asthmatic patients.65

Vitamin C Especially important to the health of the lung is vitamin C, as it is the major antioxidant substance present in extracellular fluid lining the airway surfaces.66Vitamin C intake in the general population appears to correlate with asthma, indicating that low vitamin C (in the diet and the blood) is an independent risk factor for asthma. In a survey of 771 persons with current asthma, 352 persons with former asthma, and 15,418 persons without asthma, lower vitamin C concentrations were observed among those with current or former asthma than among people who never had a~thrna.~’ Additional support is offered by the fact that children of smokers have a higher rate of asthma (cigarette smoke is known to deplete respiratory vitamin C and E levels), and symptoms of ongoing asthma in adults appear to be increased by exposure to environmentalprooxidants and decreased” by vitamin C supplementation. Nitrogen oxides are examples of oxidants that can arise from both endogenous and exogenous sources. Vitamin C has been shown to offer significant protection against nitrogen oxide damage in the lungs in animal models.68 Both treated and untreated asthmatic patients have been shown to have significantly lower levels of ascorbic acid in serum and leukocytes.68From a clinical perspective, it appears that asthmatics have a higher need for vitamin C. Since 1973 there have been 11clinical studies of vitamin C supplementation in asthma.69Seven of these studies showed significant improvements in respiratory measures and asthma symptoms as a result of supplementing the diet with 1 to 2 g of vitamin C daily. This dosage recommendation appears extremely wise based on the increasing exposure to inhaled oxidants, along with the growing appreciation on the antioxidant function of vitamin C in the respiratory system. High-dose vitamin C therapy may also help asthma by lowering histamine levels.’O The importance of vitamin C as a natural antihistamine has emerged for several reasons, including concern over the safety of antihistamine medications and recently recognized immunesuppressing effects of histamine. In the initial stages of an immune response, histamine amplifies the immune response by increasing capillary permeability and smooth muscle contraction, thus enhancing the flow of immune factors to the site of infection. Subsequently, histamine exerts a suppressive effect on the accumulated

Specific Health Problems

white blood cells in an attempt to contain the inflammatory response. Vitamin C exerts a number of effects against histamine. Specifically, it prevents the secretion of histamine by white blood cells and increases the detoxification of histamine. One study examined the antihistamine effect of acute and chronic vitamin C administration and its effect on white blood cell (neutrophil) function in healthy men and women. In the chronic study, 10 subjects ingested a placebo during weeks 1, 2, 5, and 6 and 2 g/day of vitamin C during weeks 3 and 4.Fasting blood samples were collected after the initial 2-week period (baseline) and at the end of weeks 4 and 6. Blood vitamin C levels rose signhcantly following vitamin C administration, while blood histamine levels fell by 38%during the weeks vitamin C was given. The ability of white blood cells to move to respond to an infection (chemotaxis)increased by 19% during vitamin C administration and fell 30% after vitamin C withdrawal. However, these changes were linked to histamine concentrations. Chemotaxis was greatest when histamine levels were the lowest. In the part of the study looking at the acute effects of vitamin C, blood histamine concentrations and chemotaxis did not change 4 hours after a single dose of vitamin C. This result suggests that vitamin C will only lower blood histamine if taken over a period of time. Individuals prone to allergy or inflammation are encouraged to increase their consumption of vitamin C through s~pplementation.~~

extracts appear to have an affinity for the lungs (for more information, see Chapter 119).

Flavonoids

Jonathan Wright, MD, believes that ”BIZtherapy is the mainstay in childhood asthma.’” In one clinical trial, weekly 1000 pg intramuscular injections produced definite improvement in asthmatic patients.81Of 20 patients, 18 showed less shortness of breath on exertion, as well as improved appetite, sleep, and general condition. Vitamin BI2 appears to be especially effective in sulfitesensitive individuals. It offers the best protection when given orally (1to 4 pg) before challenge, compared with other pharmacologic agents (e.g., cromolyn sodium, atropine, doxepin).82The mode of action is the formation of a sulfite-cobalamincomplex, which blocks sulfite’s effect.

Flavonoids appear to be key antioxidants in the treatment of asthma. Various flavonoids, chief among them being quercetin, have been shown to inhibit the following71-74: Histamine release from mast cells and basophils when stimulated by antigens and other ligands Phospholipase A2 in neutrophils Lipoxygenase Anaphylactic contraction of smooth muscle Phosphodiesterase in the lung (resulting in increased CAMPlevels) Biosynthesis of SRSA Calcium influx

In addition, quercetin has both a vitamin C-sparing effect and a direct stabilizing effect on membranes including mast cells. Flavonoids are also extremely effective antioxidants. Quercetin can be used, or flavonoid-richextracts such as those from grape seed, pine bark, green tea, or Ginkgo bilobu may prove even more helpful in the treatment of asthma due to their better bioavailability. In particular, the proanthocyanidins from grape seed or pine bark

Carotenes Carotenes are powerful antioxidants that may increase the integrity of the epithelial lining of the respiratory tract and act as substrates for lipoxygenase, possibly competing with arachidonic acid, thereby decreasing leukotriene formation.”

Vitamin E Vitamin E’s activity as an antioxidant, lipoxygenase inhibitor, and phospholipase inhibitor makes it a useful agent in asthma t~eatment.~6

Selenium Reduced selenium levels have been demonstrated in asthma patient^.^-^^ Glutathione peroxidase, a seleniumdependent metalloenzyme, is important for reducing hydroperoxyeicosatetraenoic acid (HPETE) to hydroxyeicosatetraenoic (HETE) acid, thereby reducing leukotriene formation. Reduced levels of glutathione peroxidase have also been reported for asthmatics.n Supplemental selenium appears warranted to address any deficiency of glutathione peroxidase. In addition, supplemental selenium may reduce the production of leukotrienes by ensuring optimal activity of glutathione peroxidase.

Vitamin BI2

Magnesium In 1912 Trendelenburg demonstrated that magnesium relaxed bovine bronchial smooth muscle in vitr0.8~Later, uncontrolled clinical studies revealed magnesium’s beneficial effect in the treatment of patients with acute attacks of bronchial asthma.@Unfortunately, this promising line of research was dropped as antihistamines and bronchodilators became available. However, the advent of calcium channel blockers for the treatment of asthma generated renewed interest in the therapeutic use of

Asthma magnesium for asthma. In fact, intravenous magnesium (2 g of magnesium sulfate infused every hour up to a total of 24.6 g magnesium sulfate) is now a well-proven and clinically accepted measure to halt an acute asthma attack, as well as acute exacerbations of COPD.85-89 Although these studies have used injectable magnesium therapy, it has been demonstrated that injectable magnesium is not necessary to restore magnesium status (except in the case of an emergency situation such as an acute heart attack or acute asthma attack).g0Oral magnesium therapy is an effective measure to raise body magnesium stores, but it will usually take 6 weeks to achieve significant elevations in tissue magnesium concentrations. Isotonic nebulized magnesium has also proved useful as an adjunct treatment to standard bronchodilation therapies in severe asthmatics, with a greater response in those with life-threatening asthma.g1Oral supplementation appears to be warranted because low levels of plasma magnesium have been found in asthmatic patients6 and dietary magnesium intake is independently related to lung function and asthma

Botanical Medicines Asthma patients commonly employ botanical selftreatments. A cross-sectional analysis of 601 adults with asthma found that 14% of asthma sufferers use either herbal products, coffee, or black tea in order to treat their condition. Unfortunately, this study illustrated that those who used these methods had a higher incidence of hospitali~ations.~~ Because of the possibility of improper use of botanicals and the inability of the users to recognize the need for acute conventional interventions, we recommend that, before using natural therapies, patients with asthma consult a naturopathic physician or other qualified practitioner who understands the proper use of botanicals and can assess the asthmatic patient's risk severity. The most popular historical herbal treatment of asthma involved the use of Ephedru sinmsis (Ma huang) in combination with herbal expectorants. Example of commonly used expectorants include the following:

Glycyrrhiza gfubru (licorice) Grindeliu cumporum (grindelia) Euphorbiu hirfu (euphorbia) Droseru rofundifoliu (sundew) Polygulu senegu (senega) This approach appears to have considerable merit, as ephedra and its alkaloids have proven effective as bronchodilatorsin treating mild to moderate asthma and hay f e ~ e r . 9The ~ ~peak ~ bronchodilation effect occurs in 1 hour and lasts about 5 hours after administration. In addition to this approach, several other botanical medicines deserve mention.

Glycyrrhiza glabra Licorice root has a long history of use as an antiinflammatory and antiallergic agent, which has been documented in the scientific literature (see Chapter 99). The primary active component of licorice root in this application is glycyrrhetinic acid, a compound that has shown cortisol-like activity. In particular, glycyrrhetinic acid has been shown to inhibit phospholipase A2 the enzyme responsible for cleaving arachidonic acid from the phospholipid membrane pool and initiating eicosanoid synthesis." Licorice is also an expectorant, which is useful to treat asthma.

Lobelia inflata Indian tobacco contains the alkaloid lobeline, an efficient expectorant. Although it has a long history of use in asthma, it does promote bronchoconstriction and is a respiratory stimulant in vit1-0.~~ Although this suggests a cholinergic effect in the respiratory system, it also binds to nicotine acetylcholine receptors in ganglions, thus promoting the release of epinephrine and norepinephrine. It is this action on adrenal hormone secretion that is responsible for lobelia's therapeutic effects.98Although effective when used alone, it has traditionally been used in combination with other botanical agents such as Capsicum frufescens and Symphlocurpus fucfidu.

Capsicum fitescens Experimental evidence has shown that capsaicin, cayenne pepper's major active component, induces long-lasting desensitization of airway mucosa to various mechanical and chemical irritants.* This effect is probably due to capsaicin-induced depletion of substance P (which normally increases vascular permeability and flow) in the respiratory tract nerves. Substance P is an undecapeptide associated with "neurogenic inflammation" via a direct effect and a synergistic action with histamine on the peripheral nervous system.lm The respiratory and gastrointestinal tracts have large numbers of substance P-containing neurons. Because of its location and physiologic action, it is believed to play an important role in atopic conditions such as asthma and atopic dermatitis. Therefore depletion of substance P may be desirable in these conditions.

Zizyphi fructus The jujube plum has been used extensively in Chinese medicine for the treatment of asthma and allergic rhinitis.'O' It contains 100 to 500 nmol/g of dry weight, a concentration 10 times greater than that of any other plant or animal tissue thus far reported in the literature.102 It also contains a beta-adrenergic receptor stimulator that raises CAMPlevels. These experimental findings, in conjunction with zizyphi's long historical use, strongly support its clinical use.

Specific Health Problems

Thea sinensis

Ginkgo biloba

Green tea is useful as an adjunctive in asthma treatment due to its methylxanthine and antioxidant components (see Chapter 74).

G. bilobu contains several unique terpene molecules known collectively as ginkgolides that antagonize platelet-activating factor (PAF), a key chemical mediator in asthma, inflammation, and allergies. Ginkgolides compete with PAF for binding sites and inhibit the various events induced by PAF. The antiasthmatic effects of orally administered or inhaled ginkgolides have been shown to produce improvements in respiratory function and reduce bronchial reactivity in several double-blind ~tudies."~*"~ Treatment consisted of 120 mg of the pure pkgolides daily-a dosage that is currently expensive to achieve using the 24% ginkgo flavonglycoside and 6%total terpenoid G. bilobu extract.

Allium Family Onions and garlic inhibit lipoxygenase and cyclooxygenases, which generate TxA2, PGD2, and PGE2.'03 Oral pretreatment of guinea pigs (who were sensitized to ovalbumin) with 1 ml of an alcohol/onion extract markedly reduced the asthmatic response to allergen inhalation challenges. Onion contains quercetin, which may account for some of its pharmacologic effect,'" but the major protective actions appear to be related to its content of benzyl and other isothiocyanates (mustard oils).lo5Although the mechanism of action is unknown, it has been suggested that it is due to inhibition of the biosynthesis of arachidonic acid metabolites.

Tylophora asthmatica The leaves of Tylophoru usthrnaticu have been used extensively in Ayurvedic medicine in asthma and other respiratory tract disorders. The mode of action of tylophora is unknown but is thought to be due to the alkaloids, especially tylophorine, which have been reported to possess antihistamine and antispasmodic activity, as well as inhibition of mast cell d e g r a n u l a t i ~ n . ' ~However, J~~ a more central mechanism may be responsible for the clinical effects in asthma. Several double-blind clinical studies have shown In one study tylophora to produce good of 135 patients, those given 200 mg of tylophora leaves twice daily for 6 days demonstrated improvements in symptoms and respiratory function during the treatment period and for up to 2 weeks after treatment.lm Symptom score, FEV in 1 second, and peak expiratory flow rate (PEFR) were used as parameters. Side effects such as nausea and vomiting occurred in 9.8% in the tylophora group and 14% in the placebo groupIn another double-blind study of 103 patients, those receiving 40 mg of the dry alcoholic extract of Tylophoru indicu daily for only 6 days demonstrated significant improvement in symptoms of asthma compared with a placebo group.'1o At the end of the first week, 56%had complete to moderate improvement, as compared with 31.6%of the 92 patients receiving the placebo. At the end of 4 weeks, the respective figures were 32% and 23.8%; at 8 weeks, 23.8%and 8.4%;and at 12 weeks, 14.8%and 7.2%.The incidence of side effects such as nausea, partial diminution of taste for salt, and slight mouth soreness was 16.3% in the tylophora group and 6.6% in the placebo group. These results, as well as the results from an additional study, indicate that the benefits of tylophora are short lived.'1'J12

Aloe Vera Administration of Aloe veyu preparations may be effective for patients who are not dependent on corticosteroids. In one study, the oral administration of an extract of A. vwu for 6 months was shown to produce good results in the treatment of asthma in some individuals of various ages.l14The extract was produced from the supernatant of fresh leaves stored in the dark at 4" C for 7 days. Subjecting the leaves to dark and cold results in an increase in the polysaccharide fraction. One gram of the crude extract obtained from leaves stored in cold and dark produced 400 mg of neutral polysaccharide compared with only 30 mg produced from leaves not subjected to cold or dark. The dosage was 5 ml of a 20% solution of the A. veru extract in saline twice daily for 24 weeks; 11 of 27 patients (40%)without corticosteroid dependence felt much better at the study's conclusion. The mechanism of action is thought to be via restoration of protective mechanisms, followed by augmentation of the immune system.

Coleus forskohlii Coleus forskohlii extracts may be particularly useful in asthma, as increasing intracellular levels of CAMPresult in relaxation of bronchial muscles and relief of respiratory symptoms. Forskolin has been shown to have remarkable effects in relaxing constricted bronchial muscles in asthmatics (see Chapter 83).'15J16 However, these studies used inhaled doses of pure forskolin. Whether orally administered forskolin in the form of C. forskohlii extract would produce similar bronchodilatory effects has yet to be determined. However, on the basis of the plant's historical use and additional mechanisms of action, it appears likely.

Boswel lia The Indian Ayurvedic botanical Boswellia is known for its ability to inhibit leukotriene bio~ynthesis.~'~ In one double-blind, placebo-controlled study, bronchial asthma was reduced in 70% of 40 patients treated with gum resin at 300 mg three times daily for 6 weeks,

Asthma

whereas only 27% of the control group improved. Disappearance of physical symptoms and signs such as dyspnea; rhonchi; the number of attacks; increased FEV, vital capacity, and PEFRs; and decreased eosinophilic counts and sedimentation rates were recorded as improvement measures.”’

Acupuncture and Acupressure In traditional Chinese medicine (TCM), chronic asthmatic symptomology is usually characterized as a lung or spleen deficiency. This model considers that acute symptoms may be caused by environmental invasion from cold wind (environmental factors) or an internal condition stemming from a lung heat condition (increased inflammation and eosinophilia). Chronic asthma is considered more of a weakness in the lung itself or a weakness of the spleen, which is responsible for nourishing the lung qi. In TCM, the emotion of grief is also known to weaken lung qi. In one prospective, randomized study of chronic asthma patients, 41 patients with chronic obstructive asthma were randomly assigned to receive acupuncture in addition to standard care, acupressure and standard care, or standard care alone. For each subject, 20 acupuncture treatments were given, and self-administered acupressure was performed daily for 8 weeks. Using the St. George’s Respiratory Questionnaire, the acupuncture subjects showed an average 18.5-fold improvement, whereas the improvement for the acupressure-only subjects was 6.57-fold. Additionally, for patients who received acupressure, the irritability domain score exhibited an 11.&fold improvement.”* Another study involved 44 patients receiving bonafide or sham acupressure. They received five treatments per week lasting 16 minutes each, for 4 weeks. Using pulmonary function and dyspnea scores, 6-minute walking distance measurements, and state anxiety scale scores, the acupressure group had significant improvements in breathing and less anxiety compared with those of the sham group.l19

THERAPEUTIC APPROACH The effective treatment of asthma requires the consideration and control of many aspects. In particular, the specific underlying defects and initiating factors must be determined, since many different defects and metabolic abnormalities result in the same clinical picture of asthma. Otherwise, only a much less successful “shotgun” approach is possible. The development of an appropriate treatment plan includes the following five steps: 1.Determining and rechfymg the underlying defect that allows the development of sensitization 2. Determining and balancing the underlying metabolic defect that causes an excessive inflammatory response

3. Finding the allergens and developing a lifestyle, diet, and environment that allow the allergens to be avoided 4. Modulating the inflammatory process to limit the severity of the response 5. Preparing an effective treatment for the bronchoconstriction of the acute attack

Environment Airborne allergens such as pollen, dander, and dust mites120are often difficult to avoid entirely, but measures can be taken to reduce exposure. Eliminating dogs, cats, carpets, rugs, upholstered furniture, and other surfaces where allergens can collect is a great first step. Also, methods to discourage the presence of dust mite and cockroach antigen should be used, although pesticide exposure should be minimized. If environmental exposures cannot be controlled entirely, make sure that the bedroom is as allergy proof as possible. Have the patient encase the mattress in an allergen-proof plastic; wash sheets, blankets, pillow cases, and mattress pads every week; consider using bedding material made from Ventflex, a special hypoallergenic synthetic material; and install an air purifier. The best mechanical air purifiers are high-effiuency particulate arresting (HEPA)filters that can be attached to central heating and air-conditioning systems. These units are available from suppliers of heating and air-conditioning units.

Diet All food allergens and food additives should be eliminated. The patient who has many food allergies may need to use a 4-day rotation diet. In the early stages of treatment, mild tryptophan reduction (see Appendix 10) should be useful but is not critical unless there is a metabolic defect in tryptophan metabolism. Garlic and onions should be liberally used unless the patient reacts to them. If the patient is willing or his or her asthma is unresponsive to this recommended therapy, a vegan diet should be tried (for a minimum of 4 months) with the possible exception of coldwater fish. Moderate fruit consumption, especially apples, should also be encouraged.

Supplements Vitamin B6: 25 to 50 mg two times/day Vitamin BI2: 1000 pg/day (oral) or weekly injection; evaluate for efficacy after 6 weeks Vitamin C: 10 to 30 mg for every kg body weight in divided dosages Vitamin E: 200 to 400 IU daily Magnesium: 200 to 400 mg three times/day Quercetin: 400 mg 20 minutes before meals Grape seed extract (95% PCO content): 50 to 100 mg three times/day

Specific Health Problems

Tylophora asthrnatica Carotenes: 25,000 to 50,000 ILJ/day Selenium: 200 pg/day (These are all adult doses. Carefully determine the content of all supplements to assure avoidance of any allergens.)

Botanical Medicines Ephedra sinica The optimum dosage of ephedra depends on the alkaloid content in the form used. The ephedra dose should have an ephedrine content of 12.5 to 25 mg and be taken two to three times daily. For the crude herb, this dosage would most likely be 500 to lo00 mg three timedday. Standardized preparations are often preferred as they have more dependable therapeutic activity. Ephedra can be combined with herbal expectorants as described earlier.

Glycyrrhiza glabra Powdered root: 1 to 2 g Fhid extract (1:l):2 to 4 ml Solid (dry powdered) extract (4:l):250 to 500 mg

Use 200 mg of tylophora leaves or 40 mg of the dry alcoholic extract twice daily.

CoZeus forsko lii Use the extract standardized to contain 18% forskolin: 50 mg (9 mg of forskolin) two to three times daily.

Counseling For patients who respond to emotional crisis with asthmatic attacks, counseling is important. From a TCM perspective, any grief issues should be considered. Counseling is also important for children with moderate to severe asthma, who may develop behavioral problems.

Acupuncture and Acupressure Regular acupuncture and home acupressure treatments should be used.

In Acute Attack An acute asthma attack can be a medical emergency. If

Liberal use (green tea only)

intravenous magnesium cannot be administered, the patient should be referred to the emergency department immediately.

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Camellia sinensis

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Specific Health Problems 71. Hope WC et al. In vitro inhibition of the biosynthesis of slow reacting substance of anaphylaxis (SRSA) and lipoxygenase activity by quercetin. Biochem Pharmacol1983;32367-371. 72. Middleton E Jr, Drzewiecki G, Krishnarao D. Quercetin. An inhibitor of antigen-induced human basophil histamine release. J Imm~011981;127546-550. 73. Foreman JC. Mast cells and the actions of flavonoids. J Allergy Clin Imm~n011984;73:769-774. 74. Hope WC, Welton AF, Fiedler-Nagy C, et al. In vitro inhibition of the biosynthesis of slow reacting substance of anaphylaxis (SRSA) and lipoxygenase activity by quercetin. B i d e m Pharmacol 1983; 32367-371. 75.Grosch W, Laskawy G. Cwxidation of carotenes requires one soybean lipoxygenase isoenzyme. Biochem Biophys Acta 1979;575: 439-445. 76. Panganamala RV, Comwell DG. The effects of vitamin E on arachidonic acid metabolism. Ann N Y Acad Sci 1982;393376-391. 77. Miss0 NL, Powers KA, Gillon RL, et al. Reduced platelet glutathione peroxidase activity and serum selenium concentration in atopic asthmatic patients. Clinical Exp Allergy 1996;26838-847. 78.Stone J, Hinks LJ, Beasley R, et al. Reduced selenium status of patients with asthma. Clin Sci (Colch) 1989;77:495-500. 79. Kadrabova J, Mad'aric A, Kovacikova Z, et al. Selenium status is decreased in patients with intrinsic asthma. Biol Trace Elem Res 1996;52241-248. 80. Wright JV. Treatment of childhood asthma with parenteral vitamin BI2 gastric re-acidification, and attention to food allergy, magnesium, and pyridoxine. J Nutr Med 1990;1:277-282. 81. Simon SW. Vitamin BI2 therapy in allergy and chronic dermatoses. J Allergy 1951;2:183-185. 82. Garrison R, Somer E. The nutrition desk reference, ch 5. Vitamin r e s e h . selected topics. New Canaan, CN: Keats, 1985:93-94. 83. Trendelenburg P. Physiolopche und pharmakologische untersuchungen an der isolierten bronchial muskulatur. Arch Exp Pharmacol Ther 1912;69:79. 84. Haury VG. Blood serum magnesium in bronchial asthma and its treatment by the administration of magnesium sulfate. J Lab Clin Med 1940;26340-344. 85. Skobeloff EM, Spivey WH, McNamara RM, et al. Intravenous magnesium sulfate for the treatment of acute asthma in the emergency department. JAMA 1989;262:1210-1213. 86. Okayama H, Aikawa T, Okayama M, et al. Bronchodilating effect of intravenous magnesium sulfate in bronchial asthma. JAMA 1987;2571076-1078. 87. Noppeen M, Vanmaele L, Impens N, et al. Bronchodilating effect of intravenous magnesium sulfate in acute severe bronchial asthma. Chest 199097373-376. 88. Skorodin MS, Tenholder MF, Yetter B, et al. Magnesium sulfate in exacerbations of chronic obstructive pulmonary disease. Arch Intern Med 1995;155496-500. 89. McLean RM. Magnesium and its therapeutic uses: a review. Am J Med 194966376. 90. Gdlestad L, Oystein Doha L, et al. Oral versus intravenous magnesium supplementation in patients with magnesium deficiency. Magnes Trace Elem 1991-92;lOll-16. 91. Hughes R, Goldkom A, Masoli M, et al. Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in treatment of severe asthma in adults: randomised placebo-controlled trial. Lancet 2003;361:21142117. 92. Britton J, Pavord I, Richards K, et al. Dietary magnesium, lung function, wheezing, and airway hyper-reactivity in a random adult population sample. Lancet 1994;344:357-362. 93. Blanc PD, Kuschner WG, Katz PP, et al. Use of herbal products, coffee or black tea, and over-the-counter medications as self-treatments among adults with asthma. J Allergy Clin Immunol1997;100:789-791.

94.Gilman AG, Goodman LS, Gilman A. Goodman and Gilman's the pharmacologic basis of therapeutics. New York MacMillan, 1980. 95. American Pharmaceutical Association. Handbook of nonprescription drugs, ed 8. Washington, DC: American Pharmaceutical Association, 1986. 96. Okimasu E, Moromizato Y, Watanabe S, et al. Inhibition of phospholipase A2 and platelet aggregation by glycyrrhizin, an antiinflammatory drug. Acta Med Okayama 1983;37385-391. 97. Cambar PJ, Shore SR, Aviado DM. Bronchopulmonary and gastrointestinal effects of lobeline. Arch Int Pharmacodyn Ther 1969; 177:l-27. 98. Halmagyi DF, Kovacs A, Neumann P. Adrenalcortical pathway of lobeline protection in some forms of experimental lung edema of the rat. Dis Chest 1958;33:285-296. 99. Lundberg JM, Saria A. Capsaicin-induced desensitization of airway mucosa to cigarette smoke, mechanical and chemical irritants. Nature 1983302:251-253. 100. Payan DG, Levine JD,Goetzl EJ. Modulation of immunity and hypersensitivity by sensory neuropeptides. J Immunol 1984;132: 1601-1604. 101. Cyong J, Otsuka Y. A pharmacological study of the anti-inflammatory activity of Chinese herbs. Acupunc Electrother Res 1982;7173-202. 102. Hanabusa K, Cyong J, Takahashi M. High-level of cyclic AMP in jujube plum. Planta Med 1981;42:380-384. 103.Vanderhoek J, Makheja A, Bailey J. Inhibition of fatty acid oxygenases by onion and garlic oils. Evidence for the mechanism by which these oils inhibit platelet aggregation. Bioch Pharmacol 1980;29:3169-3173. 104.Dorsch W, Weber J. Prevention of allergen-induced bronchial obstruction in sensitized guinea pigs by crude alcoholic onion extract. Agents Actions 1984;14:626-629. 105. Dorsch W, Adam 0, Weber J, et al. Antiasthmatic effects of onion extracts - detection of benzyl- and other isothiocyanates (mustard oils) as antiasthmatic compounds of plant origin. E m J Pharmacol 1984;10717-24. 106. Udupa AL, Udupa SL, Guruswamy MN. The possible site of antiasthmatic action of Tylophora asthmatica on pituitary-adrenal axis in albino rats. Planta Med 1991;57409-413. 107. Gopalkrishnan C, Shankaranarayanan D, Nazimudeen SK, et al. Effect of tylophorine, a major alkaloid of Tylophora indica, on immunopathological and inflammatory reactions. Indian J Med Res 1980;71:940-948. 108.Gupta S, George P, Gupta V, et al. Tylophora indica in bronchial asthma-a double blind study. Ind J Med Res 1979;69981-989. 109.Thiruvengadam KV, Haranath K, Sudarsan S, et al. Tylophoru indica in bronchial asthma (a controlled comparison with a standard anti-asthmatic drug). J Indian Med Assoc 1978;71:172-176. 110. Shivpuri DN, Singhal SC,Prakash D. Treatment of asthma with an alcoholic extract of Tylophora indica. A cross-over, double-blind study. Ann Allergy 197230407-412. 111. Shivpuri DN, Menon MP, Prakash D. A crossover double-blind study on Tylophora indica in the treatment of asthma and allergic rhinitis. J Allergy 1969;43:145-150. 112. W&ens JH, W&ens H, Uffmann J, et al. Effects of a PAF-antagonist (BN 52063) on bronchoconstriction and platelet activation during exercise induced asthma. Br J Clin Pharmacol 1990;29: 85-91. 113. Guinot P, Brambilla C, Duchier J, et al. Effect of BN 52063, a specific PAF-acether antagonist, on bronchial provocation test to allergens in asthmatic patients. A preliminary study. Prostaglandins 1987;34:723-731. 114.Shida T, Tagi A, Nishimura H, et al. Effect of Aloe extract on peripheral phagocytosis in adult bronchial asthma. Planta Med 1985;51:273-275.

Asthma 115. Lichey J, Friedrich T, Priesnitz M, et al. Effect of forskolin on methacholine-induced bronchoconstriction in extrinsic asthmatics. Lancet 1984;2:167. 116. Bauer K, Dietersdorfer F, Sertl K, et al. Pharmacodynamic effects of inhaled dry powder formulations of fenoterol and colforsin in asthma. Clin Pharmacol Ther 1993;53:76-83. 117. Wildfeuer A, Neu IS, Safayhi H, et al. Effects of boswellic acids extracted from a herbal medicine on the biosynthesis of leukotrienes and the course of experimental autoimmune encephalomyelitis. Arzneimittelforschung 1998;48:668-674.

118. Maa SH, Sun MF, Hsu KH, et al. Effect of acupuncture or acupressure on quality of life of patients with chronic obstructive asthma: a pilot study. J Altem Complement Med 2003;9:659-670. 119. Wu HS, Wu SC, Lin JG, et al. Effectiveness of acupressure in improving dyspnoea in chronic obstructive pulmonary disease. J Adv Nurs 2004;45:252-259. 120. Van Woerden H. Dust mites living in human lungs-the cause of asthma? Med Hypotheses 2004;63:193-197.

Atherosclerosis Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER C O N T E N T S Diagnostic Summary

1501

General Considerations 1501 UnderstandingAtherosclerosis 1501 Determining a Patient’s Risk 1502 Clinical Evaluation 1502 Risk Factors 1503 Therapeutic Considerations-General Guidelines 1506 Diet-General Guidelines 1506 Therapeutic Considerations-Lowering Cholesterol 1508 The Importance of Soluble Dietary Fiber in Lowering Cholesterol 1509 Natural Products to Lower Cholesterol Levels 1509 Comparing Natural Cholesterol-Lowering Agents 1512 Therapeutic Considerations-Antioxidant Status 1513 Vitamin E 1514

DIAGNOSTIC SUMMARY Characteristically associated with high blood pressure, weak pulse, and wide pulse pressure Symptoms and signs depend on arteries involved and degree of obstruction: angina, leg cramps (intermittent claudication), gradual mental deterioration, weakness or dizziness; may also be without symptoms Diagonal ear lobe crease

Vitamin C 1515 Grape Seed and Pine Bark Extracts 1515 Therapeutic Considerations-Miscellaneous Risk Factors 1516 Platelet Aggregation 1516 Fibrinogen 1516 Homocysteine 1517 “Type A Personality 1517 Other Nutritional Factors 1518 Therapeutic Considerations-Preventing a Recurrent Heart Attack 1518 Aspirin 1518 Natural Alternatives to Aspirin 1519 Preventing a Subsequent Stroke 1520 Other Considerations 1520 Therapeutic Approach 1520 Dietary Recommendations 1520 Lifestyle Recommendations 1521 Supplements 1521

age-adjusted death toll since 1980, CAD remains the leading cause of death among U.S. adults and stroke is the third leading cause.

Understanding Atherosclerosis To fully understand the important ways that various natural measures described in this chapter affect the health of the artery and treatment of cardiovascular disease, it is necessary to examine closely the structure of an artery and the process of atherosclerosis.

GENERAL CONSIDERATIONS

Structure of an Artery

Atherosclerosis refers to the process that is the underlying pathology in a group of clinical entities collectively referred to as cardiovascular disease (CVD)including heart disease (atherosclerosis of the coronary arteries); coronary artery disease (CAD); and myocardial, pulmonary, and cerebral infarction. Despite a steady decline in the

An artery is divided into three major layers:

The intima represents the endothelium or internal lining of the artery. It consists of a layer of endothelial cells. Glycosaminoglycans (GAGS) line the exposed endothelial cells to protect them from damage, as well 1501

Specific Health Problems

as promoting repair. Beneath the surface cells is the internal elastic membrane composed of a layer of GAGs and other ground substance compounds, which supports the endothelial cells and separates the intima from the smooth muscle layer. The media consists primarily of smooth muscle cells. Interposed among the cells are GAGs and other ground substance structures that provide support and elasticity to the artery. The adventitia or external elastic membrane consists primarily of connective tissue including GAGs, providing structural support and elasticity to the artery.

The Process of Atherosclerosis The lesions of atherosclerosis are initiated in response to injury to or a disruption of the normal functioning of the cells lining the inside of the artery, the arterial endothelium.' The progression of atherosclerosis via this process is detailed as follows: The initial step in the development of atherosclerosis is damage or dysfunction of the vascular endothelium. Damage results from weakening of the GAG layer that protects the endothelial cells due to the same factors that ultimately damage the endothelial cell (e.g., free radicals, oxidants, immune complexes, inflammatory mediators). These compounds ultimately lead to plaque development.' Once the endothelial cells have been sufficiently damaged, sites of injury become more permeable to plasma constituents, especially lipoproteins. The binding of lipoproteins to GAGs leads to a breakdown in the integrity of the ground substance matrix and causes an increased affinity for cholesterol. Simultaneously, monocytes, T-lymphocytes, and platelets adhere to the damaged area, where they release growth factors that stimulate smooth muscle cells to migrate from the media into the intima and replicate. 3. Local concentration of lipoproteins, monocytes, and platelets leads to the migration of smooth muscle cells from the media into the intima, where they undergo proliferation.Smooth muscle cells dump cellular debris into the intima, leading to further development of plaque. 4.Formation of a fibrous cap (consisting of collagen, elastin, and glycosaminoglycans)over the intimal surface occurs. Fat and cholesterol deposits accumulate. 5. Plaque continues to grow until eventually it either blocks the artery directly or ruptures to form a clot that travels the general circulation until it occludes a blood vessel. Plaque instability is associated with signhcantly greater risk for myocardial infarction (MI) or stroke.'

Causative Factors Prevention of CVD involves reducing and, when possible, eliminating various risk factors. Risk factors are divided

Smoking Elevated blood cholesterol levels High blood pressure Diabetes Physical inactivity Other risk factors

I with incidence of atherosclerosis Major risk factors

Increase in incidence

Presence of one of the major risk factors

30%

High cholesterol and high blood pressure

300%

High cholesterol and a smoker

350%

High blood pressure and a smoker

350%

Smoker, high blood cholesterol, and high blood pressure

720%

Insulin resistance Low thyroid function (see Chapter 179) Low antioxidant status Elevations of C-reactive protein Low levels of essential fatty acids Increased platelet aggregation Increased fibrinogen formation Low levels of magnesium and potassium Elevated levels of homocysteine "Type A personality

into two primary categories: major risk factors and other risk factors. Box 150-1 lists the major risk factors. Risk for a heart attack increases with the number of major risk factors, as Table 150-1 shows. In addition to these well-accepted major risk factors, numerous other factors have occasionally been shown to be more significant than the "major" risk factors. Box 150-2 lists these additional risk factors.

Determining a Patient's Risk To help determine a patient's overall risk for having a heart attack or stroke, we have designed the following risk determinant scale. Although this risk assessment does not take into consideration several other important factors (such as the level of C-reactive protein, lipoprotein(a) or Lp(a), fibrinogen, and coping style), the score provides a good indication of a patient's risk for a heart attack or stroke (Table 150-2).

Clinical Evaluation The complete cardiovascular assessment can include the tests listed in Box 150-3.

Atherosclerosis

Scale of Risk

Blood pressure (diastolic)

1
Smoking (cigarettedday)

None

Blood pressure (systolic)

Heredity I*

None

Heredity Ilt

0

Diabetes duration (yr)

0

Total cholesterol (mg/dl) Total cholesterollHDL ratio*

400 275 <3

Exercise (hr/wk)

A

HDL cholesterol (mg/dl)

Supplemental EPNDHA (mg) intake

>600

Supplemental vitamin C (mg) and vitamin E (IU) intake

A00

Average daily servings of fruits and vegetables

>5

Age Subtotals

<35

2

3

4

5

125-134 90-94 1-9 >65 1 1-5 200-224 65-74 3-3.9 3-4 400-599 251-499 4-5 36-45

135-149 95-104 10-19 50-64 2 6-10 225-249 55-64 4-4.9 2-3 200-399 250 3 46-55

150-164 105-114 20-29 35-49 4 11-15 250-274 35-54 5-6.4 1-2 100-199 125-249 1-2 56-65

2165 2115 230 <35 24 >15 275 <35 26.5 0.1 400 0-124 0 >65

HDL, High-density lipoprotein. 'Age of patient when he or she had a heart attack or stroke. 'Number of immediate family members having a heart attack before the age of 50. *Divide the value of the total cholesterol by the value of the high-density lipoprotein cholesterol. Risk = sum of all five columns. 14-20 =very low risk; 21-30 = low risk; 31-40 =average risk; 41-50 =high risk; 251 =very high risk.

Risk Factors

Smoking Cigarette smoking is perhaps the most important risk factor for CVD, as statistical evidence reveals smokers have a 70% greater risk of death from CVD than nonsmokers? The more cigarettes smoked and the longer the period of years a person has smoked, the greater the risk of dying from a heart attack or stroke. Overall, the average smoker dies 7 to 8 years sooner than the nonsmoker. Tobacco smoke contains more than 4000 chemicals, of which more than 50 substances have been identified as carcinogens. These chemicals are extremely damaging to the cardiovascular system. Specifically, these chemicals are carried in the bloodstream on low-density lipoprotein (LDL) cholesterol, where they either damage the lining of the arteries directly or they damage the LDL molecule, which then damages the arteries. An elevated LDL cholesterol level worsens the effect of smoking on the cardiovascular system because more cigarette toxins travel through the vascular system. Smoking contributes to elevated cholesterolpresumably by damaging feedback mechanisms in the liver, which control how much cholesterol is being manufactured? Smoking also promotes platelet aggregation and elevated fibrinogen levels, two other important independent risk factors for CVD. In addition, it is a well-documented fact that cigarette smoking is a contributing factor to high blood pressure?

Laboratory tests Total cholesterol Low-density lipoprotein cholesterol High-density lipoprotein cholesterol C-reactive protein Lipoprotein(a) Fibrinogen Hornocysteine Ferritin (an iron-binding protein) Lipid peroxides Exercise stress test Electrocardiogram Echocardiogram

Even passive exposure to cigarette smoke is damaging to cardiovascular health, as convincing evidence links environmental (second-hand or passive) smoke to heart disease mortality and morbidity. Analysis of 10 epidemiologic studies indicates a consistent dose-response effect related to e ~ p o s u r eEvidence .~ indicates that nonsmokers appear to be more sensitive to smoke including its deleterious effects on the cardiovascularsystem. Environmental tobacco smoke actually has a higher concentration of some toxic constituents. Pathophysiologic and biochemical data after short- and long-term environmental tobacco

Specific Health Problems smoke exposure show changes in the lining of the arteries and platelet function, as well as exercise capacity similar to those in active smoking. In summary, passive smoking is a relevant risk factor for CVD. In the United States it is estimated that more than 37,000 coronary heart disease (CHD) deaths each year are attributed to environmental smoke. Those exposed to second-hand smoke can help to mitigate the effects through the use of antioxidant nutrients such as vitamin C (500 mg/day) and vitamin E (400 IU/day). The magnitude of risk reduction achieved by smoking cessation in patients with CVD is quite significant. Results from a detailed meta-analysis showed a 36% reduction in relative risk of mortality for patients with CAD who quit compared with those who continued smoking6 Various measures, including nicotine-containing skin patches or chewing gum, acupuncture, and hypnosis have all been shown to provide some benefit in helping patients to quit smoking, but not much. In a systematic review of the efficacy of interventions intended to help people to stop smoking, data were analyzed from 188 randomized controlled trial^.^ Encouragement to stop smoking by physicians during a routine office call resulted in a 2% cessation rate after 1 year. Supplementary measures such as follow-up letters or visits had an additional effect. Behavioral modification techniques such as relaxation, rewards and punishment, and avoiding trigger situations in group or individual sessions led by a psychologist had no greater effect than the 2% rate achieved by simple advice from a physician. Eight studies with acupuncture have produced an overall effectiveness rate of roughly 3%. Hypnosis has been judged to be ineffective even though trials have shown a success rate of 23%. The reason hypnosis was judged to be ineffective was because no biochemical marker was used to accurately determine effectiveness. Nicotine replacement therapy (gum or patch) is effective in about 13%of smokers who seek help in quitting. Altogether, these results are not encouraging. It appears the best results occur when people quit "cold turkey." Box 150-4 lists 10 tips to help patients stop smoking.

Elevated Blood Cholesterol Levels The evidence overwhelmingly demonstrates that elevated cholesterol levels greatly increase the risk of death due to CVD. It is currently recommended that the total blood cholesterol level be less than 200 mg/dl. In addition, it is recommended that the LDL cholesterol be less than 130 mg/dl, the high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, and triglyceride levels less than 150 mg/dl. Cholesterol is transported in the blood by lipoproteins. The major categories of lipoproteins are very-low-density

List all the reasons why you want to quit smoking and review them daily. Set a specific day to quit, tell at least 10 friends that you are going to quit smoking, and then . . . DO IT! Throw away all cigarettes, butts, matches, and ashtrays. Use substitutes. Instead of smoking, chew on raw vegetables, fruits, or gum. If your fingers seem empty, play with a pencil. Take one day at a time. Realize that 40 million Americans have quit. If they can do it, so can you! Visualize yourself as a nonsmoker with a fatter pocketbook, pleasant breath, unstained teeth, and the satisfaction that comes from being in control of your life. Join a support group. Call the local American Cancer Society and ask for referrals.You are not alone. When you need to relax, perform deep breathing exercises rather than reaching for a cigarette. Avoid situations that you associate with smoking. Each day, reward yourself in a positive way. Buy yourself something with the money you have saved or plan a special reward as a celebration for quitting.

lipoprotein (VLDL), LDL, and HDL. Because VLDL and LDL are responsible for transporting fats (primarily triglycerides and cholesterol) from the liver to body cells, while HDL is responsible for returning fats to the liver, elevations of either VLDL or LDL are associated with an increased risk for developing atherosclerosis, the primary cause of a heart attack or stroke. In contrast, elevations of HDL are associated with a low risk of heart attacks. The ratios of total cholesterol to HDL cholesterol and LDL to HDL are referred to as the cardiac riskfactor ratios because they reflect whether cholesterol is being deposited into tissues or broken down and excreted. The total cholesterol-to-HDL ratio should be no higher than 4.2, and the LDL-to-HDL ratio should be no higher than 2.5. The risk for heart disease can be reduced dramatically by lowering LDL cholesterol while simultaneously raising HDL cholesterol levels: For every 1% drop in the LDL cholesterol level, the risk for a heart attack drops by 2%. Conversely, for every 1%increase in HDL levels, the risk for a heart attack drops 3% to 4%? Further Refinement of Determining Risk Although LDL cholesterol is referred to as "bad cholesterol," LDL molecules of higher density, as well as Lp(a), are associated with greater risk than larger, less dense LDL. Lp(a) is a plasma lipoprotein whose structure and composition closely resemble that of LDL, but with an additional molecule of an adhesive protein called apofipoprotein(a). Elevated plasma levels of Lp(a) are an independent risk factor for coronary heart disease, particularly in those patients with elevated LDL

Atherosclerosis cholesterol levels. In fact, in one analysis a high level of Lp(a) was shown to carry with it a 10 times greater risk for heart disease than an elevated LDL cholesterol level.9 That is because LDL on its own lacks the adhesive apolipoprotein(a).As a result, LDL does not easily stick to the walls of the artery. Actually, a high LDL cholesterol level carries less risk than a normal or even low LDL cholesterol with a high Lp(a). Levels of Lp(a)below 20 mg/dl are associated with a low risk for heart disease; levels between 20 and 40 mg/dl are associated with a moderate risk; and levels above 40 mgldl are associated with an extremely high risk for heart disease.

Inherited Elevations of Cholesterol and Triglycerides Elevations of blood cholesterol or triglycerides, or both, can be due to genetic factors. These conditions are referred to as familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCH), and familial hypertriglyceridemia (FT). Relatively speaking, these disorders are among the most common inherited disease, as they affect about 1in every 500 people. The basic problem in FH is a defect in the receptor protein for LDL in the liver. Under normal situations the LDL receptor is responsible for removing cholesterol from the blood. When the liver cell takes up the LDL after it has bound to the receptor, it signals the liver cell to stop making cholesterol. In FH the defect in the LDL receptor results in the liver not receiving the message to stop making cholesterol. Damage to the LDL receptor occurs with normal aging and in several disease states, with diabetes being chief among them due to increased glycosylation of the receptor proteins. As a result of LDL receptor damage, cholesterol levels tend to rise with age. In addition, a diet high in saturated fat and cholesterol decreases the number of LDL receptors, thereby reducing the feedback mechanism that tells the liver cell that no more cholesterol is necessary. Fortunately, lifestyle and dietary changes can increase the function or number of LDL receptors, or both. The most dramatic effects are in people without inherited causes of elevated cholesterol or triglycerides, or both, but even people with FH can benefit. FCH and FT result in similar defects to FH. In FCH the basic defect appears to be an accelerated production of VLDL in the liver. These individuals may have only a high blood triglyceride level or only a high cholesterol level, or both. In FT there is only an elevation in blood triglyceride levels, and HDL cholesterol levels tend to be low. The defect in FT is that the VLDL particles made by the liver are larger than normal and carry more triglycerides. FT is made worse by diabetes, gout, and obesity. The recommendations in Table 150-3 also help FCH and FT, although these conditions usually require more aggressive support.

Recommended cholesterol and triglyceride levels Level (mg/dl) Total cholesterol

400 200-239 2240

<1oo*

LDL cholesterol

100-130 130-159 2160 HDL cholesterol

<35 35-59

260 Triglycerides

400 200-400 400-1000

>loo0

Result Desirable Borderline High Desirable Borderline Borderline high risk High risk Low (undesirable) Normal Desirable Desirable Borderline high High Very high

HDL, High-density lipoprotein; LDL, low-density lipoprotein. ’For very-high-risk patients (those having cardiovascular disease with multiple risk factors such as diabetes, severe and poorly controlled risk factors such as continued smoking, or the presence of the metabolic syndrome), the goal is to reach c70 mg/dl for LDL.

High Blood Pressure Elevated blood pressure is often a sign of considerable atherosclerosis and is a major risk factor for a heart attack or stroke. In fact, the presence of hypertension is generally regarded as the most significant risk factor for a stroke.

Diabetes Atherosclerosis is one of the key underlying factors in the development of many chronic complications of diabetes. Individuals with diabetes have a twofold to threefold higher risk of dying prematurely of heart disease or stroke than a nondiabetic individual, and 55% of deaths in diabetes patients are caused by cardiovascular disease. For more information, see Chapter 163.

Physical Inactivity A sedentary lifestyle is another major risk factor for CVD. Physicul activity refers to ”bodily movement produced by skeletal muscles that requires energy expenditure” and produces healthy benefits. Exercise, a type of physical activity, is defined as ”a planned, structured, and repetitive bodily movement done to improve or maintain one or more components of physical fitness.” Physical inactivity denotes a level of activity less than that needed to maintain good health. Physical inactivity characterizes most Americans, as roughly 54% of adults report little or no regular leisure physical activity, and there is also a sharp decline in regular exercise in children and adolescents.’

Specific Health Problems Physical activity protects against the development of CVD and also favorably modifies other CVD risk factors including high blood pressure, blood lipid levels, insulin resistance, and obesity. Physical activity is also important in the treatment and management of patients with CVD or increased risk including those who have hypertension, stable angina, a prior MI, peripheral vascular disease, or heart failure or are recovering from a cardiovascular event.

Other Risk Factors In addition to the major risk factors for CVD (i.e., smoking, elevations in cholesterol, elevated blood pressure, diabetes, and physical inactivity/obesity), a number of other factors have, on occasion, been shown to be more sigruficant than the so-called major risk factors. In fact, more than 300 different risk factors have been identified including those listed in Box 150-2. Although there is considerable evidence that all of these risk factors and more can play a sigruficant role in the pathogenesis of atherosclerosis, much of the current research has focused on the central roles of inflammatory processes and insulin resistance.1° Inflammatory mediators influence many stages of atheroma development from initial leukocyte recruitment to eventual rupture of the unstable atherosclerotic plaque. In particular, C-reactive protein (CRP),an acute phase reactant that reflects different degrees of inflammation, has been identified as an independent risk factor for coronary artery disease. Although measuring CRP has shown to be a stronger predictor of cardiovascularevents than the LDL cholesterol level, screening for both biologic markers provided better prognostic information than screening for either alone." Elevations in CRP are closely linked to insulin resistance and the metabolic syndrome (syndrome X).12 The diagnostic criteria for the metabolic syndrome or syndrome X is the presence of at least three of the following group of metabolic risk factors in one person: Central obesity (A waist-to-hip ratio >1 for men; >0.8 for women) Atherogenic dyslipidemia (mainly high triglycerides >150mg/dl; and low HDL cholesterol [male <40 mg/dl, female <50 mg/dlJ) Hypertension (2130/85 mmHg) Insulinresistance or glucose intolerance (fasting blood sugar levels >lo1mg/dl) Prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor in the blood) Proinflammatory state (e.g., elevated high-sensitivity CRP in the blood) The metabolic syndrome has become increasingly common in the United States. It is now estimated that

more than 60 million U.S. adults may have it. Insulin resistance and the metabolic syndrome are closely tied to obesity (particularly abdominal obesity), elevations in CRP,and a significant risk for CAD.

THERAPEUTIC CONSIDERATIONSGENERAL GUIDELINES Prevention of a heart attack or stroke involves reducing risk factors. The major risk factor of smoking was discussed earlier, while obesity, physical inactivity, diabetes, and hypertension are detailed in separate chapters. Therefore the focus in this chapter is on improving blood cholesterol levels, as well as highlighting factors that address some of the additional risk factors associated with atherosclerosis (e.g., antioxidant status, elevated CRP, fibrinogen levels).

Diet-General

Guidelines

The dietary program detailed in Chapter 44 features a comprehensive dietary approach in both the prevention and treatment of CVD, as well as improving blood lipid profiles. In particular, it is important to reduce the intake of saturated fat and trans fatty acids while increasing the consumption of vegetables, fruit, dietary fiber, monounsaturated fats, and omega-3 fatty acids. An important dietary goal is to improve the structure and composition of cell membranes by making available essential structural components like the monounsaturated and omega-3 fatty acids and by preventing oxidative and free radical damage to these structures by consuming a high level of antioxidants and phytochemicals. One of the most widely studied dietary interventions in CAD is the traditional "Mediterranean diet."13 This term has a specific meaning. It reflects food patterns typical of some Mediterranean regions in the early 1960s, such as Crete, parts of the rest of Greece, and southern Italy. Unfortunately the modern Mediterranean diet has deviated significantly from its healthful origin. The original Mediterranean diet had the following characteristics: Olive oil is the principal source of fat. It centers on an abundance of plant food (fruits; potatoes, beans, and other vegetables; breads; pasta; nuts; and seeds). Foods are minimally processed, and people focus on seasonally fresh and locally grown foods. Fresh fruit is the typical daily dessert, with sweets containing concentrated sugars or honey consumed a few times per week at the most. Dairy products (principally cheese and yogurt) are consumed daily in low to moderate amounts. Fish is a consumed regularly. Poultry and eggs are consumed in moderate amounts (up to four times weekly) or not at all.

Atherosclerosis Red meat is consumed in low amounts. Wine is consumed in low to moderate amounts, normally with meals.

In one study, the effect of the Mediterranean diet on endothelial function and vascular inflammatory markers was studied in patients with the metabolic syndrome.14 Patients in the intervention group were instructed to follow the Mediterranean diet and received detailed advice about how to increase daily consumption of whole grains, fruits, vegetables,nuts, and olive oil; patients in the control group followed the American Heart Association’s diet. After 2 years, patients following the Mediterranean diet consumed more foods rich in monounsaturated fat, polyunsaturated fat, and fiber and had a lower ratio of omega-6 to omega3 fatty acids. Compared with patients consuming the control diet, patients consuming the intervention diet had sigruficantly reduced serum concentrations of CRP and other inflammatory mediators; improved endothelial function scores; and greater weight loss. Although several components of the Mediterranean diet deserve special mention, it is important to stress that the total benefits reflect the interplay among the many beneficial compounds rather than any single factor.I5

Olive Oil and Omega3 Fatty Acids One of the most important dietary aspects of the Mediterranean diet may be the combination of olive oil (a source of monounsaturated fats and antioxidants) and the omega3 fatty acid intake. Olive oil consists of not only monounsaturated fatty acid, oleic acid; it also contains several antioxidant agents that may also account for some of the health benefits. In addition to a mild effect in lowering LDL and triglycerides, olive oil increases the HDL-cholesterol level and helps prevent LDL from becoming damaged by free radicals.16 In addition to olive oil, the benefits of the longer chain omega3 fatty acids eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) to cardiovascular health has been demonstrated in more than 300 clinical trials. These fatty acids exert considerable benefits in reducing the risk for cardiovascular disease. Supplementation with EPA and DHA has little effect on cholesterol levels but does lower triglyceride levels sigruficantly, as well as produce a myriad of additional beneficial effects including an ability to reduce platelet aggregation; improve endothelial function and arterial flexibility; improve blood and oxygen supply to heart; and exert a mild effect in lowering blood pressure by vasodilation and promotion of sodium excreti0n.l’ The levels of EPA and DHA within red blood cells have been shown to be highly significant predictors of heart disease. This laboratory value has been termed the Omega3 Index. An Omega-3 Index of 8% was associated with the greatest protection, whereas an index

of 4% was associated with the least. In one analysis, the Omega3 Index was shown to be the most significant predictor of CAD compared with CRP; total, LDL, or HDL cholesterol; and homocysteine. Researchers subsequently determined that a total of a combined 1000 mg of EPA and DHA daily is required to achieve or surpass the 8% Omega3 Index target.’* The findings with the Omega-3 Index are not surprising, as a wealth of information has documented a clear relationship between dietary intake omega3 fatty acids and the likelihood of developing CHD-the higher the omega3 fatty acid intake, the lower the likelihood of CHD. It has been estimated that raising the levels of long-chain omega3 fatty acids through diet or supplementation may reduce overall cardiovascular mortality by as much as 450/o. 1920 Although the longer-chain omega3 fatty acids exert more pronounced effects than alpha-linolenic acid, the shorter omega3 fatty acid from vegetable sources, it is important to point out that the two populations with the lowest rate of heart attacks have a relatively high intake of alpha-linolenic acid: the Japanese who inhabit Kohama Island and the inhabitants of Crete.21,22 Typically, Cretans have a threefold higher concentration of alphalinolenic acid than members of other European countries, owing to their frequent consumption of walnuts and the vegetable purslane.21Of course, another important dietary factor in both the Kohamans and Cretans is their use of oleic acid-containing oils. However, although the oleic content of the diet offers some degree of protection, the rate of heart attacks in the Kohamans and Cretans is much lower than in populations that consume only oleic acid sources and little alpha-linolenic acid. The intake of alpha-linolenic acid is viewed as a more significant protective factor than oleic acid.

Nuts and Seeds Higher consumption of nuts and seeds has been shown to sigruiicantly reduce the risk for CVD in large epidemiologic studies including the Nurses Health Study, the Iowa Health Study, and the Physicians Health Studyz3 Researchers estimate that substituting nuts for an equivalent amount of carbohydrates in an average diet resulted in a 30% reduction in heart disease risk. Researchers calculated even more impressive risk reduction, 45%, when fat from nuts was substituted for saturated fats (found primarily found in meat and dairy products). Nuts have a cholesterol-lowering effect that partly explains this benefit, but they are also a rich source of arginine. By increasing nitric oxide levels, arginine may help improve blood flow, reduce blood clot formation, and improve blood fluidity (the blood becomes less viscous and therefore flows through blood vessels more easily).

Specific Health Problems Walnuts appear to be especially beneficial, as they are also a rich source of both antioxidants and alphalinolenic acid. In one study, hypercholesterolemic men and women were randomized to a cholesterol-lowering Mediterranean diet and a diet of similar energy and fat content in which walnuts replaced approximately 32% of the energy from monounsaturated fat (olive oil). Participants followed each diet for 4 weeks. Compared with the Mediterranean diet, the walnut diet improved endothelial cell function (increased endotheliumdependent vasodilation and reduced levels of vascular cell adhesion molecule-1). The walnut diet also sigruficantly reduced total cholesterol (-4.4%) and LDL cholesterol (-6.4Y0).~~

Vegetables, Fruits, and Red Wine An important contributor to the benefits noted with

the Mediterranean diet is the focus on carotene-rich and flavonoid-rich fruits, vegetables, and beverages (e.g., red wine). Numerous population studies have repeatedly demonstrated that a higher intake of dietary antioxidants significantly reduces the risk of heart disease and strokes. Higher blood levels of antioxidant nutrients are also associated with lower levels of CRP.% The importance of antioxidant intake in the prevention and treatment of CAD is discussed further later. Two valuable sources of antioxidants in the Mediterranean diet are tomato products and red wine. Tomatoes are a rich source of the carotene lycopene. In large clinical studies evaluating the relationship between carotene status and heart attack (acute MI), lycopene, but not beta-carotene, was shown to be protective. Lycopene exerts greater antioxidant activity compared with beta-carotene in general but specifically against LDL

The cardiovascular protection offered by red wine is popularly referred to as the "French Paradox." Because the French consume more saturated fat than the populations in the United States and the United Kingdom, yet have a lower incidence of heart disease, red wine consumption has been suggested to be the reason. Presumably this protection is the result of flavonoids and other polyphenols in red wine protecting against oxidative damage to LDL cholesterol, as well as helping to reduce the level of inflammatory mediator^.'^,^^ However, moderate alcohol consumption alone has also been shown to exert a protective effect in some studies by exerting positive effects on HDL-to-LDL ratios and CRP and fibrinogen levels, though red wine typically exerts the most sigruficant effects.2s Importantly, the effects of alcohol on CVD risk, morbidity, and total mortality are counterbalanced by alcohol's addictive and psychologic effects.

THERAPEUTIC CONSIDERATIONSLOWERING CHOLESTEROL Lowering total cholesterol (TC), as well as LDL cholesterol (LDL), is clearly associated with reducing CVD risk. Most of the benefits noted with lowering LDL are based on a large number of randomized clinical trials involving the use of the HMG CoA (3-hydroxy-3methylglutaryl coenzyme A) reductase inhibitors known collectively as statin drugs. The development of statin drugs owe their origin to red yeast (Monascus purpureus) fermented on rice. This traditional Chinese medicine has been used for its health-promoting effects in China for more than 2000 years. Red yeast rice is the source of a group of compounds known as rnonacofins (e.g., lovastatin, also known as monacolin K, one of the key monacolins in red yeast rice extract). The marketing of an extract of red yeast fermented on rice standardized for monacolin content as a dietary supplement in the United States caused controversy in 1997 because it contained a natural source of a prescription drug. The FDA eventually ruled that red yeast rice products could only be sold if they were free of monacolin content. Although the data are clear that statin drugs can produce decreases in total mortality, cardiovascular events, hospitalizations, and the need for revascularization procedures, the debate remains whether statin therapy represents the optimal treatment approach to primary and secondary prevention of CAD, especially in light of the growing acceptance of risk factors like CRPz9For example, one interesting study compared a diet low in saturated fat together with plant sterols and viscous fibers and the use of soy protein and nuts to 10vastatin.~~ The participants were randomly assigned to undergo one of three interventions on an outpatient basis for 1 month: a diet low in saturated fat, based on milled whole-wheat cereals and low-fat dairy foods; the same diet plus lovastatin, 20 mg/day; or a diet high in plant sterols (1 g/1000 kcal), soy protein (21.4 g/ 1000 kcal), viscous fibers (9.8 g/1000 kcal), and almonds (14 g/lOOO kcal). The control, statin, and dietary portfolio groups had mean (SE) decreases in low-density lipoprotein cholesterol of 8%, 30.9%, and 28.6%, respectively. Respective reductions in CRP were lo%, 33.3%, and 28.2%. It is therefore suggested by these results that diversifying cholesterol-lowering components in the same dietary portfolio increased the effectiveness of diet as a treatment of hypercholesterolemia and produced results comparable to a statin drug. Despite research documenting the benefits of nonpharmacologic approaches, it is unlikely that lowering LDL with statin drugs will be supplanted as the primary therapy in lipid management and prevention of CAD anytime in the near future. Therefore the focus with

Atherosclerosis

many patients will be on the support of statin therapy. For example, several natural agents appear to potentiate statin therapy (e.g., niacin, phytosterols, phytostanols, and policosanol), and it appears that individuals taking Typical reduction statin drugs need to supplement with coenzyme Qlo Fiber Dosane (a) in total cholesterol (CoQlo).HMG-CoA reductase is not only required for the Oat bran (dry) 50-100 20% synthesis of cholesterol but also CoQlo.Thus administraGuar gum 9-15 10% tion of these drugs might compromise CoQlo status by 5% Pectin 6-10 decreasing its synthesis. Even modest dosages of various Psyllium 10-20 10-20% statins have been shown to lower blood CoQlo levels. Vegetable fiber 27 10% Researchers have concluded that inhibition of CoQlo synthesis by statin drugs could explain the most commonly reported adverse effects, especially fatigue and levels (above 200 mg/dl), the consumption of the equivmuscle pain, as well as the more serious side effects such alent of 3 g of soluble oat fiber typically lowers total as rhabdomyolysi~.~~3* CoQlo supplementation in subcholesterol by 8% to 23%. This is highly significant, as jects on statin drugs has also been shown to reduce with each 1%drop in serum cholesterol level there is a markers of oxidative damage. 2% decrease in the risk of developing heart disease. In Statins are also gaining popularity as a prescription approximately one bowl of ready-to-eat oat bran cereal method to lower CRP-a marker of inflammation and a or oatmeal are 3 g of fiber. Although oatmeal's fiber conrisk factor for CVD. In one study, a group of 186 individtent (7%)is less than that of oat bran (15%to 26%),it has uals with type 2 diabetes was selected to receive 10 mg been determined that the polyunsaturated fatty acids of atorvastatin (Lipitor), 80 mg of atorvastatin, or a contribute as much to the cholesterol-lowering effects of placebo for 30 weeks. In those given placebo, CRP levels increased 6.6%. CRP levels decreased by 15%in the 10-mg oats as the fiber content. Although oat bran has a higher fiber content, oatmeal is higher in polyunsaturated fatty group and by 47% in the 80-mg group. In a study with pravastatin, 40 mg daily lowered CRP levels by 13Y0.~~ acids. In an effort to lower cholesterol with dietary fiber, Although many physicians appear to be aware of the patients should be encouraged to eat 35 g of fiber daily effect of Lipitor and Pravachol on CRP, they do not seem from fiber-rich foods, a full listing of which can be found to be aware that vitamin E (BOO IU daily) lowered CRP by 49% and niacin (1500 mg at night) lowered it by 20% in Chapter 60. Achieving higher fiber intake is not only associated with lower cholesterol levels, but also lower in these ~ t u d i e s . ~ , ~ ~ inflammatory mediators like CRP.40

The Importance of Soluble Dietary Fiber in Lowering Cholesterol

Chapter 60 provides a complete discussion on the benefits of dietary fiber. It is well established that the soluble dietary fiber found in legumes, fruit, and vegetables is effective in lowering cholesterol levels.36The greater the degree of viscosity or gel-forming nature, the greater the effect of a particular dietary fiber has on lowering cholesterol levels. New, highly viscous, soluble fiber blends are showing greater effect than previously used fiber sources leading to more reasonable dosage recommendations (the cholesterol-lowering effect of soluble fiber is clearly dose de~endent).~'J~ Table 150-4 shows the average doses and reductions noted in clinical trials with soluble fiber supplements. Many of the studies featured oat preparations containing either oat bran or oatmeal.39The overwhelming majority of these studies demonstrated that individuals with high cholesterol levels see sigruficant reductions with frequent oatmeal or oat bran consumption. In contrast, individuals with normal or low cholesterol levels see little change. In individuals with high cholesterol

Natural Products to Lower Cholesterol Levels In many cases dietary therapy, while important, is not sufficient alone to reduce lipid levels to the desired ranges. Fortunately, several natural compounds can lower cholesterol levels and other significant risk factors for CAD. In fact, when all factors are considered (e.g., cost, safety, effectiveness), the natural alternatives presented here may offer sigruficant advantages to the standard drug therapy.

Niacin Since the 1950s niacin (vitamin B3) has been known to be effective in lowering blood cholesterol levels. In the 1970s the famed Coronary Drug Project demonstrated that niacin was the only cholesterol-lowering agent to actually reduce overall mortality. Niacin typically lowers LDL-cholesterol levels by 16% to 23% while raising HDL-cholesterol levels by 20% to 33%. These effects, especially the effect on HDL, compare quite favorably to conventional cholesterol-lowering

Specific Health Problems It is now known that niacin does much more than lower total cholesterol. Specifically, niacin has been shown to lower LDL cholesterol, the more harmful Lp(a) lipoprotein, triglyceride, CRP, and fibrinogen levels while simultaneously raising beneficial HDL cholesterol levels. Despite the fact that niacin has demonstrated better overall results in reducing risk factors for CHD compared with other cholesterol-lowering agents, physicians are often reluctant to prescribe niacin. The reason is a widespread perception that niacin is difficult to work with because of the bothersome flushing of the skin. In addition, because niacin is a widely available "generic" agent, no pharmaceutic company stands to generate the huge profits that the other lipid-lowering agents have enjoyed. As a result, niacin does not benefit from the intensive advertising that focuses on the "statin" drugs. Despite the advantages of niacin over other lipid-lowering drugs, it accounts for less than 10% of all cholesterol-lowering prescriptions. Niaspan (Kos Pharmaceuticals), a prescription niacin product, accounted for 952,000 prescriptions in 2002, translating to sales of $145.7 million-a dramatic 73'3/0increase from 2001 levels. The increasing sales of niacin reflect a growing physician awareness of the advantages of niacin over statin drugs. Several studies have compared niacin with standard lipid-lowering drugs including the statin drugs. These studies have shown significant advantages for niacin. In the first published clinical study, niacin was compared with lovastatin directly in 136 subjects with LDL cholesterol levels greater than 160 mg/dl and with coronary heart disease or with more than two coronary heart disease risk factors, or both; or in patients with LDL cholesterol levels greater than 190 mg/dl and without coronary heart disease or fewer than two coronary heart disease risk factors." The controlled, randomized, openlabel, 26-week study was performed at five lipid clinics. Patients were first placed on a 4-week diet run-inperiod, after which eligible patients were randomly assigned to receive treatment with either lovastatin (20 mg/day) or niacin (1.5 g/day). On the basis of the LDL cholesterol response and patient tolerance, the doses were sequentially increased to 40 and 80 mg/day of lovastatin or 3 and 4.5 g/day of niacin after 10 and 18 weeks of treatment, respectively. h the two patient groups, 66% of patients treated with lovastatin and 54% of patients treated with niacin underwent full dosage titration. Table 150-5 shows the results. These results indicate that while lovastatin produced a greater LDL cholesterol reduction, niacin provided better overall results despite the fact that fewer patients were able to tolerate a full dosage of niacin because of skin flushing. The percentage increase in HDL cholesterol, a more significant indicator for coronary heart disease, was dramatically in favor of niacin (33% vs. 7%).Equally

Comparison of niacin to lovastatin Lipoprotein

Group

Week 10

Week 18

Week 26

LDL cholesterol reduction

Lovastatin Niacin

26%

5%

28% 16%

32% 23%

HDL cholesterol increase

Lovastatin Niacin

6% 20%

8% 29%

33%

Lp(a) lipoprotein reduction

Lovastatin Niacin

0 14%

30%

~

~

~

~~~~

0

7% 0 35%

~

HDL, High-density lipoprotein. LDL, low-density lipoprotein

as impressive was the percentage decrease in Lp(a) for niacin. Although niacin produced a 35% reduction in Lp(a) levels, lovastatin did not produce any effect. Niacin's effect on Lp(a)in this study confirmed a previous study that showed niacin (4 g/day) reduced Lp(a) levels by 38%, and a subsequent study showed similar reductions in Lp(a) in patients with d i a b e t e ~ . ~ , ~ ~ Another comparative study evaluated the lipoprotein responses to niacin, gemfibrozil, and lovastatin in patients with normal total cholesterol levels but low levels of HDL cholesterol.46The first phase of the study compared lipoprotein responses with lovastatin and gemfibrozil in 61 middle-aged men with low levels of HDL. In the second phase, 37 patients agreed to take niacin; 27 patients finished this phase at a dose of 4.5 g/day. In the first phase, gemfibrozil therapy increased HDL cholesterol levels by 10% and lovastatin by 6%. In the second phase, niacin therapy was shown to raise HDL cholesterol by 30%. Another comparative study involved niacin versus atorvastatin (Lipit~r)!~ The average dosage was 3000 mg with niacin and 80 mg for Lipitor. The patients selected had abnormal particle size of LDL in that the molecules were small and dense-these LDL molecules are considerably more atherogenic than larger, less dense LDL. The patients selected also had low levels (<40%) of a specific fraction of HDL associated with a greater protective effect than HDL alone. Although Lipitor reduced total LDL cholesterol levels substantially more than niacin, niacin was more effective in increasing LDL particle size and raising HDL and HDL2 than Lipitor (Table 150-6). Because t a h g niacin at higher dosages (e.g., 23000 mg) can impair glucose tolerance, many physicians have avoided niacin therapy in diabetics, but newer studies with slightly lower dosages (1000 to 2000 mg) of niacin have not shown it to adversely affect blood sugar regulation.# For example, during a 16-week, double-blind, placebo-controlled trial, 148 type 2 diabetes patients were randomized to placebo or 1000 or 1500 mg/day of niacin; in the niacin-treated groups there was no significant loss in glycemic control, and the favorable effects on blood lipids were still apparent.49Other studies have

The effect of atorvastatin (Lipitor) and niacin on lipid profiles Atorvastatin Parameter Total LDL (mgldl) LDL peak diameter Lipoprotein(a) (mgldl) HDL (mg/dl)

HDL2 (%)

Triglycerides (mg/dl)

Atorvastatin + Niacin

Niacin

Before

After

Before

After

Before

After

110 251

56 256

45

44

42 30 186

43 42 100

111 253 37 38 29 1 94

89 263 23 54 43 108

123 250 54 38 32 235

55 263 35 54 37 73

HDL, High-density lipoprotein; LDL, low-density lipoprotein.

actually shown hemoglobin AIC to drop, indicating improvement in blood sugar control.50 The most common blood lipid abnormality in type 2 diabetic patients is elevated triglyceride levels; decreased HDL cholesterol levels; and a preponderance of smaller, denser LDL particles. Niacin has been shown to address all of these areas much more significantly than the statin or other lipid-lowering drugs.

The Side Eflects of Niacin The side effects of niacin are well known. The most common and bothersome side effect is the skin flushing that typically occurs 20 to 30 minutes after the niacin is taken. Other occasional side effects of niacin include gastric irritation, nausea, and liver damage. In an attempt to combat the acute reaction of skin flushing, several manufacturers began marketing "sustained-release," "timed-release," or "slow-release" niacin products. These formulations allow the niacin to be absorbed gradually, thereby reducing the flushing reaction. However, although these forms of niacin reduce skin flushing, earlier timed-release preparations were proven to be more toxic to the liver than regular niacin. In one analysis 52% of the patients taking the earlier sustained-release niacin preparations developed liver toxicity, while none of the patients taking immediate-release niacin developed liver The newer timed-released preparations on the market appear to have solved this problem, as relatively large clinical trials have shown them to be extremely well tolerated even when combined with statin drug^.^*-^ Another safe form of niacin is inositol hexaniacinate. This form of niacin has long been used in Europe to lower cholesterol levels and also to improve blood flow in intermittent claudication. It yields slightly better clinical results than standard niacin but is much better tolerated, in terms of both flushing and, more importantly, long-term side effect^.^^>^ Regardless of the form of niacin being used, periodic checking (minimum every 3 months) of cholesterol and

liver function tests are indicated. Niacin should not be used in patients with preexisting liver disease or elevation in liver enzymes. For these patient groups, policosanol, garlic, or pantethine are recommended. For best results niacin should be given at night, as most cholesterol synthesis occurs while sleeping. If pure crystalline niacin is being used, it should begin with a dose of 100 mg a day and be carefully increased over 4 to 6 weeks to the full therapeutic dose of 1.5 to 3 g daily. If a timed-released preparation or inositol hexaniacinate is being used, a 500-mg dosage should be given at night and increased to 1500 mg after 2 weeks. If after 1 month of therapy the dosage of 1500 mg per day fails to effectively lower LDL cholesterol, the dosage should be increased to 3000 mg.

Plant Sterols and Stanols Phytosterols and phytostanols are structurally similar to cholesterol and can act in the intestine to lower cholesterol absorption by displacing cholesterol from intestinal micelles. Because phytosterols and phytostanols are poorly absorbed themselves, blood cholesterol levels will likely drop due to increased excretion. These compounds are showing up in functional foods (e.g., margarine and other spreads, orange juice), as well as in dietary ~upplements.5~ Phytosterolsand phytostanols are effective in lowering LDL in some people. A metaanalysis of 41 trials showed that a daily intake of 2 g of stanols or sterols reduces LDL by Taking higher dosages added little additional benefit. Effects of phytosterols and phytostanols are additive with diet or drug interventions: Eating foods low in saturated fat and cholesterol and high in stanols or sterols can reduce LDL by 20%; adding sterols or stanols to statin medication is more effective than doubling the statin dose alone. Individuals most likely to respond have been identified as having high cholesterol absorption and low cholesterolbiosynthesis. Phytosterols and phytostanols have also shown antiplatelet and antioxidant effects as

Phytosterol or phytostanol intake at lugher dosages may reduce carotenoid absorption. Human subjects consuming 6.6 g/day phytosterols showed cholesteroladjusted plasma reduction of alpha- and betatarotene levels (-190/, to -23%), lutein (-14%), and lycopene (-1lY0). However, this effect was partially reversed by increased fruit and vegetable intake.@

heart disease and strokes. Garlic preparations have also demonstrated blood pressure-lowering effects, inhibition of platelet aggregation, reduction of plasma viscosity, promotion of fibrinolysis, prevention of LDL oxidation, and an ability to exert positive effects on endothelial function, vascular reactivity, and peripheral blood flow (see Chapter 65 for more information).

Pantethine

Policosanol

Pantethine is the stable form of pantetheine, the active form of vitamin B5or pantothenic acid. Pantothenic acid is the most important component of coenzyme A (CoA). This enzyme is involved in the transport of fats to and from cells, as well as to the energy-producing compartments within the cell. Without coenzyme A, the cells' fats could not be metabolized to energy. Pantethine has significant lipid-lowering activity while pantothenic acid has little (if any) effect in lowering cholesterol and triglyceride levels due to pantethine ability to be converted to cysteamine. Pantethine administration (standard dose 900 mg/day) has been shown to sigruficantly reduce serum triglyceride (-32%), total cholesterol (-19"/), and LDL cholesterol (-21%) levels while increasing HDL cholesterol (+23%) level^.^^,^ It appears to be especially useful in lowering blood lipids in d i a b e t i ~ s . ~ " ~ The lipid-lowering effects of pantethine are most impressive when its toxicity (virtually none) is compared with conventional lipid-lowering drugs. Its mechanism of action is due to inhibited cholesterol synthesis and acceleration of the use of fat as an energy source.

Policosanol refers to a mixture of fatty substances isolated and purified from the wax of sugar cane (Saccharum oficinarum, L.). Policosanol has exceptional clinical documentation demonstrating efficacy, safety, and tolerability in lowering cholesterol and triglyceride levels. The clinical studies have included comparative studies versus conventional cholesterol-lowering drugs (e.g., lovastatin, pravastatin, simvastatin, gemfibrozil, probucol). In these studies policosanol in dosages ranging from 5 to 20 mg/day have demonstrated significant improvements in cholesterol and triglyceride levels with results typically noticeable within the first 6 to 8 weeks of use. At a daily dosage of 10 mg of policosanol at night, LDL cholesterol levels typically drop by 20% to 25% within the first 6 months of therapy. At a dosage of 20 mg, LDL levels typically drop by 25% to 30%. HDL cholesterol levels typically increase by 15% to 25% after only 2 months of use. The combined LDL reduction and HDL increase can produce dramatic improvements in the LDL-to-HDL ratio.73 In addition to its effects on cholesterol levels, policosanol also exerts additional positive effects in the battle against atherosclerosis. It prevents excessive platelet aggregation without affecting coagulation, prevents smooth muscle cell proliferation into the intima of the artery, and exerts good antioxidant effects in preventing against LDL oxidation (for more information see Chapter 116). The recommended dosage of policosanol is 5 to 20 mg at the evening meal. As with other cholesterol-lowering therapies, dosage can be adjusted as needed after checking blood cholesterol levels every 8 weeks or so.

Garlic (Allium sativum) and Onion (Allium cepa) Garlic appears to be an important protective factor against heart disease and stroke via its ability to affect the process of atherosclerosis at so many steps. A major area of focus on garlic's ability to offer significant protection against heart disease and strokes has been the evaluation of its ability to lower blood cholesterol levels, even in apparently healthy individuals. According to the results from numerous double-blind, placebo-controlled studies in patients with initial cholesterol levels greater than 200, supplementation with commercial preparations providing a daily dose of at least 10 mg alliin or a total allicin potential of 4000 pg can lower total serum cholesterol levels by about 10% to 12%; LDL cholesterol decreases by about 15%; HDL cholesterol levels usually increase by about 10%; and triglyceride levels typically drop by 15%. However, most trials not using products that can deliver this dosage of allicin fail to produce a lipid-lowering e f f e ~ t . ~ - ~ ~ Although the effects of supplemental garlic preparations on cholesterol levels are modest, the combination of lowering LDL and raising HDL can greatly improve the HDL-to-LDL ratio, a sigruficant goal in the prevention of

Comparing Natural Cholesterol-Lowering Agents Numerous natural compound products can effectively improve cholesterol and triglyceride levels. Of the several described earlier, niacin produces the best overall effect. However, the others do have a place in the clinical management of hyperlipidemia and atherosclerosis prevention (Table 150-7). Typically, along with dietary and lifestyle recommendations, niacin (1500 mg to 3000 mg at night) reduces total cholesterol by 50 to 75 mg/dl in patients with initial total cholesterol levels above 250 mg/dl within the first 2 months. In patients with initial cholesterol levels above 300 mg/dl, it may take 4 to 6 months before

Atherosclerosis ts on blood lipids of several natural compounds Niacin

Garlic

Total cholesterol (% decrease)

18

10

LDL cholesterol (Yo decrease)

23 32 26

31 13

HDL cholesterol (% increase) Triglycerides (Yodecrease)

Policosanol

Pantethine

~~

~

15

24 25 15 5

19 21 23 32

HDL, High-densitylipoprotein: LDL, low-density lipoprotein.

cholesterol levels begin to reach recommended levels. Once cholesterol levels are reduced below 200 mg/dl, the dosage of niacin is reduced to 500 mg three times daily for 2 months. If the cholesterol levels creep up above 200 mg/dl, then the dosage of niacin is raised back up to 1000 mg three times daily. If the cholesterol level remains below 200 mg/dl, then the niacin is withdrawn completely and the cholesterol levels are rechecked in 2 months, with niacin therapy reinstituted if levels have exceeded 200 mg/dl. Policosanol can be added to this protocol if after 4 months the total cholesterol remains higher than 250 mg/dl. Policosanol is also suitable for the patient who simply cannot tolerate niacin. Pantethine is recommended primarily to patients who have hypertriglyceridemia,especially patients with diabetes. As stated earlier, pantethine has demonstrated excellent effects in diabetics. It not only improves cholesterol and triglyceride levels, it also normalizes platelet lipid composition and function and blood viscosity. With regard to elevations in Lp(a), both niacin and vitamin C have shown an ability to reduce Lp(a) levels dramatically (35% and 27% reductions, respectively). In addition, it is important to rule out low thyroid function (hypothyroidism) in all cases of elevated blood lipids, especially Lp(a). It is well established that patients with overt hypothyroidism are prone to CAD because of increased LDL cholesterol and decreased HDL cholesterol. What is not so well established is the significance of ”subclinical” hypothyroidism in terms of risk for cardiovascular mortality. A recent study indicates that the risk may be greater than previously suspected. The study demonstrated that patients with subclinical hypothyroidism (defined in this study as normal T3 and FTI with a raised TSH) were shown to have not only significantly elevated levels of LDL cholesterol but also elevated L ~ ( a ) . For 7~ more information, see Chapter 179.

THERAPEUTIC CONSIDERATIONSANTIOXIDANT STATUS Dietary antioxidant nutrients like lycopene, lutein, selenium, vitamin E, and vitamin C have been shown in

epidemiologic studies to offer significant protection

against the development of C W . Fats and cholesterol are particularly susceptible to free radical damage. When damaged, fats and cholesterol form lipid peroxides and oxidized cholesterol, which can then damage the artery walls and accelerate the progression of atherosclerosis. Antioxidants block the formation of these damaging compounds. Although diets rich in antioxidant nutrients have consistently shown tremendous protection against CVD, clinical trials using antioxidant vitamins and minerals have produced inconsistent r e s ~ l t s .This ~ ~ ,failure ~ ~ may be due to several factors, most importantly the fact that the human antioxidant system represents a complex scenario of interacting components. It is unlikely that any single antioxidant would be proven to be effective, especially in the absence of a supporting cast. Most antioxidants require some sort of ”partner” antioxidant that allows them to work more efficiently. The most salient example of this point is the partnership between the two primary antioxidants in the human body-vitamin C and vitamin E. Vitamin C is an “aqueous phase” antioxidant, while vitamin E is a ”lipid phase” antioxidant. Although some studies have shown that supplementation with these nutrients reduces atherosclerotic lesions, more protection is likely required to ensure optimal effect.n In addition to vitamin C, vitamin E also requires selenium and CoQloto work efficiently (discussed in more detail later). Further adding to the shortcoming of many of the studies on antioxidant nutrients is the lack of consideration on the importance of phytochemicals and plant-derived antioxidants that, in addition to exerting benefit on their own, are well known to potentiate the activities of vitamin and mineral antioxidants. Phytochemicals like carotenes (especially lycopene and lutein) and flavonoids are especially important in fighting against free radical damage. Importantly, most scientific reviews on antioxidant supplements devote significant attention to the studies using beta-carotene because they have involved more than 70,000 subjects but fail to differentiate the facts that synthetic beta-carotene was used and that beta-carotene is of little importance in protecting against LDL oxidation. (Unlike lycopene and lutein, beta-carotene does not get incorporated into LDL effectively, though it may help protect the endothelium.)

Lutein may turn out to be the most significant carotene in the battle against atherosclerosis. On the basis of analysis of the different subtypes of LDL, lycopene, beta-carotene, and cryptoxanthin were mainly located in the larger, less dense LDL particles, whereas lutein and zeaxanthin were found preferentially in the smaller, denser LDL particles.78 Because the smaller, denser LDL subtype is most easily oxidized, lutein and zeaxanthin are particularly important in protecting against damage to LDL cholesterol. The support of nonantioxidant vitamins and minerals may also be important in assisting the effectiveness of antioxidants. Taking a multivitamin and mineral supplement seems appropriate. In one double-blind study, CRP levels were significantly lower in the multivitamin group than in the placebo group, with the reduction in CRP levels most evident in patients who had elevated levels (21 mg/L) at baseline.79Researchers found that serum vitamin B6 and vitamin C levels were inversely associated with CRP level.

Vitamin E Although clinical studies have shown inconsistent effects, it is clear that vitamin E does play a role in the protection against oxidation of LDL cholesterol because of its ability to be easily incorporated into the LDL molecule (Table 150-8). Furthermore, there is a clear-cut dosage effect (i.e., the higher the dosage of vitamin E, the greater the degree of protection against oxidative damage to LDL cholesterol). Although dosages as low as 25 mg were originally shown to offer some protection, it appears that doses of greater than 400 IU are required to produce clinically sigruficant effects.m82 Improvements have also been noted in insulin sensitivity and plasma lipids in non-insulin-dependent diabetics. Several large population studies have demonstrated that vitamin E levels may be more predictive of developing

I Dose (rnddav)

0 25 50 100 200 400

800

Effect of increasing doses of vitamin E on oxidation parameters Lag time* 94 99

Propagation ratel

7.8 8

100 106

7.9

111

7.5

116 120

6.8 6.5

7.7

‘The time before oxidation occurs after the addition of an oxidizing agent. The higher the number, the greater the beneficial effect. T h e rate at which lipid peroxidation progresses. The lower the number, the greater the beneficial effect.

a heart attack or stroke than total cholesterol Although the consumption of red wine has been suggested as the reason behind the ”French paradox,” described earlier, higher vitamin E levels provide at least as good an explanation.81,82 Vitamin E may offer additional benefit in protecting against heart disease and strokes by its ability to do the following: Reduce LDL cholesterol peroxidation and increase plasma LDL breakdown Inhibit excessive platelet aggregation Increase HDL cholesterol levels Increase fibrinolytic activity Reduce CRP levels Improve endothelial cell function Improve insulin sensitivity Two early large-scale studies with relatively low dosages of vitamin E supplements demonstrated a significant reduction in the risk of dying of a heart attack or a stroke. The Nurses Health Study of 87,245 nurses concluded that those who took 100 IU of vitamin E daily for more than 2 years had a 41%lower risk of heart disease compared with nonusers of vitamin E supplement^.^^ The Physicians Health Study of 39,910 male health care professionals found similar results: a 37% lower risk of heart disease with the intake of more than 30 IU of supplemental vitamin E daily.&lSubsequent studies have been e q u i ~ o c a b l e . ~ ~ Large-scale studies examining the impact of vitamin E supplementation in patients with existing CAD have also shown somewhat conflicting results.76,nSome of the disappointing results may have been the choice of synthetic vitamin E (D,L-alpha tocopherol) in one of the large studies versus the more active natural form (D-alpha tocopherol). There is also the problem with interference by statin drugs of vitamin E and CoQlo metabolism, thereby increasing the needs for both compounds (Table 150-9). Vitamin E and CoQlowork synergistically,and each is required for the regeneration of the other. For example, CoQlois present in the blood in both oxidized (inactive) and reduced (active) form. During times of increased oxidative stress or low vitamin E levels, more CoQlo will be converted to its oxidized (inactive form). Thus by providing higher levels of vitamin E, the biologic activity and function of CoQlois enhanced and vice versa. Several studies in humans and animals have shown that the combination of vitamin E and CoQlo work better than either alone. For example, in a study in baboons, while supplementation with vitamin E alone reduced CRP levels, cosupplementation with CoQ, however, significantly enhanced this effect of vitamin E. Similar results have been seen in other animal studies on other

Atherosclerosis

Intervention trials with vitamin E for secondary prevention Studv HOPE (2000) SPACE (2000)

GlSSl (1999) CHAOS (1996)

No. of subiects 9541 196 11,324 9541

Dosaae 400 IU (d-alpha)

Duration

Outcome

4.5 yr

No effect

800 IU (d-alpha)

1.4 yr

-70%

300 IU (synthetic)

3.5 yr

-35% (vs. placebo)

400-800 IU (d-alpha)

1.4 yr

-47%

CHAOS, Cambridge Heart Antioxidant Study; HOPE, Heart Outcomes Protection Evaluation Trial; GISSI, Gruppo ltaliano per lo Studio della Soprawivenza nell’lnfarto Miocardico; SPACE, Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease.

aspects associated with atherosclerosis including LDL oxidation and lipid peroxide content within the aorta.w87 In addition to CoQlo, vitamin E also requires adequate selenium status for optimal antioxidant effects. Selenium functions primarily as a component of the antioxidant enzyme glutathione peroxidase. This enzyme works closely with vitamin E to prevent free radical damage to cell membranes. Studies looking only at vitamin E’s ability to reduce cancer and heart disease are often faulty because they fail to factor in the critical partnership between selenium and vitamin E, not to mention the interrelationship between vitamin E and CoQlo. Several studies have clearly demonstrated that low selenium status is signhcantly associated with CAD.88”9Failure to cosupplement with selenium, as well as vitamin C and CoQlo, may be a major reason for the inconsistent results in intervention trials with vitamin E supplementation alone.

Vitamin C Vitamin C works as an antioxidant in aqueous (water) environments in the body-both outside and inside human cells. It is the first line of antioxidant protection in the body. Its primary antioxidant partner is vitamin E, as this antioxidant is fat-soluble. Along with CoQlo, vitamin C is also responsible for regenerating oxidized vitamin E in the body, thus potentiating the antioxidant benefits of vitamin E.90Vitamin C also works along with antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase. Vitamin C has been shown to be extremely effective in preventing LDL cholesterol from being oxidized, even in smokers.91 Vitamin C and E supplementation, 500 mg and 272 IU daily, respectively, for six years has shown to reduce the progression of carotid atherosclerosisby 53%in men and 14%in women?* A high dietary vitamin C intake has been shown to sigruficantly reduce the risk of death from heart attacks and strokes, as well as all other causes including cancer, in numerous population ~tudies.9~ One of the most detailed studies providing insight analyzed the vitamin C intake of 11,348 adults over 5 years and divided them into

three groups: (1) less than 50 mg daily; (2) greater than 50 mg daily dietary intake with no vitamin C supplementation; and (3) greater than 50 mg dietary intake plus vitamin C supplementation (estimated to be 2 300 mg).93 Analysis showed that the standardized mortality ratio (SMR), a comparison with the average death rate, was up to 48%lower in the high vitamin C intake group than in the low intake group for cardiovascular disease and overall mortality. These differences correspond to an increase in longevity of 5 to 7 years for men and 1 to 3 years for women. Dozens of observational and clinical studies have shown that vitamin C levels correspond to total cholesterol and HDL cholester01.9~~~ In one of the best designed studies, it was shown that the higher the vitamin C content of the blood, the lower the total cholesterol and triglycerides and the higher the HDL The benefits on HDL were particularly impressive. For each 0.5 mg/dl increase in vitamin C content of the blood, there was an increase in HDL cholesterol of 14.9 mg/dl in women and 2.1 mg/dl in men. This study is significant in that it demonstrated the association of vitamin C and HDL levels persists even in well-nourished individuals with normal levels of vitamin C in their blood who supplement their diets with additional vitamin C. Recent studies have focused on the effects of vitamin C therapy in reducing CRP and Lp(a) and its positive effects on the fibrinolytic system. In summary, vitamin C lowers the risk for cardiovascular disease by doing the f o l l ~ w i n g ~ ~ - ~ ~ : Acting as an antioxidant Strengthening the collagen structures of the arteries Lowering total cholesterol, Lp(a), and blood pressure Raising HDL cholesterol levels Inhibiting platelet aggregation Promoting fibrinolysis Reducing markers of inflammation

Grape Seed and Pine Bark Extracts One of the most beneficial groups of plant flavonoids are the proanthocyanidins (also referred to as procyanidins).

Specific Health Problems

The most potent proanthocyanidins are those bound to other proanthocyanidins. Collectively, mixtures of proanthocyanidin dimers, trimers, tetramers, and larger molecules are referred to as procyarzidolic oligorners (PCOs). Although PCOs exist in many plants, as well as in red wine, commercially available sources of PCO include extracts from grape seeds and the bark of the maritime (Landes)pine. The primary uses of PCO extracts are in the treatment of venous and capillary disorders including venous insufficiency, varicose veins, capillary fragility, and disorders of the retina (e.g., diabetic retinopathy, macular degeneration).Good clinical studies have shown positive results in the treatment of these conditions.w Because PCO has a greater antioxidant effect compared with vitamins C and E, it is only natural to assume it could offer greater protective effects than these antioxidant vitamins. In addition to preventing damage to cholesterol and the lining of the artery, PCO extracts have been shown in animal studies to lower blood cholesterol levels and shrink the size of cholesterol deposits in the artery.lOOJO' Additional mechanisms of PCO useful in preventing atherosclerosis include inhibition of platelet aggregation and inhibition of vascular constrict i ~ n . * Presumably ~ ~ J ~ ~ PCO extracts may exert similar benefits in humans.

THERAPEUTIC CONSIDERATIONSMISCELLANEOUS RISK FACTORS Platelet Aggregation Excessive platelet aggregation is another independent risk factor for heart disease and strokes. Once platelets aggregate, they release potent compounds that dramatically promote the formation of the atheroscleroticplaque or they can form a clot that can lodge in small arteries and produce a heart attack or stroke. The adhesiveness of platelets is determined largely by the type of fats in the diet and the level of antioxidants. While saturated fats and cholesterol increase platelet aggregation, omega-3 oils (both short-chain and long-chain) and monounsaturated fats have the opposite effect.lW,lo5 In addition to the monounsaturated and omega-3 fatty acids, antioxidant nutrients, and flavonoids, vitamin B6 also inhibits platelet aggregation and lowers blood pressure and homocysteine level^.'^,'^^ In one study, the effect of vitamin Bh (pyridoxine HC1) supplementation on platelet aggregation, plasma lipids, and senun zinc levels was determined in 24 healthy male volunteers (19 to 24 years old) given either pyridoxine at a dosage of 5 mg/kg body weight or a placebo for 4 weeks.'% Results demonstrated that pyridoxine inhibited platelet aggregation by 41% to 48%, while there was no change in the control group. Pyridoxine prolonged both bleeding and coagulation time but not over the

physiologic limits. It had no effect on platelet count. Pyridoxine was also shown to lower total plasma lipids and cholesterol levels considerably from pretreatment levels. Total plasma lipids were reduced from 593 to 519 mg/dl, and total cholesterol was reduced from 156 to 116 mg/dl. HDL cholesterol increased from 37.9 to 48.6 mg/dl. Serum zinc levels increased from 96 to 138 pg/dl. In another study, a significant, inverse, graded relation was observed between serum level of pyridoxal5-phosphate (P5P) and both CRP and fibrinogen.lo8The odds ratio for CAD risk related to low P5P concentrations after adjustments for the major classic CAD risk factors including CRP and fibrinogen was 1.89. In addition, the CAD risk as a result of low P5P was additive when considered in combination with elevated CRP concentrations or with an increased ratio of LDL to HDL. These results provide clear evidence concerning the possible role of vitamin B6 supplementation in reducing the risk of atherosclerotic mortality. Garlic preparations standardized for alliin content, as well as garlic oil, have also demonstrated inhibition of platelet aggregation. In one study, 120 patients with increased platelet aggregation were given either 900 mg/day of a dried garlic preparation containing 1.3% alliin or a placebo for 4 weeks.'0g In the garlic group, spontaneous platelet aggregation disappeared, the microcirculation of the skin increased by 47.6%, plasma viscosity decreased by 3.2'10, diastolic blood pressure dropped from an average of 74 to 67 mmHg, and fasting blood glucose concentration dropped from an average of 89.4 to 79 mg/dl.

Fibrinogen Elevated fibrinogen levels are another clear risk factor for cardiovascular disease. Early clinical studies stimulated detailed epidemiologic investigations into the possible link between fibrinogen and cardiovascular disease."O The first such study was the Northwick Park Heart Study in the United Kingdom. This large study involved 1510 men aged 40 to 64 years who were randomly recruited and tested for a range of clotting factors including fibrinogen. At 4 years' follow-up there was a stronger association between cardiovascular deaths and fibrinogen levels than that for cholesterol. This association has now been confirmed in at least five other prospective epidemiologic studies. Natural therapies designed to promote fibrinolysis include exercise, omega-3 oils, niacin, and garlic. In addition, the Mediterranean diet alone significantly reduces fibrinogen and other markers of inflammation."' Adherence to the Mediterranean diet was shown to be associated with a 20% lower CRP level, 17% lower interleukin-6 level, 15% lower homocysteine level, and 6% lower fibrinogen level.

Atherosclerosis

Homocysteine Homocysteine is an intermediate in the conversion of the amino acid methionine to cysteine. If a person is functionally deficient in folic acid, vitamin B6, or vitamin B12, there will be an increase in homocysteine. Elevated homocysteine levels are an independent risk factor for developing a heart attack, stroke, or peripheral vascular disease. Elevations in homocysteine are found in approximately 20% to 40% of patients with heart disease and are significantly associated with A number of interrelated atherogenic mechanisms are thought to be involved with hyperhomocyteinemia. These include advanced thickening and smooth muscle cell proliferation of endothelial vessel wall intima, enhanced lipid deposition in the vessel wall, forced detachment of endothelial cells, activation of leukocytes and thrombocytes, increased LDL oxidation, initiation of platelet thromboxane synthesis, enhanced oxidative stress induced by peroxide formation during homocysteine oxidation, and prothrombotic coagulation interference. Homocysteine is thought to promote atherosclerosis by directly damaging the artery and reducing the integrity of the vessel wall and by interfering with the formation of proper collagen. Although folic acid supplementation (400 pg daily) alone can reduce homocysteine levels in many subjects, given the importance of vitamin B12 and B6 to proper homocysteine metabolism, all three should be used together. In one study the suboptimal levels of these nutrients in men with elevated homocysteine levels were 56.8%, 59.1%, and 25% for folic acid, vitamin B12, and Bbr respectively, indicating that folic acid supplementation alone would not lower homocysteine levels in many cases.115In other words, folic acid supplementation will only lower homocysteine levels if there are adequate levels of vitamin B12 and Be This fact could reduce the effect of folic acid fortification of food. In 1998 the FDA mandated the fortification of food products with folic acid. Although homocysteine levels have decreased modestly after the fortification of food with folic acid, the effect on mortality has been minor at best.116This indicates the importance of more aggressive supplementary measures to reduce homocysteineassociated cardiovascular risk.

were examined in 86 healthy subjects.118Habitual anger expression was measured on four scales: aggression, controlled affect, gullt, and social inhibition. A positive correlation between serum cholesterol level and aggression was found. The higher the aggression score, the higher the cholesterol level. A negative correlation was found between the LDL-to-HDL ratio and controlled affect score-the greater the ability to control anger, the lower the LDL-to-HDL ratio. In other words, those who learn to control anger experience a sigruficant reduction in the risk for heart disease, while an unfavorable lipid profile is linked to a predominantly aggressive (hostile) anger coping style. Anger expression also plays a role in CRP levels. In one study greater anger and severity of depressive symptoms, separately and in combination with hostility, were sigruficantly associated with elevations in CRP in apparently healthy men and women.120Other mechanisms explaining the link between the emotions, personality, and CVD include increased cortisol secretion, endothelial dysfunction, hypertension, and increased platelet aggregation and fibrinogen levels.119These associations are independent of potential confounding factors. Ten tips that can help patients improve their coping strategies follow:

1. Do not starve your emotional life. Foster meaningful relationships. Provide time to give and receive love in your life. 2. Learn to be a good listener. Allow the people in your life to really share their feelings and thoughts uninterrupted. Empathize with them; put yourself in their shoes. 3. Do not try to talk over somebody. If you find yourself being interrupted, relax; do not try to outtalk the other person. If you are courteous and allow someone else to speak, eventually (unless he or she is extremely rude) he or she will respond likewise. If not, explain that he or she is interrupting the communication process. You can only do this if you have been a good listener. 4.Avoid aggressive or passive behavior. Be assertive, but express your thoughts and feelings in a kind way to help improve relationships at work and at home. "Type A" Personality 5. Avoid excessive stress in your life as best you can by "Type A behavior is characterized by an extreme sense avoiding excessive work hours, poor nutrition, and of time urgency, competitiveness, impatience, and inadequate rest. Get as much sleep as you can. aggressiveness. This behavior carries with it a twofold 6. Avoid stimulants like caffeine and nicotine. Stimulants increase in CHD compared with non-type A b e h a ~ i o r . ~ ~ ~ - "promote ~ the fight-or-flight response and tend to make Particularly damaging to the cardiovascular system is people more irritable in the process. the regular expression of anger. In one study, the 7. Take time to build long-term health and success by relationship between habitual anger coping styles, espeperforming stress-reduction techniques and deep cially anger expression, and serum lipid concentrations breathing exercises.

Specific Health Problems 8. Accept gracefully those things over which you have no control. Save your energy for those things that you can do something about. 9. Accept yourself. Remember that you are human and will make mistakes from which you can learn along the way. 10. Be more patient and tolerant of other people. Follow the Golden Rule.

Other Nutritional Factors

Magnesium and Potassium Magnesium and potassium are absolutely essential to the proper functioning of the entire cardiovascular system. Their critical roles in preventing heart disease and strokes are now widely accepted. In addition, there is a substantial body of knowledge demonstrating that magnesium or potassium supplementation, or both, are effective in treating a wide range of cardiovascular diseases including angina, arrhythmias, congestive heart failure, and high blood pressure. In many of these applications magnesium or potassium supplementation, or both, have been used for more than 50 years. Because the role of potassium on the cardiovascular system is described in detail in Chapter 176, the focus here is on magnesium. Most Americans do not consume enough of this important mineral. The average intake of magnesium by healthy adults in the United States ranges from 143 to 266 mg/day. This level is well below even the recommended daily allowance (RDA) of 350 mg for men and 300 mg for women. Food choices are the main reason. Because magnesium occurs abundantly in whole foods, most nutritionists and dietitians assume that most Americans get enough magnesium in the diet. But most Americans are not eating whole, natural foods. They are consuming large quantities of processed foods. Because food processing refines a large portion of magnesium, most Americans are not getting the RDA for magnesium. The best dietary sources of magnesium are tofu, legumes, seeds, nuts, whole grains, and green leafy vegetables. Fish, meat, milk, and most commonly eaten fruits are quite low in magnesium. Most Americans consume a low magnesium diet because their diet is high in low-magnesium foods such as processed foods, meat, and dairy products. People dying of heart attacks have been shown to have lower heart magnesium levels than people of the same age dying of other causes.121Low magnesium levels contribute to atherosclerosis and CVD via many mechanisms including promoting endothelial dysfunction by generating a proinflammatory, prothrombotic, proatherogenic environment.1u Intravenous magnesium therapy has now emerged as a valued treatment measure in acute MI.123-125 The major obstacle to it becoming the preferred method for

saving a person’s life may be a financial interest. Magnesium is cheap compared with new, high-tech, high-priced, genetically engineered drugs currently being promoted by drug companies. The treatment of acute MIS is big business in the United States. Each year more than 1.5 million US. citizens experience acute MIS. Although many other parts of the world are now using magnesium therapy for acute MI because of its effectiveness, low cost, safety, and ease of administration, in the United States it plays second fiddle to the high-tech drugs. During the past decade, eight well-designed studies involving more than 4000 patients have demonstrated that intravenous magnesium supplementation during the first hour of admission to a hospital for an acute MI produces a favorable effect in reducing immediate and long-term complications, as well as death rates. The beneficial effects of magnesium in an acute MI relate to its ability to do the following: Improve energy production within the heart Dilate the coronary arteries, resulting in improved delivery of oxygen to the heart Reduce peripheral vascular resistance, resulting in reduced demand on the heart Inhibit platelets from aggregating and forming blood clots Reduce the size of the infarct (blockage) Improve heart rate and arrhythmias

THERAPEUTIC CONSIDERATIONSPREVENTING A RECURRENT HEART AlTACK People who have experienced a heart attack or stroke and live through it are extremely likely to experience another. The primary prevention of subsequent cardiovascular events is to control the major cardiac risk factors (e.g., hyperlipidemia, hypertension, cigarette smoking, diabetes, physical inactivity). The most popular ”secondary” recommendation to reduce the risk of a subsequent heart attack being given by most physicians is low-dose aspirin (e.g., 325 mg/day). However, there may be effective alternatives, especially in those who cannot tolerate aspirin therapy.

Aspirin Aspirin has been shown to decrease the risk of CVD events in both primary and secondary trials. The first primary prevention study was the Physicians’ Health Study, a randomized, double-blind, placebo-controlled trial of 22,071 apparently healthy men. The study was terminated early, due principally to a statistically extreme 44% reduction in the risk of a first MI with the use of 325 mg of aspirin every other day. Since this study, three additional randomized trials including men and

Atherosclerosis women have shown aspirin to be effective in the primary prevention of MI: the Thrombosis Prevention Trial, the Hypertension Optimal Treatment Study, and the Primary Prevention Project. Among the 55,580 subjects, aspirin use was associated with a statistically significant 32% reduction in the risk of a first MI and a significant 15%reduction in the risk of all other important vascular events but had no significant effects on nonfatal stroke or vascular death. Evaluation of the data from the Physicians Health Study indicated that those with the highest CRP had the greatest decrease in risk, 55.7% versus 13.9% in those with the lowest CRP. It seems reasonable to reserve the use of aspirin as a primary prevention strategy for individuals with high CRP values.126 Regarding secondary prevention of MI, there have been seven prospective, randomized, placebo-controlled trials involving almost 15,000 survivors of heart attacks that have examined the use of aspirin to reduce the incidence of recurrent heart attack and death. These trials have used several doses of aspirin ranging from 325 to 1500 mg/day and enrolled patients at various intervals after infarction ranging from 4 weeks to 5 years. None of the studies demonstrated a statistically significant reduction in mortality with aspirin use. However, when all the results from these studies were pooled, aspirin was shown to reduce mortality rate from all causes and cardiovascular deaths. The mortality rate for all causes in the aspirin group was 5.8% compared with 8.3% in the placebo group, indicating a reduction in mortality by 30% with a ~ p i r i n . ~ ~ ~ , ' ~ ~ Although it is becoming popular to recommend dosages of aspirin lower than 325 mg (e.g., 50 to 150 mg daily), these lower dosages have not been tested in properly designed trials. Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) are associated with a sigruficant risk of peptic ulcer. However, most studies documenting the relative frequency of peptic ulcers as a consequence of aspirin and NSAIDs have focused on their use in the treatment of arthritis and headaches. The risk of gastrointestinal bleeding due to peptic ulcers has been evaluated for aspirin at daily dosages of 300,150, and 75 mg. Essentially, there is an increased risk of gastrointestinal bleeding due to peptic ulcers at all dosage levels. However, the dosage of 75 mg/day was associated with a 40% reduction in ulcers compared with 300 mg/day and 30% compared with 150 m g / d a ~ . ' ~ ~ Because it is unknown whether 75 mg/day of aspirin is helpful in preventing a second heart attack, most physicians recommend at least 300 mg. To prevent stroke, the dosage necessary appears to be 900 mg. These dosage recommendations carry with them a significant risk for developing a peptic ulcer but may be appropriate for high-risk patients unwilling to adopt the natural approach.

Natural Alternatives to Aspirin The best approach to preventing subsequent heart attacks may not be low-dose aspirin, especially in aspirin-sensitivepatients. The first alternative to aspirin to examine is one too often overlooked by many physicians-diet. Several studies have shown that dietary modifications are not only more effective in preventing heart attack recurrence than aspirin but can also reverse the blockage of clogged arteries. In addition to the studies with the Mediterranean diet, three famous studies deserve special mention. The first was the Lifestyle Heart Trial conducted by Dean 0 r n i ~ h . In l ~ this ~ study subjects with heart disease were divided into a control group and an experimental group. The control group received regular medical care, while the experimental group was asked to eat a low-fat vegetarian diet for at least 1 year. The diet included fruits, vegetables, grains, legumes, and soybean products. Subjects were allowed to consume as many calories as they wished. No animal products were allowed except egg whites and 1 cup/day of nonfat milk or yogurt. The diet contained approximately 10% fat; 15% to 20% protein; and 70% to 75% carbohydrates, which was predominantly complex carbohydrates from whole grains, legumes, and vegetables. The experimental group was also asked to perform stress reduction techniques such as breathing exercises, stretching exercises, meditation, imagery, and other relaxation techniques for an hour each day and to exercise at least 3 hours/week. At the end of the year, the subjects in the experimental group showed sigruficant overall regression of atherosclerosis of the coronary blood vessels. In contrast, subjects in the control group who were being treated with regular medical care and following the standard American Heart Association (AHA)diet actually showed progression of their disease. Ornish stated: "This finding suggests that conventional recommendations for patients with CHD (such as a 30% fat diet) are not sufficient to bring about regression in many patients." Two other famous studies showing that diet can prevent further heart attacks in patients suffering a first heart attack highlighted the importance of omega-3 fatty acids and again show the ineffectiveness of the AHA'S dietary recommendations. As stated previously, numerous population studies have demonstrated that people who consume a diet rich in omega-3 oils from either fish or vegetable sources have a sigruficantly reduced risk of developing heart disease. Two famous intervention trials upheld this protective effect. In the Dietary and Reinfarction Trial (DART), it was only when the intake of omega-3 fatty acids (from fish) was increased that future heart attacks were reduced.131In another study, the Lyon Diet Heart Study, increasing the intake of omega-3 fatty acids from plant sources (alpha-linolenic acid) was

Specific Health Problems found to offer the same degree of protection as increased fish intake.132

Preventing a Subsequent Stroke To prevent a subsequent stroke and promote recovery from a stroke, Ginkgo biloba extract should be added to the program described earlier for preventing a subsequent heart attack. The extract of G. bilobu leaves standardized to contain 24% ginkgo flavonglycosides and 6% terpenoids has been the subject of more than 300 published scientific papers and more than 40 doubleblind studies in the treatment of decreased blood supply to the brain (cerebral vascular insufficiency). It is currently the third most widely prescribed drug in Germany. G. bilobu extract has demonstrated remarkable effects in improving many symptoms associated with aging including short-term memory loss, depression, dizziness, ringing in the ears, and headache. G. biloba extract has also been shown to enhance stroke recovery (see Chapter 96 for more information).

Other Considerations Angiography, Coronary Artery Bypass Surgery, or Angioplasty A significant challenge for the clinician is determining when a patient should be referred for angiography, coronary artery bypass surgery, or angioplasty. As is fully discussed in Chapter 147, these procedures are used far more frequently than is justified by objective evaluation of their appropriateness and efficacy. Chapter 147 also gives advice for patient care when angiogram, coronary artery bypass surgery, or angioplasty are unavoidable.

The crease is seen more commonly with advancing age, until the age of 80, when the incidence drops dramatically. However, the association with heart disease is independent of age. Although the presence of an ear lobe crease does not prove heart disease, it strongly suggests it, and examination of the ear lobe is an easy screening procedure. The correlation does not hold true with Orientals, native Americans, and children with Beckwith's syndrome.134

THERAPEUTIC APPROACH There is little doubt that in most cases atherosclerosis is a disease directly related to diet and lifestyle. Treatment and prevention include reducing all known risk factors. For many patients this goal requires a major change in diet and lifestyle. Since so many factors are known to be involved in atherosclerosis, any treatment plan must be individualized to assure optimal results. What follows is a general approach that needs to be tailored according to the clinical picture and patient's willingness.

Dietary Recommendations Follow the dietary guidelines given in Chapter 44 (a modified version of the Mediterranean diet). Table 150-10 provides additional guidance in dietary selections, and Box 150-5 lists foods to avoid because of their trans-fatty acid content. Specifically,it is important to do the following: Eat less saturated fat and cholesterol by reducing or eliminating the amounts of animal products in the diet.

Intravenous EDTA Chelation Therapy The clinician is also asked for recommendations concerning the efficacy of the far less invasive intravenous ethylenediamine tetraacetic acid chelation therapy. This useful, yet controversial, procedure is also discussed fully in Chapter 147.

Decrease consumption of the following:

Substitute with the following:

Red meats

Fish and white meat of poultry

Ear Lobe Crease

Hamburgers and hot dogs

Soy-based alternatives

The presence of a diagonal ear lobe crease has been recognized as a sign of cardiovascular disease since 1973. More than 30 studies have been reported in the medical literature. The ear lobe is richly vascularized, and a decrease in blood flow over an extended period of time is believed to result in collapse of the vascular bed. This leads to a diagonal c r e a ~ e . ~ ~ ~ J ~ In one study, angiographs performed on 205 consecutive patients showed an 82%accuracy in predicting heart disease, with a false-positive rate of 12% and a falsenegative rate of 18%.In another study of 112 consecutive patients, the ear lobe crease was highly correlated with demonstrable heart disease and, less strongly, with previous MI.134

Eggs

Egg Beaters and similar products, tofu Low-fat or nonfat dairy products

High-fat dairy products Butter, lard, and other saturated fats

Vegetable oils

Ice cream, pies, cake, cookies, etc.

Fruits

Refined cereals, white bread, etc.

Whole grains, whole wheat bread

Fried foods, fatty snack foods

Vegetables, fresh salads

Salt and salty foods

Low-sodiumfoods, light salt

Coffee and soft drinks

Herbal teas, fresh fruit, and vegetable juices

Virtually all refined and processed foods Margarine Cakes Cookies Candies Doughnuts Bread Canned soups Crackers Processed cheese Canned foods Cereals Snack foods Salad oils Grocery store oils

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Increase the consumption of fiber-rich plant foods (fruits, vegetables, grains, legumes, and raw nuts and seeds). Increase the consumption of monounsaturated fats and omega-3 fatty acids. Follow a low-glycemic-load diet.

Lifestyle Recommendations Achieve ideal body weight. Exercise aerobically on a regular basis. Do not smoke.

Supplements High-potency multivitamin and mineral formula Vitamin C: 250 to 500 mg three times/day Vitamin E: 200 to 800 IU/day Fish oil supplement: minimum 1000 mg of combined EPA and DHA

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90. Frei B, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci 1989;86: 6377-6381. 91.Harats D, Ben-Naim M, Dabach Y. Effect of vitamin C and E supplementation on susceptibility of plasma lipoproteins to peroxidation induced by acute smoking. Atherosclerosis 1990; 8547-54. 92. Salonen RM, Nyyssonen K, Kaikkonen J, et al. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression. The Antioxidant Supplementation Atherosclerosis Prevention (ASAP) study. Circulation 2003;107947-953. 93. Simon JA. Vitamin C and cardiovascular disease. a review. J Am Coll Nutr 1992;11:107-125. 94. Howard PA, Meyers DG. Effect of vitamin C on plasma lipids. Ann Pharmacother 1995;29:1129-1136. 95. Jacques PF, Sulsky SI, Perrone GA. Ascorbic acid and plasma lipids. Epidemiology 1994;5:19-26. 96. Hallfrisch J, Singh VN,Muller DC.High plasma vitamin C associated with high plasma HDL- and HDL2 cholesterol. Am J Clin Nutr 1994;60100-105. 97. Padayatty SJ, Katz A, Wang Y, et al. Vitamin C as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr 2003; 218-35. 98. Tousoulis D, Antoniades C, Tountas C, et al. Vitamin C affects thrombosis/fibrinolysis system and reactive hyperemia in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2003;26:2749-2753. 99.Shi J, Yu J, Pohorly JE, et al. Polyphenolics in grape seedsbiochemistry and functionality. J Med Food 2003;6291-299. 100.Hertog MG, Feskens EJ, Hollman PC. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993;342:1007-1011. 101. Maffei Facino R, Carini M, Aldini G, et al. Free radicals scavenging action and anti-enzyme activities of procyanidines from Vitis vinifera. A mechanism for their capillary protective action. Arzneimittelforschung 1994;44:592-601. 102. Chang WC, Hsu FL. Inhibition of platelet aggregation and arachidonate metabolism in platelets by procyanidins. Prostaglandins Leukot Essent Fatty Acids 1989;38:181-188. 103.Meunier MT, Villie F, Jonadet M. Inhibition of angiotensin I converting enzyme by flavanolic compounds: in vitro and in vivo studies. Planta Med 1987;54:12-15. 104. Freese R, Mutanen M. Alpha-linolenic acid and marine long-chain n-3 fatty acids differ only slightly in their effects on hemostatic factors in healthy subjects. Am J Clin Nutr 1997;66591-598. 105.Smith RD, Kelly CN, Fielding BA, et al. Long-term monounsaturated fatty acid diets reduce platelet aggregation in healthy young subjects. Br J Nutr 2003;90597-606. 106. Lam SC,Harfenist EJ, Packham MA, et al. Investigation of possible mechanisms of pyridoxal 5’-phosphate inhibition of platelet reactions. Thromb Res 1980;20:633-645. 107. SermetA, Aybak M, Ulak G. Effect of oral pyridoxine hydrochloride supplementation on in vitro platelet sensitivity to different agonists. Arzneimittelforschung 1995;45:19-21. 108.Friso S, Girelli D, Martinelli N, et al. Low plasma vitamin B-6 concentrations and modulation of coronary artery disease risk. AmJClin Nutr 2004;79:992-998. 109. Kiesewetter H, Jung F, Pindur G. Effect of garlic on thrombocyte aggregation, microcirculation, and other risk factors. Int J Clin Pharmacol Ther Toxic01 1991;29:151-155. 110. Emst E. Fibrinogen: an important risk factor for atherothrombotic diseases. Ann Med 1994;2615-22. 111. Chrysohoou C, Panagiotakos DB, Pitsavos C, et al. Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The ATTICA Study. J Am Coll Cardiol 2004;44:152-158.

Specific Health Problems 112. Boushey C, Beresford S, Omenn G, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274 1049-1057. 113.Gauthier GM, Keevil JG, McBride PE. The association of homocysteine and coronary artery disease. Clin Cardiol2003;26 563-568. 114. Bozkurt E, Keles S, Acikel M, et al. Plasma homocysteine level and the angiographic extent of coronary artery disease. Angiology 200455265-270. 115. Ubbink JB, Vermaak WJ, wan der Merwe A, et al. Vitamin 512, vitamin 86,and folate nutritional status in men with hyperhome cysteinemia.Am J Clin Nutr 19935747-53. 116. Anderson JL, Jensen KR, Carlquist JF, et al. Effect of folic acid fortificationof food on homocysteine-related mortality. Am J Med 2004;116:158-164. 117. Matthews KA, Haynes SG.Type A behavior pattern and coronary disease risk. Am J Epiderniol1986;123923-960. 118. Muller MM, Rau H, Brody S. The relationship between habitual anger coping style and serum lipid and lipoprotein concentrations.Biol Psycho1 1995;41:69-81. 119. Strike PC,Steptoe A. Psychosocial factors in the development of coronary artery disease.Prog Cardiovasc Dis 2004;46:337-347. 120.Suarez EC. C-reactive protein is associated with psychologicalrisk factors of cardiovascular disease in apparently healthy adults. Psychosom Med 2004;66:684-691. 121. Maier JA. Low magnesium and atherosclerosis:an evidence-based link.Mol Aspects Med 2003;24137-146. 122. Maier JA, Malpuech-BrugereC, Zimowska W, et al. Low magnesium promotes endothelial cell dysfunction: implications for atherosclerosis, inflammation and thrombosis. Biochim Biophys Acts 2004;168913-21.

123. Hampton EM, Whang DD, Whang R. Intravenous magnesium therapy in acute myocardial infarction. Ann Pharmacother 1994; 28212-219. 124. Teo KK, Yusuf S. Role of magnesium in reducing mortality in acute myocardial infarction. A review of the evidence. Drugs 1993;46: 347-359. 125. Schecter M, Kaplinsky E, Rabinowitz B. The rationale of magnesium supplementation in acute myocardial infarction. A review of the literature. Arch Intern Med 1992;1522189-2196. 126. Eidelman RS,Hebert PR, Weisman SM, et al. An update on aspirin in the primary prevention of cardiovascular disease. Arch Intern Med 2003;163:2006-2010. 127. Weisman SM, Graham DY. Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events. Arch Intern Med 2002;1622197-2202. 128. Willard JE,Lange RA, Hillis LD. The use of aspirin in ischemic heart disease. N Engl J Med 1992;327175-181. 129. Weil J, Colin-JonesD, Langman M. Prophylacticaspirin and risk of peptic ulcer bleeding. BMJ 1995910827-830. 130. Omish D. Can lifestyle changes reverse coronary heart disease. Lancet 1990336:129-133. 131. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fiber intakes on death and myocardial reinfarction. Diet and reinfarction trial (DART). Lancet 1989;2:757-761. 132. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alphalinolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343:1454-1459. 133. Elliot WJ. Ear lobe crease and coronary artery disease. Am J Med 1983;75:1024-1032. 134. Elliott WJ, Powell LH. Diagonal earlobe creases and prognosis in patients with suspected coronary artery disease. Am J Med 1996; lOO:205-211.

Atopic Dermatitis (Eczema) Michael T. Murray, N D Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

1525

General Considerations 1525 Predictors of Severity 1526 Immunologic Abnormalities 1526 Therapeutic Considerations 1526 Food Allergy and Gut Permeability 1526 Candida albicans 1527 Essential Fatty Acids and Prostaglandin Metabolism 1527 Inhibition of Excess Histamine Release 1528 Nutritional Supplements 1528 Botanical Medicines 1529 Other Therapeutic Considerations 1529 Psychologic Approach 1529

DIAGNOSTIC SUMMARY Chronic, pruritic, inflammatory skin condition Skin is dry and hyperkeratotic Lesions include excoriations, papules, eczema (patches of erythema, exudation, and scaling with small vesicles formed within the epidermis), and lichenification (hyperpigmented plaques of thickened skin with accentuated furrows) Scratching and rubbing lead to lichenification, most commonly in the antecubital and popliteal flexures Personal or family history of atopy

GENERAL CONSIDERATIONS Atopic dermatitis (eczema) is a common condition with a prevalence of 2.4% to 7% of the population. Current research indicates that atopic dermatitis is, at least partially, an immediate hypersensitivity disease':

Serum immunoglobulin (Ig) E is elevated in 80% of patients. All patients have positive skin, radioallergosorbent (RAST), and other allergy tests. There is a positive family history in two thirds of eczema patients.

Environmental Considerations 1529 Dust Mite Exposure 1529 Microwave Exposure 1530 Essential Oils 1530 Therapeutic Approach 1530 Diet 1530 Supplements 1530 Botanicals 1530 Topical Treatments 1530 Psychologic 1530

Many eventually develop allergic rhinitis or asthma,

--

L-LL

u1 UULIL.

Most improve with an elimination diet. Atopic dermatitis is also characterized by various physiologic and anatomic abnormalities of the skin. The type of abnormality determines the manner in which atopic dermatitis is manifested in each patient. The major abnormalities (with possible mechanism) are the following: A lowered threshold to itch stimuli (substanceP excess?) Hypersensitivity to alpha-adrenergic agonists and a partial choknergic agents, which may be-due beta-adrenergicblockade (receptor site insensitivity) Dry, hyperkeratotic skin that has decreased waterholding capacity (dry-zinc or thyroid deficiency; hyperkeratotic-vitamin A deficiency?) A marked tendency to lichenify in response to rubbing and scratching (membrane fragility?) . * A tendency of the skin to be heavily colonized by bacteria, especially coagulase-positive Staphylococcus aureus (immune dysfunction)2

to

Other aspects of possible sigruficanceare Dennie's sign (an accentuated double pleat below the margin of the lower eyelid) and a tendency toward vasoconstriction, 1525

Specific Health Problems

which can be provoked by physical pressure (also called

Phosphodiesterase

white dermatographism).2

Predictors of Severity One longitudinal study of children examined a number of risk factors that may predict severity of atopic dermatitis in children? This study surveyed 137 children and followed them through four visits over a period of a year and a half. Parameters such as age of onset, social class, ethnic group, child's atopy, family history of atopy, and other potential risk factors were recorded. This study revealed the following: (1) Children with atopic dermatitis whose eczema started during the first year of life were more likely to have severe disease than were those whose eczema started later; (2) a history of atopy (asthma, hay fever, or both) was associated with severe atopic dermatitis; and (3) children with eczema who lived in an urban area were at increased risk of severe disease compared with their counterparts who lived in a rural environment. This urban environment risk was independent of ethnicity. Other factors such as breastfeeding, family size, sex, birth weight, gestational age, child's age, and any atopy (hay fever, asthma, or eczema) in parents and siblings were found to have no significant association with disease severity in this study. The lack of a protective effect from breastfeeding is not consistent with other studies (see later). Although the authors of this study did mention environmental allergen possibilities, there was no mention of diet history or food associationsregarding severity. Not examining the relationship of this condition to food was a major omission. Subsequent studies evaluating risk factors should include diet diaries and food association studies.

Immunologic Abnormalities Leukocytes from patients with atopic dermatitis have decreased cyclic adenosine monophosphate (CAMP) levels due to increased CAMP-phosphodiesterase activity and a decreased level of prostaglandin precursor^.^ The lack of intracellular CAMPresults in increased histamine release (Figure 151-1) and decreased bactericidal activity. One of the key immunologic abnormalities in atopic serum is a defect in serum bactericidal activity, a reaction dependent on the integrity of the alternate complement pathway (ACP).5The historic use of inulin-containing herbs such as burdock root (Arctiurn Zappa) and dandelion root (Taraxacum oficinale) appears to have some scientific validity because inulin activates the This activation could possibly result in restoration of bactericidal activity and increased levels of CAMP. These defects in immune function, coupled with scratching and the predominance of pathogenic S. aureus in the skin flora in 90% of patients with atopic dermatitis, lead to the increased susceptibility to

CGMP

CAMP -enhance-

I I

Stimulant - enhances-

inhibits-

5 AMP

Histamine

Figure 151-1 Cyclic guanosine monophosphate, cyclic adenosine monophosphate. and histamine.

Staphylococcus infections. In addition, cell-mediated immunity defects lead to increased susceptibility to cutaneous herpes simplex, vaccinia, molluscum contagiosum, and verruca vulgaris infections. The local immune response is further compromised by reduced delayed-type hypersensitivity, cutaneous anergy, and a decreased in vitro lymphocyte reactivity to mitogens and antigens. Interestingly, these cell-mediated defects normalize during clinical remission and become abnormal again during recurrences of the dermatitis.'

THERAPEUTIC CONSIDERATIONS The myriad of prescription and over-the-counter medications commonly used to treat atopic dermatitis fail to address the root cause of the condition. Medications used to treat atopic dermatitis include topical corticosteroids, topical antibiotics, calcineurin inhibitors, oral antihistamines, photochemotherapy using methoxypsoralen, and coal tar. Severe eczema has also been treated with systemic immodulatory agents (interferon gamma and cyclosporine) and systemic corticosteroids. None of these medications have shown effective long-term ability to effectively treat atopic dermatitis. Side effects such as cutaneous complications, sedation, and allergic reactions are a major ~ o n c e r n Furthermore, .~ a number of these medications can result in a rebound flare-up that is usually worse than the primary lesions. Naturopathic medicine generally attempts to understand the underlying causes of atopic dermatitis and thus focuses on basic factors affecting the digestive system, such as food allergies and candida overgrowth. The focus also includes essential fatty acid (EFA) metabolism and immunologic modulation via CAMPpromotion and histamine attenuation. Although no one treatment option may be universally effective, patient-specific combination therapeutics acting in synergy are encouraged for optimal efficacy.

Food Allergy and Gut Permeability Many studies have documented the major role of food allergy in atopic dermatitis (also see Chapter 53).

Atopic Dermatitis (Eczema)

Studies have also shown that breastfeeding offers significant prophylaxis against atopic dermatitis, as well as allergies in general.4 One study of 100 infants demonstrated that breastfeeding should be promoted for primary prevention of allergy.8Interestingly,further studies by this same group suggest that breastfed infants with allergies should be treated by allergen avoidance, and in some cases breastfeeding cessation is recommended in order to avoid breast milk traces of food antigens? However, in breastfed infants who develop atopic dermatitis, it is usually the result of transfer of allergic antigens in the breast milk, in which case mothers should then be instructed to avoid the common food allergens (especially milk, eggs, and peanuts and, to a lesser extent, fish, soy, wheat, citrus, and chocolate).10Maternal avoidance of these common allergens is associated with complete resolution in the majority of cases. We recommend that further studies regarding breastfeeding and food allergies should examine maternal food allergy restrictions in an attempt to more accurately evaluate the underlying causes of infantile eczema. In older or formula-fed infants, milk, eggs, and peanuts appear to be the most common food allergen inducing atopic dermatitis. In one study, these three foods accounted for roughly 81% of all cases of childhood atopic dermatitis,” while in another study 60% of children with severe atopic dermatitis had a positive food challenge to one or two of egg, cow‘s milk, peanut, fish, wheat, or soybean. One randomized controlled trial found that an egg-free diet was associated with an improvement in severity of atopic dermatitis with a positive RAST to eggs, with the greatest effect in those most severely affected.I2Although eggs are a major suspect, virtually any food can be the offending agent? Diagnosis of food allergy is usually best achieved via the elimination diet and challenge method. This approach is especially useful in childhood eczema. Elimination of milk products, eggs, peanuts, tomatoes, and artificial colors and preservatives results in significant improvement in at least 75% of c a s e ~ . ~ JIfJlabo~ ratory methods are used to identdy food allergies in eczema, the most useful method appears to be enzymelinked immunosorbent assay (ELISA) IgE and IgG4 (see Chapter 19).14 The presence of food allergies is thought to be responsible for children with atopic dermatitis having been shown to have a “leaky gut.”15 As a result of this increased gut permeability, there is increased antigen load on the immune system, which subsequently overwhelms the immune system and increases the likelihood of developing additional allergies. Permeability studies using urinary mannitol and lactulose confirm that hypoallergenic diets do decrease gut permeabilities and are associated with improvements in atopic eczema. It is

essential to identify offending foods as soon as possible to avoid advancing gut permeability, which enhances the development of further allergies. Trying to deal with multiple food allergies is often a difficult task for the patient, as the diet is often unrealistically restrictive. Elimination of allergenic foods appears to stop the development of new allergies.16 Patients should be encouraged to find out that if they can avoid offending foods for a period of up to 1 year, in many cases they will “lose” or “outgrow” their allergy.The loss rate of food allergy in patients with atopic dermatitis after 1year was 26%for the five major allergens (egg, milk, wheat, soy, and peanut) and 66% for other food allergie~.’~

Candida albicans An overgrowth of the common yeast Cundidu albicuns in the gastrointestinal tract has been implicated as a causative factor in allergic conditions including atopic dermatitis. Elevated levels of anti-Cundidu antibodies are common in atopic individuals. Furthermore, the severity of lesions tends to correlate with the level of IgE antibodies to Cundidu antigens. Appropriate anti-Cundidu therapy (see Chapter 52) may result in significant clinical improvement of atopic dermatitis.I8 Because the intestinal flora plays a major role in the health of the host, especially regarding atopic dermatitis, probiotic therapy is especially indicated. Studies evaluating the administration of the probiotic Lactobacillus rhurnnosus strain GG alone or in conjunction with Lactobacillus reuteri to infants with atopic dermatitis and cow’s milk allergy demonstrated significant reduction of eczematic ~everity.’~-~l However, the one randomized controlled trial2’ that prescribed both probiotic strains used a skim milk powder preparation for the placebo group. Patients were also allowed to continue any corticosteroid treatment. Both of these factors may have confounded any beneficial results, as it was noted that corticosteroid use increased in the placebo group during the active treatment period, possibly indicating allergic reaction to the milk proteins in the placebo. Another interesting note to this study is the finding that the positive therapeutic effect of probiotics was more pronounced in patients with an allergic constitution, as evidenced by positive skin prick test responses and increased IgE levels. This suggests that these tests may be useful in forecasting who may be most responsive to probiotic therapy. Although more study is warranted, given the low toxicity and overall healthy effect of probiotics, it seems reasonable to include them in a therapeutic regimen.

Essential Fatty Acids and Prostaglandin Metabolism Patients with atopic dermatitis appear to have altered EFA and prostaglandin metabolism. For example,

Specific Health Problems several analyses of fatty acids in plasma, red blood cells, and monocytes in patients with atopic dermatitis demonstrated a tendency for linoleic acid levels to be increased, while longer-chain polyunsaturated fatty acids such as gamma-linolenic acid, arachidonic acid, and the long-chain omega-3 oils-eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA)-tend to be relatively low.”,23 Initially it was thought that patients with atopic dermatitis may have a defect in delta-6-desaturase, the zinc-dependent enzyme that converts linoleic acid to gamma-linolenic acid. If such a defect exists, supplementing the diet with evening primrose, borage, or blackcurrant oil (commercialsources of gamma-linolenic acid) may prove helpful. In fact, several double-blind studies with evening primrose oil have shown benefit (studies with evening primrose oil showing benefit have typically used dosages of at least 3000 mg of evening primrose oil daily, providing 270 mg of GLA).2426 However, overall the results appear to be more favorable with omega-3 oil supplementation than with evening primrose oil, as well as less expensive. Several studies with evening primrose oil failed to demonstrate any benefit over a placebo. In the largest and highest methodologic quality of these studies, no benefit of evening primrose oil could be demon~trated.~~ Similarly, one study of 140 people including 69 children showed few beneficial effects of borage oil for atopic dermatitis.28 In general, treatment with omega-3 oils appears to produce better results, as they more effectively address the prostaglandin abn~rmalities.~~ In one study analyzing the fatty acid patterns in atopic dermatitis, the proportions of Linoleic acid in total plasma lipids and phospholipids were significantly greater, and those of oleic acid lower, in patients with atopic dermatitis than in age-matched healthy controls.30However, even more significant was the fact that the ratio of omega-3 to omega-6 fatty acids was significantly lower in patients with atopic dermatitis. Furthermore, no significant decreases in the proportions of dihomo-gamma-holenic acid and arachidonic acid were observed in plasma lipids of atopic patients, suggesting that delta-Gdesaturase activity is not impaired in atopic patients. This analysis seems to provide an answer as to why clinical studies with omega-3 fatty acids tend to be more favorable in atopic dermatitis than those with evening primrose oil. Dietary enrichment with “fish oil” supplements providing EPA and DHA or simply eating more fatty fish (e.g., mackerel, herring, salmon) results in significant incorporation of omega-3 fatty acids into the membrane phospholipid pools. Flaxseed oil, which contains alphaholenic acid, the precursor omega-3 fatty acid, may benefit patients with atopic dermatitis. But because the degree of clinical improvement correlates with the increase in concentration of DHA in serum phospholipids

and fish oils tend to be more effective in raising DHA levels than flaxseed oil, supplementationwith EPA/DHA or increasing the consumption of coldwater fish is likely to produce better overall results in atopic dermatitis than flaxseed

Inhibition of Excess Histamine Release As illustrated in Figure 151-1, agents that stimulate cAMP production or inhibit cAMP phosphodiesterase, or both, reduce the inflammatory process in atopic dermatitis by reducing the shunting to histamine. and Coleus forskolii is a strong cAMP many botanicals have been shown to inhibit diesterase, with licorice (Glycyrrhiza glabra) showing marked activity.33 A number of flavonoids also inhibit cAMP phosphodiesterase, with maximal activity from the flavonols quercetin and hyperoside, the flavones orientin and vitexin, and the flavanone naringen.% However, the common flavonol rutin has less than one tenth the activity of quercetin, which has been shown to greatly increase the level of cAMP in human platelets.35 Flavonoid extracts from Vaccinium myrtillus, Rosa damascena, Ruta graveolens, Prunus spinosa, and Crataegus pentagyiza were the most potent inhibitors, according to one study.% These flavonoids are also potent inhibitors of mast cell d e g r a n ~ l a t i o n .Flavonoid-rich ~~ extracts such as those from grape seed, pine bark, green tea, or Ginkgo biloba may prove helpful in the treatment of atopic dermatitis. In addition to flavonoids, G. biloba extract contains several unique terpene molecules known collectively as ginkgolides that antagonize platelet-activating factor (PAF),a key chemical mediator in atopic dermatitis. PAF plays a central role in many inflammatory and allergic processes including neutrophil activation, increasing vascular permeability, smooth muscle contraction including bronchoconstriction, and reduction in coronary blood flow. Ginkgolides compete with PAF for binding sites and inhibit the various events induced by PAF. Preliminary studies have indicated that mixtures of ginkgolides (BN 52063), as well as the G. biloba extract standardized to contain 24% ginkgo flavonglycosides and 6% terpenoids, are capable of demonstrating clirucally significant antiallergy effect^^^,^^ including reduced airway inflammation in asthmatics.4O

Nutritional Supplements Zinc Zinc supplementation appears to be much indicated in atopic dermatitis given that low zinc levels are common in atopic dermatitis and given the importance of zinc to proper EFA metabolism (it is required for delta6-desaturase, the enzyme responsible for converting linoleic acid to gamma-linolenic acid).37

Atopic Dermatitis (Eczema)

Vitamin E One single-blind analysis evaluated 96 patients given either 400 IU/day of vitamin E or a placebo for 8 months. Significant improvement was reported in approximately 60% of the treatment group, with significant reductions in serum IgE levels.41

Botanical Medicines The use of botanical medicines in atopic dermatitis can be generally divided into two categories: internal and external. Licorice (G. glabra) appears to be useful in either application. Internally, licorice preparations can exert significant antiinflammatory and antiallergic effects (see Chapter 99). These benefits are perhaps best exemplified in several recent double-blind studies featuring a licorice-containingChinese herbal formula.42In addition to licorice, the formula contained the following:

Ledebou riealla seseloides Potentilla chinensis Clematis chinensis Clematis armandi Rehmania glutinosa Paeonia 1actifZor-a Lophatherum gracile Dictamnus dasycarpus Tribulus terrestris Schizonepeta tenuifolia Interest in this formula by a group of researchers began after a patient with atopic dermatitis experienced tremendous improvement after taking a decoction prescribed by a Chinese doctor. Several double-blind studies have confirmed this benefit. In one study 40 adult patients with long-standing, refractory, widespread, atopic dermatitis were randomized to receive 2 months' treatment of either the active formula or placebo decoction, followed by a cross-over to the other treatment after a 4-week washout peri0d.4~ The treatment group demonstrated sigruficant superiority over the placebo in clinical evaluation. In addition, of the 31 patients completing the study, 20 preferred the active formula while only 4 preferred the placebo. There was also a subjectiveimprovement in itching and sleep during the active treatment phase. No side effects were reported, although many complained about the unpalatability of the decoction. Similar results were demonstrated in a double-blind study in children." These positive preliminary studies will hopefully be followed by more extensive investigations to determine proper dosages and perhaps different forms of administration (e.g., pills, tablets, or capsules versus unpalatable decoctions). Licorice undoubtedly plays a major role in the effectiveness of the Chinese herbal formula. At this time, until the benefits of the other components can be confirmed,

it makes the most sense to base the dosage level on the level of delivered licorice. With regard to using licorice topically, the best results are likely to be obtained by using commercial preparations featuring pure glycyrrhetinic acid. Several studies have shown glycyrrhetinic acid to exert an effect similar to that of topical hydrocortisone in the treatment of eczema, contact and allergic dermatitis, and psoriasis. In one study 9 of 12 patients with intractable eczema noted marked improvement, and 2 patients noted mild improvements when an ointment containing glycyrrhetinic acid was applied topically In another study 93%of the patients with eczema applying glycyrrhetinic acid demonstrated improvement compared with 83% using c0rtisone.4~

Other Therapeutic Considerations Endocrine Factors Hypothyroid patients with eczema respond well to

Scratching Cessation Itching is extremely detrimental in atopic dermatitis because it breaks the skin, which aids bacterial ingress, and promotes lichenification. Factors that limit itching, therefore, promote healing and prevent recurrence. Some behavior modification techniques have proven valuable in reducing the exacerbation of atopic dermatitis symptoms caused by scratching7

Psychologic Approach Emotional tension can provoke and aggravate itching in patients with atopic dermatitis, and, according to a number of studies, atopic dermatitis patients show higher levels of anxiety, hostility, and neurosis than matched controls.47Studies employing psychotherapeutics have shown promising results, with one study showing reductions in the use of corticosteroids for up to 2 years.7

ENVIRONMENTAL CONSIDERATIONS Dust Mite Exposure Environmental sensitivities such as house dust mite (Dermatophgoides pteronyssinus) allergies and detergent sensitivities may play a role in atopic dermatitis7 One study notes that those patients who present with concurrent asthma or rhinoconjunctivitis, or both, may benefit from dust mite reduction the most. Although results are conflicting regarding the individual benefits of replacing clothing and personal soaps with hypoallergenic brands and mite reduction techniques such as changing mattress covers and bedding and using air filters, employing these options in combination with other naturopathic therapies will hopefully increase the overall clinical picture as antigen load is decreased.

Specific Health Problems

Microwave Exposure One fascinating study of mobile phone use for 1 continuous hour showed significant increases in allergic response to dust and pollen in adults with eczema.& Microwave radiation exposure also increased plasma levels of substance P and vasoactive intestinal peptide in patients with atopic dermatitis. This study raises the concern that microwave radiation emitted from cell phones may actually increase sensitivity to specific allergens in some patients.

Essential Oils Finally, there is one case involving a 53-year-old patient suffering from relapsing eczema resistant to pharmacologic therapy. Careful history revealed that sensitization was caused by repeated airborne exposure via aroma lamp use to lavender, jasmine, and rosewood essential 0ils.4~This report underscores the notion that in sensitive individuals, natural substances may also encourage allergic reactions. All natural therapies, whether they be topical, environmental, or internal, should be closely chosen and monitored.

EPA and DHA: 540 and 360 mg daily or flaxseed oil 10 g daily Evening primrose oil: 3000 mg/day Probiotics: dosage: 1 to 10 billion viable Lactobacillus acidophilus and Bifdobacterium bifidurn cells daily

Botanicals The following are three times/day dosages.

Arctium lappa or Taraxacum oficinale Dried root: 2 to 8 g by infusion or decoction Fluid extract (1:l):4 to 8 ml (1to 2 tsp) Tincture: alcohol-based tinctures of dandelion are not recommended because of the extremely high dosage required Juice of fresh root: 4 to 8 ml(1 to 2 tsp) Powdered solid extract (4:l): 250 to 500 mg Coleus forskolii extract standardized to contain 18% forskolin: 50 mg (9 mg of forskolin) two to three times daily Glycyrrhiza glabra Powdered root: 1 to 2 g Fluid extract (1:l):2 to 4 ml Solid (dry powdered) extract (4:l): 250 to 500 mg

THERAPEUTIC APPROACH Effective management requires relief from, and prevention of, itching while treating the underlying metabolic abnormalities. The food and environmental allergens must be detected and controlled; prostaglandin metabolism should be normalized; and immune system abnormalities must be balanced.

Diet The patient should begin a 4-day rotation diet and eliminate all major allergens (milk, eggs, and peanuts account for the offending food in approximately 81% of cases). As the patient improves, allergens can slowly be reintroduced and a stringent rotation diet can be reduced. Limit animal products and add fatty fish such as salmon, mackerel, herring, and halibut.

Supplements Vitamin A: 50,000 IU/day Vitamin E: 400 IU/day (mixed tocopherols) Zinc: 50 mg/day (decrease as condition clears) Quercetin: 200 to 400 mg three times/day (5 to 10 minutes before meals)

Topical Treatments Glycyrrhetinic acid-containing commercial preparations may be helpful. Chamomile preparations (see Chapter 206) and witch hazel preparations are also popular, and their use is supported in the scientific Patients should also try to take the following measures: Avoid sweating and rough-textured clothing. Wash clothing with mild soaps only and rinse thoroughly. Avoid exposure to chemical irritants and any other agent that might cause skin irritation. Local application of soothing lotions ameliorates itching (zinc oxide works well), but greasy preparations should not be used for extended periods because they block the sweat ducts.

Psychologic Determine if the patient has significant levels of anxiety, hostility, or neurosis. If present, assist the patient in resolving these problems or refer him or her to a counselor for more extensive assistance.

Atopic Dermatitis (Eczema)

1. Soter N, Baden H. Pathophysiology of dermatologic disease. New York McGraw-Hill, 1984. 2. de Maat-Bleeker F, Bruijnzeel-Koomen C. Food allergy in adults with atopic dermatitis. Monogr Allergy 1996;32:157-163. 3. Ben-Gashir MA, Seed PT, Hay RJ. Predictors of atopic dermatitis severity over time. J Am Acad Dermatol2004;50349-356. 4. Saarinen UM, Kajosaari M. Breastfeeding as prophylaxis against atopic disease: prospective follow-up study until 17 years old. Lancet 1995;346:1065-1069. 5. Siccardi A, Fortunato A, Marconi M, et al. Defective bactericidal reaction by the alternative pathway of complement in atopic patients. Infect Immun 198133:710-713. 6. Cooper PD, Carter M. Anti-complementary action of polymorphic “solubility forms” of particulate inulin. Mol Immunol 1986;23: 895-901. 7. Hanifin JM, Cooper KD, Ho VC, et al. Guidelines of care for atopic dermatitis, developed in accordance with the American Academy of Dermatology (AAD)/ American Academy of Dermatology Association “Administrative Regulations for Evidence-Based Clinical Practice Guidelines.” J Am Acad Dermatol2004;50:391-404. 8. Isolauri E, Tahvanainen A, Peltola T, et al. Breast-feeding of allergic infants. J Pediatr 1999;134:27-32. 9. Arvola T, Moilanen E, Vuento R, et al. Weaning to hypoallergenic formula improves gut barrier function in breast-fed infants with atopic eczema. J Pediatr Gastroenterol Nutr 2004;38:92-96. 10. Cant AJ, Bailes JA, Marsden, et al. Effect of maternal dietary exclusion on breast fed infants with eczema: two controlled studies. Br Med J 1986;293231-233. 11. Burks AW, Williams LW, Mallory SB, et al. Peanut protein as a major cause of adverse food reaction in patients with atopic dermatitis. Allergy Proc 1989;10265-269. 12. Lever R, MacDonald C, Waugh P, et al. Randomised controlled trial of advice on an egg exclusion diet in young children with atopic eczema and sensitivity to eggs. Pediatr Allergy Immunol1998;9:13-19. 13. Van Bever HP, Docx M, Stevens WJ. Food and food additives in severe atopic dermatitis. Allergy 1989;44:588-594. 14. Gondo A, Saeki N, Tokuda Y. IgG4 antibodies in patients with atopic dermatitis. Br J Dermatol1987;117301-310. 15. Majamaa H, Isolauri E. Evaluation of the gut mucosal barrier: evidence for increased antigen transfer in children with atopic eczema. J Allergy Clin Immunol1996;97985-990. 16. Agata H, Kondo N, Fukutomi 0,et al. Effect of elimination on foodspecific IgE antibodies and lymphocyte proliferative responses to food antigens in atopic dermatitis patients exhibiting sensitivity to food allergens. J Allergy Clin Immunol 1993;91:668-679. 17. Sampson HA, Scanlon SM. Natural history of food hypersensitivity in children with atopic dermatitis. J Pediatr 1989;115:23-27. 18. Savolainen J, Lammintausta K, Kalimo K, et al. Candida albicans and atopic dermatitis. Clin Exp Allergy 1993;23:332-339. 19. Isolauri E, Arvola T, Sutas Y, et al. Probiotics in the management of atopic eczema. Clin Exp Allergy 2000;301604-1610. 20. Majamaa H, Isolauri E. Probiotics: a novel approach in the management of food allergy. J Allergy Clin hunol1997;99:179-185. 21.Rosenfeldt V, Benfeldt E, Nielsen SD, et al. Effect of probiotic Lactobacillus strains in children with atopic dermatitis. J Allergy Clin hnmunol2003;111:389-395. 22.Manku M, Horrobin D, Morse N, et al. Reduced levels of prostaglandin precursors in the blood of atopic patients: defective delta-6-desaturase function as a biochemical basis for atopy. Prostaglandins Leukot Med 1982;9:615-628. 23. Lindskov R, Holmer G. Polyunsaturated fatty acids in plasma, red blood cells and mononuclear cell phospholipids of patients with atopic dermatitis. Allergy 1992;47517-521.

24. Stewart JCM, Morse PF, Moss M, et al. Treatment of severe and moderately severe atopic dermatitis with evening primrose oil (Epogram). A multi-center study. J Nutr Med 1991;2:9-15. 25. Hederos CA, Berg A. Epogam evening primrose oil treatment in atopic dermatitis and asthma. Arch Dis Child 1996;75:494-497. 26. Fiocchi A, Sala M, Signoroni P, et al. The efficacy and safety of gamma-linolenic acid in the treatment of infantile atopic dermatitis. J Int Med Res 1994;22:24-32. 27. Berth-Jones J, Graham-Brown RA. Placebo-controlled trial of essential fatty acid supplementation in atopic dermatitis. Lancet 1993;341:1557-1560. 28. Takwale A, Tan E, Aganval S, et al. Efficacy and tolerability of borage oil in adults and children with atopic eczema: randomised, double blind, placebo controlled, parallel group trial. BMJ 2003;3271385. 29. Bjorneboe A, Soyland E, Bjorneboe GE, et al. Effect of dietary supplementation of eicosapentaenoic acid in the treatment of atopic dermatitis. Br J Dermatol1987;117463-469. 30. Sakai K, Okuyama H, Shimazaki H, et al. Fatty acid compositions of plasma lipids in atopic dermatitis/asthma patients. Arerugi 1994;43:37-43. 31. Soyland E, Funk J, Rajka G, et al. Dietary supplementation with very long-chain n-3 fatty acids in patients with atopic dermatitis. A double-blind, multicentre study. Br J Dermatol 1994;130: 757-764. 32. Seamon K, Padgett W, Daly J. Forskolin: unique diterpine activator of adenylate cyclase in membranes and in intact cells. Proc Natl Acad Sci U S A 1981;78:3363-3367. 33. Nikaido T, Ohmoto T, Noguchi H, et al. Inhibitors of cyclic AMP phosphodiesterase in medicinal plants. Planta Med 1981;43: 18-23. 34.Petkov E, Nikolov N, Uzunov P. Inhibitory effect of some flavonoids and flavonoid mixtures on cyclic AMP phosphodiesterase activity of rat heart. Plant Med 1981;43:183-186. 35. Beretz A, Stierle A, Anton R, et al. Role of cyclic AMP in the inhibition of human platelet aggregation by quercetin, a flavonoid that potentiates the effect of prostacyclin. Biochem Pharmacol 1982;31:3597-3600. 36. Amella M, Bronner C, Briancon F, et al. Inhibition of mast cell histamine release by flavonoids and biflavonoids. Planta Med 1985;51:16-20. 37. David TJ, Wells FE, Sharpe TC. Serum levels of trace metals in children with atopic eczema. Br J Dermatol 1990;122:485-489. 38. Koltai M, Hosford D, Guinot P, et al. Platelet activating factor (PAF). A review of its effects, antagonists and possible future clinical implications (Part I). Drugs 1991;42:9-29. 39. Koltai M, Hosford D, Guinot P, et al. PAF. A review of its effects, antagonists and possible future clinical implications (Part 11).Drugs 1991;42174-204. 40. Li M, Yang B, Yu H, et al. Clinical observation of the therapeutic effect of ginkgo leaf concentrated oral liquor on bronchial asthma. Zhongguo Zhong Xi Yi Jie He Za Zhi (Chin J Integr Trad West Med) 1997;3:264-267. 41. Tsoureli-Nikita E, Hercogova J, Lotti T, et al. Evaluation of dietary intake of vitamin E in the treatment of atopic dermatitis: a study of the clinical course and evaluation of the immunoglobulin E serum levels. Int J Dermatol2002;41:146-150. 42. Atherton DJ, Sheehan MP, Rustin MH, et al. Treatment of atopic eczema with traditional Chinese medicinal plants. Pediatr Dermatol 1992;9:373-375. 43. Sheehan MP, Rustin MH, Atherton DJ, et al. Efficacy of traditional Chinese herbal therapy in adult atopic dermatitis. Lancet 1992;34013-17.

44.Sheehan MP, Atherton DJ. A controlled trial of traditional Chinese medicinal plants in widespread non-exudative atopic eczema. Br J Dermatol1992;126179-184. 45. Evans FQ. The rational use of glycyrrhetinic acid in dermatology. Br J Clin Pract 1958;12269-274. 46.Barnes 8. Thyroid therapy in dermatology. Cutis 1971;8:581-583. 47. Jordan J, Whitlock F. Emotions and the skin: the conditioning of scratch responses in cases of atopic dermatitis. Br J Dermatol 1972863574585. 48.Kimata H. Enhancement of allergic skin wheal responses by microwave radiation from mobile phones in patients with atopic eczema/dermatitis syndrome. Int Arch Allergy Immunol 2002;129:348-350.

49. Schaller M, Korting HC. Allergic airborne contact dermatitis from essential oils used in aromatherapy. Clin Exp Dermatol 1995; 20:143-145. 50. Mann C, Staba EJ. The chemistry, pharmacology, and commercial formulations of chamomile. In Craker L, Simon J, eds. Herbs, spices, and medicinal plants, vol 1. New York Oryx Press, 1986: 235-280. 51. Pfister R. [Problems in the treatment and after care of chronic dermatoses. A clinical study on hametum ointment.] Fortschr Med 1981;99:1264-1268.

Attention Def icit Hyperactivity Disorder in Children Michael R. Lyon, MD CHAPTER CONTENTS Diagnostic Summary

1533

General Considerations

Intestinal Hyperpermeability 1537 Gastrointestinal Dysbiosis 1537

1533 Immune System Impairment

Attention Deficit Hyperactivity Disorder Hypotheses 1534 A Disorder of Executive Control 1534 A Reward Deficiency Syndrome 1534 “Minimal Brain Dysfunction” 1534 Genetics 1534 Therapeutic Considerations 1534 Environmental Neurotoxins 1534 Nutrient Deficiencies 1535 Diet 1536

Drug Therapy

1538

1539

Cognitive Behavioral Therapies Neurofeedback

1539

1539

Therapeutic Approach 1539 Step 1 1540 Step2 1540 Step 3 1540 Step4 1540

Food Allergy and Gastrointestinal Function 1536 Food Allergy 1536

DIAGNOSTIC SUMMARY A neurobehavioral disorder that begins in early childhood with persistence into adolescence and adulthood Typified by one or more symptoms of disabling inattentiveness, hyperactivity, and impulsivity Commonly accompanied by comorbid conditions such as mood disorders or learning disabilities

GENERAL CONSIDERATIONS Attention deficit hyperactivity disorder (ADHD) is defined by the Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) as a condition characterized by developmentally inappropriate inattention and impulsivity with or without hyperactivity. Depending on the region and the investigator, ADHD has been found in 5% to 15% of school-age children and is responsible for approximately 50% of the referrals to childhood diagnostic clinic^.^,^ It is common to refer to those with the

predominantly inattentive form of the disorder as having attention deficit disorder (ADD),whereas ADHD is commonly reserved for those with hyperactivity as a predominant feature. However, according to the DSMIV, all forms of the disorder are properly referred to as ADHD with the additional acknowledgment of three main subtypes:predominantly inattentive, predominantly hyperactive, and combined type.3 ADHD may place a child at risk for numerous challenges. If not intensively managed, a child with ADHD will likely experience academic impairment, increased risk of injuries, and problems with self-esteem and socialization.“ Later in adolescence and adulthood, those with ADHD have a high risk of experiencing psychologic disorders, substance abuse and addictions, traffic accidents, financial problems, vocational underachievement, social dysfunction, and difficulties with the Nevertheless, there are numerous examples of individuals with ADHD who have risen above their potential limitations to achieve a high level of personal success. 1533

Specific Health Problems

ATTENTION DEFICIT HYPERACTIVITY DISORDER HYPOTHESES A Disorder of Executive Control The leading hypothesis explaining the behavioral and cognitive manifestations of ADHD arises from evidence associating this disorder with diminished function of polysynaptic dopaminergic circuits belonging to executive centers within the brain’s prefrontal c o r t e ~ . ~These *’~ executive centers are largely inhibitory in nature and are responsible for impulse control and the ability to maintain sustained attention.” Evidence from studies using magnetic resonance imaging, positron emission tomography scan, single photon emission computed tomography scan imaging, and electroencephalograms (EEGs) suggests that the brains of those with ADHD exhibit differences both morphologically and metabolically from normal controls, particularly with regard to the prefrontal executive centers.12J3 Various disturbances in dopaminergic activity within these brain centers have remained the primary molecular defects implicated in ADHD, although other neurotransmitters (particularly norepinephrine) have also been incriminated. Decreased sensitivity of the dopaminergic (D4) receptor and heightened dopamine reuptake by the presynaptic dopamine transporter have both been suggested to result in diminished dopaminergic activity within executive centers.14

A Reward Deficiency Syndrome In addition to the problems of executive control conferred by diminished dopaminergic activity, decreased dopamine activity has been implicated as a primary factor in addi~ti0n.l~ ADHD has been closely associated with addiction, and some authorities support the notion that the neurologic basis for both addiction and ADHD is largely shared.16 The dopaminergic system, particularly the dopamine D2 receptor, has been clearly implicated as central to reward mechanisms in the brain (mechanisms that convey a sense of reward or satisfaction on the individual). Dysfunction of the D2 dopamine receptors leads to aberrant substance-seeking behavior (e.g., alcohol, drug, tobacco, food) and other related behaviors (e.g., sexual addiction, pathologic gambling). This need for “neurologic satisfaction” may also help to explain why individuals with ADHD tend to participate in high-risk sports, criminal activities, or other euphoriagenerating behaviors and why ADHD sufferers typically have a low tolerance to boredom.

Particularly disabling is the diminishment in nonverbal working memory exhibited by most ADHD sufferers.17J8 This feature of ADHD results in a diminished sense of time, as well as a decreased ability to hold events or tasks in the mind. Tardiness, missed appointments, procrastination, poor task planning, and failure to meet deadlines are all examples of how diminished working memory can result in serious consequences, particularly in adulthood. Diminishment of serotonergic neuronal activity may also play a sigruficantrole in ADHD comorbid features such as depression or aggressive behaviors. This may explain why antidepressants have been shown to bring about behavioral improvement in many cases.19

Genetics Epidemiologic data suggest that genetics may play a signhcant role as an antecedent factor in the etiology of ADHD.” There is little doubt that the inherited predisposition to ADHD is polygenetic. Recent studies have identified differences in genes encoding for both the D2 and the D4 dopamine receptor in ADHD, which would create a state of relative dopamine insensitivity in affected brain regions.16 Other studies have associated ADHD with genetic polymorphisms associated with increased activity of the presynaptic dopamine transporter (which would result in increased uptake of dopamine)?l Other genetic factors contributing to ADHD may include inherited tendencies toward allergic states, decreased immune competence, and various genetic polymorphisms resulting in diminished capacity to detoxdy drugs, heavy metals, and xenobiotics.

THERAPEUTIC CONSIDERATIONS Environmental Neurotoxins Environmental contributions to the development of ADHD may begin at or even before conception. Maternal-to-fetal transport of various neurotoxicants can occur readily during pregnancy.22*23 A woman who has an ongoing exposure to or a sigruficant body burden of neurotoxic substances (e.g., metals, solvents, pesticides, polychlorinated biphenyls [PCBs], alcohol or other drugs of abuse) may herself exhibit features consistent with ADHD and give birth to a child who manifests symptoms of ADHD. In such cases it might be assumed that ADHD is inherited when it is actually acquired.” Children remain susceptible to neurotoxicants following birth, and some of these agents have been shown to be common among children in North America.25

“Minimal Brain Dysfunction”

Maternal Tobacco and Drug Use

It has long been known that ADHD is often associated with other cognitive deficits. Perhaps up to 50% of people with ADHD have definable learning disabilities, and most have measurable cognitive disturbances.

Epidemiologic and clinical data have identified a number of toxicologic factors associated with ADHD.22,26 Maternal tobacco and drug use has been associated with a higher risk of ADHD. One study suggested that up to

Attention Deficit Hyperactivity Disorder in Children 25%of all behavioral disorders in children can be attributed to smoking in ~regnancy.2~ In addition, chronic, low-level lead intoxication in North American children is reported to exist in an alarmingly high incidence.

investigation has not yet been conducted in children with ADHD, many authorities believe that ADHD and autism are part of the same spectrum of disorders and may share many etiologic features.35

Lead and Other Heavy Metals

Nutrient Deficiencies Essential Fatty Acids

The Centers for Disease Control and Prevention estimated that about 2% of American children younger than age 6 currently meet the criteria for lead toxicity at a level that has been associated with cognitive deficits and behavioral disturbances (>lo pg/dl whole blood lead)?* Low-level lead intoxication has also been associated with addictive behaviors and impulsivity, suggesting neurologic changes consistent with the reward deficiency syndrome, described earlier?9In keeping with these data, pilot studies have demonstrated improvement in ADHD behaviors in some children with moderate elevations in blood lead levels who have been treated with calcium edetate ~ h e l a t i o n . ~ ~ In addition to lead, other metal neurotoxicants such as mercury, cadmium, and aluminum, as well as pesticides and PCBs, are nearly ubiquitous contaminants arising from dental amalgams, food, air, and drinking water, and these agents may act synergistically to impair neurological function and development in susceptible children.BJ1The Consumer’s Union of the United States has recently conducted the largest study to date looking at the level of human exposure to a wide range of pesticides in the U.S. food supply. In thisstartling report, it was demonstrated that human exposure to pesticides is far greater than ever previously estimated and that children are at particularly high risk for neurotoxic effects from regular inadvertent pesticide exposure from common Perhaps even more astonishing are the implications derived from a landmark study by Edelson,33ain which 56 autistic children were studied from a toxicologic perspective. In this study postprovocative urine challenge testing was performed on all children. A chelating agent was given to the children, and a urine sample was then gathered to measure heavy metal excretion. This methodology demonstrated elevated body burdens of heavy metals in 100% of the subjects.

Neurotoxins Also from Edelson’s study results, highly significant elevations of a wide range of organic xenobiotics were found in the blood in 95%of the children. Functional liver detoxification testing (caffeine, acetaminophen, aspirin clearance) was markedly abnormal in 98%.Edelson postulates that autism is primarily a neurotoxicologic phenomenon resulting from xenobiotic exposure of the fetus and infant (while the blood-brain barrier is poorly developed) combined with an inherited insufficiency of liver detoxification mechanisms. Although this type of

Multiple studies have shown that children with ADHD have a measurable reduction in tissue levels of the omega3 fatty acid docosahexaenoic acid (DHA) when compared with age-matched controls.36 Because essential fatty acids (EFAs) in the brain are critical in neuronal structure and function, it has been frequently postulated that brain EFA dysregulation plays a key role in ADHD. DHA and arachidonic acid (AA) are both important components of brain and peripheral neuron structure. They also play a vital role in the maintenance of normal immune responsiveness and in the regulation of allergy and inflammati~n.~~ In addition, DHA has been shown to play a crucial role in fetal and childhood brain and retinal development. DHA is found in particularly high concentrations around synapses in the brain and it thus plays a vital role in impulse transmission across the synapse and in the maintenance of adequate neurotransmitter pools.38 In fact, dopamineproducing nerve endings are highly fluid and are composed of approximately 80% DHA. DHA is found in high concentrations in the retina, and it plays an important role in normal visual function.39Apart from this, DHA deficiency has been shown to result in increased permeability of the blood-brain barrier in animal studies, and it is critical to the brain’s defense against neurotoxic xenobiotics.40EFA depletion may play an important role in the mediation of other toxic insults. Some researchers have suggested, in fact, that the primary effect of most xenobiotics occurs from oxidative destruction and subsequent depletion of membrane EFAs.~~ Several studies have suggested that children who are formula fed are at twice the risk of developing ADHD as those who are breastfed.42 Currently, infant formulas in most of Europe and in North America do not provide supplementary DHA, although breast milk has been repeatedly shown to contain DHA. In some countries, DHA is an additive to infant formulas and because of ethnic dietary composition, maternal intake of this EFA is also high throughout pregnancy and lactati0n.4~ Little effort has been made in North America or Europe to increase the intake of DHA during this critical period or during childhood, when the brain is developing. Additionally, the typical diet of children throughout much of the developed world, including vegetarian children, is low in EFAs. Furthermore, children with ADHD have been reported to have impaired capabilities to synthesize DHA, AA, and gamma-linolenic acid (GLA) from vegetable precursors found in the typical diet.44

Specific Health Problems Evidence of increased oxidative destruction of omega-3 fatty acids in ADHD has also been demonstrated.& EFA deficiency has also been associated with diuresis and a marked increase in renal calcium loss.&Increased thirst and enuresis has been highly associated with A D m 7and has been reported to be correctable through a reduction in food allergens.a This suggests that EFA deficiencies in ADHD may, at least in part, be the result of food hypersensitivity. Other data also suggest that atopic individuals and those with food allergies have an increased requirement for EFAs, and normalization of EFAs may actually have a salutary effect on atopic

disorder^?^ Trans fatty acids are common dietary constituents and are produced through the hydrogenation of vegetable oils. This type of fat is known to adversely affect health in many waysmincluding impairment of fetal and childhood brain d e ~ e l o p m e n t .Among ~~ their many toxic effects, trans fatty acids block the enzymatic conversion of vegetable-derived omega-3 and omega-6 fatty acids into the critical fatty acids DHA, eicosapentaenoic acid (EPA),and GLA.

Magnesium Besides fatty acids, inadequate provision of other nutrients during fetal development and early childhood may also play a significant role in the development of ADHD.52Magnesium levels in serum, red blood cells, and hair have all been shown to be low in the majority of children with ADHD.53These children also demonstrated improved behavior when administered magnesium supplements.%

Zinc Both hair and serum zinc levels have been shown to frequently accompany ADHD.55 Those children with low serum zinc were also more frequently found to have lower free fatty acid levels, suggesting that abnormalities in fatty acid metabolism may, at least in part, result from zinc deficiency.%It has also been shown that lower hair zinc levels correlate with a poorer response to treatment with amphetamine^.^^ A recent controlled trial demonstrated positive effects of zinc supplementation in hyperactive children.57

Iron Iron is known to play a role in the regulation of dopaminergic activity. One study demonstrated that iron supplementation in nonanemic children with ADHD resulted in diminished ADHD symptoms within 30 days.%

B Vitamins Low levels of vitamin B1 (thiamin) have also been demonstrated in a group of children with ADHD.59

Diet Although sucrose as a singular agent has remained a controversial contributor to ADHD, studies have shown improvement in behavior and school performance in children who are transferred to a diet in which "junk foods" high in sucrose, artificial flavors, artificial colors, and preservatives are reduced and replaced by more nutrient-dense foods.@ High refined-carbohydrate diets have also been found to correlate with high tissuecadmium levels and poor cognitive performance in Finally, it has been found that children with ADHD have impaired catecholamine control of blood sugar and may exhibit worsening of behavior following a sucrose challenge.62

FOOD ALLERGY AND GASTROINTESTINAL FUNCTION Food Allergy Several researchers have found a significant correlation between ADHD and atopic Others have linked ADHD to food allergy or food intolerances in at least a subgroup of affected children.65,66 In one study demonstrableEEG changes occurred immediately following ingestion of previously identified sensitizing Food allergies and other allergic disorders have been associated with a higher incidence of recurrent otitis media.@In turn, recurrent otitis media has been associated with an increased risk of ADHD.69Both food allergy and ADHD have been associated with sleep disturbances, which may, in turn, contribute to a worsening of ADHD symptoms. Heavy snoring and sleep apnea are particularly prevalent in atopic and food-allergic children and may sigruficantly contribute to ADHD symptom^.^^,^^ Studies have demonstrated improved sleep in children with ADHD during an low-allergy-potential (oligoantigenic) diet.R,n In several studies, oligoantigenic or allergy elimination diets have been shown to be beneficial to children with ADHD.73-76In one placebo-controlled study, enzyme-potentiated desensitization (EPD) was used in an attempt to desensitize children from allergy to a broad range of potential food antigens. This treatment resulted in improved behavior in most children with ADHD.n In a more recent study in England, EPD was compared with methylphenidate hydrochloride (Ritalin) and with psychotherapy in three groups of children with ADHD. Although little benefit was obtained from psychotherapy, EPD and Ritalin proved equally effective in the reduction of ADHD sympt~matology.~~ Numerous mechanisms have been described to explain the immediate and longer-term effects of food hypersensitivitieson brain function.79Mediators of inflammation such as histamine, bradykinins, interleukins, tumor necrosis factor-alpha, prostaglandins of the PGE2

Attention Deficit Hyperactivity Disorder in Children

series, and various neuropeptides have been shown to be present in the blood immediately after exposure to a sensitizing f ~ ~ dThe. vasoactive ~ ~ , ~ effects ~ of these substances may influence cerebral vascular function and result in various symptoms including migraine headaches. Thus migraine headaches and even some seizure disorders in children have been shown to be highly responsive to an oligoantigenic diet.81-83Neuroactive peptides from food, as well as the endogenous opioids, have been demonstrated to play a sigruficant role in the etiology of autism and other neurodevelopmental disorders. Neuroactive opioid peptides (exorphins) are common constituents of certain foods such as cow's milk or wheat gluten and can be commonly found in the urine of children with autism, as well as those with ADHD.&& Endogenous opioid peptides may also be released from immune cells following the administration of a sensitizing food. Neuroactive peptides may have increased access to the brain under certain pathologic states such as allergy87*88 or EFA deficiency. In addition, numerous gut-derived inflammatory mediators have been shown to diminish the integrity of the blood-brain banieta Even in normal health, the blood-brain barrier should not be considered a static barrier but should be recognized as a dynamic regulatory interface controlling the exchange of informational molecules, such as peptides, between the blood and central nervous system.89ADHD may, at least in part, be the result of a breakdown in the efficiency of this regulatory interface combined with an increase in the presence of certain neuroactive or neurotoxic substances. Both immediate and delayed effects are possible from exposure to food antigens. Direct effects of sensitizing foodstuffs on gut mucosa may result in mucosal edema and poor digestive and absorptive f u n ~ t i o n i n g .Thus ~,~~ numerous nutritional insufficiencies may result from chronic gut mucosal inflammation accompanying food allergy or intolerance. (See Chapters 19 and 53 for a comprehensive discussion of this important topic.)

Intestinal Hyperpermeability' Additionally, inflamed gut mucosa becomes hyperpermeable, resulting in a large increase in macromolecular transport through the mesenteric lymphoid tissues and the portal c i r c u l a t i ~ nThus . ~ ~ gut lymphoid tissue and liver Kupffer cells must engage in the processing of high amounts of antigenically active debris. An end result of this antigenic stimulation is the release of cellular messengers and mediators of inflammation such as histamine, bradykinins, and tumor necrosis factor, some of which, in turn, create increased permeability of the blood-brain Macromolecular substances may also escape the first pass through the liver and may have direct physiologic effects distant to the liver including effects on the brain."

Several studies have pointed to the usefulness of intestinal permeability testing as a marker for food This test may provide a practical means to follow the progress of patients undergoing treatment for food allergies.97 Apart from food allergy, increased intestinal permeability has been associated with autism, atopic dermatitis, arthritis, and numerous gastrointestinal diseases. Furthermore, a decrease in gut permeability may be accompanied by an improvement of the d i ~ e a s e . ~ ~ - ' ~ ' Recent research at our facility has demonstrated elevated gut permeability in 49 of 66 children (74%)with ADHD.lo2 Other emerging research suggests that there may be a profound link between gastrointestinal function and behavior. Parenteral administration of the hormone secretin has resulted in a significant and prolonged improvement in the behavior and cognitive function of children with autism.lo3The precise mechanism of action of secretin in this situation is not yet known. However, several clinicians who have been using IV secretin treatment in autistic children report evidence of improved gastrointestinal function and a concomitant decrease in microbial organic acid derivatives in the urine of these children suggestive of improved digestive function and gut mucosal immUnity.lo4Reports of IV secretin in children with ADHD have not been published to date.

Gastrointestinal Dysbiosis Increased intestinal permeability has been associated with the use of antibiotics. In addition, frequent ear infections with repeated courses of antibiotics are common historic features of ADHD.69These data suggest that disruption in normal gut flora may have far-reaching consequences and may be a sigruficant factor in the etiology of ADHD. Maintenance of normal gut flora probably plays a key role in the preservation of the mucosal barrier of the gut.105J06 Several species of Bijidobucteriu and Lactobacilli have been associated with normal gut function, and supplementation with these organisms may assist in the restoration of altered gut permeability (see Chapters 117 and 118) for a more complete discussion of this important topic). These organisms function as part of the first line of defense in gut immunity and may play a vital role in the development of normal immune responsiveness, as well as immune tolerance to dietary components. Efforts to promote the growth of these desirable organism may be important in the treatment of ADHD. In our previous study of ADHD children, Lactobacilli or BiFdobucteriu were absent in 29 of 63 stool samples (46%).'02 Appropriate quantities of secretory immunoglobulin (Ig) A result, in part, from adherence of adequate populations of beneficial bacterial species to the gut wall. Secretory IgA then, in turn, prevents the adherence of potential pathogens to the gut wall. Adequate amounts of secretory IgA also prevent passage of potential antigens across

Specific Health Problems

the gut mucosal epithelium.lo7Depressed production of secretory IgA may be a sigruficant factor in ADHD. Stool samples from our study group demonstrated markedly depressed secretory IgA in 28 of 63 subjects (44%).This may be due, at least in part, to diminished quantities of lactic acid fermenting bacteria adherent to the gut mucosa. A strategy to increase secretory IgA production in such individuals may include administration of species-specific probiotic (live bacteria) supplements.lo8 Symbiotic gut bacteria have been found to carry out other important functions. Following the digestion of food, certain bacterial species that are adherent to the small intestinal mucosa may provide signaling molecules to the gut associated lymphoid tissue and, through this mechanism, tolerance to food antigens is increased. Evidence is accumulating that probiotic supplementation can ameliorate the effects of food allergy and result in a desensitization of the patient to previously offending foods.106J09J10 Certain species of small intestinal bacteria may modify immunomodulatory properties of native food proteins through enzymatic hydrolysis, and this processing of antigens may be a primary factor in the development and maintenance of tolerance to potential food antigens."'J12 Because restrictive diets may be difficult for some to comply with and may be nutritionally inadequate, efforts to restore immunologic tolerance may be an important part of the long-term management of food-allergic patient^.^'^,"^ Symbiotic microbes have numerous other beneficial properties such as neutralization of microbial toxins and ~arcinogens"~ and inhibition of pathogenic bacterial growth including Helicobacter py10ri.l'~In contrast to the numerous physiologic benefits derived from adequate populations of symbiotic intestinal bacteria, overgrowth of potentially pathogenic bacteria, fungi, or protozoans may have a wide range of deleterious consequences. Numerous putrefactive or fermentative metabolites can be produced in vivo by intestinal microbes. Some of these agents (such as lactic acid, tartaric acid, ethanol, arabinose, dihydroxyphenylpropionic acid [DHPPA], ammonia, benzodiazepine receptor ligands, and methane) are sigruficantly neurotoxic and can be demonstrated in the urine or breath of individuals with neuropsychologic disorder^."^*"^ Other microbial components may significantly affect ADHD. For example, the bacterial enzyme beta-glucuronidase results in deconjugation of steroids intended for excretion via the stool. High amounts of this bacterial enzyme may result in heightened blood levels of certain steroid^,"^ which, in turn, may contribute to aggressive behavior in children with ADHD.Iz0 Other bacterial, fungal, protozoal, or helminthic enzymes or endotoxins may result in a direct degradation of the gut epithelium and result in the translocation of microbes across the gut wall, gut inflammation, and increased permeability.12*

At our facility, the presence of protozoal parasites in single, random stool samples was found in 26 of 63 subjects (41%), as well as heavy growth of Candida albicans in 20 of 63 (32%) and significant quantities of potential bacterial pathogens in almost every child studied. The presence of intestinal protozoans in nearly half of our study subjects was somewhat unexpected and may be of particular clinical sigruficance. Based on research evaluating the accuracy of single versus multiple stool samples, the actual incidence of intestinal protozoans in our study group was likely about 23% higher than reported because we only used one sample per subject.lZ Many of our subjects had multiple species of protozoans, some as many as five species. The incidence of intestinal protozoans in our study group was much higher than that found in other studies of North American children with or without diarrheal diseaseslD and in keeping with the incidence found in children of lower socioeconomic groups in Third World countries.124 Several studies have shown that the presence of intestinal protozoans in children increases allergic responsiveness and can be a primary cause of a t ~ p y . ' ~ ' * ~ Intestinal protozoans have also been implicated in cases of reactive arthritis, synovitis, and autoimmune In addition, certain bacterial pathogens are known to sigruficantly increase the pathogenicity of protozoal parasites. Thus the high frequency of protozoal parasites found in our study group may be of even greater sigruficance in the presence of the intestinal bacterial pathogens that were found so frequently in these children.132 Known bacterial pathogens may have many other deleterious effects. As mentioned earlier, numerous intestinal bacterial metabolites are being increasingly identified as neurotoxic and immunotoxic. In our recent research, many of the stools samples from children with ADHD had large quantities of known pathogens such as Klebsiella pneumoniae, Citrobacterfreundii, and Pseudomonas. Small intestinal overgrowth of these bacteria have been shown to play a central role in the pathogenesis of tropical malabsorption syndrome or tropical sprue and thus may contribute to poor nutrient absorption in ADHD (seeChapter 12 for a more complete discussion).133Certain bacterial species such as Klebsiella have been found to exist in association with autoimmune disorders.lMSince ADHD has been associated with higher titres of antineural antibodies, the possibility exists that ADHD or comorbid disorders may be due, in part, to autoimmune cross-reactivity between bacterial and neuronal antigen~.'~~J~

IMMUNE SYSTEM IMPAIRMENT It has been shown that subtle immune dysfunction may be a prominent problem in ADHD. Both cellular and

Attention Deficit Hyperactivity Disorder in Children

humoral immunity have been shown to be abnormal in children with ADHD as compared with age-matched controls.137Plasma complement levels have been found to be lower in children with ADHD.'= Immune dysfunction in ADHD may be either directly inherited139or it may be a result of nutritional, toxicologic, or atopic factors. ADHD may also be, in part, an autoimmune disorder. Antineural antibodies have been found in the blood and cerebrospinal fluid in ADHD.135J36Gut mucosal immunity may also be sigruficantly impaired in ADHD. Our recent investigation has demonstrated low levels of secretory IgA in the stool of the majority of children with ADHD. This finding is suggestive of diminished gut mucosal immunity and a concomitant increased susceptibility to gut pathogens and food allergies.lo2

COGNITIVE BEHAVIORALTHERAPIES All children exhibiting symptoms suggestive of ADHD should undergo thorough neurobehavioral and cognitive assessment. Many of the features often associated with gifted children can be mistaken for symptoms of ADHD. Likewise, children with mood disorders, learning disabilities, and those from abusive environments or who have suffered serious trauma may benefit from specific psychologic or cognitive behavioral interventions and will not respond appropriately to ADHD-specific pharmacotherapy. In addition, cognitive behavioral therapies that can be implemented in schools and in the home environment have been shown to be efficacious in the treatment of ADHD.Iu

NEUROFEEDBACK DRUG THERAPY The prevailing conventional approach to the treatment of ADHD relies almost entirely on monotherapy with stimulant drugs to bring about a desirable symptomatic response. Stimulants improve ADHD symptoms primarily by blocking dopamine reuptake in nerve endings via the dopamine transporter.21 Other drugs such as various antidepressants, antihypertensives, and the norepinephrine reuptake inhibitor atomoxetine are also commonly prescribed. These medications reportedly improve behavior and cognitive functioning in approximately 75% of children in formal placebo-controlled trials.140However, the success of treatment when studied in actual clinical practice may be significantly lower. Furthermore, follow-up studies have failed to demonstrate an improved prognosis for children treated with stimulant medi~ati0ns.l~~ Additionally, these drugs are associated with a high prevalence of adverse effects and their long-term impact on brain and cardiovascular health has not been adequately ~ t u d i e d . ' ~Previous J~~ research demonstrated a high frequency of cerebral atrophy in young adults treated with stimulant medication as children, whereas no cerebral atrophy was seen in age-matched controls.143 Since then, little effort has been made to determine if stimulants adversely affect brain development or result in brain damage at normally prescribed doses. Nonstimulants have been promoted as a safe alternative. However, the popular, nonstimulant atomoxetine (Strattera) has been implicated in several cases of serious hepatotoxicity. Likewise, the safety of selective serotonin reuptake inhibitors in children and adolescents has been called into question around the world. Many educators and health care providers believe that medication should not be used to treat childhood ADHD unless more conservative measures have been seriously undertaken and have failed.

In neurofeedback (EEG biofeedback) treatment, individuals are provided with real-time feedback about their brainwave activity through electronic instrumentation. This feedback allows the subject to learn self-regulation of brainwave intensity and frequency. Measurements of brain activity in many individuals with ADHD demonstrate cortical slowing and diminished brainwave intensity in the prefrontal region and frontal lobes. Neurofeedback treatment is designed to train individuals to increase the production of brainwave patterns that reduce or eliminate this cortical slowing and thus reduce or eliminate many associated ADHD symptoms. Evidence supporting neurofeedback is accumulating. For example, neurofeedback permitted cessation of methylphenidate in children without loss of treatment effect.145 Neurofeedback has also been found to improvebehavior with effectiveness comparable to methylphenidate.'% In a multicenter trial of more than 1000 children, neurofeedback was shown to effectively improve measure of attention.147Neurofeedback is often criticized because of the large number of expensive treatments usually required. Home-based, consumer-friendly equipment is now available to make neurofeedback more accessible to larger numbers of children.

THERAPEUTIC APPROACH A plethora of alternative and complementary therapies have been offered for the treatment of ADHD in children and adults. Some have good evidence for safety and efficacy, whereas the evidence for others is still lacking.148 A reasonable approach with a high probability of success will be multimodal and will address as many contributing factors as is practical. A basic workup ruling out common disorders that may present as ADHD is prudent, as these may require specific treatments and delay

Specific Health Problems of treatment may be harmful. Celiac disease, depression, lead poisoning, sleep apnea, and visual or auditory probl e m are some of the problems that should be included in the differential d i a g n o ~ i s . ' ~Other ~ , ' ~ contributory factors such as increased intestinal permeability; food allergies or intolerances; and iron, magnesium, zinc, and omega-3 fatty acid deficiency may be assessed through laboratory testing or simply treated empirically if financial constraints prevent ordering noninsured tests. In general a stepwise, rational approach is often successful.

Step 1 Assisting parents in eliminating junk foods, fast foods, and food additives from the diet (especially sugary foods and beverages, white flour products, and deep-fried foods) while increasing the quantity of whole foods is an important first step. If a child consumes more whole grains, fruits,vegetables, clean protein sources, pure water, and fiber, health benefits are inevitable. In some cases converting to a whole foods-based diet can result in marked improvements in behaviors and cognitive performance.

Step 2 Nutritional supplementation is often helpful and usually includes a pharmaceutic grade fish oil supplement or DHA/EPA concentrate; high-potency multivitamin/ trace mineral supplement; additional calcium, magnesium, and zinc (additional iron is also beneficial in children and adolescents if anemia or low iron stores are documented); and potent antioxidant support (e.g., green tea extract, Pycnogenol, grape seed extract). Although there is evidence to support each of these interventions, when combined, as well as in the context of a whole-foods diet, the results are usually significant.

Step 3 Gastrointestinal rehabilitation is a concept familiar to practitioners of natural medicine. This involves therapeutic steps to reduce intestinal permeability, improve nutrient absorption, and increase immune response to gut pathogens while diminishing hypersensitivities. A useful approach follows the mnemonic "ANT PIE" (Abstain, Nourish, Toxins/detoxification, Probiotics, Identify, Eliminate). Abstain from junk foods, deep-fried foods, sugary drinks, and other foods that harm or irritate the gut, as well as unnecessary drugs or excessive alcohol. Nourish the digestive tract with nutrients that support gut healing. Functional foods that combine low allergy potential protein and a number of nutrients helpful for gastrointestinal healing are readily available. Toxins/detoxification refers to the avoidance of pesticides by eating organic foods and consuming nutrients

that improve the efficiency of detoxification processes such as L-glutamine, N-acetylcysteine, dietary fiber, and cruciferous vegetables. Regular exercise and stress reduction are also important parts of this step. Probiotics are therapeutic bacteria (and some yeast) that may improve the gastrointestinal micro-ecology, improve immune response toward gut pathogens, reduce immune hypersensitivities, and stimulate gut repair. Identify allergenic or intolerant foods and gut pathogens. Food allergies (Type I or immediate hypersensitivity food reactions) can be identified by skin prick testing, radioallergosorbent testing, or enzyme-linked immunosorbent assay testing for IgE antifood antibodies. Patients with evidence of Type I hypersensitivity food allergies (e.g., postprandial swelling of the lips, urticaria, wheezing) should be referred to an allergist for definitive testing, as serious anaphylaxis could occur without proper avoidance. Delayed hypersensitivity reactions (usually Type I11 mediated) are best identified with a properly conducted elimination test diet followed by carefully observed reintroductions of individual food items eliminated in the test diet. IgG antifood antibodies may also be tested but only before any dietary manipulation has occurred. Intestinal parasites, yeast, and pathogenic bacteria may also be identified by stool testing, Cundida and H.pylori serology, breath testing, and urinary organic acids. Eliminate foods found to be allergic or intolerant with elimination test diet or laboratory testing. Gut pathogens, parasites, and Cundida overgrowth may be treated. This approach to gut rehabilitation follows a rational order that provides for optimal physiologic responses to treatment. The result of following this program to its completion in children with ADHD can be quite dramatic.

Step 4 Nutraceuticals can often provide additional improvements in behavior and cognition and may be a necessary intervention earlier on if parents are pressured to submit their child to drug intervention. A combination of standardized extracts of American ginseng and Ginkgo biloba was studied in my facility in an open-label trial and found to successfully improve behavior and school performance in children with ADHD.l5I More recently, we conducted a randomized, double-blind, placebocontrolled trial on 80 children with ADHD and nearly 70% of subjects demonstrated significant improvements in ADHD symptoms.'52L-theanine, an amino acid found in green tea, shows promise in the treatment of ADHD. This amino acid is known to reduce anxiety, increase

Attention Deficit Hyperactivity Disorder in Children

concentration, improve sleep quality, and stabilize mood without sedation. It improves cerebral dopaminergic activity and is patented for the treatment of ADHD in Japan and the European Union. Over the past 20 years, thousands of tons of L-theanine have been consumed as an approved food supplement in Japan, where L-theanine

is revered for its ability to produce a calm and focused state. Our facility is currently conducting a largescale, placebo-controlled trial on L-theanine in ADHD. L-theanine is currently approved for use as a food additive and nutritional supplement in the United States and

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61. Lester M, Thatcher R, Monroe-Lord L. Refined carbohydrate intake, hair cadmium levels and cognitive functioning in children. J Nutr Behavior 1982;l:l-14. 62. Connors C, Caldwell J, Caldwell L. Experimental studies of sugar and aspartame on autonomic, cortical and behavioral responses of children. Proceedings of interactions in psychology. Lubbock, TX: Texas Technical Press, 1986. 63. Marshall P. Attention deficit disorder and allergy: a neurochemical model of the relation between the illnesses. Psychol Bull 1989;3 434-446. 64. Tryphonas H, Trites R. Food allergy in children with hyperactivity, learning disabilities and/or minimal brain dysfunction. AM Allergy 1979;42:22-27. 65. Carter C, Urbanowicz M, Hemsley R, et al. Effects of a few food diet in attention deficit disorder. Arch Dis Child 1993;69:564-568. 66.Boris M. Foods and food additives are common causes of the attention deficit hyperactivity disorder in children. Ann Allergy 1994;72462-468. 67. Uhlig T, Merkenschlager A, Brandmaier R, Egger J. Topographic mapping of brain electrical activity in children with food-induced attention deficit hyperkinetic disorder. Eur J Pediatr 1997;156: 557-561. 68. Nsouli T, Nsouli S, Linde R, et al. Role of food allergy in serous otitis media. Ann Allergy 1994;73:215-219. 69. Hagerman RJ, Falkenstein MA. An association between recurrent otitis media in infancy and later hyperactivity. Clin Pediatr 1987;26: 253-257. 70. Marcotte A, Thacher P, Butters M, et al. Parental report of sleep problems in children with attentional and learning disorders. J Dev Behav Pediatr 1998;19:178-186. 71. McColley S, Carroll J, Curtis S, et al. High prevalence of allergic sensitization in children with habitual snoring and obstructive sleep apnea. Chest 1997;111:170-173. 72. Kaplan B, McNicol J, Conte R, Moghadam H. Sleep disturbance in preschool-aged hyperactive and nonhyperactive children. Pediatrics 1987;80839-844. 73. Kaplan BJ. Dietary replacement in preschool-aged hyperactive boys. Pediatrics 1989;83:7-17. 74. Egger J, Carter C, Graham P, et al. Controlled trial of oligoantigenic treatment in the hyperkinetic syndrome. Lancet 1985;1:540-545. 75. Schulte-Kome G, Deimel W, Gutenbrunner C, et al. Effect of an oligo-antigen diet on the behavior of hyperkinetic children. Z Kinder Jugendpsychiatr 1996;3:176-183. 76. Pelsser LM, Buitelaar JK. [Favourable effect of a standard elimination diet on the behavior of young children with attention deficit hyperactivity disorder (ADHD): a pilot study]. Ned Tijdschr Geneeskd 2002;146:2543-2547. 77. Egger J, Stolla A, McEwen L. Controlled trial of hyposensitisation in children with food-induced hyperkinetic syndrome. Lancet 1992;339:1150-1153. 78. McEwen L. A comparison between the effects of enzyme potentiated desensitization, methylphenidate and psychotherapy on the symptoms of attention deficit hyperactivity disorder in children. Personal communication, 1999. 79. Anderson J. Mechanisms in adverse reactions to food. The brain. Allergy 1995;5078-81. 80. Carvajal S, Mulvihill S. Intestinal peptides and their relevance in pediatric disease. Semin Pediatr Surg 1995;4:Y-21. 81. Egger J, Carter C, Wilson J, et al. Is migraine food allergy? A doubleblind controlled trial of oligoantigenic diet treatment. Lancet 1983; 2:865-869. 82.Carter C, Egger J, Soothill J. A dietary management of severe childhood migraine. Hum Nutr Appl Nutr 1985;39:294-303. 83. Egger J, Carter C, Soothill J, Wilson J. Oligoantigenic diet treatment of children with epilepsy and migraine. J Pediatr 1989;114: 51-58.

Attention Deficit Hyperactivity Disorder in Children 84. Reichelt KL, Knivsberg AM. Can the pathophysiology of autism be explained by the nature of the discovered urine peptides? Nutr Neurosci 2003;619-28. 85. Kitts DD, Weiler K. Bioactive proteins and peptides from food sources. Applications of bioprocesses used in isolation and recovery. Curr Pharm Des 2003;9:1309-1323. 86. Yoshikawa M, Takahashi M, Yang S. Delta opioid peptides derived from plant proteins. Curr Pharm Des 2003;9:1325-1330. 87. Whitcomb D, Taylor I. A new twist in the brain-gut axis. Am J Med Sci 1992304334-338. 88. Wahl M. Local chemical, neural, and humoral regulation of cerebrovascular resistance vessels. J Cardiovasc Pharmacol 1985;7(suppl3):S36-46. 89. Banks W, Kastin A. Passage of peptides across the blood-brain barrier: pathophysiological perspectives. Life Sci 1996;59: 1923-1943. 90. Eaton K, Howard M, Howard J. Gut permeability measured by polyethylene glycol absorption in abnormal gut fermentation as compared with food intolerance. J R Soc Med 1995;88:63-66. 91. van Elberg R, Uil J, De Monchy J, Heymans H. Intestinal permeability in pediatric gastroenterology. Scand J Gastroenterol 1992; 2719-24. 92. Laudat A, Amaud P, Napoly A, Brion F. The intestinal permeability test applied to the diagnosis of food allergy in paediatrics. West Indian Med J 1994;3:87-88. 93. Heyman M, Darmon N, Dupont C, et al. Mononuclear cells from infants allergic to cow’s milk secrete tumor necrosis factor alpha, altering intestinal function. Gastroenterology 1994;6: 1514-1523. 94. Simon L, Shine G, Dayan A. Translocation of particulates across the gut wall-a quantitative approach. J Drug Target 1995; 3217-219. 95. Heyman M, Grasset E, Ducroc R, Desjeux J. Antigen absorption by the jejunal epithelium of children with cow’s milk allergy. Pediatr Res 1988;24197-202. 96. Tatsuno K. Intestinal permeability in children with food allergy. Arerugi 1989;12:1311-1318. 97. Caffarelli C, Cavagni G, Menzies I, et al. Elimination diet and intestinal permeability in atopic eczema: a preliminary study. Clin Exp Allergy 1993;2328-31. 98. DEufemia P, Celli M, Finocchiaro R, et al. Abnormal intestinal permeability in children with autism. Acta Paediatr 1996;9: 1076-1079. 99. Forget P, Sodoyez-Goffaux F, Zappitelli A. Permeability of the small intestine to [51Cr]EDTAin children with acute gastroenteritis or eczema. J Pediatr Gastroenterol Nutr 1985;4393-396. 100. Jakobsson I. Intestinal permeability in children of different ages and with different gastrointestinal diseases. Pediatr Allergy Immunol 1993~433-39. 101. Paganelli R, Fagiolo U,Cancian M, Scala E. Intestinal permeability in patients with chronic urticaria-angioedema with and without arthralgia. Ann Allergy 1991;66181-184. 102. Lyon M, Cline J. The effect of an oligoantigenic diet on behavior and physiological parameters of children with attention deficit hyperactivity disorder. Unpublished data; 1999. 103. Horvath K, Stefanatos G, Sokolski K, et al. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minor Phys 1998;9:9-15. 104. Defeat Autism Now Professional Autism Discussion Group; Personal communication, 1999. 105. Salminen S, Isolauri E, Salminen E. Clinical uses of probiotics for stabilizing the gut mucosal barrier: successful strains and future challenges. Antonie Van Leeuwenhoek 1996;70347-358. 106.Majamaa H, Isolauri E. Probiotics: a novel approach in the management of food allergy. J Allergy Clin Immunol 1997;99: 179-185.

107. Albanese C, Smith S, Watkins S, et al. Effect of secretory IgA on the transepithelial passage of bacteria across the intact ileum in vitro. J Am Coll Surg 1994;179:679-688. 108. Malin M, Suomalainen H, Saxelin M, Isolauri E. Promotion of IgA immune response in patients with Crohn’s disease by oral bacteriotherapy with Lactobacillus GG. Ann Nutr Metab 1996;40: 137-145. 109. Miraglia del Giudice M, De Luca MG. The role of probiotics in the clinical management of food allergy and atopic dermatitis. J Clin

Gastroentero12004;38(suppl)S84-85. 110. von der Weid T, Ibnou-Zekri N, Pfeifer A. Novel probiotics for the management of allergic inflammation. Dig Liver Dis 2002; 34(s~ppl2):525-28. 111. Sutas Y, Soppi E, Korhonen H, et al. Suppression of lymphocyte proliferation in vitro by bovine caseins hydrolyzed with Lactobacillus casei GG-derived enzymes. J Allergy Clin Immunol1996; 98:216-224. 112. Sutas Y, Hurme M, Isolauri E. Down-regulation of anti-CD3 antibody-induced IL-4production by bovine caseins hydrolysed with Lactobacillus GG-derived enzymes. Scand J Immunol 1996; 43~687-689. 113. Isolauri E, Sutas Y, Salo M, et al. Elimination diet in cow’s milk allergy: risk for impaired growth in young children. J Pediatr 1998;1321004-1009. 114. Isolauri E, Sutas Y, Makinen-Kiljunen S, et al. Efficacy and safety of hydrolyzed cow milk and amino acid-derived formulas in infants with cow milk allergy. J Pediatr 1995;127550-557. 115. El-Nazami H, Kankaanpaa P, Salminen S, Ahokas J. Ability of dairy strains of lactic acid bacteria to bind a common food carcinogen, aflatoxin B1. Food Chem Toxic01 1998;36321-326. 116. Midolo P, Lambert J, Hull R, et al. In vitro inhibition of Helicobacter pylon NCTC 11637 by organic acids and lactic acid bacteria. J Appl Bacteriol 1995;79:475-479. 117. Shaw W. Experience with organic acid testing to evaluate abnormal microbial metabolites in the urine of children with autism. National Conference on Autism. Milwaukee, WI; 1996. 118. Yurdaydin C, Walsh T, Engler H, et al. Gut bacteria provide precursors of benzodiazepine receptor ligands in a rat model of hepatic encephalopathy. Brain Res 1995;679:42-48. 119. Martin F, Bhargava A, Adlerereutz H. Androgen metabolism in the beagle: Endogenous androgen metabolites in bile and feces and the effect of ampicillin administration. J Steroid Biochem 1977;8:753-760. 120. ScerboA, Kolko D. Salivary testosterone and cortisol in disruptive children: relationship to aggressive, hyperactive, and intemalizing behaviors. J Am Acad Child Adolesc Psychiatry 1994;33 1174-1184. 121. ODwyer S, Michie H, Ziegler T, et al. A single dose of endotoxin increases intestinal permeability in healthy humans. Arch Surg 1988;1231459-1464. 122.Hiatt R, Markell E, Ng E. How many stool examinations are necessary to detect pathogenic intestinal protozoa? Am J Trop Med Hyg 1995;5336-39. 123. Kappus K, Lundgren RJ, Juranek D, et al. Intestinal parasitism in the United States: update on a continuing problem. Am J Trop Med Hyg 1994;50:705-713. 124. Brannan D, Greenfield R, Owen W, et al. Protozoal colonization of the intestinal tract in institutionalized Romanian children. Clin Infect Dis 1996;22:456-461. 125. DiPrisco PM, Hagel I, Lynch N, et al. Possible relationship between allergic disease and infection by Giardia lamblia. Ann Allergy 1993;70210-213. 126. DiPrisco PM, Hagel I, Lynch N, et al. Association between giardiasis and allergy. Ann Allergy Asthma Immunol1998;81:261-265. 127. Cuffari C, Oligny L, Seidman E. Dientamoeba fraghs masquerading as allergic colitis. J Pediatr Gastroenterol Nutr 1998;26:16-20.

Specific Health Problems 128. Gat0 MR, Banez SF, Pascual GJ, et al. [Reactive arthritis due to Giardia lamblia in a patient with IgA deficiency (letter)]. Ann Med Intema 1998;15:398-399. 129.Russo A, Stone S, Taplin M, et al. Presumptive evidence for Blastocystis hominis as a cause of colitis. Arch Intern Med 1988;148:1064. 130. Lee M, Rawlins S, Didier M, DeCeulaer K. Infective arthritis due to Blastocystis horninis. Ann Rheum Dis 1990;49:192-193. 131.Shein R, Gelb A. Colitis due to Dientamoeba fragilis. Am J Gastrwnterol1983;78:634-636. 132. Gomes M, Martins M, Costa A, Silva E. Influence of bacteria upon cytopathic effect and erythrophagocytosis of different axenic strains of Entamoeba histolytica. Rev Inst Med Trop Sao Paulo 199537197-200. 133.TomkinsA, Wright S, Drasar B. Bacterial colonization of the upper intestine in mild tropical malabsorption. Trans R Soc Trop Med Hyg 1980;74:752-755. 134.Cooper R, Fraser S, Sturrock R, Gemmell C. Raised titres of anti-klebsiella IgA in ankylosing spondylitis, rheumatoid arthritis, and inflammatory bowel disease. Br Med J (Clin Res Ed) 1988; 296:1432-1434. 135. Swedo S, Leonard H, Kiessling L. Speculations on antineuronal antibody-mediated neuropsychiatric disorders of childhood. Pediatrics 199493323-326. 136. Kiessling L, Marcotte A, Culpepper L. Antineuronal antibodies: tics and obsessive-compulsive symptoms. J Dev Behav Pediatr 1994;15:421-425. 137. Mittleman 8, Castellanos F, Jacobsen L, et al. Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. J Immunol 1997;15929942999. 138. Warren R, Odell J, Warren W, et al. Is decreased blood plasma concentration of the complement C4B protein associated with attention-deficit hyperactivity disorder? J Am Acad Child Adolesc Psychiatry 1995;34:1009-1014. 139. Odell J, Warren R, Warren W, et al. Association of genes within the major histocompatibility complex with attention deficit hyperactivity disorder. Neuropsychobiology 1997;35181-186. 140. Greenhill L. Pharmacologic treatment of attention deficit hyperactivity disorder. Psychiatric Clin North Am 1992;15:1-27. 141. Lie N. Follow-ups of children with attention deficit hyperactivity disorder (ADHD). review of literature. Acta Psychiatrica Scandinavica 1992;368:1-40. 142. Henderson TA, Fischer VW. Effects of methylphenidate (Ritalin) on mammalian myocardial ultrastructure. Am J Cardiovasc Pathol 1995;5:68-78. 143. Nasrallah HA, Loney J, Olson SC,et al. Cortical atrophy in young adults with a history of hyperactivity in childhood. Psychiatry Res 1986;17241-246.

144. Miranda A, Presentacion M. Efficacy of cognitive-behavioral therapy in the treatment of children with ADHD, with and without aggressiveness. Psycho1Schools 2000;37169-182. 145. Monastra VJ,Monastra DM, George S. The effects of stimulant therapy, EEG biofeedback, and parenting style on the primary symptoms of attention-deficit/hyperactivitydisorder. Appl Psychophysiol Biofeedback 2002;27231-249. 146.Fuchs T, Birbaumer N, Lutzenberger W, et al. Neurofeedback treatment for attention-deficit/hyperactivitydisorder in children: a comparison with methylphenidate. Appl Psychophysiol Biofeedback 2003;28:1-12. 147.Kaiser DA, Othmer S. Effect of neurofeedback on variables of attention in a large multi-center trial. J Neurotherapy 2000; 45-15, 148. Amold LE. Alternative treatments for adults with attentiondeficit hyperactivity disorder (ADHD). Ann N Y Acad Sci 2001; 931:310-341. 149.O’Brien LM, Holbrook CR, Mervis CB, et al. Sleep and neurobehavioral characteristics of 5- to 7-year-old children with parentally reported symptoms of attention-deficit/ hyperactivity disorder. Pediatrics 2003;111:554563. 150.Zelnik N, Pacht A, Obeid R, Lemer A. Range of neurologic disorders in patients with celiac disease. Pediatrics 2004;113: 1672-1676. 151. Lyon MR, Cline JC, Totosy de Zepetnek J, et al. Effect of the herbal extract combination Panax quinquefolium and Ginkgo biloba on attention-deficit hyperactivity disorder: a pilot study. J Psychiatry Neurosci 2001;26221-228. 152. Lyon MR, Laurel1 GC. Effect of the herbal extract combination Panax quinquefolium and Ginkgo biloba on attention-deficit hyperactivity disorder: a double blind, placebo controlled trial on 78 children (pending publication, 2002). 153. Juneja LR, Chu D-C, Okobu T, et al. L-theanine: a unique amino acid of green tea and its relaxation effect in humans. Trends Food Science Technol 1999;10199-204. 154. Kobayashi K. Effects of L-theanine in the release of alpha-brain waves in human volunteers, Nippon Nogeikagako Kaishi 1998;72:153-157. 155. Kakuda T. Neuroprotective effects of the green tea components theanine and catechins. Biol Pharm Bulletin 2002; 121513-1518. 156. Lekh RJ. L-theanine - a unique amino acid of green tea and its relaxation effect in humans, Trends Food Science Technol 1999;1 0199-204. 157. Mason R. 200mg of Zen; L-theanine boosts alpha waves, promotes alert relaxation. Altem Complement Ther 2001;791-95. 158. Ueda T, Ozeki M, Okubo, et al. Improving effects of L-theanine on premenstrual syndrome. J JSPOG. 2001;6234-239.

Bacterial Sinusitis Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

1545

General Considerations 1545 Therapeutic Considerations 1545 Antibiotics 1545 Allergy 1546 Mucolytics 1546

DIAGNOSTIC SUMMARY History of acute viral respiratory infection, dental infection, or nasal allergy Nasal congestion and purulent discharge Fever, chills, and frontal headache Pain, tenderness, redness, and swelling over the involved sinus Transillumination shows opaque sinus Chronic infection may produce no symptoms other than mild postnasal discharge, a musty odor, or a nonproductive cough

GENERAL CONSIDERATIONS The most common predisposing factor in acute bacterial sinusitis is viral upper respiratory infection (the common cold). Allergic rhinitis and other factors that interfere with normal protective mechanisms may precede the viral infection and therefore are the more likely predisposing factors. Any factor that induces edema of the mucous membranes may result in obstruction of meatal drainage. The transudate that is produced serves as a suitable medium for bacterial overgrowth, with streptococci, pneumococci, staphylococci, and Huemophillus influenme being most commonly cultured. In chronic sinusitis an allergic background is commonly present, and in 25% of chronic maxillary sinusitis there is an underlying dental infection. Although vasoconstrictors and antihistamines cause transient relief, their chronic use is contraindicated

Therapeutic Approach 1546 Supplements 1546 Botanicals 1546 Local Treatment 1547 Physical Therapy 1547

because there is usually a reflex reaction following continual administration.

THERAPEUTIC CONSIDERATIONS Antibiotics Although antibiotic therapy is the dominant treatment of acute and chronic bacterial sinusitis, it is of limited value.' The effectiveness of antibiotic therapy of acute sinusitis in adults is quite controversial. A detailed analysis to determine the evidence for the effectiveness of antibiotic treatment in acute maxillary sinusitis in adults by assessing the methodologic quality of placebo-controlled double-blind randomized trials concluded: "The effectiveness of antibiotic treatment in acute maxillary sinusitis in a general practice population is not based sufficientlyon evidence."2 Nonetheless, in severe or unresponsive cases, antibiotics may be appropriate. Newer, more potent antibiotics (e.g., lactam antibiotics) appear to be more effective than penicillin, amoxicillin, and other less potent antibiotic^.^ In children, there is even less evidence that antimicrobial therapy is of significant benefit. Overuse of antibiotics in children with sinusitis or otitis media is a growing concern as it is leading to antibioticresistant strains of bacterial pathogens. No definitive trials of bacteriologic efficacy in children have been p~blished.~ In chronic sinusitis, antibiotics are also of little or no benefit.5 Clearly, addressing the underlying cause of chronic sinusitis (e.g., respiratory or food allergens) along with supportive therapy (e.g., saline nasal sprays,

1545

Specific Health Problems

immune-enhancingherbs, natural decongestants) appears to be the most rational approach.

Allergy Studies indicate that most cases of chronic sinusitis have allergies, perhaps as many as 84°/0.6,7Patients with chronic sinusitis should be aggressively screened for environmental and food allergies. Environmental control requires the elimination of dust mites (warm water washing at a temperature of least 58" C), use of air-filtering vacuum cleaners, installation of an air cleaner with a high-efficiency particulate air filter, and whatever methods are necessary to maintain the humidity under 50%. Some particularly sensitive patients may need to have all pets removed, along with carpeting and feather bedding?

Mucolytics Airway mucociliary clearance depends on the properties and volume of secreted mucus, ciliary function, and mucociliary interactions. In chronic sinusitis, m u m viscoelasticity is higher than the optimal values for mucociliary clearance. Mucolytic agents such as N-acetylcysteine (NAC) and proteolytic enzymes can reduce viscoelasticity and promote mucociliary clearance? NAC is the most commonly used mucolytic agent. The free sulfhydryl group of NAC interacts with the disulphide bonds of mucus glycoproteins, thereby breaking the protein network into less viscous strands. Although NAC is often used as a 10% solution by dilution with saline, sodium bicarbonate, and sterile water, it can also be used orally for sinusitis as it has been shown to be effective for chronic bronchitis.I0 Proteolytic enzymes may break down complex proteins at the site of inflammation, exert some antimicrobial effects, or act directly on the naked peptide region of mucus glycoproteins. Trypsin, chymotrypsin, serratia peptidase, bromelain, and streptokinase are the proteolytic enzymes that can break down mucus glycoproteins and other proteins when they are administered topically. When serratia peptidase was given at a dose of 30 mg/day for 4 weeks to patients with chronic sinusitis, it sigruficantly reduced the viscosity but not the elasticity of nasal mucus." It has been reported that the ratio of the viscosity to the elasticity is an important determinant of mucociliary transport. When serratia peptidase was administered at the same dose to patients with chronic bronchitis, it sigruficantly increased mucociliary clearance.12 A multicenter, double-blind, placebo-controlled study of 193 subjects suffering from various acute or chronic ear, nose, or throat disorders including sinusitis demonstrated a greater efficacy and rapid action of the peptidase against all the symptoms examined.13

Orally administered bromelain has also shown benefit in the treatment of chronic sinu~itis.'~

THERAPEUTIC APPROACH In acute sinusitis, the immediate therapeutic goals are to reestablish drainage and clear the acute infection. Various measures can be used: local application of heat, local use of volatile oils and botanicals with antibacterial properties, and immune system support (see Chapter 57). Because chronic sinusitis is often associated with allergy, long-term control depends on isolation and elimination of the food or airborne allergens and correction of the underlying problem that allowed the allergy to develop (seeChapter 53 for a more thorough discussion). During the acute phase, elimination of common food allergens (milk, wheat, eggs, citrus, corn, and peanuts) is indicated until a more definitive diagnosis can be made. Local applications of heat have been shown to be effective in alleviating both short- and long-term symptoms of allergic rhinitis.15

Supplements Vitamin C: 500 mg three times daily Bioflavonoids: 1000 mg/day Vitamin A: 5000 IU/day or betacarotene: 25,000 IU/day NAC: 200 mg three times daily Serratia peptidase or bromelain: Bromelain (1200 to 1800 MCU): 250 mg three times daily Serratia peptidase (enteric coated): 50 mg three times daily between meals

Botanicals Echinacea sp. Dried root (or as tea): 0.5 to 1g Freeze-dried plant: 325 to 650 mg Juice of aerial portion of Echinaceu purpurea stabilized in 22%ethanol: 2 to 3 ml Tincture (1:5): 2 to 4 ml Fluid extract (1:l): 2 to 4 ml Solid (dry powdered) extract (6.5:l or 3.5% echinacoside): 150 to 300 mg Hydrastis canadensis-the dosage should be based on berberine content. As there is a wide range of quality in goldenseal preparations, standardized extracts are recommended. Three-times-a-day dosages follow: Dried root or as infusion (tea): 2 to 4 g Tincture (1:5):6 to 12 ml(1.5 to 3 tsp) Fluid extract (1:l): 2 to 4 ml(0.5 to 1 tsp) Solid (powdered dry) extract (4:l or 8% to 12% alkaloid content): 250 to 500 mg

Bacterial Sinusitis

Local Treatment

Physical Therapy

Intranasal douche with saline water or Hydrastis tea Swab passages with oil of bitter orange Menthol or eucalyptus packs over sinuses (care should be taken to avoid irritation)

Local applications of hot packs Diathermy: 30 minutes (discontinue if pain increases without drainage)

1.Stalman WA, van Essen GA, van der Graaf Y. Determinants for the course of acute sinusitis in adult general practice patients. Postgrad Med J 2001;77:778-782. 2. Stalman W, van Essen GA, van der Graf Y. Maxillary sinusitis in adults: an evaluation of placebo-controlled double-blind trials. Fam Pract 1997;14:124-129. 3. Poole MD. Antimicrobial therapy for sinusitis. Otolaryngol Clin North Am 1997;30331-339. 4. Cohen R. The antibiotic treatment of acute otitis media and sinusitis in children. Diagn Microbiol Infect Dis 1997;2735-39. 5. Dohlman AW, Hamstreet MPB, Odrezin GT, Bartolucci AA. Subacute sinusitis: are antimicrobials necessary? J Allergy Clin Imm~n011993;91:1015-1023. . Gutman M, Torres A, Keen KJ, Houser SM. Prevalence of allergy in patients with chronic rhinosinusitis. Otolaryngol Head Neck Surg 2004;130545-552. 7.Emanuel IA, Shah SB. Chronic rhinosinusitis: allergy and sinus computed tomography relationships. Otolaryngol Head Neck Surg 2000;123:687-691. 8. Evans R III. Environmental control and immunotherapy for allergic disease. J Allergy Clin Immunol1992;90462-468.

9. Majima Y. Mucoactive medications and airway disease. Paediatr Respir Rev 2002;3104-109. 10. Grandjean EM, Berthet P, Ruffmann R, Leuenberger P. Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebocontrolled clinical trials. Clin Ther 2000;22:209-221. 11. Majima Y, Inagaki M, Hirata K, et al. The effect of an orally administered proteolytic enzyme on the elasticity and viscosity of nasal mucus. Arch Otorhinolaryngol1988;244:355-359. 12. Nakamura S, Hashimoto Y, Mkami M, et al. Effect of the proteolytic enzyme serrapeptase in patients with chronic airway disease. Respirology 2003;831&320. 13.Mazzone A, Catalani M, Costanzo M, et al. Evaluation of Serratia peptidase in acute or chronic inflammation of otorhinolaryngology pathology: a multicentre, double-blind, randomized trial versus placebo. J Int Med Res 1990;18:379-388. 14. Ryan RE. A double-blind clinical evaluation of bromelains in the treatment of acute sinusitis. Headache 1967;713-17. 15.Yerushalmi A, Karman S, Lwoff A. Treatment of perennial allere;ic rhinitis by local hyperthermia. Proc Natl A'cad Sci U S-A 1982;79:4766-4769.

'For references on botanical and nutritional recommendations, see Chapters 53. 89. and 100.

Benign Prostatic Hyperplasia Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

1549

Dietary and Nutritional Factors Botanical Medicines 1552

1550

General Considerations 1549 Diagnostic Considerations 1549 Urine and Blood Tests 1550 Prostate-Specific Antigen 1550

Therapeutic Approach 1554 Lifestyle 1554 Diet 1554 Supplements 1554 Botanicals 1554

Therapeutic Considerations 1550 Lifestyle/Exercise 1550

DIAGNOSTIC SUMMARY Symptoms of bladder outlet obstruction (progressive urinary frequency, urgency and nocturia, hesitancy, and intermittency with reduced force and caliber of urine) Enlarged, nontender prostate Uremia if prolonged obstruction

GENERAL CONSIDERATIONS Benign prostatic hyperplasia (BPH, also known in the past as benign prostatic hypertrophy) affects more than 50% of men in their lifetime. The actual incidence increases with advancing age from approximately 5% to 10% at age 30 to more than 90% in men older than 85 years of age.' Genetic predisposition plays a role in BPH. Hereditary BPH, characterized by an early onset and enlarged prostate gland, is related to an inheritance that is autosoma1 dominant or codominant, whereas the BPH type bearing the more common late-onset symptomology appears to have a weaker genetic component? Specific alleles of the genes that code for the cytochrome P45Oc17alpha enzyme, which mediates sex steroid synthesis, have also been implicated in increased BPH and prostate cancer risk? As a result of its strong pattern of inheritance, hereditary BPH may prove recalcitrant to natural means alone, whereas the more common late-onset type may be more responsive to natural therapeutics

alone. Either way, the natural treatments described in this chapter can moddy sex steroid metabolism and decrease symptomology for both types of BPH. BPH represents an androgen-dependent disorder of metabolism reflecting the many significant changes in steroid levels in aging men. Testosterone (T), particularly free testosterone, levels decrease with age after the fifth decade. Prolactin, estradiol, sex hormone-binding ligand, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels are all increased. The ultimate effect of these changes is an increased intraprostatic concentration of dihydrotestosterone (DHT), the potent androgen derived from testosterone. This increase is largely due to a decreased rate of removal combined with an increase in the activity of the enzyme 5-alphareductase, the enzyme that converts T to DHT.4 T and DHT are extensively metabolized by hydroxylation, which decreases the normally high affinity of the cytosolic receptor proteins for these hormones, thereby allowing their excretion. Estrogens inhibit this hydroxylation. The prostatic androgen receptors have a fivefold greater affinity for DHT than T, and BPH tissue has a threefold to fourfold greater net ability to increase tissue levels of DHT.

DIAGNOSTIC CONSIDERATIONS BPH originates in the periurethral and transition zones of the prostate in a microscopic (lustologically identifiable) state as early as the third decade of life. With advancing age and the presence of androgens, microscopic BPH 1549

Specific Health Problems develops into macroscopic (palpably enlarged prostate) BPHs. However, symptoms develop in only 50% to 60% of men with an enlarged prostate gland. Many men develop symptoms without macroscopic enlargement, as the hyperplasia go to the area of least resistance-the lumen of the urethra.’ In other words, about one half of men with a palpably enlarged prostate have symptoms and roughly one half of men with a normal-sized prostate experience symptoms. What all thismeans is that relying solely on digital palpation for diagnosis is unreliable.

Urine and Blood Tests Patients with suspected BPH should undergo dipstick urinalysis testing or microscopic urinalysis to screen for infection or hematuria, plus a serum creatinine determination to check kidney function. The American Urological Association and the American Cancer Societyboth recommend PSA testing and rectal examination for men 50 years of age and older. Black men and men who have a first-degree relative with prostate cancer are at a higher risk for prostate cancer and should be screened at age 45.5

Prostate-Specific Antigen Because the symptoms of BPH and prostate cancer can be quite similar, measurement of prostate-specific antigen (PSA) is often used to differentiate BPH from the more serious prostate cancer. The PSA test is a highly accurate and sensitive marker for prostate cancer. The normal value for PSA is less than 4 ng/ml. PSA levels greater than 4 should be referred to a urologist for further evaluation. An elevation greater than 10 is highly indicative of prostate cancer. Concern has been expressed that the use of PSA as a screening test for prostate cancer is not reliable enough. Although a n elevated level indicates prostate cancer in about 90% of cases, it must be kept in mind that midrange elevations in PSA can be caused by BPH and that in some instances there may be prostate cancer without elevation of PSA levels. Factors such as prostatitis, urinary retention, ejaculation, and exercise can also lead to elevations in PSA. Despite the fact that the PSA test is not perfect, it is a simple, relatively noninvasive test that can provide valuable information. PSA screening has been endorsed by the American Cancer Society, the American Urological Association, and other physicians’ groups. For men older than the age of 50, where there is a family history (any immediate relative-father, brother, or uncle) of prostate cancer, an annual prostate examination and PSA test are strongly recommended.

THERAPEUTIC CONSIDERATIONS If left untreated, BPH eventually obstructs the bladder outlet, resulting in the retention of urine and eventually

kidney damage. As this situation is potentially life threatening, proper surgical treatment is crucial. Surgery may also be indicated in patients who have failed medical therapy or have recurrent infection, hematuria, or renal insufficiency. In the past, medical treatment involved a procedure known as a TURF’ (trans-urethral resection of the prostate). Because this surgery is associated with a high rate of morbidity (sexualdysfunction, incontinence, and bleeding)5and often makes matters worse, it should be avoided unless absolutely necessary. Surgical procedures that use thermal microwave or laser to reduce hyperplastic tissue are also available. Generally, these newer procedures are less expensive than transurethral resection of the prostate and have fewer complications, although subsequent therapies are often required?

Lifestyle/Exercise An inverse association exists between physical activiV7 and BPH, and there is a positive association between abdominal obesity and BPH.6 Increases in calories ingested may encourage abdominal obesity and sympathetic nervous system activity, both of which can increase the risk of BPH. Increased sympathetic activity, which is the “fight or flight” arm of the autonomic nervous system, may cause the prostate smooth muscle to contract, resulting in a worsening of lower urinary tract symptoms. Interestingly, higher caloric intake does not seem to increase BPH risk when accompanied by increased physical activity.6 It is then possible that physical activity may serve a threefold purpose: (1)It may increase blood flow to the area, allowing the body to remove wastes efficiently; (2) it can decrease sympathetic stress responses, thus relaxing prostatic tissue; and (3)it can reduce excess abdominal weight, which increases overall lower body pressure, thus relaxing the prostate/rectal region and improving blood flow into and out of the area.

Dietary and Nutritional Factors Diet appears to play a critical role in the health of the prostate. It is particularly important to avoid pesticides, increase fruit consumption? increase the intake of zinc and essential fatty acids, decrease coffee consumption? decrease butter consumption, avoid margarine? and keep cholesterol levels below 200 mg/dl.

High-Protein Diet Research evaluating protein intake and BPH is mixed. Some evidence shows that a high-protein diet (total calories: 44% protein, 35% carbohydrate, 21% fat) can inhibit 5-alpha-reductase, while a low-protein diet (10% protein, 70% carbohydrate, and 20% fat) may stimulate the enzyme.1° Seemingly contrary, an %year study of 3523 men with BPH cited that total protein intake is positively associated with BPH, with the association being slightly stronger for animal protein intake than for

Benign Prostatic Hyperplasia

vegetable protein intake.6 A study of Chinese farmers also revealed a correlation between higher animal intake and the incidence of BPH (91.1% in those eating high animal diets vs. 11.8% in those not eating animalprotein)." A possible theoretic reason why high protein intake may not be helpful relates to a greater osmolar load, which may influence urinary output and thus impose undue extra burden on an already taxed system.6 Therefore at this time, we recommend against ingesting excess animal protein as a means to increase total protein intake. Instead, high-quality, plant-derived and coldwater fish-based protein sources in moderate amounts are probably reasonable choices until we know more about the relationship of protein intake and BPH.

6581 men in Hawaii, it was noted that an alcohol intake of at least 25 oz/month was directly correlated with the diagnosis of BPH.25The association was most sigruficant for beer, wine, and sake and less for distilled spirits. A smaller study of 889 men described an inverse association between alcohol intake and men treated surgically for BPH or in "watchful waiting" for surgical intervention. This study also mentioned the correlation of higher rates of BPH in men with coronary disease. Although these studies are apparently contradictory in relationship to alcohol, it is possible that in men at higher risk for coronary artery disease due to higher levels of lowdensity lipoproteins, alcohol may play an overall protective role by reducing these lipoproteins.

Zinc

Essential Fatty Acids

Paramount to an effective BPH treatment plan is adeThe administration of an essential fatty acid (EFA) comquate zinc intake and absorption. Zinc supplementation plex containing linoleic, linolenic, and arachidonic acids has resulted in significant improvement for many BPH has been shown to reduce the size of the prostate-as patients.z6 All 19 subjects in an uncontrolled study determined by rectal palpation, radiograph, and showed diminution of residual urine, with 12 of the 19 endoscopy-and to reduce symptomatology in the majority of patients in studies conducted in the 1970~.'~J~having no residual urine by the end of several weeks of The clinical efficacy of zinc is probably due to its critical treatment. These effects appear to be due to the correction of an underlying EFA deficiency, since these patients' involvement in many aspects of androgen metabolism. prostatic and seminal lipid levels and ratios are often Intestinal uptake of zinc is impaired by estrogens but abn0rma1.2',~~ Because of concern regarding increased enhanced by androgens. Because estrogen levels are oxidation of unsaturated acids: a basic antioxidant increased in men with BPH, zinc uptake may be low. Although zinc levels and 5-alpha-reductase activity regimen should be employed when taking EFAs. do not consistently correlate in hyperplastic tissue, zinc Amino Acids has been shown to inhibit the activity of 5-alphaThe combination of glycine, alanine, and glutamic acid reductase, the enzyme that irreversibly converts T to (in the form of two 6-grain capsules administered three DHT.l4l8Zinc also inhibits specific binding of androgens times daily for 2 weeks and one capsule three times daily to the cytosol and nuclear androgen re~ept0rs.l~ thereafter) has been shown in several studies to relieve Zinc has also been shown to inhibit prolactin many BPH symptoms. In a controlled study of 45 men, s e c r e t i ~ n .Prolactin ~ ~ , ~ ~ has been shown to increase the nocturia was relieved or reduced in 95%, urgency uptake of testosterone by the prostate, thereby leading to increased levels of DHT by providing more substrate.2O reduced in 8l%, frequency reduced in 73%,and delayed micturition alleviated in 70Y0.2~These results have also Prolactin antagonists such as bromocriptine have been been reported in other controlled studies.30The mechashown to reduce many of the symptoms of prostatic hyperplasia. However, these drugs have severe side nism of action is unknown but is likely related to the amino acids acting as inhibitory neurotransmitters and effects and are of limited Beer (but not pure alcoreducing the feelings of a full bladder. In other words, hol), tryptophan, and stress all increase prolactin secretion amino acid therapy is only palliative. and may therefore be aggravating factors.22,23 The authors of one case control study of 184 patients Cholesterol and 356 controls report a positive association between zinc and BPH. Possibly, in this study higher zinc was Cholesterol metabolites are cytotoxic and carcinogenic associated with intake of meat, a known risk factor for and have been shown to accumulate in the hyperplastic increased BPH.6J1,24It is well known that zinc is concenor cancerous human prostate. Epoxycholesterols initiate trated in the prostate gland of patients of BPH, but we degeneration of epithelial cells, leading to the increased regeneration seen in BPH. Hypocholesterolemic drugs suspect this is due to a secondary protective mechanism, have been shown to have a favorable influence on BPH, by which the body purposefully increases prostatic zinc in an attempt to modulate the activity of 5-alpha-reductase.16 preventing the accumulation of cholesterol in the prostatic cells and limiting subsequent formation of epoxycAlcohol hole sterol^.^^ Every effort should be made to decrease cholesterol levels by using the principles outlined in Although only beer raises prolactin levels, higher alcohol Chapter 150. intake may be associated with BPH. In a 17-year study of

Specific Health Problems

SOY Soybeans are especially rich in phytosterols, especially beta-sitosterol. The cholesterol-lowering effects of phytosterols are well d ~ c u m e n t e dPhytosterols .~~ have also been shown to improve BPH. The latest double-blind study consisted of 200 men receiving beta-sitosterol (20 mg) or placebo three times daily.33The beta-sitosterol produced an increase in maximum urine flow rate from a baseline of 9.9 m l / s to 15.2 m l / s and a decrease in mean residual urinary volume of 30.4 ml from 65.8 ml. No changes were observed in the placebo group. A 3.5-oz serving of soybeans, tofu, or other soyfood provides approximately 90 mg of beta-sitosterol. An increased consumption of soy and soyfoods is associated with a decrease in the risk of prostate cancer.34 Much of this protection is due to the isoflavonoids genistein and daidzein, the so-called phytoestrogens of And in addition to acting on estrogen receptors, isoflavones have been shown to inhibit 5-alphar e d ~ c t a s eCurrently, .~~ foods like soy and the botanical Trifolium praetense (red clover), which contain these phytotherapeutic isoflavones, are recommended in men with BPH, especially those in the "watchful-waiting" stage of the c ~ n d i t i o n . ~ ~

Drugs and Pesticides The diet should be as free as possible from pesticides and other contaminants because many of these compounds (e.g., dioxin, polyhalogenated biphenyls, hexachlorobenzene, and dibenzofurans) increase 5-alpha reduction of steroids.1° Diethylstilbestrol produces changes in rat prostates histologically similar to BPH.

Cadmium Although cadmium is a known antagonist of zinc and increases the activity of 5-alpha-reductase,its concentration in, and effects on, the prostate are unclear. Several studies have produced conflicting result^.^^,^

Botanical Medicines According to a recent review article published in the British Journal of Urology, plant-based medicines are much more popular prescriptions in Europe than their synthetic c0unterparts.j' Specifically, in Germany and Austria botanical medicines are considered "first-line" treatments for BPH and account for greater than 90% of all drugs in the medical management of BPH. In Italy plant extracts account for roughly 50% of all medications prescribed for BPH, while alpha-blockers and 5-alphareductase inhibitors account for only 5.1% and 4.8%, respectively.4l About 30 plant-based compounds are currently available in Europe for the treatment of BPH. At least 15 of them contain Serenoa repens (saw palmetto) extract. Other popular botanical medicines include

Pygeum africanum, Urtica dioica (stinging nettles), and Cernilton, a special flower pollen extract. On the basis of careful examination of the published literature, we rate the relative effectiveness of these agents as follows: Serenoa > Cernilton > Pygeum > Urtica However, in certain situations one herbal approach may be more effective than another. In other words, even though we rate urtica lowest, in some cases urtica may produce better results than Serenoa. Each plant has a slightly different mechanism of action. The chance of clinical success with any of the botanical treatments of BPH appears to be determined by the degree of obstruction as indicated by the residual urine content. For levels less than 50 ml, the results are usually excellent. For levels between 50 and 100 ml, the results are usually quite good. Residual urine levels between 100 and 150 ml will be tougher to produce significant improvements in the customary 4- to 6-week period. If the residual urine content is greater than 150 ml, saw palmetto extract and other botanical medicines are unlikely to produce any significant improvement on their own.

Serenoa repens (Saw Palmetto) The liposterolic extract of the fruit of this palm tree (also known as Sabal serrulata), native to Florida, has been shown to significantly improve the signs and symptoms of BPH in numerous clinical studies (see Chapter 124). The mechanism of action is related to inhibition of DHT binding to both the cytosolic and nuclear androgen receptors, inhibition of 5-alpha-reductase, and interference with intraprostatic estrogen receptors. As a result of this multitude of effects, excellent results have been produced in numerous double-blind clinical studies. The results from these studies are discussed in Chapter 124. Systematic literature reviews of clinical trials continue to report excellent results using Serenoa."-44One examination of 21 randomized, controlled trials involving a total of 3139 men (including 18 double-blind trials) demonstrated that men treated with Serenoa experienced decreased urinary tract symptom scores, less nocturia, better urinary tract symptom self-rating scores, and peak urine flow improvements compared with men receiving placebo.43This analysis also showed that matched up with men receiving the DHT inhibitor finasteride (Proscar),men treated with Serenoa had sirnilar improvements in urinary tract symptom scores and peak urine. A related review also reported that adverse effects due to Serenoa were mild and infrequent with erectile dysfunction appearing more frequently with finasteride (4.9%) than with Serenoa (1.1?40).4~ Overall, it can be stated that roughly 90% of men with mild to moderate BPH experience some improvement in symptoms during the first 4 to 6 weeks of

Benign Prostatic Hyperplasia therapy using Serenoa. All major symptoms of BPH are improved, especially nocturia. And despite an efficacy profile similar to finasteride, Serenoa is better tolerated and less expensive. It also has no known drug interactions and nominal side effe~ts.4~ One possible side effect is gastrointestinal distress, which is mild and is easily remedied by taking saw palmetto with food. Future studies will hopefully include more naturopathically designed treatment plans that incorporate combination dietary, lifestyle, and supplemental options, as well as suitably designed head-to-head trials comparing Serenoa with alpha-blockers such as tamsulosin (Flomax),doxazosin (Cardura),and prazosin (Minipress).

Cernilton Cernilton, an extract of rye-grass flower pollen, has been used to treat prostatitis and BPH in Europe for more than 35 years.&It has been shown to be quite effective in several double-blind clinical studies in the treatment of BPH.47,48 The overall success rate in patients with BPH is about 70Y0.4~ Patients who respond typically have reductions of nocturia and diurnal frequency of around YO%, as well as significant reductions in residual urine volume.48The extract has been shown to exert some antiinflammatory action and produce a contractile effect on the bladder while simultaneously relaxing the urethra. In addition, Cernilton contains a substance that inhibits the growth of prostate cells.49 In one study, the clinical efficacy of Cernilton in the treatment of symptomatic BPH was examined over a 1-year period.&Seventy-nine males of an average age of 68 years (range 62 to 89), with a mean baseline prostatic volume of 33.2 cm, were administered 63 mg Cernilton pollen extract twice daily for 12 weeks. Average urine maximum flow rate increased from 5.1 to 6 ml/sec. Average flow rate increased from 9.3 to 11 ml/sec. Residual urine volume decreased from 54.2 ml to less than 30 ml. Clinical efficacy, based on symptoms, was as follows: Urgency or discomfort-improved by 76.9% Dysuria-improved by 71.4% Nocturia-improved by 56.8% Incomplete emptying-improved by 66.2% Prolonged voiding-improved by 64.1% Delayed voiding-improved by 62.2% Intermittency-improved by 60.6% Postvoid dribbling-improved by 42.7% Overall, 85% of the test subjects experienced benefit: 11%reporting "excellent," 39% reporting "good," 35% reporting "satisfactory," and 15% reporting "poor" as a description of their outcome. A summary review of two placebo-controlled studies, two comparative trials (both lasting 12 to 24 weeks), and three double-blind studies of 444 men showed that

although Cernilton did not improve urinary flow rates, residual volume, or prostate size compared with placebo or the comparative study agents, it did improve selfrated urinary symptom scores and reduced nocturia compared with placebo and an amino acid mixture.50 Clearly, more long-term studies of Cernilton need to be conducted in order to elucidate the terms of its usefulness as an alternate or adjunct to Serenoa.

Pygeum afrcanum The bark of P. ufricunum, an evergreen tree native to Africa, has historically been used in the treatment of urinary tract disorders. The major active components of the bark are fat-soluble sterols and fatty acids. Virtually all of the research on Pygeum has featured a Pygeum extract standardized to contain 14%triterpenes including beta-sitosterol and 0.5% n-docosanol. This extract has been extensively studied in both experimental animal studies and clinical trials in humans (see Chapter 120).A study on rat prostatic cells suggests that the therapeutic effect of Pygeum may be due in part to the inhibition of growth factors EGF, bFGF, and IGF-I, which are responsible for the prostatic o~ergrowth.~' Numerous clinical trials with more than 600 patients have demonstrated Pygeum extract to be effective in reducing the symptoms and clinical signs of BPH, However, in a double-blind especially in early study that compared the Pygeum extract with the extract of saw palmetto, the saw palmetto extract produced a greater reduction of symptoms and was better tolerated.53In addition, the effects on objective parameters, especially urine flow rate and residual urine content, are better in the clinical studies with saw palmetto. However, there may be circumstances where Pygeum is more effective than saw palmetto. For example, saw palmetto has not been shown to produce some of the effects that Pygeum has produced on prostate secretion. Of course, as the two extracts have somewhat overlapping mechanisms of actions, they can be used in combination.

Urtica dioica (Stinging Nettles) Extracts of U.dioicu have also been shown to be effective in the treatment of BPH. Fewer studies have been done with urtica extract compared with the other botanical medicines discussed. Two double-blind studies have shown it to be more effective than a ~ l a c e b o . ~ ~ , ~ ~ However, like Pygeum, the results with urtica are less impressive than those with saw palmetto extract (or Cernilton). A randomized, multicenter, double-blind study in 431 patients using both the extracts of Serenoa and Urtica found clinical benefit equal to that of f i n a ~ t e r i d e .Like ~ ~ the extract of Serenoa, Urtica extracts appear to interact with binding of DHT to cytosolic and nuclear receptors.%In vitro studies also

Specific Health Problems show that lignans found in Urtica may modulate hormonal effects due to their affinity for sex hormonebinding

THERAPEUTIC APPROACH Therapeutic goals for BPH are to do the following: Normalize prostate nutrient levels Restore steroid hormones to normal levels Inhibit excessive conversion of T to DHT Inhibit DHT receptor binding Limit promoters of the hyperplastic process (e.g., prolactin) Severe BPH resulting in significant acute urinary retention may require catheterization for relief, and a sufficiently advanced case may not respond rapidly enough to therapy and may require the short-term use of an alpha-1 antagonist or surgical intervention.

Lifestyle Patients should exercise more and properly stretch the prostate/urogenital area to increase blood flow.

Diet

unsaturated oils. After the patient responds, a less strict whole-foods, balanced approach can be used. The patient should limit alcohol and coffee intake, avoid drug-, pesticide- and hormone-contaminated foods, and limit cholesterol-rich foods. Soy foods should be used regularly.

Supplements Zinc: 50 mg/day (picolinate preferred, maximum of 6 months; monitor copper status) Flax oil: 1 tbsp two times/day (take with antioxidants) Glycine: 200 mg/day Glutamic acid: 200 mg/day Alanine: 200 mg/day

Botanicals Liposterolic extract of saw palmetto (S. repens) (standardized at 85% to 95% fatty acids and sterols): 160 mg two times/day Flower pollen extract (e.g., Cernilton): 63 mg two to three times/day Pygeurn ufricunurn extract (14% triterpene content): 50 to 100 mg daily Urticu dioicu extract: 120 to 150 mg twice daily

Initially the diet should be higher in vegetable protein, low in carbohydrate, low in animal fats, and high in

1.Oesterling JE. Benign prostatic hyperplasia: a review of its histogenesis and natural history. Prostate Suppl1996;6:67-73. 2.Pearson JD, Lei HH, Beaty TH, et al. Familial aggregation of bothersome benign prostatic hyperplasia symptoms. Urology 2003; 61~781-785. 3. Habuchi T, Liqing Z, Suzuki T, et al. Increased risk of prostate cancer and benign prostatic hyperplasia associated with a CYP17 gene polymorphism with a gene dosage effect. Cancer Res 2000; 60.5710-5713. 4. Horton R. Benign prostatic hyperplasia. A disorder of androgen metabolism in the male. J Am Geri Soc 1984;32:380-385. 5 . M P, Reagan RW Jr, Bahnson RR. Managing benign prostatic hyperplasia. Am Fam Physician 2002;66:77-84. 6.Suzuki S, Platz EA, Kawachi I, et al. Intakes of energy and macronutrients and the risk of benign prostatic hyperplasia. Am J Clin Nutr 2002;75:689-697. 7.Platz EA, Kawachi I, Rimm EB, et al. Physical activity and benign prostatic hyperplasia. Arch Intern Med 1998 Nov 23;158: 2349-2356. 8. Lagiou P, Wuu J, Trichopoulou A, et al. Diet and benign prostatic hyperplasia: a study in Greece. Urology 1999;54:284-290. 9. Gass R. Benign prostatic hyperplasia: the opposite effects of alcohol and coffee intake. BJLJ Int 2002;90649-654. 10. Kappas A, Anderson KE, Conney AH, et al. Nutrition-endocrine interactions. Induction of reciprocal changes in the delta-5-alphareduction of testosterone and the cytochrome P4504ependent oxidation of estradiol by dietary macronutrients in man. Proc Natl Acad Sci U S A 1983;807646-7649.

11. Zhang SX, Yu B, Guo SL, et al. [Comparison of incidence of BPH and related factors between urban and rural inhabitants in district of Wannan]. Zhonghua Nan Ke Xue 2003;945-47. 12. Bush IM,Berman E, Nourkayhan S, et al. Zinc and the prostate. Presented at the annual meeting of the AMA, Chicago, 1974. 13. Fahim M, Fahim Z, Der R, et al. Zinc treatment for the reduction of hyperplasia of the prostate. Fed Proc 1976;35:361. 14. Leake A, Chrisholm GD, Busuttil A, et al. Subcellular distribution of zinc in the benign and malignant human prostate: evidence for a direct zinc androgen interaction. Acta Endocrinol ( C o p e d ) 1984;105:281-288. 15.Zaichick W, Sviridova TV, Zaichick SV. Zinc concentration in human prostatic fluid. Normal, chronic prostatitis, adenoma and cancer. Int Urol Nephrol1996;28:687-694. 16. h a k e A, Chisholm GD, Habib FK. The effect of zinc on the 5-alphareduction of testosterone by the hyperplastic human prostate gland. J Steroid Biochem 1984;20651-655. 17. Wallace AM, Grant JK. Effect of zinc on androgen metabolism in the human hyperplastic prostate. Biochem Soc Trans 1975;3:540-542. 18. Judd AM, Macleod RM, Login IS. Zinc acutely, selectively and reversibly inhibits pituitary prolactin secretion. Brain Res 1984;294190-192. 19.Login IS, Thorner MO, MacLeod RM. Zinc may have a physiological role in regulating pituitary prolactin secretion. Neuroendocrinology 1983;37317-320. 20. Farnsworth WE, Slaunwhite WR, Sharma M, et al. Interaction of prolactin and testosterone in the human prostate. Urol Res 1981;9:79-88.

Benign Prostatic Hyperplasia 21. Farrar DJ, Pryor JS. The effect of bromocriptine in patients with benign prostatic hyperplasia. Br J Urol1976;48:73-75. 22. DeRosa G, Corsello SM, RuffiIli MP, et al. Prolactin secretion after beer. Lancet 1981;2:934. 23. Corenblum B, Whitaker M. Inhibition of stress-induced hyperprolactinaemia. Br Med J 1977;2:1328. 24. Chyou PH, Nomura AM, Stemmermann GN, et al. A prospective study of alcohol, diet, and other lifestyle factors in relation to obstructive uropathy. Prostate 1993;22:253-264. 25. Chyou PH ,Nomura AM, Stemmermann GN, et al. A prospective study of alcohol, diet, and other lifestyle factors in relation to obstructive uropathy. Prostate 1993;22253-264. 26. Hart JP, Cooper WL. Vitamin F in the treatment of prostatic hyperplasia. Report Number 1. Milwaukee, WI: Lee Foundation for Nutritional Research, 1941. 27. Scott WW. The lipids of the prostatic fluid, seminal plasma and enlarged prostate gland of man. J Urol1945;53712-718. 28. Boyd EM, Berry NE.Prostatic hypertrophy as part of a generalized metabolic disease. Evidence of the presence of a lipopenia. J Urol 1939;41:406-411. 29. Damrau F. Benign prostatic hypertrophy: amino acid therapy for symptomatic relief. J Am Geriatr Soc 1962;10426-430. 30.Feinblatt HM, Gant JC. Palliative treatment of benign prostatic hypertrophy; value of glycine-alanine-glutamicacid combination. J Maine Med Assoc 1958;49:99-101. 31. Hinman F, ed. Benign prostatic hypertrophy. New York SpringerVerlag, 1983. 32. T h i s RS, Miettinen TA. Serum plant sterols and their relation to cholesterol absorption. Am J Clin Nutr 1986;4392-97. 33. Berges RR, Wmdeler J, Tramisch HJ, et al. Randomised, placebocontrolled, double-blind clinical trial of beta-sitosterol in patients with benign prostatic hyperplasia. Beta-sitosterol Study Group. Lancet 1995;3451529-1532. 34. Morton MS, Griffiths K, Blacklock N. The preventive role of diet in prostatic disease. Br J Urol1996;77:481493. 35. Messina M, Barnes S. The role of soy products in reducing risk of cancer. J Natl Cancer Inst 1991;83541-546. 36. Lowe FC, Fagelman E, Gregory T. Using complementary medications to treat BPH. Patient Care 2000;34:191-203. 37. Jarred RA, McPherson SJ, Jones ME, et al. Anti-androgenic action by red clover-derived dietary isoflavones reduces non-malignant prostate enlargement in aromatase knockout (ArKo) mice. Prostate 2003;565464. 38. Katz AE. Flavonoid and botanical approaches to prostate health. J Altem Complement Med. 2002;8:813-821. 39. Lahtonen R. Zinc and cadmium concentrations in whole tissue and in separated epithelium and stroma from human benign prostatic hypertrophic glands. Prostate 1985;6177-183.

40.Sinquin G, Morfin RF, Charles JF, et al. Testosterone metabolism by homogenates of human prostates with benign hyperplasia: effects of zinc, cadmium, and other bivalent cations. J Steroid Biochem 1984;20733-780. 41. Buck AC. Phytotherapy for the prostate. Br J Urol1996;78:325-336. 42. Wilt TJ, Ishani A, Stark G, et al. Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 1998;280:16041609. 43. Wilt T, Ishani A, Mac Donald R.Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 2002;3CwO1423. 44.Wilt T, Ishani A, Stark G, et al. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 2000;2:CW01423. 45. Gordon AE, Shaughnessy AF. Saw palmetto for prostate disorders. Am Fam Physician 2003;671281-1283. 46.Yasumoto R, Kawanishi H, Tsujino, et al. Clinical evaluation of long-term treatment using Cemitin pollen extract in patients with benign prostatic hyperplasia. Clin Ther 1995;1782-86. 47. Buck AC, Cox R, Rees RW, et al. Treatment of outflow tract obstruction due to benign prostatic hyperplasia with the pollen extract, Cemilton. A double-blind, placebo-controlled study. Br J Urol 1990;66:398-404. 48. Dutkiewicz S. Usefulness of Cemilton in the treatment of benign prostatic hyperplasia. Int Urol Nephrol1996;28:49-53. 49.Habib FK, Ross M, Lawenstein A. Identification of a prostate inhibitory substance in a pollen extract. Prostate 1995;26:133-139. 50.MacDonald R, Ishani A, R u t h I, et al. A systematic review of Cemilton for the treatment of benign prostatic hyperplasia. BJU Int 2000;85:836-841. 51. Yablonsky F, Nicolas V, Riffaud JP,et al. Antiproliferative effect of Pygeum africanum extract on rat prostatic fibroblasts. J Urol 1997;1572381-2387. 52. Duvia R, Radice GP, Galdini R. Advances in the phytotherapy of prostatic hypertrophy. Med Praxis 1983;4143-148. 53. Belaiche P,Lievoux 0.Clinical studies on the palliative treatment of prostatic adenoma with extract of Urtica root. Phytother Res 1991;5:267-269. 54.Romics I. Observations with Bazoton in the management of prostatic hyperplasia. Int Urol Nephrol1987;19:293-297. 55.Sokeland J. Combined sabal and urtica extract compared with finasteride in men with benign prostatic hyperplasia: analysis of prostate volume and therapeutic outcome. BJU Int 2000;86439-442. 56. Wagner H, Willer F, Samtleben R, et al. Search for the antiprostatic principle of stinging nettle (Urfica dioicd roots. Phytomedicine 1994;1:213-224. 57. Schottner M, Gansser D, Spiteller G. Lignans from the roots of Urtica dioica and their metabolites bind to human sex hormone binding globulin (SHBG). Planta Med 1997;63:529-532.

Carpal Tunnel Syndrome Douglas C. Lewis, ND CHAPTER CONTENTS Diagnostic Summary

1557

General Considerations 1557 Anatomy of the Carpal Tunnel 1557 Etiology 1557 Risk Factors and Frequency of Occurrence 1558

Therapeutic Considerations 1559 Nutrition 1559 Physical Medicine 1559 Therapeutic Approach 1560 Diet 1561 Supplements 1561 Physical Medicine 1561

Diagnostic Considerations 1558 Physical Examination 1558 Other Diagnostic Tests 1558 Differential Diagnosis 1558

DIAGNOSTIC SUMMARY Patient complains of numbness, tingling, or burning pain on the palmar surfaces of the first three digits and lateral half of the fourth digit of the hand. Positive Tinel’s sign (tingling or shocklike pain on volar wrist percussion) Positive Phalen’s sign (appearance or exacerbation of symptoms caused by flexion of the wrist for 60 seconds) Electromyography may demonstrate decreased nerve conduction velocity across the carpal tunnel.

GENERAL CONSIDERATIONS Carpal tunnel syndrome (CTS) may be defined as unilateral or bilateral paresthesia in the palmar aspect of the first three digits and the lateral half of the fourth digit of the hand due to median nerve compression within the carpal tunnel. Pain may be felt in one or more of these areas-wrist, palm, or forearm proximal to the area of compression-as a result of axonal retrograde degeneration of the median nerve.’ Loss of strength in abduction may occur, and opposition of the thumb and atrophy of the opponens pollicis muscle may develop. Loss of fine motor skills may develop. The severity of CTS ranges from mild to severe. Mild CTS often presents with intermittent symptoms. Severe CTS may result in permanent loss of sensation and paralysis of the thumb.

Anatomy of the Carpal Tunnel The carpal tunnel is formed by the seven carpal bones posteriorly and the flexor retinaculum anteriorly. The flexor retinaculum is attached medially to the pisiform and the hook of the hamate. Laterally, it is attached to the scaphoid and to the trapezium. Through this tunnel pass the tendons of the long flexors of the fingers with their tenosynovium (the ulnar bursa), the flexor pollicis longus tendon, and the tendon of the flexor carpi radialis with its tenosynovium (the radial bursa). Superficial to these tendons is the median nerve, which lies just deep to the flexor retinaculum. The flexor retinaculum acts to prevent bowstringing of the flexor tendons. With contraction of the flexors of the wrist and fingers, especially with the wrist in flexion, the tendons in the carpal tunnel try to bowstring. When this occurs, the median nerve is trapped between the tenosynovium and the flexor retinaculum placing compressive force against it.

Etiology Importantly, CTS is regarded as a syndrome. As such, it may have many different causes. For each different cause, a different treatment is most appropriate. Any condition that increases the volume of the structures within the carpal tunnel or causes a narrowing of the tunnel itself can result in impingement on the median nerve. Conditions that may decrease the volume in the tunnel include deformity from subluxation of 1557

Specific Health Problems

the carpals, separated distal radius and ulna, Colles’ fracture, arthritic spurs, tumor, or thickening of the flexor retinaculum. Conditions that may increase the volume of the contents of the carpal tunnel include fluid retention, fat deposition, carpal synovitis, tenosynovitis, or other space-occupying lesions. A large percentage of cases are considered idiopathic. Within these cases, some researchers have found decreased vitamin B6 levelsFJ while others have seen evidence of collagen dysplasia* with an accumulation of disorganized connective tissue within the flexor retinaculum. One overlooked cause of CTS may be inflammation of the epineurium of the median nerve itself. Pratt5 states that the epineurium ”plays a role in nerve regeneration, as well as nerve entrapment.” In a study published in November 2000, Nakamichi and Tachibana6 stated that their “findings indicate that idiopathic CTS is characterized by severitycorrelated intracarpal enlargement of the median nerve and not by compressive deformation.”

Risk Factors and Frequency of Occurrence Traumatic injury and occupational injury through repetitive use are often considered the most obvious causes of CTS. However, a study of 501 participants, 156 of whom were diagnosed with CTS, showed the following risk factors: repetitive activities with a flexed or extended wrist, hysterectomy without oophorectomy, and last menstrual period in menopausal women 6 to 12 months earlier.4-70thershave found an increased incidence in pregnant women, women taking oral contraceptives, menopausal women, or patients on hemodialysis.8 Patients with hypothyroidism and diabetes are known to be at greater risk of developing CTS. CTS is more prevalent among women and occurs frequently between the ages of 40 and 60 years.

DIAGNOSTIC CONSIDERATIONS Most commonly the patient complains of pain and tingling or numbness in the hand. Symptoms are often worse at night and often awaken the patient. Patients regularly claim that relief is gained from shaking or rubbing the hand (or hands if the condition is bilateral). Occasionally patients complain of clumsiness due to an inability to hold or feel an object.

Physical Examination Examination reveals impaired sensation in the distribution of the median nerve. If the condition has existed for a prolonged period, atrophy of the thenar eminence and weakness of the thumb abductor is also present. Tinel’s, Phalen’s, and reverse Phalen’s tests have been the accepted tests for diagnosing CTS in the general office. Tinel’s sign is tingling in the distribution of the median nerve when tapping the nerve in the middle of

the palm over the transverse carpal ligament. Phalen’s test is positive when symptoms are reproduced by holding the wrist in forced flexion for 60 to 90 seconds. Reverse Phalen’s test is described as numbness and tingling produced by forcibly extending the wrist and applying pressure over the median nerve. Katz and Stirrat9 have devised a self-administered hand diagram that has shown an 80%sensitivity and a 90%specificity for classic or probable CTS. This test uses a hand diagram on which the patient draws a pattern of his or her pain, numbness, and tingling. Other in-office assessments that have been suggested for evaluating CTS include subjective assessment of swelling in the hand and palpation of the hand and wrist. In a single-blind, randomized study of 186 patients, continuing subjective swelling during treatment with splinting of the wrist correlated with a poorer clinical response.’O Susher” described the use of palpation of the wrist and thumb in the various directions of motion as a predictor of CTS. He found that motion restriction of the wrist correlated with the electromyographic (EMG) diagnosis of CTS.

Other Diagnostic Tests EMG may help confirm compression of the median nerve in the carpal tunnel. Nerve conduction velocity is normal from the elbow to the wrist and diminished from the wrist to the hand and fingers (diminished across the carpal tunnel).24Both sensory and motor nerve conduction velocities are measured. More recently, magnetic resonance imaging (MRI) and high-definition ultrasound imaging have been used in the diagnosis of CTS. With these techniques it is possible to measure the size of the median nerve, as well as the interior dimensions of the carpal tunnel. These imaging methods have also found their way into the preoperative assessment of CTS to evaluate the most appropriate approach to ~urgery.’~-*~

DIFFERENTIAL DIAGNOSIS The paresthesia of CTS may be confused with the paresthesia of the brachial plexus found in thoracic outlet syndrome or with paresthesia of either the radial or ulnar nerves. Likewise, a patient might complain of hand pain that may be the presenting feature of complex regional pain syndrome (reflex sympathetic dystrophy). Occasionally, impingement of the median nerve may occur distal to the elbow where the nerve passes under the pronator teres muscle. Pronator teres syndrome is described by Cailliet’8 as compression of the median nerve in the forearm, distal to ”the elbow as it passes through the two heads of the pronator teres muscle before it goes under the proximal edge of the flexor digitorum muscle.” Direct compression of the nerve in this

Carpal Tunnel Syndrome area from pressure or impact is a common cause of nerve injury. Magee has discussed the possibility of a “double-crush ~yndrome.”’~ Although not yet proven, clinical evidence exists to support the theory that while compression at one point along the path of a nerve is insufficient to produce symptoms, compression at two or more locations can combine to produce those symptoms. Hence cervical compression of the brachial plexus or compression of the median nerve at the carpal tunnel may not individually be adequate to produce the symptoms of CTS, but compression in both places may simultaneously produce those symptoms. When left-sided, CTS may be confused with angina pectoris. The specific dermatome pattern of CTS, without proximal dysfunction, should lead the practitioner to the particular history and tests needed to establish a proper diagnosis of CTS.

Franzblau, Rock, and WemeP attempted to determine if there is a causal relationship between vitamin B6 status and symptoms of CTS. These researchers measured vitamin B6 levels, assessed ulnar and median nerve function in the wrists and hands, and noted CTS symptoms in 125 randomly selected employees at an auto parts plant. About one third of the employees reported CTS, a quarter had median nerve dysfunction, and 10had vitamin B6 deficiency. After statisticalanalysis, researchers found no c o r n lation between employees’ blood levels of vitamin B6 and the presence of or improvement in CTS symptoms. Despite the lack of clinical evaluation, the authors of the study concluded ”empiric treatment for CTS with vitamin B6 supplementation is not warranted.” A number of other studies have failed to demonstrate any benefit to C E with B6 supplementation. However, given the safety and positive clinical studies with vitamin B6 in reasonable dosages (e.g., 25 to 50 mg three times daily), a trial of vitamin B6 should still be used (especially before opting for surgery).

THERAPEUTIC CONSIDERATIONS

Medications

The majority of patients respond well to nutritional and conservative physical medicine approaches. Although a few require surgical intervention, nutritional support continues to be needed to address the underlying metabolic weakness.

A number of medications have been suggested and tried in the treatment of CTS. Oral and locally injected steroids have been used and are widely recommended. Nonsteroidal antiinflammatory medications are commonly employed and provide some symptomatic relief. No studies were found evaluating the use of the ”natural” antiinflammatory medications such as bromelain, curcumin, and boswellia. Nor were any studies found evaluating the efficacy of the various oils that have often been shown to have antiinflammatory benefits. However, with what is known both clinically and from study of these supplements, it is logical that consideration be given for at least their symptomatic benefit. Inasmuch as several studies have shown an increase in the disorganized connective tissue in the carpal tunnel, bromelain supplementation should be considered not only for its antiinflammatory benefit but also for its potential proteolytic activity.

Nutrition Vitamin B Supplementation The efficacy of vitamin B6 supplementation in the treatment of CTS has been widely discussed in the literature. Many studies have been done that fall on both sides of the fence, pro and con. Ellis and co-workers2,20-22 repeatedly demonstrated the efficacy of vitamin B6 supplementation in the treatment of CTS. B6 in the amount of 50 mg initially and increased to 200 to 300 mg as needed was shown in these studies to be significantly effective in the treatment of CTS. Another study has shown vitamin B2 to be useful in the treatment of CTS, with an even greater effect seen when B6 and B2 are given together.20This is most likely due to riboflavin-containing enzymes, which convert pyridoxine to its more active form, pyridoxal5’-phosphate. The evidence of this study may support the use of pyridoxal 5’-phosphate supplements in the treatment of CTS. The therapeutic response may require up to 3 months of supplementation. The increased incidence of CTS since its initial description by Phalen in 1950 parallels the increased presence of pyridoxine antimetabolites in the environment. These include the hydrazine dyes (Food, Drug, and Cosmetic Act yellow no. 5) and drugs (INHand hydralazine), dopamine, penicillamine, oral contraceptives, and excessive protein intake.

Physical Medicine Hydrotherapy Inflammation and edema are present in CTS, causing compression of the local capillaries with resultant decreased nutrition to the median nerve, thus making the nerve fibers hypere~citable.~~ Contrast hydrotherapy provides a simple, efficient way to increase circulation to the area. Immersion of the wrist and hand in hot water for 3 minutes followed by immersion in cold water for 30 seconds, repeated three to five times, increases local circulation, thereby increasing local nutrition, eliminating waste, and decreasing pain. This procedure should be performed once or twice daily throughout the course of treatment.

Immobilization Caillietz4 asserts that nighttime splinting only when symptoms appear is ineffective. He states that splinting of the wrist in a neutral position is required day and night for several weeks. A recent studyE comparing nighttime only to full-time splinting confirms Cailliet’s assertion that full-time splint wear is necessary to see improvement in CTS signs and symptoms. In this study 21 patients (30 hands) were enrolled to evaluate splinting. Seventeen patients (24 hands) completed the study, and outcomes were measured by EMG.

Manual Manipulation Manipulation of subluxation of the carpals or separation of the distal radius and ulna may relieve pressure in the carpal tunnel, thereby relieving impingement of the median nerve. Valente and Gibson26published a case report in 1994 describing manipulative treatment for a 42-year-old female patient with CTS symptoms. The patient was evaluated using Tinel’s, Phalen’s, EMG, and grip strength tests. All were found to be positive for CTS before treatment was begun. Manipulation of the cervical spine, right elbow, and right wrist was performed three times per week for 4 weeks. Following the treatment period, grip strength had improved, Tinel’s and Phalen’s tests were negative, and there was sigruficant improvement in the EMG studies. In 1993 S ~ c h e rdescribed ~~ improvement in four patients treated with myofascial release and self-stretching techniques. All patients were assessed with EMG and MRI in addition to the common clinical examination. Improvement was noted in all four cases with subjective improvement noted after only one to two treatments. All patients were instructed to do frequent (three to five times daily) self-stretching. At the completion of treatment, MRI demonstrated increased dimensions in the carpal tunnel and nerve conduction studies showed reduction in distal latencies or increase in motor response amplitudes. Other studies of manual manipulation show benefits from soft tissue and joint mobilization of the forearm, wrist, and hand, but not from spinal manipulation al~ne.~*,~~

Acupuncture In a study of acupuncture treatment of CTS, a positive response was demonstrated in 35 of 36 patients (14 of whom were previously treated unsuccessfully with surgery).30Treatment involved puncture of PC-7 and PC-6 on the affected side. Naeser and others3]conducted a randomized, double-blind, placebo-controlled, crossover trial of low-level laser therapy combined with microcurrent transcutaneous electrical nerve stimulation. Eleven patients with mild to moderate symptoms of CTS who had failed to improve with standard medical or surgical

treatment were treated with real or sham local applications of laser light and microcurrent for 3 to 4 weeks. Following treatment there was sigruficant improvement in McGill Pain Questionnaire scores; sensory and motor latency scores with EMG; and Tinel’s and Phalen’s tests in the treatment group, but not in the sham group.

Stretching In a study of 92 patients (81 of whom had CTS), it was found that, when compared with controls, the mean tunnel pressure was double in those patients with CTS. After 1 minute of stretching-loading exercises, intratunnel pressures dropped to normal levels, where they remained for more than 20 minutes. Exercise includes flexing the wrists and fists with the arms extended for 5 minutes. This slow, sustained movement helps to prepare the carpal tunnel for repetitive actions. These exercises should be done before work starts and during every break. The researchers suggested that these exercises might reduce the need for surgery by 50%.32 Yoga therapy has been demonstrated to significantly reduce pain from CTS.29,30

Other Nonsurgical Interventions Studies of ultrasound therapy have been both positive and n e g a t i ~ e .One ~ , ~recent ~ study of therapeutic found it to be no more useful than placebo in the 21 participants included in the study. Use of an ergonomic keyboard (one of the so-called bent keyboards) seems to reduce the pain of CT!3.2937However, other studies have not demonstrated that work practices (other than high-force work) has a direct influence on CTS.38

Surgery If all other attempts at treatment fail, surgery may be a last resort. A number of surgical procedures are used. Open carpal tunnel release has been performed with both a long incision and a short incision. Endoscopic surgery has also been used and has been done with both single-portal and dual-portal techniques. A recent review of the available literature by The Cochran failed to demonstrate that the alternatives to open carpal tunnel release offer better relief from symptoms. Surgery with tenosynovectomylO and epineur~tomf’,~~ have been employed but have not demonstrated any added benefit over release alone. Surgery with early m~bilization?~ surgery with oral homeopathic Arnica and topical Arnica ointment,+’ and surgery with controlled cold therapy5all showed benefits over surgery alone.

THERAPEUTIC APPROACH Whenever possible, prevention is obviously best. The patient should be instructed to avoid activities that cause trauma to the median nerve through repeated wrist

flexion and extension, as well as activities that cause direct trauma to the wrist. All professions that require extensive use of the hands put the patient at risk. Protecting the hands from injury, as well as maintaining wrist posture, may help in avoiding the onset of CTS. A conservative approach to treatment should be instituted as soon as possible to avoid long-term or permanent damage to the median nerve or its associated muscles. All sources of hydrazines should be avoided. If, after several months of treatment, the therapies recommended here do not produce the desired clinical effects, surgery should be considered. Antiinflammatory agents have shown some usefulness in CTS and should be considered as a part of an overall treatment protocol.

Diet Avoid foods containing yellow dyes and limit daily protein intake to a maximum of 0.75 g/kg body weight.

Supplements

Physical Medicine Confrasf hydrotherapy. Immerse for 3 minutes in hot water followed by a 30-second immersion in cold water, three to five times/day. Perform daily. Manipulation. Manipulate carpals and ensure proper spacing of distal radius and ulna. Acupuncture. Needle PC-7 and PC-6 on the affected side. Laser acupuncture should be considered. Microcurrent. Microcurrent is a simple, noninvasive intervention that benefits many patients in controlling pain. Splint. For severe or unresponsive cases, splint the wrist in the neutral position night and day. Regular wrist exercises. Probably one of the most useful interventions for CTS and one of the key elements of prevention is regular stretching of the flexors and extensors of the forearm. These exercises should be performed several times daily when treating CTS and should be used to "break up" strenuous and repetitive activities that place increased stress on the carpal tunnel.

Pyridoxine: 50 to 200 mg/day-use pyridoxal 5'-phosphate if there is no response within 6 weeks Riboflavin: 10 mg/day

1.Chang MH, Wei SJ, Chiang HL, et al. The cause of slowed forearm median conduction velocity in carpal tunnel syndrome: a Palmar stimulation study. Clin Neurophysiol2002;113:1072-1076. 2. Ellis JM, Folkers K, Levy M, et al. Response of vitamin B6deficiency and the carpal tunnel syndrome to pyridoxine. Proc Natl Acad Sci U S A 1982;797494-7498. 3. Fuhr JE, Farrow A, Nelson HS Jr. Vitamin B6 levels in patients with carpal tunnel syndrome. Arch Surg 1989;124:1329-1330. 4. Stransky G, Wenger E, Dimitrov L, Weis S. Collagen dysplasia in idiopathic carpal tunnel syndrome. Pathol Res Pract 1989;185 795-798. 5. Pratt NE. Clinical musculoskeletal anatomy. Philadelphia: Lippincott, 1991:14. 6. Nakamichi KI, Tachibana S. Enlarged median nerve in idiopathic carpal tunnel syndrome. Muscle Nerve 2OOO;231713-1718. 7. de Krom MC, Kester AD, Knipschild PG, Spaans F. Risk factors for carpal tunnel syndrome. Am J Epidemiol 1990;132:1102-1110. 8.Sandez SC Jr. Carpal tunnel syndrome. Am Fam Physician 1981;24:190-204. 9.Katz JN, Stirrat CR. A self-administered hand diagram for the diagnosis of carpal tunnel syndrome. J Hand Surg [Am] 1990; 15~360-363. 10. Burke DT, Burke MA, Bell R, et al. Subjective swelling: a new sign for carpal tunnel syndrome. Am J Phys Rehabil1999;78:504-508. 11. Sucher BM. Palpatory diagnosis and manipulative management of carpal tunnel syndrome. J Am Osteopath Assoc 199494647463. 12. Sama L, Cabada T, Cozcolluela R, et al. Carpal tunnel syndrome: usefulness of sonography. Eur Radiol 2000;101920-1925. 13.Kamolz LP, Schrogendorfer KF, Rab M, et al. The precision of ultrasound imaging and its relevance for carpal tunnel syndrome. Surg Radiol Anat 2001;23117-121.

14. Dilley A, Greening J, Lynn B, et al. The use of cross-correlation analysis between high-frequency ultrasound images to measure longitudinal median nerve movement. Ultrasound Med Biol 2001;271211-1218. 15. Martinoli C, Bianchi S, Dahmane M, et al. Ultrasound of tendons and nerves. Eur Radiol 2002;1244-55. 16.Cudlip SA, Howe FA, Clifton A, et al. Magnetic resonance neurography studies of the median nerve before and after carpal tunnel decompression. J Neurosurg 2002;961046-1051. 17.Zagnoli F, Andre V, LeDreff P, et al. Idiopathic carpal tunnel syndrome. Clinical, electrodiagnostic, and magnetic resonance imaging correlations. Rev Rhum Engl Ed 1999;66:192-200. 18. Cailliet R. Hand pain and impairment, ed 3. Philadelphia: FA Davis, 1982:91-92. 19. Magee D. Orthopedic physical assessment, ed 4. Philadelphia: WB Saunders 200222. 20. Folkers K, Ellis J. Successful therapy with vitamin B, and vitamin B2 of the carpal tunnel syndrome and need for determination of the RDA's for vitamin B6 and B2 disease states. Ann N Y Acad Sci 1990;585:295-301. 21. Ellis JM, Folkers K. Clinical aspects of treatment of carpal tunnel syndrome with vitamin Be Ann N Y Acad Sci 1990;585:302-320. 22. Folkers K, Wolaniuk A, VadhanavikitS. Enzymology of the response of carpal tunnel syndrome to riboflavin and to combined riboflavin and pyridoxine. Proc Nat Acad Sci U S A 1984;81:7076-7078. 23.Franzblau A, Rock CL, Werner RA, et al. The relationship of vitamin B6 status to median nerve function and carpal tunnel syndrome among active industrial workers. J Occup Environ Med 1996;38:485-491. 24. Cailliet R. Soft tissue pain and disability. Philadelphia: FA Davis, 1991:228-231.

Specific Health Problems 25. Walker WC, Metzler M, Cifu DX, Swartz Z. Neutral wrist splinting in carpal tunnel syndrome: a comparison of night-only versus full-time wear instructions. Arch Phys Med Rehabil 2000;81: 424429. 26. Valente R, Gibson H. Chiropractic manipulation in carpal tunnel syndrome. J Manipulative Physiol Ther 1994;17246-249. 27. Sucher BM. Myofascial manipulative release of carpal tunnel syndrome: documentation with magnetic resonance imaging. J Am Osteopath Assoc 1993;931273-1278. 28. Rozmaryn LM,Dovelle S, Rothman ER, et al. Nerve and tendon

gliding exercises and the conservative management of carpal tunnel syndrome. J Hand Ther 1998;11:171-179. 29. OConnor D, Marshall S, Massy-Westropp N. Non-surgical treatment (other than steroid injection) for carpal tunnel syndrome (Coduane Review). In The Cochrane Library, issue 1. Oxford, England: Update Software,2003. 3O.Chen GS. The effect of acupuncture treatment on carpal tunnel syndrome. Am J Acupunct 1990;18:5-9. 31. Naeser MA, Hahn KA, Lieberman BE, Branco KF. Carpal tunnel syndrome treated with low-level laser and microamperes transcutaneous electric nerve stimulation: A controlled study. Arch Phys Med Rehabil2002;8397&988. 32. Seradge H. Splints aren't enough; hand exercises improve carpal tunnel treatment. Modem Med 1996;64:1415. 33. Garfinkel MS, Singhal A, Katz WA, et al. Yoga-based intervention for carpal tunnel syndrome: a randomized trial. JAMA 1998; 280:1601-1603. 34. Oztas 0, Turan 8, Bora I, Karakaya MK. Ultrasound therapy effect in carpal tunnel syndrome. Arch Phys Med Rehabil 1998;79: 1540-1544. 35. Ebenbichler GR, Resch KL, Nicolakis P,et al. Ultrasound treatment for treating the carpal tunnel syndrome: randomized "sham" controlled trial. BMJ 1998;316731-735.

36. Blankfield RP,Sulzmann C, Fradley LG, et al. Therapeutic touch in the treatment of carpal tunnel syndrome. J Am Board Fam Pract 2001;14:335-342. 37. littiranonda P, Rempel D, Armstrong T, Burastero S. Effect of four

computer keyboards in computer users with upper extremity musculoskeletal disorders. Am J Ind Med 1999;35:647-661. 38. Chell J, Stevens A, Davis TR. Work practices and histopathological changes in the tenosynovium and flexor retinaculum in carpal tunnel syndrome in women. J Bone Joint Surg Br 1999;81:868-870. 39. Scholten RJPM, Gerritsen AAM, Uitdehaag BMJ, et al. Surgical treatment options for carpal tunnel syndrome (Cochrane Review). In The Cochrane Library, issue 1. Oxford, England: Update Software, 2003. 40.Shum C, Parisien M, Strauch RJ, Rosenwasser MP. The role of flexor tenosynovectomy in the operative treatment of carpal tunnel syndrome. J Bone Joint Surg Am 2002;84-A221-225. The role of 41. Leinberry CF, Hammond NL 111, Siegfried JW. epineurotomy in the operative treatment of carpal tunnel syndrome. J Bone Joint Surg Am 1997;79555-557. 42. Blair WF, Goetz DD, Ross MA, et al. Carpal tunnel release with and without epineurotomy: a comparative prospective trial. J Hand Surg [Am] 1996;21:655-661. 43.Cook AC, Szabo RM, Birkholz SW, King EF. Early mobilization following carpal tunnel release. A prospective randomized study. J Hand Surg [Br] 1995;20:228-230. 44.Jeffrey SL, Belcher HJ. Use of Arnica to relieve pain after carpal-tunnel release surgery. Altern Ther Health Med 2002;8:66-68. 45. Hochberg J. A randomized prospective study to assess the efficacy of two cold-therapy treatments following carpal tunnel release. J Hand Ther 2001;14208-215.

Celiac Disease Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

1563

General Considerations 1563 Chemistry of Grain Proteins 1563 Pathogenesis 1564

Supplements 1565 Pancreatic Enzymes

1565

Therapeutic Approach Patient Resources

1565

1566

Clinical Aspects 1564 Associated Conditions 1564 Diagnosis 1565 Therapeutic Considerations 1565 Diet 1565 Patient Response 1565

DIAGNOSTIC SUMMARY A chronic intestinal malabsorption disorder caused by an intolerance to gluten Bulky, pale, frothy, foul-smelling, greasy stools with increased fecal fat 0 Weight loss and signs of multiple vitamin and mineral deficiencies Increased levels of serum gliadin antibodies Diagnosis confirmed by jejunal biopsy

.

..

GENERAL CONSIDERATIONS Celiac disease, also known as nontropical sprue, glufensensitive enferopafhy, or celiac sprue, is characterized by malabsorption and an abnormal small intestine structure that reverts to normal on removal of dietary gluten. The protein gluten and its polypeptide derivative, gliadin, are found primarily in wheat, barley, and rye grains. Symptoms most commonly appear during the first 3 years of life, after cereals are introduced into the diet. A second peak incidence occurs during the third decade.' Until a few decades ago celiac disease was believed to be relatively rare (approximately 1case in 5000 within the United States), but with the development of highly sensitive and specific serologic tests, it has recently been possible to perform wide population screenings.

As a result, celiac disease is now known to affect approximately 1:250 or more of the U.S. p ~ p u l a t i o n . ~ , ~

Chemistry of Grain Proteins Gluten, a major component of the wheat endosperm, is composed of gliadins and glutenins. Only the gliadin portion has been demonstrated to activate celiac disease. In rye, barley, and oats, the proteins that appear to activate the disease are termed secalins, hordeins, and avenins, respectively, and prolamines collectively.Cereal grains belong to the family Gramineae. The closer a grain's taxonomic relationship to wheat, the greater its ability to activate celiac disease. Rice and corn, two grains that do not appear to activate celiac disease, are further removed taxonomically from wheat. The taxonomic relationship of the grains is shown in Figure 156-1. Gliadins are single polypeptide chains that range in molecular weight from 30,000 to 75,000, with a high glutamine and proline content. Gliadins have been divided into four major electrophoreticfractions: alpha-, beta-, gamma-, and omega-gliadin. Alpha-gliadin is believed to be the fraction most capable of activating celiac disease, although beta- and gamma-gliadin are also capable. Omega-gliadin does not appear to activate the disease, although it has the highest content of glutamine and proline. Gliadin that has been subjected to complete hydrolysis does not activate celiac disease in susceptible individuals! 1563

Specific Health Problems Family

Gramineae

Subfamilv

Tribe

Tripsaceae

Genus

Zea

species

2. mays

brnmon name

Corn

J/

3/

Panicoideae

Festucoideae

Paniceae Andropogoneae Oryzeae

Panicum

Saccharum

\1

P. millieceum S. officinaru

Millet

Cane sugar

Aneneae

Triticeae

Orvza

Avena

Hordeum

Secale

Triticum

0. sative

A. sativa

H. vulgare

S. cereale

T. eestivum

Rice

Oat

Barley

Rye

Wheat

\1

Figure 156-1 Taxonomic relationship of major cereal grains.

Pathogenesis Celiac disease appears to have a genetic etiology as it is associated with specific HLA molecules-HLA-DQ2 in 95% of patients and D Q S in the remainder. These gene loci are believed to be linked to the immunologic recognition of antigens and specific T-cell-regulated immune responses. Various hypotheses have been proposed to explain the pathogenesis of celiac disease. Currently, the most likely relates to abnormalities in the immune response rather than some "toxic" property of gliadin. Sensitization to gliadin occurs both in humoral and cell-mediated immunity, and it appears that T-cell dysfunction is the main factor responsible for the enter~pathy.~ A number of circulating antibodies that are specific for celiac disease, particularly antiendomysial antibody (AEA), have been identified. These serologic markers have been used successfully to screen patients and to estimate the true prevalence of celiac disease in the general population. The discovery that tissue transglutaminase (tTG) is the autoantigen for AEA led to the development of an improved enzyme-linked assay using recombinant tTG, which has been shown to be highly sensitive and specific for celiac disease. Tissue transglutaminase is a ubiquitous, predominantly cytoplasmic enzyme that can be released extracellularly,particularly in response to tissue wounding and stress. The observation that anti-tTG antibody titres fall and can become undetectable during a gluten-free diet suggests that tTG-gliadin complexes stimulate gluten-specific T cells to induce anti-tTG antibody production. T and B cells likely recognize different parts of this antigen complex, with T cells reacting to the smaller gliadin peptides and B cells responding to the larger tTG enzyme! Interestingly,breastfeeding appears to have a prophylactic effect, and breastfed babies have a decreased risk

of developing celiac d i ~ e a s e .The ~ , ~reduced risk of celiac disease was even more pronounced in infants who continued to be breastfed after dietary gluten was introduced. Not surprisingly, the risk of celiac disease was greater when gluten was introduced in the diet in large amounts than when introduced in small or medium amounts. The early introduction of cow's milk is also believed to be a major etiologic f a ~ t o r .Research ~ in the past few years has clearly indicated that breastfeeding, along with delayed administration of cow's milk and cereal grains, are primary preventive steps that can greatly reduce the risk of developing celiac disease.

CLINICAL ASPECTS The histologic lesions of celiac disease are often indistinguishable from those changes caused by tropical sprue, food allergy, diffuse intestinal lymphoma, and viral gastroenteritis. Furthermore, celiac disease often leads to the development of multiple food allergies; disaccharidase deficiency, causing lactose intolerance; and increased intestinal permeability.*

Associated Conditions Conditions such as thyroid abnormalities, insulindependent diabetes mellitus, psychiatric disturbances (including schizophrenia), dermatitis herpetiformis, and urticaria have also been linked to gluten intolerance.' A more ominous association is the increased risk for malignant neoplasms seen in celiac patients, especially for non-Hodgkin lymphoma? The hypothesis that gluten is a contributing factor in some cases of schizophrenia is substantiated by epidemiologic, clinical, and experimental studies.'@l*Pepsin hydrolysates of wheat gluten have demonstrated opioid activity. This activity is believed to

Celiac Disease be the factor responsible for the association between wheat consumption and schizophrenia.

Diagnosis Before the introduction of highly sensitive and specific serologic markers, jejunal biopsy was the definitive diagnostic procedure. Of these new markers, the test for human antitissue transglutaminase antibodies (immunoglobulin [Ig]A anti-tTG) is emerging as the most widely used, primarily due to a lower cost compared with antiendomysium (IgA EMA) and a greater sensitivity compared with antigliadin antibodies (AGAs). In one study the specificity and sensitivity of IgA anti-tTG was compared with IgA EMA and antigliadin antibodies (IgA and IgG AGA) for the diagnosis of celiac disease. Twenty-eight of 30 patients with celiac disease had anti-tTG (those whose results were negative were 1 patient with IgA deficiency and 1 infant); 27 of 30 patients had IgA EMA (1 child was IgA anti-tTG positive and IgA EMA negative); 18 of 30 had IgA AGA; and 28 of 30 had IgG AGA. On gluten-free diets, 4 of 22 patients had anti-tTG but none had IgA EMA or AGA. On normal diets, 15 of 15 children who had relapsed had anti-tTG; 9, IgA EMA; 4, IgA AGA; and 8, IgG AGA (1 child did not relapse). In subjects without celiac disease, 3 of 116 had anti-tTG; 12, IgG AGA; and 1, IgA AGA. None had IgA EMA. The positive predictive value of IgA anti-tTG was calculated to be 90%, and the negative predictive value, 98%. In comparison, results for IgA EMA were 100% and 97%; IgA AGA 94% and 90%; and IgG AGA 70% and 98%, respectively.l3

THERAPEUTIC CONSIDERATIONS Diet Once the diagnosis has been established, a gluten-free diet is indicated. This diet does not contain any wheat, rye, barley, triticale, or oats. Buckwheat and millet are often excluded as well. Although buckwheat is not in the grass family and millet appears to be more closely related to rice and corn, buckwheat and millet contain prolamines with similar antigenic activity to the alphagliadin of wheat. In addition, other foods should be rotated, and milk and milk products should be eliminated until the patient redevelops an intestinal structure and function returns to normal.

Patient Response Usually clinical improvement will be apparent within a few days or weeks (30%respond within 3 days, another 50% within 1 month, and 10% within another month). However, 10% of patients only respond after 24 to 36 months of gluten avoidance.'

If the patient does not appear to respond, the following should be considered: Incorrect diagnosis The patient is not adhering to the diet or is being exposed to hidden sources of gliadin The presence of an associated disease or complication, such as zinc deficiency The latter highlights the importance of multivitamin and mineral supplementation in these patients. In addition to treating any underlying deficiency, supplementation provides the necessary cofactors for growth and repair. Celiac disease is refractive to dietary therapy if an underlying zinc deficiency is pre~ent.'~

SUPPLEMENTS Pancreatic Enzymes The effect of pancreatic enzyme substitution therapy in the 2 months following the initial diagnosis of celiac disease (gluten enteropathy) was investigated in one double-blind study. The study sought to clarify the benefit of pancreatic enzyme therapy because previous studies had shown pancreatic insufficiency in 8% to 30% of celiac patients. In this study patients followed a gluten-free diet, the standard treatment for celiac disease, and received either two capsules of pancreatic enzymes with each meal (6 to 10 capsules a day with each capsule containing lipase 5000 IU, amylase 2900 IU, and protease 330 IU) or two placebo capsules with meals. Complete nutritional and anthropomorphic evaluations were conducted at days 0, 30, and 60. Results indicated that pancreatic enzyme supplementation enhanced the clinical benefit of a gluten-free diet during the first 30 days but did not provide any greater benefit than the placebo after 60 days. These results support the use of pancreatic enzyme preparations in the first 30 days after diagnosis of celiac disease (see Chapter 112 for a complete discu~sion).'~

THERAPEUTIC APPROACH The therapeutic approach is quite straightforward: Eliminate all sources of gliadin (see Appendix 5), eliminate dairy products initially, correct underlying nutritional deficiencies, treat any associated conditions, and determine and eliminate all food allergens. If the patient does not begin to respond within 1 month, reconsider the diagnosis and search for hidden sources of gliadin. Maintenance of a strict gluten-free diet is quite difficult in the United States due to the ubiquitous distribution of gliadin and other activators of celiac disease in processed foods. Patients must be encouraged to read labels carefully in order to avoid hidden sources of

gliadin, such as is found in some brands of soy sauce, modified food starch, ice cream, soup, beer, wine, vodka, whisky, and malt. Patients should also be encouraged to consult resources for patient education and information on gluten-free recipes.

PATIENT RESOURCES Gluten Intolerance Group 15110 10 Ave. SW, Suite A Seattle, WA 98166-1820 Website: http://utww.gluten.net

1.Cardenas A, Kelly CP. Celiac sprue. Semin Gastrointest Dis 2002;13:232-244. 2. Nelsen DA Jr. Gluten-sensitive enteropathy (celiac disease): more common than you think. Am Fam Physician 2002;66: 2259-2266. 3. Accomando S, Cataldo F. The global village of celiac disease. Dig Liv Dis 2004;36492-498. 4. Dewar D, Pereira SP, Ciclitira PJ. The pathogenesis of coeliac disease. Int J Biochem Cell Biol200436:17-24. 5. Persson LA, Ivarsson A, Hemell 0. Breast-feeding protects against evidence. Adv Exp celiac disease in childhood+pidemiologcal Med Biol2002;503:115-123. 6. Ivarsson A, Hemell 0, Stenlund H, et al. Breast-feeding protects against celiac disease. Am J Clin Nutr 2002;75:914-921. 7.Faellstroem SP, Winberg J, Andersen HJ. Cow’s milk induced malabsorption as a precursor of gluten intolerance. Acta Paediatr %and 1965;54:101-115. 8.Saalman R, Dahlgren UI, Fallstrom SP, et al. Avidity progression of dietary antibodies in healthy and coeliac children. Clin Exp h~n012003;134:328-334. 9. Green PH, Fleischauer AT, Bhagat G, et al. Risk of malignancy in patients with celiac disease. Am J Med 2003;115:191-195.

Celiac Sprue Association P.O. Box 31700 Omaha, NE 68131-0700 Website: www.csaceliacs.org Celiac Disease Foundation 13251 Ventura Blvd., Suite 1 Studio City, CA 91604 Website: h ttp://celiac.org

10. Dohan FC, Harper EH, Clark MH, et al. Is schizophrenia rare if grain is rare? Biol Psychiatry 1984;19385-399. 11. Dohan FC, Gasberger JC. Relapsed schizophrenics: earlier discharge from the hospital after cereal-free, milk-free diet. Am J Psychiatry 1973;130685-688. 12. Paroli E. Opioid peptides from food (the exorphins). World Rev Nutr Diet 1988;55:58-97. 13. Baudon JJ, Johanet C, Absalon YB, et al. Diagnosing celiac disease: a comparison of human tissue transglutaminase antibodies with antigliadin and antiendomysium antibodies. Arch Pediatr Adolesc Med 2004;158:584-588. 14.Love AHG, Elmes M, Golden M, et al. Zinc deficiency and celiac disease. In McNicholl B, McCarthy CF, Fottrell PF, eds. Perspectives in coeliac disease. Proceedings of the 3rd International Symposium on Coeliac Disease. Baltimore: University Press, 1978335-342. 15. Carroccio A, Iacono G, Montalto G, et al. Pancreatic enzyme therapy in childhood celiac disease. A double-blind prospective randomized study. Dig Dis Sci 1995;402555-2560.

Cellulite Michael T. Murray, ND Joseph E, Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

1567

General Considerations 1567 Histologic Features 1567

Therapeutic Approach 1570 Diet 1570 Physical Measures 1570 Botanical Medicines 1570

Clinical Features 1568 Therapeutic Considerations 1569 Lifestyle 1569

DIAGNOSTIC SUMMARY Demonstration of the ”mattress phenomenon’’ (i.e., pitting, bulging, and deformation of the skin) 90% to 98% of cases occur in women. Symptoms may include feeling of tightness and heaviness in areas affected (particularly the legs). Tenderness of the skin is quite apparent when the skin is pinched, pressed on, or vigorously massaged.

GENERAL CONSIDERATIONS The term cellulite is used to describe a cosmetic defect that is cause for great distress among women. This French word was adopted by the lay public in the United States before American physicians and medical literature were educated in a condition that European physicians had been treating for more than 150 years. The correct English translation would be cezlulitis. However, in the United States, cellulitis is used solely to describe a diffuse, inflammatory or infectious process involving the connective tissue, most commonly of the skin and subcutaneous structures. In cellulite there is no inflammatory or infectious process occurring. This difference in meaning in the translated term was just one source of confusion for American physicians. Researchers have suggested that the terms dermopanniculois dejomzans or adiposis edematosa be used to designate the clinical condition. In this chapter, however, the term cellulite is used.

Histologic Features The subcutaneous tissue is disturbed in cellulite. Since the thighs are the prime area of involvement, the structure of the subcutaneous tissue of the thighs is discussed here in greatest detail. The subcutaneous tissue of the thighs is composed of three layers of fat, with two planes of connective tissue (ground substance) between them. The basic construction of the subcutaneous tissue of the thigh differs in men and women, as shown in Figure 157-1. In women the uppermost subcutaneous layer consists of what are termed large ”standing fat-cell chambers,” which are separated by radial and arching dividing walls of connective tissue anchored to the overlying connective tissue of the skin (corium). In contrast, the uppermost part of the subcutaneous tissue in men is thinner and has a network of criss-crossing connective tissue walls. In addition, the corium (the connective tissue structure between the dermis and subcutaneous tissue) is thicker in men than in women.‘P2 These basic differences in subcutaneous tissue structure are the reason cellulite is seen almost exclusively in women. A simple test to illustrate these differences is the ”pinch test.” Pinching the skin and subcutaneous tissue of the thighs of women result in the previously described mattress phenomenon, while in most men the skin folds or furrows but does not bulge or pit. These structural differences between men and women are responsible for most women producing the mattress phenomenon in response to the pinch test, as illustrated in Figure 157-2.*r2 1567

Specific Health Problems

As women age, the corium (see Figure 157-l),which is already thinner in women than in men, becomes progressively thinner and looser. This allows fat cells to migrate into this layer. In addition, the connective tissue walls between the fat-cell chambers also become thinner, allowing the fat-cell chambers to enlarge excessively (hypertrophy). The breaking down or thinning of connective tissue structures followed by the formation of fibrosclerotic strands is a major contributor to the development of cellulite and is responsible for the granular "buck-shot" feel of The "mattress phenomenon" is brought about by alternating depressions and protrusions in the upper compartment systems of fat tissue. The vertical orientation of women's fat-cell compartments, in conjunction with the weakening of the tissues noted earlier, is apparently Female

Male Epidermis Corium Upper zone of subcutis

what allows the protrusion of the fat cells into the lower c0rium.l Table 157-1 summarizes the anatomic differences between men and women. Histologic examination also reveals distension of the lymphatic vessels of the upper corium and a decrease in the number of subepidermal elastic fibers.

CLINICAL FEATURES The basic clinical features of cellulite are well known. Women comprise 90% to 98% of the cases, reflecting histologic differences between men and women. Symptoms of cellulite include a feeling of tightness and heaviness in areas affected (particularly the legs). Tenderness of the skin is quite apparent when the skin is pinched, pressed on, or vigorously massaged.*P2 The areas of the body involved are typically the gluteal and thigh regions and, to a lesser extent, the lower part of the abdomen, the nape of the neck, and the upper parts of the arms. These are the areas of the body usually affected in gynecoid (female) obesity. Cellulite is classified in four major stages:

Figure 157-1 The anatomic basis of cellulite.

{

Female

)

\

I

Male

Figure 157-2 The "pinch" test.

Stage &the skin on the thighs and buttocks has a smooth surface when the subject is standing or lying. When the skin is pinched (pinch test), it folds and furrows but does not pit or bulge. This stage is the "normal" stage of most men and slim women. Stage 2-the skin surface is smooth while a subject is standing or lying, but the pinch test is clearly positive for the mattress phenomenon (pitting, bulging, and deformity of the affected skin surfaces).This is normal for most females, but in a male it may indicate deficiency of androgenic hormones. Stage 2-the skin surface is smooth while a subject is lying but when standing there is pitting, bulging,

Cutis and subcutis

Men

Women

Epidermis

Thicker (58-77 u)

Thinner (47-62 u)

Corium

Thicker (1159-1798 u)

Thinner (994-1349 u)

Border zone of corium and subcutis

Fewer papillae adiposae

More papillae adiposae

Subcutis

Variably thinner

Variably thicker

Upper zone

Small polygonal fat-cell chambers with criss-crossing septa of connective tissue

Large, standing fat-cell chambers with radially running septa of connective tissue

Status protrusis cutis ("mattress phenomenon")

Does not develop

Develops

Modiied from Pierard GE, Nizet JL, Pierard-FranchimontC. Am J Dermatopathol2OOO;22:34-37.

Cellulite and deformity of the affected skin surfaces. This stage is common in women who are obese or older than 35 to 40 years of age. Stage 3-the mattress phenomenon is apparent when a subject is lying or standing. It is common after menopause and in obesity.

seed, sweet clover, and Ginkgo biloba). The marketing materials claim that Cellasene is a safe, clinically studied formula, but none of the studies have been published for review. It is also claimed that the herbal extracts in Cellasene increase blood circulation, reduce fluid buildup, stimulate metabolism, and reduce localized fats. These claims have not been verified. The only doubleblind study that has been conducted did not show any Although most women consider stage 0 the cosmetic benefit with Cellasene use? ideal, stage 1 is the best classification most can expect, One formulation shown to be effective in a doubledue to structural predisposition. blind study contained retinol, caffeine, and ruscogenin (from butcher’s broom [Ruscus aculeatusl)? A combination THERAPEUTIC CONSIDERATIONS of different noninvasive evaluation methods (i.e., the skin macrorelief, the dermal and hypodermal structures, As usual, the best approach is prevention. However, the skin mechanical characteristics, and the cutaneous because the number and size of fat cells an individual flowmetry) demonstrated significant activity of the antihas are largely determined by maternal prenatal nutricellulite product versus baseline and showed its superitional status, many people have a significant predisposiority versus the placebo in skin macrorelief (decrease tion. The next step is maintaining a slim subcutaneous of the “orange peel” effect and increase in cutaneous fat layer. This is best done by exercising and maintaining microcirculation). a normal body weight throughout life. Slim women and The effect of this formulation is probably due to a synfemale athletes have little or no cellulite.’j2 ergistic effect of its constituents. Topically applied vitaLifestyle min A in the form of retinol has been shown to be of Weight Reduction and Exercise benefit in improving the skin histology in women with cellulite.6The study was conducted in 15 women from Weight reduction and exercise can be employed in the 26 to 44 years old who had requested liposuction to treatment of cellulite, and they should always form the improve mild to moderate cellulite. After 6 months of primary mode of treatment. However, weight reduction should be gradual, especially in women older than the treatment, skin elasticity increased by 10.7% while skin age of 40. A rapid loss of weight in individuals whose skin viscosity decreased by 15.8% at the retinol-treated site. These results indicate retinol improves the tensile propand connective tissues are already undergoing changes erties of skin. This effect was more prominent at sites from aging often make the mattress phenomenon more where the mattress phenomenon was the only evidence apparent. of cellulite. Although the lumpy-bumpy appearance of Massage the skin showed little response, there was a shift in the Massage is beneficial, particularly self-administered phenotype of connective tissue cells obtained. The main massage with the hand or brush. The physical and retinol-related change consisted of a twofold to fivefold increase in the number of factor XIIIa+ dendrocytes, both mechanical effects of massage improve circulation of in the dermis and fibrous strands of the hypodermis. blood and lymph. The direction of the massage should always be from the periphery to the heart. The caffeine in the formulation potentiates the effect of catecholamine-induced lipolysis. Topical administraTopical Treatments tion of caffeine is preferable to oral administration in the treatment of cellulite because its effects are primarily Many cosmetic formulas and herbal preparations on the market claim to be effective in ”curing” ~ellulite.~ local. Cola species is a rich source of caffeine and related However, the majority of these formulas have no sciencompounds. tific basis to support their use. Most simply contain The ruscogenin in the formula focuses on enhancing herbal extracts like Fucus vesiculosus (bladderwrack), the integrity of connective tissue structures-a major goal in the treatment of cellulite. In addition to butcher’s which soothes, softens, and tones the skin and therefore broom extract (see Chapter 121 for more information), may be beneficial in treating cellulite. This herb’s effects other botanicals that improve connective tissue strucon cellulite have not been confirmed by scientific investures may also be of benefit. Most notably are the tigation, however. extracts of Centella asiafica. Sometimes topical preparations for cellulite are marketed with tremendous hype. For example, Cellasene is Centella asiatica a proprietary formula that has been marketed all over Extracts of centella containing 70% triterpenic acids (asithe world as a miracle treatment for cellulite. It features atic acid and asiatoside) has demonstrated impressive a blend of natural herbal extracts (bladderwrack, grape

Specific Health Problems

clinical results when given orally in the treatment of cellulite, venous insufficiency of the lower limbs, and varicose veins.’,* Several experimental studies have demonstrated that centella exerts a normalizing action on the metabolism of connective tissue. Specifically, it enhances connective tissue integrity by stimulating glycosaminoglycan synthesis without promoting excessive collagen synthesis or cell growth. Glycosaminoglycansare the major components of the amorphous intercellular matrix (ground substance) in which collagen fibers are embedded. The net outcome is the development of normal connective tissue that is rich in glycosaminoglycans. The effect of centella in the treatment of cellulite appears to be related to its ability to enhance connective tissue structure and reduce sclerosis, while its action in venous insufficiencyand varicose veins is a combination of its connective tissue effects and its ability to improve the blood flow through the affected limbs.

THERAPEUTIC APPROACH It must be kept in mind that cellulite is not a disease per se. Instead, it is primarily a cosmetic disorder due to anatomic changes. Excessive subcutaneous adipose tissue or degeneration of subcutaneous connective tissue leads to fat chamber enlargement and greater visibility of the mattress phenomenon. The basic therapeutic approach is straightforward (i.e., reduce subcutaneous fat and enhance connective tissue integrity). Varicose veins are often found in conjunction with cellulite, and the two conditions share much in common.

1. Rossi AB, Vergnanini AL. Cellulite: a review. J Eur Acad Dermatol Venereol2OOO;14251-262. 2. Pierard GE, Nizet JL, Pierard-Franchimont C. Cellulite: from standing fat herniation to hypodermal stretch marks. Am J Dermatopathol 2OOO;22:34-37. 3. Sainio EL, Rantanen T, Kanerva L. Ingredients and safety of cellulite creams. Eur J Dermatol2O00;10:596-603. 4. Lis-Balchin M. Parallel placebo-controlled clinical study of a mixture of herbs sold as a remedy for cellulite. Phytother Res 1999;13627-629. 5. Pierard-Franchimont C, Pierard GE, Henry F, et al. A randomized, placebo-controlled trial of topical retinol in the treatment of cellulite. Am J Clin Dermatol2OOO;1:369-374.

In particular, both appear to result largely from a loss of integrity of supporting connective tissue (seeChapter 216 for further discussion). As stated earlier, demonstration of the mattress phenomenon in men is a highly probable sign of androgen deficiency. This may be due to either primary or secondary hypogonadism.

Diet A diet high in complex carbohydrates and low in refined carbohydrates and fats is important. Weight loss should be promoted in obese individuals.

Physical Measures Exercise: 20 to 30 minutes of aerobic exercise a minimum of 5 days/week Massage: regular self-massage of the affected area

Botanical Medicines Oral Administration C. asiatica extract (70% triterpenic acid content): 30 mg three times/day Aesculus hippocastanum Bark of root: 500 mg three times/day Escin: 10 mg three times/day

Topical Application of Retinol-Containing Creams or Ointments Twice Daily Cholesterol/escin complex: 0.5% to 1.5% Cola Vera extract (14% caffeine): 0.5% to 1.5% Fucus vesiculosus: 0.25% to 0.75%

6. Bertin C, Zunino H, Pittet JC, et al. A double-blind evaluation of the activity of an anti-cellulite product containing retinol, caffeine, and ruscogenine by a combination of several non-invasive methods. J Cosmet Sci 2001;52:199-210. 7. Kartnig T. Clinical applications of Centellu usiuticu (L.) Urb. Herbs Spices Med Plants 1988;3146-173. 8. Brinkhaus B, Lindner M, Schuppan D, Hahn EG. Chemical, phannacological and clinical profile of the East Asian medical plant Centellu nsinticu. Phytomedicine 2000;7427-448.

Cervical Dysplasia Tori Hudson, ND Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER C O N T E N T S Diagnostic Summary

1571

General Considerations 1571 Human Papillomavirus 1571 Risk Factors (Table 158-1) 1572 Therapeutic Considerations 1573

DIAGNOSTIC SUMMARY Abnormal Pap smears (atypical cells of undetermined significance [ASC-US]; low-grade squamous intraepithelial lesions [LGSEs]; high-grade squamous intraepithelial lesions [HGSILs]) Colposcopy, endocervical curettage, cervical biopsies

Nutrition 1573 Miscellaneous Considerations

1575

Therapeutic Approach 1575 Diet 1576 Supplements 1576 Sample Treatment Protocols 1576

CIN I1 = Moderate cervical dysplasia CIN I11 = Severe cervical dysplasia or carcinoma in situ LGSILs = Include CIN I HGSILs = Include CIN I1 and CIN I11

GENERAL CONSIDERATIONS

Since Bethesda 2001 and the new cervical disease management guidelines of 2002, algorithms for managing ASC-US, atypical cells for which high-grade lesions cannot be ruled out (ASC-H),LGSILs, and HGSILs have changed. The following options for the management of ASC-US are considered acceptable:

Cervical dysplasia is generally regarded as a precancerous lesion with risk factors similar to those of cervical cancer.' Therefore this discussion focuses on the following lifestyle and nutritional factors that appear to be cofactors in the development and progression of cervical dysplasias and, ultimately, cervical cancer:

1. Referral to colposcopy 2. Repeat the Pap smear twice at 4- to 6-month intervals with referral to colposcopy if there is a repeat Pap of ASC-US or worse 3. Human papillomavirus (HPV) testing with referral to colposcopy for high-risk HPV types

Early age of first intercourse Multiple sexual partners Other infectious agents (chlamydia, herpes,) History of genital warts Immunosuppression (human immunodeficiency virus, transplant patient) Smoking Oral contraceptive use Pregnancy Many nutritional factors1r2

The management guidelines for ASC-H, LGSIL, and HGSIL are as follows: 1.ASC-H = direct referral to colposcopy 2. LGSIL and HGSIL = direct referral to colposcopy

HPV testing is not considered helpful in the initial management of either of these cytologic reports because most are positive for high-risk HPV. In addition to the terms already defined, the following terms are used in this chapter: CIN I = Condyloma (warty tissue) or mild cervical dysplasia

Human Papillomavirus Epidemiology and Natural History Almost all cervical cancer is associated with long-term, persistent HPV infection. HPV is easily transmitted by genital-to-genital contact. The time from exposure to the appearance of a lesion or an abnormal Pap smear is as little as a few weeks to as much as decades. The incidence 1571

Specific Health Problems

of medical visits for HPV disease has increased more than 500% in the past 30 years and is considered epidemic by many. HPV is now so common that up to 80% of the adult population may be infected. HPV DNA tests have documented the presence of HPV DNA in at least 60% of young women. However, less than 10% develop cervical lesions. This suggests that the host immunity is able to defend against the development of clinical disease and that HPV infections often are only transient and result in minor manifestations such as A%-US. For other individuals, especially women, HPV results in a clinical expression to which the host immune response has not been able to effectively respond. The result is clinical disease that can include flat or raised genital warts; cervical, vaginal, vulvar, or perianal dysplasias; or progression to invasive cancers of the same site. The first step in the development of dysplasias or invasive cancers is viral entry. A complex interaction of host immunity, viral load, viral type, and host susceptibility determines the natural course of the disease. HPV is implicated as the etiology of cervical cancer in virtually all (99.8%)of the 320,000 cases of cervical cancers that occur annually in women throughout the world. In addition, HPV is detected in approximately 50% to 80% of vaginal, 50% of vulvar, and nearly all penile and anal cancers. Of nearly 120 HPV types, approximately 20% to 30% of these are unclassified types that have been only partially sequenced. About 30 HPV types primarily infect the squamous epithelium of the lower anogenital tracts of both men and women, resulting in both flat and raised warts or intraepithelial lesions of the vulva, vagina, cervix, and perianal region. Disease caused by HPV types 6, 11, 42, 43, or 44 most commonly present as classic genital warts with a cauliflower appearance, but they may also present as flat lesions. Types 16,18,31, 33, 35, 45, 51, 52, and 56 are considered "high-risk" types because they have been found in lower-genital tract cancers. They are also found in intraepithelial lesions. Lesions that are caused by low-risk and highrisk HPV types can regress to normal even without treatment, but currently it is not possible to predict which lesions will regress and which will persist or progress. Approximately 80% of cervical cancers are associated with types 16, 18, 31, and 45; 15% are associated with types 31,33,35,51, or 52. LGSILs can be caused by both low-risk and high-risk HPV types. In fact, high-risk types have been detected in 75% to 85% of low-grade lesions with mixed low- and high-risk types in approximately 15% and low-risk types exclusively in only 2% to 25%.

Histologic Considerations The principle reservoir of HPV is the moist mucosa and the cutaneous epithelial tissue in adjacent areas. Ninety-five percent of cervix dysplasias and cervical

cancers originate in the squamocolumnar junction of the cervical 0s.I In adolescence, glandular epithelium covers much of the exocervix, but as adolescence progresses the columnar epithelium is gradually replaced by squamous cells. This actively growing area seems to be more susceptible to multiple insults and the HPV, probably due to the metaplastic nature of the conversion process and the inflammatory process of metaplasia.

Development and Progression of Disease Exposure to HPV is common in the teens and 20s soon after unprotected intercourse in heterosexual women. Detectable disease is uncommon, yet up to 60% in this age group test positive for HPV DNA by polymerase chain reaction (PCR) testing. As stated earlier, the nature of the HPV infection is transient and the immune system responds to HPV in most individuals. One of three things can happen following infection with HPV (1)The infection remains permanently latent or produces only transient cytologic changes; (2) individuals develop HPV-associated cytologic changes diagnostic of HPV, and approximately 60% of women with atypia or LGSIL spontaneously regress and 20% to 30% persist; and (3) 10% develop HGSIL. PCR testing has shown that up to 70% of women clear the virus within the first year. Low-grade lesions can regress on their own, persist, or progress. Progression to high-grade lesions tends to peak between the ages of 25 and 29, an average of 4 to 7 years after peak incidence of mild cervical dysplasia. Most low-grade lesions, even though the majority are due to high-risk HPV types, do not progress to invasive cancer, even if allowed to follow the natural history of the disease with no treatment interventions. Even those infected with HPV type 16, the type detected in more than 60% of cervical cancers, tend to regress spontaneously over time. The incidence of invasive cervical cancer reaches a plateau in Caucasian women in the United States approximately 15 years after the peak incidence of CIN 111, usually between the ages of 40 and 45.

Risk Factors (Table 158-1) Sexual Transmission Early age at first intercourse or multiple sexual contacts with a lack of condom use, or both, are associated with an increased risk of cervical dysplasia/carcinoma.'P From this and other evidence, it has been suggested that cervical cancer is a sexually transmitted disease, in the sense that the implicated infectious agent, HPV, is easily transmitted by genital-to-genital contact. The average time from exposure to the appearance of a lesion varies from a few weeks to 3 months to years or decades. This variability in time from exposure to identification of a lesion makes it almost impossible to identify sexual partners who transmitted the virus.

Cervical Dysplasia

1

Risk factors in cervical dysplasial cancer

Risk factor Smoking (1O+ cigarettedday)

Relative risk 3.06

Multiple sexual partners (2-5)

3.46

First intercourseyounger than 18 yr old

2.76

Deficient dietary beta-carotene (<5000 IU/day)

2.813

Deficient dietary vitamin C ( ~ 3 mg/day) 0

6.716

The actual values for the absolute risk of the various risk factors are as yet somewhat controversial. The numbers listed here represent the authors’ summarization of the literature. These risks are not linearly additive because they are usually closely related, and more involved multivariant analysis is necessary to determine the actual relative risk of each.

Genital-to-oral transmission is suggested to be possible due to detection of HPV 6, 11, and 16 in some oropharyngeal cancers, but oral HPV lesions are in fact rare. Nonsexual exposure to the virus may occur from examination tables, doorknobs, tanning beds, and other inanimate objects but is difficult to document and prove. Other infectious agents such as herpes simplex, chlamydia, and bacterial vaginosis may serve as cofactors for HPV. These agents may alter cervical immunity, contribute to inflammation, facilitate entry of HPV into the basal cells, accelerate replication of HPV in the host cell nucleus, and coexist with the HPV.

Smoking A significant risk factor for cervical cancer and cervical dysplasia is cigarette smoking: Smokers have an approximately threefold increased incidence compared with nonsmokers (one study” showed the increase to be as high as seventeenfold in women aged 20 to 29).%Several hypotheses have been proposed to explain this association: Smoking may depress immune functions, allowing a sexually transmitted agent to promote abnormal cellular development, leading to the onset of cervical dysplasia. Smoking induces vitamin C deficiency, as vitamin C levels are significantly depressed in smokers.’ Cervical cells may concentrate nicotine. There may be unrecognized associations between smoking and sexual behavior.%

Oral Contraceptives Earlier studies suggested that oral contraceptive (OC)use increased the risk of cervical neoplasia, both invasive and precancerous cervical dysplasias. More recent studies that are controlled for sexual history have not confirmed this association. Three large, well-controlled studies looked at invasive cervical cancer and OC use and did not find statistically significant associations compared

with women who never used OCS.~-’~ There was no overall change in risk of invasive cervical cancer; however, one of the three studies (by Parazzinis) found a modestly increased risk in long-term OC users. The other two studies failed to find a significantly increased risk of invasive cervical cancer even with long-term OC use. Two other studies assessed OC use and risk of cervical dysplasia, and neither found any statistically significant associations.”J2 A more disturbing aspect is that OC use has been associated with an increase in the incidence of a rare cancer of the cervix, adenocarcinoma. This is a less common variant of squamous cervical cancer. It does appear that the incidence of this disease has increased over the past several decades, while the incidence of invasive squamous cervical cancer has decreased since the pill was introduced. Two studies found a modest but statistically significant increased risk of invasive cervical adenocarcinoma in OC users with more than 12 years of use.13J4 OCs are known to potentiate the adverse effects of cigarette smoking and decrease the levels of numerous nutrients including vitamins C, B6, and BI2; folic acid; riboflavin; and zinc.15

THERAPEUTIC CONSIDERATIONS Nutrition Numerous nutritional factors have been implicated as cofactors for cervical dysplasia. Although many single nutrients may play a significant role (particularly beta-carotene and retinoids, folic acid, pyridoxine, and vitamin C), it is important to recognize that a large proportion (67%) of patients with cervical cancer have abnormal anthropometric or biochemical parameters. Significant abnormalities have been found in heightto-weight ratios, triceps skin fold thickness, midarm muscle circumference, serum albumin levels, total ironbinding capacity, hemoglobin levels, creatinine height index, prothrombin time, and lymphocyte count. Many other patients have marginal but ”normal” nutritional status as determined by these cursory evaluations.I6 These suggest that multiple nutrient deficiencies are probably the rule rather than the exception. Vitamin assessment by biochemical evaluation (plasma and red cell folate; serum beta-carotene; vitamins A, B12, and C; erythrocyte transketolase for thiamin determination; erythrocyte glutathione reductase for riboflavin determination; and erythrocyte aspartate transaminase for pyridoxine determination) in patients with untreated cervical cancer shows that at least one abnormal vitamin level was present in 67% of patients, while 38% display multiple abnormal parameter^.'^ If mineral levels are also included, it is clear that nutritional aspects play a major role in the onset of cervical dysplasia / carcinoma.

Specific Health Problems General dietary factors are also important. A high fat intake has been associated with increased risk for cervical cancer, while a diet rich in fruits and vegetables is believed to offer significant protection against carcinogenesis, probably due to the higher intake of fiber, betacarotenes, and vitamin C.j

Vitamin A and Beta-carotene

and 0 progressed to a worse state of dysplasia during the course of the natural treatment protocol.

Vitamin C A significant decrease in vitamin C intake and plasma levels occurs in patients with cervical dysplasia, and it has been documented that inadequate vitamin C intake is an independent risk factor for the development of premalignant cervical disease and carcinoma in situ.27,28 Vitamin C is known to do the f~llowing’~:

A minor association apparently exists between dietary retinoids and cervical cancer /dysplasia risk and a strong inverse correlation between beta-carotene intake and the Act as an antioxidant risk of cervical cancer/dysplasia.18-20 Although only 6% Strengthen and maintain normal epithelial integrity of patients with untreated cervical cancer have belowImprove wound healing normal serum vitamin A levels, 38% have stage-related Enhance immune function abnormal levels of beta-carotene.” Low serum betaInhibit carcinogen formation carotene levels are associated with a threefold greater risk for severe dysplasia,2O and serum vitamin A and Folic Acid beta-carotene levels are significantly lower in patients with cervical dysplasia than in a control group (54 vs. Cervical cytologic abnormalities related to folic acid 104 mg/dl for vitamin A, and 21.3 vs. 13.9 pg/dl for deficiency precede hematologic abnormalities by many week^.^^,^^ As folic acid is the most common vitamin beta-carotene).21,u Carotenes and retinols offer several types of protecdeficiency in the world and quite common in women who are pregnant or taking oral contraceptive^,'^,^^ it is tion. They improve the integrity and function of the epithelial tissues, provide antioxidant properties, and probable that many abnormal cytologic smears reflect enhance immune system function (see Chapter 57). As folate deficiency rather than “true” d y s p l a ~ i a . ~ ~ , ~ ~ , ~ with other diseases, it appears that beta-carotene is more This is particularly applicable when patients take OCs. advantageous than retinoids, possibly due to greater It has been hypothesized that OCs induce a localized antioxidant properties, immune-enhancing effects, and interference with folate metabolism and, although serum levels may be increased, tissue levels at end-organ its tendency to be concentrated in epithelial tissues. targets, such as the cervix, may be d e f i ~ i e n t . ~This ~ J ~is The use of topical vitamin A was used in a study of consistent with the observation that tissue status as 301 women who received either four consecutive 24hour measured by erythrocyte folate is typically decreased applications of retinoid or placebo, followed by two (especially in those with cervical dysplasia), while serum more applications at 3 and 6 months applied with a collevels may be normal or even increased.% OCs are lagen sponge in a cervical cap. Retinoic acid increased the complete regression rate of moderate dysplasia from believed to induce the synthesis of a macromolecule that 27% in the placebo group to 43% in the treatment group. inhibits folate uptake by cells. The women with severe cervical dysplasia did not Low red blood cell (RBC) folate status has been improve.u In a University of Arizona study, vitamin A shown to enhance the effect of the other risk factors for cervical dysplasia, especially HPV infection. In other was delivered to 20 women via a cervical cap. In 10 of words, low RBC folate appears to be a major risk factor 20 women, cervical dysplasia completely disappeared. On the 10 patients with a complete response, 5 had mild for HPV infection of the ~ e r v i x . ~ ~ , ~ ~ Folic acid supplementation (10 mg/day) has resulted dysplasia and 5 had moderate dysplasia.24There were an insufficient number of severe dysplasia patients to in improvement or normalization of cytologic smears in patients with cervical dysplasia in controlled clinievaluate. Vitamin A suppositories have also been used as cal s t ~ d i e s . ~Regression ~ , ~ ~ , ~ rates ~ for patients with untreated cervical dysplasia are typically 1.3%for mild part of a multifactorial treatment plan using oral folic acid, vitamin C, and carotenes with topical vitamin A and 0% for moderate dysplasia. When treated with folic suppositories and herbal vitamin suppositories. Other acid, the regression-to-normal rate, as determined by patients with more severe disease were treated with a colposcopy/biopsy examination, was observed to be topical treatment called an escharotic treatment. In this 20% in one 63.7% in and 100°/~in yet study of atypia, mild, moderate, and severe dysplasia another.32Furthermore, the progression rate of cervical and carcinoma in situ, 43 women were s t ~ d i e d .Of ~ ~ , ~dysplasia ~ in untreated patients is typically 16% at 4 months, a figure matched in the placebo group in one the 43 patients, 38 returned to a normal disease-free cervix, 3 had partial improvements, 2 stayed the same, study, while the folate-supplemented group had a 0%

Cervical Dysplasia

progression rate.33These figures were achieved despite the fact that the women remained on the Ocs. Because the median time required for progression from cervical dysplasia to carcinoma in situ in untreated patients ranges from 86 months for patients with mild dysplasia to 12 months for patients with severe dysplasia, and regression is uncommon, it is suggested that a trial of folate supplementation (along with other considerations discussed) be instituted in mild to moderate dysplasia, with a follow-up Pap smear and colposcopy at 3 months. Vitamin BIZsupplementation should always accompany folate supplementation to rule out the possibility of folate supplementation masking an underlying vitamin BIZdeficiency.

Pyridoxine Vitamin B6 status, as determined by erythrocyte transaminase, is decreased in one third of patients with cervical cancer.37 Decreased pyridoxine status would have a significant effect on the metabolism of estrogens and tryptophan, as well as impairing immune response.

Selenium Serum,dietary, and soil selenium levels have been shown to be inversely correlated with all epithelial cancersx and to be significantly lower in patients with cervical dysplasia.21 Increased glutathione peroxidase activity resulting from increased selenium intake is believed to be the factor responsible for selenium’s anticarcinogenic effect, although other factors may be of equal sigruficance. Many toxic elements (e.g., lead, cadmium, mercury, gold) possess selenium-antagonistic properties.38 The role these heavy metals may play in cervical disease has not been determined.

Copper-to-Zinc Ratio, Zinc, and Retinol An increase in the serum copper-to-zinc ratio is a nonspecific reaction to inflammation or malignancy. Recently, in a study involving gynecologic cancer, it was suggested that the serum copper-to-zinc ratio “is clinically of utmost importance, since it constitutes a tool with which to establish the extent of the A ratio above 1.95 indicated malignancy in 90% of the patients in that study. Elevated ratios are also seen in various conditions including the following:

OC use Pregnancy Acute and chronic infections Chronic liver disease Inflammatory conditions

Therefore the serum copper-to-zinc ratio should not be used to predict malignancy in patients with these conditions. A decrease in available zinc may be the

reason retinol binding protein was either absent or undetectable in 80% of dysplastic tissue samples as compared with 23.5% in normal tissue. A large study of 206 women found an inverse relationship between serum levels of both retinol and zinc and the incidence of cervical dysplasia.40

Miscellaneous Considerations Vaginal Depletion Pack The vaginal depletion pack (or “vag pack”) has a long history of effective use by naturopathic and eclectic physicians in the treatment of cervical dysplasia. Although its mechanism of action has not yet been elucidated, it is thought to work by promoting the sloughing of the superficial cervical cells, particularly those that are abnormal. It is effective as part of a multifactorial nutritional and topical treatment a p p r o a ~ h . ~ ~ , ~ ~ (see Appendix 13 for a complete description of this technique).

THERAPEUTIC APPROACH The basic approach is to eliminate all factors known to be associated with cervical dysplasia and to optimize the patient’s nutritional status. In particular, eliminate smoking and OC use and supplement with folic acid, beta-carotenes, and vitamin C. Cases that could be considered candidates for a natural treatment protocol are as follows: ASC-US Cervical condyloma LGSIL on Pap smear with endocervicalcurettage negative and satisfactory colposcopy HGSIL with endocervical curettage negative and satisfactory colposcopy or at discretion of physician LGSIL with endocervical curettage positive and satisfactory colposcopy and patient considered to be at low risk or at discretion of physician HGSIL and endocervical curettage positive and satisfactory colposcopy and patient at low risk or at discretion of practitioner Patients should be referred for conventional treatment if the following conditions exist: unsatisfactory colposcopy, three or four quadrant lesions, significant discrepancybetween Pap smear and colposcopy/biopsy, noncompliant patient, history of abnormal Pap smears longer than one year prior, or patients determined to be at high risk. For many patients, especially ASC-US and LGSIL patients, nutritional supplementation and topical treatments, either suppositories or the escharotic treatment, are sufficient to successfully treat the disease. For patients who undergo a loop electrosurgical excision

procedure, cryotherapy, or conization, nutritional supplements and even topical suppositories 3 weeks after completion of the conventional treatment may be able to reduce the recurrence rate and affect the local cervical immunity.

Diet Increase fruits and vegetables, especially those yellow and orange in color. A general immune supportive diet is considered prudent-high in fiber, vegetables, fruits, nuts, and seeds; low in fat and saturated fat.

Supplements Folic acid: 10 mg/day for 3 months, then 2.5 mg/day Pyridoxine: 50 mg three times/day Vitamin BIZ: 1mg/day Beta-carotene: 200,000 IU/day Vitamin C: 1to 6 g/day Vitamin E: 200 IU four times/day Selenium: 400 pg/day Zinc: 30 mg/day

Sample Treatment Protocols ASC-US Topical Week 1: Insert vitamin A suppository nightly for 6 nights. Week 2: Insert herbal vaginal suppository nightly for 6 nights. Week 3: Repeat vitamin A. Week 4: Repeat herbal. Supplementation for 3-month minimum Folic acid: 10 mg Beta-carotene: 150,000 IU/ day

1. Robbins S, Cotran R, Kumar V. Pathologic basis of disease, ed 3. Philadelphia: WB Saunders, 19M1123-1128. 2. de Vet HC, Stuxmans F. Risk factors for cervical dysplasia: implications for prevention. Public Health 1994;108:241-249. 3. Clarke EA, Morgan RW, Newman AM. Smoking as a risk factor in cancer of the cervix: additional evidence from a case-conkol study. Am J Epidemiol1982;11559-66. 4. Lyon JL, Gardner JW, West DW, et al. Smoking and carcinoma in situ of the uterine cervix. Am J Public Health 1983;73:55&562. 5. Marshall JR, Graham S, Byers T, et al. Diet and smoking in the epidemiology of cancer of the cervix. J Natl Cancer Inst 1983;70:847-851. 6. Clarke EA, Hatcher J, McKeown-Eyssen GE, Lickrish GM. Cervical dysplasia: association with sexual behavior, smoking, and oral contraceptive use? Am J Obstet Gynecol 1985;151:612-616. 7. Pelleter 0. Vitamin C and tobacco. Int J Vitam Nutr Res 1977;16: 147-169. 8. Parazzini F, La Vecchia C, Negri E, Maggi R. Oral contraceptive use and invasive cervical cancer. Int J Epidemiol 1990;19:259-263.

Vitamin C: 3 to 6 g Mu1tivitamin/ mineral

LGSIL Topical Week 1: Insert Vitamin A suppository nightly for 6 nights. lnsert uag pack suppositoy on night 7. Week 2: Insert herbal suppository nightly for 6 nights. lnsert uag pack suppositoy on night 7. Week 3: Repeat vitamin A. Insert uag pack suppositoy on night 7. Week 4: Repeat herbal suppository. Insert uag pack suppositoy on night 7. Supplementation for minimum of 3 months Folic acid: 10 mg Beta-carotene: 150,000 IU/day Vitamin C: 3 to 6 g Selenium: 400 pg daily M dtivitamin/ mineral

HGSIL Topical Escharotic treatment twice weekly for 5 weeks Follow last treatment with 1 month of suppository routine as in LGSIL. Supplementation Folic acid: 10 mg Beta-carotene: 150,000 IU/day Vitamin C: 3 to 6 g/day Selenium: 400 pg Vitamin E: 800 IU/day Multivitamin/mineral

9. Brinton LA. Oral contraceptives and cervical neoplasia. Contraception 1991;43:581-595. 10.Kjaer SK, Engholm G, Dahl C, et al. Case-control study of risk factors for cervical squamous-cell neoplasia in Denmark. III. Role of oral contraceptive use. Cancer Causes Control 1993;4513-519. 11. S c h i h a n MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 1993;85: 958-964. 12. Coker AL, McCann MF, Hulka BS, Walton LA. Oral contraceptive use and cervical intraepithelial neoplasia. J Clin Epidemiol 1992;45:1111-1118. 13. Brinton LA. Oral contraceptives and cervical neoplasia. Contraception 1991;43:581-595. 14. Ursin G, Peters RK, Henderson BE, et al. Oral contraceptive use and adenocarcinoma of the cervix. Lancet 1994;344:1390-1394. 15. Mahan L, Arlin M. Krause’s food, nutrition and diet therapy, ed 8. Philadelphia: WB Saunders, 1992.

Cervical Dysplasia 16. Orr JW Jr, Wilson K, Bodiford C, et al. Nutritional status of patients with untreated cervical cancer, I. Biochemical and immunologic assessment. Am J Obstet Gynecol1985;151:625-631. 17. Orr JWJr, Wilson K, Bodiford C, et al. Nutritional status of patients with untreated cervical cancer, II. Vitamin assessment. Am J Obstet Gynecol 1985;151:632-635. 18. La Vecchia C, Franceschi S, Decarli A, et al. Dietary vitamin A and the risk of invasive cervical cancer. Int J Cancer 1984;34:319-322. 19. Romney SL, Palan PR, Duttagupta C, et al. Retinoids and the prevention of cervical dysplasias. Am J Obstet Gynecol 1981;141:890-894. 20. Wylie-Rosett JA, Romney SL, Slagle NS, et al. Influence of vitamin A on cervical dysplasia and carcinoma in situ. Nutr Cancer 1984;6:49-57. 21. Dawson E, Nosovitch J, Hannigan E. Serum vitamin and selenium changes in cervical dysplasia. Fed Proc 1984;43612. 22. Romney SL, Palan PR, Basu J, W a i l M. Nutrients antioxidants in the pathogenesis and prevention of cervical dysplasias and cancer. J Cell Biochem 1995;23(suppl):96-103. 23.Meyskens FL Jr, Surwit E, Moon TE, et al. Enhancement of regression of cervical intraepithelialneoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial. J Natl Cancer Inst 1994;86539-543. 24. Graham V, Sunvit ES, Weiner S, Meyskens FL Jr. Phase I1 trial of beta-all-trans-retinoic acid for cervical intraepithelial neoplasia delivered via a collagen sponge and cervical cap. West J Med 1986;145:192-195. 25. Hudson T. Consecutive case study research of carcinoma in situ of cervix employing local escharotic treatment combined with nutritional therapy. J Naturopath Med 1991;26-10. 26. Hudson T. Escharotic treatment for cervical dysplasia and carcinoma in situ. J Naturopath Med 1993;423. 27. Wassertheil-Smoller S, Romney SL, Wylie-Rosett J, et al. Dietary vitamin C and uterine cervical dysplasia. Am J Epidemiol 1981;114714-724.

28. Romney SL, Duttagupta C, Basu J, et al. Plasma vitamin C and uterine cervical dysplasia. Am J Obstet Gynecol 1985;151:978-980. 29. Van Niekerk W. Cervical cytological abnormalities caused by folic acid deficiency.Acta Cytol 1966;10:67-73. 30. Kitay DZ, Wentz WB. Cervical cytology in folic acid deficiency of pregnancy. Am J Obstet Gynecol 1969;104:931-938. 31. Streiff RR. Folate deficiency and oral contraceptives. J Am Med ASSOC1970;214:105-108. 32. Whitehead N, Reyner F, Lindenbaum J. Megaloblastic changes in the cervical epithelium: association with oral contraceptive therapy and reversal with folic acid. J Am Med Assoc 1973;226: 1421-1424. 33. Butterworth CE Jr, Hatch KD, Macaluso M, et al. Folate deficiency and cervical dysplasia. JAh4A 1992;267528-533. 34. Harper JM, Levine AJ, Rosenthal DL, et al. Erythrocyte folate levels, oral contraceptive use and abnormal cervical cytology. Acta Cytol 1994;38:324330. 35. Butterworth CE Jr, Hatch KD, s o n g SJ, et al. Oral folic acid supplementation for cervical dysplasia. A clinical intervention trial. Am J Obstet Gynecol1992;166:803-809. 36. Butterworth CE Jr, Hatch KD, Gore H, et al. Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 1982;3573-82. 37. Ramaswamy PG, Natarajan R. Vitamin 86 status in patients with cancer of the uterine cervix. Nutr Cancer 1984;6176-180. 38. Patterson BH, Levander OA. Naturally occurring selenium compounds in cancer chemoprevention trials: a workshop summary. Cancer Epidemiol Biomarkers Prev 1997;6:63-69. 39. Brandes JM, Lightman A, Drugan A, et al. The diagnostic value of serum copper/zinc ratio in gynecological tumors. Acta Obstet Gynecol Scand 1983;62225-229. 40. Liu T, s o n g SJ, Alvarez RD, Butterworth CE Jr. A longitudinal analysis of human papillomavirus 16 infection, nutritional status, and cervical dysplasia progression. Cancer Epidemiol Biomarkers Prev 1995;4:373-380.

Chronic Fatigue Syndrome Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

1579

Introduction 1579 Definition 1579 Etiology 1580 Epstein-Barr Virus 1580 Other Infectious Agents 1581 Immune System Abnormalities 1581 Chronic Fatigue Syndrome, Fibromyalgia, and Multiple Chemical Sensitivities 1582 Other Causes of Chronic Fatigue 1582 Diagnosis 1582

DIAGNOSTIC SUMMARY Mild fever Recurrent sore throat Painful lymph nodes Muscle weakness Muscle pain Prolonged fatigue after exercise Recurrent headache Migratory joint pain Depression Sleep disturbance (hypersomnia or insomnia)

INTRODUCTION

Therapeutic Considerations 1583 Underlying Health Problems 1583 Mind and Attitude 1586 Diet 1586 Nutritional Supplements 1587 Other Therapies 1588 Botanical Medicines 1588 Therapeutic Approach 1588 Diet 1589 Lifestyle 1589 Supplementation 1589 Botanical Medicines 1589 Counseling 1589

names including the following: Chronic mononucleosis-like syndrome or chronic Epstein-Barr virus (EBV) syndrome Yuppie flu Postviral fatigue syndrome Postinfectious neuromyasthenia Chronic fatigue and immune dysfunction syndrome (CFIDS) Iceland disease Royal Free Hospital disease

In addition, symptoms of CFS mirror symptoms of neurasthenia, a condition first described in 1869.

Definition The chronic fatigue syndrome (CFS) describes vary-

ing combinations of symptoms including recurrent fatigue, sore throats, low-grade fever, lymph node swelling, headache, muscle and joint pain, intestinal discomfort, emotional distress, depression, and loss of concentration. Although newly defined and currently popular, CFS is not a new disease at all. References to a similar condition in the medical literature go back as far as the 1860s. In the past, CFS has been known by various

In response to the growing interest, CFS was formally defined in 1988 by a consensus panel convened by the Centers for Disease Control and Prevention (CDC) in an attempt to establish a guide for evaluating patients with chronic fatigue of unknown cause by clinical physicians and researchers.' The CDC established a formal (and controversial) set of diagnostic criteria (Box 159-1).These criteria are controversial for many reasons including the fact that psychologic symptoms are both a minor criterion and 1579

potential grounds for exclusion. One of the major complaints from physicians about the CDC definition is that it appears better suited for research than for clinical purposes. A major problem with the CDC criteria is that they ignore many of the conunon symptoms reported by patients with CFS (Table 159-1). The British and Australian criteria for the diagnosis of CFS are less strict than the CDC definition.2In particular, the minor diagnostic criteria are not required and the major diagnostic criteria are not as strict. For example, in the Australian definition the major criterion is simply fatigue at a level that causes disruption of daily activities in the absence of other medical conditions associated with fatigue. Using the CDC criteria, the prevalence of CFS in individuals suffering from chronic fatigue in the United States is thought to be about 11.5%.Using British criteria, it is about 15%, and using the Australian criteria, it is about 38Y0.~

Frequency of symptoms in chronic fatigue syndrome Symptodsign Fatigue Low-grade fever Muscle pain Sleep disorder Impaired mental function Depression Headache Allergies Sore throat Anxiety Muscle weakness Postexercise fatigue Premenstrual syndrome (women) Stiffness Visual blurring Nausea Dizziness Joint pain Dry eyes and mouth Diarrhea

Major Criteria New onset of fatigue causing 50% reduction in activity for at least 6 months Exclusion of other illnesses that can cause fatigue

Cough Decreased appetite Night sweats Painful lymph nodes

Frequency (%) 100

60-95 20-95 15-90 50-85 70-85 35-85 55-80 50-75 50-70 40-70 50-60 50-60 50-60 50-60 50-60 30-50 40-50 30-40 30-40 30-40 30-40 30-40 30-40

Minor Criteria Presence of 8 of the 1 1 symptoms listed below, or 6 of the 11 symptoms and 2 of the 3 signs

Symptoms 1. Mild fever 2. Recurrent sore throat 3. Painful lymph nodes 4.Muscle weakness 5.Muscle pain 6.Prolonged fatigue after exercise 7.Recurrent headache 8.Migratory joint pain 9.Neurologic or psychologic complaints Sensitivity to bright light Forgetfulness Confusion Inability to concentrate Excessive irritability Depression 10. Sleep disturbance (hypersomnia or insomnia) 11. Sudden onset of symptom complex Signs 1. Low-grade fever 2. Nonexudative pharyngitis 3. Palpable or tender lymph nodes

ETIOLOGY Epstein-Barr Virus Many research studies have focused on iden*ing an infectious agent as the cause of CFS. The EBV emerged as the leading, yet controversial, candidate.$’ EBV is a member of the herpes group of viruses, which includes herpes simplex types 1 and 2, varicella zoster virus, cytomegalovirus, and pseudorabies virus. A common aspect of these viruses is their ability to establish a lifelong latent infection after the initial infection. This latent infection is kept in check by a normal immune system. When the immune system is compromised in any way, these viruses can become active as viral replication and spread is increased. This is commonly observed with herpes virus infections, especially in immunocompromised individuals such as those with AIDS, cancer, or drug-induced immunosuppression. Infection with EBV is inevitable among humans. By the end of early adulthood, almost all individuals demonstrate detectable antibodies in their blood to

the EBV, indicating past infection. When the primary infection occurs in childhood, there are usually no symptoms, but when it occurs in adolescence or early adulthood, the clinical manifestations of infectious mononucleosis develop in approximately 50%of the cases. Although reports of a prolonged or recurrent mononucleosis-like syndrome began appearing in the 1940s and 1950s, it was not until the 1980s that evidence had implicated EBV in this broad clinical spectrum of chronic fatigue and associated symptoms. Numerous studies have now demonstrated persistently elevated titers (levels) of serum antibodies against the EBV (specifically,anti-EBV capsid antibody titers >1:80) in a number of patients presenting with the symptom pattern of this syndrome. A careful study of 134 patients who had undergone EBV antibody testing because of suspected chronic mononucleosis-like syndrome found mixed results regarding the importance of EBV infection.8 Fifteen patients identified as having severe, persistent fatigue of unknown origin were compared with the remaining 119 with less severe illness and with 30 age- and race-matched controls. The more seriously ill patients generally had higher levels of EBV antibodies than did the comparison groups, and, interestingly, they also demonstrated higher antibody titers to cytomegalovirus, herpes simplex viruses types 1 and 2, and measles. This led the researchers to conclude that "some patients with these illnesses (syndromes of chronic fatigue) may have an abnormality of infectious and/or immunologic origin," and that there remain "questions concerning the relationship between CFS and EBV." Current knowledge about EBV infection can be summarized as follows:

EBV and the herpes group of viruses produce latent lifelong infections. The host's immune system (T-lymphocytes, interferon, and other lymphokines) normally holds the latent infection in check. Any compromise in the immune system can lead to the reactivation of the virus and recurrent infection. The infection itself can compromise or disrupt immunity, thereby leading to other diseases. Elevated EBV antibody levels are observed in a significant number of diseases characterized by immunologic dysfunction. Elevated antibody titers to the herpes group viruses, measles, and other viruses have also been observed in patients with CFS. EBV antibody testing (and antibody testing for other herpes group viruses and measles) may be useful as a measure of immune function and overall host resistance but should not be relied on for diagnosis of CFS.

Other Infectious Agents In addition to EBV, a number of other viruses have been investigated as possible causes of CFS. This search for a viral agent is consistent with the mainstream medical approach to focus on the infectious organism rather than on reducing susceptibility and supporting the individual's immune system to deal with the organism effe~tively.~-~ Box 159-2 lists the organisms currently proposed as causative agents in CFS.

Immune System Abnormalities There is little argument that a disturbed immune system plays a central role in CFS. Various immune system abnormalities have been reported in CFS patients (Box 159-3). Although no specific immunologic dysfunction pattern has been recognized, the most consistent abnormality is a decreased number or activity of natural killer (NK) cell^.^,^,^,'^ NK cells received their name because of their ability to destroy cells that have become cancerous or infected with viruses. In fact, for a time, CFS was also referred to as low natural killer cell syndrome (LNKS). Other consistent findings include a reduced ability of lymphocytes, key in the battle against viruses, to respond to stimuli.1° One reason for this lack of response may be reduced activity or decreased production of interferon. Although both low and high levels of interferon have been reported in CFS, levels are depressed in most cases. When interferon levels are low, reactivation

Epstein-Barr virus Human herpes virus-6 Inoue-Melnich virus Brucella Borrelia burgdohri Giardia larnblia Cytomegalovirus Enterovirus Retrovirus

Elevated levels of antibodies to viral proteins Decreased natural killer cell activity Low or elevated antibody levels Increased or decreased levels of circulating immune complexes Increased cytokine (e.g., interleukin-2) levels Increased or decreased interferon levels Altered T helper cell-to-T suppressor cell ratio

Specific Health Problems

of latent viral infection is likely. Conversely, when interferon (as well as other chemical mediators like interleukin-1) levels are high, many of the symptoms may be related to the physiologic effects of interferon. When interferon is used as a therapy in cancer and viral hepatitis, the side effects produced are quite similar to the symptoms of CFS.

Chronic Fatigue Syndrome, Fibromyalgia, and Multiple Chemical Sensitivities Fibromyalgia (FM) and multiple chemical sensitivities (MCS), like CFS, are recently recognized disorders with a substantial overlap of symptomatology.3~4~11~1z The only difference in diagnostic criteria for fibromyalgia and CFS is the requirement of musculoskeletal pain in fibromyalgia and fatigue in CFS. The likelihood of being diagnosed as having fibromyalgia or CFS depends on the type of physician consulted. Specifically, if a rheumatologist or orthopedic specialist is consulted, the patient is much more likely to be diagnosed with fibromyalgia (Box 159-4 presents the diagnostic criteria for fibromyalgia). One group of researchers carefully compared the symptomatology of 90 patients who had been diagnosed as having CFS, MCS, or FM (30 in each category).I2 Using the same questionnaire for all 90 patients, 70% of the patients diagnosed with FM and 30% of those with MCS met the CDC criteria for CFS. Particularly sigruficantwas the observation that 80% of both the FM and MCS patients met the CFS criteria of fatigue lasting more than 6 months with a 50% reduction in activity. More than 50% of the CFS and FM patients reported adverse reactions to various chemicals.

Major Criteria Generalized aches or stiffness of at least three anatomic sites for at least 3 months Six or more typical, reproducible tender points Exclusion of other disorders that can cause similar symptoms

Minor Criteria Generalized fatigue Chronic headache Sleep disturbance Neurologic and psychologic complaints Joint swelling Numbing or tingling sensations Irritable bowel syndrome Variation of symptoms in relation to activity, stress, and weather changes

Other Causes of Chronic Fatigue Chronic fatigue can be caused by various physical and psychologic factors. Box 159-5 lists the major causes of chronic fatigue in an order of importance that represents how common the cause is among sufferers of chronic fatigue in the general population. The list is based on the findings of several large studies, as well as the authors’ clinical experience (CFS is listed under a broader category of impaired immune function).

DIAGNOSIS A great number of factors must be considered when evaluating a patient with chronic fatigue. A detailed medical history and review of body systems goes a long way toward identifying important factors. The goal is to identify as many factors as possible that may be contributing to the patient’s feeling of fatigue. For example, if a patient has heart disease, diabetes, or some other health condition, and the condition or the drug they are taking is clearly responsible for their fatigue, the treatment of their fatigue becomes secondary to the treatment of their underlying health condition.

Preexisting physical condition Diabetes Heart disease Lung disease Rheumatoid arthritis Chronic inflammation Chronic pain Cancer Liver disease Multiple sclerosis Prescriptiondrugs Antihypertensives Antiinflammatory agents Birth control pills Antihistamines Corticosteroids Tranquilizers and sedatives Depression Stresdlow adrenal function Impaired liver function or environmental illness, or both Impaired immune function Chronic fatigue syndrome Chronic Candida infection Other chronic infections Food allergies Hypothyroidism Hypoglycemia Anemia and nutritional deficiencies Sleep disturbances Cause unknown

Chronic Fatigue Syndrome In many cases of chronic fatigue, further evaluation is necessary. The next steps can include a complete physical examination and laboratory studies. In the physical examination, look for any possible clues that may indicate the cause for chronic fatigue. For example, swollen lymph nodes may indicate a chronic infection. The presence of a diagonal crease on both earlobes usually indicates impaired blood flow to the brain, a significant cause of fatigue in the elderly. Avoid ordering expensive laboratory tests unless they are absolutely necessary. A complete blood count (CBC) and a chemistry panel (including serum ferritin in menstruating women) are useful as screening tools for other diseases. Avoid ordering laboratory tests to confirm a diagnosis that is not going to affect treatment. For example, if it is quite obvious that the patient has impaired immunity, it does not make much sense to perform elaborate and expensive blood tests on immune function because the results of these tests are not likely to influence the method of treatment. Of particular value are assessment of liver detoxification function, bowel dysbiosis, and gastrointestinal permeability (see Chapters 14 and 23).

THERAPEUTIC CONSIDERATIONS Because chronic fatigue and CFS are generally multifactorial conditions, the therapeutic approach typically involves multiple therapies that address different facets of the clinical picture. A person’s energy level, as well as his or her emotional state, is determined by an interplay between two primary factors-internal focus and physiology. Many people with chronic fatigue focus on how tired they are. They repeatedly reaffirm their fatigue to themselves and to anyone who will listen. Their physiology includes not only the chemicals and hormones floating around the body, but also the way they hold their bodies (usually slouched) and the way they breathe (shallow). In most patients with chronic fatigue, both the mind and the body need to be addressed. The most effective treatment is a comprehensive program designed to help people use their minds, attitudes, and physiology to fuel higher energy levels.

Underlying Health Problems Depression The first factor to address is any underlying depression. Depression is one of the major causes of chronic fatigue, and it is a common feature of CFS. In the absence of a preexisting physical condition, depression is generally regarded as the most common cause of chronic fatigue. However, it is often difficult to determine whether the depression preceded the fatigue or vice versa. Depression is fully discussed in Chapter 144.

Stress Stress is another factor to consider in the patient with chronic fatigue or CFS. Stress can be the underlying factor in the patient with depression, low immune function, or other cause of chronic fatigue (see Chapter 62 for guidelines on assessing the role of stress in chronic fatigue and CFS). One of the tools we recommend to rate stress levels is the Social Readjustment Rating Scale developed by Holmes and Rahe.I3 The scale was originally designed to predict the likelihood of a person getting a serious disease due to stress. Various life-changing events are numerically rated according to their potential for causing disease. Even events commonly viewed as positive, such as an outstanding personal achievement, carry with them stress.

Impaired Liver Function or Environmental Illness, or Both Exposure to food additives, solvents (e.g.,cleaning materials, formaldehyde, toluene, benzene), pesticides, herbicides, heavy metals (e.g., lead, mercury, cadmium, arsenic, nickel, aluminum), and other toxins can greatly stress liver and detoxification processes. This exposure can lead to a condition labeled by many naturopathic and nutrition-oriented physicians as the “congested liver,” ”sluggish liver,” or the more recently coined “impaired hepatic detoxification.” These terms signify a reduced ability of the liver to detoxify. The congested or sluggish liver is characterized by a diminished bile flow, a condition known in medical terms as cholestasis, while impaired hepatic detoxification refers to decreased phase I or phase II enzyme activity, or both. Phase I detoxification rates in excess of phase I1 activity also cause toxicity problems due to excessive accumulation of activated intermediates. In addition to exposure to toxic chemicals, impairment of bile flow within the liver can be caused by various other agents and conditions, as listed in Box 159-6. Although many of the conditions listed in the table are typically associated with alterations in laboratory tests of liver function (e.g., serum bilirubin, AST, ALT, LDH, GGTP), relying on these tests alone to evaluate liver function may not be adequate, as these tests are elevated only when the liver has been significantly damaged and many of these conditions in the initial or ”subclinical” stages may have normal laboratory values. Although there are more sensitive tests to determine the functional activity of the liver, such as the serum bile acid assay and various clearance tests (see Chapter M), clinical judgment based on medical history remains the major diagnostic tool for the ”sluggish liver” or impaired hepatic detoxification enzymes, the presence of chronic fatigue being the hallmark symptom.

Specific Health Problems

Dietary factors Saturated fat Refined sugar Low fiber intake Obesity Diabetes Presence of gallstones Alcohol Endotoxins and other gut-derived bacterial toxins Hereditary disorders such as Gilbert’s syndrome Pregnancy Natural and synthetic steroid hormones Anabolic steroids Estrogens Oral contraceptives Certain chemicals or drugs Cleaning solvents Pesticides Antibiotics Diuretics Nonsteroidal antiinflammatory drugs Thyroid hormone Viral hepatitis

Do you get more than two colds per year? When you catch a cold, does it take more than 5 to 7 days to get rid of the symptoms? Have you ever had infectious mononucleosis? Do you have herpes? Do you suffer from chronic infections of any kind?

An interesting multiclinic research study of chronically ill patients, many of whom were diagnosed as suffering from CFIDS, evaluated the efficacy of a comprehensive detoxification program. Patients were placed on a hypoallergenic diet and provided a dietary food supplement rich in nutrients that assist liver detoxification. The patients reported a 52%reduction in sympt o m after 10 weeks, and symptom improvement was mirrored by normalization of hepatic phase I and phase I1 detoxification.16

Excessive Gastrointestinal Permeability People with a sluggish liver may also complain of the following problems: Depression General malaise Headaches Digestive disturbances Allergies and chemical sensitivities Premenstrual syndrome Constipation Not surprisingly, people exposed to toxic chemicals often complain of the same symptoms. Many toxic chemicals (especially solvents) and heavy metals have an affinity for nervous tissue, giving rise to various psychologic and neurologic syrnptom~’~*’~: Depression Headaches Mental confusion Mental illness Tingling in extremities Abnormal nerve reflexes Other signs of impaired nervous system function A hair mineral analysis is a good screening test for heavy metal toxicity. If the hair mineral analysis is inconclusive, a more sensitive indicator is the 8-hour lead mobilization test. This test employs the chelating agent ethylenediamine tetraacetic acid (EDTA, edetate calcium disodium) and measures the level of lead excreted in the urine for a period of 8 hours after the injection of EDTA.

Excessive gastrointestinal permeability, as measured by the lactulose/mannitol absorption test (see Chapter 23), is a common finding in CFS.I7 A treatment program using food allergy control, nutrients to stimulate gastrointestinal regeneration and support hepatic phase I and I1 detoxification, and an oligoantigenic rice protein food replacement formula was provided to 22 patients who fulfilled the classic CDC/NIH criteria for CFS. The patients’ average duration of CFS was 4.6 years. The treatment resulted in symptom reduction in 81.2% of the patients, with clinical improvement being paralleled by normalization of gastrointestinal permeability and hepatic detoxification function.18

Im aired Immune Function or Chronic In ection, or Both

P

When the immune system is impaired, infections can linger and fatigue can persist. There is a good reason for this-fatigue is the body’s response mechanism to infection because the immune system works best when the body is at rest. In order to determine the role that the immune system is playing in patients with chronic fatigue, the series of questions listed in Box 159-7 can be used during the patient interview to indicate an impaired immune system. Chapter 22 describes in substantial detail the laboratory methodologies for assessing immune function.

Chronic Candida Infection One of the most common findings in individuals with impaired immune function is gastrointestinal overgrowth of Curzdidu albicans. Candidal overgrowth is

Chronic Fatigue Syndrome

Sex: female Age: 15 to 50 years General Symptoms Chronic fatigue Loss of energy General malaise Decreased libido Gastrointestinal Symptoms Thrush Bloating, gas Intestinalcramps Rectal itching Altered bowel function Genitourinary System Complaints Vaginal yeast infection Frequent bladder infections Endocrine System Complaints Primarily menstrual complaints Nervous System Complaints Depression Irritability Inabilityto concentrate Immune System Complaints Allergies Chemical sensitivities Low immune function Past History Chronic vaginal yeast infections Chronic antibiotic use for infections or acne Oral birth control usage Oral steroid hormone usage Associated Conditions Premenstrual syndrome Sensitivity to foods, chemicals, and other allergens Endocrine disturbances Psoriasis Irritable bowel syndrome Other Craving for foods rich in carbohydrates or yeast

now becoming recognized as a complex medical syndrome also known as “the yeast syndrome” and “chronic candidiasis.” This overgrowth is believed to cause a wide variety of symptoms in virtually every system of the body, with the gastrointestinal, genitourinary, endocrine, nervous, and immune systems being

Impaired immune function Antiulcer drugs Broad-spectrum antibiotics Cellular immunodeficiency Corticosteroids Diabetes mellitus Excessive sugar in the diet lntravascular catheters Intravenous drug use Lack of digestive secretions Oral contraceptive agents

the most susceptible. Box 159-8 lists the typical chronic candidiasis patient profile (see Chapter 52 for a comprehensive discussion). The diagnosis of chronic candidiasis is often quite difficult as there is no specific diagnostic test. Stool cultures and elevated antibody levels to Candida are useful diagnostic aids, but they should not be relied on for diagnosis. The best method for diagnosing chronic candidiasis in most cases is a detailed medical history and patient questionnaire (see Appendix 1). Box 159-9 lists the factors that typically predispose a patient to candidal overgrowth.

Food Allergies As far back as 1930, chronic fatigue was recognized as a key feature of food allergies.19 Originally, Rowe and Rowel9 used the term “allergic toxemia” to describe a syndrome that included the symptoms of fatigue, muscle and joint aches, drowsiness, difficulty in concentration, nervousness, and depression. Around the 1950s, this syndrome began to be referred to as the “allergic tensionfatigue syndrome.”20With the popularity of CFS, many physicians and others are forgetting that food allergies can lead to chronic fatigue. Furthermore, between 55% and 85% of individuals with CFS have allergies. For more information on food allergies, see Chapter 53.

Hypothyroidism Hypothyroidism is a common cause of chronic fatigue. However, the condition is often overlooked. The reason for this may be the reliance on standard blood measurements of thyroid hormone levels as the method of d i a g n o s i ~ .Undiagnosed ~~-~~ hypothyroidism is a serious concern, as failure to treat such a critical and underlying problem reduces the effectiveness of every other measure designed to increase energy levels. For more information, see Chapter 179.

Hypoglycemia The association between hypoglycemia and fatigue is well known. What is not as well known is the role that

hypoglycemia plays in contributing to depression. Numerous studies have shown that depressed individuals suffer from hypogly~emia.2~~’ Because depression is the most common cause of chronic fatigue, hypoglycemia must always be ruled out (see Chapter 178).

Hypoadrenalism Adrenal exhaustion was first proposed as a cause of chronic fatigue more than 50 years ago by Tintera.% A small, but growing, body of evidence now supports the role of a disruption of the hypothalamic-pituitaryadrenal (HPA) axis in CFS.29Salivary tests of chronic fatigue patients show lower cortisol levels on wakening.%Other research suggests there is no specific change to the HPA axis in CFS and that the observed changes are of multifactorial etiology, with some factors occurring as a consequence of the illness. This second school of thought suggests that the HPA axis might play a role in exacerbating or perpetuating symptoms late in the course of the illness, but not as a primary Either way, one of the major symptoms of glucocorticoid deficiency is debilitating fatigue. Glucocorticoid insufficiency is also characterized by a stressing event followed by feverishness, arthralgias, myalgias, adenopathy, postexertional fatigue, exacerbation of allergic responses, and disturbances of mood and sleep (i.e., the typical presentation of CFS). These symptoms are seen in partial or subclinical adrenal insufficiency, which may only be detected by the adrenocorticotropic hormone (ACTH) stimulation test or other endocrine testing. Glucocorticoids have a profound endogenous immunosuppressive effect. In subclinical adrenal insufficiency, this may allow for the symptoms of chronic fatigue including exacerbation of allergic responses, enhanced antibody titers to various viral antigens, and elevations in cytokine levels. A group of CFS researchers believe that these patients form a heterogenous group with various infectious and noninfectious ante~edents.2~ They feel that CFS does not represent a discrete disease with a singular cause, but rather a clinical condition. CFS is analogous to a number of complex medical conditions such as hypertension in which various direct and indirect factors lead to the development of the clinical syndrome. The researchers hypothesize that in CFS, specific pathophysiologic antecedents such as acute infection, stress, and preexisting or concurrent psychiatric illness may ultimately converge in a final common biologic pathway, resulting in the clinical syndrome of CFS. They believe that their data and others’ data suggest that a reduction in adrenal cortical secretion is an important pathophysiologic component in the development of many biologic and behavioral features of the syndrome. For example, in one of their studies, 30 patients with classically defined CFS were compared with 72 normal

volunteers and patients?* The CFS patients were found to have significantly reduced evening cortisol levels and low 24hour, urinary-free cortisol excretion. The CFS patients also had elevated basal ACTH concentrations and increased adrenal cortical sensitivity to ACTH, but a reduced maximal response, and showed attenuated net integrated ACTH response to corticotrophin-releasing hormone. These results are most compatible with a mild, central, adrenal insufficiency, secondary to either a deficiency of CRH or some other central stimulus to the pituitary-adrenal axis. The authors feel that the hyperresponsiveness of the adrenal cortex to ACTH in patients with CFS may reflect a secondary adrenal insufficiency in which adrenal ACTH receptors have become hypersensitive due to inadequate exposure to ACTH. The reduction in response to large doses of ACTH might suggest overall adrenal atrophy. The evidence suggests that the mild hypocortisolism in these patients reflects a defect at or above the level of the hypothalamus, resulting in deficiency in the release of CRH or other secretagogues, or both, that serve to activate the pituitaryadrenal axis.

Mind and Attitude The mind and attitude play a critical role in determining the status of the immune system and energy levels. Many patients with chronic fatigue (including CFS) are either depressed or just seem to have lost a sense of real enthusiasm for life. Of course, it is not easy to have much enthusiasm when you do not have much energy. But the two usually go hand in hand. Related to these psychologic difficulties, it has been shown that there is a lack of social support for CFS ~atients.3~ It is a question of whether the lack of energy affects the CFS patient’s ability to maintain a relationship or vice versa, or both. Cognitive behavior therapy has shown some effective results in clinical ~ s e . % , ~ ~ first T h estep is to convey to CFS patients that they can get better. Many patients with CFS are told that this is ”something they will have to live with” and “there is no cure.” Achieving or maintaining a positive mental attitude is critical to good health and high energy levels, especially in patients with CFS. In order to achieve a positive mind, a person needs to exercise or condition the attitude, similar to the way in which one would condition the body. In order to help patients, physicians can prescribe mental exercises such as visualizations, goal setting, affirmations, and empowering questions as detailed in Chapter 144.

Diet Energy level appears to be directly related to the quality of foods routinely ingested. Have patients adhere to the dietary guidelines given in Chapter 44. It is especially important to eliminate or restrict caffeine and refined sugar.

Chronic Fatigue Syndrome Although acute caffeine consumption provides stimulation, regular caffeine intake may actually lead to chronic fatigue. Although mice fed one dose of caffeine demonstrated sigruficant increases in their swimming capacity, when the dose of caffeine was given for 6 weeks, a sigruficant decrease in swimming capacity was observed.36 Interestingly, several studies have found caffeine intake to be extremely high in individuals with psychiatric disorders. Another interesting finding is that the degree of fatigue experienced is often related to the quantity of caffeine ingested. In one survey of hospitalized psychiatric patients, 61% of those ingesting at least 750 mg/day (at least five cups of coffee) complained of fatigue, compared with 54% of those ingesting 250 to 749 mg/day and only 24% of those ingesting less than 250 m g / d a ~ . ~ ~ In patients who routinely drink coffee, abrupt cessation of coffee drinking will probably result in symptoms of caffeine withdrawal including fatigue, headache, and an intense desire for coffee.%J9Fortunately, this withdrawal period does not last more than a few days.

Nutritional Supplements Nutritional supplementation is essential in the treatment of chronic fatigue. A deficiency of virtually any nutrient can produce the symptoms of fatigue, as well as render the body more susceptible to infection. Individuals with chronic fatigue require, at the bare minimum, a high-potency multivitamin-mineral formula, along with extra vitamin C (3000 mg/day in divided doses) and magnesium (500 to 1200 mg/day in divided doses).

Magnesium An underlying magnesium deficiency, even if subclinical,

can result in chronic fatigue and symptoms similar to CFS. In addition, low red blood cell magnesium levels, a more accurate measure of magnesium status than routine blood analysis, have been found in many patients with chronic fatigue and CFS. Literature demonstrates that magnesium deficiency is not necessarily due to low dietary intake,4oand several studies have shown good results with supplementation, with improvements in magnesium stores. For example, in one double-blind, placebo-controlled trial, 32 CFS patients received an intramuscular injection of either magnesium sulfate (1g in 2 ml injectable water) or a placebo (2 mlinjectable water) for 6 weeks. At the end of the study, 12 of the 15 patients receiving magnesium reported, on the basis of strict criteria, significantly improved energy levels, better emotional state, and less pain. In contrast, only 3 of the 17 placebo patients reported that they felt better and only one reported improved energy levels.4l This study seems to confirm some impressive results obtained in clinical trials during the 1960s on patients

suffering from chronic fatigue.4245These studies used oral magnesium and potassium aspartate (1 g each) rather than injectable magnesium. Between 75% and 91% of the nearly 3000 patients studied experienced relief of fatigue during treatment with the magnesium and potassium aspartate. In contrast, the number of patients responding to a placebo was between 9% and 26%. The beneficial effect was usually noted after only 4 to 5 days, but sometimes 10 days were required. Patients usually continued treatment for 4 to 6 weeks; afterward, fatigue frequently did not return. Injectable magnesium is not necessary to restore magnesium status.& Absorption studies indicate that magnesium is easily absorbed orally when it is bound to aspartate or citrate. In addition, both of these compounds may also help fight off fatigue. Aspartate feeds into the Krebs cycle, the final common pathway for the conversion of glucose, fatty acids, and amino acids to chemical energy (ATP), while citrate is itself a component of the Krebs cycle. Krebs cycle components including aspartate, citrate, fumarate, malate, and succinate usually provide a better mineral chelate, as evidence suggests that minerals chelated to the Krebs cycle intermediates are better absorbed, used, and tolerated compared with inorganic or relatively insoluble mineral salts including magnesium chloride, oxide, or

Essential Fatty Acids In one study, essential fatty acid supplementation was shown to improve the clinical picture and red blood cell phospholipid membrane profile of patients with postviral fatigue. The preparation given contained linoleic, gammalinolenic, eicosapentaenoic, and docosahexaenoic acids and was given as eight 500-mg capsules per day over a 3-month period.48 In another study, an essential fatty acid supplement rich in eicosapentaenoic acid (EPA) was given daily to a female patient with a 6-year history of unremitting symptoms of chronic fatigue syndrome. Within 6 to 8 weeks, the EPA-rich essential fatty acid supplementation led to a marked clinical improvement in her symptoms of CFS.49 Because lateral ventricular enlargement has been reported in CFS,% this research employed cerebral magnetic resonance scanning at baseline and 16 weeks later. Quantification of the lateral ventricular volumes in the baseline and &week follow-up showed that EPA treatment was accompanied by a marked reduction in the lateral ventricular volume during this period.

Nicotinamide Adenine Dinucleotide Nicotinamide adenine dinucleotide (NADH), the active coenzyme form of vitamin B3, has been shown effective in countering the negative effects of jet lag on cognition and wakefulness?' It is also known to encourage energy production through increased ATP generation. One small

Specific Health Problems trial of NADH found a beneficial effect and improvement in quality of life in CFS patients. This study supplemented the stabilized oral absorbable form in a 26-subject, randomized, double-blind, placebo-controlled crossover study. Subjects were randomly assigned to receive either 10 mg of NADH or placebo for 1 month. Following a 1-month washout period without supplement, subjects were then crossed to the alternate regimen for a final 1-month period. Within this cohort of 26 patients, 8 of 26 (31%)responded favorably to NADH in contrast to 2 of 26 (8%) to placebo. No severe adverse effects were observed related to NADH,52nor have studies in animals shown any toxicity, even at mega dose^.^^ More clinical research is necessary to fully elucidate the possible beneficial effects of NADH in CFS patients.

Karnitine Carnitine is an essential nutrient for the transport of long-chain fatty acids into the mitochondria1 matrix. One randomized, controlled, crossover study compared the efficacy of L-camitine to amantidine, a drug known to relieve fatigue in multiple sclerosis patients. Each intervention was given for 2 months, with a 2-week washout period between medicines. In 30 CFS patients, L-carnitine or amantadine was alternately given as the first medicine. Poorly tolerated by the CFS patients, only 15 amantadine subjects were able to complete the 8 weeks of treatment due to side effects. In those individuals who completed 8 weeks of treatment, there was no statistically sigruficantdifference in any of the clinical parameters that were followed. With L-camitine, there was a statistically sigruficant clinical improvement in 12 of the 18 studied parameters after 8 weeks of treatment with none of the clinical parameters showed any deterioration. The greatest improvement took place between 4 and 8 weeks of L-carnitine treatment. Only one patient, due to diarrhea, was unable to complete the 8 weeks of treatment.” L-Camitine is extremely safe, with no significant side effects having been reported in any of the human clinical studies. It is important to mention that only L-camitine should be used. The D form, the mirror image of the L form, has produced side effects, indicating that it interferes with the natural L form of camitine.

Other Therapies Breathing, Posture, and Bodywork Proper care of the body is critical to high energy levels. Breathing with the diaphragm, good posture, and bodywork (e.g., massage, spinal manipulation) are all important in helping to relieve the stress that is a common contributor to fatigue.

Exercise Exercise alone has been demonstrated to have a tremendous impact on improving mood and the ability to handle

stressful life ~ituations.5~ Regular exercise has also been shown to lead to improved immune status. For CFS patients, regular exercise has been shown to lead to a sigruficant increase (up to 100%) in natural killer cell a~tivity.%5~ Although more strenuous exercise is required to benefit the cardiovascular system, light to moderate exercise may be best for the immune system. One study found that immune function was significantly increased by the practice of t’ai chi exercises.%T’ai chi is a martial art technique that features movement from one posture to the next in a flowing motion that resembles dance. The research thus far suggests that light to moderate exercise stimulates the immune system, while intense exercise (e.g., training for the Olympics) can have the opposite e f f e ~ t . ~ Graded ~ 5 ~ exercise therapies, in which the patient begins with gradual walking and weight exercises and increases time and intensity as is comfortable over time, may be the best approach.60Although there is concern for overtraining, one study has shown this method to be superior to relaxation and flexibility

Botanical Medicines Eleutherococcus senticosus In addition to supporting adrenal function and acting as a nonspecific adaptogen, Siberian ginseng has been shown to exert a number of beneficial effects on immune function that may be useful in the treatment of CFS. In one double-blind study, 36 healthy subjects received either 10 ml of a fluid extract of Eleutherococcus senticosus or placebo daily for 4 The group receiving the Siberian ginseng demonstrated significant improvements in various immune system parameters. Most notable were a significant increase in T helper cells and an increase in natural killer cell activity-both of which are of value in the treatment of CFS.

Glycyrrhiza glabra Considering the possible roles of viral infection and hypoadrenalism in CFS, licorice root with its antiviral and glucocorticoid-potentiatingproperties (see Chapter 99 for documentation of these properties) would seem to be an ideal botanical for this condition.@ Unfortunately, this has not been rigorously evaluated, although an excellent response in a single patient has been reported.@The whole root must be used, as DGL has had the glucocorticoid-potentiating glycyrrhizic and glycyrrhetinic acids removed.

THERAPEUTIC APPROACH Successful treatment of CFS requires a comprehensive diagnostic and therapeutic approach. Especially important is identifying underlying factors that may be affecting energy levels or the immune system. The strong correlation between CFS, fibromyalgia, and multiple

Chronic Fatigue Syndrome

chemical sensitivities suggests that all may respond to hepatic detoxification, food allergy control, and a gut restoration diet.1618,65 Special attention should be paid to the advice on immune support in Chapter 57.

Diet Food allergies should be identified and controlled. Water consumption should increase while consumption of caffeine-containing drinks and alcohol should stop. A diet of whole, organically grown foods should be encouraged. Hypoglycemia should be controlled through the elimination of sugar and other refined foods and the regular consumption of small meals and snacks. To speed the detoxification process, a course lasting for several weeks of a medical food replacement such as an Ultraclear product can be prescribed.

Lifestyle The patient should be taught diaphragmatic breathing and proper posture. A regular exercise program should be prescribed; low-intensity activities may produce greatest benefits.

Supplementation

Vitamin E: 200 to 400 IU/day Thymus extract 750 mg of the crude polypeptide fraction once or twice daily Magnesium bound to citrate or Krebs cycle intermediates: 200 to 300 mg three times/day Pantothenic acid: 250 mg/day NADH 10 mg/day, on an empty stomach L-carnitine: 3000 to 4000 mg/day in divided doses Fish oil: 5 g/day for at least 3 to 4 months

Botanical Medicines E. senticosus Dried root: 2 to 4 g Tincture (1:5):10 to 20 ml Fluid extract (1:l):2 to 4 ml Solid (dry powdered) extract (20:l or standardized to contain >1%eleutheroside E): 100 to 200 mg G. glabra Powdered root: 1 to 2 g Fluid extract (1:l):2 to 4 ml Solid (dry powdered) extract (4:l):250 to 500 mg

Counseling

High-potency multivitamin and mineral formula according to guidelines given in Chapter 44 Vitamin C: 500 to 1000 mg three times/day

The patient should either be counseled directly or referred to a professional counselor for cognitive behavior therapy66 and to establish a regular pattern of mental, emotional, and spiritual affirmations.

1. Holmes GP, Kaplan J, Gantz N, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988;108387-389. 2. Bates DW, Schmitt W, Buchwald D, et al. Prevalence of fatigue and chronic fatigue syndrome in a primary care practice. Arch Intern Med 1993;2759-2765. 3. Shafran SD. The chronic fatigue syndrome. Am J Med 1991;90: 731-739. 4. Kyle DV, deShazo RD. Chronic fatigue syndrome. A conundrum. Am J Med Sci 1992;303:28-34. 5. Komaroff AL. Chronic fatigue syndromes: relationship to chronic viral infections. J Virol Meth 1988;21:3-10. 6. Jones JF, Ray C, Minnich, L et al. Evidence for active Epstein-Barr virus infection in patients with persistent unexplained illness: elevated anti-early antigen antibodies. Ann Intern Med 1985;1021-7. 7. Straus SE, Tosato G, Armstrong G, et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 1985;1027-16. 8. Holmes GP, Kaplan J, Stewart J, et al. A cluster of patients with a chronic mononucleosis-like syndrome. Is Epstein-Barr virus the cause? JAMA 1987;2572297-2302. 9. Caligiuri M, Murray C, Buchwald D, et al. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol1987;139:3306-3313. 10. Gupta S, Vayuvegula 8. A comprehensive immunological analysis in chronic fatigue syndrome. Scand J Immunol1991;33:319-327. 11. Komaroff AI, Goldenberg D. The chronic fatigue syndrome: definition, current studies and lessons for fibromyalgia research. J Rheumatol1989;1623-27.

12. Buchwald D, Garrity DL. Comparison of patients with chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivities. Arch Intern Med 1994;154.2049-2053. 13.Holmes TH, Rahe RH. The Social Readjustment Rating Scale. J Psychosom Res 1967;11:213-218. 14.Seaton A, Jeelinek EH, Kennedy P. Major neurological disease and occupational exposure to organic solvents. Q J Med 1992;305: 707-712. 15. Rutter M, Russell-Jones R, eds. Lead versus health: sources and effects of low level lead exposure. New York John Wiley, 1983. 16. Bland JS, Barrager E, Reedy RG, et al. A medical foodsupplemented detoxification program in the management of chronic health problems. Altern Ther Health Med 1995;1:62-71. 17. Rigden S. Entero-hepatic resuscitation program for CFIDS.CFIDS C h o n 1995;Spring:46-49. 18. Rigden S. Entero-hepatic resuscitation as a therapeutic strategy in CFIDS patients. Unpublished. 19. Rowe AH, Rowe A Jr. Food allergy. Its manifestations and control and the elimination diets. A compendium. Springfield, I L CC Thomas, 1972. 20. BrenemanJC. Basics of food allergy. Springfield, L CC Thomas, 1977. 21. Barnes 80,Galton L. Hypothyroidism: the unsuspected illness. New York Thomas Crowell, 1976. 22. Langer SE, Scheer JF. Solved the riddle of illness. New Canaan, CT: Keats, 1984. 23.Gold M, Pottash A, Extein I. Hypothyroidism and depression, evidence from complete thyroid function evaluation. JAMA 1981;2451919-1922.

24. Winokur A, Maislin G, Philips J, et al. Insulin resistance after glucose tolerance testing in patients with major depression. Am J Psychiatry 1988;145:325-330. 25. Wright JH, Jacisin J, Radin N, et al. Glucose metabolism in unipolar depression. Br J Psychiatry 1978;132:386-393. 26. Schauss AG. Nutrition and behavior: complex interdisciplinary research. Nutr Health 1984;3:9-37. 27. Jenkins DJ, Wolever TM, Taylor RH, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr 1981;24362-366. 28.Titera JW.The hypoadrenocortical state and its management. N Y State J Med 1955;55:1869-1876. 29.Demitrack MA. Chronic fatigue syndrome: a disease of the hypothalamic-pituitary-adrenal axis? Ann Med 1994;26:1-3. 30. Roberts AD, Wessely S, Chalder T, et al. Salivary cortisol response to awakening in chronic fatigue syndrome. Br J Psychiatry 2004; 1M136-141. 31.Cleare AJ. The HPA axis and the genesis of chronic fatigue syndrome. Trends Endoainol Metab 2004;15:55-59. 32. Demitrack MA, Dale JK, Straus SE, et al. Evidence for impaired activation of hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 1991;73: 12241234. 33. Prins JB, Bos E, Huibers MJ, et al. Social support and the persistence of complaints in chronic fatigue syndrome. Psychother Psychosom 2004;73:174182. 34. Sharpe M, Hawton K, Simkin S, et al. Cognitive behavior therapy for the chronic fatigue syndrome: a randomized controlled trial. BMJ 1996;312:22-26. 35. LaManca JJ,Sisto SA, DeLuca J, et al. Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome. Am J Med 1998;105:S59-65. 36. Estler CJ, Ammon HP,Herzog C. Swimming capacity of mice after prolonged treatment with psychostimulants. 1. Effects of caffeine on swimming performance and cold stress. Psychopharmacology 1978;58:161-166. 37. Greden JF,Fontaine P, Lubetsky M, et al. Anxiety and depression associated with caffeinism among psychiatric inpatients. Am J Psychiatry 1978;135:963-966. 38. Chou T. Wake up and smell the coffee. Caffeine, coffee, and the medical consequences. West J Med 1992;157544-553. 39. Hughes JR, Hisgins ST, Bickel WK, et al. Caffeineself-administration, withdrawal, and adverse effects among coffee drinkers. Arch Gen Psychiatry 1991;48:611-617. 40.Manuel Y,Keenoy B, Moorkens G, Vertommen J, et al. Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium. J Am Coll Nutr 2OOO;19:374-382. 41. Cox IM,Campbell MJ, Dowson D. Red blood cell magnesium and chronic fatigue syndrome. Lancet 1991;337757-760. 42.Ahlborg H, Ekelund LG, Nilsson CG. Effect of potassiummagnesium aspartate on the capacity for prolonged exercise in man. Acta Physiol Scand 1968;74:238-245. 43. Hicks JT. Treatment of fatigue in general practice: a double blind study. Clin Med 1964;Jan:85-90. 44.Friedlander HS. Fatigue as a presenting symptom: management in general practice. Curr Ther Res 1962;4441-449. 45. Shaw DL Jr, Chesney MA, Tullis IF, et al. Management of fatigue: a physiologic approach. Am J Med Sci 1962;243:758-769.

46.Gullestad L, Oystein Dolva L, Birkeland K, et al. Oral versus intravenous magnesium supplementation in patients with magnesium deficiency. Magnes Trace Elem 1991;lOll-16. 47. Lindberg JS, Zobitz MM, Poindexter JR, et al. Magnesium bioavailability from magnesium citrate and magnesium oxide. J Am Coll Nutr 1990;948-45. 48.Behan PO, Behan WM, Horrobin D. Effect of high doses of essential fatty acids on the postviral fatigue syndrome. Acta Neurol Scand 1990;82209-216. 49. Puri BK, Holmes J, Hamilton G. Eicosapentaenoic acid-rich essential fatty acid supplementation in chronic fatigue syndrome associated with symptom remission and structural brain changes. Int J Clin Pract 200458297-299. 50. Lange G, Holodny AI, DeLuca J, et al. Quantitative assessment of cerebral ventricular volumes in chronic fatigue syndrome. Appl Neuropsychol2001;8:23-30. 51.Birkmayer GD, Kay GG, Vurre E. [Stabilized NADH (ENADA) improves jet lag-induced cognitive performance deficit.] Wien Med Wochenschr 2002;152450-454. 52. Forsyth LM, Preuss HG, MacDowell AL, et al. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol1999;82185-191. 53. Birkmayer JG, Nadlinger K. Safety of stabilized, orally absorbable, reduced nicotinamide adenine dinucleotide (NADH): a 26-week oral tablet administration of ENADA/NADH for chronic toxicity study in rats. Drugs Exp Clin Res 2002;28:185-192. 54.PLioplys AV, Plioplys S. Amantadine and L-camitine treatment of chronic fatigue syndrome. Neuropsychobiology 199735:16-23. 55. Farmer ME, Locke BZ, Moscicki EK, et al. Physical activity and depressive symptoms: the NHANES 1 Epidemiologic Follow-up Study. Am J Epidemiol 1988;13281340-1351. 56. Fiatarone MA, Morley JE, Bloom ET, et al. The effect of exercise on natural killer cell activity in young and old subjects. J Gerontol 1989;44:M37-45. 57.Makinnon LT. Exercise and natural killer cells. What is their relationship? Sports Med 1989;7141-149. 58. Sun XS, Xu Y, Xia YJ. Determination of E-rosette-fonning lymphocytes in aged subjects with Taichiquan exercise. Int J Sport Med 1989;10:217-219. 59. Fitzgerald L. Exercise and the immune system. Immunol Today 1988;9:337-339. 60.Friedberg F. Does graded activity increase activity? A case study of chronic fatigue syndrome. J Behav Ther Exp Psychiatry 2002;33:203-215. 61. Wallman KE, Morton AR, Goodman C, et al. Randomised controlled trial of graded exercise in chronic fatigue syndrome. Med J Aust 2004;180444-448. 62. Bohn B, Nebe CT,Birr C. Flow-cytometric studies with Eleutherococcus senticosus extract as an immunomodulatory agent. Arzniemitteforschung 1987;371193-1196. 63. Brown D. Licorice root-potential early intervention for chronic fatigue syndrome. Quart Rev Nat Med 1996;Summer:95-96. 64.Baschetti R. Chronic fatigue syndrome and liquorice (letter). N Z Med J 1995;108:156-157. 65. Bell DS.Chronic fatigue syndrome update. Findings now point to CNS involvement. Postgrad Med 1994;9673-81. 66. Deale A, Chalder T, Marks L, et al. Cognitive behavior therapy for chronic fatigue syndrome: a randomized controlled trial. Am J Psychiatry 1997;154:408414.

Congestive Heart Failure Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

1591

General Considerations 1591

Therapeutic Approach 1595 Diet 1595 Nutritional Supplements 1595 Botanical Medicines 1595

Diagnostic Considerations 1591 Therapeutic Considerations 1592 Nutritional Supplements 1592 Botanical Medicines 1595

DIAGNOSTIC SUMMARY Left ventricular failure-exertional dyspnea, cough, fatigue, orthopnea, cardiac enlargement, rales, gallop rhythm, and pulmonary venous congestion Right ventricular failure-elevated venous pressure, hepatomegaly, dependent edema Both left and right ventricular failure+combinations of the above Diagnosis confirmed by echocardiograph

GENERAL CONSIDERATIONS Congestive heart failure (CHF) refers to an inability of the heart to effectively pump enough blood. The contractile function of the heart is governed by five primary factors: The contractile state of the myocardium The preload of the ventricle End-diastolic volume The impedance to left ventricular ejection The heart rate Chronic CHF is most often due to long-term effects of high blood pressure, previous myocardial infarction, disorder of a heart valve, cardiomyopathy, or chronic lung disease. These conditions produce CHF by affecting one or more of the primary determinants of myocardial contractile function (precipitating or exacerbating factors in CHF are presented in Box 160-1). One of the most serious consequences of reduced cardiac output is reduction in renal blood flow and

glomerular filtration rate, which in turn leads to sodium and fluid retention. Adding more stress is activation of the renin-angiotensin-aldosteronesystem, leading to an increase in peripheral vascular resistance; increased ventricular afterload; and increased levels of circulating vasopressin, which also serves as a vasoconstrictor and antidiuretic. In an attempt to compensate for the reduced cardiac output, several compensatory mechanisms occur: tachycardia, increased sympathetic nervous system activation, ventricular dilation, and hypertrophy. These mechanisms are a bit of a mixed blessing. For example, while the increase in sympathetic activity increases cardiac output by increasing heart rate and force of contraction, it also leads to increased vascular resistance. The signs and symptoms of CHF depend on which ventricle has failed. The clinical symptoms of left ventricular failure are dominated by symptoms of pulmonary congestion and edema, while right ventricular failure is characterized by signs of systemic venous congestion and peripheral edema. Weakness, fatigue, and shortness of breath are common to both right and left ventricular failure, as well as biventricular failure.

DIAGNOSTIC CONSIDERATIONS CHF is most effectively treated via natural measures in the early stages. Hence early diagnosis and prevention by addressing causative factors are imperative. The first symptom of CHF is usually shortness of breath. A chronic, nonproductive cough may also be the first 1591

Specific Health Problems

Increased demand Anemia Fever Infection Fluid overload Increased sodium intake High environmental temperature Renal failure Hepatic failure Thyrotoxicosis Arteriovenous shunt Respiratory insufficiency Emotional stress Pregnancy Obesity Arrhythmias Pulmonary embolism Ethanol ingestion Nutrient deficiency Uncontrolled hypertension Drugs Beta-adrenergic blockers Antiarrhythmic drugs Sodium-retaining drugs: Steroids Nonsteroidal antiinflammatory drugs

presenting symptom. Patients suspected of having CHF should have an extensive cardiovascular evaluation including a complete physical examination to look for the characteristic signs of CHF (e.g., peripheral signs of heart failure, enlarged and sustained left ventricular impulse, diminished first heart sound, gallop rhythm), electrocardiogram, and echocardiogram.

1

Stages of congestive heart failure as defined by the New York Heart Association

Stage

Symptoms

Stage I

Patient is symptom free at rest and with treatment.

Stage II

Patient experiences impaired heart function with moderate physical effort. Shortness of breath with exertion is common. There are no symptoms at rest.

Stage 111

Even minor physical exertion results in shortness of breath and fatigue. There are no symptoms at rest.

Stage IV

Symptoms such as shortness of breath and signs such as lower extremity edema are present when the patient is at rest.

Nutritional Supplements The natural approach focuses on improving myocardial energy production, as CHF is always characterized by an energy depletion status. This impaired energy production is often the result of nutrient or coenzyme deficiency (e.g., magnesium, thiamin, coenzyme Qlo [CoQlo],carnitine). The dietary recommendations given in Chapter 176 are appropriate for most patients with CHF, especially if the CHF is due to long-term hypertension. Of particular importance is a diet low in sodium and high in potassium. A high intake of sodium greatly exacerbates the hemodynamic aspects of CHF. Sodium intake should be restricted to below 1.8 g daily. Furthermore, the dietary intake of several nutrients are well below recommended levels in patients with CHF.' Most notably low are magnesium, calcium, zinc, copper, manganese, energy, thiamin, riboflavin, and folic acid. A high-potency multivitamin and mineral formula is critical in these patients, especially if they are on a diuretic.

THERAPEUTIC CONSIDERATIONS

Magnesium

In the initial stages of CHF, natural measures designed to address the underlying cause (e.g., hypertension) or improve the metabolic functions of the myocardium (described later, as well as measures described in Chapter 147) are often quite effective. In later stages, however, medical treatment involving the use of diuretics and angiotensin-converting enzyme (ACE) inhibitors or digitalis glycosides, or both, is indicated in most cases. The measures described here can be used as adjunctive therapy in these more severe cases. The New York Heart Association (NYHA) staging system for CHF can be used in an effort to better clarify likely respondents to natural therapy alone (Table 160-1). In general, excellent clinical results can be expected in stages I and II with the use of the natural measures described later.

Low magnesium levels (particularly white blood cell magnesium) are common findings in patients with CHF. This association is extremely significant as magnesium levels have been shown to correlate directly with survival rates. In one study, CHF patients with normal levels of magnesium had 1- and 2-year survival rates of 71% and 6l%, respectively, compared with rates of 45% and 42%, respectively, for patients with lower magnesium levels.2These results are not surprising, considering that magnesium deficiency is associated with cardiac arrhythmias, reduced cardiovascularprognosis, worsened ischemia, and increased mortality in acute myocardial infarction. The magnesium deficiency is probably due to a combination of inadequate intake and increased wasting due to overactivation of the renin-angiotensin-aldosterone

Congestive Heart Failure

function, routine B vitamin supplementation appears to system, as is commonly seen in patients with heart failure. It can also be the result of diuretics like furosemide. be worthwhile in this age group. In addition to providing benefits of its own in CHF, The association between thiamin deficiency and longterm furosemide use was discovered in 1980 when it was magnesium supplementation also prevents the magneshown that after only 4 weeks of furosemide use, thiamin sium depletion caused by the conventional drug therapy concentrations and the activity of the thiamin-dependent for CHF (i.e., digitalis, diuretics, and vasodilators such as enzyme transketolase were significantly reduced. The beta-blockers and calcium channel-blockers).Magnesium supplementation has even been shown to produce posifirst study looking at thiamin as a potential adjunct in tive effects in CHF patients receiving conventional drug the treatment of CHF showed only modest benefits. therapy, even if serum magnesium levels are normaL3 However, several subsequent studies have shown that However, magnesium supplementation is not indicated daily doses of 80 to 240 mg of thiamin daily improved the clinical picture as measured by a 13%to 22% increase in patients with renal failure, as this condition predisof left ventricular ejection f r a c t i ~ n .This ~ J ~ is quite signifposes them to hypermagnesemia-a sigruficant risk factor icant as an increase in ejection fraction is associated with for m~rtality.~ ACE-inhibitor drugs appear to produce a magnesium-sparing effect in patients on fur~semide.~ a greater survival rate in patients with CHF. In one study, biochemical evidence of severe thiamine deficiency Typical dosages are 200 to 300 mg one to three times was found in 98% patients receiving at least 80 mg/day per day of magnesium in the citrate form. Oral magneof furosemide and in 57% of patients taking 40 mg sium can be effective in raising white blood cell furosemide daily.” magnesium (and potassium) levels6 Monitoring serum Given the possible benefit, lack of risk, and low cost of magnesium levels is critical to preventing hypermagnethiamin supplementation, administrationof 200 to 250 mg semia in patients with renal impairment, as well as those on digoxin. Magnesium significantly reduces the freof thiamin daily appears warranted in patients with quency and complexity of ventricular arrhythmias in CHF, especially if they are on furosemide. digoxin-treated patients with CHF even without the Carnitine presence of digoxin toxicity, but too much magnesium may interfere with d i g ~ x i n . ~ Normal heart function is critically dependent on adequate concentrations of carnitine and CoQlo(discussed Thiamin later). These compounds are essential in the transport of fatty acids into the myocardium and mitochondria for Interest has recently risen regarding the potential role energy production. Although the normal heart stores of thiamin deficiency in CHF. Thiamin was the first more camitine and CoQlothan it needs, if the heart does B vitamin discovered, hence its designation as vitamin B1. not have a good supply of oxygen, camitine and CoQlo It is well established that thiamin deficiency can result in levels quickly decrease. Both of these agents have shown the cardiovascular manifestations of “wet beri-beri,” benefit in the treatment of CHF. sodium retention, peripheral vasodilation, and heart Several double-blind clinical studies have shown failure. It is also well established that furosemide carnitine supplementation to improve cardiac func(Lasix), the most widely prescribed diuretic, has been tion in patients with CHF.12-14In one double-blind study, shown to cause thiamin deficiency in animals and patients with CHF. only 1 month of treatment (500 mg three times daily) Although severe thiamin deficiency is relatively was necessary to cause significant improvement in heart fun~ti0n.l~ The longer carnitine was used, the uncommon (except in alcoholics), many Americans do not consume the recommended daily allowance of more dramatic the improvement. After 6 months of use, 1.5 mg, especially elderly patients in hospitals or nursing the camitine group demonstrated an increase in the homes. In an attempt to gauge the prevalence of thiamin maximum exercise time of 25.9% and a 13.6% increase in ventricular ejection fraction. In another doubledeficiency in the geriatric population, 30 unselected blind study in similar patients, at the end of 6 months of consecutive outpatients visiting a university outpatient clinic in Tampa, FL, were tested for thiamin levels. treatment, maximum exercise time on the treadmill Depending on the thiamin measurement, plasma versus increased 16.4% and the ejection fraction increased red blood cell thiamin, low levels (defined as a level by 12.1%.14 Even more obvious benefits were seen in a 3-year study below the lowest reference range for younger-aged of 80 patients with moderate to severe heart failure (NYHA groups) were found in 57% and 33%, respectively? These results highlight the growing body of evidence classification III to IV)caused by dilated cardiomyopathy. that a significant percentage of the geriatric population After a period of stable cardiac function up to 3 months, patients were randomly assigned to receive either is deficient in one or more of the B vitamins. Given the camitine (2 g/day orally) or placebo. After a mean of essential role of thiamin and other B vitamins to normal 33.7 months of follow-up (range 10 to 54 months), human physiology, especially cardiovascular and brain

Specific Health Problems 70 patients were in the study: 33 in the placebo group and 37 in the carnitine group. At the time of analysis, 63 patients were alive. Six deaths occurred in the placebo group, and one death in the camitine group. Survival analysis showed that patients' survival was statistically significant in favor of the camitine group.15

Coenzyme Qio Numerous studies have also shown CoQlosupplementation to be extremely effective in the treatment of CHF. Most of these studies used CoQlo as an adjunct to conventional drug therapy. In one of the early studies, 17 patients with mild CHF received 30 mg/day of CoQ10.16 All patients improved, and nine (53%) became asymptomatic after 4 weeks. In another early study, 20 patients with congestive heart failure due to either atherosclerosis or high blood pressure were treated with CoQlo at a dosage of 30 mg/day for 1 to 2 months.17 Fifty-five percent of the patients reported subjective improvement; 50% showed a decrease in NYHA classification; and 30% showed a "remarkable" decrease in chest congestion as seen on chest radiograph. Patients with mild disease tended to improve more often than those with more severe disease. Subjective improvements in these patients were confirmed by various objective tests including increased cardiac output, stroke volume, cardiac index, and ejection fraction. These results were consistent with CoQlo producing an increased force of heart muscle contraction (a positive inotropic effect) similar to, but less potent than, digital is.'*^'^ Three more studies have also shown CoQlo to be effective in significantly improving heart function in patients with CHF. In a double-blind Scandinavian study of 80 patients, participants were given either CoQlo (100 mg/day) or placebo for 3 months and then crossed. The improvements noted with CoQlo were found to be actually more positive than those obtained from conventional drug therapy alone.2O In another double-blind study, 641 patients with CHF received either CoQlo (2 mg/kg body weight) or a placebo for 1 year.21The number of patients requiring hospitalization or experiencing serious consequences due to CHF was signhcantly reduced in the CoQlogroup compared with the placebo group. In the largest study to date, a total of 2664 patients in NYHA classes I1 and 111were enrolled in an open study in Italy? The daily dosage of CoQlowas 50 to 150 mg orally for 90 days, with the majority of patients (78%) receiving 100 mg/day. After 3 months of CoQlotreatment, the proportions of patients with improvement in clinical signs and symptoms were as follows: Cyanosis-78.1% Edema (fluid retention)-78.6%

Pulmonary edema-77.8% Enlargement of liver area49.3% Venous congestion-71.81% Shortness of breath-52.7% Heart palpitations-75.4% Sweating-79.8% Subjective a r r h y t l ~ n i a 4 3 . 4 ~ / ~ Insomnia46.2% Vertigw73.1% Nocturnal urination-53.6% Improvement of at least three symptoms occurred in

54% of patients, indicating a significantly improved quality of life with CoQlosupplementation. The results also showed a low incidence of side effects-only 36 patients (1.5%) reported mild side effects attributed to CoQlo. These positive results with CoQlo,however, were not seen in one clinical trial. In this double-blind study, 55 patients with CHF NYHA class III and IV, ejection fraction less than 40%, and peak oxygen consumption less than 50% during standard therapy were randomly assigned to receive CoQlo(200 mg) or placebo. Analysis indicated that there were no changes in ejection fraction, peak oxygen consumption, and exercise duration in either group. Possible explanations for failure to achieve a therapeutic benefit in this study may be the result of CoQlo not being strong enough to produce significant effects in more severe stages of CHF or the fact that blood levels of CoQlO did not reach sufficient levels. Though the mean serum concentration of CoQlo increased from 0.95 kg/ml to 2.2 pg/ml in 19 of 22 patients on CoQlo, blood levels were below the suggested threshold of 2.5 pg/ml.=

Arginine Another amino acid of value in CHF is arginine, although via a totally different mechanism from other nutrients. One of the experimental findings in patients with CHF is that they are less able to achieve peripheral vasodilation during exercise due to endothelial dysfunction. Since the endothelial cells make the natural vasodilator nitric acid from arginine, several researchers have evaluated its efficacy in improving CHF. The first study of orally administered arginine showed promising results. In a randomized, double-blind, placebocontrolled study of 5.6 to 12.6 g/day of oral L-arginine, peripheral blood flow was found to increase by 29%, 6-minute walking distance increased by 8% and arterial compliance increased 19Y0.~~ Subsequent studies have shown arginine supplementation to improve endothelial cell function and renal function (as shown by improvements in glomerular filtration rate, natriuresis, and plasma endothelin level) in patients with CHF?5,26

Congestive Heart Failure

Botanical Medicines Crataegus oxyacantha (Hawthorn) Preparations of Crataegus sp. appear to be quite useful in CHF, especially in the early stages as a sole agent and in the latter stages in combination with digitalis cardioglycosides. The effectiveness of crataegus in CHF has been repeatedly demonstrated in double-blind s t ~ d i e s .In~ one ~ - ~of~the most recent studies, 30 patients with CHF (NYHA stage 11) were assessed in a randomized double-blind study.z8 Treatment consisted of a crataegus extract standardized to contain 15 mg procyanidin oligomers per 80 mg capsule. Treatment duration was 8 weeks, and the substance was administered at a dose of one capsule taken twice daily. The group receiving the crataegus extract showed a statistically significant advantage over placebo in terms of changes in heart function as determined by standard testing procedures. Systolic and diastolic blood pressures were also mildly reduced. Like all other studies with crataegus extracts, no adverse reactions occurred. In another study, 78 patients with CHF (NYHA stage 11) were given either 600 mg of standardized crataegus extract or placebo The parameter used to measure effectiveness was the patient’s working capacity on a bicycle ergometer. After 56 days of treatment, the crataegus group had a mean increase of 25 watts compared with the placebo group’s increase of only 5 watts. In addition, the crataegus group also experienced a mild but sigruficant reduction in systolic blood pressure (drop from 171 to 164 mmHg) and heart rate (115 to 110 beats/-). There was no change in blood pressure or heart rate with the placebo group.

Terminalia arjuna

extract (500 mg every 8 hours) from the bark of Terminalia arjuna or placebo for 2 weeks. Those receiving the medicinal plant experienced, according to echocardiogram evaluation, statistically significant improvement in several parameters of cardiac function, such as end-systolic volume and left ventricular ejection fractions. A second, uncontrolled phase of the study using a combination of T. arjuna with conventional medication found that, after 2 years, nine patients showed a remarkable improvement to NYHA class I1 with the other three improving to class I K 3 0

THERAPEUTIC APPROACH Treatment with diet and the natural agents described earlier is effective in early stages of CHF (i.e., NYHA stages I and 11). In later stages, adjunct drug therapy is usually necessary. Treatment is designed to address underlying pathophysiology and to improve myocardial function through improved energy production.

Diet Patients should be encouraged to achieve their ideal body weight, restrict sodium intake (below 1.8 g daily), increase the consumption of plant foods in the diet, reduce the intake of saturated fat, and follow the other dietary guidelines given for lowering blood pressure.

Nutritional Supplements Magnesium: 200 to 400 mg three times daily Thiamin: 200 to 250 mg daily L-Camitine: 500 to 1000 mg three times daily CoQlo:100 to 300 mg daily

Botanical Medicines

A traditional Ayurvedic botanical for cardiac failure has recently been shown to be effective in a controlled clinical study. Twelve patients with severe refractory congestive heart failure (class IV M A ) received an

C. oxyacantha (Hawthorn) extract (l.8Y0 vitexin4’-rhamnoside or 10% procyanidin content): 200 to 300 mg three times daily T. arjuna extract: 500 mg three times daily

1. Gorelik 0, Almoznino-Sarafian D, Feder I, et al. Dietary intake of various nutrients in older patients with congestive heart failure. Cardiology 2003;99:177-181. 2. Gottlieb SS, Baruch L, Kukin ML. Prognostic importance of serum magnesium concentrationin patients with congestive heart failure. J Am Coll Cardiol1990;16827-831. 3. Gottlieb SS. Importance of magnesium in congestive heart failure. Am J Cardiol1989;63:39G42G. 4. Cohen N, Almoznino-SarafianD, Zaidenstein R, et al. Serum magnesium aberrations in furosemide (frusemide) treated patients with congestive heart failure:pathophysiologicalcorrelates and prognostic evaluation. Heart 2003;89:411-416.

5.Oladapo 00, Falase AO. Serum and urinary magnesium during treatment of patients with chronic congestive heart failure.Afr J Med Med Sci 2000;29301-303. 6. Cohen N, Alon I, Almoznino-Sarafian D, et al. Metabolic and clinical effects of oral magnesium supplementation in furosemide-treated patients with severe congestive heart failure. Clin Cardiol 2000;23:433-436. 7. Crippa G, Sverzellati E, Giorgi-Pierfranceschi M, et al. Magnesium and cardiovasculardrugs: interactions and therapeutic role. Ann Ital Med Int 1999;1440-45. 8. Chen MF, Chen LT, Gold M. Plasma and erythrocyte thiamin concentration in geriatric outpatients. J Am Coll Nutr 1996;15:231-236.

Specific Health Problems 9. Leslie D, Gheorghiade M. Is there a role for thiamine supplementation in the management of heart failure. Am Heart J 1996;131: 1248-1250. 10. Mendoza CE, Rodriguez F, Rosenberg DG. Reversal of refractory congestive heart failure after thiamine supplementation: report of a case and 'review of literature. J Cardiovasc Pharmacol Ther 2003;8:313-316. 11.Zenuk C, Healey J, Donneuy J, et al. Thiamine deficiency in congestive heart failure patients receiving long term furosemide therapy. Can J Clin Pharmacol2003;10184-188. 12. Goa KL, Brogden RN. L-camitine. A preliminary review of its pharmacokinetics, and its therapeutic use in ischemic cardiac disease and primary and secondary camitine deficiencies in relationship to its role in fatty acid metabolism. Drugs 1987;34:1-24. 13.Mancini M, Rengo F, Lingetti M, et al. Controlled study on the therapeutic efficacy of propionyl-L-camitine in patients with congestive heart failure. Arzneimittelforschung 1992;42:1101-1104. 14. Pucciarelli G, Matsursi M, Latte S, et al. [The clinical and hemodynamic effects of propionyl-L-carnitine in the treatment of congestive heart failure.] Clin Ter 1992;141:379-384. 15.Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration. Am Heart J. 2000;139(2 Pt 3):S120-123. 16. Ishiyama T, Morital Y, Toyama S, et al. A clinical study of the effect of coenzyme Q on congestive heart failure. Jpn Heart J 1976; 1732-42. 17.Tsuyusaki T, Nor0 C, Kikawada R. Mechanocardiography of ischemic or hypertensive heart failure. In Yamamura Y, Folkers K, Ito Y, eds. Biomedical and clinical aspects of coenzyme Q, vol 2. Amsterdam: Elsevier/North-Holland Biomedical Press, 1980: 273-288. 18. Judy WV, Stogsdill WW, Folkers K. Myocardial effects of co-enzyme Qlo in primary heart failure. In Folkers K, Yamamura Y, eds. Biomedical and clinical aspects of coenzyme Q, vol 4. Amsterdam: Elsevier Science, 1984:353-367. 19.Vanfraechem JHP, Picalausa C, Folkers K. Coenzyme Qlo and physical performance in myocardial failure. In Folkers K, Yamamura Y, eds. Biomedical and clinical aspects of coenzyme Q, vol4. Amsterdam: Elsevier Science, 19M281-290.

20. Hofman-Bang C, Rehnquist N, Swedberg K, et al. Coenzyme Qlo as an adjunctive treatment of congestive heart failure. J Card Fail 1995;l:101-107. 21. Morisco C , Trimarco B, Condorelli M. Effect of coenzyme Qlotherapy in patients with congestive heart failure. A long-term multicenter randomized study. Clin Investig 1993;71:5134-136. 22. Baggio E, Gandini R, Plancher AC. Italian multicenter study on the safety and efficacy of coenzyme Qlo as adjunctive therapy in heart failure. CoQloDrug Surveillance Investigators. Mol Aspects Med 1994;15:~287-294. 23. Khatta M, Alexander BS, Krichten CM, et al. The effect of coenzyme QlO in patients with congestive heart failure. Ann Intern Med 2000;132:636-640. 24. Rector TS, Bank A, Mullen KA, et al. Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Circulation 1996; 93:2135-2141. 25. Hambrecht R, Hilbrich L, Erbs S, et al. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation. J Am Coll Cardiol 2000;35:706-713. 26. Watanabe G, Tomiyama H, Doba N. Effects of oral administration of L-arginine on renal function in patients with heart failure. J Hypertens 2000;18:229-234. 27.0Conolly M, Jansen W, Bemhoft G. [Treatment of decreasing performance. Therapy using standardized crataegus extract in advanced age.] Fortschr Med 1986;104:805-808. 28. Leuchtgens H. Crataegus Special Extract WS 1442in NYHA II heart failure. A placebo controlled randomized double-blind study. Fortschr Med 1993;111:352-354. 29. Tauchert M, Ploch M, Hubner WD. Effectiveness of the Hawthorn Extract LI 132 compared to ACE inhibitor Captopril. Multicentre double-blind study with 132 NYHA Stage 11. MMW Munch Med Wochenschr 1994;136(suppl l):S27-33. 30. Bharani A, Ganguly A, Bhargava KD. Salutary effect of Terminalin nrjirna in patients with severe refractory heart failure. Int J Cardiol 1995;49:191-199.

Cystitis Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

1597

General Considerations Causes 1597

1597

Diagnosis 1598 Collection of Urine Specimen for Culture 1598 Examination of the Collected Urine 1599 Therapeutic Considerations 1600 Chronic Interstitial Cystitis 1600 General Measures 1600

DIAGNOSTIC SUMMARY Burning pain on urination Increased urinary frequency, nocturia Turbid, foul-smelling, or dark urine Lower abdominal pain Urinalysis shows sigruficant pyuria and bacteriuria

GENERAL CONSIDERATIONS Bladder infections in women are surprisingly common: 10% to 20% of all women have urinary tract discomfort at least once a year, 37.5% of women with no history of urinary tract infection (UTI) will have one within 10 years, and 2% to 4% of apparently healthy women have elevated levels of bacteria in their urine, indicative of an unrecognized UTI. Women with a history of recurrent UTIs will typically have an episode at least once every year.' Recurrent bladder infections can be a significant problem for some women because 55% will eventually involve the upper urinary tract (i.e., the kidneys). Recurrent kidney infection can cause abscess formation, disseminated intravascular coagulation, acute respiratory distress syndrome, sepsis, and chronic progressive renal damage, resulting in scarring and, for some, kidney failure. UTIs are much less common in males than females, except infants, and in general indicate an anatomic

Enhancing Immune Function 1601 Nutrient Supplementation 1601 Botanical Medicines 1602 Acupuncture 1603 Therapeutic Approach 1603 General Measures 1603 Diet 1603 Nutritional Supplements 1603 Botanical Medicines 1603

abnormality, a prostate infection, or rectal intercourse. Table 161-1 lists incidence by age and sex.

Causes Urine, as it is secreted by the kidneys, is sterile until it reaches the urethra, which transports it from the bladder to the urethral opening. Bacteria can reach the urinary tract by ascending from the urethra or, much less commonly, through the blood stream. Bacteria are introduced into the urethra from fecal contamination or, in women, vaginal secretions. Important factors in aiding or perpetuating an ascending infection are anatomic or functional obstructions to flow (allowing pooling of urine) and immune system dysfunction. Free flow, large urine volume, complete emptying of the bladder, and optimal immune function are important antibacterial defenses. The body has several defenses against bacterial growth in the urinary tract? Urine flow tends to wash away bacteria. The surface of the bladder has antimicrobial properties. *The pH of the urine inhibits the growth of many bacteria. In men the prostatic fluid has many antimicrobial substances. The body quickly secretes white cells to control the bacteria.

1597

~~

Incidence of urinary tract infection

Incidence

Age group

Male-to-female ratio

1.51 1:lO 1 :30 150 1:1.5

1

Neonatal Preschool age

1.5-3 1.2 3-5 10-30

School age Reproductive age Geriatric

Modified from Rubin RH. infections of the urinary tract. In Dale DC, Federman DD, eds. Scientific American Medicine. New York: Scientific American, 1997.

Diaanosis

Percentage of subjects

Upper urinary tract infection

20

Bladder infection

40

Low levels of bacteria in urethra Urethral chlamydia

16

Unsuspected vaginitis Other (e.g., herpes, gonorrhea, pelvic inflammatory disease)

8

4

12

M d iie d from Reilly BM.Practical strategies in outpatient medicine. Philadelphia: Saunders, 1984:277.

of women with persistent bacteria in their urine, recurrent urinary

Diagnosis

Percentage of subjects

Normal

60

Abnormalities of unknown significance

10-20 15 2-8 20 (children) 5 (adults) <1 <1 <1

Kidney structural abnormalities or scarring Kidney stones Reflux of urine Hydronephrosis Bladder outlet obstruction Miscellaneous urinary tract lesions

Modified from Branch WT. Office practice of medicine. Philadelphia: Saunders. 1982:488-504, 679-685.

Many factors are associated with increased risk of bladder infections: delayed postcoital urination; the use of an unlubricated condom; pregnancy (twice as frequent); sexual intercourse (nuns have 1 / 10 the incidence); homosexual activity (in males); mechanical trauma or irritation; and, perhaps most important, structural abnormalitiesof the urinary tract that block the free flow of urine. Reflux of infected urine from the bladder into the upper urinary tract is important in the development of kidney infections and the establishment of recurrent infections. Table 161-2 lists the types and frequencies of abnormalities associated with chronic UTIs.

DIAGNOSIS The diagnosis of bladder infection is imprecise because clinical symptoms and the presence of significant amounts of bacteria in the urine do not correlate well. As indicated in Table 161-3, only 60% of women with

the typical symptoms of UTI actually have significant levels of bacteria in their urine. Equally important, however, is the fact that 20% have the more potentially serious involvement of the upper tract. In general, the diagnosis is made according to signs and symptoms and urinary findings. A pelvic examination is indicated if there is a history consistent with vaginitis, cervicitis, or if there is confusion regarding diagnosis. Microscopic examination of the infected urine shows high levels of white blood cells (WBCs) and bacteria. Culturing the urine determines the quantity and type of bacteria involved. As shown in Table 161-4, Escherichiu coli (from the colon) is by far the most common. The presence of fever, chills, and low back pain can indicate involvement of the kidneys. Those with recurrent infections should be examined by intravenous urogram to determine if a structural abnormality is present.

Collection of Urine Specimen for Culture The optimal clinical method for obtaining a urine sample is the voided midstream specimen. It involves cleaning the urethral meatus or vaginal vestibule before collecting the sample. If vaginal epithelial cells are present, a new specimen should be collected. To avoid repeating the collection, a satisfactory technique for the female, called “the clean catch,” consists of spreading the labia and cleansing the area with two gauze sponges moistened with a cleansing solution and a dry gauze sponge. The washing is accomplished by making a single frontto-back motion with each of the two moist sponges and then the dry sponge. While the labia are still held apart, a small amount of urine is allowed to pass into the toilet (or bedpan); then a midstream specimen is collected in a sterile container and immediately closed. Occasionally the urine must be collected via catheterization. This is more invasive to the patient and carries

Cystitis

I

(percentage positive) in outpatients and inpatients with urinary tract infections

Bacteria soecies

Outpatients

InDatients

_________~

Escherichia coli Proteus miribili Klebsiella pneumonia Enterococci Enterobacter aerogenes Pseudomonas aeruginosa Proteus sp.

89.2 3.2 2.4 2 0.8 0.4 0.4 0 1.6' 0

52.7 12.7 9.3 7.3 4 6 3.3 3.3 0.7 0.7

Organisms That Reduce

Organisms That Do Not

Citrobacter spp. Escherichia coli Klebsiella pneumonia Proteus spp. Pseudomonas spp. Serratia marcescens Shigella Staphylococcus spp. (most)

Gonococcus

Streptococcus faecalis Tuberculosis

with it a 1%to 2% chance of initiating a UTI as a result of introducing microorganisms into the bladder. Suprapubic aspiration is the most accurate method of urine collection, but obviously it is the most invasive as well.

Urinary infections typically increase the number of WBCs present. The leukocyte esterase test is used to detect WBCs in the urine. Because many common organisms contain enzymes that reduce nitrate in the urine to nitrite (Box 161-l), measuring urinary nitrite provides an inexpensive and rapid detection of significant bacteriuria, but it should be confirmed by culture. Although both tests have a high specificity of approximately 95%, the leukocyte esterase test is approximately 80% to 90% sensitive, whereas the nitrite test is only approximately 50% sensitive compared with a quantitative culture as the gold standard. However, combining both tests improves the sensitivity into the 85% to 90% range.5

Examination of the Collected Urine

Microscopic Examination

Several methods are routinely employed in the detection of bacteria in the urine. They range from the use of dipsticks to microscopic examination and culture. For most accurate determinations, the urine should be examined within 1 hour. If examination must be delayed, refrigeration at 58" C preserves the urine for most routine examinations. However, culturing requires that the urine not be refrigerated for more than 8 hours.

Microscopic examination should be performed within the first hour after collection. A drop of fresh urine or a drop of resuspended sediment from centrifuged fresh urine is placed on a microscope slide, covered with a cover glass, and examined with the high-dry objective under reduced illumination. The presence of more than 10 bacteria per field in an unstained specimen suggests a bacteria count of more than 100,000/ml of urine. Smears may also be made using a Gram stain and examined under the oil immersion objective. The presence of WBCs further indicates an infectious process. The presence of large quantities of protein or WBC casts in the micrographic examination, or both, may be indicative of renal involvement, most commonly p yelonephritis.

Serratia marcescens Staphylococcus epidermidis Staphylococcus aureus

Modified from Rubin RH. Infections of the urinary tract. In Dale DC, Federman DD, eds. Scientific American Medicine. New York: Scientific American, 1997. 'Recent evidence suggests that this may be more prevalent than is currently thoughtin sexually active college-age women it may account for as much as 20% of asymptomatic urinary tract infections.

Dipstick Methods The modern examination of urine specimens typically involves the use of reagent strips, which are dipped into urine and removed. Parts of the dipstick are impregnated with chemicals that react with specific substances in the urine to produce various colors. Color standards, against which the color can be compared, are provided. Careful attention must be paid to match the dipstick to the color standard at the appropriate time. Instructions accompany commercially prepared dipsticks. Dipsticks are invaluable for qualitative and rough quantitative analysis. Typically, they provide information on pH, protein, glucose, ketones, bilirubin, hemoglobin, leukocyte esterase, nitrite, and urobilinogen. Some dipsticks also allow for detection of WBCs and bacteria (including semiquantitative cultures).

Urine Culture Typically, only quantitative cultures are used. After introduction of diluted urine to the suitable medium and incubation, the colonies are counted and multiplied by the dilution factor to yield the bacterial count/ml. Bacteriuria is considered significant if it is more than 100,000/ml, but even the presence of 1000 colonies/ml is considered clinically sigrhcant in the presence of symptoms characteristic of UTI. Most physicians are

Specific Health Problems now employing semiquantitative tests using dipsticks or glass slides coated with culture media. Colonies are counted or appearance is compared as soon as 12 to 24 hours later. For recurrent or chronic infection, sensitivity studies are often performed. In more than 95% of UTIs, a single bacterial species is the problem. When mixed bacterial species are grown, the probability of contamination is high.2 Staphylococcus epidermidis, diphtheroids, and lactobacilli are commonly found in the distal urethra but rarely cause UTIs.

THERAPEUTIC CONSIDERATIONS The primary goal in the natural approach to treating infectious cystitis is enhancing normal host protective measures against UTI. Specifically, this refers to enhancing the flow of urine by achieving and maintaining proper hydration, promoting a pH that inhibits the growth of the organism, preventing bacterial adherence to the endothelial cells of the bladder, and enhancing the immune system. In addition, several botanical medicines with antimicrobial activity can be employed.

of the For a complete discussion of the pharmacology, see Chapter 78.

General Measures Increasing Urine Flow Increasing urine flow can be easily achieved by increasing the amount of liquids consumed. Ideally, the liquids should be in the form of pure water, herbal teas, and fresh fruit and vegetable juices diluted with at least an equal amount of water. The patient should be encouraged to drink at least 2 liters of liquids from this group, with at least half of this amount being water. The patient should also be advised to avoid such liquids as soft drinks, concentrated fruit drinks, coffee, and alcoholic beverages.

Cranberry juice (Vaccinium macrocarpon)

Of particular benefit in the treatment of UTIs are cranberries and cranberry juice, which have been shown to be quite effective in several clinical ~tudies.'"'~In one study, 0.5 liter/day of cranberry juice was shown to produce beneficial effects in 73% of the subjects (44 females and 16 males) with active UTIs.13 Furthermore, withdrawal of cranberry juice in the people who benefited Chronic Interstitial Cystitis resulted in recurrence of bladder infection in 61%. Studies have indicated that interstitial cystitis affects Many people believe the action of cranberry juice is 52 to 67 per 100,000 people in the United States? Some due to acidifying the urine and the antibacterial effects investigators believe these numbers are vastly underesof a cranberry component called hippuric acid.16J7 timated due to lack of proper diagnosis. Chronic interstiHowever, these are probably not the major mechanisms tial cystitis, a persistent form of cystitis that is not due to of action. In order to acidify the urine, at least 1 liter of cranberry juice would have to be consumed at one infection, is characterized by symptoms similar to cystisitting."j In addition, the concentration of hippuric acid tis, and patients may also report otherwise undiagnosed chronic pelvic pain. Patients with this condition also in the urine as a result of drinking cranberry juice is tend to have a higher incidence inflammatory bowel insufficient to inhibit ba~teria.'~J'As 0.5 liter/day of cranberry juice has been shown to be effective in the disease, systemic lupus erythematosus, irritable bowel treatment of bladder infection, another mechanism is syndrome, and fibromyalgia.6 In addition to the general measures given later for more likely! cystitis, the focus for interstitial cystitis is on enhancing Some studies have shown that components in cranthe integrity of the interstitium along with the lining berry juice reduce the ability of E. coli to adhere to the of the bladder wall. The "leaky bladder urothelium" lining of the bladder and ~ r e t h r a . ' ~In J ~order for bactetheory postulates that there is a problem with the ria to infect, they must first adhere to the mucosa. glycosaminoglycan layer of the bladder epithelium, By interfering with adherence, cranberry juice greatly which results in increased permeability to potassium reduces the likelihood of infection and helps the into the bladder wall, causing inflammation and ~ a i n . 6 , ~ body fight off infection. This is the most likely explanaEliminating food allergies to reduce inflammation tion of cranberry juice's positive effects in bladder appears to be a valid goal even though the association infections. between food allergies and cystitis is not well estabA large, double-blind, placebo-controlled study evallished. Food allergies have been shown to produce cystiuated the efficacy of 300 ml of cranberry juice in tis in some patients.g10 Repeated ingestion of a food 153 women (average age 78.5) with confirmed bacteriallergen could easily explain the chronic nature of interuria (105/mlurine).20Even this small an amount dramatstitial cystitis. Centella asiuticu appears to address some ically decreased the level of bacteria in the women's other pathologic features of chronic interstitial cystitis. urine and the frequency of recurrence of infection. Interestingly, the researchers used saccharin-sweetened Specifically, centella extracts have been shown to improve the integrity of the connective tissue that juice. Since saccharin is a suspected carcinogen, we composes the interstitium, as well as heal ulcerations strongly recommend avoiding this artificial sweetener.

Cystitis

In one study of seven juices (cranberry, blueberry, grapefruit, guava, mango, orange, and pineapple), only cranberry and blueberry demonstrated inhibitory effeds.19 Blueberry juice is a suitable alternative to cranberry juice in bladder infections. It must be pointed out that most cranberry juices on the market contain one third cranberry juice mixed with water and sugar. Because sugar has such a detrimental effect on the immune system,21-23 use of sweetened cranberry juice cannot be recommended. Fresh cranberry (unsweetened or sweetened with apple or grape juice) or blueberry juice is preferred. Cranberry extracts are also available commercially in pill form. To compare the efficacy and cost of tablets to fresh juice for prevention of UTI, 150 sexually active women aged 21 through 72 years were studied in a randomized controlled trial for 1 year." Tablets were taken twice daily, and juice 250 ml three times daily. Both cranberry juice and cranberry tablets significantly decreased the number of patients experiencing at least 1 symptomatic infection per year (20% and l8%, respectively) compared with placebo (32%).The mean annual cost of cranberry tablets was $624, whereas the juice cost $1400. Furthermore, total antibiotic consumption was less in both treatment groups compared with placebo. Although the cranberry tablets may be more cost effective, it is important to remember that sufficient fluid intake is still important, so ample water should be ingested if tablets are used. Lastly, there is a theoretic concern regarding the use of cranberry juice and kidney stone formation. Because cranberries are considered an oxalate-containing food, the thinking is that this may encourage oxalate-rich kidney stone formation. However, urinary oxalate excretion does not increase after drinking cranberry juice and none of the studies using cranberries have reported increased kidney stone incidence.EAcidify or alkalinize? Although many practitioners believe acidlfylng the urine is the best approach in addressing cystitis, several arguments can be made for alkalinizing the urine. First, it is often difficult to acidify the urine. Many popular methods of attempting to acidlfy the urine, such as ascorbic acid supplementation and the drinking of cranberry juice, have little effect on pH at commonly prescribed doses. The best argument for all
Potassium citrate or sodium citrate, or both, have long been employed in the treatment of lower UTIs. They are often used as a "holding exercise" until the results of a urine culture are available. Some clinical studies support this practice. For example, in one study, women presenting with symptoms of a UTI were given 4 g of sodium citrate every 8 hours for 48 hours.26Of the 64 women evaluated, 80% of the women had relief of symptoms, 12% had deterioration of symptoms, and 91.8% of the women rated the treatment as acceptable. Of the 64 women, 19 were shown to have positive bacterial cultures. There was more variation in response to treatment in the group of women with proven bacterial infection, with those having symptoms of urethral pain (7 of 10) and dysuria (13 of 18) improving more than those with symptoms of frequency (9 of 17) and urgency (6 of 13). These results were similar to a previous study that demonstrated significant symptomatic relief in 80% of the 159 women studied who were aba~teriuric.2~ Because of these positive results, it has been suggested that urine culture could be restricted to those women who fail to respond to alkalinization therapy. Restricting urine cultures to nonresponders would lower health care costs. One more possible advantage to alkalizing rather than acidlfylng the urine exists. Many herbs used to treat UTIs, such as Hydrastis canadensis and Arctostaphylos uva ursi, contain antibacterial components that work most effectively in an alkaline environment.

Enhancing Immune Function The recommendationsgiven in Chapter 57 are appropriate to employ during a bladder or lower urinary tract infection.

Nutrient Supplementation D-Mannose D-Mannose is a simple sugar that acts similarly to cranberry juice in that it helps to prevent the pili of E. co2i and other bacteria from adhering to the bladder wall. In fact, D-mannose is contained in cranberry juice but in lower doses than are available through specific supplementation. Although there are no clinical trials available to support the use of D-mannose powder, a handful of research articles explaining its mechanistic function strongly support its use. One in vitro study evaluated the effect of D-mannose on 73 E. coli strains of epithelial vaginal and buccal cells from women who suffered recurrent UTIs. Of the strains from urinary, vaginal, or anal isolates, 66 (90%) demonstrated adherence to epithelial cells. When applied, D-mannose inhibited completely the adherence of 25 strains (42%) that adhered to vaginal cells and inhibited an additional 11 strains (18%) by at least 50%. Similar results were obtained with buccal cells.

The inhibitory effect of D-mannose was similar regardless of the origin of the strains?* Another study of Sprague Dawley rats given intravesicular injections of D-mannose found sigruficantimprovement in bacteruria in the animals given D-mannose, in a dose-dependent manner.29 Johnathan Wright, MD, recommends an adult dose of 0.5 to 1tsp/three times a day mixed in a little water. It is sweet tasting and has been used successfully in appropriately reduced doses for pediatric UTIs as well. Admittedly, more research is necessary to fully evaluate the optimal usefulness and efficacy of this bacteriostatic therapy.

Botanical Medicines Many herbs have been used through the centuries in the treatment of UTIs (Table 161-5). The following are several that have both folk and scientific support for their use.

Arctostaphylos uva ursi Most research has focused on Arctostaphylos uva ursi's (bearberry or upland cranberry) urinary antiseptic component, arbutin, which typically comprises 6.3% to 9.6% of the leaves.30Arbutin is hydrolyzed to hydroquinone and glucose in the body. Hydroquinone is most effective in an alkaline urine. However, crude plant extracts are more effective medicinally than isolated arbutin.3l A. uva ursi, reported to be especially active against E. coli, also has diuretic proper tie^.^^ The prophylactic effect of a standardized A . uva ursi extract on recurrent cystitis was evaluated in a doubleblind study in 57 women.= At the end of 1 year, 5 of

27 women in the placebo group had a recurrence, while 0 of 30 women receiving A. uva ursi extract had a recurrence. No side effects were reported in either group. These impressive results indicate that regular use of A. uua ursi, like cranberry, may prevent bladder infections. A. uva ursi has also been shown to be helpful in increasing susceptibility of antibiotic-resistantbacteria to antibiotics like beta-lactams. A Japanese group studied the effect of corilagin, a polyphenolic compound from A. uva ursi, when used against the methicillin-resistant Staphylococcus aureus bacterium. Codagin reduced the minimal inhibitory concentration of oxacillin and other beta-lactam antibiotics by 100- to 2000-fold. The effect of corilagin and oxacillin was synergistic and bacteriocidal. Some other antibiotics studied were not enhanced by corilagin. The authors also mentioned that catechins, compound P, and epicatechin gallate from green tea, as well as baicalin from ScutelZaria amoena, may also produce similar effects4 Care must be taken to avoid excessive dosages of A. uva ursi-as little as 15 g (0.5 oz) of the dried leaves have been shown to produce toxicity in susceptible individuals. Toxic signs include31: Ringing in the ears Nausea vomiting Sense of suffocation Shortness of breath Convulsions Delirium Collapse

Allium sativum Garlic has been shown to have antimicrobial activity against many disease-causing organisms including those associated with urinary tract Bacteria species

Agent

Abacterial

Citrates

Enterobacter aerogenes Enterococci Escherichia coli Hydrastis canadensis

Allium sativum

Hydrastis canadensis

Uva ursi Klebsiella pneumonia

Allium sativum

Hydrastis canadensis Proteus miribili

Allium sativum

Hydrastis canadensis Pseudomonas aeruginosa

Hydrastis canadensis

Staphylocuccussaprophyticus

Allium sativum

Hydrastis canadensis

E . coli Proteus sp. Klebsiella pneumonia Staphylococcus sp. Streptococcus sp.

Goldenseal is one of the most effective of the herbal antimicrobial agents. Its long history of use by herbalists and naturopathic physicians for the treatment of infections is well documented in the scientific literature. Of particular importance here is its efficacy against E. coli, Proteus sp., Klebsiella sp., Staphylococcus sp., Enterobacter aerogenes (quires large dosage),and Pseudornonas sp.%J9Berberine, like hydroquinone from A. uva ursi, works better in an alkaline urine (seeChapter 100 for a full discussion).

Cystitis

Acupuncture Using a distinctive but complementarynatural approach, traditional Chinese medicine carefully notes the specific symptoms of each individual with cystitis and treats imbalances in energy according to that person's specific clinical picture. Patients employing acupuncture have reported improved pressure during urination and more complete bladder emptyrig, more energy, reduced stress level, and even better sleep."OIn the Chinese model, many UTI profiles are related to damp heat either in the bladder or in the liver and gallbladder channels. Some patients reveal kidney qi, yang or kidney and spleen deficient signs.4l One Norwegian study of 67 adult women with a history of recurrent lower UTI were randomized into three groups in whi& one received acupuncture treatment, one had sham acupuncture, and one was given no treatment. A statistically sigruficant 85% in the acupuncture group was free of cystitis during the &month observational period, as compared with 58% in the sham group and only 36% in the control group." Although more clinical studies are necessary to thoroughly elucidate the efficacy of acupuncture, this safe treatment method seems to be a reliable choice as a primary or adjunctive treatment option. Some practitioners also combine acupuncture with the Chinese herbal tradition, which also can be powerful for long-term chronic conditions.

THERAPEUTIC APPROACH Although most cases of cystitis are relatively benign, it is extremely important that the patient be properly diagnosed, treated, and monitored. Proper monitoring includes having the patient n o w the physician of any change in his or her condition. If the on@ culture was positive, it is appropriate to follow up with another culture 7 to 14 days after treatment was started. Citrates can be used to ameliorate symptoms. Due to the possibility of a kidney infection, patients should n o w their physiaan if there is fever, low back pain, nausea, or vomiting. Pyelonephritisrequires immediate antibiotic therapy and sometimes hospitalization. Although the occasional acute bladder infection is easily treated, treating women with chronic cystitis can be a sigruficant challenge. Long-term success requires determining the underlying cause: structural abnormalities, excessive sugar consumption, food allergies, nutritional deficiencies, chronic vaginitis, local foci of infection (e.g., prostate, kidneys), current or childhood sexual abuse. All potential causes must be evaluated and resolved. Although the causative agents for cystitis have not changed over time, bacterial resistance to antibiotics is fast becoming an issu-ven one-time simple acute cystitis cases have become recalatrant.43,4Resistance to common antibiotics, including trimethoprim-sulfamethoxazole,

beta-lactam drugs, and fluoroquinolone, is emerging at an alarming rate. In thismilieu, it makes sense to use natural therapeutics that involve fluid intake to protect the urinary tract; immune support; plus nutrient and botanical medicines as first-line therapy in nonpyelonephriticcases and as adjunctive therapy to increase the efficacy of antibiotic treatment if necessary.

General Measures Drink large amounts of fluids (at least 2 liters/day) including at least 0.5 liters of unsweetened cranberry or 0.25 liters of blueberry juice per day. Urinate after intercourse. Women who develop bladder infections after intercourse should wash their labia and urethra with a strong tea of H. canadensis (2 tsp/cup) both before and after. If this is inadequate, a dilute solution of povidone-iodine usually proves effective.

Diet UTIs are mostly ascending infections caused by bacteria derived from stools. Because alterations in bacterial composition of stools depend on the diet, it is reasonable that the risk for infection will change with dietary modificat i o n ~ .Patients ~ , ~ should avoid all simple sugars, refined carbohydrates, full-strength fruit juice (diluted fruit juice is acceptable), and food allergens. Yogurt products with live probiotics are also recommended. Patients should restrict calories and eat liberal amounts of garlic and onions.

Nutritional Supplements D-Mannose powder: 0.75 tsp three times/day Vitamin C: 500 mg every 2 hours Bioflavonoids: 1000 mg/day Vitamin A: 25,000 IU/day Beta-carotene:200,000 IU/day Zinc: 30 mg/day Choline: 1000 mg/day

Botanical Medicines Dosages are three-times-daily quantities: A. uva ursi Dried leaves or as a tea: 1.5 to 4 g (1to 2 tsp) Freeze-dried leaves: 500 to 1000 mg Tincture (1:5): 4 to 6 ml (1to 1.5 tsp) Fluid extract (1:l):2 to 4 ml(0.5 to 1 tsp) Powdered solid extract (10%arbutin):250 to 500 mg H . canadensis Dried root (or as tea): 1 to 2 g Freeze-dried root: 500 to 1000 mg Tincture (1:5): 4 to 6 ml (1to 1.5 tsp) Fluid extract (1:l):2 to 4 ml(0.5 to 1 tsp) Powdered solid extract (8Yo alkaloid):250 to 500 mg Sandalwood oil: 1to 2 drops

Specific Health Problems

1. Branch WT. Office practice of medicine. Philadelphia: Saunders, 1982679685,488-504. 2. Rubin RH. Infections of the urinary tract. In Dale DC,Federman D, eds. Scientific American Medicine. New York Scientific American, 1997. 3.Ronald A. The etiology of urinary tract infection: traditional and emerging pathogens. Am J Med 2002;113(suppllA):14S19S. 4. Reilly BM. Practical strategies in outpatient medicine. Philadelphia: Saunders, 19M277. 5. Bass BF HI,JarvisJA, Mitchell CK. Urinary tract infections. Primary Care 2003;30:41-61. 6. Nickel JC. Interstitial cystitis a chronic pelvic pain syndrome Med Clin North Am 2004;88:467481. 7. Parsons CL, Zupkas P, Parsons JK. Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome. Urology 2001;57428-432 discussion 432433. &Marshall FF, Middleton AW Jr. Eosinophilic cystitis. J Urol 1974;112335-337. 9. Goldstein M. Eosinophilic cystitis. J Urol1972;106:854-857. 10. Sanchez Palacios A, Quintero de Juana A, Martinez Sagarra J, et al. Eosinophilic food-induced cystitis. Allergol Immunopathol 1984; 12463-469. 11. Fam A. Use of titrated extract of Centella usiaticu (TECA)in bilharzial bladder lesions. Int Surg 1973;58:451452. 12. Etrebi A, Ibrahim A, Zaki K. Treatment of bladder ulcer with asiaticoside. J Egypt Med Assoc 1975;58:324-327. 13. Papas PN, Brusch CA, Ceresia GC. Cranberry juice in the treatment of urinary tract infections. Southwest Med 1966;4717-20. 14. Sternlieb P. Cranberry juice in renal disease. N Engl J Med 1963; 26&57. 15. Moen DV. Observations on the effectiveness of cranberry juice in Urinary infections. Wis Med J 1962;61:282-283. 16. Kahn HD, Panariello VA, Saeli J, et al. Effect of cranberry juice on urine. J Am Diet Assoc 196721251-254. 17. Bodel PT, Cotran R, Kass EH. Cranberry juice and the antibacterial action of hippuric acid. J Lab Clin Med 1959;54:881-888. 18.Sobota AE. Inhibition of bacterial adherence by cranberry juice. Potential use for the treatment of urinary tract infections. J Urol19&1; 131:1013-1016. 19. Ofek I, Goldhar J, Zafrini D, et al. Anti-Escherichia activity of cranberry and blueberry juices. N Engl J Med 19919241599. 20. Avom J, Monane M, Gurwitz JH, et al. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 1994;271:751-754. 21. Sanchez A, Reser J, Lau H, et al. Role of sugars in human neutrophilic phagocytosis. Am J Clin Nutr 1973;26:1180-1184. 22. Ringsdorf W, Cheraskin E, Ramsay R. Sucrose, neutrophil phagocytosis and resistance to disease. Dent Surv 1976;52:46-48. 23. Bernstein J, Alpert S, Nauss K, et al. Depression of lymphocyte transformation following oral glucose ingestion. Am J Clin Nutr 1977;30:613. 24. Stothers L. Arandomized trial to evaluateeffectiveness and cost effectiveness of naturopathic aanberry products as prophylaxis against urinary tract infedion in women. Can J Uro12002;9:1558-1562. 2.5. Brinkley L, McCuire J, Gregory J, et al. Bioavailability of oxalate in foods. Urology 1981;17534-538. 26. Munday PE, Savage S. Cymalon in the management of urinary tract symptoms. Genitourin Med 1990;66:461.

27. Spooner JB. Alkalinization in the management of cystitis. J Int Med Res 1984;1230-34. 28. Schaeffer AJ, Chmiel JS, Duncan JL, et al. Mannose-sensitive adherence of Escherichia coli to epithelial cells from women with recurrent urinary tract infections. J Urol1984;131:906-910. 29. Michaels EK, Chmiel JS, Plotkin BJ, et al. Effect of Dmannose and Dglucose on Escherichia coli bacteriuria in rats. Urol Res 1983;ll: 97-102. 30. Parejo I, Viladomat F, Bastida J, et al. A single extraction step in the quantitative analysis of arbutin in bearberry CArctostaphylos urn-ursi) leaves by high-performance liquid chromatography. Phytochem Anal 2001;12:336-339. 31. Merck Index, ed 10. Rahway, NJ: Merck, 1983:112-113,699. 32. Frohne V. [The urinary disinfectanteffect of extract from leaves uva ursi.] Planta Medica 1970;18:1-25. 33. Larsson B, Jonasson A, Fianu S. Prophylactic effect of UVA-E in women with recurrent cystitis.A preliminary report. Curr Ther Res 1993;53:441-443. 34. Shimizu M, Shiota S, Mizushima T, et al. Marked potentiation of activity of beta-lactams against methicillin-resistant Staphylococcus aureus by corilagin. Antimicrob Agents Chemother 2001;45: 3198-3201. 35. Adetumbi MA, Lau BH. Allium sativum (garlic)-a natural antibiotic. Med Hypotheses 1983;12:227-237. 36. Sharma VD, Sethi MS, Kumar V, et al. Antibacterial property of Allium satiourn Linn. in vivo & in vitro studies. Indian J Exp Biol 1977;15:466-468. 37. Elnima EI, Ahmed SA, Mekkawi A, Mossa JS. The antimicrobial activity of garlic and onion extracts. Pharmazie 1983;38747-748. 38. Amin AH, Subbaiah TV, Abbasi KM. Berberine sulfate: antimicrobial activity, bioassay, and mode of action. Can J Miaobiol 1969; 15:1067-1076. 39. Johnson CC, Johnson G, Poe CF. Toxicity of alkaloids to certain bacteria. 11. Berberine, physostigmine, and sanguinarine. Acta Pharmacol Toxic01 (Copenh) 1952;8:71-78. 40.Alraek T, Baerheim A. 'An empty and happy feeling in the bladder . . .': health changes experienced by women after acupuncture for recurrent cystitis. ComplementTher Med 2001;9:219-223. 41.Alraek T, Aune A, Baerheim A. Traditional Chinese medicine syndromes in women with frequently recurring cystitis: frequencies of syndromes and symptoms. Complement Ther Med 2000; 8260-265. 42. Aune A, Alraek T, LMua H. Acupuncture in the prophylaxis of recurrent lower urinary tract infection in adult women. Scand J Prim Health Care 1998;1637-39. 43. Gupta K Emerging antibiotic resistance in urinary tract pathogens. Infect Dis Clin North Am 2003;17243-259. 44. Manges AR, Johnson JR, Foxman B, et al. Widespread distribution of urinary tract infections caused by a multidrugresistant Escherichia coli clonal group. N Engl J Med 2001;345 1007-1013. 45.Kontiokari T, Nuutinen M, Uhari M. Dietary factors affecting susceptibility to urinary tract infection. Pediatr Nephrol 2004; 19:378-383. 46.Kontiokari T, Laitinen J, Jarvi L, et al. Dietary factors protecting women from urinary tract infection. Am J Clin Nutr 2003;77: 6oO-604.

Dermatitis Herpetiformis Michael T. Murray. NI) Joseph E. Pizzornojr, ND CHAPTER C O N T E N T S Diagnostic Summary

1605

Food Allergy 1606 Para-aminobenzoic Acid

1606

General Considerations 1605 Therapeutic Considerations 1605 Gluten 1605

DIAGNOSTIC SUMMARY Pruritic, blistering rash usualIy on the extensor surfaces Occurs most commonly in middle-aged Caucasian males, although it may be present in individuals of any age IgA deposits in the papillary skin; confirmed by immunofluorescence Asymptomatic "celiac" disease (gluten-sensitive enteropathy) in 75%to 90% of patients

GENERAL CONSIDERATIONS Dermatitis herpetiformis (DH) is a dermatologic condition that is almost certainly due to a gastrointestinal immunologic disorder. Jejunal biopsy in DH patients shows villous atrophy characteristic of celiac disease, although gastrointestinal symptoms are rare.1-3DH has been referred to as "celiac disease of the skin."4Just as in celiac disease, a gluten-free diet is most often all that is required to resolve the lesions. Absorption studies (see Chapter 23) can be used to assess the degree of enteropathy. The average age of onset of the rash is 7.2 years, with a predilection for the elbows, knees, and buttocks. Skin biopsy shows granular IgA deposits. The characteristic skin lesions found in patients with DH are extremely itchy grouped vesicles most frequently located on extensor surfaces.

THERAPEUTIC CONSIDERATIONS Gluten The most important factor in the treatment of patients with DH is the elimination of all sources of gluten.

Therapeutic Approach Diet 1606 Supplement 1606

1606

Frazer 's criteria for the diagnosis of gluten-sensitive enteropathy (improvement on a gluten-free diet and relapse after reintroduction) have been used in many studies and have shown conclusively that the rash and villous atrophy of DH are largely gluten Gluten elimination results in improvement in virtually all patients, including the elimination of the reticulin and gluten antibodies found in patients with DH."* Further study of the wheat connection has shown that the gliadin polypeptide of gluten is most likely the key antigen. Indirect immunofluorescence shows antibodies to gliadin in the sera of 45%of patients with DH, and the titer and correlation increase with increasing severity of the disease; 81% of patients with severe jejunal abnormalities show antibodies to gliadh9 Despite the published benefits of a gluten-free diet in the treatment of DH for more than 30 years now, it is still often omitted from conventional dermatology or medical textbooks. The advantage of a gluten-free diet over drugs like dapsone (the most widely prescribed drug for DH) is quite obvious, as this drug is often associated with severe side effects while on the glutenfree diet: Most patients (more than 65%) experience complete resolution, and the rest are substantially improved. There is complete resolution of the enteropathy associated with DH. Harsh medications can be eliminated or substantially reduced. Most patients experience an improved sense of wellbeing. 1605

Also of interest is the fact that those who used a gluten-free diet rather than drugs appear also to be protected against developing lipomas.'O

Food Allergy Although gluten control is critical in the treatment of patients with DH, some patients (about 35%) are not adequately helped. In particular, only half the patients totally eliminate the cutaneous IgA deposits and develop normal jejunal tissue. This is probably due to the presence of other food allergies that, although probably not initiating, developed as a result of the increased leakage of macromolecules across the damaged gastrointestinal membranes. Milk, in particular, has been found to be significant in some patients."J* Using a sensitive enzymelinked immunoassay (ELISA), 75% of DH patients were shown to have serum antibodies reactive against gliadin, bovine milk, or 0valb~mi1-1.'~ These results indicate that other food sensitivitiescan also induce DH. An elemental diet followed by careful food reintroduction usually produces better results than simply a gluten-free diet.I4

the gluten content of their diet.'5 However, because its use is only for symptom control and probably does not result in repair of the villous atrophy, it is not recommended as the treatment of choice but rather as an adjunct in unresponsive cases or to help in particularly severe cases.

THERAPEUTIC APPROACH After all sources of gluten and gliadin have been eliminated (see Appendix 5 for the gluten content of foods), a careful search should be made for other food allergies (for more detail see Chapter 19). Once the allergens are under control, a therapeutic regimen similar to that for atopic dermatitis (see Chapter 151) should be used. Patience is necessary because a response may take several weeks to 6 months.

Diet Use a normal, healthy, unprocessed diet free of all grains and allergic foods.

Para-aminobenzoic Acid

Supplement

Para-aminobenzoic acid (PABA) has been used successfully in the control of DH, even in those not controlling

PABA 5 g/day until remission (maximum of 3 months)

1.leOnard J, Haffenden G, Tucker W, et al. Gluten challenge in

9. Volta U, Cassani F, DeFranchis R, et al. Antibodies to gliadin in adult coeliac disease and dermatitis herpetiformis. Digestion 19&1,30:263-270. 1O.Lewis HM, Renada TL, Garioch JJ, et al. Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis. Br J Derm 1996;135:363-367. 11. Engquist A, Pock-Steen OC. Dermatitisherpetiformis and milk-free diet. Lancet 1971;2438-439. 12.Pock-Steen OC, Niordson AM. Milk sensitivity in dermatitis herpetiformis. Br J Derm 1970;8361%19. 13. Barnes Rh4, Lewis-Jones MS. Isotype distribution and serial levels of antibodies reactive with dietary protein antigens in dermatitis herpetiformis.J Clin Lab Immunol1989;30:87-91. 14.Kadunce DP, McMurry MP, Avots-Avotins A, et al. The effect of an elemental diet with and without gluten on disease activity in dermatitis herpetiformis. J Invest Dermatol 199197: 175-182. 15. Zarafonetis CJ, JohnwickEB, Kirkman LW, Curtis AC. Paraaminobenzoic acid in dermatitis herpetiformis. Arch Dermatol Syph 1951;63:115132.

dermatitis herpetiformis. N Engl J Med 1983;308:816-819. 2. Fry L, LeonardJN, Swain F, et al. Long term follow-up of dermatitis herpetiformiswith and without dietary wheat gluten withdrawal. Br J Derm 1982;107:631-640. 3.Savilahti E, Reunala T. Is dermatitis herpetiformis a glutensensitive enteropathy? Int J Dermatol 1990;10:706-708. 4. Reunala T. Dermatitis herpetifomis coeliac disease of the skin. Ann Med 1998;30:416-418. 5. Kumar V, Zane H, Kaul N. Serologic markers of gluten-sensitive enteropathy in bullous diseases. Arch Derm 1992;128:14741478. 6. Frodin T,Gotthard R, Hed J, et al. Gluten-free diet for dermatitis herpetdormis: the long term effect on cutaneous, immunological and jejunal manifestations. Ada Derm Venereol (Stockholm)1981; 61:405-411. 7 . G a r i d JJ, Lewis HM, Sargent SA, et al. 25 years' experience of a gluten-free diet in the treatment of dermatitis herpetiformis. Br J Dermatol1994;131:541-545. 8. Fry L. Dermatitis h e r p e t i f o h problems, progress and prospects. Eur J Dermatol2002;12:523-531.

Diabetes Mellitus Michael 7’. Murray, ND Michael R. Lvon, BSc, M D CHAPTER CONTENTS Diagnostic Summary

1607

General Considerations 1607 Classification 1608 Prediabetes and Syndrome X 1609 Diagnosing Diabetes 1609 Glycosylated Hemoglobin 1609 Risk Factors for Type I Diabetes 1610 Environmental and Dietary Risk Factors 1610 Early Treatment and Possible Reversal of Type I Diabetes 1612 Niacinamide 1612 Epicatechin 1613 Risk Factors in Type II Diabetes 1613 Genetics of Type II Diabetes and Obesity 1614 Diet, Exercise, Lifestyle, and Diabetes Risk 1614 Lifestyle versus Drugs to Prevent Type II Diabetes 1617 Clinical Monitoring of Diabetes 1617 Urine Glucose Monitoring 1617 Urine Ketone Testing 1617 Self-Monitoring of Blood Glucose 1618

Type I Diabetes and Self-Monitoring of Blood Glucose 1618 Type II Diabetes and Self-Monitoring of Blood Glucose 1619 C-Peptide Determination 1619 Physician Monitoring 1620

The Complicationsof Diabetes 1620 Acute Complications 1621 Chronic Complications 1622 Contributors to the Long-term Complications of Diabetes 1623 Therapeutic Considerations 1624 Diet Therapy in Managing Diabetes 1624 Psychologic Support in Diabetes 1625 Exercise and Diabetes 1625 Nutritional Supplements 1626 Recommendations for Specific Chronic Complications 1633 Therapeutic Approach 1636 Supplementationfor Type I Diabetes 1636 Supplementation for Type II Diabetes 1637 Additional Supplements for the Prevention and Treatment of Diabetic Complications 1637

DIAGNOSTIC SUMMARY Elevated blood glucose is determined by the following: Fasting (overnight):venous plasma glucose concentration greater than or equal to 126 mg/dl on at least two separate occasions Following ingestion of 75 g of glucose: venous plasma glucose concentration greater than or equal to 200 mg/dl at 2 hours postingestion and at least one other sample during the 2-hour test A random blood glucose level of 200 mg/dl or more, plus the presence of suggestive symptoms Classic symptoms of polyuria, polydipsia, and polyphagia

Fatigue, blurred vision, poor wound healing, periodontal disease, and frequent infections are often presenting symptoms as well in type I1 diabetes.

GENERAL CONSIDERATIONS Diabetes is a chronic disorder of carbohydrate, fat, and protein metabolism characterized by fasting elevations of blood glucose levels and a greatly increased risk of cardiovascular disease, renal disease, and neuropathy. Diabetes can occur when the pancreas does not secrete enough insulin or if the cells of the body become resistant 1607

Specific Health Problems

to insulin;hence the blood glucose cannot get into the cells, which then leads to serious complications. The classic symptomsof diabetes are frequent urination and excessivethirst and appetite. Because these symptoms are not serious, many people with diabetes do not seek medical care. In fact, of the more than 18.2 million Americans with diabetes, more than one third do not even h o w they have diabetes or ever consult a physician (Box 163-1).

Classification Diabetes is divided into two major categories: type I and type II. Type I, or insulin-dependent diabetes mellitus (IDDM), occurs most often in children and adolescents. For this reason it is often referred to as juvenile-onset diabetes. Type I diabetes is associated with complete destruction of the beta cells of the pancreas that manufacture the hormone insulin. Individuals with type I diabetes will require lifelong insulin for the control of blood glucose levels. The type I diabetic must learn how to manage blood glucose levels on a day-by-day basis, m ginsulin types and dosages as necessary, according to the results of regular blood glucose testing. About 5% to 10% of all diabetics are type I. Type I diabetes is the result of injury to the insulinproducing beta cells coupled with some defect in tissue regeneration capacity. What ultimately destroys the beta

Cardiovascular diseast+Adults with diabetes have death rates from cardiovascular disease about 2-4 times higher than adults without diabetes. Hypertension-About 75% of adults with diabetes have high blood pressure. Retinopathy-Diabetes is the leading cause of blindness among adults. Renal disease-Diabetes is the leading reason for dialysis treatment, accounting for 43% of new cases. Neuropathy-About 60%-70% of people with diabetes have mild to severe forms of nervous system damage. Severe forms of diabetic nerve disease are a major contributing cause of lower-extremity amputations. Amputations-More than 60% of lower-limb amputations in the United States occur among people with diabetes. Periodontal disease-Almost one third of people with diabetes have severe periodontal (gum) disease. Pain-Many diabetics fall victim to chronic pain due to conditions such as arthritis, neuropathy, circulatory insufficiency, or muscle pain (fibromyalgia). Depressio-This is a common accompaniment of diabetes. Clinical depression can often begin to occur even years before diabetes is fully evident. It is difficult to treat in poorly controlled diabetics. Autoimmune disorders-Thyroid disease, inflammatory arthritis, and other diseases of the immune system commonly add to the suffering of diabetes.

cells is the immune system. Type I diabetes appears to have an autoimmune component at its origin, as antibodies for beta cells are present in 75% of all cases of type I diabetes compared with 0.5% to 2%of people without the disease. It is probable that the antibodies to the beta cells develop in response to cell destruction due to other mechanisms (e.g., chemical or free radical damage, viral infection, food allergy). It appears that normal individuals either do not develop as severe an antibody reaction or are better able to repair the damage if it occurs. Type II or non-IDDM (NIDDM) usually has an onset after 40 years of age and is often referred to as adultonset diabetes. It is generally thought that up to 90% of all diabetics are type II. However, it is now thought that about 15% of the adults diagnosed with type I1 diabetes actually have type I. In type 11 diabetes, insulin levels are typically elevated, indicating a loss of sensitivity to insulin by the cells of the body. Later, as type II diabetes progresses, insulin levels can drop and insulin deficiency can magrufy further the effects of insulin resistance. Obesity is a major contributing factor to this loss of insulin sensitivity. Approximately 90% of individuals categorized as having type I1 diabetes are obese. Achieving ideal body weight in these patients is associated with restoration of normal blood glucose levels in many cases. Even if type I1 diabetes has progressed to the point where insulin deficiency is present, weight loss virtually always results in sigruficant improvements in blood glucose control and dramatic reductions in other health risks such as cardiovascular disease (Table 163-1). Other types of diabetes include secondary diabetesa form of diabetes that is secondary to certain conditions and syndromes such as pancreatic disease, hormone disturbances, and drugs-and gestational diabetes-a form of diabetes that occurs during pregnancy. Gestational diabetes affects about 4% of all pregnant women-about

and type II diabetes Features

TvDe I

TvDe 11

Age at onset

Usually younger than 40 yr

Usually older than 40 yr

Proportion of all diabetics


>90%

Family history

Uncommon

Common

Appearance of symptoms

Rapid

Slow

Obesity at onset

Uncommon

Common

Insulin levels

Decreased

Normal-high initially, decreased after several yr

Insulin resistance

Occasional

Often

Treatment with insulin

Always

Usually not required

Diabetes Mellitus 135,000 cases in the United States each year. Gestational diabetes is a form of glucose intolerance that is diagnosed in some women during pregnancy. Gestational diabetes occurs more frequently among African Americans, Hispanic/Latino Americans, and American Indians. It is also more common among obese women and women with a family history of diabetes. After pregnancy, 5% to 10% of women with gestational diabetes are found to have type I1 diabetes. Women who have had gestational diabetes have a 20% to 50% chance of developing diabetes in the next 5 to 10 years.

Prediabetes and Syndrome X Prediabetes (also called “impaired glucose tolerance”) is a condition that occurs when a person’s blood glucose levels are higher than normal but not high enough for a diagnosis of type I1 diabetes. There are almost as many people in the United States with impaired glucose tolerance (about 16 million) as there are diabetics. Research increasingly indicates that impaired glucose tolerance, even if diabetes never fully manifests, is accompanied by serious health risks and should be treated carefully. Many people with impaired glucose tolerance will go on to develop full-blown type I1 diabetes. Most important, it has become clear from research that impaired glucose tolerance is usually reversible and, in most cases, diabetes can be completely avoided. In addition, impaired glucose tolerance is accompanied by many of the abnormalities of cholesterol, blood pressure, inflammation, and blood clotting that is typical of type 11diabetes-perhaps on a lesser scale but still associated with a seriousincrease in the risk of cardiovascular disease, stroke, and other health catastrophes. It is certainly not wise to ignore or minimize the seriousness of impaired glucose tolerance. Syndrome X has been introduced to describe a cluster of abnormalities that owe their existence largely to a high intake of refined carbohydrates, especially in those who are genetically predisposed. The features of syndrome X usually include mild to moderately impaired glucose tolerance, elevated insulin levels due to insulin resistance, high blood cholesterol and triglyceride levels, high blood pressure, and upper body obesity (around the waist more than around the thighs). The underlying metabolic factor in syndrome X is elevated insulin levels, which result from high intake of refined carbohydrates coupled with insulin resistance (cells that respond poorly to the effects of insulin). Other terms to describe this syndrome include ”the metabolic cardiovascular risk syndrome (MCVS),””metabolic syndrome,” “Reaven syndrome,’’ “insulin resistance syndrome,” and atherothrombogenic syndrome.’’ Although there is a push to abandon the term “syndrome X,” it nonetheless persists and has, increasingly, become the most accepted term. Prediabetes, hypoglycemia, increased insulin secretion, syndrome X, as well as type IT diabetes can be

viewed as different facets of the same disease having the same underlying dietary, lifestyle, and genetic causes. The human body was simply not designed to handle the amount of refined sugar, salt, saturated fats, and other harmful food compounds that many people in the United States and other Western countries consume, especially in those who live a sedentary lifestyle. The result is that a metabolic syndrome has emerged-elevated insulin levels, obesity, elevated blood cholesterol and triglycerides, and high blood pressure.

DIAGNOSING DIABETES The classic symptoms of diabetes are frequent urination and excessive thirst and appetite. In type I diabetes the symptoms are often quite apparent, but in the type 11 diabetic patient, because the symptoms are generally milder, they may go unnoticed. For that reason and others, many people with type I1 diabetes do not even know they have the disease. Fatigue, blurred vision, poor wound healing, periodontal disease, and frequent infections are often presenting symptoms as well in type 11 diabetes. The standard method for diagnosing diabetes involves the measurement of blood glucose levels. The initial measurement is generally a fasting blood glucose level taken after avoiding food for at least 10 hours but not more than 16. The normal reading is between 70 and 99 mg/dl. If a person has a fasting blood glucose measurement greater than 126 mg/dl (7 mmol/L) on two separate occasions, the diagnosis is diabetes. When a person has a fasting glucose equal to or greater than 110 and less than 126 mg/dl, he or she has impaired glucose tolerance. A postprandial and a random glucose determination are also quite helpful in diagnosing diabetes. A postprandial measurement is usually made 2 hours after a meal, while a random measurement is one that is made anytime during the day without regard for the time of the last meal. Any reading greater than 200 mg/dl (11 mmol/L) is considered indicative of diabetes. The “gold standard” in diagnosing diabetes, however, remains the oral glucose tolerance test (GTT’). It is not the gold standard because it is the most accurate or convenient test but rather because of its longstanding use. In fact, according to some studies the GTT is SiSIuficantly less reliable than fasting blood glucose, especially if combined with a glycosylated hemoglobin level (or hemoglobin AIC [HgbA,C], as discussed later)’t2(Table 163-2).

GIycosylated Hemoglobin A valuable laboratory test for evaluating blood glucose levels is measuring glycosylated HgbAIC. Proteins that

Specific Health Problems

I

Glucose tolerance test response criteria

Type

Criteria

Normal

No elevation > 160 mg/dl (9 mmoVL);
Flat

No variation more than f 20 mg/dl (1.1 mmoVL) from fasting value

Prediabetic

Blood glucose levels of 140 mudl (7.8 mmoVL) to 180 mg/dl (10 mrnoVL) at the end of second hr

Diabetic

>I80 mg/dl (10 mmoUL) during first hr; 200 mg/dl (11.I mmoVL) or higher at the end of first hr; and 150 mg/dl (8.3 mmol/L) or higher at the end of second hr

have glucose molecules attached to them (glycosylated peptides) are elevated severalfold in diabetics. Normally about 5% to 7%of hemoglobin is combined with glucose. Mild elevations in blood glucose result in an AIC concentration of 8% to 10'3'0, while severe elevations may result in concentrationsup to 20%. Because the average life span of a red blood cell (RBC) is 120days, the AIC assay representstime-averaged values for blood glucose over the preceding 2 to 4 months. It is extremelyvaluable in providing a simple, useful method for assessing treatment effectiveness and patient compliance. AIC determination, along with a fasting blood glucose level, can also be used in some cases to diagnose diabetes: but we do not recommend it as the sole diagnostic criteria. About one third of diabetics diagnosed with the G l T have a normal A1C.4We recommend that an AIC be coupled with a fasting blood glucose level and a 2-hour postprandial glucose level for a more accurate diagnosis. The AIC assay is helpful in determining the relative glucose load on the system, as well as in monitoring therapy.

RISK FACTORS FOR TYPE I DIABETES Type I diabetes is a classic example of a "multifactorial" disease. It is hown that ultimately the insulin-producing cells of the pancreas are destroyed, in most cases by the body's own immune system, but what triggers this destruction can vary from one case to another. Most medical texts, diabetes organizations, and doctors tend to consider type I diabetes primarily as a genetic disorder. Although genetic factors may predispose one to damage to the insulin-producing cells through either impaired defense mechanisms, immune system sensitivity, or some defect in tissue regeneration capacity, genetic factors alone account for only a small percentage of patients developing type I diabetes-perhaps as little

as 5% to 10% of all cases. Dietary and other environmental factors are the chief factors that ultimately determine whether the disease develops. The entire set of genetic factorslinked to type I diabetes has been termed "susceptibility genes," as they modify the risk of diabetes but are neither necessary nor sufficient for disease to d e ~ e l o pRather .~ than acting as the primary cause, the genetic predisposition simply sets the stage for the environmental or dietary factor to initiate the destructive process? The very term predisposition clearly indicates that something else needs to occur: less than 10% of those with increased genetic susceptibility for type I diabetes actually develop the disease.' In detailed studies, the concordance rate for developing type I diabetes in identical twins was only 23% in one studf and 38% in If one twin develops type I diabetes after age 24 years, then the concordance rates drops all the way down to 6%. These results and others indicate that environmental and dietary factors are much more important than a genetic predisposition in most cases.l0 Additional evidence supporting the need to focus on dietary and environmental triggers follows: There has been a threefold to tenfold increase in the number of people with type I diabetes throughout the world over the past 40 years. Such a rise simply cannot be explained by an increased number of people genetically predisposed to type I diabetes. Changes to the human genetic code across large populations take more than one generation." The rate of type I diabetes can increase dramatically when children in areas where type I diabetes is relatively rare move to developed countries.12For example, the rate of type I diabetes increased by nearly fourfold in one 10-year period in children of Asian origin moving to Great Britain, and the rate increased more than sevenfold in Polynesians migrating to New Zealand.13J4Genetic factors cannot explain such a rapid change.

Environmental and Dietary Risk Factors Accumulating data indicate that abnormalities of the gut immune system may play a fundamental role in the development of the immune attack on beta cells and the subsequent development of type I diabetes.15The intestinal immune system serves a vital role in processing the many food and microbial antigens to protect the body from infection or allergy. What appears to happen in the development of some cases of type I diabetes is the development of antibodies by the gastrointestinal immune system that ultimately attack the beta cells. It is interesting to consider that an underlying factor that may contribute to type I diabetes is poor protein digestion.

Diabetes Mellitus In animal models, diet can m o d e the development of autoimmune diabetes. Specifically, diets containing partially digested proteins produce a lower rate of autoimmune diabetes than diet containing whole proteins. Whole proteins are more likely to result in the formation of antibodies against them. Next, some of these proteins cross-react with antigens on or within the beta cells of the pancreas. In humans, two proteins that have had the highest degree of incrimination are those found in milk (bovine serum albumin, as well as bovine insulin)and wheat (gluten).For example, dietary bovine insulin differs from human insulin by only three amino acids. If a person develops antibodies to bovine insulin, there is a good chance that these antibodies will also attack their own insulin. In addition to causing antibody-mediated destruction of the beta cells, bovine insulin is able to activate T cells in those predisposed to diabetes in a manner that can also lead to beta cell destruction by direct attack by T-killer cells. Strong evidence implicates dietary factors like cow's milk and gluten as important triggers of the autoimmune process that lead to type I diabetes. In contrast, breastfeeding has been identified as an important factor in establishing proper intestinal immune function and reducing type I diabetes risk. It is well known that breastfeeding confers a reduction in the risk of food allergies, as well as better protection against both bacterial and viral intestinal infections. In case-controlled studies, patients with type I diabetes were more likely to have been breastfed for less than 3 months and to have been exposed to cow's milk or solid foods before 4 months of age. A critical review and analysis of all relevant citations in the medical literature indicates that early cow's milk exposure may increase the risk by about 1.5 times.143 In addition, although the risk of diabetes associated with exposure to cow's milk was first thought to relate only to intake during infancy, additional studies showed that ingestion at any age may increase the risk of type I diabetes. Although the focus has been on cow's milk proteins, other food proteins may be just as problematic." In particular, there is considerable evidence that sensitivity to gluten-the major protein component of wheat, rye, and barley-may also play a role. Gluten sensitivity produces celiac disease, another autoimmune disorder. This disease is characterized by diarrhea and nutrient malabsorption and is associated with damaged small intestine structure. All of this is caused by the immune system's abnormal response to gluten. Celiac disease, like type I diabetes, is associated with intestinal immune function abnormalities.And, like diabetes, breastfeeding appears to have a preventive effect while the early introduction of cow's milk is believed to be a major causative factor. The risk of developing type I diabetes is higher in children with celiac disease. Not surprisingly, the highest

level of antibodies to cow's milk proteins are found in people with celiac disease.18

Factors That Set the Stage for Autoimmunity in Type I Diabetes Only a relatively few people develop type I diabetes, even though many are exposed to bovine insulin orally at a young age. This is because the immune system usually develops tolerance to this protein because it is so close to human insulin. Several important factors contribute to developing tolerance to foods that might otherwise lead to autoimmune reactions: the type of gut microflora, the protection offered by breastfeeding, infections of the gastrointestinal tract, and nutritional status. Our review of the scientific literature did not find any studies that examined the status of the intestinal microflora in type I diabetics. Given the growing awareness and the tremendous importance of gut microflora in human health-especially as it relates to the establishment of healthy gut-immune function-this lack of data is shocking.

Enteroviruses and Type I Diabetes Recent population-based studies, as well as experimental evidence, have strengthened the hypothesis that type I diabetes can be the result of viral infection, particularly viral infections of the gastrointestinal tract.19 Gastrointestinal infections due to enteroviruses (e.g., polioviruses, coxsackieviruses, echoviruses) and rotavirus are quite common, especially in children. All of these viruses replicate in the gut and cause stimulation of the intestinal immune system that may activate the insulin-specific immune cells to seek out and destroy beta cells. These viruses and others are also capable of infecting pancreatic beta cells, causing the leukocytes to attack and destroy the beta cells in an attempt to kill the virus. Gastrointestinalvirus infections may also increase the intestinal permeability and enhance the antibody response to dietary bovine insulin as a result of increased absorption of the intact protein. The severe "leaky gut" or increased small intestinal permeability that occurs during and for some time following rotavirus infections (one of the most common causes of acute diarrheal illness in children) exposes the gut-associated immune cells to large quantities of intact protein.

Vitamin D Deficiency Cod liver oil may offer sigruficant protection against developing diabetes because of its high content of vitamin D. The use of cod liver oil became quite popular during the 1890s to treat rickets, a vitamin A deficiency disease characterized by an inability to calcify the bone matrix, resulting in softening of the skull bones, bowing of legs, spinal curvature, and an increased size of

Specific Health Problems

the joints. Beginning in the 1930s, vitamin D was added to milk at a level of 400 IU per quart. As a result, rickets is now uncommon in most developed countries. Emerging evidence indicates that vitamin D supplmentation from cod liver oil and other sources during early childhood can not only prevent rickets but also type I diabetesJO Interestingly, vitamin D fortification may be offsetting some of the ”diabetogenic” effect of the cow’s milk, but the dosage level in milk may not be sufficient, as the level shown to be protective was about 2000 IU, much higher than the amount typically ingested from vitamin Bfortified milk consumption. In the most extensive of studies looking at vitamin D and type I diabetes, all pregnant women in northern Finland who were due to give birth in 1966 were enrolled (more than 12,000 women) and their children were monitored until December 1997.2l Final analysis of 10,366 enrollees demonstrated that children who regularly took vitamin D, primarily from cod liver oil, had an 80%reduced risk of developing type I diabetes, while those who had vitamin deficiency actually had a 300% increased risk of developing the disease. One study found that the use of vitamin D from cod liver oil during pregnancy significantly reduced the frequency of type I diabetes in their children.22Furthermore, studies looking at vitamin D status in the blood of newly diagnosed cases of type I diabetes are much lower in these patients than in healthy controls. Because vitamin D can be produced in our bodies by the action of sunlight on the skin, lack of sun exposure during childhood may also play a role and partially explain the higher type I diabetes rates in Northern countries. This research indicates that ensuring adequate vitamin D supplementation during pregnancy and early childhood may reduce the risk of type I diabetes. Vitamin D is important for normal immune system development. In addition, it is has been shown that vitamin D inhibits some of the autoimmune reactions that target the beta cells.

Omega-3 Fatty Acid Deficiency In addition to the strong case that can be made for vitamin D being a protective factor, an equally strong case can be made on the benefits of the omega-3 fatty acids in cod liver oil and other fish oils. In animal models of type I diabetes, beta cells are destroyed by administering compounds that generate free radicals (e.g., nitrosamines and alloxan).One study found that feeding fish oil to experimental animals before treating them with the drug alloxan prevented the development of chemically induced type I diabetes. The mechanisms responsible for this effect are related to improved cell membrane function leading to enhanced antioxidant status and suppression of the formation of inflammatory compounds known as cytokines.23

Nitrates Clear links between increased levels of nitrate from dietary sources and water with an increased rate for type I diabetes have been established. Nitrates are produced by agricultural m o f f from fertilizers and are in cured or smoked meats such as ham, hot dogs, bacon, and jerky to keep the food from spoiling. Nitrates react within the body to form compounds known as nitrosamines. Nitrates and nitrosamines are known to cause diabetes in animals. Infants and young children are believed to be particularly vulnerable to the harmful effects of nitrate exposure. One of the most alarming features of type I diabetes is that it is becoming much more prevalent with a current growth rate of 3% per year worldwide.1° Some areas are hit particularly hard, such as Finland, Great Britain, Canada, and the United States. Increased nitrate exposure may be a key factor, as the nitrate levels in ground and surface waters of agriculturalregions have increased over the past 40 years due to usage of nitrogen fertilizers. Nitrate contamination occurs in geographic patterns related to the amount of nitrogen contributed by fertilizers, manure, and airborne sources such as automobile and industrial emissions. Nitrate exposure may explain why some geographic pockets have a substantially higher rate of type I diabetes.”p Circumstantial evidence from population-based studies also suggests that a higher dietary intake of nitrate from smoked/cured meats is associated with a sigruficantly higher risk for type I diabetes. These foods severely stress body defense mechanisms and need to be avoided. The habit of feeding children hotdogs, cold cuts, and ham is a good one for all parents to break. Health food stores now carry nitrate-free alternatives to these rather toxic food choices. Also, investing in a highquality water purifier is good insurance against ingesting nitrate-contaminated drinking water.

EARLY TREATMENT AND POSSIBLE REVERSAL OF TYPE I DIABETES Early intervention in type I diabetes designed to affect the autoimmune or oxidative process theoretically may be capable of lengthening the “honeymoon” phase or even completely reversing the process. This goal appears to have two candidates: niacinamide and epicatechin.

Niacinamide Niacinamide, also called nicotinamide, has been shown to prevent some of the immune-mediated destruction of the pancreatic beta cells and may actually help to reverse the pro~ess.*~J~ Observations that niacinamide can prevent the development of type I diabetes in experimental animals led to several pilot clinical trials that initially confirmed these observations and suggested that if given

Diabetes Mellitus

soon enough at the onset of diabetes, niacinamide could help restore beta cells or at least slow down their destruction. In one of the first pilot studies of newly diagnosed type I diabetics, seven patients were given 3 g of niacinamide daily and nine were given a placebo. After 6 months, five patients in the niacinamide group and two in the placebo group were still not taking insulin and had normal blood glucose and hemoglobin AIC. At 12 months, three patients in the niacinamide group but none in the placebo group were in clinical remission.28 The results of this pilot study and others suggested that niacinamide can prevent type I diabetes from progressing in some patients if given soon enough at the onset of diabetes by helping restore beta cells. As of 2004, there had been 12 studies of niacinamide treatment in recent-onset type I diabetes or type I diabetes of less than 5 years’ duration and residual beta-cell mass. Ten of these studies were double-blind, placebo-controlled studies. Out of these 10, 5 studies showed a positive effect compared with placebo in terms of prolonged non-insulin-requiring remission, lower insulin requirements, improved metabolic control, and increased beta-cell function as determined by secretion of a substance known as C-peptide. The main differencesbetween the positive and negative studies in recent-onset type I diabetes were the older age and higher baseline fasting C-peptide in positive s t u d i e ~ . ~ - ~ ~ Although some of the studies have shown positive results, it is important to point out that two large studies designed to evaluate the effectiveness of niacinamide in preventing the development of type I diabetes in highrisk individuals-such as siblings of children who developed type I diabetes or in individuals who already show elevations in antibodies directed against the beta cells-did not show niacinamide to be effective. The first of these studies-the Deutsche Nicotinamide Intervention Study-did not show much of an effect with 1.2 g of niacinamide daily, while results from the larger study, the European Nicotinamide Diabetes Intervention Trial (ENDIT), did not show benefit with dosages as high as 3 g per day?”’ A possible shortcoming of these studies was the choice of a timed-released niacinamide. It is possible that such a formulation did not allow for sufficient peak levels of niacinamide required to block autoimmune mechanisms such as cytokine production.35 In the best-case scenario, niacinamide will likely work for only a few recent-onset type I diabetes patients. Nonetheless, the fact that some patients have had complete reversal of their disease makes its use certainly worth the effort, especially since there is no other reasonable alternative. The dosage recommendation is based on body weight, 25 to 50 mg of niacinamide for every 2.2 lb of body weight or a maximum dosage of 3 g per day in

divided dosages. Niacinamide is generally well tolerated and without side effects. In fact, no side effects have been reported in clinical trials in type I diabetes. It does not cause the flushing of skin characterized by high dosages of niacin. However, because it could possibly harm the liver, a blood test for liver enzymes should be performed every 3 months to rule out liver damage.

Epicatechin The second natural compound that may offer benefit is epicatechin. The line of research on its potential role in recent-onset type I diabetes began with examining the bark from the Malabar kin0 tree (Pterocarpus marsupium). This botanic medicine has a long history of use in India as a treatment for diabetes. Initially, epicatechin extracted from the bark was shown to prevent beta-cell damage in rats. Further research indicated that both epicatechin and a crude alcohol extract of P. marsupium were actually able to assist regeneration of functional pancreatic beta cells in diabetic animals.% Green tea (Camellia sinensis) extract appears to be a better choice than extracts of P. mursupium, as the epicatechin content in a high-quality green tea extract is actually higher than the level found in extracts of F? marsupium. Secondly, green tea extract exerts a broader range of beneficial effects. Another reason is that green tea polyphenols exhibit sigruficant antiviral activity against rotavirus and enterovirus-two viruses suspected of causing type I diabetes3’Lastly, green tea is considerably easier to find commerciallythan P.marsupiurn.Recommended dosages for children younger than age 6 is 50 to 150 mg; for children 6 to 12 years old, 100 to 200 mg; for children older than 12 years old and adults, 150 to 300 mg. The green tea extract should have a polyphenol content of 80% and be decaffeinated.

RISK FACTORS IN TYPE II DIABETES The major risk factor for type I1 diabetes is obesity or, more precisely, excess body fat. Approximately 80% to 90% of individuals with type II diabetes are obese (a body mass index >30). When adipocytes, particularly those around the abdomen, become full of fat, they secrete a number of biologic products (e.g., resistin, leptin, tumor necrosis factor, free fatty acids) that dampen the effect of insulin,impair glucose utilization in skeletal muscle, promote glucose production by the liver, and impair insulin release by pancreatic beta cells. Also important is that as the number and size of adipocytes increase, this leads to a reduction in the seae tion of compounds that promote insulinaction including a novel protein produced by fat cells known as diporzecfin. Adiponedin is not only associated with improved insulin sensitivity, but it also has antiinflammatory activity, lowers triglycerides, and blocks the development of

Specific Health Problems

atherosclerosis (hardening of the arteries). The net effect of all of these actions by fat cells is that they severely stress blood glucose control mechanisms, as well as lead to the development of the major complication of diabetes-atherosclerosis. Because of all of these newly discovered hormones secreted by adipocytes, many experts now consider the adipose tissue a member of the endocrine system (e.g., the pituitary, adrenals, thyr0id).~3~ Measuring blood levels of adiponectin or other hormones secreted by fat cells may turn out to be the most meaningful predictor of the likelihood of developing type 11d i a b e t e ~ . ~ , ~ ~ In the early stages of the increased metabolic stress produced by the various secretionsof adipocytes and the lack of adiponectin, blood glucose levels remain normal despite the insulinresistance because pancreatic beta cells compensate by increasing insulin output. As metabolic stress increases and insulin resistance becomes more signhcant, eventually the pancreas cannot compensate and elevations in blood glucose levels develop. As the disease progresses from insulin resistance to full-blown diabetes, the pancreas starts to "bum out" and produces less insulin. Ultimately, complete failure to output insulinmay ensue (Box 163-2).

Genetics of Type II Diabetes and Obesity In studies of identical twins, the concordance rate was between 70% and 90% for type II diabetes. This high concordance points to a strong genetic relationship. Data from family studies also provide additional support as children with one parent with type 11 diabetes have an increased risk of diabetes in their lifetime; if both parents have the disease, the risk in offspring is nearly M%." However, even with the strongest predisposition, diabetes can be avoided in most cases.

The Case of the Pima Indians The Pima Indians of Arizona have the highest rate of type 11 diabetes and obesity anywhere in the world. Research has demonstrated a strong genetic predisposition, but even with this strong tendency it is extremely clear that the high rate of type II diabetes in thisgroup is clearly related to diet and lifestyle. The Pima Indians living traditionally in Mexico still cultivate corn, beans, and potatoes as their main staples, plus a limited amount of seasonal vegetables and fruits such as zucchini squash, tomatoes, garlic, green pepper, peaches, and apples. The Pimas of Mexico also make heavy use of wild and medicinal plants in their diet. They work hard, have no electricity or running water in their homes, and walk long distances to bring in drinking water or to wash their clothes. They use no modem household devices; consequently, food preparation and household chores require extra effort by the women. In contrast, the Pima Indians of Arizona are largely sedentary and follow the dietary practices of typical Americans. The results are astounding. Although roughly 22% of Arizona Pimas have type 11diabetes and 70% are obese, type 11diabetes is a rarity in the Mexican Pimas and only about 10% could be classified as obese. The average difference in body weight between the Arizona and Mexican Pima men and women was more than 60 lb!& Further evidence that diet and lifestyle appear to be able to overcome even the strongest genetic predisposition are some of the intervention studies in Pima Indians. When placed on a more traditional diet along with physical exercise, blood glucose levels improve dramatically and weight loss occurs. The focus right now by various medical organizations such as the National Institute of Health to deal with the epidemic of diabetes and obesity in the Pima Indians is to educate children on the importance of exercise and dietary choices to reduce diabetes risk.

Other Genetic and Racial Factors Family history of diabetes (i.e., parent or sibling with type II diabetes) Obesity Increasedwaist-to-hip ratio Age-increasing age is associated with increased risk beginning at age 45 years Racdethnicity (e.g., African American, Hispanic American, Native AmericadCanadian, Native Australian or New Zealander, Asian American, Pacific Islander) Previously identified impairedfasting glucose (IFG) or impaired glucose tolerance (IGT) History of gestational diabetes (diabetes during pregnancy) or delivery of baby > 9 Ib Hypertension (blood pressure > 140/90 mmHg) Triglyceride level > 250 mg/dl Low adiponectin levels, elevated fasting insulin levels Polycystic ovary syndrome (consider in any adult woman who is overweight with acne and infertility)

Other racial and ethnic groups besides Pima Indians that have a higher tendency for type I1 diabetes include other Native Americans, African Americans, Hispanic Americans, Asian Americans, Australian Aborigines, and Pacific Islanders. In all of these higher-risk groups it is again important to point out that when they follow the traditional dietary and lifestyle practices of their original culture, the rate of diabetes is extremely low. It appears that these groups are simply sensitive to the "Western diet" and lifestyle.

Diet, Exercise, Lifestyle, and Diabetes Risk Findings from the U.S. government's Third National Health and Nutrition Examination Survey (NHANES 111) make it quite clear that diabetes is a disease of diet and lifestyle. Of individuals with type I1 diabetes,

Diabetes Mellitus ~~

69% did not exercise at all or did not engage in regular exercise; 62% ate fewer than five servings of fruits and vegetables per day; 65% consumed more than 30% of their daily calories from fat and more than 10%of total calories from saturated fat; and 82% were either overweight or obese.44 Insights into the independent role of the modern lifestyle versus diet and obesity in the development of type I1 diabetes can be gleaned from the Old Order Amish. These 30,000 or so individuals, whose ancestors arrived on US.shores in the eighteenth century, maintain religious and cultural beliefs that preclude regular use of modern conveniences such as electrical appliances, telephones, and cars, and they have a physically active lifestyle. By comparison, the 200 million typical Americans living alongside them have, over the past 250 years, willingly adopted advances of modern technology, making life less physically demanding. Although the typical Amish diet and the rate of obesity does not differ from the typical American, the rate of diabetes is considerably less-about 50% lower. Although the percentage of Amish with impaired glucose tolerance (prediabetes) is about the same as in whites in America, apparently not as many Amish go on to develop diabetes. This occurrence suggests that physical activity has a protective effect against type 11 diabetes, independent of obesity or body-fat p e r ~ e n t a g e . 4 ~ ~ ~ Results from other studies corroborate this hypothesis. Lifestyle changes alone are associated with a 58% reduced risk of developing diabetes in people at high risk due to evidence of impaired glucose tolerance based on results from the Diabetes Prevention Program-a large intervention trial of more than 1000 subjects. The two major goals of the program were a minimum of 7% weight loss/weight maintenance and a minimum of 150 &/week of physical activity similar in intensity to brisk ~ a l k i n g . 4 ~

A Diet High in Refined Carbohydrates Dietary carbohydrates play a central role in the cause, prevention, and treatment of type 11 diabetes. In an effort to quahfy carbohydrate sources as acceptable or not, two indices have been developed: the glycmic index (GI) and glycmic load (GL).The GI is a numerical value that expresses the rise of blood glucose after eating a particular food. The standard value of 100 is based on the rise seen with the ingestion of glucose. The GI ranges from about 20 for fructose and whole barley to about 98 for a baked potato. The insulin response to carbohydrate-containing foods is similar to the rise in blood sugar. The GI is often used as a guideline for dietary recommendations for people with either diabetes or hypoglycemia. In addition, eating foods with a lower GI is associated with a reduced risk for obesity and diabetes.@*49

One of the shortcomings of the GI is that it only tells us about the quality of the carbohydrates, not the quantity. Obviously, quantity matters too, but the measurement of the GI of a food is not related to portion size. That is where the GL comes into play. The GL takes the GI into account but provides much more accurate information than the GI alone. The GL is calculated by multiplying the amount of carbohydrate in a serving of food multiplied by that food's GI (as compared with glucose), then dividing it by 100. The higher the GL, the greater the stress on insulin.In Appendix 6, we provide the GI and GL for many common foods. Research studies are just starting to use the GL as a more sensitive marker for the role of diet in chronic diseases like diabetes and heart disease. The preliminary results are showing an even stronger link in predicting diabetes than the one shown for the GI.@Researchers are also showing that a high GL diet is also associated with an increased risk for heart disease. For example, when researchers from the Nurses Health Study used GL measures to assess the impact of carbohydrate consumption on women, they found that high-GL diets (and, by extension, high GI foods and greater total carbohydrate intake) correlated with even more significantly greater risk for heart disease than the GI because of lower levels of protective high-density lipoprotein (HDL) cholesterol and higher triglyceride levels.50Increased risk for diabetes and heart disease started, on average, at a daily GL of 161. Therefore we recommend using the information in Appendix 5 to help determine how to prevent the total daily GL from exceeding 150. Keep in mind the GL is based on the stated serving size; the larger the serving size, the greater the GL.

The Importance of Dietary Fiber in Modifying Glycemic IndedGlycemic Load Population studies, as well as clinical and experimental data, show diabetes to be one of the diseases most clearly related to inadequate dietary fiber intake. Different types of fibers possess different actions. The type of fiber that exerts the most beneficial effects on blood sugar control is the water-soluble form. Included in this class are hemicelluloses, mucilages, gums, and pectin substances. Foods that have these sorts of fibers or are combined with supplements containing these type of fibers typically have a lower GI. This is because these types of fibers are capable of slowing'down the digestion and absorption of carbohydrates, thereby preventing rapid rises in blood sugar. These types of fibers are also associated with increasing the sensitivity of tissues to insulin and improving the uptake of glucose by the muscles, liver, and other tissues, thereby preventing a sustained elevation of blood sugar?lS2 Particularly good sources of water-soluble fiber are legumes, oat bran, nuts, seeds, psyllium seed husks,

pears, apples, and most vegetables. Large amounts of plant foods must be consumed to obtain adequate levels of dietary fiber. Although even the simple change from white flour products to whole grain versions is associated with a reduced risk for type 11 our recommendation is to consume at least 35 g of fiber a day from various food sources, especially vegetables. Fiber supplements can also be taken to achieve greater effects in lowering the GI.

and polyunsaturated fats that improve insulinsensitivity, nuts are also rich in fiber and magnesium and have a low GI. Higher intakes of fiber and magnesium and foods with a low GI have been associated with reduced risk of type 11 diabetes in several population-based studies. Eating mostly raw or lightly roasted fresh nuts and seeds rather than commercially roasted and salted nuts and seeds should be advocated.

The Wrong Type of Fats Dietary fat also plays a central role in the likelihood of

Cumulative free radical damage leads to cellular aging and is a major factor contributing to type 11 diabetes, as well as many other chronic degenerative diseases. Several large popula tion-based studies have shown that the higher the intake of fruit and vegetables, the better blood glucose levels are controlled and the lower the risk for type I1 diabetes.59Although other factors could explain this inverse correlation (e.g., fruit and vegetable intake may be associated with reduced stress on blood sugar control due to the fiber or nutrient content), a higher level of antioxidant status is also thought to be a major factor. Even something as simple as regular salad consumption is associated with a reduced risk for type I1 diabetes.60 Studies looking at levels of individualized antioxidants have also shown similar inverse correlations-the higher the level of vitamin C, vitamin E, or carotenes, for example, the lower this risk for type 11 diabetes>143 Likewise, the lower the levels of antioxidants and higher the levels of fats damaged by free radicals (lipid peroxides), the greater the risk for developing type I1 diabetes.69In one study 944 men, age 42 to 60 years, were followed closely for 4 years. None of these men had diabetes at the beginning of the study. At the end of this time, 45 men had developed diabetes. What researchers found was that a low vitamin E concentration was associated with 3.9-fold (390%) increased risk of incidence of type I1 diabetes in the study subje~ts.6~

developing type II diabetes. Large controlled trials have shown that a reduction of fat intake as part of a healthy lifestyle, combined with weight reduction and exercise, reduces the risk of type 11diabetes. However, more important than the amount of fat in the diet is the type of fat c0nsumed.5~The type of dietary fat profile linked to type 11 diabetes is an abundance of saturated fat and trans fatty acids (hydrogenated vegetable oils) along with a relative insufficiency of monounsaturated and omega-3 fatty acids. One of the key reasons appears to be the fact that because dietary fat determines cell membrane composition, such a dietary pattern leads to reduced membrane fluidity, which in turn causes reduced insulin binding to receptors on cellular membranes or reduced insulin action, or both. Particularly harmful to cell membrane function are margarine, vegetable oil shortening, and other foods containing trans fatty acids and partially hydrogenated oils. These fatty acids interfere with the body’s ability to use important essential fatty acids. One study estimated that substituting polyunsaturated vegetable oils for (hydrogenated vegetable oil-containing) margarine would reduce the likelihood of developing type 11diabetes by do%.% In contrast to the dampening of insulin sensitivity caused by margarine and saturated fats, clinical studies have shown that monounsaturated fats and omega3 oils improve insulin action.57Adding further support is the fact that population studies have also indicated that frequent consumption of monounsaturated fats such as olive oil, nuts, and nut oils and omega-3 fatty acids from fish protect against the development of type I1 diabetes. All of this evidence clearly indicates that altered cell membrane composition and fluidity plays a critical role in the development of type I1 diabetes. One of the most usefulfood groups to reduce the risk of type II diabetes is nuts. Studieshave shown that consumption of nuts is inversely associated with risk of type 11 diabetes, independent of known risk factors for type I1 diabetes including age, obesity, family history of diabetes, physical activity, smoking, and other dietary factors.% In addition to providing beneficial monounsaturated

Low Intake of Antioxidant Nutrients

Free Radicals and Diabetes One of the hallmark features of type 11diabetes is the presence of higher levels of free radicals and prooxidants.66 In particular is the presence of an increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS).67These compounds greatly stress antioxidant mechanisms as they directly oxidize and damage cellular components such as DNA, proteins, and cell membrane fatty acids. In addition to their ability to directly inflict damage on these structures, ROS and RNS indirectly induce damage to tissues by activating a number of inflammatory compounds such as nuclear factor-kappa B that ultimately lead to both insulin resistance and impaired insulin secretion. These same compounds are also activated by high blood glucose and elevated saturated fat levels.

Diabetes Mellitus

Lifestyle versus Drugs to Prevent Type II Diabetes Several well-designed, large trials have shown that lifestyle and dietary modifications can be used to effectively prevent type II diabetes. That fact has not dissuaded drug companies from sponsoring studies attempting to prevent diabetes with their drugs. However, the degree of prevention with drugs pales in comparison to the effectiveness of diet and lifestyle. For example, in one of the most celebrated studies 3234 subjects with impaired glucose tolerance (prediabetes) were randomly assigned to be in a group receiving a placebo or the blood glucoselowering drug metformin (850 mg twice daily) or a lifestyle-modificationprogram with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The average follow-up was 2.8 years. The incidence of diabetes was 11, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence of diabetes by 58%and metformin by 31%, as compared with placebo. Clearly the lifestyle intervention was significantly more effective than metformin-a drug with sometimes serious side effects.68

CLINICAL MONITORING OF DIABETES Knowledge and awareness are the greatest allies for people with diabetes. An individual with diabetes who makes a strong commitment to learning about his or her condition and who accepts the lead role in a carefully supervised monitoring program greatly improves the likelihood that he or she will lead a long and healthy life. On the other hand, individuals who remain blissfully ignorant about their disease and who refuse to undergo regular testing or self-monitoring are far more likely to face years of unnecessary suffering and, more often than not, catastrophic health problems. Unless it is properly managed and supervised, diabetes can be viewed as a state of biochemical anarchy that will lead to organ injury and accelerated aging. Many of the complex control systems that faithfully govern and protect the body are damaged in the diabetic. In order for a diabetic to regain this control, he or she must learn how to maintain intimate awareness of blood sugar, risk factors for atherosclerosis (hardening of the arteries), blood pressure, body mass index, level of fitness, and other factors that determine the risk of developing diabetic complications and experiencing an erosion of his or her quality of life. Fortunately, diabetics who do develop a keen awareness of these risk factors through regular testing and a properly supervised self-monitoring program are also those who are much more likely to benefit from changes in lifestyle; diet; supplements; and, when necessary, medications.

Urine Glucose Monitoring Until the mid-1970s the only option that diabetics had to monitor blood glucose was indirectly through urine glucose testing. Normally, the kidneys are able to conserve all of the glucose in the blood that they have to constantly filter. However, if blood glucose gets too high, the kidneys are unable to conserve all of the glucose in the blood that it is filtering and glucose then begins appearing in the urine. Since the average diabetic’s kidneys can completely conserve glucose until the blood glucose reaches about 180 mg/dl(lO mmol/L), a negative urine glucose reading indicates that the blood glucose since the time of previous voiding has been less than 180 mg/dl(lO mmol/L). Unfortunately,urine glucose testing does not give any indication of blood glucose levels below 180 mg/dl (10 mmol/L). Therefore it is only a crude measurement of blood glucose control, and it is completely worthless in detecting severe hypoglycemia or severe hyperglycemia.@Thus urine glucose monitoring is of little value in determining the success of blood glucose control, and it does not provide adequate feedback when lifestyle, diet, or other treatments are adjusted. Nowadays, most diabetics do not need to rely on urine glucose measurements as long as they are willing and able to follow a proper program of blood glucose monitoring.

Urine Ketone Testing In any circumstance when the body must derive its primary source of energy from fat, ketones are produced as a byproduct. If the level of ketone production is high enough, ketones appear in the urine. In the diabetic, ketones appear in the urine when there is a severe deficiency in the availabilityor the activity of insulin. This can occur if an insulin-dependent diabetic accidentally or purposefully forgets to take insulin.It can also occur when a diabetic becomes iU or injured or is given high doses of cortisone-related drugs. AU of these phenomena may result in a severe loss of insulin effectiveness, resulting in an inability of cells to take up and use glucose. In such circumstances, blood glucose rises to high levels, high amounts of fat are used by cells that cannot take in glucose, and the blood becomes polluted with toxic levels of acidic ketones. Severe dehydration occurs rapidly because the kidneys are unable to conserve water in the presence of such extraordinary levels of blood glucose. This dangerous state is referred to as diabetic ketoacidosis, and it must be treated as a medical emergency, usually necessitating intravenous insulin, high amounts of IV fluids, and careful monitoring, usually in an intensive care unit. Ignoring ketoacidosis can rapidly lead to death. Because of this, urine ketone testing remains an important part of monitoring, particularly (but not only) in patients with insulin-dependent diabetes. The presence of urine ketones (accompanied by high blood sugar readings) may indicate impending or even established

Specific Health Problems ketoacidosis, thus requiring immediate medical attention. For this reason, all persons with diabetes should frequently test their urine for ketones during acute illness or severe stress, especially when blood glucose levels are consistently elevated (>300 mg/dL 116.7 mmol/L]), regularly during pregnancy, or when symptoms suggestive of ketoacidosis such as nausea, vomiting, or abdominal pain are present. Outside of these circumstances, no specific schedule of urine ketone monitoring is recommended.

Self-Monitoring of Blood Glucose In just a few years since its introduction, self-monitoring of blood glucose (SMBG) has revolutionized the management of diabetes.70Since the publication of the landmark Diabetes Control and Complications Trial7l which examined intensive glucose control in type I diabetics, and the United Kingdom Prospective Diabetes StudyR which examined intensive glucose control in type II diabetics, it has been widely accepted that the most important factor in determining the long-term risk of serious diabetic complications in both type I and type II diabetics is blood glucose control. Diabetics who do not maintain vigdant awareness of their blood glucose and who do not make every effort to keep their blood sugar under tight control can expect a sigruficant increase in their risk of serious health problems such as eye, kidney, and heart disease, as well as a whole host of other problems such as depression, fatigue, impotence, and chronic infections. Self-monitoringof blood glucose is important for various reasons? 1. Modifications of treatment to achieve appropriate blood glucose control 2. Detection and diagnosis of hypoglycemia 3. Adjusting care in response to daily life circumstances (e.g., food intake, exercise, stress, illness) 4. Detection and treatment of severe hyperglycemia 5. Increasing compliance with therapy (helps to combat apathy and denial) 6. Improvement in motivation because of immediate positive and negative feedback (Boxes 163-3 and 163-4)

Type I Diabetes and Self-Monitoring of Blood Glucose Without a doubt, all type I diabetics must monitor their blood glucose frequently if they want to achieve and maintain good health. In the absence of diabetes, the pancreas monitors blood glucose continuously and it adjusts its insulin output depending on the momentby-moment changes in blood glucose. In order to achieve blood glucose levels that are consistently as close to normal as possible, type I diabetics must replicate this natural situation as closely as possible. This means that they need to monitor their blood glucose frequently, and they must learn to use this information

Fasting or before meals-80-110 mg/dl (4.4-6.7 mmolR) 2 hours after eating (postprandial)--
~~~

Slightly higher values may be acceptable in elderly or young children because of higher nsk of dangerous hypoglycemia.

1. Test on awakening and just before each meal. Ideal blood sugar before meals is 4 2 0 mg/dl (6.7 mmoUL). 2. Test 2 hours after each meal. Ideal blood sugar 2 hours after meals is 4 4 0 mg/dl (7.7 mmoVL). 3. Test at bedtime. Ideal blood sugar at bedtime is 4 4 0 mg/dl (7.7 mmoVL).

to make ongoing adjustments to their insulin injections, diet, and exercise. Until the most recent past, type I diabetics were often prescribed combinations of short- and medium-action or long-action insulin one to two times daily and many diabetics measured their blood infrequently; some less than once daily. This trend is rapidly changing. Increasingly, diabetics are being trained to keep their blood glucose in an ideal range around the clock through a combination of intensive insulin therapy and frequent blood glucose monitoring. This is being made possible largely by a new category of rapid-acting and short-duration insulins. Intensive insulin therapy involves either the frequent injections with these newer, short-duration insulins (Humalog [InsulinLispro] or Novolog [Insulin Aspart]) or the use of an insulin pump (an electronic device that provides a continuous injection of short-acting insulins with extra "boluses" before meals). Intensive insulin therapy allows a diabetic to achieve near-normal levels of blood glucose along with enjoying improved lifestyle flexibility. With conventional, infrequent insulin injections, the diabetic must structure meals and other aspects of lifestyle around his or her injections or face serious abnormalities of blood glucose. On the other hand, with intensive insulin therapy that relies on rapid-acting, short-duration insulin,the timing and size of doses can be adjusted to suit the events of the day.74Even though it may involve multiple injections (usually before each meal and often at bedtime) and blood glucose measurements up to six times or more

Diabetes Mellitus

each day, intensive insulin therapy results in greater dietary and lifestyle freedom; a higher quality of life and well-being; and near nondiabetic blood glucose control, which is vital for long-term health.

Type II Diabetes and Self-Monitoring of Blood Glucose Self-monitoringof blood glucose has an important place in the management of type I1 diabetes as well. Each type I1 diabetic lies somewhere on a spectrum with one end of the spectrum being mild glucose intolerance (accompanied by insulin resistance and higher-thannormal levels of insulin) to the other end of the spectrum being more advanced forms (with more severe insulin resistance, the potential for high blood glucose, ketoacidosis, and partial or nearly complete pancreatic failure with an accompanying lack of insulin). Depending on the severity of the diabetic, SMBG plays a varying role. Each type I1 diabetic should own a blood glucose monitor and should become intimately familiar with its use. Even those diabetics whose blood glucose is well controlled through diet, lifestyle, and supplements should measure their blood glucose regularly. Type I1 diabetics who are not on insulin and whose blood glucose is well controlled according to regularly scheduled laboratory testing including AIC testing would still be wise to designate a day every 1 to 3 weeks to be an intensive blood glucose-measuring day. On this day, diabetics should check their blood glucose before breakfast (fasting), just before meals, 2 hours after meals, and before bed and record these measurements, along with diet, exercise, and supplements in a journal. Doing this on a regular basis and any time there are significant changes in diet or lifestyle will help type I1 diabetics to become more aware of the effects of various factors on their blood glucose. Type 11 diabetics whose blood glucose is poorly controlled should monitor their blood glucose intensively each day and seek professional assistance to help regain optimal blood glucose control. Numerous dietary factors, supplements, exercise, stress, and illness can all have a sigruficant impact on blood glucose control. Becoming intimately aware of how all these factors influence diabetes will help motivate type 11 diabetics to make positive changes and provide immediate feedback as to the success of any changes that they made. Diabetics who are more advanced and who have diminished pancreatic insulin production may also benefit from efforts to establish consistently near-normal blood glucose control using intensive insulin therapy similar to that of type I diabetics." A C-peptide blood test can provide an estimate of how much insulin type I1 diabetics are producing and is one way to help determine the appropriateness of using insulin.If diabetics are placed on an intensive insulin therapy program, they

must perform SMBG as frequently as type I diabetics on intensive insulin therapy (usually before and 2 hours after each meal). Many advanced type 11 diabetics have diminished insulin production (evidenced by less-than-normal C-peptide levels). A common trend to achieve optimal blood glucose in these individuals is to give one injection of the new, long-acting insulinglargine (Lantus),that provides a smooth, continual release of insulin for 24 hours in addition to diet and medication. Diabetics on this type of program need to measure blood glucose frequently (usually before and 2 hours after each meal).

C-Peptide Determination Often it is important to know if the pancreas of a diabetic is making insulin and, if so, how much. This assessment can greatly influence treatment, especially in a diabetic hoping to avoid or cease using insulin. The level of pancreatic insulin production can also partially determine the type of medication or natural health products that are more likely to be effective. Once it is known how well the pancreas is producing insulin, the focus may be shifted toward replacing deficiencies in insulin production, stimulating insulin production, preserving pancreatic function, reducing insulin resistance, or a combination of these therapeutic efforts. One way to determine the level of insulin production is by measuring C-peptide. The pancreas manufactures a large protein called proinsulin first. A piece of this protein (C-peptide) is then snipped off by enzymes, and both C-peptide and the remaining insulin are released into the blood stream. Injected insulin has no C-peptide. Therefore even in diabetics already on insulin, a measurement of C-peptide can help to determine the degree of remaining pancreatic function. This is particularly important for type I1 diabetics with poor blood glucose control. High or normal C-peptide levels in type I1 diabetics confirm that their pancreas is making insulin, and it should direct attention to efforts that will reduce insulin resistance and improve insulin sensitivity. On the other hand, poorly controlled type I1 diabetics with low C-peptide levels probably need to be on insulin (Table 163-3).

C-Peptide results Normal
Interpretation The insulin production is at normal level A. Newly diagnosed type I diabetic B. Chronic, long-termtype I\diabetic

>Normal

A. Newly diagnosed type II diabetic B. A benign tumor of pancreas, insulinoma (rare)

Undetectable

A. Chronic type I diabetic B.Postsurgical removal of pancreas (rare)

Specific Health Problems

Physician Monitoring Although diabetics must take charge of their conditions and be in control of their diet, lifestyle, and glucose monitoring, they are rarely successful without professional guidance. Numerous studies have determined that physician monitoring of diabetics through laboratory measurements of blood glucose control can have a major impact on a diabetic’s long-term health. One of the key determinants of blood glucose control is the AIC test (see earlier). Unlike direct measurements of blood glucose, which detect the level of blood glucose at the moment of testing, the AIC test reflects the average level of blood glucose over the preceding 3 months. Studies have shown that the level of AIC closely correlates to the level of risk for diabetic Having an AIC level of 6% or less is ideal and reflects that blood glucose levels have averaged in a range that is essentially nondiabetic. Although having this level of AIC is ideal, it might be unobtainable for many diabetics and never being able to reach this goal can lead to discouragement. Fortunately, most studies suggest that an AIC level of less than 7”/0is still in keeping with a much lower risk of diabetic complications and this is the goal

of most diabetic teaching centers. Because of its great importance, all diabetics, type I and type 11, should have their AIC level measured every 3 to 4 months depending on the stability of their condition. Although it is clear that optimal blood glucose control is critical to the health of diabetics, several other risk factors need to be carefully monitored in all diabetics. Early detection of problems thorough a program of regular screening and monitoring will allow for preventative efforts and treatments to be put in place before serious complications or catastrophic problems occur. Table 163-4 provides a checklist for proper evaluation and monitoring of patients with diabetes.

THE COMPLICATIONS OF DIABETES In diabetes, elevated blood glucose levels and the loss of sensitivity to insulin make it difficult, if nearly impossible, for the cells of the body to maintain homeostasis. The result is disease and complications. The complications of diabetes are divided into two major categories-acute and chronic (BOX163-5).

Clinical management of the patient with diabetes Quarterly Review Management Plan Blood glucose self-monitoring results Medicationhnsulin regimen Nutritional plan

Exercise program Psychosocial support Physical Examination Weight Height (for childladolescent) Sexual maturation (for childladolescent) Skin, including insulin injection sites Feet: pulses, capillary refill, color, sensation, nails, skin, ulcers Neurologic: reflexes, proprioception, vibratory sensation, touch (distal temperature sensation, distal pinprick or pressure sensation, standardized monofilament) Regular retinal examination

Annually

X X X X X X X X X X X

X

Dilated retinal examination

X

Electrocardiogram Laboratory Tests Fasting or Random Plasma Glucose NormaVtarget range: 80-120 mg/dl before meals Glycosolated Hemoglobin (A&)

X

Target range: <7% in adults, <7.5% in children Urinalysis Glucose, ketones, microalbumin, protein, sediment

X X X

Diabetes Mellitus

Clinical management of the patient with diabetes-cont'd Quarterlv Complete Cardiovascular Profile Testffarget Cholesterol 4 0 0 mgdl

Annuallv X

Triglycerides 400 mgdl Low-density lipoprotein4 3 0 mg/dl High-density lipoprotein <35 mg/dl Lipoprotein (a) <40 mg/dl C-reactive protein 4 . 6 9 mg/L Fibrinogen <400 mg/L Homocysteine 4 6 rnicromole/L Ferritin 60-200 bg/L (if elevated-transferrin saturation; if elevated genetic testing for hemochromatosis-only once) Lipid peroxides < normal Serum Creatinine (in adults; in children, only if protein is present in urine)

X

Acute Complications The acute complications of diabetes represent a medical emergency and possible life or death situation. Any diabetic experiencing any symptom even remotely suggestive of an acute complication of diabetes should consult medical care immediately. The major acute complications of diabetes are hypoglycemia, ketoacidosis, and nonketogenic hyperosmolar syndrome.

Hypoglycemia Hypoglycemia is usually seen in type I diabetes. It is the result of taking too much insulin,missing a meal, or overexercising. Severe hypoglycemia can also occur unpredictably in patients with "brittle" type I diabetes or in any diabetic on insulin or sulfonylurea drugs who neglects the need for proper monitoring of blood glucose. Daytime hypoglycemic episodes are usually recognized by the following symptoms: sweating, nervousness, tremor, and hunger. Nighttime hypoglycemia may be without symptoms or manifest as night sweats, unpleasant dreams, or early-morning headache.

Diabetic Ketoacidosis Diabetic ketoacidosis is also more likely to occur in poorly controlled or untreated type I diabetes. The lack of insulin leads to extremely high blood glucose and a buildup of acidic ketone molecules in the body. If progressive, ketoacidosis can result in numerous metabolic problems and even coma or death. Since ketoacidosis is a medical emergency, prompt recognition is imperative. The coma is usually preceded by a day or more of

Acute complications: Hypoglycemia Diabetic ketoacidosis Nonketotic hyperosmolar hyperglycemia Chronic complications: Atherosclerosis and other vascular lesions Retinopathy and cataracts Neuropathy Nephropathy Poor wound healing Foot ulcers

increased urination and thirst, as well as marked fatigue, nausea, and vomiting. A simple urine dipstick can be used at home by diabetics to measure the level of ketones in the urine. This procedure should be done during illness or severe stress. A mistake made occasionally by inexperienced medical personnel is to avoid giving insulin to a type I diabetic because he or she is fasting before surgery. This mistake can also be made at home by a misinformed diabetic when he or she is too sick to eat. Generally, the stress of illness or surgery is sufficient to drive blood glucose up even when no food is taken. This is because the stress hormones cortisol and epinephrine result in a massive release of glucose from the liver and muscles, and usual insulin doses are generally required.

Specific Health Problems ~~

~

Nonketotic Hyperosmolar Hyperglycemia

Neuropathy

Nonketotic hyperosmolar hyperglycemia is a serious condition that occurs when blood glucose rises to extreme levels, usually in those type I1 diabetics with some insulin production or in type I diabetics who are receiving inadequate levels of insulin for their acute situation. Usually this occurs in already debilitated diabetics, and it often evolves over days resulting in severe dehydration and disturbances of electrolytessuch as sodium and potassium. If the patient presents in a comatose state, this condition carries with it a mortality rate of more than 50%. It is usually the result of severe dehydration due to deficient fluid intake and inadequate insulin to compensate for precipitating events such as pneumonia, burns, stroke, a recent operation, or certain drugs (e.g., phenytoin, diazoxide, glucocorticoids, diuretics). The onset of the syndrome may develop slowly over a period of days or weeks, with symptoms of weakness, increased urination and thirst, and progressively worse signs of dehydration (weight loss, loss of skin elasticity, dry mucous membranes, rapid heart beat, and low blood pressure). This condition is completely preventable by regular blood glucose monitoring, especially during times of illness or stress.

Neuropathy usually refers to the loss of peripheral nerve function and is characterized by tingling sensations, numbness, loss of function, and a characteristic burning pain known as neuroputhic pain. Diabetic neuropathy first involves a subtle loss of sensation in the hands and feet in a pattern known as "stoking-glove" neuropathy. If it progresses, the neuropathy can affect deeper nerves of the autonomic nervous system, resulting in disturbances in stomach emptying and, later, impaired heart function, alternating bouts of diarrhea and constipation, and inability to empty the bladder. Impotence is a common occurrence and is caused by damage to the small blood vessels of the penis combined with neuropathy of autonomic nerves controlling blood flow into the penis. Approximately 60% of all people with diabetes eventually develop neuropathy.

Chronic Complications Much more common than the acute complications of diabetes are certain long-term complications, described as follows.

Atherosclerosis

Nephropathy Nephropathy due to diabetes accounts for 40% of the cases of severe kidney disease and is the most common reason for hernodialysis and kidney transplant. In addition to monitoring blood glucose levels, it is important to monitor kidney function through various laboratory measurements (microalbuminuria, 24hour urine protein, blood urea nitrogen, uric acid, matinine, and creatinine clearance).

Poor Wound Healing and Food Ulcers

Atherosclerosis and other vascular lesions are the underlying factors in the development of many chronic complications of diabetes. Individuals with diabetes have a twofold to threefold higher risk of dying prematurely of heart disease or stroke than a nondiabetic individual, and 55%of deaths in diabetes patients are caused by cardiovascular disease. Lesions to the microvascular system (small blood vessels) lead to reduced delivery of oxygen and nutrients to important tissue like nerves, the eyes, and kidneys.

Poor wound healing is common in diabetes for several reasons such as the microvascular changes leading to poor circulation and the functional deficiency of vitamin C (see pp. 1626-1627). Foot ulcers are common in individuals with diabetes due to the microvasculature changes leading to a lack of blood supply, peripheral neuropathy, poor wound healing, and immune system dysfunction leading to chronic infections in the feet. More than 50% of the cases of lower limb amputation in the United States (70,000 each year) are due to diabetic foot ulcers.

Retinopathy

Immune System Dysfunction

Diabetic retinopathy is the leading cause of blindness in the United States for people between the ages of 20 and 64. In diabetic retinopathy, the retina is damaged by microhemorrhages, scarring, and the attachment of glucose molecules (glycosylation) to structural proteins in the retina. Studies have shown that 20 years after the diagnosis of diabetes, 80% of type I and 20% of type 11 diabetics have sigruficant retinopathy. Diabetics are also prone to cataracts-opacities that occur in the lens of the eye as a result of damage to the delicate protein structures of the lens.

Immune system dysfunction often begins to OCCUT long before a diagnosis of diabetes is made. In fact, a recurrent vaginal or skin yeast infection is the clue that leads to the detection of diabetes in many cases. Immune system problems are made worse by poor glucose control, and this puts the diabetic at risk for serious infections or complications of simple infections. For example, diabetics are far more likely to develop secondary pneumonia while recovering from influenza. Susceptibility to chronic, hidden infections may be a primary reason for increased risk of cardiovascular disease in diabetics.

Diabetes Mellitus

C-reactive protein, a measurement of smoldering inflammation, is often elevated in diabetics and may be due, at least in part, to chronic infections of the oral cavity, respiratory tract, or blood.

Depression and Cognitive Difficulties Depression and cognitive difficulties are common in diabetics. In fact, depression may begin to occur decades before the onset of type II diabetes when the individual first develops insulin. The brain is more sensitive than any organ to its need for glucose, and it appears that the brain cells may suffer from some degree of glucose deprivation when insdin resistance occurs." Depression is also much more common in overweight and obese individuals, probably due to a combined effect from insulinresistance and diminished self-esteem. Cognitive changes begin to occur after the first severe hypoglycemic episode in diabetics. Hypoglycemia is profoundly stressful to the brain and, if severe hypoglycemia occurs many times, sigruficant cognitive impairment is inevitable. Blood glucose awareness training has successfully helped thousands of diabetics to avoid serious hypoglycemia. Frequent blood glucose monitoring and the use of the new-generation, immediate-acting, and long-duration insulins have allowed optimal blood glucose control to be maintained without increasing the risk for serious hypoglycemia.

Contributors to the Long-term Complications of Diabetes The major contributors to the long-term complications of diabetes are listed here, followed by a brief description of each factor, along with coping measures: Poor glucose control Glycosylation of proteins Intracellular accumulation of sorbitol Increased oxidative damage Nutrient deficiency Homocysteine High blood pressure

Poor Glucose Control A large body of evidence indicates that good blood glucose control significantly reduces the development of complications. The largest and most extensive study to date in type I diabetes is the Diabetes Control and Complications Trial (DCCT), while the largest and longest study on patients with type 11 diabetes is the United Kingdom Prospective Diabetes Study (UKPDS). Both studies conclusively demonstrated that improved blood glucose control reduces the risk of developing the long-term complications of diabetes, especially retinopathy, nephropathy and neuropathy. Maintaining hemoglobin AIC levels near normal (17%) can dramatically

help reduce the risk of eye problems (up to 76%),nerve damage (up to 60%), and kidney disease (up to 56%).

Glycosylation of Proteins As described previously, glycosylation refers to the binding of glucose to proteins. The poorer the glucose control, the greater the binding of glucose molecules to proteins. This binding leads to changes in the structure and function of the protein. Among the adverse effects of excessive glycosylation are inactivation of enzymes, inhibition of regulatory molecule binding, and the formation of abnormal protein structures. For example, when glucose molecules bind to cholesterol-carrying, low-density lipoprotein (LDL) molecules, they block LDL from binding to receptors on the liver that signal the liver to cease manufacturing cholesterol. As a result, the liver "thinks" there is a shortage of cholesterol in the body and continues to produce more and release it into the blood. This is one reason why diabetes is almost always associated with high cholesterol levels. In addition to keeping blood glucose levels as close to ideal as possible, high intakes of antioxidantsespecially vitamins C and E, flavonoids, and alpha-lipoic acid (discussed later)-help to reduce glycosylation.

Intracellular Accumulation of Sorbitol Sorbitol is a sugar molecule that is formed from glucose within cells. In people without diabetes, once sorbitol is formed it is quickly broken down into fructose. This conversion to fructose is critical because it allows any excess sorbitol to be excreted from the cell. The conversion is critical because sorbitol cannot exit the cell once it is formed. If sorbitol levels continue to increase within cells, they create an osmotic effect. When there is an increase in the concentration of soluble compounds (e.g., sorbitol) that the cell cannot get rid of, the cell leaks small molecules like amino acids, inositol, glutathione, niacin, vitamin C, magnesium, and potassium to maintain osmotic balance. Because these compounds function to protect cells from damage, their loss results in increased susceptibility to damage. Intracellular accumulation of sorbitolis a major factor in the development of most complications of diabetes, as evidenced by the fact that elevated sorbitol levels are found in high concentrationsin the tissues commonly involved in the major diabetic complications: the lens of the eye, nerve cells, kidney cells, and the cells that line blood vessels. In addition to controlling blood glucose levels, vitamin C and flavonoidslike quercetin, grape seed extract, and bilberry extract can help lower intracdular sorbitol levels.

Increased Oxidative Damage Increased oxidative stress is a major factor in the development of the chronic complications of diabetes.

As previously stated, individuals with diabetes typically have elevated levels of free radicals and oxidative comThese highly reactive compounds bind to and destroy cellular compounds. They also greatly increase the inflammatory process by adding fuel to their destructive fire via increased formation of inflammatory mediators like C-reactive proteinm One of the critical goals in diabetes prevention and treatment is to flood the body with a high level of antioxidant compounds to counteract the negative effects of free radicals and prooxidants. The implementation of this goal is achieved by following the dietary and supplement strategies given. In addition to the basic supplementation program, supplementing the diet with super antioxidants like alpha-lipoic acid and flavonoid-rich extracts is often useful in further boosting antioxidant protection.

Nutrient Deficiency A deficiency of any one of several nutrients has been shown to contribute to several chronic complications of diabetes. In general, the risk of long-term complications of diabetes is inversely proportional to micronutrient status. Sometimes the symptoms of nutrient deficiency can mimic closely a chronic complication of diabetes. For example, vitamin BI2 deficiency is characterized by numbness, "pins and needles" sensations, or a burning feeling in the hands or feet-symptoms virtually identical to diabetic neuropathy. Although vitamin BI2supplementation has been used with some success in treating diabetic neuropathy, it is really not clear if this success is due to correction of a BI2 deficiency state or the normalization of the deranged vitamin BI2 metabolism seen in diabetics. High-potency multivitamin and mineral supplementation is critical to the management of diabetes. Supplying the diabetic with additional key nutrients improves blood glucose control and reduces the development of the major long-term complications of diabetes.

Homocysteine Elevated homocysteine levels are an independent risk factor for heart attack, stroke, and peripheral vascular disease. In addition, recent research has implicated elevations of homocysteine in the development of long-term complications of diabetes, especially diabetic retinopathy.gO

Hypertension Blood pressure control is essential in preventing the complications of diabetes, especially renal disease, retinopathy, and stroke. Maintaining blood pressure in the normal range (120/80nun Hg) can reduce the risk of heart disease and stroke by approximately 33% to 50% and can reduce microvascular disease (eye, kidney,

and nerve disease) by approximately 33% in patients with diabetes. More than half of all diabetics have hypertension.

Endothelial Cell Dysfunction A single layer of endothelial cells line all blood vessels to act as a metabolically active interface between the components of blood and the blood vessel. These cells regulate many important aspects of blood flow, coagulation and clot formation, and the formation of key regulating compounds including those that control blood pressure. Endothelial cells are susceptible to damage by oxidized LDL cholesterol and other free radicalshence the importance of high dietary antioxidant intake, flavonoids, and key supplemental antioxidants like vitamins C and E, and alpha-lipoic acid. All of these factors have been shown to improve endothelial cell function and are critical in the battle against vascular disease in diabetes?l*

THERAPEUTIC CONSIDERATIONS Diet Therapy in Managing Diabetes The optimal diet for the treatment of diabetes is virtually the same as the program we have presented in Chapter 4.4. The difference is that there often needs to be an even stricter avoidance of foods with a high GL (see Appendix 6). What determines how strict the diet needs to be with the intake of carbohydrates is based on the ability to get blood glucose measurements and AIC levels under control and achieve/maintain ideal body weight. Obviously the poorer the control, the more the carbohydrate intake must be restricted. Initially, some people with diabetes-especially those who have poorly controlled blood glucose levels-may need to avoid meals with a total GL of more than 20 and space these meals at least 3 hours apart. Higher GL meals can be consumed if one of the special natural products designed to slow gastric emptying and blunt after-meal blood glucose levels is used (these compounds are discussed later).

Clinical Studies with Diet Therapy in Type I Diabetes Numerous clinical studies have shown impressive results in improving blood glucose control when diets high in fiber and low in GL are followed. This fact holds true in both adults and children, as well as in both type I and type I1 diabetes. In a study involving children, 8- to 13-year-olds in Melbourne, Australia, were divided into two groups: one group followed the American Diabetes Association's (ADA's) exchange program diet, and another group was instructed to eat low-GI foods.= Although there was no change in AIC in the exchange diet (8.6%), the group eating the low GI diet dropped

Diabetes Mellitus from 8.6% to 8Yo-an acceptable value in children. Rates of excessive blood glucose levels were 66% for the exchange diet versus 35% for those eating low-GI foods. Although these results are good, what the study really highlighted was the impact of eating a low41 diet on the quality of life. There were sigruficantly fewer family conflicts, fewer limitations placed on family activities, and fewer difficulties in meal selections. Furthermore, parents and children alike showed a clear preference for the low-GI diet. Similar results have been seen in adults including pregnant women with type I diabetes following a high-fiber, low-GI diet.8689What these studies and others indicate is that low-GI and low-GL diets are emerging as the most scientifically proven dietary support for type I diabetes. We have taken the proven diet to a much higher level by also considering the role of fats on insulinaction.

Clinical Studies with Diet Therapy in Type I1 Diabetes Diet alone can often be effective as the sole factor in treating and reversing type 11 diabetes. Other lifestyle factors and supplements are important, but treatment of type I1 diabetes begins with diet. And, just as in type I diabetes, there is considerable evidence from clinical trials that diets low in GI and GL are emerging as the most scientifically proven approach, especially when considering not only its effect on blood glucose levels but also the effects that it exerts in reducing the sequelae of diabetes such as high cholesterol levels, cardiovascular disease, hypertension, and complications of diabetes.go One of the key goals is to get the total fiber intake from foods to at least 50 g. In one study the effects of two diets on blood glucose levels were compared?l One diet contained 24 g of dietary fiber as 8 g of soluble fiber and 16 g of insoluble fiber on the basis of ADA recommendations, while the other provided a total of 50 g as 25 g of soluble fiber and 25 g of insoluble fiber. Both diets had the same calorie level and percentages of fat, carbohydrate, and protein. After 6 weeks, the average daily blood glucose levels were 13 mg/dl lower in the group on the higher-fiber diet. Furthermore, the high-fiber diet also lowered the total area under the curve for 24hour blood glucose levels, as well as insulin concentrations and reduced total cholesterol concentrations by 6.7%, triglyceride concentrations by 10.2%, and very-low-density lipoprotein (VLDL) cholesterol concentrations by 12.5%. This study shows quite clearly that a high intake of dietary fiber, particularly of the soluble type, above the level recommended by the ADA, improves glycemic control, decreases hyperinsulinemia, and lowers plasma lipid concentrations in patients with type 11 diabetes. Similar studies looking at a low-GI diet versus a high GI diet have shown quite clearly the advantages of a low-GI diet?2,93

Psychologic Support in Diabetes Helping people with diabetes deal with their diagnosis, develop a sense of empowerment, and make important lifestyle changes is an extremely important aspect of proper medical care. Cognitive therapy has proven especially effective in helping adolescents with type I diabetes deal with their disease, leading to improvements in both mood and blood glucose

Dealing with Stress Stress adversely affects blood glucose control, as higher stress levels are associated with higher blood glucose levels in both type I and type I1 diabete~?~ There is a simple explanation for this phenomenon. Exposure to stress, whether it be physical, mental, or emotional, leads to activation of the “stress response” by the body and causes increases in the adrenal gland hormones adrenaline and cortisol. Among other things, these hormones cause blood glucose levels to rise and blunt the response to insulin. They also negatively affect the immune system. Because stress seems to be an inevitable part of modern living, it is critical to develop effective methods to deal with it. Some studies have shown that positive methods for dealing with stress, such as relaxation training, can improve blood glucose control, especially in individuals who are anxious or experiencing significant stress in their live^?^,^^

Exercise and Diabetes Exercise is absolutely essential in the prevention and management of diabetes, as well as prediabetic conditions such as glucose intolerance and syndrome X. Exercise directly improves insulin sensitivity and blood glucose control from a combination of increased lean muscle mass and an improvement in muscle cell r n e t a b o l i ~ m .Exercise ~~ also has profound benefits on the cardiovascular system directly, as well as indirectly, by improvements in blood lipids (especially an improvement in HDL, the ”good cholesterol”).Exercise also decreases symptoms of anxiety and depression, improves sexual functioning, and improves confidence and self-esteem. Importantly, exercise has been shown to help attain and sustain weight Three types of exercise are important for people with diabetes: aerobic, strength training, and stretching.

Aerobic Exercises Aerobic exercises such as walking, jogging, aerobic dance classes, cycling, and swimming produce a rise in heart and respiratory rates. These sorts of activities are foundational in both the prevention and treatment of diabetes. In its simplest form, an aerobic exercise program would consist of a schedule of regular walking combined with cycling, swimming, or using low-impact indoor exercise equipment such as an elliptical trainer.

Strength Training Strength training should o c m two or three times per week and consist of light to moderate weights. Loss of lean body mass is a big problem for diabetics, and this problem increases with age. Losing lean muscle mass means there is less tissue to actively absorb glucose. The more muscle, the easier it is to control blood glucose. Also, diabetics are particularly prone to developing chronic musculoskeletal complaints. Most of these problems are related to increased susceptibility to injury of joint, ligament, and muscle as a result of loss of muscle mass.

Stretching Exercises Stretching exercises should be done daily. Stretching is extremely important, as most people with diabetes suffer from premature stiffening of the spine and joints. Stretching on a daily basis helps to maintain flexibility and avoid the chronic pain problems that occur frequently in diabetics as a result of stiff muscles and joints.

Nutritional Supplements The proper treatment of diabetes with natural medicine involves trying to achieve ideal blood glucose control and metabolic targets, as well as reducing the risk of the complications of diabetes by focusing on the following four areas: 1.Providing optimal nutrient status 2. Reducing after-meal elevations in blood glucose levels

3. Improving insulin function and sensitivity 4. Preventing nutritional and oxidative stress

Even though natural products can produce signhcant effects on their own, the proper and effective treatment of diabetes requires the careful integration of diet and lifestyle changes along with these natural medicines. Furthermore, all type I diabetics and many type II diabetics also require conventional medical treatments (oral drugs or insulin)--depending on adequacy of pancreatic insulin production (this can be determined by the Cpeptide level) and the response of the diabetic to dietary and lifestyle measures. The most important determining factor as to whether or not the diabetic needs to be managed by drugs or insulin is the adequacy of blood glucose control.

Providing Optimal Nutritional Status In addition to eating a nutrientdense diet, a high-potency multivitamin and mineral formula is an absolute must for people with diabetes. Follow the guidelines given in Appendix 8. The individual with diabetes has such an increased need for many nutrients that supplementation is critical. Supplying the diabetic with additional key nutrients has been shown to improve blood glucose control, as well as help prevent or reduce the development

of the major complications of diabetes. Taking a multivitamin and mineral supplement has also been shown to boost immune function and reduce infections in diabetics.'"'' Specific examples of nutrients for which the diabetic has increased requirements include chromium, vitamin C, vitamin E, certain B vitamins, manganese, magnesium, potassium, and zinc.

Chromium Chromium is vital to proper blood glucose control because it functions in the body as a key constituent of what is referred to as the "glucose tolerance factor." Chromium works closely with insulin in assisting the uptake of glucose into cells. Without chromium, insulin's action is blocked and glucose levels are elevated. Evidence indicates that marginal chromium status is quite common in the United States. A chromium deficiency may be an underlying contributing factor to the tremendous number of Americans who have diabetes and hypoglycemia and are obese. More than 20 clinical studies have focused on chromium supplementation in diabetes. In some of these studies in type II diabetes, supplementing the diet with chromium has been shown to decrease fasting glucose levels, improve glucose tolerance, lower insulin levels, and decrease total cholesterol and triglyceride levels while increasing HDL-cholesterollevels. Although there are also studies that have not shown chromium to exert much effect in improving glucose tolerance in diabetes, there is no argument that chromium is an important mineral in blood glucose metabolism. At this time, however, it appears that chromium supplementation is likely to produce meaningful improvements in glycemic control only in people who are deficient in this essential trace element.lo1 Although there is no recommended daily allowance (RDA) for chromium, it appears that at least 200 pg each day in the diet is required. People with diabetes need to supplement between 200 and 400 pg per day. Chromium polynicotinate, chromium picolinate, and chromium-enriched yeast are suitable forms to supplement the diet.

Vitamin C Because the transport of vitamin C into cells is enhanced by insulin,'02 many people with diabetes suffer from a relative deficiency of vitamin C inside their cells even if they consume an adequate amount of vitamin C in their diet. As a result, the individual with diabetes needs to take extra vitamin C. In addition to its role as an antioxidant, vitamin C is required in immune functions and the manufacture of collagen, the main protein substance of the human body. Because collagen is such an important protein for the structures that hold our body together (e.g., connective

Diabetes Mellitus

tissue, cartilage, tendons), vitamin C is vital for wound repair, healthy gums, and prevention of easy bruising. A chronic, latent vitamin C deficiency leads to a number of problems for the diabetic including an increased capillary permeability, poor wound healing, elevations in cholesterol levels, and a depressed immune system. Vitamin C supplementation has been shown to exert a mild effect in improving glucose control, as evident by a slightly lower AIC in the vitamin C group (8.5%) compared with a placebo (9.3%) in one double-blind study.103Probably more important than any sigruficant effect on improving blood glucose control is the fact that vitamin C supplementation has been shown to reduce the formation of compounds linked to the development of diabetic complications. In one study of vitamin C supplementation in type I1 diabetes, 30 patients who were 45 to 70 years old and not only had type I1 diabetes but also hypertension were randomly assigned in a double-blind manner to take either 500 mg ascorbic acid by mouth or a placebo daily for 4 weeks. Vitamin C supplementation decreased systolic blood pressure from 142.1 to 132.3 mmHg and diastolic pressure from 83.9 to 79.5. Additional analytic methods designed to measure vascular resistance also demonstrated signhcant improvements in arterial stiffness. These results indicate that vitamin C supplementation is effective in improving the elasticity and function of blood vessels in patients with type 11diabetes.lW The attempt to prevent sorbitol accumulation with drugs has failed due to severe side effects. In contrast, vitamin C can accomplish what these drugs could notsafe and effective inhibition of sorbitol accumulation. In one study in young adults with type I diabetes, the baseline measurement of sorbitol in RBCs was nearly double in these patients despite "adequate" dietary intakes of vitamin C. Vitamin C supplementation at a dosage of either 100 mg or 600 mg normalized RBC sorbitol within 30 days. This correction of sorbitol accumulation was independent of changes in diabetic control as monitored by fasting glucose or hemoglobin AIC. In fact, overall diabetic control during the study was moderate to poor, indicating that vitamin C's effect was not dependent on glucose concentration. These results indicate that vitamin C may.inhibit the enzyme aldose reductase, which converts glucose to sorbitol. An in vitro study was conducted to determine the necessary concentration of vitamin C required to inhibit aldose reductase in RBCs.'05 At concentrations higher than 100 micromoles, vitamin C reduced sorbitol production by about 30%. Levels between 600 and 900 micromoles reduced sorbitol production by about 50%. These concentrations of vitamin C are attainable with vitamin C supplementation. In fact, the normal level of vitamin C in plasma and RBCs is 40 to 120 micromoles. Supplementing with 500 to 1500 mg of vitamin C

daily may boost blood levels in the higher range required to inhibit sorbitol production. Although vitamin C supplementation is necessary, patients should not rely exclusively on it to meet all of their vitamin C requirements. Vitamin C-rich foods are rich in compounds such as flavonoids and carotenes, which work to enhance the effects of vitamin C, as well as exert favorable effects of their own.

Vitamin E Vitamin E functions primarily as an antioxidant in protecting against damage to the cell membranes. Without vitamin E, the cells of the body would be quite susceptible to damage. Nerve cells are particularly vulnerable. Vitamin E supplementation or a high vitamin E diet has been shown to exert a protective effect in many common health conditions including diabetes. Diabetics appear to have an increased requirement for vitamin E. Vitamin E not only improves insulin action, it exerts a number of beneficial effects when taken at dosages ranging from 400 to 800 IU that may aid in preventing the long-term complications of diabetes: Prevents free radical damage to LDL cholesterol and the vascular lining106-'08 Improves the functioning of blood vessels and cells that line the blood vesselslOgJ1O Increases the concentration of magnesium within cellS11L112 Decreases the level of C-reactive protein and other inflammatory c ~ m p o u n d s ~ ~ ~ J ~ ~ Increases the level of glutathione-an important intracellular antioxidant-within cells115 Improves the rate of conduction of the electrical impulse through the nervous system1l6 Improves blood flow to the eye and improves diabetic retinopathy Improves kidney function and normalizes creatinine clearance-an indicator of kidney function-in diabetics with mild elevations117 Because of the way the body uses vitamin E, the individual with diabetes requires lifelong supplementation for maximum benefits.ll8

Niacin and Niacinamide Niacin (vitamin B3)-containingenzymes play an important role in energy production; fat, cholesterol, and carbohydrate metabolism; and the manufacture of many body compounds including sex and adrenal hormones. Niacin, like chromium, is an essential component of the glucose tolerance factor, making it a key nutrient for hypoglycemia and diabetes. In addition to offering possible benefits in type I diabetes, niacinamide may also help in type I1 diabetes. Eighteen patients with type I1 diabetes of normal body

weight who failed to respond to oral antihyperglycemic drugs were randomly assigned to one of three treatments for 6 months: (1) insulin plus nicotinamide (500 mg three times daily); (2) insulin plus placebo; or (3) oral antihyperglycemic drug plus niacinamide (500 mg three times daily). The parameters assessed included C-peptide, AIC, and fasting and mean daily blood glucose levels. With detailed analysis, niacinamide administration was the only significant factor accountable for the improvement of C-peptide release. The data indicated that niacinamide improves C-peptide release and blood glucose control in type I1 diabetic patients who had previously failed to respond to oral antihyperglycemicdrugs

Vitamin B6 Pyridoxine, or vitamin B6, is an extremely important B vitamin involved in the formation of body proteins and structural compounds, chemical transmitters in the nervous system, RBCs, and hormonelike compounds known as prostaglandins. Vitamin B6 is also critical in maintaining hormonal balance and proper immune function. Vitamin B6 supplementation appears to offer sigruficant protection against the development of diabetic neuropathyJZ0Diabetics with neuropathy have been shown to be deficient in vitamin B6 and benefit from supplementation.lZ1The neuropathy of a vitamin B6 deficiency is indistinguishable from diabetic neuropathy. Individuals with long-standing diabetes or who are developing signs of peripheral nerve abnormalities should definitely supplement their diets with vitamin B6 Vitamin B6 is also important in preventing other diabetic complications. Vitamin B6 supplementation can be a safe and effective treatment for gestational diabetes (diabetes caused by pregnancy). One study of 14 women with gestational diabetes given 100 mg of vitamin B6 daily for 2 weeks resulted in eliminating the diagnosis in 12 of the 14 women.12

Magnesium Like manganese and chromium, magnesium is also involved in glucose metabolism. Considerable evidence indicates that diabetics should take supplemental magnesium, the reasons being that more than half of all people with diabetes show evidence of magnesium deficiency and magnesium may prevent some of the complications of diabetes like retinopathy and heart disease. Magnesium levels are usually low in diabetics and lowest in those with diabetic complications like retinopathy and neuropathy. Clinical studies have shown that magnesium supplementation (usually 400 to 500 mg/day) improves insulinresponse and action, glucose tolerance, and the fluidity of the RBC membrane in patients with d i a b e t e ~ . ~ , ' ~ ~

The RDA for magnesium is 350 mg/day for adult males and 300 mg/day for adult females. Diabetics may need twice this amount because they tend to lose excessive magnesium through their kidneys.lE Most of the magnesium should be derived from the diet. The average intake of magnesium by healthy U.S. adults ranges from 143 to 266 mg/day. This is obviously far below the RDA. Food choices are the main reason. Although magnesium occurs abundantly in whole foods, food processing refines out a large portion of magnesium. The best dietary sources of magnesium are tofu, legumes, seeds, nuts, whole grains, and green leafy vegetables. Fish, meat, milk, and the most commonly eaten fruits are low in magnesium. Most Americans consume a lowmagnesium diet because their diet is high in refined foods, meat, and dairy products. In addition to eating a diet rich in magnesium, diabetics should supplement their diet with 300 to 500 mg of magnesium. For best results, highly absorbable sources of magnesium like magnesium aspartate or citrate should be taken. Diabetics should also be sure to get at least 25 mg of vitamin B6 per day, as the level of vitamin B6 inside the cells of the body appears to be intricately linked to the magnesium content of the cell. In other words, without vitamin B6 (as well as vitamin E), magnesium will not get inside the cell and will therefore be useless.

Zinc zinc functions in more enzymatic reactions than any other mineral, as it is a cofactor in more than 200 different enzymes. Although severe zinc deficiency is rare in developed countries, many individuals in the United States have marginal zinc deficiency. This occurrence is particularly true in the elderly population, as well as in people with diabetes. Low levels of zinc in the body are associated with an increased susceptibility to infection, poor wound healing, a decreased sense of taste or smell, or skin disorders. Zinc deficiency, like chromium deficiency, has also been suggested to play a role in the development of diabetes.lZ6 Zinc is involved in virtually all aspects of insulin metabolism: synthesis, secretion, and utilization. Zinc also has a protective effect against beta-cell destruction and has well-known antiviral effects. Diabetics typically excrete too much zinc in the urine and therefore require supplementation. Diabetics should take at least 30 mg of zinc daily. Zinc is also found in good amounts in whole grains, legumes, nuts, and seeds.

Manganese Manganese functions in many enzyme systems including those involved in blood glucose control, energy metabolism, and thyroid hormone function. Manganese also functions in the antioxidant enzyme superoxide

Diabetes Mellitus

dismutase (SOD). In guinea pigs, a deficiency of manganese results in diabetes and the frequent birth of offspring who develop pancreatic abnormalities or no pancreas at all. Diabetics have been shown to have only one half the manganese of normal individuals. A good daily dose of manganese for a diabetic is 3 to 5 mg.

Biotin Biotin is a member of the B vitamin family that functions in the manufacture and utilization of carbohydrates,fats, and amino acids. Without biotin, sugar metabolism is severely impaired. Biotin supplementation has been shown to enhance insulin sensitivity and increase the activity of the enzyme glucokinase-the enzyme responsible for the first step in the utilization of glucose by the liver. Glucokinase concentrations in diabetics are low. Evidently, supplementing the diet with high doses of biotin improves glucokinase activity and glucose metabolism in diabetics. In one study, 16 mg of biotin daily resulted in significant lowering of fasting blood glucose levels and improvements in blood glucose control in type I diabetics. In another study in type I1 diabetics, similar effects were noted with 9 mg of biotin daily.lZ7 Biotin therapy has also been shown to be quite helpful in the treatment of diabetic neuropathy.lB

Ome a-3 Fatty Acids from Fish Oil Supp ements

B

Omega-3 fatty acids from fish offer sigruficantprotection against heart disease in diabetes. Initially there were concerns that omega3 fatty acid supplementation may adversely affect blood glucose control, but two intensive investigations, one conducted at Oxford University and the other at the Mayo Clinic, analyzed data from 18 double-blind clinical trials involving 823 participants followed for an average of 12 Doses of fish oil (18% eicosapentaenoic acid [EPA] and 12% docosahexanoic acid [DHA]content)ranged from 3 to 18 g/day. Both evaluations came to the same conclusions. Fish oil supplementation has no adverse effect on glycemic control, but it does appear to offer the same protection against cardiovascular disease in people with diabetes that it does to people without diabetes.131Importantly, many studies in patients with diabetes were conducted with lower-quality fish oil products that contained significant amounts of cholesterol and lipid peroxides. As a result, in some of these studies an elevation in LDL cholesterolwas noted. This occurrencehighlights the importance of using a pharmaceutic-grade fish oil product, as we have not seen increases in LDL cholesterolwith these higher-quality products. Fish oil supplements are best taken at or near the beginning of a meal to avoid any fishy aftertast-ome people experience burping up a little of the oil if they take it at the end of the meal on a fullstomach. The combined

total omega3 fatty acid supplement level should be between 600 mg and 1200 mg daily.

Reducing After-Meal Elevations in Blood Glucose Levels Elevations of blood glucose levels after a meal can wreak biochemical havoc in both type I and type I1 diabetics. In fact, an elevation in postprandial blood glucose levels is perhaps the major contributor to the development of diabetic complications, especially cardiovascular disease and diseases of the microvasculature (retinopathy, neuropathy, and nephropathy). For example, patients who have a normal fasting blood glucose measurement but an average 2-hour postprandial glucose level greater than 200 mg/dl(11 mmol/L) have a threefold increase in the incidence of diabetic retinopathy.13*Therefore blunting the after-meal increase in blood glucose levels is an important goal. In addition to dietary guidelines to reduce postprandial blood glucose levels (eating low GI/low GL meals), several natural products can be used. We limit discussion here to the most useful: fiber supplements, natural glucosidaseinhibitors, and Punax quinquefolius (American ginseng) extract.

Fiber Supplements Fiber supplements have been shown to enhance blood glucose control, decrease insulin levels, and reduce the number of calories absorbed by the body. The best fiber sources for reducing postprandial blood glucose levels, lowering cholesterol levels, and promoting weight loss are those that are rich in water-soluble fibers such as glucomannan (from konjac root), psyllium, guar gum, defatted fenugreek seed powder or fiber, seaweed fibers (alginateand carrageenan),and pectin. When taken with water before meals, these fiber sourcesbind to the water in the stomach and small intestine to form a gelatinous, viscous mass that not only slows down the absorption of glucose but also induces a sense of satiety (fullness) and reduces the absorption of calories. One of the most viscous dietary fibers is glucomannan, a soluble fiber obtained from grinding the root of konjac, a plant that has been used as a food and remedy for thousands of years in Asia. Highly refined and uniquely processed glucomannan possesses the greatest viscosity of any single dietary fiber. It is three times more viscous than guar and approximately seven times more viscous than psyllium. Combining glucomannan with alginate and xanthum gum, the viscosity of glucomannan can be amplified to a viscosity three to five times higher than any glucomannan alone. This enhanced viscosity is paramount to its effects, as the viscosity of soluble fiber is directly related to its physiologic effects and ultimately to its overall health benefits in humans.

Specific Health Problems

Clinical studies have repeatedly shown that aftermeal blood glucose levels decrease as soluble fiber viscosity increases.13JM This relationship has also been shown to hold true for the other physiologic benefits produced by soluble fibers including increased insulin sensitivity, diminished appetite, significant weight control, improved bowel movements, and decreased serum cholester01.’~~ Glucomannan lowers postprandial blood glucose by approximately 20% and also lowers insulin secretion by approximately 40%, producing a whole-body insulinsensitivity index improvement of nearly 50%-a phenomenal accomplishment that is unequalled by any drug or natural health product. The highly viscous glucomannan-alginate-xanthumgum blend was shown to sigruficantly improve all aspects of syndrome X by increasing insulin sensitivity, as evidenced by the reductions in total cholesterol (12.4%), LDL cholesterol (22.3%), the ratio of LDL-to-HDL cholesterol (15%), and serum fructosamine (5”/,).l%In another study in similar patients, postprandial blood glucose (27%),postprandial insulin levels (41%), and insulin resistance were estimated to be improved by 56%.13’

Natural Glucosidase Inhibitors Starches, complex carbohydrates, and even simple sugars (disaccharides) like sucrose are broken down in the digestive tract into glucose by the action of certain enzymes. Among the most important enzymes are the alpha-glucosidases that line the intestines. Because these enzymes are essential for the breakdown of starches, complex carbohydrates, maltose, and sucrose into absorbable glucose molecules, their inhibition can diminish the after-meal rise in both glucose and insulin. Acarbose (Precose) and miglitol (Glyset) are approved drugs for treating diabetes by inhibiting alpha-glucosidase. Although clinical studies have shown them to be quite effective, they are also characterized by a high frequency of mild-to-moderate gastrointestinal side effects such as flatulence, diarrhea, and abdominal discomfort. Although these side effects generally diminish in frequency and intensity with time, few patients are willing to put in the necessary time to get over them. Instead of the drug acarbose, we recommend trylng either touchi or mulberry extracts, which are natural and superior to their drug counterparts.

Touchi Extract Touchi is a fermented soybean product that has been used in China and Japan for more than 3000 years. Touchi extract is concentrated to possess high levels of naturally occurring alpha-glucosidase inhibitors. Several clinical studies have documented its effectiveness in

reducing postprandial elevations in blood glucose levels.l3 Longer-term studies have also shown beneFor example, when type II diabetes patients took 300 mg of touchi extract before each meal for 6 months, there were moderate changes in fasting blood glucose and hemoglobin AIC levels. The effects were apparent after only 1 month of use. After 6 months, the fasting blood glucose dropped more than 10 mg/dl in nearly 80% of the patients, and hemoglobin AIC levels fell by more than 0.5% in 60% of patients. Surprisingly, touchi extract also had a mild effect in lowering triglyceride and cholesterol levels, probably through a decrease in insulin resistance. Unlike the drug alpha-glucosidase inhibitors, no side effects have ever been seen with touchi extract and no one in the clinical trials has ever complained of the gastrointestinal side effects that are so characteristic of acarbose.

Moms indica The mulberry plant (Moms indicu) is probably best known as food for silkworms, but it has also been highly regarded in traditional Chinese and Japanese medicine. It has been shown to possess significant hypoglycemic effects in animal studies, and it contains an effective alphaglucosidase inhibitor, along with other compounds that appear to improve blood glucose c ~ n t r o l .Mulberry ~~~,~~ extract has been studied in type I1 diabetes, and the results are excellent. In one study, researchers decided to investigate its effect on blood and RBC lipids, as well as compare its blood glucose-lowering actions to the oral antihyperglycemic drug g1~buride.l~~ Patients were given either mulberry dried leaves at a dose of 3 g/day or one tablet of glyburide (5 mg/day) for 4 weeks. Mulberry therapy sisruficantlyimproved diabetic control in type II diabetic patients (Table 163-5). The results clearly show that the fasting blood glucose concentrations were sigruficantly lowered with mulberry therapy, suggesting that it is effective in controlling diabetes. Compared with glyburide treatment, mulberry therapy sigruficantly reduced fasting blood glucose concentrations of diabetic patients (27%; p c 0.01). However, no sigruficant differences were observed in the blood glucose concentrations between pretreatments and posttreatments with glyburide (p > 0.05). Mulberry extract was also superior to the approved drug in its ability to decrease hemoglobin AIC, cholesterol, LDL, and triglycerides. It also resulted in an increase in HDL (“good cholesterol”). Although these changes were not statistically sigruficant (p > 0.05), there are strong suggestions that this natural product is clearly superior to an established pharmaceutic agent (see Table 163-5). In addition to the benefits on blood glucose levels and blood lipids, mulberry therapy was also shown to reduce the amount of lipid peroxidation to the cell membranes

Diabetes Mellitus

Mulberry

Glyburide Parameter

Before

After

Fasting blood glucose (mg/dl)

154.4 12.5

141.8

190

182

AIC (“A) Cholesterol (rng/dl) Low-density lipoprotein cholesterol (mg/dl) High-density lipoprotein (mg/dl) Triglycerides (rng/dl) Free fatty acids (pmoVdl)

12.4

Chanae (%I

Before

After

Chanae (%)

-8 0

152.7 12.5

110.5 11.2

-27 -1 0

-4

193.7

170.3

-1 2

102.5

95.5

-7

102.1

78.7

-23

49.8

51.3

+3

50.1

59.2

+18

199.5

180

-1 0

200.4

168

-1 6

589.8

580

-2

590.1

520

-1 2

of RBCs, indicating a sigruficant antioxidant effect. Additionally mulberry therapy sisruficantly decreased membrane cholesterolof type II diabetic patients.

The first step in improving insulin function and sensitivity is achieving ideal body weight and following the dietary and lifestyle recommendations given earlier including taking a high-potency multivitamin and mineral formula to ensure the body has all of the necessary essential vitamins and minerals that proper insulin sensitivity requires. If additional support is necessary to bring blood glucose levels under control, we would recommend using in isolation or in scientifically formulated combinations one or more of the following: Gyrnnernu sylvestre extract, bitter melon, I? quinquefolius (American ginseng) or Punax ginseng, and fenugreek seed extract. We also recommend increasing the intake of onions and garlic.

glucose levels, as well as to improve blood glucose These results indicate that gymnema enhances the action of insulin,as these diabetics were not recently diagnosed. With regard to type I1 diabetes, gymnema extract appears to work by enhancing the action of insulin. In one study, 22 type II diabetics were given gymnema extract along with their oral antihyperglycemic drugs.’& All patients demonstrated improved blood glucose control; 21 of the 22 were able to reduce their drug dosage considerably; and 5 subjects were able to discontinue their medication and maintain blood glucose control with the gymnema extract alone. The dosage for gymnema extract (standardized to contain 24% gymnemic acid) is 200 mg twice a day. No side effects have been reported from gymnema extract; however, diabetics on insulin should be careful to monitor blood glucose when beginning this product because insulin dosages may have to be decreased to avoid hypoglycemia.

Gymnema sylvestre

Momordica charantia

Gymnema is another plant from India that has long been used as a treatment for diabetes. Recent scientific investigation has upheld its effectiveness in both type I and type I1 diabetes. Gymnema extracts have been shown to enhance glucose control in diabetic dogs and rabbits. Interestingly, in animals that have their pancreas removed, gymnema possesses no apparent effects, suggesting that it enhances the production or activity of insulin. Like pterocarpus (see earlier), there is evidence in animal studies that gymnema promotes the regeneration of insulin-producing beta cells in the pancreas. Studiesin humans also seem to support the possibility of pancreas regeneration.lU An extract of the leaves of G. sylvestre given to 27 patients with type I diabetes on insulin therapy was shown to reduce insulin requirements and fasting blood

In addition to being eaten as a vegetable in Asia, unripe bitter melon has been used extensively in folk medicine as a remedy for diabetes. The blood glucose-lowering action of the fresh juice or extract of the unripe fruit has been clearly established in modem scientific studies in both type I and type I1 diabetes. Bitter melon is composed of several compounds with confirmed blood glucose-lowering properties. Charantin, extracted by alcohol, is a hypoglycemicagent composed of mixed steroids that is more potent than the oral hypoglycemic drug tolbutamide. Bitter melon also contains an insulin-like polypeptide, polypeptide-P, which lowers blood glucose levels when injected like insulin into type I diabetics. Because it appears to have fewer side effects than insulin, it has been suggested as a replacement for some patients, although the likelihood

x

Im roving Insulin Function an Sensitivity

Specific Health Problems ~

of this application ever being developed is extremely remote. Fortunately, taking as little as 2 oz of the juice has shown good results in clinical trial^.'^^,'^ Unripe bitter melon is available primarily at Asian grocery stores. Health food stores may have bitter melon extracts, but the fresh juice is probably the best to use, as this was what was used in the studies. Bitter melon juice is difficult to make palatable. As its name implies, it is quite bitter, so it is recommended that patients plug their noses and take a 2-oz shot of the juice. The dosage of other forms should approximate this dose.

Panax quinquefolium and Panax ginseng Research conducted at the University of Toronto's Risk Factor Modification Center has uncovered important properties of some ancient natural medicines. In their first studies and published reports, the group used whole powdered American ginseng root and found that a dose of about 3 g before each meal reduced postprandial blood glucose sigruficantly in type 11 diabetic^.'*^-'^ American ginseng is now considered by authorities to be the most evidence-based herbal therapy for type II diabetes.'% P. ginseng can also be helpful. In a double-blind, controlled study, 36 non-insulin-dependent diabetic patients were treated for 8 weeks with ginseng extract at 100 or 200 mg or with a placebo. Ginseng elevated mood, improved psychophysiologic performance, and reduced fasting blood glucose and body weight. The 200-mg dose improved glycated hemoglobin, serum aminotenninalpropetide concentrations, and physical activity.'=

Fenugreek Fenugreek seeds have demonstrated sigruficant antidiabetic effects in experimental and clinical studies. The active principles are the special soluble fiber of fenugreek, along with the alkaloid trigonelline and 4hydroxyisoleucine. Fenugreek appears to be helpful in both type I and type I1 diabetes. Defatted fenugreek seed powder given twice daily at a 50-g dose to type I diabetics resulted in a sigruficant reduction in fasting blood glucose and improved glucose tolerance test results.156A 54% reduction in 24hour urinary glucose excretion and signhcant reductions in LDL and VLDL cholesteroland triglyceride values also o c e . In type II diabetics, the addition of 15 g of powdered fenugreek seeds soaked in water sigruficantly reduced postprandial glucose levels during the meal tolerance test.157 In one study, 25 patients with type I1 diabetes randomly received 1 g/day of fenugreek seed extract or placebo capsules for 2 Complex analysis of the data produced an interesting finding. The group taking the fenugreek seed extract had improved blood glucose measurements (e.g., fasting blood glucose levels

~

~~~

~~

dropped from 148.3 to 119.9 mg/dl), but there was a significant decrease in insulin output. That finding indicates that there was a significant improvement in insulin sensitivity. This effect is most likely due to the 4hydroxyleucine.

Allium cepa and Allium sativum Onions and garlic appear to have significant blood glucose-lowering action. The active principles are believed to be the sulfur-containing compounds ally1 propyl disulphide (APDS) and diallyl disulphide oxide (allicin), respectively, although other constituents such as flavonoids may play a role as well. Although garlic generally has more potent effects, onions can be given at higher dosages and the active compounds appear to be more stable than allicin. Graded doses of onion extracts (1ml of extract = 1 g of whole onion) at levels sometimes found in the diet (i.e., 1 to 7 oz of onion) reduced blood glucose levels during an oral glucose tolerance test in a dose-dependent manner. The effects are similar in both raw and boiled onion extracts, indicating that the active components are probably ~tab1e.l~~ Garlic has a wide range of additionalwell-documented effects useful for the diabetic including helping to improve blood glucose control, lower cholesterol and blood pressure, and inhibit some of the factors associated with increased risk for vascular complications of diabetes such as increased fibrinogen levels.

Preventing Nutritional and Oxidative Stress Diabetes is characterized by increased nutritional and oxidative stress. As individuals with diabetes typically have elevated levels of free radicals and oxidative compounds, they are much more likely to suffer from their damage. These highly reactive compounds bind to and destroy cellular compounds. They also greatly increase the inflammatory process by adding fuel to their destructive fire via increased formation of inflammatory mediators like C-reactive protein. One of the critical goals in nutritionally supporting individuals with diabetes is to flood the body with a high level of antioxidant compounds to counteract the negative effects of free radicals and prooxidants. The implementation of this goal is achieved by using the recommendations given earlier, along with taking a flavonoid-rich extract and alpha-lipoic acid.

Flavonoids Recent research suggests that flavonoids may be useful in treating diabetes, as well as in preventing long-term complications. Flavonoids such as quercetin promote insulin secretion and are potent inhibitors of glycosylation and sorbitol accumulation, while flavonoid-rich

Diabetes Mellitus

extracts like bilberry and hawthorn extracts have been shown to be helpful in diabetic retinopathy and microvascular abnormalities.’@’ The beneficial effects of flavonoids in battling the complications of diabetes are numerous and include the fact that as antioxidants, flavonoids are generally more potent and effective against a broader range of oxidants than the traditional antioxidant nutrients vitamins C and E, beta-carotene, selenium, and zinc. Other beneficial effects include increasing intracellular vitamin C levels, decreasing the leakiness and breakage of small blood vessels, preventing easy bruising, promoting wound healing, and providing immune system support. Good dietary sources of flavonoids include citrus fruits,berries, onions, parsley, legumes, green tea, and red wine. In individuals with diabetes who are already showing signs of a long-term complication, it is extremely important to take a flavonoid-rich extract, given the evidence. Because certain flavonoids concentrate in specific tissues, it is possible to take flavonoids that target specific body tissue. For example, because the flavonoids of bilberry (Vuccinium myrtillus) have an affinity for the eye including the retina, bilberry is probably the best choice in a diabetic already exhibiting signs of diabetic retinopathy. Idenhfy which flavonoid or flavonoid-rich extract is most appropriate for the patient and direct him or her to take it according to the recommended dosage. There is tremendous overlap among the mechanisms of action and benefits of flavonoid rich extracts; the key point here is to take the one that is most specific to the person’s needs (Table 163-6).

Alpha-lipoic Acid Alpha-lipoic acid is a vitamin-like substance that is often described as “nature’s perfect antioxidant.” First of all, alpha-lipoic acid is a small molecule that is efficiently absorbed and easily crosses cell membranes. Unlike vitamin E, which is primarily fat soluble, and vitamin C, which is water soluble, alpha-lipoic acid can quench either water- or fat-soluble free radicals both inside the cell and outside in the intracellular spaces. Furthermore, alpha-lipoic acid extends the biochemical life of vitamin C and E, as well as other antioxidants. Alpha-lipoic acid is an approved drug in Germany for the treatment of diabetic neuropathy. In fact, it has been successfully used in Germany for more than 30 years. The beneficial effects of alpha-lipoic acid in diabetic neuropathy have been confirmed in several double-blind studies Although alphaat a dosage of 300 to 600 mg daily.161J6z lipoic acid’s primary effect in improving diabetic neuropathy is thought to be the result of its antioxidant effects, it has also been shown to lead to an improvement in blood glucose metabolism, improve blood flow to peripheral nerves, and actually stimulate the regeneration of nerve fibers. Its ability to improve blood glucose metabolism is a result of its effects on glucose metabolism and an ability to inmase insulin sensitivity. Its importance in treating diabetic neuropathy cannot be overstated.

Recommendations for Specific Chronic Complications Following are additional recommendations for dealing with specific complications of diabetes. The most

Flavonoids for the treatment of diabetes and diabetic complications Flavonoid-rich extract Bilberry extract (25% anthocyanidins) Ginkgo biloba extract (24% ginkgo flavonglycosides)

Dailv dose

160-320mg 120-240mg

Indication Best choice in diabetic retinopathy or cataracts Best choice for most people older than age 50.Protects brain and vascular lining. Very important in improving blood flow to the extremities, neuropathy, and foot ulcers.

Grape seed extract or pine bark extract (95% procyanidolic oligomers)

150-300mg

Systemic antioxidant; best choice for most people younger than age 50, especially if retinopathy, hypertension, easy bruising, and poor wound healing exist Also specific for the lungs, varicose veins, and protection against cardiovascular disease

Green tea extract (60%-70% total polyphenols) Hawthorn extract (10% procyanidins)

150-300mg

Best choice in the early stage of type I diabetes or if there is a family history of cancer

Milk thistle extract (70% silymarin) Mixed citrus flavonoids Quercetin

150-300mg 100-300mg 1000-2000mg 150-300mg

Best choice in cardiovascular disease or hypertension Best choice if showing signs of impaired liver function Least expensive choice but may not provide same level of benefit; OK if no complication present Good choice if allergies, symptoms of prostate enlargement or bladder irritation, or eczema are also present

Specific Health Problems

important method for reducing the risk of these complications is achieving optimal blood glucose control.

Elevated Cholesterol Key natural products to lower cholesterol levels in diabetes are soluble fiber, garlic, and niacin. These agents are discussed fully in Chapter 150. Because taking niacin at higher dosages (e.g., 23000 mg) can impair glucose tolerance, many physicians have avoided niacin therapy in diabetics, but newer studies with slightly lower dosages (1000 to 2000 mg) of niacin have not shown it to adversely affect blood glucose regulation.lG For example, during a &week, double-blind, placebocontrolled trial, 148 type II diabetes patients were randomized to placebo or 1000 or 1500 mg/day of niacin; in the niacintreated groups there was no sigruficant loss in glycemic control, and the favorable effects on blood lipids were still apparent.la Other studies have actually shown hemoglobin AIC to drop, indicating improvement in glycemic control.16 The most common blood lipid abnormality in type II diabetic patients is elevated triglyceride levels; decreased HDL cholesterol levels; and a preponderance of smaller, denser LDL particles. Niacin has been shown to address all of these areas much more signhcantly than the statin or other lipid-lowering drugs. However, one reasons that niacin may not be as popular as it should be is the side effect of skin flushing-kind of like a prickly heat rash that typically occurs 20 to 30 minutes after the niacin is taken and disappears in about the same time frame. Other occasional side effects of niacin include gastric irritation, nausea, and liver damage. To reduce the side effect of skin flushing, the newer time-released formulas including the prescription version Niaspan should be used and taken just before going to bed. Most people sleep right through the flushing reaction. Taking cholesterol-lowering agents at night is best because most of the cholesterol manufactured by the liver happens at night. Another approach to reduce flushing is to use inositol hexaniacinate. This form of niacin has long been used in Europe to lower cholesterol levels and also to improve blood flow in intermittent claudication-a peripheral vascular disease that is quite common in diabetes. It yields slightly better clinical results than standard niacin but is much better tolerated, in terms of both flushing and, more importantly, longterm side effects.lMIf inositol hexaniacinate does not work, regular niacin can be tried. Our experience is that some people only respond to the regular niacin. If regular niacin or inositol hexaniacinate is being used, a dose of 500 mg should be given at night before going to bed for 1week. The dosage should be increased to 1000 mg the next week and 1500 mg the following week. The 1500-mg dosage should be given for 2 months before checking the response-the dosage

can be adjusted up or down depending on the response. Tie-release niacin products like Niaspan can be used at the full dosage of 1500 mg at night from the beginning. Regardless of the form of niacin being used, periodic checking (minimumevery 3 months) of cholesterol, AIC, and liver function tests are strongly indicated.

Retinopathy and Cataracts Diabetic retinopathy has two forms: (1) "simple" retinopathy consisting of bursting of blood vessels, hemorrhages, and swelling; and (2) proliferative retinopathy with newly formed vessels, scarring, more serious hemorrhage, and retinal detachment. The development of laser photocoagulation therapy is an important treatment for the more severe proliferative retinopathy but is still not indicated in milder forms of retinopathy because the risk of visual loss due to the side effects usually outweighs the benefits. As with other complications of diabetes, prevention is the best treatment with the key factor being maintaining optimal blood glucose control. Hemoglobin AIC should be monitored frequently. Extremely important in the battle against retinopathy are flavonoid-rich extracts, especiallybilberry, pine bark, and grape seed extracts. The flavonoids in these extracts exert many benefits in diabetes including an ability to increase intracellular vitamin C levels, decrease the leakiness and breakage of capillaries, prevent easy bruising, and exert potent antioxidant effects. These effects are of particular value in dealing with the microvascular abnormalities of diabetes. Because the flavonoids in bilberry, pine bark, and grape seed extract have an affinity for the blood vessels of the eye and improve circulation to the retina, they are particularly helpful in slowing the progression of diabetic retinopathy as evidenced by positive results in more than a dozen clinical

Neuropathy In addition to alpha-lipoic acid and the basic supplementation program (magnesium is particularly important), two additional natural medicines along with acupuncture deserve mention: Gamma-linolenic acid (GLA) has been shown to improve and prevent diabetic neuropathy. Diabetes is associated with a substantial disturbance in essential fatty acid metabolism. One of the key disturbancesis the impairment in the process of converting linoleic acid to GLA. As a result, providing GLA in the form of borage, evening primrose, or black currant oils can bypass some of this disturbance. In the GLA Multicenter Trial, 111 patients with mild diabetic neuropathy were given either GLA at a dose of 480 mg/day or a placebo for 1 year. Sixteen different parameters were assessed including conduction velocities, hot and cold thresholds, sensation, tendon reflexes, and muscle strength.

Diabetes Mellitus

After 1year, all 16 parameters improved, 13 of them to a statistically sigruficant degree. Treatment was more effective in relatively well-controlled than in poorly controlled diabetic patients. The latter finding highlights the need for a comprehensive approach in controlling blood glucose levels rather than expecting a single physiologic aid (i.e., GLA) to compensate for poor control. Capsaicin is the active component of cayenne pepper (Capsicum frutescms), which stimulates and then blocks the small nerve fibers that transmit the pain impulse by depleting these fibers of a transmitting substance known as substance P.169Topically applied capsaicin has been shown to be of considerable benefit in relieving the pain of diabetic neuropathy in numerous double-blind studies. Roughly 80% of people with diabetic neuropathy experience tremendous pain relief.170Commercial ointments containing 0.025% or 0.075% capsaicin are available over the counter. It is recommended to have the patient apply the 0.75% cream twice daily to the affected area (have them cover the hand with plastic wrap to avoid the capsaicin coming in contact with the eyes or mucous membranes). It may take a few days for the cream to start working, and it will only continue to work with regular application. Acupuncture can also be helpful in improving neuropathy. The scientific investigation of acupuncture in diabetes includes both experimental and clinical studies. For example, animal experiments have shown that acupuncture can act on the pancreas to enhance insulin synthesis; increase the number of receptors on target cells; and accelerate the utilization of glucose, resulting in lowering of blood glucose.171However, the best documentation for the clinical application of acupuncture is in treating chronic painful diabetic neuropathy. In one clinical study, 77% of patients treated with acupuncture noted sigruficant improvement in their symptoms with 21% noting that their symptoms were completely eliminated.'" That success rate is excellent considering the long-standing nature of the condition in most of the cases and the fact that no side effects were observed.

Nephropathy Many of the previous recommendations also apply to preventing diabetic nephropathy. In fact, one more strong reason to adhere to the dietary principles given is for the protection of the diabetic kidney. Diets that purport to control blood glucose by relying on low carbohydrate and high protein work in the short term to keep blood glucose under control, but they put a strain on the kidneys, which are forced to dispose of a great deal more waste. The main waste materials disposed of by the kidneys are nitrogenous byproducts of protein metabolism (like ammonia and urea). When excessive protein is consumed, the amount of nitrogenous waste sent for disposal is greatly increased. Although a low-protein

diet is not required except when nephropathy has progressed sigruficantly,it is wise to adhere to a diet with a moderate amount of ~ r 0 t e i n .The l ~ ~low GI/low GL diet outlined in Chapter 44 is the ideal diet to help preserve normal kidney function in diabetics. Another feature of this diet that makes it excellent for the kidneys is its high dietary fiber content. Dietary fibers (especially water soluble) are fermented in the colon to produce short-chain fatty acids. These byproducts are the primary fuel for colonic cells and, if present in high amounts, they greatly increase the waste removal capabilities of the colon. It has been shown that in the presence of a high-fermentable fiber diet, the colon turns into the "second kidney" as it collects nitrogenous wastes out of the blood and disposes of them via the feces. This has been shown to greatly reduce the workload and stress on the kidneys.174 Highlighting just how important some of basic supplement recommendations are in halting the progression of diabetic nephropathy are the results of a study of 30 type 11 diabetes patients with elevated albumin in their urine. The patients received vitamin C (1250 mg) and vitamin E (680 IU)daily or a matching placebo for 4 weeks, followed by a 3-week wash-out period before being switched to the other treatment.'75 The results were that the vitamins were successful in reducing urinary albumin levels by an average of nearly 20%, indicating that antioxidant therapy may halt or slow down the progression of kidney disease in diabetics. Finally, achieving normal blood pressure is critically important in preventing diabetic nephropathy. If drugs are necessary, the angiotensin-converting enzyme (ACE) inhibitors and ACE receptor blockers offer the greatest benefits in dealing with diabetic nephr~pathy.'~~ They are now often prescribed in low doses to help prevent nephropathy, even in the absence of high blood pressure.

Poor Wound Healing A deficiency of virtually any essential nutrient can lead to impaired wound healing. Key nutrients include vitamin C and zinc, both of which are often deficient in the diabetic. Taking a high-potency multivitamin mineral formula should improve nutritional status and promote proper wound healing. For topical application we recommend using pure (100%) Aloe vera gel. The wound healing effects of aloe Vera are well known.It contains a number of compounds necessary for wound healing including vitamin C, vitamin E, and zinc. Aloe Vera has been shown to stimulate many factors important to wound repair. Apply it to affected areas (not open wounds) two to three times daily.

Foot Ulcers Lack of blood supply, poor wound healing, and peripheral neuropathy are key factors in the development of

Specific Health Problems

diabetic foot ulcers. Key strategies in prevention and treatment are proper foot care (including professional care of nails and calluses) preferably by a podiatrist, regular physician’s examination of the feet, the avoidance of injury, the avoidance of tobacco in any form, and employing methods to improve local circulation. Proper foot care includes keeping the feet clean, dry, and warm and wearing well-fitted shoes. Tobacco use in any form constricts the peripheral blood vessels and can lead to more serious peripheral vascular disease with severe arterial blockages. Diabetes and smoking are like nitro and glycerin-a sure recipe for catastrophe. Circulation can be improved by exercising regularly, avoiding sitting cross-legged or in other positions that compromise circulation, and massaging the feet lightly upwards. Ginkgo biloba or grape seed extract can also be used to support optimal circulation.

THERAPEUTIC APPROACH Effective treatment of the diabetic patient requires the careful integration of wide-ranging therapies and patients who are willing to substantially improve their lifestyles. Trpe 11 diabetes is usually the end result of many years of chronic metabolic insult and, although treatable with the ~ t u r ametabolic l approach presented here, its ultimate resolution will take persistence. Although much of the information presented in this chapter has focused on type 11 diabetes, it is equally appropriate for the type I patient, with the exception that, according to current information, the type I diabetic will always require insulin. The first step in the therapy of either IDDM or NIDDM is a thorough diagnostic work-up. Of particular importance is identdymg any of the complications of diabetes. The patient’s diet, environment, and lifestyle should be carefully studied to rule out any exposure to agents that may be inducing his or her glucose intolerance. Then a diet, exercise, and supplement program that meets the individual needs of the patient and his or her current glucose tolerance should be developed. For maximum efficacy, the patient’s weight must be normalized (see Chapter 194 for additional recommendations). When treating patients with severe or uncontrolled diabetes, a high level of awareness of the acute diabetic complications must be maintained. The clinician should be aware of the early signs and symptoms of diabetic acidosis and hyperosmolar nonketogenic coma and have the patient hospitalized at the first signs. Finally, the patient must be monitored carefully, particularly if he or she is on insulin or has relatively uncontrolled diabetes. Patient symptomatology, home glucose monitoring, and the HgbAIC test are, at this time, the best ways to monitor the progress of the patient. It is important to recognize that as these therapies take effect, the patient’s drug dosages must be altered and that

a good working relationship with the prescribing doctor will greatly aid the healing process. The ultimate goal

is to reestablish normal glycemia and prevent the development of (or ameliorate)the complications of diabetes. Note: Under no circumstances should a patient be suddenly taken offdiabetic drugs, especially insulin. According to current information, an lDDM patient will never be able to stop taking insulin.

Diet The optimal health food diet detailed in Chapter 44 is clearly the diet of choice. All simple, processed, concentrated carbohydrates must be avoided. Complexcarbohydrate, high-fiber foods should be stressed, and fats should be kept to a minimum.Legumes, onions, and garlic are particularly useful and should be encouraged.

Supplementation for Type I Diabetes The recommended supplementation program depends on the degree of blood glucose control as evident by self-monitored blood glucose and AIC levels. Recently diagnosed type I diabetes Foundation supplements High-potency multivitamin and mineral Fish oils: 600 mg of EPA and DHA daily Vitamin C: 500 to 1500 mg daily Vitamin E: 400 to 800 IU daily Niacinamide: 25 to 50 mg per kg body weight Green tea extract: Recommended dosage for children younger than the age of 6 years is 50 to 150 mg; for children 6 to 12 years old, 100 to 200 mg; for children older than 12 years old and adults, 150 to 300 mg. The green tea extract should have a polyphenol content of 80% and be decaffeinated. Level 1-achievement of targeted blood glucose levels, AIClevels less than 770, no lipid abnormalities, no signs of complications Foundation supplements High-potency multivitamin and mineral Fish oils: 600 mg of EPA and DHA daily Vitamin C: 500 to 1500 mg daily Vitamin E: 400 to 800 IU daily Level 2-failure to achieve targeted blood glucose levels, AICbetween 7%and 8% Foundation supplements G. sylvestre extract (24% gymnemic acid): 200 mg twice daily Biotin; 8 mg twice daily Optional Bitter melon juice: 2 to 4 oz daily Level I f a i l u r e to achieve targeted blood glucose levels, AICbetween 8% and 9% Foundation supplements G. sylvestre extract (24% gymnemic acid): 200 mg twice daily

Diabetes Mellitus

Biotin: 8 mg twice daily Glucomannan (or other soluble source at equivalent dosage): 1000 mg before meals Optional: Bitter melon juice: 2 to 4 oz daily Level &failure to achieve targeted blood glucose levels, AIC greater than 9% Foundation supplements G. sylvestre extract (24% gymnemic acid): 200 mg twice daily Biotin: 8 mg twice daily Glucomannan (or other soluble source at equivalent dosage): 1000 mg before meals Glucosidase inhibitor. Use one of the following: Touchi extract: 300 mg three times daily with meals Mulberry extract: equivalent to 1000 mg dried leaf three times daily Optional: Bitter melon juice: 2 to 4 oz daily

Insulin enhancer. Use one of the following: G. sylvestre extract (24% gymnemic acid): 200 mg twice daily Fenugreek extract 1g daily Garlic: minimum 4000 pg of allicin per day Level &failure to achieve targeted blood glucose levels, AIC above 9% Foundation supplements Glucomannan (or other soluble source at equivalent dosage): 1000 mg before meals Insulin enhancer. Use one of the following: G. sylvestre extract (24% gymnemic acid): 200 mg twice daily Fenugreek extract 1g daily Garlic: minimum 4000 pg of allicin per day Glucosidase inhibitor. Use one of the following: Touchi extract: 300 mg three times daily with meals Mulberry extract: equivalent to 1000 mg dried leaf three times daily

If self-monitored blood glucose levels do not improve after 4 weeks of following the recommendations for the current level, move to the next highest level. For example, if the patient starts out having an AIC level of 8.2% and a fasting blood glucose level of 130 mg/dl, he or she should start on level 2 support. If after 4 weeks the average reading has not dropped to less than 110 mg/dl, then move to level 3 support. If blood glucose levels and AIC levels do not reach the targeted levels with level 4 support, then a prescription medication (either an oral hypoglycemic drug or insulin) is required.

If self-monitored blood glucose levels do not improve after 4 weeks of following the recommendations for the current level, move to the next highest level. For example, if the patient starts out having an AIC level of 8.2% and a fasting blood glucose level of 130 mg/dl, he or she should start on Level 2 support. After 4 weeks, if the average reading has not dropped to less than 110 mg/dl, the patient should move to Level 3 support. If blood glucose levels and AIC levels do not reach the targeted levels with Level 4 support, then a prescription medication (either an oral hypoglycemic drug or insulin) is required.

Supplementation for Type II Diabetes The recommended supplementation program depends on the degree of blood glucose control, as evident by self-monitored blood glucose and AIC levels. Level l-achievement of targeted blood glucose and AIC levels less than 7%, no lipid abnormalities, no signs of complications Foundation supplements High-potency multivitamin and mineral Greens drink: one serving daily Fish oils: 600 mg of EPA and DHA daily Vitamin C: 500 to 1500 mg daily Vitamin E: 400 to 800 IU daily Level 2-failure to achieve targeted blood glucose levels, A,C between 7% and 8% Foundation supplements Glucomannan (or other soluble source at equivalent dosage): 1000 mg before meals Level "Failure to achieve targeted blood glucose levels, AIC between 8% and 9% Foundation supplements Glucomannan (or other soluble source at equivalent dosage): 1000 mg before meals

Additional Supplements for the Prevention and Treatment of Diabetic Complications With the presence of any complication, the following should be added to the foundation supplement program: Alpha-lipoic acid: 300 to 600 mg daily Grape seed extract (or other appropriate flavonoidrich extract): 150 to 300 mg daily For specific complications, follow the foundation supplement program with the addition of alpha-lipoic acid and an appropriate flavonoid-rich extract, as well as the specified supplement(s) listed below. For high cholesterol levels and other cardiovascular risk factors Total cholesterol greater than 200 mg/dl or LDL cholesterol greater than 135 mg (100 mg if history of heart attack): Glucomannan (or other soluble source at equivalent dosage): 1000 mg before meals Niacin (or inositol hexaniacinate): 1000 to 1500 mg at night at bedtime Garlic: minimum of 4000 pg of allicin daily

Specific Health Problems

HDL cholesterol below 45 mg/dl: Niacin (or inositol hexaniacinate):1000 to 1500 mg at night at bedtime Lipoprotein (a) above 40 mg/dl: Niacin (or inositol hexaniacinate):1500 mg at night at bedtime Triglycerides above 150 mg/dl: Niacin (or inositol hexaniacinate):1500 mg at night at bedtime C-reactive protein above 1.69 mg/l: Vitamin E: 800 IU daily Fibrinogen above 400 m g / l Garlic extract: 4000 pg daily Ferritin (an iron-binding protein) greater than 200 pg/l: Eliminate red meat from the diet, avoid iron supplements, and increase consumption of whole grains.

For diabetic retinopathy Bilberry extract: 160 to 320 mg daily or grape seed extract 150 to 300 mg daily For diabetic neuropathy Gamma-linolenic acid from borage, evening primrose, or blackcurrant oil: 480 mg daily Capsaicin (0.075%) cream: apply to affected area twice daily For diabetic nephropathy Follow recommendations for high blood pressure above unless kidney function falls below 40% of normal. Be cautious when recommending magnesium and potassium supplements. For poor wound healing Aloe Vera gel: Apply to affected areas twice daily. For diabetic foot ulcers G. bilobu extract: 120 to 240 mg daily; or grape seed extract: 150 to 300 mg daily

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133. Vuksan V, Jenkins DJ, Spadafora P, et al. Konjac-mannan (glucomannan) improves glycemia and other associated risk factors for coronary heart disease in type II diabetes. A randomized controlled metabolic trial. Diabetes Care 1999;22:913-919. 134. Jenkins DJ, Kendall CW,Axelsen M, et al. Viscous and nonviscous fibres, nonabsorbable and low glycaemic index carbohydrates, blood lipids and coronary heart disease. Curr Opin Lipidol 2OOO; 11:49-56. 135. Marlett JA, McBumey MI, Slavin JL. Position of the American Dietetic Association: health implications of dietary fiber. J Am Diet ASSW2002;102993-1O00. 136. Vuksan V, Sievenpiper JL, Owen R, et al. Beneficial effects of viscous dietary fiber from Konjac-mannan in subjects with the insulin resistance syndrome: results of a controlled metabolic trial. Diabetes Care 2000;23:9-14. 137. Vuksan V, Lyon M, Breitman P, et al. %Weekconsumption of a highly viscous dietary fibre blend results in improvements in insulin sensitivity and reductions in body fat. Results of a double blind, placebo controlled trial. Presented at the 64th Annual Meeting of the American Diabetes Association, Orlando, FL; June 48,2004. 138. Fujita H, Yamagami T, Ohshima K. Fermented soybeanderived water-soluble Touchi extract inhibits alpha-glucosidase and is antiglycemic in rats and humans after single oral treatments. J Nutr 2001;131:1211-1213. 139. Hiroyuki F, Tomohide Y, Kazunori 0. Efficacy and safety of Touchi extract, an alpha-glucosidase inhibitor derived from fermented soybeans, in non-insulin-dependent diabetic mellitus. J Nub Biochem 2001;12351-356. 140. Fujita H, Yamagami T, Ohshima K. Long-term ingestion of a fermented soybean-derived Touchi-extract with alpha-glucosidase inhibitory activity is safe and effective in humans with borderline and mild type2 diabetes. J Nutr 2001;131:2105-2108. 141. Asano N, Oseki K, Tomioka E, et al. N-containing sugars from M o m alba and their glycosidase inhibitory activities. Carbohydr Res 1994;259243-255. 142. Chen F, Nakashima N, Kimura I, et al. Hypoglycemic activity and mechanisms of extracts from mulberry leaves (folium mori) and cortex mori radicis in streptozotocin-induced diabetic mice. Yakugaku Zasshi 1995;115:476-482. 143. Andallu B, Suryakantham V, Lakshmi Srikanthi B, et al. Effect of mulberry ( M m i n d h L.) therapy on plasma and erythrocyte membrane lipids in patients with type II diabetes. Clin Qlim Acta 200181447-53. 144. Porchezhian E, Dobriyal RM. An overview on the advances of Gyrnnema sylvestre: chemistry, pharmacology and patents. Pharmazie 2003;58:5-12. 145. Shanmugasundaram ER, Rajeswari G, Baskaran K, et al. Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-dependent diabetes mellitus. J Ethnopharmacol 1990;30: 281-294. 146.Baskaran K, Ahamath BK, Shanmugasundaram KR, et al. Antidiabetic effect of a leaf extract from Gymnema sylvestre in noninsulin dependent diabetes mellitus patients. J Ethnopharmacol 1990;30295-305. 147. Srivastava Y, Venkatakrishna-Bhatt H, Verma Y, et al. Antidiabetic and adaptogenic properties of Momordica charantia extract. An experimental and clinical evaluation. Phytother Res 1993;7285-289. 148.Welihinda J, Karunanaya EH, Sheriff MHR, et al. Effect of Momordica charantia on the glucose tolerance in maturity onset diabetes. J Ethnopharmacol1986;17277-282. 149.Vuksan V, Stavro MP, Sievenpiper J, et al. American ginseng (Panax quinquefolius) reduces postproandial glycemia in nondiabetic subjects with type 11 diabetes mellitus. Arch Intern Med 2000;160:1009-1013. 150. Vuksan V, Stavro MP, Sievenpiper J, et al. Similar postprandial glycemic reductions with escalation of dose and administration

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Endometriosis Tori H L I ~ S O S I II,) C H A Y 7 l 'E K C UN '1.E N '1-S Diagnostic Summary

1643

General Considerations 1643 Etiologic Theories 1643

Therapeutic Approach 1647 Diet 1647 Supplements 1647 Botanical Medicines 1647 Topical 1647

Diagnosis 1644 Therapeutic Considerations 1644 Diet 1644 Nutritional Supplements 1645 Botanical Medicines 1646 Other Considerations 1647

DIAGNOSTIC SUMMARY Triad of symptoms: dysmenorrhea, dyspareunia, and infertility Physical examination reveals one or more of the following: tenderness of the pelvic area or cul-de-sac, or both; enlarged or tender ovaries; a uterus that tips backward and lacks mobility; fixed pelvic structures; and adhesions Pelvic ultrasounds: detection and consistency of endometriomas Definitive diagnosis: a laparoscopy or laparotomy visualizing endometrial implants within the pelvic cavity

GENERAL CONSIDERATIONS Endometriosis affects 10% to 15% of menstruating women between the ages of 24 and 40 years old. The main risk factor for endometriosis is heredity. Women with a mother or a sister with endometriosis have an increased risk. Also, women with shorter menstrual cycles and longer duration of flow have been found to be at higher risk for endometriosis. Lack of exercise from an early age, a high-fat diet, use of intrauterine devices, increased or unbalanced estrogen levels, and even naturalred hair color have been suggested as factors in the development of endometriosis. A greater number of

women with adhesions or endometriosis, or both, have reported abuse in their history. Increased immune action within the pelvic cavity and the possibility of antibody reactions to sperm has prompted recognition of an immunologic basis for endometriosis. Additional possible risk factors are immune dysfunction; prenatal exposure to high levels of estrogens; exposure to environmental estrogens or endocrine disruptors (polychlorinated biphenyls [PCBs], weed killers, plastics, detergents, household cleaners, tin can liners); long-term dioxin exposure; and inappropriate liver metabolism and excretion of estrogens.

Etiologic Theories The predominant theory first proposed in 1927, retrograde flow, proposed that during menses, blood flows backward and becomes seeds of implants in the pelvic cavity. The problem found with this theory was that more than 90% of menstruating women without endometriosis have retrograde flow; thus this theory was challenged and raised questions as to the biochemical and immunologic differences causing implantation of endometrial tissue within the pelvic environment. Some theories are based on findings that endometrial implants from women with endometriosis compared with normal women are biochemically different. 1643

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Other findings suggest that cells may only implant in women with altered cell immunity. Implants found in odd locations such as the nose and lungs suggest transportation of endometrial tissue through lymphatic channels and blood vessels. Some researchers believe the implants to be of embryologic origin, when pieces of the uterus were left behind during development and, when activated, secrete a chemical causing the nearby capillaries to bleed. Other research on endometriosis in baboons suggests activation by environmental toxins that mimic estrogens. Immunologic alterations may exist in women with endometriosis. Women with endometriosis have been found to have suppressed natural killer cell activity in their peritoneal fluid, high levels of immunoglobulins IgG and IgM, and high levels of autoantibodies against ovary and endometrial cells. Currently, there is no clear-cut understanding as to the cause of endometriosis.

DIAGNOSIS In some cases symptoms begin with the onset of menstruation, but in most, symptoms begin later and progressively worsen with time. The triad of symptoms is dysmenorrhea (pain with menses), dyspareunia (pain with vaginal intercourse), and infertility. Acute pain occurs before menses and can last for a day or two during menses or throughout the month. For some women, vomiting, diarrhea, and fainting can occur concurrently with the intense pelvic/abdominal cramping and even laborlike pains. Other pains can be chronic bearing-down pain and pressure on the low back with pains sometimes radiating down the legs. Other symptoms can include lower back pain, pain with urination or bowel movements, bleeding from the nose/bladder or bowels, and fatigue. Endometriomas, enlarged areas of ectopic endometrial involvement on the ovaries, are found in two of three patients with endometriosis. Infertility may be a cause of endometriosis rather than a result. There may be immune action within the pelvic cavity and the possibility of antibody reactions to sperm, which would suggest an immunologicbasis for endometriosis. Endometriosis can result in infertility and miscarriage. Data suggest that excessive amounts of free radicals are produced in endometriosis. Free radicals are intimately involved in implantation, and there needs to be an optimum level of free radicals in carrying out this process.' Other findings suggest that infertility is a cause of endometriosis, due to the unruptured follicle, rather than a result. Whether infertility is a cause or result of endometriosis, tuba1 scarring, adhesions, and unruptured follicles are common findings in women having endometriosis and infertility problems.

Physical examination reveals one or more of the following: tenderness of the pelvic area or cul-de-sac, or both; enlarged or tender ovaries; a uterus that tips backward and lacks mobility; fixed pelvic structure; and adhesions. Endometrial tissue can be found on surgical scar tissue, in the vagina, and on the cervix. Physical examination during the first or second day of menses highhghts tender areas.in the septum between the rectum and vagina, most likely correlated with endometriosis. An ultrasound of the pelvis can be useful in assessing pelvic pain and tumors but is not a definitive tool in diagnosing endometriosis. It can detect a mass on the ovary and determine size, characteristics, and consistency of the endometriomas. A blood test, CA-125, can have positive results in endometriosis but cannot differentiate among that and uterine fibroids, malignancies, and even normal tissue. Definitive diagnosis of endometriosis can only be accomplished with a biopsy using either a laparoscopy or a laparotomy. Endometrial implants or endometriomas, or both, are then visualized. Growth of endometrial implants are thought to be stimulated by estrogen. Therapeutic treatment aimed at manipulating the body's own level of hormones has had a positive effect.

THERAPEUTIC CONSIDERATIONS Even though we are not certain as to the cause of endometriosis, and we have several possible viable theories, women seek treatment due to the severity or worsening of their symptoms. A curious feature of endometriosis is that the pain and extent of the disease correlate poorly. Women with fixed ovaries and large endometriomas may only report mild discomfort, while those with smaller lesions may report severe pain and even chronic pain. It appears that the severity of the symptoms is more correlated with the depth of the lesions rather than the number of lesions.

Diet Several dietary principles are key in a natural medicine approach to endometriosis: Normalize the immune response Optimize liver function to conjugate and metabolize hormones and to detoxify endogenous and exogenous toxins Eliminate metabolic wastes Assist optimal transit time and proper intestinal microflora Foods high in fiber are associated with optimal transit time in the intestines and an optimal balance of friendly microorganisms within the large intestines (see Chapter 118).These microorganisms, better known as gut flora,

Endometriosis crowd out the other types of flora that deconjugate estrogens and allow estrogens to recycle back through the body. Studies suggest that an intake of less protein, high fiber, and a vegetarian diet lead to a decrease of biologically active unconjugated estrogens in blood plasma? Although higher-protein diets are found to provide enzymes for the detoxification pathways of estradiol? vegetarian diets are of greater value due to their lower fat content. Animal protein diets, especially red meat, contain large amounts of arachidonic acid, which promotes inflammatory prostaglandins and thus inflammation and pain. By increasing the diet with vegetable protein, soy, nut butters such as almond, and salmon, we tip the inflammatory pathway toward antiinflammatory prostaglandins that inhibit tumor growth-possibly endometrial growth. By increasing the intake of vegetables, specifically those that enhance liver function, cell damage from toxins and metabolites is prevented. "Liver foods" to increase are carrots, beets, and cabbage-family vegetables due to their known help in phase 2 of the liver's detoxification pathway. Indole-3-carbino1,found in broccoli, Brussels sprouts, cabbage, and cauliflower, favors the less active metabolite of estrogen? Other livercleansing foods are beets, carrots, artichokes, lemons, dandelion greens, watercress, and burdock root. Onions, garlic, and leeks contain organosulfur compounds, which enhance the immune system and induce enzymes that detoxlfy in the liver. In addition, they contain the bioflavonoid quercetin, which is known to stimulate the immune response, protect against oxidation, block the inflammatory response, and inhibit tumor growth? Organically grown vegetables are expected to contain lower levels of pesticides that may also mimic estrogen. The isoflavones in soy products and the lignans in flax seeds may also be important in a dietary approach to endometriosis. Many people might claim that these phytoestrogen compounds should be avoided, thinking they would stimulate the growth of endometriosis implants, much like our concern about estrogen. However, we have found the results to be quite contrary to this claim; these compounds appear to help alleviate endometriosis symptoms. Seasonings such as turmeric (curcumin) protect against environmental carcinogens, decrease inflammation, and increase bile secretion. Adding a tablespoon of milk thistle seeds that have been soaked and ground can also help with liver function. Fresh flax seeds increase antiinftammatory fatty acids. Seasoning with fucus (a seaweed) helps stimulate T-cell production and absorb toxins? Foods to decrease include sugar, caffeine, dairy, red meat, and alcohol. Sugar is known to increase estrogen levels in males? Ehdometriosis is found to be correlated with caffeine consumption. Women consuming 5 to 7 g of

caffeine monthly had a 1.2-times incidence of endometriosis, while those consuming more than 7 g had a 1.6-timesincrease? The Environmental ProtectionAgency estimates that 90% of human dioxin exposure is through food, primarily meat and dairy products? Cheese, milk, and cottage cheese cause the lipid pathway to be tipped toward prostaglandins and leukotrienes that cause inflammation, smooth muscle contraction, and vascular constriction.Alcohol usage depletes stores of B vitamins in the liver and has estrogenic effects on the body.

Nutritional Supplements Vitamin C Studies with the use of vitamin C show increase in cellular immunity,decrease in autoimmune progression, and decrease in fatigue.1° In addition, vitamin C enhances immunity and decreases capillary fragility and tumor growth, all of which are evident at various levels in women with endometriosis. Studies on autoimmune progression indicate the effectiveness of high levels of vitamin C."

Beta-carotene Beta-carotenehelps enhance immunity.Studies show that use of betacarotene inmased T-cell levels after 7days.12In

addition, beta-carotenewas shown to be protective against early stages of tumor growth.13Impairment of phagocytosis is seen in vitamin A-deficient states.14 Although vitamin A was used in the latter study, one third of betacarotene is converted to the active form of vitamin A, that of retinol. Additional studies suggest that immune function is due to carotenoids rather than vitamin A.15

Vitamin E Vitamin E helps to correct abnormal progesterone-toestradiol ratios in patients with mammary dysplasia (increased growth of cells).16Because parallels have been found between abnormal tumor growth in cancer and abnormal growth of lesions in endometriosis, vitamin E supplementation may be advantageous. Although secondary dysmenorrhea is usually involved with endometriosis, studies on the use of vitamin E with primary dysmenorrhea" show benefit, perhaps through the inhibition of the arachidonic lipid pathway. Inhibiting the arachidonic pathway helps prevent the release of chemicals that would normally cause edema, inflammation, and smooth muscle contraction.

Essential Fatty Acids Gamma-linoleic acid (borage, black current, evening primrose oil) and alpha-linolenic acid (flax seed, canola, pumpkin, soy walnuts) help decrease the inflammatory response on the tissue level through pathways that produce prostaglandins in the body. Prostaglandins are various types of potent hormonelike unsaturated fatty

Specific Health Problems acids that act on target organs to increase inflammation, increase smooth muscle contractions, decrease inflammation, inhibit tumor growth, increase edema, and constrict vessels. Depending on one of three main pathways of prostaglandin production, the effects are helpful or harmful to the body. Although animal fats produce a pathway of prostaglandin products that increase inflammation, muscle constriction, and edema, by taking in more amounts of fats from the other two pathways, that of gamma-linoleic acid and alpha-linolenic acid, the opposite effects can happen in the body. This means these fatty acids can produce the prostaglandins involved in inhibiting tumor growth, dilating smooth muscle, and decreasing inflammation.18 Because endometriosis implants are thought to secrete chemicals that cause leakage from nearby capillary beds, decreasing the permeability of these vessels could help control the tissue destruction and adhesions, decreasing irritation in the pelvis. An interesting illustrative study looked directly at the role of essential fatty acid ratios and the viability of endometrial cells including their production of inflammatory cyt~kines.’~ The in vitro study took endometrial cells from women with and without endometriosis attending an infertility clinic. In vitro cell cultures used culture mediums supplemented with various ratios of omega-3 polyunsaturated fatty acids and omega-6 polyunsaturated fatty acids. They found that the higher the ratio of omega4 to omega-3 fatty acids, the longer the survival time and secretion of interleukin-8 (IL-8)in cells from both women with and without endometriosis. Of particular sigruficance was their observation that the cells from women with endometriosis secreted higher levels of IL-8 and that the levels were proportionately higher at higher ratios of omega4 to omega-3.

B Vitamins B vitamins help the liver to inactivate estrogen. Studies suggest that supplementationof B vitamins may cause the liver to become more efficient in processing estrogen.”

Selenium Selenium aids in the synthesis of antioxidant enzymes responsible for detoxification reactions within the liver. In addition, selenium stimulates white blood cells and thymus function.2l Individuals with decreased selenium levels have suboptimal cell-mediated immunity, decreased T cells, and associated inflammation.22

Lipotropics Lipotropics aid in enhancing liver function and detoxification reactions. Supplements that contain choline (a B vitamin), betaine, and methionine promote the flow of fat and bile (containingestrogen metabolites) from the liver out through the large intestine.23

Botanical Medicines The herbs appropriate for acute pain relief in endometriosis are the same herbs commonly used for menstrual cramps such as Valerian, crampbark, and black cohosh, in addition to other traditional herbs that might be helpful such as wild yam, chamomile, blue cohosh, ginger, passion flower, and false unicorn root.

Vitex agnus castus Vitex ugnus castus, also known as chaste tree, has traditionally been used as a treatment for hormone imbalances in women. Through action on the pituitary gland, chaste tree increases progesterone production via an increase in luteinizing hormone. This herb is useful for fibroids, premenstrual syndrome, and perimenopausal times of increased estrogen. With its use, less estrogen is available to stimulate endometrial tissue.”

Taraxacum oficinale Turaxucurn oficinule, also known as dandelion root, is one of the most detoxlfylng herbs. It works principally on the liver and gallbladder to help remove waste products. By supporting the liver, excessive estrogens and toxins can be deactivated. Researchers in Japan have found a link between dandelion and antitumor activity? In addition, dandelion leaf contains vitamins A, C, and K; calcium; and a lipotrophic substance called choline.

Xanthoxylum americanum Xunthoxylurn umericunurn, or prickly ash, is known for its specific action on capillary engorgement and sluggish circulation. Prickly ash stimulates blood flow throughout the body and enhances the transport of oxygen and nutrients in addition to removing cellular waste products. For women with pelvic congestion, this herb enhances circulation throughout the pelvis.

Leonorus Leononts, or Motherwort, is antispasmodic and gently soothes the nerves. As women with endometriosis generally experience uterine cramps and pain, Motherwort is useful in promoting relaxation during times of extreme “bearing down” pain in the uterus and other regions.‘6 As a mild sedative, Motherwort helps with the needed rest during menstrual cramps.

Turska’s Formula Turska’s formula is a well-used, old-time naturopathic treatment for decreasing aberrant cancer cell growth. A tincture of this formula is useful in endometriosis due to the similarities in cell growth found in the pelvis. This formula contains Aconite napellus (Monkshood),Gelsemiurn sempervirens (YellowJasmine),Bryoniu ulbu (Bryony),and Phytolaccu urnericunu (Poke Root). Monkshood and Yellow Jasmine contain various alkaloids that have been

Endometriosis

known to disrupt the assembly of microtubules, which eventually help in the formation of undifferentiated mesenchymal cells. Quite possibly, these herbal alkaloids interfere with the inducing of abnormal ectopic lesions within the pelvis (consistent with the theory of cells left behind in embryonic development). Bryonia is also known to provide antitumor effects. Poke Root contains glycoproteins, which are known to stimulate lymphocyte transformation for immune enhancement. In addition to immune enhancement, Poke Root also has antiinflammatory properties. Due to its toxic properties, however, this tincture can only be provided by a licensed health professional.

Other Considerations Natural Progesterone Progesterone has been known to m o d e the action of estradiol by decreasing the retention of receptors, causing a fall in serum estradiol levels. Women without enough progesterone are unable to balance out estrogen, which can then lead to problems that result from a relative excess of estrogen. In addition, progesterone has the effect of sedating painful uterine contractions. It is possible that this uterine sedative effect extends to pain relief in the pelvic region in general. Natural progesterone is usually not used alone as a treatment for endometriosis, but as part of a comprehensive natural treatment plan. Natural progesterone creams can be applied in various regimens. Some women find results from one-quarter tsp two times a day for 3 weeks on and 1week off (week off is the week of menses). Other women just need to use it the week before their menses is due. Still other cases require higher doses of natural oral micronized progesterone in a cyclic dosing pattern.

Dioxin Exposure Dioxin exposure can increase the incidence and severity of endometriosis in monkeys and can promote the growth or survival of endometrial tissue that is implanted into rodents in surgically induced models of endometriosis. Dioxin may influence growth factors, cytokines, and hormones, which may affect endometriosis. Dioxin is also a known human carcinogen. Some studies suggest that endometriosis may be a type of benign neoplasm and that women with endometriosis may have an increased risk for cancer. Dioxin-like PCBs, but not nondioxin-like PCBs, have been associated with

endometriosis. Studies should look at the association between the total toxic equivalence (TEQ), not the total PCBs, and the disease. If the association between dioxins and endometriosis is confirmed, then the reduction in exposure to dioxins that has been occurring over the past 10 to 20 years may reverse the increased incidence of this serious condition?’

THERAPEUTIC APPROACH Diet The primary dietary recommendation is to increase the consumption of fruits and vegetables, especially those high in fiber, decrease sources of omega-6 fatty acids (foods from domesticated land animals), and increase the consumption of omega-3 fatty acid foods (e.g., fish, flax seeds). Especially of value are indole-3-carbinol-rich foods such as broccoli, Brussels sprouts, cabbage, and cauliflower. Sources of caffeine should be limited.

Supplements Vitamin C: 6 to 10 g in divided doses Beta-carotene: 50,000 to 150,OO IU daily Vitamin E: 400 to 800 IU daily Fish oil: 1000 mg daily B complex: 50 to 100 mg B vitamin complex daily Selenium: 200 to 400 pg daily Lipotropics: 1000 mg choline and 1000 mg methionine or cysteine, three times daily

Botanical Medicines Chaste tree + Dandelion root + Prickly ash + Motherwort tincture (equal parts) ‘/2 tsp to 1 tsp three times daily Turska’s formula (Aconite ll/z drams + Bryoniu 1%drams + Gelsemiurn 1%drams + Phytoluccu 3 drams + ?hdram water): five drops four times daily

Topical Progesterone cream Option 1 Days 1to 7 Days 8 to 28 Option 2 Days 1to 14 Days 15 to 28 Option 3 Days 1to 21 Days 22 to 28

no cream 1/4 to 1/z tsp, twice a day no cream 1/4 to 1/z tsp, twice a day no cream 1/4 to 1/z tsp, twice a day

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1.Igarashi S, Hatazawa J, Tanaka T, Ota H. Endometriosis and free radicals. Gynecol Obstet Invest 1999;4829-35. 2. Goldin BR, Adlemeutz H, Dwyer JT, et al. Effect of diet on excretion of estrogens in p r p and postmenopausal women. Cancer Res 1981; 41:3771-3773. 3. Kappas A, Anderson KE, Conney AH, et al. Nutrition-endocrine interactions: Induction of reciprocal changes in the delta 4-5 alphareduction of testosterone and the cytochrome P-450aependent oxidation of estradiol by dietary macronutrients in man. Proc Natl Acad Sci U S A 1983;80:7&46-7649. 4.Michnovicz JJ, Bradlow HL. Altered estrogen metabolism and excretion in humans following consumption of indole-karbinol. Nutr Cancer 1991;1659-66. 5. Leibovitz BE, Mueller JA. Bioflavonoids and polyphenols: medical applications. J Opt Nutr 1993;2:17-35. 6. hung AY. Encyclopedia of common natural ingredients used in food, drugs and cosmetics. New York Wiley & Sons, 1980:17. 7. Yudkin J, Eisa 0. Dietary sucrose and oestradiol concentration in young men. Ann Nutr Metab 19883253-55. 8. Grodstein F, Goldman MB, Ryan L, Cramer DW. Relation of female infertility to consumption of caffeinated beverages. Am J Epidemiol 1993;1371353-1360. 9. Tremblay L. Reproductive toxins conference-pollution prevention network. Endometriosis Assoc News1 1996;1713-15. 10. Anderson R. The immunostimulatory, anti-inflammatory and antiallergic properties of ascorbate. Adv Nutr Res 1984;61945. 11. Leibovitz B, Siege1 BV Ascorbic acid and the immune response. Adv Exp Med Biol 1981;135:1-25. 12.Alexander M, Newmark H, Miller RG. Oral beta-carotene can increase the number of okT4-t cells in human blood. Immunol Lett 1985;9:221-224. 13.Gerster H. Anticarcinogenic effect of common cartenoids. Int J Warn Nutr Res 1993;6393-121. 14. Ongsakul M, Sirisinha S, Lamb AJ. Impaired blood clearance of bacteria and phagocytic activity in vitamin A deficient rats. Proc Soc Exp Biol Med 1985;178:204-208.

15. Watson RR, Prabhala RH, Plezia PM, Alberts DS. Effect of betacarotene on lymphoycyte subpopulations in elderly humans: evidence for a dose-response relationship. Am J Clin Nutr 19915390-94. 16. London RS, Sundaram GS, schultz M, et al. Endocrine parameters and alpha-tocopherol therapy of patients with mammary dysplasia. Cancer Res 1981;41:3811-3813. 17.Butler EB, McKnight E. Vitamin E in the treatment of primary dysmenorrhea. Lancet 1955;1:844-847. 18. Moncada S, Salmon JA. Leukocytes and tissue injury: the use of eicosapentaenoic acid in the control of white cell activation. Wien Klin Wochenschr 1986;98:104-106. 19. Gazvani MR, Smith L, Haggarty P, et al. High omega-3omega-6 fatty acid ratios in culture medium reduce endometrial-cell survival in combined endometrial gland and stromal cell cultures from women with and without endometriosis. Fertil Steril 2001; 76717-722. 20. Biskind MS, Biskind GR. Effect of vitamin B complex deficiency on inactivation of estrone in the liver. Endocrinology 1942;31: 109-114. 21. Kiremidjian-Schumacher L, Stotzky G. Selenium and immune responses. Environ Res 1987;42:277-303. 22. Spallholz JE, Martin JL, Gerlach ML, Heinzerling RH. Immunologic responses of mice fed diets supplemented with selenite selenium. Proc Soc Exp Biol Med 1973;143:685-689. 23. Murray M, Pizzorno J. Immune support. Encyclopedia of natural medicine. Rocklin, C A Prima Publishing, 1998. 24. Decapite L. Histology, anatomy and antibiotic properties of Vitex agnus castus. Ann Facul Agr Univ Studi Perugia 1967;22:109-126. 25.Baba K, Abe S, Mizuno D. [Antitumor activity of hot water extract of dandelion, Taraxacum oficinale+orrelation between antitumor activity and timing of administration.] Yakugaku Zasshi 1981;101:538-543. 26. Chevallier A. Leonurus cardiaca. Encyclopedia of Medicinal Plants. New York Dorling Kindersley Limited, 1996. 27.Birnbaum LS, Cummings AM. Dioxins and endometriosis: a plausible hypothesis. Environ Health Perspect 2002;110:15-21.

Epilepsy Peter B. Bongiorno, ND, Dip1 Ac CHAPTER C O N T E N T S Diagnostic Summary

1649

General Considerations 1649 Epidemiology 1649 Etiology 1649 Classification 1650 Diagnosis 1650 Pathophysiology 1651

Dietary Considerations 1651 Nutritional Considerations 1653 Botanical Medicines 1656 Acupuncture 1657 Spiritual Healing 1657 Therapeutic Approach 1658 Diet 1658 Lifestyle 1658 Nutritional Supplements 1658 Botanical Medicines 1658

Therapeutic Considerations 1651 Environmental Toxins 1651

DIAGNOSTIC SUMMARY Recurrent seizures Characteristic electroencephalographicchanges accompanying seizures Mental status abnormalities or focal neurologic symptoms may persist for hours postictally

GENERAL CONSIDERATIONS The word epilepsy derives from the Greek word epilepsia, which means "to take hold of" or "to seize." Epilepsy is not a disease in itself, but rather a symptom of disease. The epilepsies are a group of disorders characterized by sudden, recurrent, and episodic changes in neurologic function caused by abnormalities in the electrical activity of the brain.14 Each episode of neurologic dysfunction is called a seizure. Seizures are termed convulsive when accompanied by motor manifestations or nonconvulsive when accompanied by sensory, cognitive, or emotional events. Epilepsy can occur due to a number of abnormalities such as neurologic injuries, structural brain lesions, or some systemic diseases. Epilepsy is termed idiopathic when there is neither a history of neurologic insult nor other apparent neurologic dysfunction? Whatever the etiology, the common

This chapter is based on an earlier version written by Gaetano Morello, ND.

denominator in all these conditions is the epileptic attack or seizure.

Epidemiology The reported incidence and prevalence rates of epilepsy have varied widely because of uncontrolled methodologic factor^.^ According to the best available data, the prevalence of chronic, recurrent epilepsy is about 10 per 1000, and it has been estimated that 10% of the population will have one or more seizures at some point in life. The cumulative lifetime incidence of epilepsy is approximately 3y0.~ An additional 2% to 5% of children experience febrile convulsions during the first several years of life. About 10% of these children, especially those in whom the febrile seizure is prolonged, develop epilepsy later in life.' Prospective studies show that more than 60% of newly diagnosed patients enter remission with conventional treatment.7

Etiology Epilepsy may be idiopathic, cryptogenic, or symptomatic.8 Idiopathic epilepsies are generally genetic in origin and account for 70% to 80% of all cases of epilepsy. The role of genetic factors in the pathogenesis is complex due to diverse conditions leading to the common symptom of seizures. In general, the prevalence of seizures in close relatives is three times that of the overall population.' William Lennox meticulously 1649

Specific Health Problems

studied the relationship of epilepsy to genetics from 1934 through 1958, using twin studies. He concluded that epilepsy was a condition in which genetic and exogenous factors interact in all patients, with variable weighting in each particular case? This understanding sparked the concept that many factors play a role in the epileptic condition. Cryptogenic epilepsies are those in which an underlying cause is suspected, but the etiology remains undetected. Finally, epilepsies for which there is an underlying structural cause or major metabolic derangement are considered symptomatic, for a probable cause has been identified: As shown in Table 165-1, probable c a w s can be determined by age of onset of seizures. Box 165-1 lists the most common etiologic factors.

Classification The current classification of epileptic seizures is based on clinical and electroencephalographiccriteria proposed

Partial (focal, local) seizures Simple partial seizures (consciousness not impaired) Motor signs Somatosensory or special sensory symptoms Autonomic symptoms or signs Psychic symptoms Complex partial (consciousness impaired) Simple partial onset followed by impaired consciousness Consciousness impaired at onset Partial seizures evolving to generalized seizures (tonic, clonic, or tonicclonic) Simple partial seizures evolving to generalized seizures Complex partial seizures evolving to generalized seizures Simple partial seizures evolving to partial seizures evolving to generalized seizures Generalized seizures (convulsive or nonconvulsive) Absence seizures Typical (brief stare, eye flickering, no emotion) Atypical (associatedwith movement) Myoclonic seizures Clonic seizures Tonic seizures Tonicclonic seizures Atonic seizures Unclassified seizures Modified from Willmore W, Ferrendelli JA. Epilepsy. In Dale DC, Federman DD,

eds.ScientificAmerican medicine.New Yo&: Scientific American, 1997:11, Xll-1-14. Age of onset

Presumptive causes

Birth to 2 years 2-19 years

Birth injury, degenerative brain disease Congenital birth injury, febrile thrombosis, head trauma, infection (meningitis or encephalitis)

20-34 years

Head trauma, brain neoplasm

35-54years

Brain neoplasm, head trauma, stroke

55 years and older

Stroke, brain neoplasm

Data from references 3 and 4.

Brain damage before or at birth (congenital malformations, anemia, fetal infection) Head trauma significant enough to injure the brain and gliosis Central nervous system infections such as meningitis, encephalitis, brain abscess, neurosyphilis, rabies, tetanus, falciparum malaria, toxoplasmosis, and cysticercosis of the brain Metabolic disorders: hypocalcemia, hypoglycemia, hypoparathyroidism, phenylketonuria, and withdrawal from alcohol and drugs Brain tumors and other space-occupying lesions Stroke and other vascular disorders Degenerative brain disease Genetic disease Toxic conditions Idiopathic

by the International League Against Epilepsy. Box 165-2 lists the clinical features.

DIAGNOSIS Differentiating between partial or focal seizures and generalized seizures is of great clinical sigruficance. Partial seizures begin focally with a specific sensory, motor, or psychic aberration that reflects the affected part of the cerebral hemi~phere.~ These types of seizure may remain localized, whereas generalized seizures appear to generalize from their onset and usually affect both consciousness and motor function.” Differentiation is important because partial seizures are usually indicative of focal brain disorders such as tumors or gliosis, while generalized seizures rarely have a definable etiology (although some studies now implicate metabolic disorders). An eyewitness account of a typical attack can be of great value in classifymg a seizure. Past trauma, infections, and the use of drugs and alcohol should be fully explored, as should the family history. A complete neurologic examination should be performed as a preliminary screen for neoplasms. Laboratory work should include the following+ 9

0

Serum glucose and calcium Complete blood cell count

Epilepsy

Liver and kidney function tests Serologic test for syphilis Skull radiographs An electroencephalogram(EEG) A computed tomography (CT) scan Magnetic resonance imaging Cerebrospinalfluid examination is indicated if infection or meningeal neoplasm is suspected.' MRI is considered the gold standard in evaluating epilepsy, as the resolution is superior to the CT scan6 Newer studies also employ EEG recording during functional MRI scanning in order to map normal and pathologic brain function.1° Epilepsy should not be diagnosed on the basis of a solitary seizure. The recurrence rate after a single seizure is approximately only 27%over 3 years."

PATHOPHYSIOLOGY The hallmark of the altered physiologic state of epilepsy is a rhythmic, repetitive, synchronousdischarge of many neurons in a localized area of the brain? This discharge pattern is easily recorded on the EEG during an attack. However, the cause of the abnormal discharges is still not known. Research shows that the synchronous depolarization of masses of neurons is the result of a combination of increased excitatory mechanisms and decreased inhibitory mechanisms.12 Seizures can be induced in experimental models by blocking inhibitory mechanisms. For example, agents that block the action of the inhibitory neurotransmitter gamma-aminobutyrrc acid (GABA) are potent convulsants in humans. Conversely, the antiepileptic drugs phenobarbital and benzodiazepines enhance GABA, thus supporting the inhibitory mechanism. In some forms of chronic focal epilepsy, inhibitory terminals on neurons in areas around cortical gliotic lesions are, in fact, diminished. Other research demonstrates the instability of the nerve cell membranes in epileptics. During seizure activity, intracellular Ca2+stored in the cell organelles is released and moves toward the inner cell membranes, where it binds to specific Ca2+-receptiveproteins, causing conformational changes in the protein's structure. These changes cause the transmembranal Ca2+,K+,and Na+ channels to pathologically remain open, potentiating the excitatory state and, hence, the convulsive activity.l.2 The earliest symptomatology, or aura, that is generated by a focal discharge provides the best clue to the localization and, occasionally, to the characterization of the responsible lesion. For example, a generalized seizure following an aura of a peculiar abdominal sensation or ill-defined odor indicates a lesion in the temporal lobe. A jacksonian seizure beginning in the fingers and spreading up the arm before becoming generalized

and producing a coma indicates a focal lesion in the convexity of the opposite motor cortex.'

THERAPEUTIC CONSIDERATIONS Environmental Toxins Heavy Metals Heavy metals such as lead, mercury, cadmium, and aluminum can induce seizures by disrupting neural Heavy metal toxicity should be ruled out as a possible cause in all seizures. A hair mineral analysis provides the most cost-effective screening method for the detection of heavy metals, although other procedures may at times be more appropriate (see Chapter 31).

Neurotoxic Chemicals Many neuron-, axon-, and myelin-toxic chemicals have now been released into the environment. Despite efforts to decrease their release, the levels of many chemicals in the environment continue to increase. Chapter 36 discusses the impact of these neurotoxins.

Dietary Considerations Hypoglycemia Focal neurologic deficits associated with hypoglycemia have been well described in adults with diabete~,'~ and some researchers believe that hypoglycemia is the most important metabolic cause of seizures.13 Researchers have found the foll~wing'~,'~'~: Serum glucose levels are unusually low before a seizure. 50% to 90%of epileptics have constant or periodic low blood sugar. 70% or more of epileptics have abnormal glucose tolerance tests. Although the correlation of blood sugar abnormalities and epilepsy seems well documented, the mechanism of action is unknown. It has been suggested that low blood sugar could impair adenosine triphosphate (ATP) production in nerve cells, reducing the efficacy of the sodium ATPase pump. A defective sodium pump allows increased intracellular sodium concentrations, which depolarize the cell membrane, thus lowering the firing threshold. Single measurements of serum glucose levels are inadequate to determine glycemic status-only an extended glucose tolerance test will give a complete picture.

Ketogenic Diet Originally introduced by Wilder in 1921,'9 the ketogenic diet has a long history of use for the reduction of seizure activity.zbz The diet consists of large amounts of fat and minimal amounts of protein and carbohydrates.The low carbohydrate intake inhibits fat metabolism, resulting

Specific Health Problems diet is not without side effects. The long-term risks of a in the production of excessive levels of ketone bodies (acetone, aceto-acetic acid, and beta-hydroxybutyric high-fat diet are well known, and a ketogenic diet may acid), the intermediary oxidation products. Presumably prove unhealthy for a growing child. One retrospective the beneficial effects of such a diet are due to its inducinvestigation found that the linear growth of some chiltion of metabolic acidosis, which corrects an underlying dren might be When treating children on a tendency of epileptics toward spontaneous developketogenic diet, clinicians should recommend adequate ment of alkal0sis.2~~ This acidification is thought to intake of energy and protein, a higher proportion of normalize nerve conductivity, irritability, and membrane unsaturated to saturated dietary fats, and also consider vitamin and mineral supplement^.'^ Also, children permeability. The two main types of ketogenic diets are (1)the classhould not be allowed to eat large meals, as these may sic ketogenic diet and (2) the medium-chain triglyceride predispose them to seizures. Small, frequent meals may ketogenic diet. The classic ketogenic diet produces ketobe appropriate and may decrease hypoglycemic episodes. sis by limiting intake of carbohydrates and protein to Gaining great popularity in the past few years as less than 10% of energy combined. The medium-chain a weight loss tool, the Atkins diet theoretically may be triglyceride ketogenic diet uses medium-chain triglycuseful to treat epilepsy2’ for like the ketogenic diet, it eride fat to produce ketosis. This allows for a larger too produces a ketotic state but creates this effect with intake of carbohydrates and ~ r 0 t e i n . l ~ less restriction on protein intake. In one pilot study six patients ranging from 7 to 52 years old were prescribed Research continues to document the efficacy of these the Atkins diet for intractable focal and multifocal types of dietary therapy. For example, one study of 27 children from 1 to 16 years old using the classic diet epilepsy. Five of the patients maintained moderate to found that 40% experienced a reduction of seizures of large ketosis for periods of 6 weeks to 24 months. Three more than 50%, with 25% becoming seizure free.= patients experienced seizure reduction and, as a result, were able to reduce antiepileptic medications.28Larger However, 35% discontinued the diet due to difficulty trials are necessary to explore whether the Atkins diet in following the rigorous guidelines. A review from may be useful to treat patients with epilepsy. 1996 concluded that the ketogenic diet had efficacy in one third to one half of epilepsy cases in children and was partially effective in another one third of ~ases.2~ Food Allergy There has been little research into the correlation A review article from 1997 stated that the ketogenic between food allergy and epilepsy with only anecdotal diet’s success rate ”greatly exceeds that of the medicacase h i s t o r i e ~ ~single-case, ~,~; double-blind, placebotions” and that its side effectswere fewer and the therapy controlled studies3132;and uncontrolled studies being cheaper.= reported. It is postulated that epileptic patients may One prospective, nonrandomized study measured have allergic reactions in the brain that are similar to the nutrient intakes, growth, and biochemical indexes of swelling, anoxia, and inflammatory chemical reactions 30 children from 1 to 16 years old who had intractable seen at other sites of local allergic rea~tions.2~ epilepsy before and after a 4-month protocol using a ketogenic diet. Fourteen children on the classic diet One uncontrolled study evaluated oligoantigenic diets in 63 children with epilepsy. Of 45 children with and 11 children on the medium-chain triglyceride diet recurrent headaches, hyperkinetic behavior, or abdomicompleted the study for an 83%completion. The results nal symptoms, 25 ceased to have seizures and 11 had indicated that linear growth was maintained in patients fewer seizures during diet therapy. Headaches, abdomifrom baseline to 4 months on both therapies. However, nal pains, and hyperkinetic behavior ceased in all body weight decreased for children on both diets, which patients whose seizures ceased and in some of those could be a result of inadequate energy intake. Protein whose seizures did not cease. Reintroduction of foods intake met recommended intakes for both diets. In the reproduced symptoms. Eighteen of 24 children with medium-chain triglyceride group, there was a 0.7 decrease in the ratio of total cholesterol to high-density lipoprogeneralized epilepsy recovered or improved, as did 18 of 21 children with partial epilepsy. In double-blind provotein ratios at 4 months. All biochemical indexes including albumin levels remained within normal limits.19 cation, 15 of 16 children experienced recurrence of symptoms including seizures in 8, while none improved However, this was only a Pmonth study. Longer-term in the placebo group. Eighteen other children who evaluations may show eventual unwanted changes in these parameters. The authors concluded that the had epilepsy alone had no improvement with dietary medium-chain triglyceride diet therapy may be more change.%Thisstudy suggests that food allergy should be suspected in epileptics who suffer from multiple other nutritionally adequate and thus confer an advantage symptoms of food allergy (see Chapters 19 and 53). over the classic ketogenic diet. Another study evaluated two females, 5 and 23 years Although the previously mentioned study demonold, who had focal occipital epilepsy with cerebral strated a relatively short use of 4 months, the ketogenic

Epilepsy

calcifications and were not responding well to antiepileptic therapy. Both had celiac disease, as well as documented folic acid deficiency (a common side effect of most antiepileptic drugs). A gluten-free diet combined with supplementation with folic acid (dosage not reported) led to complete normalization of the EEG in the 5-year-old and cessation of seizures. The 23-year-old experienced sigruficant improvement in her EEG and enhanced seizure control. Folic acid returned to the normal range within several monthsM A larger study looked more closely at the association between celiac disease and epilepsy. Forty-three patients (15 male) between 4 and 31 years old were evaluated for the association between celiac disease, epilepsy, and cerebral calcifications. Intestinal biopsy on the 31 patients with cerebral calcifications of unexplained origin and epilepsy found a flat intestinal mucosa in 24, suggesting celiac disease. CT scans showed cerebral calcifications in 5 of the 12 patients with celiac disease and epilepsy. Antibodies to gluten and folic acid serum concentrations were measured, and histocompatibility leukocyte antigen typing was done in most patients. Only two patients with cerebral calcifications and epilepsy had gastrointestinal symptoms at the time of biopsy. A gluten-free diet in epilepsy was found to be inversely related to the duration of epilepsy before the diet and to the age at the beginning of the diet. The authors strongly recommended that celiac disease be considered in all cases of epilepsy and cerebral calcifications of unexplained origin, especially when the epilepsy is characterized by occipital Seizures and the calcification is located bilaterally in the posterior regions.%One recent work involving 72 epileptic children and 202 controls revealed sigruficantlyhigher rates of eczema in the mothers and rhinitis in the siblings of the epileptic patients, as well as a generally higher incidence of allergic pathologies in both of these groups compared with the controls. Additionally, a sigruficantly higher incidence of allergy to cow’s milk and asthma was also documented in the epileptic children with respect to the control group. Prick tests gave a sigruficantly higher rate of positive results for cow’s milk proteins in the cases examined with respect to the controls.36

Nutritional Considerations Pyridoxine Two types of vitamin B6-related seizures are known in newborns and infants younger than 18 months of age: B6deficient and B6 dependent. They have similar neurologic symptoms, EEG abnormalities, and a prognosis of mental retardation if not t ~ a t e d . 3 ~ Pyridoxine-dependent seizure is an autosomal, recessively inherited inborn error of metabolism. In affected patients, long-lasting seizures usually begin in infancy, but also up to 3 years of age, and recur. The seizures are

resistant to conventional anticonvulsants. The condition ends fatally if diagnosis and administration of pyridoxine in pharmacologic doses is delayed too long.%The diagnosis of pyridoxine dependency should be suspected in every infant with convulsions in the first 18 months of life. Certain clinical features may be especially suggestive, including the following: Seizuresof unknown origin in a previously normal infant without an abnormal gestational or perinatal history A history of severe convulsive disorders The occurrence of long-lasting focal or unilateral seizures,often with partial preservation of consciousness Irritability,restlessness, crying, and vomiting preceding the actual seizure Magnetic resonance with spectroscopy may be a useful tool in the neuroimaging evaluation for assessment of parenchymal changes despite a normal-appearing brain MRI in patients with pyridoxine-dependent seizures.39 Since atypical presentations of pyridoxine responsive seizures have been reported, it has been recommended that an empiric trial of parented pyridoxine be done on any neonate or infant with long-lasting convulsions, especially when no clear-cut etiology is p r e ~ e n t . ~ ~ , ~ A 100- to 200-mg intravenous dose or 20-mg dose every 5 minutes to a total of 200 mg is recommended. If the seizures stop, it is likely that the child has pyridoxine responsive ~einWs.3~.40 The chance to idenbfy a pyridoxineresponsive seizure is lost if pyridoxine is given together with, or after, most anticonvulsant Although B6-deficientseizures are promptly corrected by the administration of dietary amounts of pyridoxine, B6-dependent seizures require continuous high-dose supplementation in the range of 25 to 50 mg/da~.~~,Although the mechanism by which pyridoxine decreases seizure activity is not fully understood, it is undoubtedly related to its role as a necessary cofactor in the metabolism of various neurotransmitters, the production of which depends on amino acid decarboxylation. Once absorbed, pyridoxine is phosphorylated to pyridoxal-5-phosphater a coenzyme in the reaction converting glutamic acid to GABA (Figure 165-1). GABA, as mentioned earlier, is an important inhibitory neurotransmitter. One proposed mechanism for pyridoxine dependency is that pyridoxal phosphate does not bind with its usual affinity to glutamic acid decarboxylase, resulting in reduced GABA production. In these patients,

L-Glutamic acid

Flgure 165-1

> GABA Glutamic acid decarboxylase (Be complex dependent)

The conversion of glutamic acid to gammaarninobutyric acid.

Specific Health Problems higher-than-normal levels of pyridoxine are required for the activity of this One uncontrolled study of infants and children with uncontrollable infantile spasms or their sequelae found improvement in 2 to 14 days using oral pyridoxine phosphate (20 to 50 mg/kg). Three had complete relief, six showed transient relief, and eight showed marked reduction in seizures and improvement in their EEGs.O Some adverse reactions were seen: elevated transaminases, nausea, and vomiting. Administration of vitamin B6 to epileptics must be strictly monitored. Although some improvements have been noted, daily doses in the range of 80 to 400 mg have been shown to interfere with commonly used anticonvulsants."

Folic Acid Serum and red blood cell folate are reduced in up to 90% patients meiving phenytoin, carbamazepine, or barbiturates. These drugs interfere with the intestinal uptake of folic acid at the mucosal level. Lamotrigine and zonisamide appear to not be associated with low levels of folic acid. Most reports state valproate does not reduce folate levels, although some of the literature is inconsistent. A convincing argument now suggests that routine folic acid supplementationis important for women and men receiving antiepileptic medication.44 The U.S.Food and Drug Administration has directed that oral tablets of folic acid not exceed 1 mg because of concernsbrought forward more than 30 years ago that larger amounts might counteract the antiseizure effects of antiepilepticdrugs and increase the seizure frequency in some ~hildren.4~ Although that concern is no longer considered valid by epilepsy specialists, the dosage restriction has not been lifted. Supplementation with folic acid appears safe even up to doses as high as 15 mgldayf and can protect both against birth defects for women of childbearing potential, as well as lower homocysteine levels, a risk factor for cardiac disease for men and women using antiepileptic medications.

Thiamin In an interesting study, 16 of 50 consecutive neurologic patients with a diagnosis of thiamin deficiency showed epileptic manifestations. It is possible that thiamin deficiency may promote epileptic episodes in those who have a subclinicalpredisposition to seizures.For example, the stimulation of nerve fibers in vitro causes them to lose significant amounts of thiamin pyrophosphate in the surrounding fluid, suggestive of a significant role for thiamin in nerve-to-nerve conduction. In addition, thiamin deficiency may be accompanied by low concentrations of GABA, which, as noted earlier, is significant in seizure disorders. The authors suggested that, in patients with late-onset epilepsy, thiamin deficiency may be considered one of the possible causes.&

Taurine Taurine is one of the most abundant amino acids in the mammalian brai11.4~~~ It is involved in hyperpolarizing neurons by changing ion permeability and may mimic the effects of GABA and glycine. Since the early 1970s, considerable clinical and experimental evidence has accumulated supporting the anticonvulsive activity of the amino acid t a ~ r i n e . 4 ~ ~ The primary mode of action responsible for taurine's antiepileptic effects is its membrane-stabilizing effects (i.e., it seems to normalize the flow of Na+, K+, and Ca2+ into and out of the In addition to acting as a GABA-like neurotransmitter,47-50 taurine may also help to decrease seizure activity by increasing GABA levels through enhancement of the action of glutamic acid decarboxylase. Epileptics have been shown to have sigruficantly lower levels of taurine in platelets than control patients.5l Although several studies have shown lower taurine levels in the plasma, serum, and urine of epileptics, other research has yielded disparate r e s u l t ~ . 5Cellular ~ - ~ ~ concentration of taurine as determined by platelet level is thought to be of much greater sigruhcance. The first clinical trials of taurine were undertaken by Barbeau and Donaldson56in 1973 and Bergamini and colleagues57in 1974. The results were encouraging, and several additional reports have confirmed taurine's anticonvulsant However, the rate of effectiveness of taurine is far below the level where it could be recommended as a standard "drug" treatment for epilepsy. At this time, there is no consensus on the seizure types for which taurine is most suitable, nor is there agreement on appropriate dose. Even more, it is questionable whether taurine may even have the ability to effectively traverse the blood-brain barrier to gain an effecta Taurine, at a daily oral dose of 0.05 to 0.3 g/kg in one study and 750 mg in another, has demonstrated efficacy in some cases of intractable epilepsy, decreasingseizures by more than 30% in 11 of 34 subjects.61,62 This is highly significant because these patients were unresponsive to any other anticonvulsants. Patients with partial epilepsy demonstrated the best results, with those achieving the highest taurine concentrations showing the best response. The positive clinical response of some epileptic patients to supplemental taurine and the apparent cellular deficiency of taurine suggest that taurine supplementation be tried in most patients. Therapeutic monitoring of platelet or plasma taurine levels may prove useful.

Magnesium Epileptics have been shown to have significantly lower serum magnesium levels compared with normals, with seizure severity correlating with the level of hypomagn e ~ e m i a Although .~~ the mechanism of action is not

Epilepsy

fully understood, magnesium has been shown, in uncontrolled trials, to be of benefit in the control of ~ e i z u r e s . ~Itf ihas ~ also been postulated that like folic acid, magnesium levels may be lowered by antiepileptic medi~ations?~ Pfeiffera found that a magnesium deficiency induces muscle tremors and convulsive seizures and reported success in controlling the seizure activity of 30 epileptic patients with 450 mg/day of magnesium.

Manganese The link between epilepsy and manganese was first suggested in 1963 when Hurley and associates70observed that manganese-deficient rats were more susceptible to seizures than manganese-replete animals, and that manganese-deficient animals exhibit an epileptic-like EEG. This prompted researchers to measure manganese concentrations in epileptics. Low whole blood and hair manganese levels have been found in epileptics, and those with the lowest levels typically have the highest seizure act i ~ i t y . ~ l - ~ ~ Manganese plays a sigruficantrole in cerebral function, as it is a critical cofactor for glucose utilization within the neuron, adenylate cyclase activity, and neurotransmitter control. Obviously, optimal central nervous system function requires proper manganese levels. Manganese supplementation may be helpful in controlling seizure activity for some

Zinc Children with epilepsy have been found to have signtficantly lower levels of serum zinc, especially those with West's or Lennox syndrome.66,n More importantly, it appears that epileptics may have an elevated copperto-zinc ratio." Seizures may be triggered when zinc levels fall, as in the absence of adequate taurine. Although the exact role of zinc or the copper-to-zinc ratio is not clearly understood, it appears to involve either the storage or binding of GABA.n Zinc supplementation appears to be warranted, especially in light of the observation that anticonvulsants may cause zinc defi~iency.~~

Choline, Betaine, Dimethylglycine, and Sarcosine Choline, betaine (N,N,N,-trimethylglycine),dimethylglycine (DMG), and sarcosine have exhibited some anticonvulsant activity in human and animal studies. Choline is converted to betaine when it acts as a methyl donor, while betaine is converted to DMG when it donates a methyl group. This is most evident in the transformation of homocysteine to methionine. Supplemental betaine has also been shown to be effective in preventing various induced seizures in rats and in alleviating seizures in humans with homocy~tinuria.~-~~

DMG has also been shown to block induced seizures Roach and CarlinMreported a striking decrease in seizure frequency in a patient with longstanding mental retardation when 90 mg of DMG were administered twice daily. Despite treatment with phenobarbital and carbamazepine, the patient had an average of 16 to 18 generalized seizureseach week. Within 1 week of starting DMG, seizure frequency dropped to three per week. Two attempts to withdraw the DMG caused dramatic increases in seizure frequency. It has been suggested that glycine and betaine may act indirectly on glycine metabolism and glycine-mediated neuronal inhibition, enhance GABA activity, or simply have a nonspecific effect on biologic membranes. in rats and

Vitamin D The association of anticonvulsant drugs with disorders of mineral metabolism, including hypocalcemia, rickets, and osteomalacia, is well documented.= Conflicting results have been published concerning the serum levels of vitamin D in patients with epilepsy. Studies have reported increased,&nor1nal,8~and decreased levels.88 Supplemental vitamin D intake is recommended when climatic conditions or the patient's lifestyle do not allow adequate exposure to ~unlight.8~ Supplementing the diet of 23 epileptics with 4000 to 16,000 IUs of vitamin D resulted in a sigruficantdecrease in the number of seizures, indicating a possible therapeutic effect.%Doses of this magnitude can, however, be quite toxic, requiring careful monitoring.

Vitamin E, Selenium, and Antioxidants Vitamin E and selenium function synergisticallyin many physiologic functions. Vitamin E deficiency is known to produce seizures?l and antiepileptic drugs have been shown to decrease vitamin E level^,^,^^ as well as other antioxidants like beta-carotene. Studies have shown both vitamin E and selenium to be low in epileptic ~ a t i e n t s ? ~ . ~ ~ Phosphate diesters of vitamin E and C have been shown to prevent epileptogenic focus formation or attenuate seizure activities in experimental epilepsy animal modelsg5Supplementationwith vitamin E and selenium may result in improved control of seizures.91 For example, a double-blind, placebo-controlled study of 24 epileptic children not responding to antiepileptic drugs found that supplementing with 400 IU/day of vitamin E provided a signtficant reduction of seizures in 10 of 12 children. The two unresponsive children were noncompliant. All the children continued their normal dosages of antiepileptic drugs. No benefit occurred in the 12 placebo children, and, as expected, no negative side effects resulted from the vitamin E therapy." One report described four children with reduced glutathione peroxidase activity, intractable seizures,multiple infections, and resistance to anticonvulsant treatment. AU had seizures within their first 6 months of life. There was

Specific Health Problems ~

no evidence of known inborn errors of metabolism; however, all four patients had low intracellular glutathione peroxidase levels. Two had normal whole-blood selenium, while the other two had low levels. Discontinuing anticonvulsant therapy and administeringselenium resultedin clinical improvement in all patients.97 Other antioxidants, such as green tea's (-)-epigallocatechin and (-)-epigallocatechin-3-O-gallateand alpha-lipoic acid, have also been demonstrated to scavenge radical oxygen species and may be prophylactic for the epileptic discharges induced in animal m0dels.9~~~~

Essential Fatty Acids Animal studies have demonstrated that long-chain polyunsaturated fatty acids may alleviate or prevent cerebrovascular pathophysiology and can encourage augmentation of blood-brain barrier competency.99 One human, five-patient study using 5 g/day of a 65% omega-3 fatty acid spread demonstrated a marked reduction in both frequency and strength of epileptic seizures.'@-' However, three hospitalized schizophrenics treated with gamma-linolenic acid and linoleic acid, in the form of evening primrose oil, developed temporal lobe epilepsy following ingestion of the oil. This epilepsy ceased once carbamazepine treatment was inititated.'O' It may be important to monitor closely when using oils to help treat epilepsy, and more research is necessary to elucidate which may be most beneficial in epileptic patients. At this point, omega-3 fats seem to be the best choice, and evening primrose oil should be used with caution.

Melatonin It is well documented that melatonin (5-methoxy-Nacetyltryptamine) is a powerful antioxidant. Melatonin is often used to treat abnormalities in sleep wake cycles, jet lag, cancer, and Parkinson disease. Epileptic children have a higher incidence of sleep problems, and epilepsy is exacerbated by sleep deprivation.lm Animal studies have demonstrated melatonin to have antiepilepticactivity. Although not entirely clear, it is possible that melatonin exerts an antiexcitotoxic neuroprotection by lowering lipid peroxidation and raising coenzyme Qlo levels within the central nervous system.lo3 One randomized, double-blind, placebo-controlled trial included children 3 to 12 years of age who had been taking sodium valproate (10 mg/kg/day) for the past 6 months and were seizure free. Sixteen children each received a fast-release 3-mg melatonin tablet, while 15 others received a placebo 1 hour before bedtime. Using standard Quality of Life in Childhood Epilepsy scales, it was revealed that attention, memory, language, anxiety, behavior, and other cognitive processes all improved in the group receiving melatonin. The general health score also improved marginally. Although not

objectively assessed, perceptible increases in appetite and sleep improvements were reported by most in the melatonin g r ~ u p . Given '~ that high dosages have been well tolerated in adults (up to 300 mg/day)*" it may be possible to slowly increase the dose of melatonin from 3 mg for even better results.

Botanical Medicines

Chinese Herbal Medicine Botanical medicines have played a significant role in the treatment of epilepsy in both the Eastern and Western healing arts. Recently, Western scientific methodologieshave been used to evaluate the efficacy of a Chinese herbal medicine combination, Saiko-Keishi-To (SK).'06 SK demonstrated dramatic therapeutic effects on some difficult cases of epilepsy that had long been unsuccessfully treated with standard allopathic anticonvulsive drugs. SK is a combination of nine botanical drugs:

Bupleuri radix (5 g) Scutellaria radix (3 g) Pinelliae tuber (5 g) Paeoniue radix (6 g) Cinnamon cortex ( 2 g) Zizyphifructus (4 g) Ginseng radix (30 g) Glycyrrhizue radix (1.5 g) Zingiber rhizorna ( 2 g) In one experiment, seizurelikeactivity was induced in snail neurons by the drug pentylenetetrazol (PTZ).'07,'08 SK was found to do the following: Inhibit the intracellular shift of Ca2+toward the cell membrane Inhibit the binding of Ca2+to Ca2+-receptivemembrane proteins and the Ca2+-calmodulincomplex Inhibit the conformationalchanges of the Ca2+-receptive membrane proteins Inhibit the pathologic transmembrane current of Na+, K+,and Ca2+ The researchers presumed that SK's experimental effects are similar to its mode of action in humans. Interestingly, when an attempt was made to isolate purified chemicalsfrom the componentherbs, the crude drug's efficacy was lost. This suggests a synergistic effect between the component botanical agents. More recent clinical research has shown some benefit in epileptic patients. One study reported that 8 of 28 epileptics experienced a 25% decrease in number of seizures after 8 weeks of treatment.lo8

Coleus forskolii Research showing that the cyclic nucleotides are involved in the pathophysiology of seizures has elucidated a

Epilepsy

possible mechanism for the action of several botanical medicines used in the treatment of seizure activity..'Og Cyclic adenosine monophosphate (CAMP) has been demonstrated to depress electrical activity in cat hippocampal slices, while cGMP can produce seizurelike discharge in the same tissues.l1° In addition, CAMP inhibits Ca2+from binding to intracellular proteins like calmodulin, resulting in a decrease in the extrusion of neurotransmitters into the synapse. The botanical Coleusforskolii, an important plant medicine in the Ayurvedic treatment of epilepsy, activates adenylate cyclase, thus increasing the levels of cAMP.111,112 This action is thought to be due to forskolin, a diterpine, which has been found to increase adenylate cyclase activity by 530%.l12 This is the greatest activity found in 100 plants studied for the ability to increase CAMP.The same study found that seven of the nine botanicals in SK-B. radix, C . cortex, G. radix, l? radix, G. radix, S . radix, and Z . rhizoma-were found to display significant cAMP enhancement, either by enhancing adenylate cyclase or by inhibiting CAMPphosphodiesterase.ll*B. radix, a key component of the SK formula, was found to increase CAMPby 170%.

Ginkgo biloba Ginkgo biloba is well known for its usefulness as a memory aid, for cerebral insufficiency, and for its powerful antioxidant properties. However, some of the literature has cited the possibility that it may be responsible for precipitating seizures in two individuals with prior well-controlled seizures. In both patients (78 and 84 years old), seizures commenced after taking gingko, and they were both seizure free after the ginkgo was discontinued. The flavonoid components in gingko have been shown to exert GABAergic activity, as partial agonists at benzodiazepine receptor sites and this activity could play a role.*13 As a prudent measure, patients with a seizure history should probably stay away from this botanical until more research is conducted.

Acupuncture From work on animal models, it has been suggested that the mechanism of acupuncture in suppressing epileptic seizures is through the release of neurotransmitters such as endogenous opioid peptides, serotonin, and gammabutyric acid.l14Other studies have shown possible seizure inhibition through decreasing neuronal nitric oxide synthase transcription in hippo~ampus.ll~J~~ In humans, effective use of acupuncture, scalp needling, electroacupuncture, and embedding of acupuncture points to treat epilepsy and status epilepticus has been reported. However, one sham-controlled study of 34 patients found no benefit.l17 This research group reported similar results with a study of 29 patients.

In a second study, many of the patients reported changes in their sense of well-being.l18 In both clinical trials, drug-resistant patients considered intractable were given nearly identical treatments, save one or two points. Given the individualized nature of traditional Chinese medicine, thismay not be a reasonable representation of the acupuncture modality. Additionally, it may be possible that more benign cases of epilepsy may be more responsive even if intractable cases are not. Auricular, or ear, acupuncture was developed by Nogier, a French neurologist in the 1950s. Unlike traditional Chinese acupuncture, which uses the meridian system, ear acupuncture uses points on the ear that represent different areas on the body, similar to the way reflexology works with points on the foot. In one study, epileptiform behaviors in rats were induced by intrahippocampal injection of penicillin. Radioimmunoassay techniques demonstrated that levels of somatostatin, aspartic acid, glutamine, and GABA were increased. One hour later, the lower-half auricular lobules of seizure rats, containing the ear-points Pizhixia and Shenmen, were electricallystimulated.After auricular treatment, the convulsion behaviors of the rats improved. Concomitantly,the contents of the somatostatin, aspartic acid, and glutamine in the seizure rats' hippocampi were significantly decreased, while the contents of glycine, taurine, and GABA had increased. These results suggest that ear-point electrical stimulation had antiepilepsy effects. Physiologically, given that amino acid concentrations may be involved in the pathogenesis of an epileptic seizure, auricular treatment might be involved in the decreases of the contents of the somatostatin, aspartic acid, and glutamine and increases of the contents of glycine, taurine, and GABA in the hippocampi of seizure r a t ~ . ' ~ ~ J ~ O Ear acupuncture may then be more effective than traditional body acupuncture. More studies are necessary to determine both auricular and body acupuncture effectiveness for epilepsy. The negative side effect profile of acupuncture is low, although one case report described an episode of convulsive syncope, which occurred immediately after the insertion of acupuncture needles into the bilateral ST-36 acupuncture point.121 Given the extraordinarily common use of these points, and the extremely low appearance of side effects using acupuncture, this case report should be considered an anomaly.

Spiritual Healing There is a hypothesized connection between epileptic seizures and mystical states. Epileptic occurrences have specifically been linked to various transcendent experiences. For example, the biblical figures Mohammad, Moses, and St. Paul are thought to have suffered from recurrent epileptic seizures.lZ In the story of St. Paul,

he is described to have seen a vision on his way to Damascrus. The writer William James called this vision “a discharging legion of the occipital cortex.’’123 Accordingly, some schools of thought consider spiritual work as possibly able to reciprocally influence the biologic and energetic mechanisms of epilepsy. In a study of a state in southern Brazil, roughly 60%of the sample had tried spiritual therapies for epilepsy including blessings, home remedies, prayers, mediumship, and spiritual surgery.Iz African populations are also known to use spiritual healing to treat epilepsy. Among 265 epileptic patients from Nigeria, 47.6% used African traditional medicine alone, while 24.1% combined traditional medicine with spiritual healing, 20.4% used spiritual healing alone, and 7.5% used other forms of alternative medicine. After initiation of hospital treatment, only 14.6%of patients who had earlier used African traditional medicine continued with such treatment. However, more than two thirds of the patients who had earlier used spiritual healing continued using such treatment, suggesting that many of these patients perceived some continuing benefit.124Little research that evaluates the efficacy of spiritual healing for patients with epilepsy exists. Given the low risk and possible benefit, it is certainly worth exploring in future studies.

spontaneously, is a medical emergency that inevitably results in serious neurologic damage or death if untreated. Immediate hospitalization is required, preferably with ambulance or aid car transport, with the necessary equipment to maintain the patient’s airway, assist in ventilation, and administer intravenous glucose and antiepileptic drugs. Because endogenous depression is more prevalent in persons with epilepsy than in the general population,’25 monitoring for depression illness is important in epileptic patients.

Diet All sugar and other refined carbohydrates should be eliminated, and protein levels should be moderate. Food allergens should be identified and eliminated. Small, frequent meals are best. If a ketotic effect is desired, all carbohydrates should be strictly limited and fat intake increased. Furthermore, adequate intake of energy and protein, plus a higher proportion of omega-3 unsaturated to saturated dietary fats, should be assured. Finally, vitamin and mineral supplements should be used with ketotic diets (ketotic diets should only be used under professional supervision).

Lifestyle Regular sleep patterns should be encouraged.

THERAPEUTIC APPROACH

Nutritional Supplements

Epileptic patients should be advised to avoid situations that could be dangerous if further seizures occur. Also, they should be made aware of state laws regarding epilepsy and driving. Epileptics should avoid known initiators of seizure activity (e.g., bright flashing lights, sudden loud sounds). Therapy should continue at full dosages until the patient has been seizure free for at least 2 years. Dosage reduction should then be gradual over a period of several months. Epileptics who are not controlled with natural therapies require drug therapy. Patients should eliminate pyridoxine antagonists: isoniazid, cycloserine,hydralazine, dopamine, penicillamine, oral contraceptives, alcohol, and hydrazine dyes (Food, Drug, and Cosmetic Act yellow no. 5). Note: Status epilepticus, a prolonged seizure lasting longer than 30 minutes that is not likely to stop

(The following are adult doses; reduce proportionately for children.)

1. W h o r e LJ, Ferrendelli JA. Epilepsy. In Dale DC,Federman DD, eds. Scientific American medicine. New York Scientific American, 199711, XU-1-14. 2. Pedley TA. The epilepsies. In Bennett JC, Plum F, eds. Cecil textbook of medicine,ed 20. Philadelphia: W B Saunders, 19962113-2125. 3. Hauser WA, Hesdorfer DC.Epilepsy: frequency,causes, and consequences. New York: Demos, 1990.

4. Freeman JM, Vining EPG, Pillas DJ. Seizures and epilepsy in

Vitamin B6: 50 mg three times/day Folic acid: 0.4 to 4 mg/day Vitamin E: 400 IU/day Taurine: 500 mg three times/day Magnesium: 300 mg three times/day Manganese: 10 mg three times/day Selenium: 100 yg/day Zinc: 25 mg/day Melatonin: 3 mg in children, increase up to 20 mg or more in adults

Botanical Medicines SK 300 ml before bedtime G. biloba: contraindicated at this time

childhood: a guide for parents. Baltimore:Johns Hopkins University Press, 1990. 5. Sander JW, Shorvon SD. Incidence and prevalence studies in epilepsy and their methodological problems: a review. J Neurol Neurosurg Psychiatry 198750829-839. 6. Shneker BF, Fountain NB. Epilepsy. Dis Mon 2003;49426-478.

Epilepsy ~~

~

~

7. Kwan P, Sander JW.The natural history of epilepsy: an epidemiological view. J Neurol Neurosurg Psychiatry 2004;751376-1381. &Edwards JC. Seizure types, epilepsy syndromes, etiology, and diagnosis. CNS Spectr 2001;6750-755. 9. Vadlamudi L, Andermann E, Lornbroso CT,et al. Epilepsy in twins: insights from unique historical data of William Lennox. Neurology 2004;621127-1133. 10. Hamandi K, Salek-Haddadi A, Fish DR, et al. EEG/Functional MRI in Epilepsy: The Queen Square Experience. J Clin Neurophysiol 2004;21:241-248. 11. Schroeder SA, Krupp MA, nemey LM, et al. Current medical diagnosis and treatment.Norwalk, CT:Appleton & Lange, 19893611615. 12. Dichter MA, Ayala GF. Cellular mechanisms of epilepsy: a status report. Science 1987;237157-164. 13.Allen RB. Nutritional aspects of epilepsy. Int Clm Nutr Rev 1983;3:3-9. 14. Lahat E, Ban J, Bistritzer T. Focal epileptic episodes associated with hypoglycemia in children with diabetes. Clin Neurol Neurosurg 1995;97314-316. 15. Mackay G, Borbash H. The glucose tolerance curve in epilepsy. Ment Sci 1931;7283-85. 16. Harrad RA, Kennedy PG. Hypoglycemia-induced epilepsy during lactation. Br Med J (Clin Res Ed) 1982285607-608. 17. Tyson F, O t i s L, Joyce ET. A study of blood sugar in epileptics. Am J Med Sci 1935;190164-169. 18. Nielsen JM. Convulsions of undetermined etiology. Arch Neurol Psych 1934;31:1055-1061. 19. Liu Yh4, Williams S, Basualdo-Hmond C, et al. A prospective study: growth and nutritional status of children treated with the ketogenic diet. J Am Diet Assoc 2003;103:707-712. 20. Signore JM. Ketogenic diet containing medium-chain triglycerides. J Am Diet Assoc 1973;62:285-290. 21. Barborha CJ. Ketogenic diet treatment of epilepsy in adults. JAMA 1928;91:73-78. 22. Barborha CJ. Epilepsy in adults, results of treatment by ketogenic diet in one hundred cases. Arch Neurol Psych 1930;23904-914. 23. Batchelor L, Nance J, Short B. An interdisciplinary team approach to implementing the ketogenic diet for the treatment of seizures. Pediatr Nurs 1997;23465-471. 24. Prasad AN, Stafstrom CF, Holmes GL. Alternative epilepsy therapies: the ketogenic diet, immunoglobulins, and steroids. Epilepsia 1996; 37 SUPPI1:S81-S95. 25. Swink TD, Vining EP, Freeman JP.The ketogenic diet. Adv Pediatr 1997;44:297-329. 26. Williams S, Basualdo-HammondC, Curtis R, et al. Growth retardation in children with epilepsy on the ketogenic diet a retrospective chart review. J Am Diet Assoc 2002;102405-407. 27.Kossoff EH. More fat and fewer seizures: dietary therapies for epilepsy. Lancet Neurol2004;3:415420. 28. Kossoff EH, Krauss GL, McGrogan JR, et al. Efficacy of the Atkins diet as therapy for intractableepilepsy. Neurology2003;61:1789-1791. 29. MacKamess R. Chemical victims.London: Pan Books, 1980108-123. 30. Mandell M, Scanlon LW. Dr.Mandell's M a y allergy relief system. New York: Pan Books, 1979554,151-152. 31. Crayton JW,Stone T, Stein G, et al. Epilepsy precipitated by food sensitivity: report of a case with double-blind placebo-controlled assessment. Clin Eledroencephalogr1981;12:192-198. 32. Campbell MB. Allergy and epilepsy. In Speer F, ed. Allergy of the nervous system. Springfield, k Thomas, 1970:59-78. 33. Egger J, Carter CM, Soothill JF,et al. Oligoantigenic diet treatment of children with epilepsy and migraine. J Pediatr 1989;11451-58. 34. Ventura A, Bouquet F, Sartorelli C, et al. Celiac disease, folic acid deficiency and epilepsy with cerebral calcifications. ACTA Paediatr Scand 1991;80:559-562. 35. Gobbi G, Bouquet F, Greco L, et al. Celiac disease, epilepsy and cerebralcalcifications.The Italian Working Group on Coeliac Disease and Epilepsy. Lancet 1992;340:439-443.

36. Frediani T, Lucarelli S, Pelliccia A, et al. Allergy and childhood epilepsy: a close relationship? Acta Neurol Scand 2001;104: 349-352. 37. Crowell GF, Roach ES. Pyridoxine-dependent seizures. Am Fam Physician 1983;27183-187. 38. Akre 8, Rasmussen M, Lundby R. [Pyridoxine-dependentseizures.] Rdsskr Nor Laegeforen 2004;124:162-164. 39. Alkan A, Kutlu R, Aslan M, et al. Pyndoxine-dependent seizures: magnetic resonance spectroscopy findings. J Child Neurol 2004; 1975-78. 40.Goutieres F, Aicardi J. Atypical presentations of pyridoxinedependent seizures: a treatable cause of intractable epilepsy in infants. Ann Neurol 1985;17117-120. 41. Bankier A, Turner M, Hopkins IJ. Pyridoxine dependent seizures: a wider clinical spectrum. Arch Dis Child 1983;58:415-418. 42. Nakazawa M, Tadataka M, Takeda H, et al. High-dose vitamin B6 therapy for infantilespasms-the effect and adverse reactions. Brain Dev 1983;5:193-197. 43. Hansson 0,Sillanpaa M. Letter: pyridoxine and serum concentration of phenytoin and phenobarbitone. Lancet 1976;1:256. 44.Morrell MJ. Folic acid and epilepsy. Epilepsy Cum 2002;231-34. 45.Reynolds EH. Mental effects of anticonvulsants and folic acid metabolism. Brain 1968;91:197-214. 46. Keyser A, De Bruijn SF. Epileptic manifestations and vitamin B, deficiency. Eur Neurol199131:121-125. 47.Braverman E, Pfeiffer CC. The healing nutrients within. New Canaan, CT: Keats, 1987120-136. 48.van Celder NM. A central mechanism of action for taurine. osmoregulation, bivalent cations, and excitation threshold. Neurochem Res 1983;8:687-699. 49. Huxtable R, Barbeau A, eds. Taurine. New York: Raven Press, 1976. 50. Okamoto K, Kimura H, Sakai Y. Effects of taurine and CABA on Ca spikes and Na spikes in cerebellar Purkinje cells in vitro. Intrasomatic study. Brain Res 1983;260:249-259. 51. Goodman HO, Shihabi Z, Oles KS. Antiepileptic drugs and plasma and platelet taurine in epilepsy. Epilepsia 1989;30201-207. 52. Collins BW, Goodman HO, Swanton CH, et al. Plasma and urinary taurine in epilepsy. Clin Chem 1988;34:671-675. 53.Huxtable RJ, Laird H, Lippincott SE, et al. Epilepsy and the concentration of plasma amino acids in humans. Neurochem Int 1983; 5:125-135. 54. Janjua N, MetrakosJ, van Gelder N. Plasma amino acids in epilepsy. In Anderson VE, Hauser WA, Penry JK, et al, eds. Genetic basis of the epilepsies. New York Raven Press, 1982181-197. 55. Monaco F, Mutani R, Durelli L, et al. Free amino acids in serum of patients with epilepsy. Significant increase in taurine. Epilepsia 1975;16245-249. 56. Barbeau A, Donaldson J. Taurine in epilepsy. Lancet 1973;2:387. 57. Bergamini L, Mutani R, Delsedime M, et al. First clinical experience on the antiepileptic action of taurine. Eur Neurol1974;11:261-269. 58.Takahashi R, Nakane Y. Clinical trial of taurine in epilepsy. In Barbeau A, Huxtable RJ, eds. Taurine and neurological disorders. New York: Raven Press, 1978:375-385. 59. Nakane Y, Takahashi R. Clinical experience of taurine for the treatment of epilepsy. Sulfurcontaining Amino Acids 1978;173-180. 6O.Striano S, Buscaino GA. [lst results on the effects of taurine in human epilepsy.] Ada Neurol1974;29:537-542. 61. Fukuyama Y, Ochiai Y. Therapeutic trial by taurine for intractable childhood epilepsies. Brain Dev 1982;463-69. 62. Pasantes-MoralesH, Chapparro H, Otero E. [Clinical study on the effect of taurine on intractable epileptics (author's transl)]. Rev Invest Clin 198133:373-378. 63.Birdsall TC. Therapeutic applications of taurine. Alt Med Rev 1998;3128-136. 64.Jooste PL, Wolfswinkel JM, Schoeman JJ, et al. Epileptic-type convulsions and magnesium deficiency. Aviat Space Environ Med 1979;50734-735.

Specific Health Problems 65. Benga I, Baltescu V, T i c a R, et al. Plasma and cerebrospinal fluid concentrations of magnesium in epileptic children. J Neurol Sci 1985;6729-34. 66. Shoji Y, sasazaki Y, Suzuki M, et al. Serum magnesium and zinc in epileptic children. Brain Dev 1983;5:200-212. Ajala MO, Okubadqo N, et al. Plasma magnesium in 67. Oladipo 00, adult Nigerian patients with epilepsy. Niger Postgrad Med J 2003; 10234-237. 68. Pfeiffer CC. Mental and elemental nutrients: a physician’s guide to nutrition and health care. New Canaan, CT:Keats Pub, 1975278, 40248. 69. Jooste PL, Wolfswinkel JM, Schoeman JJ,et al. Epileptic-type convulsions and magnesium deficiency. Aviat Space Envir Med 1979;50:734-735. 70. Hurley IS, Wooley DE, Rosenthal F, et al. Influence of manganex on susceptibility of rats to convulsions. Am J Physiol 1963;204: 4934%. 71. Carl GF, Keen CL, Gallagher BB, et al. Association of low blood manganese concentrations with epilepsy. Neurology 1986;36: 1584-1587. 72. Dupont CL,Tanaka Y. Blood manganese levels in children with convulsive disorder. Biochem Med 1985;332&255. 73.Sampson P. Low manganese level may trigger epilepsy. JAMA 1977;2381805. 74. Papavasilious €5,Kutt H, Miller ST, et al. Seizure disorders and trace metals. manganese in epileptics. Neurology 1979;291466-1473. 75. Solder A, Pfeiffer CC, Casey R. A direct method for the determination of manganese in whole blood. Patients with seizure activity have low blood levels. Orthomol Psych 1979;8:275-280. 76. Pfeiffer CC, LaMola S. Zinc and manganese in the schizophrenias. Orthomol Psych 1983;12215-234. 77. Barbeau A, Donaldson J. Zinc, taurine and epilepsy. Arch Neurol 1974;30:52-58. 78. Lewis-Jones MS, Evans S, Culshaw MA. Cutaneous manifestations of zinc deficiency during treatment with anticonvulsants. Br Med J (Clin Res Ed) 1985;290:603-604. 79.Ghoz EH, Freed WJ.Effects of betahe on seizures in the rat. Pharmacol Biochem Behav 1985;22:635-640. 80. Freed WJ, Gillin JC, Wyatt RJ. Anticonvulsant properties of betaine. Epilepsia 1979;20209-213. 81. Freed WJ. Prevention of strychnine-inducedseizures and death by the N-methylated glycine derivativesbetaine, dimethylglycineand sarcosine. Pharmacol Biochem Behav 1985;22:641-643. 82. Freed WJ. N,N-dimethylglycine, betaine, and seizures. Arch Neurol 1984;41:1129-1130. 83. Smolin LA, Benevenga NJ,Barlow S. The use of betaine for the treatment of homocystinuria.J Pediatr 1981,99:467472. 84. Roach ES, Carlin L. N,Ndimethylglycine for epilepsy. N Engl J Med 1982;3071081-1082. 85. Hahn TJ. Drug-induced disorders of vitamin D and mineral metabolism. Clin Endocrinol Metab 1980;301:107-127. 86. W i l l i a m s C, Netzloff M, Folkerts L, et al. Vitamin D metabolism and anticonvulsanttherapy. South Med J 1984;77:834-836,842 87. Wmtein RS,Bryce GF, Sappington LJ, et al. Decreasedserum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endoainol Metab 1984~:1003-1009. 88. Gough H, Goggin T, Bissessar A, et al. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure, and diet on vitamin D and calcium metabolism in out-patients with epilepsy. QJM 1986;59:569-577. 89. Riancho JA, del Arc0 C, Arteaga R, et al. Influence of solar radiation on vitamin D levels in children on anticonvulsant drugs.Acta Neurol s a n d 1989;79296-299. 9O.Christiansen C, Rodbro P, Sjo 0. “Anticonvulsant action” of vitamin D in epileptic patients? A controlled pilot study. Br Med J 1974;2258-259.

91.Ogunmekan AO. Vitamin E deficiency and seizures in animals and man. Can J Neurol Sci 1979;643-45. 92. Hojo Y. Subject groups high and low in selenium. Bull Environ Contam Toxic01 1981;26466-471. 93. Verrotti A, Greco R, Latini G, et al. Obesity and plasma concentrations of alpha-tocopherol and beta-camtene in epileptic girls treated with valproate. Neuroendocrinology2004,79157-162. 94. Kataoka K, Kanamori N, Oishi M, et al. Vitamin E status in pedmtric patients receiving antiepileptic drugs. Dev Pharmacol Ther 1989; 1496-101. 95. Mori A, Yokoi I, Noda Y, et al. Natural antioxidants may prevent posttraumatic epilepsy: a proposal based on experimental animal studies. Acta Med Okayama. 2004~:111-118. 96.Ogunmekan AO, Hwang PA. A randomized, double-blindplacebo-controlled clinical trial of d-alpha-tocopheryl acetate as add-on therapy for epilepsy in children. Epilepsia 1989;30:84-89. 97. Weber GF, Maertens ,’F Meng, et al. Glutathione pemxidase deficiency and childhood seizures. Lancet 1991371443-1444. 98. Meyerhoff JL, Lee JK, Rittase BW, et al. Lipoic acid pretreatment attenuates ferric chloride-induced seizures in the rat. Brain Res 2004;1016139-144. 99.Farkas E, de Wilde MC, Kiliaan AJ, et al. Systemic effects of dietary n-3 PUFA supplementation accompany changes of CNS parameters in cerebral hypoperfusion. Ann N Y Acad Sci 2002; 97777-86. 100. !Mdanger S, Shinitzky M, Yam D. Diet enriched with omega-3 fatty acids alleviates convulsion symptoms in epilepsy patients. Epilepsia 2002;43:103-104. 101. Vaddadi KS. The use of gamma-linolenic acid and linoleic acid to differentiate between temporal lobe epilepsy and schizophrenia. Prostaglandins Med 1981;6375-379. 102. Zaiwalla Z, Stores G. Sleep and arousal disorders in childhood epilepsy. Electroencephalogr Clin Neurophysiol1989;72:107. 103. Yalcjn A, Kilinc E, Kodurk S, et al. Effect of melatonin cotreatment against kainic acid on coenzyme QlO, lipid peroxidation and Trx mRNA in rat hippocampus. Int J Neurosci 2004;114:1085-1097. 104. Gupta M, Anqa S, Kohli K. Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial. Epilepsy Behav 2004; 5316-321. 105. James SP, Sack DA, Rosenthal NE. Melatonin administration in insomnia. Neuropsychopharmacology1990;3:19-23. 106.Sugoya A, Tsuda T, Yasuda K, et al. Effects of Chinese herbal medicine ”saiko-keishi-to”on intracellular calcium and protein behavior during pentylenetetrazol-induced bursting activity in snail neuron. Planta Med 1985;2-6. 107. Sugoya A, Tsuda T, Yasuda K, et al. Effects of Chinese herbal medicine “Saiko-Keishi-To” on transmembrane ionic current of snail neurons. Planta Med 1985;60-61. 108.Nagakubo S, Niwa S, Kumagai N, et al. Effects of TJ-960 on Stemberg’s paradigm results in epileptic patients.Jpn J Psychiatry Neurol 1993;47609-620. 109. Narita Y, Satowa H, Kokubu T, et al. Treatment of epileptic patients with the Chinese herbal medicine “Saiko-Keishi-To” (SK). IRCS J Med Sci 1982;108&89. 110. Ferrendelli JA. Roles of biogenic amines and cyclic nucleotides in seizure mechanisms. Adv Neurol 1986;44.393-400. 111. Seamon KB, Daly JW. Forskolin: a unique diterpene activator of cyclic AMP-generating systems. J Cyclic Nucleotide Res 1981;7 201-224. 112. Kanatoni H, Tanimoto J, Hidaka K, et al. Search for adenylate cyclase activator in medicinal plants. Planta Med 1985;182-185. 113. Granger AS. Ginkgo biloba precipitating epileptic seizures. Age Ageing 2001;30:523-525. 114. W u D. Mechanism of acupuncture in suppressing epileptic seizures. J Tradit Chin Med 1992;12187-192.

Epilepsy 115. Huang ZN,Yang R, Chen G, et al. [Effect of electroacupuncture and 7-M on penicillin-induced epilepsy and their relation with intrahippocampalNO changes.]Sheng Li Xue Bao 1999;51:508-514. 116. Yang R, Huang ZN,Cheng JS. Anticonvulsion effect of acupuncture might be related to the decrease of neuronal and inducible nitric oxide synthases. Acupunct Electrother Res 2000;25:137-143. 117. Stavem K, Kloster R, Rossberg E, et al. Acupuncture in intractable epilepsy: lack of effect on health-related quality of life. Seizure 2000;9:422426. 118. Kloster R, Larsson PG, Lossius R, et al. The effect of acupuncture in chronic intractable epilepsy. Seizure 1999;8:170-174. 119. Shu J, Liu RY, Huang XE The effects of ear-point stimulation on the contents of somatostatin and amino acid neurotransmitters in brain of rat with experimental seizure. Acupunct Electrother Res 2004;29:43-51. 120. Allen IC, Grieve A, Griffiths R. Differential changes in the content of amino acid neurotransmittersin discrete regions of the rat brain

prior to the onset and during the course of homocysteine-induced seizures. J Neurochem 1986;46:1582-1592. 121. Cole M, Shen J, Hommer D. Convulsive syncope associated with acupuncture.Am J Med Sci 2002;324:288-289. 122. Pickover C. Transcendent experience and temporal lobe epilepsy. Available online at http://www.meta-religion.com/Psychiaty/ T h e _ P a r a n o r m t - e ~ ~ ~ s[accessed . h ~ November 16, 20041. 123. Cohen MH. Regulation, religious experience, and epilepsy: a lens on complementary therapies. Epilepsy Behav 2003;4:602-606. 124. Danesi MA, Adetunji JB.Use of alternative medicine by patients with epilepsy: a survey of 265 epileptic patients in a developing country. Epilepsia 1994;35344-351. 125. Penovich PE, Eck KE, Economou W. Recommendations for the care of women with epilepsy. Cleve Clin J Med 2004;71(suppl2): s49-57.

Erythema Multiforme Michael T. Murray, N D Joseph E. Pizzorno Jr, N D _____

Diagnostic Summary

CHAPTER C O N T E N T S

1663

Therapeutic Approach Supplements 1664

1664

General Considerations 1663 Therapeutic Considerations 1663 Potassium Iodide 1663 Zinc 1664

DIAGNOSTIC SUMMARY Sudden onset of symmetric, erythematous, edematous, macular, papular, urticarial, bullous, or purpuric skin lesions Evolves into ”target lesions” (lesions with clear centers and concentric erythematous rings) Characteristic first site: dorsum of hand Characteristic distribution: extensor surfaces of extremities with relative sparing of head and trunk Although rare, oral manifestations can range from tender superficial erythematous and hyperkeratotic plaques to painful, deep, hemorrhagic bullae and erosions. Tendency to recur in spring and fall

GENERAL CONSIDERATIONS The term erythema rnultifomze (EM) actually includes a wide range of clinical expressions, from exclusive oral erosions (oral EM) to mucocutaneous lesions ranging from mild (EM minor) to severe involvement of multiple mucosal membrane (EM major, Stevens-Johnson syndrome [SJS]) or with involvement of a large area of the total body surface (toxic epidermal necrolysis [TEN]). However, this terminology is not accepted worldwide, and often the various clinical categories show some overlapping features. Although significant differences exist among EM minor, EM major, SJS, and TEN with regard to severity and clinical expression, all variants share two common features: typical or less typical cutaneous target lesions and satellite-cell or more widespread necrosis of the epithelium.

Among the great number of suspected etiologic factors, herpes simplex virus or Mycoplasma infections are involved in roughly 90% of cases of EM minor, whereas SJSand TEN are caused in 80% of cases by systemic drugs, mainly by anticonvulsants, sulfonamides, nonsteroidal antiinflammatory drugs, and antibiotics. However, various vaccines (e.g., Vaccinia, tuberculosis, poliomyelitis, etc.); food allergy; and other infectious organisms have all induced EM minor. Evidence clearly points to hypersensitivity and immune systemmediated tissue damage caused by the release of highly reactive, polynuclear leukocyte-derived, oxygen intermediates as the common factors in all variants of EM.’

THERAPEUTIC CONSIDERATIONS Potassium Iodide Potassium iodide has historically been used to treat various erythematous disorders including the following: Erythema multiforme Erythema nodosum Nodular vasculitis Acute febrile neutrophilic dermatosis Subacute nodular migratory panniculitis Clinical studies have documented dramatic success with potassium iodide.” The mechanism is apparently related to the suppression of the generation of oxygen intermediates such as hydrogen peroxide and hydroxyl radical by stimulated neutrophils.5 Importantly, iodine therapy has occasionally been associated with various adverse skin reactions and gastrointestinal discomfort,

1663

Specific Health Problems

and it should never be used in pregnant women in the last trimester due to suppression of the fetal thyroid?

all unnecessary medications should be stopped, and an antiinflammatory program should be initiated.

Zinc

Supplements

Zinc sulfate (0.025% to 0.05%) has been used locally at the site of herpetic infection and to prevent the relapse of postherpetic EM.’

Potassium iodide: 100 mg three times/day for 4 to 6 weeks. Discontinue if there are adverse reactions. Zinc sulfate: 0.025% to 0.05% solution locally if postherpetic

THERAPEUTIC APPROACH A careful search should be made to determine the initiating factor. Underlying infections should be treated,

1.Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol1997;24726-729. 2. Horio T, Danno K, Okamoto H, et al. Potassium iodide in erythema nodosum and other erythematous dermatoses. J Am Acad Dermatol 1983977-81. 3. Schultz EJ, Whiting DA. Treatment of erythema nodosum and nodular vasculitis with potassium iodide. Br J Dermatol19769475-78. 4.Kelly F. Iodine in medicine and pharmacy since its discovery1811-1961. Proc R Soc Med 1961;54:831-836.

5. Miyachi Y, Niwa Y. Effects of potassium iodide, colchicine, and dapsone on the generation of PMN derived oxygen intermediates. Br J Dermatol1982;107209-214. 6. Zone JJ. Potassium iodide and vasculitis. Arch Dermatol 1981;117 758-759. 7.Brody I. Topical treatment of recurrent herpes simplex and postherpetic erythema multiforme with low concentrations of zinc sulphate solution. Br J Dermatol 1981;104:191-194.

Fibrocystic Breast Disease Tori Hudson, ND Michael T. Murray, ND CHAPTER CONTENTS Diagnostic Summary

1665

Nutritional Supplements 1666 Other Considerations 1667

General Considerations 1665 Differential Diagnosis 1666

Therapeutic Approach Diet 1668 Supplements 1668

1668

Therapeutic Considerations 1666 Dietary Considerations 1666

DIAGNOSTIC SUMMARY Common in reproductive-age women Pain or premenstrual (PMS) breast pain and tenderness common, although condition often asymptomatic Characteristically cyclic and bilateral with multiple cysts of varying sizes, giving the breast a nodular consistency

GENERAL CONSIDERATIONS Tender or lumpy breasts are one of the most common reasons why women consult their health practitioner for assessment and treatment. The benign breast conditions that are present in almost all women of reproductive age to some degree should never have been labeled a disease. The widespread misconception that women with painful or lumpy breasts are at increased risk of breast cancer adds fuel to the fire for women already afraid of breast cancer. It would be much more useful to create descriptive categories of symptoms and conditions to replace the generic term fibrocystic breusf diseuse (FBD). Nonetheless, we are left with a term that all health providers are familiar with, even though most agree it would be better to more accurately describe and categorize the conditions. Many women experience PMS pain or sensitivity. This may be attributed to a more prominent estrogen than progesterone effect on breast tissue at this time, when the effect of progesterone should normally be greater in the luteal phase. This does not necessarily mean that these women have lower or higher amounts

of any particular hormone but may have an increased tissue sensitivity to estrogen with related fluid retention. Most women tolerate this discomfort just fine and can be merely reassured. Other women may need to employ lifestyle changes or use supplementation. Oral contraceptives or hormone replacement therapy, or both, may similarly cause breast discomfort. These symptoms would be best described as physiologic, cyclical pain and swelling. Mastalgia, another descriptive category, refers to any breast pain severe enough to interfere with daily life and cause women to seek treatment. Cyclical mastalgia is this severe about 15% of the time. Noncyclical, severe pain is much rarer and may be due to infection, old trauma, or musculoskeletal conditions related to the chest wall. Diffuse lumpiness may be either cyclic or noncyclic and may or may not include pain. Normal breasts can also include diffuse lumpiness due to glands, fat, and connective tissue. More prominent lumpiness and more lumps in number set this apart from the normal state. Often this diffuse lumpiness is symmetrical and is an important finding in distinguishing a normal lump from a suspicious lump. Even' the majority of densities that are unilateral are benign. If the edge of the mass merges in one or more places with the surrounding breast tissue, it is considered nondominant. It is important to evaluate these masses and make a careful distinction from a dominant mass or mass of concern. Evaluation may include a fineneedle biopsy. The majority show some nonproliferative 1665

Specific Health Problems change, and about 20% show proliferative changes without atypical hyperplasia. None of these conditions places the woman at increased risk for breast cancer. Only the 5% who show atypical hyperplasia carry a significantly increased risk of breast cancer, especially when there is family history of a first-degree relative with breast cancer.' Dominant masses are noncyclical, unilateral masses and distinct on all sides from the surrounding breast tissue. They persist over time and require a thorough assessment except in the very young. They are either fibroadenomas or obvious cysts. Fibroadenomas are rubbery, smooth, benign, fibrous tumors. They usually do not grow bigger. Cysts are softer and disappear when drained with a needle aspiration in the office. Fibroadenomas and cysts are not associated with an increased risk of breast cancer but must be distinguished from a malignancy.

DIFFERENTIAL DIAGNOSIS FBD cannot be definitively differentiated from breast cancer or fibroadenoma of the breast on clinical criteria alone. Pain, cyclic variations in size, high mobility, symmetry, and multiplicity of nodules are indicative of FBD. Noninvasive procedures such as mammography and ultrasonography can further aid differentiation. However, a definitive work-up includes needle aspirations, fine-needle biopsies, or excisional biopsies.

THERAPEUTlC CONSIDERATIONS Discussion of PMS (see Chapter 204) may help to further understand factors that can influence FBD. The factors discussed here were chosen because they are not covered in depth in Chapter 204 and are particularly relevant to FBD.

Dietary Considerations Methylxanthines

their consumption. Those who continued with little change in their methylxanthine consumption showed little impr~vement.~ According to this study, women may have varying thresholds of response to methylxanthines. However, three other studies have been shown no association between methylxanthines and FBD.6l7B Stress may also play an important role, since fibrocystic breasts appear more responsive to epinephrine, the presence of which increases adenylate cyclase activity and, hence, CAMPproduction.

Fiber A comparison between the diets of 354 women with benign proliferative epithelial disorders of the breast and those of 354 matched controls and 189 unmatched controls found an inverse association between dietary fiber and the risk of benign, proliferative, epithelial disorders of the breasts? An increased intake of dietary fiber may be associated with a reduced risk to both benign breast disease and breast cancer.

SOY In an uncontrolled study, 64 premenopausal women consumed soy protein for 1year. The women and their physicians reported a subjective reduction in both breast tenderness and FBD. Evaluation by breast-enhanced scintigraphy testing also showed that a nonstatistical reduction occurred in both the average and maximal count breast activity following 1 year of daily soy consumption. There was a statistically significant reduction (p < 0.01) in variability of tissue activity following 1year of soy protein treatment.1° The findings are promising and showed both objective and subjective findings consistent with a reduction in fibrocystic disease of the breast.

Nutritional Supplements Evening Primrose Oil

The only essential fatty acid to be studied in relation to fibrocystic breasts is evening primrose oil (EPO). When Epidemiologically,2 e~perimentally,3-~ and clini~ally,3-~ 291 women with cyclic and noncyclic breast pain were studied using 3000 mg of EPO for 6 months, almost half there is strong evidence supporting an association of the 92 women with cyclic breast pain experienced between methylxanthine consumption and FBD. Caffeine, improvement, compared with one fifth of the patients theophylline, and theobromine are all known to inhibit the action of cyclic adenosine monophosphate (CAMP) who received the placebo. For those women who experienced breast pain throughout the month, 27% (of and cyclic guanosine monophosphate phosphodi33 women) improved with EPO compared with 9% on esterase and to sigruficantly elevate their levels in breast the placebo." Another study of 73 women with breast tissue.*5 In turn, increased levels of these cyclic pain randomly received 3 g/day of EPO or placebo. nucleotides excessively stimulate protein-kinase activiAfter 3 months, pain and tenderness were significantly ties and cause the overproduction of cellular products reduced in both the women with cyclic breast pain and such as fibrous tissue and cyst fluid. those with noncyclic pain. The women who took the In one study, limiting methylxanthines (coffee, tea, cola, chocolate, and caffeinated medications) in the diet placebo did not sigrufrcantly improve.12Other seed oils with gamma linolenic acid should also be considered: resulted in improvement in 97.5%of the 45 women who flaxseed oil, black currant oil, and borage oil. completely abstained, and in 75% of the 28 who limited

Fibrocystic Breast Disease ~

~~

Vitamin E Alpha-tocopherol has been shown to relieve many PMS symptoms, particularly FBD, as evidenced by several double-blind clinical studies.13,14Two studies demonstrated that vitamin E is clinically useful in relieving pain and tenderness, whether it is cyclical or noncycli~ a l . ' ~The , ' ~ mode of action remains unclear. When larger numbers of women were studied, vitamin E did not fare so well, showing no sigruficant effects either subjectively or obje~tively.~~J~ The results of the earlier studies have not been successively duplicated.

Vitamin A After 3 months of high-dose supplementation with vitamin A (150,000 IU/day), five of the nine patients who completed the study had complete or partial remission of their FBD.19 However, some patients developed mild side effects, resulting in 2 of the original 12 withdrawing due to headaches and 1 patient having her dosage reduced. Beta-carotene would appear to be a more appropriate source of retinol due to its greatly decreased toxicity and similar activity in ovarian and inflammatory disorders (see Chapter 139).

Thyroid and Iodine Experimental iodine deficiency in rats results in a mammary dysplasia histologically similar to human FBD.20 Thyroid hormone replacement therapy in hypothyroid, and some euthyroid, patients may result in clinical improvement.20,21 Research has shown that thyroid supplementation (0.1 mg/day Synthroid) decreases mastodynia, serum prolactin levels, and breast nodules in, supposedly, euthyroid patients. These results suggest that subclinical hypothyroidism or iodine deficiency, or both, may be an etiologic factor in FBD. Iodine (specifically iodine caseinate) may be an effective treatment for FBD." It is theorized that an absence of iodine renders the epithelium more sensitive to estrogen stimulation. This hypersensitivity can produce excess secretions over the limit of absorption, thus distending the breast ducts to produce small cysts and later fibrosis (hardening of the tissue due to the deposition of fibrin, similar to the formation of scar tissue). In studies in rats, it was shown that there is a hierarchical response to the type of iodine compound in correcting the abnormalities in mammary tissue due to iodine deprivation. Although iodides correct the cystic spaces and partially corred the excessive cellular reproduction, iodine in its elemental form correds the entire disease process. Thus it appears that elemental iodine is the preferential form of iodine for breast metabolism. Also, oral iodine supplementation is known to have sigruficantantiinflammatory and antifibrotic effects, in both acute and chronic experimentalmodels.=

Human studies also indicate that elemental iodine may be more effective than iodides. Since 1975, three clinical trials have been performed on women with FBD? An uncontrolled study with sodium iodide and proteinbound iodide A prospective, controlled, crossover study from iodide to molecular iodine A prospective, controlled, double-blind study with molecular iodine

Results from these studies indicate that although treatment with iodides was effective in about 70% of subjects, it was associated with a high rate of side effects (e.g., altered thyroid function in 4%, iodinism in 3'10, and acne in 15%). Results with elemental iodine were about the same but were not associated with significant side effects. The most sigruficant side effect with molecular iodine was short-term increased breast pain, which seemed to correspond to a softening of the breast and disappearance of fibrous tissue plaques on physical examination. The dosage of molecular iodine was 70 to 90 pg/kg body weight. This dosage appears to be a safe and effective treatment for FBD. The forms of iodine supplement used in the studies (iodine caseinate and liquid iodine) are becoming available in the marketplace.

Other Considerations Liver Function Because FBD may be related to an increased sensitivity to estrogen, and the liver is the primary site for estrogen clearance, any factor (e.g., cholestasis, "toxic liver syndrome," environmental pollution, or otherwise compromised liver metabolic functions) that interferes with proper liver function may lead to an increased effect of estrogen on a particular estrogen-sensitive tissue. Adequate levels of lipotropic factors and B vitamins are necessary for estrogen conjugation.

Colon Function Breast disease has been linked to the Western diet and bowel function. There is an association between epithelial dysplasia in nipple aspirates of breast fluid and the frequency of bowel movements." Women having fewer than three bowel movements per week have a risk of FBD 4.5 times greater than women having at least one a day. This association is probably due to the bacterial flora in the large intestine transforming endogenous and exogenous sterols and fatty acids into various toxic metabolites including polycyclic carcinogens and mutagens.= Fecal microorganisms are capable of synthesizing estrone, estradiol, and 17-methoxyestradiol, as well as metabolizing estrogen sulfate and glucuronate conjuresulting in absorption of bacteria-derived

estrogens and reabsorption of previously conjugated estrogen. Diet plays a major role in the colon microflora, transit time, and the concentration of absorbable metabolites.% Women on a vegetarian diet excrete two to three times more conjugated estrogens than women on an omnivorous diet who also reabsorb more estrogens.” Furthermore, omnivorous women have 50% higher mean levels of unconjugated estrogens. Lactobacillus acidophilus supplementation has been shown to lower fecal beta-gl~curonidase.~’

and swelling, as well as reducing the actual breast swelling and nodularity in some women.= Reducing the dietary fat intake to 20% of total calories results in significant decreases in circulating estrogens in women with benign breast disease.29 Exogenous estrogens should be avoided, as they may exacerbate the condition (these include oral contraceptives, hormone replacement therapy, and estrogen-augmented animal products). The diet should emphasize whole, unprocessed foods (whole grains, legumes, vegetables, fruits, nuts, and seeds). Patients should be encouraged to drink at least 48 oz of water daily.

THERAPEUTIC APPROACH

Supplements

Some women have noncyclic FBD, and others have cyclic premenstrual breast tenderness and lumpiness, so the therapeutic approach outlined in Chapter 204 may be more appropriate for individual needs. The therapy recommended here includes key factors discussed in this chapter, as well as Chapter 204. The diet should be primarily vegetarian with large amounts of dietary fiber. All methylxanthines should be eliminated until symptoms are alleviated. They can then be reintroduced in small amounts. Reducing the fat content of the diet to 15% of total calories, while increasing complex carbohydrate consumption, has been shown to reduce the severity of premenstrual breast tenderness

€3-complex: 10 times the recommended daily allowance Lipotropic factors Choline: 500 to 1000 mg/day Methionine: 500 to 1000 mg/day Vitamin B6: 25 to 50 mg three times/day Vitamin C: 500 mg three times/day Vitamin E: 400 to 800 IU/day of Dalpha tocopherol Beta-carotene: 50,000 to 300,000 IU/day Iodine (aqueousiodine): 3 to 6 mg/day (a prescription item) Zinc: 15 mg/day Evening primrose oil 1500 mg two times/day Flaxseed oil: 1 tbsp/day lactobacillus acidophilus: 1 to 2 billion live organisms/ day

1. Page DL, Dupont WD.Indicators of increased breast cancer risk in humans. J Cell Biochem Supp11992;16(;:175-182. 2. Boyle CA, Berkowitz GS, LiVolsi VA, et al. Caffeine consumption and fibrocystic breast disease: a case-control epidemiologic study J Natl Cancer Inst 1984;721015-1019. Clinical and 3. Minton JP,Abou-Issa H, Reiches N, Roseman JM. biochemical studies on methykanthine-related fibrocystic breast disease. Surgery 1981;90299-304. 4.Minton JP, Foecking MK, Webster DJT, Matthews RH. Caffeine, cyclic nucleotides, and breast disease.Surgery 1979;86:105-109. 5. Emster VL,,Mason L, Goodson WH ID,et al. Effects of caffeine-free diet on benign breast disease. A random trial. Surgery 198291: 263-267. 6. Lubii F, Ron E, Wax Y, et al. A case-control study of caffeine and methylxanthjne in benign breast disease. JAMA 1985;253:2388-2392. 7. Shairer C, Brinton LA, Hoover RN. Methylxanthine and benign breast disease. Am J Epidemiol1986;124603-611. 8.Marshd J, Graham S, Swanson M. Caffeine consumption and benign breast disease: a case-control comparison. Am J Public Health 1982;72610-612. 9. Baghurst PA, Rohan TE. Dietary fiber and risk of benign proliferative epithelial disorders of the breast. Int J Cancer 1995;63:481485. 10. Fleming RM. What effect, if any, does soy protein have on breast tissue? Integr Cancer Ther 2003;2225-228. 11. Pye J, Mansel RE, Hughes LE. Clinical experience of drug treatment for mastalgia. Lancet 1985;2373-377.

12. Pashby N, Mansel RE, Hughes LE, et al. A clinical trial of evening primrose oil in mastalgia. Br J Surg 1981;68:801-824. 13. London RS, Sundaram GS, Schultz M, et al. Endocrine parameters and alpha-tocopherol therapy of patients with mammary dysplasia. Cancer Res 1981;41:3811-3813. 14. London RS, Sundaram G, Manimekalai S, et al. The effect of alphatocopherol on premenstrual symptomatology: a double-blind study. II. Endocrine correlates. J Am Coll Nutr 1984;3351-356. 15. London R, Sundaram G, Manimekalai 5, et al. Mammary dysplasia: Endocrine parameters and tocopherol therapy. Nutr Res 1982;7243. 16. London R, Sundaram GS, Schultz M, et al. Endocrine parameters and alpha-tocopherol therapy of patients with mammary dysplasia. Cancer Res 1981;41:3811-3813. 17. Myer EC, Sommers DK, Reitz CJ, Mentis H. Vitamin E and benign breast disease. Surgery 1990;107549-551. 18. London RS, Sundaram GS, Murphy L, et al. The effect of vitamin E on mammary dysplasia: A double-blind study. Obstet Gynecol 1985;65:104-106. 19. Band PR, Deschamps M, Falardeau M, et al. Treatment of benign breast disease with vitamin A. Prev Med 1984;13549-554. 20. Eskin BA, Bartushka DG, Dunn MR, et al. Mammary gland dysplasia in iodine deficiency. JAMA 1967;200:691-695. 21. Estes NC. Mastodynia due to fibrocystic disease of the breast controlled with thyroid hormone. Am J Surg 1981;142764-766. 22. Ghent WR, Eskin BA, Low DA, Hill LP.Iodine replacement in fibre cystic disease of the breast. Can J Surg 1993;36453-460.

Diet

Fibrocystic Breast Disease 23. Mielens ZE, Rozitis J Jr, Sansone VJ Jr. The effect of oral iodides on inflammation.Tex Rep Biol Med 1968;26117-121. 24. Petrakis NL, King EB. Cytologicalabnormalitiesin nipple aspirates of breast fluid from women with severe constipation. Lancet 1981;2:1203-1204. 25. Hentges DJ. Does diet influence human fecal microflora composition? Nutr Rev 1980;38:329-336. 26. Goldin B, Aldercreutz H, Dwyer JT, et al. Effect of diet on excretion of estrogens in pre- and post-menopausalwomen. Cancer Res 1981; 41:3771-3773.

27. Goldin B, Gorback S. The effect of milk and lactobacillus feeding on human intestinal bacterial enzyme activity. Am J Clin Nutr 19&4;39:756-761. 28. Boyd NF, McGuire V, Shannon P, et al. Effect of a low fat highcarbohydrate diet on symptoms of cyclical mastopathy. Lancet 1988;2128-132. 29. Rose DP, Boyar AP, Cohen C, Strong LE. Effect of a low-fat diet on hormone levels in women with cystic breast disease. I. Serum steroids and gonadotropins.J Natl Cancer Inst 1987;78:623-626.

Fibromyalgia Syndrome John C . Lowe, MA,DC Gina Honcyman-Lowc, DC CHAPTER CONTENTS Diagnostic Summary

1671

Diagnosis 1671 Differential Diagnosis

1671

Thyroid Hormone Therapy Based on Initial Thyroid Status 1676 Rehabilitation Model: Data-Driven Clinical Decisions 1676 Objective Assessment of Patient Status 1677 Integrated Metabolic Therapies Essential for All Fibromyalgia Syndrome Patients 1680 Additional Metabolic Therapies Necessary for Some Patients 1680

General Considerations 1672 Serotonin Deficiency Hypothesis of Fibromyalgia Syndrome 1672 Hypometabolism Hypothesis of Fibromyalgia Syndrome 1672 Metabolism-RegulatingTherapies Other Than Thyroid Hormone 1674 Summary 1675 Therapeutic Considerations 1675 Laboratory Testing for Thyroid Status

Therapeutic Approach 1681 Assessment of Fibromyalgia Syndrome Status 1681 1675

DIAGNOSTIC SUMMARY Common: 2% to 13% of population; approximately 80% to 90% women *Chronic widespread pain involving axial pain and pain on the left, right, upper, and lower parts of body1 Abnormal tenderness at 11 or more of 18 specific anatomic tender point (TnF) sites (Figure 168-1)'

DIAGNOSIS The 13 most common symptoms associated with the pain and tenderness of fibromyalgia syndrome (FMS) are listed in Box 168-1."

Differential Diagnosis The purpose of the 1990 American College of Rheumatology (ACR) criteria for FMS is to distinguish patients with a putative primary disorder designated FMS from patients with similar symptoms due to other distinguishable medical disorders. The two major criteria for FMS are chronic (longer than 3 months) widespread pain and tenderness.' The criteria were established mainly for use in research that would eventually identdy the underlying pathologic mechanism

of the symptoms, but they have come to serve as diagnostic criteria in clinical practice. Some theorists have argued that widespread pain and tenderness at predictable anatomic sites are features of many medical disorders? Their argument is true only of hypothyroidism and cellular resistance to thyroid hormone, especially when the associated symptoms of FMS are also taken into account. When patients with hypothyroidism or cellular resistance to thyroid hormone meet the ACR criteria for FMS and are effectively treated with thyroid hormone therapy, they no longer meet the FMS riter ria.^'^ This finding indicates that these patients' FMS symptoms and signs are a distinct clinical phenotype of inadequate thyroid hormone tissue regu1ation.l6 It also justifies a trial of thyroid hormone therapy to distinguish whether a patient's FMS symptoms and signs are features of hypothyroidism or cellular resistance to thyroid hormone. The theorists' argument does not apply to other medical disorders, however, and is refuted by two lines of evidence.17 First, studies have not established that chronic widespread pain and multiple TnF's are features of other medical disorders. Second, many patients with rheumatoid arthritis, osteoarthritis, Lyme disease, systemic lupus erythematosus, Chiari malformation, 1671

Specific Health Problems

f -\

i\

be distinguished from medical disorders other than hypothyroidism and cellular resistance to thyroid hormone by careful pathognomy. However, diagnostic scrutiny will show that the symptoms and signs of most FMS patients are indistinguishable from those of the subclass of hypothyroid and thyroid hormone-resistant patients for whom pain is a predominant symptom.

GENERAL CONSIDERATIONS Serotonin Deficiency Hypothesis of Fibromyalgia Syndrome

Figum 1881 Location of 18 anatomic tender point sites. (Copyright John C. Lowe.)

Fatigue Stiffness Headache Sleep disturbance Irritable bowel Depression Cognitive dysfunction Anxiety Coldness Paresthesias Sicca symptoms Exercise intolerance Dysmenorrhea

and spinal stenosis also meet the ACR criteria for FMS, but when these other disorders are effectively treated, the patients still meet the criteria for FMS.lB20 The argument is false, then, that chronic widespread pain and tenderness are features of many medical disorders. Nonetheless, the argument highlights the need to differentiate FMS from other disorders with similar symptoms that may lead the clinician to misdiagnose FMS. The main disorders the clinician should distinguish from FMS are arthritis, myopathy, polymyalgia rheumatica, diabetic polyneuropathy, ankylosing spondylitis, discopathy, cardiac or pleural pain?’ multiple muscle myofascial pain syndromes,22and lupus erythematosus. A given patient may, of course, concurrently meet the criteria for FMS and one or more other disorders with overlapping symptoms. FMScan usually

The serotonin deficiency hypothesis is the oldest proposed mechanism of FMS.”= This hypothesis proposes that a central nervous system (CNS) serotonin deficiency reduces the efficiency of the brainstem-spinal cord descending antinociceptivesystem. The reduced efficiency purportedly results in heightened pain perception in response to normal afferent Several research findings, however, confute the serotonin deficiency hypothesis. First, the cerebrospinal fluid (CSF) level of the metabolite of serotonin, 5-hydroxyindoleacetic acid, was normal in tested FMS patients.” Second, the only site of low serotonin found in FMS patients was platelets.26,28 Third, drugs that increase synaptic serotonin levels produced only mild, short-term improvement on a few measures of FMS statusz9Long term, the drugs were no more effective than placebos.30-M In other studies, the drugs actually caused patients’ FMS status to deteriorate.” And fourth, low cerebral blood flow in FMS patient^^^,^' contradicts a serotonin deficiency. Serotonin is a potent vasoconstrictor; a low CNS level would produce cerebral vasodilation and increase blood flow.I6

Hypometabolism Hypothesis of Fibromyalgia Syndrome The hypometabolism hypothesis posits that FMS is chronic hyperalgesia and other symptoms and signs of hypometabolism due to hypothyroidism, partial cellular resistance to thyroid hormone, or other metabolismimpeding factors. Among the other factors are pernicious diet, nutritional deficiencies, low physical fitness, and metabolism-impeding drugs. The term ”hypometabolism” refers to the global impact on the patient of the underlying factors, most of which are catabolic and inhibitory, although some are anabolic or excitatory.’6 Considerable evidence indicates that inadequate thyroid hormone regulation (ITHR) due to hypothyroidism or cellular resistance to thyroid hormone is the underlying mechanism of the two main features of FMS:chronic widespread pain and abnormal tenderness. ITHR of metabolic processes in cells of the brainstem-spinal cord descending antinociceptive system can result in chronically enhanced pain perception. Impairment of

Fibromyalgia Syndrome

transmission of nociceptive signals in the CNS will increase, heightening pain perception. That decreased NE production is involved in the Spontaneous or ongoing pain heightened pain perception of FMS patients is indicated Tenderness (lowering of the pain threshold to mechanby low metabolites of both dopamine and NE in patients' ical stimuli) CSEZ7That inadequate T3 regulation of locus ceruleus Hyperalgesia (increased responsiveness to noxious neurons accounts for the low NE production is sug~timuli)~~,~~ gested by the crucial role T3 plays in the synthesis of ITHR can impair the antinociceptive system by two both dopamine and NE. The locus ceruleus is the brain site with the heaviest concentration of T3.62-64 Thyroid mechanisms. First, ITHR can severely increase produchormone regulates the activity levels of two rate-limiting tion of substance P, which is extremely high in the CSF enzymes in dopamine and NE synthesis.65One enzyme, of tested FMS patients." Substance P is released from tyrosine hydroxylase, catalyzes conversion of tyrosine the terminals of nociceptive and assists the summation of slow nociceptive signals.42The facilitation to DOPA, which in turn is converted to dopamine.66 Tyrosine hydroxylase activity in locus ceruleus noraamplifies the transmission of nociceptive signals in the drenergic neurons is low in hypoth~roidism.~~ Low spinal cord.& Thyroid hormone normally inhibits the activity of the enzyme and reduced conversion of DOPA synthesis and secretion of substance P in many CNS to dopamine may be responsible for low dopamine cells. It does so by repressing transcription of the levels in the striatum, hypothalamus, and superior preprotachykinin-A gene. Preprotachykinin-A is the cervical ganglia in hypothymidism.65Thyroid hormone precursor of substance P and its cognate substance P therapy increases activity of tyrosine hydro~yla~e.6~ The r e c e p t ~ r . Lowering ~,~~ thyroid hormone levels by thyroidectomy increased the substanceP level in astrocytes&; second enzyme, dopamine-beta-hydroxylase, catalyzes anterior pituitar?; many brain nuclei49;and, most conversion of dopamine to NE. Low activity of the relevant to pain, the dorsal horns of the lumbar spinal enzyme in hypothyroidism can reduce NE levels.65 Unfortunately,NE levels in the antinociceptivesystem and cord. The increase in dorsal horn substance P was highly other tissues in thyroid disorders have not been studied elevated (100%)50f'1as in FMS patients." Thyroid hormone treatment lowered the substance P level in the extensively68enough to support thisputative mechanism. Hence by raising substance P levels and possibly lowanterior pituitaqf7 brain and the dorsal horns.51 Excess thyroid hormone reduced substance P to subnor- ering NE levels in the spinal cord, ITHR can plausibly mal levels.@ heighten FMS patients' pain perception. Patients' pain, The second mechanism by which ITHR can reduce however, is probably compounded by other factors. First, most FMS patients are physically inactive because the effectiveness of the antinociceptive system is by though low motor drive from low reducing the synthesis and secretion of norepinephrine of their dopamine levelsz7probably contributes to their inactivity. (NE) in brainstem locus ceruleus cells. Adequate NE Their low physical activity level may further contribute is essential to normal function of the descending to the inefficiency of the antinociceptive antinociceptive system.53B lTHR can also plausibly account for the other sympThe antinociception pathways that descend from the brainstem to the dorsal horns contain two types of toms and objectively verified abnormalities of FMS: neurons: those that secrete serotonin and others that muscle and joint pain, paresthesias, cognitive dysfunction, secrete NE.20,53553 depression, cold intolerance, exercise intolerance, weakSerotonin secretion by the neurons is tonically augmented by NE secretion. Normal serotonin ness and fatigue, dry skin and mucous membranes, constisecretion is therefore dependent on NE secretion.54The pation, dysmenorrhea and rnen0rrhagia,7~,~~ increased reduced serotonin stimulatesinterneurons to secrete 0piates.5~5~5~platelet alpha Zadrenergic receptor ;~ peripheral blood f l o ~sleep ,~ The opiates inhibit transmission partly by blocking release brain blood f l o ~reduced disturbance,80deficient slow-wave sleeps1hypotension,82 of neurotransmitter substances such as glutamate and substance P from the afferent neurons.%The opiates also blunted sympathetic response to stres~,~ stiffness and block calcium influx and potassium efflux from the swelling,@irritable bowel syndrome,85excessive urination,sohigh serum hyaluronic acid,&low procollagen afferent mainly those of type C and A delta fibers.60The decreased potassium efflux hyperpolarizes high ground substance proteoglycanslmlow pyridinolinem terminals, inhibiting transmission of nociceptive signals and hydroxyproline,'o glycolysis abnormalities:' low conto spinothalamicneurons that otherwise would transmit centrations of high-energy phosphates in erythrocytes the signals to the brain.6l Low NE secretion by descend- and muscle and low growth hormone and somatomedinC levels.%The cellular and genomic actions ing neurons, however, may reduce the secretion of of thyroid hormone can explain the hormone's relationserotonin selectively at dorsal horn interneurons and ship to all of these factors.16Especially important is thyroid secondarily reduce opiate secretion. As a result, the the antinociceptive system in FMS patients results in the following:

Specific Health Problems

for example, is a recovered patient stopping her use of B complex vitamins, only to suffer a partial recurrence of FMS symptoms. The symptoms are again relieved by her resuming her use of the vitamins. The most common other metabolism-regulating therExperimental Support for the apies that patients must use are a wholesome diet, nutriH ometabolism H othesis tional supplementation, and exercise to tolerance. These o Fibromyalgia Syn rome therapies are necessary in order for most patients to fully recover. But except for the rare patient, they are not sufThe hypothesis that ITHR is an underlying mechanism ficient and must be used with thyroid hormone therapy. of FMS has considerable experimental support. Many researchers have noted the virtually identical features This is shown by studies of the effectiveness of these of FMS, hypothyroidism, and the peripheral form of therapies as FMS treatments. The studies indicate that cellular resistance to thyroid h ~ r m o n e . ' ~ , ~ ~ " ~ these therapies provide some improvement, but patients Several research groups have used thyroid function do not recover (they continue to meet the criteria for FMS) with the use of these therapies alone. testing to determine the incidence of thyroid disease among FMS patients. Each group has reported an In addition to the metabolic therapies, one other incidence higher than in the general populati0n.9~'~~therapy is usually necessary to completely eliminate most FMS patients' pain. This is physical treatment. A thorough analysis of all the available evidence indicates that approximately 90% of FMS patients have Wholesome Diet some form of thyroid disease, either primary or central Various diets and dietary supplements have been tested hypothyroidism, or cellular resistance to thyroid as FMS treatments. Mild-to-moderate improvements in hormone.11'J12 FMS status have been reported for vegetarian diet~"~J'~; The only clinical trials in which patients have been elimination of the excitotoxins MSG and aspartarne116; fully relieved of FMS have involved the oral use of thyChZoreZZa pyrenoidosa (unicellular freshwater green roid hormone. It should be noted, however, that in each ~J~*; study, patients also used other metabolism-regulating alga rich in proteins, vitamins, and m i n e r a l ~ ) ~ ~an therapies (see later discussion on metabolism-regulating uncooked vegan diet consisting of berries, fruits, vegetables and roots, nuts, and germinated seeds and therapies other than thyroid hormone). Euthyroid and sprout^"^; and a strict, low-salt, uncooked vegan diet hypothyroid FMS patients fully recovered in five open rich in lactobacteria.120 but highly systematic trials6-10;three double-blind, placebo-controlled crossover trials"-13; and in a randomNutritional Therapies ized, double-blind, placebo-controlled trial.I4In another randomized, double-blind trial, FMS patients had lim- Long clinical experience shows that a wide array of ited improvement with the use of transdermal T3.'13 nutritional supplements is necessary if FMS patients are to significantlyimprove or recover. As the sole treatment, A 1-to-5-year follow-up study compared the status of however, supplements provide only mild improvement control FMS patients with FMS patients who had either except for the rare patient. hypothyroidism or cellular resistance to thyroid horStudies indicate that vitamins B1, B6, B12?3,121-129 mone and underwent metabolic therapy including the C,130-134 E, and beta-~arotene'~~ have antinociceptive use of thyroid hormone. Although control patients' FMS properties. Other reports indicate that various nutristatus deteriorated, treated patients recovered and maintional supplements improve FMS status: the Myers' tained the recovery throughout the follow-up period. cocktail (intravenous formula of B vitamins, vitamin C, Results of this study are the first to demonstrate longcalcium, and magnesium) lX;5-hydro~ytryptophan'~~J~; term effectiveness of an FMS treatment.I5 S-adenosylmethi~nine~~~-'~~; magnesium and malic Metabolism-Regulating Therapies Other acid'"J4; combined aloe Vera extracts, plant saccharides, Than Thyroid Hormone freeze-dried fruits and vegetables, Dioscorea, and a vitamin/mineral complex145;collagen hydrolysat16; and Thyroid hormone therapy is necessary for most FMS a blend of ascorbigen and broccoli powder.147 patients to recover, but it is not sufficient. For example, in a study of 77 euthyroid FMS patients, those who declined to adopt a wholesome diet, take nutritional supplements, Exercise to Tolerance The results of studies of exercise in the treatment and exercise to tolerance were within the 25% who failed to benefit from the therapy. This result is consistent with of FMS have been mixed: Some have shown no improvement in FMS s t a t u ~ ~ ~ ,or~ minimal ~ J ~ ~ J ~ ~ years of clinical experience showing the necessity for patients to use other metabolism-regulating therapies impro~ement.'~~-'~~ Cardiovascular exercise has provided the most especially low-intensity in addition to thyroid hormone. A common experience,

hormone's effect on the adrenergic system. If the hypome tabolism hypothesis is verified in the fuhtre, then the definition of fibromyalgia will include an explanation of FMS as a condition of alpha-adrenergic dominance.

P

YB

Fibromyalgia Syndrome

endurance t r a i x ~ i n g . ~Endurance ~~,'~ exercise is important to reducing the physical limitations associated with FMS.159The importance of physical fitness and the high metabolic efficiency it provides160J61 was shown by deficient slow wave sleep inducing FMS-like symptoms in sedentary and not aerobically fit students.u This finding suggests that low metabolic efficiency due to ITHR renders some individuals susceptible to FMS.16 Vigorous exercise tends to exacerbate patients' FMS symptom^.^^,^^ As a result, some patients avoid exercise altogether and consequently have poor physical f i t n e ~ s . ' ~ ~ The , ' ~ ~most - ' ~ plausible explanation for the exacerbations on vigorous exercise is the high density of alpha 2-adrenergic receptors on FMS patients' ~1atelets.l~~ Platelet density of alpha 2-adrenergic receptors is a reliable indicator of the receptor density in the CNS.'& Binding of catecholamines to a high density of the receptors on cells inhibits energy metabolism. The inhibition of energy metabolism during vigorous exercise, mediated by the high density of the receptors, appears to severely worsen symptoms. During the early phase of treatment, then, exercise should be mild enough to avoid or minimize catecholamine secretion.l6 With effective thyroid hormone therapy, the density of alpha 2-adrenergic receptors decreases and the density of beta-adrenergic receptors increases, enabling cells to respond appropriately to high levels of catecholamines. The shift away from alpha 2-adrenergic receptor dominance probably explains in part the FMS patients' ability to engage in vigorous physical activity after undergoing thyroid hormone therapy.6 7 8'11-13,15

Physical Treatment Extensive clinical experience and clinical trial~~fi,'l-'~ show that despite the use of integrated metabolic therapies, physical treatment is usually necessary to completely elimSeveral studies have inate most FMS patients' ~ain.'~~-'~O shown that spinal manipulation, soft tissue manipulation, and trigger point therapy provide palliative improvement in some FMS symptoms, especially The most common lesions that exacerbate FMS symptoms are myofascial trigger points and spinal joint f i ~ a t i o n s . ' ~ ,Any ~ ~ ~ nociception-generating ,'~~ neuromusculoskeletal lesion, however, can exacerbate FMS patients' pain due to their impaired antinociceptive system. Neuromusculoskeletal lesions can also disturb ~ 1 e e p . l This ~ ~ ' can, ~ ~ in turn,increase FMS symptoms, especially in hypometabolic individuals.23

Summary It appears, then, that for most FMS patients to improve or recover, integrated metabolic therapies that include the use of thyroid hormone are necessary and sufficient, whereas no single metabolic therapy is sufficient in

itself. In addition, physical treatment is usually necessary to completely eliminate most FMS patients' pain.

THERAPEUTIC CONSIDERATIONS LaboratoryTesting for Thyroid Status Thyroid Function Tests Before beginning an FMS patient's treatment, his or her thyroid status should be determined with thyroid function tests. Primary hypothyroidism (thyroid hormone deficiency due to subnormal function of the thyroid gland) in most patients can be determined with either one of two standard thyroid batteries:

T4/ T3-uptake, free T4 index, and thyroid-stimulating hormone (TSH) Free T3, free T4/and TSH In untreated primary hypothyroidism, the TSH is elevated. The recently revised upper limit of the serum TSH reference range is 2.5 pU/mL179

Thyrotrophin-Releasing Hormone Stimulation Test Two conditions can be distinguished through the use of a thyrotrophin-releasing hormone (TRH) stimulation test: Euthyroidism (normal function of the hypothalamicpituitary-thyroid gland axis) Central hypothyroidism (thyroid hormone deficiency due to pituitary or hypothalamic dysfunction)16J60 In this test, a blood sample is taken to measure the basal TSH level. Next, TRH is injected. Thxty minutes later, another blood sample is taken to measure the TSH level again. The clinician subtracts the baseline TSH level from the 30-minute level to derive the TSH response to the injected TRH. A result between 8.5 and 20 pU/ml is consistent with normal hypothalamic-pituitary-thyroid function. A result below 8.5 pU/ml is consistent with pituitary hypothyroidism; a result above 20 pU/ml is consistent with central hypothyroidism. (An exaggerated TSH response to TRH does not distinguish between pituitary and hypothalamic hypothyroidism.) The diagnosis is tentative unless there is evidence of other pituitary or hypothalamic hormone abnormalities (from assays), pituitary or hypothalamic structural abnormalities (from imaging), or mutations of the TRH or TSH gene (from nucleotide sequencing).

Thyroid Antibodies The most common cause of primary hypothyroidism is autoimmune thyroiditis. The presence of this disorder can be determined by the patient's titer of thyroglobulin and thyroid microsomal (peroxidase) antibodies. It is especially important to order tests of antibody levels in FMS patients. Many patients who have elevated thyroid

Specific Health Problems

antibodies have also had thyroid function test results

2. The patients recover from their hypothyroid-like FMS

within the reference ranges for many years.'61But com-

symptoms and signs with supraphysiologic dosages of Tj. 3. The patients have extremely high serum-free T3 levels after beginning T3therapy. 4. The patients have no evidence of tissue thyrotoxicosis, according to the results of serial ECGs, serum and urine biochemical tests, and bone densitometry.

pared with people without chronic, widespread musculoskeletal complaints, those with such complaints were found to have a sigruhcantly higher incidence of thyroid microsomal antibodies (16% vs. 7.3%, p < 0.01). The prevalence of antibodies was also sigruhcantly higher in women than men (20.4%vs. 11.6%,p < 0.02). However, thyroid function test results did not differ significantly between those with and without musculoskeletal complaints.'0gThis study indicates that in patients with autoimmune thyroiditis, thyroid hormone levels too low to properly regulate the CNS antinociceptivesystem can escape detection by thyroid function tests including the TSH.

Thyroid Hormone Therapy Based on Initial Thyroid Status FMS patients whose test results indicate primary or central hypothyroidism should begin therapy with a thyroid hormone preparation containing both T4 and T3. Many FMS patients who have primary or central hypothyroidism do not benefit from T4 alone no matter how high the dosage. Most do benefit, however, from the use of T4/T3 preparations in a 41 ratio. The dosage range at which most patients improve or recover with T4/T3preparations is that used throughout the twentieth century without harmful effects162before TSH assays came into widespread use in the early 1970s:2-to4 grains (76 Fg T4 and 18 pg T3-to-152 pg T4 and 36 pg T3).16J83 The thyroid hormone therapy used in studies in which hypothyroid and euthyroid FMS patients recovered"I4 was not conventional T4-replacementtherapy. While T4 was used in some studies,9J0J4J5 it was T4/T3preparations and T3 alone used in a way that violated the mandates of T4 replacement. Specifically, patients were permitted to use thyroid hormone despite test results indicating the patients were euthyroid and dosages were not titrated according to TSH levels but by patients' clinical responses to particular dosages. Effective dosages usually suppressed TSH levels. Despite this, patients did not have symptoms of thyrotoxicosis, nor did they have evidence of thyrotoxicosis according to electrocardiography, bone densitometry, or serum and urine biochemical test results. FMS patients whose test results indicate euthyroidism should begin with plain T3. In studies of the thyroid status of FMS patients at intake, approximately 33% of patients were euthyroid according to thyroid function testing.'80*'&4 Of these patients, approximately 75%have partial peripheral cellular resistance to thyroid hormone according to four criteria111J12:

These patients usually benefit only from plain T3 (not sustained-release T3) in a single daily dose, due to the mechanism underlying partial peripheral cellular resistance to thyroid hormone.I6 They are likely to respond only to supraphysiologic dosages of T3+ Effective T3 dosages for most patients are between 75 and 125 pg. For some patients, however, safe and effective dosages are far higher.I6 Some FMSpatients have both hypothyroidism and cellular resistance to thyroid hormone! For these patients, the clinician should determine over the course of metabolic rehabilitation which form of thyroid hormone works best for any individual patient.

Dosa e Ad'ustments Based on Tissue Meta olic tatus (Clinical Response), Not Laboratory Tests

E A

After a patient's thyroid status is determined and thyroid hormone therapy begun, dosage changes should be titrated according to tissue responses, not according to thyroid function test results. Thyroid function tests are of no value in finding the safest and most effective dosage for any particular patient.'= There is no scientific justification for inferring the metabolic status of cells (other than the thyrotrophs of the anterior pituitary) from thyroid function test results. The belief that tissue metabolic status can be accurately inferred from TSH or thyroid hormone levels is a postulate, not a researchderived conclusion. Recently, the postulate was found to be false, at least for rats, by studies showing that the levels of T3 and T4 in cells of different tissues cannot be accurately predicted from plasma levels of TSH, T3, or T.+186,167Moreover, some studies show that TSH levels correlate poorly with measures of tissue metabolic status, such as the speed of the relaxation phase of the Achilles reflex.ls8 Conversely, other studies show that the patient's symptoms and signs are far more accurate and reliable indicators of tissue metabolic status than are thyroid function test r e s u l t ~ . ' ~ J ~ ~

Rehabilitation Model: Data-Driven Clinical Decisions The clinician should distinguish as clearly as possible all the various factors impairing the individual patient's

1. The patients are euthyroid (according to thyroid func-

tion test results including the TRH stimulation test) before beginning the use of T3.

'References6,7, 11-13, 16, 106, 111, 112. 167.

Fibromyalgia Syndrome

metabolism. Next, the clinician should provide the patient with an individualized treatment regimen designed to correct, eliminate, or compensate for the factors. The treatment regimen that is most effectivefor guiding the FMS patient to recovery conforms to a rehabilitation model. The model requires baseline and repeated monitoring of the patient’s clinical status through objective assessment methods. Thus clinical decisions, such as thyroid hormone dosage adjustments, are data driven.

Objective Assessment of Patient Status The FMS patient’s recovery of normal metabolism,a symptom-free state, and full function occurs gradually over a range of 2 to 6 months. Because of the time involved, it is best for the clinician to q u a n w the patient’s clinical status through objective measures at weekly or biweekly intervals. Scores from the measures should be posted as data points to line graphs after each evaluation of the patient. The patient’s baseline score on each measure (taken before therapy is begun) is the initial data point on each graph. Next, a line should be drawn through the data points to create a trend line that makes obvious on visual inspection changes in the patient’s clinical status. The trend lines of the data points on the graphs thus help the clinician to assess the effectiveness of the patient’s regimen at any point during treatment. In this way, the lines enable the clinician to make informed, data-driven decisions about any treatment changes needed to optimize clinical results.

The five line graphs in Figure 168-2 show the changes in FMS measures during metabolic rehabilitation of a euthyroid FMS patient reported by Honeyman-Lowe? Typically, all measures change together in a direction of improvement, no improvement, or worse. The patient’s subjective status usually corresponds closely to what the trend lines indicate. During the course of the rehabilitation process, patients and clinicians often lose sight of the severity of the patient’s clinical status before treatment. When patients occasionally experience a brief or mild exacerbation of symptoms, they are especially prone to forget the progress they have made. For some, this state of mind can lead to the false conclusion that they have made no progress at all. The false conclusion is quickly corrected, however, by a review of their graphs, which show visually and objectively the patient’s real progress. The five objective assessment methods that should be used at each patient evaluation are described as follows. The clinician should also perform a physical examination at each evaluation to further assess the patient’s changing tissue metabolic status.

Pain Distribution Body Form Four studies have shown that the most sensitive indicator for changes in FMS status is the pain distribution as a percentage of the body in pain.11-’3J90 This is convenient in that chronic widespread pain is one of the two major criteria for the assessment of FMS status.’

A

fl Feb. 12

Mar. 14

Mar. 21

Apr. 2

Apr. 9

Apr. 17

May 5

May 22

Figure 168-2 A, Pain distribution. Scores show the percentage of 36 body divisions containing pain at each evaluation (determined by the patient‘s pain drawing). At each evaluation, the percentage was posted to the graph.

Continued

B

Feb. 12

Mar. 14

Mar. 21

Apr. 2

Apr. 9

Apr. 17

May 5

May 22

Figure 168-2-cont'd B, Increases in mean tender point pressure/pain threshold during metabolic rehabilitation.

C 10

2

0 ' Feb. 12

I

Mar. 14

Mar. 21

Apr. 2

Apr. 9

Apr. 17

May 5

May 22

Flgure 168-2-cont'd C, Decreases in mean intensity of fibromyalgia syndrome symptoms, calculated from the FibroQuest form.

Small changes in pain distribution are assessed by

using a form containing drawings of the body. The patient precisely shades in where he or she has had aching, pain, soreness, or tenderness since the last evaluation. Next, a template is placed over the patient's shaded form. The template shows the body form divided into 36 areas. Each

of the 36 divisions has a percentage ~alue.'~,"-'~ To obtain the patient's pain distribution, the values of the shaded divisions are totaled. This percentage number is placed on a graph as a data point. The data points for each evaluation are connected by a line showing the trend of the pain distribution over time.

Fibromyalgia Syndrome D 80 70

7.77

10

I

0 ’ Feb. 12

Mar. 14 ’ Figure

Mar. 21 168-2-cont’d

Apr. 2

Apr. 9

Apr. 17

May 5

May 22

D, Decreasingscores on the Fibromyalgia Impact Questionnaire.

E 80 70

60

2o

I

10

0 ’ Feb. 12

Mar. 14

Mar. 21

Figure 168-2-umt’d

Apr. 2

Apr. 9

Apr. 17

May 5

May 22

E, Decreasing scores on Zung’s SeCRating DepressionScale.

Mean Pressurepain Threshold of TnPs The second major criterion for the assessment of FMS is the presence of TnPs.’ A modified version of the TnP examination measures the pressure/pain threshold of TnPs with algometry (numerical values in kg/cmz). Algometry provides more precise quantification than the 1990ACR method and enables the clinician to make more

objective, evidence-based decisions.16 The mean of the threshold values is calculated and posted to a line graph. -

FibroQuest Symptoms Survey This assessment form consists of 1oO-mm visual analog scales (VASs), 1for each of the 13most common associated FMS symptoms. These symptoms are also characteristic symptoms of hypothyroidism and the peripheral form of

Specific Health Problems

cellular resistance to thyroid hormone (see Box 16&1).16 Readers can access and print thisform freeof charge from our website, wwlodrlowe.comlforms.hfrn. The patient estimates the intensity of each symptom he or she has by marking the appropriate point on the scale (1 to 10). The values for each marked symptom are added, and this total symptom intensity is then divided by the number of symptoms the patient marked at intake (baseline). The mean score is then posted to a line graph.

Fibromyalgia Impact Questionnaire The Fibromyalgia Impact Questionnaire (FIQ)191is a measure of the functional status of the patient. The total score from the FIQ is posted as a data point to a line graph.

Zung's Self-Rating Depression Scale Depression is so common among FMS patients that an assessment specific for the presence and severity of depression is used in addition to the VAS scale for depression. Zung's is one such assessment tool.lE The score from the depression scale is posted to a line graph.

Physical Examination When the FMS patient's treatment includes thyroid hormone, the five FMS measures should be used in conjunction with physical tests that assess tissue responses to the hormone. Many such tests are available,16 but the most convenient to use are the Achilles reflex (relaxation phase), pulse rate, and basal body temperature. A combination of these are more reliable indicators of tissue metabolic status than are thyroid function test results.

Integrated Metabolic Therapies Essential for All Fibromyalgia Syndrome Patients The majority of FMS patients must control or eliminate at least four metabolism-impeding factors. First, for the approximately 90% of FMS patients who have some form of thyroid disease,111J2 the proper preparation and dosage of thyroid hormone is necessary to the patient's recovery. Second, most patients must also modify their diets so that they minimize the intake of arachidonic acid. High arachidonic acid intake can increase body levels of both the proinflammatoryeicosanoidsprostaglandin E2 and leukotriene B4,193which can contribute to chronic pain.Ig4 Patients must also reduce their refined carbohydrate intake. ITHR of glycolysis, the citric acid cycle, and the electron transport chain results in low production of ATI?and creatine phosphate. Dysglycemia and insulin resistance due to refined carbohydrate intake can worsen the low production of high-energy phosphates due to ITHR.16 Third, most patients must take a wide array of nutritional supplements. Various nutrients are synergistic to

thyroid hormone in providing optimal intracellular metabolism, and patients must provide themselves with optimal amounts. For example, a deficiency of vitamin B1 can render patients intolerant of even low dosages of thyroid hormone, dosages too low to be therape~tic.'~~ In addition, supplemental thyroid hormone can increase the expenditure of vitamin B1 in cells. If a patient has a marginal deficiency of the vitamin, supplemental thyroid hormone could induce a frank deficiency. This can result in a beriberi-type cardiorny~pathy.'~~ Fourth, most patients must also exercise to tolerance. Biochemical treatments such as thyroid hormone, optimal diet, and nutritional supplements provide the patient with increased metabolic capacity. Sufficiently vigorous physical activity, however, is necessary for optimizing metabolism in most tissues and for priming the CNS descending nociceptive inhibitory system.

Additional Metabolic Therapies Necessary for Some Patients Adrenocortical Hypofunction Some patients must be treated for adrenocortical hypofunction. Low cortisol levels can produce some symptoms that are the same as those associated with FMS such as weakness, fatigue, inability to handle stress, exercise intolerance, hypotension, and low nociception threshold. Low cortisol levels can also render the patient intolerant of a dosage of thyroid hormone high enough to be therapeutic. The clinician should also be aware, however, that ITHR alone can cause adrenocortical hypofunction. If low cortisol levels stem from ITHR,appropriate thyroid hormone therapy may correct the deficiency.

Neuromusculoskeletal Lesion Patients should be provided with physical treatment for nociception-generating neuromusculoskeletal lesions. The most common are myofascial trigger points and spinal joint lesions. Both trigger points and spinal lesions can be perpetuated by self-sustaining skeletal muscle contractures. The contractures may stem from low intramuscular high-energy phosphate production due to ITHR.2°,zJ95

Metabolism-Impairing Medications Several classes of medications may be significant factors in the development or perpetuation of FMS symptoms. Because of this, some patients must cease taking some metabolism-impairing medications, and they must convert from maintenance to as-needed use of others. Beta-blockers impair metabolism directly by reducing beta-adrenergic receptor density on cell membranes and increasing alpha 2-adrenergic receptor density, exactly as hypothyroidism does. In some patients, this shift in adrenoceptor isoform balance creates a general

mental and physical inhibitory state that may be indistinguishable from hypothyroidism or the associated The isoform shift may alsoimpair the symptoms of M.’% function of the CNS descending antinociceptive system, resulting in pain and tenderness characteristic of FMS. Narcotics, tranquilizers, and muscle relaxants are commonly prescribed as EMS treatments. Patients should be weaned from these as soon as possible. The medications can render patients disinclined to engage in vigorous physical activity. As the patient’s physical fitness level declines, anergia and heightened pain perception increase. Some antidepressants (also commonly prescribed for FMS) and decongestants can cause tachycardia when used simultaneously with exogenous thyroid hormone. Because of this, patients using these drugs must stop their use in order to increase their hormone dosage high enough to be therapeutic.

THERAPEUTIC APPROACH Assessment of Fibromyalgia Syndrome Status The patient’s FMS status should be evaluated before treatment is begun and at intervals throughout the course of treatment. Reevaluations are performed weekly to biweekly and before each increase in thyroid hormone dosage. A physical examination and five FMS measures should be used at each evaluation: Pain distribution as the percentage of 36 body divisions containing pain, according to a body drawing Mean TnP score in kg/cm2 measured by algometry Symptom intensity estimate according to visual analog scales (FibroQuest Symptoms Survey) Functional status according to the Fibromyalgia Impact Questionnaire Depression according to the Zung’s Self-Rating Depression Scale Scores for each assessment instrument should be posted to a line graph so that the trend of the scores is obvious on visual inspection. Changes in the patient’s individualized treatment regimen should be based on the trend of scores on the line graphs, combined with the physical examination and the clinician’s and patient’s subjective assessments. This process is continued (usually for 2 to 6 months) until the scores on the line graphs are representative of normal, the patient no longer meets the ACR criteria for FMS, and the patient is symptom free and fully functional.

Patient Safety All patients must have an electrocardiogram before beginning metabolic rehabilitation and, if appropriate, at intervals throughout the treatment process.

Although dysrhythmic conditions are usually not obstacles to metabolic treatment, it is essential to be aware of them before treatment with thyroid hormone. Patients should be educated extensively on the possible signs and symptoms of thyrotoxicosis and its management, should overstimulation occur. Consultation with the clinician can usually resolve this issue. When a patient’s history indicates, he or she should be tested for possible adrenocortical hypofunction. If testing reveals decreased cortisol production, the patient should be treated with physiologic doses of cortisol at least temporarily before initiating the use of thyroid hormone.

Thyroid Hormone Therapy If the Fh4S patient is hypothyroid, he or she should begin treatment with 1grain (60 mg) of desiccated thyroid or a synthetic T4/T3 preparation with a 4:l ratio. The dosage should be increased by 1-to-2 grain at approximately 1-month intervals. If the patient is euthyroid, he or she should begin treatment with plain T3, usually with a starting dosage of 50 to 75 mcg. The dosage is increased at weekly to biweekly intervals by 6.25 to 12.5 pg. Dosage increases should continue until the patient is symptom free, no longer meets the ACR criteria for FMS, and is fully functional. Neither serum nor salivary thyroid hormone levels nor TSH levels are of any value in finding the individual patient’s safe and effective dosage of thyroid hormone. Dosage should be titrated according to tissue responses to thyroid hormone.

Wholesome Diet If they have not already, patients should adopt a diet that both stabilizes their blood sugar and insulin levels and reduces pain perception. The diet involves lean meats, especially poultry; fish; fruits; vegetables; and minimal intake of whole grains. It also minimizes the intake of foods high in arachidonic acid (whichinmases the production of the proinfiammatory eicosanoids prostaglandin E2 and leukotriene B4) and additive excitotoxins such as glutamate and aspartate. We recommend that patients use organic foods and filtered drinking water to decrease the amount of chemical contaminants ingested.

Nutritional Supplements Patients should take at minimum the following nutrients in the approximate dosages given:

B Complex: at least 50 mg B1 per tablet, 1bid Vitamin BIZ:5000 to 10,000 pg daily (should be tried for pain control) Vitamin C: 1to 3 g tid Vitamin E: 800 to 1600 IU daily Carotenoids: 15 mg Multimineral formulation: bid

Specific Health Problems Calcium: 2000 mg daily

Magnesium: lo00 mg daily

Exercise to Tolerance Exercise is essential to help normalize metabolism. We recommend that patients engage in forms of exercise they enjoy and gradually increase the intensity as their symptoms diminish. Weight-bearing exercise is encouraged, as it supports bone health. Aerobic exercise is essential to strengthen the cardiovascular and pulmonary systems. Toning activities build lean muscle mass, and this in turn improves metabolism. A combination of these forms of exercise is best. Many patients who have become severely deconditioned due to their FMS symptoms find warm water exercise an ideal way to begin.

the spine and other joints are essential for completely eliminating patients’ pain. Both forms of treatment can raise the nociceptive threshold and increase mobility. The clinician should assess the patient’s need for physical treatment at each visit and provide the treatment according to examination findings. If an examination indicates, weight-bearing castings for flexible orthotics should be made. For some patients, orthotics reduce musculoskeletal stress and consequent nociceptive input to the CNS.

Abstention from Metabolism-Impairing Medications Patients must cease taking beta-blockers, antidepressants,and maintenance dosages of narcotics, tranquilizers, and muscle relaxing drugs.

Physical Treatment Myofascial therapy to eliminate trigger points in muscles and spinal manipulation to regain flexibility of

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Gallstones Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

1687

General Considerations 1687 Pathogenesis 1687 Cholesterol and Mixed Stones 1687 Risk Factors for Cholesterol and Mixed Stones 1688 Risk Factors for Pigmented Gallstones 1689

Nutritional Supplements 1691 Chemical Dissolution of Gallstones Lifestyle 1693

1692

Therapeutic Approach 1693 Diet 1693 Water 1693 Nutritional Supplements 1693 Botanical Medicines 1693 Gallstone-Dissolving Formula 1693

Therapeutic Considerations 1689 Asymptomatic Gallstones 1690 Diet 1690

DIAGNOSTIC SUMMARY May be asymptomatic or cause biliary colic with irregular pain-free intervals of days or months Real-time dtrasonography provides definitivediagnosis

GENERAL CONSIDERATIONS Gallstones are another example of a "Western diet"induced disease. In the United States, autopsy studies have shown that gallstones exist in approximately 20% of the women and 8% of the men older than age 40. Conservative estimates suggest that about 20 million Americans (l0Y0 of the U.S. population) and 5% to 22% of the population in the Western world have gallstones.' Each year 1 million more develop gallstones. More than 300,000 gallbladders are removed each year in the United States due to the presence of gallstone^.^-^ Gallstones are also considered a significant risk factor for gallbladder cancer.6~~ The bile components include bile salts; bilirubin; cholesterol; phospholipids; fatty acids; water; electrolytes; and other organic and inorganic substances? Table 169-1 shows the characteristics of the major bile components. Gallstones arise when a normally solubilized component of bile becomes supersaturated and precipitates. Gallstones can be divided into four

major categories: Pure cholesterol Pure pigment (calcium bilirubinate) Mixed-containing cholesterol and its derivatives along with varying amounts of bile salts, bile pigments, and inorganic salts of calcium Stones composed entirely of minerals Pure stones, either cholesterol or calcium bilirubinate, are extremely rare in the United States. Recent studies indicate that in the United States, approximately 80% of the stones are of the mixed variety. The remaining 20% of the stones are composed entirely of minerals, principally calcium salts, although some stones contain oxides of silicon and aluminum."

PATHOGENESIS The formation of gallstones has been divided into three steps: Bile supersaturation Nucleation and initiation of stone formation Enlargement of the gallstone by accretion

Cholesterol and Mixed Stones The requisite step in cholesterol and mixed stone formation is cholesterol supersaturation of bile within 1687

Specific Health Problems

Commnent

Percentage of bile

Water solubility

Physicchemical properties

Cholesterol

5

Very poor

Will precipitate from aqueous Solutions

Soluble; have polar and nonpolar regions

Capable of solubilizing cholesterol and phospholipid in aqueousphase

Poor

Fits between bile salt molecules, thus increasing their capacity to solubilize cholesterol

Bile salts

Phospholipid

65-90

2-25

Flgure 169-1 Mixed micelle.

Modified from Rubenstein E, Federman DD. Scientific American medicine. New Yo&. Scientific American, 1986:4. VI-1-10,

the gallbladder. Bile solubility, as well as bile supersaturation, is based on the relative molar concentrations of cholesterol, bile acids, phosphatidylcholine (lecithin), and water. Because free cholesterol is water insoluble, it must be incorporated into a lecithin-bile salt micelle (Figure 169-1). Using triangular coordinates, it is possible to demonstrate the solubility of cholesterol in bile (Figure 169-2). As illustrated in the figures, either an increase in cholesterol secretion or a decrease in bile acid or lecithin secretion will result in the bile becoming supersaturated. Once the bile is supersaturated, stone formation is initiated by such factors as biliary stasis, infection, and increased mucin secretion by the gallbladder epithelium. Once the stone begins to form, its radius increases at an average rate of 2.6 mm/year, eventually reaching a size of a few millimeters to more than a centimeter. Symptoms typically occur an average of 8 years after formation begins. Cholelithiasis is present in 95% of patients with cholecystitis?

Risk Factors for Cholesterol and Mixed Stones The major risk factors for the development of cholesterol and mixed gallstones include the following": Diet sex

Race Obesity High caloric intake Estrogens

Bile salts (mol%) Figure 169-2 Cholesterol solubility in bile.

Gastrointestinal diseases (especially Crohn's disease and cystic fibrosis) Drugs Age The role of a low-fiber, high-fat diet in the development of gallstones, as well as other dietary factors, is discussed later, while the other factors are briefly discussed here.

Sex The frequency of gallstones is two to four times greater in women than in men. Women are thought to be predisposed to gallstones because of either increased cholesterol synthesis or suppression of bile acids by estrogens. Pregnancy, use of oral contraceptivesor other

Gallstones

causes of elevated estrogen levels, and tamoxifen use greatly increase the incidence of gallstones.

Genetic and Ethnic

In addition to oral contraceptives and other estrogens, as discussed earlier, drugs that increase the risk of gallstones include the cephalosporin ceftriaxone,octreotide, HMG-CoA reductase inhibitors,' and possibly other lipidlowering drugs.

The prevalence of gallstones appears to have some genetic aspects. Gallstones are most common in Native American women older than the age of 30. Nearly 70% of this group has gallstones. In contrast, only 10% of black women older than 30 have gallstones. The difference in the prevalence rate between different ethnic and genetic groups reflects the extent of cholesterol saturation of the bile. The extent to which dietary factors affect this value probably outweighs genetic factor^.^

Gallstones have been reported from fetal age to extreme old age, but the average patient is 40 to 50 years old. Decline in the activity of cholesterol 7-alpha-hydroxylase with age' leads to an increase in biliary cholesterol hyper~ecretion'~ and thus cholesterol saturation with accelerated formation of gallstones.

Obesity

Risk Factors for Pigmented Gallstones

Obese subjects are at risk of developing gallstones both by being overweight and when initially losing weight.1° Obesity causes an increased activity of HMGCoA reductase with increased secretion of cholesterol in the bile as a result of increased cholesterol synthesis. Therefore obesity is associated with a significantly increased incidence of gallstones due to biliary cholesterol saturation. Important to note is that during active weight reduction, changes in body fat and diet can actually promote gallstone problems. During the first stages of weight loss, biliary cholesterol saturation initially increases! The secretion of all biliary lipids is reduced during weight loss, but the secretion of bile acids decreases more than that of cholesterol. Once the weight is stabilized, bile acid output returns to normal levels, while the cholesterol output remains low. The net effect is a significant reduction in cholesterol saturation. When prescribing diet therapies for obese patients with a high risk of gallstones, it should be recognized that prolonged dietary fat reduction can also promote biliary stasis> thus contributing cholesterol saturation. Studies show that at least 10 g of fat per day are necessary in order to assure proper gallbladder emptying."

Risk factors for pigmented gallstones are not related to diet as much as they are to geography,sun exposure, and severe diseases. Pigmented gallstones are more common in the Orient due to the higher incidence of parasitic infection of the liver and gallbladder by various organisms including the liver fluke Clonorchissinensis. Bacteria and protozoa can cause stasis or act as nucleating agents. In the United States, pigmented stones are usually caused by chronic hemolysis or alcoholic cirrhosis of the liver.

Gastrointestinal Tract Diseases Malabsorption of bile acids from the terminal ileum disturbs the enterohepatic circulation, thereby reducing the bile acid pool and the rate of secretion of bile. Diseases associated with this phenomenon include Crohn's disease and cystic fibrosis.

Drugs Tamoxifen treatment in postmenopausal breast cancer patients greatly increases gallstones. One retrospective cohort study of 703 women demonstrated that after 5 years, the incidence of stone formation in the tamoxifentreated patients was 37.4%, whereas it was 2% in patients who did not receive tamoxifen.12Most gallstones became apparent after 3 years.

Age

THERAPEUTIC CONSIDERATIONS Gallstones are easier to prevent than to reverse. Primary treatment, therefore, involves reducing the controllable risk factors discussed earlier. Once gallstones have formed, therapeuticinterventioninvolves avoiding aggravating foods and employing measures that increase the solubility of cholesterol in bile. If symptoms persist or worsen, cholecystectomy should be considered. A number of dietary factors are important in the prevention and treatment of gallstones. Foremost is the elimination of foods that can produce symptoms. Also important are increasing dietary fiber, eliminating food allergies, and reducing the intake of refined carbohydrates and animal protein. There is a protective effect of vegetables and fruits against gallbladder cancer, and red meat (beef and mutton) was found to be associated with increased risk of gallbladder carcinogene~is.'~ Because gallstones are a risk factor for gallbladder cancer,6p7J4 appropriate nonlithogenic dietary practices will protect against both cancer and development of gallstones. Other treatment measures involve the use of nutritional lipotropic compounds, herbal choleretics, and other natural compounds in an attempt to increase the solubility of bile. Biliary cholesterol concentrationand serum cholesterol levels do not seem to c~rrelate.'~ Although some authors have reported an inverse correlation between highdensity lipoprotein cholesterol and bile saturation and

Specific Health Problems

women with a group of vegetarian women. Ultrasound a direct correlation between LDL and bile ~aturation,l~*~~ diagnosis showed that gallstones occurred sigruficantly more detailed research does not appear to support these less frequently in the vegetarian group. correlati~ns.'~There does, however, seem to be an assoAlthough this may simply be a result of the increased ciation between increased serum triglyceride levels and fiber content of the vegetarian diet, other factors may bile saturation.I8 be equally important. Animal proteins, such as casein Asymptomatic Gallstones from dairy products, have been shown to increase the formation of gallstones in animals, while vegetable The natural history of silent or asymptomatic gallstones proteins such as soy were shown to be preventive supports the contention that elective cholecystedomy against gallstone formation.45Pz0 is not warranted. Although there is a cumulative chance of developing symptoms-10% at 5 years, 15% at Food Allergies 10 years, and 18% at 15years-if controllable risk factors Since 1948 Dr. J.C. Breneman, author of Basics of Food are eliminated or reduced, a patient should never Allergy, has used a successful therapeutic regimen to experience discomfort? prevent gallbladder attacks: allergy elimination diets. Diet The idea that food allergies cause gallbladder pain has Dietary Fiber some support in the scientificliterat~re.~~-*~ A 1968study revealed that 100%of a group of patients were free from The hypothesis that the main cause of gallstones is symptoms while they were on a basic elimination diet the consumption of fiber-depleted refined foods has (beef, rye, soybean, rice, cherry, peach, apricot, beet, and considerable research support.45 As mentioned earlier, spinach)?l Foods inducing symptoms, in decreasing gallstones are associated with the Western diet in order of their occurrence, were as follows: population studies. Such a diet, high in refined carbohydrates and fat and low in fiber, leads to a reduction in Egg the synthesis of bile acids by the liver and a lower bile Pork acid concentration in the gallbladder. Onion Another way in which fiber may prevent gallstone Fowl formation is by reducing the absorption of deoxycholic *Milk acid.43 This compound is produced from bile acids by Coffee bacteria in the intestine. Deoxycholic acid greatly lessens Citrus the solubility of cholesterol in bile. Corn Dietary fiber has been shown both to decrease the Beans formation of deoxycholic acid and to bind deoxycholic Nuts acid and promote its excretion in the feces. This Adding eggs to the diet caused gallbladder attacks greatly increases the solubility of cholesterol in the in 93% of the patients. bile. A diet high in fiber, especially those fibers capable Several mechanisms have been proposed to explain of binding to deoxycholic acid (i.e., predominantly the association of food allergy and gallbladder attacks. the water-soluble fibers found in vegetables and fruits, pectin, oat bran, and guar gum), is extremely Dr.Breneman believes the ingestion of allergy-causing substances causes swelling of the bile ducts, resulting important in both the prevention and reversal of most in impairment of bile flow from the gallbladder. gallstones? Interestingly, diets rich in legumes with high conBuckwheat centrations of water-soluble fibers are associated Buckwheat is a well-known alternative for those with an increased risk for gallstones? Chileans, Pima avoiding wheat for hypoallergenic purposes. Giving Indians, and other North American Indians have the three groups of eight hamsters a buckwheat-, soy-, or highest prevalence rates for cholesterol gallstones. All consume a diet rich in legumes. Evidently legume casein-based diet, one Japanese research group demonstrated that buckwheat can significantly decrease intake increases biliary cholesterol saturation as a result gallstone formation and reduce the concentration of of legumes' saponin content? It is therefore recommended cholesterol in the gallbladder, plasma, and liver of hamthat legume intake be restricted in individuals with sters compared with the casein diet.= Even though soy gallstones. is a known potent gallstone attenuator itself?6 these Vegetarian Diet researchers found that the positive effects of buckwheat were far stronger than those of the soy-based diet. A vegetarian diet has been shown to be protective Gallstones were clearly visible in all eight hamsters against gallstone formation.5J9A recent study in England fed the casein diet, whereas two of seven hamsters compared a large group of healthy nonvegetarian

Gallstones ~~

fed the soy diet (29%) and none of the buckwheat-fed animals had gallstones. Other studies in rats have also corroborated these findh1gs.2~The authors suggest that buckwheat can enhance bile acid synthesis and fecal excretion of steroidal compounds. Buckwheat may be useful to treat patients with both high cholesterol and gallstones and may reduce colon cancer cell proliferation.28 The authors also postulated that higher levels of arginine and glycine may play a role in buckwheat's protective function.

gallstones had sigruficantly higher baseline triglyceride and total cholesterol levels than those who did not. They also had a significantly greater rate of weight

gallstone^.^^

Nutritional Supplements Lecithin (Phosphatidylcholine)

Coffee

Although coffee can promote symptoms of gallstones, it may also inhibit their formation. In one interesting study, 400 ml of regular coffee and 165 ml of regular and decaffeinated coffee were assessed for their effect on cholecystokinin secretion. Regular coffee at both dosages and decaffeinated coffee caused significant Sugar gallbladder contractions as compared with the control sodium chloride in six healthy, regular coffee drinkers?' A Cyear study evaluated 111cases of biliary tract cancer Another study of 80,898 female nurses between the ages and compared them with 480 controls for various of 34 and 59 years found that drinking four cups of dietary parameters including sugar intake. The major caffeinated coffee per day had a 28% lowered risk of finding was an increased risk associated with the developing symptoms of gallstones. Even one to three intake of sugars, either monosaccharides or disacchacups seemed to have some protective effect, but not rides, independent of other energy sources. Sugar may as great.= be a risk factor for biliary tract cancer based on the It may be that women who began to drink coffee relationship among sugars, blood lipids, and gallstone regularly before or during early gallstone formation formation. The author also noted an association between were able to either inhibit development or clear any the intake of sugar and gallstones. Diets high in refined small stones due to the enhanced gallbladder contraccarbohydrates have been found to be associated with increased cholesterol saturation of the bile.29,30 tions from multiple daily coffee doses. In women who already have large stones present, increased contractions A 25-year follow-up study of 860 men, 54 of whom from coffee may exacerbate their condition and cause developed symptomatic gallstones, also found a untoward symptoms. positive association between sugar consumption and

Caloric Restriction In a case-controlled study in which 200 patients with gallstones were compared with 98 controls, total calorie and carbohydrate intake and serum triglyceride levels were higher in the gallstone patients. Dietary intake of refined carbohydrates was higher in the female patients with gallstones, while male patients with gallstones had an increased fat Another study of 76 patients with gallstones detected by ultrasound were matched to control subjects without cholethiasis. It was found that high caloric intake of greater than 2500 kcal/day and those diets rich in carbohydrates and saturated fats significantly increased gallstone risk.33 One intriguing note to this study was the finding that alcohol consumption of 20 to 40 g/day was protective. However, caloric restriction must be instituted carefully, as rapid weight lossM and fasting? increase the risk of gallstones (see earlier section on obesity). For example, in 179 obese patients, 9% of whom had preexisting gallstones, a low-calorie (605 kcal) diet resulted in 11%of the patients developing gallstones either during or within 6 months of completing the diet.% Another study of a 925 kcal diet found that 12.8% of the 47 women patients displayed gallstones at week 17as determined by sonography. Those who developed

As the main cholesterol solubilizer in bile, a low lecithin concentration may be a causative factor for many individuals with gallstones. For example, a pure bile salt micelle requires 50 molecules to enclose a single molecule of cholesterol, while a mixed bile salt/phospholipid micelle requires only seven molecules.6 Studies have shown that ingestion of lecithin can have the direct effect of cholesterol sol~bilization.~~ Taking as little as 100 mg of lecithin three times per day will increase the concentration of lecithin in the bile, while larger doses (up to 10 g) produce even greater increase^.^,^' This is significant, as an increased lecithin content of bile usually increases the solubility of cholesterol. However, no significant effects on gallstone dissolution have been obtained using lecithin supplementation alone.

Nutrient Deficiencies Deficiencies of either vitamins E or C have been shown to cause gallstones in experimental studies in animals.42."

Olive Oil A popular lay remedy for gallstones is the so-called olive oil "liver flush." There are several variations. A typical one involves drinking 1 cup of unrefined

Specific Health Problems olive oil with the juice of two lemons in the morning for several days. Many people tell tales of passing huge stones while on the liver flush. However, what they think are gallstones is simply a soft, saponified complex of minerals, olive oil, and lemon juice produced within the gastrointestinal tract. The olive oil liver flush is undesirable for patients with gallstones for several reasons. First, consuming a large quantity of any oil results in contraction of the gallbladder, which may increase the likelihood of a stone blocking the bile duct. This may result in cholecystitis, requiring immediate surgery to prevent death. Second, oleic acid, the main component of olive oil, has been shown to increase the development of gallstones in rabbits and rats by increasing the content of cholesterol in the gallbladder.44,45 Although this effect has not yet been observed in humans, the animal research suggests it is unwise to use an olive oil liver flush as a treatment of gallbladder disease.&This recommendation is not meant to obviate the use of the liver flush as a viable method of liver detoxification. Rather, it is a caution against its use in patients with gallstones.

Fish Oils Although human studies appear to not be available at this time, some provocative animal studies exist. For example, one study compared a diet high in lard with a diet high in fish oils in 21 male African green monkeys. One group was fed 0.8 mg cholesterol/kcal and 42"/0 of the calories as fat, with half of the fat calories derived from lard, while the other group was fed a similar diet with an isocaloric substitution of menhaden oil instead of the lard. After 2 to 3 years, necropsies were performed and it was found that 67Y0of the animals fed the lard diet had cholesterol gallstones compared with 22% of the animals fed the fish oil. The cholesterol saturation index of the gallbladder bile was also higher in the lard-fed group, although there was no difference in bile acids. There was a significantly greater biliary phospholipid secretion rate in the fish oil-fed animals compared with lard-fed animals." A more recent study found similar effects in a prairie dog model using a diet more typical of human habits. Twelve animalsconsumed a standard control diet, while 16 consumed a lithogenic 1.2% cholesterol diet. One half of the animals in each group were supplemented with 200 mg/kg/day of omega-3 fatty acids from eicosapentaenoic and docosahexaenoic acids. After 14 days, those fed the diet with added fish oil showed a n inhibition of gallstone formation accompanied by a sigruficant decrease in biliary d a w n and total protein concentration. This antilithogenic effect may be due to an enhancement in the stability of biliary phospholipid-cholesterol vesicles.48

Lipotropic Factors and Botanical Choleretics The naturopathic approach to the treatment of gallstones has typically involved the use of lipotropic and choleretic formulas. Lipotropic factors are, by definition, substances that hasten the removal or decrease the deposit of fat in the liver through their interaction with fat metabolism. Compounds commonly employed as lipotropic agents include choline, methionine, betaine, folic acid, and vitamin BIZ. Often these nutritional factors are used with herbal cholagogues and choleretics. Cholagogues stimulate gallbladder contraction to promote bile flow, while choleretics increase bile secretion by the liver. Many herbal choleretics have a favorable effect on the solubility of bile. Choleretics that are appropriate to use in the treatment of gallstones include: Turaxucum oficinale, silymarin from Silybum muriunum, Cynuru scolymus,and Curcuma Zongu. In addition, Peumus boldo contains alkaloids such as boldine that are quite useful in the treatment of gallstones. One study in rats given a diet that promoted gallstones demonstrated that the animals supplemented with 0.5% dietary curcumin for 10 weeks had only a 26% incidence of gallstone formation, compared with a 100% incidence in the group fed the lithogenic diet This effect was found to be dose dependent.

Chemical Dissolution of Gallstones Several successful nonsurgical alternatives for the treatment of gallstones now exist. These entail using a complex of plant terpenes alone or, preferably, in combination with oral bile acids. As the formation of the stone depends on either increased accumulation of cholesterol or reduced levels of bile acids or lecithin, decreasing gallbladder cholesterol levels or increasing bile acid or lecithin levels should result in dissolution of the stone. Chemical dissolution is especially indicated in the treatment of gallstones in the elderly who cannot withstand the stress of surgery and in other cases where surgery is contraindicated.

Bile Acids Promoting increased cholesterol solubility through oral chenodeoxycholic acid therapy alone (750 mg/day) has resulted in complete dissolution of gallstones in 13.5% and partial dissolution in 27% of patients.5o However, this therapy often takes several years and is associated with mild diarrhea and possible liver damage. Ursodeoxycholic acid appears to be somewhat more effective and has fewer side effects.51

Terpenes Gallstone dissolution by a natural terpene combination of menthol, menthone, pinene, bomeol, cineol, and

Gallstones

camphene has been demonstrated in several This nonsurgical approach to gallstone removal offers an effective alternative to surgery and has been demonstrated to be safe even when it has been consumed for prolonged periods of time (up to 4 years).

Combined Therapy Although terpenes are effective alone, the best results appear to be achieved when plant terpene complexes are used in combination with bile acid therapy.%%This combined approach offers better results than either bile acids or plant terpenes used al0ne.~’9Furthermore, because a lower dose of bile acid can be used, there is a sigruficant reduction in the risk of complications or side effects and in the cost of bile acid therapy. As menthol is the major component of this formula, peppermint oil, especially enteric coated, may offer similar results.

Lifestyle Sunbathing As almost all cholesterol gallstones contain a central, pigmented nucleus with radial or lamellar pigmented bands, alternating with layers of crystalline cholesterol, a researcher speculated that the activation of the pigmentary system by ultraviolet light might lead to increased concentrations of indole metabolites in the bile, triggering their polymerization. In a case-controlled study of 206 white-skinned individuals, a positive attitude toward sunbathing was associated with twice the risk of cholelithiasis, compared with those with a negative attitude. When the effect of sunbathing attitude was considered for individual skin pigmentation types, the association was found to be almost entirely restricted to those who always burn after long sunbathing. In this group, the relative risk was a remarkable 25.6 for a positive attitude toward sunbathing versus a negative 0ne.5~

Social Stress Using a fish model, one research experiment examined the effect of stress on the gallbladder function. In this work, fish were subject to prolonged cohabitation with dominant individuals. It was found that this chronic social stress could increase bile retention, increase gallbladder hypertrophy, and inhibit gallbladder emptying.@’ This study suggests that chronic stress may be a predictor of gallbladder dysfunction and eventual gallstone formation.

THERAPEUTIC APPROACH As is typical of most diseases, gallstones are much easier to prevent than reverse. The risk factors and causes of gallstones are well known, and in most cases a healthy diet rich in dietary fiber, with a limitation of excess calories and saturated fats, is adequate prevention.

Once gallstones have developed, measures to avoid gallbladder attacks and increase the solubility of the bile are necessary. To limit the incidence of symptoms, intolerant/allergic foods must be determined (see Chapter 19) and, along with fatty foods, avoided. The solubility of the bile can be increased by following the dietary guidelines and using the nutritional and herbal supplements recommended here.

Diet Patients should increase their intake of vegetables; fruits; dietary fiber, especially the gel-forming or mucilaginous fibers (e.g., flaxseed, oat bran, guar gum,pectin); and buckwheat. They should reduce their consumption of saturated fats, refined carbohydrates, cholesterol, sugar, and animal proteins. All fried foods should be avoided. An allergy elimination diet can be used to reduce gallbladder attacks (see Chapter 53 for a description of elimination diets).

Water Consumption of six to eight glasses of water is necessary each day to maintain the water content of bile.

Nutritional Supplements Vitamin C: 1 to 3 g/day Vitamin E: 200 to 400 IU/day Phosphatidylcholine: 500 mg/day Choline: 1g/day L-Methionine: 1g/day Fiber supplement (guar gum,pectin, psyllium, or oat bran): minimum of 5 g/day

Botanical Medicines 7’.oficinde (three times/day) Dried root: 4 g Fluid extract (1:l): 4 to 8 ml Solid extract (4:l): 250 to 500 mg l? boldo (three times/day) Dried leaves (or by infusion):250 to 500 mg Tincture (1:lO): 2 to 4 ml Fluid extract (1:l):0.5 to 1 ml S. marianum Sufficient dosage according to form to yield 70 to 210 mg of silymarin three times/day c.scozymus Extract (15%cynarin): 500 mg three times/day C. Zonga Use liberally as a spice Curcumin: 300 mg three times/day

Gallstone-Dissolving Formula Menthol: 30 mg Menthone: 5 mg Pinene: 15 mg

Borneol: 5 mg Camphene:5 mg Cine01 2 mg Citral: 5 mg Phosphatidylcholine:50 mg Medium chain triglycerides: 125 mg Chenodeoxycholicacid: 750 mg

1. Kalloo AN, Kantsevoy SV. Gallstones and biliary disease. Prim Care 2001;28:591-606, vii. 2.Robbins SL, Cotran RS, Kumar V. Pathologic basis of disease. Philadelphia: Saunders, 19M942-950. 3. liemey LM Jr, McPhee SJ, Papadakis MA, eds. Current medical diagnosis and treatment. Stamford, CT Appleton & Lange, 199T630-632. 4. Weisberg HF. Pathogenesis of gallstones. Ann Clin Lab Sci 19&4;14243-251. 5. Trowell H, Burkitt D, Heaton K, eds. Dietary fibre, fibre-depleted foods and disease. London: Academic Press, 1985:289-304. 6. Rizvi TJ, Zuberi SJ. Risk factors for gall bladder cancer in Karachi. J Ayub Med Coll Abbottabad 2003;15:1618. 7. Vitetta L, Sali A, Little P, et al. Gallstones and gall bladder carcinoma. Aust N Z J Surg 2000;70667-673. 8. Rubenstein E, Federman DD. Scientific American medicine. New York: Scientific American, 1986:4, VI-1-10. 9. Nervi F, Covarrubias C, Bravo P, et al. Influence of legume intake on biliary lipids and cholesterol saturation in young Chilean men. Gastroenterology 198996825-830. 10. Mathus-Vliegen EM, Van Ierland-Van Leeuwen ML, Terpstra A. Determinants of gallbladder kinetics in obesity. Dig Dis Sci 2004; 499-16. 11. Festi D, Colecchia A, Larocca A, et al. Review: low caloric intake and gallbladder motor function. Aliment Pharmacol Ther 2000; 14(s~ppl 2):51-53. 12. Akin ML, Uluutku H, Erenoglu C, et al. Tamoxifen and gallstone formation in postmenopausal breast cancer patients: retrospedive cohort study. World J Surg 2003;27395-399. 13. Wang DQ. Aging per se is an independent risk factor for cholesterol gallstone formation in gallstone susceptible mice. J Lipid Res 2002; 4 3199-1959. 14. Pandey M, Shukla VK.Diet and gallbladder cancer: a case-control study. Eur J Cancer Prev 2002;11:365-368. 15. Marks JW, Cleary PA, Albers JJ. Lack of correlation between serum lipoproteins and biliary cholesterol saturation in patients with gallstones. Dig Dis Sci 19&4;29:111&1122. 16. Petitti DB, Friedman GD, Klatsky AL. Association of a history of gallbladder disease with a reduced concentration of high-densitylipoprotein cholesterol. N Engl J Med 1981;304:1396-1398. 17. Thomton JR, Heaton KW, Macfarlane DG. A relation between highdensity-lipoprotein cholesterol and bile cholesterol saturation. Br Med J 1981;2831352-1354. 18. Van der Linder W, Bergman F. An analysis of data on human hepatic bile. Relationship between main bile components, serum cholesterol and serum triglycerides. Scand J Clin Lab Invest 1977; 37741-747. 19. Pixley F, Wilson D, McPherson K, et al. Effect of vegetarianism on development of gallstones in women. Br Med J 1985;291:11-12. 20.Kritchevsky D, Klurfeld DM. Gallstone formation in hamsters. Effect of varying animal and vegetable protein levels. Am J Clin Nutr 198337802-804.

The dosage for this formula is to take it three times daily if used in combination with meals. Note: Peppermint oil in an enteric-coated capsule can be used instead at a dosage of 1 to 2 capsules (0.2 ml/ capsule) three times daily between meals.

21. Breneman JC. Allergy elimination diet as the most effective gallbladder diet. Ann Allergy 1968;2683-87. 22. Necheles H, Rappaport BZ, Green R, et al. Allergy of the gallbladder. Am J Dig Dis 1949;723&241. 23. Walzer M, Gray I, Harten M, et al. The allergic reaction in the gallbladder. Experimental studies in rhesus monkeys. Gastroenterology 1943;1:565-572. 24. De Muro P, Ficari A. Experimental studies on allergic cholecystitis. Gastroenterology 1946;6302-314. 25. Tomotake H, Shimaoka I, Kayashita J, et al. A buckwheat protein product suppresses gallstone formation and plasma cholesterol more strongly than soy protein isolate in hamsters. J Nutr 2000; 1301670-1674. 26. Kritchevsky D, Klurfeld DM. Influence of vegetable protein on gallstone formation in hamsters. Am J Clin Nutr 1979;3221742176. 27. Tomotake H, Shimaoka I, Kayashita J, et al. Stronger suppression of plasma cholesterol and enhancement of the fecal excretion of steroids by a buckwheat protein product than by a soy protein isolate in rats fed on a cholesterol-free diet. Biosci Biotechnol Biochem 2001;65:1412-1414. 28. Liu Z, Ishikawa W, Huang X, et al. A buckwheat protein product suppresses 1,2-dimethylhydrazine-inducedcolon carcinogenesis in rats by reducing cell proliferation.J Nutr 2001;131:1850-1853. 29. Moerman CJ,Bueno de Mesquita HB, Runia S. Dietary sugar intake in the etiology of biliary tract cancer. Int J Epidemiol1993;22:207-214. 30. Thomton JR, Emmett PM, Heaton KW. Diet and gall stones: effects of refined and unrefined carbohydrate diets on bile cholesterol saturation and bile acid metabolism. Gut 1983;242-6. 31. Moerman CJ, Smeets FW,Kromhout D. Dietary risk factors for clinically diagnosed gallstones in middle-aged men. A Wyear follow-up study (the Zutphen Study). Ann Epidemiol1994;4248-254. 32.Tandon RK, Saraya A, Paul S, et al. Dietary habits of gallstone patients in northern India: a case control study. J Clin Gastroenterol 1996;22:23-27. 33. Caroli-Box FX,Deveau C, Peten EP, et al. Cholelithiasis and dietary risk factors: an epidemiologic investigation in Vidauban, Southeast France. General Practitioner's Group of Vidauban. Dig Dis Sci 1998; 432131-2137. 34.Kamrath RO, Plummer LF, Sadur CN. Cholelithiasis in patients treated with a very-low-calorie diet. Am J Clin Nutr 1992;56 255s257s. 35. van Erpecum KJ, van Berge Henegouwen GP. Intestinal aspects of cholesterol gallstone formation. Dig Liver Dis 200335(suppl3):S8-11. 36. Spirt BA, Graves LW, Weinstock R. Gallstone formation in obese women treated by a low-calorie diet. Int J Obes Relat Metab Disord 1995;19593-595. 37. Douglas BR, Jansen JB, Tham RT. Coffee stimulation of cholecystokinin release and gallbladder contraction in humans. Am J Clin Nutr 199052553-556. 38. Leitzmann MF, Stampfer MJ, Willett WC, et al. Coffee intake is associated with lower risk of symptomatic gallstone disease in women. Gastroenterology 2002;123:1823-1830.

Gallstones 39.Kasbo J, Tuchweber B, Perwaiz S, et al. Phosphatidylcholineenriched diet prevents gallstone formation in mice susceptible to cholelithiasis. J Lipid Res 2003;442297-2303. Epub July 1,2003. 40.Tuzhilin SA, Drieling DA, Narodetskaja RV, et al. The treatment of patients with gallstones by lecithin. Am J Gastroenterol1976;65:231. 41. Hanin I, Ansell GB. Lecithin. Technological, biological, and therapeutic aspects. New York Plenum Press, 1987. 42. Jenkins SA. Vitamin C and gallstone formation: a preliminary report. Experientia 1977,331616-1617. 43.Dam H, Christensen F. Alimentary production of gallstones in hamsters. Ada Path01 Mimbiol Scand 1952;30:236-242. 44.Lee SP,Tassman-JonesC, Carlisle V.Oleic acid-induced cholelithiasis in rabbits. Am J Pathol1986;124:1&24. 45.Beynen AC. Dietary monounsaturated fatty acids and liver cholesterol. Artery 1988;15170-175. 46.Baggio G, Pagnan A, Muraca M, et al. Olive-oildched diet. Effect on serum lipoprotein levels and biliary cholesterol saturation. Am J Clin Nutr 1988;47:960-964. 47. Scobey MW, Johnson FL, Parks JS. Dietary fish oil effects on biliary lipid secretion and cholesterol gallstone formation in the African green monkey. Hepatology 1991;14(4 Pt 1):679-684. 48. Magnuson TH, Lillemoe KD, High RC, et al. Dietary fish oil inhibits cholesterol monohydrate crystal nucleation and gallstone formation in the prairie dog. Surgery 1995;118517-523. 49. Hussain MS, ChandrasekhmaN. Effect on curcumin on cholesterol gall-stone induction in mice. Indian J Med Res 199296288291. 50. Schwnfield LJ, Lachin JM. Chenodiol (chenodeoxycholic acid) for the dissolution of gallstones: the National Cooperative Gallstone

Study. A controlled trial of efficacy and safety. Ann Intern Med 198195257-282. 51. F r o m H. Gallstone dissolution and the cholesterol-bile acidlipoprotein axis. Propitious effects of ursodeoxycholic acid. Gastroenterology 1984;87229-233. 52. Hordinsky BZ. Terpenes in the treatment of gallstones. Minn Med 1971;54:649-652. 53. Bell GD, Doran J. Gallstone dissolutionin man using an essential oil preparation. Br Med J 1979;1:24. 54. Doran J, Keighley RB, Bell GD. Rowachol-a possible treatment for cholesterol gallstones. Gut 1979;20312-317. 55. Ellis WR, Bell GD. Treatment of biliary duct stones with a terpene preparation. Br Med J (Clin Res Ed) 1981;282611. 56. Somerville KW, Ellis WR, Whitten BH,et al. Stones in the common bile duct: experience with medical dissolution therapy. Postgrad Med J 1985;61:313-316. 57. Ellis WR, Bell GD, Middleton B, et al. Adjunct to bile-acid treatment for gall-stone dissolution: low-dose chenodeoxycholic acid combined with a terpene preparation. Br Med J 1981;282:611-612. 58.Ellis WR, Somerville KW, Whitten BH, Bell GD. Pilot study of combination treatment for gall stones with medium dose chenodeoxycholic acid and a terpene preparation. Br Med J 1984;289: 153-156. 59. Pave1 S. Sunbathing and gallstones. Lancet 1992;339:241. 60.Earley RL, Blumer LS, Grober MS. The gall of subordination: changes in gall bladder function associated with social stress. Proc R Soc Lond B Biol Sci 2004;271:7-13.

Glaucoma: Acute (Angle Closure) and Chronic (Open Angle) Michael T. Murray, ND Joseph E. Pizzorno Jr, N D CHAPTER CONTENTS Diagnostic Summary 1697 Acute Glaucoma 1697 Chronic Glaucoma 1697 General Considerations 1697

Supplements and Diet 1698 Other Recommendations 1700

Therapeutic Approach 1700 Supplements 1700 Botanical Medicine 1700

Diagnosis 1698 Therapeutic Considerations 1698 Corticosteroids 1698

DIAGNOSTIC SUMMARY Acute Glaucoma Increased intraocular pressure, usually unilateral Severe throbbing pain in eye with markedly blurred vision Pupil moderately dilated and fixed Absence of pupillary light response Nausea and vomiting are common.

Chronic Glaucoma Persistent elevation of intraocular pressure associated with pathologic cupping of optic discs Asymptomatic in the early stages Gradual loss of peripheral vision resulting in tunnel vision Insidious onset in older individuals

GENERAL CONSIDERATIONS Glaucoma refers to increased intraocular pressure (IOP) as a result of an imbalance between production and outflow of the aqueous humor. Obstruction to outflow is the main factor responsible for this imbalance in closedangle glaucoma. Acute glaucoma can occur only with the closure of a preexisting narrow anterior chamber angle, while in chronic open-angle glaucoma, the anterior chamber appears normal.

In the United States approximately 3 million people have glaucoma, 25% of which is undetected.' The chronic open-angle type, in which there appears to be no consistent anatomic basis for the condition, accounts for 90% of these cases. Histologically, however, there is a strong correlation between the content and composition of collagen and the glaucomatous eye.2 Collagen is the most abundant protein in the body including the eye. In the eye it provides tensile strength and integrity to the tissues (e.g., cornea, sclera, lamina cribrosa, trabecular meshwork, vitreous). Inborn errors of collagen metabolism (eg., osteogenesis imperfecta, Ehlers-Danlos syndrome, Marfan's syndrome) are often associated with ocular complications: glaucoma, myopia, retinal detachment, ectopia lentis, and blue sclera.3Morphologic changes in the lamina cribrosa (the scleral area that is pierced by the optic nerve fibers and blood vessels), trabecular meshwork (the connective tissue network through which aqueous humor must pass to reach the canal of Schlemm), and papillary blood vessels in the eye have all been observed in glaucomatous eyes.2rM These changes may result in elevated intraocular pressure (IOP) readings or, perhaps more sigruficantly,lead to the progression of peripheral vision loss. Changes in collagen structure would explain the following2."6: Similar peripheral vision loss in patients with normal and elevated IOP 1697

Cupping of the optic disc even at low IOP levels No apparent anatomic reason for decreased aqueous outflow

in other conditions involving collagen abnormalities (i.e., atherosclerosis,rheumatoid arthritis, and periodontal disease).

Corticosteroids

DIAGNOSIS Patients with open-angle glaucoma initially have no symptoms, which is why this disease can be so insidious. Physical examination may reveal slight cupping of the optic disc and narrowing of the visual fields. Tonometry is key to confirmation of the diagnosis. The key challenge with acute glaucoma is early recognition, as delay in referral for surgical intervention increases the risk of blindness. Table 170-1 provides an overview of the differential diagnosis of the inflamed eye.

THERAPEUTIC CONSIDERATIONS Treatment and prevention of both acute and chronic glaucoma are dependent on reduction of IOP and improvement of collagen metabolism, particularly in the optic disc and trabecular meshwork. The optic disc is composed of the lamina cribrosa, the optic nerve fibers, and the blood vessels. The lamina cribrosa is a meshlike network rich in collagen through which the optic nerves and blood vessels must pass. The morphologic changes in the collagen of the eye (i.e., lamina cribrosa, papillary vessels, and trabecular meshwork) precede pressure changes. Therefore primary prevention of ground substance and collagen framework breakdown is important here, as it is

The importance of collagen destruction in the etiology of glaucoma is apparent in corticosteroid-induced glaucoma? Corticosteroid use should be discouraged in the glaucoma patient, as it is known to inhibit the biosynthesis of collagen and glycosaminoglycans, thereby causing glaucoma to develop?

Supplements and Diet Vitamin C Of foremost importance in achieving collagen integrity are optimal tissue concentrations of ascorbic acid (AA). Furthermore, AA has been demonstrated to lower IOP levels in many clinical studies?-" A daily dose of 0.5 g/kg body weight, whether in single or divided doses, reduces the IOP by an average of 16 mmHg." Almost-normal tension levels were achieved in some patients unresponsive to acetazolamide (a carbonic anhydrase inhibitor) and 2% pilocarpine (a miotic agent)." The hypotonic action of AA on the eye is long lasting if supplementationis continued, and intravenous administration results in an even greater initial reduction in IOP?,9-11Patient monitoring is required to determine the appropriate individual dose, as some patients respond to as little as 2 g/day, while others will respond only to extremely high doses (e.g.,35 g/day)?-ll Abdominal discomfort when using high doses is common, but usually resolves after 3 to 4 days."

ifferential diagnosis of the inflamed eye Acute conjunctivitis

Acute iritis

Acute glaucoma

Corneal trauma or infection

Incidence

Very common

Common

Uncommon

Common

Discharge

Moderate to copious

None

None

Watery or purulent

Vision

No effect

Slightly blurred

Markedly blurred

Usually blurred

Pain Conjunctival injection

None Diffuse, mostly fornices

Moderate Circumcorneal

Severe Diffuse

Moderate to severe Diffuse

Cornea

Clear

Usually clear

Steamy

Clarity may change

Pupil size

Normal

Small

Dilated and fixed

Normal

Pupil light response

Normal

Poor

None

Normal

lntraocular pressure Anterior chamber

Normal

Normal Normal depth

Elevated Very shallow

Normal Normal depth

Iris

Normal

Dull, swollen

Congested and bulging

Normal unless infected

Smear

Causative organisms

No organisms

No organisms

Causative organisms if there is infection

Modified from Distelhorst JS, Hughes GM. Am Fam Physician 2003671937-1944.

Glaucoma: Acute (Angle Closure) and Chronic (Open Angle)

The proposed mechanisms by which AA lowers IOP include the following: Increased blood osmolarity Diminished production of aqueous fluid by the ciliary epithelium Improved aqueous fluid outflow In light of recent research, however, its role in collagen formation may be key to its antiglaucomatousaction.

Bioflavonoids To further aid normal collagen metabolism,bioflavonoids should be supplemented, particularly the anthocyanosides (the blue-red pigments found in berries). These compounds elicit an AA-sparing effect, improve capillary integrity, and stabilize the collagen matrix by preventing free radical damage, inhibiting enzymatic cleavage of the collagen matrix, and cross-linking with collagen fibers directly to form a more stable collagen matrix.12-’* Vucciniurn rnyrtillus (European bilberry) extract is particularly rich in these flavonoid and anthocyanidin compounds and has been used in Europe with good results in reducing myopia, improving nocturnal vision, and reversing diabetic retin0~athy.l~ Rutin has also been demonstrated to lower IOP when used as an adjunct in patients unresponsive to miotics alone.16

Allergy The successful treatment of chronic glaucoma by antiallergy measures has been reported in the literature.” In one study, many of the 113 patients demonstrated an immediate rise in intraocular pressure of up to 20 mm (in addition to other typical allergic symptoms) when challenged with the appropriate allergen, whether food borne or environmental. The author speculated that the known allergic responses of altered vascular permeability and vasospasm could result in the congestion and edema characteristic of glaucoma.

Magnesium Since channel-blocking drugs benefit some glaucoma patients, a group of researchers at the University Eye Clinic in Basel, Switzerland, decided to evaluate the effect of supplemental magnesium, which has been referred to as ”nature’s physiologic calcium-channel blocker.” Ten glaucoma patients (six with primary openangle glaucoma, four with normal-tension glaucoma) participated in the trial. All patients had a digital coldinduced vasospasm. Magnesium was given at a dose of 121.5 mg twice daily for 1 month. After 4 weeks of treatment, the visual fields improved, as noted by a decrease in the mean defect and square root of loss variance scores. All three nail fold-capillaroscopic parameters improved, as well as digital temperature.

These results demonstrate that magnesium supplementation improves the peripheral circulation and seems to have a beneficial effect on the visual field in patients with glaucoma.l8

Chromium A case-controlled study of 400 consecutive eye patients, 52 of whom had ocular hypertension or glaucoma, or both, found that primary open-angle glaucoma was strongly associated with a deficiency of erythrocyte chromium; habitual daily intake of ascorbic acid; and elevations of erythrocyte vanadium, which is chromium’s principal antagonist. Ascorbic acid and chromium potentiate insulin receptors that help to sustain strong ciliary-muscle eyefocusing activity. Deficiencies of either ascorbic acid or chromium were associated with elevated intraocular pressure, which tends to stretch the normal eye, thereby reducing the capacity for focusing power.19

Fish Oil In an interesting speculative study, feeding rabbits food soaked with cod liver oil resulted in a 25-mmHg drop in intraocular pressure to 11 mmHg. Intramuscular injections of cod liver oil produced a dose-dependent reduction in intraocular pressure. When the animals were taken off cod liver oil, their intraocular pressure returned to baseline. Control animals given liquid lard or safflower oil experienced no change in intraocular pressure.2oPreliminary studies in humans with docosahexaenoic acid are encouraging.2l

Caffeine Many physicians instruct patients with glaucoma to avoid coffee, although clinical data supporting this practice are insufficient. To estimate the effect of drinking coffee on IOP, the effect of the consumption of regular (180 mg caffeine in 200 ml of coffee) and decaffeinated coffee (3.6 mg caffeine in 200 ml of coffee) was compared in patients with normotensive glaucoma or ocular hypertension in a double-blind crossover study. IOP was monitored in both groups at 30,60, and 90 minutes after coffee ingestion. In patients with normotensive glaucoma who drank regular coffee, the mean changes in IOP at 30, 60, and 90 minutes were 0.9, 3.6, and 2.3 mmHg, respectively; in those who drank decaffeinated coffee, they were 0.75, 0.70, and 0.4 mmHg, respectively. The corresponding values in patients with ocular hypertension were as follows: after regular coffee, 1.1, 3.4, and 3 mmHg; and after decaffeinated coffee, 0.6, 0.9, and 0.5 mmHg. This study showed quite clearly that subjects who drank regular coffee demonstrated a greater elevation in IOP, and this elevation may be clinically sigruficant.22

Specific Health Problems

Other Recommendations Exercise Exercise can lead to immediate and prolonged reduction in IOP. Within 5 minutes of starting exercise, IOP initially increases and then gradually decreases to its lowest level 60 minutes following exercise. The drop in IOP is approximately 23% in normal individuals, while people with glaucoma usually experience a greater drop and longer duration of postexercise recovery than normal eyesn Specifically, the drop in IOP for glaucoma patients following walking/jogging and running was 7.2% and 12.7%, respectively, more than the decrease in IOP experienced by normal eyes. Similarly, the mean duration of the IOP-lowering following running was approximately 84 minutes in glaucomatous eyes and 63 minutes in normal eyes. The mechanism of acute lowering of IOP is independent of systemic blood pressure and level of sympathetic stimulation but may, in part, be due to increased serum osmolarity. Exercise appears to be effective in lowering IOP in sedentary subjects engaging in moderate to heavy exercise but is somewhat less effective in physically fit subjects.24However, it must be pointed out that individuals who are more physically fit tend to have lower IOP. If one stops exercising, the effect wears off in 3 weeks. Although exercise may not be effective in lowering IOP in everyone, it can lead to sigrulicantirnprovements in many. One study found that IOP was lowered by at least 2 mmHg by exercise in 34%; however, 5770 had no change in IOP, while 9% had an IOP elevation.25

LDistelhorst JS, Hughes GM. Open-angle glaucoma. Am Fam Physician 2003;671937-1944. 2. Tengroth B, Ammitzboll T. Changes in the content and composition of collagen in the glaucomatouseye-basis for a new hypothesis for the genesis of chronic open-angle glaucoma. Acta Ophthalmol (Copenh) 1984;62:999-1008. 3.Weiss J, Jayson M. Collagen in health and disease. Edinburgh; New York Churchill Livingstone, 198238843. 4. Quigley H, Addicks E. Regional differences in the structure of the lamina cribrosa and their relation to glaucomatous optic nerve damage. Arch Ophthalmol1981;99:137-143. 5. Krakau T, Bengtsson 8, Holmin C. The glaucoma theory updated. Acta Ophthalmol (Copenh) 1983;61:737-741. 6. Rohen JW. Why is intraocular pressure elevated in chronic simple glaucoma? Anatomical considerations. Ophthalmology 1983;90 758-765. 7. Bietti G. Further contributionson the value of osmotic substances as means to reduce intra-ocular pressure. Trans Ophthalmol Soc Aust 1967;2661-71.

Helico bacter p y1ori Recently, several studies have found an association between Helicobacter pylori infection and open-angle glaucoma.26 A particularly interesting 2-year study found that successful eradication of H. pylori resulted in decreased intraocular pressure. See Chapter 200 for a discussion of H. pylori treatment.

THERAPEUTIC APPROACH Acute closed-angleglaucoma is an ocular emergency and should be referred immediately to an ophthalmologist. Unless adequately treated within 12 to 48 hours, the patient will become permanently blind within 2 to 5 days. An asymptomatic eye with a narrow anterior chamber angle may convert spontaneously to angleclosure glaucoma. The process can be precipitated by anything that dilates the pupil such as atropine and epinephrine-like drugs. Typical signs and symptoms include extreme pain, blurring of vision, conjunctivitis, and a fixed and dilated pupil.' Agents that dilate the pupils must be strictly avoided in any patient suspected of glaucoma.

Supplements Vitamin C: 0.1 to 0.5 g/kg per day in divided doses Bioflavonoids (mixed): 1000 mg/day Magnesium: 200 mg/day Chromium: 100 pg/day

Botanical Medicine V.rnyrtillus extract (25%anthocyanidin content):80 mg tid

8. Fishbein S, Goodstein S. The pressure lowering effect of ascorbic acid. Ann Ophthalmol1972;4487-491. 9. Linner E. The pressure lowering effect of ascorbic acid in ocular hypertension. Ada Ophthalmol (Copenh) 1969;47685-689. 10. Shen TM, Yu MC. Clinical evaluation of glycerin-sodiumascorbate solution in lowering intraocular pressure. Chinese Med J (Engl) 1975;1:64-68. 11. Vim0 M, Bucci M, Pecori-GiraldiJ, et al. oral treatment of glaucoma with vitamin C. Eye Ear Nose Throat Monthly 1967;46:1502-1508. 12. Gabor M. Pharmacologic effects of flavonoids on blood vessels. Angiologica 1972;9:355-374. 13. Monboisse J, Braquet P, Bore1 J. Oxygen-& radicals as mediators of collagen breakage. Agents Actions 1984;15:49-50. 14. Hagerman A, Butler L. The specificity of proanthocyanidin-protein interactions.J Biol Chem 1981;2564494-4497. 15. Bever B, Zahnd G. Plants with oral hypoglycemic action. Q J Crude Drug R ~ 1979;17139-196. s 16. Stocker F. New ways of influencing the intraocular pressure. N Y St J Med 1949;4958-63.

Glaucoma: Acute (Angle Closure) and Chronic (Open Angle) 17. Raymond LF. Allergy and chronic simple glaucoma. Ann Allergy 1964;22:146-150. 18. Gaspar AZ,Gasser P, Flammer J. The influence of magnesium on visual field and peripheral vasospasm in glaucoma. Ophthalmologica 1995;209:11-13. 19. Lane BC. Diet and glaucomas. J Am Coll Nutr 1991;10536. 20.McGuire R. Fish oil cuts lower ocular pressure. Med Tribune 1991;1925. 21.Cellini M, Caramazza N, Mangiafko P, et al. Fatty acid use in glaucomatous optic neuropathy treatment. Ada Ophthalmol %and Suppl1998;22741-42. 22. Avisar R, Avisar E, Weinberger D. Effect of coffee consumption on intraocular pressure. Ann Pharmacother 2002;36992-995. 23. Qureshi IA.The effects of mild, moderate, and severe exercise on intraocular pressure in glaucoma patients. Jpn J Physiol 1995;45: 561-569.

24. Qureshi IA. Effects of exercise on intraocular pressure in physically fit subjects. Clin Exp Pharmacol Physiol1996;23:648-652. 25. Era P, Parssinen 0, Kallinen M, et al. Effect of bicycle ergometer test on intraocular pressure in elderly athletes and controls. Acta Ophthalmol (Copenh) 1993;71:301-307. 26. Kountouras J, a v o s C, Chatzopoulos D. Induction of apoptosis as a proposed pathophysiological link between glaucoma and Helicobucfer pylon' infection. Med Hypotheses 2004;62378-381. 27. Kountouras J, Mylopoulos N, Chatzopoulos D, et al. Eradication of Helicobucfer pylon. may be beneficial in the management of chronic open-angle glaucoma. Arch Intern Med 2002;162:1237-1244.

Gout Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

1703

General Considerations 1703 Causes of Gout 1703 Signs and Symptoms 1704 Therapeutic Considerations 1706 Lead Toxicity 1706 Dietary Considerations 1706

DIAGNOSTIC SUMMARY Acute onset, frequently nocturnal, of typically monarticular joint pain, involving the metatarsophalangeal joint of the big toe in about 50% of cases Elevated serum uric acid level Asymptomatic periods between acute attacks Identification of urate crystals in joint fluid Aggregated deposits of monosodium urate monohydrate (tophi) chiefly in and around the joints of the extremities but also in subcutaneous tissue, bone, cartilage, and other tissues Uric acid kidney stones Familial disease; 95% males

Nutritional Supplements 1707 Botanical Medicines 1707

Therapeutic Approach 1708 Diet 1708 Nutritional Supplements 1708 Botanical Medicines 1708

Gout is associated with affluence and is often called the "rich man's disease." Throughout history, the sufferer of gout has been depicted as a portly, middle-aged man sitting in a comfortable chair with one foot resting painfully on a soft cushion as he consumes great quantities of meat and wine. In fact, the traditional picture does have some basis in reality, as meats, particularly organ meats, are high-purine foods, while alcohol inhibits uric acid secretion by the kidneys. Furthermore, even today, gout is primarily a disease of adult men; more than 95% of sufferers of gout are men older than the age of 3 0 . ' ~The ~ incidence of gout is approximately 3 adults in 1000, although 10%to 20% of the adult population has hyperuricemia.3

Causes of Gout GENERAL CONSIDERATIONS Gout is a common type of arthritis caused by an increased concentration of uric acid (the final breakdown product of purine metabolism) in biologic fluids. In gout, uric acid crystals (monosodium urate) are deposited in joints, tendons, kidneys, and other tissues, where they cause considerable inflammation and damage.'f2Gout is a condition characterized biochemically by increased serum uric acid levels, leukotriene levels, and neutrophil accumulation. Gout may lead to debilitation due to the tophaceous deposits around the joints and tendons, and renal involvement may result in kidney failure due to either parenchymal disease or urinary tract obstruction.

Gout is classified into two major categories: primary and secondary. Primary gout accounts for about 90% of all cases, while secondary gout accounts for only 10%. Primary gout is usually idiopathic (i.e., the underlying metabolic defect is unknown). However, there are several genetic defects in which the exact cause of the elevated uric acid is known.'~The synthesis and degradation of purines is summarized in Figure 171-1. Secondary gout refers to those cases in which the elevated uric acid level is secondary to some other disorder such as excessive breakdown of cells or some form of renal disease. Diuretic therapy for hypertension and low-dose aspirin therapy are also important causes of secondary gout because they cause decreased uric acid excretion.',* 1703

Phosphoribosylpyrophosphate

+

Glutamine

Phosphoibosylamine

Feedback inhibition

inhibition

S Y

n t h

e

s i

Body+ GMP Constituents

S

+Xanthylic acid+

lsoninic acid+

Adenylosuccinic acid+

AMP

+Body

constitutents

HGPRT salvage

HGPRT salvage

-

--D

e

Guanine

Hypoxanthinq-

Adenine

LJ Xanthine oxidase

Xanthine

\1

Xanthine oxidase

Uric acid

Figure 171-1 Purine synthesis and degradation. (From Nutrition Foundation. Nutrition reviews’present knowledge in nutrition, ed 5. Washington, DC: Nutrition Foundation, 1984:740-756.)

The inmased serum uric acid level observed in primary idiopathic gout can be divided into three categories: Increased synthesis of uric acid, found in a majority of individuals Reduced ability to excrete uric acid, typical of a smaller group (about 30%) Overproduction of uric acid, as well as underexcretion of uric acid-a small minority Although the exact metabolic defect in gout is unknown in the majority of cases, gout is one of the most controllable metabolic diseases.12 Box 171-1 summarizesthe causes of gout. About 200 to 600 mg of uric acid are excreted daily in the urine of an adult male. This is two thirds of the amount produced, the rest being excreted in the bile and other gastrointestinal tract secretions. The dietary component of uric acid is usually 10% to 20%, but in an individual with sigruficant hyperuricemia, 1mg/100 ml may be added to the serum concentration of uric acid through the diet, enough to increase precipitation into the tissues if the individual is near the saturation threshold? Almost all of the plasma urate is filtered at the glomerulus: only the small amount bound to protein is not filtered. Renal excretion is peculiar in that about 80% of the filtered uric acid is reabsorbed in the proximal tubule of the nephron. Actually, the distal tubule secretes

most of the uric acid found in the urine. Distal to this site, some postsecondary reabsorption occurs? These events are summarized in Figure 171-2. Uric acid is a highly insoluble molecule, and at pH 7.4 and body temperature, the serum is saturated at 6.4 to 7 mg/100 ml. Although higher concentrations do not necessarily result in urate deposition (some unknown factor in serum appears to inhibit urate precipitation), the chance of an acute attack is greater than 90% when the level is above 9 mg/100 ml (Table 171-1). Lower temperatures decrease the saturation point of uric acid, which may explain why urate deposits tend to form in areas such as the pinna of the ear, where the temperature is lower than the mean body temperature (Table 171-2). Uric acid is insoluble below pH 6 and can precipitate as the urine is concentrated in the collecting ducts and passed to the renal pelvis.

Signs and Symptoms The first attack of gout is characterized by intense pain, usually involving only one joint. The first joint of the big toe is affected in nearly half of the first attacks and is at some time involved in more than 90% of individuals with gout. If the attack progresses, fever and chills will appear. The first attacks usually occur at night and are usually preceded by a specific event such as dietary excess, alcohol ingestion, trauma, certain drugs, or surgery.*

Gout

Metabolic Increased production of purine (primary) Idiopathic Specific enzyme defects (e.g., Lesch-Nyhan syndrome, glycogen storage disease) Decreased enzyme activity (e.g., hypoxanthine-guanine phosphoribosyltransferase is decreased in 1%-2% of adult gouty individuals) Increased enzyme activity (e.g., phosphoribosylpyrophosphate synthetase) Increased production of purine (secondary) Increased turnover of purines Myeloproliferative disorders Lyrnphoproliferative disorders Carcinoma and sarcoma (disseminated) Chronic hemolytic anemia Cytotoxic drugs Psoriasis Increased de novo synthesis (e.g., glucose-6-phosphatase deficiency) Increased catabolism of purines Fructose ingestion or infusion Exercise

Renal Decreased renal clearance of uric acid (primary) Intrinsic kidney disease Decreased renal clearance of uric acid (secondary) Functional impairment of tubular secretion Drug-induced (e.g., thiazides, probenecid, salicylates, ethambutol, pyrazinamide) Hyperlacticemia (e.g., lactic acidosis, alcoholism, toxemia of pregnancy, chronic beryllium disease) Hyperketoacidemia(e.g., diabetic ketoacidosis, fasting, starvation) Diabetes insipidus Bartter syndrome Chronic lead intoxication Glucose-6-phosphatasedeficiency

B

I 0

0

d

Figure 171-2 Normal uric acid excretion.

Serum urate (mg/l00 ml)

<6

Men (“1.)

Women (%)

0.6

0.08

6-6.9

1.9

3.3

7-7.9

16.7

17.4

8-8.9

25

0

9+

90

0

Modified from Faller J, Fox IH. N Engl J Med 1982;307:1598-1602.

Solubility of urate ion as a function of temperature in 140 mM Na+ Temperature PC)

Maximum solubilitv (mall 00 ml)

37

6.8

35

6

30

4.5

25

3.3

20

2.5

15

1.8

10

1.2

Modified from Faller J, Fox IH. N Engl J Med 1982;307:1598-1602.

The classic description of gout was by an English physician, Sydenham, who suffered from gout in 1683. Little has changed in the clinical picture of gout in more than 300 years. Sydenham’s classic description was as follows: The victim goes to bed and sleeps in good health. About two o‘clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle, or instep. The pain is like that of a dislocation, and yet parts feel as if cold water were poured over them. Then follows chills and shivers, and a little fever. The pain which at first was moderate, becomes more intense. With its intensity the chills and fever increase. After a time this comes to a height, accommodating itself to the bones and ligaments of the tarsus and metatarsus. Now it is a violent stretching and tearing of the ligamentsnow it is a gnawing pain and now a pressure and tightening.

So exquisite and lively meanwhile is the feeling of the part affected, that it cannot bear the weight of bedclothes nor the jar of a person walking in the room. The night is passed in torture, sleeplessness, turning the part affected, and perpetual change of posture; the tossing about of the body being as incessant as the pain of the tortured joint, and being worse as the fit comes on. Hence the vain effort by change of posture, both in the body and the limb affected, to obtain an abatement of pain.

Subsequent attacks are common, with the majority having another attack within 1year. However, nearly 7% never have a second attack. Chronic gout is extremely rare, due to the advent of dietary therapy and drugs that lower uric acid levels. Some degree of kidney

Specific Health Problems

dysfunction occurs in nearly 90% of subjects with gout, and there is a higher risk of kidney stones.*

THERAPEUTIC CONSIDERATIONS The current standard medical treatment of acute gout is administration of colchicine, the antiinflammatory drug originally isolated from the plant Colchicum uutummle (autumn crocus, meadow saffron).* Colchicine has no effect on uric acid levels; rather, it stops the inflammatory process by inhibitingneutrophil migration into areas of inflammation. More than 75% of patients with gout show major improvement in symptoms within the first 12 hours after receiving colchicine. However, up to 80% of patients are unable to tolerate an optimal dose because of gastrointestinal side effects, which may precede or coincide with clinical improvement.2 Colchicine may also cause bone marrow depression, hair loss, liver damage, depression, seizures, respiratory depression, and even death. Other antiinflammatory agents are also used in acute gout including indomethacin, phenylbutazone, naproxen, and fenoprofen.2 Once the acute episode has resolved, a number of measures are taken to reduce the likelihood of recurrence:

Drugs to keep uric acid levels within a normal range Controlled weight loss in obese individuals Avoidance of known precipitating factors such as heavy alcohol consumption or a diet rich in purines Low doses of colchicineto prevent further acute attacks Several dietary factors are known to cause gout: consumption of alcohol; high purine-containing foods (e.g., organ meats, meat, yeast, poultry); fats; refined carbohydrates; and overconsumption of calorie^.^,^ Individuals with gout are typically obese, prone to hypertension and diabetes, and at a greater risk for cardiovasculardisease. Obesity is probably the most important dietary factor."' In concept, the naturopathic approach for chronic gout does not differ substantially from the standard medical approach: Dietary and herbal measures are employed instead of drugs to keep uric acid levels within the normal range. Obese individuals are put on a careful weight loss program. Known precipitating factors such as heavy alcohol consumption and numerous dietary factors are controlled. Nutritional substances are used to prevent further acute attacks.

gout, can result from lead toxicity?-9 Historically, saturnine gout was due to the consumption of alcoholic beverages stored in containers with lead in them? An unexpected and fairly common source of lead appears to be leaded crystal, as port wine elutes lead when stored in a crystal decanter.1°Lead concentration increases with storage time, reaching toxic levels after several months. Even a few minutes in a crystal glass results in a measurable increase in the level of lead in the wine. The mechanism of action is related to a decrease in renal urate excretion.

Dietary Considerations The dietary treatment of gout involves the following guidelines: Elimination of alcohol intake Low purine intake Achievement of ideal body weight Liberal consumption of complex carbohydrates Low fat intake Low protein intake Liberal fluid intake

.

Alcohol Alcohol increases uric acid production by accelerating purine nucleotide degradation and reduces uric acid excretion by increasing lactate production (a result of ethanol oxidation), which impairs kidney function. The net effect is a sigruficant increase in serum uric acid levels. This explains why alcohol consumption is often a precipitating factor in acute attacks of gout. Elimination of alcohol is all that is necessary to reduce uric acid levels and prevent gouty arthritis in many individuals.6,7J1

Low-Purine Diet A low-purine diet has been the mainstay of the dietary therapy of gout for many years. However, with the advent of potent drugs that lower uric acid levels, many physicians lower the serum urate levels without subjecting the patient to the inconvenience and deprivation associated with a purine-free diet. However, dietary restriction of purines is recommended to reduce metabolic stress. Foods with high purine levels should be entirely omitted. These include organ meats, meats, shellfish, yeast (brewer's and baker's), herring, sardines, mackerel, and anchovies. Foods with moderate levels of protein should be curtailed as well. These include dried legumes, spinach, asparagus, fish, poultry, and mushr0oms.6~~

Lead Toxicity

Weight Reduction

An additional item of concern relates to lead toxicity. A secondary type of gout, sometimes called saturnine

Excess weight is associated with an increased rate of gout.12Weight reduction in obese individualssigruficantly

Gout reduces serum uric acid levels. Weight reduction should involve the use of a low-glycemic diet designed to improve insulin sensitivity.13J4Such a diet also helps to manage the elevated cholesterol and triglycerides that are common in obesity. This diet is also an alkaline ash diet, recommended in the dietary treatment of gout, because a more alkaline pH increases uric acid solubility.

Carbohydrates, Fats, and Protein Refined carbohydrates and saturated fats should be kept to a minimum, as the former increase uric acid production while the latter increase uric acid retention.6,7J5J6 In addition, one of the key dietary goals in the treatment of gout appears to be to enhance insulin sen~itivity.'~J~ Protein intake should not be excessive (i.e., >0.8 g/kg body weight), as it has been shown that uric acid synthesis may be accelerated in both normal and gouty patients by a high protein intake.6Adequate protein is necessary (0.8 g/kg body weight); however, amino acids decrease resorption of uric acid in the renal tubules, thus increasing uric acid excretion and reducing serum uric acid c~ncentrations.~

Fluid Intake Liberal fluid intake keeps the urine dilute and promotes the excretion of uric acid. Furthermore, dilution of the urine reduces the risk of kidney stones?

Nutritional Supplements Eicosapentaenoic Acid Eicosapentaenoic acid (EPA) supplementation may prove useful in the treatment of gout. EPA limits the production of the proinflammatory leukotrienes, the mediators of much of the inflammation and tissue damage observed in gout.17Js

Vitamin E Vitamin E is indicated in the treatment of gout because it also (mildly) inhibits the production of leukotrienes and acts as an a11ti0xidant.l~ Selenium functions synergistically with vitamin E.

Folic Acid Folic acid has been shown to inhibit xanthine oxidase, the enzyme responsible for producing uric acid.20 The drug allopurinol, used in the medical treatment of gout, is a potent inhibitor of this enzyme. Research has demonstrated that a derivative of folic acid is an even greater inhibitor of xanthine oxidase than allopurinol, suggesting that folic acid at pharmacologic doses may be an effective treatment in gout.21Positive results in the treatment of gout have been reported, but the data are incomplete and uncontrolled.22

Bromelain The proteolytic enzyme of pineapple has been demonstrated to be an effective antiinflammatory agent in both clinical human studies and experimental animal models.u It is a suitable alternative to stronger prescription antiinflammatory agents used in the treatment of gout. For best results, bromelain should be taken between meals (for further discussion of this useful antiinflammatory agent, see Chapter 73).

Quercetin The bioflavonoid quercetin has demonstrated several effects in experimental studies that indicate its possible benefit to individuals with Quercetin may offer sigruficant protection by inhibiting the following: Xanthine oxidase in a similar fashion to the drug all~purin~l~~ Leukotriene synthesis and relea& Neutrophil accumulation and enzyme releaseE For best results, quercetin should be taken with bromelain between meals (bromelain is believed to enhance the absorption of quercetin and other medicationsz7).

Alanine, Aspartic Acid, Glutamic Acid, and Glycine These amino acids have been shown to lower serum uric acid levels, presumably as a result of decreasing uric acid resorption in the renal tubule. This results in an increase in uric acid excretion.6J2

Vitamin C Megadoses of vitamin C are probably contraindicated in individuals with gout, as vitamin C may increase uric acid levels in a small number of individuals.28

Niacin High doses of niacin (i.e., above 50 mg/day) are probably contraindicated in the treatment of gout, as niacin competes with uric acid for excreti0n.2~

Botanical Medicines Cherries Consuming one-half pound of fresh or canned cherries per day has been shown to be effective in lowering uric acid levels and preventing attacks of gout.30To assess the physiologic effects of cherry consumption, one study measured plasma urate and antioxidant and inflammatory markers in 10 healthy women who consumed two servings (280 g) of cherries after an overnight fast.31Blood and urine samples were taken before the cherry dose and at 1.5,3, and 5 hours afterwards. Plasma urate decreased 5 hours after the cherry consumption by an average of 30 pmol/L. This reduction correlated with an increased urine urate excretion. Plasma C-reactive

protein and nitric oxide concentrations decreased slightly after the %hour mark. Cherries, hawthorn berries, blueberries, and other dark red and blue berries are rich sources of anthocyanidins and proanthocyanidins. These compounds are flavonoid molecules, which give these fruits their deep red-blue color, and are remarkable in their ability to prevent collagen destru~tion.~~3~ Anthocyanidins and other flavonoids affect collagen metabolism in many ways:

by following simple dietary changes in most instances, the use of Devil’s claw in the long-term management of gout is probably unnecessary.

.They have the unique ability to actually cross-link collagen fibers, resulting in reinforcement of the natural cross-linking of collagen that forms the collagen matrix of connective tissue (e.g., ground substance, cartilage, tendon).32-34 They prevent free radical damage through their potent antioxidant and free radical scavenging They inhibit enzymatic cleavage of collagen by enzymes secreted by leukocytes during inflammation.M35 They prevent the release and synthesis of compounds that promote inflammation such as histamine, serine proteases, prostaglandins, and leuk~trienes.~~

Dietary and herbal measures that maintain uric acid levels within the normal range Controlled weight loss in obese individuals Avoidance of known precipitating factors (such as heavy alcohol consumption and a high-purine diet) The use of nutritional substances to prevent further acute attacks The use of herbal and nutritional substances to inhibit the inflammatory process

Harpagophytum procumbens (Devil’s claw) Harpagophytum procumbens, or Devil’s claw, has been used in folk medicine for the treatment of various diseases including gout and rheumatoid arthritis. Clinical research in Europe appears to indicate Devil’s claw may be of benefit in the treatment of gout. In addition to relieving joint pain, clinical trials found that Devil’s claw also reduced serum cholesterol and uric acid levels.% Several pharmacologic studies using experimental models of inflammation in animals have reported that Devil’s claw possesses an antiinflammatory and analgesic effect comparable to the potent drug phenylbutazone.3’ However, other studies have indicated that Devil’s claw has little, if any, antiinflammatory The equivocal research results found in experimental models may reflect a mechanism of action that is inconsistent with current antiinflammatory drugs or a lack of quality control (standardization) of the preparations used. Further clinical research is necessary to clanfy these inconsistencies. At this time it can be stated that Devil’s claw may be useful in the short-term management of gout. However, because gout can be successfully prevented and treated

1. Robbins SL, Cotran RS, Kumar V. Pathologic basis of disease, ed 3. Philadelphia: Saunders, 1984.1356-1361. 2. Petersdorf RG, Harrison, TR. Harrison’s principles of internal medicine, ed 10. New York McGraw-Hill, 1983:517-524.

THERAPEUTIC APPROACH As stated earlier, the naturopathic approach to the prevention and treatment of gout does not differ substantially from the standard medical approach. The basic approach involves the following:

Diet Eliminate alcohol intake, maintain a low-purine diet, increase consumption of complex carbohydrates, decrease consumption of simple carbohydrates, maintain a low fat intake, optimize protein intake (0.8 g/kg body weight), and consume liberal quantities of fluid. Urinary 24hour uric acid levels can be used to monitor compliance with a purine-free diet (maintained below 0.8 g/day). In addition, liberal amounts (250 to 500 g/day) of cherries, blueberries, and other anthocyanoside-rich (i.e., red-blue) berries (or extracts),should be consumed.

Nutritional Supplements EPA 1.8 g/day Vitamin E: 400 to 800 IU/day Folic acid: 10 to 40 mg/day Bromelain: 125 to 250 mg tid between meals Quercetin: 125 to 250 mg tid between meals

Botanical Medicines H . procumbens Dried powdered root: 1 to 2 g three times/day Tiicture (1:5): 4 to 5 ml three times/day Dry solid extract (3:l): 400 mg three times/day Anthocyanoside extracts (e.g., Vaccinium rnyrtillus): equivalent to 80 mg anthocyanoside content daily

3. Nutrition Foundation. Nutritionreviews’pment knowledge in nutrition, ed 5. Washington, DC:NutritionFoundation, 1984:740-756. 4. Krause MV, Mahan LK. Food, nutrition, and diet therapy: a textbook of nutritional care, ed 7. Philadelphia:Saunders, 19M677-679.

Gout 5.Faller J, Fox M. Ethanol-induced hyperuricemia: evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med 1982;3071598-1602. 6. Pi-Sunyer FX. The fattening of America. JAMA 1994;272238-239. 7. Scott JT. Obesity and hyperuricemia. clin Rheum Dis 1977;3:25-35. 8. Emmerson BT. Effect of oral fructose on urate production. Ann Rheum Dis 1974;33:276-280. 9. Terano T, Salmon JA, Higgs GA, Moncada S. Eicosapentaenoic acid as a modulator of inflammation. Effect on prostaglandin and leukotriene synthesis. Biochem Pharmacol1986;35:779-785. 10. Ford-Hutchinson AW. Leukotrienes: their formation and role as inflammatory mediators. Fed Proc 1985;M.E-29. 11. Panganamala RV, Cornwell DG. The effects of vitamin E on arachidonic acid metabolism. Ann N Y Acad Sci 1982;393:376-391. 12. Lewis AS, Murphy L, McCalla C, et al. Inhibition of mammalian xanthine oxidase by folate compounds and amethopterin. J Biol Chem 1984;25912-15. 13.Schlesinger N, Schumacher HR Jr. Gout: can management be improved? Curr Opin Rheumatol2001;13:240-244. 14. Dessein PH, Shipton EA, Stanwix AE, et al. Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum Dis 2000;59539-543. 15. Spector T, Ferone R. Folic acid does not inactivate xanthine oxidase. J Biol Chem 1984;25910784-10786. 16.Oster KA. Folic acid and xanthine oxidase. Ann Intern Med 1977;86367. 17. Taussig SJ, Yokoyama MM, Chinen A, et al. Bromelain, a proteolytic enzyme and its clinical application. A review. Hiroshima J Med Sci 1975;24:185-193. 18. Bindoli A, Valente M, Cavallini L. Inhibitory action of quercetin on xanthine oxidase and xanthine dehydrogenase activity. PharmACOL Res Commun 1985;17:831-839. 19. Busse WW, Kopp DE, Middleton E Jr. Flavonoid modulation of human neutmphjl function. J Allergy Clin Immuno11984;73801-809. 20. Yoshimoto T, Furukawa M, Yamamoto S, et al. Flavonoids: potent inhibitors of arachidonate 5-lipoxygenase. Biochem Biophys Res C O ~ 1983;116612-618. U ~ 21.Luerti M, Vignali M. Influence of bromelain on penetration of antibiotics in uterus, salpinx and ovary. Drugs Exp Clin Res 1978; 445-48.

=.Stein HB, Hasan A, Fox IH.Ascorbic acid-induced uricosuria. A consequence of megavitamin therapy. Ann Intern Med 1976;84: 385-388. 23.Gershon SL, Fox M.Pharmacologic effects of nicotinic acid on human purine metabolism. J Lab Clin Med 1974;&4:179-186. 24. Blau LW. Cherry diet control for gout and arthritis. Texas Rep Biol Med 1950;8309-311. 25. Gabor M. Pharmacologic effects of flavonoids on blood vessels. Angiologica 1972;9:355-374. 26. Kuhnau J. The flavonoids. A class of semi-essential food components: their role in human nutrition. World Rev Nutr Diet 1976; 24117-191. 27. Havsteen B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharmacol1983;32:1141-1148. 28. Middleton E. The flavonoids. Trends Pharmacol Sci 1984;5:335-338. 29. Duke JA. CRC handbook of medicinal herbs. Boca Raton, E CRC Press, 1985, p 222. 30. Tyler VE,Brady LR,Robbers JE. Pharmacognosy,ed 8. Philadelphia: Lea & Febiger, 1981, pp 480. 31. Jacob RA, Spinozzi GM, Simon VA, et al. Consumption of cherries lowers plasma urate in healthy women. J Nutr 2003;133:1826-1829. 32.Whitehouse LW, Znamirowski M, Paul CJ. Devil’s claw (Harpagophyturn procumbens): no evidence for anti-inflammatory activity in the treatment of arthritic disease. Can Med Assoc J 1983; 129249-251. 33. McLeod DW, Revell P,Robinson BV. Investigationsof Harpagophyturn procurnbens (Devil’s claw) in the treatment of experimental inflammation and arthritis in the rat. Br J Pharmacoll979;66:140P-l41P. 34.Ball GV, Sorensen LB. Pathogenesis of hyperuricemia in saturinine gout. N Engl J Med 1969;2801199-1202. 35.Appelboom T, Bennett JC. Gout of the rich and famous. J Rheumatol1986;13618-622. 36. Krupp MA, Chatton MJ. Current medical diagnosis and treatment. Los Altos, CA: Lange Medical Publications, 1974519-522. 37. Rubenstein E, Federman DD, eds. Scientific American medicine. New York Scientific American, 1986:9: IV-1-5, 15: IX-1-11, 38. Wyngaarden JB, Kelly WN. Gout. In Stanbury JB, Wyngaarden JB, Fredrickson DS,eds. The metabolic basis of inherited disease, ed 4. New York McGraw-Hill, 1978:918,920. 39. Graziano JH, Blum C. Lead exposure f?om lead crystal. Lancet 1991337141-142.

Hair Loss in Women Michael T. Murray, ND CHAPTER CONTENTS Introduction 1711

Hypothyroidism 1712 Antigliadin Antibodies 1712

Basic Physiology of the Hair Cycle 1711 Conclusion 1713 Causes of Hair Loss in Women and Therapeutic Considerations 1711 Androgenic Female Pattern Hair Loss 1711 Drug-Induced Hair Loss 1712 Nutritional Deficiency 1712

INTRODUCTION In clinical practice, one of the most common complaints from female patients is excessive hair loss. In most cases it is not severe alopecia, but rather the perception that hair loss is occurring at an increasing rate. Often these complaints are dismissed, as minor hair loss is difficult to quantdy and it is certainly not a life-threatening disorder. However, the patient wants an answer as to why it is happening, so it is important to address it.

BASIC PHYSIOLOGY OF THE HAIR CYCLE Between 100,000 and 350,000 hair follicles occupy the human scalp, but not all of these hairs undergo cyclical phases of growth and rest. During the growth (anagen) phase there is active genetic expression of protein synthesis. As the hair matures, it enters into a resting stage. Then the hair bulb migrates outward and eventually is sloughed. It is during this migratory phase that the stage is set for new hair to fill the remaining papilla after the original hair is lost. Age, pathology, and a wide variety of nutritional and hormonal factors influence the duration of the hair cycle. Generally speaking, hair loss is a normal part of aging. By the age of 40 or so, the rate of hair growth slows down. New hairs are not replaced as quickly as old ones are lost. Both men and women suffer from age-related hair loss, but the problem is more apparent in men due to the effects of androgens.

CAUSES OF HAIR LOSS IN WOMEN AND THERAPEUTIC CONSIDERATIONS Five common causes of hair loss in women are: (1)androgenic female pattern hair loss; (2) drugs; (3) nutritional deficiencies; (4) hypothyroidism; and (5) the presence of antigliadin antibodies.

Androgenic Female Pattern Hair Loss Women can suffer from androgen-related hair loss just like men.14 The female pattern hair loss, however, is more diffuse than the characteristic male pattern, so it is referred to as "diffuse androgen-dependent alopecia" or "female pattern hair 10~s."~ It is a relatively common condition.In fact, one report states that it affects approximately 30% of women before the age of 50.' Although genetic factors are clearly sigrhcant, androgen excess, insulin resistance, the polycystic ovarian syndrome, and low antioxidant (i.e., reduced glutathione) status are also associated with female pattern hair Three possible recommendations to help slow down this genetically predisposed process are: (1) improve blood glucose regulation through dietary, lifestyle, and supplementary measures (see Chapter 178); (2) increase antioxidant intake; (3) consider saw palmetto extract; and (4) consider hormone replacement therapy. Reactive oxygen species have been shown to play a central role (along with testosterone) in male pattern baldness. Higher levels of these damaging compounds are found in the hair follicles in men (and presumably women) with male pattern baldness? This appears due 1711

Specific Health Problems to lower levels of glutathione. Because vitamin C and E can help preserve glutathione, the recommendation of supplemental vitamin C (1000 to 1500 mg daily divided dosages) and vitamin E (400 IU daily) seems appropriate. Saw palmetto extract is a popular recommendation for benign prostatic hyperplasia (BPH). It is effective in BPH as a result of several mechanisms of action including an ability to inhibit the formation and transport of dihydrotestosterone (DHT). This potent androgen is formed from testosterone by the action of the enzyme 5-alpha-reductase.The activity of thisenzyme is inmased in BPH, as well as in either male or female pattern baldness.6 Saw palmetto extract may offer some benefit in androgen-related alopecia by reducing the formation of DHT. This is the same mechanism as the drug finasteride (Propecia), which is often used in female pattern hair loss? Saw palmetto extract also inhibits the transport of DHT to nuclear receptor sites and therefore may prove even more useful. The dosage for the extract standardized to contain 85% to 95% fatty acids and sterols is 320 mg per day.

Drug-Induced Hair Loss A long list of drugs can cause hair loss, but it should not be interpreted that simply because a woman is complaining of hair loss and is taking one of these drugs that the drug is the single cause of her hair loss. Of course, for some drugs, most notably chemotherapy agents like fluorouracil; they are obviously the cause because they are such powerful inhibitors of hair growth. When medically appropriate, natural altematives to suspected culprits of hair loss should be employed (Table 172-1).

Nutritional Deficiency A deficiency of any number of nutrients can lead to significant hair loss. Zinc, vitamin A, essential fatty acids, and iron should be ruled out first. The patient's nails should be examined for the characteristic white lines that indicate poor wound healing of the nail bed even with the most minor of trauma, which may be a sign of low zinc levels. The back of their arms should be examined for hyperkeratosis, a common sign of vitamin A deficiency. The elbows and general health of the skin should also be examined, looking for the dry skin associated with essential fatty acid deficiency. For evaluating iron status, a serum ferritin evaluation is recommended. When evaluating serum ferritin levels, it is important to know that many reference laboratories report low ferritin levels (e.g., 10 to 30 pg/L) to be within the normal range. If the serum ferritin is less than 30 pg/L, iron replacement is indicated. When serum ferritin levels fall below this level, hair growth and regeneration is impaired, as the body seeks to conserve the iron.IO

Classes of drugs that can cause hair loss Class

Examples

Antibiotics

Gentamycin, chloramphenicol Coumadin, heparin

Anticoagulants Antidepressants

Prozac, desipramine, lithium

Antiepileptics

Valproic acid, Dilantin

Cardiovascular drugs

Angiotensin-converting enzyme inhibitors, beta-blockers

Chemotherapy drugs Endocrine drugs

Adriamycin, vincristine, etoposide Bromocriptine, Clomid, danazol

Gout medications

Colchicine, allopurinol

Lipid-loweringdrugs Nonsteroidalantiinflammatory drugs Ulcer medications

Gemfibrozil, fenofibrate Ibuprofen, indomethacin, naproxen Tagamet, Zantac

Modified from Van Neste DJJ, Rushton H.Clin Dermatol 1997;15:113-125.

Typically, women with noticeable generalized hair loss suffer from apparent deficiencies of all of these nutrients. The treatment of hair loss secondary to nutritional deficiency is straightforward-increase dietary intake of these nutrients and supplement appropriately. One caveat is that many of these women turn out to be hypochlorhydric. In these cases, hydrochloric acid supplementationat meals may be all that is necessary. A general recommendation for women with hair loss related to nutritional status is to take a high-potency multivitamin and mineral formula that contains iron, along with 1 tablespoon of flaxseed oil per day. If serum ferritin levels are below 30 pg/L, women can supplement with additional iron, either 30 mg of iron bound to succinate, fumarate, or other chelate twice daily between meals. If this recommendation results in abdominal discomfort, the clinician can recommend 30 mg with meals three times daily. After 2 months, reassess serum ferritin levels. Improvements in serum ferritin often correlate with improved health of the hair and the halting of excessive hair loss.

Hypothyroidism It is a well-known fact that hair loss is one of the cardinal signs of hypothyroidism. Using blood levels of thyroid hormones as the criteria, an estimated 1%to 4% of the adult population has moderate to severe hypothyroidism, and another 10% to 12% have mild hypothyroidisrn."J2 The prevalence of hypothyroidism in American women is estimated to be as high as 20% even among conventional medical circles.

AntigIiadin Antibodies The protein gluten and its polypeptide derivative, gliadin, are found primarily in wheat, barley, and rye grains.

Hair Loss in Women It appears that antibodies to gliadin can lead to crossreacting antibodies that attack the hair follicles, leading to alopecia areata-an autoimmune disease characterized by areas of virtually complete hair 10ss.l~ Celiac disease, also known as nontropical sprue, glutensensitive en teropathy, or celiac sprue, is characterized by malabsorption and an abnormal small intestine structure that reverts to normal on removal of dietary gluten. Evidence is growing that many people with gluten intolerance do not have overt gastrointestinal symptoms. Instead, they may demonstrate gluten intolerance as insidiously as hair loss. Rather than testing for antigliadin antibodies in patients with general hair loss or alopecia areata, the test for human antitissue transglutaminase antibodies (IgA anti-tTG) is recommended, as it has a greater sensitivity compared with antigliadin antibodies (see Chapter 156). This recommendation is especially important with the presence of any gastrointestinal symptoms suspicious of celiac disease (Box 172-1).

Hair loss in women should not be dismissed. Although some hair loss is a natural part of the aging process, complaints of excessive or accelerated hair loss should be investigated and treated appropriately. Clinical studies have investigated the psychologic impact of increasing hair loss in women and found that is a significant source of anxiety, fear, and depression.'^^ Conversely, increasing the health of the hair results in improvement in general health, especially mental health, in these patients.

1.Van Neste DJJ, Rushton H. Hair problems in women. Clin Dermatol 1997;15:113-125. 2.Azziz R, Sanchez LA, Knochenhauer ES, et al. Androgen excess in women: experience with over lo00 consecutive patients. J Clin Endocrinol Metab 2004;89:453-462. 3. Price VH. Androgenetic alopecia in women. J Investig Dermatol Symp Proc 2003;8:2427. 4. Birch MP, Lalla X, Messenger AG. Female pattern hair loss. Clin Exp Dermatol2002;27383-388. 5.Giralt M, Cervello I, Nogues MR, et al. Glutathione, glutathione Stransferase and reactive oxygen species of human scalp sebaceous glands in male pattern baldness. J Invest Dermatol1996;107:154-158. 6. Legro RS, Carmina E, Stanczyk FZ, et al. Alterations in androgen conjugate levels in women and men with alopecia. Fertil Steril 1994;62:744-750. 7. Cela E, Robertson C, Rush K, et al. Prevalence of polycystic ovaries in women with androgenic alopecia. Eur J Endocrino12003;149439-442.

8. Matilainen V, Laakso M, Hirsso P, et al. Hair loss, insulin resistance, and heredity in middle-aged women. A population-based study. J Cardiovasc Risk 2003;10227-231. 9.Shum KW, Cullen DR, Messenger AG. Hair loss in women with hyperandrogenism: four cases responding to finasteride. J Am Acad Dermatol2002;47733-739. 10. Kantor J, Kessler LJ, Brooks DG, et al. Decreased serum ferritin is associated with alopecia in women. J Invest Dermatol 2003;12: 985-988. 11. Wang C, Crapo LM. The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am 1997; 26189-218. 12. Arem R, Escalante D. Subclinical hypothyroidism: epidemiology, diagnosis, and sipficance. Adv Intern Med 1996;41:213-250. 13. Corazza GR, Andreani ML, Venturo N, et al. Celiac disease and alopecia areata: report of a new association. Gastroenterology 1995; 1W1333-1337.

Bulky, pale, frothy, foul-smelling, greasy stools with increased fecal fat Weight loss and signs of multivitamin and mineral deficiencies Increased levels of serum gliadin antibodies Diagnosis can be confirmed by jejunal biopsy ~

~

CONCLUSION

Hepatitis Michael T. Murray, ND Peter B.Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

1715

General Considerations 1715 Diagnostic Considerations 1715

Therapeutic Approach 1720 Diet 1720 Nutritional Supplements 1720 Botanical Medicines 1720 Berkson Combination Antioxidant Approach 1721

Therapeutic Considerations 1716 Prevention 1716 Nutritional Considerations 1717 Botanical Medicines 1718

DIAGNOSTIC SUMMARY Prodrome of anorexia, nausea, vomiting, fatigue, and flulike symptoms that can occur 2 weeks to 1 month before liver involvement, depending on the incubation period of the virus Symptoms may occur abruptly or rather insidiously Fever; enlarged, tender liver; jaundice Dark urine Normal to low white blood cell count, markedly elevated aminotransaminases, elevated bilirubin levels

GENERAL CONSIDERATIONS Hepatitis is characterized by liver inflammation or injury with hepatic cell necrosis. It may be caused by many drugs, toxic chemicals, bacterial or fungal infections, immune disorders, metabolic diseases, hepatic perfusion and oxygenation problems> but in most instances it has a viral etiology, with types A, B, and C being the most common. Hepatitis A is caused by a virus from the Picornaviridae family, occurs sporadically or in epidemics, and is transmitted primarily through fecal contamination,with a high prevalence in areas having poor sanitation. Hepatitis 8, accounting for 50% of viral cases in the United States, is transmitted through infected blood or blood products, as well as through sexual contact (the virus is shed in saliva, semen, and vaginal secretion). Hepatitis C (formerlyknown as hepatitis non-A, non-B), a Hepaciuinrs and member of the Flaviviridae family, has its primary

route of transmission through blood transfusion. In fact, it is responsible for roughly 90% of all cases of hepatitis through blood transfusions (about 10% of people receiving blood transfusionsin the past developed hepatitis C). However, only 4% of cases of hepatitis C are a result of transfusions. Most cases are due to intravenous (IV) drug use, but in others the source of infection is unclear. The mortality rate (1% to 12%) is much higher than for the other forms. Other viral causes of hepatitis include hepatitis viruses D, E, and G, as well as herpes simplex, cytomegalovirus, and Epstein-Barr virus. Hepatitis can be classified as acute when duration is short and as chronic when it lasts more than 6 months. Acute viral hepatitis can be an extremely debilitating disease requiring bedrest and anywhere from 2 to 16 weeks for recovery. Most patients recover completely (usually by 9 weeks for type A and 16 weeks for types B, C, D, and G). However, about 1 in 100 die, and 10% of hepatitis B and 10% to 40% of hepatitis C cases now develop into chronic viral hepatitis forms (hepatitis C contracted from a transfusion is associated with a 70% to 80% development of chronic hepatitis). The symptoms of chronic hepatitis vary from virtually nonexistent to chronic fatigue, serious liver damage, and even death.

DIAGNOSTIC CONSIDERATIONS Diagnosis is suspected when the typical signs and symptoms (Table 173-1)are present. Diagnosis is confirmed by blood tests for elevated liver enzymes and the presence 1715

Specific Health Problems of viral antigens or virus-specific antibodies. The type of specific viral virus involved is determined by iden-g antigens or antibodies in the blood. In cases of chronic hepatitis B or C, it is necessary to perform serologic evaluation to monitor progression or clearance. In addition to liver enzymes, hepatitis C is monitored by the presence of hepatitis C viral RNA by polymerase chain reaction (HCV-RNA[PCR]). Table 173-2 lists hepatitis B serologic findings and their interpretation.

Serologic patterns and their interpretations in hepatitis B HbsAg Anti-HBS Anti-HBc HBeAa Anti-HBe InterDretation

+

+ -

~~

Incidence of symptoms in viral hepatitis Symptom

Percentage of patients

Dark urine Fatigue

94

Loss of appetite

90

Nausea

87

Fever

76

Vomiting

71

Headache

70

Abdominal discomfort

65

tight stools

52

Muscle pain Drowsiness

52 49

lrritabillty

43

Itching

42

Diarrhea

25

Joint pain

21

91

Modified from Schuppan D, Krebs A, Bauer M, et al. Cell Death Differ 2003;10(SUppl 1):559-67.

Acute hepatitis B

-

Chronic active hepatitis B

i-

THERAPEUTIC CONSIDERATIONS The best available allopathic treatment for hepatitis is the combination of pegylated interferon and ribavirin. Unfortunately this regimen is costly, fraught with side effects, and eradicates hepatitis C in only 50% to 70% of patients at best? However, patients with hepatitis can greatly benefit from natural therapies. Several nutrients and herbs have been shown to inhibit viral reproduction, improve immune system function, and greatly stimulate regeneration of the damaged liver cells. General therapies to protect and support the liver are discussed in more detail in Chapter 54. Those recommendations can be used in conjunction with the more specific recommendations given in this chapter. With regard to chronic hepatitis, it is absolutely essential to be aggressive in the treatment of this condition due to the increased risk for hepatocellular carcinoma

-

Chronic inactive hepatitis B

+or-

+or-

Chronic hepatitis B

+ or -

+or-

Acute hepatitisB

-

+or-

Recovery from hepatitis 6

-

-

Vaccinated against hepatitis B

-

-

False positive or infection in remote past

HBC, Hepatitis B core antigen; H W g , hepatitis B secretory antigen: HBsAG, hepatitis surface antigen; /gG, immunoglobulin G; /gM, immunoglobulin M.

and cirrhosis. If cirrhosis is present in chronic hepatitis B, for example, the 5-year survival rate is only 50% to 60%.

Prevention Hepatitis A For primary prevention of hepatitis A, the Centers for Disease Control recommends vaccination for (1) children living in areas with high rates of hepatitis A; (2) people at increased risk, such as travelers to endemic regions, men having sex with men, illegal drug users, workers in research laboratories who work with hepatitis A, and individuals with clotting factor disorders; (3) persons with chronic liver disease, especially chronic hepatitis B or C; and (4) outbreaks in communities with higher intermediate rates of hepatitis A? The vaccination has also been effective at curbing outbreaks when administered in a timely fa~hion.~ Postexposure prophylaxis consisting of specific hepatitis A immunoglobulins should be given intramuscularly during the first 2 weeks after an individual has been e ~ p o s e d . ~

Hepatitis B For primary prevention of hepatitis B, vaccination is prudent for high-risk occupations such as members of the medical and dental fields who are regularly exposed to blood and other body fluids. In the case of acute exposure to the hepatitis B virus (HBV), hyperimmune globulin (HBIG) is administered intramuscularly and is a concentrated solution of immune globulins specific to HBV. It is given to individuals who are known to be exposed to HBV. It confers

Hepatitis ~~

immediate but short-lived passive immunity,which lasts for 3 months. Two doses of HBIG are given within 2 weeks of the exposure,and it is said to confer adequate protective immunity to 75% of exposed individuals. HBIG administration is recommended for individuals exposed to HBV surface antigen-contaminated material via mucous membranes or through breaks in the skin. Newborns with hepatitis B surface antigen (HBsAg)positive mothers should also receive the vaccine (0.5 ml shortly after birth and at ages 3 and 6 months).

Hepatitis C As there is currently no vaccine for hepatitis C, prevention entails minimizing routes of infection. Because 50% to 80% of IV drug abusers get infected during the first year, drug abuse modification is the most important risk f a ~ t o rCessation .~ of IV drug use or using only unused, clean, sterile needles can help curb this transmission route. Similarly, mod@ng or ceasing intranasal cocaine use decreases risk.Accepting transfusionsfrom known uncontaminated blood sources also curtails a major risk factor. Health care workers should practice strict occupational safety and health standards of practice, especially when dealing with blood products, and should never recap used needles to avoid needle stick transmission. Although sexual transmission is an inefficient method of transfer, the risk is higher in male homosexuals, patients with multiple sexual partners, and those with sexually transmitted disease^.^ Someone in a monogamous heterosexual relationship with a hepatitis C patient has a low risk of infection unless the patient is coinfected with hepatitis C and human immunodeficiencyvirus.

Nutritional Considerations Diet During the acute hepatitis phase, the focus should be on replacing fluids through consumption of vegetable broths, diluted vegetable juices (diluted with 50% water), and herbal teas. Solid foods should be restricted to brown rice, steamed vegetables, and moderate intake of lean protein sources. In chronic cases, follow the dietary recommendations given in Chapter 44.The diet should be low in saturated fats, simple carbohydrates (e.g., sugar, white flour, fruit juice, honey), oxidized fatty acids (fried oils), and animal products. A diet that focuses on plant foods (i.e., a highfiber diet) has been shown to increase the elimination of bile acids, drugs, and toxic bile substances from the system. Alcohol should be completely avoided.

Vitamin C According to nutritional medicine pioneer Robert Cathcart, MD, acute hepatitis is one of the easiest diseases for vitamin C to cure?*' Cathcart demonstrated that high dosages of vitamin C (40to 100g orally or intravenously)

were able to greatly improve acute viral hepatitis in 2 to 4 days and to clear jaundice within 6 days? Other studies demonstrated similar A controlled study found that 2 g/day or more of vitamin C was able to dramatically prevent hepatitis B in hospitalized patients. Although 7"/0of the control patients (receiving4 . 5 g/day of vitamin C) developed hepatitis, none of the treated patients did."

Selenium Selenium is a trace element required for the activity of the enzyme glutathione peroxidase, an oxidant mediator essential for human health. Its deficiency is associated with various pathologies including immune dysfunction, cancer, and liver necrosis. Whole blood and plasma selenium levels in 59 patients with chronic liver pathologies including alcoholic and viral liver cirrhosis were found to be significantly lower when compared with healthy controls.12Another study of hepatocellular carcinoma cell lines reveals that liver cancer cells are able to acquire a selective survival advantage that is prominent under selenium-deficient and oxidative-stress condition~.'~ Oxidant stress is a well-known feature in latestage cirrhotic liver disease, and subsequent study has found oxidant stress occurring much earlier than previously ~0nsidered.l~ Given this information and the safety of selenium when used in doses under lo00 pg, it is reasonable to employ selenium in a hepatitis protocol.

Alpha-lipoic Acid First isolated in 1951, alpha-lipoic acid (thiocticacid) is a disulfide compound that helps lower the level of liver enzymes. It has been found to be a useful antioxidant in the treatment of diabetes15and AIDS16and as a toxic metal chelat~r,'~ and it may prove beneficial in treating age-related cardiac myopathie~.'~J~ Alpha-lipoic acid is produced in small quantities in cells and functions naturally as a coenzyme in the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase mitochondria1 enzyme c~mplexes.'~ Alpha-lipoic acid has been successfully used as a hepatoprotectant to treat a number of conditions relating to liver disease including alcoholinduced damage, metal intoxification, carbon tetrachloride poisoning, and amanita mushroom poisoning.2o A complement of B vitamins should be coadministered with alpha-lipoic acid supplementation, for it may deplete these vitamins?' Pharmacologic doses of 600 mg/day seem to garner the best results. Some studies are also beginning to focus on the "R" form of alphalipoic acid, as it may be more effective than the commercially available "R and S" racemic mixture.l6

Liver Extracts The oral administration of liver extracts has been used in the treatment of many chronic liver diseases since 1896.

Specific Health Problems Numerous scientific investigations into the therapeutic efficacy of liver extracts have demonstrated that these extracts promote hepatic regeneration and are quite effective in the treatment of chronic liver disease including chronic active he pa ti ti^.^-^^ For example, in one double-blind study, 556 patients with chronic hepatitis were given either 70 mg of a liver extract or a placebo three times daily.24At the end of 3 months of treatment, the group receiving the liver extract had far lower liver enzyme (aminotransaminases) levels. Because the level of liver enzymes in the blood reflects damage to the liver, it can be concluded that the liver extract is effective in chronic hepatitis via an ability to improve the function of damaged liver cells, as well as prevent further damage to the liver.

Thymus Extracts Good clinical data support the effectiveness of orally administered bovine thymus extracts in acute and chronic viral hepatitis (see Chapter 57 for additional information on the thymus gland). The effectiveness of the thymus extract in viral hepatitis is reflective of broad-spectrum immune system enhancement presumably mediated by improved thymus gland activity. Several double-blind studies in both acute and chronic cases of type B viral hepatitis have shown thymus extracts to be effective. In these studies, therapeutic effect was noted by accelerated decreases of liver enzymes (transaminases), elimination of the virus, and a higher rate of seroconversion to anti-me, signifymg clinical remission.25z6

Botanical Medicines Although long-term clinical trials have yet to confirm the efficacy of plant several have been investigated for their effects in viral hepatitis. The two with the most positive documentation are licorice (Glycyrrhiza glubra) and silymarin (the flavonoid complex from milk thistle [Silybum mariunuml). A third, catechin (from Uncuriu gambir), is effective but is associated with potentially serious side effects in rare cases (see Chapter 77). A fourth, Phyllunthus arnurus, sparked considerable excitement on the basis of preliminary results, but detailed follow-up studies showed it to provide no benefit. Some botanicals that are appropriate for other health conditions may not be suitable for acute and chronic liver diseases.

Glycyrrhiza glabra (Licorice Root) Glycyrrhizin is the component of licorice root most responsible for the benefits of this plant medicine. Glycyrrhizin has been shown to reduce alanine transaminase and aspartate transaminase values in the serum. Glycyrrhizin inhibits immune-mediated cytotoxicity

against hepatocytes and also antagonizes nuclear factor (NF)-kappa B, a transcription factor that activates genes encoding inflammatory cytokines?8 Licorice exerts many pharmacologic actions beneficial in the treatment of acute and chronic hepatitis including the following: Antihepatotoxic effects Immune-modulating actions Potentiation of interferon Antiviral effects Acting as a choleretic Clinical studies with a glycyrrhizin-containingproduct in Japan have shown excellent results in the treatment of acute and chronic The product, Stronger Neominophagen C (SNMC), consists of 200 mg glycyrrhizin, 100 mg cysteine, and 2000 mg glycine in 100 ml of physiologic saline solution. It is administered intravenously (oral administration may be just as effective, as discussed later). SNMC has demonstrated impressive results in treating chronic hepatitis due to either B or C ~ i r u s e s ? ~ - ~ ~ With either form, approximately 40% of patients will have complete resolution-a statistic that compares quite favorably with alpha-interferon’s 40% to 50% clearance rate. Like SNMC, alpha-interferon administration has been shown to lead to similar dramatic reductions in the risk for hepatocellular carcinoma.” However, it is expensive and associated with side effects (primarily fever, joint pain, nausea, and flulike symptoms). In one study, of 453 patients diagnosed with chronic hepatitis C at a hospital in Japan between 1979 and 1984, 84 patients were treated with SNMC at a dosage of 100 ml/day for 8 weeks followed by treatments of two to seven times weekly for periods up to 16 years.= The rates of cumulative hepatocellular carcinoma (HCC) and cirrhosis in year 10 were 7”/0and 12%,respectively; in year 15 they were 12% and 21%, respectively. The numbers compare quite favorably with alphainterferon’s success rates in both patients with early stages of the disease (O.6YO/yearprogression to HCC with alpha-interferon and 0.7%/year for SNMC) and patients with advanced stages (1.5%/year progression to HCC in alpha-interferon-treated patients compared with 1.3% for SNMC). Although the studies with SNMC used injectable glycyrrhizin, IV administration may not be necessary, as glycyrrhizin is readily absorbed from licorice. The goal is to achieve a high level of glycyrrhizin in the blood without producing side effects. The dosages given later provide roughly 50% of the dosage of glycyrrhizin used in the studies with SNMC. The main hazard of licorice administration is the production of its aldosterone-like effects.

Hepatitis

If ingested regularly, licorice root (>3g/day for % weeks) or glycyrrhizin acid (>lo0 mg/day) may cause sodium and water retention, hypertension, hypokalemia, and suppression of the renin-aldosterone system. Monitoring of blood pressure and electrolytes and increasing dietary potassium intake are suggested.*J5 Great individual variation exists in the susceptibility to the symptom-producing effects of glycyrrhizin. Adverse effects are rarely observed at levels lower than 100 mg/day, while they are quite common at levels higher than 400 m g / d a ~ . ~ ~ Prevention of the side effects of glycyrrhizin may be possible by following a high-potassium, low-sodium diet. Although no formal trial has been performed, patients who normally consume high-potassium foods and restrict sodium intake, even those with high blood pressure and angina, are free from the aldosterone-like side effects of glycyrrhizin. Nonetheless, licorice should probably not be used in patients with a history of hypertension or renal failure or a current use of digitalis preparations.

Silybum marianum (Milk Thistle) h4ilk thistle contains silymarin, a mixture of flavanolignans consisting chiefly of silybin, silidianin, and silichristine. Silymarin is one of the most potent liverprotecting substances known. Silymarin inhibits hepatic damage by doing the following:

Acting as a direct antioxidant and free radical scavenger Increasing the intracellular content of glutathione and superoxide dismutase Inhibiting the formation of leukotrienes Stimulating hepatocyte regeneration Silymarin is effective in both acute and chronic viral hepatitis. Although it has failed so far to clearly show an antifibrotic effect in human studies, silymarin has successfully prevented alcoholic cirrhosis in baboon studies, and other animal experiments suggest that silymarin may be beneficial in patients who have not yet developed c i r r h ~ s i s . ~ , ~ ~ In one study of acute viral hepatitis, 29 patients treated with silymarin showed a definite therapeutic influence on the characteristic increased serum levels of bilirubin and liver enzymes compared with a placebo gr0up.3~The laboratory parameters in the silymarin group regressed more than in the placebo group by the fifth day of treatment. The number of patients attaining normal liver values after 3 weeks of treatment was significantly higher in the silymarin group than in the placebo group. In a study of chronic viral hepatitis, silymarin was shown to result in dramatic improvement. Used at high doses (420 mg of silymarin) for periods of 3 to 12 months

resulted in a reversal of liver cell damage (as noted by biopsy), an increase in protein level in the blood, and a lowering of liver enzymes. Common symptoms of hepatitis (e.g., abdominal discomfort, decreased appetite, fatigue) all improved.39 A newer form of silymarin that may provide even greater benefit has emerged. The new form binds silymarin to phosphatidylcholine (referred to as silymarin phytosome). A growing body of scientific research indicates that phosphatidylcholine-bound silymarin is better absorbed and produces better clinical results than unbound silymarin.- These benefits were demonstrated in one study involving 232 patients with chronic hepatitis (viral, alcohol, or chemically induced) treated with silymarin phytosome at either 120 mg twice daily or 120 mg three times daily for up to 120 d a ~ s . 4 Liver ~ function tests were compared with a group of controls (49 treated with a commercially available unbound silymarin; 117 untreated or given placebo). Liver function returned to normal faster in all patients, and subtypes given silymarin phytosome compared with both the commercially available silymarin and placebo. Silymarin has a low toxicity and is well tolerated. However, because it possesses choleretic activity, it may produce a looser stool as a result of increased bile flow and secretion. If higher doses are used, it may be appropriate to use bile-sequestering fiber compounds (e.g., guar gum, pectin, psyllium, oat bran) to prevent mucosal irritation and loose stools. Because of silymarin's lack df toxicity, long-term use is feasible when necessary. (S. marianum is discussed in more detail in Chapter 125.)

Phyllanthus amarus l? umurus is an Asian herb with a long history of use in liver disorders. A preliminary report in 1988 demonstrated that 59% of patients with hepatitis B had lost the hepatitis B surface antigen when tested 15 to 20 days after treatment with a preparation of 'p. nmarus (200 mg of the dried, powdered, sterilized plant in capsules three times daily).% This report was met with a great deal In this double-blind study, only 4% of e~citement.4~ (1 of 23) placebo-treated controls tested negative. Unfortunately, these results have not been confirmed by other researcher~.4~-~ For example, in one double-blind study, 59 and 57 carriers of hepatitis B virus received 400 mg of l? amurus three times daily and placebo, respectively, for 30 days and were evaluated on days 15,30,60, and 180. HBsAg was detected during treatment and follow-up in all but one in each group at day To rule out the possibility that poor-quality herbal material was responsible for the poor response, the latest double-blind study performed in New Zealand

used a P. arrmrus extract in a capsule standardized to contain 20 mg geraniin per 290 mg of extract.%The dosage used was 3 capsules daily for 2 months. No effect was noted in the 52 patients receiving the extract. Specifically, clinical symptomatology, as well as hepatitis B surface and core antigen levels, did not change. These results indicate that either the type of extract used is not effective or phyllanthus itself is not effective. Given the benefits of thymus extracts, licorice, and silymarin in the treatment of chronic hepatitis B, as demonstrated in several double-blind studies, it simply does not seem warranted to use I? amarus at this time.

Combination AntioxidantlBotanical Therapy Approach Dr.Burton krkson published a report of three cases histories that describes a low-cost and efficacious treatment program in three patients with advanced cirrhosis, portal hypertension, and esophageal varices secondary to chronic hepatitis C infection.21Although these patients were originally given extremely poor prognoses, all patients ”recovered quickly,” showed improved liver enzymes, and were able to resume normal daily function. One case revealed substantial improvements in her condition in only 2 weeks. The other patients progressed to health within 4 to 7 months. The regimen was composed of oral supplementation of alpha lipoic acid (600 mg/day in two divided doses), selenium (as selenomethionine at 400 pg/day in two divided doses), and silymarin (900 mg/day in three divided doses). The subjects were also asked to take a B vitamin complex, eat a diet high in fruits and vegetables, 4 oz. or less of meat per meal, and eight glasses of water per day. Subjects also took between 1000 and 6000 mg of vitamin C per day and 400 IU/day of vitamin E. They were encouraged to walk l mile three times a week. Only the alpha-lipoic acid/selenium/silymarin portion of the protocol was verified, and it is not known how strictly the other nutritional and lifestyle suggestions were followed. Although the protocol described earlier is documented in only three cases, given the excellent safety record, reasonable cost, and known efficacy of these individual treatment options, it makes reasonable sense from a naturopathic standpoint and is certainly worth trymg. Hopefully, stringent clinical trials studying this type of multiantioxidant/lifestyle combination protocol will be conducted in the near future.

Hepatotoxic Botanicals Given the pharmacologic nature of plant medicines, it is important to remember that some commonly used botanicals may be hepatotoxic and should be avoided in a patient with hepatitis. Perhaps the most researched is Symphyturn oficinule (comfrey). These effects are

most likely due to various hepatotoxic pyrrolizidine alkaloids such as lasiocarpine and symphytine and their related N-oxides5l Untoward liver effects have also been reported for some Chinese herbal medicines such as Jin Bu Hum, Ma-Huang (Ephedra), Dictamnus dasycarpus, Sho-saiko-to, Teucrium chumaedrys (wild germander), Lurrea tridentata (chaparral), Atructylic gummfera, Callilepsis laureolu, and some other pyrrolizidine alkaloid-containing ~ l a n t s . 5 ~Piper 5 ~ methysticum (kava kava) has also been implicated in hepatic liver damage.% A number of these reported kava toxicity cases seemed to involve poor documentation, preexisting conditions, kava overdose, or concomitant polypharmacy. Although considered safe at normal doses for people without liver those with hepatic conditions should avoid its use as a precaution.

THERAPEUTIC APPROACH Bedrest is important during the acute phase of viral hepatitis, with slow resumption of activities as health improves. Strenuous exertion, alcohol, and other liver-toxic drugs and chemicals should be avoided. During the contagious phase (2 to 3 weeks before symptoms appear to 3 weeks after), careful hygiene and avoiding close contact with others is important. In particular, once a diagnosis is made, work in a day care center, restaurant, or other similar occupations is not recommended.

Diet A natural diet, low in natural and synthetically saturated fats, simple carbohydrates (sugar, white flour,fruit juice, honey, etc.), oxidized fatty acids (fried oils), and animal fat and high in fiber is recommended. Alcohol should be completely avoided.

Nutritional Supplements Follow the recommendations given in Chapter 44. Vitamin C: to bowel tolerance (10 to 50 g/day) in acute cases; 1000 mg three times/day in chronic cases Liver extracts: 500 to 1000 mg/day of crude polypeptides Thymus extracts: equivalent to 120 mg pure polypeptides with molecular weights less than 10,000 or roughly 750 mg of the crude polypeptide fraction

Botanical Medicines G. glabra (licorice) Powdered root: 1to 2 g tid Fluid extract (1:l): 2 to 4 ml(1 to 2 g) tid Solid (dry powdered) extract (5% glycyrrhetinic acid content): 250 to 500 mg tid

Hepatitis

(Note: If licorice is to be used over a long period of time, it is necessary to increase the intake of potassiumrich foods.)

S. marianum (milk thistle). The standard dose of milk thistle is based on its silymarin content (70 to 210 mg tid). For this reason, standardized extracts are preferred. The best results are achieved at higher dosages (i.e., 150 to 300 mg of silymarin tid). The dosage for silybin bound to phosphatidylcholine is 120 mg two to three times daily between meals.

See the earlier section on antioxidant/botanical therapy for specific protocol.

1.Stormer FC, Reistad R, Alexander J. Glycyrrhizic acid in liquoriceevaluation of health hazard. Food Chem Toxic01 199331:303-312. 2. Schuppan D, Krebs A, Bauer M, et al. Hepatitis C and liver fibrosis. Cell Death Differ 2003;10(suppl1):!39-67. 3. Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACP). h4MWR Recomm Rep 1999;48:1-37. 4. McMahon BJ, Beller M, Williams J, et al. A program to control an outbreak of hepatitis A in Alaska by using an inactivated hepatitis A vaccine. Arch Pediatr Adoles Med 1996;150:733-739. 5. Marsano LS. Hepatitis. Prim Care 20033081-107. 6. Cathcart RF. The third face of vitamin C. J Orthomol Med 1993;7 197-200. 7. Cathcart RF. The method of determining proper doses of vitamin C for the treatment of disease by titrating to bowel tolerance.J Orthomol Psychiat 1981;10125-132. 8. Klenner FR. Observations on the dose of administration of ascorbic acid when employed beyond the range of a vitamin in human pathology. J Appl Nutr 1971;23:61-88. 9. Baetgen D. [Results of treatment of epidemic hepatitis in childhood with high doses of ascorbic acid in the years 1957-1958.1 Med Monatsschr 1961;1530-36. 10. Baur H, Staub H. Treatment of hepatitis with infusions of ascorbic acid: comparison with other therapies. J Am Med Assoc 1954; 156:565. 11. Murata A. Virucidal activity of vitamin C vitamin C for prevention and treatment of viral diseases. In Hasegawa T, ed. Proceedings of the First Intersectional Congress of the International Association of the Microbiological Society, vol 3. Tokyo: Tokyo University Press, 1975432-442. 12. Czuczejko J, Zachara BA, Staubach-Topczewska E, et al. Selenium, glutathione and glutathione peroxidases in blood of patients with chronic liver diseases. Acta Biochim Pol 2003;501147-1154. 13. Irmak MB, Ince G, Ozturk M, et al. Acquired tolerance of hepatocellular carcinoma cells to selenium deficiency: a selective survival mechanism? Cancer Res 2003;636707-6715. 14. Jain SK, Pemberton PW, Smith A, et al. Oxidative stress in chronic hepatitis C: not just a feature of late stage disease. J Hepatol2002; 369305411. 15. Evans JL., Goldfine ID. Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Techno1 Ther 2000;2:401-413. 16. [No authors listed]. Thioctic acid. Notes Undergr 1995;302. 17. Pande M, Flora SJ. Lead induced oxidative damage and its response to combined administration of alpha-lipoic acid and succimers in rats. Toxicology 2002;177:187-196. 18. Suh JH,Shigeno ET, Morrow JD, et al. Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)lipoic acid. FASEB J 2001;15700-706.

19. Hagen TM, Moreau R, Suh JH, et al. Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-L-carnithe and/or lipoic acid. Ann N Y Acad Sci 2002;959:491-507. 20. Bustamante J, Lodge JK, Marcocci L, et al. Alpha-lipoic acid in liver metabolism and disease. Free Radic Biol Med 1998;241023-1039. 21. Berkson BM. A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories. Med Klin (Munich) 199994 (Suppl3):84-89. 22.Ohbayashi A, Akioka T, Tasaki H. A study of effects of liver hydrolysate on hepatic circulation. J Therapy 1972;54:1582-1585. 23. Sanbe K, Murata T, Fujisawa K, et al. Treatment of liver diseasewith particular reference to liver hydrolysates. Jap J Clin Exp Med 1973;502665-2676. 24. Fujisawa K, Suzuki H, Yamamoto S, et al. Therapeutic effects of liver hydrolysate preparation on chronic hepatitis-a double blind, controlled study. Asian Med J 1984;26:497-526. 25. Galli M, Cmchiolo P, Negri C, et al. Attempt to treat acute type B hepatitis with an orally administered thymic extract (Thymomodulin): preliminary results. Drugs Exptl Clin Res 1985;11:665-669. 26. Bortolotti F, Cadrobbi P, Criverllaro C, et al. Effect of an orally administered thymic derivative, Thymodulin, in chronic type B hepatitis in children. Curr Ther Res 1988;4367-72. 27. Malnick S, Zimhony 0. Herbal medicines have no proven efficacy for Hepatitis C. Evidence-based Healthcare 2002;6;132-133. 28. Bean P. The use of alternative medicine in the treatment of hepatitis C. Am Clin Lab 2002;21:19-21. 29. Suzuki H, Ohta Y, Takino T, et al. Effects of glycyrrhizin on biochemical tests in patients with chronic hepatitis-double blind trial. Asian Med J 1984;26:423-438. 30. Mori K, Sakai H, Suzuki S, et al. Effects of glycyrrhizin (SNMC. Stronger Neo-Minophagen C) in hemophilia patients with HIV-1 infection. Tohoku J Exp Med 1990;162183-193. 31.Eisenburg J. [Treatment of chronic hepatitis B. Part 2: Effect of glycyrrhizinic acid on the course of illness.] Fortschr Med 1992; 110:395-398. 32. Acharya SK, Dasarathy S, Tandon A, et al. A preliminary open trial on interferon stimulator (SNMC) derived from Glycyrrhiza glabra in the treatment of subacute hepatic failure. Indian J Med Res 1993;9869-74. 33. Arase Y, Ikeda K, Murashima N, et al. The long term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer 1997;79 14941500. 34. Arase Y, Ikeda K, Murashima N, et al. The superiority of laparoscopic examination in predicting hepatocellular carcinoma after interferon therapy for chronic type C hepatitis. Dig Endosc J Pharmacol1997;10613-620. 35. Farese RV Jr, Biglieri EG, Shackleton CH, et al. Licorice-induced hypermineralocorticoidism.N Engl J Med 1991;325:1223-1227.

Berkson Combination Antioxidant Approach

36. Stickel F, Brinkhaus B, Krahmer N, et al. Antifibrotic properties of botanicals in chronic liver disease. Hepatogastroenterology2002;49 1102-1108. 37.Lieber CS. New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments. Curr Gastroenterol Rep 2004; 660-65. 38. Deak G, Muzes G, Lang I, et al. [Immunomodulatoreffect of silymarin therapy in chronic alcoholic liver diseases.] Ow Hetil 1990,131:1291-1292,12951296. 39. Magliulo E, Gagliardi B, Fiori GP. [Resultsof a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres]. Med Klin 1978;73:1060-1065. 40.Schandalik R, Gatti G, Perucca E. Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients. Arzneimittelforschug 1992;42:964-968. 41. Barzaghi N, Crema F, Gatti G, et al. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholinecomplex, in healthy human subjects.Eur J Drug Metab Pharmacokinet 1990;15:333-338. 42. Vailati A, Aristia L, Sozze E, et al. Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 1993;44:219-228. 43. Moscarella S, Giusti A, Mama F, et al. Therapeutic and antilipoperoxidant effects of silybin-phosphatidylcholinecomplex in chronic liver disease: preliminary results. CLUTTher Res 1993;53:98-102. 44.Buzzelli G, Moscarella S, Giusti A, et al. A pilot study on the liver protective effect of silybin-phosphatidylchohecomplex (IdB 1016) in chronic active hepatitis. Int J Clin Pharmacol Ther Toxic01 1993; 3k456-460.

45.Marena C, Lampertico M. Preclinical development of silipide: a new complex of silybin in toxic liver disorders. Planta Med 1991;57(suppl2):A124125. 46.ThyagarajanSP, Subramanian S, Thirunalasundari T, et al. Effect of Phyllanthus umurus on chronic carriers of hepatitis B virus. Lancet 1988;2764-766. 47. klarasamee A, Trakulsomboon S, MaunwongyathiP, et al. Failure of Phyllunthus amurus to eradicate hepatitis B surface antigen from symptomless carriers. Lancet 1990335:1600-1601. 48. Blumberg BS, Millman I, Venkateswaran PS,et al. Hepatitis B virus and primary hepatocellular carcinoma: treatment of HBV carriers with Phyllunthus umrus. Vaccine 1990;8586-92. 49.Berk L, de Man RA, Schalm SW, et al. Beneficial effects of Phyllanthus amurus for chronic hepatitis B, not confirmed. J Hepatol 1991;12405-406. 50.Milne A, Hopkirk N, Lucas CR, et al. Failure of New Zealand hepatitis B carriers to respond to Phyllunthus umurus. N Z Med J 1994;107243. 51.Stickel F, Seitz HK. The efficacy and safety of comfrey. Public Health Nutr 2000 Dec3(4A):501-508. 52. Stickel F, Egerer G, Seitz HK. Hepatotoxicity of botanicals. Public Health Nutr 2OOO;3:113-124. 53.McRae CA, Agarwal K, Mutimer D, et al. Hepatitis associated with Chinese herbs. Eur J Gastroenterol Hepatol2002;14559-562. 54. Moulds RF, Malani J. Kava: herbal panacea or liver poison? Med J Aust 2003;178:451-453. 55. Teschke R. [Kava, kavapyrones and toxic liver injury.] Z Gastroenterol2003;41:395-404.

Herpes Simplex Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER C O N T E N T S Diagnostic Summary

1723

General Considerations 1723 Recurrent Rate 1723 Immunologic Aspects 1724

Therapeutic Approach 1725 Diet 1726 Supplements 1726 Topical Treatments 1726

Diagnosis 1724 Therapeutic Considerations 1724 Nutritional Supplements 1724 Topical Preparations 1725

DIAGNOSTIC SUMMARY Recurrent viral infection of the skin or mucous membranes characterized by the appearance of single or multiple clusters of small vesicles on an erythematous base frequently occurring about the mouth (herpes gingivostomatitis), lips (herpes labialis), genitals (herpes genitalis), and conjunctiva and cornea (herpes keratoconjunctivitis) Incubation period 2 to 12 days, averaging 6 to 7 Positive culture, vesicle scraping stained with Giemsa’s stain, or serologic test Regional lymph nodes may be tender and swollen Outbreak may follow minor infections, trauma, stress (emotional, dietary, and environmental), and sun exposure

GENERAL CONSIDERATIONS More than 70 viruses compose the Herpes viradue family. Of these, four are important in human disease: herpes simplex virus (HSV), varicella zoster virus, Epstein-Barr virus, and cytomegalovirus. Serologic methods have distinguished two types of HSV, which have been designated HSV-1 and HSV-2. Serologic studies have shown that 30% to 100%of adults have been infected with one or both HSV types, with the greatest incidence among the lower socioeconomic groups. Current estimates indicate that 20% to 40% of the U.S. population have

recurrent HSV infecti0ns.l Previously, HSV-1 was primarily isolated from extragenital sites, while genital infections were caused primarily by HSV-2. By 2000, however, HSV-1 replaced HSV-2 as the primary cause of genital lesions? A retrospective review of genital HSV isolates collected in a university student health service showed that HSV-1 accounted for 78% of all genital isolates in this population by 2001, compared with 31% of isolates in 1993.3

Recurrence Rate HSV-1 genital lesions have a recurrence rate of 14%, while the HSV-2 recurrence rate is 60%. Men seem more susceptible to recurrences. After resolution of the primary infection, HSV probably becomes a dormant inhabitant within sensory or autonomic ganglia, or both. Recurrencesdevelop at or near the sites of primary infection and may be precipitated by many different stimuli: Sunbum Sexual activity Menses Stress Food allergy Drugs Certain foods The risk of clinical herpes infection after sexual contact with an individual with active lesions is estimated to be 75%. 1723

Specific Health Problems

Immunologic Aspects Because not everyone exposed to HSV develops clinical infection, it appears that the host defense mechanisms are paramount in protecting against HSV infection. Chronic, persistent labial and genital infections are seen in immunosuppressed individuals. The cell-mediated immune system is undoubtedly the major factor in determining the outcome of herpes exposure: resistance, latent infection, or clinical disease.

DIAGNOSIS Isolation of HSV from tissue scrapings is the "gold standard" for diagnosis. Cytopathic effects are typically seen within 2 to 7 days. A more rapid diagnostic test for mucOcutaneous lesions is direct staining of skin scrapings. Type-specific serologic tests are now widely used to diagnose unrecognized HSV-1 and HSV-2 infections or to confirm suspected cases.

THERAPEUTIC CONSIDERATIONS Enhancement of the host's immunologic status is a key goal in the control of herpes infection. In addition to general immune support (for a complete discussion, see Chapter 57), one of the key natural measures to strengthen cell-mediated immunity is the use of bovine thymus extracts. Thymus extracts have been shown to be effective in preventing both the number and severity of recurrent infections in immune-suppressed individuals? The thymus extract appears to increase the lymphoproliferative response to HSV, natural killer cell activity, and interferon production. The thymus extract therefore appears to prevent viral activation by potentiating cellmediated immune responses.

Nutritional Supplements Zinc Oral supplementation with zinc (50 mg/day) has been shown to be effective in clinical ~ t u d i e sAlthough .~ zinc is an effective inhibitor of HSV replication in vitro, its effect in vivo is probably related to its role in enhancing cell-mediated immunity. The topical application of 0.01% to 0.025% zinc sulfate solutions has also been shown to be effective in both ameliorating symptoms and inhibiting recurrences of HSV infection.6

Vitamin C Both oral consumption and topical application of vitamin C increase the rate of healing of herpes ulcers. In a randomized, double-blind study, an ascorbic acidcontaining pharmaceutic formulation (Ascoxal) applied with a soaked cotton wool pad three times daily for 2 minutes resulted in patients reporting fewer days with

scabs and fewer cases of worsening of symptoms. Cultures yielded herpes complex viruses sigruficantly less frequently in the treatment group? In another study, 20 patients with herpes labialis were treated with a complex of 600 mg water-soluble bioflavonoids and 600 mg vitamin C given in equal increments three times daily. Twenty episodes of herpes labialis were treated with a complex of 1000 mg water-soluble bioflavonoids and loo0 mg of vitamin C in equal incrementsfive tirnes daily. Ten episodes were treated with a lactose preparation. This approach was maintained for 3 days after the recognition of symptoms. The water-soluble bioflavonoid-vitamin C complex was shown to reduce vesiculation and to prevent the disruption of the vesicular membrane. The therapy was most beneficial when initiated at the beginning of the disease. Those treated with the 1000-mg regimen experienced 4.4 days for the blister to heal compared with 10 days for the placebo group.

Lysine and Arginine A lysine-rich/arginine-poor diet has become a popular treatment for HSV infections. This approach came from research showing that lysine has antiviral activity in vitro due to antagonism of arginine metabolism.8HSV replication requires the synthesis of arginine-rich proteins, and arginine itself is suggested to be an operon coordinate i n d ~ c e r A . ~ preponderance of lysine over arginine is believed to act as either an allosteric enzyme inhibitor or an operon coordinate repressor. Double-blind studies on the effectivenessof lysine supplementation with uncontrolled avoidance of argininerich foods have shown inconsistent results?-12 These results may be due to the relatively low levels of lysine used (1200 mg/day) and the severity of the cases in some of the studies (placebo and treated groups had In lesions for 40% of the time in one negative ~tudy).~JO the most recent study, lysine was given at a larger dosage (1g tid) along with dietary restriction of nuts, chocolate, and gelatin." At 6 months, lysine was rated as effective or very effective in 74% of those receiving lysine compared with only 28% for those receiving the placebo. The mean number of outbreaks was 3.1 in the lysine group compared with 4.2 in the placebo group. Theoretically, this approach should be effective because in vitro studies have shown that HSV replication depends on adequate levels of arginine and low levels of 1~sine.l~ As dibasic amino acids, they compete with each other for intestinal transport, and rats fed a lysine-rich diet displayed a 60% decrease in brain arginine levels, although there was no change in senun levels? Because HSV is believed to reside in the ganglia during latency, lysine supplementation and arginine avoidance seem appropriate. However, this approach is not curative-it only inhibits recurrences. In some

Herpes Simplex

patients, withdrawal from lysine is followed by relapse within 1to 4 weeks.13

eruption if applied early and frequently.I8 No human studies have been reported.

Topical Preparations Melissa officinalis

THERAPEUTIC APPROACH

One of the most widely used topical preparations in the treatment and prevention of herpes outbreaks is a concentrated extract (70:l) of Melissa officinalis (lemon balm). Rather than any single antiviral chemical, melissa contains several components that work together to prevent the virus from infecting human cells. When melissa cream was used in patients with the initial herpes infection, results from comprehensive trials from three German hospitals and a dermatology clinic demonstrated that not a single recurrence 0~curred.l~ In other words, by using the cream, not a single patient with a first herpes outbreak developed another cold sore. Furthermore, it was noted in these studies that the melissa cream produced a rapid interruption of the infection and promoted healing of the herpes blisters much quicker than normal. The control group receiving other topical creams had a healing period of 10 days, while the group receiving the melissa cream completely healed within 5 days. The melissa cream was also studied in patients suffering from recurrent cold sores. Researchers found that if subjects used this cream regularly, they would either stop having recurrences or experience a tremendous reduction in the frequency of recurrences (an average cold sore-free period of >3.5months).14 The melissa cream should be applied to the lips two to four times a day during an active recurrence. It can be applied fairly thickly (1 to 2 mm). Detailed toxicology studies have demonstrated that it is extremely safe and suitable for long-term use.

The therapeutic aim is to shorten the current attack and prevent recurrences. Support of the immune system is of primary importance, necessitating control of food allergens and optimizingnutrients necessary for cell-mediated

Food

Almonds Bacon Beans, green Beans, lima Beans, mung Beans, red Beef chuck Brazil nut Bread, whole wheat Buckwheat Carob Cashews Cheese, cheddar Chicken Chocolate Clams Coconut Crustaceans Eggs Fish sticks, breaded Flax seeds Garbanzo beans Halibut Hazelnuts Lentils Glycyrrhiza glabra Liver, beef Another popular topical treatment for preventing and Milk, whole treating herpes outbreaks is to use preparations containing Millet Oatmeal, Cooked glycyrrhetinic acid. This triterpenoid component of GZycywhiza glabra (licorice root) inhibits both the growth Oysters Peanuts, wlo skins and cytopathic effects of herpes simplex, as well as vacPeas, green cinia, Newcastle disease, and vesicular stomatitisvir~~ses.'~Pecans Topical glycyrrhetinic acid has been shown in clinical Pork, lean Rice, brown studies to be quite helpful in reducing the healing time and pain associated with cold sores and genital herpes.l6,I7 Salmon Sardines Sesame seeds Resveratrol Shrimp Resveratrol (3,5,4'-trihydroxystilbene) is a natural comSoybeans, boiled Sunflower ponent of certain foods such as grapes that has been shown to have anti-HSV activity in vitro. Recent intrigu- Tuna ing research in mice has shown that a topical application Turkey Walnuts, English of a cream rich in resveratrol (12.5% to 25%) effectively Yeast

blocked replication of the HSV virus and stopped lesion

Serving

70 cuts 12 slices 314 cup 3.5 oz 3.5 oz 113 cup 3.5oz 3.5oz 4 slices 3.5 oz 3.5oz 40 nuts 3.5 02 3.5 oz 3.5 oz 112 cup 3.5 02 3.5 oz 2 large 45 sticks 3.5 oz 3.5 02 3.5 oz 3.5 oz 3.5 oz 3.5 oz 3.5 02 3.5oz 113 cup 58 medium 3.5 oz 518 cup 3.5 02 3.5 oz 2/3 cup 3.5 oz 7 medium 3.5 oz 3.5 02 2/3cup 3.5 oz 518 can 3.5oz 27 whole 3.5 oz

Arginine

Lysine

2730 2100 80 1170 1320 340 1600 2250 510 1200 710 1990 850 1930 4500 830 470 1330 840 940 2030 1900 140 3510 2100 1590 130 410 130 310 3240 420 2030 1510 120 1530 190 2590 1360 620 1190 1530 1700 2250 1940

580 2000 80 1470 1930 420 2200 470 290 460 340 740 1700 2700 2000 840 148 1260 820 1400 810 1380 2220 690 1740 1950 280 260 70 280 1090 220 810 1850 100 2350 1850 580 2130 620 540 2530 2450 490 3510

Specific Health Problems immunity. Inhibition of HSV replication through manipulation of the lysine/arginine ratio in the diet seems well indicated. Strengthening the immune system can be effective at reducing the frequency, duration, and severity of recurrences.

Diet Develop a diet that avoids major food allergens and arginine-rich foods while promoting lysine-rich foods (see Table 1741). The foods with the worst arginineto-lysine ratio are chocolate, peanuts, and almonds.

Zinc: 25 mg/day Lysine: 1000 mg three times/day Thymus extract: the equivalent to 120 mg pure polypeptides with molecular weights less than 10,000 or roughly 500 mg of the crude polypeptide fraction

Topical Treatments Ice: 10 minutes on, 5 minutes off during prodrome Zinc sulfate solution: 0.025% solution tid Melissa cream: apply bid Glycyrrhetinic acid: apply bid

Supplements Vitamin C: 2000 mg/day Bioflavonoids: 1000 mg/day

1. Makin JE. Epidemiology of genital herpes simplex virus infection in developed countries. Herpes 2004;11(suppl 1):2A-23A. 2. Lafferty WE. The changing epidemiology of HSV-1 and HSV-2 and implications for serological testing. Herpes 2002;9:51-55. 3. Roberts CM, Pfister JR, Spear SJ. Increasing proportion of herpes simplex virus type 1as a cause of genital herpes infection in college students. Sex Transm Dis 2003;30797-800. 4. Aiuti F, Sirianni M, Stella A, et al. A placebo-controlled trial of thymic hormone treatment of recurrent herpes simplex labialis infection in immunodeficient hosts. Int J Clin Pharm Ther Toxic01 1983;21:81-86. 5. Fitzherbert J. Genital herpes and zinc. Med J Aust 1979;1:399. 6. Brody I. Topical treatment of recurrent herpes simplex and postherpetic erythema multiforme with low concentrations of zinc sulphate solution. Br J Dermatol 1981;104:191-213. 7. Hovi T, Hirvimies A, Stenvik M, et al. Topical treatment of recurrent mucocutaneous herpes with ascorbic acid-containing solution. Antiviral Res 1995;27263-270. 8. Griffith R, DeLong DC,Nelson JD.Relation of arginine-lysineantagonism to herpes simplex growth in tissue culture. Chemotherapy 1981;27209-213. 9. DiGiovanna JJ, Blank H. Failure of lysine in frequently recurrent herpes simplex infection.Arch Dermatol 1984;120:48-51. 10. Griffith R, Norins A, Kagan C. A multicentered study of lysine therapy in herpes simplex infection. Dermatologica 1978;156:257-267.

11. McCune MA, Perry HO, Muller SA. Treatment of recurrent herpes simplex infections with L-lysine monohydrochlorite. Cutis 19&1;34:366-373. 12. Griffith RS,Walsh DE, Myrmel KH, et al. Success of L-lysine therapy in frequently recurrent herpes simplex infection. Dermatologica 1987;175:183-190. 13.Wolbling RH, Leonhardt K. Local therapy of herpes simplex with dried extract from Melissa officinalis. Phytomedicine 1994;1:25-31. 14. Koytchev R, Alken RG, Dundarov S. Balm mint extract (Lo-701) for topical treatment of recurring herpes labialis. Phytomedicine 1999;6:225-230. 15. Pompei R, Pani A, Flore 0, et al. Antiviral activity of glycyrrhizic acid. Experientia 1980;36:304. 16.Partridge M, Poswillo D. Topical carbenoxolone sodium in the management of herpes simplex infection. Br J Oral Maxillofac Surg 1984=:138-145. 17. Csonka G, TyrreU D. Treatment of herpes genitalis with carbenoxolone and cicloxolone creams: a double blind placebo controlled trial. Br J Vener Dis 1984;60:178-181. 18.Docherty JJ, Smith JS, Fu MM, et al. Effect of topically applied resveratrol on cutaneous herpes simplex virus infections in hairless mice. Antiviral Res 2004;61:19-26.

HIWAIDS: Naturopathic Medical Principles and Practice Kevin L. Conroy, ND Steven C. Milkis, ND Leanna J. Standish, ND, PhD, LAC CHAPTER CONTENTS Diagnostic Summary 1727 Introduction 1727 Focus and Goals of Chapter

1728

History of the HIV and AIDS Epidemic 1728 Biology of HIV 1729

Diagnosis and Work-up 1732 Diagnostic Testing 1732 History 1732 Laboratory Assessment and Monitoring 1732 Therapeutic Considerations 1733 Medical Management of HIV and AIDS Naturopathic Management of HIV and AIDS 1734

1733

Transmission 1730 Pathogenesis 1730 The Immune System’s Response 1730 Clinical Progressionto AIDS

Therapeutic Summary 1747 Diet 1747 Lifestyle 1748 Nutritional Supplements 1748

1731

DIAGNOSTIC SUMMARY Human immunodeficiencyvirus-positive (HIV+) diagnosis is made after a positive test for HIV antibodies by enzyme-linked immunosorbent assay (ELISA) and confirmed via Western blot analysis. Acute onset (acute antiretroviral syndrome) resembles common influenza. Most persons experience this syndrome 2 to 6 weeks after initial infection, and it often goes undiagnosed as HIV due to its similarity with the flu. Signs and symptoms might include fever; fatigue; lymphadenopathy; pharyngitis; maculopapular rash on the face, head, and trunk;mucocutaneous ulceration of mouth/ esophagus/ genitals; myalgia; night sweats; diarrhea; headache; nausea and vomiting; hepatosplenomegaly; weight loss; thrush; neurologic symptoms (asepticmeningitis, encephalitis, peripheral neuropathy, facial palsy, Guillain-Barr6 syndrome, brachial neuritis, cognitive impairment, or psychosis); thrombocytopenia; leucopenia; transaminase elevation. Insidious onset may present as an acquired immunodeficiency syndrome (A1DS)-associated opportunisticinfection (01) or as unexplained progressive fatigue, weight loss, fever, diarrhea, or generalized lymphadenopathy.

AIDS is diagnosed after positive serology and a CD4+ T-cell count at or below 200 cells/mm3or the presence of a designated AIDS-indicator condition,or both (from Centers for Disease Control and Prevention [CDC] guidelines of 1993 and 1997). The lower the CD4-t count and the higher the viral load, the higher the risk of contracting OIs, neoplasms, or neurologic abnormalities and the higher the mortality rate. Groups at high risk for contracting HIV include: injection drug users, gay and bisexual men, hemophiliacs and others receiving transfused blood or other blood products (highest risk to recipients before May 1985 when regular screening of the blood supply began), regular sexual partners of people in the aforementioned groups, heterosexual people with greater than one sex partner in the past 12 months, and noncondom users in the past 6 months.

INTRODUCTION HIV has been described as a retrovirus containing two single strands of RNA. It enters the body via the transfer 1727

of body fluids and subsequently binds to and infectsCD4expressing cells of the human immune system (T-helper lymphocytes, blood monocytes, tissue macrophages, Langerhans cells in the skin, and microglial and multinucleated cells in the central nervous system). AIDS is a secondary syndrome resulting from long-term HIV infection. AIDS is defined by one or more of the following: levels of CD4+ cells, the presence of certain specific indicator conditions, or secondary malignanciesknown to be associated with HIV. Many theories exist as to what causes AIDS, ranging from HN to multifactorial (environmental and infectious) assaults on the immune system. In this science’s infancy,, there is no definitive answer, but current medical thinking is that AIDS is caused by HN.

Focus and Goals of Chapter This chapter is written for the naturopathic physician, although conventionally trained physicians and other holistic practitioners may find the perspective, treatment principles, and some of the treatment suggestions helpful. The field of HIV/AIDS medicine is rapidly changing. HIV/AIDSwas only first reported to the CDC in 1981, and it has since exploded into an international pandemic. Many deaths occurred early on, and in 1996 a dramatic change in the management of HIV infection occurred with the introduction of protease inhibitors and the use of combination therapy also known as highly active antiretroviral drug therapy (HAART). The advent of the use of multiple drugs in combination targeted toward decreasing viral load and increasing CD4+ T-cell counts resulted in a dramatic slowing in the death rate from AKS. Along with the success of HAART came sigruficant side effects and drug interactions that not only require frequent follow-up between the patient and physician but have had a major impact on the quality of life of those individuals on those regimens. Complementary and alternative medicine (CAM) has been described as including naturopathic medicine, advanced nutrition, lifestyle coaching, psychoneuroimmunology, spiritual practices, and traditional healing practices throughout the world. CAM is helping patients cope with many of the issues that have manifested with the diagnosis of HIV, AIDS, and conventional treatments for each. Studies indicate that more than 70% of HIV+ persons are using some form of CAM in their treatment resulting in improvement in quality of life and better outcomes.12 CAM has a tremendous amount it can offer to those living with HIV and AIDS. The goal of this chapter is to help the naturopathic physician better understand how to appropriately help this population with unique and complicated issues and to give specific guidance in this regard.

HISTORY OF THE HIV AND AIDS EPIDEMIC On June 5,1981, the CDC’s Morbidity and Mortality Weekly Report (MMWR) published a report of Pneurnocystis carinii pneumonia (PCP) occurring in combinationswith Candida albicans (oral and esophageal); cytomegalovirus (CMV) in the eyes, lungs, and windpipe; and low T-cell counts in five homosexual men from Los Angeles? Closely following this, the CDC reported 26 cases of Kaposi’s sarcoma (KS) in homosexual men in New York and Los Angeles, occurring in combinations with other rare infections (PCP, toxoplasmosis, cryptococcal meningitis, severe recurrent herpes simplex, and low T-cell counts), suggesting immunosuppression! By the end of 1981 and into 1982, the first cases of PCP were identified in nonhomosexual persons (drug addicts, hemophiliacs, transfusion recipients, babies of intravenous (IV) drug users, and Haitian immigrants).56 In February 1983 Robert Gallo of the National Institutes of Health suggested that a retrovirus probably causes AIDS. In April 1983 Luc Montagnier of the Pasteur Institute in France isolated a new retrovims in lymph node cells of an AIDS patient and called it lymphadenopathyassociated virus (LAV). By the end of 1983,4749 cases of AIDS had been reported in 33 countries with 2122 deaths. In April 1984 Robert Gallo announced he had isolated a retrovirus from an AIDS patient and named it human T-lymphotrophic virus (HTLV-III).7In 1985 the Food and Drug Administration (FDA) approved the first commercial ELISA test kit to detect antibodies to HIV in the blood, and regular screening of the blood supply was initiated. During 1987 the FDA approved zidovudine (formerly called azidothymidine [AZT]) as the first antiretroviral drug to be used in the treatment of AIDS, as well as the Western blot test, which detects the presence of antibodies to specific viral proteins. Not until 1991 did the FDA approve additional drugs (didanosine/ ddI and dideoxycytidine/ddC) for use in treating AIDS. It also started to become clear that HIV had the capability to develop resistance to these medications, as they tended to become ineffective after about 1year of use. By the end of 1991, there were 198,466 AIDS cases reported in the United States with 121,255 deaths. By the end of 1994, 400,000 U.S. AIDS cases had been reported since 1981 with more than 250,000 deaths. In 1995 the FDA approved the first protease inhibitor (PI). In 1996 triple combination therapy (the use of three different antiretroviral drugs) was approved and was seen as more likely to suppress HIV replication and help prevent the development of drug resistance. As a result of this innovation, AIDS deaths started to decrease.8At of the end of 2001 in the United States, there had been more than 793,000 total cases of AIDS reported with more than 450,000 deaths since 1981.9

HIV/AIDS: Naturopathic Medical Principles and Practice

HIV/AIDS has become a global epidemic. It cannot be considered a homosexual disease. It cannot be considered a disease of IV drug users. Men, women, and children of all orientations and walks of life are being affected. By the end of 2003, according to the United Nations Program on HIV/AIDS (UNAIDS), as many as 42 million people worldwide were living with HIV/ AIDS. Of those, 39.8 million were adults, 18.8 million were women, and 2.5 million were children younger than 15 years old. Additionally, there were approximately 3.3 million deaths in 2003, including 2.7 million adults and almost 600,000 children. More than 20 million people have died from HIV/AIDS since it was first identified in 1981. Estimates are that between 4.2 and 6.3 million people became newly infected with HIV in 2003 alone. In all parts of the world except Africa, more men are becoming infected with HIV and dying of AIDS than women. In North and sub-Saharan Africa, women account for 55% to 58% of HIV infections. Of the estimated 42 million worldwide cases, it is estimated that two thirds live in sub-Saharan Africa. The reason these figures are estimates is that testing is not done in most of the world as a result of economics. The costs involved in testing every potential case would be astronomic, and the reality is that funds are better spent on care. In the developing countries where approximately 95% of all HIV+ people live, HIV/AIDS is diagnosed on the basis of clinical signs and symptoms.1°

BIOLOGY OF HIV Two types of HIV have been identified. HIV-1 is found throughout the world. Multiple subtypes (or clades) exist including clades A through N. The majority of infections in the United States are caused by HIV-1 clade B. HIV-2 was first identified in West Africa in 1986 and has been found to have a genetic sequence approximately 50% similar to HIV-1. HIV-2 is considered less virulent than HIV-1 and shows lower rates of sexual and perinatal transmission and a lower viral load with a slower rate of CD4 cell decline. This results in a slower rate of disease progression in infected people." Research shows that the virus is mutating, and multiple subtypes are spreading throughout the world.'* The existence of multiple clades raises the theoretic possibility that a single individual could become infected with multiple subtypes of the virus. Research has not conclusively demonstrated the existence of "superinfection," but the possibility of this phenomenon would sigruficantly enhance virulence, as well as increase resistance to present treatments. Existing research has failed to isolate an intact HIV entity. Fragments believed to belong to the HIV virus have been isolated and identified. Despite this shortcoming, the virus is believed to consist of a bilayer

lipid envelope covered with envelope glycoproteins (gp120 receptor and gp41 transmembrane), a viral core containing two single strands of RNA and the reverse transcriptase enzyme, and structural core proteins (p24 capoid protein and p18 matrix protein). It is believed that HIV binds to CD4expressing cells of the immune system and, through a series of steps, replicates itself and incorporates its genome into the host cell's genome. The various classes of antiretroviral medications have been developed to interrupt viral replication during various steps in this process. The key to understanding the mechanisms of action of the various medications is to understand those steps. Fusion is the process by which the HIV particle contacts and binds to the target cell. This occurs through the interaction of the viral gp120 and gp41 transmembrane proteins with CD4 and chemokine receptors on the cell's membrane. Fusion inhibitors are designed to inhibit this process by altering the cellular receptor sites. Transcription occurs when the magnesiumdependent viral reverse transcriptase enzyme translates the viral RNA into a double strand of DNA. Nucleoside/ tide reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs)are designed to affect this process. Integration occurs when the double strand of proviral DNA migrates to the cell's nucleus and is inserted into the host's chromosome via the integrase enzyme. The provirus is then permanently integrated into the host DNA. It can remain essentially dormant (equilibrium of viral production and destruction) or become activated and initiate the production of large chains of new viral RNA subunits, independent of the host cell's replication process. Integrase inhibitors are being developed to inhibit this part of the process. After a period of normal cell function, this infected cell becomes activated, initiating transcription of the proviral DNA into mRNA, which is then translated in the cytoplasm to viral polypeptides. Cleavage occurs when the protease enzyme cuts up the long chains of viral polypeptides, and the pieces are then joined together to form new retroviruses. Protease inhibitors block the action of the protease enzyme and thereby prevent the reassembly of new viral polypeptides. Packaging is a poorly understood step in this process where the new RNA viruses are wound up tightly and encapsulated into new viral particles. Zinc atoms in the shape of a finger are used to wrap up the viral RNA. Zinc finger inhibitors are being developed to interfere with this part of the process.13 Budding occurs when the HIV nucleocapsid containing the new viral RNA moves to the host cell's membrane and binds to the inside of the membrane. It is then enveloped by the membrane as it leaves the cell. An animated video segment of the HIV lifecycle and sites of antiviral medication intervention can be found at http://hopkins-aids.edu/hiv~l~e~cle/hiv~cle~text.html.

Specific Health Problems

TRANSMISSION H W has been found in any body fluid or tissue that contains lymphocytes. This includes blood and blood products, semen, vaginal fluids, breast milk, infected tissues, cerebrospinal fluid, synovial fluid, pleural fluid, and amniotic fluid. It has also been found in small amounts in saliva, tears, feces, and urine. According to the CDC, the only documented cases of transmission are via blood, semen, vaginal secretions, breast milk, and transplanted organs from an infected person. Variables affecting transmission rates include the infectivity of the source partner (higher viral load), the presence of STDs (especially with ulcerations), and the type of contact (increased risk with anal intercourse and vaginal intercourse during menses because blood is present). The most signhcant routes of transmission are via sexual contact (vaginal; anal; and, less frequently, oral intercourse);IV drug use (sharing contaminated needles and syringes); transfusion of blood or blood products (screening of the blood supply in the United States did not begin until May 1985); and from an HIV-infected mother to her baby (before or during birth or through breastfeeding). Transmission can also potentially occur via percutaneous needle stick, mucous membrane exposure, or exposure of infected fluid into an open wound. Studies show the risk of seroconversion following a needle stick from an HIV+ source to be 0.25% per exposure. Studies show no known seroconverters following splash exposure. The CDC has identified one documented case of transmission from acupuncture. No evidence exists that HIV can be transmitted via air, water, insects, or dried body fluids. HIV does not survive well outside the body, in contrast to hepatitis B virus. Universal precautions as developed by the CDC should always be employed by health care workers to minimize the risk of HIV transmission in the health care setting. Always assume that all blood and body fluids are potentially hazardous and that all patients are potentially infe~ted.’~

PATHOGENESIS

-

The initial or primary infection occurs shortly after an individual becomes infected with the virus. It is often unnoticed, as it resembles the symptoms normally associated with the common influenza virus. Box 175-1 lists symptoms and their relative prevalence. Primary infection is also characterized by a high level of virus production, high concentrations of viral particles and RNA in plasma, and a rapid and steep decline in CD4-t T helper cells. Peak viral titers can reach lo7 virons per milliliter during this phase. Viral production can range up to 10 billion copies per day. The half-life of an infected T cell is estimated to be between 2 and 4 days. The estimated life cycle of HIV is about 2.5 days.

Fever-96% Fatigue->90% Lymphaden0pathy-74~/~ Pharyngitis-7OY0 Rash-70% (erythematous maculopapular on face, trunk, and sometimes extremities; sometimes mucocutaneous ulceration of mouth, esophagus, or genitals) Myalgia--M% Night sweats-50% Diarrhea-32% Headache-32% Nausea and vomiting-27% Hepatosplenornegaly-l4% Weight loss-1 3% Thrush-12% Neurologic symptoms-1 2% (aseptic meningitis, encephalitis, peripheral neuropathy, facial palsy, Guillain-Barresyndrome, brachial neuritis, cognitive impairment, or psychosis) Thrombocytopenia45% Leukopenia40% Transaminase elevation-21 % Modifiedfrom the Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. DHHS. Available online at http://A/DSinb.nih.gov[accessed October 29, 20041.

After the initial viremia, high levels of viral p24 antigen appear.

THE IMMUNE SYSTEM’S RESPONSE Both the humeral and cellular immune systems have a role in the body’s response to HIV infection. The humeral response involves the initial production of transient IgM antibodies to viral core and envelope proteins. Permanent IgG antibodies are subsequently established (may take several weeks) to core p24 and envelope gp160, gp120, and gp41 and correspond to the resolution of clinical symptoms. The development of these IgG antibodies results in a rapid decrease in circulating virons and p24 antigen titers. Seroconversion occurs when the body starts making antibodies to HIV antigens and those antibodies become detectable by conventionally used laboratory tests (enzyme-linked immunoassays and Western blot analysis). There is a window of time between initial infection (when patients remain antibody- or sero-negative as measured by ELISA tests) and when seroconversion (antibody-or sero-positiveby ELISA) occurs. The length of this window varies depending on the individual and can range from 10 to 14 days up to 6 months. The cellular immune response is characterized by the elevation of various cytokines (including interferons and tumor necrosis factor), CD4-t lymphopenia, and CD8+ lymphocytosis. Cytotoxic T cells reduce the plasma viremia while natural killer (NK) cells may be involved with killing infected T cells.

HIV/AI DS: Naturopathic Medical Principles and Practice

CLINICAL PROGRESSION TO AIDS Assuming no antiretroviral treatment, a typical scenario of H N infection might occur as follows: Within 2 to 3 weeks of initial infection with the virus, an acute retroviral syndrome may occur. Recovery and seroconversion usually follow in 2 to 3 weeks. After recovery from the initial acute viral syndrome, HIV plasma concentrations decline to a viral "set point" where equilibrium is established between the production and destruction of CD4+ cells. The level of viral replication after acute infection and seroconversion, coupled with the CD4-t count, is predictive of long-term prognosis. A lower level of replication with a higher CD4+ count indicates a longer asymptomatic course. Conversely, a higher level of replication with lower CD4+ counts generally indicates a shorter asymptomatic course. Over time, a gradual decline in T-cell numbers begins to occur with a concurrent gradual increase in the amount of virus in the body. This period can last 5 to 15 years. Eventually, there are not enough T cells for the body's immune system to function properly. This is when the risk of 01s increases, with the ultimate result being death.15 Box 175-2lists the CDC's 1993surveillance case definition of AIDS for adults and children (13years or older).16 It created a series of categories of CD4+ cell counts/ percentages and clinical symptoms. The primary criterion used is positive serology (i.e., positive for antibodies to HIV via ELISA and Western blot testing and positive HIV antigen detection via polymerase chain reaction [PCR] or other specific HIV antigen test). Given a positive serology, a diagnosis of AIDS is given when CD4+ counts fall below 200/mm3 (44%) or any of the category "C" conditions occurs, or both. Clinically, patients tend to be susceptible to certain complications (both infectious and noninfectious) on the basis of their CD4+ cell c o ~ n t s . Although '~ there is always individual variation, these data are helpful in predicting probable clinical presentations. Generally, a higher viral load represents a greater risk for complications and should always be factored into any such consideration. When the CD4+ cell count is greater than 500/mm3, a patient could manifest acute retroviral syndrome, candidal vaginitis, progressive generalized lymphadenopathy (PGL), myopathy, or aseptic meningitis. When the CD4+ count is between 200 and 500/mm3, possible complicaions include: pneumococcal and other bacterial pneumonia, pulmonary tuberculosis, herpes zoster, oropharyngeal candidiasis/thrush, cryptosporidiosis (self-limited),Kaposi sarcoma, oral hairy leukoplakia, cervical intraepithelial neoplasia, cervical cancer, Bcell lymphoma, anemia, mononeuronal multiplex, idiopathic thrombocytopenic purpura, Hodgkin lymphoma, or lymphocytic interstitial pneumonitis.

CD4+ Cell Categories 1. >500/mm3(>29%) 2. 200-499/mm3(14%-28%) 3. ~ 00/ m m 3( 1 dermatome); idiopathic thrombocytopenic purpura; listeriosis; pelvic inflammatory disease; or peripheral neuropathy C. The specific AIDS indicator conditions (updated by the CDC in 1997). Once 1 of these has occurred, the person will remain classified as having AIDS. These conditions include the following: Candidiasis of esophagus, trachea, bronchi, or lungs Cervical cancer, invasive Coccidioidomycosis, extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis with diarrhea > 1 mo Cytomegalovirus (CMV) of any organ other than liver, spleen, or lymph nodes CMV retinitis Herpes simplex with mucocutaneous ulcer > 1 mo or bronchitis, pneumonitis, or esophagitis Histoplasmosis, extrapulmonary HIV-associateddementia-disabling cognitive or other dysfunction interfering with occupation or activities of daily living lsosporiasiswith diarrhea z 1 mo Kaposi sarcoma Lymphoma-Eurkitt, immunoblastic, primary (braidcentral nervous system) Mycobacterium avium, disseminated Mycobacterium tubercu/osis,pulmonary or extrapulmonary Pneumocystis carinii pneumonia Pneumonia, recurrent bacterial (>2 episodes in 12 mo) Progressive multifocal leukoencephalopathy Salmonella septicemia (nontyphoid), recurrent Toxoplasmosis of internal organ Wasting syndrome due to HlV-involuntary weight loss > 10% of baseline plus chronic diarrhea (>2loose stools/day for 3 0 days) or chronic weakness and documented enigmatic fever >30 days

When the CD4+ count is between 100 and 200/mm3, complications might include: Pneurnocystis carinii pneumonia, disseminated histoplasmosis,and cocadioidomycosis, miliary/extrapulmonary tuberculosis, progressive multifocal leukoencephalopathy (PML), wasting, peripheral neuropathy, HIV-associated dementia,

cardiomyopathy, vacuolar myelopathy, progressive polyradidopathy, or non-Hodgkin lymphoma. When the CD4+ count is between 50 and 100/mm3, complications might include: disseminated herpes simplex, toxoplasmosis, cryptococcosis,chroNc cryptosporidiosis, microsporidiosis,or candidal esophagitis. When the CD4-t count is below 50/mm3, complications might include: disseminated CMV, disseminated mycobacterium avium complex, or central nervous system lymphoma.

DIAGNOSIS AND WORK-UP DiagnosticTesting Box 175-3 lists risk groups for which HIV testing is indicated. Standard serologic testing for the presence of HIV begins with an ELISA test using recombinant antigens to measure antibodies to HIV in the blood.18If this test is positive, it is repeated on the same blood sample. If it is positive a second time, a Western blot test (using electrophoresis to detect antibodies to specific HIV proteins) is used for c~nfirmation.’~ Together, these tests have a sensitivity and specificity approaching 100%. Newer, faster tests are being developed and becoming available to health care practitioners for in-office use. These include the OraQuick ADVANCE Rapid HIV-1/2 Antibody TestFO the OraSure Oral Mucosal Transudate test,2l the Calypte HIV-1 Urine test,22and the Wellcozyme HIV-1&2vaginal secretion test.= Three test kits approved for home use include Confide, Home Access, and Home Access Express (where a sample

People with sexually transmitted disease High-risk categories: injection drug users, gay and bisexual men, hemophiliacs, regular sexual partners of people in the aforementioned groups, heterosexual people with > 1 sex partner in the past 12 mo and non-condom users in the past 6 mo People who consider themselves at risk Pregnant women Patients with active tuberculosis Recipient and source of occupational exposure Hospital admissions for patients ages 15 to 54 in areas of high prevalence Health care workers who perform exposure-prone invasive procedures (depends on institutional policies) Donors of blood, semen, and organs Medical evaluation for clinical or laboratory findings suggestive of HIV infection Modified from the Centers for Disease Control and Prevention. HIV Prevalence Trends in Selected Populations in the United States: Results from National Serosurveillance, 1993-1997. Available online at hnp:/M.cdc.gov/hiv/pubs/ hivpreva/ence/se/ected.hfm#highrisk [accessed May 26,20051.

can be taken at home and sent into a laboratory for pro~essing).~~ All of these tests use similar technology to detect antibodies to HIV. These tests can potentially produce negative results in a newly infected HIV+ patient (note the window period for seroconversion discussed earlier). If the ELISA is negative and risk factors suggest likely infection, the test should be repeated at 6-week, %month, and &month intervals. There is no reason to repeat if one of those tests comes back positive. Proper counseling of patients should be undertaken before testing. Risks should be ascertained, and the nature and meaning of potential results should be discussed. Positive test results should be given in a faceto-face meeting, and the naturopathic physician should educate the patient about his or her prognosis, treatment options, and social services available. Patients should be encouraged to notify their sexual or needle-sharing partners, and assistance in doing so should be offered.

History Initiation of care of an HN+ patient should begin with a standard medical history including a detailed diet history, exercise patterns, and a complete review of systems. A number of additional historical details should be obtained as well (Box 175-4).

Laboratory Assessment and Monitoring HIV-specific testing includes quarterly measurement of viral load and T-cell counts. The viral load detects the presence of viral RNA in the plasma and is most commonly tested via PCR. Current PCR technology is sensitive to less than 50 copies/mm3 of plasma.= Below this threshold, the viral load is deemed “undetectable.”This means the virus exists in concentrations in the blood below the ability of the given test to detect. Additionally, it is not reflective of viral presence or concentration in body compartmentsbeyond the blood (e.g., tissues, cerebrospinal fluid). This is an important point for patients to understand, as they still can infect others even if the virus is ”undetectable.” Other key tests involve T-cell counts. CD4+ helper cells and CD8+ suppressor cells are quantified, along with the CDPto-CD8 ratio. Below the threshold of 200 CD4+ cells/mm3, the risk of 01s increases and the medical management of HIV is modified (antimicrobial prophylaxis is initiated). A patient on antiretroviral therapy with a CD4+count that is falling or a viral load that is rising may be developing resistance to his or her current HAART. In this case, genetic or resistance testing should be considered. This will give the provider information about the susceptibility of the specific strain of virus to the various available medications and help in formulating a more effective regimen.

HIV/AIDS: Naturopathic Medical Principles and Practice

Female patients should have regular Pap smears with initial HPV testing, as there is a significant increase in cervical cancer rates in HIV+ women.27 Date of infection and subsequent diagnosis, as well as probable source of infection (IV drug use, sexual contact, transfusion). If date of infection is unknown, the naturopathic physician should determine if there was any history of acute retroviral syndrome. Addiionally, past and current HIV exposure risk factors should be determined.This information helps estimate overall heartiness and long-term prognosis. Vaccination history and adverse reactions to past vaccines. History of other sexually transmitted diseases. This information should include date and duration of infection, as well as therapies (efficacy, adverse reactions, and duration of treatment). Particular infections to screen for include: syphilis, gonorrhea, Cnlamydia, herpes simplex (all types), hepatitis (A, B, and C or E), and HPV (skin, genital, or anal). Chronologic history of HIV-related problems including history of 01s or cofactor virusedinfections (mononucleosis, EBV, molluscum contagiosum, CMV, or yeast infections--vaginal, gastrointestinal, skin); skin rashes or other lesions; oral lesions or tongue coating; lymphadenopathy; fevers; night sweats; weight loss; diarrhea; anorexia; fatigue; malaise; shortness of breath; or cough. Specific for females, history of abnormal Pap smears, and frequency of gynecologic examinations. HIV viral load and CD4 count trend is a good indicator of the patient’s susceptibility to 01, indication for and effectiveness of HAART, as well as long-term prognosis. History of all past and present HAART, as well as all other prophylactic antibiotic prescriptionmedication with duration of treatment, response and side effects, intolerance, and allergies. Family history of chronic disease with particular emphasis on cardiovascular disease (including lipid problems), diabetes, and cancer. History of psycho-emotional trauma and issues (abuse history, anxiety, depression). Patients’ spiritual lives and support systems, life goals, and meaning of HIV in their lives. Complete medical care team should be clearly identified, as well as reasons for seeking naturopathic medical care. The initial physical examination must be both comprehensive and appropriately focused as directed by the history. In addition, all patients should have particularly thorough examinations of the mouth and throat, skin, and genitalia. If a full pelvic examination and Pap smear cannot be done on a new female patient at the initial evaluation, these should be scheduled for shortly thereafter. ~~

~

CMK Cyiomegalovirus; .€By Epstein-Barr virus: HAAR’I; highly a c t i i antiretroviral drug therapy: HIV: human immunodeficiency virus; H f V human papillomavirus: Iv: intravenous; Or, opportunistic infection.

Basic initial screeningtests for all HIV+ patients should include a complete blood count (CBC)and a serum chemistry panel (to monitor liver, kidney, and pancreas function; electrolytes; blood proteins; glucose; and lipids). The baseline serum albumin level can serve as an independent predictor of prognosis in HIV+ women.26 Additional testing should include STD screening (venereal disease research laboratory or rapid plasma reagin for syphilis, chlamydia, gonorrhea, herpes simplex), hepatitis (A, B, and C), Siebert purified protein derivative of tuberculin and a baseline chest radiograph (for tuberculosis screening), and cytomegalovirus.

THERAPEUTIC CONSIDERATIONS Medical Management of HIV and AIDS The scientific and medical understanding of HIV and AIDS is still developing.HIV/AIDS was first recognized clinically only in 1981. Treatments are evolving on a continual basis. It would be naive to think that current medical practitioners know all there is to know about this illness at this point in time. What is known is that AIDS is a complex multifactorial disease that has both immunodeficiencyand autoimmune inflammatory aspects involving virtually every system of the body. HIV enters the body and infects CD4texpressing cells of the immune system. It inserts itself into cellular DNA and can lie dormant indefinitely. Those cells can be activated for the multiplication and reproduction of HIV virons by antigens, oxidative stress, proinflammatory cytokines, and overstressed liver detoxification and immune systems. Conventional medical management of HIV/AIDS revolves around the following treatment principles: Frequent monitoring including laboratory and physical examination Vaccination for 01s such as pneumococcal pneumonia, hepatitis B virus (HBV),and influenza Highly Active Anti-Retroviral Therapy (HAART) for inactivation or slowing HIV replication and increasing CD4+ cell counts Antibiotic prophylaxis for patients with abnormally low CD4 lymphocyte counts Antimicrobial treatment of 01s Symptomaticcare of HIV- or HAART-induced adverse drug reactions Radiation or chemotherapy, or both, for HIV-related neoplasms Psychosocial support via counseling, clinical social work, and medication The AIDSInfo website (http://www.aidsinfo.nih.gov/) provides an excellent resource for determining the most up-to-date conventional treatment guidelines. AIDSMo is administered by the U.S.Department of Health and Human Services and is a merger of the HIV/AIDS Clinical Trials Information Service (ACTIS)and its sister service, the HIV/AIDS Treatment Information Service (HIVATIS).Another fine resource is the Johns Hopkins AIDS website (http:/mkins-aids.edu). Hopkins has just launched a new service on its website called the HlV Guide (http:/hmdmpkins-hivguide.org/). This service provides information on the diagnosis and management of HIV and its associated OIs, medications, and resistance.

Specific Health Problems Hopkins also publishes a helpful text called the Medical Management of HW Infection, 2004 Edition by JG Bartlett and JE Gallant. It can be ordered from Johns Hopkins University,Division of Infectious Diseases, by phone ([800] 537-5487 [United States only]) or on the website. The best resource for patient education is http://www.thebody. com/index.shhnl. This site contains valuable information on signs, symptoms, treatments, and future possibilities.

Naturopathic Management of HIV and AIDS The naturopathic medical management of HIV and AIDS revolves around a number of treatment principles that should guide the physician in assisting patients in optimizing their health, slowing disease progression, improving quality of life, and improving immune function. Specific goals include the following: 1. Enhance overall integration with primary care physicians and build a caregiving team. 2.Complement and enhance the positive effects of conventional medical treatment and minimize the negative effects. 3. Establish a foundation of health and wellness on the basis of naturopathic principles. 4. Establish a core nutrient protocol. Replace nutrient deficiencies known to exist with HIV. Provide other nutrients to support optimal immune function. 5. Provide therapies to address constitutional symptoms, medication side effects, and symptoms of immunosuppression. 6. Provide specific antiviral therapy and immunomodulation using other nondrug treatments. 7. Educate and guide patients seeking alternatives to conventional treatment.

A resource specifically geared toward complementary practitioners is AIDS and Complementary and Alternative Medicine, Current Science and Practice by Standish, Calabrese, and Galantino, published by Churchill Livingstone in 2002.

1. Enhance Overall Integration with Primary

Care Physicians and Build a Caregiving Team In the area of HIV,naturopathic physicians should lead the effort to optimize integrated care. In fact, the nature pathic doctor may be the first and only physician coordinating or formulating a complete health care team. This provides an amazing therapeutic opportunity for the patient and physician. A holistic provider who identifies advantages of all available treatments and encourages positive relationships with all available providers

creates a unique and trusting relationship with patients who have often experienced lifetimes of fear, discrimination, victimization, and abuse. Naturopathic medicine offers an important opportunity to empower HIV+ patients. One of the first priorities is to ensure that each HIv+ patient has a complete care-providing team beginning with a conventional Western medicine HIV specialist. HIV specialists ensure the opportunity of HAART and have the greatest familiarity with the multitude of signs and symptoms unique to the HIV+ population. A growing body of literature reports that HIV+ patients have better objective indices of health (low viral load and high CD4 counts), better compliance with medications, and better long-term survival when working with HIV This expert care provides access to and ~pecialists.2~J~ detailed education on HAART and ensures the most efficacious diagnosis and therapy for the multitude of HIV-related illnesses or adverse drug reactions. The specialist's obligations are a full-time job, precluding many other aspects of care that have demonstrated efficacy for the overall health of HIV+ patients. Additional providers can support HIV+ patients with general health and lifestyle promotion, specific nutrient and other nondrug recommendations, social services, psychoneuroimmunologicsupport, counseling, personal empowerment, and end-of-life care. In fact, although naturopathic physicians might be legally able to prescribe prophylactic antimicrobial therapy and HAART in a growing number of states, the greater need is to provide nondrug holistic care in the areas just mentioned.

2. Complement and Enhance the Positive

Effects of Conventional Medical Treatment and Minimize the Negative Effects One of the paradigms of natural/preventative/holistic medicine is to avoid or minimize the use of higherforce (drug, surgery, radiation) interventions. This goal remains true in the care of HIV. However, all alternative providers must acknowledge that there are currently no therapies known to be as effective as HAART in suppressing viral load or increasing CD4 T lymphocyte cell numbers. CAM providers have a responsibility to be honest with HIV+ patients about this fact and must avoid the temptation to cater to some patients' goals of "finding an alternative" to HAART or avoiding antibiotic prophylaxis for 01s (risks of 01s increase exponentially when CD4 cell counts drop below 200 cells/pL). The current standard of care is to delay HAART in asymptomatic patients while the CD4 count is above 350 cells/uL or higher and the plasma viral load is below 100,000 c~pies/mL.~" Some HIV+ patients may never need HAART, and others may be resistant to HAART, but the option of HAART should always be considered

HIV/AIDS: Naturopathic Medical Principles and Practice in a unique position to help recognize adverse reactions and should not be discouraged. With or without and can initiate communication with the prescribing HAART, there is sigruficant evidence that HIV+ patients receive many benefits from nondrug t h e r a p i e ~ . ~ ~physician. Naturopathic physicians must actively understand, inteNucleoside and Nucleotide Reverse grate, and use the entire therapeutic order (most subtle, Transcriptuse Inhibitors lower force through most high force, often invasive therNRTIs were the first class of antktroviral drugs approved apies) to ensure that each patient has the best options to for use in the United States by the FDA. AZT was first maximize their quality of life, as well as longevity. introduced in 1986 and, after several changes in dosing, is Finally, physicians working with HIV must stay current still commonly used today? These drugs work during the with the global effort to find solutions for this pandemic transcription phase of the HIV lifecycle by competitive in order to provide the best possible treatment options to inhibition of HIV reverse transcriptase (RT) and DNA match patients’ short-term needs but also include stratechain termination. Nucleoside (or nucleotide) analogs act gic health goals and future possibilities. Physicians working with HIV must be involved in the strategic as substrates and bind to the active site of the RT enzyme. Then they are added to the new chain of DNA. Once investigations to find solutions for the pandemic. inserted, the normal links between pieces Many factors must be considered in the holistic care of the chain will not occur and the viral chain will be of HIV+ patients. Foremost are the numerous nondrug terminated without being inserted into the cell’s DNA. treatments that have demonstrated efficacy in the care The followingis a list of NRTIs (three-letter synonym/ of HIV. Also, having HIV typically complicates pregeneric name(s)/brand name). All are nucleoside analogs infection health challenges. In addition, the social, psyexcept tenofovir, which is the only FDA-approved chologic, and spiritual challenges that exist with the nucleotide analog: diagnosis of HIV create a need for health care that extends far beyond the best drug or nutrient necessary 1.AZT/azidothymidine/zidovudine/Retrovir for optimal heath. Holistic physicians have a vital role in 2.3TC/lamivudine/Epivir the care of each patient with HIV. 3. DDC/ zalcitabine/ Hivid The majority of HIV+ patients in North America are 4.DDI/didanosine/Videx using HAART. Many of those same patients are also 5. D4T /stavudine/Zerit using CAM therapies. Therefore one of the first priorities 6. ABC/abacavir/Ziagen of the naturopathic provider should be to ensure that 7. FTC/emtricitabine/Emtriva the patient is safe from adverse drug/nutrient interac8. TEN/tenofovir/Viiead (nucleoTIDE) tions. In order to ensure safety, it is necessary to underThe NRTIs are fairly well tolerated after introduction stand mechanisms of HAART, as well as mechanisms (initial mild to severe nausea usually resolves) with of common nutrients being used by HIV+ patients. minimal long-term adverse effects. Exceptions include Four main classes of HAART are currently used in the AZT and the three “ D drugs (DDC, DDI, and D4T). care of HIV+ patients32: A common side effect of AZT is bone marrow suppres1.Nucleoside and nucleotide reverse transcriptase sion leading to macrocytic anemia.34The D drugs are less inhibitors (NRTIs, or ”nukes”) commonly used today except in the case of multidrug 2. Non-nucleoside reverse transcriptase inhibitors resistance. They have been associated with mild to (NNRTIs, or ”nonnukes”) severe peripheral neuropathy and, of greater concern, 3. Protease inhibitors (PIS) pancreatitis.% These side effects manifest secondary to 4.Fusion inhibitors neural inhibition of mitochondrial DNA polymerase and reduced mitochondrial DNA content.36 Therefore When considering HAART, it is important to note patients initiating or on long-term D drug therapy that these medications have been generally fast-tracked should be provided ample mitochondrial support. through the FDA approval process. They have not been Acetyl-L-carnitine, coenzyme Qlo (CoQlo), essential subjected to the rigorous research and safety trials norfatty acids (EFAs),alpha-lipoic acid, and B vitamins have mally required by the FDA before a drug is approved for the public at large. Because of the problem of resistance been shown to decrease signs or progression of these side effects when taken in large d0ses.3’~~ to existing medications and the compelling need of As AZT and NRTIs in general have been on the HIV+ patients for these medications, they are prescribed market longer than the other drugs, it is no surprise that as soon as they are approved. Often there is little known the greatest amount of research regards nutrient interacabout the extent of the adverse drug reactions that may tions. Although there are no studies that indicate vitaoccur with their use. The doctor of naturopathy (ND) is mins or other nutrients deplete AZT, there is evidence likely to see an HIV+ patient on a more regular basis that AZT may deplete cellular levels of camitine, copper, than conventional western providers. NDs are therefore

Specific Health Problems

zinc, and vitamin B12.42*43 With the exception of carnitine, these nutrients can be found in a good hypoallergenic multivitamin and mineral supplement (MULTI).In addition to deficiency caused by NRTI drugs, carnitine deficiency has been found in HIV+ patients not on HAART. Further, there are many other indications for carnitine in patients with HIV,making this nutrient a high priority for supplementation. The root of the word carnitine is ”came,” the Spanish word for meat, highlighting the fact that patients with HIV often have greatly increased protein requirements. Some nutrients have been found to enhance the efficacy of NRTIs when taken in combination with these These drugs including vitamin E, zinc, and fo1ate.nutrients are easily supplemented through a nutritious diet full of whole grains, colorful vegetables and fruits, and a good MULTI. In other studies, Red Korean Ginseng at large doses has been found to reduce AZT resistance and increase CD4 counts, but the large dose can be cost prohibitive and energetically “overheating” for many patients, aggravating symptoms of anxiety, insomnia, heart palpitations, or s ~ e a t i n g . 4 ~ ~ ~ Overall, NRTIs are fairly well tolerated and a few have the additional benefit of being active against hepatitis B virus (3TC, FTC, TEN) as well.49-51Patient compliance is critical when taking NRTIs so as not to lose this option when HAART is indicated.

When used in combination with NRTIs, NNRTIs produce sustained reductions in plasma viral loads and improvements in immunologic responses in large randomized, double-blind, placebo-controlled studies. Two NRTIs (specifically zidovudine and lamivudine) were most efficacious when used in combination with one “ R T I (efavirenz).55” This same regimen was found to be superior to one using three NRTIs (zidovudinelamivudine-aba~avir).~’In another study, nevirapine and efavirenz showed similar efficacy in combination with two NRTIS.~~ The advantage of this type of protocol is the fewest number of side effects, excellent long-term viral suppression, and ease of dosing (fewer pills).

Nonnucleoside Rmerse Transmptase Znhibitors The second class of HAART is the nonnukes/NNRTIs (generic name/brand name):

Although PIS are effective at viral suppression, they are associated with the greatest number and most significant adverse drug reactions. These include chronic and persistent gastrointestinal (GI) abnormalities; lipodystrophy and lipoatrophy; and liver, kidney, and musculoskeletal complaints. PIS work during the cleavage part of the viral lifecycle by binding competitively to the substrate site of the viral protease (the enzyme responsible for the posttranslational processing), resulting in inhibition of the enzyme and the production of immature virus particles. It is essential to realize that NNRTIs and PIS also work by inhibiting cytochrome P450 3A4 enzyme metabolism. Inhibiting thisenzyme slows down the metabolic breakdown of the drug and effectively prolongs higher blood levels of the drug, which results in better viral suppression. Many foods, nutrients, and botanicals have been known to upregulate this enzyme function, and two have gained noteworthy attention. Some small studies (n c 25) in healthy HIV-negative (HIV-) individuals, as well as in vitro studies, have demonstrated that garlic and St. John’s wort decrease NNRTI and PI drug levels. In the human trials, HIV subjects initiated NNRTI or PI therapy to establish drug levels necessary to suppress viral load. Garlic or St. John’s wort was then introduced at levels typically used for therapeutic

1. efavirenz/Sustiva 2. nevirapinelviramune 3. delavirine/Rescriptor (rarely used)

“ R T I drugs are also fairly well tolerated after introduction (exhibiting a mild transient to severe rash and sleep disturbances) and may be the most important class of HAART. Without the NNRTIs, HIV+ patients will likely require PI combinations that typically result in more pronounced adverse drug reactions. Therefore it is essential that patients understand the significance of the NNRTI option when initiating therapy. Other than the transient rash, typical side effects (depending on the specific drug) include insomnia, abnormal dreams, elevated liver enzymes, and gynecomastia (all manageable with naturopathic support).52-54 “RTIs also affect the transcription process and work by allosterically binding to HIV-1 reverse transcriptase and inhibiting both RNA- and DNA-directed DNA polymerase functions of the RT enzyme. No nutrients are known to be depleted or to enhance the efficacy of NNRTIs.

Protease Znhibitors The third class of HAART is the PIS (generic name/ brand name): 1.ritonovir/Norvir 2. saquinavir/Invirase 3. saquinavir/Fortovase 4. indinivir/Crixivan 5. nelfinavirlviracept 6.lopinavir+ritonavir/Kaletra 7. amprenavir / Agenerase 8. atazanavir / Reyataz 9. fosamprenavir/Lexiva: a calcium phosphate ester prodrug of amprenavir

HIV/AIDS: Naturopathic Medical Principles and Practice

effect. Blood levels were then measured and found to be lower than the levels believed to be necessary to maintain optimal viral suppression. Garlic or St. John's wort were then discontinued, and NNRTI or PI blood levels were subsequently measured and found to be back in the therapeutic Although these studies certainly do not conclusively demonstrate that garlic and St. John's wort interfere with HAART viral suppression (small number of participants, single antiretroviral vs. typical multidrug HAART protocol, HIV- vs. HIV+, drug-naive vs. long-term HAART), these therapies should certainly be avoided in patients with HIV on HAART. The lesson learned from these studies is to be intimately aware of the mechanism of action when adding new nondrug therapies intended for patients on multidrug treatments. The potential for drug/nutrient interactions also should encourage and reinforce the use of the multitude of low-force interventions (e.g., diet, lifestyle, homeopathy, physical medicine, counseling)for conditions commonly treated by garlic or St. John's wort, or both. Naturopathic physicians should endeavor to use the many safe and noninterfering therapeutic options to avoid potentially decreasing "RTI blood levels and increasing drug resistance. Naturopathic physicians also quickly think of milk thistle when considering the sigruficant GI and liver complications with PIS. To date, there are two studies investigating this nutrient/drug interaction. In one with 10 HIV-,drug-naive patients taking milk thistle at 175 mg tid, investigators concluded that milk thistle did not signhcantly alter blood levels of indinavir despite trough levels being decreased by as much as 25%.@The other showed no effect on indinavir levels in healthy subjects.@More studies on milk thistle are necessary. No nutrients are known to be depleted by or enhance the efficacy of PIS. Fusion Inhibitors Fusion inhibitors are the most recent class of FDAapproved HAART. Enfuvirtide/Fuzeon, the first of this class, was approved for use in 2003. This drug is unique because it is the only HAART medication requiring injection (two subcutaneous injections per day into the upper arm, upper leg, or stomach). Fuzeon is currently being used as salvage therapy and to enhance the effect of other HAART medications. It is not designed to be used alone. It is fairly well tolerated with the exception of injection-site irritation, allergic reactions, and increased risk of bacterial pneumonia. This fusion inhibitor works by binding with cell receptor proteins gp41 that are necessary for HlV to identify and enter selective cell membranes. This drug is associated with no known drug/nutrient interactions.

3. Establish a Foundation of Health

and Wellness on the Basis of the Naturopathic Principles

The naturopathic standard of incorporating healthy diet and lifestyle practices cannot be overemphasized for HIV+ individuals. These patients are likely to be taking a large number of medications or nutritional supplements, or both, even before making a first visit to an alternativeprovider, and HIV, HAART, and prophylactic medications create additional stress on many systems. Therefore each patient should be clearly encouraged and continually reminded to maintain several habits to ensure optimal GI health and nutritional intake. The most important recommendation should be to encourage a high intake of filtered water to decrease oxidative stress and to reduce the toxic load of the HIV and medications. Secondly, these patients should also be encouraged to maintain an optimal intake of Protein requirements can be as high as 100 to 150 g per day, particularly when patients are experiencing malabsorption or diarrhea, or both, and it may be necessary to provide supplemental protein to prevent weight loss. Studies using large doses of whey protein and amino acids (L-glutamine,L-arginine) have proven effective in reversing or preventing HIV-induced ~ a s t i n g . 6 ~ ~ ~ Another core nutrient, EFAs, has been found to be deficient in HIV+ patients. Studies have demonstrated that HIV+ patients consuming generous amounts of EFAs have an increased body cell mass and a decreased risk of progression to AIDS.mn HIV+ patients and healthy subjects ingesting fruit juices or a fruit-vegetable concentrate on a long-term basis were found to have more optimal micronutrient and antioxidant level^.^,'^ From this, it can be concluded that HIV+ patients should be continually encouraged to include colorful vegetables and fruits in their diets to help maintain essential micronutrient and fiber levels, as well as provide digestive and liver supp0rt.7~,~~ HIV+ patients commonly require appetite stimulation or digestive enzyme support, or both, to combat the adverse effects of HIV, HAART, and prophylactic antibiotics on the GI system.77r78 Further, with high oxidative already present in the digestive system, all patients should be strongly encouraged to avoid additional GI stressors such as high-sodium, high-fructose corn syrup in processed foods, alcohol, caffeine, fried foods, and cigarette smoke. Raw eggs, unpasteurized milk, undercooked meat or fish, and potentially contaminated foods must also be avoided to decrease the risk of gastrointestinal OIs and parasites. Naturopathic physicians should exercise extreme caution when considering allergy elimination diets in HIV+ patients due to the likelihood of nutrient deficiencies, maldigestion, and malabsorption caused by HIV itself

Specific Health Problems

and HAART medications. Rather, physicians should recommend replacement of common food allergens one food at a time to ensure patients can maintain replacement diets without decreasing caloric and nutrient intake over time. Removing food vices and irritating foods may be one of the most challenging aspects of moving HW+ patients toward optimal wellness, as there are so many other higher-priority challenges and a vital need to maintain body mass. Other lifestyle factors should be part of the nature pathic foundation with each HIV+ patient. Aerobic exercise has been demonstrated to provide benefit to individuals with immunodeficiencydiseases, particularly through stress alleviation and mood enhancement. HIV+ individuals had increases in CD4, CD8, and NK cells immediately following aerobic exercise, and long-term exercise has demonstrated increases in immune Mind-body exercise also has an important role for patients with HIV. HIV+ individuals practicing Tai Qi demonstrated greater overall perception of health and sigruficant improvements in several measures of physical function when compared with controls.*lOther patients practicing yoga reported increased self-confidence and quicker return to athletic activities after medical All patients should be encouraged to create an optimal sleeping environment and to sleep 8 to 10 hours each night. Sleep is essential for repair and rebuilding of tissues and has been demonstrated to increase circulating NK cells and HIV+ patients involved with group activities have better prognoses, as well as decreased stress and anxiety. Anecdotal evidence links long-term AIDS survival with one or more of the following: having a positive attitude toward the illness, participating in health-promoting behaviors, engaging in spiritual activities, and taking part in activitiesthat support the HIV+ community. Structured, brief group intervention for bereavement of loss of loved ones has been shown to decrease plasma cortisol and improve several immune markers in patients with HIV.85fi Other forms of stress relief and management have proven effective for I-IIV+ patient health care. Cognitive behavioral stress management (CBSM) is a guided form of relaxation training. It has been shown to improve the quality of life in HIV+ women, decrease herpes simplex 2 antibody titers in HIV+ men, and decrease markers of ~-~l stress and improve HIV laboratory ~ a l u e s . ~Prayer, including distance healing, has demonstrated fewer new AIDSdefining illnesses, decreased illness severity, sigruficantly fewer doctor visits, fewer hospitalizations, and sigruficantimprovements in Prayer and meditation have also been correlated with self-improvementsin mental health in large numbers of resp0ndents.9~Finally, laughter has been associated with improvement in WBC values and decreased stress.%

4. Establish a Core Nutrient Protocol Replace Known Nutrient Deficiencies Caused by HIV Vitamin and mineral replenishment has been demonstrated to be efficacious.9597A recent, double-blind, placebo-controlled study involving 1078 pregnant Tanzanian women infected by HIV taking a simple multivitamin received much publicity in North American. This study reported that women taking vitamin A (preformed vitamin A and beta-carotene) and a low-cost multivitamin (vitamins B, C, and E) resulted in delayed progression to AIDS, as well as a delay in the requirement to initiate antiretroviral therapy. Adding the low-cost multivitamins was statistically significant versus placebo or vitamin A alone.98Numerous vitamin and mineral deficiencies have been identified with HIV disease progression.99These deficiencies are likely due to loss, poor absorption, or rapid use and consumption. Box 175-5summarizes nutrients that have been found to be deficient in patients with HIV. Typical daily doses required to correct these deficiencies taken in divided doses throughout the day are noted in parentheses followed by reasons for deficiencies or benefits, or both, found by replenishment. Nutrient deficiencies (high doses of beta-carotene, acetyl-L-carnitine, dehydroepiandrosterone [DHEA], testosterone, reduced glutathione and catalase) not commonly included in a MULTI must be replaced through specific dietary regimens or through additional supplementation. Natural forms of beta-carotene should be used, as evidence suggests that synthetic forms can increase the risk of lung cancer in individuals who smoke.lm Consider acetyl-L-carnitine as a high-priority nutrient despite high cost, on the basis of the number of benefits. Measure hormone levels before supplementation to guide effective dose, and minimize the risk of these higher-force interventions. Provide Other Nutrients t o Support Optimal Immune Function Box 175-6 summarizes nutrients that have been found to replace or reduce other nutrient deficiencies or have beneficial action in patients with HIV, their daily dose divided throughout the day, and effects of supplementation. All these nutrients have benefits but sigruficantly increase overall cost and pill burden. Therefore priority should be given to the most essential (EFAs) and lowercost (vitamin C) nutrients or to meet specific needs of specific symptoms as described in the next section.

5. Provide Therapies to Address Constitutional S ptoms, Medication Side Effects, an Symptoms of Immunosuppression

d"

In addition to the general nutrient considerations already discussed, the following are some approaches

HIV/AIDS: Naturopathic Medical Principles and Practice

Vitamin A (15,000-30,000 IU taken with food) slows progression to AIDS and decreases mortality, improves growth in infants and decreases stunting associated with chronic diarrhea, and prevents GI deterioration in mothers and May increase the risk of HIV transmission by breastfeeding but has no effect on mortality by 24 mo.234Deficiencies can be due to: decreased dietary intake, poor GI absorption, high urinary loss, impaired hepatic protein synthesis, and increased needs due to chronic infection. Betacarotene (60-120 mq/l50,000 IU taken with food) replenishment increased CD4+ count, CD4/CD8 ratios, total lymphocyte count, and decreased mortality.2sa7 Deficiency found in all HIV+ patients is likely due to poor digestion, decreased free radical elimination, and high lipid peroxidation.238 Folate (400 pg) normalized cell differentiation. Deficiency is most likely due to malabsorption, and m i n d u c e d deficiency may increase risk of bone marrow toxicity.239-240 Vitamin B1 (50 mg) replenishment is associated with increased survival in HIV+ patients and decreased progression to AIDS.241-243 Vitamin B6 (50 mg) is essential in nucleic acid and protein metabolism and cellular and humeral immune responses.2M~245 B6 repletion both alone and in conjunction with CoQlo increased circulating IgG, CD4+ cells, and CD4/CD8 ratios.246 Vitamin B12(1000 Fg hydroxy-, methyl- or cyanocobalamin best taken via intramuscular injections Sdweek-alternate form is daily 1000 pg sublingual) is important in several parameters of immune function, proper cell differentiation and nerve function, and decreasing homocysteine levels. BIZrepletion can improve lymphocyte counts, CD4/CD8 ratios, and NK cell Supplementation has also been found to reverse AIDS dementia complex when associated with low levels.248Deficiency has been associated with increased risk of progression to AIDS and with HIV disease in Vitamin E (800IU d-mixed tocopherols taken with food) is indicated to decrease lipid peroxidation, protect against A2T-induced oxidative damage to cardiac mitochondria, normalize immune function, and slow progression to AIDS.252-257 Deficiency is found in most HIV+ patients, with wasting, and in progression to AIDS?= Copper (2 mg) can inhibit HIV protease and viral replicati0n.2~~ Deficiencies of copper are associated with AZT therapy and AIDS.2W-26’

Magnesium (300 mg) deficiency is found in AIDS patients.262,263 Selenium (400 pg) is indicated to slow HIV proliferation, decrease HIV associated mortality, decrease anxiety in HIV+ recreational drug users and to decrease hospitalization and cost of caring for HIV+ pat i ent ~ . 2”~Increasing ~~ deficiency in all HIV+ patients progressing to AIDS may be due to decreased caloric and protein intake, malabsorption, and various infections.268 Zinc (15 mg-optimal intake levels have not been determined) has Deficiency is noted been found to decrease frequency of Ols?69.270 in all HIV+ patients progressing to AIDS?71 Acetyl-L-carnltlne (2-6 g best taken away from other protein to optimize absorption) is essential for proper energy supply, as well as critical metabolic functions. Deficiency is common in HIV+ patients and increases the risk for alterations in fatty-acid Repletion has also been linked with a reduction in serum triglycerides, decreased risk of wasting, increase in CD4 cells and reduced apoptosis, increased levels of serum insulin-like growth factor, reduction in mitochondria1neurotoxicity, and treatment of peripheral n e u r ~ p a t h yIt. has ~~~ also ~ ~been ~ demonstrated as an effective treatment for NRTI-induced lactic acidosis?*’ DHEA (15-50 mg taken with food) repletion helps to increase CD4 count and stimulate immune function.282 Testosterone (intramuscular injection weekly) is indicated if serum levels are low to decrease loss of lean body and muscle mas~.~~3 GlutathiondGSH (increased through selenium and Nacetylcysteine or whey protein powder) has been found to decrease disease progression and m ~ r t a l i t y . Deficiencies ~ ~ - ~ ~ ~ are found in both symptom-free HIV+ and AIDS patient^.^^-^^^ Many of these nutrients can be replenished through the use of a highly nutritious diet and a good MULTI. A few MULTls have been specifically developed to replace the deficiencies of HIV+ patients and include high doses of carotenoids, B vitamins, antioxidants, and sometimes digestive enzymes.Taking one MULTI designed specifically for HIV reduces pill burden and enhances compliance. Conversely, it is generally more cost effective to use a basic MULTI and supplement individually with additional nutrients.

AIDS, Acquired immunodeficiency syndrome; DHEA, dehydroepiandrosterone; GI, gastrointestinal; GSH, growth stimulating hormone; HIY human immunodeficiency virus; NK, natural killer; NRTI, nucleosidehide reverse transcriptase inhibitors; O/, opportunistic infection.

for specific health conditions and OIs. Basic naturopathic philosophic principles should apply. The naturopathic physician should endeavor to identify and remove the cause; tonify systems; and, most importantly, treat each patient as an individual. Many choices will be detailed here for any given issue. All of them are not going to be applicable to each patient. The naturopathic physician should look at each patient individually and choose the most appropriate approach or approaches. In addition, keep in mind that these are complicated patients using complicated treatment regimens. Any therapeutic tool chosen must be appropriate given a patient’s specific circumstances.

Candida albicanslOra1 Thrush Overgrowth of this fungal organism may occur as a result of HIV itself (a low CD4+ count reducing the body’s immune capacity) or secondary to prophylactic antibiotic treatment. Orally, it can create pain and make eating difficult, which can lead to reduced caloric intake and subsequent problems. In the intestines, it can create inflammation and compromise nutrient absorption. In the esophagus, it can create pain and should be dealt with swiftly via antifungal pharmaceutics. For treatment, patients should avoid foods that feed yeast and promote its growth, such as simple

Specific Health Problems

SNyhm marlanu~ilkthistle (300mg standardized extract away from HAART) is indicated for all patients on HAART to improve liver function, decrease liver damage, and increase antioxidant activity of blood cells.290 NAC (2-8 g best taken away from other nutrients but may need to be taken with food to decrease GI distress) is indicated to prevent loss of sulfur containing amino acids, increase GSH, decrease TNF-a activity, and increase CD4 cell count.a1-293 coQlo(100-300mg) optimized mitochondria1function and replaced deficiency?m Repletion with CoQlo increased circulating IgG, CD4+ cells, and CD4/CD8 Vitamin C (2-6 g) when combined with vitamin E significantly lowered oxidative stress and demonstrated a trend toward lowered viral

Alpha-lipoic acid (600 mg) protected the liver, inhibited viral replication, increased intracellular GSH, increased CD4/CD8 ratios and potentially decreases peripheral neuropathy pain by its antioxidant effect on nervous tissue.L-arginine (7.4 g taken away from food) improved lean body mass and increased NK cell activity. Large amounts of arginine can result in aggravation of herpes virus outbreaks. Prophylactic L-lysine may prevent or reduce this aggravation. EFAs (5 g taken with food; best from fish oil) improved lean body mass, increased NK cell activity, and was beneficial as adjuvant therapy in patients with tuberculosis.

C d l h Coenzyme Qto;WAS,essential fatty acids; GSH, growth stimulating hormone; HAAR'I; highly active antiviral therapy; NAC, N-acetylcysteine; NK, natural killer; TNfu. tumor necrosis lactor-alpha.

carbohydrates, sugar, baked goods, and starchy vegetables. The guidelines outlined in Appendix 1 should be followed, and these treatments should be considered: Provide and support healthy flora supplements with at least 8 billion colony-forming units (CFus) best taken with food. Different beneficial species include Lactobacillus acidophilis/bijidus; Lactobacillus GG, a well-researched strain from Germany; or Sacromyces boulardii, which is best for antibiotic-induced colitis and can help displace pathogenic f l ~ r a . ' ~ ' - ' ~ ~ Garlic (1 to 2 g best taken before meals) is a potent antifungal found to spare nonpathogenic flora; patients on HAART should avoid it, however." Oregano oil (300 mg best taken away from food) is a potent antifungal.lo7 Nystatin and fluconazole are pharmaceutic antifungals. Cardiovascular Disease This is an issue that will become inmasingly problematic and prevalent in the coming years. The adverse effects on serum lipids and glucose that accompany the use of HAART medications (specificallyPIS and D-type NRTIs) will have a signhcant effect on the promotion of cardiovascular disease. This will be even more pronounced in patients already at high risk (the presence of predisposing factors such as positive family history). All patients on HAART should be encouraged to institute preventive diet, healthy lifestyle, and other nutritional interventions as appropriate. See Chapter 150 for specific therapeutic approaches and options. Garlic should be avoided due to its adverse interaction

with HAART medications. The following specific nutrients should be considered: Acetyl-L-carnitine (2 to 6 g best taken away from other protein to optimize absorption) repletion has also been linked with a reduction in serum triglycerides. CoQlo (100 to 300 mg) may enhance cardiovascular function.lm Arginine (7.4 g taken away from food) decreases atherosclerosis.lW EFAs (5 g taken with food) may lower lipids.l1° Diarrhea This is a common complaint and an issue that can greatly affect quality of life. An HIV+ person might develop diarrhea for numerous reasons, and the specific etiology guides the choice of treatment. Causes might include HIV-associated enteropathy; HAART side effects (see specific medications; particularly an issue with PI); antibiotic side effects; gastrointestinal infections; and food allergies or intolerances.An osmotic-type diarrhea can also result from the consumption of too many indigestible gel caps (from medications and supplements) building up in the lumen of the intestines. The first treatment priority is to remove the cause if at all possible. There is an increased incidence of gluten intolerance in HIV+ individuals.'" Lactose intolerance and irritable bowel syndrome are also possibilities. Food allergies should be ruled out. The naturopathic physician should ensure that the patient is strong enough to undergo food elimination and that clear alternatives are given for eliminated foods. Stool cultures and ova and parasites testing should be done to screen for suspected infectious causes, and patients should be treated as

HIV/AIDS: Naturopathic Medical Principles and Practice

indicated for each microbial etiology. All nutrient supplementation may be stopped on a temporary basis to see if that affects the situation. Then supplements can be reintroduced one at a time to determine which one is the cause. Steps for prevention include avoiding: unfiltered tap water, unpasteurized mi& or dairy products, ice made from unfiltered tap water, raw fruits and vegetables unless they can be peeled personally or washed with appropriate antimicrobial agents, raw or rare meat and fish, meat or shellfish that is not hot when served, and food from street vendors. Dehydration can be prevented by replacing electrolytes; broths, soups, fruit and vegetable juices, or high-nutrient drinks should be included. Prevent malnutrition; if diarrhea is present, malabsorption of nutrients is a likely consequence. Ensure adequate micro- and macro-nutrient intake with a MULTI and maintain adequate protein intake (requirements may increase to 100 to 150 g/day). Initial dietary intervention may include simphfymg the diet (BRAT diet: bananas, rice, applesauce, toast) or using 1 tbls tomato juice combined with 1 tbls sauerkraut juice (a remedy from Dr. Bastyr covering electrolyte replacement and increasing glutamine intake). Carob powder is an astringent that can help symptomatically. Begin with 1tsp in applesauce and increase up to 6 tsp per day as needed. Consider these additional supplements: Provide and support healthy flora as described earlier in the care of candida.l12 L-glutamine (10 to 40 g best taken away from other proteins) is an amino acid that provides fuel for small intestine enterocytes. Using a powder is most efficient and cost effective. Start with 3 g tid. This can be increased up to 40 g daily if necessary. This high dose can create psychoses, so the patient should be monitored ~losely."~ Diphenoxylate and atropine (Lomotil), loperamide (Imodium), and psyllium husk (Metamucil) are common pharmaceutic interventions. Herpes Simplex ViruslHerpes ZosterlShingles All issues with a herpes-type virus etiology are considered together, as the treatment approach is similar for each. The sequelae of herpes viruses tend to manifest on the skin in a dermatomal pattern of distribution. These symptoms can occur secondary to various types of stress, hormonal fluctuations, or a poor immune system response. First and foremost, try to identify and remove causes of stress (including dietary, emotional, and sunlight exposure) and support the immune function.Secondarily,address the symptoms (most often pain is at the forefront).

Naturopathicphysicians should consider the following: Dietary suggestions include eliminating foods high in L-arginine (promotes herpes replication) such as chocolate, nuts, and peanuts and increasing foods high in L-lysine (antagonizes L-arginine)such as whole grains, dairy, fish, lima beans, and soy L-lysine; 1000 mg tid away from food during an outbreak; 500 mg tid away from food prophyla~tically'l~ Olive leaf extract (2000 mg) is an effective antivira1115 Monolaurin; antiviral effective against encapsulated DNA viruses; 300 to 600 mg tid116 Melissa officinalid; antiviral topical botanical"' GZycyrrhiza gluha; antiviral oral and topical botanicallla Herbal tincture (as parts): Hydrastis (l), Turuxucum oficinule (the root) (2), Lomatiurn (2), Pussifzora (l), Astrugulus (l),GeZsemium (15 drops/oz); 60 drops every 2 hours during prodrome, four times/day during an outbreak, bid for prevention Acyclovir/valacyclovir: pharmaceutic antiviral therapy Kaposi Sarcoma Kaposi sarcoma (KS) is an HIV-associated neoplasm of vascular origin that tends to occur when CD4+ counts fall below 500/mm3. KS is rarely found outside of the HIV+ population. The etiology of AIDS-associated KS is poorly understood, but several factors are thought to contribute including the presence of human herpes virus (HHV)-type 8, a compromised immune response, and hormones (it occurs rarely in women, and androgen therapy causes increased proliferation of the tumors). It is most commonly found in iron-rich geographic areas. Interestingly, 90% of AIDS-related cases in the United States occur in homosexual men, making it rare in heterosexual men, women, and IV drug users. KS begins as macules or elevated papules and can progress to large plaques or nodules. The color ranges from pink to purple or brownish-black. The lesions may be round or oval and do not blanch when pressure is applied to them (contrast this with ecchymoses). The lesions often appear first on the skin of the upper body or mucosal surfaces. In their aggressive form they can become widely disseminated and can manifest anywhere on the skin, mucous membranes, lymph nodes, or viscera (including the GI tract from mouth to anus, lungs, liver, spleen, or pancreas). KS tumors secrete increased amounts of angiogenic growth factors, tumor necrosis factor-alpha (TNF-a), interleukin (1L)-6, basic fibroblast growth factor, plateletderived growth factor, and o n c o ~ t a t i n - M . ~ ~ ~ - ~ ~ ~ The level of immunosuppression of an affected person determines the clinical course of KS in AIDS. Currently, there are no known cures and the various local and systemic approaches are aimed at palliation.

Treatment may involve the use of chemotherapeutic agents such as doxorubicin, as well as standard HAART. Surgical excision can successfully remove a lesion, but there is a high rate of recurrence at the affected site. Other researched options that have produced varying results include radiation therapy, cryotherapy with liquid nitrogen, and electrical stimulation with direct current. The following treatments should also be considered: Topical and systemic retinoidsIE Topical vitamin D (1,25dihydroxyvitamin D3)126 Iron has been shown to stimulate the growth of KS cells in vitro, while iron chelators reduced their Given this information, it may be sensible to limit iron intake and ensure that serum iron and ferritin levels are at the low end of normal. The use of various cytokine inhibitors and antiangiogenesis compounds might have a benefit for reducing the proliferation of these vascular tumors. As there are no known curative therapies and the palliative treatment of KS is difficult at best, naturopathic physicians have an opportunity to be creative and make a contribution in this area. Given the assuciation between KS and HHV-type 8, it may be potentially beneficial to use antiherpetic therapies if a patient is known to be herpes simplex virus positive.IB Topical application of medicinal peat preparation has resulted in remission of topical KS lesions in several patients. Glutathione (NAC as a precwsor) could be helpful in the treatment of KS lesions as well.1B132

Lipodystrophy Lipodystrophy is a redistribution of adipose tissue from the extremities to the trunk.It often manifests with a Cushing’s-like “buffalo hump” over the upper thoracic region of the back or truncal obesity. Self-image issues are often most sigruficant for patients experiencing this condition. Lipodystrophy can occur as a result of alterations in lipid metabolism secondary to HAART or simply chronic HIV infection (>15 years).133Given the appearance of the buffalo hump, it is possible that adrenal abnormalities are contributing to the problem. Increases in serum cortisol lead to increases in insulin release from the pancreas, which drives blood glucose into storage in adipose cells. This leads to increased truncal 0 b e ~ i t y . l ~ This ’ ~ ~is a physiologic mechanism that bears consideration in therapeutic approach, as well as in future research. Lipodystrophy has also been found to increase with lack of exercise.I3 In addition to correcting dietary nutrient insufficiencies, supplementing nutrients as per the general protocol, and increasing exercise, the following approaches can be taken: Ensure that blood glucose is appropriately regulated. Take L-glutamine (10 g in divided doses away from

Take acetyl-L-carnitine (2 to 6 g away from food) to optimize mitochondria1 fun~tion.’~~-’~ Dimethyl sulfoxide (DMSO)/bromelain(5%bromelain compounded in DMSO gel applied bid to tid) topical applications have resulted in reduction of Cushingoid adipose depositions. Conventional treatment may include surgical removal of the truncal adipose deposits. While this may not be the most desirable approach due to its invasiveness, patients who undergo this procedure tend to be happy afterward due to their more positive self-image. Buccal injections of polylactic acid (PLA/Nufill) can reduce the cosmetic signs of lipodystrophy and wasting.144

Macrocytic Anemia Macrocytic anemia can be a secondary effect from the malabsorption of nutrients or a side effect of HAART (AZT causes bone marrow toxicity, PIScause malabsorpt i ~ n ) . lThe ~ ~ following J~ treatments can be considered Vitamin BI2 (hydroxycobalamin/methylcobalamin/ cyanocobalamin 1000 pg/ml intramuscular [IM] injection 3 times/week) is an important nutrient for proper cell division and differentiati~n.’~~ If an IM injection is unavailable, sublingual tablets at 1000 pg/day can be used to bypass intestinal absorption. Folk acid (400 pg/day found in most good MuLTIs) and vitamin B12are important nutrients for proper cell division and differentiation.lm Vitamin B complex (3 ml IM each week) is indicated for proper cell division and differentiati~n.’~~

Neurop athy This is usually manifested in the periphery, particularly in the feet. It can work its way proximally as the severity increases. It is most often seen either as a result of long-term HIV infection or as a side effect of the “D”-type NRTIs and their toxic effect on the mitochondria in the n e u r ~ n s . ~ ~Diabetes O J ~ ~ mellitus (type 2) can also be a factor, as can overdoses of vitamin B6 (>200 m g / d a ~ ) . ’ ~ ~ The following treatments can also be considered: Acetyl-L-carnitine (2 to 6 g best taken away from other protein to optimize absorption) decreases the risk for alterations in fatty-acid oxidation and energy supply, as well as critical metabolic EFAs (5 g/day with food) are an antiinflammatory and component of healthy cell membranes.IX Vitamin BI2 (1000 pg/ml IM three times each week) is an important nutrient for proper cell division and differentiation. Vitamin B complex (1 ml IM three times each week) is indicated for proper cell division and differentiation.155,1%

HIV/AIDS: Naturopathic Medical Principles and Practice

die, the desire to live can wane. It is critical that practitioners always be vidant for signs of suicide or loss of hope in patients. These signs should be taken seriously, and there should be no hesitation in bringing in experiP r e pancy enced professional help to assist these patients. There is a key consideration in contemplating the The evidence is mounting that MULTI supplementatreatment of any psychologic issue in this patient popution contributes to better pregnancy outcomes in HIV+ lation. Extreme caution must be exercised due to issues women. One recent study found a reduction in adverse of polypharmacy and drug-nutrient interactions. Many outcomes including fetal loss, low birth weight, and prematurity.16oAnother study associated multinutrient of these patients are taking a substantial number of pharmaceutic medications. Interactions among many supplementation with longer gestational length, birth nutrients and these medications and even among the weight, and head circumference.161Yet another study medications themselves are likely. Before instituting any found that HlV disease progression and mortality was treatment, all potential interactions must be researched, delayed in women given multivitamin supplementation.162Vitamin supplementation in lactating HIV+ identified, and considered. An example of this problem is the potential use of women has been shown to result in higher CD4+ counts and a lower risk of diarrhea in the children.163 St. John's wort, a commonly used herbal antidepressant. Conversely, one study reported an increased risk of As previously discussed, St. John's wort is an inducer of the Cytochrome P-450 detoxification enzyme 3A4 in transmission from mother to child using vitamin A the liver and has been found to reduce serum levels of and beta-carotene. 161 Another study showed that vitavarious HAART medications. Therefore it can theomin A and beta-carotene supplementation helped to retically reduce the effectiveness of those medications decrease GI deterioration in HIV+ mothers and their and potentially lead to increased issues with resistance. children.165Vitamin A and beta-carotene should be used The use of St. John's wort should be avoided in any with caution in pregnant/lactating women. Another important consideration is that exclusive patient who is undergoing HAART. breastfeeding has been associated with a lower rate of Modalities such as counseling and homeopathy can mother-to-child transmission than breastfeeding along be quite useful in treating these psychologic conditions. Additional therapies to consider follow: with other foods.l& The following are recommended for treating pregnant Amino acids (if levels are found to be low by specialty patients: laboratory analysis) should be prescribed in combinations tailored to replenish deficien~ies.'~~J~~ High-potency hypoallergenic MULTI; use as directed Vitamin A for the newborn; 200,000 IU at birth16' Zinc (25 mg) to normalize levels and improve efficacy Replenishment of likely HIV-induced deficiencies of of antidepressantsln EFAs (5 g/day with food) have been found to be folate (400 pg) and selenium (400 pg)168J69 useful as adjunctive treatment in depressive disorders.173,174 Psychologic Conditions SAMe (1600 mg) has been shown to be as effective as Issues such as depression, anxiety, posttraumatic stress imipramine (150 mg) in treating major depression and disorder, sexual dysfunction, and substance abuse is better t01erated.l~~ are extremely common in the HIV+ population. These See Chapter 144 for more specific guidance on various problems potentially have physiologic, as well as psychologic conditions. As noted earlier, caution must psychologic, components and can be neglected by conbe exercised to ensure that any treatment chosen is ventional practitioners, largely because of the time conappropriate for the specific circumstances of any straints the medical system imposes on them. Patients patient. often relate a complaint and are simply medicated, leaving the circumstances and issues underlying that Wasting complaint unattended to. Naturopathic physicians, given their holistic approach to mind, body, and spirit In 1987 the CDC defined HIV-associated wasting are in a unique position to assist HIV+ patients with syndrome as an involuntary weight loss of greater than these complaints. As always in naturopathic medicine, 10% of baseline body weight and accompanied by each patient must be considered a unique individual, chronic fever, weakness, or diarrhea. A more complete and therapeutic choices should be made on the basis of definition is available in The AIDS Reader, Nov. 2001176 this key principle. (BOX175-7). Suicidalideations and attempts can also be an issue for Body cell mass (BCM) can be measured via bio thispopulation. As quality of life deteriorates, the burden impedance assay (BIA). Research shows that BCM is of ongoing medical treatment increases, and close friends a better predictor of survival than CD4 counts. Key issues CoQlo (100 to 300 mg) is indicated to optimize mitochondrial f u n ~ t i o n . ' ~ ~ , ' ~ ~ 0 Alpha-lipoic acid (600 mg/day) may decrease pain.159

Specific Health Problems

AIDS wasting syndrome must meet one of the following criteria: Unintentional weight loss of > 10% over 12 rno Unintentional weight loss of > 7.5% over 6 mo BCM loss of > 5% over 6 mo Men: BCM < 35% of TBW and BMI < 27 kg/mz Women: BCM < 23% of TBW and BMI < 27 kg/m2 BMI < 20 kg/m2 BCM, Body cell mass; EM/, body mass index: TBW, total body weight.

to be addressed with patients include: perceived weight loss, changes in appetite, diarrhea, energy level, and diffidties in performing activities of daily living (ADLs). The etiology of wasting is most likely multifactorial in nature; some possible etiologies include the following'": 1. Decreased food intake-anorexia (decrease in desire to eat or loss of appetite with corresponding decrease in food intake) or nausea secondary to medications, systemic illness,or GI pathology; finances; dependence on others; poor choices. 2. Malabsorption/chronic diarrhea-results in decreased nutrient intake; influenced by many pathologies and dysfunctions (affecting any part of the GI tract: oral, esophageal, stomach, pancreatic, biliary, hepatic, and small and large intestine); problems might include infections, medication side effects, enzyme deficiencies, and malignancies; all might result in the inability to absorb macro and micro nutrients. 3. Alterations of metabolism-studies show resting energy expenditure (REE) is higher in HIV/AIDS patients than in HIV- controls; studies also show the REE does not downregulate if anorexia or malabsorption is present (so the combination of decreased caloric intake with a metabolic rate that does not adjust to that state would result in a negative energy balance and weight loss). 4.Cytokine abnormalities-not well understood; TNF, IL-1 may induce anorexia and affect lipid, protein, and carbohydrate utilization; an example is cachexia in cancer. 5. Endocrine abnormalities-thyroid abnormalities, adrenal insufficiency (cortisol, DHEA), hypogonadism (testosterone),growth hormone deficiency. 6. Alcohol abuse-studies show that progression to AIDS is much quicker in HIV+ patients who consume large amounts of ethyl alcohol (ETOH)versus normal expectations; ETOH can stimulate HIV production, suppress immune defenses (lower CD4 cell counts), and deplete tissue micronutrients (specificallyantioxidants).

As per general recommendations, the naturopathic physician should endeavor to remove the cause, if it is identifiable and feasible. Then he or she should identrfy

and remove possible food allergies/intolerances (gluten, dairy in particular) and ensure adequate and appropriate nutritional intake via dietary counseling and help patients access social assistance if necessary. Patients are likely to need super-doses of nutrients. Protein intake should be increased to 100 to 150 g/day. Patients should be active and engage in daily exercise. The following therapies can be considered: EFAs (5 g/day with food) are essential in a healthy diet'78 Acetyl-L-carnitine (2 to 6 g/day) to optimize fatty acidic metabolism'" L-Glutamine (10 to 40 g) is essential amino acid for enterocytes.1s0J81 DHEA (45 mg) to promote lean body mass182 Melatonin (20 mg at bedtime) to decrease cachexia and TNFlm Progesterone (800 mg-megestrol [Megace])to decrease cachexialM Testosterone in hypogonadal men increases lean body mass and muscle strength.lS Anabolic steroids (nandrolone decanoate, oxandrolone, oxymetholone) to increase lean body m a ~ s . l ~ J ~ ' Thalidomide is a cytokine modulator that increases BCM and extracellular fluid.lM

6. Provide Specific Antiviral Therapy

and Immunomodulation Using Other Nondrug Treatments This section summarizes botanical, homeopathic, and physical medicine studies that have been found to be effective for patients with HIV. This list is intended to assist health providers to find additional nondrug solutions that resonate with the unique needs of individual HIV+ patients. Further, the majority of the following studies are based on initial or empirical findings encouraging additional areas for research and exploration.

Botanical Medicines Box 175-8 includes botanicals that have demonstrated efficacy in treating HIV. Homeopathy Homeopathy may offer a most interesting possibility in the care of HIV+ patients. The British Journal ofHorneoputhy published a report on the use of constitutional homeopathic remedies (30C-1M doses) given to 129 asymptomatic HW+ patients in India resulting in 12 patients becoming ELISA negative after 3 to 16 months.lm In another study, 100 HIV+ patients between 17and 50 years old (71% men) were randomized to receive either a single homeopathic remedy or a placebo. The experimental group receiving remedies showed statistically sigruficant increases in CD& T cells after 6 months.1go

HIV/AIDS: Naturopathic Medical Principles and Practice

Glycyrrhiza glabrdlicorice (1500 mg) inhibited HIV fusion and viral t r a n s c r i p t i ~ nIt. ~should ~ ~ not be used in patients with a history of hypertension, renal, or cardiac problems. Buxus semperviren&PV-30/European Boxwood extract (990 mg-larger doses found to be less effective) increased CD4+ and decreased viral load after 6 mo.308 Curcuma longdtumeric (1200 mg) inhibited HIV integrase and proteases and viral transcription and decreased nuclear factor-kappa beta.-31 Olea sp./Olive leaf extract (2-6 g) increased NK cell function and was effective against HIV and herpes v i r u s e ~ . ~ ~ ~ ~ ~ ~ ~ Phyllanthus amarus (1200 mg) demonstrated in vitro and ex vivo HIV-1 inhibition of reverse transcriptase, receptors, and proteases and is also effective against HBVY4 Lentinus edodeslshitake mushrooms (1-5 mg IV lwicehk) inhibited reverse transcriptase and increased CD4 and decreased p24 (surface Andfographis paniculata (1500 mg) inhibited fusion, viral replication, and HIV-1 cell-to-cell transmission. It also stimulated objective measures of immune function, increased the effectiveness of m, protected against liver damage, and decreased diarrhea.317Toxicity questions remain, and further study is necessary. Silybum marianudMilk thistle (300 mg extract) improved liver function and antioxidant activity of blood cells. Hyssopus officnalidHyssop (1-4 ml tincture) exhibited anti-HIV activity and inhibited integration of proviral genome into host genome.318.31g frunella vulgaridSelf-Heal(10 pg/ml IV) inhibited HIV replication and binding and prevented cell-to-cell infection.m-al Rosmarinus officinalidRosemary (use liberally in food) decreased HIV replication and protease activity.3p Momordica charantidBitter melon (6 oz fresh juice) normalized CD&/CD& ratios and inactivated viral DNA.323 Spirulina plafensidBlue-greenalgae (use liberally in food) reduced fusion and viral p r o d u ~ t i o n . ~ ~ Scufellaria baicalensidSkullcap(6-15 g whole root) inhibited HIV-1 reverse trans~riptase.~~ Podophyllum resin (25% solution single topical application) resulted in resolution of hairy leukoplakia.326 Melaleuca leucadendroflea tree was effective for fluconazolerefractory oropharyngeal candidiasis in patients with AIDSa7 Hypericum perforafudSt. John's wort (900 mg) inhibited protein kinase C and viral un-coating, fusion, and assembly.328Do not use in patients on NNRTI or PI. Allium sativdGarlic (4 g fresh garlic) selectively killed HIV-1 infected cells in vitro.= It should not be used in patients on NNRTI or PI. AIDS, Acquired immunodeficiency syndrome; HBY hepatitis B virus; HIY human immunodeficiency virus; /Y intravenous; NK, natural killer; NNFITI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

Other studies in homeopathy have demonstrated success with symptom care in HIV.191For example, Bissuel and colleagues192reported the use of homeopathic Bactrim preventing the hypersensitivity reaction commonly associated with this drug. Brewitt and coll e a g u e ~reported ~ ~ ~ in a randomized, double-blind, placebo-controlled trial of 24 HIV+ adults with baseline CD4+ counts between 125 and 500/ml that oral doses of homeopathic growth hormone resulted in statistically

sigruficant improvements in CD4 cells, CD8 cells, ESR, weight gain, and viral load; reduced occurrences of 01; and increased platelet counts. The use of constitutional homeopathy should be considered an essential aspect of the care of all HN+ patients considering the amazing potential, minimal side effects, and overall affordability. Acute prescribing of homeopathic remedies should also be considered in the following situations: Homeopathic nosodes: 5 to 200 times with one dose/ week for 10 weeks in ascending order of potency) to reduce the complication of concurrent viral (herpes) cofactors Ultrahigh dilutions/unstable hemoglobin disease of illicit drugs (Cannabis Sativa, cocaine, amphetamines, LSD, heroin, amyl nitrate) for detoxification of prescription drugs (i.e., Bactrim) or for desensitization Skin: Sulfur, Psorinurn, or HSV nosode Warts or benign growth: Thuja, Nitric Acid, or Medorrhinurn GI:Lycopodium, Hepar sulph, or Mercurius (for liver) Neurologic: Arsenicum, Aurum, Bufo, Calc Carb, Cannabis, Causticum, Kali Phosphorus, Lachesis, Lycopodium, Mercurius, Nux vomica, Natrum Muriaticum, Opium, Phosphorus, Phosphoricum Acid, Silica, Staphysagria, Stramonium, Sulfur, Syphilinum, Tarentula, Thuja, Thyroidinurn Respiratory and wasting: Aurum, Arsenicum, Tuburculinum, Iodum, Arsenicum, Phosphoric Acid STD-related AIDS: Medorrhinum and Mercurius Sol intercurrently Adverse effects of chemotherapy, steroids, AZT, combination drugs: homeopathic radiograph

Physical Medicine and Acupuncture Physical medicine is another low-cost therapy that HIV+ patients can seek through a naturopathic provider. A growing body of evidence suggests that these therapies also play a pivotal role in the care of HTV+ patients: Whole-body hyperthermia (twice weekly at 108" F for 20 minutes) may elevate CD4 count, but extreme caution must be used in heat-intolerant indi~idua1s.l~~ Ozone (rectal and aural insufflations) may inactivate ~1~_1.195197 Acupuncture and moxibustion (three treatments weekly) has been demonstrated to decrease diarrhea and decrease illicit drug (cocaine and heroin) cravings.198200 Electroacupuncture (by continually stimulating acupuncture/conductance skin points associated with nervous and immune systems) has been demonstrated to ameliorate the complications of HN-related

Specific Health Problems

peripheral neuropathy, raise CD4+ counts, and raise other lymphocyte counts.2°1202 Massage therapy has been demonstrated to increase NK cells, CD3 and CD4 cell counts, and CD4:CD8 ratios, improve quality of life, and decrease health care c 0 s t s . 2 Other ~ ~ ~ studies have demonstrated increased growth and development and overall behavior in HIVexposed newborns, decreased anxiety, increased relaxation, and an increase in several measures of immune functionin HIV+ adults.205It had no measurable effects on disease progression. Therapeutic touch reduced anxiety in Cranioelectrical stimulation (micro-current 0.1 mA at 100 Hz to alligator clips attached to the ear lobes 20 minutes twice daily) decreased anxiety, insomnia, and depression.207 Movement therapies: Aerobic exercise has been demonstrated to provide benefit to individuals with immunodeficiency diseases, particularly through stress alleviation and mood enhancement. One exercise study demonstrated that HIV+ individuals had sigruficant improvements in both CD8 and NK cells.2°g211 =Tai Chi in 13 HIV+ individuals demonstrated a greater overall perception of health and sigruficant improvements in all functional measures when compared with Yoga showed improvements in self-confidence and return to athletic activities after the intervention.2I3,214

7. Provide Education and Guidance

to Patients Seeking Alternatives to Conventional Treatment As mentioned earlier, there are currently no known therapies as effective as HAART in suppressing viral load or increasing CD4 lymphocyte cells. CAM providers must avoid the temptation to allow their patients to believe otherwise. If a patient is aware of the risk of high HIV viral load or low CD4 count, or both, yet still does not desire to initiate HAART or antibiotic prophylaxis, ensure that this patient has access to a conventional western HIV specialist. This specialist can provide clear education on the conventional western medical approaches to HIV and help diagnose and treat 0 1 s should they manifest. Concurrently, initiate a foundation of care including healthy diet and lifestyle, nutrient support, and additional therapies as described earlier. Furthermore, ensure that the patient is scheduled for frequent follow-upswith health care providers to regularly screen for and monitor potential or existing opportunistic infections. If operating as a sole practitioner with a patient who refuses conventional Western medical and pharmaceutic

intervention, specific use of the following therapies should be considered to decrease viral load and increase CD4 cell count

Bums sempmirens /SPV-30/European boxwood extract (990 mg-larger doses found to be less effective) increased CD4 cells and decreased viral load after 6 months of use. Curcum Zonga/Tumeric (1200 mg) inhibited HIV integrase, proteases, and viral transcription. O h sp./Olive leaf extract (2 to 6 g) increased NK cell function and was effective against HIV and herpes viruses. *PhyZZunthus arnarus (1200 mg) demonstrated in vitro and ex vivo HIV-1 inhibition of reverse transcriptase, receptors, and proteases. *Lentinus edodeslshitake mushrooms (1 to 5 mg IV twice/week) increased CD4 and decreased p24 (surface marker). Ozone (rectal and aural insufflations) may inactivate

HIV-1. For patients seeking advice on HAART Structured Treatment Interruptions (STIs), or a ”drug holiday,” naturopathic physicians should ensure that patients clearly communicate this desire to their primary care physician and HJY specialist. STIs may be indicated in the following situations215: Relieve the patient of the inconvenienceand toxicity of unsuccessful antiretroviral therapy. Improve the response to salvage therapy (treatment regimens used in patients who have failed other HAART regimens) by allowing reemergence of wild type virus (the predominant virus type in a region or population of untreated patients). “Reimmunize” the patient to HIV and stimulate his or her immune system to regenerate a specific response to HIV. This effect has been studied in patients with optimal response to HAART (no plasma RNA for 1 to 3 years) and is associated with virologic rebound of HIV species that were found before HAART. It is also associated with accelerated decrease in CD4 cell counts. Some patients responded well to reintroduction of HAART in this circumstance. Decrease the cumulative exposure to antiretroviral agents, reducing the toxicity and cost to the patient and improving overall quality of life. During the first trimester of pregnancy, some physicians recommend discontinuing antiretroviral treatment when GI tolerance is usually poor and fetal organs are being formed. Considerable controversy surrounding STIs is centered on the lack of financial support for reducing drug therapy and the probability of increased HAART

HIV/AIDS: Naturopathic Medical Principles and Practice

resistance when going off and then reintroducing HAART. The conventionalWestern medical consensus is to avoid STIs. If a patient decides on an STI knowing the risks, the naturopathic physician should communicate the following inf~rmation~'~,~'~: Patients usually revert to their original set points (preHAART CD4 count and viral load). It is estimated that the wild type virus returns at 6 weeks. This is based on the time it takes to return to drug susceptibility in patients on discontinued failed HAART therapy and is associated with increases in plasma HIV-1. HIV plasma RNA rebounds within days of STI and often overshoots the set point.218Therefore educate the patient and provide supportive therapies. Measure the viral load after 2 months of STI and then in 3-month intervals after a stable set point. Consider genotyping (test to determine potential HAART resistance) before beginning an STI (viral load must be at least 1000 copies/ml for accurate genotyping). All resistant (mutant) and wild HIV strains are archived in all cells of the body (65%of patients had HIV RNA detected in gut mucosal biopsies while undetectable in the plasma).219 Hydroxyurea may lower treatment peak HIV viral load rebound during STI and viral load remained below 5000 copies/ml in 8/9 patients on hydroxyurea.220 As there is little support for STIs, the most appropriate schedule for staying off and reintroducing HAART remains unknown. The Swiss and Spanish Intermittent Treatment Trial (SSI'IT) included 133 patients, 8 weeks 0 4 2 weeks off HAART in 133 chronically infected HIV patients who had been successfully treated with HAART. After 1 year, few patients had low viral load and only 6% remained off therapy after 96 weeks. An improved CD8 response was observed in the treatment interruption, and the best results were noted in patients with low viral load at the beginning."' Anthony Fauci and Mark Dybul's Structured Intermittent Therapy of 7 days on/7 days off demonstrated no drug resistance or viral rebound over a short period of time in a limited number of chronically infected patients.222 Studies using longer cycles (i.e., 2 months on/ 1month off) with high viral load rebounds have demonstrated resistance to 3TC and " R T I (these drugs have relatively long half-lives and low genetic barrier to resistance).m The GigaHAART trial was a small, open-label trial in which patients with advanced disease failing therapy were randomized to switch to a multidrug regimen either immediately or after an 8-week STI. The patients who waited 8 weeks were more likely to achieve viral

load less than 400 copies/ml after 24 weeks. An Argentina study in patients with stable HAART for at least 6 months with CD4 greater than 350 and viral load less than 60,000 demonstrated minimal change (mean CD4 decrease by 14 and viral load increase within 1 loglo copies/mL) in patients who discontinued therapy for 6 months. Johns Hopkins University conducted an STI study in 101 patients in which 67Y0 of the patients remained off therapy for 74 weeks. In this study patients with a baseline CD4 less than 200 were seven times more likely to resume therapy. Patients with a CD4 greater than 200 and less than 350 were four times more likely to resume therapy, and those with a CD4 greater than 350 but less than 500 were no more likely to resume therapy than CD4 greater than 500. Several smaller studies have demonstrated various time on and time off without demonstrating significant increased drug resistance. More studies are necessary to demonstrate the efficacy of STI, but with the possibility of HAART resistance and lack of profit incentive for taking patients off a medication, additional research in this area is likely to remain sparse.224227

THERAPEUTIC SUMMARY HIV and AIDS is a pandemic that offers challenges and lessons not just for patients and health care providers but also for the entire human race. As HIV is a chronic disease with no known cure, naturopathic physicians are encouraged to apply the principles of naturopathic medicine in the search for and refinement of care. In turn, naturopathic physicians must be familiar with all aspects of this disease, as HIV+ patients are actively seeking treatment options unique to naturopathic medical training. Naturopathic medicine already offers important possibilities in the care of HIV, and all fields in health care must collaborate to find solutions for this world health problem. Each patient should have a complete and appropriate care giving team including an infectious disease expert, primary care physician, and psychosocial support.

Diet A natural, whole foods diet and a high caloric intake are recommended. This diet should be low in simple carbohydrates (e.g., sugar, white flour, fruit juice, honey, processed foods), low in natural and synthetically saturated fats, and low in oxidized or trans-fatty acids (fried oils). It should also be high in protein, fiber, and filtered water. Patients should abstain from alcohol, nicotine, and caffeine. Digestive stimulation is recommended if appropriate. Broad-spectrum allergy elimination diets should be avoided.

Specific Health Problems

High-potency, hypoallergenic multivitamin and mineral supplement, preferably designed specifically to replace known nutrient deficiencies of HN Beta-carotene (150,000 JU/day best taken as food) Acetyl-L-carnitine(2 to 6 g in divided doses best taken away from other protein) EFAs (5 g taken with food) GI flora (8 billion CFUs/day taken with meals)

Botanical medicines: Silyburn rnariunurn/Milk thistle extract (300 mg) for all patients on HAART Buxus sempervirens/ SPV-30/ European boxwood extract (990 mg-larger doses found to be less effective) for patients resistant to or avoiding HAART Homeopathic medicines: Constitutional intake and remedy provided for each patient Acute remedies as indicated Physical medicine and acupuncture: Whole body hyperthermia-use extreme caution in patients with heat intolerance or peripheral neuropathies Movement therapies-as indicated Acupuncture and electroacupuncture-as indicated

1.Bica I, Tang AM,Skinner S, et al. Use of complementaryand alternative therapies by patients with human immunodeficiency virus disease in the era of h i m y active antiretroviral therapy. J Altern Complement Med 2003;9:6576. 2. Furler MD, Einarson TR, Walmsley S, et al. Use of complementary and alternative medicine by HIV-infected outpatients in Ontario, Canada. AIDS Patient Care STDS 2003;17155-168. 3.Pneumocystis pneumonia-hs Angeles. MMWR Morb Mortal Wkly Rep 1981;30:250-252. 4. Kaposi’s sarcomaand F’neumocystis pneumonia among homosexual men-New York City and California. MMWR Morb Mortal Wkly Rep 1981;30:305-308. 5. Opportunistic infections and Kaposi’s sarcoma among Haitians in the United States. MMWR Morb Mortal Wkly Rep 1982;31: 353-354,360-361. 6. Pneumocystis cariniipneumonia among persons with hemophilia A. MMWR Morb Mortal Wkly Rep 198231:365-367. 7. Gallo RC, M u d d i n , SZ, Popovic M, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-tII) from patients with AIDS and at risk for AIDS. Science 1984;224500-503. 8. Update: trends in AIDS incidence, deaths, and prevalence-United States, 1996. MMWR Morb Mortal Wkly Rep 1997;46:165-173. 9. Sepkowitz KA. -the first 20 years. N Engl J Med, 2001;344: 1764-1772. 10. United Nations Program on HIV/AIDS. 2004 Report on the Global AIDS Epidemic. June 2004. 11. Bartlett JG, Gallant JE. 2001-2 Medical Management of HIV Infection. JohnsHopkins University, Division of Infectious Diseases; 2001. 12.Takebe Y, Kusagawa S, Motomura K. Molecular epidemiology of HlV tracking AIDS pandemic. Pediatr Int 2004;46:236-244. 13. %gal DJ, Goncalves J, Eberhardy S, et al. Attenuation of HIV-1 replication in primary human cells with a designed zinc finger transcription factor. J Biol Chem 2004;27914509-14519. 14. National Institute of Allergy and Infectious Diseases, HIV infection and AIDS an overview, Oct 2003. Available online at http://www. niaid.nih.goa/factsheets/hivinf.htm[accessed May 26,20051. 15. Faua AS, Pantaleo G, Stanley S, Weissman D. Immunopathogenic mechanism of HIV infection. Ann Intern Med 1996;124654-663. Slutsker L, et al. 1993 Revised classification 16. Castro KG, Ward JW, system for HIV infedion and expanded surveillancecase definition

for AIDS among adolescents and adults. National Center for Infectious Diseases Division of HIV/AIDS.MMWR Morb Mortal Wkly Rep 1992;41(RR-17). Distribution of CD4+ 17. Hanson DL, Chu SY, Farizo KM, Ward JW. T lymphocytes at diagnosis of acquired immunodeficiency syndrome-defining and other human immunodeficiency virusrelated illnesses. Arch Intern Med 1995;155:1537-1542. 18. Sickinger E, Stieler M, Kaufman B, et al. Multicenter evaluation of a new, automated enzyme-linked immunoassay for detection of human immunodeficiency virus-specific antibodies and antigen. J Clin Microbiol2004;42:21-29. 19. Weber 8, Hess G, Enzensberger R, et al. Multicenter evaluation of the novel ABN Western blot (immunoblot)system in comparison with an enzyme-linked immunosorbent assay and a different Western blot. J Clin Microbiol1992;30691-697. 20. Reynolds SJ, Muwonga J. OraQuick ADVANCE rapid HIV-1/2 antibody test. Expert Rev Mol Diagn 2004;4587-591. 21.FDA Approves first oral HIV antibody test. AIDS Alert 1996; 11:94. 22. Almeda J, Casabona J, Matas L, et al. Evaluation of a commercial enzyme immunoassay for HIV screening in urine. Eur J Clin Microbiol Infect Dis 2004;23:831-835. 23. Belec L, Gresenguet G, Dragon MA, et al. Detection of antibodies to human immunodeficiency virus in vaginal secretions by immunoglobulin G antibody capture enzyme-linked immunosorbent assay: application to detection of seminal antibodies after sexual intercourse.J Clin Microbiol1994321249-1255. 24. At-risk groups buy home HIV blood tests. AIDS Alert 1997;12 21-22. 25. Barletta JM, Edelman DC,Constantine NT. Lowering the detection limits of HIV-1 viral load using real-time immuno-PCR for HIV-1 p24 antigen. Am J Clin Pathol2004;122.20-27. 26. Feldman JG, Bums DN, Gange SJ,et al. Serum albumin as a predictor of survival in HIV-infected women in the Women’s Interagency HIV Study. AIDS 2OOO;14863-870. 27. Hawes SE, Critchlow CW, Faye Niang MA, et al. Increased risk of high-grade cervical squamous intraepithelial lesions and invasive cervical cancer among African women with human immunodeficiency virus type 1 and 2 infections. J Infect Dis 2003;188: 555-563.

Lifestyle Aerobic or mind-body exercise (e.g., Tai Qi, yoga) and 8 to 10 hours of sleep each night is optimal. Prayer, spiritual activities, and activities that support the HIV+ community, guided forms of stress relief, and relaxation training are benefiaal.

Nutritional Supplements

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311. De Clercq E. Current lead natural products for chemotherapy of human immunodeficiency virus (HIV) infection. Med Res Rev 2000;20323-349. 312. Konlee M. A new triple combination therapy. Posit Health News 1998;1712-14. 313.Lee-Huang S, Zhang L, Huang PL, et al. Anti-HIV activity of olive leaf extract (OLE) and modulation of host cell gene expression by HIV-1 infection and OLE treatment. Biochem Biophys Res Commun 2003;3071029-1037. 314. Notka F, Meier G, Wagner R. Concerted inhibitory activities of Phyllanthus amarus on HIV replication in vitro and ex vivo. Antiviral Res 2004;61:93-102. 315. Ngai PH, Ng TB. Lentin, a novel and potent antirungal protein from shitake mushroom with inhibitory effects on activity of human immunodeficiency virus-1 reverse transcriptase and p'oliferation of leukemia cells. Life Sci 2003;73:3363-3374. 316. Gordon M, Bihari B, Goosby E, et al. A placebwontrolled trial of the immune modulator, lentinan, in HIV-positive patients: a phase I/Il trial.J Med 1998;29305-330. 317.Calabrese C, Berman SH, Babish JG, et al. A phase I trial of Andmgraphalide in HIV positive patients and normal volunteers. Phytother Res 2000;14333-338. 318.Gollapudi S, Sharma HA, Aggarwal S, et al. Isolation of a previously unidentified polysaccharide (MAR-10) from Hyssop 0ffichali.s that exhibits strong activity against human immunodeficiency virus type 1. Biochem Biophys Res Commun 1995; 210145-151. 319. Kreis W, Kaplan WH, Freeman J, et al. Inhibition of HIV replication by Hyssop officianalis extracts. Antiviral Res 1990;14: 323-337. 320. Yao XJ, Wainberg MA, Pamiak MA. Mechanism of inhibition of HIV-1 infection in vitro by purified extract of Prunella vulgaris. Virology 1992;18756-62.

321. Tabba HD, Chang RS,Smith Kh4. Isolation, purification, and partial characterization of pmellin, an anti-HIV component from aqueous extracts of Prunella vulgaris. Antiviral Res 1989;ll: 263-273. 322. Paris A, Strukelj B, R e d o M, et al.Inhibitoryeffect of camosic acid on HIV-1 protease in cell-free assays. J Nat Prod 1993;56:1426-1430. 323. Rebultan SP. Bitter melon therapy: an experimental treatment of HIV infection. AIDS Asia 1995;26-7. 324. Hayashi K, Hayashi T, Kojima I. A natural sulfated polysaccharide, calcim spirulan, isolated from Spirulina platensis: in vitro and ex vivo evaluation of anti-herpessimplexvirus and anti-human immunodeficiency virus activities. AIDS Res Hum Retroviruses 1996;121463-1471. 325. Li BQ, Fu T, Yan YD, et al. Inhibition of HIV infection by baicalha flavonoid compound purified from Chinese herbal medicine. Cell Mol Biol Res 199339:119-124. 326.Gowdey G, Lee RK, Carpenter WM. Treatment of HIV-dated hairy leukoplakia with podophyllm resin 25% solution. Oral Surg Oral Med Oral Path01 Oral Radio1 Endod 1995;7964-67. 327. Vazquez JA, Zawawi AA. Efficacy of alcohol-based and alcoholfree melaleuca oral solution for the treatment of fluconazolerefractory oropharyngeal candidiasis in patients with AIDS.HIV C l h Trials 2002;3379-385. 328.Takahashi I, Nakanishi S, Kobayashi E, et al. Hypericin and pseudohypericin specifically inhibit protein kinase C possible relation to their antiretroviral activity. Biochem Biophys Res COIIUIIUII 1989;165:1207-1212. 329. Tatarinhv AV, Vrzhets PV,Ershov DE, et al. The ajoene blockade of integrin-dependent processes in an HIV-infected cell system. Vestn Ross Akad Med Nauk 1992;(11-12):6-10.

Hypertension Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary 1757 General Considerations 1757 White Coat Hypertension 1758 Etiology 1759 Therapeutic Considerations 1759 Antihypertensive Drugs 1759 Overview of Dietary and Lifestyle Factors 1760 The “Dietary Approaches to Stop Hypertension” Diet 1761

DIAGNOSTIC SUMMARY Borderline high blood pressure: 130 to 139/85 to 89 mmHg Mild high blood pressure (stage 1): 140 to 159/90 to 99 mmHg Moderate high blood pressure (stage 2): 160 to 179/100 to 109 mmHg Severe high blood pressure (stage 3): 180+/110+ mmHg

GENERAL CONSIDERATIONS Elevated blood pressure is a major risk factor for a heart attack or stroke. In fact, it is generally regarded as the most significant risk factor for a stroke. More than 60 million Americans have high blood pressure including more than half (54.3%)of all Americans age 65 to 74 years old and almost three quarters (71.8%) of all American blacks in the same age group (Box 176-1). Individuals with a normal diastolic pressure ( 4 2 mmHg)but elevated systolic pressure (>158 mmHg), meaning an increased pulse pressure, usually suffer from decreased compliance of the aorta (arteriosclerosis)and have a twofold increase in cardiovascular death rates when compared with individuals with normal systolic pressures ( 4 3 0 mmHg). Increased stroke volume due to aortic regurgitation, thyrotoxicosis, fever, and so on can also be a cause of an increased pulse pressure. Hypertension is also classified as to the cause. However, more than 90%of patients with hypertension

Botanical Medicines 1766

Therapeutic Approach 1767 Borderline (120-160/90-94) or White Coat Hypertension or Mild Hypertension (140- 160/90-104) 1767 Moderate Hypertension (140-180/105-114) 1767 Severe Hypertension (160+/115+) 1767

are classified as suffering from essential hypertension, in which no discernable cause is given. Patients with essential hypertension are further divided into groups on the basis of the level of renin, an enzyme secreted by the juxtaglomerular cell of the kidneys and linked with aldosterone in a negative feedback loop. Renin plays a central role in vascular reactivity through its effects in generating the vasoconstricting peptide angiotensin 11. Renin secretion is influenced primarily by the fluid volume status and salt intake of the individual. Patients with low-renin essential hypertension have low renin activity. In these patients, aldosteroneproduction is not being suppressed, leading to a mild degree of hyperaldosteronism with its resulting increased sodium retention, increased fluid volume, and increased blood pressure. The same phenomenon occurs in patients with normal-renin hypertension, indicating that patients with low-renin hypertension may be at the end of a continuum of patients with essential hypertension. Patients with low renin levels can also display an increased sensitivity to angiotensin 11. Normal-renin essential hypertensives typically are insulinresistant and display abdominal obesity. However, several studies have found that hyperinsulinemia and insulin resistance are present even in lean hypertensive patients without non-insulin-dependent diabetes mellitus, suggesting that there is a strong relationship between insulin sensitivity and blood pressure. Several theories have been suggested to explain this connection, with the most plausible being that since insulin modifies ion 1757

Specific Health Problems

Optimal Systolic < 120 mmHg Diastolic < 80 mmHg Normal Systolic < 130 mmHg Diastolic < 85 mmHg Borderline (high-normal) Systolic 130-139 mmHg Diastolic 85-89 mmHg High blood pressure (hypertension) Stage 1 (mild) high blood pressure: Systolic 140-159 mmHg Diastolic 90-99 mmHg Stage 2 (moderate) high blood pressure: Systolic 160-179 mmHg Diastolic 100-109 mmHg Stage 3 (severe) high blood pressure: Systolic 2 180 mmHg Diastolic 2 110 mmHg

transport across the cell membrane, insulin insensitivity can lead to decreased cytosolic magnesium levels and increased cytosolic calcium levels within the vascular smooth muscle, resulting in increased vascular reactivity. Normal-renin essential hypertensives typically do not respond to sodium restriction. High-renin essential hypertensives make up approximately 15%of patients with essential hypertension. The elevation in renin (and high blood pressure) is thought to be secondary to an increase in adrenergic system activity. Categorizing blood pressure by renin levels does not remain constant in a given patient. For example, a patient might be labeled as having ”low-renin essential hypertension” due to insulin resistance secondary to obesity. If the patient lost weight, regained insulin sensitivity, and yet the blood pressure did not normalize, the patient would then be categorized as having “normal or high-renin essential hypertension.” The categories based on renin are primarily useful in idenhfymg possible therapeutic interventions, as shown in Box 176-2.

White Coat Hypertension White coat hypertension has been defined as the persistent elevation of blood pressure at the clinic or office only. The prevalence of white coat hypertension may be as high as 20% to 45% of people diagnosed as hypertensive.’ It appears to be more frequent in women, older patients, and persons with mild hypertension. White coat hypertension should not be confused with the white coat effect. The white coat effect signifies the difference in blood pressure between the office and daytime ambulatory blood pressure and occurs in patients with white coat hypertension, as well as in patients with other causes of hypertension. The current conventional wisdom among naturopathic physicians is to treat white

1. Essential hypertension (>go% of all cases of hypertension) A. Low renin 6.Normal renin C. High renin II. Renal etiology A. Chronic pyelonephritis B. Acute and chronic glomerulonephritis C. Polycystic renal disease D. Renovascular stenosis or renal infarction E. Most other severe renal diseases (e.g., arteriolar nephrosclerosis, diabetic nephropathy) F. Renin-producing tumors 111. Endocrine etiology A. Adrenocortical hyperfunction B. Cushing disease and syndrome C. Primary hyperaldosteronism D.Congenital or hereditary adrenogenital syndromes (17-hydroxylase and 11-hydroxylase defects) E. Pheochromocytoma F. Myxedema G. Acromegaly IV. Neurogenic etiology A. Psychogenic B. Diencephalicsyndrome C. Familial dysautonomia (Riley-Day) D. Polyneuritis (acute porphyria, lead poisoning) E. Increased intracranial pressure (acute) F. Spinal cord section (acute) V. Miscellaneous A. Toxemia of pregnancy B. Acute intermittent porphyria C. Coarctation of aorta D. Increased intravascular volume (excessive transfusion, polycythemiaVera) E.Polyarteritis nodosa F. Hypercalcemia G. Medications (e.g., glucocorticoids, cyclosporine, oral contraceptives)

coat hypertension as if it were essential hypertension. The reason for this stance is that current data suggest that the pressor response elicited mirrors real-life reactions to stress, and results from recent studies suggest that white coat hypertension is not an innocent phenomenon.23 In regards to the latter, a 21-year study in which 536 men with a white coat effect had significantly higher mortality than normotensive men and were nearly twice as likely to develop sustained hyperten~ion.~ Ambulatory blood pressure monitoring is a clinically useful tool for assessing suspected white coat hypertension and cardiovascular risk.4In patients with confirmed white coat hypertension, drug treatment is usually not indicated; instead, treatment should consist of lifestyle and dietary modification, weight reduction, regular exercise, smoking cessation, and correction of glucose and lipid abnormalities.’ In addition, semiannual or annual follow-up with ambulatory blood pressure monitoring is advised.

Hypertension

Etiology Essential hypertension is most likely the result of any number of factors that disrupt the regulation of arterial pressure and fluid volume. Vascular, hormonal, renal, and neurologic factors function in a complex interrelationship in an effort to maintain normal blood pressure, and disruption of any single facet disrupts the entire system and creates a cascading effect on regulatory mechanisms. Although genetic factors play a role, dietary, lifestyle, psychologic, and environmentalfactors are the underlying cause in most cases of essential hypertension. Dietary factors include: obesity; high sodium-to-potassium ratio; low-fiber, high-sugar diet; high saturated fat and low omega-3 fatty acid intake; and a diet low in calcium, magnesium, and vitamin C. Important lifestyle factors that may cause high blood pressure include stress, lack of exercise, and smoking. The dietary factor that has received the greatest attention is salt intake. Between 40% and 60% of hypertensives are salt sensitive. This factor is discussed later in the section on therapeutic considerations. Exposure to heavy metals like lead, mercury, cadmium, and arsenic may also be a sigruficant factor in some patients. The kidneys are end-organ targets of heavy metals. Although studies of blood lead levels have not consistently shown an association, it is important to point out that blood lead levels reflect primarily acute exp~sure.~’ Studies looking at bone lead, for example, have upheld that exposure to heavy metals is associated with an increased risk for hypertension?

THERAPEUTIC CONSIDERATIONS Because more than 80% of patients with hypertension are in the borderline-to-moderate range, most cases of hypertension can be brought under control through changes in diet and lifestyle. In fact, in head-to-head comparisons, many nondrug therapies such as diet, exercise, and relaxation therapies have proved superior to drugs in cases of borderline to mild hypertension. In fact, several well-designed, long-term clinical studies found that people taking diuretics or beta-blockers, or both, actually suffered not only from unnecessary side effects,but also showed an increased risk for heart disease. The reason for this occurrence is obvious when the side effects of the drugs (discussed later) are examined. Although the newer class of drugs, the so-called calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors, appear to be safer and have fewer side effects,they are also not without problems?

Antihypertensive Drugs The four major categories of blood pressure-lowering drugs are diuretics, beta-blockers, ACE inhibitors, and calcium channel blockers. A brief description of each

drug is given, followed by current recommendations for its use in hypertension.

Diuretics Diuretics lower blood pressure by reducing the volume of fluid in the blood and body tissues by promoting the elimination of salt and water through increased urination. In addition, diuretics also work to relax the smaller arteries of the body, allowing them to expand and increase the total fluid capacity of the arterial system. The net result of diuretics is lower pressure due to reduced volume in an expanded space. Three major types of diuretics exist: thiazides, loop diuretics, and potassium-sparing diuretics. The thiazide diuretics are often the first drugs used in treating mild to moderate high blood pressure. They are more effective in lowering blood pressure than the loop and potassium-sparing diuretics. As a result, thiazide diuretics can be used at lower dosages than the other drugs. Because they can be used at lower dosage levels, they are safer. Important side effects to look for with all diuretics are light-headedness,increased blood sugar levels, increased uric acid levels and aggravation of gout, and muscle weakness and cramps caused by low potassium levels. Decreased libido and impotence are also reported. Less frequent side effects include allergic reactions, headaches, blurred vision, nausea, vomiting, and diarrhea. Thiazide diuretics also cause the loss of potassium, magnesium, and calcium from the body. All of these minerals have been shown to exert blood pressurelowering effects and prevent heart attacks. The drugs also increase cholesterol and triglyceride levels; increase the viscosity of the blood; raise uric acid levels; and inmase the stickiness of the platelets, making them likely to aggregate and form clots. All of these factors may explain why thiazide diuretics may actually increase the risk of dying from a heart attack or stroke. Thiazide diuretics also worsen blood sugar control, making them difficult to use safely in diabetics.

Beta-blockers Beta-blockers are drugs that block the binding of catecholamineson beta-receptors, resulting in a reduced rate and force of contraction of the heart, as well as relaxing the arteries. In addition to high blood pressure, beta-blockers are also used in treating angina and certain rhythm disturbances of the heart. Because heart function is reduced, there is a decreased need for oxygen and angina is relieved. In the long term, however, this inhibition of heart function can lead to heart failure. Betablockers have fallen out of favor due to the lack of effectiveness in reducing cardiovascular mortality, as well as being shown to increase the risk of developing diabetes by about 30%.1°

Beta-blockers produce some sigruficant side effects in many patients. Because cardiac output is reduced in a more relaxed arterial system, it is often difficult to get enough blood and oxygen to the hands, feet, and brain. This results in the typical symptoms in users of betablockers such as cold hands and feet, nerve tingling, impaired mental function, fatigue, dizziness,depression, lethargy, reduced libido, and impotence. Beta-blockers also raise cholesterol and triglyceride levels considerably. This may explain some of the negative effects in the clinical studies, which failed to demonstrate any signhcant benefit of beta-blockers in reducing mortality to cardiovascular disease. It is extremely important that a beta-blocker not be discontinued suddenly. Stopping the medication suddenly can produce a withdrawal syndrome consisting of headache, increased heart rate, and dramatic increase in blood pressure.

Calcium Channel Blockers Calcium channel blocking drugs, along with ACE inhibitors, have taken over the top spots in the drug treatment of high blood pressure because they are better tolerated than diuretics and beta-blockers. Although calcium channel blockers have been shown to lower the risk for strokes, they carry the same increased risk for heart attacks as the older approach of diuretics and betablockers. Calcium channel blockers work by blocking the normal passage of calcium through certain channels in cell walls. Since calcium is required in the function of nerve transmission and muscle contraction, the effect of blocking the calcium channel is to slow down nerve conduction and inhibit the contraction of the muscle. In the heart and vascular system, this action results in reducing the rate and force of contraction, relaxing the arteries, and slowing the nerve impulses in the heart. Although much better tolerated than beta-blockers and diuretics, calcium channel blockers still produce some mild side effects including constipation, allergic reactions, fluid retention, dizziness, headache, fatigue, and impotence (about 20% of users). More serious side effects include disturbances of heart rate or function, heart failure, and angina.

Angiotension-Converting Enzyme Inhibitors ACE inhibitors prevent the formation of angiotensin II, a substance that increases both the fluid volume and the degree of constriction of the blood vessels. ACE inhibitors relax the arterial walls and reduce fluid volume. Unlike the beta-blockers and calcium channel blockers, however, ACE inhibitors actually improve heart function and increase blood and oxygen flow to the heart, liver, and kidneys. This effect may explain why ACE inhibitors are the only antihypertensive drugs

that appear to reduce the risk of myocardial infarction. Unfortunately, they do not have any effect on reducing the risk for strokes. The newer ACE inhibitors are generally well tolerated but share many of the same side effects as the other antihypertensives including dizziness, light-headedness, and headache. The most common side effect is a dry nighttime cough. ACE inhibitors can also cause potassium buildup and kidney problems, so potassium levels and kidney function should be monitored.

Current Pharmacotherapy of Hypertension For many years the drug of first choice for high blood pressure was a thiazide diuretic alone or in combination with a beta-blocker. As mentioned earlier, due to lack of effectiveness in reducing the cardiovascular death rate and side effects noted in numerous studies, thisapproach has somewhat fallen out of favor. Currently, the most common use is a diuretic used alone or in combination with newer medications designed to relax the arteries such as calcium channel blockers and ACE inhibitors. The use of a diuretic or any of these other drugs alone is referred to as a ”step 1” drug. Thiazide diuretics are still the most popular step 1 drug but may soon be displaced by calcium channel blockers or ACE inhibitors. Beta-blockers are not suitable as step 1 drugs due to their known side effects. A step 2 drug approach uses two medications, a step 3 uses three, and a step 4 approach is composed of four medications. Physicians are instructed to use single therapies before combinations of medicines. Other types of blood pressure-lowering medications that can be used in step 3 or 4 drug approaches include those that act on the central nervous system such as clonidine, methyl-dopa, and reserpine, as well as some that are potent dilators of the blood vessels like nitroprusside sodium, hydralazine, prazosin, minoxidil, and hydralazine, but these drugs have fallen out of favor with the development of the newer calcium channel blockers and ACE inhibitors. Nonetheless, these drugs may be appropriate in certain situations.

Overview of Dietary and Lifestyle Factors Hypertension is closely related to lifestyle and dietary factors. Some of the important lifestyle factors linked to hypertension include smoking, stress, and lack of exercise. The most important dietary factors include: obesity; high sodium-to-potassium ratio; low-fiber, high-sugar diet; high saturated fat and low essential fatty acids (EFAs) intake; a diet low in calcium, magnesium, or vitamin C; and excessive alcohol or caffeine intake. In addition to the following discussions, several of these dietary and lifestyle factors are also discussed in Chapter 150 because the health of the artery is critical to maintaining normal blood pressure.

Hypertension

Stress Stress can be the causative factor of hypertension in many instances, although, as in other health conditions, it has more to do with the response and processing of stress rather than stress itself. Relaxation techniques such as deep breathing exercises, biofeedback, autogenics, transcendental meditation, yoga, progressive muscle relaxation, and hypnosis have all been shown to have some value in lowering blood pressure.” Although the effect is only modest, a stress reduction technique is a necessary component in a natural blood pressurelowering program. One of the most powerful methods of producing less stress and more energy in the body is diaphragm breathing. Regular, short exercise sessions of slow and regular diaphragmatic breathing have also been shown to lower blood pressure in hypertensives in several One study has shed some light on the effect of breathing in hypertensi~n.’~ Volunteers with normal blood pressure were taught shallow breathing. Measurement of the amount of sodium and potassium excreted in the urine indicated that shallow breathing led to the retention of sodium in the body. It was suggested that this breathing pattern may play a causative role in some cases of hypertension due to the retention of sodium. However, slow breathing (6 breaths/min) has also been shown to improve oxygen saturation, exercise tolerance, and baroreflex sensitivity.16

Exercise Epidemiologic studies have consistently demonstrated an inverse association between physical activity (or fitness) and hypertension. In addition to this evidence, clinical trials in hypertensive patients have clearly established regular exercise is an effective treatment for high blood pres~ure.’~-~~ Although it is generally thought that the greater the intensity of aerobic exercise, the greater the hypotensive effect. Recently it was shown that even mild to moderate aerobic exercise in as few as three exercise sessions per week with durations as short as 20 minutes produces a hypotensive effect.2l The degree of blood pressure reduction by adopting a regular exercise program is typically in the range of 5 to 10 mmHg for both the systolic and diastolic readings. Patients with borderline and mild hypertension typically can bring blood pressure readings into the normal range with regular exercise.

Dietary Recommendations The most important dietary goal for most patients with hypertension is achieving normal body weight. Obesity is the major dietary cause of hypertension. Next to attaining ideal body weight, perhaps the most important dietary recommendation is to increase the proportion of plant foods in the diet. Vegetarians generally have

lower blood pressure levels and a lower incidence of hypertension and other cardiovascular diseases than nonvegetarians.22Although dietary levels of sodium do not differ sigruticantly between these two groups, a vegetarian’s diet typically contains more potassium, complex carbohydrates, EFAs, fiber, calcium, magnesium, and vitamin C and less saturated fat and refined carbohydrate, all of which have a favorable influence on blood pressure. Increasing fruit and vegetable intake has been shown to lower blood pressure.23This effect may be the result of increasing antioxidant concentrations. Hypertensives have been shown to have increased oxidative stress, and antioxidants have been shown to block angiotensin II-induced increases in blood pressure and promote proper nitric oxide synthesis."^ The most useful foods for people with hypertension include the following: Celery Garlic and onions Nuts and seeds or their oils for their EFA content Cold-water fish (e.g., salmon, mackerel) Green leafy vegetables for their rich source of calcium and magnesium Whole grains and legumes for their fiber Foods rich in vitamin C, like broccoli and citrus fruits Celery is a particularly interesting recommendation for hypertension. It contains 3-n-butyl phthalide, a compound that has been found to lower blood pressure. In animals,a small amount of this compound lowered blood pressure by 12%to 14%and cholesterol by about 7%?7 The equivalent dose in humans can be supplied in about four to six ribs of celery. The research was prompted by the father of one of the researchers, who, after eating a quarter pound of celery daily for 1 week, observed that his blood pressure had dropped from 158/96 to 118/82. Garlic and onions are also important foods for lowering blood pressure. Although most recent research has focused on the cholesterol-lowering properties of garlic and onions, both have also been shown to lower blood pressure in hypertension.28In addition, commercial garlic supplements may also be of benefit. The usual response when using garlic is fairly modest, roughly 8 to 11 mmHg for the systolic and 5 to 8 mmHg for the diastolic (see Chapters 64 and 65 for a full discussion and dosages).

The “Dietary Approaches to Stop Hypertension” Diet The “Dietary Approaches to Stop Hypertension” (DASH)clinical studies were funded by the National Heart, Lung, and Blood Institute (NHLBI) to fully

Specific Health Problems

evaluate the efficacy of a system of dietary recommendations in the treatment of hypertension. The DASH diet is rich in fruits, vegetables, and low-fat dairy foods and low in saturated and total fat. It is also low in cholesterol, high in dietary fiber, potassium, calcium, and magnesium and moderately high in protein. The first study showed that a diet rich in fruits, vegetables, and low-fat dairy products can reduce blood pressure in the general population and people with hypertensi0n.2~The original DASH diet did not require either sodium restriction or weight loss-the two traditional dietary tools to control blood pressureto be effective.30The second study from the DASH research group found that coupling the original DASH diet with sodium restriction is more effective than either dietary manipulation alone.31In the first trial, the DASH diet produced a net blood pressure reduction of 11.4 and 5.5 mmHg systolic and diastolic, respectively, in patients with hypertension. In the second trial, sodium intake was also quantified at a "higher" intake of 3300 mg/day; an "intermediate" intake of 2400 mg/day; and a "lower" intake of 1500 mg/day. Compared with the control diet, the DASH diet was associated with a sigruficantly lower

systolic blood pressure at each sodium level. The DASH diet with the lower sodium level led to a mean systolic blood pressure that was 7.1 mmHg lower in participants without hypertension and 11.5 mmHg lower in participants with hypertension. These results are clinically significant and indicate that a sodium intake below the recommended level of 2400 mg daily can sigruficantly and quickly lower blood pressure. Table 176-1 lists a brief description of the components of the DASH eating plan on the basis of a 2000-calorie daily diet.

Potassium and Sodium Considerable evidence indicates that a diet low in potassium and high in sodium is associated with hypertension and plays a major role in the development of cancer and cardiovascular disease (e.g., heart disease, hypertension, stroke^).^*-^ Conversely, a diet high in potassium and low in sodium is protective against these diseases. In the case of hypertension, as evident in the second DASH study and others, this type of diet can be therapeutic, It is a well-established fact that excessive consumption of dietary sodium chloride, coupled with diminished

Basic components of the DASH diet (2000 calories a day) Food group

Daily servings

Significance of each food group to the DASH diet pattern

Serving sizes

Examples

1 slice bread cup dry cereal 1/2 cup cooked rice, pasta, or cereal

Whole wheat bread, English muffin, pita bread, bagel, cereals, grits, oatmeal

Major sources of energy and fiber

lI2

Grains and grain products

7-8

Vegetables

4-5

1 cup raw leafy vegetables lI2 cup cooked vegetables 6 oz vegetable juice

Tomatoes, potatoes, carrots, peas, squash, broccoli, turnip greens, collards, kale, spinach, artichokes, sweet potatoes, beans

Rich sources of potassium, magnesium, and fiber

Fruits

4-5

6 oz fruit juice 1 mediumfruit 'I4cup dried fruit l12 cup fresh, frozen, or canned fruit

Apricots, bananas, dates, oranges, orange juice, grapefruit, grapefruit juice, mangoes, melons, peaches, pineapples, prunes, raisins, strawberries, tangerines

Important sources of potassium, magnesium, and fiber

Low-fat or nonfat dairy foods

2-3

8 oz milk 1 cup yogurt 1.5 oz cheese

Major sources of calcium and protein

Meats including poultry, and fish

12

3 oz cooked meats, poultry, or fish

Skim or 1% milk, skim or low-fat buttermilk, nonfat or low-fat yogurt, part skim mozzarella cheese, nonfat cheese Select only lean; trim away visible fats; broil, roast, or boil instead of frying; remove skin from poultry Almonds, filberts, mixed nuts, peanuts, walnuts, sunflower seeds, kidney beans, lentils

Nuts, seeds, and legumes

4-5l~k

1.5 oz or '13 cup nuts or 2 tbsp seeds '12 cup cooked legumes '12 oz

DASH, Dietary approaches to stop hypertension.

Rich sources of protein and magnesium

Rich sources of energy, magnesium, potassium, protein, and fiber

Hypertension dietary potassium, is a common cause of high blood pressure, especially in "salt-sensitive" individuals. However, numerous studies have shown that sodium restriction alone does not sigruficantly improve blood pressure control in most people-it must be accompanied by a high potassium intake. In a typical Western diet only 5% of sodium intake comes from the natural constituents in food. Prepared foods contribute 45% of the sodium intake, 45% is added during cooking, and another 5% is added as a condiment. Most Americans have a potassium-to-sodium (KNa) ratio of less than 1:2. Epidemiologic and experimental research suggests a dietary KNa ratio of greater than 5:l is necessary to maintain health. However, even this level may not be optimal. A natural diet rich in fruits and vegetables can produce a KNa ratio greater than 100:1, as most fruits and vegetables have a KNa ratio of at least 50:l. Many studies have now shown that increasing dietary In addipotassium intake can lower blood pres~ure.3~ tion, several studies have shown that potassium supplementation alone can produce sigruficant reductions in blood pressure in hypertensive subjects. Results from 33 randomized, controlled trials (2609 participants) in which potassium supplementation was the only difference between the intervention and control conditions were used in one metaanalysis. Using a random-effects model, potassium supplementation was associated with a sigruficant reduction in mean systolic and diastolic blood pressure of 4 . 4 4 and -2.45 mmHg, respectively. The effects of potassium supplementation appeared to be enhanced in subjects who had a high intake of sodium, indicating that it is an important recommendation for prevention and treatment of hypertension in those who are unable to reduce their intake of sodium. The dosage of potassium typically used in the studies ranged from 2.5 to 5 g/day. In one study 37 adults with mild hypertension received either 2.5 g/day of potassium, 2.5 g/day of potassium plus 480 mg/day of magnesium, or a placebo for 8 weeks, and then they were crossed over to receive one of the other treatments for another 8 weeks and then again in another 8 weeks.% The potassium supplementation lowered systolic blood pressure an average of 12 mmHg and diastolic blood pressure an average of 16 mmHg. Interestingly, the additional magnesium offered no further reduction in blood pressure; nonetheless magnesium supplementation has been shown to be helpful in other studies (discussed later). Potassium supplementation may be especially useful in the treatment of hypertension in persons older than the age of 65 who often do not fully respond to antihypertensive drugs. In one double-blind study, 18 untreated elderly patients (average age 75 years) with a systolic blood pressure of greater than 160 mmHg or a diastolic

blood pressure of greater than 95 mmHg, or both, were given either potassium chloride (2.5 g of potassium) or a placebo each day for 4 weeks.37After this relatively short treatment period, the group receiving the potassium experienced a drop of 12 mmHg in the systolic blood pressure and 7 mmHg in the diastolic blood pressure. These results compare quite favorably with the reduction of blood pressure produced by drug therapy, but without the negative effects and side effects.38 Potassium supplements are available by prescription, as well as over the counter (OTC). However, the FDA restricts the amount of potassium available in OTC potassium supplements to a mere 99 mg/dose because of problems associated with high-dosage prescription potassium salts, yet so-called salt substitutes such as the popular brands NoSalt and Nu-Salt are, in fact, potassium chloride and provide 530 mg of potassium per '/,j tsp. The prescription and OTC supplements are either potassium salts (chloride and bicarbonate), potassium bound to various mineral chelates (e.g., aspartate, citrate), or food-based potassium sources.Potassium chloride preparations are the most popular by prescription and are available in a vast array of formulations (timedrelease tablets, liquids, powders, and effervescent tablets) and flavors. Potassium salts are commonly prescribed in the dosage range of 1.5 to 3 g/day. However, potassium salts can cause nausea, vomiting, diarrhea, and ulcers when given in pill form at high dosage levels. These effects are not seen when potassium levels are increased through the diet only. This difference highlights the advantages of using foods or food-based potassium supplements to meet the human body's high potassium requirements rather than pills. Potassium supplementation is relatively safe, except for patients with kidney disease. Their inability to maintain appropriate potassium homeostasis may result in heart arrhythmiasand other consequences of potassium toxicity. Potassium supplementation is also contraindicated when using a number of prescription medications including digitalis, potassium-sparing diuretics, and the ACE inhibitor class of antihypertensive drugs.

Magnesium Potassium interacts in many body systems with magnesium, and low intracellular potassium levels may be the result of low magnesium intake. It is therefore appropriate to supplement magnesium (400 mg to 1200mg/day in divided dosages) along with potassium. This suggestion may also lower blood pressure. A meta-analysis of 14 clinical trials that tested the effects of magnesium supplementation on hypertension demonstrated clear dose-dependent blood pressure reductions-a drop of 4.3 mmHg systolic and 2.3 mmHg diastolic for each 10 mmol/day increase in magnesium dose.39

Specific Health Problems

In one double-blind clinical study 21 male patients with hypertension were given 600 mg/day of magnesium (as magnesium oxide) or placebo.40Mean blood pressure (the average between the systolic and diastolic) decreased from 111 to 102 mmHg. The patients who responded the best were those with reduced red blood cell potassium. After therapy with magnesium, the levels of intracellular sodium, potassium, and magnesium normalized, suggesting that one of the ways in which magnesium lowers blood pressure is through activation of the cellular membrane pump that pumps sodium out of, and potassium into, the cell. Considerable evidence indicates that a high intake of magnesium is associated with lower blood pressure in population studies. The principal source of magnesium in early studies was water. Water that is high in minerals like magnesium is often referred to as “hard water.” Numerous studies have demonstrated an inverse correlation between water hardness and high blood pressure.41 These early studies gave way to more extensive dietary studies looking at the association of magnesium with hypertension. These dietary studies found the same results as the hard water studies. In one of the most extensive studie-the Honolulu Heart Study-systolic blood pressure was 6.4 mmHg lower and diastolicblood pressure 3.1 mmHg lower in the highest magnesium intake group compared with the lowest magnesium intake gr0up.4~ The studies of magnesium supplementation in the treatment of hypertension have yielded mixed results. Although the overall results in a metaanalysis of the data are quite favorable, it appears the hypertensive patients who respond appear to be those taking a diuretic, with a high level of renin, with low RBC magnesium, or with elevated intracellular sodium or a decreased intracellular potassium. The recommended daily intake for magnesium in hypertensives appears to be approximately 6 to 10 mg/kg body weight. Magnesium is available in several different forms. Although most are equally well absorbed, magnesium bound to aspartate or the Krebs cycle intermediates (malate, succinate, fumarate, and citrate) is usually preferable to magnesium oxide, gluconate, sulfate, and chloride. Absorption studies indicate that magnesium is easily absorbed orally, especially when it is bound to citrate (and presumably aspartate and other members of magnesium bound to the Krebs c y ~ l e ) ?In ~ ,addition, ~ aspartate or Krebs cycle intermediates may also help with fatigue. Aspartate feeds into the Krebs cycle, the final common pathway for the conversion of glucose, fatty acids, and amino acids to chemical energy (ATP), while citrate, fumarate, malate, and succinate are actual components of the Krebs cycle. Minerals chelated to the Krebs cycle intermediates are better absorbed, used, and

tolerated compared with inorganic or relatively insoluble mineral salts including magnesium chloride, oxide, or carbonate. In addition, although inorganic magnesium salts often cause diarrhea at higher dosages, organic forms of magnesium generally do not. In general, magnesium is well tolerated. Magnesium supplementation can sometimes cause a looser stool, particularly magnesium sulfate (Epsom salts),hydroxide, or chloride. Magnesium supplementation must be used with great care in patients with kidney disease or severe heart disease (such as high-grade atrioventricularblock).

Calcium Population-based studies have suggested a link between hypertension and a low intake of calcium.36However, the association is not as strong as the one for magnesium and potassium. In addition to the epidemiologic data, several clinical studies have demonstrated that calcium supplementation can lower blood pressure in hypertension, but the results have been inc~nsistent.~~ To clarify the effectiveness of calcium supplementation in patients with hypertension, a recent double-blind placebo controlled cross-over study was performed on 46 patients with either salt-sensitive or salt-resistant hypertension.& During the calcium supplementation phase, patients received 1.5 g/day of calcium (as calcium carbonate)for 8 weeks. The calcium supplementation was found to effectively reduce blood pressure in blacks and in patients who are salt sensitive, but not in patients who have salt-resistant hypertension. Better results have been found for calcium citrate versus calcium carb0nate.4~ Another group that appears to respond to calcium supplementation is elderly hypertensives. One study used 24-hour monitoring of blood pressure to evaluate the effect of calcium supplementation on mild to moderate essential hypertension in elderly hospitalized patients. The mean systolic and diastolic blood pressures over a period of 24 hours declined by 13.6 mmHg and 5 mmHg, respectively, in patients whose diets were supplemented with 1 g of elemental calcium.48

Vitamin C Population-based and clinical studies have shown that the higher the intake of vitamin C, the lower the blood pressure. The results from several preliminary studies showing a modest blood pressure-lowering effect with vitamin C supplementation in people with mild elevations of blood pressure has been confirmed in two recent double-blind trial~.~~3’ One of the key findings of these studies was that a daily dosage of 500 mg produced the same benefit as higher dosages (i.e., 1000 and 2000 mg daily).Vitamin C supplementationcan produce decreases of up to 4.5 mmHg in the systolic and 2.5 mmHg for the diastolic.

Hypertension ~

One of the mechanisms by which vitamin C exerts this antihypertensiveeffect is by promoting the excretion of lead. Chronic exposure to lead from environmental sources including drinking water is associated with hypertension and increased cardiovascular mortality. Areas with a soft water supply have an increased lead concentration in drinking water due to the increased acidity of the water, and people living in these areas may be predisposed to hypertension. It should be noted that soft water is also, of course, low in calcium and magnesium, two minerals that have also been shown to protect against hypertension. Vitamin C is likely to be more effective when used with other antioxidant nutrients. The combination of 500 mg of vitamin C, 600 mg of alpha-tocopherol,200 mg of zinc sulfate, and 30 mg of beta-carotene daily produced mild reductions in the systolic blood pressure compared with the placebo phase both in subjects receiving antihypertensive therapy and those who were normotensive.51

for the diastolic blood pressure, and daytime BP fell 3.5 and 2 mmHg, respectively. Although fish oils have been the subject of most of these studies,flaxseed oil may be the better choice for lowering blood pressure, especially when cost-effectiveness is considered. The key to getting results with flaxseed oil may require reducing the intake of saturated fat and omega-6 fatty acids. In one study, along with reducing the intake of saturated fat, 1tbsp/day of flaxseed oil can reduce both the systolic and diastolic readings by up to 9 mmHg.%Another study found that for every absolute 1%increase in body alpha-linolenic acid content, there was a decrease of 5 mmHg in the systolic, diastolic, and mean blood press~res.~’

Arginine

Arginine is an amino acid that plays an important role in the formation of nitric oxide. This compound plays a central role in determining the tone of blood vessels and renal function. Specifically,it exerts a relaxing effect Folic Acid and Vitamin B6 on blood vessels, thereby improving blood flow, and Folic acid and vitamin B6 reduce plasma homocysteine improves renal plasma flow and glomemlar filtration rate. Normally, the body makes enough arginine, even levels-a known contributor to atherosclerosis.A 2-year trial of folic acid and B6 therapy to lower homocysteine when the diet is lacking. However, in some instances the was associated with a 3.7-mmHg lower systolic and a body may not be able to keep up with increased require1.9-mmHg lower diastolic blood pres~ure.~’ Vitamin B6 ments and supplementation may prove useful. In high supplementation alone has also been shown to lower blood pressure, even in mild cases, there appears to blood pressure. In one study, vitamin B6 supplementa- be a derangement of endothelial nitric oxide production, tion at a single oral dosage of 5 mg/kg body weight for especially in the kidneys. 4 weeks in 20 people with hypertension demonstrated Arginine supplementation has been shown to be beneficial in a number of cardiovascular diseases sigruficant reductions in systolic and diastolic blood pressures, as well as serum norepinephrine le~els.5~ The including hypertension. By increasing nitric oxide levels, effects on blood pressure were significant: systolic arginine supplementationimproves blood flow, reduces pressure dropped from 167 to 153 mmHg, and the diasblood clot formation, and improves blood fluidity. In tolic pressure dropped from 108 to 98 mmHg. hypertension, the degree of improvement offered by arginine supplementation can be quite significant based Omega-3 Oils on preliminary studies.Arginine supplementation Increasing the intake of omega-3 fatty acids can lower may prove to be most beneficial in younger subjects with essential hypertension, as aging hypertensives appear to blood pressure. More than 60 double-blind studies have have a derangement in nitric oxide-dependent renal demonstrated that either fish oil supplements or flaxseed oil are effective in lowering blood p r e s ~ u r e . ~ mechanisms. In a study comparing the renal response Typically,fish oils produced a reduction of 2.1 mmHg for with an intravenous infusion of arginine, in young and the systolic blood pressure and 1.6 mmHg for the dias- aged essential hypertensives, arginine induced a sigrufitolic blood pressure at a typical dosage of 3000 mg of cant increase in renal plasma flow, the arginine glomerular omega3 (as typically found in ten 1000 mg pills of fish filtration rate, and natriuresis and kaliuresis in the oil) daily. Better results are likely to be achieved by using younger subjects, without changes in filtration fraction.6l preparations yielding a higher content of docosahexa- These effects were not observed in older subjects. noic acid (DHA). In one double-blind trial of overAnti-ACE Peptides weight, mildly hyperlipidemic men who received either 4 g/day of purified eicosapentaenoic acid, DHA, or olive Various naturally occurring peptides have been shown oil (placebo)capsules and continued their usual diets for to inhibit ACES including peptides from milk, chicken, 6 weeks, only DHA reduced 24-hour and daytime ambu- and fish. The most well-studied of these peptides is latory blood p r e s ~ u r eRelative .~ to the placebo group, in composed of a purified mixture of nine small peptides the subjects taking DHA, 24hour blood pressure fell (proteins) derived from muscle of the fish bonito (a 5.8 mmHg for the systolicblood pressure and 3.3 mmHg member of the tuna far nil^).^'-^^ Anti-ACE bonito

peptides do not appear to produce the side effects typical of ACE inhibitor drugs according to human safety studies and do not lower blood pressure in people with normal blood pressure-even when administered at levels 20 times greater than the dosage level that lowers blood pressure in people with high blood pressure. A possible reason is that its mechanism of action in inhibiting ACEs is different than that of the drugs. Research bears out this theory. The drugs basically indiscriminately block ACEs by interfering with their action, while the bonito anti-ACE peptides interact much differently. ACEs convert angiotensin I to angiotensin II by cleaving off a small peptide. Drugs work by directly blocking this action. Naturally occurring anti-ACE peptides work differently, as ACEs actually react with the peptides instead of angiotensin. In addition to competing with angiotensin via thiseffect, anti-ACE peptides are transformed into even more potent inhibitors of ACEs. Technically speaking, the bonito anti-ACE peptides are considered a ”pro-drug,” as the transformed peptides exert an 800% greater activity. Four clinical studies have shown fish-derived antiACE peptides (three with the bonito peptides and one with a dipeptide from sardine) exert sigruficant blood pressurelowering effects in people with high blood pressure (hypertension).- The degree of blood pressure reduction in these studies was quite significant, typically reducing the systolic blood pressure by at least 10 mmHg and the diastolic by 7 mmHg in people with borderline and mild hypertension. Greater reductions are seen in people with higher initial blood pressure readings.

Coenzyme Qio Coenzyme Qlo (CoQlo),also known as ubiquinone, is an essential component of the mitochondria. Although CoQlo can be synthesized within the body, deficiency states have been reported. In hypertension, CoQlo deficiency has been shown to be present in 39% of patients. This finding alone suggests a need for CoQlo supplementation. However, CoQloappears to provide benefits beyond correction of a deficiency. In several studies, CoQlohas actually been shown to lower blood However, the pressure in patients with hypertensi0n.6’~~ effect of CoQlo on blood pressure is usually not seen until after 4 to 12 weeks of therapy. Thus CoQlois not a typical blood pressurelowering drug; rather, it seems to correct some metabolic abnormality,which in turnhas a favorable influence on blood pressure. Typical reductions in both systolic and diastolic blood pressures with CoQlo therapy in patients with hypertension are in the 10% range. For example, when 10 patients with hypertension were given 100 mg/day of CoQlo for 10 weeks, systolic blood pressure dropped from 161.5to 142mmHg and diastolic pressure dropped from 98.5 to 83 mmHg,

but there were no changes in renin, sodium, or aldosterone le~els.6~ Cholesterol levels decreased from 227 to 204 mg/dl and peripheral vascular resistance in the arteries of the arms and legs improved sigruficantly.

Caffeine Caffeine consumption from coffee or tea can produce an immediate, short-lived increase in blood pressure, and regular coffee drinking has been associated with slight increases in blood pressure, but it is generally thought that in habitual coffee or tea drinkers, a tolerance to the hypertensive effects of caffeine develop^.^^^ However, some studies showed that with repeated administration of caffeine, a persistent pressor effect was produced. For example, in 11 short-term trials looking at the pressor effect of caffeine consumption (ranging from 14 to 79 days), the average dose of 5 cups of coffee per day was associated with an increase in systolic blood pressure by 2.4 mmHg and diastolic blood pressure by 1.2 mmHg.” Although the overall benefit of long-term avoidance of caffeine (from coffee, tea, chocolate, cola drinks, and some medications) on blood pressure is unclear, it appears that because some patients appear to respond quite favorably to caffeine avoidance, it should at least be attempted in patients with hypertension.

Botanical Medicines

Crataegus sp. Extracts of hawthorn berries, as well as of the flowering tops, are widely used by physicians in Europe because of their cardiovascular activities. Several studies including a recent double-blind trial74have demonstrated that hawthorn extracts are effective in lowering blood pressure and improving heart function. However, the blood pressure-lowering effect of hawthorn is mild. It usually requires at least 2 to 4 weeks before it begins to exert any effect.

Allium sativum and Allium cepa As discussed earlier, garlic and onion are useful antihypertensive additions to the diet, as are various garlic extracts. A metaanalysis of published and unpublished, randomized, controlled trials of garlic preparations was conducted to determine the effect of garlic on blood pressure relative to placebo.= Eight trials (seven double blind, one single blind) were identified as meeting analytic criteria. A total of 415 subjects were included in the analysis. All trials used a dried garlic powder standardized to contain 1.3% alliin at a dosage of 600 to 900 mg daily (corresponding to 7.8 and 11.7 mg of alliin or the equivalent of approximately 1.8 to 2.7 g of fresh garlic daily). The metaanalysis concluded that garlic preparations designed to yield allicin can lower systolic and diastolic blood pressures over a 1-to 3-month period. The typical drop from pooled data was 11 mmHg in the

Hypertension

systolic blood pressure and 5 mmHg in the diastolic blood pressure.

Olive (Olea europaea) Administration of olive leaf extract may reduce hypertension. In a small, double-blind study of patients with essential hypertension, 12 consulting for the first time and 18 currently on antihypertensive drugs, an aqueous extract of olive leaf at a dosage of 400 mg four times daily for 3 months produced a modest yet statistically significant decrease of blood pressure with no side effects.’5

Viscum album Viscum exhibits hypotensive action in animal studies. The mechanism of action for its hypotensive effect is not fully understood, however, and no recent investigations have been published. Viscum has been shown to inhibit the excitability of the vasomotor center in the medulla oblongata and to possess cholinomimetic activity.” The hypotensive activity may depend on the form in which the mistletoe is administered and the host tree from which it was collected. Studies indicate that aqueous extracts are more effective; the highest hypotensive activity was demonstrated by a macerate of leaves of mistletoe parasitizing on willow and gathered in January (see Chapter 137 for further discussion).

THERAPEUTIC APPROACH Borderline (120-160/90-94) or White Coat Hypertension or Mild Hypertension (140-160/90-104)

Reduce or eliminate the intake of animal fats while increasing the intake of vegetable oils. Supplement the diet with the following: High-potency multivitamin and mineral formula Vitamin C: 500 to 1000 mg three times/day Vitamin E: 400 to 800 KJ/day Magnesium: 800 to 1200 mg/day Garlic: the equivalent of 4000 mg/day of fresh garlic Flaxseed oil: 1 tbsp/day or fish oils: 3 g total EPA/DHA content per day If after following these recommendations for a period of 3 to 6 months blood pressure has not returned to normal, add anti-ACE peptides. If after an additional 3 months blood pressure has not returned to normal, antihypertensive medications are appropriate to bring the blood pressure down. When a prescription drug is necessary, calcium channel blockers or ACE inhibitors appear to be the safest.

Moderate Hypertension (140-180/105-114) Employ all the measures mentioned earlier. Anti-ACE peptides from bonito: 1500 mg/day CoQlo: 50 mg two to three times/day Arginine: 0.5 g/10 kg body weight Take either one of the following: Hawthorn extract (10%procyanidins or 1.8%vitexin4’-rhamnoside): 100 to 250 mg three times daily Olive leaf extract (17%to 23% oleuropein content): 250 to 500 mg three times daily These guidelines should be followed for 1 to 3 months. If the blood pressure has not dropped below 140/105, the patient may need to be placed on antihypertensive medications.

Reduce excessive weight. Eliminate salt (sodium chloride) intake. Follow a healthy lifestyle. Avoid alcohol, caffeine, and smoking. Exercise and use stress-reduction techniques. Follow a high-potassium diet rich in fiber and complex carbohydrates. Increase dietary consumption of celery, garlic, and onions.

Drug intervention is required. All the measures mentioned previously should be employed. When satisfactory control over the high blood pressure has been achieved, the patient can taper off the medication gradually.

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Severe Hypertension (160+/115+)

Specific Health Problems without occupational exposure to metals. Environ Res 2001;87 57-68. 9.Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospedively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet 2OOO; 35619551961. 10. Freis ED. Rationale against the drug treatment of marginal diastolic systemic hypertension. Am J Cardiol1990;66:368-371. 11.Blumenthal JA, Sherwood A, Gullette EC, et al. Biobehavioral approaches to the tmafment of essential hypertension. J Consult Clin Psycho12002;70569-589. 12.Grossman E, Grossman A, Schein MH, et al. Breathing-control lowers blood pressure. J Hum Hypertens 2001;15263-269. 13. Driscoll D, Diacco G. The effects of metronome breathing on the variability of autonomic activity measurements. J Manipulative Physiol Ther 2000;23:610-614. 14. Schein MH, Gavish B, Herz M, et al. Treating hypertension with a device that slows and regularises breathing: a randomised, double-blind controlled study. J Hum Hypertens 2001;15271-278. 15.Anderson DE, Bagrov AY, Austin JL. Inhibited breathing decreases dsodium excretion. Psychosom Med 199537373-380, 16.Bemardi L, Porta C, Spicuzza L, et al. Slow breathing increases arterial baroreflex sensitivity in patients with chronic heart failure. Circulation 2002;105:143-145. 17.Arakawa K. Exercise, a measure to lower blood pressure and reduce other risks. Clin Exp Hypertens 1999;21:797-803. 18.Lesniak KT, Dubbert PM. Exercise and hypertension. Curr Opin Cardiol2001;16356-359. 19. Ohkubo T, Hozawa A, Nagatomi R, et al. Effects of exercise training on home blood pressure values in older adults: a randomized controlled trial.J Hypertens 2001;191045-1052. 2O.Blumenthal JA, Sherwood A, Gullette EC, et al. Exercise and weight loss reduce blood pressure in men and women with mild hypertension: effects on cardiovascular, metabolic, and hemodynamic functioning. Arch Intern Med 2000;160:1947-1958. 21.Moreira WD,Fuchs FD, Ribeiro JP,Appel LJ. The effects of two aerobic training intensities on ambulatory blood pressure in hypertensive patients: results of a randomized trial. J Clin Epidemiol1999;52637-642. 22. Rouse IL,Beilin LJ, Mahoney DP, et al. Vegetarian diet and blood pressure. Lancet 1983;2:742-743. Ziebland S, Yudkin P, Roe LS, Neil HA. Effects of fruit 24. John JH, and vegetable consumption on plasma antioxidant concentrations and blood pressure: a randomised controlled trial. Lancet 2002; 3591969-1974. 25. Yasunari K, Maeda K, Nakamura M, Yoshikawa J. Oxidative stress in leukocytes is a possible link between blood pressure, blood glucose, and C-reacting protein. Hypertension 2002;39777-780. 2 6 . M MC, Manriquez MC, Romero JC, Juncos LA. Antioxidants block angiotensin II-induced increases in blood pressure and endothelin. Hypertension 2001;38:655-659. 27. Tsi D, Tan BKH. Cardiovascular pharmacology of 3-n-butylphthalide in spontaneouslyhypertensive rats. Phytother Res 1997;11:576-582. 28. Silagy CA,Neil HA. A meta-analysis of the effect of garlic on blood pressure. J Hypertens 1994;12:463-468. 29. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 1997336:1117-1124. 30.Moore TJ, Conlin PR, Ard J, Svetkey LP.DASH (Dietary Approaches to Stop Hypertension)diet is effective treatment for stage 1isolated systolic hypertension. Hypertension2001;38:155-158. 31. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension(DASH) diet. DASH-Sodium CollaborativeResearch Group. N Engl J Med 2001;344:3-10.

32. Jansson B. Dietary, total body, and intracellular potassium-tosodium ratios and their influence on cancer. Cancer Detect Prev 1990;14563-565. 33. Khaw KT, BarrrttConnor E. Dietary potassium and stroke-associated mortality. A 12-year prospective population study. N Engl J Med 1987316235-240. 34.Langford HG. Dietary potassium and hypertension: epidemiological data. Ann Intern Med 1983;98:770-772. 35. Whelton PK, He J. Potassium in preventing and treating high blood pressure. Semin Nephrol1999;19494499. 36.Patki PS, Singh J, Gokhale SV, et al. Efficacy of potassium and magnesium in essential hypertension: a double-blind, placebccontrolled, crossover study. BMJ 1990fl1:521-523. 37. Fotherby MD, Potter JF. Potassium supplementation reduces clinic and ambulatory blood pressure in elderly hypertensive patients. J Hypertens 1992;10:1403-1408. 38.Thijs L, Amery A, Birkenhager W, et al. Age-related effects of placebo and active treatment in patients beyond the age of 60 years. The need for a proper control group. J Hypertens 1990; 8:997-1002. 39. Jee SH, Miller ER III, Guallar E, et al. The effect of magnesium supplementationon blood pressure: a meta-analysis of randomized clinical trials. Am J Hypertens 2002;15691-696. 40. Motoyama T, Sano H, Fukuzaki H. Oral magnesium supplementation in patients with essential hypertension. Hypertension 1989;13 227-232. 41.Whelton PK, Klag MJ. Magnesium and blood pressure: review of the epidemiologic and clinical trial experience. Am J Cardiol 1989;63:26(5-30<;. 42. Joffres MR, Reed DM, Yano K. Relationship of magnesium intake and other dietary factors to blood pressure. The Honolulu Heart Study. Am J Clin Nutr 1987;45:469-475. 43.Lindberg JS, Zobitz MM, Poindexter JR, Pak CY. Magnesium bioavailability from magnesium citrate and magnesium oxide. J Am Coll Nutr 1990;9:4&55. 44.bhmer T, Roseth A, Holm H, et al. Bioavailabilityof oral magnesium supplementation in female students evaluated from elimination of magnesium in 24hour urine. Magnes Trace Elem 1990;9:272-278. 45. Cappuccio FP, Elliott P, Allender PS, et al. Epidemiologic association between dietary calcium intake and blood pressure: a meta-analysis of published data. Am J Epidemiol 1995;142:935-945. 46.Meese RB, Gonzales DG, Casparian Jh4,et al. The inconsistent effects of calcium supplements upon blood pressure in primary hypertension. Am J Med Sci 1987;294219-224. 47.Sowers JR, Zemel MB, Standley PR, Zemel PC. Calcium and hypertension. J Lab Clin Med 1989;114338-348. 48. Takagi Y, Fukase M, Takata S, et al. Calcium treatment of essential hypertension in elderly patients evaluated by 24 H monitoring. Am J Hypertens 1991;4836-839. 49. Hajjar IM,George V, Sasse EA, Kochar MS. A randomized, doubleblind, controlled trialof vitamin C in the management of hypertension and lipids. Am J Ther 2002;9289-293. 50. Fotherby MD, Williams JC, Forster LA, et al. Effect of vitamin C on ambulatory blood pressure and plasma lipids in older persons. J Hypertens 2000;18:411-415. 51.Galley HF, Thornton J, Howdle PD, et al. Combination oral antioxidant supplementation reduces blood pressure. Clin Sci (Lond) 199792361-365. 52.van Dijk RA, Rauwerda JA, Steyn M, et al. Long-term homqsteine-lowering treatment with folic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiffness: a 2-year, randomized, placebo-controlled trial. Arterioscler Thromb Vasc Biol2001;21:2072-2079. 53. Aybak M, Sermet A, Ayyildiz MO, Karakilcik AZ. Effect of oral pyridoxine hydrochloride supplementation on arterial blood

Hypertension pressure in patients with essential hypertension. Arzneimittelforschung 1995;451271-1273. 54. Geleijnse JM, Giltay EJ, Grobbee DE, et al. Blood pressure response to fish oil supplementation:metaregression analysis of randomized trials. J Hypertens 2002;20:1493-1499. 55. Mori TA, Bao DQ, Burke V, et al. Docosahexaenoic acid but not eicosapentaenoicacid lowers ambulatory blood pressure and heart rate in humans. Hypertension 1999;34:253-260. 56. Singer l? Alpha-linolenic acid vs. long-chain n-3 fatty acids in hypertension and hyperlipidemia.Nutrition 1992;8:133-135. 57. Berry EM, Hirsch J. Does dietary linolenic acid influence blood pressure? Am J Clin Nutr 1986;44:336-340. Dreyer D, et al. Oral arginine improves 58. Kelly BS, Alexander JW, blood pressure in renal transplant and hemodialysis patients. JPEN J Parenter Enteral Nutr 2001;25:194-202. 59.Kelly JJ, Williamson P, Martin A, Whitworth JA. Effects of oral L-arginine on plasma nitrate and blood pressure in cortisol-treated humans. J Hypertens 2001;19:263-268. 60. Siani A, Pagano E, Iacone R, et al. Blood pressure and metabolic changes during dietary L-arginine supplementation in humans. Am J Hypertens 2000;13:547-551. 61. Campo C, Lahera V, Garcia-Robles R, et al. Aging abolishes the renal response to L-arginine infusion in essential hypertension. Kidney Int Suppl1996;55:S126-128. 62. Fujita H, Yoshikawa M. LKPNM: A prodrug-type ACE-inhibitory peptide derived from fish protein. Immunopharmacology 1999; 44:123-127. 63. Fujjta H, Yamagami T, Ohshima K. Effects of an ace-inhibitory agent, katsuobushi oligopeptide, in the spontaneously hypertensive rat and in borderline and mildly hypertensive subjects. Nutr Res 2001;21:1149-1158. 64.Fujita H, Yasumoto R, Hasegawa M, Ohshima K. Antihypertensive activity of “Katsuobushi Oligopeptide” in hypertensive and borderline hypertensive subjects. Jpn Pharmacol Ther 1997;s: 147-151. 65. Fujita H, Yasumoto R, Hasegawa M, Ohshima K. Antihypertensive activity of ”Katsuobushi Oligopeptide” in hypertensive and

borderline hypertensive subjects. Jpn Pharmacol Ther 1997;25: 153-157. 66. Kawasaki T, Seki E, Osajima K, et al. Antihypertensive effect of valyl-tyrosine, a short chain peptide derived from sardine muscle hydrolysate, on mild hypertensive subjects. J Hum Hypertens 2000;14519-523. 67. Digiesi V, Cantini F, Bisi G, et al. Mechanism of action of coenzyme Ql0 in essential hypertension. Curr Ther Res 1992;51:668-672. 68. Langsjoen P, Langsjoen P, Willis R, Folkers K. Treatment of essential hypertensionwith coenzymeQlo Mol Aspects Med 1994;15(suppl): S265-272. 69. Digiesi V, Cantini F, Oradei A, et al. Coenzyme Qla in essential hypertension. Mol Aspects Med 1994;15(suppl):S257-263. 70.Nurminen ML, Niittynen L, Korpela R, Vapaatalo H. Coffee, caffeine and blood pressure: a critical review. Eur J Clin Nutr 1999; 53831-839. 71. Hodgson JM, Puddey IB,Burke V, et al. Effects on blood pressure of drinking green and black tea. J Hypertens 1999;17457-463. 72.Jee SH, He J, Whelton PK, et al. The effect of chronic coffee drinking on blood pressure: a meta-analysis of controlled clinical trials. Hypertension 1999;33647-652. 73. Hartley TR, Lovallo WR, Whitsett TL, et al. Caffeine and stress: implicationsfor risk, assessment, and management of hypertension. J Clin Hypertens (Greenwich)2001;3:354-361. 74. Walker AF, Marakis G, Morris AP, Robinson PA. Promising hypotensive effect of hawthorn extract: a randomized double-blind pilot study of mild, essential hypertension. Phytother Res 2002;1648-54. 75. Cherif S, Rahal N, Haouala M, et al. [A clinical trial of a titrated Olea extract in the treatment of essential arterial hypertension.] J Pharm Belg 1996;51:69-71. 76. Steiner M, Khan AH, Holbert D, Lin RI. A double-blind crossover study in moderately hypercholesterolemicmen that compared the effect of aged garlic extract and placebo administration on blood lipids. Am J Clin Nutr 1996;64:866-870.

Hyperthyroidism Michael T. Murray, ND Peter B.Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

1771

General Considerations 1771 Disease Risk 1771 Diagnosis 1772 Clinical Presentation 1772 Differential Diagnosis 1773 Laboratory Diagnosis 1773

Botanical Medicines 1776 Other Therapies 1777

Therapeutic Approach 1777 Diet 1777 Supplements 1777 Botanical Medicines 1777 Hydrotherapy 1777

Therapeutic Considerations 1773 Diet 1774 Nutritional Supplements 1774

DIAGNOSTIC SUMMARY Weakness, sweating, weight loss, nervousness, loose stools, heat intolerance, irritability, fatigue Tachycardia; warm, thin,moist skin; stare; and tremor Diffuse, nonpainful goiter Increased T4,free T4, and free T4 index Failure of thyroid suppression with T3 administration In Graves’ disease: goiter (often with bruit), ophthalmopathy

GENERAL CONSIDERATIONS Hyperthyroidism, also known as thyrotoxicosis, denotes a group of clinical disorders characterized by increased levels of free thyroxine, also known as tetruiodothyronine (Ta) and friiodofhyronine (T3).The autoimmune disorder Graves’ disease accounts for up to 85% of all cases of hyperthyroidism. It is much more common in women than men (ratio 8:l) and typically begins between the ages of 20 and 40. Diffuse, nonpainful goiter with hyperthyroidism is the most common presentation of Graves’ disease. Other less common signs and symptoms include exophthalmos, pretibial myxedema and other skin changes, nail changes (acropachy), and even paralysis in some groups.’ Although no single immunologic abnormality explains all of the clinical features of the disease, the common

denominator is the presence of antibodies against thyroidstimulating hormone (TSH) receptors. The exophthalmos and skin changes can progress independently from thyroid dysfunction (euthyroid Graves’ disease), making it difficult to predict the course of the disease in a given individual. There are definite patterns of susceptibility in autoimmune disease in general, and in Graves’ disease in particular. Many of these patterns have been recognized by common observation, while others have come to light only with careful study.

Disease Risk Gender The most obvious pattern is that of gender. Practically all the original cases described by Parry, von Basedow, and Graves were women. The female-to-male ratio in published series is 7 1 to lO:l, but the ratio in those with ophthalmic complications is about 13.2

Stress Recent stress has been recognized as a precipitating factor since Graves’ disease was first recognized. In fact, the most common precipitating event is an “actual or threatened separation from an individual upon whom Studies now the patient is emotionally de~endent.”~ support the long-held observation that the onset of Graves’ disease often follows some kind of emotional 1771

Specific Health Problems

shock, in particular some sort of loss, such as divorce, death, or difficult separations?

Genetics Genetic susceptibility to Graves’ disease is apparently sisruficantin some people. Graves’ disease is statistically more prevalent in some human leukocyte antigen (HLA) haplotypes such as HLA-B, and HLA-DR3in Caucasians; HLA-Bw3 in the Japanese; and, in the Chinese, HLABwe3 HLA identical twins have a 50% chance of manifesting Graves’ disease if one twin is affected and a 9% chance for fraternal twins? Some haplotypes appear to offer protection from manifesting Graves’ disease.6 Genetic haplotype does not seem to affect the clinical course of Graves’ disease or the response to treatment. Additional evidence, but not proof, for a genetic etiology comes from an interesting case of bone marrow transplantation between siblings-a sister donated her bone marrow to her brother 8 years before her diagnosis with Graves‘ disease. His bone marrow genotype was 98% 46,XX 8 years after the transplant. He contracted Graves’ disease 2 months after his sister’s subtotal thyroidectomy7The authors, while admitting that the manifestation of Graves’ disease in both siblings could be due to chance, proposed that the brother passively acquired a clone of programmed or activated lymphocytes from his sister and that his hyperthyroidism was not primarily dependent on any exposure to a specific thyroid-derived antigen.’

Left-handedness One study showed a statistically signhcant trend for left-handed people to manifest Graves’ disease and other autoimmune diseases. Wood and Cooper,8 using only male subjects, found that 70% of the Graves’ patients had some degree of left-handedness as compared with only 24% of controls. They also found some evidence for a higher rate of dyslexia in Graves’ patients.

Smoking A statistically sigruficant correlation exists between smoking and Graves’ disease, especially in patients with ophthalmic complications? The risk estimate is comparatively less for smoking (1.5) than that associated with heredity (3.6) and negative life events (6.3).There is little immunologic evidence to support an immunologic role for smoking in Graves’ disease. The group at the highest increase in risk for severe endocrine ophthalmopathy is those who already have some eye manifestation and who continue to smoke.lOJ

Iodine Supplementation An interesting study evaluated the effects of mandatory consumption of iodized salt in a whole population of 267,330 inhabitants of Galicia. The incidence of

thyrotoxicosis, diagnosed as elevated T4 and suppressed TSH levels, increased throughout the whole study period, with 4.89 new cases per 100,000 population. The rate of increase for females (8.03)was much greater than for males (1.34). The increased inadence of thyrotoxicosis comprised both nodular and diffuse goiters. The authors concluded that dietary iodine supplementation in iodine-sufficient areas can increase the incidence of thyrotoxicosis in susceptible individuals.12

Mercury and Cadmium Exposure Animal research has shown that exposure to toxic levels of cadmium or mercury will induce an immediate hyperthyr~idism.’~ Similar effects have been reported in a 13-year-old boy who had played with liquid mercury in his small bedroom with closed windows during cold weather for approximately 2 weeks. One month after exposure he began to have extremity pain, which became so severe that he was hospitalized. He had cold extremities that were cyanotic, with red palms and soles, a maculopapular rash across his trunk,tremors and hypertension, and he perspired heavily. Raised mercury levels were found in the blood and urine, and a diagnosis of acrodynia was made. A thyroid nodule was noted, and a thyroid test indicated possible hyperthyroidism. A thyroid scan found an enlargement of the gland and the increased uptake of the is0t0pe.l~ Chelating agents returned his mercury levels to normal, and carbimazole treatment alleviated symptoms after 4 weeks.

Drugs In older patients with hyperthyroidism, a toxic reaction to prescription drugs must be considered. The most common cause of hyperthyroidism in the elderly is a low intake of iodine and higher use of amiodarone, an antihypertensive drug.15 In addition, symptoms of hyperthyroidism vary somewhat in older adults, with apathy, tachycardia, and weight loss being more common.

DIAGNOSIS Clinical Presentation The typical clinical presentation of Graves’ disease is a young adult female complaining of the following: Nervousness Irritability Sweating Palpitations Insomnia Tremor Frequent stools Weight loss despite a good appetite

Hyperthyroidism

Physical examination often reveals a smooth, diffuse, nontender goiter; tachycardia, especially after exercise; loud heart sounds (often a systolic murmur); and mild proptosis, lid retraction, lid lag, and tremor. Other signs and symptoms include muscle weakness and fatigue, anxiety, heat intolerance, and pretibial myxedema. However, in atypical cases, especially in elderly patients, any or all of the previously mentioned symptoms may be absent. This presentation is known as apathetic thyrotoxicosis and has been known to present in the elderly with the only symptom being depression. Special care must be taken to avoid missing the diagnosis with this presentation. A screening laboratory test for suppressed TSH is helpful in these patients. Also, it is useful to keep in mind that an increase in thyroid hormone can present as a worsening of already present cardiac symptoms such as angina pectoris, congestive heart failure, and atrial fibrillation. The skin can show characteristic changes, becoming moist, warm, and finely textured. Perspiration increases as a response to the increasedbody temperature. Pigment changes such as vitiligo can be associated with Graves, as well as increased pigmentation of areas such as skin creases and the knuckles. Hair may thjn or fall out in patches or altogether (alopecia).Nails may separate prematurely from the nail bed (onycholysis). Localized, nonpitting edema typically occurs along the shins (myxedema)but may occur elsewhere, generally on the extensor surfaces, and is often pruritic and red. Other symptoms can be associated with Graves including glucose intolerance,’6 osteoporosis, dyspnea, polyuria and polydipsia, myopathy, paralysis, parkinsonian or choreoathetoid affect, and others.’

Differential Diagnosis Graves’ disease is the most common diagnosis of hyperthyroidism, but several other conditions present with a similar symptom picture. Several types of thyroiditis cause hyperthyroidism including Hashimoto’s thyroiditis (earlystage),subacute thyroiditis,painless thyroiditis, and radiation thyroiditis. Hyperthyroidism can also result from exogenous causes including iatrogenic hyperthyroidism, factitious hyperthyroidism (often seen in dieters who are taking thyroxine for weight loss), and iodine-induced hyperthyroidism (Jod-Basdow disease). Toxic nodular goiters are another source of hyperthyroidism. These include toxic adenoma and multinodular goiter. Other rare causes of hyperthyroidism include thyroid carcinoma, ectopic hyperthyroidism,trophoblastic tumors (i.e., hydatidifom mole, choriocarchoma, embryonic carcinoma of the testis), excessive thyroid-stimulating hormone (i.e., pituitary adenoma, nonneoplastic pituitary secretion of TSH), and struma ovarii. Table 177-1 indicates the relative frequency of the various causes of hyperthyroidism.

Relative frequency of primary causes of hyperthyroidism Etioloav

Relative freauencv’

Graves’ disease

70%-85%

Toxic multinodular goiter

5%-15%

Toxic uninodular goiter

3%-30%

Thyroiditis (including so-called hashitoxicosis)

4%-23%

Drug-induced

Common in the elderly; rare in the young (except in cases where I-administered to population)

Postradiation ‘Overall frequency; relative frequency may be altered in certain populations (e.g.. the elderly, regions of endemic goiter).

Laboratory Diagnosis The laboratory is where the definitive diagnosis is made, and quite a number of tests are available to the physician to assess thyroid function and functional anatomy. Although many tests are available, for the vast majority of cases a few simple tests will confirm the diagnosis. Serum T3, T4,thyroid resin uptake, and free thyroxine are usually all elevated. A reliable, sensitive TSH assay will show low levels, except in rare cases. TSH receptor antibodies (TSH-RAb) are present in 80% of cases. If a nodular goiter is present, a thyroid scan should be performed to help rule out cancer and to guide treatment. Determining serum antibodies can also be useful in ruling out cancer in patients with lobular firm goiters. High antibody levels suggest chronic thyroiditis in these cases.

THERAPEUTIC CONSIDERATIONS The chief objective of the natural treatment of Graves‘ disease and hyperthyroidism is to reduce symptoms while trying to reestablish normal thyroid status. Unfortunately, the natural approach has not received much research attention. Nonetheless, here are some general measures that should be employed, followed by a description of additional modalities that may offer some benefit. Reduce risk factors (i.e., stress, smoking, excess iodine intake) and increase rest. Stress control is the single most important action the patient can take to assist normalization of the thyroid. The patient should avoid anything that will excite him or her and increase agitation. Counseling can and should be used to prevent a return to stress-generating life strategies. Rest should be increased including a daily nap after lunch and a full night’s sleep.17

Specific Health Problems

Diet Balanced Whole Foods Diet The diet should be high in calories to compensate for the increase in metabolism and should be eaten in the form of small, frequent meals. Protein should be supplemented if the patient is nutritionally de~1eted.l~ Evidence concerning iodine in the diet is conflicting, but none should be taken as a supplement. Caffeine-containing foods and other stimulants should be avoided.

Dietary Goitrogens Some foods contain goitrogenic substances that prevent the utilization of iodine. These compounds are primarily isothiocyanates that are similar in action and structure to propylthiouracil. They are found in such foods as turnips, cabbage, rutabagas, mustard, rapeseeds, cassava root, soybeans, peanuts, pine nuts, and millet. However, these foods are unreliable in the treatment of hyperthyroidism because of the following reasons: Their goitrogen content is quite low, especially when compared with the dosages of propyl thiouracil (PTU) required to treat hyperthyroidism (100 to 200 mg three to four times/day). 9 Cooking inactivates the goitrogens. No substantial documentation exists that these naturally occurring goitrogens interfere with thyroid function to any sigrdicant degree when dietary iodine levels are adequate. An interesting note is that goitrogens are transmitted from cow's milk to humans.18 Despite these shortcomings, practitioners may want to use naturally occurring goitrogens in mild cases instead of PTU and related drugs. In order to achieve clinical results, large amounts of these foods must be consumed in their raw state, and iodine intake must be restricted. The highest levels of isothiocyanates are found in raw soymilk (0.46 to 2.5 mg/dl). In the Brassica family, rutabagas, cabbage, and turnips usually contain the highest levels. However, the quantity varies considerably according to climatic and soil factors. Anecdotally, a half head of raw cabbage per day is the typical prescription. Since iodine is found in kelp and other seaweeds, vegetables grown near the ocean, seafood, iodized salt, and some nutritional supplements, these should be avoided.

Nutritional Supplements Antioxidants Bodily tissues exposed to high levels of thyroid hormone are known to be susceptible to free radical-mediated injury.19 Special concern is warranted for thyrotoxic myopathy and cardiomyopathy, which are the major complications of hyperthyroidism. Low antioxidant

status is clearly prevalent in hyperthyroid and given this information alone, it is pragmatic to treat hyperthyroid patients with an antioxidant regimen. What research also demonstrates is that hyperthyroid patients given conventional therapy and antioxidants simultaneously return to the euthyroid state quicker. In Group A of one study" evaluating Graves' disease patients, 29 patients received methimazole dosed by the following regimen: 120 mg daily for the first week, 80 mg daily the second week, 60 mg daily the third and fourth weeks, and 40 mg daily for the following4 weeks. Group A patients were also given an additional daily capsule that included the following antioxidants: 10,000 IU of beta-carotene, 200 mg C vitamin, 55 IU vitamin E, and 60 mcg of selenium for all 8 weeks. Twenty-eight patients in Group B were given only methimazole for 8 weeks. Group A patients attained euthyroidism faster than the patients in Group B, as indicated by serum levels of TSH, T3, and T4. Selenium in the serum Group A patients also increased significantly during treatment, with no statistically significant change in Group B. Activity of glutathione peroxidase in whole blood also increased during treatment in both groups of patients with a statistically more sigruficant increase in Group A as compared with Group B. The degree of cell damage in Graves' disease is in direct correlation with the level of oxidative stress." As such, an antioxidant regimen is strongly encouraged for any patient who is hyperthyroid or receiving thyrostatic therapies, or both. Even though the previously mentioned study used doses generally lower than typically prescribed for the given antioxidants, it may be that combination therapies like this have a synergistic effect beyond what would be expected for each nutrient. Following is research regarding individual antioxidants.

Vitamin A Vitamin A in large amounts has an inhibitory effect on thyroid function and has been shown to ameliorate the symptoms of Graves' disease.= The exact mechanism is unknown, but evidence suggeststhat iodine metabolism is altered.18Animal studies have shown an alteration in cellular uptake of thyroxin, capacity of nuclear T3 receptors, and thyroid hormone

Vitamin C Early in the twentieth century, a considerable amount of research was conducted attempting to elicit the effects of hyperthyroidism on ascorbate metabolism. Experimental administration of thyroid, thyroxin, or thyrotrophic hormone results in a reduction in the ascorbic acid content of the serum, blood, liver, adrenal, thymus, and kidney.20,21Somewhat surprising was the observation that antithyroid drugs such as thiourea and thiouracil caused the same effect.20 Research in hyperthyroid

Hyperthyroidism

humans found a decreased excretion of axorbate.= Although supplemental vitamin C alone does not appear to directly affect the course of this disease, supplementation seems warranted to help ameliorate the symptoms and metabolic effects.

Vitamin E Some evidence indicates that this antioxidant may be protective against the oxidative damage of hyperthyr~idism.’~ In a rat model of hyperthyroid-induced animals, vitamin E helped to prevent the lipid peroxidation that is associated with hyperthyroidism.Although it is unknown whether sole vitamin E supplementation of hyperthyroid patients would protect against oxidative research that demonstrates low vitamin E status in hyperthyroid patients suggests that supplementation is warranted.=

Selenium Low selenium status in hyperthyroidismis well known.3o It is also been observed that subclinical hyperthyroidism may result from low selenium intake. One study demonstrated increases of serum T3 and serum triacylglycerol accompanied by losses of body fat in healthy men fed foods low in selenium.31Given this information and the research described earlier:4 selenium should be included in a supplemental regimen.

Calcium Calcium metabolism is altered in hyperthyroidism, and Graves patients are more susceptible to osteoporosis than normal^.'^

Iodine Worldwide, iodine deficiency continues to be a problem, but in developed countries, iodine excess is more common. Sources of iodine include additives to food products (e.g., salt and iodine used to sterilize pipes in dairies) and in medical products (e.g., Betadine washes, iodine-containing drugs such as amiodarone, radiographic dyes).32 The effects of iodine in patients with hyperthyroidism are as follows: In large doses, iodine temporarily reduces symptoms by stopping hormone synthesis (Wolff-Chaikoff effect). The thyroid can remain suppressed or can eventually resume hormone synthesis at a reduced, former, or even increased rate (escape from W~lff-Chaikoff).~~ Excess iodine can trigger hyperthyroidism (JodBasedow disease)in an euthyroid person or can trigger an overactive thyroid to return to normal. From the brief descriptions of these threepossibilities, it is clear that, aside from the initial suppression of thyroid function, the action of iodine is unpredictable.

Zinc Red blood cell (RBC) zinc is decreased in patients with hyperthyroidism. Treatment with antithyroid drugs normalizes RBC zinc levels but not until 2 months after T4 and T3levels normalize.As RBC zinc during the 12 weeks before treatment shows that the T4 and T3 levels correlated with RBC zinc levels, zinc RBC concentrations in hyperthyroid patients apparently reflect a patient’s mean thyroid hormone level over the preceding several months, just as glycosylated hemoglobin indicates mqan glucose levels in diabetic patientsM The oral zinc tolerance test (done by obtaining a baseline zinc level after a 10-hour fast followed by an oral dose of 165 mg of zinc sulfate heptahydrate-37.5 mg zincdissolved in 20 ml deionized water with blood samples drawn at 30-minute intervals over the next 3 hours) shows that hyperthymid patients have a basal serum zinc concentration similar to euthyroid individuals, but with greater urinary zinc excretion, which suggests zinc depletion from tissues to the blood stream caused by catabolism from the hyperthyroid state. Hyperthyroidism also caused lower zinc assimilation by tissues after ingestion.35

L-Carnitine Carnitine is a quaternary amine used for the transport of long-chain fatty acids into the mitochondria1 matrix. Camitine (beta-hydroxy/gamma-butyrobetaine) was originally isolated from meat extracts in 1905, and its exact chemical structure was determined in 1932. Carnitine is available in several different forms. L-Carnitine is a ubiquitous nutrient in tissues, where it plays an important role in energy metabolism. Camitine is already known for its important implications for cardiovascular disease, Alzheimer’s disease, acquired immunodeficiency syndrome (AIDS), and a number of other conditions (seeChapter 76). L-camitine has been shown to be an antagonist of thyroid hormone effect in peripheral tissues by inhibiting thyroid hormone entry into the nucleus of human and animal cells.%One &month, randomized, double-blinded, placebo-controlled study evaluated the use of L-camitine in iatrogenically induced hyperthyr~idism.~’ During this study, 50 women with benign nodular goiter already prescribed a suppressive dose of L-thyroxine were randomly assigned to 5 groups of 10 subjects each. Group 1 was given a placebo for 6 months. Two groups started with the placebo for 2 months, then were prescribed 2 or 4 g camitine/day, and then returned to the placebo for the last 2 months. The last two groups were started with either 2 or 4 g camitine/day for the first 4 months and then were given placebos for the last 2 months. Symptoms of hyperthyroidism, bone mineralization markers, and liver parameters were recorded. In Groups 2 and 3, the symptoms/signs that had worsened while on t-thyroxine plus placebo returned to

Specific Health Problems baseline once the placebo had been substituted with carnitine. In Groups 4 and 5, symptoms/signs remained stable or even ameliorated as long as camitine was given with L-thyroxine, implying that the carnitine effect prevailed over the T4 effect. For those given supplemental carnitine, liver profiles improved, although cholesterol levels were virtually unaffected. Symptoms and biochemical parameters only worsened in the placebo group. .Two persons given camitine and one person in the placebo group experienced nausea and gastralgia. Neither subject had to discontinue camitine administration. Due to its extremely low toxicity, the authors of this study recommend considering carnitine for Graves‘ diseaeinduced thyrotoxicosis during pregnancy, lactation, or other conditions in which antithyroid drugs may be unwanted, such as liver disease and blood disorders. The form being used must always be L-carnitine alone or bound to either acetic or propionic acid. The *form of carnitine should never be used (discussed in Chapter 76).

Coenzyme Qio Also known as ubiquinone, coenzyme Qlo (CoQlo) is a cofactor in the electron-transport chain that is involved in the synthesis of ATl? Because most cellular functions depend on an adequate supply of Am, CoQlois essential for the health of virtually all human tissues and organs. CoQlo has been found to be at low plasma concentrations in both adults2338 and children39with hyperthyroidism. Correction of hyperthyroidism by conventional treatments seems to return CoQlo levels to baseline. Although direct treatment of the hyperthyroidism should be the first line of therapy to restore CoQlolevels, given this information, it may be useful to supplement with CoQloin patients who present with a long-standing history of uncorrected hyperthyroidism or for those patients who have concomitant cardiac disease and hyperthyroidism.

Botanical Medicines Table 177-2 lists medicinal plants that have traditionally been used in the treatment of hyperthyroidism. Unfortunately, these plants have not been adequately evaluated in clinical studies.

Yo!

Lithospermum oflicinale, and Melissa Lycopus o ‘cinalis Aqueous, freeze-dried extracts of Lycopus spp., Lithospermum oficinale, and Melissa officinalis have been studied both in vivo and in vitro, with preliminary results supporting their use in the treatment of Graves’ disease. However, additional clinical research is necessary before these plants can be relied on clinically.

~~~~

Medicinal plants traditionally used in the treatment of hyperthyroidism Medicinal plant

Traditional indications

Valerian officinalis

Nervine effect

Scutellaria lateriflora

Nervine effect

Cactus grandiflorus

Heart tonic; use with elevated pulse

Iris versicolor

Traditional use for hyperthyroidism

Fucus spp.

Use with caution, as a high iodine content can improve symptoms at first and then later cause aggravation

Lycopus spp.

Blocks the TSH receptors; blocks peripheral conversion of T4 to T3

Lithospermum officinale

Blocks the TSH receptors

Melissa officinalis

Blocks the TSH receptors

Data from references40 and 41. TSH, Thyroid-stimulatinghormone.

Effects noted for these three plants include an ability to inhibit the effects of exogenous TSH on the thyroid glands of rats, block the effects of TSH on the TSH receptor sites located on thyroid membranes, inhibit the peripheral deiodination of T4to T3, and block the effects of antithyroid immunoglobulins on TSH r e ~ e p t o r s . 4 ~ ~ ~ Eight isolated compounds, mainly oxidation products of derivatives of 3,4-dihydroxycinnamic acid, were found to be responsible for most of these effects. The blocking effects of the isolated compounds of the TSH receptors were reversible, and none of the compounds combined irreversibly, damaged, or altered the TSH receptors in situ. An alcohol extract of Lycopus europeus administered orally to rats caused a long-lasting decrease in T3 levels, presumably due to reduced peripheral T4 deiodination. A pronounced reduction in TSH was also observed 24 hours later, as were drops in luteinizing hormone and testosterone.&Water extracts did not have as strong an effect, explaining the lack of results in some earlier studies. This finding is consistent with the observation that the active constituents are the unoxidized phenolic compounds, which are not present in the aqueous extract. These findings support the traditional use of these plants for patients with hyperactive thyroids. Unfortunately, there is no research on the clinical use of these plants or documented guidelines for dosage recommendations. Although it is unknown how effective the historical dosage schedules for these plants are, the dosage recommendations from the British Herbal Pharmacopoeia for Lycopus spp. and M. officinalis (no mention is made of L. oflcinare) are given as follows.47

Hyperthyroidism

Emblica officinalis Commonly known as amla, Emblica officinalis is employed in many Ayurvedic formulations and has been used against many chronic ailments including diabetes@and cataract^:^ and some research is discovering its use as a possible anticarcinogenic agent.500ne study evaluated the effect of this fruit extract on mice given high doses of ~-thyroxine.~l Oral administration of the plant extract at a dose of 250 mg/kg/day for 30 days in hyperthyroid mice reduced T3 and T4 concentrations by 64% and 70%, respectively, as compared with PTU, which decreased the levels of the thyroid hormones by 59% and 40%, respectively. The plant extract also decreased hepatic lipid peroxidation and increased the activity of superoxide dismutase and catalase in these mice, exhibiting an antioxidant and hepatoprotective function. Although there are no human studies at this point, hyperthyroidism treatment using Em blica seems promising.

Other Therapies Hydrotherapy The traditional approach is to use calming hydrotherapy such as neutral baths, particularly before bed?* A cold compress to the throat 15minutes a day has been reported to improve symptoms. Also, an ice bag over the heart will reduce the heart rate but should not be overused.

Acupuncture Traditional Chinese medicine views the constellation of hyperthyroid symptoms as an uprising of liver fire, sometimes with accompanying qi and yin deficiency. Using this perspective, Chinese medicine attempts to soothe the liver and clear the fire.In one study, acupuncture has been reported as an effective treatment for hyperthyroidi~m.5~

THERAPEUTIC APPROACH Acute Graves’ disease is not easily treated by naturopathic methods. In severe cases, there is no guarantee that natural treatments will alleviate the symptoms adequately. Thyroid storm is a potentially fatal complication and should be treated aggressively with antithyroid drugs or iodine, or both. In mild cases, natural therapeutics can manage the patients’ symptoms well but must be monitored carefully to avoid sudden exacerbation of the illness. Patients will often do well for a time and then relapse. Mild cases should be treated

symptomatically and allowed to return to a euthyroid status if possible. If iodine is used, then some sort of ablative treatment should be scheduled, as the risk of escape (with a potential for a return to even more intense symptoms) increases with time. The allopathic treatment of Graves’ disease is unusual in that there are three relatively equal treatments from which to choose. As physicians, we need to do our best to educate patients about the advantages and disadvantages of each treatment option and allow them to decide which treatment best fits their needs. Importantly, for many patients, decision making is difficult while in a thyrotoxic state. For these patients, symptomatic relief must be rendered before a decision is made. Antithyroid drugs can manage symptoms indefinitely while waiting for a possible return to euthyroid status. If drugs are not well tolerated, then ablative therapies must be considered. Surgery has a higher rate of euthyroid results than radioactive iodine but carries a greater risk of serious complications. Regardless of the treatment selected, supportive treatment can and should be rendered.

Diet A whole-foods diet with increased levels of calories, micronutrients, and protein is recommended to meet the increased metabolic needs of the hyperthyroid patient. In mild cases, consumption of large amounts of raw Brassica family foods and raw soy products may be adequately combined with restricted iodine consumption to control symptoms.

Supplements Vitamin A: 50,000 IU/day or beta-carotene: 6 mg/day, or both Vitamin C: 2000 mg bid Vitamin E: 800 ILJ/day Selenium: 60 mcg/day L-carnitine: 2 to 4 g/day CoQlo: 50 to 100 mg/day

Botanical Medicines Lycopus spp., L. oficinale, or M. oficinalis Dried herb: 1 to 3 g or by infusion tid Tinctuw (1:5):2 to 6 ml tid Fluid extract (1:l): 1to 3 ml tid

Hydrotherapy Cold packs are placed over the thyroid tid.

Specific Health Problems

1.McDougall JR.Graves’ disease. Current concepts. Med Clin North Am 1991;7579-95. 2. Behwaltes WH.Treatment of hyperthyroidism with l3lI. In Falk SA, ed. Thyroid disease: endocrinology, surgery, nuclear medicine and radiotherapy. New York Raven Press, 1990:233. Foster DW, 3. Larson PR, Ingbar SH. The thyroid gland. In Wilson JD, eds. Williams’ textbook of endocrinology, ed 8. Philadelphia: WB Saunders, 1992, pp 367-487. 4. Sonino N, Girelli ME, Boscaro M, et al. Life events in the pathogenesis of Graves‘ disease. A controlled study. Acta Endocrinol (COP&) 1993;128:293-296. 5. Doniach D. Humoral and genetic aspof thyroid autoimmunity. Clin Endocrinol Metab 1975;4:267-268. 6. Cavan DA, Penny MA, Jacobs KH, et al. The HLA assodation with Graves’ disease is sexspecificin Hong Kong Chinese subjects. Clin Edoainol (Oxf) 1994;40:63-66. 7. Holland FJ, McCommom JK, Volpe R, et al. Concordant Graves’ disease after bone marrow transplantation: implication for pathogenesis. J Clin Endocrinol Metab 1991;72837-840. 8. Wood LC, Cooper DS.Autoimmune thyroid disease,left-handedness, and developmental dyslexia. Psychoneuroendoainology 1992;17 95-99. 9. Winsa B, Karlsson A. Graves’ disease, endocrine ophthalmopathy and smoking. Acta Endocrinol (Copenh) 1993;128:156-160. 10. Bartalena L, Bogazzi F, Tanda ML, et al. Cigarette smoking and the thyroid. Eur J Endoainol1995;133507-512. 11. Shine B, Fells P, Edwards OM, et al. Association between Graves’ ophthalmopathy and smoking. Lancet 1990;335:1261-1263. 12. Galofre JC,Femandez-Calvet L, Rios M, et al. Increased inadence of thyrotoxicosis after iodine supplementation in an iodine suffident area. J Endocrinol Invest 1994;1723-27. 13.Ghosh N, Bhattacharya S. Thyrotoxicosis of the chlorides of cadmium and mercury in rabbit. Biomed Envhn sd 19925:23&240. 14. Karpathios T, ZervoudakisA, Theodoridis C, et al. Mercury vapor poisoning associated with hyperthyroidism in a child. Acta Paediatr %and 1991;80:550-552. 15. Trivalle C, Doucet J, Chassagne P, et al. Differences in the signs and symptoms of hyperthyroidism in older and younger patients. J Am Geriatr Soc 1996;44:50-53. 16. Paul DT, Mollah FH, Alam MK, et al. Glycemic status in hyperthyroid subjects. Mymensingh Med J 2004;1371-75. 17. Federman DD. Thyroid. In Dale DC,Federman DD, eds. Scientific American medicine. New York Scientific American, 1997, p 3. 18. Newbeme PM. Naturally occurring food-borne toxicants. In Shils ME, Young VR,eds. Modern nutrition in health and disease, ed 7. Philadelphia: Lea & Febiger, 1988, pp 689-690. 19. Asayama K, Koto K. Oxidativemuscular injury and its relevance to hyperthyroidism.Free Radical Biol Metab 1990;8:293-303. 20. Sure B, Theis RM. Hyperthyroidism and vitamin C.Proc Soc Exp Biol Med 193837646. 21. Johnson RB, Hansen RG, Hardy HA. Studies of thyroid toxicity. Arch Biochem 1948;19:246. 22.Lewis RA. Effect of hyperthyroidism on vitamin C. Bull Johns Hopkins Hosp 1938;63:13. 23.Bianchi G, Solaroli E, Zaccheroni V, et al. Oxidative stress and anti-oxidant metabolites in patients with hyperthyroidism: effect of treatment. Horm Metab Res 19993k620-624. 24. Vrca VB, Skreb F, Cepelak I, et al. Supplementation with antioxidants in the treatment of Graves’ disease; the effect on glutathione peroxidase activity and concentration of selenium. Clin Chim Acta 2004;341:55-63. 25. Arai M, Tsushima T, Isozaki 0, et al. Effects of retinoid on iodine metabolism, thyroid peroxidase gene expression, and

deoxyribonucleic acid synthesis in porcine tyroid cell in culture. Endocrinology 1991;1292827-2833. 26. Higeuret P,Garcin H. Triiodothyronine and vitamin A deficiency in the rat. J Endovinol1984;79:373-377. 27. Higeuret P, Pailler I, Garcin H. Vitamin A deficiency and triiodothyronine action at the cellular level in the rat. J Endocrinol 1989;121:75-79. 28. Higeuret P, Garcin H. Peripheral metabolism of thyroid hormones in vitamin A deficient rats. Ann Nutr Metab 198226191-200. 29. Seven A, Seymen 0,Hatemi S, et al. Lipid peroxidationand vitamin E supplementation in experimental hyperthyroidism. Clin Chem 1996;42:1118-1119. 30. Aliciguzel Y, Ozdem SN, Ozdem SS, et al. Erythrocyte, plasma, and serum antioxidant activities in untreated toxic multinodular goiter patients. Free Radic Biol Med 2001 15;30665-670. 31. Hawkes WC, Keim NL. Dietary selenium intake modulates thyroid hormone and energy metabolism in men. J Nutr 2003;133:

3443-3448. 32. Woeber KA. Iodine and thyroid disease. Med Clin N Am 1991;75:169-178. 33. Philippou G, Koutras DA, Piperingos G, et al. The effect of iodide on serum thyroid hormone levels in normal persons, in hyperthyroid patients, and in hypothyroid patients on thyroxine replacement. C h Endocrinol (Oxf) 199236573-578. 34.Yoshida K, Kiso Y, Watanabe TK. Erythrocyte zinc in hyperthyroidism: reflection of integrated hormone levels over the previous few months. Metabolism 1990;39182-186. 35. Pimenta WP. The assessmentof zinc statusby the zinc tolerancetest and thyroid disease. Trace Element Med 1992;9:34-37. 36. Benvenga S, Lakshmanan M, Trimarchi F.Carnitine is a naturally occurring inhibitor of thyroid hormone nuclear uptake. Thyroid 2000;101043-1050. 37. Benvenga S, Ruggeri RM, Russo A, et al. Usefulness of L-camitine, a naturally occurring peripheral antagonist of thyroid hormone action, in iatrogenic hyperthyroidism: a randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab 2001;W. 3579-3594. 38. Ogura F, Morii H, Ohno M, et al. Serum coenzyme Qlo levels in thyroid disorders. Horm Metab Res 1980;12537-540. 39. Menke T, Niklowitz P, Reinehr T, et al. Plasma levels of coenzyme Q l O in children with hyperthyroidism. Horm Res 2004;61:153-158. Epub 2003 Dec 18. 40.Felter HW.The eclectic materia medica, pharmacology and therapeutics. Portland, OR Eclectic Medical Publications, 1985 (first published Cincinnati, 1922). 41.Hoffman D. The new holistic herbal: a herbal celebrating the wholeness of life. Rockport, MA: Element, 1990. 42. Aufmkolk M, Amir SM, Kubota K, et al. The active principles of plant extracts with antithyroid activity: oxidation products of derivatives of 3,4-diihydrooxycinnamic acid. Endocrinology 1985;116:1677-1686. 43. Wmterhoff H, Sourgens H, Kemper FH. Antihormonal effects of plant extracts. Pharmacodynamic effects of Lithospmum oficinule on the thyroid gland of rats. Comparison with the effects of iodide. Horm Metabol Res 1983;15:503-507. 44. Aufmkolk M, Ingbar JC, Amir SM, et al. Inhibition by certain plant extracts of the binding and adenylate cyclase stimulatory effects of bovine thyrotropin in human thyroid membranes. Endocrinology 1984;115527-534. 45. Aufmkolk M, Kohrle J, Gumbinger H, et al. Antihormonaleffects of plant extracts. Iodothyronine deiodinase of rat liver is inhibited by extracts and secondary metabolites of plants. Horm Metab Res 1984;16:188-192.

Hyperthyroidism 46. Winterhoff H, Gumbinger HG, Vahlensieck U, et al. Endocrine effects of Lycopus europaeus L. following oral application. Arzneimittelforschung 1994;44:41-45. 47. British Herbal Medicine Association, Scientific Committee. British herbal pharmacopoeia. Great Britain: British Herbal Medicine Association, 1983:136,141. 48. Sabu MC, Kuttan R. Anti-diabetic activity of medicinal plants and its relationship with their antioxidant property. J Ethnopharmacol 2002;81:155-160. 49. Suryanarayana P, Kumar PA, Saraswat M, et al. Inhibition of aldose reductase by tannoid principles of Emblica officinalis: implications for the prevention of sugar cataract. Mol Vis 2004;10148-154.

50. Khan MT, Lampronti I, Martello D, et al. Identification of pyrogallol as an antiproliferative compound present in extracts from the medicinal plant Emblica officinalis: effects on in vitro cell growth of human tumor cell lines. Int J Oncol 2002;21: 187-192. 51. Panda S, Kar A. Fruit extract of Emblica officinalis ameliorates hyperthyroidism and hepatic lipid peroxidation in mice. Pharmazie 2003;58:753-755. 52.Boyle W, S i n e A. Lectures in naturopathic hydrotherapy. East Palestine, OH: Buckeye Naturopathic Press, 1988:127. 53. Wu ZS, Jin SB, Zheng ZT. The effect of acupuncture on 40 cases of endocrine ophthalmopathy. J Trad Chin Med 1985;5:19.

Hypoglycemia Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS

Introduction 1781

Therapeutic Considerations 1785 Dietary Factors 1785 Lifestyle Factors 1787

Diagnostic Considerations 1782 The Glucose-InsulinTolerance Test 1782 The Hypoglycemia index 1783 The Hypoglycemia Questionnaire 1783

Therapeutic Approach 1788 Diet 1788 Supplements 1788 Exercise 1788

Diagnostic Summary

1781

General Considerations 1783 Health impacts of Hypoglycemia 1784

DIAGNOSTIC SUMMARY Blood glucose level at or below 40 to 50 mg/dl A normal response curve during the first 2 to 3 hours of a glucose tolerance test (GTT) followed by a decrease of 20 mg or more below the fasting glucose level during the final hours of the test, with symptoms developing during the decrease

INTRODUCTION Both low and high blood glucose levels can cause s i p f icant physiologic dysfunction. Normally, the body maintains blood sugar levels within a narrow range through the coordinated effort of several glands and their hormones. If these control mechanisms are disrupted, hypoglycemia (low blood sugar) or diabetes figh blood sugar) may result. The beta cells of the pancreas respond to the rise in blood glucose levels after meals by secreting the hormone insulin, which lowers blood glucose by increasing the rate at which glucose is taken up by cells throughout the body. Reductions in blood glucose, such as occur during food deprivation or exercise, cause the release of the hormone glucagon by the ct cells of the pancreas. Glucagon stimulates the release of glucose stored in body tissues as glycogen, especially the liver. Rapidly falling blood sugar levels, anger, fright, and stress may stimulate the release of epinephrine and corticosteroidsby the adrenal glands. These hormones provide a quicker breakdown

of stored glucose for extra energy during a crisis or increased need. Americans overstress these control mechanisms through improper diet and lifestyle. As a result, diabetes and hypoglycemia are common diseases. Hypoglycemia is divided into two main categories: reactive hypoglycemia and fasting hypoglycemia. Reactive hypoglycemia, the most common, is characterized by the development of symptoms of hypoglycemia 3 to 5 hours after a meal and may herald the onset of early type II diabetes. Gastric surgeries may induce this condition,l and anorexia nervosa has been a reported cause in the literature? Reactive hypoglycemia may also result from the use of oral hypoglycemic drugs. These sulfa drugs (sulfonylureas) appear to stimulate the secretion of additional insulin by the pancreas, as well as enhance the sensitivity of body tissues to insulin. Common examples of this class of drugs are listed in BOX178-1. Some researchers, however, recommend that, for many patients, this syndrome instead be designated idiopathic postprandial syndrome (IPPS) because, although symptoms do exist and are related to rapid drops in blood glucose, the absolute glucose levels are not reliable indicators of the syndrome. Many asymptomatic controls have glucose levels below 50, while many symptomatic patients have normal postprandial glucose levelss5 Fasting hypoglycemia is rare, as it usually appears only in severe disease states such as pancreatic tumors, extensive liver damage, prolonged starvation, autoantibodies 1781

Specific Health Problems

Chlorpropamide (Diabinese) Glipizide (Glucotrol) Glibenclamide, Glyburide (DiaBeta, Micronase) Tolazamide (Tolinase) Tolbutamide (Orinase) Metformin (Glucophage) Thiazolidinediones: P i o g l i o n e (Actos) or Rosiglitazone (Avandia) Acarbose (Precose, Glucobay) Glimepiride (Amaryl) Gliclazide (Gen-Gliclazide) Nateglinide (Starlix) Repaglinide (Prandin)

Diagnosis Normal

Headache Depression, anxiety, irritability, and other psychologic disturbances Blurredvision Excessive sweating Mental confusion Incoherent speech Nocturnal hypoglycemic episodes Bizarre behavior Convulsions

DIAGNOSTIC CONSIDERATIONS Clinical hypoglycemia is identified by modified Whipple's criteria consisting of (1) central nervous system symptoms including confusion, aberrant behavior, or coma; (2) a simultaneous blood glucose level equal to or less than 40 mg/dl; and (3) relief of these symptoms by the administration of glucose.' The normal fasting blood glucose level is between 65 and 109 mg/dl. A fasting plasma blood glucose measurement greater than 126 mg/dl on two separate occasions is diagnostic of diabetes.8 Although the most specific criterion for the presence of hypoglycemia is a blood glucose level of 40 mg/dl or less, a blood glucose level less than 50 mg/dl should arouse clinical suspicion.'

No elevation >160 mg

4 5 0 mg at the end of first hr 4 2 0 mg at the end of second hr Never < 20 mg below fasting Flat

No variation more than f 20 mg from fasting value

Prediabetic

>120 mg at the end of second hr

Diabetic

>180 mg during first hr S O 0 mg at the end of first hr 5150 mg at the end of second hr A normal 2- or 3-hr response curve followed by a decrease of 220 mg from the fasting level during the final hrs

Reactive hypoglycemia

against insulin or its receptor, various cancers, or as a result of excessive exogenous insulin in diabetics. Pregnant diabetic women using insulin or oral glycemic medications also have a high incidence of asymptomatic hypoglycemic events.6 Hypoglycemia can promote untoward physiologic changes in the body. Insulin-induced hypoglycemia is known to increase the levels of C-reactive protein, a known cardiac risk factot7 Because glucose is the primary fuel for the brain, low levels affect the brain first. Symptoms of hypoglycemia can range from mild to severe including the following:

Response

Probable reactive hypoglycemia

A normal 2- or 3-hr response curve followed by a decrease of 10-20 mg from the fasting level during the final hrs

Flat hypoglycemia

An elevation of 9 0 mg, followed by a decrease of S O mg below the fasting level

Prediabetic hypoglycemia

A 2-hr response identical to the prediabetic but showing a hypoglycemic response during the final 3 hrs

Hyperinsulinism

A marked hypoglycemic response, with a value of <50 mg during the third, fourth, or fifth hr

A more functional test of blood sugar control is the oral GTT. It is used in the diagnosis of both reactive hypoglycemia and diabetes, although it is rarely required for the latter. After fasting for at least 12 hours, a baseline blood glucose measurement is made. Then the subject is given a liquid containing glucose to drink. The amount consumed is based on body weight, 1.75 g/kg body weight. Blood sugar levels are measured at 30 minutes, 1 hour, and then hourly for up to 6 hours. Basically, blood sugar levels greater than 200 mg/dl indicate diabetes. Levels below 50 mg/dl indicate reactive hypoglycemia. Table 178-1 explains in detail how to interpret results from a GTT.

The Glucose-Insulin Tolerance Test Relying on blood sugar levels alone is often not enough to diagnose hypoglycemia, as it is now widely recognized that the signs and symptoms of hypoglycemia can occur in individuals having blood glucose levels well above 50 mg/dl and there is a wide overlap between symptomatic patients and asymptomatic controls? Many of the symptoms linked to hypoglycemia appear to be the result of increases in insulin or epinephrine. Therefore it has been recommended that insulin or epinephrine (adrenaline) be measured during a GTT because

Hypoglycemia

symptoms often correlate better with elevations in these hormones than with glucose levels.h1° Several studies have shown that the glucose-insulin tolerance test (GITT) leads to a greater sensitivity in the diagnosis of both hypoglycemia and diabetes than the standard GTT.'o*ll The G-ITT uses a standard 6-hour GTT coupled with measurements of insulin levels. The G-ITT appears to be one of the best diagnostic indicators for faulty sugar metabolism." As many as two thirds of subjects with suspected diabetes or hypoglycemia who have normal GTTs will demonstrate abnormal insulin tolerance tests. Table 178-2 lists the various patterns seen with the G-ITT. The downside to this test is that it tends to be costly. For example, the G-ITT costs around $200, while a standard GTT is usually less than $30.

The Hypoglycemic Index Another laboratory parameter that can aid in the diagnosis of hypoglycemia, especially in the borderline case, is the so-called hypoglycemic index. This value is determined by calculating the fall in blood glucose levels during the 90-minute period before the lowest point divided by the value of the lowest point. A hypoglycemic index greater than 0.8 usually indicates reactive hypoglycemia.

disappear with the ingestion of food, hypoglycemia should be considered. The questionnaire shown in Table 178-3 is an excellent screening method for hypoglycemia.

GENERAL CONSIDERATIONS In the 1970s hypoglycemia was a popular "self-diagnosis" for a long list of symptoms; every symptom on the hypoglycemia questionnaire in Table 178-3 was linked to hypoglycemia. Although all of these symptoms may be due to hypoglycemia, there are obviously other causes in many cases. The tremendous public interest in hypoglycemia and sugar intake was fueled by a number of popular books like Sugar Blues by William Duffy, Hopefor Hypoglycemia by Broda Barnes, and Sweet and Dangerous by John Yudkin. The popularity of these books and the diagnosis of hypoglycemia were met by much skepticism from the medical community. Editorials in the [ournal of the American Medical Association and the N a u England \ournu1 ofMedicine during the 1970s denounced this public interest in hypoglycemia and tried to invalidate the concept of hyp~glycemia.'~,'~ Research in the past 15 years has provided an everincreasing amount of information concerning the role that refined carbohydrates and faulty blood sugar

The Hypoglycemia Questionnaire When all is considered (especially cost to the patient), the most useful measure of diagnosing hypoglycemia in many cases remains assessing symptoms. In general, when symptoms appear 3 to 4 hours after eating and

Hypoglycemia questionnaire No

Mild

0 0 0

Dizziness when standing suddenly Frequent headaches

Moderate

Severe

1

2

1

2

1

2

3 3 3

0

1

2

3

0 0

1

2

1

2

3 3

Feel tired an hr or so after eating

0

1

2

3

Heart palpitations Feel shaky at times Afternoon fatigue

0 0 0 0 0 0 0

3 3 3 3

Crave sweets Irritable if a meal is missed Feel tired or weak if a meal is missed

Pattern Pattern 1

Pattern 2

Response Normal fasting insulin 0-30 units. Peak insulin at 0.5-1 hr. The combined insulin values for the second and third hours is c 60 units. This pattern is considered normal. Normal fasting insulin. Peak at 0.5-1 hr with a "delayed return to normal." Second and third hr levels between 60 and 100 units are usually associated with hypoglycemia and are considered borderline for diabetes; values > 100 units considered definite diabetes.

Pattern 3

Normal fasting insulin. Peak at second or third hr instead of 0.5-1 hr. Definite diabetes.

Pattern 4

High fasting insulin. Definite diabetes.

Pattern 5

Low insulin response. All tested values for insulin < 30. If this response is associated with elevated blood sugar levels, it probably indicates insulin-dependent diabetes ("juvenile pattern").

Poor memory (forgetful) or concentration

Vision blurs on occasion Depression or mood swings Overweight Frequently anxious or nervous Total Scoring:

45,hypoglycemia is not likely a factor. 6-15,hypoglycemia is a likely factor. >I 5,hypoglycemia is extremely likely.

1

2

1

2

1

2

1

2

1

2

3

1

2

1

2

3 3

Specific Health Problems control play in many disease processes. New terminology and descriptions are now used to describe the complex hormonal fluxes that are largely a result of ingesting too many refined carbohydrates. For example, the term "syndrome X" has been introduced to describe a cluster of abnormalities that owe their existence largely to a high intake of refined carbohydrates leading to the development of hypoglycemia, excessive insulin secretion, and glucose intolerance, followed by diminished insulin sensitivity leading to high blood pressure, elevated cholesterol levels, obesity, and, ultimately, type Il diabetes. Syndrome X is discussed in greater detail later. Hypoglycemia (or IPS) is, without question, a valid clinical entity. A substantial amount of information indicates that hypoglycemia is caused by an excessive intake of refined carbohydrates.15J6Although most medical and health organizations, as well as the US. government, have recommended that no more than 10% of the total caloric intake be derived from refined sugars that are added to foods, added sugar accounts for roughly 30%of the total calories consumed by most Arneri~ans.'~ The average American consumes more than 100 lb of sucrose and 40 lb of corn syrup each year. This sugar addiction plays a major role in the high prevalence of ill health and chronic disease in the United States.

Health Impacts of Hypoglycemia Hypoglycemia and the Brain The brain depends on glucose as an energy source. When glucose levels are low, as occurs during hypoglycemia, the brain dysfunction results in dizziness, headache, clouding of vision, blunted mental acuity, emotional instability, confusion, and abnormal behavior. The association between hypoglycemia and impaired mental function is well known. What is not as well known is the effect that hypoglycemia plays in various psychologic disorders. For example, despite numerous studies of depressed individuals showing a high percentage of abnormal glucose or insulin tolerance tests, rarely is hypoglycemia considered and rarely are depressed individuals prescribed dietary There is no explanation for this oversight by so many physicians, especially since dietary therapy (usually simply eliminating refined carbohydrates from the diet) is occasionally all that is necessary for effective therapy in patients who suffer from depression due to reactive hypoglycemia.

Aggressive and Criminal Behavior A strong yet controversial link exists between hypoglycemia and aggressive or criminal behavior. Several controlled studies in psychiatric patients and habitually violent and impulsive criminals have shown that reactive hypoglycemia (as determined by an oral G'IT) is a common finding.2°,21Furthermore, during the GTT, abnormal and sometimes emotionally explosivebehavior

is often observed. In one study, reactive hypoglycemia was shown to induce fire-setting behavior in arsonists.22 Several large studies involving more than 6000 inmates in 10 penal institutions in three states have now evaluated the effect of dietary intervention (i.e., the elimination of refined sugar) on antisocial or aggressive behavior.=J4 In the first study, 174 incarcerated juvenile delinquents were placed on a sugar-restricted diet while another 102 offenders were placed on a control diet.23 During the 2-year study the number of incidents of antisocial behavior was reduced by 45% in the treatment group. The most significant changes were in the reduction of assaults (83%),theft (To/,), "horseplay" (&YO), and refusal to obey an order (55%).Antisocial behavior changed the most in those charged with assault, robbery, rape, aggravated assault, auto theft, vandalism, child molestation, arson, and possession of a deadly weapon. In the largest study 3999 incarcerated juveniles were studied over a period of 2 years.24This study limited the dietary revisions to replacing sugary soft drinks with fruit juices and high-sugar snacks with nonrefined carbohydrate snacks (e.g., replacing a candy bar with popcorn). When the 1121 young men on the sugarrestricted diet were compared with the 884 on the control diet, there were significant differences: suicide attempts were reduced 100%; the need for restraints to prevent self-injury was reduced 75%; disruptive behavior was reduced 42%; and assaults and fights were reduced by 25%. Interestingly, the dietary changes did not seem to affect the behavior of female subjects. This lack of effect seems to indicate that men may react to hypoglycemia in a different manner from women. From an anthropologic and evolutionary view, this makes sense. Low blood sugar levels were undoubtedly an internal signal for men to hunt for food. The link between hypoglycemia and aggressive behavior also extends to men without a history of criminal activity. In one study, a G'IT was given to a group of men who did not have a history of aggressive behavior or hypoglycemia.16In these subjects a significant correlation was found between the tendency to become mildly hypoglycemic and scores on questionnaires used to measure aggression. These results indicated that aggressiveness often coincided with hypoglycemia.

Premenstrual Syndrome The premenstrual syndrome (PMS) is a recurrent condition of women characterized by troublesome yet often ill-defined symptoms that usually appear 7 to 14 days before menstruation. The syndrome affects about one third of women between 30 and 40 years of age, about 10% of whom may have a significantly debilitating form. An authority on PMS, Guy Abraham, MD, attempted to clanfy the different forms by subdividing PMS into

Hypoglycemia four distinct subgroups (A, C, D, and H).= Each subgroup is linked to specific symptoms, hormonal patterns, and metabolic abnormalities (see Chapter 204 for further information). PMS-C is associated with increased appetite, craving for sweets, headache, fatigue, fainting spells, and heart palpitations. GTTs on PMS-C patients during the 5 to 10 days before their menses typically displayed a flattening of the early part of the curve and reactive hypoglycemia, whereas during other parts of the menstrual cycle their GTT was normal. A flat early part of the G'IT curve usually implies excessive secretion of insulin in response to sugar consumption. This excessive secretion appears to be hormonally regulated, but other factors may also be Sodium chloride ingestion enhances insulin response to sugar ingestion, and decreased magnesium levels in the pancreas can result in increased secretion of insulin in response to glucose. Regardless of the cause, women with PMSC appear to be extremely sensitive to hypoglycemia.

Migraine Headaches Migraine headaches are probably caused by excessive dilation (expansion) of a blood vessel in the head (see Chapter 191). Migraines are a surprisingly common disorder, affecting 15%to 20% of men and 25% to 30% of women at some time in their lives. More than half of the patients have a family history of the illness. Hypoglycemia has been shown to be a common precipitating factor in migraine headaches since 1933F7 Several studies have found that eliminating refined sugar from the diet of migraine sufferers with confirmed hypoglycemia results in sigruficant improvement. In one study of 48 migraine sufferers with reactive hypoglycemia, 27 (56%)showed a greater than 75%improvement in symptoms, 17 (35%)showed a greater than 50% improvement, and 4 (8%) showed a greater than 25% improvement.B

disturbances, high blood cholesterol and triglyceride levels, elevated blood pressure, and android obesity. Other terms to describe this syndrome include "the metabolic cardiovascular risk syndrome (MCVS)," Reaven syndrome, insulin resistance syndrome, and "atherothrombo-genic syndrome." Although there is a push to abandon the term "syndrome X," it has nonetheless p e r s i ~ t e d . ~ 3 ~ The underlying metabolic denominator in syndrome X is elevated insulin levels. There is little doubt about what contributes to these elevations: an elevated intake of refined carbohydrates. An increased simple sugar intake leads first to hypoglycemia and later to diabetes. Adding support to the contention that prolonged consumption of refined sugars and the resulting elevations in insulin eventually lead to type 11 diabetes are the results from a recent 25-year study in which the development of type 11 diabetes was shown to be preceded by elevations of serum insulin values and insulin insensitivity? In most cases these defects presented themselves decades before the development of diabetes. Hypoglycemia, increased insulin secretion, syndrome X, and type 11 diabetes can be viewed as a progression of the same illness-maladaptation to the "Western diet." The human body was not designed to handle the amount of refined sugar, salt, saturated fats, and other harmful food compounds that many people in the United States and other "Western" countries feed it. The result is that a metabolic syndrome emerge-levated insulin levels, obesity, elevated blood cholesterol and triglycerides, and high blood pressure.

THERAPEUTIC CONSIDERATIONS Dietary Factors

Dietary carbohydrates play a central role in the cause, prevention, and treatment of hypoglycemia. Simple carbohydrates, or sugars, are quickly absorbed by the body, resulting in a rapid elevation in blood sugar, stimulating Atherosclerosis, Intermittent Claudication, a corresponding excessive elevation in serum insulin and Angina levels. It is thought by some that the assortment of Substantial evidence indicates that reactive hypoglycemia natural, simple sugars in fruits and vegetables has an or impaired glucose tolerance is a sigruficant factor in the advantage over sucrose and other refined sugars in that development of atherosclerosis. Although a high sugar they are balanced by a wide range of nutrients that aid intake leads to elevations in triglyceride and cholesterol in the utilization of the sugars. However, of greater levels, the real culprit may be the elevations of ins~din.2~ importance is the fact that in whole, unprocessed foods Abnormal GTTs and elevations in insulin secretion are the sugars are more slowly absorbed, as they are concommon findings in patients with heart disease.3031 tained within cells and are associated with fiber and In addition to playing a role in atherosclerosis, high other food elements. sugar consumption and reactive hypoglycemia can be a Problems with carbohydrates begin when they are cause of angina and intermittent claudi~ation.~u~ refined, which strips them of associated nutrients and increases their rate of absorption. Virtually all of the Syndrome X vitamin and trace mineral content has been removed The term syndrome X is used to describe a set of carfrom white sugar, white breads, pastries, and many diovascular risk factors including glucose or insulin breakfast cereals. When high-sugar foods are eaten

alone, blood sugar levels rise quickly, producing a strain on blood sugar control. Eating foods high in simple sugars in any form (e.g., sucrose, honey, or maple syrup) is harmful to blood sugar control. Large amounts of fruit juice and even vegetable juice may be a problem for hypoglycemics, as the cell disruption characteristic of juicing increases the rate of the sugars in the juices. Currently, more than half of the carbohydrates consumed in the United States are in the form of sugars added to processed foods as sweetening agents.17 Patients should be instructed to read food labels carefully for clues to sugar content. They should know that various words are used to describe refined simple carbohydrates; any of the following might appear on the label sucrose, glucose, maltose, lactose, fructose, corn syrup, or white grape juice concentrate.

A Closer Look at Simple Carbohydrates Glucose is not particularly sweet tasting compared with fructose and sucrose. It is found in abundant amounts in fruits, honey, sweet corn, and most root vegetables. Glucose is also the primary repeating sugar unit of most complex carbohydrates. Fructose or fruit sugar is the primary carbohydrate in many fruits, maple syrup, and honey. Fructose is very sweet, roughly 1.5 times sweeter than sucrose. Although fructose has the same chemical formula as glucose, its structure is quite different. In order to be used by the body, fructose must be converted to glucose within the liver. Many physicians have recommended that individuals with diabetes or hypoglycemia avoid fruits and fructose. However, recent research challenges this. Fructose does not cause a rapid rise in blood sugar levels. Because fructose must be changed to glucose in the liver in order to be used by the body, blood glucose levels do not rise as rapidly after fructose consumption as they do with other simple sugars. For example, the ingestion of sucrose results in an immediate elevation in the blood sugar level. Although most diabetics and hypoglycemics cannot tolerate sucrose, most can tolerate moderate amounts of fruits and fructose without loss of blood sugar control. In fact, fructose and fruits are not only much better tolerated than white bread and other refined carbohydrates, but they also produce less sharp elevations in blood sugar levels compared with most sources of complex carbohydrates (starch).%As a bonus, fructose has actually been shown to enhance the sensitivity to insulin.37 Regular fruit consumption also may help to control sugar cravings and promote weight loss in overweight individuals. Although studies have shown aspartame (NutraSweet), glucose, and sucrose to increase the

appetite, fructose has actually been shown to decrease the amount of calories and fat consumed in several double-blind studies. Typically, subjects are given food or drink containing an equivalent caloric amount of fructose or other sweetener 30 minutes to 2.5 hours before allowing them to consume as much food as they desire at a dinner buffet. Consistently, subjects receiving the fructose-sweetened food or drink eat substantially fewer calories and fat compared with the groups receiving aspartame, sucrose, or glucose.384o

The Glycemic Index and Glycemic Load Two helpful methods of categorizing food on the basis of its ability to alter blood sugar are the "glycemic index" (GI) and the "glycemic l o a d (GL). The GI was developed in 1981 to express the rise of blood glucose after eating a particular food.4l The standard value of 100 is based on the rise seen with the ingestion of glucose. The GI ranges from about 20 for fructose and whole barley to about 98 for a baked potato. The insulin response to carbohydrate-containing foods is similar to the rise in blood sugar. The GI is used as a guideline for dietary recommendations for people with either diabetes or hypoglycemia (see Table 178-4). People with blood sugar problems are advised to avoid foods with high values and choose carbohydrate-containing foods with lower values. However, the GI should not be the only dietary guideline. For example, high-fat foods like ice cream and sausage may have a low GI, but because a diet high in fat has been shown to impair glucose tolerance, these foods are not good food choices for people with hypoglycemia or diabetes. The GL uses the information the GI provides in a more comprehensive way to assess the impact of carbohydrate consumption." Although the GI reveals how quickly a particular food's carbohydrate content can raise blood glucose levels, it still does not help us to understand how much of the blood sugar-increasing carbohydrate is in a certain food. The dietary GL is defined as the value of a food's GI divided by 100 and then multiplied by its available carbohydrate content. A GL of 20 or more is considered high, 11 to 19 is considered intermediate, and 10 or less is considered low. For the case of watermelon, its GI is 72, while a typical serving of 120 g has 6 g of available carbohydrate: GL for watermelon = (72/100) x 6 = 4.32

The point of this example is that even though the GI for watermelon is fairly high, its GL is low, indicating that within reasonable serving amounts, it does not adversely stress blood sugar control. For a complete

Hypoglycemia

Glycemic index of isocaloric amounts of some common foods Food Sugars

Fruits

Fructose Glucose Honey Maltose Sucrose Apples Bananas Orange juice Oranges Raisins

Vegetables

Beets Carrot, cooked Carrot, raw Potato, baked Potato (new), boiled

Grains

Bran cereal Bread, white Bread, whole grain Corn Cornflakes Oatmeal Pasta Rice Rice, puffed Wheat cereal

Legumes

Beans Lentils Peas

Other foods

Ice cream Milk Nuts Sausages

Glycemic index

20 100 75 105

60 39 62 46 40 64 64 36 31 98 70 51 69 72 59 80 49 45 70 95 67 31 29 39 36 34 13 28

Modified from Truswell AS. Eur J Clin Nutr 1992;46(suppl2):S91-101

listing of foods and their GI, fiber content, and GL, see Appendix 6. The GL reinforces the idea that foods containing natural soluble and insoluble fibers, as well as whole foods that are minimally processed, remain as better choices in terms of glycemic influence and insulin response.43 Further research indicates that diets with a high GL are directly linked to conditions such as diabetes,"Acoronary heart disease,&colon,46ovarian," and pancreatic47 cancer risk.

The Importance of Fiber Population studies, as well as clinical and experimental data, show blood sugar disorders to be clearly related to inadequate dietary fiber intake.l7r4 These results indicate that although the intake of refined sugars should be

curtailed, the intake of complex carbohydrate sources that are rich in fiber should be increased. The term dietary fiber refers to the components of the plant cell wall, as well as the indigestible residues from plant foods. Different types of fibers possess different actions. The water-soluble forms exert the most beneficial effects on blood sugar control. Included in this class are hemicelluloses, mucilages, gums, and pectin substances. These types of fiber are capable of the following actions: Slowihg down the digestion and absorption of carbohydrates, thereby preventing rapid rises in blood sugar Increasing cell sensitivity to insulin, thereby preventing the excessive secretion of insulin Improving uptake of glucose by the liver and other tissues, thereby preventing a sustained elevation of blood sugar (For a full discussion of the importance of fiber, see Chapter 60.) The majority of fiber in most plant cell walls is water soluble. Particularly good sources of water-soluble fiber are legumes, oat bran, nuts, seeds, psyllium seed husks, pears, apples, and most vegetables. Patients should be advised to consume a large amount of plant foods to obtain adequate levels of dietary fiber. A daily intake of 50 g is a healthful goal.

Chromium Chromium is vital to proper blood sugar control, as it functions in the body as a key constituent of the "glucose tolerance factor." Without chromium, insulin's action is blocked and glucose levels are elevated. A chromium deficiency may be an underlying contributing factor to the tremendous number of Americans who have hypoglycemia or diabetes or who are 0bese.4~Evidence exists that marginal chromium deficiency is quite common in the United States and may be responsible for many cases of reactive hypoglycemia.50 In one double-blind, cross-over study of eight female patients, 200 mcg of chromium (as chromium chloride) given twice daily for 3 months alleviated hypoglycemic symptoms and the glucose nadir at 2 to 4 hours after a glucose load.50 In addition, insulin binding improved and the number of insulinreceptors increa~ed.5~9~~

Lifestyle Factors Alcohol Alcohol consumption severely stresses blood sugar control and is often a contributingfactor to hypoglycemia. Alcohol induces reactive hypoglycemia by interfering with normal glucose utilization, as well as increasing the secretion of insulin. The resultant drop in blood sugar

produces a craving for food, particularly foods that quickly elevate blood sugar, as well as a craving for more alcohol. The increased sugar consumption aggravates the reactive hypoglycemia, particularly in the presence of more alcohol, again due to alcoholinduced impairment of normal glucose utilization and increased secretion of insulin. Hypoglycemia is an important complication of acute and chronic alcohol abuse. Hypoglycemia aggravates the mental and emotional problems of the alcoholic and the withdrawing alcoholic with such symptoms as the following3: Sweating Tremor Rapid heart beat Anxiety Hunger Dizziness Headache Visual disturbance Decreased mental function Confusion Depression Although acute alcohol ingestion induces hypoglycemia, in the long run it leads to hyperglycemia and diabetes. Eventually the body becomes insensitive to the augmented insulin release caused by the alcohol. In addition, alcohol itself can cause insulin resistance even in healthy individuals3 There is also evidence from large population studies that alcohol intake is strongly correlated with diabete~.'~5~ The higher the alcohol intake, the more likely it is that an individual will have diabetes.

sensitivity and improving glucose tolerance in existing diabetics. Some effects of exercise on blood sugar control may stem from the fact that exercise increases tissue chromium concentrations.56

THERAPEUTIC APPROACH The primary treatment of hypoglycemia is the use of dietary therapy to stabilize blood sugar levels. Reactive hypoglycemia is not a disease; it is simply a complex set of symptoms caused by faulty carbohydrate metabolism induced by an inappropriate diet.

Diet All simple, processed, and concentrated carbohydrates, as well as food choices with a high GL, must be avoided. Foods rich in soluble fiber such as legumes and lowglycemic vegetables should be consumed regularly. Frequent, small meals may be more effective in stabilizing blood sugar levels. Alcohol must be avoided, as it can cause hypoglycemia. Further dietary recommendations mirror those in Chapter 163.

Supplements The recommendations for the daily intake levels of vitamins and minerals given in Chapter 127 are especially important in hypoglycemia, as many essential nutrients are critical to proper carbohydrate metabolism. The recommended levels are most easily attained by taking a multivitamin-mineral formula. Critically important is chromium: 200 to 400 yg/day.

Exercise

An appropriate exercise training program is an important part of a hypoglycemia treatment and prevention plan. Regular exercise has been well documented to prevent type II diabetes, and it improves many aspects of glucose metabolism including enhancing insulin

Because the beneficial effects of exercise that improve insulin sensitivity decrease within 3 days after exercise and are no longer evident after 1 week, a sustained program is req~ired.5~ A graded long-term exercise program should be developed. The program should be appropriate to the individual's fitness level and interest yet elevate heart rate at least 60% of its maximum for half an hour three times a week. For a fulldiscussion, see Chapter 37.

1. Pourmotabbed G, Kitabchi AE. Hypoglycemia. Obstet Gynecol Clin North Am 2001;28:383-400. 2. Yasuhara D, Deguchi D, Tsutsui J, et al. A characteristicreactive h p glycemia induced by rapid change of eating behavior in anorexia nervosa: a case report. Int J Eat Disord 2003;34:273-277. 3. Chalew SA, Koetter H, Hoffman S, et al. Diagnosis of reactive hypoglycemia. pitfalls in the use of the oral glucose tolerance test. South Med J 1986;79:285-287. 4. Palardy J, Havrankova J, Lepage R, et al. Blood glucose measurements during symptomatic episodes in patients with suspected postprandial hypoglycemia.N Engl J Med 1989921:1421-1425.

5. Kwentus JA, Achilles JT,Goyer PF. Hypoglycemia etiologic and psychosomatic aspects of diagnosis. Postgrad Med 1982;71:99-104. 6. Yogev Y, Ben-Haroush A, Chen R, et al. Undiagnosed asymptomatic hypoglycemia: diet, insulin, and glyburide for gestational diabetic pregnancy. Obstet Gynecol2004;104:88-93. 7. Galloway PJ, Thomson GA, Fisher BM, et al. Insulin-induced hypoglycemia induces a rise in C-reactive protein. Diabetes Care 2000;23:861-862. 8. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Department of Noncommunicable Disease Surveillance, Geneva, 1999.

Exercise

Hypoglycemia 9. Chalew SA, McLaughlin JV, Mersey JH, et al. The use of the plasma epinephrine response in the diagnosis of idiopathic postprandial syndrome. JAMA 1984;251:612-615. 10. Hadji-GeorgopoulusA, Schmidt MI, Margolis S, et al. Elevated hypoglycemic index and late hyperinsulinism in symptomatic postprandial hypoglycemia.J Clin Endocrinol Metabl1980;50:371-376. 11. Fabrykant M. The problem of functional hyperinsdinism on functional hypoglycemia attributed to nervous causes. 1.Laboratory and clinical correlations. Metabolism 1955;4469-479. 12.Truswell AS. Glycemic index of foods. Eur J Clin Nutr 1992;46 (SUPPI 2):S91-101. 13.Statement on hypoglycemia. JAMA 1973;223682. 14. Cahill GF Jr, Soeldner JS. A non-editorial on non-hypoglycemia. N Engl J Med 1974;291:905-906. 15. Hofeldt FD. Patients with bona fide meal-related hypoglycemia should be treated primarily with dietary restriction of refined carbohydrate. Endocrinol Metab Clin North Am 1989;18:185-201. 16. Sanders LR, Hofeldt FD, Kirk MC, Levin J. Refined carbohydrate as a contributing factor in reactive hypoglycemia. South Med J 1982; 751072-1075. 17. National Research Council. Diet and health. Implicationsfor reducing chronic disease risk. Washington, Dc:National Academy Press, 1989. 18. Winokur A, Maislin G, Phiillips JL, et al. Insulin resistance after glucose tolerance testing in patients with major depression. Am J Psychiatry 1988;145:325-330. 19. Wright JH, Jacisin JJ, Radin NS, et al. Glucose metabolism in unipolar depression. Br J Psychiatry 1978;132386-393. 2O.Schauss AG. Nutrition and behavior: complex interdisciplinary research.Nutr Health 198439-37. 21. Benton D. Hypoglycemia and aggression: a review. Int J Neurosci 1988;41:163-168. 22. Virkkunen M. Reactive hypoglycemic tendency among arsonists. Acta Psychiatr Scan 1984;69445452. 23. Schoenthaler SJ. Diet and crime: an empirical examination of the value of nutrition in the control and treatment of incarcerated juvenile offenders. Int J Biosocial Res 1983;4:25-39. 24. Schoenthaler SJ.The northern California diet-behavior program. An empirical evaluation of 3,000 incarcerated juveniles in Stanislaus County Juvenile Hall. Int J Biosocial Res 198359-106. 25. Abraham GE. Nutritional factors in the etiology of the premenstrual tension syndromes. J Reprod Med 1983;28:446-464. 26. Walsh CH, OSullivan DJ. Studies of glucose tolerance, insulin and growth hormone secretion during the menstrual cycle in healthy women. Ir J Med Sci 1975;144:18-24. 27. Critchley M. Migraine. Lancet 1933;1:123-126. 28. Dexter JD, Roberts J, Byer JA. The five hour glucose tolerance test and effect of low sucrose diet in migraine. Headache 1978;18:91-94. 29. Mykkanen L, Laakso M, Pyorala K. High plasma insulin levels associated with coronary heart disease in the elderly. Am J Epidemiol 1993;1371190-1202. 30. Yudkin J. Metabolic changes induced by sugar in relation to coronary heart disease and diabetes. Nutr Health 1987;5:5-8. 31. Pyorala K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. Diabetes Care 1979;2131-141. 32. Bansal S, Toh SH, LaBresh KA. Chest pain as a presentation of reactive hypoglycemia. Chest 1983;84:641-642. 33. Hanson M, Bergentz SE, Ericsson BF, et al. The oral glucose tolerance test in men under 55 years of age with intermittent claudication. Angiology 1987;38:469473. 34. Hjermann I. The metabolic cardiovascular syndrome: syndrome X, Reaven’s syndrome, insulin resistance syndrome, atherothrombogenic syndrome. J Cardiovasc Pharmacoll992;2O:S5-10.

35. Maseri A. Syndrome X. Still an appropriate name. J Am Coll Cardiol 1991;171471-1472. 36. Gregersen S, Rasmussen 0,Larsen S, Hermansen K. Glycaemic and insulinaemic responses to orange and apple compared with white bread in non-insulin dependent diabetic subjects. Eur J Clin Nutr 1992;46:301-303. 37. Koivisto VA, Yki-Jarvinen H. Fructose and insulin sensitivity in patients with type 2 diabetes. J Intern Med 1993;233:145-153. 38. Rodin J. Effects of pure sugar vs. mixed starch fructose loads on food intake. Appetite 1991;17213-219. 39. Rodin J. Comparative effects of fructose, aspartame, glucose, and water preloads on calorie and macronutrient intake. Am J Clin Nutr 1990;51:428435. 40. Spitzer L, Rodin J. Effects of fructose and glucose preloads on subsequent food intake. Appetite 1987;8:135-145. 41. Jenkins DJ, Wolever TM, Taylor RH, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr 1981;34:362-366. 42.Lukaczer D. Sweet, hot and deadly-the link between glycemic index, inflammation, and cardiovascular disease: evolving research and practical applications. Proceedings of the American Association of Naturopathic Physicians 18th Annual Convention and Exposition, Portland, OR, 2003. 43. Granfeldt Y, Eliasson AC, Bjorck I. An examination of the possibility of lowering the glycemic index of oat and barley flakes by minimal processing. J Nutr 2000;1302207-2214. 44.Willett W, Manson J, Liu S. Glycemic index, glycemic load, and risk of type 2 diabetes. Am J Clin Nutr 2002;76274S278OS. 45. Liu S, Wdett WC, Stampfer MJ, et al. Aprospective study of dietary glycemic load, carbohydrate intake, and risk of coronary heart disease in US women. Am J Clin Nutr 2OOO;71:1455-1461. 46. Franceschi S, Dal Maso L, Augustin L, et al. Dietary glycemic load and colorectal cancer risk. Ann Oncol2001;12:173-178. 47. Michaud DS,Liu S, Giovannucci E, et al. Dietary sugar, glycemic load, and pancreatic cancer risk in a prospective study. J Natl Cancer Inst 2002;941293-1300. 48. Trowell H, Burkitt DP. Western diseases: their emergence and prevention. Cambridge, MA: Harvard University Press, 1981. 49. Anderson RA. Chromium, glucose tolerance, and diabetes. Biol Trace Elem Res 19923219-24. 50. Anderson RA, Polansky MM, Bryden NA, et al. Effects of supplemental chromium on patients with symptoms of reactive hypoglycemia. Metabolism 198726351-355. 51. McCarty MF. Chromium and other insulinsensitizers may enhance glucagon secretion: implications for hypoglycemia and weight control. Med Hypoth 1996;46:77-80. 52. Anderson RA. Nutritional factors influencing glucose/insulin system: chromium. J Am Coll Nutr 1997;16:404-410. 53. Wyngaarden JB, Smith LH, Bennett JC, eds. Cecil textbook of medicine. Philadelphia: WB Saunders, 1992. 54. Hirata Y. Diabetes and alcohol. Asian Med J 1988;31:564-569. 55. Selby JV, Newman 8, King MC, et al. Environmental and behavioral determinants of fasting plasma glucose in women. A matched cotwin analysis. Am J Epidemiol1987;125:979-988. 56. Vallerand AL, Cuemer JP,Shapcott D, et al. Influence of exercise training on tissue chromium concentrations in the rat. Am J Clin Nutr 1984;39:402409. 57. Sat0 Y, Nagasaki M, Nakai N, et al. Physical exercise improves glucose metabolism in lifestyle-related diseases. Exp Biol Med (Maywood) 2003;228:120&1212.

Hypothyroidism Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

Nutritional Considerations 1794 Exercise 1795 Thyroid Hormone Replacement 1796

1791

General Considerations 1791 Causes of Hypothyroidism 1792

Therapeutic Approach 1796 Treatments for Autoimmune Hypothyroidism (Hashimoto Disease) 1796 Treatment for Wilson’s Syndrome 1797 Treatments for Nonautoimmune Overt or Subclinical Hypothyroid Disorder 1797 Exercise/Physical Therapy/Lifestyle 1798

Diagnostic Considerations 1792 Clinical Symptomatology 1793 Laboratory Evaluation 1793 Functional Assessment 1794 Therapeutic Considerations 1794 DieVFood Allergy 1794 PhysiologidHormonal Considerations

1794

DIAGNOSTIC SUMMARY Depression Difficulty in losing weight mDryskin Headaches Lethargy or fatigue Memory problems Menstrual problems Hyperlipidemia Recurrent infections Sensitivity to cold

GENERAL CONSIDERATIONS Because the hormones of the thyroid gland regulate metabolism in every cell of the body, a deficiency of thyroid hormones can affect virtually all bodily functions. The degree of severity of symptoms in the adult ranges from mild deficiency states that are not detectable with standard blood tests (subclinical hypothyroidism) to severe deficiency states which can be life threatening (myxedema).l4 Deficiency of thyroid hormone may be due to lack of stimulation by the pituitary gland, defective hormone synthesis, or impaired cellular conversion of T4 to T3. The pituitary gland regulates thyroid activity through the secretion of thyroid-stimulating hormone (TSH).

The combination of low thyroid hormone and elevated TSH blood levels usually indicates defective thyroid hormone synthesis, which is defined as primary hypothyroidism. When TSH and thyroid hormone levels are both low, the pituitary gland is responsible for the low thyroid function, a situation termed secondary hypothyroidism. Normal blood thyroid hormone and TSH blood levels combined with low functional thyroid activity (as defined by a low basal metabolic rate) suggest cellular hypothyroidism. Most estimates on the rate of hypothyroidism are based on the levels of thyroid hormones in the blood. This may result in a large number of people with mild hypothyroidism going undetected. Nonetheless, using blood levels of thyroid hormones as the criteria, it is estimated that between 1% and 4%of the adult population have moderate to severe hypothyroidism, and another 10% to 12% have mild hypothyroidism.’-’ The rate of hypothyroidism increases steadily with advancing age. Using only blood tests, thyroid function is commonly low in older adults. One study evaluated 370 elderly subjects, 60 to 97 years of age. About 18%of the patients already had an established history of past or current thyroid disease. Another 5.4% had a history of thyroid surgery. Of the remaining 283 patients with no history of thyroid disease, 14.6%of the women and 15.4%of the men had subclinical hypothyroidism. In other words,

1791

Specific Health Problems 40"/0 of these elderly had current or past problems with

Subclinical Hypothyroidism

their thyroid! Some writers of popular books using medical history, physical examination, and basal body temperatures along with the blood thyroid levels as the diagnostic criteria estimate the rate of hypothyroidism in the general adult population to be as high as 40%.9JoIt is likely that the true rate of hypothyroidism using these criteria is somewhere near 25% of the adult population and sigruficantlyhigher in the elderly.

In this condition, TSH is elevated while serum thyroid hormone levels are normal. In subclinical hypothyroidism, the body can compensate for decreased thyroid function by increasing TSH pituitary output. These cases may be caused by a mild autoimmune thyroid destruction or may be due to drug or surgical interventions. Subclinical hypothyroidism is a relatively common finding in primary care, affecting 2% to 7% of adults."

Causes of Hypothyroidism Overt Hypothyroidism

Functional Hypothyroidism

About 95% of all cases of overt hypothyroidism are primary. In the past, the most common cause of hypothyroidism was iodine deficiency. The thyroid gland adds iodine to the amino acid tyrosine to create the thyroid hormones. Iodine deficiency leads to hypothyroidism or the development of an enlarged thyroid gland (i.e., a goiter), or both. Goiters are estimated to affect more than 200 million people worldwide. In all but 4% of these cases, the cause is an iodine deficiency. Iodine deficiency is now quite rare in the United States and other industrialized countries due to the addition of iodine to table salt. Adding iodine to table salt began in Michigan, where in 1924 the goiter rate was an incredible 47%. Few people in the United States are now considered iodine deficient, yet some still develop goiters. These goiters are probably a result of the excessive ingestion of goitrogens-foods that block iodine utilization. These include the following: The Brassica family: turnips, cabbage, broccoli, Brussels sprouts, mustard, kale, cauliflower Cassava root Soybeans Peanuts Pine nuts Millet Cooking usually inactivates goitrogens. Currently, the most frequent cause of overt hypothyroidism in the United States is the autoimmune disorder Hashimoto disease. In this disease antibodies that bind to the thyroid (specificallyagainst the thyroid peroxidase enzyme, thyroglobulin, and TSH receptors) are formed and prevent the manufacture of sufficient levels of thyroid hormone. In addition to binding to thyroid tissue, these antibodies may also bind to the adrenal glands, pancreas, and acid-producing cells of the stomach (parietal cells). Other causes of overt hypothyroidism include thyroid surgery and ablation and postpartum hypothyroidism, which is a transient form of hypothyroidism that affects 5% to 10%of women in the United States.

Another method of evaluating subclinical sluggish thyroid activity is by a functional test developed by Broda Barnes, which measures thyroid hormone's effect on the body rather than looking solely at blood thyroid hormone levels. This is achieved by measuring a person's resting metabolic rate, which is controlled by the thyroid gland. Barnes found that measuring basal body temperature was a good way of assessing basal metabolic rate and thus the body's response to thyroid hormones, regardless of their blood level. When employing this test, the incidence of hypothyroidism is a surprising 25%? Functional tests show a far greater incidence of low thyroid than blood tests for several reasons. The most important is that typical blood tests measure thyroxine (T4), which accounts for 90%of the hormone secretion by the thyroid. However, the form that affects the cells the most is T3 (triiodothyronine),which cells make from T4. If the cells cannot convert T4 to the four-times-more-active T3, a person can have normal levels of thyroid hormone in the blood yet be thyroid deficient. "Wilson's syndrome" is a name used for the condition in which subclinical hypothyroidism is thought to be associated with deficient peripheral conversion of T4 to T312 Blood tests for T3 were medically popular for awhile, but research found they missed low thyroid function in 50% of patients. Some physicians look for a high reverse T3-to-T3 ratio as evidence of this condition.

DIAGNOSTIC CONSIDERATIONS Before the use of blood measurements, it was common to diagnose hypothyroidism on the basis of basal body temperature (the temperature of the body at rest) and Achilles reflex time (reflexes are slowed in hypothyroidism). With the advent of sophisticated laboratory measurement of thyroid hormones in the blood, these "functional" tests of thyroid function fell by the wayside. However, it is now known that routine blood tests may not be sensitive enough to diagnose milder forms of hypothyroidism in all cases. As mild hypothyroidism is the most common form of hypothyroidism, many people with hypothyroidism are going undiagnosed.

Hypothyroidism

The basal body temperature is perhaps the most sensitive functional test of thyroid function?Jo In order to distinguish between autoimmune Hashimoto thyroiditis and other nonautoimmune subclinical and functional conditions, laboratory TSH, antithyroid peroxidase, and antithyroglobulin antibody tests should be performed. Wilson's syndrome may be suspected via observing low basal body temperature and a high reverse T3-to-T3ratio.

Clinical Symptomatology Metabolic A lack of thyroid hormones leads to a general decrease in the rate of utilization of fat, protein, and carbohydrate. Moderate weight gain combined with sensitivity to cold weather (demonstrated by cold hands or feet) is a common finding. Cholesterol and triglyceride levels are increased in even the mildest forms of hypothyroidism.This elevation greatly increases the risk of serious cardiovascular disease. Studieshave shown an increased rate of heart disease due to atherosclerosisin individualswith hyp~thyroidism.'~ Hypothyroidism also leads to increases in capillary permeability and slow lymphatic drainage. Often this results in swelling of tissue (edema).

Endocrine Various hormonal symptoms can exist in hypothyroidism. Perhaps the most common is a loss of libido (sexual drive) in men and menstrual abnormalities in women. Women with mild hypothyroidism have prolonged and heavy menstrual bleeding, with a shorter menstrual cycle. Infertility may also be a problem. If the hypothyroid woman does become pregnant, miscarriages, premature deliveries, and stillbirths are common. Rarely does a pregnancy terminate in normal labor and delivery in the overtly hypothyroid woman.

Skin, Hair, and Nails Dry, rough skin covered with fine superficial scales is seen in most hypothyroid individuals while the hair is coarse, dry, and brittle. Hair loss can be quite severe. The nails become thin and brittle and typically show transverse grooves.

Psychologic The brain appears to be quite sensitive to low levels of thyroid hormone. Depression, along with weakness and fatigue, are usually the first symptoms of hypothyroidi~m.'~'~ Later the hypothyroid individual has difficulty concentrating and is extremely forgetful.

Muscular and Skeletal Muscle weakness and joint stiffness are predominate features of hyp~thyroidism.'~ Some individuals with

hypothyroidism may also experience muscle and joint pain, as well as tenderness.'*

Cardiovascular Both overt and subclinical hypothyroidism are thought to predispose one to hardening of the arteries (atherosclerosis) due to the increase in cholesterol and triglyce r i d e ~ " J ~ ' as ~ J well ~ as homocysteine and C-reactive protein (CRP) For instance, in a Dutch study of more than 1100 elderly people, subclinical hypothyroidism was present in 10.8% and was shown to be a strong independent risk factor for aortic atherosclerosis and myocardial infarction?' The inverse relationship between atherosclerotic risk and concentrations of highdensity lipoprotein cholesterol and its constituent apoprotein A1 has also been characterized.2O Hypothyroidism can also cause hypertension, reduce the function of the heart, and reduce heart rate.

Other Manifestations Shortness of breath, constipation, and impaired kidney function are some of the other common features of hypothyroidism. Several diseases have been shown to be associated with low thyroid function, even some of which seem to have no apparent relationship. For example, one study compared the thyroid function of 56 patients suffering from dermatitis herpetiformis with that of 26 control subjects. The patients with dermatitis herpetiformis had sigruficantly increased abnormalities of thyroid function tests (32% vs. 4%), with signhcant hypothyroidism being the most common abnormality affecting 12 of the 56 patients.22

Laboratory Evaluation Thyroid dysfunction is quite common in adults. The American Thyroid Association recommends TSH screening every 5 years beginning at age 35.11The diagnosis of hypothyroidism by laboratory methods is primarily based on the results of total T4,free T4,T3,and TSH levels (Table 179-1 lists normal levels). The diagnosis is straightforward in overt cases. In subclinical cases the diagnosis is not so clear. An elevation in TSH with a normal T4 level is generally considered as subclinical. The accepted normal range is extremely broad, 0.35 to

I values T4 Free T4

4.8-1 3.2 yg/dl

0.9-2 ng/dl

T3

80-220ng/dl

Thyroid-stimulating hormone

0.35-5.50 yIU/ml

Specific Health Problems

5.50 pIU/ml. In conventional circles, treatment is not recommended unless the TSH is greater than 10 pIU/ml. Given the importance of adequate thyroid hormone to human health, our recommendation is more aggressive. If the patient does not respond to nutritional intervention, we recommend low-dose thyroid hormone therapy (detailed later) in patients with TSH values greater than 2.5 pIU/ml-slightly higher than the accepted level of 2 @J/ml demonstrating disturbance of the thyroidpituitary axis-especially in the presence of antithyroid antibodies, which should be examined in anyone with a TSH value greater than 2.5 pIU/ml.

Functional Assessment Functional thyroid activity, as indicated by basal metabolic rate, can be estimated by measuring basal body temperature. According to Barnes, the normal basal body temperature is 97.6"F to 98.2" F. However, Barnes' approach can also be in error, as a low basal metabolic rate could also indicate nutritional deficiencies, inadequate physical activity, etc., while fever from an infection or other disease can result in an inaccurately high body temperature. Patient instructions for taking basal body temperature are provided in Appendix 9.

THERAPEUTIC CONSIDERATIONS Figure 179-1 provides an algorithm for managing hypothyroid patients that combines clinical evaluation, basal body temperature, and laboratory evaluation.

Diet/Food Allergy A clear correlation exists among autoimmune diseases, intestinal permeability, and food allergy. One study of celiac disease patients revealed 2% had overt autoimmune thyroid disease.In these, the serologic autoantibody markers became undetectable 6 months after beginning a gluten-& diet.u Because many people do harbor subclinical allergies to wheat and other foods, an elimination diet or detoxification regimen (see Chapters 53 and 54), or both, may be of use to decrease antigen load and strengthen gut integrity and thereby beneficially mod@ autoantibody activity in autoimmune thyroid patients.

Physiologicklormonal Considerations Thyroid binding globulin (TBG) is a protein made in the liver that transports thyroid hormones including 75% of circulating T4.Certain factors may lead to increased TBG levels including excess estrogen conditions like pregnancy and oral estrogen supplementation regimens from birth control pills and hormone replacement therTamoxifen therapy for breast canceI.25and liver diseases also increases TBG levels. High TBG levels can hinder the availability of free thyroid hormone for use in

the peripheral tissues, thus contributing to a hypothyroid symptomology. Depending on the clinical picture, it may be useful to moderate hormonal excesses by decreasing the intake of oral estrogens, changing to nonoral regimens that do not involve a "first pass" through the liver, or helping the liver to more efficiently metabolize these estrogens.

Nutritional Considerations It is important to nutritionally support the thyroid gland by ensuring adequate intake of key nutrients required in the manufacture of thyroid hormone and by avoiding goitrogens.

Iodine, Tyrosine, and Goitrogens Thyroid hormones are made from iodine and the amino acid tyrosine. The mommended dietary allowance (RDA) for iodine in adults is quite small, 150 pg. The average intake of iodine in the United States is estimated to be more than 600 pg/day Too much iodine can actually inhibit thyroid gland synthesis. For this reason and because the only function of iodine in the body is for thyroid hormone synthesis, it is recommended that dietary levels or supplementation of iodine not exceed 600 pg/day for any length of time. Deficiencies of iodine intake are rare since the addition of iodine to salt. However, goitrogens can induce an iodine deficiency by combining with the iodine and making it unavailable to the thyroid. These foods include Brassica family foods (turnips, broccoli, cabbage, rutabagas, kale, mustard greens, radishes, horseradishes), cassava root, soybeans, peanuts, pine nuts, and millet.26In general, cooking inactivates these goitrogens. This is not to suggest that these foods should not be eaten, but rather that they should not be eaten in excess.

Vitamins and Minerals Zinc, vitamin E, and vitamin A function together in many body processes including the manufacture of thyroid hormone. A deficiency of any of these nutrients would result in lower levels of active thyroid hormone being produced. Low zinc levels are common in the elderly, as is hypothyroidism?' There may be a correlation. The B vitamins riboflavin (B2), niacin (B3), and pyridoxine (B6) and vitamin c are also necessary for normal thyroid hormone manufacture. The trace minerals zinc, copper, and selenium are the required cofactors for iodothyronine iodinase, the enzyme that converts T4 to the far more active T3. This enzyme has several different forms, each requiring a different trace mineral. Supplementation with zinc (the second most common mineral deficiency) has been shown to reestablish normal thyroid function in hypothyroid patients who were zinc deficient, even though they had normal serum T4levels.28

Hypothyroidism Suspected hypothyroidism

Clinical and blbod evaluation

Laboratory test normal

Free T4 low TSH high

Free T4 normal TSH slightly to moderately elevated

Basal body temperature

Primary hypothyroidism

Subclinical hypothyroidism

Normal

I

Low

I

I

Treatwith thyroid hormones

Secondary hypothyroidism

I

Thyroid peroxidase antibodies Treat with pituitary support

1

K--l

Negative

Normal thyroid Functional hypothyroidism

Positive If no response, treat with thyroid hormones

I

I

I

.1

.1

1

Supplement with selenium andlor consider trial of low-dose natural thyroid

Free T, low TSH normal or low

Treat with thyroid hormones

TSH > 2.5

3 month trial with thyroid hormones

L-+

No improvement

Improvement

Continue

Discontinue

Figure 179-1 Hypothyroidism diagnosis flow chart.

Similarly, selenium supplementation may be important, as those living in areas of the world where selenium is deficient have a greater incidence of thyroid disea~e.2~ Of particular significance is the fact that while a selenium deficiency does not decrease the conversion of T4 to T3 in the thyroid or the pituitary! it does result in a great decrease in this conversion in other cells of the People with a selenium deficiency have elevated levels of T4 and TSH. Supplementation with selenium results in a decrease in T4 and TSH, a normalization of thyroid activity,3l and selenium is known to decrease thyroid antibody levels in autoimmune thyroid condit i o n ~Selenium .~~ is deficient in about 50% of people’s diets, which may account for the large number of people with low thyroid a~tivity.3~ This research appears to clearly demonstrate that a selenium deficiency results in low thyroid activity in the cells, even though hormone levels are normal or even elevated, and provides some support for Barnes’ contentions.

Antioxidant supplementation has been shown to increase thyroid function in rats with methimazoleinduced hypothyroidism. Statistically significant results were reported in rats given vitamin C, vitamin E, and Curcuma longa (tumeric) extract with decreased abnormal thyroid weight changes, less suppression of T4 and T3 levels, and attenuated increases in cholesterol levels.M Furthermore, thyroid hormone abnormalities also correlated with decreased glutathione antioxidant status in testicular tissues in one animal Although there are no human studies to corroborate these findings, given the safety and beneficial profile of these supplements, it seems a reasonable approach to consider these in an antiinflammatory, antioxidant treatment regimen.

Exercise Exercise is particularly important in a treatment program for hypothyroidism. Exercise stimulates thyroid

gland secretion and increases tissue sensitivity to thyroid hormone. Many of the health benefits of exercise may be a result of improved thyroid function. The health benefits of exercise are especially important in overweight hypothyroid individuals who are dieting. A consistent effect of dieting is a decrease in the metabolic rate as the body strives to conserve fuel. Exercise has been shown to prevent the decline in metabolic rate in response to dieting.%

Thyroid Hormone Replacement If nutritional and lifestyle intervention are inadequate to reestablish normal thyroid activity, prescription of thyroid hormones is necessary. Although synthetic hormones have become popular, many physicians (particularly naturopathic physicians) still prefer the use of desiccated natural thyroid, complete with all thyroid hormones, not just thyroxine. Many people in the standard medical community believe that only T4 replacement is necessary because the body’s peripheral tissues will reliably convert T4 to T3. However, studies in rats whose thyroids were removed demonstrated that normal tissue levels of T4 and T3 were achieved only The with an infusion of T4 and T,, and not by T4 medical literature confirms that physicians recognize many patients, when treated with desiccated thyroid, do tend to feel better.” Several thyroid hormone preparations are available, each with advantages and disadvantages. The advantages of preparations containing only T4 (e.g., Synthroid, Levothroid) are that it provides consistent potency and prolonged duration of action. T3is rarely used alone as thyroid hormone replacement therapy, as it is roughly four times more potent with a shorter duration of action than T4,making it difficult to work with. The advantage of desiccated thyroid is that it provides both T4 and T3, as well as relevant amino acids and micronutrients. The main drawback with natural thyroid is that it lacks consistency. However, according to the United States Pharmacopoeia (USP), these preparations must contain not less than 85% and not more than 115%of the labeled amount of T4, and not less than 90%and not more than 110%for T3.The labeled amount is 38 pg of T4 and 9 pg T3 per grain (65 mg). Synthetic mixtures of T4 and T3 (e.g., Liotrix, Thyrolar) in similar ratios are available, and they provide the consistency that whole, natural desiccated thyroid is thought to lack. The equivalencies of the thyroid agents based on clinical response are as follows: 100 pg of T4(e.g., Synthroid) 20 to 25 pg T3 (e.g., Cytomel) 1grain desiccated thyroid 12.5 pg T4+ 50 pg T4 (e.g., Thyrolar)

Values for the different forms of thyroid hormones are referred to here as 1“thyroid unit.” Therefore 0.5 thyroid units would be equal to 50% of the values shown in the list. One study reports that the intake of fiber supplements or high-fiber diets can cause poor absorption or availability of T4 in the body, or both, thus necessitating increased levels of replacement.%Because these patients were given no instruction to consume the supplement away from meals, there may have been a direct effect of absorption inhibition. Furthermore, wheat bran, psyllium supplements, and wheat bread, which are known to contain allergenic components, were the sources of fiber in this study. Less allergenic vegetable and fruit fibers may not produce the same effect. It also may be that any fiber does indeed inhibit absorption of supplemental thyroid hormone even away from food, and as such, consideration is warranted when using oral supplementation with patients who necessitate unusually high levels of replacement. Curiously, there have been conflicting results concerning lipid profile improvements of patients using thyroid replacement. Regarding four randomized, controlled trials evaluating thyroxine replacement in subclinical hypothyroidism, two studies found a benefit and two found no benefit.” These results possibly reflect the need to implement other lifestyle and diet changes as mentioned earlier, along with hormone replacement. Additionally, it may be of use to study a more complete hormone replacement such as desiccated thyroid or synthetic replacement of T4 and T3 together in order to achieve consistent results regarding lipid profiles.

THERAPEUTIC APPROACH Natural treatment strategies for normalizing thyroid function vary depending on whether there is an autoimmune hypothyroid condition, Wilson syndrome, or subclinical or overt hypothyroidism.

Treatments for Autoimmune Hypothyroidism (Hashimoto Disease) Thyroid Replacement The use of thyroid replacement achieves two objectives in the autoimmune hypothyroid patient: decreased thyroid hormone levels can be normalized, and thyroid activity can be suppressed, thus decreasing autoimmune processes. Either desiccated or synthetic thyroid replacement may be used in high enough doses in order to decrease TSH levels at or near zero. It should be noted that some literature reports TSH values equal to or less than 0.1 pIU/ml may carry a risk of developing atrial fibrillation and are associated with bone density losses but not additional fracture.14

Desiccated thyroid is thought to be beneficial by stimulating blocking antibodies to antithyroid antibodies and by acting as decoys for thyroid antibodies.12 Some patients are found to recover from Hashimoto thyroiditis after an extended treatment time with thyroid hormone and no longer need to be maintained on replacement.'* Some patients may not benefit from desiccated thyroid, possibly due to an adverse reaction to antigenic thyroid substances. These patients should be promptly placed on a synthetic thyroid option instead. In either case, frequent TSH and antibody tests are essential in order to venfy suppression of thyroid activity and to monitor autoimmune activity. One caveat is an occurrence, often early in Hashimoto disease, where a hyperthyroid picture is more prevalent. In this case, thyroid replacement may be contraindicated.

Diet/Lifestyle Food elimination, detoxification, and gut healing options may be useful treatment aimed at ameliorating a possible root factor of antigenic autoimmune activity (see related chapters).

Other Recommendations Dehydroepiandrosterone (DHEA) is a beneficial supplement in the treatment of a number of autoimmune condition^.^^ Although many clinical studies have employed high dosages (100 to 200 mg/day), much lower doses in the physiologic range of 5 to 10 mg/day or 10 to 20 mg/day in women and men may be beneficial and safe. Untoward effects such as hirsutism and acne have been observed in a minority of patients using high doses.39Therefore it may be best to start at a low level and increase slowly while monitoring for DHEA blood levels and clinical symptoms of excess androgens. As the long-term effects of DHEA administration are unknown, DHEA should therefore be used with caution, particularly in patients at risk for developing hormonedependent cancers.4o Turmeric (Curcurnu longa) may be useful for its antiinflammatory and antioxidant effects. We recommend 400 mg three times a day of curcumin capsules or liberal amounts of turmeric on food. Selenium at 200 pg/day is recommend for Hashimoto autoimmune thyroiditis, especially in those patients who have high titers of anti-PO antibodies?*

Treatment for Wilson's Syndrome Thyroid Replacement When laboratory reverse T3 and basal body temperature recordings suggest Wilson's syndrome (see earlier section on subclinical hypothyroidism), T3 hormone may be prescribed orally, as basal body temperature is monitored until a normal temperature of 98.6" F is maintained. This change in basal body temperature

also decreases adrenal corticosteroid output, thus mitigating fatigue, depression, and insulin resistance. Some side effects of T3 supplementation may include antioxidant depletion, tremor, anxiety, and palpitations.25

Other Recommendations See recommendations for thyroid support later.

Treatments for Nonautoimmune Overt or Subclinical Hypothyroid Disorder Treatment of hypothyroidism of a nonautoimmune overt or subclinical nature should begin with optimization of the nutrients needed not only for thyroid hormone production, but also for the critical cellular conversion of T4to T3. If, after a few months, the patient does not respond, then thyroid hormone replacement is indicated.

Diet The diet should be low in goitrogens and high in foods rich in the trace minerals needed for thyroid hormone production and activation. Goitrogens to be limited include Brassica family foods (turnips, cabbage, rutabagas, mustard greens, radishes, horseradishes), cassava root, soybeans, peanuts, pine nuts, and millet. When eaten, these foods should be cooked to break down their goitrogenic constituents. Good sources of iodine include sea fish, sea vegetables (kelp, dulse, arame, hijiki, nori, wakame, kombu), and iodized salt. Good sources of zinc include seafood (especially oysters), beef, oatmeal, chicken, liver, spinach, nuts, and seeds. Copper is found in liver and other organ meats, eggs, yeast, beans, nuts, and seeds. Finally, the best sources of the B vitamins are yeast, whole grains, and liver. The best source of selenium is Brazil nuts, especially those that are unshelled. Organically grown foods should be recommended due to their higher levels of trace minerals.

Supplements Zinc: 25 mg/day Copper: 5 mg/day Selenium: 200 pg/day Vitamin C: 1to 3 &day in divided doses Vitamin E: 400 IU/day

Thyroid Hormones Treatment should begin at levels ranging from 0.5 to 2 thyroid units (see earlier discussion) daily based on the patient's size and serum hormone levels. Reevaluation of basal body temperature, TSH,T4,T3, and free T4 levels 4 to 6 weeks after initiating therapy is recommended, with the treatment goal being to normalize basal body temperature, as well as serum hormone levels.

After stabilization of dosage, periodic evaluations are based on the individual patient's needs or are recommended to be carried out at least once a year. In the treatment of subclinical hypothyroidism, the dosage should be no more than 0.5 thyroid units daily for at least the first 3 months of treatment. Thyroid hormone replacement therapy is recommended to be taken on an empty stomach to increase absorption. The patient should avoid taking thyroid hormones at the same time as other medications and supplements (especially those containing iron), which may affect absorption.Once-a-day dosage generally produces stable increases in thyroid hormone levels.

1.Bennet JC, Plum F, eds. Cecil textbook of medicine, ed 20. Philadelphia: Saunders, 19961227-1245. 2. Wang C, Crapo LM. The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am 1997;26189-218. 3. Weetman AP. Hypothyroidism: screening and subclinical disease. BMJ 19973141175-1178. 4. Drinka PJ, Nolten WE. Subclinical hypothyroidism in the elderly: to treat or not to treat? Am J Med Sci 1988;295:125-128. 5. Banovac K, Zakarija M, McKenzie JM. Experience with routine thyroid function testing: abnormal results in 'normal' populations. J Fla Med Assoc 1985;72:835-839. 6. Rosenthal MJ, Hunt WC, Gamy PJ, et al. Thyroid failure in the elderly: Microsomal antibodies as discriminate for therapy. JAMA 1987;258:209-213. 7. Arem R, Escalante D. Subclinical hypothyroidism. Epidemiology, diagnosis, and sigruficance.Adv Intem Med 1996;41:213-250. 8. Bemben DA, W m P, Hamm RM, et al. Thyroid disease in the elderly. Part 1. Prevalence of undiagnosed hypothyroidism. J Fam Pract 1994; 38:577-582. 9.Bames BO, Galton L. Hypothyroidism: the unsuspected illness. New York Crowell, 1976. 10. Langer SE, Scheer JF. Solved the riddle of illness. New Canaan, CT: Keats, 1984. 11. Evans TC. Thyroid disease. Prim Care 200330625-640. 12. Powell DW. Fndca-inology and Naturopathic Therapies. Bothell, WA: Published by the author, 2001:39-47. Fowler PB. Exaggerated responsiveness to thyrotrophin 13. Dean JW, releasing hormone: a risk factor in women with artery disease. Br Med J ( C h Res Ed) 1985;29015551561. 14. Tumbridge WM, Evered DC,Hall R. Lipid profiles and cardiovascular disease in the Wickham area with particular reference to thyroid failure.Clin Endocrho1 1977;7495-508. 15. Gold MS, Pottash AL, Extein I. Hypothyroidism and depression, evidence from complete thyroid function evaluation. JAMA 1981; 2451919-1922. 16. Esposito S, Prange AJ Jr, Golden RN. The thyroid axis and mood disorders: overview and future prospects. Psychopharmacol Bull 199733205217. 17. Krupsky M, Flatan E, Yarom R, et al. Musculoskeletal symptoms as a presenting sign of long-standing hypothyroidism. Isr J Med Sci 1987;231110-1113. 18. Hochberg MC, Koppes GM, Edwards CQ, et al. Hypothyroidism presenting as a polymyositis-like syndrome. Arthr Rheum 1976; 191363-1366.

The dosage of thyroid hormone during pregnancy will likely have to be increased due to the effects that estrogens have on increasing serum thyroid hormone binding globulin, thereby reducing the level of free thyroxine. Careful monitoring is required during pregnancy. Typically, dosage requirementsincrease by 30%to 50% during pregnancy and return to prepregnancy levels shortly after delivery.

Exercise/PhysicalTherapy/Lifestyle Invigorating activity such as water sports, avoidance of overheated environments, and cold hydrotherapy can stimulate thyroid function.12

19. Althaus U,Staub JJ, Ryff-De Leche A, et al. LDL/HDL-changes in subclinical hypothyroidism. Possible risk factors for coronary heart disease. Clin Endocrinol1988;28157-163. 20. Cappola AR, Ladenson PW. Hypothyroidismand Atherosclerosis. J Clin Endocrinol Metab 2003;8&2438-2444. 21. Hak AE, Pols HA, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intem Med 2000; 132270-278. 22. Gaspari AA, Huang CM,Davey RJ, et al. Prrvalence of thyroid abnormalities in patients with dermatitis herpdormis and in control subjects with HLA-B8/-DR3. Am J Med 1990;88:145-150. 23. Mainardi E, Montanelli A, Dotti M, et al. Thyroid-related autoantibodies and celiac disease: a role for a gluten-free diet? J Clin Gastroenterol2002;35:245-248. 24.Utiger RD. Estrogen, thyroxine binding in serum, and thyroxine therapy. N Engl J Med 2001;344:1784-1785. 25. Mamby CC, Love RR, Lee KE. Thyroid function test changes with adjuvant tamoxifen therapy in postmenopausal women with breast cancer. J Clin Oncol1995;13:854-857. 26. Newbeme PM. Naturally occurring food-borne toxicants. In Shils ME, Young VR. Modem nutrition in health and disease. Philadelphia: Lea & Febiger, 1988. 27. Prasad A. Clinical, biochemical and nutritional spectrum of zinc deficiency in human subjects: an update. Nutr Rev 1983;41: 197-208. 28. Nishiyama S, Futagoishi-Suginohara Y, Matsukura M, et al. Zinc supplementation alters thyroid hormone metabolism in disabled patients with zinc deficiency. J Am Coll Nutr 1994;13:62-67. 29.Toro T. Selenium's role in thyroid found. New Scientist 1991; 12927. 30.Meinhold H, Campos-Barros A, Behne D, et al. Effects of selenium and iodine deficiency on iodothpnine deiodinases in brain, thyroid and peripheral tissue. Acta Med Austriaca 1992;19:8-12. 31. Berry MJ, Larsen PR. The role of selenium in thyroid hormone action. Endocr Rev 1992;13207-219. et al. Selenium supplementa32. Gartner R, Gasnier BCH, Dietrich JW, tion in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations. J Clin Endocrinol Metab 2002; 8F1687-1691. 33. Werbach MR. Nutritional influences on illness, vols I and II. Tarzana, CA Third Line Press, 1987 (vol I), 1993 (vol2). 34. Deshpande UR, Joseph LJ, Patwardhan UN, et al. Effect of antioxidants (vitamin C, E and turmeric extract) on methimazole induced hypothyroidism in rats. Indian J Exp Biol2002;40.735-738.

Hypothyroidism 35. Choudhury S, Chainy GB, Mishro MM. Experimentally induced hypo- and hyper-thyroidism influence on the antioxidant defense system in adult rat testis. Andrologia 200335131-140. 36. Lemon D, Nagle F, Stratman F, et al. Diet and exercise training effects on resting metabolic rate. Int J Obes 1985;9:39-47. 37.Escobar-Morreale HF, Obreg6n MJ, Escobar del Rey FE, et al. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest 1995;962828-2838.

38. Lie1 Y, Harman-Boehm I, Shany S. Evidence for a clinically important adverse effect of fiber-enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients. J Clin Endocrinol Metab 1996;81:857-859. 39. van Vollenhoven RF. Dehydroepiandrosterone for the treatment of systemic lupus erythematosus. Expert Opin Pharmacother 2002;3: 23-31. 40. DHEA. Monograph. Altern Med Rev 2001;6314-318.

Infectious Diarrhea Peter B. Bongiorno, ND, Dip1 Ac CHAPTER C O N T E N T S Diagnostic Summary

1801

General Considerations 1801 Infectious Agents and Symptoms Viral Agents 1802 Bacterial Agents 1802 Parasitic Agents 1803

1802

Therapeutic Approach 1810 Underlying Factors 1810 Diet 1810 Nutritional Supplements 1810 Botanicals 1810

Laboratory Diagnosis 1804 Therapeutic Considerations 1804 Conventional Medicines 1804 Underlying and Predisposing Factors

Hydration/Electrolyte Balance 1804 Diet 1805 Supplements 1805 Botanical Medicines 1807 Homeopathy 1808 Acupuncture 1809

1804

DIAGNOSTIC SUMMARY

.

Increased bowel movement frequency (usually more than three bowel movements per day) Increased stool liquidity Abdominal pain A sense of fecal urgency Fecal incontinence Perianal discomfort Blood or mucus, or both, may be present in the stool

.

GENERAL CONSIDERATIONS Diarrhea is not only an important clinical entity, it has also played a central role in the course of human history. Since the ancient times of Herodotus, the ”Father of History,” diarrhea has had a particularly sigruficant effect on the course of military strategies and consequently on world events. Infectious diarrhea has modified wartime outcomes of the Roman Empire and the Crusades, as well as the relatively modem-day military campaigns of Henry V, the Union army during the civil war, World War I, and World War 11.’ Walt Whitman, who visited the sick and wounded Union in Washington, D.C., hospitals, wrote that war consisted of ”about 999 parts diarrhea to 1 part glory.”l

Because there is considerable variation in normal bowel habits, a precise definition of the term diarrhea does not exist. Diarrheal disease can be classified into three major clinical syndromes: acute watery diarrhea, bloody diarrhea, and persistent diarrhea. For most patients, any increase in stool mass, stool frequency, or stool fluidity is perceived as diarrhea. For most adults, this consists of a daily stool production in excess of 250 g, containing 70% to 95% water. More than 14 L of fluid may be lost daily in severe cases.*Low-volume, painful, and bloody diarrhea is known as dysentery. Even today, diarrheal illness is a common cause of morbidity and mortality. Infectious agents cause more than 200 million cases of diarrhea in the United state^.^ Although a major cause of mortality in developing nations, infectious diarrhea also has significant costs in developed nations in terms of hospitalization and lost time? Intestinal infection is the most common cause of diarrhea worldwide and is responsible for the deaths of 3 to 4 million individuals annually, the majority of whom are preschool children5 According to the World Health Organization, nearly 2 million children die each year because of diarrheal illness.’ Despite these alarming statistics, approximately 90% of acute diarrhea cases are mild and self-limited and respond within 5 days to simple rehydration therapy or antidiarrheal agents6 1801

Specific Health Problems

INFECTIOUS AGENTS AND SYMPTOMS An increasingly wide variety of viral and bacterial

agents are being recognized as causes of serious diarrheal illness? Overall, etiologic causes of infectious diarrhea can be categorized as being viral, bacterial, or parasitic in nature. In general, these pathogens create a diarrhea effect by inhibition of intestinal absorption and increased secretion, and they encourage an inflammatory response in order to promote secretory and exudative diarrheal symptoms.

Viral Agents Viruses are important causes of diarrhea. In healthy adults, generally, the clinical manifestation of viral diarrhea is an acute, self-limited gastroenteritis. Although at least 25 different bacteria and protozoa can cause an identical clinical syndrome, greater than 75% of diarrheaassociated cases of gastroenteritis are caused by viruses. V i s e s are suspected when vomiting is prominent, the incubation period is longer than 14 hours, and the entire illness is over in less than 72 hours. Viral pathogens are likely when there are no warning signs of bacterial infection (such as high fever, bloody diarrhea, severe abdominal pain, more than 6 stools/24 hours) and there are no epidemiologic clues from the history (i.e., travel, sexual contact, antibiotic use) that suggest an alternative diagnosis?

Rotavirus Rotavirus is one of the most ubiquitous agents of diarrhea. Rotavirus can contribute to a diarrhea of acute, dehydrating nature in children and is estimated to cause more than 800,000 annual deaths of young children in developing countries.8 Rotavirus-associated diarrheal disease is seasonal and in the United States begins in the autumn and ends in the spring in the Southwest and Northeast, respectively. Rotaviruses are spread in a fecaloral route that includes person-to-person transmission. Although the precise mechanisms of disease have yet to be fully elucidated, rotaviruses are known to infect the villous enterocytes of the small intestine and cause a watery diarrhea. In addition to diarrhea, patients often have fever and v ~ m i t i n g . ~

Parvovirus (Norwalk Virus) Often categorized within the family of the Norwalk virus are the caliciviruses, also referred to as Nonuulk-like viruses or small, round-structured viruses. The Centers for Disease Control and Prevention (CDC) estimates that 66% of 13.8 million cases of food-related illnesses are caused by these viruses each year in the United States. This family of viruses is often suspected when acute gastroenteritis sweeps through a semiclosed community (e.g., family, school, residential home, hospital, ship,

d ~ r m i t o r y ) These .~ viruses are transmitted through contaminated food and water or from person to person. Sources of outbreaks have included well water, raspberries, lunch meat, and, in several instances, oysters? Individuals infected by caliciviruses experience nausea/ vomiting, diarrhea, abdominal cramping, and headache; low-grade fever, malaise, and myalgias also occur?

Cytomegalovirus Cytomegalovirus (CMV) is present in a latent state in most people, having been acquired either at birth or through sexual or parenteral exposure. CMV comes out of latency when there is strong allergenic or antigenic stimulation of the immune system. Oftentimes, those with severe immunodeficiency also have activation and replication of CMV. When CMV becomes active in the bowel wall, gastrointestinal disease may occur. The disease is seen primarily in patients with severe immune deficiency such as acquired immunodeficiencysyndrome (AIDS),transplantation, and cancer chemotherapy7and is a major cause of diarrhea in these conditions.

Epstein-Barr Virus By the age of 20 years, almost all adults are infected with Epstein-Barr virus (EBV). This virus infects B cells, then persists for life because these cells proliferate indefinitely. Proliferation is usually controlled by virus-specific cytotoxic T lymphocytes. EBV mainly causes diarrhea in immunocompromised patients.

Bacterial Agents Escherichia coli At least four distinct varieties of diarrheogenicEscherichia coli exist: enterotoxigenic (ETEC), enterohemorrhagic (EHEC), enteroinvasive (EIEC), and enteroadherent. In North America, the most prominent diarrheogenic E . coli is the EHEC serotype, E . coli 0157H7.9 Contaminated ground beef is the most common vehicle of transmission because contaminating bacteria are distributed throughout the meat during grinding and are not killed if hamburgers are undercooked. After an incubation period from 1 to 8 days, typical symptoms include abdominal cramping and diarrhea that can present as mild, moderate, or severe. Early in the disease course, bowel movements may be loose and watery, but in time may often contain gross blood. A subset of patients, often children, may develop the severe, life-threatening hemolytic-uremic syndrome. Hemolytic-uremic syndrome is characterized by the clinical triad of hemolytic anemia, renal failure, and thrombocytopenia?

Campylobacter jejuni Campylobacters are part of the intestinal flora in many mammals. Contaminated and improperly cooked meat contributes significantly to the spread of disease.

Infectious Diarrhea Unpasteurized dairy products, contaminated water, and other foods also may encourage transmission. Symptoms begin 1 to 7 days after ingestion of the bacteria and consist of fever, headache, and malaise. These may herald the onset of diarrhea and abdominal cramps by 1 to 2 days. The nature of the diarrhea varies from watery to bloody. Campylobacter enterocolitis is usually acute and self-limited over 7 to 10 days. Rarely, relapses, complications, severe disease, and death may occur?

Clostridium diflicile Clostridium difficile infection has become the most common cause of infectious diarrhea in hospitalized patients.’O This pathogen is most likely to affect the elderly. Clostridium can be catalyzed by the use of antibiotics.

Salmonella As the spread of resistant Salmonella strains continues to increase worldwide,ll there are more than 2200 currently known serotypes. Spread chiefly through contaminated food, salmonella enteritidis accounts for 85%of all salmonella infections in the United States. Other prominent salmonella infections include Salmonella typhi and Salmonella paratyphi, which are responsible for typhoid fever. Nontyphoidal salmonellosis may present as fever, gastroenteritis-related diarrhea, and localized infections of the gastrointestinal tract, endothelial surfaces, pericardium, meninges, lungs, joints, bones, urinary tract, or soft tissues. Typhoidal symptoms include gradual onset of fever, headache, arthalgias, pharyngitis, constipation, anorexia, and abdominal discomfort.

S higel 1a Among the bacterial enteric pathogens, Shigella is unique in that ingestion of fewer than 200 organisms, and possibly as few as 10 organisms, may cause clinically apparent disease. Shigella, like other enteric pathogens, may be transmitted through contaminated food and water. However, person-to-person spread and transmission by flies may also occur, since so few organisms are necessary to cause disease? The incubation period is usually 1 to 4 days. Adults present with nonbloody diarrhea, with or without fever, and possible gripping abdominal pain, urgency, and relief with defecation. As the infection progresses, episodes may increase with the presence of mucus and blood in the stool. Mild cases often spontaneously resolve in 4 to 8 days for mild cases or 3 to 6 weeks in severe cases.

Yersinia enterocolitica Yersinia enterocolitica, like Salmonella and Shigella, is a member of the Enterobacteriaceae family. Yersinia species are significantly less frequent causes of bacterial enterocolitis in North America. Pathogenic strains of

Y. enterocolitica are usually transmitted through fecally contaminated food or water but infrequently are transmitted by contaminated blood products. A 4- to 7-day incubation period occurs, followed by watery to bloody diarrhea. This organism is invasive and demonstrates a propensity for lymphoid tissues, causing mesenteric lymphadenitis that may be clinically mistaken for acute appendicitis? Disease usually resolves within 1 to 4 weeks, but occasionally complicating septicemia may develop, usually in patients with underlying disease.

Laribacter hongkongensis12 Described and characterized in 2001, Laribacter hongkongensis is a novel genus and species originally isolated from the blood and empyema pus cultures of a cirrhotic patient with bacteremic empyema thoracis. Since then, it has been described in six patients with diarrhea in Hong Kong and Switzerland. Although more extensive epidemiologic studies are necessary, there is reason to consider its role in future studies of diarrhea outbreaks worldwide.

Parasitic Agents Diarrheal diseases caused by parasites still constitute the greatest single worldwide cause of illness and death. The problem is more severe in underdeveloped countries with poor sanitation, but even in the United States diarrheal diseases are a major cause of sickness and death. Furthermore, the ease and frequency of worldwide travel and increased migration to the United States is resulting in growing numbers of parasitic infections. In addition to normal inhabitants of the gastrointestinal system acting as parasites, there are also significant diarrheal diseases associated with protozoa and helminthes. Giardia lamblia is the most frequent cause of parasitic enteritis in the United States and should be suspected in cases where history suggests someone recently hiking and drinking out of streams. Waterborne infection is also important in the developed world, particularly as a result of contamination of domestic water supplies with the cysts of Giardia intestinalis and Cryptosporidium p a r ~ u m .Other ~ diarrhea-associated parasites include Entamoeba histolytica, Microsporidium, lsospora belli, and S trongyloides species. Although the most commonly reported symptoms of parasitic infection are abdominal pain and cramping with concomitant explosive diarrhea, these symptoms do not occur in all cases. In fact, a growing number of individuals are experiencing milder than usual gastrointestinal symptoms due to parasitic infections or symptoms not traditionally considered to be linked to parasitic infections. For example, in some cases of irritable bowel syndrome, indigestion, and poor digestion, parasites may be causing the symptoms. In addition,

Specific Health Problems

parasitic infections are often an unsuspected cause of chronic illness and fatigue.

LABORATORY DIAGNOSIS Numerous laboratory procedures exist for analysis of patients with diarrhea. Bacterial cultures using selective media, detection of pathogen-specific genes using polymerase chain reactions (polymerase chain reaction [PCR]), electron microscopic examination and antigen detection for viruses, as well as direct examination with or without using special stains for protozoa are some of the plethora of diagnostic tests available. Despite this wide array, a microbiologic cause is identified in 50% of patients at best.12 One hospital survey of more than 30,000 stool specimens sent for testing revealed a specific pathogen in only 5.6% of cases. In descending order, the most commonly identified pathogens were Cumpylobacter jejuni, Salmonella, Shigella, and E. coli 0157:H7.3 Confounding this issue, it has been shown that substantial variation exists in the use of stool testing, which typically does not correlate with the clinical characteristics of affected p a t i e n t ~ . ~ One J ~ study has identified several important independent variables that may be predictive of positive stool culture in adult patients with a clinical picture of infectious diarrhea. These variables are month of presentation, fever, duration of abdominal pain at presentation, and requirement of IV fluid therapy. Surprisingly, this study demonstrated that neither a history of bloody diarrhea nor persistent diarrhea was associated with positive stool ~u1ture.l~ In general, persons with diarrhea should be considered for testing if they are febrile or have bloody stool. When visible blood was present in the stool, more than one third of cases were caused by Shiga toxin-producing E . coli 0157H7.3 Testing for ova and parasites is of low yield in most cases and should be run only in cases where diarrheal illness persists for more than 7 days3

THERAPEUTIC CONSIDERATIONS Conventional Medicines Although appropriate in certain cases, the antibiotics and opiates used to treat diarrhea sufferers are also well known to have their limitations, as many of these drugs adversely affect gastrointestinal motility, as well as the fact that increasing numbers of pathogens are proving resistant to antimicrobial agents. Increasing numbers of isolates resistant to antimicrobial agents and the risk of worsened illness (e.g., hemolytic uremic syndrome with Shiga toxin-producing E . coli 0157H7) further complicate antimicrobial and antimotility drug use.3 Additionally, available antiperistaltic or antisecretory drugs to reduce the severity of diarrhea can cause serious side effects in children.8

Generally, selective antibiotic treatment is recommended for traveler's diarrhea, ShigeZZa, and Carnpylobucteriu infection. Bismuth salts (e.g., PeptoBismol) can be used for travel abroad in order to coat the intestinal lining and help prevent infection. The role of antibiotic therapy in salmonellosis and E. coli 0157H7 infection remains unclear. Avoidance of antimotility agents in bloody diarrhea is emphasized, especially when illness is caused by E . coli 0157H7, which could inmase the risk of subsequent hemolytic-uremic syndrome. In selected at-risk populations, wider use of vaccines including oral typhoid vaccine and oral cholera vaccine (available only outside the United States) is recommended? Some newer therapeutic approaches include 5-HT2 and 5-HT3 receptor antagonists, calcium-calmodulin antagonists, and alpha-receptor agonists. These may be useful to avoid adverse affects on gastromotilility?

Underlying and Predisposing Factors Although a pathogenic agent is often responsible for infectious diarrhea, a number of host factors can predispose individuals to experience illness. Poor digestive function, which is often characterized by low stomach acid output or achlorhydria and inadequate pancreatic enzyme output, should be explored in patients who are susceptible to infectious diarrhea. In these cases, hydrochloric acid and pancreatic enzyme supplementation may be advisable. Immunoglobulin A (IgA)antibodies help discourage epithelial adherence of pathogenic organisms. Depressed levels of secretory IgA can leave the gastrointestinal immune system tract feeble and unable to deal with pathogenic infection. Decreased intestinal motility, which can be caused by chronic stress and high sugar intake, can also allow microbes to foster in an intestinal environment. Recurrent infectious diarrhea may be encouraged by food allergy and sensitivities as well. The clinician should also be aware that many drugs may actually increase susceptibility to infectious diarrheal illness. Theses include proton pump inhibitors, antifolate drugs, and antibiotics. Hospitalized patients who receive proton pump inhibitors are at increased risk of Clostridium difficile-induced diar~-hea.'"'~Asin the case of achlorhydria, it is likely that inhibition of upper gastrointestinal digestive acids by proton pump inhibitors may allow pathogens and undigested food to reach the intestines without being properly broken down. Also, antibiotic-associated diarrhea is known to occur with broad-spectrum antibiotics." Antibiotics can disrupt local bowel flora, allowing pathogenic organisms to flourish, and are well-known to leave patients susceptible to diarrhea (see the section on probiotics later).

Hydration/Electrolyte BaIance It is of paramount importance to keep the diarrhea patient well hydrated and assure electrolyte balance.

Infectious Diarrhea

This is most crucial in children. Of course, rehydration does not treat the diarrhea itself, which will persist until the infection resolves. Signs of dehydration may include decreased or absent urination, decreased skin turgor, and dry tongue. Rehydration using solutions of glucose, sodium, and potassium is appropriate. In cases of severe dehydration with weight loss of more than 10% or unconsciousness, intravenous rehydration is indicated.Is

lower risk of persistent diarrhea. However, there was no change in the duration or average stool frequency. Interestingly, the group of children who were not breastfed had a shorter average duration of diarrhea. In these children, the mean number of stools passed after the intervention, the proportion of episodes lasting greater than 14 days, and the percentage of children who passed watery stools on any study day were also significantly lower in those treated with vitamin A.21

Diet

Folic Acid and Vitamin BI2

Prevention of infectious diarrhea may be accomplished by avoiding undercooked meat or seafood, unpasteurized milk, or soft ~ h e e s eOnce . ~ the patient has symptoms, traditional use of the "BRAT diet" can usually help decrease gastric motility. The components of this diet are foods that can slow peristalsis and tend to be more binding. These are banana, white rice, apple, plain white toast or bread, and tea. Evidence indicates that larger, less frequent meals are more taxing to the digestive and absorptive capacities of the gastrointestinal system. In one porcine study, 3week-old piglets were assigned to one of four dietary regimens and were subsequently all infected with rotavirus, followed 24 hours later with enteropathogenic E . coli. The dietary regimen designed to tax the digestive and absorptive capacities of the piglets (a high nutrient intake with a thrice-a-day feeding) sigruficantly produced the most prolonged diarrhea, as well as most advanced colonization of the gut by hemolytic enteropathogenic E. coli, and persistent shedding of rotavirus. The same nutrient intake divided into 24 equal increments and administered hourly produced a less severe response. The least severe diarrhea was seen in piglets fed one-third the nutrient intake either hourly or three times a day.19 Traditional dietary preparations for diarrhea such as carrot soup and products based on rice can be useful by having essentially an absorbent power. They have been known to reduce stool output and the duration of diarrhea, although these may not necessarily diminish intestinal loss of water and electrolytes.18*20 For patients who experience vomiting, administration of a small amount of glucose can help.18

Studies are beginning to emerge correlating low levels of folic acid and vitamin BIZwith increased susceptibility to diarrhea. Folic acid deficiency is known to promote malabsorption due to altered structure of the intestinal mucosal cells.= Thirteen patients diagnosed with megaloblastic anemia suffering from chronic diarrhea showed significant histologic changes of the ileum mucosa including inflammation, atrophy, erosion and flattening of the villi, lymphatic ectasia, and focal fibrosis. When given folate and cyanocobalamin supplementations, these patients quickly demonstrated decreased diarrhea episodes, as well as intestinal restoration.u Antifolate chemotherapeutic drugs such as methotrexate can contribute to folic acid and BIZdeficiency and can cause or contribute to diarrhea symptomology. Cancer patients treated with this class of drugs who had lowered folic acid and vitamin BIZwere found to be more susceptible to subsequent development of serious drug-related toxicities such as myelosuppression, diarrhea, mucosal toxicity, and infection. This suggests that toxicity is related to relative folate deficiency in some cancer patients.z4 In this study, nutritional supplementation led to a marked reduction in toxicity and the abolition of treatment-related deaths without affecting the efficacy of the antineoplastic drugs. Tangential to the conversation of infectious diarrhea and folic acid, there is a concern for neural tube defects (NTDs) with folic acid and BIZ deficiency. It has been suggested that gastrointestinal disturbances such as those caused by diarrhea might negatively affect the availability of these vitamins to the pregnant mother and fetus, thereby increasing the risk of birth defects. In one study evaluating the risk of neural tube defects with periconceptional diarrhea, it was observed that one or more episodes of periconceptional diarrhea were associated with increased risk of NTD-affected pregnancies compared with no episodes of diarrhea. This association was independent of fever, obesity, maternal age, maternal birthplace, income, prior unproductive pregnancy, and dietary plus multivitamin folate intake.25Whether the cause of diarrhea is infectious or of any other origin, it is prudent to ensure proper folic acid and B12 nutrition in females who are trying to conceive, as well as in newly pregnant females.

Supplements Vitamin A The administration of vitamin A to children can reduce the incidence of severe diarrhea. One double-blind controlled trial examined 900 children with acute diarrhea from ages 1 to 5. These young subjects were assigned to receive either 60 mg vitamin A or a placebo. Children were followed up at home on alternate days until they recovered from the diarrheal episode. In all study children, those treated with vitamin A had a significantly

Folic acid supplementation appears to be without side effects, even at high doses (e.g., 15 mg/day). It has been reported that 8 of 14 healthy human subjects who consumed 15 mg/day of folic acid for 1 month developed abdominal distension, flatulence, nausea, anorexia, sleep disturbances with vivid dreams, malaise, and irritability.26 This, however, has not been confirmed in a double-blind clinical study27and other investigation^.^^,^^ Vitamin BIZ is not carcinogenic, teratogenic, or mutagenic. It is considered safe even at 1000 times the recommended daily allowance. However, during such treatment, care should be given to not take large amounts of folic acid, since this may mask the nerve damage associated with vitamin BI2 deficiency.

Zinc In recent years the nutritional importance of zinc has been established, as zinc deficiency and its symptoms have been well recognized. Diarrhea has been found to be one of the clinical manifestations of zinc deficiency. Zinc has demonstrated an antimicrobial effect on enteric pathogens such as S. typhi, Salmonella, E. coli, Enterobacter, Shigella, Staphylococcus albus, Streptococcirs pyogenes, and Vibrio ~holerae30,~~ and may contribute to the treatment of diarrhea. Zinc absorption occurs throughout the small intestine, not only in the duodenum, jejunum, and ileum. Many illnesses distinguished by chronic diarrhea entail insufficient absorption of zinc. In fact, in some cases of chronic enteropathies in infants, like celiac disease and cystic fibrosis, a deficiency of zinc has been isolated.32 Good dietary sources of zinc are meat; fish; and, to a less extent, human milk. Acroderrnatitis enteropathica is a rare but severe disease in which skin lesions, chronic diarrhea, and recurring infections are the main symptoms. The disease is related to the malfunctioning of intestinal absorption of zinc and can be treated by administering pharmacologic doses of zinc orally. The amount of zinc absorbed in the small intestine is influenced by other nutrients: some compounds such as dietary fiber and phytates (which are found foods including soy, wheat bran, peas, carob, and brown rice) may inhibit this process, while picolinic and citric acid facilitate it. Citric acid is thought to be the ligand that accounts for the high level of bioavailability of zinc in human milk.32 As a cautionary note, it is theoretically possible that some of the dietary treatments used by practitioners of natural medicine for persistent postenteritis diarrhea, such as elimination of cow’s milk and increased fiber and carob powder, as well as use of soy formula in infants, can contribute to a scarce supply of zinc and therefore could promote the persistency of diarrhea When using these therapeutic approaches, zinc supplementation during this time may be warranted, especially if the patient tends to have diarrhea symptoms.

Glutamine Glutamine is the most abundant amino acid in the blood. As one of the principal fuels used by the intestinal lining cells, it accounts for 35% of their energy production. Although glutamine is readily available in the diet and synthesized in the body, supplementation improves the energy metabolism of the gastrointestinal mucosa, thus stimulating r e g e n e r a t i ~ n .Glutamine ~~ prevents intestinal mucosal damage and has been shown to decrease bacterial leakage across the intestines after they are damaged, presumably by stimulating repair.34 Clearly, glutamine holds promise for enhancing repair of mucosal injury by a wide range of infections or toxic agents and thus has great potential as a new oral rehydration and nutrition therapeutic for patients with enteric infection, malnutrition, or chemotherapy- or radiation-induced enteritis.35 Animal models have definitely shown the usefulness of this amino acid in diarrhea. Glutamine has been shown to enhance sodium and water absorption in a rabbit model of cholera and Cryptosporidium-infected piglet intestine and has proven effective in a bovine model of Cryptosporidium as well. One rat model of cholera toxin-induced diarrhea also showed that alanylglutamine (a more stable derivative of glutamine) enhanced water and electrolyte intestinal absorption even better than the traditional glucose s0lutions.3~ In one double-blind clinical study of 128 healthy children ages 6 to 24 months old with acute diarrhea, 63 received 0.3 g/kg/day of glutamine while 65 controls received a placebo for 7 days. The average duration of diarrhea in the glutamine-treated group was significantly shorter than that of the placebo group (3.4 days vs. 4.57 days, re~pectively).~~ Glutamine, even at high doses, is without side effects and is well t0lerated.3~A typical dosage of glutamine is 100 mg three times a day (see Chapter 98 for a more comprehensive discussion of glutamine).

Probiotics: Lactobacillus and Saccrornyces Probiotics, translated ”for life,” refer to bacteria in the intestine considered beneficial to health. The most important healthful bacteria are LactobaciIlus acidophiIus and Bifidobacteriurn bifidurn. Other bacteria (including such beneficial strains as Lactobacillus casea, Lactobacillus fermenturn, Lactobacillus salivores, and Lactobacillus brevis) also become established in the gut (see Chapter 118 for an extensive discussion of these useful clinical agents). A substantially growing body of scientific evidence has now demonstrated that lactobacilli and fermented foods play a significant role in human health. Probiotics are thought to have a protective effect against acute diarrheal disease and have been shown to be successful in the treatment or prevention of various types of

Infectious Diarrhea

infectious diarrhea including rotavirus, Clostridium Furthermore, studies dificile, and traveler's show that probiotic supplementation may also prevent future nosocomial rotaviral gastroenteritis, thus demonstrating an immune-modulating effect of pr0biotics,4,~~ possibly by significantly increasing the number of cells secreting IgA. Lactobacillus sp. have also shown remarkable ability to inhibit E. coli 0157:H7 but not Salmonella in refrigerated storage.40Lactobacillus may be considered as a future addition to stored foods used for low immune status and high susceptibility to E. coli 0157H7. However, one published report casts doubt on using Lactobacillus to treat traveler's diarrhea. A randomized, double-blind, placebo-controlled trial was conducted on 282 British soldiers deployed to Belize. They received two capsules containing L. fermenfum, L. acidophilus or a placebo daily for 3 weeks. There were 10" colony-forming units (CFUs) of bacteria in each capsule of lactobacilli. Neither species provided protection from traveler's diarrhea.41Unfortunately, the Hz02-producingstatus of the supplement was not reported. Given the large body of positive studies, Lactobacillus still seems a good choice. Children are especially susceptible to infectious diarrhea and its sequelae. In one double-blind, placebocontrolled study, a standard infant formula was supplemented with the probiotics Bifidobacteria bifdum and Streptococcus therrnophilus. Subjects in the probiotic group developed diarrhea at a statistically lower rate than those in the control group (7% vs. 31%). Additionally, rotavirus shedding was decreased statistically in the A second randomized, probiotic group (10% vs. 39Y0).~* placebo-controlled trial evaluated probiotics in a different, but also high-risk, population. In this case 204 undernourished Peruvian children received Lactobacillus GG (L. GG) or placebo. Although a difference in rates of diarrhea was observed, where the treated group had statistically fewer episodes of diarrhea, the reduction was minor (from 6 episodes/ child / year to 5.2 episodes/ child/year). Interestingly, children who were breastfed did not seem to benefit at all, raising the possibility that probiotics provide a similar action as breast milk in the prevention of infection.42A third double-blind study of 81 children aged 1to 36 months were enrolled in a trial and randomly assigned at admission to receive 6 x lo9CFUs of L. GG or placebo twice daily orally for the duration of their hospital stay. The Lactobacillus-treatedchildren enjoyed a dramatically reduced risk of nosocomial diarrhea of 6.7% versus 33.3%in those who were not given the probiotic. Once again, the use of L. GG significantly reduced the risk of rotavirus gastroenteritis (2.2%vs. 16.7Y0):~ Saccromyces boulardii, also known as Saccromyces cerevisiae, is a nonpathogenic probiotic yeast that may be most helpful in diarrhea caused by Clostridium dzficile, a pathogen most likely to affect the elderly. Although in the conventional medical world vancomycin is the preferred

treatment of severe cases, S. boulardii alone or in combination with vancomycin has been reported to be an effective therapeutic alternative for recurrent infection.'O Although generally safe, a few case reports have demonstrated that fungemia and sepsis are rare complications of the administration of S. boulardii in immunocompromised patients4 and may be contraindicated. The daily adult dose is usually 1 g/day in divided doses (500 mg twice a day) for at least 4 weeks. Metaanalyses have shown an overall reduction in the risk of antibiotic-associated diarrhea during treatment with probiotics, as well as a reduced hospital stay from L. acidophilus has been shown to correct the increase of gram-negative bacteria observed following the administration of broad-spectrum antibiotics, as occurs with any acute or chronic diarrhea.47-52 Similarly, a mixture of B. bifidum and L. acidophilus inhibited the lowering of fecal flora induced by ampicillin and maintained the equilibrium of the intestinal Although it is commonly believed that acidophilus supplementsare not effective if taken during antibiotic therapy, the research actually supports usage of L. acidophilus during antibiotic administration.5051 Reductions of friendly bacteria or superinfectionwith antibiotic-resistantflora, or both, may be prevented by administering L. acidophilus products during antibiotic therapy. A dosage of at least 15 to 20 billion organisms is required. Probiotic supplements should, however, be taken as far away from the antibiotic as possible. Evidence indicates that the conventional medical world is beginning to take notice of the benefits of giving Lactobacillus with antibiotic therapy. In one double-blind, controlled study, the antibiotic containing ampicillin (250 mg) and cloxacillin (250 mg) with or without protected lactobacilli was evaluated in 740 patients undergoing cataract surgery. The incidence of diarrhea in patients receiving antibiotic alone was 13.3%compared with 0% in patients receiving antibiotic with protected 1a~tobacilli.l~ Although antibiotics should be used judiciously, and only in cases where the benefits outweigh the risks, adjunctive therapy may decrease the untoward effects of antibiotictherapy on the gastrointestinal system. Although many excellent companies provide highquality probiotic products, it is difficult to sort through all of manufacturers' claims of superiority, and some products have been shown to contain no active L. a c i d o p h i l ~ s . ~ ~ Only high-quality, laboratory-tested probiotics should be used.

Botanical Medicines Berberine-Containing Plants Berberine-containing plants include goldenseal (Hydrastis canadensis), barberry (Berberis vulgaris), Oregon grape (Berberis aquifolium), and goldthread (Coptis chinensis). Berberine, an alkaloid, has been extensively

studied in both experimental and clinical settings for its antibiotic activity. Berberine exhibits a broad spectrum of antibiotic activity having shown antibiotic activity against bacteria, protozoa, and fungi including Candida albicans.54-60 Berberine’s antibiotic action against some of these pathogens is actually stronger than that of antibiotics commonly used for the disease these pathogens cause. Berberine-containing plants should be considered in infectious processes involving the previously mentioned organisms. Berberine’s action in inhibiting Candida, as well as pathogenic bacteria, prevents the overgrowth of yeast, which is a common side effect of antibiotic use. Diarrhea is a common symptom in patients with chronic candidiasis. Berberine has shown remarkable antidiarrheal activity in even the most severe cases. Positive clinical results have been shown with berberine in relieving diarrhea in cases of cholera, amebiasis, giardiasis, and other causes of acute gastrointestinal infection (e.g., E. coli, Shigella, Salmonella, and Klebsiella) and may also relieve the diarrhea seen in patients with chronic c a n d i d i a s i ~ . ~ ~ ~ ~ The dosage of any berberine-containing plant should be based on berberine content. As there is a wide range of quality in goldenseal preparations, standardized extracts are preferred. Three-times-a-day dosages are as follows: Dried root or as infusion (tea), 2 to 4 g Tincture (1:5), 6 to 12 ml(l.5 to 3 tsp) Fluid extract (l:l),2 to 4 ml(0.5 to 1 tsp) Solid (powdered dry) extract (4:l or 8% to 12% alkaloid content), 250 to 500 mg Note that the dosage recommendations for berberine would be 25 to 50 mg tid or a daily dosage of up to 150 mg. This dosage is consistent with the dosage range in the positive clinical studies in patients with gastrointestinal infections. For children, a dosage based on body weight is appropriate. The daily dosage would be the equivalent to 5 to 10 mg of berberine/kg (2.2 lb) body weight. As there is a wide range of quality in goldenseal preparations, standardized extracts are preferred. Berberine and berberine-containingplants are generally nontoxic at the recommended dosages; however, berberine-containing plants are not recommended for use during pregnancy and higher dosages may interfere with B vitamin metabolism.

Potentilla tormentilla (Tormentil Root) Tormentil root contains more than 15% tannic acid, which makes this plant astringent,68and may be useful to treat infectious diarrhea, shorten the duration of rotavirus diarrhea, and decrease the requirement for rehydration solutions.8A randomized, double-blinded, placebo-controlled trial was conducted at a children’s

hospital in St. Petersburg, Russia. In this study, 40 children ranging in age from 3 months to 7 years with rotavirus diarrhea were divided into two groups: a treatment group that consisted of 20 children given 3 drops of tormentil root extract/year of life tid until discontinuation of diarrhea or a maximum of 5 days and a control group of 20 children who received a placebo. The duration of diarrhea in the tormentil root extract treatment group was 60% less than the placebo group (3 days compared with 5 days in the control group). In the treatment group 8 of 20 (40%) children were diarrhea free 48 hours after admission to the hospital, compared with 1 of 20 (5%) in the control group. Children in the treatment group also received smaller volumes of parenteral fluids than subjects in the control group.8 For adults, a reasonable dose is 60 drops of tincture twice daily in adults. Some clinicians find the powdered herb more effective at doses of ‘/4 teaspoon twice daily for adults.68

Other Antiparasitic Botanicals A wide variety of botanicals have been used alone or in combination with antiinflammatory and demulcent herbs to specifically stop parasitic infections and heal the digestive tract. Unfortunately, few clinical trials have been conducted to assess the safety and efficacy of their use. Future studies should evaluate the potential benefits and toxicities of the following antiparasitic herbs: Arteinisia absinthium (wormwood), Chenopodium abrosioides (wormseed), Curcuma longa (turmeric), Phytolacca decandra (pokeweed, pokeroot), Juglans sp. (black and white walnut), and Tanacetum vulgare (tansy).

Homeopathy A metaanalysis of three double-blind clinical trials of diarrhea found that individualized homeopathic treatment decreases the duration of acute childhood diarrhea. In this review 242 children ages 6 months to 5 years were analyzed as one group. Children were randomized to receive either an individualized homeopathic medicine or placebo to be taken as a single dose after each unformed stool for 5 days. Parents recorded daily stools on diary cards, and health workers made home visits daily to monitor the children. The duration of diarrhea was defined as the time until there were fewer than three unformed stools per day for 2 consecutive days. A meta-analysis of the effect-size difference of the three studies was also conducted. Combined analysis shows a statistically significant duration of diarrhea of 3.3 days in the homeopathy group versus 4.1 in the placebo group. Homeopathicscommonly included as possible diarrhea remedies include podophyllum (which is well known for its almost universal application for traveler’s diarrheah9), aloe, china, mercurius, phosphorus, nux vomica, sulfur,

Infectious Diarrhea the animals treated with acupuncture or antibiotics maintained a mucosa of the colon and stomach that were relatively similar to those of the normal Another corroborating similar study of 34 animals employed Du-20 (Bai-hui), BL-20 (Pishu), CV-12 (ZongWan), and ST-25 (TianShu). This study found no extra benefit in using electric stimulation.n Acupuncture Many Chinese practitioners find benefit in using acupuncture and Chinese herbs together in order to From a traditional Chinese medicine perspective, diarrhea decrease the side effects associated with Western is generally due to an imbalance of large intestine regulamedicine.78One study of Keishi-ka-shakuyaku-to (Guition, as well as deficiency of the spleen and stomach. Zhi-Jia-Shao-Yao-Tang) on diarrhea induced by piloAlthough there are variations depending on a particular carpine, barium chloride, or castor oil found a significant patient’s presentation, the four basic diagnoses are reduction when the herbal combination was dosed at diarrhea due to Cold-Damp, Damp-Heat, Spleen-Yang 1000 mg/kg. This herb may mechanistically act to inhibit Depletion, and Kidney Yang defiaency. Typically, diarrhea excessively accelerated small intestinal movement. caused by infectious pathogens falls into the category of Another trial of 162 children suffering from chronic proDamp-Heat and may present with pain, mucus, and tracted diarrhea involved randomly dividing them into blood in the stool. two groups and observing them clinically.In the Chinese A few studies have shown the effect that acupuncherbal medicine group, Xiang Cheng San was externally ture70-” and Chinese herbal preparations have on applied to the umbilicus of patients, while in a second intestinal m ~ v e r n e n t .One ~ ~ , study ~ ~ demonstrated that group, Western drugs were routinely given. The results intestinal peristalsis was accelerated significantly by showed that the therapeutic effects were markedly better acupuncture at the abdomen but suppressed by moxiin the herbal medicine Although no control was bustion, which is the warming of certain acupuncture points with nearby burning Artemisia ~ r g y i . ~ O - used ~ ~ in this experiment, the results are encouraging. A wider variety of patent, granular, and loose herb Depending on the desired result, the acupuncture practicombinations are used to treat various Chinese diagtioner may want to focus on moxa therapy for some noses for infectious diarrhea. Future clinical research cases where slower peristalsis is desired. Two studies will help elucidate their use. measured the influence of electrical stimulation of Finally, complex chronic immune deficiency condiacupuncture points including ST-36 (Zusanli) and SP-6 tions leave the patient quite susceptible to pathogenic (Sanyinjiao) on the myoelectric activity of the small infection and are difficult to treat. Diarrhea affects more intestine and recorded a clear ability of acupuncture than 60% of persons living with human immunodefito alter intestinal motility. One of these trials employed 3 Hz of electroacupuncture on the ST-36 (Zusanli) point ciency virus (HIV)/AIDS. AIDS patients already on a polyphannaceutic regimen have shown good response to and demonstrated increased regularity of the gastric acupunctureand moxibustion used to alleviate symptoms myoelectric system.” However, another evaluation did not find acupuncture plus electrostimulation to be of diarrhea.s0*81 In one pilot study, 15 HIV-positive men with chronic diarrhea received the same acupuncture/ effective enough to effect a normalization of gastric dysrhythmia after pretreatment with atropine.75 moxibustion treatment for six sessions over a 3-week Arumal research has supported the historical use of period. In all subjects, stool frequency reduced approximately one episode per day. Stool consistency also acupuncture for infectious diarrhea. The effect of acupuncimproved from baseline to week 3 and week 4 by more ture was evaluated in the treatment of 32 young pigs than 1 point on Hansen’s stool consistency scale. Once with induced enteropathogenic E. coli diarrhea. The animals were all inoculated with E . coli and then divided again, more studies are necessary, but preliminary results are promising for antidiarrheal therapy that does into three groups. One control group remained untreated, while a second group was treated with the antibiotic not require additional pharmaceutics. enrofloxacin, and the third group was treated with Overall, Chinese medicine modalities have proven to be quite safe. In one 6-year Japanese study, the results traditional acupuncture using GV-1 (Jiaochao). Using histopathologic evaluation by hematoxylin and eosin of 84 therapists and 65,482 treatments were evaluated. stain, it was observed that severe infiltration of inflamParticipants were required to report all adverse events. matory cells in the lamina propria was observed in the In total, only 94 (0.14%) adverse events were recorded and none were serious (serious events were considered ascending and descending colons and in the fundic conditions like pneumothorax, infection, and spinal stomach of the untreated control group. Destruction of the fundic gland architectureand necrotic lesions was also cord injury). The authors concluded that serious or severe adverse events are rare in standard practice. observed. However, in these same anatomic locations, aconite, veratrum album, and arsenicum. Although these results still need to be further evaluated with larger-scale studies, given the safety and historical effectiveness of homeopathy, it should be thoroughly considered as part of the natural medicine practitioner’s therapeutic choices.

Specific Health Problems Although more research is clearly necessary to elucidate the benefits of acupuncture, given the little risk and long history of positive anecdotal evidence, it is certainly worth usingF2 More research on Chinese herbs is also necessary to elucidate the toxicity in those preparations that appear therapeutically beneficial.

THERAPEUTIC APPROACH Overall, natural treatments can adequately manage most cases of non-life-threatening diarrhea. Importantly, diarrhea itself is an eliminative function used by the body to clear toxins and should not be completely suppressed. Of course, chronic diarrhea and diarrhea that causes extreme or rapid electrolyte and water loss may require conventional interventions. It is imperative to maintain hydration and electrolyte balance. Nowhere is this need more immediate than in children younger than 5 years of age.

Underlying Factors Addressing underlying factors such as low stomach and pancreatic output and depressed levels of IgA helps decrease the chances of pathogenic infection. When possible, eliminating iatrogenic causes such as proton pump inhibitors and antibiotics also helps prevent recurrences. Low-refined sugar diets are encouraged. Food allergies and intolerances should be assessed in those with recurrent infections. Methods to relieve stress also help encourage proper digestive function. Proper treatment with either an antibiotic or a natural alternative requires close monitoring by standard laboratory methods (e.g., repeating multiple stool samples 2 weeks after initiation of therapy).

Diet The BRAT diet may be useful to discourage large volume loss in infectious diarrhea. Small, frequent meals (hourly, if possible) may be best.

Nutritional Supplements Dosages are for adults unless otherwise indicated. Vitamin A: 60 mg/day in children and up to 50,000 IU/ day for 1to 2 days for adults with infections. Caution against high doses (above 10,000 IU/day in pregnant women).

Folic acid: 1 mg/day BI2(cyanocobalamin): 600 to 1000 pg/day Zinc piccolinate: 30 mg/day Glutamine: 100 mg tid Lactobucillus: 6 x lo9 CFUs of L. GG or placebo twice daily orally. For prevention of antibiotic-induced diarrhea, a dosage of at least 15 to 20 billion organisms is required. Probiotic supplements should be taken as far away from the antibiotic as possible. In children younger than age 6 experiencing antibiotic-induced diarrhea, the probiotic should be taken every day of the antibiotic dose and continued for 1 week after discontinuing the antibiotic. Saccromyces boulardi: specifically to treat Clostridium dificile. Daily adult dose is 1 g/day in divided doses (500 mg bid) for at least 4 weeks. Can be used adjunctively with vancomycin.

Botanicals Berberine: Dosage recommendations for berberine would be 25 to 50 mg tid or a daily dosage of up to 150 mg. For children, a dosage based on body weight is appropriate. The daily dosage would be the equivalent to 5 to 10 mg of berberine/kg (2.2 lb) body weight. Please see earlier discussion for more details. Tormentil dosage: 60 drops of tincture bid or powdered herb at '/? tsp twice daily. In children, 3 drops of tormentil root extract per year of life tid until discontinuation of diarrhea or a maximum of 5 days.

Homeopathy Typical remedies for diarrhea include podophyllum, aloe, china, mercurius, phosphorus, nux vomica, sulfur, aconite, veratrum album, and arsenicum. Specific choice of remedy should be based on the individual patient and his or her presentation.

Acupuncture Acupuncture points may include: ST-36 (Zusanli) and SP-6 (Sanyinjiao),Du20 (Bai-hui),BL-20 (Pishu), CV-12 (ZongWan),and ST-25 (TianShu). Acupuncture is appropriate stress relief, as well as direct treatment of intestinal issues, and is excellent to treat HIV / AIDS-related diarrhea.

Infectious Diarrhea

1. Lim ML, Wallace MR. Infectious diarrhea in history. Infect Dis Clin North Am 2004;18:261-274. 2. Cotran RS,Kumar V, Collins T. Robbin's pathologic basis of disease, ed 6. Philadelphia: Saunders, 1999:805-806. 3. Guerrant RL, Van Gilder T, Steiner TS,et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001;32: 331-351. 4. Majamaa H, Isolauri E, Saxelin M, et al. Lactic acid bacteria in the treatment of acute rotavirus gastroenteritis. J Pediatr Gastroenterol Nutr 1995;20333-338. 5. Farthing MJ. Diarrhoea: a significant worldwide problem. Int J Antimicrob Agents 2000;1465-69. 6.McQuaid KR. Alimentary tract. In Tiemey LM, McPhee SJ, Papadakis MA, eds. Current medical diagnosis and treatment, 2000, ed 39. New York: Lange Medical Books/McGraw-Hill, 2000562. 7. Goodgame RW. Viral causes of diarrhea. Gastroenterol Clin North Am 2001;30:779-795. 8. Subbotina MD, Tmchenko VN,Vorobyov MM, et al. Effect of oral administration of tormentil root extract (Potentilla tormentilla) on rotavirus diarrhea in children: a randomized, double blind, controlled trial. Pediatr Infect Dis J 2003;22706-711. 9. Procop GW. Gastrointestinal infections. Infect Dis Clin North Am 2001;151073-1108. 10. Stroehlein JR. Treatment of Clostridium dificile infection. C m Treat Options Gastroenterol2004;7235-239. 11. Chiappini E, Galli L, Pecile P, et al. Results of a 5-year prospective surveillancestudy of antibioticresistance among Salmonella enterica isolates and ceftriaxone therapy among children hospitalized for acute diarrhea. Clin Ther 2002;241585-1594. 12. Woo PC, Kuhnert P, Bumens AP, et al. Laribacter hongkongensis: a potential cause of infectious diarrhea. Diagn Microbiol Infect Dis 2003;47551-556. 13. Chan SS, Ng KC, Lam PK, et al. Predictors of positive stool culture in adult patients with acute infectious diarrhea. J Emerg Med 2002;23125-130, 14. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium dificile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004;171:33-38. 15. Khatami SS, Mukunda B, Ravakhah K. Coinfection with Giardia lamblia and Clostridium difficile after use of ranitidine. Am J Med Sci 2004;32791-93. 16. Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. J Hosp Infect 2003; 54:243-245. 17. Ahuja MC, Khamar B. Antibiotic associated diarrhoea: a controlled study comparing plain antibiotic with those containing protected lactobacilli.J Indian Med Assoc 2002;100:334-335. 18. Girardet JP, Fontaine JL. [Current treatment of acute diarrhea in infants.] AM Pediatr (Paris) 1988;35:609-612. 19. Lecce JG, Clare DA, Balsbaugh RK, et al. Effect of dietary regimen on rotavirus-Escherichia coli weanling diarrhea of piglets. J Clin Microbiol 1983;17689-695. 20. Pietschnig B, Javaid N, Haschke F, et al. [Acute diarrheal diseases. Treatment with carrot-rice viscous solution is more effective than ORS solution.] Monatsschr Kinderheilkd 1992;140:426-430. 21. Bhandari N, Bahl R, Sazawal S, et al. Breast-feeding status alters the effect of vitamin A treatment during acute diarrhea in children. J Nutr 1997;12759-63. 22.Carruthers LB. Chronic diarrhea treated with folic acid. Lancet 1946;1:849-850. 23. Ayala E, Frisancho 0, Chacon Yupanqui P. [Histological changes of the distal ileum in chronic diarrhea associated with megaloblastic anaemia.] Rev Gastroenterol Peru 2004;24117-121.

24. Calvert H. Folate status and the safety profile of antifolates. Semin On~012002;29(2SUPPI 5):3-7. 25. Felkner M, Hendricks K, Suarez L, et al. Diarrhea: a new risk factor for neural tube defects? Birth Defects Res Part A Clin Mol Teratol 2003;67504-508. 26. Hunter R, Barnes J, Oakeley HF,et al. Toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet 1970;l: 61-63. 27. Hellstrom L. Lack of toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet 1971;1:59-61. 28. Sheehy T. Folic acid. Lack of toxicity. Lancet 1973;1:37. 29. Boss G, Ragsdale RA, Zettner A, et al. Failure of folic acid (pteroglutamic acid) to affect hyperuricemia. J Lab Clin Med 1980; 96783-789. 30.Surjawidjaja JE, Hidayat A, Lesmana M. Growth inhibition of enteric pathogens by zinc sulfate: an in vitro study. Med Princ Pract 2004;13:286-289. 31. Basit N, Mahmood I, Siddiqui F, et al. Studies on the inhibitory effects of zinc heptanoate on microorganisms. G Batteriol Virol Imm~n011979;72:10-20. 32. Giorgi PL, Catassi C, Guerrieri A. [Zinc and chronic enteropathies.] Pediatr Med Chir 1984;6:625-636. 33.Souba WW. Glutamine. A key substrate for the splanchnic bed. Annu Rev Nutr 1991;11:285-308. 34. Klimberg VS, Salloum RM, Kasper M, et al. Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation. Arch Surg 1990;125:1040-1045. 35. Cameiro-Filho BA, Bushen OY, Brit0 GA, et al. Glutamine analogues as adjunctive therapy for infectious diarrhea. Curr Infect Dis Rep 2003;5114-119. 36. Yalcin SS, Yurdakok K, Tezcan I, et al. Effect of glutamine supplementation on diarrhea, interleukin-8 and secretory immunoglobulin A in children with acute diarrhea. J Pediatr Gastroenterol Nutr 2004;38494-501. 37. Markowitz JE, Bengmark S. Probiotics in health and disease in the pediatric patient. Pediatr Clin North Am 2002;49127-141. 38. Saavedra JM, Bauman NA, Oung I, et al. Feeding of Bfidobucteriunr bzFdum and Streptococcus thermophilus to infants in hospital for prevention of diarrhoea and shedding of rotavirus. Lancet 1994; M1046-1049. 39. Isolauri E, Juntunen M, Rautanen T, et al. A human Lactobacillus strain (Lactobacillus casei sp strain GG) promotes recovery from acute diarrhea in children. Pediatrics 1991;8890-97. 40. Brashears MM, Durre WA. Antagonistic action of Lactobacillus lactis toward Salmonella spp. and Escherichia coli 0157H7 during growth and refrigerated storage. J Food Prot 1999;621336-1340. 41. Katelaris PH, Salam I, Farthing MJ. Lactobacilli to prevent traveler's diarrhea? N Engl J Med 1995;333:1360-1361. 42. Oberhelman RA, Gilman RH, Sheen P, et al. A placebo-controlled trial of Lactobacillus GG to prevent diarrhea in undernourished Peruvian children. J Pediatr 1999;134:15-20. 43.Szajewska H, Kotowska M, Mrukowicz JZ, et al. Efficacy of Lactobacillus GG in prevention of nosocomial diarrhea in infants. J Pediatr 2001;138:361-365. 44. Lestin F, Pertschy A, Rimek D. [Fungemia after oral treatment with Saccharomycesboulardii in a patient with multiple comorbidities.] Dtsch Med Wochenschr 2003;128:2531-2533. 45. Goossens D, Jonkers D, Stobberingh E, et al. Probiotics in gastroenterology: indications and future perspectives. Scand J Gastroenterol SUPPI 2003;239:15-23. 46. Rosenfeldt V, Michaelsen KF, Jakobsen M, et al. Effect of probiotic Lactobacillus strains in young children hospitalized with acute diarrhea. Pediatr Infect Dis J 2002;21:411-416.

Specific Health Problems ~

47. Hentges DJ, ed. Human intestinal microflora in health and disease. New York Academic Press, 1983. 48. Shahani KM, Ayebo AD. Role of dietary lactobacilliin gastrointestinal micr01~010gy.Am J Clin Nutr 1980;33:2448-2457. 49.Friend BA, Shahani KM. Nutritional and therapeutic aspects of lactobacilli. J Appl Nutr 1984;36:125-152. 50. Zoppi G, Deganello A, BenoN G, et al. Oral bacteriotherapy in clinical practice. I. The use of different preparations in infants treated with antibiotics. Eur J Ped 1982;13918-21. 51. Gotz W, Romankiewics JA, Moss J. Prophylaxis against ampicillinassociated diarrhea with a lactobacillus preparation. Am J Hosp Pharm 197936754-757. 52. Zoppi G, Balsam0 V, Deganello A, et al. Oral bacteriotherapy in clinical practice. II. The use of different preparations in the treatment of acute diarrhoea. Eur J Fed 1982;13922-24. 53. Hughes VL,Hillier SL. Microbiologiccharacteristics of Lactobadus products wd for colonization of the vagina. Obstet Gynecol1990; 75244-248. 54. Hahn FE,Ciak J. Berberine. Antibiotics 19763577-588. 55. Amin AH, Subbaiah TV, Abbasi KM. Berberine sulfate. Antimicrobial activity, bioassay, and mode of action. Can J Microbiol 1969;151067-1076. 56. Johnson CC, Johnson G, Foe CF. Toxiaty of alkaloids to certain bacteria. 11. Berberine, physostigmine, and sanguinarine. Acta Pharmacol Toxic01 (Copenh) 1952;8:71-78. 57. Kaneda Y, Toni M, Tanaka T, et al. In vitro effects of berberine sulfate on the growth and structure of Entarnoeba histolytica, Giurdiu lambliu and Tricomonus vaginalis. Ann Trop Med Parasitol 1991; 85:417-425. 58. Subbaiah TV, Amin AH. Effect of berberine sulfate on Entamoebu histolyticu. Nature 1967215527-528. 59. Ghosh AK, Rakshit MM, Ghosh DK. Effect of berberine chloride on Leishmania donovani. Indian J Med Res 1983;78:407-416. 60.Majahan VM,Sharma A, Rattan A. Antimycotic activity of berberine sulphate. An alkaloid from an Indian medicinal herb. Sabouraudia 1982;2079-81. 61. Gupte S. Use of berberine in the treatment of giardiasis. Am J Dis Child 1975;129:866. 62. Bhakat Ml? Therapeutic trial of Berberine sulphate in non-specific gastroenteritis. Indian Med J 1974;68:19-23. 63.Kamat SA. Clinical trial with berberine hydrochloride for the control of diarrhoea in acute gastroenteritis. J Assoc Physicians India 1967;15525-529. 64.Desai AB, Shah KM, Shah DM. Berberine in the treatment of diarrhoea. Indian Pediatr 1971;8:462-465. 65. Sharma R, Joshi CK, Goyal RK. Berberine tannate in acute diarrhea. Indian Pediatr 1970;7496-501.

~

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66. Choudry VP, Sabir M, Bhide VN.Berberine in giardiasis. Indian Pediatr 1972;9:143-146. 67. Rabbani GH, Butler T, Knight J, et al.Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae. J Infect Dis 1987;155: 979-984. 68. Mitchell WA. Plant medicine in practice: using the teachings of John Bastyr. St Louis: Churchill Livingstone, 2003. 69. Reichenberg J, Ullman R. Podophyllum: a nearly routine medicine for traveler's diarrhea. Townsend Lett Doctors Patients 2004;252: 32-33. 70.1wa M, Sakita M. Effects of acupuncture and moxibustion on intestinal motility in mice. Am J Chin Med 1994;22:119-125. 71. Tabosa A, Yamamura Y, Fomo ER, et al. Effect of the acupoints ST-36 (Zusanh) and SP-6 (Sanyiniiao) on intestinal myoelectric activity of Wistar rats. Braz J Med Biol Res 2002;35:731-739. 72. Chang CS, Chou JW, KO CW, et al. Cutaneous electrical stimulation of acupuncture points may enhance gastric myoelectrical regularity. Digestion 2002;66:106-111. 73. Saitoh K, Kase Y, Ishige A, et al. Effects of Keishi-ka-shakuyaku-to (Gui-Zhi-Jia-Shao-Yao-Tang) on diarrhea and small intestinal movement. Biol Pharm Bull 1999;22:87-89. 74. Li YL. [Clinical and experimental study on the treatment of children diarrhea by granule of children-diarrhea fast-stopping.] Zhong Xi Yi Jie He Za Zhi 1991;11:79-82,67. 75.Chang CS, Chou JW,Wu CY, et al. Atropine-induced gastric dysrhythmia is not normalized by electroacupuncture. Dig Dis Sci 2002;472466-2472. 76. Park ES, Jo S, S o n g JK, et al. Effect of acupuncture in the treatment of young pigs with induced Escherichia coli diarrhea. J Vet Sci 2003;4125-128. 77. Hwang YC, Jenkins EM. Effect of acupuncture on young pigs with induced enteropathogenic Escherichia coli diarrhea. Am J Vet Res 1988;49:1641-1643. 78. Chavez C. Prickly business. The finer points of acupuncture. Posit Aware 1995;Jan-Feb:1415. 79. Yang S. Application of xiang cheng san in treatment of chronic protracted diarrhea in children. J Tradit Chin Med 1995;15214-219. 80.Huson C. Acupuncture and traditional Oriental medicine in the treatment of HIV and AIDS. STEP Perspect 1996;8:2-3. 81. Anastasi JK, McMahon DJ. Testing strategies to reduce diarrhea in persons with HW using traditional Chinese medicine: acupuncture and moxibustion. J Assoc Nurses AIDS Care 2003;1428-40. 82.Yamashita H, Tsukayama H, Tanno Y, et al. Adverse events in acupuncture and moxibustion treatment a six-year survey at a national clinic in Japan. J Altern Complement Med 1999;5: 229-236.

Inflammatory Bowel Disease (Crohn’s Disease and Ulcerative Colitis) AlexVasquez, DC, ND Michael T. Murray, ND CHAPTER C O N T E N T S Diagnostic Summary

1813

General Considerations 1813 Definition 1813 Common Features of Crohn’s Disease and Ulcerative Colitis 1814 Etiology 1814 Therapeutic Considerations 1815 Control of Causative Factors 1815 Diet 1819 Minerals 1820 Vitamins 1821 Other Nutrients 1822

DIAGNOSTIC SUMMARY Crohn’s disease: Itermittent bouts of diarrhea, low-grade fever, and right lower quadrant pain Anorexia, weight loss, flatulence, and malaise Abdominal tenderness, especially in the right lower quadrant, with signs of peritoneal irritation and an abdominal or pelvic mass Radiographic evidence of abnormality of the terminal ileum Ulcerative colitis:

.

Bloody diarrhea with cramps in the lower abdomen Mild abdominal tenderness, weight loss, and fever Perianal irritation, fissures, hemorrhoids, fistulas, and abscesses possibly detected on rectal examination Diagnosis confirmedby radiography and sigmoidoscopy

GENERAL CONSIDERATIONS Definition Inflammatorybowel disease (IBD) is a general term for a group of chronic inflammatory disorders of the bowel.

Botanical Medicines 1823 Other Interventions 1824

Therapeutic Monitoring and Evaluation 1824 Fecal Calprotectin 1824 Crohn’s Disease Activity index 1824 Monitoring of the Pediatric Patient 1824 Therapeutic Approach 1825 Diet 1826 Supplements 1826 Botanical Medicines 1826

It is divided into two major categories, Crohn’s disease and ulcerative colitis. Clinically, IBD is characterized by recurrent inflammatory involvement of specific intestinal segments resulting in diverse clinical manifestations.

Crohn’s Disease Crohn’s disease is characterized by a granulomatous inflammatory reaction throughout the entire thickness of the bowel wall. In approximately 40% of cases, however, the granulomas are either poorly developed or totally absent. The original description in 1932 by Crohn and colleagues localized the disease to segments in the ileum. However, the same granulomatous process may involve the buccal mucosa, esophagus, stomach, duodenum, jejunum, and colon. Crohn’s disease of the small intestine is also known as regional enteritis. Involvement of the colon is known as Crohn’s disease of the colon or granulomatous colitis; the latter term is less accurate because granulomatous lesions develop in only a portion of the patients.

Ulcerative Colitis In ulcerative colitis a nonspecific inflammatory response is limited largely to the colonic mucosa and submucosa. Well-developed granuloma formation does not occur. 1813

Specific Health Problems Crohn's disease and ulcerative colitis do have many features in common, however, and the diseases are discussed together when appropriate. Otherwise they are considered as separate entities.

Common Features of Crohn's Disease and Ulcerative Colitis The colon is frequently involved in Crohn's disease and is invariably involved in ulcerative colitis. Although rarely, patients with ulcerative colitis who have total colon involvement may experience a so-called backwash ileitis. Thus, both conditions may cause changes in the small intestine. Patients with Crohn's disease often have close relatives with ulcerative colitis, and vice versa. When there is no granulomatous reaction in Crohn's disease of the colon, the two lesions may resemble each other clinically as well as pathologically. There are many epidemiologic similaritiesbetween the two diseases, including age, race, sex, and geographic distribution. The two conditions are associated with similar extraintestinal manifestations. There appear to be etiologic parallels between the two conditions. Both conditions are associated with a higher frequency of colonic carcinoma.

Etiology The epidemiologic and etiologic data on ulcerative colitis and Crohn's disease are quite similar.',2 The incidence and prevalence of the two diseases differ slightly, with most studies showing ulcerative colitis to be more common. The current estimate of the incidence of ulcerative colitis in western Europe and the United States is approximately 6 to 8 cases per 100,000, and the estimated prevalence is approximately 70 to 150 cases per 100,000. The estimate for the incidence of Crohn's disease is 2 cases per 100,000, and that for the prevalence is 20 to 40 cases per 100,000. The incidence of Crohn's disease is rising in Western culture^.^" IBD may occur at any age, but it most often occurs between the ages of 15 and 35 years. Females are affected slightly more frequently than males. White people have the disease two to five times more often than African or Oriental Americans, and Jews have a threefold to sixfold higher incidence than non-Jews.I4 Theories about the etiology of IBD can be divided into several groups as follows',2: Genetic predisposition Infectious agent or agents Immunologic abnormality Dietary factors An assortment of miscellaneous concepts implicating

psychosomatic, vascular, traumatic, and other mechanisms

Genetic Predisposition Although the search for a specific genetic marker for IBD has been futile, several factors suggest a genetic predisposition. As already mentioned, IBD is two to four times more common in white than nonwhite people, and four times more common in Jews than in non-Jews. In addition, multiple members of a family have Crohn's disease or ulcerative colitis in 15% to 40% of cases.'T2

Infectious Etiology Many microorganisms have been hailed as putative causes of IBD, but in spite of numerous attempts to confirm a bacterial, mycobacterial, fungal, or viral etiology, the idea that a transmissible agent is responsible for IBD is still a hotly debated subject. Viruses-rotavirus, Epstein-Barr virus, cytomegalovirus, and an uncharacterized RNA intestinal cytopathic virus-and mycobacteria continue to be favored candidates. Gastrointestinal infections with Aeromonas bacteria (Amomonas sobriu and Aeromonas hydrophila) and the yeast Cundida albicuns can initiate and perpetuate colitis, and all patients with IBD should be tested for these infections at the start and during the course of their Other etiologic candidates are as follow~'~~J'-'~: Pseudomonas-like organisms Enteric anaerobes Chlamydia spp. Yersiniu enterocolitica

Antibiotic Exposure Antibiotic exposure is being linked to Crohn's disease.' Before the 1950s, Crohn's disease was found in selected groups with a strong genetic component. Since this time there has been a rapid climb in developed countries, particularly the United States, and in countries that previously had virtually no reported cases. In fact, Crohn's disease has spread like an epidemic since 1950. Are antibiotics to blame? Penicillin and tetracycline have been available in oral form since 1953. The annual increase in prescriptions of antibiotics parallels the rise in the annual incidence of Crohn's disease. Comparative statistics have shown that wherever antibiotics have been used early and in large quantities, the incidence of Crohn's disease is now quite high. Over the years researchers have sought to identify Crohn's disease as an infectious process. The problem may be that the infectious agent is a component of the normal intestinal flora that suddenly produces immunostimulatory toxins or becomes invasive as a direct result of sublethal doses of antibiotics. Administration of sublethal amounts of antibiotics has been shown to induce

Inflammatory Bowel Disease (Crohn’s Disease and Ulcerative Colitis) a capacity for toxin production in intestinal organisms. When microbes are not given a full lethal dose, their usual response is to adapt and become even stronger in virulence and numbers.

Immune Mechanisms An overwhelming amount of evidence points to immunologic derangements in IBD, but whether they are causal or secondary phenomena remains unclear. Theories relating humoral mechanisms, immunologic deficiencies, and cell-mediated reactions to the etiology of IBD have all been proposed, but the current evidence seems to indicate that these derangements are probably secondary to the disease process.’r2

Dietary Factors Despite the fact that a dietary etiology of Crohn’s disease is barely considered (if mentioned at all) in most standard medical and gastroenterology texts, several lines of evidence strongly support dietary factors as being the most important etiologically.1426 The incidence of Crohn’s disease is increasing in cultures consuming the Western diet, but it is virtually nonexistent in cultures consuming a more primitive diet.1419 Food is the major factor in determining the intestinal environment, so the considerable change in dietary habits over the last century could explain the rising incidence of IBD. Several studies that analyzed the pre-illness diet of patients with Crohn’s disease have found that people who experience Crohn’s disease habitually eat more refined sugar and less raw fruit and vegetables and dietary fiber than healthy people.1418In one study, the pre-illness intake of refined sugar in patients with Crohn’s disease was nearly twice that in controls (122 g/day versus 65 g/day).18One researcher found that before the onset of disease, patients with Crohn’s disease had eaten corn flakes more frequently than controls.21 Although other researchers could not verify this specific finding, corn flakes are high in refined carbohydrates and are derived from a very common allergen (corn). Much of controversy over the role of pre-illness diet in the etiology of Crohn’s disease is largely due to the fact that the only way to assess this diet is from postdiagnostic interviews. Studies in which the interview has taken place within the first 6 months of diagnosis tend to be more supportive than studies in which the interview was conducted more than 7 months after diagnosis. In contrast, patients with ulcerative colitis do not show a higher consumption of refined carbohydrate than control

subject^.^' Another important dietary factor that is entirely overlooked in the standard texts is the role of food allergy. Support for this hypothesis is offered in clinical studies that have utilized an elemental diet, total parenteral nutrition, or an exclusion diet with great success in the

treatment of IBD.2025The role of food allergy is discussed in greater detail later in the chapter, as is the effect of dietary fiber in the etiology and treatment of IBD (see “Therapeutic Considerations”). A reduced intake of omega-3 oils and an increased intake of omega-6 oils is also being linked to the growing rise of Crohn’s disease in Japan. Because the genetic background of the Japanese is relatively homogenous, this higher incidence is most likely due to the incorporation of Western foods in the diet. To examine the contribution of diet to the increased incidence of Crohn’s disease in Japan, the incidence and daily intake of a number of dietary components were compared annually from 1966 to 1985. The analysis showed that the greater incidence of Crohn’s disease was strongly correlated with increased dietary intake of total fat, animal fat, omega-6 fatty acids, animal protein, milk protein, and the ratio of omega-6 to omega-3 fatty acids. It was less correlated with intake of total protein, was not correlated with fish protein, and was inversely correlated with vegetable protein. Multivariate analysis showed that higher intake of animal protein was the strongest independent factor, followed by an increased ratio of omega-6 to omega-3 fatty acids.26Correction of this increased ratio by reduction of omega-6 oil intake and increase of omega-3 oil intake may lead to sigruficant clinical benefit through an effect on eicosanoid metabolism (discussed later).

Miscellaneous Factors Psychosomatic factors, primary vascular disease within mural arteries or arterioles, and chronic trauma have received consideration in the etiology of IBD but at present are not considered significant pathogenic Mental and emotional stress can promote exacerbation of IBD, so stress management techniques may prove useful for some

THERAPEUTIC CONSIDERATIONS Inflammatory bowel disease is the end result of a complex interplay of several factors. This section discusses the key nutritional, microbial, and toxic issues that must be addressed for the successful management of this difficult disease.

Control of Causative Factors Natural History of Crohn’s Disease Little is known about the natural course of Crohn’s disease, because virtually all patients with the disease undergo standard medical care (drugs and/or surgery) or alternative therapy. The only exceptions are patients in clinical trials who are assigned to the placebo gr0up.2~-~~ However, even these patients do not represent the natural course of the disease, because they are

Specific Health Problems

seen frequently by physicians and other members of a health care team and are taking medication, even if it is only in the form of a placebo. If proper evaluation of therapies for IBD is to occur, there must be a greater understanding of its natural history. This is particularly important for alternative practitioners, because it is commonly believed that standard medical care often interferes with the normal efforts of the body to restore health. Some aspects of the “natural” course of Crohn’s disease support this idea, especially when coupled with the limited efficacy of current medications and surgery and their known toxicity. However, heroic measures do have their place in many instances and should be used when appropriate. Researchers in the National Cooperative Crohn’s Disease Study (NCCDS) reviewed 77 patients who received placebo therapy in part 1of the 17-weekstudy?” They all had active disease, as defined by a Crohn’s disease activity index (CDAI) (see Appendix 2) higher than 150. Of the patients completing the study: None died. Only seven (9%) suffered a major worsening of their disease (i.e., either a major fistula developed or the patient required abdominal surgery). 25 (32%) suffered a lesser worsening (increase in the CDAI to A50 or presence of fever of 100” F for 2 weeks). Treatment was considered to have failed in 25 (32%), because their CDAIs remained higher than 150. 20 (26%)achieved clinical remission. On at least one occasion during the 17 weeks of therapy, 49% of the patients were found to have a CDAI lower than 150. The patients who showed favorable response to the placebo continued to be observed with placebo therapy for up to 2 years (part 1,phase 2). It is interesting to note that although none of these patients’ intestinal radiographs showed worsening during phase 1 or phase 2, 18% showed improvement. Of the patients whose disease responded to placebo (20; 26% of the 77), the majority (70%)remained in remission at 1year, and a fair number (45%) remained in remission at 2 years. These results indicate that many patients undergo spontaneous remission, approximately 20% at 1 year and 12% at 2 years. However, when another factor is considered, the “success” of placebo therapy rises dramatically. Of patients in the placebo group who had no previous history of steroid therapy, 41% achieved remission after 17 weeks. In addition, 23% of this group continued in remission after 2 years, compared with only 4% of the group with a history of steroid use. The European Cooperative Crohn’s Disease Study (ECCDS), although different in some methodologic details, is quite similar to the NCCDSZ9J1In the ECCDS, 110 patients constituted the placebo group, 68 patients

with prior treatment and 42 patients with no prior treatment. The results of the study showed that 55% of the total placebo group achieved remission by 100 days, 34% remained in remission at 300 days, and 21% remained in remission at 700 days. Like the NCCDS, the ECCDS demonstrated that patients with no prior therapy have a greater likelihood of remission. Although one group of researchers did not advocate placebo therapy, they did carefully point out that once remission is achieved, 75% of the patients continue in remission at the end of 1year and up to 63% at 2 years, regardless of the maintenance therapy used. These results would suggest that the key is achieving remission, which, once attained, can be maintained by conservative nondrug therapy rather than the “medicines we are currently using with their limited efficacy and known t o ~ i c i t y . ” ~ ~

Eicosanoid Metabolism in Inflammatory Bowel Disease Patients with IBD show greatly increased levels of inflammatory chemicals in the colonic mucosa, serum, and stool samples. Specifically, these patients show an increase in the synthesis of the lipoxygenase products, leukotrienes, and mono-hydroxyeicosatetraenoic acids (rnono-HETE~).~~-” These compounds are produced by neutrophils and are known to amplify the inflammatory process and cause smooth muscle contraction. Release of lipoxygenase products is promoted by activation of the alternative complement pathway. The therapeutic efficacy of sulfasalazine and corticosteroids is due to their effect on eicosanoid metabolism. Sulfasalazine is an inhibitor of both cyclooxygenase and neutrophil lipoxygenase, whereas corticosteroids inhibit phospholipase A2 and thus block the release of arachidonic acid from the membrane phospholipid pool. Sulfasalazine also inhibits the degranulation of mast cells. Several naturally occurring compounds, such as the flavonoid quercetin, also interact favorably with these enzymes. The formation of these inflammatory compounds can be decreased by reduction or elimination of the consumption of beef, liver, pork, lamb, and milk/dairy products and an increase in the consumption of omega-3 fatty acids through higher intake of cold-water fish like salmon, mackerel, herring, and halibut. These fish are good sources of the longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Double-blind studies with fish oil supplements (2.7 to 5.1 g total omega-3 oils) have demonstrated an ability to prevent or delay relapses in both Crohn’s disease and ulcerative c o l i t i ~ .Flaxseed ~ ~ , ~ ~ oil is also of value. Flaxseed oil contains alpha-linolenic acid, the essential omega-3 fatty acid that has antiinflammatory effects and can be converted to EPA in limited amounts.39

Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis)

Mucin Defects in Ulcerative Colitis Mucins are an ill-defined class of high-molecular-weight, carbohydrate-rich (85% by weight of N-acetylgalactosamine, galactose, sialic acids, N-acetylglucosamine, and fructose)glycoproteins that are thought to be largely responsible for the viscous and elastic characteristics of secreted mucus. Alterations in mucin composition and content in the colonic mucosa have been reported in patients with ulcerative colitis?ga The factors responsible for these changes appear to be a dramatic drop in the mucous content of the goblet cells (proportional to the severity of the disease) and a diminution of the major sulfomucin subfraction (designated species N according to diethylaminoethanol-cellulose differentiation). In contrast, these abnormalities are not found in patients with Crohn's disease. It is sigrufrcant that although the much content of the goblet cells returns to normal during remission, the sulfomucin deficiency does not. The specific components of the sulfomucin and the cause of its lower concentration have not yet been determined. These mucin abnormalities are also thought to be a major factor in the higher risk of colon cancer in these patients. Many of the herbs used historically in the treatment of ulcerative colitis are demulcents, that is, agents that soothe irritated mucous membranes and promote the secretion of mucus. This effect appears to be very beneficial and supports the use of demulcents in ulcerative colitis.

Intestinal Microflora The intestinal microflora is extraordinarily complex and contains more than 400 distinct microbial species.l1,l2 Accurate simultaneous quantification of all possible species is not possible with current conventional culture techniques. In addition, measurement techniques such as stool cultures do not indicate bacterial metabolic activity, locations of growth within the gastrointestinal tract, or turnover rates. These last two factors may prove to be the more important determinants of the role of the intestinal bacterial flora in IBD than the actual numbers of specific bacterial species. In an effort to describe a nonspecific (qualitative or quantitative) alteration in the intestinal flora, the term dysbiosis is often used (see Chapters 12 and 14 for a full discussion of this important topic).l1 The fecal flora of patients with IBD has been found to contain higher numbers of gram-positive anaerobic coccoid rods and Bucteroides vulgutus, a gram-negative rod.*' Studies have indicated that these alterations in fecal flora are not secondary to the disease, and alterations in the metabolic activity of the various bacteria are thought to be more important than alterations in the number of bacteria per se. In addition, specific bacterial cell components (which vary even within the same species) are

thought to be responsible for promoting lymphocyte cytotoxic activity against the colonic epithelial cells."J*

Carrageenan It is very interesting to note that researchers investigating the intestinal flora of ulcerative colitis often use the carrageenan (a sulfated polymer of galactose and D-anhydrogalactoseextracted from red seaweeds, principally Eucheurnu spinosurn and Chondrus crispus) model to experimentally induce the disease in animals. In the initial experiments reported by Marcus and WatP3in 1969, 1%and 5% carrageenan solutions were provided as the exclusive source of oral fluids for guinea pigs. Over a period of several days the animals lost weight, demonstrated anemia, and had bloody diarrhea. Gross anatomical studies after sacrifice at 20 and 45 days revealed a loss of haustral folds, mucosal granularity, pseudopolyps, and strictures, and microscopic examination showed crypt abscesses, lymphocytic infiltration, capillary congestion of the lamina propria, and gross ulcerations. These results have since been confirmed by numerous investigators and in studies involving other animal species, including In its native state the carrageenan polymer has a molecular weight of 100,000 to 800,000 daltons, but in the studies it is degraded by mild acidic hydrolysis to yield products with weights in the vicinity of 30,000 daltons. Carrageen compounds are used by the food industry as stabilizing and suspending agents, with polymers of different molecular weight being used for a variety of purposes. Typically, carrageenans used in the food industry have a molecular weight greater than 100,000 daltons. Carrageenan is widely used in milk and chocolate milk products (e.g., ice cream, cottage cheese, milk chocolate) because of its ability to stabilize milk proteins. As suggestive as the animal studies are in linking ulcerative colitis with carrageenan, and despite the higher consumption of carrageenan in Western diets, there appears to be no correlation between human consumption of carrageenan and development of ulcerative colitis at this time. In one study, no lesions of IBD were observed in healthy human subjects fed enormous quantities of degraded ~arrageenan.4~ However, differences in intestinal bacterial flora are probably responsible for this discrepancy, because germ-free animals do not display carrageenan-induced damage. Upon further examination, it was discovered that the bacteria that has been linked to facilitating the carrageenan-induced damage in animals is a strain of B. vulgutus." As mentioned earlier, this organism is found in much higher concentrations (six times as high) in the fecal cultures of patients with IBD. When all the data are evaluated, they appear to imply that although carrageenan can be metabolized into nondamaging components in most human subjects, those individuals with

Specific Health Problems an overgrowth of B. vulgutus may be at risk. Strict avoidance of carrageenan appears warranted at this time for patients with IBD until further research clarifies its safety for them.

Aspirin and Intestinal Permeability A very interesting study evaluated 30 patients with Crohn's disease and 37 first-degree relatives of patients with Crohn's disease for intestinal permeability by means of the lactulose/mannitol ratio. First-degree relatives had a 110% higher intestinal permeability after ingesting acetylsalicylic acid, compared with an increase of 57% in the control subjects. Thirty-five percent were "hyperresponders."48A familial permeability defect causing increased permeability would be a sigruficant predisposing factor for Crohn's disease, because a leaky gut is associated with higher incidence of food allergy and greater absorption of intestinal toxins (see Chapter 23).

Endotoxemia and the Alternative Complement Pathway Endotoxemia is associated with both Crohn's disease and ulcerative ~ o l i t i s .Endotoxemia-induced ~,~~ activation of the alternative complement pathway could explain some of the extraintestinal (i.e., outside the gastrointestinal tract) manifestations of IBD (discussed later). Whole-gut irrigation significantly reduces the endotoxin pool in the gut and has been shown to have a very beneficial anti-endotoxinemia effect.50Colonic irrigation may offer similar benefit. However, colon irrigation during an acute inflammatory flare may be contraindicated.

Extraintestinal Manifestations More than 100 disorders, known as extraintestinallesions (EILs), constitute a diverse group of systemic complications of IBD.25152The most common EIL in adults is arthritis, which is found in about 25% of patients. Two types are typically described, the more common being peripheral arthritis affecting the knees, ankles, and wrists. Arthritis is more common in patients with colon involvement. Severity of symptoms is typically proportional to disease activity.25152 Less frequently, the arthritis affects primarily the spine. Symptoms are low back pain and stiffness, with eventual limitation of motion. This EIL occurs predominantly in men with HLA-BZ7and is fairly indistinguishable from typical ankylosing spondylitis. In fact, it may antedate the bowel symptoms by several years. There is probably a consistent underlying factor in both the progression of ankylosing spondylitis and IBD.25152 Skin manifestations are also common, being seen in approximately 15% of patients. Typical lesions are erythema nodosum, pyoderma gangrenosum, and aphthous ulcerations. Recurrent aphthous stomatitis occurs in approximately 10% of patients.23152

Serious liver disease (i.e., sclerosing cholangitis, chronic active hepatitis, cirrhosis) is also a common EIL, affecting 3% to 7% of the patients with IBD. It probably relates to the increased endotoxin load associated with IBD. If patients are demonstrating liver enzyme abnormalities, hepatoprotection appears indicated, with botanical medicines such as Silybum rnariunurn (i.e., silymarin) and c u r c ~ m i n . ~ ~ ~ ~ Other common EILs are as follows25152: Thrombophlebitis Finger clubbing Ocular manifestations (episcleritis, iritis, and uveitis) Nephrolithiasis Cholelithiasis In children: failure to grow, thrive, and mature normally

Malnutrition Many nutritional complications occur during the course of IBD."% Because these complications can have a sigruficant influence on the morbidity, and perhaps also the mortality, of these patients, every effort should be made to ensure optimal nutritional status. The major mechanisms that contribute to nutritional depletion in patients with IBD are listed in Box 181-1. A decreased food intake is the most important mechanism of nutritional deficiency in patients with IBD, and a deficient calorie intake is the most common nutritional deficit in patients requiring hospitalization. Often the patient feels sigruficant pain, diarrhea, nausea, and/or other symptoms after a meal, resulting in a subtle diminution in dietary intake. Weight loss is prevalent in 65% to 75% of patients with IBD.% Malabsorption can be anticipated in patients with extensive mucosal involvement of the small intestine and in patients who have undergone resection of segments of the small intestine. Particularly common is fat

Decreased oral intake: Disease-induced (pain, diarrhea, nausea, anorexia) Iatrogenic (restrictive diets without supplementation) Malabsorption Decreased absorptive surface due to disease or resection Bile salt deficiency after resection Bacterial overgrowth Drugs (e.g., corticosteroids, sulfasalazine, cholestyramine) Increased secretion and nutrient loss Protein-losing enteropathy Electrolyte, mineral, and trace mineral loss in diarrhea Increased utilization and increased requirements Inflammation, fever, infection Increased intestinal cell turnover

Inflammatory Bowel Disease (Crohn’s Disease and Ulcerative Colitis) malabsorption, which results in sigruficant loss of calories as well as loss of fat-soluble vitamins and minerals. Involvement of the ileum or surgical resection of that area typically leads to malabsorption of vitamins and bile acid. Because of the cathartic effect of bile acids on the colon, the malabsorption may result in a chronic watery diarrhea. Electrolyte and trace mineral deficiencies should be suspected in patients with a history of chronic diarrhea, whereas calcium and magnesium deficiencies may be a result of chronic steatorrhea. Increased secretion of protein into the intestinal lumen and nutrient loss due to the exudative and inflammatory nature of IBD are common. In particular, there is a significant loss of plasma proteins across the damaged and inflamed mucosa. The loss of protein may exceed the ability of the liver to replace plasma proteins, despite a high protein intake. The chronic loss of blood often leads to iron depletion and anemia. The drugs most commonly used in the allopathic treatment of IBD are corticosteroids and sulfasalazine, both of which increase nutritional needs. Corticosteroids are known to have the following effects: Stimulate protein catabolism Depress protein synthesis Decrease the absorption of calcium and phosphorus Increase the urinary excretion of ascorbic acid, calcium, potassium, and zinc Increase blood glucose, serum triglyceride, and serum cholesterol levels Increase the requirements for vitamin B6, ascorbic acid, folate, and vitamin D Decrease bone formation Impair wound healing Sulfasalazine has been shown to have the following effects59: Inhibit the absorption and transport of folate Decrease serum folate and iron Increase the urinary excretion of ascorbic acid The last consideration in the causes of nutrient deficiency in patients with IBD is the nutritional consequences of a chronic inflammatory and/or infectious disease. This topic has not been fully investigated, and the only conclusion that currently can be made is that protein requirement may be raised in patients with acute exacerbations of IBD. An elevated erythrocyte sedimentation rate sigrufies a rise in both protein breakdown and protein synthesis. Typically, patients with IBD require perhaps as much as 25% more protein than the usual recommended a l l o ~ a n c e . ~ ~ ~

Prevalence of Nutritional Deficiencies As shown in Table 181-1,the prevalence of nutritional deficiencies is quite high in hospitalized patients with IBD.

Prevalence of nutritional deficiency in hospitalized patients with inflammatory bowel disease Deficiency

Prevalence (%)

Hypoalbuminemia

25-80

Anemia

60-80

Iron deficiency Low serum vitamin B,*

40 48

Low serum folate

54-64

Low serum magnesium

14-33

Low serum potassium

6-20

Low serum retinol

21

Low serum ascorbate

12

Low serum 25-OH-vitaminD

25-65

Low serum zinc

40-50

Modified from Aoki K. Acta Med Okayama 1978;32:147-158

Although it is generally agreed that the prevalence of nutritional deficienciesis greater in hospitalized patients (who typically are in a more severe condition) than in outpatients, a great number of ambulatory patients with Crohn’s disease display one or more nutrient deficienIn addition to the deficiencies listed in cies as Table 181-1, low levels of vitamin K, copper, niacin, and vitamin E have been reported.%

Diet The importance of correcting nutritional deficiencies in patients with IBD cannot be overstated. Deficiencies of both macronutrients and micronutrients cause alterations in gastrointestinal function and structure, which may lead to a vicious circle-the secondary effects of malnutrition on gastrointestinal tract function and structure may further exacerbate malabsorption, further reducing nutrient status. Foremost in nutritional therapy is providing adequate caloric intake. It should be assumed that the majority of patients suffer from micronutrient deficiency, although the deficiency often is subclinical and can be detected only by appropriate laboratory investigation. In general, patients with IBD should be started therapeutic vitamin supplements of at least five times the recommended dietary allowances (RDAs). Several minerals may also have to be supplemented at equally high levels. Dietary treatment involves the use of either an elemental diet or an elimination diet (described later).

Elemental Diet The elemental diet has been shown to be an effective nontoxic alternative to corticosteroids as the primary treatment of acute IBD?O-= An elemental diet is one that is purported to contain all essential nutrients,

Specific Health Problems with protein being provided only as predigested or freeform amino acids. The improvements noted on an elemental diet are probably not primarily related to nutritional improvement, however. The improvement could be a result of alterations in the intestinal flora (which have been noted to occur in patients consuming an elemental diet), but a stronger case could be made for a secondary immune mechanism being bypassed during elemental feeding: The elemental diet is serving as an allergy elimination diet. The main drawbacks of the widespread use of elemental diets are their unpalatability and their hyperosmolality, which often results in diarrhea. In addition, hospitalization is often required for satisfactory administration, and relapse is quite common when patients resume normal eating. An elimination diet, rather than an elemental diet, may be a more acceptable alternative in the treatment of acute IBD and particularly in the treatment of chronic IBD.

Elimination (Oligoantigenic) Diet Although food allergy has long been considered an important etiologic factor in the pathogenesis of IBD, it is only recently that studies utilizing an elimination diet in the treatment of IBD have been performed (elimination diets are described in Chapter 19).2426These studies demonstrate that an elimination diet is the primary therapy of choice in the treatment of chronic IBD. The most common offending foods were found to be wheat and dairy products. An alternative approach is to determine the actual allergens with laboratory methods, preferably a method that measures both immunoglobulin G ($$)-mediated and IgE-mediated reactions. The allergens are then avoided or a rotary diversified diet is used as appropriate (see Chapters 47 and 53).

High-Complex Carbohydrate, High-Fiber Diet Treatment with a high-complex carbohydrate, high-fiber (HFC) diet has been shown to have a favorable effect on the course of Crohn’s disease.19This finding is in direct contrast to one of the oldest allopathic dietary treatments of IBD, a low-fiber diet. Although some foods may be too “rough to handle, the dietary treatment of IBD should utilize an unrefined-carbohydrate, fiber-rich diet combined with an avoidance or rotary-diversified diet. This latter combination is much more effective than just a high-fiber diet alone.= Dietary fiber has a profound effect on the intestinal environment and is thought to promote a more optimal composition of intestinal flora.61 However, because of the high degree of intolerance to wheat found in patients with IBD, and the known roughness of wheat bran, supplemental wheat bran is not the fiber of choice for such patients.

Minerals Zinc Zinc deficiency, a well-known complication of Crohn’s disease, occurs in approximately 45% of patients with the Low serum zinc concentrations, low hair zinc levels, malabsorption of zinc, altered urinary excretion of zinc, and impaired taste acuity are commonly found in patients with Crohn’s d i s e a ~ e ?The ~ , ~deficiency ~ of zinc is due to low dietary intake, poor absorption, and excess fecal 10sses.5~-~~,~* Zinc deficiency may be the direct cause of the following complications of Crohn’s disease624: Poor healing of fissures and fistulas Skin lesions (acrodermatitis) Hypogonadism Growth retardation Retinal dysfunction Depressed cell-mediated immunity Anorexia Many patients with Crohn’s disease show no response to oral or intravenous zinc supplementation, because such patients appear to have a defect in tissue transport of zinc. Intravenous supplementation results in a tremendous rise in urinary zinc excretion, but insigIuficant clinical results. Several clinical trials using oral zinc sulfate have shown the same lack of positive effect.65 Supplying zinc orally in the picolinate form may be more advantageous than other forms of zinc administration, possibly improving both intestinal absorption and tissue transport, although one study displayed no s i g h c a n t difference in zinc absorption between zinc sulfate and zinc picolinate in patients with pancreatic insufficiency.& Zinc citrate may also be an appropriate alternative. In any event, every attempt should be made to ensure that adequate tissue stores of zinc are maintained, because disease activity is correlated with zinc deficiency. Parenteral zinc administration may be needed in some cases. Although less than ideal, intravenous administration of zinc is often the only way to attain even marginal zinc levels in patients with Crohn’s disease.65

Magnesium Magnesium deficiency is quite prevalent in patients with IBD.57*67,68 However, a poor correlation exists between serum magnesium levels, which may be low in only a few patients, and intracellular magnesium levels, which are commonly decreased in patients with IBD.57Patients with low intracellular magnesium levels may present with the following problems57: Weakness Anorexia Hypotension

Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis)

Confusion Hyperirritability Tetany Convulsions Electrocardiographic or electroencephalographicabnormalities These symptoms are generally responsive to parenteral magnesium supplementation. A daily intravenous dose of 200 to 400 mg elemental magnesium may be necessary for cases not responding to oral supplementation. Patients with IBD may require this route of supplementation owing to magnesium's somewhat cathartic action and poor absorption in patients with a short bowel. Oral supplementation should be with magnesium chelates (i.e., citrate, aspartate) rather than inorganic magnesium salts (i.e., carbonate).

Iron Iron deficiency anemia is very common in IBD, largely because of chronic blood loss through the Serum ferritin levels are the most useful indices of iron status. A serum ferritin concentration greater than 55 n g / d indicates adequate bone marrow iron reserves, whereas a concentration less than 18 ng/ml is highly predictive of iron deficiency (see Chapter 27 for further discussion). The clinician should attempt to increase the patient's iron stores by improving absorption, as with supplemental vitamin C, rather than through direct iron supplementation, which promotes intestinal infe~tion.~~

Calcium Patients with Il3D are also at risk for development of calcium deficiency, probably owing to the following factors57: Loss of absorptive surfaces Steatorrhea Corticosteroid use Vitamin D deficiency

Potassium Diarrheal diseases are often associated with potassium and other electrolyte deficiencies. Although symptoms of potassium deficiency are quite rare in patients with IBD, levels of this mineral are probably below optimum. In one study, nutritional support to correct potassium deficiency resulted in sigruficantly reduced rates of surgical

Vitamins Vitamin A Low serum retinol levels are found in approximately 20% of patients with Crohn's disease and are correlated

with the activity of the d i s e a ~ e . 5 ~Vitamin r~ A can profoundly affect the metabolism and differentiation of the intestinal epithelial mucosa, because it can increase the number of goblet cells, the production of mucins, and the secretion of mucus and can restore normal barrier function. Preliminary case reports indicated that vitamin A may be of therapeutic use in Crohn's d i s e a ~ e . ' ~However, ,~ long-term controlled trials have shown that vitamin A (50,000 IU twice daily) has no therapeutic effect in the majority of Crohn's disease case^.^^,^^ It should be kept in mind, however, that certain cases may respond to vitamin A therapy and that zinc supplementation will often normalize disturbances of vitamin A metabolism, as zinc is a necessary component of retinol-binding protein (RBP).64

Vitamin D There is evidence that vitamin D deficiency is quite common in patients with IBD, particularly those with other signs of nutritional deficiency.57," This is probably a result of decreased absorption of 25-hydroxyvitamin D. Patients with IBD are at an increased risk for the development of metabolic bone diseases such as osteoporosis and osteomalacia. This fact relates to previously mentioned factors in calcium deficiency.

Vitamin E Vitamin E deficiency can occur in IBD, as observed in one case rep0rt.7~The patient had a =-year history of Crohn's disease and had undergone multiple small bowel resections. Presenting symptoms relating to vitamin E deficiency were as follows: Bilateral visual field scotomata Generalized motor weakness A broad-based gait with marked ataxia Brisk reflexes A bilateral Babinski response

Serum vitamin E concentration was 0.03 m g / d (normal 0.8 to 1.2 mg/d), and in vitro peroxide hemolysis was 100% (normal 40%). Supplementation with 270 IU/day eventually brought complete recovery over a period of 2 years. Vitamin E supplementation is also indicated because its ability to inhibit leukotriene formation and reduce free radical damage."

Vitamin K Vitamin K deficiency, resulting in the formation of abnormal prothrombin (deficient in gamma-carboxyglutamic acid), is quite common in patients with IBD.7*tmVitamin K deficiency also contributes to the osteoporosis and osteopenia that are very common in patients with Crohn's disease.80

Optimal range of nutrients

Folic Acid Low serum concentrations of folic acid are quite common in IBD, with reports of occurrence ranging between 25% and 64% of cases.57,8082 The drug sulfasalazine exacerbates the condition by interfering with folate-dependent enzymes and with the intestinal folate transport system.83A folate deficiency promotes further malabsorption through alteration in structure of the intestinal mucosal cells.@These cells have a very rapid turnover (1 to 4 days) compared with red blood cells (RBCs) (3 to 4 months), so deficiency affects these cells much earlier than RBCs. Patients with Crohn's disease commonly have genetically determined defects in folic acid metabolism and therefore require supplemental folate to reduce the higher risk of cardiovascular disease resulting in part from this defect. Patients with ulcerative colitis, on the other hand, require supplemental folate to reduce their higher risk of colon cancer.

Vitamin B12 A significant correlation exists between vitamin BI2 absorption and the extent of terminal ileal disease and/or r e s e c t i ~ nOverall, . ~ ~ ~ ~abnormal ~ Schilling test results are found in 48% of patients with Crohn's disease. When ileal resection exceeds 90 cm, the Schilling test result is abnormal in all patients and does not improve with time. If the length of the resection is less than 60 cm, or the extent of the inflammatory lesion is less than 60 cm, adequate absorption may occur.

Ascorbic Acid A low vitamin C intake is common in patients with IBD, particularly in those patients on a low-fiber Serum and leukocyte ascorbic acid levels are significantly lower in patients with Crohn's disease than in matched control^.^^,^ Vitamin C is thought to be particularly important in the prevention of fistula formation. It has been shown that patients with fistulas have lower ascorbic acid levels than patients without

fistula^."^

Nutrient

Ranae for adults ~

~~

~~

Vitamins Vitamin A (retinol)

5000 IU*

Vitamin A (from beta-carotene)

5000-25,000 IU

Vitamin D

100-400 IU

Vitamin E (D-alpha tocopherol)

100-200 IU

Vitamin K (phytonadione)

60-300 pg

Vitamin C (ascorbic acid)

100-1,000 mg

Vitamin B1 (thiamin)

10-100 mg

Vitamin B2 (riboflavin)

10-50 mg

Niacin

10-100 mg

Niacinamide

10-30 mg

Vitamin B6(pyridoxine)

25-100 mg

Biotin

100-300 pg

Pantothenic acid

5-100 mg

Folic acid

400 c19

Vitamin B12

400 10-100 mg

Choline lnositol Minerals Boron

10-100 mg 1-6 mg

Calcium

250-500 mg

Chromium

200-400 pg

Copper

1-2 mg

Iodine

50-150 pg

Iron

15-30 mgt

Magnesium

250-500 mg

Manganese

10-15 mg

Molybdenum

10-25 1.19

Potassium

200-500 mg

Selenium

100-200 pg

Silica

1-25 mg

Vanadium

50-100 pg

Zinc

15-45 mg

'Women of childbearing age for whom becoming pregnant is a possibility should not take more than 2500 IU/day of retinol because of the possible risk of birth defects. +Menand postmenopausal women rarely need supplemental iron.

Other Nutrients Obviously, patients with IBD are at risk for development of any nutrient deficiency, including nutrients not discussed here. However, there is probably no real need for laboratory investigation to determine micronutrient deficiencies, other than for the nutrients discussed

Recommendation for a High-Potency Multiple Vitamin and Mineral Formula It is absolutely essential that patients with IBD take a high-potency multiple vitamin and mineral supplement

all of the known vitamins and minerals. Table 181-2 lists recommendations for an optimum intake range. In addition to taking a high-potency multiple vitamin and mineral formula, patients with IBD need to consume additional antioxidants. Increased oxidative stress and decreased antioxidant defenses in the mucosa are hallmark features of IBD.%This association provides a strong rationale for therapeutic modulation with antioxidants. The two primary antioxidants in the human body are vitamin C and vitamin E. Vitamin C is an "aqueous

Inflammatory Bowel Disease (Crohn’s Disease and Ulcerative Colitis)

phase” antioxidant, whereas vitamin E is a “lipid phase” antioxidant. Recommended dosages in patients with IBD are as follows: Vitamin E (mixed tocopherols with approximately 40% gamma-tocopherol): 400 to 800 IU Vitamin C (ascorbic acid): 1000 to 3000 mg

Botanical Medicines Quercetin

(Neutrophils and monocytes contain lysosomes that, upon secretion of their contents, contribute greatly to the inflammatory process.) Quercetin has been shown to inhibit many steps in eicosanoid metabolism. Probably of most significance in IBD is its inhibition of phospholipase A2 and lipoxygenase enzymes (see Figure 165-1 in Chapter 165).89,90,97 The net result is a significant reduction in the formation of leukotrienes. Excessive leukotriene formation has been linked to asthma, psoriasis, atopic dermatitis, gout, and, possibly, cancer as well as IBD?8,99The leukotrienes C4, D4, and E4 (composing the slow-reacting substances of anaphylaxis [SRS-A]) are derived from arachidonic acid and are 1000 times as potent as histamine in promoting inflammation. Leukotrienes promote inflammation by causing vasoconstriction (thereby increasing vascular permeability) and other smooth muscle contraction, and by promoting white blood cell (WBC) chemotaxis and aggregation. The reduction of leukotriene formation has significant antiinflammatory effects, particularly in IBD. (For more information on quercetin, see Chapter 95).

The plant flavonoid quercetin appears to be particularly indicated in the treatment of IBD. Flavonoids, in general, are considered natural biologic response modifier^.*^,^^ Quercetin, as perhaps the most pharmacologically active flavonoid, has remarkable effects on a variety of enzyme ~ y s t e m s . 8Many ~ ~ ~ of the enzymes affected by quercetin are important in the secretory, contractile, and motility processes associated with the inflammatory response: the release of histamine and other inflammatorymediators from mast cells, basophils, neutrophils, and macrophages; migration and infiltration of leukocytes; and smooth muscle contraction. Bastyr Formula (Modified Robert Formula) Quercetin’s effect on these enzymes and processes is likely due to a common action-antagonizing calmodAlthough no research has been done to document its efficacy, an old naturopathic remedy, Robert formula, or ~lin.~ When l bound to calmodulin, calcium activates a great variety of enzymes, including those involved in its modification (Bastyr formula) has a long history of use in IBD (Box 181-2). It is composed of the following cyclic nucleotide metabolism, protein phosphorylation, secretory function, muscle contraction,microtubule assem- botanical medicines: bly, glycogen metabolism, and calcium flux. Quercetin is Althea officinalis (also known as marshmallow root)believed to interact directly with calmodulin and calcium a demulcent with soothing effects on the mucous channels. This has been shown in many experimental membranes studies and would explain quercetin’s effect on such a Baptisia tinctoru (also known as wild indigo)-used for wide number of enzymes. gastrointestinal infections Quercetin and many other flavonoids have been Echinacea angustifolia (also known as purple coneshown to be potent inhibitors of mast cell and basophil flower)-antibacterial and used to promote normalizad e g r a n ~ l a t i o n ?A ~ -generally ~~ accepted hypothesis for tion of the immune system (see Chapter 89) this action is that quercetin inhibits receptor-mediated Geranium maculatum-a gastrointestinal hemostatic calcium influx, thereby inhibiting the primary signal for Hydrasfis canadensis (also known as goldensea1)degranulation. However, quercetin is also active under inhibits the growth of many enteropathic bacteria conditions in which the calcium channel mechanism is (see Chapter 100) not operative, indicating that other mechanisms are responsible as well. Quercetin has been shown to inhibit many of the inflammatory processes attributed to activated neuEight parts Althea officinalis trophils.%This inhibitionis probably due to its membraneFour parts Baptisia tinctora stabilizing action, potent antioxidant effect (which Eight parts Echinacea angustifolia prevents the production of freeradicals and inflammatory Eight parts Geranium maculatum leukotrienes),and inhibition of the enzyme hyaluronidase Eight parts Hydrastis canadensis (thus preventing the breakdown of the collagen matrix Eight parts Phytolacca americana Eight parts Ulmus fulva of connective tissue and ground substance). Quercetin’s Eight parts cabbage powder membrane-stabilizing effect could also account for its Two parts pancreatin action in preventing mast cell and basophil degranOne part niacinamide ulation. The effect also inhibits inflammation by *Two parts duodenal substance decreasing neutrophil lysosomal enzyme ~ e c r e t i o n . ~ ~

Specific Health Problems

Phytolacca arnericana (also known as poke root)-used for healing ulcerations of the intestinal mucosa Symphyturn ofinale (also known as comfrey)-antiinflammatory and promotes tissue growth and wound healing Ulrnus film (also known as slippery elm)-has a demulcent effect The cabbage powder is used because of its documented ability to heal gastrointestinal ulcers (see Chapter 127); pancreatin is used to assist in the digestive process (see Chapter 112); niacinamide is used for its antiinflammatory effects; and duodenal substance is used because it also heals gastrointestinal ulcers.

Other Interventions Butyrate Enemas in Ulcerative Colitis Short-Chain Fatty Acids and Colon Function The short-chain fatty acids (SCFAs),mainly acetate, propionate, and butyrate, arise in the colon as end products of bacterial carbohydrate fermentation. These SCFAs function as primary energy sources for the luminal colon cells, especially in the distal segments. Decreased levels or decreased utilization of SCFAs leading to impaired cellular energetics has been hypothesized to play a major role in ulcerative colitis. On the basis of this hypothesis, several clinical trials have been conducted with enemas providing SCFAs (usuallycomposed of either butyrate as a sole agent in concentrations ranging from 80 to 100 mmol/L, or SCFA combinationscomposed of acetate 60 mmol/L, propionate 25 mmol/L, and butyrate 40 mmol/L). Excellent preliminary results in pilot studies led to a well-designed double-blind In this study, 47 patients with distal ulcerative colitis randomly received either a combination of SCFAs, butyrate, or a placebo in an enema form retained for 30 minutes twice daily.n The primary end point in the study was the disease activity index composed of stool frequency, rectal bleeding, mucosal appearance, and physician’s rating of disease activity as well as endoscopic examination. After 8 weeks of therapy, there was a drop in activity in all three groups, with the butyrate group showing the lowest disease activity. Endoscopic examination demonstrated less disease in the butyrate and SCFA combination groups. Complete remission occurred in 47”/0receiving SCFAs, 38%receiving butyrate, and 25% receiving placebo. This study and others indicate that butyrate and SCFA enemas may prove to be useful adjuncts in the treatment of ulcerative colitis.

Probiotics in Crohn’s disease Probiotics refers to beneficial yeast and bacteria that can be administered orally to achieve a therapeutic benefit. Supplementation with the beneficial yeast Saccharomyces

boulardii is safe and effective treatment for patients with Crohn’s disease that helps reduce diarrhea, intestinal inflammation, and the risk of relapse.101J02 Common doses of S. boulnrdii are 250 mg 3 to 4 times per day. Likewise, supplementation with LactobacilZus-GG has proven benefit in patients with Crohn’s disease, and the customary dose is 10’O colony-forming units [CFUs] in enteric-coated tablets twice a day.lo3-lo5

THERAPEUTIC MONITORING AND EVALUATION Fecal Calprotectin Calprotectin is a protein secreted into the intestinal lumen in direct proportion to inflammation. Measurement of calprotectin in stool samples has been shown to be a sensitive and specific noninvasive assessment for inflammation in patients with IBD, and the test is helpful for distinguishing IBD from other, noninflammatory gastrointestinal conditions, such as irritable bowel syndrome.’06

Crohn’s Disease Activity Index The CDAI was developed as a monitoring tool in the NCCDS.lo7It met the basic requirements necessary for the study-it provided uniform clinical parameters that could be assessed and produced a consistent numerical index for recording the results of the study of several centers over a several years. The CDAI is calculated by adding together eight variables (Table 181-3). It incorporates both subjective and objective information in determining relative disease activity. A form is provided in Appendix 2 that may be photocopied for giving to patients to fill out. When the patient returns with the completed form, the calculation of disease activity can be completed. In general, CDAI scores below 150 indicate a better prognosis than higher scores. The CDAI is a very useful way to monitor progress of therapy.

Monitoring of the Pediatric Patient Pediatric patients with IBD present a particularly difficult problem, in that it is often very difficult for them to achieve normal growth and development. Growth failure occurs in 75% of children with Crohn’s disease and in 25% of children with ulcerative The pediatric patient with IBD should be evaluated at least twice yearly. Evaluation should include a pertinent history, clinical anthropometry, Tanner staging, and appropriate laboratory testing. Box 181-3 outlines the necessary components of a comprehensive twice-yearly nutritional evaluation in pediatric patients with IBD. An aggressive nutritional program should be instituted, including supplements (it may be necessary to use enteral or

Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis)

Independent variables and formula used to calculate the Crohn's Disease Activity Index (CDAIY History Number of liquid or very soft stools in 1 week

Appetite, extracurricular activities Type and duration of inflammatory bowel disease, frequency of relapses Severity and extent of ongoing symptoms Medication history

Sum of seven daily abdominal pain ratings: 0 = none 1 =mild 2 = moderate 3 = severe

3-Day Diet Diary

Sum of seven daily ratings of general well-being: 0 = well 1 = slightly below par 2 = poor 3 = very poor 4 =terrible

Physical Examination Height, weight, arm circumference, triceps skinfold measurements Loss of subcutaneous fat, muscle wasting, edema, pallor, skin rash, hepatomegaly

Symptoms or findings presumed related to Crohn's disease. Add 1 point for each category correspondingto patient's symptoms: Arthritis or arthralgia lritis or uveitis Erythema nodosum, pyoderma gangrenosum, aphthous stomatitis Anal fissure, fistula, or perirectal abscess Other bowel-relatedfistula Episode of fever >looo F during past week

LaboratoryTests Complete blood count and differential, reticulocyte and platelet count, sedimentation rate, urinalysis Serum total proteins, albumin, globulin, and retinol-bindingprotein Serum electrolytes, calcium, phosphate, ferritin, folate. carotenes, tocopherol, and B12 Leukocyte ascorbate, magnesium, and zinc Creatinine height index, blood urea nitrogenkreatinine ratio

Taking diphenoxylate HCVatropine sulfate tablets (Lomotil) or opiates for diarrhea: 0 = no 1 =yes

THERAPEUTIC APPROACH

Abdominal mass: 0 = none 0.4 = questionable 1 = present 47 - hematocrit value, males

42 - hematocrit value, females 100 x (standard weight - body weight) c standard weight Adapted from Ford-Hutchinson AW. J Allergy Clin lmmunol 1984;74:437-440. 'CDAI = 2 X XI + 5 x X2 + 7 x X3 + 20 x X4 + 30 x X, + 10 x X, 6 x X7 + Xs

+

parented methods in some patients), which is similar to the approach outlined for the adult patient, with the doses adjusted as appropriate. The CDAI is not as accurate in monitoring the disease in children as it is in adults. To overcome this shortcoming, Lloyd-Still and Green1O8devised a clinical scoring system for IBD in children. The scoring system is divided into five major divisions (the maximum score is in parentheses): general activity (lo), physical examination and clinical complications (30), nutrition (20), radiography (15), and laboratory (25). An elevated score (i.e., scores in the 80s) represents good status, whereas scores in the 30s and 40s represent severe disease. Table 181-4 outlines the determination of clinical score.

It is important to recognize that in some patients Crohn's disease and ulcerative colitis are life-threatening diseases that at times require emergency treatment. A small percentage of patients who have severe colitis may experience severe exacerbations requiring hospitalization. This is more common in patients with ulcerative colitis, who typically present with a fever of 101" F or higher; profuse, constant, loose, bloody stools; anorexia; apathy and prostration; and, although abdominal signs may be normal, physical examination will uncover a distended abdomen, tympany, absence of bowel sounds, and even rebound tenderness. For the typical patient, IBD is a chronic disease requiring long-term therapy and follow-up. The first step is to identify and remove all factors that may be initiating or aggravating the inflammatory reaction, such as food allergens and carrageenan. The patient is started on a diet that maximizes macronutients and micronutrients while minimizing aggravating foods and nonfoods. A broad-based individualized nutritional supplementation plan is necessary for all patients with IBD. Particularly important are the nutrients zinc, magnesium, folic acid, and vitamin A. Nutritional supplements are used as appropriate to correct deficiencies, normalize the inflammatory process, and promote healing of the damaged mucosa. Botanical medicines are used to promote healing and normalize the intestinal flora.

Specific Health Problems Clinical score in chronic inflammatory bowel disease Measure

Score

Clinical assessment

General Activity Normal school attendance <3 bowel movements per day 5 Lacks endurance 3-5 bowel movements per day Misses <4 weeks schooVyear Physical Examination and Complications 10 Normal Abdomen 5 Mass 1 Distension, tenderness 10

Proctoscope

10 5 1

Normal, no fissures Friability, one fissure Ulcers, bleeding, fistulas, multiple fissures

Arthritis

5 3 1

Nil One joinvarthralgia Multiple joints

Skin/stomatitis/eyes

5 3

Normal Mild stomatitis Erythema nodosum, pyoderma, severe stomatitis, uveitis

4

Diet All allergens, wheat, corn, and dairy products, and carrageenan-containing foods should be eliminated. The diet should be high in complex carbohydrates and fiber, and low in sugar and refined carbohydrates.

Supplements 0

Multivitamin and mineral supplement Magnesium: 200 mg/day

1.Robbins SL, Cotran RS,K m a r V. Pathologic basis of disease. Philadelphia, PA WB sunders, 1984:836841,859-862. 2. Petersdorf R.Harrison’s principles of internal medicine. New York McGraw-Hill. 1983:1738-1752. 3. Calkins BM, Lilieneld A M ,Garland CF, et al. Trends in incidence rates of ulcerative colitis and Crohn’s disease. Dig Dis Sci 1984; 29913-920. 4. Maybeny JF. Some aspects on the epidemiology of ulcerative colitis. Gut 1985;26:968-974. 5. Deutsch SF, Wedzina W. Aerornonas sobria-associated left-sided segmental colitis. Am J Gastroenterol1997;92:2104-2106. 6.Farraye FA, Peppercorn MA, Ciano PS, Kavesh WN. Segmental colitis associated with Aeronioiias hydrophila. Am J Gastroenterol 1989;84:436438. 7. WiUoughby JM, Rahman AF, Gregory MM. Chronic colitis after Aeromonas infection. Gut 1989;30:686-690.

Measure Nutrition Height

X-rays

Score 10 5 1

>2 inches/year
15 10 5

Normal Ileitis Total colon or ileocecal involvement Toxic megacolon or obstruction

1

Laboratory Hematocrit (%)

Erythrocyte sedimentation rate (mm/hr) White blood cell count (celldpl)

5 3 1

90

5

Normal

3 1

20-40 >40

5 3

1 Albumin (g/dl)

Clinical assessment

10 5

1

25-35 4 5

Normal

<20,000 >20,000 Normal 3.0 s/dl 4 . 5 g/dl

Zinc picolinate: 50 mg/day Vitamin A: 50,000 IU/day Vitamin E: 400 to 800 IU/day mixed tocopherols with a 4 0 % concentration of gamma-tocopherol Fish oil: 3 g/day of combined EPA and DHA

Botanical Medicines Quercetin: 400 mg 20 minutes before meals Bastyr formula: 2 to 3 ”00” capsules with each meal

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Specific Health Problems 65. Main AN, Hall MJ, Russell RI, et al. Clinical experience of zinc supplementation during intravenous nutrition in Crohn’s disease: value of serum and urine zinc measurements. Gut 1982;23984-991. 66. Boosalis MG, Evans GW, McClain CJ. Impaired handling of oral zinc in pancreatic insufficiency. Am J Clin Nutr 1983;37: 268-271. 67. LaSala MA, Lifshitz F, Silverberg, et al. Magnesium metabolism studies in children with chronic inflammatory disease of the bowel. J Ped Gastroenterol N u b 1985;475-81. 68. Nyhlin H, Dyckner T, Ek B, Wester PO. Magnesium in Crohn’s disease. Acta Med Scand Suppl1982;661:21-25. 69. Ward CG. Jnfluence of iron on infection.Am J Surg 1986;151:291-295. 70.Lehr L, Schober 0, Hundeshagen H, Pichlmayr R. Total body potassium depletion and the need for preoperative nutritional support in Cmhn’s disease. Ann S q 1982;196:709-714. 71. Skogh M, Sunquist T, Taggeson C. Vitamin A in Crohn‘s disease. Lancet 1980;1:766. 72.Dvorak AM. Vitamin A in Crohn’s disease. Lancet 1980;1:1303-1304. 73. Wright JP, Mee AS, Parfitt A, et al. Vitamin A therapy in patients with Crohn’s disease. Gastroenterology 1985;88:512-514. 74.Norrby S, Sjodahl R, Taggeson C. Ineffectiveness of vitamin A therapy in severe Crohn’s disease. Acta Chir Scand 1985;151: 465468.

75. Hames AD, Brown R, Heatley RV, et al. Vitamin D status in Crohn’s disease. Association with nutrition and disease activity. Gut 1985; 261197-1203. 76.Howard L, Ovesen L, Satya-Murti S, Chu R. Reversible neurological symptoms caused by vitamin E deficiency in a patient with short bowel syndrome. Am J Clin Nutr 1982;36:1243-1249. 77. Scheppach W. Treatment of distal ulcerative colitis with short-chain fatty acid enemas. A placebo-controlled trial. German-Austrian SCFA Study Group Dig Dis Sci 1996;41:2254-2259. 78.Krasinski SD, Russell RM, Furie BC, et al. The prevalence of vitamin K deficiency in chronic gastrointestinal disorders. Am J Clin Nutr 1985;41:639-643. 79. Vitamin K deficiency in chronic gastrointestinal disorders. Nutr Review 1986;44:10-12. 80. Schoon EJ, Muller MC, Vermeer C, et al. Low serum and bone vitamin K status in patients with longstanding Crohn’s disease: another pathogenetic factor of osteoporosis in Crohn’s disease? Gut. 2001;48473-477. 81. Elsborg L, Larsen L. Folate deficiency in chronic inflammatory bowel diseases. Scand J Gastroenterol 1979;14:1019-1024. 82.Hellberg R, Hulten L, Bjom-Rasmussen E. The nutritional and haematological status before and after primary and subsequent resectional procedures for classical Crohn‘s disease and Crohn’s colitis. Acta Chir Scand 1982;148:453-460. 83. Franklin JL, Rosenberg IH. Impaired folic acid absorption in inflammatory bowel disease: effects of salicylazosulfapyridine (Azulfidine). Gastroenterology 1973;64:517-525. 84.Carruthers LB. Chronic diarrhea treated with folic acid. Lancet 1946;1:849-850. 85.Filipsson S, Hulten L, Lindstedt G. Malabsorption of fat and vitamin 812 before and after intestinal resection for Crohn’s disease. Scand J Gastroenterol1978;13529-536. 86.Hughes RG, Williams N. Leukocyte ascorbic acid in Crohn’s disease. Digestion 1978;17272-274. 87.Gerson CD, Fabry EM. Ascorbic acid deficiency and fistula formation in regional enteritis. Gastroenterology 1974;67428-433.

88. Lih-Brody L, Powell SR, Collier KP, et al. Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease. Dig Dis Sci 1996;41:2078-2086. 89. Middleton E. The flavonoids. Trends Pharmaceut Sci 1984; 5:335-338. 90. Havsteen B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharmacol1983;321141-1148. 91. Nishino H, Naitoh E, Iwashima A, Umezawa K. Quercetin interacts with calmodulin, a calcium regulatory protein. Experientia 1984; 403184-185. 92. Middleton E, Drzewieki G. Flavonoid inhibition of human basophil histamine release stimulated by various agents. Biochem Pharmacol 1984;33:3333-3338. 93. Middleton E, Drzewieki G. Naturally occurring flavonoids and human basophil histamine release. Int Arch Allergy Appl Imm~n011985;77:155-157. 94. Amella M, Bronner C, Briancon F, et al. Inhibition of mast cell histamine release by flavonoids and bioflavonoids. Planta Med 1985;l:16-20. 95. Pearce FL, Befus AD, Bienenstock J. Mucosal mast cells. III. Effect of quercetin and other flavonoids on antigen-induced histamine secretion from rat intestinal mast cells. J Allergy Clin Immunol 1984;73:819-823. 96. Busse WW, Kopp DE, Middleton E. Flavonoid modulation of human neutrophil function. J Allergy Clin Immunol1984;73801-809. 97. Yoshimoto T, Furukawa M, Yamamoto S, et al. Flavonoids: potent inhibitors of arachidonate 5-lipoxygenase. Biochem Biophys Res Common 1983;116612-618. 98. Ford-Hutchinson AW. Leukotrienes: their formation and role as inflammatory mediators. Fed Proc 1985;44:25-29. 99. Ford-Hutchinson AW. Leukotriene involvement in pathological processes. J Allergy Clin Immunol1984;74437-440. 100. Steinhart AH, Brzezinski A, Baker JP. Treatment of refiactory ulcerative proctosigmoiditis with butyrate enemas. Am J Gastroenterol 1994;89:179-183. 101. Plein K, Hotz J. Therapeutic effects of Saccharomyces boulardii on mild residual symptoms in a stable phase of Crohn’s disease with special respect to chronic diarrhea-a pilot study. Z Gastroenterol. 1993;31:129-134. 102. Guslandi M, Mezzi G, Sorghi M, Testoni PA. Saccharornyces boulardii in maintenance treatment of Crohn’s disease. Dig Dis Sci 2000;45:1462-1464. 103. Guandalini S. Use of Lactobacillus-GG in paediatric Crohn‘s disease. Dig Liver Dis 2002;34(Suppl2):S63-S65. 104. Gupta P, Andrew H, Kirschner BS, Guandalini S. Is lactobacillusGG helpful in children with Crohn’s disease? Results of a preliminary, open-label study. J Pediatr Gastroenterol Nutr 200031:453457. 105. Malin M, Suomalainen H, Saxelin M, Isolauri E. Promotion of IgA immune response in patients with Crohn’s disease by oral bacteriotherapy with Lactobacillus GG. Ann Nutr Metab 1996;40: 137-145. 106. Tibble JA, Bjamason I. Non-invasive investigation of inflammatory bowel disease. World J Gastroenterol2001;7460-465. 107. Best WR, Becktel JM, Singleton JW, Kern F. Development of a Crohn’s disease activity index. Gastroenterology 1976;70 439-444. 108.Lloyd-Still J, Green OC. A clinical scoring system for chronic inflammatory bowel disease in children. Dig Dis Sci 1979;24 620-624.

Insomnia Michael T. Murray, ND Joseph E.Pizzorno Jr, ND CHAPTER C O N T E N T S Diagnostic Summary

Therapeutic Approach 1834 Lifestyle 1834 Supplements 1834 Botanical Medicines 1834

1829

General Considerations 1829 Normal Sleep Patterns 1830 The Importance of Adequate Sleep

1831

Therapeutic Considerations 1831 Lifestyle 1831 Serotonin Precursor and Cofactor Therapy 1831 Botanicals with Sedative Properties 1833

DIAGNOSTIC SUMMARY Difficulty falling asleep (sleep-onset insomnia) Frequent or early awakening (sleep-maintenance insomnia) Affects one of every four people in the United States

GENERAL CONSIDERATIONS Insomnia represents one of the most common complaints seen by physicians and is a symptom that can have many causes. Table 182-1 summarizes some of the more common of these. Insomnia is an extremely common complaint. Within the course of a year, up to 30%of the population suffers from insomnia, and roughly 10% of the adult population has chronic insomnia.' Many use over-the-counter (OTC) medications to combat the problem, and others seek stronger sedatives. Approximately 12.5% of the adult population uses a prescribed anxiolytic or sedative hypnotic in the course of a year; about 2%of the population takes one on any given day. More than half of these drugs, especially benzodiazepines, are prescribed by primary care physicians. Nearly 100 million prescriptions are written each year for these drugs? A thorough history and physical examination are indicated in the patient presenting with insomnia. Psychological factors account for 50% of all insomnias evaluated in sleep laboratories.' Insomnia is closely associated with affective disorders (see Chapter 144). Cognitive behavioral therapy is often indicated and can

produce effective improvements in sleep q ~ a l i t yA .~ detailed recreational, prescription, and nonprescription drug use history along with a dietary and beverage history is also required to determine whether the patient is consuming any stimulants or other agents known to interfere with sleep. The following agents may be responsible: Thyroid preparations Oral contraceptives Beta-blockers Marijuana Alcohol Coffee Tea Chocolate Among serious diseases to be considered in the differential diagnosis are narcolepsy and sleep apnea syndromes. Sleep apnea is the most common example of sleep-disordered breathing. First described in 1965, sleep apnea is a breathing disorder characterized by brief interruptions of breathing during sleep. These breathing pauses are almost always accompanied by snoring between apnea episodes, although not everyone who snores has this condition. Sleep apnea can also be characterized by choking sensations. The frequent interruptions of deep, restorative sleep often lead to excessive daytime sleepiness and may be associated with an early morning headache. Approximately 18 million Americans are thought to suffer from sleep apnea. 1829

Causes of insomnia Sleep-onset insomnia

Sleep-maintenance insomnia

Anxiety or tension

Depression

Environmental change

Environmental change

Emotional arousal

Sleep apnea

Fear of insomnia

Nocturnal rnyoclonus

Phobia of sleep Disruptive environment

Hypoglycemia Parasomnias

Pain or discomfort

Pain or discomfort

Caffeine

Drugs

Alcohol

Alcohol

The boundary between the categories is not entirely distinct

Early recognition and treatment of sleep apnea is important because it is associated with marked daytime fatigue, irregular heartbeat, high blood pressure, heart attack, and stroke as well as a loss of memory function and other intellectual capabilities. The patient usually does not know he or she has a problem and may not believe it when told. It is important that people see a doctor if they snore heavily or if their sleep partners have noticed periods of interrupted breathing during sleep. Sleep apnea should also be considered in anyone with sigruficant daytime drowsiness or changes in intellectual function. Sleep apnea can be properly diagnosed only through the services of a sleep disorder specialist and usually in a sleep laboratory. Sleep apnea is most often caused by narrowing of the airway by an excess accumulation of fatty tissueobstructive sleep apnea. With a narrowed airway, the person continues efforts to breathe, but air cannot easily flow into or out of the nose or mouth. This narrowing results in heavy snoring, periods of no breathing, and frequent arousals (causing abrupt changes from deep sleep to light sleep).Ingestion of alcohol and sleeping pills increases the frequency and duration of breathing pauses in people with sleep apnea. In some cases sleep apnea occurs even if no airway obstruction or snoring is present. This form of sleep apnea, central sleep apnea, is caused by a loss of perfect control over breathing by the brain. In both obstructive and central sleep apneas, obesity is the major risk factor, and weight loss is the most important aspect of long-term management. People with sleep apnea experience periods of anoxia (oxygen deprivation of the brain) with each apneic episode, which ends in arousal and a re-initiation of breathing. Seldom does the sufferer awaken enough to be aware of the problem. However, the combination of frequent periods of oxygen deprivation (20 to several hundreds of times per night) and the greatly disturbed sleep can greatly diminish the quality of life and lead to serious problems4

The most common treatment of sleep apnea is the use of nasal continuous positive airway pressure (CPAP). In this procedure, the patient wears a mask over the nose during sleep, and pressure from an air blower forces air through the nasal passages. The air pressure is adjusted so that it is just enough to prevent the throat from collapsing during sleep. The pressure is constant and continuous. Nasal CPAP prevents airway closure while in use, but apnea episodes return when CPAP is stopped or is used improperly. Surgery to reduce soft tissue in the throat or soft palate should only be used as a last resort because it often does not work or can make the problem worse. Laser-assisted uvulopalatoplasty is a highly promoted surgical option. In this procedure lasers are used to surgically remove excessive soft tissue from the back of the throat and from the palate. This procedure works well initially in about 90% of sleep apnea sufferers, but within 1year many people are the same as or even worse than before because of the scar tissue that invariably forms.4

Normal Sleep Patterns Human sleep is perhaps one of the least understood physiologic processes. Its value to human health and proper functioning is without question. Sleep is absolutely essential to both the body and the mind. Impaired sleep, altered sleep patterns, and sleep deprivation impair mental and physical function. Normal adult sleep-wake patterns repeat themselves on an approximately 24-hour cycle, of which sleep constitutes one third. Exactly how much sleep is required varies from one person to the next. Sleep tends to decrease with age, but whether this tendency is a normal or abnormal progression is unknown. A 1-year-old baby requires about 14 hours of sleep a day, a 5-year-old about 12 hours, and adults about 7 to 9 hours. Women tend to require more sleep than men. The elderly tend to sleep less at night but doze more during the day than younger adults. From observation of eye movement and electroencephalographic (EEG) recordings, sleep is divided into two distinct types of sleep, REM (rapid eye movement) sleep and non-REM sleep. During REM sleep the eyes move rapidly and dreaming takes place. When people are awakened during non-REM sleep, they report that they were thinking about everyday matters but rarely report dreams. Non-REM sleep is divided into stages 1 through 4 according to level of EEG activity and ease of arousal. As sleep progresses there is a deepening of sleep and slower brain wave activity until REM sleep, when suddenly the brain becomes much more active. In adults, the first REM sleep cycle is usually triggered 90 minutes after going to sleep and lasts about 5 to 10 minutes. After the flurry of activity, brain wave

Insomnia

patterns return to those of non-REM sleep for another 90-minute sleep cycle. Each night most adults experience five or more sleep cycles. REM sleep periods grow progressively longer as sleep continues; the last sleep cycle may produce a REM sleep period that can last about an hour. Non-REM sleep lasts approximately 50% of this 90-minute sleep cycle in infants and about 80% in adults. As people age, in addition to less REM sleep, they tend to awaken at the transition from non-REM to REM sleep.

The Importance of Adequate Sleep Adequate sleep is absolutely necessary for long-term health and regeneration. Many different physiologic processes occur during sleep, but perhaps the most important are the increased secretion of growth hormone and the scavenging of free radicals in the brain. Many of the benefits of sleep are probably mediated through growth hormone (GH). A s an anabolic hormone, GH has been called by some the “antiaging” hormone. Several research projects are now studying its rejuvenating effects when it is injected. The reason for the excitement is that GH stimulates tissue regeneration, liver regeneration, muscle building, breakdown of fat stores, normalization of blood sugar regulation, and a whole host of other beneficial processes in the body. In other words, it helps convert fat to muscle. Small amounts of GH are secreted at various time during the day, but essentially all GH secretion occurs during sleep. Sleep functions as an antioxidant for the brain because free radicals are removed during this time. Sleep is required to ensure minimal neuronal damage from free radicals accumulated during waking. Most people can tolerate a few days without sleep and fully recover. However, chronic sleep deprivation appears to accelerate aging of the brain, causes neuronal damage, and leads to nighttime elevations in cortisol.5

THERAPEUTIC CONSIDERATIONS Because insomnia is largely due to psychological and physiologic factors, the clinician should consider and handle these factors before simply inducing sleep pharmacologically. Counseling and/or stress reduction techniques (including biofeedback and hypnosis) may be indicated in many cases. The following topics are discussed here as they relate to promoting sleep: Exercise Progressive relaxation Nocturnal glucose levels Serotonin precursor and cofactor therapy 5-Hydroxytryptophan (5-HTP) Cofactors for serotonin synthesis Melatonin

Restless legs syndrome and nocturnal myoclonus Botanicals with sedative properties

Lifestyle Exercise Regular physical exercise is known to improve general well-being as well as to promote improvement in sleep q ~ a l i t yExercise .~ should be performed in the morning or early evening, not before bedtime, and should be of moderate intensity. Usually 20 minutes of aerobic exercise at a heart rate between 60% and 75% of maximum (approximately 220 - the patient’s age in years) is sufficient.

Progressive Relaxation Numerous techniquescan promote relaxation and prepare the body and mind for sleep. One of the most popular and easy-to-use techniques is progressive relaxation. The technique is based on a very simple procedure of comparing tension with relaxation. Many people are not aware of the sensation of relaxation. In progressive relaxation an individual is taught what it feels like to relax by comparing relaxation with muscle tension. Each muscle is first made to contract forcefully for a period of 1 to 2 seconds and then to give way to a feeling of relaxation. Because the procedure goes progressively through all the muscles of the body, a deep state of relaxation eventually results. The procedure begins with contraction of the muscles of the face and neck, with the contraction held for at least 1or 2 seconds, and then relaxation of the muscles. Next the upper arms and chest are contracted and then relaxed, followed by the lower arms and hands. The process is repeated progressively down the bodyabdomen, buttocks, thighs, calves, and feet. This whole practice is repeated two or three times, or until sleep is produced.

Nocturnal Glucose Levels Low nocturnal blood glucose levels are an important cause of sleep-maintenance insomnia. The brain is highly dependent on glucose as an energy substrate, and a drop in blood glucose level promotes awakening via the release of glucose regulatory hormones, i.e., epinephrine, glucagon, cortisol, and growth hormone. Hypoglycemia must be ruled out in maintenance-type insomnia (see Chapter 178).

Serotonin Precursor and Cofactor Therapy Serotonin is an important initiator of sleep. The synthesis of central nervous system (CNS) serotonin depends on availability of tryptophan (discussed in more detail in Chapter 101). L-Tryptophan has shown modest effects in the treatment of insomnia.”8It is certainly not a panacea; however, excellent results have been reported even in severe cases. Although not every patient has shown response to L-tryptophan in the clinical trials, those who

Specific Health Problems ~~

do have experienced dramatic relief. It is generally more effective in sleep-onset insomnia and less effective in sleep-maintenance insomnia. The key advantage of L-tryptophan over OTC and prescriptions pills is that, unlike these agents, L-tryptophan does not produce any sigruficant distortions of normal sleep processes whether it is given one time, for a prolonged period, or upon withdrawal. Dosages smaller than 2000 mg are generally ineffective. Current knowledge on the sleep-inducing effects of L-tryptophan are consistent with that finding that its effectiveness is somewhat limited to sleep-onset insomnia! The sleep-promotingeffect is often thought to be the result of enhanced serotonin synthesis, but there is evidence to suggest that other mechanisms may also be responsible or contributory, including L-tryptophan+nhanced melatonin synthesis. Administration of L-tryptophan c a w s a massive elevation of plasma melatonin concentration? Although L-tryptophan reduces sleep latency, it exerts effects in normal subjects that are at odds with the serotonin system, such as reducing E M sleep and increasing non-REM Drugs that prevent the conversion of tryptophan to serotonin enhance these effects. From this information, it is concluded that some of L-tryptophan’s effects on sleep do not involve the serotonin or melatonin system. As discussed in Chapter 101, the effects of L-tryptophan can be negated by the conversion via the kynurenjne pathway. This conversion can be partially inhibited by niacin (30 mg is an appropriate dosage),thereby enhancing the effects of L-tryptophan. It appears that the insomnia-relieving and sleeppromoting actions of L-tryptophan are cumulative, in that it often takes a few nights for L-tryptophan to start working, as shown by the results from one of the double-blind studies. In the study, the effects of 3 g L-tryptophan on sleep performance, arousal threshold, and brain electrical activity during sleep were assessed in 20 males with chronic sleep-onset insomnia.’2After a sleep laboratory screening night, all subjects received placebo for 3 consecutive nights; then 10 subjects received L-tryptophan and 10 placebo for 6 nights. All subjects received placebo on 2 withdrawal nights. L-Tryptophan had no effect on sleep latency during the first 3 nights of administration. However, on nights 4 through 6 of administration, sleep latency was significantly reduced. Consistent with other studies, this study found that unlike sleeping pills (benzodiazepines especially), L-tryptophan did not alter sleep stages, impair performance, or alter brain electrical activity during sleep. What can be learned from this study is that L-tryptophan should be used for a minimum of 1week to gauge effectiveness in chronic insomnia. L-Tryptophan does have good sleep-promoting effects with a single administration, because giving it to subjects who regularly experience insomnia when they are sleeping in a “strange place” is often very effective.

~

Administration of high-dose L-tryptophan (4 g) during the day can promote sleep. This research information indicates that consumption of foods high in tryptophan during the day may contribute to daytime sleepiness. Conversely, an evening meal high in tryptophan in relationship to competing amino acids may promote sleep.

5Hydroxytryptophan 5-HTP is one step closer to serotonin than L-tryptophan and does not depend on a transport system for entry into the brain. Several clinical studies have shown 5-HTP to produce dramatically better results than L-tryptophan in promoting and maintaining One of the key benefits of 5-HTP is its ability to increase REM sleep (typically by about 25%) while increasing deep sleep stages 3 and 4 without lengthening total sleep time.lOJ1The sleep stages that are reduced to compensate for the increases are non-REM stages 1 and 2-the least important stages. The dosage recommendation to take advantage of the sleep-promoting effects of 5-HTP is 100 to 300 mg 30 to 45 minutes before retiring. Have the patient start with the lower dose for at least 3 days before increasing it.

Cofactors for Serotonin Synthesis The important cofactors vitamin B6, niacin, and magnesium should be administered along with the tryptophan to ensure its conversion to serotonin. Also, because other amino acids compete with tryptophan for transport into the CNS across the blood-brain barrier and insulin increases tryptophan uptake by the CNS, protein consumption should be avoided near administration and a carbohydrate source such as fruit or fruit juice should accompany tryptophan administration. Niacin has been reported to have a sedative effect, probably owing to its peripheral dilating action and shunting of tryptophan metabolism toward serotonin synthesis.

Melatonin One of the best natural aids for sleep is melatonin. Supplementation with melatonin has been shown in several studies to be very effective in helping induce and maintain sleep in both children and adults and in both people with normal sleep patterns and those with insomnia. However, the sleep-promoting effects of melatonin are most apparent only if melatonin levels are low.l7 In other words, using melatonin is not like taking a sleeping pill or even 5-HTP. It has a sedative effect only when melatonin levels are low. When melatonin is taken just before going to bed in normal subjects or in patients with insomnia who have normal melatonin levels, it produces no sedative effect. This is because just before going to bed, people normally have a rise in melatonin

Insomnia

secretion. Melatonin supplementation is effective as a sedative only when the pineal gland's own production of melatonin is very low. Melatonin appears to be most effective in treating insomnia in the elderly, in whom low melatonin levels are quite common.'8 In one of the most interesting studies, 26 elderly insomniacs with lower than normal melatonin levels were given 1 to 2 mg of melatonin 2 hours before the desired bedtime for 1 week. Rapid- and slow-release melatonin preparations were used. Both sleep latency and sleep quality were evaluated. Although there was no discernible difference in sleep onset and sleep efficiency (time asleep as a percentage of total time in bed) between the two forms, the slow-release form yielded better effects on sleep maintenance.19 A dose of 3 mg at bedtime is more than enough, because doses as low as 0.1 and 0.3 mg have been shown to produce a sedative effect when melatonin levels are low.2oAlthough melatonin appears to have no serious side effects at recommended doses, melatonin supplementation could conceivably disrupt the normal circadian rhythm. In one study, a dosage of 8 mg/day for only 4 days resulted in significant alterations in hormone secretions.2l

Restless Legs Syndrome and Nocturnal Myoclonus Restless legs syndrome and nocturnal myoclonus are significant causes of insomnia. The restless legs syndrome is characterized during waking by an irresistible urge to move the legs. Almost all patients with restless legs syndrome have nocturnal myoclonus.' Nocturnal myoclonus is a neuromuscular disorder characterized by repeated contractions of one or more muscle groups, typically of the leg, during sleep. Each jerk usually lasts less than 10 seconds. The patient is normally unaware of the myoclonus and complains only of either frequent nocturnal awakenings or excessive daytime sleepiness, but questioning the sleep partner often discovers the myoclonus. If there is a family history of restless legs syndrome (present in about one third of all cases of the syndrome), high-dose folic acid, 35 to 60 mg daily, can be helpfuLZ Doses in this range require a prescription, because the U.S. Food and Drug Administration (FDA) limits the amount available per capsule to 800 pg. Patients with familial restless legs syndrome appear to have a higher need for folic acid. Restless legs syndrome is also a common finding in patients with malabsorption syndromes.Z If there is no family history, serum ferritin levels should be measured to determine iron stores. The association between low iron levels and the restless legs syndrome was documented in clinical studies more than 30 years ago. A later study reproduced these

observations, finding serum ferritin levels to be lower in the 18 patients with the restless legs syndrome than in 18 control subjects.23Serum iron, vitamin BIZ, folic acid, and hemoglobin levels did not differ in the two groups. A rating scale with a maximum score of 10 was used to assess the severity of symptoms of the restless legs syndrome. Serum ferritin levels were inversely correlated with the severity of symptoms. Fifteen of the patients with the syndrome were treated with iron (ferrous sulfate) at a dosage of 200 mg three times daily for 2 months. The severity of restless legs syndrome improved by an average of 4 points in 16 patients with an initial ferritin level lower than 18 pg/L, by 3 points in 4 patients with ferritin levels between 18 and 45 pg/L, and by 1point in 5 patients with ferritin levels between 45 and 100 pg/L. The conclusion of the study is an important contribution to the understanding of the development of restless legs syndrome in elderly patients, and iron supplements can produce a significant reduction in symptoms. In addition to the restless legs syndrome, low serum ferritin levels have been found in psychiatric patients experiencing a condition called akathisia, coming from the Greek word meaning "cannot sit down." Akathisia is a drug-induced state of agitation. The drugs that most commonly produce akathisia are antidepressant drugs, such as fluoxetine (Paxil, Prozac) and sertraline (Zoloft). The level of iron depletion correlates with the severity of akathisia. Anyone suffering from drug-induced akathisia should ask his or her physician to perform a serum ferritin assessment. If serum ferritin levels are below 35 pg/L, the physician should recommend that the patient take 30 mg of iron bound to either succinate or fumarate twice daily between meals. If this recommendation causes abdominal discomfort, the patient should try 30 mg with meals three times daily. For nocturnal myoclonus as well as muscle cramps occurring at night, magnesium (250 mg at bedtime) and/or vitamin E (400 to 800 IU/day) may be helpful. For the patient older 50 years, Ginkgo biloba extract (80 mg three times daily) may also be used.

Botanicals with Sedative Properties Numerous plants have sedative action. Plants commonly prescribed as aids in promoting sleep are as follows:

8

Valeriana officinalis Passiflora incarnata Humulus lupulus Scutellaria lateriflora Matricaria charnornilla

Valeriana officinalis Of the herbs listed, the one with the most clinical research is V. oficinalis (see Chapter 136). More than

Specific Health Problems 20 double-blind clinical studies have now substantiated valerim’s ability to improve sleep quality and relieve ins0mnia.~~3 Additional research is warranted, but these studies show that extracts of valerian root improve sleep quality and sleep latency (the time required to go to sleep). The studies, which were usually performed under strict laboratory conditions, demonstrated quite clearly that valerian is as effective in reducing sleep latency as small doses of barbiturates or benzodiazepines. However, although these latter compounds also increase morning sleepiness, valerian usually reduces morning sleepiness.

Pussifloru incurnatu (Passion Flower) Passion flower was widely used by the Aztecs as a diaphoretic, sedative, and analgesic. Its constituents include harmol, harman, harmine, harmalol, harmaline, and passicol. Harmine was originally known as telepathine because of its peculiar ability to induce a contemplative state and mild euphoria. It was used by the Germans in World War I1 as ”truth serum.” Harma alkaloids are monoamine oxidase inhibitors, so their use with tryptophan or 5-HTP would have an additive effect. In addition, the flavonoid constituents contribute greatly to the pharmacology of passion flower by exhibiting a variety of anxiolytic effects.26

THERAPEUTIC APPROACH The treatment should be as conservative as possible and should include some means of dealing with the psychological factors contributing to the insomnia. Metabolically, the foremost component of treatment is the elimination of any factors known to disrupt normal sleep patterns, such as the following: Stimulants (e.g., coffee, tea, chocolate, coffee-flavored ice cream) Alcohol Hypoglycemia Stimulant-containing herbs (e.g., ephedra, guarana) Marijuana and other recreational drugs Numerous OTC medications Prescription drugs

1. Roth T, Roehrs T. Insomnia: epidemiology, characteristics, and consequences.Clin cornerstone 2003;55-15. 2.Vermeemn A. Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs 2004;18297-328. 3. Montgomery P, Dennis J. A systematicreview of non-pharmacological therapies for sleep problems in later life. Sleep Med Rev 2004;8: 47-62. 4. Victor LD. Treatment of obstructive sleep apnea in primary care. Am Fam Physician 2004;69:561-568.

If this approach produces no response, more aggressive measures can be taken. Once a normal sleep pattern has been established, the recommended supplements and botanicals should be slowly decreased. If the patient suffers from restless leg syndrome, 5 to 10 mg/day of folic acid should be added to the therapy. Nocturnal myoclonus can be aided with 400 IU/day of natural vitamin E.

Lifestyle The patient should institute a regular exercise program that elevates heart rate to 60% to 75% of maximum for at least 20 minutes a day.

Supplements The following supplements should be taken 45 minutes before bedtime: Niacin: 100 mg (decrease dose if uncomfortable flushing interferes with sleep induction) Vitamin B6: 50 mg Magnesium: 250 mg Tryptophan, 3 to 5 g, or 5-Hm, 100 to 300 mg Melatonin: 3 mg

Botanical Medicines The following botanical medicines should also be taken 45 minutes before bedtime.

V: oficinalis: Dried root (or as tea): 2 to 3 g Ticture (1:5):4 to 6 ml(1 to 1‘/2 tsp) Fluid extract (1:l):1to 2 ml (‘/z to 1tsp) Dry powdered extract (0.8% valerenic acid): 150 to 300 mg

P. incarnata: Dried herb (or as tea): 4 to 8 g Ticture (1:5): 6 to 8 r n l ( 1 ’ / 2 to 2 tsp) Fluid extract (1:l):2 to 4 ml (‘/z to 1 tsp) Dry powdered extract (2.6% flavonoids): 300 to 450 mg

5. Leproult R, Copinschi G, Buxton 0, et al. Sleep loss results in an elevation of cortisol levels the next evening. Sleep 1997;20865-870. 6. Hartmann E. L-Tryptophan: a rational hypnotic with clinical potential. Am J Psychiatry 1977;134:366-370. 7. George CF, Millar TW, Hanly PJ.The effect of L-tryptophan on daytime sleep latency in normals. Correlation with blood levels. Sleep 1989;12:345-353. 8. Thorleifsdottir B, Bjornsson JK, Kjeld M. Effects of L-tryptophan on daytime arousal. Neuropsychobiology 1989;21:170-176.

Insomnia 9.Hajak G, Huether G, Blanke J. The influence of intravenous L-tryptophan on plasma melatonin and sleep in men. Pharmacopsychiatry 1991;24:17-20. 10.Zarcone VP Jr, Hoddes E. Effects of 5-hydroxytryptophan on fragmentation of REM sleep in alcoholics. Am J Psychiatry 1975; 1327476. 11. Soulairac A, Lambinet H. [Effect of 5-hydroxytryptophan, a serotonin precursor, on sleep disorders]. Ann Med Psycho1 (Pans) 1977;1:792-798. 12.Hartmann E, Elion R. The insomnia of 'sleeping in a strange place': effects of L-tryptophane. Psychopharmacology 1977;53: 131-3. 13. Wyatt RJ. The serotonin-catecholamine-dream bicycle. A clinical study. Biol Psychiatry 1972;5:33-64. 14. Guilleminault C, Cathala HP,Castaigne P. Effects of 5 - H " on sleep of a patient with brain stem lesion. Electroencephalogr Clin Neurophysiol1973;34177-184. 15. Wyatt RJ, Zarcone V, Engelman K. Effects of 5-hydroxytryptophan on the sleep of normal human subjects. Electroencephalogr Clin Neurophysiol 1971;30505-509. 16. Autret A, Minz M, Bussel B, et al. Human sleep and 5-HTP. Effects of repeated high doses and of association with benserazide. Electroencephalogr Clin Neurophysiol 1976;41: 408-413.

17. Nave R, Peled R, Lavie P. Melatonin improves evening napping. Eur J Pharmacol 1995;275:213-216. 18. Olde Rikkert MG, Rigaud AS. Melatonin in elderly patients with insomnia. A systematic review. Z Gerontol Geriatr 2001;34: 491-497. 19. Haimov I, Lavie P, Laudon M, et al. Melatonin replacement therapy of elderly insomniacs. Sleep 1995;18:598-603. 20. Dollins AB, Zhdanova IV,Wurtman RJ, et al. Effect of inducing noctumal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci U S A 1994;91:1824-1828. 21. Mallo C, Zaidan R, Faure A, et al. Effects of a four-day nocturnal melatonin treatment on the 24 h plasma melatonin, cortisol and prolactin profiles in humans. Acta Endocrinol (Copenh) 1988;119:474-480. 22.Botez MI, Cadotte M, Beaulieu R, et al. Neurologic disorders responsive to folic acid therapy. Can Med Assoc J 1976;115:217-223. 23.O'Keeffe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age Ageing 1994;23:200-203. 24. Hadley S, Petry JJ. Valerian. Am Fam Physician 2003;671755-1758. 25. Stevinson C, Emst E. Valerian for insomnia: a systematic review of randomized clinical trials. Sleep Med 2000;1:91-99. 26. Dhawan K, Kumar S, Sharma A. Anti-anxiety studies on extracts of Pussifloru incurnatu Linneaus. J Ethnopharmacol2001;78:165-170.

Irritable Bowel Syndrome Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER C O N T E N T S Diagnostic Summary 1837 General Considerations 1837 Therapeutic Considerations 1838 Diet 1838 Nutritional Supplements 1839 Botanical Medicines 1839 Miscellaneous Considerations 1840

DIAGNOSTIC SUMMARY Irritable bowel syndrome (IBS)is a functional disorder of the large intestine with no evidence of accompanying structural defect that is characterized by some combination of: Abdominal pain Altered bowel function, constipation, or diarrhea Hypersecretion of colonic mucus Dyspeptic symptoms (flatulence, nausea, anorexia) Varying degrees of anxiety or depression Less acceptable synonyms are nervous indigestion, spastic colitis, mucous colitis, and intestinal neurosis. The splenic flexure syndrome is a variant of the irritable bowel syndrome in which gas in the bowel leads to pain in the lower chest or the left shoulder. Many patients with IBS also have extraintestinal symptoms, including sexual dysfunction, fibromyalgia, dyspareunia, urinary frequency and urgency, poor sleep, menstrual difficulties, lower back pain, headaches, chronic fatigue, and insomnia. These conditions tend to increase in number with the severity of IBS. The more extraintestinal symptoms a patient presents with, the more likely the patient is to have a severe case of IBS.'

GENERAL CONSIDERATIONS IBS is the most common gastrointestinal disorder seen in general practice, representing 30% to 50% of all referrals to gastroenterologists.z~3Determining incidence or

Therapeutic Approach 1840 Diet 1840 Supplements 1841 Botanical Medicine 1841 Physical Therapy 1841 Counseling 1841

prevalence figures is virtually impossible, as many sufferers never seek medical attention. It has been estimated, however, that approximately 15%of the population has complaints of IBS, with women predominating in a ratio of 2:l (it is likely that an equal number of men have IBS but that they do not report symptoms as often). The etiology of the greater colonic motility seen in IBS has been attributed to physiologic, psychological, and dietary factors. Although IBS is often a diagnosis of exclusion, clinical judgment must be used to determine the extent of the diagnostic process required. A detailed history and physical examination have been shown to eliminate much of the vagueness involved in diagnosing IBS.4 Distension, relief of pain with bowel movements, and the onset of loose or more frequent bowel movements with pain seem to correlate best with the diagnosis of IBS (any three p = 0.84; just one p = 0.25): In most cases, a comprehensive stool and digestive analysis (see Chapter 14), complete blood count, and measurements of erythrocyte sedimentation rate, thyroid-stimulating hormone level, and serum protein concentration should be performed to establish the diagnosis. If diarrhea-predominant IBS symptoms are more pervasive, an antiendomysial antibody test should be considered in the initial evaluation to rule out celiac disease (see Chapter 156). If no discemible cause can be identified, screening for occult fecal blood and flexible sigmoidoscopy are indicated in patients younger than 50 years and colonoscopy in older patients. Conditions that may mimic IBS are listed in BOX183-1.

1837

Gastrogenic dietary factors such as excessive tea, coffee, carbonated beverages, and simple sugars Infectious enteritis such as amebiasis and giardiasis Inflammatory bowel disease Lactose intolerance Laxative abuse (an easy test to eliminate this possibility is to add a few drops of sodium hydroxide solution to a stool specimen; since most laxatives contain phenolphthalein, the stool will turn red) Intestinal candidiasis Disturbed bacterial microflora as a result of antibiotic or antacid usage Malabsorption diseases such as pancreatic insufficiency and celiac disease Metabolic disorders such as adrenal insufficiency, diabetes mellitus, and hyperthyroidism Mechanical causes such as fecal impaction Diverticular disease Neoplasm

THERAPEUTIC CONSIDERATIONS Once other conditions have been ruled out, there appear to be three major treatments to consider in the formulation of a therapeutic regimen for IBS: Increasing dietary fiber Eliminating allergic/intolerant foods Controlling psychological components

Diet Dietary Fiber The treatment of irritable bowel syndrome through an increase in dietary fiber has a long, though irregular, history.*Patients with constipation are much more likely to show response to dietary fiber than those with diarrhea. One problem that has not been addressed in studies on the therapeutic use of dietary fiber is the role of food allergy. The type of fiber often used in both research and clinical practice is wheat bran.5 Wheat and other grains are among the most commonly implicated foods in malabsorptive and allergic conditions and food allergy is a significant etiologic factor in IBS, so the use of wheat bran is usually contraindicated. hcreasing dietary fiber from fruit and vegetable sources rather than cereal sources may offer more benefit to some individuals, although in one uncontrolled clinical study there was no significant difference in improvement when a diet composed of 30 g of fruit and vegetable fiber and 10 g of cereal fiber was compared with a diet consisting of the opposite ratio.6 Although the two diets resulted in similar significant improvement in abdominal pain, bowel habits, and state of well-being,

the presence of large quantities of potentially allergic cereal fiber in both diets would probably have obscured any differences. One type of fiber that may be useful and that is without the allergenic component of a wheat-based fiber is partially hydrolyzed guar gum (PHGG). The guar plant, Cyumopsis tetragonolobus, has been grown in India and Pakistan since ancient times. PHGG is a natural, water-soluble dietary fiber derived from the p a r plant.’ One study of 134 patients found that consumption of 5 g/day of PHGG decreased the frequency of IBS symptoms such as abdominal spasms, flatulence, and abdominal tension.* The researchers concluded that PHGG works well in cases of altered intestinal motility and is easy to use because of its nongelling properties, unlike unhydrolyzed gum, which is much higher in viscosity and more difficult to incorporate into the diet. Put simply, for most cases of irritable bowel syndrome, nonwheat sources of fiber, such as vegetables and fruits, may be the best choice to help reduce symptoms associated with IBS. For some cases of IBS, especially those with a strong diarrhea component, cooked vegetables in small quantities at first may be most helpful. Because each case is unique, clinical judgment and close patient monitoring are needed. In some cases, fiber may aggravate diarrhea and is therefore contraindicated. For a more detailed explanation of dietary fiber, see Chapter 60.

Food Allergy The importance of food allergies in the etiology of IBS has been recognized since the early 1 9 0 0 ~ . ~Later J~ studies have further documented the association between food allergy and the irritable The type of food allergy most significant in IBS is believed to be nonimmunologic, so food intolerance rather than food allergy may be a more appropriate diagnosis (see Chapter 53 for definitions and further discussion). According to double-blind challenge methodologies, the majority of patients with IBS (approximately two thirds) have at least one food intolerance, and some have multiple intolerances.” Foods rich in carbohydrates, as well as fatty food, coffee, alcohol, and hot spices, are most frequently reported to cause symptoms.’ The most common allergens are dairy products (40% to 44%) and grains (40% to 60%).13 Because in most cases the reaction appears to be related to prostaglandin synthesis or immunoglobulin G (1gG)-mediated rather than IgE-mediated reactions, skin tests and the IgEradioallergosorbent test (RAST) are poor indicators of food intolerance in these patients. The enzyme-linked immunosorbent assay allergen challenge test (ELISA ACT) or ELSA IgE/IgG, may be a better indicator (see Chapter 19), although many sensitivities may

Irritable Bowel Syndrome

still be undetectable by currently available laboratory proced~res.’~ Many patients have noted marked clinical improvement with the use of elimination diet^.'^-'^,'^ It is interesting to note that many patients with IBS have associated symptoms suggestive of vasomotor instability (such as palpitation, hyperventilation, fatigue, excessive sweating, and headaches), which are consistent with food allergy/intolerance reactions.

Sugar Meals high in refined sugar can contribute to IBS as well as small intestinal bacterial overgrowth by decreasing intestinal motility.” When blood glucose levels rise too rapidly, gastrointestinal tract peristalsis slows down. Because glucose is absorbed primarily in the duodenum and jejunum, the message affects this portion of the gastrointestinal tract the strongest. The result is that the duodenum and jejunum become atonic. A diet high in refined sugar may be the most important reason that IBS is such a common condition in the United States.

Nutritional Supplements Lactobacillus Although probably significant, the role of altered microbial flora in IBS has not been well investigated. Some of the beneficial effects attributed to increasing dietary fiber may be mediated by alterations in colon bacteria concentrations. One study in which 20 patients were given either Lactobacillus or placebo for 4 weeks demonstrated an improvement with regards to all IBS symptoms in 95% of patients in the Lactobacillus group, compared with only 15% of patients in the placebo group. There was also a trend towards normalization of stool frequency in constipated patients in 6 of 10 patients in the Lactobacillus group compared with 2 of the 11 treated with placebo.I8Lactobacillus acidophilus supplementation appears to be indicated in IBS (see Chapter 118).

L-Tryptophan The amino acid L-tryptophan or its metabolic derivative, 5-hydroxytryptophan (5-HTP), has been considered for IBS owing to the relationship with serotonin, a neurotransmitter that is produced in both the digestive tract and the brain.19 Because comorbidity of psychiatric conditions such as depression and anxiety is highly correlated with IBS, modulation of the serotonin pathway with the use of L-tryptophan or 5-HlT seems logical and should be further evaluated.

Botanical Medicines Enteric-Coated Volatile Oils Peppermint oil, and presumably similar volatile oils, inhibits gastrointestinal smooth muscle action in both laboratory animal preparations and humans. Clinically,

peppermint oil has been used to reduce colonic spasm during endoscopy,20and an enteric-coated peppermint oil (ECPO) capsule has been used in the treatment of IBS.21Enteric coating is believed to be necessary because menthol (the major constituent of peppermint oil) and other plant monoterpenes in peppermint oil are rapidly absorbed.22 This rapid absorption tends to limit its effects to the upper intestine, resulting in relaxation of the cardioesophageal sphincter and common side effects, such as esophageal reflux and heartburn, after administration. A transient hot burning sensation in the rectum during defecation, due to unabsorbed menthol, has been noted in some patients taking the ECPO. Most of the studies have used ECPO at a dosage of 0.2 ml twice daily between meals.22A meta-analysis of five studies supported the efficacy of peppermint oil in IBS.= A well-designed study of ECPO involved 110 patients with symptoms of IBS?4 The patients took one capsule of either ECPO (0.2 ml) or a placebo three to four times daily, 15 to 30 minutes before meals, for 1 month. The effects on the major symptoms of IBS are listed in Table 183-1. These results are quite impressive, especially given the safety of ECPO. Only two cases of side effects were reported; one patient experienced heartburn (because of chewing the tablet), and one patient had a transient rash. ECPO is thought to work by improving the rhythmic contractions of the intestinal tract and relieving intestinal spasm. An additional benefit of these volatile oils is their efficacy against Candida albicans.25This benefit is of use in IBS,in which an overgrowth of C. albicans may be an underlying factor, especially in patients who do not respond to dietary advice and those who consume large amounts of sugar. Administration of nystatin (600,000 IU/day for 10 days) to patients whose IBS did not respond to an elimination diet produced dramatic clinical improvement.*2Furthermore, in one randomized, double-blind, controlled trial of 42 children with moderate levels of pain from IBS, peppermint oil was considered safe and effective treatment.26

Herbal Formulas Although no research has been done to document its efficacy, an old naturopathic remedy, Robert’s formula, Iffects on the major symptoms of irritable bowel syndrome Parameter

ECPO (%)

Placebo (%) ~

Abdominal pain

79

43

Abdominal distension

83

29

Stool frequency

83

Borborygmi

73

Flatulence

79

33 31 22.5

Specific Health Problems

has a long history of use in this condition (see Chapter 181 for a full description). The Tibetan herbal formula Padma Lax has also shown efficacy for patients with constipation-predominant IBS in one %month, doubleblind, randomized pilot study. A small number of patients did have loose stools with this formula, but this effect was easily remedied by lowering the dosage.27

Asian Medicines Positive results in symptoms have also been reported from small studies using both Chinese herbal medicines and acupuncture, as well as some Ayurvedic herbal preparations.' In one 16-week, randomized, doubleblind, placebo-controlled trial, a total of 116 patients with IBS were randomly assigned to receive Chinese individualized herbal formulations, standard formulations, or placebo. Compared with patients in the placebo group, patients in the active treatment groups had sigrulicant improvement in bowel symptom scores and marked global improvement as rated by patients and gastroenterologists. Patients given individualized herbal formulations also showed a decrease in recurrence Given the safety profile and detail for individualized treatment, these Asian medicines seem to be reasonable choices for patients who are interested in reducing their symptoms without pharmacologic intervention.

Miscellaneous Considerations Psychological Factors

subjects and people suffering from IBS.32This finding apparently accounts for the greater abdominal pain and irregular bowel functions seen in patients with IBS and normal subjects during periods of emotional stress. Distressed patients with IBS are also known to have decreased immune function, as evidenced by lower percentages of activated T cells and natural killer ~ells.3~ This finding suggests that patients with long-term IBS have lowered immune function, which may leave them susceptible to a host of other illnesses. Some researchers believe that IBS sufferers have difficulty adapting to life events, although this belief has not been well demonstrated in clinical studies. Psychotherapy, in the form of relaxation therapy,34bi~feedback;~hypn0sis,3~ counseling,36or stress management has been shown to reduce symptom frequency and severity and to enhance the results of standard medical treatment of IBS. Hypnosis, which the patient may practice at home using simple audio compact disc recording has been shown to reduce both fasting colonic motility39 and rectal sensitivity? In contrast to psychotherapeutic modalities, the use of anxiolytic drugs, a combination of tranquilizers and antispasmodics, or antidepressants, has not yielded effective results.

Physical Medicine An increase in physical exercise also appears helpful for patients with IBS. Many find that daily leisurely walks markedly reduce symptoms, probably owing to the known stress-reducing effects of exercise. A specific massage therapy known as foot reflexology was evaluated in a small study of 34 individuals; no benefit for the use of foot reflexology in IBS was found.4l

Mental/emotional problems-anxiety, fatigue, hostile feelings, depression, and sleep disturbances-are reported by almost all patients with IBS.29Severity and frequency of symptoms tend to correlate with these psychological factors. Anxiety predicts a high degree of food-related symptoms in IBS.' Especially significant THERAPEUTIC APPROACH is sleep quality; poor sleep quality results in a rise in Because it is a multifactorial disease, the approach to the symptom severity.w patient with IBS requires the consideration and integraSeveral theories link psychological factors to the tion of the following factors: symptoms of IBS. The "learning model" holds that when exposed to stressful situations, some children learn to Dietary fiber develop gastrointestinal symptoms to cope with the Determination and elimination of food allergies/ stress. Another theory holds that IBS is a manifestation intolerances of depression, chronic anxiety, or both. Personality assessStress reduction ments of IBS sufferers have shown them to have higher Exercise anxiety levels and a greater feeling of d e p r e ~ s i o n . ~ ~ As necessary, peppermint oil and Robert formula However, these studies were based on postmorbid permay be used to temporarily ameliorate symptoms. sonality assessments, and it has since been determined Also, because the diagnosis is typically made by with premorbid personality assessment that IBS sufferexclusion, a careful diagnostic evaluation is always ers have normal personality profiles. Therefore, many of indicated. the psychological symptoms may be either secondary to the bowel disturbances (particularly malabsorption) Diet or the result of a common etiologic factor (e.g., stress, Increase fiber-rich foods (see Chapter 60) and eliminate food allergy, or candidiasis). foods that are allergenic, contain refined sugar, or are Greater colonic motility during exposure to stressful highly processed. situations has been shown to occur in both normal

Supplement

Counseling

Lactobacillus acidophilus: 1to 2 billion live organisms/day

The clinician should help the patient develop an effective stress reduction program. Biofeedback may be particularly useful for patients with IBS.

Botanical Medicine Enteric-coated volatile oil preparations (e.g., peppermint oil): 0.2 to 0.4 ml twice daily between meals

Physical Therapy Take leisurely 20-minute walks daily.

1. Simren M, Mansson A, Langkilde AM, et al. Food-related gastrointestinal symptoms in the irritable bowel syndrome. Digestion 2001;63:108-115. 2.Spiro H. Clinical gastroenterology, ed 3. New York: Macmillan, 1983713-735. 3. Longstreth GF. Irritable bowel syndrome: a multibillion-dollar problem. Gastroenterology 1995;109:2029-2031. 4. Fielding JF. Detailed history and examination assist positive clinical diagnosis of the irritable bowel syndrome. J Clin Gastroenterol 1983;5:495-497. 5. Cann PA, Read NW, Holdsworth CD. What is the benefit of coarse wheat bran in patients with irritable bowel syndrome? Gut 1984;25:168-173. 6. Fielding JF, Kehoe M. Different dietary fibre formulations and the irritable bowel syndrome. Ir J Med Sci 1984;153178-180. 7. Slavin JL, Greenberg NA. Partially hydrolyzed guar gum: clinical nutrition uses. Nutrition 2003;19:549-552. 8. Giaccari S, Grasso G, Tronci S, et al. [Partially hydrolyzed guar gum: a fiber as coadjuvant in the irritable colon syndrome.] Clin Ter 2001;15221-25. 9. Hollander E. Mucous colitis due to food allergy. Am J Med Sci 1927;174:495-500. 10. Gay L. Mucous colitis, complicated by colonic polyposis, relieved by allergic management. Am J Dig Dis 1937;3:326-329. 11. Jones VA, McLaughlan P, Shorthouse M, et al. Food intolerance. A major factor in the pathogenesis of irritable bowel syndrome. Lancet 1982;2:1115-1117. 12. Petitpierre M, Gumowski P, Girard JP. Irritable bowel syndrome and hypersensitivity to food. Ann Allergy 1985;54538-540. 13. Nanda R, James R, Smith H, et al. Food intolerance and the irritable bowel syndrome. Gut 1989;30:1099-1104. 14. Gertner D, Powell-Tuck J. Irritable bowel syndrome and food intolerance. Practitioner 1994;238:499-504. 15. Zwetchkenbaum J, Burakoff R. The irritable bowel syndrome and food hypersensitivity. Ann Allergy 1988;61:47-49. 16. Drisko JA, Bischoff 8, Hall MA, et al. Treating irritable bowel syndrome with a food elimination diet followed by food challenge and probiotics. Am J Gastroentero12003;98:S276. From an abstract submitted for the 68th Annual Scientific Meeting of the American College of Gastroenterology. 17. Russo A, Fraser R, Horowitz M. The effect of acute hyperglycemia on small intestinal motility in normal subjects. Diabetologia 1996;39:984-989. 18. Niedzielin K, Kordecki H, Birkenfeld 8.A controlled, double-blind, randomized study on the efficacy of Lactobacillus pluntururn 299V in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol2001;131143-1147. 19. Agazzi A, De Ponti F, De Giorgio R, et al. Review of the implications of dietary tryptophan intake in patients with irritable bowel syndrome and psychiatric disorders. Dig Liver Dis 2003;35590-595.

20. Leicester RJ, Hunt RH. Peppermint oil to reduce colonic spasm during endoscopy. Lancet 1982;2989. 21. SomenrilleKW, Richmond CR, Bell GD. Delayed release peppermht oil capsules (Colpermin) for the spastic colon syndrome. A pharmacokinetic study. Br J Clin Pharmacol1984;18638-640. 22. Rees WD, Evans BK, Rhodes J. Treating irritable bowel syndrome with peppermint oil. Br Med J 1979;2835-836. 23. Pittler MH, Ernst E. Peppermint oil for irritable bowel syndrome: a critical review and metaanalysis. Am J Gastroenterol 1998;93: 1131-1135. 24. Liu JH, Chen GH, Yeh HZ, et al. Enteric-coated peppermint oil capsules in the treatment of irritable bowel syndrome: a prospective, randomized trial. J Gastroente 25. StilesJC, Sparks W, Ronzio RA oregano. J Appl Nutr 1995;4796-102. 26. Kline RM, Kline JJ, Di Palma J, et al. Enteric-coated, pH-dependent peppermint oil capsules for the treatment of irritable bowel syndrome in children. J Pediatr 2001;138:125-128. 27.Sallon S, Ben-Arye E, Davidson R, et al. A novel treatment for constipation-predominant irritable bowel syndrome using Padma Lax, a Tibetan herbal formula. Digestion 2002;65:161-171. 28. Bensoussan A, Talley NJ,Hing M, et al. Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized controlled trial. JAh4A 1998;280:1585-1589. 29. Svedlund J, Sjodin I, Dotevall G, et al. Upper gastrointestinal and mental symptoms in the irritable bowel syndrome. Scand J Gastroenterol1985;20595-601. 30.Goldsmith G, Levin JS. Effect of sleep quality on symptoms of irritable bowel syndrome. Dig Dis Sci 1993;38:1809-1814. 31. Ryan WA, Kelly MG, Fielding JF. The normal personality profile of irritable bowel syndrome patients. Ir J Med Sci 1984;153:127-129. 32. Narducci F, Snape WJ Jr, Battle WM, et al. Increased colonic motility during exposure to a stressful situation. Dig Dis Sci 1985; 30:40-44. 33. Motzer SA, Jarrett M, Heitkemper MM, et al. Natural killer cell function and psychological distress in women with and without irritable bowel syndrome. Biol Res Nurs 2002;431-42. 34. Blanchard EB, Greene B, Scharff L, et al. Relaxation training as a treatment for irritable bowel syndrome. Biofeedback Self Regul 1993;18:125-132. 35. Goldsmith G, Patterson M. Irritable bowel syndrome. Treatment update. Am Fam Physician 1985;31:191-195. 36. Schwarz SP, Taylor AE, Scharff L, et al. Behaviorally treated irritable bowel syndrome patients: a four-year follow-up. Behav Res Ther 1990;28331-335. 37. Shaw G, Srivastava ED, Sadlier M, et al. Stress management for irritable bowel syndrome. A controlled trial. Digestion 1991;50:36-42. 38. Palsson OS, Whitehead WE, Turner MJ. Hypnosis home treatment for irritable bowel syndrome (IBS): exploratory study. Am J Gastroenterol2003;98:5274.

39. Whorwell PJ, Houghton LA,Taylor EE, et al. Physiological effects of emotion: assessment via hypnosis. Lancet 1992;340:69-72. 40. Prior A, Colgan SM, Whorwell PJ.Changes in rectal sensitivity after hypnotherapy in patients with irritable bowel syndrome. Gut 1990;31:896-898.

41. Tovey P. A single-blind trial of reflexology for irritable bowel syndrome. Br J Gen Pract 2002;5219-23.

Kidney Stones Michael T. Murray, ND Peter B. Bongiomo, ND, Dip1 Ac CHAPTER C O N T E N T S Diagnostic Summary

1843

General Considerations 1843 Diagnostic Considerations 1844 Stone Formation 1844 Therapeutic Considerations 1844 Stone Composition 1844 Gut Flora 1847 Nutrients 1847

DIAGNOSTIC SUMMARY Usually asymptomatic Diagnosed adventitiously or from acute symptoms of urinary tract obstruction Excruciating intermittent radiating pain originating in the flank or kidney Nausea, vomiting, abdominal distension Chills, fever, and urinary frequency if infection present

GENERAL CONSIDERATIONS Stone formation in the urinary tract has been recognized for thousands of years, but during the last few decades the pattern and incidence of the disease have changed markedly. In the past, stone formation was almost exclusively in the bladder, but today most stones form in the upper urinary tract. More than 10% of all men experience a renal stone during their lifetimes, with an annual incidence of 0.1% to 6% of the general population. Once a kidney stone does occur, there is a 50% chance of recurrence within 5 to 7 years if there is no treatment.' In the United States, 1 of every 1000 hospital admissions is for kidney stones. The incidence has been steadily growing, paralleling the rise in other diseases associated with the so-called western diet-ischemic heart disease, cholelithiasis, hypertension, and diabetes.

Botanicals 1848 Lifestyle 1848 Miscellaneous 1849

Therapeutic Approach 1849 Acute Obstruction 1849 Calcium Stones 1849 Uric Acid Stones 1850 Magnesium Ammonium Phosphate Stones Cystine Stones 1850 Bushite and Struvite Stones 1850

1850

In the western hemisphere, kidney stones are usually composed of calcium salts (7% to 85%),uric acid (5% to 8%), or struvite (10% to 15%). Molecular research is beginning to link certain mutations in genes responsible for handling renal chloride, which can lead to hypercalciuria. Other identified genetic changes are being linked to excess urinary excretions of oxalate, cystine, and uric acid.2 The incidence of renal stones varies geographically, reflecting differences in environmental factors, diet, and components of drinking water. Males are affected more than females, and most patients are older than 30 years. Human urine is supersaturated with respect to calcium oxalate, uric acid, and phosphates. These substances normally remain in solution because of pH control and the secretion of inhibitors of crystal growth. The following that primary and secondary metabolic diseases cause kidney stones must be ruled out early in the clinical process: Hyperparathyroidism Cystinuria Vitamin D excess Milk-alkali syndrome Destructive bone disease Primary oxaluria Cushing syndrome Sarcoidosis

1843

Specific Health Problems

DIAGNOSTIC CONSIDERATIONS Stone Formation Conditions favoring stone formation can be divided into two groups: factors increasing the concentration of stone crystalloids; and factors favoring stone formation at normal urinary concentrations. The first group includes reduction in urine volume (dehydration) and an increased rate of excretion of stone constituents. The second group of factors is related to urinary stasis, pH changes, foreign bodies, and reduction of normal substances which solubilize stone constituents. See Tables 184-1 and 184-2 for an outline of the diagnostic possibilities.

THERAPEUTIC CONSIDERATIONS Stone Composition

of the stone, if one is not available for chemical analysis: Diet Underlying metabolic or disease factors Serum and urinary calcium, uric acid, creatinine, and electrolyte levels Urinalysis Urine culture Table 184-3 summarizes the findings in the major types of kidney stones.

Dietary Factors Calcium-containing stones are composed of calcium oxalate, calcium oxalate mixed with calcium phosphate, or, very rarely, calcium phosphate alone. The high incidence of calcium-containing stones in affluent societies is directly associated with the following dietary patterns:

Diagnosing the type of kidney stone is critical to identifymg the appropriate therapy. Careful evaluation of the following criteria usually determines the composition

Low amounts of fibeI3 Intake of highly refined carbohydrates42

Causes of excessive excretion of relatively insoluble urinary constituents Constituent

Cause of excess excretion

Calcium

(>250 mg/day excreted) Absorptive hypercalciuria Renal hypercalciuria(renal tubular acidosis) Primary hyperparathyroidism Hyperthyroidism High vitamin D intake Excess intake of milk and alkali Aluminum salt intake

Laboratory findings Low serum PO, 30%-40% of all stone formers High serum parathyroid hormone High urinary cyclic AMP High serum calcium High 1,25(OH)2D3 High serum calcium Low serum phosphate High 1,25(OH)J13

Destructive bone disease Sarcoidosis Prolonged immobility Oxalate

Familial oxaluria Ileal disease, resection, or bypass Steatorrhea High oxalate intake Ethylene glycol poisoning Vitamin C excess (extremely unlikely)

Rare

Vitamin B6 deficiency or abnormal oxalate metabolism

Methoxyflurane anesthesia Uric acid

(>750mg/day excreted) Gout Idiopathic hyperuricosuria Excess purine intake Anticancer drugs Myeloproliferative disease

Cystine

Hereditarycystinuria

Rapid cell destruction

High alcohol consumption6 Large amounts of animal protein6<’ High intake of fats High intake of calcium-containing food High intake of vitamin D-enriched food The classification of most stones as either due to “idiopathic” hypercalciuria or just ”idiopathic” reflects an ignorance of the dietary factors that induce hyperuricemia, hypercalciuria, and stone formation. The cumulative effect of these dietary factors is undoubtedly the reason for the rising incidence of kidney stones. As a group, vegetarians have a lower risk of stone de~elopment.~,~ Studies have shown that even among meat eaters, those who ate higher amounts of fresh fruits

Physical changes in the urine and kidney Condition

Possible cause

Increased concentration

Dehydration Stasis Obstruction Foreign body concretions

Urinary pH

Low-uric acid, cystine High-calcium oxalate and PO4

Infection

Proteus-struvite

Uricosuria

Crystals of uric acid initiate precipitation of calcium oxalate from solution

Nuclei for stone formation

Cells, bacteria, blood clots, etc., initiate precipitation Sponge kidney

Deformities of kidney

Horseshoe kidney Caliceal obstruction or defect

and vegetables had a lower incidence of stones.1° Bran supplementation, as well as the simple change from white to whole wheat bread, has resulted in lower urinary calcium levels? Dietary factors may also play a role in acidifying or alkalinizing urine. Depending on the type of stone, this ability to alter urinary pH may help treat and prevent stones. In one study, 12 healthy men were given a standardized diet plus cranberry, black currant, or plum juice. These subjects then provided 24-hour urine collections for evaluation. The researchers found that cranberry juice decreased the urinary pH and significantly increased the excretion of oxalic acid and the relative supersaturation for uric acid. Black currant juice increased urinary pH, excretion of citric acid, and loss of oxalic acid. Plum juice effected no change.” The researchers concluded that black currant juice could support the treatment and prevention of uric acid stones through its alkalizing effect. Conversely, because cranberry juice acidifies urine, it could be useful in the treatment of brushite and struvite stones as well as for urinary tract infections.

Low Oxalate Diet A low oxalate diet is a common prescription for recurrent calcium oxalate kidney stones. The ultimate goal is to reduce the level of oxalic acid being excreted in the diet. It appears that people with recurrent kidney stones have a tendency to absorb higher levels of dietary oxalates compared with normal subjects not prone to kidney stones who absorb only 3% to 8% of dietary oxalate. A low oxalate diet is usually defined as less than 50 mg oxalate per day, so foods in the high and moderate oxalate category will have to be curtailed. Box 184-1is designed to provide an estimation of the oxalate content of food as it is so highly variable. The level of oxalate

Chemical and physical characteristicsof urinary stones Composition

Crystal name

Calcium oxalate

Whewellite

Calcium oxalate + calcium phosphate

Frequency

X-ray appearance

Urine characteristics

Crystal characteristics

30-35

Opaque

Nonspecific

Small, hempseed or mulberry-shaped, brown or black

30-35

Opaque

pH>5.5

Small, hempseed or mulberry-shaped, brown or black

(“w

Calcium phosphate

Apatite

6-8

Opaque

pH>5.5

Staghorn configuration, light in color

Magnesium ammonium phosphate

Struvite

15-20

Opaque

pHS.2

Staghorn configuration, light in color

Triple phosphate

Infection

Uric acid

6-10

Translucent

pH<6.0

Ellipsoid, tan or red-brown

Cystine

2-3

Opaque

pH<7.2

Multiple, faceted, maple syrup color

Specific Health Problems

Vegetables High Oxalate > 10 mg per Serving Beets-reens or root* Celery Collards Dandelion greens Eggplant Escarole Green beans Kale Leeks Okrat Parsley Parsnips Peppers, green Potatoes Pumpkin Spinach' Squash, yellow summer Sweet potatoes Swiss chard' Tomato sauce, canned Turnip greens Watercress Moderate Oxalate 4 0 mg per Serving Asparagus Artichokes Broccoli Brussels sprouts Carrots Cucumber Garlic Lettuce Mushrooms Mustard greens Onions Peppers, green Potato chips Potato salad (1/4 cup) Pumpkin Radishes Snow peas Tomato, fresh* Tomato sauce, canned (1/4 cup)

Low Oxalate 2-5 rng per Serving Acorn squash Arugula Ketchup (1 tbsp) Onions Pepper, red Zucchini squash Fruits High Oxalate > 10 rng per Serving Concord grapes Figs, dried+ Kiwi Lemon peel

Lime peel Orange peel Rhubarb' Moderate Oxalate e 10 mg per Serving Apples Apricots Berries (1/4 cup) Blackberries Blueberries Cherries, red sour Cranberries, dried Currants, black Oranges Peaches Pears Pineapple Plums Prunes, Italian Red raspberries Tangerines

Low Oxalate 2-5 mg per Serving Apples, peeled Avocado Cantaloupe Cherries, bing Cranberries Grapes Lemon juice (1 cup) Lemons Lime juice (1 cup) Raisins Grains High Oxalate >I0 mg per Serving Bread, whole wheat Buckwheat* Oatmeal Popcorn Spelt Stone ground flour Wheat bran Wheat germ Whole wheat flour Moderate Oxalate el0 mg per Serving Bagel (1 medium) Barley, cooked Bread, white (2 slices) Corn Corn tortilla (1 moderate) Cornbread Cornmeal, yellow (1 cup dry) Cornstarch ( V 4 cup) Pasta Rice, brown Spaghetti Wheat, white flour

Low Oxalate 2-5 rng per Serving Rice, white

Rice, wild Rye bread Legumes High Oxalate >10 rng per Serving Garbanzo beans Lentils Soy and all soy products Moderate Oxalate 4 0 mg per Serving Lima beans Split peas

Low Oxalate 2-5 mg per Serving Peas, green Nuts and Seeds High Oxalate >10 rng per Serving Almondst Brazil nuts Hazelnuts Peanuts+ Peanut butter$ Pecans Sesame seeds* Sunflower seeds Moderate Oxalate e l 0 rng per Serving Cashews Flaxseed Walnuts

Low Oxalate 2-5 mg per Serving Coconut Herbs High Oxalate >10 rng per Serving None Moderate Oalate c10 mg per Serving Cinnamon, ground (1l/z tsp) Ginger, powdered (1 tbsp) Pepper, black (1 tsp per day) Thyme, dried (1 tsp)

Low Oxalate 2-5 mg per Serving Basil, fresh (1 tbsp) Dill (1 tbsp) Ginger, raw, sliced (1 tsp) Malt, powder (1 tbsp) Mustard, Dijon (Vz cup) Nutmeg (1 tbsp) Pepper (1 tsp) Miscellaneous High Oxalate > 10 rng per Serving Beer Chocolate Cocoa Soy sauce (1 tbsp)

Kidney Stones

High Oxalate > 10 mg per Serving-cont'd

Tea, rosehip ire 2-3 mg per

Sardines

Ham serving

Lamb

Fish, haddock, plaice, and flounder

'Greater than 200 mg per serving. 'Greater than 100 mg per serving. *Greater than 50 mg per serving.

in a particular food in published reports can vary twofold to fifteen fold. Differences in climate, soil quality, state of ripeness, or even which part of the plant is analyzed will also affect the value.

Weight and Carbohydrate Metabolism Weight control and correction of carbohydrate metabolism are important, because excess weight and insulin insensitivity lead to hypercalciuria and are high-risk factors for stone formation.l2J3After glucose ingestion, there is a rise in urinary calcium rises and phosphate reabsorption decreases. This leads to a low plasma phosphate concentration, which stimulates production of 1,25-dihydroxycholecalciferol and results in increased intestinal absorption of calcium and, concurrently, hypercalciuria. The ingestion of sucrose and other simple sugars causes an exaggerated rise in the urinary calcium oxalate content in approximately 70% of people with recurrent kidney stones.14

Gut Flora Studies are beginning to find a correlation between the proper balance of intestinal flora and lower risk of oxalate kidney stones. Oxalate homeostasis depends in part, on the intestinal anaerobe bacterium, Oxulobucter formigenes. It now appears that 0.forrrzigenes contributes to oxalic acid homeostasis and that its absence may predispose individuals to idiopathic calcium oxalate kidney stone disease.I5 This bacterium is found primarily in the colon, and its loss through prolonged widespread use of antibiotics is associated with an increased risk of hyperoxaluria and calcium-oxalate stone formation.16 Studies in animals and human volunteers have indicated that, when administered therapeutically, 0.formigenes can repopulate the gut and reduce the urinary oxalate concentration after an oxalate load, hence reducing the incidence of calcium oxalate kidney stone f0rmati0n.l~Although more research is needed, it seems possible that supplementing deficient individuals with

0. formigenes may confer a protection against future kidney stone disease.

Nutrients

Magnesium and Vitamin B6 A magnesium-deficient diet accelerates deposition of calcium in renal tubules in rats." Magnesium has been shown to increase the solubility of calcium oxalate and inhibit the precipitation of both calcium phosphate and A low urinary magnesium/calcium calcium ~xalate.'~-'~ ratio is an independent risk factor for stone formation,2O and supplemental magnesium alone has been shown to be effective in preventing recurrences of kidney stones.1g20 However, when magnesium is used in conjunction with vitamin B6 an even greater effect is noted.21,22 Pyridoxine is known to reduce the endogenous production and 'uinaryexcretion of oxalates,B25and patients with recurrent oxalate stones have abnormal activation levels of erythrocyte glutamate pyruvate transaminase (EGPT), erythrocyte glutamic-oxaloacetic transaminase (EGOT),urinary glutamic-pyruvic acid transaminase (UGPT), and urinary glutamic-oxaloacetic transaminase (UGOT), indicating clinical insufficiency of vitamin B6 and impaired glutamic acid synthesis. These levels return to normal after 3 months of treatment.25Induced pyridoxine deficiency in rats has been shown to produce oxaluria and calcium oxalate lithiasis (which is prevented by magnesium supplementati~n).~~

Glutamic Acid Depressed levels of glutamic acid (from vitamin B6 deficiency or for other reasons) are significant in the formation of kidney stones, because a higher concentration of glutamic acid in the urine induces precipitation of calcium oxalate. Glutamic acid supplementation in rats significantly reduces the incidence of calculi, and it may do Supplementation with glutamic so in humans as acid may, however, be superfluous if adequate vitamin B6 levels are attained.

Specific Health Problems

Calcium

However, rather than potassium or sodium citrate, magnesium citrate appears to offer the greatest benefit. Although most doctors still tell their patients with kidney stone to avoid calcium supplements, this advice Vitamin K is outdated. A strong body of evidence has emerged The urinary glycoprotein that is a powerful inhibitor refuting the general trend to restrict calcium supplemenof calcium oxalate monohydrate growth requires posttation in patients with kidney stone. transcription carboxylation of glutamic acid to form One study has even shown that calcium supplemengamma-carboxyglutamic acid. Vitamin K is an essential tation reduces oxalate excretion.27This study measured factor for this carboxylationto occur.3QImpairment of gluthe urinary oxalate excretion after calcium supplementatamic acid formation or a vitamin K deficiency reduces tion and the administration of oxalic acid. Calcium was the formation of this glycoprotein. The presence of vitagiven in the form of calcium carbonate or calcium citrate min K in leafy green vegetables may be one reason that malate at a dosage of 300 mg elemental magnesium. vegetarians have a lower incidence of kidney st0nes.3~ Compared with baseline assessment, calcium supplementation sigruhcantly reduced oxalate absorption and Uric Acid Metabolism excretion. The level of dietary purine consumption is linearly Another study evaluated calcium intake and the dietary related to the rate of urinary uric acid excretion%; this profile in 37 outpatients with kidney stones and 45 conrelationship is important, because hyperuricosuria is a trol subjects. Dietary calcium, assessed from 4-day causative factor in recurrent calcium oxalate stones. dietary records, was significantly lower for patients High levels of supplemental folic acid promote purine with urinary calculiB A third study further supporting scavenging and xanthine oxidase inhibition, resulting in the benefits of calcium intake is a 5-year randomized trial comparing the effect of two diets in 120 men with decreased excretion of uric acid (see Chapter 171). recurrent calcium oxalate stones and hyper~alciuria.2~ Botanicals Upon completion, the men consuming the normal calcium diet experienced a 51% reduction in the risk of Anthraquinones isolated from the Rubia, Cassia, and Aloe stone recurrence. During follow-up, urinary calcium species bind calcium and significantlyreduce the growth levels dropped significantly in both groups, but urinary rate of urinary crystals when used in oral doses lower oxalate was reduced in the normal calcium intake group than the laxative Rubia tinctura, Rumex, Rheum, and increased in the low calcium intake group. Finally, Polygonum aviculare, Aloe,39 Senna, Rhamnus alnus, and Mitchella repens are sources of these anthraquinones and one large prospective epidemiologic investigation also reported that kidney stones were more likely to manifest may be used to prevent stone formation and, during in individuals with the lowest daily calcium intakes acute attacks, to reduce the size of the stone. (516 mg) than in those with the highest daily calcium The furanocoumarin-containing herb Ammi visnaga has been shown to be unusually effective in relaxing the intakes (1326 mg).30 ureter and allowing the stone to pass.40This action is due These studies clearly demonstrate that calcium supto its calcium channel-blocking capabilities, which act plementation (300 to 1000 mg daily) may prove to be primarily on the ureters. Atropine and papaverine have an effective preventive measure against calcium oxalate similar, but less active, smooth muscle-relaxing effects. kidney stones. Peucedanum, Leptotania, Ruta graveolens, and Hydrangea Citrate contain similar furanocoumarins that also promote smooth muscle relaxation, and all of these herbs have Low urinary citrate excretion is known as a risk for historical uses in the treatment of kidney stones. nephr~lithiasis.~~ Although urinary calcium rises in patients consuming calcium citrate, some of citrate’s Lifestyle effects inhibit the formation of kidney stones. Specifically, Sleep Position citrate has the ability to reduce urinary saturation of calcium oxalate and calcium phosphate and to retard the Even though the etiology of recurrent unilateral kidney nucleation and crystal growth of calcium salts. The stones is unclear, patients with recurrent renal calculi use of potassium or sodium citrate in the treatment of most often present with calculi on the same side. Data from the literature support the notion that sleep recurrent calcium oxalate has been shown to be quite posture may contribute to alterations of renal hemodyeffective in clinical studies, ending stone formation in namics. Researchers studied 110 patients who suffered nearly 90%of the subje~ts.3~3~ For example, in one study, 31 mmol/day of potassium citrate provided to recurrent from kidney stones confined to one side of their bodies. stone formers who were also hypocitraturic resulted in Of these patients, 93 consistently favored sleeping with a drop of stone formation from 0.7 to 0.13 per year.33 one side in a dependent position. Further study showed

Kidney Stones that the side of the stone was identical to the dependent sleep side in 76%,with positive predictive values of rightside-down and left-side-down sleep postures for ipsilatera1 stone formation at 82% and 70%, re~pectively.~~

Stress

each 100-mmol (2300-mg) increase in dietary sodium. Patients with renal calcium stones and hypercalcemia demonstrate a larger increase in urinary calcium per 100-mmol increase in salt k1take.4~

THERAPEUTIC APPROACH

One case-control study of 200 patients with symptomatic Effective treatment of kidney stones requires accurate kidney stones and 200 matched controls demonstrated differentiation between the various stone types and the a statistically significantly higher rate of kidney stone recognition and control of any underlying metabolic formation in people who had more stressful life events. diseases or structural abnormalities of the urinary tract. Stressful life events were defined as those that the Tables 184-1 and 184-2 list diagnosable causes of kidney subjects perceived as highly stressful through inflicting stones. upon them an intense emotional impact, with apprehenPrevention of recurrence is the therapeutic aim in the sion and distress, for at least 1week!* It is hypothesized treatment of kidney stones. Because dietary management that stressful events may encourage loss of litholytic is effective, inexpensive, and free of side effects, it is the urinary constituents such as magnesium and ~itrate.4~ treatment of choice. The specific treatment is determined Additionally, the sympathetic "fight or flight" response by the type of stone and may include the following: may increase vasopressin release, thus contributing to a more hypertonic urine.44 Reducing urinary calcium Reducing purine intake Miscellaneous Avoiding foods high in oxalate Heavy Metals Increasing intake of foods with a high magnesium/ Hair mineral analysis may be of value, because many calcium ratio heavy metals (mercury, gold, uranium, and cadmium) Increasing intake of vitamin K-rich foods are nephrotoxic. Cadmium, in particular, has been For all types of stones, increasing urine flow to dilute shown to greatly increase the incidence of kidney stones. A prospective study of coppersmiths showed a 40% the urine is vital. Enough fluids should be consumed to produce a urine with a specific gravity lower than incidence of kidney stones, which correlated with eleva1.015 and urinary volume of at least 2000 ml. tions of serum cadmium concentratio11.4~ As far as lifestyle changes are concerned, if stones Vitamin C and the Risk of Oxalate Stones occur on one side only, it may be helpful to avoid sleeping on that side. Stress reduction techniques and counVitamin C is often cited in the medical literature as seling should be considered for anyone with stones and a potential factor in the development of calcium oxalate a history of significant stress. kidney stones. However, numerous studies have now demonstrated that in persons not undergoing hemodialAcute Obstruction ysis or suffering from recurrent kidney stones, severe Surgical removal or lithotripsy may be necessary; the kidney disease, or gout, high-dosage vitamin C therapy following agents may also be used: does not cause kidney stones. Vitamin C ingestion of up to 10 g/day has not had any effect on urinary oxalate Ammi visnaga extract (12% khellin content): 250 mg level^.^,^^ three times daily Rubia tinctura, Rumex crispus, or Aloe Vera at doses Inositol Hexaphosphate lower than used for laxative effect Inositol hexaphosphate, a naturally occurring compound found in whole grains, cereals, legumes, seeds, Calcium Stones and nuts, is known for its antineoplastic activity. Diet One medical literature review finds that an inadequate intake of this compound may result in higher calcium Increase intake of fiber, complex carbohydrates, and oxalate concentration in urine, thus predisposing to green leafy vegetables. urolithiasis.48 Decrease intake of simple carbohydrates and purines (meat, fish, poultry, yeast). Sodium Chloride .Increase consumption of foods with high magnesium/calcium ratio (barley, bran, corn, buckwheat, Another possible intervention is to reduce sodium rye, soy, oats, brown rice, avocado, banana, cashew, chloride consumption. In normal adults, urinary calcium excretion increases approximately 1 mmol (40 mg) for coconut, peanut, sesame seed, lima beans, potato).

Specific Health Problems If the stones are oxalate, reduce consumption of oxalate-containing foods (black tea, cocoa, spinach, beet leaves, rhubarb, parsley, cranberry, nuts). Limit consumption of dairy products.

Supplements Vitamin B6:25 mg/day Vitamin K: 2 mg/day Magnesium: 600 mg/day Calcium: 300 to 1000 mg/day

Botanicals Use any of the following agents in a dose less than that used for laxative effect:

R. tinctura R. crispus A. V e r a

Supplements Folic acid: 5 mg/day

Miscellaneous Alkalinize urine: citrate, bicarbonate, black-currant juice.

Magnesium Ammonium Phosphate Stones Miscellaneous Eradicate infection (see Chapter 53). Acidify urine with ammonium chloride (100 to 200 mg tid).

Cystine Stones Diet

Miscellaneous

Avoid methionine-rich foods (soy, wheat, dairy products [except whole milk], fish, meat, lima beans, garbanzo beans, mushrooms, and all nuts except coconut, hazelnut, and sunflower seeds).

Avoid aluminum compounds and alkalis.

Miscellaneous

Uric Acid Stones Diet

Alkalinize urine: optimal pH is 7.5 to 8.

Decrease consumption of purines (see list given for calcium stones). Ensure adequate fluid intake and a high alkali load with plenty of fruits and vegetables.

1. Bushinsky DA. Nephrolithiasis. J Am Soc Nephrol 1998;9917-924. 2. Langman CB. The molecular basis of kidney stones. Curr Opin Pediatr 2004;16188-193. 3. Shah P, Williams G, Green N. Idiopathic hypercalciuria: its control with unprocessed bran. Br J Urol1980;52426-429. 4. Thom J, Moms J, Bishop A, et al. The influence of refined carbohydrate on urinary calcium excretion. Br J Urol 1978;50459-464. 5. Lemann J, Piering W, Lemon E. Possible role of carbohydrateinduced calciuria in calcium oxalate kidney-stone formation. N h g l J Med 1969;280:232-237. 6. Zechner 0, Latal D, Pfluger H, et al. Nutritional risk factors in urinary stone disease. J Urol1981;125:51-54. 7. Robertson W, Peacock M, Marshall D. Prevalence of urinary stone disease in vegetarians. Eur Urol1982;8334-339. 8. Griffith H, OShea B, Kevany J, et al. A control study of dietary factors in renal stone formation. Br J Urol 1981;53:416-420. 9. Siener R, Hesse A. The effect of a vegetarian and different omnivorous diets on urinary risk factors for uric acid stone formation. Eur J Nutr 2003;42:332-337. 10. Rose G, Westbury E. The influence of calcium content of water, intake of vegetables and fruit and of other food factors upon the incidence of wnal calculi. Urol Res 19759:61-66. 11. Kessler T, JansenB, Hesse A. Effect of blackcurrant-, cranberry- and plum-juice consumption on risk factors associated with kidney stone formation. Eur J Clin Nutr 2002;56:1020-1023. 12.Ulmann A, Aubert J, Bourdeau A, et al. Effects of weight and glucose ingestion on urinary calcium and phosphate excretion:

Bushite and Struvite Stones Acidify urine with cranberry juice.

implications for calcium urolithiasis. J Clin Endocrinol Metab 1982; w1063-1068. 13. Rao N, Gordon C, Davies D, et al. Are stone formers maladaptive to refined carbohydrates? Br J Urol1982;54:575-577. 14.Blacklock NJ. Sucrose and idiopathic renal stone. Nutr Health 1987;59-17. 15. Stewart CS, Duncan SH, Cave DR. Oxdobucter formigenes and its role in oxalate metabolism in the human gut. E M S Microbiol Lett 2OO4;230:1-7. 16. Sidhu H, Hoppe B, Hesse A, et al. Absence of Oxulobacterformigenes in cystic fibrosis patients: a risk factor for hyperoxaluria. Lancet 1998;352:1026-1029. 17.Rushton H, Spector M. Effects of magnesium deficiency on intratubular calcium oxalate formation and crystduria in hyperoxaluric rats. J Urol1982;127598-604. 18. Wunderlich W. Aspects of the influence of magnesium ions on the formation of calcium oxalate. Urol Res 1981;9157-161. 19. Hallson P, Rose G, Sulaiman SM. Magnesium reduces calcium oxalate crystal formation in human whole urine. Clin Sci 1982;6217-19. 20. Johansson G, Backman U, Danielson B, et al. Magnesium metabolism in renal stone formers. Effects of therapy with magnesium hydroxide. %and J Urol Nephrol Suppl1980;53125-134. 21. Prien E, Gershoff S. Magnesium oxide-pyridoxine therapy for recurrent calcium oxalate calculi. J Urol1974;112509-512. 22. Gershoff S, Prien E. Effect of daily MgO and vitamin B6administration to patients with recurring calcium oxalate kidney stones. Am J Clin Nutr 1967;20393-399.

Kidney Stones ~~~

23. Will E, Bijvoet 0.Primary oxalosk clinical and biochemical response to high-dose pyridoxine therapy. Metabolism 1979;28:542-548. 24. Lyon E, Borden T, Ellis J, et al. Calcium oxalate lithiasis produced by pyridoxine deficiency and inhibition with high magnesium diets. Invest Urol 1966;4133-142. 25. Murthy M, Farooqui S, Talwar H, et al. Effect of pyridoxine supplementation on recurrent stone formers. Int J Clin Pharmacol Ther Toxic01 1982;20:434-437. 26. Azoury L, Garti N, Perlberg S, et al. May enzyme activity in urine play a role in kidney stone formation? Urol Res 1982;10:185-189. 27. Liebman M, Chai W. Effect of dietary calcium on urinary oxalate excretion after oxalate loads. Am J Clin Nutr 1997;65:1453-1459. 28. Pizzato AC, Barros EJG. Dietary calcium intake among patients with urinary calculi. Nutr Res 2003;23:1651-1660. 29. Curhan GC, Willett WC, Rimm EB, et al. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 1993;328:833-838. 30. Lemann 1, Pleuss JA, Worcester EM, et al. Urinary oxalate excretion increases with body size and decreases with increasing dietary calcium intake among healthy adults. Kidney Int 1996;49200-208. 31. Usui Y, Matsuzaki S, Matsushita K, et al. Urinary citrate in kidney stone disease. Tokai J Exp Clin Med 2003;28:65-70. 32. Pak CY, Fuller C. Idiopathic hypocitraturic calcium-oxalate nephrolithiasis successfully treated with potassium citrate. Ann Intem Med 1986;10433-37. 33. Whalley NA, Meyers AM, Martins M, et al. Long-term effects of potassium citrate therapy on the formation of new stones in groups of recurrent stone formers with hypocitraturia. Br J Urol 1996;78: 10-14. 34. Nakagawa Y, Margolis H, Yokoyama S, et al. Purification and characterization of a calcium oxalate monohydrate crystal growth inhibitor from human kidney tissue culture medium. J Biol Chem 1981;256:393&3944. 35. Dharmsathaphorn K, Freeman D, Binder H, et al. Increased risk of nephrolithiasis in patients with steatorrhea. Dig Dis Sci 1982;27 401405.

36. Coe F, Moran E, Kavalich A. The contribution of dietary purine over-consumption to hyperuricosuria in calcium oxalate stone formers. J Chronic Dis 1976;29:793-800. 37. Anton R, Haag-Berrurier M. Therapeutic use of natural anthraquinone for other than laxative actions. Pharmacology 1980; 20:104-112. 38. Berg W, Hesse A, Hensel K, et al. [Influence of anthraquinones on the formation of urinary calculi in experimental animals.] Urologe A 1976;15:188-191. 39. Riley K. The biological efficacy of aloes. J John Bastyr Coll Nat Med 1981;2:18-27. 40. Samaan K. The pharmacological basis of drug treatment of spasm of the ureter or bladder and of ureteral stone. Br J Urol 1933;5: 213-224. 41. Shekarriz 8, Lu HF, Stoller ML. Correlation of unilateral urolithiasis with sleep posture. J Urol2001;165:1085-1087. 42. Najem GR, Seebode JJ, Samady AJ, et al. Stressful life events and risk of symptomatic kidney stones. Int J Epidemiol 1997;26: 1017-1023. 43. Brundig P, Berg W, Schneider H. [Stress and risk of urolith formation. 11. The influence of stress on litholytic urinary substances. ] Urol Int 1981;36265-273. 44. Walters DC.Stress as a prinicipal cause of calcium oxalate urolithiasis. Int Urol Nephrol 1986;18:271-275. 45. Scott R, Cunningham C, McLelland A, et al. The importance of cadmium as a factor in calcified upper urinary tract stone diseasea prospective 7-year study. Br J Urol1982;54584-589, 46. Rivers JM. Safety of high-level vitamin C ingestion. Int J Vitam Nutr Res Suppl 1989;3095-102. 47. Wandzilak TR, DAndre SD, Davis PA, et al. Effect of high dose vitamin C on urinary oxalate levels. J Urol1994;151:834-837. 48. Inositol hexaphosphate. Altem Med Rev 2002;7244-248. 49. Massey LK, Whiting SJ. Dietary salt, urinary calcium, and kidney stone risk. Nutr Rev 1995;53:131-139.

Leukoplakia Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

1853

Therapeutic Approach 1854 Supplements 1854

General Considerations 1853 Therapeutic Considerations 1853 Vitamin A and Beta-carotene 1853 Other Antioxidants 1854

DIAGNOSTIC SUMMARY Adherent white patch or plaque appearing anywhere on the oral mucosa Asymptomatic until ulceration, fissuring, or malignant transformation Diagnosis confirmed by biopsy

GENERAL CONSIDERATIONS Leukoplakia is a clinical term signifying a white, plaquelike lesion occurring anywhere on the oral mucosa. It is generally a reaction to irritation, such as cigarette smoking or tobacco or betel nut chewing as well as an early sign in human immunodeficiency virus (HIV)infection. It appears most commonly in men age 50 to 70 years. In 90% of cases, leukoplakia represents epithelial hyperkeratosis and hyperplasia.' In the remaining 10% of cases there is also epithelial dysplasia; these lesions are considered precancerous. Oral cancer is among the most common malignant neoplasms, with nearly 50,000 new cases and 12,000 deaths reported in the United States alone each year. Survival rates for patients undergoing chemotherapy, irradiation, and surgical procedures have been unchanged in the past few decades. Success in preventing death due to oral cancer is achieved through prevention of oral cancer. Abstinence from tobacco and a higher intake of antioxidant nutrients are the primary preventive measures.

THERAPEUTIC CONSIDERATIONS Treatment of leukoplakia involves removal of all irritants. Electrodessication, cryosurgery, and proteolytic

enzymes have not given predictably favorable results.*

Vitamin A and Beta-carotene Historically, vitamin A supplementation and, more recently, beta-carotene supplementation have been clinically effective in the treatment of leukoplakia.3-8 Stich et a1p:8 using the micronucleus test to monitor efficacy, were among the first to evaluate vitamin A and beta-carotene for leukoplakia. The micronucleus test is a useful indicator of the cancerous tendency of epithelial cells, because it provides immediate information about genotoxic damage. Micronuclei are formed during chromatid or chromosomal breakage, with the rate of formation tied closely to carcinogenesis in the oral cavity. This rate is a good predictor of cancer, which typically takes years or decades to generate clinically recognizable signs. On the basis of results of the micronucleus test, Stich et a1 found that these two dietary factors, particularly beta-carotene, were quite effective in decreasing the mean proportion of cells with micronuclei on the buccal mucosa in Asian betel nut and tobacco chewer^.^,^ The subjects continued to chew betel nut and tobacco during the study. The epidemiologic and experimental data documenting the protective effect of carotenoids and retinoids against epithelial cancers are overwhelming. The inverse relationship between serum retinol and carotene levels and cancer incidence holds true for oral carcinomas as we11.9J0 Dosages used in clinical studies testing vitamin A in the treatment of leukoplakia generally were fairly high (i.e., 150,000 to 900,000 IU/day) but extremely

1853

Since beta-carotene appears to be as effective as retinol in decreasing micronuclei levels and has a much higher therapeutic index, beta-carotene should probably be the treatment of choice for this condition. (Note: Vulvar leukoplakia is also responsive to retinol and could therefore respond to beta-carotene as well.)"J2 However, the only head-to-head comparison study of the two supplements did find an advantage for retinol (see Table 185-1). In the study 160 men and women with leukoplakia were randomly assigned to receive oral vitamin A (retinyl acetate 300,000 IU/week x 12 months; n = 50), oral beta-carotene (360 mg/week x 12 months; n = 55), or placebo (n = 55).13The complete regression rates were 10% in the placebo arm, 52% with vitamin A, and 33% with beta-carotene. Homogeneous leukoplakias and smaller lesions responded better than nonhomogeneous and larger lesions. No major toxicities were observed even in the group given prolonged vitamin A supplementation.

Other Antioxidants Antioxidants in addition to beta-carotene may be helpful. For example, studies have shown vitamin E (400 mg/day) to produce a 65% response rate.I4 However, it makes the most sense to use a combination of antioxidant nutrients, given their interactions and limitations, as monotherapy. Preliminary results using a combination of vitamin C (1000 mg/day), betacarotene (30 mg/day), and vitamin E (400 mg/day) are en~ouraging.'~

1.van der Waal I, Axell T. Oral leukoplakia: a proposal for uniform reporting. Oral Oncol2002;38:521-526. 2. Krupp M, Chatton M. Current medical diagnosis and treatment. Los Altos, CA. Lange Medical Publications, 198236. 3. Johnson JE, Ringsdorf WM Jr, Cheraskin E. Relationship of vitamin A and oral leukoplakia. Arch Dermatol1963;88:607-612. 4. Mulay DN, Urbach F. Local therapy of oral leukoplakia with vitamin A. AMA Arch Derm 1958;78:637-638. 5. Smith JF. Clinical evaluation of massive buccal vitamin A dosage in oral hyperkeratosis. Oral Surg Oral Med Oral Pathol1962;15:282-292. 6.ZegareUi E, Kutscher A, Stevers H. Keratotic lesions of the oral mucosa membranes treated with high dosage topical and systemic vitamin A. N Y State Dent J 1959;25:244-252. 7. Stich HF, Rosin MP, Vallejera MO. Reduction with vitamin A and beta-carotene administration of proportion of micronucleated buccal mucosal cells in Asian betel nut and tobacco chewers. Lancet 1984;1:1204-1206. 8. Stich HE Stich W, Rosin MI', Vallejera MO. Use of the micronucleus test to monitor the effect of vitamin A, beta-carotene and canthaxanthin on the buccal mucosa of betel nut/tobacco chewers. Int J Cancer 1984;34:745-750. 9. Garewal HS, W a n t 2 S. Emerging role of beta-carotene and antioxidant nutrients in prevention of oral cancer. Arch Otolaryngol Head Neck Surg 1995;121:141-144. 10. Ibrahim K, Jafarey NA, Zuberi SJ. Plasma vitamin " A and carotene levels in squamous cell carcinoma of oral cavity and orepharynx. Clin Oncol 1977;3:203-207.

Beta-carotene trials Study

Dosage

Stich et a17

180 rng/week

Response rate (%) 15

Stich et ale

180 rng/week

27

Garewal et all6

30 rng/day

71

Brandt et all7

90 rng/day

60

Toma et all8

90 rng/day

44

Malaker et all9

30 rng/day

50

Garewal et aIm

60 rng/day

56

Sankaranarayananet all3

360 rng/week

33

THERAPEUTIC APPROACH Because leukoplakia is due to a combination of excessive carcinogenic irritation in the context of marginal or low levels of vitamin A, the approach is simple: Eliminate all sources of irritation and establish optimal vitamin A, beta-carotene, and antioxidant levels. Particularly significant irritation results from smoking or chewing of tobacco, chewing of betel nut, and exposure to ultraviolet light.

Supplements Vitamin A: 5000 IU/day Beta-carotene: 30 to 90 mg/day Vitamin C: 1000 to 3000 mg/day Vitamin E: 400 IU/day

11. Hyams M, Gallagher P. Vitamin A therapy in the treatment of vulvar leukoplakia. Am J Obstet Gynecol 1950;59:1346-1354. 12. Hunt E. Vitamin A in leukoplakia. Lancet 1947;2:141. 13. Sankaranarayanan R, Mathew B, Varghese C, et al. Chemoprevention of oral leukoplakia with vitamin A and beta carotene:an assessment. Oral Oncol 1997;33231-236. 14. Benner SE, W m RJ, Lippman SM, et al. Regression of oral leukoplakia with alpha-tocopherol. J Natl Cancer Inst 1993;8544-47. 15. Kaugars GE, Silverman S Jr, Lovas LG, et al. Use of antioxidant supplements in the treatment of human oral leukoplakia. Oral Surg Oral Med Oral Pathol Oral Radio1 Endod 1996;81:5-14. 16. Gari?walHS, Meyskens FL Jr, Killen D, et al. Response of oral leukoplakia to beta-carotene. J Clin Oncol1990;8:1715-1720. 17. Brandt R, et al. Response of oral lesions with the use of antioxidant vitamins and beta-carotene supplements. In Laidlaw S, Swendseid M, eds. Vitamins and cancer prevention. Baton Rouge: Louisiana State Press, 1991. 18. Toma S, Benso S, Albanese E, et al. Treatment of oral leukoplakia with beta-carotene. Oncology 1992;49:77-81. 19. Malaker K, Anderson BJ, Beecroft WA, Hodson DI. Management of oral mucosal dysplasia with beta-carotene and retinoic acid. A pilot crossover study. Cancer Detect Prev 1991;15:335-340. 20. Garewal HS. Beta-carotene in oral leukoplakia. Proc Am Soc Clin Oncol 1992;11:141.

Lichen Planus Sam Russo, ND,MSAc CHAPTER CONTENTS Diagnostic Summary

1855

General Considerations 1855 Variants 1855 Incidence, Onset, and Course 1856

Antifungal Therapy 1856 Supplements and Botanical Medicines 1857 Therapeutic Approach Supplements 1857

1857

Therapeutic Considerations 1856 Dental Amalgams 1856

DIAGNOSTIC SUMMARY Pruritus is the primary complaint and can be severe. The patient may also complain of a rash or skin eruption. Skin lesions are flat-topped, violaceous to purple, polygonal or oval, papules 1 to 10 mm wide with edges that are sharply defined and shiny. Lesions may be grouped, linear (Koebner phenomenon), annular, or disseminated when generalized. White lines (Wickham striae) may be present. A hand-held lens and application of a clear oil over a lesion intensifies the visibility of Wickham striae. In dark-skinned patients, postinflammatory hyperpigmentation commonly occurs. Lesions tend to occur on the flexor surfaces of wrists, lumbar region, eyelids, shin, scalp, glans penis, and mouth, although they may occur anywhere. Uncommon presentations include plaque-size lesions and location on the nails or hair follicles with dystrophic changes and scarring. Oral lesions demonstrate inflammation and leukohyperkeratosis manifesting as reticulated, white puncta or papules and lines in a lacelike pattern. Plaques may form. Erosions with blisters may result from the inflammatory process. The buccal mucosa is the most common site of involvement, and the disorder is bilateral in nearly all patients. The tongue, lips, and gingivae may also be affected. Skin lesions occur in 10% to 60% of cases of oral lichen planus. Other locations include: (1) the genitalia, where papular, annular, or erosive lesions may arise on the penis, scrotum, labia majora, labia minor, and vagina, (2) the scalp, where atrophic skin and scarring alopecia can be seen, and (3) the nails, in which destruction of the

nail fold and nail bed with longitudinal splintering may occur. Biopsy should be performed if there is doubt about the diagnosis or if blisters, plaques, or erosions occur in oral lichen planus.

GENERAL CONSIDERATIONS Lichen planus is an inflammatory, pruritic disease of the skin and mucous membranes that can be either generalized or localized. It is characterized by distinctive purplish, flat-topped papules having a predilection for the trunk and flexor surfaces. The lesions may be discrete or may coalesce to form plaques. Etiology is unknown in most cases. Drugs (see later), metals (gold, mercury), or infection (hepatitis C virus) resulting in alteration of cell-mediated immunity may also play a role. Human leukocyte antigen-associated genetic susceptibility may explain a disposition in some patients. Epidemiologic studies have demonstrated a higher prevalence of hepatitis C virus infection in patients with lichen planus than in the normal population. However, a pathogenic relationship has yet to be established. Lichen planus tends to affect women more than men, and the age of onset is 30 to 60 years. Hypertrophic lichen planus is more common in African Americans.

Variants Hypertrophic: Large thick plaques arise on the foot and shins; more common in African-American males. Although the typical lichen planus papule is smooth, hypertrophic lesions may become hyperkeratotic. 1855

Specific Health Problems Follicular: Individual keratotic-follicular papules and plaques that lead to cicatricial alopecia. Graham Little syndrome is the complex of spinous follicular lesions, any lichen planus, and cicatricial alopecia. Vesicular: Development of vesicular or bullous lesions within or independent of lesions. In the latter, direct immunofluorescence is consistent with bullous pemphigoid, and patients have bullous pemphigoid immunoglobulin (Ig) G autoantibodies. Actinicus: Papular lesions in sun-exposed areas, especially dorsum of hands and arms. Ulcerative: Therapy-resistant ulcers, particularly on the soles, requiring skin grafting. Oral/mucous membranes: Reticular, hyperkeratotic, erosive, plaque-type, atrophic, and bullous types may been seen.

Incidence, Onset, and Course Although not common, lichen planus occurs in 6 per 1000 patients seen by dermatologists, with an annual prevalence of 4.4 per 1000 people in the United States per year. However, oral lichen planus may be the most common cause of white lesions in the mouth, having been found in 0.5% to 1% of dental patients. Women tend to be affected more than men. Oral lichen planus may occur alone or in association with skin lesions, with a tendency to occur in those 40 to 60 years old. Onset can be acute or can be insidious with lesions remaining for months to years. Lesions may be asymptomatic or mildly to severely pruritic. Lesions on mucous membranes are more painful, particularly if ulcerated. The course of oral lichen planus may be chronic, lasting from months to years. Approximately two thirds of patients experience spontaneous resolution w i t h 1 year. Recurrence is uncommon in both forms, being seen in less than 20% of patents. Patients with mucous membrane involvement usually have a more prolonged course, possibly lasting months to decades, although 50% experience remittance in 2 years. The incidence of oral squamous cell carcinoma in individuals with oral lichen planus is 5% higher. Lichen planus-like eruptions can occur as a manifestation of graft-versus-host disease or dermatomyositis and as cutaneous manifestations of malignant lymphoma as well with certain drugs.

THERAPEUTIC CONSIDERATIONS The underlying mechanism of lichen planus is unknown. The immune system plays a role as evidenced by two findings: First, immunoglobulins (primarily IgM; possibly IgA, IgG) and complement (C3) are found at the dermal/epidermal junction in 95% of lichen planus lesions. Second, lesions due to certain drug eruptions and to graft-versus-host reactions in patients undergoing

bone marrow transplantation mimic those of lichen planus. The primary immune factor involved appears to be cell-mediated processes. In early lesions, activated helper T (TH) cells target basal cells, which may have antigenic alterations. Suppressor T (T,) cells predominate in older lesions.

Dental Amalgams Oral lichen planus tends to be more resistant to therapy than skin lesions. Dental amalgams appear to play a role in the etiology of oral lichen planus. In one study, 161 patients with chronic lichenoid reactions (142) or oral lichen planus (19), differentiated according to location in relation to amalgam fillings and number of oral surfaces affected, underwent replacement of mercury amalgam fillings with alternative substances.Five patients served as controls, receiving no restoration. Evaluation after 6 to 12 months after restoration showed that 95% of the patients with chronic lichenoid reactions had marked improvement or complete restoration of normal mucosa. The effect was more apparent for those with gold crowns than those with CM (palladium-based) crowns. In the oral lichen planus group, those areas of lesions in contact with amalgam showed an improvement in 63% of patients, but lesions in other sites were not affected.' A second study found that if gold crowns are already present, patients should undergo patch testing for gold allergy; removal of the crowns should be considered in those with positive results? (The former study downplays the significance of patch testing for mercury as many patch-negative patients still responded to amalgam removal.)

Antifungal Therapy Griseofulvin In a double-blind, controlled study involving 34 patients with lichen planus, 17 patients received griseofulvin, 500 mg qid, and 17 patients received placebo (substance not indicated) for 4 to 6 weeks. In 18 patients, lesions showed complete regression, but 16 patients experienced no response. In the griseofulvin group, 12 patients (70.6%) showed regression of symptoms, whereas in the placebo group, 6 patients (35.3%) demonstrated regression, a sigruficant difference. Biopsy of 8 patients whose lesions responded to griseofulvin and 2 whose lesions responded to placebo demonstrated uniform histologic change^.^

Photodynamic Therapy In a case report of a 64-year-old man with lichen planus of the penis that did not respond to steroids (and was initially diagnosed as intraepidermal carcinoma), photodynamic therapy was preceded by application of 5-aminolevulinic acid (20%) ointment (4 hours prior to treatment). The area was irradiated with

Lichen Planus a Paterson-Whitehurstlamp (Paterson Institute, Christie Hospital, Manchester, UK) at a center wavelength of 630 nm and a rectangular pass band of 27 nm. The dose was gradually increased to 50 J/cm2 at a fluence rate of 55 mW/cm2 to prevent edema and phimosis. Treatment was repeated after 6 weeks. Lesions completely resolved after another 4 weeks, with no recurrence at 6 months, at which time a biopsy showed mild changes identifying the condition as lichen p l a n ~ s . ~

whom completely. Patients with stable disease were then treated with isotretinoin (Accutane; 10 mg tid) in conjunction with beta-carotene, and 3 showed improvement. The response to treatment was much higher in smokers (30 pack/yr or more) than in nonsmoker^.^ Vitamin A can be applied with folic acid in an adhesive base such as benzocaine (Orabase).

Supplements and Botanical Medicines Vitamin A and Beta-carotene

Seventeen patients with oral lichen planus and hepatitis C were divided into two groups. Nine patients received intravenous glycyrrhizin, and eight were given information on dental hygiene. The treatment group received 40 ml of a 0.2% solution of glycyrrhizin daily for four consecutive weeks. Six of the nine treated patients demonstrated clinical improvement. The patients with responses tended to have only mildly raised serum alanine transaminase (ALT) and aspartate transaminase (AST).8(Note: Sci Bot Glycyrrhiza SE is standardized to 17”/0 glycyrrhizin; a comparable oral dose would be approximately 500 mg solid extract.)

Six patients with hypertrophic lichen planus of the palms or soles used topical retinoic acid (0.1% in petroleum jelly base) three times daily for 3 weeks. This frequency caused irritation, so application was switched to two to three times every other day. Regression occurred after 2 to 3 weeks. Duration of treatment was unspecified in the study report. Two cases showed slight recurrences after 3 to 4 month^.^ A second study compared topical retinoic acid 0.05% (RA) and fluocinolone acetonide 0.1% (FA) applied four times daily. Thirty-three patients with varied stages of oral lichen planus were alternately given RA (15) or FA (18). Fifty-six percent of patients receiving FA improved, but only 13% of patients receiving RA improved. The extent of change was greater in the FA group as we11.6 In another study, 18 patients with mucosal dysplasia (10 leukoplakia, 4 lichen planus, 3 erythroplasia, 1 leukokeratosis) were evaluated for serum vitamin A, betacarotene, and cis-retinoic acid levels, which were low-normal.All patients received beta-carotene,30 mg qid. Disease in 1 patient showed worsened, disease in 9 remained stable, and lesions in 8 improved, in 6 of

1. Bratel J, Hakeberg M, Jontell M. Effect of replacement of dental amalgam on oral lichenoid reactions.J Dent 1996;2441-45. 2. Izumi AK. Allergic contact gingivostornatitis due to gold. Arch Dermatol Res 1982;272:387-391. 3. Sehgal VN, Abraham GJ, Malik GB. Griseofulvin therapy in lichen planus. A double-blind controlled trial. Br J Dermatol 1972;87 383-385. 4. Kirby B, Whitehurst C, Moore JV,Yates VM. Treatment of lichen planus of the penis with photodynamic therapy. Br J Derrnatoll999; 1411765-766. 5. Gunther S. Topical administrationof vitamin A acid (retinoic acid) in palmar keratoses:callosities, hyperkeratotic eczema, hypertrophic

Glycyrrhizin

THERAPEUTIC APPROACH The causes of lichen planus have not been determined, so the curative approach is unclear. If the lesions are oral and the patient has significant metal-based fillings, heavy metal detoxification and replacement of the metal fillings should be considered.

Supplements Vitamin A (0.1% solution): topical application 4 times/ day Beta-carotene: 30 mg 4 times/day Glycyrrhizin: topical application

lichen planus, pityriasis rubra pilaris. Dermatologica 1972;145: 344-347. 6. Buajeeb W, Kraivaphan P, Pobrurksa C. Efficacy of topical retinoic acid compared with topical fluocinolone acetonide in the treatment of oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radio1 Endod 1997;8321-25. 7. Malaker K, Anderson BJ, Beecroft WA, Hodson DI. Management of oral mucosal dysplasia with beta-carotene retinoic acid: a pilot crossover study. Cancer Detect Prev 1991;15:335-340. 8. Da Nagao Y, Sata M, Suzuki H, et al. Effectiveness of glycyrrhizin for oral lichen planus in patients with chronic HCV infection. J Gastroenterol 1996;31:691-695.

Macular Degeneration Michael T. Murray, ND Peter B. Ebngiorno, ND, Dip1 Ac C H A P T E R CONTENTS Diagnostic Summary

Nutritional Supplements 1861 Lifestyle 1862

1859

General Considerations 1859 Types of Macular Degeneration 1859 Therapeutic Considerations 1860 Reducing and Preventing Atherosclerosis Diet 1860

1860

DIAGNOSTIC SUMMARY Progressive visual loss due to degeneration of the macula. Ophthalmologic examination may show spots of pigment near the macula and blurring of the macular borders.

GENERAL CONSIDERATIONS

Therapeutic Approach 1862 Diet 1862 Supplements 1862 Botanical Medicines 1862 Exercise 1862

feasibility of linkage studies. Interestingly, higher birth weight and lower head circumference/birth weight ratio are associated with sigrulicantly higher risk for this disorder.6

Types of Macular Degeneration The two most common types of ARMD are the atrophic (dry) form, by far the more common, and the neovascular (wet) form.*s4In either form, patients may experience blurred vision. The patient may note that straight objects appear distorted or bent; the presence of a dark spot near or around the center of the visual field; and, while reading, that parts of words are missing.

The macula, the area of the retina where most images focus, is the portion of the eye responsible for fine vision. Degeneration of the macula is the leading cause of severe visual loss in the United States and Europe in persons 55 years or older and is second only Dry Age-Related Macular Degeneration to cataracts as a cause of decreased vision in persons Between 80% and 95% of people with ARMD have the older than 65 years. It is estimated that more than 150,000 Americans are legally blind from age-related dry form of the disease. The primary lesions are atrophic changes in the retinal pigmented epithelium (WE),which macular degeneration (ARMD), with 20,000 new cases constitutes the innermost layer of the retina. Apparently, occurring each year.'P2 The number of people affected beginning in early life and continuing throughout life, by ARMD is predicted to double in the next 25 years and may reach epidemic proportions in this ~ e n t u r y . ~ cells of the W E gradually accumulate sacs of cellular The major risk factors for macular degeneration are debris (lipofuscin). The lipofuscin bodies are either smoking, aging, atherosclerosis, and hyperten~ion.',~,~ remnants of incompletely degraded abnormal molecules Apparently, the degeneration is a result of free radical from damaged WE cells or derivatives of phagocytized damage similar to the type of damage that induces rod and cone membranes. Progressive engorgement of the RPE cells with lipofuscin is associated with the cataracts (see Chapter 210). However, decreases in blood extrusion of tissue components like hyaline, sialomucin, and oxygen supply to the retina are the harbinger of and cerebro~ide.'~~~~ The hallmark excrescences beneath macular degeneration. Although genomic family scans of 364 families the W E apparent on ophthalmoscopic examination are have revealed a region of chromosome 10 as possibly referred to as drusen. containing an association with ARMD? diversity in The disease progresses slowly and only central vision is lost; peripheral vision remains intact. It is rare for phenotype and the late onset of disease complicate the 1859

Diet

anyone to become totally blind from dry ARMD.’T~,~ Fruits and Vegetables Currently there is no standard medical treatment for this common form of ARMD. A diet rich in fruits and vegetables is associated with a lower risk for ARMD. Presumably this protection is Wet Age-Related Macular Degeneration the result of greater intake of antioxidant vitamins and The other form of ARMD is the wet or neovascular minerals?-” However, various “nonessential” food comform. It affects 5% to 20% of persons with ARh4D. It is ponents such as flavonoids and the non-provitamin A characterized by the growth of abnormal blood vescarotenes lutein, zeaxanthin, and lycopene are provsels. Wet ARMD can be further subdivided into ing to be even more significant in protecting against classic and occult forms; the classic form is more ARMD than traditional nutritional antioxidants. The threatening to sight.’ Unlike the dry form, wet ARMD rnacula, especially its central portion, the fovea, owes can be treated quite effectively, in the early stages, with its yellow color to its high concentration of lutein and zeaxanthin. These yellow carotenoids function in prelaser photocoagulation therapy. Because the disease venting oxidative damage to the area of the retina can rapidly progress to a point at which surgery responsible for fine vision and, obviously, have a cencannot be used, surgery should be performed as soon as tral role in protecting against the development of macular degeneration.I2 For example, one study compared patients with soft THERAPEUTIC CONSIDERATIONS drusen, retinal pigment abnormalities, ARMD, and/or The traditional treatment of the wet form of ARMD neovascular or exudative macular degeneration with has been laser photocoagulation. Photodynamic therapy controls. Individuals with lycopene content in the lowest using photosensitive drugs (verteporfin) and a lowquintile were twice as likely to have ARMD.l1 powered laser’ or low-dose radiation therapy is a newer Zeaxanthin technique. The treatment of the dry form and prevention of the Another study of 380 men and women age 66 to wet form of ARMD involve the use of antioxidants and 75 years compared plasma concentrations of zeaxanthin and found that those with the lowest levels natural substances that correct the underlying pathophysiology-free radical damage and poor oxygenation had a 2.0 odds ratio for risk of ARMD. This ratio was of the macula. This can be accomplished by reducing the adjusted for age and other risk factors. Risk of agerisk factors for atherosclerosis, increasing dietary intake related macular degeneration was higher in people with the lowest plasma concentrations of lutein plus of fresh fruits and vegetables, and supplementing with zeaxanthin and in those with the lowest concentrations nutritional and botanical antioxidants. of lutein, but neither of these relationships was statistiReducing and Preventing cally ~ignificant.’~

Atherosclerosis

Although atherosclerosis is a well-accepted risk factor for macular degeneration, this association was unconfirmed until 1995.4In the confirmation study, 104 subjects with and 1324 subjects without macular degeneration were evaluated for atherosclerosis via ultrasonographic determination of the intima-media thickness, assessment of the presence of atherosclerotic plaque in the carotid arteries, and measurement of the ankle/arm systolic blood pressure ratio (an indicator of peripheral atherosclerosis). The results indicated that in subjects younger than 85 years, plaques in the carotid bifurcation were associated with a 4.7 times higher prevalence of macular degeneration. Lower extremity atherosclerosis was associated with a 2.5 times greater risk. These results indicate that measures designed to reduce the risk of atherosclerosis are of great significance in the prevention and treatment of macular degeneration (see Chapter 150 for a comprehensive program for prevention and reversal).

Animal Fat A cohort study of 261 individuals with early or intermediate stages of ARMD revealed a twofold increased risk of progression with animal fat and processed baked goods intake although the trend for increasing risk with higher animal fat intake was not significant. Higher fish intake was associated with a lower risk of AMD progression among subjects with lower linoleic acid intake and nuts were also found to be pr0te~tive.l~

Egg Yolks Dietary egg yolk is also an excellent source of bioavailable lutein and zeaxanthin. One study using a supplement of 1.3 yolks per day found increased levels of bioavailable lutein and zeaxanthin, but noted an untoward effect on plasma low-density lipoprotein (LDL) cholesterol levels, with an increase of 8% to 11°/0.15It should be noted that other studies have found no change in cholesterol levels of healthy volunteers with moderate egg consumption,16

Macular Degeneration

and one report suggests that only patients with concomitant high plasma cholesterol and triglyceride levels are subject to hyperlipidemic increases when fed foods with dietary cholesterol such as eggs.17

Alcohol Products In an examination survey, 3072 adults age 45 to 74 years with macular changes indicative of ARMD were evaluated for alcohol intake and the risk for development of ARMD. The survey showed that moderate wine consumption is associated with decreased risk of macular degeneration.l8As elaborated further in the later discussion on flavonoids, red-purple foods like wine contain anthocyanins, powerful antioxidants that are probably responsible for the protective effect. It is important to note that beer consumption increased h e n accumulation and the risk of exudative macular disease19 and therefore should be avoided.

Nutritional Supplements In addition to recommending a diet high in antioxidants, supplementation with nutritional antioxidants like vitamin C, selenium, beta-carotene, and vitamin E is certainly important in the treatment and prevention of macular degeneration. Studies conducted by the Age-Related Eye Disease Study Research Group confirm that a combination of these nutrients will likely produce better results than any single nutrient alone, because other studies have shown that none of these antioxidants alone accounts for the impaired antioxidant status in ARMD.20Instead, the lower antioxidant status reflects decreases in a combination of nutrients?

Antioxidant Preparations Several studies utilizing various commeraally available broad-based antioxidant formulas have shown promising results.For example, a l'/z-year study demonstrated that the progression of dry ARMD could be halted (but not reversed) with a broad-spectrum, lkomponent antioxidant capsule (Ocuguard)?l!" A retrospective study of a nutritional supplement called ICAPS Plus (whichcontains beta-carotene, vitamins C and E, zinc, copper, manganese, selenium, and riboflavin) compared 38 patients who used the preparation regularly with 37 patients who used only one bottle and who served as controls. Fifteen of the treated patients showed improvement in their vision by one line or more on a vision acuity chart compared with only six of the control group. In addition, three of the 38 in the treatment group lost one line or more of vision, compared with 13 in the control group.23In a second prospective blinded clinical trial reported in the same review, vision and contrast sensitivity were evaluated. After 6 months, visual acuity was the same or better in 36 of 61 controls compared with 168 of 192 treated patients.

Lutein In addition to a high-lutein diet, supplementation with additional lutein is of benefit. One 12-month doubleblind study, the Lutein Antioxidant Supplementation Trial (LAST)," sought to determine whether nutritional supplementation with lutein or lutein together with antioxidants, vitamins, and minerals improves visual function and symptoms in atrophic ARMD.24Patients receiving lutein (10 mg) alone or in combination with other vitamins and minerals in a broad-spectrum supplementation formula showed improvements in mean eye macular pigment optical density; Snellen equivalent visual acuity; and contrast sensitivity. Patients who received the placebo, however, showed no significant changes in any of the measured findings.

Zinc Zinc plays an essential role in the metabolism of the retina, and the elderly are at high risk for zinc deficiency. A 2-year, prospective, randomized, double-blind, placebocontrolled trial involving 151 subjects with dry ARMD demonstrated that the group taking 200 mg/day of zinc sulfate (approximately80 mg of elemental zinc) had significantly less visual loss than the placebo g r o u ~This .~ initial report prompted the Age-Related Eye Disease Study Group to further evaluate whether antioxidant or zinc supplements delay age-related macular degeneration. The study, which used 500 mg vitamin C, 400 IU vitamin E, 15 mg of beta-carotene, 80 mg of zinc (as zinc oxide), and 2 mg of copper (as cupric oxide), found that these supplements sigruficantly lowered the chances of development of advanced ARMD. In their conclusion, the researchers recommended that the combination of zinc and antioxidants should be considered in patients older than 55 years who demonstrate risk for ARMD.20 These results were not confirmed, however, in another double-blind study in 112 patients with wet ARMD.26

Flavonoid-Rich Extracts Flavonoid-rich extracts of bilberry (Vuccinium myrtillus), Ginkgo bilobu, or grape seed (Vitis vinifera)offer sigruficant benefits in the prevention and treatment of ARMD. In addition to possessing excellent antioxidant activity, all three extracts have been shown to exert positive effects on retinal blood flow and function. Clinical studies in humans have demonstrated that all three are also capable of halting the progressive visual loss of dry ARMD and possibly even improving visual f u n c t i ~ n . ~ Of~ -the ~ three extracts, bilberry extracts standardized to contain 25% anthocyanidins appear to be the most useful. The anthocyanosides of V myrtillus have a very strong affinity for the retinal pigmented epithelium that constitutes the optical or functional portion of the retina, reinforcing the collagen structures of the retina and preventing free

radical damage. Because the WE is the portion of the eye affected in ARMD, V. rnyrtillus anthocyanosides appear to be ideal therapeutic agents in the disorder. However, the G. biloba extract with a 24% ginkgo flavoglycoside content is perhaps a better choice if the patient is also showing signs of cerebrovascular insufficiency. Grape seed extract may be the most useful in the patient with sigruhcant photophobia or poor night vision.

Lifestyle

conditions should be investigated and treated if diagnosed.

Diet Foods to avoid in ARMD are as follows: Fried and grilled foods, and other sources of free radicals Animal fat Processed baked goods Beer

Oxidant exposure is a major factor in macular degenerFoods to add to the diet of a patient with ARMD are as follows: ation, so it is not surprising that smoking raises the risk of macular degeneration in both men and ~ o m e n . ~ ~ , ~ ~ Legumes (high in sulfur-containing amino acids) For example, in a 12-year study of 31,843 registered Yellow vegetables (carotenes) female nurses, those who currently smoked 25 or more Flavonoid-rich berries (blueberries, blackberries, cigarettes per day had a relative risk of 2.4 for agecherries, etc.) related macular degeneration compared with those Vitamin E- and vitamin C-rich foods (fresh fruits and who had never smoked. Past smokers of 25 cigarettes vegetables), nuts, and fish or more per day still had a twofold increased risk relaModerate wine consumption (advisable in those tive to never smokers. Their risk did not return to the without contraindications to alcoholic beverages) control rate until after they had stopped smoking for 15 years.32

Exercise Although exercise may not play a role in reversing or directly preventing ARMD, patients with visual impairment should consider strength and balance training in order to minimize the risk of falling.33

Supplements

Vitamin C: 1 g three times/day Vitamin E: 600 to 800 IU/day Selenium: 400 pg/day Beta-carotene (mixed carotenoids recommended): 50,000 IU/ day Lutein: 15 mg/day

THERAPEUTIC APPROACH

Botanical Medicines

As with most diseases, prevention or treatment of ARMD at an early stage is most effective. The treatment of the wet form is clearly laser photocoagulation, applied as soon as possible. Because free radical damage and lack of blood and oxygen supply to the macula appear to be the primary causes of macular degeneration, consumption of antioxidants and promotion of retinal blood flow are the keys to effective treatment. Any patient 55 years or older who complains of visual loss should be referred to an ophthalmologist for complete evaluation, especially if the visual loss is progressing rapidly. Underlying diabetic and/or hypertensive

One of the following extracts should be chosen:

1. Young RW. Pathophysiology of age-related macular degeneration. Survey Ophthalmol 1987;31:291-306. 2. Newsome DA. Medical treatment of macular diseases. Ophthalmol Clin North Am 1993;6307-314. 3. Flaxel CJ.Use of radiation in the treatment of age-related macular degeneration.Ophthalmol Clin North Am 2002;15:437-444. 4. Vinderling JR, Dielemans I, Bob ML. Age-related macular degeneration is associated with atherosclerosis. The Rotterdam Study. Am J Epidemiol 1995;142:40449.

5. Chung M, Lotery AJ. Genetics update of macular diseases. Ophthalmol Clin North Am 2002;15:459-465. 6. Hall NF, Gale CR, Syddall H, et al. Relation between size at birth and risk of age-related macular degeneration.Invest Ophthalmol Vis Sci 2002;43:3641-3645. 7. Meads C, Salas C, Roberts T, et al. Clinical effectiveness and costutility of photodynamic therapy for wet age-related macular degeneration: a systematic review and economic evaluation. Health Techno1 Assess 2003;71-98.

G. biloba extract (24% ginkgo heterosides): 40 to 80 mg three times/day V. rnyrfillus (bilberry) extract (25% anthocyanidin content): 40 to 80 mg three times/day Grape seed extract (95% procyanidolic content): 150 to 300 mg/day

Exercise Balance training and strength exercises, especially for patients who are visually impaired

Macular Degeneration 8. [The results of randomized controlled trial of low-dose radiation for wet-type age-related macular degeneration on a 1 year term basis.] Treatment of Age-related Macular Degeneration with Lowdose Radiation Therapy Study Group. Jpn J Ophthalmol 2003;47626-627. 9. Antioxidant status and neovascular age-related macular degeneration. Eye Disease Case-Control Study Group. Arch Ophthalmol 1993;111:104-109. 10. Snodderly DM. Evidence for protection against age-related macular degeneration by carotenoids and antioxidant vitamins. Am J Clin Nutr 1995;62:1448S1461S. 11. Mares-Perlman JA, Brady WE, Klein R, et al. Serum antioxidants and age-related macular degeneration in a population-based casecontrol study. Arch Ophthalmol1995;1131518-1523. 12. Landnun JT, Bone RA, Kilbum MD. The macular pigment: a possible role in protection from age-related macular degeneration. Adv Pharmacol1997;38:537-556. 13. Gale CR, Hall NF, Phillips DI, et al. Lutein and zeaxanthin status and risk of age-related macular degeneration. Invest Ophthalmol Vis Sci 2003;44:2461-2465. 14. Seddon JM, Cote J, Rosner B. Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake. Arch Ophthalmol2003;121:172&1737. 15. Handelman GJ, Nightingale ZD,Lichtenstein AH, et al. Lutein and zeaxanthin concentrations in plasma after dietary supplementation with egg yolk. Am J Clin Nutr 1999 Aug;70247-251. 16.Ginsberg HN, Karmally W, Sidduqui M, et al. A dose-response study of the effects of dietary cholesterol on fasting and postprandial lipid and lipoprotein metabolism in healthy young men. Arterioscler Thromb 1994;14576-586. 17. Knopp RH, Retzlaff BM, Walden CE, et al. A double-blind, randomized, controlled trial of the effects of two eggs per day in moderately hypercholesterolemic and combined hyperlipidemic subjects taught the NCEP step I diet. J Am Coll Nutr 1997;16551-561. 18. Obisesan TO, Hirsch R, Kosoko 0, et al. Moderate wine consumption is associated with decreased odds of developing age-related macular degeneration in NHANESl. J Am Geriatr Soc 1998; 46:1-7. 19. Ritter LL, Klein R, Klein BE, et al. Alcohol use and age-related maculopathy in the Beaver Dam Eye Study. Am J Ophthalmoll995; 120190-196.

20. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS Research Group. Arch Ophthalmol2001;119:1417-1436. 21. Richer S. Multicenter ophthalmic and nutritional age-related macular degeneration study. Part 1: design, subjects and procedures. J Am Optom Assoc 1996;6712-29. 22. Richer S. Multicenter ophthalmic and nutritional age-related macular degeneration study. Part 2: antioxidant intervention and conclusions. J Am Optom Assoc 1996;6730-49. 23. Bartlett H, Eperjesi F. Age-related macular degeneration and nutritional supplementation: a review of randomised controlled trials. Ophthalmic Physiol Opt 2003;23383-399. 24.Richer S, Stiles W, Statkute L, et al. Double-masked, placebocontrolled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry 2004;75216-230. 25. Newsome DA, Swartz M, Leone NC, et al. Oral zinc in macular degeneration. Arch Ophthalmol 1988;106:192-198. 26. Stur M, Tittle M, Reitner A, et al. Oral zinc and the second eye in age-related macular degeneration. Invest Ophthalmol Vis Sci 1996; 371225-1235. 27. Scharrer A, Ober M. Anthocyanosides in the treatment of retinopathies. Klin Monatsbl Augenheilkd 1981;178:386-389. 28. Caselli L. Clinical and electroretinographic study on the activity of anthocyanosides. Arch Med Int 1985;3729-35. 29.Lebuisson DA, Leroy L, Riga1 G. [Treatment of senile macular degeneration with Ginkgo biloba extract. A preliminary doubleblind, drug vs. placebo study.] Presse Med 1986;15:1556-1558. 30. Corbe C, Boisin JP,Siou A. [Light vision and chorioretinal circulation. Study of the effect of procyanidolic oligomers (Endotelon).] J Fr Ophthalmol1988;11:453-460. 31.Olson RJ. Supplemental antioxidant vitamins and minerals in patients with macular degeneration [abstract 521. J Am Coll Nutr 1991;10550. 32. Seddon JM, Wdett WC, Speizer FE. A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996;2761141-1146. 33. Singh MA. Exercise to prevent and treat functional disability. Clin Geriatr Med 2002;18:431-462.

Male Infertility Michael T. Murray, ND JosephE. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

1865

General Considerations 1865 Review of the Male Sexual System 1865

Therapeutic Approach 1873 General Measures 1873 Diet 1873 Nutritional Supplements 1873 Botanical Medicines 1873

Diagnostic Considerations 1867 Therapeutic Considerations 1868 Controlling Sperm-Damaging Factors Nutritional Considerations 1870 Botanical Medicines 1872

1868

DIAGNOSTIC SUMMARY Inability to conceive a child after 6 months of unprotected sex in the absence of female causes A total sperm count less than 5 million per ml The presence of more than 50% abnormal sperm Inability of sperm to impregnate egg as determined by the postcoital or hamster egg penetration test

GENERAL CONSIDERATIONS In the United States, it is estimated that as many as 18%of all couples have difficulty conceiving a child. In about one third of the cases of infertility, it is the man who is responsible; in one third, both the man and the woman are responsible; and in one third, it is the woman who is responsible. Current estimates suggest that about 6% of men between the ages of 15 and 50 years are infertile.' Most causes of male infertility reflect an abnormal sperm count or quality. Although it only takes one sperm to fertilize an egg, a man ejects nearly 200 million sperm in an average ejaculate. Because of the natural barriers in the female reproductive tract, only about 40 sperm ever reach the vicinity of an egg. There is a strong correlation between the number of sperm in an ejaculate and fertility. In about 90% of cases of low sperm count, the reason is deficient sperm production. Unfortunately, in about 90% of patients with deficient sperm production, the

cause cannot be identified and the condition is called idiopathic oligospermia or azoospermia. Oligospmia means a low sperm count, whereas azoospermia is defined as a complete absence of living sperm in the semen. Other causes of male infertility are ductal obstruction, ejaculatory dysfunctions,and infections or disorders of accessory glands (BOX188-1). Because the overwhelming majority of men who are infertile suffer from deficient sperm production, this disorder is the major focus of this chapter.

Review of the Male Sexual System The male sexual system is composed of the scrotal sac, testes, genital ducts, accessory glands, and penis. The scrotal sac performs an important role in maintaining the testes at a temperature about 2" C below the temperature of the internal organs so that sperm formation can occur. The cremasteric muscles help maintain the appropriate scrotal temperature by pulling the testes close to the body when they get too cold and dropping them loose when their temperature rises too high. In addition to being the location for sperm formation, the testes are responsible for hormonal output. Each testicle is surrounded by a thick, sturdy capsule of connective tissue known as the tunica albuginea, which serves as a protective shield for this somewhat exposed organ. Inside the testis are about 250 compartments known as testicular lobules, each of which is composed of one to four seminiferous tubules. Each tubule is 1.5 to 2 feet long if straightened out. 1865

Deficient sperm production Ductal obstruction: Congenital defects Postinfectious obstruction Cystic fibrosis Vasectomy Ejaculatory dysfunction: Premature ejaculation Retrograde ejaculation Disorders of accessory glands: Infection Inflammation Antisperm antibodies Coital disorders: Defects in technique Premature withdrawal Erectile dysfunction

Inside the seminiferoustubule, sperm formation takes place with the aid of nutrient-providing cells called Sertoli cells. Sertoli cells are known to have at least four main functions, as follows: Support, protection, and nutritional regulation of the developing sperm Breaking down of cellular debris cast off by developing sperm Secretion of a fluid that is utilized for sperm transport Excretion of estrogen and a binding protein for testosterone The seminiferous tubules are immersed in a web of blood and lymphatic vessels, loose connective tissue, nerves, and Leydig cells. These cells are responsible for the production and secretion of testosterone. Leydig cells are almost nonexistent in the testes during childhood but are numerous and quite active in the newborn male infant and in the adult male after puberty, the two times when the testes secrete large quantities of testosterone. The fully developed sperm (spermatozoa) is produced via a process known as spermatogenesis. Sperm production usually begins around puberty as a result of the release of the pituitary hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the Leydig cells to produce testosterone, and FSH stimulates the Sertoli cells to produce sperm. Other hormones are also critical, especially testosterone, which is essential for the growth and division of the germinal cells in the production of sperm. Estrogens, formed from testosterone by the Sertoli cells, are also critical to sperm function.

Genital Ducts The genital ducts function by transporting the sperm produced in the testis out of the body. The first passageway

is the epididymis, one long, highly tortuous tube about 20 feet long. As the sperm pass through the epididymis, they begin to mature. After being in the epididymis for 18 to 24 hours, the sperm become more motile (inhibitory fluids secreted by the epididymis prevent fullmotility until after ejaculation). From the epididymis, the sperm travel up through the ductus (vas) deferens, a straight tube with thick walls. Before the vas penetrates the prostate it dilates, forming a region known as the ampulla. At the final portion of the ampulla, the seminal vesicles join. Upon entering the prostate, the duct is called the ejaculatory duct before it empties into the urethra.

Accessory Glands It was previously thought that sperm were stored in the seminal vesicles-hence their name. We now know that the primary function of the seminal vesicles is the secretion of a fluid that provides nutrients to sperm and increases sperm motility. Substancessecreted by the seminal vesicles include fructose, which nourishes the sperm, and large quantities of prostaglandins and fibrinogen. Prostaglandins are thought to aid fertilization by reacting with the mucus of the vagina and cervix to make it more receptive to sperm and possibly by causing contractions in the uterus and fallopian tubes to move the sperm toward the ovaries. The fibrinogen combines with prostatic secretions to form a weak coagulate, which holds the semen together after ejaculation, allowing it deeper penetration into the vagina. The coagulate also limits sperm motility, but when the coagulate dissolves 15 to 20 minutes after ejaculation, the sperm become highly motile. About 60% of the volume of semen is composed of secretions from the seminal vesicles. The remainder of the semen is composed of prostatic fluid (30%of the total volume) and secretions from the vas deferens, including sperm and fluid (lO0/o of total volume). The prostate, a doughnut-shaped gland about the size of a walnut lying below the bladder and surrounding the urethra, secretes a thin,milky, alkaline fluid that lubricates the urethra to prevent infection and increases sperm motility. The alkaline nature of the prostatic secretion is extremely important to successful fertilization of the egg, because the fluid of the vas deferens as well as the vaginal secretions is relatively acidic. Sperm do not become optimally mobile until the pH of the surrounding fluids rises to approximately 6 to 6.5. Consequently, the prostatic fluid plays an important role in promoting sperm motility by neutralizing the acid and raising the pH of semen to 7.5. The final accessory sexual glands are the bulbourethral glands, pea-sized formations located below the prostate and around the urethra. The bulbourethral glands produce a thin,milky secretion that lubricates the urethra and prepares it for the transport of the semen.

Male Infertility

The Penis The penis consists primarily of erectile tissue, the urethra, and blood vessels, all surrounded externally by skin. The penis is divided into two distinct sections, the shaft and the head (glans penis). The glans is the most important source of nerve impulses to signal the sexual response. The shaft of the penis contains erectile tissue that is housed in three cylindrical masses. Two of the masses, the corpus cavernosum, are located around central arteries, and the other, the corpus spongiosum, surrounds the urethra. Erection is the result of dilatation of the arteries in the penis combined with the filling of the erectile tissue. In simple terms, an erection requires that the volume of blood entering the penis exceed the volume leaving it. The erectile tissue is really nothing more than large, cavernous, blood storage compartments, which are normally relatively empty but become dilated when arterial blood flows rapidly into them under pressure and the outflow is partially occluded. The erectile tissue is surrounded by a strong membrane composed of hard fibers, which greatly increases the pressure within the ballooning erectile tissue; thus the penis becomes hard and elongated.

DIAGNOSTIC CONSIDERATIONS Semen analysis is the most widely used test to estimate fertility potential in the male. The semen is analyzed for concentration of sperm and quality of sperm. The total sperm count as well as sperm quality of the general male population has been deteriorating over the last few decades. In 1940, the average sperm count was 113 million/ml; by 1990 that value had dropped to 66 million/mL2 Adding to this problem, the amount of semen fell almost 20% from 3.4 to 2.75 ml. Altogether, these changes mean that men are now supplying about 40% of the number of sperm per ejaculate compared

with 1940 levels (Box 188-2 presents possible causes for this drop). The downward trend in sperm counts has led to speculation that environmental, dietary, or lifestyle changes in recent decades may be interfering with a man's ability to manufacture sperm. Although this speculation is controversial, there is substantial evidence supporting it. This evidence and methods for improving sperm quality are discussed in greater detail later. Concerning the diagnosis of male infertility on the basis of sperm concentration, it is important to point out that as sperm counts in the general population have declined, there has also been a parallel reduction in the accepted line differentiatingbetween infertile and fertile men, from 40 million/ml, to 20 million/ml, to 10 million/ml, to 5 million/ml. One of the key reasons these values have dropped so drastically is that researchers are learning that quality is more important than quantity of sperm (Table 188-1). A high sperm count means absolutely nothing if the percentage of healthy sperm is not also high. Whenever the majority of sperm are abnormally shaped or are entirely or relatively nonmotile, a man can be infertile despite having a normal sperm concentration. Conversely, a low sperm count does not always mean a man is infertile (Box 188-3). Numerous pregnancies have occurred for couples with men who have very low sperm counts. For example, in studies at fertility clinics, 52% of couples whose sperm counts were less than 10 million/ml, and 40% of those with sperm counts as low as 5 million/ml, achieved pregnancy.' Because of these confirmed successesin men with low sperm counts,

Criteria

1.5-5 ml

Density

>20 million sperm/rnl >30% motile >60%

Motility Normal forms Increased scrotal temperature: Tight-fitting clothing and briefs Varicoceles are more common Environmental: Increased pollution Heavy metals (lead, mercury, arsenic, etc.) Organic solvents Pesticides (DDT, PCBS, DBCP, etc.) Dietary: Increased saturated fats Reduced intake of fruits, vegetables, and whole grains Reduced intake of dietary fiber Increased exposure to synthetic estrogens

Value

Volume

Increased scrotal temperature Infections, the common cold, the flu, etc. Increased stress Lack of sleep Overuse of alcohol, tobacco, or marijuana Many prescription drugs Exposure to radiation Exposure to solvents, pesticides, and other toxins

following nutritional factors must be considered; they are discussed in detail later: Test

Fertility prediction accuracy (Oh)

Semen analysis

30

Hamster egg penetration test

66

it is recommended that conventional semen analysis be interpreted with caution regarding the likelihood of conception and that more sophisticated functional tests should be used, especially in screening of couples for in vitro fertilization. Until recently, pregnancy was the only proof of the ability of sperm to achieve fertilization. Now several functional tests are in use (Table 188-2). The postcoital test measures the ability of the sperm to pene_trate the cervical mucus after intercourse. In vitro variants of this test are also available. One of the most encouraging tests is based on the discovery that human sperm can, under appropriate conditions, penetrate hamster eggs. It was established that fertile males exhibit a range of penetration of 10% to 100% and that penetration of less than 10% indicates infertility. The hamster egg penetration test is considered to predict fertility in 66% of the cases, compared with about 30% for conventional semen analysis.' Another important test in the diagnosis of infertility is the detection of antisperm antibodies. These antibodies, when produced by the man, usually attack the tail of the sperm, thereby impeding the sperm's ability to move and penetrate the cervical mucus. In contrast, the antisperm antibodies produced by women are typically directed against the head. The presence of antisperm antibodies in semen analysis is usually a sign of past or current infection in the male reproductive tract.

THERAPEUTIC CONSIDERATIONS Standard medical treatment of oligospermia can be quite effective when the cause is known-increased scrotal temperature, chronic infection of male sex glands, prescription medicines, and endocrine disturbances (including hypogonadism and hypothyroidism). However, as stated previously, the cause is unknown is 90% of cases of oligospermia (idiopathic oligospermia). With regard to azoospermia, if the cause is ductal obstruction, new surgical techniques are showing some good results.' The rational approach to the treatment of idiopathic oligospermia or azoospermia is to focus on enhancing those factors that promote sperm formation. In addition to scrotal temperature, sperm formation is closely linked to nutritional status. Therefore, it is critical that men with low sperm counts have optimal nutritional intake. In addition to consumption of a healthful diet, the

Antioxidants Fats and oils zinc Vitamin BI2 Carnitine Arginine

Controlling Sperm-Damaging Factors Scrota1 Temperature The scrotal sac normally keeps the testes at a temperature of between 94" and 96" E2At temperature above 96" F, sperm production is greatly inhibited or stopped completely. Typically, the mean scrotal temperature of infertile men is significantly higher than that of fertile men. Reducing scrotal temperature in infertile men is often enough to make them fertile. This temperature reduction is best achieved by having them avoid tightfitting underwear, tight jeans, and hot tubs. In addition, the following exercise or exercise equipment can raise scrotal temperature, especially if a man is wearing synthetic fabrics, exceptionally tight shorts, or tight bikini underwear: rowing machines, simulated cross-country ski machines, treadmills, and jogging. After exercising, a man should allow his testicles to hang free to allow them to recover from heat buildup. Infertile men should wear boxer-type underwear and periodically apply a cold shower or ice to the scrotum. They can also choose to use a device called a testicular hypothermia device or "testicle cooler" to reduce scrotal temperatures. The testicle cooler looks like a jock strap from which long, thin tubes have been extended. The tubes are attached to a small fluid reservoir filled with cold water that attaches to a belt around the waist. The fluid reservoir is also a pump that causes the water to circulate. When the water reaches the surface of the scrotum, it evaporates and keeps the scrotum cool. Because of the evaporation, the reservoir must be filled every 6 hours or so. It is recommended that the testicle cooler be worn daily during waking hours. Most users claim that it is fairly comfortable and easy to conceal? Increased scrotal temperature can be due to the presence of a varicocele. A large varicocele can cause scrotum temperatures high enough to inhibit sperm production and motility. Surgical repair may be necessary, but scrotal cooling should be tried first.

Infections and Infertility Infections in the male genitourinary tract, including infections of the epididymis, seminal vesicles, prostate, bladder, and urethra, are thought to play a major role in many cases of infer ti lit^.^ The exact extent of the role they play is largely unknown because of the lack of

Increased exposure to environmental estrogens and suitable diagnostic criteria coupled with the asymptoother environmental pollutants during fetal developmatic nature of many infections. The presence of antiment, as well as during the reproductive years, is sugsperm antibodies is considered a good indicator of a chronic infection in the absence of other clinical findings. gested to be a major cause of the tremendous rise in the incidence of disorders of development and function of A wide number of bacteria, viruses, and other organthe male sexual system? isms can infect the male genitourinary system. It is beyond the scope of this chapter to discuss every type One can best view the relationship between estrogens and male sexual development by examining the of infection, so the discussion is limited to Chlamydia traeffects of the synthetic estrogen diethylstilbestrol (DES). chomatis. Chlamydial infection is now recognized as the Between 1945 and 1971 several million women were most common as well as the most serious infection in treated with DES. By 1970, the side effects of DES became the male genitourinary tract.5 more known. DES is now recognized to have led to subChlamydial infection is considered a sexually transstantial increases in the number of men suffering from mitted disease. In women, it can lead to pelvic inflammatory disease (PID) and scarring of the fallopian tubes. developmental problems of the reproductive tract as Previous chlamydial infection accounts for a large well as decreased semen volume and sperm count^.^ As number of cases of female factor infertility. In men, well as being used in humans, DES and other synthetic chlamydial infection can lead to equally disabling effects. estrogens were used for 20 to 30 years in the livestock industry to fatten the animals and help them grow faster. Chlamydia is the major cause of acute nonbacterial prostatitis and urethritis. Typically the symptoms are pain or Although most synthetic estrogens like DES are now burning sensations upon urination or ejaculation. More outlawed, many livestock and poultry are still hormonally manipulated, especially dairy cows. Cow’s milk conserious is chlamydial infection of the epididymis and vas deferens. The resultant damage to these organs parallels tains substantial amounts of estrogen because of modem the tuba1 damage in women. Serious scarring and blockfarming techniques. The rise in dairy consumption since age can occur. During an acute chlamydial infection, the 1940s inversely parallels the drop in sperm counts. antibiotics are essential. The organism is sensitive to Avoidance of hormone-fed animal products and milk tetracyclines and erythromycin. Unfortunately, because products is important for male sexual vitality, especially Chlamydia lives within human cells, total eradication in men with low sperm counts or low testosterone levels. may be difficult with antibiotics alone. There are reports that estrogens have been detected Although acute chlamydial infections are usually in drinking ~ a t e r .Presumably ~,~ the estrogens are recyassociated with severe pain, chronic infections of the cled from excreted synthetic estrogens (birth control urethra, seminal vesicles, or prostate can occur with little pills) at water treatment plants. These estrogens may be or no symptoms. It is estimated that 28%to 71%of inferharmful to male sexual vitality because they are more tile men have evidence of a chlamydial infe~tion.~ potent-they do not bind to sex hormone-binding Because of the possible link between Chlamydiu and low globulin (SHBG). Purified or bottled water may be a suitable option to prevent exposure. sperm counts, several double-blind studies have been conducted on the effects of antibiotics on sperm counts. Other sources of estrogen in the environment (food, These studies have shown only limited improvements water, and air) can weaken male sexual vitality. For examin sperm count and sperm quality5However, there have ple, many of the chemicals that we have contaminated been isolated cases of tremendous increases in sperm our environment with in the past 50 years are weakly counts and sperm quality after antibiotic treatment. If estrogenic. Most of these chemicals, like polychlorinthe affected man elects this form of treatment, both partated biphenyls (PCBs), dioxin, and dichlorodiphenylners should take the antibiotic. However, it should be trichloroethane (DDT), are resistant to biodegradation used only if there is reason to believe that a chronic infecand are recycled in our environment until they find a tion is present and after the recommendations given in safe haven in our bodies. For example, even though Chapter 148 have been employed for at least 3 months. DDT has been banned for nearly 30 years, it is still often The presence of antisperm antibodies may indicate a found in the soil and root vegetables such as carrots and chronic chlamydial infection. In the absence of a positive potatoes. These toxic chemicals are known to interfere culture result, rectal ultrasonography and the detection with spermatogenesis, but their effects during sexual of antibodies directed against Chlamydia can confirm the development may be more important. diagnosis. All of the estrogenic factors previously discussed are thought to have their greatest impact during fetal develAvoiding Estrogens opment. On the basis of animal studies, these estrogens According to experts on the impact of the environment inhibit the multiplication of the Sertoli cells. The number and diet on fetal development, we now live in an environof Sertoli cells is directly proportional to the amount of ment that can be viewed as “a virtual sea of e~trogens.”~,~sperm that can be produced, because each Sertoli cell can

Specific Health Problems support only a fixed number of germ cells that will develop into sperm. Sertoli cell multiplication occurs primarily during fetal life and before puberty. It is controlled by FSH. In animal studies, estrogens administered early in life inhibit FSH secretion, resulting in a reduced number of Sertoli cells and, in adult life, diminished sperm counts. There is evidence indicating that the same events occur in humans6 The best example are the sons of women exposed to DES during pregnancy, who, like the animals exposed to estrogens, show reduced sperm counts. Even if a mother did not take DES, she may have followed the typically low-fiber, high-fat diet of most Americans. Such a diet is associated with higher levels of estrogens because, without the fiber, excreted estrogens are reabsorbed. If testosterone levels are low or marginal, or if estrogen levels are elevated, a diet rich in legumes (beans), especially soy foods, may be of benefit. Soy is a particularly good source of isoflavonoids. These compounds are also known as "phytoestrogens," signifying their mild estrogenic activity. The isoflavonoids in soybeans have about 0.2% of the estrogen activity of estradiol, the principal human estrogen. Isoflavones actually bind to estrogen receptors. Their weak estrogenic action is in actuality an antiestrogenic effect, because it prevents the binding of the body's own estrogen to the receptor. In addition, phytoestrogens may reduce the effects of estrogens on the body by stimulating the production of SHBG so that the estrogen is bound.8Soy as well as other legumes, nuts, and seeds is also a good source of phytosterols, which may aid in the manufacture of steroid hormones including testosterone.

Heavy Metals Sperm are also particularly susceptible to the damaging effects of heavy metals such as lead, cadmium, arsenic, and mercury.' A hair mineral analysis for heavy metals should be performed on all men with reduced sperm counts to rule out heavy metals as a cause.

Nutritional Considerations Antioxidants Free radical or oxidative damage to sperm is thought to be responsible for many cases of idiopathic oligospermia, high levels of free radicals being found in the semen of approximately 40% of infertile The following three factors combine to render sperm particularly susceptible to damage by free radicals: A high membrane concentration of polyunsaturated fatty acids Active generation of free radicals A lack of defensive enzymes All of these factors combine to make the health of the sperm critically dependent on antioxidants.

Although most free radicals are produced during normal metabolic processes, the environment contributes greatly to the free radical load. Men exposed to higher levels of sources of free radicals are much more likely to have abnormal sperm and sperm counts?-" Sperm are extremely sensitive to free radicals because they depend so much on the integrity and fluidity of their cell membrane for proper function. Without proper membrane fluidity, enzymes are activated, possibly leading to impaired motility, abnormal structure, loss of viability, and, ultimately, death of the sperm. The major determinant of membrane fluidity is the concentration of polyunsaturated fatty acids, particularly omega-3 fatty acids like docosahexaenoic acid, which are very susceptible to free radical damage. The sperm have a relative lack of superoxide dismutase and catalase, which can prevent or repair oxidative damage. Adding to this more susceptible state is the fact that sperm generate high quantities of free radicals to help break down barriers to fertilization. A common source of oxidants is cigarette smoking, which is associated with decreased sperm counts and sperm motility as well as a higher frequency of abnormal sperm.'* Cigarette smoking, as well as the increase in environmental pollution, is thought to be a major contributor to the diminution in sperm counts seen in many industrialized nations during the past few decades. Antioxidants such as vitamin C, beta-carotene, selenium, and vitamin E have been shown to be very important in protecting the sperm against damage. Vitamin C plays an especially important role in protecting the sperm's genetic material (DNA) from damage. Ascorbic acid levels are much higher in seminal fluid compared with other body fluids, including the blood. When dietary vitamin C was reduced from 250 to 5 mg/day in healthy human subjects, the seminal fluid ascorbic acid content decreased by 50% and the number of sperm with damage to their DNA rose by 91Y0.'~These results indicated that dietary vitamin C plays a critical role in protecting against sperm damage and that low dietary vitamin C levels were likely to lead to infertility. It is now well documented that cigarette smoking greatly reduces vitamin C levels throughout the body. Even the Food and Nutrition Board, the organization that calculates the recommended dietary allowances (RDAs), acknowledges that smokers require at least twice as much vitamin C as nonsmoker^.'^ In one study, men who smoked one pack of cigarettes a day received either 0, 200, or 1000 mg of vitamin C. After 1 month, sperm quality improved in proportion to the level of vitamin C ~upp1ementation.l~ Nonsmokers also appear to benefit from vitamin C as much as smokers. In one study, 30 infertile but otherwise healthy men received either 200 or 1000 mg vitamin C or placebo daily.l6 Sperm count, viability, motility, agglutination, abnormalities, and immaturity

were measured weekly. After 1week, the 1000-mg group demonstrated a 140%increase in sperm count, the 200-mg group a 112% increase, and the placebo group no change. After 3 weeks both vitamin C groups continued to improve, with the 200-mg group catching up to the improvement of the 1000-mg group. One of the key improvements was observed in the number of agglutinated sperm. Sperm become agglutinated when antibodies produced by the immune system bind to them. Antibodies to sperm are often associated with chronic genitourinary tract or prostatic infection. When more than 25% of the sperm are agglutinated, fertility is very unlikely. At the beginning of the study all three groups had more than 25% agglutinated sperm. After 3 weeks, the proportion of agglutinated sperm in the vitamin C groups dropped to 11%.Although this result is significant, the most impressive result of the study was that at the end of 60 days, all of the vitamin C groups had impregnated their wives, compared with none of the placebo group. Therefore, vitamin C supplementation can be very effective in treating male infertility, particularly if it is due to antibodies against sperm. Other dietary antioxidants, such as vitamin E, selenium, and beta-carotene, are also important and should be supplemented. Vitamin E supplementation appears to be especially warranted because this vitamin is the main antioxidant in various cell membranes, including sperm membranes. Vitamin E has been shown to play an essential role in inhibiting free radical damage to the unsaturated fatty acids of the sperm mernbraneI7and to enhance the ability of sperm to fertilize an egg in test tubes. In one study, supplementation with vitamin E was found to decrease malondialdehyde concentration in sperm pellet suspensions. Even more important, however, 11 of 52 treated infertile men impregnated their spouses.18In another study, vitamin E (400 mg) and selenium (225 pg) sigruficantly improved sperm quality? Supplementation appears to be indicated on the basis of its physiologic effects alone. Vitamin E may prove to exert more beneficial effects on sperm counts or motility when given at higher levels (600 to 800 IU/day) and in combination with selenium (100 to 200 pg/day). Lycopene supplementation has also been shown to be helpful. Lycopene is found in high concentrations in the testes and seminal plasma, and reduced levels have been demonstrated in men with infertility. In one clinical trial, 30 men with idiopathic nonobstructive oligo/astheno/ teratozoospermia were administered 2 mg of lycopene twice a day for three months. Twenty patients (66%) showed an improvement in sperm concentration, 16 (53%) had improved motility, and 14 (46%)showed improvement in sperm morphology. In patients showing an improvement, the median changes were 22 million/ml in concentration, motility 25% in motility, and 10% in

Proanthocyanidins may also prove effective in some cases. In one study, 19 subfertile men were given 200 mg proanthocyanidins daily for 90 days. The therapy improved capacitated sperm morphology and yielded functionally normal spermF1 It should be pointed out that although most studies of antioxidants have shown positive results, some clinical trials have demonstrated no significant effects of antioxidant supplementation in improving sperm q ~ a l i t y . The ~ , ~ likely explanation is that antioxidant supplementation produces clinical results only when increased oxidative stress is a primary factor.

Fats and Oils Because of the effects of fats and oils on agglutination and cell membrane dynamics, certain fats are best avoided in infertile men, and consumption of others should be increased. Saturated fats, hydrogenated oils, trans-fatty acids, and cotton, coconut, and palm oils should be avoided. Coconut and palm oils are primarily saturated fat, and cotton seed may contain toxic residues because of the heavy spraying of cotton and its high levels of gossypol, a substance known to inhibit sperm function. In fact, gossypol is being investigated as the "male birth control pill." Its use as an antifertility agent began after studies demonstrated that men who had used crude cottonseed oil for cooking were shown to have low sperm counts followed by total testicular fail~ r eExcessive . ~ ~ consumption of saturated fats combined with inadequate intake of essential fatty acids changes the fatty acid composition of the sperm membranes, thus reducing fluidity and interfering with sperm motility. The patient must be informed to read food labels carefully and to avoid all sources of cottonseed oil and other damaging oils. Although the intake of saturated and hydrogenated fats must be eliminated, the intake of polyunsaturated oils should be increased. These latter oils function in all aspects of sexual function, including sperm formation and activity.

Zinc Zinc is perhaps the most critical trace mineral for male sexual function. It is involved in virtually every aspect of male reproduction, including hormone metabolism, sperm formation, and sperm motility. Among many other problems, zinc deficiency is characterized by decreases in testosterone levels and sperm counts. Zinc levels are typically much lower in infertile men with low sperm counts, indicating that a low zinc status may be the contributing factor in the infertility.24,25 Several studies have evaluated the effect of zinc supplementation on sperm counts and m ~ t i l i t y . ~ ~ - ~ ~ The results of all of the studies support the use of zinc supplementation in the treatment of oligospermia,

Specific Health Problems Conversely, when camitine levels are low, sperm develespecially in the presence of low testosterone levels. opment, function, and motility are drastically reduced? The effectiveness of zinc is best illustrated by a study in Several clinical studies have shown that camitine 37 men with infertility of greater than 5 years’ duration whose sperm counts were less than 25 m i l l i ~ n / m l . ~ ~supplementation can produce dramatic improvements in sperm counts and sperm motility. In the Italian Study Blood testosterone levels were also measured. The Group on Carnitine and Male Infertility, 100 subjects men received a supplement of zinc sulfate (60 mg elewere given 3000 mg of L-carnitine daily for 4 months.31 mental zinc daily) for 45 to 50 days. In the 22 patients Carnitine was able to increase sperm counts and sperm with initially low testosterone levels, mean sperm count rose signhcantly from 8 to 20 million/ml. Testosterone motility in both a qualitative and a quantitative manner, as follows: levels also increased, and 9 of the 22 wives became pregnant during the study. This result is quite impresThe number of ejaculated sperm per ml increased from sive given the long-term nature of the infertility and 142 billion to 163 billion. the rapidity of the results. In contrast, in the 15 men The percentage of motile sperm increased from 26.9% who had had normal testosterone levels before the to 37.7%. study, sperm count increased slightly, but there was no The percentage of sperm with rapid linear progression change in testosterone levels and no pregnancies increased from 10.8% to 18%. occurred. The mean sperm velocity increased from 28.4% to Optimal zinc levels must be attained if optimum male 32.5%. sexual vitality is desired. Although severe zinc defiThe results are even more impressive if results for ciency is quite rare in this country, many men consume only the patients with the poorest sperm motility are a diet that does not provide the RDA for zinc (15 mg). examined. This subgroup saw even more significant Zinc is found in whole grains, legumes, nuts, and seeds. gains on all parameters. For example, the percentage of In addition to consumption of these zinc-containing motile sperm increased from 19.3% to 40.9%, and the foods, a recommendation for supplementary zinc (45 to percentage of sperm with rapid linear progression 60 mg/day) appears warranted. increased from 3.1% to 20.3%. These results have been Vitamin BI2 confirmed in several double-blind ~ t u d i e s . ~ ~ ” ~ It is clear that supplementing the diet with L-carnitine Vitamin Blz is involved in cellular replication. A may be useful in restoring male fertility in some cases. deficiency of BIZ leads to reduction in sperm count and However, because L-carnitine tends to be relatively motility. Even in the absence of a vitamin B12 deficiency, expensive, the other nutritional measures should be supplementation appears to be worthwhile in men tried first. The optimal dosage is 1000 mg of L-carnitine who have sperm counts less than 20 million/ml or a three times daily. motility rate of less than 50%. In one study, 27% of men with sperm counts less than 20 million/ml who were Arginine given 1000 pg/day of vitamin BIZwere able to achieve a total sperm count in excess of 100 m i l l i ~ n / m l .In~ ~ The amino acid arginine is required for the replication of cells, making it essential in sperm formation. Arginine another study, 57% of men with low sperm counts who supplementation is often, but not always, an effective took 6000 pg/day demonstrated improvements.m treatment for male infertility. The critical determinant Carnitine appears to be the level of oligospermia. If sperm counts are less than 20 million/ml, arginine supplementation is The antioxidant with the greatest amount of clinical less likely to be of benefit. In order to be effective, the research behind it for the treatment of male infertility dosage of L-arginine must apparently be at least 4 g/day is carnitine. Because carnitine is essential in the transport for 3 months. In perhaps the most favorable study, 74% of fatty acids into the mitochondria, a carnitine defiof 178 men with low sperm counts had significant ciency results in a decrease in fatty acid concentrations improvements in sperm counts and motility after argiin the mitochondria and reduced energy production. nine therapy.% L-Arginine should be reserved for use Carnitine concentrations are extremely high in the after other nutritional measures have been tried. epididymis and sperm, suggesting a role for this antioxidant in male reproductive function. The epididymis Botanical Medicines derives the majority of its energy requirements from Ginseng fatty acids, as do the sperm, during transport through Current scientific investigation suggests that both Panax the epididymis. After ejaculation, the motility of sperm ginseng (Chinese or Korean ginseng) and Eleutherococcus correlates directly with camitine content. The higher setzticosus (Siberian ginseng) are likely to be effective in the carnitine content, the more motile the sperm.

Male Infertility

the treatment of male infertility. Both botanicals have a long history of use as male "tonics." Although human clinical studies are lacking, P. ginseng has been shown to promote the growth of the testes, raise sperm formation and testosterone levels, and increase sexual activity and mating behavior in studies with animals (see Chapter 133 for references). Siberian ginseng has also shown some benefit to the male reproductive function in animal studies, as it has been shown to increase reproductive capacity and sperm counts in bulls (see Chapter 109 for references). These results seem to support the use of either ginseng as a fertility and virility aid. In general, F! ginseng is regarded as being more potent in its effects (particularly stimulant effects) than E. senticosus. Although Siberian ginseng contains no ginsenosides and is not a true ginseng, it does possess many of the same effects as I? ginseng but is generally regarded as being milder.

Pygeum aficanum Pygeum africanum may be effective in improving fertility

underwear made of cotton, avoidance of activities that raise testicular temperature (e.g., hot tubs) and application of cold water to the testes should be utilized. Nutritional status should be optimized (especially consumption of antioxidants and zinc), environmental pollutants identified and eliminated, and fertilityenhancing botanicals such as the ginsengs consumed.

General Measures Maintain scrotal temperatures between 94" and 96.8"F. Avoid exposure to free radicals. Identify and eliminate environmental pollutants. Stop or reduce all drugs, especially antihypertensives, antineoplastics such as cyclophosphamide, and antiinflammatory drugs such as sulfasalazine. Utilize effective stress-reduction techniques and employ psychological counseling if needed.

Diet Avoid dietary sources of free radicals, saturated fats, hydrogenated oils, trans-fatty acids, and cottonseed oil. Increase consumption of legumes, especially soy (high in phytoestrogens and phytosterols), good dietary sources of antioxidant vitamins, carotenes, and flavonoids (dark vegetables and fruits), and essential fatty acids and zinc (nuts and seeds). Recommend the daily consumption of 8 to 10 servings of vegetables, 2 to 4 servings of fresh fruits, and half a cup of raw nuts or seeds.

in cases in which diminished prostatic secretion plays a significant role. Pygeum has been shown to increase prostatic secretions and improve the composition of the seminal f l ~ i d . Specifically, ~ ~ - ~ ~ pygeum administration to men with decreased prostatic secretion has led to increased levels of total seminal fluid plus increases in alkaline phosphatase and protein content. Pygeum appears to be most effective in men in whom the level of alkaline phosphatase activity is reduced (i.e., less than Nutritional Supplements 400 IU/cm3) and there is no evidence of inflammation or infection (i.e., absence of white blood cells and Multiple vitamin and mineral immunoglobulin A [IgA]).The lack of IgA in the semen Vitamin C: 1000 to 3000/day in divided doses is a good indicator of clinical success. In one study, the Vitamin E:600 to 800 IU/day patients with no IgA in the semen demonstrated an alkaBeta-carotene: 100,000 to 200,000 IU/day line phosphatase increase from 265 to 485 I U / C ~In~ . ~ Folic ~ acid: 400 Fg/day contrast, those subjects with IgA showed only a modest Vitamin BIZ:1000 yg/day Zinc: 30 to 60 mg/day increase from 213 to 281 IU/cm3. Pygeum extract has also shown an ability to improve Botanical Medicines the capacity to achieve an erection in patients with benign prostatic hypertrophy (BPH) or prostatitis as P. ginseng (three times/day dosages): determined by nocturnal penile tumescence in a doubleHigh-quality crude ginseng root: 1.5 to 2 g/day blind clinical trial.4O BPH and prostatitis are often Standardized extract (5% ginsenosides):500 mg associated with erectile dysfunction and other sexual disturbances. Presumably, by alleviating the underlying E . senticosus: condition, pygeum can improve sexual function. Dried root 2 to 4 g Tincture (1:5):10 to 20 ml THERAPEUTIC APPROACH Fluid extract (13):2.0to 4.0ml Solid (dry powdered) extract (20:l):100 to 200 mg Male infertility is most often due to an abnormal sperm count or semen quality. Referral to a urologist or fertility The dosage of ginseng is related to the ginsenoside specialist for a complete evaluation is often necessary. content. The typical dose (taken one to three times daily) Because elevated scrotal temperature is a common cause should contain a saponin content of at least 25 mg of of infertility, scrotal cooling through the use of loose ginsenosides with an Rbl/Rgl ratio of 2:l.For example,

Specific Health Problems

for a high-quality ginseng root extract containing 5% ginsenosides, the dose would be 500 mg. Because each person’s response to ginseng is unique, care must be taken to observe possible ginseng toxicity (see Chapter 111). It is best to begin at a lower dose

and increase it gradually. The Russian approach for long-term administration of either Punux or Siberian ginseng is to use ginseng cyclically for a period of 15 to 20 days followed by a 2-week interval without any ginseng; this practice appears prudent.

1. Brugh VM 3 4 Lipshultz LI. Male factor infertility: evaluation and management. Med Clin North Am 2004;88:367-385. 2. Carlsen E, Giwercman A, Keiding N, Shakkebaek NE. Evidence for decreasing quality of semen during past 50 years. BMJ 1992; 305: 609-613. 3. Zorgniotti AW, Cohen MS, Sealfon AI.ChroNc scrotal hypothermia: results in 90 infertile couples. J Urol1986;135:944-947. 4. Purvis K, Christiansen E. Review: infection in the male reproductive tract. Impact, diagnosis and treatment in relation to male infertility. Int J Androl1993;16:1-13. 5. Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproduction tract? Lancet 1993;341:1392-1395. 6. Field 8, Selub M, Hughes CL. Reproductive effects of environmental agents. Semin Reprod Endocrinol1990;8:44-54. 7. Joffe M. Infertility and environmental pollutants. Br Med Bull 2003; W.47-70. 8. Messina M, Messina V. Increasing the use of soyfoods and their potential role in cancer prevention. J Am Diet Assoc 1991;91: 836-840. 9. Agarwal A, Nallella KP, Allamaneni SS, et al. Role of antioxidants in treatment of male infertility: an overview of the literature. Reprod Biomed Online 2004;8:616-627. 10. Zini A, de Lamirande E, Gagnon C. Reactive oxygen species in semen of infertile patients: levels of superoxide dismutase- and catalase-like activities in seminal plasma and spermatozoa. Int J Androl1993;16183-188. 11. Pasqualotto FF, Sharma RK, Nelson DR, et al. Relationship between oxidative stress, semen characteristics, and clinical diagnosis in men undergoing infertility investigation. Fertil Steril 2000;73: 459464. 12. Saleh RA, Agarwal A, Sharma RK, et al. Effect of cigarette smoking on levels of seminal oxidative stress in infertile men: a prospective study. Fertil Steril2002 Sep;78:491499. 13. Fraga CG, Motchnik PA, Shigenaga MK, et al. Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. Proc Natl Acad Sci U S A 1991;88:11003-11006. 14. National Research Council. Recommended dietary allowances, 10th ed. Washington, DC:National Academy Press, 1989. 15. Dawson E, Harris W, Powell L. Effect of vitamin C supplementation on sperm quality of heavy smokers. FASEB J 1991;5A915. 16. Dawson EB, Harris WA, Rankin WE, et al. Effect of ascorbic acid on male fertility. Ann NY Acad Sci 1987;498:312-323. 17. Aitken RJ, Clarkson JS, Hargreave TB, et al. Analysis of the relationship between defective sperm function and the generation of reactive oxygen species in cases of oligozoospermia. J Androll989; 10: 214220. 18. Suleiman SA, Ali ME, Zaki ZM, et al. Lipid peroxidation and human sperm mobility: protective role of vitamin E. J Androl 1996;17530-537. 19.Keskes-Ammar L, Feki-Chakroun N, Rebai T, et al. Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men. Arch Androl2003; 49:83-94.

20.Gupta NP, Kumar R. Lycopene therapy in idiopathic male infertility-a preliminary report. Int Urol Nephrol 2002;34: 369-372. 21. Roseff SJ. Improvement in sperm quality and function with French maritime pine tree bark extract. J Reprod Med 2002;47 821-824. 22.Rolf C, Cooper TG, Yeung CH, et al. Antioxidant treatment of patients with asthenozoospermia or moderate oligoasthenozoospermia with high-dose vitamin C and vitamin E a randomized, placebo-controlled, double-blind study. Hum Reprod 1999;14 1028-1033. 23. Weller DP, Zaneveld JD, Famsworth NR. Gossypol. Pharmacology and current status as a male contraceptive. Econ Med Plant Res 1985;1:87-112. 24.Prasad AS. Zinc in growth and development and spectrum of human zinc deficiency. J Am Coll Nutr 1988;7377-384. 25. El-Tawil AM. Zinc deficiency in men with Crohn’s disease may contribute to poor sperm function and male infertility. Andrologia 2003;35:337-341. 26.Takihara H, Cosentino MJ, Cockett AT. Zinc sulfate therapy for infertile males with or without varicocelectomy. Urology 1987; 29638-641. 27. Netter A, Hartoma R, Nakoul K. Effect of zinc administration on plasma testosterone, dihydrotestosterone and sperm count. Arch Androl 1981;769-73. 28. Wong WY, Merkus HM, Thomas CM, et al. Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. Fertil Steril2002;77:491-498. 29. Sandler B, Faragher B. Treatment of oligospermia with vitamin B12. Infertility 1984;7133-138. 30.Kumamoto Y, Maruta H, Ishigami J, et al. [Clinical efficacy of mecobalamin in treatment of oligozoospermia. Results of a doubleblind comparative clinical study.] Acta Urol Japan 1988;34: 1109-1132. 31.Costa M, Canale D, Filicori M, et al. L-Camitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Camitine and Male Infertility. Andrologia 1994;26155-159. 32. Vitali G, Parente R, Melotti C. Camitine supplementation in human idiopathic asthenospermia. Clinical results. Drugs Exp Clin Res 1995;21:157-159. 33. Vicari E, La Vignera S, Calogero AE. Antioxidant treatment with carnitines is effective in infertile patients with prostatovesiculoepididymitis and elevated seminal leukocyte concentrations after treatment with nonsteroidal anti-inflammatory compounds. Fertil Steril2002;78:1203-1208. 34. Lenzi A, Sgro P, Salacone P, et al. A placebo-controlled double-blind randomized trial of the use of combined -camithe and -acetylcarnitine treatment in men with asthenozoospermia. Fertil Steril 2004;81:157&1584. 35.Lenzi A, Lombard0 F, Sgro P, et al. Use of camitine therapy in selected cases of male factor infertility: a double-blind crossover trial. Fertil Steril2003;79:292-300. 36. Schacter A, Goldman JA, Zukerman 2 . Treatment of oligospermia with the amino acid arginine. J Urol 1973;110311-313.

Male Infertility 37. Lucchetta G, Weill A, Becker N, et al. Reactivation of the secretion from the prostatic gland in cases of reduced fertility. Biological study of seminal fluid modifications. Urol Int 1984;39222-224. 38. Menchini-Fabris GF, Giorgi,'F Reini F, et al. [New perspectives of treatment of prostato-vesicular pathologies with Pygeurn uficunum.] Arch Int Urol1988;60313-322.

39. Clavert A, Cram C, Riffaud JP, et al. Effects of an extract of the bark of Pygeurn ufricunurn on prostatic secretions in the rat and man. AM Urol 1986;20:341-343. 40.Carani C, Salvioli C, Scuteri A, et al. [Urological and sexual evaluation of treatment of benign prostatic disease using Pygcum ufiicnnum at high dose.] Arch Ital Urol Nefrol Androl 1991;63:341-345.

Menopause Tori Hudson, ND CHAPTER C O N T E N T S Diagnostic Summary 1877 Introduction 1877 General Considerations 1878 Hormone ReplacementTherapy 1878 Types of Hormone ReplacementTherapy 1888 The Major Symptoms of Menopause 1889

Botanical Medicines 1893 Natural Topical Preparations 1896 Lifestyle Factors 1896 Therapeutic Approach 1896 Diet 1897 Supplements 1897 Botanical Medicines 1897 Lifestyle 1897

Therapeutic Considerations 1890 Diet 1890 Nutritional Supplements 1892

DIAGNOSTIC SUMMARY Last spontaneous menstrual period 12 months prior. Average age of onset is 51 years. Symptoms can but do not necessarily consist of hot flashes, night sweats, palpitations, headaches, insomnia, mood swings, anxiety, vaginal dryness, urinary incontinence, rheumatism, fatigue, hair thinning, skin dryness, acne, facial hair, low libido, bladder infections, vaginal infections, nausea, mild cognitive changes, irregular bleeding with perimenopause. Physical examination: vaginal thinning, hair thinning and facial hair, height, weight, abdominal fat, general physical. Laboratory test follicle stimulating hormone (FSH) measurement. Laboratory and imaging findings may be used to assess risks for osteoporosis and cardiovascular disease.

INTRODUCTION Menopause denotes the cessation of menstruation in a woman, which usually occurs when she reaches the age 51 years. Twelve months without a period is the commonly accepted rule for diagnosing menopause. The time prior to menopause is referred to as perimenopausal, whereas the time after menopause is referred to as postmenopausal. During the perimenopausal period,

many women ovulate irregularly and therefore begin to have changes in the menstrual cycle, with or without other symptoms. With the prolongation of life expectancy, the menopausal and postmenopausal periods are becoming more sigruficant in a woman’s life. In fact, today’s average woman can expect to live at least one third of her life in the postmenopausal stage. Current conventional medical treatment of menopause primarily involves short-term (1 to 5 years) hormone replacement therapy (HRT) for the primary indication of menopause symptoms, utilizing a combination of estrogen and a progestogen. The obvious question is, “Is hormone replacement therapy necessary?” The goal of this chapter is to answer this question and offer an approach to perimenopause and menopause that provides many different options. By the year 2015, nearly 50% of the women in the United States will be menopausal. Between 1990 and 2020, the menopausal population in the country will double. This dramatic rise in the number of menopausal women is changing the way health care providers work with women, and changing medicine itself. At no other time in history have so many individuals been dealing with the same set of health care issues. Now more than ever, clinicians have options for the management of menopause: diet, exercise, stress management, nutrition, botanicals, natural hormones, conventional hormones, and additional pharmaceuticals. 1877

GENERAL CONSIDERATIONS Hormone Replacement Therapy The Evolution of Estrogen Replacement Therapy During the 1940s and 1950s, estrogen became a popular prescription for ameliorating the symptoms of menopause. By the 1970s, estrogen replacement therapy (ERT) became firmly entrenched as the medical treatment of choice for women in menopause. Unfortunately, the consequences of long-term estrogen therapy were not well understood. It is now well established that ERT without an appropriate progestogen is associated with an increased risk of endometrial cancer.' To combat the link between estrogen and endometrial cancer, pharmaceutical companies and physicians began recommending that estrogen be combined with a progestogen. ERT thus became HRT. The combination of estrogen with a progestogen (either a progestin or oral micronized progesterone) reduces the risk of endometrial cancer with HRT to a lower value than the risk of a natural perimenopause transition without HRT.

The Benefits and Risks of Hormone Replacement Therapy and the Role of Natural Hormones One of the most complicated and most difficult health care decisions that menopausal women face today is whether to use HRT. Women look to their health care providers for definitive answers to these questions. Practitioners are faced with an even greater challenge, evaluating the benefits and risks of conventional hormone replacement therapy (cHRT)and natural hormone replacement therapy (nHRT) for an individual patient. In the year 2000, 46 million prescriptions for the conjugated estrogen preparation kemarin were written in the United States. An additional 22.3 million prescriptions were written for the preparation with medroxyprogesterone (PremPro). Almost one in three women given a prescription for cHRT never have it filled. Of those who do start cHRT, the majority discontinue its use shortly after starting therapy. Reasons given for discontinuation include uterine bleeding; side effects including mood changes, breast tenderness, bloating and weight gain; a fear of breast cancer; and not understanding or believing in the need for long-term use. Lack of compliance can also be attributed to inadequate education of many women's practitioners regarding the needs of menopausal women, both gynecologic and nongynecologic. Many health care practitioners also have a limited understanding of the many therapeutic options for menopause symptoms and of more global issues of menopause. In addition, holistic menopause practitioners who utilize both cHRT and nHRT hold that compliance improves with the use of

nHRT and many side effects disappear or improve when patients switch from cHRT to nHRT. Sadly, many menopausal women have a limited understanding of the long-term health risks associated with this change in hormone status, and very few women believe that they are well informed about the benefits and risks of cHRT (or nHRT). Each woman wants to know whether HRT is right for her-how she may benefit, how long she will have to take it to receive those benefits, and what the short-term side effects as well as the potential long-term negative effects are. Scientific evidence regarding the use of postmenopausal hormone therapy comes in many shapes: observational studies, large-scale randomized trials, small clinical trials, biologic plausibility, in vitro studies, and animal studies. Other factors involved in the hormone conundrum are theoretical questions, areas of scientific uncertainty, popular consumer opinions and fears, and history. Definitive evidence for the benefits and risks of hormone replacement has been clarified by the two Heart and Estrogen/progestin Replacement Studies (HERS I and 11) trials and the Women's Health Initiative (WHI). Another large-scale trial conducted in 14 countries, the Women's International Study of long Duration Oestrogen after Menopause (WISDOM), was discontinued in November 2004 for scientific and practical reasons. Because WISDOM was to be completed after the publication of WHI results, "there were no safety concerns for the 5,700 women enrolled in the study. However, the trial was not expected to provide substantial evidence that would have an impact on clinical practice decisions in the next 10 years."2 Women and their health care practitioners are faced with trying to make the best decision possible on the basis of what we do know, what we do not know, and what we are still uncertain about. Benefits Symptoms The decline of endogenous estrogen leads to multiple tissue and organ changes and problems. In addition to the reproductive and urinary tracts, estrogen-sensitive tissues are skin, bone, vascular lining, teeth and gums, eyes, the brain, and the central nervous system. Fdty percent to 80% of women in the United States report menopause-related hot flashes, night sweats, vaginal dryness, insomnia, mood swings and depression. During the first 5 to 10 years of menopause, vulvovaginal symptoms begin to appear. Later, as the other mucous membranes of the urogenital tract become affected, rates of incontinence and infections rise. There is strong evidence and data from randomized clinical trials that estrogen therapy is very effective in controlling vasomotor symptoms and genitourinary symptoms. Vaginal estrogen is as efficacious as oral

Menopause or transdermal estrogen for genitourinary symptoms and may be an advantageous method because of the local delivery and local effect. Sex steroids also affect sleep, libido, cognitive function, motor coordination, and pain sensitivity. Data are mixed regarding the role of menopause in depression and mood swings; however, depression and mood disorders appear to be more common or at least exacerbated in perimenopause or early menopause compared with the reproductive period, and hormone therapy benefits many women. The North American Menopause Society (NAMS) and its advisory panel published a post-WHI report and recommendations on postmenopausal hormone therapy. One of its basic recommendations is that the treatment of menopause symptoms (especiallyvasomotor and urogenital) remains the primary indication for HRT or ERT.

Osteoporosis Estrogen is known to inhibit the age-related bone loss that occurs in most menopausal women. Observational studies have indicated that the use of estrogen reduces the risk of vertebral fracture by approximately 50% and the risk of hip fracture by 25% to 30%? Estrogen has been considered the therapeutic agent of choice for both prevention and treatment of postmenopausal osteoporosis in women for many years, until the WHI results. It has been the most-studied agent for prevention and has been shown to decrease bone resorption, prevent osteoporosis, and reduce fractures. Nevertheless, the U.S. Food and Drug Administration (FDA) has removed estrogen from the list of agents approved as effective in treating women who already have osteoporosis. This decision has nothing to do with any new discovery of a decrease in effectiveness for this indication; rather it arose as an issue of fairness in new standards that have been applied to approving other drugs for osteoporosis treatment, such as the bisphosphonates (risedronate and alendronate). These agents have involved prospective fracture reduction studies on women with low bone mass and/or fracture. The data on estrogen treatment for existing osteoporosis are largely observational and retrospective in nature. These studies do demonstrate the efficacy of estrogen in treating patients with osteoporosis, but randomized clinical trials will be required before the FDA reinstates its indication! That being said, the WHI was a large clinical trial in which 16,608 postmenopausal women age 50 to 79 years were studied at 40 U.S. clinical centers? The regimen used, was continuous-combined estrogen-progestogen therapy (CCEPT) (e.g., PremPro). Women in the CCEPT group experienced lower rates of hip fracture (10 per 10,000 person-years versus 15 per 10,000 person-years in the placebo group, a 34% lower relative risk) and vertebral fracture (9 events per 10,000 women annually

versus 15 events per 10,000 women annually for placebo, also a 34% lower relative risk). Statistically significant fracture reductions were also seen in other osteoporotic fractures (23%)and total fractures (24%). The different estrogen agents approved for the prevention of osteoporosis and their antiresorptive effects are as follows: Oral micronized estradiol, 1.0 mg Conjugated equine estrogens (CEE), 0.625 mg Ethinyl estradiol, 5 pg Transdermal estradiol, 50 pg Esterified estrogen, 0.3 mg It is important to keep in mind that some women derive benefits from these doses, some will need higher doses, and others will have adequate bone protection with lower doses. Dual-energy x-ray absorptiometry (DEXA) scans provide the most reliable objective information on the status of bone mineral density.

Colorectal cancer Observational studies have accumulated that now suggest that the use of ERT reduces the risk for development of colorectal cancer as well as the risk of dying from colon cancer? Although not all study findings are consistent, some studies have shown that the risk of development of fatal colon cancer was reduced by 33%; and others show as little as an 8% reduction in risk.8

Risks Endometrial cancer Unopposed estrogen administration is associated with an increase in the risk of endometrial cancer by a factor of 8 to 10. This results in an excess of 46 cases per 10,000 women for women who use unopposed estrogen for at least 10 years? The risk decreases after discontinuation of the ERT, but it is still elevated after more than 10 years. Adding a proven dose and delivery method of a progestogen (progestins or progesterone), which opposes the effects of estrogen on the endometrium, reduces the risk to a minimum and is essential to preventing endometrial hyperplasia and endometrial cancer. A boon to the use of natural hormones, particularly oral micronized progesterone (OMP), came in the form of the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial and its study of the effects of HRT on endometrial histology in postmenopausal women.'O This trial confirmed that daily CEE, 0.625 mg, enhanced the development of endometrial hyperplasia, and that combing CEE with cyclic or continuous medroxyprogesterone acetate (MPA) protected the endometrium from hyperplastic changes. What was new was that the trial also concluded that cyclic OMP (200 mg daily for 12 days per month) also protected the endometrium from the

hyperplastic changes associated with estrogen-only therapy. Thus the PEP1 was the first clinical trial proving that OMP was as appropriate as MPA for use in the protection of the endometrium. Compounded OMP was already available, but the product Prometrium came on to the market as a result of that study.

Venous thromboembolism Venous thromboembolisrn (VTE) is a complication expected of postmenopausal hormones. Observational studies have demonstrated that in postmenopausal women who use ERT, the risk of deep vein thromboembolism is increased by a factor of 2 to 3.5. These observations are consistent with the data found in HERS I (discussed later). The investigators reported that the risk of thromboembolic events was increased by a factor of 2.7 in the women receiving the estrogen-progestin therapy? HERS 11 showed that the relative risk (RR) of venous thromboembolism increased 108%(RR 2.08) and the absolute risk was 0.59%in the HRT group, compared with 0.29%in the placebo group (59 events vs. 28 events annually per 10,000 women, respectively).” The WHI reported similar results. The relative risk was 2.11 in the HRT group, a 111% increased risk. The absolute risk was 34 events in the HRT group compared with 16 events in the placebo group per 10,000 women.7 Owing to the uncommon presence of idiopathic venous thromboembolisrn in women older than 50 years, the absolute risk associated with postmenopausal HRT is pretty small. For women who are already at risk for thromboembolisrn or who are older, the absolute risks of HRT will be higher.

Coronary heart disease For the past 30 years, practitioners have been advising menopausal women of the conviction that HRT reduces the risk of coronary heart disease. More than 40 observational studies in these past three decades have suggested that this risk is 35% to 50% lower among women who take estrogen than in women who do not.12J3These observational data have been reinforced by additional research demonstrating some of the impact of estrogen on individual factors known to be associated with coronary artery disease (CAD),thereby also establishing a biologically plausible mechanism for the association of HRT and reduced CAD. Randomized trials have shown that estrogen therapy reduces plasma levels of lowdensity lipoprotein (LDL) by 10% to 14% and raises plasma levels of high-density lipoprotein (HDL) by 7% to 8%.’J4Estrogen has also been shown to reduce Lp(a) lipoprotein, inhibit oxidation of LDL, improve the endothelial vascular function, reduce fibrinogen, and reduce the thickening in the arterial walls. However, estrogen may have detrimental effects on cardiovascular risk markers, such as raising triglyceride

levels, increasing clotting, and raising levels of C-reactive protein. These detrimental effects of estrogen may override the beneficial effects of estrogen on cardiovascular function and may explain the surprising results of randomized, placebo-controlled trials indicating that HRT did not reduce the overall rate of coronary heart disease (CHD); and in HERS I1 and the WHI, it actually increased the rate of CHD. These new data from randomized trials, compared with the 30 years of observational data and the biologically plausible mechanisms, have rendered making recommendations to postmenopausal women about HRT more complex and challenging. Both patients and practitioners have questions with no clear-cut answers, and concerns about the benefits and risks of HRT are more difficult to sort out. Heart disease is the leading cause of morbidity and mortality in women, and understanding the current state of the evidence and the potential for the cardioprotective effects of HRT, as well as the cardiovascular negative effects of HRT, is of vital importance to women’s health. In this discussion, however, one must not forget the potential cardioprotective effects of nutrition, exercise, stress management, and selected nutrients such as niacin, red yeast rice, magnesium, fish oils, pantethine, vitamin C, vitamin E, folic acid, vitamins BI2 and Bb garlic, soy, hawthorne, gugulipid, and policosanols. The basic problem with HRT and CHD is that the later randomized trials of estrogen among women with preexisting CHD have not confirmed the 40 observational studies of the last 30 years. The first large-scale, randomized, double-blind, placebo-controlled trial of HRT (a combination of CEEs [Premarin] and CEEs with medroxyprogesterone acetate [Provera]) for secondary prevention of CHD was the Heart and Estrogen/ progestin Replacement Study (HERS I).7 In a total of 2763 women with established CHD studied at 20 clinical centers throughout the United States, the death rates from coronary causes and nonfatal myocardial infarctions in the hormone group and the placebo group were similar. Perhaps more worrisome was the 50% increase in the risk of CHD events (thromboembolisrn) during the first year in the women receiving hormone therapy. The HERS I data prompted a barrage of questions, as follows: Are the HERS data simply wrong? Does one clinical trial outweigh the vast array of observational studies? Is the pattern of early risk real, and if so, what caused it? Is the early risk related to some other factor present in a subgroup of women but not others? Were the results related to the hormone regimen used? Would the results be different with a natural estradiol and/or a natural progesterone?

Menopause

Did the MPA counteract the potential beneficial effects of estrogen? Do these HERS I results for secondary prevention have implications for questioning HRT's role in primary prevention?

A short attempt at some answers was made after HERS I: The early risk for increased CHD events in the hormone-treated group has been a pattern seen in subsequent studies-the Puget Sound Group Health Cooperative of Seattle,15the Nurses' Health Study,16 and the early data from WHI.17 An early risk for blood clots in the legs and lungs, heart attacks, and strokes appears to be a real phenomenon in postmenopausal women who begin HRT. Two hypotheses to explain this finding are that estrogen has a prothrombotic effect and a proinflammatory effect on the vascular endothelium. There indeed may be some subgroup of women with predispositions for the prothrombotic and/or proinflammatory effects of estrogen-for example, hyperinsulinemia, hypertension, elevated homocysteine levels, increased C-reactive protein and Lp(a) lipoprotein levels, obesity, elevated LDL. Interestingly, in the HERS I trial, differences were observed between hormone-treated women who also took lipid-lowering therapy (statins) and hormone-treated women who did not. The rate of CHD events after 1year was much lower in the HRT plus statin group than in non-statin users. The same was true for risk of venous thromboembolic events. Another controlled trial attempted to address the question whether estrogen inhibits atherosclerosis. In the placebo-controlled Estrogen Replacement and Atherosclerosis (ERA) Trial, neither estrogen alone nor estrogen plus the progestin18affected the progression of coronary atherosclerosis. Plasma levels of LDL cholesterol were reduced by 9.4% in the unopposed estrogen group and by 16.5% in the estrogen plus MPA group. Both groups had significant increases in HDL cholesterol (18.8% and 14.2%, respectively) compared with the placebo group. The two estrogen groups had rises in triglyceride levels (6.1% and 10.1%, respectively) but these changes were not significantly different from the levels in the placebo group. The ERA trial provided the first anatomic end point (angiographically determined effects on coronary arteries) in women who had known coronary artery disease (CAD). The ERA trial supported the overall null effect found by the HERS I trial, and also showed that the MPA did not cancel out the beneficial effects of estrogen as was suspected in the HERS I trial. These data and other study results indicate that hormone therapy does not have a significant impact on the progression of atherosclerosis in women with established heart disease. Preliminary data from the Papworth HormoneReplacement Therapy Atherosclerosis Study (PHASE),

a small clinical trial in 225 postmenopausal women with angiographically proven CAD, showed no cardiovascular benefits of HRT and also possibly a slight increase in the rates of cardiovascular events during the first 2 years of HRT.I9This trial evaluated transdermal natural estradiol alone or with a different progestin, norethindrone. An interim analysis of the WHI data also suggested that there had been a slight increase in the number of heart attacks, strokes, and thromboembolic events during the first 1 or 2 years in postmenopausal women undergoing hormone therapy.2O One clinical trial looked at estrogen use in postmenopausal women without clinical coronary disease. The Estrogen in the Prevention of Atherosclerosis Trial (EPAT) was designed to determine whether unopposed natural estradiol reduces the progression of subclinical atherosclerosis.*' Postmenopausal women with high cholesterol levels but no preexisting cardiovascular disease, diabetes, or smoking history received either oral micronized natural estradiol or placebo, and also lipidlowering medication if serum LDL exceeded 160 mg/dl. The women were monitored for 2 years. The investigators evaluated the rate of change in carotid artery intimamedia thickness. Women in the placebo group had an expected progression in the thickening of the carotid arteries over the 2 years. The women taking estradiol had a small amount of regression of the thickness of the carotid arteries. In women not receiving lipid-lowering therapy, the placebo group had a greater progression and the estradiol group had no progression of intimamedia thickness, a dramatic difference. Curiously, in the women who received lipid-loweringdrugs, there was no difference in the rate of progression between the women receiving estrogen and those receiving placebo. On the basis of data from these randomized clinical trials conducted before HERS I1 and WHI, HRT did not appear to reduce the risk of cardiovascular events in postmenopausal women who already had coronary heart disease. Then along came the world-shifting news of July 2002, when the results of HERS 11 and the WHI were published less than a week apart. HERS 11investigated the effect of the effects of 0.625 mg CEE + 2.5 mg MPA on the prevention of CHD in older U.S. women (average age 71 years) with pre-existing CHD." This study was a continuation of HERS I intended to determine whether a trend toward prevention of heart disease would appear if the study were continued longer. Once again, though, the results were not positive for women with heart disease. In HERS II there were no significant decreases in rates of primary CHD events (or strokes or clots) among women assigned to the HRT treatment group who had already had CHD before starting the HRT regimen (RR 1%decreased risk and absolute risk of 3.66%for HRT vs 3.68%for placebo). The investigators concluded that "postmenopausal

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hormone replacement therapy should not be used to reduce the risk of CHD events in women who already have CHD."" A few days later, results of the landmark WHI study were published? The WHI investigated the effect of the most common HRT regimen in the United States (0.625mg Premarin + 2.5 mg Provera = PremPro) on the incidence of heart disease, breast and colomtal cancer, and fractures in postmenopausal women. The cardiovascularm a r c h was intended to investigate the effect of this HRT regimen on prevention of CHD in healthy postmenopausal U.S. women (aged 50 to 79 years) who do not have CHD. After a mean of 5.2 years of follow-up, the trial was stopped earlier than planned for the women using combined HRT (mostly owing to harm from breast cancer incidence). In the WHI, there was a siphcantly higher risk of CHD, consisting of a 29% inmase in the relative risk and 37 more events in the HRT group, compared with 30 events in the placebo group, annually per 10,OOO women. These findings, showing that estrogen plus progestin does not confer benefit in preventing CHD among women with a uterus, concurs with the HERS findings among women with clinical CHD as well as those of the ERA trial and others. The WHI results extend the findings of the earlier trials to include a wider range of women.

Stroke In the WHI, there was no excess risk of stroke in the estrogen plus progestin group in the first year, but such a risk did appear in the second year and persistedP The mechanism does not seem to be related to an increase in blood pressure. The WHI findings were consistent but more dramatic than those of the HERS, which reported a nonsigTuficant 23% increase in the treatment group." WHI results were also more extreme than those of the Women's Estrogen for Stroke Trial (WEST) of estradiol (without progestin) in women with a history of a prior stroke. Overall, the WEST trial found no effect of estrogen on recurrent strokes but some rise in rates in the first 6 months.= Some might criticize the WHI statistics because it includes older women. However, there was no indication that excess strokes were more likely to occur in older women, in women with prior stroke, through differences in race/ethnicity, or in women with high blood pressure. It is apparent that estrogen plus a progestin increases the risk of stroke in women who have been judged to be healthy. The estrogen-only arm of the WHI showed a slight increase in stroke for women in the youngest age group at study entry.24The ERT arm was quite different than the HRT arm. One of the most recent studies on estrogen leads us to the most provocative question: Do different kinds of estrogens have different effects? In this study, the risk of VTE was compared among those who used esterified estrogen, conjugated equine estrogen, and no estrogen at all.25 The findings concluded that CEE but not

esterified estrogen was associated with venous thrombotic risk.

Gallstones The risk of gallstones or cholecystectomy appears to be raised by a factor of 2 to 3 in postmenopausal women who are taking ERT. This finding has been reported by several large observational studies. In HERS I, the women taking estrogen plus progestin were at a 38% higher risk of gallbladder disease than women who were taking p l a ~ e b oHERS . ~ I1 found similar results, reporting a higher incidence of biliary tract surgery with a 48% increased relative risk for those in the HRT group and an absolute risk of 191 versus 129 events annually per 10,000 women.26

Areas of Uncertainty Breast cancer Fears about breast cancer and higher risk of breast cancer from HRT dominate many women's decisionmaking process about menopause management. Clinicians must be educated about this topic and must be prepared to summarize the results of relevant research in order to counsel each woman about the benefits and the risks in her particular situation. It is true that there are unanswered questions about the long-term safety of HRT, especially regarding the risk of breast cancer. What is .often forgotten is that the clinical trials data on ERT spans the last 100 years. No other pharmacologic agent has been as thoroughly studied as estrogen. A half-century of research preceded the early 1940s, when HRT became commercially available. Even though patient fears are high and alternative practitioners are particularly suspicious and skeptical about its safety, no data clearly and consistently demonstrate a higher risk of breast cancer associated with HRT. Nevertheless, many patients and practitioners continue to be certain that taking HRT will cause breast cancer. Close to 60 observational studies of the association between HRT and breast cancer have been published during the past 25 years, and no definitive answer exists because of inconsistency in the results of those studies. One analysis (prior to the M I ) of the evidence in those studies found that more than half of them reported either no difference in risk or a decrease in risk of breast cancer with ERT/HRT ~ s e . The 2 ~ remainder of the studies reported only slight rises in breast cancer risk. Another group of researchers attempted to reanalyze more than 90% of the published data on breast cancer and HRT use.28 They reported that postmenopausal women who had ever used HRT had a small but statistically significant increase in risk for breast cancer compared with women who had never used HRT. In women who were currently using HRT or had recently used it, the relative risk rose by a factor of 1.02 to 1.04 for each year of use. After HRT had been discontinued for

Menopause 5 years, no significant excess risk remained. Also, breast cancers diagnosed in women who had used HRT tended to be less advanced and were more localized. Later reports from observational studies are also inconsistent. The report from the National Cancer Institute’s Breast Cancer Detection Demonstration Project (BDCCP) was published in January 2000.29These findings showed that the risk associated with recent HRT use (both current use and use within the previous 4 years) was twice that associated with ERT. However, the relative risk for recent use of ERT was not statistically sigruficant, and the difference between risks with ERT and HRT was not tested for statistical significance. Right after that report was published, another group of investigators published and reported higher risk estimates for sequential HRT regimens for 5 years or more of use than for continuous combined HRT, although the difference was not statistically significant.30In contrast to previous reports, this study found no difference in risk between current and past users. At the end of 2000, the Nurses’ Health Study published its estimates of breast cancer risk associated with HRT in postmenopausal women.3I The results were expressed as percentage increases in the cumulative risk of breast cancer and were frightening to many: The use of estrogen alone for 10 years was found to lead to a 23% increase by age 70 years, and the use of estrogen plus progestin for 10 years to a 67% increase by age 70 years. It is important for clinicians to realize (1) that the result is not an actual mathematical conclusion but the conclusion of the model-the consequences of a small difference in risk at the beginning that then is magrufied as the math is carried out into the future-and (2) that risk estimates represent a projection, not an actual measurement. One of the most disturbing reviews was published in 1998. cold it^^^ summarized the evidence that endogenous estrogen and ERT not only increase the risk but are causally related to breast cancer. In his review on hormone and breast cancer, he included reports on cell proliferation and endogenous hormone levels as well as epidemiologic studies of the relationship between the use of postmenopausal hormones and the risk of breast cancer. He found evidence of a causal relationship between female hormones and breast cancer based on consistency, dose-response pattern, biologic plausibility, temporality, strength of association, and coherence. He stated that the magnitude of the increase in breast cancer risk per year of hormone use is comparable to that associated with delaying menopause by a year. The fact that women who menstruate longer have a higher risk of breast cancer also provides support for a biologic mechanism for the relationship between use of exogenous hormones and increased risk. He concluded that existing evidence supports a causal relationship between use of estrogens and progestins, levels of endogenous

estrogens, and breast cancer incidence in postmenopausal women. The WHI was the first randomized controlled trial confirming that conjugated equine estrogens combined with progestins do increase the incidence of breast cancer, and quanhfying the increase. The 26% higher risk of breast cancer occurred after about 4 years and translated to 8 more cases annually per 10,000 women.5 This is consistent with other epidemiologic data. The study was discontinued primarily because of the breast cancer incidence, which crossed the monitoring boundary for safety. On the other end of the pendulum, investigations that have found no increased risk of breast cancer with HRT or ERT use receive much less attention. The Iowa Women’s Health Study is prospectively following a cohort of women who were selected in 1985.33After 6 years of monitoring, a statistically significant increase in the risk of breast cancer could not be detected in women who either had ever used or were currently using HRT. Another report through 8 years of follow-up examined whether postmenopausal HRT raised the risks for breast cancer and death from death cancer in women with a family history of breast cancer.34There was no significant increase in the rate of breast cancer even in women who had a family history of breast cancer and had been using HRT longer than 5 years. These results are consistent with those of other reports that there is no additional risk in using HRT/ERT by women who have a first-degree relative with breast cancer. My main criticism of these kinds of reports is that using the term “no significant increase” is disturbing, in that even a single additional woman with breast cancer is significant. With a current incidence of one in nine, one more woman with breast cancer is one too many. The latest analysis from the Iowa Women‘s Health Study, an 11-year follow-up, showed an association between women who had ever used postmenopausal HRT and the risk of breast cancers that were more localized and had a better pr0gnosis.3~The researchers did not find an increased risk of invasive ductal or lobular carcinoma in women who had used HRT either less than or more than 5 years. A slight increase in risk was observed in current users and users for less than 5 years; current users with more than 5 years of use had no increase in risk. These results are the opposite of those seen in the Nurses’ Health Study, that women who use HRT for more than 5 years have a higher risk.36Two other studies, the Carolina Breast Cancer Studf7 and analyses from the National Health and Nutrition Examination Survey (NHANES),38found no increase in risk with postmenopausal hormones. These later studies perpetuate the inconsistency in research on this issue that has been seen in the last 25 years. This pattern provides some logic to the point of view that if there is an increased risk of breast cancer associated with

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ERT/HRT, the risk must be small, because by now, after this many years, we would have seen more consistency in the data and the size of the risk estimates would be large rather than slight. It is to be hoped that in consultations with our patients, we clinicians can offer a balanced view, reassuring them that no studies find an increased risk of breast cancer with short-term use of HRT and that the conflicting, inconsistent results of more than 60 studies shows that if there is an increased risk with long-term use, it is a small one. We can evaluate the benefits and risks for each patient and make our recommendations on a short-term basis, which can help her make decisions that she does not feel are permanent. Research in this area of medicine is prolific, and if we keep up to date on the latest findings, we can inform our patients so that they can make informed, timely choices about their health care.

Cognitivefunction Observational studies have suggested that there is a relationship between endogenous estrogen exposure and cognition.39A number of other observational reports have demonstrated that HRT use may prevent or delay the onset or progression of Alzheimer’s disease, but additional observational results have been conflicting.4o A metaanalysis and systematic review was conducted in March of 2001 in which 29 studies were rated.4I In women who were symptomatic from menopause, postmenopausal use of estrogen improved verbal memory, vigilance, reasoning, and motor speed. There were no consistent effects on visual recall, working memory, complex attention, mental tracking, mental status, or verbal functions. Estrogen did not appear to enhance asymptomatic women’s performance consistently on formal cognitive testing. The metaanalysis did suggest that HRT was associated with a lower risk of dementia, but the reviewers acknowledged that the studies analyzed had important methodology problems and information was inadequate to allow proper assessment of the effects of various estrogen preparations or doses, progestin use, and duration of use. Studies in animals and the laboratory suggest plausible mechanisms for the potential of estrogen and the prevention and/or treatment of Alzheimer’s disease. Estrogen increases dendritic spine growth, axonal elongation, synapse formation, and neuronal survival. It also influences several neurotransmitters, including acetylcholine, modulates nerve growth factor, increases apolipoprotein E, enhances blood flow, is a n antioxidant, and enhances the uptake and metabolism of glucose. All of these effects could possibly inhibit the neurotoxicity of beta-amyloid and the damaging effects of free radicals, moderate the inflammatory events involved in plaque formation in the brain, enhance

cerebral blood flow, and facilitate neuronal repair after brain injury. Results of randomized trials of ERT and Alzheimer’s disease, and the potential of estrogen for the treatment of this disorder have not been impressive in benefits. In one study, estrogen replacement for 1 year did not slow disease progression or improve global, cognitive, or functional outcomes in women with mild to moderate Alzheimer’s disease.“ In another, participants at 10 of the 20 HERS centers were enrolled in the cognitive function substudy. The mean age of participants at the time of cognitive function testings was 71 f 6 years. Among these older women with coronary disease, 4 years of treatment with conjugated equine estrogens plus progestins did not result in better cognitive function as measured on six different standardized tests.” In the latest prospective study of dementia, prior use of HRT was associated with reduced risk of Alzheimer’s disease, but duration of use very specifically affected the benefit; there was no apparent benefit from current use of HRT unless the use exceeded 10 years.44

Ovarian cancer Evidence concerning a possible positive association between HRT use and ovarian cancer risk is less consistent and of lesser sigruficance than that for endometrial and breast cancer. Most of the data shows a weak positive association. A large prospective cohort (observational) U.S.study of 211,581 postmenopausal women treated for longer than 10 years with conventional HRT was associated with an increased risk of ovarian cancer.&No distinction was made regarding type or regimen of HRT or whether a progestogen was added to the ERT. Participants had no history of cancer, hysterectomy, or ovarian surgery. The study, monitoring women from 1982 to 1996, showed that women who were using HRT at study entry had higher death rates from ovarian cancer than women who had never used HRT. Risk was slightly but not sigruficantlyhigher among former estrogen users. Women who used HRT at baseline and for 10 years or more had a relative risk of 2.20 and former users with at least 10 years of use had a relative risk of 1.59. The annual age-adjusted cancer death rates from ovarian cancer per 100,000 women were 64.4 for baseline HRT users with 10 or more years of use, 38.3 for former users with 10 or more years of use, and 26.4 for women who had never used HRT. In this observational study, as in the Nurses’ Health Study, the lack of information is almost more disturbing than the actual information. We have no data as to the type, dose, and combination of estrogen and progestogen used by the participants. As a result, many assumptions were made that influenced data analysis and the effect on relative risk. We know that how hormones have been prescribed has changed during 1982 through 1996 and

Menopause

since then. In the early 1980s, most women were prescribed unopposed daily estrogen. During the 1980s, sequential estrogen plus progestogen therapy was introduced to eliminate the increased risk of endometrial cancer. Most women began to take 7 to 10 days of progestogen per month along with their estrogen. In the 1990s, common prescribing habits involved continuous and combined estrogen/progestogen regimens and lower doses of both hormones. Whether sequential or cyclic, progestogen is generally prescribed for at least 12 days per month. The number of different estrogens and progestogens has also sigruficantlyexpanded and changed since the early 1980s and even in the last few years. The investigators also reported on relative risk. Given the low incidence of ovarian cancer, even if there is a sigruficantincrease in relative risk, it may not have much of an impact on absolute risk. Although thisstudy shows a doubling of the relative risk, the incidence of ovarian cancer mortality in postmenopausal women is extremely low, at 1.6%. It is also interesting to remember that 7 years or more of oral contraceptive use in reproductiveage women actually lowers the incidence of ovarian cancer. A large, prospective study reported a sigruficant twofold higher risk of ovarian cancer among long-term users of HRT and ERT.46 A total of 44,241 postmenopausal women were selected from the BCDDP; 329 women who experienced ovarian cancer were identified. Women who used estrogen-only replacement therapy, especially for more than 10 years, were at significantly higher risk of ovarian cancer, with a relative risk of 1.8; women who used estrogen only for 20 or more years had a relative risk of 3.2 . The good news was that women who used short-term combination replacement therapy were not at increased risk.

Focus on Estrogen Only The WHI originally had three components: hormone therapy, a low-fat dietary modification, and supplementation with calcium and vitamin D. In addition, many of the women who did not quahfy for the active treatments of the WHI became part of an observational group that was studied. Both arms of the placebo-controlled hormone therapy component (estrogen plus progestin [HRT] and estrogen only [ERT]) were terminated before the planned ending date. The ERT arm of the WHI was halted on March 1,2004, after 6.8 years of follow-up, and less than a year before the planned closing date.” The ERT arm was quite different than the HRT arm in that the risks in the ERT arm did not exceed the benefits. The study showed a slight increased risk of stroke, a decreased risk of hip fracture, a lack of increase in the risk of breast cancer and a possible reduction in breast cancer risk, and no effect on the incidence of coronary heart disease.

The key clinically relevant issues from the WHI ERT study are as follows: CHD was reduced by almost half in the youngest age group (the most common age group of women who initiate ERT). The risk of stroke increased only slightly for women in the youngest study entrance age group. The risk of VTE was increased in all three age groups, but the degree of risk increased with age at study entry. The risk of invasive breast cancer was reduced in all three age groups. The risk of colorectal cancer was decreased in the two younger groups, especially in women age 50 to 59; it was increased in women age 70 and older. The overall reduction in risk of fracture was most evident in younger women. ERT was associated with a lower death rate in the group that was youngest at study entrance. The middle age group had about the same death rate in the ERT group versus the placebo group, and there was a slightly higher death rate in the oldest age group. What the WHI ERT study basically showed us is that ERT, using CEE, is safe for most menopausal women who do not have a uterus. ERT reduced the risk of CHD in those women who started ERT near the age of menopause; it decreased the risk of fractures; use of ERT did not increase the risk of breast cancer; the risk of colorectal cancer was increased in women who started therapy at age 70 or older; ERT was associated with a slight increase in the risk of stroke and VTE but there was no increase in death rates. It would appear that using ERT alone for women without a uterus is safer than using estrogen plus a progestin.

Natural Hormones It is important to understand that most of the research on hormone regimens is on CEEs and MPA. However, that is not exclusively the case, and certainly some of the cardiovascular research has equally implicated 17-beta-estradiol (bio-identical estradiol). Nonetheless, in the most damaging data to date, HERS I and I1 and the WHI, the hormones used were the equine estrogens and pro-gestin. So what we definitely know to be negative effects are associated with those regimens, and we do not in fact know whether the data can be applied to other regimens. It would be naive to dismiss the data and not to admit the possibility that the results would be the same. When hormones are determined to be appropriate or even necessary, however, it would at the very least seem logical to use the hormones we know not to be those with adverse effects.

Specific Health Problems Natural compounded estrogens and natural compounded progesterone, as well as natural testosterone and dehydroepiandrosterone (DHEA), such as those used by compounding natural pharmacies and the natural progesterone creams sold over the counter, are distinct and different in several critical ways from CEEs, conjugated plant estrogens, synthetic estrogens, and synthetic progestins. Natural hormones are made from either betasitosterol extracted from the soybean or from diosgenin extracted from Mexican wild yam root. Those compounds are then made into the desired hormone and are biochemically identical to the hormone the body produces. By definition, a natural hormone is plant derived and bio-identical. The natural compounded estrogens that are made are either estriol, estrone, or estradiol. Estriol is particularly unique because it has approximately one fourth the potency of estradiol and estrone. Natural compounded estrogens are generally used in lower doses owing to the combined effect of the weaker estriol along with the estradiol and/or estrone. These natural estrogens are thought to be metabolized significantly differently by the body, have a shorter halflife, can be used in customized dosing regimens and potencies to fit each individual woman and clinical situation, and can be adjusted to be stronger or weaker in small units to taper someone off or onto hormones. CEEs, those that were used in the WHI study, are quite different. In the 1970s it was believed that Premarin consisted only of 10 estrogens: 17-beta-estradiol,17-betadihydroequilin, 17-beta-dihydroequilenin, 17-alphadihydroequilin, 17-alpha-estradiol, estrone, equilin, 17-alpha-dihydroequilenin, delta-8-9-dehydroestrone sulfate, and equilenin. Since then, advancements in technology have shown that the original 10 estrogens make up less than 40% of the hormonal content of Premarin. Through the use of modem analytical techniques, more than 200 individual components have been identified, including androgens and pr0gestins.4~The composition of Premarin is complex, and different estrogens have various effects in different tissues. Herein may lie an explanation for problems with conjugated equine estrogens versus natural bio-identical estradiol, estrone, and estriol. Dr. Joel Hargrove has been shedding light on these distinctions for years.& I credit his analysis and paraphrase the following explanation with some of my own thoughts. The steroid hormones, including the sex steroids produced by the ovary, represent a subclass of lipids that share a four-ring steroid structure. The native compound from which all the sex steroids are derived is cholestane, the parent of cholesterol. When nutritional states of the individual and cell are normal, the principal precursor of steroid production is cholesterol in the plasma. The cholesterol enters the cells through a lipoprotein receptor system. The activity of the enzymes within the cells of

that tissue determine the particular classes of steroids produced. Steroids, either endogenous or exogenous, enter the cells via passive diffusion. The tissues that are responsive to steroids have very specific intracellular receptors with a high affinity for their particular steroid. The primary action of the steroids is the binding of a steroid hormone to a receptor and the interactions of this receptor-hormone complex with the components of the cell. When the steroid binds, the steroid-receptor complex becomes activated and binds with very specific regions within the steroid-responsive region of the genes. Most of the effects of steroids on responsive cells are mediated through the activation of very specific genes. The hypothesis is that a non-bio-identical hormone may act like a constant and indiscriminant environmental toxin to the genetic material within the cell, because even though it can bind to the receptor hormone complex, it is a foreign substance. Consider CEEs, which consist of more than 200 substances mostly foreign to a human. These substances, once ingested, are a part of that complex and therefore are activating those genes within the cell. This, I contend, is a profound distinction between a hormone that is bio-identical to human hormones and one that is not. Besides the effect on the genes themselves, bio-identical hormones and non-bio-identical hormones may very well leave different metabolic footprints on the rest of the body, with different metabolic consequences. They may be directly cytotoxic to estrogen-sensitive tissues, alter binding of other hormones to those receptors, or change the liver’s metabolism of carcinogens. It is this distinction and potential difference in metabolic consequences, as well as the shorter half-life of natural hormones, that when hormones are required I use bioidentical natural hormones almost exclusively for the treatment of symptomatic menopause. The distinctions between synthetic progestins and progesterone are even clearer. Natural progesterone has been studied and shown to have less adverse effects on the cardiovascular system than synthetic progestins such as MPA. Specifically, natural progesterone lowers HDL significantlyless than MPA, is less atherogenic, and does not cause coronary artery spasm, whereas MPA does. Natural estradiol may not be without concerns about its effects on the cardiovascular system and breast. However, it is typically used in a half-strength dose (0.5 mg total, daily) because it is combined with the significantly weaker estriol. Estriol has been shown to have some ability to act as an antiestrogen in the breast and no significant effect on the cardiovascular system. Further consideration of a natural hormone approach and a more holistic approach to menopause would lead one to use the hormones in combination with other strategies that are known to reduce the risk of breast cancer and heart disease. For examples, soy, flax seeds,

Menopause cabbage family foods, and supplements can promote the metabolism of estrogens to their anticarcinogenic breakdown products. Breast cancer and heart disease prevention diets can also be emphasized with nutritional and botanical supplements to be considered, such as vitamins E and C, the carotenes, soy, coenzyme Qlo, green tea, and garlic. Women who are using CEE and MPA should consider other natural estrogen and natural progesterone regimens or nonhormonal menopause management. Women who are using natural estrogens and natural progesterone, should consider a reevaluation of the hormone regimen to establish the lowest dose achieving the benefits and to minimize the risks. Regular, at least annual, consideration should be given to duration of use on an individual basis. Women who do not have a uterus and are being treated with any hormone regimen should take estrogen alone. Neither synthetic MPA nor natural progesterone is needed. Additional herbal and nutritional supplements may be considered as well. Studies on black cohosh, red clover, soy, bioflavonoids, kava, and a proprietary formula, ”Women’s Phase 11,” have all shown proven scientific efficacy in menopausal symptoms. Many women require only these nonhormonal supplements for their symptom relief and never need any kind of hormone therapy. Other women may be able to lower their dose of cHRT or natural hormones by using them in combination with the herbal and nutritional supplements.

Advisory Body Recommendations Basic Recommendations j+om the Scientific Advisoy Panel of the North American Menopause Society 1.Treatment of menopause symptoms remains the primary indication for HRT and ERT. 2. The only menopause-related indication for long-term use of progestogen appears to be endometrial protection from unopposed estrogen therapy. For all women with an intact uterus who are using estrogen therapy, clinicians are advised to prescribe adequate progestogen, whereas women without a uterus should not be prescribed a progestogen. 3. No HRT regimen should be used for primary or secondary prevention of coronary heart disease (CHD). Proven alternative cardioprotective regimens should be considered. The effect of ERT on CHD is not yet clear. Until confirming data are available, ERT should not be used for primary or secondary prevention of CHD. 4.WHI and HERS data cannot be directly extrapolated to symptomatic perimenopausal women or to women experiencing early menopause (i.e., 40 to 50 years) or premature menopause (i-e., <40 years). 5.Many HRT and ERT products are FDA-approved for the prevention of postmenopausal osteoporosis;

however, because of the risks associated with these forms of therapy, alternatives should also be considered, with the risks and benefits of each being considered. 6. Use of HRT or ERT should be limited to the shortest duration consistent with treatment goals, benefits, and risks for the individual woman. 7. Lower-than-standard doses of HRT and ERT should be considered. The Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) trial demonstrated that lower doses of HRT achieved equivalent symptom relief and preservation of bone density without an increase in endometrial hyperplasia. &Alternative routes of administration of HRT may offer advantages, but the long-term benefit/risk ratio has not been demonstrated. 9.An individual risk profile is essential for every woman contemplating any regimen of HRT or ERT. Women should be informed of known risks. 10. The risk of ET may be different than the risk of HRT. The panel did not reach consensus on the following questions: 9

What are current acceptable definitions of short-term and long-term hormone therapy? How long should hormone therapy be prescribed for symptom relief? Do reasons exist for extended hormone therapy? The majority of the panel agreed that the circumstances include: (1)any woman for whom, in her opinion, benefits of symptom relief outweigh risks; (2) women with menopause symptoms who are at risk for osteoporosis; and (3) women with increased osteoporosis risk who are unable to tolerate other therapeutic options. Does either premature menopause or premature ovarian failure represent an indication for prevention HRT or ERT? Is there a consensus on how best to discontinue hormone therapy? Is it possible to make general conclusions about all members of the estrogen and progestogen families?

Recent Recommendationsfrom the US.Preventive Services Task Force Therapy with estrogen and progestin should not be routinely used to prevent chronic conditions in postmenopausal women; however, evidence is insufficient to recommend for or against the use of unopposed estrogen for prevention in postmenopausal women who have had a hysterectomy, according to recommendations from the US. Preventive Services Task Force (www.preventiveservices.ahrq.gov/).The Task Force states that although both benefits and harms were found for estrogen plus progestin therapy (EPT), the harmful

effects are likely to exceed the chronic disease prevention benefits in most women. Furthermore, the Task Force states that although the risks outweigh the benefits, the absolute increase in risk associated with EPT is modest. Benefits cited include increased bone mineral density, reduced risk for fracture, and reduced risk for colorectal cancer. Harms cited include increased risk for breast cancer, venous thromboembolism, coronary heart disease, stroke, and cholecystitis. Evidence was insufficient to determine the effects of EPT on dementia and cognitive function, ovarian cancer, mortality from breast cancer or cardiovascular disease, or all-cause mortality. The Task Force did not evaluate EPT effects on vasomotor or urogenital symptoms. It also notes that the quality of evidence for the risks and benefits varies for different hormone regimens.

Conclusions Practitioners must carefully analyze the potential benefits and risks of HRT in perimenopausal and postmenopausal women. We should first establish whether the patient has a need to initiate HRT (or nHRT).The two most valid indications are menopausal symptoms and the prevention or treatment of osteoporosis. Appreciating the woman’s preferences, educating her as to her nutritional and botanical and hormone options, reviewing the benefits and the risks of HRT, discussing side effects, acknowledging the lack of certainty in some areas, and discussing the differences (known and hypothetical) between synthetic hormones, horse urine estrogens, plant-derived nonbio-identical hormones, and plant-derived bio-identical “natural” hormones constitute a respectful, well informed and well advised approach to this challenging but rewarding aspect of health care for women. Overall, one must remember that the absolute risks associated with Premarin and Provera in the current WHI study were small although statistically sigruficant and certainly important. As always, especially in alternative medicine, each woman must be evaluated individually, and benefits and risks must be determined for her particular situation. Conventional medicine now acknowledges the wisdom of this approach as well. Low-dose, compounded, plantderived natural hormones can be used very effectively to manage menopause symptoms and lower the risk of fractures. When HRT is needed, lowdose natural hormones, for an individually determined amount of time, along with breast cancer and heart disease prevention strategies, offer women the safest, most gentle, least invasive form of hormone replacement. Each woman should be evaluated and reevaluated at least yearly for a benefits/risks assessment to determine the best course of action. For a large percentage of women, herbal and nutritional supplements as well as lifestyle changes compose a safe and effective plan for the perimenopausal and menopausal symptoms as well as a safe

and fundamental prevention strategy for disorders such as heart disease, osteoporosis, and breast cancer.

Types of Hormone Replacement Therapy If, after weighing all the evidence, a woman elects to utilize HRT for short-term relief or if she requires longterm therapy because of a high risk for osteoporosis, it is important that she participates in choosing the right combination and dosage pattern for her needs. There is no well-accepted “best program” among many experts. However, on the basis of the current evidence, the general consensus is to choose the lowest dose possible for the shortest duration possible. Current recommendations from the NAMS consensus panel are generally 2 to 3 years for symptom management, after which attempts should be made to decrease and/or discontinue the therapy. Again, the benefits and the risks of long-term therapy should be assessed for each woman. Giving estrogen alone, without a progestin, is known as unopposed estrogen therapy. This regimen carries the higher risk for endometrial cancer. In an effort to reduce the risk of endometrial cancer, estrogen is usually given in combination with a progestin or oral progesterone. The hormones can be given either in a cyclical fashion or continuously. The cyclical fashion involves taking estrogen for 25 to 30 days and progestin or oral micronized progesterone for the last 10 to 12 days of the cycle. A 3- to &day hormone-free interval follows, during which planned bleeding occurs. In other words, with cyclical administration, menstruation continues in about 90% of women. In order to prevent monthly bleeding, estrogen and progestin/progesterone can be given every day without a hormone-free interval. This regimen is known as combined continuous HRT. As shown in Box 189-1, when administered according to recommended guidelines (the lowest dose of estrogen possible along with 2.5 mg of MPA or 100 mg of oral micronized progesterone), combined continuous HRT offers several advantages over other regimens.

Avoidance of cyclical bleeding Continuous protection of the endometrium against the cancer-causing effects of estrogen Lower daily and cumulative amounts of progestins are required Avoidance of symptoms of premenstrual syndrome which often accompany estrogen Prolongationof the synergistic effects of estrogen and progesterone on bone integrity Prevention of rare conceptions by promoting endometrial atrophy Greater convenience and patient compliance

Menopause Estrogens come in many forms. It is helpful to understand the following distinctions amongst different kinds of estrogens. First, bio-identical natural hormones are hormones manufactured from compounds that have been extracted from either soybeans or Mexican wild yam root; the end product is an estrogen that is biochemically identical to endogenous estradiol, estrone, or estriol. These can be utilized from either of two main sources: Compounded estradiol, estrone, or estriol from a compounding pharmacy Pharmaceutical company version with bio-identical estradiol or estrone but with patentable binder, filler, preservative, adhesive, or dye Examples of pharmaceutical company versions of bioidentical hormones are as follows: Estrace, Gynodiol, Estraderm, Vivelle, Climara, Alora, Esclim, Orthoest, Ogen cream, Vagifem cream, Estrace cream, and Estring. Second, hormones can be derived from a natural substance that are not biochemically identical to endogenous estrogens. Examples are conjugated equine estrogens (Premarin, Premarin cream) and esterified plant estrogens (Estratab, Menest). Third, hormones can be made from a synthetic origin and are not bio-identical; an example is Cenestin. A fourth kind of estrogen can be found in the numerous combination estrogen/progestins; in some cases, testosterone products are also available with varying combinations. Refer to Appendix 3, which lists some of these combinations as well as current prescription hormone replacement therapy products.

The Major Symptoms of Menopause Common complaints of perimenopause and menopause are as follows: Irregular bleeding (perimenopause) Hot flashes Atrophic vaginitis Bladder infections Mood changes Cognitive changes Body aches Sleep disturbances Other common symptoms are fatigue, sexual dysfunction, hair thinning, facial hair, headaches, dry skin, joint pains, and urinary incontinence.

Hot Flashes Hot flashes are the most common menopause symptom for which women seek help. A hot fzash refers to peripheral vasodilation that leads to a rise in skin temperature and flushing. In the typical hot flash, the skin, especially of the head and neck, becomes red and warm for a few

seconds to 2 minutes, with cold chills thereafter. Hot flashes can be accompanied by other symptoms, such as increased heart rate, headaches, dizziness, weight gain, fatigue, and insomnia. In the United States, 65% to 80% of menopausal women experience hot flashes to some extent. Hot flashes are often the first sign that perimenopause or menopause is approaching, and they may appear before the cessation of menses. In most cases, hot flashes are most uncomfortable in the first 2 to 4 years of menopause. As the body adapts to decreased estrogen levels, hot flashes subside in most, but not all, women.

Atrophic Vaginitis After menopause, the vaginal lining may become thin and dry owing to the lack of estrogen. As a result, penmenopausal and postmenopausal women may experience painful intercourse, a greater susceptibility to infection, and symptoms of vaginal itching or burning. Women with atrophic vaginitis should try to avoid substances that tend to dry the mucous membranes, including antihistamines, alcohol, caffeine, and diuretics. In addition, it is critical that the body stays well hydrated. Clothes made from natural fibers, particularly cotton, are often recommended because they allow the skin to breathe, thus decreasing the incidence of vaginal infections. Regular intercourse is beneficial because it increases blood flow to vaginal tissues, which helps improve tone and lubrication. However, good lubrication (e.g., with oil or K-Y Jelly) must be maintained. Atrophic vaginitis is a strong indication of the need for HRT or at least vaginal estrogens such as estriol cream or suppositories (compounded by a compounding pharmacy), estradiol cream (Estrace cream), conjugated equine estrogens cream (Premarin cream), vaginal estradiol tablet (Vagifem), or an estradiol ring (Estring).

Bladder Infections About 15% of menopausal women experience frequent bladder infections. Apparently, there is a breakdown in the natural defense mechanisms that usually protect against bacterial growth in the urinary tract. The primary goal in the natural approach to treating bladder infections is to enhance normal host-protectivemeasures against urinary tract infection. Specifically, this approach entails enhancing the flow of urine by achieving and maintaining proper hydration, promoting a pH that will inhibit the growth of the organism, using vaginal estrogens to help maintain vaginal pH and proper tone and anatomy of urethra, and preventing bacterial adherence to the endothelial cells of the bladder. In addition, several botanical medicines can be employed (see Chapter 161 for further information).

Cognition Cognition involves learning and concentration as well as memory and planning. Estrogen, progesterone, and testosterone modulate brain function via neurotransmitter systems, including acetylcholine, serotonin, noradrenalin, and dopamine. The effects of estrogen on acetylcholine, as well as other actions, have the potential to affect memory and learning. Changes in concentration and memory may also be impaired by sleep disturbances, hot flashes, and stressors.

THERAPEUTIC CONSIDERATIONS The goal of a holistic and integrative approach to menopause is to recognize that there are seven levels of intervention, as follows: 1. Diet, exercise, and stress management 2. Nutritional supplementation 2. Botanical medicines 4. Natural hormone replacement therapy (nHRT) 5. Friendlier, conventional hormones (fcHRT)-bioidentical but with the addition of filler, binder, preservative, dye, or adhesive that is patented by the pharmaceutical company manufacturer 6. Less friendly conventional hormones (cHRT) 7. Condition-specific nonestrogen pharmaceuticals (for either symptom relief or disease prevention and/or treatment)

There are three fundamental goals in treatment: relief of symptoms, prevention of disease, and treatment of disease. Each woman is assessed individually to determine the scope and severity of her symptoms and is evaluated subjectively and objectively as to her risks of osteoporosis, heart disease, breast cancer, Alzheimer’s disease, and colorectal cancer as well as other chronic health problems. The baseline evaluation of the menopausal woman should consist of the following assessments:

Detailed personal medical history, including an understanding of the chief complaint, review of other systems, medical history, past and present medications, family history, dietary habits and history, exercise habits and history, social history, occupation General physical examination Breast examination Pelvic examination Laboratory tests to consider: complete blood count, blood chemistry panel, lipid panel, thyroid function panel, measurements of FSH, homocysteine, C-reactive protein, and lipoproteins, screening mammography Bone density testing Papanicolaou smear

Electrocardiogram Colonoscopy Some of these tests are routinely performed either initially or on a yearly basis. Indications and frequency for other tests are determined by individual health history, disease risks, current health problems, and family history.

Diet The most important dietary recommendation may be to increase the consumption of plant foods, especially those high in phytoestrogens, while reducing the consumption of animal foods. Consumption of fruit and vegetables also confers a protective effect.

Phytoestrogen-Containing Foods Foods that contain phytoestrogens may be an important part of a menopause diet. Phytoestrogens are plant-derived substances that are able to weakly bind to the estrogen receptors in mammals and have a very weak, estrogen-like effect in some tissues and a weak anti-estrogen effect in other tissues. Phytoestrogens are classes of compounds that are mainly nonsteroidal in structure and are either of plant origin or derived by the body’s metabolism of precursors present in dietary components. They are present in virtually all plants, from negligible amounts in some plants to particularly high levels in others. Overall, phytoestrogens have only a fraction of the strength of endogenous or typically exogenous doses of estrogen. Some estimates place them at l / l O O t h the strength, and others at 1/ 1000th the strength. The ability of phytoestrogens to act as both estrogen agonists and estrogen antagonists appears to depend on the target organ, the dose, the nature of the estrogen receptor (alpha or beta), the total estrogens in the body, and the kind of phytoestrogen. Phytoestrogens are best understood as one understands the class of pharmaceuticals called selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene. Phytoestrogens should be considered nature’s SERMs. Soybeans are thought to contain the highest content of phytoestrogens of any edible food. Another signhcant source is flax seeds. Many other foods, such as apples, carrots, fennel, celery, parsley, and other legumes, contain small amounts of phytoestrogens. Dozens of medicinal plants contain phytoestrogens and are discussed in the botanicals section. A high dietary intake of phytoestrogens is thought to explain why hot flashes and other menopausal symptoms appear to occur less frequently in cultures consuming a predominantly plant-based diet. In addition, such a diet is promising for disease prevention, with some research showing a lower incidence of breast,

Menopause

colon, and prostate cancer in those consuming highphytoestrogen diets.49 SOY

The use of soy in the diet dates back to the Chinese Emperor Shen Nung in 2838 BC. Tofu (a protein-rich curd made from a hot water extract of soybeans) was developed in China and was introduced by Buddhist missionaries to Japan and Korea between the second and seventh centuries. Tofu was even a revered food of the Chinese Emperors in the Ming to Chin dynasties. Soybeans have been a staple in the diet of Southeast Asians for several centuries. It is estimated that the protein from soy foods constitute 20% to 60% of their daily protein. Soybeans do not seem to have become part of the Western diet, via France and England, until the eighteenth century. In the late 18OOs, immigration of Chinese laborers to the United States is thought to have led to the introduction of soy foods into the U.S. diet. By 1890, soybeans were being grown all over the country. Americans mostly use soy for the production of one of its least healthy products, vegetable oil. After the crushed soybeans are exposed to extraction with hexane, and the oil has been removed, the defatted soybeans are pulverized to form soy flour. The soy flours have been exposed to various levels of heat. The least heat-treated grade is used in protein-enriched breads. The heat treatment inactivates the protease inhibitors contained in soy. Ninety-five percent of soy flour is toasted and fed to livestock and other commercially bred animals. Soy flour can be further treated to create isolated soy protein products with a high protein content. These dried products contain at least 90% protein, compared with the 50%protein found in soy flour. Currently, a host of soy products can be found in most grocery stores, and even some unusual ones found in natural foods stores. They include dried soybeans, soy oil, soy milk, soy flour, roasted soy nuts, tofu, tofu pate, tempeh, miso, soy sauce, natto, edamame, soy ice cream, soy cheese, soy candy bars, soy burgers and hot dogs, even soy marshmallows. See Chapter 126 for a comprehensive discussion of the metabolism and health effects of soy and soy constituents.

Soy constituents Soybeans are noteworthy for their high protein content, approximately 38%.They also contain 18%fat, primarily polyunsaturated fats and only a small amount of saturated fats. Thirteen percent of the soybean is made up of soluble carbohydrates (sucrose, stachyrose, raffinose, and others, 15% insoluble carbohydrates (dietary fiber), and 14%moisture, ash, and miscellaneous compounds. Many common specific vitamin and mineral nutrients are also found in soy. Many soy foods are a good source of calcium. Not only does cup of cooked soybeans

provide 88 mg of calcium, many brands of tofu are made using calcium sulfate as a coagulant and can contain between 120 mg and 750 mg of calcium per cup of tofu. Many soy milks are now also fortified with calcium; some contain 80 mg of calcium per cup, but others as much as 300 mg of calcium per serving. Soy foods also contain iron, zinc, copper, magnesium, niacin, pyridoxine, and folic acid. Perhaps the most well-known compounds found in soy are the phytoestrogens. Soybeans contain a particular phytoestrogen called isoflavones. These substances behave like weak estrogens and are able to bind to estradiol receptors in the uterus, breast, brain, bone, arteries, and so on. In some cases, they behave in a way that enables them to weakly mimic the effects of estrogen in some tissues, and in other situations, they are able to block the effect of estrogens. Soybeans are the richest food source of isoflavones, containing 1 to 2 mg of isoflavones per gram of soy protein. The isoflavones of soy are genistein, daidzein, and glycitein. Not all soy protein products contain phytoestrogens. Some soy protein isolates have been processed with an alcohol extraction that removes the phytoestrogens. When eating soy foods, this is not really a concern, but when using a soy powder or soy capsule, be sure to look for the isoflavone content on the label. Soy protein that has not had the phytoestrogens removed usually contains about 1.2 mg per gram of protein as genistein, 0.5 mg per gram of protein as daidzein, and small quantities of glycitein. All the different soy products contain different amount of isoflavones. It is valuable to know the isoflavone content of the various soy foods and soy products in order to target the desired dose per day (Table 189-1). Genestein has a sixfold greater affinity for the beta estrogen receptor than for the alpha receptor. That is why it may act differently in different tissues, depending on the nature of the estrogen receptors in that tissue. It may act as a pro-estrogen in the bones but an antiestrogen in the breast. Some of the controversy about soy lies not only in its ability to selectively modulate estrogen receptors but also in its content of phytates and trypsin inhibitors, interference with thyroid function, and difficult digestibility for some individuals. Soy foods, especially cooked soybeans are difficult for some people to digest, causing gas and stomach upset. Soy's content of trypsin inhibitors can block the enzymes needed for protein digestion. When the protein is improperly digested, fermentation and gas production ensue. However, many researchers believe that so few trypsin inhibitors are left behind after processing the soy food that digestion is not affected in most people. The phytate content in soybeans is also considered possible cause for concern about soy foods. Phytates block

Specific Health Problems lsoflavone content of soy foods Sov food

Amount

lsoflavones (ma)

Textured soy protein granules

62

Roasted soy nuts Tofu, low-fat and regular Tempeh

60 35 35 25-90(varies with

Soy beverage powders

product) 30

Regular soy milk

1 cup

Low fat soy milk Roasted soy butter

2 tbsp

20 17

Cooked soybeans Soy isoflavone pills

ll2 CUP

150

Varies with the Varies with the

1 cup

manufacturer; read label

Fermented soy isoflavone pills

manufacturer;

read label Will contain lower amount of isoflavones but may be better absorbed

the uptake of minerals such as calcium, magnesium, iron, and zinc. Although the phytate content of soybeans is higher than that of other grains or legumes, the mineral-blocking effect of phytates is reduced when they are eaten with meat or fish. Eating soy products in the context of a healthy varied diet results in adequate dietary intake of minerals. Phytate levels are reduced in fermented products like tempeh and miso. The genestein and daidzein in soy can also inhibit thyroid hormone synthesis. High-soybean diets have been implicated in diet-induced goiter. This problem is not likely to occur when an average amount of soy is consumed, again in the context of a healthy varied diet. In some susceptible individuals, or in some who take very high doses of soy isoflavones (>200 mg/day), it is prudent to be aware of this potential interaction.

Clinical effects of soy The clinical effects of soy for a menopausal woman are varied. At least eight published studies report improve.~~~ ments with soy protein rich in i s o f l a v o n e ~Although not all studies are consistent, a reduction in hot flashes and/or night sweats is generally in the range of 3Oo/o to 55%. Other soy studies demonstrate that increasing the soy foods in the diet stabilizes bone density.A meta-analysis of the effects of soy protein intake on serum lipids concluded that the consumption of soy protein rather than animal protein significantly decreased serum concentrations of total cholesterol, LDL cholesterol, and triglycerides.61 Subsequent studies have continued to be quite consistent in finding a favorable metabolic effect of soy foods on cardiovascular risk

profiles, including reducing LDL, homocysteine, and total cholesterol levels, and even blood pressure.62,63 The use of soy in breast cancer survivors has been fraught with much confusion and controversy. A critical review of the literature published in 2001 concluded that there is no clear evidence for adverse effects of soy in patients with breast cancer as well as no clear evidence that soy is safe.@There is no convincing data to support either claim, and strongly conflicting data for both perspectives. Overall, evidence was not conclusive for either the notion that the adult consumption of soy affects the risk of developing breast cancer or that soy consumption affects the survival of patients with breast cancer. The investigators concluded that the best approach may be to use the Asian diet as a guide for daily intake. Native Japanese adults consume an isoflavone intake of 30 to 40 mg/day of isoflavones, roughly 1to 1*/2servings daily; Chinese adults consume up to twice as much.

Flax Seeds Another good dietary source of phytoestrogens to consider is flax seeds. Flax seeds contain a different class of phytoestrogens called lignans. Flax seed flour and its defatted meal are the richest plant sources of lignans. The evidence that lignans can reduce the risk for cancer is still unclear, although the biologic properties of lignans and data from various cultures suggest that they do. Many lignans have antitumor, antioxidant, weak estrogenic, and antiestrogenic characteristics. Flax seeds probably have minimal impact on menopause symptoms but there may be a limited reduction in vaginal dryness and hot flashes or night sweats; there is no strong clear data in this regard.

Dietary Recommendations A menopause diet should have other considerations besides those that recommend soy and flax seeds. Symptom relief is important, but perhaps of greater concern is to reduce the risks of illnesses that increase mortality and morbidity. Diets intended to prevent heart disease, osteoporosis, diabetes, and cancer prevention are clearly warranted, as these conditions are the most common in aging women. Diets that are higher in fruits, vegetables, whole grains, vegetarian proteins, nuts, seeds, and legumes as well as low in saturated fats, trans-fats, simple carbohydrates, and fast foods are the foundation of a disease prevention diet, although individual needs and physiologic differences are fundamental to the approach. For example, women with diabetes and/or insulin resistance may need a higher-protein and lower-carbohydrate approach.

Nutritional Supplements Several nutrients have been shown to be effective in relieving hot flashes and atrophic vaginitis in clinical

studies, including vitamin E, hesperidin in combination with vitamin C, and gamma-oryzanol.

Gamma-oryzanol is an extremely safe natural substance. No sigruficant side effects have been produced in experimental and clinical studies. In addition to being Vitamin E helpful in improving the symptoms of menopause, gamma-oryzanol has also been shown to be quite effecIn the late 1940s, several clinical studies found vitamin E tive in loweringblood cholesterol and triglyceride levels.71 to be effective in relieving hot flashes and menopausal vaginal complaints compared with a p l a ~ e b o . ~ ~ - ~ ~ Botanical Medicines Unfortunately, there have been no further clinical investigations. In one study, vitamin E supplementation was Many plants have been shown to exert a tonic effect on the female glandular system. As a class, these botanicals shown to improve not only the symptoms but also the are often referred to as ”uterine tonics.” Much of their blood supply to the vaginal wall when taken for at least 4 weeks6 A follow-up study published in 1949 demoneffect is thought to be a result of phytoestrogens in the strated that vitamin E (400 IU/day) was effective in plants as well as the plants’ ability to improve blood about 50% of postmenopausal women with atrophic flow to the female organs. Some of the botanicals used in vaginitis.66 menopausal women work to nourish and tone the female Vitamin E oil, creams, ointments, or suppositories glandular and organ system rather than exerting a drugcan be used topically to provide symptomatic relief of like effect. This nonspecific mode of action makes many botanicals useful ,in a broad range of female conditions. atrophic vaginitis. Vitamin E may be effective in relieving the dryness and irritation of atrophic vaginitis as well as Other plants are used for specific symptoms, such as valerian for insomnia or chaste tree for dysfunctional uterine other forms of vaginitis.68 bleeding. Their mechanism of action does have a pharmaHesperidin and Vitamin C ceutical effect, whether it be a sedative effect in the case of Like many other flavonoids, hesperidin is known to valerian or increasing LH and an indirect progesteroneimprove vascular integrity and relieve capillary perlike effect in the case of chaste tree. Mechanisms of action of other botanicals have so far eluded us. meability. Combined with vitamin C, hesperidin and other citrus flavonoids may be effective in relieving Phytoestrogens are found in many medicinal herbs with a historical use in conditions that are now treated hot flashes. by estrogens. Phytoestrogen-containing herbs offer In one clinical study, 94 women suffering from hot flashes were given a formula containing 900 mg of hessigruficant advantages over the use of estrogens in the peridin, 300 mg of hesperidin methyl chalcone (another treatment of menopausal symptoms. Although both citrus flavonoid), and 1200 mg of vitamin C daily.@At synthetic and natural estrogens may pose significant the end of 1 month, symptoms of hot flashes were health risks, phytoestrogens have not been associated relieved in 53% of the patients and reduced in 34%. with these side effects. In fact, epidemiologic data and Improvements in nocturnal leg cramps, nose bleeds, and experimental studies in animals have demonstrated that phytoestrogens are extremely effective in inhibiting easy bruising were also noted. The only side effect was a slightly offensive body odor with a tendency for the mammary tumors, not only because they occupy estrogen receptors but also through other unrelated antiperspiration to discolor the clothing. cancer m e ~ h a n i s r n s . ~ ~ , ~ Gamma-Oryzanol Plants manufacture thousands of chemical comGamma-oryzanol (ferulic acid) is a growth-promoting pounds vital to the health and function of the plant. substance found in grains and isolated from rice bran oil. Those chemical compounds, generally known as In the treatment of hot flashes, its primary action is to micronutrients, are consumed in the diet by humans enhance pituitary function and promote endorphin whenever the plants are eaten. One of these classes of release by the hypothalamus. Gamma-oryzanol was first chemical compounds manufactured by plants is known shown to be effective in menopausal symptoms, includas phytoestrogens. More than 300 plants contain phytoing hot flashes, in the early 1960~:~Subsequent studies estrogen compounds. They compose a large part of our have further documented its effectivene~s.~~ diet, and are found in medicinal plants as well. There are In one of the earlier studies, 8 menopausal women several subclassifications of phytoestrogens; the partial and 13 women whose ovaries had been surgically list in Table 189-2 may be helpful. removed were given 300 mg/day of gamma-oryzanol. Phytoestrogens in medicinal herbs are capable of At the end of the 38-day trial, more than 67% of the exerting estrogenic effects, although their activity is at women had a 50% or greater reduction in menopausal most only 2%as strong as estrogen.” However, because sympt0ms.6~In a later study, the benefit of a 300 mg/day of this low activity, phytoestrogens have a balancing action on estrogen effects. If estrogen levels are low, dose of gamma-oryzanol was even more effective, in that 85% of the subjects reported improvement in phytoestrogens will cause an increase in estrogen effect menopausal symptoms.7o because they have some estrogenic activity. If estrogen

Specific Health Problems Sources of phytoestrogens Phvtoestrwen

Plant sourcek)

Lignans

Vegetables, fruits, nuts, cereals, spices, seeds; especially flax seeds

lsoflavones

Spinach, fruits, clovers, peas, beans; especially soy

Flavones

Beans, green vegetables, fruits, nuts

Chalcones

Licorice root

Diterpenoids

Coffee

Triterpenoids

Licorice root, hops

Coumarins

Cabbage, peas, spinach, licorice, clover

Acyclics

Hops

levels are high, phytoestrogens cause a decrease in estrogen effects because they bind to estrogen receptor binding sites, thereby competing with estrogen.74 Isoflavones have a similar structure to endogenous steroidal sex hormones. They have the ability to bind to estrogen receptors on human cells, and in women, they have a preference for binding to the beta form of the estrogen receptor. As a result, they preferentially express estrogenic effects in the central nervous system, blood vessels, bone, and skin without causing stimulation of the breast or ~ t e r u s . 7 ~ In light of the new research from the HERS II and WHI, even more women are looking for safe and effective botanical alternatives for symptom relief. Botanical alternatives for menopause symptoms are increasingly popular, despite small amounts of research to demonstrate efficacy. Many women are determined to utilize nonhormonal therapies, natural hormones, or lowerdose hormones in combination with botanicals in order to create a risk/benefit ratio they feel comfortable with.

Trifoliurn pretense (Red Clover) Red clover, a member of the legume family, has been used worldwide as a source of hay for cattle, horses, and sheep and used by humans in the past as a source of protein in the leaves and young sprouts. Historically, it has also been recognized as a medicinal plant for humans and, more recently, as a menopausal herb. The principal substances of red clover are the flavonoid glycosides, coumestans, volatile oils, L-dopa caffeic acid conjugates, polysaccharides, and some miscellaneous resins, fatty acids, hydrocarbons, alcohols, chlorophylls, minerals, and vitamins. At least four clinical trials have been conducted on the effect of red clover isoflavones on vasomotor symptoms. Two show benefit, and two do not. The first two published studies on red clover and vasomotor symptoms showed no statistically sigruficant difference between

the red clover standardized extract and placebo during a 3-month period, although both groups did i m p r o ~ e . ’ ~ , ~ It was suggested that the negative results of these studies were due to inadequate controls and that women in the control group were in fact obtaining meaningful amounts of phytoestrogens in their diets. Two other studies using 40 mg standardized extract of red clover produced a 75% reduction in hot flashes after 16 weeks in 30 women. The difference between placebo and red clover isoflavones was statistically significant (p < .001).78A similar study, evaluating 40 mg of red clover standardized isoflavones for 2 months in 23 postmenopausal women, found that red clover users had a 54% reduction in hot flushes versus 30% in the placebo group.79Other intriguing effects of red clover reported by these studies are as follows: no endometrial thickening, increase in HDL, and no abnormalities in liver function parameters, complete blood count, or estradiol determination. The two most recent studies continue the contradictions. In 2002, 80 mg of isoflavones per day resulted in a significant reduction in hot flushes as compared with baseline.@’ The other, called the ICE study, compared two different doses of red clover isoflavones with placebo for 12 weeks. One dose was 82 mg and the other was 57 mg/day. The reductions in mean daily hot flash count at 12 weeks were similar for the 82-mg group, the 57-mg group, and the placebo group. However, in comparison with the placebo group, the 82-mg isoflavone group reduced hot flashes more rapidly! Lastly, a published study showed that red clover isoflavones may reduce risk of coronary vascular disease by increasing arterial elasticity by 23y0.~’

Cirnicifigu rucemosa (Black Cohosh) Black cohosh has emerged as the single most important herb for the treatment of menopausal symptoms. Although the bulk of the research has been uncontrolled studies, there have been six well-publicized ~tudies.8~ In one of the largest studies, 629 women with menopausal complaints were given a liquid standardized extract of black cohosh twice per day for 6 to 8 weeks.&4 As early as 4 weeks, clear improvements in the menopausal ailments were seen in 80% of the women. Complete disappearance of symptoms occurred in approximately 50%. Symptoms included hot flashes, night sweats, headaches, insomnia, and mood swings. The other studies reported improvements in fatigue, irritability, hot flashes, and vaginal dryness. A later study of black cohosh involved 85 women diagnosed with breast cancer who were experiencinghot flashes.85Fifty-nine of them (70%)were taking tamoxifen during the trial. Participants took either black cohosh standardized extract of 40 mg twice daily or placebo. Both the black cohosh and placebo groups had a decline in the number and intensity of hot flashes during the

Menopause first month of about 27%. Women in the black cohosh group did report a greater reduction in sweating. Although the results of this study are not consistent with those of other studies showing benefit from black cohosh for menopausal symptoms, it is important to acknowledge that the results should take into account that black cohosh may not work in the presence of an anti-estrogen such as tamoxifen. Further weaknesses in the study are that the duration was only 2 months and there was a high dropout rate, with most of the women remaining in the black cohosh group taking the tamoxifen. The latest technology in determiningplant constituents has not identified phytoestrogens in black cohosh. In addition, a recent study has demonstrated a lack of sigruficant changes in the levels of gynecologically relevant hormones, a lack of an estrogenic effect on vaginal cytology, and, in general, a lack of an overall estrogenic effect. This, despite a substantial effect on decreasing the Kupperman Index for menopause symptoms.86 See Chapter 80 for a more complete discussion.

Ginseng Panax ginseng, also known as Korean or Chinese ginseng, contains at least 13 different triterpenoid saponins, collectively known as ginsenosides. Whether it involves reducing mental or physical enhancing the ability to cope with various physical and mental stressors by supporting the adrenal glands?l or treating the atrophic vaginal changes due to lack of ginseng is a valuable tool for many menopausal women.

Combination Products Most of the herbal combination products available contain five or more plants, some that contain phytoestrogens and some that have some other therapeutic benefits specific to menopause. Other combination products contain a mixture of plants and nutrients such as soy and vitamin E. Almost none of these combination products has been researched, although individual ingredients may have been. One herbal combination product that has been the subject of a clinical trial contains dong quai, motherwort, licorice root, burdock root, and wild yam r0ot.9~Women were randomly assigned to receive either the herbal combination 2 capsules 3 times daily or a placebo for 3 months. After 3 months, 100% of the women taking the botanical formula experienced reduction in symptom severity, whereas only 6% of women receiving placebo did so. Seventy-one percent of women taking the herbal formula reported a reduction in the total number of symptoms, compared with 17% of the women taking placebo. The botanical formula was most effective in treating hot flashes, mood changes, and insomnia. There were no clear effects of blood levels of estradiol or total estrogens, although there was actually

a trend for a decrease in the treatment group. Serum progesterone levels also appeared to diminish in the herbal group. No clear effects of the botanical formula were apparent on HDL cholesterol, triglyceride, or total cholesterol levels.

Ginkgo biloba Ginkgo biloba extract is often indicated in menopausal and postmenopausal women for its effects on the vascular system. It may be especially useful in improving both cold hands and feet as well as the forgetfulness that often accompany menopause. G. biloba extract has also been shown to improve blood flow to the hands and feet in human clinical trials and has been shown to be effective in the treatment of peripheral vascular disease of the extremities, including Raynaud syndrome, a disease characterized by extremely cold fingers or toes?496 G. biloba extract has repeatedly been used to improve mental health in patients with cerebral vascular insufficiency and may exert similar effects in menopause. The extract appears to work not only by increasing blood flow to the brain but also by enhancing energy production within the brain, increasing the uptake of glucose by brain cells, and actually improving the transmission of nerve signals." Improving the transmission rate of the nerve signal is critical to memory, which is directly related to the speed at which the nerve impulse can be transmitted. Although the effect of G. bilobu extract on the forgetfulness of menopause has not been studied in a controlled fashion, there is ample evidence to suggest that it is worth a clinical t i a l in the menopausal woman with forgetfulness and/or an inability to concentrate. Ginkgo has been shown in double-blind studies to sigruficantly improve memory in elderly as well as college-age It must be pointed out that in the treatment of cerebral vascular insufficiency, G. biloba extract should be taken consistently for at least 12 weeks in order to determine effectiveness. Although most report benefits within 2 to 3 weeks, some individuals may take longer to respond. It s e e m that the longer the treatment is continued, the more obvious and lasting the result.

Other Botanicals Numerous other botanicals have been used historically in the practice of traditional herbal medicine for the treatment of menopausal symptoms. Some have no research, no confirming research, or only a small study showing some efficacy. They include wild yam, dong quai, licorice, chaste tree, kava, sage, and hops. For other individual symptoms, the clinician might consider St. John's wort for mild to moderate depression,101J02 kava for anxiety and hot flashes,Io3 and ginkgo to improve memory.

Natural Topical Preparations Progesterone Cream Natural progesterone by itself, can also be used very effectively in the perimenopause. Problems that can be addressed include regulation of the menstrual cycle, hot flashes, night sweats, mood swings, sleep disruption, and premenstrual symptoms. A transdermal progesterone cream was studied for its ability to control vasomotor symptoms (hot flashes) and to evaluate its ability to prevent bone loss. One hundred two healthy women within 5 years of menopause were randomly assigned to receive either transdermal progesterone cream or a placebo.104Subjects were instructed to apply a 1/4 teaspoon of cream (this amount contained 20 mg progesterone or placebo) to the skin daily. Each also received a multivitamin and 1200 mg of calcium. Measurements included medical history, physical examination, DEXA scanning of the hip and spine, measurements of TSH and FSH, a lipids profile (cholesterol, etc.), and a regular blood chemistry profile. The women kept weekly symptom diaries and were seen every 4 months for 1 year. Bone density scanning and blood chemistry profiles were obtained again at the end of 1year. Before the initiation of the study, 30 of the 43 (69%) in the treatment group and 26 of the 47 (55%)in the placebo group had hot flashes. Twenty five of 30 (83%)women in the treatment group experienced improvement or resolution of the hot flashes, and 5 of 26 (19%) placebo subjects showed improvement or resolution. The numbers of women who showed a gain in bone mineral density did not differ in the two groups. The latest randomized clinical tial compared the effect of a transdermal natural progesterone cream (32 mg daily) with a placebo cream. Eighty postmenopausal women in Australia were randomly assigned to each group. Women were evaluated using the familiar Greene Climacteric Scale and the Menopause Quality of Life Questionnaire, as well as serum lipid levels and bone markers over 12 weeks. No detectable change was seen in vasomotor symptoms, moods, libido, serum lipid levels, or metabolic markers of bone turnover. There was a slight elevation of blood levels of progesterone. The researchers concluded that the use of 32 mg of transderma1 progesterone was not sufficiently absorbed into the blood stream to achieve biologic effects.'OS

Lifestyle Factors Exercise The hypothesis that impaired endorphin activity within the hypothalamus is a major factor in provoking hot flashes led researchers in Sweden to design a study to determine the effect of regular physical exercise on the frequency of hot flashes.'% In the study, the frequency of moderate and severe hot flashes was investigated in

79 postmenopausal women who took part in physical exercise on a regular basis and were compared with a control group of 866 postmenopausal women between 52 and 54 years old. The study clearly demonstrated that regular physical exercise definitely reduced the frequency and severity of hot flashes: The women in the exercising group passed through a natural menopause without the use of HRT. The physically active women who had no hot flashes whatsoever spent an average of 3.5 hours/week exercising, whereas women who exercised less were more likely to have hot flashes. Similar results, including mood elevation in premenopausal, perimenopausal, and postmenopausal women who were exercising or sedentary have been reported in other studies.'07 The benefits of exercise were experienced in women who did and did not take HRT. Given the many benefits of regular exercise on mood and the health of bone and the cardiovascular system (Box 189-2),along with these positive results in reducing the frequency and severity of hot flashes, it is clear that regular physical exercise is a key component of menopause care.

Cigarette Smoking Cigarette smoking significantly raises the risk of early menopause, as smokers have approximately double the risk of menopause between the ages of 44 and 55 years. Women who were former smokers had a lower risk, showing the possibility of a partial reversal of the effect of smoking.10s

THERAPEUTIC APPROACH Many natural measures can help alleviate the most common symptoms of menopause. In most cases, HRT either is not necessary or is needed for only 1to 4 years. However, in women at high risk for osteoporosis and women who have already experienced significant bone loss and also have menopause symptoms or do not tol-

Relief from hot flashes Decreased bone loss Improved heart function improved circulation Reduced blood pressure Decreased blood cholesterol levels Improved ability to deal with stress Improved oxygen and nutrient utilization in all tissues Increased self-esteem, mood, and frame of mind Increased endurance and energy levels

Menopause

erate osteoporosis medications, HRT may be indicated. For women who have menopause symptoms that they are not tolerating well, nHRT, fcHRT, or cHRT can be used with periodic attempts at reducing or discontinuing the hormones.

Diet Increase consumption of foods that may provide modest symptoms relief, such as soy foods, legumes in general, flax seeds, fennel, celery, and parsley.

Supplements *Vitamin E: 800 IU/day until symptoms have improved, then 400 IU/day Hesperidin. 900 mg/day Vitamin C: 1200 mg/day Gamma-oryzanol: 300 mg/day

Botanical Medicines

biochemical marker to indicate therapeutic effect. The dosage of the cimicifuga extract used in the majority of clinical studies has been 20 mg of 27-deoxyacteine twice daily. Here are the approximate dosage recommendations using other (nonstandardized) forms of C. racemosa: Powdered rhizome: 1to 2 g Tincture (1:5):4 to 6 ml Fluid extract (1:l):3 to 4 ml(1 tsp) Solid (dry powdered) extract (4:l): 250 to 500 mg

G. biloba extract: 24% @go flavoglycoside content: 40 mg Red clover extract: 40 mg of red clover isoflavones twice daily

Lifestyle Facilitate a regular exercise program, at least 30 minutes four times a week.

The dosage of Cimicifuga racemosa is based on its content of 27-deoxyacteine, which serves as an important

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Menopause and blood pressure in hyperlipidemic men and women. Am J Clin Nutr 2002;76:365-372. 64.Messina M, Loprinzi C. Soy for breast cancer survivors: a critical review of the literature. J Nutr 2001;131:3095S3108S. 65. Christy CJ. Vitamin E in menopause. Am J Obstet Gynecol 1945; 50:8487. 66. McLam HC. Vitamin E in the menopause. Br Med J 1949;21378-1381. 67.Finkler RS. The effect of vitamin E in the menopause. J Clin Endocrinol Metab 1949;9:89-94. 68. Wilson RA. Feminine forever. New York Evans, 1966. 69.Murase Y, Iishima H. Clinical studies of oral administration of gamma-oryzanol on climacteric complaints and its syndrome. Obstet Gynecol Prac 1963;12:147-149. 70. Ishihara M. Effect of gamma-oryzanol on serum lipid peroxide levels and climacteric disturbances. Asia Oceania J Obstet Gynecol 1984;10:317-323. 71. Yoshino G, Kazumi T, Amano M, et al. Effects of gamma-oryzanol on hyperlipidemic subjects. Curr Ther Res Clin Exp 1989;45543-552. 72. Rose DP. Dietary fiber, phytoestrogens, and breast cancer. Nutrition 1992;8:47-51. 73. Elghamry MI, Shihata A4.Biological activity of phytoestrogens. 3. Experimental studies on some biological properties of betasitosterol. Planta Med 1966;14352-357. 74. Tamaya T, Sat0 S, Okada H. Inhibition by plant herb extracts of steroid bindings in uterus, liver, and serum of the rabbit. Acta Obstet Gynecol Scand 1986;65:839-842. 75. Kuiper GG, Carlsson 8, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997;138:863-870. 76. Baber RJ, Templeman C, Morton T, et al. Randomized placebocontrolled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric 1999;2:85-92. 77. Knight D, Howes J, Eden J. The effect of Promensil, an isoflavone extract, on menopausal symptoms. Climacteric 1999;2:79-84. 78. Jeri A, deRomana C. The effect of isoflavone phytoestrogens in relieving hot flushes in Peruvian post-menopausal women. In Proceedings of the 9th International Menopause Society World Congress on Menopause. Yokohama, Japan: 1999. 79. Nachtigall L, La Grega L, Lee W, Fenichel R. The effects of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness. In. Proceedings of the 9th International Menopause society World Congress on the Menopause. Yokohama, Japan: 1999. 80.van de Weijer P, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas 2002;42:187-193. 81. Tice J, Ettinger B, Ensrud K, et al. Phytoestrogen supplements for the treatment of hot flashes: the isoflavone clover extract (ICE) study. JAMA 2003;290207-214. 82. Nestel PJ, Pomeroy S, Kay S, et al. Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. J Clin Endocrinol Metab 1999;84:895-898. 83. Lieberman S. A review of the effectiveness of Cimicifigu rucemosu (black cohosh) for the symptoms of menopause. J Womens Health 1998;7525-529. 84. Stolze H. An alternative to treat menopausal complaints. Gyne 1982;3:14-16. 85. Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol2001;192739-2745. 86. Liske E, Hanggi W, Zepelin HH, et al. Physiologicalinvestigation of a unique extract of black cohosh (Cimicifugae racemosae rhizoma): a 6-month clinical study demonstrates no systemic estrogenic effect. J Womens Health Gend Based Med 2002;11:163-174. 87. Hikino H. Traditional remedies and modem assessment the case of ginseng. In Wijesekera R, ed. The medicinal plant industry. Boca Raton, FL: CRC Press, 1991:149-166.

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Menorrhagia Tori Hudson, N D

Michael T. Murray, N D Joseph E. Pizzorno Jr, N D CHAPTER CONTENTS Diagnostic Summary 1901 General Considerations 1901 Etiology 1901 Abnormalities in Prostaglandin Metabolism 1902 Thyroid Abnormalities 1902 Estimating Menstrual Blood Loss 1902

Botanical Medicines 1904 Natural Hormones 1905

Therapeutic Approach 1905 Diet 1905 Supplements 1906 Botanical Medicines 1906 Natural Hormones 1906

Therapeutic Considerations 1902 Psychological 1903 Nutrition 1903

DIAGNOSTIC SUMMARY Excessive menstrual bleeding-blood loss greater than 80 ml-occurring at regular cyclical intervals (cycles are usually, but not necessarily, of normal length) May be due to dysfunctional uterine bleeding (no organic cause); often due to local lesions (e.g., uterine myomas [fibroids], endometrial polyps, endometrial hyperplasia, endometrial cancer, adenomyosis, and endometritis); other causes are bleeding disorders and hypothyroid The key to diagnosis begins with the history and physical examination. The following tests and procedures are performed for diagnosis and management on an asneeded basis: pelvic ultrasonography, hysterosonography, hysteroscopy, Papanicolaou smear, thyroid function studies, pregnancy test, complete blood count (CBC), ferritin measurement, liver function or coagulation studies, measurement of follicle-stimulating hormone (FSH), luteinizing hormone (LD), serum progesterone, testosterone, and dehydroepiandrosterone sulfate (DHEA-S), testing for sexually transmitted disease (STDs), endometrial biopsy, dilation and curettage (D&C).

GENERAL CONSIDERATIONS Abnormal uterine bleeding comes in many sizes and shapes. This chapter focuses on menorrhagia (regular/ normal intervals, with excessive flow and duration). Other patterns of abnormal bleeding are oligomenorrhea

(interval greater than 35 days), polymenorrhea (interval less than 21 days), metrorrhagia (irregular/frequent intervals with excessive flow and duration) menometrorrhagia (prolonged heavy bleeding at irregular intervals), and intermenstrual bleeding (variable amounts occurring between regular menses). The normal menstrual cycle is defined as 28 days ( f 7 days) in length, 4 days (*4 days) in duration, with a blood loss of 40 ml (f20 ml). The complaint of menorrhagia is largely subjective, as objective measurement of blood loss is rarely made. Furthermore, there is a poor correlation between measured blood loss and a patient’s assessment of her bleeding (discussed in more detail later). Studies that have measured blood loss have demonstrated that patients with menorrhagia have a considerable increase in menstrual blood flow during the first 3 days (up to 92% of their total menses being lost at this time). This finding suggests that the mechanisms responsible for cessation of menstruation are as effective in women who have menorrhagia as in normal women, despite the very high blood loss.

Etiology As with any disease, proper determination of the cause is essential for effective treatment. The appropriate methodology for ruling out pathologic causes is beyond the scope of this text and can be found in any good text on gynecology (Table 190-1).l It is important to realize the scope of causes so that one does not 1901

Specific Health Problems Pathological causes of menorrhagia Cause

Possible etiology

Anovulation

Excessive estrogen Failure of midcycle surge of luteinizing hormone Hypothyroidism Hyperprolactinemia Polycystic ovarian disease

Intrauterine structural defects

Fibroids Polyps Cancer Ectopic pregnancy Intrauterinedevices

Bleeding disorders

See Table 190-2

Modified from Federman DD. Ovary. In Dale DC, Federman DD. Scientific American medicine. New York: Scientific American, 1997, pp 3:111:9-3:111:10.

just presume dysfunctional uterine bleeding (DUB)defined as abnormal uterine bleeding without any demonstrable organic cause. DUB can include menorrhagia, oligomenenorrhea, polymenorrhea, metrorrhagia, menometrorrhagia, and intermenstrual bleeding. Abnormal bleeding is best understood through thinking in categories of abnormalities: hormonal, mechanical, and clotting. Hormonal causes include anovulation and luteal phase defects and stress (DUB), exogenous hormones, hypothyroidism, and ovarian cysts. Mechanical causes include uterine polyps, uterine fibroids, uterine cancer, intrauterine devices (IUDs), atopic pregnancy, pregnancy, endometriosis, and endometritis. Clotting abnormalities include vitamin K deficiency, druginduced hemorrhage (heparin, warfarin, aspirin), dysproteinemias, disseminated intravascular coagulation, severe hepatic disease, primary fibrinolysis, and circulating inhibitors of coagulation; not all of these will cause menorrhagia, but rather, they give rise to other abnormal bleeding patterns.

(PG) E2 and PGIz and the antiaggregating activity of PG12 whereas the pain of dysmenorrhea is due to the overproduction PGFz,.

Thyroid Abnormalities The association of overt hypothyroidism or hyperthyroidism with menstrual disturbances is well known. However, even minimal thyroid dysfunction, particularly minimal, subclinical insufficiency (as determined by the thyroid stimulation [TRH] test) may be responsible for menorrhagia and other menstrual disturbances! Patients with minimal thyroid insufficiency and menorrhagia have shown dramatic response to thyroxine? It has been recommended that patients with longstanding menstrual dysfunction (who have no obvious uterine disease) should be considered for TRH testing. This approach is preferable to the empirical use of thyroid hormone.

Estimating Menstrual Blood Loss

Physicians often believe they can assess menstrual blood loss by asking the patient to estimate the number of pads or tampons used during each period and the duration of the period. However, studies have demonstrated that there is no correlation between measured blood loss and these asse~sments.l-~,~ A woman’s assessment of her blood loss is extremely subjective, as demonstrated by one study finding that 40% of women with a menstrual blood loss exceeding 80 ml considered their periods only moderately heavy or scanty, whereas 14% of those with a measured loss of less than 20 ml judged their periods to be heavy.6 Serum ferritin levels may be the best indicator of excessive menstrual blood loss but their determination may not be practical in terms of immediate need to know. Despite inaccuracies of patient reporting, it is important for the clinician to make an attempt at understanding blood loss. Excessive blood loss should be a concern if a woman is bleeding longer than 7 straight days or more frequently than every 21 days, and is Abnormalities in Prostaglandin Metabolism changing a pad or tampon every hour for more than half a day. Women who are changing a pad and/or The etiology of functional menorrhagia is currently tampon every half hour or more often require urgent, believed to involve abnormalities in the biochemical perhaps emergency, attention. Any amount of bleeding processes of the endometrium that control the supply in a postmenopausal woman is considered abnormal. of arachidonic acid for prostaglandin s y n t h e s i ~ . ~ , ~ Menorrhagic endometrium incorporates arachidonic acid into neutral lipids to a much greater extent than THERAPEUTIC CONSIDERATIONS normal, whereas its incorporation into phospholipids Many women have often been subjected to needless is lower. The greater arachidonic acid release during hysterectomy because of inadequate medical managemenstruation results in higher production of series ment of their heavy bleeding cycles. This practice 2 prostaglandins, which are thought to be the major was more common 20 years ago or longer, but it is still factor both in the excessive bleeding seen at menstrufollowed in varying and disturbing fashion in different ation and in the symptoms of dysmenorrhea. The parts of the country. Clearly, the standard of care in excessive bleeding during the first 3 days appears to conventional medicine is not the same throughout the be due to the vasodilatory properties of prostaglandin

Menorrhagia country. The time for a hysterectomy should be determined by the inability to adequately manage menorrhagia with nonsurgical interventions, patient safety and health, lack of a clear diagnosis, and the stress and fatigue wearing on the patient so that she expresses a preference for the procedure. Although we recognize the need for hysterectomy in selected circumstances, most cases of menorrhagia can be treated with nonsurgical therapies, including botanicals, nutritional interventions, and hormonal and pharmaceutical therapies. Less permanent surgical procedures than hysterectomy now spare the uterus-D&C, hysteroscopic resections and ablations, and uterine artery embolization.

Psychological Stress affects bleeding patterns directly by influencing the hypothalamic/pituitary/ovarianaxis. This influence causes anovulation and the subsequent lack of progesterone production. As a result, the endometrium is in an estrogen-dominant state and becomes thickened and plump without the opposing and stabilizing effect of progesterone. This state can then lead to heavy bleeding at the next menstrual cycle. Adolescents account for many of these cases, and the remainder are often perimenopausal women.

Nutrition Iron Deficiency A menstrual blood loss exceeding 60 ml per period is associated with negative iron balance in most cases.' Although menstrual blood loss is well recognized as a major cause of iron deficiency anemia in fertile women, it is not as well known that chronic iron deficiency can be a cause of menorrhagia. Taymor et aP have made such a suggestion on the basis of several observations: Response to iron supplementation alone in 74 of 83 patients (in whom organic diseasehad been excluded) High rate of organic disease (fibroids, polyps, adenomyosis, etc.) in the patients with no response to iron supplementation Associated rise in serum iron levels in 44 of 57 patients Decreased response to iron therapy when initial serum iron levels were high Correlation of menorrhagia with depleted tissue iron stores (bone marrow) irrespective of serum iron level A significant double-blind placebo-controlled study displaying improvement in 75% of those given iron supplementation, compared with 32.5%of those given the placebo Hematologic screening and serum femtin determination (the first parameter to indicate decreased iron levels) should be performed for patients complaining of menorrhagia. In one study, women who were menorrhagic

(according to subjective information) displayed sigruficantly lower serum ferritin levels than controls, but hemoglobin concentration,. mean corpuscular volume, and mean corpuscular hemoglobin were not significantly different between the two group^.^ (The investigators in this study erroneously stated that such women do not require prophylactic iron supplementation since no hematologic abnormalities appeared despite sigruficantly reduced iron stores.) Iron supplementation, at a daily dose of 100 mg elemental iron, has been recommended as a prophylactic therapy by several researchers, because chronic iron deficiency appears to promote menorrhagia and ironcontaining enzymes are depleted before hematologic changes are observed. A decreased serum ferritin level is a good indication of the need for iron supplementation.

Vitamin A In one study, serum retinol levels were found to be significantly lower in women with menorrhagia than in healthy controls. In this study, vitamin A was used as a treatment in 40 women diagnosed as having menorrhagia due to a number of different causes. In the group who received 60,000 IU of vitamin A for 35 days, menstruation returned to normal in 23 patients (57.5%)and was reduced in 14 (35%). Overall, the vitamin A was ineffective in only 3 of the 40 women (7.5%),and 92.5% of the 37 women had either complete relief or significant improvement.lo

Vitamin C and Bioflavonoids Capillary fraghty is believed to play a role in many cases of menorrhagia. Supplementation with vitamin C (200 mg tid) and bioflavonoids (dose not specified) was shown to reduce menorrhagia in 14 out of 16 patients." One of the patients with no response had endometriosis, and the other had metrorrhagia. Bioflavonoids, like vitamin C, can help strengthen the vessel walls of capillaries. Bioflavonoids may also reduce heavy bleeding through their antiinflammatory effect. A natural antiinflammatory such as bioflavonoids may be used to reduce heavy bleeding just as conventional medicine uses nonsteroidal antiinflammatory agents. As vitamin C is known to significantly increase iron absorption, its therapeutic effect could be also due to enhanced iron absorption.

Vitamin E One group of investigators has suggested that free radicals have a causative role in endometrial bleeding, particularly in the presence of an intrauterine device.'2 Vitamin E supplementation (100 IU every 2 days) resulted in improvement in all patients by the end of 10 weeks.13Although vitamin E may have produced its effects via its antioxidant activity, it is equally plausible

Specific Health Problems that the vitamin affected prostaglandin metabolism in a manner that would reduce bleeding.

generalized hemorrhagic disorders

Vitamin K and Chlorophyll Although bleeding time and prothrombin levels in women with menorrhagia are typically normal, the use of vitamin K (historically in the form of crude preparations of chlorophyll) has clinical and limited research support.14J5Also, some women are found to have an inherited or acquired bleeding disorder. Table 190-2 lists some causes of acquired hemorrhagic disorders.

Essential Fatty Acids Menorrhagia is associated with increased arachidonic acid availability in the uterus.16 It now appears that the majority of tissue arachidonic acid is derived from the diet, so it is possible that reducing the intake of animal products and/or increasing intake of linoleic, linolenic, and di-homo-gamma-linolenic acid could curtail blood loss by decreasing the availability of arachidonic acid. Consuming larger proportions of fish, nuts, and seeds can have an effect over time in altering the production of arachidonic acid. Using fish oils, flax oil, and other seed oils in supplementation form my produce this favorable effect more quickly.

Vitamin B Complex There may be a correlation between a nutritional deficiency of B vitamins and menorrhagia. It has been shown that in vitamin B complex deficiency, the liver loses its ability to inactivate estrogen. Some cases of menorrhagia are due to an excess estrogen effect on the endometrium. Therefore, supplementing with a complex of B vitamins may normalize estrogen metabolism. A study conducted in the 1940s in a series of consecutive cases showed that a B-complex preparation was effective in “prompt” improvement in both menorrhagia and metrorrahia.” The preparations used were thiamin 3 to 9 mg, riboflavin 4.5 to 9 mg, and niacin up to 60 mg.

Botanical Medicines Zingiber officinale (Ginger) Ginger has been shown to inhibit prostaglandin synthetase, the enzyme believed to be related to the altered prostaglandin-2 ratio associated with excessive menstrual loss.1s The inhibition of prostaglandin and leukotriene formation could explain the traditional use of ginger as an antiinflammatory agent.

Vitex agnus castus (Chaste Tree) Chaste tree is probably the best-known herb in all of Europe for treatment of hormonal imbalances and abnormal bleeding in women. Since at least the time of the Ancient Greeks, chaste tree has been used for the full scope of menstrual disorders, including heavy menses.

Factor

Possible cause

Deficiency of vitamin K

Low intake, impaired absorption, antimicrobial inhibition of gut flora that synthesize vitamin K

Drug-induced hemorrhage

Heparin, warfarin

Dysproteinemias

Myeloma, rnacroglobinernia

Disseminated intravascular coagulation Severe hepatic disease Circulating inhibitors of coagulation Primary fibrinolysis Modified from Gubner R. Ungerleider HE. South Med J 1944;37:556-558.

It is mainly the seeds that are used for medicine in Europe and in the United States. Chaste tree acts on the hypothalamus and pituitary glands. It increases LH production and mildly inhibits the release of FSH. The result is a shift in the ratio of estrogen and progesterone that effectively becomes a progesterone-like action. Chaste tree has been studied and shown to effect improvement in amenorrhea, polymenorrhea, oligomenorrhea, and men~ r r h a g i a . ’In ~ -a~ study ~ observing 126 women with menstrual disorders, the duration between periods lengthened from an average of 20.1 days to 26.3 days in the 33 women with polymenorrhea, and the number of heavy bleeding days was shortened in the 58 patients with menorrhagia, with the use of 15 drops of chaste tree liquid extract. Chaste tree is the most important herb for normalizing the menstrual flow but is not a fast-acting herb. Its effects may not be known for 3 or 4 months.

Traditional Astringent Herbs Astringent herbs are used to reduce blood loss from the reproductive tract as well as the gastrointestinal tract, respiratory tract, and skin. The astringents most effective in uterine blood loss are often those that are high in tannins, although the tannins are most likely not the only constituent responsible. The following eight herbs are major astringent and hemostatic herbs used in chronic and acute menorrhagia; these herbs are usually used in combination formulations for weeks or months to bring about their results. Yarrow (Achillea millefolium) Ladies’ mantle (Alchemilla vulgaris) Cranesbill (Geranium maculatum) Beth root (Trillium erecturn) Greater periwinkle Winca major) Horsetail (Equisetum arvense)

Menorrhagia

Goldenseal (Hydrastis canadensis) Shepherd’s purse (Capsella bursa pastoris) Shepherd’s purse has a long history of use in the management of obstetric and gynecologic hemorrhage. Intravenous and intramuscular injections of this herb have been found to be effective (in uncontrolled studies) in menorrhagia due to functional abnormalities and f i b r o i d ~ . ’ ~Its, ~hemostatic action is believed to be a result of its high concentration of oxalic and dicarboxylic acids.

Traditional Uterine Tonics Uterine tonics have enjoyed a long history of use in traditional herbal medicine for easing menstrual flow. Tradition and empirical uses of uterine tonics hold that if the uterus is hypotonic, there may be heavy bleeding, and that improving uterine tone tends to normalize and regulate menstrual bleeding. Uterine tonics or amphoterics that regulate tone and potentially reduce bleeding are as follows: Blue cohosh (Caulophyllurn thalictroides) Helonia (Charnaeliriurn luteurn) Squaw vine (Mitchella repens) Raspberry leaves (Rubus idaeus) Life root (Senecio aureus) Astringent and uterine tonic herbs can be used in combination formulations or for weeks to several months as a tea, liquid extract, or powdered capsule. These herbs usually must be taken combination formulations for weeks and months to bring about their results.

Traditional Herbs for Semiacute and Acute Blood Loss when the Patient Is Stable The traditional herbs listed here have dose-specific toxicities and should be used only in after reference to a botanical reference text to ensure proper dosing. Cinnamon essential oil should be used at 1 to 5 drops every 3 to 4 hours. The other herbs should not exceed 20 drops every 2 hours or 1 capsule every 4 hours. Cinnamon essential oil (Cinnarnornurnverurn) Life root (Senecio aureus) Canadian fleabane (Erigeron canadensis) Greater periwinkle (Vinca major) Shepherd’s purse (Capsella bursa pastorus) Yarrow (Achillea rnillefoliurn) Savin (Sabina oficinalis) Beth root (Trillium erecturn) These botanicals should be used as the sole treatment only in women who are stable. In unstable patients, they should be used only as adjuncts to intravenous estrogens or other pharmaceutical or surgical

interventions. These herbs can be used in patients with chronic menorrhagia who are stable and for semiacute blood loss or acute blood loss if the patient shows no signs of instability and improves within 12 to 24 hours.

Natural Hormones Natural estradiol and natural progesterone can be extremely effective in managing menorrhagia, just as conjugated equine estrogens (CEEs) or synthetic estrogens and progestins are used in conventional medicine. For control of an acute bleeding episode, the use of natural estradiol should be just as effective as one of the dosing regimens of CEE. These hormones are prescription items and should be administered by a practitioner qualified to use them. Cyclic natural progesterone can be used to correct recurring menorrhagia, and a short course of natural progesterone can be used in many cases of acute menorrhagia. Natural progesterone creams will not have as significant an effect as the higher-dose pills or oral micronized natural progesterone.

THERAPEUTIC APPROACH Patients who are unstable, as evidenced by hypotension, dizziness, loss of consciousness, chills or fever, or passage of large amounts of tissue, require transfer to the hospital for intravenous estrogens, D&C, and/or hysterectomy or uterine ablation. The first step in treating a woman with menorrhagia is to control the cause. When the excessive bleeding has been determined to be related to prothrombin time, hematologic status, or thyroid function, such abnormalities can be corrected. Mechanical causes of menorrhagia may be managed without removal of the cause, such as an endometrial polyp or uterine fibroid but if no improvement occurs, conventional treatment including surgery may be necessary. Endometrial hyperplasia requires definitive and proven progesterone or progestin treatment with biopsy-proven improvement. Endometrial cancer requires a hysterectomy. Infections of the uterus need to be treated appropriately. Ectopic pregnancy with or without bleeding necessitates immediate conventional intervention. In cases of chronic menorrhagia or episodic acute blood loss that is effectively managed, a CBC and serum ferritin measurement can be used to help monitor the patient’s anemia status.

Diet The diet should be relatively low in sources of arachidonic acid (animal fats), high in fish oils (docosahexaenoic acid and eicosapentaenoic acid), and high in linolenic and linoleic acids (vegetableoil sources). Green leafy vegetables and other sources of vitamin K should

be eaten freely. Fruits, vegetables and spices with antiinflammatory effects include garlic, onions, cumin, pineapple, and citrus.

Supplements Vitamin C: 1000 to 3000 mg/day Bioflavonoids: 250 to 2000 mg/day Vitamin A: 25,000 to 30,000 IU bid for a maximum of 3 months Vitamin E: 200 to 800 IU/day Chlorophyll: 25 mg/day (use a crude form) Iron succinate or fumarate, 30 mg bid, or iron sulfate, 325 mg 1to 2 times daily

For semiacute cases, the following botanicals should be given: Botanical tincture of equal parts of each herb (20 to 30 drops every 2 to 3 hours): yarrow, greater periwinkle, shepherd's purse, life root Cinnamon oil: 1 to 5 drops every 3 to 4 hours

Natural Hormones

Bioflavonoids: 1000 mg bid Vitamin C: 1to 3 g/day Chaste tree tincture, '/z to 1 tsp daily or standardized extract of 175 mg/day

Oral micronized progesterone: 100 mg bid given 7 to 12 days per month for recurring menorrhagia; 200 to 400 mg per day for 7 to 12 days may be used for semiacute blood loss Progesterone cream (use a product that contains at least 400 mg progesterone per oz): 1/4 to l/z tsp bid for 12 days per month for cases of mild recurring menorrhagia Natural estradiol: High-dose regimen for acute bleeding is as follows: 2 mg estradiol every 4 hours for 24 hours, then a single daily dose for 7 to 10 days, followed by oral micronized progesterone, 200 mg before bed for 7 to 12 days.

1. Federman DD. Ovary. In Dale DC,Fedennan DD. Scientific American medicine. New York Scientific American, 19973~.9-3:IIklO. 2. Downing I, Hutchon DJ, Poyser NL. Uptake of [3H]-arachidonic acid by human endometrium. Differences between normal and menorrhagic tissue. Prostaglandins 1983;26:55-69. 3. Stott PC. The outcome of menorrhagia: a retrospective case control study. J R Coll Gen Pract 198333:715-720. 4.Stoffer SS. Menstrual disorders and mild thyroid insufficiency: intriguing cases suggesting an association. Postgrad Med 1982;72 75-82. 5. Chimbira TH, Anderson AB, Tumbull A. Relation between measured blood loss and patients' subjective assessment of loss, duration of bleeding, number of sanitary towels used, uterine weight and endometrial surface area. Br J Obstet Gynaecol 1980;87603-609. 6. Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood l o s s - a population study. Variation at different ages and attempts to define normality. Ada Obstet Gynecol Scand 1966;45:320-351. 7. Arvidsson B, Ekenved G, Rybo G, Solve11 L. Iron prophylaxis in menorrhagia. Acta Obstet Gynecol Scand 1981;60:157-160. 8. Taymor ML, Sturgis SH, Yahia C. The etiological role of chronic iron deficiency in production of menorrhagia. JAMA 1964;187323-327. 9. Lewis GJ. Do women with menorrhagia need iron? Br Med J (Clin Res Ed) 1982;284:1158. 10. Lithgow DM, Politzer WM.Vitamin A in the treatment of menorrhagia. S Afr Med J 1977;51:191-193. 11. Cohen JD,Rubin HW. Functional menorrhagia: treatment with bioflavonoids and vitamin C. Curr Ther Res 1960;2:539-542. 12. Dasgupta PR, Dutta S, Banejee P, Majumdar S. Vitamin E (alpha tocopherol) in the management of menorrhagia associated with the

use of intrauterine contraceptive devices (IUCD). Int J Fertil 1983;2855-56. 13. Stone KJ, Willis AL, Hart WM, et al. The metabolism of di-homogamma-linolenic acid in man. Lipids 1979;14:174-180. 14. Schumann E. Newer concepts of blood coagulation and control of hemorrhage. Am J Obstet Gynecol1939;38:1002-1007. 15.Gubner R, Ungerleider HE. Vitamin K therapy in menorrhagia. South Med J 1944;37556-558. 16.Kelly RW, Lumsden MA, Abel MH, Baird DT. The relationship between menstrual blood loss and prostaglandin production in the human: evidence for increased availability of arachidonic acid in women suffering from menorrhagia. Prostaglandins Leukot Med 1984;1669-78. 17. Biskind M. Nutritional deficiency in the etiology of menorrhagia, metrorrhagia, cystic mastitis and premenstrual tension: treatment with vitamin B complex. J Clin Endocrinol Metab 1943;3:227-234. 18. Macalo N, Jain R, Jain S et al. Ethnophannacologic investigations of ginger. J Ethnopharm 1989;27129-140. 19. Probst V, Roth 0. On a plant extract with a hormone like effect. Dtsch Me Wschr 1954;791271-1274. 20. Bleier W. Phytotherapy in irregular menstrual cycles or bleeding periods and other gynecological disorders of endocrine origin. Zentralblatt Gynakol 1959;81:701-709. 21. Milewica A, Gejdel E, et al. V i t a ugnus custus extract in the treatment of luteal phase defects due to hyperprolactinemia: results of a randomized placebo-controlled double-blind study. ArzneimForsch Drug Res 1993;43:752-756. 22. Steinberg A, Segal HI, Parris HM. Role of oxalic acid and certain related dicarboxylic acids in the control of hemorrhage. Ann Otol Rhino1 Laryngol 1940;49:1008-1021.

Botanical Medicines The following botanical medicines should be used for chronic recurring menorrhagia:

Migraine Headache Nancy Sudak, MD Michael T. Murray, ND JosephE. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

1907

General Considerations 1907 Classification and Diagnosis 1907 Pathophysiology 1908

Nutritional Supplements 1914 Botanical Medicines 1916 Hormones 1917 Physical Medicine 1918 Therapeutic Approach

1919

Therapeutic Considerations 1911 Drug Reaction 1911 Diet 1913

DlAG NOSTlC SUMMARY Recurrent, paroxysmal attacks of headache Headache is typically pounding and unilateral but may become generalized Attacks often preceded by psychologic or visual disturbances (auras); accompanied by anorexia, nausea, and gastrointestinal upset; and followed by drowsiness Physical examination reveals no focal neurologic deficit

GENERAL CONSIDERATIONS The lifetime prevalence of migraine headache is at least l8%.' Women are more frequently affected than men, and more than half of patients with migraine have a family history of the illness. Although many migraines come without warning, migraineurs often have warning symptoms (auras) before the onset of pain. Typical auras last a few minutes and include the following: Blurring or bright spots of vision Anxiety Fatigue Disturbed thinking Unilateral peripheral numbness or tingling

In vascular headaches such as migraine, the pain is characterized by a throbbing or pounding sharp pain. In nonvascular headaches like tension headache, the pain is characterized as a steady, constant, dull pain that starts at the base of the skull or in the forehead and spreads over the entire head, giving the sensation of pressure,

as if a vise has been applied to the skull (Box 191-1 lists primary classifications of headaches). The pain of headache results from sensory responses distinct from brain tissue because the brain itself is insensate. Cephalic pain arises from the meninges, large cranial vessels, proximal intracranial vessels, and scalp vasculature and muscles when stretched or tensed. The most common nonvascular headache is the tension headache. This headache is usually caused by tightening in the muscles of the face, neck, or scalp as a result of stress or poor posture. Tightening of the muscles results in nerve impingement or vascular compromise, resulting in pain and pressure. Relaxation of the musculature often affords prompt relief.

Classification and Diagnosis Migraine headache has been subdivided into several types on the basis of the presence or absence of preceding or concomitant neurologic manifestations and the nature of the manifestations. Although there are several subtypes, the three most typical (common, classic, and complicated)comprise the vast majority of patients, and differentiation, while important, does not appear to have any therapeutic significance. Table 191-1 summarizes the differentiation and diagnosis of these types. Cluster headache was once considered a migrainetype headache because vasodilation is a key component, but it is now classified separately. Also referred to as histamine cqhalgia, Horton's headache, or atypical facial neuralgia, it is much less common than migraine. Another headache to be considered in this chapter is chronic daily headache (CDH).Approximately 40% of 1907

Migraine classification Vascular Headache Migraine headache Classic migraine Common migraine Complicated migraine Variant migraine Cluster headache Episodic cluster Chronic cluster Chronic paroxysmal hemicrania Miscellaneous vascular headaches Carotidynia Hypertension Exertional Hangover Toxins and drugs Occlusive vascular disease

Common

Classic

Complicated

Incidence Pain

80%

10% Unilateral

10% Unpredictable, may be absent

Aura

Unusual

0.5 hr, striking

Neurologic aura, vertigo, syncope, diplopia, hemiparesis

Duration of headache

1-3 days

2-6 hr

Unpredictable

Physical examination

Uncomfortable

Pallor, vomiting

Mild neurologic signs, speech disorder, hemiparesis, unsteadiness, cranial nerve 111 palsy

Frontal, unilateraV bilateral

Nonvascular Tension headache Common tension headache Temporomandibular joint dysfunction Increased or decreased intracranial pressure Brain tumors Sinus infections Dental infections Inner or middle ear infections

patients seen in headache clinics suffer from CDH. Other terms used to describe CDH include the following: Chronic tension headache Migraine with interparoxysmal headache Transformed migraine Evolutive migraine Mixed headache syndrome Tension-vascularheadache

To simplify matters, CDH has now been divided into four major types (Box 191-2).

Pathophysiology Considerable evidence supports an association between migraine headache and vasomotor instability, but a singular pathophysiologic mechanism has not been identified. Much disagreement exists regarding the sequence of events producing migraine headache, but migraine headache is no longer believed to simply be a primary vascular Migraineurs experience heightened central nervous system (CNS) activity, which appears to be mediated by the trigeminovascular system.

Vasomotor Instability It is a well-known clinical observation that superficial temporal vessels are visibly dilated during migraine, and

Transformed migraine Drug induced Non-drug induced Chronic tension-type headache New daily persistent headache Posttraumatic headache

local compression of these vessels or the carotid artery temporarily relieves migraine pain? However, other types of extracranial vasodilation (e.g., heat or exercise induced) are not associated with migraine. Despite the extracranial vasodilation, the patient appears pale during the headache, suggesting constriction of the small vessels. This observation is supported by the presence of lower skin temperature on the affected side. The clinical manifestations of focal or diffuse cerebral or brainstem dysfunction have been attributed to intracranial vasoconstriction. A majority, but not all, of the studies measuring cerebral blood flow have confirmed a reduction of blood flow, sometimes to low and critical levels, during the prodroma1 stage. The aura of migraine may be caused by cortical spreading depression,5-s a process that produces transient depression of spontaneous and evoked neuronal activity. During this time, the brain fails to maintain normal ionic homeostasis and efflux of excitatory amino acids from neuron^.^ Cortical spreading depression may represent a significant link to the decrease in cerebral blood flow observed during a migraine This stage may be followed by a phase of increased blood flow that can persist for more than 48 hours. Evidence indicates that migraine patients have a functional abnormality of vasomotor control. Migraineurs

Migraine Headache

suffer from orthostatic symptoms more often than patients without migraine and also seem to be abnormally sensitive to the vasodilatory effects of physical and chemical agents.

Platelet Disorder The migraine platelet shows significant differences from the normal platelet both during and between headaches.12 These differences include a significant increase in spontaneous aggregation, highly sigruficant differences in the manner of serotonin release, and significant differences in platelet composition. The major proponent of the platelet hypothesis is Hanington,’2 who observed that the most common precipitant of migraine is an emotional stressor. Stress results in a rise of plasma catecholamines, which triggers the release of serotonin, thus resulting in platelet aggregation and vasoconstriction. The platelets of migraineurs aggregate more readily than controls, both spontaneously and when exposed to serotonin (and to adenosine diphosphate and catecholamines). The increase in spontaneous aggregation is similar to that reported in patients suffering from transient cerebral ischemic attacks (TIAs). This is significant, considering the close resemblance of the symptomatology of TIAs to the prodromal phase of the migraine headache. The onset of an attack is accompanied by a significant rise in plasma serotonin levels, followed by an increase in urinary 5-hydroxyindoleacetic acid (5HIAA), the metabolic breakdown product of serotonin. Serotonin is normally stored in platelets and is released by platelet aggregation and in response to various stimuli, such as catecholamines. There is no difference in total serotonin content between normal platelets and the platelets of migraine patients. However, the quantity of serotonin released by the platelets of the migraine patient in response to serotonin stimulation, although normal (or even subnormal) immediately after an attack, becomes progressively higher as the next attack approaches.I2The rise of plasma serotonin may not be causative in migraine but could represent a self-defense me~hanism.~ Platelet activation has been observed in electron micrographs during migraine, which may be an epiphenomenon produced by the neurogenic inflammation.6 It is worth noting, on the other hand, that platelet-deactivating agents such aspirin, feverfew, and essential fatty acids (EFAs) appear to be effective in migraine prevention. The platelet hypothesis is strengthened by the observation that patients with classic migraine have a twofold increase in incidence of mitral valve prolapse.I3J4 Using careful clinical and echocardiographic criteria and matched controls, the researchers found in the migraine patients definite mitral prolapse in 16% and possible prolapse in 15%. The controls had 7% and

8%, respectively. This is of sigruficance because the prolapsing mitral valve is known to damage platelets, increase their aggregation, and possibly release serotonin and other vasoactive substances that promote susceptibility to migraine. This work has been confirmed in other ~tudies.’~,’~

Neuronal Disorder A third major hypothesis is that the nervous system plays a role in initiating the vascular events in migraine. Some researchers have suggested that the trigeminovascular neurons, which innervate the pial arteries, release the peptide substance P either directly from various cell signals or secondarily to CNS a~tivati0n.l~ Substance P is a key pain mediator, and its release into the arteries is associated with vasodilation, mast cell degranulation, and increased vascular permeability. It is believed that the endothelial cells of the arteries respond to substance P by releasing vasoactive substances such as arachidonic acid metabolites, purine compounds, or molecules containing carbonyl groups. This theory suggests that functional changes within the noradrenergic system constitute the threshold for migraine activation, and it is through modulation of sympathetic activity that potentiators exert their effects.17Chronic stress is an important potentiator in this model.

Migraine as a ”Serotonin Deficiency” Syndrome The final hypothesis is that migraine headache represents a serotonin deficiency state. The connection between serotonin and headaches began in the 1960s when researchers found that there was an increase in 5-HIAA in the urine during a migraine.’* Initially, serotonin excess was implicated; however, newer information indicates that the factor responsible for the increase in 5-HIAA is more likely the increased breakdown of serotonin as a result of increased activity of monoamine Because migraineurs appear to have oxidase (MAO).1920 low levels of serotonin in their tissues, researchers began to refer to migraine as a “low serotonin syndrome.”21 Low serotonin levels are thought to lead to a decrease in the pain threshold in patients with chronic headaches. This contention is strongly supported by more than 35 years of research including positive clinical results in double-blind studies with the serotonin precursor 5-hydroxytryptophan (5-HTP). For more information on the clinical studies with 5-H” in migraine headaches, see Chapter 101. The link between low serotonin levels and headache is the basis for many prescription drugs in the treatment of migraine headaches. For example, the serotonin agonist drug sumatriptan (Imitrex) is now among the most popular migraine prescriptions. In addition to sumatriptan, monoamine oxidase inhibitors (which

Specific Health Problems increase serotonin levels) have also been shown to preAlthough selective SRIs are frequently used for migraine prophylaxis, the scientific effect is unknown, the quality vent headaches. The basis for employing these subof evidence poor, and the impression of clinical impact stances makes use of the considerable evidence that is OW.^^^^^ increasing serotonin levels leads to relief from chronic migraine headaches. Unified Hypothesis The effects that 5-HTP, sumatriptan, and other drugs The mechanism of migraine can be described as a threeexert on the serotonin system are extremely complex because of the multiple types of serotonin receptors. stage process: initiation, prodrome, and headache. Although a particular stressor may be associated with The manner in which many substances produce their the onset of a specific attack, it appears that initiation effects on cells is by first binding to receptor sites on depends on the accumulation over time of several the cell membrane. Some serotonin receptors are stressors. These stressors ultimately affect serotonin involved in triggering migraines, while others prevent metabolism (Box 191-3).Once a critical threshold of susthem. Drugs that bind to serotonin receptors are desigceptibility is reached, a cascade of events is initiated. nated as 5-HT1, trigger migraines, while drugs like methysergide that inhibit 5-HT1, are used to prevent This susceptibility is probably based on a combination of migraines.22In addition, the serotonin receptor ~ - H T ~ Ddecreased tissue serotonin levels, platelet modulation, may prevent migraine headaches because drugs like alteration in the responsiveness of key cerebrovascular end-organs, increased sensitivity of the intrinsic norasumatriptan, which bind to these receptors and mimic the effects of serotonin, are quite effective in the acute drenergic system of the brain, and the accumulation of treatment of migraine.23 histamine, arachidonic acid metabolites, or other mediaSupplementation with 5-HTP affects these different tors of inflammation. The platelet changes include increased adhesiveness, receptors in several ways; some serotonin receptors enhanced tendency to release serotonin, and increased appear to undergo desensitization when exposed to levels of arachidonic acid in the membranes. Once higher levels of serotonin. It is believed that increased platelets are stimulated to secrete serotonin, platelet serotonin levels preregulate 5-HTIDreceptor binding aggregation, vasospasm, and inflammatory processes and downregulate 5-HT1, receptors. In other words, result in local cerebral ischemia. This is followed by higher levels of serotonin produced over time from use of 5-HTP result in decreased sensitivity of the rebound vasodilation and the release of peptide substance I' and other mediators of pain. These events 5-HT1, receptors and an increased sensitivity for 5-HTID are summarized in Figure 191-1. receptors." As a result, there would be a lowered tendency to experience headache. A key piece of evidence to support this concept is the fact that 5-HTP is more effective over time (better results are seen after 60 days of use than after 30). Low serotonin levels We may learn substantially by studying the mechaGenetics nism of action of the migraine drugs sumatriptan, naraShunting of tryptophan into other pathways triptan, rizatriptan, and zolmitriptan, which are 5-HTlb Foods and 5-HTID receptor agonists. These agents constrict Food allergies blood vessels, block neurogenic inflammation and Histamine-releasingfoods Histamine-containing foods neural peptide release, and may also inhibit neuronal Alcohol, especially red wine activity within the trigeminovascular The Chemicals safety of these agents has been questioned because Nitrates the triptans activate serotonin receptors on cerebral vesMonosodium glutamate sels and, to a lesser extent, coronary arteries. The chest Nitroglycerin Withdrawal from caffeine or other drugs that constrict blood vessels pain that is reported by 3% to 5% of patients taking oral Stress triptans has generally not been associated with electroEmotional changes, especially letdown after stress, and intense cardiographic changes, and does not appear to be due emotions such as anger to cardiac ischemia.28 However, triptans should be Hormonal changes (e.g., menstruation, ovulation, birth control pills) avoided in patients with ischemic heart disease, unconToo little or too much sleep Exhaustion trolled hypertension, and cerebrovascular disease. It Poor posture is generally advisable to avoid using triptans, ergotamineMuscle tension based drugs, and serotonin reuptake inhibitors (SRIs) Weather changes (e.g., barometric pressure changes, simultaneously, although the risk of serotonin synexposure to sun) drome appears to be low.28 Some practitioners use Glare or eyestrain 5-HTP successfully with SRIs, but caution is advised.

Migraine Headache

Catecholamine release

1 1

Platelet serotonin release

Food allergy Dietary amines

Platelet aggregation

Sterile neurogenic inflammation

1

Vasoconstriction Rebound vasodilitation

Release of substance P and other mediators of inflammation Figure 191-1 Suggested pathogenesis of migraine headache.

Profile of 200 patients with chronic daily headache Medications

Range of no. of tabletdwk

Average no. of tabletdwk

No. of oatients

Percentage of Datients

ButalbitaVaspirin, acetaminophenkaffeine with or without codeine

30

14-86

84

42

Codeine

28

10-84

80

40

Aspirin or acetaminophen with caffeine Ergotamine

42

14-108

50

25

44

22

Acetaminophen

52

15-105

34

17

Propoxyphene

26

14-56

32

16

6-30

24

12

10-64

8

4

Nasal decongestantsand antihistamines

14

Aspirin

28

THERAPEUTIC CONSIDERATIONS Modern pharmacologic treatment of headache tends to be inadequate because it fails to address the underlying cause. The first step in treating migraine headache is to idenhfy the precipitating factor or factors. Although food intolerance/allergy is the most important, many other factors must be considered as either primary causes or contributors to the migraine process. Particularly important is to assess the role that headache medications may be playing, especially in chronic headaches.

Drug Reaction Severalclinical studies have estimated that approximately 70% of patients with chronic daily headaches suffer from drug-induced headaches.3l Two principal forms of druginduced chronic daily headaches exist: analgesic rebound headache and ergotamine rebound headache.32 Withdrawal of medication results in prompt clinical improvement in most cases. In one study (summarized in Table 191-2) of 200 patients suffering from analgesicrebound headache, discontinuation of these symptomatic

6-42 mg

15 mg

'

medications resulted in 52% improvement in the total headache index; improvements in headache frequency and severity; general well-being; sleep patterns; and a reduction in irritability, depression, and These 200 patients were typical in that they sought relief from various drugs. Table 191-3 lists the types of drugs used for symptomatic relief; most of these patients took at least three of these preparations simultaneously.

Analgesic-Rebound Headache In the early 1980s it became apparent that headache medications could paradoxically increase the tendency to experience chronic headache. Early reports identified increased frequency and intensity of headaches in heavy analgesic users. In one study migraineurs who took more than 30 analgesic tablets per month had twice as many headache days per month as those who This finding led to the took fewer than 30 recommendation that analgesic use should be restricted in patients with chronic daily headaches. In another study 70 patients with daily headaches who were consuming 14 or more analgesic tablets weekly were

Drua

Adult daily dosaae

Common side effects

Aspirin

650-1950 mg

Gastric irritation, ulcer formation

Propranolol

80-240 mg

Fatigue, lassitude, depression, insomnia, nausea, vomiting, constipation

Amitriptyline and imipramine

10-150 mg

Drowsiness, dry mouth, constipation, weight gain, blurred vision, water retention

Sertraline

50-200 rng

Anxiety, insomnia, sweating, tremor, gastrointestinal disturbances

Fluoxetine

20-60 mg

Similar to those of sertraline

Ergonovine maleate

0.6-2 mg

Nausea, vomiting, abdominal pain, diarrhea

Cyproheptadine

12-20 rng

Sedation, dry mouth, gastrointestinal disturbances

Clonidine

0.2-0.6 mg

Dry mouth, drowsiness, sedation, headache, constipation

Methysergide

4-8 mg

Nausea, vomiting, diarrhea, abdominal pain, cramps, weight gain, insomnia, edema, decreased blood flow to extremities, heart and lung fibrosis

Calcium-channel blockers (e.g., verapamil, nifedipine, diltiazem)

80-160 mg

Headache, low blood pressure, flushing, water retention, constipation

~

advised to discontinue their use.33One month later, 66% of the patients were improved, and at the end of the second month, this percentage had grown to 81%. Analgesic-rebound headaches should be suspected in any patient with chronic headaches who is taking large quantities of analgesics and experiencing daily predictable headache.%The critical dosage that can lead to analgesic-rebound headache is estimated to be 1000 mg of either acetaminophen or aspirin. Analgesic medications typically contain substances in addition to the analgesic such as caffeine or a sedative like butabarbital. These substances further contribute to the problem and may lead to withdrawal headache and related symptoms such as nausea, abdominal cramps, diarrhea, restlessness, sleeplessness, and anxiety. Withdrawal symptoms typically start at 24 to 48 hours and in most cases subside in 5 to 7 days.

Ergotamine-Rebound Headache Ergotamine is a commonly used drug in the treatment of severe acute migraine and cluster headaches. Ergotamine works by constricting the blood vessels of the head, thereby preventing or relieving the excessive vascular dilation that occurs in migraine and cluster headaches. Ergotamine, poorly absorbed when given orally, is administered intramuscularly by inhalation or suppository. Although usually quite effective, ergotamine is also associated with some significant side effects. Symptoms of acute poisoning include the following: Vomiting Diarrhea Dizziness

~ ~ _ _ _ _ _______

Rise or fall of blood pressure Slow, weak pulse Dyspnea Convulsions Loss of consciousness Chronic ergotamine poisoning includes two types of symptom manifestations: (1) those resulting from blood vessel constriction and reduced circulation-numbness and coldness of the extremities, tingling, pain in the chest, heart valve lesions, hair loss, decreased urination, and gangrene of the fingers and toes; and (2) those resulting from nervous system disturbances-vomiting, diarrhea, headache, tremors, contractions of the facial muscles, and convulsions. Regular use of ergotamine in migraine headaches is also associated with a dependency syndrome characterized by severe chronic headache with an increase in headache intensity on cessation of medication. Because most migraine headaches rarely occur more than once or twice a week, the presence of an almost daily migraine-type headache in individuals taking ergotamine is a clue for ergotaminerebound headache. Dosage of ergotamine can also be suggestive; in most cases of ergotamine-rebound headache, individuals take weekly dosages in excess of 10 mg. In some cases, patients may take dosages as high as 10 to 15 mg daily. Withdrawing ergotamine causes predictable, protracted, and extremely debilitating headaches, usually accompanied by nausea and vomiting. These symptoms usually appear within 72 hours and may last for another 72 hours. Improvement after stopping the medication is common. Ginger (discussed later) may reduce ergotamine-related withdrawal symptoms.

Migraine Headache

Diet Food Allergyhntolerance There is little doubt that food allergy/intolerance plays a role in many cases of migraine headache. Doubleblind, placebo-controlled studies have demonstrated that the detection and removal of antigenic/intolerable foods eliminate or greatly reduce migraine symptoms in the majority of patients. What is unclear is the percentage of migraine patients for whom food control is the most important factor. Table 191-4 summarizes the results of several clinical studies. Success ranges from 30% to 93%, with the majority of studies showing a remarkably high degree of success.354* A plausible explanation for the large difference between the results of Mansfield and colleagues35and the others is that the Mansfield design was carefully selected for food allergy only, while the others included food intolerance. These studies found the incidence of food allergy to be similar among the three major types of migraine. The foods most commonly found to induce migraine headaches are listed in Table 191-5. The mechanism by which food allergy/intolerance induces a migraine attack is still unknown. Several theories have been proposed: Idiopathic response to a pharmacologically active substance, such as tyramine Monoamine oxidase deficiency Platelet phenolsulfotransferase deficiency; immunologically mediated food allergy Platelet abnormalities Egger and colleagues38 suggested that migraine headache may occur through chronic activation of the nonspecific responsiveness of cerebral vascular end-organ, as a result of long-term antigenic stimulation. This mechanism would be analogous to the bronchiolar response in asthma to exercise or cold after antigen contact.

Food allergyhntolerance and migraine headache Study

Percentage responding

Method

Mansfield et aIs

30

Elimination

Carter et a13

93

Oligoantigenic diet

Hughes et aB7

80

Fasting, rotation, elimination

Egger et a P

93

Elimination

Monro et a13e

70

Radioallergosorbent test, elimination, sodium

Grant40

85

Elimination

Imigraine headaches Food

Ewer et a P (yo)

Hughes et aI3’ (%)

Cow’s milk

67

57

Wheat

52

43

Chocolate

55

57

Egg Orange

60

24 -

52

-

Benzoic acid

35

Cheese

32

Tomato

32

Tart razine

30

14 -

Rye Rice

30 -

-

Fish

22

29 (shell)

Grapes

33

Onion

12 -

SOY Pork

17

24

22

-

12 -

29

Alcohol Monosodium

-

19

Walnuts

-

19

Peanuts

Monro et aP9 I%)

-

24

29

glutamate Beef

20

Tea

17

14 -

Coffee

15

19

Nuts

12

19 (cashew)

Goat’s milk

15

14

Corn

20

Oats

15

9 -

7

19

Yeast

12

Apple Peach

12

14 -

12

Potato

Cane sugar

12

-

Chicken

7

14

Banana

7

-

Strawberry

7

-

Melon

7

-

7

-

Carrot

Allergic reactions to foods are known to cause platelet degranulation, with resultant serotonin release.4* Several methods may be used to detect food allergies, most of which are described in Chapter 19.Although laboratory procedures are probably the most convenient for

Specific Health Problems

the patient, challenge testing is thought to be the most reliable. Unfortunately, challenge testing has limitations: some foods evoke a delayed response, which may require several days of repeated challenge to elicit recognizable symptoms. Also, ingestion of large amounts of several foods may be necessary to detect those that are marginally reactive. The recommended procedure for the diagnosis and management of food allergy/intolerance is described later in the section on therapeutic approach.

Dietary Amines Foods such as chocolate, cheese, beer, and wine may precipitate migraine attacks because they contain histamine or other vasoactive compounds that have a vasodilatory effect (Box 191-4).424 Red wine is more likely than white wine to trigger a headache because it contains 20 to 200 times the amount of histamine and stimulates the release of vasoactive compounds by platelet^.'**^^*^^ Red wine is additionally much higher in flavonoids-the antioxidant components shown to help prevent heart disease. These compounds can also inhibit the enzyme phenolsulfotransferase, which normally breaks down serotonin and other vasoactive amines in platelets. Many migraineurs have been found to have significantly lower levels of this enzyme.&Because red wine contains substances that are potent inhibitors of this enzyme, it often triggers migraines in these individuals, especially if consumed along with high vasoactive amine content foods like cheese or chocolate. A standard treatment for

Histamine Levels Increased By the Following: Histamine in alcoholic beverages (particularly red wine) Histamine in food Histamine-releasing foods Food allergy Vitamin B6 deficiency Histamine Breakdown Inhibited by the Following: Vitamin B6 antagonists Alcohol Drugs Food additives (e.g.. yellow dye no. 5, monosodium glutamate) Vitamin C deficiency Histamine Release Prevented by the Following: Di-sodium chromoglycate Quercetin Antioxidants (e.g., vitamin C, vitamin E,selenium) Histamine Breakdown Promoted by the Following: Vitamin B6 Vitamin C

histamine-induced headaches is to use a histamine-free diet, along with vitamin B6 The activity of the enzyme diamine oxidase, which breaks down histamine in the lining of the small intestine before it is absorbed into the circulation, appears to play a key role in determining reactivity to dietary histamine. Individuals sensitive to dietary histamine have lower levels (about 50%) of this enzyme in their tissues compared with control ~ubjects.4~ Diamine oxidase is a vitamin B6-dependent enzyme. Not surprisingly, compounds that antagonize vitamin B6 also inhibit diamine 0xidase.4~These inhibitory factors include food coloring agents (specificallythe hydrazine dyes like yellow no. 5); some drugs (isoniazid, hydralazine, dopamine, and penicillamine); oral contraceptives; alcohol; and excessive protein intake. Vitamin B6 supplementation (usually 1 mg/kg body weight) has been shown to improve histamine tolerance, presumably by increasing diamine oxidase a ~ t i v i t y . ~ ~ , ~ ~ Women have lower levels of diamine oxidase, which may explain their higher incidence of histamine-induced headaches. Women are also much more frequently unable to tolerate red wine.43Interestingly, the level of diamine oxidase in a woman increases by more than 500 times during pregnan~y.~’,~ Women with histamineinduced headaches commonly experience complete remission of their headaches during pregnancy.

Miscellaneous Diet-Related Triggers Hypoglycemia can be a trigger for migraine and is readily modified by dietary manipulation. Glycemic dysregulation is common in the setting of the standard American diet, given a tendency to consume unregulated quantities of high glycemic index carbohydrates. Hypoglycemia may be a result of inappropriate carbohydrate intake, especially when insulin levels become elevated. Excessive sodium intake may also represent a migraine trigger mechanism,5l perhaps as a consequence of increasing angiotensin levels in response to sodium ingestion. For individuals who are lactose intolerant, avoidance of dairy products may afford improvement in the experience of migraine headache.52Finally, aspartame, a common sweetener, may be associated with an increased likelihood of migraine i n c i d e n ~ e and ~ ~ sis easily avoided.

Nutritional Supplements 5-Hydroxytryptophan The role of 5-HTP in preventing migraine headaches by increasing serotonin levels is discussed earlier. In addition to this mechanism of action, 5-HTP may also increase endorphin levels. The use of 5-HW in the prevention of migraine headache offers considerable advantages over drug therapy. Although a number of drugs have been shown to be useful in the prevention

Migraine Headache

of migraine headache, all of the currently used drugs carry with them a risk of significant adverse effects. 5-HTP is at least as effective as other pharmacologic agents used in the prevention of migraine headaches and is safer and better tolerated. Although some studies have employed a dosage of 600 mg/day, equally impressive results have been achieved at a dosage as low as 200 mg/day. The clinical studies with 5-HTP in migraine headaches are discussed in Chapter 101.

Essential Fatty Acids The role of EFAs in the pathogenesis of migraine may be quite important but does not appear to have received much research attention. Considering the significance of platelet aggregation and arachidonic acid metabolites in the mediation of the events leading to the cerebral ischemia of migraine, manipulation of dietary EFAs may be useful. It has been demonstrated that reducing the consumption of animal fats and increasing the consumption of fish will significantly modify platelet and membrane EFA ratios and decrease platelet a g g r e g a t i ~ n . ~It~is” ~also noteworthy that 60% of the brain is composed of lipids-appropriate consumption of the essential fats is mandatory for proper neurologic function. In two small placebo-controlled ~ t u d i e s , 5omega-3 ~ , ~ ~ fatty acids performed significantly better than placebo in reducing headache frequency and intensity. A small, randomized, double-blind cross-over study of 27 adolescents with migrainem revealed marked improvement in migraine headache frequency, duration, and severity with fish oil. The adolescents responded equally well to olive oil supplements, the chosen placebo for this study. Proposed mechanisms of action of the omega-3 fatty acids include reduced platelet serotonin release, modulation of prostaglandin synthesis, and diminution of cerebral vasospasm. Bic and colleagues61proposed that free fatty acids are an important underlying factor in the development of migraine headache because elevated blood lipids and free fatty acids are associated with increased platelet aggregability, decreased 5-HT, and increased prostaglandin levels, all of which may play a role in migraine. They list biologic states that produce increased free fatty acids and lipids including: high dietary fat intake, obesity, insulin resistance, vigorous exercise, hunger, consumption of alcohol and caffeine, oral contraceptive use, tobacco abuse, and stress. These variables may be manipulated successfully through lifestyle practices, diet, and pharmacologic measures.

Riboflavin (Vitamin B2) A deficit of mitochondrial energy metabolism may play a role in migraine pathogenesis.‘j2 Riboflavin (vitamin B2) is a precursor of flavin mononucleotide and flavin

adenine dinucleotide, which are required for the activity of flavoenzymes involved in the electron transport chain. A randomized, placebo-controlled, doubleblinded study demonstrated that a daily oral dose of 400 mg of riboflavin was superior to placebo for migraine prophylaxis. The effect began at 1 month, with maximal effect after 3 months of therapy.63The hypothesis that B2 benefits migraine by increasing complex I and I1 activity in mitochondrial energy metabolism can B2~ *appears ~ to be tested by NMR s p e c t r o ~ c o p y . ~ improve mitochondrial function without changing neuronal excitability, which could explain the excellent tolerance and lack of CNS adverse effects. Diarrhea and polyuria may be associated with administration of high dose B2.65It is notable that riboflavin is well tolerated, less expensive than typical migraine-targeted medications, and may provide protection from oxidative toxicity in the brain, making it an excellent therapeutic option.66Other B vitamins including folic acid may also be instrumental in aborting or preventing migraine heada~he.6~

Magnesium The high frequency of magnesium deficiency is well established. Magnesium is the least abundant serum electrolyte and the second must abundant intracellular cation; it is integral to the metabolism of calcium, potassium, phosphorus, zinc, copper, iron, sodium, lead, calcium, hydrochloric acid, acetylcholine, nitric oxide, and many enzymes. Magnesium absorption depends on dietary adequacy, selenium, parathyroid hormone, and vitamins B6 and D. Absorption is hindered by excess fat. Magnesium levels are depleted by a multitude of common factors including stress, excess alcohol intake, high estrogen levels, low progesterone, dietary excesses, certain drugs, hyperthyroidism, and hyperparathyroidism. Inadequate dietary intake of magnesium is likely in 75% of the U.S. population68and is thought to be the most common micronutrient deficiency, manifested by a diverse range of associated p a t h o l ~ g i e sPhysiologic .~~ and psychologic stress result in magnesium depletion, and both acute and chronic stress are associated with increased episodes of migraines. Substantial documentation linking low magnesium levels to both migraine and tension headaches exists in the medical literatu~-e.~O-~ Low brain and tissue magnesium concentrations have been found in patients with migraine, indicating a need for supplementation. Among magnesium’s central functions are to maintain vascular tone and prevent neuronal h y p e r e x c i t a t i ~ n . ~ ~ ~ Two recent double-blind studies have provided conflicting results in the prevention of migraine in people prone to recurrent migraine headaches. In the first 250 mg of magnesium or placebo was given

Specific Health Problems twice daily to 69 patients (35 received magnesium, 34 the placebo) for 12 weeks. The number of responders was 10 in each group (28.6% with magnesium and 29.4% with placebo). There was no benefit from magnesium compared with placebo, with respect to migraine frequency or intensity. In the other double-blind study,'5 81 patients experiencing recurrent migraines were given either 600 mg of oral magnesium daily for 12 weeks or placebo. By the ninth week, the attack frequency was reduced by 41.6% in the magnesium group compared with only 15.8% in the placebo group. Drug consumption for symptomatic treatment per patient also decreased sigruficantly in the magnesium group. Side effects with magnesium supplementation included diarrhea (18.6%) and gastric irritation (4.7%). Apparently magnesium supplementation is specifically effective in those individuals with low tissue or low ionized levels of magnesium. Low tissue levels of magnesium are common in patients with migraine, but most cases go unnoticed because physicians generally rely on serum magnesium levels to assess magnesium status. Because most of the body's magnesium is intracellular, serum levels are unreliable indicators. A low magnesium level in the serum reflects late-stage deficiency. More sensitive tests of magnesium status include erythrocyte magnesium levels or ionized magnesium, the most physiologically active form. The hypothesis that patients with an acute migraine episode and low serum levels (<0.54 mmol/L) of ionized magnesium are more likely to respond to an intravenous infusion of magnesium sulfate (MgS04) than patients with higher serum ionized magnesium levels has been t e ~ t e d . Serum ~ ~ , ~ ionized magnesium levels were drawn immediately before infusion of 1 g of MgSO, in 40 patients with an acute migraine headache. Pain reduction of 50% or more, as measured on a headache intensity verbal scale of 1 to 10, occurred within 15 minutes of infusion in 35 patients. In 21 patients, at least this degree of improvement or complete relief persisted for 24 hours or more. Pain relief lasted at least 24 hours in 18 of 21 patients (86%) with serum ionized magnesium levels below 0.54 mmol/L and in 3 of 19 patients (16%)with ionized magnesium levels at or above 0.54 mmol/L. The average ionized magnesium level in patients with relief lasting for at least 24 hours was significantly lower than that in patients with no relief or only fleeting relief. Intravenous magnesium has been shown to be an extremely effective treatment in some cases of acute migraine, tension, and cluster headaches. A dosage of 1g of intravenous magnesium (over a 10-minute period) generally results in a nearly 90% success rate in patients with low ionized magnesium levels.'6-79 Patients treated with MgSO, typically observe complete elimination of

migraine-associated symptoms such as nausea, photosensitivity, and phonosensitivity. Adverse effects are rare, with the exception of a brief flushed feeling. Another possible benefit of magnesium in migraineurs may be its ability to improve mitral valve prolapse. Mitral valve prolapse is linked to migraines because it causes mechanical damage to platelets, promoting their release of vasoactive substances like histamine, plateletactivating factor, and serotonin.1s16Because research indicates that 85% of patients with mitral valve prolapse have chronic magnesium deficiency, magnesium supplementation is advisable.80This recommendation is further supported by several studies demonstrating that oral magnesium supplementation improves mitral valve prolapse (patients improve morphologically and have fewer symptoms). Magnesium bound to citrate, malate, aspartate, or some other Krebs cycle intermediate is better absorbed and better tolerated than inorganic forms such as magnesium sulfate, hydroxide, or oxide, which tend to produce a laxative effect?l If magnesium produces loose stools or diarrhea, patients should be advised to reduce intake to a tolerable level. Also, it is a good idea to prescribe at least 50 mg of pyridoxine (vitamin B6) daily, as it has been shown to increase the intracellular accumulation of magnesium.82

Botanical Medicines Botanical medicines have a lengthy history of use as traditional remedies for migraine headache. Although many botanicals have been used, feverfew (Tanaceturn parthenium), ginger (Zingiber oficinalis), and butterbur (Petasides hybridus) tend to be widely used for migraine prophylaxis and treatment.

Tanacetum parthenium Perhaps the most popular preventive treatment of migraine headaches is the herb feverfew. Scientific interest in feverfew began when a 1983 survey found that 70% of 270 migraine sufferers who had eaten feverfew daily for prolonged periods found that the herb decreased the frequency or intensity of their attacks.83Many of these patients had been unresponsive to routine medications. This survey prompted several clinical investigations that support the therapeutic and preventive effects of feverfew in the treatment of migraine frequency and i n t e n ~ i t y . However, ~ ~ - ~ ~ at least three crossover, randomized, controlled trials found no benefit with feverfew, though each study had limitation^.^' Feverfew has been suggested to inhibit serotonin release, inhibit prostaglandin synthesis and platelet aggregation, inhibit polymorphonuclear leukocyte degranulation and phagocytosis of neutrophils, inhibit mast cell

Migraine Headache release of histamine, promote cytotoxic activity against human tumor cells, and possess both antimicrobial activity and antithrombotic potential.= In vitro studies have demonstrated that feverfew extract inhibits serotonin release from p l a t e l e t ~ , ~The B ~ active constituent remains incompletely appreciated; the plant is rich is sesquiterpene lactones, the principal one being parthenolide. Given the diversity of pharmacologic activity, parthenolide may not be the sole active principal. Feverfew should be avoided or used with caution in patients on anticoagulants because of its platelet inhibitory effects.88Feverfew is generally well tolerated, but oral ulceration (especially for those who chew feverfew leaves) and gastrointestinal symptoms are the most common adverse events-these effects are mild and reversible with discontinuation. Because feverfew is in the same family as ragweed and chamomile, individuals with such allergies should avoid feverfew as well.

Zingi ber oficinalis The common ginger root has been shown to exert sigruficant effects in suppressing inflammation and platelet a g g r e g a t i ~ nWith . ~ ~ respect ~ to migraine headache, there is much anecdotal information and speculation about its usefulness based on its known properties. Ginger may be commonly used in clinical practice for migraine treatment, but little clinical investigation has been performed to date. The most active antiinflammatory componentsof ginger are found in fresh preparations and the oil.

Petasides hybridus Butterbur (P.hybridus) has been identified as effective herbal therapy for migraine, and its recorded use dates back at least 900 ~ e a r s . 9It~purveys vascular wall antispasmodic properties, has an affinity for cerebral vessels, and inhibits leukotriene synthesis and lipoxygenase activity.94Leukotriene synthesis is apparently inhibited by the active principles petasine and isopetasine, which In a randomized, placeboalso produce vas~dilation.~~ migraine controlled, double-blind study of 60 frequency was decreased by 60% without adverse events (and dysmenorrhea incidentally improved markedly in 8 patients). Butterbur is administered prophylactically, and supplementation should be carried out daily for 4 to 6 months and tapered until migraine incidence begins to increase. Butterbur is generally well tolerated, but diarrhea has been reported in some individuals. No drug interactions have been identified, but it is not known to be safe during pregnancy or lactation.95Because the plant's pyrrolizidine alkaloids are thought to be hepatotoxic and carcinogenic, only extracts that have removed these specific alkaloids should be ~ s e d . 9The ~ typical adult dosage ranges from 50 to 100 mg twice daily with meals.

Hormones Melatonin Given the serotonergic involvement in migraine, it is logical to consider melatonin's function as well. Melatonin is the product of CNS serotonin, which is a downstream metaboli:e of dietary tryptophan. Nearly 90% of serotonin is produced in the walls of the GI tract, stored in platelets, and distributed to the rest of the body, except the CNS (serotonin cannot cross the blood-brain barrier).96Tryptophan and 5-HTPcan cross the bloodbrain barrier to be converted into serotonin in the pineal gland, which contains 90% of the CNS serotonin and most of the melatonin." The pineal gland serves as an important interface between the environment and the CNS, and as such may play a role in triggering various external and internal factors such as certain foods, toxins/odors, flickering lights, sleep deprivation, travel through time zones, and menses. Decreased levels of plasma and urinary melatonin have been observed in migraine patient^?^-^ Deficiency of melatonin appears to produce excessive stimulation of the trigeminovascular s y ~ t e r n . ~ ~ J ~ ~ Melatonin therapy is successful in some individuals, particularly those with delayed sleep phase syndrome,lo1and may resynchronize circadian rhythms to lifestyle, subsequently relieving triggers and sympt o m ~ ?Also, ~ melatonin 5eems to produce headache in susceptible individuals. In patients with migraines, the brain does not seem to tolerate the peaks and troughs of life well. Regular sleep, regular meals, exercise, avoidance of both excessive stimulation and relaxation, and evasion of dietary triggers can all help to reduce activation.'

Sex Steroid Hormones Studies have determined that the onset of migraine rises with menarche.lo2Episodes are linked to menstruation in 60% of female migraineurs, a condition described as menstrual migraine.lo3It usually improves with pregnancy, perhaps due to sustained estrogen levels.l@' Oral contraceptives are known to induce, improve, or exacerbate migraines. Migraine incidence tends to decrease with advancing age but may either regress or worsen during menopause.lo5It has been noted that headaches occur during and after the simultaneous decline of both estrogen and progesterone. There is no uniform agreement over the relationship between hormone levels and migraine, though falling estrogen levels have been noted to be associated with menstrual migraine. Estrogens given premenstrually can delay migraine but not menstruation, whereas progesterone given premenstrually delays menstruation but not migraine.'06 DeLignieres and colleagueslo7used percutaneousestradiol

Specific Health Problems gel perimenstrually with significant headache reduction. Plasma taken from menstruating women and reinfused at another point of the menstrual cycle reproduces menstrual symptoms including headache; this phenomenon may be indicative of the presence of a prostaglandingenerating factor in plasma.lo3Estrogens increase the number of progesterone, muscarinic, and serotonin (5-HT2) receptors and decrease the numbers of 5-HT1 and beta-adrenergic receptors. Estrogens also increase the trigeminal mechanoreceptor receptive fields, thereby increasing receptive input from the trigeminal system. Progesterone blocks the estrogen-induced increase in 5-HT2 receptor^.'"^ Transdermal progesterone therapy has been successful in preventing migraine for some patients. Hysterectomy and oophorectomy have not been demonstrated to be he1pf~l.l"~

Physical Medicine Many forms of physical medicine have been used in the treatment of migraine headache. Although most have been shown to be effective in shortening the duration and decreasing the intensity of an attack, they appear relatively ineffective in actually eradicating this disorder. Although effective for headaches that have a significant muscular contraction component, these methods appear to have more limited success in reducing the frequency of attacks of true migraine.

Cervical Manipulation In a 6-month trial in Australia, 85 patients were studied to determine the efficacy of manipulation of the cervical spine by a chiropractor in the treatment of migraine headache. The study was controlled by comparing chiropractic manipulation with manipulation by a medical practitioner or physiotherapist and with simple cervical mobilization. Although the study found no difference in frequency of recurrence, duration, or disability, the chiropractic patients reported greater reduction in the intensity of pain associated with the episodes.10s

Tem oromandibular Joint Dysfunction Syn rome

B

Some researchers and clinicians have claimed that a substantial portion of headaches diagnosed as classic or common migraine are manifestations of temporomandibular joint (TMJ) dysfunction syndrome. However, a careful investigation found that the incidence of migraine in patients with TMJ dysfunction is similar to that in the general population, while the incidence of headache due to muscle tension is much higher.10g These results suggest that, while correction of TMJ dysfunction may be of use in the treatment of migraine headaches, it is far more important in muscle tension headaches.

Transcutaneous Electrical Stimulation Transcutaneous electrical stimulation (TENS) has been shown in a placebo-controlled trial to be effective in the treatment of patients with migraine and muscle tension headaches (55% responded to treatment vs. an 18% placebo response)."O However, the study also found that inappropriately applied TENS (i.e., TENS applied below perception threshold) was ineffective.

Acupuncture Sufficient evidence exists to support the use of acupuncture to relieve migraine Interestingly, the mechanism of relief is not clearly endorphin mediated. One study found that the injection of saline or naloxone did not affect the efficacy of the therapy,'16 and another found that, while acupuncture increased endorphin levels in controls, the low levels of serum endorphins found in migraine patients did not increase with treatment.lI7The mechanism of action may instead involve normalization of serotonin levels. One study found that acupuncture was effective in relieving pain when it normalized serotonin levels but ineffective in relieving pain and raising serotonin levels in patients with low levels of serotonin.116 Although limitations in experimental design make interpretation difficult, acupuncture appears to be successful in reducing the frequency of migraine episodes, generally by around 50%. Patients may be blinded with "sham" acupuncture treatments, but practitioners cannot be blinded. More recent studies and systematic review^"^-'^ shed a favorable light on acupuncture, despite the difficulties posed by study design.

Biofeedback and Relaxation Therapy The most widely used nondrug therapy for migraine headaches is thermal biofeedback and relaxation training. Thermal biofeedback uses a feedback gauge to monitor the temperature of the hands. The patient is then taught how to raise (or lower) the temperature of the hand, while the device provides feedback regarding temperature measurements. Relaxation training involves teaching patients techniques designed to produce the "relaxation response"-a term used to describe the physiologic state that opposes the stress response. This term was originally coined by Harvard professor and cardiologist Herbert Benson, MD, in his best-selling book, The Relaxation Response (William Morrow, 2000). The effectiveness in reducing the frequency and severity of recurrent migraine headaches with biofeedback and relaxation training has been the subject of more than 35 clinical studies.'= When the results from these studies were compared with studies using the beta-blocking drug propranolol (Inderal), it was apparent that the nondrug approach was as effective as the drug approach but was without adverse effects (Table 191-6).

Migraine Headache Biofeedbacklrelaxationcompared with propranolol-average percentage improvement per patient Biofeedbackhelaxation

56.4%

Propranolol

55.2%

Placebo

14.3%

Untreated

3.2%

THERAPEUTIC APPROACH Migraine headache is a multifaceted condition and should be understood as a symptom rather than a disease. Symptoms are often debilitating, frequently interfering sigruficantlywith an individual's quality of life. A holistic, multidisciplinary approach is necessary for a satisfactory outcome. The challenge for the clinician isto determine which of many factors are responsible for each patient's migraine process. Identificationand avoidance of precipitating factors is important in reducing the frequency of headaches. Avoidance of initiators is particularly sigruficant, considering that they are cumulative in effect. Due to the high incidence (SOYO to 900/)of food allergy/intolerance in patients with migraine headache, diagnosis and management may begin with at least a l-week trial (dependingon migraine headache frequency) of careful avoidance of all foods to which the patient may be allergic or intolerant. This may be accomplished through either a supervised pure water fast or the use of an elemental diet. All other possible allergens (e.g., vitamins, unnecessary drugs, herbs) should also be avoided. During this procedure, food-sensitive patients are likely to exhibit a sigruficant exacerbation of symptoms early in the week, followed by almost total relief by the end of the fast/modified diet. This sequence has to do with the addictive characteristic of the reactive foods. Once the patient is symptom free, one new food is reintroduced (and eaten several times) each day while symptoms are carefully recorded. Some authors recommend reintroduction on a 4-day cycle. Suspected foods (symptom onset ranges from 20 minutes to 2 weeks) are eliminated, and apparently safe foods are rotated through a $-day cycle (see Chapter 47). Once a symptom-freeperiod of at least 6 months has been established, the 4-day rotation diet should no longer be necessary. An oligoantigenic diet may also be used successfully in some patients, but a longer trial (4 to 8 weeks) is typically necessary depending on the frequency of episodes. Foods that are commonly eliminated during this period include dairy products, gluten-containing grains, eggs, corn, chocolate, peanuts, coffee, black tea, soft drinks,alcoholic beverages, and all processed foods. Some clinicians

employ food allergy immunoglobulin testing, with mixed results. The cause of migraine headache is often not a simple matter of food intolerance. Aberrations in digestive function and detoxification may also complicate the migraine picture. Metabolic waste products of pathogenic organisms may produce distant symptoms such as headache, and foundational care for patients with migraine headache should include correcting intestinal dysbiosis, if identified clinically or in the laboratory through stool culture, organic acids analysis, or intestinal permeability assessment. In a study of 225 patients'" with migraine headache, Helicobucter pylori was detected in 40% (90 patients); eradication of the bacterium through standard pharmacologic measures resulted in improvement of migraine intensity, duration, and frequency in 100% of patients treated. Those who did not experience eradication of the bacterium had no improvement in migraine outcomes. Toxic overload or suboptimal function of detoxification enzymes may theoretically trigger headaches and should be addressed, if suspected.125Susceptibility to toxicity is produced by excessive environmental exposures, genetic polymorphisms in detoxification enzyme production, and depletion of nutrient cofactors catalyzing phase I or phase I1 detoxification reactions.126

Diet As discussed earlier, all food allergens must be eliminated and a 4-day rotation diet used until the patient is symptom free for at least 6 months. Foods containing vasoactive amines should initially be eliminated. After symptoms have been controlled, they can be carefully reintroduced. The primary foods to eliminate initially are alcoholic beverages, cheese, chocolate, citrus fruits, and shellfish. The diet should be low in sources of arachidonic acid (land animal fats) and high in foods that inhibit platelet aggregation (e.g., vegetable oils, fish oils, garlic, onion).

Supplements Magnesium: 250 to 800 mg daily in divided doses; titrate to symptoms and bowel tolerance Vitamin B6:50 to 75 mg daily, balanced with B-complex 5-HTP: 100 to 200 mg once to twice daily Vitamin B2 (riboflavin): 400 mg once daily, balanced with B-complex

Hormonal Therapies Trial of melatonin 0.3 to 3 mg at bedtime Trial of transdermal progesterone or estradiol, carefully individualized to clinical picture

Botanical Medicines T. partheniurn (feverfew): 0.25 to 0.5 mg parthenolide bid (or 25 to 100 mg dried leaves bid)

Specific Health Problems ~

Z. oficinalis (ginger): Fresh ginger: approximately 10 g/day (6-mm slice) Dried ginger: 500 mg four times/day Extract standardized to contain 20% of gingerol and shogaol100 to 200 mg tid for prevention and 200 mg every 2 hours (up to six times daily) in the treatment of an acute migraine P. hybridus (butterbur): 50 to 100 mg bid with meals

Headache Help: A Complete Guide to Understanding Headaches and the Medicines That Relieve Them, by

Lawrence Robbins, MD, and Susan S. Lang,Houghton Mifflin Company, Boston/New York, 2000 Headache Relief for Women, by Alan M. Rapoport, Little Brown, Boston, 1996 Managing Your Migraine; A Migraine Suferer's Practical Guide, by Susan L. Burks, Humana Press, NJ, 1994 The Hormone Headache: New Ways to Prevent, Manage, and Treat Migraines and Other Headaches, by Seymour Diamond, MD, with Bill Still and Cynthia Still, Simon & Schuster Macmillan Company, New York, 1995 Taking Control of Your Headaches: How to Get the Treatment You Need, by P.N. Duckro, PhD, W.D. Richardson, MD, J.E. Marshall, RN, et al, Guilford Press, New York, 1995 Headache Free, by Roger Cady, MD, and Kathleen Farmer, PsyD, Bantam Books, New York, 1996 Migraine: Everything You Need to Know about Their Cause and Cure, by Arthur H. Elkind, MD, Avon Publishing, 1997 The Headache Alternative: A Neurologist's Guide to DrugFree RelieJ by Alexander Mauskop, MD, and Marietta Abrams Brill, Dell Publishing, 1997 Headache and Diet: Tyramine-Free Recipes, by Seymour Diamond, MD, Bill Still, and Cynthia Still, International University Press, 1990 Headaches in Children, by Leonard0 Garcia-Mendez, MD, Lemar Publishing, 1996

1. Goadsby P, Lipton R, Ferrari M. Migraine--current understanding and txeatment. N Engl J Med 2002;346;42!57-270. 2. Rose FC. The pathogenesis of a migraine attack. TINS 1983;6:247. 3. ShinhojE. Hemodynamic studies within the brain during migraine. Arch Neurol 1973;29:257-266. 4. Blacklow RS. Macbryde's signs and symptoms, ed 6. New York: Lippincott, 1983:64-68. 5. Ferrari MD. Migraine. Lancet 1998;351:1043-1051. 6. Silberstein SD. Advances in understanding the pathophysiology of headache. Neurology 1992;42(3 suppl2):6-10. 7. Simkins RT, Tepley N, Barkley GL, Welch KM. Spontaneous neuromagnetic fields in migraine: possible link to spreading cortical depression. Neurology 1989;39(suppl 1):325. 8. Goadsby PJ. How d o the currently used prophylactic agents work in migraine? Cephalalgia 1997;178592. 9.Olesen J, Edvinsson L, eds. Basic mechanisms of headache. Amsterdam: Elsevier, 1988. 10. Lauritzen M, Skyhoj Olsen T, et al. Changes in regional cerebral blood flow during the course of classic migraine attacks. Ann Neurol 1983;13:633-641. 11. Lauritzen J. Pathophysiology of the migraine aura. The spreading depression theory. Barin 1994;117199-210. 12. Hanington E. The platelet and migraine. Headache 1986;26: 411-415.

13. Spence JD, Wong DG, Melendez LJ, et al. Increased prevalence of mitral valve prolapse in patients with migraine. Can Med Assoc J, 1984;131:1457-1460. 14. Amat G, Jean Louis P, Loisyy C, et al. Migraine and the mitral valve prolapse syndrome. Adv Neurol1982;33:27-29. 15.Gamberini G, D'Alessandro R, Labriola E, et al. Further evidence on the association of mitral valve prolapse and migraine. Headache 1984;24:39-40. 16. Lanzi G, Grandi AM, Gamba G, et al. Migraine, mitral valve prolapse and platelet h c t i o n in the pediatric age group. Headache 1986;26142-145. 17. Welch KMA. Migraine. A biobehavioral disorder. Arch Neuroll987; 44:323-327. 18. Ferrari MD, Odink J, Tapparelli C, et al. Serotonin metabolism in migraine. Neurology 1989;33:1239-1242. 19. Fioroni L, Andrea GD, Alecci M, et al. Platelet serotonin pathway in menstrual migraine. Cephalalgia 1996;16:427-430. 20. Lance JW, Lambert GA, Goadsby PJ, Azagami AS. 5-hydroxytryptamine and its putative aetiological involvement in migraine. Cephalalgia 1989;9(suppl9):7-13. 21. Sicuteri F. Hypothesis: migraine, a central biochemical dysnociception. Headache 1976;16:145-149. 22. Fozard JR, Gray JA. 5-HTCl receptor activation: a key step in the initiation of migraine? Trends Pharmacol Sci 1989;10:307-309.

Physical Medicine and Relaxation Therapies Transcutaneous electrical nerve stimulation to control secondary muscle spasm Acupuncture to balance meridians Biofeedback The Association for Applied Psychophysiology and Biofeedback 10200 West 44th Avenue, Suite 304 Wheat Ridge, CO 80033 (303) 422-8436 Guided imagery: The Academy for Guided Imagery PO Box 2070 Mill Valley, CA 94942 1-800-726-2070

Patient Resources

Migraine Headache 23. Ferrari MD, Saxena PR. Clinical effects and mechanism of action of sumatriptan in migraine. Clin Neurol Neurosurg 1992;94(suppl S):73-77. 24. Kagaya A, Mikuni M, Kusumi I, et al. Serotonin-inducedacute desensitization of serotonin2receptors in human platelets via mechanism involving protein kinase C. J Pharmacol Exp Ther 1990;255305-311. 25. Moskowitz MA, Cutrer FM. Sumatriptan: a receptor-targeted treatment for migraine. Annu Rev Med 1993;44:145-154. 26. Silberstein SD, Goadsby PJ, Lipton RB. Management of migraine; an algorithmic approach. Neurology 2000;55(9 suppl2):46-52. 27. Humphrey PPA, Fenuik W, et al. Serotonin and migraine. Ann N Y Acad Sci 1990;600:587-598. 28. Jamieson DG. The safety of triptans in the treatment of patients with migraine. Am J Med 2002;112135-140. 29. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;55754-762. 30. Saper JR, Silberstein SD, Lake AE III, Winters ME. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache 1994;34:497-502. 31. Mathew NT. Chronic refractory headache. Neurology 1993;43: S26-S33. 32. Mathew NT. Transformed migraine. Cephalalgia 1993;1378-83. 33.Isler H. Migraine treatment as a cause of chronic migraine. In Rose FC, ed. Advances in migraine research and therapy. New York Raven Press, 1982:159-164. 34. Olesen J. Analgesic headache. BMJ 1995;310479-480. 35. Mansfield LE, Vaughan TR, Waller SF, et al. Food allergy and adult migraine: double-blind and mediator confirmation of an allergic etiology. Ann Allergy 1985;55126-129. 36. Carter CM, Egger J, Soothill JF. A dietary management of severe childhood migraine. Hum Nutr Appl Nutr 1985;39294303. 37. Hughes EC, Gott PS, Weinstein RC, Binggeli R. Migraine: a diagnostic test for etiology of food sensitivity by a nutritionally supported fast and confirmed by long-term report. Ann Allergy 1985; 55~28-32. 38. Egger J, Carter CM, Wilson J, et al. Is migraine food allergy?A doubleblind controlled trial of oligoantigenic diet treatment. Lancet 1983; 2865-869. 39. Monro J, Brostoff J, Carini C, ZiLkha K. Food allergy in migraine. Study of dietary exclusion and RAST. Lancet 1980;21-4. 40. Grant EC. Food allergies and migraine. Lancet 1979;1:966-969. 41. Little CH, Stewart AG, Fennessy MR. Platelet serotonin release in rheumatoid arthritis: a study in food-intolerant patients. Lancet 1983;2:297-299. 42. Peatfield RC. Relationship between food, wine, and beer-precipitated migrainous headaches. Headache 1995;35:355-357. 43. Jarisch R, Wantke F. Wine and headache. Int Arch Allergy Immunol 1996;1107-12. 44. Wantke F, Gotz M, Jarisch R. Histamine freediet treatment of choice for histamine-induced food intolerance and supporting treatment for chronic headaches. Clin Exp Allergy 1993;23:982-985. 45. Jarman J, Glover V, Sandler M. Release of ('T)5hydroxytryptamine from human platelets by red wine. Life Sci 1991;48:2297-2300. 46. Martner-HewesPM, Hunt IF, Murphy NJ,et al. Vitamin EM nutriture and plasma diamine oxidase activity in pregnant Hispanic teenagers. Am J Clin Nutr 1988;44.907-913. 47.Sabbah A, Heulin M, Drouet M, et al. [Antihistaminic or antidegranulating activity of pregnancy serum]. Allerg Immunol (Paris) 1988;20236-240. 48. Lindberg S. 14C-histamine elimination from blood of pregnant and non-pregnant women with special reference to the uterus. Acta Obst Gynecol Scand 1963;42(suppl1):3-25. 49. Witkinson CF Jr. Recurrent migrainoid headaches associated with spontaneous hypoglycemia. Am J Med Sci 1949;218:209-212.

50. Dexter JD, Roberts J, Byer JA. The five hour glucose tolerance test and effect of low sucrose diet in migraine. Headache 1978;18:91-94. 51. Brainard JB. Angiotensin and aldosterone elevation in salt-induced migraine. Headache 1981;21:222-226. 52. Ratner D, Shoshani E, Dubnov B. Milk protein-free diet for nonseasonal asthma and migraine in lactase-deficient patients. Isr J Med Sci 1983;19:806-809. 53.Koehler SM, Glaros A. The effect of aspartame on migraine headache. Headache 1988;28:10-14. 54. Blumenthal HR, Vance DA. Chewing gum headaches. Headache 1997;37665-666. 55. Gerrard JM, White JG, Krivit W. Labile aggregation stimulating substance, free fatty acids and platelet aggregation. J Lab Clin Med 1976;87 73-82. 56. Sanders TA, Roshanai F. The influence of different types of omega3 polyunsaturated fatty acids on blood lipids and platelet function in healthy volunteers. Clin Sci (Lond) 1983;64:91-99. 57. Woodcock BE, Smith E, Lambert WH, et al. Beneficial effect of fish oil on blood viscosity in peripheral vascular disease. Br Med J 1984; 288592-594. 58. McCarren T, Hitzemann R, Allen C, et al. Amelioration of severe migraine by fish oil (w-3) fatty acids. Am J Clin Nutr 1985;41:874. 59. Glueck CJ, McCarren T, Hitzemann R, et al. Amelioration of severe migraine with omega-3 fatty acids: a double-blind, placebocontrolled clinical trial. Am J Clin Nutr 1986;43:710. 60. Hare1 Z, Gascon G, Riggs S, et al. Supplementation with omega-3 polyunsaturated fatty acids in the management of recurrent migraines in adolescents. J Adolesc Health 2002;31:154-161. I', Leslie FM. In search of the ideal treatment 61. Bic Z , Blix GG, Hopp H for migraine headache. Med Hypotheses 1998;501-7. 62. Montagna P, Sacquegna T, Cortelli P, Lugaresi E. Migraine as a defect of brain oxidative metabolism: a hypothesis. J Neurol 1989;236: 124-125. 63. SchoenenJ, Jacquy J, Lenaerts M. Effectiveness of highdose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology 1998;50:46&470. 64. Welch KMA, Levine SR, DAndrea G, et al. Preliminary observations on brain energy metabolism in migraine studied studied by in vivo phosphorus 31 NMR spectroscopy.Neurology 1989;39:53&541. 65. Sandor, PS,Afra J, Ambrosini A, SchoenenJ. Prophylactic treatment of migraine with beta blockers and riboflavin: differential effects on the intensity dependence of auditory evoked cortical potentials. Headache 2000;4030-35. 66. Schoenen J, Lenaerts M, Bastings E. High-dose riboflavin as a prophylactic treatment of migraine: results of an open pilot study. Cephalalgia 1994;14328-329. 67. Kopjas TL. The use of folic acid in vascular headache of the migraine type. Headache 1969;8:167-170. 68. Altura BM, Brodsky MA, Elin RJ, et al. Magnesium: growing in clinical importance. Patient Care 1994;10130-150. 69. Johnson S. The multifaceted and widespread pathology of magnesium deficiency. Med Hypotheses 2001;56:163-170. 70. Swanson DR. Migraine and magnesium: eleven neglected connections.Perspect Biol Med 1988;31:526-557. 71. Ramadan NM, Halvorson H, Vande-Linde A, et al. Low brain magnesium in migraine. Headache 1989;29:590-593. 72. Gallai V, Sarchielli P, Morucci P,Abbritti G. Magnesium content of mononuclear blood cells in migraine patients. Headache 1994;34: 160-165. 73. Mazzotta G, Sarchielli P, Alberti A, Gallai V. Electromyographical ischemic test and intracelldar and extracellular magnesium concentration in migraine and tension-type headache patients. Headache 1996;36357-361. 74. Pfaffenrath V, Wessely P, Meyer C, et al. Magnesium in the prophylaxis of migraine-a double-blind placebo-controlled study. Cephalalgia 1996;16436-440.

75. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia 1996;16257-263. 76. Mauskop A, Altura BT, Cracco RQ, et al. Intravenous magnesium sulphate relieves migraine attacks in patients with low serum ionized magnesium levels: a pilot study. Clin Sci (Lond) 1995;89:

633-636. 77. Mauskop A, Altura BM. Role of magnesium in the pathogenesis and treatment of migraines. Clin Neurosci 1998;5:24-27. 78. Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulfate rapidly alleviates headaches of various types. Headache 1996;36:154-160. 79. Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulfate relieves cluster headaches in patients with low serum ionized magnesium levels. Headache 1995;35:597-600. 80.Galland LD, Baker SM, McLellan RK. Magnesium deficiency in the pathogenesis of mitral valve prolapse. Magnesium 1986;5:165-174. 81.Lmdberg JS, Zobitz MM, Poindexter JR, Pak CY. Magnesium bioavailability from magnesium citrate and magnesium oxide. J Am Coll Nutr 1990;9:4&55. 82. Majumdar P, Boylan M. Alteration of tissue magnesium levels in rats by dietary vitamin 86 supplementation. Int J Vitamin Nutr Res 1989;59:300-303. 83. Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efficacy of feverfew as prophylactic treatment of migraine. Br Med J 1985;291: 569-573. 84.Murphy JJ,Heptinstall S, Mitchell JR. Randomised double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet 1988;2:189-192. 85. Barsby RW, Man U, Knight BW, Hoult JR. Feverfew and vascular smooth musde: extracts from fresh and dried plants show opposing pharmacological profiles, dependent upon sesquiterpene lactone content. Planta Medica 19935920-25. 86. Heptinstall S, Awang DV, Dawson BA, et al. Parthenolide content and bioactivity of feverfew (Tanaceturnpartheniurn (L.) Schultz-Bip.). Estimation of commercial and authenticated feverfew products. J Pharm Pharmacol 1992;44:391-395. 87. Emst E, Pittler MH. The efficacy and safety of feverfew (Tanaceturn partheniurn L.): an update of a systematic review. Public Health Nutrition 2OOO;3509-514. 88. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:2200-2211. 89. Heptinstall S,White A, Williamson L, Mitchell JR. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes. Lancet 1985;1:1071-1074. 90. Mustafa T, Srivastava KC. Ginger (Zingiber oficinule) in migraine headaches. J Ethnopharmacol1990;29:267-273. 91. Kiuchi F, Iwakami S, Shibuya M et al. Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids. Chem Pharm Bull (Bull) 1992;40:387-391. 92. Srivastava KC. Isolation and effects of some ginger components on platelet aggregation and eicosanoid biosynthesis. Prostaglandins Leurot Med 1986;25:187-198. 93. Grossman M, Schmidramsl H. An extract of Petasites hybridus is effective in the prophylaxis of migraine. Int J Clin Pharm 200038 430-435. 94. No authors listed. Petasites hybridus (butterbur). Altem Med Rev 2001;6:207-209. 95. Eaton J. Butterbur, herbal help for migraine. Nat Pharm 1998; 293-24. 96. Toglia JLJ.Melatonin: a significant contributor to the pathogenesis of migraine. Med Hypotheses 2001;57432-434.

97. Gagnier JJ. The therapeutic potential of melatonin in migraines and other headache types. Altern Med Rev 2001;6383-389. 98. Claustrat B, Loisy C, Brun J, et al. Nocturnal plasma melatonin levels in migraine: a preliminary report. Headache 1989;29: 242-245. 99. Brun J, Claustrat B, Saddier P, Chazot G. Nodumal melatonin excretion is decreased in patients with migraine without aura associated with menses. Cephalalgia 1995;15:136-139. 100. Anton-Tay F, Chou C, Anton S, Wrutman RJ. Brain serotonin concentration following intraperitoneal administration of melatonin. Science 1968;162277-278. 101. Nagtegaal JE, Smits MG, Swart AC, et al. Melatonin-responsive headache in delayed sleep phase syndrome: preliminary observations.Headache 1998;38303-307. 102. Epstein MT, Hockaday JM, Hockaday TD. Migraine and reproductive hormones through the menstrual cycle. Lancet 1975;l: 543-548. 103. Silberstein SD. The role of sex hormones in headache. Neurology 1992;42 (3 suppl2):3742. 104. Silberstein SC,Merriam GR. Estrogens, progestins, and headache. Neurology 1991;41:786-793. 105.Whitty CW, Hockaday JM. Migraine: a follow-up study of 92 patients. Br Med J 1968;1:735-736. 106. Somerville BW. The role of estradiol withdrawal in the etiology of menstrual migraine. Neurol1972;22:355-365. 107. deLignieres B, Vicens M, Mauvais-Jarvis P, et al. Prevention of menstrual migraine by percutaneous oestradiol. Br Med J (Clin Res Ed) 1986;2931540. 108. Parker GB, Tupling H, Pryor DS. A controlled trial of cervical manipulation for migraine. Aust N Z J Med 1978;8:589-593. 109. Watts PG, Peet KM, Juniper RP. Migraine and the temporomandibular joint: the final answer? Br Dent J 1986;161: 170-173. 110. Solomon S,Guglielmo KM. Treatment of headache by transcutaneous electrical stimulation. Headache 1985;25:12-15. 111. Doeer-Proske H,Wittchen HU. [A muscle and vascular oriented program for the treatment of chronic migraine patients. A randomized clinical comparative study]. Z Psychosom Med Psychoanal 1985;31:247-266. 112. Vesnina VA. [Current methods of migraine reflexotherapy]. Zh Nevropatol Psikhiatr Im S S Korsakova 1980;80703-709. 113. Kurland HD.Treatment of headache pain with auto-acupressure. Dis Nerv Sys 1976;37:127-129. 114. Lindeberg T. Acupuncture in headache. Cephalalgia 1999;19 (SUPPI25):65-68. 115. Melchant D,Linde K, Fischer P, et al. Acupuncture for recurrent headache: a systematic review of randomized controlled trials. Cephalalgia 1999;19(suppl):779-786. 116. Lenhard L, Waite PM. Acupuncture in the prophylactic treatment of migraine headache: pilot study. N Z Med J 1983;96 663-666. 117. Facchinetti F, Nappi G, Savoldi F, Genazzani AR. Primary headaches: reduced circulating beta-lipotropin and beta-endorphin levels with impaired reactivity to acupuncture. Cephalalgia 1981;1:195-201. 118. Markelova VF, Vesnina VA, Malygina SI, Dubovskaia LA. [Changes in blood serotonin levels in patients with migraine headaches before and after a course of reflexotherapy]. Zh Nevropatol Psikhiatr Im S S Korsakova1984;84:1313-1316. 119. Baischer W. Acupuncture in migraine: long-term outcome and predicting factors. Headache 1995;35:472-474. 120. Holroyd KA, Penzien DB. Pharmacological versus nonpharmacological prophylaxis of recurrent migraine headache: a meta-analytic review of clinical trials. Pain 1990;42:1-13.

Migraine Headache 121. Manias P, Tagaris G, Karageorgiou K. Acupuncture in headache: a critical review. Clin J Pain 2000;16334-339. 122. Vincent CA. A controlled trial of the treatment of migraine by acupuncture. Clin J Pain 1989;5:305-312. 123. Holroyd KA, Penzien DB. Pharmacological versus non-pharmacological prophylaxis of recurrent migraine headache: a metaanalytic review of clinical trials. Pain 1990;421-13.

124. Gasbanini A, De Luca A, Fiore G, et al. Beneficial effects of Helicobacter pylori eradication on migraine. Hepatogastroenterology 1998;45:765-770. 125. Liska DJ, Rountree R. The role of detoxification in the prevention of chronic degenerative diseases. Appl Nutr Sci Rep 2002;6501-8. 126. Ioannides C. Effect of diet and nutrition on the expression of cytochromes P450. Xenobiotica 1999;29:109-154.

Multiple Sclerosis Lynne Shinto, N D Dennis Bourdette, MD CHAPTER CONTENTS Diagnostic Summary

1925

General Considerations 1925 Epidemiology 1926 Pathogenesis 1926 Etiology 1928 Diagnostic considerations 1929 Therapeutic Considerations 1929 Allopathic Treatments 1929 Natural Medicine Therapeutic Considerations 1929 Diet Therapy 1929

DIAGNOSTIC SUMMARY Episodic, neurologic symptoms depending on the parts of the central nervous system (CNS) affected Typically occurs in adults between 20 and 55 years old Symptomatology not consistent with a single neurologic lesion

GENERAL CONSIDERATIONS Multiple sclerosis (MS) is a disease of the CNS in which there are typically relapses and remissions, various symptoms depending on the parts of the CNS that are affected, and varying levels of permanent disability. Pathologically, MS is an inflammatory disease of the CNS in which there is multifocal destruction of the myelin sheaths, referred to as demyelination, and axons within the brain, spinal cord, and optic nerves. MS is the most common disabling neurologic disease of young and middle aged adults in North America and Europe.’ Physicians have recognized its pathologic and clinical features since the mid-nineteenth century. Pathologically, MS consists of multifocal areas of demyelination, referred to as ”plaques,” in the brain, spinal cord, and optic nerves. In these areas there is destruction of the myelin sheath around axons with

Vitamin BI2 1933 Botanical Medicine 1933

Other Considerations 1934 Exercise 1934 Stress and Multiple Sclerosis 1934 Food Allergy 1934 Malabsorption 1935 Hyperbaric Oxygen 1935 Therapeutic Approach 1935 Diet 1935 Nutritional Supplements 1935 Exercise 1935 Stress Reduction 1935

relative sparing of axons, although axon damage also occurs in MS. Inflammatory cells composed of macrophages and lymphocytes are present when there is active demyelination within MS plaques, indicating that MS is an inflammatory disease. Magnetic resonance imaging (MRI) provides a means of visualizing MS lesions within the brain and spinal cord (Figure 192-1). Clinically, MS can cause various neurologic problems depending on the location and severity of MS plaques (Table 192-1). In about 85% of cases, MS starts with a relapsing-remitting course.2 Patients experience relapses or attacks of MS during which they develop a new neurologic problem, return of an old problem that had resolved, or worsening of preexistent symptoms. Relapses develop over a few days or weeks, and then a period of improvement and stability ensues. Patients average about one clinical relapse every 2 years. In between relapses, patients are clinically stable, although they may have various permanent neurologic symptoms resulting from previous relapses of MS. However, relapses that cause symptoms represent only the “tip of the iceberg” of disease activity in this stage of the illness. Serial MRI studies in MS patients have disclosed that asymptomatic, new MS lesions appear within the brain 5 to 10 times more commonly than symptomatic lesions, and these asymptomatic “relapses” 1925

Specific Health Problems after onset. Steady worsening characterizes this phase of the illness, called seconduy progressive MS. Patients with secondary progressive MS may or may not continue to have relapses. About 15% of MS patients have progressive worsening from the onset of their illness, a form of MS referred to as prima y progressive MS. Although MS is rarely fatal, it is often disabling with about one third of patients losing the ability to walk 15 to 20 years after onset. In benign forms of MS, comprising up to 15%of patients, patients never develop any permanent disability from MS. Most patients, however, develop varying degrees of permanent disability.

Epidemiology

Figure 192-1 Coronal section through brain of a patient with multiple sclerosis (MS). With this imaging sequence, the MS lesions appear as large areas of increased signal intensity or white "spots"adjacent to the lateral ventricles.

Symptoms

Causes

Weakness and numbness and tingling in legs and arms; stiffness in legs

Spinal cord lesions

Urinary urgency, retention, incontinence and recurrent infections

Spinal cord lesions

Constipation

Spinal cord lesions; diet

Sexual dysfunction

Spinal cord lesions

Blurred vision and blindness

Optic nerve lesions

Double vision

Brainstem lesions

Imbalance

Spinal cord and cerebellar lesions

Tremor of arms

Cerebellar lesions

Impaired memory and concentration

Cerebral lesions

Fatigue

Effects of inflammatory cytokines on neuronal function; nerve fiber fatigability resulting from demyelination

Heat sensitivity

Sensitivity of demyelinations to elevations in body temperature

Depression and other mood disorders

Cerebral lesions and changes in neurotransmitters

cause permanent damage that contributes to overall MS disease b ~ r d e n . ~ About 50% of patients with relapsing-remitting MS enter a progressive phase of the disease 5 to 15 years

MS affects about 1 of 1000 persons in the United States, Canada, and Northern Europe. MS typically begins between the ages of 20 and 55 but may occur at any age. Women are more commonly affected than men with about 60% of cases being female. A strong racial influence on the risk of developing MS exists, with it being most common among Caucasians, particularly those of Northern European de~cent.4,~ Typical MS is rare among Asians and black Africans but is relatively common among African Americans. The racial predilection of MS is one piece of evidence indicating the strong influence of genes on the risk of developing MS. Besides racial influences, there is also an interesting geographic distribution of the disease. Areas with the highest prevalence are located in higher latitudes, in both the northern and southern hemisphere^.^,^ These high-risk areas include the northern United States, Canada, Great Britain, Scandinavia, northern Europe, New Zealand, and Ta~mania.~,~ In the United States, some of the geographic influence on the prevalence of the disease may reflect a genetic effect resulting from the tendency of Scandinavians, who have the highest prevalence of MS, to migrate to northern states. The influence of latitude on the prevalence of MS appears to relate to where one lives the first two decades of life. People who move from a low-risk to a high-risk area before age 15 acquire a higher risk of developing MS, whereas those who make the same move after adolescence retain a lower risk?JO These observations suggest that an environmental exposure in the first two decades of life influences the risk of developing MS.

Pathogenesis All of the signs and symptoms of MS relate to damage to the brain, spinal cord, and optic nerves. This damage includes loss of the myelin sheath or demyelination of axom and, to a lesser extent, loss of axons. It is widely accepted that inflammatory cells cause the destruction of myelin and axons during the developmentof the acute MS plaques (Figure 192-2). The inflammatory cells involved

Multiple Sclerosis

Role of Free Radicals

In1

Blood

\

CNS

Figure 192-2 Model of acute multiple sclerosis plaque. Activated T cells enter the central nervous system (CNS) by passage through the blood-brain barrier (1). Pathogenic T cells then recognize antigens within the CNS, which may be fragments of myelin proteins or viral antigens expressed as part of a latent infection (2). The activated T cells then release proinflammatory cytokines (lymphotoxin, LT; tumor necrosis factor-alpha, TFNu;interferon-gamma, IFN-7) that directly injure myelin and activated macrophages (3). Activated macrophages release cytokines, free radicals, and proteases that injure myelin and axons (4, 5). Plasma cells within the CNS release antimyelin antibodies (6) that bind to myelin and cause demyelination by complement activation or by assisting myelin phagocytosis by macrophages. Regulatory T cells that enter the CNS release regulatory cytokines (transforming growth factor-beta, TGF-P; interleukin-4, IL-4; IL-70) that downregulate pathogenicT cells and help to "turn off" the acute inflammatoryresponse. (Reprinted with permission from Program of the American Academy of Neurology. "Multiple sclerosis"continuum, vol 5. Philadelphia: Lippincott Williams 8 Wilkins, 199936.)

The role of free radical injury in MS is worth discussion because of its therapeutic implications. In MS, oxygen and nitrogen free radicals have been implicated in demyelination and axonal damage and also in upregulation of proinflammatory factors such as tumor necrosis factor-alpha (TNF-a),inducible nitric oxide (NOS), and nuclear transcription factor-kappaB.l1-l3Oxygen and nitrogen free radicals have also been implicated in the activation of matrix metalloproteinase (MMP), which is an important mediator of T lymphocyte trafficking into the CNS.14J5 Several studies have reported a significant increase in metabolites related to oxidative and nitrosative stress in the cerebrospinal fluid (CSF) of MS subjects when compared with control subjects.'+18One study reported a significant decrease in reduced glutathione and a significant increase in oxidized glutathione in the CSF of MS subjects compared with healthy control subjects.I7 A pilot study assessing the relationship between active MRI lesions and polymorphisms of antioxidant enzymes in MS patients found a significant association with a specific genotype for glutathione Stransferase (GST) and an increase in the number of active 1esi0ns.l~This GST genotype is associated with an impaired ability to detoxify oxidized lipids and DNA. Given the potential importance of free radicals in the pathogenesis of MS, use of natural antioxidants as part of a natural medicine approach to MS appears indicated.

Viruses and Autoantigens in MS include T lymphocytes, macrophages, and plasma cells. It is believed that a subset of T lymphocytes initiates the acute MS lesions, recognizes one or more antigens within the CNS, becomes activated, and then initiates an inflammatory cascade that results in demyelination and axonal injury. The targets of this T cell-mediated inflammation are uncertain but may be myelin antigens or perhaps antigens expressed as part of a latent viral or atypical bacterial infection. The actual mediators of tissue damage include macrophages that can cause damage by releasing soluble inflammatory mediators such as cytokines and free radicals or by actively stripping myelin from the axon sheath. Activated T cells can also release proinflammatory cytokines that can contribute to tissue damage. Finally, antimyelin antibodies can damage myelin either by initiating complement-mediated demyelination or assisting macrophage phagocytosis of myelin. The disease process is "turned off" by apoptosis of the disease initiating T cells and by recruitment of regulatory T cells into the CNS. This model of the acute MS lesion is consistent with the most prevalent theory about the MS, namely that it is an immune-mediated disease.

Considerable interest lies in identifymg the target or targets of the pernicious inflammatory response in MS?O Two general categories of targets have been postulated to be critical to MS, viruses and autoantigens. For decades there has been interest in the possibility that one or more viruses or other microbial infections might cause MS. This interest stems from the inflammatory nature of MS and the apparent influence of environment on the risk of developing MS, both suggesting the possibility of an infectious etiology. In addition, viruses cause several demyelinating diseases in humans and animals that are similar to MS. Progressive multifocal leukoencephalopathy and subacute sclerosing panencephalitis are human demyelinating diseases caused by the human papovavirus and the measles virus, respectively. In animals, a number of viruses can produce demyelinating diseases with similarities to MS.8,9,21 These observations have spurred research by various investigators using a range of techniques seeking to demonstrate an infectious etiology for MS. However, although various infectious agents have been reported to be associated with MS including measles, Epstein-Barr virus, distemper virus,comnavirus, retrovirus, herpes simplex, human herpes virus-6, and chlamydia pneumoniae,

Specific Health Problems there is presently no convincing evidence of a linkage between any infectious agent and MS.= The lack of evidence does not exclude the possibility that an infectious agent causes MS, but presently there is no widely accepted evidence associating MS with any specific virus or other microbe. Most investigators believe that the primary targets of the pathogenic immune response in MS are myelin antigens, making MS an autoimmune disease.= The autoimmune hypothesis of MS has grown out of the extensive work that has been done on an animal model, experimental autoimmune encephalomyelitis (EAE). Various species of animals are susceptible to EAE, which is induced by immunizing the animals with myelin or several different myelin proteins including myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein. Given an appropriate genetic background and method of disease induction, EAE can have a chronic relapsing course with clinical and pathologic features similar to MS. On the basis of EAE research, many investigators have sought to link MS to a pathogenic response to a single myelin antigen, but these attempts have largely failed. Various studies, however, suggest that MS patients compared with healthy controls are immunologically sensitized to various myelin antigens, a finding consistent with the autoimmune hypothesis. It may be that by the time MS patients are diagnosed, they have become immunologically sensitized to an array of myelin antigens and that attempts to find a single autoantigen in MS will not succeed. In summary, T lymphocytes, macrophages, and their soluble mediators of inflammation cause demyelination and axonal injury in MS. How individuals acquire the disease remains uncertain, but considerable evidence supports the notion that MS is an immune-mediated disease and that the pernicious immune response in MS is directed at multiple myelin antigens not against a viral or other infection within the CNS. However, it remains possible that viral infections might induce an autoimmune response in genetically susceptible individuals that ultimately results in MS.

Etiology Although there is general agreement that MS is an immune-mediated disease, why people develop MS remains uncertain. Epidemiologic studies indicate that genes and the environment influence the risk of acquiring MS.

Genes Substantial evidence indicates that genetic background influences the risk of developing MS.24,25 Race is a strong influence on the risk of developing MS, with Caucasians and blacks being much more at risk of developing MS

than Asians. Having a first-order relative (parent or sibling) increases the risk of developing MS by fivefold to tenfold. Perhaps the most compelling evidence of the genetic influence on the risk of developing MS comes from studies of twins in which at least one twin has MS.26 Among nonidentical twins, the chances of the second twin having MS are 1% to 2%, which is similar to that of nontwin sibling pairs. Among identical twins, the chance of the second twin having MS is 25%, indicating a strong influence of genetic background on the risk of acquiring MS. An estimated 10 to 15 different genes may affect the risk of developing MS, and major research efforts are under way to identify these genes. Thus far, only the human leukocyte antigen DR2 gene has been definitively shown to be associated with an increased risk of developing MS among individuals of northern European descent.

Environment The environment appears to sigruficantly influence the risk of developing MS.6,7This is apparent from studies showing the effect of latitude on disease prevalence and observations on “outbreaks” of MS, such as those that occurred in the Faroe Islands after World War The nature of the environmental risk factors are unknown. Much attention has focused on the possibility of a viral or other microbial infection as the environmental exposure affecting the risk of developing MS. However, as already discussed, no clear causative linkage between MS and any microbial infection has yet to be substantiated. Besides infections, diet may play a role as an environmental risk factor in acquiring MS. The first investigations into diet and MS centered around trying to explain why inland farming communities in Norway had a higher incidence than areas near the coastline. It was discovered that the diets of the farmers were much lugher in animal and dairy products than the diets of the coastal dwellers whose diet was enriched in cold-water fish.2s Subsequently, other researchers have attempted to correlate various dietary patterns and the geographic distribution of MS. Epidemiologic studies assessing associations between dietary factors and the risk of developing MS have yielded mixed results. In a review of epidemiologic data reporting the relationship between diet and MS from 1952 through 1995, the authors concluded that multiple studies suggested that the risk of MS was significantly correlated with the following parameters: consumption of animal fat; animal protein; and meat from nonmarine mammals.29However, a recent large cohort study using data from the Nurses Health Study (NHS) and Nurses Health Study I1 (NHSII) found no evidence linking risk of MS with intake of saturated fats. The authors did note, however, that intake of linolenic acid, an omega-3

Multiple Sclerosis fatty acid, but not fish oils or docosahexanoic acid (DHA), was associated with a trend toward a lower risk for MS.30 Using data from the same cohorts, this same group also found no relationship between intake of fruits and vegetables and risk of MS.3l A case-control study in Canada assessing the relationship between nutritional factors and risk of MS in 197 incident cases of MS and 202 frequency matched controls found a positive association between animal fat intake and risk of MS. This study also identified a significant protective effect with cereals/breads, vegetable protein, dietary fiber, vitamin C, thiamin, riboflavin, calcium, potassium for all cases, and fish in cases of women Taken together, these studies suggest that there is a modest influence of diet on the risk of developing MS. In summary, the environmental factors that influence the risk of acquiring MS remain uncertain. From a natural medicine viewpoint, the observations that dietary fats may influence the risk of developing MS are of interest, as they have therapeutic implications.

DIAGNOSTIC CONSIDERATIONS MS remains a clinical diagn0sis.3~No single test such as a blood test, MRI examination, or CSF study ”diagnoses” MS. The diagnosis rests on a knowledgeable physician taking a history, performing a neurologic examination, conducting various tests, and then making a diagnosis on the basis of all of the data. In general, only neurologists have sufficient training and experience to make an accurate diagnosis. The diagnosis of MS rests on the objective demonstration of two or more areas of demyelination in the CNS that have occurred at more than one time point, and a diagnosis cannot be based just on a patient’s symptoms. Means of ”objective” demonstration of areas of demyelination include the neurologic examination, MRI of the brain and spinal cord, and electrophysiologic tests called evoked potentials that assess visual, auditory, and somatosensory pathways. CSF examination can also be useful in establishing the inflammatory nature of a given patient’s condition. In evaluating patients for possible MS, the CSF is evaluated for the presence of plasma cells that are producing immunoglobulins (Igs) within the CNS by assessing for qualitative (oligoclonalbands) and quantitative (total IgG, IgG index, and IgG synthesis rate) immunoglobulin changes. Excluding the presence of other disorders that can masquerade or be misdiagnosed as MS is also important, such as unusual causes of cerebrovascular disease, vitamin BIZdeficiency, spinal cord compression from tumors, herniated disks or spinal canal stenosis, vascular malformations of the spinal cord, Lyme disease, and various other disorders. Although MS was formerly difficult to diagnose, MRI

scanning has sigruficantly improved the ability to diagnose MS in its early stages, as it allows imaging of areas of demyelination in the brain and spinal cord and also helps exclude the presence of other diseases that might explain the patient’s symptoms.

THERAPEUTIC CONSIDERATIONS Allopathic Treatments The allopathic approach to treating MS includes the use of medications to control disease activity and medications and rehabilitation interventions designed to alleviate symptoms resulting from damage to the CNS. Medications that help decrease disease activity in relapsing-remitting MS include human recombinant interferon-beta (Avonex, Betaseron, and Rebif) and glatiramer acetate (Copaxone), a random polymer of four amino acids that stimulates protective T Compared with placebo, these medications decrease relapse rate by about one third, decrease new lesion formation in the brain as detected by MRI, and decrease the risk of developing permanent neurologic disability. Corticosteroids, such as methylprednisolone, given in high doses can decrease the duration of relapses of MS but do not affect the degree of eventual recovery for relapses.% An immunosuppressant/chemotherapy agent, mitoxantrone (Novantrone),has also been shown to decrease disease activity in patients with rapidly progressive forms of MS.39 A number of different medications are useful for treating various symptoms of MS, such as fatigue, bladder dysfunction, and spasticity, but these medications do not reverse damage that has already occurred or decrease disease activity.

Natural Medicine Therapeutic Considerations From a natural medicine standpoint, there are four major approaches to treating MS: Dietary therapy Nutritional supplements Exercise Stress management Including all four provides the most comprehensive natural medicine treatment plan and should be used in combination with appropriate allopathic therapies.

Diet Therapy The Swank Diet Dr.Roy Swank has provided evidence that a diet low in saturated fats, maintained over a long period of time, tends to retard the disease process, reduce the number of attacks, and decrease mortality!wz Swank began treating patients with his low-fat diet in 1948. The approach

Specific Health Problems to use a low-fat diet supplemented with cod liver oil is based on epidemiologic studies that found a decreased incidence of MS in populations that had a low consumption of animal fats with a high consumption of coldwater fish. Dr.Swank’s diet recommends the following: A saturated fat intake of no more than 15 g/day An unsaturated fat intake of a minimum of 20 g/day

and maximum of 50 g/day No red meat consumption for the first year (this includes dark meat of turkey and chicken); following the first year, only 3 oz of red meat per week White meat poultry, fish, and shellfish are permissible in any amounts as long as they contain low saturated fats Elimination of dairy products containing 1%butterfat or more 1 tsp or 4 capsules of nonconcentrated cod-liver oil and one multivitamin and mineral Based on our current knowledge of the pathogenesis of MS, the rationale of using the Swank diet or other diets low in saturated fats in patients with MS relates to the general health benefits of such a diet and the antiinflammatory and perhaps neuron membranestabilizing effects of a diet enriched in omega-3 fatty acids. Although red meat consumption is significantly restricted on the Swank diet, fish appears to be particularly indicated due to its excellent protein content and, perhaps more importantly, its high omega-3 fatty acid content. Cold-water fish such as mackerel, salmon, and herring are rich in omega-3 fatty acids, which include eicosapentaenoic (EPA) and DHA. As reviewed in the nutritional supplement section, omega-3 fatty acids have antiinflammatory effects that may benefit MS. In addition, because optimal neuronal functioning depends on cell membrane fluidity, which in turn depends on lipid composition, optimal essential fatty acid (EFA) levels may be important in exerting neuroprotective effects by maintaining healthy neuronal f u n ~ t i o n i n g . Decreasing 4~~ animal fats and increasing omega-3 fatty acids in the diet thus may improve neuronal function by modulating neuronal lipid composition. Besides Dr.Swank‘s observational studies suggesting that his diet is beneficial for patients with MS, a recent open-label study evaluated the effects of a diet low in saturated fats combined with fish oil supplementation and vitamin B-complex and vitamin C in newly diagnosed relapsing-remitting MS.& Besides dietary modifications, subjects were advised to reduce their intake of sugar, coffee, tea, and alcohol consumption and to stop smoking. Diet was monitored over 2 years by 4-day dietary record at the end of each year, and plasma fatty acid levels were monitored at baseline, year 1, and year 2. A significant increase occurred in the intake of fish and a reduction of food items containing saturated fats

occurred after 2 years. A significant increase occurred in plasma levels of omega-3 fatty acids, and a sigruficant decrease occurred in plasma omega-6 fatty acids. Over the 2 years of the study, patients had a sigruficant reduction in both relapse rates and disability. This study, however, had significant limitations because there was no comparison group. Although caution is warranted in interpreting the results of this small, open-label study, the outcome of this study does concur with those of Dr. Swank‘s long-term studies on diet and fish oil supplementation for MS. Unless following a specifically prescribed diet such as the Swank diet, the diets of MS patients in general may be suboptimal. One study assessed the diet of 67 women with MS using a 3-day ”diet diary.” Nutritional information obtained from the diet diaries was compared with the recommended daily intake (RDI) for each nutrient assessed. Women with MS in this study had a 10%or less intake of carbohydrates, dietary fiber, vitamin E, calcium, and zinc compared with RDI. They consumed saturated fat, protein, vitamin A, vitamin C, folate, and iron at levels higher than the RDL4’ In this study the authors also noted that depression scores had a low but significant correlation to total fat intake with subjects who were more depressed consuming more fat. This latter observation is of interest in that depressed patients may be inclined to eat a less healthy diet, and unhealthy diets may contribute to depression. The epidemiologic studies suggesting a link between a high-fat diet and an increased risk of MS coupled with the results from studies reporting a benefit from lowfat diet interventions in MS provide a rationale for recommending a low-fat diet as part of a natural medicine treatment program for MS. A person with MS following a low-fat diet regimen will gain general health benefits. A diet enriched in omega-3 fatty acids, which have immunomodulatory effects, may also provide more specific MS disease-modifying support benefit.

Nutritional Supplements Essential Fatty Acids EFAs are divided into two major groups, the omega-3 fatty acids and the omega-6 fatty acids. Linolenic Acid (Omega-3 Fatty Acids) Apparently there is a good rationale for supplementation with EPA and DHA, the so-called marine lipids, in the treatment of MS. General agreement exists that MS results from an acquired immune-dysregulation and aberrant immune activation leading to T cell-driven inflammatory processes in the CNS that cause demyelination and axonal damage. Increased levels of proinflammatory cytokines such as TNF-a, interferon (EN)-y, and IL,-2 have been found in the peripheral blood, cerebrospinal fluid (CSF), and brain lesions of MS patients.4953

Multiple Sclerosis

Numerous reports document the association between these cytokines and disease activity, thus implicating them as mediators of immunopathogenesis of MS.48952 Recently, MMPs have also been implicated in the pathogenesis of MS. MMPs are a family of proteases that aid in the remodeling of the extracellular matrix, basement membrane, and other tissues in the body by digesting collagen components in these tissues. MMPs are thought to have a significant role in the transmigration of inflammatory cells into the CNS by aiding in the disruption of the blood-brain barrier.15pMSeveral studies have shown higher serum levels of MMP-9 in MS pa tient~.~~-5' Finding agents that can suppress inflammatory cytokines and MMP levels are important in developing new therapies for altering the course of MS. The immunomodulatory effects of omega-3 fatty acids have been well documented. In vitro, animal, and, ex vivo human studies have reported a decrease in mRNA and protein levels of a number of cytokines including TNF-a, IFN-y, IL-1, IL-2, and VCAM-1.5* One published study documented the effects of fish oil supplementation, which are enriched with the omega-3 fatty acids EPA and DHA, on cytokine secretion in MS.59 In this study production of IL-1-p, TNF-a, IL-2, IFN-y, prostaglandin E2 (PGE2), and LTB4 in unstimulated and stimulated PBMC in people with MS and healthy controls was evaluated. Twenty subjects with MS and 15 age-matched healthy controls were supplemented with 6 g/day of fish oil containing 3 g EPA and 1.8 g DHA for 6 months. All MS subjects had a stable course of MS for at least 3 months before enrollment, had not modified their diet as a consequence of developing MS, and were not on any disease-modifying therapies. Outcome measures compared baseline levels of the cytokines mentioned to levels after 3 and 6 months of supplementation in both MS subjects and healthy controls. No differences were demonstrated in baseline ex vivo cytokine levels between MS subjects and controls. After 3 and 6 months of fish oil supplementation, there was a significant decrease in the levels of soluble IL-IP (p < 0.03), TNF-a ( p < 0.02), IL-2 (p < 0.002), and IFN-y ( p < 0.01) in the unstimulated PBMC of both groups. A significant difference was observed after 3 and 6 months of supplementation in the levels of soluble IL-lP ( p < O.Ol), TNF-a ( p < 0.02), E-2 (p < 0.003), and IFN-y ( p < 0.005) from stimulated PBMC of both groups. Cytokine levels returned to baseline values after a 3-month wash-out period. This study demonstrated the ability of fish oil supplementation to decrease proinflammatory cytokines believed to be important in the pathogenesis of MS in both patients and healthy controls. Two in vitro studies and one ex vivo animal study evaluated the effects of omega-3 fatty acids, DHA, and EPA on cytokines and

MMP levels.60-62 These studies indicate that fish oil supplementation decreases the gene expression and protein levels of proinflammatory cytokines, as well as MMPs. These studies provide a theoretic rationale for using omega-3 fatty acid supplementation in the treatment of MS. Only one study has examined the use of omega-3 fatty acid supplementation in MS.'j3 This was a large (n = 312), double-blind, placebo-controlled trial in which MS patients were randomized to receive either 20 capsules of fish oil per day or olive oil containing 72%oleic acid for 2 years. The total daily dose of EPA was 1.71 g, and the total daily dose of DHA was 1.41 g. This study reported a trend in improvement in the omega-%treated subjects compared with controls, p = 0.07. Although the results did not achieve statistical significance favoring omega-3 fatty acid supplementation, the study was not optimally designed. Both groups in the study were advised to follow a diet low in animal fat and high in omega-6 fatty acids. Importantly, both groups developed changes in serum fatty acid content over the 2 years of the study. The lack of comparing fish oil supplementation to a placebo oil in patients who did not have other dietary modifications may have affected the ability of the study to detect a statistically significant therapeutic benefit of omega-3 fatty acid supplementation. Omega-3 fatty acid supplementation may also be beneficial in treating depression in MS. Inflammatory cytokines that have been implicated in MS disease pathogenesis have recently been correlated with depression in MS.& This study reported a significant positive correlation in the gene expression levels of TNF-a and IFN-y and scores on a depression inventory (a high score indicating greater depression) in MS patients during relapses. Depression is a common problem in MS, and many MS patients take antidepressants. Ethyl-EPA has recently been reported in two pilot studies to significantly improve depression scores on standard self-rating scales of depression among non-MS The improvements in depression scores were observed in subjects diagnosed with primary depression who were on stable doses of antidepressants. The doses of ethyl EPA used in these studies ranged from 1 to 4 g per day. Omega-3 fatty acid supplementation might be useful in the management of depression in MS in conjunction with the appropriate use of counseling and, where indicated, antidepressant medications. Apparently there is a sigruficant rationale for supplementation with omega-3 fatty acids. Based on various studies, considerable evidence indicates that omega-3 fatty acids decrease proinflammatory cytokines and MMP, which are associated with MS pathogenesis. Although the only clinical trial of fish oil supplementation in MS failed to show a statistically sigruficant benefit over placebo, this study showed a strong trend favoring fish oil

Specific Health Problems supplementation. As mentioned earlier, diet modifications in both groups may have reduced the ability of this study to detect a sigruficant treatment effect. In addition, Western diets are often low or even deficient in omega-3 fatty acids while maintaining high amounts of omega-6 fatty a~ids.6~ Finally, ethyl-EPA has been reported to improve depression, a common MS symptom, in people diagnosed with primary depression and may therefore provide some symptomatic benefit to patients with MS. Linoleic Acid (Omega-6 Fatty Acids) The scientific rationale for omega-6 fatty acid supplementation in MS is less well substantiated than it is for omega-3 fatty acid supplementation. Supplementation of omega-6 fatty acids sigruficantlyincreased the production of transforming growth factor beta-1 (TGF-PI) in the peripheral blood mononuclear cells of healthy subjects.& TGF-01 is an antiinflammatory cytokine that might be beneficial for MSF9 Two studies, in an animal model of MS, reported that supplementation with linoleic acid, which is rich in omega-6 fatty acids, decreased the severity of disease70and reduced inflammation in the CNS.71 Thus there is some experimental basis for considering omega-6 fatty acid supplementation in MS. Linoleic acid supplementation for the treatment of MS has been investigated in at least three double-blind clinical trial^.^-^^ Although the results of the studies were mixed (two showed a positive effect and one did not), combined analysis indicated that patients supplemented with linoleic acid had a smaller increase in disability and reduced severity and duration of relapses compared with patients supplemented with olive oil as a control.75 These studies used a sunflower seed oil emulsion at a sufficient dosage to provide a daily supplementation of 17.2 g of linoleic acid. Unlike the trial using fish oil supplementation, subjects in these studies were not advised to alter their diets. Evening primrose oil, which is rich in the omega-6 fatty acid gamma-linoleic acid, is commonly used by MS patients. Gamma-linolenic acid might be more effective than linoleic acid due to its easier incorporation into brain lipids and its possibly greater effect on immune function.76However, evening primrose oil contains low levels of gamma-linolenic acid and the product is relatively expensive. Large and prohibitively expensive amounts of evening primrose oil would need to be used to obtain adequate supplementation. In addition, a single pilot trial of evening primrose oil in MS failed to demonstrate any benefit.n Despite its common use among MS patients, we do not recommend the use of evening primrose oil as a supplement in MS. In summary, evidence from clinical trials indicates that supplementation with the omega-6 fatty acid linoleic acid has a modest benefit in the treatment of MS.

Antioxidants As already reviewed, free radicals may play an important role in tissue injury in MS. This provides a strong rationale for incorporating antioxidant supplementation into any natural medicine treatment program for MS.

Selenium Many studies have demonstrated a reduction in glutathione peroxidase (GSH-Px)activity in the erythrocytes and leukocytes of patients with MS.7-l The literature also reports one pilot study that found a significant positive association between an impaired glutathione Stransferase genotype and increased numbers of active lesions in MS patients.ly Selenium is a component of a wide range of selenoproteins, glutathione peroxidase enzymes being a major class among them. Release of selenoproteins is part of the innate cellular responses to oxidative stress.82In a macrophage cell line, selenium deficiency resulted in an increase in both gene and protein expression of both iNOS and NO levels in lipopolysaccharide stimulated cells.83 Only one published study assessed the effects of selenium supplementation in MS. This study reported that supplementation of 18 MS patients with 6 mg/day of sodium selenite, 2 g/day of vitamin C, and 480 mg/day of vitamin E for 5 weeks increased GSH-Px fivefold.% Unfortunately, clinical parameters were not evaluated. Thus there is little clinical research to support the use of selenium as a supplement in MS; however, selenium is a safe and relatively inexpensive supplement and may provide some benefit to MS patients given its antioxidant properties.

Vitamins C and E Although there have been no therapeutic trials evaluating the effects of vitamin C and vitamin E supplementation alone in MS, both appear indicated because of their ability to decrease lipid peroxidation. Isoprostane levels, a measure of lipid peroxidation, are increased in a number of neurologic disorders including MS, Alzheimer’s disease, Huntington’s disease, and Creutzfeldt-Jakob di~ease.8~ One study reported a significant increase in isoprostane levels in the CSF of MS patients compared with subjects with other neurologic diseases.16 Although there are mixed reports on the effects of vitamin C and E supplementation on lipid peroxidation in various subject types including healthy subjects, congestive heart failure patients, smokers, nonsmokers, and hypercholesteremic the majority of these studies report a decrease in isoprostane level from supplementation of either vitamin.88-y1 Given that both vitamins C and E are antioxidants that have been shown in a number of studies to decrease lipid peroxidation and are safe and inexpensive, supplementation with a combination of vitamins C and E seems reasonable in patients with MS.

Multiple Sclerosis

Alpha-Lipoic Acid Alpha-lipoic acid (ALA) and its reduced form, dihydrolipoic acid (DHLA), are potent antioxidants with multiple modes of action. ALA/DHAL can regenerate other antioxidants such as glutathione, vitamin C, and vitamin E, serve as a reactive oxygen species scavenger, repair oxidative damage, and chelate metallic ions involved in oxidative injury. DHLA acts by restoring reduced levels of other antioxidants such as glutathione and by repairing oxidative damage.92-94 ALA is absorbed from the diet and synthesized de novo, converts readily intracellularly to DHLA, and crosses the blood-brain barrier. Both ALA and DHLA are present in both extracellular and intracellular environment^.^^ Although there are no reports on the effectiveness of ALA in people with MS, one study in an animal model of MS demonstrated a significant benefit for ALA. ALA supplementation at doses of 10 to 100 mg/kg/day suppressed disease and did so by inhibiting T lymphocyte trafficking into the spinal cord.96The antioxidant properties of ALA and the therapeutic benefits of ALA in an animal model of MS suggest that it may be a useful supplement in patients with MS.

Vitamin BI2 Acquired deficiency of vitamin BID as well as inborn errors of metabolism involving this vitamin, are wellknown causes of demyelination in the CNS. It is also known that vitamin B12 deficiency can mimic MS. Reports in the literature that vitamin BI2 levels in the serum are low in MS are conflicting. Two studies reported an increased incidence of serum BI2 deficiency in MS patient^?^,^^ while a subsequent larger study found that BI2deficiency was uncommon in MS.99 One study reported no decrease in serum BI2 levels but a significant decrease in the binding capacity of unsaturated Bl2.lW In this study 24 Japanese patients with MS were given massive oral doses of vitamin BI2 (60 mg/day) to determine if supplementation provided any therapeutic benefit in progressive MS. In six patients with severe progressive MS, the orally administered vitamin B12 improved both visual and brainstem auditory evoked potentials by nearly 30%, but motor function did not improve. A randomized, double-blind, placebo-controlled pilot study designed to evaluate the effectiveness of a combination therapy in MS patients demonstrated an improvement in disability by 2 points on the Guy's neurologic disability scale (GNDS) after starting BI2 injections, yet thisimprovement was not statistically sigruficant.'O' This study enrolled 138 MS patients and randomized them to two groups (placebo or treatment). The treatment included B12 injections (1 mg intramuscularly weekly), lofepramine (70 mg/day), L-phenylalanine (500mg bid). All subjects received BI2 injections 2 weeks before

receiving placebo or treatment capsules and continued weekly injections for an additional 24 weeks (treatment intervention period). No significant differences occurred between groups in outcomes of disability by GNDS and expanded disability status scale (EDSS), depression, fatigue, or MS symptoms. As mentioned earlier, the only outcome measure that demonstrated a difference was the reduction in GNDS points in both groups within the first 2 weeks after receiving B12injections. This reduction in score remained stable throughout the study. Because the B12 injections were not placebo controlled and the change in GNDS occurred in such a short time, during the run-in phase, the results could likely be explained by placebo effect.

Botanical Medicine Ginkgo biloba Ginkgo biloba (GB) is a botanical with both antioxidant and antiplatelet activities. GB's antioxidant properties might make it useful in treating MS given the importance of oxidative injury in MS. In addition, some investigators have suggested that its ability to block platelet activating factor (PAF) also might provide benefit in treating MS. Overproduction of PAF has been implicated in neurodegeneration.'02 In addition, one study reported a sigruficant increase in both plasma and CSF levels of PAF in 20 MS patients compared with healthy controls.103This study also found that both plasma and CSF PAF levels were positively correlated with the number of active lesions visualized by MRI. Treatment of rats with an MSlike disease with PAF increased disease, and treatment with a PAF antagonist suppressed the development of disease.IMGinkgolide B, a terpenoid constituent of G. biloba, is an antagonist of PAF. One randomized, double-blind, placebo-controlled trial evaluated the effects of ginkgolide B in the treatment of MS relapses in 104 patients. Forty-three patients received a placebo, 29 received 240 mg/day of pkgolide B, and 32 received 360 mg/day of gmkgolide B; all were treated for 7 days. No statistically significant difference occurred among the three groups in changes in functional scores.1o5Although this study was negative, one must be cautious in overinterpreting the results. This short study focused on one constituent of G. biloba that has antiplatelet but not antioxidant properties and assessed only its effects on the treatment of relapses of MS. It is currently unknown whether G. biloba extract, which has both antioxidant and antiplatelet activities, is effective as either a treatment of relapses of MS or useful in the long-term treatment of MS. G. biloba might have a role in the symptomatic management of cognitive dysfunction in MS. Sigruficant cognitive impairment occurs in 40% to 60% of MS patients, and there are no allopathic, symptomatic therapies for this problem. A meta-analysis of published clinical trials

Specific Health Problems stress, and disease activity as measured by MRI found found that G. bilobu had a modest effect in slowing that increased conflicts and disruptions in routine were the progression of Alzheimer's disease.'" A doublefollowed by an increased risk of developing new brain blind, placebo-controlled, crossover pilot trial of GB (240 mg/day) in 23 MS patients with mild cognitive lesions 8 weeks later.'I6 This study reports no strong relationship between psychologic stress or distress and impairment found GB to have a modest benefit in improving some aspects of cognitive dysfun~tion.'~~exacerbations. In addition, the authors concluded that although they had identified a relationship between GB supplementation might therefore provide some benantecedent stressors and disease activity, this relationefit to MS patients with cognitive complaints. ship was not sufficiently robust to predict clinical exacerbations reliably in individual patients. In a subsequent OTHER CONSIDERATIONS study on the same subjects, the relationship among Exercise coping skills, stress, and the development in new brain lesions (measured by MRI) was e~amined."~ This study In the past MS patients were often advised not to exerreports that greater use of distraction was found to be a cise because increased body temperature and nerve fiber significant moderator of the relationship between stress fatigue resulting from exercise was thought to induce and new lesions. Emotional preoccupation was margintransient symptomatic worsening and provide no longally associated with an increased relationship between term benefit. However, research has since shown that regular exercise is beneficial for people with MS.'og114 stress and new lesions. The authors of this report concluded that these findings provide modest support for Four studies reported that compared with an MS nonexthe hypothesis that coping can moderate the relationship ercise group, the MS exercise group demonstrated an between stress and MS disease activity. improvement in the subjects' reports of fatigue, quality of life, and ~ell-being.'~,"~,"~,''~ Two reported pilot One open-label, nonrandomized study in patients with chronic disabilities (chronic pain, chronic obstrucstudies evaluated the use of Tai Chi in people with MS.11'J12To evaluate the effects of training in the princitive pulmonary disease, and MS) reported that after completing eight 2-hour stress management training ples of "mindfulness of movement" from Tai Chi/@ Gong in MS, 16 secondary progressive MS patients were programs, subjects reported a significant decrease in divided into 8 matched pairs. Each pair was randomized anxiety and somatization."8 The results suggest that into a "mindfulness" group or a "usual care" group subjects were less preoccupied with physical symptoms after undergoing stress management training. (standard medical care for MS). Although there was no A number of approaches for stress management exist difference between groups in measures of balance, there was a sigruflcant improvement in the "mindfulness" including exercise, yoga, Tai Chi, prayer, meditation, and massage therapy. Many studies have demonstrated group in self-reported measures of MS-related symptoms.'" In a nonrandomized, uncontrolled pilot study, the ability of meditation to lower stress and improve 19 people with MS underwent Tai Chi training twice symptoms in patients with chronic illnesses such as rheumatic disease,'l9 irritable bowel syndrome,'20 and weekly for 8 weeks. Outcomes measures compared pretraining to posttraining scores. Posttraining outcomes cancer.121*122 In addition to the psychologic benefits of demonstrated an improvement in walking speed, hammeditation, experienced meditators have been reported to have enhanced biochemical and physiologic functioning string flexibility, and subjects' reports of well-being and when compared with noruneditators.lB-lz quality of life.'I2 Yoga is another commonly used form of Given the emerging evidence that antecedent stresexercise among people with MS, but thus far there have been no published reports on the benefits of yoga in MS. sors may contribute to the development of new lesions In summary, evidence indicates that regular exercise in MS and that specific coping mechanisms may reduce the risk of developing new lesions, therapies that reduce is beneficial in MS and should be part of any natural stress are highly recommended in MS. medicine approach to treating MS.

Stress and Multiple Sclerosis

Food Allergy

MS patients often report that stress worsens their MS symptoms and consequently triggers an exacerbation. In a review of the scientific literature reporting associations between psychologic stress and worsening of MS symptoms, an expert panel concluded that there was a possible relationship between antecedent stress and either MS onset or exacerbation^."^ A prospective longitudinal study of Ms patients designed to examine the relationship between stressful life events, psychologic

Clinical evidence for the efficacy of a gluten-free diet is minimal. A clinical trial of a gluten-free diet in 40 patients with MS indicated that the relapse rate was no better than average.lZ6Another study demonstrated the absence of gluten antibodies in 35 of 36 MS patient~.'~'Although there is no convincing evidence that gluten-free or allergy elimination diets are beneficial in the management of MS, it certainly is generally healthful to eliminate food allergens, as long as other

Multiple Sclerosis dietary measures are also included (e.g., low-fat diet, the Swank diet).

Malabsorption Some evidence indicates that MS patients may have some degree of m a l a b s ~ r p t i o n . ' ~InJ ~one ~ study 42% of MS patients were shown to have fat malabsorption, 42% were shown to have high levels of undigested meat fibers in their feces, 27% had an abnormal D-xylose absorption, and 12% had malabsorption of vitamin Bl2.lZ8Malabsorption appears to be a factor to consider in assessing MS patients because multiple subclinical deficiencies may result from the inability to absorb the proper nutrients.

Hyperbaric Oxygen

be beneficial for MS in randomized, controlled trials, it should help the general health of patients and may provide specific benefit to help control the disease and improve symptoms. This approach also can be used in conjunction with allopathic therapies that have been proven in controlled trials to be beneficial for MS.

Diet Swank's dietary protocol is recommended: An unsaturated fat intake of a minimum of 20 g/day

and maximum of 50 g/day No red meat consumption for the first year (this includes dark meat of turkey and chicken); following the first year, only 3 oz of red meat weekly White meat poultry, fish, and shellfish are permissible in any amounts as long as they contain low saturated fats Elimination of dairy products containing 1%butterfat or more One multivitamin and mineral is recommended

Early reports described promising results from the use of hyperbaric oxygen (HBO) in the treatment of MS. However, these reports were largely anecdotal or from uncontrolled clinical trials. Subsequently, the National MS Society commissioned further trials to be performed The Swank diet recommends supplementation with one to four capsules of nonconcentrated cod-liver oil, or on a larger number of subjects, with longer periods of f o l l ~ w - u p The . ~ ~ results ~ ~ ~ ~ showed ~ no significant patients can use fish oil concentrate for cod-liver oil at 3 to 4 capsules/day. Fresh whole foods should be improvement, apart from a subjective improvement in emphasized, and animal foods (with the exception of bowel and bladder functions in one of the studies. cold-water fish) should be reduced, if not completely The results from these larger, well-designed studies eliminated. cast substantial doubt on the efficacy of HBO treatment of MS. Two published reports reviewed the data Nutritional Supplements from a majority of controlled trials of HBO treatment for MS.'32J33 Fish oil concentrate containing 1.8 g/day EPA and 1 g/day DHA Kleijnen and K n i p s ~ h i l d 'reviewed ~~ the results of Selenium: 200 pg/day 14 controlled trials, 8 of which were considered to be of Vitamin E: 800 IU/day reasonably high quality. Only one of these eight showed G. biloba extract (24% &go flavonol glycosides and favorable results. In most of the trials reviewed in this 6% terpene lactones): 40 to 80 mg tid is recommended report, hyperbaric oxygen was supplied at pressures for patients with cognitive impairment of 1.75 to 2 ATA during 20 sessions of 90 minutes over a period of 4 weeks. Side effects were generally minor Exercise but included ear and visual problems. A more recent The type and amount of exercise should be tailored review of randomized, controlled trials of HBO treatto the patient. Mild to moderate exercise for at least ment concluded that there is little evidence for the 30 minutes, three times per week is recommended. efficacy of HBO therapy in MS, which is in agreement Types of exercises recommended for MS include: with the conclusion made by Kleijnen and Knip~child.'~~ walking, stretching, bicycling, low-impact aerobics, Given the expense of HBO and the lack of evidence of stationary bicycling, swimming or water aerobics, yoga, efficacy in MS, HBO should not be recommended for the and Tai Chi. treatment of MS.

THERAPEUTIC APPROACH Treatment of MS with diet, nutritional supplementation, exercise, and stress reduction should be the basis for the natural medicine approach to MS. Although this approach (combined therapies) has not been proven to

Stress Reduction As with exercise, the therapy used to reduce stress should be tailored to the patient. Exercise can be used as a stress reduction therapy. Stress reduction therapies recommended for MS include exercise, meditation, deep breathing or breathing exercises, and prayer.

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Specific Health Problems 86. Meagher EA, Barry OP, Lawson JA, et al. Effects of vitamin E on lipid peroxidation in healthy persons. JAMA 2001;2851178-1182. 87. Keith ME, Jeejeebhoy KN, Langer A, et al. A controlled clinical trial of vitamin E supplementation in patients with congestive heart failure. Am J Clin Nutr 2001;73:219-224. 88. Reilly M, Delanty N, Lawson JA, FitzGerald GA. Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation 19969419-25. 89. Huang HY,Appel LJ, Croft KD, et al. Effects of vitamin C and vitamin E on in vivo lipid peroxidation: results of a randomized controlled trial. Am J Clin Nutr 2002;76:549-555. 90. Marangon K, Devaraj S, Tirosh 0, et al. Comparison of the effect of alpha-lipoic acid and alpha-tocopherol supplementation on measures of oxidative stress. Free Radic Biol Med 1999;271114 1121. 91. Kaikkonen J, Porkkala-Sarataho E, Morrow JD, et al. Supplementation with vitamin E but not with vitamin C lowers lipid peroxidation in vivo in mildly hypercholesterolemic men. Free Radic Res 2001;35:967-978. 92. Packer L, Roy S, Sen CK. Alpha-lipoic acid: a metabolic antioxidant and potential redox modulator of transcription. Adv Pharmacoll99~38:79-101. 93. Moini H, Packer L, Saris NE. Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid. Toxicol Appl Pharmacol 2002;18284-90. 94. Hagen TM, Liu J, Lykkesfeldt J, et al. Feeding acetyl-L-camitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A 2002,%:1870-1875. 95.Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol1997;29315-331. 96. Marracci GH, Jones RE, McKeon GP, Bourdette DN. Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J Neu-

roimmunol2002;131:104-114. 97. Sandyk R, Awerbuch GI. Vitamin B12 and its relationship to age of onset of multiple sclerosis. Int J Neurosci 1993;71:93-99. 98. Reynolds EH, Bottiglieri T, Laundy M, et al. Vitamin B12 metabolism in multiple sclerosis. Arch Neurol 1992;49:649-652. 99. Goodkin DE, Jacobsen DW, Galvez N, et al. Serum cobalamin deficiency is uncommon in multiple sclerosis. Arch Neurol 1994;51: 1110-1114. 100. Kira J, Tobimatsu S, Goto I. Vitamin 812 metabolism and massivedose methyl vitamin B12 therapy in Japanese patients with multiple sclerosis. Intem Med 1994;3382-86. 101. Wade DT, Young CA, Chaudhuri KR, Davidson DL. A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the “Can Loder regime”) in the treatment of multiple sclerosis.J Neurol Neurosurg Psychiatry 2002;73:246-249. 102. Bazan NG. The neuromessenger platelet-activating factor in plasticity and neurodegeneration. Prog Brain Res 1998;118:281-291. 103. Callea L, Arese M, Orlandini A, et al. Platelet activating factor is elevated in cerebral spinal fluid and plasma of patients with relapsing-remitting multiple sclerosis. J Neuroimmunol 1999;94 212-221. 104. Howat DW, Chand N, Braquet P, Willoughby DA. An investigation into the possible involvement of platelet activating factor in experimental allergic encephalomyelitis in rats. Agents Actions 1989;27473-476. 105. Brochet 8, Guinot P, Orgogozo JM, et al. Double blind placebo controlled multicentre study of ginkgolide B in treatment of acute exacerbations of multiple sclerosis.The Ginkgolide Study Group in multiple sclerosis. J Neurol Neurosurg Psychiatry 1995;58:36&362. 106. Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 1998;55:1409-1415.

107. Kenney C, Norman M, Jacobson M, et al. A double-blind, placebocontrolled, modified crossover pilot study of the effects of @go biloba on cognitive and functional abilities in multiple sclerosis. Neurology 2002;58(suppl3):A45&459. 108. Petajan JH, White AT. Recommendations for physical activity in patients with multiple sclerosis. Sports Med 1999;27179-191. 109. Sutherland G, Andersen MB. Exercise and multiple sclerosis: physiological, psychological, and quality of life issues. J Sports Med Phys Fitness 2001;41:421-432. 110. Mostert S, Kesselring J. Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis. Mult Scler 2002;8161-168. 111. Mills N, Allen J. Mindfulness of movement as a coping strategy in multiple sclerosis.A pilot study. Gen Hosp Psychiatry 2000;22425431. 112. Husted C, Pham L, Hekking A, Niederman R. Improving quality of life for people with chronic conditions: the example of t’ai chi and multiple sclerosis. Altem Ther Health Med 1999;5:70-74. 113. Di Fabio RP,Soderberg J, Choi T, et al. Extended outpatient rehabilitation: its influence on symptom frequency, fatigue, and functional status for persons with progressive multiple sclerosis. Arch Phys Med Rehabil1998;79:141-146. 114. Gehlsen GM, Grigsby SA, Wmant DM. Effects of an aquatic fitness program on the muscular strength and endurance of patients with multiple sclerosis. Phys Ther 1984;64:653-657. 115. Goodin DS,Ebers GC, Johnson KP, et al. The relationship of MS to physical trauma and psychological stress: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1999;521737-1745. 116. Mohr DC,Goodkin DE, Bacchetti P, et al. Psychological stress and the subsequent appearance of new brain MRI lesions in MS. Neurology 2OOO;55:55-61. 117. Mohr DC,Goodkin DE, Nelson S, Cox D, Weiner M. Moderating effects of coping on the relationship between stress and the development of new brain lesions in multiple sclerosis.Psychosom Med 2002;64:803-809. 118. Mandel AR, Keller SM. Stress management in rehabilitation. Arch Phys Med Rehabil1986;67375-379. 119. Yocum DE, Castro WL, Comett M. Exercise, education, and behavioral modification as alternative therapy for pain and stress in rheumatic disease. Rheum Dis Clin North Am 2OOO;26:145-159, x-xi. 120. Keefer L, Blanchard EB. The effects of relaxation response meditation on the symptoms of irritable bowel syndrome: results of a controlled treatment study. Behav Res Ther 2001;39:801-811. 121. Carlson LE, Ursuliak Z, Goodey E, et al. The effects of a mindfulness meditation-based stress reduction program on mood and symptoms of stress in cancer outpatients: 6-month follow-up. Support Care Cancer 2001;9:112-123. 122. Speca M, Carlson LE, Goodey E, Angen M. A randomized, waitlist controlled clinical trial: the effect of a mindfulness meditationbased stress reduction program on mood and symptoms of stress in cancer outpatients. Psychosom Med 2000;62:613-622. 123. Walton KG, Pugh ND, Gelderloos P, Macrae P. Stress reduction and preventing hypertension: preliminary support for a psychoneuroendocrine mechanism. J Altem Complement Med 1995;1:263-283. 124. MacLean CR, Walton KG, Wenneberg SR, et al. Effects of the transcendental meditation program on adaptive mechanisms: changes in hormone levels and responses to stress after 4 months of practice. Psychoneuroendocrinology1997;22:277-295. 125. Infante JR, Peran F, Martinez M, et al. ACTH and beta-endorphin in transcendental meditation. Physiol Behav 1998;64:311-315. 126. Liversedge LA. Treatment and management of multiple sclerosis. Br Med Bull 1977;3378-83. 127. Hunter AL, Rees BW, Jones LT. Gluten antibodies in patients with multiple sclerosis. Hum Nutr Appl Nutr 1984;38:142-143.

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Nausea and Vomiting of Pregnancy Lori Kimata, ND Morgan Martin, ND CHAPTER C O N T E N T S Introduction 1941 General Considerations 1941 Diagnostic and Etiologic Summary

1941

Therapeutic Considerations 1941 Psychologic, Emotional, and Lifestyle Aspects 1941 Nutrition and Nutrients 1942 Botanical Medicines 1942 Other Therapies 1943

Therapeutic Approach 1943 Psychologic, Emotional, and Lifestyle Support 1943 Diet 1944 Nutritional Supplementation 1944 Botanical Medicine 1944 Chinese Medicine 1944 Homeopathy 1944 Conclusion 1944

INTRODUCTION

DIAGNOSTIC AND ETIOLOGIC SUMMARY

The best support we can give a pregnant mother is simply to listen to her and love her. She is undoubtedly going through physiologic and emotional changes, which require compassion and sensitivity on many different levels. She may need to find new forms of support, nourish herself in different ways, or make fresh lifestyle changes to balance her pregnancy. Although natural pregnancy support includes everything from preconception and pregnancy to postpartum care, this chapter focuses primarily on one of the most common complaints of pregnancy-nausea and vomiting. We use the exploration of this condition as an example of the wide range of support available for pregnant women.

This chapter refers to nausea and vomiting that occurs during pregnancy. Like so many other health conditions facing us today, the etiology of NVP is still largely a mystery. Many have hypothesized hormonal or digestive changes, blood and qi imbalances, altered thyroid function, emotional blocks, improper nutrition, stress, or lifestyle habits,’P4-l0and probably all of these play a part at one time or another. The bottom line is that there is not one cause that applies to everyone, and to best support a pregnant woman experiencing NVP,we must look at the individual rather than the condition. The origin of nausea and vomiting might be a physiologic or metabolic change such as reduced gastric motility, oxidative stress, or carbohydrate/vitamin B deficiency.4fS On the other hand, symptoms might be primarily due to environment,emotional, family, relationship, job, or financial stress. Usually, women are confronted with a combination of stressors that contribute to their discomfort.

GENERAL CONSIDERATIONS Nausea and vomiting of pregnancy (NVP), also known as ”morning sickness,” occurs at a much higher rate than previously estimated. In recent studies,’” nausea and vomiting affects approximately 75% of pregnancies, and although higher incidence of NVP are reported in the first trimester, only 50% of cases resolve by week 14, while 90% resolve by week 22. In addition, as many as 80% of women reported their nausea lasted all day. Hyperemesis gravidarum is a severe form of NVP characterized by severe vomiting, weight loss, and dehydration. It is important to keep in mind that this can become a serious, life-threatening condition that may require inpatient care.

THERAPEUTIC CONSIDERATIONS Psychologic, Emotional, and Lifestyle Aspects Generally, researchers agree that both physiologic and psychologic factors contribute to NVP. It is therefore important for the clinician to address psychologic, emotional, or lifestyle contributors. Discuss whether a pregnancy is planned or whether there is anger, fear, 1941

ambivalence, doubt, resentment, disgust, denial, or unresolved conflict involved.6 In addition, because numerous studies have linked stress to illness in general, it is likely that stress exacerbates NVP as well. Asking questions about family, relationship, job and finances, or stressors such as environmental toxicity exposure might prove extremely valuable when working with a woman presenting with NVP.

Nutrition and Nutrients In general, both a balanced diet that supplies a person with all the basic nutrients and a highly functioning digestive system that can absorb these nutrients are crucial to health. These aspects are especially important in pregnancy, when extra nutrients are necessary to maintain the health of the mother and newly developing baby. Eating small, regular meals prevents the stomach from getting completely empty and the blood sugar from dropping, two things associated with nausea and vomiting."J2 Drinking plenty of fluids prevents dehydration, another known contributing factor. Hyperemesis, postpartum depression, and lactation failure have all been linked to deficiencies of zinc, magnesium, vitamin B6, and essential fatty acids (EFAs).Usually a prenatal multivitamin is necessary to supplement even a balanced healthy diet. One study examining multivitamin use and the development of birth defects found incidentally that multivitamins decreased nausea and vomiting more than a placebo. The multivitamin contained less than 3 mg of vitamin B6, which suggests that the benefit of the multivitamin was likely due to the combination of nutrients rather than simply the Be2

Clinical Trials Unit, Department of Obstetrics and Gynecology at the University of Adelaide in Australia, who is examining ginger compared with B6 in ongoing studies.

Vitamins K and C Vitamins K and C, when used together, have shown considerable clinical efficacy, with 91%of patients in one study showing complete remission of nausea and vomiting within 72 hours.I7 Both vitamins alone show little effect.

Botanical Medicines Zingiber oficinale

Traditionally,ginger has been used as a common remedy and an effective antiemetic. It has been reported to decrease nausea and vomiting associated with surgery and anesthesia, chemotherapy, seasickness, and NVP.18 A 1990 study involved 27 first-trimester pregnant women with hyperemesis, the most severe form of pregnancy related nausea and vomiting. In a double-blind, randomized, cross-over trial, ginger root powder at a dose of 250 mg four times a day as compared with 250 mg of lactose four times a day brought about a significant reduction of symptom^.'^ A review of randomized, controlled trials that came out in 2000 suggested that ginger is definitely more effective than placebo and as effective as metoclopramide to control vomiting.ls In 2001 researchers found this same effect in 70 pregnant women with nausea and vomiting before 17 weeks' gestation, over 4 days, in a double-masked design study and found similar results.2O In 2002 a study with 26 women, 14 in the study group and 12 in the placebo, found a marked improvement Pyridoxine, Vitamin B6 (10 of the 13 subjects, 77%, who received ginger had The beneficial effects of vitamin B6 have been studied as at least a 4-point improvement on the nausea scale by early as 1942 and 1944 when Willis and his colleagues day 9, whereas only 2 of 10,20%, in the placebo group and Weinstein and his colleagues gave vitamin B6 to had the same improvement). pregnant women and found an improvement or relief In addition, no woman in the ginger group and 7 (70%) of their nausea and ~omiting.'~ Although these earlier of the women in the placebo group had a 2-point or less studies were largely uncontrolled, more recent, doubleimprovement on the nausea scale. Eight of the 12 (67Y0) blind, randomized studies have reported positive women in the ginger group stopped vomiting by day 6, effects." One example is a double-blind study done in and only 2 of 10 (20%)in the placebo group had stopped 1991, where 59 women were randomly assigned to receive by day 6.21Of all the herbal remedies, the only one that either 25 mg of vitamin B6 every 8 hours or a placebo. has undergone successful clinical or scientific investigaAfter 72 hours, only 8 of the 31 B6-treated women had tion with regard to nausea and vomiting in pregnancy nausea compared with 15 of 28 in the placebo g r 0 ~ p . I ~ is ginger.1'*22,z In a more recent double-blind study, 342 women Rubus idaeus received either 30 mg of vitamin B6 or placebo and were followed for 5 consecutive days of treatment. Compared Rubcis idueus (raspberry leaf) has a long history of use with the control group, there was a statistically signififor various complaints. It is used as a general support cant reduction in nausea scores and vomiting episodes.I6 for pregnant women in China, Europe, and North A m e r i ~ a .The ~ ~ ,herb ~ ~ contains vitamins A, B complex, Because the results were not that impressive, researchers are interested in studies comparing or combining B6, C, and E, as well as calcium, iron, phosphorus, potasginger, and acupressure. An example is Smith of the sium, and many other n ~ t r i e n t sAlso . ~ contributing to

Nausea and Vomiting of Pregnancy

its mechanism of action is raspberry leaf’s high level of tannins, which lead to its astringent properties and use as a uterine tonic.28The herb is not implicated in any childbirth complications, and no evidence of long-term toxic or teratogenic effects have been f ~ u n d ? ~ , ~ Generally, herbs that stimulate liver function and improve gastrointestinal tone are helpful in nausea and vomiting, as well as carminative herbs, which have a calming or soothing effect. Mentha piperita (peppermint) in tea form has also been used; clinical anecdotes and personal communication abound. Documented research in this area is inadequate. Some concern exists over the safety of botanical medicines for pregnancy in general.30J1More research is necessary to verify or dissolve these concerns. Currently, there is no documented research to prove that any of the herbs mentioned earlier have caused detrimental side effects to pregnant women or their fetuses.29

adjustable Acuband wristband that puts pressure on the P6 point relieves the symptoms of motion sickness and reduces gastric tachyarrhythmia, the abnormal electrical activity of the stomach that is a reliable physiologic marker for motion sickness.%In studies that did not show success of this acupressure point, nonadjustable wristbands (Seabands) were used, and it is postulated that not enough pressure was applied to the specific P6 p0int.3~ In a 2002 published study of a randomized, placebocontrolled, cross-over study of 23 women using a product called the ReliefBand, which provides electrical stimulation to P6 and is also adjustable, 87% of the pregnant women experienced improvement of their nausea and vomiting versus 43% with the placebo device.37Another study on the Rehemand, with 26 subjects, had similar findings.=

Other Therapies Acupressure/Acupuncture

The practice of homeopathy has been a longstanding, widely accepted, successful tradition in many parts of Europe and the United States for centuries. Clinical trials and clinical anecdotes are manifold, yet double-blind placebo research studies are currently unavailable. Instead, as references, there are excellent textbooks on homeopathy covering NVP. Homeopathy for Pregnancy, Birth, and Your Baby‘s First Year by Miranda Castro and the Desktop Companion by Roger MorrisongJoare examples. Experienced practitioners can prescribe specific remedies for different pregnant women with the same apparent condition. Homeopathic treatment is specific to each woman.

Acupressure, acupuncture, and Chinese herbal formulas have been widely used for nausea and vomiting in pregnancy in China and elsewhere for centuries. Giovanni Maciocia’s book Obstetrics and Gynecology in Chinese Medicine, published in 1998, details differing pathologies that contribute to NVP.Maciocia outlines specific treatment principles depending on which pathology is at play8 Most research has been done on one specific point, Pericardium 6 (P6), also called the Neiguan point, and its efficacy in relieving nausea and vomiting. In 1989 a prospective, controlled 10-day clinical trial examined the efficacy of acupressure therapy for morning sickness using a two-group, random-assignment, cross-over design. Acupressure wristbands were used, and the study revealed that morning sickness was relieved for 12 of 16 subjects. Acupressure therapy also resulted in statistically sigruficant reductions in anxiety, depression, behavioral dysfunction, and nausea.32 Similar results were found in a larger group of pregnant women with nausea in a 1988 study.33 In addition, studies have been conducted to see whether acupressure at P6 helps nausea and vomiting of motion sickness and postsurgical recovery. A study in 1999 found acupressure at P6 sigruficantly reduced nausea and vomiting following laparoscopic surgery.34 Another 1999 study with outpatient gynecologic surgery found acupressure at P6 and a placebo point both decreased nausea; however, only pressure at P6 decreased both nausea and A more recent 2001 study with 25 healthy subjects set out to determine whether a device called an Acuband, a commercially available acupressure wristband, would relieve symptoms of motion sickness. Results concluded that an

Homeopathy

THERAPEUTIC APPROACH Practitioners can make the following suggestions to pregnant women suffering from Nvp:

Psychologic, Emotional, and Lifestyle Support Guidance to provide the pregnant woman includes the following: Create a strong support system for this pregnancypeople and activities you can rely on to keep you balanced and healthy. Discuss any of your unresolved conflicts about this pregnancy with a counselor who is trained in this type of work. Balance stress with stress-management techniques such as meditation, and be sure to get enough quality sleep, as well as enough relaxation and play time. Engage in an appropriate exercise or stretching practice that includes deep breathing and enhances circulation. Avoid or minimize contact with chemicals and cigarette smoke.

Specific Health Problems Stay well hydrated with cool water, electrolyte drinks without refined sugars, diluted juices, teas, and broths. Apply cool cloths to the face and spend time in fresh air (outdoors or in rooms with good natural ventilation. Avoid recirculated air or stuffy enclosed rooms.)

Diet In general, pregnant women should eat an abundance of fresh vegetables, especially green leafy vegetables, along with balanced proteins, complex carbohydrates, and fiber. Food-combining techniques such as not combining protein and starch or starchy vegetables in the same meal may be of value. Small, frequent meals eaten slowly are helpful and also maintain blood sugar levels. Food should be thoroughly chewed and eaten at a leisurely pace. The main meal should be in the middle of the day. Liquids should be avoided with meals. Eating small amounts of complex carbohydrates such as a biscuit or dry toast, especially after waking up, while still lying down, helps settle the stomach. The woman should sit up slowly and have a drink of lemon or ginger and honey in water, herbal tea, or a tablespoon of apple cider vinegar in a cup of warm water with or without a tabIespoon of honey. Keeping a small, easily digested snack in the bathroom can keep blood sugar normal and the stomach from getting empty in the middle of the night. Idenhfy and avoid odors or spices that might trigger nausea. Reducing intake of saturated fats or foods high in fat and eating more protein or adjusting diet according to blood type can also be helpf1.11.~~

Vitamin K: 5 mg daily Extra calcium supplementation, especially if calf cramps occur EFAs: 1 to 2 Tbls or 2 to 4 capsules daily

Botanical Medicine *Pregnant women should avoid almost all botanical medicines in the first trimester except for the following: Ginger: 1 to 2 g as a dry powder, decoction, extract, or natural ginger ale Raspberry leaf, mint, or chamomile tea: 1 to 3 cups daily Ginger, raspberry leaf, mint, and other safe botanicals can be used throughout pregnancy when indicated.

Chinese Medicine Acupuncture and Chinese herbs: The pregnant woman or physician should refer to an acupuncturist for specific points or botanical formulas, or both. Acupressure therapy: P6

Homeopathy Refer to a practitioner trained in homeopathy for a specific remedy.

CONCLUSION

Vitamin B6: 25 mg two to three times/day *Vitamin C: 250 mg to 1000 mg two to three times/ day

Pregnancy is a powerful and transformative time for women. It is a time of tender balance, vulnerability, and important growth. More study is necessary in documenting much of what folklore and tradition have proven efficacious over time. Until then, it seems best to inform women as completely as possible regarding the research that is available, along with the risks and benefits of different treatments. Then, most importantly, we need to approach each woman as a unique, wise individual and support her in a holistic, loving way.

1. Winbery SL, Blah0 KE. Dyspepsia in pregnancy. Obstet Gynecol Clin North Am 2001;28:333-350. 2. Emelianova S, Mazzotta P, Einarson A, et al. Prevalence and severity of nausea and vomiting of pregnancy and effect of vitamin supplementation.Chn Invest Med 1999;22:106-110. 3.Erick M. Morning sickness impact study. Midwifery Today Int Midwife 2001;59:30-32. 4. Lacroix R, Eason E, Melzack R. Nausea and vomiting during pregnancy:A prospective study of its frequency, intensity, and patterns of change. Am J Obstet Gynecol 2O00;182:931-937. 5. Fait V, Sela S, Ophir E, et al. Hyperemesis Gravidarum is associated with oxidative stress. Am J Perinatol2002;19:93-98.

6. Fitzgerald CM. Nausea and vomiting in pregnancy. Br J Med Psycho1 1984;57159-165. 7. Weed SS. Wise woman herbal for the childbearing - year. . New York Ash Tree Pub, 1986. 8. Maciocia G. Obstetrics and gynecology in Chinese medicine. San Francisco: Churchill Livingston, 1998. 9.Castro M. Homeopathy for pregnancy, birth and your baby's first year. New York: St. Martin's Press, 199290,95,297-298. 10. Morrison R. Desktop companion to physical pathology. Nevada City, CA: Hahnemann Clinic Publishing, 1998:205-215. 11. Niebyl JR. Drug therapy during pregnancy. Cum Opin Obstet Gynecol 1992;443-47.

Nutritional Supplementation Pregnant women should ingest whole foods that are easy to digest, prenatal vitamins, and the following additions depending on individual needs:

Nausea and Vomiting of Pregnancy 12.Niebyl JR, Goodwin TM. Overview of nausea and vomiting of pregnancy with an emphasis on vitamins and ginger. Am J Obstet Gynecol2002;186(5 suppl):S253-255. 13. Weinstein B, Wohl Z, Mitchell G, et al. Oral administration of pyridoxine hydrochloride in the treatment of nausea and vomiting of pregnancy. Am J Obstet Gynecol 1944;47389-394. 14.Carl Pfeiffer’s MD, PhD work, Alan Gaby MD review of the literature published in 86, the Natural Healer in 1987. 15.Sahakian V, Rouse D, Sipes S, et al. Vitamin B6 is effective for nausea and vomiting of pregnancy. A randomized, double-blind placebo-controlled study. Obstet Gynecol1991;7833-36. 16. Vutyavanich T, Wongtra-ngan S, Ruangsri R. Pyridoxine for nausea and vomiting of pregnancy: a randomized, double-blind, placebocontrolled trial. Am J Obstet Gynecol 1995;173881-884. 17. Merkel R. The use of menadione bisulfite and ascorbic acid in the treatment of nausea and vomiting of pregnancy; a preliminary report. Am J Obstet Gynecol 1952;64:416-418. 18. Ernst E, Pittler h4H. Efficacy of ginger for nausea and vomiting: a systematic review of randomized clinical trials. Br J Anaesth 2000;84:367-371. 19. Fischer-Rasmussen W, Kjaer SK, Dahl C, et al. Ginger treatment of hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 1991;38:19-24. 20.Vutyavanich T, Kraisarin T, Ruangsri R. Ginger for nausea and vomiting in pregnancy: randomized, double-masked, placebocontrolled trial. Obstet Gynecol2001;97577-582. 21. Keating A, Chez RA. Ginger syrup as an antiemetic in early pregnancy. Altem Ther Health Med 2002;8:89-90. 22. Fulder S, Tenne M. Ginger as an anti-nausea remedy in pregnancy: the issue of safety. Herbal Gram 1996;38:47-50. 23.Meyer K, Schwartz J, Crater D. Zingiber oflcinnle (ginger) used to prevent 8-Mop associated nausea. Dermatol Nurs 1995;7: 242-244. 24. Aikins Murphy P. Alternative therapies for nausea and vomiting of pregnancy. Obstet Gynecol 1998;91:149-155.

25. Jewel1D, Young G. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev 2000;2:CW00145. 26. Lieberman L. Remedies . . . to file for futurr reference. Birthkit 1995;5:1-8. 27. Duke JA. The Green Pharmacy. Emmaus, PA: Rodale, 1997. 28. Bartram T. Bartram’s Encyclopedia of Herbal Medicine, London, LJK: Robinson, 1998. 29. Westfall R. Herbal medicine in pregnancy and childbirth. Adv Ther 2001;18:47-55. 30. Stapleton H. The use of herbal medicine in pregnancy and labour. Part I: An overview of current practice. Complement Ther Nurs Midwifery 1995;1:148-153. 31. Hardy ML. Herbs of special interest to women. J Am Pharm Assoc (Wash) 2000;40:234-242. 32. Hyde E. Acupressure therapy for morning sickness. A controlled clinical trial. J Nurse Midwifery 1989;34:171-178. 33. Dundee JW, Sourial FB, Ghaly RG, et al. P6 acupressure reduces morning sickness. J R Soc Med 1988;81:456-457. 34.Harmon D, Gardiner J, Harrison R, et al. Acupressure and the prevention of nausea and vomiting after laparoscopy. Br J Anaesth 1999;82387-390. 35. Alkaissi A, Stalnert M, Kalman S. Effect and placebo effect of acupressure (P6) on nausea and vomiting after outpatient gynaecological surgery. Acta Anaesthesiol Scand 1999;43:270-274. 36. Stem RM, Jokerst MD, Muth ER. Acupressure relieves the symptoms of motion sickness and reduces abnormal gastric activity. Altem Ther Health Med 2001;791-94. 37. Evans AT, Samuels SN, Marshall C, et al. Suppression of pregnancy-induced nausea and vomiting with sensory afferent stimulation. J Reprod Med 1993;38:603-606. 38. Slotnick RN. Safe, successful nausea suppression in early pregnancy with P-6 acustimulation. J Reprod Med 2001; 46:811-814. 39. DAdamo P. Eat right 4 your type, the individualized diet solution to staying healthy longer and achieving your ideal weight. New York GP Putnam’s Sons, 1996.

Obesity Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

1947

General Considerations 1947 Prevalence

1948

Determination of Body Composition 1948 Visual Observation 1948 Skinfold Thickness 1949 Body Density 1949 Bioelectric Impedance 1949

Therapeutic Considerations 1953 Behavioral Therapy 1954 Dietary Strategies 1954 Natural Weight Loss Aids 1955 Medium-Chain Triglycerides 1958 Hydroxycitrate 1958 Therapeutic Approach 1958 Diet 1958 Psychologic Support 1559 Lifestyle 1559 Supplements 1559 Botanical Medicine 1559

Types of Obesity 1950 Causes of Obesity 1950 Psychologic Factors 1950 Physiologic Factors 1950

DIAGNOSTIC SUMMARY

well to a person's total body fat. The BMI is calculated as follows:

Obesity is defined as the following: Having a body mass index greater than 30 Having a body fat percentage greater than 30% for women and 25% for men

GENERAL CONSIDERATIONS Obesity is now regarded as the major contributor to mortality in the United States.' The simplest definition of obesity is an excessive amount of body fat. It must be distinguished from overweight, which refers to an excess of body weight relative to height. A muscular athlete may be overweight yet have a low body fat percentage. With this in mind, it is obvious that using body weight alone as an index of obesity is not entirely accurate. Nonetheless, a simple measure known as the body mass index (BMI) is now the accepted standard for classifying individuals with regard to their body composition (Table 194-1). BMI generally correlates

BMI = (Ib x 703)/in2 (Ib = pounds; in = height in inches) Metric: BMI = kg/m2 (kg = kilograms; m = height in meters)

Despite promotion of the BMI as the definitive measure of adiposity within the medical community, height and weight indices are still popular measurements made in the determination of obesity. The indices in widest use are the tables of desirable weights for height provided by the Metropolitan Life Insurance Company. However, the Metropolitan tables are often criticized for three major shortcomings: The stated weight ranges merely reflect the weights of those with the lowest mortality of insured persons, which may not reflect the U.S.population. Weight ranges for lowest mortality do not necessarily reflect optimal healthy weight for height. The standard values make it difficult to assess the degree of obesity (e.g., a person within the proper

1947

Specific Health Problems

weight range may have excess body fat and lowerthan-optimal lean body mass, or an individual with increased muscular development may be “overweight” despite having a low body fat percentage). Again, it is important to recognize that weight alone is a poor reflector of body fat composition.

individuals (BMI 20 to 25).’ Most of the increased risk is due to cardiovascular causes, as obesity carries with it a tremendous risk for type I1 diabetes, elevated cholesterol levels, high blood pressure, and other risk factors for atherosclerosis. In 2002 the estimated annual medical spending due to overweight and obesity was estimated to be $92.6 billion?

PREVALENCE The prevalence of obesity has reached epidemic proportions and has steadily increased over the years among both genders, all ages, all racial/ethnic groups, and all educational levels. From 1960 to 2000, the prevalence of overweight (BMI > 25 to < 30) increased from 31.5% to 33.6%in US.adults aged 20 to 74. The prevalence of obesity (BMI >30) during this same time period more than doubled from 13.3%to 30.9%,with most of this rise occurring in the past 20 years. From 1960 to 2000, the prevalence of extreme obesity (BMI > 40)increased from 0.8%to 4.7%.Childhood and adolescent obesity has also increased dramatically. In the decade of the 1990s, the average adult in the United States gained 10 lb. Given the health challenges associated with obesity, these increases are staggering, as shown in Table 1942.24 Obese individuals have a 50% to 100%increased risk of death from all causes, compared with normal-weight

of body mass index Underweight

48.5

Normal

18.5-24.9

Overweight

24.9-29.9

Obesity

30-39.9

Extreme obesity

90

Statistical findings from NHANES 1999-2000 for adults 20+ years old Overweight (BMI > 25, including Those Who Are Obese) All adults: 64.5% Women:

61.9%

Men: Obese (BMI > 30) All adults:

67.2%

Women:

33.4%

Men:

27.5%

30.5%

Modified from Mokdad AH, Ford ES. Bowman BA, et al. JAMA 2003;289:76-79. BMI, Body mass index; NHANES, National Health and Nutrition Examination Survey.

DETERMINAT10 N 0F BODY COMPOSIT10N The significance of accurately determining body fat composition and classifymg obesity cannot be overstated, as it offers valuable monitoring, prognostic, and therapeutic information. In terms of body fat percentage, obesity is defined as a body fat percentage greater than 30% for women and 25% for men. Because direct analysis of body composition cannot at this time be performed on live subjects, indirect methods must be employed, such as those listed in Box 194-1.

Visual Observation Superficial visual observation is often all that is required for a qualitative analysis of obesity. One popular way of classifying body types is somatotyping-a physical, anthropologic classification of physique based on body size and proportion: The endomorph has a relatively large body and short arms and legs. The mesomorph has a large muscular chest that dominates over the abdomen and has prominent bony joints. The ectomorph has a relatively small frame (a slender and delicate bone structure) and long arms and legs.

Visual observation (somatotypes) Anthropometric measurements Height and weight Circumferences and diameters Skinfold thickness Isotope or chemical dilution Body water Body potassium Body fat Body density and body volume Conductivity Total body electrical conductivity Bioelectric impedance Neutron activation Imaging techniques Ultrasound Computer tomography Nuclear magnetic resonance Nuclear magnetic spectroscopy

Obesity ___

The endomorph is at greatest risk of developing obesity, the mesomorph is at moderate risk, and the ectomorph is extremely unlikely to develop obesity. The distribution of body fat is also important in the classification of obesity. Two basic distribution patterns exist: gynecoid- and android- or female- and malepatterned obesity. These types are discussed in greater detail under Types of Obesity.

Skinfold Thickness The amount of total body fat can be estimated by measuring the thickness of the subcutaneous fat (skinfold or fatfold thickness). Skinfold thickness is measured with skinfold calipers at several sites on the body to improve accuracy. The most common measurement sites are the triceps, biceps, subscapular, and suprailiac skinfolds. Although skinfold thickness measurements are easy to obtain and are generally accurate in estimating body fat percentage, their limitations include the inability to control intersubject and intrasubjectvariation in skinfold compressibility, the inability to palpate the fat-muscle interface, and the impossibility of obtaining interpretable measurements on very obese individuals. Additionally, interobserver variability, as well as the use of different types of skinfold calipers, may contribute to measurement errors. However, for most clinical purposes, skinfold measurements provide the easiest and least expensive method for estimating body fat percentage. For more precise estimations, other methods (e.g., bioelectrical impedance, ultrasound, total body electrical conductivity [TOBEC], and hydrostatic weighing) offer sigruhcant advantages.

Body Density Measurement of body density provides a quantitative technique for measuring body fat. Density is determined from the specific gravity, which is calculated through measuring the different weight of the body in and out of water, In thisprocedure, individuals are weighed under water and out of water, taking into account the residual volume of the lungs. This information is used to fractionate the body into its fat and nonfat components because fat is lighter than water and other tissues are heavier than water. The method is relatively easy if appropriate facilitiesare available. However, with the advent of more sophisticated body composition analyzers, the procedure has generally fallen out of favor, although many experts still consider it to be the “gold standard” of body composition determination. The major limitation of hydrostatic weighing is that it requires considerable subject cooperation.The test subject must exhale completely and then submerge totally under water up to 10 times, making the method impossible for use with the elderly, the ill, or hospitalized patients.

Bioelectric Impedance The bioelectrical impedance method for determining body composition is based on measuring the conduction of an applied electrical current through body tissues. In biologic structures, application of a constant low-level alternating current results in an impedance to the flow of the current that is frequency dependent, according to the type of tissue. Intracellular and extracellular fluids behave as electrical conductors, while the cell membranes act as electrical condensers. At low frequencies, such as 1 kHz, the current mainly passes through the extracellular fluids, whereas at higher frequencies, such as 500 to 800 kHz, it penetrates the intracellular and extracellular fluids. Thus body fluids and electrolytes function as electrical conductors, while cell membranes behave as capacitors. Because fat-free mass has a much greater conductivity than does fat, there is a strong relationship between conductance and lean body mass. Body composition analysis, as determined by bioelectrical impedance, is a safe, noninvasive procedure that provides rapid measurement. Home scales equipped with bioelectrical impedance units to assess body fat percentage at the same time as weight are now available. These scales typically cost between $50 and $200 (Table 194-3).

Male Age

19-24 25-29 30-34 35-39 40-44

45-49 50-54 55-59 60t Female Age

19-24 25-29 30-34 35-39 40-44

45-49 50-54 55-59 60t

Risky

Excellent

Good

Fair

Poor

<6% <6% <6% <6% <6% <6% <6% <6% <6%

10.8% 12.8% 14.5% 16.1% 17.5% 18.6% 19.8% 20.2% 20.3%

14.9% 16.5% 18% 19.4% 20.5% 21.5% 22.7% 23.2% 23.5%

19% 20.3% 21.5% 22.6% 23.6% 24.5% 25.6% 26.2% 26.7%

23.3% 24.4% 25.2% 26.1% 26.9% 27.6% 28.7% 29.3% 29.8%

Risky

Excellent

Good

Fair

Poor

<9%

18.9% 18.9% 19.7% 21% 22.6% 24.3% 26.6% 27.4% 27.6%

22.1% 22% 22.7% 24% 25.6% 27.3% 29.7% 30.7% 31%

25.0% 25.4% 26.4% 27.7% 29.3% 30.9% 33.1% 34% 34.4%

29.6% 29.8% 30.5% 31.5% 32.8% 34.1% 36.2% 37.3%

<9% <9% <9% <9% <9% <9% <9% <9%

38%

Specific Health Problems

TYPES OF OBESITY Obesity is divided into several different categories on the basis of the size and number of fat cells and also on how the fat is distributed in the body (e.g., in the abdomen vs. the hips). In hyperplastic obesity an increased number of fat cells exist throughout the body. The number of fat cells that a person has depends primarily on the diet of the mother while the person was still in the womb, as well as early infant nutrition. An excess of calories during these early stages of development can lead to the formation of an increased number of fat cells for the rest of the baby's life. Because it is harder to develop new fat cells in adulthood, hyperplastic obesity usually begins in childhood. Fortunately, hyperplastic obesity tends to be associated with fewer serious health effects compared with other types of obesity. Hypertrophic obesity is characterized by an increase in the size of each fat cell and is linked to diabetes, heart disease, high blood pressure, and other serious disturbances of metab~lism.~ Usually with hypertrophic obesity, the fat distribution is around the waist. This fat cell distribution is referred to as male-patterned or android because it is typically seen in the obese male. Lf the waist is larger than the hips, a person is said to have android obesity. If the hips are larger, then a person has femalepatterned or gynecoid obesity. The waist-to-hip ratio is determined by measuring the circumference of the waist about a '/*-inch above the navel and measuring the circumference of the hips at the greatest protrusion of the buttocks. The waist circumference is divided by the hip circumference. A waist-to-hip ratio above 1 for men and above 0.8 for women is associated with the metabolic syndrome (a.k.a. syndrome X) and increases the risk of developing type I1 diabetes, high blood pressure, coronary heart disease, stroke, and gout. Finally, in hyperplastic-hypertrophic obesity, there is an increase in both the number and size of fat cells.

CAUSES OF OBESITY Although there may or may not be a specific "obesity gene," the tendency to be overweight is definitely inherited. Nonetheless, even high-risk individuals can avoid obesity, indicating that dietary and lifestyle factors (primarily little or no physical activity) are chiefly responsible for obesity. In looking at possible causes beyond diet and lifestyle, researchers have focused on both psychological factors and physiologic factors.

Psychologic Factors In the past, psychologic factors were thought largely responsible for obesity. An early popular theory proposed that overweight individuals were insensitive

to internal signals for hunger and satiety while simultaneously being extremely sensitive to external stimuli (sight, smell, and taste) that can increase the appetite. One source of external stimuli that has definitely been shown to be associated with obesity is watching television (TV). Watching TV has been demonstrated to be linked to the onset of obesity, and there is a dose-related effect. Increased TV viewing and decreased physical activity are thought to be primary causes of the growing number of obese children in the United States.6 TV viewing in childhood and adolescence is not only associated with being overweight, but also with poor fitness and the presence of obesity, smoking, and raised cholesterol levels in adulthood, indicating that excessive viewing has long-lasting adverse effects on health.7 In addition to leading to childhood obesity, TV viewing also contributes to being overweight in adults. In one study 50,277 women who had a BMI less than 30 completed questions on physical activity and sedentary behaviors at baseline. During 6 years of follow-up, 3757 (7.5%) became obese (BMI 2 30) and 1515 new cases of type I1 diabetes occurred. Time spent watching TV was positively associated with risk of obesity and type I1 diabetes. Each 2-hour-per-day increment in TV watching was associated with a 23% increase in obesity and a 14% increase in risk of diabetes. In contrast, each 2-hour-perday increment in sitting at work was associated with a 5% increase in obesity and a 7% increase in diabetes? Although watching TV fits nicely with the psychologic theory (increased sensitivity to external cues), several physiologic effects of watching television promote obesity, such as reducing physical activity and the actual lowering of resting (basal) metabolic rate to a level similar to that experienced during trancelike states. These factors clearly support the physiologic view.

Physiologic Factors Although the psychologic theories primarily propose that obese individuals have a decreased sensitivity to internal cues of hunger and satisfaction, an emerging theory of obesity states almost the opposite: Obese individuals appear to be extremely sensitive to specific internal cues! Unfortunately, these cues relate to dysfunctional appetite control due to a combination of genetic, dietary, and lifestyle factors. At the center of this dysfunction in many cases is resistance to the hormone insulin as a result of a conditioned reaction to a high glycemic diet. The development, progression, and maintenance of obesity is a vicious positive feedback cycle consisting of insulin resistance, central adiposity, alterations in adipokine secretion by adipocytes and gut-derived hormones, impaired dietinduced thermogenesis, and low brain serotonin levels. All of these factors are interrelated and support the theory that obesity is primarily an adaptive physiologic response that is out of control. Failure to address these underlying

Obesity

areas and provide proper psychologic support results in only temporary weight loss at best.

The "Set Point" Body weight is closely tied to what is referred to as the "set point"-the weight that a body tries to maintain by regulating the amount of food and calories consumed. Research with animals and humans has found that each person has a programmed "set point" weight. It has been postulated that individual fat cells control this set point: When the enlarged fat cells in obese individuals become smaller, they either send powerful messages to the brain to eat or they block the action of appetitesuppressing compounds like leptin. The existence of this set point helps to explain why most diets do not work. Although the obese individual can fight off the impulse to eat for a time, eventually the signals become too strong to ignore. The result is rebound overeating with individualsoften exceeding their previous weight. In addition, their set point is now set at a higher level, making it even more difficult to lose weight. This has been termed the "ratchet effect" and "yo-yo dieting." The key to overcoming the fat cell's set point appears to be increasing the sensitivity of the fat cells to insulin. This sensitivity apparently can be improved, and the set point lowered, by exercise, a specially designed diet, and several nutritional supplements (discussed later). The set point theory suggests that a diet that does not improve insulin sensitivity will most likely fail to provide longterm results. When fat cells, particularly those around the abdomen, become full of fat, they secrete a number of biologic products (e.g., resistin, leptin, tumor necrosis factor, free fatty acids) that dampen the effect of insulin,impair glucose utilization in skeletal muscle, and promote glucose production by the liver. Also important is that as the number and size of fat cells increase, they lead to a reduction in the secretion of compounds that promote insulin action including a novel protein produced by fat cells known as adiponectin. Adiponectin is not only associated with improved insulin sensitivity, it also has antiinflammatory activity, lowers triglycerides, and blocks the development of atherosclerosis. The net effect of all of these actions by fat cells is that they severely stress blood sugar control mechanisms, as well as lead to the development of the major complication of diabetes-atherosclerosis. Because of all of these newly discovered hormones secreted by fat cells, many experts now consider the adipose tissue a member of the endocrine system?-"

Adipokine and Gut-Derived Hormone Alterations It could be argued that obese individuals are more sensitive to internal signals to eat. Appetite reflects a complex system that has evolved to help humans deal with food

shortages.As a result, it is extremely biased toward weight

gain. It makes sense that people who survived famines were those who were more adept at storing fat than burning it. So, there is a built-in tendency to overeat even though food is readily available in developed countries. To combat the tendency to eat more than is required, it is important to accentuate the normal physiologic processes that curb the appetite. An elaborate system exists that is supposed to tell the hypothalamus when the body requires more food, as well as when enough food has been consumed. In addition, adipokines like leptin, a strong signal of appetite control, actually originate from the gastrointestinal tract. In addition to nerve signals feeding back to the central nervous system is a growing list of gut-derived hormones and peptides such as neuropeptide Y and analogs, ghrelin, and cholecystokinin.12For example, peptide YY 3-36 (or PYY for short) dramatically reduced appetite in both obese and normal-weight indi~idua1s.l~ The subjects consumed about 30% less at an "all-you-can-eat" buffet after the infused hormone compared with when they were given only saline solution. The subjects also ate significantly less over the next 24 hours. Unlike PYY, the stomach-derived hormone ghrelin increases appetite. Ghrelin levels are highest when the stomach is empty and during calorie restriction. Obese individuals tend to have elevated ghrelin levels, and when they try to lose weight, ghrelin levels increase. Part of the success of gastroplasty in producing permanent weight loss is thought to be the result of significantly reduced ghrelin levels. For example, although a dietinduced weight loss of 17% of initial body weight was associated with a 24% increase in the area under the curve (AUC) for the 24-hour ghrelin profile, despite a 36% weight loss after gastric bypass, the AUC for the ghrelin profile in the gastric-bypass group was 77% lower than in normal-weight controls and 72% lower than in matched obese control^.'^ Although using various appetite regulators as therapeutic agents in human obesity is possible, preliminary studies seem to indicate that in humans compensatory actions may negate the effect. The perfect drug or natural product to affect appetite must possess an ability to increase insulin sensitivity and produce a targeted effect of reducing factors that increase appetite while simultaneously increasing factors that decrease appetite. Highly viscous dietary fiber blends may prove useful in this application.

Gut-Derived Appetite Regulators The main hormones inhibiting food intake are cholecystokinin (CCK), glucagon-like peptide-1 (GLP-l),oxyntomodulin, and PYY, while hormonal stimulators of appetite include ghrelin and orexin A.'* It could be strongly argued that secretion of these regulators, as well

Specific Health Problems

as overall enteroendocrine cell function, is regulated by the presence or absence of highly viscous dietary fiber, especially since the main target for these neurotransmitters is vagal afferent neurons and the appetite inhibiting effects of CCK are enhanced by the mechanical effects of dietary fiber (gastric distension). Brief descriptions of these gut-derived appetite regulators follow.

stomach rumble, and it is a powerful appetite stimulator.u Not surprisingly, plasma concentrations of ghrelin are depressed in patients with anorexia nervosa and elevated in obesity. Concentrations of ghrelin decrease on feeding, especially with meals with dietary fiber. However, because this effect is mediated by insulin, resistance to insulin is associated with higher ghrelin levels.23

Cholecystokinin The role of CCK as a regulator of protein and fat digestion in the upper small intestine has been recognized for several decades. CCK determines the capacity for digestion by controlling the gastric emptying, as well as delivery of enzymes from the pancreas. The inhibition of appetite by CCK has been demonstrated in human s t u d i e ~ . ’ ~The J ~ reduction of food intake by low-dose exogenous CCK is enhanced with moderate gastric distension, implying synergistic interactions between CCK and gastric mechanoreceptor stimulation. Not surprisingly, viscous dietary fiber has been shown to increase CCK ~ecretion.’~,’~

Orexin A The peptide orexin A has been most intensively studied in the hypothalamus, but it also occurs in enteric neurons and in gut endocrine cells, particularly enterochromaffin cells. Orexin A is a stimulator of appetite and is thought to mhibit CCK-stimulated excitation of vagal afferent fibers (thereby negating the appetite suppressing effect of CCK). Plasma concentrations of orexin A increase with fasting and may contribute to people overeating during or immediately after a meal by suppressing satiety signaling by CCK.I2

Diet-Induced Thermogenesis

Another physiologic difference between obese and thin people is how much of the food consumed is converted immediately to heat. This process is known as dietinduced thermogenesis (heat production). Researchers have found that in lean individuals a meal may stimulate up to a 40% increase in diet-induced thermogenesis. In contrast, overweight individuals often display only a 10% or less increase.24In overweight individuals the food energy is stored instead of being converted to heat like it is in lean individuals. A major factor for the decreased thermogenesis in Oxyntomodulin overweight people is, once again, insulin insensitivity.2s Therefore enhancing insulin sensitivity may go a long Oxyntomodulin (OXM)is released from the gut postpranway toward reestablishing normal thermogenesis, as dially in proportion to food volume and energy content. well as resetting the set point in overweight individuals. Circulating levels of OXM are elevated in several condiResearchers have also shown that even after weight tions associated with anorexia. Injection of OXM reduces loss has been achieved, individuals predisposed to obefood intake presumably by suppressing ghrelin. Elevated sity still have decreased diet-induced thermogenesis levels of endogenous OXM associated with disorders with lean individuals.26Therefore it is imporof the gastrointestinal tract may contribute to ~ t o ~ x i a . compared ~~ tant to continue to support insulin sensitivity and proper Peptide W 3 - 3 6 metabolism indefinitely if weight loss is to be maintained. In addition to insulin insensitivity and reduced symPYY is secreted by enteroendocrine cells of the ileum and pathetic nervous system activity, another factor detercolon, while a related compound pancreatic polypeptide mines diet-induced thermogenesis-the amount of is secreted by the pancreas.Z0In obese subjects basal and brown fat. Most fat in the body is “white fat,” consisting postprandial plasma concentrations of P W are reduced of an energy reserve containing triglycerides stored in a compared with normal subjects. Administration of PYY single compartment. Tissue composed of white fat looks inhibits food intake, with effects lasting up to 24 hours white or pale yellow. Brown fat cells contain multiple fat after a 2-hour infusion, suggesting that PYY exerts sigstorage compartments. The triglycerides are localized in nificant long-term appetite suppressing action.21 Like smaller droplets surrounding numerous mitochondria. CCK, viscous dietary fiber likely raises PYY. An extensive blood vessel network and the density of Ghrelin the mitochondria give the tissue its brown appearance, Ghrelin is an interesting peptide that originates from as well as its increased capacity to metabolize fatty acids.27 X-cells in the stomach lining. This compound makes the

Glucagon-like Peptide-1 The distal intestinal peptide GLP (7-36)-1 is derived from different regions of the glucagon precursor. Infusion of GLP-1 inhibits food intake, decreases sensations of hunger, and inhibits plasma ghrelin (discussed later). The secretion of GLP-1 is clearly influenced by food intake, but the specific food components, as well as the role of dietary fiber, have not yet been determined.”

Obesity

Brown fat does not metabolize fatty acids to ATP as efficiently as other tissues of the body including white fat. This inefficiency results in increased heat production. Brown fat plays a major role in diet-induced thermogenesis. Some theories suggest that lean people have a higher ratio of brown-to-white fat than overweight individuals. Evidence supports this theory. The amount of brown fat in modern humans is extremely small (estimates are 0.5% to 5% of total body weight), but because of its profound effect on diet-induced thermogenesis, as little as 1 oz of brown fat (0.1% of body weight) could make the difference between maintaining body weight or putting on an extra 10 l b / ~ e a r . ~ ~ Lean individuals also tend to respond differently to excess calories than overweight individuals. In one experiment, lean individuals were overfed to increase their weight. In order to maintain the excess weight, they had to increase their caloric intake by 50% over their previous The opposite appears to be the case in overweight and formerly overweight individuals. In addition to requiring fewer calories to gain and maintain their weight, studies have shown that in order to maintain a reduced weight, formerly obese persons must restrict their food intake to approximately 25% less than a lean person of similar weight and body ~ i z e . 2 ~ Individuals predisposed to obesity because of decreased diet-induced thermogenesis have been shown to be extremely sensitiveto marked weight gain when consuming a high-fat diet compared with lean individuals.3O These individuals are not only more sensitive to the weight gain-promoting effects of a high-fat diet, they tend to consume much more dietary fat than lean individuals and exercise less.

brain simply puts out such a strong message to eat that it cannot be ignored. This situation sets up the scenario to explain why most diets do not work. Cravings for carbohydrates due to low serotonin levels can be mild or quite severe. They may range in severity from the desire to nibble on a piece of bread or a cookie to uncontrollable binging. At the upper end of the spectrum of carbohydrate addiction is bulimia, a potentially serious eating disorder characterized by binge eating and purging of the food through forced vomiting or the use of laxatives. The medical comequences of bulimia can be quite severe (e.g., rupture of the stomach, erosion of the dental enamel, and heart disturbances due to loss of potassium).

THERAPEUTIC CONSIDERATIONS

Long-term, successful control of obesity is one of the greatest clinical challenges. Few people want to be overweight, most express a strong desire to lose weight, yet only 5% of obese individuals can attain and maintain "normal" body weight for a year or more, while 66% of those just a few pounds or so overweight are able to do the same. The successful program for obesity is consistent with the basic foundations of good health-a positive mental attitude, a healthy lifestyle (especially important is regular exercise), a health-promoting diet, and supplementary measures. All of these components are interrelated, creating a situation where no single component is more important than the other. Improvement in one facet may be enough to result in some positive changes, but incorporating all components yields the greatest results. Literally hundreds of diets and diet programs claim to be the answer to the problem of obesity. Dieters are The Low Serotonin Theory constantly bombarded with new reports of yet another "wonder" diet. However, the basic equation for losing A considerable body of evidence demonstrates that weight never changes. In order for an individual to lose brain serotonin plays a major role in influencing eating weight, energy intake must be less than energy expendibehavior. Initial studies showed that when animals and ture. This goal can be achieved by decreasing caloric humans are fed diets deficient in tryptophan, appetite intake or by increasing the rate at which calories are is significantly increased, resulting in binge eating of carbohydrate^.^^^^^ The diet low in tryptophan leads to low metabolized. brain serotonin levels, a condition the brain interprets as To lose 1 lb, a person must consume 3500 fewer calories than he or she expends. The loss of 1 lb each week starvation, resulting in the stimulation of the appetite requires a negative caloric balance of 500 calories/day. control centers. This stimulation results in a preference This can be achieved by decreasing the amount of calofor carbohydrates. Feeding animals or humans a carbories ingested or by exercise. Reducing a person's caloric hydrate meal leads to increased tryptophan delivery to intake by 500 calories is often difficult, as is increasing the brain, resulting in the elevated manufacture of serotonin. This scenario has led to the idea that low serotonin metabolism by an additional 500 calories/day by exercise (accomplished by a 45-minute jog, playing tennis for an levels lead to "carbohydrate cravings" and play a major hour, or a brisk walk for 1.25 hours). The most sensible role in the development of obesity. approach to weight loss is to both decrease caloric intake Furthermore, it has been demonstrated that concenand increase energy expenditure through exercise. trations of tryptophan in the blood stream and subseMost individuals begin to lose weight if they decrease quent brain serotonin levels plummet with dieth1g.3~ their caloric intake below 1500 calories/day and exercise In response to severe drops in serotonin levels, the

Specific Health Problems for 15 to 20 minutes three to four times per week. Starvation and crash diets usually result in rapid weight loss (largely muscle and water) but cause rebound weight gain. The most successful approach to weight loss is gradual weight reduction (0.5 to 1 lb/week) through adopting long-standing dietary and lifestyle habits that promote health and the attainment and maintenance of ideal body weight. Although many obese individuals may require the loss of considerable weight to achieve their long-term goals, it is important to stress that even modest reductions in body weight can produce sigruficant health benefits. For example, a 5% to 10% reduction in weight is accompanied by clinically meaningful improvements in cholesterol, blood pressure, blood glucose, and other health indices.

Behavioral Therapy Although clinical studies indicate that behavioral approaches to the management of obesity are often successful in achieving clinically significant weight loss, the lost weight is generally regained. The great majority of patients return to their pretreatment weight within 3 years. In order to provide the best insights on effective interventions, it is important to examine the psychologic characteristics of people who have lost significant amounts of weight and experienced only minimal weight regain.% Three main behavioral characteristics have been identified in individuals who avoid sigruficant weight regain: Maintenance of a high level of physical activity Consumption of a low-fat diet Active monitoring of body weight These characteristics are intertwined within a whole host of additional factors that provide necessary leverage for successful weight loss. For example, most patients presenting for treatment of obesity want to lose 20% to 30% of their initial body weight. Because only modest weight loss is generally achieved, many patients quickly lose the motivation and determination to keep the weight off. However, if there is a significant boost to self-esteem and self-confidence, as well as the experience of improving their appearance, feeling more attractive, and being able to wear more fashionable clothing, it can provide tremendous impetus for continued weight loss until goals are achieved or effective maintenance of weight loss. Important to remember is that the majority of people want to lose weight for the changes in their physical appearance, not the health benefits. Although there is widespread awareness that being overweight is associated with increased health risks, the reality is that relatively few patients give this as their reason for seeking treatment. Identifying the primary goals of weight

loss in patients is a key step in helping them achieve success.

Dietary Strategies The dietary strategy that we recommend for obesity is the same given in Chapter 44.The principles and goals detailed there reinforce some of the key goals in achieving weight loss and maintaining ideal body weight. Although literally hundreds of fad diets have been promoted over the years, we would be remiss if we did not mention the most famous weight loss diet of all time-the “Atkins Diet.”

The Atkins Diet This high-protein, high-fat, low-carbohydrate diet was developed by Robert Atkins, MD, during the 1960s. In the early 1990s Dr. Atkins brought his diet back into the nutrition spotlight with the publication of his bestselling book Dr. Atkins‘ New Diet Revolution. An estimated 50 million people or more worldwide have tried the Atkins Diet, which emphasizes the consumption of protein and fat. Individuals following the Atkins Diet are permitted to eat unlimited amounts of all meats, poultry, fish, eggs, and most cheeses. The Atkins Diet is divided into four phases: induction, ongoing weight loss, premaintenance, and maintenance. During the induction phase (the first 14 days of the diet), carbohydrate intake is limited to no more than 20 g per day. No fruit, bread, grains, starchy vegetables, or dairy products except cheese, cream, and butter are allowed during this phase. During the ongoing weight loss phase, dieters experiment with various levels of carbohydrate consumption until they determine the most liberal level of carbohydrate intake that allows them to continue to lose weight. Dieters are encouraged to maintain this level of carbohydrate intake until their weight loss goals are met. Then, during the premaintenance and maintenance phases, dieters determine the level of carbohydrate consumption that allows them to maintain their weight. To prevent regaining weight, dieters must stick to this level of carbohydrate consumption, perhaps for the rest of their lives. Although we agree with the underlying principle of the Atkins Diet, that diets high in sugar and refined carbohydrates cause weight gain and ultimately lead to obesity, we disagree with the solution. One of the big reasons why the Atkins Diet is so attractive to dieters who have tried unsuccessfully to lose weight on low-fat, low-calorie diets is that while on the Atkins Diet, they can eat as many calories as desired from protein and fat, as long as carbohydrate consumption is restricted. As a result, many Atkins dieters are spared the feelings of hunger and deprivation that accompany other weight loss regimens. However, we simply do not agree that such a diet is conducive to long-term health.

Obesity Despite its enormous popularity, the Atkins program was not evaluated in a proper clinical trial until 2003. In this initial study, although people following the Atkins Diet did experience initial weight loss, though likely as a result of water loss rather than true fat loss, in the long run they gained it all back plus more. In the study, 63 obese men and women were randomly assigned to the Atkins Diet or a low-calorie, high-carbohydrate, low-fat diet. Professional contact was minimal to replicate the approach used by most dieters. Although subjects on the Atkins Diet had lost more weight than subjects on the conventional diet at 6 months, the difference at 12 months was not sigruficant. Adherence was poor, and attrition was high in both groups.35 Since this initial clinical evaluation, other studies have shown similar results. For example, in one study of 34 adults with impaired glucose tolerance, 12 weeks of a low-fat (18% of total calories), high-complex carbohydrate (62+% of total calories) diet alone (High-CHO) or paired with an aerobic exercise training program (High-CHO+Ex) was compared with the effects of an Atkin's-style diet (41% fat, 14% protein, 45% carbohydrate of total calories). Fiber intake averaged 58 to 61 g/day in the two high-carbohydrate groups versus 18.5 &day in the control group. Participants engaged in aerobic exercise for 45 minutes per day, 4 days per week, at 80% of peak oxygen consumption in the HighCHO+Ex group. All participants were instructed to consume food ad libitum. Although caloric intake was similar in all three groups, both High-CHO groups (with and without exercise) lost more weight (mean loss 10.5 lb with exercise and 7 Ib without exercise than the control group (mean loss: a fraction of 1 lb). Similarly, a higher percentage of body fat was lost by HighCHO+Ex (3.5%) and by High-CHO without exercise (2.2%)than controls (0.2%increase in body fat). Thigh fat area also decreased significantly in both High-CHO groups but not in the control group. Resting metabolic rate and rate of fat oxidation were not decreased in the High-CHO (or control) group^.^ In another study, 132 obese adults (BMI > 35) of whom 83% had type II diabetes or metabolic syndrome were counseled to consume either an Atkins-like diet limited to less than 30 g of carbohydrates per day or to a diet restricted by 500 Kcal per day with less than 30% of Kcal coming from fat. Although initially the Atkins Diet did promote weight loss during the first 6-month period, this effect began to disappear during the second 6-month period. At 12 months, the difference between average weight loss in the groups was no longer statistically sigruficant (11lb in the Atkins group vs. 7 Ib in the low-fat group), though changes in triglyceride levels favored the Atkins Diet (-57 mg vs. +4 mg/dl), as did HgAlc reductions (-0.7 vs. -0.lY0) in the patients with type 11 diabetes.37

Another study worth commenting on was funded by the Atkins Foundation. In this study, 120 overweight but otherwise healthy adult subjects with elevated lipid levels followed either the Atkins Diet or a diet containing fewer than 30% calories from fat, 10% or fewer calories from saturated fat, less than 300 mg cholesterol, and a deficit of 500 to 1000 calories. At 24 weeks, the Atkins group had lost a mean of 26 Ib versus a mean loss of 14 lb in the reduced-fat group. Triglyceride levels fell more in the Atkins group (-74 mg/dl) than in the restricted-fat group (+28 mg/dl) as well, and highdensity lipoprotein (HDL) levels increased in the Atkins group (5.5 mg/dl) while they decreased in the low-fat group (-1.6 mg/dl). The main criticism of this dietary study was that the so-called "low-fat" group received almost 30% of its caloric intake from fat, and the dieticians administering the dietary recommendations made no clear attempt to significantly restrict sugar and refined carbohydrate sources. Thus the control diet to which the Atkins Diet was compared was significantly less than ideal.% The findings from these clinical trials indicate that while adhering strictly to the Atkins Diet (dramatically reducing carbohydrate intake while allowing free access to high-fat and high-protein foods) can lead to more weight loss in the first 6 months, eating a more healthful diet as described in Chapter 44 is associated with equal efficacy in the long run and is considerably more health promoting. Although the low-carbohydrate diet was associated with a greater improvement in some risk factors, on the basis of the current evidence, we do not recommend the Atkins Diet. Furthermore, since the high protein content of the Atkins Diet stresses the liver and kidneys, we do not recommend it for anyone with impaired liver or kidney function.

Natural Weight Loss Aids Several natural weight loss aids can be useful in helping either to reduce appetite or enhance metabolism. In decreasing order of efficacy, we rate these items as follows: 5-hydroxytryptophan (5-HTP) Meal replacement formulas Fiber supplements chromium Medium-chain triglycerides Hydroxycitrate

5-Hydroxytryptophan More than three decades ago, researchers demonstrated that administering 5-HTP to rats that were genetically bred to overeat and be obese resulted in a significant reduction in food intake. Further research revealed that these rats have decreased activity of tryptophan hydroxylase, which converts tryptophan to 5-H", itself

Specific Health Problems

subsequently converted to serotonin. In other words, these rats are fat as a result of a genetically determined low level of activity of the enzyme that starts the manufacture of serotonin from tryptophan. As a result, these rats never get the message to stop eating until they have consumed far greater amounts of food than normal rats. Circumstantialevidence indicates that many humans are genetically predisposed to obesity. This predisposition may involve the same mechanism as rats genetically predisposed to obesity (i.e., decreased conversion of tryptophan to 5-HTP and, as a result, decreased serotonin levels). By providing preformed 5-HlT, this genetic defect is bypassed and more serotonin is manufactured. (For a complete discussion of this interesting nutrient, see Chapter 101.) The early animal studies with 5-HTF' as a weight loss aid have been followed by a series of three human clinical studies in overweight women.3941The first study showed that 5-HTP was able to reduce calorie intake and promote weight loss despite the fact that the women made no conscious effort to lose weight.39The average amount of weight loss during the 5-week period of 5-HTP supplementation was a little more than 3 lb. The second study sought to determine if 5-H" helped overweight individuals adhere to dietary recommendations.40The 12-week study was divided into two 6-week periods. For the first 6 weeks there were no dietary recommendations, and for the second 6 weeks the women were placed on a 1200-calorie diet. As shown in Table 194-4, the women taking the placebo lost 2.28 lb, while the women taking the 5-HTP lost 10.34 lb. Like the previous study, 5-HTP appeared to promote weight loss by promoting satiety, leading to fewer calories being consumed at meals. All women taking 5-HTP reported early satiety. The third study with 5-HTP was similar to the second study: for the first 6 weeks there were no dietary restrictions, and for the second 6 weeks the women were placed on a diet of 1200 calories/day? The group receiving the 5-Hm lost an average of 4.39 lb after the first 6 weeks and an average of 11.63 lb after 12 weeks. In comparison, the placebo group lost an average of only

Placebo

5-HTP arow

Weight (Ib) Baseline

207.68

229.46

After 6 wk

206.58

225.94

After 12 wk Total weight loss (Ib) After 6 wk

205.4

219.12

~~~~~

~

~

After 12 wk

1.1

3.52

2.28

10.34

0.62 lb after the first 6 weeks and 1.87 lb after 12 weeks. The lack of weight loss during the second &week period in the placebo group obviously reflects the fact that the women had difficulty adhering to the diet. Early satiety was reported by 100% of the subjects during the first 6-week period. During the second 6-week period, even with severe caloric restriction, 90% of the women taking 5-HTP reported early satiety. Many of the women receiving the 5-HlT (300 mg tid) reported mild nausea during the first 6 weeks of therapy. However, the symptom was never severe enough for any of the women to drop out of the study. No other side effects were reported.

Meal Replacement Formulas Meal replacement formulas are a popular weightloss strategy. Their effectiveness has been confirmed in several clinical trials."45 In these studies, dietary compliance and convenience were viewed more favorably by participants who consumed meal replacement formulas than by those in a conventional weight-loss program. These formulations should be of high-quality nutrition; low in glycemic load; and high in viscous, soluble fiber.

Fiber Supplements A tremendous amount of clinical evidence indicates that increasing the amount of dietary fiber promotes weight loss. The best supplemental fiber sources for weight loss are glucomannan, gum karaya, psyllium, chitin, guar gum, and pectin because they are rich in water-soluble fibers. When taken with water before meals, these fiber sources bind to the water in the stomach to form a gelatinous mass that induces a sense of satiety. As a result, individuals are less likely to overeat. The benefits of fiber go well beyond this mechanical effect, however. Fiber supplements have been shown to enhance blood sugar control, decrease insulin levels, and reduce the number of calories absorbed by the body. In some of the clinical studies demonstrating weight loss, fiber supplements were shown to reduce the number of calories absorbed by 30 to 180 caloriedday. Although modest, this reduction in calories would, over the course of a year, result in a 3- to 18-lb weight ~ O S S . ~ Two important recommendations to make to patients to assist their choice of fiber supplements are as follows: Avoid products that contain a lot of sugar or other sweeteners to camouflage the taste. Be sure to drink adequate amounts of water when taking any fiber supplement, especially if it is in a pill form.

.

Several studies have used guar gum, a water-soluble fiber obtained from the Indian cluster bean (Cyurnopsis tefrugonolobu), with good results (Table 194-5).4g59 In one study, nine women weighing between 160 to 242 lb were given 10 g of guar gum immediately before lunch

, ~ ~

Obesity

Fiber

No. of subjects

Guar

9

Guar

7

Guar

Length of study

Dosage (@day)

Calorie restriction

Average weight loss (fiber, Ib)

Average weight loss (placebo)

Reference

2 mo

20

None

9.4

No placebo group

48

None

61.9

No placebo group

49

21

1 Yr 2.5 mo

20 20

None

15.6

No placebo group

50

Guar

33

2.5 mo

15

None

5.5

0.9 Ib in placebo group

51

Glucomannan

20

2 rno

3

5.5

Weight gain of 1.5 Ib

52

Glucomannan

20

2 mo

3

None None

8.14

0.44Ib in placebo group

53

Citrus pectin

14

4 wk

5.56

Yes

12.8

No placebo group

54

Mixture A

60

12 wk

5

Yes

18.7

14.7 Ib in placebo group

55

Mixture A

89

11 wk

10

Yes

13.9

9.2 Ib in placebo group

56

Mixture B

45

3 mo

7

Yes

13.6

9 Ib in placebo group

57

Mixture B

97

3 mo

7

Yes

10.8

7.3 Ib in placebo group

58

Mixture B

52

6 rno

7

Yes

12.1

6.1 Ib in placebo group

59

Mixture A = 80% fiber from grains, 20% fiber from citrus; mixture B = 90% insoluble and 10% soluble fiber from beet, barley, and citrus.

and dinner. They were told not to consciously alter their eating habits. After 2 months, the women reported an average weight loss of 9.4 lb. Reductions were also noted for cholesterol and triglyceride levels.& Studies with soluble fiber in the treatment of elevated cholesterol levels have shown a dose-dependent e f f e ~ t . Dietary ~ , ~ ~ fiber supplements appear to exert a dose-dependent effect in weight loss studies as well. Therefore to achieve the greatest benefit, the dosage should be as high as possible. As water-soluble fibers are fermented by intestinal bacteria, a great deal of gas can be produced, leading to increased flatulence and abdominal discomfort. Advise the patient to start out with a dosage between 1 and 2 g before meals and at bedtime and gradually increase the dosage to 5 g.

Chromium One of the key goals for enhancing weight loss is to increase the sensitivity of the cells throughout the body to insulin. Chromium plays a key role in cellular sensitivity to insulin. Chromium has recently gained a great deal of lay attention as an aid to weight loss. The importance of this trace mineral in human nutrition was not discovered until 1957, when it was shown that it was essential to proper blood sugar control. Although there is no recommended dietary allowance (RDA) for chromium, health requires a dietary intake of at least 200 pg/day. Chromium levels can be depleted by refined sugars, white flour products, and lack of exercise.@ In some clinical studies in diabetics, supplementing the diet with chromium has been shown to decrease fasting glucose levels, improve glucose tolerance, lower

insulin levels, and decrease total cholesterol and triglyceride levels, while increasing HDL cholesterol levels.61 Obviously chromium is a critical nutrient in diabetes, but it is also important in hypoglycemia. In one study, eight female patients with hypoglycemia given 200 pg/day for 3 months demonstrated alleviation of their symptoms.62 In addition, glucose tolerance test results were improved and the number of insulin receptors on red blood cells were increased. Chromium supplementation has been demonstrated to lower body weight yet increase lean body mass, presumably as a result of increased insulin ~ensitivity.~~ In one study, patients were given chromium bound to picolinic acid (chromium picolinate) in one of three doses daily for 2.5 months: placebo, 200 pg, or 400 pg.@ Patients taking the 200- and 400-1.1.8 doses lost an average of 4.2 lb of fat. The group taking the placebo lost only 0.4 lb. Even more impressive was the fact that the chromium groups gained more muscle (1.4 vs. 0.2 lb) than those taking the placebo. The results were most striking in elderly subjects and in men. The men taking chromium picolinate lost more than seven times the amount of body fat as those taking the placebo (7.7 vs. 1lb). The 400-pg dose is more effective than the 200-mcg dose (Table 194-6). The results of these preliminary studies with chromium are encouraging. Particularly interesting is the fact that in these initial studies, chromium picolinate promoted an increase in lean body weight percentage, as it led to fat loss but also to muscle gainG Greater muscle mass means greater fat-burning potential. However, two clinical trials in women involved in an exercise program did not show any sigTuficant changes in body c o m p ~ s i t i o n . ~ , ~ ~

Specific Health Problems

Dosaae

Fat loss

Muscle gain

Total weight loss

200 pg chromium picolinate

-3.3 Ib

+1.5 Ib

-1.8 Ib

400 pg chromium

4 . 6 Ib

+1.1 Ib

-3.5 Ib

All of the effects of chromium appear to be due to increased insulin sensitivity. Several forms of chromium are on the market. Chromium picolinate, chromium polynicotinate, chromium chloride, and chromium-enriched yeast are each touted by their respective suppliers to provide the greatest benefit. No firm evidence indicates that one is a sigruficantly better choice than another. Medium-Chain Triglycerides Medium-chain triglycerides (MCTs) are saturated fats (extracted from coconut oil) that range in length from 6 to 12 carbon chains. MCTs are used by the body differently from the long-chain triglycerides (LCTs), which are the most abundant fats found in nature. LCTs are the storage fats for both humans and plants that range in length from 18 to 24 carbons. This difference in length makes a substantial difference in how MCTs and LCTs are metabolized. Unlike regular fats, MCTs appear to promote weight loss rather than weight gain. MCTs may promote weight loss by increasing thermogenesis and energy expenditure.6870In contrast, the LCTs are usually stored in the fat deposits, and because their energy is conserved, a high-fat diet tends to decrease the metabolic rate. In one study the thermogenic effect of a high-calorie diet containing 40% fat as MCTs was compared with one containing 40% fat as LCTs. The thermogenic effect (calories wasted 6 hours after meal) of the MCTs was almost twice as high as the LCTs--120 versus 66 calories. The researchers concluded that the excess energy provided by fats in the form of medium-chain triglycerides would not be efficiently stored as fat, but rather would be wasted as heat. A follow-up study demonstrated that MCT oil given over a 6-day period can increase diet-induced thermogenesis by 50°/0?' In another study, researchers compared single meals of 400 calories composed entirely of MCTs or LTCS.~~ The thermic effect of MCTs over 6 hours was three times greater than that of LCTs. In addition, while the LCTs elevated blood fat levels by 68%, MCTs had no effect on the blood fat level. Researchers concluded that substituting MCTs for LCTs would produce weight loss as long as the calorie level remained the same. In order to gain the benefit from MCTs, a diet must remain low in LCTs. MCTs can be used as an oil for salad dressing, a bread spread, or simply taken as a

supplement. A good dosage recommendation for MCTs is 1 to 2 Tbls/day. Diabetics and individuals with liver disease should be monitored closely when using MCTs, as they may develop ketoacidosis.

Hydroxycitrate Hydroxycitrate (HCA) is a natural substance isolated from the fruit of the Malabar tamarind (Garcinia cambogid The Malabar tamarind is a yellowish fruit that is about the size of an orange, with a thin skin and deep furrows similar to an acorn squash. It is native to southern India, where it is dried and used extensively in curries. The dried fruit contains about 30%hydroxycitric acid. HCA has been shown to be a powerful lipogenic inhibitor in animal^.'^,'^ Whether or not it demonstrates this effect in humans has not yet been proven. The weight loss-promoting effects in animals are perhaps best exemplified in a study that shows HCA producing a "significant reduction in food intake, and body weight gain" in rats.75HCA may not only be a powerful inhibitor of fat production; it may also suppress appetite. It is critical when using an HCA formula that a low-fat diet be maintained, as it only inhibits the conversion of carbohydrates into fat. By itself, HCA may offer a safe, natural aid for weight loss when taken at a dosage of 1500 mg tid. In one clinical trial, 60 moderately obese subjects (ages 21 to 50, BMI > 26) were randomly divided into three groups. Group A was administered HCA 4667 mg; group B was administered a combination of HCA 4667 mg, niacinbound chromium 4 mg, and Gymnema sylvestre extract 400 mg; while group C was given placebo daily in three equally divided doses 30 to 60 minutes before meals. All subjects received a 2000-kcal diet/day and participated in a supervised walking program. At the end of 8 weeks, body weight and BMI decreased by 5% to 6% in both groups A and B.76

THERAPEUTIC APPROACH A successful program for weight loss must be consistent with the four cornerstones of good health: Proper diet Adequate exercise A positive mental attitude The right support for the body through natural measures All of these components are critical and interrelated.

Diet The recommendations given in Chapter 44 should be followed.

Obesity

Psychologic Support Referral to counseling should be considered. Overweight individuals tend to suffer a great deal of assaults on their self-esteem and self-image.

Lifestyle Exercise is absolutely critical to an effectiveweight loss program. Follow the recommendations given in Chapter 37.

Supplements 5-HTP: begin at 50 to 100 mg 20 minutes before meals for 2 weeks and then double the dosage (to a maximum

1. Fontaine KR, Redden DT, Wang C, et al. Years of life lost due to obesity. JAMA 2003;289:187-193.

2. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;28976-79. 3. Ogden CL, Flegal KM, Carroll MD, et al. Prevalence and trends in overweight among U.S. children and adolescents, 1999-2000. JAMA 2002;288:1728-1732. 4. Brown CD, HigginsM, Donato KA, et al. Body mass index and prevalence of hypertension and dyslipidemia. Obes Res 2000;8:605-619. 5. Finkelstein EA, Fiebelkom IC, Wang G. National medical spending attributable to overweight and obesity: How much, and who's paying? Health Affairs Web Exclusive 2003;W3219-226. 6.Dietz WH, Gortmaker SL. Do we fatten our children at the television set? Pediatrics 1985;75:807-812. 7. Hancox RJ, Mihe BJ, Poulton R. Association between child and adolescent television viewing and adult health: a longitudinal birth cohort study. Lancet 2004;3&2:257-262. 8. Hu FB, Li TY, Colditz GA, et al. Television watching and other sedentary behaviors in relation to risk of obesity and type 2 diabetes mellitus in women. JAMA 2003;289:1785-1791. 9. Have1 PJ. Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. Diabetes 2004; 53(S~ppl.1):S143-151. 10. Jazet IM, Pijl H, Meinders AE. Adipose tissue as an endocrine organ: impact on insulin resistance. Neth J Med 2003;61:194-212. 11. Guerre-Millo M. Adipose tissue hormones. J Endocrinol Invest 2002; 252355-861. 12. Small CJ, Bloom SR. Gut hormones and the control of appetite. Trends Endocrinol Metab 2004;15259-263. 13. Batterham RL, Cohen MA, Ellis SM, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003;349941-948. 14. Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346:1623-1630. 15. Burton-Freeman B, Davis PA, Schneeman BO. Plasma cholecystokinin is associated with subjective measures of satiety in women. Am J Clin Nutr 2002;76659-667. 16. Bourdon I, Olson B, Backus R, et al. Beans, as a source of dietary fiber, increase cholecystokinin and apolipoprotein b48 response to test meals in men. J Nutr 2001;131:1485-1490. 17. Heini AF, Lara-Castro C, Schneider H, et al. Effect of hydrolyzed guar fiber on fasting and postprandial satiety and satiety hormones: a double-blind, placebo-controlled trial during controlled weight loss. Int J Obes Relat Metab Disord 1998;22:906-909.

of 300 mg) if weight loss is less than 1lb/week. Higher dosages of 5-HTP (e.g., 300 mg) are associated with nausea, but this symptom disappears after 6 weeks of use. Viscous, soluble fiber: 5 g before meals Chromium: 200 to 400 pg/day Medium-chain triglycerides: incorporate 1 to 2 Tbsp into the diet

Botanical Medicine Hydroxycitrate (from G. carnbogiu): 1500 mg tid

18. Naslund E, Barkeling B, King N, et al. Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int J Obes Relat Metab Disord 1999;23:304-311. 19.Cohen MA, Ellis SM, Le Roux CW, et al. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab 2003;88:4696-4701. 20. Batterham RL, Le Roux CW, Cohen MA, et al. Pancreatic polypeptide reduces appetite and food intake in humans. J Clin Endocrinol Metab 2003;883989-3992. 21. Batterham RL, Cohen MA, Ellis SM, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003;349 941-948. 22. Cummings DE, Frayo RS,Marmonier C, et al. Plasma ghreli levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am J Physiol Endocrinol Metab 2004,287E297-304. 23. Anderwald C, Brabant G, Bemoider E, et al. Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients. Diabetes 2003;52: 1792-1798. 24. L a d e M, Comu C, Normand S, et al. Decreased glucoseinduced thermogenesisat the onset of obesity. Am J Clin Nutr 1993;57851-856. 25. Ravussin E, Acheson KJ, Vemet 0,et al. Evidence that insulin resistance is responsible for the decreased thermic effect of glucose in human obesity. J Clin Invest 1985;761268-1273. 26. Nelson KM, Weinsier RL, James LD, et al. Effect of weight reduction on resting energy expenditure, substrate utilization, and the thermic effect of food in moderately obese women. Am J Clin Nutr 1992;55:924933. 27. Schulz LO. Brown adipose tissue: regulation of thermogenesis and implications for obesity. J Am Diet Assoc 1987;87761-764. 28. Sims EA, Danforth E Jr., Horton ES, et al. Endocrine and metabolic effects of experimental obesity in man. Recent Prog Horm Res 1973;29457-496. 29. Leibel RL, Hirsch J. Diminished energy requirements in reduced obese patients. Metabolism 1984;33:161-170. 30. Eck LH, Klesges RC, Hanson CL, et al. Children at familial risk for obesity: an examination of dietary intake, physical activity, and weight status. Int J Obes Relat Metab Disord 1992;1671-78. 31. Wurtman RJ, Wurtman JJ. Brain serotonin, carbohydrate-craving, obesity and depression. Adv Exp Med Biol1996;398:35-41. 32. Wurtman J, Suffes S. The serotonin solution. New York Fawcett Columbine, 1996. 33. Goodwin GM, Cowen PJ, Fairbum CG, et al. Plasma concentrations of tryptophan and dieting. BMJ 1990;300:1499-1500.

34. McGuire MT, Wing RR, Klem ML, et al. Behavioral strategies of individuals who have maintained long-term weight losses. Obes Res 1999;7334-341. 35. Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a lowcarbohydrate diet for obesity. N Engl J Med 2003;34&2082-2090. 36. Hays NP,Starling RD, Liu X, et al. Effects of an ad libitum low-fat, high-carbohydrate diet on body weight, body composition, and fat distribution in older men and women. Arch Intern Med 2004;164:210-217. 37. Stem L, Iqbal N, Seshadri P, et al. The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial. Ann Intern Med 2004;140:769-777. 38. Yancy WS Jr, Olsen MK, Guyton JR, et al. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia. Ann Intern Med 2004;140:769-777. 39. Ceci F, Cangiano C, Cairella M, et al. The effects of oral 5hydroxytryptophan administration on feeding behavior in obese adult female subjects. J Neural Transm 1989;76:109-117. 40. Ced F, Cangiano C, Cairella M, et al. Effects of 5-hydroxytryptophan on eating behavior and adherence to dietary prescriptions in obese adult subjects. Adv Exp Med Biol 1991;294:591-593. 41. Cangiano C, Ceci F, Cascino A, et al. Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydroxytryptophan. Am J Clin Nutr 1992565363-867. 42. Noakes M, Foster PR, Keogh JB, et al. Meal replacements are as effective as strudured weight-loss diets for treating obesity in adults with features of metabolic syndrome. J Nutr 2004;134:1894-1899. 43. Ashley JM, St Jeor ST, Perumean-Chaney S, et al. Meal replacements in weight intervention. Obes Res 2001;9(suppl4):312S32OS. 44.Ditschuneit HH, Flechtner-Mors M. Value of structured meals for weight management: risk factors and long-term weight maintenance. Obes Res 2001;9(supp14):28452895. 45. AUison DB, Gadbury G, Schwartz LG, et al. A novel soy-based meal replacement formula for weight loss among obese individuals: a randomized controlled clinical trial. Eur J Clin Nutr 200357514522. 46.Howarth NC, Saltzman E, Roberts SB. Dietary fiber and weight regulation. Nutr Rev 2001;59129-139. 47. Spiller GA. Dietary fiber in health and nutrition. Boca Raton, FL: CRC Press, 1994. 48. Krotkiewski M. Effect of guar on body weight, hunger ratings and metabolism in obese subjects. Br J Nutr 1984;52:97-105. 49. Krotkiewski M, Smith U. Dietary fibre in obesity. In Leeds AR, Avenell A, eds. Dietary fiber perspectives. Reviews and bibliography. London: John Libbey, 198561-66. 50. Krotkiewski M. Effect of guar gum on body-weight, hunger ratings and metabolism in obese subjects. Br J Nutr 1984;52:97-105. 51. Anonymous. Better than oat bran. Sci News 1994;14528. 52. Walsh DE, Yaghoubian V, Behforooz A. Effect of glucomannan on obese patients: a clinical study. Int J Obes 1984;8:289-293. 53. Biancardi G, Palmier0 L, Ghirardi PE. Glucomannan in the treatment of overweight patients with osteoarthrosis. Curr Ther Res 1989;46:908-912. 54. El-Shebini SM, Hanna LM, Topouzada ST, et al. The role of pectin as a slimming agent. J Clin Biochem Nutr 1988;4255-262. 55.Solum lT,Ryttig KR, Solum E, et al. The influence of a highfibre diet on body weight, serum lipids and blood pressure in slightly overweight persons. A randomized, double-blind, placebo-controlled investigation with diet and fibre tablets (DumoVital). Int J Obes 1987;11(suppl1):67-71. 56. Ryttig KR, Larsen S, Haegh L. [Treatment of slightly to moderately overweight persons. A double-blind placebo-controlled study with diet and fibre tablets (DumoVital)]. Tidsskr Nor Laegeforen 1984;1O4:989-991.

57. Rossner S, von Zwigbergk D, OhIin A, et al. Weight reduction with dietary fibre supplements. Results of two double-blind studies. Acta Med Scand 1987;222:83-88. 58. Ryttig KR, Tellnes G, Haegh L, et al. A dietary fibre supplement and weight maintenance after weight reduction. A randomized, doubleblind, placebo-controlled long-term trial. Int J Obes 1989;13165-769. 59. Rigaud D, Ryttig KR, Leeds AR, et al. Mild overweight treated with energy restriction and a dietary fiber supplement: a 6-month randomized, double-blind, placebo-controlled trial. Int J Obesity 1990;14:763-771. 60.Mertz W. Chromium in human nutrition: a review. J Nutr 1993;123626-633. 61. Anderson RA. Chromium, glucose tolerance, and diabetes. Biol Trace Elem Res 1992;3219-24. 62. Anderson RA, Polansky MM, Bryden NA, et al. Effects of supplemental chromium on patients with symptoms of reactive hypoglycemia. Metabolism 1987;36:351-355. 63. McCarthy MF. Hypothesis: sensitization of insulin-dependent hypothalamic glucoreceptors may account for the fat-reducing effects of chromium picolinate. J Optimal Nutr 1993;21:36-53. 64.Evans GW, Pouchnik DJ. Composition and biological activity of chromium-pyridine carboxylate complexes. J Inorg Biochem 1993;49:177-187. 65. Evans GW. Chromium picolinate is an efficacious and safe supplement. Int J Sport Nutr 1993;3:117-122. 66. Campbell WW, Joseph LJ, Anderson RA, et al. Effects of resistive training and chromium picolinate on body composition and skeletal muscle size in older women. Int J Sport Nutr Exerc Metab 2002;12:125-135. 67. Volpe SL, Huang HW,Larpadisorn K, et al. Effect of chromium supplementation and exercise on body composition, resting metabolic rate and selected biochemical parameters in moderately obese women following an exercise program. J Am Coll Nutr 2001;20 293-306. 68.Baba N, Bracco EF, Hashim SA. Enhanced thermogenesis and diminished deposition of fat in response to overfeeding with diet containing medium chain triglyceride. Am J Clin Nutr 1982;35678-682. 69. St-Onge MP, Jones PJ. Greater rise in fat oxidation with mediumchain triglyceride consumption relative to long-chain triglyceride is associated with lower initial body weight and greater loss of subcutaneous adipose tissue. Int J Obes Relat Metab W o r d 2003;27 1565-1571. 70. St-Onge MP, Ross R, Parsons WD, et al. Medium-chain triglycerides increase energy expenditure and decrease adiposity in overweight men. Obes Res 2003;11:395-402. 71. Seaton TB, Welle SL, Warenko MK, et al. Thermic effect of mediumchain and long-chain triglycerides in man. Am J Clin Nutr 1986;44630-634. 72. Hill JO, Peters JC, Yang D, et al. Thermogenesis in humans during overfeeding with medium-chain triglycerides. Metabolism 1989; 38:641-648. 73. Chee H, Romsos DR, Leveille GA. Influence of (-)-hydroxycitrate on lipogenesis in chickens and rats. J Nutr 1977;107112-119. 74. Sullivan AC, Triscari J, Hamilton JG, et al. Effect of (-)-hydroxycitrate upon the accumulation of lipid in the rat. I. Lipogenesis. Lipids 1974; 9~121-128. 75.Rao RN, Sakariah KK. Lipid-lowering and antiobesity effect of (-)-hydroxycitric acid. Nutr Res 1988;8:209-212. 76. Preuss HG, Bagchi D, Bagchi M, et al. Effects of a natural extract of (-)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX plus niacin-bound chromium and Gymnema sylvestre extract on weight loss. Diabetes Obes Metab 2004;6:171-180.

Osteoarthritis Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

1961

General Considerations 1961 Diagnosis

1962

Therapeutic Considerations 1962 Conventional Pharmacologic Treatment 1963 Hormonal Considerations 1964 Dietary and Exercise Considerations 1964 Nutritional Supplements 1965 Physical Therapy 1969 Botanical Medicines 1971 Topical Applications 1972

DIAGNOSTIC SUMMARY Clinical symptoms-mild, early-morning stiffness, stiffness following periods of rest, pain that worsens on joint use, and loss of joint function Clinical signs-local tenderness; soft tissue swelling; joint crepitus; bony swelling; restricted mobility; Heberden’s (proximal interphalangeal joints) or the less common Bouchard‘s (distal interphalangeal joints) nodes, or both; and other signs of degenerative loss of articular cartilage X-ray findings-narrowed joint space, osteophytes, increased density of subchondral bone, subchondral sclerosis, bony cysts, soft tissue swelling, and periarticular swelling

GENERAL CONSIDERATIONS Osteoarthritis(OA),or degenerativejoint disease, is characterized by joint degeneration, loss of cartilage, and alterations of the subchondral bone. The most common form of arthritis, OA probably has the highest morbidity rate of any illness.’ An estimated 12%of 25- to 75-year-olds in the United States have symptoms and signs of OA.2 Although primarily seen in the elderly, there is a 35% incidence in the knee as early as age 30 (often diagnosed as

Therapeutic Approach 1972 Diet 1972 Supplements 1972 Botanical Medicines 1972 Topical Application 1972 Physical Therapy and Exercise 1972 Acupuncture 1972

chondromalacia ~ a t e l l a e ) .Its ~ incidence increases dramatically with age. Surveys have indicated that more than 40 million Americans have OA4 including 80% of persons older than the age of 50. Men and women are equally affected, but symptoms occur earlier and appear to be more severe in women. Table 195-1 lists some of the diseases that are now thought to be OA of specific joints. The weight-bearing joints and peripheral and axial articulations are the joints principally affected by the degenerative changes associated with OA. Much hyaline cartilage destruction occurs, followed by hardening and formation of large bone spurs (calcified osteophytes) in the joint margins. Pain, deformity, and limitation of joint motion result from this degeneration. Inflammation is usually minimal.’ OA is divided into two categories, primary and secondary. In primary OA, the degenerative ”wear-andtear” process occurs after the fifth and sixth decades, with no apparent predisposing abnormalities. The cumulative effects of decades of use lead to the degenerative changes by stressing the collagen matrix of the cartilage. Damage to the cartilage results in the release of enzymes that destroy collagen components. With aging, the ability to restore and synthesize normal collagen structures decreases.’s35 Secondary OA is associated with some predisposing factor that is responsible for the degenerative changes. 1961

Specific Health Problems Diseases thought to be osteoarthritis of specific joints Joint

Disease

Hands

Heberden’s and Bouchard’s nodes

Hip

Malum coxae senilis

Temporomandibular

Costen syndrome

Knee

Chondromalacia patellae

Spine

Ankylosing hyperostosis (interstitial skeletal hyperostosis)

Hypermobility/joint instability Age-related changes in collagen matrix repair mechanisms Hormonal and sex factors Altered biochemistry Genetic predisposition Inflammation Fractures and mechanical damage Inflammatory joint disease Acromegaly Others

Bone Periosteal elevation by osteophytes Trabecular microfractures Pressure on subchondral bone Hypertension in bone marrow Articular Synovial inflammation Pinching of synovial villi Joint capsule distension Periarticular Ligament damage Muscle spasm Bursitis Psychologic factors Anxiety Depression Lack of social support Secondary gain Physical demands Occupational Obesity Neuromuscular integrity Protective reflexes Muscle weakness

DIAGNOSIS Predisposing factors in secondary OA include the following: Congenital abnormalities in joint structure or function (e.g., hypermobility and abnormally shaped joint surfaces) Trauma (e.g., obesity, fractures along joint surfaces, surgery) Crystal deposition Presence of abnormal cartilage Previous inflammatory disease of the joint (e.g., rheumatoid arthritis, gout, septic arthritis) Box 195-1 summarizes the many factors involved in the pathogenesis of OA. One of the most interesting clinical features of OA is the lack of correlation between its severity as determined by a radiograph and the degree of pain. In some cases the joint appears normal with little, if any, joint space narrowing, yet the pain can be excruciating. Conversely, there are cases where there is tremendous deformity yet little, if any, pain. In fact, about 40% of individuals with the worst x-ray classification for OA are pain free.5The exact cause of the pain in OA is still not well defined, but there are numerous potential causes (Box 195-2). Depression and anxiety appear to increase the experience of the pain of OA.

The onset of OA can be subtle. Morning joint stiffness is often the first symptom. As the disease progresses, pain on motion of the involved joint is worsened by prolonged activity and relieved by rest. There are usually no signs of inflammation.’ The specific clinical picture varies with the joint involved. Disease of the hands leads to pain and limitation of use. Knee involvement produces pain, swelling, and instability. OA of the hip causes local pain and a limp. Spinal OA (which is common) may result in compression of nerves and blood vessels, causing pain and vascular insufficiency.’ The classic presentation of OA is easy to distinguish from other arthritides, especially rheumatoid arthritis, which is usually associated with much more inflammation of surrounding soft tissues. After a detailed medical history and physical examination, the best diagnostic tool to confirm the diagnosis of OA is a radiograph of the suspected joint. The classic finding in joints affected with OA is joint space narrowing, loss of cartilage, and the presence of bone spurs (osteophytes).’Box 195-3lists important causes of misdiagnosis of OA.

THERAPEUTIC CONSIDERATIONS Data collected from the earliest lesions to the most advanced stages of clinical OA suggest that cellular and

Osteoarthritis joints with OA inflammation may be present, it is usually mild and involves only the periarticular tissue^.^ Given this information, it seems obvious that drugs to reduce inflammation would only be mild to moderately The source of the pain is not osteoarthritis (OA), but the following: Arthritis of other origin effective at reducing pain, and not at all effective in Pathologic changes of the adjacent bone (e.g., tumor, osteomyelitis, enhancing repair. metabolic bone disease) The first drug generally employed in the allopathic Mechanical injuries treatment of OA is aspirin. It is often quite effective in Pathologic fractures relieving both the pain and inflammation. It is also relaReferred pain of neuritis, neuropathy, or radiculopathy tively inexpensive. However, because the therapeutic Other neurologic disorders causing stiffness of joints The source of the pain is OA, but not at the joint suspected: dose required is relatively high (2 to 4 g/day), toxicity OA of the hip, pain localized to the knee often occurs. Tinnitus (ringing in the ears) and gastric OA of the cervical spine, causing pain in the shoulder irritation are early manifestations of to xi city.'^^ OA of the lumbar spine, causing pain in the hip, knee, or ankle Other nonsteroidal antiinflammatory drugs (NSAIDs) OA of the shoulder, causing pain in the elbow The source of pain is caused by secondary soft tissue alterations are often used as well, especially when aspirin is inefof OA: fective or not tolerated. These drugs are associated with Tendonitis or ligamentitis (especially of the knee) such side effects as gastrointestinal upset, headaches, Enthesopathy, tendinopathy, due to joint contracture and dizziness and are therefore recommended for only Bursitis short periods of time. Although these drugs provide Misinterpretationof deformity: short-term symptomatic relief, unexpected side effects Pseudohypertrophic osteoarthropathy Psoriatic arthritis may increase the rate of degeneration of the joint cartiFlexion contracture of the joints lage. Experimental studies have shown that aspirin and Mucopolysaccharidoses other NSAIDs inhibit collagen matrix synthesis and Neurogenic arthropathies accelerate cartilage destruction.’ Retrospective clinical Calcium pyrophosphate dihydrate crystal deposition disease studies have shown that NSAID use is associated with Genu varum and valgum Misinterpretationof x-ray films: acceleration of OA and increased joint Arthritis with previous OA changes Simply stated, NSAIDs appear to suppress the sympInitial stage of osteoarthritis; may have normal radiograph toms but accelerate the progression of OA. Flexion contracture can cause a virtual loss of joint space width The cyclooxygenase-2 (COX-2) inhibitors celecoxib Neurogenic and metabolic arthropathies (Celebrex) and rofecoxib (Vioxx) appear to cause fewer gastrointestinal side effects. Although they are no more effective than other NSAIDs, if necessary these may be a safer choice for patients with a history of gastrointestinal tissue response is purposeful and aimed at repair of bleeding or for those who may be taking certain medicathe anatomic defects. The process contributing to OA appears to be arrestable and sometimes re~ersible.~ tions such as warfarin (Coumadin) or oral steroids. The COX-2 inhibitors have not been shown to be safer than The major therapeutic goal should be to ultimately acetaminophen, and they have been associated with an enhance collagen matrix repair and regeneration by the increase in cardiovascular events? connective tissue cells. Sodium hyaluronate (Synvisc, Hyalgan) is an injectable Several studies have attempted to determine the ”natsubstance used to protect against articular grinding in ural course” of OA.3,6One group of researchers studied patients with OA of the knee. This treatment is an alterthe natural course of OA of the hip over a 10-year period. native to consider in patients who do not respond to All subjects had pseudocystic changes suggestive of NSAID therapy or who have a history of gastric ulcer advanced OA, yet the researchers reported marked clindisease, with some evidence suggesting symptomatic ical improvement and radiologic recovery of the joint and functional improvement following a series of weekly space in 14 of 31 hips.6The authors purposely applied no injection^.^ Intraarticular steroidal injections are also therapy and regarded their results as reflecting the natuemployed and can relieve pain but may also increase the ral course of the disease. rate of degeneration by inhibiting blood flow to the area. These results, as well as others, raise the serious conFollowing are the main drug categories and individcern that medical intervention may actually promote ual drugs used to treat OA4: disease progression.

Conventional PharmacologicTreatment Conventional medical treatment is generally based on decreasing inflammation to relieve pain. Although in

NSAIDs: salicylates (aspirin); propionic acids (ibuprofen [Motrin]; naproxen [Anaprox],oxaprozin [Daypro], flurbiprofen [Ansaid], ketoprofen [Orudis]); scetic

acids (diclofenac [Voltarin];tolmetin [Tolectin];etodolac [Lodine]; sulindac [Clinoril]; indomethacin [Indocin]); and oxicams (piroxicam [Feldone]) Cyclooxygenaseinhibitors: (celecoxib [Celebrex],rofecoxib [Woxx]) Imtants/counterirritants:capsaicin 0.025% cream Hyaluronic acids: hylan G-F 20 (Synvisc), sodium hyaluronate (Hyalgan) Glucocorticoids:prednisone Overall, conventional pharmaceutic treatment is moderately effective at giving pain relief. However, the pharmaceutics’ ability to help repair the joint tissue is negligible.

Hormonal Considerations A considerable amount of evidence indicates that endocrine forces may initiate or accelerate the development of OA by altering the chondrocyte’s microenvironment. Virtually all hormones act, directly or indirectly, on connective tissue cells: fibroblasts, osteoblasts, and chondrocyte~.~

Estrogen The higher prevalence of OA in women suggests that estrogens may play a role. Estradiol worsens, and tamoxifen, an antiestrogen drug, improves experimental OA by decreasing erosive lesions. This suggests a therapeutic role for estrogen blockade. Several botanicals (e.g., Glycyrrhiza glubru and Medicugo sufivu) commonly used in the treatment of OA contain compounds with phytoestrogen activity capable of binding to estrogen receptors and acting as estrogen antagonists. However, although phytoestrogen-containingherbs may be of value in OA, perhaps the best way to increase the intake of phytoestrogens is to increase the intake of food sources of phytoestrogens. Good food sources of phytoestrogens include soy, fennel, celery, parsley, nuts, whole grains, and apples.

Insulin Growth Hormone and Somatomedin Diabetic patients have a greater incidence and more Diabetes is charsevere form of OA than nondiabetic~.~ acterized by insulininsensitivity or deficiency, increased growth hormone levels, and decreased somatomedin levels (somatomedins are insulin-like growth factors secreted by the liver in response to growth hormone). Insulin stimulates chondrocytes to increase the synthesis and assembly of proteoglycans? As the most prominent early change seen in the articular cartilage is a decrease in both proteoglycan content and state of aggregation, insulin insensitivity or deficiency predisposes to OA. Excessive growth hormone has detrimental effects on bone and joint structures, as demonstrated by the

increased incidence of OA in acromegaly. Women with primary osteoporosis have been shown to have significantly higher basal growth hormone levels than cont r o l ~ . ’Growth ~ hormone appears to be detrimental to chondrocytes, while somatomedins appear to mediate normal chondrocyte a~tivity.~ Impaired hepatic function, diabetes, malnutrition, and other metabolic abnormalities suppress the liver’s secretion, in response to growth hormone, of somatomedin. This could lead to increased risk of developing OA.

Thyroid Patients with hypothyroidism have been shown to have an increased risk of OA compared with age- and sexmatched population sample^.^ Clearly, correction of underlying endocrine imbalance or liver dysfunction is of critical importance in normalizing chondrocyte function.

Dietary and Exercise Considerations Dietary therapy primarily involves the achievement of normal body weight, as excess weight means increased stress on weight-bearing joints affected with OA.13J4Lack of exercise decreases the hydration of the joint cartilages and retards diffusion of nutrients into the affected area. When OA pain develops, sufferers often tend to reduce activity, which in turn decreases muscle strength. Greater muscle weakness increases joint wear, and the inactivity can lead to weight gain, which can exacerbate OA, causing this cycle to repeat itself. In addition, patients with diabetes and cardiovascular concerns may also increase their risks for these illnesses as exercise diminishes. Weight loss,l5 dieting, and exercise has independently been effectively used to decrease the causative factors of OA and, when approached in a manner appropriate for the patient, can gently break this cycle. A generally healthy diet, rich in complex carbohydrates and dietary fiber, is recommended (for further discussion see Chapter 194). Regimens combining diet and exercise are certainly superior to protocols using only one of these. One study involved 252 obese elderly patients with a body mass index of greater than 28 and radiographically confirmed OA who were randomized into healthy-lifestyle (control), diet-only, exercise-only, and diet-plus-exercise groups.I6 The exercise program involved hour-long sessions that focused on aerobics and resistance training three times a week. An average weight loss of 5% during the 18-month period was the focus of the dietary interventions. The most benefit was demonstrated in the dietplus-exercise group. Compared with control patients, subjects in the dietplus-exercise group gained a significant improvement in self-reported physical function, 6-minute walking distance, stair-climb times, and knee pain scores.

Osteoarthritis

Improvements in the exercise-only group were limited to the 6-minute walk distance. The diet-only intervention appeared to offer no functional benefits over usual care. However, patients in the dietary intervention groups lost significantly more weight than those in the usual care group. Despite these reported improvements, changes in joint space width were not different among any of the groups.

Nightshade Vegetables Childers, a horticulturist, popularized a diet that treated OA by eliminating foods from the family Solanaceae (nightshade family). He arrived at this method after finding that this simple dietary elimination cured his own OA.17Childers developed a theory that genetically susceptible individuals might develop arthritis and other complaints from long-term, low-level consumption of the Solanurn alkaloids found in tomatoes, potatoes, eggplant, peppers, and tobacco. Presumably, these alkaloids inhibit normal collagen repair in the joints or promote inflammatory degeneration of the joint. Although as yet unproven, this diet has been of benefit to some individuals (the authors have seen OA in several patients respond well to such a diet) and is certainly worth a try.

Nutritional Supplements Because Americans spend more on natural remedies for OA than for any other medical c~ndition,’~ both the practitioner and OA sufferer should be well informed about the clinical indications for these supplements. Many botanical and nutritional supplements are not evaluated for quality control, so it is imperative that only reputable and independently verified products are used in order to gain the desired therapeutic effect.

Antioxidant Nutrients Results from the Framingham Osteoarthritis Cohort Study indicate that a high intake of antioxidant nutrients, especially vitamin C, may reduce the risk of cartilage loss and disease progression in people with 0A.Is A threefold reduction in the risk of OA progression was found in both the middle tertile and highest tertile of vitamin C intake. These results highlight the importance of a diet rich in plant-based antioxidant nutrients protecting against chronic degenerative diseases including OA.

Glucosamine Sulfate Glucosamine is a simple molecule composed of glucose and an amine. The main physiologic function of glucosamine on joints is to stimulate the manufacture of glycosaminoglycans GAGS).^^,*^ Glucosamine also promotes the incorporation of sulfur into cartilage. It appears that as some people age, they lose the ability to manufacture sufficient levels of glucosamine. The result

is that cartilage loses its gellike nature and ability to act as a shock absorber. The inability to manufacture glucosamine may be the major factor leading to OA. The clinical benefits of glucosamine sulfate in the treatment of OA are impressive. A recent metaanalysis, funded by a grant from the National Institutes of Health, concluded that glucosamine shows efficacy over placebo in relieving painful symptoms.” In one of the more individual recent studies comparing glucosamine sulfate with a placebo, 252 patients with OA of the knee were given either a placebo or 500 mg glucosamine sulfate tid for 4 weeks.= Glucosamine sulfate was significantly more effective than the placebo in improving pain and movement after only 4 weeks of use. Previous studies have shown that the longer glucosamine sulfate is used, the more obvious the therapeutic benefit. The rate and severity of side effects with glucosamine did not differ from the placebo. These results are consistent with other double-blind studies versus a placebo.”-28 Head-to-head, double-blind studies have shown glucosamine sulfate to produce better long-term results than NSAIDs in relieving the pain and inflammation of OA despite the fact that glucosamine sulfate exhibits little direct antiinflammatory effect and no direct analgesic or pain-relieving effe~ts.2~”’Although NSAIDs offer purely symptomatic relief and may actually promote the disease process, glucosamine sulfate appears to address the cause of OA. By treating the root of the problem through the promotion of cartilage synthesis, glucosamine sulfate not only improves the symptoms, including pain, but also helps the body to repair damaged joints. The clinical effect is impressive, especially when glucosamine’s safety and lack of side effects are considered. In one of the earlier comparative studies, glucosamine sulfate (1500 mg/day) was compared with the common antiinflammatory drug ibuprofen (1200 mg/day). Although pain scores decreased faster in the first 2 weeks in the ibuprofen group, by week 4 the group receiving the glucosamine sulfate improved more than the ibuprofen Physicians rated the overall response as good in 44% of the glucosamine sulfatetreated patients as compared with only 15% of the ibuprofen group. Two more studies designed to further evaluate the comparative effectiveness of glucosamine sulfate to NSAIDs provide even better evidence. The first study consisted of 200 subjects with OA of the knee given either glucosamine sulfate (500 mg tid) or ibuprofen (400 mg tid) for 4 weeks.30 Consistent with previous studies, the ibuprofen group experienced quicker pain relief. However, by the end of the second week, the group taking glucosamine sulfate experienced as good results as the ibuprofen group with one major exception-although the rate of side effects with glucosamine were mild and only affected 6% of the group, ibuprofen

produced more sigruficant side effects much more frequently, with 35% of the group experiencing side effects. In the second study, 329 patients were given one of 1500 mg glucosamine sulfate; 20 mg piroxicam; both compounds; or a placebo for 90 days.31The main efficacy variable was represented by the Lequesne index, a common assessment of disease activity. The results of the study were strikingly in favor of glucosamine sulfate alone. These impressive results with glucosamine sulfate were achieved without side effects. In fact, patients on glucosamine sulfate had fewer side effects than the placebo and no dropouts. In addition to showing benefit in double-blind studies, oral glucosamine sulfate was shown to offer significant benefit in a n open trial involving 252 doctors and 1506patients in Portugal.32The patients received 500 mg of glucosamine sulfate three times daily over a mean period of 50 days. Symptoms of pain at rest, on standing, and on exercise and limited active and passive movements improved steadily throughout the treatment period. Objective therapeutic efficacy was rated by doctors as "good" in 59% of patients and "sufficient" in an additional 36%. Therefore a total of 95% of patients achieved benefit from glucosamine sulfate. The results with glucosamine sulfate were rated by both doctors and patients as being significantly better than those obtained with previous treatment including NSAIDs, vitamin therapy, and cartilage extracts. Glucosamine sulfate produced good benefit in a significant portion of patients who had not responded to any other medical treatment. In the study, obesity was associated with a sigruficant shift from good to fair. This finding may indicate that higher dosages may be required for obese individuals or that oral glucosamine is not enough to counteract the stress of obesity on the joints. Patients with peptic ulcers and individuals taking diuretics were also associated with a shift from good to sufficient in efficacy, as well as tolerance. Individuals with current peptic ulcers should try to take glucosamine sulfate with foods. Individuals taking diuretics may need to increase the dosage to compensate for the reduced effectiveness. The improvement with glucosamine lasted for a period of 6 to 12 weeks after the end of treatment. This result indicates that glucosamine may have to be taken for long periods of time or in repeated short-term courses. So far, there have been no published studies documenting arthroscopic regeneration of articular cartilage following glucosamine administration.u It does appear that at least 1 month of treatment is necessary before achieving therapeutic re~u1ts.l~ Although most studies use the sulfate form, there are some studies that also use the hydrochloride form of glucosamine. In one trial using this form, 200 patients used 2000 mg per day of glucosamine hydrochloride for

5 months, which provided significant pain relief and improved function after 8 weeks.33More studies are necessary to test both forms of glucosamine against each other and in various population subsets in an effort to characterize which form may be indicated in which conditions or populations. Theoretic concern has been expressed that glucosamine may adversely affect blood sugar levels, which could be a concern to diabetic patients, who are known to have an increased incidence of OA. To evaluate this risk, 1500 mg of glucosamine (and 1200 mg of chondroitin) were given daily to a group of diabetics, most of whom were on antiglycemic medications. Studies of hemoglobin Alc levels before and after the 90-day trial revealed no significant changesM This study corroborates a previous 3-year study cited by the authors that used a 1500-mg daily glucosamine dose. Given the safety and excellent tolerability of glucosamine, it is suitable for long-term use, even if continuous. (For additional discussion about the physiologic effects and clinical efficacy of glucosamine sulfate, see Chapter 97.)

Chondroitin Sulfate Chondroitin sulfate, as well as shark cartilage, bovine cartilage extracts, and sea cucumber, contains a mixture of intact or partially hydrolyzed GAGSof molecular weights ranging from 14,000 to more than 30,000. Chondroitin sulfate is composed of repeating units of derivatives of glucosamine sulfate with attached sugar molecules. Although the absorption rate of glucosamine sulfate is 90% to 9870, the absorption of intact chondroitin sulfate is estimated to be anywhere from 0% to 13%.3537The difference in absorption is largely due to the difference in size. Chondroitin sulfate is at least 50 to 300 times larger than glucosamine sulfate, too large to pass the normal intact intestinal barrier. If chondroitin sulfate molecules were absorbed intact or partially digested, they are still unlikely to produce any significant benefit, as the chondroitin sulfate molecules are too large to be delivered to cartilage cells. One of the key reasons why glucosamine sulfate is so effective is that its small molecular size allows it to penetrate the joint cartilage and be delivered to the chondrocyte and stimulate GAG synthesis. It would be nearly impossible for large chondroitin sulfate molecules to produce this effect. Furthermore, chondroitin sulfate levels are typically elevated in the synovial tissues in patients with OA.38These absorption problems suggest that any direct effect of these compounds in OA is highly unlikely. However, conflicting evidence supports the notion that exogenous chondroitin sulfate is indeed absorbed as a high molecular mass polysaccharide together with derivatives originating from a partial depolymerization or desulfatation, or b ~ t h . ~ ~ , ~

Osteoarthritis

Any clinical benefit from chondroitin sulfate is most likely due to the absorption of sulfur or smaller GAG molecules broken down by the digestive tra~t.2~ However, even this is controversial, as in one human study, 1 g of chondroitin sulfate failed to increase serum GAG concentration at all based on a highly sensitive measure of intact or depolymerized GAG absorption. These results prompted the researchers to conclude: “We suggest that chondroprotection by orally administered chondroitin sulfate is a biologically and pharmacologically unfounded theory.”36In a further analysis, these experts on chondroitin sulfate concluded41: Pooled literature on chondroitin sulfate biochemistry offers enough information to assert that neither intact nor polymerized chondroitin sulfate is absorbed by the mammalian gastrointestinal tract. Therefore any direct action of orally administered chondroitin sulfate on cartilage and chondrocytes is not possible.

Despite this unlikely direct action, two published metaanalyses indicated that chondroitin may be superior to placebo in reducing the pain of OA.19One of these analyses may have been exaggerated by publication bias related to the manufacturer’s sponsorship. The second metaanalysisdid find chondroitin to be superior to placebo in reducing the painful symptoms of OA, although these authors did call for trials of longer duration. Finally, one study using 800 mg of chondroitin sulfate for two separate periods of 3 months over 1year did show decreased pain and improved knee function, as well as a decrease in joint space progression over placebo.42This study reveals that even intermittent use of chondroitin may be effective. The few clinical studies that have been done with orally administered chondroitin sulfate demonstrate that it is less effective than glucosamine sulfate.4M6 Furthermore, there is no evidence that using both glucosamine and chondroitin together is more effective than either a l ~ n e .In ~ ,general ~~ the more impressive results have been achieved with glucosamine sulfate. Glucosamine sulfate is faster acting and provides much greater overall benefit. Nevertheless, given the safety record of chondroitin and the evidence of modifying joint space pathology, chondroitin is a reasonable addition to an ostoarthritis patient’s glucosamine regimen.

Niacinamide In the 1940s and 1950s Dr. William Kaufman, and later Dr. Abram Hoffer, reported good clinical results in the treatment of hundreds of patients with rheumatoid arthritis and OA using high-dose niacinamide (i.e., 900 to 4000 mg/day in divided dose^).^,^^ Dr. Kaufman documented improvements in joint function, range of motion, increased muscle strength and endurance, and reduction in the sedimentation rate. Most patients achieved

noticeable benefits within 1to 3 months of use, with peak benefits noted between 1 and 3 years of continuous use. These clinical results were more recently evaluated in a well-designed, double-blind, placebo-controlled trial.50 Seventy-two patients with OA were randomized for treatment with niacinamide (3000 mg daily in six divided dosages) or placebo for 12 weeks. Outcome measures included global arthritis impact and pain, joint range of motion and flexibility, erythrocyte sedimentation rate (ESR), complete blood count, liver function tests, serum cholesterol, serum uric acid, and fasting blood sugar. The researchers found that niacinamide produced a 29% improvement in global arthritis impact compared with a 10% worsening in the placebo group. Pain levels did not change, but those on niacinamide reduced their NSAID use. Niacinamide supplementation reduced the ESR by 22% and increased joint mobility by 4.5 degrees over controls (8 degrees vs. 3.5 degrees); otherwise, there were no other changes in blood chemistry. Side effects, primarily mild gastrointestinal complaints, were more common in the niacinamide group but could be effectively managed by recommending the pills be taken with food or fluids. Niacinamide at this high dose can result in significant side effects (e.g., glucose intolerance, liver damage) and therefore requires strict supervision.

S-Adenosylmethionine (SAMe) S-Adenosylmethionine (SAMe) is an important physiologic agent formed in the body by combining the essential amino acid methionine to adenosine triphosphate (ATP). A deficiency of SAMe in the joint tissue, just like a deficiency of glucosamine, leads to loss of the gellike nature and shock-absorbing qualities of cartilage. A metaanalysis of 11studies reports the benefits of SAMe in the treatment of OA by reducing pain and improving functional limitation^.^^ SAMe has been shown to be important in the manufacture of cartilage component^.^^ In one double-blind study, supplemental SAMe increased cartilage formation, as determined by magnetic resonance imaging (MRI),in 14 patients with OA of the In addition to this effect, SAMe has also demonstrated some mild painrelieving and antiinflammatory effects in animal studies. A total of 21,524 patients with OA have been treated with SAMe in published clinical trials. In double-blind trials, SAMe has demonstrated similar reductions in pain scores and clinical symptoms to NSAIDS like ibuprofen, indomethacin, naproxen, and piroxicam. In one double-blind study, SAMe was compared with the popular drug ibuprofen (e.g., Advil, Motrin, Nuprin).% The 36 subjects with OA of the knee, hip, spine, or all three received a daily oral dose of 1200 mg of SAMe or 1200 mg of ibuprofen for 4 weeks. Morning stiffness, pain at rest, pain on motion, swelling, and

limitation of motion of the affected joints were assessed before and after treatment. The total score of the individual clinical parameters improved to the same extent in patients treated with SAMe or ibuprofen. In two other studies SAMe was shown to produce slightly better results than ibupr0fen.5~3 SAMe has been compared with naproxen (Naprosyn) in several studies. In one double-blind study, 20 patients with OA of the knee were given either SAMe or naproxen for 6 ~ e e k s . During 5~ the first week, SAMe was administered at a dose of 400 mg tid and afterward at a dose of 400 mg bid, whereas the dose of naproxen during the first week was 250 mg tid and subsequently 250 mg bid. During the first 2 weeks, the patients were allowed to take the drug paracetamol as an additional analgesic if the pain was severe. The patients were examined at the beginning of the study and after 2,4, and 6 weeks. The parameters tested were: pain, joint swelling, circumference of joint, extent of motility and walking time over 10 m. At the end of the sixth week, no statistically significant difference between the two patient groups treated was found; both groups exhibited a marked improvement on all parameters. Another double-blind study compared SAMe with both naproxen and placebo in the treatment of OA of the hip, knee, spine, and hand.% The study involved 33 rheumatologc and orthopedic medical centers and a total of 734 subjects. SAMe administered orally at a dose of 1200 mg daily was shown to exert the same analgesic (pain-relieving) activity as naproxen at a dose of 750 mg daily. However, SAMe was significantly more effective than naproxen, both in terms of physicians’ and patients’ judgments and in terms of the number of patients with side effects. In fact, SAMe was better tolerated than the placebo. Ten patients in the SAMe group and 13 in the placebo group withdrew from the study because of intolerance to the drug. Other double-blind studies have shown SAMe to offer the pain-relieving and antiinflammatory benefit of drugs like indomethacin (Indocin and Indometh) and piroxicam (Feldene), but it is generally much better tolerated than these potent N S A I D S . ~ ~ , ~ Perhaps the most meaningful study of SAMe in the treatment of OA was a long-term, multicenter, open 2year trial of 97 patients with OA of the knee, hip, and spine.6lThe patients received 600mg of SAMe for the first 2 weeks and thereafter 400 mg daily until the end of the 24 months of treatment. Separate evaluations were made for OA of the knee, hip, cervical spine, and dorsal/lumbar spine. The severity of the clinical symptoms (morning stiffness, pain at rest, and pain on movement) was assessed using scoring before the start of the treatment, at the end of the first and second weeks of treatment, and then monthly until the end of the 24month period. Clinical improvement was evident after the first

week of treatment and continued through 24 months. Nonspecific side effects occurred in 20 patients, but in no case did therapy have to be discontinued. Most side effects disappeared during the course of therapy. Moreover, during the last 6 months of treatment, no adverse effect was recorded. Detailed laboratory tests carried out at the start and after 6,12,18, and 24 months of treatment showed no pathologic changes. SAMe administration also helped to relieve the depression often associated with OA. The largest study evaluated 20,641 patients with OA of the knee, hip, and spine and also with osteoarthritic polyarthritis of the fingers over an 8-week The patients were given 400 mg three times of SAMe daily for the first week, 400 mg twice daily for the second week, and 200 mg twice daily from the third week on. No additional analgesic/antiinflammatory treatment was allowed. The efficacy of SAMe was comparable to results achieved with NSAIDs. Efficacy was described as very good or good in 71% of cases, moderate in 21%, and poor in 9% of cases. The tolerance was assessed as very good or good in 87%,moderate in 8%, and poor in 5% of cases. All of these studies indicate that SAMe offers sigruficant advantages over NSAIDs. Although the drugs are associated with a significant risk of toxicity, side effects, and actual promotion of the disease process in OA, SAMe offers similar benefits with minimal risk or side effects. Side effects include occasional gastrointestinal disturbances, mainly diarrhea.19

Superoxide Dismutase Intraarticular injections of superoxide dismutase (SOD) have demonstrated sigruficant therapeutic effects in the keatment of OA.63*61 Whether oral SOD preparations are absorbed orally is yet to be determined. Preliminary indications are that they probably are not.65

Vitamin E A clinical trial using 600 IU of vitamin E in patients with OA demonstrated significant benefit.%The benefit was thought to be due to vitamin E’s antioxidant and membrane-stabilizing actions. In vitro studies have shown that vitamin E has an ability to inhibit the activities of lysosomal enzymes and stimulate increased deposition of pr~teoglycan.~~ However, one 6-month, double-blinded trial using 500 IU/day did not show any benefit.@

Vitamin C Deficient intake of vitamin C is common in the elderly, resulting in altered collagen synthesis and compromised connective tissue repair.67Several in vitro studies have demonstrated that vitamin C has an anabolic effect on ~ a r t i l a g e . Research ~ ~ , ~ ~ has confirmed the importance, indeed necessity, for an excess of ascorbic acid in human

Osteoarthritis

chondrocyte protein synthesis.71One in vivo study of experimental OA in guinea pigs found that cartilage erosion was much less and the overall histologic and biochemical changes in and around the OA joint much milder in animals kept on high doses of vitamin C.67 Vitamins C and E appear to possess synergistic effects.67 The researchers concluded: Thus, both vitamins E and C appear to enhance the stability of sulfated proteoglycans in the complex structure comprising articular cartilage. Judicious use of these vitamins in the treatment of OA, either alone or in combination with other therapeutic means, may thus be of great benefit to the patient population by retarding the erosion of cartilage.

supplementation (6 to 9 mg daily) produced effective relief in 90% of arthritis patients including patients with OA, juvenile arthritis, and rheumatoid arthritisn The preliminary indication is that boron supplements are of value in arthritis, with many OA patients experiencing complete resolution.

Physical Therapy

Skewed musculoskeletal dynamics play a role in abnormally stressing involved joints. Despite this relatively simple concept, it is only recently that this idea has been researched. An 18-month study of 230 patients with tibiofemoral osteophytes and at least some difficulty with knee-requiring activity revealed conclusively that Vitamin D patients with v a n s alignment had a fourfold increased risk of medial OA progres~ion.’~ Similarly, those with A study of vitamin D levels in 556 participants of the valgus alignment showed almost five times the risk Framingham Heart Study indicates that low intake and of lateral OA progression. Not surprisingly, these low serum levels of vitamin D each appear to be associresearchers learned that the decline was greater for those ated with an increased risk for progression of OA of the with more extensive misalignments. This clearly docuknee.72Low serum levels of vitamin D also predict loss ments the importance of considering musculoskeletal of cartilage, as assessed by loss of joint space and osteodynamics when evaluating any subject presenting with phyte growth. It seems reasonable to consider that OA. Those with misalignments may need to consider exposure to adequate amounts of sunlight, as well as manual manipulation therapies, orthotics, and extremity sufficient intake in childhood and young adulthood, adjustments, along with techniques such as regular masmay help decrease the risk of OA. Although vitamin D sage therapy, to relax hypertonic muscles. From a premay help prevent OA, it is unknown whether increasing vention standpoint, assessing and treating younger vitamin D intake will help decrease or reverse already individuals may also decrease the risk of OA later in life. established OA pathology. In addition to addressing alignment issues, various Pantothenic Acid physical therapy modalities (e.g., exercise, heat, cold, diathermy, ultrasound) are often beneficial in improving Acute deficiency of pantothenic acid in the rat causes joint mobility and reducing pain in OA, especially when a pronounced failure of cartilage growth and eventuadministered regularly (Box 195-4). Much of the benefit ally produces lesions similar to OA. Clinical improveof physical therapy is thought to be a result of achieving ment in OA symptomatology with the administration of 12.5 mg pantothenic acid has been r e p ~ r t e d . ~ ~proper , ~ ~ hydration within the joint capsule. Clinical and experimental studies seem to indicate Results often did not manifest for 7 to 14 days. However, that short-wave diathermy may be of the greatest benea larger, double-blind study in patients with primafit.79-81 Combining short-wave diathermy therapy with rily rheumatoid arthritis displayed no significant periodic ice massage, rest, and appropriate exercises benefit from administration of 500 mg of pantothenic acid.75

Vitamins A and E, Pyridoxine, Zinc, Copper, and Boron These nutrients are required for the synthesis of collagen and maintenance of normal cartilage structures. A deficiency of any one of these would allow accelerated joint degeneration. In addition, supplementation at appropriate levels may promote cartilage repair and synthesis. For example, boron supplementation has been used in the treatment of OA in Germany since the mid-1970s. This use was recently evaluated in a small, double-blind, clinical study and an open trial. In the double-blind study, of the patients given 6 mg of boron (as sodium tetraborate decahydrate), 71% improved compared with only 10% in the placebo In the open trial, boron

Acupuncture Psychologic aids Exercise Physical therapy Ultrasound Transcutaneous nerve stimulation Laser therapy Diathermy Thermal baths Massage Weight loss

appears to be the most effective approach. Ultrasound and laser therapy have also been shown to be helpfdS2fi3 The best exercises are isometrics and swimming. These types of exercises increase circulation to the joint and strengthen surrounding muscles without placing excess strain on joints. Increasing quadriceps strength has been shown to improve the clinical features and reduce pain in OA of the knee.84Walking programs help to improve functional status and relieve pain in patients with OA of the knee.S5 Patient-specific physical therapies may also be useful. For example, four older adults with hand OA benefitted from keyboard playing for 20 minutes a day, 4 days a week.%

Acupuncture Traditional Chinese medicine typically views OA as a “bi” or pain syndrome, with pathogenic etiologies stemming from coldness, dampness, heat, and wind. Each one of these types typically has a separate clinical picture and requires specific acupuncture points for that respective condition. Standard Western medical systems have been slow to adopt acupuncture practice as standard adjunctive care despite the mounting research evidence that supports the safety and efficacy of reducing pain from OA with a c u p u n ~ t u r e . ~ ~ , ~ For example, a number of studies have focused on knee OA. One observational study of 563 patients (88% female) with chronic knee OA found that 75% of the remainder achieved a reduction in pain of 45% or more with a c ~ p u n c t u r eAn . ~ ~open, randomized, controlled trial evaluated the effect of acupuncture with and without adjunct conventional medications.g0In this study 30 patients with symptomatic knee OA were randomized to one of three treatment groups. Those patients given acupuncture only or acupuncture combined with conventional medications achieved a highly significant improvement in pain. The acupuncture-free group experienced no change until after a course of acupuncture later in the study, when their improvement became sigruficant. Similarly, significant positive changes were seen with pain and stiffness scores. These benefits were maintained during the month following the acupuncture course. Traditional Chinese medicine considers an etiology of pain as “stuck qi.” In this case, an addition of electrical energy to the area can reestablish qi flow, thus alleviating pain. One single-blinded, randomized, controlled study examined the effectiveness of electroacupuncture and a Western electrical treatment called transcutaneous electrical nerve stimulation (TENS) to alleviate osteoarthritic-induced knee pain.91 In this research 24 subjects (23 women and 1 man) with a mean age of 85 were given electroacupuncture, TENS, or no treatment. Subjects in the electroacupuncture group received low frequency (2 Hz) on two local acupuncture points

(ST-35, Dubi and Neixiyan) of the painful knee for 20 minutes. Subjects in the TENS group received lowfrequency TENS of 2 Hz and pulse width of 200 ps on the same acupuncture points for 20 minutes. In both treatment groups, electrical treatment was carried out for a total of eight sessions in 2 weeks. The other control subjects received osteoarthritic knee care and education only. After eight sessions, there was significant reduction of knee pain in both the electroacupuncture and TENS groups with prolonged analgesic effect at a 2-week follow-up evaluation. Electroacupuncture also gained an advantage by lowering scores for the TimedUp-and-Go Test, which TENS did not achieve. Electroacupuncture has also been tested in a headto-head, 186-patient, randomized, single-blind, placebocontrolled trial against the NSAID d i ~ l o f e n a cFor . ~ ~these knee patients, improvement of OA symptoms in most outcome parameters was greatest in the electroacupuncture group. Unlike the diclofenac and placebo groups, most of the patients rated their results with electroacupuncture as “much better,” and substantiallybetter pain management and functionality were obtained in the electroacupuncture group as well. When considering an acupuncture regimen, researchers of one randomized, controlled trial for patients with OA of the knee concluded that acupuncture is most effective when employed early in the treatment plan. Additionally, on the basis of patient evaluations, it seems that treatments should be administered with a tapering, methodic decrease in frequency once the acute treatment period is completed to avoid a rebound effect.93Because it has been reported that the density of peripheral nerve endings in the skin or muscles is much greater in the acupuncture points as compared with areas beyond these it is possible that an abrupt lack of stimulation in these areas may untowardly affect neurotransmitter release to contribute to a rebound effect. Although more accurate methodologies are clearly necessary to expound on the benefits of a~puncture?~ given its few-thousand-year history of efficacy and safety, acupuncture is an excellent treatment option for OA pain. We recommend combination naturopathic treatment protocols with acupuncture to optimally repair and nourish the affected areas and reduce pain.

Magnetic Therapies Magnetic therapy has been used in the treatment of a wide variety of chronic pain syndrome^.^^ Magnetic fields may have the ability to stimulate chondrocyte proliferation and increase synthesis of proteoglycans.” A number of studies clearly support magnetic therapy when used for knee OA.97-100One is a multicenter, double-blind, randomized, placebo-controlled trial that enrolled 75 patients with OA of the knee who had

Osteoarthritis

previously been unable to obtain acceptable results using conventional treatment^.^^ Using low-frequency pulsed fields, improvements in the level of pain, functionality, and physician global evaluation of patients' condition were notable. Mean morning stiffness also decreased by 20 minutes in the group using magnetic therapy, while increasing by 2 minutes in the placebo group. A second placebo-controlled, randomized, double-blind clinical study of 176 patients with osteoarthritic knees also showed significant results using low-amplitude and low-frequency fields.99 Reduction in pain after a treatment session was significantly greater in the magnet-on group (46%) compared with the magnet-off group (8%). A smaller, 29-subject study of knee OA used either high-strength magnetic or placebo knee-sleeve treatment for 4 hours in a monitored setting and self-treatment 6 hours daily for 6 weeks.98This study demonstrated a significant decrease in pain scores in the active group and only a minimal improvement in the placebo group at 4 hours of treatment, but no significant differences at 6 weeks. Magnetic therapies may be a useful treatment for OA.

Relaxation Relaxation techniques such as meditation, deep breathing, and guided imagery have been used for many types of pain conditions. A study of 66 elderly people suffering from chronic OA pain evaluated the effect of daily music listening on pain levels from OA.'O' Differences in perceptions of pain were measured over 14 days in an experimental group who listened to Mozart selections for 20 minutes daily and a control group who sat quietly for 20 minutes daily. Those who listened to music had less pain when compared with those who sat quietly and did not listen to music. The amount of pain perceived by the Mozart group also decreased incrementally over the 14-day study period.

Botanical Medicines Historically, many herbs have been used in the treatment of OA. When inflammation is present, those botanicals and nutritional factors possessing antiinflammatory activity are indicated. Examples include bromelain, curcumin, and ginger.

Yucca A double-blind clinical trial found that a saponin extract of yucca demonstrated a positive therapeutic effect.lo2 Results were of gradual onset, and no direct joint effects of the yucca saponin were noted. The researchers suggested that the clinical improvement was due to indirect effects on the gastrointestinal flora. This is a n interesting suggestion because bacterial lipopolysaccharides (endotoxins) have been shown to depress the biosynthesis of proteogly~ans.'~~ It is entirely possible

that yucca decreases bacterial endotoxin absorption and thus reduces this inhibition of proteoglycan synthesis. If this is the mechanism of action, then other saponin-containing herbs and other ways of reducing endotoxin load may be useful.

Harpagophytum procumbens (Devil's Claw) Several pharmacologic studies using experimental animal models of inflammation have reported that Devil's claw possesses an antiinflammatory and analgesic effect comparable to pheny1b~tazone.l~~ However, other studies have indicated that Devil's claw has little, if any, antiinflammatory activity in experimental inflarnmati~n.'~~J" The equivocal research results may reflect a mechanism of action that is inconsistent with current antiinflammatory models or a lack of quality control (standardization) of the preparations used. Because the main components of Devil's claw are saponins, its therapeutic effect in OA may be similar to that observed for yucca.

Boswellia serrata

Another herb historically used in the treatment of osteoarthritis is Boswellia serrutu, a large branching tree native to India. Boswellia yields an exudative gum resin known as salai guggul. Although salai guggul has been used for centuries, newer preparations concentrated for the active components (boswellic acids) are giving better results. Boswellic acid extracts have demonstrated antiarthritic effects in various animal models. Among several mechanisms of action are inhibition of inflammatory mediators, prevention of decreased GAG synthesis, and improved blood supply to joint t i s s ~ e s . ~ ~ ~ J ~ ~ Clinical studies using herbal formulas with Boswellia have yielded good results in both OA and rheumatoid arthritis.lWThe standard dosage for boswellic acids in arthritis is 400 mg tid. No side effects due to boswellic acids have been reported.

Zingiber oflicialinalis (Ginger) A 6-week, multicenter, randomized, controlled trial of 261 patients with knee OA given ginger extract or placebo found a moderate effect on symptoms where 63% of the ginger subjects found relief versus 50% of the placebo users.11oThose in the ginger group resorted to acetaminophen less frequently and had a reduction in knee pain on standing and after walking. Albeit mild, patients receiving ginger extract experienced more gastrointestinal adverse events than did the placebo group (59 patients vs. 21 patients). One double-blind, crossover trial found efficacy of 170 mg of ginger tid before the crossover. By the end of the study, there was no benefit of ginger over placebo."'

Specific Health Problems Clearly, more studies are necessary to assess ginger’s effectiveness for OA.

Topical Applications Fatty Acids

to a minimum.Plants of the Solanaceae family should be eliminated (tomatoes, potatoes, eggplant, peppers, and tobacco). Liberal consumption of flavonoid-rich berries or extracts is also important.

Cetylated fatty acids are similar to omega-3 fatty acids such as those found in fish oils. Omega-3 fatty acids have been employed for both the internal and topical treatment of OA. One group studied the use of cetylated fatty acids in patients with OA of the knee. Two groups of 20 patients were randomized to receive either the cetylated fatty acid or placebo cream.l12Patients applied creams bilaterally to the anterior, posterior, and lateral surfaces of the knees. Using functional tests including range of motion and timed evaluations of patients getting up from a chair and walking up and down steps, patients were tested before treatment, 30 minutes after the initial applications, and after 30 days of two treatments per day. Compared with the placebo, significant decreases in timing were reported for stair climbing and for getting up from a chair after the initial treatment, as well as at 1 month. Range of motion was also clearly improved. There was slight improvement in the placebo group as well, and the authors of this study postulated that the massaging of the knees to apply the cream may have been responsible for the benefit in the placebo group.

Supplements

THERAPEUTIC APPROACH

Topical Application

Although there appear to be several worthwhile approaches to control OA through natural therapies, a direct clinical study of a comprehensive, integrated program has yet to be conducted. The therapeutic approach recommended here is based on reducing joint stress and trauma, promoting collagen repair mechanisms, and eliminating foods and other factors that may inhibit normal collagen repair. All diseases or predisposing factors (see Table 195-1) should, of course, be controlled. Nonsteroidal antiinflammatory drugs such as aspirin should be avoided as much as possible. If aspirin must be used, deglycyrrhizinated G. glabra (or Robert’s formula) should be used to help protect the gastrointestinal tract from its damaging effects and its use should be discontinued as soon as possible.

Cetylated fatty acid cream can be applied to the affected area bid.

Diet All simple, processed, concentrated carbohydrates must be avoided; complex-carbohydrate, high-fiber foods should be emphasized; and fats should be kept

Glucosamine sulfate: 1500 mg/day ~Niacinamide:500 mg six times/day (under strict supervision-liver enzymes must be regularly assayed) Vitamin E: 600 IU/day Vitamin A: 5000 IU/day Vitamin C: 1000 to 3000 mg/day Vitamin B6: 50 mg/day Pantothenic acid: 12.5 mg/day SAM: 400 mg tid Zinc: 45 mg/day Copper: 1 mg/day Boron: 6 mg/day

Botanical Medicines M. sativu: equivalent to 5 to 10 g/day Yucca leaves: 2 to 4 g tid Haryagophytum procumbens Dried powdered root-1 to 2 g tid Tincture (1:5)-4 to 5 ml tid Dry solid extract (3:1)-400 mg tid B. serruta: equivalent to 400 mg boswellic acids tid

Physical Therapy and Exercise Physical activity that induces physiologic or traumatic strain such as occupational or recreational overuse of a joint must be avoided. Normalization of posture and orthopedic correction of structural abnormalities should be used to limit joint strain. Daily, nontraumatic exercise (isometrics and swimming) is important but should be carefully monitored. Short-wave diathermy, hydrotherapy, and other PT modalities that improve joint perfusion are indicated.

Acupuncture Acupuncture can be administered two to four times weekly until acute symptoms resolve. Then the frequency of treatments should be gradually decreased. Maintenance treatments once every 2 weeks to once a month may help prevent recurrence.

Osteoarthritis

1.SchnitzerTJ.Osteoarthritis. In Bennett JC, Plum F, eds. Cecil textbook of medicine. Philadephia: Saunders, 19961517-1521. 2. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletaldisorders in the United States. Arthritis Rheum 1998;41:77&799. 3. Bland JH, Cooper SM. Osteoarthritis a review of the cell biology involved and evidence for reversibility. Management rationally related to known genesis and pathophysiology. Semin Arthritis Rheum 1984;14106-133. 4. Hinton R, Moody RL, Davis AW, et al. Osteoarthritis: diagnosis and therapeutic considerations. Am Fam Physician 2002;65: 841-848. et al. Radiographic assess5. Summers MN, Haley WE, Reveille JD, ment and psychologic variables as predictors of pain and functional impairment in osteoarthritis of the knee or hip. Arthritis Rheum 1988;31:204-209. 6. Perry GH, Smith MJ, Whiteside CG. Spontaneous recovery of the hip joint space in degenerative hip disease. Ann Rheum Dis 1972; 31:440-448. 7. Shield MJ. Anti-inflammatory drugs and their effects on cartilage synthesis and renal function. Eur J Rheumatol Inflam 1993;13:7-16. 8. Brooks PM, Potter SR, Buchanan WW. NSAID and osteoarthritishelp or hindrance. J Rheumatol19829:3-5. 9. Newman NM,Ling RS.Acetabular bone destruction related to nonsteroidal anti-inflammatory drugs. Lancet 1985;Zll-13. 10. Solomon L.Drug induced arthropathy and necrosis of the femoral head. J Bone Joint Surg 1973;55246-261. 11. Ronningen H,Langeland N. Indomethacin treatment in osteoarthritis of the hip joint. Acta M o p Scand 1979;50:169-174. 12.Dequeker J, Burssens A, Bouillon R. Dynamics of growth hormone secretion in patients with osteoporosis and in patients with osteoarthrosis. Horm Res 1982;16353-356. 13. Hartz AJ, Fischer ME, Bril G, et al. The association of obesity with joint pain and osteoarthritis in the Hanes data. J Chronic Dis 1986; 39~311-319. 14. Felson D, Zhang Y, Anthony JM, et al. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. Ann Intern Med 1992;116535-539. 15. Huang MH,Chen CH, Chen TW, et al. The effects of weight reduction on the rehabilitation of patients with knee osteoarthritis and obesity. Arthritis Care Res 2000;13398405. 16. Messier SP,Loeser RF, Miller GD, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum 2004;501501-1510. 17.Childers NF, Russo GM. The nightshades and health. Somerville, NJ: Horticulture Publications, Somerset Press, 1977. 18. McAlindon TE,Jacques P, Zhang Y, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum 199639:648-656. 19. Morelli V, Naquin C, Weaver V. Alternative therapies for traditional disease states: osteoarthritis. Am Fam Physician 2003;67339-344. 20. Karzel K, Domenjoz R. Effect of hexosamine derivatives and uronic acid derivatives on glycosaminoglycan metabolism of fibroblast cultures. Pharmacology 1971;5:337-345. 21. Vidal y Plana RR, Bizzarri D, Rovati AL. Articular cartilage pharmacology. I. In vitro studies on glucosamine and non steroidal antiinflammatory drugs. Pharmacol Res Commun 1978;10557-569. 22. McAlindon TE,LaValley MP, Gulin JP, et al. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA2OOO;283:1469-1475. 23.Noack W, Fischer M, Forster KK, et al. Glucosamine sulfate in osteoartluitis of the knee.Osteoarthritis Cartilage 1994;2:51-59.

24. Crolle G, D’Este E. Glucosamine sulfate for the management of arthrosis: a controlled clinical investigation. Cum Med Res Opin 1980;7104-109. 25. Pujalte JM, Llavore EP, Ylescupidez FR, et al. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis. Curr Med Res Opin 1980;7110-114. 26. Drovanti A, BignaminiAA, Rovati AL, et al. Therapeutic activity of oral glucosamine sulfate in osteoarthrosis: a placebo-controlled double-blind investigation. Clin Ther 1980;3:260-272. 27. Vajaradul Y. Double-blind clinical evaluation of intra-articular glucosamine in outpatients with gonarthosis. Clin Ther 1981;3: 336-343. 28. DAmbrosio E, Casa B, Bompani R, et al. Glucosamine sulphate: a controlled clinical investigation in arthrosis. Pharmatherapeutica 1982;2:504-508. 29. Lopes Vaz L. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulfate in the management of osteoarthrosis of the knee in out-patients. Curr Med Res Opin 1982;8:145-149. 30.Muller-Fassbender H, Bach GL, Haase W, et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee.Osteoarthritis Cartilage 1994;261-69. 31. Reichelt A, Forster KK, Fischer M, et al. Efficacy and safety of intramuscular glucosamine sulfate in osteoarthritis of the knee. A randomised, placebo-controlled, double-blind study. Arzneimittelforschung 1994;44:75-80. 32. Tapadinhas MJ,Rivera IC, Bignamini AA, et al. Oral glucosamine sulfate in the management of arthrosis. Report on a multi-centre open investigation in Portugal. Pharmatherapeutica 1982;3157-168. 33. Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med 20039745-49. 34. Scroggie DA, Albright A, Harris MD. The effect of glucosaminechondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003; 1631587-1590. 35. Setnikar I, Palumbo R, Canali S, et al. Pharmacokinetics of glucosamine in man. Arzneimittelforschung 1993;43:1109-1113. 36. Baici A, Horler D, Moser 8, et al. Analysis of glycosaminoglycans in human sera after oral administration of chondroitin sulfate. Rheumatol Int 1992;1281-88. 37. Conte A, Volpi N, Palmieri L, et al. Biochemical and pharmacokinetic aspects of oral treatment with chondroitin sulfate. Arzneimittelforschung 1995;45:918-925. 38. Shinmei M, Kobayashi T, et al. Significanceof the levels of carboxy terminal type II procollagen peptide, chondroitin sulfate isomers, tissue inhibitor of metalloproteinases, and metalloproteinases in osteoarthritis joint fluid. J Rheumatol Suppl1995;4378-81. 39. Volpi N, Oral bioavailability of chondroitin sulfate (Condrosulf) and its constituents in healthy male volunteers. Osteoarthritis Cartilage 2002;1076&777. 40.Conte A, de Bernardi M, Palmieri L, et al. Metabolic fate of exogenous chondroitin sulfate in man. Arzneimittelforschung 1991;41: 768-772. 41. Baici A, Wagenhauser FJ.Bioavailability of oral chondroitin sulfate. Rheumatology Int 1993;134143. 42. Uebelhart D, Malaise M, Marcolongo R, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a oneyear, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage 2004;12:269-276. 43. Pipitone VR. Chondroprotection with chondroitin sulfate. Drugs Exp Clin Res 1991;18:3-7.

Specific Health Problems 44.L' Hirondel JL. [Double-blind clinical study with oral administration of chondroitin sulfate versus placebo in tibiofemoral gonarthrosis.] Litera Rheumatologica 1992;1477-82. 45. Conrozier T, Vignon E. [The effect of chondroitin sulfate treatment in coxarthritis.A double-blind placebo study.] Litera Rheumatologica 1992;1469-75. 46.Morreale P, Manopulo R, Galati M, et al. Comparision of the antiinflammatory efficacy of chondroitinsulfate and diclofenac sodium in patients with knee osteoarthritis. J Rheumatol 1996;23:1385-1391. 47. Kelly GS. The role of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease. Altem Med Rev 1998; 3~27-39. 48. Kaufman W. The common form of joint dysfunction: its incidence and treatment. Brattleboro, VT: EL Hildreth, 1949. 49. Hoffer A. Treatment of arthritis by nicotinic acid and nicotinamide. Can Med Assoc J 1959;81:235-238. 50.Jonas WB, Rapoza CF', Blair WF. The effect of niacinamide on osteoarthritis. A pilot study. Inflamm Res 1996;45:330-334. 51. Soeken KL, Lee WL, Bausell RB, et al. Safety and efficacy of Sadenosylmethionine (SAMe) for osteoarthritis. J Fam Pract 200251:425-430. 52. Harmand MF, Vilamitjana J, Maloche E, et al. Effects of Sadenosylmethionine on human articular chondrocyte differentiation: an in vitro study. Am J Med 1987;83:48-54. 53. Konig H, Stahl H, Sieper J, et al. [Magnetic resonance tomography of finger polyarthritk morphology and cartilage signals after ademetionine therapy.] Aktuelle Radio1 1995;5:36-40. 54. Muller-Fassbender H. Double-blind clinical trial of Sadenosylmethionine versus ibuprofen in the treatment of osteoarthritis. Am J Med 1987;83:81-83. 55. Glorioso S, Todesco S, Mazzi A, et al. Double-blind multicentre study of the activity of Sadenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharmacol Res 1985;5:3949. 56. G l o r i w S, TodescoS, Mazzi A, et al. Double-blind multicentre study of the activity of Sadenosyl-methionine in hip and knee osteoarthritis. Int J Clin Pharmacol Res 1985;5:39-49. 57. Domljan Z, Vrhovac B, Durrigl T, et al. A doubleblind trial of ademetionine vs naproxen in activated gonarthrosis. Int J C l i Pharmacol Ther Toxic01 1989;27329-333. 58. Caruso I, Pietrogrande V. Italian double-blind multicenter study comparing Sadenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease. Am J Med 1987;8366-71. 59. Vetter G. Double-blind comparative clinical trial with Sadenosylmethionine and indomethacin in the treatment of osteoarthritis. Am J Med 1987;83:78-80. 60.Maccagno A, DiGiorgio EE, Caston OL, et al. Double-blind controlled clinical trial of oral Sadenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med 1987;8372-77. 61. Konig B. A long-term (twoyears) clinical trial with Sadenosylmethionine for the treatment of osteoarthritis. Am J Med 1987;83: 89-94. 62. Berger R, Nowak H. A new medical approach to the treatment of osteoarthritis. Report of an open phase N study with ademetionine (Gumbaral). Am J Med 1987;83:84-88. 63. Lund-Olesen K, Menander KB. Orgotein: a new anti-inflammatory metalloprotein drug. Preliminary evaluation of clinical efficacy and safety in degenerative joint disease. Curr Ther Res Clin Exp 1974;16:706-717. 64.Huskisson EC, Scott J. Orgotein in osteoarthritis of the knee joint. Eur J Rheumatol Inflam 1981;4:212. 65. Zidenberg-Cherr S, Keen CL, Lonnerdal B, et al. Dietary superoxide dismutase does not affect tissue levels. Am J Clin Nutr 1983;375-7. 66. Machtey I, Ouaknine L. Tocopherol in osteoarthritis: a controlled pilot study. J Am Ger Soc 1978;26328-330. 67. Schwartz ER. The modulation of osteoarthritic development by vitamins C and E. Int J Vitam Nutr Res Suppl1984;26141-146.

68. Brand C, Snaddon J, Bailey M, et al. Vitamin E is ineffective for symptomatic relief of knee osteoarthritis: a six month double blind, randomised, placebo controlled study. Ann Rheum Dis 2001;60 946-949. 69. Bates CJ. Proline and hydroxyproline excretion and vitamin C status in elderly human subjects. Clin Sci Mol Med 1977;52535-543. 70. Prins AP, Lipman JM, McDevitt CA, et al. Effect of purified growth factors on rabbit articular chondrocytes in monolayer culture. II. Sulfated proteoglycan synthesis. Arthr Rheum 1982;25:1228-1238. 71. Krystal G, Morns GM, Sokoloff L. Stimulation of DNA synthesis by ascorbate in cultures of articular chondrocytes. Arth Rheum 1982;25:318-325. 72. McAlindon TE, Felson DT, Zhang Y, et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knees among participants in the Framingham Study. Ann Intern Med 1996;125:353-359. 73. Anand JC. Osteoarthritis and pantothenic acid. J Coll Gen Pract 1963;5136-137. 74. Anand JC. Osteoarthritis and pantothenic acid. Lancet 1963;41:1168. 75.Calcium pantothenate in arthritis conditions. A report from the General Practitioner Research Group. Practitioner 1980;22420&211. 76. Travers RL, Rennie GC, Newnham RE. Boron and arthritis. The results of a double-blind pilot study. J Nutr Med 1990;1:127-132. 77. Newnham RE. Arthritis or skeletal fluorosis and boron. Int Clin Nutr Rev 1991;11:68-70. 78. Sharma L, Song J, Felson DT, et al. The role of knee alignment in disease progression and functional decline in knee osteoarthritis. JAMA 2001;286:792. 79. Wright V. Treatment of osteo-arthritis of the knees. Ann Rheum Dis 1961;23:389-391. 80.Clarke GR, Willis LA, Stenners L, et al. Evaluation of physiotherapy in the treatment of osteoarthrosis of the knee. Rheumatol Rehabil 1974;13:190-197. 81. Vanharanta H. Effect of short-wave diathermy on mobility and radiological stage of the knee in the development of experimental osteoarthritis. Am J Phys Med 1982;61:59-65. 82. Falconer J, Hayes KW, Chang RW. Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial. Arthritis Care Res 1992;5:29-35. 83. Stelian J, Gil I, Habot B, et al. Improvement of pain and disability in elderly patients with degenerative osteoarthritis of the knee treated with narrow-band light therapy. J Am Geriatr Soc 1992;4023-26. 84. Fisher NM, Pendergast DR, Gresham GE. Muscle rehabilitation: its effects on muscular and functional performance of patients with knee osteoarthritis. Arch Phys Med Rehabil1991;72367-374. 85. Kovar PA, Allegrante JP, MacKenzie CR, et al. Supervised fitness walking in patients with osteoarthritis of the knee. A randomized controlled trial. Ann Intern Med 1992;116:529-534. 86. Zelazny CM. Therapeutic instrumental music playing in hand rehabilitation for older adults with osteoarthritis: four case studies. J Music Ther 2001;38:97-113. 87. Soeken KL. Selected CAM therapies for arthritis-related pain: the evidence from systematic reviews. Clin J Pain 2004;2013-18. 88. Ferrandez Infante A, Garcia Olmos L, Gonzalez Gamarra A, et al. [Effectiveness of acupuncture in the treatment of pain from osteoarthritis of the knee.] Aten Primaria 2002;30:602-608. 89. Vas J, Perea-Milla E, Mendez C. Acupuncture and moxibustion as an adjunctive treatment for osteoarthritis of the knee-a large case series. Acupunct Med 2004;22:23-28. 90. Tukmachi E, Jubb R, Dempsey E, et al. The effect of acupuncture on the symptoms of knee osteoarthritis-an open randomised controlled study. Acupunct Med 2004;2214-22. 91. Ng MM, Leung MC, Poon DM. The effects of electro-acupuncture and transcutaneous electrical nerve stimulation on patients with painful osteoarthritic knees: a randomized controlled trial with follow-up evaluation. J Altem Complement Med 2003;9:641-649.

Osteoarthritis 92. Sangdee C, Teekachunhatean S, Sananpanich K. Electroacupuncture versus diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. BMC Complement Altem Med 2002;2:3. 93. Singh BB, Berman BM, Hadhazy V, et al. Clinical decisions in the use of acupuncture as an adjunctive therapy for osteoarthritis of the knee. Altem Ther Health Med 2001;758-65. 94. Li AH, Zhang JM, Xie YK. Human acupuncture points mapped in rats are associated with excitable muscle/skin-nerve complexes with enriched nerve endings. Brain Res 2004;1012:154-159. 95. Boutron I, Tubach F, Giraudeau B, et al. Methodological differences in clinical trials evaluating nonpharmacological and pharmacological treatments of hip and knee osteoarthritis. JAMA 2003;2901062-1070. 96. Panagos A, Jensen M, Cardenas DD. Treatment of myofascial shoulder pain in the spinal cord injured population using static magnetic fields: a case series. J Spinal Cord Med 2004;27 138-142. 97. Pipitone N, Scott DL. Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlledstudy. Curr Med Res Opin 2001;17190-196. 98. Wolsko PM, Eisenberg DM, Simon LS, et al. Double-blind placebocontrolled trial of static magnets for the treatment of osteoarthritis of the knee: results of a pilot study. Altem Ther Health Med 2004; 1036-43. 99. Jacobson JI, Gorman R, Yamanashi WS, et al. Low-amplitude, extremely low frequency magnetic fields for the treatment of osteoarthritic knees: a double-blind clinical study. Altem Ther Health Med 2001;754-64,66-69. 100. Nicolakis P, Kollmitzer J, Crevenna R, et al. Pulsed magnetic field therapy for osteoarthritis of the knee-a double-blind sham-controlled trial. Wien Klin Wochenschr 2002;114:678-684. 101. McCaffrey R, Freeman E. Effect of music on chroNc osteoarthritis pain in older people. J Adv Nurs 2003;44:517-524.

102. Bingham R, Bellew BA, Bellew JG. Yucca plant saponin in the management of arthritis. J Appl Nutr 1975;2745-50. 103. Morales TI, Wahl LM, Hascall VC. The effect of bacterial lipopolysaccharides on the biosynthesis and release of proteoglycans from calf articular cartilage cultures. J Biol Chem 1984; 259:6720-6729. 104. Brady LR, Tyler VE,Robbers JE. Pharmacognosy, ed 8. Philadelphia: Lea & Febiger, 1981:480. 105.Whitehouse LW, Znamirowski M, Paul CJ. Devil’s claw (Hurpugophytum procumbens): no evidence for anti-inflammatory activity in the treatment of arthritic disease. Can Med Assoc J 1983;129:249-251. 106. McLeod DW, Revel1 P, Robinson BV. Investigations of Harpugophyfum procumbens (Devil’s claw) in the treatment of experimental inflammation and arthritis in the rat. Br J Pharmacol 1979;66:140P-141P. 107. Singh GB, Atal CK. Pharmacology of an extract of salai guggal ex-Bosewellia serrata, a new non-steroidal anti-inflammatory agent. Agents Action 1986;18:407-412. 108. Reddy GK, Chandrakasan G, Dhar SC.Studies on the metabolism of glycosaminoglycans under the influence of new herbal antiinflammatory agents. Biochem Pharmacol1989;38:3527-3534. 109. Kulkani RR,Patki PS,Jog VP, et al. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study. J Ethnopharmacol1991;33:91-95. 110. Altman RD, Marcussen KC. Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum 2001;44: 2531-2538. 111. Bliddal H,Rosetzsky A, SchlichtingP, et al. A randomized, placebocontrolled, cross-over study of ginger extracts and ibuprofen in osteoarthritis. Osteoarthritis Cartilage 2000;8:9-12. 112. Kraemer WJ, Ratamess NA, Anderson JM, et al. Effect of a cetylated fatty acid topical cream on functional mobility and quality of life of patients with osteoartluitis. J Rheumatol20@4;31:767-774.

Osteoporosis Tori Hudson, ND Michael T. Murray, ND CHAPTER CONTENTS Diagnostic Summary

1977

General Considerations 1977 Pathophysiology 1977 Risk Factors 1978 Genetic Factors 1978 Lifestyle 1978 Hormonal Factors 1978 Additional Factors 1979

Therapeutic Considerations 1981 Drug Therapy 1981 Lifestyle Factors 1982 Exercise 1982 General Dietary Factors 1982 Nutritional Supplements 1984 Therapeutic Approach Exercise 1988 Diet 1988 Supplements 1988

1988

Diagnostic Considerations 1979 Radiologic Tests of Bone Mineral Density 1980 Laboratory Tests of Bone Metabolism 1980

DIAGNOSTIC SUMMARY Usually asymptomatic until severe backache Most common in postmenopausal Caucasian women Spontaneous fractures of the hip and vertebra Decrease in height Defined as a T-score at or below a bone mineral density of -2.5 standard deviations below that of a young normal adult

GENERAL CONSIDERATIONS Osteoporosis is the most common bone disease in humans and poses a serious health threat for postmenopausal women. It is characterized by low bone mass and deterioration of the microarchitecture of bone tissue, leading to fragility of the bones and an increase in the risk of a fracture. It currently affects 4 to 6 million postmenopausal Caucasian women in the United States (between 13% and 18%). In the United States, approximately 1.5 million fractures occur every year related to osteoporosis.' Of these, 250,000 are fractures of the hip. An additional 30% to 50%, or 13 to 17 million, have osteopenia (low bone density of the hip). Up to 20% of women with hip fractures die within a year of the fracture, and an additional 25% require long-term nursing care.

Approximately half the women who suffer from a hip fracture are unable to walk without assistance. The hip is not the only site where fractures result in serious morbidity. Vertebral fractures cause significant pain, as well as height loss and an exaggerated kyphosis or deformity of the thoracic spine. In addition to pain, restricted range of motion, changes in posture, restricted lung function, and digestive problems can all be caused by vertebral fractures of the thoracic or lumbar region, or both. Other tolls accumulate due to osteoporosis. Depression, anxiety, low self-esteem, and tooth loss are other physical burdens of the disease. Economically, osteoporosis presents an enormous stress to the health care system. The cost of the disease is estimated to be $14 billion annually. Hip fractures are the most costly due to initial hospital care, first-year postfracture care, and long-term treatment.

PATHOPHYSIOLOGY The process of bone resorption (breakdown) and bone formation is called bone remodeling. Osteoclasts stimulate the production of enzymes that dissolve minerals and protein in bone and thus promote bone resorption. Osteoblasts create a protein matrix primarily of collagen, resulting in remineralization of the bone, 1977

Specific Health Problems thereby promoting bone formation. Bone remodeling is normally a balance of bone resorption and bone formation. An imbalance between bone removal and bone replacement results in bone loss and an increase in the risk of bone fracture. In childhood, bone mass rapidly increases and then slows in the late teens but continues to increase during the 20s. In women, the bone-building process is nearly complete by age 17. After a peak bone mass, which is achieved around age 28, bone is slowly lost an average of 0.4% per year in the femoral neck. After menopause, the rate of loss is faster, with an average of 2% annually during the first 5 to 10 years. Bone loss continues in older women past age 70 but at a much slower rate.

young women. The renal enzymatic activity that produces vitamin D metabolites and thus the control on calcium absorption also decreases.

RISK FACTORS

Women smokers tend to lose bone more rapidly and have a lower bone mass.8~~ Some studies show that smokers also have a higher fracture rate as well.l0J1In addition, smokers reach menopause up to 2 years earlier. It may be that smoking interferes with estrogen metabolism, although the mechanism is not clearly known.

Genetics, lifestyle factors, and hormonal status are the major factors that influence the balance between bone resorption and bone formation.

Genetic Factors The level of peak bone mass is largely due to genetic factors. Some studies suggest that up to 80% of the determination in peak bone mass might be due to genetic factors.24Young daughters of women with osteoporotic fractures have lower bone mass compared with other children their age, and first-degree relatives of women with osteoporosis tend to have lower bone mass when compared with other women who do not have a family hi~tory.~ The greater bone mass of black women compared with white women also suggests a genetic influence.

Lifestyle If 80% of the variability in peak bone mass is due to genetics, then lifestyle and hormonal factors have far less impact. So, to a far lesser extent, calcium and vitamin D intake, exercise, age of menarche, menstrual regularity, and alcohol and tobacco use also affect peak bone mass. All women lose bone mass in menopause, but several lifestyle factors affect the risk of developing osteoporosis including physical activity, animal protein intake, acid-base homeostasis, calcium and vitamin D intake, smoking, and heavy alcohol consumption. In order for a woman to achieve her genetically determined peak bone mass, she requires a balanced diet, adequate calories, protein, and calcium? Good nutrition throughout life is necessary for maintaining bone mass and bone strength. Adequate calcium and vitamin D have crucial roles in maintaining bone mass in older women. Calcium requirements change with age, and during and after menopause the need for calcium increases. After age 65, women absorb 50% less calcium than

Dietary Protein Not all studies have been consistent about whether or not excess dietary protein contributes to osteoporosis. The Nurses' Health Study showed that high intake of animal protein, but not plant protein, was associated with an increased risk of forearm fracture? Diets high in red meat are acid producing, and salts from the bone may be mobilized to balance the acid and maintain the acidbase homeostasis OUT body requires. Diets high in fruits and vegetables and plant proteins are alkaline forming.

Smoking

Alcohol Alcohol consumption of 7 oz or more weekly has been shown to increase the risk of falls and hip fractures. Although this amount of alcohol consumption is considered heavy, moderate alcohol consumption seems to lower the risk of hip fractures in older women." It is thought that moderate amounts of alcohol inhibit bone resorption by increasing estradiol concentrations and calcitonh excretion.'2,13

Physical Activity The effect of physical activity on the risk of osteoporosis cannot be overlooked. Highly active individuals have higher bone and those who have prolonged bed rest or are confined to a wheelchair have rapid and dramatic bone loss. Exercise functions primarily to reduce osteoporosis risk by stimulating osteoblasts.

Hormonal Factors A woman's hormonal status clearly influences bone mass in women and the rate of bone resorption. At menopause, all women lose bone and it is especially accelerated in the first 5 years. The drop in estrogen production that comes with menopause, no matter the age, increases the rate of bone resorption. The earlier that occurs, before the average age of menopause (51),the sooner the bones have the protective effect of endogenous estrogen. Women who have premature menopause (before age 40), late onset of menarche in adolescence, and periods of amenorrhea or infrequent menses are at greater risk of osteoporosis. Women who missed up to half of their expected menstrual periods had 12% less vertebral

Osteoporosis

bone mass than did women with normal menstrual cycles; those who missed more than half had 31% less bone mass than healthy control^.'^ The concentration of calcium in the blood is strictly maintained within narrow limits. If levels start to decrease, there is an increase in the secretion of parathyroid hormone by the parathyroid glands and a decrease in the secretion of calcitonin by the thyroid and parathyroids. If calcium levels in the blood start to increase, there is a decrease in the secretion of parathyroid hormone and an increase in the secretion of calcitonin. An understanding of how these hormones increase (parathyroid hormone) and decrease (calcitonin) serum calcium levels is necessary in understanding osteoporosis. Parathyroid hormone increases serum calcium levels primarily by increasing the activity of the osteoclast catabolism of bone, although it also decreases the excretion of calcium by the kidneys and increases the absorption of calcium in the intestines. In the kidneys, parathyroid hormone increases the conversion of 25-(OH)D3 to 1,25-(OH)2D3. One theory relating bone loss to estrogen deficiency is that an estrogen deficiency makes the osteoclasts more sensitive to parathyroid hormone, resulting in increased bone breakdown and thereby raising blood calcium levels. This elevation in blood calcium leads to a decreased parathyroid hormone level that results in diminished levels of active vitamin D and increased calcium excretion as well. This theory appears to best explain the hormonal effects in osteoporosis.

Additional Factors No one risk factor or combination of risk factors will accurately predict which patients will or will not experience osteoporosis or osteoporotic fractures. The more risk factors present, the greater the potential for lower bone mass and the higher the risk of fracture. Risk factors alone do not provide adequate assessment of low bone mass, but rather are important guides in the clinical assessment of osteoporosis risks that contribute to optimal preventive strategies. Ultimately, an individual woman’s risk of fracture is the most relevant parameter for her future with regard to osteoporosis. Various medical conditions and medications can interrupt normal bone physiology and lead to osteoporosis. Endocrine disorders, malignancies, and collagen metabolism disorders can have a direct effect on the ability of bones to remodel. Many factors have been observed to identify those at greatest risk: Genetic factors: First-degree relative with low-trauma fracture Caucasian/Asian race Slender physical frame Family history of osteoporosis

Menstrual status: Early menopause without hormone replacement therapy (HRT) or oral contraceptives History of amenorrhea (due to anorexia nervosa, hyperprolactinemia, or exercise-induced amenorrhea), infrequent menses, late menstrual onset, anovulation Premenopausal hypogonadism Diseases and Conditions: Kidney disease and kidney stones, rheumatoid arthritis, multiple myeloma, chronic obstructive pulmonary disease, scoliosis, history of anorexia nervosa, diabetes mellitus, Cushing’s disease, hyperthyroidism, primary hyperparathyroidism, hypercalciuria, vitamin D deficiency Gallbladder disease, primary biliary cirrhosis, fat malabsorption, hypochlorhydria, lactose intolerance History of chronic low back pain for more than 15 years History of stress fractures Being on prolonged bedrest, paralyzed, or wheelchair bound History of other fractures after the age of 45 Underweight Dental conditions: bone loss in the jaw, dentures before age 60, increased tooth loss Nulliparous (never had a full-term pregnancy; i.e., no periods of sustained high estrogens) Environmental/lifestyle factors: Little exposure to sunlight Inadequate calcium and vitamin D intake during pregnancies and nursing Dietary factors: excessive caffeine, high animal protein, high sodium, high phosphate, low dietary calcium Lifestyle factors: sedentary, moderate (or more) alcohol intake, cigarette smoking Medications: Isoniazid, furosemide, heparin, tetracycline, anticonvulsants, gonadotropin-releasing hormone, cortisone or prednisone, lithium, and aluminumcontaining antacids Surgeries: Total thyroidectomy, removal of part or all of intestines, intestinal bypass surgery for weight control

DIAGNOSTIC CONSIDERATIONS All postmenopausal women should be assessed for risk factors associated with osteoporosis. This assessment requires a history, physical examination, and diagnostic tests. The goals of evaluation should be to identify those women at risk for osteoporosis or fracture; establishing a diagnosis of osteoporosis or determining the severity of the diagnosis, or both; ruling out secondary

causes of bone loss in patients with osteoporosis; and identifying risk factors for falls and injuries. The history and physical examination should be focused on identrfylng the woman’s risk factors. There can be physical signs of osteoporosis. Loss of height greater than 1.5 inches may be associated with compression of vertebrae due to fractures on the anterior vertebral body. Measuring height annually is the simplest of procedures that can be used to identify risk of osteoporosis. Excessive kyphosis of the thoracic spine, dowager’s hump, dental caries, tooth loss, receding gums, and back pain should raise suspicion of osteoporosis.

Radiologic Tests of Bone Mineral Density Bone mineral density (BMD)testing is the optimal method to establish a diagnosis of osteoporosis. There are several techniques to measure BMD, but the gold standard is dual energy x-ray absorptiometry (DEXA).l6Other methods of assessing bone mass include computerized tomography (CT) scans, ultrasounds of the heel, and radiographs, none of which are as optimal for diagnosis and follow-up as the DEXA scan. The following tests measure bone mineral density and show their comparison in accuracy (Table 196-1). In addition to providing the most reliable measurement of bone density, the DEXA test requires less radiation exposure than a conventional radiograph or CT scan. Usually, the DEXA scan is used to measure both the hip and the lumbar spine densities. The hip is the preferred site for BMD testing, especially in women older than 60, because the spinal measurements can be unreliable due to extraosseous ossification. The spine is useful in early postmenopausal women because the rates of bone loss are greater due to lower estrogen levels. Although peripheral DEXA sites are accurate, they may be less useful because they may not correlate

as well with fracture risk and BMD at the hip and spine. The North American Menopause Society has established these guidelines for indications for BMD testing: Secondary causes of bone loss (e.g., steroid use, hyperparathyroidism) Radiologic evidence of osteopenia All women 65 years and older Younger postmenopausal women with fragility fractures since menopause, low body weight, or family history of spine or hip fracture Many practitioners are increasing their use of BMD testing in order to aid women in their decision-making process about managing their menopause symptoms. Results of BMD tests are reported as standard deviations-either a Z-score or a T-score. A Z-score is based on the standard deviation from the mean BMD of women in the same age group. A T-score is based on the mean peak BMD of a normal, young woman. The World Health Organization (WHO) criteria for the diagnosis of osteoporosis uses T-scores (Table 196-2).

Laboratory Tests of Bone Metabolism Biochemical markers of bone turnover appeal to some practitioners. A urine test measures the breakdown products of bone such as cross-linked N-telopeptide of type I collagen or deoxypyridium. These tests measure bone turnover and can be correlated with the rate of bone loss but are not intended to be used for the diagnosis of osteoporosis or monitoring bone loss. Such tests of bone turnover may be used to monitor the success (or failure) of therapy. They provide quicker feedback compared with DEXA, which can take up to 2 years to detect a therapeutic response. The DEXA test is best used to measure bone density, while urinary bone resorption assessments can be used to measure the rate of bone turnover. Reducing urinary levels of these markers of bone breakdown Bone mineral density score interpretation

Method

Site/Accuracy

DEXA

Hip, spine, total body/90%-99%

Status

T-score

Interpretation

PDXA

Forearm, finger, heeV90%-99%

Normal

Above -1

SXA

HeeV98%-99%

BMD within 1 SD of a young normal adult

QUS

Heel, shin/not available

Osteopenia

Between -1 and -2.5

QCT

Spinel95%-97%

PQTC

Forearm/92%-98%

BMD between 1 and 2.5 SD below a young normal adult

Osteoporosis

Below -2.5

BMD is 2.5 SD or more below a young normal adult

Adapted from Jergas M, Genant HK. Arthritis Rheum 1993;36:1649-1662. DEXA. Dual-energy x-ray absorptiometry; PDXA, peripheral dual-energy x-ray absorptiometry; POTC, peripheral quantitative computed tomography; OCT quantitated computed tomography; OUS. quantitative ultrasound; SXA, single-energy x-ray absorptiometry.

BMD, Bone mineral density; SO, standard deviation.

Osteoporosis

over a 2-year period has produced increases in bone density measurements,ls but the value of these markers in clinical practice has yet to be definitively confirmed. Additional tests may be used to determine secondary causes of bone loss. These include serum calcium, 24hour urinary calcium, parathyroid hormone, thyroidstimulating hormone, free thyroxine levels, serum albumin, serum alkaline phosphatase, erythrocyte sedimentation rate, complete blood cell count, and vitamin D levels. Indirect tests of calcium absorption such as gastric acid levels and vitamin D levels may also be important.

THERAPEUTIC CONSIDERATIONS Recently there has been considerable public advocation of an increase in dietary calcium to prevent osteoporosis. This appears to be sound medical advice for many people, but osteoporosis is much more than simply a lack of dietary calcium. It is a complex condition involving hormonal, lifestyle, nutritional, and environmental factors. A comprehensive plan that addresses these factors offers the greatest protection against developing osteoporosis. The primary goals in the treatment and prevention of osteoporosis are as follows: Preserve adequate bone mass Preserve bone strength Prevent skeletal fragility Prevent deterioration of microarchitecture Prevent or reduce the risk of fractures The primary role of alternative therapies is to prevent osteoporosis and, fortunately, osteoporosis is largely a preventable disease. Pharmacologic therapy reduces the risk of vertebral and hip fractures by about 50%. The following guidelines are indications for pharmacologic therapy according to the North American Menopause Society: Postmenopausal women with: Previous vertebral fractures BMD T-score values less than -2.5 BMD T-score less than -2 and previous nonspine fraghty fracture, weight less than 127 lb or family history of hip or spine fracture Individuals with secondary causes of bone loss require individualized management. Older postmenopausal women with a history of a previous nontraumatic, nonpathologic vertebral fracture are at high risk of having another spine or hip fracture. These women in particular are candidates for treatment with proven conventional pharmacologic treatments, no matter what their bone density is.

Drug Therapy Hormone Replacement Therapy As estrogen levels decline, bone remodeling increases and bone resorption outpaces bone formation. Both estrogen replacement therapy (ERT) and HRT reduce the rate of bone turnover and res0rpti0n.l~ ERT can return the high resorption rates in postmenopausal women to those of the rates in premenopausal women. Long-term data on the effects of ERT and HRT on bond density and fracture risk come mainly from observational and epidemiologic studies. Recent epidemiologic research found a 54% reduction in risk of fractures in current users of ERT/HRT compared with those who never used it.20Researchers also found that ERT/HRT is more effective in reducing the fracture risk if it is begun within 5 years of menopause. If it was used more than 10 years ago, it produced an even greater risk reduction-75% for wrist fractures and 73% for hip fractures. The most recent randomized clinical trial, the Women's Health Initiative (WHI), has confirmed that HRT reduces the risk of hip fractures (34%),vertebral fractures (%YO), and total body fractures (24%)." However, other findings in the WHI have raised concern about using HRT longer than 4 years. The risk of breast cancer, blood clots, strokes, and nonfatal myocardial infarctions was increased and, more poignantly, the study was discontinued early for the group on PrernarinlProvera (but not Premarin only) due to the risks outweighing the benefits. Other potential side effects of ERT/HRT include cholelithiasis, breast tenderness, fluid retention, uterine bleeding, and headaches. Now more than ever, it is important to individualize treatment options and more clearly identify the risk-versus-benefit ratio. Generally, ERT/HRT is believed to work best during the first 5 to 10 years after menopause. The optimal duration and maximal duration have not yet been clearly determined and, for this reason, in the face of the results of the WHI, ERT/HRT will not be seen as a primary long-term treatment for osteoporosis except in those who do not tolerate bisphosphonates or who have menopause symptoms that are not responding well to other therapies.

Bisphosphanates In addition to ERT/HRT, a class of drugs called bisphosphonates offers another appealing option for the treatment of osteoporosis. Bisphosphonates work by inhibiting osteoclast activity, thereby reducing bone resorption. Alendronate, etidronate, and risedronate are potent bisphosphonates. They all demonstrate similar antiresorptive activity, increase BMD, and reduce fracture risk.

Specific Health Problems ~~

Other Drugs

Gastric Acid

Selective estrogen receptor modulators, calcitonin, and tibolone (not yet available in the United States) round out the proven drug therapies for osteoporosis and fracture reduction.

General Dietary Factors

It has long been believed that the absorption of calcium depends on it becoming ionized in the intestines largely on the basis of the secretion of gastric acid. Furthermore, it has been believed that the poor ionization of calcium is a major problem with calcium carbonate-the most widely used form of calcium for nutritional supplementation, as it has been believed that in order for calcium carbonate to be absorbed, it must first be solubilized and ionized by stomach acid. Although decreased gastric acidity may be seen in as high as 40% of postmenopausal women,% a critical review of the available human studies indicated that the effects of increased gastric pH are only apparent when poorly soluble calcium salts like calcium carbonate are taken after an overnight fast.37In a fasting state patients with insufficient stomach acid output can only absorb about 4% of an oral dose of calcium as calcium carbonate, while a person with normal stomach acid can typically absorb about 22%.38Patients with low stomach acid secretion need a form of calcium that is already in a soluble and ionized state such as calcium citrate, calcium lactate, or calcium gluconate. About 45% of the calcium is absorbed from calcium citrate in patients with reduced stomach acid compared with 4% absorption for calcium carbonate.37However, when taken with meals, there is little difference in calcium absorption even in elderly subjects with atrophic gastritis or those taking H2-receptorantagonists.

Many dietary factors have been suggested as causes of osteoporosis including the following30J’:

Sugar

Lifestyle Factors Certain lifestyle factors significantly affect bone health. For example, coffee, alcohol, and smoking cause a negative calcium balance and are associated with an increased risk of developing osteoporosis, while regular exercise reduces the risk.22,23In fact, as important as hormonal and dietary factors are, exercise is more critical for maintaining healthy bones.

Exercise Numerous studies have demonstrated that physical fitness is the major determinant of bone density. Physical exercise consisting of 1 hour of moderate activity three times a week has been shown to prevent bone loss and actually increase bone mass in postmenopausal In contrast to exercise, immobilization doubles the rate of urinary and fecal calcium excretion, resulting in a significant negative calcium balance.29 Although nutritional factors are important, an effective practice for strengthening bones and reducing fractures would be remiss if it did not emphasize physical activity.

Low-calcium, high-phosphorus intake High-protein diet High-acid-ash diet High-salt intake Trace mineral deficiencies A vegetarian diet (both lacto-ovo and vegan) is associated with a lower risk of o s t e o p o r ~ s i s . Although ~~,~~ bone mass in vegetarians does not differ significantly from omnivores in the third, fourth, and fifth decades, there are sigruficant differences in the later decades. These findings indicate that the decreased incidence of osteoporosis in vegetarians is not due to increased initial bone mass, but rather to decreased bone loss. Several factors are probably responsible for the decrease in bone loss observed in vegetarians. The most important of these is probably a lowered intake of protein. A high-protein diet or a diet high in phosphates is associated with increased excretion of calcium in the urine. Raising daily protein from 47 to 142 g doubles the excretion of calcium in the urine.MA diet this high in protein is common in the United States and may be a significant factor in the increased number of people suffering from osteoporosis in this country.

Another dietary factor that increases the loss of calcium from the body is refined sugar. Following sugar intake, there is an increase in the urinary excretion of calcium.39 Considering that the average American consumes, in 1 day, 125 g of sucrose, 50 g of corn syrup plus other refined simple sugars, and a glass of a carbonated beverage loaded with phosphates, along with the high amount of protein, it is little wonder that so many suffer from osteoporosis in this country.

Soft Drinks Soft drinks may be a major factor for osteoporosis, as they are high in phosphates but contain virtually no calcium. This leads to lower calcium levels and higher phosphate levels in the blood. The United States ranks first among countries for soft drink consumption with a per capita consumption of approximately 15 oz/day. The link between soft drink consumption and bone loss is going to be even more significant as children practically weaned on soft drinks reach adulthood. Soft drink consumption in children poses a significant risk factor for impaired calcification of growing bones. Because there is such a strong correlation between

Osteoporosis

maximum bone mineral density and the risk of osteoporosis, the rate of osteoporosis may reach even greater epidemic proportions. The severe negative impact that soft drinks exert on bone formation in children was clearly demonstrated in a study that compared 57 children, aged 18 months to 14 years, with low blood calcium to 171 matched controls of children with normal calcium levels.40The goal of the study was to assess whether the intake of at least 1.5 quarts/week of soft drinks containing phosphates is a risk for the development of low blood calcium levels. Of the 57 children with low blood calcium levels, 38 (66.7%) drank more than four bottles (12 to 16 oz) per week, but only 48 (28%) of the 171 children with normal serum calcium levels drank as many soft drinks. For all 228 children, a significant inverse correlation between serum calcium level and the number of bottles of soft drinks consumed each week was

Green Leafy Vegetables Consumption of green leafy vegetables (e.g., kale, collard greens, parsley, lettuce) offers significant protection against osteoporosis. These foods are a rich source of a broad range of vitamins and minerals important to maintaining healthy bones including calcium, vitamin K1, and boron.

Vitamin K Vitamin K1 is the form of vitamin K that is found in plants. A function of vitamin K1 that is often overlooked is its role in converting inactive osteocalcin to its active form. Osteocalcin, the major noncollagen protein in bone, anchors calcium molecules into the protein matrix.42 A deficiency of vitamin K leads to impaired mineralization of bone due to inadequate osteocalcin levels. Low blood levels of vitamin K1 have been found in patients with fractures due to 0steoporosis.4~The severity of fracture strongly correlated with the level of circulating vitamin K. Other studies have shown that the lower the level of circulating vitamin K, the lower the bone density? This evidence clearly indicates the importance of vitamin K1.The richest sources of vitamin K1 are dark green leafy vegetables, broccoli, lettuce, cabbage, spinach, and green tea. Good sources are asparagus, oats, whole wheat, and fresh green peas.

Boron In addition to vitamin K1,the high levels of many minerals like calcium and boron in green leafy vegetables may also be responsible for this protective effect. Boron is a trace mineral gaining recent attention as a protective factor against osteoporosis (see Chapter 72)j5 Supplementing the diet of postmenopausal women with 3 mg/day of boron reduced urinary calcium

excretion by 44% and dramatically increased the levels of 17-beta-estradiol, the most biologically active estrogen. It appears that boron is required to activate certain hormones including estrogen and vitamin D. Boron is also apparently required for the conversion of vitamin D to its most active form (1,25-(OH),D3) within the kidney. A boron deficiency may contribute greatly to osteoporosis, as well as menopausal symptoms. As fruits and vegetables are the main dietary sources of boron, diets low in these foods may be deficient in boron. Typically, the standard American diet is severely deficient in these foods. According to several large surveys, including the U.S. Second National Health and Nutrition Examination, less than 10% of Americans met the minimum recommendation of two fruit servings and three vegetable servings per day and only 51% ate one serving of vegetables per In order to guarantee adequate boron levels, supplementing the diet with a daily dose of 3 to 5 mg of boron is indicated. Boron has been shown to mimic some of the effects of estrogen therapy in postmenopausal w0men.4~

Soy Foods Soy appears to have a pro-estrogen effect on bone in some experimental evaluations, and bone-trophic effects of soy phytoestrogens are biologically plausible. Possible mechanisms of action include binding to estrogen receptors, stimulating formation of sex hormone-binding globulin, and inhibiting tyrosine kinase. Numerous studies lay a groundwork on which more research is necessary. The bone density of ovariectomized rats was evaluated by replacing casein with soy in the diet, compared with another group that received estrogen. The addition of soy inhibited bone loss, although not to the same extent as was achieved with the estrogen Another study of ovariectomized rats also reported a positive effect of the soy phytoestrogen genistein in maintaining bone.49These authors also reported that genistein suppresses the bone-losing cells (osteoclasts), both in the test tube and in vivo. Several human studies have provided further insight and comfort in the possible role of soy in bone health. A study conducted at the University of Illinois found that menopausal women had an increase in mineral levels and density in their lumbar spines after taking 55 to 90 mg of isoflavones for 6 months.50The placebo group showed the lowest bone density and the greatest bone loss, while the estrogen group showed the highest bone density and the slowest bone loss. What was surprising was that the soybean protein diet was effective in preventing bone loss in the fourth lumbar vertebra and, although less so, in the right hip as well.

Specific Health Problems Soybean protein seems to have more of an effect on trabecular bone (more predominant in the spine) than on cortical bone (more predominant in the hip). The soybean protein did not show as great an ability in preventing bone loss as the estrogen group, but the positive effect it showed is encouraging. The relationship between soy isoflavone intake and BMD was analyzed using data from the Study of Women's Health Across the Nation, a U.S. communitybased cohort study of women age 42 to 52 years old.51 The analysis included 497 African-American women, 1003 Caucasian women, 200 Chinese women, and 227 Japanese women. Median intakes of genistein, one of the main isoflavones found in soy, were too low to analyze in African Americans and Caucasians. For Chinese women, no association between genistein and BMD was found. Premenopausal, but not perimenopausal, Japanese women who had higher intakes of soy isoflavones had higher spine and femoral neck BMD. Similarly, in a 24-week, randomized controlled trial of bone density comparing two different doses of isoflavones in postmenopausal women, no BMD effect was found in the women who received 56 mg/day of genisteiddaidzein, but those who received 90 mg/day of genistein/daidzein had an approximate 2% increase in spinal BMD compared with baseline.s2 Another aspect of soy to keep in mind is as a source of calcium. A diet that includes greater amounts of soy products can account for a meaningful amount of calcium, and some soy foods can offer as much or more calcium than a serving of dairy products (Table 196-3).

Nutritional Supplements As stated earlier, but worth repeating, osteoporosis involves much more than calcium. Bone depends on a constant supply of many nutrients. A deficiency of any one of these nutrients adversely affects bone health. In addition to vitamin K and boron (discussed earlier), there are other key nutrients critical to bone health, which are discussed later.

Form

Quantity

Calcium ( ~ Q P -

Tofu, firm

'I4

block

553

Tofu, regular

'14

block

406

Soy milk, calcium fortified

1 cup

80-300

Soy milk

1 cup

7

Soybeans, roasted

'I4

cup

119

Soybeans, boiled

'I4

cup

88

Ternpeh

'14

cup

77

Calcium Supplementation of calcium has become the primary focus in both the prevention and treatment of osteoporosis. In a detailed metaanalysis, 15 double-blind trials, representing 1806 participants, demonstrated that calcium supplementation was more effective than placebo in reducing rates of bone loss after 2 or more years of treatment. The pooled difference in percentage change from baseline in the calcium group was 2.05% for total body bone density, 1.66%for the lumbar spine at 2 years, 1.6% for the h p , and 1.91% for the distal radius. The relative risk of fractures of the vertebrae dropped 21%, but the relative risk for nonvertebral fractures was only 14%. In contrast to the studies with calcium supplements, the same sort of observations with dietary sources of calcium (e.g., milk) have failed to show any association between dietary calcium and osteoporosis unless the intake of calcium is extremely 1 0 w . ~ Although there has been a great deal of research investigating the difference in absorption of one calcium source versus another, the reality is that clinical studies looking at their effect against osteoporosis and hip fracture have not shown an advantage to any one form, especially when either form is given along with vitamin D. In other words, both insoluble and soluble calcium salts have shown benefit. Although it is true that ionized forms like calcium citrate are better absorbed than calcium carbonate by approximately 22% to 27%,either on an empty stomach or coadministered with meals, this difference represents an increase in net absorption of only a relatively small amount of calcium (e.g., with a 500-mg dose the difference is likely only 15 to 25 mg of calcium).55The difference in absorption is probably not clinically meaningful. Furthermore, studies using a different measure of calcium absorption indicate that when taken with food, calcium from the insoluble salt (e.g., carbonate) is fully as absorbable as from a soluble salt (e.g., citrate)." As stated, clinical studies have shown little difference among various forms of calcium ~upplements.5~ For example, in one study, 118 healthy white women who had experienced the onset of menopause 3 to 6 years previously were randomly allocated to receive either 1700 mg of calcium as calcium carbonate, a placebo, or Premarin with 1700 mg of calcium.s7The nearly 3-year-long study indicated that calcium carbonate supplementation ~ ~ alone significantly prevented bone loss. Although calcium alone was less effective than the Premarin-calcium combination, because calcium supplementation carries with it no significant health risks, this study reinforces the opinion that HRT should definitely be reserved for women at significant risk for osteoporosis. In another study, 86 postmenopausal women received, for 4 years, either 1 g of elemental calcium from an effervescent form containing 5.24 g calcium-lactate-gluconate

Osteoporosis

and 0.8 g calcium carbonate or a placebo of an identical effervescent tablet containing no Clinical status, calcium intake, physical activity, and bone mineral density were assessed at baseline and every 6 months. The study found that continued calcium supplementation produces a sustained reduction in the rate of loss of total bone mineral density in healthy postmenopausal women. As a result, the incidence of bone fractures was far lower in the group taking calcium (2 of 38) compared with the placebo (9 of 40). And finally, in another 4-year study, the long-term effect of calcium supplementation on bone density was determined in 84 elderly women (54 to 74 years) more than 10 years past menopause.59A placebo group who did not take calcium supplements at all during the 4-year study served as a comparison. Changes in bone density at the lumbar spine, hip, and ankle sites; current calcium intake; and activity were monitored. Over 4 years, the calcium supplement group (average calcium intake of nearly 2000 mg/day) did not lose bone at the hip and ankle sites. The control group (average calcium intake, 950 mg/day) lost significantly more bone than the calcium supplement group at all sites of the hip and ankle. No overall bone loss was seen at the spine, in either group, over the 4 years of this study. A strong correlation exists between premenopausal bone density and the risk of osteoporosis. That being the case, building strong bones should be a lifelong goal, beginning in childhood. However, most women are probably not concerned about osteoporosis until a few years before menopause. Fortunately, calcium supplementation slows bone loss in perimenopausal women. In a 2-year study, 214 perimenopausal women received either 1000 or 2000 mg of calcium provided in an effervescent mixture as described earlier.@While the control group actually lost 3.2% of the bone density of their spine, the calcium-treated groups increased their density by 1.6% (there was no difference between the two calcium groups). These results highlight the importance of calcium supplementation before menopause in a prevention strategy. The best form of calcium is certainly neither oyster shell nor bone meal. Studies have indicated that these calcium supplements may contain substantial amounts of lead.61(For a discussion of the toxic effects of lead in children and adults, see Chapters 36 and 152.) In 1981 the FDA cautioned the public to limit intake of calcium supplements derived from either dolomite or bone meal because of the potentially high lead levels in these calcium supplements. More recent studies have shown that other calcium sources such as carbonate (from oyster shells) and various chelates may also contain high amounts of lead.61One study measured the lead level in 70 brands of calcium

supplements and found some forms and brands to have high levels.61The 70 products were divided into five categories: Refined calcium carbonate produced in a laboratory ( n = 17) Unrefined calcium carbonate derived from limestone or oyster shells (n = 25) Calcium bound to various organic chelates such as citrate, gluconate, and lactate ( n = 13) Dolomite ( n = 9) Bone meal (n = 6) Table 196-4lists the results (lead content in pg/800 mg calcium). None of the products tested in the dolomite and bone meal groups and only 2 of 25 in the unrefined calcium carbonate group had lead levels below the recommended level of 1 pg/SOO mg of calcium. The group that displayed the greatest range of lead content was the unrefined calcium carbonate group (the source was oyster shells)-although two products contained little lead, most contained higher levels. One product contained 25 pg of lead per 800 mg of calcium, a cause for great concern. As the total tolerable daily intake of lead for children aged 6 years and younger is less than 6 pg/day, young children should use refined calcium carbonate or chelated calcium products as calcium sources for supplementation. Some reports, but not all, have shown that chelated calcium, especially calcium citrate, is better absorbed than calcium carbonate. Natural oyster shell calcium, dolomite, and bone meal products should be avoided unless the manufacturer can provide reasonable assurance that lead levels are within acceptable levels. Refined calcium carbonate and other refined sources have the lowest lead content. Calcium bound to citrate and other Krebs cycle intermediates such as fumarate, malate, succinate, and aspartate is considered by many alternative practitioners to probably be the best form. The Krebs cycle

Lead content of calcium supplements (pg/800 mg of calcium) Supplement

Lead content

Refined calcium carbonate

0.92

Calcium chelate

1.64

Dolomite Unrefined calcium carbonate

6.05

Bone meal

4.17 11.33

Specific Health Problems intermediates fulfill every requirement for an optimum calcium &elating agent:

to account for this decreased conversion, including relationships to estrogen and magnesium deficiency. Recently, the trace mineral boron has been theorized to They are easily ionized. play a role in this conversion. They are almost completely degraded. In addition to studies that used calcium supplementaThey have virtually no toxicity. tion alone are several studies that used calcium in comThey have been shown to increase the absorption of bination with vitamin D (usually vitamin D3),as well as not only calcium, but other minerals as well. vitamin D alone. One study using vitamin D3 alone One popular calcium supplement is calcium found that supplementation with 700 IU/day reduces the annual rate of hip fracture from 1.3%to 0.5Yo-nearly hydroxyapatite-basically a purified bone meal. It is a 60% r e d ~ c t i o n In . ~ ~another study 348 women aged interesting to note that among calcium supplements tested for absorption, this form tested at 20% absorp70 and older received either 400 IU/day of vitamin D3or tion compared with 30% for either calcium carbonate a placebo for 2 years.66Bone density at the hip (femoral neck) increased by 1.9% in the left hip and 2.6% in the or calcium citrate. Recommendations for calcium intake follow. right hip in the vitamin D-treated group. In comparison, the placebo group demonstrated decreases of 0.3% in Adequate intake (elemental calcium mglday) Age the left hip and 1.4% in the right hip. Studies that com9-18 1300 bined vitamin D with calcium produced slightly better 19-50 1000 results. For example, in one study of 3270 elderly women 250 1200 living in nursing homes, the hip fracture rate in those receiving 1200 mg/day of calcium and 800 IU/day of Vitamin D vitamin D3 was reduced by 43% compared with the placebo group."7 Vitamin D is known to stimulate the absorption of calIn another study, the effects of 3 years of dietary supcium. Because vitamin D can be synthesized by the plementation with calcium and vitamin D3on bone minaction of sunlight on 7-dehydrocholesterol in the skin, many experts consider it more of a hormone than a eral density and the incidence of hip fractures in 176 men vitamin. Sunlight changes the 7-dehydrocholesterol and 213 women age 65 years or older who were living into vitamin D3 (cholecalciferol). It is then transported at home was evaluated.68 The participants received either 500 mg/day of calcium plus 700 IU/day of vitato the liver and converted into 25-hydroxycholecalciferol min D3 (cholecalciferol)or placebo. Bone mineral density (25-(OH)D3),which is five times more potent than cholewas measured by DEXA, and cases of hip fracture were calciferol(D3).The 25-hydroxycholecalciferolis then converted by the kidneys to 1,25-dihydroxycholecalciferol ascertained by means of interviews and verified using hospital records. The average changes in bone mineral (1,25-(0H),D3), which is 10 times more potent than cholecalciferol and the most potent form of vitamin D3 density in the calcium-vitamin D group were 4.5% for the hip, +2.12% for the spine, and + O . O ~ O / O for the (Table 196-5). whole body. In contrast, the values for the placebo group Disorders of the liver or kidneys result in impaired were -0.70, +1.22, and -1.09%, respectively. Of 37 subconversion of cholecalciferol to more potent vitamin D compounds. Many patients with osteoporosis have a high jects who had hip fractures, 26 were in the placebo group level of 25-OH-D3but quite a low level of 1,25-(OH)2D3. and 11were in the calcium-vitamin D group. This signifies an impairment of the conversion of One of the most interesting aspects of vitamin D is its ability to reduce the risk of falling in elderly populations. 25-(OH)D3to 1,25-(OH)2D3within the kidneys in people Based on five randomized controlled trials, vitamin D with Many theories have been proposed reduced the risk of falling by 22% in the elderly with a mean age of 60.69 In recent years, much attention has been focused on Relative activities of vitamin D forms the need for increased levels of calcium. It is now generally accepted that much greater attention should be Form Relative activity focused on vitamin D. Its metabolic products not only 1 Vitamin D3 stimulate calcium absorption but slow bone loss, Vitamin D2 1 increase bone formation, and reduce the risk of falling. On the basis of what we know about vitamin D, older 25-(OH)D3 2-5 women, and possibly all adults, probably need 800 to 25-(OH)D2 2-5 1000 IU daily. This is substantially more than the current 1,25-(OH)PDs 10 established levels of adequate intake. Vitamin D can also 1,25-(OH)*D* 10 be given in single weekly doses of 5000 IU. These doses

Osteoporosis will most likely raise serum 25-hydroxyvitamin D concentrations well into the normal range and minimize seasonal variations, especially for those living in northem latitudes. Fortunately we have a good margin of safety with dosing of vitamin D. Excess vitamin D causes hypercalciuria and hypercalcemia, but these problems do not occur unless the daily dose exceeds at least 2400 IU/day.

Folic acid supplementation has been shown to reduce homocysteine levels in postmenopausal women even though none of the women were deficient in folic acid according to standard folic acid laboratory criteria.74 Vitamins B6 and BIZ are also necessary in the metabolism of homocysteine. Combinations of these vitamins will produce better results than either one of them alone.75

Magnesium

Silicon

Magnesium supplementation may turn out to be as important as calcium supplementation in the prevention and treatment of osteoporosis. Women with osteoporosis have lower bone magnesium content and other indicators of magnesium deficiency than people without osteoporosis.70~71 In human magnesium deficiency, a decrease in the serum concentration of the most active form of vitamin D (1,25-(0H),D3) has been observed in osteoporosis.” This finding could be due either to the enzyme responsible for the conversion of 25-(OH)D3 to 1,25-(OH)2D3being dependent on adequate magnesium levels or to magnesium’s ability to mediate parathyroid hormone and calcitonin secretion. The benefits of magnesium supplementation were investigated in a small 2-year trial in 31 postmenopausal women.73 The women received an initial dosage of either 250 mg of magnesium (as magnesium hydroxide) or a placebo. Dosages were increased to a maximum of 750 mg for the first 6 months followed by a maintenance dosage of 250 mg for the remaining 18 months of the trial. After 1 year, the women in the magnesium-treated group showed a slight improvement in the bone density. In contrast, the placebo group showed a slight decrease in bone density. Hopefully there will be follow-up studies to this preliminary study to better assess the benefits of magnesium in osteoporosis.

Silicon is necessary for cross-linking collagen strands, thereby contributing greatly to the strength and integrity of the connective tissue matrix of bone.76Since silicon concentrations are increased at calcification sites in growing bone, recalcification in bone remodeling may depend on adequate levels of silicon. Whether the typical American diet provides adequate amounts of silicon is unknown. In patients with osteoporosis or where accelerated bone regeneration is desired, silicon requirements may be increased and therefore supplementation may be indicated.

Vitamin Bb Folic Acid, and Vitamin BI2 Low levels of these nutrients are quite common in the elderly population and may contribute to osteoporosis. These vitamins are important in the conversion of the amino acid methionine to cysteine. If deficient in these vitamins or if a defect exists in the enzymes responsible for this conversion, there will be an increase in homocysteine. This compound has been implicated in various conditions including atherosclerosis and osteoporosis (see Chapter 150 for a complete discussion). Increased homocysteine concentrations in the blood have been demonstrated in postmenopausal women and are thought to play a role in osteoporosis by interfering with collagen cross-linking leading to a defective bone matrix. Because osteoporosis is known to be a loss of both the organic and inorganic phases of bone, the homocysteine theory has much validity, as it is one of the few theories that addresses both factors.

Fluoride Fluoride administration is a popular therapy in many parts of the world, but its validity is still in question. Early studies showed that fluoride is largely ineffective.n Fluoride’s predominant effects are stimulation of osteoblastic activity and positive calcium balance. Fluoride is incorporated into the crystalline structure of bone as fluorapatite, but the bone matrix is poorly formed and weak, and long-term excessive exposure typically results in more fragile bones. The therapeutic index for fluoride is quite narrow, and at the recommended daily dose of 60 to 75 mg, sodium fluoride causes side effects in 33% to 50% of patients. Joint pain is the most common, but stomachaches, nausea, and vomiting also occur, although they are less troublesome if the fluoride is taken with meals. Newer sodium fluoride preparations (i.e., entericcoated and timed-release to prevent digestion in the stomach) are showing better results in terms of both fewer side effects and better clinical results.78However, at this time we do not recommend fluoride supplementation in the treatment of osteoporosis.

Ipriflavone A semisynthetic isoflavonoid similar in structure to soy isoflavonoids has been approved in Japan, Hungary, and Italy for the treatment and prevention of osteoporosis.79 The compound, ipriflavone, has shown impressive results in a number of clinical studies. For example, in one study, ipriflavone (200 mg tid) increased bone density measurements by 2% and 5.8% after 6 and 12 months, respectively, in 100women with osteoporosis.8o

In another 1-year study in women with osteoporosis, ipriflavone (600 mg/day) produced a 6% increase in bone mineral density after 12 months, while the bone density of the placebo group was reduced by 0.3%.s1 Longer-term studies are showing equally promising results given the safety and apparent efficacy of ipriflavone.82m The effectiveness of ipriflavone suggests that naturally occurring isoflavonoids like genistein and daidzein in soy may exert similar benefits. Given the benefits of soy isoflavonoids against breast cancer alone, the regular consumption of soy foods is encouraged. The mechanism of action appears to be due to enhancement of calcitonin effects (see earlier) on calcium metabolism, as ipriflavone exerts no estrogen-like effectsM The most recent study on ipriflavone was not nearly so positive: 474 postmenopausal Caucasian women with bone mineral densities less than 0.86 g/cm2 were enrolled in a prospective, randomized, double-blind, placebo-controlled, 4-year study.85Patients were randomly assigned to receive ipriflavone 200 mg tid plus calcium 500 mg or placebo plus calcium 500 mg. Bone density tests were measured including the spine, hip, and forearm, as well as biochemical markers of bone resorption. After 36 months of treatment, the annual percentage change in BMD did not differ significantly between the two groups in any of the sites. The biochemical markers were also similar between groups. The number of women with new spinal fractures was the same in the two groups at all points in the 36 months. Unexpected results included decreased lymphocyte concentrations in women treated with ipriflavone. Of concern, 31 women in the ipriflavone group developed subclinical lymphocytopenia. Fifteen women recovered spontaneously by 1 year, and 22 recovered by 2 years. So why did previous studies of early- and laterpostmenopausal women and of women with osteoporosis show positive results with ipriflavone? The most likely explanation is that the current study population could have been too osteoporotic to show benefit. However, it could also mean that these women were lacking sufficient vitamin D, mirroring the results of studies that used calcium alone. Due to the incidence of decreased lymphocyte concentrations and lack of effect, we recommend monitoring bone density to confirm any benefit and monitoring

1. Eggs BL, Melton LJ III. The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 1995;17(suppl5):505S511S. 2. Smith DM, Nance WE, Kang KW, et al. Genetic factors in determining bone mass. J Clin Invest 1973;52:2800-2808.

lymphocyte levels to detect any adverse effect would be advised.

THERAPEUTIC APPROACH Osteoporosis is a preventable illness if appropriate dietary and lifestyle measures are followed. Women of all ages, from the very young to the very old, should make building healthy and strong bones a lifelong priority. This involves avoiding those dietary and lifestyle practices that leach calcium from the bone and choosing those dietary and lifestyle factors that promote bone health. Although calcium intake is the primary focus of many physicians, strong bones require much more than this important mineral. Bone is dynamic, living tissue that requires a constant supply of high-quality nutrition and regular stimulation (exercise). The primary goal in the treatment of osteoporosis is prevention. In cases of actual osteoporosis (vs. osteopenia), the recommendations given in this chapter should be used in conjunction with appropriate medical care, which may include the use of various prescription drugs. Although drugs like bisphosphonates and estrogen replacement therapy, as well as calcitonin, have side effects, the benefits (prevention of fracture) usually outweigh these side effects in severe case^.^,^'

Exercise Weight-bearing exercise four times per week plus strength training/weight training twice per week is recommended.

Diet The guidelines in Chapter 44 are appropriate. Patients should be advised to avoid dietary factors that promote calcium excretion such as salt, sugar, protein, and soft drinks. Special attention should be paid to increasing consumption of green leafy vegetables and soy foods.

Supplements High-potency multivitamin and mineral formula Calcium: 800 to 1200 mg/day (estimate dietary intake and supplement the difference to reach the total) Vitamin D: 400 to 600 IU/day (consider higher) Magnesium: 400 to 800 mg/day Boron (as sodium tetrahydraborate): 3 to 5 mg/day Ipriflavone: 600 mg daily

3. Slemenda CW, Christian JC, Williams CJ, et al. Genetic determinants of bone mass in adult women: a reevaluation of the twin model and the potential importance of gene interaction on heritability estimates. J Bone Miner Res 1991;6:561-567.

Osteoporosis 4. Pocock NA, Eisman JA, Hopper JL, et al. Genetic determinants of bone mass in adults: A twin study. J Clin Invest 1987;80:706-710. 5. Evans RA, Mare1 GM, Lancaster EK, et al. Bone mass is low in relatives of osteoporotic patients. Ann Intern Med 1988;109:870-873. 6. Nieves JW, Golden AL, Siris E, et al. Teenage and current calcium intake are related to bone mineral density of the hip and forearm in women aged 30-39 years. Am J Epidemiol1995;141:342-351. 7. Feskanich D, Wdett WC, Stampfer MJ, Colditz GA. Protein consumption and bone fractures in women. Am J Epidemiol1996;143 472-479. 8.Slemenda CW, Hui SL, Longcope C, Johnston CC Jr. Cigarette smoking, obesity, and bone mass. J Bone Miner Res 1989;4737-741. 9. Krall EA, Dawson-Hughes 8. Smoking and bone loss among postmenopausal women. J Bone Miner Res 1991;6331-338. 10. Seeman E, Melton LJ III, OFallon WM, Riggs BL. Risk factors for spinal osteoporosis in men. Am J Med 1983;75977-983. 11.Cummings S, Nevitt M, Browner W, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1995;332767-773. 12. Laitinen K, Valimaki M. Alcohol and bone. Calcif Tisue Int 1991; 49(suppl):S70-73. 13. Rico H. Alcohol and bone disease. Alcohol Alcohol 1990;25:345-352. 14. Slemenda CW, Johnston CC. High intensity activities in young women: site specificbone mass effects among female figure skaters. Bone Miner 1993;20125-132. 15. Lloyd T, Myers C, Buchanan JR, Demers LM. Collegiate women athletes with irregular menses during adolescence have decreased bone density. Obstet Gynecol1988;72639-642. 16. Kanis J. Bone density measurements and osteoporosis. J Intern Med 1997;241:173-175. 17. Jergas M, Genant HK. Current methods and recent advances in the diagnosis of osteoporosis. Arthritis Rheum 1993;36;1649-1662. 18. Chestnut CH III, Bell NH,Clark GS, et al. Hormone replacement therapy in postmenopausal women: urinary N-telopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density. Am J Med 1997;102:29-37. 19.Christiansen C. Treatment of osteoporosis. In Lob0 RA, ed. Teatment of the postmenopausal woman: basic and clinical aspects, ed 2. Philadelphia: Lippincott Williams ?L Willcins, 1999, pp. 315-328. 20. Cauley JA, Seeley DG, Ensrud K, et al. Estrogen replacement therapy and fractures in older women. Study of the Osteoporotic Fractures Research Group. Ann Intern Med 1995;122:9-16. 21. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288321-333. 22.Aloia JF, Cohn SH, Vaswani A, et al. Risk factors for postmenopausal osteoporosis. Am J Med 1985;78:95100. 23. Jaglar SB, Kreiger N, Darlington G. Past and recent physical activity and the risk of osteoporosis. Am J Epidemiol1993;138107-118. 24. Prior JC, Barr SI, Chow R, Faulkner RA. Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 5. Physical activity as therapy for osteoporosis. CMAJ 1996;155:940-944. 25. Marcus R, Drinkwater B, Dalsky G, et al. Osteoporosis and exercise in women. Med Sci Sports Exerc 1992;24(suppl6):S301-307. 26. Pocock NA, Eisman JA, Yeates MG, et al. Physical fitness is the major determinant of femoral neck and lumbar spine density. J Clin Invest 1986;7861&621. 27. KroIner B, Toft B, Pors Nielsen S, Tondevold E. Physical exercise as prophylaxis against involutional vertebral bone loss: a controlled trial. Clin Sci (Lond) 1983;64541-546. 28. Yeater RA, Martin RB. Senile osteoporosis: the effects of exercise. Postgrad Med 1984;75147-149. et al. Effect of prolonged bed 29. Donaldson CL, Hulley SB, Vogel JM, rest on bone mineral. Metabolism 1970;19:1071-1084.

30. Eaton-Evans J. Osteoporosis and the role of diet. Br J Biomedical Sci 1994;51:358-370. 31. Saltman PD, Strause LG. The role of trace minerals in osteoporosis. J Am Coll Nutr 1993;12384-389. 32. Ellis F, Holesh S, Ellis J. Incidence of osteoporosis in vegetarians and omnivores. Am J Clin Nutr 1972;2555-58. 33. Marsh AG, Sanchez TV,Chaffe FL, et al. Bone mineral mass in adult lacto-ovo-vegetarian and omnivorous adults. Am J Clin Nutr 1983; 37453-456. 34. Licata AA, Bou E, Bartter FC, West F. Acute effects of dietary protein on calcium metabolism in patients with osteoporosis. J Geron 1981; 3614-19. 35. Cooper C, Atkinson EJ, Hensrud DD, et al. Dietary protein intake and bone mass in women. Calcif Tiisue Int 1996;58320-325. 36. Grossman M, Kirsner J, Gillespie I. Basal and histalog-stimulated gastric secretion in control subjects and in patients with peptic ulcer or gastric cancer. Gastroenterology 1963;45:15-26. 37. Wood RJ, Serfaty-LacrosniereC. Gastric acidity, atrophic gastritis, and calcium absorption. Nutr Rev 1992503340. 38. Nicar MJ, Pak CY.Calcium bioavailability from calcium carbonate and calcium citrate. J Clin Endocrinol Metab 1985;61:391-393. 39.Thom JA, Morris JE, Bishop A, Blacklock NJ. The influence of refined carbohydrate on urinary calcium excretion. Br J Urol 1978; 50459-464. 40. Mazariegos-RamosE, Guerrero-RomeroF, Rodriguez-Moran M, et al. Consumption of soft drinks with phosphoric acid as a risk factor for the development of hypocalcemia in children: a case-control study. J Pediatr 1995;126940-942. 41. Wyshak G, Frisch RE. Carbonated beverages, dietary calcium, the dietary calcium/phosphorus ratio, and bone fractures in girls and boys. J Adolesc Health 1994;15210-215. 42. Vermeer C, Gijsbers BL, Cracium AM, et al. Effects of vitamin K on bone mass and bone metabolism. J Nutr 1996;126(suppl 4): 1187s-1191s. 43.Bitensky L, Hart JP,Catterall A, et al. Circulating vitamin K levels in patients with fractures. J Bone Joint Surg Br 1988;70 663-664. 44. Kanai T, Takagi T,Masuhiro K, et al. Serum vitamin K level and bone mineral density in post-menopausal women. Int J Gynaecol Obstet 19975625-30. 45. Neilsen FH,Hun€CD, Mullen LM, Hunt JR. Effect of dietary boron on mineral, estrogen, and testosterone metabolism in postmenopausal women. FASEB J 1987;1:394397. 46.Block G. Dietary guidelines and the results of food consumption surveys. Am J Clin Nutr 1991;53356!+357S. 47. Nielsen FH, Gallagher SK, Johnson LK, Nielsen EJ. Boron enhances and mimics some of the effects of estrogen therapy in postmenopausal women. J Trace Elem Exp Med 1992;5:237-246. 48. Arjmandi B, Alekel L, Hollis B, et al. Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis. J Nutr 1996;126:161-167. 49. Blair H, Jordan S, Peterson T, Barnes S. Variable effects of tyrosine kinase inhibitors on avian osteoclasticactivity and reduction of bone loss in ovariedomized rats. J Cell Biochem 1996;61:629-637. 50. Erdman J, Stillman R, Lee K, Potter S. Short-term effects of soybean isoflavones on bone in postmenopausal women. Program and abstract book, second international symposium on the role of soy in preventing and treating chronic disease. Brussels, Belgium, 1996. 51.Greendale GA, FitzGerald G, Huang MH, et al. Dietary soy isoflavones and bone mineral density: results from the study of women’s health across the nation. Am J Epidemiol 2002;155 746-754. 52. Potter SM, Baum JA, Teng H, et al. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr 1998;68(supp16):137551379S.

53. Shea 8, Wells G, Cranney A, et al. Calcium supplementation on bone loss in postmenopausal women. Cochrane Database Syst Rev 2004;(1):CwO4526. 54. Xu L, McElduff P, DEste C, Attia J. Does dietary calcium have a protective effect on bone fractures in women? A meta-analysis of observational studies. Br J Nutr 2004;91:625-634. 55. Sakhaee K, Bhuket T, Adams-Huet B, Rao Ds.Meta-analysis of calcium bioavailability: a comparison of calcium citrate with calcium carbonate. Am J Ther 1999;6313-321. 56. Heaney RP, Dowell MS, Barger-Lux MJ. Absorption of calcium as the carbonate and citrate salts, with some observations on method. OSteOpO~SInt 1999;919-23. 57. Aloia JF, Vaswani A, Yeh JK, et al. Calcium supplementation with and without hormone replacement therapy to prevent postmenopausal bone loss. Ann Intern Med 1994;120:97-103. 58. Reid IR, Ames RW, Evans MC, et al. Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomized controlled trial. Am J Med 1995;98331-335. 59. Devine A, Dick IM, Heal SJ, et al. A 4-year follow-up study of the effects of calcium supplementation on bone density in elderly postmenopausal women. Osteoporos Int 1997;723-28. 60.Elders PJ, Lips P, Netelenbos JC, et al. Long-term effect of calcium supplementation on bone loss in perimenopausal women. J Bone Miner Res 1994;9:963-970. 61. Bourgoin BP, Evans DR, Comett JR, et al. Lead content in 70 brands of dietary calcium supplements. Am J Public Health 1993;83: 1155-1160. 62. Carr CJ, Shangraw RF. Nutritional and pharmaceutical aspects of calcium supplementation. Am Pharm 1987;2749-50;54-57. 63. Lore F, Nuti R, Vattimo A, Caniggia A. Vitamin D metabolites in postmenopausal osteoporosis. Horm Metab Res 1984;1658. 64. Brautbar N. Osteoporosis: is 1,25-(OH)2D3of value in treatment? Nephron 1986;44:161-166. 65. Dawson-Hughes B, Hams SS, Krall EA, et al. Rates of bone loss in postmenopausal women randomly assigned to one of two dosages of the vitamin D. Am J Clin Nutr 1995;61:1140-1145. 66.Ooms ME, Roos JC, Bezemer PD, et al. Prevention of bone loss by vitamin D Supplementation in elderly women: a randomized double-blind study. J Clin Endocrinol Metabol 1995;80:1052-1058. 67. Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. BMJ 19943081081-1082. 68.Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;337: 701-702. 69. Bischoff-Ferrari H, Dawson-Hughes B, Wdlett W, et al. Effect of vitamin D on falls: a meta-analysis. JAMA 2004;291;16:1999-2006. 70. Cohen L, Kitzes R. Infrared spectroscopy and magnesium content of bone mineral in osteoporotic women. Isr J Med Sci 1981;17 1123-1125.

71. Stendig-Lindberg G, Tepper R, Leichter I. Trabecular bone density in a two-year controlled trial of peroral magnesium in osteoporosis. Magnes Res 1993;6:155-163. 72. Rude RK, Adams JS, Ryzen E, et al. Low serum concentration of 1,25dihydroxyvitamin D in human magnesium deficiency. J Clin Endocrinol Metab 1985;61:933-940. 73. Stendig-Lindberg G, Tepper R, Leichter I. Trabecular bone density in a two-year controlled trial of peroral magnesium in osteoporosis. Magnes Res 1993;6155-163. 74.Brattstrom LE, Hultberg BL, Hardebo JE. Folic acid responsive postmenopausal homocysteinemia. Metabolism 1985;34: 1073-1077. 75.Ubbink JB, van der Merwe A, Vermaak WK, Delport R. Hyperhomacysteinemia and the response to vitamin supplementation. Clin Investig 1993;71:993-998. 76. Fessenden RJ, Fessenden JS. The biological properties of silicon compounds. Adv Drug Res 1967;495-132. 77.Riggs BL, Seeman E, Hodgson SF, et al. Effect of the fluoride/ calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis. Comparison with conventional therapy. N Engl J Med 1982;306:446-450. 78. Murray TM, Ste-Marie LG. Fluoride therapy for osteoporosis. CMAJ 1996;155:949-954. 79. Brandi ML. New treatment strategies. Ipriflavone, strontium, vitamin D metabolites and analogs. Am J Med 1993;95(5A): 69574s. 80. Moscarini M, Patacchiola F, Spacca G, et al. New perspectives in the treatment of postmenopausal osteoporosis. Ipriflavone Gynecol Endocrinol 1994;8:203-207. 81. Passeri M, Biondi M, Costi D, et al. Effect of ipriflavone on bone mass in elderly osteoporotic women. Bone Miner 1992;19(suppll): S57-62. 82. Agnusdei D, Crepaldi G, Isaia G, et al. A double blind, placebocontrolled trial of ipriflavone for prevention of postmenopausal spinal bone loss. Calcif Tissue Int 1997;61:142-147. 83. Adami S, Bufalino L, Cervetti R, et al. Ipriflavone prevents radial bone loss in postmenopausal women with low bone mass over 2 years. Osteoporos Int 1997;7119-125. 84. Melis GB, Paoletti AM, Cagnacci A, et al. Lack of any estrogenic effect of ipriflavone in postmenopausal women. J Endocrinol Invest 1992;15:755-761. 85. Alexandersen P, Toussaint A, Christiansen C, et al. Ipriflavone in the treatment of postmenopausal osteoporosis: a randomized controlled trial. JAMA 2001;285:1482-1488. 86. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;3331437-1443. Calcitonin for prevention and treatment of osteoporo87. Reginster JY. sis. Am J Med 1993;95:44547S.

Otitis Media Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

1991

Diagnostic Considerations 1991 Standard Medical Treatment 1991 Causes 1993 Therapeutic Considerations 1993 Bottle-feeding 1993 Food Allergy 1993 Thymus Grand Extract 1994 Naturopathic Ear Drops 1994

DIAGNOSTIC SUMMARY Acute otitis media is characterized by the following: Earache or irritability History of recent upper respiratory tract infection or allergy Red, opaque, bulging ear drum with loss of the normal features Fever and chills Chronic or serous otitis media is characterized by the following: Painless hearing loss Dull, immobile tympanic membrane

GENERAL CONSIDERATIONS Otitis media occurs as a result of inflammation, swelling, or infection of the middle ear. Otitis media is of two types: chronic and acute. Acute otitis media is usually preceded by an upper respiratory infection or allergy. The organisms most commonly cultured from middle ear fluid during acute otitis media include Streptococcus pneumoniue (40%) and Huemophilus influenme (25%).Chronic otitis media-also known as serous, secretory, or nonsuppurative otitis media; chronic otitis media with effusion; and "glue ear"-refers to a constant swelling of the middle ear.

Xylitol 1995 Humidifiers 1995 Homeopathy 1995

Therapeutic Approach 1995 Diet 1996 Nutritional Supplements 1996 Botanical Medicines 1996 Physical Medicine 1996

Acute otitis media affects two thirds of American children by 2 years of age, and chronic otitis media affects two thirds of children younger than the age of 6.' Otitis media is the most common diagnosis in children and is the leading cause of all visits to pediatricians. It is the main reason for antibiotic and surgical interventions in kids. A conservative estimate is that approximately $8 billion is spent annually on medical and surgical treatment of earache in the United States.

Standard Medical Treatment The standard medical approach to otitis media in children is antibiotics, analgesics (e.g., acetaminophen), or antihistamines. If the ear infection is long standing and unresponsive to the drugs, surgery is performed. The surgery involves the placement of a tiny plastic myringotomy tube through the ear drum to assist the normal drainage of fluid into the throat via the Eustachian tube. It is not a curative procedure, as children with myringotomy tubes in their ears are in fact more likely to have further problems with otitis media. Myringotomies are currently being performed on nearly 1 million American children each year. It appears that the unnecessary surgery of the past, the tonsillectomy, has been replaced by this new procedure. In fact, there is a direct correlation between the decline of the tonsillectomy and the rise of the myringotomy. More than 2 million myringotomy tubes are inserted into 1991

Specific Health Problems ~~~

children's ears each year, along with 600,000 tonsillectomies and adenoidectomies.These surgeries are unnecessary for most children. A 1994 evaluation of the appropriateness of myringotomy tubes in children younger than 16 years of age in the United States found that only 42% were judged as being appropriate.* These results mean that several hundred thousand children are subjected to a procedure that will do them little good and possibly significant harm. A number of well-designed studies have demonstrated that there were no sigruficant differences in the clinical course of acute otitis media when conventional treatments were compared with placebo. Specifically, no differences were found between nonantibiotic treatment, ear tubes, ear tubes with antibiotics, and antibiotics alone.$' Interestingly, in some studies, children not receiving antibiotics did have fewer recurrences than those receiving antibiotics. This reduced recurrence rate is undoubtedly a reflection of the suppressive effects antibiotics have on the immune -system, as well as disturbing the normal flora of the upper respiratory tract.* Although some reviews showed a slight benefit with antibiotics, in the most recent analysis, a group of eight international experts from the United States, Britain, and the Netherlands reported that antibiotics are not recommended for the otitis media in most ~ h i l d r e n .Their ~ extensive review of the scientific literature on the value of antibiotics in the treatment of otitis media over the past 30 years led to the following conclusions: The benefit of routine antimicrobial use for otitis media, judged by either short-term or long-term outcomes, is unproven. Existing research offers no compelling evidence that children with acute otitis media routinely given antimicrobials have a shorter duration of symptoms, fewer recurrences, or better long-term outcomes than those who do not receive them. Although preventing mastoiditis and meningitis is a rationale for antimicrobial treatment, little evidence exists that routine treatment is effective for this purpose. Antimicrobials did not improve outcome at 2 months, and no differences in rates of recovery were found for either antimicrobial type or duration. These results have been accepted by U.S. pediatricians, but others still rely heavily on antibiotics to treat otitis media. Instead of antibiotics, the recommendation from this group of experts was to use analgesics (e.g., acetaminophen) and close observation by the parent. Results from clinical trials have shown that more than 80% of the children with acute otitis media respond to a placebo within 48 hours. Although analgesics may be of use to limit the child's pain, they have their own toxicity profile. As such, we recommend other proven

pain-relieving options like botanical eardrops as a replacement analgesic (see later). In addition to not being very effective in otitis media, the widespread use and abuse of antibiotics is becoming increasingly alarming. Risks of antibiotics include allergic reactions, gastric upset, accelerated bacterial resistance, and unfavorable changes in nasopharyngeal bacterial flora. Antibiotics not only fail to eradicate the organisms but can induce middle ear superinfection. Moreover, antibiotic prescribing can increase return office visit rates and the likelihood of seeking medical care for future illness? Additionally, studies on concomitant antibiotic and steroid treatment have revealed poor results on long-term efficacy for chronic otitis media.lo Antibiotics are encouraging the near-epidemic proportion of chronic candidiasis sufferers, as well as the development of "superbugs" that are resistant to currently available antibiotics. The position of the American Academy of Otolaryngology-Head and Neck Surgery states that there is no evidence indicating systemic antibiotics alone can improve treatment outcome and that they should not be used save the situation of an underlying systemic infection." According to many experts, as well as the World Health Organization, we are coming dangerously close to arriving at a "postantibiotic era" in which many infectious diseases will once again become almost impossible to treat because of an overreliance on antibiotics (see Chapter 57 for further information).12 The bottom line is that otitis media is normally a selflimiting disease. It normally remits on its own, regardless of treatment. High rates of spontaneous resolution have been well documented in the medical literature. Three meta-analyses independently found that approximately 80% of children with acute otitis media had spontaneous clinical relief within 2 to 14 days. Some studies of children younger than 2 years do suggest a lower spontaneous resolution of about 30%after a few days.9 The risks and failure with antibiotics, when coupled with the high rate of spontaneous resolution and the high rate of recurrent otitis media following insertion of ear tubes, suggest that conservative (nonantibiotic, nonsurgical) treatment alone would reduce the frequency rate and decrease the yearly financial costs of otitis media. To examine this concept, one clever study had the parents of children with nonsevere acute otitis media given a "safety prescription" of antibiotics to be filled only if there was no improvement within 2 days. This method of "wait and see" reduced median antibiotic prescriptions by 31% compared with 12% in a control practice.13 Although standard antibiotic and surgical procedures may not be statistically effective, each child must be evaluated individually, and appropriate follow-up

Otitis Media

including physician-family communication should be devised and assured before making a decision not to use these procedures. Special circumstances in the interest of preventing hearing loss-induced developmental delays would suggest a more appropriate use of ear tubes. Finally, pneumococcal and viral vaccines have been designed but have also shown little benefit, probably due to the multifactorial nature of this condition? Given the risks and complications inherent, vaccinations do not appear to be warranted at this time.

Causes The primary risk factors for otitis media are as follows’: Day care attendance Wood-burning stoves Parental smoking or exposure to other second-hand smoke Food allergies Not being breastfed Pacifier use9 All of these factors share a common mechanismabnormal Eustachian tube function, the underlying cause in virtually all cases of otitis media. The Eustachian tube regulates gas pressure in the middle ear, protects the middle ear from nose and throat secretions and bacteria, and clears fluids from the middle ear. Swallowing causes active opening of the Eustachian tube due to the action of the surrounding muscles. Infants and small children are particularly susceptible to Eustachian tube problems because it is smaller in diameter and more horizontal. Obstruction of the Eustachian tube leads first to fluid buildup and then, if the bacteria present are pathogenic and the immune system is impaired, to bacterial infection. Obstruction results from collapse of the tube (due to weak tissues holding the tube in place or an abnormal opening mechanism, or both), blockage with mucus in response to allergy or irritation, swelling of the mucous membrane, or infection. Otitis media may also have a genetic component because in twin studies, monozygotic twins tend to have a higher concordance rate in otitis media histories than dizygotic twins.9 Although immunoglobulin markersI4 and human leukocyte antigen (HLA)15have also been a focus of research, no specific genetic associations have been elucidated thus far.

THERAPEUTIC CONSIDERATIONS The primary treatment goals are to ensure patency of Eustachian tubes and to promote drainage by identifying and addressing causative factors. Supporting the immune system is also important. The recommendations

that follow should be used along with those recommendations for immune support given in Chapter 57.

Bottle-feeding Recurrent ear infection is strongly associated with early bottle-feeding, while breastfeeding (a minimum of 3 months) has a protective effect.16J7Whether this is due to cow’s milk allergy or to the protective effect of human milk against infection has not yet been conclusively determined. It is probably a combination. In addition, bottle-feeding while a child is lying on his or her back (bottle-propping) leads to regurgitation of the bottle’s contents into the middle ear and should be avoided. Whatever the ”causative” organism in otitis mediaviral (respiratory syncytial virus, rhinovirus, or influenza A) or bacterial (S. pneurnoniae, Moraxella catarrhah, or H. influenza)-human milk offers protection due to its high antibody content, which helps to inhibit infectious agents.l8 Breastfed infants also have a thymus gland (the major organ of the immune system) roughly 20 times larger than formula-fed infants.19

Food Allergy The role of allergy as the major cause of chronic otitis media has been firmly established in the research literature.2”-zSince the previous publication of this textbook, eight clinical studies have shown similar results. Most studies show that 85% to 93% of these children have allergies: 16% to inhalants only, 14% to food only, and 70% to both. One way in which prolonged breastfeeding prevents otitis media may be by the avoidance of food allergies, particularly if the mother avoids sensitizing foods (i.e., those to which she is allergic) during pregnancy and lactation. In addition to breastfeeding, also of value is the exclusion or limited consumption of the foods to which children are most commonly allergic-wheat, egg, peanuts, corn, citrus, chocolate, and dairy-particularly during the first 9 months. Because a child’s digestive tract is quite permeable to food antigens, especially during the first 3 months, careful control of eating patterns (no frequent repetitions of any food, avoiding the common allergenic foods, and introduction of foods in a controlled manner [i.e., introduction of one food at a time and carefully watching for a reaction]) will reduce and prevent the development of food allergies. The allergic reaction causes blockage of the Eustachian tube by two mechanisms: inflammatory swelling of the mucous membranes lining the tube and inflammatory swelling of the nose, causing the Toynbee phenomenon (swallowingwhen both mouth and nose are closed, forcing air and secretions into the middle ear). In chronic

Specific Health Problems earaches, an allergic cause should always be considered, and the offending allergens determined and avoided. One illustrative study of 153 children with earaches demonstrated that 93.3% of the children (using the radioallergosorbent [RAST] test for diagnosis-see Chapters 19 and 53 for further discussion) were allergic to foods, inhalants, or both. The 12-month success rate for 119 of the children, when treated with serial dilution titration therapy for inhalant sensitivities and an elimination diet for food allergens, showed that 92% improved. This compares favorably with the surgically treated control group (ear tubes and, as indicated, removal of the tonsils and adenoids), which showed only a 52% response.20 In another study, a total of 104 children with recurrent otitis media ranging in age from 1.5 to 9 years were evaluated for food allergy by means of skinprick testing, specific IgE tests, and food challenge.25 Results indicated a statistically significant association between food allergy and recurrent otitis media in 81/104 patients (78%). The elimination diet led to a significant amelioration of chronic otitis media in 70/81 (86%) patients as assessed by detailed clinical evaluation. The challenge diet with the suspected offending food provoked a recurrence of serous otitis media in 66/70 patients (94%). The frequency distribution of allergies to individual foods is listed in Table 197-1, while the frequency distribution according to number of food allergens is listed in Table 197-2.

Thymus Gland Extract The thymus gland secretes a family of hormones, which act on white cells to ensure their proper development and function. Studies with calf thymus extracts given orally have demonstrated impressive clinical results in various clinical conditions in Specifically, thymus extracts have been shown to improve immune function, decrease children’s food allergies, and improve a child’s resistance to chronic respiratory infections. Thymus extracts may be of particular benefit in chronic otitis media. For more information, see Chapter 57.

Naturopathic Ear Drops Even though most cases of otitis media resolve spontaneously, oftentimes otalgia (ear pain) can persist during the period of improvement, sometimes motivating anxious parents to request unnecessary antibiotic therapy. Naturopathic botanical ear drops have been shown to be as effective as either antibiotic and anesthetic dropsBSmand offer a much less toxic approach to pain management. In a double-blind outpatient one group from Israel studied 171 children ages 5 to 18 who were randomly assigned to receive treatment with naturopathic

No. of patients

Percentage of patients

Cow’s milk

31

38

Wheat

27

33

Egg white

20

25

Peanut

16

20

SOY

14

17

Corn

Food

12

15

Tomato

4

5

Chicken

4

5

Apple

3

4

The frequency distribution according to number of food allergens No.of food allergens

No.of allergic patientdtotal

Percentage

1

11/81

13.6

2-4

66/81

81.5

5-7

3181

3.7

8-10

1/81

1.3

herbal extract ear drops (NHEDs) or anesthetic ear drops (amethocaine and phenazone), with or without amoxicillin (80 mg/kg/day). The plant medicine was a combination of Calendula oficicinalis flowers (marigold, 28%), Hypericum petJorutum complete herb (St. John’s wort, 30%),and Verbuscumthapsus flowers (mullein, 25%) in olive oil with the essential oils Allium sutivurn (garlic) in 0.05% in olive oil (lo%), Lavendulu oficinulis (lavender5%),and tocopherol acetate oil (vitamin E-2%) and was dosed at 5 drops tid. All groups had a statistically significant improvement in ear pain over the course of the 3 days, with a 95.9% reduction in the NHED-alone group. The NHED plus antibiotics had a 90.9% pain diminution. The anesthetic alone and anesthetic with antibioticshad 84.7%and 77.8% reductions, respectively. Although a notable study, we would like to see future studies designed with a control as well because this study does not confirm whether the improvements are superior to elapsing time alone.. Furthermore, this study does not address the sometimes more refractory management of children younger than 5 years of age. Nevertheless, given the positive outcomes in this study, and significantly lower toxicity profile than conventional antibiotic or anesthetic medications, the naturopathic eardrops are clearly the superior choice for children with ear pain-associated otalgia. As a side note, there are numerous other botanical anodynes not

Otitis Media ~

employed in this formula that would be worthy of study as well as part of an eardrop formula.

Xylitol Xylitol is a commonly used sweetener known mostly for its anticariogenic properties. It is a sugar-alcohol derived mainly from birch and other hardwood trees and has demonstrated inhibition of S. pneumoniue. Two randomized trials illustrated xylitol’s ability to reduce acute otitis media incidence by 40%. In one studfl of 306 day care children with recurrent acute otitis media, 157 children were given xylitol (8.4 g/day) chewing gum and 149 children were given a sucrose control gum. During the 2 months, at least one event of acute otitis media was experienced by 20.8% of the children who received sucrose compared with only 12.1% of those receiving chewing gum containing xylitol. Sigruficantly fewer antimicrobials were prescribed among those receiving xylitol. In a second randomized and controlled blinded trialp2 857 healthy children were randomized to one of five treatment groups to receive control syrup, xylitol syrup, control chewing gum, xylitol gum, or xylitol lozenge. The daily dose of xylitol varied from 8.4 g (chewing gum) to 10 g (syrup). The design was for 3 months. Although at least one event of otitis was experienced by 41%of the 165 children who received control syrup, only 29% of the 159 children receiving xylitol syrup were affected. Likewise, the occurrence of otitis decreased by 40% compared with control subjects in the children who received xylitol chewing gum and by 20% in the lozenge group. Thus the occurrence of acute otitis media during the follow-up period was significantly lower in those who received xylitol syrup or gum, and these children required antimicrobials less often than did controls. As a note, xylitol has been criticized as a practical method because the studies suggest that dosing needs to be four to five times per day, which may decrease compliance and therefore its overall effectiveness. Although two children in the xylitol group experienced diarrhea, no other untoward effects were reported for this safe and useful treatment.

Humidifiers Humidifiers are popular treatments for otitis media and upper respiratory tract infections in children. This may be justified according to a 1994 study that evaluated the role of low humidity in this disorder.33The study examined the effect of low humidity on the middle ear using a rat model. Twenty-three rats were housed for 5 days in a low-humidity environment (10% to 12%relative humidity), and 23 control rats were housed at 50% to 55% relative humidity. Microscopic ear examinations were graded for otitis media before testing and on test days 3 and 5. The lining of the

middle ears and Eustachian tubes were examined by biopsy. Significantly more effusions (fluid in the Eustachian tubes) were observed in the low-humidity group on both days 3 and 5, but biopsy results were similar in both groups. This study indicated that low humidity may be a contributing factor in otitis media. Possible explanations are that low humidity may induce nasal swelling and reduce ventilation of the eustachian tube, or that it may dry the eustachian tube lining, which could lead to an inability to clear fluid, as well as to increased secretions. The mast cells that reside in the lining of the eustachian tubes may also come into play by releasing histamine and producing swelling. Although preliminary, this research indicates that increasing humidity with the help of a humidifier may be an important goal in the treatment of otitis media with effusion.

Homeopathy Homeopathy is an energetic medicine based on the law that “like cures like.” Used extensively in Europe and India, homeopathy is gaining some acceptance as a viable, nontoxic, individualized option to treat various conditions. Research is beginning to amass regarding its use. One randomized, double-blind, placebo-controlled pilot study was conducted in a private pediatric practice with 75 children ages 18 months to 6 years. All had middle ear effusion and ear pain or fever, or both, for no more than 36 hours. Each child received either an individualized homeopathic medicine or a placebo three times daily by mouth for 5 days or until symptoms subsided. Results demonstrated a statistically significant decrease in symptoms using homeopathy over placebo and nonstatistically significant fewer treatment failures in the group receiving homeopathy? Similarly, a second study found excellent results regarding the homeopathic pain reduction rate of almost two and a half times over placebo controls with 39% of the patients improving after 6 hours and another 33% after 12 hours. A follow-up different homeopathic was given if results were not seen in the first 6 hours.35 A German prospective study has also found comparable results when evaluating homeopathic treatment with conventional therapies.% More clinical trials are necessary to elucidate the optimal uses of homeopathy. But in the meantime, homeopathy is proving to be an effective and extremely safe option to consider for pediatric otitis sufferers.

THERAPEUTIC APPROACH The key factor in the natural approach to chronic otitis media in children appears to be the recognition and

Specific Health Problems elimination of allergies, particularly food allergies, and support for the immune system.

Diet Because it is usually not possible to determine the exact allergen during an acute attack, the most common allergic foods should be eliminated from the diet:

Milk and other dairy products Eggs Wheat corn Oranges Peanuts Chocolate The diet should also eliminate concentrated simple carbohydrates (e.g., sugar, honey, dried fruit, concentrated fruit juice) because they inhibit the immune system. These simple dietary recommendations bring relief to most children in a matter of days.

Nutritional Supplements

polypeptides with molecular weights less than 10,000 or roughly 500 mg of the crude polypeptide fraction daily

Botanical Medicines Echinaceu sp.: One-half the adult dosage is appropriate for children younger than the age of 6, and the full adult dosage (given later) is appropriate for children older than the age of 6 (Echinacea is safe for children). The following dosages can be given up to tid. Dried root (or as tea): 0.5 to 1 g Freeze-dried plant: 325 to 650 mg Juice of aerial portion of Echinaceu purpurea stabilized in 22% ethanol: 2 to 3 ml Tincture (1:5): 2 to 4 ml Fluid extract (1:l):2 to 4 ml Solid (dry powdered) extract (6.5:l or 3.5% echinacoside): 150 to 300 mg Xylitol: approximately 8 g/day as either chewing gum chewed throughout the day or 10 g of the syrup per day in divided doses Naturopathic eardrop formula: five drops in the affected ear tid

Children’s multivitamin and mineral formula Vitamin A: 50,000 IU/day for up to 2 days in children younger than 6 years old, and 4 days in children older than 6 years old Beta-carotene (natural mixed carotenoids): age in years x 20,000 IU/day (up to 200,000 IU/day) Vitamin C: age in years x 50 mg every 2 hours Bioflavonoids: age in years x 50 mg every 2 hours Zinc: age in years x 2.5 mg daily (up to 30 mg) *Thymus extract: the equivalent of 120 mg pure

Local application of heat is often helpful in reducing discomfort. It can be applied as a hot pack, with warm oil (especially mullein oil), or by blowing hot air into the ear with the aid of a straw and a hair dryer. These treatments help to reduce pressure in the middle ear and promote fluid drainage.

1. Daly KA. Epidemiology of otitis media. Otolaryngol Clin North Am 1991;24:775-786. 2. Kleinman LC, Kosecoff J, Dubois RW, et al. The medical appropriateness of tympanostomy tubes proposed for children younger than 16 years in the United States. JAMA 1994;271:1250-1255. 3. Bluestone CD. Otitis media in children: to treat or not to treat? N Engl J Med 1982;306:1399-1404. 4. van Buchem FL, Dunk JH, van’t Hof MA. Therapy of acute otitis media: myringotomy, antibiotics, or neither? Lancet 1981;2:883-887. 5. Williams RL, Chalmers TC, Stange KC, et al. Use of antibiotics in preventing recurrent acute otitis media and in treating otitis media with effusion. A meta-analytic attempt to resolve the brouhaha. JAMA 1993;270:1344-1351. 6. Rosenfeld RM, Vertrees JE, Cam J, et al. Clinical efficacy of antimicrobial drugs for acute otitis media: metaanalysis of 5400 children from thirty-three randomized trials. J Pediatr 1994;124355-367. 7. Froom J, Culpepper L, Jacobs M, et al. Antimicrobials for acute otitis media? A review from the International Primary Care Network. Br Med J 1997;315:98-102. 8. Del Castillo F, Baquero-Artigao F, Garcia-Perea A. Influence of recent antibiotic therapy on antimicrobial resistance of Streptococcus pneumoniae in children with acute otitis media in Spain. Pediatr Infect Dis J 1998;1794-97.

9. Rovers MM, Schilder AG, Zielhuis GA, et al. Otitis media. Lancet 2004;363:465-473. 10. Mandel EM, Casselbrant ML, Rockette HE, et al. Systemic steroid for chronic otitis media with effusion in children. Pediatrics 2002; 1101071-1080. 11. Hannley MT, Denneny JC 111, Holzer SS. Use of ototopical antibiotics in treating three common ear diseases. Otolaryngol Head Neck Surg 2OOO;122:934-940. 12. Woodhead M. Antibiotic resistance. Br J Hosp Med 1996;56314-315. 13. Cates C. An evidence based approach to reducing antibiotic use in children with acute otitis media: controlled before and after study. BMJ 1999318~715-716. 14. Kelly KM. Recurrent otitis media: genetic immunoglobulin markers in children and their parents. Int J Pediatr Otorhinolaryngol 1993; 25~279-280. 15. Kalm 0, Johnson U, Prellner K. HLA frequency in patients with chronic secretory otitis media. Int J Pediatr Otorhinolaryngol 1994;30:151-157. 16. Saarinen UM.Prolonged breast feeding as prophylaxis for recurrent otitis media. Acta Ped S a n d 1982;71:567-571. 17. Uhari M, Mhtysaari K, Niemela M. A meta-analytic review of the risk factors for acute otitis media. Clin Infect Dis 1996;22: 1079-1083.

Physical Medicine

Otitis Media 18.Editor. Breast feeding prevents otitis media. Nutr Rev 1983;41: 241-242. 19. Hasselbalch H, Jeppesen DL, Engelmann MD, et al. Decreased thymus size in formula-fed infants compared with breastfed infants. Acta Periatr 1996;85:1029-1032. 20. McMahan JT, Calenoff E, Croft DJ, et al. Chronic otitis media with effusion and allergy:modified RAST analysis of 119 cases. Otol Head Neck Surg 1981;89427-431. 21. Viscomi GJ. Allergic secretory otitis media: an approach to management. Laryngoscope 1975;85:751-758. 22. Van Cauwenberge PB. The role of allergy in otitis media with effusion. Ther Umschau 1982;39:1011-1016. 23. Bellionin P, Cantani A, Salvinelli F. Allergy: a leading role in otitis media with effusion. Allergol Immunol1987;15:205-208. 24. Hurst DS.Association of otitis media with effusion and allergy as demonstrated by intradermal skin testing and eosinophil protein levels in both middle ear effusions and mucosal biopsies. Laryngoscope 1996;1061128-1137. 25. Nsouli TM, Nsouli SM, Linde RE, et al. Role of food allergy in serous otitis media. Ann Allergy 1994;73215-219. 26. FiocchiA, Borella E, Riva E, et al. A double-blind clinical trial for the evaluation of the therapeutical effectiveness of a calf thymus derivative (Thymomodulin) in children with recurrent respiratory infections. Thymus 1986;8:831-839. 27.Genova R, Guerra A. Thymomodulin in management of food allergy in children. Int J Tissue React 1986;8:239-242.

28. Cazzola P, Mazzanti P, Bossi G. In vivo modulating effect of a calf thymus acid lysate on human T lymphocyte subsets and CD&/ CD8+ ratio in the course of different diseases. Curr Ther Res 1987; 421011-1017. 29. Sarrell EM, Cohen HA, Kahan E. Naturopathic treatment for ear pain in children. Pediatrics 2003;111:574-579. 30. Sarrell EM, Mandelberg A, Cohen HA. Efficacy of naturopathic extracts in the management of ear pain associated with acute otitis media. Arch Pediatr Adolesc Med 2001;155796-799. 31. Uhari M, Kontiokari T, Koskela M, et al. Xylitol chewing gum in prevention of acute otitis media: double blind randomised trial. BMJ 1996;3131180-1184. 32. Uhari M, Kontiokari T, Niemela M. A novel use of xylitol sugar in preventing acute otitis media. Pediatrics 1998;102:879-884. 33. Lovejoy HM, McGuirt WF,Ayres PH, et al. Effects of low humidity on the rat middle ear. Laryngoscope 1994;104:1055-1058. 34. Jacobs J, Springer DA, Crothers D. Homeopathic treatment of acute otitis media in children: a preliminary randomized placebocontrolled trial. Pediatr Infect Dis J 2001;20:177-183. 35. Frei H, Thumeysen A. Homeopathy in acute otitis media in children: treatment effect or spontaneous resolution? Br Homeopath J 2001; 90180-182. 36. Friese KH, Kruse S, Moeller H. [Acute otitis media in children. Comparison between conventional and homeopathic therapy.] HNO 1996;44:462-466.

Parkinson’s Disease Peter B. Bongiorno, ND, Dipl Ac

Pina LoGiudice, ND, Dipl LAC CHAPTER CONTENTS Diagnostic Summary

1999

General Considerations 1999 Etiology 1999 Genetics 2000 Apoptosis 2000 Toxic Exposures-Pesticides, Solvents, Metals, and Manganese 2000 Oxidative Stress and Glutathione Deficiency 2001 Detoxification Dysfunction 2002 Diagnostic Considerations 2002

DIAGNOSTIC SUMMARY Resting tremor (trembling or shaking). The tremor usually gets worse when the person is at rest and better when the person moves. This tremor often begins on one side of the body. “Pill rolling” motion of the thumb and forefinger Slow movement (bradykinesia)or an inability to move (akinesia) Difficulty initiating movement Rigid limbs, shuffling gait, stooped posture Reduced or fixed facial expressions (”masked face”) and low volume or monotone voice, or both Small handwriting (micrographia) that decreases in size toward the end of a writing sample Dysphagia may indicate later disease stage Lewy bodies, microscopic protein aggregates that can be seen only during an autopsy, are regarded as a hallmark of classical Parkinson’s disease

GENERAL CONSIDERATIONS First described by James Parkinson in 1817, Parkinson’s disease occurs in approximately 0.3% of the general population and about 1% of the population older than the age of 55 to 60 in industrialized countries.lt2 This progressive neurologic disorder results from

Therapeutic Considerations 2003 Conventional Medicine 2003 Detoxification 2004 Nutritional Considerations 2004 Botanical Medicines 2007 Other Therapeutic Considerations 2008 Therapeutic Approach 2010 Diagnosis 2010 Dietary Recommendations 2010 Lifestyle Recommendations 2010 Nutritional Supplementation 2010 Botanical Medicines 2010 Acupuncture 2011

a deterioration of neurons in the region of the brain that controls muscle movements. This degeneration creates a shortage of the neurotransmitter dopamine, causing the movement impairments that characterize the disease. People with Parkinson’s disease often experience trembling, muscle rigidity, difficulty walking, and problems with balance and coordination. In the United States at least 500,000 people are believed to suffer from Parkinson’s disease, and about 50,000 new cases are reported annually. These figures are expected to increase as the average age of the population increases. The disorder appears to be slightly more common in men than women. The prevalence and incidence of Parkinson’s disease rises with age, with the average age of onset being around 60. The disease rates are low in people younger than 40 and rise among people in their 70s and 80s. Parkinson’s disease is found in many geographic regions of the world. The rates vary from country to country, but it is not clear whether this reflects true ethnic or geographic differences or just discrepancies in data collection.

Although there are many theories about the cause of Parkinson‘s disease, the etiology remains largely unexplained. Various research groups have suggested 1999

mitochondrial abnormalities, environmental neurotoxic exposures, selective generation of potential toxins or reduced detoxification capacity, infectious agents, and genetic factors as possible reasons for this disease. Some researchers believe that neurons from the involved brain regions are selectively vulnerable to this disease due to their heightened propensity to take up both endogenous and extrinsic toxic compounds through selective carrier mechanisms, such as the dopamine tran~porter.~ Most likely a combination of all of the aforementioned, over the course of time, leads to clinical disease.

etiology of Parkinson’s disease. The authors went on to explain that compared with other complex diseases, the importance of genetic effects in Parkinson’s is ”notably This study is quite valuable for it substantiates the importance of working to prevent and treat environmental, lifestyle, and nutritional factors, many of which are under our control, as risk factors for this neurogenerative condition. Nevertheless, future genetic studies may still help us understand some of the mechanistic events of Parkinson’s disease.

Genetics

Apoptosis accounts for much of the pathology seen in Parkinson‘s disease, as well as diseases like Alzheimer’s, Huntington‘s, and amyotrophic lateral sclerosis (Lou Gehrig disease), which are marked by the loss of brain neurons. Elevated apoptosis in these neurologic diseases seems to be related to lack of production of nerve growth factor and to free radical damage. A combination of such factors could likely cause many cells to destroy themselves. Manipulation of this process of apoptosis may help in treating these neurologic diseases. In fact, studies in animal models imply that long-term delivery of nerve growth factors could protect against programmed cell death in these conditions?-” Until the mechanisms of apoptosis are elucidated, some natural therapeutics that may decrease programmed cell death, such as melatonin therapy, may be of benefit in Parkinson’s disease (see melatonin later).

Although the rates of heritability for Alzheimer’s disease are between 40% and 60%; research is beginning to show evidence that late-onset Parkinson’s disease is probably not a question of genetic susceptibility. Most likely the onset of Parkinson’s disease may require the interaction of genetic and environmental factors.45Most people with Parkinson’s disease do not have a family history, and only about 15% of patients have a first-degree relative with the disease, typically without a clear mode of inheritance.’ Surprisingly, the risk of Alzheimer’s disease is not increased among relatives of patients with Parkinson’s disease compared with relatives of controls.6Although many neurogenerative schools of thought believe there may be a major shared genetic etiology between these two diseases, the data do not support this possibility. Population-based studies have shown some increased risk for relatives of Parkinson’s patients. Some data suggest a recessive or an oligogenic inheritance where the interaction of two or more genes is ne~essary.~ Mutations have been identified in five genes: a-synuclein, parkin, ubiquitin carboxy-terminal hydrolase L l , 01-1, and NR4A2 and six loci have been linked to Parkinson’s disease.’ Most of these genes are associated with early-onset Parkinson’s, whch accounts for only a small percentage of total Parkinson’s cases. Genetic variations do not appear to explain most intermittent cases of Parkinson’s disease, which are typically of the late-onset type. Further dissuading information tells us that genetic mutations found in late-onset individuals usually show no clinical correlation with disease states, in comparison with those with Parkinson’s disease who do not have genetic mutations! One fascinating study of all Swedish twins born in 1950 or earlier who were alive in 1998 was conducted to evaluate the role of genetics in Parkinson’s disease. To accomplish this, the authors screened 33,780 twins for Parkinson’s disease by telephone interviews. Of these, 247 with self-reported Parkinson’s disease or possible Parkinson’s disease and 517 twins who reported parkinsonian symptoms or use of antiparkinsonian medication (”suspected parkinsonism or movement disorder”) were identified. The somewhat surprising results suggest to us that environmental factors are most important in the

Apoptosis

Toxic Exposures-Pesticides, Solvents, Metals, and Manganese Long- and short-term exposures to pesticides, solvents, certain metals, and manganese have been implicated in the etiology of Parkinson’s disease. Even short-term toxicity exposure has been demonstrated to hasten disease onset. Pesticide exposure, living in rural areas of industrialized countries, and drinking well water have all been linked to Parkinson’s disease.l2,l3One report demonstrated that rats exposed to the organic pesticide rotenone develop Parkinson’s-like symptoms, as well as changes in the brain resembling those seen in Parkinson’s disease in humans. It was observed that chronic, systemic inhibition of mitochondrial complex I by the lipophilic pesticide rotenone can cause highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Additionally, nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-~ynuclein.’~ These inclusions are the major constituent of intracellular protein inclusions forming the Lewy bodies and Lewy neuritis in dopaminergic neurons of the substantia nigra. Other studies have also shown that chronic administration of rotenone over a

’*

Parkinson’s Disease

pallidus, and caudate nucleus with depletion of long period can increase nitric oxide and lipid peroxidadopamine and serotonin levels and has been linked to tion products in the brain cortex and striatum and psychiatric changes followed by impaired motor activity clearly mimics Parkinson’s-like behavioral symptoms with muscle rigidity and tremors.16 such as akinesia and rigidity in rats.15 Although poorly understood as to the cause, iron One report was based on a series of patients who accumulation has been related to some neurologic disdeveloped parkinsonism after exposure to l-methylorders such as Alzheimer’s disease, Parkinson’s disease, 4-phenyl-1,2,3,6-tetrahydropyridine(MI”), a neurotoxic type I neurodegeneration with brain iron accumulation, product of pesticide production and a contaminant and other disorders. Increased levels of iron, as well as found in synthetic heroin.16It was found that M I ” may an accompanying lipid peroxidation combined with a freely cross the blood-brain barrier, is selectively taken up by dopaminergic cells, and inhibits mitochondrial decreased level of glutathione and superoxide dismutase activity, are present in the substantia nigra of patients complex 1 function in the respiratory chain.17 M I ” is with Parkinson’s disease.22DAlthough it is not well eluthe only environmental agent that has been directly cidated whether the accumulation of iron in the brain is linked to development of levodopa-responsive parkinprimary or secondary to development of neurodegenersonism, a form that is clinically indistinguishable from ative disorders,” one animal study has shown that uniParkinson’s disease.’ However, since similar chemicals lateral injection of FeC13into the substantia nigra of adult like this are ubiquitous in our environment, it is probable that chronic exposures to other pesticides can contribute rats results in a 95% decrease of striatal dopamine, which impaired dopamine-related behavioral responses. This to this disorder. supports the assumption that iron may trigger the Some case-control studies and case reports have dopaminergicneurodegenerationof Parkinson’s disease.= shown an association between solvent exposure and parkinsonisms.18Records from a major United Kingdom Oxidative Stress and Glutathione engineering company were culled in order to explore Deficiency the relationship of metal and solvent exposure and Biochemical changes including increased levels of neuParkinson’s disease. The results of this survey demonrotoxic metals, the inhibition of mitochondrial complex I strated a significant exposure-response relationship for activity, and depleted glutathione levels occurring in solvents and almost a 400% increase in risk for employsubstantia nigra26all suggest that oxidative stress is presees exposed for 30 years or more. This study suggests ent and pathologically involved in Parkinson’s disease that sustained cumulative exposure is probably signifipatients.22Using healthy patients as a control, studies in cant because there was no evidence of overall increase in areas of patients dying from Parkinson’s disease have risk for those exposed for shorter durations. The authors observed 40% reduced glutathione levels in these noted that possibly the heavier exposures workers expepatients while oxidized glutathione was insignificantly rienced before the introduction of stricter industrial marginally elevated.27Depletion of glutathione levels environmental controls later in the twentieth century or exposure to older solvents such as trichloroethylene, l,l,l- may be an early component of the process because these suboptimal levels have also been found to occur in trichloroethane, carbon tetrachloride, kerosene, white presymptomatic Parkinson’s disease, also known as incispirit, and acetone, which were more widely used three or dental Lewy body disease,% although some animal more decades ago, may play a greater etiologic r01e.I~ studies demonstrate that depletion is not the primary Although the study mentioned previously showed no factor.29 increased risk of Parkinson’s disease in relation to metal Some researchers are finding that this glutathione defiexposure, occupational exposure to specific metals, especiency may be a common denominator in all parkinsonian cially manganese, copper, lead, iron, mercury, zinc, and conditions associated with nigral damage.26Although not aluminum, appears to be a risk factor for Parkinson’s completely elucidated, it is known that glutathione disease based on epidemiologic studies.20 Elevated exhibits several functions in the brain by acting as an levels of several of these metals have also been reported antioxidant and a redox regulator. Glutathione depletion in the substantia nigra of Parkinson’s disease subjects. has been shown to affect mitochondrial function probaLike pesticides, several divalent and trivalent metal bly via selective inhibition of mitochondrial complex I ions are also found to contribute to accelerations in the activity. Oxidative damage due to glutathione depletion rate of alpha-synuclein fibril formation. In one study, may also encourage aggregation of defective proteins aluminum contributed to fibril formation, along with leading to cell death of nigral-striatal dopaminergic copper(II), iron(III), cobalt(III), and manganese(II).20 neuronsz Chronic mercury inhalation has also been linked to Glutathione depletion may enhance the susceptibility cortical and cerebellar atrophy, dementia, Parkinson’s of substantia nigra to destruction by endogenous or syndrome, and ataxia of the lower limbs.2I Manganeseexogenous toxins. Replenishment of normal glutathione induced damage is found in the substantia nigra, globus

Specific Health Problems levels within the brain may hold an important key to therapeutics for Parkinson’s disease.26

Detoxification Dysfunction Research has begun to validate the hypothesis that the dysfunction of the body’s detoxification ability may underlie various chronic neurologic diseases such as Parkinson’s and Alzheimer’s diseases.30Research into the etiology of Parkinson’s disease has discovered defects in patients’ abilities to adequately metabolize sulfurcontaining xenobiotics.30 Altered detoxification, then, may render susceptible individuals at higher risk to neurotoxicity when exposed to sulfur-containing Connectionswith Alzheimer’s disease and other motor neuron diseases have also been Certainly genetic determination is but one factor and must be looked at in light of the strong support that has been found for the role of nutritional and environmental factors discussed elsewhere in this ~hapter.3~

DIAGNOSTIC CONSIDERATIONS No diagnostic test can clearly identdy Parkinson’s disease. It is usually diagnosed by a neurologist who can evaluate symptoms and their severity. However, diagnosis is typically left to clinical judgment. Some individuals with suspected Parkinson’s disease can receive therapeutic trials of dopamine, to which a positive response would be strongly suggestive of disease. Other tests such as brain scans can help differentiate as to whether a patient may have true Parkinson’s disease or some other similar disorder such as vascular parkinsonism. Interestingly, approximately 25% to 40% of patients with Parkinson’s disease develop dementia, thereby making it difficult to distinguish Parkinson’s disease with Lewy bodies from Alzheimer’s disease with parkinsonian characteristics. Furthermore, individuals with Parkinson’s disease may not exhibit the classic resting tremor but may exhibit more of an essential tremor. The essential tremor is characterized by a unilateral postural trcmor most evident in the upper extremities. In this case, the most reliable way to determine Parkinson’s disease is by characterizing the presence of an accompanying bradykinesia and rigidity. Parkinson’s disease is divided into five stages, which are listed in Table 198-1.M Pathologically, Lewy bodies are considered the hallmark of classical Parkinson’s disease. Found in the substantia nigra, Lewy bodies are acidophilic inclusions of the cytoplasm characterized by a dense core and peripheral halo. Diffuse neuronal loss is observed in the substantia nigra with an associated deficit of dopamine production in the nigrostriatal path~ay.3~ The presence of Lewy bodies cannot be used as diagnostic criteria because these can only be seen during an autopsy. Autopsies have uncovered Lewy bodies in a

Ifor motor dysfunction Stage

Description

0

No signs of disease

1

Unilateral disease

1.5

Unilateral plus axial involvement

2

Bilateral disease, without impairment of balance

2.5

Mild bilateral disease, with recovery on pull test

3

Mild to moderate bilateral disease; some postural instability; physically independent

4

Severe disability; still able to walk or stand unassisted

5

Wheelchair bound or bedridden unless aided

surprising number of older persons without diagnosed Parkinson’s disease: 8% of people older than 50, almost 13% of people older than 70, and almost 16% of those older than 80. Since its introduction in 1987, the Unified Parkinson Disease Rating Scale (UPDRS)34has been used extensively by researchers and clinicians around the world to help grade the patient on a number of criteria: behavior, activities, motor function, therapeutic complications, staging by symptoms, and a scale of daily living. Several neuro-imaging tests aid in the diagnosis of Parkinson’s disease (positronemission tomography [PET] scan using 18-flourodopa,Beta-carbomethoxy-3beta-(4iodophenyltropane single photon emission computed tomography [SPECT]).However, the UPDRS and neurological examination are sensitive enough to make the diagnosis. The differential diagnosis of this disorder includes normal aging, essential tremor, drug-induced parkinsonism, the Parkinson’s-plus syndromes, v a d a r parkinsonism, and normal pressure hydrocephalus. Less common entities with parkinsonism include dopa-responsive dystonia, juvenile-onset Huntington’s disease, and pallidopontonigral degeneration.’ Some related diagnoses include the following: Parkinsonism plus syndrome is defined when parkinsonism is accompanied by other abnormal neurologic symptoms. The most notable is progressive supranuclear palsy. In this condition, the patient develops early symptoms of Parkinson’s disease but then later develops characteristic abnormal eye movements. These patients also demonstrate neck dystonia, dysphagia, and a decreased response to levodopa. Shy-Drager syndrome (multisystem atrophy) is characterized by parkinsonism with concomitant autonomic nervous system abnormalities. These patients may have cranial nerve abnormalities, peripheral polyneuropathy, spasticity and anterior horn cell dysfunction.

Parkinson’s Disease

Drug-induced parkinsonism is due to phenothiazines, butyrophenones, reserpine and related hypertensives, manganese poisoning, and exposure to carbon monoxide.

THERAPEUTIC CONSIDERATIONS Conventional Medicine Unfortunately, no conventional therapy can modify the progressive pathology of Parkinson’s disease‘s neurologic degeneration.%However, unlike other serious neurologic diseases, Parkinson’s disease is somewhat treatable. For decades, the drug levodopa, commonly known as L-dopa, has been the mainstay of Parkinson’s disease treatment. It is synthesized by the enzyme tyrosine hydroxylase from the food-derived aromatic amino acid tyrosine. Modem treatment combines levodopa with a peripheral decarboxylase enzyme inhibitor to minimize conversion of levodopa to dopamine outside the nervous system.= Although initially effective in the early stages of the disease, L-dopa provides only symptomatic relief without altering disease progression, and it loses efficacy with time.2L-Dopa side effects include motor complications, particularly fluctuations and dyskinesias, as well as nausea, vomiting, orthostatic hypotension, sedation, hallucinations, delusions, and accelerated growth of malignant melanoma.37L-Dopa contributes to decreased slow wave peristaltic activity,% which may contribute to inadequate digestive function. It may also contribute to subtle detrimental effects on cognitive as well as a wide array of other psychiatric manifestations such as propensity to gamble.4oResponses to the drug may become more erratic over time. For that reason, newer drugs are now also used either alone or in combination with levodopa. Table 198-2 lists the medications commonly used to treat Parkinson’s disease. After being virtually abandoned for 20 years, another allopathic treatment that is gaining more prominence is deep brain stimulation (DBS). DBS involves implanting a brain stimulator, a device similar to a heart pacemaker, in certain areas of the brain. The desired effect is to decrease the overactivity of the excitatory glutamatergic subthalamo-internal pallidurn pathway caused by the loss of dopaminergic neurons within the substantia nigra. How DBS works is not well known, but it has been hypothesized that the stimulatory effect may modulate the neuronal activity and thus avoid disease-related abnormal neuronal discharges. Potential candidates for DBS are selected according to strict criteria. For some people, DBS may control symptoms so well that medications can be greatly reduced.4l Large randomized studies are necessary to compare stimulation at different brain targets and to contrast neurosurgical techniques.

Conventional medications Medication

DescriDtion

Sinemet Amantadine (Symmetrel)

Combination of L-dopa and carbidopa Modulates motor fluctuations; a dopamine receptor agonist.

Tolcapone (Tasrnar) or

Inhibit dopamine breakdown

~~

~

Entacapone (Comtan) Clozapine

For levadopa-induceddyskinesias

All of these medications can produce hallucinations and daytime somnolence. ‘Other dopamine receptor agonists are bromocriptine, pergolide, pramipexole, and ropinirole.

Fetal nigral transplantation has also been attempted to restore neuronal tissue lost to neurodegeneration. Due to mixed results and a high percentage of postsurgical dyskinesias, transplantation is not currently a treatment option for Parkinson’s disease.In the future,stem cells may offer various means to restore dopaminergic circuitry. In theory these cells could become dopamine-producing cells or possibly be programmed to release neurotrophic factors necessary for proper function.’

Diet Healthy dietary habits might be useful to treat and prevent Parkinson’s disease. In terms of detoxification from heavy metals, high sulfur-containing foods like garlic, onions, and eggs, as well as water-soluble fibers such as guar gum, oat bran, pectin, and psyllium seed, are recommended. From an antioxidant point of view, vegetables and fruits would be important. One large case-control s t ~ d y revealed ~ , ~ ~ that Parkinson’s disease patients tended to consume fewer raw vegetables, less alcohol and coffee, and more meat than control subjects. Patients with Parkinson’s disease also reported higher carbohydrate consumption and equivalent intakes of protein and fat. Other researchers have shown an increased consumption of animal source fat in patients with Parkinson’s d i s e a ~ e . ~Although ;Q~ researchers need to learn more about how food choices relate to Parkinson’s disease, a higher intake of vegetables and a low intake of fat seem to be reasonable choices in helping to prevent and possibly treat neurodegeneration.

Food Source Levodopa Interestingly, certain foods are a good source of natural levodopa. Anecdotal reports have demonstrated that patients with Parkinson’s disease show improved symptom control when consuming meals of broad beans. In some cases, the response to Viciafubu (fava beans) may be even greater than to conventional levodopa medication. Fava beans are a good source of levodopa: a 100-g serving

Specific Health Problems

of Vfaba pods contains about 250 mg of levodopa, equivalent to the levodopa content of one of the standard pharmaceutic formulationsa Until more is known about how to use fava beans as an Ldopa source, unsupervised replacement or coadministration of L-dopa with fava beans is not recommended.

Ketogenic Diets Ketogenic diets have been used for more than 70 years in order to help stabilize patients with epileptic seizures. D-beta-hydroxybutyrate (DPHB) is a ketone body produced by hepatocytes and, to a lesser extent, by a s t r q t e s when diets extremely low in carbohydrates and glucose are administered. One study infused DPHB into MI”-induced Parkinson’s mice models and demonstrated that the infusion conferred partial protection against dopaminergic neurodegeneration and motor deficits. The authors of this study support the use of this diet, citing the safety record of ketone bodies in the treatment of epilepsy.%In one clinical study, DPHB had been administered orally for several months to two 6-month-old infants with hyperinsulinemic hypoglycemia. Although some of these infants were given dosages of up to 32 &day, tolerance for the treatment was high.” However, the long-term effectsof the chronic use of DPHB on the cell metabolism and mitochondrial function are not known.

Low-Protein Diet For those patients taking levodopa, a low-protein diet may be useful. One double-blind study compared a lowprotein intake of 50 g/day for men and 40 g/day for women with high-protein intake of 80 g/day for men and 70 g/day for women. By the end of the trial, total performance scores were significantly improved in the treatment group given lower protein intakes. Additionally, tremor, hand aghty, and mobility in the low-protein groups also improved.@ Levodopa absorption is delayed or diminished by amino acids in protein meals.37It has been shown that modlfylng meal patterns so that the majority of protein intake was in the evening also improved symptoms.@As result, it is recommended that patients on levodopa take their medication with a high-carbohydratemeal and delay protein intake until the finalmeal of the day in an effort to optimize the therapeutic efficacy of the medication.u

toxicity and detoxification are discussed in detail in Chapters 26 and 31.

Nutritional Considerations 5Hydroxytryptophan The use of 5-hydroxytryptophan (5-H”) in Parkinson’s disease provides some benefit, but only if used in combination with the drug Sinemet (the combination of L-dopa with the decarboxylase inhibitor, carbidopa). Although brain levels of serotonin are decreased in Parkinson’s disease, the reduction in dopamine receptors is more severe.% One of the key benefits of taking 5-HTP in Parkinson’s disease is that it can help to counteract the negative effects that the L-dopa in the Sinemet has on sleep and In addition, 5-HTP has also been shown to improve the physical symptoms of Parkinson’s disease. About 9 of 10 people with Parkinson’s disease suffer from depression, the degree to which is a reflection of their serotonin levels. The lower the level of serotonin, the more severe the depression. One study examined the effect of 5-HTP in seven Parkinson’s disease patients, all of whom were on Sh1emet.5~The initial dosage of 5-HTP was 75 mg, which was increased by 25 mg every 3 days until the patients reported a relief of their depression or up to a maximum of 500 mg/day for 4 months. The impressive results obtained in these patients are shown in Table 198-3. Six of seven patients responded to 5-HTP. The dosages of 5-HTP in these five of the six patients who responded ranged from only 75 to 125 mg. The only patient who did not respond took 500 mg of 5-HTP. As a cautionary note, increasing serotonin levels with 5-HTP in patients not taking Sinemet are associated with worsening of symptoms, especially rigidity?

Antioxidants

Because vitamins C and E and carotenoids prevent damage from oxidation, they may reduce the risk of developing Parkinson’s disease. In some studies, antioxidant nutrients like vitamins C and E have been shown to be quite effective in slowing the progression of Parkinson’s disease in those patients not yet on medications. However, high dosages are required because it is more difficult to increase antioxidant levels in brain tissue compared with other body compartments. In one pilot study using vitamins C and E, 21 patients Detoxification with early Parkinson’s disease were given 3000 mg/day of vitamin C and 3200 IU/day of vitamin E. The patients Nutritional factors can combat heavy metal p o i s ~ n i n g ? ~ - ~ were followed closely for a period of 7 years. Although These include a high-potency multivitamin and mineral all patients eventually required drug treatment (Sinemet supplement; minerals such as calcium, magnesium, and or Deprenyl), the progression of the disease as deterchromium; vitamin C and B-complex vitamins; and mined by the need for medication was considerably sulfur-containing amino acids (methionine, cysteine, delayed in those receiving the nutritional antioxidants. and taurine). For natural ways to support the detoxificaDividing the patients in both groups into younger-onset tion and elimination, please see Chapter 54. Heavy metal

Parkinson’s Disease

I Parkinson’s disease Patient no.

L-dopa fmddav)

Carbidopa (rnddav)

HDS

5-HTP

Before

1

1000

175

125

22

11

2

300

75

75

14

3

3

400

150

100

21

13

4

1000

100

100

12

6

5

500

125

500

18

22

6

1125

112.5

300

18

7

7

500

50

100

17

13

After

and older-onset patients, those not receiving antioxidants required medication at 40 and 24 months, respectively, after the onset of the disease. In contrast, the two age groups in the pilot study were able to delay the need for drug therapy for 65.3 and 59.2 months, respectively. Thus the patients receiving the vitamins were effectively able to delay the need for medication for up to 2 to 3 years longer.% Another study evaluated 76,890 women for 14 years and 47,331 men for 12 years. All the participants were health care professionals, mostly doctors and nurses. Every 2 to 4 years they filled out detailed surveys about their diets including their vitamin intake from both foods and pills. A total of 371 people developed Parkinson’s disease during the study. The investigators found that neither vitamin C nor carotenoid intake lowered the Parkinson’s risk. The results were the same for the use of vitamin E supplements. This case seems to support the idea that vitamin E supplementation does not help protect against Parkinson’s disease. However, those participants who ate vitamin E-rich foods as part of their diets curiously developed the fewest cases of Parkinson’s disease.59The authors dismissed this fact by stating that “other constituentsof foods rich in vitamin E may be protective.” More likely is that the dosages or quality of supplementation in many of the participants may have been low, whereas the quality of antioxidants in the actual foods eaten may have been higher. Furthermore, even though alpha-tocopherol is the main form of vitamin E measured in food and the primary form of vitamin E in supplements, it is known that beta-, gamma-, and delta-tocopherol are also present in food. These other forms of vitamin E also play important antioxidant roles. For instance, gamma-tocopherol is more effective than alpha-tocopherol at inhibiting peroxynitrite-induced oxidation.60 Furthermore, supplementation of only alpha-tocopherol is known to

substantially decrease the levels of the other forms of vitamin E.61Although food may be the best source of all vitamin E forms, vitamin E supplements that contain the mixed tocopherols would be a better choice than less expensive supplements that only contain alpha-tocopherol.

Glutathione Given the importance of glutathione as a powerful brain tissue antioxidant, effective repletion should be a therapeutic priority. Combined intravenous and oral glutathione replacement is safe, well tolerated, and known to provide ongoing benefit.48 N-acetylcysteine and alpha-lipoic acid are glutathione precursors that may also be of use. As a systemic antioxidant, glutathione’s ongoing repletion may help ameliorate Parkinson’srelated damage in the heart, liver, muscles, and other organs as well. It is also recommended to take other antioxidants for synergistic support. Especially noteworthy is high-dose vitamin C, which provides antioxidant-reducing equivalents known to conserve glutathione.&

B Vitamins, Folic Acid Epidemiologic evidence has linked elevation of serum homocysteine to an increased risk of coronary artery disease, stroke, and dementia. An increase in homocysteine levels in Parkinson’s disease recently has been discovered. Although B vitamin status and genetic factors are important modlfylng influences determining the degree of this elevation, the main cause appears to be therapy with levodopa. It has been suggested that breakdown of this medication by catechol-0-methyltraferase results in increased homocysteine formation.6zTherefore there are reasons to suggest that management of Parkinson’s disease may render patients at an increased risk of stroke, heart disease, dementia, and possibly accelerated nigral degeneration. Pyridoxine (vitamin B6) is one of the B vitamins useful for lowering homocysteine levels (see Chapter 55). Confoundedly, it has been shown that the effects of levodopa may be enhanced through low intake of pyridoxine where daily doses of 5 mg or more of pyridoxine can cause reversal of the drug effect. Because vitamin B6 is present in many foods in varying amounts, some literature warns patients who take levodopa that they should avoid foods containing high amounts of the vitamin.= Instead of globally restricting foods that contain B6, possibly lowered B6 should be encouraged in those unresponsive to levodopa treatment. Conversely, those Parkinson’s patients with high homocysteine with a high risk for cardiac disease who are responding well to the medication may consider increasing levels of the B vitamins, with careful monitoring for exacerbated parkinsonian symptoms.

Coenzyme QIO Also known as ubiquinone, the primary biochemical action of coenzyme Qlo (CoQlo)is as a cofactor in the electron-transport chain, the series of redox reactions involved in the synthesis of adenosine triphosphate (ATP). Known for its use in cardiovascular diseases, acquired immunodeficiency syndrome, and cancer, animal models of Parkinson’s disease have shown effectiveness related to neurogenerative c0nditions.6~ Although more study is necessary, enough studies support the use and safety of CoQlo, even at higher dosages. One randomized, placebo-controlled, doubleblind, clinical pilot study has suggested that high-dose CoQlo may also help slow symptom progression in early Parkinson’s disease. In this study 80 m e d i c a t e d patients with early-stage disease were randomly given CoQloat dosages of 300,600, or 1200mg/day or a placebo. Using the UPDRS, they were followed up for 16 months or until disability requiring treatment with levodopa had developed. It was found that patients on CoQlo fared sigruficantlybetter than their placebo counterparts,with those taking 1200 mg showing the greatest results (LJF’DRS rating was +11.99 for placebo and 6 . 6 9 for the 1200 mg/day group).64A second placebo-controlled, double-blind experiment used 360 mg CoQlofor 4 weeks in 28 treated and stable PD patients. CoQlosupplementation provided a sigruficant mild symptomatic benefit on PD symptoms and a sigruficantlybetter improvement in visual defects compared with placebo.65 High doses of CoQlohave proven to be safe in the short term. A 2-week, open-label trial in which 17 patients with Parkinson’s disease received an increasing dosage of CoQlo (1200, 1800, 2400, and 3000 mg/day) with an unvarying dosage of 1200 IU/day of the alpha-tocopherol form of vitamin E. The plasma level of CoQlowas measured at each dosage. Thirteen of the subjects were increased to the 3000 mg dose, with no CoQlo-related side effects. One patient became orthostatic and one was dyspeptic, but these conditions were unrelated to the CoQlo. Looking at the blood, plasma levels of ubiquinone reached a plateau at the 2400 mg/day dosage. This study was not long enough to assess any clinical effect on the disease itself.66 Although serum levels of CoQlo are not necessarily lower in Parkinson’s patients versus healthy c0ntrols,6~ there may be an added benefit of doses up to 2400 mg for symptomatic patients. Due to the expense of CoQl0 it may be most practical to start at the 1200-mg dose and ramp up if benefits are not seen in the first few months.

Melatonin Melatonin is a hormone manufactured from serotonin and is secreted by the pineal gland. Known as a powerful antioxidant, melatonin is an established treatment

option for jet lag, various types of sleep problems, and cancer. Although studies show melatonin does not induce any increase in cerebral vascular blood flow,@ evidence supports the role of melatonin as a protector of neuronal cells, most likely by supporting mitochondrial function and preventing apoptosis. As an antioxidant, melatonin can directly scavenge oxidants produced during the normal metabolism and it indirectly promotes the activity of the antioxidant enzymes such as superoxide dismutase and catalase. Secondly, melatonin increases the activities and the expression of electron transport chain complexes during physiologic and pathologic situations. As a result, melatonin increases ATP production and promotes glutathione homeostasis. It has also been postulated that melatonin may interact with the mitochondrial genome in order to enhance production of proteins.69 Tissue culture models of Parkinson’s disease using low doses of 6-hydroxydopamine to induce apoptosis of undifferentiated and neuronal rat adrenal pheochromocytoma cells have also shown melatonin to prevent apoptosis in these models.” It is theoretically possible that melatonin exacerbates symptoms of Parkinson’s disease because of its putative interferencewith dopamine release.71But the larger body of literature agrees that Parkinson’s disease is probably due to multiple issues of compromised mitochondrial activity in the substantia nigraIn loss of glutathione,” oxidative damage, and increased apoptotic events. Reasonably, melatonin supplementation may yield a direct benefit. Clinical studies are necessary to evaluate the effectiveness of melatonin in Parkinson’s disease. At this point, if the clinician chooses to use melatonin, it may be best to start with a low dose (1 to 5 mg) and gradually increase the dose while carefully monitoring symptoms.

Reduced Nicotinamide Adenine Dinucleotide Found useful in treating animal models of Parkinson’s disease,63 the coenzyme nicotinamide adenine dinucleotide (NADH) is known to enhance endogenous dopamineproduction by supplying reducing equivalents to the rate-limiting, tyrosine hydroxylase-catalyzed step of dopamine synthesis in both tissue culture and human e ~ a l u a t i o n sA . ~positive ~ effect has been found using NADH both intravenously and intramuscularly in 34 Parkinson’s patients in an open-label trial. In this trial each patient experienced a beneficial clinical effect: 21 showed a “very good” (better than 30%) improvement of disability, and 13patients showed a ”moderate” (up to 30%) improvement. The effect of NADH was dependent on both the dosage given and the severity of the case. Optimal therapeutic range for NADH was 25 to 50 mg per day. Intravenous administration seemed to

Parkinson’s Disease ~

~

work better than intramuscular injection. Presence of homovanillinic acid in the urine was significantly increased in all patients. The presence of this metabolite indicates a stimulation of the endogenous L-dopamine biosynthesisE A second study of 15 patients prospectively investigated the administrationof one 10-mg treatment over 30 minutes a day for 7 days. These patients were also taking levodopa medications. These patients’ UPDRS scores improved, and sigruficant increases in plasma levodopa were observed.76 Nevertheless, due to lack of sufficient studies and theoretic considerations for underlying NADH disposal, many in the medical community do not currently recommend its widespread use for Parkinson’s disease.74As with many newer therapies, more rigorous studies are necessary to confirm their benefit and elucidate any side-effect risk.

Phosphatidylserine Phosphatidylserine is the major phospholipid in the brain, where it plays a critical role in determining the integrity and fluidity of cell membranes. Low levels of phosphatidylserine in the brain are associated with impaired mental function and depression in the elderly. Known to be clinically effective in patients with senile dementia,” phosphatidylserine is considered a promising treatment for the early stages of Alzheimer’s disease, with greater treatment effects in patients with less severe cognitive deficits.%Using electroencephalogram (EEG) brain studies, one double-blind study found the acceleration of a slowed EEG in parkinsonian patients with senile dementia of the Alzheimer’s disease type. Positive effects on anxiety, motivation, and affect were observed clinically as ~ e l l . 7 ~ Deficient phospholipid metabolism found in the Parkinson’s brain may be due to toxic insult or oxidative s t r e s ~ Normally .~ the brain can manufacture sufficient levels of phosphatidylserine, but if there is a deficiency of methyl donors like S-adenosylmethionine (SAMe), folic acid, and vitamin B1, or essential fatty acids, the brain may not be able to make sufficient phosphatidylserine. This may make adequate intake of these nutrients important as well. In addition, cosupplementation with DHA should be encouraged when using phosphatidylserine from soy sources (see Chapter 114 for more information). Absorption studies in animals indicate that phosphatidylserine is well absorbed orally.

Creatine Creatine is an important player in brain homeostasis and acts as a temporal and spatial buffer for cytosolic and mitochondria1 pools of the cellular energy currency; adenosine triphosphate; and its regulator, adenosine diphosphateFl Well known mostly as a body-building supplement, oral creatine monohydrate supplementation

has also been shown to enhance memory and is being studied for the treatment of neurologic, neuromuscular, and atheroscleroticdisease.@ In a placebo-controlled study, 36 patients with various types of muscular dystrophies found mild but significant improvement in muscle strength and daily-life activitiesF2In another study, one patient with extrapyramidal movement disorder and extremely low creatinine concentrations in serum and urine found that oral intake of creatine sigruficantly increased brain creatine levels. Phosphorus magnetic resonance spectroscopy of the brain revealed no detectable creatine phosphate before oral substitution of creatine and a sigruficant increase afterward. Partial restoration of cerebral creatine concentrations was accompanied by improvement of the patient’s neurologic symptoms as well.83 Other studies using creatine for neuromuscular diseases have not proven much benefit from creatine. A double-blind, cross-over trial study of 34 patients with myotonic dystrophy found no sigruficant improvement when measuring manual and quantitative muscle strength or assessing daily-life activities and patients’ own global assessment. As in the other studies, creatine supplementation was well tolerated without clinically relevant side effects; however, the supplement did not result in sigrufrcant improvement of muscle strength or dailylife activities.84A third study used 5 g/day in a doubleblind trial of 41 patients with Huntington’s disease. After 1 year of creatine intake at a level known to improve muscle functional capacity in healthy subjects, patients with Huntington’s disease did not experience improvements in functional, neuromuscular, or cognitive status.%Finally, one placebo-controlled trial using creatine did not find evidence of a beneficial effect of creatine monohydrate on survival or disease progression in patients with amyotrophic lateral sclerosis.@j It is doubtful whether creatine intake will prove beneficial to Parkinson’s patients in the future.

Botanical Medicines Camellia sinensis (Green Tea) As a good source of polyphenols, green tea may play a role in preventing and treating the oxidative stress. The biologic properties of green tea polyphenols reported in the literature include sigruficant blood-brain barrier penetration of these polyphenols, antioxidant actions, free radical scavenging, iron-chelating properties, (3)Hdopamine and (3)H-methyl-4-phenylpyridine uptake inhibition, catechol-0-methyltransferaseactivity reduction, protein kinase C or extracellular signal-regulated kinases signal pathway activation, and cell survival/cell cycle gene m0dulation.8~flGreen tea polyphenols have demonstrated neuroprotectant activity in cell cultures and animal models such as the prevention of neurotoxin-induced cell injuryF7fi9

Green tea polyphenols such as the major green tea polyphenol (-)-epigallocatechin-3-gallateare now being considered as therapeutic agents in well-controlled epidemiologic studies, aimed at altering brain-aging processes and serving as possible neuroprotective agents.goAlthough human clinical data are still limited, circumstantial data from several recent studies suggest that green tea polyphenols may promote health, reduce disease occurrence, and possibly protect against Parkinson’s disease and other neurodegenerativediseases.8’ In animal models of Parkinson’s disease, both green tea and the oral administration of (-)-epigallocatechin-% gallate prevented the loss of tyrosine hydroxylase positive cells in the substantia nigra and of tyrosine hydroxylase activity in the striatum. They also prevented neurotoxin-induced elevations in the antioxidant enzymes superoxide dismutase and catalase. These treatments also retained striatal levels of dopamine and its metabolite homovanillic acid and inhibited of nitric oxide synthetase in the substantia nigra.=B9

Ginkgo biloba (Ginkgo) Ginkgo biloba extrad (GBE) exerts profound, widespread tissue effects including membrane-stabilizing, antioxidant, and free radical-scavenging effects. GBE also enhances the utilization of oxygen and glucose. GBE is an extremely effective inhibitor of lipid peroxidation of cellular membranes. Although there are no clinical studies in Parkinson’s patients, gmkgo is well researched for its beneficial effects in Alzheimer’s d i ~ e a s e ~and l ” ~has been shown useful in animal models of Parkinson’s disease.6393 GBE possesses a protective effect on the Parkinson’s disease models both in vivo and in vitro. The antioxidation and antiapoptosis may be one of the mechanisms underlying the neuroprotectiveeffect of GBE?3 Ginkgo may also help decrease levodopa toxicity. In order to observe the toxic neuronal effect of levodopa and investigate if using levodopa together with GBE would be a feasible method to treat Parkinson’s disease, rat models of Parkinson’s disease were administered either levodopa (50 mg/kg every day for 3 days, 5 days, 7 days) or levodopa combined with GBE (100 mg/kg daily). The results showed that in the L-dopa group, the numbers of apoptosis of substantia nigra, which are rings of rotational behavior, were more than those in the group that took levodopa with the &go. These results suggest that levodopa had a neurotoxic effect and that GBE may decrease the toxicity of levodopa. The authors concluded that a combined use of GBE with levodopa may be a practical method to treat Parkinson’s patients and may be better than using levodopa alone.% Although a dose-response relationship is not yet established for humans, 240 mg/day of GBE seems to show a higher rate of treatment response than does

120 mg per day. Regarding safety, in all trials reviewed the adverse event profile of GBE was not different from that of the placeb0.9~Importantly, GBE should be taken consistently for at least 12 weeks in order to determine its effectiveness.Although some people with Alzheimer’s disease report benefits within a 2- to 3-week period, most need to take GBE for a longer period of time.

Mucuna puriens In Ayurvedic medicine, Parkinson’s disease, or ”kampavata,” is described as an imbalance of the vata dosha.u Mucuna puriens is a legume and is a rich source of the antioxidant vitamin E. Although not well understood, rat studies have demonstrated a clear antiparkinson effect, which may be due to components other than levodopa or that it has a levodopa-enhancing effect?6 One 12-week open clinical trial of 60 patients with Parkinson’s disease were treated with a powdered preparation of this legume. Of these patients, 26 patients were taking synthetic levodopa/carbidopa formulations before treatment, and the remaining 34 had not used the medications. The preparation is called HP-200 and is a powder supplied as a 7.5-g sachet that is mixed with water and given orally three to six times a day. Statistically significant reductions in Hoehn and Yahr stage and UPDRS scores were seen from baseline to the end of the 12-week treatment. Adverse effects were mild and were mainly gastrointestinal in nature.97 More research is needed to learn more about this legume.

Piper rnethysticum (Kava-Kava)-Caution Although no side effects have been reported using standardized kava extracts at recommended levels in clinical studies, there have been isolated reports of kava causing onset of Parkinson’s-like symptoms.98 Additionally, several case reports have indicated that kava may interfere with dopamine and worsen Parkinson‘s disease.99J00 Until this issue is resolved, kava extract should not be used in Parkinson’s patients or those considered genetically susceptible.

Other Therapeutic Considerations Smoking A number of epidemiologic studies demonstrate that smoking is associated with a lower incidence2 and delayed onset’O’ of Parkinson’s disease. Although unclear which mechanisms account for this effect, it is postulated that nicotine may enhance striatal stimulation of dopaminergic neurons that are selectively damaged in Parkinson’s disease. The inverse association between smoking and Parkinson’s disease has been demonstrated in more than 40 studies authored by different investigators conducted over the past 50 years? Other nonnicotine chemicals in cigarettes may also play

Parkinson's Disease a role in neuroprotection by decreasing monoamine oxidase B activity, which effectively lowers the levels of hydrogen peroxide, a byproduct of dopamine metabolism.lo2 Other possible explanations include a newprotective effect of a substance in cigarette smoke, possibly carbon monoxide, which can act as a freeradical scavenger.Finally, since cigarettesmoking often has the effect of dietary intake reduction, this may possibly confer an advantage by decreasing the overall oxidative load of food.' Because the risk-to-benefit ratio is quite high with smoking, it is not advised to suggest smoking as a reasonableprevention for Parkinson's disease. Smoking should be further studied because there may be components of cigarettes that, once elucidated, may prove useful for future therapies.

Estrogen Increasing evidence suggests that estrogens may modulate the activity of dopamine,1°3t104 may act as an antiapoptotic agent,lo5 and could affect the n e w n a l pathways affected in Parkinson's disease.lMAnimal studies have demonstrated that estrogens influence the synthesis, release, and metabolism of dopamine and may actually modulate dopamine receptor expression and function. Some clinical studies have also suggested that Parkinson's symptoms may worsen after menopause and that hormone replacement therapy can be protective,lwJW while others hypothesize that estrogen decreases may improve Parkinson's disease.lm The conflicting findings suggest that several variables including age, estrogen dose, and formulation, as well as timing and length of dosing period, may determine whether benefits are seen and what their nature is.lo6 At thistime, it may be best for clinicians to pay close attention to menstrual pattern correlations to symptomatic disease in order to make the best patient specific choices with regard to hormone replacement.

Homeopathy No clinical studies are available to support the use of homeopathy for Parkinson's disease, although anecdotal success stories are known.Some of the Parkinson's remedies and their symptom picture may include the following:

Aguricus muscarius: crawling sensations, vertigo with impulse to fall backwards, symptoms worse in cold weather Antimonium crudum: Parkinsonism movements associated with gastric symptoms; desire for sour foods that do not sit well in the digestive tract; a thickly white coated tongue; stubbomness; anxiousness; a general disgust of life with worse symptomology caused heat, wine, or moonlight Argentum nitricum: tremulousness

Weak Electromagnetic Fields Extracranial treatment with low-frequency picoTesla magnetic fields may prove to be an effective, safe, revolutionary modality in the symptomatic management of Parkinson's disease. The theory behind it is that intermittent, pulsed applications of picoTesla electromagnetic frequencies (EMFs) may induce in Parkinson's disease a reactivation of reticular-limbic-pineal systems,'0g and nondopaminergic systems might be positively affected by weak Ems. Some success has been recorded in individual case studies in which there has been a decrease in the need for Parkinson's medicationsllO;decreased micrographic symptoms'"; and the return of absent dream recall, a symptom associated with right hemispheric dysfunction.lW Unfortunately, only one researcher is mainly responsible for this work, and no follow-up has been attempted in a decade since the original work.

Hypnosis Although mechanistically not well understood, the clinical association between mindset and severity of most movement disorders including Parkinson's disease has been observed in that symptoms improve with relaxation and are exacerbated by anxiety? In one case study, hypnotic sessions were employed while the patient was monitored with a polygraphic electroencephalogramelectromyogram. These recordings showed a direct correlation between the degree of trance and tremor cessation. Although this effect only lasted for a few hours after each session, significant clinical gains were achieved over a period of 6 months with repeated practice consisting mostly of guided imagery. Among the different techniques used during the trance, one called roZe-pZay time distortion was the most effective in halting tremors.11*

Acupuncture and Tui Na In traditional Chinese medicine, pathogenic wind is the main agent responsible for the symptoms of Parkinson's disease. The treatment strategy is thus to calm this wind and tranquilize the mind. In more conventional terms, it is hypothesized that acupuncture may increase levels of dopamine in the brain and augment the excitability of the dopamine neurons.'13 Animal studies have shown neuroprotective effects of acupuncture on the nigrostriatal sy~tem.l'~J'~ Acupuncture and tui nu, which is a Chinese therapeutic massage, have both improved clinical disease symptoms and signs and possibly delayed disease p r o g r e ~ s i o n . ' ~ In ~ J ~one ~ study, 20 patients with Parkinson's disease were treated twice a week with acupuncture. Standard scales including the UPDRS and Hoehn and Yahr staging were used. In addition, quantitative motor tests including timed evaluations of arm pronation supination movements,

finger dexterity, finger movements between two fixed measured points, the stand-walk-sit test, and a patient questionnaire designed for the study were employed. Objective improvements were noted in the sleep and rest categories, with no other obvious improvements. However, on the patient questionnaire, 85% of patients reported subjective improvement of individual symptoms including tremor, walking, handwriting, slowness, pain, sleep, depression, and anxiety.l18 Another study of 26 patients found improvements in auditory-evoked brainstem potential examinat i o n ~ . "Acupuncture ~ treatments are considered safe and well tolerated118and should be considered as a safe means to improve sleep and patient perception of parkinsonian symptoms. More studies are necessary to confirm objective improvements in clinical presentations.

THERAPEUTIC APPROACH Diagnosis Besides standard neurologic rating scales and imaging, serum iron, ferritin and total iron binding may be useful to look for iron overload. Blood levels of homocysteine may also uncover homocysteinuria. Consider a careful history and testing that can evaluate heavy metal and pesticide toxicities.

Dietary Recommendations Patients should be encouraged to follow these recommendations: Eat a low-fat, low-animal, high-fiber vegetable diet. Eat vitamin E-rich foods: sunflower seeds, almonds, chard, mustard greens, broccoli, olives, kale, turnip greens, and papaya. *Avoid foods high in pesticides and attempt to eat organic foods exclusively. To detoxlfy heavy metals, eat high sulfur-containing foods like garlic, onions, and eggs, as well as watersoluble fibers such as p a r gum, oat bran, pectin, and psyllium seed. For patients taking levodopa, lower protein intake is recommended (50 g/day for men and 40 g/day for women). They should take their medication with a high-carbohydrate meal and delay protein intake until the final meal of the day in an effort to optimize the medication's therapeutic efficacy. Due to constant movement, weight loss may be an issue with some patients; therefore caloric intake may need to be adjusted to specific patient needs.

0

0

Lifestyle Recommendations The following measures are suggested as wek Avoid cooking in aluminum pots. Hang on to banisters along walls to ease walking and sit in chairs with higher arms to ease sitting. Install thick carpeting to avoid falls, especially in areas that may become wet and slippery, such as the bathroom and kitchen.

Nutritional Supplementation Patients should be advised of the following: Iron and manganese supplements should be avoided. 5-€3" should be taken in doses of 75 to 125 mg/day in those patients taking Sinemet (levodopa plus carbidopa). Those not on this drug should avoid 5-HTP. 3000 mg/day of vitamin C should be taken. 1000 IU/day of vitamin E should be taken as mixed tocopherols. Vitamin E supplements that are solely alpha-tocopherol should be avoided. Glutathione should be taken orally or intravenously, or both. It may be best to restrict B vitamins in those patients who are levodopa unresponsive to see if drug treatment efficacy improves. B vitamins and folic acid may be increased in patients with high homocysteine levels and those who are at a greater cardiac risk, providing there is careful monitoring of Parkinson's symptoms (see earlier discussion of B vitamin in the section on therapeutic considerations). 1200 to 2400 mg/day of CoQloshould be taken. 100 mg tid of phosphatidylserine should be taken.

Botanical Medicines Patients can be advised to take the following: Green tea: Drink three cups daily or take about 3 g of soluble components providing roughly 240 to 320 mg of polyphenols. For a green tea extract standardized for 80% total polyphenol and 55% epigallocatechin gallate content, this would mean a daily dose of 300 to 400 mg. GBE: Take 240 mg/day for at least 12 weeks. 0 M. puriens: Mix 7.5 g with water and take orally three to six times daily.

Acupuncture Treatments involving needling and tui nu massage according to traditional Chinese medicine diagnosis are recommended.

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106.Shulman LM. Is there a connection between estrogen and Parkinson’s disease? Parkinsonism Relat Disord 2002;8289-295. 107. Marder K, Tang MX, Alfaro B, et al. Postmenopausalestrogen use and Parkinson’s disease with and without dementia. Neurology 1998;501141-1143. 108.Saunders-Pullman R, Gordon-Elliott J, Parides M, et al. The effect of estrogen replacement on early Parkinson’s disease. Neurology 1999;521417-1421. 109. Sandyk R. Treatment with weak electromagnetic fields restores dream recall in a parkinsonian patient. Int J Neurosci 1997;90: 75-86. 110. Sandyk R. Treatment of Parkinson’s disease with magnetic fields reduces the requirement for antiparkinsonian medications. Int J Neurosci 1994;74191-201. 111. Sandyk R. Parkinsonian micrographia reversed by treatment with weak electromagneticfields. Int J Neurosci 1995;81:83-93. 112. Wain HJ, Amen D, Jabbari B. The effects of hypnosis on a parkinsonian tremor: case report with polygraph/EEG recordings. Am J Clin Hypn 1990;339498. 113. Wang L, He C, Liu Y, et al. Effect of acupuncture on the auditory evoked brain stem potential in Parkinson’s disease. J Tradit Chin Med 2002;22:15-17. 114. Zhu W, Xi G, Ju J. [Effect of acupuncture and Chinese medicine treatment on brain dopamine level of MPTP-lesioned C57BL mice.] B e n Ci Yan Jiu 1996;21:4649. 115. Park HJ, Lim S, Joo WS, et al. Acupuncture prevents 6-hydroxydopamine-inducedneuronal death in the nigrostriatal dopaminergic system in the rat Parkinson’s disease model. Exp Neurol 2003;180:93-98. 116. Zhuang X, Wang L. Acupuncture treatment of Parkinson’s diseareport of 29 cases. J Tradit Chin Med 2000;20:265-267. 117. Walton-Hadlock J. Primary Parkinson’s disease: the use of Tui M and acupuncture in accord with an evolving hypothesis of its cause from the perspective of Chinese traditional medicinepart 2.Am J Acupunct 1999;2731-49. 118.Shulman LM, Wen X, Weiner WJ, et al. Acupuncture therapy for the symptoms of Parkinson’s disease. Mov Disord 2002;17 799-802.

Pelvic Inflammatory Disease Nancy Roberts, ND Tori Hudson, ND CHAPTER CONTENTS Diagnostic Summary 2015 General Considerations 2015 Etiology 2015 Complications 2017 Risk Factors 2017 Pathogen Access to the Upper Female Tract 2017 Diagnosis 2018 Laboratory Diagnosis 2019

Nutritional Supplements 2020 Botanical Medicines 2021 Prevention 2021

Therapeutic Approach 2022 Diet 2022 Supplements 2022 Botanical Medicines 2022 Physical Medicine 2022

Therapeutic Considerations 2019 Antibiotics 2020 Physical Medicine 2020

DIAGNOSTIC SUMMARY

GENERAL CONSIDERATIONS

Dyspareunia Mucopurulent cervical discharge Pelvic pain; bilateral adnexal tenderness Palpable adnexal mass Elevated temperature (>loloF) Cervical motion tenderness *White blood count (WBC) 20,0OO/pl, with marked leukocytosis or elevated sedimentation rate, or both Neisseriu gonorrhea (GC)and Chlamydia truchomatis (CT) most common, followed by Ureuplusmu ureulyticurn, Mycoplusmu hominis, Streptococcus sp., Escherichia coli, Haemophilus injluenzue,Peptostreptococcus,and Peptococcus* Transvaginal ultrasound that shows thickened, fluidfilled tubes or tubo-ovarian mass Acute and chronic endometritis on endometrialbiopsy Laparoscopy-the gold standard

Pelvic inflammatory disease (PID) is a categorical name for a range of pelvic infections and inflammations. The CDC defines PID by the presence of abdominal and adnexal tenderness and cervical motion tenderness in the absence of another definable cause of the patient's symptoms. The diagnosis does not require the presence of elevated WBC or erythrocyte sedimentation rate (ESR), nor of fever. PID causes women to make an estimated 2.5 million outpatient visits to health care providers each year. One fourth of these women will suffer serious long-term sequelae, and all are at risk for recurrence.' The social and physical costs of PID are also significant: the risk of ectopic pregnancy increases sixfold after a single episode of PID, and there is an estimated 13% risk of infertility after one infection and 70% risk after three infections? For these reasons, as well as costs, prevention and aggressive full-spectrum care of the acute phase cannot be undervalued.

Testing methods for GC and chlamydia include: cell culture (the gold standard), direct fluorescent antibody (DFA) testing, enzyme immunoassay (EIA) antigen detection technique, nucleic acid hybridization tests (DNA probes), nucleic acid amplification (polymerasechain reaction [PCR] or ligase chain reaction [LCR]), and the newer ThinPrep Pap Collection system. New Centers for Disease Control and Prevention (CDC) recommendations are that all sexually active adolescents undergo routlne screening for chlamydia during annual pelvic examinations. The CDC also recommendsthat routine screening of asymptomaticwomen between 20 and 24 years old should be considered, particularly if they have a new male sexual partner, more than one male sexual partner. or do not use barrier contraception.

Etiology Several organisms (listed in Table 199-13)are known to be implicated in the etiology of PID, but N. gonorrhoeue and C. truchomtis are the two most common. Because of the complexities of and inconsistencies in sampling and laboratory verification, it is difficult to make definitive 2015

Specific Health Problems ~

1inflammkory disease Organism Neisseria gonorrhea

Incidence (%) 40-60

Chlamydia tmchomatis

30

Mycoplasma hominis

8

Ureaplasma urealyficum

4

Modified from Karchmer AW. Sexually transmitted diseases. In Dale DC, Federman OD,eds. Scientific American medicine. New York:Scientific American, 1996:7:XXll-10-13.

statements about the causal agents in PID. Asymptomatic chlamydial infections are a big cause of PID. An estimated 1 million new infections with GC occur in the United States annually. More than 4 million infections occur annually due to CT. The true incidence of CT is probably higher because not all states require reporting. A higher proportion of PID has been ascribed to CT than to GC.4

Neisseria gonorrhea The incidence of GC in the United States increased by a factor of 2.7 from 1960 to 1980.5 The infection has reached pandemic proportions in the United States, where it is estimated that for each reported case, four go unreported.6 Gonococci have been recovered from the urethra of 2.2%of sexually active servicemen who had minimal or no symptoms and from 40% of asymptomatic males who had contact with symptomatic women.7 In addition, an estimated 80% of the men and women exposed to Gonococcus will develop infections? For a seemingly delicate and fastidious species, Neisseria has impressive infective abilities, preferring human columnar and transitional epithelia. In less than 1 hour after intercourse, Gonococcus can establish itself on the urethral mucosa, where it successfully resists the flow of Favored sites in the lower female genital tract are the Bartholin's and Skene's glands, the urethra, and the endocervical canal? Direct spreading can occur from the endocervix across the endometrial surface to the tuba1 mucosa, or migration can occur through subendothelialvascular and lymphatic channels? Perhaps the most common method of spreading, however, is by vector: GC attached to spermatozoa are physically carried to the fallopian tubes.6 Primary pathogens can also enter the upper tract from retrograde menstruation or uterine contractions during intercourse.10 In the acute state, the gonococci and polymorphonucleocytes accumulate in the subepithelial connective tissue, resulting in patchy destruction of the overlying mucosa?," The consequent thinning of the mucosal lining is thought to assist GC penetration into deeper tissue?

~

It is probably for this reason that gonococci are reported to survive only a short time in the fallopian tubes.12 However, they may not only be surviving, but thriving. The descent of the microbe beyond the surfaces being examined makes detection difficult.12 Concomitant infections are known to occur with GC.13 Some researchers have even proposed that GC's primary role appears to be paving the way for secondary invaders from normal vaginal flora, allowing access to the upper tract.14The associated infection will frequently be CT, but a superinfection can also be present, in which case one will find that anaerobic bacteria have colonized as well.13

Chlamydia trachomatis In the United States it is estimated that 20% to 30%of PID cases are caused by CT.3J5Further, one study found that acute chlamydia1 PID may be subclinical or silent in 66% to 75%of the cases.16Laboratory diagnosis of chlamydial infection is difficult, which, combined with CT's propensity to be asymptomatic, renders thorough assessment of the scope of these infections nearly impossible. A 5-year study conducted in urban Sweden showed that, despite a decrease in the numbers of gonococcal PID, the total cases of acute PID were unchanged or even increased in the last year of the study.17 Another European study, conducted in 1977, found that 62% of women with acute salpingitis had elevated (titer 2 1:64) chlamydial IgG antibodies.18However, most other studies completed to date show much lower percentages. These numbers will no doubt change as diagnostic technology improves and the clinical presentation of CT is more widely understood.

Anaerobic Infections Anaerobes are the organisms most commonly isolated from the fallopian tubes or cul-de-sacs of patients with PID.19 Anaerobic bacteria are probably not the chief causative agents, but rather are opportunists, establishing themselves in unsuccessfully defended tissues. Anaerobic infections are commonly found in immunocompromised hosts and are generally of endogenous origin." The cervix and vagina of normal healthy women contain both anaerobic and aerobic bacteria.21 Anaerobic infections establish themselves more often in older patients and in women with a history of prior PID.5

Other Organisms Facultative aerobic organisms found in tuboperitoneal fluids from women with salpingitis have included coliforms, H. influenzae, S. sp., and M . horninkZ M. horninis has not been demonstrated as a sole etiologic agent but rather seems to be a common contributor to the polymicrobial milieu that is often discovered in PID. One study found M. horninis in cervical cultures from

Pelvic Inflammatory Disease

81% of women patients with GC and 64% of those without GC.23

study showed that 1 in 24 women will have an ectopic pregnancy?

Complications

Risk Factors

There are serious physical consequences for women who have had PID. It has been estimated that, in the postinfection state, one of four women suffer from one or more sequelae such as abdominal pain, infertility, or ectopic pregnancy? Dyspareunia is a symptom that is often not investigated, but which, when relevant questions are asked, is frequently found in the post-PID sufferer. Death from salpingitis is rare and is generally due to rupture of the tubo-ovarian abscess with subsequent peritonitis. A mortality rate of 5.2% to 5.9% has been calculated for tubo-ovarian abscesses and, before 1950, mortality was 80%to 100%.”~25 Better diagnostic understanding of this complication, treatment with antibiotics, and prompt surgical intervention have phenomenally improved both morbidity and mortality statistics. The Fitz-Hugh-Curtis syndrome is a perihepatitis complicating the primary condition of PID.Characteristic violin-string adhesions attach the liver to the abdominal wa11.20,26These adhesions are due to local peritonitis involving the anterior liver surface and the adjacent 2~ GC was thought to be the abdominal ~ a l l . Historically, main contributor to this syndrome, but CT is now found more frequently.2°,21 Infertility is a serious concern. Once a woman has had PID, she is at risk for additional attacks. This is in part because, after the fallopian tubes have been damaged by the infectious process, normal defense mechanisms are impaired. Reinfection has been found to be the most important cause of infertility after PIDF8One study comparing the rate of nonsurgical infertility in 1973with that of 1976 noted a 45% increase. This translates to 122,000 infertile couples per year.29 This increased incidence is consistent with the concurrent epidemic of sexually transmitted disease (STD)-associated PID. An alarming statistic analysis has shown that for each 1000 girls born in 1950,138had one or more bouts of PID by age 30; 26 are infertile because of the PID; and 9 have had surgery for ectopic pregnancy5 Further, it has been postulated that by the year 2000 there will be one episode of salpingitis for each two women reaching reproductive age in 1970.2l Ectopic pregnancy is a severe sequel, and any woman with a history of PID faces a sevenfold to tenfold increased risk.5 Ectopic pregnancies tripled in the United States from 1967to 1977. In 1977ruptured ectopic pregnancies accounted for 12% of maternal deaths and were the leading cause of maternal death in nonwhite women.29In another study, which followed women with PID for 9.5 years, 12.8% were infertile after one infection, 35.5% after two,and 75% after three infections. The same

Besides the obvious factor of sexual contact, the main risk factors are age, use or history of use of an intrauterine device (IUD), and previous history of PID. An earlier “sexual debut” puts a young woman in a high-risk group for PID, especially when there are multiple sexual partners. The risk in sexually active 15-year-olds is 1 in 8, while in the average 24-year-old it is 1 in 80.5 One interesting hypothesis for these data is that the cervical mucus in the younger woman may be estrogendominated, creating an environment that is more accessible to pathogens.22Women with multiple partners have a 4.6 times greater risk than women in monogamous relationships.21 A woman bears an increased risk of PID if she uses an IUD. Oral contraceptive (OC) users are somewhat less likely to have GC but, on the other hand, are at increased risk for chlamydia1 invasion. Birth control remains a potent issue, with barrier methods being techniques of choice because of their decreased PID risk. It should also be noted that one author included his own clinical observation that women in his practice who had vasectomized men as partners were only seldom in his office with PID.3l The last risk factor to be considered is iatrogenic. This occurs when invasive procedures have introduced pathogens, or in some other way disturbed the tract flora, and induced PID. Among these procedures are the following: Cervical dilation Abortion Curettage Tuba1 insufflation Hysterosalpingography Insertion of an IUD A hospital in Lund, Sweden, reported that 15% of its PID cases were iatrogenic. This indicates that PID may not be strictly an STD.2O

Pathogen Access to the Upper Female Tract The route by which the pathogens gain access to the upper female tract has only recently been explored. Menstruation, sperm, and trichomonads have all been shown to be important in the transportation of pathogens into the salpinx. Often the onset of menses corresponds with the onset of an episode of PID. Infections occurring around the menses tend to be GC rather than CT, a clinical curiosity that may ultimately illuminate more about the etiology. One hypothesis is that menstrual regurgitation assists

the inflammatory response by carrying sloughed endometrial epithelium, which may have attached GC or intracellular CT. These organisms can then proliferate in the tubal epithelium or on peritoneal surfaces.103z Human sperm has proved an interesting and multifaceted variable in the precipitation of PID. Some of the research targets bacteriospermia as a cause of infertility in men, findings that are clearly relevant to PID. Increasingly, STD research is noting the incidence of asymptomatic male c a r r i e r ~ ? , ~ J ~A3large * ~ population study discovered that 66%to 75%of the men who tested positive for GC were asymptomatic? Designed to travel during intercourse, sperm also serve as effective vectors. Researchers took an interesting look at this most basic interaction between man and woman by means of a laboratory experiment. They introduced organisms into capillary tubes containing cervical mucus, either alone or with added spermatozoa, and observed microbial motility. Cervical mucus had already been considered an effective mechanical and immunologic barrier between the abundant flora of the vagina and the upper tract, and the test results confirmed this idea. However, they also demonstrated that organisms attached to sperm could easily traverse the length of the mucus column. This may be particularly important during menses because sperm migration has been observed through menstrual plasma but not during the luteal phase or through the cervical mucus of pregnancy. Electron microscopy has produced amazing photographic evidence of organisms attached to ~ p e r m . The 6~~ mechanism observed with piliated GC is that pili twist together with the tails of the spermatozoa in a ropein-a-spider-web arrangement around the bacteria. Sperm have also been found intimately associated with cytomegalovirus, Toxoplasma, Ureaplasma urealyticum,3* and CT.= Motile trichomonads serve as another transporter of PID. They can ascend from the vagina to the fallopian tubes, carrying additional invaders. In fact, it has been observed that trichomonads are never isolated from humans when heavy bacterial contamination is absent.32

Many PID patients have atypical signs and symptoms and some have no signs and symptoms at all.5 Table 199-23lists those most commonly found. The woman with GC may appear more toxic and febrile and manifest leukocytosis, while CT-caused PID may give her an elevated sedimentation rate (ESR). Most episodes of gonococcal PID occu at or shortly after menses.40Gonococcal PID has a generally more severe clinical picture, but tissue damage and long-term sequelae can be more severe in CT. This attempt to differentiate clinical pictures becomes meaningless, of course, in the presence of mixed infections. Any mucopurulent discharge should yield oxygensensitive organisms because offensive odor is considered diagnostic of anaerobic infection. Any woman who has such a discharge probably has well-developed PID, with opportunistic anaerobes following the primary invadersB Box 199-1 shows the differential diagnoses of PID. Potentially lethal conditions to consider include ectopic pregnancy, tubo-ovarian abscess, ovarian cyst rupture with hemorrhage, and appendicitis.

Common signs and symptoms in acute pelvic Inflammatory disease SvmDtom Lower abdominal pain

90

Adnexal tenderness on palpation Pain on movement of the cervix

90 90

Vaginal discharge

55

Adnexal mass or swelling

50

Fever or chills

40

Irregular vaginal bleeding

35

Anorexia, nausea, and vomiting

25

Modified from Karchmer AW. Sexually transmitted diseases. In Dale DC, Federman DD, eds.Scientific American medicine. New York: Scientific American, 1996:7:XXll-10-13.

DIAGNOSIS Pelvic or lower abdominal pain is the most dependable symptom of PID but, unfortunately, is not specific. Rebound tenderness is not reliably reported; cervical motion tenderness and adnexal tenderness are much more common. The clinical picture of the various types of PID can easily mislead: In a large study the clinical diagnosis of PID was confirmed at laparoscopy in only 65% of the patients. Appendicitis, hemorrhagic corpus luteum, pelvic endometriosis, ectopic pregnancy, mesenteric adenitis, and ovarian tumors accounted for 12%, while 23% were found to be normal.39

Incidence (%)

Acute appendicitis Acute cholecystitis Acute pyelonephritis Ectopic pregnancy Endometriosis Hemorrhagic ovarian cysts Intrauterine pregnancy Mesenteric lymphadenitis Ovarian cyst with torsion Ovarian tumor Pelvic thrombophlebitis Septic abortion

Pelvic Inflammatory Disease

In light of the Fitz-Hugh-Curtis syndrome, symptoms from the upper right quadrant in a sexually active woman may be an indirect sign of genital infection. The pain usually has a sudden onset and can overshadow the signs and symptoms of the underlying In the event of rupture of a tubo-ovarian abscess, a sudden severe exacerbation of the pain can be observed. The pain is referred to the side of the rupture and is typically followed by generalized peritonitis and collapse. Shoulder pain may be present. The pulse will likely be elevated out of proportion to the fever and is frequently as high as 170.25Surgery must be performed within 12 hours or mortality becomes probable. A careful history is, as always, invaluable. The patient’s risk factors and history should be assessed for likelihood of infection with a sexually transmitted organism. The patient should be questioned about any new sexual partner, method of contraception, and recent medical procedures. The source, severity, and characteristics of the pelvic/abdominal pain should be evaluated. Mucopurulent cervicitis should be considered as well, and the cervix should be cultured for N. gonorrhoeue and C. trachornutis.

Laboratory Diagnosis Laboratory findings during active PID are inconsistent in the research literature. Such confusion may be inevitable because we lack knowledge of the normal flora of the female upper genital tract. Historically, this tract had been considered a sterile environment, but researchers have now begun to question this.l In the large number and variety of laboratory and surgical examinations performed by physicians over the past 25 years, there has been a consistent lack of correlation between the organisms found in the different sectors of the female a n a t ~ m y . ’ ~ J Pathogens ~ J ~ , ~ ~ cultured from the cervix are frequently not retrieved from the adnexa, and gonococci from the peritoneum are not found in the upper tract. Some researchers report the adnexa as being free from an organism because they cannot isolate it from the exudate, but since CT is intracellular and gonococci are thought to be below the submucosa by the second day, these findings are unreliable.12 Determining the most appropriate diagnostic approach is difficult. As has been eloquently stated,19 PID results from infection of the endometrium and fallopian tubes by a wide array of bacterial pathogens, often in synergistic combination, and the inaccessible site of infection makes microbiologic confirmation difficult. Perhaps the best guideline to recommend is a conservative search. Invasive sampling of exudate and tissue should only be employed as a last resort. Diagnostic laparoscopies have a death rate of 5.2/100,000 and major complications in 4.6/1000 The most recent and least invasive

technique is an upper tract culture via cervical entrance using a double-lumen, catheter-protected Perhaps with more studies this procedure can be improved or elaborated; however, currently it is poorly correlated and frequently compromised by lower tract contamination. A complete blood cell count and ESR are absolutely essential. The sedimentation rate in pregnancy is elevated from the increased plasma fibrinogen and globulin levelsMand will also be increased in anemia due to the higher plasma-to-erythrocyte ratio. An infection should be suspected with a sedimentation rate above 35 in the absence of pregnancy and anemia. The C-reactive protein (CRP)has been investigated as a diagnostic tool in pelvic i n f e ~ t i o n s . ~ The ~ ’ evaluation is based on the local inflammatory reaction that follows cell death in internal organs. This reaction induces an increased synthesis of a series of plasma proteins. The C-reactive protein is one of these acute-phase reactants, and its levels increase 1 to 2 days after any tissue injury that affects more than the epithelial layer. The increase of CRP is quantitatively matched with the degree of tissue injury. This nonspecific test does not stand alone, however, and should be evaluated with the WBC and the ESR. Other diagnostic procedures to consider are the following: Culture of endocervical sampling is the preferred method when the diagnosis is problematic and in cases of suspected sexual assault. The main advantages are that cultures are highly specific and the organisms can be preserved for additional testing. Enzyme immunoassay (EIA) Direct fluorescent antibody (DFA) Nucleic acid probes (DNA PROBES) Nucleic acid amplification techniques (PCR and LCR) Urinalysis (to help with the differential diagnosis) Serum human chorionic gonadotropin (to help rule out pregnancy) Abdominal or transvaginal ultrasound, or both Liver enzymes will not be elevated with a chlamydia1 perihepatitis as the parenchyma is not involved.27 Finally, however a case of PID is being worked up, the physician should always consider the possibility that the infection is polymicrobial. Mixed infections are common; isolation of a particular microbe from the cervix does not absolutely establish it as the sole etiologic agent of the PID, nor does isolation rule out other organisms.

THERAPEUTIC CONSIDERATIONS Criteria for hospitalization include surgical emergency or septic-appearingpatient, pregnancy, failure to respond to oral antibiotics, and suspicion of tubo-ovarian abscess. Referral is necessary if the diagnosis is uncertain or

Specific Health Problems

a surgical emergency threatens. Should the physician decide not to hospitalize, a regimen of antibiotic therapy, combined with the supportive therapies discussed later, can be tried if the patient’s clinical and laboratory status can be reassessed in 48 to 72 hours. Laboratory values and objective patient criteria should direct all acutephase treatment. The CDC leaves it to the individual practitioner to decide on the severity of the disease and the most optimal treatment. Its guidelines do say that “Most experts encourage hospitalization and treatment with intravenous antibiotics.”

Antibiotics PID is a complex syndrome,with inconsistent and variable presentationsin differentwomen and including a range of symptoms and etiologic microorganisms. Due to this, broad-spectrum antibiotic regimens are employed that allow for some flexibility on the part of the practitioner. Regimens aw tailod on the basis of the clinical severity and laboratory findings, patient compliance, cost of medications, and availability of medications. Because some antibiotics cover just one organism, the CDC outpatient recommendations (January 2004) take into account the limited anaerobic activity of any one regimen: *Ceftriaxone 500 mg IM plus doxycycline 100 mg PO bid for 14 days or Ofloxacin 400 mg PO bid plus metronidazole 500 mg PO bid for 14 days Azithromycin 1 g for 2 days, then 250 mg for 5 days equivalent to above regimens Consider adding metmnidazoleor clindamycin to.doxycycline or azithromycin for better anaerobic coverage. Always add metronidazole for women with BV and for immunosuppressed women. Reexamine the woman-including bimanual pelvic exam-within 72 hours to ascertain improvement. The physician can consider adding metronidazole to either regimen for better anaerobic coverage. Metronidazole should always be added for women with BV and for immunosuppressed women. Reexamine the woman within 72 hours to ascertain improvement. Fifteen percent of women with PID fail to respond to primary antimicrobial treatment, 20% have at least one recurrence, and 15%are rendered infertile.19 Given the polymicrobial nature of PID, the complexities of isolation, antibiotic-resistant strains of microorganisms, and the realities of recurrence rate with antibiotic use, an approach that combines immune system enhancement and nontoxic therapies concurrently with antibiotics seems sound. However, there are no evidence-based therapies using natural therapies exclusively for the treatment of PID. Antibiotics can help with the first phase of treatment but may not offer sufficient intervention for the devastation that regularly occurs in the wake of the primary infection.

Physical Medicine Diathermy Pulsed, high-frequency diathermy is beneficial in the treatment of women with PID.4g50Pulsing electric energy for a short duration (65 pievery 1600 p)at high intensity achieves the desired therapeutic result without the hyperpyrexia typically associated with diathermy. Local recovery is enhanced, the reticuloendothelial system is stimulated,and gamma-globulinfractions are increased.21

Sitz Baths Traditionally, sitz baths have been an important component of the naturopathic treatment of PID.The contrast sitz bath is primarily used to increase pelvic circulation, bring an influx of macrophages to the area, and provide decongestion of the pelvic inflammatory reaction (for further discussion, see Chapter 40).

Nutritional Supplements Chlorophyll Chlorophyll derivatives are cell-stimulating agents that aid in the regeneration of t i s s ~ e s and ~ ~ ,enhance ~~ production of hemoglobin and erythrocytes. They have the added benefit of being nontoxic. The following has been suggested53:

. . . [tlhe action of chlorophyll consists for the most part of increasing the resistance of cells in some physiochemical manner so that enzymatic digestion of the cell membrane by invading bacteria or their toxin is checked. Chlorophyll is theorized to break down carbon dioxide, resulting in the liberation of oxygen, which inhibits anaerobic bacteria.% Careful vaginal douching with chlorophyll is recommended in all cases of PID to forestall or diminish the inevitable anaerobic population and to encourage cervical and possibly upper tract healing. These tissues must be healed to reduce the risk of infertility or ectopic pregnancy. One researcher reported that the discharge from several leukorrhea cases was cleared up in almost every instance, with comparatively few applications of ~hlorophyll.~~

Vitamin C Vitamin C may be useful in the treatment of women with PID for the following reasons: Its antiinflammatory effects help to decrease tissue destruction. Its support of collagen tissue repair helps to prevent the spread of infection (especially important in GC infections, which can spread through the subepithelial connective tissue, resulting in disorganization of the collagen matrix8). Its fibrinolytic activity helps to prevent pelvic scarring.

Beta-carotene The normal ovary has a high concentration of betacarotene. As these structures are bombarded by inflammation and the unwelcome company of aggressive microbes, it is essential to maintain optimal levels of carotene to allow for an optimal defense. Beta-carotene potentiates the beneficial effects of interferon and enhances numerous other immune functions such as antibody levels and white blood cell activity?5- Betacarotene is also important as an antioxidant, helping to limit the cell damage induced by the inflammatory process (see Chapter 71 for a fulldiscussion of this nutrient).

Bromelain Bromelain should be considered an important component of the treatment regimen. A d n e d exudate in PID frequently suppurates to form abscesses. If tissue irritation is relieved or ameliorated during the acute stage, much of the exudate can be absorbed and fewer adhesions formed.& Adhesions will form as the exudate lingers, the structures being overwhelmed by the inflammation. Also, after resolution, agglutination of the villous fold in the lumen of the tube may occur, resulting in scarring and tubal occlusion.6 Bromelain activates fibrinolysis, which can greatly diminish the enduring sequelae of the inevitable exudate. Bromelain also demonstrates antimicrobial properties, and an Italian study has shown that it penetrates the ~ a l p i n (see x ~ ~Chapter 73 for further discussion).

Botanical Medicines Vaginal Depletion Packs Use of the vaginal depletion pack is recommended as part of PID treatment, as it promotes the drainage of exudate from the involved tissues. (The vaginal depletion pack is discussed in more detail in Appendix 13.) It may also stimulate the immune cells within the vagina to provide a first line of defense.

Hydrastis canadensis The immune-potentiating, specific antimicrobial properties and the general antibacterial nature of goldenseal make it indispensable in the care of PID. Since Hydrastis canadensis is also a trophorestorative to mucous membranes, the herb should be used throughout the rehabilitation period. (H.canadensis is discussed in more detail in Chapter 100.)

Symphytum oficinale Comfrey is a soothing demulcent that is best used in the second phase of treatment. Its allantoin content encourages cell regeneration, which is crucial for uncomplicated recovery from PID.%

Prevention STD prevention is an extremely important issue for all heterosexually and bisexually active women. The woman

with no history of PID still should be concerned about the sigruficant population of asymptomatic male carriers of STDs. The choice of birth control is pivotal. Women who use barrier methods of contraception have a lower risk of PID.

Oral Contraceptives A surprising number of articles laud the use of oral contraceptives (OCs) for their apparent inhibition of gonococci.21 Burnham19 suggested OC use after a first episode of PID to prevent recurrence. Apparently, estrogens create a thicker cervical plug, which offers protection against gonococci.8JoO C s also decrease the length and volume of menstrual blood flow, thus decreasing the exposure of the GC to this handy culture medium. On the other hand, OC users have a higher risk of chlamydia1 i n f e c t i o n ~ . ~ *Progesterone ~~,~3~ induces hyperplasia and hypersecretion, which can then produce cervical eversion, exposing the endocervical columnar epithelium-the target tissue of CT.40Estradiol has been implicated in suppressing endocervical antibodies necessary for resolution of CT.40 Animal experimentation finds that estrogen-treated individuals have a higher number of infected cervical cells and a longer duration of infection.6oBecause women are probably not selectively exposed to GC versus CT, O C s are not recommended.

Intrauterine Devices The IUD has a bad reputation in PID.*This reputation of IUDs is a carryover from the former Dalkon Shield. This IUD is no longer available, and current IUDs such as the Copper T are generally considered safe. However, the use of an IUD is associated with a small increased risk of PID, especially in the first four months of use. An IUD allows the colonization of bacteria on its surface while simultaneously reducing local immunologic capacityY If a woman with suspected PID has an IUD, it needs to be removed 12 to 24 hours after initiation of antibiotic therapy in order to prevent spread of the infection during its removal.

Barrier Methods Barrier methods of contraception are excellent choices for the prevention of PID. The condom is preferred to cervical protectors, as with this method the sperm more rarely reach the vaginal vault.

Douching Haphazard douching is to be avoided because it disturbs the vaginal flora. All forms of douching increase the risk of PID and cause organisms to ascend into the upper genital tract.

'References 5,16, 19. 22, 27, 61, 62.

Specific Health Problems One study compared 100 consecutive patients hospitalized for PID with 762 controls and 119 women suspected of having PID.&Current douching (defined as any douching during the previous 2 months) was more common among those with PID than among those in both control groups. Among current douchers, PID was related to the frequency of douching. Those who douched three or more times per month were 3.6 times more likely to get PID than those who douched less than once per month. A much larger study surveyed 6984 women older than the age of 18 and found that 32% said they had douched within the past week, and 13% reported regular douching more than once a week.&

Women should avoid intercourse until all signs and symptoms are resolved and their male partners have been examined and treated. In addition, all partners from up to 2 months before the illness should be examined19and treated if a diagnosis of PID is made. Increased bed rest must also accompany all forms of treatment. These therapies are recommended as an adjunct to appropriate antibiotic treatment and immune support as discussed in Chapter 57.

Intercourse during Menses

Supplements

Intercourse during menses is not recommended unless a condom is used. GC risk is increased by the loss of the protective cervical mucus plug and by the prevalence of blood, a medium of choice for Gonococcus. The endometrium is also thought to offer local protection against bacterial invasion, and it is this layer that is being sloughed off during menses.

.

Smoking When 197 women hospitalized for their first PID infection were compared with 667 controls with nongynecologic conditions, it was found that cigarette smokers, compared with women who had never smoked, had an elevated risk of PID of 1.7 and former cigarette smokers had an elevated risk of 2.3. There was not a dose-response relationship.66 A more rigorous study found similar results. This was a case-controlled, population-based study of 131 women between 18 and 40 years of age who were treated for their first episode of PID compared with 294 randomly selected patients from the same health maintenance organization. Current smokers, compared with those who had never smoked, had an increased risk of PID. Women who smoked 10 or more cigarettes a day had a higher risk than those who smoked l e ~ s . 6 ~

Education A physician should review the signs and symptoms of PID with all sexually active women and encourage any woman to seek counsel if she appears to fit the clinical picture for PID. The diagnosis is easier to make and the recovery more rapid when treatment is instituted early.

THERAPEUTIC APPROACH Treatment consists of two phases, both of which are important. The first therapeutic goal is to eliminate all pathogens and normalize the microflora of the adnexa. The second is to rehabilitate the damaged tissues.

All dietary inhibitors of immune function (sugar, alcohol, and processed and allergic foods) should be limited during both phases of treatment.

Beta-carotene: 100,000 IU/day for 2+ months Vitamin E: 400 IU/day for 3 months Vitamin C: 500 mg four times/day for the first week of treatment and then decrease over 3 days to 250 mg tid Chlorophyll: 10 mg of fat/oil soluble four times/day for 1month Bromelain: 250 mg (1800 MCU) four times/day for the first week and three times/day for 6 weeks

Botanical Medicines Symphytum oficinale (after the acute phase) 500 mg of freeze-dried herb tid 1:l fluid extract, 30 drops bid H.canadensis: 400 mg of the solid extract tid during the acute phase; 200 mg tid during recovery Chlorophyll: douches alternating with vaginal packs Vaginal packs. daily during the acute phase until there is adequate clinical and laboratory response. After the acute phase, vaginal packs need to be used three times/ week, alternatingwith chlorophyll douches, for 3 weeks.

.

Physical Medicine Diathermy: pulsed, high-intensity diathermy for 10 minutes over the suprapubic area, 10 minutes over the liver, and 10 minutes in the area of the left adrenal (the right being presumably stimulated with the liver) Sitz baths: one to two times/day throughout the acute phase. Contrast sitz baths are given in groups of three alterations of hot to cold. Two separate tubs are necessary during this process. The hot is at 105" F to 115"F, the cold at 55" F to 85" F, with the temperatures dependent on the tolerance of the patient. Standard treatment is 3 minutes hot and 30 seconds cold. The water level in the hot tub is set 1 inch higher than in the cold. Adequate draping is necessary to prevent chilling. As with all hydrotherapy treatments, one always finishes with the cold.

Pelvic Inflammatory Disease

1.Washington AE, Am0 P, Brooks A. The economic cost of pelvic inflammatory disease. JAMA 19862551735-1738. 2. Dodson FS. The polymicrobial etiology of acute pelvic inflammatory disease and treatment regimens. Rev Inf Dis 1985;7s6996-~7002. 3.Karchmer AW. Sexually transmitted diseases. In Dale DC, Federman DD, eds. Scientific American medicine. New York: ScientificAmerican, 19967XXII-10-13. 4. Black C. Current methods of laboratory diagnosis of Chlamydia truchomutis infections. Clin Micr Rev 1997;Jan:160-184. 5. Westrom L. Incidence, prevalence and trends of acute pelvic inflammatory disease and its consequences in industrialized countries. Am J Ob Gyn 1980;138:880-892. 6.Spence M. The role of gonococcus in salpingitis. J Repro Med 1977;19:31-35. 7.Handsfield H, Lipman T, Harisch J et al. Asymptomatic gonorrhoeae in men. N Engl J Med 1974;290117-123. 8. Ringsdorf W, Cheraskin E. Vitamin C and human wound healing. Oral Surgery 1985;March231-233. 9. Ward M, Watt P, Robertson J. The human fallopian tubes. A laboratory model for gonococcal infection. J Inf Dis 1974;129:650-659. 10.Denhanm I. Pelvic inflammatory disease. Austral Fam Phy 1986;15:254-256. 11. McGee ZA, Stephens D, Hoffman LH, et al. Mechanisms of mucosal invasion by pathogenic Neisseria. Rev Infect Dis 19835 Suppl 4 708-714. 12. Lip J, Burgoyne X. Cervical and peritoneal bacterial flora associated with salpingitis. Ob Gyn 1966;28:561-563. 13.Cunningham FG, Hath J, Gilstrap L. The bacterial pathogenesis of acute pelvic inflammatory disease. Ob Gyn 197852161-164. 14. Chow A, Malkasian K, Marshall J et al. The bacteriology of acute pelvic inflammatory disease. Am J Ob Gyn 1974;122:876-879. 15.Thompson S, Washington E. Epidemiology of sexually transmitted Chlamydia trachomatis infections. Epid Rev 1983;5:96-123. 16. Guderian AM, Trobough G. Residues of pelvic inflammatory disease in intrauterine device users. A result of intrauterine device or Chlamydia trachomatis infection? Am J Ob Gyn 1986; 1W497-503. 17.Forslin L, Falk V, Danielsson D. Changes in the incidence of acute gonococcal and nongonococcal salpingitis. Br J Vener Dis 1978;W 247-250. 18.Treheame JD,Ripa KT, Mardh P-A. Antibodies to Chhmydia truchomutis in acute salpingitis. Br J Vener Dis 1979;55:26-29. 19. Bumham RC. Therapy for acute pelvic inflammatory disease. A critique of recent treatment trials. Am J Ob Gyn 1984;148235-240. 20. Mardh PA. An overview of infectious agents of salpingitis, their biology and recent advances in methods of detection. Am J Ob Gyn 1980;138:933-951. 21. Shafer M, Irwin C, Sweet R. Acute salpingitis in the adolescent female. J Ped 1982;100339-350. 22. Holmes K, Eschenbach D, Knapp J. Salpingitk overview of etiology and epidemiology. Am J Ob Gyn 1980;138893-900. 23. Eschenbach D, Buchanan T, Pollock H et al. Polymicrobial etiology of acute pelvic inflammatory disease. Am J Ob Gyn 1975;122:166-177. 24. Mickal A, S e h a n n A, Beebe J. Ruptured tuboovarian abscess. Am J Ob Gyn 1968;100:432-436. 25. Pedowitz P, Bloomfield R. Ruptured adnexal abscess. Am J Ob Gyn 1964;88:721-729. 26.Umes A, Stray-Pedersen B, Raknerud N. Case report: massive ascites as a complication to subclinical perihepatitis and pelvic inflammatory disease. Acta Obstet Gyn Scand 1986;65:277-278. 27.Wolner-Hanssen P, Westrom L, Mardh PA. Perihepatitis and chlamydial salpingitis. Lancet 1980;i:901-903. 28.Bartlett J. Anaerobic infections of the pelvis. Clin Ob Gyn 1979;21:351-359.

29. Curran J. Economic consequences of pelvic inflammatory disease in the U.S. Am J Ob Gyn 1980;138848-851. 30. Westrom L. Effect of acute pelvic inflammatory disease on fertility. Am J Ob Gyn 1975;121:707-713. 31.Toth A, OLeary W, Ledger W. Evidence for microbial transfer by spermatozoa. Ob Gyn 1982;59:556-559. 32. Kinghom GR, Waugh MA. Oral contraceptive use and prevalence of infection with Chlamydia truchomntis in women. Br J Vener Dis 1981;57187-190. 33.Lang D, Kummer J. Cytomegalovirus in semen: observation in selected populations. J Inf Dis 1975;132472-473. 34. Dahlberg B. Asymptomatic bacteriospermia. Urology 1976;wI: 563-566. 35. Lang D, Kummer J. Demonstration of cytomegalovirus in semen. N Engl J Med 1972;287756-758. 36. Eschenbach DA. Acute pelvic inflammatory disease: etiology, risk factors and pathogenesis. Clin Ob Gyn 1976;19:147-169. 37.Gomez C, Stenback W, James A, et al. Attachment of Neisseria gonorrhoeue to human sperm. Br J Ven Dis 1979;55:245-255. 38.Friberg J. Chlamydia attached to spermatozoa. J M Dis 1985; 152854. 39. Jacobson L, Westrom L. Objectivized diagnosis of acute pelvic inflammatory disease: diagnostic and prognostic value of routine laparoscopy. Ob Gyn 1969;105:1088. 40. Cromer B, Heald F. Pelvic inflammatory disease associated with Neisseria gonorrhwae and Chlamydia trachomatis. Clinical correlates. Sex Trans Dis 1987;14:125-129. 41. Sweet R, Mills J, Hadley K et al. Use of laparoscopy to determine the microbiologic etiology of acute salpingitis. Am J Ob Gyn 1979;134:6&70. 42.Phillips J, Hulka J, Keith D et al. Laparoscopic procedures. a national survey for 1975. J Reprod Med 1977;18:219-226. 43. Hemsell D, Heard M, Nobles B et al. Single-agent therapy for women with acute polymicrobial pelvic infections. Am J Ob Gyn 1987;157488-490. 44.Charles D. Value of erythrocyte sedimentation rate in gynecologic infections. Clin Ob Gyn 1976;19:171-193. 45.Lehtinen M, Laine S, Heinonen P. Serum C-reactive protein determination in acute pelvic inflammatory disease. Am J Ob Gyn 1980;1W15&159. 46. Jacobson L, Laurel1 CB, Gennser G. Plasma protein changes induced by acute inflammation of the fallopian tubes. In J Gyn Ob 1975;13:249-256. 47. Angerman N, Evans M, Moravec W et al. C-reactive protein in the evaluation of antibiotic therapy for pelvic infection. J Reprod Med 1980;25:63-66. 48. Gellhom G. Diathermy in gynecology. JAMA 1928;March 1005-1008. 49. Horowitz E, Derow D, Bierman W. Temperature determination in the female pelvis during diathermy. Am J M Sc 1935;189:555-556. 50. Kottke F, Gullickson G, Erickson H, et al. Study of the reactive value of long wave diathermy and microwave diathermy for heating the pelvis. Arch Phys Med Rehab 1955;March137-140. 51. Smith L. Chlorophyll-an experimental study of its water soluble derivatives in wound healing. Am J Surg 1943;62358-369. 52. Rafsky H, Krieger C. The treatment of intestinal disease with solutions of water soluble chlorophyll. Rev Gastro Ent 1945;15:549-553. 53. Gruskin B. Chlorophyll-its therapeutic place in acute and suppurative disease. Am J Surg 1940;xID(:49-55. 54. Smith L. Chlorophyll: an experimental study of its water-soluble derivatives. Remarks on the history, chemistry, toxicity and antibacterial properties of water soluble chlorophyll derivatives as therapeutic agents. Am J Med Sci 1944;207:647-654.

Specific Health Problems 55. Rhodes J. Human interferon action: reciprocal regulation by retinoic acid and beta-carotene. J Natl Cancer Inst 1983;70: 833-837. 56.Alexander M, Newmark H, Miller RG. Oral beta-carotene can increase the number of OKT4? cells in human blood. Immunol Letters 1985;9:221-224. 57.Luerti M, V i e M. Influence of bromelain on penetration of antibiotics in uterus, salpinx and ovary. Drugs Exp Clin Res 1978;445-48. 58. Priest AW, Priest LR. Herbal medication. London: LN Fowler, 1982. 59. Washington AE, Gove S, Schachter J, et al. Oral contraceptives, Chlamydia trachomatis infection and pelvic inflammatory disease. JAMA 1985;2532446-2450. 6O.Rank R, White H, Hough A. Effect of estradiol on Chlamydial genital infection of female guinea pigs. Infect Immun 19823: 699-705.

61. Burkman R. Intrauterine device use and the risk of pelvic inflammatory disease. Am J Ob Gyn 1980;138:861-863. 62. Eschenbach D, Hamisch J, Holmes K. Pathogenesis of acute pelvic inflammatory disease. Role of contraception and other risk factors. Am J Ob Gyn 1980;128:838-850. 63. Keith L, Berger G, Edelman D, et al. On the causation of pelvic disease. Am J Ob Gyn 1984;149:215-224. 64.Wolner-Hanssen P. Association between vaginal douching and acute pelvic inflammatory disease. JAMA 1990;263:1936-1941. 65.Tucker ME. Douching raises pelvic inflammatory disease risk. Fam Pract News 1996;August 15. 66. Marchbanks P, Lee NC, Peterson HB.Cigarette smoking as a risk factor for pelvic inflammatory disease. Am J Ob Gyn 1990;162: 639-644. 67. Scholes D. Current.cigarette smoking and risk of acute pelvic inflammatory disease. Am J Pub Health 1992;82:1352-1355.

Peptic Ulcer-Duodenal

and Gastric Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac

CHAPTER CONTENTS Diagnostic Summary 2025 General Considerations 2025 Helicobacter pylori 2026 Aspirin and Other Nonsteroidal Antiinflammatory Drugs 2026 Therapeutic Considerations 2026 Lifestyle Factors 2026

DIAGNOSTIC SUMMARY Epigastric distress 45 to 60 minutes after meals or nocturnal pain; both relieved by food, antacids, or vomiting Epigastric tenderness and guarding Symptoms chronic and periodic Gastric analysis shows acid in all cases, with hypersecretion in about half the patients with duodenal ulcers Ulcer crater or deformity usually occurring at the duodenal bulb (duodenal ulcer) or pylorus (gastric ulcer) on radiograph or fiberoptic examination Positive test for occult blood in stool

GENERAL CONSIDERATIONS Peptic ulcer formation occurs in the stomach (gastric ulcer) and the first portion of the small intestine (duodenal ulcer). Duodenal ulcers are more common, with an estimated prevalence of 6% to 12%in the United States. Approximately 10% of the U.S.population has clinical evidence of duodenal ulcer at some time in their lifetime. It is four times more common in men than in women and four to five times more common than clinically evident benign gastric ulcer. Although symptoms of a peptic ulcer may be absent or quite vague, most peptic ulcers are associated with abdominal discomfort noted 45 to 60 minutes after meals or during the night. In the typical case the pain is described as gnawing, burning, cramplike, aching, or "heartburn." Eating or using antacids usually results in great relief. In the elderly, the presentation of peptic ulcer disease may also be subtle and atypical when

Nutritional Factors 2027 Miscellaneous 2028 Therapeutic Approach 2029 Psychologic 2029 Diet 2029 Supplements 2029 Botanical Medicine 2029

compared with younger patients, leading to a delay in diagnosis. Even though duodenal and gastric ulcers occur at different locations, they appear to be the result of similar mechanisms. Specifically the development of a duodenal or gastric ulcer is a result of some factor damaging the protective factors that line the stomach and duodenum. In the past, the focus has primarily been on the acidic secretions of the stomach as the primary cause of both gastric and duodenal ulcers. However, more recently the focus has been on the bacteria HeZicobacter pylori and nonsteroidal antiinflammatory drugs (NSAIDs). Gastric acid is extremely corrosive with a pH of 1 to 3. To protect against ulcers, the lining of the stomach and small intestine is protected by a layer of mucin. In addition, the constant renewing of intestinal cells and the secretion of factors that neutralize the acid when it comes in contact with the stomach and intestinal linings also protect against ulcer formation. Excessive gastric acid output is rarely a factor in gastric ulcers, as in these patients gastric acid output is usually normal or reduced. In contrast, almost half of patients with duodenal ulcers have increased gastric acid output. This increase may be due to an increased number of parietal cells. As a group, patients with duodenal ulcers have twice as many parietal cells as normal controls. Even with an increase in gastric acid output, under normal circumstancesthere are enough protective factors 2025

Specific Health Problems ~~~~~~

~

to prevent the ulcer formation. However, when the integrity of these protective factors is impaired, an ulcer can form. A loss of integrity can be a result of H. pylori, NSAIDs, alcohol, nutrient deficiency, stress, and many other factors. Of these factors, H. pylori and NSAIDs are by far the most signrficant. Several chronic diseases have also been associated with an increased risk of developing peptic ulcers. These include Crohn's disease, chronic renal failure, liver cirrhosis, cystic fibrosis, chronic obstructive pulmonary disease, systemic mastocytosis (a condition where there are too many immune mast cells in the body), and myeloproliferative disorders (polycythemia Vera, chronic myelogenous leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia).*

A study conducted at five test hospitals in England found an increased risk of gastrointestinal bleeding due to peptic ulcer at all dosage levels. However, the dosage of 75 mg/day was associated with 40% less bleeding than 300 mg/day and 30% less bleeding than 150 mg/day. The researchers concluded: "No conventionally used prophylactic aspirin regimen seems free of the risk of peptic ulcer complications." Although there has been a reduction in ulcers induced by NSAIDs with the development of the selective cyclooxygenase-2 inhibitors (Rofecoxib, Celecoxib) for arthritic conditions, aspirin-induced ulcers continue to remain an ongoing issue due to the increased use of aspirin for protection against cardiovascular events.6

Helicobacfer pyIori

THERAPEUTIC CONSIDERATIONS

The role of H. pylori in peptic ulcer disease has been Individuals experiencing any symptoms of a peptic ulcer extensively investigated. It has been shown that need competent medical care. Peptic ulcer complications 90% to 100% of patients with duodenal ulcers, 70% such as hemorrhage, perforation, and obstruction represent medical emergencies that require immediate with gastric ulcers, and about 50% of people older than hospitalization. the age of 50 test positive for H. pyZori2However, more Obviously, the best treatment of a peptic ulcer involves than 80% of H. pylori-infected people never actually identification of the causative factor and its appropriate develop an ulcer.3 Although it is has been discovered that certain genotypic strains of H. pylori may confer elimination. additional cytotoxic risk for gastric p a t h ~ l o g i e s , ~ Lifestyle Factors conflicting information warrants further r e s e a r ~ h . ~ , ~ Stress and Emotions The presence of H.pylori is determined by determinStress is universally believed to be an important factor in ing the level of antibodies to H. pylori in the blood or saliva or by culturing material collected during the pathogenesis of peptic ulcers. However, this belief is based on uncontrolled observations. The medical an endoscopy, as well as measuring the breath literature is controversial, and every substantial attempt for urea. Low gastric output, as well as low antioxidant conto examine this assumption has been fraught with tent in the gastrointestinal mucosa, is thought to premethodologic errors.'O dispose to H. pylori colonization. H. pylori colonization This problem is further complicated by the observaincreases gastric pH, thereby setting up a positive tion that men and women with peptic ulcers appear to feedback scenario and increasing the likelihood for the have distinctly different psychologic profiles. In addition, several studies have shown that the number of colonization of the stomach and duodenum with other stressful life events is not significantly different in organism^.^ peptic ulcer patients as compared with carefully Aspirin and Other Nonsteroidal selected, ulcer-free controls. These data suggest that it Antiinflammatory Drugs is not simply the amount of stress, but rather the Aspirin and other nonsteroidal antiinflammatory drugs patient's response to it that is the significant factor. are associated with a sigruficant risk of peptic ulcer. A large prospective study of 4000 persons who had no history of peptic ulcer disease revealed that those who In addition, the combination of NSAID use and smoking perceived stress in their lives are at increased risk of is particularly harmful to the ulcer patient.8Although developing peptic ulcers" (see Chapter 62 for a more most studies documenting the relative frequency of complete discussion). peptic ulcers as a consequence of aspirin and NSAIDs Psychologic factors are probably important in some have focused on their use in the treatment of arthritis patients with peptic ulcer disease, but not in others. and headaches, recently the risk of gastrointestinal As a group, ulcer patients have been characterized as bleeding due to peptic ulcers was evaluated for aspirin tending to repress emotions. At the least, patients at daily dosages of 300,150, and 75 mg-dosages comshould be encouraged to discover enjoyable outlets of monly recommended to prevent heart attacks and self-expression and emotions. strokes.'

Peptic Ulcer-Duodenal and Gastric ~

Smoking Increased frequency, decreased response to peptic ulcer therapy, and an increased mortality due to peptic ulcers are all related to smoking. Three postulated mechanisms for this association are the following": Decreased pancreatic bicarbonate secretion (an important neutralizer of gastric acid) Increased reflux of bile salts into the stomach Acceleration of gastric emptying into the duodenum Bile salts are extremely irritating to the stomach and initial portions of the duodenum. Bile salt reflux induced by smoking appears to be the most likely factor responsible for the increased peptic ulcer rate in smokers. However, the psychologic aspects of smoking are also important because the chronic anxiety and psychologic stress associated with smoking appear to worsen ulcer activity.

Nutritional Factors Food Allergy Clinical and experimental evidence points to food allergy as a prime etiologic factor.12-15The lesions of peptic ulcers and the Arthus reaction (local inflammatory response due to deposition of immune complexes in tissues) show the same microanatomic changes? In one study, 98% of patients with radiographic evidence of a peptic ulcer had coexisting lower and upper respiratory tract allergic disease.I4In another study, 25 of 43 allergic children had x-ray-diagnosed peptic ulcers.15Clinically, an elimination diet has been used with great success in treating and preventing recurrent ~ l c e r s . ' ~Food J~ allergy is also consistent with the high recurrent rate of peptic ulcers. Ironically, many people with peptic ulcers soothe themselves by consuming milk, a highly allergic food. Milk should be avoided on this basis alone. However, there is additional evidence suggesting that milk should be avoided in patients with peptic ulcers; for example, population studies show that the higher the milk consumption, the greater the likelihood of ulcer, and milk sigruficantly increases stomach acid production.16

Fiber A diet rich in fiber and low in refined sugar is associated with a reduced rate of duodenal ulcers as compared with a low-fiber diet? The therapeutic use of a high-fiber diet in patients with recently healed duodenal ulcers reduces the recurrence rate by half.17This is probably a result of fiber's ability to delay gastric emptying of the liquid phase, counteracting the rapid movement of this phase into the duodenum normally seen in ulcer patients. Although several fibers often used to supplement the diet (e.g., pectin, guar gum, psyllium) have been shown

to produce beneficial effects, a diet rich in plant foods is best.18J9

Cabbage Raw cabbage juice has been well documented as having remarkable success in treating peptic u1cers.20-zOne liter per day of the fresh juice, taken in divided doses, resulted in total ulcer healing in an average of only 10 days. Further research has shown that the high glutamine content of the juice is probably responsible for the efficacy of cabbage in treating these ulcers. In a doubleblind clinical study of 57 patients, 24 using 1.6 g/day of glutamine and the rest using conventional therapy (antacids, antispasmodics, diet, milk, and bland diet), glutamine proved to be the more effective treatment. Half of the glutamine patients showed complete healing (according to radiographic analysis) within 2 weeks, and 22 of the 24 showed complete relief and healing within 4 weeks.23Although the mechanism for these results is not known, it is postulated by the authors to be due to the role of glutamine in the biosynthesis of the hexosamine moiety in certain mucoproteins. This could stimulate much synthesis, which would benefit peptic ulcer patients.

Bismuth subcitrate Bismuth is a naturally occurring mineral that can act as an antacid, as well as exerting activity against H. pyZori. The best known and most widely used bismuth preparation is bismuth subsalicylate (PeptoBismol). However, bismuth subcitrate has produced the best results against H. pylori and in the treatment of peptic u l ~ e r s . ~InJ ~the United States, bismuth subcitrate preparations are available through compounding pharmacies (to find a compounding pharmacist in your area, call the International Academy of Compounding Pharmacists at 1-800-927-4227). A key advantage of bismuth preparations over standard antibiotic approaches to eradicating H. pylori is that although the bacteria may develop resistance to various antibiotics,it is unlikely to develop resistance to bismuth. As concerns in the medical community grow regarding the failures of current regimens due to resistance, nonpharmacologic management options are becoming required.= In India for example, 80% of isolates from 259 peptic ulcer patients tested have shown resistance to metronidazole.26 Although resistance to ciprofloxacin and tetracycline was minimal YO to 4%) in this study, it is evident from recent medical history that greater resistance to these antibiotics will continue to develop. This makes bismuth a rational treatment choice in order to prevent further recalcitrant strains. The usual dosage for bismuth subcitrateis 240 mg twice daily before meals. For bismuth

Specific Health Problems

subsalicylate, the dosage is 500 mg four times daily. Bismuth preparations are extremely safe when taken at prescribed dosages. Bismuth subcitrate may cause a temporary and harmless darkening of the tongue or stool, or both. Bismuth subsalicylate should not be taken in children recovering from the flu, chicken pox, or other viral infection, as it may mask the nausea and vomiting associated with Reye syndrome, a rare but serious illness.

Flavonoids Flavonoids are known to counteract both the production and secretion of histamine, an important factor in ulcer formation. They are generally regarded as antiallergy compounds. The use of these compounds seems particularly indicated due to the probable allergic etiology of peptic ulcers. Catechin, via its ability to inhibit histidine decarboxylase, offers antiulcer activity. Experimental studies in guinea pigs and rats have demonstrated that catechin has significant antiulcer activity in various model^?^,^ In a human clinical study, oral administration (1000 mg five times/day) resulted in reduced histamine levels in the gastric tissue (determined by biopsy) of normal patients and those with gastric and duodenal ulcers and acute gastritis.28 It was also demonstrated that the histamine levels, which significantly increase in patients with urticaria and food allergy after the local application of the antigen to the gastric mucosa, could be decreased by the prior administration of catechin. In a recent study, several flavonoids were shown to inhibit H. pylori in a clear-cut concentration-dependent m a ~ e r . In 2 ~addition, unlike antibiotics the flavonoids were also shown to augment natural defense factors which prevent ulcer formation. The activity of flavone, the most potent flavonoid in the study, was shown to be similar to that of bismuth subcitrate.

Miscellaneous Vitamins A and E have been shown to inhibit the development of stress ulcers in rats and are important factors in maintaining the integrity of the mucosal barrier.3031 Zinc increases mucin production in vitro and has been shown to have a protective effect on peptic ulcers in anim a l and ~ ~a ~curative effect in h ~ m a n s . 3 ~ Melatonin is a pineal hormone commonly used to treat jet-lag and insomnia-type conditions. Known for its antioxidant properties, it is now being considered useful in gastric ulcer situations. Experimental studies have shown melatonin to be successful in mitigating gastric lining breakdown and ulcer formation." Because this research has focused more on hypersecretion situations, melatonin may be more applicable for duodenal ulcer conditions where the acid secretion is generally increased.

Botanical Medicines Glycyrrhiza glabra Licorice has historically been regarded as an excellent medicine for peptic ulcer. However, due to the known aldosterone-like side effects of glycyrrhizinic acid (GA), a procedure was developed to remove GA from licorice and form deglycyrrhizinated liquorice (DGL).The result is a very successful anti-ulcer agent without any known side effects (see Chapter 99).'*35-39 The proposed mechanism of DGL is that it stimulates or accelerates the differentiation to glandular cells, as well as mucus formation and secretion.35Clinical studies have demonstrated no sigruficant differences in recurrence rates between cimetidineand DGL drug regimens, and rat and human studies have shown its efficacy in preventing aspirin-induced ulceration and gastric b l e e d h ~ g ? ~ - ~ ~ An obvious question related to DGL is: "Does DGL have any effect on H. pylori?" The answer appears to be "yes," as DGL is composed of several flavonoids that have been shown to inhibit H. p y l ~ r i . * ~ / ~ It appears that in order to be effective in healing peptic ulcers, DGL must mix with saliva. DGL may promote the release of salivary compounds that stimulate the growth and regeneration of stomach and intestinal cells. DGL in capsule form has not been shown to be effective. The standard dosage for DGL is two to four 380-mg chewable tablets between or 20 minutes before meals. Taking DGL after meals is associated with poor results. DGL therapy should be continued for at least 8 to 16 weeks after there is a full therapeutic response. Rheum Species In cases of active intestinal bleeding, rhubarb (Rheum sp.) preparations can be extremely effective. In one doubleblind study, three kinds of alcohol-extracted rhubarb tablets were studied (Rheum officinale Baill; Rheum Their palmatum L.; Rheum tanguticum Maxim ex efficacies in a group of 312 cases of bleeding gastric and duodenal ulcers were 90.7%, 93.7%, and 92.870, respectively. The time taken for the stool occult blood to change from positive to negative was 57.1, 53.4, and 56 hours, respectively. The beneficial actions are due to the presence of astringent anthraquinones and flavonoids. Plantain banana In rats the dried extract of the unripe plantain banana (Musa sapientum var. paradisiaca) has been found to have antiulcerogenic activity against various experimentally induced ulcers."-44 This effect appears to be similar to that of DGL (i.e., stimulation of mucosal cell growth rather than inhibition of gastric acid secretion). Zingiber oficinale Ginger root (Zingiber oficinale) has been used traditionally for the treatment of gastrointestinal ailments such

as indigestion, motion sickness, and nausea associated with pregnancy. One study used in vitro experimentation to test a methanol extract ginger root as an agent against 19 strains of H. pylori. Results showed that growth was inhibited against all 19 strains.& Although more research is required to characterize the best form of this botanical medicine and to learn of its efficacy in actual patients, given its safety profile and cost effectiveness, it is certainly worth a try. Artemisia douglasiana Located on the western slopes of the Rockies, the folk remedy Artmisiu douglusiunu has been used in Argentina to treat gastric ulcers and skin lesions since the late 1960s. A. douglusiunu and its active constituent dehydroleucodine are known to act as potent antioxidants, and, similar to DGL and plantain, they confer gastric lining protection via significantly enhanced mucus ~ecretion.~,~~ Allium sativum People whose diets are high in garlic and onions are well known to have a lower incidence of stomach cancer. Since H. pylori is a risk factor for stomach cancer, as well as peptic ulcers, in vitro studies have demonstrated that garlic does indeed inhibit its growth. Also noteworthy is the report that garlic can be useful for antibioticresistant strains as well. The author points out in this paper that human clinical trials are necessary in order to verify the efficacy of this low-cost treatment

THERAPEUTIC APPROACH

difficult, however; a more general approach may be necessary. The first step is to identify and eliminate or reduce all factors implicated in the etiology of peptic ulcers: food allergy, cigarette smoking, stress, and drugs-especially aspirin and other nonsteroidal analgesics. Once the causative factors have been controlled, attention should be directed at healing the ulcers, inhibiting exacerbating factors (e.g., reducing excess acid secretion if present), and promoting tissue resistance. Finally, the proper diet and lifestyle should be developed to prevent further recurrence. Peptic ulcer complications-hemorrhage, perforation, and obstruction-represent medical emergencies that require immediate hospitalization.

Psychologic The physician should assist the patient in developing an effective stress reduction program: eliminating or controlling of stressors and designing a regular relaxation plan.

Diet The patient should eliminate allergic food, eat foods high in dietary fiber and low in refined sugars, and eat various members of the cabbage family and garlic.

Supplements Vitamin A 20,000 IU tid Vitamin C: 500 mg tid Vitamin E: 100 IU tid Flavonoids: 500 mg tid Zinc: 20 mg/day Glutamine: 500 mg tid Bismuth subcitrate: 240 mg bid before meals

Peptic ulcer disease should be recognized as a heterogeneous group of disorders with a common final pathway leading to an ulcerative lesion in either the gastric or duodenal mucosa. Patients must be carefully evaluated to determine which of the previously mentioned factors is most relevant to their health problem. This is

DGL can be taken (380 to 760 mg) 20 minutes before meals tid.

1.Smoot DT, Go MF, Cryer B. Peptic ulcer disease. Prim Care 2001;28: 487-503. 2. Berstad K, Berstad A. Helicobucfw pylori infection in peptic ulcer disease. Scand J Gastroenterol1993;28:561-567. 3.Misciagna G, Cisternino AM, Freudenheim J. Diet and duodenal ulcer. Dig Liver Dis 2OOO;32:468-472. 4. Bulent K, Murat A, Esin A, et al. Association of CagA and VacA presence with ulcer and non-ulcer dyspepsia in a Turkish population. World J Gastrwnterol2003;9:1580-1583. 5. Zhang Y, Liu H, Zhou K. Lack of correlation of vacA genotype, cagA gene of Helicobucferpylori and their expression products with various gastroduodenal diseases. Chin Med J (Engl) 2001;114703-706.

6. Faundez G, Troncoso M, Figueroa G. cagA and vacA in strains of Helicobucferpylori from ulcer and non-ulcerative dyspepsia patients. BMC Gastroenterol2002;2:20. 7. Sarker SA, Gyr K. Non-immunological defense mechanisms of the gut. Gut 1992;33987-993. 8. Gray GM. Peptic ulcer diseases. In Dale DC, Federman DD, eds. Scientific American medicine. New York Scientific American, 1995. 9. Weil J, Colin-Jones D, Langman M. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ 1995;310827-830. 10.Feldman EJ, Sabovich KA. Stress and peptic ulcer disease. Gastroenterology 1980;78:1087-1089.

Botanical Medicine

Specific Health Problems 11. Anda RF, Williamson DF, Escobedo LG, et al. Self-perceived stress and the risk of peptic ulcer disease.A longitudinal study of US adults. Arch Intern Med 1992;152829-833. 12. Siegel J. Gastrointestinal ulcer-Arthus reaction! Ann Allergy 1974; 32~127-130. 13. An& C, Moulinier B, Andre F, et al. Evidence for anaphylactic reactions in peptic ulcer and varioliform gastritis. Ann Allergy 1983; 51:32!5-328. 14. Siegel J. Immunologic approach to the treatment and prevention of gastrointestinal ulcers. Ann Allergy 1977;38:27-41. 15. Rebhun J. Duodenal ulceration in allergic children. Ann Allergy 1975;34.145-149. 16. Kumar N, Kumar A, B m r SL, et al. Effect of milk on patients with duodenal ulcers. Br Med J 1986;293666. 17.Rydning A, Berstad A, Aadland E, et al. Prophylactic effect of dietary fiber in duodenal ulcer disease. Lancet 1982;2736-739. 18. Kang JY, Tay HH, Guan R, et al. Dietary supplementation with pectin in the maintenance treatment of duodenal ulcer. A controlled study. Scand J Gastroenterol 1988;23:95-99. 19. Harju E, Larmi TK. Effect of guar gum added to the diet of patients with duodenal ulcer. JPEN J Parenter Enteral Nutr 1985;9:496--500. 20. Cheney G. Rapid healing of peptic ulcers in patients receiving fresh cabbage juice. Calif Med 1949;7010-14. 21.Cheney G. Anti-peptic ulcer dietary factor. J Am Diet Assoc 1950;26668-672. 22. Shive W, Snider RN, DuBilier 8, et al. Glutamine in treatment of peptic ulcer; preliminary report. Tex State J Med 1957;53:840-842. 23. Marshall BJ, Valenzuela JE,McCallum RW, et al. Bismuth subsalicylate suppression of Helicobucter pylori in nonulcer dyspepsia. A doubleblind placebo-controlled trial. Dig Dis Sci 1993;38:16741680. 24. Kang JY, Tay HH, Wee A, et al.Effect of colloidal bismuth subcitrate on symptoms and gastric histology in non-ulcer dyspepsia. A double blind placebo controlled study. Gut 1990;31:476-480. 25. Loughlin MF. Novel therapeutic targets in Helicobucter pylori. Expert Opin Ther Targets 2003;7725-735. 26. Thyagarajan SP, Ray P, Das BK, et al. Geographical difference in antimicrobial resistance pattern of Helicobucter pylori clinical isolates from Indian patients: Multicentric study. J Gastroenterol Hepatol 2003;18:1373-1378. 27. Parmar NS, Ghosh MN. Gastric anti-ulcer activity of (+)qanidanol-3, a histidme decarboxylase inhibitor. Eur J Pharmacol1981;6925-32. 28. Wendt P, Reiman H, Swoboda K, et al. The use of flavonoids as inhibitors of histidine decarboxylase in gastric diseases. Experimental and clinical studies. Naunyn Schmiedebergs Arch Pharmacoll980313(suppl):238. 29. Beii W, Birkholz C, Sewing KF. Effects of flavonoids on parietal cell acid secretion, gastric mucosal prostaglandin production and Helicobacter pylori growth. Arzneimittelforschung 1995;45697-700. 30.Schumpelick V, Farthmann E. [Study on the protective effect of vitamin A on stress ulcer of the rat (author’s transl).] Arzneimittelforschung 1976;26386-388.

31.al-Moutairy AR, Tariq M. Effect of vitamin E and selenium on hypothennic restraint stress and chemically-induced ulcers. Dig Dis Sci 1996;41:1165-1171. 32. h e r G, Bor NM, Onuk E, et al. The role of zinc ion in the development of gastric ulcers in rats. Eur J Pharmacol1981;70241-243. 33. Frommer DJ. The healing of gastric ulcers by zinc sulphate. Med J Aust 1975;2793-796. 34.Bandyopadhyay D, Biswas K, Bhattacharyya M, et al. Gastric toxicity and mucosal ulceration induced by oxygen-derived reactive species: protection by melatonin. Curr Mol Med 2001;1:501-513. 35. van Marle J, Aarsen PN, Lind A, et al. Deglycyrrhizinised liquorice (DGL) and the renewal of rat stomach epithelium. Eur J Pharmacol 1981;72:219-225. 36. Morgan AG, McAdam WA, Pacsoo C, et al. Comparison between cimitidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy. Gut 1982;23:545-551. 37. Tewari SN, Trembalowicz FC. Some experience with deglycyrrhizinated liquorice in the treatment of gastric and duodenal ulcers with special reference to its spasmolytic effect. Gut 1968; 948-51. 38.Balakrishnan V, Pillai MV, Raveendran PM, et al. Deglycyrrhizinated liquorice in the treatment of chronic duodenal ulcer. J Assoc Physicians India 1978;26:811-814. 39. Rees WD, Rhodes J, Wright JE, Stamford LF, et al. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gastroenterol1979;14:605-607. 40.Fukai T, Manuno A, Kaitou K, et al. Anti-Helicobucter pylori flavonoids from licorice extract. Life Sci 2002;71:1449-1463. 41. Zhou H, Jiao D. [312 cases of gastric and duodenal ulcer bleeding treated with 3 kinds of alcoholic extract rhubarb tablets.] Zhong Xi Yi Jie He Za Zhi 1990;10:150-151,131-132. 42. Best R, Lewis DA, Nasser N. The anti-ulcerogenic activity of the unripe plantain banana (Musa species). Br J Pharmacol 1984;82: 107-116. 43. Sanyal AK, Gupta KK, Chowdhury NK.Banana and experimental peptic ulcer. J Pharm Pharmacol1963;15283-284. 44.Goel RK, Sairam K, Rao CV. Role of gastric antioxidant and antiHelicobuctor pylori activities in antiulcerogenic activity of plantain banana (Musu sapienturn var. purudisiacu). Indian J Exp Biol 2001; 39719-722. 45. Mahady GB, Pendland SL, Yun GS, et al. Ginger (Zingiber oficinule Roscoe) and the gingerols inhibit the growth of Cag A+ strains of Helicobucter pylori. Anticancer Res 2003;233699-3702. 46.Repetto MG, Llesuy SF. Antioxidant properties of natural compounds used in popular medicine for gastric ulcers. Braz J Med Biol Res 2002;35:523-534. 47. Repetto M, Maria A, Guzman J, et al. Protective effect of Artemisiu douglusiunu Besser extracts in gastric mucosal injury. J Pharm Pharmacol2003;55551-557. 48. Sivam GP. Protection against Helicobucter pylori and other bacterial infections by garlic. J Nutr 2001;131:1106S1108S.

Periodontal Disease Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary 2031 General Considerations 2031 Prevalence and Epidemiology 2031 Pathophysiology 2031

Therapeutic Approach 2036 Hygiene 2036 Diet 2036 Supplements 2036 Botanical Medicines 2036

Therapeutic Considerations 2033 Nutrition 2033 Botanical Medicines 2035

DIAGNOSTIC SUMMARY Gingivitis-inflammation of the gingiva characterized by erythema, contour changes, and bleeding Periodontitis-localized pain, loose teeth, demonstration of dental pockets, erythema, swelling, or suppuration; radiograph may reveal alveolar bone destruction

GENERAL CONSIDERATIONS Periodontal disease is an inclusive term used to describe an inflammatory condition of the gingiva (gingivitis) or periodontium (periodontitis), or both. Periodontal disease usually refers to a disease process that typically progresses from gingivitis to periodontitis.l.2Periodontal disease may be a manifestation of a more systemic condition such as diabetes mellitus, collagen diseases, leukemia or other disorders of leukocyte function, anemia, or vitamin deficiency states.' Periodontal disease may also contribute to systemic disease. For example, periodontal disease has been linked to atherosclerosis via an increased level of serum C-reactive protein, a marker for inflammation and a strong risk factor for coronary artery disease? Because alveolar bone loss may be noninflammatory, our definition of periodontal disease excludes the processes causing only tooth loss (the majority of which are due to osteoporosis or endocrine imbalances).' These conditions reflect systemic disease, with local factors playing only a minor role; therefore the focus should be on treating the underlying condition rather than the "periodontal disease.'' In this context, noninflammatory

alveolar bone loss should be viewed as a separate entity, as it involves a different etiology (see Chapter 196). The focus of this chapter is the use of nutrition and lifestyle improvement as an adjunctive therapy to aid in the control and prevention of the causes of inflammatory periodontal disease. This is a good example of a condition that is probably best treated with combined expertise (i.e., a dentist or periodontist and a nutritionally minded physician). Although oral hygiene is of great importance in treating and preventing periodontal disease, it is insufficient in many cases. The host defense must be normalized if development and progression of the disease are to be ~ontrolled.',~ To a large extent, the nutritional status of the individual determines the status of host defense factors.

Prevalence and Epidemiology The prevalence of periodontal disease increases directly with age. The rate of periodontal disease is approximately 15%at age 10,38%at age 20,46% at age 35, and 54%at age 50. As a group, men have a higher prevalence and severity of periodontal disease than women. Periodontal disease is inversely related to increasing levels of education and income. Rural inhabitants have a higher level of severity and prevalence than their urban counterparts.'

Pathophysiology Understanding the underlying pathophysiology of any disease process leads to a more effective treatment plan. In periodontal disease this involves understanding the normal host protective factors in the periodontium. 2031

Specific Health Problems

Page and SchroedeIA concluded: "Clearly bacteria are essential agents, but their presence is in itself insufficient; host factors must be involved if the disease is to develop and progress." Factors involved in host resistance include the following: The environment of the gingival sulcus Bacterial factors Leukocyte function Complement activation Immunoglobulin (1g)E and mast cell function Amalgam restoration Miscellaneous local factors The structure and integrity of the collagen matrix of the periodontium and gingiva

Gingival Sulcus The gingival sulcus, a V-shaped crevice that surrounds each tooth, is bounded by the surface of the tooth on one side and the epithelium lining the free margin of the gingiva on the other. The anatomy of the gingival sulcus is ideal for bacterial growth, as it is resistant to the washing and cleansing action of saliva. Furthermore, the gingival fluid (sulcular fluid) provides a rich nutrient source for microorganisms. The clinical determination of the depth of the gingival sulcus is an important diagnostic parameter. Patients with periodontal disease should be monitored; biannual visits to the dentist should be sufficient in most cases.

Bacterial Factors Bacterial plaque has long been considered the etiologic agent in most forms of periodontal disease.' However, an appreciation of host defense factors has now developed.'j4 Bacteria are known to produce and secrete numerous compounds that are quite detrimental to the status of the host's defense mechanisms. These compounds include the following': Endotoxins and exotoxins Free radicals and collagen-destroyingenzymes Leukotoxins Bacterial antigens, waste products, and toxic compounds

Polymorphonuclear Leukocytes Polymorphonuclear neutrophils (PMNs) constitute a first line of defense against microbial overgrowth. Defects in PMN functions are "catastrophic" to the peri~dontium.',~PMN functions are depressed in the geriatric population as a whole and in patients with diabetes, Crohn's disease, Chkdiak-Higashi syndrome, Down syndrome, and juvenile period on ti ti^.',^ These patients are at extremely high risk for developing

rapidly progressing periodontal disease, as are people with transient neutropenia. Transient defects in PMN function may be responsible for the periods of quiescence and exacerbation noted in periodontal disease. In addition to serving a vital role in protecting against periodontal disease, PMNs also play a major role in tissue destruction. PMNs release numerous free radicals, collagenases, hyaluronidases, inflammatory mediators, and an osteoclast stimulator.'^^

Macrophages and Monocytes These leukocytes are found in increased numbers in periodontal disease. These cells serve to phagocytize bacteria and debris. They are the primary source of prostaglandins in the diseased gingiva and release large quantities of enzymes believed to play a major role in collagen de~truction.',~

Lymphocytes The major role lymphocytes play in periodontal disease is via lymphokine production. Their role in periodontal disease is overshadowed by the roles of the other immune system components discussed, but lymphokines are involved in promoting PMN and monocyte chemotaxis, fibroblast destruction, and osteoclast activation.'^^

Complement The complement system is composed of at least 22 proteins and accounts for more than 10% of the total serum globulin. On activation, complement components act in a cascade fashion. Complement can be activated via the classical or alternative pathway. The complement system plays a critical role in immunologic and nonspecific resistance to infection and in the pathogenesis of tissue injury. The products of complement activation regulate a number of events including the release of mediators from mast cells; promotion of smooth muscle contraction; chemotaxis of PMNs, monocytes, and eosinophils; and phagocytosis by immune adherence? The net effect is an increase in gingival permeability, resulting in increased penetration of bacteria and bacterial byproducts and, in essence, the initiation of a positive feedback cycle.'r4 Other effects of complement activation include solubilization of immune complexes, cell membrane lysis, neutralization of viruses, and the killing of bacteria? In periodontal disease, activation of complement via the alternative pathway within the periodontal pocket is possibly the major factor in tissue destruction.

Mast Cells and Immunoglobulin E Mast cell degranulation is also a major factor in periodontal disease. Degranulation results in the release of inflammatory mediators (i.e., histamine, prostaglandins, leukotrienes, kinins, serotonin, heparin,

Periodontal Disease

and serine proteases).' Mast cell degranulation can be initiated by IgE complexes, complement components, mechanical trauma, endotoxins, and free radicals. The finding of increased IgE concentrations in the gingiva of patients with periodontal disease suggests that allergic reactions may be a factor in the progression of the disease in some patients?

Amalgam Restorations Faulty dental restorations and prostheses are common causes of gingival inflammation and periodontal destruction.' Overhanging margins provide an ideal location for the accumulation of plaque and the multiplication of bacteria. If the restoration is a silver amalgam filling, there may be even more involvement, due to decreased activities of antioxidant enzymes. Mercury accumulation results in a depletion of the free radicalscavenging enzymes, glutathione peroxidase, superoxide dismutase, and catalase.' The proteoglycans and glycosaminoglycans of the collagen matrix are particularly sensitive to free radical damage?

Miscellaneous Local Factors Numerous local factors favor the progression of periodontal disease including the following: Food impaction Unreplaced missing teeth Malocclusion Tongue thrusting Bruxism Toothbrush trauma Mouth breathing Tobacco (discussed later)

Tobacco and Alcohol

the dissipation of the tremendous amount of pressure exerted during ma~tication.'~ The status of the collagen matrix of the periodontium, specifically the extracellular proteoglycans of the gingival epithelium, determines the rate of diffusion and the permeability of inflammatory mediators, bacteria and their byproducts, and destructive enzymes from the oral ~avity.'~,'~ Due to the high rate of protein turnover in periodontal collagen, the integrity of the collagen matrix in this area is extremely vulnerable to atrophy when the necessary cofactors for collagen synthesis (e.g., protein, vitamin C, B6 and A, zinc, copper) are absent or defi~ient.'~ The collagen of the periodontium is particularly rich in glycosaminoglycans.'5-'8 Heparin sulfate, dermatan sulfate, and chondroitin Csulfate are the major glycosaminoglycans present. Stabilization of collagen is the major treatment goal (see later).

THERAPEUTIC CONSIDERATIONS Therapeutic goals in treating periodontal disease from a nutritional perspective follow: Decrease wound healing time (the time span for wound healing is longer in patients who are more susceptible to periodontal disease19) Improve membrane and collagen integrity Decrease inflammation and free radical damage (inflammation can induce a vicious cycle and promote periodontal disease) Enhance immune status (defects in the immune system, particularly PMNs, are catastrophic to the periodontium) Individual nutrients are discussed later in the context of their role in achieving these therapeutic goals.

Nutrition

Tobacco smoking is associated with increased susceptibility to severe periodontal disease and tooth ~ O S S . ' ~ ~ J ~Vitamin C (Tobacco smoking is associated with increased susceptibility to Vitamin C (ascorbic acid) plays a major role in preventvirtually every major chronic disease.) Many of the harmful ing periodontal disease, as is evident from many experieffects of tobacco smoking are a result of free radical mental studie~.',~O-~~ The classical symptom of gingivitis damage, particularly to epithelial cells. Furthermore, seen in scurvy illustrates the vital function vitamin C smoking greatly reduces ascorbic acid levels, thereby plays in maintaining the membrane and collagen integrity and immunocompetence. Deficiency of vitamin C is potentiating its damaging effects.'l Carotenes and flavonoids have been shown to greatly reduce some of associated with defective formation and maintenance the toxic effects of ~moking.'~J~ of collagen, ground substance, and intercellular cement In addition to cigarette smoking, there is a dosesubstance in mesenchymal tissue.' The deficiency effects dependent association between alcohol consumption on bone include retardation or cessation of osteoid forand periodontal disease.14Presumably, the combination mation, impaired osteoblastic activity, and osteoporosis. of smoking and drinking alcohol produces an even Subclinical vitamin C deficiency plays a sigruficant role greater negative effect on periodontal health. in periodontal disease via these effects and its role in delaying wound healing.1,20-24 Structure and Integrity of Collagen Matrix Decreased vitamin C levels are also associated with The collagen matrix of the periodontal membrane increased permeability of the oral mucosa to endotoxin serves as periosteum to the alveolar bone and allows and bacterial byproducts, as well as impaired leukocyte

Specific Health Problems functions (particularly Ph4Ns). The role vitamin C plays in increasing chemotaxis and phagocytosis by PMNs is best exemplified by its effect on Chkdiak-Higashi syndrome. This autosomal recessive trait is associated with compromised PMN and monocyte chemotaxis and phagocytosis, all of which are responsive to vitamin C supplementation.25This syndrome is also associated with an extremely rapidly progressing period on tit is.'^^ Vitamin C’s other effects on immune status include enhancing lymphoproliferative response to mitogens and increasing interferon levels, antibody response, immunoglobulin levels, and secretion of thymic hormones. Vitamin C also possesses significant antioxidant and antiinflammatory properties and decreases wound healing time.26

Sucrose Sugar is known to significantly increase plaque accumulation while simultaneously decreasing PMN chemotaxis and p h a g o c y t ~ s i s . ’This ~ ~ ~ inhibition of PMN function is due to osmotic effects and competition with vitamin C. Vitamin C and glucose are known to compete for intracellular transport sites, with this intracellular transport being largely insulin dependent (see Chapter 57 for further information on nutrient factors and immune function). Considering the fact that the average American consumes in excess of 175 g/day of sucrose and other refined carbohydrates, it is safe to say that most Americans have a chronically depressed immune status that puts them at increased risk for periodontal disease.**

Vitamin A Vitamin A deficiency predisposes people to periodontal disease. Deficiency of vitamin A is associated with the following’: 0

Keratinizing metaplasia of the gingival epithelium Early karyolysis of gingival epithelial cells Inflammatory infiltration and degeneration Periodontal pocket formation Gingival calculus formation Increased susceptibility to infection Abnormal alveolar bone formation

Vitamin A is necessary for collagen synthesis and wound healing, maintaining the integrity of epithelial and mucosal surfaces and their secretions, and enhancing numerous immune functi0ns.2~Beta-carotenemay be a more advantageous supplement due to its affinity for epithelial tissue and potent antioxidant a~tivity.’~

Zinc and Copper Zinc functions synergistically with vitamin A in many metabolic processes? The severity of periodontal disease

is positively associated with increased serum copper levels while zinc levels are significantly decreased (i.e., an increased copper-to-zinc ratio)?O This is consistent with other causes of chronic inflammation and signifies activation of metallothionein, which increases ceruloplasmin formation while increasing zinc sequestration in response to inflammati0n.2~ Zinc’s importance in treating periodontal disease cannot be overstated. In the United States, marginal zinc deficiency is widespread, particularly in the elderly.30,31 This may be a factor in the increasing prevalence of periodontal disease with age, although the geriatric population as a whole is at higher risk for development of numerous nutrient deficiencies. Zinc functions in the gingiva and periodontium include the Stabilization of membranes Inhibition of calcium influxes Antioxidant activity Metallo-component in at least 40 enzymes including enzymes for DNA, RNA, and collagen synthesis Inhibition of plaque growth Inhibition of mast cell degranulation Numerous immune activities including increased PMN chemotaxis and phagocytosis Zinc is also known to significantly reduce wound healing time.2629 Zinc’s positive effects in established periodontal disease are also due to its action on calcium- and calmodulinmediated processes such as mast cell degranulation, tissue damage induced by endotoxin, and increased vascular ~ermeability.2~ These calcium-mediated events are responsible for much of the tissue destruction seen in periodontal disease.34 Regular (twice daily) use of a mouthwash that contains a 5% zinc solution inhibits plaque growth?2 However, lower concentrations or less frequent mouth washing are not particularly successful.

Vitamin E and Selenium These two nutrients function synergistically in antioxidant mechanisms and seem to potentiate each other’s effects. Vitamin E alone has been demonstrated to be of considerable value in patients with severe periodontal disease.’J5 This can largely be attributed to the decreased wound healing time associated with vitamin E.% The antioxidant effects of vitamin E are particularly needed if silver amalgam is present. Mercury depletes the tissues of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase. In animal studies, this toxic effect of mercury is prevented by supplementation with vitamin E.7 Selenium and vitamin Es antioxidant activities also deter periodontal disease, as the effects of free radicals are extremely damaging to gingival proteoglycans and glycosaminoglycans.*

Periodontal Disease

Coenzyme Qlo

Folic Acid

Ubiquinone, an essential coenzyme involved in mitochondrial oxidative phosphorylation, is also an effective a n t i ~ x i d a n t .Coenzyme ~~.~ Qlo(CoQlo)is widely used in Japan for many conditions including periodontal disease. A review of seven studies using CoQlo found that 70% of the 332 patients involved responded favorably A double-blind study comprising to ~upplementation.3~ 56 subjects found the supplemented group to respond significantly, while the placebo group displayed very little change in periodontal pocket depth and tooth mobility.38

The use of folate, either topically or systemically, in double-blind studies produced sigruficant reductions of gingival inflammation as determined by reduction in color changes, bleeding tendency, gingival exudate flow, and plaque sc0res.4~-~~ The folate mouthwash, 0.1% folic acid, is significantly more effective than the oral supplementation of either 2 or 5 mg/day, suggesting a local mechanism of action.5132Folate has been demonstrated to bind plaque-derived end0toxin.5~-~~ The use of folate mouthwash is particularly indicated for pregnant women and oral contraceptive users, as well as for other conditions associated with an exaggerated gingival inflammatory response or folate antimetabolites (e.g., phenytoin, methotrexate).51$2 Epithelial cells of the cervix and the oral cavity appear to suffer from a similar “end-organ” deficiency of folic acid under the hormonal influences of pregnancy and oral contraceptive use.5233The cervical dysplasia associated with oral contraceptive use also responds to pharmacologic doses of folic acid (i.e., 8 to 30 m g / d a ~ ) . % $ ~ (Whitehead’s work% was the inspiration for the use of folic acid by Pack and in the treatment of gingivitis of pregnancy.) The sera and leukocytes of pregnant women and oral contraceptive users contain a macromolecule that binds folate, which, more than malabsorption or decreased intake, appears to be the major factor for the ”end-organ” folate deficiency.% (It should be noted, however, that folic acid deficiency is the most common deficiency in the worldF6) Double-blind studies have shown that the beneficial effects of folic acid are not limited to w0men,4~35~ and the positive effects are not limited to gingivitis because periodontitis improves as ~ e l l . 5 ~

Flavonoids As a group, these compounds are perhaps the most important components of an antiperiodontal disease program. Flavonoids are extremely effective in reducing inflammation and stabilizing collagen structures. Flavonoids affect collagen structure by doing the f~llowin$~-+

Decreasing membrane permeability, thereby decreasing the load of inflammatory mediators and bacterial products Preventing free radical damage with their potent antioxidant properties Inhibiting enzymatic cleavage by hyaluronidases and collagenases Inhibiting mast cell degranulation Cross-linking with collagen fibers directly The more biologically active flavonoids (i.e., quercetin, catechin, anthocyanidins, and proanthocyanidins) should be supplemented, as rutin has little collagen-stabilizing effect. Remarkableeffects have been displayed by 3-0-methyl(+)-catechin in the treatment of hamsters with experimentally induced periodontitis. Large doses of this flavonoid derivative significantly retarded plaque growth and alveolar bone resorption.“ The flavonoid components of Camellia sinensis (green tea) have demonstrated not only activity against gingival bacteria, but also direct antiinflammatory effects as well. Clinical studies have used either soft-chewable candy or hydroxypropylcellulose strips impregnated with green tea catechin. In the study with the hydroxypropylcellulose strips, the pocket depth and the proportion of pathogenic bacteria were markedly decreased.MThe study using the soft candy was doubleblind and indicated by the approximal plaque index (API) and the sulcus bleeding index (SBI) scores that the green tea soft-chews significantly reduced plaque and double-blind the inflammatory degree of the gingi~a.4~A study also showed that chewing gum containing procyanidolic oligomers (PCOs) also minimizes gingival bleeding and plaque accumulation.48

Botanical Medicines A number of botanical compounds have shown an ability to inhibit plaque formation, but perhaps the most popular botanical medicine in a toothpaste is an alcoholic extract of Sanguinariu canadensis (bloodroot). This extract contains a mixture of benzophenanthridine alkaloids, but chiefly sanguinarine is available in commercial toothpastes and mouth rinses. Sanguinarine demonstrates properties useful in preventing dental plaque formation. It has broad antimicrobial activity, as well as antiinflammatory properties. In vitro studies indicate that the antiplaque action of sanguinaria is due to its ability to inhibit bacterial adherence. Electron microscopic studies of bacteria exposed to sanguinarine demonstrate that bacteria aggregate and become morphologically irregular.57 Sanguinarine appears to be less effective than chlorhexidine mouthwash, but it is effective in many cases and does have the advantage of being a natural compound versus a syntheti~.~’,~~

Another useful botanical medicine in periodontal disease is the triterpenoid extract of CentelZa asiutica (gotu kola). This extract has demonstrated impressive wound healing properties (see Chapter 78).One study demonstrated that centella extract was helpful in speeding up recovery after laser surgery for severe periodontal disease.%

THERAPEUTIC APPROACH As discussed earlier, many factors are involved in the initiation and promotion of periodontal disease. Effective therapy requires that all relevant factors be controlled. Since there are as yet no clear guidelines for determining which factors are most important for a given patient, a general approach is recommended here. All smoking patients should be assisted in stopping, as continued smoking greatly decreases the success of any therapy for periodontal disease.

Hygiene Patients should visit a dentist periodically, as needed, to eliminate plaque and calculus accumulation. Brushing after meals and daily flossing are necessary.

Diet

Supplements Vitamin C: 3 to 5 g/day in divided doses Vitamin E: 400 to 800 IU/day Beta-carotenes: 250,000 IU/day (higher doses if indicated) for up to 6 months (although not clinically tested in this condition, beta-carotenes are recommended instead of vitamin A due to their similar effects and greater safety) Selenium: 400 pg/day Zinc: 30 mg/day of Zn picolinate (60mg/day if another form); wash mouth with 15 ml of a 5% solution bid Folic acid: 2 mg/day; wash mouth with 15 ml of a 0.1% solution bid Quercetin: 500 mg tid

Botanical Medicines High-flavonoid-containing extracts such as those from bilberry (Vaccinium myrtillus), hawthorn (Crataegus sp.), grape seed (Vitis vinifera), or green tea (Camellia sinensis), can be used according to the dosages in the corresponding chapter. Of these extracts, green tea extract or the liberal consumption of green tea as a beverage may be the most cost effective. For a green tea extract with a 50% polyphenol content, the dosage would be 200 to 300 mg bid. Additional recommendations follow:

A diet high in dietary fiber may have a protective effect via increased salivary secretion.20Avoidance of sucrose and all refined carbohydrates is extremely important.

Sanguinaria canadensis: use toothpaste containing extract Centella asiatica triterpenoids: 30 mg bid of pure triterpenoids

1.Carranza F. Glidunan's clinical periodontology, ed 6. Philadelphia: WB sunders, 1984. 2.Robbins S, Cotran R. Pathologic basis of disease, ed 2.Philadelphia: WE3 Sunders, 1979893-895. 3. Deliargyris EN, Madianos PN, Kadoma W, et al. Periodontal disease in patients with acute myocardial infarction: prevalence and contribution to elevated C-reactive protein levels. Am Heart J 2004;1471005-1009. 4.Page RC, Schroeder HE. Current status of the host response in chronic marginal periodontitis. J Periodontol1981;52477-491. 5. James K. Complement: activation, consequences, and control. Am J Med Techno1 1982;48:735-742. 6. Hyyppa T. Gingival IgE and histamine concentrations in patients with asthma and in patients with periodontitis. J Clin Periodontol 1984;11:132-137. 7. Addya S, Chakravarti K, Basu A, et al. Effects of mercuric chloride on several scavenging enzymes in rat kidney and influence of vitamin E supplementation. Acta Vitamin01 Enzymol1984;6103-107. 8. Bartold PM, Wiebkin OW, Thonard JC. The effect of oxygen-derived free radicals on gingival proteoglycans and hyaluronic acid. J Periodontal Res 1984;19:390400. 9.Schenkein HA, Gunsolley JC, Koertge TE,et al. Smoking and its effects on early-onset periodontitis. J Am Dent Assoc 1995;126: 1107-1113.

10. Kaldahl WB, Johnson GK, Patil KD, et al. Levels of cigarette consumption and response to periodontal therapy. J Periodontoll996; 67675-681. 11. Pelletier 0. Smoking and vitamin C levels in humans. Am J Clin Nub 1968;21:1259-1267. 12. h r o v s k y I, Hladovec J. Suppression of the desquamating effect of smoking on the human endothelium by hydroxyethylrutosides. Blood Vessels 1979;16239-240. 13. Burton GW, Ingold KU. Beta-carotene. An unusual type of lipid antioxidant. Science 1984;224:569-573. 14. Tezal M, Grossi SG,Ho AW, et al. Alcohol consumption and periodontal disease. J Clin Periodontol200431:484-488. 15. Junqueira L, Cameiro J. Basic histology, ed 3. Los Altos, C A Lange Medical Publications, 1980, p 312. 16. Bartold PM, Wiebkin OW, Thonard JC. The active role of gingival proteoglycans in periodontal disease.Med Hypotheses 1983;12377-387. 17. Bartold PM, Wiebkin OW, Thonard JC. Proteoglycans of human gingival epithelium and connective tissue. Biochem J 1983;11:119-127. 18. Bartold PM, Wiebkin OW, Thonard JC. Glycosaminoglycans of human gingival epithelium and connective tissue. Connect Xssue Res 1981;9:99-106. 19.Abbas F, van der Velden U, Hart AA. Relation between wound healing after surgery and susceptibility to periodontal disease. J Clin Periodontol 1984;11:221-229.

Periodontal Disease 20. Alvares 0.Nutrition, diet and oral health. In Worthington-RobertsB, ed. Contemporary developments in nutrition. St Louis:Mosby, 1981. 21. Alvares 0,Altman LC, Springmeyer S, et al. The effect of subclinical ascorbate deficiency on periodontal health in nonhuman primates. J Periodontal Res 1981;16628-636.

22. Woolfe SN, Hume WR, Kenney EB. Ascorbic acid and periodontal disease: a review of the literature. J West SOC Periodontol Periodontal Abstr 1980;28:4456. 23. Alfano MC, Miller SA, Drummond JF. Effect of ascorbic acid deficiency on the permeability and collagen biosynthesis of oral mucosal epithelium. Ann N Y Acad Sci 1975;258253-263. 24. Alvares 0, Siege1 I. Permeability of gingival sulcular epithelium in the development of scorbutic gingivitis. J Oral Pathol 1981;lO: 40-48. 25. Stephens CG, Snyderman R. Cyclic nucleotides regulate the morphologic alterations required for chemotaxis in monocytes. J Imm~011982;1281192-1197. 26.Krause M, Mahan L. Food, Nutrition and Diet Therapy, ed 7. Philadelphia: WB Sunders, 1984. 27. Ringsdorf WM Jr, Cheraskin E, Ramsay RR Jr. Sucrose,neutrophilic phagocytosis and resistance to disease. Dent Surv 1976;52:46-48. 28.Sanchez A, Reeser JL, Lau HS, et al. Role of sugars in human neutrophilic phagocytosis. Am J Clin Nutr 1973;261180-1184. 29. Prasad AS. Clinical, biochemical and nutritional spectrum of zinc deficiency in human subjects: a n update. Nutr Rev 1983;41:197-208. 30. Freeland JH,Cousins RJ, Schwartz R. Relationship of mineral status and intake to periodontal disease. Am J Clin Nutr 1976;29745-749. 31. Nordstrom J. Trace mineral nutrition in the elderly. Am J Clin Nutr 1982;36:788-795. 32. Harrap GJ, Saxton CA, Best JS. Inhibition of plaque growth by zinc salts. J Periodontal Res 1983;18634642. 33. Hsieh S, Hayali A, Navia J. Zinc. In Curzon M, Cutress T, eds. Trace elements in dental disease. Boston: John Wright PSG, 198399-220. 34.Aleo JJ, Padh H, Subramoniam A. Possible role of calcium in periodontal disease. J Periodontal 1984;55:642-647. 35. Hazen S, Cowan E, eds. Diet, nutrition and periodontal disease. Chicago: Am Soc Prev Dent, 1975. 36. Kim JE, Shklar G. The effect of vitamin E on the healing of gingival wounds in rats. J PeriodontoI1983;54:305-308. 37. Folkers K, Yamamura Y. Biomedical and clinical aspects of coenzyme Q, vol 1. Amsterdam: Elsevier/North Holland Biomedical Press, 1977294311. 38. Folkers K, Yamamura Y. Biomedical and clinical aspects of coenzyme Q, vol 3. Amsterdam: Elsevier/North Holland Biomedical Press, 1981:109-125. 39. Monboisse J, Braquet P, Bore1 J. Oxygen-free radicals as mediators of collagen breakage. Agents Actions 1984;1549-50. 40. Rao CN, Rao VH, Steinmann B. Influence of bioflavonoids on the metabolism and crosslinking of collagen. Ital J Biochem 1981;30: 259-270. 41. Ronziere MC, Herbage D, Garrone R, Frey J. Influence of some flavonoids on reticulation of collagen fibrils in vitro. Biochem Pharmacol1981;3O:1771-1776.

42. Jones CJ, Cummings C, Ball J, et al. A clinical and ultrastructural study of osteogenesis irnperfecta after flavonoid (Catergen) therapy. S Afr Med J 1984;66:907-910. 43. Pearce FL, Befus AD, Bienenstock J. Mucosal mast cells. In. Effect of quercetin and other flavonoids on antigen-induced histamine secretion from rat intestinal mast cells. J Allergy Clin Immunol 1984;73:819-823. 44.Busse WW, Kopp DE, Middleton E Jr. Flavonoid modulation of human neutmphd function. J Allergy Clin Immunol1984;73801-809. 45. Gineste M, de Crousaz P, M o r t JF,et al. Influence of 3-methoxy 5,7,3??4?-tetrahydroxyflavan(ME) on experimental periodontitis in the golden hamster. J Biol Buccale 1984;12:259-265. 46. Hirasawa M, Takada K, Makimura M, et al. Improvement of periodontal status by green tea catechin using a local delivery system: a clinical pilot study. J Periodontal Res 2002;37:433-438. 47. Krahwinkel T, Wdershausen B. The effect of sugar-free green tea chew candies on the degree of inflammation of the gingiva. Eur J Med Res 2000;5:463-467. 48. Kimbrough C, Chun M, dela Roca G, et al. Pycnogenol chewing gum minimizes gingival bleeding and plaque formation. Phytomedicine 2002;9:410-413. 49. Vogel RI, Fink RA, Schneider LC, et al. The effect of folic acid on gingival health. J Periodontol1976;47667-668. 50. Vogel RI, Fink RA, Frank 0, et al. The effect of topical application of folic acid on gingival health. J Oral Med 1978;33:20-22. 51. Pack AR, Thomson ME. Effects of topical and systemic folic acid supplementation on gingivitis in pregnancy. J Clin Periodontol 1980;7402-414. 52. Thomson ME, Pack AR. Effects of extended systemic and topical folate supplementation on gingivitis of pregnancy. J Clin Periodontal 1982;9:275-280. 53. Pack AR. Folate mouthwash. Effects on established gingivitis in periodontal patients. J Clin Periodontol1984;11:619-628. 54. Whitehead N, Reyner F, Lindenbaum J. Megaloblastic changes in the cervical epithelium association with oral contraceptive therapy and reversal with folic acid. J Am Med Assoc 1973;2261421-1424. 55. Butterworth CE Jr, Hatch KD, Gore H, et al. Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 1982;3573-82. 56. da Costa M, Rothenberg SP. Appearance of a folate binder in leukocytes and serum of women who are pregnant or taking oral contraceptives. J Lab Clin Med 1974;83:207-214. 57. Godowski KC.Antimicrobial action of sanguinarine. J Clin Dent 1989;1:96-101. 58. Grossman E, Meckel AH, Isaacs RL, et al. A clinical comparison of antibacterial mouthrinses. Effects of chlorhexidine, phenolics, and sanguinarine on dental plaque and gingivitis. J Periodontol 1989;60:435-440. 59. BenedicentiA, Galli D, Merlini A. [The clinical therapy of periodontal disease, the use of potassium hydroxide and the water-alcohol extract of Centella asiatica in combination with laser therapy in the treatment of severe periodontal disease.] Parodontol Stomatol 1985;2411-26.

Pneumonia: Bacterial, Mycoplasmal, and Viral Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS General Considerations 2039 Immunoglobulin Respiratory System Defenses 2039 Therapeutic Considerations for All Types of Pneumonia 2040 Expectorants 2040 Vitamin C 2040 Vitamin A 2040 Vitamin E 2041 Bromelain 2041 Bottle Blowing 2041 Therapeutic Approach for All Types of Pneumonia 2041 Supplements 2041 Botanicals 2041 Physical Therapy 2041 MYCOPLASMAL PNEUMONIA 2042

Therapeutic Considerations 2042 Additional Therapies 2042 PNEUMOCOCCAL (STREPTOCOCCAL) PNEUMONIA 2042 Diagnostic Summary 2042 Therapeutic Considerations 2042 Bovine Spleen Extracts 2042 Hydrasfis canadensis 2043 Garlic 2043 Antibiotics 2043 Additional Therapies 2043 VIRAL PNEUMONIA 2043

Diagnostic Summary 2043 Therapeutic Considerations 2043 Additional Therapy 2043

Diagnostic Summary 2042

GENERAL CONSIDERATIONS Acute pneumonia is the seventh leading cause of death in the United States.' It is particularly dangerous in the elderly. Although pneumonia may appear in healthy individuals, it is usually seen in immune-compromised individuals, particularly in drug and alcohol abusers. The growing population of those with chronic lung diseases and other debilitating illnesses and the use of respiratory therapy, immunosuppressive drugs, and other such technologies have contributed to the further increase of nosocomial and opportunistic pneurnonias, which have high mortality rates. In healthy individuals, pneumonia most often follows an insult to the host defense mechanisms: viral infection (especially influenza), cigarette smoke and other noxious fumes, impairment of consciousness (which depresses the gag reflex, allowing aspiration), neoplasms, and hospitalization (Table 202-1). In immune competent, nonelderly adults, cigarette smoking is the

strongest independent risk factor for invasive pneumococcal di~ease.~ The airway distal to the larynx is normally sterile due to several protective mechanisms, both mechanical and humoral. The mucus-covered ciliated epithelium that lines the lower respiratory tract propels sputum to the larger bronchi and trachea, evoking the cough reflex. The respiratory secretions contain substances that exert nonspecific antimicrobial actions: alpha-1 antitrypsin, lysozyme, and lactoferrin. At the level of the alveoli, potent defense mechanisms are present including alveolar macrophages, a rich vasculature capable of rapidly delivering lymphocytes and granulocytes, and an efficient lymphatic drainage network.

Immunoglobulin Respiratory System Defenses Immunoglobulin A Immunoglobulin (Ig) A is present in high concentrations in the secretions of the upper respiratory tract and 2039

Specific Health Problems Etiologies of common pneumonias Type Viral (influenza) Mycoplasmal Bacterial Bacterial superimposed on viral

Percentage 20 (3) 10-20

12 6

Chlamydia

10

Unknown cause (legionnaires’ disease, toxic)

38

Modified from Branch WT Jr. Office practice of medicine. Philadelphia:Saunders, 198257-76.

protects against viral infection. In the lower tract, IgA aids in the following: Agglutinating bacteria Neutralizing microbial toxins Reducing bacterial attachment to mucosal surfaces Activating the alternative complement pathway when complexed with an antigen

Immunoglobulin G IgG is present in the lower respiratory tract and does the following:

Serum agglutinates and opsonizes bacteria Activates complement Promotes chemotaxis of granulocytesand macrophages Neutralizes bacterial toxins and viruses Lyses gram-negative bacteria

THERAPEUTIC CONSIDERATIONS FOR ALL TYPES OF PNEUMONIA Expectorants Botanical expectorants have a long history of use in pneumonia. Because impaired cough reflexes have been theorized to play a role in recurrent pneumonia: it seems reasonable that these botanicals would be useful to help this condition and to prevent recurrences. Botanical expectorants act to increase the quantity, decrease the viscosity, and promote expulsion of the secretions of the respiratory mucous membranes. Many also have antibacterial and antiviral activity. Some expectorants are also antitussives; however, Lobelia injatu, a commonly used expectorant, actually helps promote the cough r e f l e ~Therefore .~ lobelia is much more effective at clearing the lungs than an expectorant like Glycyrrhiza glabra (licorice),which also exerts some antitussive effect. If the cough is productive, lobelia should be used. If it is nonproductive, licorice should be used. Other useful expectorants include balsam of Peru, senega root, grindelia, wild cherry bark, and horehound.

In addition, bromelain (the proteolytic enzyme complex from pineapple) can be used as a mucolytic (discussed later in the section on pneumococcal pneumonia).

Vitamin C In the early part of this century, before the advent of effective antibiotics, many controlled and uncontrolled studies demonstrated the efficacy of large doses of vitamin C, but only when started on the first or second day of infection? If administered later, vitamin C tended only to lessen the severity of the disease. Researchers also demonstrated that in pneumonia white cells take up large amounts of vitamin C.6 The value of vitamin C supplementation in elderly patients with pneumonia was demonstrated quite clearly in a recent double-blind study of 57 elderly patients hospitalized for severe acute bronchitis and pneumonia.’ The patients were given either 200 mg/day of vitamin C or a placebo. Patients were assessed by clinical and laboratory methods (vitamin C levels in the plasma, white blood cells, and platelets; sedimentation rates; and white blood cell counts and differential). Patients receiving the modest dosage of vitamin C demonstrated substantially increased vitamin C levels in all tissues even in the presence of an acute respiratory infection. Using a clinical scoring system based on major symptoms of respiratory infections, results indicated that the patients receiving the vitamin C fared sigruficantly better than those on placebo. The benefit of vitamin C was most obvious in patients with the most severe illness, many of whom had low plasma and white blood cell vitamin C levels on admission.

Vitamin A Vitamin A supplementation appears to be of value in pneumonia, especially in children with measles. This may be due to the increased rate of excretion of vitamin A found during severe infections such as pneumonia. An interesting study evaluated 29 patients with pneumonia and sepsis and found their mean excretion rate of vitamin A was 0.78 pmol/day. Subjects with fever excreted significantly more retinol than did those without fever. A remarkable 34% of the patients excreted more than 1.75 pmol/day of retinol, which is equivalent to 50% of the U.S. recommended daily allowance.8 This may be particularly important for children. A randomized, double-blind trial of 189 children with measles (average age 10 months) in South Africa evaluated the efficacy of vitamin A in reducing complications. Providing 400,000 IU (120 mg retinyl palmitate), half on admission and half a day later, reduced the death rate by more than 50% and the duration of pneumonia, diarrhea, and hospital stay by 33%? However, another study did not show any benefit from vitamin A supplementation. The difference may be

due to the lower dosage (100,000 IU)or to the fact that it was not limited to children with pneumonia as a complication of measles, a condition known to also decrease vitamin A levels.1° Evidence also indicates there are positive associations with using vitamin A and concomitant zinc supplementation. One study of 2482 children aged 6 months to 3 years revealed that those children given initial high doses of vitamin A followed by 4 months of elemental zinc (10 mg/day for infants and 20 mg/day for children older than l year) had a reduced incidence of pneumonia that was not present in the group given only vitamin A."

Vitamin E Patients with influenza complicated by pneumonia experience a sharp rise in lipid peroxidation (LPO) products, especially those who are seriously ill. Administration of alpha-tocopherol promotes a significant decrease in LPO levels and more apparent clinical response.12

Bromelain

pulmonary function impairment and an increase in total lung capacity in patients who had undergone coronary artery bypasses." It may well prove useful for patients who are prone to respiratory infections like pneumonia to consider this or another similar activity, like a playing a wind instrument, as a means to decrease the frequency of respiratory events and limit their duration.

THERAPEUTIC APPROACH FOR ALL TYPES OF PNEUMONIA The general approach to all pneumonias includes enhancement of the immune system and support of respiratory tract drainage (for a full discussion of immune system stimulation, see Chapter 57). Multivitamin supplements that include a full complement of essential vitamins and trace minerals is recommended for all persons older than 50 to strengthen their immune system and reduce the risk of respiratory infection.18 Drainage is supported by the use of local heat, massage, and expectorants. For more discussion on cause-specific therapies for the various pneumonias, see the subsections later.

Bromelain is a useful adjunct therapy for pneumonia due to its fibrinolytic, antiinflammatory, and mucolytic actions and enhancement of antibiotic ab~orpti0n.l~ Supplements Vitamin A: 50,000 IU/day for 1 week or beta-carotene: Bromelain's mucolytic activity is responsible for its 200,000 IU/day (Note: Vitamin A should not be particular effectiveness in respiratory tract diseases used in menstruating women due to teratogenic including pneumonia, bronchitis, and sinusitis.14 effect) Bottle Blowing Vitamin C: 500 mg q2h Vitamin E: 200 IU/day A Swedish study was carried out with 145 adults hosBioflavonoids: 1000 mg/day pitalized for community-acquired pneumonia.15 These Zinc: 30 mg/day patients were divided into three groups. Group A was Thymus extract: the equivalent to 120 mg pure polypepgiven early mobilization with no breathing-associated tides with molecular weights less than 10,000 or roughly exercises, group B was instructed to sit up and take 500 mg of the crude polypeptide fraction 20 deep breaths 10 times daily, and group C was instructed to sit up and blow bubbles in a bottle conBotanicals taining 10 ml water through a plastic tube 20 times Lobelia inflata on 10 occasions daily. In this study, length of hospitalDried herb: 0.2 to 0.6 g tid ization was significantly modified: group A patients Tincture: 15 to 30 drops tid were hospitalized for a mean of 5.3 days, group B for Fluid extract: 8 to 10 drops tid 4.6 days, and group C for only 3.9 days. The number Echinacea sp. of days with fever were least in the bottle blowing Dried root (or as tea): 0.5 to 1g group. It should be noted that early mobilization itself Freeze-dried plant: 325 to 650 mg is known to significantly decrease hospital stays in Juice of aerial portion of Echinacea purpurea stabipneumonia patients already.16 Despite the positive lized in 22% ethanol: 2 to 3 ml clinical results, C-reactive protein levels, peak expiraTincture (1:5):2 to 4 ml tory flow, and vital capacity were not significantly Fluid extract (1:l):2 to 4 ml affected. Solid (dry-powdered) extract (6.5:l or 3.5% echinaAlthough it is not completely understood why the coside): 150 to 300 mg patients who performed bottle blowing had shorter hospital stays, it seems that respiratory pressure Physical Therapy changes associated with thisexercise may be involved in Diathermy to chest and back: 30 min/day providing an environment for more efficient bacterial Mustard poultice: once/day clearance. Another study also found decreased

Specific Health Problems Lymphatic massage: tid Postural drainage: tid Bottle-blowing therapy: blow bubbles in a bottle containing 10 ml water through a plastic tube 20 times on 10 occasions daily For best results, the physician should use diathermy, then lymphatic massage, and finally postural drainage.

Gram-positive diplococci are present in the sputum smear Initially chest excursion is diminished on the involved side, breath sounds are suppressed, and fine inspiratory rales are heard Later classic signs of consolidation appear (bronchial breathing, crepitant rales, dullness) kukocytosis Radiograph shows lobar or segmental consolidation

THERAPEUTIC CONSIDERATIONS DIAGNOSTIC SUMMARY Most commonly occurs in children or young adults Insidious onset over several days Nonproductive cough, minimal physical findings, temperature generally less than 102" F Headache and malaise are common early symptoms White blood cell count is normal or slightly elevated X-ray pattern patchy or inhomogeneous

THERAPEUTIC CONSIDERATIONS Mycoplasma are bacteria that lack cell walls. Mycoplasmu pneumoniue is the most frequent cause of communityacquired, nonp yogenic pneumonia. Tracheobronchitis is more common than pneumonia, often with pharyngitis (especially in children). Slow recovery is the general rule, but the course is quite variable. As there are no specific natural medicine recommendations for mycoplasmal infections available at this time, an antibiotic, typically an erythromycin, is indicated. Enhancement of general immune function is recommended.

Additional Therapies Antibiotic Patients should take 250 to 500 mg erythromycin four times/day.

DIAGNOSTIC SUMMARY Pneumonia usually preceded by upper respiratory tract infection Sudden onset of shaking, chills, fever, and chest pain Sputum is pinkish or blood specked at first, then becomes rusty at the height of the infection, and finally yellow and mucopurulent during resolution

Pneumococcal pneumonia (Streptococcus pneumoniae) is the most common bacterial pneumonia and the most common cause of pneumonia requiring hospitalization. Careful clinical judgment is necessary in determining the severity of the disease and the status of the patient's immune system because it is often necessary to administer antibiotics or to refer for hospitalization, especially for elderly or immunocompromised patients. Unfortunately, most reports show an increase not only of resistance rates to antibiotic therapy, but also of the proportion of highly resistant ~ t r a i n s . * In ~ - ~two ~ multinational studies, the worldwide prevalence of penicillin-resistant and macrolide-resistant S. pneumoniue ranged from 18% to 22% and from 24% to 31%, respectively.22,uGiven this information, it is important to consider natural treatment therapeutics in cases resistant to antibiotics or as an adjunctive treatment to strengthen the immune response and increase therapeutic effect. A blood culture is a more accurate method of diagnosis than sputum culture because 15% to 25% of all cultures are positive early in the disease, regardless of whether the patient has a bacterial pneumonia or not. This is not surprising considering that the nasopharynx is the natural habitat of Pneumococcus (humans are the only known hosts).

Bovine Spleen Extracts The most specific natural medicine for pneumococcal pneumonia appears to be bovine spleen extracts (see Chapter 39). The importance of spleen function in preventing pneumococcal pneumonia is demonstrated by examining postsplenectomy syndrome. One of the hallmark features of this syndrome is an increased risk of pneumococcal pneumonia. About 2.5% of patients having their spleen removed will die from pneumococcal pneumonia within 5 years of splenectomy. For a child who has undergone a splenectomy, a pneumococcal vaccine and long-term antibiotic treatment are often recommended. Use of spleen extracts, especially those rich in tuftsin, may be an effective natural alternative.

Pneumonia: Bacterial, Mycoplasmal, and Viral

As far back as the 1930s, orally administered bovine spleen extracts were shown to possess some physiologic action in increasing white blood cell counts in patients with extreme deficiencies of white blood cells, as well as being of some benefit in patients with malaria and typhoid

Hydrastis canadensis Hydrastis canadensis and probably other berberinecontaining botanicals are important in treating this difficult infection. Berberine has well-documented antibiotic activity against pathogenic streptococci.2’ In addition, its sparing effect on the normal gastrointestinal microbial flora is an advantage as compared with conventional antibiotics.

Garlic Allium sativum (garlic)has exhibited a broad spectrum of antibiotic activity against both gram-positive and gramnegative bacteria.28In vitro studies have demonstrated garlic to be an effective antibacterial agent against S. pneumonid9and should be considered in cases of antibiotic resistance or as an adjunct to antibiotic therapy.

Antibiotics Bacterial pneumonia is a condition in which the conventional antibiotic approach, typically penicillin G or V, is clearly of great value for the patient. In general, an appropriately prescribed course of antibiotics leads to substantial clinical improvement within a few days.

Additional Therapies Supplements Bovine spleen extracts: hydrolyzed (predigested) products concentrated for tuftsin and splenopentin content are preferable to crude preparations50 mg/day tuftsin and splenopentin or roughly 1.5 g/day of total spleen peptides Bromelain (1200 to 1800 MCU): 500 to 750 mg tid between meals

Botanical Medicines Hydrastis canadensis The dosage should be based on berberine content. Because of a wide range of quality in goldenseal

1.Centers for Disease Control and Prevention. National vital statistics

reports, vol52, no 9, November 7,20039. 2. Branch WT Jr. Office practice of medicine. Philadelphia: Saunders, 198257-76.

preparations, standardized extracts are recommended. The following dosages are for three times a day: Dried root or as infusion (tea): 2 to 4 g Tincture (1:5): 6 to 12 ml(1.5 to 3 tsp) Fluid extract (1:l):2 to 4 ml(0.5 to 1 tsp) Solid (powdered dry) extract (43 or 8-12% alkaloid content): 250 to 500 mg

Garlic A commercial garlic product should provide a daily dose equal to at least 4000 mg of fresh garlic, which translates to at least 10 mg alliin or a total allicin potential of 4000 pg (see Chapter 65).

Antibiotic Patients should take 500 mg penicillin V four times/day (for uncomplicated cases).

DIAGNOSTIC SUMMARY Onset typical of influenza: fever, myalgia, and headache Other symptoms, signs, and x-ray findings similar to mycoplasmal pneumonia

THERAPEUTIC CONSIDERATIONS In addition to the treatment recommendations given under the general discussion of pneumonia, G. glubru is useful for its antiviral properties, immune-enhancing effects, and expectorant effects (see Chapter 99). However, it has some antitussive effect. In the case of viral pneumonia, this action is usually warranted. However, if the cough is productive, lobelia should be used.

Additional Therapy G. glubru:

Powdered root: 1to 2 g Fluid extract (1:l):2 to 4 ml Solid (dry-powdered) extract (4:l): 250 to 500 mg

3. Nuorti JC, Butler JC, Farley MM, et al. Cigarette smoking and invasive pneumococcaldisease. N Engl J Med 2000;342.681-689. 4. Niimi A, Matsumoto H, Ueda T, et al. Impaired cough reflex in patients with recurrent pneumonia. Thorax 2003;58:152-153.

Specific Health Problems 5.Cambar PJ, Shore SR, Aviado DM. Bronchopulmonary and gastrointestinal effects of lobeline. Arch Int Pharmacodyn 1969;177: 1-27. 6. Bicknell F, Prescott F. The vitamins in medicine. New York Grune & Stratton, 1953. 7.Hunt C, Chakravorty NK, Annan G, et al. The clinical effects of vitamin C supplementation in elderly hospitalized patients with acute respiratory infections. Int J Vitam Nutr Res 1994;64: 212-219. 8. Stephensen CB, Alvarez JO, Kohatsec J. Vitamin A is excreted in the urine during acute infection.Am J Clin Nutr 1994;60.8&92. 9. Hussey GD, Klein M. A randomized, controlled trial of vitamin A in childxm with severe measles. N Engl J Med 1990;323160-164. 10. Kjolhede CL,Chew FJ,Gadomski AM, et al. Clinical trial of vitamin A as adjuvant treatment for lower respiratory tract infections. J Pediatr 1995;126807-812. 11. Bhandari N, Bahl R, Taneja S, et al. Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum. BMJ 2002; 3241358. 12.Nagibina MV, Neifakh EA, Krylov VF, et al. The treatment of pneumonias in influenza using antioxidants. Ter Arkh 1996;68: 33-35. 13.Kelly GS. Bromelain. A literature review and discussion of its therapeutic applications. Altem Med Rev 1996;1:243-257. 14. Rimoldi R, Ginesu F, Giura R. The use of bromelain in pneumological therapy. Drugs Exp Clin Res 1978;4:55-66. 15. Bjorkqvist M, Wiberg B, Bodin L, et al. Bottle-blowing in hospitaltreated patients with community-acquiredpneumonia. Sand J Infect Dis 1997;29:77-82. 16. Mundy LM, Leet TL, Darst K, et al. Early mobilization of patients hospitalized with community-acquired pneumonia. Chest 2003; 124883-889.

17. Westerdahl E, Lindmark B, Almgren So,et al. Chest physiotherapy after coronary artery bypass graft surgery-a comparison of three different deep breathing techniques. J Rehabil Med 20013379-84. 18.Jain A. Influence of vitamins and trace-elements on the incidence of respiratory infection in the elderly. Nutr Res 2002;2285-87. 19.Bauer T, Ewig S, Marcos MA, et al. Streptococcus pneurnoniae in community-acquired pneumonia. How important is drug resistance? Med Clin North Am 2001;85:1367-1379. 20. Cunha BA. Clinical relevance of penicillin-resistant Streptococcus prieunroniae. Semin Respir Infect 2002;17204214. 21. Garau J. Treatment of drug-resistant pneumococcal pneumonia. Lancet Infect Dis 2002;2404-415. 22. Felmingham D. Evolving resistance patterns in communityacquired respiratory tract pathogens: first results from the PROTEKT global surveillance study. Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin. J Mect 2002;44(~~ppl A):3-10. 23. Jacobs MR, Felmingham D, Appelbaum PC, et al. The Alexander Project 1998-2oOO:susceptibility of pathogens isolated from community-acquired lower respiratory tract infection to commonly used antimicrobial agents. J Antimicrob Chemother 2003;52229-246. 24. Minter MM. Agranulocytic angina: treatment of a case with fetal calf spleen. Texas State J Med 1933;233&343. 25.Gray GA. The treatment of agranulocybc angina with fetal calf spleen. Texas State J Med 1933;29:366-369. 26.Greer AE. Use of fetal spleen in agranulocytosk preliminary report. Texas State J Med 1932;28:338-343. 27. Hahn F, Ciak J. Berberine. Antibiotics 197633577-584. 28. Sivam GP. Protection against Helicobacter pylori and other bacterial infections by garlic. J Nutr 2001;131:1106S1108S. 29. Dikasso D, Lemma H, Urga K, et al. Investigation on the antibacterial properties of garlic (Allium sativunt) on pneumonia causing bacteria. Ethiop Med J 2002;40241-249.

Porphyrias Thomas A. Kruzel, ND CHAPTER CONTENTS Diagnostic Summary 2045 General Considerations 2045 Classifications of Porphyria 2045 Signs and Symptoms of Hepatic Porphyria 2046 Biochemistry of Porphyria 2046 Heme Formation 2046 Porphyria Manifestation 2047 Etiologic Agents Triggering Porphyria 2047 Laboratory Diagnosis of Porphyria 2048

DIAGNOSTIC SUMMARY Unexplained abdominal pain, possibly including nausea and vomiting Acute peripheral or central nervous system dysfunction Mental abnormalities can range from confusion to acute psychosis Urinary porphobilinogen during attack The majority of carriers are usually asymptomatic except when exposed to drugs or chemicals, which exacerbate the condition

GENERAL CONSIDERATIONS Until recently, cases of porphyrias have been considered rare. It has only been within the past decade or so that an increasing number of patients have been diagnosed with this disorder, leading some clinicians to question their prevalence. Although allopathic medicine offers therapies that are effective in treating these disorders, naturopathic medicine possesses a considerable array of therapeutic modalities that are effective in combating the disease and preventing recurrence. Porphyria as a disease was first described three centuries ago by Sir Theodore Turquet de Mayerne of France, physician to the English court of King James I. He described accounts of paralysis, bilious urine, colic, insanity fits, permanent insanity, deaths at childbirth,

Therapeutic Considerations 2049 Diet 2049 Antioxidants 2049 B-Complex 2050 Carotenoids 2050 Iron 2050 Detoxification 2050 Constitutional Hydrotherapy 2051 Ozone Therapy 2051 Therapeutic Approach 2051 Diet 2051 Supplements 2051

and premature death in those afflicted. The disease probably afflicted King George III of England and was thought to have impaired his judgment during the American Revolution.' In 1911 G h t h e r described what is now known as the classic triad of abdominal pain, constipation (or diarrhea), and vomiting. Waldenstrom later added to the understanding of the diseases by describing acute intermittent porphyria (AIP) as characterized by periods of exacerbation and remission.2 Various classifications of porphyria were arrived at as greater recognition of their variations occurred. Genetic and environmentally induced manifestations of the disease were found, with considerable variation in the clinical presentation of the different forms. The genetic deficits of porphyria affect all tissues but primarily the hematopoietic-forming tissues of the bone marrow and the cytochrome P-450system in the liver because of the greater number of porphyrin precursors required. The liver is the major site where inherited or acquired deficits in heme synthesis manife~t.~

Classifications of Porphyria Porphyrias are classified as being either hepatic or erythropoietic in origin. In both classes they are characterized by the overproduction of porphyrin or their precursors. Biosynthesis of heme is controlled differently in liver and bone marrow with the rate-limiting enzyme in liver being 2045

BIOCHEMISTRY OF PORPHYRIA Hepatic Porphyrias

Erythropoletic Porphyrias

AM-dehydrase-deficiency porphyria Acute intermittent porphyria Porphyria cutanea tarda Herediiary coproporphyria Variegate porphyria X-linked sideroblastic anemia Congenital erythropoietic porphyria Erythrocytic protoporphyria

Modified from Braunwald E, ed. Hamson’s principles of internal medicine, ed 15. New Yo& McGraw-Hill, 2001. A M . Aminolevulinic acid.

aminolevulinic acid (ALA) synthase, while the biosynthesis of heme in the bone marrow is partly regulated by the uptake of iron. Acute hepatic porphyrias are characterized by a rapid onset of symptoms that are largely neurologic, while the erythropoietic variety manifests primarily in the skin leading to cutaneous photosensitivity (Box 203-1).

Signs and Symptoms of Hepatic Porphyrias Acute attacks consist of a wide variety of symptomology ranging from skin lesions to abdominal pain to neurologic manifestations of varying degrees of intensity. Abdominal, back, or extremity pains grow in intensity over a 2 4 to a h o u r period, which may lead the clinician to consider appendicitis or an acute abdomen. Rebound tenderness is not usually present. Nausea and vomiting are frequently seen, as is anxiety and restlessness. Often these patients have some degree of constipation that worsens as the condition develops. Tachycardia may also be present, suggesting an infectious process or an increase in bowel toxicity. In general, the severity of the symptom pattern seems to the clinician to be out of proportion to the presenting signs. It is thought that the bowel symptoms are due to a neurologic disturbance of normal function. Mental abnormalities can range from confusion to acute psychosis and be the first presentations of an attack. With prolonged attacks, sensory and motor functions are impaired and can result in respiratory paralysis and death.5 Many patients are diagnosed with schizophrenia, and a considerable number confined to mental institutions are thought to be afflicted with one of the porphyrias.6,7 The majority of carriers are usually asymptomatic except when they are exposed to drugs or chemicals that exacerbate the condition. Neurologic symptoms and the sequelae of an acute or prolonged attack can take months to clear, but eventual recovery occurs in the majority of cases.

Biosynthesis of heme is the main purpose for the porphyrogenic pathway. Heme, a large-molecular-weight metalloprotein, is a member of a group of chemicals that include cy tochromes (oxidation/ reduction reactions), chlorophyll (photosynthesis), and vitamin BI2. Heme is formed from succinyl coenzyme (CoA) and glycine and is ultimately involved in aerobic metabolism after it is combined with globin chains. These globin chains are synthesized on the ribosomes in the plasma of the developing erythrocyte. In the liver, heme production is largely used for the production of cytochrome P-450 in response to the toxic substances that the body needs to eliminate. Heme synthesis begins and ends in the mitochondrion with part of it occurring in the cytoplasm. All tissues form heme, but the primary sites are the bone marrow and liver. The rate-limiting enzyme for heme synthesis is ALA synthase, which is the initial enzyme in the cascade. ALA synthase requires vitamin cofactors and energy input. All other reactions in the sequence are the result of thermodynamics and are irreversible once initiated. ALA synthase is regulated by a feedback mechanism that is responsive to the tissues’ demand for heme production. With the formation of uroporphyrinogen, branching occurs and results in different porphyrin isomers. Isomer I proceeds only as far as coproporphyrin I and normally is considered inconsequential. Isomer I11 results in the formation of uroporphyrinogen III, which undergoes modification to render it more lipophilic so that it can be excreted from the body. Thus the majority of the pathway favors heme production.

Heme Formation Final heme formation is regulated by the action of ferrochelatase in the mitochondria. Reducing substances such as ascorbic acid, cysteine, or glutathione are required. Iron must be in the ferrous rather than ferric form. Ferrochelataseactivity is inhibited by high concentrations of heme. Thus the feedback system prevents further formation. Heme concentration also feeds back on ALA synthase, the rate-limiting step in the biosynthetic pathway. As heme formation is essential for aerobic metabolism, its absence would be lethal. Therefore multiple control systems have evolved to regulate the metabolic pathway, which has made it difficult to elucidate the exact mechanism of the deficit, be it genetic or acquired. Recent advances in identifying specific DNA encoding the heme biosynthetic enzymes, however, has resulted in a more precise diagnosis of the specific genetic deficit. Red blood cell (RBC)incorporation of heme, iron, and glycine occurs in maturing cells up through and including reticulocytes but is eventually lost as the red cell ages. Hypoxia and erythropoietin will increase ALA

Porphyrias Glycine + Succinyl CoA

Enzyme

\1 -4 -4

6-Aminolevulinic Acid

, lHydroxymrthylbilane, (Nonenzymatic

I

Uroporphyrinogen I

\1

I

Uroporphyrinogen 111

444-

Coproporphyrinogen I Coproporphyrinogen 111

Major Symptoms

i Accumulation Products

Urinary ALA

6-Aminolevulinate Dehydratase

ALA-DehydraseDeficiency Porphyria

Neurovisceral

Porphobilinigen Deaminase

Acute Intermittent Porphyria

Neurovisceral

Urinary A M and PBG

Uroporphyrinogen 111 Cosynthase

Congenital Erythropoietic Porphyria

Photosensitivity

Erythrocyte and Urinary Uroporphyrin I and Coproporphyrin I

Uroporphyrinogen Decarboxylase

Photosensitivity Porphyria Cutanea Tarda; Hepatoerythropoietic Porphyria

Coproporphyrinogen Oxidase

Hereditary Coproporphyria

-

Porphobilinogen

Disease

Urinary 7-Carboxylate Porphyrin; Fecal lsocoproporphyrin

~

Neurovisceral and Photosensitivity

Urinary ALA, PBG, and Coproporphyrin; Fecal Coproporphyrin

Protoporphyrinogen IX

Protoporphyrin IX Fe2+y

Protoporphyrinogen Oxidase Ferrochelatase

J/ Heme

Photosensitivity Erythropoietic Protoporphyria

Photosensitivity

Urinary ALA and PBG; Fecal Protoporphyrin Erythrocyte, Plasma, and Fecal Protoporphyrin

Figure 203-1 The heme synthesis and porphyria. (From Sassa S,Kappas A. The porphyrias. Scientific American Medicine. New York: Scientific American. 2003:9:V:1-9.)

synthase activity in RBCs but not liver, while drugs and chemicals will affect liver but not erythropoietic tissues. Figure 203-1 shows heme synthesis and porphyria.

PORPHYRIA MANIFESTATION Specific genetic or acquired deficiencieslimit the flow of heme precursors through the cascade of steps needed to form hemoglobin. The deficiency can become manifest due to an increased demand for heme precursors. Certain drugs, chemicals, steroids, estrogens, oral contraceptives, progesterone, testosterone, or any substance that places an excess burden on the cytochrome P-450 system can act to precipitate an acute attack. This results from the partial removal of the feedback mechanism on delta-ALA synthase. Depending on the specific enzyme deficit present, heme precursors follow different pathways resulting in their accumulation in the tissues. Their presence affects the skin and nervous system and manifests as the signs and symptoms of the disease. Attacks o c m more frequently in women than men, especially premenstrudy. As the person ages, the likelihood of exposure of an underlying porphyria deficit increasesbecauseof increased exposures to environmental toxins and the aging body's decreasing ability to adapt. Cutaneous manifestations occur because some porphyritic precursors absorb light at 400 nm, resulting in photosensitivity. Absorption of light causes a raising of the potential energy of the molecule to an "excited state,

resulting in a highly reactive oxygen species. A histamine and proteolytic enzyme release resulting in oxidative damage follow. Beta-carotene protects against these inj~uies.3,~B Neuropsychiatric changes occur in the hepatic porphyrias (ALA-dehydrase-deficiency porphyria, AIP, porphyria cutanea tarda, hereditary coproporphyria, and variegate porphyria) with excess production of ALA and porphobilinogen (PBG), and there is a somewhat linear relationship between their concentration and the severity and duration of symptoms. A buildup of porphyrin intermediaries has been found in various tissues and may induce the neuropsychiatric symptoms accompanying acute flare-up~.~J~ The exact mechanism of how porphyrins affect the central nervous system is not well understood. Patients with familial porphyria cutanea tarda (PCT) usually present at a younger age than patients who spontaneously develop PCT despite there being no difference in biochemical features of the disease." This may be due to a corresponding genetic predisposition to sequestering ferritin in the liver or due to an increased sensitivity to ethanol ingestion.11J2Additionally, even in families with known genetic deficits, manifestations of the disease among family members vary.

Etiologic Agents Triggering Porphyria Numerous agents that trigger an episode of porphyria have been identified, and patients afflicted must be

Specific Health Problems careful when taking prescription medications, estrogens, some herbal medicines and of environmental exposures to heavy metals, organo-phosphates, or any substance that places an excess burden on the cytochrome P-450 system. In particular, exogenous estrogens, whether oral contraceptives, estrogen patches, or with estrogen replacement therapy, are strong contributors to an underlying porphyria defi~it.’~.’~ This is one reason why acute porphyria attacks are seen more often in women than men, especially premenstrually. Additionally, some studies have suggested that estrogens enhance the porphyrininducing activities of other agents, making women more vulnerable to environmental exposures than their male ~ounterparts.’~J~ Herbicide-induced porphyria has been shown to decrease activity of several enzymes involved in the porphyritic pathway, as well as increase the porphyrin A considerable number of content in nerve ti~sue.’~,’~ chemicals have also been linked to porphyria or porphyrinuriain humans and generally involve chronic industrial exposures or environmental exposures. An example of an epidemic of PCT produced by accidental ingestion of wheat treated with the fungicide hexachlorobenzene occurred in Turkey in the 1950s. Some researchers have hypothesized that several otherwise unexplained chemical-associated illnesses such as multiple chemical sensitivity syndrome (MCSS) may represent mild chronic cases of porphyria or other acquired abnormalities in heme synthesi~.’~,’~ According to William Morton, MD, who has written extensively on porphyrias, MCSS as first described by Cullen in 1979 may, in fact, be porphyria. Morton speculates that exposures to porphyrogenic chemicals, medications, or severe infection overpower the already deficient enzyme system, resulting in accumulation of the specific porphyrin because of diminished enzyme function. He proposed that the resultant symptoms are due to an increase of the porphyrinogen and not an accumulation of the toxin itself. Many diagnosticians have tried to expedite the distinction between “real” porphyria and secondary porphyrinopathies by requiring that a porphyria diagnosis be based on urinary or fecal porphyrin excretions, or both, 2 to 20 times the upper limit of normal. This classification would exclude individuals demonstrating lesser degrees of porphyrinogenic activity, possibly some of those whose conditions are in remission or not subject to environmental Intensities of porphyria symptoms vary widely. About 10% of the cases present with acute severe attacks, while approximately 25%are seen with chronic symptomology of varying degrees. The remaining percentage (65%)presents with no symptomology but may become susceptible under the right Not all researchers agree with Morton’s and others’ premise that environmental toxicities induce underlying

genetic deficits leading to symptomatic porphyria. According to Hahn and Bonkovsky, “patients with multiple chemical sensitivity syndrome may, at times, have modest increases in urinary coproporphyrin excretion; this is a common finding found in many asymptomatic subjects or patients with diverse other conditions (e.g., diabetes mellitus, heavy alcohol use, liver disease, and many kinds of anemia). Such secondary coproporphyrinuria does not indicate the existence of coproporphyria.”22 Regardless of which ”school of thought” is correct, an increasing number of cases are being diagnosed by clinicians. Certainly, with the increasing levels of pollutants in the environment, hormonal additives to the food chain, and the unmonitored multiple pharmacy prescriptions encountered by most humans, the potential for unmasking an underlying deficit increases.

LABORATORY DIAGNOSIS OF PORPHYRIA Small amounts of porphyrins are excreted in normal human urine, the most predominant of which is coproporphyrin. Coproporphyrin is also present in the bile and feces. ALA, PBG, and uroporphyrin are largely excreted in the urine, while coproporphyrin is preferentially and protoporphyrin exclusively excreted in the bile and feces. Fecal excretion is also affected by diet and bowel flora, thus contributing to its wide variation. Geographic distribution, dietary preferences, ethnic diversities, and differences in test methodologies make it difficult to arrive at “normal” values. PBG excretion in the urine of healthy individuals is usually below 1.5 mg/day and is undetectable by conventional testing. The Watson-Schwartz qualitative test for PBG will be positive in AIP in acute attacks and variegate porphyria and hereditary coproporphyria in latent periods.= There is a high false-negative rate due to its subjective nature. A false increase in porphyrins from a substance present in yeast tablets has been demonstrated to provide a false-positive Watson-Schwartz test.” A cost-effective strategy for diagnosis of porphyric syndromes when presented with acute symptoms has been suggested: “If neurovisceral features suggest an acute porphyric syndrome, a rapid screening test for urinary porphobilinogen should be performed. If clinical features suggest a cutaneous porphyria, then for solar urticaria and acute photosensitivity (suggesting protoporphyria) screening tests for increased erythrocytic porphyrins should be done; for vesiculobullous formation (suggesting porphyria cutanea tarda, hereditary coproporphyria, or variegate porphyria) a screening test for urinary porphyrins should be done. Positive screening tests should be confirmed with targeted quantitative testing.”25 Enzymatic assays and DNA-based testing are not usually necessary for rapid diagnosis or management of symptomaticsubjects when presented with acute disease.

Porphyrias

They are, however, useful for evaluation and genetic counseling. Isolation of specific DNA encoding the heme biosynthetic pathway enzymes makes it possible to now provide precise heterozygote identification, as well as prenatal diagnosis in families with known defe~ts.4,~~,~~ Other cell markers may also help in identifymg porphyria patients in the absence of symptomology. Leukocyte concentrations of manganese, calcium, iron, zinc, and erythrocyte calcium have been shown to be present at different concentrations between groups classified as AIP gene carriers. Of the cell markers, manganese was found to be the most discriminative component of all the variables investigated. An increase in cellular manganese by a factor of four suggests an increase in the likelihood of development of AIP?7 Because of the many possible genetic deficits leading to porphyria, it is important that the specific deficit is determined, as successful treatment outcomes depend on the correct diagnosis. See also Chapter 31 for more discussion of the diagnosis of porphyrinopathies.

THERAPEUTIC CONSIDERATIONS Identification of those patients predisposed and susceptible to the development of porphyritic episodes is important. Patients with a past medical history of periodic psychotic episodes or nervous breakdowns, unexplained abdominal pains, or unusual symptoms that have led to numerous diagnoses should alert the physician to the possibility of an underlying porphyria. Prevention is clearly the first option, as porphyritic episodes can be difficult to control once initiated.28 Treatment of patients afflicted with acute episodes can be quite demanding on the physician and difficult to manage due to the severity and frequently changing clinical picture. Each patient presentation is different depending on the degree of toxicity, genetic component, and patient response to therapy. Homeopathic treatment has proven successful, but different homeopathic medicines are required depending on the clinical picture, which, as has been mentioned, can often change quickly. Constitutionalprescribing does not seem to work as well while the person is in an acute state, and several prescriptions may be necessary for the patient to stabilize. The prescriptions may need to be changed frequently as the patient progresses through the varying stages of the disease. During an acute episode, frequent follow up is necessary in order to assess the clinical state. In some cases, patients must be seen daily and medications altered depending on the presentation. Education of the patient as to his or her condition is one of the most important tasks. Often the patient

does not want to believe a genetic affliction exists and seeks another diagnosis. He or she has often received various diagnoses and may still believe this condition is another disorder. It will be important to delineate which symptoms go with each condition, but they will all probably be related to the porphyria. Additionally, informing other physicians the patient is seeing as to his or her condition will help keep prescription drugs to a minimum, thus decreasing the likelihood of an exacerbation. The course of therapy in order for the patient to reach a state where he or she is not as susceptible to environmental toxins is usually long and has periods of exacerbations and remissions. Helping the patient to understand this will assist the recovery. Eliminate environmental and chemical exposures by identifymg offending agents and limiting exposures. Lists of prescription medicines and environmental toxins that cause exacerbation of porphyria are available (Boxes 203-2 and 203-3). A complete history as to environmental and work-related exposures is in order. Often, simply changing the patient's work environment will decrease exposure, eliminating attacks.

Diet During attacks of AIP, increasing complex carbohydrates in the diet helps to alleviate symptoms. Often the patient is ingesting high amounts of carbohydrates when first seen, and weight gain often follows. Intravenous glucose can also be given (300 to 400 g/day). A more complete parenteral nutritional regimen is preferable, however. Fasting or rapid weight loss diets can precipitate AIP and should be avoided. A diet rich in high-fiber fruits and vegetables has been shown remarkably effective in improving several porphyria measures. A 3-week study of 13 male PCT patients found that 500 kcal/day of fruits and vegetables resulted in a signhcant decrease in body mass index from 26.8 to 25.8, serum ALT activity from 122 to 75.6 U/L, serum AST from 91.8 to 55.2 U/L, serum iron levels from 188.6 to 140.2 mg/dl, and serum ferritin concentrations from 574 to 499 ng/ml. Skin lesions also improved, and urinary coproporphyrin excretion decreased. There was a statistically insigruficant reduction in uroporphyrin excretion.30

Antioxidants Antioxidant therapy, along with homeopathy, is the mainstay of case management during acute porphyritic episodes.31Once the patient has stabilized, an ongoing regimen of antioxidants such as vitamin C, vitamin E, glutathione, beta-carotene, and N-acetylcysteine should be undertaken in order to prevent Vitamin C has been found to be low in PCT patients.33High-dose vitamin E supplementation (1 g/day alpha-tocopherol) in patients with PCT decreased urinary excretion of

Specific Health Problems uroporphyrins (50% of the C8 carboxyls) with clinical improvement in all patients.MThe effect lasted only as long as vitamin E was being supplemented. Intoxications Alcoholism Foreign and environmental chemicals (e.g., hexachlorobenzene, polyhalogenated biphenyls, dioxins [2,3,7,8-tetrachlorodibenzo-pdioxin], vinyl chloride, carbon tetrachloride, benzene, chloroform) Heavy metals such as lead, arsenic, and mercury Drugs Adverse effect of drugs Analgesics Sedatives Hypnotics Anesthetics Sex hormones Sulfadrug antibiotics

Antipyrine Aminopyrine Aminoglutethimide Barbiturates Captopril Carbamazepine Carbromal Chloral hydrate Chloramphenicol Chlordiazepoxide Chlorpropamide Danazol Dapsone Diazepam Diclofenac Diltiazem Diphenhydramine Diphenylhydantoin Doxycycline Ergot preparations Erythromycin Estrogen Ethanol (acute) Ethchlorvynol Ethinamate Furosemide Glutethimide Griseofulvin Hydralazine Hydrochlorothiazide lmipramine lsopropylmeprobamate Lidocaine Mephenytoin Meprobamate Methyldopa

Methylprylon Metoclopramide Metronidazole N-butylscopolammaonium bromide Nifedipine Nitrous oxide Novobiocin Oral contraceptives Orphenadrine Oxycodone Pentazocine Phenobarbital Phenylbutazone Phenytoin Piroxicam Pivampicillin Primidone Progesterone Pyrazimide Pyrazolone preparations Sodium valproate Succinimides Sulfonamide antibiotics Sulfonethylmethane Sulfonmethane Synthetic estrogens, progestins Terfenadine Tetracyclines Theophylline Tolazamide Tolbutamide Trimethadione Valproic acid Verapamil

M ifrom Sassa S, Kappas A. The porphyrias. Scientific A m e i m medicine. New Yo&: Scientific American, 2003:9:V1-9. Although this list includes many of the better-known drugs that can exacehate porphyria, it should not be considered complete.

B-Complex Because pantothenic acid is required for the formation of succinyl CoA (generated by the tricarboxylic acid cycle) and glycine, which are the precursors to formation of ALA, supplementation is helpful. Additionally, a step in the transformation of succinyl CoA requires a vitamin B12-dependent enzyme, and evaluation of vitamin BI2 and folic acid status may be in order. The initial reaction is oxygen dependent, which may mean that oxygen therapy is contraindicated in delta-ALA porphyria. ALA formation requim and is dependent on pyridoxal5’-phosphate, and any substance that inhibits enzyme systems is countered in part by the addition of pyridoxal-5-phosphate. However, experimental models suggest that P5’P does not play an important role?

Carotenoids All cutaneous porphyrias can be alleviated by avoidance of sunlight. Treatment of erythropoietic protoporphyria with large doses of beta-carotene has been shown effective and may improve tolerance to sunlight.%Another study showed that mixed carotenoids (alpha-carotene, beta-carotene, and lycopene) were effective in cell cultures, while any alone were ineffective.

Iron Several lines of evidence suggest that excessive iron stores and consumption aggravate several porphyrias.% Iron should be avoided unless clearly indicated by low iron stores.

Detoxification Detoxification of the liver and colon is indicated as an ongoing process to eliminate toxins that may exacerbate the condition. Regardless of whether the toxin actually precipitates an attack of porphyria, elimination on an ongoing basis reduces the chance of an acute flare-up of the disease. Detoxification can be achieved through colon hydrotherapies, constitutional hydrotherapies, saunas, antioxidants, or oxygen therapies such as ozone. Supplementation with lipotrophic factors that enhance the function of the liver’s cytochrome P-450 system are contraindicated during acute attacks but are useful when the patient is in a period of normality. Incorporating them, as well as high doses of antioxidants, helps decrease the episodes of acute attacks. Additionally, chelation therapies with ethylenediamine tetraacetic acid and ethanol extracts of botanical medicines are contraindicated in patients with a predisposition to develop porphyria.

Porphyrias

Constitutional Hydrotherapy

THERAPEUTIC APPROACH

Constitutional hydrotherapy during an acute flare-up is effective in normalizing liver function, as well as neurologic symptoms. Daily sessions may be necessary to accomplish this while allowing the physician to monitor the patient closely3’

The primarily clinical approach is to identify the condition early and avoid imitating and aggravating factors. Sun exposure should be limited when cutaneous manifestations are present.

Ozone Therapy

The patient’s diet should be rich in fruits and vegetables and low in iron.

Ozone therapy is primarily indicated when there is a deficit of coproporphyrinogen oxidase resulting in a deficit of coporphyrinogen in hereditary coproporphyria. It is contraindicated when there is a deficit of ALA synthase, as higher amounts of oxygen enhance the pathway and exacerbate the symptoms.

1. Lofton E. Porphyrias: demons in disguise? Diagn Med October 1984;21-30. 2. Mcalpine I, Hunter R. The “insanity” of King George I11 a classic case of porphyria. Br Med J 1966;5479:65-71. 3. Meyer UA, Sdunid R. The porphyrias. In Stanbury JB, Wyngaarden JB, Fredrickson DS,eds. The metabolic basis of inherited disease,ed 4. New York McGraw-Hill, 1978:1166-1220. 4. Braunwald E, ed. Hamson’s principles of internal medicine, ed 15. New York: McGraw-Hill, 2001. 5.Ziegler T. Those nonspecific symptoms may mean porphyria. Diagn Med 1983;July/August:21-24. 6.Burgovne K, Swartz R, Ananth J. Porphyria: reexamination of psychiatric implications. Psychother Psychosom 1995;64:121-130. 7. Crimlisk HL. The little imitator-porphyria: a neuropsychiatric disorder. J Neurol Neurosurg Psychiatry 1997;62:319-328. 8. Bissell DM. Disorders of porphyrins or metals. In Wyngaarden JB, Smith LH Jr, eds. Cecil textbook of medicine, ed 18. Philadelphia: WB Saunders, 1988. 9. Meyer UA, Schuurmans Mh4, Lindberg RL. Acute porphyrias:pathogenesis of neurological manifestations. Semin Liver Dis 1998;18:43-52. 10. Krijt J, Stranska P, Maruna P,et al. Herbicide-induced experimental variegate porphyria in mice: tissue porphyrinogen accumulation and response to porphyrogenic drugs. Can J Physiol Pharmacol 1997;75:1181-1187. 11. Siersema PD, Rademakers LH, Cleton MI, et al. The difference in liver pathology between sporadic and familial forms of porphyria cutanea tarda: the role of iron. J Hepatol1995;23259-267. 12. Elder GH. Update on enzyme and molecular defects in porphyrias. PhotodermatolPhotoimmunol Photomed 1998;14:66-69. 13. Moore MR, Hift RJ. Drugs in the acute porphyrias-toxicogenetic diseases. Cell Mol Biol1997;4389-94. 14. Wetterberg L, Olsson MB, Alm-Agvald I. IEstrogen treatment caused acute attacks of porphyria.] Lakartidningen 1995922197-2198,2201. 15. Legault N, Sabik H, Cooper SF, et al. Effect of estradiol on the induction of porphyria by hexachlorobenzene in the rat. Biochem Pharmacol1997;54:19-25. 16. Krijt J, Stranska P, Maruna P, et al. Herbicide-induced experimental variegate porphyria in mice: tissue porphyrinogen accumulation and response to porphyrogenic drugs. Can J Physiol Pharmacol 1997;75:1181-1187. 17. Mylchreest E, CharbonneauM. Studies on the mechanism of uroporphyrinogen decarboxylase inhibitionin hexachlorobenzene-induced

Diet

Supplements Vitamin E: 400 to 1000 IU/day Mixed-carotenes: 100,000 to 150,000 IU/day Vitamin C: 3000 to 5000 mg/day

porphyria in the female rat. Toxic01 Appl Pharmacol 1997; 145:23-33. 18. Daniel1WE, StockbridgeHL, Labbe RF, et al.Environmentalchemical exposures and disturbances of heme synthesis. Environ Health Perspect 1997;105(suppl 1):37-53. 19.Tenhunen R, Savolainen H, Jappinen P. Changes in haem synthesis associated with occupational exposure to organic and inorganic sulphides. Clin Science 1983;64:187-191. 20. Morton WE. Chemical-induced porphyrinopathy and its relation to multiple chemical sensitivity (MCS). Proceedings of the Gordon Research Conference on Biology. Newport, RI, 1998. 21. Morton WE. Redefinition of abnormal susceptibility to environmental chemicals. In hazardous waste: impacts on human and ecological health. Princeton, NJ: Princeton Scientific Pub, 1997 320-327. 22. Hahn M, Bonkovsky HL. Multiple chemical sensitivity syndrome and porphyria. A note of caution and concern. Arch Intern Med 1997;157281-285. 23. JacobsD, Demott W, eds. Laboratory test handbook, ed 2. Baltimore: Williams & Wilkins, 1990. 24. Schoenfeld N, Sztern M, Mamet R. Yeast, creatinine and false diagnosis of porphyria. Cell Mol Biol1997;43:81-88. 25. Bonkovsky HL, Barnard GF. Diagnosis of porphyric syndromes: a practical approach in the era of molecular biology. Semin Liver Dis 1998;18:57-65. 26. Nissen, H, Petersen NE, Mustajoki S, et al. Diagnostic strategy, genetic diagnosisand identification of new mutations in intermittent porphyria by denaturing gradient gel electrophoresis. Hum Mutat 1997;9:122-130. 27. Thunell S, Andersson C, Carlmark 8, et al. Markers for vulnerability in acute porphyria. A hypothesis paper. Eur J Clin Chem Clin Biochem 1995;33:179-194. 28. Floderus Y, Harper P, Henrichson A, et al. Prevention of acute intermittent porphyria is the best solution. Most important are early diagnosis and counseling. Lakartidningen 1998;95: 3045-3050. 29. Sassa S, Kappas A. The porphyrias. Scientific American medicine. New York Scientific American, 20039:V:1-9. 30.Dabrowska E, Jablonska-KaszewskaI, Falkiewicz B. Effect of high fiber vegetablefruit diet on the activity of liver damage and serum iron level in porphyria cutanea tarda (PCT). Med Sci Monit 2001;7(~~ppl1):282-286.

Specific Health Problems 31. Bohm F, Edge R,Foley S, et al. Antioxidant inhibition of porphyrininduced cellular phototoxiaty. J Photochem Photobiol B 2001; 65177-183. 32. Thunell S, Andersson D, Harper P, et al. Effects of administration of antioxidants in acute intermittent porphyria. Eur J Clin Chem Clin Biochem 199735427433. 33.Siclair PR, Gorman N, Shedlofsky SI, et al. Ascorbic acid deficiency in porphyria cutanea tarda. J Lab Clin Med 1997;130:197-201. 34. PinelliA, Trivulzio S, Tomasoni L, et al. High-dose vitamin E lowers

urine porphyrin levels in patients affected by porphyria cutanea tarda. Pharmacol Res 2002;45355-359.

35. Badminton MN, Elder GH. Management of acute and cutaneous porphyrias. Int J Clin Prad 2002;56272-278. 36. Rocchi E, Ventura P, Ronzoni A, et al. Pro-oxidant and antioxidant factors in acute intermittent porphyria: family studies. J Inherit Metab Dis 2004;27251-266. 37.Boyle W, Saine A. Lectws in naturopathic hydrotherapy. East Palestine, OH: Buckeye Naturopathic Press,1988.

Premenstrual Syndrome Tori Hudson, ND C H A P T E R C 0 N T E N TS Diagnostic Summary 2053 General Considerations 2053 Diagnosis and Classifications 2054 Therapeutic Considerations 2054 Estrogen Metabolism 2055 Dietary Considerations 2056

DIAGNOSTIC SUMMARY Recurrent signs and symptoms that develop during the late luteal phase of the menstrual cycle and disappear by the end of the full flow of menses Typical symptoms are: decreased energy, tension, irritability, depression, headache, altered sex drive, breast pain, backache, abdominal bloating, and edema of the fingers and ankles.

GENERAL CONSIDERATIONS Premenstrual syndrome (PMS) refers to the cyclic constellation of troublesome symptoms that appears during the luteal phase of the menstrual cycle-more so in the late luteal phasdisappear by the end of the full flow of menses, and do not appear during the follicular phase.' Although some 150 symptoms have been listed as premenstrual, the most common symptoms are as follows (see also Box 204-1): Decreased energy Tension Irritability Anger Food cravings Depression Headache Altered sex drive Breast pain Muscle aches

Hormone Therapy 2057 Stress, Endorphins, and Exercise 2058 Nutritional Supplements 2058 Botanical Medicines 2061

Therapeutic Approach 2062 Nutritional Supplements 2063 Botanical Medicines 2063

Abdominal bloating Edema of the fingers and ankles PMS is estimated to affect between 30% and 40% of menstruating women; 80% of women experience premenstrual emotional or physical changes but do not have much difficulty. Peak occurrence is among women in their 30s and 40s. In most cases symptoms are relatively mild; however, in about 2.5% to 5% of women symptoms can be severe enough to have a negative impact on the women's lives, putting home life and work in jeopardy. Severe PMS with depression, irritability, and severe mood swings is referred to as premenstrual dysphoric disorder (PMDD)2and has a separate diagnostic category in the Diagnostic and Statistical Manual of Mental Disorders (DSM). Although PMS has been a well-defined clinical entity for more than 60 years, some physicians still argue that it really does not exist.3As a result many women suffering from PMS do not receive proper treatment. Until the advent of therapy with selective serotonin reuptake inhibitors (SSRls), conventional mainstream medicine had not been able to offer women a known cause for PMS nor has it been able to offer satisfactory interventions.Women were by and large left to self-care or to seek the advice of alternative medicine practitioners. The etiology of PMS has not yet been fully understood, but endocrine studies have clarified that the premenstrual symptoms are not a result of a simple excess or deficiency of any given hormone? Several theories have been proposed to explain the causes of PMS, and 2053

Specific Health Problems

Behavioral: Nervousness, anxiety, and irritability Mood swings and mild to severe personality change Fatigue, lethargy, and depression Gastrointestinal: Abdominal bloating Diarrhea and/or constipation Change in appetite (usually craving of sugar) Female: Tender and enlarged breasts Uterine cramping Altered libido General: Headache Backache Acne Edema of fingers and ankles

the current strongest is the interaction of the ovarian steroids and the brain neurotransmitters. Genetic predispositions and sociocultural beliefs about menstruation may also influence what women experience. At present, the dominant thinking is that cyclic changes in the ovarian steroids estrogen and progesterone cause changes in many body systems, including brain neurotransmitters, which then have emotional and physical manifestat i o n ~ Therefore, .~ normal ovarian function, and not a true hormonal imbalance, triggers the central nervous system and predisposes a woman to hormone-induced instability.'j We do not currently know why the extent of sensitivity to the ovarian steroid-induced neurotransmitter changes varies in different women. Of the neurotransmitters studied, serotonin is the principal one implicated in the pathogenesis of PMS and PMDD.7*s Whether PMS and PMDD are related to absolute levels or reduced blood levels of serotonin or to serotonin transport remains unclear? Other neurotransmitter systems may also be involved in PMS and PMDD. They include the adrenergic, opioid, and gamma-aminobutyric acid (GABA) systems. Research over the last 10 years has shown that serotonin agents can alleviateboth the psychologicaland physical symptoms in most women with PMDD. Fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and venlafaxine have all been found to be sigruficantlymore effective than placebo for treatment of PMDD.

To aid in the diagnosis, symptom questionnaires are often used. Recalled information is less accurate, so in addition to a symptom questionnaire, it is a good idea to have the patient keep a menstrual symptom diary. The diary helps document improvement as well as further clarlfy the symptom pattern. The key defining feature of both PMS and PMDD is the timing of the symptoms. Symptoms appear only during the luteal phase and disappear before or during menstruation. Fundamental to making the diagnosis is to rule out other psychiatric and medical disorders. The clinician should obtain a medical and psychiatric history and be aware that many mental and physical disorders mimic premenstrual symptoms as well as coexist with them. The results of the medical, psychiatric, and psychosocial evaluations, along with the symptom diary offered by the patient, help the clinician determine whether the symptoms represent PMS or PMDD, a psychiatric or medical illness only, coexisting PMS or PMDD and another illness, or premenstrual exacerbation of an underlying psychiatric or medical illness. Only one of the following symptoms is required for a diagnosis of PMS: mild psychological discomfort, bloating and weight gain, breast tenderness, swelling of hands and feet, various aches and pains, poor concentration, sleep disturbance, and change in appetite. The symptoms must (1) occur only in the luteal phase, (2) peak close to menstruation, and (3) subside at the onset of menses or during menstrual flow. A diagnosis of PMDD is reserved for women who have at least five of the following symptoms, at least one of which is a core symptom, and which occur during the luteal phase and remit with menses or a few days after the onset of menses for at least two cycles: Depressed mood or dysphoria (core symptom) Anxiety or tension (core symptom) Affective lability (core symptom) Irritability (core symptom) Decreased interest in activities Poor concentration Lack of energy Change in appetite, overeating, or food cravings Hypersomnia or insomnia Feeling overwhelmed Additional physical symptoms (breast tenderness, bloating, headache, joint or muscle pain)

THERAPEUTIC CONSIDERATIONS DIAGNOSIS AND CLASSIFICATIONS Diagnosis of PMS is usually made through the association of the symptoms attributed to PMS with their occurrence during the luteal phase of the menstrual cycle.

Even though we now have proof that there is no frank increase or decrease in serum estrogen or progesterone levels, one should still consider a possible relative excess in terms of its effect on the central nervous system.

Premenstrual Syndrome

Owing to the lack of scientificunderstanding in this area and the clinical experience in improving estrogen metabolism in women with PMS, we should still recall some clinical considerations from the past.

Estrogen Metabolism In the early 1940s, Dr. Morton Biskind observed an apparent relationship between B vitamin deficiency and PMS.'OJ He postulated that PMS, as well as excessive menstruation and fibrocystic breast disease, was due to an excess in estrogen levels caused by decreased detoxification and elimination in the liver as a result of B vitamin deficiency. The liver utilizes various B vitamins to detoxify estrogen and excrete it in the bile. There appears to be support for Dr. Biskind's theory. Estrogen excess is known to produce cholestasis, a term that signifies diminished bile flow or stasis of bile. Naturopathic physicians often refer to this condition as a "sluggish liver." It reflects minimal impairment of liver functionbecause normal indicators of liver status (such as concentrations of liver enzyme alkalines phosphatase, serum glutamic-oxalo-acetic transaminase [SGOT], serum glutamate pyruvate transaminase [SGPT], and gamma-glutamyl-transpeptidase [GGlT]) are not elevated. These enzyme measurements, the conventional means of assessing liver status, are not very useful as they really only indicate liver damage, being elevated only when the liver is damaged. They have little correlation with liver function. Because of the liver's important role in numerous metabolic processes, even minor impairment of liver function can have profound effects. Cholestasis can be caused by a large number of factors besides estrogen excess (Box 204-2). The presence of cholestasis may be a predisposing factor in PMS, because with cholestasis there is reduced estrogen detoxification and clearance. Hence, a positive feedback scenario is produced. The high incidence of gallstones is a clear indication that many American women suffer from cholestasis. Again, even though elevated serum estrogen values cannot be confirmed in PMS studies, it is interesting to note that estrogen excess during the luteal phase

Estrogen excess or birth control pills Pregnancy Presence of gallstones Alcohol Endotoxins Hereditary disorders such as Gilbert's syndrome Anabolic steroids Various chemicals and drugs Nutritional deficiencies

negatively affects endorphin levels. One study found a direct correlation between an increased estrogen/ progesterone ratio and endorphin activity in the brain.'* In essence, when the estrogen/progesterone ratio was increased there was a decline in endorphin levels. This reduction is sigruficant, considering the known ability of endorphins to normalize or improve mood. Other studies have shown that low endorphin levels during the luteal phase are common in women with PMS.I3 Endorphins are lowered by stress and raised by exercise. The role of endorphins is further discussed later.

Estrogen Impairs Vitamin B6 The way in which estrogen levels during the luteal phase negatively affects neurotransmitter and endorphin levels may be secondary to impairment of vitamin B6 action. It is well known that estrogens negatively affect vitamin B6 function. Vitamin B6 levels are typically quite low in depressed patients, especially women taking estrogens (birth control pills or conjugated estrogens [P~-ernarin]).'~,'~ Vitamin B6 supplementation has been shown to have positive effects on all PMS symptoms (particularly depression) in many women (discussed in greater detail later). The improvement is achieved via a combination of a reduction in midluteal estrogen levels and an increase in midluteal progesterone levels.

Gut Microecology One of the key ways in which the liver detoxifies cancercausing chemicals as well as the body's hormones, such as estrogen, is via attaching glucuronic acid to the toxin and excreting it in the bile. Beta-glucuronidase is a bacterial enzyme that uncouples (breaks) the bond between excreted toxins and glucuronic acid. Not surprisingly, a high beta-glucuronidase activity is associated with a greater cancer risk, particularly estrogen-dependent breast cancer, and presumably PMS. The activity of this enzyme can be reduced by establishment of a proper bacterial flora.16 The dietary guidelines go a long way toward this goal. In addition, supplementation with probiotics helps establish a normal intestinal flora. Probiotics, literally translated, means "for life," and is a term used to signify the health-promoting effects of "friendly bacteria.'' The most important friendly bacteria are Lactobacillus acidophilus and Bifidobacterium bifidum. Prebiotics and probiotics are discussed in depth in Chapters 117 and 118. The dosage of a commercial probiotic supplement is based on the number of live organisms. The ingestion of 1 billion to 10 billion viable L. acidophilus or B. bifdum cells daily is a sufficient dosage for most people. Larger amounts may induce mild gastrointestinal disturbances, and smaller amounts may not be able to colonize the gastrointestinal tract. Probiotics are extremely safe and are not associated with any side effects.

Specific Health Problems

Liver Detoxification Supporting liver function focuses on protecting the liver by following a diet that is low in saturated fats and trans fats, high in plant foods such as vegetables, fruits, legumes, whole grains, nuts, and seeds, and low in sugar and white flour products. In addition, most naturopathic physicians often use formulas containing “lipotropic factors.” By definition, lipotropic factors are substances that hasten the removal or decrease the deposition of fat and bile in the liver through their interaction with fat metabolism. In essence, they have a “decongesting” effect on the liver and promote liver function and fat metabolism. Compounds commonly employed as lipotropic agents include choline, methionine, betaine, folic acid, and vitamin BIB along with herbal cholagogues and choleretics. Most major manufacturers of nutritional supplements offer lipotropic formulas. The typical daily doses are 1000 mg of choline and 500 mg of methionine and/or cysteine.

Environmental Estrogens Widespread environmental contamination has occurred with a group of compounds known as halogenated hydrocarbons. Included in this group are the toxic pesticides dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethane(DDE), polychlorinated biphenyl (PCB), polychlorinated phenols (PCP), dieldrin, and chlordane. These molecules are hard to break down and are stored in fat cells. They mimic estrogen in the body and are thought to be a major factor in the growing epidemics of estrogen-related health problems such as PMS, breast cancer, and low sperm count^.'^,'^

Dietary Considerations Women suffering from PMS typically eat a diet that is even worse than the standard American diet. AbrahamI9 reports that, compared with symptom-free women, PMS patients consume the following substances:

62% more refined carbohydrates 275%more refined sugar 79% more dairy products 78%more sodium 53%less iron 77Y0 less manganese 52% less zinc In addition to providing benefits against PMS symptoms, the dietary recommendations given here also provide significant protection against the development of breast cancer, other cancers, heart disease, strokes, osteoporosis, diabetes, and virtually every other chronic degenerative disease. The seven most important dietary recommendations for PMS are listed in Box 204-3.

Follow vegetarian or predominantly vegetarian diet Reduce intake of fat Eliminate sugar Reduce exposure to environmental estrogens Increase intake of soy foods Eliminate caffeine Keep salt intake low

Vegetarian Diet and Estrogen Metabolism Vegetarian women have been shown to excrete two to three times more estrogen in their feces and to have 50% lower levels of free estrogen in their blood than ornnivores.20,21 These differences are thought to be a result of the lower fat and higher fiber intake of the vegetarian women. These dietary differences may also explain the lower incidence of breast cancer, heart disease, and menopausal symptoms in vegetarian women. At the very least, the clinician should recommend a diet lower in saturated fat and cholesterol (achieved by reducing or eliminating the amounts of animal products) and higher in fiber-rich plant foods (fruits, vegetables, grains, and legumes). The intake of animal protein sources should be limited to no more than 110 to 170 mg/day, and fish, skinless poultry, and lean cuts should be recommended rather than fat-laden choices. It appears that many of the effects that a vegetarian diet has on lowering circulating estrogen levels are related to a higher intake of dietary fiber. The fiber promotes the excretion of estrogens directly and indirectly by promoting a more favorable bacterial flora with lower levels of beta-glucuronidase activity.

Fat Intake and Estrogen Metabolism Decreasing the percentage of calories as fat, in particular saturated fat, has dramatic effects on the reduction of circulating e ~ t r o g e n . QIn~ ~one study, when 17 women switched from the standard American diet, composed of 40% of calories as fat and only 12 g as fiber daily, to a low-fat, high-fiber diet, consisting of 25% of calories as fat and 40 g as fiber daily, there was a 36% reduction in blood estrogen levels, with 16 out of the 17 women demonstrating significant reductions in only 8 to 10 weeks.24 A low-fat diet has also been shown to improve PMS symptoms.24 Besides possibly improving PMS symptoms, another good reason to reduce the intake of fat is the great deal of research linking a diet high in saturated fat and cholesterol to numerous cancers, heart disease, and strokes. Both the American Cancer Society and the American

Premenstrual Syndrome

Heart Association have recommended a diet in which less than 30%of calories are fat. The easiest way for most people to achieve this goal is to eat fewer animal products and more plant foods. With the exception of nuts and seeds, most plant foods are very low in fat. Nuts and seeds do contain high levels of fat calories, but the calories are derived largely from polyunsaturated essential fatty acids. It is also very important to eliminate the intake of margarine and foods containing trans-fatty acids and partially hydrogenated oils.

through an increase in the intake of high-potassium foods (i.e., fruits and vegetables) and a decrease in intake of high-sodium foods (most processed foods). Total daily sodium intake should be less than 1800 mg.

HormoneTherapy Progesterone Therapy

Although progesterone administration is a popular recommendation made by many physicians (MDs and NDs alike), it is reasonable to have some reservations. First of all, although progesterone administration has been the most common prescription for PMS in the medical comSugar munity, controlled clinical trials have failed to consistently demonstrate the superiority of progesterone therapy over Sugar has several detrimental actions in PMS. Eating a placebo (there is a significant placebo response in foods high in simple sugars increases insulin secretion PMS).2p34 The studies showing positive effect have used and can be harmful to blood sugar control, especially if the patient is hypoglycemic or diabetic. Sugar, especially dosages far exceeding the normal levels for progesterone (200 to 400 mg twice daily as a vaginal or rectal supposwhen combined with caffeine, also has a detrimental itory from 14 days before the expected onset of menstrueffect on PMS and mood (discussed later). The most sigation until the onset of vaginal bleeding).=rMSide effects, nificant symptom-producing food in PMS appears to be chocolate.25A high intake of sugar also impairs estrogen although generally mild, may occur in 5%of individuals metabolism. The evidence is based on the higher fre- using transdermal creams that include 20 mg of USP progesterone per l/4 tsp. In one of the later double-blind quency of PMS symptoms in women consuming a highstudies that did show a positive effect for progesterone sugar diet and the fact that a high sugar intake is also therapy (400 mg twice a day by vaginal or rectal adminassociated with higher estrogen istration), adverse events were reported by 51% of The clinician should encourage patients to read food labels carefully for clues about sugar content. patients in the progesterone treatment group (compared with 43% in the placebo g r o u ~ )Irregularity .~ of menAppearance of the words sucrose, glucose, maltose, lacstruation, vaginal itching, and headache were reported tose, fructose, corn syrup, or white grape juice concenmore frequently by the women taking the progesterone. trate appear on the label indicates added simple sugars. Secondly, philosophically I would rather help the body Caffeine improve the estrogen and progesterone ratio naturally by addressing the underlying causative factors, such as Caffeine must be avoided by patients with PMS, espereduced detoxification and clearance of estrogen along cially if anxiety or depression, or breast tenderness and fibrocystic breast disease is a major ~ y m p t o m . ~ ~with , ~ ~reduced corpus luteum function, rather than artificially and drastically tipping the ratio in favor of progesThere is considerable evidence demonstrating that cafterone. I do not recommend progesterone creams as the feine consumption is strongly related to the presence first step for treating PMS, but rather as an option in and severity of PMS. The effect of caffeine is particularly more difficult cases and when other nonhormonal significant in the psychological symptoms associated methods have failed. with PMS, such as anxiety, irritability, insomnia, and depression. The effect of caffeine on fibrocystic breast Thyroid Function disease is discussed in Chapter 167. Low thyroid function (hypothyroidism)has been shown Salt to affect a large proportion of women with PMS.35*36 For example, in one study, 51 of 54 subjectswith PMS demonExcessive salt (sodium chloride) consumption, coupled strated low thyroid status, compared with 0 of 12 in the with diminished dietary potassium, greatly stresses the control group.%In another study, 7 of 10 subjects in the kidney’s ability to maintain proper fluid volume. As a PMS group had low thyroid status, compared with 0 of result some people are “salt sensitive,” in that high salt 9 in the control group.% Other studies have also shown intake increases their blood pressure and/or water hypothyroidism to be only slightly more common retention. Patients who experience more water retention in women with PMS than in c0ntrols.3~3~ Many women during the midluteal phase may be especially sensitive with PMS and confirmed hypothyroidism who are to salt intake. However, it is simply not a matter of given thyroid hormone experience complete relief of reducing salt intake, because potassium intake must be simultaneously increased. This goal is easily achieved symptoms.%For more information, see Chapter 179.

Stress, Endorphins, and Exercise As in many common conditions associated with "modern" living, stress definitely plays a role in PMS. When stress is extreme, unusual, or long-lasting, it triggers biologic changes in the brain, largely as a result of alteration in adrenal gland function and endorphin secretion or action. These changes have a "domino effect," in that they lead to alterations in normal physiology. Effective treatment of PMS must include stress management.

Feelings of helplessness Overeating Watching too much television Emotional outbursts Overspending Excessive behavior Dependence on chemicals: drugs, legal and illicit; alcohol; cigarettes

Exercise Several studies have shown that women engaged in a regular exercise program do not suffer from PMS nearly as often as sedentary women.3941In one of the more thorough studies, mood and physical symptoms during the menstrual cycle were assessed in 97 women who exercised regularly and in a second group of 159 women who did not exercise.39Mood scores and physical symptoms assessed throughout the menstrual cycle showed sigruflcant effects of exercise on negative mood states and physical symptoms. The regular exercisers obtained sigruflcantly lower scores for impaired concentration, negative mood, behavior change, and pain. In another study, 143 women were monitored for 5 days in each of the three phases of their cycles (midcycle, premenstrual, and menstrual).4oThe women were 35 competitive athletes, two groups of exercisers (33 high-frequency exeIcisers and 36 low-frequency exercisers),and 39 sedentary women. The high-frequency exercisers experienced the greater positive mood scores,and sedentary women the least. The hi&-frequency exercisers also reported the least depression and anxiety. The differences were most apparent during the premenstrual and menstrual phases. These results are consistent with the belief that women who frequently exercise (but not competitive athletes) are protected from PMS symptoms. In particular, regular exercise protects against the deterioration of mood before and during menstruation. These studies provide evidence that women with PMS need to exercise. One of the ways exercise may positively affect PMS is through elevations in endorphin values and reductions in cortisol levels.

Coping Style Many women with PMS tend to employ "negative" coping styles," examples of which are listed in Box 204-4. It is important to identify the manner in which the patient deals with stress and to counsel her on more positive ways of coping.

Psychotherapy Various psychotherapy methods have been successful in improving the psychological aspects of PMS. In particular, biofeedback and short-term individual counseling

(especially cognitive therapy) have documented clinical effi~acy!~,~One of the advantages of cognitive therapy over antidepressantdrug therapy in the treatment of PMS is that learning techniques such as cognitive-behavioral coping skills can produce excellent results that are maintained over time.

Depression and Low Serotonin Levels There are some important relationshipsbetween PMS and depression. Depression is a common feature in many cases of PMS, and PMS symptoms are typically more severe in depressed women.' The reason appears to be a decrease in the brain level of various neurotransmitters, with serotonin and GABA being the most significant."" Use of antidepressant drugs like fluoxetine (Prozac) is quickly becoming the dominant medical treatment for PMS.' Approximately 80% of the 12 million Americans undergoing fluoxetine therapy are women between the ages of 25 and 50 years; not surprisingly, this age range also represents the highest frequency of PMS.

Nutritional Supplements Although all essential nutrients are critical to good health and in dealing with PMS symptomatology, this discussion focuses on the six key nutrients, followed by some practical recommendations.

Vitamin B6 The first use of vitamin B6 in the management of cyclical conditions in women was in the successful treatment of depression caused by birth control pills, as noted in several studies in the early 1970s. These results led researchers to try to determine the effectiveness of vitamin B6 in relieving PMS symptoms. Since 1975 at least a dozen double-blind clinical trials have been p e r f ~ r m e d ?The ~ ? ~majority have demonstrated a positive effect. For example, in one double-blind crossover trial, 84% of the subjects had a lower symptomatology score during the B6 treatment peri0d.4~Although PMS has multiple causes, B6 supplementation alone appears to benefit most patients. It is important to note, however, that not all double blind studiesof vitamin B6have shown a positive e f f e ~ t . 4 ~ ~ ~

Premenstrual Syndrome The negative results in some trials may have been caused by many factors, such as the inability of some women to convert B6 to its active form owing to a deficiency in another nutrient (e.g., vitamin B2 or magnesium) that was not supplemented. These results suggest that supplementing pyridoxine by itself may have adequate clinical results for all women suffering from this disorder and that some women may have difficulty converting vitamin B6 into its active form, pyridoxal5-phosphate. To overcome this conversion difficulty, it may be necessary to use a broader-spectrum nutritional supplement or to use injectable pyridoxal-5-phosphate. For most indications, the therapeutic dosage of vitamin B6 is 50 to 100 mg daily. This dosage level is generally regarded as being safe, even for long-term use. With use of dosages greater than 50 mg, it may be important to divide it into 50-mg doses taken throughout the day. A single dose of 100 mg of pyridoxine did not lead to sigruficanthigher pyridoxal-5-phosphate levels in the blood than a 50-mg dose, possibly indicating that a 50-mg oral dose of pyridoxine is about all the liver can handle at once.5o Vitamin B6 is one of the few water-soluble vitamins associated with some toxicity when taken in large doses or in moderate dosages for long periods. One-time doses larger than 2000 mg/day can produce symptoms of nerve toxicity (tingling sensations in the feet, loss of muscle coordination, and degeneration of nerve tissue) in some individuals. Long-term intake of dosages larger than 500 mg daily can be toxic if taken for many months or years.51There are also a few rare reports of toxicity occurring at long-term dosages as low as 150 rng/day5l-% The toxicity is thought to occur when supplemental pyridoxine overwhelms the liver’s ability to add a phosphate group to produce the active form of vitamin B6 (pyridoxal-5-phosphate).As a result, it is speculated that pyridoxine either is toxic to the nerve cells or actually acts as an antimetabolite by binding to pyridoxal5-phosphate receptors, thereby creating a relative deficiency of vitamin B6. Another possibility is that minute amounts of contaminants or vitamin B6 analogues may have been introduced during synthesis. Although not a problem at normal dosages of vitamin B6, contaminants present in larger dosages may block B6 activation sites. Again, it appears to make sense to limit dosages to 50 mg at a time. If more than 50 mg/day is desired, the doses should be spread out throughout the day. There are extensive interactions between vitamin B6 and magnesium, which work together in many enzyme systems. In fact, one of the ways in which vitamin B6 may improve the symptoms of PMS is by increasing the accumulation of magnesium within the cells of the body.% Without vitamin B6, magnesium does not get inside the cell.

Magnesium Magnesium deficiency is strongly implicated as a causative factor in premenstrual syndr0me.5~Red blood cell (RBC) magnesium levels in patients with PMS have been shown to be sigruficantly lower than in normal subject^.'^^ Because magnesium plays such an integral part in normal cell function, magnesium deficiency may account for the wide range of symptoms attributed to PMS. Furthermore, magnesium deficiency and PMS have many common features, and magnesium supplementation has been shown to be an effective treatment of PMS.5’ A recent study designed to improve understanding of the association between magnesium and the menstrual cycle measured plasma, RBC, and mononuclear blood cell (MBC)magnesium concentrationsin 26 women with confirmed PMS and in a control group of 19 women during the follicular, ovulatory, early luteal, and late luteal phases of the menstrual The principal findings of the study were as follows: There were no sigruficant differences in plasma magnesium levels between patients with PMS and control subjects, nor was there a menstrual cycle effect on plasma magnesium in either group. Patients with PMS had sigruficantly lower RBC and MBC magnesium concentrations than control subjects. These lower RBC and MBC magnesium concentrations were consistent throughout the menstrual cycle. Magnesium measures did not correlate with the severity of mood symptoms. The observation of low RBC magnesium concentrations in patients with PMS has now been confirmed by four independent studies. In general, it is thought that women with PMS have a ”vulnerability to luteal phase mood state destabili~ation”~~ and that chronic and enduring intracellular magnesium depletion serves as a major predisposing factor for destabilization. In addition to emotional instability, magnesium deficiency in PMS is characterized by excessive nervous sensitivity with generalized aches and pains and a lower premenstrual pain threshold. One clinical trial of magnesium in PMS showed a reduction of nervousness in 89%, breast tenderness in 96%, and weight gain in 95% of subjects.I9 In another double-blind study, high-dose magnesium supplementation (360 mg three times daily) was shown to dramatically relieve PMSrelated mood changes.57 Although magnesium has been shown to be effective on its own, even better results may be achieved by combining it with vitamin B6 and other nutrients. Several studies have shown that when PMS patients are given a multivitamin and mineral supplement containing high doses of magnesium and pyridoxine, they experience a substantial reduction in PMS

Specific Health Problems

The optimum intake for magnesium should be based on body weight, 6 mg/kg. For a 50-kg woman, the recommendation would be 300 mg; for a 90-kg woman, 540 mg. As these dosages are difficult to achieve by diet alone, supplementation is recommended. In the treatment of PMS, a dosage of twice this amount, 12 mg/kg, may be needed. Magnesium bound to aspartate or one of the Krebs cycle intermediates (malate, succinate, fumarate, or citrate) is preferred to magnesium oxide, gluconate, sulfate, or chloride because of better absorption and fewer side effects (laxative effects).61,62

Calcium Calcium appears to be a bit of a double-edged sword in PMS. High calcium intake due to high milk consumption has been identified as a possible causative factor, perhaps through the reduction in absorption of magnesium by a combination of calcium, vitamin D, and phosphorus of millc.19 Nevertheless, some studies show improvements in PMS symptomatology with calcium supplementation (1000 to 1336 mg).@TMIn one of the later studies, calcium and manganese supplementation (1336 and 5.6 mg, respectively)improved mood, concentration, and behavior. In another study, 1000 mg/day improved mood and water retention.@It is theorized, primarily from animal research, that calcium improves the altered hormonal patterns, neurotransmitter levels, and smooth muscle responsiveness noted in PMS. Further support for the importance of calcium supplementation in PMS is the finding that women with PMS have reduced bone mineral density (on the basis of dual-photon absorptiometry).65

Zinc Zinc levels have been shown to be low in women with PMS.&Zinc is required for proper action of many body hormones, including the sex hormones, as well as in the control of the synthesis and secretion of hormones. In particular, zinc serves as one of the control factors for prolactin se~reti0n.gWhen zinc levels are low, prolactin release increases, and high zinc levels inhibit thisrelease. Hence, in high-prolactin states, zinc supplementation is very useful. A n effective dosage range for zinc supplementation for elevated prolactin levels in women is 30 to 45 mg in the picolinate form.

Vitamin E Although vitamin E research concerning PMS has focused primarily on breast tenderness, significant reduction of other PMS symptomatology has also been demonstrated in double-blind s t u d i e ~ . 'Nervous ~,~ tension, headache, fatigue, depression, and insomnia were all significantly reduced. In one double-blind study, patients receiving vitamin E (400 IU/day) demonstrated

a 33% reduction in physical symptoms (such as weight gain and breast tenderness), a 38% reduction in anxiety, and a 27%reduction in depression after 3 months of use. In contrast, the placebo group reported only a 14% reduction in physical symptoms. The group taking vitamin E also noted higher energy levels, fewer headaches, and fewer cravings for sweets.

Essential Fatty Acids Women with PMS have been shown to exhibit essential fatty acid and prostaglandin abnormalities, the chief abnormality being a decrease in gamma-linolenic acid (GLA).69GLA is derived from linoleic acid. This conversion requires adequate levels of vitamin B6, magnesium, and zinc, because these nutrients function in the key enzyme responsible for this conversion, delta6-desaturase. Given the fact that deficiency of one or more of these nutrients is common in PMS, decreased GLA levels could almost be expected. Evening primrose, black currant, and borage oils contain GLA, typical levels being 9%, 12%,and 22%, respectively. Although these essential fatty acid sources are quite popular, the research on GLA supplements in the treatment of PMS is controversial. Specifically, the double-blind studies with GLA supplements like evening primrose oil in PMS are largely negative, in that the supplements show no greater benefit over a placebo. A metaanalysis of the clinical trials of evening primrose oil for the treatment of PMS concluded that evening primrose is of little value in the management of PMS.'O The three best-controlled studies failed to show any beneficial effects for evening primrose.71-n A better approach to the essential fatty acid and prostaglandin abnormalities of PMS may be to provide the necessary nutrients required for proper essential fatty acid metabolism along with providing adequate levels of the essential fatty acids and GLA. In other words, it may be more appropriate to provide a broader range of support than simply trying to increase GLA levels.

Multiple Vitamin and Mineral Supplements A high-quality multiple vitamin and mineral supplement providing all of the known vitamins and minerals serves as a foundation upon which to build. Women with PMS have two very sound reasons for taking a high-potency multiple vitamin, as follows: Nutritional deficiency is relatively common among women with PMS. High-potency multiple vitamin and mineral formulations have been shown to have sigruficant benefits in PMS. The frequency of nutritional supplementation and the calculated intake of selected nutrients have been shown to be much lower in patients with PMS than in

Premenstrual Syndrome

normal women. Women with PMS have been shown to consume vitamins in their food at levels close to the recommended daily allowance, but compared with women who did not have PMS, their intake levels were only 2.2% as much for thiamin, 2.2% for riboflavin, 16.7% for niacin, 8.7% for pantothenic acid, and 2.7% for pyrid~xine.'~ Several double-blind studies have shown that patients with PMS who were given a multivitamin and mineral supplement containing high doses of magnesium and pyridoxine experience reductions (typically at least a 70% reduction) in both premenopausal and postmenstrual symptoms.59@

Botanical Medicines Although a wide variety of herbs has been used in folk medicine for the many disorders of menstruation, and many have been evaluated for their "phytoestrogen" effects, few have been specifically evaluated for their efficacy in relieving premenstrual symptoms. The herbs that have been used traditionally are those with a tonic effect on the female glandular system. This tonic effect is thought to be a result of phytoestrogens in the plants or other compounds that help improve the hormonal balance of the female system as well as the plant's ability to improve blood flow to the female organs. Although phytoestrogensare capable of exerting estrogenic effects, the activity is only 2% as strong as estrogen. However, because of this low activity, phytoestrogens have a balancing action on estrogen effects. If estrogen levels are low, phytoestrogens will cause an increase in estrogen effect because they have some estrogenic activity. If estrogen levels are high, there will be a decrease in estrogen effects, because phytoestrogens bind to estrogen receptor binding sites, thereby competing with estrogen. Because of the balancing action of phytoestrogens on estrogen effects, it is common to find the same plant recommended for conditions like PMS menopause and irregular menses. Many of these herbs have been called "uterine tonics" because they work to nourish and tone the female glandular and organ system rather than exerting a druglike effect. This nonspecific mode of action makes many herbs useful in a broad range of female conditions, including PMS. Four of the most commonly used traditional herbs in the treatment of PMS are Angelica sinensis (angelica or dong quai), Glycyrrhizu glubra (licorice root), Cimicifuga racemosa (black cohosh), and Vitex agnus castus (chaste berry). These herbs have been used historically to lessen a variety of female complaints, including hot flashes.

Angelica sinensis In Asia, angelica's reputation is perhaps second only to ginseng. Predominantly regarded as a "female" remedy,

angelica has been used in menopausal symptoms (especially hot flashes), as well as in such conditions as dysmenorrhea (painful menstruation),amenorrhea (absence of menstruation), metrorrhagia (abnormalmenstruation), and to assure a healthy pregnancy and easy delivery. Angelica has demonstrated good uterine tonic activity, causing an initial increase in uterine contraction followed by rela~ation.'~ In addition, administration of angelica to mice resulted in an increase of uterine weight and an increase of glucose utilization by the liver and uterus." These effects reflect phytoestrogenic activities. Angelica is particularly helpful when, in addition to PMS, a woman experiences painful menstruation (dysmenorrhea). The typical dosage schedule is to start angelica on day 14 and continue until menstruation begins, unless the woman typically experiences dysmenorrhea, in which case it should be continued until menstruation has stopped.

Glycyrrhiza glabra The medicinal use of licorice (G. glabru) in both Western and Eastern cultures dates back several thousand years. In addition to use in a variety of female disorders, it was used primarily as an expectorant and antitussive in respiratory tract infections and asthma. Other traditional uses are in treatment of peptic ulcers, malaria, abdominal pain, insomnia, and infections. Many of these uses have been substantiated by modern research. Licorice is particularly useful in premenstrual syndrome because it is believed to lower estrogen while simultaneously raising progesterone level^.^^,^ It raises progesterone levels by inhibiting the enzyme responsible for breaking the enzyme down. Licorice is also useful in reducing water retention by blocking the hormone aldosterone. Licorice works to block the effects of aldosterone much in the same way that it affects estrogen.7E,79 Its chief component, glycyrrhetinic acid, binds to aldosterone receptors, but its activity is only about 25% as strong as the body's own aldosterone.This lower level of activity means that in cases of high aldosterone levels (such as often occur in PMS), licorice may actually reduce the aldosterone effect by competing with aldosterone for binding sites. If aldosterone levels are normal, the long-term ingestion of licorice in large doses may cause symptoms of aldosterone excess, namely high blood pressure due to sodium and water retention. The side effects of glycyrrhizin may be prevented with the use of a high-potassium, low-sodium diet. Although no formal trial has been performed, patients who normally consume high-potassium foods and restrict sodium intake, even those with high blood pressure and angina, have been reported to be free from the aldosterone-like

Specific Health Problems

side effects of glycyrrhizin.soLicorice should probably not be used in patients with a history of hypertension or renal failure or current use of digitalis preparations. The typical dosage schedule is to begin licorice on day 14 of the cycle and continue till menstruation.

Cimicifiga racemosa Black cohosh (C. racemosa) was widely used by the American Indians and later by American colonists for the relief of menstrual cramps and menopause. Recent scientific investigation into Remifemin, an extract of black cohosh standardized to contain lmg of triterpenes calculated as 27-deoxyacteine per tablet that has been used in Germany for more than 40 years, has shown that it is a safe and effective natural alternative to hormone replacement therapy in the treatment of menopause and may offer some benefits in PMS as well. In one study of 135 women, Remifemin was judged to have ”performed very well” against PMS, in that it reduced feelings of depression, anxiety, tension, and mood swings.8l

and bloating. At the end of the trial, women taking the Vitex reported a 52% overall reduction in PMS symptoms, compared with only 24%for those taking placebo. Women taking the chaste tree reported sigruficantly greater reductions in irritability, mood changes, anger, headache, and breast tenderness than the women taking the placebo. Bloating was the only symptom that did not change significantly with Vitex.

Ginkgo biloba One randomized clinical trial evaluated Ginkgo biloba to determine its effectiveness in PMS symptoms. One hundred sixty-five women of reproductive age who had fluid retention, breast tenderness, and vascular congestion were assigned to receive either a ginkgo extract of 25% @go flavonglycosides at 80 mg twice daily or a placebo from day 16 to day 5 of their cycles. Symptom diaries kept by patients and physician evaluation of symptoms demonstrated that @go extract was effective against the congestive symptoms of PMS, particularly breast pain and breast t e n d e m e ~ s . ~ ~

Vitex agnus castus

Hypericurn perforatum

The chaste tree (V. agnus castus) is native to the Mediterranean, where its berries have long been used for female complaints. As its name sigrufies, chaste berries were used in suppressing the libido. Chaste berry extract is probably the single most important herb in the treatment of PMS, not only because of its long tradition and known historical uses, but also as a result of modem scientific research. In two surveys of gynecologic practices in Germany, physicians graded chaste berry extract as good or very good in the treatment of PMS. More than 1500 women participated in the One third of the women experienced complete resolution of their symptoms, and another 57% reported sigruficant improvement. The beneficial effects of chaste tree in PMS and these other conditions appear to be related to alterations in gonadotropin-releasing hormone (GnRH) and folliclestimulating hormone-releasing hormone (FSH-RH). In other words, it appears that chaste berry extract has profound effects on the hypothalamus and pituitary function. As a result, it is able to normalize the secretion of other hormones-for instance, reducing the secretion of prolactin and reducing the estrogen to progesterone ratio. In the best study to date, a randomized clinical trial compared a Vitex standardized extract (20-mg tablet standardized for casticin) with placebo in women with PMS.@ One hundred seventy women with PMS were assigned to take either the Vitex or a placebo once daily for three consecutive menstrual cycles. Women were asked to rate changes in PMS symptoms, such as irritability, mood changes, anger, headache, breast tenderness,

In a prospective, open, uncontrolled, observational study, 19 women who were diagnosed with premenstrual syndrome completed a daily symptom rating for one cycle and underwent a screening interview with physicians. The participants then took St. John’s wort tablets (300 mg St John’s wort standardized to 900 pg hypericin) for two complete menstrual cycles.% Symptoms were rated daily by means of the Hospital Anxiety and Depression scale and modified Social Adjustment Scale, which were administered at baseline and after each of the two cycles. The degree of improvement in overall premenstrual syndrome scores between the beginning of the study and the end was 51%, with more than two thirds of the women having at least a 50% decrease in the severity of symptoms. The mood subscale showed the most improvement (57%) and the symptoms with the greatest reductions in scores were crying (92%), depression (85%),confusion (75%),feeling out of control (72%), nervous tension (71%), anxiety (69%), and insomnia (69%).

THERAPEUTIC APPROACH The approach to the woman with premenstrual symptoms first involves evaluation of symptoms and a correct diagnosis. In an effort to clarify the treatment approach, the clinician should consider the following seven key steps:

1. Evaluate PMS symptoms by having the patient complete a questionnaire. 2. Rule out psychiatric or other medical condition.

Premenstrual Syndrome

3. Have the patient start following the dietary recommendations for PMS: Follow a vegetarian or predominantly vegetarian diet. Reduce the intake of fat. Eliminate sugar. Reduce exposure to environmental estrogens. Eliminate caffeine. Keep salt intake low. 4.Have the patient the guidelines for nutritional supplementation given below. 5. Select the appropriate herbal support, as follows: If the patient has PMSassociated breast pain, infrequent periods, or a history of ovarian cysts, utilize I? agnus castus. If the patient typically experiences menstrual cramps, utilize A. sinensis. If the patient is bothered by PMS water retention, use G. glabra. If the patient suffers from perimenopause symptoms as well as PMS, use C. racemosa. 6. Establish a program for stress reduction and recommend regular exercise. 7. If after at least three complete periods the patient is not experiencing a significant improvement or complete resolution of symptoms, work to idenhfy additional causative factors as detailed above or change the treatment program.

Nutritional Supplements

Magnesium: 500 mg/day Vitamin E: 400 IU/day

Botanical Medicines A. sinensis, three times a day: Powdered root or as tea: 1to 2 g Tincture (1:5):4 ml(1 tsp) Fluid extract: 1ml tsp) G. glabra, three times a day:

Powdered root or as tea: 1to 2 g Fluid extract (1:l):4 ml(1 tsp) Solid (dry powdered) extract (4:l):250 to 500 mg

C. racemosa: Standardized extract (4mg 27-deoxyacteine): 1 tablet one or two times daily

V.agnus castus, daily dosage: Standardized extract (0.5% agnuside): 175 to 225 mg daily or 20 mg standardized to casticin Liquid extract: 2 ml G. biloba:

80 mg standardized extract two times daily

Hypericum perforaturn: 300 mg standardized extract (900 pg hypericin) one to three times daily

Multivitamin and mineral Vitamin B6: 100 mg/day

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45. Eriksson E, Alling C, Andersch B, et al. Cerebrospinal fluid levels of monoamine metabolites. A preliminary study of their relation to menstrual cycle phase, sex steroids, and pituitary hormones in healthy women and in women with premenstrual syndrome. Neuropsychopharmacology 1994;11:201-213. 46.Halbreich U, Petty F, Yonkers K, et al. Low plasma gammaaminobutync acid levels during the late luted phase of women with premenstrual dysphoric disorder. Am J Psychiatry 1996;153:718-720. 47. Berman MK, Taylor ML, Freeman E. Vitamin 86 in premenstrual syndrome. J Am Diet Assoc 1990;90:859-861. 48. Kliejnen J, Ter Riet G, Knipschild P. Vitamin B6 in the treatment of premenstrual syndrome-a review. Br J Obstet Gynaecol 1990;97 847-852. 49. Barr W. Pyridoxine supplements in the premenstrual syndrome. Practitioner 1984;228:425-427. 50. Zempleni J. Pharmacokineticsof vitamin E36 supplements in humans. J Am Coll Nutr 1995;14579-586. 51. Cohen M, Bendich A. Safety of pyridoxine-a review of human and animal studies. Toxicol Lett 198634129-139. 52. Parry GJ, Bredesen DE. Sensory neuropathy with low-dose pyridoxine. Neurology 1985;351466-1468. 53. Waterston JA, Gilligan BS. Pyridoxine neuropathy. Med J Aust 1987; 146640-642.

54. Majumdar P, Boylan M. Alteration of tissue magnesium levels in rats by dietary vitamin B6 supplementation. Int J Vitamin Nutr Res 1989;59:300-303. 55. Posaci C, Erten 0, Uren A, Acar B. Plasma copper, zinc, and magnesium levels in patients with premenstrual tension syndrome. Acta Obstet Gynecol Scand 1994;73:452-455. 56. Piesse JW. Nutritional factors in the premenstrual syndrome. Int Clin Nutr Rev 1984;4:54-81. 57. Facchinetti F, Borella P, Sances G, et al. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol1991;78: 177-181. 58. Rosenstein DL, Elin RJ, Hosseini Jh4, et al. Magnesium measures across the menstrual cycle in premenstrual syndrome. Biol Psychiatr 1994;35557-561. 59. London RS,Bradley R, Chiamori NY. Effect of a nutritional supplement on premenstrual symptomatology in women with premenstrual syndrome: a double-blind longitudinal study. J Am Coll Nutr 1991;10494-499. 60.Stewart A. Clinical and biochemical effects of nutritional supplementation on the piemenstrual syndrome. J Reprod Med 1987;32: 435-441. 61.Lindberg JS, Zobitz MM, Poindexter JR, Pak CY. Magnesium bioavailability from magnesium citrate and magnesium oxide. J Am Coll Nutr 1990;948-55. 62. Bohmer T, Roseth A, Holm H, et al. Bioavailabilityof oral magnesium supplementation in female students evaluated from elimination of magnesium in 24hour urine. Magnes Trace Elem 1990;9:272-278. 63. Penland JG, Johnson PE. Dietary calcium and manganese effects on menstrual cycle symptoms. Am J Obstet Gynecol 1993;168: 1417-1423. 64.Thys-Jacobs S, Ceccarelli S, Bierman A. Calcium supplementation in premenstrual syndrome: a randomized crossover trial. J Gen Intern Med 1989;4183-189. 65. Thys-Jacobs S, Silverton M, Alvir JM. Reduced bone mass in women with premenstrual syndrome. J Womens Health 1995;4161-168. 66. Chuong CJ, Dawson EB. Zinc and copper levels in premenstrual syndrome. Fertil Steril1994;62:313-320. 67. Judd AM, Macleod RM, Login IS. Zinc acutely, selectively and reversibly inhibits pituitary prolactin secretion. Brain Res 1984;294: 190-192. 68.London RS,Sundaram G, Manimekalai S, et al. The effect of alphatocopherol on premenstrual symptomatology: a double-blind study. II. Endocrine correlates. J Am Coll Nutr 19849:351-356.

Premenstrual Syndrome 69. Horrobin DF, Manku M, Brush M, et al. Abnormalities in plasma essential fatty acid levels in women with premenstrual syndrome and with non-malignant breast disease. J Nutr Med 1991;2259-264. 70. Budeiri D, Li Wan Po A, Dornan JC. Is evening primrose oil of value in the treatment of premenstrual syndrome? Control Clin Trials 1996;1760-68. 71. Khoo SK, Munro C, Battistutta D. Evening primrose oil and treatment of premenstrual syndrome. Med J Austral 1990;153189-192. 72. Cerin A, Collins A, Landgren BM, Eneroth P. Hormonal and biochemical profiles of premenstrual syndrome. Treatment with essential fatty acids. Acta Obstet Gynecol Scand 1993;72337-343. 73. Collins A, Cerin A, Coleman G, Landgren BM. Essential fatty acids in the treatment of premenstrual syndrome. Acta Obstet Gynecol 1993;81:93-98. 74. Harada M, Suzuki M, Ozaki Y. Effect of Japanese angelica root and peony root on uterine contraction in the rabbit in s i b . J Pharmacobiodyn 1984;7:304-311. 75. Yoshiro K. The physiological actions of tang-kuei and cnidium. Bull Oriental Healing Arts Inst USA 1985;10269-278. 76. Costello CH, Lynn EV. Estrogenic substances from plants. I. Glycyrrhiza. J Am Pharm Soc 1950;39177-180. 77. Kumagai A, Nishino K, Shimomura A, et al. Effect of glycyrrhizin on estrogen action. Endocrinol Japon 1967;1434-38.

78. Farese RV Jr, Biglieri RG, Shackleton CH, et al. Licorice-induced hypermineralocorticoidism. N Engl J Med 1991;325:1223-1227. 79. Stormer FC, Reistad R, Alexander J. Glycyrrhizic acid in liquoriceevaluation of health hazard. Fd Chem Toxic01 1993;31:303-312. 80. Baron J, Nabarro JD, Slater JD,Tuffley R. Metabolic studies, aldosterone secretion rate and plasma renin after carbonoxolone sodium. Br Med J 1969;2793-795. 81. Schildge E. Essay on the treatment of premenstrual and menopausal mood swings and depressive states. Rigelh Biol Umsch 1964;19: 18-22. 82. Dittmar FW.Premenstrual syndrome. Treatment with a phytopharmaceutical. Therapiewoche Gynakol1992;5:60-68. 83. Peteres-Welte C, Albrecht M. Menstrual abnormalities and PMS. Vitex agnus-castus. Therapiewoche Gynakol1994;749-52. 84.Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomized, placebo controlled study. Bh4J 2001;322:134-137. 85.Tamborini A, Tawlle R. [Value of standardized Ginkgo bilobn extract in the management of congestive symptoms of premenstrual syndrome.] Rev Fr Gynecol Obstet 1993;88447457. 86. Stevinson C, Ernst E. A pilot study of Hypericurn perforaturn for the treatment of premenstrual syndrome. BJOG 2OOO;107870-876.

Proctologic Conditions Thomas A. Kruzel, ND CHAPTER CONTENTS Anorectal Anatomy

2067

Anal Diseases 2068 Anal Fistula and Anal Abscess 2068 Anal Cryptitis 2068 Anal Fissure 2068 Treatment 2069 Hemorrhoids 2070 Internal Hemorrhoids 2070 External Hemorrhoids 2073

ANORECTAL ANATOMY The anorectal region is divided into the anus, which extends anywhere from 3 to 4 cm above the anal verge to its merge with the rectum, and the rectum, which is 12 to 18cm long. The anal verge is the demarcation point from perianal skin to anal skin. The anal canal can further be divided into the dentate and anorectal lines. The dentate line is the demarcation point between the ectoderm of the external squamous epithelium and the rectal entodermal mucosa. The anal canal does not contain sebaceous or sweat glands and is innervated by somatic nerves up to and slightly beyond the dentate line which make it sensitive to pain to varying degrees. Above the dentate line the rectal mucosa is relatively insensitive to pain but registers distention and inflammation as diffuse visceral pain. The anorectal line is the point above which the rectum expands outward into the pelvic bowl. The area between the dentate and anorectal lines contains the rectal columns, anal valves, anal glands, and anal crypts. The anal glands normally provide mucus for lubrication with passage of stool and empty into the anal crypts. This area becomes the source of an anal fistula or perirectal abscess if the crypt becomes impacted and can not discharge its mucus. Anal fissures lie below the dentate line. Midway between the dentate and anorectal lines lies the white line of Hilton, or pectinate line. This is the location of the intersphincteric groove, the region that lies between the internal and external sphincters. The internal sphincter is under control of the autonomic

Perianal Dermatologic Disorders 2073 Condylomata Acuminata 2073 Condyloma Lata 2074 Lymphogranuloma Venereum 2074 Herpes 2074 Pilonidal Sinus 2074 Proctalgia Fugax 2075 Proctitis 2075 Pruritus Ani 2076 Treatments 2076

nervous system, and the external sphincter is under somatic or voluntary control. The anorectal region is highly vascularized and receives its blood supply from both the inferior mesenteric artery and the internal iliac artery. Arterial flow is then diverted from these sources through the superior, middle, and inferior rectal arteries. There is considerable anastomosisamong these branches. Venous return is facilitated by the superior and middle hemorrhoid veins, which empty into the inferior mesenteric veins and subsequently the portal vein, and the internal iliac vein that subsequently empties into the vena cava, bypassing the liver. The levator ani muscle forms the floor of the pelvis and helps form the puborectalis sling. The pull of the puborectalis sling causes the bowel to change direction as it penetrates the pelvic floor, making passage of stool easier. Along with the internal and external rectal sphincters, these muscles form the sphincter mechanism that controls continence. The anal canal receives its innervation via the pudendal nerves originating from S2, S3, and S4.',* A wide variety of presenting symptoms are related to disorders of the anorectum. Among them are pain, tenderness, rectal spasm, bleeding, itching, protrusions, eruptions, discharges, constipation, diarrhea, changes in stool pattern, sacral backache, shooting pains down the limbs, crampy and painful menses, urinary disturbances, anemia, prostatitis, restlessness in children, and foreign bodies3 The clinician should be aware that seemingly 2067

Specific Health Problems

unrelated symptoms might, in fact, have their origin in the anorectal tract.

ANAL DISEASES Anal Fistula and Anal Abscess Anal fistula and anal abscess are the result of an infection of an anal crypt whose distal end lies near the dentate line. The anal glands, which lie within the intersphincteric groove and empty into the anal crypts, become infected because of impacted feces. The resulting infection makes its way into the intersphincteric space but generally does not penetrate beyond the external sphincter. Most of the anal glands lie posteriorly; therefore, most abscesses drain from a line posterior to the ischial tuberosities, whereas anterior abscesses drain radially from their points of origin. The presence of a rectal fistula or abscess may indicate presence of an internal bowel disease such as diverticulitis, trauma to the area, or immune system incompetence such as with the human immunodeficiency virus (HIV). Under normal conditions the highly vascularized rectal mucosa is able to provide adequate protection against the spread of infection. The weak points are the anal glands, however, because they may become impacted with fecal matter, setting up an infective process in the anal crypt and intersphincteric space. The surrounding perianal tissue is swollen, red, and painful to palpation. If the infection remains in the intersphincteric space, the patient has rectal pain seemingly without specific findings. Eliciting the pain with pressure upon examination may provide a clue to the source of the lesion. The patient may also present with a fever of unknown origin. The adjacent ischiorectal fossae are regions filled with fatty tissue that allow for distention of the rectum. Therefore, an abscess has many different directions in which to track, setting up areas for pockets of pus. In a true perianal abscess, incision and drainage are usually not recommended because the bulk of the lesion would remain untouched owing to the probable invasion of the underlying tissues and the propensity of such an access to form caverns of pus. Unlike other abscesses formed by the body, perianal abscesses should not be allowed to come to a head and rupture on their own; failure to do so can lead to excessive amounts of inflammatory necrosis of the anal sphincter. Generally a surgical consultation is warranted for a rectal abscess. Surgery allows for laying open of the tract and healing by second intention. However, localized treatment can be undertaken to help the abscess drain if it has ruptured on its own or the patient presents acutely and immediate referral is not possible. Such treatment affords some relief and helps decrease the morbidity associated with this condition. Imgation with herbal

antibacterial agents such as Hydrastis, Usneu, and calendula succus in 0.9%saline helps drainage. Another, often encountered scenario is that of folliculitis with resultant abscess formation. These abscesses can be incised and drained, because they do not involve the anal canal or ischiorectal fossa. Homeopathic medicines such as calcarea sulphuricum, silicea, hepar sulphuris, and Myristicu are some of the more often indicated medicines. Poulticesmade from onion, garlic, or potatoes exert a drawing action, bringing the lesion to a head faster. Alternating hot and cold sitz baths is also useful. Once the abscess has broken open or has been incised and drained, irrigation with the previously mentioned solution hastens healing.

Anal Cryptitis Anal crypts are pockets created between the grooves formed by the rectal columns at their distal points ending at the dentate line. Anal glands empty into the crypts and, as previously mentioned, are believed to be the source of anal fistula. That anal cryptitis is a separate entity is open to some debate, and it is rarely seen. The patient complains of pain that is worse with bowel movement. Examination shows localized tenderness and redness at the dentate line, and there may be some rectal spasm. Rectal fissure should be ruled out. Chronic cases suggest bacterial infection, usually gonorrhea. Treatment is by herbal suppository, sitz baths, increasing dietary fiber intake, and, if necessary, localized anesthesia. The crypt may be cleaned out with a crypt hook if needed and irrigated with a solution of calendula succus and Hydrastis in normal saline.

Anal Fissure An anal fissure is a slitlike separation of the anal mucosa that lies below the dentate line. The majority of fissures are usually found in the posterior midline region (70%to SO%), but anterior midline lesions (10% to 20%) are more commonly seen in women. Some investigators report that fissures are more common in men than women: but other studies do not bear this out? In some patients the anal sphincter is more oval rather than round, coming to a Y or narrow point at the posterior midline, making for a greater predisposition for anal fissure. Anal fissure in children is not all that uncommon, often being associated with chronic diarrhea or hard stool? Fissure may also be a complication of a lesion associated with a congenital anal deformity. Lesions located in the anteroposterior vertical axis suggest an internal bowel disease, such as Crohn’s disease, squamous cell carcinoma or adenocarcinoma of the rectum, syphilitic fissure, or ulceration due to tuberculosis. Anal fissures are very painful because of their somatic innervation, which results from spasm of the anal sphincter in response to stretching during the passage of stool.

Proctologic Conditions

setbacks that are often encountered.Educating the patient The presence of an anal fissure triggers a vicious circle on this point upon initiation of therapy is essential to of pain causing sphincter spasm, which contributes to a its success. tightening of the sphincter and increased pain with passage of stool. Patients usually have severe pain during Treatment and for some time after defecation, and bleeding is not Initial treatment should be to alleviate the pain and spasm uncommon. As the lesion enlargers it may ulcerate and become infected. Conventional medical treatment consists because often they are what has brought the patient to the office. Homeopathic medicines provide prompt of rectal dilation, internal sphincterotomy, electrodessirelief if the simillimum is found and aids the healing cation, or surgical excision? process. Remedies such as Charnornilla, graphites, nitric Anal fissure can be caused by passage of large, hard acid, Ratanhia, Sepia, silicea, and Thuja are some of the stools, childbirth trauma, chronic diarrhea, trauma, food more often indicated medicines, but others may also be allergy, or prolonged straining to pass stool. Infants and needed.6,9Frequent dosing is generally the rule. Protease young children who consume large amounts of cow’s 315 mg, two capsules between meals tid and before bed, milk are more likely to have anal fissure and chronic conwill help to alleviate pain as well. A preparation of 0.2% stipation, especially if they were breast-fed for a shorter period.’ Many of the patients in whom anal fissures glycerol trinitrite can be used topically to relieve rectal spasm,l0 as can 5% lidocaine cream for localized pain. develop display intense, compulsive personalities that Glycerol trinitrite has been shown in a number of studmay contribute to the formation of such fissures as well as the ability to heal. A previous anal or rectal operation, ies to be effective in relieving rectal spasm as well as increasing blood flow to the anal ~ p h i n c t e r .Reduced ~~-~~ syphilis, or Crohn’s disease also predisposes the patient anal sphincter blood flow has been postulated as one of to fissure development. the precipitating mechanisms for development of anal Examination may be difficult because of the pain and fissure. spasm, and anoscopicexamination is often out of the quesA topical cream consisting of vitamins A and E, pantion unless anesthesia is used. A localized injection of 1% thenol, calendula, and comfrey will considerably enhance or 2% lidocaine into the rectal sphincter at the 3 o’clock the healing process by providing nutrients essential for and 9 o’clock positions can help relax it enough for an examination to occur. One can often see anal fissures healing by second intention. Some of the commercial preparations also contain boric acid, which acts as a without using an anoscope, simply by pulling back on the anal skin and examining the tissue. Presence of a sen- styptic. Initially, the cream should be applied topically after every bowel movement and at bedtime. As healing tinel pile or enlarged papilla suggests chronic anal fisoccurs, twice-daily application usually suffices until the sure and is the result of inflammation and the body’s lesion has resolved. attempt to protect the inflamed area. Anal spasm may be marked, making it difficult to perform an examination, Iontophoresis using a zinc electrode and applying a positive current helps facilitate healing by hardening and anal stenosis and fibrosis may be present if the condition has been chronic. the underlying fissure, decreasing bleeding, and affording pain relief.14 The patient lies on the negative disClinicians should consider the presence of Crohn’s persing pad, and current is applied for 10 minutes at disease, especially if the patient is younger, there is a history of periodic or chronic diarrhea, and the fissure 10 milliamps. The patient should be instructed not to strain during lies in the anteroposterior vertical axis. Squamous cell carcinoma, syphilitic ulcers, and, rarely, tuberculosis passage of stool and to use cotton balls that have been moistened with water rather than toilet paper or chemishould be considered as part of the differential diagnocal or alcohol wipes. Some patients are excessive cleansis.Spasm of the levator ani muscle may also make one think of anal fissure, but no lesion is present in this case. ers, and they should be instructed that it is unnecessary to wipe deep into the anal canal, because doing so makes Treatment of anal fissure can prove to be one of the the condition worse. more difficult courses of therapy for both the patient and the clinician.Although surgicalintervention removes Sitz baths also aid in the healing process by providing the lesion and alleviates the pain, the lesion invariably increased blood flow to the area. If performing a sitz returns because the underlying cause has not been bath is not possible, alternately spraying hot and cold addressed. Additionally, surgical intervention often water on the perineal area will achieve the same re~u1t.l~ predisposes to fecal incontinence later in life. Therefore Increasing dietary fiber is necessary if the condition medical management both in the short and long terms is is due to chronic constipation, whereas chronic diarrhea necessary for complete resolution. Patients must be caucan be managed through a variety of therapeutic tioned that the healing of a rectal fissure has its periods approaches once the cause is found. Dietary changes are a must, especially if the anal fissure is associated with of exacerbation and remission and that continuing with the treatment protocol is important despite the periodic irritable bowel syndrome or Crohn’s disease. The higher

Specific Health Problems rates of hemorrhoids and Crohn’s disease seen in blood group 0 individuals are believed to be due to food intolerance.16 As previously mentioned, the clinical course varies from patient to patient and seems to depend partially on whether the patient follows the treatment plan religiously. Frequent follow-up is needed to assess the healing process and reassure the patient. Once healing has occurred, maintajning proper bowel function and good dietary and bowel habits is necessary for prevention of further episodes. Patients who experience an anal fissure are at risk for further episodes.

HEMORRHOIDS Internal Hemorrhoids Affliction from hemorrhoids has been noted in the writings of various cultures throughout historyBabylonian, Hindu, Greek, Egyptian, and Hebrew. In the United States as well as other industrialized countries, hemorrhoidal disease is extremely common. Although most individuals may begin to have hemorrhoids in their 20s, hemorrhoidal symptoms usually do not become evident until the fourth decade.17J8Estimates have indicated that 50% of persons older than 50 years have symptomatic hemorrhoidal disease at one time or another and up to one third of the total U.S. population has hemorrhoids to some degree.19 The causes of hemorrhoidal disease are similar to those of varicose veins. As with varicose veins, predisposition to development of hemorrhoidsdepends on genetic makeup. Excessive venous pressure, pregnancy, long periods of standing or sitting, straining at stool, and heavy lifting are considered the major factors. Most patients have more than one predisposing factor.20 Because the portal venous system contains no valves, factors that increase venous congestion in the perianal region can precipitate hemorrhoid formation. They include increasing intraabdominal pressure (e.g., defecation, pregnancy, coughing,sneezing, vomiting, physical exertion, and portal hypertension due to cirrhosis), increase in straining during defecation, and standing or sitting for prolonged periods. Presenting symptoms are itching, burning, irritation with passage of stool, swelling of the anus and perianal region, blood on the toilet paper or in the bowl, and seepage of mucus. Most patients attribute all rectal symptoms to hemorrhoids; however, internal hemorrhoids only rarely are painful or cause itching. Usually the hallmark of a hemorrhoid eruption is bleeding or protrusion that is noted after passage of stool. Pain from internal hemorrhoids occurs when they become strangulated from prolapse and with thrombosis. Any other pain associated with hemorrhoids is usually due to a coexisting lesion such as a fissure. Itching is rarely associated with

internal hemorrhoids except if there is excess mucus discharge. Internal hemorrhoids originate above the anorectal line and are primarily found in the right anterior, right posterior, and left lateral quadrants. Other areas of the rectum demonstrate secondary hemorrhoidal veips, which are associated with excess venous congestion. Occasionallyan internal hemorrhoid enlarges to such an extent that it prolapses and descends below the anal sphincter. Internal hemorrhoids are classified according to symptomology and physical findings. Stage I hemorrhoids bleed but do not protrude. Stage 11hemorrhoids protrude after bowel movement, and then spontaneously reduce. Stage I11 hemorrhoids protrude with stool and must be manually reduced. Stage IV hemorrhoids protrude and are not reducible. Stages 11, 111, and IV may or may not bleed. With stage IV hemorrhoid, there is a possibility of strangulation, resulting in decreased blood flow and eventual thrombosis. Internal-external, or mixed hemorrhoids, are a combination of contiguous external and internal hemorrhoids that appear as baggy swellings. Often with treatment of the internal hemorrhoidal plexus, the external portion resolves. As a general rule, if a patient has external hemorrhoids, internal hemorrhoids are probably present as well. In contrast to the United States and the United Kingdom, hemorrhoids are rarely seen in parts of the world where high-fiber, unrefined food diets are consumed.19 A low-fiber diet high in refined foods contributes greatly to the development of hemorrhoids. Individuals consuming a low-fiber diet tend to strain more during bowel movements, since their smaller and harder stools are more difficult to pass. This straining raises the pressure in the abdomen, obstructing venous return. The greater pressure will increase pelvic congestion and may significantly weaken the veins, causing hemorrhoids to form.

Treatment A high-fiber diet is perhaps the most important component in the prevention of hemorrhoids. A diet rich in vegetables, fruits, legumes, and grains promotes peristalsis because many fiber components attract water and form a gelatinous mass that keeps the feces soft, bulky, and easy to pass. The net effect of a high-fiber diet is significantly less straining during defecation. Natural bulking compounds can be used to reduce fecal straining. These fibrous substances, particularly psyllium seeds and p a r gum, possess mild laxative action owing to their ability to attract water and form a gelatinous mass. They are generally less irritating than wheat bran and other cellulose fiber products. Several double-blind clinical trials have demonstrated that

supplementing the diet with bulk-forming fibers can sigruficantlyreduce the symptoms of hemorrhoids (bleeding, pain, pruritus, and prolapse) and improve bowel habits.2lrZ The use of psyllium seed fiber has been shown to afford significant relief in bleeding and pain within 6 weeks in hemorrhoid suffers.= A placebo-controlled, randomized study evaluated the efficacy of fiber supplements in 50 patients with bleeding internal hemorrhoids. Patients in the study group were treated with a commercially available preparation of Plantago ovuta, and those in the control group were treated with a placebo. Endoscopy was performed in every patient before and after treatment to establish the degree of hemorrhoidal prolapse as well as the numbers of congested hemorrhoidal cushions and contact bleeding hemorrhoids. During the first 15 days of treatment, the average number of bleeding episodes was 4.8 f 3.8 for the study group versus 6.4 f 3 for the control group (NS). During the following 15 days, it decreased to 3.1 &2.7 in the study group versus 5.5 f 3.2 (p < 0.05) in the control group, and in the last 10 days of treatment a further reduction to 1.1 f 1.4 was found in the study group compared with 5.5 f 2.9 in the control group (p < 0.001). The number of congested hemorrhoidal cushions diminished from 2.6 f 1 to 1.6 f 2.2 after fiber treatment (p < 0.01) but no differences were found in the control group. In the fiber group, hemorrhoids bled on contact in 5 out 22 patients before treatment and in none after treatment; no differences were found in the control group. No modification of the extent of prolapse was observed after treatment.” Although the effect took a few weeks to develop, the final results were very impressive. Another important, but only recently recognized dietary factor is breakfast. An age-, sex-, and pregnancymatched case-control study carried out in an outpatient clinic found a remarkable 7.5-fold increase in the odds of suffering from hemorrhoids or anal fissures in matched subjects who did not eat breakfast!= Flavonoid preparations have been shown to be beneficial in the prevention and treatment of hemorrhoids through their strengthening effect on venous tissues. Although early studies primarily utilized rutin, later research has used hydroxyethylrutosides (HERS). Several of the studies have been performed in pregnant women where HERS were shown to be of great benefit in helping relieve hemorrhoidal signs and symptoms. In one study, 90% of the women given HER (1000 mg daily for 4 weeks) experienced improvement of symptoms, compared with only 12% in the placebo gr0up.2~Similar results in hemorrhoids not associated with pregnancy have been rep0rted.2~BAnother study provided a micronized flavonoid combination (diosmin 90% and hesperidin 10%)for a median of 8 weeks before delivery and 4 weeks after delivery to 50 pregnant women with acute hemorrhoids. Their therapy was

very successful, with 66% of patients reporting relief from symptomsby the fourth day of treatment and fewer suffering relapses during the antenatal peri0d.2~Treatment was well accepted and did not affect pregnancy, fetal development, birth weight, infant growth, or feeding. In most circumstances, topical treatments for acute or chronic hemorrhoids involving the use of suppositories, ointments, and anorectal pads provide only temporary relief. Many over-the-counter products for hemorrhoids primarily contain natural ingredients, such as witch hazel (Humamelis), cocoa butter, Peruvian balsam, zinc oxide, allantoin, and homeopathic preparations. Many patients use hydrocortisone cream to help with itching that they associate with hemorrhoids; prolonged use of this agent can often aggravate the pruritus ani, setting up a circle of continued use.

Botanical Medicines Botanical medicines have had a long history of use for hemorrhoids. They can be used topically, used as suppositories, or taken orally to support redundant tissue and facilitate healing. Use of rectal suppositories after galvanic, infrared or laser therapy helps facilitate healing and decrease bleeding. Some of the more commonly used botanical medicines are discussed later in this chapter. Hydrotherapy The warm sitz bath is an effective noninvasive treatment for uncomplicated hemorrhoid^.'^,'^ Although a warm sitz bath is a useful treatment for an acute hemorrhoidal flare-up, alternating hot and cold sitz baths is better suited to facilitate healing of chronic conditions. Surgical Treatment A variety of surgical and nonsurgical methods of treating hemorrhoids exist, the choice of which often depends on the stage of the hemorrhoid and the expertise of the physician. Stage I or 11 hemorrhoids can often be managed medically, especially if they are acute. Herbal rectal suppositoriesalong with the indicated homeopathic medicine often aid quick resolution of the flare-up. In uncomplicated cases of stage I or I1 hemorrhoids, unless the patient is exhibiting symptoms, treatment is usually not recommended except for increasing dietary fiber and addressing the patient’s dietary choices. Injection of sclerosing agents are useful in stage I and stage 11hemorrhoids but are contraindicated in patients with anal fissure, inflammatory bowel disease, Crohn’s disease, leukemia, or portal hypertension. Sclerosing therapy is not usually effective against stage I11 and IV hemorrhoids. Rubber-band ligation of hemorrhoids is a widely used in-office procedure that removes redundant tissue and causes scarring, which is replaced then by new tissue. Patients often have a sense of fullness or pressure in the

Specific Health Problems

rectum, and pain occurs if the band is placed too close to the pectinate line. Postbanding bleeding can occur, and there have been reports of complications resulting in septicemia and death.2O Rubber-band ligation is used primarily for stage I, stage 11, and occasionally stage Lll hemorrhoids, and its success is largely a function of the physician‘s ability to place the bands. Cryosurgery involves the application of liquid nitrogen or nitrous oxide to the hemorrhoid, which causes destruction of the venous plexus, scarring, and eventual tissue replacement. Used primarily for stage 11and stage III hemorrhoids, the procedure is also useful if condyloma is present. It is contraindicated for stage IV hemorrhoids, chronic ulcers, and acutely thrombosed hemorrhoids. Pain, swelling, and bleeding may occur after cryosurgery. Hemorrhoidectomy, or the surgical removal of redundant tissue, is by far the most invasive of the hemorrhoid procedures. This procedure often requires an outpatient surgical setting and causes the patient to lose time from activities of daily living so healing can take place. Most patients seek alternative treatments in order to avoid surgery and its complications, such as pain and rectal sphincter instability. The monopolar direct current technique for hemorrhoid management is becoming a sigruficant treatment of choice in the United Statesm According to a report by Machicado et a1,3’ this painless outpatient treatment of all grades of hemorrhoids is effective and safe. This methodology warrants consideration as the treatment of choice for hemorrhoidal disease. The first published work on monopolar direct current (also called inverse galvanism) was published by Keesef2 of Chicago. Dr. Keesey dated the first use of this approach to 1897, although the technical problems (producing a smooth uninterrupted galvanic current source) were not worked out until approximately 1925. The technique then began to be used in general practice. Monopolar ablution of hemorrhoidal tissue lost favor in conventional medicine not because it was ineffective but because newer techniques and advances in surgery made it less attractive. Without the naturopathic medical schools teaching the Keesey treatment over the last 60 years, it is very possible that this irreplaceable technique would have been lost to the healing arts. A later study showed that direct current electrotherapy also relieves the chronic anal fissures often associated with internal hemorrhoids. All 10 of the patients in the reported study experienced relief of chronic anal pain within two treatments, and anal fissures healed in 9 within 4 weeks. One patient experienced a perianal abscess and fistula, requiring surgery.There were no recurmces in 20 months (mean) of follow-up.3l The monopolar direct current technique is purely an office procedure. No anesthesia is needed, except a local

anesthetic for the occasional hypersensitive or nervous patient (in such instances, a 2% procaine solution is injected directly into the hemorrhoid). To date, there have been no reported cases of stricture or metastatic abscesses, a fact that speaks well for the procedure’s safety. The chemicophysiologic action, which causes the absorption and destruction of a vein, is responsible for the permanency of the cure. The mechanism of action of monopolar direct current is well understood. When introduced into the interior of the hemorrhoid, the negative pole of the galvanic current makes contact with the water of the blood and tissues and generateshydrogen gas and hydroxide ions. The hydroxide destroys the organized structure of the hemorrhoid and its capillary circulation. This produces first a hydrolysis and then a hardening of the hemorrhoid. The final disappearance of the hemorrhoid is brought about in one of two ways. It is either absorbed like any bodily contusion or, if the hemorrhoid is large, it ruptures, causing a discharge of the thrombosed elements into the rectum, followed by a contraction of the residual hemorrhoidal tissues. What makes the Keesey technique attractive is that the patient may be freely ambulant after completion of the procedure and can return to normal activities of daily living. The hemorrhoid disappears 7 to 10 days after the treatment. Each separate hemorrhoid is treated in the same manner, and larger hemorrhoids may have to be treated more than once. Generally it is a good policy to treat only one hemorrhoid, or at most two hemorrhoids, at a time because of the healing that must occur and the higher risk of bleeding. Infrared coagulation (IRC) is effective with stage I and stage 11hemorrhoidsbut can be combined with the Keesey treatment for stage I11 and stage IV lesions. Whereas the Keesey technique utilizes current, the infrared coagulator utilizes a burst of intense heat generated internally and shot through a blue anodized sapphire tip to the surface of the hemorrhoid. The IRC “coagulates”the redundant tissue to a depth that is a function of the duration of the light burst, usually 1 to 1.5 seconds. As with the Keesey technique, a 7- to 10-day period of healing should occur between treatments. Many naturopathic physicians who utilize the Keesey treatment also incorporate IRC, as doing so usually reduces the number of treatments needed per hemorrhoid. Compared with rubber-band ligation, laser therapy and cryotherapy, IRC has been shown to produce better results and less morbidity.3s35

Prevention As with all diseases, the primary treatment of hemorrhoids is prevention. This involves reducing factors that may be responsible for increasing pelvic congestion, such as straining during defecation, sitting or standing for prolonged periods, and underlying liver disease. Ahigh-fiber

Proctologic Conditions

diet is crucial for the maintenance of proper bowel activity, and nutrients and botanical substances that enhance the integrity of venous structures may also be of benefit. Warm sitz baths and topical preparations are useful to ameliorate the discomfort but have only transient results. A high-complex carbohydrate diet rich in dietary fiber is indicated. The diet should contain liberal amounts of proanthocyanidin- and anthocyanidin-rich foods, such as blackberries, cherries, and blueberries, to strengthen vein structures. Supplements such as vitamins A and B complex, antioxidants such as vitamins C and E, and zinc will help maintain vascular integrity and facilitate healing. When indicated, the monopolar direct current method, specifically designed for hemorrhoid treatment, will give permanent results. This technique is especially useful in advanced hemorrhoidal disease and, when coupled with the necessary diet and lifestyle changes, considerably decreases the likelihood of recurrence.

External Hemorrhoids External hemorrhoids occur when there is dilatation of the external rectal plexus or thrombosis after an episode of constipation, diarrhea, heavy lifting, or Valsalva effect from sneezing, coughing, or childbirth.The patient notices an often painful perianal lump, and some bleeding may be associated with it. External hemorrhoids usually pose mild to little discomfort and largely resolve on there own if homeostasis is restored. External anal skin tags found on examination are the remnants of previous external hemorrhoids. If, however, the hemorrhoid becomes thrombosed, a circle of acute edema and pain is set up that may lead to surgical intervention. As the lesion becomes increasingly distended, varying degrees of pain and swelling can be found, which are often exacerbated by passage of stool or from prolonged sitting. The patient may report bleeding after stool, which is due to a disruption of the hemorrhoid.% A prolapsed internal hemorrhoid should also be considered as part of the differential diagnosis for external hemorrhoid, as should perianal abscess, rectal fissure with sentinel pile, hypertrophied anal papillae, irritated skin tag, condyloma latum, and condyloma acuminata.

Treatment Unless the hemorrhoid has thrombosed and the patient is in excessive pain, an external hemorrhoid can usually be managed medically. Initial treatment should be to relieve the pressure and dissolve whatever thrombosis has formed. As healing occurs, long-term management in the form of patient education, dietary changes, and enhancement of vascular integrity should be undertaken to help prevent further episodes. Initial treatment with the enzyme protease 315 mg, two capsules between meals tid and two capsules

at bedtime, will help reduce the thrombosis and decrease pain. Alternating hot and cold sitz baths act to relieve pain and increase blood flow. A number of homeopathic medicines, such as Aesculus, aloe, Hamamelis, muriatic acid, Ratanhia, and Sepia,83’are effective in relieving pain and speeding the course of healing. A clinical repertory or materia medica should be consulted, because there are a number of remedies that will provide relief. Long-term management should involve identification and removal of the precipitating cause and education of the patient as to the cause and how to prevent further episodes. Dietary changes to eliminate offending foods while increasing dietary fiber in the form of fruits and vegetables or an over-the-counter fiber supplement are warranted. Herbal medicines such as Aesculus, Collinsonia, Hamamelis, and Althea or U l r n ~will s ~ help restore venous sufficiency and soothe inflamed tissues. In some cases regulation of bowel function with the use of herbal laxatives may be necessary while normal intestinal and colon function is restored. A variety of commercially available herbal medicines and fiber compounds are effective. In patients who are experiencing an acute episode of a thrombosed external hemorrhoid, prompt surgical excision or incision is in order. Because the external skin is innervated by somatic nerves, administration of anesthesia is needed before evacuation of the clot. Excision leaves a wound that should not be sutured but should be allowed to heal by second intention, but causes greater postoperative pain. Incision and debridement of the clot allow for less pain, but the wound may close too early, leading to re-formation of the thrombus. A minor or rectal and colon surgical text should be consulted as to proper surgical technique. Starting the patient on herbal anodynes such as Piscidia, belladonna if pain is due to rectal spasm, and Hyoscyamus niger can facilitate postoperative management. Healing and pain relief can be afforded with the topical use of Arnica, Hypericurn, and in particular calendula succus. Alternating sitz baths with 1/2 oz of povidone-iodine added enhances healing and helps reduce the chance of infection. As with medical treatment, protease 2400 MCUs can be added for pain relief. Homeopathic agents such as Arnica, Calendula, and staphysagria should also be considered for pain relief.

PERIANAL DERMATOLOGIC DISORDERS Condylomata Acuminata A patient presenting with condylomata acuminata may complain of a sticking or foreign body sensation perianally. If the lesion is large enough, defecation can be interfered with and hygiene becomes a problem. The lesion is usually soft, moist, reddish pink, and pedunculated. Differentiation from condylomata lata

Specific Health Problems of secondary syphilis is necessary because the treaments differ and the potential for transmission is greater with the latter disorder. A rapid plasma reagin (RPR) test with reflexive fluorescent treponemal antibodies (ETA)is warranted. If darkfield microscopic examination is available, it should also be performed. Diagnosis of condylomata acuminata is made through biopsy. A solution of 25% podophyllum applied topically for 6 to 8 hours, at which time it is washed off by the patient, has been shown to be effective. Several applications may be necessary in order to eradicate the lesion3 Cryosurgery is also available, as is IRC after subcutaneous injection of 1%or 2%lidocaine.40Althoughnaturopathic and homeopathic philosophy decries the "suppression" of lesions as contributing to a deepening of the disease process, concomitant administration of the proper homeopathic medicine coupled with a good nutritional program rarely causes this to happen. Often, administration of homeopathic Thuju is indicated, but a number of other homeopathic remedies cover genital warts. The taking of a constitutional case not only helps with the eradication of the lesion but also acts to decrease the patient's susceptibility to development of further lesions, a frequent occurrence.

Condyloma Lata Condyloma lata, or anogenital wart, is caused by human papillomavirus(HPV) types 6,11,16,18,31,33, and 35 and is transmitted by sexual contact. Lesions appear as soft, moist, pink to gray, flat to pedundated excrescencesthat are often found in clusters. More often located in warm, moist regions of the anogenital region, they are more commonly found clustered around the anus in homosexual men and in women who practice anal intercourse.4l Lesions must be differentiated from the flat lesion seen with the condyloma lata of secondary syphilis. A diagnosis of squamous cell carcinoma should be considered if the lesion does not respond to therapy, or biopsy can be performed." Various naturopathic therapies are available, among them being treatment with 25% podophyllum, Thuju ointment, homeopathic prescription, cryotherapy, IRC, and electrosurgical des~ication.4~

Lymphogranuloma Venereum The infective agent in lymphogranuloma venereum (LGV) is one of the serotypes of Chlamydia truchomtis, and the lesion may first appear as a papule that ulcerates and heals rapidly. If the primary lesion is in the rectal mucosa, the patient presents with the signs and symptoms of proctitis. This is then followed by the development of inguinal adenitis or buboes that are extremely painful. The later stages may manifest as fistulation, ulceration, fibrosis, and rectal or anal stenosis and can lead to lymphedema of the legs and genitalia.

Non-LGV Chlamydia serotypes can also be implicated in proctitis but generally do not have as severe presenting symptoms. White blood cell counts may reach 20,000 cells/mm3 if there is lymphatic involvement, and the patient may exhibit anemia. Culture of the chlamydia1 serotype from an infected lesion is diagnostic, but complement fixation and immunofluorescentantibody tests are available.44 If treated promptly the prognosis is good, but once the disease has begun to affect cellular changes, the prognosis becomes worse as the degree of pathology can be considerable.For the most part allopathic treatment consists of antibiotics such as doxycycline, erythromycin, and sulfisoxazole which have been found to be effective against LGV.44Various homeopathic as well as herbal medicines can be used. See treatments under Proctitis.

Herpes Probably the most commonly encountered perianal lesion, herpes typically manifests as a burning, searing pain that may be confused with that of a rectal fissure. Examination reveals vesicles on an erythematous base that soon erode and form ulcerations. In patients with HIV or other immunocompromising conditions, the lesions can form deep ulcerations and have a prolonged course of duration. Diagnosis is by Tzanck smear or viral culture. Initially treatment protocols should address the current eruption, because longer-term prevention strategies usually take time to work. Topical preparations consisting of deglycyrrhized licorice (DGL) and Melissa officinalis extracts can help alleviate local symptoms of burning and pain as well as facilitate the healing process. Zinc sulfate 2% has also been used topically with some success. Various homeopathic medicines not only address the pain and eruptions but also help decrease the patient's susceptibility to development of outbreaks. Stress reduction is important as well because herpes eruptions often occur during periods of excessive stress or other illness. Long-term strategies include decreasing the argininecontaining foods in the diet, such as nuts, legumes (especially peanuts), and chocolate. Supplementing lysine at 500 to 1000 mg/day is useful in eliminating outbreaks. Antioxidants such as vitamins C and E as well as B complex vitamins, zinc, and copper have all been shown to be of benefit.

Pilonidal Sinus Pilonidal sinus is a rare congenital tract that m from the coccyx or sacrum to the perineum with constant drainage. Both congenital and acquired factors play a role in the development of a pilonidal sinus. The condition is most commonly seen in young white adults, rarely in black persons, and almost never in Asians. Congenital postanal dimples predispose to the formation

Proctologic Conditions of a pilonidal tract as well as obesity, a deep intergluteal cleft, and excess body hair. The condition is usually differentiated from anal fistula and furunculosis because of its midline orientation and through the passing of a probe through the sinus, noting its passage toward the sacrum rather than the anus. Patients seek treatment because of the often chronic nature of the discharge. If the sinus becomes infected, incision and drainage may be needed, but irrigation with the herbal formula mentioned for abscess can be performed. Weight reduction and removal of excess hair in the region also helps reduce the risk of infection and symptoms. Homeopathic medicines selected according to the presentation, such as silicea, calcarea sulphuricum, and hepar sulphuris, have proved useful. Additionally, homeopathic Thuja as an intercurrent treatment has resolved a number of obstinate cases.

Proctalgia Fugax Proctalgia fugax, or levator spasm syndrome, is more common in men than women and manifests as an often searing pain near the coccyx or rectum that lasts for a brief but intense period, usually resolving on its own. The episode often wakens the person from sleep but may OCCLU at any time. Caused by a spasm of the levator ani or pubococcygeal muscle, proctalgia fugax produces a deep-seated, often heavy, aching or searing pain that feels as if it is localized in the rectum and/or prostate in men. Examination reveals a tense and tight levator ani muscle that is tender with pressure and is often drawn up above the anal sphincter. Mechanisms that are thought to trigger an episode are poor posture, chronic anxiety, and mental fixation on the rectal area as well as misalignment of the coccyx or other bones composing the pelvic bowl. Differential diagnosis includes lumbar disc disease, coccygodynia, prostatitis, presacral tumor, developing ischiorectal abscess, spinal cord tumor, and rectal lesion. Treatment often takes the form of reassuring the patient as to the etiology of the condition. Muscle relaxants and hot packs may be of benefit. Spinal and pelvic bone adjustments may also be of use, as is massage to the lower abdomen, lumbosacral spine, and perineum. Chronic cases often respond to deep tissue work such as Rolfing.

Proctitis Proctitis usually manifests as rectal pain, tenesmus, rectal discharge, and blood in the stool. White blood cells may be present in large numbers, being evident on wet preparation, Gram stain, or Wright stain. As there are a variety of causes for the inflammation, an anoscopic examination is warranted to examine the rectum for inflammation, mucopurulent discharge, mucosal friability, bleeding,

and ulceration. Severe ulceration and bleeding are associated with infection by the LGV Chlamydia serotype. Among the causative agents are Chlamydia (usually of the genital immunotypes but also the LGV immunotypes), yeast, bacteria such as Neisseria gonorrhoeae, parasites, trauma, lectins, excessive fiber in the diet, external irradiation, syphilis, Trichornonas, and Crohn’s disease. One study demonstrated a higher risk for development of ulcerative proctitis in smokers and persons who had a previous appendectomy? Determination of the etiologic agent dictates the course of treatment and expected outcomes. If the cause is extemal-beam irradiation for colon cancer or radium seed implants for prostate cancer, the therapy should commence before cancer treatment and continue during it and for several weeks after treatment has ceased. In a study examining the effects of radiation and antioxidant it was demonstrated that a “substantial number of patients with radiation proctitis seem to benefit from antioxidant therapy.” Despite admonitions by radiation oncologists that antioxidant therapy should be discontinued, a review by Lamson and B r i g x ~ a l l ~ ~ , ~ demonstrated no ill effects when irradiation was combined with antioxidant therapy. As part of the therapeutic regimen for radiation proctitis, concomitant administration of homeopathic radium bromatum 200c before and after treatment helps decrease skin burning. Other homeopathic medicines may also be indicated, such as X-Ray, Sol, and cadmium metallicum. Additionally, the use of demulcent rectal suppositorieshelps soothe the inflamed rectal mucosa and decrease pain. If the proctitis is secondary to an inflammatory bowel condition, treatment of the underlying disease results in healing of the rectum as well. This can be accomplished by addressing the patient’s diet, providing adequate fiber, and administering herbal demulcents and entericcoated peppermint to soothe the inflamed intestinal tract. Short-chain fatty acids administered rectally were shown in one study to alleviate symptoms of proctocolitis, and a deficiency of such acids should be considered as part of the clinical pre~entation.4~,~ In cases in which an infective agent such as bacteria, Chlamydia, yeast, fungi, trichomonads, or a parasite is identified as the etiologic agent, a variety of naturopathic treatments have been found empirically to be effective. Among them are injection of ozone, use of herbal suppositories, homeopathic medicines, and a retention enema consisting of Hydrastis, Usnea, Echinacea, yarrow for T’chomonas, and Altka in a base of 0.9% NaCl has proven effective. This combination can be applied topically during the initial examination to begin treatment. Antioxidantssuch as vitamins C and E, as previously mentioned, facilitate healing. As a general rule, treatment of proditis should continue for 10 to 14 days before reexamination and assessment.

Specific Health Problems In cases of ulcerative disease, treatment may need to be continued longer to allow for complete healing.

Pruritus Ani Pruritus ani is characterized by chronic itching of the perianal skin with excoriation from scratching and an eventual thickening of chronically affected areas. Patients often scratch at night during sleep or are awakened from sleep by the itching. Patients may complain of intermittent to constant itching, burning, and soreness that often awake them at night. Use of topical ointments may provide some relief, but symptoms return when they wear off. Examination may show varying degrees of erythema, swelling, excoriation, thickening, and fissuring due to scratching. The stage is set for development of pruritus ani when the normal skin protective barriers have broken down. Various agents contribute to this process, such as excessive wiping with harsh toilet papers, use of "wipes" that are impregnated with drylng alcohol, dyes, and antibacterial or fungal agents, reactions to synthetic undergarments or detergents used to launder them, and the wearing of too tight underclothing, which decreases air circulation. Patients with chronic diarrhea or loose stools are at increased risk because of the stools' often acidic nature.5152In some cases, removal of normal hair growth for cosmetic purposes also contributesbecause it disrupts the normal bacterial flora in this region of the body. Pinworms and Cundida are the two most common infecting agents in pruritus ani.In particular, a history of perianal itching largely at night should alert the physician to the possibility of Enterobius vermiculuris infestation (pinworms). This is a common etiologic agent in children and can be spread to other members of the family with considerable ease. A wet preparation will demonstrate Candidu, and a clear adhesive tape preparation for pinworms helps establish the diagnosis. Patients with episodes of periodic or chronic diarrhea are also at increased risk of pruritus ani. It can occur because of the acidic nature of the stool but most often is due to aggressive cleaning of the area afterwards. Compulsive cleaners should be instructed on the use of cotton wipes, bath or shower cleansing, or the use of moist towels. The frequent use of soaps, detergents, bleaches dyes, or perfumes can also contribute to the development of pruritus ani. A recent onset may be due to a change in a product, and the physician should ask questions about it. Certain foods that frequently aggravate the condition are peanuts, coffee, colas, beer, and spicy foods?," Highly acidic foods and foods that are responsible for an allergic reaction in the patient should be suspected and eliminated for several weeks. Psoriasis, contact dermatitis, precancerous or cancerous lesions, Bowen disease (interepithelialepithelioma),

keratoacanthoma, melanoma, squamous cell carcinoma, and basal cell carcinoma can also cause pruritus ani. Laboratory tests to consider are culture and sensitivity testing if bacterial infection is suspected, a potassium hydroxide and/or wet preparation to look for yeast or fungi, Wood lamp examination for Tineu cruris, and a punch biopsy for suspicious lesi0ns.5~

Treatments Treatmentsinclude eliminationof spicy or offending foods or of food allergies and improvement of the patient's digestion. If an infective agent is identified, a course of topical therapy to remove the yeast, fungi, or bacteria should be initiated. Initial washing with 3% hydrogen peroxide followed by application of a topical herbal formula containing Usneu, Hydrastis, Spilunthes, oregano, and tea tree oil, which is then allowed to dry, helps eliminate the infective agents. In order to reestablish the skin's defensive barrier, this step should be followed by a healing salve containing Calendula, comfrey, and vitamins E and A. Relief should be obtained within 7 to 10 days if the underlying cause has been eliminated. For pinworms, numerous naturopathic treatments have proved to be effective. Additionally, all clothing and bedding should be washed in warm to hot water to eliminate the eggs that have been laid outside the rectum at night. Various homeopathic medicines are also effective and may help prevent future episodes in chronic cases. Having the patient use moist cotton wipes after stool and eliminating excess moisture in the perineal area helps break the circle. Topical application of zinc oxide also has proved effective in the treatment of pruritus ani.

Botanicals Use of botanical medicines for the treatment of anorectal diseases has been utilized throughout history by many different cultures. Many of the plants used by the various folk traditions are of the same genus, varying by species only, whereas others are unique to their locations. More recent examinations of the various botanical medicines have elicited their chemical properties and actions, but the Eclectic and herbalist traditions have also placed an importance on the symptom specificity of the medicine. Doing so enhances its healing effect. Aesculus hippocustunum is classified as a tonic, astringent, febrifuge, narcotic, and antiseptic. High in tannic acid and aesculin, this herbal medicine is good for pain relief of internal viscera and is indicated for hemorrhoids and rectal irritation when there is marked congestion and a sense of spasmodic closing of the rectum as if there were a foreign body present. Additionally, it is effective for itching, a sensation of heat, aching, and rectal pains. It also has been found to be useful for rectal neuralgia and proctitis.38

Proctologic Conditions

Achillea millejblium (yarrow)p ~ ~ ~ e sslightly s e s astringent properties as well as being an alterative and dimtic. It acts as a tonic on mucous membranes to stem the flow of mild hemorrhage, and thus is used for bleeding hemorrhoids, especiallyif they are accompanied by mucoid discharges.% Althea oficinalis (marsh mallow) is high in mucilage, which helps restore the electrical charge to inflamed rectal mucosa. It is often put into rectal suppositories because of its ability to decrease swelling, irritation, and inflammation.38 Cinnamomum (cinnamon) is largely found in herbal rectal suppositories because if its ability to stem hem~rrhaging.~~ Collinsoniu canadensis (stone root) is an alterative, tonic, stimulant, and diuretic. It is used primarily for its effects on the venous system, because it tones vascular tissue. It is especially indicated for hemorrhoids due to chronic constipation and venous insufficiency. Patients do affected have a sense of constriction, weight, and heat in the rectum and pass very dry stools. It is also useful for proctitis, anal fistulas, and rectal ulcer.% Hamamelis virginiana (witch hazel) is primarily a tonic and astringent. It affects the venous system by restoring vascular integrity, so is an excellent medicine for varicose veins, hemorrhages, and hemorrhoids. Indications for its use are venous tissues that are pale and in various states

of flaccidity but may also possess a deep redness because of vascular engorgement and stagnation of blood flow. The hemorrhoidal tissues are usually very painful and may have a tendency to ulceration.% Hydrastis canadensis (goldenseal) contains hydrastine, berberine, canadine, and acrid resins. It exerts its action upon the mucous membranes and affects the healing of ulcerations while controlling mild hemorrhages in addition to having antibacterial properties. Additionally it has an astringent effect upon hemorrhoids.Goldensealis indicated for hemorrhoids due to constipation with a sinking feeling in the stomach and a dull headache and for anal fissures that are painful with severe burning before, during, and after Ruscus aculeatus (butcher’s broom) acts upon the venous system, where it reduces swelling and has a vasoconstrictive action, thus reducing bleedh1g.5~

1.Moore K. Clinically Oriented Anatomy. Baltimore: Williams & Wilkins, 1980. 2. Clemente C. Anatomy: a regional atlas of the human body, ed 2. Baltimore: Urban & Schwarzenberg, 1981. 3. Hirschman L. Synopsis of ano-rectal diseases, ed 2. St Louis: CV Mosby, 1942. 4. JanickeDM, Pundt MR. Anoredal disorders. Emerg Med Clin North Am 1996;14757-788. 5.Goldstein S. Anal fissures and fistulas. Postgrad Med 1987;82 86-92. 6.Kempe H, Silver H, OBrien D. Current pediatric diagnosis & treatment, 8th ed. Los Altos, C A Lange Medical, 1984. 7. Andiran F, Dayi S, Mete E. Cows milk consumptionin constipation and anal fissure in infants and young children. J Paediatr Child Health 2003;39:329-331. 8. Kruzel T. The homeopathic emergency guide: a quick reference handbook to effective homeopathic care. Berkley, CA: North Atlantic Books, 1992. 9. Vermeulen F.Concordant rnateria medica. Haarlem, The Netherlands: Emryss bv Publishers, 1997. 10. Scholefield JH, Lund JN.A nonsurgical approach to chronic anal fissure. Hosp Pract 1997;32:181-188. 11. Kua KB, Kocher HM, Kelkar A, et al. Effect of topical glyceryl trinitrate on anodermal blood flow in patients with chronic anal fissures. A N Z J Surg 2001;71:548-550. 12. Kennedy ML, Sowter S, Nguyen H, et al. Glyceryl trinitrate ointment for the treatment of chronic anal fissw: results of a placebocontrolled trial and long-term follow-up. Dis Colon Rectum 1999; 42:1o00-1006.

13. Nelson R. A systematic review of medical therapy for anal fissure. Dis Colon Redurn 2004;47:422-431. 14. Mc Dowell B, Kruzel T. Physiotherapy-supplemental notes. Portland, OR NCNM Press, compiled 1997-1998. 15.Boyle W, h e A. Lectures in naturopathic hydrotherapy. East Palestine, OH: Buckeye Naturopathic Press, 1988. 16.DAdamo P. Eat right 4 your type. Complete blood type encyclopedia: the A-Z reference guide for the blood type connection to symptoms, disease, conditions, vitamins, supplements, herbs, and food. New York Riverhead Books, 2002. 17. Robbins SL, Cotran RS, Kumar V. Pathologic basis of disease. Philadelphia: WB Saunders, 1984:836-841,859-862. 18. Berkow R, ed. The Merck manual of diagnosis and therapy, ed 14. Rahway, NJ: Merck Sharp & Dohme Research Laboratories, 1982 560-566. 19. Trowell H, Burkitt D, Heaton K. Dietary fibre, fibredepleted foods and disease. London, Orlando: Academic Press, 1985. 20. Leff E. Hemorrhoids. Postgrad Med 1987;8295-101. 21. Moesgaard F, Nielsen ML, Hansen JB, et al. High-fiber diet reduces bleeding and pain in patients with hemorrhoids. Dis Colon Rectum 1982;253454-456. 22. Webster DJ, Gough DC,Craven JL. The use of bulk evacuant in patients with haemorrhoids. Br J Surg 1978;65:291-292. 23. Burbrick ME’, Benjamin RB. Hemorrhoids and fissures: common problems, current solutions. Post Graduate Medicine 1985;77: 165-169,172-174. 24.Perez-Miranda M, GomezCedenilla A, LeonColombo T, et al. Effect of fiber supplements on internal bleeding hemorrhoids. Hepatogastroenterology1996;43:1504-1507.

Homeopathic Medicines Various homeopathic medicines have proved to be very effective in the treatment of anorectal diseases. Often a few key symptoms manifesting during the initial consultation guide the practitioner to the correct medicine, thus decreasing the need to take a full constitutional case. A number of homeopathic references are available for consultation.

25.Ahmed SK, Thomson HJ. The effect of breakfast on minor anal complaints: a matched case-control study. J R Coll Surg Edinb 1997;42:331-333. 26.Annoni F, Boccasanta P, Chiurazzi D, et al. [Treatment of acute symptoms of hemorrhoid disease with high-dose oral @@etahydroxyethy1)-rutosides.]Minerva Med 1986;77:1663-1668. 27. Wijayanegara H, Mow JC, Achmad L, et al. A clinical trial of hydroxyethylrutosidesin the treatment of haemorrhoids of pregnancy. J Int Med Res 1992;2054-60. 28. Wadworth AN, Faulds D. Hydroxyethylrutosides.A review of its pharmacology, and therapeutic efficacy in venous insufficiency and related disorders. Drugs 1992;44:1013-1032. 29. Buckshee K, Takkar D, Aggarwal N. Micronized flavonoid therapy in internal hemorrhoids of pregnancy. Int J Gynaecol Obstet 1997; 57145-151. 30.Norman DA, Newton R, Nicholas GV. Direct current electrotherapy of internal hemorrhoids: an effective, safe, and painless outpatient approach. Am J Gastroenterol1989;84:482-487. 31. Machicado GA, Cheng S, Jensen DM. Resolution of chroNc anal fissures after treatment of contiguous internal hemorrhoids with direct current probe. Gastrointest Endosc 1997;45157-162. 32. Keesey WE. Obliteration of hemorrhoids with negative galvanism. Arch Phys Ther X-ray, Rad 1934;September. 33. Eitan A, Bishara B, Duek DS,et al. Comparison of infrared coagulation and rubber band ligation for treatment of haemorrhoids. Anus 1989;x11/90:88-91. 34. Antonelli A. Infrared coagulation of hemorrhoids. Endosc Rev 1989; Jan-Feb75-76. 35. O’Connor JJ. Infrared coagulation of hemorrhoids. Pract Gastroenterol1986;108. 36. Jongen J, Bach S, Stubinger SH, et al. Excision of thrombosed external hemorrhoid under local anesthesia: a retrospective evaluation of 340 patients. Dis Colon Rectum 2003;%1226-1231. 37.Guemsey W. Homeopathic therapeutics of hemorrhoids, ed 2. Philadelphia: Boericke & Tafel, 1892. 38.Felter HW, Lloyd JU. King’s American dispensatory, ed 18. Cincinnati Ohio Valley Co, 1983. 39. Beutner KR, von Krogh G. Current status of podophyllum for the treatment of genital warts. Semin Dermatol1990;9:14&151.

4O.Bekassy Z, Westrom L. Infrared coagulation in the treatment of condyloma acuminata in the female genital tract. Sex Transm Dis 1987;14209-212. 41. Beers MH, Berkow R. The Merck manual of diagnosis and therapy, ed 17. Whitehouse Station, NJ: Merck Research Laboratories, 1999. 42. Lookingbill D, Marks JG Jr. Principles of dermatology. Philadelphia: WB Saunders, 1986. 43. Traub M. Dermatological diagnosis and natural therapeutics, ed 2. Portland, OR NCNM Press, 1985. 44.Tanagho E, McAninch J. Smith’s general urology, ed 14. Norwalk, CT.Appleton & Lange, 1995. 45. Ghirardi M, Nascimbeni R, Mariani PP, et al. [Course and natural history of idiopathic ulcerative proctitis in adults.] Ann Ital Chir 2OO2;73:155-158. 46.Kennedy M, Bruninga K, Mutlu EA, et al. Successful and sustained treatment of chronic radiation proctitis with antioxidant vitamins E and C. Am J Gastroenterol2001;961080-1084. 47. Lamson DW, Brignall MS. Antioxidants in cancer therapy: their actions and interactions with oncologic therapies. Altem Med Rev 1999;4:304-329. 48. Lamson D, Brignall M. Antioxidants and cancer therapy II: quick reference guide. Altem Med Rev 2000;5:152-163. 49. Kiely EM, Ajayi NA, Wheeler RA, et al. Diversion procto-colitis: response to treatment with short-chain fatty acids. J Pediatr Surg 2001;36:1514-1517. 50.Head KA, Jurenka JS. Inflammatorybowel disease part I ulcerative colitis-pathophysiology and conventional and alternative treatment options. Altem Med Rev 2003;8247-283. 51. Alexander-Williams J. Pruritus ani. What to do, what not to do to control this internal itch. Postgrad Med 1985;77:56-59,62,65. 52. Aucoin EJ. Pruritus ani. Postgrad 1987;82:76-80. 53. Jacobs DS, ed. Laboratory test handbook with key word index, ed 2. Baltimore: William & Wilkins, 1990. 54.Boericke W. Materia medica with repertory, ed 9. Philadelphia: Boericke & Runyon, 1927. 55. Tiiper S. Herbal medicine: from the heart of the earth. Creswell, OR Wise Acres, 1999.

Psoriasis Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER C O N T E N T S Diagnostic Summary

2079

General Considerations 2079 Therapeutic Considerations 2080 Gastrointestinal Function 2080 Nutrition 2082 Psychological Aspects 2083 Physical Therapeutics 2083 Topical Treatments 2083

DIAGNOSTIC SUMMARY Sharply bordered reddened rash or plaques covered with overlapping silvery scales Characteristically involves the scalp, the extensor surfaces (backside of the wrists, elbows, knees, buttocks, and ankles), and sites of repeated trauma Family history in 50% of cases Nail involvement results in characteristic ”oil drop” stippling (yellowish brown spots under the nail plate) Possible arthritis

GENERAL CONSIDERATIONS Psoriasis is an extremely common skin disorder. Its rate of occurrence in the United States is between 2% and 4% of the population. Psoriasis affects few black people in tropical zones but is more common among those in temperate zones. It appears commonly among Japanese but is rare in American Indians. Psoriasis affects men and women equally, and the mean onset is 27.8 years of age, although 2% of patients show onset by 2 years of age. Psoriasis is the classic example of a hyperproliferative skin disorder. The rate of cellular division rate in psoriatic lesions is very high (1000 times greater than in normal skin), exceeding the rate in squamous cell carcinoma. Even in uninvolved skin/ the number of proliferating cells is up to 2.5 times greater than in people without psoriasis. It is thought that the basic defect lies within the skin cells themselves, in combination with abnormal immune

Therapeutic Approach 2084 Diet 2084 Supplements 2084 Botanical Medicines 2085 Psychological 2085 Physical Medicines 2085 Topical Treatment 2085

system stimulation. The incidence of psoriasis is increased in human leukocyte antigen (HLA)types HLABI3, HLA-B16, and HLA-BI7, reflecting a possible genetic error in mitotic control that is confirmed by the observation that 36%of affected patients have one or more family members with ps0riasis.l The rate at which cells divide is controlled by a delicate balance between two internal control compounds+yclic adenosine monophosphate (CAMP)and cyclic guanosine monophosphate (cGMP). Increased levels of cGMP are associated with greater cell proliferation; conversely, increased levels of CAMP are associated with enhanced cell maturation and decreased cell proliferation. Both decreased CAMP and increased cGMP have been measured in the skin of individuals with psoriasis.*J The result is excessive cell proliferation. Regarding abnormal immune stimulation, astute investigators noticed that immunosuppressive drugs were effective in demasing psoriasis.4 Furthermore, it was noted that the condition also developed in patients without psoriasis who were given bone marrow transplants from donors with psoriasis? This suggested that the immune system may play a role in this condition. Since these observations, it has been reported that activation of T lymphocytes leading to release of cytokines also results in proliferation of keratinocytes. The literature reports that this activated response is initiated by unidentified antigens causing maturation of epidermal antigenpresenting cells (Langerhans cells) that migrate to regional lymph nodes. In the lymph node, these antigenpresenting cells interact with naive T cells, resulting in T-cell activation! These activated immune cells then 2079

enter the circulation and eventually extravasate through the blood vessels to the sites of inflammation in the skin as a part of the cytokine cascade found in psoriatic lesions. It is interesting that researchers have recognized "unidentified antigens" as ostensibly at the root of this cascade. A clear relationship of psoriasis with conditions like celiac disease6 and Crohn's disease7 has been reported. Furthermore, bowel mucosa of psoriatic patients without bowel symptoms have shown rnicroscopic lesions and greater intestinal permeability, even when the mucosa appeared macroscopically n0rmal.8,~ Given information regarding bowel toxemias, food allergies, low proteolytic and bile enzymes as well as suboptimal liver function and food allergies (see the following sections), a naturopathic suggestion here would be to consider that factors leading to poor intestinal function most likely encourage greater intestinal permeability and inflammation, which ultimately allow these antigenic and endotoxic compounds to leave the intestinal confines, travel through the blood stream, and initiate activated immune cascades in susceptible tissues.

THERAPEUTIC CONSIDERATIONS Although psoriasis may have a significant genetic component, decreasing the source of bloodbome antigenic immune activators and rebalancing the cAMP/cGMP ratio can be substantially achieved through natural medicine intervention.A number of controllable factors appear to cause or contribute to etiologic bases and pathogenesis of psoriasis, as follows: Incomplete protein digestion Bowel toxemia Impaired liver function Bile deficiencies Alcohol consumption Excessive consumption of animal fats Nutritional deficiencies stress These factors are briefly discussed here.

Omithine decarboxylase

Estrogen Arginine

Gastrointestinal Function Incomplete Protein Digestion Incomplete protein digestion or poor intestinal absorption of protein breakdown products can mult in elevations of amino acids and polypeptides in the bowel. These are metabolized by bowel bacteria into several toxic compounds. The toxic metabolites of the amino acids a r m e and omithine are known as polyamines (e.g., putrescine, spermidine, and cadaverine) and have been shown to be higher in individuals with psoriasis. Polyamines inhibit the formation of CAMPand therefore contribute to the excessive rate of cell proliferation (Figure 20f3-1).10-12 Lowered skin and urinary levels of polyamines are associated with clinical improvement in psoriasis.1o A number of natural compounds can inhibit the formation of polyamines and may be of benefit in the treatment of psoriasis. For example, vitamin A and the alkaloids of Hydrastis canadensis (goldenseal) such as berberine inhibit bacterial decarboxylase, the enzyme that converts the amino acids into p~lyamines.'~,'~ However, the best way to prevent the excessive formation of polyamines is to evaluate digestive function with the aid of Heidelberg Gastric Analysis and/or a comprehensive digestive stool analysis and then take the action necessary (e.g., hydrochloric acid supplementation) to ensure complete protein digestion and absorption (chapters on these assessment methods can be found in Section 2).

Bowel Toxemia A number of gut-derived toxins are implicated in the development of psoriasis, including endotoxins (cell wall components of gram-negativebacteria), streptococcal products, Candida albicans, yeast compounds, and immunoglobulin (Ig) E and IgA immune c ~ r n p l e x e s . ~ ~ ' ~ Endotoxins have been found in high levels in the blood of psoriatic patients,18 and these compounds lead to increases in cGMP levels within skin cells, thereby increasing the rate of proliferation dramatically. Overgrowth of C. albicans in the intestines (chronic candidiasis) may play a major role in many cases.

Dietary arginine

+

Ornithine

S I T Urea

Putrescine

co2

+Spermidine +Spermine

\/ ATP

Figure 206-1

+CAMP

Amino acids, polyamines, and inhibition of adenylate cyclase

Psoriasis A diet low in dietary fiber is associated with increased levels of gut-derived toxins.l5 Dietary fiber is critical to maintaining a healthy colon. Many fiber components bind bowel toxins and promote their excretion in the feces. It is therefore essential that the diet of an individual with psoriasis be rich in beans, fruits, and vegetables. Natural compounds that bind endotoxins and promote their excretion may also be used. For example, an aqueous extract of the herb Smilax sarsaparilla was found in a 1942 study to be effective in psoriasis, particularly the more chronic, large plaque-fonning variety.I9In this controlled study of 92 patients, sarsaparilla greatly improved the psoriasis in 62% of the patients and resulted in complete clearance in another 18%(i.e., 80% of the subjects experienced significant benefits). This benefit is apparently due to sarsaparilla components' binding to and promoting the excretion of bacterial endotoxins. Because clinical severity as well as therapeutic response have been shown to correlate well with the level of circulating endotoxins, control of gut-derived toxins is critical in the treatment of psoriasis. Every effort should be made to promote proper binding and elimination of these compounds through support of their excretion in the feces as well as proper handling of absorbed endotoxins by the liver.

Liver Function Correcting abnormal liver function is of great benefit in the treatment of psoriasis?o The connection between the liver and psoriasis relates to one of the liver's basic tasks-filtering and detoxifying the blood returning through the portal circulation from the bowels. Structurally, the hepatic architecture may already be altered in psoriasis sufferers?' As mentioned previously, psoriasis has been linked to the presence of several microbial byproducts in the blood. If the liver is overwhelmed by excessive levels of these toxins from the bowel, or if there is a decrease in the liver's detoxification ability, the systemic toxin level rises and the psoriasis worsens. Alcohol consumption is known to significantly worsen psoriasis." Alcohol has this effect because it both increases the absorption of toxins from the gut (by damaging the gut mucosa) and impairs liver function. Alcohol intake must be eliminated in individuals with psoriasis. Silymarin, the flavonoid component of Silybum m r i anurn, has been reported to be of value in the treatment of Presumably this is a result of its ability to improve liver function, inhibit inflammation, and reduce excessive cellular proliferati~n.~J~

Bile Deficiencies In the psoriatic patient, endotoxins are able to translocate from the intestine into the blood stream.18 Bile acids normally present in the intestines act to detoxify

bacterial endotoxins. In the absence of sufficient amounts of bile acids, endotoxins can translocate into the blood stream and produce pathologic conditions that vary in severity depending on the amount of endotoxins, including the release of inflammatory cytokines known to play a role in psoriasis. A fascinating Hungarian study of 800 psoriatic patients was conducted in which 551 were treated with oral bile acid (dehydrocholic acid) supplementation for 1 to 6 weeks or 3 to 8 weeks for acute or chronic cases, respectively. Conventional therapies were administered to 249 patients as a comparison group. Both groups were recommended to eat a diet high in vegetables and fruits and were instructed to avoid hot spices, alcohol, raw onion, garlic, and carbonated soft drinks. Of the 551 patients receiving bile acid, 434 (78.8%) became asymptomatic,whereas only 62 (24.9%)of the 249 patients receiving conventional therapies demonstrated clinical recovery during this treatment period. Additionally the curative effect of bile acid supplementation was more pronounced in the acute form of psoriasis; 95.1% of the patients in this group became asymptomatic. In followup assessments 2 years later, 319 of the 551 patients with acute and chronic psoriasis who had been treated with bile acid (57.9%) were asymptomatic, compared with only 15 of the 249 patients (6%) who had received the conventional treatment.'* The bile acid supplements used in the preceding study were either 2 or 3 Suprachol sugar-coated pills one time daily, or dehydrocholic acid powder (acidum dehydrocholicum pulvis) at 2 to 3 doses of 0.25 g each day. Because there is a theoretical risk of malignant tumors in patients with sluggish intestinal function given longterm bile acid therapy, the investigators in this study recommended that their subjects not continue ingesting bile acids on a regular basis, but to supplement with them only after a fatty meal once the initial treatment period was completed. Two separate evaluations of bile acid effects on the proliferation of colonic mucosa report conflicting resUlts.*lz6 Two other studies actually found a protective effect of ursodeoxycholic acid. One was an observational study of 114 patients with primary biliary cirrhosis in whom a reduction in colon adenoma risk was discovered. The prevalence of colorectal adenomas was 13% in the treated group versus 24% in the untreated group. Additionally, the colon epithelial cell proliferation index was significantly lower in treated patients than in untreated patient^.^' A second randomized controlled clinical trial of 52 subjects found s i p & cant drops in the risk for development of colorectal dysplasia or cancer in patients with ulcerative colitis and primary sclerosing cholangitis.28 More clinical research is needed to examine the different varieties of bile acids, their efficacy, as well as their safety profile. Nevertheless, given the preceding information, it seems reasonable to consider the use of bile acids for

Specific Health Problems short-term treatment of psoriasis and to monitor the colon before and after treatment in the patient at high risk for colon cancer.

Nutrition Omega-3 Fatty Acids The manipulation of dietary oils is extremely important in the management of psoriasis because serum free fatty acid levels are typically abnormal in affected patients.B Of particular benefit are the omega3 fatty acids. Most of the clinical research has utilized fish oils rich in eicosapentaenoicacid (EPA)and docosahexaenoicacid @HA). Several double-blind clinical studies have demonstrated that supplementing the diet with 10 to 12 g of fish oils (providing 1.8 g EPA and 1.2 g DHA) results in sigruficant improvement.w32This amount of EPA and DHA would be equivalent to the amount of EPA in about 150 g of salmon, mackerel, or herring. Consumption of cold-water fish and the daily supplementation with 1 tbsp of flaxseed oil may be more advantageous than fish oil supplementation, given the problem with lipid peroxides in many commercially available fish oil supplements. The improvement in psoriasis from EPA is largely due to the competition of EPA for arachidonic acid binding sites, which results in the inhibition of the production of inflammatory compounds. In the skin of individuals with psoriasis, the production of inflammatory leukotrienes from arachidonic acid is many times greater than normal.= Leukotrienes are potent inflammatory agents and promoters of guanylate cyclase activity. In the involved epidermis, the cellular contents of free arachidonic acid and 12-hydroxyeicosatetraenoic acid (12-HETE; a product of lipoxygenase metabolism of arachidonic acid) are 250 and 810 times greater, respectively, than in uninvolved epidermal tissue.33 These elevations appear to be due to the presence in the plaques of a yet-to-be-defined inhibitor of cyclooxygenase, which normally metabolizes arachidonic acid to less inflammatory compounds. Trauma also induces the release of free arachidonic acid and may account for the common clinical observation of plaques at the sites of repeated trauma. These observations are sigruficant,because the increase in 12-HETE stimulates the 5-lipoxygenase pathway, promoting leukotriene formation. This pathway is inhibited by EPA and glutathione peroxidase, suggesting that a selenium deficiency may be a contributory factor (see later nutritional considerations). As might be expected, cyclooxygenase inhibitors (e.g., aspirin and most other nonsteroidal antiinflammatory agents) may exacerbate psoriasis, whereas lipoxygenase inhibitors (e.g., benoxaprofen) may c a w improvement.34 Naturally occurring substances, such as quercetin (the ubiquitous plant flavonoid),vitamin E, onion, and garlic,

are known to inhibit lipoxygenase and therefore may be of benefit. Because arachidonic acid is found only in animal tissues, patients with psoriasis must limit their intake of animal products, particularly animal fats and dairy products.

Diet, Fasting, and Food Allergy Control An evaluation of 316 patients with psoriasis and 366 control subjects, both groups being in the age range 16 to 65 years, found that psoriasis was positively associated with body mass index and inversely related to intake of carrots, tomatoes, and fresh fruits, and the index of betacarotene intake.%Research at a Swedish hospital studying the effects of fasting and vegetarian regimens on chronic inflammatory disease found that such diets helped psoriatic patients.%The improvement was probably due to decreased levels of gut-derived toxins and polyamines. Patients have also benefited from glutenfree and elimination

Individual Nutrients Decreased levels of vitamin A and zinc are common in patients with psoriasis?" Given the critical roles of these nutrients in the health of skin, supplementation might be warranted even without this association. Chromium supplementation may be indicated to increase insulin receptor sensitivity, as psoriatic patients typically have increased serum levels of both insulin and glucose.42 Glutathione peroxidase (GP) levels are low in psoriatic patients, possibly due to such factors as alcohol abuse, malnutrition, and the excessive skin loss of the hyperproliferative disease. The depressed levels of GP normalize with oral selenium and vitamin E thera~y.4~ One investigation learned that patients with longer-term psoriasis (3 years or more) demonstrated low plasma selenium status.@Another study comparing 113patients with moderate to severe psoriasis and 104 healthy controls found that male psoriatic patients between 20 and 49 years of age and women with the disease of longer than 20 years' duration had particularly low selenium concentrations.The lowest whole blood selenium values were found in the subgroup of male patients with widespread disease of long duration who also required treatment with methotrexate and re ti no id^.^^ A growing body of evidence that indicates that the active form of vitamin D (1,25-dihydroxycholecalciferol) has a role in controlling keratinocyte proliferation and differentiation. Vitamin D also encourages a shift towards type 2 helper T-cell cytokine expression, with an increase in interleukin-10 (IL-10) and a decrease in IL-8, which may be responsible for the improvements seen in psoriasis.46This recognition has led to clinical trials of both oral and topical forms of vitamin D in the treatment

Psoriasis of psoriasis. One controlled study found that 2 to 5 weeks of topical 1,25-dihydroxycholecalciferolresulted in definite to total improvement in all five patients t~eated.4~ Another study by the same researchers, this one uncontrolled, found that four of seven patients had complete remission (after 1to 3 months) with daily oral doses of 1.0 pg of la(OH)D3.48 Patients with severe psoriasis have also been found to have significantly low serum levels of 1,25-dihydroxycholecalciferol,which normalized after treatment with oral l ~ x ( o H ) D ~The ? ~ clinical use of vitamin D has been limited by hypercalcemia, so commercial preparations of synthetic vitamin D analogues have been developed that have less of an effect on calcium homeostasis. Additonally, if ultraviolet light therapy is employed, the topical vitamin D should be applied after phototherapy to avoid degradation of the active compound in the ointment.50

Fumaric Acid Over the past three decades, fumaric acid therapy has become increasingly popular in Western Europe for psoriasis. Therapy consists of the oral intake of dimethylfumaric acid (240 mg daily) or monoethylfumaric acid (720 mg daily) and the topical application of 1%to 3% of monoethylfumaric acid. Clinical studies have shown that it is useful in many patients with psoriasis?l but side effects such as flushing of the skin, nausea, diarrhea, general malaise, gastric pain, and mild liver and kidney disturbances can occur?2 We recommend using fumaric acid therapy only after other natural therapies have proved ineffective.

Psychological Aspects Research work concerning the role of stress in psoriatic exacerbations is mixed. One investigation revealed that a large proportion (39%) of patients with psoriasis report the occurrence of a specific stressful event within 1month before their initial episode. Such patients have a better prognosis.53Yet other findings show a limited relationship between stress and vulnerability to psoriasis, whereby correlation seemed to occur mostly in patients with repeated stressors occurring four times or more in 1 year.%A few case histories have been reported that document the successful treatment of psoriasis with hypnosis and biofeedback alone.=

Physical Therapeutics Sunlight and Ultraviolet Light Sunlight (which contains ultraviolet light) is extremely beneficial for individuals with psoriasis. Outdoor 4-week heliotherapy was shown to promote sigruficant clearance of psoriatic symptoms in 84% of 373 subjects?6 Studies employing nonprescription commercial tanning beds have shown that a majority of patients believe they are and also objectively facilitate

improvements in both psoriasis severity and healthrelated quality of life.%An open-label retrospective trial also studied the combined use of the retinoid Acitretin (a vitamin A derivative) along with a 4- to 5-day-per-week tanning regimen;83% of 23 subjects experienced complete or near-complete rec0very.5~ Specific ultraviolet exposure may also be of benefit owing to its induction of vitamin D synthesis in the skin. The standard ultraviolet medical treatment of psoriasis typically involves the use of the drug psoralen and ultraviolet A (PUVA therapy; 320 to 340 nm). Ultraviolet B (UVB; 280 to 320 nm) exposure alone also leads to inhibition of cell proliferation and has been shown to be as effective as PUVA therapy with fewer side effects in UVB wavelengths are known to be certain studies.',the dominant light at the Dead Sea, where 80% to 85% of psoriatic conditions clear in 4 weeks.64*65 In one investigation of 28 patients, UVB had a clear advantage over PUVA therapy.ls Conversely, another report of 100patients comparing UVB with PUVA demonstrated clearance of psoriasis in a signrficantly greater proportion of patients treated with PUVA (84%) than with UVB (63%), and with significantly fewer treatments.66Other studies have found both to be effective, with similar untoward side effects.'j7.@It is clear that more study is needed to clarify both the risks and benefits of these therapies, and whether certain presentations of psoriasis may respond best to a specific ultraviolet therapy. As noted above, ultraviolet light deactivates vitamin D topical agents, so if they are used in conjunction, the topical agent should be applied only after ultraviolet treatment. Furthermore, any light therapy should be monitored carefully, especially in patients at risk for skin cancers.

Other Physical Therapeutics The induction of localized elevation of temperature (42" C to 45" C) to the affected area by ultrasound and heating pads has been shown to be an effective treatment of p s o r i a ~ i s . ~Italian ~ , ~ ~ researchers have conducted small clinical trials using a hypotonic sulfate water (Leopoldinewater) in a baleotherapeutic manner. These treatments have yielded favorable immunohistologic profiles of the affected tissues with significant decreases in the numbers of T lymphocytes, Langerhans cells, and markers of keratinocyte inflammatory expre~sion.~~

Topical Treatments A number of natural proprietary formulas as well as over-the-counter preparations can be used to provide symptomatic relief. Three botanical agents are worth discussing as alternatives to hydrocortisone: glycyrrhetinic acid from licorice (Glycyrrhizu glabru), chamomile (Mutricuriu chamomilZu), and capsaicin from cayenne pepper (Capsicum fiutescens).

Specific Health Problems

Glycyrrhiza glabra (Licorice Root) The licorice component glycyrrhetinic acid exerts an effect similar to that of topical hydrocortisone in the treatment of psoriasis and eczema. In fact, in several studies, glycyrrhetinic acid was shown to be superior to topical cortisone, especially in chronic cases. For example, in one study in patients with eczema, 93% of the patients applying glycyrrhetinic acid demonstrated improvement, compared with 83% of those using cortisone.72Glycyrrhetinic acid can also be used to potentiate the effects of topically applied hydrocortisone by inhibiting the 11-beta-hydroxysteroid dehydrogenase that catalyzes the conversion of hydrocortisone to an inactive form.”

Matricaria Charnomilla (Chamomile) Chamomile preparations are widely used in Europe for the treatment of a variety of common skin complaints, including psoriasis, eczema, and dry, flaky, irritated skin. The flavonoid and essential oil components of chamomile possess sigruficant antiinflammatory and antiallergy activity.74

Capsicum fhtescens (Cayenne Pepper) Capsaicin is the active component of cayenne pepper (C. frutescens). When topically applied, capsaicin is known to stimulate and then block small-diameter pain fibers by depleting them of the neurotransmitter substance P. Substance P is thought to be the principal chemomediator of pain impulses from the periphery. In addition, substance P, which is elevated in the skin of psoriatic patients, has been shown to activate inflammatory mediators in psoriasis. Several clinical studies have found that the topical application of 0.025% or 0.075%capsaicin is effective in improving psoriasis.75p76 In one double-blind study, 44 patients with symmetrically distributed psoriasis lesions applied topical capsaicin to one side of their bodies and a placebo to the other side.40After 3 to 6 weeks, sigruficantly greater reductions in scaling and redness were observed on the capsaicin side. Burning, stinging, itching, and skin redness were noted by nearly half of the patients initially, but this effect diminished or vanished upon continued In a more recent study, patients applied capsaicin 0.025%cream (n = 98) or vehicle alone (n = 99) four times a day for 6 weeks.75Efficacy was based on a physician’s global evaluation and a combined psoriasis severity score involving scaling, thickness, erythema, and pruritus. Capsaicin-treated patients demonstrated significantly greater improvement in global evaluation and in pruritus relief, as well as a sigruficantly greater reduction in combined psoriasis severity scores.

Aloe Vera A very exciting, double-blind, placebo-controlled study found that topical application of an Aloe uem extract

in a hydrophilic cream was highly effective in psoriasis vulgaris. Sixty patients with slight to moderate, chronic, plaque-type psoriasis, and psoriasis area and severity index (PASI) scores between 4.8 and 16.7 (mean 9.3), whose mean duration of disease averaged 8.5 years (range 1 to 21 years) applied either the aloe or a placebo gel three times a day. The treatment was well tolerated by all the patients, with no adverse drug-related symptoms and no dropouts. By the end of the study (4 to 12 months of treatment), the A. vem extract cream had cured 25 of 30 patients (83.3%)compared with the placebo cure rate of only 2 of 30 (6.6%), resulting in sigruficant clearing of the psoriatic plaques (328/396 [82.8°/~]vs. placebo 28/366 [7.7%]),and a decrease in PASI score to a mean of 2.2.n

Other Possible Therapies Numerous in vitro investigationshave yielded good preliminary results, showing keratinocytic antiproliferative activity with the use of traditional botanical preparations. These plant medicines have included Muhonia aquifolium,78 Centella usi~ticu,7~Zunthoxylurn species,8O Tubebuiu irnpetiginosa (lapacho),8l Chelidonium mujus,82 cureumh~,~ pine bark,s4 and Sicilian traditional botanicals like verbena.85It remains unknown which of these, if any, may prove efficacious in future human clinical trials. But given the complexity and intractable nature of psoriasis, these botanicals require further study because they may indeed provide new clues to the mechanistic etology of psoriasis as well as eventual therapeutic successes.

THERAPEUTIC APPROACH Despite the complexity of this disease, the therapeutic approach is fairly straightforward: decrease bowel toxemia, rebalance fatty acid levels and inflammatory processes in the skin, and utilize the listed therapeutic regimen to further balance the abnormal cell proliferation.

Diet Limit sugar, meat, animal fats, and alcohol. Increase intake of dietary fiber and cold-water fish and, if necessary, bring weight to normal levels. Eliminate sources of gluten. Identdy and address any food allergies.

Supplements High-potency multiple vitamin and mineral formula Flaxseed oil: 1tbsp/day Vitamin A: 50,000 IU/day (should not be used by women who are pregnant or at risk for pregnancy) Vitamin E: 400 IU/day Chromium: 400 pg/day Selenium: 200 pg/day

Psoriasis

Zinc: 30 mg/day Consider digestiveenzymes and/or bile acids with meals Water-soluble fiber (psyllium, pectin, guar gum, etc.): 5 g at bedtime

Botanical Medicines H . canadensis (goldenseal): The dosage should be based on berberine content; as there is a wide range of quality in goldenseal preparations, standardized extracts are preferred three times/day. Dried root or as infusion (tea): 2 to 4 g three times/day Fluid extract (1:l):2 to 4 ml (0.5 to 1 tsp) three times/ day Solid (powdered dry) extract (4:l or 8%to 12%alkaloid content): 250 to 500 mg three times/day

S. marianurn (milk thistle): Silymarin: 70 to 210 mg three times/day

Psychological Evaluate stress levels and utilize stress reduction techniques as appropriate.

Physical Medicines Ultrasound: 42"to 45"C, 20 minutes, three times/week UVB: 295 to 305 nm, 2 mW/cm2, 3 minutes, three times/ week

Topical Treatment Preparations containing one or more of the ingredients described previously. Apply to affected areas of the skin two to three times/day.

S. sarsaparilla:

Dried root or by decoction: 1 to 4 g three times/day Liquid extract (1:l):8 to 16ml(2 to 4 tsp) threetimes/day Solid extract (4:l):250 to 500 mg three times/day

1.Katayama H, Hori H. The influence of UVB irradiation on the excretion of the main urinary metabolite of prostaglandin Fla and F2a in psoriatic and normal subjects.Acta Derm Venereoll984; 64:1-4. 2. Voorhees J, Duell E. Imbalanced cyclic AMP-cyclic GMP levels in psoriasis. Adv Cyc Nucleotide Res 1975;5:755757. 3. Robbins S, Cotran R. Pathological basis of disease. Philadelphia: WB Saunders, 1979:1449. 4. Lebwohl M. Psoriasis. Lancet 2003;361:1197-1204. 5. SnowdenJA, Heaton DC.Development of psoriasis after syngeneic bone marrow transplant from psoriatic donor: further evidence for adoptive autoimmunity. Br J Dermatol1997;137130-132. 6. ojetti V, Aguilar Sanchez J, Guerriero C, et al.. High prevalence of celiac disease in psoriasis. Am J Gastroentero12003;98:25742575. 7.Najarian DJ, Gottlieb AB. Connections between psoriasis and Crohn's disease. J Am Acad Dermato12003;48:805821. 8. Scarpa R, Manguso F, DArienzo A, et al. Microscopic inflammatory changes in colon of patients with both active psoriasis and psoriatic arthritis without bowel symptoms.J Rheumatol2OOO;271241-1246. 9. Humbert P, Bidet A, Treffel P, et al. Intestinal permeability in patients with psoriasis. J Dermatol Sci 1991;2324326. 10. Proctor M, Willcenson D, OrenbergE, et al. Lowered cutaneous and urinary levels of polyamines with clinical improvement in treated psoriasis. Arch Dermatol1979;115945-949. 11. Voorhees JJ. Polyamines and psoriasis. Arch Dermatol 1979;115: 943-944. 12. McDonald CJ. Polyamines in psoriasis. J Invest Dermatol 1983;81:385-387. 13.Haddox M, Scott KF, Russel D. Retinol inhibition of omithine decarboxylase induction and G1 progression in Chinese hamster ovary cells. Cancer Res 1979;394930-4938. 14. Kuwano S, Yamauchi K. Effect of berberine on tyrosine decarboxylase activity of Streptococcus faeculis. Chem Pharm Bull 1960;8: 491-496. 15. Rosenberg E, Belew F? Microbial factors in psoriasis. Arch Dermatol 1982;1181434-1444.

16. Rao M, Field M. Enterotoxinsand ion transport. Biochem Soc Trans 1984;12177-180. 17.Juhlin L, Vahlquist C. The influence of treatment and fibrin microclot generation in psoriasis. Br J Dermatol1983;108:33-37. 18.Gyurcsovics K, Bert6k L. Pathophysiology of psoriasis: coping endotoxins with bile acid therapy. Pathophysiology 2OO3;1057-61. 19. Thurmon FM. The treatment of psoriasis with sarsaparilla compound. N Engl J Med 1942337128-133. 20. Weber G, Galle K. [The liver, a therapeutic target in dermatoses.] Med Welt 1983;34:108-111. 21. Pietrzak A, Lecewicz-Torun B, Kadziela-Wypyska G. Changes in the digestive system in patients suffering from psoriasis. Ann UNv Mariae Curie Sklodowska [Med] 1998;53:187-194. 22.Monk BE, Neill SM. Alcohol consumption and psoriasis. Dermatologica 1986;173:57-60. 23. Hikino H, Kiso Y, Wagner H, et al. Antihepatotoxic actions of flavonolignans from Silyhm marianum fruits.Planta Media 1984;50:248-250. 24. Adzet T. Polyphenolic compounds with biological and pharmacological activity. Herbs Spices Medicinal Plants 1986;1:167-84. 25. Ochsenkuhn T, Marsteller I, Hay U, et al. Does ursodeoxycholic acid change the proliferation of the colorectal mucosa? A randomized, placebo-controlledstudy. Digestion 2003;68:209-216. 26. Ochsenkuhn T, Bayerdorffer E, Meining A, et al. Colonic mucosal proliferation is related to serum deoxycholic acid levels. Cancer 1999;85:1664-1669. 27. Serfaty L, De Leusse A, Rosmorduc 0, et al. Ursodeoxycholic acid therapy and the risk of colorectal adenoma in patients with primary biliary cirrhosis an observationalstudy. Hepatology2003;38:203-209. 28. Pardi DS,Loftus Ev Jr, Kremers WK,et al. Ursodeoxycholicacid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 2003;124889-893. 29. Zlatkov NB, licholov JJ, Dourmishev AL. Free fatty acids in the blood serum of psoriatics. Ada Derm Venereol1984;64:22-25. 30.Bittiner SB, Tucker WF, Cartwright I, et al. A double-blind, randomized, placebo-controlled trial of fish oil in psoriasis. Lancet 1988;1:378-380.

Specific Health Problems 31. Grimmunger F, Mayser P, Papavassilis C. A double-blind, randomized,placebo-controlled trial of 0-3 fatty acid based lipid infusion in acute, extended guttate psoriasis. Rapid improvement of clinical manifestations and changes in neutrophil leukotriene profile. Clin Invest 1993;71:634-643. 32. Maurice PD, Allen BR, Barkley AS, et al. The effects of dietary supplementation with fish oil in patients with psoriasis. Br J Dermatol 1987;1117599606. 33. Voorhees JJ.Leukotrienes and other lipoxygenase products in the pathogenesis and therapy of psoriasis and other dermatoses.Arch De~tOl1983;119:541-547. 34. Kragballe K, Herlin MD. Benoxaphren improves psoriasis. A doubleblind study. Arch Dexmatol1983;119548-552. 35. Naldi L, Parazzini F, Peli L, et al. Dietary factors and the risk of psoriasis. Results of an Italian case-controlled study. Br J Dermatol 1996;134:101-106. 36. Lithell H, Bruce A, Gustafsson IB, et al. A fasting and vegetarian diet treatment trial on chronic inflammatory disorders. Acta Derm Veneml1983;63:397-403. 37. Bazex A. Diet without gluten and psoriasis. Ann Derm Symp 1976; 103648. 38. Douglas JM. Psoriasis and diet. Calif Med 1980;133:450. 39. Majewski S, Janik P, Langer A, et al. Decrrased levels of vitamin A in serum of patients with psoriasis. Arch Dermatol Res 1989;280:499-501. 40.Hinks LJ, Young S,Clayton B. Trace element status in eczema and psoriasis. Clin Exp Dermatol 1987;1293-97. 41. Donadini A, Dazzaglia A, Desirello G. [Plasma levels of Zn, Cu and Ni in healthy controls and in psoriatic patients. Possible correlations with vitamins.] Acta Vitamin Enzymol 1980;1:9-16. 42. Fratho P, Pelfini C, JucciA, et al. Glucose and insulin in psoriasis: the role of obesity and genetic history. Panminerva Medica 1979;21:167. 43. Juhlin L, Edqvist LE, Ekman LG, et al. Blood glutathione-peroxidase levels in skin diseases. Effect of selenium and vitamin E treatment. Acta Derm Venereol1982;62:211-214. 44.Serwin AB, Wasowicz W, Gromadzinska J, et al. Selenium status in psoriasis and its relations to the duration and severity of the disease. Nutrition 2003;19:301-304. 45. Michaelsson G, Beme B, Calmark B, et al. Selenium in whole blood and plasma is decreased in patients with moderate and severe psoriasis. Acta Derm Venereol1989;6929-34. 46.Mendonqa CO, Burden AD. Current concepts in psoriasis and its treatment. Pharmacol Ther 2003,99:133-147. 47. Morimoto S, Onishi T, Imanaka S, et al. Topical administration of 1,254ihydroxyvitamin D3 for psoriasis: report of five cases. Calcif Tissue Int 198638119-122. 48. Takamoto S, Onishi T, Morimoto S, et al. Effect of l-alpha-hydroxycholecalciferol on psoriasis vulgaris. A pilot study. Calcif Tissue Int 198639360-364. 49. Staberg B, Oxholm A, Klemp P, et al. Abnormal vitamin D metabclism in patients with psoriasis. Ada Derm Venereol1987;6765-68. 50. Lebwohl M, Qujije J, Gilliard J, et al. Topical calcitriol is degraded by ultraviolet light. J Invest Dermatol2003;121:594595. 51.Altmeyer PJ, Matthes U, Pawlak F, et al. Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol1994;30:977-981. 52. Nieboer C, de Hoop D, van Loenen AC, et al. Systemic therapy with fumaric acid derivates: new possibilitiesin the treatment of psoriasis. J Am Acad Dermatol1989;20601-608. 53. Seville RH. Psoriasis and stress. Br J Dermatol1977;97297-302. 54. Picardi A, Pasquini P,Cattaruzza MS, et al.Only limited support for a role of psychosomatic factors in psoriasis: results from a casecontrol study. J Psychosom Res 200355189-196. 55. Wmchell SA, Watts RA. Relaxation therapies in the treatment of psoriasis and possible pathophysiologic mechanism. J Am Acad Dermatol 1988;18101-104.

56. Snellman E, Lauharanta J, Reunanen A, et al. Effect of heliotherapy on skin and joint symptoms in psoriasis: a &month follow-up study. Br J Dermatol 1993;128:172-177. 57. Fleischer AB Jr, Feldman SR, Rapp SR, et al. Alternative therapies commonly used within a population of patients with psoriasis. Cutis 1996;58:216-220. 58.Fleischer AB Jr, Clark AR, Rapp SR, et al. Commercial tanning bed treatment is an effective psoriasis treatment: results from an uncontrolled clinical trial. J Invest Dermatol1997;109:170-174. 59. Carlin CS, Callis KP, Krueger GG. Efficacy of acitretin and commercial tanning bed therapy for psoriasis. Arch Dermatol 2003;139 436-442. 60. Parrish J. Phototherapy and photochemotherapy of skin diseases. J Invest Dermatol 1981;77:167-171. 61. Lark0 0,Swanbeck G. Is UVB treatment of psoriasis safe? A study of extensively WB-treated psoriasis patients compared with a matched control group. Acta Derm Venereol1982;62507-512. 62. Boer J, Hermans J, Schothorst AA, et al. Comparison of phototherapy (UV-B) and photochemotherapy(PUVA) for clearing and maintenance therapy of psoriasis. Arch Dermatol1984;120:52-57. 63. Dawe RS,Cameron H, Yule S, et al. Randomized controlled t i a l of narrowband ultraviolet B vs bath-psoralen plus ultraviolet A photochemotherapy for psoriasis. Br J Dermatol2003;14&11941204. 64.Kudish AI,Abels D, Harari M. Ultraviolet radiation properties as applied to photoclimatherapy at the Dead Sea. Int J Dermatol 2003;42:359-365. 65.Kushelevsky AP, Harari M, Kudish AI, et al. Safety of solar phototherapy at the Dead Sea. J Am Acad Dermatol199838447-452. 66. Gordon PM, Diffey BL, Matthews JN, et al. A randomized comparison of narrow-band TL-01 phototherapy and PUVA photochemotherapy for psoriasis J Am Acad Dermatol1999;41:728-732. 67. Markham T, Rogers S, Collins P. Narrowband W - B (TL-01) phototherapy vs oral fbmethoxypsoralen psoralen-W-A for the treatment of chronic plaque psoriasis. Arch Dermatol2003;139:325-328. 68.Das S, Lloyd JJ, Walshaw D, et al. Response of psoriasis to sunbed treatment comparison of conventional ultraviolet A lamps with new higher ultraviolet B-emitting lamps. Br J Dermatol 2002;147 966-972. 69. Urabe H, Nishitani K, Kohda H. Hyperthennia in the treatment of psoriasis. Arch Dermatol1981;117770-774. 70. Orenberg EK, Deneau DG, Farber EM. Response of chronic psoriatic plaques to localized heating induced by ultrasound. Arch Dermatol1980;116893-897. 71. Tsoureli-Nikita E, Menchini G, Ghersetich I, et al. Alternative treatment of psoriasis with balneotherapy using Leopoldine spa water. J Eur Acad Dermatol Venereol2002;16260-262. 72. Evans FQ. The rational use of glycyrrhetinic acid in dermatology. Br J Clin Pract 1958;12269-279. 73. Teelucksingh S, Mackie AD, Burt D, et al. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990335 1060-1063. 74. Mann C, Staba EJ. The chemistry, pharmacology, and commercial formulations of chamomile. Herbs, Spices, and Medicinal Plants 1986;1:235-280. 75. Ellis CN, Berberian B, Sulica VI,et al. A double-blind evaluation of topical capsaicin in pruritic psoriasis. J Am Acad Dermatol 1993; 29:438442. 76.Bemstein JE, Parish LC, Rapaport M, et al. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol1986;15:504-507. 77. Syed TA, Ahmad SA, Holt AH, et al. Management of psoriasis with Aloe Vera extract in a hydrophilic cream: a placebo-controlled, double-blind study. Trop Med Int Health 1996;1:505-509. 78. Muller K, Ziereis K, Gawlik I. The antipsoriatic Mahonk aquifoliurn and its active constituents. II.Antiproliferativeactivity against cell growth of human keratinocytes. Planta Med 1995;61:7475.

Psoriasis 79. SampsonJH,Raman A, Karlsen G, et al. In vitro k e r a t i n w e antiproliferant effect of Centella asiaticu extract and triterpenoid saponins. Phytomedicine 200;8230-235. 80. Kumar S, Muller K. Inhibition of keratinocyte growth by different Nepalese zanthoxylum species. Phytother Res 1999;13214217. 81. Muller K, Sellmer A, Wiegrebe W. Potential antipsoriatic agents: lapacho compounds as potent inhibitors of HaCaT cell growth. J Nat Prod 1999;621134-1136. 82. Vavreckova C, Gawlik I, M d e r K. Benzophenanthridine alkaloids of Chelidonium rnujus. II. Potent inhibitory action against the growth of human keratinocytes. Planta Med 1996;62491494.

83. Pol A, Bergers M, srhalkwijk J. Comparison of antiproliferative effects of experimental and established antipsoriatic drugs on human keratinocytes, using a simple 96-well-plate assay. In Vitro Cell Dev Biol Anim 2003;3936-42. 84. Rihn B, Saliou C, Bottin MC, et al. From ancient remedies to modem therapeutics: pine bark uses in skin disorders revisited. Phytother Res 2001;1576-78. 85. Amenta R, Camarda L, Di Stefan0 V, et al. Traditional medicine as a source of new therapeutic agents against psoriasis. Fitoterapia 2000;71:513-S20.

Rheumatoid Arthritis Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

2089

General Considerations 2089 Pathogenesis 2089 Diagnosis 2091 Laboratory and Radiographic Findings 2092 Standard Medical Therapy 2093 Nonsteroidal Antiinflmmatory Drugs and Cyclooxygenase Inhibitors 2093 Corticosteroids 2094 Disease-ModifyingAntirheumatic Drugs 2094 Biologic Agents 2095 Therapeutic Considerations 2095 Diet 2095

DIAGNOSTIC SUMMARY Fatigue, low-grade fever, weakness, weight loss, joint stiffness, and vague joint pain may precede the appearance of painful, swollen joints by several weeks. Severe joint pain with considerable inflammation that begins insidiously in the small joints and progresses to affect all joints. Radiography usually shows soft tissue swelling, erosion of cartilage, and joint space narrowing. Rheumatoid factor usually present in serum. Extraarticular manifestations are common, including vasculitis, muscle atrophy, subcutaneous and systemic granulomas, pleurisy, pericarditis, pulmonary fibrosis, lymphadenopathy, splenomegaly, anemia, and leukopenia.

GENERAL CONSIDERATIONS Rheumatoid arthritis (RA) is a chronic inflammatory condition that affects the entire body but especially the synovial membranes of the joints. The joints typically involved are the hands, feet, wrists, ankles, and knees. Between 0.3% and 1%of the population is affected;

Gut Issues 2096 Psychological Aspects 2097 Dietary and Supplemental Fatty Acids Nutritional Supplements 2098 Dietary Antioxidants 2100 Other Nutrients 2101 Botanical Medicines 2101 Physical Medicine 2103 Balneotherapy 2103

Therapeutic Approach 2104 Diet 2104 Supplements 2105 Botanical Medicines 2105 Physical Medicine 2105 Counseling/PsychologicalTherapy

2098

2105

women outnumber males almost 3:1, and the usual age of onset is 20 to 40 years, although RA may begin at any The onset of RA is usually gradual, but occasionally it is quite abrupt. Fatigue, low-grade fever, weakness, joint stiffness, and vague joint pain may precede the appearance of painful, swollen joints by several weeks. Several joints are usually involved at the onset, typically in a symmetric fashion-both hands, both wrists, or both ankles. In about one third of persons with RA, initial involvement is confined to one or a few joints.'f2 Involved joints are characteristically quite warm, tender, and swollen. The skin over the joint takes on a ruddy purplish hue. As the disease progresses, deformities develop in the joints of the hands and feet. Colloquial terms used to describe these deformities include swan neck, boutonni6re, and cock-up toes.l.2

Pathogenesis There is abundant evidence that RA is an autoimmune reaction, whereby antibodies develop against components of joint tissues. Balance between types of helper T cells4 and production of tumor necrosis factor-alpha 2089

Specific Health Problems

(TNF-a)? a proinflammatory cytokine, may play a key role in the inflammatory response in RA. Yet what triggers this autoimmune reaction remains largely unknown. Speculation and investigation have focused on genetic susceptibility, abnormal bowel permeability lifestyle and nutritional factors, food allergies, and microorganisms. RA is a classic example of a multifactorial disease in which an assortment of genetic and environmental factors contribute to the disease process.

Genetic Factors Numerous studies have linked the major histocompatibility complex on chromosome 6 to RA susceptibility. Specifically, the HLA region on 6p21 has consistently been implicated. Severe RA is also found at four times the expected rate in first-degree relatives of probands with seropositive disease. This finding strongly implies that susceptibility to RA is influenced by genetic factors that govern immune response. As strong as these genetic associations are, environmental factors such as low economic status, smoking, poor diet, and psychological factors have a major role in the development of the disease and may affect the levels of pain and physical disability experienced by patients with RA.6 This is evident from the discordance demonstrated in monozygotic twin studies.*Therefore, despite a greater understanding of possible genetic underpinnings of this illness, there are no current recommendations to use genetic testing as a reliable indicator of disease risk.

Abnormal Bowel Permeability An interesting association between RA and abnormal bowel function may provide a unified theory as to the cause of RA. Individuals with RA have greater intestinal permeability to dietary and bacterial antigens as well as alterations in bacterial Food allergies may contribute greatly to the increased permeability of the gut in RA. Nonsteroidal antiinflammatory drugs (NSAIDs) have also been implicated. This altered permeability to gut-derived antigens contributes greatly to the increased levels of circulating endotoxins (lipopolysaccharide components of the cell walls of gram-negative bacteria) and immune complexes characteristic of RA. The greater gut permeability and inappropriate bacterial flora could also result in the absorption of antigens that are very similar to antigens in joint tissues. Antibodies formed to microbial antigens are hypothesized to cross-react with the antigens in the joint tissues. Increasing evidence appears to support this concept. For example, antibodies to Campylobacter, Salmonella, and Shigeh have been shown to cross-react with collagen, whereas antibodies to Klebsiella pneurnoniae, Proteus vulgaris, and Yersinia enterocolitica have been shown to cross-react with other joint

Dysbiosis and Small Intestinal Bacterial Overgrowth Perhaps more important than specific causative organisms is the fact that many patients with RA exhibit altered microbial flora and small intestinal bacterial overgrowth (SIBO). In fact, the level of SIBO has been shown to be associated with the severity of symptoms and disease activity.12 For more information on SIBO, see Chapter 12.

The Presence of Abnormal Antibodies and Immune Complexes The serum and joint fluid of nearly all individuals with RA contain the rheumatoid factor (RF). The RF is the number of antibodies against the Fc fragment of immunoglobulin (Ig) G. RF antibodies belong to the ISM, IgG, and IgA classes, but only IgM RF is readily measured by currently available methods, which include latex agglutination, bentonite flocculation, and the sensitized sheep or human red blood cell test. Most of the RF is formed locally in the affected joints by the inflammatory infiltration of activated B cells and plasma cells. The serum titer of RF usually correlates well with the severity of arthritis symptoms. The presence of circulating immune complexes is one of the major factors thought to contribute to the pathogenesis of RA. The cell-mediated, humoral, and nonspecific immune responses to the immune complexes lead to much of the proliferative inflammation seen in RA. These abnormalities are quite similar to the Arthus reaction and serum sickness, immune complex-induced reactions that depend on neutrophils, and complement activation. Although the amount of circulating immune complexes has not correlated well with disease activity, there is little doubt that the formation of immune complexes and abnormal antibodies and the sequence of events that follow it are major factors in the progression of RA.

Microbial Hypotheses As interesting as the various microbial hypotheses are, they are not in themselves comprehensive enough to explain all of the events observed in RA. A variety of microorganisms (e.g., Epstein-Barr virus [EBV], rubella virus, amebic organisms, and Mycoplasma) have been suggested as causative factors in the pathogenesis of RA, despite the fact that no microbial agent has been consistently isolated in patients with the disease.13 The fact that studies have focused on attempting to isolate whole organisms from synovial fluids and on the presence of antibodies to viable and whole organisms, coupled with the failure to isolate any offending organisms, has prompted many researchers committed to the ”germ theory” to suggest that some atypical virus-like agent(s) may be responsible in RA.13

Rheumatoid Arthritis

Microbial factors, particularly their role in raising the level of circulating immune complexes, definitely contribute to the pathogenesis of RA, but at this time it appears highly unlikely that there is a single causative microbe in RA. Nonetheless, researchers continue to search for a causative agent. One popular microbial hypothesis, which was later disproved, involved the EBV.14 The link between EBV and RA was initially based on the following three basic immunopathologic observations: EBV is a polyclonal activator of B cells, which induce autoantibody and rheumatoid factor production both in vitro and in vivo. Lymphocytes from patients with RA show evidence of impaired regulation of EBV infection in vitro. Antibodies to EBV-determined antigens such as RA nuclear antigen (RANA), EBV nuclear antigen, and viral capsid antigen are elevated in sera from patients with RA. Researchers have subsequently concluded that EBV is an unlikely etiologic agent, on the basis of the prevalence of EBV antibodies in healthy contr01s.l~ Mycoplasmas have also received some attention as possible etiologic factors in RA.15 Mycoplasmas can infect joints and induce arthritis. Mycoplasmal antigens have been detected in the synovial fluid of patients with RA, implying that frequent and persistent colonization by mycoplasmas may lead to host sensitization and immune complex formation. However, these effects are not specific to mycoplasmas alone. Another popular microbial hypothesis is based on the work of Wyburn-Mason.16 During the 1960s, WybumMason routinely identified an amebic organism in the synovial fluid of patients with arthritic conditions. The potent antibiotic metronidazole (Flagyl) was shown to be active against the organism and is part of the protocol recommended by the Rheumatoid Disease Foundation (Route 4, Box 137, Franklin, TN 37064; telephone: 615646-1030), an organization that promotes additional research in this area. In summary, it appears that the presence of high levels of circulating immune complexes containing microbial antigens in general, as well as the higher microbial antigenic load observed in patients with RA, are of greater sigruficance than antibodies to one particular organism or group of organisms.

(DHEAS) levels were measured in 185 postmenopausal women (aged 45 to 65 years) with RA.18 Compared with 518 postmenopausal women in the control group, DHEAS levels were below normal in the 120 patients with RA who had never taken corticosteroids, and levels were even lower in the 39 patients who were currently taking corticosteroids. Adrenocortical hormones such as DHEA and testosterone are being found at decreased levels in patients with early-stage RA as well.19 One small open-label trial involving 11elderly patients with RA who were taking antirheumatic drugs found little benefit from supplementing with 200 mg/day of DHEA.20However, supplemental DHEA has shown therapeutic benefits in patients with systemic lupus erythematosus (SLE) in studies conducted at Stanford Medical Center.21,22In a double-blind study, 28 female patients with mild to moderate SLE were given DHEA (200 mg/day) or placebo for 3 months.22Outcomes were evaluated through the SLE Disease Activity Index (SLEDAI)score, patient's and physician's overall assessments of disease activity, and concurrent corticosteroid usage. In the patients receiving DHEA, the SLEDAI rose by nearly 2 points, whereas the placebo group's average score rose by almost a full point. Patient and physician assessments also showed improvements in the SLE group and exacerbation in the placebo group. The average dosage of corticosteroids dropped by 30% in the SLE group and rose by 40% in the control group. There were three lupus flare-ups in the SLE group, compared with eight in the placebo group. Mild acne was a common side effect of DHEA. Given DHEA's positive effects in SLE,2ltz even in the absence of double-blind clinical studies in RA, DHEA supplementation appears warranted. Conservativepractitioners should use DHEA supplementation at least to correct the physiologic deficit, which can be determined with a 24-hour urinary measure. More aggressive practitioners may wish to use DHEA supplementation to try to sigruficantly affect disease activity. For this latter goal, the dosage required will likely be larger than 50 mg. The major side effects at this and larger dosages are mild to severe acne and possibly increased androgenization in women. More clinical studies are warranted to elucidate the benefits and optimum dosage of DHEA in patients with RA.

Decreased Dehydroepiandrosterone Levels

DIAGNOSIS

Defective androgen synthesis has been proposed as a potential predisposing factor for RA. Dehydroepiandrosterone (DHEA) is a known inhibitor of cytokines due to nuclear factor-kappa B (NF-kappaB) inhibition, and chronically low levels of this hormone have been found in RA.'7 For example, in one large study DHEA sulfate

RA is easily recognized in its most advanced and characteristic form. However, diagnosis of early RA is often much more difficult. The American Rheumatism Association has established criteria for the diagnosis of "classic," "definite," "probable," and "possible" RA, which are summarized in Box 207-1.23

Specific Health Problems

Classic RA The diagnosis of RA requires seven of the following criteria to be observed by a physician. In criteria 1 through 5 the joint signs or symptoms must be continuous for at least 6 weeks. Any one of the features listed in the exclusions section of the chapter will exclude a patient from this and other categories. 1. Morning stiffness. 2. Pain on motion or tenderness in at least one joint. 3.Swelling (soft tissue thickening or fluid, not bony overgrowth alone) in at least one joint. 4. Swelling of at least one other joint with any interval free of joint symptoms between the joint involvements not longer than 3 months. 5.Symmetric joint swelling with simultaneous involvement of the same joint on both sides of the body (bilateral involvement of proximal interphalangeal, metacarpophalangeal, or metatarsophalangeal joints is acceptable without absolute symmetry). Terminal phalangeal joint involvement does not fulfill this criterion. 6.Subcutaneous nodules over bony prominences, on extensor surfaces. or in juxtaarticular regions. 7. Radiographic changes typical of RA, which must include bony decalcification localized to or most marked adjacent to the involved joints and not just degenerative changes. Degenerative changes do not exclude patients from any group classified as having RA. 8. Positive agglutination test result-demonstration of the 'rheumatoid factor" by an acceptable method. 9. Poor mucin precipitate from synovial fluid or an inflammatory synovial effusion with 2000 or more white blood cells per mm3and without crystals. 10. Characteristic histologic changes in synovium with three or more of the following features: marked villous hypertrophy; proliferation of superficial synovial cells often with palisading; marked infiltration of chronic inflammatory cells with tendency to form lymphoid nodules; deposition of compact fibrin either on the surface or interstitially;foci of necrosis. 11. Characteristic histologic changes in nodules showing granulomatous foci with central zones of cell necrosis, surrounded by a palisade of proliferated mononuclear and peripheral fibrosis and chronic inflammatory cell infiltration.

Definite RA This diagnosis requires five of the preceding criteria. In criteria 1 through 5, the joint signs must be continuous for at least 6 weeks. Probable RA This diagnosis requires three of the preceding criteria. In at least one of criteria 1 through 5, the joint signs or symptoms must be continuous for at least 6 weeks.

Possible RA This diagnosis requires two of the following criteria and total duration of joint symptoms must be at least 3 months: 1. Morning stiffness. 2. Tenderness or pain on motion with history of recurrence or persistence of 3 weeks. 3. History or observation of joint swelling. 4. Elevated sedimentation rate or C-reactive protein concentration. 5. Iritis.

Laboratory and Radiographic Findings Rheumatoid Factor A variety of nonrheumatoid diseases cause elevations of RF. These diseases usually have in common chronic inflammation with persistent antigenic challenge; they include other connective tissue diseases (e.g., SLE, Sjogren's syndrome, polymyositis, and scleroderma) as well as infectious diseases (e.g., tuberculosis, leprosy, syphilis, viral hepatitis, bacterial infections, infectious mononucleosis, and influenza). Positive results are also found in patients who have idiopathic pulmonary fibrosis, sarcoidosis, chronic active hepatitis and cirrhosis, lymphomas, or cryoglobulinemia, or who have received multiple blood transfusions.'

RF may also be transiently elevated after immunizations and other assaults to the immune system. Studies of apparently healthy individuals show that the overall prevalence is about 4'3'0, but in persons older than 60 years, some surveys have demonstrated a prevalence rate of more than 40%. However, titers of RF in the elderly and in apparently healthy individuals are typically quite low, less than 1:80.'

Antinuclear Antibodies Antinuclear antibodies (ANAs) are found in 20% to 60% of patients with RA. Titers specific for native DNA are typically normal, whereas titers for single-stranded or denatured DNA are usually elevated. ANA titers are typically lower in RA than in SLE.'

Rheumatoid Arthritis ~

~~~

Epstein-Ban Virus Antibodies Antibodiesto an EBV antigen can be identified by immunodiffusion or by immunofluorescence in the serum of most patients with RA. These antibodies are referred to as anti-RA precipitin (anti-RAP) and anti-RA nuclear antigen ( a n t i - M A ) .The significance of these antibodies remains to be determined.

Other Laboratory Abnormalities Anemia, usually normocytic and normochromic or hypochromic, is quite common in RA. Decreased erythropoiesis is also common in chronic inflammatory conditions like RA. Although the serum iron level and total iron-binding capacity are usually low, supplemental iron is of no value and may actually promote further free radical damage.'," Therefore iron supplementation is not indicated unless the anemia is due specifically to blood loss. Serum ferritin measurements may be useful in determining the appropriateness of iron therapy; however, it must be kept in mind that serum femtin is elevated during acute inflammation and correlates well with other indicators of disease activity such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)value. The ESR is commonly elevated and may be used as a rough estimator of disease activity in patient monitoring, with the caveat that occasionally the ESR does not accurately reflect disease activity.

Synovial Fluid Synovial fluid findings usually reflect the level of inflammation. The high fibrinogen content may lead to spontaneous clotting of the fluid, but this finding should not be confused with the mucin clot. Adding 1%acetic acid dissolves the fibrin. In RA the mucin clot is poor because of smaller-than-normal polymers of hyaluronic acid. Neutrophils are the primary cells found in the fluid and their concentration may range from 10,000 to 50,000 cells/mm3. Complement levels are generally low, and the neutrophils typically contain cytoplasmic inclusion bodies with ingested immune complexes.

Radiographs Radiographic findings usually show soft tissue swelling, erosion of cartilage, and subtle joint space narrowing early in the disease process. As the disease progresses, the erosion of joint spaces is more pronounced, as is the evidence of diffuse osteoporosis.

STANDARD MEDICAL THERAPY Standard medical therapy is of limited value in most cases of RA because it fails to address the complex underlying causes of this disease. Standard medical treatment of RA involves, in addition to drugs, such

physical therapy modalities as exercise, heat, cold, massage, diathermy, lasers, and paraffin baths.I.2

Nonsteroidal Antiinflammatory Drugs and Cyclooxygenase Inhibitors The first drug generally employed is aspirin. It is often quite effective in relieving both the pain and inflammation and is also relatively inexpensive. Because the therapeutic dose required is relatively high, toxicity often occurs. Tinnitus and gastric irritation are early manifestations of aspirin toxicity.'J Other NSAIDs are often used as well, especially when aspirin is ineffective or is not well tolerated. Typical representatives of this class of drugs are as follows: ibuprofen (Motrjn, Advil, Nuprin, piroxicam [Feldene]) diclofenac (Voltaren) fenoprofen (Nalfon) indomethacin (Indocin) naproxen (Naprosyn) tolmetin (Tolectin) sulindac (Clinoril) Although they are more expensive, none of these drugs has demonstrated efficacy superior to that of aspirin. Like their use in osteoarthritis, use of NSAIDs in the treatment of RA is a classic example of suppression of symptoms with acceleration of the factors that promote the disease process. In the case of RA, NSAIDs have been shown to greatly increase the gastrointestinal tract hyperpermeabilityalready present in patients with RA.25 The use of NSAIDs in RA is also a sigruficant cause of serious gastrointestinal tract reactions, including ulcers, hemorrhage, and perforation. Peripheral edema, platelet inhibition, and renal toxicity are other side effects of NSAIDs.6 Approximately 20,000 hospitalizations and 2600 deaths each year occur as a result of NSAIDs in individuals with RA.26 Although most NSAIDs nonselectively inhibit both cyclooxygenase 1 and 2 (COX-1 and COX-2) enzymes, studies have demonstrated that their analgesic and antiinflammatory effects are mediated mainly through inhibition of the COX-2 isoenzyme. As a result, selective COX-2 inhibitors were developed. The most commonly used of these are celecoxib, rofecoxib, and valdecoxib. These agents tend to have a somewhat better safety profile than dual-action NSAIDs, although some studies still do not find better protection for the gastrointestinal tract overall and sales of these drugs were temporarily halted due to an association with cardiovascular events?' Also, although platelet inhibition with resultant bleeding is not an issue for these COX-2 inhibitors, peripheral edema and renal toxicity are still concerns.28 If NSAIDs and COX-2 inhibitors are not effective, corticosteroids may be used. However, most experts and medical textbooks clearly state that long-term use of

Specific Health Problems

corticosteroids in RA is not advised owing to the side effects. Nonetheless, long-term corticosteroid use is quite common in patients with RA. If NSAIDs, COX-2inhibitors, and cortisone therapy do not offer benefit, more aggressive and potentially more toxic treatments are tried along with continued use of NSAIDs and corticosteroids. Hydroxychloroquine, gold therapy, penicillamine, azathioprine, methotrexate, and cyclophosphamide are examples of drugs currently in use. Unfortunately, in most cases, the benefit produced by these drugs is greatly outweighed by the significant toxicity they possess. The use of these drugs often requires additional drugs to deal with the side effects. It is not uncommon for individuals with RA to be taking 12 or more prescription drugs at one time. And finally, joint surgery and joint replacement are reserved for the most severe cases.

Corticosteroids Prednisone is by far the most commonly prescribed oral corticosteroid. Other drugs in this category are prednisolone, methylprednisolone,dexamethasone, and betamethasone. Prednisone blocks many key steps in the allergic and inflammatory response, including the production and secretion of the inflammatory mediators such as histamine, prostaglandins, and leukotrienes by white blood cells. This disruption of the normal defense functions of the white blood cells is effective in stopping the inflammatory response but essentially cripples the immune system. Although prednisone is often of great benefit in the short-term management of many chronic inflammatory diseases, its long-term use generally causes more problems than benefits. Because long-term corticosteroid use has many sigruficant side effects, most physicians try to reserve the use of prednisone for acute worsening of the RA. Long-term treatment with corticosteroids suppresses the natural production of the corticosteroids produced by the adrenal gland, so sudden withdrawal of the drugs may lead to collapse, coma, and death. The side effects of oral corticosteroids are a function of dosage levels and duration of use. Most of the problems of side effects are not due to taking too much of the drug for a short period, but rather reflect long-term use. At lower doses (less than 10 mg/day), the most notable side effects are usually increased appetite, weight gain, retention of salt and water, and greater susceptibility to infection. Common side effects of long-term corticosteroid use at higher dosage levels are as follows: Depression and other mental/emotional disturbances (up to 57% of patients being treated with high doses of prednisone for long periods have these symptoms) High blood pressure

Diabetes Peptic ulcers Acne Excessive facial hair in women Insomnia Muscle cramps and weakness Thinning and weakening of the skin Osteoporosis Susceptibility to the formation of blood clots

Disease-Modifying Antirheumatic Drugs The other drugs used in RA are often referred to as ”disease-modifying antirheumatic drugs” (DMARDs). They include hydroxychloroquine, gold therapy, penicillamine, azathioprine, methotrexate, cyclophosphamide, and leflunomide. Used individually and increasingly in combination, they nevertheless have largely not been proven effective in halting joint erosion. Additionally, many patients do not actually continue long-term therapy with any DMARDs beyond the first few years owing to side effects or lack of efficacy?’

Hydroxychloroquine (Plaquenil) Hydroxychloroquinewas originally used to treat malaria. In the treatment of RA, it is thought to work via inhibition of the immune system. Hydroxychloroquine must be used for at least 6 months to determine whether it is of value in RA. Because hydroxychloroquine is associated with a high rate of side effects, its use is often discontinued before this time. Mild adverse effects include rashes, loss of hair, headache, blurring of vision, ringing in the ears, loss of appetite, nausea, vomiting, stomach cramps, and diarrhea. More severe side effects are emotional or psychotic mental changes, seizures, excessive muscle weakness, damage to the eyes with sigruficant impairment of vision, anemia, decreased white blood cell counts, and frequent infections.

Gold Therapy Gold salt injection aids about 50% of patients with RA, but severe side effects occur in nearly one third of patients. Oral gold salts are slightly less toxic, but still cause rashes, painful mouth ulcers, bone marrow suppression, and, in some cases, even more serious side effects such as kidney damage. As with hydroxychloroquine, a 6-month trial is required to determine the likely benefit of gold therapy.

Penicillamine Penicillamine was originally used in the treatment of copper, mercury, and lead poisoning. It works by binding to these metals and promoting their excretion. Penicillamine has been used in the treatment of RA since the early 1960s. Its use fell out of favor in the 1990s because of a growing concern for its safety as well as

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questionable effectiveness. Penicillaminecan cause kidney damage, blood and bone marrow toxicity, and severe muscular weakness. Like other DMARDs, it must be used for at least 6 months to determine effectiveness.

Azathioprine Azathioprine is a drug that suppresses the immune system. It is often used to severely impair the immune system after organ transplantation in an attempt to prevent tissue rejection. Azathioprine is more powerful than the previously discussed DMARDs and provides more immediate benefits. With this greater potency comes significant toxicity. Side effects include rash, loss of appetite, nausea, vomiting, diarrhea, sores on lips and mouth, bone marrow suppression, weakness, and fatigue. Azathioprine may also raise the risk of certain cancers.

Methotrexate Methotrexate is used primarily in the treatment of cancer and a severe disabling form of psoriasis, but it is growing in its popularity in autoimmune diseases. It works by inhibiting the utilization of folic acid, which is required for cell reproduction. Without the ability to utilize folic acid, cells are unable to divide and multiply. The goal in the case of RA is to inhibit the replication of white blood cells and thus the immune system. Side effects include gastrointestinal ulceration and bleeding, loss of hair, mouth and throat ulcers, severe bone marrow suppression, damage to the lungs, liver, and kidneys, increased rate of infections, and higher risk for development of cancer.

Cyclophosphamide Cyclophosphamideis used primarily in the treatment of various forms of cancer. It is more powerful than all the previously described DMARDs. Toxicity is a major problem, with side effects being comparable to those of methotrexate, but more severe.

Leflunomide Leflunomide is the latest addition to the current list of DMARDs. It has been known to effectively improve functional status while delaying the progression of radiographically assessed joint damage. Unfortunately, leflunomide is metabolized quite slowly and can cause acute toxicity, including alopecia, liver function abnormalities, and bone marrow suppression.

Biologic Agents New agents such as TNF-a inhibitors and interleukin-1 (IL-1) receptor antagonist (IL-lra) have been developed to suppress specific immune system components. IL-lra can cause neutropenia and headache as well as raise the risk of infection. So far IL-lra seems to be not as effective as TNF-a inhibitors.

The three currently approved TNF-a inhibitors are infliximab, etanercept, and adalimumab. Etanercept has also been approved for use in juvenile RA. Because these inhibitors act quickly, most patients demonstrate significant improvement within a few weeks. Unfortunately, drug-free remission is still very rarely achieved, and most patients experience higher disease activity upon discontinuation of therapy2’ For all patients using TNF-ainhibitors, vigdance for hypersenstitivities, anemias, and infections, including opportunistic infections, is required. Long-term studies are needed to assess possible higher risk of malignancy and autoimmune conditions with this agent.

THERAPEUTIC CONSIDERATIONS There is little argument that RA is an aggressive disease calling for aggressive treatment measures. There is also little argument that current medical treatment of RA is aggressive. The big question is: Is aggressive chemotherapy for RA actually providing benefit, and at what cost to the patient? Research is only beginning to determine the effects of treatment on the long-term outcome of RA because in order to fully answer the question just raised, patients must be monitored for at least 20 years. Many of the disease-moddying drugs have been used for only the last two or three decades. A revealing study evaluated the long-term outcome of therapy in 112 patients with RA treated with conventional drug therapy.29After 20 years, despite aggressive therapy with standard drug regimens, only 18% of all patients were able to lead a normal life. Most patients (54%)were either dead (35%) or severely disabled (19%). Most deaths were directly related to RA. The results of this study clearly indicate that, although current drug therapy may be effective in providing short-term benefit, this approach is not providing long-term benefits to patients with RA. RA as a multifactorial condition requires a comprehensive therapeutic approach that focuses on reducing the factors known to be involved in the disease process (gut permeability, circulating immune complexes, free radicals, immune dysfunction, etc.), controlling inflammation, and promoting joint regeneration. The natural approach involves improving poor digestion, food allergies, greater gut permeability, higher levels of circulating immune complexes, and excessive inflammatory processes. Foremost in the natural approach is the use of diet to control inflammation.

Diet Diet has been strongly implicated in RA for many years, in terms of both cause and m e . Population studies have demonstrated that RA is not found in societies that eat

Specific Health Problems a more “primitive” diet and is found at a relatively high rate in societies consuming the so-called Western diet.30 Therefore, a diet that is rich in whole foods, vegetables, and fiber and low in sugar, meat, refined carbohydrate, and saturated fat appears to offer some protection against development of RA. In addition, dietary therapy is showing tremendous promise in the treatment of RA.3’-34 The major focus in dietary therapy is as follows: Eliminating food allergies Following a vegetarian diet Modifying the intake of dietary fats and oils Increasing the intake of antioxidant nutrients

Food Allergy Elimination of allergenic foods has been shown to offer sigruficant benefit to some individuals with RA.-% Virtually any food can aggravate RA, but the most common offending foods are wheat, corn, milk and other dairy products, beef, and nightshade family foods (tomato, potato, eggplants, peppers, and tobacco) as well as food additives. A well-designed study highlighted the effectiveness of eliminating food allergens as part of a healthy diet and lifestyle program in the treatment of RA.39 In this 13-month study, two groups of patients with RA were studied to determine the effect of diet on their condition. One group followed a therapeutic diet, and the other group continued to eat as they wished. Both groups started the study by visiting a spa for 4 weeks The treatment group began their therapeutic diet by fasting for 7 to 10 days. Dietary intake during the fast consisted of herbal teas, garlic, vegetable broth, decoction of potatoes and parsley, and the following juices: carrots, beets, and celery. No fruit juices were allowed. It should be noted that this protocol included potatoes, whereas other restrictive diet plans would remove nightshades to treat arthritic conditions. Patients with RA have historically benefited from fasting; however, strict water fasting should be done only under direct medical supervision. Fasting reduces the absorption of allergic food components as well as the levels of inflammatory mediators. A juice fast or a fast similar to the one used in this study is probably safer than a water fast and may actually have better results. Short-term fasts of 3 to 5 days’ duration are recommended during acute worsening of RA (see Chapter 50 for a full discussion of therapeutic fasting.) After the fast, the patients reintroduced a “new“ food item every second day. If they noticed an increase in pain, stiffness, or joint swelling within 2 to 48 hours, the item was omitted from the diet for at least 7 days before being reintroduced a second time. If the food caused

worsening of symptoms after the second time, it was omitted permanently from the patient’s diet. The results of the study further supported the positive results noted in other studies showing that shortterm fasting followed by a vegetarian diet results in a substantial reduction in disease activity in many patients.40442 The results indicated a therapeutic benefit beyond elimination of food allergies alone. The researchers suggested that the additional improvements were due to changes in dietary fatty acids (discussed later). In addition, other studies have shown that improvementswith a vegetarian diet are associated with improvements in fecal flora (also discussed later). In a 1-year follow-up to this important study, all the patients whose RA responded to the diet were still following it.43 Significant benefits were noted in the patients whose disease responded to the diet compared with subjects whose disease did not respond as well as with the control group following an omnivorous diet. These long-term results support recommending a vegetarian diet in the treatment of RA.

Gut Issues Fecal Flora Altered gastrointestinal tract flora has been linked to RA and other autoimmune diseases (see previous discussion). Two randomized, clinical studies demonstrated that significant changes in microbial flora are associated with clinical improvernent~.~,~~ In the first study, researchers sought to determine the effect of vegetarian diet-induced improvement of RA on fecal flora in 53 patients.U Rather than the traditional method of isolating, idenhfymg, and enumerating different bacterial species in fecal samples, the researchers examined bacterial fatty acid profiles. Human fecal flora is a very complex ecosystem with more than 400 different species, making it very difficult to isolate and idenhfy the species. Because of the lack of reproducibility and the fact that many bacteria do not grow well on selective culture media and many prevent the growth of other species, classic bacteriologic techniques are generally regarded as unsuitable for the study of the microecology of the human gut. Instead of focusing on specific species, the researchers used another approach to detect overall changes in bacterial flora of stool cultures collected at baseline, 4 weeks, and thereafter every 3 months for 1 year. The technique used was computerized comparison of bacterial fatty acid profiles produced by gas-liquid chromatography of stool samples. The fatty acids extracted are structural components of bacterial cell membranes. Each bacterial species has its own characteristic composition. In a stool sample, the profile of fatty acids represents all the bacteria present in the sample. This technique has proved to be more sensitive than classic

Rheumatoid Arthritis

quantitative culture in detecting microecologic changes in stool samples. In the first study, the 53 patients were assigned, on the basis of repeated clinical assessments, either a highimprovement index (HI) or a low-improvement index (Ll). Significant alteration in the intestinal flora was observed when the patients changed from the omnivorous diet to the vegetarian diet. These results further document a direct association between intestinal flora and disease activity in RA. The second study, of 43 patients, provided additional support for the positive effects of a vegetarian diet in producing clinical improvements in RA?5 Forty-three patients with RA were divided into a treatment group or a control group. The treatment group followed a vegetarian diet for 1 month, and the control group consumed their normal diets. At the end of only 30 days, positive changes in fecal flora correlated with improvements in RA. These findings are not surprising. Fecal flora undoubtedly plays a major role in health. The total surface area of the gastrointestinal system is approximately 300 to 400 m2. Only a single epithelial layer separates the host from enormous amounts of dietary and microbial antigens. Fortunately, the gut-associated lymphoid tissue, the largest lymphoid organ, helps protect the individual from antigens that pass through this epithelial layer. Alterations in intestinal flora change the antigenic challenge. In an autoimmune condition like RA, this change may significantly affect disease activity. Gas-liquid chromatography of stool samples may prove to be a relatively quick and easy method of forecasting clinical improvement in RA.

Digestion Proper digestion is a requirement for optimum health, and incomplete or disordered digestion can be a major contributor to the development of many diseases, including RA. The problem is not only that ingestion of foods and nutritional substances is of little benefit when breakdown and assimilation are inadequate but also that incompletely digested food molecules can be inappropriately absorbed. Because many individuals with RA are deficient in digestive factors, including hydrochloric acid and pancreatic enzymes, incomplete digestion may be a major factor in RA.%J~~ Supplementation with appropriate digestive aids appears warranted. Beyond their physiologic role in digestion, pancreatic enzymes may offer additional benefits. Specifically, the proteases in pancreatin have been shown to reduce circulating levels of immune complexes in the following autoimmune .RA SLE

Periarteritis nodosa Scleroderma Ulcerative colitis Crohn’s disease Multiple sclerosis Acquired immunodeficiency syndrome Because clinical improvements usually correspond with decreases in immune complex levels (the ESR can be used as a rough indicator), pancreatin or bromelain (discussed later) supplementation is often warranted.

Psychological Aspects Evidence is gathering that underscores the importance of the psychological makeup of the patient with RA. Also salient is the patient’s style of coping as well as the support given by the patient’s social circles, belief systems, and relationship with the physician. Pessimistic patients who adopt passive coping strategies like staying in bed for many hours a day experience higher rates of depression and worse physical functioning. Conversely, optimistic patients with RA report better psychosocial and physical functioning6 Patients who rate their ability to control and decrease pain utilizing spiritual/religious coping methods as high tend to have less joint pain and negative moods and are much more likely to have positive mood and higher levels of general social support.50 Positive support of a spouse51or family is inversely related to depression and can significantly enhance quality of life. Within the psyche of the patient with RA are a number of common concepts that the physician should be aware of. One study of Korean women demonstrated the importance of sense of empowerment when dealing with an illness like RA.52Using phenomenologic methodologies, this study identified eight major themes that the physician treating a patient with RA should keep in mind; these were severe pain, self-esteem, negative feelings, reflections of their past, concentration on recovery from disease, a comfortable mind in pain, support of family and others, and new life. The idea here would be to explore these issues with rheumatoid sufferers in an effort to help them express themselves and take control of their lives. Not surprisingly, the doctor-patient relationship is a very important factor. The medical literature describes the frequent occurrence of doctors’ frustration with patients, who often have little social support and have histories of previous abuse, somatization disorders, and obsessive-compulsive disorders. Unmarried status and loss of control over the illness have been demonstrated to be key issues for the patient. Patients with aforementioned issues often rely on their health care providers for social support and can be considered “frustrating” by their phy~icians.5~ Once a poor dynamic between the

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physician and the patient is established, the healing relationship is signhcantly compromised. Another report cites the need of the rheumatic patient "to be seen" as an individual and not as a mere diagnosis, "to be believed as far as pain and suffering were concerned, and to have his or her subjective experience acknowledged.54In this spirit, many patients with RA view quick dispersal of antidepressant medications as a sign of disinterest on the doctor's part rather than as an attempt to truly understand and treat the problems at hand. The patient with RA regards the relationship with his or her physician as one of the important in his or her life, and the need for validation and understanding from the physician is vital.

Dietary and Supplemental Fatty Acids Fatty acids are important mediators of allergy and inflammation through their role as precursors of inflammatory prostaglandins, thromboxanes, and leukotrienes. Altering dietary oil intake can sigruficantly increase or decrease inflammation, depending on the type of balance of fatty acids. The basic goal is twofold: (1)to reduce the level of arachidonicacid and (2) to raise the levels of the precursor to prostaglandinsof the 1seridomogamma-linolenic acid (DHGLA) and the precursor to prostaglandins of the 3 series-eicosapentaenoicacid (EPA). Vegetarian diets are often beneficial in the treatment of many chronic allergic and inflammatory conditions, including RA, presumably because such diets decrease the availability of arachidonic acid for conversion to inflammatory prostaglandins and leukotrienes and simultaneously supply linoleic and linolenic acids. An important nutritional approach to reducing the inflammatory response is the consumption of cold-water fish such as mackerel, herring, sardines, and salmon. These fish are rich sources of EPA, which competes with arachidonic acid for prostaglandin and leukotriene production. The net effect of consumption of these fish is a sigruficantlylower inflammatory/allergic response. To test the hypothesis that omega-3 fatty acids may protect against the development of RA, a populationbased case-control study in women living in the Seattle area compared fish consumption in 324 cases of RA with 1245 control cases.55Consumption of broiled or baked fish was associated with a lower risk of RA. An apparent dose-dependent response was noted, in that consuming more than two servings per week offered greater protection than consuming one serving per week. On the basis of results of this study and of the one described previously on the benefits of a vegetarian diet, it appears that the best diet for the prevention of RA is a vegetarian diet with the addition of cold-water fish. Flaxseed oil supplementation (discussed later) may also be useful.

Nutritional Supplements Gammalinoleic Acid Evening primrose, blackcurrant, and borage oil contain gamma-linolenic acid, an omega-6 fatty acid that eventually acts as a precursor to the antiinflammatory prostaglandins of the 1 series. Although quite popular, the research on gamma-linoleicacid (GLA) supplements in RA is controversial and not as strong as the research on omega-3 oils. Studies have actually shown that over the long term, GLA supplementation increases tissue arachidonic acid levels while decreasing tissue levels of EF'A.% Obviously, this effect is contrary to the treatment goal of trying to reduce inflammation by reducing tissue levels of arachidonic acid and raising levels of EPA. Some studies in RA have shown benefit with GLA supplementation,but others have not.57-59 The key factor appears to be whether or not subjects are allowed to take their antiinflammatory drugs. These drugs inhibit the formation of inflammatory prostaglandins and would mask the negative effects of the alteration in tissue fatty acid profile produced by GLA supplements. Although positive results have been reported with GLA supplementation, closer examination is required. For example, in one double-blind study, 37 patients with RA were given either GLA (1.4 g/day) or placebo for 24 weeks. GLA supplementationreduced the number of tender joints by 36%, the tender joint score by 45%, the swollen joint count by 28%, and the swollen joint score In contrast, no patients in the placebo group by 41Y0.~~ showed sigruficant improvement on any measure. The superficial results of this study indicate that borage oil may be useful in reducing the inflammatory process of RA. However, in this study the subjects continued to take their antiinflammatory drugs, which probably masked the detrimental effects on tissue arachidonic acid and EPA levels. The recommended daily dosage for GLA in the treatment of FL4 is 1.4 g, preferably from borage or black currant oil. Evening primrose oil is 9% GLA, so approximately 31 500-mg capsules of evening primrose oil would have to be consumed each day. This dosage would typically cost a person nearly $100 per month. Taking less than the recommended dosage is not likely to produce benefit. For several reasons, including cost, omega-3 oils appear to be a better choice. Also, another controversial aspect is the fact that because GLA can be formed from linoleic acid, it is difficult to determine to what extent the effects are due to GLA rather than linoleic acid. Most sources of GLA are much richer in linoleic acid than in GLA. For example, evening primrose contains only 9% GLA but contains 72% linoleic acid.

Omega-3 Fatty Acids The studies of fish oil supplementation in the treatment of RA have demonstrated far better and more consistent responses than the studies with GLA supplementation. The first double-blind, placebo-controlled study of patients with RA using 1.8 g/day of EPA showed that GLA was associated with less morning stiffness and less tender joints.@These results led to considerable scientific interest as well as numerous popular press accounts of the possible benefits of fish oil for allergic and inflammatory conditions. More than a dozen follow-up studies have consistently demonstrated positive benefits.6149As well as improvements in symptoms (morning stiffness and joint tenderness), fish oil supplementation has produced favorable changes in suppressing the production of inflammatory compounds secreted by white blood cells. One review of randomized controlled trials using fish oil supplementation demonstrates significant clinical improvements compared with placebo and a substantial reduction in the long-term utilization of NSAIDs.7O Some studies show that benefits of the omega-3 fatty acids are not apparent unless they are consumed for at least 12 weeks at a minimum daily dose of 3 g EPA and docosahexaenoic acid (DHA).71Unfortunately, some commercially available fish oils have been shown to contain very high levels of heavy metals, polychlorinated biphenyls (PCBs), dioxins, and lipid peroxides. These substances greatly stress antioxidant defense mechanisms, so it may make the most sense at this time to rely on cold-water fish and flaxseed oil for the omega-3 oils rather than fish oil capsule^.^-^^ If the physician chooses a fish oil supplement, it is best to use a brand that ensures a contaminant-free product via rigorous laboratory testing. Amazingly, standard medical care has not embraced fish oil as a relatively inexpensive and effective treatment for RA. An informed author from one well known medical journal summarized the situation as follows: Since fish oils do not provide industry with the opportunities for substantial profit associated with patented prescription items, they have not received the marketing inputs that underpin the adoption of usual pharmacotherapies. Accordingly, many prescribers remain ignorant of their biochemistry, therapeutic effects, formulations, principles of application and complementary dietary modification^.^^

Although several studies have shown that flaxseed oil is not as effective in increasing tissue concentrations of EPA and lowering tissue concentrations of arachidonic acid as fish oils, these studies failed to address an important The studies were all performed on subjects who continued to consume a diet rich in omega4 fatty acids. The desaturation and elongation enzymes prefer

alphalinolenic acid to the omega-6 oils, but in these studies, only relatively small amounts of alphalinolenic acid were converted to EPA because of the much higher concentrations of omega-6 oils. A later study was undertaken to determine the potential for dietary flaxseed oil to increase tissue EPA concentration in healthy human s~bjects.’~ Unlike the previous studies, this study incorporated a diet low in omega-6 oils by restricting the use of other vegetable oils while supplementing the diet with 13 g (approximately 1 tbsp) of flaxseed oil daily. The results of the study indicated that flaxseed oil supplementation, along with restriction of linoleic acid, raises tissue EPA levels to an extent comparable to the effects of fish oil supplementation. Furthermore, several human and animal studies have demonstrated that flaxseed oil supplementation can inhibit the autoimmune reaction as well as EPA.79 Unfortunately, a small double-blind study conducted in 22 patients over a 2-month period did not show any benefit for flaxseed oil (30 g/day) over the same amount of safflower However, upon examination of the data, a possible explanation presents itself. In order to provide clinical benefit, flaxseed oil would have to reduce the tissue concentration of arachidonic acid while simultaneously increasing the tissue concentration of EPA and DHA. Tissue analysis in patients involved in this study who were taking flaxseed oil did not demonstrate sigruficant changes in tissue levels of either arachidonic acid or EPA and DHA. Previous studies have shown that it is possible to raise tissue levels of EPA and DHA and lower levels of arachidonic acid with flaxseed oils if the intake of omega-6 oils is restricted. The failure to improve tissue lipid concentrations in this study made the flaxseed oil ineffective. The reason behind the failure to improve lipid concentrations is either failure to restrict the use of other vegetable oils while supplementing the diet with flaxseed oil or failure to correct an underlying zinc deficiency. Evidence to support a failure to restrict the intake of omega-6 oils is offered by the fact that there was no significant change in the alphalinolenic acid/linoleic acid ratio in test subjects. Evidence to support failure to correct an underlying zinc deficiency comes from serum zinc analysis on test subjects. Zinc functions in delta-6-desaturase, the enzyme involved in the conversion of alphalinolenic acid to EPA and DHA. Zinc deficiency is common in RA. In fact, several studies have shown zinc supplementation to improve RA. The fact that tissue levels of alphalinolenic acid rose in patients taking the flaxseed oil and that EPA and DHA levels did not suggests zinc deficiency. This finding led researchers to measure

Specific Health Problems serum zinc in the patients in the study. They concluded as follows: Low conversion of alpha-linolenic acid to EPA and DHA [due to a zinc deficiency], together with a low alpha-linolenic acid to linoleic acid ratio, might explain why a short term alpha-linolenic acid supplementation did not alter the RA disease activity.

At this time, our recommendation is to follow the dietary recommendations of a vegetarian diet with the exception of cold-water fish, to restrict omega4 fatty acid intake, and to supplement the diet with a minimum 3 g EPA and DPA in supplemental fish oil or 1 tbsp of flaxseed oil daily. If supplemental fish oils are used, only oils laboratory tested to be free of toxic contaminants should be used.

Dietary Antioxidants The importance of consuming a diet rich in fresh fruits and vegetables in the dietary treatment of RA cannot be overstated. These foods are the best sources of dietary antioxidants. Although the benefits of vitamin C, betacarotene, vitamin E, selenium, and zinc as antioxidant nutrients are becoming well recognized and well accepted, there are still other plant compounds that promote healthy joints. Of particular benefit in RA are flavonoids, owing to their neutralization of inflammation and support of collagen structures.81In short, the antioxidant benefits of fresh fruits and vegetables go well beyond those of vitamins and minerals. Several studies have shown that the risk of RA is highest in people with the lowest levels of nutrient antioxidants (e.g., serum concentrations of alphatocopherol, beta-carotene, and vitamin C). For example, in one study, people with RA and SLE that developed 2 to 15 years after they donated blood for a serum bank in 1974 were designated as For each case, four controls were selected from the serum bank donors, matched for race, sex, and age. Stored serum samples from cases and controls were assayed for alphatocopherol, beta-carotene, and retinol. Patients with both diseases had lower serum concentrations of alphatocopherol, beta-carotene, and retinol in 1974 than their matched controls. One study also supports the use of antioxidants with conventional therapy in newly diagnosed patients with RA.83 In this research, 40 patients were divided into two groups, one of which was used as a control and given no treatment. The other group was divided in half; 10 patients were prescribed steroids and/or NSAIDs, and 10 were given these conventional treatments plus vitamins A, C, and E. Results showed a higher level of blood antioxidant levels in patients in the antioxidant group, with lipid peroxidation markers reduced in that group as well.

Selenium and Vitamin E Selenium levels are low in patients with RA.8Qss Low selenium levels may be a significant nutritional factor because this nutrient is an important antioxidant and serves as the mineral cofactor in the free radicalscavenging enzyme glutathione peroxidase. This enzyme is especially important in reducing the production of inflammatory prostaglandins and leukotrienes. Because free radicals, oxidants, prostaglandins, and leukotrienes cause much of the damage to tissues seen in RA, a deficiency of selenium would result in even more sigruficant damage. Clinical studies have not yet clearly demonstrated that selenium supplementation alone improves the signs and symptoms of RA. However, one clinical study indicated that selenium combined with vitamin E had a positive effect.& The best food sources of selenium are Brazil nuts, fish, and grains. However, the amount of selenium in grains and other plant foods is directly related to the amount of selenium available in the soil in which these foods are grown.

Zinc Zinc has antioxidant effects and is a cofactor to the antioxidant enzyme superoxide dismutase (copper-zinc SOD). Zinc levels are typically reduced in patients with RA, and several studies have used zinc in the treatment of RA, with some of the studies demonstrating a slight therapeutic effect.8749 Most of the studies utilized zinc in the form of sulfate. Better results may be obtained with the use of a form of zinc with a higher absorption rate such as zinc picolinate, zinc monomethionhe, or zinc citrate. Foods rich in zinc include oysters, whole grains, nuts, and seeds.

Manganese and Superoxide Dismutase Manganese functions in a different form of the antioxidant enzyme superoxide dismutase (manganese SOD). Manganese-containing SOD is deficient in patients with RA.w The injectable form of this enzyme (available in Europe) has been shown to be effective in the treatment of RA?l However, it is not clear whether any orally administered SOD can escape digestion in the intestinal tract and exert a therapeutic effect. In one study, oral SOD was shown not to affect tissue SOD levels?2 Perhaps a better and more economical method of raising SOD levels is to supplement the diet with additional manganese. Manganese supplementation has been shown to increase SOD activity.93Although no clinical studies have been conducted to determine the effectiveness of manganese supplementationin RA, it appears to be indicated on the basis of the low levels seen in patients with RA as well as its biochemical functions. Good dietary sources of manganese include nuts,

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whole grains, dried fruits, and green leafy vegetables. Meats, dairy products, poultry, and seafood are considered poor sources of manganese.

Vitamin C Vitamin C functions as an important antioxidant. The white blood cell and plasma concentrations of vitamin C are significantly decreased in patients with RA.94 Supplementation with vitamin C increases SOD activity, reduces histamine levels, and provides some antiinflammatory a ~ t i o n .Foods ~ ~ , ~rich ~ in vitamin C include broccoli, Brussels sprouts, cabbage, citrus fruits, tomatoes, and berries.

Other Nutrients Pantothenic Acid

copper-containing substances may be indicated in patients with RA who need a ~ p i r i n . ' ~ ~ J ~ The wearing of copper bracelets has been a long-time folk remedy that appears to have some scientific support, as found in a double-blind study performed in Australia. Presumably, copper is absorbed through the skin and is chelated to another compound that is able to exert antiinflammatory action.lo5 Copper is a component, along with zinc, in one type of SOD (copper-zinc SOD).Deficiency may result in significant susceptibility to free radical damage as a result of decreased SOD levels. However, an excess intake of copper may be detrimental because of its ability to combine with peroxides and damage joint tissues.lmJM

Sulfur

The sulfur (cysteine) content in fingernails of arthritis Whole blood pantothenic acid levels have been reported sufferers is lower than that in healthy controls.107 to be lower in patients with RA than in normal controls?' Normalizing the sulfur content of the nails by adminisIn addition, disease activity was found to be inversely tering intravenous or intragluteal colloidal sulfur was correlated with pantothenic acid levels. Correction of low reported to alleviate pain and swelling, according to pantothenic acid levels to normal brings about some ~ ~ , ' ~ raising the clinical data from the 1 9 3 0 ~ . ~Presumably, alleviation of RA symptoms. In one double-blind study, sulfur content of the body through greater consumption subjective improvement of RA symptoms was noted in patients receiving 2 g/day of calcium p a n t ~ t h e n a t e . ~ ~of sulfur-rich foods like legumes, garlic, onions, Brussels sprouts, and cabbage or through supplementation may Patients noted improvements in duration of morning be of equal benefit. stiffness, degree of disability, and severity of pain. Good dietary sources of pantothenic acid are whole grains Niacinamide and legumes. Kaufman"O and Hoffer"' have reported very good cliniPyridoxine (Vitamin B6) cal results in the treatment of hundreds of patients with RA and osteoarthritis with the use of high-dose niaciThere is a clear relationship between low levels of blood pyridoxal 5'-phosphate (vitamin B6) and inflammatory namide (i.e., 900 to 4000 mg in divided doses daily). Although these promising results have been confirmed indicators of RA. One cross-sectional study evaluated plasma B6 levels in patients with RA before and after in osteoarthritis (see Chapter 195), they have never been fully evaluated in detailed clinical studies of patients a methionine load challenge test. Plasma B6 levels were with RA. Niacinamide has been shown to affect the higher in patients with lower ESRs, lower CRP levels, autoimmune process involved in insulin-dependent less disability, less pain and fatigue, and fewer swollen diabetes mellitus (see Chapter 163). joints. It seems that low levels of this vitamin are due not to deficiency of intake but more probably to ongoing Botanical Medicines chronic inflammatory processes. Higher levels of homoMany botanicals possess sigruficant antiinflammatory cysteine were also noted in these B,-deficient patients, creating an increased risk of cardiovascular disease.99 action and are useful in the treatment of RA. The suggestions made here represent some of the more popular and Because patients with RA are known to be at higher risk of for comorbidity and mortality from cardiovascular better researched of these botanical medicines. Several herbs are also discussed in relation to their ability to disease,lmincluding left ventricular diastolic dysfuncenhance the function or secretion of endogenous cortition and pulmonary hypertension'O' as well as first-time costeroids as well as to prevent or reverse some of the heart attack,'02 vitamin B6 supplementation may be very negative effects of orally administered cortisone. useful in patients with rheumatic arthritis as a means to correct chronic disease-related deficiency as well as to Curcuma longa prevent cardiovascular maladies. Curcumin, the yellow pigment of Curcuma h g u Copper (turmeric),exerts excellent antiinflammatory and antioxidant e f f e c t ~ . l lCurcumin ~ - ~ ~ ~ is as effective as cortisone Copper aspirinate (salicylate) is a form of aspirin that or the potent antiinflammatory drug phenylbutazone yields better results in reducing pain and inflamin models of acute inflammation. However, although mation than standard aspirin preparations. These

phenylbutazone and cortisone are associated with significant toxicity, curcumin is without side effects. Curcumin exhibits many direct antiinflammatory effects, including inhibition of the formation of leukotrienes and other mediators of inflammation. However, curcumin also appears to exert some indirect effects. In models of chronic inflammation, curcumin is much less active in animals from which the adrenal glands have been removed. This observation suggests that curcumin works to enhance the body's own antiinflammatory mechanisms. Possible mechanisms of action are as follows: Stimulation of the release of adrenal corticosteroids "Sensitizing" or priming of cortisone receptor sites, thereby potentiating cortisone action Preventing the breakdown of cortisone Curcumin has demonstrated some beneficial effects in human studies comparable to those of standard drugs. In one double-blind clinical trial in patients with RA, curcumin (1200 mg/day) was compared with phenylbutazone (300mg/day).*lsThe improvements in the duration of morning stiffness, walking time, and joint swelling were comparable in both groups. However, it must be pointed out that although phenylbutazone is associated with significant adverse effects, curcumin has not been shown to produce any side effects at the recommended dosage level. In another study that used a new human model for evaluating NSAIDs, the postoperative inflammation model, curcumin was again shown to exert comparable antiinflammatory action to phenylbuta~one."~ It must be pointed out that while curcumin has an antiinflammatory effect similar to phenylbutazone and various NSAIDs, it does not possess direct analgesic action. The results of these studies indicate that turmeric or curcumin may provide benefit in the treatment of acute exacerbations of inflammation in RA. Furthermore, the safety and excellent tolerability of curcumin compared with standard drug treatment is a major advantage. Toxicity reactions to curcumin have not been reported. Animals fed very high levels of curcumin (3 g/kg body weight) have not exhibited any significant adverse effects.'" The recommended dosage for curcumin as an antiinflammatory is 400 to 600 mg three times a day. To achieve a similar amount of curcumin using turmeric would require a dosage of 8,000 to 60,000 mg. Because there remains a question as to the absorption of orally administered curcumin, this substance is often formulated in conjunction with bromelain to possibly enhance absorption. Bromelain also has antiinflammatory effects (see later). If a curcumin-bromelain combination is used, it must be taken it on an empty stomach, either

20 minutes before meals or between meals. Providing curcumin in a lipid base such as lecithin, fish oils, or essential fatty acids may also increase absorption.

Bromelain Bromelain refers to a mixture of enzymes found in pineapple. Bromelain was introduced as a medicinal agent in 1957, and since that time more than 200 scientific papers on its therapeutic applications have appeared in research literature.121Bromelain has been reported to exert a wide variety of beneficial effects, including reducing inflammation in RA.lZ Several mechanisms may account for bromelain's antiinflammatory effects, including the inhibition of proinflammatory compounds. Much of bromelain's antiswelling effects are due to activation of compounds that break down fibrin. Fibrin's role in the promotion of the inflammatory response is to form a matrix that walls off the area of inflammation, resulting in blockage of blood vessels and inadequate tissue drainage and edema. Bromelain also blocks the production of kinins, compounds produced during inflammation that increase swelling as well as cause pain.

Zingiber oflicina lis Ginger (Zingibw oficinalis) possesses numerous pharmacologic properties, the most relevant in RA being its antioxidant effects; its inhibition of prostaglandin, thromboxane, and leukotriene synthesis; and its antiinflammatory effects. Fresh ginger, which contains a protease that may have action on inflammation similar to that of bromelain, may be more effective in the treatment of RA than dried preparation^.'^^ Ginger's ability to inhibit the formation of inflammatory mediators along with its strong antioxidant activities and protease component suggest a possible benefit in inflammatory condition^.'^^ To test this hypothesis, a preliminary clinical study was conducted in seven patients with RA in whom conventional drugs had provided only temporary or partial relief.lz All patients were treated with ginger. One patient took 50 g/day of lightly cooked ginger, and the other six took either 5 g/day of fresh ginger or 0.1 to 1 g/day of powdered ginger. Despite the difference in dosage, all patients reported a substantial improvement, including pain relief, joint mobility, and a decrease in swelling and morning stiffness. In the follow-up to this study, 28 patients with RA, 18 with osteoarthritis, and 10 with muscular discomfort who had been taking powdered ginger for periods ranging from 3 months to 2.5 years were evaluated.lZ6On the basis of clinical observations, it was reported that 75%of the patients with arthritis and 100% of those with muscular discomfort experienced relief in pain or swelling. The recommended dosage was 500 to 1000 mg/day, but

Rheumatoid Arthritis many patients took three to four times this amount. Patients taking the higher dosages also reported quicker and better relief. There remain many questions concerning the best form of ginger and the proper dosage. Most studies have utilized 1 g of dry powdered ginger root. This amount is a relatively small dose of ginger compared with the average daily dietary dose of 8 to 10 g consumed in India. Although most scientific studies have used powdered ginger root, fresh (or possibly freeze-dried) ginger root at an equivalent dosage may yield better results because it contains higher levels of gingerol as well as the active protease. In an effort to provide some practical application of the information presented here on ginger, we can recommend that a daily dosage of 2 to 4 g of dry powdered ginger may be effective. This amount would be equivalent to approximately 20 g or 2/3 oz of fresh ginger root, roughly a 0.5-inch slice. These amounts of ginger can easily be incorporated into the diet in fresh fruit and vegetable juices. There do not appear to be any side effects with ginger at these dosage levels.

Bupleurum falcatum Chinese thoroughwax root (Bupleumm fulcutum) is an important component in various Chinese traditional medicine prescriptions, particularly in remedies for inflammatory conditions.These formulas have also been used in combination with corticosteroid drugs like prednis~ne.’~~ Chinese thoroughwax has been shown to enhance the activity of cortisone. The active constituent components of Chinese thoroughwax are steroidlike compounds known as saikosaponins. These compounds have diverse pharmacologic activities, including sigruficantantiinflammatory action.lZ8 The saikosaponins apparently both increase the release of cortisone and other hormones by the adrenal gland and potentiate their effects. Saikosaponins have also been shown to prevent the adrenal gland atrophy caused by cortico~teroids.~~~ It has been recommended that patients on corticosteroid drugs should take herbal formulas containing Chinese thoroughwax to help protect their adrenal glands.Im Glycyrrhiza glabru (licorice root) and Punax ginseng (ginseng) appear to enhance the action of Chinese thoroughwax, and the three botanicals are almost always used together in traditional Chinese herbal formulas. Both licorice root and ginseng have components with antiinflammatory activity.lWIn addition, these herbs have also been shown to improve the activity of the adrenal glands. Perhaps licorice’s major effect is its ability to inhibit the breakdown of adrenal hormones by the liver. When licorice is used in combination with Chinese thoroughwax, the net effect is higher levels of corticosteroids in the circulation.

Preparationscontaining Chinese thoroughwax, licorice, and I? ginseng may help restore adrenal function in patients with a history of long-term or high-dosage corticosteroid use.

Physical Medicine Physical therapy has a major role in the management of patients with RA. Although not curative, proper physical management can improve patient comfort and preserve joint and muscle function. Heat is typically used to help relieve stiffness and pain, relax muscles, and increase range of motion. Moist heat (e.g., moist packs, hot baths) is more effective than dry heat (e.g., heating pad), and paraffin baths are used if skin irritation from regular water immersion develops. Cold packs are of value during acute flare-ups. Strengthening and range-of-motion exercises are important for improving and maintaining joint function as well as general health. Patients with well-developed disease and significant inflammation should begin with progressive, passive range-of-motion, and isometric exercises. As inflammation is ameliorated, active rangeof-motion and isotonic exercises are more appropriate. One randomized, controlled, multicenter trial broached the controversial idea of using high-intensity long-term exercise in patients with RA. More than 300 study participants were given either standard physical therapy or a high-intensity exercise program for 2 years. It was demonstrated that intensive exercise did not increase radiographic damage of the large joints, except possibly in those patients who had considerable baseline damage. This high-intensity exercise also improved functionality and created better mood and a sense of ~e1l-being.l~~

Balneotherapy Balneotherapy,the therapeutic use of mineral baths and mud packs, is a form of physical therapy often recomconmended in cases of RA in Europe. Sukenik et ducted in Israel provides some evidence of benefit. The study was conducted along the western shore of the Dead Sea at the Ein Gedi Spa. This area along the Dead Sea is renowned for its many hot, thermomineral springs and a large natural concentration of mud useful for therapeutic purposes. The area is also popular to persons with RA because of its unique climatic conditions-high barometric pressures, low humidity, high temperatures, paucity of rainfall, and absence of air pollution. Standard spa therapy for RA in this region consists of mud packs, sulfur baths, and bathing in the waters of the Dead Sea. In a previous study, it was shown that sulfur and mud pack therapy, alone or in combination, are effective in reducing inflammation and pain in active RA. A further study was conducted to determine whether there was any treatment advantage to sulfur baths or bathing in the Dead Sea, alone or in combination, in the

treatment of active RA. Thirty-six patients with active RAwere treated for 12 days at the spa. The patients were divided randomly into four study groups: group 1 was treated with daily baths in the Dead Sea; group 2 was treated with daily sulfur baths; group 3 was treated with a combination of daily Dead Sea bathing and sulfur baths; and group 4 served as a control group. All patients were assessed by a rheumatologist who was blinded as to the treatment modalities and group allocations. Clinical parameters assessed were duration of morning stiffness, 15-m walk time, grip strength, activities of daily living assessment, patient's assessment of disease activity, number of active joints, and the Ritchie articular index. The study found a statistically sigruficant improvement lasting up to 3 months only in the three treatment groups. In morning stiffness, 15-m walk time, grip strength, activities of daily living assessment, and patient's assessment of disease activity, an advantage was shown for Dead Sea baths, either alone or in combination with sulfur baths. The number of active joints and the Ritchie index improved to a similar degree in all three treatment groups. Table 207-1 lists the results of the ICltchie index for the treatment groups. Several research studies have attempted to determine why the Dead Sea baths were so effective. The Dead Sea is extremely saline, 10 times more so than the Mediterranean Sea. However, this is not the most likely explanation; a double-blind study in RA that compared Dead Sea bath salts with regular table salt dissolved in the patient's home bath heated to 35" C for 20 minutes a day for 2 weeks found statistically significant improvements in most of the clinical variables in the group using the Dead Sea bath salts compared with the group using table salt. Although muscle tone, joint mobility, and pain intensity are somewhat influenced by hydromechanical and thermal stimuli, the improvement noted with Dead Sea bathing is generally superior to that with regular hot baths. A possible explanation may be in the trace mineral content of the Dead Sea. It is possible that trace elements such as zinc and copper-key components in the antioxidant enzyme superoxide dismutase-as well as boron, selenium, rubidium, and

Baseline

Group 1

15.9

End of treatment

1 month

3 months

27.3

13.1

12.6 14.8

Group 2

11.2

23.2

10.1

Group 3

19.3

21.4

7.8

Group 4

27.1

25.4

28

12.7 28.5

other minerals may be absorbed through the skin. Below-normal levels of several trace minerals have been reported in patients with RA. The results of the study conducted by Sukenik et are quite impressive, in that most patients had severe active RA but no patient in the treatment group experienced any side effect or aggravation of disease. Compare this result with standard drug therapy for RA. Hopefully further studies will be conducted to improve the understanding of the beneficial effects of Dead Sea baths.

THERAPEUTIC APPROACH RA is a disease known to have many contributing factors. Effective treatment using natural therapies requires controlling as many of these factors as possible. Foremost is the use of dietary measures to reduce the causes and ameliorate the symptoms of RA. Symptom relief can also be attained through the use of standard physical therapy techniques (i.e., exercise, heat, cold, massage, diathermy, lasers, and paraffin baths), antiinflammatory botanicals and nutrients, and, in appropriate patients, bowel detoxification. Rheumatoid arthritis is often an aggressive disease that needs aggressive treatment. In mild to moderate RA, the measures listed previously are extremely effective on their own. In severe cases, NSAIDs and other drugs may be necessary, at least in the acute phase. However, the physician should encourage patients not to abandon the natural measures, because they will actually enhance the effectiveness of the drugs, allowing for lower dosages. When the drugs are necessary, deglycyrrhized licorice (DGL) should be prescribed to protect against development of peptic ulcers.

Diet The first step is a therapeutic fast or an elimination diet, and the second is careful reintroduction of foods to detect those that determine symptoms. Virtually any food can aggravate RA, but the most common offenders are as follows: Wheat corn Milk and other dairy products Beef Nightshade (Solanurn) family foods-tomato, eggplants, peppers, and tobacco

potato,

After all allergens have been isolated and eliminated, a general healthy diet rich in whole foods, vegetables, and fiber and low in sugar, meat, refined carbohydrates, and animal fats is indicated. Foods particularly beneficial for the patient with RA are cold-water fish (mackerel, herring, sardines, and salmon) and flavonoid-rich

Rheumatoid Arthritis

berries (cherries, hawthorn berries, blueberries, blackberries, etc.) and their extracts.

recommend ginger extracts standardized to contain 20% gingerol and shogaol at a dosage of 100 to 200 mg three times/ day

Supplements DHEA: 50 to 200 mg/day EPA: 1.8 g/day; or flaxseed oil: 1tbsp/day Niacinamide: 500 mg four times/day (monitor liver enzymes) Pantothenic acid: 500 mg four times/day Quercetin: 250 mg between meals three times/day Vitamin A: 5000 IU/day Vitamin C: 1 to 3 g/day in divided doses Vitamin E: 400 IU/day Copper: 1 mg/day Manganese: 15 mg/day Selenium: 200 pg/day Zinc: 45 mg/day Betaine HC1: 5 to 70 grains with meals (see Appendix 7) Pancreatin (10 x USP): 350 to 750 mg between meals three times/day; or bromelain: 250 to 750 mg (1800 to 2000 MCU)between meals three times/day Fish oil supplement: If cold water-fish is not available, take minimum daily dose of 3 g eicosapentaenoic and docosahexaenoic acids/day and use a high-quality, laboratory-tested product.

Botanical Medicines The following botanicals may be used alone or in combination with others. Severe inflammation and joint destruction require more aggressive therapy. Patients with a history of corticosteroid use (e.g., prednisone) and those being weaned off corticosteroids need the botanicals B. fulcutum, G. glubru, and l? ginseng, which prevent and/or reverse the adrenal gland atrophy induced by these drugs. Dosages are as follows:

B. falcatum: Dried root: 2 to 4 g Tincture (1:5): 5 to 10 ml Fluid extract (1:l):2 to 4 ml Solid extract (4:l): 200 to 400 mg

P. ginseng: Crude herb: 4.5 to 6 g/day Standardized extract (5% ginsenosides): 100 mg one to three times/day G. glabru:

Dried root: 2 to 4 g Tincture (1:5): 10 to 20 ml Fluid extract (1:l):4 to 6 ml Solid extract (41): 250 to 500 mg

Physical Medicine Heat (moist packs, hot baths, etc.):20 to 30 minutes one to three times/day Cold packs for acute flare-ups Paraffin baths (if skin irritation is caused by hot water) Active (or in severe cases passive) range-of-motion exercises: 3 to 10 repetitions one to two times/day Progressive isometric (and isotonic as the joints improve) exercise: 3 to 10 repetitions several times per day with generous periods of rest Massage: one to three times/week

Counseling/PsychologicalTherapy

400 mg three times/day; or ginger: incorporate 8 to 10 g of fresh ginger into the diet each day or

The clinician should focus on the typical concerns of the rheumatoid patient (see earlier discussion of psychological aspects), and evaluate the patient’s support network. Attempts should be made to work with spouses and family members if possible.

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Curcumin:

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2ooO;59(S~ppl2):II/lO8-II/ll8. 18. Hall GM, Spector TD. Depressed levels of dehydroepiandrosterone sulphate in postmenopausal women with rheumatoid arthritis but no relation with axial bone density. Ann Rheum Dis 1993; 52:211-214. 19. Kanik KS, Chrousos GP, Schumacher HR,et al. Adrenocorticotropin, glucocorticoid, and androgen secretion in patients with new onset synovitis/rheumatoid arthritis: relations with indices of inflammation. J Clin Endocrinol Metab 2ooO;85:1%1-1466. 20. Giltay EJ, van Schaardenburg D, Gooren LJ, et al. Effects of dehydroepiandrosterone administration on disease activity in patients with rheumatoid arthritis. Br J Rheumatol 1998;37705-706. 21. van Vollenhoven RF, Engelman EG, McGuire JL. An open study of dehydroepiandrosterone in systemic lupus erythematosus. Arthritis Rheum 1994;371305-1310. 22. van Vollenhoven R, Engleman EG, McGuire JL. Dehydroepiandrosterone in systemic lupus erythematosus. Results of a double-blind, placebo-controlled, randomized clinical trial. Arthritis Rheum 1995; 381826-1831. 23.Clegg DO, Ward JR. Diagnostic criteria in rheumatoid arthritis. Scand J Rheum 1987;65:3-11. 24. Nishiya K, Matsueda H, Shirakami T, et al. Serum and urinary ferritin levels in patients with rheumatoid arthritis.Acta Med Okayama 1985;39:321-328. 25. Jenkins R, Rooney P, Jones D, et al. Increased intestinal permeability in patients with rheumatoid arthritis: a side effect of oral nonsteroidal anti-inflammatory drug therapy? Br J Rheumatol 1987;26 103-107. 26. Fries JF,Miller SR, Spitz PW, et al. Toward an epidemiology of gastropathy associated with nonsteroidal antiinflammatory drug use. Gastroenterol1989;96647-655. 27. Lee SJ, Kavanaugh A. Pharmacological treatment of established rheumatoid arthritis. Best Pract Res Clin Rheumatol 2003;17 811-829. 28. Chan FK, Hung LC, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;3472104-2110. 29. Scott DL, Symmons DP, Coulton BL, et al. Long-term outcome of treating rheumatoid arthritis. Results after 20 years. Lancet 1989;i: 1108-1111. 30. Trowell H, Burkitt D. Western diseases: their emergence and prevention. Cambridge, MA: Harvard University Press, 1981. 31.Darlington LG, Ramsey NW. Clinical review. Review of dietary therapy for rheumatoid arthritis. Br J Rheumatol1993;32:507-514. 32. Buchanan HM, Preston SJ, Brooks PM, et al. Is diet important in rheumatoid arthritis? Br J Rheumatol1991;30:125-134. 33. McCrae F, Veerapen K, Dieppe P. Diet and arthritis. Practitioner 1986,230.359-361. 34. Kjeldsen-Kragh J. Rheumatoid arthritis treated with vegetarian diets. Am J Clin Nutr 1999;7O(Suppl):594S6OOS.

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Rheumatoid Arthritis 57. Brzeski M, Madhok R, Capell HA. Evening primrose oil in patients with rheumatoid arthritis and side effects of non-steroidal antiinflammatory drugs. Br J Rheumatol1991;30371-372. 58. Belch JJ,Ansell D, Madhok R, et al. Effects of altering dietary essential fatty acids on requirements for non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis. A double blind placebo controlled study. Ann Rheum Dis 1988;4796-104. 59. Leventhal LJ, Boyce EG, Zurier RB. Treatment of rheumatoid arthritis with gammalinoleic acid. Ann Intern Med 1993;119867-873. 60. Kremer JM, Bigauoette J, Michalek AV, et al. Effects of manipulation of dietary fatty acids on clinical manifestations of rheumatoid arthritis. Lancet 1985;1:184-187. 61. Kremer J, Jubiz W, Michalek A, et al. Fish-oil fatty acid supplementation in active rheumatoid arthritis: a double-blinded, controlled cross-over study. Ann Intern Med 1987;106:497-502. 62. Sperling R, Weinblatt M, Robin JL et al. Effects of dietary supplementation with marine fish oil on leukocyte lipid mediator generation and function in rheumatoid arthritis. Arthritis Rheum 1987; 30:988-997. 63.Cleland LG, French JK, Betts WH, et al. Clinical and biochemical effects of dietary fish oil supplements in rheumatoid arthritis. J Rheumatol 1988;151471-1475. 64.Magaro M, Altmonte L, Zoli A, et al. Influence of diet with different lipid composition on neutrophil composition on neutrophil chemiluminescence and disease activity in patients with rheumatoid arthritis. Ann Rheum Dis 1988;47793-796. 65. van der Tempe1 H, Tulleken JE, Limburg PC, et al. Effects of fish oil supplementation in rheumatoid arthritis. Ann Rheum Dis 1990;49: 76-80. 66. Kremer JM, Lawrence DA, Jubiz W, et al. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects. Arthritis Rheum 1990;33810-820. 67. Lau CS, Morley KD, Belch JJ. Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis-a double-blind placebo controlled study. Br J Rheumatol 1993;32:982-989. 68. Nielsen GL, Faarvang KL, Thomsen BS, et al. The effects of dietary supplementation with 0-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: a randomized, double-blind trial. Eur J Clin Invest 1992;22:687-691. 69. Voker D, Fitzgerald P,Major G, et al. Efficacy of fish oil concentrate in the treatment of rheumatoid arthritis. J Rheumatol 2000; 272343-2346. 70. Ariza-Ariza R, Mestanza-Peralta M, Cardiel MH. Omega-3 fatty acids in rheumatoid arthritis: an overview. Semin Arthritis Rheum 1998;27366-370. 71. Kremer JM. 01-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr 2000;71(1Suppl):349S351S. 72.Shukla VKS, Perkins EG. The presence of oxidative polymeric materials in encapsulated fish oils. Lipids 1991;26:23-26. 73. Fritshe KL, Johnston PV. Rapid autoxidation of fish oil in diets without added antioxidants. J Nutr 1988;118:425-426. 74. Harats D, Dabach Y, Hollander G, et al. Fish oil ingestion in smokers and nonsmokers enhances peroxidation of plasma lipoproteins. Atherosclerosis 1991;90127-139. 75. Cleland LG, James h4J, Proudman SM. The role of fish oils in the treatment of rheumatoid arthritis. Drugs 2003;63:845-853. 76.Nettleton JA. Omega-3 fatty acids. Comparison of plant and seafood sources in human nutrition. J Am Diet Assoc 1991;91: 331-337. 77.Cunnane SC, Chen ZY, Yang J, et al. Alpha-linolenic acid in humans: direct functional role or dietary precursor? Nutrition 1991; 7437-439. 78. Mantzioris E, James MJ, Gibson RA, et al. Dietary substitution with alpha-linolenic acid-rich vegetable oil increases eicosapentaenoic acid concentrations in tissues. Am J Clin Nutr 1994;591304-1309.

79. Kelley DS. Alpha-linolenic acid and immune response. Nutrition 1992;8:215-217. 80. Nordstrom DC, Honkanen VE, Nasu Y, et al. Alpha-linolenic acid in the treatment of rheumatoid arthritis: a double-blind placebo-controlled and randomized study. Flaxseed vs. safflower oil. Rheumatol Int 1995;14231-234. 81. Cody V, Middleton E, Harborne JB. Plant flavonoids in biology and medicine- biochemical, pharmacological, and structureactivity relationships. New York Alan R Liss, 1986; Cody V, Middleton E, Harborne JB, Beretz A. Plant flavonoids in biology and medicine II-biochemical, pharmacological, and structure activity relationships. New York Alan R Liss, 1988. 82. Comstock GW, Burke AE, Hoffman SC, et al. Serum concentrations of alpha tocopherol, beta carotene, and retinol preceding the diagnosis of rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis 1997;56:323-325. 83. Jaswal S, Mehta HC, Sood, et al. Antioxidant status in rheumatoid arthritis and role of antioxidant therapy. Clin Chim Acta 2003;338: 123-129. 84. Tarp U,Overvad K, Hansen JC, et al. Low selenium level in severe rheumatoid arthritis. Scand J Rheumatol 1985;14:97-101. 85. Tarp U, Overvad K, Thorling EB, et al. Selenium treatment in rheumatoid arthritis. Scand J Rheumatol1985;14364-368. 86. Munthe E, Aaseth J, Jellum E. Trace elements and rheumatoid arthritis (RA)-pathogenetic and therapeutic aspects. Acta Pharmacol Toxic01 1986;59(Suppl7):365-373. 87. Pandley SP, Bhattacharya SK, Sundar S. Zinc in rheumatoid arthritis. Indian J Med Res 1985;81:618-620. 88. Simkin PA. Treatment of rheumatoid arthritis with oral zinc sulfate. Agents Actions Suppl1981;8:587-595. 89. Mattingly PC, Mowat AG. Zinc sulphate in rheumatoid arthritis. Ann Rheum Dis 1982;41:456-457. 90. Pasquier C, Mach PS, Raichvarg D, et al. Manganese-containing supemxide-dismutase deficiency in polymorphonuclear leukocytes of adults with rheumatoid arthritis. Inflammation 1984;8:27-32. 91. Menander-Huber KB. Orgotein in the treatment of rheumatoid arthritis. Eur J Rheumatol Mlamm 1981;4:201-211. 92. Zidenberg-CherrS, Keen CL, Lonnerdal B, et al. Dietary superoxide dismutase does not affect tissue levels. Am J Clin Nutr 1983;375-7. 93. de Rosa GD, Keen CL, Leach RM, et al. Regulation of superoxide dismutase activity by dietary manganese. J Nutr 1980;110795-804. 94. Mullen A, Wilson CW. The metabolism of ascorbic acid in rheumatoid arthritis. Proc Nutr Sci 1976;35:8A-9A. 95. Subramanian N. Histamine degradative potential of ascorbic acid. Agents Actions 1978;8:484-487. 96. Levine M. New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med 1986;314:892-902. 97. Barton-Wright EC, Elliott WA. The pantothenic acid metabolism of rheumatoid arthritis. Lancet 1963;ii:862-863. 98. General Practitioner Research Group. Calcium pantothenate in arthritic conditions. Practitioner 1980;224:208-211. 99. Chiang EP, Bagley PJ, Selhub J, et al. Abnormal vitamin Bh status is associated with severity of symptoms in patients with rheumatoid arthritis. Am J Med 2003;114:283-287. 100. DeMaria AN. Relative risk of cardiovascular events in patients with rheumatoid arthritis. Am J Cardiol2002;89:33D-38D. 101. Gonzalez-Juanatey, Testa A, Garcia-Castelo A, et al. Echocardiographic and Doppler findings in long-term treated rheumatoid arthritis patients without clinically evident cardiovascular disease. Semin Arthritis Rheum 2004;33:231-238. 102. Fischer LM, Schlienger RG, Matter C, et al. Effect of rheumatoid arthritis or systemic lupus erythematosus on the risk of first-time acute myocardial infarction. Am J Cardiol2004;93:19&200. 103. Sorenson JRJ, Hangarter W. Treatment of rheumatoid and degenerative disease with copper complexes. A review with emphasis on copper salicylate. Inflammation 1977;2217-238.

Specific Health Problems 104. Lewis AJ. The role of copper in inflammatory disorders. Agents Actions 1984;513-519. 105. Walker WR, Keats DM. An investigation of the therapeutic value of the "copper bracelet"derma1 assimilation of copper in arthritic/rheumatoid conditions. Agents Actions 1976;6:454-458. 106. Chung MH,Kessner L, Chan PC. Degradation of articular cartilage by copper and hydrogen peroxide. Agents Actions 1984;15: 328-335. 107. Sullivan MX, Hess WC. Cystine content of finger nails in arthritis. J Bone Joint Surg 1935;16:185-188. 108. SenturiaBD. Results of treatment of chronic arthritisand rheumatoid conditions with colloidal sulphur. J Bone Joint Surg 1934;16119-125. 109. Wheeldon K. The use of colloidal sulphur in the treatment of arthritis. J Bone Joint Surg 1935;17693-726. 110. Kaufman W. The common form of joint dysfunction: its incidence and treatment. Brattleboro, VT: EL Hildreth, 1949. 111. Hoffer A. Treatment of arthritisby nicotinic acid and nicotinamide. Can Med Assoc J 1959;81;235-239. 112. Ammon HPT, Wahl MA. Pharmacology of Curcunra longa. Planta Medica 1991;571-7. 113. Sharma OP.Antioxidant properties of curcumin and related compounds. B i d e m Pharmacol 1976;25:1811-1825. 114. Toda S, Miyase T, Arich H, et al. Natural antioxidants. Antioxidative compounds isolated from rhizome of Curcurna longa L. Chem Pharm Bull 1985;331725-1728. 115. Srimal R, Dhawan B. Pharmacology of diferuloyl methane (curcumin), a non-steroidal anti-inflammatory agent. J Pharm Pharmacol1973;25447-452. 116. Srivastava R. Inhibition of neutrophil response by curcumin. Agents Actions 1989;28:298-303. 117. Flynn DL, Rafferty MF, Boctor AM. Inhibition of 5-hydroxyeicosatetraenoic acid (5-HETE) formation in intact human neutrophils by naturally-occurring diarylheptanoids: inhibitory activities of curcuminoids and yakuchinones. Prostaglandins Leukot Med 1986;22.357-360. 118. Deodhar SD, Sethi R, Srimal RC. Preliminary studies on antirheumatic activity of curcumin (diferuloyl methane). Indian J Med Res 1980;71:632-634. 119. Satoskar RR,Shah SJ,Shenoy SG.Evaluation of anti-inflammatory property of curcumin (diferuloyl methane) in patients with

postoperative inflammation. Int J Clin Pharmacol Ther Toxic01 1986;24:651-654. 120. Shankar TNB, Shantha NV, Ramesh HP,et al. Toxicity studies on turmeric (Curcurnu longa): acute toxicity studies in rats, guinea pigs & monkeys. Indian J Exp Biol1980;1873-75. 121. Taussig S, Batkin S. Bromelain: the enzyme complex of pineapple (Ananas comosus) and its clinical application. An update. J Ethnopharmacol1988;22191-203. 122. Cohen A, Goldman J. Bromelain therapy in rheumatoid arthritis. Perm Med J 1964;67:27-30. 123. h u n g A. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York John Wiley, 1980. 124. Kiuchi F, Iwakami S, Shibuya M, et al. Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids. Chem Pharm Bull 1992;40:387-391. 125. Srivastava KC, Mustafa T. Ginger (Zingiber oficinnle) and rheumatic disorders. Med Hypothesis 1989;29:25-28. 126. Srivastava KC, Mustafa T. Ginger (Zingiber oficinale) in rheumatism and musculoskeletal disorders. Med Hypotheses 1992;39: 342-348. 127. Shimizu K, Amagaya S, Ogihara Y. Combination of Shosaikoto (Chinese traditional medicine) and prednisolone on the antiinflammatory action. J Pharmacobiodyn 1984;7891-899. 128. Yamamoto M, Kumagai A, Yamamura Y. Structure and actions of saikosaponins isolated from Bupleurum falcatum L. I. Antiinflammatory action of saikosaponins. Arzniemitteforschung 1975;25:1021-1023. 129. Hiai S,Yokoyama H, Nagasawa T, et al. Stimulation of the pituitary-adrenocortical axis by saikosaponin of bupleuri radix. Chem Pharm Bull 1981;29:495-499. 130. Hikino H. Recent research on Oriental medicinal plants. Economic and Medicinal Plant Research 1985;1:53-85. 131. de Jong 2 , Munneke M, Zwinderman AH, et al. Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial. Arthritis Rheum 2003;48:2415-2424. 132. Sukenik S, Neumann L, Flusser D, et al. Balneotherapy for rheumatoid arthritis at the Dead Sea. Isr Med J 1995;31:210-214.

Rosacea Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary 2109 General Considerations 2109 Etiology 2109 Therapeutic Considerations 2110 Hypochlorhydria 2110 Helicobacter pylori 2110

DIAGNOSTIC SUMMARY Chronic acneiform eruption on the face of middle-aged and older adults associated with facial flushing and telangiectasia. The acneiform component is characterized by papules, pustules, and seborrhea; the vascular component by erythema and telangiectasia; and the glandular component by hyperplasia of the soft tissue of the nose (rhinophyma). The primary involvement occurs over the flush areas of the cheeks and nose. More common in women (3:1), but more severe in men.

GENERAL CONSIDERATIONS Rosacea is a common, chronic, progressive inflammatory skin disorder in which the nose and cheeks are abnormally red and may be covered with pimples similar to those seen in acne (see Chapter 143). Rosacea was originally called “acne rosacea” because its inflammatory papules and pustules so closely mimic those of acne vulgaris. Unlike in acne vulgaris, whose etiology is based on the interaction of abnormal keratinization, increased sebum production, and bacterial-induced inflammation, rosacea’s inflammation is vascular in nature. Rosacea generally occurs in patients between the ages of 25 and 70 years, and it is much more common in people with fair complexions. Women are three times more likely than men to have rosacea, although the disease is generally more Severe in men. At least 13 million Americans are known to be

Food Allergy 21 10 B Vitamins 21 10

Therapeutic Approach 2111 General Recommendations 2111 Diet 2111 Supplements 2111

Rosacea is divided into the following three stages’: Stage I: In stage I or erythematotelangiectaticrosacea, erythema triggered by hot beverages, spicy foods, and alcohol may persist for hours; telangiectasias are noticeable on the central third of the face; and buming, stinging, and itching after the application of cosmetics, fragrances, and sunscreens becomes a major complaint. Stage 11: Inflammatory papules and pustules are the hallmarks of stage I1 or papulopustular rosacea. Flushing, telangiectasia, and seborrhea increase, and minimal facial pore enlargement becomes obvious. Stage III: A small number of patients progress to stage I11 or phymatous rosacea, which exhibits deep inflammatory nodules, large telangiectatic vessels, markedly dilated facial pores, sebaceous gland hyperplasia, and tissue hyperplasia, especially of the nose (rhinophp a ) .

Ocular rosacea is a term used to describe the spectrum of eye findings associated with the skin involvement. Ocular rosacea can cause the eyes to have a watery or bloodshot appearance, the sensation of a foreign body, burning or stinging, dryness, itching, light sensitivity, and a host of other signs and symptoms. Sties are a common sign of rosacea-related ocular disease, and some individuals may have decreased visual acuity owing to corneal complications.

Etiology The cause of rosacea is poorly understood, although numerous theories have been offered. Included in the 2109

factors that have been suspected of causing acne rosacea are the following: The mite Demodex folliculorurn Alcoholism Menopausal flushing Vasomotor neurosis Seborrheic diathesis Local infection Food allergies B-vitamin deficiencies Gastrointestinal disorders Most cases of rosacea are associated with moderate to severe seborrhea, although sebum production is not increased in many. Vasomotor lability is prevalent, and migraine headaches are three times more common in persons with rosacea than in age- and sex-matched controls.

THERAPEUTIC CONSIDERATIONS One of the first recommendations to the patient with rosacea is to avoid those stimuli that tend to exacerbate the diseas-xposure to extremes of heat and cold, excessive sunlight, and ingestion of hot liquids, alcohol, and spicy foods. The conventional medical treatment of rosacea is usually oral tetracycline, especially for the papular or pustular lesions, although this treatment usually only controls rather than eradicates the disease. Topical therapy for rosacea with antibiotics or synthetic retinoids is generally less successful than systemic antibiotic treatment. Also, although topical corticosteroids may initially improve signs and symptoms, long-term corticosteroid therapy is not advisable because it may actually lead to rosacea. The treatment of chronic skin changes and severe rhinophyma may require laser treatments and surgical intervention, respectively. The natural approach to rosacea is to try to identify and eliminate contributing factors if possible. Key factors to address are hypochlorhydria, eradication of Helicobucter pylori, elimination of food allergies, and optimal intake of B vitamins.

Hy pochIorhydria Gastric analysis of patients with rosacea has led to the postulate that it is the result of hypochlorhydria.' Psychological factors, such as worry, depression, and stress, often reduce gastric acidity.2 Hydrochloric acid supplementation results in marked improvement in those patients with rosacea who have achlorhydria or hyp~chlorhydria.~,~ Patients with rosacea have also been shown to have diminished secretion of lipase (although bicarbonate and chymotrypsin secretion were normal) and to benefit from pancreatic ~upplementation.~

Helicobacter pylori Given the high incidence of hypochlorhydria, it is perhaps not surprising that a high incidence of H. pylori infection in the stomach has also been found in patients with rosacea.6 In a pilot study, H. pylori was found in 46 of 94 patients with rosacea, 38 of 88 patients with other inflammatory diseases, and 5 of 14 patients without an inflammatory disease. The researchers believed that the flushing reaction in rosacea is caused by gastrin or vasoactive intestinal peptides. They also quoted an Irish study that found that 19 of 20 patients with acne rosacea tested positive for H. pylori. Another study that evaluated histologic sections of the stomach mucosa found that 84%of 31 patients were H . pylori-p~sitive.~Interestingly, 20% of the patients who tested histologically positive also tested serologically negative for the organism. The consistency between clinical success in the treatment of rosacea with metronidazole and the abatement of H . pylori isolates and serologic results after treatment provides additional evidence suggesting an etiologic relationship between rosacea and H . pylori infection. However, it is also possible that H. pylori is simply associated with rosacea and is not a causative factor per se, because patients with rosacea may have rates of H. pylori infection similar to those in healthy subjects.8It is interesting to note that patients with rosacea complain significantly more frequently of "indigestion" and use more antacids than the general population.8 A large number of studies have now confirmed a strong association between H. pylori and rosacea, with a 2003 study showing a correlation between the severity of rosacea and the level of infection?

Food Allergy The statistically significant incidence of indigestion and migraine headaches accompanying rosacea points to food intolerance, as does the reflex flushing caused by vasodilator substances. Some of the later studies seem to support the concept of rosacea as a hypersensitivity disorder. Although these studies have focused on local factors, it is possible that given the known association of rosacea with dietary factors exacerbating the skin flushing, food hypersensitivity plays a significant role.

B Vitamins The administration of large doses of B vitamins has been shown to be quite effective,1° with riboflavin appearing to be the key factor. It is interesting to note that researchers were able to infect the skin of riboflavin-deficient rats with the mite D. folliculorurn, but not the skin of normal rats." This mite was once considered a causative factor in rosacea and may still be a factor in some patients, especially those with more granulomatous lesions. Evidence suggests that a delayed hypersensitivity

reaction in follicles is triggered by D. folliculorum antigens and stimulates the progression of the affection to the papulopustular stage.12 Although B vitamins are important for patients with rosacea, care must be exercised because some patients’ rosacea may be aggravated by large dosages of these common nutrients. There is a case report of a 53-year-old female who presented to a dermatology clinic with a 9-month history of a facial eruption resembling acne rosacea. Treatment with oral hydroxychloroquine, ibuprofen, terfenadine, prednisone, erythromycin, and tetracycline had been tried during the 9 months without success. Topical desoximetasone, hydrocortisone, and cosmetic elimination also yielded no benefit. Patch test showed a positive reaction to nickel. The eruption began at the time of a personal stress when the patient went through a marital separation. To help with her stress, the patient began taking 100 mg/day of pyridoxine and 100 pg/day of vitamin B12. Discontinuation of the vitamins resulted in dramatic improvement, and with rechallenge, the condition reappeared. The investigators noted that inflammation and exacerbations of acne related to vitamins B2, B6, and B12have been reported in the European 1iterat~1re.l~

treat most affected patients. Eradication of H. pylori infection (when present) and control of hypochlorhydria and food intolerance form the basis of therapy. This approach is supported with B-complex supplementation and the avoidance of vasodilating foods.

General Recommendations See Chapter 143 for general recommendations for acne.

Diet Have the patient avoid coffee, alcohol, hot beverages, spicy foods, and any other food or drink that causes a flush. Eliminate from the diet all refined and/or concentrated sugars, foods containing trans fatty acids such as milk, milk products, margarine, shortening and other synthetically hydrogenated vegetable oils as well as fried foods. The patient should avoid milk and foods high in iodized salt.

Supplements B-complex: 100 mg/day (avoid niacin) Pancreatin (8-1OX USP): 350 to 500 mg before meals Hydrochloric acid: Follow guide provided in Appendix 7.

THERAPEUTIC APPROACH Although the causes of rosacea have not yet been determined, sufficient information is available to adequately

1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol2002;46: 584-587. 2. Blount BW, Pelletier AL. Rosacea: a common, yet commonly overlooked, condition. Am Fam Physician 2002;66:435-440. 3. Ryle J, Barber H. Gastric analysis in acne rosacea. Lancet 1920;2: 1195-1196. 4. Poole W. Effect of vitamin B complex and Sfactor on acne rosacea. S Med J 1957;50:207-210. 5. Barba A, Rosa B, Angelini G, et al. Pancreatic exocrine function in rosacea. Dermatologica 1982;165:601-606. 6. Baker B. Helicobucter pylori strikes again: thistime it’s rosacea. Family Practice News 1994; Sept 1:6. 7. Rebora A, Drago F, Parodi A. May Helicobucter pylori be important for dermatologists? Dermatology 1995;191:6-8. 8. Sharma VK,Lynn A, Kaminski M, et al.A study of the preva-lence of Helicobucter pylori infection and other markers of upper gastrointestinal

tract disease in patients with rosacea. Am J Gastroenterol 1998;93220-222. 9. Diaz C, OCallaghan CJ, Khan A, Ilchyshyn A. Rosacea: a cutaneous marker of Helicobacter pylori infection? Results of a pilot study. Acta Derm Venereol2003;83:282-286. 10. Tulipan L. Acne rosacea: a vitamin B complex deficiency. N Y State J Med 1929;29:1063-1064. 11. Johnson L, Eckardt R. Rosacea keratitis and conditions with vascularization of the cornea treated with riboflavin. Arch Ophth 1940; 23:899. 12. Georgala S, Katoulis AC, Kylafis GD, et al. Increased density of Demodex folliculorum and evidence of delayed hypersensitivity reaction in subjects with papulopustular rosacea. J Eur Acad Dermatol Venereol2001;15:441-444. 13. Sherertz E. Acneiform eruption due to ‘megadose’ vitamins B6 and B12. Cutis 1991;48:119-120.

Seborrheic Dermatitis Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER C O N T E N T S Diagnostic Summary

2113

General Considerations 2113

Therapeutic Approach 2114 Diet 21 14 Supplements 21 14 Topical Treatments 21 14

Therapeutic Considerations 21 13 Nutrition 2113 Botanical Medicines 21 14 HomeopathicTherapy 21 14

DIAGNOSTIC SUMMARY Superficial erythematous papules and scaly eruptions occurring on the scalp, cheeks, and intertrigo of the axilla, groin, and neck Usually nonpruritic Seasonal; worse in winter

THERAPEUTIC CONSIDERATIONS Nutrition Food Allergy

.

Seborrheic dermatitis usually begins as "cradle cap" and, although not primarily an allergic disease, has been associated with food allergy (67% of patients exhibit some form of allergy by 10 years of age).'

GENERAL CONSIDERATIONS

Biotin

Seborrheic dermatitis is a common papulosquamous condition similar in appearance to eczema. Clinically it may be associated with excessive oiliness (seborrhea) and dandruff. The scale may be yellowish and either dry or greasy. The erythematous, follicular, scaly papules may coalesce to form large plaques or circinate patches. Flexural involvement is often complicated with Cundidu infection. The condition occurs either in infancy (usually between 2 and 12 weeks of age) or in the middle-aged or elderly and has a prognosis of lifelong recurrence. The cause of seborrheic dermatitis is unknown. Genetic predisposition, emotional stress, diet, hormones, and infection with yeastlike organisms have all been implicated. Seborrheic dermatitis is now recognized as one of the most common manifestations of acquired immunodeficiency syndrome (AIDS), affecting as many as 83% of persons with the syndrome. This recent observation has given greater credence to the infection theory for the cause of seborrheic dermatitis.

The underlying factor in infants appears to be a biotin deficiency.2A syndrome clinically similar to seborrheic dermatitis has been produced by feeding rats a diet high in raw egg white (high in avidin, a glycoprotein that binds biotin, making it unavailable for absorption). Because a large portion of the human biotin supply is provided by intestinal bacteria, it has been postulated that the absence of normal intestinal flora may be responsible for biotin deficiency in infants2A number of articles have demonstrated successful treatment of seborrheic dermatitis with biotin in both the nursing mother and the i n f a ~ ~ t . ~ , ~ In adults, treatment with biotin alone is usually of no value. It has been postulated that long-chain fatty acid synthesis is impaired in seborrheic lesions. B vitamins (biotin, pyridoxine, pantothenic acid, niacin, thiamin, and the lipotropics) are vital for fatty acid metabolism.

Pyridoxine Both the administration of desopyridoxine, which induces pyridoxine deficiency in humans, and the placing of rats

2113

on a pyridoxine-deficient diet cause dermatological lesions indistinguishable from seborrheic dermatitis: Despite these results, oral and parenteral applications of pyridoxine have shown little success. However, in the sicca form of the disorder (involvement of the scalp [dandruff], brow, nasolabial folds, and bearded area with varying degrees of greasy adherent scales on an erythematous base), all cases cleared completely within 10 days of local application of a water-soluble ointment containing 50 mg/g of pyridoxine. Other types of seborrheic dermatitis, particularly flexural and infected, did not respond to this mode of therapy. In one study of patients with elevated levels of urinary xanthurenic acid, oral, parenteral, and local applications of pyridoxine all returned excretion levels to normal, implying transcutaneous absorption of pyridoxine!$ These results are clouded, however, by those of another study indicating that the improvement from topical application may be due more to reduction in sebaceous secretion rate by the ointment itself, the added pyridoxine having no effect? The patient should be checked for exposure to pyridoxine antimetabolites. Examples are the hydrazine dyes (Food Drug and Cosmetic Act [FD&C]yellow no. 5) and drugs (isoniazid and hydralazine), dopamine, penicillamine, oral contraceptives, and excessive protein intake.7

emulsion cream twice a day for 4 to 6 weeks produced improvements in scaling and itching in 62% of subjects, compared with improvements in only 25% of the placebo group.ll

B Vitamins

Supplements

HomeopathicTherapy A 2002 study evaluated the efficacy of a homeopathic combination remedy in the control of seborrheic dermatitis and chronic dandruff. The homeopathic therapy (potassium bromide lx, sodium bromide 2x, nickel sulfate 3x, sodium chloride 6x) was studied in a placebo crossover trial in 41 patients with seborrheic dermatitis and/or chronic dandruff. At the end of 10 weeks all patients crossed over to the active medication under a different label for an additional 10 weeks in an openstudy format. Twenty-nine patients completed the 10-week blinded portion of the study. After 10 weeks of treatment, the disease state of the patients receiving active medication showed significant improvement compared with the patients receiving placebo (p < 0.04). Ten weeks after crossover, the placebo patients experienced improvement as well ( p < 0.O1).l2

THERAPEUTIC APPROACH

Although the optimal approach to treating all patients with seborrheic dermatitis is not clear at this time, effective therapy is available for most patients. In infants, Folic Acid alleviation of the biotin deficiency and control of the food allergies are the keys. For adults, correcting the Oral treatment with folic acid has been only moderately impaired long-chain fatty acid synthesis by supplementsuccessful (the use of the tetrahydro form showed dramatic results for one patient whose disease became me- ing with large doses of vitamin B complex is the primary therapy. To maximize therapeutic results, we recomsponsive to folic acid after childbirth). Patients with the mend a broad-spectrum approach. (Note that the followsicca form showed no response? Parenteral injections ing dosages are for adults; children’s doses should be of vitamin Biz, both synthetic and liver-extracted, have modified according to weight.) been shown to be very effective in many cases.9This may be due to vitamin B1is role as a cofactor (with choline) Diet in 5-methyl-tetrahydrofolate methyltransferase, which The physician should detect and treat food allergens. In regenerates tetrahydrofolate. It has been hypothesized nursing infants, the food allergies of the mother should that folate becomes trapped as 5-methyl-tetrahydrofolate be considered. by a lack of BIZand/or choline. Other B vitamins have also been shown to be involved in seborrheic dermatitis; experimentally induced ariboflavinosis produces the sicca form of the disorder.I0

Botanical Medicine Aloe Vera Aloe Vera gel can be quite helpful when applied topically. In one double-blind trial in people with seborrheic dermatitis, the application of a 30% crude aloe

Biotin: 3 mg two times/day B complex: 50 mg two times/day Zinc: 25 mg/day (picolinate) Flaxseed oil: 1 tbsp/day

Topical Treatments Pyridoxine ointment: 50 mg/g (in water-soluble base) Aloe Vera gel: Apply twice daily to affected areas.

1.Eppig JJ. Seborrhea capitis in infants: a clinical experience in allergy therapy. Ann Allergy 1971;29:323-324. 2. Nisenson A. Seborrheic dermatitis of infants and Leiner‘s disease: a biotin deficiency.J Pediatr 1957;51:537-548. 3. Nisenson A, Bamess LA. Treatment of seborrheic dermatitis with biotin and vitamin B complex. J Pediatr 1972;81:630-631. 4. Schreiner A, Slinger W, Hawkins V, et al. Seborrheic dermatitis. A local metabolic defect involving pyridoxine. J Lab Clin Med 1952; 40:121-130. 5. Callaghan T. The effect of folic acid on seborrheic dermatitis. Cutis 1967;3:584-588. 6. Andrews GC, Post CF, Domonkos AN. Seborrheic dermatitis: supplemental treatment with vitamin BIZ.N Y State J Med 1950;50 1921-1925. 7. Bicknell F, Prescott F. The vitamins in medicine. Milwaukee, W I Lee Foundation for Nutritional Research, 1962:309.

8. Schreiner A, Rockwell E, Vilter R. A local defect in the metabolism of pyridoxine in the skin of persons with seborrheic dermatitis of the “sicca” type. J Invest Dermatol 1952;19:95-96. 9. Effersoe H. The effect of topical application of pyridoxine ointment on the rate of sebaceous secretion in patients with seborrheic dermatitis. Acta Derm Venereol1954;3:272-278. 10. Roe DA. Drug-induced nutritional deficiencies. Westport, CT AVI Publications, 1976:168-177. 11. Vardy DA, Cohen AD, Tchetov T, et al. A double-blind, placebocontrolled trial of an aloe Vera (A.barbadensis) emulsion in the treatment of seborrheic dermatitis. J Dermatol Treat 1999;10:7-11. 12. Smith SA, Baker AE, Williams JH. Effective treatment of seborrheic dermatitis using a low dose, oral homeopathic medication consisting of potassium bromide, sodium bromide, nickel sulfate, and sodium chloride in a double-blind, placebo-controlled study. Altem Med Rev 2002;759-67.

Senile Cataracts Michael T. Murray, ND Joseph E. Pizzorno Jr, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

2117

General Considerations 2117

Therapeutic Approach 2121 Diet 2121 Supplements 2121 Botanical Medicines 2121

Therapeutic Considerations 2118 Antioxidants 21 18 Other Nutritional Factors 21 19 Botanical Medicines 2120

DIAGNOSTIC SUMMARY Clouding or opacity in the crystalline lens of the eye Absence or alteration of red reflex (small cataracts stand out as dark defects) Gradual loss of vision

GENERAL CONSIDERATIONS Cataracts are the leading cause of impaired vision and blindness in the United States. Approximately 4 million people have some degree of vision-impairing cataract, and at least 40,000 people in the United States are blind because of cataracts. Cataracts are a source of a tremendous financial burden on our society; cataract surgery is the most common major surgical procedure performed in the United States each year (600,000 per annum) for persons receiving Medicare benefits. Cataracts may be classified by location and appearance of the lens opacities, by cause or significant contributing factor, and by age of onset. Many factors may cause or contribute to the progression of lens opacity, including ocular disease, injury, surgery, systemic diseases (e.g., diabetes mellitus, galactosemia), toxins, ultraviolet and near-ultraviolet light, radiation exposure, and hereditary disease. Aging-related (or senile) cataracts are discussed in this chapter; diabetes- and galactose-induced cataracts (sugar cataracts) are discussed in Chapter 163. The crystalline lens is, obviously, a vital component of the optical system owing to its ability to focus light (via changes in shape) while maintaining optical transparency. Unfortunately, this transparency diminishes with age.

The majority of the geriatric population displays some degree of cataract formation. In the normal aging eye there is a progressive increase in size, weight, and density of the lens throughout life. Cataract formation is characterized histopathologically by the following features: Fibrous metadasia of the etithelium I I Liquefaction of fibers resulting in morgagnian globule formation (drops of fluid beneath the capsule and between the lens fibers) Sclerosis (melding of fibers) Posterior migration and swelling of the epithelium According to a topoanatomic classification, these basic alterations result in the following five types of cataracts:

Anterior subcapsular cataract: Fibrous metaplasia of lens epithelium (usually follows iritis and adherence of the iris to the lens-posterior synechia). Anterior cortical cataract: Liquefaction of lens fibers occurs and morgagnian globules form in the cortex anteriorly. Nuclear cataract: An exaggeration of the normal, agingrelated, melding of fibers in the nucleus. Posterior cortical cataract: Liquefaction and globular degeneration of the posterior lens cortex. Posterior subcapsular cataract: Epithelial cells migrate posteriorly under the capsule and form large irregular nucleated cells. About 75% of senile cataracts are cortical, and the rest are nuclear. Clinically, cortical cataracts take three forms: Spoke wheel, beginning in the periphery and coursing anteriorly and posteriorly to the nucleus 2117

Specific Health Problems Perinuclear punctate opacities Granular opacities under the posterior capsule (subcapsular cataracts)

THERAPEUTIC CONSIDERATIONS The etiology of cataract formation is ultimately related to an inability to maintain normal homeostatic concentrations of Na+,K+, and Ca2+within the lens. These abnormalities are apparently the result of decreased Na+,K+ATPase activity,14 a defect usually due to free radical damage to some of the sulfhydryl proteins in the lens, including Na+,K+-ATPase,which contains a sulfhydryl component. In cataract formation, the normal protective mechanisms are unable to prevent free radical damage. The lens, like many other tissues of the body, depends on adequate levels and activities of superoxide dismutase (SOD), catalase, and glutathione (GSH), and adequate levels of the accessory antioxidants such as lutein, vitamins E and C and selenium, to aid in prevention of damage by free radicals. Individuals with higher dietary intakes of vitamin C and E, selenium, and carotenes (especially lutein) have a much lower risk for development of cataracts7 Several studies have shown that various nutritional supplements-multiple vitamin formulas, vitamins C and E, B vitamins (especially B12and folic acid), and vitamin A-also offer significant protection against both nuclear and cortical cataracts.811

Antioxidants Lutein Lutein, the yellow-orange carotene that offers sigruficant protection against macular degeneration, also exerts protection against cataract formation.'* Like the macula, the human lens concentrates lutein. In 1992, a prospective cohort study showed that consumption of spinach Wgh in lutein) was inversely related to the risk of cataracts severe enough to require e~traction.'~ This initial investigation was followed by three prospective studies showing that intake of lutein was inversely associated with In a cataract extraction (20% to 50% risk double-blind intervention trial, 17 patients clinically diagnosed with age-related cataracts were randomly assigned to receive dietary supplementation with lutein (15 mg), alpha-tocopherol (100 mg), or placebo three times a week for up to 2 years.17 Visual performance (visual acuity and glare sensitivity) improved in the lutein group, whereas there was trend toward the maintenance of visual acuity with alpha-tocopherol and a decrease with placebo supplementation.

Vitamin C A high dietary intake of vitamin C from either dietary sources or supplements has been shown to protect

against cataract formation.8-11J81n addition to preventing cataracts, antioxidant nutrients like vitamin C may offer some therapeutic effects. Several clinical studies have demonstrated that vitamin C supplementation can halt cataract progression and, in some cases, significantly improve vision. For example, in one study conducted in 1939, 450 patients with cataracts were started on a nutritional program that included 1 g/day of vitamin C, which resulted in a significant reduction in cataract development.' Similar patients had previously required surgery within 4 years, but in the vitamin C-treated patients in this study, only a small handful needed surgery, and in most there was no evidence that the cataracts had progressed over the 11-year study period. It appears the dosage of vitamin C necessary to increase the vitamin C content of the lens is 1000 mg.2 The lens of the eye and active tissue of the body require higher concentrations of vitamin C. The level of vitamin C in the blood is about 0.5 mg/dl, whereas that in the adrenal and pituitary glands is 100 times this concentration. In the liver, spleen, and lens of the eye, the vitamin C level is increased by at least a factor of 20. In order for these concentrations to be maintained in these tissues, the body has to generate enormous amounts of energy to pull vitamin C out of blood against this tremendous gradient. Keeping blood vitamin C concentrations elevated helps the body concentrate vitamin C into active tissue by reducing the gradient. That is probably why dosages of at least 1000 mg are required to raise the vitamin C content of the lens. In another study, 450 patients with incipient cataract were started on a nutritional program that included 1 g/day of vitamin C, which led to a sigruficant reduction in cataract de~elopment.~

Glutathione A tripeptide composed of glycine, glutamic acid, and cysteine, GSH is found at very high concentrations in the lens. GSH plays a vital role in maintaining a healthy lens and has been postulated as a key protective factor against toxins of both intralenticular and extralenticular origin. It functions as an antioxidant, maintains reduced sulfhydryl bonds within the lens proteins, acts as a coenzyme of various enzyme systems, participates in amino acid transport with gamma-glutamyl transpeptidase, and is involved in cation transport? GSH levels are diminished in virtually all forms of cataracts. Ascorbic Acid and Glutathione Interactions The antioxidants ascorbic acid (AA) and GSH work in close conjunction and are the most important of all the host-protective factors against the induction of cataracts. The reactions between them are as follows: AA

+ superoxide + dehydroascorbate + H202

Senile Cataracts

Light may also cause oxidation of AA, leading to hydrogen peroxide formation as follows: AA

+ light + dehydroascorbate + H202

An interesting cycle is then set into motion. The dehydroascorbate and hydrogen peroxide produced are reduced by selenium-containingglutathione peroxidase as follows:

2GSH + dehydroascorbate + GSSG + AA 2GSH + H202 + GSSG + 2H20

The oxidized glutathione (GSSG)serves as an inducer of the hexose monophosphate shunt, which provides the NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) necessary for reducing GSSG via riboflavin-dependent glutathione reductase, as follows: GSSG + 2NADPH + 2GSH + 2NADP

The NADP is reduced by hexose monophosphate dehydrogenase as follows: NADP + glucose-6-(P)

+ NADPH + ribulose 5-(P) + COP

This combination of enzymatic and nonenzymatic scavenging of free radicals is a key mechanism for the protection of the lens from photochemical and other forms of oxidative damage.

Selenium and Vitamin E Selenium and vitamin E, antioxidants known to function synergistically, are discussed together. Maintaining proper selenium levels appears to be especially important because human lens glutathione peroxidase is selenium dependent. Low selenium levels would greatly promote cataract formation. Previous studies have shown that selenium content in the human lens with a cataract is only 15%of normal level^.^ A later study was conducted to better examine the role of selenium in cataract formation? Selenium levels in the serum, lens, and aqueous humor were determined in 48 patients with cataracts and compared with levels in matched controls. Selenium levels in the serum and aqueous humor were found to be significantly lower in the patients with cataracts (serum, 0.28 pg/ml; aqueous humor, 0.19 pg/ml) than in normal controls (serum, 0.32 pg/ml; aqueous humor, 0.31 pg/ml). However, the selenium levels in the lens itself did not sigruficantly differ between the patients with cataracts and the controls. The most important finding of the study was the decreased level of selenium in the aqueous humor in patients with cataracts. Excess hydrogen peroxide levels, up to 25 times normal, are found in the aqueous humor in patients with cataracts. An excess of hydrogen peroxide is associated with higher lipid peroxidation and

altered lens permeability as a result of damage to the sodium-potassium pump. These changes ultimately leave the lens unprotected against free radical and sun damage. As a result, a cataract is formed. Because selenium-dependent glutathione peroxidase is responsible for the breakdown of hydrogen peroxide, it is quite obvious why low selenium levels appear to be a major factor in the development of a cataract. As previously described, vitamin E supplementation alone does not slow the progression of cataract formation." A double-blind study in which vitamin E was given at a dose of 500 IU daily also found that supplementation did not slow cataract f~rmation.'~ In a 7-year trial, supplement with vitamin E (400 IU)combined with vitamin C (500 mg) and beta-carotene (15 mg) had no effect on the development or progression of cataracts.20

Superoxide Dismutase The activity of SOD is lower in the human lens than in other tissues as a result of the greater ascorbate and glutathione levels in the lens. A progressive decrease in SOD is encountered in cataract progression. Oral supplementation is probably of little value, because it does not affect tissue SOD activity.2l Of greater value is supplementation with the trace mineral cofactors of SOD, the levels of which are greatly reduced in the cataractous lens (copper, by > 90%; manganese, by 50%; and zinc, by > 90%)."

Catalase Catalase is concentrated in the epithelial portion of the lens (anterior surface), with very low levels found in the rest of the lens. Its primary function is to reduce (to water and oxygen) the hydrogen peroxide formed from the oxidation of ascorbate.

Tetrahydrobiopterin Pteridine compounds are believed to play a protective role against cataract formation via prevention of oxidation and damage by ultraviolet light. This action prevents the formation of high-molecular-weight proteins in the lens. Tetrahydrobiopterin functions as an essential coenzyme in the hydroxylation of monoamines such as phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase. Studies of human senile cataractshave demonstrated decreased levels of pteridinesynthesizingenzymes and tetrahydrobi~pterin.~~ Supplemental folic acid may help compensate for this deficiency.

Other Nutritional Factors Riboflavin Lenticular GSH requires flavin adenine dinucleotide (FAD) as a coenzyme for glutathione red~ctase.",~ Deficiency of riboflavin, the precursor of FAD, is believed to enhance

cataract formation through depression of glutathione redutase activity. Although riboflavin deficiency is fairly common in the geriatric population (33%),original studies demonstrating an association between riboflavin deficiency and cataract formation were followed by studies demonstratingno such association. The patient’s riboflavin status can be determined by measuring red blood cell glutathione reductase activity before and after stimulation with FAD.25 Although correction of the deficiency is warranted, no more than 10 mg/day of riboflavin should be prescribed for patients with cataracts, because it is a photosensitizing substance-superoxide radicals are generated by the interaction of light, ambient oxygen, and riboflavin/FAD. Riboflavin and light (at physiologic levels) have been used experimentally to induce cataracts. The evidence appears to suggest that excess riboflavin does more harm than good in the patient with a cataract.

cataract formation appears to be sigruficant only in diabetic cataract formation and is probably not relevant to senile cataract formation (for further discussion, see Chapter 163).

Amino Acids

Botanical Medicines

Methionine is a component of the lenticular antioxidant enzyme methionine sulfoxide reductase and a precursor of cysteine, a component of GSH. Cysteine, along with the other amino acid precursors of GSH, has been shown to be of some aid in cataract treatment.26

A number of excellent choices from the botanical world are available to help with antioxidant mechanisms. They are discussed here.

Zinc, Vitamin A, and Beta-carotenes Zinc, vitamin A, and beta-carotene are known antioxidants vital for normal epithelial integrity. Adequate status of these nutrients is important for the epithelial portion of the lens. In particular, beta-carotene may act as a filter, protecting against light-induced damage to the fiber portion of the lens. Beta-carotene is the most significant of the singlet oxygen free radical scavengers and is used in treating photosensitive dis0rders.2~

Melatonin Melatonin is a very efficient free radical scavenger and antioxidant that can neutralize hydroxyl and peroxyl radicals as well as enhance endogenous and exogenous antioxidant efficiency. In animal models, melatonin has been an effective inhibitor of DNA damage, lipid peroxidation, and cataract formation. Melatonin is present at significant levels in the cell nucleus, aqueous cytosol, and lipid-rich cellular membranes.28

Dairy Products Cataracts often develop in infants with a homozygous deficiency of either galactokinase or galactose-1-phosphate uridyl transferase and in laboratory animals fed a highgalactose diet. Abnormalities of galactose metabolism can be identified by measurements of the activity of these enzymes in red blood cells. It has been suggested that such abnormalities are an important mechanism in approximately 30% of cataracts.E However, this mechanism of

Heavy Metals A number of heavy metals have been shown to have higher concentrations in both the aging lens and the cataractous lens. Although the levels are higher in the latter, the significance of this finding is u n k n ~ w n . ~ The cadmium concentrationis two to three times higher in cataractous lenses than in lenses of age-matched controls. Because cadmium displaces zinc from binding in enzymatic proteins by binding to the sulfhydryl groups, it may contribute to deactivation of free radical quenching and other protective/repair mechanisms. Other elevated elements of unknown significance are bromine, cobalt, iridium, and

Flavonoid-Rich Extracts Among the best may be flavonoid-rich extracts from Vuccinium myrtillus (bilberry), Vitis vinifera (grape seed), and Pinus muritima (pine bark). The occurrence of cataracts in rats can be retarded by changing their diet from a commercial laboratory chow to a ”well-defined diet.”29 Preliminary research suggests that flavonoid components in the well-defined diets may be responsible for the protective effects.30 Of the flavonoid-rich extracts, bilberry anthocyanosides may offer the greatest protection. In one human study, bilberry extract plus vitamin E stopped progression of cataract formation in 97% of 50 patients with senile cortical cataract^.^^

Hachimijiogan An ancient Chinese herbal formula, Hachimijiogan has

been shown to raise the antioxidant level of the lens of the eye?* This activity may explain its use in treatment of cataracts for hundreds of years. According to clinical research, its therapeutic effect is quite impressive in the early stages of cataract formation. In one study, 60% of the subjects receiving Hachimijiogan noted significant improvement, 20% of the group showed no progression, and only the remaining 20% of the group displayed progression of cataracts. Hachimijiogan contains the following eight herbs (per 24 g):

Rehmuniu glutinosa: 6000 mg Poria COCOS sclerotium: 3000 mg Dioscoreu opposita: 3000 mg

Cormus officinalis: 3000 mg Epimedium grandiflorurn: 3000 mg Alisma plantago: 3000 mg Astragalus membranaceus:2000 mg Cinnamonurn cassia: 1000 mg

THERAPEUTIC APPROACH In cases of marked vision impairment, cataract removal and lens implant may be the only alternative. As with most diseases, prevention or treatment at an early stage is most effective. Free radical damage appears to be the primary factor in the induction of senile cataracts, so avoidance of oxidizing agents and promotion of free radical scavenging are critical to successful treatment. The patient should avoid direct ultraviolet light, bright light, and photosensitizing substances; wear protective lenses when outdoors; and greatly increase intake of antioxidant nutrients. Progression of the pathologic process can be stopped and early lesions can be reversed. However, sigruficant reversal of welldeveloped cataracts does not appear possible at this time. Because the geriatric population is especially susceptible to nutrient deficiencies, every effort should be

1. Bouton S. Vitamin C and the aging eye. Arch Intern Med 1939;63: 930-945. 2. Ringvold A, Johnsen H, Blika S. Senile cataract and ascorbic acid loading. Acta Ophthalmol (Copenh) 1985;63:277-280. 3. Atkinson DT. Malnutrition as an etiological factor in senile cataract. Eye Ear Nose Throat Mon 1952;31:79-83. 4. Rathbun W, Hanson S. Glutathione metabolic pathway as a scavenging system in the lens. Ophthalmic Res 1979;11:172-176. 5. Swanson AA, Truesdale AW. Elemental analysis in normal and cataractous human lens tissue. Biochem Biophys Res Comm 1971; 45:1488-1496. 6. Karakucuk S, Ertugrul Mirza G, Faruk Ekinciler 0. Selenium con-

centrations in serum, lens, and aqueous humour of patients with senile cataract. Arch Ophthalmol %and 1995;73:329-332. 7. Taylor A. Cataract: relationships between nutrition and oxidation. J Am Coll Nutr 1993;12:138-146. 8. Taylor A, Jacques PF, Chylack LT Jr, et al. Long-term intake of vitamins and carotenoids and odds of early age-related corticaland posterior subcapsular lens opacities. Am J Clin Nutr 2002;75:540-549. 9. Jacques PF, Chylack LT Jr., Hankinson SE, et al. Long-term nutrient intake and early age-related nuclear lens opacities. Arch Ophthalmol2001;119:1009-1019. 10. Kuzniarz M, Mitchell P,C d g RG, et al. Use of vitamin supplements and cataract: the Blue Mountains Eye Study.A m J Ophthalmol 2001;132:19-26. 11. Mares-Perlman JA, Lyle BJ, Klein R, et al. Vitamin supplement use and incident cataracts in a population-based study. Arch Ophthalmol 2ooO;118:1556-1563. 12. Granado F, Olmedilla B, Blanco I. Nutritional and clinical relevance of lutein in human health. Br J Nutr 2003;90:487-502. 13.Hankinson SE, Stampfer MJ, Seddon JM, et al. Nutrient intake and cataract extraction in women: a prospective study. BMJ 1992; 305335-339.

made to ensure that the patient is ingesting and assimilat-

ing adequate macronutrients and micronutrients.

Diet Patients should avoid rancid foods and other sources of free radicals and increase consumption of legumes (high in sulfur-containing amino acids), yellow vegetables (carotenes), and foods rich in vitamins E and C .

Supplements High-potency multiple vitamin and mineral formula Lutein: 5 to 15 mg/day Vitamin C: 1 g three times/day Vitamin E: 600 to 800 KJ/day Selenium: 400 pg/day L-Cysteine or N-acetylcysteine: 400 mg/day L-Glutamine: 200 mg/day L-Glycine: 200 mg/day

Botanical Medicines Bilberry extract (25% anthocyanidin content): 80 mg three times/day Hachimijiogan formula: 1000 mg three times/day

14.Brown L, Rimm EB, Seddon JM, et al. A prospective study of carotenoid intake and risk of cataract extraction in US men. Am J Clin Nutr 1999;70517-524. 15. Chasan-Taber L, Willett WC, Seddon JM, et al. A prospective study of carotenoid and vitamin A intakes and risk of cataract extraction in US women. Am J Clin Nutr 1999;70509-516. 16. Lyle BJ, Mares-Perlman JA, Klein BE, et al. Antioxidant intake and risk of incident age-related nuclear cataracts in the Beaver Dam Eye Study. Am J Epidemiol1999;149801-809. 17.Olmedilla B, Granado F, Blanco I, et al. Lutein, but not alphatocopherol, supplementation improves visual function in patients with age-related cataracts: a 2-y double-blind, placebo-controlled pilot study. Nutrition 2003;19:21-24. 18. Valero ME', Fletcher AE, De Stavola BL, et al. Vitamin C is associated with reduced risk of cataract in a Mediterranean population. J Nutr 2002;132:1299-1306. 19. McNeil JJ, Robman L, Tikellis G, et al. Vitamin E supplementation and cataract: randomized controlled trial. Ophthalmology 2004;111:75-84. 20. A randomized, placebo-controlled, clinical trial of highdose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS port no. 9. Age-Related Eye Disease Study Rw& Group. Arch Ophthalmol2001;1191439-1452. 21. Whanger P, Weswig .'I Effects of selenium, chromium and antioxidants on growth, eye cataracts, plasma cholesterol and blood glucose in selenium deficient, vitamin E supplemented rats. Nutr Rep Int 1975;12:345-358. 22.Swanson AA, Truesdale AW. Elemental analysis in normal and cataractous human lens tissue. Biochem Biophys Res Comm 1971; 45:148&1496. 23. Rao GN, Cotlier E. The enzymatic activities of GTP cyclohydrolase, sepiapterin reductase, dihydropteridine reductase and dihydrofolate reductase; and tetrahydrobiopterin content in mammalian

ocular tissues and in human senile cataracts. Comp Biochem Physiol B 1985;80B61-66. 24. Skalka H, Prchal J. Cataracts and riboflavin deficiency. Am J Clin N U ~1981;34:861-863. I 25.Prchal JT,Conrad ME, Skalka HW. Association of pre-senile cataracts with heterozygosity for galadosemic states and riboflavin deficiency. Lancet 1978;1:12-13. 26. Rathbun WB. Influence on lenticular glutathione research. Ophthalmic Res 1995;27(Suppl1):13-17. 27. Burton GW, Ingold KU. Beta-carotene: an unusual type of Lipid antioxidant. Science 1984;224:569-573. 28. Reiter RJ. Oxygen radical detoxification processes during aging.The functional importance of melatonin. Aging (Milano) 1995;7340-351.

29.Hess HH, Knapka JJ, Newsome DA, et al. Dietary prevention of cataracts in the pink-eyed RCS rat. Lab Anim Sci 1985;35: 47-53. 30. Pautler EL, Maga JA, Tengerdy C. A pharmacologically potent natural product in the bovine retina. Exp Eye Res 1986;42: 85-288. 31. Bravetti G. Preventive medical treatment of senile cataract with vitamin E and anthocyanosides. Clinical evaluation. Ann Ottalmol Clin Ocul 1989;115:109. 32.Yoshida H, Kusukawa R, Watanabe N, et al. The effects of Bawei-wan (Hachimijiogan) on plasma levels of high density Lipoprotein-cholesterol and lipoperoxide in aged individuals. Am J Clin Med 1985;13:71-76.

Streptococcal Pharyngitis Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

2123

Bacteriotherapy 2124 Lactoferrin 2124

General Considerations 2123 Therapeutic Considerations 2124 Vitamin C 2124 Hydrasfiscanadensis and Echinacea Species 2124

DIAGNOSTIC SUMMARY Abrupt onset of sore throat, fever, malaise, nausea, and headache Throat red and edematous, with or without exudation Tender cervical lymph nodes Positive rapid detection of streptococcal antigen Group A streptococci on throat culture

GENERAL CONSIDERATIONS Signs and symptoms of streptococcal pharyngitis (”strep throat”) resemble those of viral pharyngitis, requiring a culture for definitive diagnosis. Throat cultures yield group A beta-hemolytic streptococci in less than 20% of patients presenting clinically with a sore throat. However, 10% to 25% of the general, asymptomatic population is carriers for group A streptococci. Rapid “strep” screens that detect the presence of group A streptococcal antigens are a major clinical advancement. Because definitive diagnosis with a positive culture usually takes 2 days, antibiotic therapy during this period for presumed group A strep throat leads to unnecessary exposure to antibiotics and a greater likelihood of development of antibiotic-resistant organisms. Rapid strep screens, such as the Strep A OM test, have now shown excellent sensitivity and specificity and will someday soon replace throat culture as the diagnostic ”gold standard.”’ In addition, the hope is that the use of these rapid strep screens will likely eliminate the unnecessary use of antibiotics. Even in positive cases, antibiotics may not be necessary, because strep throat is usually a self-limiting disease and most

Therapeutic Approach 2124 Supplements 2124 Botanical Medicines 2124 Local Treatment 2125

research has shown that clinical recovery is similar in cases in which antibiotics are prescribed and those in which they are The primary concern about not using antibiotics is the development of the ”nonsuppurative poststreptococcal syndromes” (rheumatic fever, poststreptococcal glomerulonephritis, etc.). However, antibiotic administration does not significantly reduce the incidence of these sequelae. In developed countries, most cases of rheumatic fever and glomerulonephritis due to group A beta-hemolytic strep throat occur because affected persons do not consult a phy~ician.~ It is also important to point out that although the dogma holds that acute rheumatic fever can be caused only by group A streptococcal infection of the upper respiratory tract, epidemiology indicates that streptococcal pyoderma is a major cause in Aboriginal people of northern Australia and perhaps other highincidence communities. In contrast, in settings in which rheumatic fever has become rare, the group A streptococcal strains causing pharyngitis are of relatively lower virulence in terms of causing rheumatic fever.5 At this time, it appears that the use of antibiotics should be reserved those patients who are suffering from severe infection or whose sore throat is unresponsive to therapy (i.e., no response after 1 week of immune supportive therapy) and those with a prior history of rheumatic fever or glomerulonephritis. Even then, antibiotics such as penicillin fail to eradicate the streptococci in more than 20%of patients. The primary reason is the presence of beta-lactase-positive organisms (Staphylococcus aureus and Bacteroides spp.), which shield streptococci by deactivating the penicillin. In these instances, stronger antibiotics, such as cephalosporin, may be required? 2123

Antibiotics are often praised for their role in effectively eliminating rheumatic fever as a serious concern. However, the dramatic decrease in the incidence of rheumatic fever began before the advent of effective antibiotics.7 As for most infectious diseases, improvements in socioeconomic, hygienic, and nutritional conditions were more important thanthe liberal use of penicillin. The present attack rates after a streptococcal infection are 0.4% to 2.8% for rheumatic fever and 0.2% to 20% for glomerulonephritis. Obviously, such a wide range of reported sequelae makes accurate evaluation of the risk difficult.

THERAPEUTIC CONSIDERATIONS The primary therapeutic consideration is the status of the patient's immune system. If the patient's immune system is in good function, the illness will be short-lived. Enhancing general immune function, as described in Chapter 57, may shorten the course. In cases of poor immune function, every effort should be made to strengthen the immune system by following the recommendations given in that chapter.

Vitamin C During the 1930s there was considerable interest in the relationship between malnutrition and the development of the sequelae of streptococcal pharyngitis. Both experimental animal work and epidemiologic surveys demonstrated a correlation between vitamin C deficiency and the development of sequelae. Rheumatic fever is virtually nonexistent in the tropics, where vitamin C intake is higher, and 18% of children in high-risk groups have subnormal serum vitamin C levels. Vitamin C supplementation of streptococcal-infected, vitamin C-deficient, rheumatic fever-susceptible guinea pigs totally prevents the development of rheumatic f e ~ e r .Uncontrolled ~,~ clinical studies demonstrated very positive results when children were given orange juice supplementation. Unfortunately, this promising line of research appears to have been dropped, probably owing to the advent of supposedly effective antibiotics.

Hydrastis canadensis and Echinacea Species The guidelines for enhancing the immune system, as presented in Chapter 57, are particularly well indicated for streptococcal pharyngitis, particularly the botanicals Hydrastis canadensis and Echimcen spp. The berberine alkaloid of hydrastis exerts antibiotic activity against streptococci and, perhaps more importantly, has been shown to inhibit the attachment of group A streptococci to pharyngeal epithelial cells. To promote the spread of colonies, streptococci secrete large amounts of hyaluronidase. This enzyme is inhibited by echinacea and bioflavonoids. Echinacea also promotes greater

phagocytosis, natural killer cell activity, and properdin levels (see Chapters 89 and 100 for further discussion of these botanical effects).

Bacteriotherapy Colonizing the throat with group A non-beta-hemolytic streptococci may prove to be an effective treatment for recurrent group A beta-hemolytic streptococcal pharyngitis. In a double-blind study, 130 patients with recurrence of group A beta-hemolytic streptococcal pharyngotonsillitis received antibiotic treatment for 10 days, followed by 10 days of spray treatment with either placebo or group A non-beta-hemolytic streptococcal alpha-streptococci.'O The clinical recurrences (bacteriologically verified) in the alpha-streptococci- and placebo-treated patient groups were 2% and 23%, respectively, in patients given spray for at least 5 days. No side effects were reported.

Lactoferrin Low concentrations of bovine lactoferrin have significantly hindered the in vitro invasion of cultured epithelial cells by group A streptococci isolated from patients with pharyngitis. The ability of lactoferrin to decrease streptococcal invasion was confirmed by in a trial carried out in 12 children with pharyngitis and already scheduled for tonsillectomy. A lower number of intracellular group A streptococci was found in tonsil specimens from children treated for 15 days before tonsillectomy with both oral erythromycin (500 mg tid) and lactoferrin gargles (100 mg tid) than in those from children treated with erythromycin alone (500 mg tid)."

THERAPEUTIC APPROACH For further information, consult Chapter 57. If antibiotics are used, follow the recommendations for Lactobacillus acidopldirs supplementation given in Chapter 118.

Supplements Vitamin C: 500 mg every 2 hours Bioflavonoids: 1000 mg/day Zinc: 30 mg/day

Botanical Medicines Echinncen spp.: Dried root (or as tea): 0.5 to 1 g Freeze-dried plant: 325 to 650 mg Juice of aerial portion of Echinacea pzirpurea stabilized in 22% ethanol: 2 to 3 ml Tincture (1:5): 2 to 4 ml Fluid extract (1:l):2 to 4 ml Solid (dry powdered) extract (6.5:l or 3.5% echinacoside): 150 to 300 mg

The dosage of H. canadensis should be based on berberine content. Because there is a wide range of quality in goldenseal preparations, standardized extracts are recommended. Three-times-a-daydosages are as follows: Dried root or as infusion (tea):2 to 4 g Tincture (1:5): 6 to 12 ml(1.5 to 3 tsp) Fluid extract (1:l):2 to 4 ml(0.5 to 1tsp)

1. Comeli HM. Rapid Detection and diagnosis of group A streptococcal pharyngitis. Curr Infect Dis Rep 2004;6181-186. 2. Zwart S, Rovers MM, de Melker RA, et al. Penicillin for acute sore throat in children: r a n d o d , double blind trial. BMJ 20039271324. 3. Dagnelie CF, van der Graaf Y, De Melker RA. Do patients with sore throat benefit from penicillin? A randomized double-blind placebocontrolled clinical trial with penicillin V in general practice. Br J Gen Pract 1996;46:589-593. 4. McIsaac WJ, Goel V, Slaughter PM, et al. Reconsideringsore throats. Part I: problems with current clinical practice. Can Fam Physician 1997;43485-493. 5. McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: a chink in the chain that links the heart to the throat? Lancet Infect Dis 2004;4240-245. 6. Casey JR, Pichichero ME. Meta-analysis of cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis in children. Pediatrics 2004;113:866-882.

Solid (powdered dry) extract (43or 8% to 12%alkaloid content):250 to 500 mg

Local Treatment The patient should gargle with lactoferrin (100 mg) dissolved in water three times daily. An alternative recommendation is a salt water gargle consisting of 1 tbsp salt per 240 ml of warm water.

7. McKowen T. The role of medicine. Dream, mirage, or nemesis? London: Nufield Provincial Hospitals Trust, 1976. 8. Rinehart JF. Studies relating vitamin C deficiency to rheumatic fever and rheumatoid arthritis. Experimental, clinical, and general considerations. I. Rheumatic fever. Ann Intern Med 1935;9: 586-599. 9. Rinehart JF. Studies relating vitamin C deficiency to rheumatic fever and rheumatoid arthritis: experimental, clinical, and general considerations. II. Rheumatoid (atrophic) arthritis. Ann Intern Med 1935;9:671-689. 10. Roos K, Holm SE, Grahn-Hakansson E, et al. Recolonization with selected alpha-streptococci for prophylaxis of recurrent streptococcal pharyngotonsillitis-a randomized placebo-controlled multicenter study. Scand J Infect Dis 1996;28:459-462. 11. Ajello M, Greco R, Giansanti F, et al. Anti-invasive activity of bovine lactoferrin towards group A streptococci. Biochem Cell Biol 2002;80119-124.

Trichomoniasis Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary

2 27

General Considerations 2127 Diagnosis 2128 Trichomonal Vaginitis 2 28 Trchomonas in the Male 2128 Therapeutic Considerations 2128 Conventional Treatment 2128 Diet 2129 Lifestyle 2129

DIAGNOSTIC SUMMARY Profuse, malodorous, white to green discharge from the vagina. Discharge usually has a pH greater than 4.5, a weak amine odor, and large numbers of white blood cells and trichomonads on wet mount. Vulvovaginal pruritus, burning, and/or irritation. Vulva and introitus usually show erythema. Cervix may or may not have a mottled erythema“strawberry cervix” (less than 5%). Dysuria and/or dyspareunia may be present. Rule out trichomoniasis in males exhibiting signs of prostatitis, urethritis, or epididymitis.

GENERAL CONSIDERATIONS Trichomoniasis is a remarkably common disease, as shown by the following statistics’”:

One in five women in the United States will have trichomoniasis at some time in her life. About 5 million cases appear each year? with approximately 2.5 million women acquiring this infection annually. Trichomonas is present in 3% to 15% of asymptomatic women attending gynecologic clinics and 20% to 50% of women attending clinics for sexually transmitted diseases (STDs).

Nutritional Supplements 2129 Botanical Medicines 2130 Topical Trichomonacides 2130 Therapeutic Approach 2130 Diet 2130 Nutritional Supplements 2131 Botanical Medicines 2131 Topical Treatments 2131

In addition, gonorrhea and trichomoniasis are common coexisting infections, up to 40% of women with trichomonas having gonorrhea, and vice versa.5 Aside from these alarming statistics, there are other reasons for taking trichomonal infections seriously, as follows:~ Trichomoniasis is a common cause (goo/,) of cervical erosion and therefore may be a factor in malignant transformation. Trichomoniasis may complicate interpretation of Papanicolaou smears, increasing the number of falsepositive results. Trichomoniasis raises the rate of sterility among males and females, in the latter as a result of salpingitis and in the former because of toxic products that decrease motility of spermatozoa. The rate of postpartum fever and discharge is higher in women in whom Trichomonas vaginalis infection occurs at delivery. Neonates infected via the birth canal may manifest serious illness (rare). Prostatitis and epididymitis are common in infected males. Trichomoniasis increases transmission and infectivity of human immunodeficiency virus (HIV) such that HIV-seropositive men with concomitant trichomoniasis may have a sixfold higher concentration of HIV RNA in their seminal plasma.6 2127

Infection may confuse and/or complicate other urinary or genital tract problems. Metronidazole (Flagyl), the most commonly used antitrichomonal agent, has been found to be carcinogenic and teratogenic in rodents.

DIAGNOSIS T. vaginulis is a flagellate 15 to 18 microns in length. It is shaped like a turnip, with three to four anterior flagella and one posterior flagellum mounted in an undulating membrane.7 It is transmitted via sexual intercourse. Although women in the past have been thought to be the primary reservoir for Trichomonas and men merely the vector, the medical literature now suggests that men are also reservoirs.'-+10 Diagnosis is made from clinical signs and symptoms (seethe diagnostic summary), saline wet mount, and culture.Trichomonal cultures (usingthe Feinberg T'chomom medium) have recently been advocated to improve diagnostic sensitivity. Although the wet mount is one of the most commonly used and quickest methods to achieve a diagnosis, multiple studies have demonstrated that, compared with culture, the sensitivity of a wet mount ranges from only 45% to ~OYO.~," In men, a reliable culture site has not been established, and cultures from urine and seminal samples have consistently afforded a low yield. Among patients with trichomonal vaginitis, the organism can be cultured from the vagina and paraurethral glands in 98%, from the urethra in 82%, and from the endocervix in 13%. In only 56% to 65% of patients is T. ziaginalis seen on a Papanicolaou smear, thus making the smear an m e liable form of diagnosis."J2A commercially available DNA-based test called the Affirm VP system uses synthetic oligonucleotide probes for detection of T. vaginalis, Gardnerella vaginalis, and Candida species in the specimen from a single vaginal swab, with a sensitivity of 92% and a specificity of 98% compared with wet mount and a sensitivity of 92% and a specificity of 99%compared with culture. Newer diagnostic methods such as the polymerase chain reaction (PCR)can increase identificationof trichomoniasis in both men and women. Unfortunately, PCR techniques are currently restricted to research settings because of technical complexity and c0st.l

endocervix, Bartholin glands, Skene glands, or bladder. The vagina appears to be a good reservoir for the organism. Under stimulation of estrogen, the vaginal walls are well glycogenated-essential for T. vaginalis to thrive. Prepubescent and postmenopausal women seldom have symptomatic trichomonal infecti0ns.S In addition to estrogen, an elevated pH increases susceptibility to Trichomonas. The normal adult vagina maintains a pH of 3.5 to 4.5 owing to the metabolism of free glucose into lactic acid by vaginal Lactobacillus acidophilus.A decrease in the number of lactobacilli raises pH. Trichomonas organisms grow optimally at a vaginal pH of 5.5 to 5.8.13Other conditions that increase vaginal pH are as follows8: Progesterone, which rises in the latter half of the menstrual cycle and during pregnancy Excess intravaginal secretions (i.e., cervical mucus) Overgrowth of certain bacteria, such as Streptococcus and Proterts

Trichomonas in the Male Although the incidence is lower in men, 5%to 15%of cases of nongonococcal urethritis are estimated to be caused by trichomonal infections.2*8 In one study, a transmission rate of 70% was seen among men having sexual contact with infected women in the previous 48 hours." Men with T. vaginalis are most often asymptomatic, yet mild cases of urethritis, prostatitis, and epididymitis have been reported.l0As might be expected, trichomoniasis is a factor in male infertility." Trichomonads have been identified in semen, urethral discharge, urine, and prostatic fluid and have been found in the prostatic secretions and semen of up to 23% of men with chronic nongonococcal prostatitis.14J5 Although men were thought to be only vectors for Trichomonas, the parasite is now known to persist in the male reproductive tract. The reinfection of treated females who are sexually active is well documented.10J6 Therefore, treatment of both sexual partners is necessary. Furthermore, among both women and men, the association of T. vaginalis with enhanced HIV acquisition and transmission has been well documented."

Trichomonal Vaginitis

THERAPEUTIC CONSIDERATIONS ConventionalTreatment

Sexual transmission is the clear route of Trichomonas infection. Prevalence is highest among women with multiple sexual partners and in women with other sexually transmitted infections. Transmission rates seem to be high from men to women, because an 80% to 100% prevalence is found in female partners of infected rnen.l In the female, T. vaginalis usually infests the vagina and urethra. However, infection may involve the

Conventional therapy of trichomoniasis involves metr~nidazole'~ and tinidazole, a second-generation nitroimidazole used to treat metronidazole-resistant infection. Paromomycin may be useful for difficult cases of nitroimidazole-resistant trichomonal vaginitis, although severe local side effects are common.18 Metronidazole cure rates are greater than 90% at the dosage 500 mg twice a day for 7 days, or as a single

Trichomoniasis 2-g dose. In order to reduce recurrence rates, sexual partners should be treated at the same time. Common side effects of metronidazole are nausea, vomiting, metallic taste, and gastrointestinal upset. In addition, patients should be instructed to avoid alcohol during therapy. With long-term high-dose use, as might be encountered in treatment of antibiotic-resistant trichomoniasis, metronidazole has been associated with rare occurrences of peripheral neuropathy, but the incidence of such reactions is less than 1% in over 35 years of use?

Diet Dietary factors affect the body's ability to defend itself against foreign bodies and substances both directly and indirectly. As with any infection, it is not the pathogenicity of the organism but rather the "fertility of the soil" that allows the organism to grow and flourish. A wellbalanced diet high in natural fiber (vegetable, fruits) and low in fat, sugar, and refined carbohydrates aids immune function (see Chapter 57 for more discussion) and may discourage any concomitant overgrowth of Candida.

Lifestyle Depression and anxiety have been associated with exacerbations of trichomonal infections? Therefore, reducing stress is definitely indicated. Reduction may be achieved by a variety of means, including exercise and meditation. The practice of safe sex or abstinence (while infected) also lowers the incidence of infection and reinfection. More than 66% of prostitutes who do not practice safe sex have trichomonal infections.16

Nutritional Supplements For years, it has been the view of many alternative health care providers that the supplementation of vitamins and minerals is beneficial in the prevention and treatment of disease.Although considerable research has supported this view, it is only recently that such groups as the American Medical Association (AMA) have considered the importance of single nutrients in disease. An interesting report sponsored by the AMA summarizes how nutrients such as iron, zinc, B-complex, and vitamins A and C, as well as calcium and magnesium increase immune

B Complex Pyridoxine, pantothenic acid, vitamin B12, and folate aid the phagocytic and bactericidal effects of neutrophils and B- and T-cell activity?O

Ascorbic Acid Vitamin C aids in phagocytic cell migration and killing functions?' In addition, vitamin C preserves cell integrity

by inactivating free radicals and oxidants produced during phagocytosis.22

Vitamin A Secretory immunoglobulin A production appears to be impaired in vitamin A-deficient humans. Many studies indicate that modest increases in vitamin A enhance resistance to infection.23-25 Vitamin A maintains the composition of external cell membranes and surface glycoproteins, diminishing susceptibility to infectious 0rgani~ms.l~ Excess vitamin A is a known teratogen and can be toxic in high dosages. Therefore particular caution must be observed in the treatment of pregnant women, children, and the elderly (see Chapter 138 for a full discussion).

Vitamin E Vitamin E in doses twofold to tenfold greater than the minimum requirements have been found to enhance antibody responses and accelerate the clearance of particulate matter by the reticuloendothelial system (RES) as well as to enhance host resistance.26Conversely, one study found that megadoses of vitamin E in healthy volunteers inhibit multiple immune functions.27

Calcium and Magnesium Many minerals, especially divalent cations, have regulatory influences on the external membrane functions of all body cells. Calcium and magnesium ions also participate in the activation of the complement pathway.19 This may be important for the prevention and treatment of T. vaginalis. Trichomonas activates the alternative complement pathway, which can lead to parasite lysis.28 Unlike the classical complement pathway, which requires both calcium and magnesium, the alternative pathway requires only magnesium.

Zinc Zinc supplementation is important in the treatment of trichomonal infections in both men and women. The antimicrobial spectrum of zinc is broad and includes many potential genitourinary pathogens, such as grampositive and gram-negative bacteria, T. vaginalis, Candida albicans, and Chlamydia trachomatis as well as many v i r u s e ~Of . ~particular ~~~ significance is the fact that trichomonads are readily killed by zinc at a concentration of 0.042%(6.4 rnmol/L),'O a concentration that can occur in the prostatic fluid of men. The zinc concentration of prostatic fluid ranges from 0.015% to 0.10% (2.3 to 15.3 m m ~ l / L ) .This ~ ~ ,finding ~~ suggests that persistent trichomonal infections in men may be due to a low-level zinc deficiency. Zinc sulfate (220 mg two times/day for 3 weeks) has been recommended as a possible treatment for trichomonal infections that are refractory to metr~nidazole.~~

Specific Health Problems For women with drug-resistant trichomoniasis, zinc douches in combination with metronidazole may provide welcome relief. In a small study, the women with recalcitrant trichomoniasis (4 months to 4 years culturepositive despite conventional treatment) all became culture-negative through the use of a combination of 1% zinc sulfate douching (for 3 days after each menstrual period) and 1.6 to 2.2 g/day of metronidazole (suppositories plus oral administration).34

Iron Iron deficiency, often too mild to lower hemoglobin values, causes immune dysfunction^.^^ Iron-deficient humans demonstrate defective macrophage and neutrophil function^.'^ Too much iron, however, increases its availability to microorganisms, leading to greater growth of the pathogen.36

Botanical Medicines Trichomonas, as mentioned earlier, activates the alternative complement pathway.28Complement has the ability to lyse T. vaginalis in vitro and in vivo.37,38 Several botanical medicines activate the alternative complement pathway. Of these, Angelica spp. and Echinacea purpura are the most widely used. Angelica spp. contain coumarin compounds, which have been shown to activate both classical and alternative pathways (see Chapter 67). Inulin,an active constituent of Echinacea, also activates complement and promotes chemotaxis of neutrophils, monocytes, and eosinophils (see Chapter 89).

Topical Trichomonacides Povidone-Iodine Iodine has long been recognized as being a highly potent trichomonacide. Povidone-iodine (PVP) has a broad therapeutic effect in killing a large number of different microorganisms that cause vaginitis, including T. ~ a g i n a l i s . Povidone-iodine ~~,~ (iodine which is absorbed into polyvinyl pyrrolidine) has several advantages over iodine, in that it has little sensitizing potential, does not sting, is water soluble, and washes out of clothing. A success rate of 98.1%has been reported in patients with intractable trichomonal, monilial, nonspecific, and mixed vaginitis for a 2 week treatment regimen using povidone-iodine (Betadine) preparation^.^^,^^ Other studies suggest a 28-day course of povidone-iodine pessaries, particularly if the patient is using oral

contraceptive^.^^

of contact.?4This extract has also been shown to diminish the inflammation associated with trichomonal vaginitis.

Essential Oils The diverse antimicrobial action of essential oils has been well demonstrated. Many possess strong antitrichomonal properties. In a study of 40 essential oils tested for their ability to kill Trichomonas, Mentha piperita (peppermint) and Lauandula angustifolia (lavender) had the fastest killing effects (20 and 15 minutes, re~pectively).~~

Mela leuca a 1ternifo 1in Melaleuca alternifolia (tea tree) oil is a powerful cidal agent (see Chapter 104). Commonly used as a germicidal agent in Great Britain and Australia, a 40% solution of tea tree oil has been found to be a highly effective treatment.& The 40% solution of the oil produced no irritation, burning, or other side effects. Daily vaginal douches with a 0.4% solution of Melaleuca oil in 1liter of water was also found to be effe~tive.~’

Berberine-Containing Botanicals The plant alkaloid berberine sulfate has been shown in vitro to inhibit the growth of several protozoa, including Entamoeba histolytica, Giardia lamblia, and T. ~ a g i n a l i s . 4 ~ ~ ~ ~ No clinical trials of this agent have been reported in trichomonas vaginalis (see Chapter 100 for further discussion).

THERAPEUTIC APPROACH Given the risk of serious sequelae of trichomoniasis and the high success rate of conventional pharmaceutical intervention, systemic metronidazole should be carefully considered as a possible first-line treatment, with simultaneous and subsequent naturopathic therapies to decrease risk of future recurrence and to treat some of the contributing underlying susceptibilities. Naturopathic therapies may be used as first-line therapy in patients who are allergic to metronidazole or are pregnant. However, studies have shown metronidazole does not increase teratogenic risk.50 Discussion with the patient of such factors as diet, sexual habits, and lifestyle is a must. The clinician should inform the patient that Trichomonas infection is an STD and that treatment of the sexual partners is necessary to prevent reinfection. During the treatment, sexual intercourse should be avoided. If intercourse does occur, a condom must be used.

Propolis

Diet

An ethanol extract of propolis (150 pg/ml) has been shown to have a 100% lethal effect in vitro on the protozoans T. vaginalis and Toxoplasmu gondii after 24 hours

The patient should decrease consumption of refined carbohydrates, alcohol, and fats and increase intake of fiber.

Nutritional Supplements Vitamin A: 25,000 IU/day; or beta-carotene: 200,000 IU/ day Vitamin C: 500 to 1000 mg every 4 hours B complex: 20 to 50 mg/day Zinc (picolinate): 10 to 15 mg/day Vitamin E: 200 IU/day L. acidophilus: 2 caps two times/day. If effective, L. acidophilus treatment will change the quantity and quality of the stool; if this change does not occur, the clinician should check the quality of the L. acidophilus product being used (see Chapter 118 for further discussion).

Botanical Medicines Frequency of all dosages shown is three times/day. Hydrasfis canadensis: Dried root: 0.5 to 1.0 g Tincture (1:lO): 6 to 12 ml Fluid extract (1:l): 1 to 2 ml Solid extract (4:l): 250 mg

1. Wiesne PJ, Jones OG, Blount JH. World trends in STDs the situation in the US. In Catterall RD, Nicol CS, eds. Sexually transmitted diseases. New York Academic Press, 19765-17. 2. Hume JC. Trichomoniasis-eight reasons why you should take it seriously. Med T i e s 1978;106:59-63. 3. Rein MF, Chapel TA. Trichomonas, candidiasis and the minor venereal diseases. Clin Obstet Gynecol1975;1873-88. 4. Soper D. Trichomoniasis: under control or undercontrolled? Am J Obstet Gynecol2004;190281-290. 5. Fonts AC, Kraus ST. Trichomonas vaginalis. Reevaluation of its clinical presentation and laboratory diagnosis. J Infect Dis 1980;141: 137-143. 6. Hobbs MM, Kazembe P, Reed AW, et al. Trichomonas vaginalis as a cause of urethritis in Malawian men. Sex Transm Dis 1999;26381-387. 7. Robbins SL, Cotran RS,Kumar V. Pathologic basis of disease, ed 3. Philadelphia: WE5 Saunders, 1984:365. 8. Hildebrandt RJ. Trichomoniasis: always with u s - b u t controllable. Med Times 1978;106:44-48. 9. Jirovec 0, Petru M. Trichomonas vaginalis and trichomoniasis. Adv Parasitol 1968;6117-188. 10. Langley JG, Goldsmid JM, Davies N. Venereal trichomoniasis: role of men. Genitourin Med 1987;63:264-267. 11.Per1 G. Errors in the diagnosis of Trichomonas vaginalis infection as observed among 1199 patients. Obstet Gynecol1972;39:7-9. 12.Karchmer AW. Sexually transmitted diseases. In Dale DC, Federman DD, eds. Scientific American medicine. New York ScientificAmerican, 1997:7xW: 13-14. 13. Trussel RE, Plass ED. The pathogenicity and physiology of a pure culture of Trichomonas vaginalis. Am J Obstet Gynecoll940;40:883. 14. Andreeva N, Tzvetkova A, Gikov D, et al. Studies on the etiological role of Tr. vaginalis in chronic prostatitis, and efficacy of diagnostic methods employed. Folia Med (Plovdiv) 1981;23:36-39. 15. Gardner WA Jr, Culberson DE, Bennet BD. Trichornonas vaginalis in the prostate gland. Arch Pathol Lab Med 1986;110430-432.

Echinacea angustifoliu: Dried root: 1to 2 g Tincture (1:lO): 8 to 12 ml Fluid extract: 1.5 to 3.0 ml Solid extract (6.5:l): 250 mg

Angelicu spp.: Dried root or rhizome: 1 to 2 g Tincture (1:5): 3 to 5 ml Fluid extract (1:l): 0.5 to 2 ml

Topical Treatments Betadine douche, pessary, or saturated tampon: 2 times/day for 14 days M. alfernifoliu oil (40% solution): swab on affected area two times/day or use as a douche, 1 liter of a 0.4% solution two times/day, or a suppository, one at night Zinc sulfate douche: 1%solution two times/day Lactobacillus culture yogurt douches daily, preferably in the morning

16. Dunkelberg WE Jr, Skaggs R, Kellogg DS Jr, et al. Relative incidence of Corynebacterium vaginale (Haemophilus vaginalis), Neisseria gonorrhoeae and Trichomonas spp. among women attending a venereal disease clinic. Br J Vener Dis 1970;46.187-190. 17. Workowski KA, Levine WC. Sexually transmitted diseases treatment guidelines 2002.MMWR Morbid Mortal Wkly Rep 2002; 51(RR06):1-78. 18. Poppe WA. Nitroimidazole-resistantvaginal trichomoniasis treated with pammomycin. Eur J Obstet Gynecol Reprod Biol2001;96119-120. 19. Biesel WR, Edelman R, Nauss K, et al. Single nutrient effects on immunologic functions.JAMA 1981;245:53-58. 20. Axelrod AE. Immune processes in vitamin deficient states. Am J Clin Nutr 1971;24265-271. 21. Thomas WR, Holt PG. Vitamin C and immunity. Clin Exp Immunol 1978;32370-379. 22. Stankova L, Gerhardt NB, Nagel L, et al. Ascorbate and phagocyte function. Infect Immun 1975;12:252-256. 23. Darip MD, Sirisinka S, Lamb AJ. Effect of vitamin A deficiency on susceptibility of rats to Angiostrongylus cantonensis. Proc Soc Exp Biol Med 1979;161:600-604. 24. Dowling JE, Wald G. The biological function of vitamin A acid. Proc Natl Acad Sci U S A 1960;46:587-608. 25.Sinsinha S, Darip MD, Moongkarundi P, et al. Impaired local immune response in vitamin A deficient rats. Clin Exp Immunol 1980;40127-135. 26. Nockeb CF. Protective effects of supplemental vitamin E against infection. Fed Proc 1979;38:2134-2138. 27. Prasad JS. Effect of vitamin E supplementation on leukocyte function. Am J Clin N u b 1980;33606-608. 28. Gillin FD, Sher A. Activation of alternate complement pathway by Trichomonas vaginalis. Infect Immun 1981;3426&273. 29. Tennican P, Carl G, Frey J, at al. Topical zinc in the treatment of mice infected intravaginally with Herpes virus. Proc Soc Exp Biol Med 1980;164:593-597.

30.Greenberg SB, Harris D, Martin RR. Zinc inhibits Chlurnydiu truchomutis in prostate cells. In: Program and abstracts of the 20th interscience conference on antimicrobial agents and chemotherapy. Washington, DC:American Society of Microbiology, 1980. 31. Krieger JN, Rein MF. Zinc sensitivity of Trickornonus vuginulis: in vitro studies and clinical implications. J Inf Disease 1982;1%:341-345. 32. Pfeiffer CC. Mental and elemental nutrients: a physician’s guide to nutrition and health care. New Canaan, C N Keats Publications, 1975: 47.2. 33. Willmott F, Say J, Downey D, et al. Zinc and recalcitrant trichome niasis. Lancet 1983;1:1053. 34. Houang ET, Ahmet Z, Lawrence AG. Successful treatment of four patients with recalcitrant vaginal trichomoniasis with combination of zinc sulfate douche with metronidazole therapy. Sex Transm Dis 1997;24116-119. 35.Chandra RK, Au B, Woodford G, et al. Iron status, immune response and susceptibility to infection. Ciba Found Symp 1976;(51):249-268. 36. Murray MJ, Murray AB, Murray MB, et al. Adverse effect of iron in the course of infection. Br Med J 1978;21113-1115. 37. Demes P, Gombosova A, Valent M. Fewer trichomonads in vaginas of infected women during menstruation. Genitourin Med 1988;M 22-24. 38.Demes P, Gombosova A, Valent M. Differential susceptibility of T. vaginalis isolates to complement in menstrual blood and cervical mucus. Genitourin Med 1988;64:176-179. 39. Gershenfeld L. Povidone-iodine (PVP-I) as a trichomonacide. Am J Pharm Sci Support Public Health 1962;134:324-331.

40.Gershenfeld L. Povidone-iodine as a topical antiseptic. Am J Surg 1957;94:938-939. 41. Shook DM. Clinical study of povidone-iodine regimen for resistant vaginitis. Curr Ther Res Clin Exp 1963;5256-263. 42. Mayhew SR. Vaginitis: a study of the efficacy of povidone-iodine in unselected cases. J Int Med Res 1981;9:157-159. 43. Henderson JN, Tait IB. The use of povidone-iodine (“Betadine”) pessaries in treatment of candidal and trichomonal vaginitis. Curr Med Res Opinion 1975;3:157-162. 44.Starzyk J, Scheller S, Szaflarski J, et al. Biological properties and clinical application of Propolis. II. Studies on the antiprotozoan activity of ethanol extract of propolis. Arzneimittelforschung 1977;271198-1199. 45. Jankov N, Baltova E, Topalov V, et al. Action of some essential oils on Trichomonus vaginalis. Folia Med (Plodiv) 1968;10308. 46.Humphrey EM. New Australian germicide. Med J Aus 1930;1:417. 47. Pena EF. Meluleicca ulternifolia oil. Its use for trichomonal vaginalis and other vaginal infections. Obstet Gynecol1962;19:793-795. 48. Kaneda Y, Torii M, Tanaka T, et al. In vitro effects of berberine sulphate on the growth and structure of Entamoebu histolyticu, Giurdiu lumbliu and Trichornonus vuginulis. Ann Trop Med Parasitol 1991;85: 417-425. 49. Kaneda Y, Tanaka T, Saw T. Effects of berberine, a plant alkaloid, on the growth of anaerobic protozoa in axenic culture. Tokai J Exp Clin Med 1990;15:417-423. 50. Burtin P, Taddio A, Ariburnu 0, et al. Safety of metronidazole in pregnancy: a meta-analysis. Am J Obstet Gynecol 1995;172: 525-529.

Urticaria Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Diagnostic Summary 2133 Introduction 2133 Pathophysiology 2134 Causes of Urticaria 2134 Physical Causes 2134 Autoimmune Urticaria 2136 Drugs 2136 Food-RelatedCauses 2137 Infections 2141 Therapeutic Considerations 2142 Psychological Aspects 2142 Ultraviolet Light Therapy 2142 Thyroid 2142

DIAGNOSTIC SUMMARY Urticaria (hives): Well-circumscribed erythematous wheals with raised serpiginous borders and blanched centers that may coalesce to become giant wheals; limited to the superficial portion of the dermis. Angioedema: Eruptions similar to those of urticaria, but with larger well-demarcated edematous areas that involve subcutaneous structures as well as the dermis. Chronic versus acute: Recurrent episodes of urticaria and/or angioedema of less than 6 weeks' duration are considered acute, whereas attacks persisting beyond this period are designated chronic. Specialfomzs: Special forms have characteristicfeaturesdermographism, cholinergic urticaria, solar urticaria, cold urticaria.

INTRODUCTION Urticaria is named for the stinging nettle plant (Urtica dioica), which is known to contain histaminic acid. Urticaria is a localized pruritic edema of the skin characterized by white or pink papules or plaques with surrounding axon flare. The lesions are consistent with lesions of histamine-induced wheals. The lesions may

Traditional Chinese Medicine/Acupuncture Therapy 2142 Supplements 2143

Diagnosis 2143 Physical Evaluation and History 2143 Laboratory Testing 2143 Therapeutic Approach 2143 Diet 2144 Supplements 2144 Psychological 2144 Physical Medicine 2144 Traditional Chinese Medicine/ Acupuncture 2144

develop variable erythema and coalesce to form plaques. About 50% of patients with urticaria experience angioedema-a deeper, less well-defined edema of the subcutaneous and soft tissues. Urticaria and angioedema are relatively common conditions: It is estimated that they occur in 14% to 25% of the general population.' Although persons in any age group may experience acute or chronic urticaria and/or angioedema, young adults (postadolescence through the third decade of life) are the most often affe~ted.~,~Despite the prevalence of this condition, there is little interest from the general research community, possibly because mortality is rare and there is not an obvious genetic component for most of these conditions! The basic pathophysiology of urticaria involves the release of inflammatory mediators from mast cells or basophilic leukocytes. Although classically, this inflammation occurs as a result of immunoglobulin (Ig) E-antigen complex interacting with these cells, other non-IgE-mediated mechanisms are probably also critical in many patients with urticaria. A growing body of evidence shows that at least 40% of patients with idiopathic chronic urticaria have clinically relevant functional autoantibodies to the high-affinity IgE receptor

2133

on basophils and mast cells. The term autoimmune urticaria is used for this subgroup of patients presenting with continuous ordinary ~ r t i c a r i a . ~

PATHOPHYSIOLOGY The signs and symptoms of acute and chronic urticaria show consistent patterns despite the many diverse etiologic and initiating factors (see later) that have been found, yet the pathogenesis of urticaria cannot be entirely ascribed to any one mechanism. However, at present, it appears that mast cells and mast cell-dependent mediators play the most prominent role in the pathogenesis of urticaria.6 Mast cells are widely distributed throughout the body and are found primarily near small blood vessels, particularly in the skin. The granule-containing mast cell is a secretory cell capable of releasing both preformed and newly synthesized molecules, termed mediators. These mediators (listed in Box 213-1) play key roles in the pathogenesis of both immunologic and nonimmunologic inflammatory reactions. The three distinct sources of mediators are as follows: 0

Preformed mediators, which are contained in the granules and are released immediately

Preformed, rapidly released: Histamine Eosinophil chemotactic factors of anaphylaxis (ECF-A) Eosinophil chemotactic oligopeptides Neutrophil chemotactic factor Superoxide anions Exoglycosidases (beta-hexosaminidase, beta-delta-galactosidase,' beta-glucuronidase) Serotonin' Arylsulfatase A Secondary or newly generated: Slow-reacting substances (SRS-A): leukotrienes (LT) C, LTD, LTE Prostaglandins Monohydroxyeicosatetraenoicacids (HETEs) Hydroperoxyeicosatetraenoic acids (HPETEs) Thromboxanes Platelet-activating factor (PAF)' Prostaglandin-generating factor of anaphylaxis (PGF-A) Preformed, granule-associated: Heparin Proteases (chymotrypsinhypsin) Peroxidase' Superoxide dismutase' Arylsulfatase B Inflammatory factors of anaphylaxis (IFA)' Modified from Keahey TM. Dermatol Clin 1985313-28. 'Found in mast cells of species other than human.

Secondarily formed mediators, which are generated immediately or within minutes by the interaction of the primary mediators and nearby cells and tissues Granule matrix-derived mediators, which are preformed but slowly dissociate from the granule after discharge and remain in the tissues for hours The most common immunologic mechanism is mediated

by IgE. The early vascular changes appear to be the result of mast cell-dependent vasoactive mediators, particularly histamine and some secondarily generated end products of arachidonic acid metabolism. The wheal-and-flare reactions occur within minutes of initiation and last 30 to 60 minutes. The more prolonged, and delayed, reactions reflect leukocytic infiltration in response to the release of mast cell granulederived chemotactic factors. These late-phase reactions develop over time and are characterized by erythema, edema, and induration beginning within 2 hours and lasting 12 to 24 hours. Leukocyte infiltration may contribute to the urticaria1 tissue response by inducing a second wave of mast cell activation or by releasing toxic lysosomal enzymes and mediators characteristic of the type of infiltrating cell. The actual events initiated by the mediators also depend on the tissues into which they are released. For example, the release of histamine into the skin primarily produces pruritus and vascular permeability, whereas histamine release into the lung may induce bronchospasm.

CAUSES OF URTICARIA Fundamental to the treatment of urticaria is the recognition and control of causative factors.

Physical Urticarias Urticaria can be produced as a result of reactions to various physical stimuli. The most common forms of physical urticarias are dermographic, cholinergic, and cold urticarias (Table 213-1). These are briefly described here. Less common types of physical urticarias or angioedema are as follows2: Contact Solar Pressure Heat contact Aquagenic Vibratory Exercise-induced

Dermographism Dermographism or dermographic urticaria is a readily elicited whealing of the skin that evolves rapidly when

Urticaria

.. -

d Clinical aspects of physical urticarias

-r.

Time of onset

Duration of lesion

Diagnostic test

Associated symptoms

Stroking, scratching (rubbing for red dermographism)

2-5 rnin (0.5-5 hr)

1-5 hr (48 hr)

Firm stroking of skin

Headache, malaise

Cholinergic urticaria

Physical exercise + ovemeating; mental stress

2-20 min

30-60 rnin

Bicycling, running, sauna

Headache, gastrointestinal upset, wheezing, salivation, lacrimation, syncope

Cold urticaria

Cold contact

2-5 rnin

1-2 hr

Ice cube, cold arm bath, cold air

Wheezing, syncope

Solar urticaria

Light of varying wavelengths

2-15 rnin

0.25-3 hr

Phototest

Wheezing, dizziness, syncope

Pressure urticaria

Pressure

3-8 hr

8-24 hr

Locally applied weights

Flulike syndrome, fever, leukocytosis, arthralgias

Heat contact urticaria

Contact with heat

2-15 min

30-60 rnin

Hot arm bath

Gastrointestinal upset, dizziness, fatigue, wheezing, dyspnea

Aquagenic urticaria

Contact with water

2-30 rnin

30-60 min

Bath, compresses

None

Vibratory angioedema

Vibration

0.5-4 min

1 hr

Vibrating motor

Faintness, headache

Exercise-induced anaphylaxis

Exercise after a heavy meal

2-5 rnin

10-30 rnin

Exercise

Flushing, headache, disorientation, glottis edema, dyspnea, collapse

Familial cold urticaria

Cold wind, change from cold to warm air

0.5-3 hr

48 hr

Cold wind and subsequent rewarming

Tremor, headache, arthralgias, fever

Type

Eliciting stimulus

Dermographic urticaria (tarda)

Modified from Czarnetzki BM. Urticaria. New York: Springer-Verlag, 1986.

moderate amounts of pressure are applied. It may occur as a result of simple contact with furniture, garters, bracelets, watch bands, towels, or bedding. The incidence of dermographic urticaria has been estimated at 1.5% to 5% in the general population. The most common type of physical urticaria, it is found twice as frequently in women as in men, with the average age of onset in the third decade. The incidence is much greater among the obese, especially those who wear tight clothing. Dermographic lesions usually start within 1to 2 minutes of contact as an erythema, which is replaced within 3 to 5 minutes by edema and surrounding reflex urticaria. Maximal edema is usually produced within 10 to 15 minutes. Although the erythema generally regresses within an hour, the edema can persist up to 3 hours. Dermographism may be associated with other diseases, including? Parasitosis Insect bites Neuropsychiatric disorders Hormonal changes Thyroid disorders Pregnancy

Menopause Diabetes Immunologic alterations Other urticarias During or following drug therapy Candida albicans Angioedema Hypereosinophiha

Cholinergic Urticaria Cholinergic, or heat reflex, urticaria is the second most common physical urticaria. These lesions, which depend on the stimulation of the sweat gland via cholinergic afferent fibers, consist of pinpoint wheals surrounded by reflex erythema. The wheals arise at or between follicles and develop preferentially on the upper trunk and arms. The three basic types of stimuli that may produce cholinergic urticaria are passive overheating, physical exercise, and emotional stress. Typical eliciting activities, besides physical exercise, may include taking a warm bath or sauna, eating hot spices, and drinking alcoholic beverages. The lesions usually arise within 2 to 10 minutes after provocation and last for 30 to 50 minutes. A variety of systemic symptoms may also occur, suggesting a more generalized mast cell release of the

mediators than in the skin. Headache, periorbital edema, lacrimation, and burning of the eyes are common symptoms. Less common symptoms are nausea, vomiting, abdominal cramps, diarrhea, dizziness, hypotension, and asthmatic attacks2

Cold Urticaria Cold urticaria is an urticarial and/or angioedematous reaction of the skin when it comes into contact with cold objects, water, or air. Lesions are usually restricted to the area of exposure and develop within a few seconds to minutes after the removal of the cold object and rewarming of the skin. The lower the object's or element's temperature, the faster the reaction. Children with cold urticaria have a higher risk of anaphylaxis, especially triggered by ~wimming.~ Widespread local exposure and generalized urticaria can be accompanied by the following symptoms: Flushing Headaches

chills Dizziness Tachycardia Abdominal pain Nausea Vomiting Muscle pain Shortness of breath Wheezing Unconsciousness Cold urticaria has been observed to accompany a variety of clinical conditions, including the following':

Studies have identified these autoantibodies in 24% to 76%of patients with chronic urticaria. From a clinical perspective, these patients tend to have a somewhat more severe, prolonged course of disease. Middle-aged women are disproportionately represented in the population of patients with urticaria, and higher rates of autoimmunity in this group, particularly for thyroid disease, may account for this preponderance. Thyroid autoantibodies are found more frequently in patients with these IgE receptor autoantibodies (see later discussion of thyroid). Autoimmune diseases are well known to be associated with bowel permeabilities?-12Because subclinical impairments of small bowel enterocyte function have been postulated to induce a higher sensitivity to histamine in the digestive tract,13 it makes sense from a naturopathic standpoint to treat overt and subclinical digestive system permeabilities to decrease systemic inflammatory responses to endotoxins in these autoimmune conditions.

Drugs Drugs make up the leading cause of urticarial reactions in adults. In children, the reactions are usually due to foods, food additives, or infections.2 Most drugs are composed of small molecules incapable of inducing antigenidallergenic activity on their own. Typically, they act as haptens that bind to endogenous macromolecules, ultimately causing the production of hapten-specific antibodies. Alternatively, drugs can interact directly with mast cells to induce degranulation. Many drugs have been shown to produce urticaria. Box 213-2 provides a condensed list.14 The two most common urticaria-inducing drugs, penicillin and aspirin, are briefly discussed here.

Viral infections Parasitic infestations

syphilis Multiple insect bites Penicillin injections Dietary changes Stress

The association of cold urticaria with infectious mononucleosis is well established. Other conditions associated with cold urticaria are cryoglobulinemia and myeloma, in which cold urticaria may precede the diagnosis by several years.*

Autoimmune Urticaria Although much remains unknown regarding the specific pathophysiologic mechanisms underlying most cases of chronic urticaria, a minority seem to have an autoimmune basis. Research has discovered that a significant percentage of patients previously categorized as having idiopathic urticaria have autoantibodies to IgE or the FceRIa subunit of the high-affinity IgE mast cell receptor!

Acetylsalicylic acid Allopurinol Antimony Antipyrines Barbiturates Bismuth Chlorhydrate Chlorpromazine Corticotropin (adrenocorticotropic hormone) Eucalyptus Fluorides Gold Griseofulvin (cold urticaria) Insulin lodines Liver extract Menthol

Meprobamate Mercury Morphine, opium Paraaminosalicylicacid Penicillin Phenacetin Phenobarbital Pilocarpine Poliomyelitis vaccine Potassium sulfocyanate Procaine Promethazine Quinine Reserpine Saccharin Thiamine chloride Thiouracil

Modified from Andrews GC. Andrews' diseases of the skin, ed 7. Philadelphia: WB Saunders, 1962131.

Urticaria

Penicillin Antibiotics, including penicillin and related compounds, are the most common cause of drug-induced urticaria. The allergenicity of penicillin in the general population is thought to be at least 10%. Nearly 25% of these individuals display urticaria, angioedema, or anaphylaxis upon ingestion of penicillin?J5 An important characteristic of penicillin is that it cannot be destroyed by boiling or steam distillation.This is a problem because penicillin and related contaminants can exist undetected in foods. To what degree penicillin in the food supply contributes to urticaria1 reactions is not known. However, urticaria and anaphylactic symptoms have been traced to penicillin in milk,16 soft drinks,17 and frozen dinners.ls In one study of 245 patients with chronic urticaria, 24% had positive skin test results and 12% had positive RAST results for penicillin ~ensitivity.’~ Of those 42 patients sensitive to penicillin, 22 experienced clinical improvement with a dairy product-free diet whereas only 2 out of 40 patients with negative skin test results experienced improvement with the same diet. This study would seem to provide indirect evidence of the importance of penicillin in the food supply in urticaria. In an attempt to provide direct evidence, penicillincontaminated pork was given to penicillin-allergic volunteers. No significant reactions were noted other than transient pruritus in two volunteers?O Penicillin in milk appears to be more allergenic than penicillin in meat.16 Presumably the reason is that penicillin can be degraded into more allergenic compounds in the presence of carbohydrate and metals, suggesting that penicillin in milk may be more allergenic than artificially contaminated meat.16

aspirin sensitivity. While taking the aspirin, patients also became nonresponsive to foods to which they usually reacted, such as pineapple, milk, egg, cheese, fish, chocolate, pork, strawberries, and plums.57Others have noted this effect in patients with asthma, but they have also found that the effect disappears within 9 days after the treatment is stopped, suggesting the loss of effect or a possible placebo

Food-Related Causes Food Allergy

IgE-mediated urticaria can occur upon the ingestion of a specific reaginic antigen. Although any food can be the agent, the most common offenders are milk, fish, meat, eggs, beans, and n ~ t sOther . allergens ~ ~ are ~ citrus, ~ ~ kiwis, peanuts, and a ~ p l e s . 5 Individuals ~ with atopy are most likely to experience urticaria as a result of IgErelated mechanisms, although reports confirm the presence of pseudoallergic reactions, whereby direct mast cell histamine release are involved in this reactivity. Aromatic volatile ingredients in tomatoes, wine, and culinary herbs (basil, fenugreek, cumin, dill, ginger, coriander, caraway, curcuma, parsley, pepper, rosemary, and thyme) have been considered the initiating factors in some of these non-IgE Food allergies may contribute greatly to the increased permeability of the gut in urticaria. A basic requirement for the development of a food allergy is the absorption of the allergen through the intestinal barrier. Several factors are known to significantly increase gut permeability, including vasoactive amines ingested in foods or produced by bacterial action on essential amino acids, alcohol, NSAIDs, and, possibly, many food additives (see Chapter 23 for a full discussion). Gut permeabilities are also associated with autoimmune condition^.^-'^ Because Aspirin and Nonsteroidal Antiinflammatory chronic urticaria is now known to be at least partially Drugs related to an autoimmune process (see earlier discussion Urticaria is a more common indicator of aspirin sensiof autoimmune urticaria), it is possible that, depending tivity than is asthma (see Chapter 149).The incidence of on the genetic susceptibility of individual, these bowel permeabilities may play a key role in the instigation and aspirin sensitivity in patients with chronic urticaria is at least 20 times greater than in normal controls.21-25 prolonged immune activity that leads to chronic Studies (summarized in Table 213-2)2”55have demonurticaria. In addition, several investigators have reported alterstrated that 2% to 67% of patients with chronic urticaria ations in gastric acidity, intestinal motility, and the funcare sensitive to aspirin. tion of the small intestine and biliary tract in up to 85% Aspirin inhibition of cyclooxygenase apparently shunts eicosanoid metabolism towards leukotriene synof patients with chronic urticaria.@-” Selective IgA deficiency, gastroenteritis, hypochlorhydria or achlorhydria, thesis, thereby increasing smooth muscle contraction and other disruptive factors reported in patients with and vascular permeability. In addition, aspirin and other chronic urticaria may temporarily or permanently alter nonsteroidal antiinflammatory drugs (NSAIDs) have the barrier and immune function of the gut wall, predisbeen shown to increase gut permeability dramatically posing an individual to allergic sensitization. and may alter the normal handling of In one study of 77 patients with chronic urticaria, NSAIDs are also known be associated with prolonged and more pronounced autoreactivity in urticaria.55The 24 (31%)were diagnosed as achlorhydric and 41 (53%) daily administration of 650 mg of aspirin for 3 weeks has were shown to be hypochl~rhydric.~~ Treatment with hydrochloric acid and a vitamin B complex gave been shown to desensitize patients with urticaria and

~

~

Percent Positive Tests Studv

Year

No. of patients

Samter and Beers%

1969

40

8

Benzoates 44

Tartrazine

Other azo dyes

Annatto

Michaelsson and JuhlinZ7

1973

52

36

Thune and Granholtz8

1975

100

21

10

Doeglass

1975

23

30

23

Warin and Smithm

1976

108

12

Settipane et aP1

1976

38

8

16 -

KaabeP

1978

65

Fujita et a P

1978

57

5 -

23

Neuman et aI3

1978

30

23

-

August35

1979

86

23

22

Meynadier et aI%

1979

24

24

25 29 -

Lindemayr and SchmidP7

1979

90

19

Mikkelsen et aIB

Aspirin

3

1979

24

24

Wutrich and Ha~ki-Herrmann~~1980

81

21

18

Gibson and Clancy4O

1980

76

34

Juhlin41

1981

330

28 -

Wutrich and F a b r ~ ~ ~

1981

306

6

6

Kirchoff et a143

1981

100

15

8

40

37 24

17 -

11

Egyedi and ToroP

1982

Merk and G o r e p

1983

25

Hannuksela&

1983

137

1

4

Ortolani et al"

1984

75

13

21

Simon@

1984

25

0

-

Genton et a P

1985

17

59

30

Pigatto et aIm

1985

61

10

-

Kemp and Schembrisl

1985

23

7

7

Zieger and Hamsteinsz

1986

100

10

-

Supramaniam and WarnoP

1986

43

26

15

impressive clinical results, highlighting the importance of correcting any underlying factor in the treatment of chronic urticaria (see Chapter 21). Although IgE-mediated reactions are thought to predominate in immunologic urticaria, it has been suggested that IgG-mediated reactions are probably responsible for the majority of adverse reactions to foods seen in general practice (see Chapter 53). IgG antigenantibody complexes are capable of promoting complement activation and subsequent generation of anaphylatoxins that promote mast cell degranulation. This could be a significant factor in some cases of urticaria. Figure 213-1 summarizes the basic aspects of a hypothetical model of immune defense in the normal gut and the urticaria1 gut.

BHNBHT

Food Colorants Food additives are a major factor in many cases of chronic urticaria in children. Colorants (azo dyes), flavorings (salicylates, aspartame), preservatives (benzoates, nitrites, sorbic acid), antioxidants (hydroxytoluene, sulfite, gallate), and emulsifierslstabilizers (polysorbates, vegetable gums) have all been shown to produce urticarial reactions in sensitive individuals.* The importance of the control of food additives was well demonstrated in a study of 64 patients with common urticaria. After 2 weeks of an additive-free diet, 73% of the patients had a signhcant reduction

'References 2 , 15,26-50, 52-55, 64, 67,73-77.

Urticaria Lumen

Gut wall

Circulation

Skin

Normal gut

Result

Mast cell

/

T-suppressor cells

Insufficient IgA 1 I 1

Gut of patient with urticaria

Enhanced IgE production (atopy)

.

. r

I

\

r

O

00

Increased number of mast cells (from food additives)

Decreased T suppressor cell activity Figure 213-1

Hypothetical model of immune defense in the normal and urticaria1gut.

in symptoms. The diet strictly forbade preservatives, dyes, and antioxidants. No fruits or refined sugars were allowed except honey. Rice, potatoes, and unprocessed cereals were allowed as well as fresh milk.78

Tartrazine In 1959, the azo dye tartrazine (FD&C [Food, Drug and Cosmetic Act] Yellow no. 5) was the first food dye reported to induce ~rticaria.7~ Tartrazine is one of the most widely used colorants. It is added to almost every packaged food as well as many drugs, including some antihistamines, antibiotics, steroids, and sedatives.80 Reactions to this food additive are so common that its use has been banned in Sweden.81 In the United States, the average daily per capita consumption of certified dyes is 15 mg, of which 85% is tartrazine. Among children, consumption is usually much higher. Tartrazine sensitivity has been calculated as occurring in 0.1% of the population?*

Tartrazine sensitivity is extremely common (20% to 50%) in individuals sensitive to a s ~ i r i n . ' Like ~,~~ aspirin, tartrazine is a cyclooxygenase inhibitor and a known inducer of asthma, urticaria, and other allergic conditions, particularly in children. Inhibition of cyclooxygenase by tartrazine or aspirin apparently shunts eicosanoid metabolism toward leukotriene synthesis, thereby increasing smooth muscle contraction and vascular permeability. In addition, tartrazine, as well as benzoate and aspirin, increases the production of the lymphokine leukocyte This results in an increase in perivasinhibitory cular mast cells and mononuclear cells. Histologic examination of patients with urticaria shows that more than 95% have an increase in perivascular mast cells and mononuclear cells.83 Table 213-2 summarizes the findings in studies using provocation tests to determine sensitivity to tartrazine and other food additives in patients with urticaria. Rates have varied from 5% to 46%.Diets eliminating tartrazine as

Percentage study

Year

Michaelsson and JuhlinZ7

1973 1975 1976 1976 1977 1978 1979 1979 1979 1980 1980 1981 1981 1983 1985

Thune and GranhoP

Ros et aI7' Warin and Smith% Douglas72 KaabeP August35 Meynadier et aIs Lindemayr and SchmidP7 Gibson and Clancy40 Valverde et a173 Wutrich and Fabro4' Kirchoff et a P Verschave et a174 Kemp and SchembrP

No. of patients

Free of urticaria

16 100 75 58 18 23 22 98 90 65 258 51

81 12

41

44

67 18

73 39

well as other azo dyes and food additives in sensitive individuals have in many cases been shown to be of great benefit. These studies are summarized in Table 213-3. Table 213-4 shows a recommended test battery.=

Food Flavorings Salicylates A broad range of salicylic acid esters are used to flavor foods such as cake mixes, puddings, ice cream, chewing gum, and soft drinks. The mechanism of action of these agents is thought to be similar to that of a~pirin.'~ Salicylates are also found naturally in many foodstuffs. It is estimated that daily salicylate intake from foods is in the range of 10 to 200 mg/day.@ Because this is very close to the level of salicylate used in clinical testing (usually 300 mg), dietary salicylate may be a significant factor in aspirin-sensitive individuals. Most fruit, especially berries and dried fruits, contain salicylates. Raisins and prunes have the highest amounts. Salicylates are also found in appreciable amounts in candies made of licorice and peppermint. Moderate levels of salicylate are found in nuts and seeds. Vegetables, legumes, grains, meat, poultry, fish, eggs, and dairy products typically contain insignificant levels of salicylates. Salicylate levels are especially high in some herbs and condiments, including curry powder, paprika, thyme, dill, oregano, and turmeric. Although the intake of these herbs and spices is relatively small, they can make a significant contribution to dietary salicylate.a

Better

6 50 57 75 67 30 23 12 55 15 22 57 29 73 39

24

75 67 44 45

80 20 75 62 31

Same

13 38 19 25 33 26 32 8 25 10 16 12 27 37 22

with recurrent urticaria Day

1 2

Substance(s) tested

Amount (mg)

Control (lactose)

100,000

Azodyes: Tartrazine New coccine Sunset yellow

3

Control (lactose)

4

Benzoates: Sodium benzoate 4-Hydroxybenzoic acid

5

Carotene Canthazanthine

6 7 8 9 10 11 12 13

Annatto BHT-BHA Yeast extract Control (lactose) Aspirin Sorbic acid

50,500 50,200 50,100,100 10,200,200 5,10 1, 10,50,50 600 100,100 0.1,1, 10,100,250+,500+ 50,200,200

Control Sodium nitrite Sodium nitrate

14 15 16

0.1,1,lO 0.1,1,lO 0.1,1,lO 100,100

Sodium glutamate Quinoline yellow Potassium metabisulfate

Data from references 41 and 75.

100 100 100,200 1, 5,10 1, 5, 10,50

Urticaria

Other Flavoring Agents Other flavoring agents, such as cinnamon, vanilla, menthol, and other volatile compounds, may produce urticaria in some individ~als.’~ For example, the artificial sweetener aspartame has been shown to induce urticaria.85

Food Preservatives Benzoates Benzoic acid and benzoates are the most commonly used food preservatives. Although the incidence of adverse reactions to these compounds is thought to be less than 1%for the general population, the frequency of positive challenges in patients with chronic urticaria varies from 4% to 44%, as illustrated in Table 213-2. Fish and shrimp frequently contain extremely high quantities of benzoates. This may be one reason why adverse reactions to these foods are so common in patients with urticaria. Butylated Hydroxytoluene and Butylated Hydroxyanisole Butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) are the primary antioxidants used in prepared and packaged foods. Typically, 15% of patients with chronic urticaria test positive to oral challenge with BHT.28,41,50,54 The use of chewing gum containing BHT was enough to induce urticaria in one patient.% Sulfites Sulfites,like tartrazine, have been shown to induce asthma, urticaria, and angioedema in sensitive indi~iduals.8~ The source may be varied, because these compounds are ubiquitous in foods and drugs. They are typically added to processed foods to prevent microbial spoilage and to keep them from browning or changing color. The earliest known use of sulfites was in the treatment of wines with sulfur dioxide by the Romans. Sulfites are sprayed on fresh foods such as shrimp, fruits, and vegetables. They are also used as antioxidants and preservatives in many pharmaceuticals.Sulfites have caused such a wide range of health problems, such as asthma and urticaria, that their use on fruits and vegetables has been banned in the United Statesg1 The average person consumes an average of 2 to 3 mg/day of sulfites. Wine and beer drinkers typically consume up to 10 mg/day, and individuals who rely on restaurants for meals may ingest up to 150 mg/dayS7 Normally, the enzyme sulfite oxidase metabolizes sulfites to safer sulfates, which are excreted in the urine. People with a poorly functioning sulfoxidation system, however, have an increased ratio of sulfite to sulfate in their urine. Sulfite oxidase depends on the trace mineral molybdenum. Although most nutrition textbooks list molybdenum deficiency as uncommon,

an Austrian study of 1750 patients found that 41.5% were molybdenum-deficient.88

Food Emulsifiers and Stabilizers A variety of compounds is used to emulsify and stabilize many commercial foods to ensure that the solids, oils, and liquids do not separate out. Most of the foods containing these compounds are heterogeneous, because they usually contain antioxidants, preservatives, and dyes. Polysorbate in ice cream has been reported to induce urticaria, and vegetable gums such as acacia, gum arabic, tragacanth, quince, and carrageenan may also induce urticaria in susceptible individ~als.’~

Infections Infections are a major cause of urticaria in children.2 Apparently in adults, immunologic tolerance occurs to many microorganisms owing to repeated massive antigen exposure. The role of bacteria, viruses, and yeast (C. albicans) in urticaria is briefly reviewed here. Chronic Tvichornonas infections have also been found to cause urticaria.

Bacteria Bacterial infections contribute to urticaria in two major settings-in acute streptococcal tonsillitis in children and in chronic dental infections in adults. In the first setting, acute urticaria predominates, whereas in the second, chronic urticaria predominates?

Viruses Hepatitis B is the most common cause of virally induced urticaria. One study found that 15.3% of patients with chronic urticaria had anti-hepatitis B surface antibodi e ~Urticaria . ~ ~ has also been strongly linked to infectious mononucleosis and may develop several weeks before clinical manifestations. The incidence of urticaria during infectious mononucleosis is

Candida albicans The association between C. albicans and chronic urticaria has been suggested in several clinical studies. The number of patients with chronic urticaria who react positively to an immediate skin test with Candida antigens is 19% to 81%compared with 10% to 15%of normal subject^.^^,^@^^ It appears that sensitivity to C. albicuns is an important factor in at least 25% of patients with chronic urti~aria.9~ Approximately 70% of patients with a positive skin reaction also react to oral provocation tests using foods prepared with yeasts. Treatment with nystatin has proved that elimination of the organism can achieve a cure in a number of individuals with positive skin test results, although a placebo response cannot be ruled out. However, more patients have responded to a “yeast-free” diet than to simple

elimination of the organism in c h c a l trials. The yeast-free One study evaluated a group of 624 patients with diet employed excluded bread, buns, sausage, wine, presumed idiopathic chronic urticaria and angioedema. beer, cider, grapes, sultanas, marmite, Bovril, vinegar, From these, 90 patients were found to have thyroid tomato, ketchup, pickles, and prepared foods containing aut~immunity.'~~ Forty-six of these patients were treated food yeasts. For example, in a study of 49 patients with with L-thyroxine therapy, 8 of whom had remission proven sensitivity to Cundidu, 9 showed response to a within 4 weeks of therapy. Four patients with high thy3-week course of nystatin, whereas 18 became symptomroid antibody titers had repeated exacerbations when free only after adopting the yeast-free diet.93This finding therapy was discontinued and had repeated remissions would seem to support the importance of diet along when therapy with L-thyroxine was resumed. Although with elimination of the yeast. in most cases treatment with L-thyroxine did not Further support for the importance of diet can be improve the patient's urticaria or angioedema, a few did found in a study of 36 patients with a positive skin-prick demonstrate a dramatic response. test response to Cundidu.Only 3 patients became asympAnother study reported that thyroid hormone tomatic with nystatin alone, compared with 23 with diet replacement therapy dramatically improved chronic therapy after the nystatin thera~y.9~ urticaria in patients who had normal thyroid function Desensitizing patients to C. ulbicuns with the use of a but had evidence of thyroid autoimmunity. In seven Cundidu cell wall extract also demonstrated encouraging patients with chronic urticaria, five were started on thyresults in some patients, although the treatment of these roid hormone, and dosages were increased in two. Their individuals also included increasing gastrointestinal ferurticaria resolved within 2 to 4 weeks, at which time the mentation and acidity as well as elimination of y e a ~ t ? ~ , thyroid ~~ therapy was discontinued. In five patients, the symptoms returned within 4 weeks, then resolved within 4 weeks of their restarting the hormone therapy. THERAPEUTIC CONSIDERATIONS Antithyroid antibodies did not correlate with clinical Psychological Aspects response.Io5 In one retrospective study involving 236 cases of chronic There have been cases in which resolution of chronic urticaria, psychological factors, such as stress, were urticaria associated with thyrotoxicosis has also been reported to be the most common primary cause?' Stress seen in patients treated with antithyroid medication and appears to play an important role through a reduction of in those treated with radioactive iodine.'" These findintestinal secretory IgA levels. ings underscore the importance of fully diagnosing the thyroid condition and not treating presumptively with In one study of 15 patients with chronic urticaria, suppressive thyroid medication. relaxation therapy and hypnosis were shown to provide Although the usefulness of thyroid hormone therapy significant benefit.98Patients were given an audiotape in patients who are euthyroid and have chronic urticaria and asked to use the relaxation techniques described has not been demonstrated in a controlled trial, looking on the tape at home. At a follow-up examination 5 to for thyroid autoimmunity is certainly warranted in cases 14 months after the initial session, 6 patients were free of refractory to other forms of therapy. hives and 7 others reported improvement.

Ultraviolet Light Therapy Ultraviolet light has been shown to be of some benefit to patients with chronic urticaria.99J00Both ultraviolet A ( W A ) and ultraviolet B (UVB) light have been used. Patients with cold, cholinergic, and dermographic urticarias display the greatest therapeutic response.

Thyroid The association of thyroid disease and autoimmunity with urticaria has been established for decades.lo1-'" The prevalence of antithyroid antibodies in the normal population has been estimated at 3% to 6%, and they are commonly found in association with other autoimmune conditions, such as pernicious anemia and vitiligo.'" A subset of patients with chronic urticaria may be best helped by suppressing glandular inflammation, by thyroid hormone therapy (as described in the following studies), by surgery, or by antithyroid medication.

Traditional Chinese Medicine/Acupuncture Therapy Acupuncture has long been used in traditional Chinese medicine (TCM) to effectively treat urticarialwJw and type I allergic conditions.lWKnown as "wind wheal," urticaria is also referred to by Chinese practitioners as the "hidden rash" owing to its ephemeral nature. Three standard TCM etiologies are considered for urticaria. Urticaria1 disease due to wind heat typically manifests as red rashes with pruritus. Wind damp etiology correlates with lighter-colored rashes and a heavy sensation in the body. Alternately, red rashes that appear with concomitant epigastric or abdominal pain and diarrhea or constipation are considered a derivation of stomach and small intestine heat. Acute urticaria can be easily and effectively treated with acupuncture, in which LIll (Quchi), SplO (Xuehai), Sp6 (Sanyinjiao), and 536 (Zusanli) are the acupuncture points most

Urticaria

involving 6462 patients, demonstrated no relationship between numbers of identified diagnoses and numbers of performed tests.l14 This review noted that systemic diseases (which excluded physical urticarias, allergens, infections, and psychologic causes) were identified and believed to be related causally to the urticaria only in 1.6%of patients; these diseases included vasculitis, thyroid disease, systemic lupus erythematosus, other rheumatic disease, hereditary angioedema, and hematologic Supplements or oncologic conditions. Vitamin BI2 The use of screening skin testing for food allergies is also contro~ersial.8,~~ It is known that many patients Vitamin B12has been anecdotally reported to be of value with food-induced urticaria have diagnosed themselves in the treatment of acute and chronic urticaria.llOJ1l without the help of a specialist. Skin testing for foods Although serum vitamin B12 levels are normal in most in the patient with chronic urticaria is fraught with falsepatients, additional B12appears to be of value. However, positive and false-negative results. In the absence of a because injectable BI2 was used, the placebo effect (see specific history suggestive of a particular food allergy Chapter 7) cannot be ruled out. (hstory of exposure and time course of subsequent Quercetin symptoms consistent with typical food allergy), such skin Considering the importance of mast cell degranulation testing can be counterproductive, particularly in patients with dermatographism and "twitchy" mast cells. in the pathogenesis of urticaria, quercetin's significant in If symptoms do not remit after proper history and vitro activity as a mast cell stabilizer (and inhibitor of physical examination have been performed and the thermany of the pathways of inflammation; see Chapter 95) apies listed here have been tried, it may be useful to persuggests that it may be very useful in treating urticaria. form a complete blood count with differential, This possibility is strengthened by the observation that urinalysis, erythrocyte sedimentation rate measurement, sodium cromoglycate (at 200 to 400 mg four times/day), liver function tests, antinuclear antibody titer measurea compound similar to quercetin, confers excellent proments, and thyroid panel with antithyroid autoantibody tection against the development of urticaria and measurements. These tests may help ferret out most of angioedema in response to ingested food allergens.ll2 the uncommon cases with a detectable but unsuspected underlying cause (such as infectious, parasitic, rheumatic, thyroid, and hematologic conditions). Physical Evaluation and History Although not recommended for most cases of chronic urticaria, some medical literature suggests that a skin A thorough history and physical evaluation are imperative for proper diagnosis of urticaria and should include biopsy specimen can provide useful information to rule a careful history listing all medications, supplements, out urticaria1 vasculitis when this condition is suspected and botanicals. Evaluation should also detail travel, clinically.8 Research laboratories can also focus on recent infection, occupational exposure, timing and autoimmune urticaria and detect the presence of antionset of lesions, morphology, associated symptoms, FceRIa autoantibodies, but these tests are neither stanfamily medical history, and preexisting allergies. Contact dardized nor routinely or widely available. Some urticaria specialists assess for such autoantibodies clinisensitivities such as latex1I3 and exposure to physical stimuli should be documented. History of tattoos should cally and indirectly through autologous serum skin testbe explored for possible correlations. A diet and lifestyle ing (ASST), whereby the patient's serum is centrifuged diary that chronicles date and time, foods eaten, major and used for skin prick testing in this form of a semiactivities, bowel and urine habits, and stress should be quantitative functional assay for autoimmunity to IgE or gathered in order to fully to characterize potential temIgE receptors bound to cutaneous mast cells. This test is poral relationships of urticaria with specific ingested about 75y0 sensitive and 74% specific for the presence of foods and activities. A comprehensive physical examinathe autoantibodies8 tion can also uncover important diagnostic clues that may help diagnose comorbidities. commonly prescribed.'@' Auricular acupuncture may also accompany body acupuncture points for enhanced effect. External herbal washes with Fructus arctii (burdock) are also used in TCM. Controlled studies are needed to fully elucidate the benefits of TCM for allergic disease and urticaria, but given its safety and history of effective use, it is certainly worth a try.

~~

THERAPEUTIC APPROACH

Laboratory Testing The appropriate role of laboratory testing and studies in chronic urticaria remains controversial.8One review of 29 large studies of laboratory testing in chronic urticaria,

Regarding conventionalmanagement of chronic urticaria, patients often show incomplete response to antihistamines and are often uncomfortable and frustrated by chronic pruritus. Some cases do respond to systemic

corticosteroids, but the potentially serious side effects associated with these medications preclude their safe chronic use.8The wide variety of drugs used singly or in combination for this condition is a testament to conventional medicine’s inability to fully address and treat the symptoms as well as the underlying causes of urticaria; see Box 213-3 for a complete list of conventional drugs used to treat urticaria. The basic natural therapeutic approach involves identification and control of all factors that promote the patient’s urticaria1response. Obtaining a careful and thorough history is paramount to this process. Acute urticaria

Second-generation histamine, (H,)receptor antagonists: Cetirizine (Zyrtec) Fexofenadine (Allegra D) Desloratadine (Clarinex) Loratadine (Claritin) First-generation H, receptor antagonists: Hydroxyzine (Atarax) Diphenhydramine (Benadryl) Ranitidine (Zantac) H, and histamine, (H,) receptor antagonists: Doxepin (Sinequan)-sedation, increased appetite, and resultant weight gain Cyproheptadine (Periactin) Cimetidine (Tagametwnterference with hepatic microsomal enzymes and androgen receptors Leukotriene modifiers: Montelukast (Singulair) Zafirlukast (Accolate) 5Lipoxygenase inhibitors: Zileuton (Zyflo) Nonsteroidal antiinflammatory drugs Corticosteroid: Prednisone Immunosuppressive treatments: Cyclosporin A Tacrolimus Azathioprine Cyclophosphamide Mycophenolate mofetil Plasmapheresis Intravenous immunoglobulin Others: Calcium channel blocker antihypertensives Hydroxychloroquine Dapsone Colchicine Methotrexate Sulfasalazine Intramuscular gold Capsaicin Impeded androgens Warfarin Data from references 1 and 8

is usually a self-limiting disease, especially once the eliciting agent has been removed or reduced. Chronic urticaria also responds to the removal of the eliciting agent(s). In severe anaphylaxis, appropriate emergency care procedures should be followed.

Diet Although rarely utilized in conventional medical therapy, even the standard medical literature is beginning to recognize the wisdom of the elimination diet? An elimination or oligoantigenic diet is of utmost importance in the treatment of chronic urticaria (see Chapters 19 and 53). The diet should eliminate not only suspected allergens but also all food additives. The strictest elimination diets allow only water, lamb, rice, pears, and vegetables. Those foods most commonly associated with inducing urticaria (i.e., milk, eggs, chicken, fruits, nuts, and additives) should definitely be avoided.64 Foods containing vasoactive amines should be eliminated even if no direct allergy to them is noted. The primary foods to eliminate are cured meat, alcoholic beverages, cheese, chocolate, citrus fruits, and shellfish. The importance of eliminating food additives cannot be overstated. If food additives do in fact increase the number of perivascular mast cells in the skin, they may also do the same in the small intestine, thereby greatly raising the risk of development of a ”leaky” gut. Also of value is control of arachidonic acid-dependent prostaglandins through the use of a diet low in animal fat.

Supplements Vitamin C: 1 g three times/day Vitamin BIZ:1000 pg intramuscularly per week Quercetin: 250 mg 20 minutes before meals

Psychological The patient should perform relaxation techniques daily. Listening to audiotaped relaxation programs may be an appropriate way to induce the desired state.

Physical Medicine Daily sunbathing for 15 to 20 minutes or the use of a W A solarium, especially in chronic physical urticaria, is recommended. Tepid oatmeal baths may also help calm urticarial symptoms, but caution should be taken with physical modalities when physical triggers such as heat, cold, and water are salient for a particular patient.

Traditional Chinese Medicine/Acupuncture Acupuncture can work quite well together with naturopathic therapies to treat causes and symptoms of urticaria.

Urticaria

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30. Warin RP, Smith RJ. Challenge test battery in chronic urticaria. Br J Dermatol1976;94401410. 31. Settipane GA, Chafee FH, Postman IM,et al. Significance of tartrazine sensitivity in chronic urticaria of unknown etiology.J Allergy Clin IIIIIIIU~OI 1976;57:541-549. 32. Kaaber K. [Colouring and preservative agents and chronic urticaria. Value of a provocative trial and elimination diet.] Ugeskr Laeger 1978;140:1473-1476. 33. Fujita M, Yakimoto T, Aoki T, et al. [Provocation tests with aspirin and sodium benzoate in urticaria.] Japan J Derm 1978 88: 709-713. 34. Neuman I, Elian R, Nahum H, et al. The danger of "yellow dyes" (tartrazine) to allergic subjects. Clin Allergy 1978;8:65-68. 35. August PJ. Successful treatment of urticaria due to food additive with sodium cromoglycate and an exclusion diet. In Pepys J, Edward AM, eds. The mast cell: its role in health and disease. Tunbridge Wells, UK:Pitman Medical, 1979. 36. Meynadier J, Guilhou J, Meynadier J, et al. [Chronic urticaria. Etiologic and therapeutic evaluation of 150 cases.] Ann Dermatol Venereol1979;106:153-158. 37. Lindemayr H, Schmidt J. [Intolerance to acetylsalicylic acid and food additives in patients suffering from chronic urticaria.] Wien Klin Wochenschr 1979;91:817-822. 38. h4ikkelsen H, Larsen JC, Tarding F. Hypersensitivity reactions to food colours with special reference to the natural colour annatto extract (butter colour). Arch Toxic01 Suppl 1978;1:141-143. 39. Wutrich B, Hacki-Herrmann D. Zur atiologie der urticaria. Eine retropektive studie anhand von 316 konsekutiven fallen. Z Hautkr 1980;55:102-111. 40. Gibson A, Clancy R. Management of chronic idiopathic urticaria by the identification and exclusion of dietary factors. Clin Allergy 1980;10699-704. 41. Juhlin L. Recurrent urticaria. Clinical investigation of 330 patients. Br J Dermatol1981;104:369-381. 42. Wutrich B, Fabro L. Acetylsalicylsaure unc lebensmittel-additivaintleranz bei urticaria, asthma bronchiale and chronischer rhinopathie. Schweiz Med Wochenschr 1981;111:1445-1450. 43. Kirchhof €3, Haustein UF, Rytter M. [Acetylsalicylic acid-additive intolerance phenomenon in chronic recurring urticaria.] Dermatol Monatsschr 1982;168:513-519. 44.Egyedi K, Torok L. Nachweis einer intoleranz von lebensmitteladditvstoffen durch proben mit salizylaten bei chronischer urticaria. Allergologie 1982;5:234-235. 45. Merk, Goerz G. Analgetika-intoleranz. Z Hautkr 1983;58:535-554. 46.Hannuksela M. Food allergy and skin diseases. Ann Allergy 1983;51:269-271. 47. Ortolani C, Pastorello E, Luraghi MT, et al. Diagnosis of intolerance to food additives. Ann Allergy 1984;53:587-591. 48.Simon RA. Adverse reactions to drug additives. J Allergy Clin Imm~n011984;74:623-630. 49. Genton C, Frei PC, Pecoud A. Value of oral provocation tests to aspirin and food additives in the routine investigation of asthma and chroNc urticaria. J Allergy Clin Immunol1985;764045. 50. Pigatto PD, Riva F, CattaneoA, et al. [chronic urticaria. Clinico-therapeutic study on 300 cases.] G Ital Dermatol Venereoll985;12011>117. 51. Kemp AS, Schembri G. An elimination diet for chronic urticaria of childhood. Med J Aust 1985;143:234-235. 52. Ziegler B, Haustein UF. [Intolerance reactions to non-steroidal antiphlogistics and analgesics in chronic recurrent urticaria.] Dermatol Monatsschr 1986;172313-317. 53. Supramaniam G, Warner JO. Artificial food additive intolerance in patients with angio-oedema and urticaria. Lancet 1986;2: 907-909.

54. Perry CA, Dwyer J, Gelfand JA, et al. Health effects of salicylates in foods and drugs. Nutr Rev 1996;54:225-240. 55. Grattan CE. Aspirin sensitivity and urticaria. Clin Exp Dermatol 2003;28:123-127. 56. Bjarnason I, Williams F’, Smethurst P, et al. Effect of non-steroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine. Gut 1986;271292-1297. 57. Asad SI, Youlten LJ, Lessof MH. Specific desensitization in aspirin sensitive urticaria; plasma prostaglandin levels and clinical manifestations. Clin Allergy 1983;13459-466. 58. Kowalski ML, Grzelewski-Ryzmowski I, Roznieki J, et al. Aspirin tolerance induced in aspirin-sensitive asthmatics. Allergy 1984;39 171-178. 59.Mattila L, Kilpelainen M, Terho EO, et al. Food hypersensitivity among Finnish university students: association with atopic diseases. Clin Exp Allergy 200333:600-606. 60.Atkins FM. The basis of immediate hypersensitivity reactions to foods. Nutrition Rev 1983;41:229-234. 61. Wraith DG, Merrett J, Roth A, et al. Recognition of food-allergic patients and their allergens by the RAST technique and clinical investigation. Clin Allergy 1975;9:25-36. 62. Golbert TM, Patterson R, Pruzansky JJ. Systemic allergic reactions to ingested antigens. J AUergy 1969;44:96-107. 63. Galant SP, Bullock J, Frick OL. An immunological approach to the diagnosis of food sensitivity Clin Allergy 1973;3:363-372. 64.Pachor ML, Andri L, Nicolis F, et al. [Elimination diet and challenge test in diagnosis of food intolerance.] Italian J Med 1986;21-6. 65. Treudler R, Tebbe 8 , Steinhoff M, et al. Familial aquagenic urticaria associated with familial lactose intolerance. J Am Acad Dermatol 2002;47611-613. 66. Zuberbier T, Pfrommer C, Specht K, et al. Aromatic components of food as novel eliciting factors of pseudoallergic reactions in chronic urticaria. J Allergy Clin Immunol2002;109:343-348. 67. H e m BM, Zuberbier T. Most chronic urticaria is food-dependent, and not idiopathic. Exp Dermatol 1998;7139-142. 68.Rawls WB, Ancona VC. Chronic urticaria associated with h y p d o r h y d r i a or achlorhydria. Rev Gastroenterol1951;18:267-271. 69. Baird PC. Etiology and treatment of urticaria: diagnosis, prevention and treatment of poison-ivy dermatitis. N Engl J Med 1941;224 649-658. 70. AUisonJR.The relation of hydrochloric acid and vitamin B complex deficiency in certain skin diseases. South Med J 1945;38:235-241. 71. Gloor M, Heinkel K, Schulz U. [Pathogenetic significance of gastric functional disorders in allergic, chronic urticaria.] Dermatol Monatsschr 1972;158:96-102. 72. Husz S, Berko G, Szabo R, et al. [Immunoelectrophoresis in the dermatologic practice. III. Dysproteinemias (chronic urticaria, drug allergy).] Dermatol Monatsschr 1974;160:93-100. 73. Ros AM, Juhlin L, Michaelsson G . A follow-up study of patients with recurrent urticaria and hypersensitivity to aspirin, benzoates and azo dyes. Br J Dermatol 1976;9519-24. 74. Doeglas HM. Dietary treatment of patients with chronic urticaria and intolerance to aspirin and food additives. Dermatologica 1977’;154:308-310. 75. Valverde E, Vich JM, Garcia-Calderon JV,et al. In vitro stimulation of lymphocytes in patients with chronic urticaria induced by additives and food. Clin Allergy 1980;10691-698. 76. Verschave A, Stevens E, Degreef H. Pseudo-allergen free diet in chronic urticaria. Dermatologica 1983;167256-259. 77. Juhlin L. Additives and chronic urticaria.Ann Allergy 198759119-123. 78. Zuberbier T, Chantraine-Hess S, Hartmann K, et al. Pseudoallergenfme diet in the treatment of chronic urticaria. A prospective study. Acta Derm Venereol (Stockh) 1995;75:484-487. 79. Lockey SD. Allergic reactions to F D and C Yellow No. 5, tartrazine, an aniline dye used as a coloring and idenhfymg agent in various steroids. Ann Allergy 1959;17719-721.

80. Collins-Williams C. Clinical spectrum of adverse reactions to tartrazine. J Asthma 1985;22.139-143. 81. Lessof MH. Reactions to food additives. Clin Exp Allergy 1995;25(S~ppl1):27-28. 82. Warrington RJ, Sauder PJ, McPhillips S. Cell-mediated immune responses to artificial food additives in chronic urticaria. Clin Allergy 1986;16527-533. 83. Natbony SF, Phillips ME, Elias JM, et al. Histologic studies of chronic idiopathic urticaria. J Allergy Clin Immunol 1983;71: 177-183. 84. Swain AR, Dutton SP, Truswell AS. Salicylates in foods. J Am Diet ASSOC1985;85:950-960. 85. Kulczycki A. Aspartame-induced urticaria. Ann Intern Med 1986; 104:207-208. 86. Moneret-Vauhin DA, Faure G, Bene MC. Chewing-gum preservative induced toxidermic vasculitis. Allergy 1986;41:546-548. 87.Yang WH, Purchase EC. Adverse reactions to sulfites. CMAJ 1985;133:865-880. 88. Birkmayer JGD, Beyer W. Biological and clinical relevance of trace elements. Artzl Lab 1990;36284-287. 89. Vaida GA, Goldman MA, Bloch KJ. Testing for hepatitis B virus in patients with chronic urticaria and angioedema. J Allergy Clin Imm~n011983;72193-198. 90. Schade C, Kaben U, Westphal HJ. [Occurrence of yeasts and therapeutic results in chronic urticaria.] Dermatol Monatsschr 1975; 161~187-195. 91. Holti G. Management of pruritus and urticaria. Br Med J 19671: 155-158. 92. Serrano H. [Hypersensitivity to “candida albicans” and other fungi in patients with chronic urticaria.] Allergol Immunopathol 1975;3:289-298. 93. James J, Warin RP. An assessment of the role of Candida albicans and food yeast in chronic urticaria. Br J Dermatol 1971;84: 227-237. 94. Rives H, Pellerat J, Thivolet J. [Chronic urticaria and Quincke’s oedema. 100 case reports. Allergology and therapeutic results.] Dermatologica 1972;144:193-204. 95. Vivarelli I, Mancosu A. [Data on 2 therapeutic trends in the treatment of urticaria. Desensitization to Candida. Use of vitamin K.] Minerva Dermatol 1967;42:441-442. 96. Westphal HJ, Schade C, Kaben U. [Specific desensitization in patients with chronic urticaria due to yeasts and intestinal colonization of yeasts.] Dermatol Monatsschr 1976;162:912-915. 97. Green G, Koelsche G, Kierland R. Etiology and pathogenesis of chronic urticaria. Ann Allergy 1965;2330-36. 98. Shertzer CL, Lookingbill DP. Effects of relaxation therapy and hypnotizability in chronic urticaria. Arch Dermatol 1987;123: 913-916. 99. Hannuksela M, Kokkonen EL. Ultraviolet light therapy in chronic urticaria. Acta Derm Venereol 1985;65:449-450. 100.Olafsson JH, Larko 0, Roupe G, et al. Treatment of chronic urticaria with PUVA or UVA plus placebo: a double-blind study. Arch Derm Res 1986;278:228-231. 101. Chapman EW, Maloof F. Bizarre clinical manifestations of hyperthyroidism. N Engl J Med 1956;254:1-5. 102. Caravati CM Jr, Richardson DR, Wood BT, et al. Cutaneous manifestations of hyperthyroidism. South Med J 1969;621127. 103. Isaacs NJ, Ertel NH. Urticaria and pruritus: uncommon manifestations of hyperthyroidism. J Allergy Clin Immunol 1971;48:73-81. 104. Rumbyrt JS, Schocket AL. Chronic urticaria and thyroid disease. Immunol Allergy Clin North Am 2004;24215. 105. LRnoff A, Sussman GL. Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients. J Allergy Clin Immunol1989;84:66-71. 106. Cusack C, Gorman DJ. Role of thyroxine in chronic urticaria and angio-oedema. J R Soc Med 2004;97:257.

107. Chen CJ, Yu HS. Acupuncture treatment of urticaria. Arch Dermatol 1998;134:1397-1399. 108. Chen CJ, Yu HS. Acupuncture, electrostimulation, and reflex therapy in dermatology. Dermatol Ther 2003;1687-92. 109. Lai X. Observation on the curative effect of acupuncture on type I allergic diseases. J Tradit Chin Med 1993;13:243-248. 110. Simon SW. Vitamin BI2 therapy in allergy and chronic dermatoses. J Allergy 1951;22:183-185. 111. Simon SW. Edmonds P. Cyanocobalamin (B12): Comparison of aqueous and repository preparations in urticaria; possible mode of action. J Am Geriatr Soc 1964;12:79-85.

112. Canonica GW, Ciprandi G, Bagnasco M, et al. Oral cromolyn in food allergy: in vivo and in vitro effects. Clin Immunol Immunopathol 1986;41:154-158. 113. Valks R, Conde-Salazar L, Cuevas M. Allergic contact urticaria from natural rubber latex in healthcare and non-healthcare workers. Contact Dermatitis 2004;50:222-224. 114. Kozel MM, Bossuyt PM, Mekkes JR, et al. Laboratory tests and identified diagnoses in patients with physical and chronic urticaria and angioedema: a systematic review. J Am Acad Dermatol2003; 48:409-416.

Uterine Fibroids Tori Hudson, ND CHAPTER CONTENTS Diagnostic Summary

2149

Nutritional Supplements 2151 Botanical Medicines 2151

General Considerations 2149 Diagnosis

2150

Therapeutic Considerations 2150 Diet 2150

DIAGNOSTIC SUMMARY Majority are asymptomatic. Symptoms include vague feeling of discomfort, pressure, congestion, bloating, heaviness; can include pain with vaginal sexual activity, urinary frequency, backache, abdominal enlargement, and abnormal bleeding. *Abnormal bleeding occurs in 30% of women with fibroids. Fibroids can undergo degenerative changes with necrosis, resulting in cystic degeneration. Calcification can occur. Examination by pelvic palpation and/or pelvic ultrasonography. The main diagnostic consideration is differentiating a possible fibroid from: ovarian malignant tumor, abscess in the fallopian tube/ovarian region, diverticulum from the colon, pelvic kidney, endometriosis, adenomyosis, congenital anomalies, and uterine sarcoma.

GENERAL CONSIDERATIONS Uterine fibroids are not actually fibrous but consist of muscle, probably both smooth muscle cells and connective tissue. The growth of fibroids is thought to be stimulated by estrogen. The tendency of fibroids to arise during the reproductive years, grow during pregnancy, and regress postmenopausally implicates estrogen as one factor in their cause and growth. Fibroids often demonstrate a growth spurt in the perimenopausal years, likely because of anovulatory cycles with a relative estrogen excess that commonly occurs irregularly during this time.

Therapeutic Approach 2153 Diet 2153 Nutritional Supplements 2153 Herbal Medicines 2153 Topical Treatment 2153

Uterine fibroids occur in 20% to 25% of women by age 40 and in more than 50% of women overall, with African American women experiencing a higher incidence. Fibroids are the most common indication for major surgery in women and the most common solid tumor in women. The cause of uterine fibroids remains poorly understood. Increases in local estradiol concentration within the fibroid itself may play a role in the cause and growth. Concentrations of estrogen receptors in fibroid tissue are higher than in the surrounding myometrium but lower than in the endometrium. Fifty percent to 80% of fibroids do not cause symptoms. Abnormal bleeding, including menorrhagia and metrorrhagia, occurs in 30% of women with fibroids. Other symptoms are pelvic pressure, bloating, congestion, urinary frequency, backache, and pain with vaginal sexual activity. Sometimes the urinary complications may be cause for concern because they may be due to compression of the ureter, which can then cause hydronephrosis. Fibroids are thought to be the cause of 2% to 10% of cases of infertility. Large fibroids can also interfere with a normal pregnancy, by interfering with fetal growth or causing premature rupture of membranes, retained placenta, postpartum hemorrhage, abnormal labor, or an abnormal fetal lie. The incidence of miscarriage due to fibroids is estimated to be two to three times greater than in women without fibroids. Fibroids can undergo degenerative changes. One type of degenerative change occurs when the continued growth of the fibroid outgrows the blood supply. A more common type of degenerative change involves a loss of cellular detail as a result of a decrease in the 2149

Specific Health Problems vascularity of the tumor. Necrosis leads to cystic degeneration. Calcification can occur over time and is usually seen in postmenopausal women.

DIAGNOSIS On the basis of mitotic count, nuclear atypia, and other morphologic features, uterine smooth muscle tumors can be classified as leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMPS),and leiomyosarcomas (LMSs). A presumptive diagnosis of fibroids can often be made simply with a thorough history and adequate pelvic examination. An enlarged firm uterus or a uterus with irregular edges is the main palpation finding. The diagnostic consideration that the practitioner needs to determine is differentiating a possible fibroid from ovarian malignant tumor, fallopian tube or ovarian region abscess, diverticulum, pelvic kidney endometriosis, congenital anomalies, pelvic adhesions, and rare retroperitoneal tumors. Not all of these distinctions can be made with a medical history, physical examination, and pelvic ultrasonography. Submucosal pedundated fibroids can be visualized with laparoscopy, as can intramural and subserous fibroids. Uterine fibroids are classified according to their location, as follows:

Submucosal (just under the endometrium) Intramural (within the uterine muscle wall) Subserosal (from the outer wall of the uterus) Interligamentous (in the cervix between the two layers of the broad ligament) Pedunculated (on a stalk, either submucosal or subserous)

THERAPEUTIC CONSIDERATIONS Natural therapies for uterine fibroids largely involve managing any troublesome symptoms. Women who are seeking an alternative to surgical intervention for uterine fibroids will not find a reliable alternative to shrink their tumors. The following therapies may be able to help to keep a fibroid from growing larger and are usually able to successfully m l v e or improve most symptoms related to the tumor. Expectations to reduce the size of fibroids need to be low, although there are individual case reports of such results. Reduction in fibroid size due to treatment is difficult to assess, especially in perimenopausal women in their &,who at some point will have lower endogenous estrogen production, with resultant diminution of the fibroid.

Diet Dietary change by itself is unlikely to reduce the size of fibroids, but good dietary habits are still important. Clinical observation has demonstrated that all natural

therapies work best in the context of a healthy lifestyle, including dietary changes. Improving one’s diet can help decrease heavy bleeding or the pain and discomfort caused by the fibroids. Besides these potential benefits, dietary improvements enhance general well-being. The tradition of naturopathic medicine holds fondly to the influence of the health of the liver on the health and vitality of an individual. The liver metabolizes estrogen, so it can be eliminated from the body, by converting it to estrone and finally to estriol, a weaker form of estrogen that has very little ability to stimulate the uterus. Failure of the liver to effectively metabolize estradiol may be one mechanism by which the uterus becomes overestrogenized and responds with fibroid growths. Saturated fats, sugar, caffeine, alcohol and ”junk foods” are presumably problematic in two main ways. First, they interfere with the body’s ability to metabolize estradiol to estrone to estriol. Second, some of them are deficient in vitamin B or interfere with B vitamin metabolism. If B vitamins are lacking in the diet, the liver is missing some of the raw materials it needs to carry out its metabolic processes and regulate estrogen levels. Diets high in whole grains such as brown rice, oats, buckwheat, millet, and rye are excellent sources of B vitamins. Whole grains also help the body excrete estrogens through the bowel. The role of whole grain fiber in lower estrogen levels was first reported in 1982.’ The study found that vegetarian women who eat a high-fiber, lowfat diet have lower blood estrogen levels than omnivorous women with low-fiber diets. Once again, the logic of a high-fiber diet would have implications in preventing and perhaps reducing uterine fibroids through the stimulating effect of estrogen on fibroid growth. A high-fiber diet may also help relieve some of the bloating and congestion associated with some fibroids. By bulking up the stool and regulating the bowel movements, some of these symptoms may improve. Some women have a hard time tolerating increased fiber in their diet because they have some other compromise in their digestive function. Because there is an association between having uterine fibroids and a fourfold increase in the risk of endometrial cancer,’ three dietary considerations stand out above the others: to increase dietary fiber, lower dietary fat, and increase the intake of soy products and other legumes. A case-control study in a multiethnic population (Japanese, white, Native Hawaiian, Filipino, and Chinese) examined the role of dietary soy,fiber, and related foods and nutients on the risk of endometrial cancer.2 Three hundred h r t y - t w o women with endometrial cancer were compared with women in the general multiethnic population, and all women were interviewed by means of a dietary questionnaire. The researchers found positive associations between a higher level of fat intake and endometrial cancer, between a higher level of fiber intake and a reduction in risk

Uterine Fibroids

for endometrial cancer, and between a high consumption of soy products and other legumes and a d-ased risk of endometrial cancer. Similar reductions in risk were found for greater consumption of other sources of phytcestrogens, such as whole grains, vegetables, fruits,and seaweeds. The researchers concluded that plant-based diets low in calories from fat, high in fiber, and rich in legumes (especially soybeans), whole-grain foods, vegetables, and fruitsreduce the risk of endometrial cancer. These dietary associations may explain at least in part the lower rates of uterine cancer in Asian countries than in the United States. Some have suggested that since soy foods are high in phytoestrogens (specifically isoflavones), which have a weak estrogenic effect, women with uterine fibroids or endometrial cancer should avoid phytoestmgens. This issue deserves some clarification. Soy phytoestrogens do not appear to have an estrogenic effect on the human uterus, except in doses higher than 150 mg isoflavones/ day in postmenopausal women. They appear to be selective in terms of the tissues in which they have an estrogenic effect and the tissues or organs in which they have an antiestrogenic effect. Soy foods may be analogous to a newer class of drugs called selective estrogen receptor modulators (SE W ); they act one way in one part of the body and another way in a different part of the body. It seems that in the uterus, soy isoflavones have a n antiestrogeniceffect.

Nutritional Supplements Many of the symptoms related to uterine fibroids can be effectively treated with natural therapies. This section presents nutritional supplements that may favorably affect the growth of fibroids. Unfortunately, these recommendations are based more on tradition, theory, logic, and clinical experiences than on scientific evidence.

Lipotropic Factors Supplements such as inositol and choline exert a ”lipotropic”effect-that is, promoting the removal of fat from the liver. Lipotropic supplements usually are a combination vitamin-and-herbal formulation and sometimes an animal liver extract designed to support the liver’s function in removing fat, detoxifying the body’s wastes, detoxifying external harmful substances (pesticides, fossil fuels, etc.), and metabolizing and excreting estrogens. These lipotropic products vary in their formulations depending on the manufacturer, but they are all similar and have the same uses in mind.

and dissolve the fibroids. When used for this purpose, the pancreatic enzyme supplement must be taken between rather than with meals.

Botanical Medicines Traditional Herbs Many plants have been used in traditional herbal medicines in an attempt to treat women with uterine fibroids. The plants and herbal formulations described here are used to attempt to reduce uterine fibroids or slow their growth. They have been anecdotally reported to achieve modest success in reducing the size and number of uterine fibroids. There is no scientific research to document the outcomes, but I present the protocol here as an option for consideration:

Scudder’s Alterative Scudder’s alterative should be used at 30-40 drops in a small amount of warm water tid. Its components are as follows: Corydalis tubers (Dicentra canadensis) Black alder bark (Alnus serrulata) Mayapple root (Podophyllurn peltaturn) Figwort flowering herb (Scrophularia nodosa) Yellow dock root (Rurnex crispus)

Compounded EchinacealRed Root Echinacea (Echinacea spp.) Red root (Ceanothus arnericunus) Baptisia root (Baptisiu tincforia) Thuja leaf (Thuju occidentalis) Stillingia root (Stillingiu sylvaticu) Blue flag root (Iris versicolor) Prickly ash bark (Xunthoxylurnclava-herculus) Compounded FraxinuslCeonothus The constituents of compounded FraxinuslCeonothus are as follows: Mountain ash bark (Fraxinus arnericanus) Red root (Ceanothus arnericanus) Life root (Senecio aureus) Mayapple root (Podophyllurn peltaturn) Helonias root (Charnaeliriurnluteurn) Goldenseal root (Hydrastis canadensis) Lobelia (Lobelia in$&) Ginger root (Zingiber oficinalis)

Pancreatic Enzymes Supplementation with pancreatic enzymes is usually done to treat pancreatic insufficiency with symptoms of abdominal bloating, gas, indigestion, undigested food in the stool, and malabsorption. The logic for the treatment of uterine fibroids is the assertion is that the pancreatic enzymes help digest the fibrous/smooth muscle tissue

Compounded GelsemiumPhytolacca Compounded Gelsemiurn/Phytolacca is also known as the Turska formula; it has the following constituents: Gelsemium root (Gelsemiurn sernpervirens) Poke root (Phytolaccu arnericana)

Specific Health Problems Aconite (Aconitum napellus) Bryonia root (Bryoniu dioicu)

Other Herbal Extracts to Consider Chaste tree (Vitex ugnus castus) Nettles (Urticu dioicu) Burdock root (Arctiurn Zappa) Dandelion root (Turuxucurn oficinulis) Oregon grape (Berberis aquifoliurn) Topical Applications Poke root oil: Rub onto the belly over the uterus nightly before bed. Castor oil packs: Apply over pelvis 3 to 5 times/week.

Herbal Phytoestrogens Three types of phytoestrogens are found in medicinal plants: resorcylic acid lactones, steroids and sterols, and phenolics. Phytoestrogens are present in virtually every plant in at least modest levels, with some plants having particularly high levels. Resorcylic acid lactones are not true phytoestrogens, because they come from plant mold contamination rather than being synthesized by the plant. Steroids are the classic steroidal estrogens, estradiol and estrone, which are found in very minute amounts in a few plants such as apple seeds, date palms, and pomegranate seeds in the range of 1 to 10 parts per billion."5 Diosgenin is a steroid derivative found in at least 20 plants, including wild yam species. Beta-sitosterol is the most common phytosterol and hence is distributed widely through the plant kingdom. It is found in plants oils, such as wheat germ oil, cottonseed oil, and soybean oil, and is the dominant phytosterol found in garlic and onions. Herbal sources include licorice root, saw palmetto, and red clover. Stigmasterol is closely related to beta-sitosterol. Soybean oil is an important source of stigmasterol and it is a better source for laboratory synthesis of progesterone than beta-sitosterol. Some herbal sources are burdock, fennel, licorice, alfalfa, anise, and sage. The phenolic phytoestrogens are members of the largest single family of plant substancesthe flavonoids, which has over 4,000 individual members. The term flavonoid derives from the Latin fluvus, meaning "yellow," because the flavonoids are responsible for the yellow, red, white, and blue pigments in plants. Phenolics include the following substances: Isoflavones, which are present in higher concentrations in legumes, especially soybeans, than in any other plants Coumestans, of which coumestrol is the one known estrogenic member; coumestrol is approximately six times more estrogenic than the isoflavones6 Lignans, found in high concentrations in grains and cereals, and highest in flaxseeds

There has been some concern and controversy about how phytoestrogens affect the uterus as well as whether, because they have an estrogenic effect, they should be avoided in women with uterine fibroids or endometrial cancer. Research has shown that phytoestrogens actually reduce the incidence of uterine cancer. Most of the research on the effects of phytoestrogens on the uterus is found in relationship to the agricultural industry and the health of grazing animals. In the 1940s, it was reported that the grazing of sheep on red clover in Australia was responsible for their infer ti lit^.^ A Finnish study of pasture legumes identified red clover as containing the highest concentrations of phytoestrogensS and showed that abundant intake of red clover resulted in fertility problems in ~ a t t l e . ~ In one study on the effects of phytoestrogens in sheep, it was noted that both coumestans and isoflavones produce changes similar to stimulation with steroidal hormones such as estradiol in all of the target organs.1° Among these changes was an increase in uterine weight. Other investigators have examined the binding of phytoestrogens to the uterus and vagina. Coumestrol has temporarily enhanced the uptake of estradiol by the uterus and vagina only 1 hour after injection into mice." The researchers of this study also noted that coumestrol actually inhibited the uptake of estradiol by the uterus in a prolonged manner, and they postulated that there was actually an inhibitory effect at the estradiol receptor sites. Other researchers have observed that coumestans and isoflavones compete with estradiol for uterine receptor sites but have less affinity for them than estradiol. l2 Coumestrol has been found to increase uterine weight at a 100-pg dose when given to rats at a certain time in the development of glands.13 The estrogenic effect of phytoestrogens appears to be dose dependent. When given in high enough doses, phytoestrogens have estrogenic effects on all the tissues that are targets of estradiol. Two questions must be answered: What is an excessively high dose? and Are the observations in animals translatable to humans? One way of answering the first is to note that countries with a high intake of phytoestrogens (Japan, Thailand, China) do not have an increase in rates of uterine fibroids. Like breast cancer, data on women of different cultures support the conclusion that soy phytoestrogens are not an estrogen stimulus for the endometrium. Soy is probably an estrogen antagonist in the uterus, at least in doses of less than 150 mg/day, and associated with low rates of endometrial cancer in countries where soy phytoestrogen intake is high.I4 One recent study did raise some concern about high doses of soy phytoestrogens and endometrial effects.15 Two hundred ninety eight women completed a 5-year study of either 150 mg/day of soy isoflavones or placebo tablet. Seventy percent of women using 150 mg of soy isoflavones had an endometrium classified as atrophic

Uterine Fibroids versus 81% receiving the placebo. The occurrence of endometrial hyperplasia was higher in the soy group versus the placebo group as well. (3.37%vs. 0%). There were no endometrial cancers in either group. The estrogenic effect was not detectable at 30 months but only at the end of the study of 5 years.

Tripteygium wilfordii Hook. f. An uncontrolledbut well-designed study looked at the efficacy of a traditional Chinese herbal therapy, Tripterygiurn wilfordii Hook. f., on uterine fibroids.16The researchers utilized several objective measures for clinical response, including ultrasonographic measurement of fibroid size and determination of blood estradiol, progesterone, testosterone, follicle-stimulatinghormone (FSH), luteinizing hormone (LH), and prolactin levels by radioimmunoassay. Measurements were taken at baseline and 3 and 6 months. Treatment was effective and time-dependent; 28% of fibroids responded in 3 to 4 months and 52"/0in 5 to 6 months. Twenty-fiveof the 65 patients were amenorrheic during the course of treatment. Compared with pretreatment values, treatment with T. wilfordii Hook. f. induced a rise in mean LH and FSH levels and a decrease in mean estradiol and progesterone levels. The researchers speculated that the treatment effect was likely due to a reversible inhibitory effect on the o v q .

Natural Progesterone Several older studies have suggested that progesterone may inhibit growth of uterine fibroids. Lip~chutz'~ demonstrated that progesterone administered to guinea pigs prevented formation of tumors that had been induced by estrogen. In 1946 Goodmanls reported six cases of clinically diagnosed uterine fibroids that regressed after use of progesterone therapy. The issue of uterine fibroid estrogen and progesterone receptor site expression and responsiveness to these hormones is c~mplex.'~ Leez0posed that because uterine fibroids are a result of estrogen stimulation, and what he calls "estrogen dominance," the problem is a relative progesterone deficiency and the corrective solution is to use natural progesterone. He asserted that estrogen dominance is a much greater problem than recognized by conventional medicine: Since many women in their midthirties begin to have nonovulating cycles, they are producing much less progesterone than expected, but still producing normal (or more) estrogen. They retain water and salt, their breasts swell and become fibrocystic, they gain weight (especially around the hips and torso), they become depressed and lose sex drive, their bones suffer mineral loss, and they develop fibroids. All are signs of estrogen dominance relative to a progesterone deficiency. When sufficient natural progesterone is replaced, fibroid tumors no longer grow in size (they generally decrease in size) and can be kept from growing until menopause, after which they will atrophy. This is the effect of reversing estrogen dominance.

The preferred form of natural progesterone for treating fibroids (unless the patient has heavy bleeding) is a topical cream with about 400 mg of progesterone per one ounce of cream. The cream is to be applied l/4 tsp one to two times daily for 1 week after the menses, and then l/4 to l/2 tsp twice daily for the next 2 weeks (the second half of the cycle). The progesterone cream is not used for 1week, during the menstrual flow. The cream is applied to the inner arms, chest, inner thighs, and/or palms. Another theory and counter-opinion about the relationship of progesterone to uterine fibroids raises some questions about the use of the hormone in women with uterine fibroids. Rein et aP1 at Brigham and Women's Hospital published a report in 1995 stating that not only is there no evidence that estrogen directly stimulates myoma growth, but progesterone and progestins promote the growth of fibroids.21They cite the biochemical, histologic, and clinical evidence supporting an important role for progesterone and progestins in the growth of uterine myomas. Their comprehensive hypothesis is based on an analysis of many different technical studies, which they conclude suggests that the development and growth of myomas involve a multistep chain of events.

THERAPEUTIC APPROACH Diet The patient should consume a diet low in fat and high in fiber, whole grains, flaxseeds, and soy foods and should avoid saturated fats, sugar, caffeine, and alcohol.

Nutritional Supplements Lipotropic factors: 1to 4 tablets/day with meals Pancreatic enzymes: 2 to 4 capsules 3 times/day between meals Scudder's alterative: 30 to 40 drops in small amount of warm water, 3 times/day

Herbal Medicines Echinacea/red root compound: 30 drops in small amount of warm water, 3 times/day Fruxinus/Ceonothus compound: 30 drops in small amount of warm water, 3 times/day Turska formula: 5 drops in small amount of warm water, 3 times/day

Topical Treatment Natural progesterone cream: */4 tsp 2 times daily from day 15 to day 26

Surgery Some women will need to consider their surgical options, which are based on the size, number, and location of fibroids, as follows: Myomectomy

Specific Health Problems

Laparoscopic surgery for subserous and pedunculated fibroids Uterine embolization

1. Goldin B, Allercreutz H, Gorbach SL, et al. Estrogen excretion patterns and plasma levels in vegetarian and omnivorous women. N Engl J Med 1982;3071542-1547. 2. Goodman MT, Wilkens LR, Hankin JH, et al. Association of soy and fiber consumption with the risk of endometrial cancer. Am J Epidemiol1997;146:294306. 3. Dean D, Exley D, Goodwin T. Steroid oestrogens in plants: re-estimation of oestrone in pomegranate seeds. Phytochemistry 1971;lO 22152216. 4. Verdeal R, Ryan D. Naturally-occurring oestrogens in plant foodstuffs-a review. J Food Protection 1979;42577-583. 5. Price K, Fenwick G. Naturally occurring oestrogens in foods-a review. Food Addit Contam 1985;2:73-106. 6. Miksicek R. Estrogenic flavonoids: structural requirements for biological activity. Proc Soc Exp Biol Med 1995;208:44-50. 7. Bennetts H, Underwood E, Shier F. A breeding problem of sheep in the south-west division of Western Australia. J Dept Agric West Aust 1946;23:1-12. 8. Saloniemi H, Wahala K, Nykanen-Kurki P, Saastamoinen I. Phytoestrogen content and effect of legume fodder. Proc Soc Exp Biol Med 1995;20813-17. 9. Kallela K, Heinonen K, Saloniemi H. Plant oestrogens: the cause of decreased fertility in cows. A case report. Nord Vet Med 1984;36: 124128. 10. A d a m N. Cervical mucus and reproductive efficiency in ewes after exposure to oestrogenic pashues. Aust J Agric Res 1977;28481-489. 11. Folman Y, Pope G. Effect of norethisterone acetate, dimethylstilbestrol, genistein, and coumestrol on uptake of oestradiol by uterus,

Hysteroscopic resection Supracervical hysterectomy Laparoscopy-assistedvaginal hysterectomy

vagina, and skeletal muscle of immature mice. J Endocrinol 1969;44:213-218. 12.Shutt D, Cox R. Steroid and phyto-oestrogen binding to sheep uterine receptors in vitro. J Endocrinol1972;52299-310. 13. Medlock K, Branham W, Sheehan D. Effects of coumestrol and equol on the developing reproductive tract of the rat. Proc Soc Exp Biol Med 1995;20867-71. 14. Parkin D, Muir C, Whelan S, et al, eds. Cancer incidence in five continents. Lyon: International Agency for Research on Cancer scientific Publications No. 120.1992;6301-431,486-509. 15. Unfer V, Casini M, Costabile L, et al. Endometrial effects of longterm treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil SterilZOO4;82( 1):145-148. 16. Gao Y, Chen D. [Clinical study on effect of Tripferygiurn wilfordii Hook. f. on uterine leiomyoma]. Zhonghua Fu Chan Ke Za Zhi 200035:430-432. 17. Lipschutz A. Experimental fibroids and the antifibromatogenic action of steroid hormones. JAMA 1942;120:171. 18. Goodman A. Progesterone therapy in uterine fibromyoma. J Clin Endocrinol Metab 1946;6402. 19. Bodner K, Bodner-Adler B, Kimberger 0, et al. Estrogen and progesterone receptor expression in patients with uterine smooth muscle tumors. Fertil Steril2004;81:1062-1066. 20. Lee J. What your doctor may not tell you about menopause. New York Warner Books, 1996. 21. Rein M, Barbieri R, Friedman A. Progesterone: a critical role in the pathogenesis of uterine myomas. Am J Obstet Gynecol1995;172:1418.

Vaginitis and Vulvovaginitis Tori Hudson, ND Paul Reilly, ND, LAC CHAPTER C O N T E N T S Diagnostic Summary

2155

Botanical Medicines 2161 Other Agents 2161

General Considerations 2155 Diagnostic Approach

Types of Vaginitis 2156 Hormonal Vaginitis 2156 Irritant Vaginitis 2156 Infectious Vaginitis 2156 Therapeutic Considerations 2159 Dietary Considerations 2159 Nutritional Supplements 2160

DIAGNOSTIC SUMMARY Increased volume of vaginal secretions. Abnormal color, consistency, or odor of vaginal secretions. Vulvovaginal itching, burning, or irritation. Introitus may show patchy erythema, and vaginal mucosa may exhibit congestion, or petechiae. Dysuria or dyspareunia may be present.

GENERAL CONSIDERATIONS Vaginitis, one of the most common reasons for women to seek medical attention, is the most common gynecologic problem encountered by physicians providing primary care to women. It affects all age groups and has a variety of etiologies.An initial vaginitis may be easily diagnosed if the practitioner utilizes objective tools and easily treated, but recurrent vaginitis can be among the most troublesome and challenging conditions for both practitioners and patients. Early misdiagnosis leads to repeat office visits as well as inappropriate or delayed treatment. Undetected coinfections or an incorrect diagnosis can also have consequences, sometimes serious, especially in pregnant women. In addition to causing physical discomfort and embarrassment, vaginitis is medically important for several reasons. It may coexist with cervicitis and may be related to a sexually transmitted disease, and some organisms may

2162

Therapeutic Approach 2162 Diet 2162 Supplements 2162 Botanical Medicine 2163 Topical Treatments 2163 General Recommendations 2163 Specific Recommendations 2164

be able to ascend and cause pelvic inflammatory disease (PID). PID may in turn lead to tuba1 scarring, infertility, or ectopic pregnancies. Chronic asymptomatic vaginal infections have been implicated in recurrent urinary tract infections through their action as reservoirs of the infectious agent.'P2 Some types of vaginal infections such as bacterial vaginitis (BV) during pregnancy are associated with preterm delivery, premature rupture of membranes, amnionitis, chorioamnionitis, and postpartum endometritis and, if present at delivery, may be associated with an increase in the incidence of neonatal infections, with potentially serious or fatal consequences. The vaginal ecosystem is an environment consisting of an important relationship between normal endogenous microflora, metabolic products of the microflora and the host, estrogen, and the pH level. The normal microflora of a healthy vagina is made up of numerous microorganisms, including Candida, Lactobacillus spp., and gramnegative aerobicbacteria, facultative (Mycoplasm spp. and Gardnerella vaginalis) and obligate anaerobic bacteria (primarily Preuotella, Peptostreptococcus spp.,E ubacterium spp., and Mobiluncus). Lactobacillus spp. dominate the healthy vagina, and although it is difficult to say with certainty which species are most common, molecular biology methods have found that Lactobacillus plantarum, Lactobacillus fermentum, and Lactobacillus acidophilus are the most c011unon.~Other species of Lactobacillus may be more signhcant due to their production of H202;these include Lactobacillus rhumnosus, Lactobacillus casei, and 2155

Specific Health Problems LactobaciZZus bulgaricus. The production of H202and lactic acid by the Lactobacillus spp. then maintains the acidic environment of the vagina.

TYPES OF VAGINITIS The three general categories of vaginitis are hormonal, irritant, and infectious. Each is further divided into several specific subgroups on the basis of etiology.

Hormonal Vaginitis Atrophic Vaginitis Atrophic vaginitis is primarily a problem of perimenopausal and postmenopausal women. The vagina undergoes several changes with declining estrogenic stimulation, including a decrease in Lactobacillus spp. in the vagina, a shift to a more alkaline pH, vaginal thinning, less lubrication, more easily irritated and inflamed tissue, and greater susceptibility to infection. The most commonly reported symptoms are itching or burning and a thin watery discharge that may occasionally be blood tinged. (Note that any vaginal bleeding in a postmenopausal woman requires a complete evaluation to rule out the presence of endometrial hyperplasia and endometrial carcinoma.) For a more extensive discussion, see Chapter 189. Prepubescent girls may also experience atrophic vaginitis because of poorly estrogenized vaginal and vulvar tissue.

Increased Vaginal Discharge When increased quantities of normal secretions exist in the absence of other symptomatology, the diagnosis of "physiologic vaginitis" is often applied.This is inappropriate, because no inflammation actually exists. The greater discharge frequently reflects increased hormonal stimulation, such as occurs during pregnancy and at some stages of the menstrual cycle. It is primarily a diagnosis of exclusion after other causes have been d e d out. In most cases, no further treatment is required other than reassurance that the discharge is normal. Overly zealous douching or washing briefly alleviates symptoms but may ultimately aggravate the situation by causing an irritant vaginitis.

Irritant Vaginitis Irritant vaginitis is caused by physical or chemical agents that damage the delicate membranes of the vagina. In most cases, the cause is easily identified through careful history and physical examination. Even semen may be an irritant cause of vaginitis in some women.

Chemical Vaginitis Chemical vaginitis is due to the use of medications or hygiene products that directly irritate the vaginal mucosa. A variant of this subgroup is allergic vaginitis, in which the damage is elicited by an immunologic reaction to a

product rather than a direct toxic reaction. Perfumed toilet paper, douches, spermicides, condoms, and lubricants are examples of irritating agents that can cause vaginitis.

Traumatic Vaginitis Injury caused by physical agents or sexual activity can cause vaginitis.

Foreign Body Vaginitis A foul-smelling discharge may signal the presence of a foreign body in the vagina-the most common being a forgotten tampon. Contraceptive devices, pessaries, and a wide variety of other items may also be found upon examination. Very young girls and adolescents may leave foreign bodies in their vaginas as a result of exploring their bodies and then either forget about them or are embarrassed to tell someone that they cannot retrieve the items.

Infectious Vaginitis More than 90% of vaginitis in reproductive-agedwomen in caused by BV, candidiasis, or trichomoniasis. BV is the most common of the three. Less common causes of infectious vaginitis include herpes simplex virus, gonorrhea, and chlamydia. Infections of the vulva can cause local itching and/or discharge, including folliculitis, hydradenitis, scabies, condyloma, herpes, syphilis, and Candidu. Rare conditions of the vulva causing itching and/or discharge include chancroid, lymphogranuloma venereum inguinale, and molluscum contagiosum. Infectious vaginitis may be sexually transmitted or may arise from a disturbance to the delicate ecology of the healthy vagina. Va@ "infections" frequentlyinvolve common organisms found in the cervix and vagina of many healthy, asymptomatic women! The urufying factor in the pathogenesis of vaginal infections is not so much which organisms are present in the patient's genital tract but rather what happens to the patient to make her susceptible to infection. Factors influencing the vaginal environment are the pH, glycogen content, glucose level, presence of other organisms (particularly lactobacilli), natural flushing action of vaginal secretions, presence of blood, and presence of antibodies and other compounds in the vaginal secretions. Many of these factors are, in turn, affected by the woman's internal milieu and general health. Immune dysfunction may predispose a woman to increased infections, including vaginal infections. Depressed immunity may occur as a result of nutritional deficiencies,medications (e.g., steroids),pregnancy, or serious illness. Other medical conditions may predispose a woman to infectious agents, such as diabetes mellitus, hypothyroidism, leukemia, Addison's disease, Cushing's syndrome, and pregnancy. Predisposing factors for sexually transmitted infections include higher numbers of sexual partners, unsafe sex,

Vaginitis and Vulvovaginitis Diagnostic differentiation of common causes of infectious vaginitis

Keynote symptom(s) Discharge PH Odor Appearance

Candida

NSV

Trchomonas

Gonorrhea

HerDes

Chlamvdia

Itching

Odor

Odor and itching

Asymptomatic or cervicitis

Vesicles or ulcers

Asymptomatic

4.5

A.5

>5.0

<4.5

4.5

4.5

None Curdy, adherent, scant to thick

Fishy/amines

May be fishy

None

None

None

Gray, homogeneous

Greenish yellow, frothy May show petechial lesions on cervix or vagina mucosa; a "strawberry cervix"

Mucopurulent cervicitis

None

None

Cervical discharge; may have adenexal tenderness

Small, multiple vesicles or ulcers on cervix or vulva

Unremarkable or may show signs of pelvic inflammatory disease

Pelvic examination

Adherent white patches with an erythematous border

Unremarkable

Microscopic examination

Mycelia (10% KOH)

"Clue cells"; few white blood cells (WBCs)

Motile, flagellated organisms; few WBCs

Many WBCs with gram-negative intracellular diplococci

Unremarkable

Unremarkable

Culture media

Sauerbaud

CNAF

Diamond

Thayer-Martin

Live cell

Live cell or antibody test

NSV Nonspecific vaginitis.

birth control pills, steroids, antibiotics, tight-fitting garments, occlusive materials, douches, chlorinated pools, perfumed toilet paper, and decrease in Lactobacillus in the vagina. Table 215-1 summarizes the diagnostic differentiation of the most common causes of infectious vaginitis.

Trichomonas vaginalis Trichomonus vuginuIis is a flagellated protozoan slightly larger than a leukocyte. It may be found in the lower urogenital tract of both men and women. Humans appear to be its only host, and sexual transmission appears to be its primary mode of dissemination. Tichomonus does not invade tissues and rarely causes serious complications. The most common symptom is leukorrhea associatedwith itching and burning.The dd-targe is frequently malodorous, greenish yellow, and frothy. The "strawberry cervix" with punctate hemorrhages is found in only a small percentage of T'chomoms cases. Trichomonads grow optimally at a pH of 5.5 to 5.8: Thus, conditions that elevate the pH, such as increased progesterone, will favor overgrowth of Trichomonus.Conversely, a vaginal pH of 4.5 in a woman with vaginitis is suggestive of an agent other than Trichomonus. A saline wet mount of fresh vaginal fluid demonstrates the presence of small motile organisms to confirm the diagnosis in 80%to 90% of symptomatic carrier^."^

Candida albicans Both the relative frequency and the total incidence of candidal vaginitis have risen dramatically, 2.5-fold, in the past 20 years. This increaseparallels a declining incidence Several factors have of gonorrhea and Trichornon~s.~

contributed to this increased incidence, chief among them being the greater use of antibiotics. The alterations that antibiotics make in both intestinal and vaginal ecology favor the growth of Cundidu. In the 1970s,Miles et a17 found a 100% correlation between genital and gastrointestinal Cundidu cultures, leading to the suggestion that significant intestinal colonization with Cundidu may be the single most sigruficantpredisposing factor in vulvovaginal candidiasis. However, this suggestion has not been confirmed by adequate research. Steroids, oral contraceptives, and the continuing rise in incidence of diabetes mellitus all contribute to the problem. Cundida is 10 to 20 times more common during pregnancy,owing to the elevated vaginal pH, increased vaginal epithelial glycogen, elevated blood glucose, and intermittent glycosuria. Yeast infections are three times more prevalent in women wearing pantyhose than those wearing cotton underwear, because the pantyhose prevents drymg of the area.9 A woman who has four or more episodes of vulvovaginal candidiasis within 1 year is classified as having recurrent disease. Many cases of recurrent yeast infections may be caused by non-ulbicuns strains of Cundidu. These resistant strains have become more problematic in recent years as women have used more and more an%gal agents (see Box 215-1). There are three main theories to explain why women have recurring yeast vaginitis:One is the intestinal reservoir theory, which hypothesizes that a patient's r e i n d a t i o n is due to Cundidu populating in the gastrointestinal tract and migrating into the vagina. The sexual transmission theory points to the possibility that the sexual partner is the source of the recurrence.

Specific Health Problems

Allergies Antibiotics Diabetes mellitus Elevated vaginal pH Gastrointestinal candidiasis Oral contraceptives Pantyhose Pregnancy Steroids

The vaginal relapse theory maintains that some women maintain small numbers of yeast, even after treatment, that later cause a symptomatic episode. A considerable body of research supports this last theory.'O*" These studies include immunologic research suggesting that women with recurrent infections have an abnormal immune response to infection that leaves them susceptible to further episodes.12 The primary symptom of candidal vaginitis is vulvar itching, which can be quite severe. Burning of the vulva may also be experienced and can be exacerbated by urination or vaginal sexual activity.It is also common to have an increase or change in the consistency of the vaginal discharge. In a classic case, this is associated with the presence of a thick, curdy, or "cottage cheese" discharge that adheres to the vaginal walls. The presence of such a discharge is strong evidence of a yeast infection, but its absence does not rule out Cundidu. Fewer than 20% of symptomatic patients with Cundidu infection actually display classic thrush patches. Other clues to a candidal etiology are the presence of erythema of the vulva and excoriations due to scratching. The vaginal pH is not usually altered. Neither the character of the discharge nor the symptomatology is sufficient alone to make a diagnosis of Cundidu. A wet mount in saline or 10% KOH should always be performed, and the presence of mycelia confirmed. Budding forms of yeast may be found in both normal and symptomatic vaginas, but the mycelial stage is found only in symptomatic women.

Bacterial Vaginosis The term bacterial vuginosis has now been used most often to describe a shift in flora from a predominance of lactobacilli to a predominance of anaerobes and facultative bacteria that results in a degradation of the mucins that form a natural gel barrier on the vaginal epithelium. This destruction of the mucin layer causes a vaginal discharge characteristic of BV. In addition, destruction of these mucins exposes the cervical epithelium and allows other organisms to affect the cervix, resulting in the appearance of clue cells. The changes on the epithelial surface also cause immunologic shifts. Women with BV have an upregulation of interleukin-1-beta and a decrease in

protectant molecules such as secretory leukocyte protease inhibitor. Three main factors have been identified to explain how the shift from a lactobacilli-dominant environment to one in which the anaerobes and facultative bacteria dominate and therefore why some women experience BV-sexual activity, douching, and the absence of peroxide-producing lactobacilli in the vagina. A new sexual partner and frequent sexual activity are associated with an increased incidence of BV. Overall, sexual transmission of BV is not well understood. It may not be truly sexually transmitted but, rather, may occur by various other mechanisms other than sexual transmission of pathogens. Routine douching is associated with a loss of vaginal lactobacilli and the occurrence of BV. Women who douche regularly for hygiene purposes have BV twice as often as women who do not douche r0utine1y.l~ It is possible that women with an absence of peroxideproducing lactobacilli in the vagina did not have the normal habitation of lactobacilli at menarche, or perhaps the lactobacilli were present but were eliminated through the use of broad-spectrum antibiotics. Other factors have been associated with the development of BV. Cigarette smoking is associated with BV but may be related to the downregulation of the immune response. Racial background has also been associated with BV. Hispanic women are 50% more likely to have BV, and African American women are twice as likely.14 Although the reasons for these differences are not clear, we do know that African American women practice douching twice as often as white women and that African American women are less likely to have lactobacilli in the vagina. Examination for BV involves a medical history, observation of the discharge, and determination of vaginal pH. In the woman with symptomatic BV, the vagina has a fishy odor. The characteristic discharge is thin, dark, or dull gray. Itching is not common with BV but may be present if there is a profuse discharge. A whiff test should be performed, and a wet mount test to detect clue cells and observe the vaginal flora. An abundance of various bacteria and the absence or decrease in lactobacilliis consistent with a diagnosis of BV. The numbers of bacteria rise from 100-fold to 1000-fold. For a diagnosis of BV to be made, three of the following four criteria must be met: Thin, dark or dull gray, homogeneous, malodorous discharge that adheres to the vaginal walls Vaginal pH A.5 Positive KOH (whiff/amine) test result Presence of clue cells on wet mount microscopic examination

The pH is elevated to 5 to 5.5 in most cases, and there appears to be a correlation between elevated pH and the presence of 0d0r.l~

Vaginitis and Vulvovaginitis ' M e n a patient has four or more BV episodes in a year, her underlying problem is most likely an inability to reestablish a normal vaginal ecosystem with the dominant lactobacilli. There is no definition of recurrent BV but most clinicians would probably agree that more than four episodes in a year would define the disorder. About 30% of women experience a recurrence of symptomaticBV within 1 to 3 months, and about 70% have a recurrence within 9 rnonths.l6It is not always clear whether the recurrence represents a relapse or a reinfection. Another possibility is that a woman may be asymptomatic at times but, because of the abnormal vaginal ecosystem, she has a chronic underlying condition, so sometimes is symptomatic and at other times is not. Women who are asymptomatic, yet have no lactobacilli are four times more likely to experience BV. Unfortunately, we do not have a proven treatment for asymptomaticwomen. There are potential sigruficant consequences of altered vaginal flora in addition to susceptibility to BV. Women with BV and without sufficient lactobacilli are more susceptible to human immunodeficiency virus (HIV)and gon~rrhea.'~J~ PID is also associated with BV. There is also now good evidence that the organisms in pregnant women with BV can ascend the genital tract and cause preterm delivery, and such women are more likely to have postpartum endometritis. Women with BV are also at increased risk for infection after gynecologic surgery.

Gonorrhea Neisseria gonorrhoeue is an uncommon cause of vaginitis, responsible for less than 4% of cases. Gonococcal (GC) vaginitis is more common in young girls because the vaginal epithelium is thinner before puberty. During reproductive years, mucopurulent cervicitis is the primary symptom. Spread of the infection commonly causes other symptoms, such as urethritis, bartholinitis, or salpingitis, which finally prompt the seeking of medical treatment. Gonorrhea, either alone or in combination with other organisms, is cultured in 40% to 60%of cases of PID, a major cause of infertility. Because of the potential for serious sequelae, and the fact that up to 80% of gonorrheal infections in women are asymptomatic, all evaluations for vaginitis should include routine gonococcal cultures on Thayer-Martin medium. In addition, any purulent discharge from the cervical 0s should be cultured and examined microscopically. The presence of three or more polymorphonuclear leukocytes with gram-negative intracellular diplococci per high-power field is highly suggestive of GC, with a false-positive result rate less than 2%.

Herpes Simplex Herpes simplex infection is the most common cause of genital ulcers in the United States. Other causes to be ruled out are syphilis, chancroid, lymphogranuloma venereum,

and granuloma inguinale. For a more thorough discussion, see Chapter 174.

Chlamydia trachornatis Chlamydia trachornatis is an obligate intracellular parasite that rarely causes vaginitisbut is frequently found in association with other common etiologic agents. With the availability of better culture techniques and antibody tests, Chlamydia is now recognized as a major health problem in the United States and in most Western societies. Chlamydia infects 5% to 10Y0of women and is usually asymptomatic until the development of complications such as cervicitis, salpingitis, or urethritis. Certain populations have infection rates as high as W%.19Chlamydia is the organism most commonly recovered in cultures of women with and tubal scarring appears to be more frequent after chlamydial infection than after GC. Thus Chlamydia may be far more important in causing infertility and ectopic pregnancy than has been previously recognized. Chlamydia1infection during pregnancy raises the risk of prematurity and neonatal death. If a healthy baby is born to an infected woman, there is a 50% chance that the baby will have chlamydia1 conjunctivitis and a 10% chance of pneumonia. Because of the considerable risks of untreated Chlamydia, testing for this agent should be considered in all women with vaginitis, particularly those who are also pregnant.

THERAPEUTIC CONSIDERATIONS Dietary Considerations The internal milieu of the vagina is a reflection of the condition of the entire body. Vaginal secretions are continuously released that affect, and are affected by, the microbial flora. These secretions contain water, nutrients, electrolytes, and proteins, such as secretory immunoglobulin (Ig)A. The quantity and character of these components are altered by hormonal and dietary factors. A general healthful diet is recommended in all cases to ensure availability of all nutrients in sufficientquantity to optimize the body's ability to respond to changing conditions. A well-balanced diet low in fats, sugars, and refined foods is particularly important in vaginitis due to infectious organisms, particularly Candida. Patients with depressed immunity are susceptible to higher rates of infection, particularly those due to Candida, Trichornonas, and herpes (seeChapter 57 for further discussion of the effects of diet on immune function). Nutrients particularly important for proper immune function are zinc, vitamins A, C, and E, manganese, and vitamin B complex. A diet high in lysine-containing foods and low in arginine-containing foods reduces the number and severity of herpetic outbreaks.However, many of the foods high in lysine are animal products, which are also high in fats. A low-arginine diet combined with lysine supplements

Specific Health Problems ensures adequate levels of lysine without excessive intake of fats. No other food could be considered as specifically medicinal as Lactobacillus yogurt. A study was published in 1992 on the daily ingestion of yogurt containing L. acidophilus in women with recurrent candidal vaginitis. In the women who ate 8 oz of the yogurt daily, there was a threefold reduction in infections and in candidal colonization compared with the women who did not eat the yogurt.21

Nutritional Supplements For general maintenance of health and immune competence, a high-quality multivitamin and multimineral supplement provides low-cost compensation for most dietary inadequacies. In addition, the nutrients discussed here may be useful in one or more types of vaginitis.

Vitamin A and Beta-carotene Both vitamin and beta-carotene are necessary for normal growth and integrity of epithelial tissues, such as vaginal mucosa. Vitamin A is essential for adequate immune response and resistance to infection. Secretory IgA, a major factor in resistance to infection, is lower in vitamin Adeficient subjects.22Beta-carotene is a source of nontoxic vitamin A precursors. In addition, it has been shown to enhance T-cell numbers and to favorably alter their ratios.= Excessive vitamin A can be toxic and teratogenic. This is of particular concern in women of reproductive age. Total vitamin A intake should be limited to 5000 IU/day. If larger doses of vitamin A are used, patients should be cautioned to be particularly careful about contraception. Mixed carotenoids rather than synthetic beta-carotene should be used.

are also useful in diminishing the frequency and severity of herpetic ~ u t b r e a k s . ~ * ~

Vitamin E Lack of vitamin E depresses immune response and host resistance. This situation may be corrected by high doses of supplemental vitamin E. Several experiments have shown increased resistance to chlamydia1infection when subjects were supplemented with vitamin E. Vitamin E also regulates retinol in humans, and an inadequacy of vitamin E hinders the utilization of vitamin A, despite adequate retinol intake.30The use of vitamin E for treatment of atrophic vaginitis has been reported since the 1930s. Excessive vitamin E intake (>1200 IU/day), however, may be immunosuppressive and may transiently elevate blood pressure. This vitamin is reported to improve glycogen storage and the tone of heart muscle. Thus, extra caution should be exercised in patients with diabetes, hypoglycemia, hypertension, or heart disease. For such high-risk patients, supplementation should begin with a daily dose of 100 IU and, with monitoring of blood glucose or blood pressure values, the dosage should be increased slowly, over time (e.g., by 50 IU/day).

Zinc

All DNA and RNA polymerases and repair and replication enzymes require zinc. Zinc enhances prostaglandin (PG) El synthesis, normalizes lymphocyte activity, and enhances epithelial growth. Low levels of zinc are associated with depressed immunity and thymic atrophy, both of which are correctable when zinc is replenished. Zinc is also essential for proper utilization of vitamin A. Many otherwise well nourished adults receive less than 50% of the recommended dietary allowance of zinc from their diets and have one or more measurable signs of B Vitamins zinc defi~iency.~l-~~ Treatment with topical and oral zinc has been shown One or more of the B vitamins is used in virtually every to reduce the duration and severity of herpes outbreaks. metabolic activity of the body. B vitamins are needed for carbohydrate metabolism, protein catabolism and synThis effect may be due either to the effect of the zinc on thesis, cell replication, and immune function. Vitamins production of prostaglandins or to the direct antiviral activity of the zinc ion. High levels of zinc are also toxic B2 and B6 have been shown to have estrogen-like effects to Chlamydia and Trichomonas and have been used sucand to act synergistically with estradiol. Vitamin B1 and pantothenic acid enhance the action of estradiol, cessfully in vaginitis that did not respond to antibiotic although they have no estrogenic activity t h e m s e l v e ~ . ~ ~therapy.%% This finding suggests that B vitamins may be of use in Lysine estrogen deficiency conditions such as atrophic vaginitis, especially if combined with phytoestrogens. Oral supplementation with lysine has been shown to decrease the frequency and severity of herpes outbreaks Vitamin C and Bioflavonoids but not necessarily to shorten healing time. The postuVitamin C and bioflavonoids are essential in any process lated mechanism of action is that the lysine becomes related to immune function. Deficiency of vitamin C incorporated into the virus capsule in place of arginine, reduces the phagocytic activity of leukocytes. Both vitaresulting in an inactive virus. Lysine should be taken at min C and bioflavonoids improve connective tissue low doses prophylactically and at higher doses at the integriv, thus reducing spread of infection. Both nutrients first sign of prodromal symptoms, which correspond to

Vaginitis and Vulvovaginitis the time of greatest viral replication. Effectiveness is dose-related, and best results are obtained if lysine is combined with the low-arginine diet.39,40

Botanical Medicines Glycyrrhiza glabra Licorice (Glycyrrhiza glabru) has antiviral activity against RNA and DNA viruses and has been used successfully in the treatment of herpes. The number and severity of recurrences may be reduced by the repeated applications of licorice gel to active lesi0ns.4~The isoflavonoid compounds in licorice are reported to be effective against candid^.^^ (For further discussion see Chapter 99.)

Chlorophyll Chlorophyll has a bacteriostatic action and a soothing action. Water-soluble chlorophyllmay be added to douching solutions for symptomatic relief of vaginitis.-

Alliurn sativum Garlic (Alliurn sativurn), which is antibacterial, antiviral, and antifungal, has even been shown to be effective against some antibiotic-resistant 0rganisms.4~-~* The major growth-inhibitory component in garlic extract is allicin; therefore, garlic products with the highest amount of allicin are preferable. Garlic cloves may be carefully peeled so as not to knick them, then pierced with thread and used as a tampon. A garlic capsule may also be inserted into the vagina.

Hydrastis canadensis and Berberis vulgaris Goldenseal (Hydrasfis canadensis) and Oregon grape (Berberis vulgaris) contain berberine, which has a significant effect against many bacteria. Berberine enhances immune function when taken internally as a tea and offers symptomatic local relief when used in douching solutions, because it is soothing to inflamed mucous r n e m b r a n e ~(for ~ ~ -further ~ ~ discussion, see Chapter 100).

Estrogenic Plants Atrophic vaginitis is best treated with vaginal estrogenas a cream, suppository, tablet, or vaginal ring as used in conventional medicine. A few plants taken orally have been shown to have very modest effects on the vaginal epithelium, although they have not studied as true treatments for atrophic vaginitis. They include soy, ginseng, black cohosh, and flaxseeds. (See appropriate chapters in Section 5 on these plants for further discussion.)

Melaleuca alternifolia An alcoholic extract of the oil of the tea tree (Melaleucu alternifolia), diluted to 1%in water, exerts a strong antibacterial and antifungal action. It was shown in one study to be effective in treatment of trichomoniasis, candidiasis, and cervicitis. Treatment consists of daily douching

combined with saturated tampons used weekly. No adverse reactions were reported, and patients commented favorably on its soothing effect? (for further discussion, see Chapter 104).Various tea tree oil preparations have demonstrated antimicrobial activity against Sfaphylococcus aureus and C. albi~ans.5~

Melissa oflicinalis Melissa officinalis, a member of the mint family, has a long history of use as an antiviral agent. Studies conducted in Europe have shown that Melissa extracts are effective in controlling herpetic symptoms and reducing the frequency and severity of both oral and genital herpes lesions. Melissa may be taken orally in the form of water extracts or applied topically in the form of creams.58

Botanical Mixture Women with abnormal vaginal discharge who presented to a gynecologic clinic in India were randomly assigned to receive either a cream containingAzadirachtu indica (neem) seed oil, Sapindus mukerossi (reetha)saponin extract, and quinine, or placebo. They applied the cream intravaginally at bedtime for 14 days. The results were quite impressive. Symptomatic and microbial assessment showed that 10 of 12 women with C. trachomatis vaginitis recovered within 1 week, and 10 of 17 with bacterial vaginosis within 2 weeks. No benefit was found in women with candidal or trichomonal infections, and none of the women using the placebo recovered from any of the

Other Agents Lactobacillus Species As stated earlier, the desirable Lactobacillus spp. are an integral component of the vaginal flora. Lactobacilli help maintain a healthy vaginal ecology by preventing the overgrowth of less desirable species. They do this by the production of lactic acid and maintenance of an acidic pH, natural antibiotic substances, and peroxides. In addition, they compete with other bacteria through the utilization of glucose and have been shown to interfere with how pathogenic bacteria adhere to and colonize the cells of the vagina.@ Whenever there is a disturbance of the vaginal flora, reestablishment of the dominance of Lactobacillus spp. is of vital importance. It may be accomplished through the insertion of live Lactobucillus-culture yogurt (careful reading of labels is important, because most commercially available yogurts do not use lactobacilli), but a more efficient and less messy method is to insert one capsule of Lactobacillus into the vagina twice daily for 1 to 2 weeks. Although not well studied, this approach has been a common practice for most alternative practitioners. Oral and intravaginal administration of Lactobacillus may be one of the most important aspects of effective treatment of yeast and bacterial vaginitis. Whenever antibiotics

(particularly broad-spectrum) are taken for any reason, regular use of Lactobacillus will reduce the risk of complications, such as Candida overgrowth61(see Chapter 118for further discussion).

Iodine Iodine used topically as a douche is effective against a wide range of organisms, including Trichornonas, Candida, Chlamydia, and nonspecific vaginitis. Povidone-iodine (Betadine) has all the advantages of iodine without the disadvantages of stinging and staining. A study published in 1969 found povidone-iodine to be effective in treating 100% of cases of candidal vaginitis, 80% of cases due to Trichornonas, and 93% of combination infections. Although douching in recent years is not as strongly recommended, this study found a douching solution diluted to 1 part iodine in 100 parts water (e.g., 1.5 to 3 teaspoons povidone-iodine to 1 quart of water) used twice daily for 14 days to be effective against most organisms.6269

Boric Acid Capsules of boric acid have been used to treat candidiasis with success rates equal to or better than those for nystatin. In the most impressive study, 100 women with chronic resistant yeast vaginitis for whom extensive and prolonged conventional therapy had failed were treated with vaginal suppositories containing 600 mg boric acid twice a day for 2 or 4 weeks. This regimen was effective in curing 98% of the women with failure of response to the most commonly used antifungal agents.7O This treatment offers an inexpensive, easily accessible therapy for vaginal yeast infection^.^*,^

Gentian Violet Swabbing the vagina with gentian violet has been called "as close to a specific treatment for candida as exists.""

DIAGNOSTIC APPROACH Some women are hesitant to mention symptoms of vaginitis to their doctors out of embarrassment, associating them with poor personal hygiene or "venereal disease." Because of the relative frequency of occurrence, and the potential for serious consequences if untreated, all female patients should be questioned M y regarding the presence of pruritus, va@ discharge, dysuria, or other symptoms of vaginitis. The following protocol outlines the basic approach to making the correct diagnosis; Table 215-1 summarizes the key diagnostic criteria: 1. Obtain a complete gynecologic and sexual history, including details of the sexual activity and practices of the patient and her partner(s). Determine method

of contraception, personal hygiene habits, and any self-medications. Rule out the presence of associated symptoms suggestive of PID or systemic infection. Inquire about previous occurrences and their diagnosis, treatment, and resolution. Identification of the causative agent is essential for successful treatment and evaluation. To facilitate diagnosis, the patient should be instructed to avoid douching, intercourse, and vaginal medications for 1to 2 days prior to the office visit. Determine by speculum examination whether the discharge emanates from the vagina or the cervix. Note the condition of the vaginal mucosa and the character of any discharge. Specimens should be collected and then placed on slides for saline and KOH examination. Use pH paper, amines testing strips, and microscopy skills of wet mounts. Appropriate culture specimens should be taken if the diagnosis remains in question, or if screening for GC or Chlamydia is desired (highly recommended). The best time to test for low-level persistent infection is just before the menstrual period. Candida and other yeasts are particularly likely to be demonstrated at that time.

THERAPEUTIC APPROACH Because approximately 90% of all cases of vaginitis are due to Candida, Trichomonas, or Gardnerella infections, the following recommendations are primarily directed to treatment of these organisms. Owing to the infectious nature of these organisms, immune support (through proper diet, nutritional supplementation, and botanical medicines) is an important aspect of the therapy. For further recommendations on treating atrophic vaginitis, see Chapter 189; for herpes simplex, see Chapter 174.

Diet For all causes of vaginitis, a nutrient-dense diet is recommended. All refined foods and simple carbohydrates should be eliminated, and trans fats and saturated fats kept to a minimum. If food allergies are suspected, they should be determined and eliminated.

Supplements Vitamin A 5000 IU/day; or beta-carotene: 50,000 W/day Vitamin C: 500 to 1000 mg every 4 hours B complex: a good balanced B complex averaging 20 to 50 mg of each of the major components Zinc: 10 to 15 mg/day (picolinate is best; 30 to 50 mg/ day if other forms are used) Vitamin E: 200 IU/day of Dalpha-tocopherol Lactobacillus spp.: 0.5 tsp twice daily

Vaginitis and Vulvovaginitis

G1ycywhiza gla bra

Botanical Medicines

+ Echinacea either of two ways:

Hydrastis

+ Phytolacca

(2:2:1) can be used in

Tincture: 20 to 60 drops every 2 to 4 hours Tea: 1 tsp/cup every 2 to 4 hours

Topical Treatments Douches and Saturated Tampons Douches and saturated tampons are effective methods of achieving high concentrations of therapeutic agents in the vagina. The following agents are useful in the treatment of the common forms of vaginitis. The list is by no means exhaustive; only the agents that have been mentioned in several articles or texts are included. Many other agents are doubtlessly also effective. In treating a particular woman, the clinician should choose one or more of the agents listed here-not try to include all at once. The variety provides alternatives for use in resistant cases.

Betadine Various gels, pessaries, and fluids are available. A 1:lOO dilution in a retention douche kills most organisms within 30 seconds.

Licorice may be inserted as a capsule or applied as a gel locally to the vulva.

Mela leuca alternifolia A 1%dilution of tea tree oil may be used as a douche, combined with insertion of a saturated tampon for 24 hours once a week. (Repeated use may result in sensitivity in some women.) Douching is no longer a recommended method of delivering medication.

Zinc Sulfate One tablespoon of a 2% solution in 1 pint of water may be used as a douche or combined with galvanic therapy.

Other Botanicals The following herbs have been repeatedly mentioned by traditional texts and modem practitioners as effective in treating vaginitis. They may be used alone or in combination with other agents in capsules or suppositories to be placed in the vagina.

H. canadensis (goldenseal) Eucalyptus Calendula oficinalis (marigold; use the succus form) Chlorophyll

Boric Acid Acute infection: 600 mg placed in capsules twice a day for 3 to 7 days Chronic infection: 600 mg vaginal suppositories twice a day for 2 weeks (4weeks if patient is not free of symptoms and wet mount examination still shows organisms at 2 weeks) Prevention: 600 mg vaginal suppository once daily, 4 days per month during menses for 4 consecutive months To prevent vulvar irritation from the boric acid dispensed from the dissolved capsule, vitamin E oil or petroleum jelly can be applied to the external genitalia.

Allium sativum Cloves of garlic can be peeled and pierced with thread for use as a tampon, wrapped in gauze, and then inserted as a suppository. If irritation results, the garlic should be removed immediately.

Gentian Violet Swab Note that sensitivity reactions are common, and staining of clothes can occur if a sanitary pad is not used.

Hydrastis canadensis Goldenseal can be inserted as a capsule or made into a suppository with cocoa butter.

General Recommendations 1.In ail cases of vaginitis, Lactobacillus capsules or Lactobucillus-culture yogurt should be used daily, at least orally if not vaginally, to reinoculate the vagina with these desirable organisms. 2. Treatment failures may be due to incorrect diagnosis, reinfection, failure to treat predisposing factors, or patient resistance to the treatment used. 3. Sexual activity should be avoided during treatment to avoid reinfection and to reduce trauma to inflamed tissues. If this is not possible, the clinicians should at least ensure that condoms are used during treatment, because semen is alkaline and an acidic pH is the normal pH of the vagina. 4.Trichornonas infections in women also require concurrent treatment of male partner. 5. Women, particularly those with candidal vaginitis, should be instructed to wear cotton underwear. 6. Early symptomatic relief of pruritus and burning is often possible with the use of warm sitz baths, either plain or with herbs or Epsom salts. 7. In severe cases, it is often helpful to thoroughly cleanse the vagina with a Calendula succus-saturated cotton swab to remove the microbe-saturated discharge. 8. In cases of recurrent or chronic BV or yeast vaginitis, the clinician should consider treating male or female

Specific Health Problems partners, infection in whom is a possible explanation for recurrent disease.

Specific Recommendations Candida Due to the high correlation of vaginal Candida with intestinal overgrowth of the same organism, it is suggested that the internal condition be treated simultaneously to prevent recurrences.

Acute Infection Boric acid caps: Inserted daily in the vagina for 3 to 7 days Daily ingestion of 8 oz L. acidophilus yogurt One garlic capsule or raw clove, daily

Trichomonas Povidone-iodine: two times/day Zinc sulfate: daily M. altemifolia oil: daily

Herpes Patient should avoid arginine-rich foods. Lysine: 1000 to 2000 mg/day maintenance dose, double during outbreak Zinc sulfate: daily Lithium sulfate: added to the zinc sulfate douching solution M . oficirzalis: ointment or cream three times/day

Bacterial Vaginitis Povidone-iodine: daily Hydrastis canadensis: daily Lactobacillus yogurt, 8 oz daily, and/or Lactobacillus species capsules, 1 or 2 capsules daily

Atrophic Vaginitis Intravaginal Estriol cream, 1mg/g. Insert 1g daily for 2 weeks, then 1 g twice weekly as maintenance. Patient should increase intake of soy foods and flax meal.

Chlamydia Povidone-iodine: daily Zinc sulfate: daily

1.Stamey T.The role of introital enterobacteria in recurrent urinary infections. J Urol1973;109:467-472. 2. Netto NR, Rangel P, DaSilva R, et al. The importance of vaginal infection on recurrent cystitis in women. Int Surg 1979;64:79-82. 3. McGroarty J. Probiotic use of lactobacilli in the human female urogenital tract. FEMS Immunol Med Microbiol 1993;6251-264. 4. Larsen B, Galask R. Vaginal microbial flora. Practical and theoretic relevance. Ob Gyn 1980;55:1005113S. 5. Hildebrandt RJ. Trichomoniasis.Always with us-but controllable. Med T i e s 1978;106.44-48. 6.Sparling PF. Introduction to sexually transmitted diseases and common syndromes. In Bennett JC, Plum F eds. Cecil textbook of medicine. Philadelphia: WB Saunders, 1996:1669-1700. 7. Miles MR, Olsen L, Rogers A, et al. Recurrent vaginal candidiasisimportance of an intestinal reservoir. JAMA 1977;238:1836-1837. 8. Meeker CI. Candidiasis-an obstinate problem. Med T i e s 1978; 10626-32. 9. Heidrich F, Berg A, Gergman F, et al. Clothing factors and vaginitis. J Fam Pract 1984;19:491-494. 10. OConnor M, Sobel J. Epidemiology of recurrent vulvovaginal candidiask identification and strain differentiation of Candida albicans. J Infect Dis 1986;154:358-363. 11. Mercure S, Poirier S, Lemay G, et al. Application of biotyping and DNA typing of Candida albicans to the epidemiology of recurrent vulvovaginal candidiasis. J Lnfect Dis 1993;168:502-507. 12. Fidel P, Sobel J. Immunopathogenesis of recurrent vulvovaginal candidiasis. Clin Microbiol Rev 1996;9:335-348. 13. H a w s S, Hillier S, Benedetti J, et al. Hydrogen-peroxideproducing lactobacilli and acquisition of vaginal infections. J Infed Dis 1996; 174:1058-1063.

14. Goldenberg R, Klebanoff M, Nugent R, et al. Bacterial colonization of the vagina during pregnancy in four ethnic groups. Am J Obstet Gynecol 1996;174:1618-1624. 15. Fleury FJ. Is there a "non-specific" vaginitis? Med T i e s 1978;106 3743. 16. Blackwell A, Fox A, Phillips I, Barlow D. Anaerobic vaginosis (nonspecific vaginitis): clinical, microbiological, and therapeutic findings. Lancet 1983;2:1379-1382. 17. Martin J, Richardson B, Nyange P, et al. Vaginal lactobacilli,microbial flora, and risk of human immunodeficiencyvirus type 1and sexually transmitted disease acquisition. J Infect Dis 1999;180:1863-1868. 18.Taha T, Hoover D, Dallabeta G, et al. Bacterial vaginosis and disturbances of vaginal flora: association with an increased acquisition of HIV. AlDS 1998;121699-1706. 19. Holmes KK. The Chlamydia epidemic. JAMA1981;245:1718-1723. 20. Khatamee M. Chlamydia mycoplasmu: what are the hidden risks of these STDs? Mod Med 1984;52156-174. 21. Hilton E, Isenberg H, Alperstein P, et al. Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis. Ann Intern Med 1992;116:353-357. 22. Sirisnha S, Daziy M, Moongkamdi P, et al. Impaired local immune response in vitamin A deficient rats. Clin Exp Immunol 1980;40: 127-135. 23. Alexander MM, Newmark H, Miller R. Oral betacarotene can increase the number of OKT4? cells in human blood. Immunol Letters 1985;9:221-224. 24. Sharaf A, Gomaa N. Interrelationship between vitamins of the B-complex group and oestradiol. J Endo 1974;62:241-244. 25. Beisel WR, Edelman R, Nauss K, Suskind R. Single-nutrient effects on immunologic functions. JAMA 1981;245:53-58.

Vaginitis and Vulvovaginitis 26. Stankova L, Gerhardt N, Nagel L, Bigley R. Ascorbate and phagocyte function. Infect Immun 1975;12:252-256. 27. Havsteen B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharm 1983;321141-1148. 28. Holden M, Resnick R. The in-vitro adion of synthetic crystalline vitamin C (ascorbicacid) on Herpes virus. J Immunol1936;31:455%2. 29. Terezhalmy G, Bottomley W, Pelley G. The use of water soluble bioflavonoid-ascorbic acid complex in the treatment of recurrent herpes labialis. Oral Surg 1978;45:60-62. 30. Stephens L, McChesney A, Nockels C. Improved recovery of vitamin E treated lambs that have been experimentally infected with intertracheal Chlamydia. Br Vet J 1979;135291-293. 31. Pones W, Henzel J, Rob C, Strain W. Acceleration of wound healing in man with zinc sulphate given by mouth. Lancet 1967;1:121-124. 32. Sandstead H, Lanier V Jr, Shepard G, Gillespie D. Zinc and wound healing. Am J Clin Nutr 1970;23:514519. 33. Liszewski R. The effect of zinc on wound healing: a collective review. J Am Osteopath Assoc 1981;81:104-106. 34. Greenberg S, Harris D, Giles P, et al. Inhibition of Chlamydia truchomfis growth by zinc. Antimimb Agents Chemother 1985;27953-957. 35. Krieger J, Rein M. Zinc sensitivity of Trichomonas vaginulis: in vitro studies and dinical implications. J Infect Dis 1982;146:341-345. 36. Willmott F, Say J, Downey D, Hookham A. Zinc and recalcitrant trichomoniasis [letter]. Lancet 1983;1:1053. 37. Tennican P,Carl G, Frey J, et al. Topical zinc in the treatment of mice infected intravaginally with Herpes genitalis virus. Proc Soc Exp Biol Med 1980;164:593-597. 38. Gordon Y, Asher Y, Becker Y. Irreversible inhibition of herpes simplex virus replication in BSC-cells by zinc ions. Antimicrob Agents Chemother 1975;8:377-380. 39. Griffith R, Norins AL, Kagan C. A multicentered study of lysine therapy in herpes simplex infection. Dermatologica 1978;156:257-267. 40. McCune M, Perry H, Muller S, OFallon WM. Treatment of recurrent herpes simplex infections with L-lysine monohydrochloride. Cutis 19&4;34:366-373. 41. Lieb J. Remission of recurrent herpes infection during therapy with lithium [letter]. N Engl J Med 1979;301:942. 42. Skinner G, Hartley C, Buchan A, et al. The effect of lithium chloride on the replication of herpes simplex virus. Med Microbiol Immunol 1980;168:139-148. 43. Mitchell W. Naturopathic applications of the botanical remedies. Seattle, WA: JBC Publications, 1983. 44.Mowbray S. The antibacterial activity of chlorophyll. Br Med J 1957; 1~268-270. 45. Goldberg S. The use of water soluble chlorophyll in oral sepsis. Am J Surg 1943;62117-122. 46. Smith L, Livingston A. Chlorophyll: an experimental study of its water soluble derivatives in wound healing. Am J Surg 1943;62: 358-369. 47. Sharma V, Sethi MS, Kumar V, Rarotra JR. Antibacterial property of Allium sativum Linn. in vivo and in vitro studies. Ind J Exp Bio 1977; 15:466-468. 48. Moore G, Atkins R. The fungicidal and fungistatic effects of an aqueous garlic extract on medically important yeast-like fungi. Mycologia 1977;69341-348. 49. Cavallito C, Bailey J. Allicin, the antibacterial principle of Allium sativum. I. Isolation, physical properties and antibacterial action. J Am Chem Soc 1944;661950-1951.

50. Barone F, Tansey M. Isolation, purification, identification, synthesis, and kinetics of activity of the anticandidal component of Allium sativum, and a hypothesis for its mode of action. Mycologia 1977;69: 793-825. 51. Prat M. Algunas consideraciones sobre la accion antibiotica del Allium sativum y sus preparados [trans]. Biol Abstr 1950;24:264. 52. Hahn F, Ciak J. Berberine. Antibiotics 1976;3:577-588. 53. Sabir M, Bhide N. Study of some pharmacological actions of berberine. Ind J Phys Pharm 1971;15:111-132. 54.Sabir M, Mahajan V, Mohaptra L, Bhide NK.Experimental study of the antitrachoma action of berberine. Ind J Med Res 1976;64: 1160-1167. 55. Dutta N, Panse M. Usefulness of berberine (an alkaloid from Berberis aristafa) in the treatment of cholera (experimental). Ind J Med Res 1962;50:732-735. 56. Pena EF. Melaleuca alfernifolia oil. Its use for trichomonal vaginitis and other vaginal infections. Ob Gyn 1962;19:793-795. 57. Williams L, Home V. A comparative study of some essential oils for potential use in topical applications for the treatment of the yeast Candida albicans. Aust J Med Herbal 1995;757-62. 58. Wolbing RH, Leonhardt K. Local therapy of herpes simplex with dried extract from Melissa oficinus. Phytomedicine 1994;1:25-31. 59. Mittal A, Kapur S, Garg S, et al. Clinical trial with Praneem polyherbal cream in patients with abnormal vaginal discharge due to microbial infections. Aust N Z J Obstet Gyn 1995;35190-191. 60. Chan R, Bruce A, Reid G. Adherence of cervical, vaginal and distal urethral normal microbial flora to human uroepithelial cells and the inhibition of adherence of gram-negative uropathogens by competitive exclusion. J Urol1984;131:596-601. 61. Vincent J, Veomett R, Riley R. Antibacterial activity associated with Lactobacillus acidophilus. J Bacteriol 1959;78477-484. 62. Shook D. Aclinical study of a povidone-iodine regimen for resistant vaginitis. Cum Ther Res 1963;5256-263. 63. Maneksha S. Comparison of povidone-iodine (Betadine) vaginal pessaries and lactic acid pessaries in the treatment of vaginitis. J Int Med Res 1974;2236-239. 64.Reeve P. The inactivation of Chlamydia trachomtis by povidone iodine. J Antimicrob Chemo 1976;277-80. 65. Ratzen J. Monilial and trichomonal vaginitis-topical treatment with povidone iodine treatments. Cal Med 1969;110:24-27. 66. Mayhew S. Vaginitis. A study of the efficacy of povidone iodine in unselected cases. J Int Med Res 1981;9:157-159. 67. Gershenfeld L. Povidone iodine as a trichomoniacide. Am J Pharm 1962;134:324331. 68.Gershenfeld L. Povidone iodine as a vaginal microbicide. Am J Pharm 1962;134:278-291. 69. Singha H. The use of a vaginal cleansing kit in non-specific vaginitis. Practitioner 1979;223:403404. 70. Jovanovic R, Congema E, Nguyen H. Antifungal agents vs boric acid for treating chronic mycotic vulvovaginitis. J Reprod Med 1991;36593-597. 71. Swate T, Weed J. Boric acid treatment of vulvovaginal candidiasis. Ob Gyn 1974;43:894895. 72. Keller Van Slyke K. Treatment of vdvovaginal candidiasis with boric acid powder. Am J Obstet Gynecol1981;141:145-148. 73. Meeker CI. Candidiasis-an obstinate problem. Med Times 1978; 106~26-32.

Varicose Veins Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Diagnostic Summary

2167

Physical Measures 2168 Botanical Medicines 2168

General Considerations 2167 Etiology 2167 Therapeutic Considerations 2168 Dietary Factors 2168

DIAGNOSTIC SUMMARY Dilated, tortuous, superficial veins in the lower extremities. May be asymptomatic or associated with fatigue, aching discomfort, feeling of heaviness, or pain. Edema, pigmentation, and ulceration of the skin of the distal leg may develop. Women are affected four times as frequently as men.

GENERAL DISCUSSION Veins are fairly frail structures. Defects in the wall of a vein lead to dilation of the vein and damage to the valves.' When the valves become damaged, the higher static pressure results in the bulging veins known as varicose

veins. Varicose veins affect nearly 50% of middle-aged adults. The subcutaneous veins of the legs are the veins most commonly affected, owing to the gravitational pressure that standing exerts on them. When an individual stands for long periods, the pressure buildup in the vein can increase up to 10 times. Hence, individuals with occupations that require long periods of standing are at greatest risk for development of varicose veins.2 Women are affected about four times as frequently as men; obese individuals have a much greater risk; and the risk rises with age owing to loss of tissue tone, loss of muscle mass, and weakening of the walls of the veins. Pregnancy, which increases venous pressure in the legs, may also lead to the development of varicose veins.2

Therapeutic Approach 2170 Diet 2170 Supplements 2170 Botanical Medicines 2170 Additional Recommendations 2170

In general, varicose veins pose little harm if the involved vein is near the surface. These types of varicose veins are, however, cosmetically unappealing. Although significant symptoms are not common, the legs may feel heavy, tight, and tired. If the varicose veins are associated with sigruficant chronic venous insufficiency (CVI), leg ulcers may form that are often difficult to resolve. A more serious form of varicose vein involves obstruction and valve defects of the deeper veins of the leg. This type of varicose vein can lead to problems such as thrombophlebitis, pulmonary embolism, myocardial infarction, and stroke. Phlebography and Doppler ultrasonography are the most accurate methods of diagnosis of deep vein involvement.

ETIOLOGY The following theories explain the cause of varicose veins: Genetic weakness of the veins or venous valves. Excessive venous pressure due to a low dietary fiberinduced increase in straining during defecation. Long periods of standing and/or heavy lifting. Damage to the veins or venous valves secondary to thrombophlebitis. Weakness of the vascular walls due to either abnormalities in the proteoglycans of the interendothelial cement substance or excessive release of lysosomal enzymes (beta-N-acetylglucosaminidase, beta-glucuronidase, and arylsulfatase), which break down the ground substance, leading to increased capillary permeability and loss of venous structural integrity.

2167

Specific Health Problems

THERAPEUTIC CONSIDERATIONS Several nutritional and botanical agents can assist in improving the structural integrity of the veins, but longterm success depends on correcting the common problem inadequate dietary fiber.

Dietary Factors Fiber Unlike in the United States and England, varicose veins are rarely seen in parts of the world where high-fiber, unrefined diets are ~ o n s u m e d .A~ ,low-fiber ~ diet that is high in refined foods contributes to the development of varicose veins. Individuals consuming a low-fiber diet tend to strain more during bowel movements, because their smaller and harder stools are more difficult to pass. This straining raises the pressure in the abdomen, obstructing the flow of blood up the legs. The increased pressure, over time, may significantly weaken the vein walls, leading to the formation of varicose veins or hemorrhoids, or may weaken the wall of the large intestine and produce di~erticuli.~ A high-fiber diet is the most important component in the treatment and prevention of varicose veins (and hemorrhoids). A diet rich in vegetables, fruits, legumes, and grains promotes peristalsis; and many fiber components attract water and form a gelatinous mass, which keeps the feces soft, bulky, and easy to pass. The net effect of a high-fiber diet is significantly less straining during defecation. Natural bulking compounds can also be used. These substances, particularly psyllium seed, pectin, and guar gum, possess mild laxative action owing to their ability to attract water and form a gelatinous mass. This process, as previously mentioned, keeps the feces soft and promotes peristalsis, significantly reducing straining during defecation. These types of fibers are generally less irritating than wheat bran and other cellulose fiber products.

Physical Measures Exercise and avoidance of standing for long periods reduce the risk of development of varicose veins. Exercise, especially walking, riding a bike, or jogging, is particularly beneficial, because contraction of the leg muscles pushes pooled blood back into circulation. Elastic compression stockings are occasionally beneficial. Surgical stripping of the vein can be performed in severe cases.

Botanical Medicines Centella asiatica When given orally, an extract of Centella asiatica containing 70% triterpenic acids (asiatic acid, madecassic acid, and asiatoside) has demonstrated impressive clinical results in the treatment of cellulite, venous insufficiency

of the lower limbs, and varicose veins (see Chapter 78 for more information).6-'0 Several experimental studies have discovered that centella exerts a normalizing action on the metabolism of connective tissue. Specifically, it possesses an ability to enhance connective tissue integrity by stimulating glycosaminoglycan synthesis without promoting excessive collagen synthesis or cell g r ~ w t hGlycosaminoglycans .~ are the major components of the amorphous intercellular matrix (ground substance) in which collagen fibers are embedded. The net outcome of centella's effect on connective tissue is the development of normal tissue. The effect of centella in venous insufficiency and varicose veins appears to be related to its ability to enhance connective tissue structure, reduce sclerosis, and improve the blood flow through the affected limbs.G1o

Aesculus hippocastanum (Horse Chestnut) Horse chestnut (Aesculus hippocastanurn) was once native to Western Asia but has been widely distributed all over the world because of its beauty. In addition to bringing aesthetic pleasantries to city streets and parks, this hearty tree possesses significant medicinal effects. In particular, the seeds of the horse chestnut tree have been valued for centuries for their ability to improve hemorrhoids and varicose veins." This historical use, seemingly successful, ultimately has led to the development of topical and oral preparations with confirmed clinical benefits for these very same condition^.'^,'^ The chief component of horse chestnut seed extract (HCSE) is escin, a triterpenic saponin, although other molecules such as proanthocyanidin A2 and esculin also exert significant effects.I2 These horse chestnut compounds have shown a number of pharmacologic effects beneficial in the treatment of CVI. First of all, all three active components have been shown to exert significant vasoprotective and venotonic effects, such as antioxidant effects, combined with an ability to inhibit enzymes that destroy venous structures, such as collagenase, hyaluronidase, beta-glucuronidase, and elastase, thus shifting the equilibrium between degradation and synthesis of proteoglycans and other critical venous structures toward a net synthesis. In addition, HCSE prevents the accumulation of leukocytes in varicose vein-affected limbs and their subsequent activation, an important pathophysiologic mechanism in varicose veins. It appears that the ultimate effect of HCSE treatment is the prevention of vascular leakage along with increase in the tone of the vein it~e1f.I~ The therapeutic benefits of HCSE has been confirmed in more than 16 double-blind clinical trials that demonstrate a positive effect in the treatment of varicose veins and thrombophlebitis.12In fact, extracts of HCSE standardized for escin appear to be as effective as compression stockings without the nuisance. For example, in a

Varicose Veins ~~

well-designed study, the effectiveness of HCSE versus leg compression stockings was examined in 240 patients with varicose veins.15 Patients received either HCSE (50 mg of escin per day), compression stockings, or a placebo for 12 weeks. Effectiveness was evaluated by a phlethysmograph-a machine that measures the volume of fluid in the leg. After the 12-week trial, lowerleg volume of the more severely affected leg decreased an average of 56.5 ml with compression therapy and 53.6 ml with HCSE, whereas it rose by 9.8 ml with the placebo. In the treatment of varicose veins, escin can be given orally as well as topically. The topical formula is also of benefit in the treatment of bruises, owing to escin's ability to reduce capillary fragility and swelling.

Ruscus aculeatus (Butcher's Broom) The shrub butcher's broom (Ruscus acu2eatus) is a member of the lily family that grows in the Mediterranean region. The rhizome from butcher's broom has a long history of use in treating venous disorders such as hemorrhoids and varicose veins. This historical effect has been confirmed in experimental and double-blind studies in patients with varicose The active ingredients in butcher's broom are ruscogenins. These compounds have demonstrated a wide range of pharmacologic actions, including antiinflammatory and vasoconstrictor effects. In Europe, butcher's broom extracts are used extensively, both internally and externally, in the treatment of varicose veins and hemorrhoids. Double-blind clinical studies have shown that these preparations offer benefits in both symptomatic relief and improved venous blood flow.16-'*

Flavonoid-Rich Extracts Because improving the integrity of the wall of the vein may also reduce the risk of varicose veins, flavonoidrich berries, such as hawthorn berries, cherries, blueberries, and blackberries appear to be beneficial in the prevention and treatment of varicose veins. These berries are very rich sources of proanthocyanidins and antho-

cyan id in^.'^-^^ These bioflavonoids give the berries their blue-red color. Proanthocyanidins and anthocyanidins also improve the integrity of ground substance and the vascular system. Extracts of several of these berries are used widely in Europe for various circulatory condition^.'^-^^ Another rich source of flavonoids is buckwheat, which is high in rutin. In one double-blind, placebocontrolled study, 77 patients with CVI were given placebo tea or Fagopyrurn esculenturn (buckwheat) tea for 12 weeks. The tea was standardized to contain 5% total flavonoids, yielding a daily dosage of 270 mg of rutin. A statistically sigruficant reduction in total leg volume was seen in the treated group, along with statistically

insignificant improvements in capillary permeability and symptoms. No adverse effects were noted.z These extracts' efficacy is related to their ability to accomplish the f ~ l l o w i n g ' ~ - ~ ~ : Reduce capillary fragility Increase the integrity of the venous wall Inhibit the breakdown of the compounds composing the ground substance Improve the muscular tone of the vein Consumption of these berries or of their extracts is indicated for individuals with varicose veins as well as for those who wish to prevent them.

Micronized Diosmin The most useful single flavonoid for varicose veins may be micronized diosmin. Micronization involves a hightechnology grinding process with a jet of air at supersonic velocities, reducing the size of standard particles from more than 20 pm to less than 2 pm. As a result there is better and faster absorption, and thus an increased bioavailability, which lends greater clinical efficacy. Micronized diosmin has been extensively studied flavonoid in the treatment of CVI. In addition to showing considerable improvements in signs and symptoms, purified micronized diosmin decreases the levels of some plasma markers of endothelial activation, including soluble endothelial adhesion molecules.23Micronized diosmin has also shown considerable benefits in promoting the healing of venous ulcers and her nor rho id^.^^

Bromelain and Other Fibrinolytic Compounds Individuals with varicose veins have a decreased ability to break down fibrin.25This fact is extremely important because fibrin is deposited in the tissue near the varicose veins. The skin then becomes hard and "lumpy" owing to the presence of the fibrin and fat (lipodermatosclerosis). In addition, decreased fibrinolytic activity raises the risk of thrombus formation, which may result in thrombophlebitis, myocardial infarction, pulmonary embolism, or stroke. Herbs that increase the fibrinolytic activity of the blood are therefore indicated. Capsicum onion,28 and ginger29 all promote fibrin breakdown. Liberal consumption of these spices in foods is recommended for individuals with varicose veins and other disorders of the cardiovascular system. The proteolytic enzyme from pineapple, bromelain, also appears to be indicated in the treatment of varicose veins. Vein walls are an important source of plasminogen activator, which promotes the breakdown of fibrin. Veins that have become varicosed have decreased levels of plasminogen activator. Bromelain acts in a similar manner to plasminogen activator to cause fibrin breakdown.30

Specific Health Problems

Bromelain may help prevent the development of the hard and lumpy skin found around varicosed veins.

THERAPEUTIC APPROACH Varicose veins are extremely common in our society, largely because of dietary and lifestyle factors. The supplements and botanicals are recommended in order to strengthen the walls of the vein and increase fibrinolytic activity. To treat and reduce risk of varicose veins, it is important that people: Consume a diet high in fiber Exercise regularly Avoid standing in one place for long periods (and use elastic support stocking if standing is necessary) Avoid obesity Employ measures that increase the integrity of the connective tissue and vein wall Enhance fibrinolytic activity

Vitamin C: 500 to 3000 mg/day Vitamin E: 200 to 600 IU/day Bioflavonoids: 100 to 1000 mg/day Zinc: 15 to 30 mg/day

Botanical Medicines A. hippocastanurn:bark of root, 500 mg three times/day Escin: 50 mg two to three times/day; alternatively, escin preparations may be applied topically in a 1% concentration C. asiatica extract (70% triterpenic acid content): 30 mg three times/day R. aculeatus extract (9% to 11%ruscogenin content): 100 mg three times daily Vaccinium myrtillus: fresh berries: 55 to 110 g three times/day; or extract containing 25% anthocyanoside: 80 to 160 mg three times/day Micronized diosmin: 500 to 1000 mg/day Bromelain (minimum 1500 MCU): 500 to 750 mg three times/day between meals

Diet

Additional Recommendations

A diet rich in dietary fiber is indicated. The diet should contain liberal amounts of proanthocyanidin- and anthocyanidin-rich foods, such as blackberries, cherries, and blueberries. Garlic, onions, ginger, and cayenne should also be consumed liberally.

For severely affected veins, sclerotherapy with segmental phlebectomy (stripping of the vein) or surgical phlebectomy may be necessary. In sclerotherapy with segmental phlebectomy, a sclerosing agent is injected at the highest portion of the vein that is causing a clot to form and pinch off the vein. Only the most badly diseased segments of vein are stripped away with segmental phlebectomy.

Supplements Vitamin A: 10,000 KJ/day Vitamin B: complex, 10 to 100 mg/day

1. Rose S. What causes varicose veins? Lancet 1986;1:320-321. 2. Berkow R, ed. The Merck manual of diagnosis and therapy, ed 14. Rahway, NJ: Merck & Co, 1982560-566. 3. Trowell H, Burkitt D, Heaton K. Dietary fibre, fibre-depleted foods and disease. London: Academic Press, 1985. 4. Vahouny G, Kritchevsky D. Dietary fiber in health and disease. New York Plenum Press, 1982. 5. Latto C, WiucinsOn RW, Gilmore OJ. Diverticular disease and varicose veins. Lancet 1973;1:1089-1090. 6. AUegra C, Pollari G, Criscuolo A, et al. [Centella asiatica extract in venous disorders of the lower limbs. Comparative clinico-instrumental studies with a placebo.] Clin Ter 1981;99:507-513. 7. Brinkhaus B, Lindner M, Schuppan D, Hahn EG. Chemical, pharmacological and clinical profile of the East Asian medical plant Centella nsiatica. Phytomedicine 2000;7427-448. 8. A l l q a C. [Comparativecapillaroscopicstudy of certain bioflavonoids and total triterpenic fractions of Centella asiatica in venous insufficiency.] Clin Ter 1984;110:555-559. 9. Pointel JP, Boccalon H, Cloarec M, et al. Titrated extract of Centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. Angiology 1987;38:46-50. 10. Marastoni F, Baldo A, Redaelli G, Ghiringhelli L. [Centella asiatica extract in venous pathology of the lower limbs and its evaluation as compared with tribenoside.] Minerva Cardioangiol1982;30:201-207.

11. Felter HW, Lloyd JU. King’s American dispensatory, ed 18. 1898 (reprint). Portland, OR Eclectic Medical Publications, 1983990-992. 12. Pittler MH, Emst E. Horse-chestnut seed extract for chronic venous insufficiency. A criteria-based systematic review. Arch Dermatol 1998;134;1356-1360. 13. Incandela L, De Sanctis MT, Cesarone MR, et al. Treatment of superficial vein thrombosis: clinical evaluation of Essaven gel-a placebo-controlled, 8-week, randomized study. Angiology 2001; 52(S~ppl3):S69-572. 14. Annoni F, Mauri A, Marincola F, Resele LF. Venotonic activity of escin on the human saphenous vein. Arzneimittelforschung 1979; 29:672-675. 15. Diehm C, Trampisch HJ, Lange S, Schmidt C. Comparison of leg compression stocking and oral horse-chestnut seed extract therapy in patients with chronic venous insufficiency. Lancet 1996;347 292-294. 16. Boccalon H, Causse C, Yubero L. Comparative efficacy of a single daily dose of two capsules of Cyclo 3 Fort in the morning versus a repeated dose of one capsule morning and noon. A one month study. Int Angi011998;17155-160. 17. Cappelli R, Nicora M, Di Perri T. Use of extract of Ruscus aculeatus in venous disease in the lower limbs. Drugs Exp Clin Res 1988;14 277-283.

Varicose Veins 18. Beltramino R, Penenory A, Buceta AM. An open-label, randomized multicenter study comparing the efficacy and safety of Cyclo 3 Fort@ versus hydroxyethyl rutoside in chronic venous lymphatic insufficiency. Angiology 2000;51:535-544. 19. Gabor M. Pharmacologic effects of flavonoids on blood vessels. Angiologica 1972;9:355-374. 20. Kuhnau J. The flavonoids. A class of semi-essentialfood components: their role in human nutrition. World Rev Nutr Diet 1976;24117-191. 21. Pourrat H. Anthocyanidin drugs in vascular disease. Plant Med Phytother 1977;11:143-151. 22. Ihme N, Kieswetter H, Jung F, et al. Leg edema protection from buckwheat herb tea in patients with chronic venous insufficiency: a single-center, randomized, double-blind, placebo-controlled clinical trial. Eur J Clin Pharmacol1996;50443-447. 23. Nicolaides AN. From symptoms to leg edema: efficacy of Daflon 500 mg. Angiology 2003;54(Suppll):S33-S44. 24. Lyseng-Williamson KA, Perry CM. Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs 2003;63:71-100.

25. Kreysel HW,Nissen HP,Enghofer E. A possible role of lysosomal enzymes in the pathogenesis of varicosis and the reduction in their serum activity by Venostasin. Vasa 1983;12:377-382. 26. Visudhiphan S,Poolsuppasit S, Piboonnukarintr 0,Tumliang S. The relationship between high fibrinolytic activity and daily capsicum ingestion in Thais. Am J Clin Nutr 1982;35:1452-1458. 27. Bordia A, Sharma KD, Parmar YK, Verma SK. Protective effect of garlic oil on the changes produced by 3 weeks of fatty diet on serum cholesterol, serum triglycerides, fibrinolytic activity and platelet adhesiveness in man. Indian Heart J 1982;34:86-88. 28. Baghurst KI,Raj MJ, Truswell AS. Onions and platelet aggregation. Lancet 1977;l:lOl. 29. Srivas KC. Effects of aqueous extracts of onion, garlic and ginger on the platelet aggregation and metabolism of arachidonic acid in the blood vascular system. In vitro study. Prostaglandins Leukot Med 1984;13227-235. 30. Ako H,Cheung AH, Matsuura PK. Isolation of a fibrinolysis enzyme activator from commercial bromelain. Arch Int Pharmacodyn Ther 1981;254:157-167.

Candida Questionnaire* PURPOSE The purpose of this questionnaire is to estimate the likelihood of having an overgrowth of intestinal yeast.

QUESTIONNAIRE History 25 20

-

For each of your symptoms, enter the appropriate figure in the "point score" column: If a symptom is occasional or mild, score 3 points. If a symptom is frequent or moderately severe, or both, score 6 points. If a symptom is severe or disabling, or both, score 9 points.

Point score 6

25

3 5 8 15

6

15

5 20

20

1.Fatigue or lethargy 2. Feeling of being "drained" 3. Poor memory 4. Feeling "spacey" or "unreal" 5. Depression 6. Numbness, burning, or tingling 7. Muscle aches 8. Muscle weakness or paralysis 9. Pain and/or swelling in joints 10. Abdominal pain 11. Constipation 12. Diarrhea 13. Bloating 14. Persistent vaginal itch 15. Persistent vaginal burning 16. Prostatitis 17. Impotence 18. Loss of sexual desire 19. Endometriosis 20. Cramps or other menstrual irregularities, or both 21. Premenstrual tension 22. Spots in front of eyes 23. Erratic vision

Total score of this section 10 20

10 10

'Adapted from Crook WG.The yeast connection, ed 2. Jackson, TN: Professional

Books, 1984.

Total score of this section

10 10

Major Symptoms Point score

1. Have you taken antibiotics for acne for 1 month or longer? 2. Have you, at any time in your life, taken other "broad-spectrum" antibiotics for respiratory, urinary, or other infections for 2 months or longer, or in short courses four or more times in a 1-year period? 3. Have you ever taken a broad-spectrum antibiotic (even a single course)? 4. Have you, at any time in your life, been bothered by persistent prostatitis, vaginitis, or other problems affecting your reproductive organs? 5. Have you been pregnant? One time Two or more times 6. Have you taken birth control pills? For 6 months to 2 years For more than 2 years 7. Have you taken prednisone or other cortisone-type drugs? For 2 weeks or less For more than 2 weeks 8. Does exposure to perfumes, insecticides, fabric shop odors, and other chemicals provoke: Mild symptoms Moderate to severe symptoms? 9. Are your symptoms worse on damp, muggy days or in moldy places? 10. Have you had athlete's foot, ringworm, "jock itch," or other chronic infections of the skin or nails? Mild to moderate Severe or persistent 11. Do you crave sugar? 12. Do you crave breads?

13. Do you crave alcoholic beverages? 14. Does tobacco smoke really bother you?

Other Symptoms For each of your symptoms, enter the appropriate figure in the "point score" column: If a symptom is occasional or mild, score 1point. If a symptom is frequent or moderately severe, or both, score 2 points. 2173

If a symptom is severe or disabling, or both, score 3 points. Point score 1. Drowsiness 2. Irritability 3. Incoordination 4.Inability to concentrate 5. Frequent mood swings 6. Headache 7. Dizziness/loss of balance 8. Pressure above ears, feeling of head swelling and tingling 9. Itching 10. Other rashes 11. Heartburn 12. Indigestion 13. Belching and intestinal gas 14. Mucus in stools 15. Hemorrhoids 16. Dry mouth 17. Rash or blisters in mouth 18. Bad breath 19. Joint swelling or arthritis 20. Nasal congestion or discharge 21. Postnasal drip

Point score 22. Nasal itching 23. Sore or dry throat 24. Cough 25. Pain or tightness in chest 26. Wheezing or shortness of breath 27. Urinary urgency or frequency 28. Burning on urination 29. Failing vision 30. Buming or tearing of eyes 31. Recurrent infections or fluid in ears 32. Ear pain or deafness

-

-

Total score of this section TOTAL SCORE OF ALL THREE SECTIONS -

Yeast-connected health problems

Women

Men

>180

>140

Probably present

120-180

90-1 40

Possibly present

60-119

40-89

<60

<40

Almost certainly present

Less likely present

Crohn's Disease Activity Index Patient name:

Chart #:

Date: Sum

x

-

X

Factor 2

= -

-

__

X

5

-

-

-

X

7

-

-

Number of six listed categories the patient now has: 1.Arthritis/arthralgia 2. Iritis/uveitis 3. Erythema nodosum/pyoderma gangrenosum/aphthous stomatitis 4.Anal fissure, fistula, or abscess 5. Other fistula 6. Fever >loo" F during past week

X

20

-

-

-

X

30

-

-

-

X

10

-

-

6

-

-

(standard: males = 47, females = 42)

Standard - HCT X (add or subtract according to sign)

Body weight (BW):Standard weight (SW): -

(SW - BW)/SW X 100 (add or subtract according to sign)

-

-

=

-

XI

Number of liquid or very soft stools

X2

Abdominal pain (0 = none, 1= mild, 2 = moderate, 3 = severe)

Day1 2 3 4 5 6 7 I I I I I I I

1 1 1 1 1 l 1

X3 General well-being

1 1 1 1 1 1 1 (0 = well, 1 = slightly under par, 2 = poor, 3 = v. poor, 4 = terrible)

X,

X5 Taking Lomotil/opiates for diarrhea

Subtotal

(0 = no, 1= yes)

X6 Abdominal mass (0 = none, 2 = questionable, 5 = definite)

X7 Hematocrit (HCT):Xs

Crohn's disease activity index (sum of XI through X,)

CDAI

2175

Current Hormone Replacement Therapy Prescriptions 2005 Tori Hudson, ND

Oral Estrogens Nine synthetic plant-derived conjugated estrogens; Cenestin slow release tablet 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, 1.25 mg Estratab

Esterifiedestrogens 0.3 mg, 0.625 mg, 1.25 mg, 2.5 mg

Estrace

Estradiol-17-beta; most active form of endogenous estrogen; up to 90% of the oral dose is converted to estrogen by the gut and liver 0.5 mg, 1 mg, 2 mg

Gynediol

Estradiol-17-beta; micronized formulation; 2-mg tablet contains tartrazine (dye) that may cause allergy in patients with a sensitivity to aspirin 0.5 mg, 1 mg, 1.5 mg; 2 mg

Menest

Esterified estrogens (synthetic plant derived) 0.3 mg, 0.625 mg, 1.25 mg, 2.5 mg

Ogen

Estropipate; 0.625 mg contains 0.75 mg estropipate; 1.25-mg tablet contains 1.5 mg estropipate; 2.5-mg tablet contains 3 mg estropipate 0.625 mg, 1.25 mg, 2.5 mg

Ortho-Est

Premarin

Transdermal Estrogens Estradiol-17-beta (2 times/wk); 0.05 mg/24-hr patch Alora 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg Climara

Estradiol-17-beta (1 time/wk); 0.05 mg/24-hr patch 0.025 mg, 0.0375 mg, 0.05 mg, 0.06 mg, 0.075 mg, 0.1 mg

Esclim

Estradiol-17-beta (2 timedwk); 0.05mg/24-hr patch 0.025 mg, 0.0375 mg, 0.05mg, 0.075 mg, 0.1 mg

Estraderm

Estradiol-17-beta (2 times/wk); 0.05 mg/24-hr patch Includes a drug reservoir of estradiol and alcohol, and a copolymer membrane that controls the rate of drug diffusion 0.05mg, 0.1 mg

Estropipate; one 0.625-mg tablet contains 0.75 mg estropipate; 1.25-mg tablet contains 1.5 mg estropipate 0.625 mg, 1.25 mg

Estrasorb

Topical emulsion of estradiol hemihydrate 1 g emulsion = 2.5 mg estradiol; each foil-laminated pouch contains 1.74 g (4.35 mg estradiol hemihydrate); nominal estradiol delivery rate of 0.05mg/day

Conjugated equine estrogens; 50%-60% estrone sodium sulfate; 20%-35% equilin sodium sulfate and 17 beta-dihydroequilin, small amounts of estradiol-17-beta and equilenin; contains more than 200 compounds, including androgenic compounds 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, 1.25 mg

Estrogel

Estradiol-17-beta; nonaerosol, metered-dose pump; gel dries in as little as 2-5 min; 1.25 g (0.75 mg estradiol) 1 time/day; 1 pump = 0.05 patch

FemPatch

Estradiol-17-beta 0.025 mg (2 timedwk)

Menostar

Estradiol-17-beta One patch provides 14 pg of estradioVday (1 time/wk)

Indications Moderate to severe vasomotor symptoms, vulvar and vaginal atrophy, osteoporosis prevention (Cenestin and Menest are not FDA approved for the prevention of osteoporosis; Cenestin 0.3 mg is indicated only for vasomotor symptoms; Menest is indicatedfor atrophic vaginitis) Adverse Effects Common: breakthrough bleeding, breast tenderness, nausea, bloating, abdominal cramps, vomiting, headache, dizziness, depression, peripheral edema, weight changes, rash, intolerance to contact lenses, migraine, libido changes Rare: thromboembolism, stroke, endometrial cancer, breast cancer (when used with a progestogen), hepatic adenoma, gallbladder disease, increased blood pressure, myocardial infarction Dosing Continuous or cyclic (21 days on, 7 days off); add a progestogen 10-14 days of month for women with uterus ~

Drug Interactions Drugs affected by oral estrogens: corticosteroids (increase), levothyroxine (decrease), theophylline (increase), warfarin (decrease), antibiotics (decrease), androgens (decrease), nicotine (eliminates more rapidly) Drugs that affect oral estrogens: barbiturates (decrease), rifampin (decrease)

Vivelle or Estradiol-17-beta (2 times/wk); 0.05 mg/24 hr-patch Vivell-Dot 0.025 mg, 0.0375 mg, 0.05mg, 0.075 mg, 0.1 mg Indications Moderate to severe vasomotor symptoms, vulvar and vaginal atrophy (Alora and Vivell-Dot are also indicated for the prevention of osteoporosis; Estrasorb is indicated only for moderate to severe vasomotor symptoms.) Adverse Effects Common: erythema and skin irritation (occurs in 10%-17% of patients using reservoir-type patches compared with =5% with newer matrixtype patches), breakthrough bleeding, breast tenderness, nausea, abdominal cramps, headache, peripheral edema, migraine Rare: rash, thromboembolism, stroke, endometrial cancer, breast cancer (when used with a progestogen), increased blood pressure

~~

Resource: McGriff-Lee N, Calis KA. The 2004 Guide to Hormone Therapy Products, Ob/Gyn Special Edition Spring 2004

Continued

2177

Dosing and Administration Discontinue oral therapy for 1 wk before initiating transdermal estrogen; patch should be applied to the trunk of the body (avoid application on the breasts); rotate application site weekly to minimize irritation; patch may be worn while showering or swimming. Potential Drug Interactions See Oral Estrogens (except antibiotics and nicotine). Vaginal Estrogens Micronized estradiol-17-beta; O.0lo/~cream; 1 g Estrace cream 1-3 times/wk 0.1 mg/g Consider starting with 2-4 g every day intravaginally for 2-4 wk, and then 1-2 g for 1-2 wk; maintenance dose usually 1 g 1-3 timedwk Estradiol-17-alpha; biologically inert liquid polymer matrix with pure crystalline estradiol; releases 7.5 pg/24 hr over 90 days 2 mg delivered over 90 days; replace ring every 90 days

Estring

Femring

Estradiol acetate 0.05 mg/24 hr, 0.1 mg/24 hr; replace every 3 months

Ogen cream

Estropipate; 2-4 g 1-3 timedwk 1.5 mg/g

Premarin cream

Vagifem

Conjugated equine estrogens 0.625 mg/g of cream; 0.5 mg-2 g 1-3 g/wk; applicator marked in 0.5-g intervals; absorbed slower than other estrogen preparations and therefore a longer duration of action Estradiol-17-betavaginal tablets; a gel forms when the tablet is in contact with the vagina; initial dose of 1 tablet every day for 2 wk, then maintenance of 2 timedwk 25 pg in singe use applicator; 1 tablet 2 timedwk

Indications Vulvar and vaginal atrophy (Premarin and Vagifem are indicated for atrophic vaginitis; Femring is also indicated for moderate to severe vasomotor symptoms.) Adverse Effects Common: headache, nausea, vaginal discomfort, vaginal candidiasis Rare: vaginal trauma from the applicator if patient has severe atrophy Dosing and Administration Daily dosing will achieve systemic concentrations: low dose, 1-3/wk will achieve predominantly local effects.

A single tablet contains one of the four dosing options;

continuous combined regimen Indications Combination therapy is indicated for women with an intact uterus. Adverse Effects See Oral Estrogens and Oral Progestins. Dosing and Administration Addition of a progestin for at least 10-12 daydmonth protects against the increased risk of endometrial hyperplasia that occurs with unopposed estrogen use; continuous combined therapy is an alternative regimen that reduces and often eliminates withdrawal bleeding compared with a cyclic regimen. Potential Drug Interactions See Oral Estrogens (except antibiotics and nicotine) and Oral Progestins. Transdermal Estrogen-Progestln Combinations CombiPatch

Estradiol-17-beta0.05mu0.14 mg NE acetate 1 patch 2 timedwk Estradiol-17-beta0.05mu0.250 mg norethindrone acetate 2 times/wk

ClimaraPro

0.045 estradioV0.015 mg levonorgestrel 1 patch/wk

Indications Moderate to severe vasomotor symptoms (Combi-Patch is also indicated for vulvar and vaginal atrophy.) Adverse Effects See Transdermal Estrogens and Oral Progestins. Dosing and Administration Complete the current cycle of therapy before initiating combination transdermal therapy; apply to lower abdomen. Potential Drug Interactions See Oral Estrogens (except antibiotics and nicotine) and Oral Progestins.

Oral Progestins Amen Aygestin

Norethindrone acetate 5 mg

Cycrin

Medroxyprogesterone acetate 2.5 mg, 5 mg, 10 mg

Nor-QD

Norethindrone 0.35 mg

Ovrette

Norgestrel0.075 mg; 19-nor derivative of testosterone with progestogenic, estrogenic, androgenic, and antiestrogenic effects

Provera

Medroxyprogesterone acetate 2.5 mg, 5 mg, 10 mg; usual maintenance dose of 5-10 mg daily for 12-14 daydmonth

Drug Interactions See Oral Estrogens (except antibiotics and nicotine); interactions are based on extent of systemic absorption. Oral Estrogen-Progestln Combinations 1 mg estradiol-17-betal0.5 mg norethindrone acetate Activella Continuous combined regimen one pill daily

Medroxyprogesterone acetate 5 mg, 10 mg

Indications

Femhrt

5 pg ethinyl estradioV1 mg norethindrone acetate Continuous combined regimen one pill daily

To reduce the incidence of endometrial hyperplasia in nonhysterectomized women receiving estrogen Adverse Effects

Prefest

1 mg estradiol plus 1 mg estradioV0.09 mg norgestimate 3 days; 3 days alternating continuously; packaged as two separate tablets

Common: breast tenderness, nausea, irritability, weight change, fluid retention, sleep disturbance

Premphase 0.625 CEE 1-14 days and a combo tablet of CEE 0.625 mS/MPA 5 mg days 15-28 Packaged as two separate tablets Prempro

0.625/MPA 2.5 mg; or 0.625/MPA 5 mg Or 0.3/MPA 1.5 mg; or 0.45NPA 1.5 mg

Rare: thromboembolism, edema, rash; increased risk of breast cancer when used with estrogens Dosing and Administration Use for 12-14 consecutive days; start on day 16 or 21 of cycle when used in combination with estrogen.

Appendixes Potential Drug Interactions

Female

Drugs affected by oral progestins: warfarin (decrease), digoxin (decrease) Drug that affects oral progestins: rifampin (decrease) Progesterone Prometrium Oral micronized progesterone 100 mg, 200 mg; 200 mg daily for 12-14days or 100 mg daily Prochieve

4% vaginal progesterone

Progesterone is generally associated with less nuisance effects than progestins. It is unclear if progesterone has a better safety profile for more serious side effects. Natural progesterone may be used as a sleep aid. Estrogewlestosterone Estratest h.s. Esterified estrones 0.625h.25methyltestosterone Estratest

1.2512.5

Testosterone Androgel 1 % gel Testoderm

10 mglg (formulatedfor men) 1 patch delivers 4 mg over 24 hours (formulated for men) 1 patch delivers 6 mg over 24 hours

Androderm

1 patch delivers 2.5 mg over 24 hours (formulatedfor men) 1 patch delivers 5 mg over 24 hours

300 pg patch (not commercially available yet) testosterone patch

Indications Treatment of vasomotor symptoms in patients who do not respond to estrogen alone; androgens may improve libido, energy, and overall well-being Adverse Effects Common: virilization, changes in libido (increased or decreased), nausea, abdominal cramps, headache, breakthrough bleeding, breast tenderness, edema Rare: increased liver function tests, polycythemia,cholestatic hepatitis, jaundice, hypercalcemia, thromboembolism, stroke, endometrial cancer, breast cancer, hepatic adenoma, gallbladder disease, increased blood pressure Dosing and Administration Cycle 21 days on, 7 days off; can be used continuous Potential Drug Interactions Drugs affected by oral estrogens-androgens: warfarin (increase), cyclosporine (increase) Drugs that affect oral estrogens-androgens: barbiturates, phenytoin

Fasting-Patient

Guidelines Trevor K. Salloum, ND

WHY FAST? Fasting is one of the quickest ways to increase elimination of wastes and to enhance the reparative processes of the body. Fasting has been practiced throughout history and is universally employed in the animal kingdom. Scientific inquiry into fasting began in the early 1900s. Research has found it to be useful in the treatment of the following: Diabetes Epilepsy Obesity Psychologic illnesses Arthritis Heart disease Skin disease Toxic poisoning

Loss of minerals or vitamins is usually not of concern during a short fast; humans have effective biochemical mechanisms for adapting to long periods without food. The short fast (3 to 5 days) is a good chance for the body to acquire optimal rest, both mental and physical. This is an opportunity to build health, break old habits, and increase awareness of oneself. Although longer fasts are required in chronic disease, the short fast can be conducted at home, rather than at an inpatient facility. The ideal time to begin a fast is when hunger disappears or at the first sign of an illness. Although a short fast can be implemented at any time, it is better to begin on a weekend or during a time period when you can be inactive. The more rest, the better the results: energy can be directed toward healing instead of other body functions. Before embarking on a fast, check with your physician. If you are on any medications (including herbs and nutritional supplements) or have any chronic disease, slight alterations may be necessary. A physical examination is important before a fast to ensure there are no contraindications and to allow your physician to monitor your progress more effectively.

A positive mental outlook is important. The benefits of fasting include:

Decreased weight Clearer skin Increased elimination Tissue repair Decreased pain and inflammation Increased concentration Relaxation and spare time Savings in food costs Perhaps the greatest benefit is the satisfaction that you are taking a major role in improving your health.

FASTING DIRECTIONS StartingYour Fast Prepare for your fast on the day before you stop eating by making your last meal one of only fresh fruits and vegetables (some authorities recommend a full day of raw food to start a fast). In addition, finish all last-minute errands so that you can establish an environment as free of stress and responsibility as possible.

During the Fast Only water-distilled or spring water is best-should be taken by mouth while fasting. (Some authorities recommend fruit or vegetable juice, but this is actually an elimination diet rather than a fast.) The quantity of water should be dictated by thirst, but drink at least a few glasses every day. Take no coffee, tea, juice, soft drinks, cigarettes, or anything else by mouth except water. If possible, avoid the smell and sight of food. If you have to prepare food for other family members, satisfy your senses with the aroma-no sampling! Try to keep your mind away from food by reading a book (especially a book on fasting), listening to music, writing a letter, watching a movie, taking a leisurely walk in a park, driving to a pleasant destination, etc. Exercise is not usually encouraged while fasting. You want to conserve fuel and allow maximal healing. Short walks and light stretching are useful, but heavy 2181

workouts tax the system and inhibit repair and elimination. Cleansing the skin with lukewarm water is encouraged, but extremes of temperature can be tiring. Try to avoid deodorants, soaps, sprays, detergents, synthetic shampoos, and exposure to other chemicals. These only hinder elimination and add to the body's detoxification and elimination burden. Sunlight is essential for healthy cells, but excessive exposure will strain the body's protective systems. Try to obtain at least 10 to 20 minutes of direct sun exposure per day. Many fasting institutions have s o l a r i m in which guests sunbathe. Rest is one of the most important aspects of the fast. Try to take a nap or two during the day. You will probably require less sleep at night because your daily activity has decreased. Enemas are not usually necessary, but this will depend on your individual health. If you are worried about constipation, a longer prefast period of fresh fruits and vegetables will assist elimination. Body temperature usually drops during a fast, as do blood pressure and pulse and respiratory rates-all measures of the slowing metabolic rate of the body. Therefore it is important to stay warm. If needed, you may use a hot water bottle at night.

Breaking Your Fast Breaking your fast is a good time for you to consider carefully what you are eating and why. While breaking your fast, as outlined in Table A4-1, and in the days that follow, it can be helpful to you and your physician to carefully record what you eat and how you feel after eating. Many of today's health problems are due to food allergies and overeating. Take this time to choose which eating habits you truly want to establish. As you break your fast, eat slowly, chew thoroughly, limit quantities, eat foods at room temperature, and enjoy!

If You Have Problems Most discomfort during fasting is usually brief as the body works quickly to restore homeostasis. You may experience headaches, dizziness, nausea, coated tongue, bad odor, mild palpitations, and mucous discharge. If your symptoms are intolerable and persist, notify your physician or break your fast with an orange and resume fasting when symptoms disappear.

SUMMARY Importantly, although fasting is an effective way to improve your health, it is only one part of a total health-building program, not a panacea. Fresh air, rest, exercise, sunshine, pure food and water, emotional poise, and wholesome foods eaten in appropriate quantities are equally important in building and maintaining health.

Breakfast

Lunch

Dinner

Day 1 8 oz of any fruit One of the following: A different fruit from '12 melon the breakfast list l h nectarine l/4 pineapple Day 2 12 oz of one type 14 oz of whole pears, Raw vegetable salad of fresh fruit papaya, or citrus fruit with leafy greens, tomato, celery, and cucumber or two pears, two apples, and an avocado Day 3 Resume healthy diet-raw fresh fruits, rawlsteamed vegetables, whole grains, nuts, seeds, and legumes

Gluten and Gliadin Content of Selected Foods Food

Prolamines" (?A of total protein)

Gliadin (mg/l00 g)

Glutelins' (% of total protein)

Cross-reactivity with gliadin

1 0-15 9-14 8-14 7-13 8-10

40-50 30-50 10-15 50-55 1-5

6900 580 100 0 0

30-40 30-50 =5 30-45 85-90

+++ ++ +

9-13 7-16 1 3-15

S O

NA

NA

NA

57

0

30

NA

NA

4

High

-

Total Drotein ~~

Wheat Rye Oats Corn (maize) Rice Sorghum Millet Buckwheat

++++

-

Data from Baker PG. Lancet 1975;ii:1307; Friis SU. Clin Chim Acta 1988;178:261-270; and Chartrand W, Russo PA, Duhaime AG. et al. J Am Diet Assoc 1997;97:612-618. NA, No data available; +, degree of reactivity; -, no reactivity. 'Primarily gliadin. 'Primarily gluten.

2183

Glycemic Index, Carbohydrate Content, and Glycemic Load of Selected Foods A complete list of the glycemic index (GI) and glycemic load (GL) of all tested foods is beyond the scope of this book-it would be a book in itself. Therefore we have selected the most common foods. This listing provides a general sense of what is a high-GL and low-GL food. We have listed the items by food groups, from low to high GLs. Some food groups are not listed. For example,

Food

nuts, seeds, fish, poultry, and meats are not listed-they have little impact on blood sugar levels because they are low in carbohydrates. For a more complete listing, visit www.mendosa.com, a free website operated by medical writer Rick Mendosa. It is an excellent resource.

Glycemic index

Carbohydrates (9)

Fiber (9)

Glycemic load

Beans (Legumes) Soybeans, cooked, l/2 cup, 100 g Peas, green, fresh, frozen, boiled, I/z cup, 80 g

14

12

7

1.6

48

5

2

2

White navy beans, boiled,

38

11

6

4.2

cup, 90 g

Kidney beans, boiled, I/z cup, 90 g

27

18

7.3

4.8

Peas, split, yellow, boiled,

32

16

4.7

5.1

Lentils, VZ cup, 100 g

28

19

3.7

5.3

Lima beans, baby, l/2 cup cooked, 85 g

32

17

4.5

5.4

Black beans, canned, '/z cup, 95 g

45

15

7

5.7

Pinto beans, canned, % cup, 95 g

45

13

6.7

Chickpeas, canned, drained,

42

15

5

Kidney beans, canned and drained, I/z cup, 95 g

52

13

7.3

6.7

Broad beans, frozen, boiled, I/z cup, 80 g

79

9

6

7.1

Peas, dried, boiled, l/2 cup, 70 g

22

4

4.7

8

Baked beans, canned in tomato sauce, V2 cup, 120 g

48

21

8.8

10

Black-eyed peas, soaked, boiled, l/2 cup, 120 g Bread Multigrain, unsweetened, 1 slice, 30 g

42

24

5

10

43

9

cup, 90 g

l/2 cup,

95 g

1.4

5.8 63.

4

Oat bran and honey loaf, 1 slice, 40 g

31

14

1.5

4.5

Sourdough, rye, 1 slice, 30 g

48

12

0.4

6

Stoneground whole wheat, 1 slice, 30 g

53

11

1.4

6

Wonder, enriched white bread, 1 slice, 20 g

73

10

0.4

7

Sourdough, wheat, 1 slice, 30 g

54

14

0.4

7.5

Pumpernickel, 1 slice, 60 g

41

21

0.5

8.6

Whole wheat, 1 slice, 35 g

69

14

1.4

Healthy Choice, hearty 7-grain, 1 slice, 38 g

56

18

1.4

White (wheat flour), 1 slice, 30 g

70

15

0.4

10.5

Healthy Choice, 100% whole grain, 1 slice, 38 g

62

18

1.4

11

Gluten-free multigrain, 1 slice, 35 g

79

15

1.8

12

French baguette, 30 g

95

15

0.4

14

Hamburger bun, 1 prepacked bun, 50 g

61

24

0.5

15

Rye, 1 slice, 50 g

65

23

0.4

15

9.6 10

Continued

2185

Low- to high-glycemic foods by food groups-cont’d Glvcemic index

Carbohvdrates (a)

68 76 67 73 57 72

23 21 27 25 38 35

0.4 0.4 0.2 0.4 0.4 0.4

55 47 58 33 42 42 67 58 39 69 74 55 75 56 72 76 48 71 80 74 72 69 77 82 83 60 84 82 89 87 62 77 73 71

7 12 14 26 22 24 18 21 33 19 20 27 20 27 22 22 35 24 22 24 25 27 26 25 25 36 26 27 25 26 38 31 35 47

1 12.5 14 7 6.5 1.6 1.2 4.4 6 2 2 1 1 1 2 2 2 2 2 2 2 1 1 1 1 2 0.3 0.3 1 1 2 2 4 2

4 5.6 8 8.5 9.2 10 12 12 13 13 15 15 15 15 16 16.7 16.8 17 17.6 18 18 18 20 20.5 20.75 21.6 21.8 22 22 22.6 23.5 24 25.5 33.3

67 46 Cup cake, with icing and cream filling, 1 cake, 38 g 73 Chocolate fudge, mix (Betty Crocker), 73 g cake + 33 g frosting 38 Banana cake, 1 slice, 80 g 47

17 32 26 54 46

<1 <1 <1 <1 <1

11.5 14.7 19 20.5 21.6

Food Light rye, 1 slice, 50 g Dark rye, black, 1 slice, 50 g Croissant, 1, 50 g Kaiser roll, 1 roll, 50 g Pita, 1 piece, 65 g Bagel, 1,70g Breakfast Cereals Oat bran, raw, 1 tbsp, 10 g Bran with psyllium, l/3 cup, 30 g Bran, l/3 cup, 30 g All-Bran Soy ‘n Fiber, ’12 cup, 45 g All-Bran,

lh

cup, 40 g

Oatmeal (cooked with water), 1 cup, 245 g Shredded wheat,

l/3 cup,

25 g

Mini Wheats (whole wheat), 1 cup, 30 g All-Bran Fruit ’n Oats, l/z cup, 45 g Weet-Bix, 2 biscuits, 30 g Cheerios, l / ~cup, 30 g Frosties, 3/4 cup, 30 g Corn Bran, l/2 cup, 30 g Honey Smacks, 3/4 cup, 30 g Wheatbites, 30 g Total, 30 g Healthwise for Heart Health, 45 g Mini Wheats (blackcurrant), 1 cup, 30 g Puffed wheat, 1 cup, 30 g Bran Flakes, 3/4 cup, 30 g Crunchy Nut Cornflakes (Kellogg’s), 30 g Froot Loops, 1 cup, 30 g Cocoa Puffs, 3/4 cup, 30 g Team, 30 g Corn Chex, 30 g Just Right, 3/4 cup, 30 g Corn Flakes, 1 cup, 30 g Rice Krispies, 1 cup, 30 g Rice Chex, 1 cup, 30 g Crispix, 30 g Just Right Just Grains, 1 cup, 45 g Oat ’n Honey Bake, 45 g Raisin Bran, 1 cup, 45 g Grape Nuts, l/2 cup, 58 g Cake Angel food, 1 slice, 30 g

Sponge cake, 1 slice, 60 g

Fiber (a)

Glvcemic load

16 16 18 18 22 25

Appendixes Low- to high-glycemic foods by food groups-cont’d Food Pound cake, 1 slice, 80 g French vanilla (Betty Crocker), 73 g cake + 33 g frosting Lamingtons, 1, 50 g Flan, 1 slice, 80 g Scones, made from packet mix, 1 scone, 40 g Crackers Corn Thins, puffed corn cake, 2,12 g Kavli, 4,20 g Breton wheat crackers, 6,25 g Ryvita or Wasa, 2,20 g Stoned Wheat Thins, 5, 25 g Premium soda crackers, 3,25 g Water cracker, 5, 25 g Graham, 1,30g Rice Cake, 2,25 g Milk, Soy Milk, and Juices Milk, full fat, 1 cup, 250 ml Soy, 1 cup, 250 ml Milk, skim, 1 cup, 250 ml Grapefruitjuice, unsweetened, 1 cup, 250 ml Nesquik chocolate powder, 3 tsp in 250 ml milk Milk, chocolate flavored, low fat, 1 cup, 250 ml Orange juice, 1 cup, 250 ml Gatorade, 1 cup, 250 ml Pineapple juice, unsweetened, canned, 250 ml Apple juice, unsweetened, 1 cup, 250 ml Cranberry juice cocktail (Ocean Spray USA), 240 ml Coca-Cola, 375 ml Other sofl drinks, 375 ml Milk, sweetened condensed, VZ cup, 160 g Fruit Cherries, 20 cherries, 80 g Plums, 3-4small, 100 g Peach, fresh, 1 large, 110 g Apricots, fresh, 3 medium, 100 g Apricots, dried, 5-6pieces, 30 g Kiwi, 1, raw, peeled, 80 g Orange, 1 medium, 130 g Peach, canned, natural juice, l/z cup, 125 g Pear, canned in pear juice, l/z cup, 125 g Watermelon, 1 cup, 150 g Pineapple, fresh, 2 slices, 125 g Apple, 1 medium, 150 g Grapes, green, 1 cup, 100 g Apple, dried, 30 g Prunes, pitted (Sunsweet), 6 prunes, 40 g Pear, fresh, 1 medium, 150 g

Glycemic index

Carbohydrates (9)

54 42 87 65 92

42 58 29 55 90

Fiber (g)


22.6 24.4 25 35.75 83

87 71 67 69 67 74 78 74 82

9 13 14 16 17 17 18 22 21


0.4

7.8 9.2 9.4 11 11.4 12.5 14 16 17

27 31 32 48 55 34 46 78 46 40 68 63 68 61

12 12 13 16 14 23 21 15 27 33 34 40 51 90

0 0 0 1 0 0 1 0 1 1 0 0 0 0

3 3.7 4 7.7 7.7 7.8 9.7 11.7 12.4 13.2 23 25.2 34.7 55

22 39 42 57 31 52 44 38 43 72 66 38 46 29 29 38

10 7 7 7 13 8 10 12 13 8 10 18 15 24 25 21

2.4 2.2 1.9 1.9 2.2 2.4 2.6 1.5 1.5 1 2.8 3.5 2.4 3.0 3.0 3.1

3 2 3 1 0 0

I .4

Glycemic load

2.2 2.7 3 4 4 4 4.4 4.5 5.5 5.7 6.6 6.8 6.9 6.9 7.25 8 Continued

Food

Glvcemic index

Carbohvdrates (Q)

Fiber (0)

55

15

1.5

8.25

64

13

1.5

8.3

52

18

1.5

9.4

Mango, 1 small, 150 g

55

19

2.0

10.4

Figs, dried, tenderized (water added), 50 g

Fruit cocktail, canned in natural juice,

'12

cup, 125 g

Apricots, canned, light syrup, llz cup, 125 g Peach, canned, light syrup,

'12

cup, 125 g

Glvcemic load

61

22

3.0

13.4

Sultanas, '14 cup, 40 g

56

30

3.1

16.8

Banana, raw, 1 medium, 150 g

55

32

2.4

17.6

Raisins, '14 cup, 40 g

64

28

3.1

18

103

27

3.0

27.8

Dates, dried, 5, 40 g Grains Rice bran, extruded, 1 tbsp, 10 g

19

3

1

0.57

Barley, pearled, boiled, l/2 cup, 80 g

25

17

6

4.25

Millet, cooked, '12 cup, 120 g

71

12

1

Bulgur, cooked, '13 cup, 120 g

48

22

3.5

10.6

8.52

Brown rice, steamed, 1 cup, 150 g

50

32

1

16

Couscous, cooked, 2/3 cup, 120 g

65

28

1

18

White rice, boiled, 1 cup, 150 g

72

36

0.2

26

Arborio risotto rice, white, boiled, 100 g

69

35

0.2

29

Basmati rice, white, boiled, 1 cup, 180 g

58

50

0.2

29

Buckwheat, cooked, '12 cup, 80 g

54

57

3.5

30

Instant rice, cooked, 1 cup, 180 g

87

38

0.2

33

Tapioca (steamed 1 hr), 100 g

70

54


38

Tapioca (boiled with milk), 1 cup, 265 g

81

51

<1

41

109

39

0.2

Jasmine rice, white, long grain, steamed, 1 cup, 180 g Ice Cream Low-fat French vanilla, 100 ml

42.5

38

15

0

5.7

Full fat, 2 scoops, 50 g Jam No sugar, 1 tbsp, 25 g

61

10

0

6.1

55

11

<1

6

Sweetened, 1 tbsp Muffins and Pancakes Chocolate butterscotch muffins, from mix, 50 g

48

17

<1

8

53

28

1

15

Apple muffins, oat and sultana, from mix, 50 g

54

28

1

15

Apricot muffins, coconut and honey, from mix, 50 g

60

27

1.5

16

Banana muffins, oat and honey, from mix, 50 g

65

28

1.5

18

Apple muffins, 1 muffin, 80 g

44

44

1.5

19

Bran muffins, 1 muffin, 80 g

60

34

2.5

20

Blueberry muffins, 1 muffin, 80 g

59

41

1.5

24

102

30

2

30

67

58

1

39

Tortellini, cheese, cooked, 180 g

50

21

2

Ravioli, meat-filled, cooked, 1 cup, 220 g

39

30

2

10.5 11.7

Vermicelli, cooked, 1 cup, 180 g

35

45

2

15.7

Rice noodles, fresh, boiled, 1 cup, 176 g

40

44

0.4

17.6

Spaghetti, whole meal, cooked, 1 cup, 180 g

37

48

3.5

17.75

Fettucini, cooked, 1 cup, 180 g

32

57

2

18.2

Spaghetti, gluten free in tomato sauce, 1 small tin, 220 g

68

27

2

18.5

Buckwheat pancakes, from dry mix, 40 g Pancake, from dry mix, 1 large, 80 g Pasta

Appendixes

Food Macaroni and cheese, packaged, cooked, 220 g Star pastina, cooked, 1 cup, 180 g Spaghetti, white, cooked, 1 cup, 180 g Rice pasta, brown, cooked, 1 cup, 180 g Sugars Fructose, 10 g Honey, VZ tbsp, 10 g Lactose, 10 g Sucrose, 10 g Glucose, 10 g Maltose, 10 g Snacks Corn chips, Doritos original, 50 g Snickers, 59 g Tofu frozen dessert (nondairy), 100 g Real fruit bars, strawberry, 20 g Twix cookie bar (caramel), 59 g Pretzels, 50 g Mars candy bar, 60 g Skittles, 62 g soups Tomato, canned, 220 ml Black bean, 220 ml Lentil, canned, 220 ml Split pea, canned, 220 ml Vegetables Carrots, raw, VZ cup, 80 g Low-glycemic vegetables:

Glycemic index

Carbohydrates (9)

Fiber (9)

Glycemic load

64 38 41 92

30 56 56 57

2 2 2 2

19.2 21 23 52

23 58 46 65 102 105

10 16 10 10 10 10

0

2.3 4.6 4.6 6.5 10.2 10.5

42 41 115 90 44

<1 0 <1 <1 <1

83 65 70

33 35 13 17 37 22 41 55

38 64 44 60

15 9 14 13

1.5 3.4 3 3

6 6 6 8

16 =20

6 17

1.5 ~1.5

1 =1.4

49 64 75

3 5 6

1.5 1 3.4

1.5 3 4.5

0

<1 0

0

13.9 14.3 15 15.3 16.2 18.3 26.6 38.5

Asparagus, 1 cup cooked or raw Bell peppers, 1 cup cooked or raw Broccoli, 1 cup cooked or raw Brussels sprouts, 1 cup cooked or raw Cabbage, 1 cup cooked or raw Cauliflower, 1 cup cooked or raw Cucumber, 1 cup Celery, 1 cup cooked or raw Eggplant, 1 cup Green beans, 1 cup cooked or raw Kale, 1 cup cooked, 2 cups raw Lettuce, 2 cups raw Mushrooms, 1 cup Spinach, 1 cup cooked, 2 cups raw Tomatoes, 1 cup Zucchini, 1 cup cooked or raw Carrots, peeled, boiled, VZ cup, 70 g Beets, canned, drained, 2-3slices, 60 g Pumpkin, peeled, boiled, Vz cup, 85 g

Continued

Low- to high-glycemic foods by food groups--cont'd Food

Glycemic index

Fiber (9)

Glycemic load

3

8

14

2.9

8

15 16

3 3.4

8.5 8.6

55

18

3

10

Potatoes, peeled, boiled, 1 medium, 120 g

87

13

1.4

10

Potatoes, with skin, boiled, 1 medium, 120 g

79

15

2.4

11

Yam, boiled, 80 g

51

26

3.4

13

Potatoes, baked in oven (no fat),l medium, 120 g

93

15

2.4

14

Potatoes, mashed, '12 cup, 120 g

91

16

1

14

Potatoes, instant, prepared, VZ cup

83

18

1

15

Potatoes, new, unpeeled, boiled, 5 small (cocktail), 175 g

78

25

2

20

Cornmeal (polenta), l/3 cup, 40 g

68

30

2

20

French fries, fine cut, small serve, 120 g

75

1

36

Gnocchi, cooked, 1 cup, 145 g Yogurt Yogurt, low fat, artificial sweetener, 200 g

68

49 71

1

48

14

12

26

30

Yogurt, low fat, 200 g

33

26

0 0 0

2

Yogurt, with fruit, 200 g

Parsnips, boiled, '12 cup, 75 g

Carbohydrates (9)

97

8

Sweet corn on the cob, boiled 20 min, 80 g

48

Corn, canned and drained,

Sweet potato, peeled, boiled, 80 g

55 54

Sweet corn,

l12

l l cup, ~

80 g

cup boiled, 80 g

8 8.5

Hydrochloric Acid Supplementation: Patient Instructions PURPOSE The purpose of this self-test is to estimate the amount of supplemental hydrochloric acid (HC1) you need to reestablish adequate stomach acid. Adequate stomach acid is critical for initiating digestion and protecting the intestinal tract from microbial pathogens.

DIRECTIONS 1. Begin by taking 1 HC1 capsule (10 grains) at your next large meal. At every meal after that of the same size, take 1 more capsule (1 capsule at the next meal, 2 at the meal after that, then 3 at the next meal, and so on). 2. Continue to increase the dose until you reach 7 capsules or you feel a warmth in your stomach, whichever occurs first. A feeling of warmth in the stomach means that you have taken too many capsules for a meal of

that size. Take 1 less capsule the next time. However, it is a good idea to try the larger dose again at another meal to make sure that it was the HC1 that caused the warmth and not something else. 3. After you have determined the largest dose that you can take at your large meals without feeling any warmth, maintain that dose at all meals of similar size. Take fewer capsules with smaller meals. 4.When taking several capsules, it is best to take them throughout the meal rather than all at once. 5. As your stomach begins to regain the ability to produce the amount of HC1 needed to properly digest your food, you will notice the warm feeling again. This is the time to start decreasing the dose level. 6. Every 3 days, decrease by 1 capsule per meal. If the warmth continues, decrease more rapidly. If maldigestion symptoms return, add capsules back until digestion improves again.

2191

The Optimal Health Food Pyramid The Optimal Health Food Pyramid, shown in Figure A8-1, incorporates the best from two of the most healthful diets ever studied-the traditional Mediterranean diet and the traditional Asian diet. In addition, The Optimal Health Food Pyramid more clearly defines what the healthy components within the categories are and stresses the importance of vegetable oils and regular fish consumption as part of a healthful diet (Table AS-1).

FOODS TO AVOID ENTIRELY Refined white flour products: pastas, cakes, muffins, pretzels, etc. Refined sugar-loaded cereals, candies, baked goods, etc. Processed foods packed full of empty calories (sugar and fat) or salt ( e g , soups, theater-style popcorn, chips, etc.) Margarine, butter, and shortening Smoked or cured meats: bacon, hot dogs, smoked luncheon meats, sausages, ham, spam, etc. Meats cooked at extremely high temperatures or cooked to well done Heavily sweetened or artificially sweetened soft drinks, Kool-Aid, juice-flavored drinks, etc. Fried foods, including French fries, potato chips, corn chips, and doughnuts

We have divided vegetable intake into three categories: green leafy and cruciferous vegetables; low-glycemicvegetables; and starchy vegetables. This approach encourages eating a variety of these life-giving foods, helps achieve a "rainbow assortment" in the diet, and enables a focus on low-glycemicchoices. One serving of vegetables equals any of the following: 1cup raw leafy vegetables (such as lettuce or spinach) */2 cup raw nonleafy vegetables '/2 cup cooked vegetables or fresh vegetable juice Box AS-1 offers easy tips to increase daily intake of fruits and vegetables.

Green Leafy and Cruciferous Vegetables: 2 to 4 Servings Daily Alfalfa sprouts Beet greens Bok choy Broccoli Brussels sprouts Cabbage Cauliflower Chard Chinese cabbage

VEGETABLES: 5 TO 7 SERVINGS DAILY In Latin, the word vegetable means "to enliven or animate." Vegetables give us life and should be the main focus of any health-promoting diet. Vegetables provide the broadest range of nutrients of any food class. They are rich sources of vitamins, minerals, carbohydrates, and protein. Vegetables also provide high quantities of anticancer phytochemicals. It is very important not to overcook vegetables. Overcooking not only results in loss of important nutrients but it also alters the flavor of the vegetable. Light steaming, baking, and quick stir-frying are the best ways to cook vegetables. Do not boil vegetables unless you are making soup, as much of the nutrients will leach into the water. If fresh vegetables are not available, frozen vegetables are preferred over their canned counterparts. The only exception is tomato products (e.g., soup, paste, sauce, etc.); especially when they also contain oil, canned tomato products actually provide more absorbable lycopene than raw tomatoes.

Exercise Stretching

Figure A8-1

Pure Water 8-12 glasses

The Optimal Health Food Pyramid.

2193

Starchy Vegetables: 1 to 2 Servings Daily

Collard greens Dandelion Endive Escarole Kale Lettuce (the darker, the better) Mustard greens Parsley Spinach Turnip greens Watercress

Beets Parsnip Potato Pumpkin Rhubarb Rutabaga Winter, acorn, or butternut squash Yam or sweet potato

NUTS, SEEDS, AND GOOD OILS: 4 SERVINGS DAILY

Low-Glycemic Vegetables: 2 to 3 Servings Daily Artichoke (1 medium) Asparagus Bean sprouts Bell peppers Carrots Celery Cucumber Fennel Mushrooms Okra Onions Peas (fresh or frozen) Radishes Rhubarb String beans, green or yellow Summer squash Tomatoes, tomato paste, tomato sauce, tomato juice, vegetable juice cocktail zucchini

I

Daily food group recommendations for a 2000-calorie diet

Food

No. servinas

Vegetables: Total servings Green leafy and cruciferous vegetables Low-glycemic vegetables Other vegetables

5-7 2-4 2-3 1-2

Good oils: Total servings Nuts and seeds Olive, macadamia, flaxseed, or canola oil Whole grains Legumes High-quality protein Fruit Dairy

4 1 2-3 3-5 2-3(4-5if vegetarian) 2-3 2-3 1-2(optional)

Nuts and seeds provide the beneficial oils, especially the monounsaturated and medium-chain fatty acids. Regular consumption of nuts has been shown to

Buy many kinds of fruits and vegetables when grocery shopping,

so plenty of choices are available. Stock up on frozen vegetables for easy cooking so that a vegetable dish can easily be served with every dinner. Use the fruits and vegetables that go bad quickly (peaches, asparagus) first. Save hardier varieties (apples, acorn squash) or frozen goods for later in the week. Keep fruits and vegetables where they are easily and frequently seen. The more often they are seen, the more likely they are to be eaten. Keep a bowl of cut-up vegetables on the top shelf of the refrigerator. Make up a big tossed salad with several kinds of greens, cherry tomatoes, cut-up carrots, red pepper, broccoli, scallions, and sprouts. Refrigerate in a large glass bowl with an air-tight lid, so a delicious mixed salad will be ready to enjoy for several days. Keep a fruit bowl on your kitchen counter, table, or desk at work. Treat yourself to a fruit sundae: Top a bowl full of your favorite cut up fruits with vanilla yogurt, shredded coconut, and a handful of nuts. Pack a piece of fruit or some cut-up vegetables in your briefcase or backpack; carry moist towelettes for easy cleanup. Add fruits and vegetables to lunch by having them in soup or salad or cutting them up to eat raw. Use thinly sliced pears or apples in omelets. At dinner, serve steamed or microwaved vegetables. Increase portions when serving vegetables. One easy way of doing so is adding fresh greens such as Swiss chard, collards, or beet greens to stir-fry dishes. Serve fresh fruit for dessert. Add visual and taste appeal by serving with nuts, cheese, or yogurt. For example, serve grapes or sliced apple with cheese or a fruit parfait made with low-fat yogurt or topped with berries. Add extra varieties of vegetables to soups, sauces, and casseroles (for example, add grated carrots and zucchinis to spaghetti sauce). Take advantage of salad bars, which offer ready-to-eat raw vegetables and fruits and prepared salads made with fruits and vegetables. Use vegetable-basedsauces such as marinara sauce and juices such as low-sodium vegetable juice (V-8) or tomato juice. Freeze lots of blueberries and grapes, to use as summer replacements for ice cream, popsicles, and other sugary foods.

.

Appendixes

improve blood sugar regulation and lower the risk for diabetes, heart disease, obesity, and cancer. Focus on raw nuts and seeds. Definitely avoid nuts and seeds roasted in oils or coated with sugar. Nuts and seeds make excellent additions to salads and sauteed greens. Try to eat a variety of nuts and seeds, such as almonds, Brazil nuts, walnuts, pecans, flaxseeds, sunflower seeds, and pumpkin seeds. Use olive, macadamia, flaxseed, or canola oil both in salad dressings and to replace butter, margarine, and shortening used for cooking. Never cook with flaxseed oil; it is too rich in polyunsaturated fats, which are easily damaged by heat. Coconut and macadamia nut oil are the best cooking oils because of their ability to remain stable during high temperatures, but olive oil is a good choice for sauteed vegetables, and canola oil is usually best for baked goods because it has the mildest flavor. Coconut oil is also very stable in cooking and is fine to use in small quantities; it contains saturated fat but is metabolized differently from animal-derived saturated fats and can be used safely in moderation. Avoid using safflower, sunflower, soy, and corn oils because they contain too much omega-6 fatty acid (as discussed in Chapter 44). We recommend at least 1 serving of nuts or seeds (1 serving equals '14 cup) and 3 tbsp of the healthy oils daily. In addition, we recommend taking a high-quality fish oil supplement.

WHOLE GRAINS: 3TO 5 SERVINGS DAILY It is very important to choose whole-grain products (e.g., whole-grain breads, whole-grain flour products, brown rice) over their processed counterparts (white bread, white flour products, white rice, etc.). Whole grains provide substantially more nutrients and healthpromoting properties. Whole grains are a major source of complex carbohydrates, dietary fiber, magnesium and other minerals, and B vitamins. The content and quality of the protein in whole grains are also greater than in refined grains. Diets rich in whole grains have been shown to be helpful in both prevention and treatment of diabetes, heart disease, and cancer. Table A8-2 defines servings of various whole grains.

beans retain their fiber content and anticancer flavonoids. Plus, given the long preparation time for cooking beans, canned beans are extremely quick and convenient. A serving size for beans is '12 cup.

FRUITS: 3TO 4 SERVINGS DAILY Fruits are a rich source of many beneficial nutrients, and regular fruit consumption has been shown to offer significant protection against chronic degenerative diseases, including cancer, heart disease, cataracts, diabetes, and strokes. Fruits make nutrient-dense, easy between-meal snacks and desserts (e.g., nothing could be simpler than phytonutrient-rich fresh berries alone). It is easy to get into the habit of eating only a few varieties of fruit. We encourage eating a "rainbow assortment" of fruits over the course of a week. A general rule of thumb is that 1 serving of fruit equals one of the following: 1 medium fruit '12 cup of small or cut-up fruit 4 oz of 100% juice '14 cup dried fruit

See Box A8-1 for easy tips to increase daily intake of fruits and vegetables.

HIGH-QUALITY PROTEIN: 2 to 3 SERVINGS DAILY The detriment of diets high in saturated fat and cholesterol has been stressed for decades. Likewise, the importance of the omega-3 fatty acids in the battle against development of chronic disease is now also well known. Fish consumption, in particular, has shown tremendous protection against heart disease and cancer. Choose smaller species of fatty fish such as wild salmon, mackerel, herring, and sardines. Their smaller size and shorter

Single servings of whole grains

BEANS (LEGUMES): 2 TO 3 SERVINGS DAILY Beans are a mainstay in most diets of the world and are second only to grains in supplying calories and protein to the world's population. Compared with grains, they supply about the same number of total calories but usually provide 2 to 4 times as much protein and are a richer source of the soluble fiber that lowers cholesterol and stabilizes blood glucose levels. Although we do not recommend using canned vegetables or fruit, canned

Bread: whole wheat, rye or other whole grain

1 slice

Cereals:whole grain Corn: Cooked whole kernel corn Corn on the cob

'12

cup

'12

cup

Flour and flour products: Whole-wheat flour (uncooked) Whole-grain pasta (cooked) Whole grains (cooked): rice, oats, wheat, barley, quinoa, spelt, etc.

1 small

2% tbsp '12 'I2

cup cup

lifespan translate into a lower accumulation of mercury (BOXA8-2). Therefore we recommend eating fish at least three, but no more than six, times per week. Keep intake of red meat (beef, veal, or lamb) to no more than 2 servings per month, and choose the leanest cuts possible; keep the portion size limited to about the size of a deck of cards, and do not charbroil or cook the meat until well done, because this practice increases the formation of

Fish consumption offers significant protection against heart disease and many forms of cancer, especially the major cancers like those of the lung, colon, breast, and prostate. Although we encourage the eating of more fish, some guidelines are necessary. Nearly all fish contain trace amounts of methyl mercury. In most cases this is of little concern, because the level is so low. The fish most likely to have the lowest level of methyl mercury are salmon (usually nondetectable levels), cod, mackerel, cold-water tuna, farm-raised catfish, and herring. But certain seafood, particularly swordfish, shark, and some other large predatory fish, may contain high levels of methyl mercury. Fish absorb methyl mercury from water and aquatic plants. Larger predatory fish also absorb mercury from their prey. Methyl mercury binds tightly to the proteins in fish tissue, including muscle; cooking does not reduce the mercury content significantly. We suggest limiting intake to no more than about 2 Ib (1 kg) per week. That translates to six 7-02 servings per week maximum. Limit intake of swordfish, shark, and warm-water tuna to no more than once a week (or once a month for women of childbearing age who might get pregnant).

cancer-causing compounds. Also, consider some of the alternatives to beef, such as venison, buffalo, elk, rabbit, and ostrich; these emerging beef alternatives are lower in saturated fat and provide higher levels of omega-3 fatty acids. Chicken and turkey can also provide excellent protein with very little fat, especially if only the white meat (breast) without the skin is eaten. Eggs are also a very good source of high-quality protein, and if produced by free-range hens fed flaxseed meal, they will be rich in beneficial omega-3 fatty acids. One serving equals about the size of a deck of cards; that translates to roughly 4 oz.

DAIRY: 1 OR 2 SERVINGS DAILY (OPTIONAL) We have found that many people are allergic to milk or lack the enzymes necessary to digest dairy products. Even for people who do tolerate dairy foods, milk consumption should be limited to no more than 1 or 2 servings per day. Use nonfat or reduced-fat dairy products rather than whole-milk varieties. Also, fermented dairy products like yogurt, kefir, and acidophilus-fortified milk are preferred over milk. Some of the soy milk alternatives to cow’s milk are delicious, especially when flavored with vanilla or chocolate. If dairy products are not consumed, we recommend a calcium supplement. One serving of dairy products equals 1 cup of milk, yogurt, or cottage cheese or 1 oz of cheese.

Patient Instructions for Measuring Basal Body Temperature PURPOSE

INTERPRETATION

Your body temperature reflects your metabolic rate, which is largely determined by hormones secreted by the thyroid gland and by the ability of your cells to convert these hormones to their more active form. Your level of thyroid activity can be determined simply by measuring your basal body temperature. All you need is a high-quality thermometer.

Your basal body temperature should be between 97.6" and 98.2" F. Low basal body temperatures are quite common and may reflect hypothyroidism. Common signs and symptoms of hypothyroidism are as follows: - _- .

PROCEDURE 1. Place the thermometer by your bed before going to sleep at night. If using a mercury thermometer, shake it down to below 95" F. 2. On waking, place the thermometer in your armpit for a full 10 minutes. It is important to make as little movement as possible. Lying and resting with your eyes closed is best. Do not get up until the 10-minute measurement is completed. 3. After 10 minutes, read and record the temperature and date (a convenient form is printed as Figure A9-1). 4. Record the temperature for at least 3 momings (preferably at the same time of day) and give the information to your physician. Menstruating women must perform the test on the second, third, and fourth days of menstruation. Men and postmenopausal women can perform the test at any time.

Depression Difficulty in losing weight Dry skin Headaches Lethargy or fatigue Menstrual problems Recurrent infections Sensitivity to cold High basal body temperatures (>98.6" F) are less common but may be evidence of hyperthyroidism. Common signs and symptoms of hyperthyroidism are as follows: Bulging eyeballs Fast pulse Hyperactivity Inability to gain weight Insomnia Irritability Menstrual problems Nervousness

2197

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Figure A9-1

Form for recording temperature and date when measuring basal body temperature.

Temp.

Rotation Diet Master Chart, Plans I and 11% Sally J. Rockwell, PhD, CCN

PLAN I Table A10-1 contains the information for Plan I of the Rotation Diet.

Food family Proteins: Fin fish Shellfish Fowl flesh and eggs Red meat Dairy Legumes

Day 1 (green)

Day 2 (yellow)

Day 3 (blue)

Fish may be eaten daily as long as a different fish is selected each day Oysters, scallops, abalone Mussel,escargot, clam Shrimp Chicken, goose Turkey tf Cornish game hen, quail, pheasant Beef (veal, liver, etc.) Cow (milk, yogurt, cheeses) Kidney, soy, and lima beans

Pork (ham, bacon, etc.), lamb Goat (milk, yogurt, cheeses) Pinto, garbanzo, and black beans; black-eyed and split peas Nut, seed, and legume

Day 4 (red)

Crab, squid, octopus Duck Rabbit

Nut and seed

Nut, seed, and legume

Nut and seed

Nuts, Seeds and Oils

Soy, walnuts Filbert H Sesame t)

Almonds Pine nuts t) Brazil nuts t) Sunflower, apricot

Peanut, pecan, pumpkin Chestnuts tf Macadamia t)

Cashew, pistachio, safflower, corn Avocado t) Olive tf

Grains and Flours

Buckwheat, soy, quinoa, tofu, arrowroot, guar gum

Rice, millet, rye, potato, flaxseed, xanthan gum

Amaranth, garbanzo, kudzu root, chestnut

Barley, oats, wheat, corn, tapioca, agar t)

Sweeteners

Honey, raisins

Dates, molasses, rice syrup

Figs, currants

Coconut, malt, sago palm, maple syrup

Beets, Swiss chard Cabbage, broccoli, white radish, kale, nappa

Carrots, parsley

Spinach Bok choy, red radish, Brussels sprouts, cauliflower

Avocado Parsnip, celery

Sprouts

Vegetables: Beet Mustard

Leaf and bib lettuce, common artichoke

Cornposite Gourd Lily Nightshade Miscellaneous

Cucumber, winter squash Onion, garlic String beans

White potato, peppers Yams tf Jicama tf Mushrooms t)

Iceberg lettuce, romaine Summer squash, pumpkin, zucchini Chives, leeks, shallots, asparagus Chestnuts Peas Okra H Olives t)

Tomato, eggplant, peppers Bamboo shoots Jerusalem artichoke t) Sweet potato tf

~

A food that is essentially the only food of a family and that will not cross-react with other foods.

t),

Continued

All infomation from The Rotation Game, Copyright Q 2003. All rights reserved, SJ Rodwell, PhD.

2199

Rotation Diet master chart, Plan Lcont’d Food family

Day 1 (green)

Fruits: Plum Apple Citrus Berries

Apple

Day 2 (yellow)

Day 3 (blue)

Peach, cherry, nectarine

Plum, prune, apricot

Gourd Miscellaneous

Boysenberry, blackberry, strawberry Melons Rhubarb, grapes Papaya t) Persimmon tf

Bulk

Pectin

Day 4 (red)

Pear, quince Lemon, orange, kumquat Huckleberry, cranberry Logan berry, raspberry, gooseberry

Kiwi tf Guava t) Flaxseed ts

Lime, grapefruit, tangerine Blueberry

Cantaloupe, melons Pineapple tf

Pomegranate tf Mango, banana tt

Chia seed tf

Psyllium seed

PLAN II Table A10-2 contains the information for Plan I1 of the Rotation Diet.

Rotation Diet master chart, Plan II

Proteins

Nuts and

seeds Oils

Grains and Flours

Sweeteners

Day 1 (green)

Day 2 (yellow)

Day 3 (blue)

Day 4 (red)

Fin fish: Anchovy, bass, butterfish, catfish, cod, flounder. herring, mackerel, halibut, perch, salmon, snapper, sole, trout, tuna, turbot, etc.

Red meat: Beef (veal, liver, etc.), lamb, pork (ham, bacon, etc.), rabbit

Shellfish: Abalone, clam, crab, escargot, mussel, octopus, oysters, scallops, shrimp, squid Frog legs tf

Fowl (flesh and eggs): Chicken, Cornish game hen, duck, goose, pheasant, quail, turkey Rabbit tf

Legumes (all beans and peas): Black, garbanzo, kidney, lima, pinto, and soy beans; black-eyed and split peas; tofu Sprouts

Dairy: Cow (milk, yogurt, cheeses), goat (milk, yogurt, cheeses) Sprouts

Grass family: Bamboo shoots, barley, corn, millet, oats, rice, rye, wheat, kamut, spelt. teff Sprouts

Peanut, soy, pecans, walnut Sesame t)

Filbert tf Pine nut tf Pumpkin seeds

Peanut, soy Sesame tj Walnut Arrowroot tt Garbanzo, peanut, soy Kudzu root tf

Animal fat, butter Avocado ts Olive tf Agar agar tf Amaranth, quinoa Flaxseed meal tf Gelatin Molasses, rice syrup Whey, lactose

Almond Brazil nut tf Chestnut t) Macadamia tf Almond, apricot, coconut Corn Cotton seed Grass family flours Chestnut flour tf Xanthan gum t)

Honey tf Fig t) Raisins tf

Palm family: Coconut, date, sago Corn syrup

Sprouts Cashew, pistachio, sunflower seeds

Safflower, sunflower Chicken, turkey, and other poultry fats Buckwheat Potato Quinoa ts Tapioca t) Malt syrup tf Currants tf

Appendixes Rotation Diet master chart, Plan Il-cont'd

Vegetables

Fruits

Bulk tf,A

Day 1 (green)

Day 2 (yellow)

Day 3 (blue)

Day 4 (red)

Carrot family: Carrot, celery, dill, parsley, parsnip

Gourd family (all squash): Cucumber, pumpkin, summer squash, winter squash, zucchini

Mustard family: Bok choy, broccoli, Brussels sprouts, cabbage, cauliflower, kale, nappa, radish

Composite family: Common artichoke, dandelion greens, and bib, iceberg, leaf, and romaine lettuces

Lily family: Asparagus, chives, garlic, leeks, onion, shallots

Beet family: Beets, spinach, Swiss chard

Bamboo shoots, corn

Nightshade: Eggplant, white potato, peppers, pimento, and tomato

Peas, string beans, fava beans

Avocado tf Olives t) Sweet potato tj Heather family: Blueberry, cranberry, huckleberry

Okra Chestnuts fs

Rhubarb Yam, yucca t) Mushroom t) Citrus family: Grapefruit, kumquat, lemon, lime, orange, tangerine

All melons, cantaloupe

Guava t)

Gooseberry

Pomegranate t) Kiwi t)

Persimmon t) Pineapple tf

Flaxseed

Chia seed

Currant t) Mango tf Banana tf Psyllium seed

Apple family: Apple, pear, quince

Rose family: Boysenberry, blackberry, strawberry, Logan berry, raspberry Papaya tf Fig t) Grape, raisin tf Pectin

Prune family: Apricot, cherry, nectarine, peach, plum, prune

food that is essentially the only food of a family and that will not cross-reactwith other foods.

Seligman’s Attributional Style Questionnaire What distinguishes an optimist from a pessimist is the way in which they explain both good and bad events. Dr. Martin Seligman has developed a simple test to determine your level of optimism (from Learned Optimism, Knopf, 1981). Take as much time as you need. There are no right or wrong answers.It is important that you take the test before you read the interpretation. 1. The project you are in charge of is a great success.

A. I kept a close watch over everyone’s work. B. Everyone devoted a lot of time and energy to it. 2. You and your spouse (boyfriencUgirlfriend) make up after a fight. A. I forgave hidher. B. I’m usually forgiving. 3. You get lost driving to a friend’s house.

PsG 1

0 PmG 0

Read the description of each situation and vividly imagine it happening to you. Choose the response that most applies to you by circling either A or B. Ignore the letter and number codes for now; they will be explained after you take the test.

13. You owe the library ten dollars for an overdue book. A. When I am really involved in what I am reading, I often forget when it‘s due.

1

B. I was so involved in writing the report that I forgot to return the book.

0

14. Your stocks make you a lot of money.

1

A. My broker decided to take on something new.

PsB

B. My broker is a top-notch investor.

A. I missed a turn.

1

15. You win an athletic contest.

B. My friend gave me bad directions.

0

A. I was feeling unbeatable.

4. Your spouse (boyfriendgirlfriend) surprises you with a gift.

PsG

8. I train hard.

A. He/shejust got a raise at work. B. I took hidher out to a special dinner the night before. 5.You forget your spouse’s (boyfriend‘dgirlfriend‘s) birthday. A. I’m not good at remembering birthdays. B. I was preoccupied with other things. 6. You get a flower from a secret admirer. A. I am attractive to himher. B. I am a popular person. 7. You run for a community office position and you win.

0 1

A. I devote a lot of time and energy to campaigning. B. I work very hard at everything I do. 8. You miss an important engagement. A. Sometimes my memory fails me. 8. I sometimes forget to check my appointment book. 9.You run for a Community office position and you lose. A. I didn’t campaign hard enough. B. The person who won knew more people.

PmB 1 0

PvG 0

1 PvG

0 1

PmG 0

1 PmG

0 1

16.You fail an important examination.

PsB

A. I wasn’t as smart as the other people taking the exam.

1

B. I didn’t prepare for it well.

0

17. You prepared a special meal for a friend and he/she barely touched the food.

PvB

A. I wasn’t a good cook.

1

B. I made the meal in a rush.

0

18.You lose a sporting event for which you have been training for a long time.

A. I’m not very athletic. B. I’m not good at that sport. 19. Your car runs out of gas on a dark street late at night.

PvB 1

0 PsB

PvB

A. I didn’t check to see how much gas was in the tank.

1

1

B. The gas gauge was broken.

0

0

20. You lose your temper with a friend.

PmB

PsB

A. He/she is always nagging me.

1

1

B. He/.he was in a hostile mood.

0

0

10.You host a successful dinner.

PmG

A. I was particularly charming that night. B. I am a good host. 11. You stop a crime by calling the police. A. A strange noise caught my attention. B. I was alert that day.

0

12.You were extremely healthy all year.

PmB

1 PsG 0

1 PsG

A. Few people around me were sick, so I wasn’t exposed.

0

B. I made sure I ate well and got enough rest

1

21. You are penalized for not returning your income-tax forms on time.

A. I always put off doing my taxes. 8. I was lazy about getting my taxes done this year. 22. You ask a person out on a date and he/she says no. A. I was a wreck that day. B. I got tongue-tied when I asked himhe on the date. 23. A game-show host picks you out of the audience to participate in the show. A. I was sitting in the right seat. B. I looked the most enthusiastic.

PmB 1 0

PvB 1 0

PsG

0 1 Continued

2203

24. You are frequently asked to dance at a party.

PmG

37. Your doctor tells you that you are in good physical shape.

PVG

A. I am outgoing at parties.

1

B. I was in perfect form that night.

0

A. I make sure I exercise frequently

0

PsB

B. I am very healthconscious.

1

25. You buy your spouse (boyfriend/girlfriend) a gift he/she doesn’t like.

A. I don’t put enough thought into things like that.

1

38. Your spouse (boyfriendgirlfriend) takes you away for a romantic weekend.

B. Hdshe has very picky tastes.

0

A. He/she needed to get away for a few days.

PmG

B. He/she likes to explore new areas.

26. You do exceptionally well in a job interview.

39. Your doctor tells you that you eat too much sugar.

PmG

0 1

PsB

A. I felt extremely confident during the interview.

0

B. I interview well.

1

A. I don’t pay much attention to my diet.

1

PsG

8. You can’t avoid sugar, it’s in everything.

0

27. You tell a joke and everyone laughs.

A. Thejoke was funny

0

B. My timing was perfect. 28. Your boss gives you too little time in which to finish a project, but you get it finished anyway.

1

0

PVG

B. I am a good supervisor.

1

0

B. I am an efficient person.

1

PmB

A. I never get a chance to relax. B. I was exceptionally busy this week.

1

0

30.You ask someone to dance and he/she says no.

PsB

A. I am not a good enough dancer. B. He/she doesn’t like to dance. 31. You save a person from choking to death. A. I know a technique to stop someone from choking. B. I know what to do in crisis situations.

1

32. Your romantic partner wants to cool things off for a while.

0 PVG 0

1

PVB

A. I’m too self-centered.

1

B. I don’t spend enough time with h i h e r .

0

33. A friend says something that hurts your feelings.

PrnB

A. She always blurts things out without thinking of others

1

B. My friend was in a bad mood and took it out on me.

0

34.Your employer comes to you for advice.

PmG

A. I just successfully completed a similar project.

A. I am good at my job. 29. You’ve been feeling run-down lately.

40. You are asked to head an important project.

PVG

41. You and your spouse (boyfriendgirlfriend) have been fighting a great deal.

PsB

A. I have been feeling cranky and pressured lately

1

B. He/she has been hostile lately

0

42. You fall down a great deal while skiing.

PrnB

A. Skiing is difficult. B. The trails were icy 43. You win a prestigious award.

0

A. I solved an important problem. B. I was the best employee. 44. Your stocks are at an all-time low. A. I didn’t know much about the business climate at the time. B. I made a poor choice of stocks. 45. You win the lottery. A. It was pure chance. B. I picked the right numbers. 46. You gain weight over the holidays and you can’t lose it.

1

PvG 0 1 PvB 1

0 PsG 0 1

PmB

A. I am an expert in the area about which I was asked.

0

A. Diets don’t work in the long run.

1

B. I’m good at giving useful advice.

1

B. The diet I tried didn’t work.

0

35. A friend thanks you for helping h i h e r get through a bad time.

PVG

A. I enjoy helping h i h e r through tough times. B. I care about people. 36. You have a wonderful time at a party. A. Everyone was friendly

0

A. I’m irritable when I am sick.

1

1

B. My friends are negligent about things like that.

0

B. I was friendly

Scoring Key

PmB: PVB HOB: PsB: Total B: G-B:

PmG: PVG:

PsG: Total G:

PsG

47. You are in the hospital and few people come to visit.

48. They won’t honor your credit card at a store.

PsB

PvB

0

A. I sometimes overestimate how much money I have.

1

1

B. I sometimes forget to pay my credit-card bill.

0

The test results will give you a clue as to your explanatory style. In other words, the results will tell you about how you explain things to yourself, or your habit of thought. Again, remember that there are no right or wrong answers. There are three crucial dimensions to your explanatory style: permanence, pervasiveness, and personalization. Each dimension, plus a couple of others, will be evaluated on the basis of your answers to the questionnaire.

Now total all the questions coded PmG (for Permanent Good): 2, 10, 14, 15, 24, 26, 38, and 40. Write the total on the line in the scoring key marked PmG. If you totaled 7 or 8, you are very optimistic on this dimension; 6 is a moderately optimistic score; 4 or 5 is average; 3 is pessimistic; and 0, 1, or 2 is extremely pessimistic. Are you starting to see a pattern? If you are scoring as a pessimist, you may want to learn how to be more optimistic. Your anxiety may be due to your belief that bad things are always going to happen and that good things are only "flukes."

Permanence

Pervasiveness

When pessimists are faced with challenges or bad events, they view them as being permanent. In contrast, people who are optimists tend to view the challenges or bad events as temporary. Here are some statements that reflect the subtle differences:

Pervasiveness refers to the tendency to describe things either in universals (everyone, always, never, etc.) versus specifics (a specific individual, a specific time, etc.). Pessimists tend to describe things in universals, whereas optimists describe things in specifics, as shown in the following examples:

INTERPRETINGYOUR TEST RESULTS

Permanent (Pessimistic) . Temporary (Optimistic) "My boss is in a bad "My boss is always a jerk." mood today." "You are not "You never listen." listening." "My luck has got "This bad luck will never stop." to turn."

To determine how you view bad events, look at the 8 items coded PmB (for Permanent Bad): 5,13,20,21,29, 33, 42, and 46. Each answer with a " 0 after it is optimistic; each one followed by a "1" is pessimistic. Total the numbers at the right-hand margin of the questions coded PmB, and write the total on the PmB line on the scoring key. If you totaled 0 or 1, you are very optimistic on this dimension; 2 or 3 is a moderately optimistic score; 4 is average; 5 or 6 is quite pessimistic; and 7 or 8 is extremely pessimistic. Now let's take a look at the difference in explanatory style between pessimists and optimists when there is a positive event in their lives. It's just the opposite of what happened with a bad event. Pessimists view positive events as temporary, whereas optimists view them as permanent. Here again are examples of some subtle differences in how pessimists and optimists might communicate their good fortune: Temporary (Pessimistic) "It's my lucky day." "My opponent was off today." "I tried hard today."

Permanent (Optimistic) "I am always lucky." "I am getting better every day." "I always give my best."

Universal (Pessimistic) "All lawyers are jerks." "Instruction manuals are worthless." "He is repulsive."

Specific (Optimistic) "My attorney was a jerk." "This instruction manual is worthless." "He is repulsive to me."

Total your score for the questions coded PvB (for Pervasive Bad): 8,17,18,22,32,44, and 48. Write the total on the PvB line. If you totaled 0 or 1, you are very optimistic on this dimension; 2 or 3 is a moderately optimistic score; 4 is average; 5 or 6 is quite pessimistic; and 7 or 8 is extremely pessimistic. Now let us look at the level of pervasiveness of good events. Optimists tend to view good events as universal, and pessimists view them as specific. Again, it is just the opposite of how each views a bad event. Total your score for the questions coded PvG (for Pervasive Good): 6,7,28,31,34,35,37, and 43. And write the total on the line labeled PVG. If you totaled 7 or 8, you are very optimistic on this dimension; 6 is a moderately optimistic score; 4 or 5 is average; 3 is pessimistic; and 0, 1, or 2 is extremely pessimistic.

Hope Our level of hope or hopelessness is determined by our combined level of permanence and pervasiveness. Your level of hope may be the most significant score for this test. Take your PvB and add it to your PmB score. This is your hope score. If it is 0, 1, or 2, you are extraordinarily hopeful; 3, 4, 5, or 6 is a moderately hopeful score; 7 or 8 is average;

9,10, or 11 is moderately hopeless; and 12,13,14, 15, or 16 is severely hopeless. People who make permanent and universal explanations for their troubles tend to suffer from stress, anxiety, and depression; they tend to collapse when things go wrong. According to Dr.Seligman, no other score is as important as your hope score.

Total your score for those questions coded PsG (for Personalization Good): 1,4,11,12,23,27,36, and 45. Write your score on the line marked PsG on the scoring key. If you totaled 7 or 8, you are very optimistic on this dimension;6 is a moderately optimisticscore;4 or 5 is average; 3 is pessimistic; and 0,1, or 2 is extremely pessimistic.

Personalization

YOUR OVERALL SCORES

The final aspect of explanatory style is personalization. When bad things happen, we can either blame ourselves (internalize)and lower our self-esteem as a consequence, or we can blame things beyond our control (externalize). Although it may not be right to deny personal responsibility, people who tend to externalize blame in relation to bad events have higher self-esteem and are more optimistic. Total your score for those questions coded PsB (for Personalization Bad): 3,9, 16,19,25,30,39,41, and 47. A score of 0 or 1 indicates very high self-esteem and optimism; 2 or 3 indicates moderate self-esteem; 4 is average; 5 or 6 indicates moderately low self-esteem; and 7 or 8 indicates very low self-esteem. Now let us take a look at personalization and good events; the pattern is the exact opposite of that for bad events. When good things happen, the person with high self-esteem internalizes, whereas the person with low self-esteem externalizes.

To compute your overall scores, first add the three B scores (PmB + PVB + PsB); the total is your B (bad event) score. Do the same for all of the G scores (PmG + PvG + PsG); the total is your G score. Subtract B from G to obtain your overall score. If your B score is 3 to 6, you are marvelously optimistic when bad events occur; 10 or 11 is average; 12 to 14 is pessimistic; anything above 14 is extremely pessimistic. If your G score is 19 or above, you think about good events extremely optimistically; 14 to 16 is average; 11to 13 indicates pessimism; and a score of 10 or less indicates great pessimism. If your overall score (G - B) is above 8, you are very optimistic across the board; if it is 6 to 8, you are moderately optimistic; 3 to 5 is average; 1 or 2 is pessimistic; and a score of 0 or less is very pessimistic.

Sit and Reach Test PURPOSE The sit and reach test is used to measure the extensibility of the muscles of the posterior thigh and back.

possible along the top of the stick with both hands extended. 5. The distance reached to the nearest half inch in the best of three trials is the person’s score.

EQUIPMENT Yardstick measured in inches Tape for stick Data cards

EVALUATION Good score: 19 to 21 inches

PROCEDURE 1. The person sits on a mat with the legs fully extended and the feet about 4 to 6 inches apart. 2.The yardstick is placed between the legs with the 15-inch mark at the soles of the feet for males and the 14-inch mark at the soles of the feet for females. 3.All individuals should be given an opportunity to warm up by stretching before testing. 4.With the legs held down by a partner, the person bends forward slowly and reaches as far as

Figure A12-1

Sit and reach test.

2207

Vaginal Depletion Pack INTRODUCTION The vaginal depletion pack ("vag pack") was originally developed by the eclectic physicians of the nineteenth century and later modified to its present form by John Bastyr, ND. Over the last 50 years, it has been regularly used by most naturopathic physicians in the treatment of various vaginal disorders. Although no controlled studies of the clinical efficacy of the vag pack have been published, it has a long, and apparently successful, history of use. Its primary application has been in the treatment of cervical erosions, cervical dysplasia, pelvic inflammatory disease (PID), and pelvic congestion. The mode of action is apparently through its local antibacterial, anhydrous, alterative, and sclerotic activities. These are thought to inhibit local microbial growth, stimulate the body to slough off abnormal cervical cells, and promote lymphatic drainage. However, no research has been done to determine the actual mechanism.

Procedure Supplies Open-mouth l-lb container with tight-sealing lid Anhydrous magnesium sulfate (MgSO,; keep tightly closed) Glycerin Hydrastis canadensis tincture: 0.5 oz Thuja occidentalis oil (not thuja in oil): 0.5 oz Melaleuca alternifolia oil: 0.25 ounce Bitter orange oil: 0.25 oz Vita Minerals 120 (iron sulfate solution): 1 oz Cotton: 0.5 inch thick, 2 inches wide, and 3 inches long Cotton string (surgical grade): 4 inches long (dental floss also works well)

7. Store in a tightly sealed container in a cool, dry place. The solution will require stirring if not used regularly.

The Tampon The cotton is folded lengthwise and tied at one end to make a tampon 1 inch thick and 3 inches long, with approximately 3 inches of string hanging from the tied end.

Application The best time for application is during times of normal uterine drainageright before or after the menses and during ovulation. The procedure is as follows: 1.Fold 1 tbsp of the formula into the untied end of the cotton tampon (some find it easier to put the solution into the cotton tampon before folding and tying it). 2. Expose the cervix with a vaginal speculum and open it wide enough to insert the tampon. 3.Slide the vag pack, formula-end first, through the speculum until it fits tightly against the cervix. (A uterine forceps can be used to hold the pack and aid its insertion.) 4. Carefully remove the speculum while leaving the pack in place. Avoid touching the sides of the vagina because the fresh pack can cause some irritation. The uterine forceps is used to hold the pack in contact with the cervix as the speculum is removed. Ensure that the string is left exposed in the introitus. 5. Leave the pack in for 24 hours, at which time the patient can remove it by simply pulling on the string. 6. Have the patient douche after an additional 24 hours. A mild vinegar solution is recommended. 7.The procedure can be performed weekly until the desired results are obtained.

Mixing the Solution The following steps must be carefully followed. Deviation results in either a m y , inconvenient liquid or a rock-hard, unusable precipitate. Each step requires vigorous stirring before proceeding to the next! 1.Fill the container half fullwith anhydrous MgSO,. 2.Add glycerin until soupy. Mix until the solution begins to cool. 3. Add oils. 4.Add H. canadensis. 5. Add Vita Minerals 120. 6. Stir occasionally over the next 2 to 3hours until the solution cools. It should have a thick, tarlike consistency.

CLINICAL APPLICATIONS Typically, the patient notices an increase in drainage, both while the vag pack is in place and during the following 24 to 48 hours. If she experiences any buming or discomfort, the pack can be removed early, followed by douching. Suggest that she wear a sanitary pad to absorb the typical secretions.

Cervical Dysplasia When the vag pack is used in the treatment of abnormal cervical cells (see Chapter 158), inspection of the cervix within a few days of the application reveals a red, eroded 2209

appearance where the cells have sloughed off. This typically heals within 7 to 10 days. The number of applications needed varies with the patient and the condition: Those with class I1 Papanicolaou smear results typically show clearance after 4 to 6 applications, and those with class III results, after 8 to 12 applications. The senior editor has successfully treated women with class IV Pap smear results (with confirmed dysplasia), which required 1 year of biweekly vag packs in conjunction with the therapies listed in Chapter 158. However, considering the high risk associated with class IV results and cervical dysplasia, the authors recommend conization in these cases.

During therapy, Papanicolaou smears should be repeated every 2 months to ensure adequate response (the cervix should be allowed to heal for at least 10 days after application of a vag pack to ensure an accurate result).

Pelvic Inflammatory Disease As part of the therapy for PID, best results are obtained when the vag pack is used in conjunction with the alternating sitz bath (which also stimulates drainage; see Chapter 40) and immune stimulation (see Chapter 57). In this situation, women report much greater drainage, requiring the use of mini-pads. The therapy appears to help prevent the adhesions typical of PID.

Index A ABH antigens brush-border hydrolases and, 443 description of, 441-442 immunity and, 443 Lewis blood groups and, 445-446 nonsecretors of, 442-443 0-linked glycans, 443-444 secretors of, 442443,445 sources of, 444 Ablutions, 413 ABO blood groups antibodies in, 444 bacterial flora and, 443 brush-border hydrolases and, 443 cancer and, 448-450 cardiovascular disease and, 447-448 cholesterol and, 446-447 clinical applications of, 455-456 combinations of, 441,442t coronary artery bypass grafting and, 448 description of, 441 factor VIII and, 446 gastric acidity and, 446 gastrin and, 446 genetics of, 445 heart disease and, 448 infection and, 450,451t infertility caused by incompatibility of, 444 lectins and, 451-455 naturopathic treatments that affect,456t pepsinogen A levels and, 446 peripheral artery disease and, 448 rheology and, 447 soluble endothelial cell markers and, 447 stress and, 447 stroke and, 447-448 venous thromboembolism and, 448 ABO genes, 445 Abortifacient, 710 Absinthe, 756 Absinthin, 756f Absinthism, 756 Acacia catechu, 823 Acanthopanax senticosus. See Eleufherococcus senticosus Acarbose, 1630 Accreditation Commission for Acupuncture and Oriental Medicine, 9 Acemannan antiviral uses of, 740 AZT and, for HIV/AIDS, 743-744,744t description of, 738 dosage of, 745 immune system effects of, 740 Page numbers followed by f indicate figures; t, tables; b, boxes.

Acetaldehyde, 1450 Acetaminophen biotransformation of, 25 challenge test for, 25 history Of, 27-28 metabolites of, 25 Acetate, 670 Acetic acid, 172 Acetylcholinesterase citicoline effects on, 854 inhibitors of, 815 Acetyl-coenzyme A description of, 290,537 fatty acid conversion to, 539 Acetyl-L-camitine, 1739b, 1742 Achillea millefoliurn (yarrow), 2077 Achlorhydria Heidelberg pH capsule gastric analysis findings in, 219,589 Helicobacter pylori and, 662 Acid base homeostasis, 994 Acidosis, 540 Acinetobacfer, 1155-1156 Acipimox, 1176 Acne vulgaris androgen levels and, 1422 azelaic acid for, 1424 bacteria associated with, 1421 characteristics of, 1421 chromium for, 1422 diet and, 1422,1424 endocrine disorders and, 1422 insulinfor, 1422 isotretinoin for, 1424 Melaleuca nlfemifolia for, 1055, 1423-1424 pantothenic acid for, 1423 retinok for, 1422 selenium for, 1423-1424 supplements for, 1424 terms associated with, 1421 topical treatments for, 1423-1424 vitamin A for, 1386,1422,1424 zinc for, 1422-1424 Acquired immunity, 585 Acquired immunodeficiency syndrome. See also Human immunodeficiency virus Aloe Vera for, 743-744 apoptosis in, 149 CDC definition of, 1731b coenzyme Qlo for, 861 epidemiology of, 1729 glutathione levels and, 1094 history of, 1728-1729 HlV progression to, 1731-1732 Hypericurn perforaturn activity and, 1042-1043 opportunistic infections, 1727 oral glycyrrhizin and, 1007

Acquired immunodeficiency syndrome-cont‘d prayer benefits for, 525 thymus extracts for, 383 vitamin A for, 1386 Acrid, 710 Acrodermatitis enteropathica, 650 Acrylamide, 345 Active placebo, 92t, 101 Acupressure asthma treated with, 1495 nausea and vomiting of pregnancy treated with, 1943 Acupuncture Ah Shi points, 312 alarm and associated points, 513 angina pectoris managed with, 1478 asthma treated with, 1495 carpal tunnel syndrome treated with, 1560-1561 cystitis treated with, 1603 definition of, 310,312 diabetic retinopathy treated with, 1635 ear, 1657 evidence-based, 312-314 five elements in, 312 fundamentals of, 312 history of, 310-311 human immunodeficiency virus treated with, 17451746 hyperthyroidism treated with, 1777 infectious diarrhea treated with, 1809-1810 mechanism of action, 437 migraine headaches treated with, 1918,1920 nausea and vomiting of pregnancy treated with, 1943 online resources for, 314-315 osteoarthritis heated with, 1970,1972 pain control using, 436-438 Parkinson’s disease treated using, 2010-2011 points in, 312,504 popdarity of, 309-310 practitioners of, 10 Q312 i, research regarding, 313,437 resources regarding, 313-314 s e i z w s treated with, 1657 in United States, 9,309-310 urinary tract infections treated with, 1603 urticaria treated with, 2142-2144 Zang Fu,312 Acute intermittent porphyria, 1007-1008 Acute myelogenous leukemia, 343 ADAM33 gene, 1485 Adaptation, 515 Adaptogens description of, 707-708,710,921 Panax ginseng as, 1121

I1

Index Addison's disease, 1008 A-delta fibers, 432 Adenosine triphosphate, 538,1085-1087 Adenosylcobalamin, 612-613 Adenylate cyclase, 872 Adipate, 289t, 292-293 Adipokine, 1951 Adiponectin, 1613-1614,1951 Adjuvant chemotherapy as, 557 definition of, 710 Adrenal gland asthma and, 1487 depression caused by dysfunction of, 1430 extracts, 379,379t Adrenal leukodystrophy, 943 Adrenocorticotropic hormone, 683,1061 Adriamycin description of, 563 toxicity of, 818,864-865 Adverse effects, 121 Adverse food reactions, 583 Aerobic, 357 Aerobic exercise blood pressure affected by, 493 coronary artery disease affected by, 361 description of, 357-358 diabetes meltitus treated with, 1625 end-stage renal disease treated with, 364 pain management by, 364-365 weight loss benefits of, 363 Aesculus hippocastanum (horsechestnut), 2076,2168-2169 Affective disorders depression. See Depression description of, 1428 diagnostic summary for, 1427-1428 Agaricus bisporus, 456t Age-related macular degeneration, 1859-1860 Aging coenzyme Qlofor, 861 dehydroepiandrosterone for, 900-901 depression associated with, 901 interleukin-6 production during, 903 Panax ginseng for, 1124-1125 phosphatidylserine effects on, 1164 water requirements and, 1404-1405 Agitation, 1067 Agnuside, 1396f Ah Shi points, 312,505 AIDSrelated complex, 861 Air pollution, 369 Ajoene, 731 Akathisia, 1833 Alactasia, 257-258 Alavidze, Zemphira, 11551156 Alcohol Aloe VUQ for detoxification from, 741 atherosclerosis prevention and, 1508 benign prostatic hyperplasia and, 1551 depression caused by, 1432,1454-1455 gout and, 1706 hypoglycemia caused by, 1452,1787-1788 liver disease induced by, catechin for, 825 metabolic effects of, 1451-1452 osteoporosis and, 1978

Alcohol-cont'd periodontal disease and, 2033 psoriasis and, 2081 selenium levels affected by, 1299, 1453 stress and, 706 withdrawal symptoms, 1451,1456 Alcohol abuse camitine deficiency caused by, 816,1453 homocysteine levels in, 610 prayer benefits for, 525 Alcohol intoxication, 1451 Alcoholics Anonymous, 1454 Alcoholism amino acid abnormalities in, 1453 antioxidant deficiencies in, 1452-1453 ascorbic acid deficiency in, 1453 B vitamins' deficiency in, 1453-1454 camitine deficiency in, 816,1453 consequences of, 14% counseling for, 1456 definition of, 1449 demographics of, 1449-1450 depression and, 1454-1455 diagnostic summary for, 1449 dietary considerations for, 1455-1456 essential fatty acid metabolism affected by, 1454 exercise benefits for, 1454 fatty liver secondary to, 1451-1452 genetic basis for, 1451 glutamine and, 999,1454 homocysteine levels in, 623 immune fimction affected by, 648 intestinal microflora abnormalities in, 1455 intestinal permeability affected by, 244 magnesium deficiency in, 1454 metabolic effects of, 1451-1452 Michigan Alcoholism ScreeningTest for, 145Ot nutritional deficiencies associated with, 1452 psychosocial aspects of, 1454 selenium levels and, 1299,1453 therapeutic approach to, 1455-1456 tryptophan levels and, 1454 vitamin A deficiency and, 1452 zinc deficiency in, 1452 Aldose reductase quercetin effects on, 969 vitamin C effects on, 1627 Algal polysaccharides, 668-669 Alginate, 668 Alkaloids, 710 Alkylamides, 909 Alkylating agents, 557 ALkylglycerols absorption of, 714-715 antiangiogenesis properties of, 721 bacteriostatic effects of, 716 biologic effects of, 716-717 blood-brain barrier permeability affected by, 721 cancer treated with, 719 chemistry of, 714-716 clinical uses of, 719-722 definition of, 713

Alkylglycerols-cont'd diacylglycerols affected by, 720 dosage of, 722 excretion of, 715-716 hematopoietic effects of, 716-717 history of, 713-714 immunologic aspects of, 717-719 indications for, 722 macrophage activation by, 718-719 male infertility treated with, 720 methoxy-substituted antitumor activity of, 721-722 description of, 715 structure of, 716f plasmalogen levels and, 719 protein kinase C affected by, 720 radiation damage protection from, 717, 719-720 from shark liver oil, 714715 structure of, 715f summary of, 722 toxicity of, 722 tumor regression using, 719 Allergic rhinitis, 1348 Allergic tension-fatigue syndrome, 706,1585 Allergic toxemia, 706 Allergies food anxiety and, 706 aphthous stomatitis and, 1481 asthma and, 1489 atopic dermatitis and, 1526-1527 attention deficit hyperactivity disorder and, 1536-1537 autoimmune diseases and, 1794 breastfeeding for, 1527 chronic candidiasis and, 576 chronic fatigue syndrome and, 1585 comprehensive digestive stool analysis for, 587 depression secondary to, 1436 dermatitis herpetiformis and, 1606 epilepsy and, 1652-1653 fecal secretory immunoglobulin A tests for, 587 gallstones and, 1690 hypothalamic-pituitary-adrenal axis and, 587-588 intestinal permeability and, 243-244,587 irritable bowel syndrome and, 1838-1839 lactose intolerance vs., 256-257 microbial enzyme therapy for, 1081 migraine headaches and, 1913-1914, 1919 multiple sclerosis and, 1934-1935 otitis media and, 1993-1994,1994t peptic ulcers and, 2027 rheumatoid arthritis and, 2096 rosacea caused by, 2110 sinusitis and, 1546 testing for challenge testing, 205-207 description of, 604,2143 dietary fast with food challenge, 206t, 206-207 electroacupuncture for, 205,206t

Allergies-cont'd food-cont'd testing for-cont'd enzyme-linked immunosorbent assay, 203-204,206t experiential challenge methods, 205-207 fasting, 206t, 206-207,536 follow-up, 587 kinesiologic method of, 205,206t laboratory methods, 203-205 oligoantigenic diet, 205-206,206t, 588 provocation-neutralization testing, 204-205,206t purpose of, 203 radioallergosorbent procedure, 204,206t radioallergosorbent test, 204,206t, 586-587 serial-dilution titration test, 205 treatment of diversified rotation diet, 588 gut healing, 589 intestinal microflora, 588-589 probiotics, 588-589 urticaria caused by, 2137-2138 Ginkgo biloba for, 984 to tartrazine, 470 thymus extracts for, 383 water intake and, 1407 Allergy-free cookbooks, 500 Allicin chemical structure of, 734f description of, 729 hypoglycemic properties of, 731 Allicin potential, 732 Allicin yield, 732 Allilin, 734f Allium usculonicum (shallots), 727 Allium cepa (onion) antiasthmatic actions of, 726-727 antimicrobial activity of, 726 antitumor effects of, 727 asthma treated with, 1494 blood glucose levels reduced using, 1632 cardiovascular effects of, 726 chemical composition of, 725 cholesterol reductions using, 1512 description of, 725 diabetes mellitus and, 726,1632 dosage of, 727 folk uses of, 725-726 global production of, 726 hair tonic effects of, 727 history of, 725-726 hypertension treated with, 1761,1766 nutritional qualities of, 726 pharmacology of, 726-727 quercetin, 726 toxicology of, 727 Allium sativum (garlic) anthelminthic effects of, 730 anticancer effects of, 731 antifungal activity of, 730 antijnflammatory effects of, 731 antimicrobial activity of, 730 antiviral effects of, 731

Allium sativurn-cont'd asthma treated with, 1494 blood glucose levels reduced using, 1632 cancer treated with, 731 Candida albicans treated with, 579 cardiovascular effects of, 731 chemical composition of, 729 cholesterol-lowering activity of, 732-733, 1512 clinical applications of, 732-734 commercial preparations of, 732 cystitis treated with, 1602 description of, 729 dosage of, 734 drug interactions, 734 fibrinolyhc activity of, 733 folk uxs Of, 729-730 history Of, 729-730 human immunodeficiency virus treated with, 1745b hypertension treated with, 733, 1761,1766 hypoglycemic action of, 731 immune-enhancing effects of, 731 low-density lipoprotein oxidation prevention using, 733-734 peptic ulcers and, 2029 pharmacology of, 730-732 platelet aggregation inhibition with, 733 pneumococcal pneumonia treated with, 2043 protozoan infestations treated with, 657 toxicity of, 734 urinary tract infections treated with, 1602 vaginitis treated with, 2161,2163 Allopathic physicians description of, 44 in early colonial America, 131 gender predilection of, 127 increases in, 419 statistics regarding, 127 women as, 134 Allopathy definition of, 389 description of, 419-420 multiple sclerosis treated with, 1929 All-trans retinol, 1381 Ally1 propyl disulphide, 726 Aloe burbadensis, 745 Aloe Vera (Cape aloe) acquired immunodeficiency syndrome treated with, 743-744 alcohol detoxification uses of, 741 anthraquinones, 738,739b antibacterial activity of, 740 antifungal activity of, 740 antiinflammatory activity of, 741 asthma treated with, 744,1494 bowel detoxification uses of, 739 bums treated with, 741-742 cancer prevention using, 745 chemical composition of, 738,739b clinical applications of, 741-745 contraceptive uses of, 745 description of, 737 diabetes mellitus treated with, 744-745 dosage of, 745

Aloe vera-cont'd drug interactions, 745-746 folk uses of, 738-739 frostbite treated with, 742 gastric acid secretion inhibition using, 739-740 gastric ulcers treated with, 743 gastrointestinal effects of, 739-740 history Of, 738-739 human immunodeficiency virus treated with, 744 hypoglycemic effects of, 744,746 immunologic effects of, 740-741 laxative effects of, 739 necrotizing fasciitis treated with, 742 potassium depletion and, 746 prostanoids, 738 psoriasis treated with, 743,2084 radiation bums treated with, 742-743 saccharides, 738,739b seborrheic dermatitis treated with, 2114 spermicide use of, 745 superoxide dismutase, 738 terminology of, 737-738 tissue damage treated with, 741-742 toxicology of, 745 wound healing using, 741,1635 Aloe-emodin, 738,738f Aloin alcohol detoxification and, 741 description of, 738f, 738-739 Alopecia areata, 727 Alpha-carotene, 774 7-Alpha-dehydroxylase, 167 Alpha-hydroxybutyrate, 289t, 291 Alpha-ketoglutarate, 289t Alpha-ketoisocaproate, 289t, 291 Alpha-ketoisovalerate, 289t, 291 Alpha-keto-beta-methylvalerate,289t, 291 Alpha-lapachol, 1323-1324 Alpha-linolenic acid clinical uses of, 943t description of, 939 food sources of, 192t, 946 profiling of, 190t, 191 Alpha-lipoic acid, 10941095,1633,1717,1933 5-Alpha-reductase, 1550-1551 Alpha-thujone, 756f, 758 Alpha-tocopherol, 2041 Alterative, 710 Altered states of consciousness, 104-105 Althea oficinalis (marsh mallow), 2077 Altitude, 369 Aluminum Alzheimer's disease and, 1460-1461,1463 brain levels of, 344 hair analysis of, 271t sources of, 596t, 1460-1461,1463 Alzheimer's disease aluminum exposure and, 1460-1461,1463 antioxidants for, 1463-1464 Ayurvedic medicines for, 1468 beta-amyloid in, 854-855 carnitine for, 815 cholinergic neuron degeneration in, 854 citicoline uses in, 856

Index Alzheimer's disea-ont'd Curcuma longa for, 896 definition of, 1459 dehydmepiandmsterone for, 901,1467 dementia assodated with, 1459 diagnostic considerations for, 1461-1462 diagnostic summary for, 1459 diet and, 1462-1463,1469 Down syndrome and, 161-1463 estrogen for, 1463 etiology of, 1460 genetics of, 1460,2000 Ginkgo biloba for, 981,1467-1468 homocysteine levels and, 621 hormone replacement therapy and, 1463,1884 huperzine A for, 1468 L-acetylcamitine for, 815,1466-1467,1469 lifestyle changes for, 1469 melatonin for, 1062,1467,1469 neurofibrillary tangles, 1460 neurologic examination for, 1461 neuropathologic features of, 1459 oxidative damage and, 1463 phosphatidylcholine for, 1466 phosphatidylserine for, 1164,1466, 1469,2007 presenilin gene in, 1464 thiamin supplementation for, 1464,1469 treatment of, 1462-1463,1469 vitamin BI2deficiency and, 1464-1465 vitamin E for, 1463 zinc deficiency and, 1465-1466 Amalgams, 1856,2033 Amanita phalloides, 1252 Amblyopia, 857 Amenorrhea, 371,1398 Amentoflavone hypericin and, 1038 Hypm'cum petforatum activity and, 1040 American Academy for Medical Acupuncture, 10 American Association of Naturopathic Medical Colleges, 30-31 American Association of Naturopathic Physicians, 30,61 American College of Sports Medicine, 359 American Holistic Health Association, 15 American Medical Association Constitution Clause, 133 description of, 47-48,60-61 founding of, 133 medical schools,136 American Naturopathic Association, 61,69 Amino acids. See also specific amino acid alcoholism effects on, 1453 benign prostatic hyperplasia treated with, 1551 branched-chain, 683-684 conjugation of, 618 metabolism of, during fasting, 540 Amino-imidazoazaarenes, 680 5-Aminolevulinate synthase, 758 Aminolevulinic acid, 302 Aminolevulinic acid dehydrogenase, 266 Aminolevulinic acid synthase, 2046

Aminopyrine, 349 Ammonia, 1190 Amni visnaga, 1477-1478, 1479, 1848 Amoebic dysentery, 451t Amylase, 1137t Amyloid precursor protein, 855 Anabolic steroids, 372 Anal abscess, 2068 Anal cryptitis, 2068 Anal fissure, 206&2069 Anal fistula, 2068 Analgesia acupuncture, 436-437 Mmtha piperata and, 1072 transcutaneous electrical nerve stimulation, 435-436 Ana Igesic(s) Angelica spp. as, 751 Croton lechlm' use as, 888-889 definition of, 710 Epilobium angustifilium as, 932 Opuntia sp. as, 1114 Piper methysticum as, 1170 Zingiber oficinale, 1413 Analgesic-rebound headaches, 1911-1912 Anaphylaxis, exercise-induced, 370 Androgen receptor prostate cancer and, 969 quercetin effects on, 969 Androgenic steroids, 372 Androgens, 710 Andrograph is paniculata, 1745b Anemia, 2092 Angelica spp. A. acutiloba, 749 A . archangelica, 750, 752 A . at ropu rpurea, 750,752 A . sinensis, 749,752,2061 analgesic activity of, 751 antimicrobial activity of, 751 cardiovascular effects of, 751 chemical composition of, 750 coumarin compounds of, 751 description of, 749 dosage of, 752 folk uses of, 750 history of, 750 menopause uses of, 752 pharmacologic activities of, 750-751 phytwstrogen effects of, 750-751 smooth muscle-relaxing activity of, 751 toxicology of, 752 Angina pectoris acupuncture for, 1478 Ammi visnaga for, 1477-1478, 1479 angioplasty for, 1474 camitine for, 812-813,1476,1479 coenzyme Qlo for, 864,14761477,1479 coronary artery bypass surgery for, 1474-1475 Crataegus oxyacantha for, 1477,1479 diagnosis of, 1473 diagnostic summary for, 1473 dietary guidelines for, 1479 EDTA chelation therapy for, 1478 fish oils for, 951-952

Angina pectori-ont'd khella for, 1477 lifestyle changes for, 1479 magnesium deficiency and, 1477 nutritional supplements for, 1475-1477 pantethine for, 1476 pathophysiology of, 1473 percutaneous transluminal coronary angioplasty for, 1474 policosanol for, 1178 Prinzmetal's variant, 1473 relaxation for, 1478 statistics regarding, 1474 treatment of, 1474-1479 Angioedema, 2133 Angiotensin-converting enzyme, 882 Angiotensin-converting enzyme inhibitors, 1760 Angiotensinogen gene, 493 Aniline, 349 Animal studies description of, 124-125 in homeopathy, 395 Anisidine, 960 Ankle sprain, 479 Ankylosing spondylitis intestinal permeability in, 244 peat therapeutics for, 480 Anorectal region, 2067-2068 Anthelminthics Allium sativum, 730 definition of, 710 Anthocyanidins antioxidant properties of, 1097 collagen metabolism affected by, 1708 description of, 710 in Vaccinium macrocarpon, 1355 Anthocyanosides diabetes mellitus treated with, 1368 in Vacciniurn myrtillus, 1365-1366 Anthraquinones in Aloe Vera, 738,739b kidney stones and, 1M8 Antiangiogenic agents alkylglycerols, 721 cancer treated with, 557-558 Antibacterial activity of Allium sativum, 730 of Aloe Vera, 740 of Echinacea spp., 911-912 of Glycyrrhiza glabra, 1005 of Hypericurn perforaturn, 1041 of Tabebuia avellanedae, 1322-1324 Antibiotics chronic candidiasis caused by prolonged use of, 573-574 Crohn's disease and, 1814-1815 gastrointestinal tract, 1201-1202 intestinal permeability increases associated with, 1537 otitis media treated with, 1992 overuse of, 573-574,1992 pelvic inflammatory disease treated with, 2020 resistance to, 574 risks associated with, 1992

Index Antibiotics-cont'd sinusitis treated with, 1545-1546 small intestinal bacterial overgrowth treated with, 157 streptococcal pharyngitis treated with, 2123-2124 urticaria caused by, 2137 Antibodies. See also Immunoglobulins definition of, 717 types of, 717 Antidepressant activity of 5-hydroxytryptophan, 1025-1026 of Hypericum perforatum, 1039-1040 Antidote, 710 Antifungals Allium sativum as, 730 Aloe Vera as, 740 Tabebuia avellanedae as, 1325 Antigen ABH, 441-442 CD4,225 CD8, 225 CD11,224-225 CDlla, 227 CDllb, 227 CD16,226 CD19,225 CD25,226-227 CD26,227 CD29,226 CD38,227 CD45RA epitope, 227 CD45RO molecule, 227 CD56,226 CD69,227 definition of, 221,585 Friedenreich-Friedenreich,449-450 13,227 Thomsen-Friedenreich,449-450 Antigen-presenting cells, 221-222 Antigliadin antibodies, 1565, 1712-1713 Antiinflammatory activity of Allium sativum, 731 of Aloe Vera, 741 of bromelain, 792 of Commiphora mukul, 879 of Curcuma longa, 894-895 of Echinacea spp., 910 of Epilobium spp., 932 of Glycyrrhiza glabra, 1004-1005 of omega-3 fatty acids, 949 of Opuntia sp., 1114 of pseudoephedrine, 926 of quercetin, 968,970-971 of Ruscus aculeatus, 1228 of Silybum marianum, 1252 of Tabebuia avellanedae, 1326-1327 of Uva ursi, 1351-1352 Antimicrobial activity of Allium cepa, 726 of Allium sativum, 730 of Angelica spp., 751 of berberine, 10141015,1015t of Croton lechleri, 888 of Curcuma longa, 896 of Epilobium spp., 932

Antimicrobial activity-cont'd of Ruscus aculeatus, 1228 of Tabebuia avellanedae, 1322-1324 of Uva ursi, 1351 Antimony, 271t Antinuclear antibodies, 2092 Antioxidants alcoholism effects on, 1452-1453 alpha-carotene, 775t alpha-lipoic acid, 1094-1095 Alzheimer's disease prevention using, 1463-1464 ascorbic acid, 251, 252t,685,1091-1092, 1390t, 1391-1392,1453,1698, 2118-2119 asthma and, 1491 atherosclerosis and, 1513-1516 beta-carotene. See Beta-carotene carotenoids, 774,1092-1093 catalase, 1089 catechins, 824,1097-1098 chemotherapy and, 567-568 coenzyme Qlo,863,1094 cranberry, 1359 Curcuma longa, 894 flavonoids, 968-969,1096 free radicals, 1085-1087 glutathione. See Glutathione glutathione peroxidase, 1089-1090 hyperthyroidism treated with, 1774 leukoplakia treated with, 1854 liver detoxification and, 599 lycopene, 1508 macular degeneration treated with, 1860 male infertility treated with, 1870-1871 melatonin, 1095 multiple sclerosis treated with, 1932 naturally occurring adequacy of, 1100-1101 body's production of, 1093-1096 botanical extracts, 1096-1097 cell function regulation by, 1099 comparison of, 1098-1099 defenses of, 1088t enzymes, 1088-1090 free radicals, 1085-1087 guidelines for use of, 1101 inflammation treated with, 1087-1088 nonnutrient oxidants, 1096 nutrients, 1090-1093 precautions in use of, 1011-1102 reactive oxygen species, 1086f, 1086-1087 selection criteria for, 1102-1103,1103t osteoarthritis treated with, 1965 oxidative damagemediated conditions, 1086t Panax ginseng, 1124-1125 Parkinson's disease and, 2005 polyfunctiond organic acids, 1095 porphyrias treated with, 2049-2050 procyanolidic oligomers, 1218,1218t radiation therapy and, 568 rheumatoid arthritis treated with, 2100 seizures treated with, 1656 storage and transport proteins, 1095-1096 superoxide dismutase, 1088-1089 targets for, 1086f, 1086-1087

Antioxidants--cont'd thymus functioning affected by, 650-651 type II diabetes mellitus treated with, 1616 uric acid, 1095 Vaccinium macrocarpon, 1359 vitamin C. See Vitamin C vitamin E. See Vitamin E zinc, 1303 Zingiber oficinale, 1412 Antisperm antibodies, 1868 Antitumor antibiotics, 557 Antiviral activity of acemannan, 740 of Allium sativum, 731 of catechin, 823 of Croton lechleri, 888-889 of Echinacea spp., 911 of flavonoids, 823 of Glycyrrhiza glabra, 1005 of Hypericum perforatum, 1040 of Melissa oficinalis, 1066 of Opuntia sp., 1114 of quercetin, 823,970 of Tabebuia avellanedae, 1324 Anxiety Centella asiatica for, 832 food allergies and, 706 ginseng for, 707 5-hydroxytryptophan for, 1026-1027 irritable bowel syndrome and, 1840 Melissa officinalis and, 1067 Piper methysticum for, 1170 selenium for, 1298-1299 Valeriana oficinalis for, 1373 Aortic glycosaminoglycans, 379t, 379-380 Aphrodisiac, 710 Aphthous stomatitis, 1481-1483 Aphthous ulcers, 1006 Aplastic anemia, 344 Apocarotenes, 771 Apolipoprotein E, 491-492 Apolipoprotein(a), 1504 Apoptosis in acquired immunodeficiency syndrome, 149 in autoimmune diseases, 147-148 benzene induction of, 147 in brain, 149-150 cell membrane changes caused by, 145 chemical induction of, 146-147 clinical applications of, 147-150 definition of, 145 detection of, 146f DNA fragments caused by, 145 in heart, 149-150 inducing of, 145 malignancy and, 146-147 measurable features of, 145 mitosis and, 149t in neurologic diseases, 150 in Parkinson's disease, 2000 stages of, 146 summary of, 150 taspine inducement of, 888 tissue growth regulation by, 146-147 viral infection and, 148

Appetite regulation, 1951-1952 Applied kinesiology, 205,206t Aquaporins, 1403 Arabinitol, 294 Arabinose, 294 Arachidic acid, 191t, 195 Arachidonic acid asthma and, 1486 description of, 940 food sources of, 193 metabolism of, 1486,1487f profiling of, 190t, 193,195 psoriasis and, 2082 Arachidonic acid/eicosapentaenoic acid ratio, 191t, 196 Arbutin, 1351 Arcfosfaphylos uva ursi, 1602-1603 Arginine boron and, 786-787 congestive heart failure treated with, 1594 description of, 683 food sources of, 1725t herpes simplex virus treated with, 17241725 male infertility treated with, 1872 Amdt-Schulz law, 392 Aromatic oils, 157 Arrhythmias camitine for, 813 coenzyme Qlofor, 864 Arsenic, 266,27lt, 596t Arteether, 761,762f Artemether description of, 761,762f grapefruit juice effects on, 764 Arfemisia absinthium (wormwood) antiparasitic effects of, 757 chemical composition of, 755 clinical applications of, 757 description of, 755 digestive effects of, 756 dosage of, 757 drug interactions, 758 folk uses of, 755-756 hepatic effects of, 756-757 history Of, 755-756 neurologic effects of, 757 toxicity Of, 757-758 Artemisia annua (sweet wormwood) antineoplastic uses of, 762 chemical composition of, 761 description of, 761 dosage of, 763 drug interactions, 763-764 folk uses of, 761 history of, 761 malaria treated with, 762-763 parasitic infections treated with, 762 protozoan infestations treated with, 657 schistosomiasis treated with, 763 toxicity of, 763 Artemisia douglasiana, 2029 Artemisinin description of, 657,761 drug interactions, 763-764 structure of, 762f

Artemisinin-cont'd sulfadoxine-pyrimethamineinteractions with, 764 Arterial trunk reflex, 408 Artery, 1501-1502 Artesunate, 761,762f Arthritis. See also Osteoarthritis; Rheumatoid arthritis boron for, 1291 Echinaceu spp. for, 914 exercise benefits for, 365 fasting for, 535-536 food intolerance and, 535 gouty, 1705t inflammatory bowel disease and, 1818 peat therapeutics for, 479 Urtica dioica for, 1348 Arthus reaction, 2090 Articulation, 504t Artocarpus infegriifolia,456t Ascorbates, 500 Ascorbic acid, 251, 252t, 685,1091-1092,139Ot, 1391-1392,1453, 1698,2118-2119. See also Vitamin C Asiaticoside, 833 Aspartame, 1786 Aspergillus n i p , 1080-1081 Aspergillus oyme, 1075-1079 Aspirin intestinal permeability and, 1818 myocardial infarction prophylaxis using, 1518-1520 osteoarthritis treated with, 1963 peptic ulcers and, 2026 urticaria caused by, 2137 Asthma acupressure/acupunchm for, 1495 acute attack of, 14% adrenal functioning and, 1487 Allium spp. for, 726727,1494 Aloe Vera for, 744,1494 antiinflammatory drugs for, 38 antioxidant intake and, 1491 arachidonic acid metabolism and, 1486 autonomic nervous system and, 1487 Boswellia for, 14941495 botanical medicines for, 1493-1495 breastfeeding benefits for, 1489-1490 Candida albicans and, 1488 Capsicumfrufescens for, 1493 carotenes for, 1492,1496 causes of, 1486 characteristics of, 1485 in children, 1490-1491 chronic, osteopathic treatment of, 641-642 coenzyme Qlofor, 863 Coleusforskohlii for, 872-873, 1494,1496 dehydroepiandrosterone and, 1489 diagnostic summary for, 1485 dietary considerations, 1489-1490, 1495-1496 environment changes for, 1495 Ephedra spp. for, 926-927,1496 estrogen therapy and, 1488-1489 exercise-induced, 370,1407 extrinsic, 1486

Asthma-cont'd flavonoids for, 1492 food additives and, 1488 food allergies and, 1489 genetic factors, 1485 Ginkgo biloba for, 984,1494 Glycyrrhizaglabra for, 1493 hypochlorhydria and, 1488 influenza vaccine and, 1488 intrinsic, 1486 lipoxygenase products and, 1486-1487 Lobelia influfa for, 1493 magnesium for, 1492-1493,1495 mediators of, 1486 melatonin and, 1489 nutritional considerations for, 1490-1493 omega-3 fatty acids and, 1490 pertussis vaccine and, 1487 progesterone therapy and, 1488-1489 pyridoxine for, 1491 salt intake and, 1488 selenium for, 1492,1496 tartrazine and, 1486-1487 Then sinensis for, 1494 treatment of, 1488-1496 tryptophan metabolism in, 1490-1491 Tylophora asthmafica for, 1494,1496 vegan diet for, 1490 vitamin BI2for, 1492 vitamin C for, 1491-1492,1495 vitamin E for, 1492,1495 water intake and, 1407 Zizyphifructus for, 1493 Astragalus membranaceus, 652 Astringent, 710 Atheromatous plaque, 1473 Atherosclerosis antioxidants for, 1513-1516 chromium and, 1292-1293 clinical evaluation for, 1503b Crataegus oxyacantha for, 883 Curcuma longa for, 895 definition of, 1501 diagnostic summary for, 1501 dietary guidelines for liuits, 1508 Mediterranean diet, 1506-1507 nuts, 1507-1508 olive oil, 1507 omega-3 fatty acids, 1507 overview of, 1506-1507,152Ot, 1520-1521 red wine, 1508 seeds, 1507-1508 vegetables, 1508 estrogen effects on, 1881 flavonoids and, 1360 grape seed for, 1515-1516 homocysteine and, 1289,1517 hypoglycemia and, 1785 hypothyroidism and, 1793 lifestyle recommendations, 1521 macular degeneration and, 1860 pathophysiology of, 1502 policosanol for, 1512 proanthocyanidins for, 1515-1516 procyanolidic oligomers for, 1219

Atherosclerosis-cont'd risk factors for cholesterol, 1504-1505,1508-1513 C-reactive protein levels, 1506 diabetes mellitus, 1505, 1622 fibrinogen levels, 1516 homocysteine levels, 1289,1517 hypertension, 1505 overview of, 1502b, 1502t physical inactivity, 1505-1506 platelet aggregation, 1516 smoking, 1503-1504 "type A" personality, 1517-1518 therapeutic approach to, 1520-1521 vitamin C for, 1515 vitamin E for, 1514-1515 Atheroscleroticheart disease, 372 Athletes. See also Exercise; Sports nutrition camitine use by, 690 Eleutherococcus senticosus use by, 689 Athlete's heart, 370 Athletic menstrual dysfunction, 371 Atkins diet, 1652,1954-1955 Atopic dermatitis botanical medicines for, 1529 Candida albicans and, 1527 characteristics of, 1525-1526 Coleusforskohlii for, 872-873,1530 diagnostic summary for, 1525 dietary guidelines for, 1530 dust mites and, 1529 environmental considerations for, 1529-1530 essential fatty acids metabolism and, 1527-1528 food allergy in, 1526-1527 Glycyrrhiza glabra for, 1529-1530 histamine release inhibited in, 1528 immunologic abnormalities associated with, 1526 omega-3 fatty acids for, 1528 peat therapeutics for, 480 probiotics for, 1530 prostaglandin metabolism and, 1527-1528 psychologic approach, 1529 quercetin for, 1530 severity of, 1526 Staphylococcus aureus and, 1526 topical treatment for, 1530 treatment of, 1526-1529 vitamin A for, 1530 vitamin E for, 1529-1530 zinc supplementation for, 1528,1530 Atopic disease fructooligosaccharides for prevention of, 1187 probiotics for, 1203-1204 Atopic eczema, 1187 Atorvastatin, 1175-1176 Atrophic vaginitis, 1889,2156,2161,2164 Attention deficit hyperactivity disorder camitine for, 817 challenges for, 1533 characteristics of, 1533 cognitive deficits associated with, 1534 diagnostic summary for, 1533

Attention deficit hyperactivity disorder+ont'd diet and, 1536 docosahexanoic acid deficiency in, 1535 environmental toxins associated with, 1534 essential fatty acids deficiency in, 1535-1536 food allergy and, 1536-1537 genetics of, 1534 hypotheses of, 1534 immune system dysfunction in, 1538-1539 intestinal hyperpermeability and, 1537 intestinal protozoans and, 1538 lead exposure and, 1535 magnesium deficiency in, 1536 maternal tobacco and drug use, 1534-1535 melatonin activity and, 1059 metal toxicity and, 1535 neurotoxins associated with, 1535 nutritional deficiencies associated with, 1535-1536 secretory IgA in, 1537-1538 thiamin deficiency in, 1536 treatment of approach for, 1539-1541 cognitive behavioral therapies, 1539 considerations for, 1534-1536 drug therapy, 1539 neurofeedback, 1539 zinc deficiency in, 1536 Attitude cardiovascular health and, 112 explanatory style, 111 self-actualization and, 112-114 Attributional Style Questionnaire, 111 Aucubin, 1396f Autism, 1139 Autoimmune diseases apoptosis in, 147-148 bowel permeabilities associated with, 2136 description of, 148 fasting for, 535 fish oils for, 954 food allergies and, 1794 pancreatic enzymes and, 1139 thymus extracts for, 383 Autoimmune thyroiditis, 1675-1676 Autoimmunity chemical exposure and, 342 description of, 147-148 in type I diabetes mellitus, 1611 Axonopathies, 344-345 Ayweda branches of, 318,318t characteristics of, 6t Chinese medicine vs., 6t chronology of, 318f description of, 317 development of, 317-318 dietary emphasis in, 323 disease in, 322-323 doctrines of, 322,3231, Doshas, 320,322 five basic elements and senses in, 319-320 fundamental philosophies of, 7-8 health in, 322 history Of, 317-318

Ayurveda+ont'd humors in, 7 Kaph, 320 medicinal therapy, 323-324 mental constitutions, 321-322 modem medicine and, 324-325 origins of, 6-7 pharmacy in, 324 philosophy Of, 318-320 physiology of, 320-322 Pit, 320 Prakriti, 319-321 psychosomatic constitutions, 321t-322t Rajas, 322 research of, 324 Satva, 322 school of physicians, 318 school of surgeons, 318 specialties in, 318t Tamas, 322 therapeutic modes in, 323-324 treatment pMciples of, 8 Tridosha, 320 Vat, 320 Azathioprine, 2095 Azelaic acid, 1424 Azoospermia, 1865,1868 AZT acemannan and, 743-744,744t camitine prevention of toxicity associated with, 817 description of, 1735-1736 history of, 1728 Hypericum perforaturn activity and, 1043

B B cells CD19 for identification of, 225 function assessments, 230-232 B vitamins. See also spec@ B vitamin Parkinson's disease treated with, 2005-2006 rosacea treated with, 2110-2111 seborrheic dermatitis treated with, 2114 vaginitis and, 2160 Bacopa monniera, 1468 Bacteria alkylglycerols' effect on, 716 Allium sativum for, 730 Aloe Vera for, 740 pathogenicity, 1157 Vaccinium macrocarpon for, 1360 Bacterial overgrowth of the small intestine. See Small intestinal bacterial overgrowth Bacterial sinusitis, 1545-1547 Bacterial vaginitis, 2155-2156,2164 Bacterial vaginosis, 1203,2158 Bacteriophage advantages of, 1158 bacterial pathogenicity and, 1157 future applications of, 1159-1160 history Of, 1147-1149 institutional research on, 1154-1157 intracellular growth cycle of, 1151,1151f lysogenic phages, 1150-1152 lytic phages, 1150-1151,1151f

Bacteriophage-cont ‘d physiology of, 1149-1152,1150f T-e~enphage and, 1157-1158 Bacteriophage Institute, 1155-1156 Bacteriuria, 1356-1357 Bacteroides spp. eczema and, 1187 ladulose and decreased growth of, 1189 Baer, 73-74,76 Balm, 710 Balneology, 475 Balneotherapy circadian rhythms and, 477 clinical applications of, 479-481 conditions treated with, 476 definition of, 475 direct actions of, 476 history of, 476 indirect actions of, 476-477 peloid therapy and, 475 physiologic effects of, 476-477 rheumatoid arthritis treated with, 2103-2104 therapies used with, 476 Baptisia tinctoralis, 456t Barbaloin, 738 Basal metabolic rate, 536 Bastyr, John Bartholomew, 28,7475 Bastyr formula, 1823b. 1823-1824 Baths hot full-immersion, 411 neutral, 411-412 peat hyperthermic medicinal, 481-483 medicinal peat peloid, 483-484 partial-immersion, 484,484b sitz, 412-413,2020,2022,2069,2073 Batyl alcohol, 714,716f, 717 Beach, Wooster, 43-44 Bearberry. See Uva ursi Bee pollen, 767-768 Bee prod~cts,767-768 Beecher, Catherine, 134 Behenic acid, 191t, 195 Bell’s theorem, 90 Belt test, 423-424 Benign prostatic hyperplasia alcohol consumption and, 1551 5-alpha-red~~tase, 1550-1551 amino acids for, 1551 botanical medicines for, 1552-1554 cemilton for, 1553 cholesterol metabolites and, 1551 diagnosis of, 1549-1550 diagnostic s u m m a r y for, 1549 dietary factors, 1550-1552,1554 essential fatty acids for, 1551 exercise and, 1550 genetic predisposition for, 1549 high-protein diet and, 1550-1552 incidence of, 1549 Opuntia sp. for, 1115 physical activity and, 1550 pmstate-spedic antigen tests for, 1550 Pygeum aficanum for, 1222-1224,1223t, 1553,1873

Benign prostatic hyperplasia-cont’d Serenoa repens for, 1246-1248,1552-1553, 1712 soy for, 1552 treatment of, 1550-1554 Urtica dioica for, 1346-1348, 1553-1554 zinc intake and, 1551 Benign symptoms, 83 Bennett’s neurovascular reflexes, 512 Benzene, 147 Benzoates, 2141 Berberine antibiotic actions of, 579 Candida albicans treated with, 579 chemical cornpition of, 1014,1014f clinical applications of, 1016-1018 dosage of, 579,1018 drug interactions with, 1018 folk uses of, 1014 history of, 1014 infectious diarrhea treated with, 1807-1808, 1810 pharmacology of, 10141016 protozoan infestations treated with, 657 toxicity of, 1018 Berberis aquifolium. See also Berberine chemical composition of, 1014,1014f clinical applications of, 1016-1018 dosage of, 1018 drug interactionswith, 1018 folk uses of, 1014 history of, 1014 pharmacology of, 10141016 toxicity of, 1018 Berberis vulgaris. See also Berberine chemical composition of, 1014,1014f clinical applications of, 1016-1018 description of, 2161 dosage of, 1018 drug interactions with, 1018 folk uses of, 1014 history of, 1014 pharmacology of, 1014-1016 toxicity of, 1018 Beriberi, 1290 Beside manner, 100 Beta-amyloid, 854-855 Beta-blockers, 1759-1760 Beta-carotene. See also Vitamin A absorption of, 773,1383 antioxidant activity of, 774,1092-1093 cancer protections using, 1281-1282 cardiovasculardisease prevention using, 777-778 cataract prevention and, 2120 cervical dysplasia and, 1574,1576 commercial forms of, 775 definition of, 710 dietary sources of, 771-772,772t dosage of, 779 drug interactions,779 endometriosis treated with, 1645 erythropoieticprotoporphyria treated with, 778-779 in human immunodeficiency virus, 1739b

Beta-carotene-cont‘d human immunodeficiency virus treated with, 1386 immune system effects of, 774 intestinal mucosa transformationof, 773,1383 leukoplakia treated with, 1853-1854,1854t lichen planus treated with, 1857 pelvic inflammatory disease and, 2020-2021 periodontal disease treated with, 2036 photoprotectivebenefits of, 775 photosensitivitydisorders treated with, 778-779 reproduction and, 774775 structure of, Vlf, 1382f studies of, 776 suggested optimum nutrient intake for, 1281-1282,1282t toxicity of, 779 urinary tract infections treated with, 1603 vaginal candidiasis and, 778 vaginitis and, 2160 Beta-glucuronidase, 172,2055 Beta-hydroxy-beta-methylbutyrate, 680-681 Beta-hydroxybutyrate brain oxidation of, during fasting, 538-539 description of, 289t, 291 Beia-hydroxyisovalerate,289t, 291 Betain aldehyde dehydrogenase, 615 Betaine, 613-614,1655 Beta-lapachol, 1323-1324,1326 Beta-sitosterol, 2152 Beta-thujone, 756f, 758 Bicarbonate, 633 Bifidobacteria antibiotic therapy, gastrointestinaltract stabilization and recolonization after, 1201-1202 atopic disease prevention using, 1203-1204 bacterial vaginosis treated with, 1203 cancer therapy using, 1204 characteristicsof, 1197t, 1197-1199 clinical applications of, 1200t, 1200-1207 commercial forms of, 1199-1200 Crohn’s disease treated with, 12051206 definition of, 1195-1196 description of, 1196,1196t diarrhea treated with, 1206 dosage of, 1207-1209 drug interactions with, 1209 eczema treated with, 1187,1204 fructooligosaccahrides and enhancement Of, 1185-1186 gastrointestinalenvironment, 1201,1207 gastrointestinal tract colonizers of, 1196,1196t growth promotion techniques for, 1209 immune system stimulation, 1207 importance of strain in, 1198-1199 inflammatorybowel disease treated with, 1205 irritable bowel syndrome treated with, 1204-1205 lactose intolerance treated with, 1206-1207 lactulose as growth promoter for, 1188-1189 mechanisms of action, 1196-1197

Bifidobacteria-ont‘d nomenclature issues with, 1198 oligosaccharide/disaccharide promotion of, 1209 properties of, 1197 sources of, 1199-1200,1209 spirulina as source of, 1209 strain developmentand selection issues, 1207,1208t supplementswith, 1200,1207-1208 toxicity of, 1209 ulcerative colitis treated with, 1205 urinary tract infection treated with, 1202-1203 uws Of, 1197-1198,1198t vaginal yeast infections treated with, 1202 yogurts as source of, 1209 Bilbeny. See Vaccinium myrtillus Bile Artemisia absinthium effects on, 756 components of, 1687 digestive role of, 167 toxic metal excretion in, 270 Bile acids colon cancer and, 172 deficiency of, 168 digestion role of, 167 lithocholic acid to deoxycholic acid ratio, 172 in small intestinal bacterial overgrowth, 154-155 Bile salts deficiency of, 168 digestion role of, 167 gastric effects of, 2027 in small intestinal bacterial overgrowth, 154-155 Bilz, Professor EE., 54-55 Biochanin A, 1267 Bioelectrical impedance, 1949 Biofeedback adjunctive uses of, 22 migraine headaches treated with, 1918,1920 pain control using, 438 Bioflavonoids, 1903,1906. See also Flavonoids Biologic response modifiers, 235,557-558 Biomarkers blood tests, 266 urinary porphyrins as, 299 Biomedicine, 31-32 Biopsychosocial medicine, 120 Biotin assessment of, 251 deficiency of, 282 diabetes mellitus treated with, 1629 seborrheic dermatitis and, 2113 side effects of, 139Ot toxicity of, 139Ot Bipolar depression, 1428,1442-1444 Bismuth subcitrate,2027-2028 Bisphosphonates, 1981 Bitter almond. See Pygam africanum Black cohosh. See Cimicifuga rucemosa (black cohosh) Black Plague, 331

Black tea cancer prevention and, 799 green tea vs., 798 low-density lipoprotein cholesterol reductions using, 800 Blackwell, Elizabeth, 133-134 Bladder infections, 1889 Bleeding time, 959 Blinding, 123 Blood flow, 406408 Blood glucose alcohol consumption effects on, 1788 Allium cepa effects on, 1632 Allium sativum effects on, 1632 chromium effects on, 1787,1957 control of, in diabetes mellitus, 1623 fiber effects on, 1787 glucosamine sulfate effects on, 1966 glycosylated hemoglobin and, 1620 insomnia and, 1831 Morus indica effects on, 1630 postprandial, 1629 self-monitoring of, 1618 stress effects on, 1625 Blood pressure. See also Hypertension aerobic exercise effects on, 493 angiotensin-converting enzyme inhibitors’ effect on, 493 caffeine effects on, 1766 classification of, 1757-1758,1758b diastolic, 1757 fish oils effect on, 951 magnesium effects on, 1764 potassium effects on, 1297-1298,1763 soy consumption and, 1269 systolic, 1757 Blood tests biomarkers of, 266 lactose intolerance diagnosed by, 260 toxic metal exposure diagnosed using, 265-266 Blood Type Diet, 455 Blood-brain barrier, 721 Bloodroot, 330 Blue cohosh, 330 Body cell mass, 1743-1744 Body composition, 358 Body density, 1949 Body fat measurements of bioelectrical impedance, 1949 body density measurements, 1949 description of, 358 skinfold thickness measurements, 1949 menstruation and, 371 visual observation, 1948-1949 Body mass index, 358,358t, 1947,1948t Body systems form and function in, 14 functional medicine perspective of, 19-21 historical perspective of, 19-20 philosophical perspective of, 19-20 support for, 36-37 Body temperature capsaicin effects on, 804 during fever, 403

Body temperature--cont’d hydrotherapy and, 403 neutral bath effects on, 412 pancreatic enzyme absorption and, 1135 Bohr effect, 633 Bombesin, 247 Bone loss estrogen deficiency and, 1979 menopause and, 1978 soft drink consumption and, 1982-1983 Bone metabolism, 970 Bone mineral density calcium and, 1292 soy isoflavones’ effect on, 1984 testing of, 1980 vitamin D effects on, 1986 Bonesetters of England, 418-419 Bony end-feel, 425 Borg scale of perceived exertion, 359 Boric acid description of, 784-785 toxicity of, 788 vaginitis treated with, 2162-2163 Boron arginine and, 786-787 arthritis and, 1291 biochemistry of, 784-785 biologic functions of, 785 brain function affected by, 785,1291 calcium metabolism affected by, 786 chemical properties of, 784 clinical applications of, 787-788 deficiency of, 785-786 description of, 685,783 dosage of, 788 in drinking water, 784,789 drug interactions, 789 embryo maturation and, 785 food sources of, 784t hematologic effects of, 785 hormone interactions,787 magnesium and, 786 metabolism of, 784-785 methionine and, 786-787 mineral metabolism affected by, 785 nutrient interactionswith, 786 osteoarthritis and, 787-788 osteoporosis prevention using, 787,1983 phosphorus levels affected by, 786 for postmenopausal women, 1291 prostate cancer treated with, 788 recommended intake of, 1291t rheumatoid arthritis and, 787-788 sources of, 783-784,784t, 1983 suggested optimum nutrient intake for, 1290-1291 summary of, 789 toxicity Of, 788-789 vitamin D synthesis and, 786-787 Boswellia, 1494-1495,1971 Botanical extracts, 1096-1098 Botanical medicine, 119 Bovine colostrum, 247 Bovine spongiform encephalopathy, 378 Bowman-Birk inhibitor, 1261 Boyd, William, 389

Index Brachial plexus, 424 Brachytherapy, 566 Brain aluminum toxicity in, 344 apoptosis in, 149-150 beta-hydroxybutyrate oxidation by, 538-539 boron effects on, 785,1291 citicoline applications for, 856 energy sources for, 538 fasting effects on, 538 fatty acids’ effect on, 943 glucose use by, 1293 glutamine effects on, 999 iron deficiency effects on, 1295 manganese-induced damage in, 344 Branched-chain amino acids, 683-684 Breast cancer chemotherapy for, 997 cwnzyme Qlufor, 861 dehydroepiandrosterone levels in, 902-903 environmental toxins and, 343 genistein for, 1267,1271 glutamine for, 997 hormone replacement therapy and, 1882-1884 ligandlike complex and, 450 organochlorine compounds and, 343 phytoestrogens for, 1267 prevention of Camellia sinensis for, 798-799 dietary fiber for, 674 docosahexanoic acid, 956-957 eicosapentaenoic acid, 956-957 fish oils for, 948,956 omega-3 fatty acids for, 948,956 soy isoflavones for, 1267,1891 Breastfeeding for asthma, 1489-1490 celiac disease and, 1564 diabetes mellitus risks and, 1611 for food allergies, 1527 otitis media prophylaxis, 1993 Breath testing for lactose intolerance, 259-260 for small intestinal bacterial overgrowth false-positive and false-negative results, 156-157 hydrogen vs. methane, 156 indications, 154b interpretation of, 156 lactulose, 156 principles Of, 155-156 Breath-holding-time test, 637 Breathing altered patterns of, 631-632 chemical control of, 639 diaphragmatic, 704,704b, 1761 emotions’ effect on, 634 muscles of, 638-639 neural regulation of, 639 normal pattern of, 630 physiology of, 630,639 rehabilitation exercises for, 641,642b retraining of, 640441,642b stress management by, 704,704b structure-function continuum in, 638 voluntary control of, 639

Breathing pattern disorders. See Hyperventilation syndrome/ breathing pattern disorders Bromelain absorption of, 792 antiinflammatory activity of, 792 antitumor effects of, 793 cancer treated with, 794 chemical composition of, 791 clinical applications of, 793-794 description of, 556,791 disorders treated with, 793t dosage of, 794 dysmenorrhea treated with, 794 fibrinolysis activation by, 792 gout treated with, 1707 history of, 791 immunomodulation effects of, 793 pelvic inflammatory disease treated with, 2021 pharmacology of, 791-793 platelet aggregation inhibited by, 792 pneumonia treated with, 2041 postoperative uses of, 794 quercetin and, 971-972 respiratory tract diseases treated with, 793 rheumatoid arthritis treated with, 2102 sports-related injuries treated with, 794 thrombophlebitis treated with, 794 toxicity of, 795 varicose veins treated with, 2169-2170 Brown fat, 1952-1953 Bruessow, Harold, 1157 Brush-border hydrolases, 443 Brush-border membrane, 167 Buckwheat, 1690-1691 Budden, William A., 71 Bulbourethral glands, 1866 Bupleurum falcatuni, 2103 Burkitt, Denis, 462463 Bums Aloe Vera for, 741-742 Centella asiafica for, 831 glutamine and, 998-999 radiation, 742-743 Bushite stones, 1850 Butcher‘s broom. See Ruscus aculeatus Butylated hydroxyanisole, 2141 Butylated hydroxytoluene, 2141 Butyrobetaine hydroxylase, 810 Bitxus semperoirens, 17451,

,.

L

C fibers, 432 CA19-9,449t Cabbage glutamine in, 998 peptic ulcers treated with, 2027 Cachexia, 562,957-958,997,lOOO Cadmium, 267,27lt, 596t, 1772,1849 Caffeic acid, 909,909f Caffeine blood pressure affected by, 1766 chronic fatigue syndrome and, 1586-1587 depression and, 1432

Caffeine-cont‘d description of, 680,706 endometriosis and, 1645 ephedrine and, 927 glaucoma and, 1699 premenstrual syndrome and, 2057 Calcium. See also Osteoporosis body status assessments of, 276,276t bone mineral density and, 1292 boron effects on metabolism of, 786-787 deficiency of description of, 282t in inflammatory bowel disease, 1821 dietary sources of, 258 erythrocyte membrane tests for, 276 functions of, 1291 gastric acid effects on, 1982 hair analysis for, 210 hypertension treated with, 1764 kidney stones and, 1848 osteoporosis and, 1292,1984-1986 parathyroid hormone effects on, 1979 premenstrual syndrome treated with, 2060 recommended intake of, 1292t serum levels of, 276 sugar consumption and, 1982 suggested optimum nutrient intake for, 1291-1292,1292t supplements description of, 1292 lead content in, 1985t trichomoniasis treated with, 2129 vitamin D and, 1282,1986 Calcium channel blockers, 329,1760 Calcium oxalate urolithiasis, 1361 Calicivirus, 471 California Medical Association, 60 Calomel, 130 Caloric intake, 1953-1954 Calprotectin conditions associated with, 172b description of, 1824 in irritable bowel disorder, 171-172 Camellia sinensis (green tea) antiinflammatory effects of, 2035 cancer prevention and, 798-799 cardiovascular disease and, 799-800 catechins in, 560-562 chemical composition of, 797-798 during chemotherapy, 560-562 clinical applications of, 798-800 description of, 797 dosage of, 800 drug interactions, 800 oral cavity diseases treated with, 800 oxidative stress and, 2008 Parkinson’s disease treated with, 2008,2011 pharmacology of, 798 photoprotective effects of, 800 polyphenols, 797,2008 toxicity of, 800 Campylobacter jejuni, 173-174,471,1802-1803 Canada, 75 Ca-Na2-EDTA DMSA and, 269 toxic metal retention assessments using, 267

Cancer ABO blood groups and, 448-450 alkylglycerols for, 719 Alliurn sativum for, 731 Aloe Vera for, 745 berberine and, 1016-1018 biologic response modifiers for, 557-558 breast. See Breast cancer cachexia in, glutamine and, 997 cervical description of, 1571 oral contraceptives and, 1573 chemotherapy for. See Chemotherapy clinical care pattern for, 554 clinical trials for, 568-569 colon beta-glucuronidase levels and, 172 CA19-9 expression in, 449t dietary fat and, 172 dietary fiber for, 674 DU-PAN-9 expression in, 449t hormone replacement therapy and, 1879 lactulose for prevention of, 1189-1190 definition of, 550 development of, 147 dietary considerations, 569 dietary fiber for prevention of, 674 Echinacea spp. for, 914 environmental factors, 550 erythrocyte sedimentationrate in, 181-182 exercise training benefits for, 362 fatty acids and, 943 immune system and, 111-112 lycopene and, 774,1282 naturopathic support for, 554 nitrate consumption and, 468 pancreatic docosahexanoic acid for, 957 eicosapentaenoic acid for, 957 weight loss associated with, 957 pancreatic enzymes effect on, 1138-1139 performance indexes for, 552,553t personality types and, 112 polyerga for, 382 prayer benefits for, 524525 prevalence of, 549 prevention of Aloe Vera for, 745 beta-carotene for, 775-776,1281-1282 black tea for, 799 Camellia sinensis for, 798-799,826 carotenes for, 775-777 carotenoids and, 1093 dietary fiber for, 674 Eleutherococcus senticosus for, 922 glutathione for, 1094 Glycyrrhiza glabra for, 1005 melatonin activity and, 1059-1060 omega-3 fatty acids for, 948 Panax ginseng and, 1125 probiotics for, 1204 selenium for, 1298 Taraxacum oficinale for, 1337 tea consumption for, 798-799,826 Vaccinium macrocarpon for, 1360 vitamin B12 for, 1286

Cancer-cont'd radiation therapy for antioxidants and, 568 brachytherapy, 566 machinegenerated beams, 565-566 natural remedies that potentiate, 566-567 naturopathic support during, 566 radioimmunotherapy,566 radiopotentiation,566-567 radioprotedion, 567 side effects of, 566 skin protection during, 567 types of, 56566 remission of, 553 signs of, 420 staging of, 551-552 statisticsregarding, 550 surgical treatment of complications of, 554 fractionated citrus pectin use before, 555 micrometastases secondary to, 555 natural medicine support, 555-556 nutrition after, 555-556 preoperative guidelines, 555,556b prevalence of, 554 tumor cell spread after, 555 terminology associated with, 553 thymus extracts for, 383 TNh4 staging of, 551-552 toxin-associated, 342-34.4 treatment of alkylglycerols, 719 Aloe Vera, 745 antiangiogenic agents, 557-558 biologic response modifiers, 557-558 bromelain, 794 chemotherapy. See Chemotherapy clinical trials, 568-569 coenzyme QIO, 861 complete response to, 553 Curcuma longa, 894,896 dehydroepiandrosterone,902-903 description of, 553-554 fish oils,956-958 hormones, 558 immune response modulators, 558 naturopathic support, 554 paclitaxel, 1339-1343 palliative, 553 partial response to, 553 protease inhibitors, 1261-1262 radiation therapy. See Cancer, radiation therapy for Ruscus aculeatus, 1227 soy isoflavones, 1265-1268 surgery. See Cancer, surgical treatment of Taxus brevifolia, 1341 Viscum album, 1377-1378 tumor markers for, 552,552t tumor response criteria, 552-553 types of, 551 vitamin C for, 562 vitamin E and, 1283 Candida albicans Allium sativum for, 579 asthma and, 1488

Candida albican-ont'd atopic dermatitis and, 1527 caprylic acid for, 579 chronic fatigue syndrome and, 1584-1585 description of, 170 Echinacea spp. for, 914 enteric-coated peppermint oil for, 1839 enteric-coated volatile oils for, 579-580 Giardia lamblia and, 655 lactulose effect on, 1189 Melaleucn alternifolia for, 580 natural agents for, 578-580 oral thrush, in HIV patients, 1739-1740 overgrowth of. See Chronic candidiasis probiotics, effects on, 1203 propolis for, 580 pruritus ani caused by, 2076 urticaria caused by, 2141-2142 vaginitis caused by, 2157-2158,2164 Candida camage, 451t Candidiasis,chronic antibiotics and, 573-574,1992 antibody levels in, 575 antigen levels in, 575 beta-carotene levels and, 778 causal factors of, 573-575 comprehensive digestive stool analysis for, 575 definition of, 573 diagnosis of, 575 diarrhea associated with, 579,1808 Echinacea spp. for, 914 patient profile, 573,574b, 158% predisposing factors, 574b treatment of detoxification, 577-578 diet, 575-576 elimination, 578 high-fiber diet, 578 hypochlorhydria, 576 immune function enhancements, 576-577 natural antiyeast agents, 578-580 panmatic enzymes, 576 probiotics, 578 program for, 580 vaginal, 778,2157 Cape aloe. See Aloe Vera Capillary disorders, 1219 Capillary fragility, 1903 Capillary permeability, 1366-1367 Capric acid, 19Ot, 194 Caprylic acid, 579 Capsaicin clinical applicationsof, 804805 cluster headaches treated with, 805 diabetic retinopathy treated with, 805,1635 mouth pain caused by chemotherapyor radiation therapy treated with, 805 osteoarthritis treated with, 805 pain control using, 803,894 postherpetic neuralgia treated with, 804 pruritus ani treated with, 806 psoriasis treated with, 805 trigeminal neuralgia treated with, 804

Index Capsicumfnrfescens (cayenne pepper) asthma treated with, 1493 chemical composition of, 803 clinical applicationsof, 804 description of, 803,1050 diabetic retinopathy treated with, 805 dosage of, 806 folk uses of, 803 mouth pain caused by chemotherapyor radiation therapy treated with, 805 pharmacology of, 803-804,804f postherpetic neuralgia treated with, 804 postmastectomy pain treated with, 804-805 pruritus ani treated with, 806 psoriasis treated with, 805,2084 rheumatoid arthritis treated with, 805 toxicity of, 806 trigeminal neuralgia treated with, 804 Capsular end-feel, 425 Carbidopa, 1033 Carbohydrase, 1080-1081 Carbohydrates dietary intake of, 463 digestion of, 168 exercise-related intake of, 694 fat conversion of, 941f hypoglycemia and, 1785-1786 kidney stones and, 1847 maldigestion of, 168 refined, 706,17851786 type II diabetes mellitus and, 1615 whey protein and, 682 Carbon clearance test, 911 Carbon dioxide bicarbonate from, 633 hydrogen ions and, 632-633 pH and, 633 Carbon monoxide, 369 Carboplatin, 564 Carcinwmbryonicantigen, 552,552t Carcinoma, 551 Cardiomyopathy coenzyme Qlofor, 863-864 dilated, 863 Cardiorespiratoryexercise, 359-360 Cardiovascular disease ABO blood groups and, 447-448 angina, 813 atherosclerosis. See Atherosclerosis beta-carotene for prevention of, 777-778 Camellia sinensis effects, 799-800 camitine for, 812-813 carotenoids as protection against, 1093 Coleus forskohlii for, 873-874 coronary artery disease. See Coronary artery disease coronary heart disease. See Coronary heart disease definition of, 1501 dehydroepiandrosterone-sulfatein, 902 ear lobe crease as sign of, 1520 fish oils for, 949-950 flavonoids as protection against, 1096 glutamine and, 999 highly active antiretroviral therapy and, 1740

Cardiovasculardisease-cont’d human immunodeficiency virus and, 1740 hydrotherapy and, 409-410 myocardial infarction. See Myocardial infarction nutrigenomics and, 491-494 Panax ginseng and, 1125-1126 pancreatic enzymes and, 1139 prayer benefits for, 522-523 prevalence of, 491 recurrent, 1518-1520 smoking and, 1504 soy consumption and, 1268 vitamin C for, 1092,1285,1515 vitamin E for, 1090-1091 Cardiovascularendurance, 357-358 Cardiovascular system Alliitm cepa effects on, 726 Alliitm sativum effects on, 731 Angelica spp. effects on, 751 attitude effects on, 112 Capsicumfrufescens effects on, 803 citrus flavonoids’ effect on, 970 Crataegus oxyacantha effects on, 882-883 Curcuma longa effects on, 895 ephedrine effects on, 926 magnesium effects on, 1518 potassium effects on, 1518 Viscuni album effects on, 1376 Carminative,710 CARN 750,740-741 Camitine. See also L-acetylcarnitine alcoholism treated with, 1456 Alzheimer’s disease treated with, 815 angina pectoris treated with, 1476,1479 arrhythmias treated with, 813 athlete use of, 690 attention deficit hyperactivity disorder treated with, 817 biosynthesis of, 809-810,810f cardiovasculardisease treated with, 812-813 choline interactionswith, 817 chronic fatigue syndrome treated with, 1588 chronic obstructive pulmonary disease treated with, 817 clinical applications of, 812-818 congestive heart failure treated with, 813-814,1593-1595 deficiency of in AIDS patients, 817 alcohol consumption and, 816,1453 description of, 811,811b degradation of, 810 description of, 809 diabetes mellitus treated with, 816 dietary content of, 812 dosage of, 690,817 Down syndrome treated with, 815816 drug interactions,817 drug toxicity protection using, 817 elderly use of, 815 excretion of, 810 exercise benefits of, 814-815 fatty acid metabolites and, 1476

Carnitinwont’d forms of, 812 heart disease treated with, 1476 hemodialysis uses of, 816 history of, 809 homocysteine effects on, 615 inborn errors of metabolism treated with, 817 in infant diet, 811-812 interferon-a-induced fatigue treated with, 817 intermittent claudication treated with, 813 kidney disease treated with, 816 lipids oxidation and, 809 liver disease treated with, 816-817 in long-chain fatty acid transport, 811f male infertility treated with, 1872 male reproductive role of, 811 metabolism of, 810 muscular dystrophies and, 817 myocardial infarction recovery and, 813 nutrient uses of, 811-812 peripheral vascular disease treated with, 814 physical performance enhancements using, 689-691,814815 physiologic functions of, 810-811 pregnancy supplementation, 812 senile depression treated with, 815 sperm count affected by, 817 sperm motility affected by, 817 sports nutrition uses of, 689-691,814815 synthesis of, 690 tissue transport of, 810 toxicity of, 691,817 word origin of, 1736 Carotene alpha-, 774 asthma treated with, 1492,1496 beta-. See Beta-carotene cancer prevention using, 775-777 cardiovascular disease prevention using, 777-778 clinical applications of, 775-779 commercial forms of, 775 definition of, 710 description of, 466t dosage of, 779 drug interactions,779 immune function affected by, 648-649, 774,778 palm oil, 775 photoprotective benefits of, 775 side effects of, 1390t suggested optimum nutrient intake for, 1281-1282 toxicity of, 779,1390t vaginal candidiasis and, 778 Carotene and Retinol Efficacy Trial, 776 Carotenodennia, 774 Carotenoids. See also Vitamin A absorption of, 772-773,1383 antioxidant activity of, 774,1092-1093,1099, 1101-1102 description of, 771,1391 dietary sources of, 771-772,772t

index Carotenoids--cont'd dosage of, 779 intestinal mucosa transformation of, 773,1383 lycopene, 773,773f, 774t metabolism of, 772-774 photoprotectivebenefits of, 775 physiologic roles of, 774-775 phytosterols and phytostanols effect on, 1512 porphyrias treated with, 2050b storage of, 773-774 structure of, 771,771f tissue distribution of, 773t transport of, 773 zeaxanthin, 773f Carpal tunnel syndrome acupuncture for, 1560-1561 definition of, 1557 diagnosis of, 1558 diagnostic summary for, 1557 differential diagnosis, 1558-1559 etiology of, 1557-1558 hydrotherapy for, 1559,1561 immobilizationfor, 1560 manual manipulation for, 1560-1561 risk factors for, 1558 stretching exercises for, 1560-1561 treatment of, 1559-1561 vitamin 86 for, 1559 Carrageenan, 669,1817-1818 Catalase, 1089,2119 Cataracts classification of, 2117 cortical, 2117-2118 diabetes mellitus and, 1622 diagnostic summary for, 2117 riboflavin and, 1289,2119-2120 senile antioxidantsfor, 2118-2129 beta-carotenefor, 2120 catalase for, 2119 cysteine for, 2120 description of, 2117-2118 diary products and, 2120 flavonoid-richextracts for, 2120 glutathione for, 2118-2119 Hachimijiogan for, 2120-2121 heavy metals and, 2120 lutein for, 2118 melatonin and, 2120 riboflavin for, 2119-2120 selenium for, 2119 tetrahydrobiopterinfor, 2119 treatment of, 2118-2121 vitamin C and, 2118 types of, 2117 Vaccinium myrtillus and, 1368 vitamin C and, 1285,2118 vitamin E and, 1283 Catechin [(+)-cyanidanol-3],1097-1098 alcohol-inducedliver disease treated with, 825 antiendotoxineffects of, 824 antioxidantproperties of, 824 antiviral effects of, 823-824

Catechin-cont'd collagen metabolism affected by, 824 description of, 823 dosage of, 826 drug interactions, 826 hepatitis treated with, 824-825 histidine decarboxylaseinhibition by, 824 immunostimulatoryeffects of, 823-824 osteogenesis imperfecta treated with, 825 peptic ulcers treated with, 825,2028 pharmacology of, 823-824,824f postoperative complications managed using, 825 rheumatoid arthritis treated with, 825-826 scleroderma treated with, 826 structure of, 824f toxicity of, 826 Catecholamines description of, 96 epinephrine, 617 metabolism of, 1439f norepinephrine, 1673 Catechol-0-methyltransferase,1039-1040 Cathartic, 710 Caulophyllum thalictroides animal studies of, 395 description of, 330 Cause/effect dualism, 18 Cayenne pepper. See Capsicum frutescens CD4 CD29 and, 225 CD8 ratio with, 225 helper T cells identified using, 225 CD8,225 CD11,224225 CDlla, 227 CDllb, 227 CD16,226 CD19,225 CD25,226-227 CD26,227 CD29,226 CD38,227 CD45RA epitope, 227 CD45RO molecule, 227 CD56,226 (369,227,232 Celecoxib, 1963 Celery, 1761 Celiac disease breastfeeding prophylaxis against, 1564 characteristicsof, 1563 conditions associated with, 1564-1565 diagnosis of, 1565,1713b diagnostic summary for, 1563 diet for, 1565 epilepsy and, 1653 grain proteins and, 1563,1564f hair loss and, 1713 immune function affected by, 1611 intestinal permeability alterations caused by, 243 lactose maldigestion associated with, 257 microbial enzyme therapy for, 1080-1081 pancreatic enzymes for, 1565

Celiac diseas-ont'd pathogenesis of, 1564 resources for, 1566 Cell cycle chemotherapeuticagents and, 550 in chronic fatigue syndrome patients, 162-163 flow cytometry assessments of, 162 in patients exposed to carcinogenic chemicals, 162-163 phases of, l61,162f, 550 Cell cycle clock, 161 Cell death. See Apoptosis Cell function antioxidants and regulation of, 1099 Panax ginseng effects on, 11241125 Cell signaling, 161 Cell-mediated immunity description of, 221,585 macrophages' role in, 224 Cellular retinol-binding protein, 1384 Cellulite Centella asiatica for, 831, 1569-1570 clinical features of, 1568-1569 description of, 1567 diagnostic summary for, 1567 exercise for, 1569 histologic features of, 1567-1568 treatment of, 1569-1570 varicose veins and, 1570 Cellulitis, 1567 Cellulose, 667 Centella asiatica (gotu kola) anxiety relief using, 832 asiaticoside, 833 burns treated with, 831 cellulite treated with, 831,1569-1570 chemical composition of, 829-830 chronic venous insufficiency treated with, 832 cirrhosis of the liver treated with, 831 clinical applications of, 831-832 connective tissue affected by, 830b description of, 829 dosage of, 833 folk uses of, 830 history of, 830 keloids treated with, 831-832 leprosy treated with, 832 mental function improvements using, 832 periodontal disease treated with, 2036 pharmacology of, 830-831 scleroderma treated with, 832 stria gravidarum treated with, 831 toxicity of, 833 triterpene compounds of, 829,830f varicose veins treated with, 2168,2170 wound healing benefits of, 830,832 Central nervous system ephedrine effects on, 926 Lobelia injlata effects on, 1050 Central sleep apnea, 1830 Centralization, 422 Cerebral lesions, 420 Cerebral vascular insufficiency,979-981,98Ot Cemilton, 1553

Index Ceruloplasmin, 10951096 Cervical cancer descriptionof, 1571 oral contraceptives and, 1573 Cervical dysplasia beta-carotene and, 1574,1576 cervical cancer and, 1571 copper-to-zinc ratio in, 1575 diagnosticsummary for, 1571 folic acid deficiency and, 15741576 human papillomavirus, 1571-1572 nutrition factors associated with, 1573-1574 oral contraceptivesand, 1573,2035 progression of, 1575 risk factors for, 1572-1573 selenium and, 1575-1576 sexual transmission, 1572-1573 smoking and, 1573 treatment of, 1573-1576 vaginal depletion pack for, 1575 vitamin A and, 1574 vitamin 86 and, 1575-1576 vitamin C and, 1574,1576 zinc for, 1575 Cervical spine manipulation of, 424,1918 vertebrobasilar stroke, 424 Chain-breaking antioxidants description of, 1088,1088f heart disease treatment with, 1091-1093 Chamomile. See Matricaria charnomilla Chapman's neurolymphaticreflexes, 512 Charantin, 1631 CharCOt-Marie-Toothdisease, 365-36 Chaste tree.See Vitex agnus castus Cheilosis, 281,282t Chemical vaginitis, 2156 Chemotherapy actions of, 557 adjuvant uses, 557 administration of, 558-559 adriamycin, 563,818,864-865 agents, 556-557,558t, 563-565 alkylating agents, 557 antimetabolites, 557 e 567-568 antioxidant u ~ with, antitumor antibiotics, 557 biologic response modifiers, 557-558 carboplatin, 564 cell cycle phases and, 550 chromatin inhibitors, 557 duonotherapy considerations, 558-559 cisplatin, 564 clinical uses of, 557 cyclophosphamide, 563-564 cytoxan, 563-564 definition of, 556 docetaxel, 565 doxorubicin, 563 eicosapentaenoic acid during, 562 enzymes during, 563 fish oils during, 562 flax oil during, 562 5-fluorouracil, 564 "fractionated," 558 glutamine and, 996-997,999-10oO

Chemotherapy-cont'd green tea during, 560-562 high-dose, 557 indications for, 559-560 intestinal permeability affected by, 245 melatonin during, 560-561 methotrexate, 564-565 microtubule inhibitors, 557 modes of administration, 558-559 mouth pain caused by, 805 multivitamin use during, 561t, 562 mushroom extracts during, 562-563 neoadjuvant uses, 557 oxidative byproduds of, 568 paclitaxel, 565 palliative uses, 557 polyerga during, 382 resistance testing, 559 second-line, 557 side effects of, 559b, 559-560,996997 support program during, 560463,561t survival benefits of, 560 Taxol, 565 Taxotere, 565 topoisomerase inhibitors, 557 vitamin C during, 562 Chenodeoxycholic acid, 1692 Childbirth pain acupuncture for, 436-437 attention-focusingtechniques for, 434 cultural influences on,433 description of, 431-433 transcutaneous electrical nerve stimulation for, 435-436 Children elimination diet in, 499 exercise by, 367 fasting by, 543 food allergies in, 584 infectious diarrhea in, 1807 inflammatorybowel disease in, 18241825, 1825b obesity in, 1950 pesticide exposure in, 467 Chimy1 alcohol, 716f Chinese medicine Ayurveda vs., 6t characteristics of, 6t fundamental philosophies of, 8 origins of, 6-7 Tibetan medicine vs., 6t traditional, 7 transformations in, 7 treatment principles of, 8 Chinese prepared medicine adulterants in, 839 dispensary guide for, 840-845,841t-844t endangered species used in, 839 FDA restrictions on, 838 formulations,838-839 global market for, 838 history Of, 837-838 preparations, 838-839 prescribing of, 840 standards for, 839-840 in United States, 837

Chiropractic history of, 61 in United States, 9 Chiropractic manipulation, 419 Chlamydia trachomatis, 2016,2075,2159,2164 Chlamydia1infection, 1869 Chlordanes, 342 Chlorophenoxy acid herbicide, 343 Chlorophyll, 2020,2022,2161 Chloroquine, 762 Cholagogue, 710 Cholecystitis, 1017 Cholecystokinin, 1952 Cholelithiasis, 1073 Cholera, 451t, 1151-1153 Choleretic, 710 Cholestasis, 710,1584b,2055,2055b Cholesterol ABO blood groups and, 446-447 Allium satimrn effects on, 732-733 atherosclerosis and, 1504-1505 benign prostatic hyperplasia and, 1551 bile solubility of, 1688f diabetes mellitus and, 1634 dietary interventions for, 492 fish oils' effect on,950 gallstones and, 1687-1688 genetics and, 1505 in hypothyroidism, 1793 lowering of Allium cepa for, 1512 Allium sativum for, 732-733,1512 benefits, 1508-1509 black tea for, 800 dietary fiber for, 672-673,673t, 1509 inositol hexaniacinate, 1634 ~ t u r aproducts l for, 1509-1513 niacin for, 1509-1513,1634 pantethine, 1512-1513 phytostanols, 1511-1512 phytosterols, 1511-1512 plant sterols and stanols, 1511-1512 policosanol for, 1512-1513 statins for, 1508-1509 Opuntia sp. effect on, 1115 policosanol's effects on, 1173-1176, 1174f-1177f saponin binding to, 1262 vitamin C and, 1515 Zingiber oficinale effects on, 1413 Choline camitine interactions with, 817 citicoline effects on,854 epilepsy treated with, 1655 sports nutrition uses of, 691 urinary tract infections treated with, 1603 Cholinergic, 710 Cholinergic urticaria, 2135t, 2135-2136 Chondrocytes, 1964 Chondroitin sulfate homocysteine effects on, 615-616 osteoarttuitis treated with, 1966-1967 Chromatography, 336 chromium acne vulgaris treated with, 1422 age-related decreases in, 210

Index Chromium-ont’d atherosclerosisand, 1292-1293 body status assessments of, 276t, 276-277 depression treated with, 1435-1436,1442 diabetes mellitus treated with, 1626 glaucoma treated with, 1699 glucose levels affected by, 1787,1957 glucose tolerance factor and, 277,1293 hair analysis for, 210 physical performance and, 685-686 plasma levels of, 276-277 psoriasis treated with, 2082,2084 recommended intake of, 1293t, 1626,1957 safety of, 1293 suggested optimum nutrient intake for, 1292-1293,1293t urinary tests for, 277 weight loss using, 1957-1959 Chromium picolinate, 1957-1958 Chronic candidiasis antibiotics and, 573-574,1992 antibody levels in, 575 antigen levels in, 575 beta-carotene levels and, 778 causal factors of, 573-575 comprehensivedigestive stool analysis for, 575 definition of, 573 diagnosis of, 575 diarrhea associated with, 579,1808 Echinuceu spp. for, 914 patient profile, 573,574b, 158% predisposing factors, 5741, treatment of detoxification, 577-578 diet, 575-576 elimination, 578 high-fiber diet, 578 hypochlorhydria, 576 immune function enhancements, 576-577 natural antiyeast agents, 578-580 pancreatic enzymes, 576 probiotics, 578 program for, 580 vaginal, 778,2157 Chronic daily headaches description of, 1907-1908,1908b, 1911t drug-induced, 1911 Chronic fatigue immune dysfunction syndrome, 655 Chronic fatigue syndrome caffeine and, 1586-1587 Cundidu ulbicuns and, 1584-1585 camitine for, 1588 causes of, 1582b cognitive behavior therapy for, 1586 counseling for, 1589 definition of, 1579-1580 depression and, 1583,1586 diagnosis of, 1580b, 1582-1583 diagnostic summary for, 1579 diet and, 1586-1587,1589 Eleutherococcus senticosus for, 1588-1589 enterohepaticresuscitation program for, 603 Epstein-Ban virus and, 1580-1581

Chronic fatigue syndrome-cont’d essential fatty acids for, 1587 etiology of, 1580-1582 exercise for, 1588 fibromyalgia and, 1582 food allergies and, 1585 gastrointestinal permeability associated with, 1584 glucocorticoid deficiency and, 1586 Glycyrrhizu glubru for, 1588-1589 hypoadrenalism and, 1586 hypoglycemia and, 1585-1586 hypothalamic-pituitary-adrenalaxis disruptions in, 1586 hypothyroidism and, 1585 immune system abnormalities associated with, 1581t, 1581-1582 liver function impairments and, 1583-1584 magnesium for, 1587 multiple chemical sensitivities and, 1582 nicotinamide adenine dinucleotide for, 1587-1588 nutritional supplements for, 1587-1588 stress and, 1583 symptoms of, 1580t terminology associated with, 1579 thymus extracts for, 383 treatment of, 1583-1589 vitamin C for, 1589 vitamin E for, 1589 water intake and, 1408 Chronic fatigue/fibromyalgia,366 Chronic heartburn, 661 Chronic illness, 33 Chronic interstitial cystitis, 1600 Chronic obstructive pulmonary disease camitine for, 817 exercise effects, 364 ginseng for, 688 Chronic venous insufficiency Centellu usiaticu for, 832 Ruscus uculeutus for, 1228-1230,1229t Chronotherapy,558-559 Chuan Xin Lian, 840 Chvostek‘s sign, 635 Chylomicrons, 940 Chymotrypsin clinical applicationsof, 1137t description of, 170 extraction of, 1133 as pancreatic enzyme, 1132 Ci W u Jia. See Eleutherococcus senticosus Cichorium intybus, 1183-1884 Cilostazol, 983 Cimicifigu rucemosu (black cohosh) bone loss prevention using, 848 bone resorption affected by, 850 chemical composition of, 847,848f clinical applicationsof, 848-850 description of, 847 dosage of, 850 estrogenic activity of, 848,850 history of, 847 hormone replacement therapy vs., 850 luteinizing hormone effects, 848

Cimicijhgu rucemosu+ont‘d menopause treated with, 848-850,849t, 1894,1896 pharmacology of, 848 premenstrual syndrome treated with, 2062 toxicity of, 850-851 triterpene glycosides in, 847 Cinnumomum (cinnamon),2077 Circadian rhythms, 477 Cirrhosis berberine for, 1017 CenteIlu usiuticu for, 831 Sadenosylmethionine for, 1238 Silybum mariunum for, 1253,1455 Cis-aconitate, 289t Cisplatin, 564 Citicoline acetylcholinesteraseproduction affected by, 854 age-related cognitive deficits treated with, 855 Alzheimer’s disease uses of, 856 amblyopia treated with, 857 beta-amyloid inhibition by, 854-855 brain trauma rehabilitation uses of, 856 chemical structure of, 854f choline levels affected by, 854 clinical applications of, 855-857 description of, 853 dosage of, 857 drug interactions, 857 glaucoma treated with, 856-857 glutathione levels affected by, 857 memory improvementsand, 856 neurotransmitter levels increased by, 855 oxidative stress reductions by, 857 pharmacokinetics of, 853 phospholipase activity affected by, 854 stroke therapy using, 855-856 toxicity of, 857 Citrate description of, 287-288,290 kidney stone formation inhibited by, 1848 Citrate acid cycle, 287-288,290 Citric acid cycle, 287,288f Citrus flavonoids, 968,970 Citrus pectin, 555 Classical conditioning, 102 Clinical diagnosis, 21 Clinical Global Impression scale 5-hydroxytryptophan and, 1025-1026 Hypericum perforaturn activity and, 1042 clinical trials approaches to, 119 blinding in, 123 combination therapeutics, 121 controls in, 123 description of, 568-569 double-blind, 123 individualizationof treatment, 120-121 measures, 122-123 nonspecific healing effects, 121-122 outcomes, 122-123 overview of, 118-119 standardization of, 119-120 whole practice models, 123

Index Clostridium spp. C. botulinurn, 470 C. dificile, 174,1803 eczema and, 1187 phage therapy and, 1158 Cluster headaches capsaicin for, 805 Capsicumfrufescensfor, 805 descriptionof, 1907 Cobalamin descriptionof, 612 metabolism of, 613f Coccidioidomycosis, 451t Cochlear deafness, 982 Cod liver oil, 1611 Coenzyme, 710 Coenzyme A, 616 Coen~ymeQM acquired immunodeficiency syndrome treated with, 861 adriamycin toxicity prevented using, 864-865 aging and, 861 angina pectoris treated with, 864, 14761477,1479 antioxidant properties of, 863,1094 arrhythmias treated with, 864 asthma treated with, 863 beta-blocker interactionswith, 866 breast cancer treated with, 861 cancer treated with, 861 cardiac surgery uses of, 865 cardiomyopathytreated with, 863-864 cardiovascular disease and, 863 clinical applicationsof, 860-866 congestive heart failure treated with, 864, 1594.1595 deficiency of in cardiovascular disease, 863 description of, 860 in hypertension, 865 description of, 859 diabetes mellitus treated with, 865 dosage of, 866 drug interactions, 866 exercise performance and, 691,695,862 Friedrich ataxia treated with, 860 gastric ulcers treated with, 862 heart disease and, 1477 heart disease treated with, 1091 homocysteine effects on, 616 hypertension treated with, 865,1766 hypexthyroidism effects on, 1776 immune function affected by, 860-861 infertility treatment using, 865-866 ischemic heart disease and, 863 in Krebs cycle, 860 mitochondrial diseases and, 860 mitral valve prolapse treated with, 865 muscular dystrophies treated with, 862-863 neuropathy treated with, 1743 Parkinson'sdisease treated with, 860,2006 in peptic ulcer disease, 862 periodontal disease treated with, 861-862, 2035 physical performance affected by, 862

Coenzyme Q,-ont'd reperfusion injury and, 1475 statins' interaction with, 866,1509 supplemental, 859 synthesis of, 617f, 859,861 therapeutic levels for, 867 toxicant exposure treated with, 866 toxicity of, 867 vitamin E and, 1513-1515 warfarin interactionswith, 866 Cognition citicoline effects on, 855 description of, 115 hormone replacement therapy effects on, 1884 menopause and, 1889 Panax ginseng activity and, 1122 phosphatidylserine effects on, 1164 soy isoflavones' effect on, 1270-1271 Cognitivebehavioral stress management, 1738 Cognitive therapy attention deficit hyperactivity disorder treated with, 1539 chronic fatigue syndrome treated with, 1586 depression treated with, 1430 description of, 115 Colchicine, 1706 Cold compress, 410 Cold diuresis, 1405 Cold double compress, 410-411 Cold friction rubs,413 Cold injury, 369 Cold pack, 410 Cold sik bath, 412 Cold sponging 405 Cold therapy description of, 404-405 reflex effects of, 408t Cold urticaria, 2135t, 2136 Cold weather exercising, 369 Coleusforskohlii asthma treated with, 872473,1494,1496 atopic dermatitis treated with, 1530 cardiac failure treated with, 873 cardiovasculareffects of, 873-874 chemical composition of, 871 clinical applications of, 872-874 depression treated with, 874 description of, 871 dosage of, 874 drug interactions,874 eczema treated with, 872-873 epilepsy treated with, 16561657 folk ws Of, 871-872 forskolin, 872f glaucoma treated with, 874 history Of, 871-872 hypertension treated with, 873-874 hypothyroidism treated with, 874 malabsorption treated with, 874 pharmacology of, 872,872f platelet aggregation inhibition by, 874 psoriasis treated with, 873 toxicity of, 874

Collagen anthocyanidins' effect on, 1708 catechin effects on metabolism of, 824 citrus flavonoids' effect on, 970 Crataegus oxyacantha effects on, 882 in eye, 1697-1698 of periodontium, 2033 procyanolidic oligomers, 1218 silicon effects on, 1987 Vaccinium myrtillus effects on, 1366 vitamin C effects on, 1626-1627 Collateral circulation effect, 407-408 Collinsonin canadensis (stone root), 2077 Colon cancer beta-glucuronidaselevels and, 172 CA19-9 expression in, 449t dietary fat and, 172 dietary fiber for, 674 DU-PAN-9 expression in, 449t hormone replacement therapy and, 1879 lactulose for prevention of, 1189-1190 Colonic foods, 1191t, 1191-1192 Colonic irrigation, 350-351 Colony-forming units, 229 Combination therapeutics, 121 Comedones, 1421 Commiphora mukul (mukul myrrh tree) antiatherosclerotic effects of, 879 antiinflammatoryeffects of, 879 chemical composition of, 877,878f description of, 877 dosage of, 879 folk uws of, 877-878 history of, 877 lipid disorders treated with, 878-879 osteoarthritis treated with, 879 toxicity of, 879 Common cold Astragalus membranaceus prophylaxis against, 652 Echinacea spp. for, 912-914 Ephedra spp. for, 927 Menth piperata for, 1073 naturopathic medicine perspective of, 33 propolis for, 768 susceptibilityfactors, 33 Communication, 705,705b Complement, 717-718,2032 Complementaryand alternative medicine acupuncture. See Acupuncture description of, 1728 insurance coverage for, 9 integration tools for, 10-11 National Certification Commission for Acupuncture and Oriental Medicine certification, 9-10 NIH support of, 9 reimbursement of, 9,124 resources regarding, 313 third-party coverage of, 124 in United States, 9-10 Comprehensive Digestive Stool Analysis 2.0 absorption assessments, 170-171 Carnpylobacter jejuni, 173-174 chronic candidiasis assessmentsusing, 575 Clostridiurn dificile, 174

Index Comprehensive Digestive Stool Analysis 2.O-cont’d description of, 165 digestive function assessments, 170-174 fecal occult blood testing, 174 food allergy testing, 587 gut immunology assessments, 171-172 Helicobacter pylori stool antigen test, 173 metabolism assessments, 172 microbiology assessments, 173 mycology assessments, 173 Shiga toxin-producing Eschprichia coli, 173 Compresses definition of, 710 types of, 410411 Concanavalin A, 230 Conditioning (exercise) flexibility, 360-361 muscular, 360 Conditioning phase, of cardiorespiratory exercise, 360 Conditioning (psychological) classical, 102 operant, 102 therapeutic, 102-104 Condyloma lata, 2074 Condylomata acuminata, 2073-2074 Congestive heart failure arginine for, 1594 berberine and, 1018 camitine for, 813-814,15951595 coenzyme Qlofor, 864,1594-1595 Crataegus oxyacantha for, 883,1595 definition of, 1591 diagnosis of, 1591-1592 diagnostic summary for, 1591 dietary guidelines for, 1595 magnesium for, 1592-1593,1595 precipitating factors, 1592b stages of, 1592t Tminalia arjuna for, 1595 thiamin for, 1593,1595 treatment of, 1592-1595 vitamin E and management of, 1090-1091 Conjugated equine estrogens, 1885-1886 Conjugated linoleic acid, 468 Connective tissue Centella asiatica effects on, 830b collagen matrix of, 970 Connective tissue massage, 512,514 Conscious control, 95 Consortium of Naturopathic Medical Colleges, 30 Constipation, 1189 Constitutional hydrotherapy, 413414,2051 Continuous positive airway pressure, 1830 Contraception Aloe Vera uses in, 745 intrauterine device, 2017,2021 methods of, 2021 oral. See Oral contraceptives Contrast hydrotherapy, 406-407 Contrast sitz bath, 412-413 Conventional medicine, 8 Cool-down phase, of cardiorespiratory exercise, 360

Copper body status assessments of, 276t, 277 boron effects on, 786 deficiency of, 1294 descriptionof, 1293-1294 fructose consumption and, 1294 hair analysis for, 210,277 health effects of, 1293-1294 in human immunodeficiency virus, 1739b recommended intake of, 1294t rheumatoid arthritis treated with, 2101 suggested optimum nutrient intake for, 1293-1294,1294t Copper-to-zinc ratio, 1575 Coproporphyrin,2048 Coptis chinensis. See also Berberine chemical composition of, 1014,1014f clinical applications of, 1016-1018 dosage of, 1018 drug interactionswith, 1018 folk uses of, 1014 history of, 1014 pharmacology of, 10141016 toxicity of, 1018 Cori cycle, 539 Coronary artery disease aerobic exercise benefits, 361 alcohol intake and, 492 erythrocyte sedimentation rate as predictor of, 181 exercise effects, 361-362 homocysteine and, 619 Mediterranean diet for, 1506-1507 melatonin activity and, 1061-1062 vitamin E for, 361 weight-resistance training effects on, 362 Coronary heart disease carnitine for, 1476 coenzyme Qlodeficiency and, 1477 C-reactive protein levels and, 952 dietary fiber benefits for, 671 fasting for, 535 fatty acids and, 942 folic acid for prevention of, 620 homocysteine and, 619 hormone replacement therapy and, 1880-1882 omega-3 fatty acids and, 942,946 prayer benefits for, 523 vitamin I36 and, 1289 vitamin E and, 1514 water intake and, 1406 Corpus luteum insufficiency, 1396-1397, 1397t Cortical spreading depression, 1908 Corticosteroids inflammatory bowel disease treated with, 1819 mechanism of action, 96 rheumatoid arthritis treated with, 2094 side effects of, 2094 Corticotropin-releasing hormone, 1039-1040 Cortisol cigarette smoking effects on, 1431 depression and, 1430-1431 description of, 97

Cortisol-ont’d Glyqrrhiza glabra and, 1004-1005 melatonin activity and, 1061 Corydalis rhizome, 438 coumarin Angelica spp., 751 description of, 466t Coumestans, 1262 Coumestrol, 1264,2152 Counseling, 115 alcoholism treated with, 1456 chronic fatigue syndrome treated with, 1589 depression treated with, 1430 rheumatoid arthritis managed with, 2105 Cowpox virus, 148 C-peptide, 1619,1619t Cranbeny. See Vaccinium macrocarpon Cranial shear, 428 Crataegus oxyacantha (hawthorn) angina pectoris treated with, 1477,1479 atherosclerosis treated with, 883 cardiovascular effects of, 882-883 chemical composition of, 881,882f clinical applicationsof, 883 collagenstabilizing action of, 882 congestive heart failure treated with, 883,1595 description of, 881 dosage of, 884 drug interactions, 884 folk uses of, 881 hypertension treated with, 883,1766 side effects of, 884 toxicity of, 884 vitamin C and, 881 C-reactive protein anger expression and, 1517 atherosclerosis and, 1506 coronary heart disease and, 952 description of, 179,480 diabetes mellitus and, 1623 fish oil effects on, 952 pelvic inflammatory disease and, 2019 statins’ effect on, 1509 Creatine adenosine tiphosphate and, 678 amino-imidazoazaarenes, 680 arginine and, 683 brain levels of, 678 caffeine effects on, 680 cardiac muscle use of, 678 description of, 677-678 dosage of, 679 food sources of, 678 formation of, 617 homocysteine effects on, 617 insulineffects on uptake of, 679 Parkinson’s disease and, 2007-2008 performance enhancementsusing, 678-679 toxicity of, 679-680 Creatine kinase, 371 Crinnion depuration protocol, 350-351

Index Crohn’s disease.See also Inflammatory bowel disease anal fissures and, 2069 antibiotic use and, 574,1814-1815 characteristics of, 1813 dehydroepiandrosteronesulfatelevels in, 903 diagnostic summary for, 1813 dietary factors, 1815 endotoxemia in, 1818 etiology of, 1814 features of, 1814 gut-associated lymphoid tissue response in, 242-243 incidence of, 1814 natural history of, 1815-1816 N-butyrate in, 171 nuclear factor kappa B in, 171 omega-3 fatty acids and, 1815 probiotics for, 12051206,1824 propolis for, 768 therapeutic approach to, 1825-1826 vitamin A for, 1821 zinc deficiency in, 1820 Crohn’s Disease Activity Index, 1824-1825, 1825t Croton lechleri (dragon’s blood), 887-889 Crypt cells, 167 C/T-13910,257 Curcuma longa (turmeric) anticarcinogenic effects of, 894,896 antiinflammatory effects of, 894-895 antimicrobial effects of, 896 antioxidant effects of, 894 cardiovascular effects of, 895 chemical composition of, 893,894f clinical applications of, 896-897 description of, 893 dosage of, 897 drug interactions, 897 folk uses of, 893 gastrointestinal effects of, 895-896 hepatic effects of, 895 history of, 893 human immunodeficiency virus treated with, 174% neuroprotective effects of, 896 pharmacology of, 893-896 rheumatoid arthritis treated with, 896, 2101-2102 toxicity of, 897 Curcumin, 894897,1693,2102 Cure, 82b, 552 Cyanocobalamin. See Vitamin B,, Cyclic adenosine monophosphate Crataegus oxyacantha effects on, 882 description of, 646 forskolin effects on, 872 Glycyrrhiza glabra and, 1004-1005 Cyclic adenosine monophosphate phosphodiesterase description of, 1253 flavonoids effect on, 1528 Cyclic guanosine monophosphate, 646-647 Cyclic mastalgia, 1398 Cyclin-dependent kin-, 550

Cyclins, 550 Cyclooxygenasel, 244 Cyclooxygenase-2 inhibitors, 1963-1964, 2093-2094 Cyclophosphamide, 563-564,2095 Cyriax, James,419-420 Cystathionine synthase deficiency of, 623 description of, 614 Cystatin C, 614-615 Cysteamine, 616,616f Cysteine, 2120 Cystic fibrosis, 663 Cystine stones, 1850 cystitis acupuncture for, 1603 Alliurn sativurn for, 1602 Arctostnphylos uva ursi for, 1602 causes of, 1597-1598 chronic interstitial, 1600 description of, 1597-1598 diagnostic summary for, 1597 Hydrastis canadensis for, 1602-1603 menopause and, 1889 treatment of, 1600-1603 urine specimens, 1598-1600 Vacciniurn macrocarpon for, 1600-1601 Cytochrome C oxidase deficiency, 288,290 Cytochrome P450 biotransformation role of, 596-597 description of, 25 fasting effects on, 599 genetic polymorphism of, 598 high-carbohydrate diet effects on, 600 cytokines description of, 221-222 essential fatty acids effect on, 1646 helper T type 1cell production of, 232-233 inducible nitric oxide synthase induced by, 230 melatonin activity and, 1061 Thl, 646 m,646 Cytomegalovirus, 1802 cytoxan, 563-564

D 2,4-D, 343 Daidzein breast cancer and, 1267 description of, l259,1260f, 1891 excretion of, 1261 structure of, 1260f Dairy allergy, 256-257 Dan Shen Pian, 842t Dandelion. See Tarnxncurn oficinale Dandelion root, 1337 Dandruff, 1055 DASH diet, 1761-1766,1762 pbeta-hydroxybutyrate, 2004 DDE, 340,467 DDT, 340-341,341t, 467,535,594 Decoctions, 710 Deep brain stimulation, 2003

Deglycyrrhizinated licorice aphthous stomatitis treated with, 1482 chemical composition, 1003 clinical applications of, 1006 dosage instructions for, 1009 peptic ulcers treated with, 2028 Dehydration description of, 471 in elderly, 1404 hypertension and, 1407 jet lag and, 1405 signs and symptoms of, 1402 subclinical, 1405-1406 Dehydroepiandrosterone age-related variations in levels of, 899 aging and, 900-901 Alzheimer’s disease and, 1467 aromatase inhibitors interaction with, 904 asthma and, 1489 biochemistry of, 899-900,900f breast cancer and, 902-903 cancer and, 902-903 clinical applications of, 900-904 depression treated with, 901 description of, 97,899 dosage of, 904 drug interactions, 904 Hashimoto disease treated with, 1797 hypoadrenalism treated with, 901 metabolism of, 900f myotonic dystrophy and, 902 osteoporosis and, 901-902 rheumatoid arthritis and, 2091 sex steroid biosynthesis and, 900 sexual functioning and, 902 steroid sulphatase inhibitors interaction with, 904 systemic lupus erythematosus treated with, 903 toxicity of, 904 Dehydrwpiandrosterone-sulfate Alzheimer’s disease treated with, 901 biochemistry of, 899-900,900f cardiovascular disease and, 902 Crohn’s disease and, 903 description of, 899 erectile dysfunction treated with, 902 interleukin-6 and, 903 rheumatoid arthritis and, 903 Delbruck, Max, 1151 Delta-aminolevulinic acid, 301f Delta-6-desaturase, 939,1528 Dementia. See also Alzheimer’s disease causes of, 1461t, 1462 homocysteine levels in, 621 phosphatidylcholine for, 1466 phosphatidylserine effects on, 1164 reversible causes of, 1462 senile, 1461t Demulcent, 710 Dengue fever, 451t Dennie’s sign, 1525-1526 Dental amalgams, 1856,2033 Deoxycholic acid, 1690

Index Depression adrenal gland dysfunction and, 1430 aging-related, 901 alcohol consumption and, 1432,1454-1455 biogenic amine hypothesis of, 1429 botanical medicines for, 1441-1442 caffeine and, 1432 camitine for, 815 causes of, 1429-1430,1430b chromium for, 1435-1436,1442 chronic fatigue syndrome and, 1583,1586 cognitive therapy for, 1430 Coleusforskohlii for, 874 cortisol levels and, 1430 cortisol-to-dehydroepiandrosterone ratios in, 901 counseling for, 1430 definition of, 1427 dehydroepiandrosteronefor, 901 dietary guidelines for, 1433,1442 environmental toxins and, 1431 exercise for, 1432-1433 folic acid for deficiency of, 1433-1435 description of, 1442 food allergies and, 1436 forskolin for, 874 Ginkgo biloba for, 983-984,1441-1442 health effects of, 111-112 heavy metal exposure and, 1431 homocysteine levels and, 621 hormonal factors associated with, 1430-1431 5-hydroxytryptophanfor, 1023t-l026t, 1023-1026,1032,1438 Hypericum perforaturn for, 1041-1043, 1042t,1441 hypoglycemia and, 706,1433 hypothyroidism and, 1430 learned helplessness model of, 1429 lifestyle factors associated with, 1431-1433, 1442 melatonin activity and, 1060-1061 monoamine metabolism and, 1436-1440 in multiple sclerosis, 1931 nutrition and, 1433-1436 omega-3 fatty acids and, 1436 optimism and, 1429 Parkinson’s disease and, 1031-1032, 1032t, 2004 phenylalaninefor, 1438,1439t phosphatidylserineeffects on, 1164 Piper methysticum for, 1441 placebo effect for, 520 premenstrual syndrome and, 2058 prevalence of, 1428 S-adenosylmethionine for, 1235-1236,1238, 1438-1440,144Ot selenium for, 1435 senile, 815 signs and symptoms of, 1427 smoking and, 1431-1432 stress and, 1430 supplements for, 1442 theoretic models of, 1428-1429 thyroid function and, 1430

Depression-ont’d treatment of, 1429-1442 tryptophan for, 1436-1438 tyrosine for, 1438,1439t Valeriana officinalis for, 1373 vitamin B6 and, 1435 vitamin BI2 and, 1433-1435,1442 zinc for, 1435,1442 Zung’s Self-Rating Depression Scale, 1679f, 1680 Depuration Crinnion protocol for, 350-351 definition of, 349-350 methods of, 350 Derivative effect, 407 Dermatitis atopic. See Atopic dermatitis seborrheic, 2113-2114 Dermatitis herpetiformis, 1605-1606 Dermatophytosis, 452 Dermographism, 2134-2135 Desaturase enzymes, 938 Descartes, 4 Detoxification Aloe Vera for, 739 chronic candidiasis treated by, 577-578 dietary fiber effects on, 600 exercise effects on, 600 fasting effects on, 599 lifestyle for, 602-603 lipotropic agents for, 578,2056 metallothioneins for, 598-599 nutrition for, 603 Parkinson’s disease treated with, 2004 phase 2 description of, 599-600 homocysteine effects on, 618 porphyrias treated by, 2050 promotion of, 577-578 urinary organic acids profiling and, 289t DeWolff, Herman, 60 Dexamethasone suppression test, 1431 d’Herelle, Felix, 1147-1149 Diabetes mellitus Allium cepa for, 726 Aloe Vera for, 744-745 alpha-lipoic acid for, 1633 anthocyanosides for, 1368 atherosclerosis and, 1505 biotin for, 1629 blood glucose levels and, 1609 camitine for, 816 characteristics of, 1607-1608 cholesterol levels in, 1634 chromium for, 1626 citrus flavonoids for, 971 classification of, 1608-1609 clinical monitoring of description of, 1617 glycosylated hemoglobin, 1620 by physician, 1620 self-monitoring of blood glucose, 1618 urine glucose levels, 1617 urine ketone testing, 1617-1618 coenzyme Qla levels in, 865

Diabetes mellitus-cont‘d complications of acute, 1621-1622 atherosclerosis, 1622 cataracts, 1622 chronic, 1622-1624 contributors to, 1623-1624 diabetic ketoacidosis, 1621 endothelial cell dysfunction and, 1624 flavonoids for, 1633t foot ulcers, 1622,1635-1636,1638 homocysteine and, 1624 hypertension and, 1624 hypoglycemia, 1621 immune system dysfunction, 1622-1623 nephropathy, 1635,1638 neuropathy, 1622,1633-1635 nonketotic hyperosmolar hyperglycemia, 1622 nutrient deficiency and, 1624 overview of, 1608b, 1620-1621,1621b recommendations for, 1633-1636 retinopathy, 1622 supplementation for, 1638 wound healing alterations, 1622, 1635,1638 C-reactive protein levels in, 1623 definition of, 1607 diagnosis of, 1609-1610 diagnostic summary for, 1607 diet therapy for, 16241625 dietary fiber and, 671 exercise for, 363-364,1625-1626 fasting for, 535 fenugreek for, 1632 fiber supplements for, 1629-1630 fish oils for, 958,1629 flavonoids for, 971,1632-1633,1633t gestational, 1608-1609,1628 gluten-sensitive enteropathy in, 244 Gymnema sylvestre for, 1631 homocysteine levels in, 622,1624 hydrotherapy contraindications, 408-409 intestinal permeability affected by, 244 low-fiber diet and, 671 magnesium for, 1628 maldigestion in, 244 management of, 1620t-1621t manganese for, 1628-1629 Momordica charantia for, 1631-1632 Moms indicu for, 1630-1631 natural glucosidase inhibitors for, 1630 niacin for, 1392,1627-1628 niacinamide for, 1627-1628 nutritional supplements for, 1626-1633 omega-3 fatty acids for, 1629 Opuntia sp. for, 1115 osteoarthritis and, 1964 oxidative stress and, 1623-1624,1632 Punax ginseng for, 1123-1124,1632 Panax quinquefolium for, 1632 policosanol for, 1176,1177t postprandial blood glucose reductions for, 1629 psychologic support in, 1625 secondary, 1608

Index Diabetes mellitus-cont’d sorbitol and, 1623,1627 stress and, 1625 symptoms of, 1608-1609 Taraxacum oficinale for, 1337 therapeutic approach for, 1636-1638 touchi extract for, 1630 w eI autoimmunity in, 1611 characteristics of, 1608t description of, 363,1608 diet therapy for, 16241625 dietary factors, 1610-1611 early treatment of, 1612-1613 enterovirusesand, 1611 environmental factors, 1610-1611 epicatechin for, 1613 fenugreek for, 1632 genetic factors, 1610 gluten sensitivity and, 1611 insulin therapy for, 1618-1619 niacinamide for, 1612-1613 nitrates and, 1612 omega-3 fatty acid deficiency and, 1612 risk factors for, 1610-1612 self-monitoring of blood glucose in, 1618-1619 supplementation for, 1636-1637 vitamin D deficiency and, 1611-1612 w e JJ antioxidantsfor, 1616 characteristics of, 1608t C-peptide levels in, 1619,1619 description of, 363,622,1608 diet and, 16141615 diet therapy for, 1625 dietary fat intake and, 1616 fenugreek for, 1632 free radicals and, 1616 genetic factors, 1614 high-carbohydratediet and, 1615 lifestyle modifications, 16141615,1617 nuts for, 1616 obesity and, 1608,1613-1614 racial factors, 1614 risk factors in, 1613-1617 self-monitoring of blood glucose in, 1619 supplementation for, 1637 Vaccinium myrtillus for, 1368 vanadium effects, 686,1301 vitamin 86 for, 1628 vitamin C for, 1626-1627 vitamin E for, 1627 zinc supplementation in, 1628 Diabetic ketoacidosis breathing pattern alterations caused by, 632 definition of, 1617 description of, 1621 Diabetic neuropathy, 1622,1628,1633-1635, 1638 Diabetic retinopathy acupuncture for, 1635 capsaicin for, 805 Capsicumfrutescens for, 805,1635 description of, 1622 flavonoids for, 1634

Diabetic retinopathy-ont’d forms of, 1634 Ginkgo biloba for, 982 procyanolidic oligomers for, 1219 Ruscus aculeatus for, 1230 treatment of, 1634,1638 Vaccinium myrtillus for, 1368 l,Z-Diacylglycerols, 168,720 Diagnosis clinical, 21 differential, 21-22 word origin of, 21 Diamine oxidase, 1914 2,CDiaminoanisole sulfate, 346 Diaphragmaticbreathing, 704,704b, 1761 Diarrhea breathing pattern alterations secondary to, 632 Canipylobacter jquni, 173 chronic candidiasis and, 579 classification of, 1801 Clostridium dipcile, 174 Croton lechleri for, 888-889 glutamine and, 995,1000 in human immunodeficiency virus, 1740-1741 infectious acupuncture for, 1809-1810 agents that cause, 1802-1804 berberhxontaining plants for, 1807-1808,1810 Campylobacter jquni, 1802-1803 in children, 1807 classification of, 1801 Clostridium dificile, 1803 cytomegalovirus, 1802 diagnostic summary for, 1801 dietary considerations,1805 Epstein-Barr virus, 1802 Escherichia coli, 1802 folic acid deficiency and, 1805,1810 Giardia lamblia, 1803 glutamine for, 1806,1810 history of, 1801 in HIV/AIDS patients, 1809 homeopathy for, 1808-1810 hydration/electrolyte balance for, 1804-1805 laboratory diagnosis of, 1804 Lactobacillus acidophilus for, 1806-1807, 1810 Laribacter hongkongensis, 1803 nutritional supplements for, 1810 parasitic agents that cause, 1803-1804 Potentilla t o r m t i l l a for, 1808, 1810 predisposing factors for, 1804 probiotics for, 1806-1807 Saccharomyces boulardii for, 1807,1810 Salmonella, 1803 Shigella, 1803 treatment of, 1804-1810 viral agents that cause, 1802 vitamin A for, 1805,1810 vitamin BI2 deficiency and, 1805,1810 Yersinia enterocolitica, 1803 zinc deficiency secondary to, 1806,1810

Diarrhea-ont’d probiotics for, 1206 in small intestinal bacterial overgrowth, 154 traveler’s, 1807 Diathermy, 2020,2022 Dibromochloropropane, 346 Diet acne vulgaris and, 1422,1424 Alzheimer’s disease and, 1462-1463,1469 angina pectoris and, 1479 apolipoprotein E levels and, 491492 asthma and, 1489-1490,1495-1496 atherosclerosis prevention. see Atherosderosis, dietary guidelines for Atkins, 1652,1954-1955 attention deficit hyperactivity disorder and, 1536 Ayurveda emphasis on, 323 benign prostatic hyperplasia and, 1554 bipolar depression treated with, 1444 Blood Type, 455 cancer prevention and, 569 celiac disease treated with, 1565 chronic candidiasis and, 575-576 chronic disease and, 462463,4631, chronic fatigue syndrome and, 1586-1587, 1589 congestive heart failure and, 1595 diabetes mellitus and type I, 1610-1611,1624-1625 type II, 1625 diversified rotation description of, 499-500 food allergies treated with, 588 elimination. See Elimination diet endometriosis treated with, 1644-1645,1647 epilepsy and, 1651-1653 fibrocystic breast disease and, 1668 fibromyalgia and, 1674 fructooligosaccahrides sources in, ll84t, 1184-1185 gluten-free, 1605-1606 health and, 35-36 hemorrhoids and, 2070-2071 hepatitis and, 1717 herpes simplex virus treated with, 1726 high-fiber, 1625,2027,2070,2150 high-protein, 455,1550-1552,1982 hunter-gatherer, 462,665-666 hypertension and, 1760 hyperthyroidism treated with, 1777 hypoglycemia and, 1785-1786 improvement in, 35-36 inflammatory bowel disease and, 1815, 1819-1820 ketogenic epileptic seizures treated with, 1651-1652 Parkinson’s disease treated with, 2004 kidney stones and, 1844-1845 low oxalate, 1845-1847,1846t low-fat, 941 low-fiber, 670-671 low-protein, 2004 low-purine, 1706 lung cancer and, 957 macular degeneration treated with, 1860

Index Diet-cont’d Mediterranean, 469,1462,1506-1507 melanoma and, 957 melatonin synthesis and secretion and, 1058 myocardial infarction recurrence and, 1519-1520 oligoantigenic, 1919 otitis media and, 1996 Parkinson’s disease and, 2003-2004,2010 plant-based, 462 porphyrias and, 2049 premenstrual syndrome and, 2056-2057 psoriasis and, 2084 rheumatoid arthritis and, 2095-2096,2104 salt content in Fantus test for assessing, 185186 hypertension and, 493 normal levels for, 186 sodium-restricted,493 stress reduction by, 705-706 Swank, 1929-1930,1935 trichomoniasisand, 2129 Type 0,455 uterine fibroids and, 2150-2151 vaginitis and, 2159-2160 vegan, 1490,1690,1982,2056,2098 Western, 665,1785 Dietary fast with food challenge, 206t, 206-207 Dietary fiber cancer prevention using, 674 cholesterol reductions using, 672-673, 673t, 1509 chronic degenerative disease and, 666,666b classification of, 668t in Colonic foods, 1191t, 1191-1192 composition of algal polysaccharides,668-669 cellulose, 667 gums, 668 hemicelluloses, 667-668 lignans, 669 lignins, 669 mucilages, 668 noncellulosepolysaccharides, 667 overview of, 666-667 pectin, 668 pectinlike substances, 668 phytic acid, 669,669t constipation treated with, 669,2069 definition of, 666-667,1787 detoxificationaffected by, 600 diabetes mellitus and, 671,1629-1630 digestion affected by, 670 dosage of, 674 drug interactions, 674 end-products of, 670 fermentation of, 670 food consumption patterns, 463,464t, 666,667t food sources of, 672t gallstones and, 671,1690,1693 glycemic index/glycemic load affected by, 1615-1616 heart disease and, 671

Dietary fiber-cont’d intestinalbacterial flora maintained by, 670,2081 irritablebowel syndrome treated with, 672,1838 low-fiber diet, diseases associated with, 670-671 mercury affected by, 601 mineral malabsorption caused by, 674 obesity treated with, 671,673,673t overview of, 671-672 peptic ulcers and, 2027 physiologic effects of, 669-670 satiation and, 669 short-chain fatty acids production from, 670 sources of, 671-672,672t, 1509t, 1956 stool weight affected by, 669-670 supplements, 674 transit time affected by, 669-670 varicose veins and, 2168 water-soluble, 1615-1616,1787,1957 weight loss, 1956-1957 Dietary practices, 120 Dietary reference intakes, 1280 Dietary supplementation, 1279 Diethylstilbestrol,1869 Diet-induced thermogenesis, 1952-1953 Differentialdiagnosis, 21-22 Digestion abnormalities of, 168-169 carbohydrates, 168 Comprehensive Digestive Stool Analysis 2.0 assessments of, 170-171 definition of, 166 dietary fiber effects on, 670 hypochlorhydria effects on, 584 lactose intolerance and, 1078-1079 lipid, 168 malabsorptive disorders of, 1077-1078 nutrient absorption during, 168 pancreatic enzymes and disorders of, 1137-1138 physiology of, 166-168 rheumatoid arthritis and, 2097 in stomach, 217-218 Taraxacum oficinale for, 1336-1337 Dihomogammaholenic acid, 190t, 193,195 Dihomogammalinolenicacid/ eicosapentaenoicacid ratio, 191t, 196 Dihydroartemisinin, 762 Dihydrotestosterone, 1246,1549,1712 Dihydroxyacetone,692 Dilated cardiomyopathy,863 Dilute juice fast, 498 Dimethylglycine,613,1655 Diosmin, 2169-2170 Dioxin, 1647 Diploid cells, 161 Directed prayer, 528 Disaccharides,168,1209 Discopathy, 479 Disease in Ayurveda, 322-323 homeopathic view of, 389,391

Disease-modifying antirheumatic drugs, 2094-2095 Distraction techniques, for pain control, 434 Dithiolthiones,466t Diuretics, 1115,1759-1760 Diversified rotation diet description of, 499-500 food allergies treated with, 588 D-Lactate, 294 DMPS challenge test for, 269,602,602b description of, 267-268 oral provocation protocol for, 268-269 side effects of, 268 toxic metal retention assessments using, 267-269 DMSA Ca-Na2-EDTAand, 269 metal detoxificationuses of, 604 toxic metal retention assessments using, 269-270 Docetaxel, 565,1341 Docosadienoic acid, 190t, 193 Docosahexanoic acid angina pectoris treated with, 951 atherosclerosisand, 1507 attention deficit hyperactivity disorder treated with, 1535 breast cancer prevention and, 956-957 C-reactive protein levels and, 952 description of, 19Ot, 192 developmentaldisorders and, 942 dietary requirement, 947 hypertension treated with, 951 pancreatic cancer-related weight loss treated with, 957 during pregnancy, 953 rheumatoid arthritis treated with, 954 studies of, 945 Docosapentaenoicacid, 190t, 192 Docosatetraenoicacid, 190t, 193 Doctor of naturopathy degree as, 71-72 licensing of, 72-73 schools for, 71-72 Doctor-patient relationship desuiption of, 99-100,106 rheumatoid arthritis and, 2097-2098 treatment outcomes affected by, 122, 2097-2098 Dodecylglycerol, 718 Doshns, 320, 322 “Double-crush syndrome,” 1559 Douching, 2021-2022,2158,2163 Doxorubicin, 563 Dragon’s blood. See Croton lechleri Drug(s) biotransformation of, 25 Food and Drug Administration approval of, 328 urticaria caused by, 2136-2137 Drug abuse, 525 Drug-induced hyperhomocysteinemia, 623-624 Drusen, 1859 Dry eyes, 1386-1387 Du26,513

Dual energy x-ray absorptiometry, 1980 D u b , R a e , 1152 Duffy, John, 62 Duodenal ulcers, 1006,2025-2029 DU-PAN-9,449t Dust mites, 1529 Dysbiosis description of, 170,170b intestinal permeability affected by, 245, 1537-1538 Dysentery, 1152-1153 Dysfunctional uterine bleeding, 1902 Dysmenorrhea bromelain for, 794 endometriosisand, 1645 Vaccinium myrfillus for, 1368 Dyspareunia, 2017 Dyspepsia, 1407 Melissa officlnalisand, 1067 M e n t h piperuta for, 1072-1073 Dysplasia, 550 Dysthymia, 1427-1428

E Ear acupuncture, 1657 Ear drops, for otitis media, 19941996 Ear lobe crease, 1520 Eastern medicine diagnostics in, 8 historical origins of, 4 5 overview of, 5-6 philosophy of, 5 treatment principles of, 8 Western medicine vs., 5,6t Eating Right Pyramid, 464,464f Echinacea spp. alkylamides of, 909 antibacterial properties of, 911-912 antkfhmmatory properties of, 910 antineoplasticproperties of, 912 antiviral properties of, 911 caffeic acid derivatives, 909,909f cancer treated with, 914 candidiasistreated with, 914 chemical composition of, 908-910 clinical applications of, 912-914 commercial preparations of, 914915 common cold treated with, 912-914 descriptionof, 907 dosage of, 912,915,915b E. ungustifolia, 651,907,910 E. paradoxa, 907 E . purpurea, 651,907 essential oils in, 909 extracts, 912 flavonoids from, 909 folk uses of, 910 history of, 910 immune system affectedby, 651-652 immunostimulatoryproperties of, 910-911 otitis media treated with, 1996 pharmacology of, 910-912 pneumonia treated with, 2041 polyacetylenes in, 909-910 polysaccharides of, 90849,911 during pregnancy, 916

Eckinacea spp.-cont’d rheumatoid arthritis treated with, 914 sinusitis treated with, 1546 snakebites treated with, 914 streptococcal pharyngitis treated with, 2124 . . taxonomic classification, 907,908t tissue regeneration and, 910 toxicity of, 915-916 wound healing uses of, 914 Echinacin, 910,915 Eclectic movement, 332 Eclectic school of medicine, 4344 Eclipta alba, 1096-1097 ECOG index, 552,553t Ectopic pregnancy, 2017 Eczema. See also Atopic dermatitis fructooligosaccharidesfor, 1187 Glycyrrkiza glabra for, lo08 probiotics for, 1204 Edema, 1230,1231t EDTA angina peaoris treated with, 1478 atherosclerosis treated with, 1520 description of, 267 porphyrias treated with, 2050 Effleurage, 504t EGb761,1098 Egg yolks, 1860-1861 Eicosanoids definition of, 935 fish oils‘ effect on, 961 formation of, 940,940f metabolism of in inflammatorybowel disease, 1816 quercetin effects on, 969,1823 Eicosapentaenoic acid atherosclerosis and, 1507 breast cancer prevention and, 956-957 during chemotherapy, 562 description of, 19Ot, 191-192,946 dietary requirement, 947 flaxseed oil effects on, 2099 gout treated with, 1707 hypertension treated with, 951 immune function affected by, 953 inflammatory reaction treated with, 589 myocardial infarction and, 952 pancreatic cancer-dated weight loss treated with, 957 psoriasis treated with, 955,2082 rheumatoid arthritis treated with, 954 Elaidic acid, 191t, 195,939t Elderly camitine use by, 815 citicoline for, 856 dehydration in, 1404 exercise by, 368 policosanol’s effects in, 1177 selenium use by, 1299 thyroid functioning in, 1791 urinary tract infections in, 1358 zinc deficiency in, 1794,1861 Electroampuncture food allergy testing using, 205,206t osteoarthritis treated with, 1970 Voll technique for, 205,206t

Electrolytes, 540. See also specific electrolyte Electromagnetic fields, for Parkinson’s disease, 2009 Electron microscopy, 1150 Elemental diet, 1819-1820 Eleuthero, 919-923 Eleutherococcus senticosus (Siberian ginseng) adaptogenic activity of, 921-923 carcinogenesis inhibition using, 922 chemical composition of, 919,92Of, 920t chronic fatigue syndrome treated with, 1588-1589 clinical applicationsof, 922-923 description of, 919 digoxin interactionswith, 923 dosage of, 689,923 drug interactions,923 eleutherosides,919,920f exercise benefits of, 689 folk uws of, 919-921 history of, 919-921 male infertility treated with, 1872-1873 Panax ginseng and, 922 pharmacology of, 921-922 radiation protection uses of, 922 sports nutrition uses of, 689 stress management uses of, 707,922 toxicity of, 689,923 Wu Cha Seng tablet, 842t Eleutherosides, 919,920f Eliava, George, 1148 Elimination diet indications for, 4981, inflammatory bowel disease treated with, 1820 procedure for, 498499 steps involved in, 497 variations of caveman plan, 498 description of, 497498 dilute juice fast, 498 fruit and/or vegetable plan, 498 water fast, 498 Emaho, 3 Emblica officinalis, 1777 Emotions, 95 Emulsification, 1385 Emulsify, 710 End-feels, 425 Endocrine system, 19 Endometrial cancer, 1879-1880,1888,2150 Endometriomas, 1644 Endometriosis beta-carotene for, 1645 caffeine and, 1645 diagnosis of, 1644 diagnostic summary for, 1643 dietary guidelines for, 1644-1645,1647 dioxin exposure and, 1647 dysmenorrhea and, 1645 essential fatty acids for, 1645-1646 etiologies theories for, 1643-1644 infertility caused by, 1644 pain relief in, 1646-1647 progesterone for, 1647 risk factors for, 1643

Index Endometriosis-cont’d selenium for, 1646 symptoms of, 1644 treatment of, 16441647 Turska’s formula for, 1646-1647 vitamin C for, 1645 vitamin E for, 1645 Endorphins, 97-98,98t, 366,1432 Endothelial cells, 1624 Endotoxemia, 1190,1818 Endotoxins cat& effects on, 824 phage therapy and, 1149 End-range pain, 423 End-stage renal disease aerobic exercise for, 364 exercise benefits for, 364 Enema, 1141 Energy medicine, 19 Energy/matter dualism, 18-19 English Act of 1512,129-130 Enkephalins,97 Entarnoeba histolytica, 656, 1016 Enteric-coated, 710 Enteric-coated peppennint oil description of, 1839 irritable bowel syndrome and, 1072 nonulcer dyspepsia treated with, 1073 toxicity of, 1073-1074 Enteric-coated volatile oils description of, 579-580 irritable bowel syndrome treated with, 1839 Enterococcus, 1155 Enterohepaticcirculation, 167 Enteropathy gluten-sensitive,244 nonsteroidal antiinflammatory drug, 244 Enteroviruses, 1611 Entropy, 81 Environment definition of, 488 genes and, interactions between, 488-489 Environmental Protection Agency, 339 Environmental toxins adrenal gland affected by, 345 air purifiers for, 347 antioxidant efficacy and, 1100 attention deficit hyperactivity disorder and, 1534 avoidance of, 347 botanical medicines for, 349 DDE, 340,467 DDT, 340-341,341t, 467,535,594 depuration of, 349-350 estrogenic effects of, 346 health effects of acute myelogenous leukemia, 343 aplastic anemia, 344 autoimmune disease, 342 axonopathies, 344-345 breast cancer, 343 cancers, 342-344 childhood cancers, 343 depression, 1431 description of, 341 diagnosis of, 346-347

Environmental toxins-cont’d health effects of-cont’d endocrinotoxicities,345-346 hematologic malignancies, 343-344 immunotoxiaty,341-342 myelinopathies, 345 neuronopathies, 344 neurotoxicity, 344-345 non-Hodgkin’s lymphoma, 343 reproduction, 346 treatment for, 347-351 heavy metals. See Metal toxicity hexachlorobenzene,342 nutritional support for damage caused by description of, 347 glutathione, 349 iron, 349 magnesium, 349 overview of, 351 protein, 347-348 pyridoxine, 349 riboflavin, 348 selenium, 349 thiamin, 348 vitamin A, 348 vitamin C, 349 vitamin E, 348 organochlorine compounds, 341-342 organophosphates, 342,594 phthalate compounds, 340 polycyclic aromatic hydrocarbons, 342 prevalence of, in humans, 339-340 sources of, 340-341 thyroid gland affected by, 345-346 types of, 339-340 xenobiotics, 340 Enzymelinked immunosorbent assay, 203-204,206t Enzymes. See also Microbial enzyme therapy antioxidants as, 1088-1090 definition of, 710 pancreatic absorption of, 1133-1136,1135t activity of, 1134-1136,1135t Artemisin absinthiurn effects on, 756 autoimmune/immune complex-mediated diseases treated with, 1139 bacterial disorders treated with, 1139 cancer treated with, 1138-1139 cardiovascular disorders treated with, 1139 during chemotherapy,563 chronic candidiasis treated with, 576 clinical applicationsof, 1136-1139,1137t dosage for, 1139-1140,1140t extraction processes for, 1132-1133 history of, 1131-1132 inflammatory diseases treated with, 1138 injectableform of, 1141 measurement of activity, 1136 protein absorption and, 1133-1134 recycling of, 1076-1077 supplements, 663 supplements from, 1132 topical application of, 1141 toxicology of, 1140-1141 replacement therapy with, 1077

Eosinophilprotein X, 171 Eosinophilia-myalgiasyndrome, 1022, 1032-1033,1436-1437 Ephedra spp. asthma treated with, 926-927,1496 chemical composition of, 925-926 clinical applicationsof, 926-927 common cold treated with, 927 description of, 925 dosage of, 927 drug interactions, 928 E. sinica, 925-928 expectorantsand, 927 history of, 926 pharmacology of, 926 pregnancy contraindications, 927-928 toxicity Of, 927-928 Ephedrine, 926,926f Epicatechin, 1613 Epidermal growth factor receptor, 450 Epididymis, 1866 Epigallocatechingallate, 797 Epigallocatechin-3-gallate,799 Epilepsy betaine for, 1655 celiac disease and, 1653 Chinese herbal medicine for, 1656-1657 choline for, 1655 classificationof, 1650 Coleusforskohlii for, 1656-1657 diagnosis of, 1650-1651 diagnostic summary for, 1649 dietary considerationsfor, 1651-1653,1658 dimethylglycine for, 1655 epidemiology of, 1649 etiology of, 1649-1650,1650b fasting for, 535 folic acid and, 1654 food allergies and, 1652-1653 magnesium levels in, 1654-1655 manganese and, 1655 melatonin for, 1656 nutritional considerationsfor, 1653-1656 pathophysiology of, 1651 sarcosine for, 1655 seizures associated with acupuncture for, 1657 antioxidants for, 1656 classificationof, 1650,1650b description of, 1649 essential fatty acids for, 1656 Ginkgo biloba for, 1657 heavy metal toxicity and, 1651 hypoglycemia and, 1651 ketogenic diet for, 1651-1652 selenium for, 1655 spiritual healing for, 1657-1658 vitamin 86,1653-1654 vitamin E and, 1655 sleep disorders in, 1656 taurine for, 1654 therapeutic approach for, 1658 thiamin deficiency and, 1654 vitamin D for, 1655 zinc and, 1655 Epilobiurn spp. (fireweed),931-933

Index Epinephrine, 617 Epstein-Barr virus, 148,1040,1580-1581, 1802,2091 Erectile dysfunction dehydruepiandmsterone-sulfatefor, 902 Ginkgo biloba for, 983 Erection, 1867 Ergogenic aids, 1123 Ergotamine-rebound headache, 1912 Emac acid, 19Ot, 194 Erythema multiforme, 1663-1664 Erythrocyteb) acute-phase reactant proteins' effect on, 18Ot aggregation of, 179-180 sedimentationdeterminants for, 179 Erythrocyte membrane fatty acid profiling, 189 Erythrocyte sedimentationrate in asymptomaticpatients, 180-181 in cancer, 181-182 coronary artery disease and, 181 decreased, 182 definition of, 179 elevated, 180-182 factors that affect, 181b in inflammatory arthritis, 182 interpretation of, 179-183 in polymyalgia rheumatica, 182 procedures, 179 in proteinemias, 179 in rheumatoid arthritis, 182 in symptomaticpatients, 181 in temporal arteritis, 182 Westerpen method, 179,179t Wmtrobe method, 179,179t Erythroplakia, 282,282t Erythropoietic protoporphyria, 778-779,2050 Erythropoietin, 816 Escherichia coli ABO polymorphismsand, 4 5 2 diarrhea caused by, 1802 foodborne illness caused by, 471 phage therapy research using, 1151, 1155-1157 Shiga toxin-producing, 173 E-selectins, 447,492 Esophageal cancer, 999 Esotericia, 84 Essential fatty acids in attention deficit hyperactivity disorder, 1535-1536 benign prostatic hyperplasia treated with, 1551 chronic fatigue syndrome treated with, 1587 cytokine production by, 1646 description of, 935 encapsulated, 961t endometriosistreated with, 1645-1646 human immunodeficiency virus treated with, 1737 lipid oxidation products in, 960-961 menorrhagia treated with, 1904 metabolism of alcoholism effects on, 1454 in atopic dermatitis, 1527-1528

Essential fatty acids-cont'd migraine headaches and, 1915 premenstrual syndrome treated with, 2060 seizures treated with, 1656 Essential oils definition of, 710 in Echinaceu spp., 909 trichomoniasistreated with, 2130 Estrogen Alzheimer's disease and, 1463 asthma and, 1488-1489 atherosclerosis and, 1881 bone loss secondary to defiaency of, 1979 conjugated equine, 1885-1886 environmental, 1869,2055 fat intake and, 2056-2057 fibrocystic breast disease and, 1668 Glycyrrhiza glabra and, 1004 male infertility and, 1869-1870 osteoarthritis and, 1964 Parkinson's disease treatment and, 2009 in postmenopausal women, 1881 uterine fibroids and, 2153 vegetarian diet effects on, 2056 vitamin B6 impairment caused by, 2055 Estrogen replacement therapy, 1981. See also Hormone replacement therapy Etanercept, 2095 Ethers glycerol, 715 lipid, 714715 Ethics, 105106 Ethylmalonate, 289t, 292-293 Etretinate, 955,1381 European mistletoe. See Viscum album Eustachian tube, 1993 Euthyroidism, 1676 Evening primrose oil fibrocystic breast disease treated with, 1666 multiple sclerosis treated with, 1932 Exercise. See also Athletes; Sports nutrition acute muscle injury caused by, 371 aerobic blood pressure affected by, 493 coronary artery disease affected by, 361 description of, 357-358 diabetes mellitus treated with, 1625 end-stage renal disease treated with, 364 pain management by, 364365 weight loss benefits of, 363 air pollution considerations,369 alcoholism and, 1454 altitude effects, 369 antidepressant effects of, 1432 arthritis, 365 athlete's heart, 370 benign prostatic hyperplasia and, 1550 cancer, 362 carbohydrate ingestion during, 694 cardiorespiratory, 359-360 camitine benefits for, 814815 cellulite treated with, 1569 by children, 367 chronic fatigue syndrome treated with, 1588 chronic fatigue/fibromyalgia, 366 chronic obstructive pulmonary disease, 364

Exercise-cont'd chronic pain, 364-365 in cold weather, 369 contraindications,370 coronary artery disease, 361-362 depression, 1432-1433 diabetes mellitus, 363-364,1625 by elderly, 368 Eleutherococcus senticosus benefits for, 689 endorphins released by, 366 end-stage renal disease, 364 environmental considerations, 368-369 during fasting, 541-542 fibromyalgia and, 16741675,1682 free fatty acid metabolism during, 356 glutamine and, 684,998-999 glutathione depletion secondary to, 681 guidelines for, 358-361 heat-caused illness,368 in hot weather, 368 hypertension, 362 hypoglycemia treated with, 1788 hypothyroidism treated with, 1795-1796 immune function affected by, 368,1588 insomnia treated with, 1831 intensity of, 356 intraocular pressure reductions by, 1700 isometric, 356 isotonic, 356 low back pain, 365 menopause treated with, 1895-1896 mental health benefits of, 366 multiple sclerosis and, 1934-1935 muscular conditioning, 360 neuromuscular disease, 365-366 obesity, 362-363 osteoarthritis treated with, 1964-1965, 1970,1972 osteoporosisprevention and, 1981 overview of, 355-356 peripheral vascular disease, 365 physical fitness body composition, 358 body mass index, 358,358t cardiovascularendurance, 357-358 flexibility, 358 muscular endurance, 358 muscular strength,358 physiology of, 356 by postmenopausal women, 367-368 during pregnancy, 366-367 premenstrual syndrome and, 2058 pulmonary disease, 364 scrota1temperature increases secondary to, 1868 side effects of amenorrhea, 371 asthma, 370 heat stroke, 372 hematuria, 370 incontinence, 371 menstrual dysfunction, 371 osteoporosis,371 sports anemia, 370 sudden death, 372 urticaria, 370

Index Exercise-cont’d sleep promotion from, 1831 steroid use and, 372 stress reduction benefits of, 705 sweat rate during, 693 water consumption during, 368 water intake during, 693 Exercise-induced asthma, 370,1407 Exercise-induced hemolysis, 370 Expectorants, 2040 Experimentation, 124 Explanatory style, 111 Exponential Therapeutics, 1156-1157 External hemorrhoids, 2073 Extracts definition of, 333,710 drying of, 335 fluid, 710 Ginkgo biloba, 975,976f native, 711 powdered, 711 solid, 711 standardized, 333-334,337 strength of, 711

F FABER test, 424 Factor VIII, 446 Faith. See Religious faith Familial combined hyperlipidemia, 1505 Familial hypercholesterolemia, 1505 Familial hypertriglyceridemia, 1505 Family practice, 86 Fantus test, 185-186 Fasting acidosis secondary to, 540 amino acid metabolism during, 540 arthritis treated by, 535-536 attitude of patient during, 542 autoimmune diseases treated by, 535 basal metabolic rate during, 536 by children, 543 contraindications, 542-543 DDT contamination treated by, 535 deaths caused by, 543 definition of, 533 detoxification affected by, 599 diabetes mellitus treated by, 535 dietary fast with food challenge, 206t, 206-207 dilute juice fast, 498 electrolyte balance during, 540 energy production and utilization during, 537-538,538t epilepsy treated by, 535 exercise during, 541-542 food allergies determined by, 206t, 206-207,536 glucose release secondary to, 538,539f heart disease treated by, 535 history of, 534 hormonal changes during, 540-541 hypertension treated by, 536 immune function effects of, 541 ketosis mechanisms, 539-540 laboratory changes during, 540

Fasting+ont‘d length of, 542 metabolic events during, 538t nutritionally controlled, 603-604 obesity treated by, 535 pancreatitis treated by, 535 PCB contamination treated by, 535,603 physical changes during, 540 physiologic effects of during early fasting, 538-539 glucose production, 538,539f overview of, 536-537 research regarding, 534-535 triglyceride production, 539 during pregnancy, 543 protocol for, 541-542 m a r c h regarding, 534-536 rheumatoid arthritis treated by, 2096 side effects of, 542 starvation vs., 533 sugar levels reduced by, 648 toxic exposure treated by, 603-604 triglyceride use during, 539 urinalysis during, 540 vitamin supplement use during, 541 water fast diet, 498,541 Wemicke encephalopathyduring, 542 Fasting hypoglycemia, 1781-1782 Fat(s) body measurements of biwlectrical impedance, 1949 body density measurements, 1949 description of, 358 skinfold thickness measurements, 1949 menstruation and, 371 visual observation, 1948-1949 dietary description of, 468-469 estrogen metabolism and, 2056-2057 male infertility and, 1871 natural killer cells affected by, 957 premenstrual syndrome treated by reduction of, 2056-2057 saturated, 468 type II diabetes mellitus and, 1616 Fat-soluble vitamins. See also spec@ vitamin assessment of, 253 side effects of, 139Ot suggested optimum nutrient intake for, 1280-1284 toxicity of, 139Ot Fatty acid(s).See also Lipoproteins; Triglycerides abnormalitiesof, 942t acetyl CoA conversion of, 539 assimilation of, 940-941 brain function affected by, 943 cancer and, 943 catabolism of, 537 definition of, 935 developmentaldisorders and, 942 dietary sources of, 94Ot digestion of, 940-941 diseases and, 941-943 distribution of, 941

Fatty acid(sbont’d fish oil content of, 947t heart disease and, 942 longchain, 690 low-fat diet effects on, 941 media awareness of, 935 metabolic roles of, 935,936f neurologic disorders and, 943 omega-3. See Omega-3 fatty acids omega-6. See Omega-6 fatty acids oxidation of, 941 polyunsaturated, 939t, 939-940 rheumatoid arthritis treated with, 2098 saturated arachidic acid, 191t, 195 behenic acid, 191t, 195 capric acid, 190t, 194 description of, 936 hexacosanoic acid, 191t, 195 lignoceric acid, 191t, 195 palmitic acid, 19Ot, 194,938 profiling Of, 190t-l91t, 194195 stearic acid, 191t, 194195 shortchain Colonic foods and, 1191t, 1191-1192 description of, 167,667,670,1824 fructooligosaccahrides and enhanced mineral absorption using, 1186 reduction using, 1185 lactulose effect on, 1189-1191 probiotic effects on, 1201-1202 structure of, 935-940 synthesis of, 938,941 terminology associated with, 936t-937t trans, 191t, 195,938-939 Fatty acid profiling alpha-linolenic acid, 190t, 191 arachidic acid, 191t, 195 arachidonic acid, 190t, 193 arachidonic acid/eicosapentaenoicacid ratio, 191t, 196 behenic acid, 191t, 195 concentration vs. percentage, 190 description of, 189 dihomogammalinolenic acid, 19Ot, 193 dihomogammalinolenic acid/ eicosapentaenoic acid ratio, 191t, 196 docosadienoic acid, 190t, 193 docosahexaenoic acid, 190t, 192 docosapentaenoic acid, 19Ot, 192 docosatetraenoic acid, 19Ot, 193 eicosapentaenoic acid, 19Ot, 191-192 elaidic acid, 191t, 195 erucic acid, 19Ot, 194 erythrocyte membrane, 189 gamma-lholenic acid, 19Ot, 193 heneicosanoic acid, 191t, 195 heptadecanoic acid, 191t, 195 hexacosanoic acid, 191t, 195 lignoceric acid, 191t, 195 lholeic acid/dihomogammalinolenicacid ratio, 191t, 196 mead acid, 19Ot, 193 methodologic issues for, 189-190 monounsaturated fatty acids, 19Ot, 193-194

Index Fatty acid profiling-cont'd myristoleic acid, 19Ot, 194 nervonic acid, 19Ot, 194 nonadecanoic acid, 191t, 195 odd-numbered fatty acids, 191t, 195 oleic acid, 19Ot, 194 omega-3 fatty acids, 19Ot, 191-192 omega4 fatty acids, 19Ot, 192-193 palmitelaidic acid, 191t, 195 palmitoleic acid, 19Ot, 194 pentadecanoic acid, 191t, 195 plasma, 189 polyunsaturated-to-saturatedfatty acid ratio, 191t, 196 ratios, 195-196 red cell stearic/oleic index, 191t, 196 results Of, 190-196 saturated fatty acids, 190t-l91t, 194195 total fatty acid calculation, 196 trans fatty acids, 191t, 195 tricosanoicacid, 191t, 195 triene/tetraene ratio, 191t, 196 vaccenic acid, 19Ot, 193-194 Fatty liver, 1451-1452 Fecal occult blood testing, 174 Feline leukemia, 740 Feminist movement, 132-133 Fenofibrate description of, 614 homocysteine levels affected by, 623-624 Fenugreek, 1632 Fermented foods, 1199-1200,1209 Ferritin, 277,277t, 1095-1096,1712,1833,1902 Ferrdelatase, 2046 Ferulic acid, 1892 Ferulic acid esters, 1222 Feulgen, Robert,713 Fever body temperature elevation during, 403 cold sponging for reduction of, 405 Feverfew, 1331-1333. See also Tanaceturn partheniurn Fiber. See Dietary fiber Fibrates, 1176 Fibrin, 792,793f Fibrinogen, 1516 Fibrinolysis bromelain activation of, 792 fish oils' effect on, 792 therapies to promote, 1516 Zingiber oficinule effects on, 1413 Fibrocystic breast disease colon function and, 1667-1668 description of, 674,1665-1666 diagnostic summary for, 1665 dietary guidelines for, 1668 differential diagnosis, 1666 evening primrose oil for, 1666 iodine for, 1667 methylxanthines and, 1666 premenstrual syndrome and, 1665 soy and, 1666 treatment of, 1666-1668 vitamin A for, 1667 vitamin E for, 1667 Fibroids. See Uterine fibroids

Fish oils-cont'd Fibromyalgia nephrotic syndrome treated with, 953-954 adrenocortical hypofunction and, 1680 oxidative reactions, 960 chronic fatigue syndrome and, 1582 pharmacology of, 948-949 diagnosis of, 1582b, 1671-1672 during pregnancy, 953 diagnostic summary for, 1671 psoriasis treated with, 955-956 diet and, 1674,1681 rancidity of, 960 exercise for, 16741675.1682 Raynaud's disease treated with, 958 5-hydroxytryptophan for, 1030-1031,1031t rheumatoid arthritis treated with, 954-955 hypometabolism hypothesis of, 1672-1674 sodium excretion facilitated by, 951 hypothyroidism and, 1672-1673 stroke prevention and, 952 metabolism-regulating therapies for, studies of, 945-946 16741675,1680 sudden death and, 951 norepinephrine and, 1673 summary of, 961-962 nutritional therapies for, 1674,1681-1682 thrombosis prevention using, 949-950 pain distribution assessments, 1677-1678 thromboxane A2 production decreased patient status assessments, 1677,1681 by, 948 rehabilitationmodel for, 1676-1677 toxicity of, 959 Sadenosylmethionine for, 1237-1238 toxin contamination considerations,959 serotonin deficiencyhypothesis of, 1672 triglyceride reductions using, 950 SymptOmS Of, 1672b, 1673-1674 tumor necrosis factor-a production therapeutic approach for, 1681-1682 reduced by, 949 thyroid hormones and, 1672-1676,1681 vitamin E deficiency caused by, 959 FibroQuest symptoms survey, 1679-1680 Fishbein, Morris, 58-59 "Fight or flight'' response, 97,701-702 Fitz-Hugh-Curtis syndrome, 2017,2019 FIGLU,289t Five basic elements Fireweed. See Epilobiurn spp. in acupuncture, 312 Fish oils in Ayurveda, 319 angina pectoris treated with, 951-952 Flavonoids autoimmune diseases treated with, 954 antioxidant effects of, 968-969,1096-1099, bleeding time affected by, 959 1101-1102 for bypass patients, 952 antiviral activity of, 823 cancer treated with, 956-958 in Arternisia annua, 761 cardiovasculardisease and, 949-950 asthma treated with, 1492 during chemotherapy, 562 atherosclerosis and, 1360 cholesterol reductions using,950 cataracts treated with, 2120 circulatory benefits of, 948 citrus clinical applications of, 949-950 bone metabolism effects of, 970 content of, 946 cardiovascular effects of, 970 C-reactive protein levels affected by, 952 clinical uses of, 970 cyclophosphamideand, 564 commercialpreparations of, 971 description of, 946-948 description of, 968 diabetes mellitus treated with, 958,1629 diabetes meatus treated with, 971 diseases treated with, 562 thalassemiastreated with, 971 docosahexanoic acid. See Docosahexanoic classificationof, 1259-1260 acid cyclic adenosine monophosphate dosage of, 961 phosphodiesterase inhibition drug interactions, 961 by, 1528 eicosanoid-modifyingeffects of, 961 definition of, 710,1259 eicosapentaenoic acid. See Eicosapentaenoic description of, 466t, 567,967 acid diabetes mellitus treated with, 1632-1633, encapsulated forms of, 947-948 1633t fatty acid content in, 947t diabetic retinopathy treated with, 1634 fibrinolysis affected by, 792 dietary sources of, 968 gallstones treated with, 1692 in Echinacea spp., 909 glaucoma treated with, 1699 fireweed, 932 hypertension treated with, 951 of Ginkgo biloba extract, 975,976f immune function affected by, 953 hemorrhoids treated with, 2071 inflammatory response treated with, 589 histamine affected by, 2028 lipid levels reduced using, 950 history Of, 967-968 low-density lipoprotein cholesterol reduced inflammatory bowel disease treated with, using, 950 1823 malaria treated with, 958-959 macular degeneration treated with, migraine headaches treated with, 958 1861-1862 multiple sclerosis treated with, 1931-1932, periodontal disease treated with, 2035 1935 pharmacology of, 968-969 myocardial infarction survival and, 951-953

Index ~

Flavonoids-cont'd proanthocyanidins, 967 proteolytic enzymes and, 971-972 sinusitis treated with, 1546 toxicity of, 972 vaginitis and, 2160 varicose veins treated with, 2169 Flax seeds, 1892 Flaxseed oil, 562,1816,2099 Flexner, Abraham, 136 Flexner, Simon, 136 Flexner Report, 48,332 Flora. See Microflora Flow cytometry bacterial phagocyte measurements using, 229 cell cycle assessments, 162 definition of, 162 lymphocyte enumeration using, 22324,227 sample preparation for, 224 Fluid extracts, 710 Fluorescent-tagged deoxyuridine triphosphate nucleotides, 145 Fluoride, 1987 5-Fluorouracil, 564 Fluvoxamine, 1025t, 1025-1026 Foam cells, 194 Folate assessments of, 199-200,251 coenzymes, 199 description of, 199 health requirements for, 1287 homocysteine levels and, 619 recommended intake of, 1287t synthesis of, 611 Folic acid antidepressanteffects of, 1236 cyclophosphamide and, 564 depression treated with, 1442 description of, 1275 epilepsy and, 1654 gout treated with, 1707 homocysteine levels affected by, 624,1517, 1765,1987 immune function affected by, 649 inflammatory bowel disease and, 1822 macrocyhc anemia treated with, 1742 periodontal disease treated with, 2035-2036 recommended intake of, 1287t seborrheic dermatitis treated with, 2114 side effects of, 139Ot status assessments for, 199-200 stroke prevention and, 620 suggested optimum nutrient intake for, 1287,1287t toxicity of, 139Ot, 1392 Folic acid deficiency aging and, 1287 causes of, 611-612 cervical dysplasia and, 15741576 depression secondary to, 1433-1435 description of, 199-200 high-risk groups for, 1287 in human immunodeficiency virus,1739b infectious diarrhea and, 1805,1810 neural tube defects and, 620,1287,1805 oral manifestations of, 282t

Folinic acid, 612 Follicle-associated epithelium cells, 1134 Follicle-stimulating hormone Sertoli cells and, 1870 sperm production and, 1866 Follicular hyperkeratosis,1383 Food additives, 470 Food allergies anxiety and, 706 aphthous stomatitis and, 1481 asthma and, 1489 atopic dermatitis and, 1526-1527 attention deficit hyperactivitydisorder and, 1536-1537 autoimmune diseases and, 1794 breastfeeding for, 1527 causes of, 584 in children, 584 chronic candidiasis and, 576 chronic fatigue syndrome and, 1585 comprehensive digestive stool analysis for, 587 depression secondary to, 1436 dermatitis herpetiformis and, 1606 description of, 497,583 development of, 584 epilepsy and, 1652-1653 fecal secretory immunoglobulin A tests for, 587 gallstones and, 1690 history Of, 583-584 hypothalamic-pituitary-adrenalaxis and, 587-588 immune system's role in, 585-586 immunoglobulin E and, 586 immunoglobulin G and, 586 incidence of, 584 intestinal permeability and, 243-244,587 irritable bowel syndrome and, 1838-1839 lactose intolerance vs., 256-257 microbial enzyme therapy for, 1081 migraine headaches and, 1913-1914,1919 multiple sclerosis and, 1934-1935 otitis media and, 1993-1994,1994t peptic ulcers and, 2027 rheumatoid arthritis and, 2096 rosacea caused by, 2110 signs and symptoms of, 584t, 584-585 sinusitis and, 1546 testing for challenge testing, 205-207 description of, 604,2143 dietary fast with food challenge, 206t, 206-207 eledroacupuncturr for, 205,206t enzyme-linked immunwrbent assay, 203-204,206t experientalchallenge methods, 205-207 fasting, 206t, 206-207,536 fOllOW-Up, 587 kinesiologic method of, 205,206t laboratory methods, 203-205 oligoantigenic diet, 205-206,206t, 588 provocation-neutralizationtesting, 204-205,206t purpose of, 203

Food allergies-cont'd testing for-cont'd radioallergosorbent procedure, 204,206t radioallergosorbenttest, 204,206t, 586-587 serial-dilution titration test, 205 treatment of components of, 584 diversified rotation diet, 588 gut healing, 589 intestinal microflora, 588-589 oligoantigenic diet, 588 probiotics, 588-589 urticaria caused by, 2137-2138 Food colorants, 2138-2140 Food consumption, 463,464t, 666,667t Food hypersensitivity, 584 Food intolerance, 535 Food preservatives,2141 Food reactions adverse, 583 classification of, 583 food allergies. See Food allergies Foodbome illness, 470471 Foot ulcers, 1622,1635-1636,1638 Forceps, 128 Foreign body vaginitis, 2156 Formiminoglutamate, 292 Formononetin, 847,848f Forskolin asthma treated with, 873 cardiac failure treated with, 873 depression treated with, 874 dosage of, 874 drug interactions,874 glaucoma treated with, 874 hypertension treated with, 873 hypothyroidism treated with, 874 malabsorption treated with, 874 platelet-activating factor inhibited by, 872 structure of, 872f toxicity of, 874 Fractionated citrus pectin, 555 Fractures hip, 1977 signs of, 422 Free fatty acids, 356,1915 Free radicals description of, 149 in multiple sclerosis, 1927 as naturally occurring antioxidants, 10851087 procyanolidic oligomers, scavenging activity of, 1218,1218t Silybum marianum effects on, 1251-1252 sleep effects on, 1831 sperm affected by, 1870 type Il diabetes mellitus and, 1616 "French paradox," 1097,1508,1514 Friedenreich-Friedenreichantigen, 449450 Friedrich ataxia, 860 Fructooligosaccharides atopy development prevented using, 1187 bifidobacteria, enhanced growth of, 1185-1186,1186f clinical applications of, 1185-1187

index Fructooligosaccharides-cont’d commercial forms of, 1184 description of, 589 dosage, 1187 eczema treated with, 1187 food sources of, 1184t, 1184-1185 lipid-lowering effects of, 1186 mineral absorption enhanced by, 1186 phytoestrogen bioavailability improved with, 1186-1187 as prebiotics, 1183-1884 supplements from, 1184 toxicity of, 1187-1188 FlUctOSe characteristicsof, 1786 intolerance to, 260 Fruits, 465-466 Fu Ke Ba Zhen Wan, 843t-844t Fucus vesiculosus, 456t Full-immersionbaths, 411 Fumarate, 289t Fumaric acid, 2083 Functional medicine assessment and, 21-25 biochemical mechanisms, 23 body systems, 19-21 cause/effect dualism in, 18 c l i c a l application of, 21-25 concepts in, 21 definition of, 490 depth of action and, 23 early detection and, 24 energy/matter dualism in, 18-19 genomics, 17-18 health as viewed by, 21 inside/outside dualism in, 16-17 laboratory diagnosis and, 2425 microbeassociated illness assessed by, 23 outcomes, 23-24 part/whole dualism in, 15-16 patient-centered focus of, 24 pattern recognition, 25 philosophy of, 13-21 prevention and, 24 theoretical aspects of, 14-21 total load, 23 treatment perspectives of, 21-25 word origin of, 14 Fungal lipase, 1077-1078 Fungal nail infections, 1055-1056 Fungal protease, 1079-1080 Fusion inhibitors, 1737 FUTl, 445 F U R . 445

G GABA receptors, 1170 Gaenslen‘s test, 428 Gait, 428 Galanthus nimlis, 1468-1469 Galen, 91,330-331,389 Gallstones buckwheat for, 1690-1691 caloric restriction and, 1691 chemical dissolution of, 1692-1693 chenodeoxycholicacid for, 1692

Gallstones-ont’d cholesterol and, 1687-1688 classificationof, 1687 coffee consumption and, 1691 description of, 671,1687 dietary considerations for, 1689-1691,1693 dissolving formula for, 1693-1694 fish oils for, 1692 food allergies and, 1690 gender and, 1688-1689 hormone replacement therapy and, 1882 incidence of, 1687 lecithin and, 1691 lifestyle factors, 1693 lipotropic formulas for, 1692 obesity and, 1689 olive oil for, 1691-1692 pathogenesis of, 1687-1689 pigmented, 1689 prevalence of, 1689 risk factors for, 1688-1689 Silybum marianum for, 1254 stress and, 1693 sunbathing and, 1693 tamoxifen and, 1689 terpenes for, 1692-1693 treatment of, 1689-1694 Gamma-interferon, 382 Gamma-linolenicacid in Aloe Vera, 738 clinical uses of, 943t description of, 19Ot, 191,193 -diabetic neuropathy prevention using, 1634-1635 dosage of, 2098 premenstrual syndrome and, 2060 rheumatoid arthritisand, 2098 Gamma-oryzanol, 1892 Gapping test, 428 Garcinia cambogia, 1958 Garlic. See Alliurn satiourn Gastric acid calcium absorption affected by, 1982 corrosive properties of, 2025 secretion of, Aloe Vera effects on, 739-740 Gastric acidity ABO blood groups and, 446 epidermal growth factor receptor and, 450 low, 662b in postmenopausal women, 1982 Gastric emptying, 693 Gastric lipase, 167 Gastric ulcers Aloe Vera for, 743 characteristics of, 2025-2029 coenzyme Qlofor, 862 deglycyrrhizinated licorice and, 1006 Gastrin ABO polymorphisms and, 446 description of, 217 Gastroesophagealreflux disease, 166167, 1073 Gastrointestinal tract antibiotic therapy in, probiotic stabilization and recolonization after, 1201-1202 Curcuma longa effects on, 895-896

Gastrointestinaltract-cont’d description of, 655 eosinophil protein X in, 171 esophagus, 166-167 functions of, 165-166 glutamine effects on, 995996,1000 hyperventilation syndrome/breathing pattern disorders findings, 635 immune system of, 242,655 large intestine, 167-168 Lobelia inflata effects on, 1050 Melissa oficinalis effects on, 1067 mouth, 166 probiotic activity in, ll96,1196t, 1201,1207 problems associated with, 165 rehabilitation of, 604 small intestine, 167 stomach, 167 Gate control theory of pain, 432 Gemfibrozil, 189-190 Gene@.) environment and, interactionsbetween, 488489 susceptibility,489 Gene regulatory networks, 17 General adaptation syndrome, 701-702 General tonic, 707 Genetic code, 1404 Genistein absorption of, 1260-1261 antiangiogenic properties of, 1266 atheroscleroticprocess affected by, 1269 breast cancer and, 1267,1271 description of, 567,1259-1260,1891 excretion of, 1261 in soy products, 1261 structure of, 1260f thrombin formation inhibited by, 1269 Genistin, 1261 Genomic testing clinical challenges for, 494 lactose intolerance diagnosed by, 260 nutritional, 494 preventive, 494 Genomics clinical utility of, 489 description of, 17-18 preventive, 489 Gestalt, 487 Gestational diabetes, 1608-1609,1628 Ghrelin, 1951-1952 Giardia larnblia berberine and, 1016 Candida albicans and, 655 diarrhea caused by, 1803 immunologic hypersensitivity to, 655 systemic illness caused by, 655 Gilbert‘s syndrome, 1238 Gingerol, 1411,1412f Gingival sulcus, 2032 Gingivitis, 281,282t, 2031 Ginkgo biloba (@go tree) absorption of, 977,979 allergies treated with, 984 Alzheimer’s disease treated with, 981, 1467-1468

Index Ginkgo biloba-cont’d antidepressanteffects of, 983-984 antioxidant activity of, 1098 asthma treated with, 984,1494 cerebral vascular insuHiciency treated with, 979-981,98Ot chemical composition of, 975976,976f clinical applications of, 979-984 cochlear deafness treated with, 982 cognitive performance and, 1122 depression treated with, 1441-1442 description of, 975 diabetic retinopathy treated with, 982 distribution of, 977,979 dosage of, 984 extract, 975 flavonoids of, 975,976f folk uses of, 976 high altitude sickness and, 984 history of, 976 Ihydroxytryptophan and, 1025 intermittent claudication treated with, 982-983 levodopa toxicity reduced using, 2008 macular degeneration treated with, 1862 menopause treated with, 18941896 mental performance enhanced using, 979,981 multiple sclerosistreated with, 1933-1934 nerve cell effects of, 976-977 ototoxicity treated with, 982 Parkinson’s disease treated with, 2008,2011 peripheral arterial insufficiency treated with, 982-983 pharmacology of, 976-979 platelet effects of, 977,1528 premenstrual syndrome treated with, 983, 2062-2063 Raynaud’s disease treated with, 984 seizures treated with, 1657 senile macular degeneration treated with, 982 sexual dysfunction treated with, 983 stroke prophylaxis using, 1520 tinnitus treated with, 981-982 tissue effects of, 976 toxicity of, 985 vascular effects of, 977,978t Ginkgolides,977,984-985,1528 Ginseng Chinese, 707 description of, 330 export of, 839 Korean. See Panax ginseng Siberian, 707, 919-923. See also Eleutherococcus senticosus Ginsenosides,688,1873-1874 Giving-up/given-up complex, 100 G-Jo, 513 Gland definition of, 377 endocrine, 377 Glandular preparations adrenal extracts, 379,379t aortic glycosaminoglycans, 379t, 379-380 clinical applications of, 379t, 379-384

Glandular preparatio-ont’d description of, 377 freeze-drying of, 378 liver extracts, 379t, 380 manufacture of, 377-378 pancreatic extracts, 379t, 380 polyerga, 381-382 predigestion of, 378 protein absorption, 378-379 sources of, 377-378 spleen extracts, 379t, 380-381 spongiform encephalopathyconsiderations, 378 thymus extracts, 383-384 thyroid extracts, 384 Glaucoma acute, 1697 bioflavonoids for, 1699 caffeine and, 1699 chromium for, 1699 chronic, 1697 citicoline for, 856-857 Coleusforskohlii for, 874 definition of, 1697 diagnosis of, 1697 differential diagnosis, 1697t exercise for, 1699 fish oils for, 1699 Helicobacter pylon’ and, 1700 magnesium for, 1699 treatment of, 1698-1700 Vaccinium myrtillus for, 1367-1368 Gliadin, 1080-1081,1563 Glossitis, 281,282t Glucagon-like peptide-1,1952 Glucarate, 289t, 294 Glucomannan, 1629-1630 Gluconeogenesis,539 Glucosamine description of, 987 forms Of, 987-988 structure of, 988f Glucosaminehydrochloride, 988,1966 Glucosaminesulfate clinical applicationsof, 988-991 description of, 987 dosage of, 991 glucosamine hydrogen chloride vs., 988 homocysteine effects on, 616 ibuprofen vs., 990, 1965 N-acetylglucosaminevs., 987-988 nonsteroidala n t i i d h u mtory drugs vs., 988 osteoartluitis treated with, 988-991, 1965-1966 toxicity of, 991 Glucose blood alcohol consumption effects on, 1788 Allium cepa effects on, 1632 Allium sativum effects on, 1632 chromium effects on, 1787,1957 control of, in diabetes mellitus, 1623 fiber effects on, 1787 glucosamine sulfate effects on, 1966 glycosylated hemoglobin and, 1620 insomnia and, 1831

Glucose-cont’d blood-cont‘d Morus indica effects on, 1630 postprandial, 1629 self-monitoring of, 1618 stress effects on, 1625 brain consumption of, 1293 fasting-related production of, 538,539f glycosylated hemoglobin evaluations, 1609-1610 immune system effects of, 648 postprandial levels of, 1609 serum levels of, 1609 urine, 1617 Glucose challenge test, 24 Glucose tolerance, 1609 Glucose tolerance factor, 277,1293 Glucose tolerance test, 16@,161Ot, 1782-1783 Glucose-insulin tolerance test, 1783 Glucosinolates,466t Glutamic acid, 1847 Glutamine acid base balance and, 994 alcoholism treated with, 1454,1456 clinical applicationsof, 995-999 diarrhea treated with, 1741 dosage of, 999-1000 drug interactions, 1000 exercise effects on, 684 food sources of, 993 formation of, 993 glutathione repletion and, 994 growth hormone release and, 684 immune support from, 995 infectious diarrhea treated with, 1806,1810 insulin and, 684 intestinal mucosa protected using, 589 intestinal repair and protection, 993-994 methotrexate affected by, 565 overtraining and, 687 physiologic effects of, 993-995 protein sparing and, 994-995 radioprotection benefits of, 567 skeletal muscle affected by, 684 sports nutrition uses of, 684-685 toxicity of, 1000 Glutathione as antioxidant, 1093-1094 ascorbic acid interactions with, 2118-2119 cataract prevention and, 2118-2119 citicoline effects on, 857 description of, 349,564,1252 exercise effects on, 681 glutamine and repletion of, 994 mercury effects on, 595 Parkinson’s disease caused by deficiency Of, 2001-2002,2005 whey protein effects on synthesis of, 681 Glutathioneperoxidase, 1089-1090,1423, 1932,2082 Glutathionereductase, 1093-1094,1289 GlutathioneStransferase M1,1485 Glutathione-Stransferase artemisinin effects on, 762 description of, 489,598 multiple sclerosis and, 1927

Index Gluten dermatitis herpetiformisand, 16051606 description of, 1563 Gluten sensitivity aphthous stomatitis and, 1482 type I diabetes mellitus and, 1611 Gluten-sensitive enteropathy,244,1563. See also Celiac disease Glycans, 443-444 Glycemic index, 464-465,467,1615-1616, 17f36-1787

Glycemic load, 467,16151616,17861787 Glycerol ethers, 715 Glycosaminoglycans, 379t, 379-380,987,1475, 1501-1502,196,1967 Glycosides, 710 Glycosylated hemoglobin, 1609-1610, 1620 Glycosylation, 1623 Glycosyltransferases, 441

Clycyrrhiza glabra (licorice) antiinflammatory and antiallergic activity of, 10051006 antiviral effects of, 1005 asthma treated with, 1493 atopic dermatitis treated with, 1529-1530 Bupleurum falcatum and, 2103 chemical composition, 1003,1004f chronic fatigue syndrome treated with, 1588-1589

clinical applications of, 10051008 deglycyrrhizinatedlicorice, 1006 dosage of, 1008-1009 drug interactionswith, 1009 estrogenic activity of, 1004 folk use of, 1004 hepatitis treated with, 171E-1720 herpes simplex virus treated with, 1725 history of, 1004 human immunodeficiency virus treated with, 174% mechanism of action, 2061-2062 oral licorice preparations, 1007-1008 peptic ulcers treated with, 2028 pharmacology of, 1004-1005 premenstrual syndrome treated with, 2061-2063

pseudoaldosteroneactivity of, 1004 psoriasis treated with, 2084 side effects of, 1009 topical applications of, 1008 toxicology of, 1009 vaginitis treated with, 2161,2163 Glycyrrhizin, 1719,1857 Glycyrrhizinic acid, 2028 GlyObesity, 1008 Goiter incidence of, 1792 toxic nodular, 1773 Goitrogens, 1774,1792,1794 Gold therapy, 2094 Goldenseal. See Hydrastis canndensis Goldthread. See Coptis chinensis Gonococcal vaginitis, 2159 Gotu kola. See CenteZla asiatica

Gout alcohol and, 1706 bromelain for, 1707 causes of, 1703-1704 cherries for, 1707-1708 chronic, 1705-1706 colchicine for, 1706 definition of, 1703 diagnostic summary for, 1703 dietary considerations,1706,1708 eicosapentaenoic acid for, 1707 folic acid for, 1707 Harpagophytum procumbens for, 1708 homocysteine levels in, 623 lead toxicity and, 1706 low-purine diet for, 1706 primary, 1703 protein intake and, 1707 quercetin for, 1707 secondary, 1703 signs and symptoms of, 1704-1706 treatment of, 1706-1708 uric acid and, 1704 weight reduction for, 1706-1707 Gouty arthritis, 1705t Graham, Sylvester, 133 Grahamites, 133 Grain proteins, 1563,1564f Gram-negativebacteria, 1189-1190 Grape seed atherosclerosis and, 15151516 macular degeneration treated with, 1862 Graves' disease allopathic treatment of, 1777 antioxidants for, 1774 clinical presentation of, 1772-1773 diagnosis of, 1772-1773 differentialdiagnosis, 1773 Emblica officinalis for, 1777 genetics of, 1772 Melissa officinalis for, 1776 smoking and, 1772 stress and, 1771-1772 vitamin A for, 1774 Greece, 127-128 Green allopathy,37 Green tea. See also Camellia sinensis black tea vs., 797 breast cancer prevention and, 798-799 cancer prevention and, 798-799 catechins in, 560-562 during chemotherapy,560-562 clinical applications of, 798-800 pharmacology of, 798 Gregory, R. J., 1169 Grifonia simplicifolia, 456t, 1032 Griseofulvin, 1856 Growth hormone, 1831,1964 Guar gum, 668,673t, 1838,19561957 Guggulsterone, 878f Guguhpid, 877-879 GW g ~ g g u l877-879,878f ~, Gut mucosal integrity conditions or diseases that disrupt alcoholism, 244 ankylosing spondylitis, 244

Gut mucosal integrity+ont'd conditions or diseases that disrupt-cont'd bacteria, 242 celiac disease, 243 chemotherapy, 245 diabetes mellitus, 244 dysbiosis, 245,1537-1538 food allergies, 243-244 inflammatory bowel disease, 242-243 inflammatory joint diseases, 244 intestinal infection, 245 malnutrition, 245 nonsteroidal antiinflammatory drugs, 244-245

nutritional depletion, 245 trauma, 245 treatment considerations,246-247 description of, 241-242 measurements of, 245-246 Gut-associated lymphoid tissue, 241-242 Gymnema sylvestre, 1631

H H substance, 441-442 Hachimijiogan, 2120-2121 Hageman factor, 792 Hahnemann, Samuel, 44,387-390,396 Hair analysis calcium, 210,276 chromium, 210 conditions and diseases tested for using, 209 copper, 210,277 drug abuse applications of, 211 experimentalnature of, 212 factors that affect, 212 iron, 211 lithium, 211 magnesium, 210 manganese, 210 minerals, 209-211 potassium, 211 ratios, 211-212 research uses of, 209 selenium, 211 sodium, 211 toxic metal exposure, 264-265,271t zinc, 211 Hair loss in women, 1711-1713 Hair tonic, 727 Hamamelis virginiana (witch hazel), 2077 Hamilton Anxiety Scale, 1170-1171 Hamilton Depression Scale depression assessment with, 1024t-l025t, 10241025

Hypm'cum perforaturn activity and, 1042-1043

Hamstring strain, 479 Hand reflexology, 434-435 Harpagophytum procumbens (Devil's claw) gout treated with, 1708 osteoarthritis treated with, 1971-1972 Hashimoto disease. See also Hypothyroidism description of, 1792-1793 treatment of, 1796-1797 Hatha yoga, 105 Hauser, Gaylord, 59

Index ~~

~

Hawthorn. See Crataegus oxyacuntha Hawthorne effect, 100 Head McKenzie sensory zones, 437 Headaches analgesic-rebound,1911-1912 chronic daily description of, 1907-1908,1908b, 1911t drug-induced, 1911 cluster, 1907 ergotarnine-rebound,1912 5-hydroxytryptophanfor, 1029t, 1029-1030 Mentha piperata for, 1073 migraine. See Migraine headache peat therapeutics for, 479 tension, 1907 Healing omithine alpha-ketoglutarateeffects on, 685 spirituality in, 520-522 wound. See Wound healing Healing crisis, 392 Healing reactions, 82t, 82-83 Health Ayurveda definition of, 322 conditions for, 34-36 determinants of, 34,34b diet and, 35-36 functional medicine view of, 21 homeopathic view of, 391 regimen of, 35-36 Heart apoptosis in,149-150 camitine levels in, 812-813 Heart attack. See Myocardial infarction Heart disease. See Coronary heart disease Heartburn, 661 Heat injury, 368-369 Heat shock proteins, 478 Heat stroke, 372 Heat therapy description of, 405-406 otitis media treated with, 1996 reflex effects of, 408t Heating compress, 410-411 Heavy metals. See Metal toxicity Heidelberg pH capsule gastric analysis achlorhydria findings, 219 clinical application of, 219 development of, 217 hyperchlorhydria findings, 219 hypochlorhydria findings, 218-219 indications for, 219,589 interpretation of results, 218-219 methods of, 218 procedure for, 218 Helicobacter pylori ABO polymorphisms and, 452t achlorhydria and, 662 Allium sativum for, 730 bismuth subcitrate for, 2027 Comprehensive Digestive Stool Analysis 2.0 applications, 173 glaucoma and, 1700 hypochlorhydria and, 662 lactoferrin for, 662-663 peptic ulcer disease caused by, 2026

Helicobacter pylori-cont’d rosacea caused by, 2110 stool antigen test for, 173 treatment of, 662-663 Vaccinium macrocarpon for, 1360 Helix pomatia agglutinin, 456t Helminthic infections, 730 Helper T cells asthma and, 1486 CD4 for identification of, 225 function of, 232-233 suppressor T cell ratio with, 225-226 type 1,232-233 type 2,232-233 Hematoma, 480 Hematuria, exercise-induced, 370 Heme biosynthesis, 300,30lf, 2046-2047 Hemodialysis, 816 Hemoglobin glycosylated, 1609-1610,1620 policosanol’s effects on, 1176,1177t Hemolytic-uremicsyndrome, 471 Hemorrhoidectomy, 2072 Hemorrhoids cryosurgery for, 2072 external, 2073 internal, 2070-2073 prevention of, 2072-2073 rubber-band ligation of, 2071-2072 Ruscus aculeatus for, 1230 surgical treatment of, 2071-2072 Heneicosanoicacid, 191t, 195 Hepatic encephalopathy, 1190 Hepatic function, 1177 Hepatitis A, 1715-1716 alpha-lipoic acid for, 1717,1720 B, 1715-1717 C, 1715,1717 catechin for, 824-825 characteristicsof, 1715 classification of, 1715 diagnosis of, 1715-1716 diagnostic summary for, 1715 dietary considerations for, 1717 Glycyrrhiza glabra for, 1718-1719 glycyrrhizin for, 1007 liver extracts for, 1717-1718 nutritional considerations for, 1717 Phyllanthus amarus for, 1719-1720 selenium for, 1717 Silybum marianum for, 1254,1719 symptoms of, 1716t thymus extracts for, 383,1718 treatment of, 1716-1721 vitamin C for, 1717 Hepatitis B e antigen, 824-825 Hepatitis B immune globulin, 1716-1717 Hepatocellular carcinoma, 1718 Hepatoprotective botanicals antioxidant properties of, 1096-1097 Panax ginseng as, 1126 Heptadecanoic acid, 191t, 195 Herb(s).See also specific herb cultivation of, 334 definition of, 327

Herb(s)-cont’d drylng of, 334 evaluative and analytic methods for, 335-336 garbling of, 334 German monograph system for, 328-329 grinding of, 334 pharmaceutical uses of, 328-330 pharmacologic actions of, 329 processing of, 334-335 therapeutic actions of, 329 Herbal medicine advantages of, 329-330 consumer expenditures on, 327 description of, 327 in early America, 331 Galen’s influence, 330-331 global use of, 327 history Of, 330-332 rebirth Of, 327-328 science benefits for, 329 study Of, 330-332 summary of, 337 Herbal preparations description of, 332-333 dosage of, 337 extracts, 333 production of, 334-335 quality control of, 336-337 quality of, 333 standardized extracts, 333-334,337 Herbicide-induced porphyria, 2048 Hering, Constantine, 388,393 Hering-Breuerreflex, 639 Hering’s Law of Cure, 391 Herpes simplex description of, 480,889,1723-1726, 1741,2074 glycyrrhetinicacid, topical application of, 1008 Melissa oficinalis and, 1066-1067 Hershey, Alfred, 1151 Herxheimer reaction, 579 Hesperidin, 971,1892 Hexachlorobenzene,342 Hexachlorophene,345 Hexacosanoic acid, 191t, 195 High altitude sickness, 984 High density lipoproteins, 1504 High-density lipoprotein cholesterol, 1173-1178,1174f-1177f,1177t-1178t High-fiber diet, 1625,2027,2070,2150 Highly active antiretroviral drug therapy, 1728,1734-1735 Hildegarde, St., 128 Hip fractures, 1977 Hippocrates, 91,98-99,402,583 Histamine allergies and, 1407 asthma and, 1407 flavonoidseffect on, 2028 migraine headaches and, 1407,1914 quercetin effects on, 969 vitamin B6 effects on, 1914 vitamin C effects on, 1491-1492 Histidine decarboxylase,824

Hives. See Urticaria HMG-CoA reductase,671 HMGCoA reductase inhibitors, 616,779 Holbrook, Martin Luther, 46-47 Holistic medicine, 15-16 Homeodynamics, 21 Homeopathic effect, 388 Homeopathy acceptance of, 19 case evaluation, 391 clinical application of, 390-394 definition of, 387,390 descriptionof, 19 difficulties assodated with, 396 disease as viewed by, 389,391 environmentaltoxins treated with, 351 follow-up, 391 global prevalence of, 388 Hahnemann’s contributionsto, 44, 387-390,396 health as defined by, 391 history of, 44,387-388 human immunodeficiency virus managed by, 1744-1745 infectious diarrhea treated with, 1808-1810 initial interview for, 390-391 medicines used in goals of, 393 materia medica, 391,393-394 mechanism of action, 392-393 pharmacologic effects of, 392 physical properties of, 395-396 potency selection and determination, 392-393 prescribing of, 391 metal toxicity treated with, 395 nausea and vomiting of pregnancy treated with, 1943 otitis media treated with, 1995 Parkinson’s disease treated using, 2009 philosophy of, 388-391 placebo’s role in, 93 porphyrias bated by, 2049 principles of, 24 provings, 388,393-394 research in animal studies, 395 basic, 395-396 human trials, 394-395 meta-analyses, 394 seborrheic dermatitis trrated by, 2114 seds of, 44-45 side effects as viewed by, 390 standardization of, 120 summary of, 396 vitalism, 389-390 word origin of, 387 Homeostasis conscious control over, 95 description of, 21,81 respiratory, 633 Homocysteine alcohol abuse effects on, 610 alcoholism effects on, 623 atherosclerosis and, 1289,1517 coronary artery disease and, 619

Homocysteinc+cont’d definition of, 609 dementia and, 621 depression and, 621 diabetes mellitus and, 622,1624 elevated levels of fenofibrate effects, 614 health conditions associated with, 493494,609 R M function ~ impairments and, 614-615 ethanol ingestion effects on, 623 folate levels and, 619 folic acid supplementation effects on, 624, 1517,1765,1987,2005 gout and, 623 heart disease and, 619 in men, 610 mental disorders and, 621-622 metabolism of betaine, 613-614 gender effects on, 610 lifestyle effects on, 610 methionine, 610-611 methylcobalamin, 612-613 methyltetrahydrofolate,611-612 nutrition effects on, 610 pathways for, 609-610 pyridoxal 5’-phosphate, 614 remethylation pathway, 610,611f transsulfuration pathway, 610-611,611f methylation reactions of, 493 neural tube defects and, 620 neurologic disorders and, 621-622 as neurotoxin, 621 nutrients affected by carnithe, 615 chondroitin sulfates, 615-616 coenzyme A, 616 coenzyme Qlo,616,617f creatine, 617 epinephrine, 617 glucosamine sulfate, 616 melatonin, 617 overview of, 615 phosphatidylcholine,618 proteoglycans, 615-616 Sadenosylmethionine,615,618 taurine, 618 in Parkinson‘s disease, 2005 peripheral vascular disease and, 619-620 pharmaceutical drug effects on, 615 phase 2 detoxification and, 618 in postmenopausal women, 610 pregnancy and, 620-621 psoriasis and, 622 race-based differences in, 610 renal failure effects on, 622 rheumatoid arthritis and, 622 stroke and, 620 vitamin I36 effects on, 624,2006 in women, 610 Homocystinuria cystathionine synthase deficiency as cause of, 623 description of, 609 osteoporosisand, 623

Homovanillate,289t, 293 Honey, 767-769 Hookwonns, 452 Hope, 101,106 Hormesis, 392 Hormone(s) boron interactionswith, 787 cancer treatment using, 558 fasting-related changes in, 540-541 inhibitors of, 558 Hormone replacement therapy advisory body recommendationsfor, 1886-1887 Alzheimer’s disease and, 1463,1884 benefits of, 1878-1879 breast cancer and, 1882-1884 cognitive function effects of, 1884 coloredal cancer and, 1879 continuous, 1888b conventional, 1878 evolution of, 1878 natural, 1878 natural hormones, 1885-1886 osteoporosis and, 1879,1981 ovarian cancer and, 1884-1885 risks associated with coronary heart disease, 1880-1882 description of, 1879-1882 endometrial cancer, 1879-1880 gallstones, 1882 stroke, 1882 venous thromboembolism, 1880 types of, 1887-1888 Horse chestnut seed extract, 2168-2169 Hot compress, 410 Hot flashes, 1888-1889 Hot full-immersion baths, 411 Hot sitz bath, 412 Hsiao Yao Wan, 843t Hua Tuo, 514t Huangu Mi, 311 Human Genome Project, 17 Human immunodeficiency virus. See also Acquired immunodeficiency syndrome AIDS progression of, 1731-1732 Aloe Vera for, 743-744 biology of, 1729 CD4+ T cells in, 1730-1732 complementaryand alternative medicine for, 1728 complications of Candida albicans oral thrush, 1739-1740 cardiovascular disease, 1740 diarrhea, 1740-1741,1809 herpes simplex virus, 1741 Kaposi sarcoma, 1741-1742 lipodystrophy, 1742 macrocybc anemia, 1742 neuropathy, 1742-1743 psychologic conditions, 1743 wasting, 1743-1744,1744b diagnosis of, 1732-1733 diagnostic summary for, 1727 epidemiology of, 1729 glutamine and, 997-998

Index Human immunodeficiency virus-cont’d high-risk groups for, 1727,17321, history of, 1728-1729 history-taking, 1732,1733b Hypericurn perforaturn and, 1040,1043 immune system’s response to, 1730 laboratory tests, 1732-1733 management of acupuncture, 1745-1746 botanical medicines, 1744,17451, diet, 1737,1747 essential fatty acids, 1737 fusion inhibitors, 1737 highly active antiretroviral drug therapy, 1728,1734-1735, 1746-1747 homeopathy, 1744-1745 lifestyle, 1748 massage, 1746 medical, 1733-1734 naturopathic, 1734-1747 nonnucleotide reverse transcriptase inhibitors, 1736 nucleotide reverse transcriptase inhibitors, 1735-1736 nutritional supplements, 1748 patient education and guidance, 1746-1747 physical medicine, 1745-1746 protease inhibitors, 1728,1736-1737 nutrient deficiencies caused by, 1737, 1738b-1740b oral glycyrrhizin and, 1007 pathogenesis of, 1730,1730b Pneumocystis carinii pneumonia, 1728 in pregnancy, 1743 saponins for, 1262 transmission of, 1730 viral structure, 1727-1728 Human papillomavirus condyloma lata caused by, 2074 epidemiology of, 1571-1572 natural history of, 1571-1572 peat therapeutics for, 480 Humoral immunity, 221,222f, 585,646 Humoral pathology, 7-8 Hunter-gatherer diet, 462,665-666 Huntington’s disease, 2007 Huperzine A, 1468 Hyaluronidase description of, 911 quercetin effects on, 969 Hydrastis canadensis. See also Berberine anorectal diseases treated with, 2077 chemical composition of, 1014,1014f clinical applicationsof, 1016-1018 cystitis treated with, 1602-1603 description of, 330 dosage of, 1018 drug interactionswith, 1018 folk uses of, 1014 hemorrhoids treated with, 2077 history of, 1014 pelvic inflammatory disease treated with, 2021-2022 pharmacology of, 10141016

Hydrastis canadensis-cont’d pneumococcal pneumonia treated with, 2043 psoriasis treated with, 2085 sinusitis treated with, 1546 streptococcal pharyngitis treated with, 2124-2125 toxicity of, 1018 urinary tract infections treated with, 1602 vaginitis treated with, 2161 Hydration in elderly, 1404 hypertension and, 1407 for infectious diarrhea management, 1804-1805 winter, 1405 Hydrogen, breath testing for in lactose intolerance, 259 in small intestinal bacterial overgrowth, 156 Hydrogen peroxide catalase action on, 1089 as ~ t ~ ~ aoccurring l l y antioxidant, 1086-1087 probiotic effects on, 1202-1203 Hydrogen sulfide, 477478 Hydrostatic weiglung, for body density, 1949 Hydrotherapy ablutions, 413 adverse reactions to, 409 arterial trunk reflex, 408 baths. See Baths blood movement principles, 406408 body temperature considerations, 403 cardiovascular disease and, 409410 carpal tunnel syndrome treated with, 1559,1561 cold applications, 404-405 cold friction rubs, 413 collateral circulation effect, 407408 compresses, 410-411 constitutional, 413414,2051 contrast, 406407 in Crinnion depuration protocol, 350 definition of, 401 derivative effect, 407 description of, 36 diabetes mellitus contraindications,40849 hemorrhoids treated with, 2071 history Of, 135-136,402 hot applications, 405-406 hypertension and, 409410 hyperthyroidism treated with, 1777 Kellogg’s work with, 56 literatw regarding, 401402 physiologic effects of, 403 during pregnancy, 409 research regarding, 403-406 revulsive effect, 406-407 rules of, 408-409 safety considerationsfor, 409410 sauna, 415 side effects of, 409 spinal reflex effect, 407 techniques for, 410415 in twentieth century, 402 water properties, 402403 wet sheet pack, 414-415 women’s involvementin, 135-136

Hydroxychloroquine, 2094 25Hydmxycholecalcifero1,1986 Hydroxycitrate, 1958-1959 Hydroxyethylrutosides,968,2071 5-Hydroxyindolacetate, 289t, 293 5-Hydroxyindoleacetic acid description of, 1909-1910 5-hydroxytryptophanand, 1025 Hypericurn perforaturn activity and, 1040 Hydroxyl radical, 1085-1087 Hydroxymethylglutarate, 289t, 291 IHydroxytryptophan clinical applicationsof, 1022-1032,1023t depression treated with, 1438 dosage of, 1032 drug interactionswith, 1033 Hypericum perforaturn activity and, 1040 insomnia treated with, 1832 irritable bowel syndrome treated with, 1839 migraine headaches treated with, 19141915 Parkinson’s disease treated with, 2004-2005 pharmacology of, 1022 seasonal affective disorder treated with, 1444 side effects of, 10251026,1026t toxicity Of, 1032-1033 tryptophan metabolism and, 1021-1022, 1022f weight loss using, 1955-1956,1959 Hygienic Movement, 133 Hyperalgesic skin zones, 513-514 Hyperbaric oxygen, for multiple sclerosis, 1935 Hypercalciuria, 1845 Hyperchlorhydria, 219 Hypercholesterolemia, 1176-1178,1177t-1178t Hyperemesis gravidanun, 1941 Hyperglycemia, nonketotic hyperosmolar, 1622 Hyperhomocysteinemia description of, 619 drug-induced, 623-624 Hypericin antidepressant activity of, 1039-1040 antiviral activity of, 1040 chemical composition of, 1037-1038,1038f description of, 329 Hypericurn perforaturn (St. John’s wort) antiviral effects of, 1040 chemical composition of, 1037-1038,1038f clinical applications of, 1041-1044 depression treated with, 1441,1743 dosage of, 1044 drug interactions with, 104.5 folk use of, 1038 history of, 1038 human immunodeficiency virus treated with, 1745b 5-hydro~ytrypt0phanand, 1025 pharmacology of, 1038-1041 premenstrual syndrome treated with, 2062-2063 seasonal affective disorder treated with, 1444-1445 topical application of, 1044 toxicity of, 1044-1045

Index Hyperinsulinism, 1782 Hyperkeratosis, 1386 Hyperlipidemia, 1115 Hyperplasia, 550 Hyperplasticobesity, 1950 Hyperpnea, 631 Hypertension. See also Blood pressure atherosclerosis and, 1505 balneotherapy for, 480 borderline, 1757,1767 classification of, 1757,1758b diabetes metlitus-related complications and, 1624 diagnostic summary for, 1757 essential, 1757 etiology of, 1759 exercise training benefits for, 362 fasting for, 536 hydrotherapy and, 409410 lifestyle factors associated with, 1760-1761 metal toxicity and, 1759 moderate, 1757,1767 peat therapeuticsfor, 480 policosanol's effects on, 1176-1177 prayer benefits for, 523-524 salt-restrictive diet for, 493 severe, 1757,1767 sodium and, 1300,1762-1763 stress and, 1761 stroke and, 1757 treatment of Allium cepa, 1766-1767 Allium sativum, 733,1766 angiotensin-converting enzyme inhibitors, 615,1760 anti-ACE peptides, 1765-1766 antihypertensive drugs, 1759-1760 arginine, 1765 beta-blockers, 1759-1760 calcium, 1764 calcium channel blockers, 1760 coenzyme Qlo,865,866,1766 Coleus forskohlii, 873-874 Crataegus oxyacanthu, 883,1766 DASH diet, 1761-1766,1762t diet, 1760 diuretics, 1759-1760 fish oils, 951,1765 folic acid, 1765 magnesium, 1763-1764 Olea europaea, 1767 omega-3 fatty acids, 1765 potassium, 1762-1763 Viscum album, 1767 vitamin 86,1765 vitamin C, 1764-1765 white coat, 1758 Hyperthermia full-immersion baths to produce, 411 heat shock proteins affected by, 478 peat therapeutics for inducing, 478-479 whole-body, 479 Hyperthyroidism acupuncture for, 1777 antioxidantsfor, 1773 cadmium exposure and, 1772

Hyperthyroidism-ont

'd camitine for, 175-1776 characteristicsof, 1771 coenzyme Qlo and, 1776 diagnosis of, 1772-1773 diagnostic summary for, 1771 genetics of, 1772 hydrotherapy for, 1777 iodine effects, 1775 mercury exposure and, 1772 primary causes of, l773t risk factors for, 1771-1772 selenium for, 1775 toxic nodular goiters and, 1773 treatment of, 1773-1777 vitamin C for, 17741775 vitamin E for, 1775 zinc for, 1775 Hypertrophic obesity, 1950 Hyperuricemia, 1705f Hyperventilation provocation test, 637 Hyperventilation syndrome/breathing pattern disorders. See also Breathing acute progression of, 635-636 arterial blood gas tests in, 637 biomechanical considerations,638-639 breath-holding-timetest for, 637 breathing retraining in, 640-641,642b cardiac signs of, 635,636t causes of, 632 chronic, 636-637 gastrointestinalsigns of, 635,636t gender rates of, 630 hydrogen ions and, 632 hypoglycemia effects, 633 impact of, 631 laboratory and office tests for, 637 metabolic disturbances associated with, 635 muscular signs of, 636t naturopathic protocol for, 641 neurologic s i p of, 636t Nijmegan questionnaire for, 637-638,638f osteopathic protocol for, 641 overview of, 629-630 pathophysiology of, 631-635 positron emission tomography carbon dioxide test for, 637 psychological influences on, 634 rehabilitation for, 640642 respiratory signs of, 636t signs and symptoms of, 630,631f, 635,636t somatic changes caused by, 634-635 think test for, 637 treatment of, 640-642 HypervitaminosisA, 1389 Hypnosis description of, 104 pain control using, 434 Parkinson's disease treatment and, 2009 Hypoadrenalism,901 Hypocapnia, 636 Hypochlorhydria asthma and, 1488 chronic candidiasis and, 576 description of, 168 digestion affected by, 584

Hypochlorhydria-ont'd etiology of, 662-663 Heidelberg pH capsule gastric analysis findings in, 218-219,589 Helicobacter pylori and, 662 rosacea caused by, 2110 signs and symptoms of, 662 Hypochlorite, 1086-1087 Hypocholesterolemia, 1115 Hypoglycemia aggressivebehavior and, 1784 alcohol consumption and, 1432,1452, 1787-1788 Allium cepa and, 726 Allium sativum and, 731 Aloe Vera and, 744,746 atherosclerosis and, 1785 carbohydrate intake and, 1785-1786 chronic fatigue syndrome and, 1585-1586 criminal behavior and, 1784 depression and, 706,1433 description of, 1621,1783-1784 diagnosis of, 1782-1783 diagnostic summary for, 1781 dietary factors, 17851786,1788 drugs for, 1782b exercise for, 1788 fasting, 1781-1782 glucose tolerance test for, 1782-1783 glycemic index for, 1786 health effects of, 1784-1785 hyperventilation syndrome/breathing pattern disorders caused by, 633 intermittent claudication and, 1785 lifestyle factors associated with, 1787-1788 mental function impairments associated with, 1784 migraine headaches and, 1914 Opuntia sp. for, 1115-1116 premenstrual syndrome and, 1784-1785 questionnaire for, 1783,1783t reactive, 1781 seizures caused by, 1651 symptoms of, 1433,1782 Hypoglycemic index, 1783 Hypohydration, 1405-1406 Hypomagnesemia, 1296 Hypometabolism hypothesis, of fibromyalgia, 1672-1674 Hypoproteinemia, 155 Hypothalamic-pituitary-adrenalaxis chronic fatigue syndrome and, 1586 depression and, 1430 description of, 587-588 Hypericum perforaturn activity in, 1039-1040 phosphatidylserine effects on, 1164 tests of, 1431 Hypothalamus, 96 Hypothyroidism. See also Hashimoto disease autoimmune, 1796-1797 causes of, 1792 chronic fatigue syndrome and, 1585 depression and, 1430 diagnosis of, 1792-1794,1795f diagnostic summary for, 1791 dietary considerations for, 1797

Index Hypothyroidism-ont ’d exercise for, 1795-1796 fibromyalgia and, 1672-1673 functional, 1792 hair loss caused by, 1712 iodine deficiency and, 1792 laboratory evaluations, 1793-1794 osteoarthritisand, 1964 overt, 1792,1797-1798 premenstrual syndrome and, 2057 primary, 1791 secondary, 1791 subclinical, 1792,1797-1798 symptomatology of, 1793 testing for, 1675 thyroid hormone replacement therapy for, 1796 treatment of, 17941798 Hyssopus oficinalis, 1745b

I 13, 227 Iberogast compounds, 1067 Idiopathic postprandial syndrome, 1781 IgA nephropathy, 953 Illness chronic, 33 functional medicine perspective of, 22 as information, 22 microbe-associated, 23 as process, 32-34 spiritual healing and, 528 stress-induced, 646 Imipramine, 1040,1042,1042t Immune complex-mediated diseases, 1139 Immune complex-mediated reactions, 585-586 Immune function age-related declines in, 860 assessments of, 222-223 berberine and, 1016 boron effects, 1291 chronic candidiasis and, 576-577 coenzyme Qloeffects on, 860-861 cyclic adenosine monophosphate effects on, 646 cyclic guanosine monophosphate effeds on, 646-647 enhancing of, 576-577 fasting effects on, 541 fish oils’ effect on, 953 glutamine and, 995 Glycyrrhiza glabra and, 1005 impairments in, 15841, omega-3 fatty acids’ effect on, 953 Panax ginseng and, 1125 phage therapy and, 1152-1153 probiotic stimulation of, 1207 stress effects on, 646 vitamin C effects on, 2034 vitamin E effects on, 1283 Immune reactions, 585-586 Immune system acemannan effects on, 740 activation of, 718 adverse food reactions’ effect on, 583 Allium sativum effects on, 731

Immune system-cont’d Astragalus membranaceus effects on, 652 in attention deficit hyperactivity disorder, 1538-1539 cancer and, 111-112 catechin effects on, 823-824 celiac disease effects on, 1611 central nervous system and, 98 chronic fatigue syndrome caused by abnormalitiesof, 1581t, 1581-1582 complement, 717-718 description of, 645 diabetes mellitus effects on, 1622-1623 dietary factors that affect alcohol, 648 B vitamins, 649 beta-carotene, 774 carotenes, 648-649,774,778 folic acid, 649 iron deficiency, 649-650 lipids, 648 mineral deficiencies, 649-650 nutrient deficiency, 647 obesity, 648 overview of, 647 protein, 647 pyridoxine, 649 selenium, 650 sugar consumption, 647-648 trace minerals, 650 vitamin A, 648,1382-1383,1385 vitamin C, 649, 707,2034 vitamin E,649,2160 zinc deficiency, 650 disorders of, 223b divisions of, 221 Echinacea spp. effects on, 651-652,910-911 endorphins effect on, 97,98t exercise effects on, 368,1588 food allergies and, 585-586 functions of, 233 hexachlorobenzene effects on, 342 lifestyle effects on, 647 negative emotions’ effect on, 112 nonspecific response by, 717 organochlorine compounds effect on, 341-342 organophosphatepesticides effect on, 342 overview of, 717 Panax ginseng effects on, 651-652 peat therapeutics effect on, 480-481 polycyclic aromatic hydrocarbonseffect on, 342 propolis effects on, 768 responses by, 717 specific response by, 717 splenopentin effects on, 381 stress effects on, 97,100-101,646 support for benefits of, 645 botanicals for, 651-652 recommended approach, 652 thymus function improvementsfor, 650-651 Viscum album effects on, 1376-1378 zinc’s role in, 650,1302

Immunity acquired, 585 beta-carotene effects on, 1645 cell-mediated, 221,585 humoral, 221,222f, 585,646 innate, 585 Immunoglobulins A, 2039-2040 classes of, 585 E, 586 food allergies and, 585 G, 586,2040 types of, 717 Impotence, 1224 Inactive placebo, 92t Inbom errors of metabolism camitine for, 817 description of, 488 Incontinence, 371 Indian tobacco. See Lobelia inflata Indigestion, 661 Individualizationof treatment, 120-121 Inducible nitric oxide synthase, 230 Induration technique, 510,510f Infection ABO blood groups and, 450,451t foodbome, 470-471 male infertility and, 1868-1869 spinal, 420 viral, 383 Infectious diarrhea acupuncture for, 1809-1810 agents that cause, 1802-1804 berberine-containing plants for, 1807-1808, 1810 Campylobacterjejuni, 1802-1803 in children, 1807 classification of, 1801 Clostridium dijicile, 1803 cytomegalovirus, 1802 diagnostic summary for, 1801 dietary considerations, 1805 Epstein-Barr virus, 1802 Escherichia coli, 1802 folic acid deficiency and, 1805,1810 Giardia lamblia, 1803 glutamine for, 1806,1810 history of, 1801 in HIV/AIDS patients, 1809 homeopathy for, 1808-1810 hydration/electrolyte balance for, 1804-1805 laboratory diagnosis of, 1804 Lactobacillus acidophilus for, 1806-1807, 1810 Laribacter hongkongensis, 1803 nutritional supplements for, 1810 parasitic agents that cause, 1803-1804 Potentilla tormentilla for, 1808, 1810 predisposing factors for, 1804 probiotics for, 1806-1807 Saccharomyces boulardii for, 1807,1810 Salmonella, 1803 Shigella, 1803 treatment of, 1804-1810 viral agents that cause, 1802

Index Infectious diarrhea-cont’d vitamin A for, 1805,1810 vitamin B12deficiency and, 1805,1810 Yminia enterocolitica, 1803 zinc deficiency secondary to, 1806,1810 Infertility ABO blood group incompatibility as cause of, 444 alkylglycerols for, 720 coenzyme Qlo for, 865-866 endometriosisand, 1644 male anatomic considerations, 1865-1866 antioxidants for, 1870-1871 arginine for, 1872 botanical medicines for, 1872-1874 camitine for, 1872 causes of, 1866b description of, 720 diagnosis of, 1867-1868 diagnostic summary for, 1865 estrogen exposure and, 1869-1870 fats consumption and, 1871 incidence of, 1865 infections and, 1868-1869 lycopene and, 1871 nutritional considerationsfor, 1870-1872 oils consumption and, 1871 Panax ginseng for, 1872-1873 proanthocyanidinsfor, 1871 Pygeurn aficanurn for, 1224,1873 semen analysis for, 1867 tests for, 1867-1868,1868t treatment of, 1868-1874 vitamin B12deficiency and, 1872 vitamin C for, 1870-1871 zinc deficiency and, 1871-1872 peat therapeutics for, 480 pelvic inflammatory disease and, 2017 Vitex agnus castus for, 1398 Inflammation Allium sativum for, 731 Aloe vera for, 741 antioxidants and, 1087-1088 Curcuma longa for, 896-897 fish oils for, 589 oral glycyrrhizin and, 1008 pancreatic enzymes for, 1138 quercetin for, 589 signs of, 425 stages of, 425-426 Zingiber oficinule for, 1415-1416 Inflammatory arthritis, 182 Inflammatory bowel disease allopathic treatment of, 1819 arthritis associated with, 1818 Bastyr formula for, 1823b, 1823-1824 calcium deficiency in, 1821 calprotectin and, 1824 in children, 18241825,1825b corticosteroids for, 1819 Crohn’s disease. See Crohn’s disease definition of, 1813 dehydroepiandrosterone-sulfatelevels in,903

Inflammatorybowel disease-cont‘d diet description of, 1815,1819 elemental, 1819-1820 elimination, 1820 highcomplex carbohydrate, high-fiber, 1820 oligoantigenic, 1820 eicosanoid metabolism in, 1816 extraintestinal manifestationsof, 1818 flavonoids for, 1823 folic acid levels in, 1822 genetic predisposition for, 1814 high-potency multiple vitamin for, 1822-1823 immunologic factors in, 1815 infectious causes of, 1814 iron deficiency in, 1821 magnesium deficiency in, 1820-1821 malnutrition associated with, 1818-1819 minerals for, 1820-1821 nutritional deficiencies associated with, 1819,1819t potassium deficiency in, 1821 probiotics for, 1205 quercetin for, 1823 therapeutic approach to, 1825-1826,1826t ulcerative colitis. See Ulcerative colitis vitamin D deficiency and, 1821 vitamin E deficiency and, 1821 vitamin K deficiency and, 1821 Influenza, 452t, 1488 Infrared coagulation, for hemorrhoids, 2072 Infusion, 333,710 Inhibition/ischemic compression, 504t Inositol hexaniacinate, 1511,1634 Inositol hexaphosphate, 1849 Inside/outside dualism, 16-17 Insomnia botanicals for, 1833-1834 causes of, 183Ot diagnostic summary for, 1829 exercise for, 1831 5-hydroxytryptophanfor, 1029,1032,1832 Hypericum perforaturn activity and, 1042 melatonin activity and, 1059 melatonin for, 1832-1833 Melissa oficinalis and, 1067 nocturnal myoclonus and, 1833 Passiflora incarnata for, 1834 prevalence of, 1829 restless legs syndrome and, 1833 serotonin therapy for, 1831-1832 treatment of, 1831-1834 tryptophan for, 1831-1832 Valeriana oficinalis for, 1372-1373,1833-1834 Institute of Immunology and Experimental Medicine, 1154-1155 Insulin acne vulgaris treated with, 1422 creatine uptake affected by, 679 fish oils’ effect on, 958 glutamine and, 684 Gymnema sylvestre effects on, 1631 improvements in, 1631-1632 in syndrome X, 1785

Insulin-cont’d type I diabetes mellitus treated with, 1618-1619 vitamin C effects on, 1626 Insulin sensitivity, 1631-1632,1951-1952 Insulin-like growth factor, 687 Insulin-like growth factor 1,478 Integrative medicine modem applicationsof, 8-9 terminology associated with, 3-4 word origin of, 3 Intentionality, 121-122 Interferon-alpha,817 Interferon-t, 586 Interleukin-1 assessment of, 228 description of, 221 monocyte production of, 228 Interleukin-1receptor antagonist, 228 Interleukin-2,1060 Interleukin-4,586 InterIeukin-6,903,1039 Intermittent claudication carnitine for, 813 description of, 619-620 Ginkgo biloba for, 982-983 hypoglycemia and, 1785 policosanol for, 1178 International Association of Hygienic Physicians, 534 International Society of Naturopathic Physicians, 70-71 Interstitial cystitis. See Cystitis Intestinal alkaline phosphatase, 443 Intestinal flora. See Probiotics Intestinal permeability antibiotics and, 1537 aspirin effects on, 1818 attention deficit hyperactivity disorder and, 1537 chronic fatigue syndrome and, 1584 conditions or diseases that disrupt alcoholism, 244 ankylosing spondylitis, 244 bacteria, 242 celiac disease, 243 chemotherapy, 245 diabetes mellitus, 244 dysbiosis, 245,1537-1538 food allergies, 243-244 glutamine and, 995 inflammatorybowel disease, 242-243 inflammatoryjoint diseases, 244 intestinal infection, 245 malnutrition, 245 microenzyme therapy for, 1076-1077 nonsteroidal antiinflammatorydrugs, 244-245 nutritional depletion, 245 trauma, 245 treatment considerations, 26247,588-589 food allergies and, 587 lactulose-to-mannitol ratio and, 242 lectins’ effect on, 454t measurements of, 245-246 rheumatoid arthritis and, 2090

Index Intestine acupuncture effects on, 1809 Aloe Vera for detoxificationof, 739 ComprehensiveDigestive Stool Analysis 2.0 assessments of. See Comprehensive Digestive Stool Analysis 2.0 dysbiosis of, 170,170b flora in alcohol consumption effects on, 1455 atopic dermatitis and, 1527 description of, 169,173,1817 dietary fiber for maintenance of, 670,2081 kidney stones and, 1847 probiotics effect on, 2055 rheumatoid arthritis and, 2096-2097 gastric emptying affected by, 693 large, 167-168 pH assessments, 172 protozoan infestations of Allium sativum for, 657 Artemisia annua for, 657 berberine for, 657 diagnosis of, 657 Entamoeba histolytica, 656 Giardia lamblia, 655-656 intestinal bacterial milieu and, 657 treatment of, 657 small. See Small intestine IntestiPhage, 1155 Intraocular pressure description of, 1697 exercise effects on, 1700 Intraoral burning, 281-282,282t Intrauterine device, 2017,2021 Intuition, 122 Inulin, 908,910 Iodide, 345 Iodine deficiency of description of, 1294 hypothyroidism and, 1792 fibrocystic breast disease treated with, 1667 recommended daily allowance for, 1294-1295 recommended intake of, 1293 suggested optimum nutrient intake for, 1294-1295,1295t thyroid functions and, 1294 vaginitis treated with, 2162 Iodopsins, 1384 Iodothyronine iodinase, 1794 Ipe Roxo. See Tabebuiu avellanedae Ipriflavone, 1987-1988 Iron assessment of, 276t-277t, 277 body stores of, 1295 femtin, 277,277t hair analysis for, 211,271t nonheme, 1295 Parkinson’s disease and, 2001 porphyrias treated with, 2050b recommended intake of, 1293 suggested optimum nutrient intake for, 1295 toxic chemical metabolism affected by, 349

Iron deficiency brain function affected by, 1295 description of, 277,1295 immune function affected by, 649-650 inflammatory bowel disease and, 1821 lead absorption affected by, 600 menstrual blood loss as cause of, 1903 oral manifestations of, 282t vitamin A metabolism affected by, 1384 Irritable bowel disorder, 171 Irritable bowel syndrome anxiety and, 1840 conditions that mimic, 1838b definition of, 1837 dietary fiber for, 672,1838 enteric-coatedvolatile oils for, 1839 food allergies and, 1838-1839 herbal formulas, 1839-1840 incidence of, 1837 irritable bowel disorder vs., 171 Lactobacillus for, 1839,1841 lactose intolerance as cause of, 256 Mentha piperata and, 1072 physical medicine for, 1840 probiotics for, 12041205 psychologicalfactors associated with, 1840 small intestinal bacterial overgrowth and, 153 sugar consumptionand, 1839 treatment of, 1838-1841 tryptophan for, 1839 yeast and, 170 Imtant vaginitis, 2156 Iscador, 1376-1377 Ischemic heart disease, 863 Isoagglutinins,444 Isobutyrate, 171 Isocitrate, 289t Isoflavones, 1645,1870 Isoflavonoids,466t, 1260 Isokinetic contraction, 509t Isometric contraction, 509t Isometric exercises, 356,1970 Isometric tests, 424 Isotonic contraction, 509t Isotonic eccentric contraction, 509t Isotonic exercise, 356 Isotretinoin, 1381,1424

J Jennings, Augusta, 134 Jennings,Ella,134 Jennings,Emily Howard, 134 Jet lag dehydration and, 1405 melatonin activity and, 1058-1059 John Bastyr College of Naturopathic Medicine, 62 Joints, end-feels for, 425-426 Judo revival, 513 Juglans nigra, 657 Just, Adolph, 55 Juvenileheadache, 1030,1031t

K Kaph, 320 Kaposi sarcoma, 656,1741-1742

Karnofsky index, 552,553t Kauffman, Martin, 63 Kava. See Piper methysticum Kava ceremony, 1168-1169 Kavalactones chemical composition of, l167,1168f, 1168t isolated vs. crude extracts of, 1169-1170 Keesey technique, 2072 Kellogg, John Harvey, 56,402 Keloids Centella asiatica for, 831-832 characteristics of, 831-832 Kempo, 1468 Ketogenic diet epileptic seizures treated with, 1651-1652 Parkinson’s disease treated with, 2004 Ketone bodies, 539-540 Ketones, 1617-1618 Ketosis, 539-540 Khella, 1477-1478 Khellin, 1477-1478 Kidney failure, 622 Kidney stones Amni visnaga for, 1848 anthraquinones for, 1848 botanicals for, 1848 bushite, 1850 cadmium exposure and, 1849 calcium, 1849-1850 calcium supplementation and, 1848 carbohydrate metabolism for, 1847 characteristicsof, 1845t citrate effects on, 1848 composition of, 1843-1847,1845t cranberry juice and, 1601 cystine, 1850 diagnostic summary for, 1843 dietary factors, 1844-1845 diseases that cause, 1843 formation of, 1844 glutamic acid and, 1847 intestinal flora and, 1847 lifestyle considerations, 1848-1849 low oxalate diet for, 1845-1847,1846t magnesium ammonium phosphate stones, 1850 magnesium and, 1847 oxalates and calcium effects on, 1848 dietary considerations, 1845-1847,1846t vitamin B6 effects on, 1847 vitamin C and, 1849 recurrence of, 1849 sleep position and, 1848-1849 sodium chloride and, 1849 stress and, 1849 struvite, 1850 Taraxacum oficinale for, 1337 treatment of, 1844-1850 uric acid, 1850 vitamin K and, 1848 weight control for, 1847 Kim&, 1199-1200 Kinesiologic tests, 205,206t Klebsiella spp., 1155, 1159 Kluyveromyces lactis, 1079

Kneading, 504t Kneipp, Father Sebastian, 4849,54,67 Kneipp Society, 48 Known placebo, 92t Koch’spostulates, 169 Koebner phenomenon, 1855 Korean ginseng. See Panax ginseng Korean mistletoe. See Viscum album coloratum Krebs cycle, 287-288,290,537,860,19851986 Kuhne, Louis,54-55 Kunitz-Trypsin inhibitor, 1261 Kupperman Menopausal Index, 849,849t Kynurenate, 289t, 292

L Labor pain acupuncture for, 436-437 attention-focusing techniques for, 434 cultural influences on, 433 description of, 431433 transcutaneouselectrical nerve stimulation for, 435-436 L-acetylcamitine. See also Camitine acetylcholine and, comparisonbetween, 815,1466 acetylcholinesterase inhibitors and, 815 Alzheimer’s disease treated with, 815, 1466-1467,1469 description of, 812 Down syndrome treated with, 815-816 senile depression treated with, 815 Lacrimatory factor, 725 Lactase, 1079 Lactase deficiency acquired-type, 257 adult-type, 257,260 congenital, 257-258 lactose intolerance vs., 256 Lactase-phlorizin hydrolase, 256 Lactate, 289t, 290-291 Lactation, fish oil consumption during, 953 Lactic acid, 172,357 Lactobacilli antibiotic therapy, gastrointestinal tract stabilization and recolonization after, 1201-1202 atopic disease prevention using, 1203-1204 bacterial vaginosis h a t e d with, 1203 cancer therapy using, 1204 characteristics of, 1197t, 1197-1199 clinical applicationsof, 12OOt, 1200-1207 commercial forms of, 1199-1200 in common use, 1197-1198, 1198t Crohn’s disease treated with, 1205-1206 definition of, 1195-1196 description of, 1196,1196t diarrhea treated with, 1206 dosage of, 1207-1209 drug interactionswith, 1209 eczema treated with, 1204 fermented dairy sources of, 1199 gastrointestinalenvironment, activity on, 1201,1207 gastrointestinaltract colonizers of, 1196, 1196t growth promotion techniques for, 1209

Lactobacilli-ont‘d immune system stimulation of, 1207 importance of strain in, 1198-1199 inflammatorybowel disease treated with, 1205 irritable bowel syndmme treated with, 1204-1205 lactose intolerance treated with, 1206-1207 lactulose as growth promoter for, 1188-1189 mechanisms of action, 1196-1197 nomenclature issues with, 1198 oligosaccharide/disaccharidepromotion of, 1209 properties of, 1197 sources of, 1199-1200,1209 spirulina as source of, 1209 strain development and selection issues, 1207,1208t supplements with, 1200,1207-1208 toxicity of, 1209 ulcerative colitis treated with, 1205 urinary tract infection treated with, 1202-1203 vaginal yeast infections treated with, 1202 yogurts as source of, 1209 Lactobacillus acidophilus, 1806-1807,1810, 1839, 1841,2155,2160-2162 Lactobacillus plantarum, 1196-1197 lactobacillus rhamnosus atopic disease treated with, 1203-1204 colorectal disease and, 1204-1206 description of, 247 probiotic mechanisms of action of, 1196-1197 urinary tract infection and, 1202-1203 Lactofemn, 662-663,2124 Lactose digestion of, 257f in prescription and over-the-counter drugs, 2581, sources of, 258b Lactose intolerance colic and, 256 controversies regarding, 258 dairy allergy vs., 256-257 definition of, 255 diagnosis of blood tests, 260 breath testing, 259-260 empirical testing, 258-259 genomic testing, 260 histology, 260 nutritional history, 258,258b urine tests, 260 factors associated with, 256 irritable bowel syndrome caused by, 256 lactase deficiency vs., 256 microbial enzyme therapy for, 1078-1079 pathophysiology of, 256,257f prevalence of, 255-256,256t probiotics for, 1206-1207 Symptoms of, 255-256 LaCtUlOse

clinical applications of, 1188-1191 colon cancer prevention using, 1189-1190 commercial forms of, 1188

Lactulose--cont’d constipation treated with, 1189 dosage of, 1191 endotoxemia treated with, 1190 hepatic encephalopathytreated with, 1190 lactobacilli and bifidobacteria growth and promotion with, 1188-1189 pathogenic microorganisms, decreasing growth with, 1189 toxicity of, 1191 urinary tract infection prevention of, 1190-1191 Lactulose breath test, for small intestinal bacterial overgrowth, 156 Lactulose-to-mannitol ratio, 242 Lahman, Dr.H., 54 LaPacho. See Tabebuin avellanedae Lapachol, 1322f, 1322-1327 Large granular lymphocytes, 233 Large intestine, 167-168 Laribacter hongkongensis, 1803 Laxative Aloe Vera as, 739 definition of, 710 L-camitine. See Camitine LDSO definition of, 710 of Echinacin, 915 Lead daily intake of, 1985 exposure to attention deficit hyperactivity disorder secondary to, 1535 detection of, 265-266 encephalopathy caused by, 345 gout and, 1706 health effects of, 595 history of, 594 hypertension secondary to, 1765 porphyrins affected by, 302 sources of, 596t iron deficiency effects on absorption of, 600 Leading causes of death, 367 ”Leaky gut,” 167,584,1527 Learned helplessness, 1429 Learned optimism, 114115 Lecithin description of, 691,718 gallstones and, 1691 Ledins ABO blood TOU UPS and, 451-455 actions of, 453-455 binding of, 454 biologic effects of, 453,454t definition of, 451 dietary, 451455 Lee, Elmer, 56 Leflunomide, 2095 Left ventricular ejection fraction, 1018 Lemon balm. See Melissa officinalis Lentinus edodes, 174513 Leonorus (motherwort),1646 Leprosy, 832 Leptin, 1451-1452 Leucine, 683-684 Leucopenia, 405

Index Leukemia, 551 Leukocytosis, 182 Leukoplakia, 282,282t,1853-1854 Leukotrienes, 1823,1917 Levator ani,2067 Levodopa, 2003-2004,2008 Lewin, Louis, 1169 Lewis blood groups, 44546,449 Lewy bodies, 2002 L-Glutamine, 246,993 Lichen planus, 1855-1857 Licorice. See Deglycyrrhizinated licorice; Glycyrrhiza glabra Lifestyle Alzheimer’s disease-related changes, 1469 angina pectoris-related changes, 1479 atherosclerosisprevention and, 1521 depression and, 1431-1433 detoxification affected by, 602-603 healthy, 85 homocysteine metabolism affected by, 610 hypertension and, 1760-1761 immune system affected by, 647 macular degeneration and, 1862 natural killer cell activity affected by, 647,647b nausea and vomiting of pregnancy and, 1943-1944 osteoporosis and, 1978,1988 Parkinson’s disease and, 2010 peptic ulcers and, 2026-2027 recommended daily allowances and, 1276-1277 stress management and, 704-705,705b trichomoniasis and, 2129 type II diabetes mellitus prevention and, 1616 Ligandlike complex, 450 Light therapy, for seasonal affective disorder, 1444 Lignans, 466t, 669,1262,1892 Lignins, 669 Lignoceric acid, 191t, 195 Limonoids, 466t Lindlahr, Henry, 29,36,55-56 Lindlahr College of Natural Therapeutics, 55 Lindner’s test, 423 Linoleic acid, 190,19Ot, 192-193,938 Linoleic acid/dihomogammalinolenicacid ratio, 191t, 196 Linolenic acid. See Alpha-linolenic acid; Gamma-linolenic acid Lipase, 1137t Lipid($ Allium sativum effects on, 732-733,733t camitine effects on, 809,816 complex, 714 definition of, 714 digestion of, 168 ethers from, 714-715 fish oil effects on, 950 fructooligosaccacharides and lowering of, 1186 immune function affected by, 648 neutral, 714

Lipid(shont’d policosanol’s effects on, 1173-1178, 1174f-l177f, 1178t soy isoflavones’effect on, 1268-1269 Lipid peroxide inflammation and activation of, 1087 as naturally occurring antioxidant, 1086-1087 Lipodystrophy, 1742 Lipoprotein(a), 1504 Lipoproteins description of, 1176,1504 high density, 1504 low-density Allium sativum effects on, 733-734 atherosclerosis and, 1504-1505 beta-carotene effects on, 778 Commiphora mukul effects on, 878-879 fish oils’ effect on, 950 oxidation of, 733-734 phytosterols and phytostanols effect on, 1511 Lipotropic, 711 Lipotropic agents description of, 578 gallstones treated with, 1692 uterine fibroids and, 2151 Lipotropics, 1646 Lithium hair analysis for, 211 thyroid hormone release blocked by, 345 Lithocholic acid to deoxycholic acid ratio, 172 Liu Wei Di Huang, 843t Liver Artemisia absinthium effects on, 756-757 chronic fatigue syndrome caused by impairments of, 1583-1584 Curcuma longa effects on, 895 fatty, 1451-1452 Piper methysticum effects on, 1720 policosanol’s effects on, 1177 psoriasis and, 1254,2081 Silybum marianum effects on, 1252-1253 “sluggish,” 1583 Symphytum oficinale effects on, 1720 Taraxacum oficinale for, 1337-1338 Liver disease alcohol-induced, 825,1451-1452 camitine for, 816-817 fatty infiltration, 816 Liver extracts, 379t, 380 Lobelia inflata asthma treated with, 1493 chemical composition of, 1049,1050f clinical applications of, 1050 description of, 330 dosage of, 1050 folk use of, 1049 history of, 1049 pharmacology of, 1049-1050 pneumonia treated with, 2041 toxicology of, 1050 Long-chain fatty acids camitine’s role in transport of, 811f description of, 690 dietary sources of, 940t

Long-chain triglycerides, 1958 Lovastatin, 1175 Low back pain, 365 Low natural killer cell syndrome, 1581 Low oxalate diet, 1845-1847,1846t Low-birth-weight infants, 998 Low-density lipoprotein Allium sativum effects on, 733-734 atherosclerosis and, 1504-1505 beta-carotene effects on, 778 Commiphora mukul effects on, 878-879 fish oils’ effect on, 950 oxidation of, 733-734 phytosterols and phytostanols effect on, 1511 Low-density lipoprotein cholesterol, 1173-1178,1174f-l177f, 1177t-1178t Lower motor neuron disease, 421t Low-fat diet, 941 Low-fiber diet, 670-671 Low-protein diet, 2004 Low-purine diet, 1706 L-propionylcamitine angina and, 813 description of, 812 LSD-25,94 L-selectins, 447 L-tyrosine, 1026 Lung cancer, 957 Luria, Salvador, 1151 Lust, Benedict, 27, 41,48-53,59, 67, 134 Lutein, 775, 777’-778,1092-1093,1514, 1860,2118 Luteinizing hormone Cimicifuga racemosa effects on, 848 sperm production and, 1866 Lycopene antioxidant effects of, 1092-1093,1508 cancer and, 777,1282 description of, 773 food sources of, 774t male infertility and, 1871 prostate cancer treated with, 777,1282 structure of, 773f Lymphocytes B. See B cells classification of, 223 enumeration of activation markers for, 226-227,231f description of, 223 flow cytometry for, 223-224,227 monoclonal antibodies for, 224-226 s ~ m m a r yOf, 227-228 large granular, 233 macrophage activation by, 718 natural killer cells. See Natural killer cells polyerga effects on, 382 proliferation of assay procedure for assessing, 230-232 definition of, 230 T.See T cells Lymphogranuloma venereum, 2074 Lymphoma, 551 Lysine description of, 810 food sources of, 1725t

Index Lysine-cont’d herpes simplex virus treated with, 1724 vaginitis and, 2160-2161 Lysogenic phages, 1151-1152 Lysophosphatidylcholine, 719 Lytic phages, 1150-1151,1151f

M MacFadden, Bemarr, 57 Macrocyhc anemia, 1742 Macromolecules, 1076 Macrophage(s) activation of, 718-719,911 alkylglycerol activation of, 718-719 assessment of, 228-230 carbon clearance test for, 911 in cell-mediated immunity, 224 description of, 718 dodecylglycerol effects on, 718 lysophosphatidylcholineeffects on, 719 nitric oxide production by, 230 phagocytic properties of, 718 secretory products produced by, 718 Macrophage respiratory burst, 740 Macula, 1859 Macular degeneration age-related, 1859-1860 antioxidantsfor, 1860 atherosclerosis and, 1860 diagnostic summary for, 1859 dietary considerationsfor, 1860 flavonoid-rich extracts for, 1861-1862 lifestyle considerationsfor, 1862 lutein for, 1860 nutritional supplements, 1860 risk factors for, 1859 batment of, 1860-1862 types of, 1859 Magnesium alcoholism treated with, 1456 assessment of, 24 asthma treated with, 1492-1493,1495 body status assessmentsof, 276t, 277-278 boron interactionswith, 786 cardiovascular system functioning and, 1518 chronic fatigue syndrome treated with, 1587 congestive heart failure treated with, 1592-1593,1595 deficiency of in alcoholism, 1454 in angina pectoris, 1477 in attention deficit hyperactivity disorder, 1536 description of, 1296 in inflammatory bowel disease, 1820-1821 migraine headaches and, 1915-1916 premenstrual syndrome secondary to, 2059-2060 diabetes mellitus treated with, 1628 epilepsy and, 1654-1655 erythrocyte membrane tests for, 278 food sources of, 1518 forms of, 1764

Magnesium+ont’d functions of, 1295-1296 glaucoma treated with, 1699 hair analysis for, 210 in human immunodeficiency virus, 1739b hypertension treated with, 1763-1764 hypomagnesemia, 1296 mitral valve prolapse and, 1916 myocardial infarction treated with, 1477 orotate and, 294 osteoporosisprevention and, 1986-1987 recommended intake of, 1296t, 1628 retention test for, 277-278 serum levels of, 278 suggested optimum nutrient intake for, 1294-1295 toxic chemical metabolism affected by, 349 trichomoniasis treated with, 2129 vitamin B6 and, 2059 Magnesium ammonium phosphate stones, 1850 Magnetic therapies, 1970-1971 Maitake mushrooms, 563 Major depression. See Depression Malabar tamarind, 1958 Malabsorption Coleusforskohlii for, 874 description of, 168-169 forskolin for, 874 in inflammatorybowel disease, 1818-1819 microbial enzyme therapy for, 1077-1078 in multiple sclerosis, 1935 pathogens that cause, 169-170 vitamin deficiencies and, 171 Malaria ABO polymorphisms and, 452t Artemisia annua for, 762-763 fish oils for, 958-959 Malate, 289t Maldigestion description of, l68,169f, 661 in diabetes mellitus, 244 treatment of, 661-663 Male infertility anatomic considerations,1865-1866 antioxidants for, 1870-1871 arginine for, 1872 botanical medicines for, 1872-1874 camitine for, 1872 causes of, 1866b description of, 720 diagnosis of, 1867-1868 diagnostic summary for, 1865 estrogen exposure and, 1869-1870 fats consumption and, 1871 incidence of, 1865 infections and, 1868-1869 lycopene and, 1871 nutritional considerations for, 1870-1872 oils consumption and, 1871 Panax ginseng for, 1872-1873 proanthocyanidins for, 1871 Pygeum africnnum for, 1224,1873 semen analysis for, 1867 tests for, 1867-1868,1868t treatment of, 1868-1874

Male infertility--cont’d vitamin BI2 defiaency and, 1872 vitamin C for, 1870-1871 zinc deficiency and, 1871-1872 Male pattern baldness, 1711-1712 Male reproductive tract cancer, 799 Male sexual system accessory glands, 1866 genital ducts, 1866 overview of, 1865-1866 penis, 1867 Malnutrition in inflammatorybowel disease, 1818-1819 intestinal permeability affected by, 245 streptococcal pharyngitis and, 2124 Maltose endurance athlete’s use of, 693 intoleranceto, 260-261 Manganese body status assessmentsof, 276t, 278 diabetes mellitus treated with, 1628-1629 dietary sources of, 1296 epilepsy and, 1655 hair analysis for, 210 neurotoxicity caused by, 344 recommended intake of, 1297t rheumatoid arthritis treated with, 2100-2101 suggested optimum nutrient intake for, 1296 Mania. See Bipolar depression Manipulation active movement tests, 424 assessmentsbefore, 423-424 barriers to success, 427 brachial plexus irritation and, 424 carpal tunnel syndrome treated with, 1560-1561 cervical distraction, 424 cervical spine, 424 chiropractic, 419 controversiesregarding, 418 definition of, 417 end-feels, 425 forces created during, 423 guidelines for, 426-427 history of, 418 inflammationand, 425 isometric tests, 424 joint end-feels of, 425426 fixation of, 427 motion palpation, 427-429 overview of, 417418 passive movement tests, 425 preparation for, 426 pretreatment assessments, 423-424 range of motion testing, 424 relaxation techniques before, 417 sacroiliac joint fixation, 427-429 schools of thought in, 418-420 soft tissue articulation, 504t Bennett‘s neurovascular reflexes, 512 Chapman’s neurolymphatic reflexes, 512 connective tissue massage, 512,514

Index Manipulation-ont’d soft tissue-cont‘d effleurage, 504t hyperalgesic skin zones, 513-514 indications for, 501 inhibition/ischemiccompression, 504t kneading, 504t neuromuscular technique, 514 points anatomy of, 504 classification systems, 505-510 connective tissues under, 504-505 description of, 503-505 identification of, 502-503 muscle types, 510-511 palpatory literacy of, 504 reflex, 512-513 size of, 503-504 tender, 505-506 trigger, 506-510 positional release, 504t potential of, 515 psychogenic influences, 511-512 rhythmic traction, 504t sacro-occipital technique, 512 springing, 504t, 513 stretching, 504t techniques for, 503,504t vibration, 504t viscerosomatic reflexes, 513 soft tissue injuries, 424-425 space-occupying lesions of the spine assessed before, 423-424 stabilization, 427 straight leg raise test before, 423 structural integrity and, 37 thrust used in, 427 troubleshooting of, 427 vertebrobasilar stroke considerations,424 Mannitol, 245 mmamose, 1601-1603 Mannose-6-phosphate, 741 Manual medicine, 419 Maple sugar urine disease, 21 Marrubium spp., 456t Maslow’s hierarchy of needs, 112-113,113f Massage connective tissue, 512 human immunodeficiency virus treated with, 1746 pain control by, 438 in United States, 9 Mast cells, 969,1816,2032-2033,2134b Mastalgia, 1665 Materia medica, 330,391,393-394 Matricaria charnomilla (chamomile),2084 Matrix metalloproteinases, 1931 Maximum heart rate, 359 Mead acid, 19Ot, 193 Meal planning, 706 Meal replacement formulas, 1956 Measles, 1385 Mechanical diagnosis and therapy approach, 420,422 Mechanistic medicine, 81,84 Medical education, 47-48

Medical Outcomes Study, 122 Medical schools founding of, 136 women in, 136,138 Medicated herbal plaster, 844t Medicine in early America, 42-48 early twentieth century, 57-6 eclectic school of, 43-44 Era I, 520-521 Era II, 520-521 Era III, 521-522 goals of, 487 ideal role of, 38 ideals for, 487 mechanistic, 81 orthodox, 57-58 professional, 42-43 scientific, 47,84 Thomsonianism, 43 traditional Chinese, 309,313 Meditation descriptionof, 529 pain control benefits of, 434 stress management uses of, 707 Mediterraneandiet, 469,1462,1506-1507 Medium-chain acyl CoA dehydrogenase deficiency, 294 Medium-chain triglycerides, 693,1958 Medroxyprogesterone acetate, 1879 Mefloquine, 762 Melaleuca alternifolia (tea tree) acne vulgaris treated with, 1423-1424 Candida albicans treated with, 580 chemical composition of, 1053,1054f clinical applications of, 1054-1056 dosage of, 1056 drug interactions of, 1056 folk use of, 1053-1054 history of, 1053-1054 pharmacology of, 1054,1054t toxicity of, 1056 trichomoniasis treated with, 2130 vaginitis treated with, 2161,2163 Melaleuca leucadendron, 174% Melanin, 1352 Melanoma diet and, 957 sunlight exposure and, 1283 Melasma, 1008 Melatonin Alzheimer’s disease and, 1467,1469 as antioxidant, 1095 asthma and, 1489 cataracts and, 2120 chemical composition of, 1057,1057f during chemotherapy, 560-561 clinical applicationsof, 1058-1062 deficiency of, 1917 dosage of, 1062 epilepsy treated with, 1656 homocysteine effects on, 617 insomnia treated with, 1832-1833 interactions with, 1062 migraine headaches treated with, 1917 Parkinson‘s disease and, 2006-2007

Melatonin-ont’d peptic ulcers treated with, 2027 pharmacology of, 1058 research regarding, 561 seasonal affective disorder treated with, 1444 secretion of, 1057-1058,1058f sleep-inducing effects of, 1832-1833 synthesis of, 1057-1058,1058f toxicology of, 1062 Melissa oficinalis (lemonbalm) antiviral activity of, 1066 chemical composition of, 1065,1066f clinical applicationsof, 1066-1067 dosage of, 1067-1068 drug interactions of, 1068 folk use of, 1065 Graves’ disease treated with, 1776 herpes simplex virus treated with, 1725 history of, 1065 pharmacology of, 1066 thyroid effects of, 1066 toxicology of, 1068 vaginitis treated with, 2161 Membrane attack group, 718 Memes, 119 Memory citicoline’s effects on, 856 Glycyrrhiza glabru enhancement of, 1005 Menarche, 371 Menometrorrhagia, 1901 Menopause Angelica spp. for, 752 atrophic vaginitis associated with, 1889 bladder infections and, 1889 bone loss associated with, 1978 botanical medicines for, 1892-1895 Cirnicifiga racemosa for, 848-850,849t, 1894,1896 cognition and, 1889 definition of, 1877 diagnostic summary for, 1877 dietary considerationsfor description of, 1889-1890 nutritional supplements, 1892 phytoestrogens, 1890-1892 exercise benefits for, 1895-1896 Ginkgo biloba for, 18941896 hormone replacement therapy for. See Hormone replacement therapy hot flashes associated with, 1888-1889 Kupperman Menopausal Index, 849,849t lifestyle factors, 1895-1896 Panax ginseng for, 1124,1894 progesterone cream for, 1895 smoking and, 1896 soy isoflavones for, 1269-1270 Symptoms Of, 1878-1879,1888-1889 Trifolium pretense for, 1893-1894 vitamin C for, 1892 vitamin E for, 1892 Menorrhagia astringent herbs for, 1904-1905 bioflavonoids for, 1903,1906 definition of, 1901 diagnostic summary for, 1901

Menorrhagia-cont ‘d dietary considerations, 1905-1906 essential fatty acids for, 1904 etiology of, 1901-1902,1902t natural hormones for, 1905-1906 prostaglandin metabolism abnormalities and, 1902 thyroid abnormalities and, 1902 treatment of, 1902-1906 uterine tonics for, 1905 vitamin A for, 1903 vitamin B complex for, 1904 vitamin C for, 1903,1906 vitamin E for, 1903-1904,1906 vitamin K for, 1904 Vitex agnus castus for, 1904,1906 Zingiber oficinale for, 1904 Menstrual blood loss estimating of, 1902 iron deficiency secondary to, 1903 Menstrual cycle, 1901 Menstruation, 371 Menstrums, 711 Mental attitude, positive cardiovascular health and, 112 description of, 111 development of, 114 goal setting and, 114-115 health effects of, 111 self-actualization and, 112-114 Mental function Centella asiatica effects on, 832 Ginkgo biloba effects on, 979,981 Hypericum perforatum activity and, 1042 hypoglycemia effects on, 1784 phosphatidylserine effects on, 1164 vitamin BI2and, 1465 Mental health, 366 Mental state, 100-101 Mentha piperata (peppermint) chemical composition of, 1071,1072f clinical applications of, 1072-1073 dosage of, 1073 drug interactions with, 1074 folk use Of, 1071-1072 history Of, 1071-1072 pharmacology of, 1072 toxicology of, 1073 Mercury in dental amalgams, 595-596 excretion of, 600-601 exposure to assessment of, 265-266 central nervous system function affected by, 596 fecal analysis of, 270 hair analysis for, 271t health effects of, 596 hyperthyroidism and, 1772 retention assessments for, 267-268 fiber effects on, 601 glutathione production affected by, 595 sources of, 596t vapors, 595 Metal ions, 1135

Metal toxicity arsenic, 266 biliary excretion of, 270 cadmium, 267 combined effects of, 264 depression secondary to, 1431 description of, 263-264,594,597-598 environmental contamination from, 263 excretion, 270,600 exposure assessments blood analysis, 265-266 description of, 601 hair elemental analysis, 264-265,271t history-taking, 601 laboratory tests, 601 urinalysis, 266-267 urinary porphyrins. See Urinary POrphyrins fecal analysis of, 270-271 homeopathy for, 395 hypertension and, 1759 individual variability in susceptibility to, 264 kinetic models of, 265 lead detection of, 265-266 encephalopathy caused by, 345 health effects of, 595 history of, 594 porphyrins affected by, 302 sources of, 596t mercury. See Mercury mitochondrial disruption caused by, 598 nutritional factors for, 2004 oxidative injury caused by, 597-598 Parkinson’s disease and, 2001 retention assessments Ca-Na2-EDTA for, 267 description of, 267 DMFS for, 267-269,602,602b DMSA for, 269-270,604 nonpharmaceutical agents for, 270 seizures caused by, 1651 sperm affected by, 1870 Metalloenzyme, 711 Metallothioneins description of, 598,1095-1096 genetic polymorphisms for, 598-599 mercury conversion to, 600 variations in concentration of, 598-599 Metchnikoff, Elie, 1199 Methane, breath testing for in lactose intolerance, 259 in small intestinal bacterial overgrowth, 156 Methionine boron and, 786-787 description of, 610-611 Sadenosylmethionine manufactured from, 1235 Methotrexate, 56565,997,2095 Methoxy-substituted alkylglycerols, 715,716f Methylcobalamin Alzheimer’s disease treated with, 1469 description of, 612-613 metabolism abnormalities, 622 5,10-Methylenetetrahydrofolate reductase, 493

Methyl-guanidinoacetic acid, 617 2-Methylhippurate, 289t, 295 Methylmalonate, 289t, 292 Methylmalonic acid, 253 Methylmercury, 344

l-Methyl4-phenyl-l,2,3,6-tetrahydropyridine, 344,2001 Methyltetrahydrofolate, 611-612 Methyltetrahydrofolate reductase deficiency, 614 Methylxanthines, 1666 Metrorrhagia, 1901 Miasmas, 391 Micellization, 1385 Michigan Alcoholism Screening Test, 1450t Microbe-associated illness, 23 Microbial enzyme therapy celiac disease treated with, 1080-1081 clinical applications of, 1077-1081 food allergies treated with, 1081 history of, 1075 lactose intolerance treated with, 1078-1079 malabsorption treated with, 1077-1078 pharmacology of, 1076-1077 steatorrhea treated with, 1077-1078,1078t vascular disease treated with, 1079-1080, 1081t Microflora intestinal alcohol consumption effects on, 1455 atopic dermatitis and, 1527 description of, 169,173,1817 dietary fiber for maintenance of, 670,2081 kidney stones and, 1847 probiotics effect on, 2055 rheumatoid arthritis and, 2096-2097 vaginal, 2155-2156 Micronized diosmin, 2169-2170 Microtubule inhibitors, 557 Midwives demise of, 137-138 discrediting of, 130 outlawing of, 137 Miglitol, 1630 Migraine headaches acupuncture for, 1918,1920 analgesic-rebound, 1911-1912 auras associated with, 1907-1908 biofeedback for, 1918,1920 cervical manipulation for, 1918 classification of, 1907-1908,1908t diagnostic summary for, 1907 dietary amines and, 1914 dietary considerations for, 1919 drugs for preventing, 1912t ergotamine-rebound, 1912 essential fatty acids and, 1915 feverfew for, 1332 fish oils for, 958 food allergies and, 1913-1914,1919 functional medicine treatment of, 22 histamine and, 1407,1914 hormones for, 1917-1918 5-hydroxytryptophan for, 1029t, 1029-1030, 1914-1915

Index Migraine headachewont’d hypoglycemia and, 1914 magnesium deficiency and, 1915-1916 mechanism of action, 1910 melatonin for, 1917 neuronal disorder and, 1909 nutritional supplements for, 1914-1916 oligoantigenicdiet for, 1919 pain associated with, 1907 pathophysiology of, 1908-1910,1911f Petasides hybridus for, 1917,1920 physical medicine for, 1918,1920 platelet disorder and, 1909 prevalence of, 1907 prevention of, 1912t relaxation therapy for, 1918 riboflavin for, 1289,1915 Sadenosylmethionine for, 1238 serotonin deficiency syndrome and, 1909-1910 sex steroid hormones for, 1917-1918 sodium intake and, 1914 Tanacetum parthenium for, 1916-1917,1919 temporomandibular joint dysfunction syndrome and, 1918 transcutaneous electricalnerve stimulation for, 1918 treatment of, 1911-1920 triggers for, 1910b vasomotor instability and, 1908-1909 water intake and, 1407-1408 Zingiber oficimlis for, 1917,1919-1920 Milgram’s bilateral leg raising, 423 Mills Report, 75 Mind-body medicine, 520-521 Minerals boron effects on metabolism of, 785 calcium. See also Osteoporosis body status assessments of, 276,276t bone mineral density and, 1292 boron effects on metabolism of, 786-787 deficiency of, 282t description of, 282t in inflammatory bowel disease, 1821 dietary sources of, 258 erythrocyte membrane tests for, 276 functions of, 1291 gastric acid effects on, 1982 hair analysis for, 210 hypertension treated with, 1764 kidney stones and, 1848 osteoporosis and, 1292,1984-1986 parathyroid hormone effects on, 1979 premenstrual syndrome treated with, 2060 recommended intake of, 1292t serum levels of, 276 sugar consumption and, 1982 suggested optimum nutrient intake for, 1291-1292,1292t supplementation of, 1292 supplements description of, 1292 lead content in, 1985t trichomoniasis treated with, 2129 vitamin D and, 1282,1986

Minerals-cont’d Chromium acne vulgaris treated with, 1422 age-related decreases in, 210 atherosclerosisand, 1292-1293 body status assessments of, 276t, 276-277 depression treated with, 1435-1436,1442 diabetes mellitus treated with, 1626 glaucoma treated with, 1699 glucose levels affected by, 1787,1957 glucose tolerance factor and, 277,1293 hair analysis for, 210 physical performance and, 685-686 plasma levels of, 276-277 psoriasis treated with, 2082,2084 recommended daily allowance for, 1276 recommended intake of, 1293t, 1626,1957 safety of, 1293 suggested optimum nutrient intake for, 1292-1293,1293t urinary tests for, 277 weight loss using, 1957-1959 conditions and diseases tested for using, 209 copper body status assessments of, 276t, 277 boron effects on, 786 deficiency of, 1294 description of, 1293-1294 fructose consumption and, 1294 hair analysis for, 210,277 health effects of, 1293-1294 in human immunodeficiencyvirus, 17391, recommended intake of, 1294t rheumatoid arthritis treated with, 2101 suggested optimum nutrient intake for, 1293-1294,1294t disease and, 275-276 drug abuse applicationsof, 211 experimental nature of, 212 factors that affect, 212 fructooligosaccharidesand enhanced absorption of, 1186 hair analysis Of, 209-211,275 iodine deficiency of, 1294 description of, 1294 hypothyroidism and, 1792 fibrocystic breast disease treated with, 1667 recommended daily allowance for, 12941295 recommended intake of, 1295t suggested optimum nutrient intake for, 12941295,1299 thyroid functions and, 1294 vaginitis treated with, 2162 iron. See Iron lithium, 211 magnesium alcoholism treated with, 1456 assessment of, 24,276t, 277-278 asthma treated with, 1492-1493,1495 body status assessments of, 276t, 277-278 boron interactions with, 786 cardiovascular system functioning and, 1518

Minerals-cont’d magnesium+ont ’d chronic fatigue syndrome treated with, 1587 congestive heart failure treated with, 1592-1593,1595 deficiency of, 1296 in alcoholism, 1454 in angina pectoris, 1477 in attention deficit hyperactivity disorder, 1536 description of, 1296 in inflammatory bowel disease, 1820-1821 migraine headaches and, 1915-1916 premenstrual syndrome secondary to, 2059-2060 diabetes mellitus treated with, 1628 epilepsy and, 1654-1655 erythrocyte membrane tests for, 278 food sources of, 1518 forms of, 1764 functions Of, 1295-1296 glaucoma treated with, 1699 hair analysis for, 210 in human immunodeficiencyvirus, 1739b hypertension treated with, 1763-1764 hypomagnesemia, 1296 mitral valve prolapse and, 1916 myocardial infarction treated with, 1477 orotate and, 294 osteoporosis prevention and, 1986-1987 recommended intake of, 1296t, 1628 retention test for, 277-278 serum levels of, 278 suggested optimum nutrient intake for, 12941295 toxic chemical metabolism affected by, 349 trichomoniasis treated with, 2129 vitamin B6 and, 2059 malabsorption of, from dietary fiber, 674 manganese body status assessments of, 276t, 278 diabetes mellitus treated with, 1628-1629 dietary sources of, 1296 epilepsy and, 1655 hair analysis for, 210 neurotoxicity caused by, 344 recommended intake of, 1297t rheumatoid arthritis treated with, 2100-2101 suggested optimum nutrient intake for, 1296 phosphorus boron effects on, 786 deficiency of, 1296 recommended intake of, 1297t suggested optimum nutrient intake for, 1296 potassium Aloe Vera effects on, 746 blood p r e ~ s ~and, r e 1297-1298 body status assessments of, 276t, 278 cardiovascular system functioning and, 1518

Index Minerakont'd potassium-cont'd descriptionof, 1297 fasting-related changes in, 540 hair analysis for, 211 hypertension treated with, 1762-1763 inflammatory bowel disease and, 1821 recommended intake of, 1298t suggested optimum nutrient intake for, 1297-1298 ratios, 211-212 research uses of, 209 Selenium acne vulgaris treated with, 1423-1424 alcohol effects on, 1299,1453 alcoholism treated with, 1456 anxiety treated with, 1298-1299 asthma and, 1492,1496 body status assessments of, 276t, 278 cancer and, 1298 cataract prevention and, 2119 cervical dysplasia and, 1575-1576 cisplatin and, for cancer, 564 coronary artery disease and, 1515 deficiency of, 1299 depression treated with, 1435,1442 description of, 1298 elderly use of, 1299 endometriosistreated with, 1646 glutathione peroxidases and, 1089-1090, 1423 hair analysis for, 211 hepatitis treated with, 1717 in human immunodeficiency virus, 17391, hyperthyroidism treated with, 1775 immune function affected by, 650 multiple sclerosis treated with, 1932,1935 periodontal disease treated with, 2034,2036 recommended intake of, 1299,1300t reproductive uses of, 1299 rheumatoid arthritis treated with, 2100 seizures treated with, 1655 suggested optimum nutrient intake for, 1298-1299 thyroid hormones and, 1795 toxic chemical metabolism affected by, 349 vitamin C and, 1299 vitamin E and, 1513,1515,2119 sodium dietary intake of, 540,1300 Fantus test for, 185-186 fasting-related changes in, 540 fish oils' effect on excretion of, 951 hair analysis for, 211 hypertension and, 1300,1762-1763 recommended intake of, 1300t suggested optimum nutrient intake for, 1300 suggested optimum nutrient intake for, 1290-1303 toxic metal exposure assessments, 264-265, 271t

Minerals-cont'd vanadium description of, 1300-1301 diabetes mellitus and, 686,1301 forms of, 1301 recommended intake of, 1301 sports nutrition uses of, 686-687 suggested optimum nutrient intake for, 1300-1301 zinc. See Zinc Minnesota Multiphasic Personality Inventory, 111 Mistletoe. See Viscum album Mistletoe lectin I, 1376-1377 Mitral valve prolapse, 865 Mixed function oxidase, 347-348 Model validity, 118 Modern medicine ApNeda and, 324325 historical origins of, 4 5 Modified citrus pectin, 555 Molecular medicine, 18 Molluscum contagiosum, 479-480 Momordica charanfin diabetes mellitus treated with, 1631-1632 human immunodeficiency virus treated with, 174% Monoamine oxidase inhibitor 5-hydroxytryptophanand, 1025,1025t Hypericum perforutum and, 1039-1040,1045 Monoamine oxidase-A, 488 Monoclonal antibodies, 224226 Monocytes assessment of, 228-230 bacterial phagocytosis by, 228-229 description of, 718 hydrogen peroxide released from, 229-230 oxidative burst in, 229-230 phagocytosisby, 228-229,718 Monopolar direct current technique, for hemorrhoids, 2072 Monosaccharides, 168 Monounsaturated fatty acids formation of, 938f palmitoleic acid, 190t, 194 profiling of, 190t, 193-194 vaccenic acid, 19Ot, 193-194 Morbid symptoms, 83 Morphogenetic field, 90 Morton, Henry, 1152 Morus indica, 1630-1631 Motherwort. See Leonorus Motion sickness, 1414-1416 Mouth anatomy of, 166 health of, 281 oral membrane abnormalities, 281-282,282t MPTP. See l-Methyl4phenyl-l,2,3,6tetrahydropyridine Mucilages, 668 Mucins, 1817 Mucolytics, 1546 Mucuna puriens, 2008,2011 Mukul myrrh tree.See Contmiphora mukul Multiple chemical sensitivity, 339,2048

Multiple organ dysfunction syndrome, 995-996 Multiple sclerosis allopathic treatments for, 1929 alpha-lipoic acid for, 1933 antioxidants for, 1932 autoantigens and, 1927-1928 cognitive dysfunction in, 1933-1934 definition of, 1925 demyelination in, 1928 depression in, 1931 diagnosis of, 1929 diagnostic summary for, 1925 diet therapy for omega-3 fatty acids, 1930-1931 omega-6 fatty acids, 1931 Swank diet, 1929-1930,1935 dietary influences, 1928-1929 environmental factors, 1928-1929 epidemiology of, 1926 etiology of, 1928-1929 evening primrose oil for, 1932 exercise for, 19341935 fish oils for, 1931-1932,1935 food allergies and, 1934-1935 free radical injury in, 1927 genetic factors, 1928 Ginkgo biloba for, 1933-1934 high-fat diet and, 1930 hyperbaric oxygen for, 1935 malabsorption in, 1935 matrix metalloproteinasesand, 1931 melatonin activity and, 1061 natural medicine treatment for, 1929 pathogenesis of, 1926-1928 pathology of, 1925,1926f primary progressive, 1926 relapsing-remitting, 19251926 secondary progressive, 1926 selenium for, 1932,1935 stress and, 1934-1935 symptoms of, 1926t tissue damage in, 1927 viruses associated with, 1927-1928 vitamin B12deficiency and, 1933 vitamin C for, 1932 vitamin E for, 1932,1935 Muscle(s) acute injury of, 371 cold therapy effects on, 404 creatine effects on, 678-679 flexibility of, 358,360-361 physiology of, 356,357f postural, 510,511f psychogenic influences on, 511-512 stretching of, 360-361 Muscle energy technique induration technique, 510,510f joints and, 507,508t Nimmo's receptor tonus technique, 510 postisometric relaxation, 507 reciprocal inhibition, 507 research of, 507 slow eccentric isotonic stretch, 507 trigger points treated with, 507-508, 509t, 510

Index Muscle energy technique-cont’d variations of, 507,507f zones of irritation, 510,514t Muscle spasm, 417 Muscle stretch reflexes, 421,421t Muscular dystrophies camitine for, 817 coenzyme Qlofor, 862-863 Muscular end-feel, 425 Muscular endurance, 358 Muscular strength description of, 358 grading of, 421t Mushroom extracts, 562-563 Mycoplasma hominis, 2016-2017 Mycoplasmal pneumonia, 2042 Myelin basic protein, 621 Myelinopathies, 345 Myocardial infarction aspirin prophylaxis, 1518-1520 camitine benefits for recovery after, 813 dietary considerations to prevent, 1519-1520 fish oils’ effect on survival after, 951-953 magnesium for, 1477 magnesium therapy for, 1518 recurrent, 1518-1520 Myofascial pain conditioning therapy for, 103-104 psychosomatic component of, 429 Myofascial trigger points, 506 Myopathy, 479 Myotonic dystrophy, 902 Myringotomy, 1991-1992 Myristoleic acid, 190t, 194 N N-acetylcysteine, 567,1094,1546 N-acetyl-D-glucosamine,247 N-acetyl-beta-D-glucosaminidase,267 N-acety lglucosamine absorption of, 988 glucosamine sulfate vs., 987-988 N-acetyl-L-cysteine, 270 Nail infections, 1055-1056 Naproxen, 1237,1968 Naringin, 972 National Center of Complementary and Alternative Medicine, 310 National Certification Commission for Acupuncture and Oriental Medicine, 9-10 National Chiropractic Association, 71 National Coalition on Immune System Disorders, 222 National College of Naturopathic Medicine, 72 Native extracts, 711 Natural killer cells activity of assays for, 234 buffered vitamin C effects on, 236 apoptosis of, 149 biologic response modifiers and, 235 CD16 for determination of, 226 CD56 for determination of, 226

Natural killer cells-ont’d characteristics of, 233-234 chronic fatigue syndrome and, 1581 cytotoxicity of, 233-236 in diseases, 234-236 fat intake effects on, 957 hematologic malignancies and, 235 immunocompetence of, 233 lifestyle practices that affect, 647,647b malignancy and, 234-235 negative emotions’ effect on, 112 personality types and, 112 protein kinase C and, 236 in viral disease, 235-236 Natural medicine “body, mind, spirit” leitmotif of, 120 definition of, 117 description of, 85-86 multiple sclerosis treated with, 1929 practices and procedures classified as, 117 principles of, 117 research in animal studies, 124-125 basic science studies, 124-125 clinical trials. See Clinical trials communication about, 119 observational studies, 123-124 problems and strategies, 118-125 program criteria, 125 purpose Of, 117-118 replicability of, 118 tools for, 118 Natural selection, 490 Natural therapies description of, 86 standardization of, 119-120 Naturally occurring antioxidants adequacy of, 1100-1101 body‘s production of, 1093-1096 botanical extracts, 1096-1097 cell function regulation by, 1099 comparison of, 1098-1099 defenses of, 1088t enzymes, 1088-1090 free radicals, 1085-1087 guidelines for use of, 1101 inflammation treated with, 1087-1088 nonnutrient oxidants, 1096 nutrients, 1090-1093 precautions in use of, 1011-1102 reactive oxygen species, 1086f, 1086-1087 selection criteria for, 1102-1103,1103t Naturopathic medicine ABO polymorphisms affected by, 456t American Association of Naturopathic Physicians, 30 American influences, 55-57 in Canada, 75 cancer treated with, 554 concepts of, 38 conflicts in, 37 decline in, 27-28,71-73 definition of, 29,38 description of, 8,18,419 development of, 67-76 education in, 69-71

Naturopathic medicin-ont’d emergence of, 67-69 founding of, 48-58 Germanic influences, 53-55 Halcyon’s contributions, 58-60 history of overview of, 41-42 twenty-first century, 74-75 illness as process, 32-34 mechanism in, 80-82 modalities of, 8Ob modem rejuvenation of, 61-63 philosophy Of, 13,28-29,31,79-87 principles of, 14,18 rejuvenation of, 61-63,73-74 scholarship in, 75-76 sch00ls Of, 69-71 theory of description of, 31-32,38-39 modem, 29-31 original, 28-29 training in, 13 in twenty-first century, 74-75 uniqueness of, 32 in United States, 9,27-28 vital force principles in, 14 word origin of, 41 Naturopathic nutrition, 32b Naturopathic physicians family practice by, 86 health determinants by, 34,34b medicines used by, 85-86 specialty practice by, 86 therapies used by, 86 Naturopathic Society of America, 49-50 Nausea and vomiting of pregnancy acupressure for, 1943 acupuncture for, 1943 description of, 1415-1416 homeopathy for, 1943 5-hydroxytryptophan, 1024,1032 incidence of, 1941 lifestyle recommendations, 1943-1944 nutritional considerations, 1942, 1944 psychologic aspects of, 1941-1942 Rubus idaeus for, 1942-1943 vitamin 86 for, 1942 vitamin C for, 1942 vitamin K for, 1942 Zingiber oficinale for, 1415-1416, 1942 N-butyrate, 171 Necrotizing fasciitis, 742 Negative thinking, 101-102 Neisseria gonorrhoeae ABO polymorphisms and, 452t pelvic inflammatory disease caused by, 2016 vaginitis caused by, 2159 Neoplasms, 420 Nephrolithiasis, 1848 Nephrotic syndrome, 953-954 Nerve root tension signs, 421 Nervonic acid, 19Ot, 194 Neural tube defects, 620,1287,1805 Neurofeedback, 1539 Neurofibrillary tangles, 1460

Neurologic lesions, 420-421 Neuromodulator, 1372 Neuromuscular disease, 365 Neuromuscular technique, 514 Neuronopathies,344 Neuropathic pain, 1622 Neuropathy diabetic, 1622,1628,1633-1635,1638 peripheral, 1742-1743 Neurotransmitters citicoline effects on, 855 description of, 97 Neutral bath, 411-412 Neutral lipids, 714 Neutral sitz bath, 412 Neutrophils, 200 Niacin assessment of, 251 atorvastatin vs., 1510 cholesterol reductions using, 1509-1513, 1634 deficiency of, 282t description of, 1288 diabetes mellitus treated with, 1627-1628 dosage of, 1511 gout and, 1707 inositol hexaniacinate, 1511 lovastatin vs., 1510,151Ot recommended intake of, 1288t side effects of, 139Ot, 1392,1511 statins and, comparisonsbetween, 1510 suggested optimum nutrient intake for, 1288,1288t toxic chemical metabolism and, 348 toxicity of, 1390t, 1392 Niacinamide description of, 139Ot, 1392 osteoarthritis treated with, 1967,1972 rheumatoid arthritis treated with, 1967, 2101 type I diabetes mellitus treated with, 1612-1613,1627-1628 Nichols, Mary Gove, 136 Nichols, Thomas, 135-136 Nickel, 271t Nicotinamide, 1288 Nicotinamide adenine dinucleotide chronic fatigue syndrome treated with, 1587-1588 description of, 1451 Parkinson’s disease treated with, 2007 Nicotinamide adenine dinucleotide phosphate, 348 Nicotinic acid, 1288 Nijmegan questionnaire, 637438,638f Nimmo’s receptor tonus technique, 510 Nitrates desaiption of, 1599b type I diabetes mellitus and, 1612 Nitric oxide arginine and, 1765 as free radical, 1085-1087 macrophage production of, 230 Nitrites, 15991, Nitrosamines, 468 Nocebo effects, 92,92t

Nocturnal myoclonus, 1833 Nonadecanoic acid, 191t, 195 Noncellulose polysaccharides, 667 Nonheme iron, 1295 Non-Hodgkin’s lymphoma, 343 Nonketotic hyperosmolar hyperglycemia, 1622 Nonnucleotide reverse transcriptase inhibitors, 1736 Non-REM sleep, 1830 Nonsteroidal a natory drugs curcumin similarities to, 897 enteropathy, 244 glucosaminesulfate vs., 988 intestinal permeability affected by, 244-245 osteoarthritis treated with, 1963 peptic ulcers and, 2026 rheumatoid arthritis treated with, 2093-2094 urticaria caused by, 2137 Nonulcer dyspepsia, 1072-1073 Noradrenergic noncholinergic system, 639 Norepinephrine, 1673 Norwalk virus ABO polymorphisms and, 452t diarrhea caused by, 1802 foodborne illness caused by, 471 Nosocomial infection, 1155-1156 Nuclear factor-kappa B activation of, 237 antioxidants and, 1099 in Crohn’s disease, 171 dehydroepiandrosteroneeffects on, 2091 Nucleotide reverse transcriptase inhibitors, 1735-1736 Nutraceuticals,36,1540 Nutrient intakes Birmingham study, 1278 guideline for, 1277 optimum development of, 1277-1279 suggested. See Suggested optimum nutrient intakes Nutrigenomics clinical application of, 491-494 description of, 490-491 nutrients as viewed by, 490-491 Nutrition alcoholism effects on, 1452 Basic Four Food Groups model of, 463-464 depression and, 1433-1436 for detoxification, 603 evolutionary aspects of, 461-463 food consumption pattems in United States, 463,464t, 666,667t nausea and vomiting of pregnancy and, 1942 Optimal Health Food Pyramid of, 465-471 recommendationsfor animal products, 468 blood sugar control, 467-468 fat intake, 468-469 food additives, 470 foodborne iUness prevention, 470-471 fruits,465-466 meat, 468

Nutrition-ont’d recommendations for-cont’d pesticide exposure limitations, 466-467 salt intake, 469-470 vegetables, 465-466 water intake, 471 Nutrition education Eating Right Pyramid, 464,464f government’s role in, 463-464 Optimal Health Food Pyramid, 465-471 Nutritional medicine, 461 Nutritional supplementation, 471-472 Nuts for atherosclerosis, 1507-1508 for dietary fat reductions,2057 for type II diabetes mellitus prevention, 1616

0 0 blood group description of, 444-445 heart disease and, 448 Obermeyer test, 305-306 Obesity adipokine and, 1951 appetite regulation, 1951-1952 behavioral therapy for, 1954 body composition determinations, 1948-1949 body mass index and, 1947 caloric intake and, 1953-1954 childhood, 1950 definition of, 1947 dietary strategies for, 1954-1955 diet-induced thermogenesisand, 1952-1953 exercise training to prevent, 362-363 fasting for, 535 fiber and, 671,673 gallstones and, 1689 glucosamine sulfate dosing and, 991 hyperplastic, 1950 hypertrophic, 1950 immune function affected by, 648 low-fiber diet and, 671 mortality risks and, 1948 physical inactivity as cause of, 362 physiologic factors of, 1950-1951 prevalence of, 1948 psychologic factors of, 1950,1959 serotonin levels and, 1953 ”set point,” 1951 sleep apnea and, 1830 television viewing and, 1950 treatment of, 1953-1959 type II diabetes mellitus and, 1613-1614 types of, 1950 weight loss methods chromium, 1957-1958 fiber supplements, 1956-1957,1957t hydroxycitrate, 1958-1959 5-hydroxytryptophan, 1955-1956,1959 meal replacement formulas, 1956 medium-chain triglycerides, 1958 Observation, 123-124 Observational studies, 123-124 Obsessive compulsive disorder, 1025

Index Obstructive sleep apnea, 1830 Octasanol.See Policosanol Odd-numbered fatty acids, 191t, 195

oils fish. See Fish oils male infertility and, 1871 oxidation prevention, 960-961 rancidity of, 960 Oleic acid, 190t, 194,935 Oleoresins, 711 Olestra, 603 Oligoantigenic diet, 205-206, ZMt, 588,1820 Oligofructose, 1185-1186,1186f Oligomenorrhea,1901 Oligomeric proanthocyanidins, 1097-1098 Oligosaccharides,1209 Oligospermia, 1865,1868 0-linked glycans, 443-444 Olive oil, 469,948,1507,1691-1692 Omega-3 fatty acids alpha-linolenicacid, 190t, 191,192t antiinflammatoryeffects of, 949 asthma and, 1490 atherosclerosisand, 1507 atopic dermatitis treated with, 1528 bipolar depression treated with, 1443 breast cancer prevention and, 948 coronary heart disease and, 942,946 Crohn’s disease and, 1815 deficiency of, 948 depression and, 1436 diabetes mellitus treated with, 1629 dietary requirements, 946-948 docosahexanoic acid. See Docosahexanoic acid eicosapentaenoicacid. See Eicosapentaenoic acid gastrointestinal mucosal inflammation prevented by, 247 hypertension treated with, 1765 immune function affected by, 953 multiple sclerosis treated with, 1930-1931 omega-6 fatty acid ratio to, 946 osteoarthritis treated with, 1972 oxidation affected by, 959 during pregnancy, 953 profiling of, 190t, 191-192 psoriasis and, 2082 rheumatoid arthritis and, 954,2098-2100 in Swank diet, 1930 type I diabetes mellitus and, 1612 Omega-6 fatty acids docosadienoicacid, 19Ot, 193 docosatetraenoicacid, 19Ot, 193 gastrointestinal mucosal inflammation prevented by, 247 linoleic acid, 19Ot, 192-193,938 mead acid, 190t, 193 multiple sclerosis treated with, 1931 omega-3 fatty acid ratio to, 946 profiling of, 190t, 192-193 One repetition maximum, 358 Onion. See Allium cepa Onion oil, 726 1-0-Pentylglycerol,721 Operant conditioning, 102

Opsonin, 718 Optimal Health Food Pyramid, 465-471 Optimism, learned, 114-115 Opuntia sp. analgesic effect of, 1114 antiinflammatory effect of, 1114 antiviral effect of, 1114 chemical composition of, 1113 cicatrizant effect of, 1114 clinical applications of, 1115 diabetes treated with, 1115 dosage of, 1116 drug interactions of, 1116 folk u ~ Of, e 1113-1114 history Of, 1113-1114 hyperlipidemia treated with, 1115 hypocholesterolemiceffects of, 1115 hypoglycemiceffect of, 1114-1115 pharmacology of, 1114-115 prostatic hyperplasia treated with, 1115 rend effects of, 1114 toxicology of, 1116 weight loss treated with, 1115 Oral candidiasis, 1055 Oral contraceptives cervical cancer and, 1573 cervical dysplasia and, 1573,2035 Hypericum perforatum and, 1045 migraine headaches and, 1917 pelvic inflammatory disease prevention and, 2021 Oral membrane abnormalities, 281-282,282t Oregon grape. See Berberis aquifolium Orexin A, 1952 Organic acids, 286-287 Organic solvents, 594 Organochlorine compounds estrogenic effects of, 346 immunotoxicityeffects of, 341-342 neurotoxicity effects of, 344 Organohalogens,594 Organoleptic,335 Organon of Medicine, 389,392-393 Organophosphatepesticides description of, 594 immunotoxicityeffects of, 342 neurotoxicity effects of, 344 Ornithine, 683 Omithine alpha-ketoglutarate, 685 Oropharyngeal mucositis,996-997,999 Orotate, 289t, 294-295 Osmosis, 1402 Osmotic pressure, 1402 Osteoarthritis acupuncture for, 1970,1972 antioxidants for, 1965 aspirin for, 1963 boron deficiency and, 787-788 Boswellia serrata for, 1971-1972 capsaicin for, 805 Capsicumfitescens for, 805 characteristicsof, 1961 chondroitin sulfate for, 1966-1967 Commiphora mukul for, 879 course of, 1963 cyclooxygenase-2 inhibitors for, 1963-1964

Osteoarthritis-ont’d diabetes mellitus and, 1964 diagnosis of, 1962 dietary considerationsfor, 1964-1965,1972 differential diagnosis, 1962s 19631, electroacupuncturefor, 1970 estrogen and, 1964 etiology of, 1962t exercise for, 1964-1965,1970,1972 glucosamine sulfate for, 988-991,1965-1966, 1972 growth hormone and, 1964 Harpagophytum procumbens for, 1971-1972 hormonal therapies for, 1964 hypothyroidism and, 1964 incidence of, 1961 magnetic therapies for, 1970-1971 niacinamide for, 1967,1972 nonsteroidal antiinflammatory drugs for, 1963 nutritional supplements for, 1965-1969 omega-3 fatty acids for, 1972 pain associated with relaxation techniques for, 1971 transcutaneous electrical nerve stimulation for, 1970 pantothenic acid for, 1969 physical therapies for, 1969-1972 primary, 1961 rheumatoid arthritis vs., 1962 Sadenosylmethionine for, 1236-1238, 1967-1968 secondary to, 1961-1962 s i p and symptoms of, 1961 sodium hyaluronate for, 1963 superoxide dismutase for, 1968 treatment of, 1962-1972 vitamin C for, 1968-1969,1972 vitamin D for, 1969 vitamin E for, 1968,1972 yucca for, 1971 Zingiber oficcinale for, 14151416,1971-1972 Osteogenesisimperfecta, 825 Osteopathy asthma treated with, 641-642 chronic asthma treated with, 641-642 description of, 419,515 hyperventilationsyndrome/breathing pattern disorders care protocol, 641 Osteopenia, 1977 Osteoporosis. See also Calcium alcohol consumption and, 1978 bisphosphonatesfor, 1981 bone metabolism tests, 1980-1981 bone mineral density tests, 1980 characteristicsof, 1977 definition of, 1977 dehydroepiandrosteronedeficiency and, 901-902 diagnosis of, 1979-1981 dietary factors, 1982 dual energy x-ray absorptiometrytest for, 1980 exercise for, 1981 exercise-induced amenorrhea and, 371 fluoride and, 1987

Osteoporosis--cont’d genetic factors, 1978 homocystinuria and, correlation between, 623 hormonal factors, 1978-1979 hormone replacement therapy for, 1879, 1981 lifestyle considerations, 1978,1982, 1988 menopause and, 1978-1979 nutritional supplementsfor, 1984-1988 pathophysiology of, 1977-1978 in postmenopausal women, 1987-1988 prevalence of, 1977 prevention of boron for, 787,1983 calcium for, 1292,19841986 Cimicijiga racemosa for, 850 green leafy vegetables, 1983 ipriflavone for, 1987-1988 magnesium for, 1986-1987 vitamin D for, 1282,1391,1986 vitamin K for, 1284 rheumatoid arthritis and, 903 risk factors for, 1978-1979 smoking and, 1978 soft drink consumption and, 1982-1983 soy foods and, 1983-1984 soy isoflavones for, 1270 treatment of, 1981-1988 vitamin B6 for, 1987 vitamin BI2for, 1987 vitamin K and, 1983 Otitis media acute, 1991 bottle-feeding and, 1993 causes of, 1993 chronic, 1991 dietary considerationsfor, 1996 ear drops for, 19941996 Echinacea spp. for, 1996 food allergies and, 1993-1994 heat therapy for, 1996 homeopathy for, 1995 humidifiers for, 1995 naturopathic ear drops for, 19941996 nutritional supplements for, 1996 risk factors for, 1993 Self-hited MhUV Of, 1992 thymus gland extract for, 1994 treatment of antibiotics, 1992 approach for, 1995-1996 medical, 1991-1993 myringotomy, 1991-1992 nonpharmacologic, 1993-1996 xylitol for, 1995-1996 Ototoxicity, 982 Outcomes for clinical trials, 122-123 prayer benefits for, 526 Outcomes research, 124 Ovarian cancer, 1884-1885 “Oxidation hypothesis,” 1090-1091 Oxidative burst, 229-230 Oxidative damage, 1086t, 1283

Oxidative stress antioxidant defenses and, 1087-1088,1088t Camellia sinensis effects on, 2008 cirrhotic liver disease and, 1717 citicoline effects on, 857 description of, 237 diabetes mellitus and, 1623-1624,1632 Parkinson’s disease and, 2001-2002 prevention of, 1632 vitamin C as marker for, 1092 Oxihumate, 480 Oxiliplatin, 564 Oxygen delivery, 633 Oxygen radical absorbance capacity, 1219 Oxygen trwprt, 1403-1404 Oxygen-free radicals, 149 Oxyhemoglobin, 633 Oxyntomodulin, 1952 Ozone therapy, 2050

P p53 protein, 147 Pacific yew. See Taxus brevfilia Paclitaxel, 565,1339-1343 Pain acceptance of, 101 childbirth-related acupuncture for, 436-437 attention-focusingtechniques for, 434 cultural influences on, 433 description of, 431-433 transcutaneouselectrical nerve stimulation for, 435436 chronic, 364-365 description of, 431 end-range, 423 gate control theory of, 432 during labor, 128 low back, 365 migraine headache, 1907 during motion, 423 myofascial conditioning therapy for, 103-104 psychosomatic component of, 429 neuropathic, 1622 neuropsychological mechanisms of, 432 postmastectomy, 804-805 psychological model of, 431-432 psychosomatic component of, 429 reactions to, 431 subjective nature of, 431 Pain control acupuncture for, 436-438 attention-focusingtechniques for, 434 biofeedback for, 438 botanical agents for, 438 capsaicin for, 803,894 Capsicum frutescens for, 803 cognitive strategies for, 433-434 counterstimulus methods for, 434-438 distraction techniques for, 434 exercise training for, 364-365 hypnosis for, 434 massage for, 438 meditation for, 434 modalities for, 104

Pain control-cont’d multidisciplinary approach to, 438 psychological strategies for, 433 relaxation training for, 434 stress management for, 434 transcutaneous electrical nerve stimulation for, 435-436 Palliation, 82b,553 Palm oil carotenes, 775 Palmer, B.J.,419 Palmer, Daniel David, 48,419 Palmitelaidic acid, 191t. 195 Palmitic acid, 19&, 194,938 Palmitoleic acid, 19Ot, 194 Panax ginseng (Korean ginseng). See also Ginseng adaptogenic activity of, 1121-1122 animal studies of, 688 antiaging effects of, 1124-1125 anticancer properties of, 1125 antifatigue activity of, 1121-1122 antioxidant effects of, 1124-1125 antistress activity of, 1122-1123 Bupleurum falcatum and, 2103,2105 cardiovasculareffects of, 1125-1126 cell-proliferatingeffects of, 11241125 chemical composition of, 1119-1120,1120f clinical applications, 1120-1126,1121t cognitive performance and, 1122 description of, 330,687-688 diabetes mellitus treated with, 1123-1124, 1632 dosage of, 688,1126-1127 drug interactions with, 1127 as ergogenic aid, 1123 folk use of, 1120,1121t hepatic effects of, 1126 history of, 1120 immune system affected by, 651-652 immunomodulatingeffects of, 1125 male infertility treated with, 1872-1873 menopause treated with, 1124,1894 pharmacology of, 1120-1126 radiation protection with, 1126 reproductive effects of, 1124 stress management uses of, 707 toxicity of, 688-689 toxicology of, 1126 Panax quinqwfolium, 1123-1124,1632 Pancreas alpha cells of, 1781 beta cells of, 1781 age-related declines in, 171 e T e s Artemisia absinthium effects on, 756 for nutritional support during chemotherapy,563 supplements, 663 exocrine insufficiency, 168,169f extracts from, 379t, 380 insufficiency of, 663 Pancreatic cancer docosahexanoic acid for, 957 eicosapentaenoicacid for, 957 weight loss associated with, 957 Pancreatic elastase 1,170-171

Index Pancreatic enzymes absorption of, 1133-1136,1135t activity of, 1134-1136,1135t autoimmune/immune complex-mediated diseases treated with, 1139 bacterial disorders treated with, 1139 cancer treated with, 1138-1139 cardiovascular disorders treated with, 1139 celiac disease treated with, 1565 clinical applications of, 1136-1139,1137t dosage for, 1139-1140,114Ot extraction processes for, 1132-1133 history Of, 1131-1132 inflammatorydiseases treated with, 1138 injectable form of, 1141 measurement of activity, 1136 protein absorption and, 1133-1134 recycling of, 1076-1077 supplements from, 1132 topical application of, 1141 toxicology Of, 1140-1141 uterine fibroids treated with, 2150 viral disorders treated with, 1139 Pancreatin clinical applications of, 1137t description of, 663 extraction of, 1133 fungal lipase compared with, 1077 as pancreatic enzyme, 1132 Pancreatitis,535,999 Panmlipase, 1133 Panic disorder, 1026-1027 Pantethine angina pectoris treated with, 1476,1479 cholesterol reductions using, 1512-1513 description of, 616 Pantotheine, 616f Pantothenic acid acne vulgaris treated with, 1423 description of, 251,616f, 707,139Ot osteoarthritis treated with, 1969 rheumatoid arthritis and, 2101 Pantothine, 616f Para-aminobenzoicacid, 1606 Paracelsus, 130,331,389 Parasitic infections Artemisia absinthium for, 757 Artemisia annua for, 762 diarrhea caused by, 1803-1804 propolis for, 768 Tabebuia avellanedae for, 13241325 Parasympathetic nervous system, 703 Par&Ambroise, 130 Parkinson’sdisease apoptosis in, 2000 botanical medicines for, 2008-2011 characteristicsof, 1999-2000 depression and, 2004 detoxification dysfunction and, 2002 diagnosis of, 2002-2003 diagnostic summary for, 1999 dietary considerationsfor, 2003-2004,2010 differential diagnosis, 2003 etiology of, 2000-2002 gene mutations associated with, ZOO0 genetics of, 2000

Parkinson’sdisea-ont’d glutathione deficiency and, 2001-2002 history of, 1999 homocysteine levels in, 2005 5-hydroxytryptophanfor, 1031-1032,1032t iron accumulation and, 2001 Lewy bodies associated with, 2002 lifestyle considerations, 2010 melatonin and, 2006-2007 metal toxicity and, 2001 nutritional considerations for, 2004-2008, 2010 oxidative stress and, 2001-2002 pesticide exposure and, 2000-2001 Piper methysticum and, 2008-2009 Sadenosylmethionine contraindications, 1239 smoking and, 2009 toxic exposures and, 2000-2001 treatment of acupuncture, 2010-2011 antioxidants, 2005 approach for, 2010-2011 B vitamins, 2005-2006 Camellia sinensis, 2008,2010-2011 coenzyme Qlo,860,2006 conventional, 2003-2004 creatine, 2007-2008 deep brain stimulation,2003 detoxification,2004 diet, 2003-2004 electromagneticfields, 2009 estrogen, 2009 folic acid, 2005-2006 Ginkgo biloba, 2008,2011 glutathione, 2005 homeopathy, 2009 5-hydroxyS.ptophan, 2004-2005 hypnosis, 2009 ketogenic diets, 2004 levodopa, 2003-2004 low-protein diet, 2004 Mucuna puriens, 2008,2011 nicotinamide adenine dinucleoside, 2007 tui na, 2010 vitamin E, 2005 Unified Parkinson’s Disease Rating Scale, 2002 Partial-immersionmedicinal peat bath, 484,484b Part/whole dualism, 15-16 Parvovirus, 1802 Passiflora incamata, 1834 Patent medicines, 837 Pathogenic agent definition of, 80 vitalism view of, 82 Pathogenic microorganisms fructooligosaccahridesand reduction of, 1185 lactulose and decreased growth of, 1189-1190 Pathology pharmacologic substances for, 38 suppression of, 38 therapeutic order approaches to, 37-38

Pattern recognition,25 Pau D’Arco. See Tabebuia avellanedae PCBs, 535,594,601602 Pe Min Kan Wan, 841t “Peak X compound, 1033 Peat therapeutics baths hyperthermic medicinal, 481-483 medicinal peat peloid, 483484 partial-immersion, 484,4841, circulatory benefits of, 478 clinical applications of, 479-481 history of, 477 hyperthermic effects of, 478-479,481-483 peat used in antirheumatic activity of, 478 sulfoglycolipids in, 478 variations in, 477 physiologic effects of, 478 skin response to, 477-478 Peloids definition of, 475 medicinal bath using, 483-484 Pelvic inflammatory disease anaerobes and, 2016 antibiotics for, 2020 bacterial organisms associated with, 2015-2016 beta-carotene for, 2020-2021 bromelain for, 2021 Chlamydia trachomatis, 2016 chlorophyll for, 2020,2022 complications of, 2017 C-reactive protein and, 2019 definition of, 2015 diagnosis of, 2018-2019 diagnostic summary for, 2015 diathermy for, 2020,2022 differential diagnosis, 2018b douching and, 2021-2022 ectopic pregnancy and, 2017 etiology of, 2015-2017 Hydrastis canadensis for, 2021-2022 infertility and, 2017 intrauterine device and, 2017,2021 laboratory diagnosis of, 2019 Mycuplasma hominis, 2016-2017 Neisseria gonorrhoeae, 2016 oral contraceptivesfor prevention of, 2021 pathogen access to upper female tract, 2017-2018 prevention of, 2021 risk factors for, 2017 sexual intercourse contraindications, 2022 signs and symptoms of, 2018,2018t sitz baths for, 2020,2022 smoking and, 2022 supplements for, 2022 Symphytum oficinale for, 2022 treatment of, 2019-2022 vaginal depletion pack for, 2021-2022 vaginitis and, 2155 vitamin C for, 2020,2022 vitamin E for, 2022 Pelvic torsion, 428 Penicillamine,20942095

Index Penicillin, 1153 Penicillin-related urticaria, 2137 Penis, 1867 Pentadecanoic acid, 191t, 195 Peppermint. See Mentha piperata Peppermint oil irritable bowel syndrome treated with, 1072 in Mentha piperata, 1071,1072f small intestinal bacterial overgrowth treated with, 157 Pepsin, 167 Pepsin A, 217 Pepsinogen, 167 Pepsinogen A, 446 Peptic ulcers Allium sativum for, 2029 Artemisia douglasiana for, 2029 aspirin and, 1519,2026 bismuth subcitrate for, 2027-2028 cabbage for, 2027 catechin for, 825,2027 diagnostic summary for, 2025 dietary fiber and, 2027 duodenal, 2025-2029 flavonoids for, 2027 food allergies and, 2027 formation of, 2025 gastric, 2025-2029 glutamine and, 998,1000 Glycyrrhiza glabra for, 2028 Helicobacterpyloti and, 2026 high-fiber diet for, 2027 lifestyle factors, 2026-2027 melatonin for, 2027 nonsteroidal antiinflammatory drugs and, 2026 plantain banana for, 2028 Rheum sp. for, 2028 smoking and, 2027 stress and, 2026 subclinical dehydration and, 1407 vitamin A for, 2027 vitamin E for, 2027 Zingiber oficinale for, 2028-2029 Peptide W 336,1951-1952 Perceived exertion rating of, 694 scale for, 359 Percutaneous transluminal coronary angioplasty, 1474 Perez-Otero, Enrique, 1152 Performance drinks,693-695 Periodontal disease alcohol and, 2033 amalgam restorations and, 2033 bacterial factors in, 2031 beta-carotene for, 2036 botanical medicines for, 2035-2036 Centella asiatica for, 2036 coenzyme Qlofor, 861-862,2035 complement system in, 2031 diagnostic s u m m a r y for, 2031 epidemiology of, 2031 flavonoids for, 2035 folic acid for, 2035-2036 leukocytes in, 2031

Periodontal disease-cont’d lymphocytes in, 2031 mast cell degranulation in, 2031-2033 pathophysiology of, 2031-2033 polymorphonuclear leukocytes in, 2031 prevalence of, 2031 Sanguinaria canadensis for, 2035-2036 selenium for, 2034,2036 smoking and, 2033 sucrose intake and, 2034 treatment of, 2033-2036 vitamin A deficiency and, 2034 vitamin C for, 2033-2034,2036 vitamin E for, 2034,2036 zinc for, 2034,2036 Periodontitis, 2031 Peripheral arterial disease ABO blood groups and, 448 Ginkgo biloba for, 982-983 Peripheral vascular disease camitine for, 814 exercise benefits for, 365 homocysteine and, 619-620 Peripheralization, 422 Pertussis vaccine, 1487 Pesticides Parkinson’s disease and, 2000-2001 pediatric exposure to, 466-467 Petasides hybridus, 1917,1920 PH carbon dioxide and, 633 oxyhemoglobin dissociation affected by, 633 Phage therapy advantages of, 1158 bacteriophage physiology and, 1149-1152, 1150f clinical application of, 1153-1158 commercialization of, 1148-1149 drug interactions with, 1159 future applications of, 1159-1160 history of, 1147-1149 immune system and, 1152-1153 lysogenic phages, 1151-1152 lytic phages and, 1150-1151,1151f properties of phages and, 1150 side effects of, 1159 specific problems with, 1149 toxicology of, 1158-1159 Phage typing, 1148-1149 PhagoBioDerm polymer, 1156 Phagocytosis assessment of, 228-229 complement’s role in, 717-718 by monocytes, 228-229,718 sugar consumption effects on, 647-648, 648f Phalen‘s sign, 1557-1558 Pharmaceutical industry, 332 Pharmacodynamics, 94 Pharmacognosy, 328 Pharmacokinetic studies of Hypericuni perforaturn, 1041 of melatonin, 1058 of phage therapy, 1152-1153 Pharyngitis, streptococcal, 2123-2125

Phase 2 detoxification description of, 599-600 homocysteine effects on, 618 Phenolics, 2152 Phenylacetate, 293-294 Phenylalanine, 1438,1439t Phenylethylamine, 1438 Phenylketonuria, 21 Phenylpropionate, 293-294 Phosphatidylcholine Alzheimer’s disease treated with, 1466 bipolar depression treated with, 1443-1444 in fetal development, 620 homocysteine effects on, 618 metabolism of, 614f Phosphatidylcholine-boundsilybin, 1254-1255 Phosphatidylserine Alzheimer‘s disease treated with, 1466, 1469,2007 clinical applications of, 1164 description of, 683 dosage of, 1164 drug interactions with, 1164 Parkinson’s disease treated with, 2007 pharmacology of, 1163-1164 physiologic role of, 1163 toxicology of, 1164 Phospholipase, 854 Phosphorus boron effects on, 786 deficiency of, 1296 recommended intake of, 1297t suggested optimum nutrient intake for, 1296 Photodynamic therapy, 1856-1857 Photoprotection beta-carotene for, 775 Camellia sinensis for, 800 Photosensitivity beta-carotene and, 778-779 Hypericum perforaturn, 1045 riboflavin and, 1290 Phrenology, 14 p-Hydroxybenzoate, 293-294 p-Hydroxyphenylacetate, 293-294 p-Hydroxyphenyllactate, 289t, 295 p-Hydroxyphenylpropionate, 293-294 Phyllanthus amarus hepatitis treated with, 1719-1720 human immunodeficiency virus treated with, 1745b Phylloquinone, 1284 Physical inactivity, 1505-1506 Physical therapy description of, 420 hyperventilation syndrome/breathing pattern disorders treated with, 640 Physiologic stress, 97 Phytates, 1262 Phytic acid, 669,669t Phytochemicals cell function and, 1099 cytochrome P-450 enzymes affected by, 599 description of, 466,466t Phytoequivalence, 336

Index Phytoestrogens Angelica spp. as, 750-751 antiestrogeniceffect of, 1265,2061 benign prostatic hyperplasia treated with, 1552 breast cancer treated with, 1267 definition of, 1870 flax seeds, 1892 frudooligosaccacharidesand improved bioavailability of, 1186-1187 in infants, 1263 menopause treated with, 1890-1892 sources of, 1893,1893t soy, 2151 uterine fibroids and, 2151-2152 Phytoplankton, 946 Phytostanols, 1511-1512 Phytosterols, 1262,1511-1512 Picrorhiza kurroa, 1096-1097 Pilonidal sinus, 2074-2075 "Pinch test, 1567,1568f Piper methysticum (kava) analgesic effects of, 1170 antiischemiaeffects of, 1170 anxiolytic effects of, 1170 chemical composition of, l167,1168f, 1168t clinical applications of, 1170-1171 depression treated with, 1441 dosage of, 1171 drug interactions of, 1172 folk US^ of, 1167-1168 history of, 1167-1168 isolated vs. crude kavalactone extracts, 1169-1170 Kava ceremony using, 1168-1169 liver damage caused by, 1720 Parkinson's disease and, 2008-2009 pharmacology of, 1169-1170 physiologicaleffects of, 1169 sedative effects of, 1170 side effects of, 1171-1172 toxicology of, 1171-1172 Piper rotundurn, 323 Pit, 320 Placebo active, 92t, 101 analgesia, 96 brain region activity and, 96 conditions that response to, 93t definition of, 91 double-blind research and, 93 ethical use of, 105-106 healing mechanisms, 9495 history of, 91 hope as, 101 inactive, 92t interactions, 94 "known," 92t, 92-93 literature regarding, 90-91 myths of, 93-94 overview of, 89-90 physician's role in stimulating,91 physiologic changes induced by, 93t "power of," 90 pure vs. impure, 106 reasons for studying, 90-91

Placebwont'd stress physiology and, 96-97 types of, 91,92b unknown, 92t word origin of, 91 Placebo burst, 104 Placebo effect conditioning to, 102 for depression, 520 description of, 95,520 doctor-patient relationship and, 99-100 hypnosis and, 104 physiologicmechanisms of, 95 Placebo response definition of, 90 delivery modes and, 94 emotions and, 95 mechanisms of, 95 patient expectation and, 94 principles for optimizing, 98b side effects of, 92b symptoms of, 92b therapeutic exercises to effect changes, 105 Placebo sag, 104 Plasmalogens alkylglycerols'effect on, 719 definition of, 713-714 Plasmids, 1157 Plasmodium spp., 959 Platelet(s) aggregation of Allium sativum for, 733 atherosclerosisrisks, 1516 bromelain effects on, 792 Coleusforskohlii effects on, 874 feverfew effects on, 1331 fish oils' effect on, 952 garlic effects on, 1516 smoking effects on, 1503 Vaccinium rnyrtillus effects on, 1367 vitamin B6 effects on, 1516 Zingiber oficinale effects on, 1413 Ginkgo biloba effects on, 977 migraine headaches and, 1909 Platelet-activatingfactor forskolin effects on, 872 Ginkgo biloba effects on, 977,1528 Plurifunctioning, 17 Pneumococcal pneumonia, 2042-2043 Pneumocystis carinii pneumonia, 1728 Pneumonia bottle blowing for, 2041 bromelain for, 2041 description of, 2039 Echinacea sp. for, 2041 etiology of, 2 M t expectorants for, 2040 Lobelia inflatu for, 2041 mycoplasmal, 2042 pneumococcal, 2042-2043 streptococcal, 2042-2043 treatment of, 2040-2041 viral, 2043 vitamin A for, 2040-2041 vitamin C for, 2040,2041 Podophyllum, 1808,2074

Poke Root, 1647 Policanol, 1177-1178 Po1icosano1 acipimox vs., 1176 angina pectoris treated with, 1178 antiplatelet effects of, 1177-1178 atorvastatin vs., 1175-1176 chemical composition of, 1173 cholesterolreductions using, 1512-1513 clinical applications of, 11741178 diabetes mellitus treated with, 1176,1177t double-blind comparative studies of, 1175f-l177f, 1175-1176 drug interactions with, 1179 in elderly patients, 1177 fibrates vs., 1176 folk use of, 1173 history of, 1173 hypercholesterolemiatreated with, 1176-1177,1177f hypertension treated with, 1176-1177 intermittent claudication treated with, 1178 lovastatin vs., 1175 pharmacology of, 1173-1174 pravastatin vs., 1176,1176f probucol vs., 1176,1177f simvastatin vs., 1176 tOxiCOlOgy Of, 1178-1179 Polish Academy of Science, 1154-1155 Pollen, 767-768 Polyacetylenes,909-910 Polychlorinated biphenyls, 339 Polycyclic aromatic hydrocarbons, 342 Polyerga, 381-383 Polymenorrhea, 1901 Polymerase chain reaction, 223 Polymorphisms apolipoprotein E, 492 definition of, 487-488 in genome, 489 natural selection and, 490 reasons for, 490 single nucleotide, 488 Polymorphonuclear leukocytes, 2031 Polymyalgia rheumatica, 182 Polyphenols, 466t, 1260f, 2008 Polysaccharide krestin, 562-563 Polysaccharides description of, 168 in Echinacea spp., 908-909,911 Polyunsaturated fatty acids, 939t, 939-940 Polyunsaturated-to-saturatedfatty acid ratio, 191t, 196 Poor metabolizers, 598 Porphobilinogen, 2047-2048 Porphyria cutanea tarda, 2047 Porphyrias antioxidants for, 2049-2050 biochemistry of, 2046-2047 carotenoids for, 2050b causes of, 303t classificationsof, 2045-2046 constitutional hydrotherapy for, 2050 description of, 299-300 detoxificationfor, 2050 diagnostic summary for, 2045

Index Porphyrias--cont'd dietary considerations for, 2049 drugs that exacerbate, 303t, 2050b etiologic agents, 2047-2048 heme synthesis and, 2047f hepatic, 2046,2046b herbicide-induced, 2048 history of, 2045 homeopathy for, 2049 iron for, 2050b laboratory diagnosis of, 2048-2049 manifestations of, 2047-2048 multiple chemical sensitivity syndrome and, 2048 oral glycyrrhizin and, 1007-1008 ozone therapy for, 2050 signs and symptoms of, 2046 treatment of, 2049-2051 Porphyrinogens, 300 Porphyrinopathies, 300-302,302t Porphyrins definition of, 299-300 lead exposure effects on, 302 metabolism of, 299-300

urinary

biomarker uses of, 299 clinical applications of, 302 heavy metal exposure detected using, 299 interpretation of, 304t technique for, 300,302 Porphyrinuria, 300 Positive emotions, 101 Positive mental attitude cardiovascular health and, 112 description of, 111 development of, 114 goal setting and, 114115 health effects of, 111 self-actualization and, 112-114 Positive thinking, 101-102 Postherpetic neuralgia, 804 Postisometric relaxation, 507 Postmastectomy pain, 804-805 Postmenopausal women. See also Women boron intake by, 1291 estrogen reductions in, 367,1881 exercise by, 367-368 gastric acidity in, 1982 homocysteine levels in, 610 osteoporosis in, 1987-1988 Postural muscles, 510,511f Potassium Aloe Vera effects on, 746 blood PRSSUR and, 1297-1298 body status assessments of, 276t, 278 cardiovascular system functioning and, 1518 description of, 1297 fasting-related changes in, 540 hair analysis for, 211 hypertension treated with, 1762-1763 inflammatory bowel disease and, 1821 recommended intake of, 1298t suggested optimum nutrient intake for, 1297-1298

Potassium citrate, 270,1601 Potassium iodide, 1663-1664 Potassium-to-sodium ratio, 706 Potential pathogen, 169,169b Potentilla tormentilla, 1808, 1810 Povidone-iodine, 2130 Powdered extract, 711 Pmkriti, 319-321 Pranayama, 105 Pravastatin, 1176,1176f Prayer. See also Spirituality applications of AIDS,525 alcohol abuse, 525 cancer, 524-525 cardiovascular disease, 522-523 coronary heart disease, 523 delinquency, 526-527 drug abuse, 525 hypertension, 523-524 length of life, 526 quality of life, 526 suicide, 525-526 surgical outcome, 526 description of, 90 directed, 528 healing effects of, 522 undirected, 528 Prebiotics clinical applications of, 1185-1187 colonic foods as, 1191-1192 commercial forms of, 1184-1185 dosage of, 1187 fructooligosaccharides as, 1183-1186, 1184t, 1186f lactulose as, 1188-1191 toxicity of, 1187-1188 Prediabetes, 1609 Prednisone, for rheumatoid arthritis, 2094 Pregnancy carnitine supplementation during, 812 chlamydia1 infection during, 2159 dietary guidelines during, 1944 docosahexanoic acid use during, 953 Eclzirzncea spp. use during, 916 ectopic, 2017 Ephedra spp. use during, 927-928 exercise during, 366-367 fasting during, 543 fish oil consumption during, 953 homocysteine levels during, 620-621 human immunodeficiency virus during, 1743 hydrotherapy during, 409 Hypericum perforaturn taken during, 1045 nausea and vomiting during acupressure for, 1943 acupuncture for, 1943 description of, 1415-1416 homeopathy for, 1943 incidence of, 1941 lifestyle recommendations, 1943-1944 nutritional considerations, 1942,1944 psychologic aspects of, 1941-1942 Rubus idaeus for, 1942-1943 vitamin 86 for, 1942

Pregnancy--cont'd nausea and vomiting during--cont'd vitamin C for, 1942 vitamin K for, 1942 Zingiber oficinale for, 1415-1416,1942 neural tube defects, 620,1287,1805 thyroid hormone levels during, 1798 vitamin A intake during, 620,1387, 1389-1390 vitamin D intake during, 1612 Zingiber offrcinale intake during, 1415 Preissnitz, Vincent, 53 Premature ventricular beats, 864 Premenstrual dysphoric disorder, 2053-2054 Premenstrual syndrome Angelica sinensis for, 2061, 2063 botanical medicines for, 2061-2062 caffeine and, 2057 calcium for, 2060 cholestasis and, 2055,2055b Cimicificga racemosa for, 2062 classification of, 2054 coping styles and, 2058 definition of, 1784,2053 depression and, 2058 diagnosis of, 2054 diagnostic summary for, 2053 dietary considerations for, 2056-2057 essential fatty acids for, 2060 estrogen metabolism and, 2055 etiologic theories of, 2053-2054 exercise for, 2058 fibrocystic breast disease and, 1665 Ginkgo biloba for, 983,2062-2063 Glycyrrhiza glabra for, 2061-2063 hormone therapy for, 2057 Hypericum perforaturn for, 2062-2063 hypoglycemia and, 1784-1785 hypothyroidism and, 2057 incidence of, 2053 magnesium deficiency and, 2059-2060 mineral supplements for, 2060-2061 nutritional supplements for, 2058-2061 probiotics for, 2055-2056 progesterone therapy for, 2057 psychotherapy for, 2058 Ruscus aculeatus for, 1230 salt intake and, 2057 serotonin levels and, 2058 signs and symptoms of, 2053,2054b stress and, 2058 subtypes of, 1784-1785 sugar consumption and, 2057 treatment of, 2054-2063 vitamin B6 for, 2058-2059 vitamin E for, 2060 Vitex agnus castus for, 1397t, 1397-1398, 2062-2063 zinc for, 2060 Preprotachykinin- A, 1673 Presenilin, 1464 Preventive genomics, 489 Prickly pear. See Opuntia sp. Priessnitz, Vincent, 135 Primum non nocere, 80b, 98-99 Prinzmetal's variant angina, 1473

Index Proanthocyanidin 82,882f Proanthocyanidins antioxidant properties of, 1097 atherosclerosisprevention and, 1515-1516 description of, 967,976 male infertility treated with, 1871 in Vaccinium macrocarpon, 1355 Probiotics antibiotic therapy, gastrointestinal tract stabilization and recolonization after, 1201-1202 atopic dermatitis treated with, 1530 atopic disease prevention using, 1203-1204 bacterial vaginosis treated with, 1203 cancer therapy using, 1204 characteristicsof, 1197t, 1197-1199 chronic candidiasis treated with, 578 clinical applications of, 1200t, 1200-1207 commercial forms of, 1199-1200 Crohn’s disease treated with, 1205-1206, 1824 definition of, 1195-1196 description of, 1196,1196t diarrhea treated with, 1206,1806-1807 dosage of, 1207-1209 drug interactions with, 1209 eczema treated with, 1204 fermented dairy sources of, 1199 gastrointestinal environment, activity on, 1201,1207 immune system stimulation by, 1207 importance of strain in, 1198-1199 inflammatory bowel disease treated with, 1205 intestinal elimination promoted using, 578 intestinal flora affected by, 2055 intestinal mucosa protections by, 246, 588-589 irritable bowel syndrome treated with, 1204-1205 lactobacilli and bifidobacteria growth promotion with, 1209 lactose intolerance treated with, 1206-1207 mechanisms of action, 1196-1197 nomenclature, 1198 properties of, 1197 small intestinal bacterial overgrowth treated with, 158 sources of, 1199-1200,1209 spirulina as source of, 1209 strain development and selection issues, 1207,1208t supplements with, 1200,1207-1208 toxicity of, 1209 toxins affected by, 600 ulcerative colitis treated with, 1205 urinary tract infection treated with, 1202-1203 uses of, 1197-1198,1198t vaginal yeast infections treated with, 1202 yogurts as source of, 1209 Probucol, 1176,1177f Proctalgia fugax, 2075 Proctitis, 2075-2076

Procyanolidicoligomers antioxidant and free radical scavenging activity of, 1218,1218t atherosclerosistreated with, 1219 chemical composition of, 1217,1218t clinical applicationsof, 1219 collagen protection using, 1218 description of, 967,1516 dosage of, 1219-1220 drug interactions of, 1220 folk use Of, 1217-1218 history Of, 1217-1218 pharmacology of, 1218,1218t toxicity of, 1220 venous and capillary disorders treated with, 1219 visual function and retinopathy treated with, 1219 Progesterone, 1488-1489,1647,1879,1895, 2057,2153 Progressive relaxation, 704,1831 Proinsulin, 1619 Prolactin, 1551 Pronator teres syndrome, 1558 Properdin, 911 Propionate, 670 Propionibacterium acnes, 1421,1424 Propolis, 580,767-769,2130 Proprioceptive neuromuscular facilitation, 507 Prostacyclin 13, 948 Prostaglandins definition of, 1645-1646 metabolism of atopic dermatitis and, 1527-1528 menorrhagia and, 1902 Zingiber oficinale and, 1412 seminal vesicle production of, 1866 Prostanoids, 192,738 Prostate cancer androgen receptor and, 969 boron for, 788 lycopene for, 777 soy consumption for prevention of, 1267-1268,1552 Prostate gland, 1866. See also Benign prostatic hyperplasia l’rostate-specific antigen, 552,552t, 1550 Protease inhibitors, 1261-1262,1728, 1736-1737 Protein glycosylationof, 1623 metabolism of, 1404 phase 2 detoxificationand, 599 soy, 682-683 whey, 681-682 Protein absorption microenzyme therapy and, 1076-1077 of pancreatic enzymes, 1133-1134 Protein deficiency mixed function oxidase affected by, 347-348 toxic chemical metabolism affected by, 347-348 Protein kinase C alkylglycerols’ effect on, 720 description of, 236

Protein sparing, 994-995 Protein-caloriemalnutrition, 647 Proteoglycans, 615-616 Proteus spp., 1155 Protozoan infestations Allium sativum for, 657 Arfemisia annua for, 657 berberine for, 657 diagnosis of, 657 Entamoeba histolytica, 656 Giardia lamblia, 655-656 intestinal bacterial milieu and, 657 treatment of, 657 Provings, 388,393-394 Provocation-neutralizationtesting, 204-205,206t Prunella vulgaris, 1745b Prunus afiicanum, 1346 Pruritus ani, 2076 capsaicin for, 806 Capsicumfrutescens for, 806 P-selectins, 447 Pseudcephedrine,926 Pseudohypericin antiviral activity of, 1040 chemical composition of, 1037-1038,1038f Pseudomonas spp., 1153-1156,1158 Psoriasis alcohol consumption and, 2081 Aloe Vera for, 743,2084 bile deficiencies and, 2081-2082 bowel toxemia and, 2080-2081 capsaicin for, 805 Capsicumfrutescens for, 805,2084 chromium for, 2082,2084 Coleusforskohlii for, 873 definition of, 955 diagnostic summary for, 2079 dietary considerationsfor, 2084 eicosapentaenoicacid for, 955,2082 epidemiology of, 2079 fish oils for, 955-956 fumaric acid for, 2083 gastrointestinal function and, 2080 glutathione peroxidase levels in, 2082 glycyrrhetinicacid for, 1008 Glycyrrhiza glabra for, 2084 homocysteine levels in, 622 human leukocyte antigens and, 2079 immune system and, 2079-2080 liver function and, 1254,2081 Matricaria charnomilla for, 2084 nutritional considerationsfor, 2082-2083 omega-3 fatty acids and, 2082 peat therapeutics for, 480 protein digestion and, 2080 psychological aspects of, 2083 sarsaparilla for, 1242 Silybum marianum for, 1254,2085 substance P and, 805 sunlight for, 2083 treatment of, 2080-2085 ultraviolet light therapy for, 2083 vitamin A for, 2084 vitamin D and, 2082-2083 vitamin E for, 2084

Index Psychobiology, 106 Psychologic stress, 97,100

Psycho-neuro-immune-endneendocrineaxis, 100 Psychoneuroimmunology, 97,102-103, 111,645 Psychosomatic therapies, 105 Pulmonary disease, 364 Pure water, 1402-1403 Purine, 1704f Pumsha, 319 Putrefaction, 711 Pygeurn africnnurn (bitter almond) benign pmtatic hyperplasia treated with, 1553,1873 chemical composition of, 1221,1222f clinical applicationsof, 1222-1224 dosage of, 1224 drug interactionswith, 1224 ferulic acid esters in, 1222 folk use of, 1221 history of, 1221 male infertility treated with, 1224,1873 pharmacology of, 1221-1222 prostate disorders treated with, 1222-1224, 1223t semoa vs., 1224 toxicology of, 1224 Pyridoxal 5’-phosphate, 614 Pyridod-alpha-ketoglutarate,691-692 Pyridoxine. See Vitamin B6 Pyroglutamate, B9t, 295 Pyruvate description of, 289t, 290,692 dihydroxyacetoneand, 692 dosage of, 692-693 exercise performance and, 692,695 Pyuria, 1356-1357

Q Qi, 8,312

Qinghaosu, 761 Quadratus lumborum, 507f, 507-508 Quality control definition of, 336 of herbal products, 336-337 Quality of life, 526 Queen Phillippa, 128 Quercetagetin, 762 Quercetin aldose reductase inhibition by, 969 Allium cepa, 726 androgen mceptor inhibition by, 969 antiinflammatoryeffects of, 968,970-971 antitumor activity of, 970 antiviral activity of, 823,970 aphthous stomatitis and, 1482 atopic dermatitis treated with, 1530 bromelain and, 971-972 chelathg effects of, 1326 commercial preparations of, 971 description of, 567,589 dosage of, 971-972 eicosanoid metabolism affected by, 969,1823 enzymes inhibited by, 1326 gout treated with, 1707

Quercetin-ont’d histamine release inhibited by, 969 hyaluronidase inhibition by, 969 inflammatorybowel disease treated with, 1823 pharmacology of, 968-970 structure of, 968 toxicity of, 972 urticaria treated with, 2143 Vaccinium myrtillus, 1365 Qurnolinate,289t

R Radiation damage alkylglycerols for, 717,719-720 Aloe VUR for, 742-743 Panax ginseng effects on, 1126 Radiation poisoning, 1095 Radiation protection, 922 Radiation therapy antioxidants and, 568 brachytherapy,566 glutamine and, 996-997,999-lo00 machinegenerated beams, 565-566 mouth pain caused by, 805 natural remedies that potentiate, 566-567 naturopathic support during, 566 radioimmunotherapy,566 radiopotentiation, 566567 radioprotection, 567 side effects of, 566,996-997 skin protection during, 567 types of, 565-566 Radioallergosorbent procedure, 204,206t Radioallergosorbent test, 204,206t, 586-587 Radioimmunotherapy,566 Rajas, 319,322 Range of motion testing, 424 RANTES, 18 Rapid dark adaptation test, 283-284,1383 Raspbeny leaf. See Rubus idaeus Raynaud’s disease fish oils for, 958 Ginkgo biloba for, 984 Reactive hypoglycemia, 1781 Reactive oxygen species description of, 1616 inflammation and activation of, 1087 as naturally occurring antioxidants, 1086f, 1086-1087 “Rebound scurvy,’’1391-1392 Reciprocal inhibition, 507 Recommended daily allowances description of, 1275-1276 history of, 1276 limitations of, 1277b weaknesses associated with, 1276-1277 Recommended daily intakes, 1275 Recommended dietary allowance, 711 Recurrent aphthous stomatitis. See Aphthous stomatitis Red cell stearic/oleic index, 191t, 196 Red clover. See Trifoliurn pretense Reductionism, 4,80 Refined carbohydrates, 706 Reflex grading, 421t

Reflux esophagitis, 661 Relaxation angina pectoris management by, 1478 cognitive behavioral stress management for, 1738 migraine headaches treated with, 1918 osteoarthritis-relatedpain managed by, 1971 pain control using, 434 postisometric, 507 progressive, 704,1831 Relaxation response, 703-704,704b Religious faith applications of AIDS, 525 alcohol abuse, 525 cancer, 524525 cardiovasculardisease, 522-523 coronary heart disease, 523 delinquency, 526-527 drug abuse, 525 hypertension, 523-524 length of life, 526 quality of life, 526 suicide, 525-526 surgical outcome, 526 description of, 90 healing effects of, 522 REM sleep, 1830 Remefemin, 850 Renal failure, 622 Renshenfengwangijang, 842t Repression-sensitization axis, 433 Reproduction beta-carotene effects on, 774775 Panax ginseng for, 1124 vitamin A effects on, 1384-1385 Research acupuncture, 313,437 of Ayurveda, 324 hydrotherapy, 403-406 in natural medicine animal studies, 124-125 basic science studies, 124125 clinical trials. See Clinical trials communication about, 119 observational studies, 123-124 problems and strategies, 118-125 program criteria, 125 purpose of, 117-118 replicability of, 118 tools for, 118 Resins, 711 Resorcylic acid lactones, 2152 Respiratory centers, in brainstem, 639 Respiratory function, 630-631,1049-1050 Respiratory syncytial virus, 1385-1386 Restless legs syndrome, 1833 Resveratrol, 1725 Retinal, 1382 Retinal pigmented epithelium, 1859 Retinaldehyde, 1382f Retinoic acid description of, 1381 metabolism of, 1384 structw of, 1382f

Index Retinol acne vulgaris treated with, 1422 description of, 1381,1385 structure of, 1382f vitamin E effects on, 1423 Retinol activity equivalents, 1280 Revulsive effect, 406-407 Rhamnose, 246 Rheology, 447 Rheumatoid arthritis anemia and, 2092 antinuclear antibodies in, 2092 Ayurveda view of, 323 boron deficiency and, 787-788 capsaicin for, 805 classification criteria for, 2092b counseling for, 2105 definition of, 2089 dehydroepiandrosterone levels and, 903,2091 diagnosis of, 2091-2093 diagnostic summary for, 2089 dietary considerations for, 2095-2096 digestion and, 2097 Epstein-Barr virus and, 2091 erythrocyte sedimentation rate in, 182 fecal flora and, 2096-2097 feverfew for, 1332 food allergies and, 2096 genetic factors involved in, 2090 homocysteine levels in, 622 immune complexes in, 2090 intestinal permeability and, 2090 laboratory findings, 2092-2093 microbial hypotheses of, 2090-2091 mycoplasmas and, 2091 onset of, 2089 osteoarthritis vs., 1962 osteoporosis and, 903 pathogenesis of, 2089-2090 psychological aspects of, 2097-2098 small intestinal bowel overgrowth and, 2090 synovial fluid findings in, 2092 treatment of antioxidants, 2100 approach for, 2104-2105 azathioprine, 2095 balneotherapy, 2103-2104 biologic agents, 2095 bromelain, 2102 Bupleurumfulcutum, 2103,2105 Capsicumfrutescens, 805 catechin, 825-826 considerations for, 2095-2103 copper, 2101 corticosteroids, 2094 Curcuma longa, 896,2101-2102 cyclooxygenaseinhibitors, 2093-2094 cyclophosphamide, 2095 diet, 2095-2096,2104 disease-modifying antirheumatic drugs, 2094-2095 Echinaceu spp., 914 fasting, 2096 fatty acids, 2098

Rheumatoid arthritis-cont’d treatment of-cont’d fish oils, 954-955 gamma-linoleic acid, 2098 gold therapy, 2094 hydroxychloroquine, 2094 leflunomide, 2095 manganese, 2100-2101 methotrexate, 2095 niacinamide, 1967,2101 nonsteroidal antiinflammatory drugs, 2093-2094 nutritional supplements, 2098-2100 omega-3 fatty acids, 2098-2100 pantothenic acid, 2101 penicillamine, 2094-2095 pharmacologic, 2093-2095 physical medicine, 2103,2105 selenium, 2100 sulfur, 2101 tumor necrosis factor-alpha inhibitors, 2095 vegetarian diet, 2098 vitamin 86,2101 vitamin C, 2101 vitamin E, 2100 zinc, 2100 Zingiber oficinulis, 2102-2103 Rheumatoid factor, 2090,2092 Rhizopus arrhizus, 1075 Rhodiola rosea dosage of, 708 stress management uses of, 707-708 Rhodopsin, 1384 Rhythmic traction, 504t Riadore, J. Evans, 419-420 Riboflavin assessment of, 252,252t cataract prevention and, 1289,2119-2120 deficiency of, 282t migraine headaches prophylaxis and, 1289,1915 photosensitization caused by, 1290 recommended intake of, 1290t side effects of, 139Ot suggested optimum nutrient intake for, 1289-1290 toxic chemical metabolism and, 348 toxicity of, 1390t Rich, 451 Rickli, Arnold, 54 Rifaximin, 157 Rofecoxib, 1963 Role-play time distortion, 2009 Rosacea, 2109-2111 Rosmarinic acid, 1066 Rosmarinus oficinalis, 1745b Rotavirus, 1802 Royal jelly, 767-769 R-proteins, 612 Rubus idaeus, 1942-1943 Ruscus aculeatus (butcher’s broom) antielastase effects of, 1227-1228 antiinflammatory effects of, 1228 antimicrobial effects of, 1228 chemical composition of, 1227

Ruscus aculeatus-cont‘d chronic venous insufficiency treated with, 1228-1230,1229t clinical applications of, 1228-1230 description of, 1227 diabetic retinopathy treated with, 1230 dosage of, 1230 drug interactions, 1230,1232 edema treated with, 1230,1231t fibrinolytic effects of, 1228 hemorrhoids treated with, 1230 history of, 1227 pharmacology of, 1227-1228 premenstrual syndrome treated with, 1230 soft tissue injuries treated with, 1230 toxicity of, 1230 varicose veins treated with, 2169-2170 varicosities treated with, 1230,1231t Rush, Benjamin, 131

S Saccharides, 738,739b Saccharomyces boulurdii, 1807,1810 Sacchnrum officinurum, 1173 Sacral thrust, 428 Sacroiliac joint fixation of, 427-429 motion palpation of, 427-429 Sacro-occipital technique, 512 Sadenosylhomocysteine, 677 Sadenosylmethionine antidepressant effects of, 1235-1236 cirrhosis treated with, 1238 clinical applications of, 1235-1238 creatine formation and, 677 depression treated with, 1235-1236,1238, 1438-1440,1440t description of, 1235 dosage of, 1238 ethanol ingestion effects on, 623 fibromyalgia treated with, 1237-1238 forms of, 1235 Gilbert’s syndrome treated with, 1238 homocysteine effects on, 615,618 liver disorders treated with, 1238 methionine as source of, 1235 migraine headaches treated with, 1238 naproxen vs., 1237,1968 osteoartluitis treated with, 1236-1238, 1967-1968 Parkinson‘s disease contraindications, 1239 pharmacology of, 1235 structure of, 1236f toxicity Of, 1238-1239 transcutaneous electrical nerve stimulation VS., 1237-1238 Saikc-Keishi-To, 1656 Salicylates, 2140-2141 Salivary glands, 166 Salmonella spp. description of, 471,1803 lactulose and decreased growth of, 1189 phage therapy and, 1153 Salpingitis, 2017

Salt intake asthma and, 1488 dietary,469470 Fantus test for assessing, 185-186 migraine headaches and, 1914 premenstrual syndrome and, 2057 recommendations for, 469-470 water consumption and, 186 Salvia spp. Dan Shen Pian, 842t description of, 456t Sanguinaria canadensis description of, 330 periodontal disease treated with, 2035-2036 Saponins, 711,1003,1004f, 1262 Sarcoma definition of, 551 Kaposi, 656 Sarcosine, 1655 Sarsaparilla, 331,1231-1232 Satiation, 102 Saturated fats, 468 Saturated fatty acids arachidic acid, 191t, 195 behenic acid, 191t, 195 capric acid, 19Ot, 194 description of, 936 hexacosanoic acid, 191t, 195 lignoceric acid, 191t, 195 palmitic acid, 19Ot, 194,938 p d i h g Of, 190t-l91t, 194195 stearic acid, 191t, 194195 Satva, 322 Sauerkraut, 1199-1200 Sauna,415 Saw palmetto. See Serenoa repens Schistosomiasis ABO polymorphismsand, 453t Artemisia annua for, 763 Tabebuia avellanedae for, 1324 Schroth, Johann, 53-54 Scientific medicine, 47,84 Scientific method definition of, 4 replicability, 119 Scleroderma catechin for, 826 Centella asiatica for, 832 peat therapeutics for, 480 scoliosis, 479 scoploetin, 1346f Scrod temperature, 1868 Scudder‘s alterative, 2151 SCUIVY, 1391-1392 Scutellaria baicalensis, 174% Seasonal affective disorder description of, 1428,1444-1445 Hypm‘curn perforaturn activity and, 1042 melatonin synthesis and secretion and, 1058 Seborrheic dermatitis, 2113-2114 Secretory IgA in attention deficit hyperactivity disorder, 1537-1538 description of, 242,246 food allergy testing, 587

sects, 44-45,48 Segmentation index, 200 SeiZUreS

acupuncture for, 1657 antioxidants for, 1656 classification of, 1650,165Ob description of, 1649-1650 essential fatty acids for, 1656 Ginkgo biloba for, 1657 heavy metal toxiaty and, 1651 5-hydroxytryptophan for, 1032 hypoglycemia and, 1651 ketogenic diet for, 1651-1652 selenium for, 1655 spiritual healing for, 1657-1658 vitamin 86,1653-1654 vitamin E and, 1655 Selachyl alcohol, 714,716f Selectins, 447 Selective serotonin reuptake inhibitors 5-hydroxytryptophanand, 1025 Hypericum perforaturn and, 1045 Selenium acne vulgaris treated with, 1423-1424 alcohol effects on, 1299,1453 alcoholism treated with, 1456 anxiety treated with, 1298-1299 asthma and, 1492,1496 body status assessmentsof, 276f 278 cancer and, 1298 cataract prevention and, 2119 cervical dysplasia and, 1575-1576 cisplatin and, for cancer, 564 coronary artery disease and, 1515 deficiency of, 1299 depression treated with, 1435,1442 description of, 1298 elderly use of, 1299 endometriosis treated with, 1646 glutathione peroxidases and, 1089-1090, 1423 hair analysis for, 211 hepatitis treated with, 1717 in human immunodeficiency virus, 1739b hyperthyroidism treated with, 1775 immune function affected by, 650 multiple sclerosis treated with, 1932,1935 periodontal disease treated with, 2034,2036 recommended intake of, 1299,1300t reproductive uses of, 1299 rheumatoid arthritis treated with, 2100 seizures treated with, 1655 suggested optimum nutrient intake for, 1298-1299 thyroid hormones and, 1795 toxic chemical metabolism affected by, 349 vitamin C and, 1299 vitamin E and, 1513,1515,2119 Selenocysteine, 1298 Self-actualization, 112-114 Self-esteem, 113,113t Self-healing mechanisms, 36 Self-help groups, 139 Self-monitoring of blood glucose, 1618 Selye, Hans,701-702 Semen analysis, 1867

Seminal vesicles, 1866 Seminiferous tubules, 1866 Senile cataracts. See Cataracts, senile Serenoa repens (sawpalmetto) antispasmodic effects of, 1246 benign prostatic hyperplasia treated with, 1246-1248,1552-1553,1712 chemical composition of, 1245 clinical applications of, 1246-1248 description of, 1245 dosage of, 1248-1249 history Of, 1245-1246 male-pattern baldness treated with, 1248 pharmacology of, 1246 Pygeum africanum vs., 1222-1224 toxicity of, 1249 Serial-dilutiontitration test, 205 Seroconversion, 1730 ”Serotonergic syndrome,” 1045 Serotonin conditions associated with, 1023,1023t deficiency of fibromyalgia and, 1672 migraine headaches and, 1909-1910 5-hydr0~ytrypt0phanand, l021,1022f, 1024t Hypericum perforaturn activity and, 1039-1040 melatonin synthesis and secretion and, 1057-1058,1058f obesity and, 1953 premenstrual syndrome and, 2058 tryptophan effects on, 1953 Serotonin reuptake inhibitors, 1910 Sertoli cells, 1866, 1869-1870 Serum glutamate oxaloacetate transaminase, 1421 Serum glutamate pyruvate transaminase, 1421 Sex hormone-bindingglobulin, 1265 Sexual dysfunction dehydroepianhsterone-sulfatefor, 902 Ginkgo biloba for, 983 Sexually transmitted infections, 2156-2157 Shark liver oil alkylglycerols from, 714715 description of, 714 Shelton, Herbert M., 534 Shepherd’s purse, 1905 Shiga toxin-producing Escherichia coli, 173 Shigella dysenteriae description of, 1803 phage therapy research using, 1152 Shigellosis, 453t Shogaol, 1412f Short bowel syndrome, 995-996 Short-chain fatty acids Colonic foods and, 1191t, 1191-1192 description of, 167,667,670,1824 fructooligosaccahridesand enhanced mineral absorption using, 1186 reduction using, 1185 lactulose effect on, 1189-1191 probiotic effects on, 1201-1202

Index Short-wave diathermy, 1969-1970 Sialyl Lewis X, 445 Sigma receptors, 1040 Silent Spring, 28 Silicon, 1987 Silybin, 1254-1255 Silybum marianum (milk thistle) antiinflammatory effects of, 1252 antioxidant effects of, 1096-1097 chemical composition of, 1251 chemical-induced renal damage treated with, 1254 cirrhosis treated with, 1253,1455 clinical applications of, 1253-1255 description of, 1251 dosage of, 1255 drug interactions, 1255 folk uses of, 1251 free radical scavenging prevented by, 1251-1252 gallstones treated with, 1254,1693 glutathioneaffected by, 1252 hepatic protein synthesis stimulated by, 1252 hepatitis treated with, 1254,1719,1721 highly active antiretroviraltherapy and, 1740b human immunodeficiency virus treated with, 1745b liver and, 578,1252-1253 pharmacology of, 1251-1253 phytoequivalence of, 336 psoriasis treated with, 1254,2085 toxicity of, 1255 Silymarin antiinflammatory effects of, 1252 clinical applications of, 1253-1255 cyclic adenosine monophosphate phosphodiesteraseinhibition by, 1253 description of, 1251 hepatitis treated with, 1719 liver function benefits of, 578 Simvastatin, 1176 Single nucleotide polymorphisms, 488 Singlet oxygen, 776 Sinusitis bacterial, 1545-1547 bromelain for, 793 Sitosterol, 1346f Sitz baths, 412-413,2020,2022,2069,2073 Skeletal muscle anatomy of, 356,357f creatine content in, 677 energy stores for, 356t glutamine effects on, 684 phosphate compounds in, 356 Skinfold thickness, 1949 Sleep 5-hydroxytryptophan for, 1832 melatonin for, 1832-1833 normal patterns of, 1830-1831 tryptophan effects, 1832 Sleep apnea, 1829-1830 Slopek, Stefan, 1154 Slow eccentric isotonic stretch, 507

Small intestinal bacterial overgrowth antibiotics for, 157 aromatic oils for, 157 bile acids in, 154-155,155f breath testing for false-positive and false-negative results, 156-157 hydrogen vs. methane, 156 indications, 154b interpretation of, 156 lactulose, 156 principles of, 155-156 causes of, 154b definition of, 153 diagnosis of, 154-155 in distal ileum, 157 endoscopy for, 155 fat malabsorption in, 155 frequency of, 153 gastric acidity and, 158 high-risk patients, 153 intestinal stasis and, 158 irritable bowel syndrome and, 153 laboratory assessment of, 155-157 lactulose-to-mannitol ratio in, 245 pathophysiology of, 153-154 peppermint oil for, 157 probiotics for, 158 rheumatoid arthritis and, 2090 signs and symptoms of, 154-155 supportive measures for, 158 treatment of, 157-158 vitamin BI2 deficiency caused by, 155 Small intestine description of, 167,241 functions of, 241 immune system of, 242 intrinsic factors of, 241 tight junctions in, 241-242 Smallpox, 453t Smilax sarsaparilla, 2085 Smoking atherosclerosis and, 1503-1504 bacterial vaginitis and, 2158 cervical dysplasia and, 1573 cessation of, 1504,1504b depression and, 1431-1432 Graves' disease and, 1772 menopause and, 1896 osteoporosis and, 1978 oxidants from, 1870 Parkinson's disease and, 2009 pelvic inflammatory disease and, 2022 peptic ulcers and, 2027 periodontal disease and, 2033 vitamin C levels affected by, 1870 Snakebites, 914 Social readjustment rating scale, 702,703t Sodium dietary intake of, 540,1300 Fantus test for, 185-186 fasting-related changes in, 540 fish oils' effect on excretion of, 951 hair analysis for, 211 hypertension and, 1300,1762-1763 recommended intake of, 1300t

Sodium-cont'd suggested optimum nutrient intake for, 1300 Sodium chloride, 1300,1849 Sodium cromoglycate, 247 Sodium hyaluronate, 1963 Softtissue approximationend-feel, 425 Softtissue manipulation articulation, 504t Bennett's neurovascular reflexes, 512 Chapman's neurolymphaticreflexes, 512 connective tissue massage, 512,514 effleurage, 504t hyperalgesic skin zones, 513-514 indications for, 501 inhibition/ischemic compression, 504t kneading, 504t neuromuscular technique, 514 points anatomy of, 504 classification systems, 505-510 connective tissues under, 504-505 description of, 503-505 identification of, 502-503 muscle types, 510-511 palpatory literacy of, 504 reflex, 512-513 size of, 503-504 tender, 505-506 trigger, 506-510 positional release, 504t potential of, 515 psychogenic influences, 511-512 rhytluruc traction, 504t sacro-occipital technique, 512 springing, 504t, 513 stretching, 504t techniques for, 503,504t vibration, 504t viscerosomatic reflexes, 513 Soft tissue stressors, 501b-502b Solid extracts, 711 Solvents, 594 Sorbitol, 969,1623,1627 SOY benign prostatic hyperplasia treated with, 1552 cardiovascular disease and, 1268 clinical effects of, 1891-1892 description of, 68243,1259 fibrocystic breast disease and, 1666 historical uses of, 1890 hypotensive effects of, 1269 lipid-loweringeffects of, 1268-1269 OSteOpOroSis and, 1983-1984 phytoestrogens,1890-1891 Soy constituents description of, 1261-1262,1890-1891 pharmacology of, 1262 Soy isoflavones absorption of, 1260-1261 bone mineral density and, 1984 breast cancer treated with, 1267 cancer treated with, 1265-1268 cardiovascular disease treated with, 1268-1270

Soy isoflavon-ont’d chemical composition of, 1259 clinical applicationsof, 1265-1271 cognitive function and, 1270-1271 daidzein, 1259-1260,1260f description of, 1891t drug-nutrient interactions, 1271 estrogenic effect of, 1264 excretion of, 1261 eye disorders treated with, 1270 genistein, 1259-1260,1260f hormonal effects of in adults, 1263-1265 in infants, 1262-1263 mechanism of action, 1265 menopausal symptoms treated with, 1269-1270 osteoporosis treated with, 1270 prostate cancer prevention and, 1267-1268, 1552 structure of, 1264f thyroid hormone levels affected by, 1270 SP-303,88&889 Spa therapy, 476 Specialty practice, 86 Sperm antioxidants’ effect on, 1870-1871 antisperm antibodies, 1868 damaging factors, 1868-1870 free radicals effect on, 1870 genital ducts for, 1866 heavy metal exposure effects on, 1870 motility of, 817 pelvic inflammatory disease and, 2018 scrotal temperature effects on, 1868 Sperm count arginine for, 1872 camitine effects on, 817,1872 infertility and, 1865 low causes of, 1867b description of, 1865 temporary, 1867b vitamin BI2deficiency effects on, 1872 zinc effects on, 1871 Spermatogenesis,1866,1867t Spermatozoa, 1866 Spennicide,745 Spinal disorders classification of, 4 2 0 4 3 infection, 420 lower motor neuron disease, 421t mechanical causes of, 422-423 neoplasms, 420 neurologic lesions, 420-421 psychosocial, 421 upper motor neuron disease, 421t Spinal reflex effect, 407 Spirit, 528-530 Spiritual crisis, 35 Spiritual integrity, 35 Spirituality. See also Prayer description of, 120,519-520 epilepsy and, 1657-1658 in healing, 520-522 health benefits of, 519

Spirituality-ont’d medical practice integration of, 527-528 physician recognition of, 527 Spirulina, 1209 Spirulina platensis, 1745b Spleen extracts, 379t, 380-381 Splenectomy,381 Splenic flexure syndrome, 1837 Splenopentin, 381 Spondylogenic reflex syndromes, 510 Spongform encephalopathy,378 Sports anemia, 370 Sports nutrition. See also Exercise arginine, 683 beta-hydroxy-beta-methylbutyrate,680-681 boron, 685 branched-chain amino acids, 683-684 bromelain, 794 carnitine, 689-691 choline, 691 chromium, 685-686 coenzyme Qlo,691,695,862 creatine monohydrate adenosine triphosphate and, 678 amino-imidazoazaarenes, 680 brain levels of, 678 caffeine effects on, 680 cardiac muscle use of, 678 description of, 677-678 dosage of, 679 food sources of, 678 insulin effects on uptake of, 679 performance enhancements using, 678-679 toxicity of, 679-680 Eleutlwrococcus senticosus, 689 for endurance athletes, 687-695 glutamine, 684-685 ornithine alpha-ketoglutarate,685 Panax ginseng, 687-689 performance drinks, 693-695 phosphatidykrine, 683 pyridoxal-alpha-ketoglutarate,691-692 pyruvate, 692493,695 selenium, 686 soy, 682-683 for strength athletes, 677-687 vanadium, 686-687 vitamin C, 685 whey protein, 681-682 zinc, 687 Spray and stretch techniques, for trigger points, 506-507 Springing, 504t, 513 Spurling’s maneuver, 424 St. Hildegarde, 128 St. John’s Wort. See Hypericurn perforaturn Staging of cancer, 551-552 Standardized extracts, 333-334,337 Staphylococcus spp. description of, 1155 S. nureus, 453t Starvation definition of, 533 fasting vs., 533 physiology of, 539

State bound information, 105 Statins, 866,1508-1509 Status epilepticus, 1658 Steam, 405 Stearic acid, 191t, 194195 Steatorrhea enzyme replacement therapy for, 1077 microbial enzyme therapy for, 1077-1078, 1078t Steroid hormones, 1885-1886 Steroid sulphatase inhibitors, 904 Steroids, 372 Sterols, 466t Still, A.T., 55,134,419 Stinging nettle. See Urtica dioica Stomach anatomy of, 167 digestion in, 217-218 gastric acidity in, 219b gastric emptying in, 693 ulcers of, 2025-2029 Stomatitis, aphthous, 1481-1483 Straight leg raise, 423 Strain specificity, 1198-1199,1207,1208t Strength training, 1626 Streptococcalpharyngitis, 2123-2125 Streptococcalpneumonia, 2042-2043 Streptococcus spp. ABO polymorphism and, 453t phage therapy for, 1155 Stress ABO blood groups and, 447 adaptation to, 515 childbirth and, 434 chronic fatigue syndrome and, 1583 control of, 434 definition of, 515,701 depression caused by, 1430 diagnosis of, 702 diseases and conditions associated with, 97,702b exhaustion secondary to, 702 fight-or-flight response to, 97,701-702 gallstones and, 1693 general adaptation syndrome and, 701-702 Graves’ disease and, 1771-1772 healthy view of, 702 hypertension and, 1761 immune system affected by, 97,100-101,646 interpersonal relationships as cause of, 704-705 intestinal microflora affected by, 169 kidney stones and, 1849 management of. See Stress management multiple sclerosis and, 1934-1935 peptic ulcers and, 2026 physiologic, 97 placebo and, 96-97 premenstrual syndrome and, 2058 psychologic, 97,100 reduction of, 1519 social readjustment rating scale for, 702, 703t sources of, 704705 therapy as, 515 zinc levels affected by, 1303

Index “Stress inoculation,” 433 Stressmanagement botanical medicines for, 707-708 breathing, 704,704b cognitive behavioral, 1738 description of, 1625 diaphragmatic breathing, 704,704b diet, 705-706 Eleutherococcus senticosus for, 707,922 exercise, 705 lifestyle factors, 704-705,705b meditation for, 707 nutritional supplements, 706-707 overview of, 702-703 Panax ginseng for, 707 programs for, 707 progressive relaxation, 704 relaxation response, 703-704,704b Rhodiola rosea for, 707-708 time management, 704-705,705b Stress response, 703-704 Stretchingexercises for carpal tunnel syndrome, 1560-1561 for diabetes mellitus, 1626 Stretchingof muscles, 360-361 Stria gravidarum, 831 Stroebele, Aloysia, 134 Stroke ABO blood groups and, 447-448 citicoline for, 855-856 Curcuma longa for, 896 fish oils for prevention of, 952 folic acid for prevention of, 620 Ginkgo biloba for prevention of, 1520 homocysteinelevels and, 620 hormone replacement therapy and, 1882 Strongyloidiasis,453t Structural integrity, 37 Struvite stones, 1850 Subacute combined degeneration of the spinal cord, 621-622 Subclinical dehydration, 1405-1406 Subclinical hypothyroidism, 1792 Suberate, 289t, 292-293 Substance P capsaicin effects on, 1635,2084 pain and, 803,1909,2084 psoriasis and, 805 Substrate concentrations, 1135 Succinate, 289t Succinate dehydrogenaseCoQloredudase, 860 Succinyl CoA, 2050 Sucrose intolerance, 260 Sudden death, 372 Sugar annual consumption of, 1784 calcium loss secondary to, 1982 fasting to reduce, 648 irritable bowel syndrome and, 1839 phagocytosis affected by, 647-648,648f premenstrual syndrome and, 2057 Sugar intolerances fructose, 260 lactose. See Lactose intolerance maltose, 260-261 sucrose, 260

Suggested optimum nutrient intakes beta-carotene, 1281-1282 boron, 1290-1291 calcium, 1291-1292,1292t carotenes, 1281-1282 ~ U O ~ ~ I U X1292-1293,1293t I, copper, 1293-1294,1294t fat-solublevitamins, 1280-1284 folic acid, 1287,1287t iodine, 12941295,1295t iron, 1295 magnesium, 1294-1295 manganese, 1296 minerals, 1290-1303 niacin, 1288,1288t phosphorus, 1296 potassium, 1297-1298 riboflavin, 1289-1290 selenium, 1298-1299 sodium, 1300 survey questionnairefor, 1278-1279 thiamin, 1290 vanadium, 1300-1301 vitamin A, 1280-1281 vitamin B6,1288-1289 vitamin BIB 1285-1286 vitamin C, 1284-1285 vitamin D, 1282-1283 vitamin E, 1283-1284,1284t vitamin K, 1284,1284t water-soluble vitamins, 1284-1290 zinc, 1301-1303 Suicide, 525-526 Sulfasalazine,1816 Sulfate, 289t, 295 Sulfites, 1488,2141 Sunlight exposure melanoma and, 1283 psoriasis treated with, 2083 vitamin D and, 1282-1283 Superoxide dismutase, 277,1088-1089,1968, 2100,2118-2119 Supplements. See also spec@ supplement coatings of, pancreatic enzyme absorption and, 1135-1136 from fructooligosaccahrides,1184 probiotics in, 1200,1207-1208 Suppression, 82b Suppressor T cells CD4/CD8 ratio for identification of, 225 helper T cells ratio with, 225-226 SWFrY cancer treated with complicationsof, 554 fractionated citrus pectin use, 555 micrometastases,555 natural medicine suppofi, 555-556 nutrition after, 555-556 preoperative guidelines, 555,556b prevalence of, 554 tumor cell spread after, 555 postoperative period bromelain use during, 794 catechin use during, 825 Susceptibilitygenes, 489 Swank diet, 1929-1930,1935

Sweat rate, 693 Sweet wormwood. See Artemisia annua Sweeteningagent, 1008 Sympatheticnervous system, 703 Symphlocarpus factida, 1050 Symphytum oficinale (comfrey),1720,2022 symptoms benign, 83 morbid, 83 situations that produce, 83 Syndrome X, 635,1008,1506,1609,1784-1785 Synergetics, 15 S y ~ h i l i s331,1241-1242 , Systematics, 1150 Systemic inflammatory response syndrome, 995-996 Systemic lupus erythematosus, 903 Szent-Gyorgyi, Albert, 967-968

T T cells activation markers on, 231f activation of, 221,231,911 CD4+, 1730-1732 CDll for identification of, 224225 cytokines produced by, 221-222 dehydroepiandrosteroneeffects on, 903 Echinacea spp. effects on, 911 Entamoeba histolytica and, 656 function assessments, 230-232 helper, 225 T helper cells asthma and, 1486 CD4 for identification of, 225 function of, 232-233 suppressor T cell ratio with, 225-226 type 1,232-233 type 2,232-233 Tabebuia avellanedae (LaPacho, Pau DArco, Ipe Roxo) antibacterial activity of, 1322-1324 antifungal activity of, 1325 antiinflammatoryactivity of, 1326-1327 antimicrobial activity of, 1322-1324 antineoplastic activity of, 1325-1326 antiparasitic activity of, 1324-1325 antiviral activity of, 1324 chemical composition of, 1321-1322 clinical applicationsof, 1327 description of, 1321 dosage of, 1327 drug interactions, 1327 folk uses of, 1322 history of, 1322 lapachol, 1322f, 1322-1327 pharmacology of, 1322-1327 quercetin, 1326-1327 toxicity of, 1327 vitamin K and, 1325 Tachypnea, 631 Tamas, 322 Tamoxifen, 558,1060,1271, 1689 Tanacetum parthenium (feverfew) description of, 1331-1333 migraine headaches treated with, 1916-1917,1919

index Taraxacin, 1336 Taraxacum oficinale (dandelion) chemical composition of, 1336,1336f clinical applications of, 1337-1338 description of, 1335-1336 detoxification properties of, 1646 dosage of, 1338 drug interactions, 1338 folk uses of, 1336 gallstones treated with, 1693 history of, 1336 pharmacology of, 1336-1337 toxicity of, 1338 Taraxasterol, 1336f Taraxerol, 1336f Tarhazine, 470,1486-1487,2139-2140 Taspine, 887,888f Taurine, 1654 Taxanes, 1340 Taxines, 1340 Taxol, 565,1339-1343 Taxus brevifolia (Pacific yew) chemical composition of, 1340 clinical applications of, 1341 description of, 1339-1340 folk uses of, 1340-1341 history of, 1340-1341 paclitaxel from, 1339-1343 pharmacology of, 1341 taxanes, 1340 toxicity of, 131-1343 Tea. See Camellia sinensis; Green tea Tea tree. See Melaleuca alterni/olin Temporal arteritis, 182 Temporomandibular joint dysfunction syndrome, 1918 Tender points, 505-506 Tension headache, 1029t, 1029-1030,1907 Tertninalia arjuna, 1595 Tminalia chebuli, 323 Testicle, 1865 Testosterone boron effects on, 685,787 ginseng effects on, 688 zinc effects on, 687 Tetracycline, for small intestinal bacterial overgrowth, 157 Tetrahydrobiopterin, 1434,2119 Tetraiodothyronine, 1771 Tetraploid cells, 161 T-even phages, 1151,1157-1158 Thl cytokines, 646 Th2 cytokines, 646 Thalassemias, 971 Thea sinensis, 1494 Therapeutic conditioning, 102-104 Therapeutic order conditions for health, 34-36 definition of, 34 list of, 3% pathology, 37-38 self-healing mechanisms, 36 structural integrity, 37 support weakened or damaged systems or organs,36-37 in training curriculum, 31

Thermal chambers, in Crinnion depuration protocol, 350 Thermogenesis diet-induced, 1952-1953 longchain, 1958 mediumchain triglycerides’ effect on, 1958 Tluamin Alzheimer’s disease prevention using, 1464,1469 assessment of, 252t, 252-253 attention deficit hyperactivity disorder and, 1536 congestive heart failure treated with, 1593, 1595 deficiency of description of, 348,1290,1593 epilepsy and, 1654 recommended intake of, 1291t side effects of, 1390t suggested optimum nutrient intake for, 1290 toxicity of, 1390t Thiamin pyrophosphate, 348 Thiazide diuretics, 1759 ”Thigh thrust,“ 428 Thiobarbituric acid-reactive substances, 1219 Thiocyanates, 466t Thioredoxin, 1099 Thioredoxin reductase, 1099 Thirst, 1402,1405 Thomas, Louis,59 Thomsen-Friedenreich antigen, 449-450 Thomson, Samuel, 43,132 Thomsonianism, 43,132-133,332 Thrombomodulin, 447 Thrombophlebitis, 794 Thromboxane Az 948 Thymus gland antioxidants’ effect on, 650-651 extracts from description of, 383-384 otitis media treated with, 1994 pneumonia treated with, 2041 function enhancements for, 650-651 Iscador effects on, 1377 zinc effects on, 651 Thyroid binding globulin, 1794 Thyroid gland age-related declines in, 1791 antibodies, 1675-1676 antioxidant effects on, 1795 depression caused by dysfunction of, 1430 in elderly, 1791 environmental toxins that affect, 345-346 extracts, 384 function tests for, 1675 iodine effects on, 1294 soy isoflavones’ effect on, 1270 urticaria and, 2142 Thyroid hormones deficiency of, 1791 dosing of, 1797-1798 fibromyalgia and, 1672-1676,1681 hypothyroidism treated with, 17961798 iodine and, 1794 normal values for, 1793t

Thyroid hormones-ont’d nutritional considerations for, 1794-1795 during pregnancy, 1798 replacement therapy, 1796-1797 selenium supplementation for, 1795 soy isoflavones’ effects on, 1270 zinc deficiency effects on, 687 Thyroid stimulation test, 1431 Thyroid storm, 1777 Thyroid-stimulating hormone, 345,1791,1796 Thyrotrophh releasing hormone stimulation test, 1675 Thyroxine, 384,686,1676 Tibetan medicine Ayurveda vs., 6t characteristics of, 6t Chinese medicine vs., 6t continuity of, 7 fundamental philosophies of, 7-8 humors in, 7 origins of, 6 treatment principles of, 8 Tidd, Jacob, 43-44 Tight junctions, 241-242 Tiden, John, 56 Time management, 704-705,705b Tin, 271t Tictures definition of, 711 description of, 333,337 Tiel’s sign, 1557-1558 T i t u s , 981-982 Tinospora cojdifolia, 1096-1097 Tissue regeneration, 910 TNM staging, 551 Tocopherols, 1090-1091,1283-1284. See also Vitamin E Tocotrienols, 1091,1283 Tolle causam, 8Ob Tonic definition of, 711,1241 hair, 727 uterine, 1893,1905 Topoisomerase inhibitors, 557 Tormentil root, 1808,1810 Total fatty acid calculation, 196 Total load, 23 Total oxidative value, 960 Touch, 100 Touchi, 1630 Tower, Donald B., 419 Toxemia, 35,2080-2081 Toxic metals arsenic, 266 biliary excretion of, 270 cadmium, 267 combined effects of, 264 depression caused by exposure to, 1431 description of, 263-264,594,597-598 environmental contamination from, 263 excretion, 270,600 exposure assessments blood analysis, 265-266 description of, 601 hair elemental analysis, 264-265,271t history-taking, 601

Index Toxic metals-ont’d exposure assessments-ont’d laboratory tests, 601 urinalysis, 266-267 urinary porphyrins. See Urinary POTphYh fecal analysis of, 270-271 homeopathy for, 395 hypertension and, 1759 individual variability in susceptibility to, 264 kinetic models of, 265 lead. See Lead mercury. See Mercury mitochondria1 disruption caused by, 598 nutritional factors for, 2004 oxidative injury caused by, 597-598 Parkinson’s disease and, 2001 retention assessments Ca-Na2-EDTAfor, 267 description of, 267 DMPS for, 267-269,602,602b DMSA for, 269-270,604 nonpharmaceutical agents for, 270 seizures caused by, 1651 sperm affected by, 1870 Toxic nodular goiters, 1773 Toxins adrenal gland affected by, 345 air purifiers for, 347 attention deficit hyperactivity disorder and, 1534 avoidance of, 347 biotransformation of, 596-597 botanical medicines for, 349 DDE, 340,467 DDT, 340-341,341t, 467,535,594 depuration of, 349-350 detoxification of cytochrome P450 enzymes for, 598 dietary fiber effects on, 600 exercise effects on, 600 fasting effects on, 599 lifestyle for, 602-603 metallothioneins for, 598-599 phase 2,599-600 environmental factors that affect susceptibility to, 599-600 estrogenic effects of, 346 exposure assessments description of, 601 history-taking, 601 laboratory tests, 601 organic toxicants, 601-602 health effects of acute myelogenous leukemia, 343 aplastic anemia, 344 autoimmune disease, 342 axonopathies, 344-345 breast cancer, 343 cancers, 342-344 childhood cancers, 343 description of, 341 diagnosis of, 346-347 endocrinotoxicities, 345-346 hematologic malignancies, 343-344

Tox-ont’d health effects of-cont’d immunotoxicity, 341-342 myelinopathies, 345 neuronopathies, 344 neurotoxicity, 344-345 non-Hodgkin’s lymphoma, 343 reproduction, 346 treatment for, 347-351 heavy metals. See Metal toxicity hexachlorobenzene, 342 hormone disruption caused by, 597 monofunctional, 599 multifunctional, 599 nutritional factors that affect susceptibility to, 599-600 nutritional support for damage caused by description of, 347 glutathione, 349 iron, 349 magnesium, 349 overview of, 351 protein, 347-348 pyridoxine, 349 riboflavin, 348 selenium, 349 thiamin, 348 vitamin A, 348 vitamin C, 349 vitamin E, 348 organic solvents, 594 organochlorine compounds, 341-342 organohalogens, 594 organophosphates, 342,594 overview of, 593-594 PCBs, 535,594,601-602 phthalate compounds, 340 polycyclic aromatic hydrocarbons, 342 prevalence of, in humans, 339-340 probiotics effect on, 600 sources of, 340-341 susceptibility to, 599-600 targets of, 596 thyroid gland affected by, 345-346 types of, 339-340 xenobiotics, 340 Trachoma, 1017 Traditional Chinese medicine, 7,309,313, 2142-2143 Trall, Russell, 45-46 Trans fatty acids, 191t, 195,938-939 Transcellular intestinal absorption, 1076 Transcutaneous electrical nerve stimulation migraine headaches treated with, 1918 osteoarthritis-related pain treated with, 1970 pain control using, 435-436 Sadenosylmethionine vs., 1237-1238 Transferrin, 1095-1096 Traveler’s diarrhea, 1807 Treatment combination, 121 functional medicine perspectives of, 21-25 individualization of, 120-121 intentionality of, 121-122 outcomes of, 23-24

Triacylglycerol, 168 Tricarballylate, 293-294 Trichomonaddes, 2130 Trichomonal vaginitis, 2128 Trichomonas vaginalis, 2128, 2157 Trichomoniasis diagnosis of, 2128 diagnostic summary for, 2127 dietary factors, 2129 facts regarding, 2127-2128 lifestyle considerations for, 2129 metronidazole for, 2128-2129 nutritional supplements for, 2129-2130 treatment of, 2128-2131 Tricosanoic acid, 191t, 195 Tridosha, 320 Triene/tetraene ratio, 191t, 196 Trifolium pretense (red clover), 1893-1894 Trigeminal neuralgia capsaicin for, 804 Capsicurnfrutescens for, 804 Trigger points definition of, 417418,506 myofascial, 506 “satellite,” 506 size of, 503-504 symptoms of, 506 treatment of description of, 506-507 muscle energy technique. See Muscle energy technique myofascial, 1682 spray and stretch techniques, 506-507 Trig1ycerides camitine effects on, 813 definition of, 715 during fasting, 539 fish oils’ effect on, 950 fructooligosaccacharidesand lowering of, 1186 genetics and, 1505 medium-chain, 1958 structure of, 715f Triiodothyronine, 384,686,1676,1792,1796 Trimethyllysine,810 Tripterygium wilfordii Hook. f, 2152-2153 Triterpenes, 1222 Trotula, 127-128 Trousseau test, 635 Trowell, Hugh, 462-463 Trypanosoma cruzi, 1324-1326 Tiypsin clinical applications of, 1137t description of, 218 extraction of, 1133 as pancreatic enzyme, 1132 Tryptophan. See also 5-Hydroxytryptophan alcoholism effects on, 1454 asthma and, 1490-1491 bipolar depression treated with, 1443 depression treated with, 1436-1438 description of, 305,1430 eosinophilia-myalgia syndrome caused by, 1436-1437 5-hydroxytryptophan vs., 1022,1024t insomnia treated with, 1831-1832

Tryptophaneont'd irritable bowel syndrome treated with, 1839 metabolism of, 1021-1022,1022t,1431f, 1490-1491 seasonal affective disorder treated with, 1444 serotonin levels affected by, 1953 sleep-inducing effects of, 1832 Tsubo, 513 Tu Jin Liniment, 844t Tuber, 438 Tuberculosis, 453t Tubo-ovarian abscess, 2019 Tuftsin, 381 Tui na, 2010 Tumor(s) akylglycerol-induced regression of description of, 719 methyoxy-substituted, 721-722 Allium cepa for, 727 bromelain for, 793 Epilobium spp. for, 932 staging of, 719 Tumor markers, 552,552t Tumor necrosis factor, 1060 Tumor necrosis factor-alpha description of, 949,2089-2090 inhibitors of, 2095 Tungsten, 271t Turmeric. See Curcuma longa Turska's formula, 1646-1647 Twort, Edward, 1147 Tylophora asthmatica, 1494,1496 "Type A personality, 1517-1518 Tyrosine, 1438,1439t

U Ubiquinol-l0,863 Ubiquinone. See Coenzyme Qlo Ulcerative colitis. See also Inflammatory bowel disease butyrate enemas in, 1824 carrageenan and, 1817-1818 characteristics of, 1813-1814 dehydroepiandrostersdfate levels in, 903 diagnostic summary for, 1813 endotoxemia in, 1818 etiology of, 1814 features of, 1814 gut-associated lymphoid tissue response in, 242-243 incidence of, 1814 much defects in, 1817 probiotics for, 1205 propolis for, 768 short-chain fatty acids and, 1824 Ulcers, peptic Allium sativum for, 2029 Artemisia douglasiana for, 2029 aspirin and, 1519,2026 bismuth subcitrate for, 2027-2028 cabbage for, 2027 cat& for, 825,2027 Croton lechleri for, 888 diagnostic s u m m a r y for, 2025

Ulcers, peptic-ont'd dietary fiber and, 2027 duodenal, 2025-2029 flavonoids for, 2027 food allergies and, 2027 formation of, 2025 gastric, 2025-2029 Glycytrhiza glabra for, 2028 Helicobacter pylori and, 2026 high-fiber diet for, 2027 lifestyle factors, 2026-2027 melatonin for, 2027 nonsteroidal antiinflammatory drugs and, 2026 plantain banana for, 2028 Rheum sp. for, 2028 smoking and, 2027 stress and, 2026 subclinical dehydration and, 1407 vitamin A for, 2027 vitamin E for, 2027 Zingiber oficinale for, 2028-2029 Ultraviolet radiation, 800 Uncaria gumbier, 823 Undirected prayer, 528 Unified Parkinson's Disease Rating Scale, 2002 Unipolar depression. See Depression Unknown placebo, 92t Unsaturated fatty acids description of, 936 omega-3. See Omega-3 fatty acids omega-6. See Omega4 fatty acids omega-9,936 Upper motor neuron disease, 421t Uranium, 271t Urate, 1704 Urethritis, 2128 Uric acid, 1095,1704,1848 Uridine tiphosphate, 1326 Urinalysis arsenic exposure assessments, 266 fasting-related findings, 540 mercury exposure assessments, 266 renal toxicity biomarkers, 267 toxic metal exposure assessments using, 266-267 Urinary organic acids profiling abnormal levels, 289t-290t adipate, 289t, 292-293 alpha-hydroxybutyrate, 291 arabinitol, 294 arabinose, 294 beta-hydroxybutyrate, 289t, 291 carbohydrate metabolism, 289t citrate, 287-288,290 clinical applications of, 286t-287t detoxification indicators, 289t Dlactate, 294 dysbiosis markers, 29Ot ethylmalonate, 289t, 292-293 fatty acid oxidation, 289t formiminoglutamate, 292 glucarate, 289t, 294 gut microflora products, 293-294 homovanillate, 289t, 293 alpha-hydroxybutyrate, 291

Urinary organic acids profiLing-cont'd alpha-ketoisocaproate, 289t, 291 alpha-ketoisovalerate, 289t, 291 alpha-keto-beta-methylvalerate, 289t, 291 beta-hydroxybutyrate, 289t, 291 beta-hydroxyisovalerate,289t, 291 5-hydroxyindolacetate, 289t, 293 hydroxymethylglutarate, 289t, 291 kynurenate, 289t, 292 lactate, 289t, 290-291 2-methylhippurate, 295 methylmalonate, 289t, 292 neurotransmitter metabolism, 289t organic acids, 286-287 orotate, 289t, 294295 overview of, 285-286 p-hydroxybenzoate, 293-294 phydroxyphenylacetate, 293-294 p-hydroxyphenyllactate, 289t, 295 p-hydroxyphenylpropionate,293-294 pyroglutamate, 295 pyruvate, 289t, 290 suberate, 289t, 292-293 sulfate, 289t, 295 vanilmandelate, 289t, 293 vitamin deficiency indicators, 289t xanthurenate, 289t, 292 Urinary porphyrins biomarker uses of, 299 clinical applications of, 302 heavy metal exposure detected using, 299 interpretation of, 304t technique for, 300,302 Urinary tract infections. See also Cystitis acupuncture for, 1603 Allium sativum for, 1602 after antibiotic treatment, 1357-1358 Arctostaphylos uva ursi for, 1602-1603 beta-carotene for, 1603 catheterization and, 1357 causes of, 1597-1598 diagnosis of, 1598-1600 incidence of, 1598t lactulose for prevention of, 1190-1191 Dmannose for, 1601-1603 potassium citrate for, 1601 prevalence of, 1597 probiotics for, 1202-1203 recurrent, 1356 risk factors for, 1598 urine specimens, 1598-1600 Uva ursi for, 1352 Vaccinium macrocarpon for, 1355-1359, 1359t, 1361 vitamin C for, 1603 Urine dietary factors' effect on, 1845 stone formation. See Kidney stones Urine indican test, 305-306 Urine specimens, 1598-1600 Urine tests, 260 Urolithiasis, 1361 Uroporphyrinogen I, 301f Uroporphyrinogen III, 301f Ursodeoxycholic acid, 2081

Urtica dioica (stingingnettle) allergic rhinitis treated with, 1348 arthritis treated with, 1348 benign prostatic hyperplasia treated with, 1346-1348,1553-1554 chemical composition of, 1345 clinical applications of, 1347-1348 description of, 1345 dosage of, 1348,1348t drug interactions, 1349 folk uses of, 1345-1346 pharmacology of, 1346 Prunus africanum and, 1346 scopoletin, 1346f sitosterol, 1346f toxicity of, 1348-1349 Urticaria acupuncture for, 2142-2144 autoimmune, 2134,2136 Gmdida albicans and, 2141-2142 causes of, 2134-2142 cholinergic, 2135t, 2135-2136 cold, 2135t, 2136 dermographic, 2134-2135,2135t diagnosis of, 2143 diagnosticsummary for, 2133 dietary considerations for, 2144 drug-related, 2136-2137 exercise-induced, 370 food-related causes of allergy, 2137-2138 colorants, 2138-2140 emulsifiers, 2141 flavorings, 2140-2141 preservatives, 2141 tartrazine, 2139-2140 infectiouscauses of, 2141-2142 pathophysiology of, 2133-2134 physical, 2134,2135t physical medicine for, 2142,2144 psychological aspects of, 2142,2144 quercetin for, 2143 thyroid disease and, 2142 traditional Chinese medicine for, 2142-2143 ultraviolet light therapy for, 2142 vitamin BI2 for, 2143 Uterine fibroids degenerative changes, 2149-2150 diagnosis of, 2150 diagnostic summary for, 2149 dietary considerations for, 2150-2151 endometrial cancer and, 2150 estrogen and, 2153 herb therapy for, 2151-2152 pancreatic enzymes for, 2150 phytoestrogens and, 2151-2152 progesterone for, 2153 symptoms of, 2149 treatment of, 2150-2153 Tripteygium wiljbrdii Hook.f. for, 2152-2153 Uva ursi (bearbeny), 1351-1352,1602 V Vaccenic acid, 190t, 193-194 Vaccinium macrocarpon (cranberry) adverse effects of, 1362

Vaccinium macrocarpon+ont'd antioxidant uses of, 1359 calcium oxalate urolithiasis managed using, 1361 chemical composition of, 1355 cystitis treated with, 1600-1601 description of, 1355 dosage of, 1361-1362 drug interactions, 1362 folk uses of, 1356 Helicobacter pylori treated with, 1360 history of, 1356 oral bacteria treated with, 1360 proanthocyanidins in, 1355 urinary odor reduced using, 1358,1362 urinary tract infections treated with, l3551359,1359t, 1361,1600-1601 vascular disease treated with, 1360 Vaccinium myrtillus (bilberry) anthocyanosides in, 1365-1366 cancer cells affected by, 1367 capillary permeability effects, 1366-1367 cataract prevention using, 1368 chemical composition of, 1365-1366 clinical applications of, 1367-1368 collagen stabilization using, 1366 description of, 1365 diabetes mellitus treated with, 1368 diabetic retinopathy prevention using, 1368 dosage of, 1369 drug interactions, 1369 dysmenorrhea treated with, 1368 folk uses of, 1366 glaucoma uses of, 1367-1368 inflammatory joint disease treated with, 1368 macular degeneration treated with, 1861-1862 microscopic hematuria treated with, 1368 night vision and, 1367 ophthalmologicapplications of, 1367-1368 pharmacology of, 1366-1367 platelet aggregation inhibited by, 1367 quercetin in, 1365 resveratrol in, 1365 toxicity of, 1369 Vagina, 2155-2156 Vaginal depletion pack cervical dysplasia treated with, 1575 pelvic inflammatory disease treated with, 1575,2022 Vaginal infections Melaleuca altemifolia for, 1056 probiotics for, 1203 Vaginitis Allium sativum for, 2161,2163 atrophic, 1889,2156,2161,2164 bacterial, 2155-2156,2164 boric acid for, 2162-2163 Candida albicans, 2157-2158,2164 chemical, 2156 diagnosis of, 2162 diagnostic summary for, 2155 dietary considerationsfor, 2159-2160 douches for, 2163 foreign body, 2156

Vaginitis-cont'd Glycyrrhiza glabra for, 2161,2163 gonococcal, 2159 Hydrastis canadensis for, 2161 infectious, 21562159,2157t iodine for, 2162 irritant, 2156 Lactobacillus sp. for, 2161-2162 Melaleuca alternifolia for, 2161,2163 Melissa oficinalis for, 2161 nonspecific, 2158-2159 nutritional supplements for, 2160-2161 pelvic inflammatory disease and, 2155 treatment of, 2159-2163 trichomonal, 2128 Trichomonas vaginalis, 2157 vitamin A and, 2160 Valeopotriates, 1372f Valerate, 171 Valetiana officinalis (valerian) anxiety treated with, 1373 benzodiazepine withdrawal and, 1373 chemical composition of, 1371 clinical applications of, 1372-1373 depression treated with, 1373 description of, 1371 dosage of, 1373-1374 folk uses of, 1371 insomnia treated with, 1372-1373,1833-1834 pediatric uses of, 1373 pharmacology of, 1371-1372 toxicity of, 1374 valepotriates in, 1372f Vanadium bipolar depression treated with, 1443 description of, 1300-1301 diabetes mellitus and, 686,1301 forms of, 1301 recommended intake of, 1301 sports nutrition uses of, 686-687 suggested optimum nutrient intake for, 1300-1301 Vanadyl sulfate, 686-687 Vanilmandelate,289t, 293 Varicocele, 1868 Varicose veins Aesculus hippocastanum for, 2168-2170 bromelain for, 2169-2170 cellulite and, 1570 Centella asiatica for, 2168 description of, 2167 diagnostic summary for, 2167 dietary considerationsfor, 2170 etiology of, 2167 flavonoids for, 2169 micronized diosmin for, 2169-2170 Ruscus aculeatus for, 2169-2170 treatment of, 2168-2170 Vascular disease microbial enzyme therapy for, 1079-1080, 108Ot procyanolidic oligomers for, 1219 Vaccinium macrocarpon for, 1360 Vat, 320 Vegans, 499 Vegetables, 465-466,1645

Vitamin B1. See Thiamin Vitamin A-cont’d Vegetarian diet, 1490,1690,1982,2056,2098 Vitamin &. See Riboflavin description of, 1280,1381 Venous disorders, 1219 Vitamin B6 diarrhea treated with, 1805,1810 Venous thromboembolism acne vulgaris treated with, 1423 dietary sources of, 1382,1382t ABO blood groups and, 448 alcoholism-related deficiency of, 1454 discovery of, 1381 hormone replacement therapy and, 1880 assessment of, 251-252 dosage of, 1387 Ventricular premature complexes, 1018 asthma treated with, 1491,1495 drug interactions, 1387 Ventricular tachycardia, 1018 bipolar depression treated with, 1444 dry eyes treated with, 1386-1387 Vertebrobasilar stroke, 424 carpal tunnel syndrome treated with, 1559 epithelial tissue development and, 1384 Very-lowdensity lipoproteins,941,1186,1504 cervical dysplasia and, 1575-1576 excretion of, 1384 Vibration, 504t coronary heart disease and, 1289 fibrocystic breast disease treated with, 1667 Viciafabn, 456t deficiency of, 282t in fish oils, 947 Vieu, Jean-Francois, 1152 depression and, 1435 Graves’ disease treated with, 1774 viral infections diabetes mellitus treated with, 1628 growth and development affected by, 1384 description of, 383 dosage of, 707 immune function affected by, 648, Hypericum perforaturn activity and, estrogen effects on, 2055 1382-1383,1385 1042-1043 5-fluorouracil and, for cancer, 564 intestinal mucosa transformation of, 1383 pancreatic enzymes and, 1139 histamine affected by, 1914 leukoplakia treated with, 1853-1854 Viral interference, 389 homocysteine levels affected by, 624,2006 levels of, 348 Virend, 889 in human immunodeficiency virus, 1739b lichen planus treated with, 1857 Vis medicatrix naturae, 79,85,9495,98,119,332 hypertension treated with, 1765 measles prevention and, 1385 Viscerosomatic reflexes, 513 immune function affected by, 649 menorrhagia treated with, 1903 Viscum album (European mistletoe) magnesium and, 2059 metabolism of, 1383-1384 antineoplasticeffects of, 1376-1377 nausea and vomiting of pregnancy treated methotrexate and, for cancer, 565 cancer treatment using, 1377-1378 with, 1942 monitoring of, 1387 cardiovascular effects of, 1376 osteoporosisand, 1987 nomenclature for, 1381 chemical composition of, 1375 oxalates and, 1847 peptic ulcers treated with, 2027 description of, 1375 platelet aggregation inhibited by, 1516 physiologic effects of, 564 dosage of, 1378 premenstrual syndrome treated with, physiologic roles of, 1384-1385 drug interactions, 1378 2058-2059 pneumonia treated with, 2040-2041 folk uses of, 1375-1376 recommended intake of, 1289t pregnancy-relatedintake of, 620,1387, history of, 1375-1376 rheumatoid arthritis treated with, 2101 1389-1390 hypertension treated with, 1767 seborrheicdermatitis treated with, provitamin A carotene conversion to, 773 immune system effects of, 1376-1378 2113-2114 psoriasis treated with, 2084 pharmacology of, 1376 seizures caused by, 1653-1654 rapid dark adaptation test for, 283-284,1383 toxicity of, 1378 side effects of, 139Ot recommended dietary allowance of, Viscum album coloratum (Korean mistletoe), suggested optimum nutrient intake for, 1381-1382,1382t 1378 1288-1289 reproductive functions and, 1384-1385 Visual function, 1219 toxic chemical metabolism affected by, 349 respiratory syncytial virus infections Vitalism, 14,80-82,389-390 toxicity of, 1390t, 1392 treated with, 1385-1386 Vitamin(s) Vitamin BIZ retinol activity equivalents, 1280 fat-soluble. See also specific vitamin arteriosclerosisand, 1286 side effects of, 13% assessment of, 253 asthma treated with, 1492,1495 sinusitis treated with, 1546 side effects of, 13% cancer and, 1286 skin disorders treated with, 1386 suggested optimum nutrient intake for, depression treated with, 1442 sources of, 1382,1382t 1280-1284 description of, 1285 storage of, 1383 toxicity of, 139Ot forms of, 612,1465 suggested optimum nutrient intake for, water-soluble. See also specipc vitamin homocysteine levels affected by, 624,1286 1280-1281 assessment of, 251-253 in human immunodeficiency virus, 1739b teratogenicity of, 1390 side effects of, 139Ot macrocytic anemia treated with, 1742 tissue distribution of, 1383,1384t suggested optimum nutrient intake for, melatonin activity and, 1062 toxicity Of, 1280-1281,1386-1387,1389-1391, 1284-1290 neural tube defects and, 620 1390t toxicity of, 139Ot ”empathy treated with, 1742 trichomoniasis treated with, 2129 Vitamin A. See also Beta-carotene; Carotenoids osteoporosis and, 1987 vaginitis and, 2160 absorption of, 72773,1383 for pernicious anemia patients, 1286 vision affected by, 1384 acne vulgaris treated with, 1422,1424 recommended intake of, 1286t vitamin D interactions with, 1283,1387 acquired immunodeficiency syndrome R-proteins and, 612 Vitamin A deficiency treated with, 1386 serum levels of, 253 alcoholism and, 1452 alcoholism treated with, 1455 side effects of, 1390t causes of, 1382 as antioxidant, 1092-1093,1101-1102 suggested optimum nutrient intake for, follicular hyperkeratosis caused by, 1383 assessment of, 253 1285-1286 in human immunodefiaencyvirus, 1739b atopic dermatitis treated with, 1530 toxicity of, 139Ot immune system effects, 1382-1383 carotenoids, 771772,772t urticaria treated with, 2143 periodontal disease and, 2034 cervical dysplasia and, 1574 rapid dark adaptation test for, 283-284,1383 Vitamin BIZdeficiency cisplatin and, for cancer, 564 Alzheimer’s disease and, 1464-1465 toxic chemical metabolism affected by, 348 clinical applications of, 1385-1387 in Alzheimer’s disease, 621 xerophthalmia, 1383,1383t Crohn’s disease treated with, 1821

Index Vitamin B12deficiency-cont‘d depression caused by, 621,1433-1434 description of, 1285-1286 infectious diarrhea and, 1805,1810 multiple sclerosis and, 622,1933 oral manifestations of, 282t small intestinal bacterial overgrowth and, 155 Vitamin C. See also Ascorbic acid acne vulgaris treated with, 1424 age-related declines in, 1285 alcoholism treated with, 1455 aldose reductase inhibition by, 1627 Alzheimer’s disease treated with, 1469 angina pectoris treated with, 1479 as antioxidant, 1091-1092 aphthous stomatitis, 1483 assessment of, 251,252 asthma treated with, 1491-1492,1495 atherosclerosis prevention and, 1515 bipolar depression treated with, 1444 buffered contraindications, 500 natural killer cell activity affected by, 236 cancer treated with, 562 cardiovascular disease and, 1285,1515 cataracts and, 1285,2118 cervical dysplasia and, 1574,1576 cholesterol levels and, 1515 chronic fatigue syndrome treated with, 1589 cisplatin and, for cancer, 564 collagen production and, 1626-1627 Crataegus oxyacantha and, 881 deficiency of in alcoholism, 1453 description of, 282t smoking and, 1431 depression treated with, 1442 description of, 1284-1285 diabetes mellitus treated with, 1626-1627 dosage of, 1391 elderly use of, 1285 endometriosis treated with, 1645 gout and, 1707 hepatitis treated with, 1717 herpes simplex virus treated with, 1724 histamine and, 1491-1492 hypertension treated with, 1764-1765 hyperthyroidism treated with, 174-1775 immune function affected by, 649,707 insulin effects on, 1626 iron absorption affected by, 1285 male infertility treated with, 1870-1871 menopause treated with, 1892 menorrhagia treated with, 1903,1906 multiple sclerosis treated with, 1932 nausea and vomiting of pregnancy treated with, 1942 osteoarthritistreated with, 1968-1969,1972 pelvic inflammatory disease treated with, 2020,2022 periodontal disease treated with, 2033-2034, 2036 physical performance and, 685 pneumonia treated with, 2040,2041

Vitamin C-cont‘d radioprotection benefits of, 567 ”rebound SCUTV~”and, 1391-1392 recommended intake of, 1286t rheumatoid arthritis treated with, 2101 selenium and, 1299 sinusitis treated with, 1546 smoking effects on, 1870 streptococcal pharyngitis and, 2124 suggested optimum nutrient intake for, 1284-1285 Taxol and, for cancer, 565 toxic chemical metabolism affected by, 349 toxicity of, 1391 trichomoniasis treated with, 2129 urinary tract infections treated with, 1603 vaginitis and, 2160 Vitamin D assessment of, 253 bone mineral density affected by, 1986 boron effects on, 787 calcium and, 1282 cod liver oil for, 1611-1612 colorectal tumor prevention using, 1282 deficiency of description of, 282t, 1282 inflammatory bowel disease and, 1821 type I diabetes mellitus and, 1611-1612 definition of, 1282 dosage of, 1391 epilepsy treated with, 1655 in fish oils, 947 forms of, 1986,1986t multiple sclerosis relapses prevented using, 1282 osteoarthritistreated with, 1969 osteoporosis prevention and, 1282,1391 during pregnancy, 1612 psoriasis and, 2082-2083 recommended intake of, 1283t side effects of, 139Ot suggested optimum nutrient intake for, 1282-1283 sunlight exposure and, 1282-1283 toxicity of, l283,139Ot, 1391 vitamin A interactionswith, 1283,1387 Vitamin E. See also Tocopherols alcoholism treated with, 1456 Alzheimer’s disease and, 1463,1469 angina pectoris treated with, 1479 as antioxidant, 1090-1091,1099 assessment of, 253 asthma treated with, 1492,1495 atherosclerosis prevention using, 1514-1515 atopic dermatitis treated with, 1529-1530 bipolar depression treated with, 1444 cancer and, 1283 cataract prevention and, 1283,2119 cervical dysplasia treated with, 1576 chronic fatigue syndrome treated with, 1589 coenzyme Qloand, 1513-1515 contraindications, 1284 coronary artery disease and, 361 cyclophosphamide and, 564

Vitamin E-cont’d deficiency of description of, 282t, 649 fish oils and, 959 inflammatory bowel disease and, 1821 seizures and, 1655 definition of, 1283 depression treated with, 1442 description of, 348 diabetes mellitus treated with, 1627 dosage of, 1391 endometriosistreated with, 1645 fibrocystic breast disease treated with, 1667 5-fluomuracil and, for cancer, 564 health benefits of, 1283 heart disease prevention and, 1514 in human immunodeficiency virus, 1739b hyperthyroidism treated with, 1775 immune function affected by, 649, 1283,2160 leukoplakia treated with, 1854 menopause treated with, 1892 menorrhagia treated with, 1903-1904,1906 multiple sclerosis treated with, 1932,1935 osteoarthritistreated with, 1968,1972 oxidative damage prevented by, 1283 Parkinson’s disease and, 2005 pelvic inflammatory disease treated with, 2022 peptic ulcers treated with, 2027 periodontal disease treated with, 2034,2036 postoperative indications for, 556 premenstrual syndrome treated with, 2060 psoriasis treated with, 2084 radioprotectionbenefits of, 567 recommended intake of, 1284t retinol regulation by, 1423 rheumatoid arthritis treated with, 2100 selenium and, 1513,1515,2119 side effects of, 139Ot suggested optimum nutrient intake for, 1283-1284,1284t supplementation of, 649 tocopherols, 1283-1284 tocotrienols, 1283 toxicity of, 1284,139Ot trichomoniasis treated with, 2129 vaginitis and, 2160 Vitamin K assessment of, 253 inflammatory bowel disease and, 1821 kidney stones and, 1848 menorrhagia and, 1904 nausea and vomiting of pregnancy treated with, 1942 osteoporosis and, 1983 recommended intake of, 1284t side effects of, 139Ot suggested optimum nutrient intake for, 1284,1284t Tabebuia avellanedae and, 1325 toxicity of, 1390t, 1391 Vitamin K,,1391 Vitex agnus castus (chaste tree) chemical composition of, 1395,1396f clinical applications of, 1396-1398

Vitex agnus castus-cont'd corpus luteum insufficiency and, 1396-1397, 1397t cyclic mastalgia treated with, 1398 description of, 1395 dosage of, 1398 drug interactions, 1399 folk uses of, 13951396 history Of, 1395-1396 hyperprolactinemia and, 1398 infertility treated with, 1398 menstrual disorders treated with, 1396,1904 pharmacology of, 1396 premenstrual syndrome treated with, 1397t, 1397-1398,1646,2062-2063 prolactin secretion modulated by, 1396 secondary amenorrhea treated with, 1398 side effects of, 1399t toxicity of, 1398-1399,1399t Vitexin-P'-rhamnoside, 882f Vithoulkas, George, 391 Volatile oils Candida albicans treated with, 579-580 enteric-coated, 579-580 garlic, 729 Vomiting. See Nausea and vomiting of PregnancY von Wdebrand factor, 446 Vulvar leukoplakia, 1854

W Waist-to-hip ratio, 1950 Wardwell, Walter, 71,73-74 Warfarin, 866 Warm-up phase, of cardiorespiratory exercise, 359-360 Water. See also Dehydration; Hydration; Hydrotherapy aging-related changes, 1404-1405 allergies and, 1407 asthma and, 1407 in beverages, 1402-1403 body composition, 1401-1402 chronic fatigue syndrome and, 1408 clinical applications of, 1404-1406 cold therapy, 404-405 conditions improved with, 1406-1408 coronary heart disease and, 1406 dehydration, 1402 description of, 1401 dietary intake of, 471 DNA metabolism and, 1404 dyspepsia, 1407 elderly requirements, 1404-1405 exercise-related intake of, 693 hot therapy, 405 hydrolysis and, 1404 hypertension and, 1407 metabolism of, 1403-1404 migraine headaches and, 1407-1408 myocardial infarction and, 1406 peptic ulcers and, 1407 properties of, 402-403 protein metabolism and, 1404 pure, 1402-1403 RNA metabolism and, 1404

Water-cont'd salt intake and, 186 special-needs populations, 1403 temperature of, 1403 thirst, 1402 toxic compounds in, 171 winter requirements, 1405 Water concentration gradient, 1402 Water fast diet, 498 Watersoluble vitamins. See also spec@ vitamin assessment of, 251-253 side effects of, 1390t suggested optimum nutrient intake for, 1284-1290 toxicity of, 1390t Weight loss behavioral therapies for, 1954 cancer-related, 957-958 dietary strategies for, 1954-1955 Ephedra spp. for, 927 ephedrine for, 927 fish oils for, 957-958 5-hydroxytryptophan for, 1027t-l028t, 1027-1029 natural methods of chromium, 1957-1959 fiber supplements, 1951957,1957t hydroxycitrate, 1958-1959 5-hydroxytryptophan, 19551956,1959 meal replacement formulas, 1956 medium-chain triglycerides, 1958 Opuntia sp. for, 1115-1116 pyruvate for, 692 Taraxacum oficinale for, 1337 Weight training by children, 367 coronary artery disease and, 362 glutamine and, 998-999 Weltmer, Professor, 56-57 Wemicke encephalopathy, 542 Westergren method, 179,179t Western medicine Eastern medicine vs., 5,6t historical origins of, 4-5 overview of, 5-6 philosophy of, 5 Wet sheet pack, 414-415 Whey protein, 681-682 White coat hypertension, 1758 White dermatographism, 1526 Whole-body hyperthermia, 479 Whorton, James, 67-68,74-76 Wickham striae, 1855 Wilson's syndrome, 1797 Wmd chill factor, 369 Winter hydration, 1405 Wmtrobe method, 179,179t Witch hazel. See Hamamelis virginiana Witch hunts, 129-130 Women. See also Postmenopausal women androgenic hair loss pattern in, 1711-1712 in early colonial America, 130-131 hair loss in, 1711-1713 as healers, 128 in history of medicine, 127-138 in industrial revolution, 132

Women-cont 'd in medical schools, 136,138 persecution of, 129 self-help groups for, 139 as sexual objects, 139 witch hunts against, 129-130 Wormwood. See Artemisia absinthium Wound healing Aloe Vera for, 741,1635 Centellu asiaticu for, 830,832 diabetes mellitus-related alterations in, 1622,1635,1638 Echinacea spp. for, 914 Ginkgo biloba for, 1638 ornithine alpha-ketoglutarate effects on, 685 Wu Cha Seng, 842t

X Xanthine oxidase, 1707 Xanthophylls, 771,1092-1093 Xanthoxylum arnerkanurn (prickly ash), 1646 Xanthurenate, 289t, 292 Xenobiotics. See also Metal toxicity; Toxic metals; Toxins depuration of, 350 description of, 340 excretion of, 603-604 fasting for release of, 603-604 Xerophthalmia, 1383,1383t Xylitol, 1995-1996 Xyloidone, 1323

Y Yang, 8,312 Yarrow. See Achilleu millefolium Yeast, 170 Yeast syndrome. See Chronic candidiasis Yersinia enterocolitica, 1803 Yin, 8,312 Yin Chiao Chieh Tu Pien, 840,841t Yogurt, 1199,1209 Yucca, 1971 Yunnan Baiyao, 840

Z Zang Fu, 312 Zeaxanthin, 773f, 1092-1093,1860 zinc acne vulgaris treated with, 1422-1424 alcoholism treated with, 1456 antioxidant functions of, 1303 aphthous stomatitis treated with, 1482 atopic dermatitis treated with, 1528,1530 benign prostatic hyperplasia treated with, 1551 body status assessments of, 276t, 278-279 cervical dysplasia treated with, 1575 depression treated with, 1435 diabetes mellitus treated with, 1628 dietary intake of, 1302 epilepsy and, 1655 erythema multiforme treated with, 1664 f h c t i o n ~Of, 1301-1302 hair analysis for, 211 herpes simplex virus treated with, 1724

Index Zinc-cont'd homeostatic regulation of, 1303 in human immunodeficiency virus, 17391, hyperthyroidism treated with, 1775 infant requirements, 1302 periodontal disease treated with, 2034, 2036 premenstrual syndrome treated with, 2060 pubertal development and, 1302 recommended intake of, 1303t rheumatoid arthritis treated with, 2100 sources of, 1806 stress effects on, 1303 suggested optimum nutrient intake for, 1301-1303 testosterone levels affected by, 687 thymus functioning affected by, 651 toxic chemical metabolism affected by, 349 toxicity of, 687 trichomoniasis treated with, 2129-2130 urinary tract infections treated with, 1603 vaginitis and, 2160 Zinc deficiency alcoholism and, 1452 Alzheimer's disease and, 1465-1466 attention deficit hyperactivity disorder and, 1536 Crohn's disease and, 1820 description of, 282t diarrhea as cause of, 1806,1810

Zinc deficiency-cont'd in elderly, 1794,1861 immune function affected by, 650,1302 insulin-like growth factor production secondary to, 687 male infertility and, 1871-1872 signs of, 1302 thyroid hormone metabolism affected by, 687 vitamin A metabolism affected by, 1384,1387 Zinc metdoenzymes, 1302t Zinc protoporphyrin, 266 Zingerone, 1411,1412f Zingiber oficinale (ginger) analgesic effects of, 1413 antibiotic activity of, 1414 antioxidant effects of, 1412 antiulcer effects of, 1413 cardiotonic properties of, 1413 chemical composition of, 1411-1412 cholesterol levels affected by, 1413 clinical applications of, 14'341416 description of, 323,1411 dosage of, 1416 fibrinolysis and, 1413 folk uses of, 1412 gastrointestinal smooth muscle affected by, 1413 gingerol, 1411,1412f

Zingiber oficinale--cont'd hepatic effects of, 1413 history of, 1412 hypotensive properties of, 1413 inflammatory conditions treated with, 1415-1416 leukotriene metabolism and, 1412 menorrhagia treated with, 1904 migraine headaches treated with, 1917, 1919-1920 motion sickness treated with, 14141416 nausea and vomiting of pregnancy treated with, 1415-1416,1942 osteoarthritis treated with, 1415-1416, 1971-1972 peptic ulcers treated with, 2028-2029 pharmacology of, 1412-1414 platelet aggregation affected by, 1413 during PIEPXICY, 1415-1416 prostaglandin metabolism and, 1412 rheumatoid arthritis treated with, 2102-2103 shogaol, 1412f thermogenic properties of, 1413-1414 toxicity of, 1416 zingerone, 1411,1412f Zizyphifiuctus,1493 Zones of irritation, 510,514t Zung's Self-Rating Depression Scale, 1679f, 1680